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Abstract. The aim of the present study was to analyze the changes of plasma and urinary prostaglandin E2 (PGE2) levels in preterm infants with symptomatic patent ductus arteriosus (sPDA) treated with oral ibuprofen and acetaminophen. A total of

87  preterm infants with sPDA admitted to the Neonatal

Ward of the Affiliated Xuzhou Hospital of Medical College of Southeast University from October, 2012 to June, 2015 were selected and randomly divided into the ibuprofen group (n=43, 10  mg/kg ibuprofen administered orally as initial dose, followed by 5 mg/kg during the first 24 and 48 h later) and acetaminophen group (n=44, 15 mg/kg acetaminophen administered orally once every 6 h for three days). The levels of plasma and urinary PGE2 in the two groups were estimated before and after treatment. The treatment of sPDA infants with ibuprofen (ibuprofen group) or acetaminophen (acetaminophen group) caused a significant decrease in the plasma and urinary PGE2 levels in comparison with plasma and urinary PGE2 levels before treatment (P<0.05). Furthermore, plasma and urinary PGE2 levels in the acetaminophen group (45.0±36.9 ng/l) were significantly lower than those in the ibuprofen group (73.5±44.8 ng/l, P=0.002). The arterial duct closure rate was similar between the acetaminophen [31 (70.5%)] and ibuprofen groups [33 (76.7%), P=0.506]. The incidence of oliguria was less among sPDA infants of the acetaminophen group [1 (2.3%)] than observed among the sPDA infants of the ibuprofen group [6 (14.0%)]; however, this difference was not statistically significant (P=0.108). Additionally, the incidences of fecal occult blood positive rate, intraventricular hemorrhage, neonatal necrotizing enterocolitis and bronchopulmonary dysplasia were distributed similarly in the ibuprofen and acetaminophen groups (P>0.05). The levels of platelet, serum creatinine and alanine transaminase showed no significant changes between the ibuprofen and acetaminophen groups (P>0.05). Following treatment with ibuprofen or acetaminophen, the extent of decrease of plasma and urinary PGE2 was significantly higher among sPDA infants with oliguria (135.0±38.0 ng/l) than that observed in sPDA infants without oliguria (52.5±37.0 ng/l) (P=0.01). The study also found a significant correlation between plasma and urinary PGE2 levels (r=0.648, P=0.01) and the coefficient of variation of urinary PGE2 (0.427) was less than that of plasma PGE2 (0.539). The clinical efficacy of oral ibuprofen and acetaminophen in the treatment of preterm infants with sPDA was similar with low adverse events, whereas acetaminophen‑induced PGE2 levels were less than the levels observed in the ibuprofen‑treated group. The incidence of oliguria was also lower in the acetaminophen group compared to the ibuprofen group. In addition, monitoring urinary PGE2 levels was more suitable because of its non-invasiveness in the clinical setting than monitoring of plasma PGE2 in preterm infants with sPDA.

Introduction The arterial catheter is located between the descending part of aortic arch and the pulmonary artery bifurcation, approaching the arteriae pulmonalis sinistra and it is an important channel for fetal circulation. Normally, the function of arterial cath­ eter would close between 10-15 h after birth. The arterial catheter that continues to open after 10-15 h is defined as patent ductus arteriosus (PDA). The arterial ducts of prema­ ture infants due to the maldevelopment of arterial duct wall and the abnormal secretion of prostaglandin, always fail to close in time, thus resulting in left-to-right shunt. Due to their poor left ventricular systolic functions, premature infants are vulnerable to heart failure and pulmonary edema, and even symptomatic PDA (sPDA), which is also known as hemody­ namically significant PDA (hsPDA) (1,2). Oral administration of indomethacin or ibuprofen to premature infants could significantly lower the level of prostaglandin E2 (PGE2), and promote constriction and closure of the arterial duct (3-5). Hammerman et al (6) reported that, acetaminophen caused Oral paracetamol vs. oral ibuprofen in the treatment of symptomatic patent ductus arteriosus in premature infants: A randomized controlled trial

BO YANG, XIANGYU GAO, YI REN, YUN WANG and QINGLIN ZHANG

Department of Pediatrics, The Affiliated Xuzhou Hospital of Medical College of Southeast University, Xuzhou, Jiangsu 221009, P.R. China Received February 3, 2016; Accepted August 23, 2016 DOI: 10.3892/etm.2016.3676 Correspondence to: Dr Xiangyu Gao, Department of Pediatrics, The Affiliated Xuzhou Hospital of Medical College of Southeast University, 199 South Jiefang Road, Xuzhou, Jiangsu  221009, P.R. China E-mail: g.xy@163.com Key words: ibuprofen, acetaminophen, patent ductus arteriosus, prostaglandin E2, infant, preterm

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arterial duct closure in 5 premature hsPDA infants that were not successfully treated with ibuprofen. In this context, to understand the effect of acetaminophen treatment on prema­ ture sPDA infants, we designed prospective randomized controlled trials (RCTs), aiming to utilize and develop plasma and urinary PGE2 levels as indicators of progress of arterial duct closure in a non-invasive manner.

Patients and methods Patients. The patients of this RCT were premature infants who were admitted to the Neonatal Ward of Pediatrics Division of the Affiliated Xuzhou Hospital of Medical College of Southeast University between October, 2012 and June, 2015. Sample size estimation. The sample size for this RCT was calculated based on the results of a previous study (5) and literature (4). Efficacy (1-false negative rate β) was set at 80% and the false‑negative rate at α=0.05. According to our estima­ tion, the sample size for each group was 39 patients. Inclusion and exclusion criteria. The patients satisfying the following criteria were included in the presen study:

i) gestational age, <37 weeks; ii) admitted to hospital within

24 h after birth; iii) sPDA diagnosis was made between 15 h

to 10 days after birth and confirmed through echocardiogram to be sPDA if the patient showed at least three of the six clinical manifestations. These were: i) systolic or consecu­ tive murmur in left border of sternum; ii) strengthened beat of anterior thorax; iii) locomotive pulse; iv) tachycardia in quiet state; v) unexplainable deterioration of respiratory condition; and vi) increased pulmonary vasculature shadows and enlarged heart or signs of pulmonary edema under chest X-ray examination. Diagnostic criteria of echocardiography was: i) left atrial: aortic root diameter ratio, (LA:Ao) >1.4; ii) pulmonary artery diastolic back flow (reflux); and iii) PDA catheter diameter >1.4 mm (1,7).

The patients were excluded from the study if: i) patients presented with any of the following medication contrain­ dications such as thrombocytopenia (blood platelet count <50x109/l), hemorrhagic disease, oliguria (urine volume per

8 h <8 ml/kg), necrotizing colitis, intestinal perforation, high

serum creatinine (>159.1 µmol/l), and alanine aminotrans­ ferase (>40 U/l) levels (1,2); ii) patients with congenital heart diseases such as ventricular septal defect, complex heart disease; and iii) patients with incomplete treatment or willing to depart from the study due to personal reasons. A total of 95 patients met the inclusion criteria, of whom

8 patients were excluded for various reasons (reduced platelet

count in 2 patients, 1 patient had sepsis with disseminated intravascular coagulation, 1 patient had oliguria, 1 patient had necrotizing colitis, 1 patient had complex heart disease and lack of required data for this study in 2 patients). Subsequently, 87 patients were included in the study.

Collection of data and analyses of parameters prior to treatment. Once the premature infants were admitted to hospital, information was collected and recorded including:

i) gender, with or without use of a full course of hormone of

the pregnant mother 7 days to 24 h before delivery; ii) presence or absence of infection in the pregnant mother; iii) premature

rupture of membrane >18  h or less; iv)  gestational age;

v) delivery mode; vi) birth weight; vii) 5-min Apgar scoring

<8 or >8; viii) with or without respiratory distress syndrome; and ix) number of days of positive pressure ventilation. Tests such as platelet count, serum creatinine glutamic‑pyr­ uvic transaminase, and fecal occult blood were also carried out in patients.

Treatment of patients and analysis of parameters. The patients were randomly divided into the ibuprofen group (n=43) and acetaminophen group (n=44) based on a computer‑generated random number table. The patients in the ibuprofen group were treated by oral administration of 10 mg/kg ibuprofen suspension initially, followed by 5 mg/kg during first 24 and

48 h later. Patients in the acetaminophen group were treated

with oral administration of 15 mg/kg acetaminophen orally once in every 6 h for a total of 3 days. On the completion of

3 days, ultrasonic cardiogram, platelet count, serum creati­

nine, glutamic pyruvic transaminase, and fecal occult blood were re-examined. The incidence of intraventricular hemor­ rhage (IVH), neonatal necrotizing enterocolitis (NEC) and bronchopulmonary dysplasia (BPD) were also recorded. Detection of PGE2 in blood and urine. The PGE2 level was estimated using a commercially availed ELISA kit following the manufacturer's instructions (VICMED Bioengineering Co., Ltd., China).

The present study conformed to ethical requirements of the Affiliated Xuzhou Hospital of Medical College of Southeast University. The parents of the patients were aware of the treat­ ment and signed informed consent.

Statistical analysis. The χ2 test was applied to compare the collected information between the two groups. The t-test was applied to compare data having normal distribution, whereas, the Mann‑Whitney U test method was utilized to compare data having skewed distribution between the groups. The paired‑samples Student's t-test was used for intra-group comparison of the data having normal distribution before and after treatment. The Pearson correlation coefficient test was applied in the correlation analysis of the bivariate normal distribution data. Statistical analyses were carried out using IBM SPSS 20.0 software (Armonk, NY, USA). P<0.05 was considered of statistical significance.

Results Clinical characteristics of sPDA infants of the ibuprofen and acetaminophen groups. The various clinical characteristics including weight at birth, arterial catheter diameter, and gestational week between the two groups of sPDA infants were not significantly different (P>0.05; Table I). Effect of treatment in sPDA infants of the ibuprofen and acetaminophen groups. PDA closure rate, fecal occult blood positive rate, IVH, NEC, and BPD incidence rates were similar in the patients of the two groups (P>0.05). Oliguria was less frequent in the acetaminophen group than in the ibuprofen group, but this difference was insignificant (P=0.108; Table II).

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PGE2 level in sPDA infants of the ibuprofen and acetamino­ phen groups. The treatment of sPDA infants with ibuprofen or acetaminophen resulted in a significant decrease of plasma and urinary PGE2 levels compared with their levels before treatment (P<0.05). Furthermore, plasma and urinary PGE2 levels were significantly lower among ibuprofen group patients than the acetaminophen group (P<0.05; Table III). However, the descent range of the plasma [avg.12.6 (5.7, 19.5) ng/l] PGE2 level in the acetaminophen group [avg.12.6 (5.7, 19.5) ng/l] was significantly lower than that of the ibuprofen group [avg.18.5 (10.1, 33.8) ng/l], and the difference was statistically significant (Z=-2.158, P=0.031), and the descent range of urinary PGE2 of the acetaminophen group (45.0±36.9 ng/l) was lower than that of the ibuprofen group (73.5±44.8 ng/l) and the difference was statistically significant (t=3.244, P=0.002). The comparison on platelets, serum creatinine and glutamic-pyruvic transaminase between the two groups of patients before treatment (P>0.05) and after treatment (P>0.05) revealed no significant difference (Table III). Descent range of PGE2 in PDA closed and PDA unclosed, oliguria and non-oliguria patients after treatment. The descent range of plasma and urinary PGE2 between PDA closed and PDA unclosed patients was not significantly different (P>0.05; Table IV). However, the descent range of plasma and urinary PGE2 in oliguria patients was higher than non-oliguria patients (P<0.05; Table IV).

Plasma and urinary PGE2 levels are highly correlated. The plasma and urinary PGE2 levels were highly correlated (Pearson correlation coefficient r=0.648, P=0.01) as shown in Fig.  1 and the variable coefficient of urinary PGE2 (67.1/157.1=0.427) level was lower than the plasma PGE2 (33.9/62.9=0.539) level.

Table I. Clinical characteristics of sPDA infants of the ibuprofen and acetaminophen groups.

Ibuprofen group Acetaminophen group Characteristics (n=43) (n=44) χ2/t/Z P-value Male, n (%)

25 (58.1)

27 (61.4)

χ2=0.094

0.759

Hormone in full pregnancy course, n (%)

28 (65.1)

25 (56.8)

χ2=0.629

0.428

Maternal infection, n (%)

4 (9.3)

6 (13.6)

χ2=0.089

0.766

Premature rupture of membrane >18 h, n (%)

8 (18.6)

10 (22.7)

χ2=0.225

0.635

Gestational age (weeks) 33.4±2.1 33.6±2.1 t=-0.491

0.625

Cesarean delivery, n (%)

24 (55.8)

28 (63.6)

χ2=0.553

0.457

Birth weight (g) 2,091±657 2,219±606 t=-0.946

0.347

SGA, n (%)

9 (20.9)

6 (13.6)

χ2=0.811

0.368

5 min Apgar scoring <8, n (%)

15 (34.9)

18 (40.9)

χ2=0.335

0.563

RDS, n (%)

14 (32.6)

12 (27.3)

χ2=0.290

0.590

Positive pressure ventilation (days)a

3.7 (1.9, 6.1)

4.5 (3.0, 6.7)

Z=1.277

0.201

Age at ultrasonic cardiogram examination (days) 5.8±2.0 6.4±1.8 t=-1.527

0.131

Urine amount (ml/kg•h) 2.52±0.54 2.48±0.76 t=0.222

0.825

Pulse pressure difference (mmHg) 24.2±3.9 23.3±4.7 t=0.880

0.381

LA:Ao 1.55±0.31 1.53±0.31 t=0.323

0.748

Arterial catheter diameter (mm) 1.84±0.43 2.09±0.46 t=-1.491

0.140

aPositive pressure ventilation (d): range, 0-35; asymmetry coefficient was 3.181, kurtosis coefficient was 13.060, P<0.01, showed skewed distribution, presented by median (25th and 75th percentile). sPDA, symptomatic patent ductus arteriosus. Table II. Effect of ibuprofen and acetaminophen treatment in sPDA infants.

Ibuprofen group Acetaminophen group

(n=43), n (%) (n=44), n (%) χ2 P-value PDA occlusion

33 (76.7)

31 (70.5)

0.442

0.506

Oliguria

6 (14.0)

1 (2.3)

2.587

0.108

Positive stool OB

4 (9.3)

2 (4.5)

0.205

0.651

IVH

4 (9.3)

5 (11.4)

0.000

1.000

NEC

5 (11.6)

4 (9.1)

0.001

0.971

BPD

6 (14.0)

5 (11.4)

0.132

0.716

PDA, patent ductus arteriosus; sPDA, symptomatic patent ductus arteriosus; IVH, intraventricular hemorrhage; NEC, neonatal necrotizing entero­ colitis; BPD, bronchopulmonary dysplasia.

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Incidence of adverse reactions among sPDA infants of acet­ aminophen and ibuprofen groups. The various incidences of adverse reactions including PDA occlusion, oliguria, and fecal occult blood observed are shown in Table II. None of the adverse reactions showed a significant association with administration of either acetaminophen or ibuprofen (P>0.05). Additionally, no significant changes were observed on the transcutaneous oxygen saturation, pulse rate, blood pressure, peripheral blood glucose, transcutaneous bilirubin, tempera­ ture, feeding, and bleeding tendency during the treatment period. The incidence of NEC that occurred several days later could not be confirmed to be associated with the drugs. Discussion General. Inside the uterus, low arterial oxygen partial pres­ sure, prostaglandin and nitric oxide are the major factors that maintain the opening of the arterial catheter, of which PGE2 plays the key role (1,2). Cyclooxygenase (COX) is a key rate‑limiting enzyme synthesized by prostaglandin, which has the active sites of COX and peroxidase. COX can catalyze arachidonic acid to transform into prostaglandin via its COX activity, and then catalyze the prostaglandin to transform into active PGE series via the activity of peroxidase. COX has two types of isozymes, COX-1 and COX-2. COX-3 has been quite widely used in recent years after first discovered by Chandrasekharan et al (8) in their study on the mechanism of action of acetaminophen. COX-3 was quite sensitive to the inhibiting effect of acetaminophen, thus being deemed as the effector target of acetaminophen. Ibuprofen, as the non-selec­ tive inhibitor of COX-1 and COX-2 could play the inhibiting role by blocking or modifying the COX active sites. However, the exact mechanism for the effect of acetaminophen on COX activity remains controversial. At present, two theories are quite prevalent: i) acetaminophen could selectively inhibit COX-3; and ii) acetaminophen has no affiliation to the active sites of COX, but it may restore the active oxydic COX into non-active COX and then obstruct its biological activity (9). Influence of ibuprofen and acetaminophen treatment on PGE2 of premature infants with sPDA. In the current study, ibuprofen and acetaminophen treatment reduced the level of plasma and urinary PGE2. From this it could be inferred that Figure 1. Correlation of plasma and urinary PGE2 levels. PGE2, prosta­ glandin E2.

Table III. PGE2, platelet, creatinine, and glutamic-pyruvic transaminase before and after treatment (mean ± standard deviation).

Ibuprofen group (n=43) Acetaminophen group (n=44)

---------------------------------------------------------------------------------

------------------------------------------------------------------------------------

Before After

Before After Indicators treatment treatment t P-value treatment treatment t P-value P-valuea Plasma PGE2 (ng/l) 70.0±35.7 47.3±24.7

7.091

0.000

74.2±35.5 59.9±32.9

7.298

0.000

0.046

Urine PGE2 (ng/l) 189.0±62.4 115.4±46.3 10.765

0.000

184.4±73.8 139.3±54.0

8.100

0.000

0.030

Platelet (x109/l) 192.4±94.6 224.4±88.0

1.807

0.078

183.8±107.7 195.0±84.3 -0.506

0.615

0.115

Serum creatinine (µmol/l) 69.0±33.6 74.1±35.7

0.747

0.459

67.0±33.2 60.9±30.9

0.874

0.387

0.068

Glutamic-pyruvic 15.4±7.4 16.8±4.9

1.309

0.198

15.9±11.2 17.4±6.6

-0.815

0.419

0.635

transaminase (U/l) aComparisons between the two groups after treatment. PGE2, prostaglandin E2. Table IV. Descent range of PGE2 in PDA closed and PDA unclosed, oliguria and non-oliguria patients. Descent range of PGE2 PDA closed PDA unclosed

Oliguria Nonoliguric after treatment (ng/l) group (n=64) group (n=23) Z/t P-value group (n=7) group (n=80) Z/t P-value Plasmaa

13.7 (7.3, 25.6) 15.7 (9.1, 25.3) Z=0.067

0.946

35.0 (26.3, 49.8) 13.3 (6.7, 20.8) Z=-3.326

0.001

Urineb 61.1±44.7 53.7±39.2 t=0.708

0.481

135.0±38.0 52.5±37.0 t= 5.649

0.000

aMedian (25th and 75th percentile). bMean ± standard deviation. PGE2, prostaglandin E2; PDA, patent ductus arteriosus.

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the two drugs may reduce the PGE2 levels and promote the closure of sPDA. The present study has also shown that, the descent range of plasma and urinary PGE2 levels of the acet­ aminophen group was lower than those of the ibuprofen group. This may be because COX3 was selectively inhibited by acetaminophen activity of COX and peroxidase, although the activity was only 20% of COX-1 (9). Shetty et al (10) showed that, ibuprofen reduced the level of PGE2 in gingival crevicular fluid, but acetaminophen had no significant effect on the level of PGE2. No reports are available at present on the influence of acetaminophen on PGE2 level in premature infants with sPDA. The action mechanisms of ibuprofen and acetaminophen on COX activity are different, the descended ranges of plasma and urinary PGE2 levels due to the drugs were different in this study, but their curative effects on promoting sPDA closure were similar and this curative effect was not related to the descent range of PGE2 level. A possible explanation for this may be that although the plasma prostaglandin level is an important factor in inhibiting the contraction of arterial duct, the closure of arterial catheter is affected by multiple factors including the maturity of arterial catheter, family genetic background and other unknown factors promoting and inhib­ iting the arterial duct contraction (1).

Association of ibuprofen and acetaminophen with adverse reactions and the descent range of PGE2 levels. Antonucci et al (4) in an earlier study reported that, ibuprofen treatment reduced the urinary PGE2 level and caused acute renal failure in 3 of 20 hsPDA patients. Antonucci et al (4) suggested that, ibuprofen inhibited COX thereby lowering the PGE2 level and this resulted in reduced peripheral blood vessel flow, increased oliguria, acute renal failure and NEC. In our study, the incidence of oliguria in acetaminophen group was significantly lower than that of the ibuprofen group. This may be because of the descending ranges of plasma and urinary PGE2 levels of acetaminophen group being lower than the ibuprofen group. Additionally, the descent ranges of plasma and urinary PGE2 levels of the oliguria group were more than those of the non-oliguria group. Our results substantiated the study of Antonucci et al (4). Although the descent range of plasma and urinary PGE2 between oliguria and non-oliguria patients showed a significant difference in the absolute values, the incidence of oliguria being very low among patients of the ibuprofen and acetaminophen groups may be due to the low sample size (sample size of this study was estimated on the basis of major research indicator ‘changes of plasma and urine PGE2 levels before and after treatment’).

Walker et al (11) showed that, indometacin induces NEC and PEG2 and its receptor plays a key role in regulating the intestinal blood flow. The more the reduction in the level of PEG2, the less was the intestinal blood flow. Dang et al (12) reported that, the incidence of gastrointestinal bleeding in patients administered with acetaminophen was significantly lower than the patients administered with ibuprofen. In our study, the incidence of positive fecal occult blood in the acet­ aminophen group was relatively lower than those observed in the ibuprofen group. We suggest that, acetaminophen selectively inhibited COX-3 and its inhibiting effect on COX-1 (associated with the synthesis of the protective prostaglandin in stomach and duodenum) was lower than that exerted by ibuprofen. Moreover, no COX-3 has been discovered in the small intestinal epithelial cells of human beings (13). Correlation of plasma and urinary PGE2 levels. The findings of the present study showed that the plasma and urinary PGE2 levels were highly correlated, and the variable coefficient of urinary PGE2 level was lower than that of plasma PGE2. Thus, for monitoring PGE2 levels in sPDA infants, urine samples are optimal in the clinical setting, because it can be collected in a non‑invasive manner.

Efficacy and safety of ibuprofen and acetaminophen in clinical setting. In 2011, Hammerman et al (6) first reported that, oral administration of 15 mg/kg acetaminophen caused closure of the arterial catheter in 5 sPDA infants who were unresponsive to ibuprofen treatment without any significant adverse reac­ tions. Since then, the majority of studies (14-19) have used oral or intravenous administration of acetaminophen as a replace­ ment therapy for the closure of arterial catheter in sPDA patients who were unresponsive by ibuprofen/indometacin treatments. Additionally, a low concentration of peroxide activated the activity of peroxidase, but a higher concentration of peroxide was needed to activate COX. Therefore, in the hypoxic environment, such as arterial duct endothelial cells, acetaminophen inhibits COX, rather than ibuprofen, in a better manner (9). This may be one of the reasons for the use of acet­ aminophen as a replacement therapy for patients who failed in the ibuprofen treatment. In the present study, we showed that, the effect of acetaminophen in promoting the closure of sPDA in premature infants was similar to that of ibuprofen, which was consistent with recent studies (14,20). A RCTs study which included 80 premature infants with sPDA (gestational age, ≤30 weeks; birth weight, ≤1,250 g) showed that, the arte­ rial catheter closure rate among ibuprofen‑treated patients was similar to that of acetaminophen‑treated patients (21). Another non-inferiority RCTs study which included 160 premature infants with sPDA (gestational age, ≤34 weeks) showed that, the arterial catheter closure rate in acetaminophen‑treated patients was not inferior to patients treated with ibuprofen (81.2 vs. 78.8%) (12).

Previous findings have shown that the tolerance for acet­ aminophen is good, and only few patients had their liver enzymes elevated (14). In this study, we showed that, oral administration of ibuprofen and acetaminophen exerted no significant influ­ ence on the platelet, serum creatinine, and glutamic-pyruvic transaminase and also there was no occurrence of NEC. This indicates that, oral administration of ibuprofen or acetamino­ phen at the dosage level described in this study is safe during a short-term administration of the drug.

Limitations of this study. The present study did not include a placebo control group and thus, we were not able to estimate the spontaneous arterial catheter closure rate and physiological changes of plasma and urinary PGE2 levels.

In conclusion, the clinical efficacy of oral ibuprofen and acetaminophen in the treatment of preterm infants with sPDA are relatively similar with low adverse events. Since a high correlation exists between plasma and urinary PGE2, the urinary PGE2 level can be used for predicting the occurrence of drug associated adverse reactions including oliguria, renal

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damage and gastrointestinal tract side effects in a non-invasive manner in preterm infants with sPDA.

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Erdeve O and Dilmen U: An alternative drug (paracetamol) in the management of patent ductus arteriosus in ibuprofen-resistant or contraindicated preterm infants. Arch Dis Child Fetal Neonatal Ed 98: F94, 2013.

17. Nadir E, Kassem E, Foldi S, Hochberg A and Feldman M:

Paracetamol treatment of patent ductus arteriosus in preterm infants. J Perinatol 34: 748-749, 2014.

18. Sinha R, Negi V and Dalal SS: An interesting observation of

PDA closure with oral paracetamol in preterm neonates. J Clin Neonatol 2: 30-32, 2013.

19. Ozdemir OM, Doğan M, Küçüktaşçı K, Ergin H and Sahin O:

Paracetamol therapy for patent ductus arteriosus in premature infants: a chance before surgical ligation. Pediatr Cardiol 35:

276-279, 2014.

20. Terrin G, Conte F, Scipione A, Bacchio E, Conti MG, Ferro R,

Ventriglia F and De Curtis M: Efficacy of paracetamol for the treatment of patent ductus arteriosus in preterm neonates. Ital J Pediatr 40: 21, 2014.

21. Oncel MY, Yurttutan S, Erdeve O, Uras N, Altug N, Oguz SS,

Canpolat  FE and Dilmen U: Oral paracetamol versus oral ibuprofen in the management of patent ductus arteriosus in preterm infants: a randomized controlled trial. J Pediatr 164: 510-514.e.1, 2014.

Comparison of Oral Paracetamol versus Ibuprofen in Premature Infants with Patent Ductus Arteriosus: A Randomized Controlled Trial Dan Dang1, Dongxuan Wang2, Chuan Zhang3, Wenli Zhou1, Qi Zhou1, Hui Wu1* 1 Department of Neonatology, The First Hospital of Jilin University, Changchun, China, 2 Department of Ultrasonic Diagnosis, The First Hospital of Jilin University, Changchun, China, 3 Department of Pediatric Surgery, The First Hospital of Jilin University, Changchun, China Abstract Trial Design: Oral ibuprofen has demonstrated good effects on symptomatic patent ductus arteriosus (PDA) but with many contraindications and potential side-effects. In the past two years, oral paracetamol administration to several preterm infants with PDA has been reported. Here, a randomized, non-blinded, parallel-controlled and non-inferiority trial was designed to evaluate the efficacy and safety profiles of oral paracetamol to those of standard ibuprofen for PDA closure in premature infants.

Methods: One hundred and sixty infants (gestational age #34 weeks) with echocardiographically confirmed PDA were randomly assigned to receive either oral paracetamol (n = 80) or ibuprofen (n = 80). After the initial treatment course in both groups, the need for a second course was determined by echocardiographic evaluation. The main outcome was rate of ductal closure, and secondary outcomes were adverse effects and complications. Result: The ductus was closed in 65 (81.2%) infants of the paracetamol group compared with 63 (78.8%) of the ibuprofen group. The 95% confidence interval of the difference between these groups was [20.080,0.128], demonstrating that the effectiveness of paracetamol treatment was not inferior to that of ibuprofen. In fact, the incidence of hyperbilirubinemia or gastrointestinal bleeding in the paracetamol group was significantly lower than that of the ibuprofen group. No significant differences in other clinical side effects or complications were noted. Conclusion: This comparison of drug efficacy and safety profiles in premature infants with PDA revealed that oral paracetamol was comparable to ibuprofen in terms of the rate of ductal closure and even showed a decreased risk of hyperbilirubinemia or gastrointestinal bleeding. Therefore, paracetamol may be accepted as a first-line drug treatment for PDA in preterm infants.

Trial Registration: ChiCTR.org ChiCTR-TRC-12002177 Citation: Dang D, Wang D, Zhang C, Zhou W, Zhou Q, et al. (2013) Comparison of Oral Paracetamol versus Ibuprofen in Premature Infants with Patent Ductus Arteriosus: A Randomized Controlled Trial. PLoS ONE 8(11): e77888. doi:10.1371/journal.pone.0077888 Editor: Imti Choonara, Nottingham University, United Kingdom Received June 16, 2013; Accepted September 11, 2013; Published November 4, 2013 Copyright: 2013 Dang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The trial ‘‘Comparison of Oral Paracetamol versus Ibuprofen in Premature Infants with Patent Ductus Arteriosus: A Randomized Controlled Trial’’ was funded from Jilin Department of Health (2012Z033). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing Interests: The authors have declared that no competing interests exist.

* E-mail: wuhui97@126.com

Introduction Patent ductus arteriosus (PDA) in preterm infants is common, with an incidence rate as high as 30% in very low birth weight infants. [1] Persistent PDA in preterm infants can lead to serious clinical consequences, and it is one of the main factors affecting the survival rate of premature children and sequelae incidence. [2,3] Consequently, clinical intervention to promote ductal closure is necessary.

Currently, the first choice of treatment for PDA is with medication, primarily indomethacin and ibuprofen. The ductal closure rates for these drugs are similar, ranging from approximately 70–85%, [4,5] but they carry many contraindications and potential side effects.[6–11] When drug treatment fails, clinicians may resort to surgical intervention of symptomatic PDA in preterm infants, and the risk of complications from the operation is high. [12,13] Therefore, a safe and effective alternative drug for the treatment of PDA is urgently needed. Recent studies have shown that paracetamol, a common antipyretic and analgesic drug, can be used to treat PDA in preterm infants with good efficacy and seemingly few side effects. [14] However, it has not been evaluated in a prospective randomized controlled trial. To determine whether oral paracetamol may be used as a first-line drug for PDA in preterm infants, we conducted a randomized, non-blinded, parallel-controlled, non-inferiority trial to compare its efficacy and safety levels to those of ibuprofen. The findings are expected to help extend clinical selections for PDA in preterm infants.

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Patients and Methods Patients The trial was entered in the Chinese Clinical Trial Register (http://www.chictr.org/cn/registration number: ChiCTR-TRC- 12002177) and approved by the Hospital Ethics Committee of the First Hospital of Jilin University (No.2012-057). Informed written consent was obtained from parents of the subjects before enrollment. Enrollment criteria were as follows: gestational age #34 weeks; postnatal age #14 days; echocardiographic diagnosis of hemodynamically significant PDA. Exclusion criteria were: congenital heart disease which required PDA to maintain blood flow; life-threatening infection; recent (within the previous 24 h) intraventricular hemorrhage, grade 3–4; urine output ,1 ml per kg per h during the preceding 8 h; serum creatinine .88.4 mmol/ L; platelet count of ,506109/L; hyperbilirubinemia requiring exchange transfusion; active necrotizing enterocolitis (NEC) and/ or intestinal perforation; liver disfunction. Patients meeting any single exclusion criterion were excluded from the study. The definition of hyperbilirubinaemia is according to Maisels et al. Treatment of jaundice in low birthweight infants [15]. Intestinal bleeding is tendency to bleed as revealed by hematuria, blood in the endotracheal or gastric aspirate or stools, or oozing from puncture sites. Retinopathy (RetCam II, digital imaging system, Clarity Medical Systems, Inc. United States) is based on International Committee for the Classification of Retinopathy of Prematurity [16]. The definition of NEC is on the basis of Bell staging criteria of NEC [17]. Bronchopulmonary dysplasia (BPD) is defined by NICHD (the United States National Institute of Child Health and Human Development ) criteria in 2001 [18]. Study Design The protocol for this trial and supporting CONSORT checklist are available as supporting information; see Checklist S1 and Protocol S1. The participants were randomly assigned at a 1:1 ratio between oral paracetamol and ibuprofen groups by using cards in sealed opaque envelopes. And doctors and nurses were not blind. Infants received oral paracetamol (Acetaminophen suspension drops, Shanghai Johnson & Johnson, 15 ml:1.5 g) at the dose of 15 mg/kg every 6 h for 3 days, or oral ibuprofen (Ibuprofen suspension, Shanghai Johnson & Johnson, 100 ml:2 g) at the initial dose of 10 mg/kg followed by 5 mg/kg after 24 and

48 h. Between doses of oral ibuprofen, infants of ibuprofen group

received the same volume of dextrose 5% in water (D5W) as that given for drug administration in the paracetamol group. Whether a subject received a second course of treatment depended on echocardiography evaluation after the first course. If only minor ductal shunting was present after two courses without the need of respiratory support, no further treatment was given. Drug safety factors were assessed daily during the treatment, including 24-h urine output, tendency to bleed, intraventricular hemorrhage (IVH) grade, and serum creatinine and bilirubin levels. An eye examination was conducted 4 weeks after birth. The occurrence of any of the following conditions would prompt the stopping of treatment: renal failure, NEC, IVH grade 3–4, gastrointestinal bleeding.

Main outcome measures were the rates of ductal closure of both drugs after treatment. Every infant was monitored by echocardiography daily during the treatment. Secondary outcomes were the safety of both drugs, including early adverse events (e.g., oliguria, emerging IVH, tendency to bleed, NEC, hyperbilirubinemia, death) and late adverse events, for example BPD, periventricular leukomalacia(PVL), NEC, retinopathy of prematurity (ROP), sepsis, death). The early adverse events were defined as those occurring during and up to 1 week after administration of the drug treatment.

Statistical Analysis A study group of 65 patients was needed to detect a difference of at least 20% in the closure rate between the oral paracetamol and ibuprofen groups, assuming a closure rate of 70% [10] with oral ibuprofen, with a 95% confidence interval (CI) and a power of 80%. In anticipating that a few patients could be excluded due to various causes during the study, 80 patients in total were enrolled in each group. Interim analyses were performed for main and secondary outcomes at 50% recruitment. The study would be terminated if a difference of 20% in the main outcome or a significant increase in the secondary outcome of the composite variable of death was found. Continuous data were given as means

6 SD. Differences between groups were determined by the t test

for parametric continuous data, x2 or Fisher`s exact test for categorical data, and Wilcoxon rank-sum test for nonparametric continuous data.

Non-inferiority analysis is a statistical method that is used to determine whether a new drug is non-inferior to a drug of known efficacy. A new drug is considered at least as effective as the known drug if P,0.05 or CL.-d (CL is the lower limit of the 95% CI of the difference between two groups; d is the non-inferiority margin). SPSS software (version 20.0) was used for all statistical analyses. Results Baseline Characteristics Between May 21, 2012 and March 30, 2013, 1279 preterm infants were treated in our hospital, including 913 infants (71.3%) born at gestational age #34 weeks. A total of 249 infants (81.1%) met the enrollment criteria, of whom 89 were excluded (Fig.1). No Figure 1. Flow diagram of study infants.

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significant differences in baseline clinical characteristics were observed between the two groups (Table 1).

Efficacy of Treatment The ductus was closed in 65 infants (81.2%) of the paracetamol group compared with 63 (78.8%) of the ibuprofen group, and there was no significant difference between the two treatments (P = 0.693). Meanwhile, the 95% CI for the difference between the two groups was [20.080, 0.128]. Thus, the efficacy of paracetamol was non-inferior to the ibuprofen group. After the 1st course of treatment, ductal closure occurred in 45 infants (56.3%) given paracetamol and in 38 infants (47.5%) administered ibuprofen (P = 0.268). Reopening of the ductus after closure occurred in five infants of the paracetamol group and in six of the ibuprofen group. After continuing to receive the assigned drug treatment, the ductus closed again in four patients of each group (Table 2). Safety of Treatment Eight patients in the paracetamol group and fourteen of the ibuprofen group who did not receive the complete course of treatment were removed from the trial. There were no significant differences between the two groups in the incidence of oliguria, renal failure, NEC, IVH grade and serum creatinine concentration. However, differences in the incidence rates of gastrointestinal bleeding and hyperbilirubinemia between the two groups were significant (P,0.05).

There were no significant differences between the two groups in adverse events, including BPD, PVL, NEC, sepsis, ROP and death from one week after treatment onward during the hospitalization period (Table 3).

Discussion Few studies [14,19–21] have been conducted on paracetamol treatment of PDA in preterm newborns to date. In addition, paracetamol was not used as the drug of choice but rather as a Table 1. Baseline characteristics of study patients. Characteristic Ibuprofen group (n = 80) Paracetamol group (n = 80) P value Gestational age (week)

30.962.2

31.261.8

0.474

Birth weight (g)

1531.06453.5

1591.96348.6 g

0.342

Gender

0.874

Male

42

41

female

38

39

Cesarean birth, n (%)

48(60%)

52(65%)

0.447

PIH, n (%)

33(41.2%)

34(42.5%)

0.873

Antenatal glucocorticoid n (%)

45(56.2%)

47(58.8%)

0.749

Perinatal asphyxia, n (%)

10(12.5%)

11(13.8%)

0.815

Early-onset infection, n (%)

11(13.8%)

10(12.5%)

0.815

Surfactant treatment, n (%)

38(47.5%)

39(48.8%)

0.874

NCPAP, n (%)

52(65.0%)

58(72.5%)

0.306

NSIMV, n (%)

31(38.8%)

29(36.2%)

0.744

SIMV, n (%)

10(12.5%)

12(15.0%)

0.646

IVH grade 1–2, n (%)

11(13.8%)

9(11.3%)

0.633

Mean ductal diameter (mm)

2.3660.49

2.4160.44

0.459

Mean max shunt velocity (mm/s)

191.9630.0

190.8627.5

0.805

LA/Ao

1.6060.27

1.6760.23

0.103

pregnancy induced hypertension syndrome(PIH). doi:10.1371/journal.pone.0077888.t001 Table 2. Efficacy of paracetamol and ibuprofen treatments. Paracetamol group (n = 80) Ibuprofen group (n = 80) P value Overall closure rate, n (%)

65(81.2%)

63(78.8%)

0.693

Primary closure rate

45(56.3%)

38(47.5%)

0.268

Secondary closure rate

20 (25%)

25(31.3%)

0.379

Reopening after closure

5(7.7%)

6(9.5%)

0.712

Reclosure rate a

4 (80%)

4(66.7%)

0.621

Mean days needed for closure

3.2260.14

3.7160.16

0.020

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supplementary medication in cases where COX inhibitors were ineffective or contraindicated in the majority of several related cases, including the first case [14] reported, in which paracetamol was first used to close ductus arteriosus. As these previous studies lacked sufficient sample sizes for analysis of efficacy and safety-related factors, such as gastrointestinal bleeding, NEC, IVH, hyperbilirubinemia and death, they cannot be used to support paracetamol as a first-line drug for PDA in preterm newborns. Therefore, we conducted a randomized, non-blinded, parallel-controlled, noninferiority trial in order to compare oral paracetamol and ibuprofen for PDA closure in premature infants. In our study, subjects born at #34 weeks of gestation were chosen for enrollment based on the population demographics and clinical needs in China. We found that oral paracetamol had good efficacy on PDA in preterm infants, and the closure rate of paracetamol was comparable to that of oral ibuprofen. Furthermore, the mean number of days to ductal closure was shorter in the paracetamol group than in the ibuprofen group (3.2260.14 days vs. 3.7160.16 days, P = 0.020). Ductal closure in newborns is known to be dependent on increased blood oxygen and decreased vasodilators, including prostaglandin E2 and I2. [2] Prostaglandin synthetase has two different catalytic activities: a cyclooxygenase and a peroxidase. The cyclooxygenase activity catalyzes arachidonic acid to form PGG2, which is then catalyzed by the peroxidase into PGH2. COX inhibitors such as indomethacin and ibuprofen compete with the arachidonic acid substrate for the cyclooxygenase site; thus, the effects of these drugs are influenced by endogenous arachidonic acid levels. [22,23] Although the precise mechanism of action of paracetamol remains uncertain, it may act at the peroxidase segment of the prostaglandin synthetase to inhibit prostaglandin synthesis. [24,25] Peroxidase is activated at 10-fold lower peroxide concentrations than that for cyclooxygenase, [25,26] suggesting that paracetamol can still work well at decreased local peroxide concentrations (e.g., hypoxia). Theoretically, these differences may enable paracetamol to work effectively in the situation where a cyclooxygenase inhibitor is ineffective. Reopening of the ductus after closure was observed in five infants in the paracetamol group and in six infants of the ibuprofen group. After continuing the drug treatment, the ductus closed again in four patients in which it had reopened in each group, suggesting that paracetamol is still effective after the ductal reopening. Regarding the drug safety profile, the incidence rates of gastrointestinal bleeding and hyperbilirubinemia in the paracetamol group were significantly lower than those of the ibuprofen group. Ibuprofen is 99% protein bound, and at higher concentrations, it can be a competitive displacer of bilirubin for albumin binding sites, thereby potentially increasing the risk of hyperbilirubinemia.[27–30] In addition, two in vivo studies have demonstrated that ibuprofen treatment results in higher peak levels of total serum bilirubin and longer durations of phototherapy. [31,32].

This current study has provided several important implications for the clinical treatment of PDA. First, it demonstrated that paracetamol may become the choice drug for PDA in preterm infants. Furthermore, the mean days to closure were shorter in the paracetamol group than in the ibuprofen group (3.2260.14 days vs. 3.7160.16 days, P = 0.020), indicating that paracetamol can treat PDA more rapidly compared with ibuprofen, and be better suited for severe cases in which quick relief of symptoms is needed. Finally, the incidence rates of gastrointestinal bleeding and hyperbilirubinemia in the paracetamol group were significantly lower than those of the ibuprofen group. So, paracetamol may be indicated for PDA in preterm infants with hyperbilirubinemia. Although this study clearly showed that a two-course regimen of paracetamol for premature infants is safe and feasible, some limitations were evident. For example, the results were obtained from the patient population of one medical center. In order to generalize the conclusions, further analysis from a multiple-center, randomized, controlled trial is warranted.

In conclusion, we have demonstrated in this randomized, controlled, non-inferiority trial that paracetamol may be utilized as the drug of choice for PDA in preterm infants with good efficacy and lower risk of gastrointestinal bleeding or hyperbilirubinemia compared with ibuprofen treatment, and is especially suited for those with hyperbilirubinemia. Evidently, paracetamol merits the attention of pediatricians as a new alternative treatment for PDA in preterm newborns.

Table 3. Safety profiles of paracetamol and ibuprofen treatments. Paracetamol group (n = 80) Ibuprofen group (n = 80) P value Early outcomes Oliguria

6

9

0.42

Renal failure

0

1

0.32

NEC

3

2

0.65

IVH 1–2

6

7

0.77

IVH 3–4

3

3

1

Hyperbilirubinemia

16

28

0.03

Gastrointestinal bleeding

2

8

0.03

Serum creatinine (mg/dl)

61.62614.53

62.40615.24

0.74

Late outcomes

BPD

4

5

0.73

PVL

6

5

0.59

NEC

3

2

0.65

ROP

7

9

0.60

Sepsis

18

23

0.37

Death

10

12

0.65

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Supporting Information Checklist S1 CONSORT Checklist.

(DOC)

Protocol S1 Trial Protocol.

(DOC)

Author Contributions Conceived and designed the experiments: HW. Performed the experiments: DXW DD. Analyzed the data: CZ. Contributed reagents/ materials/analysis tools: DD WLZ QZ. Wrote the paper: DD. References

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birth weight outcomes of the National Institute of Child health and human development neonatal research network, January 1995 through December 1996. NICHD Neonatal Research Network. Pediatrics (107): E1.

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versus intravenous ibuprofen for patent ductus arteriosus closure: a randomized controlled trial in extremely low birthweight infants. Arch Dis Child Fetal Neonatal Ed (97) : 279–283.

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course of cyclooxygenase inhibitor to close a PDA is a risk factor for developing chronic lung disease in ELBW infant. BMC Pediatrics 12: 10.

12. Kabra NS, Schmidt B, Roberts RS, Doyle LW, Papile L, et al (2007)

Neurosensory impairment after surgical closure of patent ductus arteriosus in extremely low birth weight infants: results from the Trial of Indomethacin Prophylaxis in Preterms J Pediatr (150) : 229–234, 234.e1.

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(2011) Ductal closure with paracetamol: a surprising new approach to patent ductus arteriosus treatment. Pediatrics (128): e1618–e1621.

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first-choice drug in the medical management of patent ductus arteriosus: oral paracetamol. J Matern Fetal Neonatal Med (26): 825–827.

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ibuprofen increase neonatal hyperbilirubinemia. Pediatrics (124): 480–484.

32. Rheinlaender C, Helfenstein D, Walch E, Berns M, Obladen M, et al (2009)

Total serum bilirubin levels during cyclooxygenase inhibitor treatment for patent ductus arteriosus in preterm infants. Acta Paediatr (98): 36–42. Paracetamol Treatment for Patent Ductus Arteriosus PLOS ONE | www.plosone.org

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UNIVERSIDAD CENTRAL DEL ECUADOR

FACULTAD DE CIENCIAS MÉDICAS

INSTITUTO SUPERIOR DE POSTGRADO

POSTGRADO EN PEDIATRÍA

Prevalencia de la persistencia del conducto arterioso en prematuros tratados con paracetamol. Hospital Carlos Andrade Marìn octubre

2014-2016

Informe final de investigación presentado como requisito para optar por el título de especialista en pediatría

Autora: Curichumbi Guacho Myriam Jhesica Tutor: Dr. Washington Hernán Vinelli Merino

Quito, febrero 2017

ii

© DERECHOS DE AUTOR

Yo, Myriam Jhesica Curichumbi Guacho en calidad de autor del trabajo de investigación: PREVALENCIA DE LA PERSISTENCIA DEL CONDUCTO

ARTERIOSO EN PREMATUROS TRATADOS CON PARACETAMOL.

HOSPITAL CARLOS ANDRADE MARÌN OCTUBRE 2014-2016, autorizo a la universidad central del ecuador a hacer uso del contenido total o parcial que me pertenecen, con fines estrictamente académicos o de investigación.

Los derechos que como autor me corresponden, con excepción de la presente autorización, seguirán vigentes a mi favor, de conformidad con lo establecido en los artículos 5, 6, 8; 19 y demás pertinentes de la ley de propiedad intelectual y su reglamento.

También autorizo a la universidad central del ecuador realizar la digitalización y publicación de este trabajo de investigación en el repositorio virtual, de conformidad a lo dispuesto en el art. 144 de la ley orgánica de educación superior.

Firma:

Myriam Jhesica Cuichumbi Guacho C.C.N° 060386283-0

iii

APROBACIÓN DEL TUTOR DEL TRABAJO DE TITULACIÓN

Yo Washington Hernán Vinelli Merino en mi calidad de tutor del trabajo de titulación, modalidad Proyecto de Investigación, elaborado por MYRIAM JHESICA CURICHUMBI GUACHO; cuyo título es: PREVALENCIA DE

LA PERSISTENCIA DEL CONDUCTO ARTERIOSO EN PREMATUROS

TRATADOS CON PARACETAMOL. HOSPITAL CARLOS ANDRADE

MARÌN OCTUBRE 2014-2016, previo a la obtención de Grado de Especialista en Pediatría; considero que el mismo reúne los requisitos y méritos necesarios en el campo metodológico y epistemológico, para ser sometido a la evaluación por parte del tribunal examinador que se designe, por lo cual APRUEBO, a fin de que el trabajo sea habilitado para continuar con el proceso de titulación determinado por la Universidad Central del Ecuador.

En la ciudad de Quito, a los 20 días del mes de febrero de 2017

Dr. Washington Hernán Vinelli Merino

DOCENTE-TUTOR

C.C. 1703523074

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DEDICATORIA

Este trabajo de titulación está dedicado a Dios por darme la vida, brindarme su protección y sabiduría, a mis padres y hermanos por ser el pilar fundamental para todos mis proyectos y por su apoyo incondicional, a mi hijo Ethan por ser mi aliento y fuerza para continuar día a día.

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AGRADECIMIENTO

A Dios por darme la oportunidad de culminar un sueño más y así servir a una población indefensa e inocente como son los niños.

Dejo constancia un especial agradecimiento a la Universidad Central del Ecuador por brindarme conocimientos de calidad inculcados por medio de sus docentes.

Agradezco de sobremanera a mis tutores, quienes muy comedidamente y de forma acertada me guiaron en la elaboración de la presente tesis.

Al personal médico y directivo del Hospital Carlos Andrade Marín quienes facilitaron la infraestructura hospitalaria y las autorizaciones correspondientes para realizar las diferentes actividades para la culminación de este trabajo.

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INDICE GENERAL

© DERECHOS DE AUTOR ............................................................................ ii APROBACIÓN DEL TUTOR DEL TRABAJO DE TITULACIÓN .................. iii DEDICATORIA .............................................................................................. iv AGRADECIMIENTO ....................................................................................... v INDICE GENERAL ........................................................................................ vi ÍNDICE DE TABLAS ..................................................................................... ix LISTA DE ANEXOS ...................................................................................... xi RESUMEN .................................................................................................... xii ABSTRACT ................................................................................................. xiii INTRODUCCIÓN .......................................................................................... 14 CAPÍTULO I.................................................................................................... 3

1. DEFINICIÓN DEL PROBLEMA ................................................................ 3

1.1.

Planteamiento del problema ........................................................... 3

1.2.

Descripción del problema ............................................................... 4 1.4. Hipótesis .................................................................................................. 4 1.5. Objetivos .................................................................................................. 5 1.5.1. Objetivo general. ................................................................................... 5 1.5.2. Objetivos específicos. ........................................................................... 5 CAPÍTULO II ................................................................................................... 6

2. MARCO REFERENCIAL .......................................................................... 6

2.1. Generalidades .......................................................................................... 6

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2.2. Conducto arterioso ................................................................................... 7 2.2.1 Desarrollo embriológico ......................................................................... 7 2.2.2. Conducto hemodinámicamente significativo. ........................................ 8 2.2.3. Conducto persistentemente prolongado. .............................................. 8

2.2.4. Clasificación con base en hallazgos clínicos y/o eco cardiográficos ..... 9

2.2.5. Cierre normal del conducto arterioso. ................................................... 9 2.2.6. Fisiopatología. ....................................................................................... 9 2.2.7. Diagnóstico. ........................................................................................ 10

2.2.9. Los problemas clínicos asociados a la persistencia del conducto

arterioso. ....................................................................................................... 11

2.2.10. Indicaciones para el cierre del conducto arterioso persistente. ......... 12

2.2.11. Contraindicaciones para el cierre del conducto arterioso. ................ 12

2.2.12. Cardiopatías asociadas a la persistencia del conducto arterioso. ..... 12

2.2.13. Tratamiento. ...................................................................................... 12

2.2.14. Factores asociados a fracaso del tratamiento farmacológico. .......... 13

2.2.15. Mecanismo de acción del paracetamol como tratamiento para la

persistencia del conducto arterioso. .............................................................. 13

2.2.16. Tiempo promedio para el cierre del conducto arterioso persistente

tras la administración de paracetamol. ......................................................... 13

2.2.17. Dosis y tiempo de duración del tratamiento con paracetamol. ......... 13

2.2.18. Vía de administración del paracetamol. ............................................ 14

2.2.19. Toxicidad del paracetamol como fármaco utilizado para el cierre del

conducto arterioso. ....................................................................................... 14

2.2.20. Estudios con paracetamol como tratamiento para el cierre de la

persistencia del conducto arterioso. .............................................................. 15 CAPÍTULO III ................................................................................................ 16 3.1. Diseño de la investigación ..................................................................... 16 3.2. Población y muestra .............................................................................. 17 3.3. Criterios de selección. ............................................................................ 17 3.3.2. Criterios de exclusión: ......................................................................... 17 3.3.3. Criterios de eliminación. ...................................................................... 18

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3.4. Matriz de variables ................................................................................. 18 3.5. Operacionalización de variables. ........................................................... 20 3.6. Metodología o flujograma....................................................................... 22 3.7. Técnicas, instrumentos y estandarización. ............................................ 23 Autorización, fuente de información, recolección y procesamiento:.............. 23 3.7.1. Autorización: ....................................................................................... 23 3.7.2. Fuente de información y recolección de datos: ................................... 23 3.8. Normas éticas ........................................................................................ 23 3.8.1. Autonomía. .......................................................................................... 24 3.8.2. Beneficencia. ...................................................................................... 24 3.8.3. Confidencialidad: ................................................................................ 24 3.8.4. Bondad ética: ...................................................................................... 24 3.8.5. No maleficencia: ................................................................................. 24 3.9. Plan de análisis y tabulación de datos ................................................... 24 CAPÍTULO IV ............................................................................................... 25

4. MARCO ADMINISTRATIVO ................................................................... 25

4.1. Recursos ................................................................................................ 25 4.1.1. Recursos humanos. ............................................................................ 25 4.1.2. Recursos técnicos. .............................................................................. 25 4.1.3. Recursos económicos. ........................................................................ 25 4.2. Cronograma de actividades. .................................................................. 26 CAPÍTULO V ................................................................................................ 27

5. Resultados .............................................................................................. 27

CAPÍTULO VI ............................................................................................... 34

6. Discusión ................................................................................................ 34

CAPÍTULO VII .............................................................................................. 41

7. Conclusiones y recomendaciones .......................................................... 41

REFERENCIAS ............................................................................................ 43 ANEXOS ....................................................................................................... 46

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ÍNDICE DE TABLAS

Tabla 1. Recién nacidos prematuros por género, Hospital Carlos Andrade Marín, octubre 2014- 2016 ................................................................................ 28 Tabla 2. Distribución de casos según peso al nacimiento, Hospital Carlos Andrade Marín, octubre 2014- 2016 ............................................................... 28 Tabla 3. Distribución de casos según prematurez, Hospital Carlos Andrade Marín, octubre 2014- 2016 ................................................................................ 29 Tabla 4. Distribución de casos según factores de riesgo, Hospital Carlos Andrade Marín, octubre 2014- 2016 ............................................................... 29 Tabla 5. Distribución de casos según enfermedades asociadas a la persistencia del conducto arterioso, Hospital Carlos Andrade Marín, octubre

2014- 2016 .......................................................................................................... 30

Tabla 6. Distribución de casos según edad de inicio de tratamiento con paracetamol, Hospital Carlos Andrade Marín, octubre 2014- 2016 ........... 30 Tabla 7. Distribución de casos según la duración de tratamiento con paracetamol, Hospital Carlos Andrade Marín, octubre 2014- 2016 ........... 31 Tabla 8. Distribución de casos según la duración de tratamiento con paracetamol y cierre del conducto arterioso, Hospital Carlos Andrade Marín, octubre 2014- 2016 ............................................................................................ 31

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Tabla 9. Distribución de casos según la edad de inicio de tratamiento con paracetamol y cierre de conducto arterioso, Hospital Carlos Andrade Marín, octubre 2014- 2016 ............................................................................................ 32 Tabla 10. Distribución de casos según prevalencia de la persistencia del conducto arterioso en prematuros tratados con paracetamol, Hospital Carlos Andrade Marín, octubre 2014- 2016 ............................................................... 32

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LISTA DE ANEXOS

Anexo 1. Hoja de recolección de datos.…………………………………………...47 Anexo 2. Formulario de Evaluación de Trabajos de Titulación……………........49 Anexo 3. Declaración de Confidencialidad………………………………………..51 Anexo 4. Aprobación del Protocolo del Trabajo de Titulación de los Tutores y Coordinador del Postgrado………………………………………………………….53 Anexo 5. Abstract…………………………………………………………………….54 Anexo 6. Certificado de aprobación hospitalaria………………………………….55 Anexo 7. Hoja de Verificación en el Repositorio Institucional…………………..56 Anexo 8. Certificado de aprobación del protocolo de investigación…...............57

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TEMA: “Prevalencia de la persistencia del conducto arterioso en prematuros tratados con paracetamol. Hospital Carlos Andrade Marìn octubre 2014-2016”

Autora: Jhesica Curichumbi Tutor: Dr. Washington Hernán Vinelli Merino

RESUMEN

Introducción: la persistencia del conducto arterioso es un defecto en el que el vaso sanguíneo provisorio que comunica la arteria pulmonar izquierda a la aorta en el corazón fetal no se cierra después del nacimiento, las complicaciones asociadas a la falta de cierre incluyen la prolongación de la ventilación asistida, displasia broncopulmonar, hemorragia pulmonar, enterocolitis necrosante, hemorragia intraventricular, entre otras. Objetivo: establecer la prevalencia de la persistencia del conducto arterioso en prematuros tratados con paracetamol. Materiales y Métodos: se realizó un estudio descriptivo, transversal, en el Servicio de Cuidados Intensivos Neonatales en el Hospital Carlos Andrade Marín, en el período octubre 2014 - 2016, en recién nacidos con diagnóstico de persistencia del conducto arterioso hemodinámicamente significativo que fueron tratados con paracetamol intravenoso (15mg/kg/dosis) cada seis horas por tres a seis días. Resultados: se incluyeron 200 recién nacidos prematuros, de los cuales el 52,5% correspondió a una edad gestacional menor a 27,6 semanas y con un peso menor a 1000 gramos. Se detectó cierre del conducto arterioso en el 81,5% y cierre fallido en el 18,5%; encontrándose una edad de inicio del tratamiento entre los 4 a 6 días de vida en el 58% quienes tuvieron un cierre 82,8%, p=0,754. En tanto que se registró una duración de 3 días de tratamiento en el 95% con el cierre del conducto arterioso en el 83,7%, p=0,001. Conclusiones: a menor edad gestacional y menor peso al nacimiento, aumenta la aparición de persistencia del conducto arterioso. Existen alternativas farmacológicas distintas a tratamientos clásicos utilizados actualmente que pueden ser usados con seguridad en pacientes prematuros, con contraindicaciones absolutas o relativas para el cierre farmacológico clásico o quirúrgico.

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PALABRAS CLAVE: PERSISTENCIA DEL CONDUCTO ARTERIOSO,

PREMATUROS, PARACETAMOL.

TITLE: “Prevalence of persistence of artery duct in pre-term children treated with paracetamol, in Hospital Carlos Andrade Marìn october 2014 to october 2016”

Author: Myriam Jhesica Curichumbi Guacho Tutor: Dr. Washington Hernán Vinelli Merino

ABSTRACT

Introduction: persistence of the artery duct is a defect, when the temporary blood vessel communicating the left lung artery to the fetal heart aorta, does not closes after birth. Complications associated to the non-closure, include the prolongation of the assisted ventilation, bronchuspulmonary dysplasia, pulmonary hemorrhage, necropsying enterocolitis, intra-ventricular hemorrhage, among others. Objective: establishing prevalence of the persistence of the artery duct in pre-term babies treated with paracetamol. Materials and Methods: a descriptive, transversal study was conducted in the Newborn Intensive Care Service of Hospital Carlos Andrade Marín, from October 2014 to October 2016, in newborn diagnosed of persistence of the artery duct, significant in the hemodynamic sense, treated with intravenous paracetamol (15mg/kg/doses) every six hours for three to six days. Results: 200 preterm newborns were enrolled, out of which 52.5% were to a gestational age of less than 27.6 weeks and weighing less than 1000 grams. Closure of the artery duct was detected in 81.5% and failed closure in 18.5%. The treatment was started from 4 to 6 days of life in the 58%, out of which closure occurred in 82.8%, p=0.754. There was a duration of 3 days of treatment in 95% with the closure of the artery duct in 83.7%, p=0.001. Conclusions: at lower gestational age and weight at birth, the appearance of persistence of the artery duct increases. Pharmacologic alternatives exist to classic treatments currently used, that can be used with safety in pre-term patients, with absolute or relative counterindications for classic or surgical pharmacological.

KEY WORDS: DUCTUS ARTERIOSUS, PREMATURE NEWBORNS,

PARACETAMOL

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INTRODUCCIÓN

Silvero, Oreggioni, &Mir 2012 indican “El ductus arterioso durante la vida fetal es un vaso que conduce la sangre desde la arteria pulmonar a la aorta permitiendo que el 90% del gasto del ventrículo derecho sea derivado a la circulación sistémica y solo el 10% a la circulación pulmonar”

1.

Carrillo, Valencia, & Oliveros 2015 indican que la persistencia del conducto arterioso ocurre en 7 a 25% de los recién nacidos prematuros y está asociada con incremento de la mortalidad neonatal, en estos las concentraciones bajas de oxígeno en el útero y las concentraciones elevadas de prostaglandinas contribuyen a mantener la persistencia del conducto arterioso 2.

El paracetamol es un fármaco de fácil acceso y de inocuidad demostrada en neonatos, que posee propiedades para el cierre del conducto arterioso permeable hemodinámicamente significativo con lo que se podrá lograr que la estancia intrahospitalaria disminuya y con ello la morbilidad asociada 3.

Carrillo, Valencia, & Oliveros 2 2015 indican lo siguiente:

Que el paracetamol parece inhibir el segmento peroxidasa de la prostaglandina sintetasa, la peroxidasa es activada a concentraciones de peróxido diez veces más bajas en relación a la ciclooxigenasa y su inhibición mediada por el paracetamol es facilitada por la reducción de las concentraciones locales de peróxido en situaciones como hipoxia. Esto permite que la inhibición de la

peroxidasa sea efectiva en condiciones en que la inhibición de la ciclooxigenasa es menos activa.

En los recién nacidos a término, el conducto arterioso normalmente se contrae después del nacimiento hasta las 72 horas de vida, en recién nacidos prematuros, este cierre se retrasa, permaneciendo abierto hasta los 4 días de edad en aproximadamente el 10% de los bebes nacidos a las 30 a 37 semanas de gestación, el 80% en los nacidos a las 25 a 28 semanas, y el 90% en los nacidos a las 24 semanas 4. Dani et al. 2016 5 indican sobre el tratamiento con paracetamol para la persistencia del conducto arterioso lo siguiente: El paracetamol podría ofrecer varias ventajas terapéuticas importantes sobre las opciones de tratamiento actuales, teniendo en cuenta que en la población neonatal, aparece bien tolerado cuando se usa en el régimen de dosificación de analgésico administrado comúnmente en la unidad de cuidados intensivos neonatales. Además podría llegar a ser el tratamiento de elección para la persistencia del conducto arterioso

hemodinámicamente significativo, principalmente debido a su perfil de efectos secundarios más favorable.

CAPÍTULO I

1. DEFINICIÓN DEL PROBLEMA

1.1. Planteamiento del problema

Actualmente no se dispone de datos estadísticos sobre esta cardiopatía, por lo que se considera de interés realizar este trabajo investigativo para establecer dicha prevalencia, además para la realización de protocolos a fin de brindar un tratamiento óptimo que permita evitar secuelas originadas por complicaciones por la falta del cierre de este conducto. Arias I. et al. indican que en la mayoría de los casos de persistencia del conducto arterioso no se puede identificar una causa específica y es probable una etiología multifactorial. Al igual que se ha observado una fuerte asociación con las alteraciones cromosómicas como trisomía 21, 18 y 13, síndrome de Char, Noonan, HoltOram, Meckel Gruber y rubéola congénita” 6.

La incidencia de la persistencia del conducto arterioso oscila entre 50 y 70% en recién nacidos pretérmino y es más frecuente cuanto menor es la edad gestacional7.

Así en el estudio realizado en México 2015, eficacia del paracetamol intravenoso para el cierre del conducto arterioso en recién nacidos prematuros, se identificó persistencia del conducto arterioso en el 18% de los 67 prematuros, en nueve (75%) se observó por ecocardiografía persistencia del conducto arterioso hemodinámicamente significativo; de éstos 44% pesaban menos de 1500 gr, la edad gestacional media de 33 semanas y el peso medio de 1500 gr y que la afección fue identificada con más frecuencia en el grupo de pacientes de 1000 a 1500 gramos 2.

1.2. Descripción del problema

Rozé, Cambonie, Martin 2015 indican que el cierre del conducto arterioso se completa en la mayoría de los lactantes normales dentro de las 72 horas posteriores al nacimiento. Sin embargo, la falta de cierre es común en los recién nacidos extremadamente prematuros, lo que resulta en una condición llamada ductus arterioso permeable8.

La permeabilidad del ductus arterioso es una complicación frecuente en los prematuros que sufren de síndrome de dificultad respiratoria y afecta al 60 a 70% de los recién nacidos prematuros con edad gestacional menor a las 28 semanas 5.

La permeabilidad prolongada del conducto arterioso se asocia con numerosos resultados adversos, incluyendo larga estancia en ventilación asistida, mayor mortalidad, displasia broncopulmonar, hemorragia pulmonar, enterocolitis necrosante, hemorragia intraventricular, leucomalacia periventricular, y parálisis cerebral4.

1.3. Interrogantes de la investigación

¿Cuál es la prevalencia de la persistencia del conducto arterioso? ¿Cuáles son los factores de riesgo asociados con la persistencia del conducto arterioso?

¿Cuáles son las enfermedades asociadas a la persistencia del conducto arterioso?

¿Cuál es la dosis y la duración del tratamiento ideal con paracetamol para el cierre del conducto arterioso?

¿El tratamiento con paracetamol es efectivo en estos pacientes?

1.4. Hipótesis

Existe una prevalencia alta de persistencia del conducto arterioso en los prematuros tratados con paracetamol, que están hospitalizados en la

Unidad de Cuidados Intensivos Neonatales en el Hospital Carlos Andrade Marín de la ciudad de Quito, en el período de octubre de 2014 a octubre de 2016.

1.5. Objetivos

1.5.1. Objetivo general.

Establecer la prevalencia de persistencia de conducto arterioso en prematuros tratados con paracetamol, hospitalizados en la Unidad de Cuidados Intensivos Neonatales en el Hospital Carlos Andrade Marín de la ciudad de Quito, en el período de octubre de 2014 a octubre de 2016. 1.5.2. Objetivos específicos.

 Identificar factores de riesgo que predisponen a la persistencia del conducto arterioso.

 Determinar las enfermedades asociadas a la persistencia del conducto arterioso.

 Establecer las dosis, días de tratamiento, inicio del tratamiento, forma de administración y posibles efectos adversos del paracetamol mediante revisión de historias clínicas.

1.6. Justificación

La persistencia del conducto arterioso es un cardiopatía frecuente en nuestros hospitales, por lo que establecer su diagnóstico oportuno durante los primeros días de vida de los recién nacidos promete evitar complicaciones a corto y largo plazo.

Son conocidos los factores de riesgo que influyen para el desarrollo de esta patología por lo que saber reconocer los mismos, prevenirlos o tratarlos a tiempo hará que la tasa de incidencia y prevalencia de la persistencia del conducto arterioso disminuya significativamente.

Sabemos que no contamos con datos estadísticos sobre esta cardiopatía y que siendo la misma muy frecuente no disponemos de protocolos de manejo estandarizados por lo que sería ideal implementar normas que regulen el tratamiento de la misma.

El tratamiento farmacológico con paracetamol en la actualidad está en auge por sus bajos costos, su disponibilidad en el mercado y sobre todo por los pocos o escasos efectos adversos que se tiene al termino del tratamiento, además por su efectividad con respecto al cierre temprano de conducto arterioso, por ello es nuestro objetivo recomendar la creación y actualización continua de protocolos que nos permitan establecer las dosis, días de tratamiento y criterios de uso en las unidades de cuidados intensivos neonatales.

CAPÍTULO II

2. MARCO REFERENCIAL

2.1. Generalidades

En la actualidad, las malformaciones congénitas constituyen la segunda causa de mortalidad en menores de cinco años y específicamente las

malformaciones cardiacas aisladas se encuentran en noveno lugar. La prevalencia de las cardiopatías congénitas es de 60 a 105 por cada

10.000 nacimientos; al excluir a los niños prematuros y recién nacidos

menores de seis semanas, la prevalencia de la persistencia de conducto arterioso se estima en 2.9 por cada 10 000 nacidos vivos 9. La persistencia del conducto arterioso (PCA) es una de las dos cardiopatías congénitas más frecuentes en pacientes con síndrome de Down, con una incidencia hasta de 58 %. En un alto porcentaje (40%), la PCA se encuentra asociada con otras cardiopatías, principalmente con las comunicaciones interventricular e interauricular, la válvula aórtica bivalva, la estenosis pulmonar (valvular y supravalvular) y la coartación de aorta9. El conducto arterioso es probable que se cierre sin tratamiento en recién nacidos mayores de 28 semanas de gestación (73%), en aquellos con peso al nacer mayor de 1000 g (94%), y en los bebés nacidos a las 26 a

29 semanas de gestación que no tienen síndrome de dificultad

respiratoria4.

Tofé, Jaraba, Ruiz, Rodríguez, Parraga2016 indican que el paracetamol es una nueva alternativa prometedora a la indometacina, el ibuprofeno y la cirugía para alcanzar el cierre del conducto arterioso persistente, con menos acontecimientos adversos 10.

2.2. Conducto arterioso

El conducto arterioso es una estructura vascular, que conecta la arteria pulmonar con la aorta descendente, este orificio se localiza inmediatamente a la izquierda de la bifurcación del tronco de la arteria pulmonar y a nivel aórtico en la unión del arco aórtico con la aorta descendente, a 1cm de la emergencia de la subclavia izquierda 6.

2.2.1 Desarrollo embriológico

En el desarrollo embriológico normal, el conducto arterioso se presenta con arco aórtico izquierdo por persistencia del cuarto arco aórtico izquierdo e involución del derecho; el conducto arterioso se origina de la porción distal del sexto arco aórtico izquierdo, mientras que de la porción proximal se origina el segmento proximal de la rama izquierda de la arteria pulmonar, lo que ocasiona la comunicación con la aorta. Si bien es más frecuente encontrar arco izquierdo con conducto izquierdo, llega a presentarse conducto arterioso derecho con arco derecho (0.04 a 0.14 %); en 98 % de los casos asociado con anomalías intracardíacas9. 2.2.2. Conducto hemodinámicamente significativo.

Conducto de gran tamaño y con cortocircuito de izquierda derecha elevado, que puede llevar a complicaciones graves. Generalmente es sintomático, si no se cierra, la evolución natural es hacia una mayor morbimortalidad 11.

En pacientes con conductos que repercuten la hemodinamia del paciente pueden presentarse complicaciones y secuelas al generar un impacto en el aparato respiratorio, como sobrecarga pulmonar vascular, insuficiencia respiratoria, edema pulmonar, hemorragia pulmonar, dependencia al apoyo ventilatorio, fracaso en las extubaciones, apneas y displasia pulmonar. Desde el punto de vista hemodinámico genera disminución del flujo sanguíneo sistémico, por lo que conlleva a hipoperfusión e isquemia en órganos vitales, por lo tanto está asociado a insuficiencia renal, enterocolitis necrosante, hemorragia interventricular y retinopatía del prematuro12.

2.2.3. Conducto persistentemente prolongado.

Larruscain, Olmedo, De Miguel Serrano 2011 refieren que la mayoría de autores consideran conducto persistentemente prolongado el que excede los 14 y 21 días. Su presencia asocia mayor morbilidad (displasia broncopulmonar, retinopatía de la prematuridad, etc.) así como mayor estancia hospitalaria11.

2.2.4. Clasificación con base en hallazgos clínicos y/o eco cardiográficos

El conducto arterioso varía en longitud, diámetro y forma, de acuerdo a su morfología puede ser tubular, en embudo, largo y tortuoso, corto tipo ventana y aneurismático. Krichenko y sus colaboradores describieron una clasificación de la morfología de la luz ductal y su relación espacial con la tráquea, a partir de la cual establecieron cinco tipos: A, B, C, D y E 9. Arias, Benítez, Ruiz, Peralta, Miranda, 2010 6, indican: Silente: Aquellos que no presentan soplo, ni datos de hipertensión arterial pulmonar y es diagnosticado solo por ecocardiografía. Pequeño: Pacientes con soplo continuo audible, con insignificante cambios hemodinámicos, sin sobrecarga en cavidades izquierdas, sin hipertensión arterial pulmonar.

Moderado: Presentan soplo continuo, pulsos amplios, sobrecarga de volumen en cavidades izquierdas, hipertensión arterial pulmonar leve a moderada. Con ó sin datos de insuficiencia cardiaca leve. Grande: Presenta soplo continuo, pulsos amplios, sobrecarga importante de volumen en cavidades izquierdas, con hipertensión arterial pulmonar moderada ó severa, con datos clínicos de insuficiencia cardiaca descompensada.

2.2.5. Cierre normal del conducto arterioso.

El conducto arterioso esta permeable desde las 8 semanas de gestación y durante todo el desarrollo intrauterino y mantiene el 70% del gasto cardiaco, su cierre se inicia a las semanas 35-36 de gestación y al nacimiento el proceso de cierre se realiza así:

Primera etapa se inicia en las primeras horas de vida (12 a 15 horas), con vasoconstricción de las fibras elásticas de la capa media y proliferación de tejido conectivo en capa media con disrupción de la lámina elástica interna. Segunda etapa por proliferación de tejido conectivo en la íntima y media, con atrofia de células musculares, forman un tejido fibroso llamado ligamento arterioso 9.

2.2.6. FISIOPATOLOGÍA.

Benítez, W 4 2016 con respecto a la fisiopatología de la persistencia del conducto arterioso permeable indica lo siguiente:

Mientras que el conducto permanece abierto, la sangre fluye de izquierda a derecha desde la aorta hacia las arterias pulmonares, la resistencia vascular pulmonar disminuye durante los primeros días después del nacimiento, la proporción de flujo de sangre de la aorta que se desvía en la circulación pulmonar aumenta, los resultados del flujo excesivo de sangre a través de los pulmones predispone al desarrollo de congestión pulmonar, edema pulmonar, y el empeoramiento de la insuficiencia respiratoria. La desviación de flujo de sangre de la circulación sistémica puede exceder las capacidades para aumentos compensatorios en el gasto cardíaco total, lo que resulta en el compromiso de la perfusión de los órganos vitales en peligro, incluyendo el intestino, el riñón, y el cerebro. 2.2.7. Diagnóstico.

Con base en la presencia o ausencia de soplo, la persistencia del conducto arterioso puede ser:

 Sin soplo (PCA silente): se descubre al realizar estudios de imagen por otras indicaciones no relacionadas.

 Con soplo sistólico: soplo sistólico y diastólico o continuo (máquina de vapor): puede ser grado > 3/6, se escucha mejor en la región infraclavicular izquierda y no se modifica con los cambios de posición 9.

Carrillo, Valencia, Oliveros 2015 “El diagnóstico de persistencia del conducto arterioso en el prematuro debe ser eco cardiográfico ya que los signos clínicos son con frecuencia poco fiables y puede existir un conducto arterioso grande con gran paso de flujo de izquierda a derecha en ausencia de síntomas” 2.

2.2.8. Factores de riesgo que se asocian con la persistencia del conducto

arterioso.

 Antecedente de hermanos con persistencia del conducto arterioso.  Consanguinidad entre padres.

 Prematuros y Recién Nacidos de bajo peso.

 Alteraciones cromosómicas como trisomía 21, 18 y 13, síndrome de Char, Noonan, HoltOram, Meckel Gruber y rubéola congénita.  Hipotiroidismo neonatal.

 Antecedente materno de diabetes o fenilcetonuria.  Exposición materna a: Busulfan, Litio, Talidomida, Trimetadiona Calcio antagonistas Esteroides Anticonvulsivos Drogas (mariguana y cocaína) 6.

En la mayoría de los casos de PCA no se puede identificar una causa específica y es muy probable que la etiología sea multifactorial. Puede presentarse con un patrón autosómico dominante o recesivo. La PCA con aneurisma y disección de aorta torácica se asocia con una mutación en el cromosoma 16p12.2-p13 (mutación en el gen MYH11). La PCA que coexiste con válvula aórtica bivalva, hipoplasia del quinto metacarpiano y braquidactilia puede asociarse con una variante del síndrome de Char9.

2.2.9. Los problemas clínicos asociados a la persistencia del conducto

arterioso.

La PCA de gran tamaño y con flujo de izquierda a derecha elevado se asocia con serias complicaciones e incrementa el riesgo de presentación de procesos infecciosos. Estas se relacionan con el descenso del gasto cardíaco secundario al cortocircuito de izquierda a derecha. La distribución del flujo sistémico está alterada por la disminución en la presión diastólica y la vasoconstricción arteriolar reactiva por disminución del gasto cardíaco, dando como resultado una reducción de la perfusión, que contribuye a la aparición de algunas morbilidades tales como:  Hemorragia pulmonar.

 Hipotensión.

 Hemorragia intraventricular.

 Enterocolitis necrotizante.

 Mortalidad13.

2.2.10. Indicaciones para el cierre del conducto arterioso persistente. Signos de sobrecarga de volumen del ventrículo izquierdo. Hipertensión arterial pulmonar, pero con presión sistólica de la arteria pulmonar o con resistencia vascular pulmonar < 2/3 de las sistémicas. Crecimiento de ventrículo o aurícula izquierda. Hipertensión arterial pulmonar.

Antecedentes de endarteritis 9.

2.2.11. Contraindicaciones para el cierre del conducto arterioso. Hipertensión pulmonar no reactiva o cortocircuito de derecha a izquierda. Hipertensión arterial pulmonar severa e irreversible 9. 2.2.12 . Cardiopatías asociadas a la persistencia del conducto arterioso. Comunicación interauricular.

Comunicación interventricular.

Estenosis pulmonar (valvular y supravalvular). Válvula aórtica bivalva sin estenosis.

Coartación aórtica 6.

2.2.13. Tratamiento.

Se recomienda el inicio precoz del tratamiento (ante los primeros signos clínicos, entre los 2 y 5 días de vida) ya que en estos estadios precoces las posibilidades de éxito son mayores. Existe una mayor eficacia del tratamiento del conducto sintomático de forma precoz frente al tratamiento tardío (signos de fallo cardíaco) 11.

El tratamiento clásico para la persistencia del conducto arterioso con repercusión hemodinámica sintomático.

 Restricción hídrica  Diuréticos intravenosos  Manejo de la insuficiencia cardiaca congestiva14.

2.2.14. Factores asociados a fracaso del tratamiento farmacológico. Edad gestacional: a mayor inmadurez, mayor tasa de fracaso del cierre con el tratamiento farmacológico.

Empleo de ventilación de alta frecuencia.

Indometacina prenatal 48 h antes del parto.

Comienzo tardío del tratamiento 11.

2.2.15. Mecanismo de acción del paracetamol como tratamiento para la

persistencia del conducto arterioso.

Carrillo, Valencia, & Oliveros20152, indican lo siguiente: Que el paracetamol parece inhibir el segmento peroxidasa de la prostaglandina sintetasa, la peroxidasa es activada a concentraciones de peróxido diez veces más bajas en relación a la ciclooxigenasa y su inhibición mediada por el paracetamol es facilitada por la reducción de las concentraciones locales de peróxido en situaciones como hipoxia. Esto permite que la inhibición de la peroxidasa sea efectiva en condiciones en que la inhibición de la ciclooxigenasa es menos activa.

2.2.16. Tiempo promedio para el cierre del conducto arterioso persistente

tras la administración de paracetamol.

El tiempo promedio de cierre del conducto arterioso después de la administración de paracetamol es 3.4 ± 1.7 días y sugiere que este fármaco es eficaz en el tratamiento de esta enfermedad y comparable con los días de tratamiento con indometacina e ibuprofeno que se requieren para el cierre del conducto arterioso 2.

2.2.17. Dosis y tiempo de duración del tratamiento con paracetamol. Se ha evidenciado que la dosis de paracetamol varía según los diversos autores así como también los días de administración, pero por lo general la dosis propuesta es de 15mg/ kg por dosis intravenoso cada 6 horas durante 3 días.

Varios estudios han puesto de manifiesto la posible eficacia del paracetamol en una fase temprana de la persistencia del conducto arterioso. En 2011, Hammerman et al. presentaron la primera serie de casos de recién nacidos prematuros y observaron que la administración oral de paracetamol durante un periodo de 3 días a una dosis de

60 mg/kg/4 veces al día era eficaz para alcanzar el cierre del conducto

arterioso persistente 10.

Dani et al. 2016 en su estudio comparativo con el ibuprofeno indica que los pacientes recibieron una solución de paracetamol por vía intravenosa,

15 mg / kg por dosis (correspondiente a 1,5 ml / kg) cada 6 h durante 3

días, para un total de 12 dosis, y este se administra de acuerdo con la práctica clínica para el tratamiento de alivio del dolor en el recién nacido 5. 2.2.18. Vía de administración del paracetamol.

La vía intravenosa es sin duda más adecuada que la vía enteral en el recién nacido prematuro, cuya absorción enteral de la drogas es a menudo incierta y que con frecuencia se desarrolla intolerancia a la alimentación y por lo tanto no pueden ser tratados con medicamentos orales. Es así que el paracetamol intravenoso es eficaz en el cierre de persistencia del conducto arterioso 5.

2.2.19. Toxicidad del paracetamol como fármaco utilizado para el cierre

del conducto arterioso.

Dani et al. 2016 indica el cierre exitoso de la persistencia del conducto arterioso con el paracetamol se ha informado recientemente en varios recién nacidos prematuros, sin signos de toxicidad y de un total de 74 recién nacidos prematuros que fueron tratados con paracetamol (oral o intravenosa), con cierre en 66 (89%) no presentaron efectos adversos 5.

2.2.20. Estudios con paracetamol como tratamiento para el cierre de la

persistencia del conducto arterioso.

Peña-Juárez et al 20163, con respecto al tratamiento con paracetamol indican:

Se han utilizado diversos fármacos para el cierre del conducto arterioso permeable hemodinámicamente significativo, como la indometacina, pero por su elevado coste se han buscado otras opciones, como el ibuprofeno pero se asocia con reducción de la perfusión renal, mesentérica y cerebral, recientemente se ha demostrado la utilidad del paracetamol para este fin, sin reportar toxicidad hasta el momento. El cierre farmacológico del ducto arterioso con paracetamol tiene un éxito similar al de otros antiinflamatorios no esteroideos, con un porcentaje del 70%, además existió una aparente inocuidad del medicamento (paracetamol), ya que durante su estudio no se documentaron complicaciones a corto y medio plazo.

Carrillo, Valencia, & Oliveros20152 sobre la eficacia del paracetamol intravenoso para el cierre del conducto arterioso en recién nacidos prematuros indican lo siguiente:

La frecuencia de cierre del conducto arterioso fue de 89%. En el único paciente en el que no se consiguió el cierre del conducto arterioso se administró previamente ibuprofeno oral por falta de disponibilidad temporal de paracetamol intravenoso y se decidió, después de tres días de tratamiento con este fármaco, la administración de paracetamol intravenoso ante la falta de cierre del conducto arterioso.

Existen datos de estudios realizados con paracetamol así: Dan Dang y Cols. 2015 reportaron 80 pacientes prematuros, a quienes se les administró paracetamol VO vs. ibuprofeno VO, el éxito fue del 81.2% vs. 78.8%, respectivamente. Con menor incidencia de hemorragia gastrointestinal e hiperbilirribinemia en el grupo de paracetamol. Oncel M y Cols., 2013 reportaron 45 casos que recibieron paracetamol VO,

15 mg/kg una dosis cada 6 horas por 3 días el éxito de cierre fue del

72.5% 14.

CAPÍTULO III

3. MARCO METODOLÓGICO

3.1. Diseño de la investigación

Se realizó un estudio descriptivo de corte transversal, por cuanto se realizó en un determinado período de tiempo y se efectuó algunas asociaciones.

En primera instancia se solicitó la autorización correspondiente para la respectiva revisión de las historias clínicas de los recién nacidos

hospitalizados en la Unidad de Cuidados Intensivos Neonatales en el Hospital Carlos Andrade Marín de la ciudad de Quito, en el período de octubre de 2014 a octubre de 2016 y que tuvieron el diagnóstico de persistencia del conducto arterioso.

3.2. Población y muestra

La población de este estudio, fueron los prematuros con diagnóstico de persistencia del conducto arterioso hospitalizados en la Unidad de Cuidados Intensivos Neonatales en el Hospital Carlos Andrade Marín de la ciudad de Quito, en el período de octubre de 2014 a octubre de 2016. Para obtener mejores resultados este estudio se realizó con el total del universo sin cálculo de la muestra, pues se contó con 200 recién nacidos. 3.3. Criterios de selección.

3.3.1. Criterios de inclusión:

 Recién nacidos prematuros, ingresados en la unidad de cuidados intensivos neonatales en el período de octubre de 2014 a octubre de 2016.

 Recién nacidos prematuros que fueron diagnosticados de persistencia del conducto arterioso mediante ecocardiograma.  Recién nacidos prematuros que recibieron tratamiento con paracetamol para esta patología.

 Recién nacidos prematuros de ambos sexos.

 Pacientes que presenten factores de riesgo que pueden desencadenar en persistencia del conducto arterioso.

3.3.2. Criterios de exclusión:

 Participación en otro ensayo con cualquier fármaco en investigación.

 El tratamiento previo con paracetamol, ibuprofeno, o cualquier inhibidor de la COX, para cualquier propósito.  Que no cumplan con alguno de los criterios de inclusión. 3.3.3. Criterios de eliminación.

Recién nacidos que no hayan sido diagnosticados con persistencia del conducto arterioso.

3.4. Matriz de variables

VARIABLES

INDEPENDIENTES

Prematuros Sexo Peso al nacimiento

VARIABLES

INTERVINIENTES

Antecedentes familiares Alteraciones cromosómicas Hipotiroidismo Exposición de la madre a diversas sustancias

VARIABLES

DEPENDIENTES

Persistencia del conducto arterioso

3.5. Operacionalización de variables.

VARIABLE

DEFINICIÓN

TIPO

ESCALA

INDICADOR

Persistencia del conducto arterioso Permeabilidad prolongada del conducto arterioso Categórica Silente Pequeña Moderada Severa Cualitativa

Sexo Condición biológica Categórica Masculino Femenino Cualitativa Edad Recién nacido prematuro Categórica Extremo Muy prematuro Moderado Tardio Cualitativa Peso bajo al nacimiento

Peso bajo del ideal con el que nace el recién nacido Categórica Recién nacido de bajo peso al nacer: < 2500 gr y >1500 gr Recién nacido de muy bajo peso al nacer: <

1500 gr y > 1000 gr

Recién nacido de peso extremadamente bajo al nacer: < 1000 gr Cuantitativa

Factores de riesgo Patologías que predisponen para la aparición de la persistencia del conducto arterioso Categórica Prematuridad Bajo peso al nacer Antecedentes familiares Malformaciones Explosión materna a determinadas sustancias Cualitativa Complicaciones por la persistencia del conducto arterioso Situaciones desencadenadas por compromiso hemodinámico Categórica Hemorragia cerebral Enterocolitis necrotizante Hemorragia pulmonar Muerte Cualitativa Inicio de tratamiento Tiempo que transcurre en el que se inicia el tratamiento farmacológico (paracetamol) a partir del diagnostico Categórica

1 – 3 días

4 – 6 días

7 - 9 días

Más de 10 días Cuantitativa Duración del tratamiento Tratamiento óptimo instaurado Categórico

3 días

6 días

Más de 6 días Cualitativo

3.6. Metodología o flujograma

Recién nacidos Factores de riesgo Ambos sexos Hospitalizados en la Unidad de Cuidados Intensivos Neonatales Prematuridad Bajo peso al nacimiento Sepsis Malformaciones Explosión materna a sustancias toxicas Otros Ecocardiograma Persistencia del conducto arterioso Tratamiento con paracetamol

3.7. Técnicas, instrumentos y estandarización.

Autorización, fuente de información, recolección y procesamiento:

3.7.1. Autorización:

Se solicitó la autorización del Jefe del Servicio de la Unidad de Cuidados Intensivos Neonatales.

3.7.2. Fuente de información y recolección de datos:

Una vez obtenida la autorización correspondientes se procedió a la revisión respectiva de las historias clínicas de los recién nacidos prematuros hospitalizados en la Unidad de Cuidados Intensivos Neonatales y que fueron diagnosticados de persistencia del conducto arterioso en el Hospital Carlos Andrade Marín en la ciudad de Quito, en el período de octubre de 2014 a octubre de 2016.

Se obtuvo la información de las historias clínicas de 200 recién nacidos de ambos sexos, la información incluyo variables como: diagnóstico de persistencia del conducto arterioso, el sexo, edad gestacional al momento del tratamiento, peso bajo al nacimiento, días de tratamiento con paracetamol, dosis de este fármaco, complicaciones por persistencia del conducto arterioso, factores de riesgo asociados para desarrollar esta patología.

Posterior a la recolección de los datos, estos fueron colocados en la hoja de recolección de datos elaborada para el efecto (ANEXO1). Luego de obtener los datos correspondientes, se procedió a la tabulación y análisis estadístico de los mismos.

3.8. Normas éticas

El presente estudio cumplió con estos principios éticos:

3.8.1. Autonomía: la integridad de estos pacientes estuvo protegida bajo

nuestra absoluta reserva, además para llevar a efecto este estudio se contó con le respectiva autorización.

3.8.2. Beneficencia: nuestro objetivo fue desarrollar normas en bien de

nuestros pacientes.

3.8.3. Confidencialidad: no existió entrega de datos a terceros para evitar

que exista daño alguno a nuestros pacientes.

3.8.4. Bondad ética: se brindó los resultados finales de nuestro estudio

con el fin de crear protocolos basados en los mimos.

3.8.5. No maleficencia: bajo ningún motivo existió daño a los pacientes o

sus apoderados.

3.9. Plan de análisis y tabulación de datos

Los datos se recogieron de las historia clínicas de los pacientes en estudio y que en su estancia hospitalaria presentaron diagnóstico de persistencia del conducto arterioso.

Para tabulación de los datos obtenidos, se utilizó en programa EXCEL

2010 y el análisis se realizó con el paquete estadístico SPSS versión

22.0. La comparación entre las diferentes variables fue aceptada con la

prueba de Chi cuadrado, se aceptó como significancia estadística una p menor a 0.05.

CAPÍTULO IV

4. MARCO ADMINISTRATIVO

4.1. Recursos

4.1.1. Recursos humanos.

Tutor Científico: Dr. Hernán Vinelli Merino. Tutor Metodológico: Dr. Marcelo Chiriboga Urquizo. Investigador: Md. Jhesica Curichumbi. Postgradista en Pediatría de la Universidad Central del Ecuador.

4.1.2. Recursos técnicos.

Para la tabulación y análisis de datos se utilizó el programa EXCEL 2010 y se analizó con el paquete estadístico SPSS versión 22.0. 4.1.3. Recursos económicos.

El financiamiento es aporte personal de la aspirante a Pediatra. Denominación del rubro Cantidad Valor unitario

USD

Valor total USD Hojas de papel bond

200

0.10

20.00

Internet banda ancha

5

10.00

50.00

Cartuchos de tinta para impresora

1

50.00

50.00

Copias

200

0.05

10.00

Revisión de bibliografía

10

25.00

250.00

TOTAL

380.00

Autor: Md. Jhesica Curichumbi

4.2. Cronograma de actividades. No. ACTIVIDADES

SEMANAS

1 2 3 4 5 6 7 8 9 10 11 12

1

Problema, objetivos, hipótesis, justificación

2

Marco referencial

3

Marco metodológico

4

Aprobación protocolo

5

Autorización del hospital seleccionado

6

Recolección de los datos

7

Diseño y depuración de base de datos

8

Procesamiento y análisis de resultados

9

Redacción de resultados

10

Discusión, conclusiones y recomendaciones

11

Edición del documento

final

12

Entrega del documento final

Autor: Md. Jhesica Curichumbi

CAPÍTULO V

5. RESULTADOS

5.1. Descripción

El estudio se realizó sobre una muestra de 200 pacientes, para lograr los objetivos planteados la información obtenida fue tabulada mediante la aplicación del programa Excel 2010 y con el Software SPSS 22.0, de igual forma los datos están expuestos en tablas, que están elaboradas de acuerdo a la diferentes variables expuestas en esta investigación, así: por sexo, prevalencia de la persistencia del conducto arterioso en prematuros tratados con paracetamol peso al nacimiento, factores de riesgo, enfermedades asociadas a la persistencia del conducto arterioso, edad de inicio de tratamiento con paracetamol, duración de tratamiento con paracetamol. Los datos de este estudio se expresan en número y porcentaje, para esto se utilizó análisis de distribución de frecuencias debido a que es necesario el ordenamiento de los valores observados de acuerdo con su magnitud numérica para permitir identificar la distribución de las mismas; se consideró chi cuadrado, valor p <0.05 como significativo.

A fin de conocer la prevalencia de la persistencia del conducto arterioso en prematuros que recibieron tratamiento farmacológico con paracetamol para su cierre en la unidad de cuidados intensivos del Hospital Carlos Andrade Marín se obtuvo la información de la base de datos del sistema AS400, como número de historia clínica, edad de inicio de tratamiento, duración del tratamiento, dosis, vía de administración y frecuencia de administración del paracetamol siendo los resultados los siguientes:

5.2. Característica del pacientes

Análisis e interpretación: El estudio se realizó en 200 recién nacidos prematuros, el 56,5% (113) correspondió al sexo femenino y el 43,5% (87) al sexo masculino.

Análisis e interpretación: En el estudio se observó el 52,5% (105) de prematuros con peso extremadamente bajo y el 47,5% (95) con peso muy bajo.

Tabla 1. Recién nacidos prematuros por género, Hospital Carlos Andrade Marín, octubre 2014- 2016 Sexo Frecuencia Porcentaje Femenino

113

56,5

Masculino

87

43,5

Total

200

100,0

Fuente: Historias Clínicas, sistema AS400 Hospital Carlos Andrade Marín Elaboración: MD. Myriam Jhesica Curichumbi Guacho Tabla 2.Distribución de casos según peso al nacimiento, Hospital Carlos Andrade Marín, octubre 2014- 2016 Peso Frecuencia Porcentaje Extremadamente bajo

105

52,5

Muy bajo

95

47,5

Total

200

100,0

Fuente: Historias Clínicas, sistema AS400 Hospital Carlos Andrade Marín Elaboración: MD. Myriam Jhesica Curichumbi Guacho

Análisis e interpretación: En el estudio se observó predominio de recién nacidos prematuros extremos 52,5% (105).

Análisis e interpretación: Al mencionar los factores de riesgo que influyeron en la persistencia del conducto arterioso encontramos a la prematuridad, bajo peso y enfermedades maternas ya sean infección del tracto urinario, diabetes gestacional como las más frecuentes.

Tabla 3.Distribución de casos según prematurez, Hospital Carlos Andrade Marín, octubre 2014- 2016 Prematurez Frecuencia Porcentaje Extremo

105

52,5

Muy prematuro

95

47,5

Total

200

100,0

Fuente: Historias Clínicas, sistema AS400 Hospital Carlos Andrade Marín Elaboración: MD. Myriam Jhesica Curichumbi Guacho Tabla 4.Distribución de casos según factores de riesgo, Hospital Carlos Andrade Marín, octubre 2014- 2016 Factores de riesgo Frecuencia Porcentaje Prematuridad, bajo peso ITU materna* Diabetes gestacional Antecedentes familiares

165

82,5

20

10,0

12

6,0

3

1,5

Total

200

100,0

* ITU: Infección del tracto urinario

Fuente: Historias Clínicas, sistema AS400 Hospital Carlos Andrade Marín Elaboración: MD. Myriam Jhesica Curichumbi Guacho

Análisis e interpretación: De los pacientes estudiados el 88,5% (177) no presentó ninguna enfermedad asociada a la persistencia del conducto arterioso, el 3,5% (7) enterocolitis necrotizante, el 3,0% (6) falla renal, el 2,5% (5) hemorragia cerebral, el 1,5% (3) muerte, el 1% (2) hemorragia pulmonar.

Tabla 6. Distribución de casos según edad de inicio de tratamiento con paracetamol, Hospital Carlos Andrade Marín, octubre 2014- 2016 Edad de inicio de tratamiento con paracetamol Frecuencia Porcentaje

4 a 6 días

116

58,0

1 a 3 días

83

41,5

7 a 9 días

1

0,5

Total

200

100,0

Fuente: Historias Clínicas, sistema AS400 Hospital Carlos Andrade Marín Elaboración: MD. Myriam Jhesica Curichumbi Guacho

Análisis e interpretación: El inicio del tratamiento farmacológico en este estudio ocurrió en su mayoría a los 4 a 6 días de vida con el 58,0% (116). Tabla 5.Distribución de casos según enfermedades asociadas a la persistencia del conducto arterioso, Hospital Carlos Andrade Marín, octubre 2014- 2016 Enfermedades asociadas al conducto arterioso Frecuencia Porcentaje Enterocolitis necrotizante

7

3,5

Falla renal

6

3,0

Hemorragia cerebral

5

2,5

Muerte

3

1,5

Hemorragia pulmonar

2

1,0

Total 200*

100,0

*Se obtuvo el 88,5% (177) de prematuros que no presentaron enfermedades asociadas a la persistencia del conducto arterioso Fuente: Historias Clínicas, sistema AS400 Hospital Carlos Andrade Marín Elaboración: MD. Myriam Jhesica Curichumbi Guacho

Tabla 7.Distribución de casos según la duración de tratamiento con paracetamol, Hospital Carlos Andrade Marín, octubre 2014- 2016 Duración de tratamiento Frecuencia Porcentaje

3 días

190

95,0

6 días

10

5,0

Total

200

100,0

Fuente: Historias Clínicas, sistema AS400 Hospital Carlos Andrade Marín Elaboración: MD. Myriam Jhesica Curichumbi Guacho

Análisis e interpretación: La duración del tratamiento farmacológico en este estudio en su mayoría fue de tres días 95% (190)

Análisis e interpretación: Los recién nacidos con tratamiento farmacológico de tres días de duración fueron los que tuvieron mayor cierre del conducto arterioso. Al establecer la relación que existe entre la duración del tratamiento y el cierre del conducto arterioso se encontraron diferencias estadísticamente significativas, así: Chi-cuadrado de Pearson: 12,024; p= 0,001.

Tabla 8.Distribución de casos según la duración de tratamiento con paracetamol y cierre del conducto arterioso, Hospital Carlos Andrade Marín, octubre 2014- 2016 Duración de tratamiento Cierre del conducto arterioso Total Si No

3 Días

Numero

159

31

190

Porcentaje

83,7

16,3

95

6 Días

Numero

4

6

10

Porcentaje 40

60

5

Total Numero

163

37

200

Porcentaje 81,5

18,5

100

Chi-cuadrado de Pearson= 12,024 Valor de P=0,001 Fuente: Historias Clínicas, sistema AS400 Hospital Carlos Andrade Marín Elaboración: MD. Myriam Jhesica Curichumbi Guacho

Análisis e interpretación: Los prematuros que iniciaron el tratamiento farmacológico entre los 4 a 6 días de vida fueron los que tuvieron mayor cierre del conducto arterioso. Al establecer la relación que existe entre la edad de inicio del tratamiento y el cierre del conducto arterioso no se encontraron diferencias estadísticamente significativas, así: Chi-cuadrado de Pearson: 0,565; p= 0,754.

Análisis e interpretación: Los recién nacidos prematuros con persistencia del conducto arterioso que recibieron paracetamol como Tabla 9.Distribución de casos según la edad de inicio de tratamiento con paracetamol y cierre de conducto arterioso, Hospital Carlos Andrade Marín, octubre 2014- 2016 Edad de inicio de tratamiento Cierre de conducto arterioso Total Si No

4 a 6 Días

Numero

96

20

116

Porcentaje 82,8

17,2

58

1 a 3 Días

Numero

66

17

83

Porcentaje 79,5

20,5

41,5

7 a 9 Días

Numero

1

0

1

Porcentaje 100

0

0,5

Total Numero 163

37

200

Porcentaje 81,5

18,5

100

Chi-cuadrado de Pearson= 0,565 Valor de P= 0,754 Fuente: Historias Clínicas, sistema AS400 Hospital Carlos Andrade Marín Elaboración: MD. Myriam Jhesica Curichumbi Guacho Tabla 10. Distribución de casos según prevalencia de la persistencia del conducto arterioso en prematuros tratados con paracetamol, Hospital Carlos Andrade Marín, octubre

2014- 2016

Cierre de conducto arterioso Frecuencia Porcentaje Si No

163

37

81,5

18,5

Total

200

100,0

Fuente: Historias Clínicas, sistema AS400 Hospital Carlos Andrade Marín Elaboración: MD. Myriam Jhesica Curichumbi Guacho

tratamiento farmacológico para su cierre, el 81,5% (163) tuvieron un cierre exitoso y el 18,5% (37) cierre fallido.

CAPÍTULO VI

6. DISCUSIÓN

Factores de riesgo que predisponen a la persistencia del conducto arterioso.

Este estudio se realizó en el servicio de cuidados intensivos neonatales del Hospital Carlos Andrade Marín con una muestra de 200 pacientes, encontrándose que 113 pacientes corresponden al sexo femenino y 87 al sexo masculino.

Existen múltiples factores de riesgo asociados a la persistencia del conducto arterioso y en esta investigación se detallan algunos de ellos. En relación al género entre masculino y femenino los resultados obtenidos indicaron que el sexo femenino es predominante con el 56,5% (113) frente el sexo masculino con un 43,5% (87), relación mencionada por Miranda R. et al. 9, en donde se reporta que existe mayor relación con el sexo femenino, con una relación de 2:1, lo cual coincide con este estudio. La edad gestacional también es un factor influyente en la persistencia del conducto arterioso, siendo este inversamente proporcional a la edad gestacional, así en este estudio se encontró que los recién nacidos prematuros extremos fueron los de mayor prevalencia con el 52,5% (105), seguidos por los recién nacidos prematuros muy prematuros con el 47,5% (95), resultados de esta investigación son similares a los encontrados por otros autores, Benitz W 4, sostiene que existe persistencia del conducto arterioso en el 10% de los prematuros entre las 30 y 37 semanas de gestación, 80% entre las 25 y 28 semanas de gestación y el 90% a las 24 semanas de gestación. Valerio E. et al.15, indican que en su estudio de

196 recién nacidos entre 23 y 32 semanas de gestación, 102 (52%)

fueron positivos en el cribado de ultrasonido para persistencia del conducto arterioso. Al igual que según Sivanandan S.et al.16, sostienen que en prematuros menos de 100 gramos y menos de 29 semanas hay una incidencia del 70%. Así mismo Ávila R. et al. 17, mencionaron en su estudio que se observó 45 a 55% de prematuros menores de 29 semanas afectados con persistencia del conducto arterioso. En otro estudio de Polania M. et al.7, también hubo predominio de neonatos prematuros, 175 (88.5%). De ellos, hubo un 23.5% de neonatos extremadamente pre término.

Con respecto al peso se observó que existe un predominio de peso extremadamente bajo en un 52,5% (105), seguido de peso muy bajo con un 47,5% (95), según el estudio realizado por Carrillo H. et al. 2, con 67 recién nacidos prematuros (52% del total de los ingresos) diagnosticaron persistencia del conducto arterioso en 12 (18%) pacientes. De estos 44% pesaban entre 1000 a 1500 gramos datos que se contraponen a este estudio, en tanto que Silvero R. et al. 1, en su trabajo indican que de un total de 1972 niños estudiados de hasta 1500 gramos presentaron una incidencia de 42% (826) de persistencia del conducto arterioso, en el Grupo 1 (21 a 29 semanas) tuvieron un promedio de peso de 953.15 gramos que se considera peso extremadamente bajo, en ellos se encontró una incidencia del 51,06%, la cual fue mucho mayor al Grupo 2 (30 a 28 semanas) con un promedio de peso 1287.25 gramos y una incidencia de 28,24% datos que se asemejan al presente estudio. Dentro de otros factores de riesgo se observó la presencia de afecciones maternas tales como la infección de vías urinarias en el 10% (20), seguido de diabetes gestacional con un 6% (12) y de antecedentes familiares con persistencia del conducto arterioso en el 1,5% (3), relación mencionada por Arias l. et al. 6, que indican que son factores asociados las infecciones maternas y diabetes gestacional al igual que los antecedentes de familiares con persistencia del conducto arterioso, sin embargo Polania M.

et al. 7, menciona que existen algunos factores de riesgo para PCA en recién nacidos pretérmino como son la exposición prenatal a sulfato de magnesio, diabetes materna, hemorragia preparto y embarazo múltiple, y la altitud ya que a mayor altitud se requiere mayor concentración de oxígeno, datos que no se relacionan con este estudio, aunque cabe mencionar que no fueron estudios exclusivos para detectar factores de riesgo asociados. Martínez-Roque A. et al. 12, encontraron dentro del estudio de los antecedentes prenatales, diabetes gestacional y obesidad materna en el 10%, preeclampsia en el 35%, procesos febriles maternos en el 40% de los casos y el 10%con toxicomanías (alcohol y tabaco). Enfermedades asociadas a la persistencia del conducto arterioso Es evidente que se pueden encontrar múltiples enfermedades asociadas a la persistencia del conducto arterioso, entre las cuales mencionaremos algunas de ellas.

Se observó que el 88,5% (177) de los pacientes estudiados no presentaron ninguna enfermedad asociada, seguidos del 3,5% (7) enterocolitis necrotizante, el 3,0% (6) falla renal, el 2,5% (5) hemorragia cerebral, el 1,5% (3) muerte y el 1,0% (2) hemorragia pulmonar. Sin embargo otros estudios como en el de Ávila R. et al. 17, mencionan que la persistencia del conducto arterioso sintomático puede prolongar los requerimientos de oxígeno o permanecer más tiempo en ventilación mecánica, provocar hemorragia pulmonar y broncodisplasia pulmonar. Al igual que Tofé Valera I. et al.10, mencionan en su estudio que si existen comorbilidades severas asociadas, como enterocolitis necrotizante, enfermedad pulmonar crónica, hemorragia pulmonar, hemorragia intraventricular, de igual forma Carrillo H. et al. 2, señalan que en su trabajo realizado con 67 recién nacidos prematuros de los cuales el 18% fueron diagnosticados de persistencia del conducto arterioso, los diagnósticos más frecuentemente asociados fueron síndrome de dificultad respiratoria por déficit de surfactante en cuatro (44%) pacientes, neumonía en 8 pacientes (89%), enterocolitis necrotizante en 2 (22%)

pacientes y sepsis neonatal temprana en nueve (100%) pacientes, datos que no se correlacionan con lo encontrado en este estudio sin embargo estas enfermedades se relacionan con una alta mortalidad. Edad de inicio de tratamiento con paracetamol y cierre de conducto arterioso Con respecto a la edad de inicio de tratamiento se observó que el 58% (116) iniciaron a los 4 a 6 días, el 41,5% (83) de 1 a 3 días, el 0,5% (1) de

7 a 9 días de edad. Los prematuros que iniciaron el tratamiento

farmacológico entre los 4 a 6 días de vida fueron los que tuvieron mayor cierre del conducto arterioso con un 82,8% (96), seguido del 79,5% (66) de los prematuros de 1 a 3 días de edad. Al establecer la relación que existe entre la edad de inicio del tratamiento y el cierre del conducto arterioso no se encontraron diferencias estadísticamente significativas, así: Chi-cuadrado de Pearson: 0,565; p= 0,754. Y es así que según Tofé I. et al. 10, en su estudio que se realizó cierre farmacológico en tres recién nacidos prematuros, el primero diagnosticado a los cinco días de vida, el segundo a los 14 días de vida y el tercero a los 2 días de vida en los que se detectó cierre exitoso a las 48 horas del tratamiento, datos que se correlacionan con este estudio. De igual forma Peña R. et al.3, menciona en su estudio realizado en 10 recién nacidos prematuros entre 30 a 36 semanas de gestación con persistencia del conducto arterioso hemodinámicamente significativo en sus 10 primeros días de vida, de los cuales se obtuvo una tasa de éxito final del 70 % datos que son similares a los de este estudio.

Duración de tratamiento con paracetamol y cierre del conducto arterioso.

Sobre la duración del tratamiento se observó en este estudio que en su mayoría fue de tres días con un 95% (190), seguido del 5,0% (10) de seis días de duración. Los recién nacidos con tratamiento farmacológico de

tres días de duración fueron los que tuvieron mayor cierre del conducto

arterioso con el 83,7% (159).Al establecer la relación que existe entre la duración del tratamiento y el cierre del conducto arterioso se encontraron diferencias estadísticamente significativas, así: Chi-cuadrado de Pearson: 12,024;p= 0,001. Carrillo H. et al. 2, reportaron 9 prematuros con edades gestacional entre 30-36 semanas se les administró paracetamol intravenoso a 15 miligramos/kilo/ dosis cada 6 horas durante 3 días logrando un cierre completo en el 89% (8). Al igual que Yurttutan S. et al.18, reporta que en neonatos de 26-32 semanas de gestación, 920- 1,600grs con criterios ecográficos de conducto arterioso ofreció paracetamol vía oral en seis pacientes, 15mg/kg/ dosis cada 6 h por 3 días con ecocardiograma al final del tratamiento y dos días posterior al mismo, reportó éxito en cinco de los seis pacientes. Hammerman C. et al.19, en su trabajo presentaron la primera serie de casos de recién nacidos prematuros y observaron que la administración oral de paracetamol durante un periodo de 3 días a una dosis de 60 mg/kg/4 veces al día era eficaz para alcanzar un cierre del conducto arterioso, por lo que con los resultados obtenidos hacemos énfasis que con un primer ciclo de paracetamol existe alta probabilidad de cierre exitoso. Persistencia del conducto arterioso en prematuros tratados con paracetamol Con respecto al cierre del conducto arterioso en prematuros previamente tratados con paracetamol, se observó un cierre exitoso en el 81,5% (163)y cierre fallido en el 18,5% (37). Carrillo H. et al. 2, en su trabajo refiere que la frecuencia de cierre del conducto arterioso fue del 89%, similar a la obtenida por Hammerman C. et al. 19, quienes describieron una frecuencia de cierre con paracetamol oral en el 100% de los casos. En tanto que Oncel M. et al. 20, refiere que el paracetamol dio lugar al cierre de PCA en el 87,5%. En estudios con paracetamol intravenoso efectuados por Serafettin T. et al. 21, indican un cierre del conducto arterioso en el 100% de casos.

De igual forma Peña R. et al.3, refiere que el primer fármaco empleado con este fin fue la indometacina, con una tasa de éxito del 70% y reapertura del 35%; sin embargo, por su elevado coste se han buscado otras opciones, como el ibuprofeno; pero estas no son inocuas y se asocian con reducción de la perfusión renal, mesentérica y cerebral, además, e indica que hasta el momento el cierre farmacológico del conducto arterioso con paracetamol tiene un éxito similar al de otros antiinflamatorios no esteroideos, con un porcentaje del 70%. Otro estudio, realizado por Jones L. et al.22, compara la indometacina frente al ibuprofeno para el conducto arterioso permeable hemodinámicamente significativo en pacientes prematuros, y señala una efectividad de esta del 70% en un primer ciclo y un 60% cuando requieren un segundo ciclo; con el ibuprofeno se ha observado una tasa de cierre del 75% y con segundo ciclo del 55%. En el estudio realizado por Ozmert M.et al.23, se registró una tasa de éxito del 71,4% con el empleo de paracetamol. El presente estudio reafirma que el paracetamol puede ser una excelente alternativa ya que presenta tasa de eficacia superior al 70% similar a la descrita en los estudios mencionados.

Con respecto a la dosis usada fue de 15 miligramos/kilo/dosis cada 6 horas, vía intravenosa en el total de los pacientes, al igual como menciona Carrillo H. et al.2, en su estudio se reportaron 9 prematuros con edades gestacionales entre 30-36 semanas peso promedio de 1.509 gramos se administró paracetamol intravenoso en dosis de 15 mg/kg/día cada 6 horas, lográndose cierre del conducto arterioso hemodinámicamente significativo, corroborado por ecografía, en el 89% de los casos sin reportar reacciones adversas, al igual que aclara en su estudio que una ventaja adicional es que el paracetamol intravenoso pudo administrarse en pacientes sin posibilidad de recibir medicación vía oral, como los que tuvieron enterocolitis necrotizante o que no tenían un volumen significativo de la misma. Araújo J. et al.14, menciona que se optó por cierre farmacológico con paracetamol intravenoso a 15 mg/kg una dosis cada 6

horas con control eco cardiográfico cada 24 horas, corroboró el cierre total del conducto arterioso a los 3, 5 y 7 días de tratamiento, respectivamente. No se observaron efectos adversos a corto plazo relacionados con la administración del paracetamol en la totalidad de los casos. Khuffash A. et al. 24, en su estudio reportaron 80 pacientes prematuros, a quienes se les administró paracetamol vía oral versus ibuprofeno vía oral con menor incidencia de hemorragia gastrointestinal e hiperbilirrubinemia en el grupo de paracetamol. Carrillo H. et al. 2, en su estudio reporta que no encontraron ninguna reacción adversa a la administración de paracetamol intravenoso lo que constituye una ventaja adicional en comparación con los fármacos que actualmente se utilizan para su tratamiento. De la misma forma Peña R. et al. 3, en su estudio señala que hay aparente inocuidad del paracetamol intravenoso ya que no se documentaron complicaciones a corto y medio plazo, datos que se asemejan a este estudio.

CAPÍTULO VII

7. CONCLUSIONES Y RECOMENDACIONES

7.1. CONCLUSIONES

-

A menor edad gestacional y menor peso al nacimiento en los recién nacidos prematuros, se produce un incremento en la aparición de persistencia del conducto arterioso.

-

Existen alternativas farmacológicas, distintas a los tratamientos clásicos utilizados actualmente (antiinflamatorios no esteroideos) que pueden ser utilizados con seguridad en pacientes prematuros inestables, con contraindicaciones absolutas o relativas para el cierre farmacológico clásico o quirúrgico.

7.2. RECOMENDACIONES

-

Garantizar controles prenatales adecuados a todas las mujeres embarazadas, para prevenir partos pretérmino y sus comorbilidades.

-

Implantar y actualizar continuamente protocolos con evidencia científica sobre el uso del paracetamol como terapia electiva para el cierre farmacológico del conducto arterioso.

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in newborn child less than 1500 grams and in the persistence of ductus arteriosus. AnFac Cienc Méd (Asunción). 2012;45(2):39-48.

2. Carrillo H, Valencia J, Oliveros L. Eficacia del paracetamol

intravenoso para el cierre del conducto arterioso en recién nacidos prematuros. Acta Pediatrica Mexicana. Ac Ped Mex. 2015;36(1):18-

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Cierre de conducto arterioso con paracetamol: estudio piloto. Rev Esp Cardiol. 2015;68(5):441-442.

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Romagnoli C et al. Efficacy and safety of intravenous paracetamol in comparison to ibuprofen for the treatment of patent ductus arteriosus in preterm infants: study protocol for a randomized control trial. Bio med central. Trials 2016;17(182):1-13.

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Arias l, Benitéz Z, Jauregy O, Peralta M, Miranda R. Persistencia de Conducto Arterioso en niños, adolescentes y adultos. GPC Mex 2010;380:1-57.

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ecocardiográfico de persistencia del conducto arterioso en recién nacidos hospitalizados en la Unidad de Cuidados Intensivos Neonatales. An Med (Mex) 2015; 60(3):185-190.

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Guía de práctica clínica Persistencia del conducto arterioso. Rev

Med Inst Mex Seguro Soc 2012;50(4):453-463.

10. Tofé I, Jaraba M, Ruiz M, Rodríguez M, Parraga M. Papel del

paracetamol en el cierre del conducto arterioso permeable. ¿Una alternativa?. Rev Esp Cardiol 2016;69(11):1103-1115.

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12. Martínez-Roque A, Valle J, Martínez A, Álvarez-Bastidas

L.Repercusión hemodinámica en pacientes neonatos con conducto arterioso persistente:factores asociados. Arch Cardiol Mex. 2016. Disponible en: http://dx.doi.org/10.1016/j.acmx.2016.05.008.

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C, Goldsmita G, Lemusa L, Miuraa E, Pellicera A, Péreza J. et al. Primer consenso clínico de SIBEN: enfoque diagnóstico y terapéutico del ductus arterioso permeable en recién nacidos pretérmino.An Pediatr (Barc) 2008;69(5):454-81.

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Araújo J, Echeverry M, Palacio A, Lema A, Lema A, Fernández M. Acetaminofén intravenoso en el cierre del conducto arterioso permeable en prematuros. Rev Colomb Cardiol 2016;12(2):1-5.

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PDA closure in the preterm: a single-center experience. Eur J Pediatr 2016; 16(9):1-14.

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DuctusArteriosus: Selecting the Agent and Route of Administration. Pediatr Drugs 2016;165(5):1-16.

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conducto arterioso con paracetamol. Pediatr Mex 2013;15(4): 14-18.

18. Yurttutan S, Yekta M, Arayici S, Uras N, Altug N, Erdeve O,

DilmenUgur. A different first-choice drug in the medical management of patent ductus arteriosus: oral paracetamol. J Matern Fetal Neonatal Med2013; 26(8): 825–827.

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ductus arteriosus in premature infants: a chance before surgical ligation. Pediatr Cardiol. 2014; 35:276-9.

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Anexo 1. Hoja de recolección de datos.

UNIVERSIDAD CENTRAL DEL ECUADOR

INSTITUTO SUPERIOR DE INVESTIGACIÒN Y POSTGRADO

POSTGRADO EN PEDIATRÍA

HOJA DE RECOLECCIÓN DE DATOS

HOSPITAL CARLOS ANDRADE MARÍN

PERSISTENCIA DEL CONDUCTO ARTERIOSO

SEXO

MASCULINO

FEMENINO

PESO

AL

NACIMIENTO

Recién nacido de bajo peso al nacer Recién nacido de muy bajo peso al nacer:

Recién nacido de peso extremadamente bajo al nacer:

Especifique <

2500

gr y >1500 gr < 1500 gr y >

1000 gr

< 1000 gr

Factores de riesgo Prematuridad Bajo peso malformaciones Antecedentes familiares Otros

COMPLICACIONES POR PERSISTENCIA DEL CONDUCTO ARTERIOSO

Hemorragia cerebral Hemorragia pulmonar Enterocolitis necrotizante Fallo renal Muerte Otros

EDAD AL INICIO DEL TRATAMIENTO CON PARACETAMOL

1 – 3 días

4 – 6 días

7 - 9 días

Más de 10 días

FORMA DE ADMINISTRACION DEL PARACETAMOL

ORAL

INTRAVENOSO

DOSIS DEL TRAMIENTO Y FRECUENCIA

DOSIS

FRECUENCIA

DURACIÓN DEL TRATAMIENTO CON PARACETAMOL

3 días

6 días

Más de 6 días

EFECTOS ADVERSOS DEL TRATAMIENTO CON PARACETAMOL

ESPECIFIQUE

CIERRE DE CONDUCTO ARTERIOSO

ESPECIFIQUE

Elaborado por: Md. Jhesica Curichumbi Fecha: Octubre del 2016

Anexo 2 Formulario de Evaluación de Trabajos de Titulación.

Anexo 3. Declaración de Confidencialidad

UNIVERSIDAD CENTRAL DEL ECUADOR

INSTITUTO SUPERIOR DE POSTGRADO

POSTGRADO EN PEDIATRÍA

TEMA DE INVESTIGACIÓN:

PREVALENCIA DE LA PERSISTENCIA DEL CONDUCTO ARTERIOSO

EN PREMATUROS TRATADOS CON PARACETAMOL. HOSPITAL

CARLOS ANDRADE MARÌN OCTUBRE 2014-2016

AUTOR:

Médico Myriam Jhesica Curichumbi Guacho

DESCRIPCIÓN:

Este estudio será descriptivo de corte transversal, por cuanto se realizará en un determinado período de tiempo y se efectuarán algunas asociaciones. La población de este estudio, serán los prematuros con diagnóstico de persistencia del conducto arterioso hospitalizados en la Unidad de Cuidados Intensivos Neonatales en el Hospital Carlos Andrade Marín de la ciudad de Quito, en el período de octubre de 2014 a octubre de 2016, la información será registrada en la hoja de recolección de datos destinada para el efecto.

PROPOSITO DE ESTA INVESTIGACIÓN:

Establecer cuál es la prevalencia de la persistencia del conducto arterioso en prematuros tratados con paracetamol, hospitalizados en la Unidad de Cuidados Intensivos Neonatales en el Hospital Carlos Andrade Marín de la ciudad de Quito, en el período de octubre de 2014 a octubre de 2016.

BENEFICIOS Y RIESGOS DE LA INVESTIGACIÓN:

Identificar los factores de riesgo que predisponen a la persistencia del conducto arterioso. Determinar las enfermedades asociadas a la persistencia del conducto arterioso. Conocer las dosis, días de tratamiento, inicio del tratamiento, forma de administración y posibles efectos adversos del paracetamol mediante revisión de historias clínicas. La presente investigación no implica ningún riesgo para los participantes puesto que se trata de un estudio descriptivo transversal.

CONFIDENCIALIDAD:

Toda información obtenida de los pacientes participantes será mantenida con absoluta confidencialidad por parte de la investigadora. Los datos de esta investigación serán utilizados exclusivamente para garantizar la veracidad de los mismos, y de estos tendrán acceso solamente los investigadores y los organismos de evaluación de la Universidad Central del Ecuador.

DERECHOS:

La realización de la presente investigación, no proporciona ningún derecho a los investigadores, a excepción del estrictamente académico. Además, soy consciente de las implicaciones legales de la utilización de los datos, información y resultados recolectados o producidos por esta investigación con cualquier otra finalidad, que no se a la estrictamente académica y sin el consentimiento informado del o los pacientes y sus padres o representantes legales.

Anexo 4.Aprobación del Protocolo del Trabajo de Titulación de los Tutores y Coordinador del Postgrado.

Anexo 6. Certificado de Aprobación Hospitalaria

Anexo7. Hoja de Verificación en el Repositorio Institucional

Anexo8. Certificado de aprobación del Protocolo de Investigación

Iran J Pediatr. 2016 August; 26(4):e3975.

Published online 2016 May 15.

doi: 10.5812/ijp.3975.

Research Article Comparison of Oral Acetaminophen Versus Ibuprofen in Premature Infants With Patent Ductus Arteriosus Mohammad Mehdi Bagheri,1 Pedram Niknafs,1 Fatemeh Sabsevari,1,* Mohammad Hosein Torabi,1 Bahareh Bahman Bijari,1 Elahe Noroozi,1 and Hamid Mossavi1 1Afzalipour Medical Center, Kerman University of Medical Sciences, Kerman, IR Iran *Corresponding author: Fatemeh Sabsevari, Afzalipour Medical Center, Kerman University of Medical Sciences, Kerman, IR Iran. Tel: +98-9131951947, E-mail: fasabzvari@gmail.com Received 2015 October 30; Revised 2016 January 28; Accepted 2016 February 05. Abstract Background: Patent ductus arteriosus (PDA) is a common cause of morbidity. The aim of this study was to compare the efficacy of oral Acetaminophen and oral Ibuprofen for the closure of patent ductus arteriosus (PDA) in preterm infants. Objectives: This study demonstrated that, there was no significant difference between treatment of PDA with either oral Acetaminophen or oral Ibuprofen in preterm neonates. Patients and Methods: This clinical trial, randomized study, enrolled 120 infants, with a gestational age of < 37 weeks, who were admitted in neonatal intensive care unit of Afzalipour hospital, Kerman, Iran, in 2014. PDA was confirmed echocardiographically. The trial was registered in Iranian registry of clinical trials (Reg. No. 25542). Sixty-seven infants received oral Acetaminophen (15mg/kg every six hours for three days) and 62 infants received Ibuprofen (an initial dose of 20 mg/kg, followed by 10 mg/kg at 24 and 48 hours). To evaluate the efficacy of the treatment, a second echocardiography was done after completing the treatment. Results: After the first course of the treatment, PDA closed in 55 (82.1 %) patients who received oral Acetaminophen vs. 47 (75.8 %) of those given oral Ibuprofen (P = 0.38). After the second course of treatment, PDA closed in 50 % of oral Acetaminophen group and 73.3% of oral Ibuprofen group (P = 0.21).

Conclusions: This study demonstrated that, there was no significant difference between treatment of PDA with either oral Acetaminophen or oral Ibuprofen in preterm neonates. Oral Ibuprofen can effectively close PDA but is unfortunately associated with some adverse effects limiting its utility thus we studied an alternative drug with similar efficacy and less adverse effects. This study has recommends Acetaminophen with minimal complications for the treatment of PDA in preterm neonates instead of Ibuprofen. Keywords: Patent Ductus Arteriosus (PDA), Neonatal Intensive Care Unit (NICU), Acetaminophen, Ibuprofen, Echocardiography

1. Background

Patent ductus arteriosus (PDA) is common amongst preterm infants with an incidence of 30% in very low birth weight infants (Bwt < 1500 g) (1) and 50 % in extremely low birth weight ones (Bwt < 1000 g) (2).

Subsequently, prolonged ductal patency in preterm infants was linked to more severe respiratory distress syndrome (RDS), prolonged assisted ventilation, pulmonary hemorrhage, bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), renal impairment, intraventriculur-hemorrhage (IVH), periventricular leukomalacia (PVL), cerebral palsy, and death (3). Taking these aforementioned associations into consideration, appreciation of the hemodynamic effects of a large left-to-right shunt through the ductus, and certain morbidities caused by excessive blood flow in the lungs or ischemia elsewhere led many practitioners to adopt strategies for closing the ductus.

Currently, the first choice of treatment for PDA is medical, primarily Indomethacin and Ibuprofen. These drugs are cyclooxygenase inhibitors, blocking the conversion of arachidonic acid to prostaglandins (4).

The treatment success with Ibuprofen for the management of PDA was reported between 70% - 85% (5). The adverse effects such as peripheral vasoconstriction, gastrointestinal bleeding and perforation, decreased platelet aggregation, hyperbilirubinemia, and renal failure havebeen reported withcyclooxygenase inhibitors (6). Acetaminophen acts by inhibiting the activity of prostaglandin synthase at the peroxidase region of the enzyme (7).

Recent studies have shown that Acetaminophen can be used to treat PDA in preterm infants with good efficacy and a few side effects, unlike cyclooxygenase inhibitors (8). When drug treatment fails or is contraindicated, clinicians may resort to surgical intervention although the risk of operation in preterm infants is high.

Copyright © 2016, Growth & Development Research Center. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited.

Bagheri MM et al.

To determine whether oral Acetaminophen may be used as the first line or an alternative drug for PDA in preterm infants, we conducted a randomized trial to compare its efficacy and safety level to those of Ibuprofen.

2. Objectives

This study demonstrated that, there was no significant difference between treatment of PDA with either oral Acetaminophen or oral Ibuprofen in preterm neonates.

3. Patients and Methods

Thestudywasperformedintheneonatalintensivecare unit (NICU) of Afzalipour medical center, Kerman, Iran between July and November, 2014.

This trial was approved by the ethics committee, and infants were enrolled in the study after parental consent was obtained.

The enrollment criteria included a gestational age of under 37 weeks, a postnatal age of less or equal to fourteendaysandanechocardiographicallydiagnosedPDAfollowing an echocardiographic detection of a duct size more than1.5mmandaleftatriumtoaortaratioof morethan1.2. The exclusion criteria were as follow: 1, a major congenital heart disease; 2, confirmed sepsis; 3, intraventricular hemorrhage grade > II (IVH on the basis of Volpe staging); 4, platelet count < 50000/mm3; 5, severe coagulopathy or liver dysfunction; 6, the presence of major congenital or chromosomal abnormalities; 7, severe asphyxia at birth (Apgar score less than 5 in minute five or pH < 7 in ABG); 8, necrotizing enterocolitis (NEC on the basis of Bell staging); 9, tendency to bleeding as revealed by hematuria, blood in the endotracheal or gastric aspirate or stools, or oozing from puncture sites; 10, urine output < 1 mL/kg/hour or serum creatinine > 1/6 mg/dL; 11, retionpathy of prematurity.

Before and after treatment, all patients were evaluated with complete blood count, serum creatinine, blood urea nitrogen, urine output, bilirubin levels, cranial ultrasonography and two-dimensional color Doppler echocardiography using a 4MH2 transducer (model: MEDISON AC- CUVIlXV 100, South Korea).

The participants were randomly assigned at a 1: 1 ratio between oral Acetaminophen and Ibuprofen groups by using cards. Doctors and nurses were not blind but a pediatric cardiologist in charge of the patients was blinded to the treatment.

Infants received oral Acetaminophen (Acetaminophen suspension, Hakim, 5 mL :120 mg) at the dose of 15 mg/kg every 6 hours for 3 days or oral Ibuprofen (Ibuprofen suspension, Exir 5 mL: 100 mg) at the initial dose of 20 mg/kg followed by 10 mg/kg after 24 and 48 hours. Both Acetaminophen and Ibuprofen were administered via an orogastric-tube, which was flushed with 1 - 2 mL of sterile water to ensure delivery of the drug. Minimal enteral feeding was attempted for all infants from the second day of life, and patients continued their current enteral feeding regimen during the study. At the beginning of the study, daily oral intake ranged between 10 and 60 mL/kg for patients in both groups. For all infants enrolled in the study, fluid intake was started at 60 - 80 mL/kg/day, consistently for three days and after that, it was increased by increments of 20 mL/kg/day, to a maximum of 150 mL/kg/day.

During the treatment, drug safety factors were assessed daily. If birth weight was less than 2 kg an eye examination was conducted 4 weeks after birth. Occurrence of any exclusion criteria would prompt stopping of treatment.

The success rate was defined as a closed duct on echocardiographyafterthecompletecourseof bothdrugs. Secondaryoutcomeswerethesafetyof bothdrugs, and adverse events (e.g. oliguria, IVH, tendency to bleeding, NEC, death).

3.1. Statistical Analyses

A study group of at least 57 patients was needed for the study to facilitate detecting a difference of at least 25 percentage points in the closure rate between the oral Acetaminophen and Ibuprofen groups, assuming a closure rate of 85% with oral Ibuprofen with a P = 0.05 and a power of 50%. Thestudywouldbeterminatedif adifferenceof 25% in the main outcome was found.

Continuous data were given as mean (SD). Differences betweenthegroupsweredeterminedbyt-testforparametric continuous data, or Fisher’s exact test for categorical data.

A new drug is considered at least as effective as the known drug if P < 0.05 of the difference between the two groups. SPSS software (version 20) was used for all statistical analyses.

4. Results

Among 160 patients enrolled in our study which had significant PDA with inclusion criteria, finally 31 patients wereexcluded. ThestudyflowchartisdemonstratedinFigure 1.

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Iran J Pediatr. 2016; 26(4):e3975.

Bagheri MM et al.

160 Preterm Infants with Significant PDA

1 Died

Before Completed Treatment

9 Died

Before Completed Treatment Treatment Treatment Exclusion Criteria Exclusion Criteria Oral Acetaminophen (N = 67) Oral Ibuprofen (N = 71) IVH Grade IV (2) Died (2) Oral Ibuprofen (N = 62) Oral Acetaminophen (N = 79) IVH Grade III (1) Sepsis (1) Rop (1) Died (9) Figure 1. Study Flow Chart No significant difference was observed clinically between the two groups in baseline. The clinically characteristic findings of the preterm infants are summarized in Table 1.

After the first course of treatment, PDA was completely closed in 55 (82.1%) infants of the Acetaminophen group compared with 47 (75.8%) of the Ibuprofen group and there was no significant difference between the two treatments (P = 0.381). In oral Ibuprofen group, fifteen (24.2 %) patients required a second course of drug therapy compared with twelve (17.9%) patients in the oral Acetaminophen group. After the second course of the drugs, closure rates were 50% (six of twelve patients) in the Acetaminophen group compared with 73.3 % (eleven of seventeen patients) in the Ibuprofen group, and there was no significant difference between them (P = 0.212).

Finally, closure rates after the two courses of treatment were 91% in the oral Acetaminophen group and 90.3% in the oral Ibuprofen group (Table 2).

Table 1. Clinical Characteristica Characteristics Acetaminophen Ibuprofen P Value Gestational age, wk

31.53 (2.31)

31.7 (2.24)

0.69

Age, d

2.85 (1.28)

3.42 (2.12)

0.098

Birth weight, Kg

1646.26 (59.14)

1642.62 (58.46)

0.965

Gender, No. (%) Female

31 (46.3)

29 (46.8)

0.954

Male

36 (53.7)

33 (53.2)

-

Normal vaginal delivery (NVD), No. (%)

20 (30.3)

15 (24.2)

0.438

Respiratory score, unit

5.28 (2.04)

5.22 (1.75)

0.864

Surfactante, No. (%)

37 (55.2)

29 (46.8)

0.337

aValues are expressed as mean (SD) unless otherwise indicated.

5. Discussion

Ductal constrict was stimulated by the rapid postnatal increase in arterial oxygen tension and a decrease in va- Iran J Pediatr. 2016; 26(4):e3975.

Bagheri MM et al.

Table 2. Outcomes According to Each Treatmenta Acetaminophenb Ibuprofenc P Value PDA closure rate after the first course

55 (82.1)

45 (75.8)

0.381

PDA closure rate after the second course

6 (50)

11 (73.3)

0.212

Total PDA closure rate

61 (91)

56 (90.3)

0.885

aValues are expressed as No. (%).

bn = 67.

cn = 62.

sodilators including prostaglandin E2 (9). Prostaglandin synthetase has two different activities including cyclooxygenase and peroxidase. Acetaminophen inhibits prostaglandin synthesis at the peroxides’ segment (7) while Ibuprofen is cyclooxygenase inhibitor (10).

Some studies have been conducted on Acetaminophen treatment of PDA in preterm infants when Ibuprofen was not effective or contraindicated.

Hammerman et al. for the first time, showed that oral Acetaminophen was effective in five patients with large, hemodynamically significant PDA, that either failed or had contraindications to Ibuprofen therapy. Ductal closure was achieved in all treated infants (8). Alsoaseriesof eightpretermneonates, treatedwithAcetaminophen for a significant PDA because of contraindications to Ibuprofen were reported by Terrin (11). Acetaminophen as the first choice of treatment of PDA was used in six preterm infants, five infants were successfully treated (12).

Ibuprofen and Acetaminophen was compared in two clinical trials. The trial conducted by Oncel et al. compared the efficacy and safety of oral Acetaminophen and oral Ibuprofen for the closure of PDA in 90 preterm infants with a gestational age less than or equal to thirty weeks of gestation. After the first course of treatment, PDA closed in

77.5 % (31 of 45 patients) of the infants assigned to the oral

Ibuprofen group vs. 72.5% (29 of 45 patients) in the oral Acetaminophen group (P = 0.6) (13).

The second study was done by Dang et al. comparing oral Acetaminophen with Ibuprofen in treatment of 160 preterm PDA infants. The results demonstrated no significant difference between Acetaminophen and Ibuprofen

(14).

Recent Small case series have suggested that acetaminophen may be an alternative cyclooxygenase inhibitor for PDA management, but the role of this agent in management of preterm infants with PDA remains to be determined. As the two aforementioned studies suggested, in order to generalize their conclusions, it is necessary to run randomized analysis from a multiple center. There are only two articles comparing oral Ibuprofen and oral Acetaminophen. The first has been performed in Turkey, enrolling neonates < 30 weeks and a same study done in China on neonates < 34 weeks.

In contrast, we enrolled neonates < 37 weeks. Closure ratesof PDAinOnceletal. trialwere72.5% (Acetaminophen group) and 77.5% (Ibuprofen group) (13). Furthermore, closure rates were 81.2% (Acetaminophen group) and 78.8% (Ibuprofen group) in Dang et al. trial (14). Our findings showed closure rates of 82.1 % (Acetaminophen group) and 75.8 % (Ibuprofen group). We found a similar responsiveness of PDA to both drugs. This finding was compatible to those in Turkey and China trials. Thus, our study supports their results and demonstrated that oral Acetaminophen and Ibuprofen are effective similarly for the closure of PDA with one and two courses of treatment.

In addition, the results clearly show that both drugs are well-tolerated and safe, and have no significant difference regarding the complications (bleeding, especially gastrointestinal bleeding, NEC, IVH, liver or renal dysfunction, ROP and hyperbilirubinemia).

This study had several limitations; firstly, PDA of infants may spontaneously be closed by the time, therefore daily echocardiography and a clinical trial with control group was necessary.

Secondly, the trial was not completely blinded because of the different daily doses of Acetaminophen.

5.1. Conclusion

Oral Ibuprofen can effectively close PDA but is unfortunately associated with some adverse effects limiting its utility thus we studied an alternative drug with similar efficacy and less adverse effects and contraindication. On the basis of identical efficacy of Ibuprofen and Acetaminophen and higher safety of Acetaminophen it is recommended to use Acetaminophen as the drug of first choice.

Although we have demonstrated that Acetaminophen may be utilized as the drug of choice for PDA in preterm infants with good efficacy, further studies are warranted. Footnote Authors’ Contribution: MohammadMehdiBagheri,concept, design and critical revision of the manuscript; Pedram Niknafs, concept, design and critical revision of the manuscript; Fatemeh Sabsevari, acquisition of data, data analysis, data, interpretation and drafting of the

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Bagheri MM et al.

manuscript; Bahareh Bahman Bijari, critical revision of themanuscript; ElaheNoroozi, MohammadHoseinTorabi, design and critical revision of the manuscript; Hamid Mossavi, critical revision of the manuscript.

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Fink D. Ductal closure with paracetamol: a surprising new approach to patent ductus arteriosus treatment. Pediatrics. 2011;128(6):e1618–21.

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Mehdizadegan N. High-Dose Oral Ibuprofen in Treatment of Patent Ductus Arteriosus in Full-Term Neonates. J Pediatr. 2015;25(4):e2005. .

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Clinical Report Oral paracetamol versus oral ibuprofen for treatment of patent ductus arteriosus Manar Al-lawama, Iyad Alammori, Tariq Abdelghani and Eman Badran Abstract Objective: This study was performed to investigate the safety and efficacy of oral paracetamol versus oral ibuprofen in the treatment of patent ductus arteriosus (PDA) in premature infants. Methods: Premature infants with PDA with a gestational age of
32 weeks or birth weight of
1500 g were included in this randomized study. Results: A total of 120 premature infants fulfilled the inclusion criteria. Of these 120 infants, 34 fulfilled the treatment criteria and 22 were finally randomized. We found no significant difference in the mortality or primary closure rates between the two groups. We also found no significant difference in the short-term neonatal outcomes. Conclusions: Either oral paracetamol or oral ibuprofen can be used safely and effectively to treat PDA in premature infants. Keywords Premature infants, patent ductus arteriosus, ibuprofen, paracetamol, randomized study, safety Date received: 15 May 2017; accepted: 5 July 2017 Introduction Hemodynamically significant patent ductus arteriosus (hsPDA) is a major risk factor for mortality and morbidity in very-lowbirth-weight infants.1 The standard of care is to treat all cases of hsPDA. The methods of treatment, which medications to use, and treatment timing continue to be subjects of research.2 Intravenous indomethacin and intravenous ibuprofen are both widely used for PDA treatment.3,4 In Jordan, however, as in many other low-resource countries, these two medications are not available.

Studies from these countries Pediatric Department, University of Jordan, Jordan University Hospital, Jordan Corresponding author:

Manar A Al-lawama, Pediatric Department, School of Medicine, University of Jordan, Jordan University Hospital, Queen Rania Street, Amman 11943, Jordan. Emails: Manar-76@hotmail.com; M.allawama@ju.edu.jo Journal of International Medical Research 2018, Vol. 46(2) 811–818 ! The Author(s) 2017 Reprints and permissions:

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have investigated oral preparations of paracetamol5–8 and oral and rectal forms of ibuprofen.9–13 Many studies have shown that oral ibuprofen is both safe and effective in treating PDA.10–13 Furthermore, recent reports on the use of oral paracetamol are promising.5–8 Paracetamol inhibits prostaglandin synthetase activity by acting at the peroxidase segment of the enzyme.14 Peroxidase is activated at a 10-fold lower concentration of peroxide than cyclooxygenase. The peroxide concentration is decreased in certain neonatal morbidities that are accompanied by hypoxemia. Hypothetically, under these conditions paracetamol should be a more effective drug than cyclooxygenase inhibitors.15 Paracetamol is also the only option when a patient has a contraindication for ibuprofen use.16 Oral paracetamol is a safe and readily available medication that is much less expensive than the intravenous preparation.

Few studies have compared the safety and efficacy of oral preparations of ibuprofen and paracetamol in treating PDA.17–19 To help fill this knowledge gap, we conducted the present study to evaluate the incidence of PDA in our population and compare oral ibuprofen and oral paracetamol for the treatment of PDA in premature infants.

Materials and methods This randomized parallel study was conducted in the Neonatal Intensive Care Unit of Jordan University Hospital, Amman, Jordan, from March 2015 to October 2016. The study was approved and funded by the Deanship of Scientific Research at the University of Jordan and is registered in the ISRCTN registry under the number ISRCTN12302923 DOI 10.1186. All procedures performed in this study were in accordance with the ethical standards of and granted ethical approval by the institutional review board of Jordan University Hospital (reference number

108/2014/IRBJ).

The study was performed in accordance with the ethical standards as laid down in the

1964 Declaration of Helsinki and its later

amendments.

Patients’ characteristics All premature infants with a gestational age of
32 weeks or birth weight of
1500 g were included. The exclusion criteria were as follows:

ductal-dependent congenital heart diseases, major congenital malformation, grade 3 to 4 intraventricular hemorrhage, renal impairment (defined as a creatinine concentration of >1.5 mg/dl), pulmonary hemorrhage, thrombocytopenia of <60,000/mm3, and an elevated alanine transaminase concentration. Echocardiography was performed for all included infants from

3 to 5 days of age or when they showed

symptoms of PDA, whichever occurred earlier. PDA was considered hemodynamically significant if two of the following criteria were present: wide pulse pressure (defined as systolic blood pressure diastolic blood pressure of >1=2 systolic blood pressure), reversal of flow in the descending aorta by Doppler echocardiography, left atrial dilatation determined by a left atrial:aortic root ratio of >1.4:1.0 on M-mode echocardiographic evaluation from the parasternal view, or left ventricular dilatation. We did not include the size of the ductus as a criterion because it is relative to the size of the infant. Symptoms of PDA were metabolic acidosis, increased respiratory demands not explained by respiratory distress syndrome or its complications (usually after a period of improvement), decreased urine output, delayed capillary refill, and newly onset persistent mottling.20,21 To fulfill the treatment criteria, infants were required to either demonstrate hsPDA by echocardiography or signs indicating the presence of symptomatic PDA. The parents of newborns who fulfilled

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these criteria were subsequently approached for informed consent. Informed consent was obtained from the parents of all individual participants included in the study. Randomization and treatment protocol The qualifying preterm infants were randomized by computer to receive either oral paracetamol or oral ibuprofen. Randomization numbers were placed inside sequentially numbered opaque envelopes. The following laboratory investigations were conducted within 24 hours before treatment was initiated and within 24 hours after treatment was finished:

complete blood count, platelet count, creatinine, and alanine transaminase. A head ultrasound was also performed before and after treatment. The oral paracetamol group received 10 mg/kg/dose followed by 1 to 2 ml of 0.9% saline every 6 hours for

3 days. Regarding ibuprofen treatment pro-

tocol, previous studies used a loading dose of

10 mg/kg17,18 or 20 mg/kg19 on the first day

and then half of this dose for the first and second days of treatment. We used the same dose for the 3-day course to minimize errors. The oral ibuprofen group received 10 mg/kg/ dose followed by 1 to 2 ml of 0.9% saline once daily for 3 days. Echocardiography was repeated within 24 hours of the last treatment.

Response to treatment was defined as resolution of symptoms with either complete closure of the PDA or a very small hemodynamically insignificant PDA evident by echocardiography. In these cases, echocardiography was repeated before discharge. If no response was found after the first course of treatment, a second course of treatment with the same drug was given for another 3 days. If no response as seen after two courses, a third course of treatment was started using the other drug. If three courses of medical treatment failed, surgery was performed only if the PDA was causing ventilation difficulties. Primary closure was defined as response to treatment after a 3-day course of the assigned drug.

Secondary closure was defined as response to treatment after two courses or a total of 6 days of treatment with the assigned drug. Tertiary closure was defined as response to treatment after switching to the other drug in the trial after failure of two courses of treatment.

During the study period, all infants received the same fluid and enteral feeding protocol. They all started at 80 ml/kg/day, which was increased daily in increments of

20 ml/kg/day. If the PDA required treat-

ment, fluid administration was kept at a maximum of 120 ml/kg/day until the end of the treatment. Feeding was started on day 1 or 2 at 20 ml/kg/day according to the availability of breast milk. It was increased to 20 ml/kg/day, but was not progressively increased during the treatment period.

Statistical analysis SPSS version 21 (IBM Corp., Armonk, NY, USA) was used to conduct the statistical analyses. Numerical data are represented by mean  standard deviation.

Categorical data are represented by their respective rates or proportions. A t-test was used to compare means, and the chisquare test was used to compare proportions. P values of <0.05 were considered statistically significant.

Results In total,

128

premature infants were included. Eight of them died before day 3 of life and did not show signs of PDA. The

120

surviving premature infants were screened, and 22 fulfilled the treatment and randomization criteria as shown in Figure 1. All infants who were screened because of PDA-related symptoms were found to have hsPDA by echocardiography.

Al-lawama et al.

The treatment group was divided into two subgroups:

the paracetamol group and the ibuprofen group. The mean gestational age was 28 weeks in both groups. Apart from a lower Apgar score in the first minute of life in the paracetamol group, there were no statistically significant differences in the demographic characteristics between the two groups (Table 1). The mortality rate was 23% in the paracetamol group and 22% in the ibuprofen group. The primary closure rate was 69% in the paracetamol group and 78% in the ibuprofen group. Other neonatal outcomes are shown in Table 2. A summary of three previously published randomized trials on the present study topic as well as the current study is presented in Table 3. Discussion Only a few studies to date have compared oral paracetamol and oral ibuprofen for the treatment of PDA in premature infants. Prior to the present study, three randomized studies were published.17–19 Although our study examined a relatively lower number of patients, it was conducted using very strict diagnostic and treatment criteria. Echocardiography was performed based on symptoms or age. When infants were asymptomatic, they were screened Assessed for eligibility (n= 128) Excluded (n= 106) ♦Not meeting inclusion criteria (n=94) ♦Declined to participate (n=2) ♦Other reasons (n=10) Analysed (n=13) Lost to follow-up (give reasons) (n= 0) Discontinued intervention (give reasons) (n=0) Allocated to Paracetamol (n= 13) ♦Received allocated intervention (n=13) Lost to follow-up (give reasons) (n= 0) Discontinued intervention (give reasons) (n=0) Allocated to Ibuprofen (n= 9) ♦Received allocated intervention (n=9) Analysed (n=9) Allocation Analysis Follow-Up Randomized (n=22) Enrollment Figure 1. Study flow diagram

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Journal of International Medical Research 46(2)

between days 3 and 5 of life. Screening asymptomatic newborns before day 3 of life can lead to unnecessary treatment of a potentially spontaneously closing ductus. Additionally, screening should not be performed later than day 5 of age because this might affect the response to therapy.

However, later detection of PDA in asymptomatic newborns might also reflect an insignificant ductus that may not require treatment. Because symptoms were not considered in the previously published studies, we surmise that echocardiography was performed for screening regardless of age. Table 3 summarizes the differences between the present study and the three previously published studies.

In the present study, the rate of any PDA was 42% and the rate of hsPDA was 28%; both are lower than previously reported rates.17–19 This difference may reflect the timing of the screening and treatment criteria. None of the infants who did not fulfill the treatment criteria had complications related to PDA.

The mortality rate was similar in the two treatment groups. Deceased neonates were smaller and less mature, and most of them had a PDA that failed to close after the first course of treatment (Table 4). Primary closure was accomplished in most patients in both treatment groups. Because most PDAs were closed after a 3day course of the assigned drug, it might be more advisable to treat PDA for 3 days and then confirm failure of treatment before extending the duration of therapy to avoid further side effects of the medication.

Tertiary closure was accomplished in one patient randomized to the ibuprofen group whose PDA failed to close after two Table 1. Demographic characteristics of infants included in the study Paracetamol group (n=13) Ibuprofen group (n=9) P value Gestational age (wks)

28 (23–32)

28 (25–35)

Birth weight (g) 1059386 1192269 0.861 Small for age

3

3

0.595

Cesarean section 9

7

0.658

Inborn

12

9

0.394

Male sex

11

6

0.323

Multiple gestation

4

6

0.096

Apgar score First minute

5

7

0.013* Fifth minute

7

9

0.104

Data are presented as mean (range), mean  standard deviation, or number of infants. All infants had a gestational age of
32 weeks or birth weight of
1500 g. *P <0.05 Table 2. Comparison of premature infant mortality and neonatal morbidity in the paracetamol and ibuprofen groups Paracetamol group (n=13) Ibuprofen group (n=9) P value Mortality

3

2

0.962

Primary closure

9

7

0.658

Secondary closure 3

1

Tertiary closure

0

1

RDS

12

6

0.125

Surfactant therapy 9

6

0.898

Pulmonary hemorrhage

1

1

0.783

BPD

1

0

0.394

MV

9

5

0.512

Sepsis

7

4

0.664

NEC

3

2

0.962

ROP

0

0

IVH

7

2

0.137

Grade 1

5

2

Grade 2

2

0

Grade 3

0

0

Grade 4

0

0

PVL

0

0

Data are presented as number of patients. RDS: respiratory distress syndrome, BPD: bronchopulmonary dysplasia, MV: mechanical ventilation, NEC: necrotizing enterocolitis, ROP: retinopathy of prematurity, IVH: intraventricular hemorrhage, PVL: periventricular leukomalacia Al-lawama et al.

courses of ibuprofen and closed after switching to paracetamol. Failure of a PDA to close after a 6-day course of either medication should not discourage treating physicians from trying the other medication before sending the infant to surgery. Data on the safety of paracetamol have been reported, and little evidence of side effects has been found.21 None of the infants in the present study showed any signs of hepatic toxicity. Ibuprofen has milder vasoconstrictive side effects than other nonsteroidal anti-inflammatory drugs. Mild elevation of blood urea nitrogen and insignificant gastrointestinal symptoms were reported in a previous study.22 In our study, the included neonates did not show any significant elevation in the blood urea nitrogen concentration or any gastrointestinal side effects. There were no differences in the neonatal complications between the paracetamol and ibuprofen groups as shown in Table 2. Long-term safety data of paracetamol and ibuprofen are scarce. A follow-up Table 3. Comparison between previously published studies that investigated the use of oral paracetamol and oral ibuprofen in treatment of PDA in premature infants and the current study Study China15 Turkey16 Iran17 Jordan Method Randomized Randomized Exclusion performed after randomization Randomized Sample size

160

90

150

22

Gestational age (wks)
34
30 <37
32 Birth weight (g) NA
1250 NA
1500 Paracetamol dose

15 mg/kg/dose

for 3 days

15 mg/kg/dose

for 3 days

15 mg/kg/dose

for 3 days

10 mg/kg every

6 h for 3 days

Ibuprofen dose

10 mg/kg (day1)

5 mg/kg

(days 2–3)

10 mg/kg (day 1)

5 mg/kg

(days 2–3)

20 mg/kg (day 1)

10 mg/kg

(days 2–3)

10 mg/kg/day

for 3 days Rate of any PDA NA

82%

NA

42%

Rate of hsPDA NA

46%

NA

28%

Primary closure Paracetamol vs. ibuprofen 81.2% vs. 78.8% 72.5% vs. 77.5 82.1% vs. 75.8% 69.0% vs. 78.0% Mortality Paracetamol vs. ibuprofen 12.5% vs. 15.0% 7.5% vs. 5.0% NA 23.0% vs. 22.0% PDA: patent ductus arteriosus, hsPDA: hemodynamically significant patent ductus arteriosus, NA: not available Table 4. Comparison between survivors and nonsurvivors among premature infants included in the study Nonsurvivors (n=5) Survivors (n=17) P value Gestational age (wks) 26.01.5 29.01.9

0.0042

Birth weight (g) 776192 1212301

0.0066

Primary closure

1

15

0.0026

Data are presented as mean  standard deviation or number of patients.

816

Journal of International Medical Research 46(2)

study of one trial investigating the neurodevelopmental outcomes of children who received oral ibuprofen and oral paracetamol at 18 to 24 months of age showed no difference between the two groups.23 We conclude that both oral ibuprofen and oral paracetamol are safe and effective in treating

PDA

in premature infants.

Implementing fluid and feeding protocols might help to decrease both the complications of the PDA and the side effects of the treatment medication. This study included a small number of patients. Multicenter studies are needed to recruit adequate numbers of patients within a reasonable period of time. Acknowledgments We thank the patients’ parents for their help and cooperation. We also thank the neonatal unit nurses for their patience and help in executing the first randomized trial in our department. Declaration of conflicting interests The authors declare that there is no conflict of interest.

Funding This study was funded by the Deanship of Scientific Research at the University of Jordan. References

1. Sellmer A, Bjerre JV, Schmidt MR, et al.

Morbidity and mortality in preterm neonates with patent ductus arteriosus on day

3. Arch Dis Child Fetal Neonatal Ed 2013;

98: 505–510.

2. Sallmon H, Koehne P and Hansmann G.

Recent Advances in the Treatment of Preterm Newborn Infants with Patent Ductus Arteriosus. Clin Perinatol 2016; 43: 113–129.

3. Van Overmeire B, Smets K, Lecoutere D,

et al. A comparison of ibuprofen and indomethacin for closure of patent ductus arteriosus 2000; 343: 674–681.

4. Gulack BC, Laughon MM, Clark RH, et al.

Comparative effectiveness and safety of indomethacin versus ibuprofen for the treatment of patent ductus arteriosus. Early Hum Dev 2015; 91: 725–729.

5. Nadir

E, Kassem E, Foldi S, et al.

Paracetamol treatment of patent ductus arteriosus in preterm infants. J Perinatol 2014; 34: 748–749.

6. Ohlsson A and Shah PS. Paracetamol (acet-

aminophen) for patent ductus arteriosus in preterm or low-birth-weight infants.

Cochrane Database Syst Rev 2015; 3:

CD010061.

7. Terrin G, Conte F, Oncel MY, et al.

Paracetamol for the treatment of patent ductus arteriosus in preterm neonates: a systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed 2016; 101: 127–136.

8. Oncel MY, Yurttutan S, Degirmencioglu H,

et al. Intravenous paracetamol treatment in the management of patent ductus arteriosus in extremely low birthweight infants.

Neonatology 2013; 103: 166–169.

9. Demir N, Peker E, Ece _I, et al. Efficacy and

safety of rectal ibuprofen for patent ductus arteriosus closure in very low birth weight preterm infants. J Matern Fetal Neonatal Med 2017; 25: 1–10.

10. Erdeve O, Yurttutan S, Altug N, et al. Oral

versus intravenous ibuprofen for patent ductus arteriosus closure: a randomised controlled trial in extremely low birthweight infants. Arch Dis Child Fetal Neonatal Ed 2012; 97: 279–283.

11. Yang

EM, Song ES and Choi YY.

Comparison of oral Ibuprofen and intravenous indomethacin for the treatment of patent ductus arteriosus in extremely low birth weight infants. J Pediatr (Rio J) 2013; 89: 33–39.

12. Olgun H, Ceviz N, Kartal _I, et al. Repeated

Courses of Oral Ibuprofen in Premature Infants with Patent Ductus Arteriosus:

Efficacy and Safety. Pediatr Neonatol 2016; 58: 29–35.

13. Oncel MY and Erdeve O. Safety of thera-

peutics used in management of patent ductus arteriosus in preterm infants. Curr Drug Saf 2015; 10: 106–112.

14. Hammerman C, Bin-Nun A, Markovitch E,

et al. Ductal closure with paracetamol: a surprising new approach to patent ductus Al-lawama et al.

arteriosus treatment. Pediatrics 2011; 128: 1618–1621.

15. Oncel MY, Yurttutan S, Uras N, et al. An

alternative drug (paracetamol) in the management of patent ductus arteriosus in ibuprofen resistant or contraindicated preterm infants. Arch Dis Child Fetal Neonatal Ed 2013; 98: F94.

16. Bagheri MM, Niknafs P, Sabsevari F, et al.

Comparison of oral acetaminophen versus ibuprofen in premature infants with patent ductus arteriosus. Iran J Pediatr. 2016; 26:

3975.

17. Oncel MY, Yurttutan S, Erdeve O, et al.

Oral paracetamol versus oral ibuprofen in the management of patent ductus arteriosus in preterm infants: a randomized controlled trial. J Pediatr 2014; 164: 510–514.

18. Dang

D, Wang D, Zhang C, et al.

Comparison of oral paracetamol versus ibuprofen in premature infants with patent ductus arteriosus: a randomized controlled trial. PLoS One 2013; 8: 77888.

19. Kluckow M and Evans N. Early echocardio-

graphic prediction of symptomatic patent ductus arteriosus in preterm infants undergoing mechanical ventilation.

J Pediatr 1995; 127: 774–779.

20. Carlo WA. Respiratory tract disorders. In:

RM Kliegman, RE Behrman, HB Jenson, BF Stanton (eds) Nelson textbook of pediatrics. Philadelphia (PA): Saunders Elsevier, 2011, pp. 579–599.

21. H€arkin

P, H€arm€a A, Aikio O, et al.

Paracetamol accelerates closure of the ductus arteriosus after premature birth: a randomized trial. J Pediatr 2016: 177: 72–77.

22. El-Mashad AE, El-Mahdy H, El Amrousy

D, et al. Comparative study of the efficacy and safety of paracetamol, ibuprofen, and indomethacin in closure of patent ductus arteriosus in preterm neonates.

Eur J Pediatr 2017; 176: 233–240.

23. Oncel

MY, Eras Z, Uras N, et al.

Neurodevelopmental outcomes of preterm infants treated with oral paracetamol versus ibuprofen for patent ductus arteriosus. Am J Perinatol 2017. doi: 10.1055/s-

0037-1601564

818

Journal of International Medical Research 46(2)

Observational infant exploratory [14C]-paracetamol pharmacokinetic microdose/therapeutic dose study with accelerator mass spectrometry bioanalysis Colin R. Garner,1,2 Kevin B. Park,3 Neil S. French,3 Caroline Earnshaw,3 Alessandro Schipani,3 Andrew M. Selby,4 Lindsay Byrne,4 Sarah Siner,4 Francis P. Crawley,5 Wouter H. J. Vaes,6 Esther van Duijn,6 Rianne deLigt,6 Heili Varendi,7 Jane Lass,7 Grzegorz Grynkiewicz,8 Wioletta Maruszak8 & Mark A. Turner9 1Hull York Medical School, University of York, Heslington York YO1 5DD, United Kingdom, 2United Kingdom and Garner Consulting, 5 Hall Drive, Sand Hutton, York YO41 1LA, United Kingdom, 3Institute of Translational Medicine, University of Liverpool, Crown Street, Liverpool L69 3BX, United Kingdom, 4Alder Hey Children’s NHS Foundation Trust, Eaton Road, West Derby, Liverpool L12 2AP, United Kingdom, 5Good Clinical Practice Alliance – Europe, Schoolbergenstraat 47, BE-3010 Kessel-Lo, Belgium, 6TNO Zeist, Utrechtseweg 48, PO Box 360, 3700 AJ Zeist, The Netherlands, 7Department of Paediatrics, Tartu University Hospital, University of Tartu, 51014, Tartu, Estonia, 8Pharmaceutical Research Institute, 8 Rydygiera Street, 01-793 Warsaw, Poland and 9Department of Women’s and Children’s Health, Institute of Translational Medicine, University of Liverpool, University of Liverpool, Liverpool L69 3BX, United Kingdom Correspondence Professor R. C. Garner, Garner Consulting, 5 Hall Drive, Sand Hutton, York YO41 1LA, United Kingdom.

Tel: +44 (0)19 0446 8719 E-mail: garner.consulting@btconnect.com

----------------------------------------------------

Keywords accelerator mass spectrometry, exploratory clinical study, microdosing, paediatric pharmacokinetics, paracetamol

----------------------------------------------------

Received

12 September 2014

Accepted

16 January 2015

Accepted Article Published Online

24 January 2015

AIMS

The aims of the study were to compare [14C]-paracetamol ([14C]-PARA) paediatric pharmacokinetics (PK) after administration mixed in a therapeutic dose or an isolated microdose and to develop further and validate accelerator mass spectrometry (AMS) bioanalysis in the 0–2 year old age group.

METHODS

[14C]-PARA concentrations in 10–15 μl plasma samples were measured after enteral or i.v. administration of a single [14C]-PARA microdose or mixed in with therapeutic dose in infants receiving PARA as part of their therapeutic regimen.

RESULTS

Thirty-four infants were included in the PARA PK analysis for this study: oral microdose (n = 4), i.v. microdose (n = 6), oral therapeutic (n = 6) and i.v. therapeutic (n = 18). The respective mean clearance (CL) values (SDs in parentheses) for these dosed groups were 1.46 (1.00) l h–1, 1.76 (1.07) l h–1, 2.93 (2.08) l h–1 and 2.72 (3.10) l h–1, t1/2 values 2.65 h, 2.55 h, 8.36 h and 7.16 h and dose normalized AUC(0-t) (mg l–1 h) values were 0.90 (0.43), 0.84 (0.57), 0.7 (0.79) and 0.54 (0.26).

CONCLUSIONS

All necessary ethical, scientific, clinical and regulatory procedures were put in place to conduct PK studies using enteral and systemic microdosing in two European centres. The pharmacokinetics of a therapeutic dose (mg kg–1) and a microdose (ng kg–1) in babies between 35 to 127 weeks post-menstrual age. [14C]- PARA pharmacokinetic parameters were within a two-fold range after a therapeutic dose or a microdose. Exploratory studies using doses significantly less than therapeutic doses may offer ethical and safety advantages with increased bionalytical sensitivity in selected exploratory paediatric pharmacokinetic studies.

WHAT IS ALREADY KNOWN ABOUT

THIS SUBJECT

• The paediatric pharmacokinetics of paracetamol are

well described as are the pharmacokinetics of a paracetamol microdose in the adult population. The use of [14C]-labelled drugs to study adult pharmacokinetics with accelerator mass spectrometry bioanalysis has also been documented. The current observational study was conducted to establish if it was feasible to conduct a paediatric (0–2 years of age) isolated microdose study using [14C]-paracetamol and accelerator mass spectrometry bioanalysis and to compare the pharmacokinetic data obtained with that after a therapeutic dose.

WHAT THIS STUDY ADDS

• This study reports that it is possible to put in place an

operational plan to permit paediatric microtracer and microdose [14C]-paracetamol administration in the 0–2 year old age group. The paracetamol microdose used of 6 ng kg–1 is lower than any other isolated microdose reported in the literature and yet the pharmacokinetics were still approximately dose proportional with therapeutic doses for both enteral and intravenous administrations. The methods reported here need to be extended to other drugs to establish the general utility of the microdose approach.

British Journal of Clinical Pharmacology DOI:10.1111/bcp.12597 © 2015 The British Pharmacological Society Br J Clin Pharmacol / 80:1 / 157–167 /

Introduction Paediatric drug treatment is frequently based on ‘bestguess’ modifications of adult dosage regimens without detailed knowledge of pharmacokinetics (PK) in children [1]. PK data are pivotal in understanding a drug’s safety and efficacy and are essential to determine therapeutic dosages in specific age groups [2, 3]. The ontogeny of many enzymes and physiological processes involved in PK are reflected in age-specific effects on drug disposition [4, 5]. US and European regulations require the separate investigation of new medicines in children as well as investigations into already existing medicines used in paediatric care [6]. As a consequence of these regulations, new medicines are now being more regularly evaluated in children as part of clinical development plans.

When there is no prior knowledge of the appropriate dosage in children, an empiric choice is often made based on allometry and/or paediatric physiologically based pharmacokinetic modelling (PBPK) [7]. This approach may lead to over- or under-dosage which does not provide a complete picture of the PK situation while running the risk of exposure to toxic concentrations of parent drug or metabolites [8]. This problem can arise because extrapolation from adults or animals does not take into account gaps in our knowledge of the ontogeny of drug disposition (for example the activity of drug metabolizing enzymes in the liver) [9, 10].

An alternative approach is to obtain exploratory PK data using doses that are substantially below the anticipated therapeutic dose, see for example ICH M3 R2 [11]. Microdosing or human phase 0 studies have been widely used to obtain adult PK data [12–14] but infrequently in infants. Microdose studies assess drug metabolism and PK/PD parameters as a basis for future therapeutic dose determination. These studies involve limited human exposure to the drug, have no therapeutic intent and are not designed to examine clinical tolerability [11]. In children this approach could overcome the issues with dose selection by providing directly relevant PK data, as long as the PK are approximately dose-proportional between a microdose and a therapeutic dose.

Microdosing can be conducted with a microtracer [14C] label as is required for AMS bioanalysis [15] or with a trace of cold drug and LC/MS analysis [16]. For definitions of microtracer and microdose see reference [15]. A comparison of PK between a microtracer [14C]-labelled therapeutic dose and a microdose can be used to establish whether or not PK are dose-proportional across the doses used. In adult microdose validation studies, dose proportionality was assumed if the PK parameters between a microdose and a therapeutic dose were within a two-fold margin [17, 18], a margin routinely used when making allometry comparisons to establish PK equivalency between animal models and humans.

GC/MS or LC/MS are currently the main methods of bioanalysis to study paediatric PK [19, 20] but insensitivity (low pg ml–1) in analyzing drug concentrations in small volume blood samples after microdose administration could be a significant barrier to use in paediatric PK studies. Furthermore because only small blood volumes can be withdrawn from babies, sparse sampling methods are generally used [21]. An alternative methodology is accelerator mass spectrometry (AMS) capable of measuring a drug’s plasma concentration in the atto- to zeptogram ml–1 range (10
18 to 10
21 g ml–1) [22, 23]. This provides up to a million-fold increase in sensitivity over LC/MS. Furthermore AMS can detect [14C]-labelled drug concentrations when the drug is labelled at the level of background radiation exposures. AMS has been extensively demonstrated to be an effective methodology to study drug metabolism and PK in the adult population [24, 25]. However, only two examples in limited numbers of children have been reported for the paediatric population [26, 27].

Gordi et al.

demonstrated the utility of microdosing and microtracing research in paediatric research using 14C-ursodiol [26]. The microdose varied between 3–30 ng kg–1 and in total eight patients were included. Mooij et al., in a preliminary communication, reported on a fundamentally different study design to that described here (see Discussion section). They focused on intestinal and hepatic drug disposition of 14C-PARA using an absolute bioavailability study design of an oral paracetamol microdose administered together with a concomitant i.v. therapeutic paracetamol dose. The Mooij et al. study dosed approximately 3 ng kg–1 and nine patients were included, up to the age of 6 years. No group PK data were presented in this short communication. This paper reports the results of a European-wide collaborative research programme known as the Paediatric Accelerator Mass Spectrometry Evaluation Research Study (PAMPER). The collaborators put together an operational plan in two European countries viz. the United Kingdom and Estonia to address the necessary legal/ethical, regulatory, clinical and scientific procedures required to permit the application of AMS in paediatric microdose studies. The study involved a well-characterized and regularly used drug in paediatric medicine, paracetamol (PARA) (paracetamol) whose PK have been reported in this population (paediatric PK studies summarized in [28]. Here we aimed to examine the feasibility of giving an isolated microdose in young children through an assessment of whether PK parameters of PARA in infants and neonates following a therapeutic dose (using [14C]-PARA mixed in a therapeutic dose as a microtracer) are similar to PK parameters for the single isolated microdose of [14C]-PARA not administered at the same time as a therapeutic dose, to determine dose-linearity of the approach. The results highlight the potential to use an AMS microdosing approach also for (new) less characterized compounds than PARA in the paediatric population.

R. C. Garner et al.

158

/ 80:1 / Br J Clin Pharmacol

The objectives of this proof of concept exploratory study were:

1. To prepare all the necessary ethical, regulatory and sci-

entific documentation to permit a [14C]-microtracer and an isolated microdose paediatric study using PARA as a model drug, in two European countries.

2. To conduct a microtracer/isolated microdose compar-

ison study in children up to the age of 2 years.

3. To establish the PK of a microtracer of [14C]-PARA

ncorporated in a therapeutic dose using noncompartmental analysis (NCA) and extant data.

4. To compare NCA PARA PK parameters for an isolated

microdose not administered at the same time as a therapeutic dose.

Methods Test substances and reagents Oral PARA syrup (Efferalgan, 30 mg ml–1; Bristol Myers Squibb or Pharmacopoiea grade equivalent) and PARA (Perfalgan, Bristol Myers Squibb or European Pharmacopoiea grade) for intravenous administration were used for this study. [14C]-PARA (Moravek Biochemicals Inc, Brea, USA), specific radioactivity 2.85 GBq mmol–1 was repurified and certificated by the Pharmaceutical Research Institute, Warsaw, Poland to a purity of 99.9% w/w, (1.1 ml ethanol solution contained approximately 5.55 MBq [14C]- PARA concentration 0.27 mg ml–1, 5.032 MBq ml–1) and shipped to Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK for GMP i.v. formulation. Stability testing of the ethanol stock solution of [14C]-PARA when stored at
20°C showed no degradation over a 12 month period. PARA standards for HPLC were USP grade or equivalent. All other chemicals and reagents used were pharmacopoeia grade or equivalent.

For UPLC method development and AMS validation

[14C]-PARA

purchased from American Radiolabeled Chemicals Inc (ARC Inc, United Kingdom) was used. 12C- PARA was purchased from Sigma-Aldrich (Zwijndrecht, The Netherlands). Blank human EDTA-plasma was obtained from Bioreclamation Inc (USA). All plasma samples were screened for background PARA concentrations. Only blank plasma samples, negative for PARA, were included in the study. A pool of blank plasma was prepared by mixing equal volumes from six individuals. Dose formulation and administration An intravenous sterile formulation of [14C]-PARA in 5% w/v glucose solution (0.22 ml containing 111Bq [14C]- PARA, specific radioactivity 2.85 GBq mmol–1 equivalent to 5.91 ng PARA) was prepared in the MHRA GMP accredited Radiopharmacy Department, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK. This sterile formulation was used both for enteral or intravenous administration to paediatric patients. The sterile formulation was stored at 2–8°C and showed no degradation over the study period nor was there any evidence of non-specific binding to the filtration apparatus or storage vials.

Administration of [14C]-PARA was either enterally or intravenously (111 Bq kg–1) in one of two scenarios. Scenario 1 (microtracer dose) involved administration of the sterile [14C]-PARA formulation alongside either an enteral or i.v. therapeutic PARA dose. The latter dose was determined by the baby’s body weight and is documented in Table 1. Scenario 2 involved administration of the sterile [14C]-PARA formulation (111 Bq kg–1, 5.91 ng kg–1) either enterally or intravenously alone (microdose). Scenario 1 dosing was part of normal clinical practice with [14C]-label administration occurring alongside a scheduled therapeutic dose of PARA. Scenario 2 dosing was only in infants not given PARA, providing information on dose linearity. All details of the dosing procedures can be found in Table 1.

Paediatric patients Children were eligible to be included in this study if they were preterm neonates (32–36 gestational weeks at birth) up to 2 years of age and had intravenous lines in place (for i.v. administration) or were able to tolerate enteral administration of [14C]-labelled PARA and had suitable vascular access for blood sampling. Exclusion criteria were a history of allergy or hypersensitivity to PARA, serious hepatic or renal impairment, haemofiltration, peritoneal/haemodialysis or ECMO (extracorporeal membrane oxygenation). Ethical approval was obtained from the relevant Research Ethics Committees for the hospitals where patient enrolment occurred and all parents or an adult who carried parental responsibility provided fully informed consent for their child to be included as defined in the Declaration of Helsinki [29]. No radioactive substance administration approval was required as the administered radioactive dose was below 1 μSievert, the UK Administration of Radioactive Substances Advisory Committee (ARSAC) exemption level. The clinics participating in this study were Paediatric Intensive Care Unit (PICU), Alder Hey Children’s NHS Foundation Trust, Liverpool, UK and Tartu University Hospital, Tartu, Estonia.

All i.v. microdosed children received i.v. therapeutic PARA prior to the microdose at varying preceding time intervals. Two out of the four enterally microdosed babies had no preceding PARA.

Blood collection Blood samples were obtained from an arterial line, central venous line or capillary sample. A predose sample was obtained before administration of the [14C]-PARA and subsequently up to five post dose samples at selected time points (typical sampling times: enteral dosing 0.5, 1, 2, 3 and 8 h; i.v. dosing 0.1, 0.25, 5, 5.5 and 6 h) Paediatric paracetamol microdose/therapeutic exploratory PK study Br J Clin Pharmacol / 80:1 /

which had previously been determined from PARA PK modelling using literature data as likely to provide the most informative PK data. Blood 100–250 μl was collected in Microtainers (Becton Dickenson) containing EDTA and centrifuged shortly after collection to obtain plasma. Aliquots (10 or 15 l) of plasma were saved into small cryotubes (usually 2–3 per sample) and immediately frozen for storage at a minimum of
20°C. The total volume of blood obtained from each baby did not exceed 1.1 ml, a volume well within the European Medicines Agency recommended limits for blood sampling for all age groups included in the study [30]. Samples were shipped on dry ice to TNO Zeist, The Netherlands for UPLC and AMS bioanalysis.

Plasma [14C]-PARA measurement by UPLC-AMS Plasma 10 or 15 μl was diluted with 0.9% w/v NaCl to 45 μl and subsequently extracted using 175 μl 100% v/v methanol containing 6.6 μg ml–1 PARA in 96-well protein precipitation plates. The pellet was washed with 100 μl 0.9% NaCl : 100% methanol (1 : 4 v/v). Resulting filtrates were evaporated to dryness and redissolved in 30 μl 10 mM ammonium phosphate pH 3.4 (Eluent A) of which

25 μl was used for UPLC analysis. A PARA solution, spe-

cific radioactivity = 3700 Bq [14C]-PARA 100 μg–1 PARA in blank pooled plasma was used to prepare eight calibrator levels and three quality control sample levels from 0.4 to 180 mBq ml–1, and from 1.7 to 131 mBq ml–1, respectively.

Table 1 Detailed patient information with individual pharmacokinetic parameters (AUC(0,t) and CL) for APAP Patient number Route of administration *Dose kg –1 Post-menstrual age (weeks) Body weight (kg) Gender †AUC(0-t) (ng ml –1 h) †‡CL (l h –1) AH15 i.v.

6 ng

44.9

3.0

M

0.0261

0.6848

AH17 i.v.

6 ng

73.7

8.0

F

0.0234

2.0815

AH19 i.v.

6 ng

36.3

2.6

F

0.0255

0.6166

AH21 i.v.

6 ng

127.0

9.8

F

0.0200

2.8451

AH23 i.v.

6 ng

42.9

5.1

F

0.0234

1.2721

AH35 i.v.

6 ng

35.6

3.0

M

0.0058

3.0660

AH14 Oral

6 ng

39.1

2.3

M

0.0174

0.7941

AH16 Oral

6 ng

75.4

5.5

F

0.0111

2.9355

AH18 Oral

6 ng

44.1

2.9

M

0.0211

0.8228

AH20 Oral

6 ng

77.0

6.3

F

0.0294

1.2887

AH01 i.v.

7.4mg

41.0

3.4

F

18964.88

1.3182

AH03 i.v.

14.9mg

57.7

6.7

F

46125.36

2.1680

AH05 i.v.

14.1mg

75.4

7.1

M

53037.72

1.8855

AH08 i.v.

15.0mg

76.3

8

M

63645.26

1.8855

AH09 i.v.

15.0mg

86.0

10

M

50845.19

2.9501

AH10 i.v.

15.0mg

79.3

5.9

M

55117.83

1.6329

AH12 i.v.

20.0mg

38.6

2.6

F

15527.7

1.2880

AH13 i.v.

7.8mg

39.9

3.2

M

30322.2

0.8245

AH24 i.v.

14.1mg

66.9

6.4

F

43440.96

2.0718

AH25 i.v.

14.8mg

52.0

4.1

F

21867.59

2.7438

AH26 i.v.

7.1mg

40.1

3.5

M

13069.82

1.9128

AH27 i.v.

7.0mg

41.3

3.6

M

8119.676

3.0789

AH28 i.v.

7.4mg

38.6

3.2

M

11855.91

2.0243

AH29 i.v.

15.2mg

49.1

3.3

M

19569.3

2.5550

AH31 i.v.

7.3mg

41.9

3.7

F

11848.15

2.2788

TP09 i.v.

8.0mg

36.0

3.9

F

2069.503

14.4962

TP13 i.v.

9.0mg

36.0

2.3

F

18410.7

1.0863

AH02 Oral 7.2mg

38

2.5

M

134629.9

0.4457

AH04 Oral 15.4mg

79.4

7.8

F

41954.4

2.8602

AH06 Oral 15.0mg

68.7

6.0

M

40109.02

2.2439

AH11 Oral 13.6mg

52.1

4.4

M

11495.91

1.5658

AH32 Oral 15.0mg

50.9

5.0

F

15655.72

4.7906

AH33 Oral 15.0mg

43.6

4.0

M

12051.86

4.9785

*Infants were administered either a) 111 Bq kg –1 [ 14C]-PARA as a microdose (6 ng kg –1) or b) a microtracer dose alongside the therapeutic dose listed in the table. †Individual AUC (0-t) and CL values based on dose of PARA administered. ‡Apparent clearance (CL/F) was obtained for oral route. R. C. Garner et al.

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Calibrators (duplicate), QCs (triplicate) and sample extracts were injected onto a UPLC coupled to a PDA. Chromatograpic conditions can be found in Table 2. PARA in 100% methanol was added to each collected fraction to increase the [12C] carbon content to 25 μg. Fractions were transferred to a tin foil cup and evaporated to dryness.

A novel AMS sample introduction method was used in this study [31]. Briefly, a tin foil cup was combusted using an elemental analyzer (Vario Micro, Elementar, Germany), and the resulting CO2 was captured on a zeolyte trap. CO2 was released by heating of the trap and transferred to a vacuum syringe using helium. The resulting 6% v/v gas mixture of CO2 with helium was infused at a pressure of 1 bar at 60 μl min–1 into the titanium target in the SO110 ion source of a 1 MV Tandetron AMS (High Voltage Engineering Europe B.V., The Netherlands).

The scientific method of validation for the LC/AMS analysis was based on the recommendation of the European Bioanalytical Forum [32]. Details of the validation results are presented in the supporting information. AMS data processing The combustion-CO2-AMS method uses a calibration line (CAL) procedure in which the individual baby’s PARA plasma concentration is determined by extrapolating from the CAL line. Results are expressed as mBq ml–1 plasma which is then converted to the PARA concentration from the specific radioactivity of the dose administered to each baby. For the microdose arm of the study (Scenario 2) a dose value of 6 ng kg–1 paracetamol was assumed. Concentrations of PARA in plasma were calculated from the concentration in the UPLC fraction, the volume of plasma extracted and the volume of extract analyzed. Pharmacokinetics PK parameters were calculated using a noncompartmental model with WinNonLin software version

6.3 (Certara, St Louis, Missouri, USA). The input data were

the plasma concentration values of PARA in ng ml–1, sampling times (h) and doses administered. Output parameters were time to Cmax, terminal half-life, clearance, apparent volume of distribution and area under the curve (AUC). AUCs were calculated by use of a combination of linear and log trapezoidal approximations. Results Study setup The UK Medicines and Healthcare products Regulatory Agency (MHRA) agreed that this was a physiological study of a medicine used within the terms of its marketing authorization to validate a new methodology and so was not a Clinical Trial of an Investigational Product (CTIMP). Radiation dose calculations were undertaken using ICRP’s recommended model [33] where the body is regarded as a single compartment with a biological half-life of 40 days. Assuming an administered dose of

1387 Bq (111 Bq kg–1 to a 12.5 kg infant) this gave a

whole body effective dose value of 0.8 μSieverts or 0.3 μSieverts using an alternative model [34]. Based on the ICRP conservative estimate this radioactive dose equates to less than 10% of background exposure. 50% of parents approached about the trial agreed to the participation of their child.

The study recruited at two paediatric clinics between January 2013 and December 2013 in Liverpool, United Kingdom (Alder Hey Children’s NHS Foundation Trust) and Tartu, Estonia (Tartu University Hospital). The youngest baby recruited was 35.6 weeks and the oldest 127 weeks post-menstrual age (see Tables 1 and 3). In general it was not possible to administer an isolated microdose of PARA to PARA naïve infants because PARA therapy is a normal part of treatment for sick babies in intensive care. PARA microdose administration was separated in time from the pre- and post-therapeutic PARA dose administration. Ten babies in total received either an enteral or i.v. microdose of [14C]-PARA alone whilst the remainder received [14C]-PARA mixed with a therapeutic PARA dose. The microdose route of administration was selected on the basis of whether or not the babies might have required therapeutic PARA by this route at some stage during their treatment. Only babies who had a) blood collected from in-dwelling cannulae, b) a minimum of a predose sample and three time points after [14C]-PARA and c) valid AMS bioanalysis measurements were included in the non-compartmental analysis making a total of 33 Table 2 UPLC conditions for recovery of [14C]-PARA from plasma extracts Eluent A

10 mM ammonium

phosphate pH 3.4 Eluent B

100 % v/v methanol

UPLC column Aquity UPLC (Waters), BEH C18 1.7 μm

2.1 × 100 mm column

Flow rate

0.3 ml min

–1 Column temperature 30°C Chromatography conditions 0–1 min 100% A and 0% B 1–10 min linear gradient from 100% A and 0% B to 95% A and 5% B 10–12 min 95% A and 5% B 12–15 min linear gradient from 95% A and 5% B to 0% A and 100% B 15–20 min 0% A and 100% B 20–20.10 min linear gradient from 0% A and 100% B to 100% A and 0% B 20.10–20.50 min 100% A and 0% B 20.50–28 min 100% A and 0% B at a flow rate of

0.4 ml min

–1 28–29 min 100% A and 0% B Paediatric paracetamol microdose/therapeutic exploratory PK study Br J Clin Pharmacol / 80:1 /

babies for PK analysis. This dataset was substantially larger with more children of a younger age group than the previously published PARA microtracer study [27] Optimal blood sampling time windows were estimated using PopDes software [35], where a structural PK model (values of the PK parameters, the betweensubject variability of the PK parameters, the residual variability and an initial sampling scheme) was specified using literature data.

PK analysis A summary of the PK analysis is presented in Table 4 which presents the PARA PK parameters. The Cmax and AUC(0,t) values are presented non-normalized and dose-normalized. Table 4 shows that for both enteral and i.v. routes the microdose tmax, clearance and half-life was approximately half the values found with the microtracer incorporated into a therapeutic dose. The results of the PK NCA conducted with the i.v. microtracer mixed with a therapeutic dose were similar, but not identical, to the results from a similar NCA conducted with unlabelled PARA [31]. Time to Cmax was slightly longer in this study and t1/2 was slightly shorter in this study. The differences were within the two-fold variation we used as an a priori threshold for discrepant parameters. Figure 1 is a semi-logarithmic plot of the PARA clearance curve after i.v. administration of either a therapeutic or a microdose (6 ng kg–1). The data are presented as a scatter plot with the line of best fit drawn since the blood collection times after PARA dosing were not identical between babies or between doses. Figure 2 presents clearance data from the enteral therapeutic and microdosing arm of this study also with dose-normalization. Discussion This European collaborative project, known as PAMPER, was set up to develop methodology using [14C]-PARA as a model drug to conduct a paediatric exploratory clinical microdose study in the 0–2 year old age group and to examine the relationship between PK for a microdose given at a different time to a therapeutic dose and a microtracer mixed in with a PARA therapeutic dose. PARA is a widely prescribed drug whose paediatric PK have been well-documented [36]. The feasibility of the methodology has been demonstrated using a wellcharacterized probe molecule. The data illustrate that the systemic PARA PK parameters between the two doses are comparable when dose-normalized. Preparation and formulation of the labelled medicines did not pose any practical problems. We encountered no significant barriers to the setup of this study from ethical or radiological perspectives. This study was conducted in the United Kingdom and Estonia and so met the regulatory requirements for a clinical study in two EU Member States. In other jurisdictions the Table 3 Summary of patient details and dosing information for infants dosed with [14C]-PARA Dose and dosing route Number of infants and gender (Male/ Female) Median postmenstrual age (weeks) (range) Median body weight (kg) (range) ¶Age classification –

ICH E11

i.v. microdose*

6 (2M/4F)

43.9 (35.6–127) 4.1 (3–9.8)

Preterm – 2 Term – 1 Infants – 3 i.v. therapeutic dose†

18 (10M/8F) 41.9 (36–86)

3.7 (2.3–10)

Preterm – 2 Term – 7 Infants – 9 Oral microdose‡

4 (2M/2F)

59.7 (39.1–77)

4.2 (2.3–6.3) Preterm – 1

Term – 1 Infants – 2 Oral therapeutic dose§

6 (4M/2F)

51.5 (38–79.4)

4.7 (2.5–7.8) Preterm – 0

Term – 2 Infants – 4 *6ng kg –1 PARA and 111 Bq [ 14C] kg –1 PARA i.v. †i.v. therapeutic PARA dose as appropriate for age and weight of infant plus 111 Bq [ 14C] PARA kg –1, 6 ng PARA kg –1. ‡Oral 6ng kg –1 PARA and 111 Bq [ 14C] PARA kg –1 administered by enteral tube. §Oral therapeutic PARA dose as appropriate for age and weight of infant plus 111 Bq [ 14C] PARA kg –1, 6 ng kg –1 PARA by enteral tube. ¶Based on post-menstrual age where term is 40 weeks. Table 4 PARA pharmacokinetic parameters in neonates and infants *Dose and route tmax (h) †Cmax (mg l –1) †AUC(0,t) (mg l –1 h) ‡AUC(0,t) (mg l –1 h) t1/2 (h) §¶CL (l h –1) **††Vss (l) i.v. therapeutic

0.93 (1.84)

0.16 (0.06)

0.54 (0.26)

28.46 (19.32)

3.78 (3.09)

2.72 (3.10)

7.16

i.v. microdose

0.47 (0.72)

0.30 (0.19)

0.84 (0.57)

2.071 x 10

5 (0.760 x 10
6)

1.69 (0.88)

1.76 (1.07)

2.55

Oral therapeutic

1.05 (0.74)

0.14 (0.12)

0.70 (0.79)

21.326 (47.122)

2.62 (3.05)

2.93 (2.08)

8.36

Oral microdose

0.65 (0.36)

0.24 (0.1)

0.90 ((0.43)

1.975 x 10

5 (0.766 x 10
6)

1.64 (1.02)

1.46 (1.00)

2.65

Data are presented as mean and (SD). tmax, time to maximum concentration; t1/2, half-life; Cmax, maximum concentration; AUC(0,t), Area under the curve from 0 h to last time point t (last time point was ~ 6 h in i.v. and ~8 h in oral PARA); Vss, apparent volume of distribution calculated from dose/ AUC(0,t) assuming 100% bioavailability. *all plasma concentrations from subjects listed in Table 1 were used in the PK calculations. †Dose normalized. ‡Values not normalized. §Systemic clearance (CL) was calculated by Dose/ AUC(0,t). ¶Apparent clearance CL/F. **Vss was calculated by CL × mean residence time (MRT). ††Apparent volume of distribution V/F. R. C. Garner et al.

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regulatory authorities may have different requirements. Whilst this study did not offer any prospect of direct benefit to the participants, the additional [14C]-labelled PARA dose of 6 ng kg–1 was trivial in comparison with the therapeutic dose and for the microdose represented less than permitted API impurity levels for the glucose vehicle. The radiological exposure was calculated using a worst case scenario to be well below background exposures. Accordingly the participants will have experienced no harm due to participation in the study. On the other hand, the results from the study could be of general utility for the development of drugs for the paediatric population and hence the study can be ethically justified. The 50% acceptance rate among parents approached about the study suggests that any concerns relating to the radiation exposure for a number of families were overcome. This acceptance rate was similar to that for PK studies conducted on these units which do not use labelled probes [37]. The parents who gave a reason for not participating most commonly said that they were concerned that their child was too sick to be in any studies and/or that they were concerned about the volume of blood that would be sampled. None of the parents expressed concerns about the radioactivity after the explanations had been given. Our participants were inpatients in a paediatric intensive care unit and all had intra-arterial access. Review of the blood biochemistry indicated that there were no clinically relevant abnormalities in liver function or renal function among the participants.

The results of the PK NCA conducted with the i.v. microtracer mixed with a therapeutic dose were similar, but not identical, to the results from a similar NCA conducted with unlabelled PARA [38]. Time to Cmax was longer and the clearance was slower. The changes were within the two-fold variation we used as an a priori threshold for discrepant parameters. Encouragingly the values for CL (apparent clearance for enteral route) obtained in our study for therapeutic and microdoses (enteral and i.v.) of PARA were broadly in agreement with those reported by others of approximately 2.0–3.0 l h–1 [36,38, 39] accepting that our study had a relatively small numbers of babies. In contrast the type of care received by the participants in the Zuppa et al. study [38] was not stated although all participants had intravenous access. It is possible that comorbidities in our group prolonged distribution and elimination without leading to changes in biochemical measures of renal or hepatic function.

The values for tmax and t1/2 following the administration of a microdose appear to be similar to what would be seen following the administration of a therapeutic dose to a PARA naïve infant. In the paper by Zuppa et al., tmax for i.v. administration to infants was median

0.29 h, range 0.3–1.4 h which is similar to the mean

0.47 (SD 0.75) observed here for the microdose not ad-

ministered at the same time as a therapeutic dose [38]. In the light of clinical circumstances in an ICU where PARA is routinely used and where there is little possibility of recruiting a PARA naïve baby, the microdoses were administered a median of 4 h (range 1.5–17 h) after a previous therapeutic dose and a median of 9 h (range 0.5–15.3 h) before the next therapeutic dose. Given an elimination half-life for PARA of circa 2 h the microdose time separation from a therapeutic dose is a reasonable approximation to a true microdose in a PARA-naïve participant. Figure 1 Semilog plots of the dose-normalized PARA plasma concentration–time profiles after administration of either i.v. single therapeutic doses or a single 6 ng kg–1 microdose. Results are presented as mean ± 1 SD. i.v. therapeutic dose; i.v. microdose Paediatric paracetamol microdose/therapeutic exploratory PK study Br J Clin Pharmacol / 80:1 /

Most of the parameters in the non-compartmental analyses for microtracer and microdose were within the a priori threshold of a two-fold difference. This threshold provides a frame of reference for comparison between different PK studies ([40–42] but is not intended to provide a criterion for the acceptance or rejection of this technique. Comparisons also need to take into account other aspects of the similarities and differences between dosing regimens. The shape of the plasma clearance curve for either an enteral or i.v. dose was similar for a microdose not administered at the time of a therapeutic dose and a microtracer mixed with therapeutic dose administration.

The microdose used here was administered at a different time from a therapeutic dose but the patients were not PARA naïve. A true microdose would have required the recruitment of PARA naïve infants. This was a consequence of conducting this study in infants with appropriate vascular access and a medicine that parents are familiar with. Since the microdose was so small (ng kg–1), it is possible in microdose babies, that a residual pool of PARA was present from prior therapeutic dose PARA administration and that the [14C]-PARA microdose pulse labelled this pool. In other words, the PK data obtained were that associated with pool turnover rather than the isolated microdose per se. This does not detract from our demonstration of proof-of-concept for exploratory PK studies involving enteral and systemic microdoses in young children.

The patient numbers in this study are still relatively small, particularly when broken down into the separate dosing groups. For example only four babies were administered an enteral microdose. This reflected the opportunities available in clinical practice. Nevertheless despite the small group size, PK parameters between a microdose and a therapeutic dose were similar and compared with literature values.

Paediatric microdosing with AMS bioanalysis may offer some advantages over current LC/MS methods to gather exploratory PK data including a) the use of 10–15 microliter sample plasma volumes, which is even two to three times lower than used in both other microdosing/tracing articles in paediatric patients [26, 27], b) the ability to take multiple blood samples at time points after drug administration, c) high analytical sensitivity (attograms to zeptograms) permitting trace drug doses to be administered and d) reduction or elimination of safety and pharmacology issues since there is no chance that drug targets become saturated. Conversely routine AMS bioanalysis after microdose administration requires a) the administered drug to be [14C]-labelled albeit at background levels of radioactivity,

b) that there is wide availability of AMS instruments for

bioanalysis and c) that there is dose-proportionality between a microdose and a therapeutic dose. A preliminary report of the PAMPER study after five babies were recruited was presented at the European Society for Developmental, Perinatal and Paediatric Pharmacology in Salzburg, Austria in June 2013. A short communication, published by Mooij et al. [27], appeared whilst our manuscript was under review and differs substantially from this study. Our study reports on the PK of an isolated microdose given either Figure 2 Semilog plots of the dose-normalized mean PARA plasma concentration–time profiles after administration of either oral single therapeutic doses or a single 6 ng kg–1 microdose. Results are presented as mean ± 1 SD. therapeutic dose; microdose R. C. Garner et al.

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orally or i.v. whereas the Mooij et al. communication reported on an oral microdose given at the same time as an i.v. therapeutic dose [43].

This observational study has demonstrated that an operational plan can be put in place to meet the scientific, legal, regulatory and ethical challenges in order to conduct paediatric microdose studies with AMS bioanalysis. The procedures developed here, when extended to other drugs, could be used to establish if microdosing has general utility for routine paediatric development of appropriate drugs, such as those which are not transporter dependent and which are metabolized before elimination. This could permit new drugs to enter into the neonate and infant population earlier than currently practised. Microdose PK data, obtained after intensive blood sampling, could be used to compare PK parameters calculated from paediatric PBPK modelling studies in order to determine more accurately the therapeutic dose for clinical efficacy studies. Furthermore microdose PK data alongside PBPK modelling studies [44] should give greater confidence that modelling data truly reflects a drug’s metabolism in this sensitive population. Finally we suggest that further microdose/therapeutic dose paediatric PK studies should be undertaken with other model drug substrates to establish when these methods could be used in selected Paediatric Investigation Plans. Competing Interests All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare no support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work.

This research programme was funded under the ERA- Net PRIOMEDCHILD programme (Proposal No 40-41800- 98-022). Individual country contributions were as follows; United Kingdom, Medical Research Council grant number G1100801 as part of the Medical Research Council Drug Safety Science Centre (grant number G0700654) awarded to the University of Liverpool; The Netherlands, ZonMW grant 113205022; Estonia, Estonian Science Foundation, grant no 18/2011; Poland, Narodowym Centrum Bada I Rozwojugrant.

We would like to thank Kishor Solanki, Radiopharmacy Department, Addenbrookes Hospital, Cambridge, United Kingdom for GMP PARA formulation, Babs Fabriek for management of the AMS activities, Hugo Sandman, Hans Mocking and Dimitri Grossouw, TNO the Netherlands for laboratory execution of the LC+AMS analysis, Lenne-Triin Kõrgvee, University of Tartu for preparation of the study protocol and ethics application, Elaine Scott, Alder Hey Children’s NHS Foundation Trust for supporting the clinical research team and Mark Gannon, Nuclear Medicine, Cambridge University Hospitals, Cambridge, United Kingdom for dosimetry calculations.

Contributors

• Professor Colin Garner managed the PAMPER project

on behalf of the Consortium. He wrote the manuscript and designed part of the research programme.

• Dr Mark Turner contributed to all clinical aspects of this

study as Principal Investigator. He also part wrote the manuscript and analyzed data.

• Professor Kevin Park was the PAMPER Project Co-

ordinator and assisted in designing and implementing the research programme as well as being involved in manuscript preparation.

• Dr Neil French assisted in the co-ordination of the PAMPER

programme including study design and implementation.

• Dr Caroline Earnshaw contributed to developing new

analytical assays.

• Dr Alessandro Schipani conducted all pharmacokinetic

analysis of the data including modelling.

• Dr Andrew Selby was the main Clinical Investigator at

Alder Hey Children’s NHS Foundation Trust and contributed to the design of the study and writing of the manuscript.

• Ms Lindsay Byrne and Ms Sarah Siner were responsible

for recruitment, dose administration and blood collection at Alder Hey Children’s NHS Foundation Trust.

• Mr Francis Crawley provided expertise on the ethical

aspects of the study and contributed to the writing and reviewing of the manuscript.

• Dr Wouter Vaes was in overall charge of AMS

bioanalysis.

• Dr Esther vanDuijn and Dr Rianne deLigt were respon-

sible for day to day supervision of the AMS bioanalysis programme and data calculation.

• Dr Heili Varendi participated in the design of research,

study protocol and writing of the manuscript; performed clinical research.

• Dr Jana Lass participated in the design of research and

study protocol.

• Professor Grzegorz Grynkiewicz was responsible for

supervising the purification and certification of [14C]-

PARA.

• Dr Wioleta Maruszak was responsible for purification

land certification of [14C]-PARA.

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35 Gueorguieva I, Ogungbenro K, Graham G, Glatt S, Aarons L. A program for individual and population optimal design for univariate and multivariate response pharmacokinetic– pharmacodynamic models. Comput Methods Programs Biomed 2007; 86: 51–61.

36 Wang C, Allegaert K, Tibboel D, Danhof M, van der Marel CD, Mathot RA, Knibbe CA. Population pharmacokinetics of paracetamol across the human age-range from (pre)term neonates, infants, children to adults. J Clin Pharmacol 2013. doi: 10.1002/jcph.259 [Epub ahead of print]. 37 Zhao W, Hill H, Le Guellec C, Neal T, Mahoney S, Paulus S, Castellan C, Kassai B, van den Anker JN, Kearns GL. Population pharmacokinetics of ciprofloxacin in neonates and young infants less than 3 months of age. Antimicrobial Agents Chemother 2014; 58: 6572–80.

38 Zuppa AF, Hammer GB, Barrett JS, Kenney BF, Kassir N, Mouksassi S, Royal MA. Safety and population pharmacokinetic analysis of intravenous acetaminophen in neonates, infants, children, and adolescents with pain or Fever. J Pediatr Pharmacol Therapeut 2011; 16: 246–61. 39 Anderson BJ, Pons G, Autret-Leca E, Allegaert K, Boccard E. Pediatric intravenous paracetamol (propacetamol) pharmacokinetics: a population analysis1. Pediatr Anesth 2005; 15: 282–92.

40 Rowland M. Microdosing: a critical assessment of human

data. J Pharm Sci 2012; 101: 4067–74.

41 Madan A, O’Brien Z, Wen J, O’Brien C, Farber RH, Beaton G, Crowe P, Oosterhuis B, Garner RC, Lappin G, Bozigian HP. A pharmacokinetic evaluation of five H1-receptor antagonists after an oral and intravenous microdose to human subjects. Br J Clin Pharmacol 2009; 67: 288–98.

42 Lappin G, Shishikura Y, Jochemsen R, Weaver RJ, Gesson C, Houston B, Oosterhuis B, Bjerrum OJ, Rowland M, Garner C. Pharmacokinetics of fexofenadine: evaluation of a microdose and assessment of absolute oral bioavailability. Eur J Phramaceut Sci 2010; 40: 125–31.

43 Lappin G, Rowland M, Garner RC. The use of isotopes in the

determination of absolute bioavailability of drugs in humans. Expert Opin Drug Metab Toxicol 2006; 2: 419–27.

44 Jiang X, Zhao P, Barrett J, Lesko L, Schmidt S. Application of

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Supporting Information Additional Supporting Information may be found in the online version of this article at the publisher’s web-site: Table S1 Mean deviations for calibration standards. Table S2 Accuracy and precision details for the quality control samples. Paediatric paracetamol microdose/therapeutic exploratory PK study Br J Clin Pharmacol / 80:1 /

ORIGINAL RESEARCH ARTICLE

Pharmacokinetics and Bioavailability of a Fixed-Dose Combination of Ibuprofen and Paracetamol after Intravenous and Oral Administration Hartley C. Atkinson1 • Ioana Stanescu1 • Chris Frampton2 • Isam I. Salem3 • Charles P. H. Beasley1 • Richard Robson4 Published online: 3 September 2015 The Author(s) 2015. This article is published with open access at Springerlink.com Abstract Background and Objectives Previously published studies have suggested the lack of a pharmacokinetic interaction between ibuprofen and paracetamol when they are delivered as a fixed-dose oral combination. The aim of this study was to determine the pharmacokinetic profile and safety of a fixed-dose intravenous (IV) combination, containing 3 mg/mL ibuprofen and 10 mg/mL paracetamol, in comparison with its individual components. The study also assessed the relative bioavailability of the same doses of the active ingredients when they were administered as an oral formulation.

Methods A single-dose, open-label, randomized, fiveperiod cross-over sequence pharmacokinetic study was undertaken in 30 healthy volunteers. Serial plasma samples were assayed for both paracetamol and ibuprofen concentrations, using validated liquid chromatography–tandem mass spectrometry methods. Pharmacokinetic parameters were computed using standard non-compartmental analyses. Adverse events were also assessed. The ratios of the maximum measured plasma concentration (Cmax), the area under the plasma concentration–time curve (AUC) from time zero to the time of the last measurable plasma concentration (AUCt) and AUC from time zero to infinity (AUC?) were analysed for bioequivalence as determined by 90 % confidence intervals.

Results The pharmacokinetic parameters of ibuprofen and paracetamol were very similar for the combination and monotherapy IV preparations; the ratios of the Cmax, AUCt and AUC? values fell within the 80–125 % acceptable bioequivalence range. Precise dose proportionality for both compounds was also determined for the half dose of the IV formulation in comparison with the full dose. The relative bioavailability of paracetamol (93.78 %) and ibuprofen (96.45 %) confirmed the pharmacokinetic equivalence of the oral and IV formulations of the fixed-dose combination. Conclusion Concomitant administration of

3 mg/mL

ibuprofen and 10 mg/mL paracetamol in a fixed-dose IV combination does not alter the pharmacokinetic profiles of either drug. The IV and oral dose forms of such a combination are pharmacokinetically equivalent. Key Points Concomitant administration of 3 mg/mL ibuprofen and 10 mg/mL paracetamol in a fixed-dose intravenous combination does not alter the pharmacokinetic profile of either drug.

The intravenous and oral dose forms of such a combination are pharmacokinetically equivalent. This study was registered on the Australian New Zealand Clinical Trials Registry (trial ID: ACTRN12614000809639). & Richard Robson richard@ccst.co.nz Charles P. H. Beasley charles.beasley@aftpharm.com

1

AFT Pharmaceuticals Ltd, PO Box 33203, Takapuna, Auckland 0740, New Zealand

2

University of Otago, PO Box 4345, Christchurch 8140, New Zealand

3

International Pharmaceutical Research Centre, 1 Queen Rania Street-Sport City Circle, Amman 11196, Jordan

4

Christchurch Clinical Studies Trust Ltd, PO Box 2856, Christchurch 8140, New Zealand Clin Drug Investig (2015) 35:625–632 DOI 10.1007/s40261-015-0320-8

1 Introduction

Ibuprofen and paracetamol are among the most commonly used analgesics and are widely available without a prescription [1]. Ibuprofen is a non-steroidal anti-inflammatory drug

(NSAID),

which non-selectively inhibits cyclooxygenase isozymes 1 and 2 (COX-1 and COX-2), resulting in inhibition of prostaglandins and related compounds at peripheral sites [2]. Contrastingly, the mode of action of paracetamol is not fully understood but is thought to relate to inhibition of either prostaglandin synthesis or cannabinoid receptors [3].

A fixed-dose combination of ibuprofen

300 mg ? paracetamol 1000 mg (FDC 300/1000), when

formulated as oral tablets (henceforth referred to as ‘FDCoral’), has been shown to provide superior pain relief in comparison with its individual components [4]. An intravenous (IV) formulation of FDC 300/1000 (henceforth referred to as ‘FDC-IV’) has been developed to permit its administration to patients in whom the use of oral analgesics is limited by various patient factors, such as inability to swallow, the presence of postoperative nausea and vomiting, or reduced gastric motility.

Previous studies have demonstrated that oral ibuprofen and paracetamol are rapidly absorbed after oral administration and are not subject to significant first-pass metabolism [5–9], and that concomitant administration of both compounds does not result in a pharmacokinetic interaction [10–12]. In comparison with oral dosing, the same doses of ibuprofen and paracetamol administered in an IV formulation result in twofold and 70 % increases in the maximum measured plasma concentration (Cmax) values, respectively [5, 13]. Furthermore, IV ibuprofen demonstrates great dose proportionality with respect to the area under the plasma concentration–time curve (AUC) and Cmax [6, 14]. The results of this study, which was conducted with aims to (1) describe the pharmacokinetic profile of the IV formulation of FDC-IV; (2) confirm the lack of a pharmacokinetic interaction between ibuprofen and paracetamol following IV administration; (3) determine whether dose proportionality is apparent from comparison of the full-dose combination of FDC-IV and the half-dose combination; and (4) establish the relative bioavailability of FDC-oral versus that of FDC-IV, are reported here.

2 Methods

2.1 Trial Design

This study was a phase I, single-centre, single-dose, openlabel, randomized, five-way cross-over trial in 30 healthy adult participants. After an initial screening period of up to

28 days, there were five study periods, separated by

washout periods of at least 48 h, and a subsequent final follow-up period of up to 7 days. The research was conducted in accordance with Good Clinical Practice (GCP), including the Declaration of Helsinki and all applicable regulatory requirements. The study protocol received approval by the Health and Disability Ethics Committee, Ministry of Health, New Zealand, and the trial was registered with the Australian New Zealand Clinical Trial Registry (trial ID: ACTRN12614000809639).

2.2 Study Population

Healthy volunteers of both genders, 18–50 years of age with a body mass index (BMI) of 18.0–32.0 kg/m2, were recruited from the Christchurch Clinical Studies Trust databases. Informed consent was obtained by the principal investigator from all individual participants included in the study prior to the screening visit. Screening involved a physical examination and recording of demographic data, vital signs, the medical history and concomitant medications. A blood sample was taken for haematology, biochemistry and serology screening, and a urine sample was collected for urinalysis, and illicit-drug and alcohol breath screening tests were performed. Suitable participants had to comply with all study inclusion and exclusion criteria (presented in Table 1).

2.3 Treatment and Study Procedures

Participants were randomized in a cross-over fashion to a study sequence of four IV doses and one oral dose, using a computer-generated list prior to commencement. For all doses, participants were confined to the study centre from the previous evening to approximately 12 h after study drug administration. The study drug was administered in the morning, following a 10-h fast, and a standard lunch and snacks were provided at 4 and 8 h after study drug administration, respectively.

Patients received each of the following five treatments in a randomized order:

• Treatment A (FDC-IV: 3 mg/mL ibuprofen ? 10 mg/ mL paracetamol, 100 mL IV) • Treatment B (10 mg/mL paracetamol, 100 mL IV) • Treatment C (3 mg/mL ibuprofen, 100 mL IV) • Treatment D (FDC-IV half dose: 1.5 mg/mL ibuprofen ? 5 mg/mL paracetamol, 100 mL IV) • Treatment E (FDC-oral: ibuprofen 150 mg ? paracetamol 500 mg per tablet, 2 tablets) Treatments A, B, C and D were manufactured by SM Farmaceutici SRL, Italy, and administered as a slow

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IV infusion over 15 min into an indwelling cannula. Treatment E was manufactured by Sigma Laboratories, India, and administered orally with 240 mL of water.

2.4 Sampling Schedule

Blood samples (approximately 5 mL) for pharmacokinetic analysis were collected into lithium–heparin tubes. The blood sampling schedules were different for the IV and tablet formulations, as outlined below:

Sampling time points for the intravenous formulations Blood samples were drawn pre-dose, on completion of the 15-min IV infusion, at 5, 10, 15, 20, 30 and 45 min, and at 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10 and 12 h postcompletion of the infusion.

Sampling time points for the tablet formulation Blood samples were drawn pre-dose, at 5, 10, 20, 30 and

45 min, and at 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10 and 12 h after

study drug administration.

2.5 Bioanalytical Methods

All haematology, biochemistry and urinary analyses were conducted using standard methodologies within a single laboratory. Plasma concentrations of paracetamol and ibuprofen in human plasma (lithium–heparin) were determined using validated liquid chromatography–tandem mass spectrometry (LC–MS/MS) procedures. Paracetamol plasma concentrations were analysed using API 3000 and Quattro premier mass spectrometry in multiple reaction monitoring (MRM) mode, using a turbo ion spray with positive ionization. The chromatographic separation of paracetamol employed a C18 column, using a mobile phase consisting of de-ionized water, formic acid and acetonitrile. The calibration curves were linear over the working range of 50–20,000 ng/mL, with a regression coefficient (R2) of C0.99937. The lower limit of quantification (LLOQ) was 50 ng/mL (precision 3.44 %, accuracy

93.69 %).

Ibuprofen plasma concentrations were analysed using a Sciex API 3000 and API 4000 triple quadrupole mass spectrometer in MRM mode, using a turbo ion spray with negative ionization. Selective analysis of ibuprofen was achieved on a Symmetry C18 column by using a mobile phase consisting of ammonium formate, methanol and acetonitrile. The calibration curves were linear over the concentration range of 50–35,000 ng/mL, with an R2 of C0.9975. The LLOQ was 50 ng/mL (precision 8.85 %, accuracy 104.25 %). These methods have also been described elsewhere [10].

2.6 Pharmacokinetic Analysis

The pharmacokinetic parameters of paracetamol and ibuprofen were calculated using Excel 2013. Cmax and the time to reach Cmax (Tmax) were determined directly from the raw data. The elimination rate constant (ke) was calculated from the slope of the linear relationship between the loge concentration and the time during the terminal elimination phase. AUC from time zero to the time of the last measurable plasma concentration (AUCt) was calculated by the linear trapezoidal rule, and AUC from time zero to infinity (AUC?) was calculated after extrapolation from time t to infinity as the ratio of the last measurable plasma concentration (Clast) to ke. The elimination half-life (t) was estimated from the elimination rate constant as ln(2)/ke.

Table 1 Study inclusion/exclusion criteria Inclusion criteria Male and female volunteers aged 18–50 years (inclusive) on the day of consent Voluntary provision of written informed consent before initiation of any study-related procedures Body mass index of 18.0–32.0 kg/m2 No significant disease (cardiac, pulmonary, gastrointestinal, hepatic, renal, haematological, neurological, infective or psychiatric) according to the medical history, physical examination and laboratory tests, as determined by the principal investigator Exclusion criteria Pregnant or nursing women Women of childbearing potential who were unwilling to take adequate contraceptive precautions or who were unwilling to undergo a urine pregnancy test Alcohol intake [14 units/week for females and [21 units/week for males History of drug abuse or positive test results for drug abuse Use of prescription drugs (not including oral contraceptives) within 14 days prior to study drug administration; or use of over-the-counter drugs, herbal products or vitamins within 7 days prior to study drug administration, unless the principal investigator and sponsor agreed that the product that was taken would not have an impact on the study conduct, study results or participant safety BE and PK of an FDC of Intravenous Ibuprofen/Paracetamol

2.7 Statistical Methods

Statistical analysis was performed using the validated program SPSS v22.0. The ratios used to test bioequivalence were calculated from loge-transformed data for Cmax, AUCt and AUC?. The differences between the loge means and the 90 % confidence intervals (CIs) of the differences, derived from the residual variance from the analysis of variance (ANOVA) model, were back-transformed to estimate the ratios of the two formulations and the 90 % CIs of these ratios.

2.8 Safety

Safety was assessed in terms of the overall proportion of subjects with adverse events (AEs) and by haematological and biochemical assessment of blood samples. AEs were evaluated for their severity (mild, moderate or severe) according to the subjective impact they had on the performance of daily activities and their likely relationship to the medication (not related, unlikely, possibly, probably or definitely related) according to the likelihood of a temporal association between the onset of the event and the administration of the medicinal product.

3 Results

3.1 Participants

Thirty subjects were enrolled in this study; 23 (77 %) were male, and all were Caucasian. The mean (± standard deviation) age and BMI were 29.9 (±19.4) years and 24.5 (±2.9) kg/m2, respectively. Twenty-nine participants completed the study, each of whom received all five treatments and was included in the pharmacokinetic analysis.

3.2 Pharmacokinetic Results

The mean paracetamol plasma concentration–time curves for ibuprofen and paracetamol are presented in Figs. 1 and 2, respectively. A tabulated summary of the pharmacokinetic data for both compounds is also presented in Table 2. Intravenous infusions resulted in mean Cmax values of 26,709.6 ng/mL (FDC-IV) and 26,236 ng/mL (paracetamol IV) immediately after the 15-min infusion. A half dose of FDC-IV provided a mean Cmax of 12,880 ng/mL. The concentration of paracetamol from the FDC-oral tablets peaked at 0.73 h, with a mean Cmax of 14,907 ng/mL. The oral route provided paracetamol Cmax values 44 % lower than those observed after administration of FDC-IV or paracetamol IV.

Similarly, IV infusions resulted in Cmax values of 39,506.7 ng/mL

(FDC-IV)

and 40,292.97 ng/mL (ibuprofen IV) immediately after the 15-min infusion. A half dose of FDC-IV provided a mean Cmax of 20,352 ng/ mL. The concentration of ibuprofen from the FDC-oral tablets peaked at 1.49 h, with a mean Cmax of 19,637 ng/ mL. The oral route provided ibuprofen Cmax values 50 % lower than those observed after administration of FDC-IV or ibuprofen IV.

The corresponding AUCt and AUC? values were very similar across both the full-dose IV formulation and the

30000

35000

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25000

ation in plasma (ng/mL)

FDC-IV

Paracetamol IV

5000

10000

15000

Paracetamol concentr FDC-IV Half dose FDC-Oral

0

0

2

4

6

8

10

12

Time, hr (since the start of infusion/administration of tablets) Fig. 1 Mean (standard error of the mean) paracetamol plasma concentrations after single administration of FDC-IV (treatment A:

3 mg/mL ibuprofen ? 10 mg/mL paracetamol, 100 mL IV), parac-

etamol IV (treatment B: 10 mg/mL paracetamol, 100 mL IV), FDC- IV half dose (treatment D: 1.5 mg/mL ibuprofen ? 5 mg/mL paracetamol,

100 mL

IV) and FDC-oral (treatment E:

ibuprofen

300 mg ? paracetamol 1000 mg, 2 tablets). FDC fixed-dose combi-

nation, IV intravenous

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20000

30000

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2

4

6

8

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12

Ibuprofen concentration in Time, hr (since the start of infusion/administration of tablets) FDC-IV Half dose FDC-Oral Tablets Fig. 2 Mean (standard error of the mean) ibuprofen plasma concentrations after single administration of FDC-IV (treatment A: 3 mg/mL ibuprofen ? 10 mg/mL paracetamol, 100 mL IV), ibuprofen IV (treatment C: 3 mg/mL ibuprofen, 100 mL IV), FDC-IV half dose (treatment D:

1.5 mg/mL

ibuprofen ? 5 mg/mL paracetamol,

100 mL IV) and FDC-oral (treatment E: ibuprofen 300 mg ? parac-

etamol 1000 mg, 2 tablets).

FDC fixed-dose combination, IV intravenous

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H. C. Atkinson et al.

FDC-oral tablets. The back-transformed 90 % CIs for FDC-IV in comparison with paracetamol IV and ibuprofen IV all fell within the 80–125 % acceptable bioequivalence range, thus confirming the lack of any pharmacokinetic interaction when both paracetamol and ibuprofen are given in combination as a parenteral preparation (Table 3). Comparisons of the Cmax, AUCt and AUC? values for FDC-IV and a half dose of FDC-IV demonstrated consistent dose proportionality for both paracetamol and ibuprofen (Table 4). The t values for paracetamol and ibuprofen were found to be comparable between all treatment groups (Table 2).

The relative bioavailability of paracetamol and ibuprofen from the FDC-oral tablets was calculated from the back-transformed ratios of the loge means of the AUC? values for the oral and IV formulations (AUCFDC-oral/ AUCFDC-IV). For FDC-oral, the relative bioavailability of paracetamol was 93.78 % (90 % CI 90.98–96.67 %) and the absolute bioavailability of ibuprofen was 96.45 % (90 % CI 93.13–99.89 %), suggesting nearly complete absorption of both compounds from the gastrointestinal mucosa. These results are summarized in Table 5.

3.3 Safety Analysis

Twenty-five non-serious AEs were reported by 15 subjects (50 %). The majority of AEs were mild (80 %), and all other AEs were moderate (20 %). There were no severe AEs. Seventy-six percent of AEs were not related to the study medication in that a temporal association between the onsets of the events relative to the administration of the product was not reasonable. Twenty-four percent of AEs had a reasonable temporal relationship between their onset and administration of the study medication, and were deemed either ‘unlikely related’ or ‘possibly related’ on the basis of the subjective likelihood of the association. These data, and the distribution of AEs across the study periods (study drug or washout), are presented in Table 6. One subject did suffer a serious AE: bilateral ankle fractures due to a fall.

Table 2 Mean ± standard deviation pharmacokinetic parameters of paracetamol and ibuprofen from each treatment Paracetamol Treatment (mean ± standard deviation) FDC-IV: treatment A Paracetamol IV: treatment B FDC-IV half dose: treatment D FDC-oral: treatment E Cmax (ng/mL) 26,709.57 ± 5814.74 26,236.06 ± 5430.52 12,880.39 ± 2553.15 14,907.16 ± 6255.10 AUCt (ngh/mL) 37,553.97 ± 9816.96 35,846.20 ± 8734.15 18,327.40 ± 4758.34 34,980.80 ± 9430.21 AUC? (ngh/mL) 39,419.95 ± 10,630.63 37,651.43 ± 9454.60 19,337.01 ± 5146.46 37,023.82 ± 10,388.31 Tmax (h)a

0.00 ± 0.00

0.00 ± 0.00

0.00 ± 0.02

0.73 ± 0.42

t (h)

2.39 ± 0.27

2.38 ± 0.25

2.44 ± 0.25

2.51 ± 0.33

Ibuprofen Treatment (mean ± standard deviation) FDC-IV: treatment A Ibuprofen IV: treatment C FDC-IV half dose: treatment D FDC-oral: treatment E Cmax (ng/mL) 39,506.69 ± 6874.06 40,292.97 ± 7460.04 20,352.05 ± 3090.87 19,637.38 ± 5178.29 AUCt (ngh/mL) 73,492.69 ± 16,509.61 72,169.59 ± 15,608.70 39,642.48 ± 9679.16 70,417.75 ± 16,260.16 AUC? (ngh/mL) 74,743.31 ± 17,388.69 73,410 ± 16,500.76 40,333.88 ± 10,240.30 72,202.48 ± 17,445.46 Tmax (h)a

0.00 ± 0.00

0.00 ± 0.00

0.00 ± 0.00

1.49 ± 0.89

t (h)

1.87 ± 0.27

1.88 ± 0.28

1.88 ± 0.30

1.99 ± 0.36

AUCt from time zero to the time of the last measurable plasma concentration, AUC? area under the plasma concentration–time curve from time zero to infinity, Cmax maximum measured plasma concentration, t half-life, Tmax time to reach Cmax a Hours after the end of administration Table 3 Bioequivalence comparison of FDC-IV (treatment A) and standalone IV preparations of paracetamol (treatment B) and ibuprofen (treatment C) Cmax, AUCt and AUC? [point estimate % (90 % CI) from log-transformed data] Paracetamol: treatment A/B Ibuprofen: treatment A/C Cmax (ng/mL)

101.67 (95.97–107.72)a

98.30 (93.82–102.99)a

AUCt (ngh/mL)

104.24 (101.42–107.13)a

101.57 (98.35–104.89)a

AUC? (ngh/mL)

104.15 (101.13–107.26)a

101.55 (93.82–105.00)a

AUCt from time zero to the time of the last measurable plasma concentration, AUC? area under the plasma concentration–time curve from time zero to infinity, CI confidence interval, Cmax maximum measured plasma concentration, FDC fixed-dose combination, IV intravenous a Within the bioequivalence range BE and PK of an FDC of Intravenous Ibuprofen/Paracetamol

4 Discussion

For oral medications, increased absorption time and firstpass metabolism, or inconsistent absorption in hospitalized patients, due to delayed gastric emptying perioperatively, may result in a latency to or lack of clinical effect [15]. Indeed, in a study of 106 patients undergoing ear, nose and throat surgery, plasma concentrations of paracetamol

1000 mg sufficient to provide an analgesic effect (10 mg/L)

were reached in 96 % of patients who received the drug parenterally and in only 67 % patients who received it orally [16]. FDC-IV has been developed for use in instances where oral therapy is limited by sedation, severe illness or debilitation, or in patients with difficulty in swallowing.

4.1 Interaction

The results of this study demonstrate that concurrent administration of ibuprofen and paracetamol in a novel IV fixed-dose combination did not significantly alter the extent of absorption of ibuprofen or paracetamol, in comparison with either agent alone. A lack of a pharmacokinetic interaction between ibuprofen and paracetamol has been documented for the following oral formulation, fixed-dose combinations: ibuprofen 300 mg ? paracetamol 1000 mg [10], ibuprofen 400 mg ? paracetamol 1000 mg [11] and ibuprofen 400 mg ? paracetamol 650 mg [12]. In these products, after oral administration, the values of the pharmacokinetic parameters Cmax, AUCt and AUC? for both ibuprofen and paracetamol were similar with the fixed-dose combinations and monotherapies, and the back-transformed

90 % CI for each parameter fell within the acceptable

bioequivalence range (80–125 %) [10, 11]. Similar results were obtained from comparison of pharmacokinetic parameters by ANOVA for the third fixed-dose combination [12]. Consequently, the results from the present study confirm and extend such results for an IV formulation.

4.2 Dose Proportionality

The dose proportionality of the FDC-IV formulation provided here is consistent with that reported for IV ibuprofen; a twofold lesser dose results in decreases of 44–51 % in Cmax, AUCt and AUC? [6, 14]. Absorption of paracetamol from a half dose of FDC-IV appeared to be slightly delayed; however, the longer mean Tmax in this group was due to a single patient whose paracetamol Cmax occurred

20 min after the start of the 15-min infusion (5 min after

the end of the infusion). The clearance of both compounds remained constant (2.4 h for paracetamol and 1.8 h for ibuprofen), which is consistent with previous findings for ibuprofen [6]. The clear dose proportionality of absorption of both active ingredients in FDC-IV could provide practitioners with the ability to easily titrate analgesia according to their patient’s pain.

4.3 Relative Bioavailability

This study determined that both active ingredients in the FDC-oral formulation have very high bioavailability. In comparison with FDC-IV, the relative bioavailability values for ibuprofen and paracetamol in the FDC-oral tablets Table 4 Dose proportionality of FDC-IV, expressed as a comparison between FDC-IV (treatment A) and FDC-IV half dose (treatment D) for paracetamol and ibuprofen Cmax, AUCt and AUC? [point estimate % (90 % CI) from log-transformed data] Paracetamol: treatment A/D Ibuprofen: treatment A/D Cmax (ng/mL)

206.89 (196.27–218.08)

193.49 (185.70–201.61)

AUCt (ngh/mL)

204.49 (199.31–209.79)

185.84 (181.10–190.71)

AUC? (ngh/mL)

203.89 (198.37–208.58)

185.81 (180.90–190.87)

AUCt from time zero to the time of the last measurable plasma concentration, AUC? area under the plasma concentration–time curve from time zero to infinity, CI confidence interval, Cmax maximum measured plasma concentration, FDC fixed-dose combination, IV intravenous Table 5 Relative bioavailability of FDC-oral determined by ratios of FDC-oral and FDC-IV geometric means of ibuprofen and paracetamol AUC? values [point estimate % (90 % CI) from log-transformed data] FDC-oral: treatment Ea FDC-IV: treatment Aa Relative bioavailability: treatment E/A Paracetamol AUC? (ngh/mL)

35,721.16

38,091.23

93.78 (90.98–96.67)b

Ibuprofen AUC? (ngh/mL)

70,233.598

72,814.966

96.45 (93.13–99.89)b

AUC? area under the plasma concentration–time from time zero to infinity, CI confidence interval, FDC fixed-dose combination, IV intravenous a Geometric mean b Within the bioequivalence range

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are 93.59 and 96.34 % respectively, confirming the assertion that both compounds are not subject to significant presystemic metabolism. These results are congruent with previously published data [5–9].

Absorption via the gastrointestinal mucosa results in delayed absorption and decreased Cmax values. In comparison with FDC-IV, the Cmax values for ibuprofen and paracetamol were reduced by 50 and 44 %, respectively, after administration of FDC-oral. For ibuprofen, the results of this study are in line with other published data; an equivalent oral dose of ibuprofen results in a Cmax value that is 50 % of the value observed after an IV dose (63 versus 120 lg/mL) [5]. For paracetamol, oral dosing has been shown to reduce Cmax of paracetamol 1000 mg by 41–43 % in healthy volunteers [9, 13].

5 Conclusion

This study confirmed that a combination of 3 mg/mL ibuprofen and 10 mg/mL paracetamol (FDC-IV) produces ibuprofen and paracetamol plasma concentration–time Table 6 Distribution of adverse events by study period/treatment, severity and relationship with medication Treatment period and adverse event Grading of adverse events Severitya Relationship to study medicationb

FDC-IV

Right superficial radial nerve irritation secondary to cannulation on right wrist Mild Not related Bruised cannulation site on left forearm Mild Not related Upper respiratory tract infection Mild Not related Nausea Mild Possibly related Paracetamol IV Upper respiratory tract infection Mild Not related Lethargy Mild Possibly related Vasovagal episode Moderate Not related Headache Moderate Not related Dyspepsia Moderate Possibly related Ibuprofen IV Upper respiratory tract infection Mild Not related Rectal bleeding Mild Unlikely related Diarrhoea Moderate Unlikely related FDC-IV half dose Sore throat Mild Not related FDC-oral Vasovagal episode Mild Not related Bruising at cannula site on left forearm Mild Not related Presyncopal episode Moderate Not related Washout Upper respiratory tract infection Mild Not related Dry cough Mild Not related Nasal congestion Mild Not related Headache Mild Not related Headache Mild Not related Upper respiratory tract infection Mild Not related Bruising at cannula site on right forearm Mild Not related Bruising at failed cannula site on right wrist Mild Not related Rectal bleeding Mild Unlikely related FDC fixed-dose combination, IV intravenous a Mild: discomfort noticed but no disruption of normal daily activity; moderate: discomfort sufficient to reduce or affect daily activity b Unlikely related: a temporal (timely) relationship of the onset of the event, relative to the administration of the product, is unlikely but cannot be ruled out; possibly related: a temporal (timely) relationship of the onset of the event, relative to the administration of the product, is reasonable, but the event could have been due to an equally likely cause BE and PK of an FDC of Intravenous Ibuprofen/Paracetamol

profiles that are similar to those observed after IV administration of each component on its own. The pharmacokinetic profile of the IV formulation has been demonstrated to be dose proportional following administration of single doses of 1.5 mg/mL ibuprofen and 5 mg/mL paracetamol (FDC-IV half dose) and 3 mg/mL ibuprofen and 10 mg/ mL paracetamol (FDC-IV).

The pharmacokinetic parameters were observed to be similar when a single dose of FDC 300/1000 was administered in either an IV formulation (FDC-IV) or an oral formulation (FDC-oral), except for Cmax of the IV formulation, which was twice that of the oral formulation, and, as expected, Tmax was much shorter than with the oral dose. The relative bioavailability of paracetamol (93.78 %) and ibuprofen

(96.45 %)

confirmed the pharmacokinetic equivalence of the oral and IV FDC 300/1000 formulations. Consequently, in instances where delayed gastric emptying is expected, an IV formulation of FDC 300/1000 may provide more efficient analgesic delivery.

Acknowledgments We thank the staff at Christchurch Clinical Studies Trust Ltd (CCST; Christchurch, New Zealand) for the administration of the study protocol and data collection. We thank the staff at the International Pharmaceutical Research Centre (IPRC; Amman, Jordan) for the data analysis. We are grateful to the volunteers who participated in this study. This study was funded by AFT Pharmaceuticals Ltd (Auckland, New Zealand). Author Contributions H. Atkinson supervised the project and was involved in the design of the study, development of the protocol, interpretation of the data and writing of the manuscript. I. Stanescu was involved in the study design, protocol development, data analysis, data interpretation and writing of the manuscript. C. Frampton conducted the statistical analysis of the data and reviewed the manuscript. I. Salem performed the plasma drug assays and reviewed the manuscript. C. Beasley contributed to the statistical data interpretation and assisted in drafting the manuscript. R. Robson was involved in the data interpretation and critically reviewed the manuscript. All authors had full access to all of the data. The authors have full control of all primary data and agree to allow the journal to review their data if requested. Compliance with Ethical Standards The study protocol received approval by the Health and Disability Ethics Committee, Ministry of Health, New Zealand, and was conducted in accordance with Good Clinical Practice (GCP), including the Declaration of Helsinki. Informed consent was obtained from all individual participants prior to their inclusion in the study. This study was funded by AFT Pharmaceuticals Ltd. H. Atkinson is a shareholder and Managing Director of AFT Pharmaceuticals Ltd, and I. Stanescu and C. Beasley are employees of AFT Pharmaceuticals Ltd. I. Salem is an employee of the IPRC.

C. Frampton provides consultancy services to AFT Pharmaceuticals

Ltd. R. Robson is the Director of CCST.

Open Access This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

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H. C. Atkinson et al.

Paracetamol for the treatment of patent ductus arteriosus in preterm neonates: a systematic review and meta-analysis Gianluca Terrin,1 Francesca Conte,2 Mehmet Yekta Oncel,3 Antonella Scipione,2 Patrick J McNamara,4 Sinno Simons,5 Rahul Sinha,6 Omer Erdeve,7 Kadir S Tekgunduz,8 Mustafa Dogan,9 Irena Kessel,10 Cathy Hammerman,11 E Nadir,12 Sadik Yurttutan,3 Bonny Jasani,13 Serdar Alan,14 Francesco Manguso,15 Mario De Curtis2 ▸Additional material is published online only. To view please visit the journal online (http://dx.doi.org/10.1136/ archdischild-2014-307312).

For numbered affiliations see end of article.

Correspondence to Dr Gianluca Terrin, Department of Gynecology-Obstetrics and Perinatal Medicine, Sapienza University of Rome, Viale del Policlinico 155, Rome 00161, Italy; gianluca.terrin@uniroma1.it Received 4 August 2014 Revised 16 July 2015 Accepted 24 July 2015 To cite: Terrin G, Conte F, Oncel MY, et al. Arch Dis Child Fetal Neonatal Ed Published Online First:

[please include Day Month Year] doi:10.1136/ archdischild-2014-307312

ABSTRACT

Objectives We performed a systematic review and meta-analysis of all the available evidence to assess the efficacy and safety of paracetamol for the treatment of patent ductus arteriosus (PDA) in neonates, and to explore the effects of clinical variables on the risk of closure.

Data source MEDLINE, Scopus and ISI Web of Knowledge databases, using the following medical subject headings and terms: paracetamol, acetaminophen and patent ductus arteriosus. Electronic and manual screening of conference abstracts from international meetings of relevant organisations. Manual search of the reference lists of all eligible articles. Study selection Studies comparing paracetamol versus ibuprofen, indomethacin, placebo or no intervention for the treatment of PDA. Data extraction Data regarding efficacy and safety were collected and analysed.

Results Sixteen studies were included: 2 randomised controlled trials (RCTs) and 14 uncontrolled studies. Quality of selected studies is poor. A meta-analysis of RCTs does not demonstrate any difference in the risk of ductal closure (Mantel–Haenszel model, RR 1.07, 95% CI 0.87 to 1.33 and RR 1.03, 95% CI 0.92 to 1.16, after 3 and 6 days of treatment, respectively). Proportion meta-analysis of uncontrolled studies demonstrates a pooled ductal closure rate of 49% (95% CI 29% to 69%) and 76% (95% CI 61% to 88%) after 3 and 6 days of treatment with paracetamol, respectively. Safety profiles of paracetamol and ibuprofen are similar. Conclusions Efficacy and safety of paracetamol appear to be comparable with those of ibuprofen. These results should be interpreted with caution, taking into account the non-optimal quality of the studies analysed and the limited number of neonates treated with paracetamol so far.

INTRODUCTION

A persistent patent ductus arteriosus (PDA) has significant clinical consequences, and is a main factor affecting the survival rate of preterm neonates.1 2 A prompt ductal closure is crucial to reduce morbidity and mortality in this particular population. Pharmacological treatment with ibuprofen and indomethacin is the first therapeutic choice for PDA.3 4 By inhibiting the cyclo-oxygenase (COX) component of prostaglandin-H2 synthase (PGHS), these two drugs reduce the levels of circulating prostaglandins, on which depends the persistency of ductus arteriosus in the first period of life.5 Recent studies have shown that paracetamol, an inhibitor of the peroxidase component of PGHS,6 may be considered as an alternative drug for the treatment of PDA.7–22 However, many aspects regarding paracetamol use for ductal closure in preterm neonates, such as efficacy in extremely preterm and low birthweight (BW) infants, safety profile, optimal dose, timing of the first dose and route of administration remain largely unexplored. Thus, to address these issues, we performed a systematic review and meta-analysis of the evidence available in the literature. In particular, we systematically reviewed and analysed controlled and uncontrolled studies to compare the efficacy of paracetamol with other COX inhibitors (COX-i) and explore the influence of different variables on the probability of ductal closure.

METHODS

In compliance with PRISMA guidelines, we performed a systematic review and meta-analysis of the studies published.23 The study was approved by the What is already known on this topic? ▸Paracetamol has been proposed for the treatment of patent ductus arteriosus in preterm neonates.

▸Ibuprofen and indomethacin are the first choice for the treatment of patent ductus arteriosus in preterm neonates.

What this study adds?

▸Meta-analysis of controlled and uncontrolled studies demonstrated an efficacy of paracetamol comparable with that reported for ibuprofen.

▸Efficacy of paracetamol seems to depend on gestational age and postnatal age of neonate and on modalities of drug administration. Terrin G, et al. Arch Dis Child Fetal Neonatal Ed 2015;0:F1–F10. doi:10.1136/archdischild-2014-307312 F1 Original article

ADC-FNN Online First, published on August 17, 2015 as 10.1136/archdischild-2014-307312 Copyright Article author (or their employer) 2015. Produced by BMJ Publishing Group Ltd (& RCPCH) under licence. group.bmj.com on August 17, 2015 - Published by http://fn.bmj.com/ Downloaded from

Ethics Committee of ‘La Sapienza’ University in Rome (n.

13409).

Eligibility criteria We considered eligible all studies fulfilling the following criteria:

1. studies of any design including controlled and uncontrolled

trials, such as randomised controlled trials (RCTs), open trials, retrospective studies, case series and case reports, published until November 2014;

2. studies including preterm neonates (gestational age (GA) at

birth <37 weeks) who received pharmacological treatment for haemodynamically significant PDA (defined by echocardiographic examination) regardless of their postnatal age;

3. studies in which the intervention applied was paracetamol

given for PDA closure versus COX-i or placebo or no intervention; studies in which paracetamol was not used for the purpose of PDA closure were excluded.

Outcomes The main outcome was PDA closure. Secondary outcomes were mortality during hospital stay, morbidity during hospital stay (ie, intraventricular haemorrhage, necrotising enterocolitis, bronchopulmonary dysplasia, retinopathy of prematurity) and reopening of the ductus arteriosus.

We also investigated the safety profile of PDA treatment (ie, gastrointestinal bleeding, liver, haematopoietic or renal toxicity, hypersensitivity reactions, skin reactions, hypotension and hypothermia). All dichotomous outcomes were measured as number of patients with the event divided by the total number of patients who had received any kind of intervention. Search strategy A standard systematic review technique was adopted.24 We conducted electronic searches in MEDLINE, Scopus and ISI Web of Knowledge databases, with no language restriction, using the following medical subject headings and terms: paracetamol, acetaminophen and patent ductus arteriosus. Electronic and manual screening of conference abstracts from international meetings of relevant organisations (Pediatric Academic Societies and European Society for Paediatric Research and Perinatal Society of Australia and New Zealand) was also performed. Finally, we made a manual search of the reference lists of all eligible articles.

Study selection Three authors independently assessed study eligibility for inclusion according to pre-established criteria. We used a specifically designed form to include or exclude the studies identified. An accurate check to exclude duplicate publications was performed. Corresponding authors were contacted when the eligibility criteria of their papers were unclear. Differences in opinion were resolved after discussion between the researchers to achieve consensus.

Data extraction Three authors independently extracted the data from the selected articles using a specifically designed form. For each selected study, the form summarised data on authorship, year of publication, study design, number of patients enrolled, postnatal age, GA and BW of the patients enrolled in each treatment group for each study, presence of a control group (ie, COX-i, placebo or no intervention), criteria used to diagnose PDA, timing of paracetamol use (ie, paracetamol given as first-line therapy or after COX-i), dosing regimen used, closure of ductus after any treatment (ie, the number of patients with closure of PDA divided by the total number of patients who had received any kind of intervention in each study), occurrence of reopening (ie, the number of patients with echocardiographic evidence of closure after any treatment followed by reopening of PDA on the total number of patients experiencing ductal closure in each treatment group of each study), morbidity (ie, the number of patients with morbidities on total number of neonates in each treatment group of each study), mortality (ie, the number of non-survival patients on total number of neonates in each treatment group in each study), occurrence of adverse events and side effects specifically associated with pharmacological treatment of PDA (ie, the number of patients with adverse events or side effects on total number of neonates in each treatment group in each study).

The authors of the studies selected were contacted and invited to supply line-by-line raw data for each individual patient. These data were checked for missing information, errors and inconsistencies with published reports. The data extracted were compared for any difference. If evidenced, differences were resolved by discussion and consensus between researchers.

Risk of bias For controlled studies, we assessed selection bias (random sequence generation and allocation concealment), performance bias (blinding of the study personnel as to which intervention a neonate had received), detection bias (blinding of personnel evaluating outcomes), attrition bias (completeness of reporting data, reason and balance across groups of missing data), reporting bias (reporting of the study’s prespecified or expected outcomes of interest to the review) and other source of bias (early interruption of the trial due to data-dependent process or bias related to the specific study design). We categorised for each study the risks of bias as high, low or unclear, using standard methods.24 For uncontrolled studies, randomisation and allocation bias could obviously not be evaluated. For these studies, we judged the risk of selection bias as low or high if patients had been enrolled or not enrolled as consecutively observed based on a pre-existent study protocol and if numbers and reasons for possible exclusions were reported or not reported specifically. Selection bias was judged as unclear when these aspects were not evaluable. Performance bias, detection bias, attrition bias and other sources of bias were evaluated using the criteria previously described.

The risk of bias was assessed independently by three researchers using a specific form. Differences in opinion were resolved by discussion and consensus. The corresponding authors of selected studies were contacted when information useful to assess the risks of bias was unclear or missing in their manuscripts as published.

Statistics For RCTs, we used the Mantel–Haenszel method for calculating the weighted summary risks. To measure the heterogeneity, we used Cochran’s Q test. Homogeneity between studies was assessed using I2 statistic. Fixed effect meta-analysis models were used when there was minimal evidence of heterogeneity, while random effect models were used if the I2 value was >30% for effect estimates.24 The p value cut-off used for the test of heterogeneity was <0.1. We reported dichotomous outcome data using relative risk (RR) with respective 95% CI. Analyses were performed on an intention-to-treat basis (ITT). Missing data were dealt with by using the last available F2 Terrin G, et al. Arch Dis Child Fetal Neonatal Ed 2015;0:F1–F10. doi:10.1136/archdischild-2014-307312 Original article group.bmj.com on August 17, 2015 - Published by http://fn.bmj.com/ Downloaded from

measurement for each individual at the time point prior to withdrawal from the study.

For uncontrolled studies, we used proportion meta-analysis to measure outcomes by calculating proportions and 95% CI for each study and then pooled the data to derive a pooled proportion and 95% CI.25 The impact of heterogeneity on the pooled estimates of the individual outcomes of the meta-analysis was assessed with the Cochran Q statistic and I2 statistic. As the Cochran Q test has a low sensitivity for detecting heterogeneity, a p value of 0.1 was considered significant for the presence of statistical heterogeneity. Fixed effect meta-analysis models were used when there was minimal evidence of heterogeneity, while random effect models were used if the I2 value was >30% for effect estimates.

We planned to perform a subgroup analysis to determine efficacy of drugs for PDA in relation to GA (<28 and ≥28 weeks), BW (<1000 and ≥1000 g), postnatal age (≤7 and >7 days), dose (low (≤45 mg/Kg/day) or high (>45 mg/Kg/day)), route of administration (oral or intravenous), timing of paracetamol use (as first-line therapy or after failure of COX-i). For subgroup analyses, the weighted results were calculated separately in every subgroup, and were then compared with χ2 tests. A sensitivity analysis was planned to determine if the findings would be affected by including only studies with low selection bias. We reported efficacy after 3 and 6 days of treatment from the enrolment and secondary outcomes at the end of hospitalisation period because negative consequences of PDA treatment failure were usually observed only after several days. Statistics were performed using StatsDirect V.2.8.0 and IBM SPSS Statistics V.22 softwares.

RESULTS

Studies’ characteristics We selected 16 studies as indicated in figure 1. The main characteristics of the selected studies, two RCTs21 22 and 14 uncontrolled studies,7–20 are reported in tables 1 and 2, respectively. We received additional information and raw data for each individual patient from the corresponding authors of 15 of the

16 studies selected.7–20 22 Dang et al21 did not provide add-

itional information, and the data of this study were analysed as published.

Risk of bias Risks of bias for the two RCTs are reported in table 3. We judged the risk of selection bias as high in all uncontrolled studies.7 12–16 In all 14 uncontrolled studies, any blinding method was adopted. Attrition bias was judged as low for all 14 studies. Other sources of bias were not clearly evaluable for all 14 uncontrolled studies.

Outcomes Evidence from randomised controlled studies Pooled results from the two RCTs showed no difference in PDA closure for paracetamol compared, with ibuprofen, after

3 and 6 days of treatment (figures 2 and 3). The data available

were not suitable for subgroup and sensitivity analyses.

Figure 1 PRISMA flow chart. PDA, patent ductus arteriosus; RCT, randomised controlled trial.

Terrin G, et al. Arch Dis Child Fetal Neonatal Ed 2015;0:F1–F10. doi:10.1136/archdischild-2014-307312 F3 Original article group.bmj.com on August 17, 2015 - Published by http://fn.bmj.com/ Downloaded from

Table 1 Characteristics of randomised controlled trials Authors Publication year Sample size Birth weight*, g Gestational age*, weeks Postnatal age, days Echocardiographic criteria defining hs-PDA Route Dose, mg/kg/die Timing Dang et al

201321

P: 80 I: 80 P:1592 (349) I: 1531 (453) P: 31.2 (1.8) I: 30.9 (2.2) 0–14 Ductal diameter LA: Ao root ratio Reverse diastolic flow in Ao Left ventricular enlargement P: oral I: oral P: 60 I: 10-5-5 First-line therapy Oncel et al

201422

P: 45 I: 45 P: 929 (224) I: 974 (249) P: 27.5 (2.1) I: 27.3 (2.2) 2–4 Ductal diameter LA: Ao root ratio Reverse diastolic flow in Ao Poor cardiac function P: oral I: oral P: 60 I: 10-5-5 First-line therapy *Data are expressed as mean (SD).

Ao, aorta. I, ibuprofen; hs-PDA, haemodinamically significant patent ductus arteriosus; LA, left atrium; P, paracetamol. Table 2 Characteristics of uncontrolled studies Authors Publication year Sample size Birth weight*, g Gestational age*, weeks Postnatal age*, days Echocardiographic criteria defining hs-PDA Route Dose, mg/kg/die Timing Alan et al 201312

3

840 (810–1240)

26 (26–33)

9 (8–19)

Ductal diameter, LA:Ao root ratio, ductus arteriosus:birth weight ratio Intravenous

60

After COX-i failure El-Khuffash et al 201419

21

790 (530–1200)

25 (24–28)

25 (3–56)

Ductal diameter, plus pulmonary overcirculation or systemic hypoperfusion

9 intravenous

12 oral

60

16 after COX-i failure

5 first-line therapy

Hammerman et al 20117

5

935 (720–1210)

26 (26–29)

10 (3–17)

Ductal diameter, LA:Ao root ratio, gradient across PDA, reverse diastolic flow in Ao, ductus diameter:aorta ratio Oral

60

2 after COX-i failure

3 first-line therapy

Jasani et al 201315

6

1107 (1040–1234)

29 (28–31)

5.5 (3–10)

Ductal diameter, LA:Ao root ratio Oral

60

4 after COX-i failure

2 first-line therapy

Kessel et al 201416

7

991 (789–1322)

28 (26–30)

6 (2–27)

LA:Ao root ratio, left ventricular and left atrial enlargement, moderate left-to-right PDA flow, plus ventilation Oral

60

2 after COX-i failure

5 first-line therapy

Nadir et al 201418

7

853 (656–951)

26 (24–27)

5 (2–22)

Ductal diameter, plus ventilation or feeding intolerance Oral

60

3 after COX-i failure

4 first-line therapy

Oncel et al 20138

8

995 (630–2970)

28 (23–36)

9.5 (5–27)

Ductal diameter, LA:Ao root ratio, reverse diastolic flow in Ao, poor cardiac function, plus clinical symptoms Oral

60

6 after COX-i failure

2 first-line therapy

Oncel et al 20139

10

775 (590–990)

27 (24–29)

6 (2–15)

Ductal diameter, LA:Ao root ratio, reverse diastolic flow in Ao, left-to-right shunting of blood Intravenous

60

First-line therapy Ozdemir et al 201314

7

820 (620–1615)

25 (23–32)

35 (20–47)

Ductal diameter, LA:Ao root ratio, reverse diastolic flow in Ao, left ventricular enlargement Oral

60

After COX-i failure Roofthooft et al 201313

10

700 (365–950)

25 (23–26)

22 (13–30)

Ductal diameter, LA:Ao root ratio, pattern of diastolic flow in Ao, flow on ductus, LPA end diastolic flow

9 intravenous

1 oral

60

6 after COX-i failure

4 first-line therapy

Sinha et al 201311

10

995 (800–1380)

29 (27–33)

5 (4–7)

Ductal diameter, LA:Ao root ratio, left-to-right shunting of blood, mean pulmonary arterial pressure, peak systolic pulmonary arterial pressure Oral

45

First-line therapy Tekgunduz et al 201420

13

950 (470–1390)

29 (24–31)

3 (2–9)

Ductal diameter, LA:Ao root ratio Intravenous 30–60 First-line therapy Terrin et al 201417

8

700 (530–930)

26 (23–29)

2 (2–5)

Ductal diameter, LA:Ao root ratio, reverse or absent diastolic flow in Ao, unrestrictive pulsatile transductal flow Intravenous 30–60 First-line therapy Yurttutan et al 201310

6

1260 (920–1600)

28 (26–32)

4 (3–7)

Ductal diameter, LA:Ao root ratio, reverse diastolic flow in Ao, left-to-right shunting of blood, poor cardiac function Oral

60

First-line therapy *Data are expressed as median (min–max). Ao, aorta; COX-i, cyclo-oxygenase inhibitor; hs-PDA, haemodinamically significant patent ductus arteriosus; LA, left atrium; LPA, left pulmonary artery. F4 Terrin G, et al. Arch Dis Child Fetal Neonatal Ed 2015;0:F1–F10. doi:10.1136/archdischild-2014-307312 Original article group.bmj.com on August 17, 2015 - Published by http://fn.bmj.com/ Downloaded from

There was no significant difference between the paracetamol and ibuprofen groups in terms of mortality, morbidity or ductal reopening (table 4, see online supplementary figures S1–S6).

Evidence from uncontrolled studies Pooled rate of patients with ductal closure after paracetamol treatment in selected studies, evaluated by proportion meta-analysis, is reported in figures 4 and 5. Subgroup analysis is reported in table 5 (see online supplementary figures S7–S12). A significant improvement in efficacy was observed when paracetamol was used in subjects with GA ≥28 weeks, postnatal age <7 days and when it was used as first-line therapy (table 5; see online supplementary figures S7, S9 and S12). We also observed a trend to greater benefit when paracetamol was used by oral route and at lower dose (table 5, see online supplementary figures S10 and S11). Sensitivity analysis was not applicable considering similar degree of selection bias in the uncontrolled studies. Table 6 shows pooled mortality and morbidity rate, such as pooled rate of ductal reopening for uncontrolled studies enrolling neonates treated with paracetamol calculated by proportion meta-analysis (see online supplementary figures S13–S18).

Safety Evidence from randomised controlled studies The safety profile for paracetamol compared with ibuprofen was shown in table

7

(see online supplementary figures S19–S21). Risk of hyperbilirubinaemia was higher for ibuprofen compared with paracetamol (table 7; see online supplementary figure S20).

Evidence from uncontrolled studies The pooled rate of patients showing side effects and adverse events for uncontrolled studies7–20 was reported in table 7 (see online supplementary figure S22). A transient increase in aspartate and alanine aminotransferases or γ-glutamyl transpeptidase was reported only in six patients enrolled in three of the 14 uncontrolled studies.12 16 20

DISCUSSION

This systematic review meta-analysed, for the first time, RCTs and uncontrolled studies on the use of paracetamol for PDA in the neonate.

There has been increasing interest on the use of paracetamol for the treatment of PDA in the last few years. The first study was published by Hammerman et al7 in 2011 as a case report. Table 3 Risk of bias in randomised controlled trials Selection bias I (random sequence generation) Selection bias II (allocation concealment) Blinding I (performance bias) Blinding II (detection bias) Incomplete outcome data (attrition bias) Reporting bias Other bias Dang et al (2013)21* Unclear Low High High Low Low Unclear Oncel et al (2014)22† Unclear Low High Low Low Low Low Percentage of bias across studies High

0

0

100%

50%

0

0

0

Low

0

100%

0

50%

100%

100%

50%

Unclear

100%

0

0

0

0

0

50%

*Random sequence generation method not clearly specified. Cards in sealed opaque envelopes were used for allocation concealment to the two study groups. Blinding was not assured for caregivers, parents of treated children, cardiologist evaluating treatment efficacy and researchers evaluating other outcomes. Outcome data were reported for all enrolled neonates. Outcomes of interest included in the study protocol were completely reported. No clear information was provided on concomitant treatment that could affect ductal closure. †Random sequence generation method not clearly specified. Cards in sequentially numbered sealed opaque envelopes were used for allocation concealment to the two study groups. Blinding was not assured for caregivers, parents of treated children. Blinding was adopted for physician who evaluated the main outcome, but was not assured for researchers evaluating other outcomes. Outcome data were reported for all neonates enrolled. Outcomes of interest included in the study protocol were completely reported. No other source of bias was identified.

Figure 2 Ductal closure after ibuprofen or paracetamol treatment in randomised controlled trials after 3 days from starting treatment. Cochran Q=1.255; p=0.263; heterogeneity: I2=0%. Note Analysis performed per intention to treat (Dang et al: 8 and 14 subjects withdrawn in the paracetamol and ibuprofen arms, respectively. Oncel et al: five and five subjects withdrawn in paracetamol and ibuprofen arms, respectively). M-H, Mantel–Haenszel.

Terrin G, et al. Arch Dis Child Fetal Neonatal Ed 2015;0:F1–F10. doi:10.1136/archdischild-2014-307312 F5 Original article group.bmj.com on August 17, 2015 - Published by http://fn.bmj.com/ Downloaded from

Within a few years, another 15 studies were published,8–22 including, however, only two RCTs.21 22 In published studies,

246 neonates were treated with paracetamol for PDA (125

patients in RCTs and 121 in uncontrolled studies). Although a limited number of neonates has been studied, in a small number of trials, our results indicate a similar efficacy rate and safety profile of paracetamol and ibuprofen,3 4 while further RCTs are necessary to explore the relation between clinical features (ie, GA, BW, postnatal age), modalities of administration and the efficacy of paracetamol. To address these aspects, an individual patient meta-analysis would be very valuable. However, analysis of evidence derived from uncontrolled studies7–20 suggests that efficacy of paracetamol may vary according to some clinical characteristics and modalities of drug administration. In particular, a reduced efficacy of paracetamol was observed in uncontrolled studies7–20 for extremely preterm neonates (GA<28 weeks). This phenomenon is not surprising because in more immature neonates, the expression of prostaglandin receptors is greater in the wall of the ductus,26 and extremely preterm neonates have a thin-walled ductus arteriosus that fails to develop extensive neointimal mounds. Due to these structural limitations in these subjects, functional closure induced by PGHS inhibitors is less frequently followed by the structural closure of the ductus.27 However, these considerations apply also to COX-i.28 29 The analysis of the uncontrolled trials7–20 also suggests the importance of early treatment of PDA. The greater efficacy of paracetamol observed when treatment was started in the first week of life may depend on the circulating levels of prostaglandins, which are high in the first days of life and decrease as postnatal age increases. This physiological aspect explains, at least in part, the reduced efficacy observed for all PGHS-inhibitory drugs, including ibuprofen and indomethacin, when not administered early in life.30 31 Improved efficacy was suggested for paracetamol administered orally compared with the intravenous route when we analysed data derived from uncontrolled studies.7–20 This difference probably depends on the more steady plasma levels of the drug administered orally, similarly to what observed for the oral use of ibuprofen.4 32 33 Nevertheless, the higher efficacy rate of the oral route compared with the intravenous route needs to be further explored in specifically designed trials. The analysis of uncontrolled studies suggests that the use of high doses appears unnecessary. This result should be interpreted with caution considering the high proportion of subjects with GA >28 weeks treated with low doses.11 20 By the analysis of the data from uncontrolled studies,7–20 we observed an impaired efficacy if paracetamol was used after a previous treatment with COX-i, probably because of the delay in administering paracetamol to treat PDA. On the other hand, when paracetamol was administered after COX-i failure, we were unable to rule out that successful closure of ductus may be due to an additive effect of the two drugs rather than paracetamol per se. Data from both RCTs and uncontrolled trials indicate a good safety profile for paracetamol, at least in the short term. Any Figure 3 Ductal closure after ibuprofen or paracetamol treatment in randomised controlled trials after 6 days from starting treatment. Cochran Q=0.002; p=0.964; Heterogeneity: I2=0%. Note. Analysis performed per ITT (Dang et al: 8 and 14 subjects withdrawn in paracetamol and ibuprofen arms, respectively. Oncel et al: five and five subjects withdrawn in paracetamol and ibuprofen arms, respectively). M-H, Mantel–Haenszel. Table 4 Secondary outcomes: meta-analysis of randomised controlled trials Number of studies Paracetamol (n/N) Ibuprofen (n/N) Statistical method24 RR (95% CI) Mortality

221 22

18/125 19/125 M-H, fixed*

0.95 (0.52 to 1.72)

Intraventricular haemorrhage

221 22

45/125 49/125 M-H, fixed†

0.92 (0.73 to 1.15)

Necrotising enterocolitis

221 22

6/125 4/125 M-H, fixed‡

1.50 (0.43 to 5.18)

Bronchopulmonary dysplasia

221 22

15/125 21/125 M-H, fixed§

0.71 (0.40 to 1.28)

Retinopathy of prematurity

221 22

13/125 18/125 M-H, fixed¶

0.72 (0.37 to 1.41)

Ductal reopening

221 22

12/104 11/101 M-H, fixed**

1.06 (0.49 to 2.28)

*I2=0%, p=0.609.

†I2=0%, p=0.943.

‡I2=0%, p>0.999.

§I2=0%, p=0.835.

¶I2=0%, p=0.821.

**I2=0%, p=0.507.

M-H, Mantel–Haenszel; n/N, number of events/number of participants; RR, relative risk. F6 Terrin G, et al. Arch Dis Child Fetal Neonatal Ed 2015;0:F1–F10. doi:10.1136/archdischild-2014-307312 Original article group.bmj.com on August 17, 2015 - Published by http://fn.bmj.com/ Downloaded from

Figure 4 Ductal closure after paracetamol treatment in uncontrolled studies after 3 days from starting treatment. Cochran Q=78.485; p<0.001; heterogeneity: I2=83%.

Figure 5 Ductal closure after paracetamol treatment in uncontrolled studies after 6 days from starting treatment. Cochran Q=43.056; p<0.001; heterogeneity: I2=70%.

Terrin G, et al. Arch Dis Child Fetal Neonatal Ed 2015;0:F1–F10. doi:10.1136/archdischild-2014-307312 F7 Original article group.bmj.com on August 17, 2015 - Published by http://fn.bmj.com/ Downloaded from

Table 5 Pooled ductal closure rate in uncontrolled studies according to clinical characteristics and modalities of paracetamol administration Pooled ductal closure at 3 days Pooled ductal closure at 6 days Subgroup Number of studies Number of participants Number of responders Proportion, % (95% CI) Statistical method25 Number of responders Proportion, % (95% CI) Statistical method25 Gestational age <28 weeks 137–10 12–20

71

23

39 (20 to 60)

Proportion, randoma

46

67 (50 to 82)

Proportion, randomb ≥28 weeks 127–12 14–17 19 20

50

35

66 (44 to 85)*

Proportion, randomc

46

89 (80 to 96)**

Proportion, fixedd Birth weight <1000 g 137–14 16–20

82

35

48 (26 to 70)

Proportion, randome

59

74 (57 to 89)

Proportion, randomf ≥1000 g

107 8 10–12 14–16 19 20

39

23

59 (37 to 79)

Proportion, randomg

33

82 (70 to 91)

Proportion, fixedh Postnatal age ≤7 days 117–11 15–20

57

37

65 (41 to 86)

Proportion, randomi

50

85 (76 to 93)

Proportion, fixedj >7 days 117–9 12–16 18–20

64

21

40 (19 to 62)°

Proportion, randomk

42

69 (48 to 87)°°

Proportion, randoml Route Intravenous

69 12 13 17 19 20

52

21

30 (6 to 62)

Proportion, randomm

38

69 (37 to 94)

Proportion, randomn Oral

107 8–10 11 14–16 18 19

69

37

55 (28 to 81)

Proportion, randomo

54

78 (63 to 90)

Proportion, randomp Dose High 137–10 12–16 18–20

94

39

42 (23 to 61)

Proportion, randomq

68

72 (54 to 86)

Proportion, randomr Low

311 17 20

27

19

61 (8 to 100)

Proportion, randoms

24

87 (63 to 99)

Proportion, randomt Timing First-line therapy 127–9 11 13 15–20

65

40

58 (33 to 81)

Proportion, randomu

55

83 (74 to 91)

Proportion, fixedv After COX-i failure

107 8 12–16 18–20

56

18

37 (20 to 56)†

Proportion, randomw

37

66 (41 to 86)‡

Proportion, randomx Heterogeneity: (a) I2=72%, p<0.001. (b) I2=59%, p=0.004. (c) I2=65%, p=0.001. (d) I2=0%, p=0.520. (e) I2=79%, p<0.001. (f) I2 68%, p<0.001. (g) I2=56%, p=0.014. (h) I2=10%, p=0.350. (i) I2=75%, p<0.001. (j) I2=0%, p=0.677. (k) I2=73%, p<0.001. (l) I2=69%, p<0.001. (m) I2=84%, p<0.001. (n) I2=85%, p<0.001. (o) I2=84%, p<0.001. (p) I2=55%, p=0.018. (q) I2=75%, p<0.001. (r) I2=71%, p<0.001. (s) I2=91%, p<0.001. (t) I2=57%, p=0.098. (u) I2=80%, p<0.001. (v) I2=16%, p=0.282. (w) I2=56%, p=0.015. (x) I2=74%, p< 0.001.

Subgroup significant χ2: *p<0.001, **p=0.001; °p<0.001, °°p=0.004; †p=0.001, ‡p=0.017. COX-i, cyclo-oxygenase inhibitor.

F8 Terrin G, et al. Arch Dis Child Fetal Neonatal Ed 2015;0:F1–F10. doi:10.1136/archdischild-2014-307312 Original article group.bmj.com on August 17, 2015 - Published by http://fn.bmj.com/ Downloaded from

case of severe adverse events strictly associated with the use of paracetamol was not reported. An increased risk of hyperbilirubinaemia was observed for ibuprofen compared with paracetamol. This effect could be attributable to the ibuprofen albumin binding with consequent bilirubin displacement.34 A transient increase in aspartate and alanine aminotransferases or γ-glutamyl transpeptidase, without long-term consequences on liver function, has been reported in a small number of neonates receiving paracetamol.12 16 20 These events were observed only in patients receiving high doses of the drug. Although not statistically significant, a higher number of cases of gastrointestinal bleeding were observed in the ibuprofen group compared with the paracetamol group. This condition may be considered a COX-i-specific side effect, as paracetamol does not induce any damage on the gastrointestinal mucosa.6 In any case, by the analysis of the available data, it is not possible to establish whether this symptom is related to the drugs or to the other stressful conditions that typically affect premature babies. The results of this analysis should be interpreted considering the high risk of bias and the limitations of the studies analysed. In particular, the meta-analysis included only two RCTs with a relatively small number of neonates.21 22 Non-optimal blinding and randomisation methods were adopted in both RCTs. Additionally, two RCTs used paracetamol by the oral route, which is contraindicated in the first days of life in unstable extremely preterm neonates. Most of the studies reviewed, which did not have a comparative arm, showed poor quality and included a small number of patients.7–20 Finally, the risk that studies showing positive results have a greater likelihood of being published, should also be considered.

In conclusion, a potential role of paracetamol in the management of PDA emerges by this analysis. However, additional well-designed studies are advocated to support the use of paracetamol for PDA in the current clinical practice. Author affiliations 1Department of Gynecology-Obstetrics and Perinatal Medicine, Sapienza University of Rome, Rome, Italy 2Department of Pediatrics and Pediatric Neuropsychiatry, Sapienza University of Rome, Rome, Italy 3Division of Neonatology, Zekai Tahir Burak Maternity Teaching Hospital, Ankara, Turkey 4Department of Neonatology, The Hospital for Sick Children, Toronto, Canada 5Division of Neonatology, Department of Pediatrics, Erasmus MC-Sophia Children’s Hospital, Rotterdam, The Netherlands 6Department of Pediatrics and Neonatology, 167 Military Hospital, Pathankot, Punjab, India 7Division of Neonatology, Department of Pediatrics, Ankara University School of Medicine Children’s Hospital, Ankara, Turkey 8Department of Neonatology, Ataturk University Medical Faculty, Erzurum, Turkey 9Division of Cardiology, Department of Pediatrics, Pamukkale University, Denizli, Turkey 10Department of Neonatology, Carmel Medical Center, Haifa, Israel 11Department of Neonatology, Shaare Zedek Medical Center, Hebrew University, Jerusalem, Israel 12Department of Neonatology, Hillel Yaffe Medical Center, Hadera, Israel 13Department of Neonatology, KEM Hospital, Mumbai, India 14Division of Neonatology, Hitit University, Corum, Turkey 15Division of Gastroenterology, Cardarelli Hospital, Naples, Italy Contributors GT and FC conceptualised and designed the study, coordinated and supervised the data collection, carried out the analyses and wrote the first draft of the manuscript. MYO, PJM, SS, RS, OE, KST, MD, IK, CH, EN, SY, BJ, AS and SA participated critically in the study design, coordinated and supervised data collection at their centre, carried out the initial analyses and critically reviewed and revised the Table 7 Safety profile of pharmacological treatments of patent ductus arteriosus Number of studies Paracetamol (n/N) Ibuprofen (n/N) Statistical method24 RR (95% CI) (A) Randomised controlled studies Gastrointestinal bleeding

221 22

2/125 9/125 M-H, fixed*

0.26 (0.07 to 1.03)

Hyperbilirubinaemia

121

16/80 28/80 M-H, fixed†

0.57 (0.34 to 0.97)

Oliguria

221 22

6/80 9/80 M-H, fixed‡

0.67 (0.25 to 1.79)

(B) Uncontrolled studies Number of studies Paracetamol (n/N) Statistical method25 Proportion, % (95% CI) Increase in liver enzymes 147–20 6/121 Proportion, fixed§

5 (2 to 10)

*I2=0%, p=0.872.

†I2=not applicable.

‡I2=not applicable.

§I²=29%, p=0.142.

M-H, Mantel–Haenszel; n/N, number of events/number of participants; RR, relative risk. Table 6 Secondary outcomes: meta-analysis of uncontrolled studies Number of studies Number of events Number of participants Statistical method25 Proportion, % (95% CI) Mortality 118–13 15–18 20

9

88

Proportion, fixed*

11 (6 to 18)

Intraventricular haemorrhage 118–13 15–18 20

32

88

Proportion, random†

37 (19 to 57)

Necrotising enterocolitis 118–13 15–18 20

4

88

Proportion, fixed‡

6 (2 to 12)

Bronchopulmonary dysplasia 118–13 15–18 20

17

88

Proportion, fixed§

20 (13 to 29)

Retinopathy of prematurity 118–13 15–18 20

11

88

Proportion, fixed¶

14 (8 to 22)

Ductal reopening 137–11 13–20

10

86

Proportion, fixed**

11 (6 to 18)

*I²=2%, p=0.424.

†I²=76%, p<0.001.

‡I²=0%, p=0.788.

§I²=20%, p=0.248.

¶I²=0%, p=0.7.

**I²=21%, p=0.225.

Terrin G, et al. Arch Dis Child Fetal Neonatal Ed 2015;0:F1–F10. doi:10.1136/archdischild-2014-307312 F9 Original article group.bmj.com on August 17, 2015 - Published by http://fn.bmj.com/ Downloaded from

manuscript. GT, MDC and FM screened data sources, selected studies, extracted data, evaluated risk of bias and critically reviewed and revised the final version of the manuscript.

Competing interests None declared.

Patient consent Obtained.

Ethics approval Ethics Committee of University of Rome Sapienza. Provenance and peer review Not commissioned; externally peer reviewed. Data sharing statement Database is available on request.

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Jasani B, Kabra N, Nanavati RN. Oral paracetamol in treatment of closure of patent ductus arteriosus in preterm neonates. J Postgrad Med 2013;59:312–14.

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Kessel I, Waisman D, Lavie-Nevo K, et al. Paracetamol effectiveness, safety and blood level monitoring during patent ductus arteriosus closure: a case series. J Matern Fetal Neonatal Med 2014;27:1719–21.

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El-Khuffash A, Jain A, Corcoran D, et al. Efficacy of paracetamol on patent ductus arteriosus closure may be dose dependent: evidence from human and murine studies. Pediatr Res 2014;76:238–44.

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Tekgündüz KS, Ceviz N, Caner I, et al. Intravenous paracetamol with a lower dose is also effective for the treatment of patent ductus arteriosus in pre-term infants. Cardiol Young 2014;27:1–5.

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Dang D, Wang D, Zhang C, et al. Comparison of oral paracetamol versus ibuprofen in premature infants with patent ductus arteriosus: a randomized controlled trial. PLoS ONE 2013;8:e77888.

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Dani C, Bertini G, Corsini I, et al. The fate of ductus arteriosus in infants at 23–27 weeks of gestation: from spontaneous closure to ibuprofen resistance. Acta Paediatr 2008;97:1176–80.

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Chorne N, Jegatheesan P, Lin E, et al. Risk factors for persistent ductus arteriosus patency during indomethacin treatment. J Pediatr 2007;151:629–34.

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31

Van Overmeire B, Van de Broek H, Van Laer P, et al. Early versus late indomethacin treatment for patent ductus arteriosus in premature infants with respiratory distress syndrome. J Pediatr 2001;138:205–11.

32

Barzilay B, Youngster I, Batash D, et al. Pharmacokinetics of oral ibuprofen for patent ductus arteriosus closure in preterm infants. Arch Dis Child Fetal Neonatal Ed 2012;97:F116–19.

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Tulin Gokmen MD, Omer Erdeve MD, Nahide Altug MD, et al. Efficacy and safety of oral versus intravenous ibuprofen in very low birth weight preterm infants with patent ductus arteriosus. J Pediatr 2011;158:549–54.

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F10 Terrin G, et al. Arch Dis Child Fetal Neonatal Ed 2015;0:F1–F10. doi:10.1136/archdischild-2014-307312 Original article group.bmj.com on August 17, 2015 - Published by http://fn.bmj.com/ Downloaded from

systematic review and meta-analysis ductus arteriosus in preterm neonates: a Paracetamol for the treatment of patent Francesco Manguso and Mario De Curtis Hammerman, E Nadir, Sadik Yurttutan, Bonny Jasani, Serdar Alan, Erdeve, Kadir S Tekgunduz, Mustafa Dogan, Irena Kessel, Cathy Scipione, Patrick J McNamara, Sinno Simons, Rahul Sinha, Omer Gianluca Terrin, Francesca Conte, Mehmet Yekta Oncel, Antonella published online August 17, 2015 Arch Dis Child Fetal Neonatal Ed

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Cochrane Database of Systematic Reviews Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Ohlsson A, Shah PS Ohlsson A, Shah PS.

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants. Cochrane Database of Systematic Reviews 2015, Issue 3. Art. No.: CD010061. DOI: 10.1002/14651858.CD010061.pub2.

www.cochranelibrary.com Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

T A B L E O F C O N T E N T S

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ABSTRACT

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PLAIN LANGUAGE SUMMARY

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SUMMARY OF FINDINGS FOR THE MAIN COMPARISON

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METHODS

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RESULTS

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Figure 5.

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21

DISCUSSION

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AUTHORS’ CONCLUSIONS

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ACKNOWLEDGEMENTS

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REFERENCES

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CHARACTERISTICS OF STUDIES

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DATA AND ANALYSES .

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Analysis 1.1. Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 1 Failure of ductal closure after the first course of treatment. .

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Analysis 1.2. Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 2 All-cause mortality during initial hospital stay.

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Analysis 1.3. Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 3 Neonatal mortality (deaths during the first 28 days of life).

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Analysis 1.4. Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 4 Infant mortality (death during the first year of life).

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Analysis 1.5. Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 5 Re-opening of the ductus arteriosus.

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Analysis 1.6. Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 6 Surgical closure of the PDA following treatment failure with paracetamol or ibuprofen. .

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Analysis 1.7. Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 7 Duration of ventilator support (days).

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Analysis 1.8. Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 8 Pulmonary haemorrhage.

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Analysis 1.9. Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 9 Pulmonary hypertension.

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Analysis 1.10. Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 10 Duration for need of supplementary oxygen (days). .

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Analysis 1.11. Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 11 BPD at 28 days.

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Analysis 1.12. Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 12 BPD at 36 weeks PMA.

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Analysis 1.13. Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 13 Moderate to severe BPD (according to the new criteria). .

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Analysis 1.14. Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 14 Severe BPD (according to the new criteria). .

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Analysis 1.15. Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 15 Intraventricular haemorrhage (grade I- IV).

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Analysis 1.16. Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 16 Severe IVH (Grade III-IV).

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Analysis 1.17. Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 17 Periventricular leukomalacia. .

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Analysis 1.18. Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 18 Necrotizing enterocolitis.

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Analysis 1.19. Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 19 Intestinal perforation.

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Analysis 1.20. Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 20 Gastrointestinal bleed.

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Analysis 1.21. Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 21 Retinopathy of prematurity - any stage. .

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i Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Analysis 1.22. Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 22 Retinopathy of prematurity stage =/>

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Analysis 1.23. Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 23 Retinopathy of prematurity requiring laser therapy.

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Analysis 1.24. Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 24 Sepsis.

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Analysis 1.25. Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 25 Oliguria (<1cc/kg/h)).

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Analysis 1.26. Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 26 Serum levels of creatinine after treatment mmol/L.

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Analysis 1.27. Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 27 Serum levels of aspartate transaminase

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Analysis 1.28. Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 28 Serum levels of alanine aminotransferase

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Analysis 1.29. Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 29 Serum bilirubin following treatment (mmol/L).

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Analysis 1.30. Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 30 Hyperbilirubinaemia (serum bilirubin level higher than the exchange level according to the postnatal age and BW.

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Analysis 1.31. Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 31 Duration of hospitalisation (days).

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CONTRIBUTIONS OF AUTHORS

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DECLARATIONS OF INTEREST .

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SOURCES OF SUPPORT

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DIFFERENCES BETWEEN PROTOCOL AND REVIEW

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INDEX TERMS

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ii Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

[Intervention Review] Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants Arne Ohlsson1, Prakeshkumar S Shah2 1Departments of Paediatrics, Obstetrics and Gynaecology and Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada. 2Department of Paediatrics and Health Policy, Management and Evaluation, University of Toronto Mount Sinai Hospital, Toronto, Canada Contact address: Arne Ohlsson, Departments of Paediatrics, Obstetrics and Gynaecology and Institute of Health Policy, Management and Evaluation, University of Toronto, 600 University Avenue, Toronto, ON, M5G 1X5, Canada. aohlsson@mtsinai.on.ca. Editorial group: Cochrane Neonatal Group.

Publication status and date: New, published in Issue 3, 2015.

Citation: Ohlsson A, Shah PS. Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants. Cochrane Database of Systematic Reviews 2015, Issue 3. Art. No.: CD010061. DOI: 10.1002/14651858.CD010061.pub2. Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

A B S T R A C T Background In preterm newborns, the ductus arteriosus frequently fails to close and the infants require medical or surgical closure of the patent ductus arteriosus (PDA). A PDA can be treated surgically or medically with one of two prostaglandin inhibitors, indomethacin or ibuprofen. Case reports suggest that paracetamol may be an alternative for the closure of a PDA. Concerns have been raised that in neonatal mice paracetamol may cause adverse effects on the developing brain, and an association between prenatal exposure to paracetamol and later development of autism or autism spectrum disorder has been reported. Objectives To determine the efficacy and safety of intravenous or oral paracetamol compared with placebo or no intervention, intravenous indomethacin, intravenous or oral ibuprofen, or with other cyclo-oxygenase inhibitors for closure of a PDA in preterm or low-birthweight infants.

Search methods We used the standard search strategy of the Cochrane Neonatal Review Group. This included electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL, Cochrane Library), MEDLINE, EMBASE and CINAHL. We searched abstracts from the meetings of the Pediatric Academic Societies and the Perinatal Society of Australia and New Zealand. We searched clinicaltrials.gov; controlled-trials.com; anzctr.org.au; World Health Organization International Clinical Trials Registry Platform at who.int/ictrp for ongoing trials and the Web of Science for articles quoting identified randomised controlled trials. We searched the first 200 hits on Google ScholarT M to identify grey literature. All searches were conducted in December 2013. A repeat search of MEDLINE in August 2014 did not identify any new trials.

Selection criteria We identified two randomised controlled trials (RCTs) that compared oral paracetamol to oral ibuprofen for the treatment of an echocardiographically diagnosed PDA in infants born preterm (≤34 weeks postmenstrual age (PMA)). Data collection and analysis We performed data collection and analyses in accordance with the methods of the Cochrane Neonatal Review Group.

1

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Main results Two unmasked studies of treatment of PDA that enrolled 250 infants were included. The sequence of randomisation and the allocation to treatment groups were concealed in both studies. In one study the cardiologist assessing PDA closure was blinded to group allocation of the infant. In the other study it was not stated if that was the case or not. The quality of the trials, using GRADE, was low for the primary outcome of PDA closure and moderate for all other important outcomes. There was no significant difference between treatment with oral paracetamol versus oral ibuprofen for failure of ductal closure after the first course of drug administration (typical relative risk (RR) 0.90, 95% confidence interval (CI) 0.67 to 1.22; typical risk difference (RD) -0.04, 95% CI -0.16 to 0.08; I2 = 0 % for RR and 23% for RD).

There were no significant differences between the paracetamol and the ibuprofen groups in the secondary outcomes except for ’duration for need of supplemental oxygen’ (mean difference -12 days, 95% CI -23 days to -2 days; 1 study, n = 90) and for hyperbilirubinaemia (RR 0.57, 95% CI 0.34 to 0.97; RD -0.15, 95% CI -0.29 to -0.01; number needed to treat to benefit (NNTB) 7, 95% CI 3 to 100 in favour of paracetamol; 1 study, n = 160).

Authors’ conclusions Although a limited number of infants with a PDA have been studied in randomised trials of low to moderate quality according to GRADE, oral paracetamol appears to be as effective in closing a PDA as oral ibuprofen. In view of a recent report in mice of adverse effects on the developing brain from paracetamol, and another report of an association between prenatal paracetamol and the development of autism or autism spectrum disorder in childhood, long-term follow-up to at least 18 to 24 months postnatal age must be incorporated in any studies of paracetamol in the newborn population. Such trials are required before any recommendations for the use of paracetamol in the newborn population can be made.

P L A I N L A N G U A G E S U M M A R Y Paracetamol (acetaminophen) for patent ductus arteriosus in preterm and low-birth-weight infants Background:

A common complication for very preterm (premature) or very small babies is a PDA (patent ductus arteriosus). PDA is an open channel between the lungs and heart. It should close after birth, but sometimes remains open because of the baby’s premature stage of development. A PDA can lead to life-threatening complications. The usual treatment for PDA has been indomethacin or ibuprofen. Recently paracetamol (acetaminophen), a commonly used drug to treat fever or pain in children and infants, has been suggested as an alternative to ibuprofen, with potentially fewer side effects. A number of case reports and case series have suggested that paracetamol may be an attractive alternative for the closure of a PDA.

Study characteristics:

We identified two studies that enrolled 250 preterm infants and compared the effectiveness and safety of paracetamol versus ibuprofen in the treatment of a PDA in early life. The studies were conducted in Turkey and China.

Key findings:

When the results of the two studies were combined, the success rate for paracetamol to close a PDA was similar to that of ibuprofen. Adverse events were similar in both groups. However, in general the trends favoured infants who received paracetamol and additionally the adverse events were lower in the paracetamol group. Infants who were treated with paracetamol had a reduced duration of needing extra oxygen and a lower risk of hyperbilirubinaemia than those treated with ibuprofen.

Quality of the evidence:

Although the healthcare providers were not blinded to which drug the infants received (paracetamol versus ibuprofen) the quality of the studies was good.

Conclusions:

Paracetamol appears to be a promising new alternative to indomethacin and ibuprofen for the closure of a PDA with possibly fewer adverse effects.

2

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Additional studies testing this intervention and including longer-term follow-up are needed before paracetamol can be recommended as standard treatment for a PDA in preterm infants. Several studies are ongoing that will eventually provide additional information.

3

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation] Oral paracetamol compared to oral ibuprofen for patent ductus arteriosus in preterm or low-birth-weight infants Patient or population: patients with patent ductus arteriosus in preterm or low-birth-weight infants Settings: hospitals in China and Turkey Intervention: oral paracetamol Comparison: oral ibuprofen Outcomes Illustrative comparative risks* (95% CI) Relative effect (95% CI) No of participants (studies) Quality of the evidence

(GRADE)

Comments Assumed risk Corresponding risk Oral ibuprofen Oral paracetamol Failure of ductal closure after the first course of treatment Echocardiogram Study population RR 0.9 (0.67 to 1.22)

250

(2 studies) ⊕⊕⃝⃝ low

408 per 1000

367 per 1000

(273 to 498) Moderate

363 per 1000

327 per 1000

(243 to 443) Allcause mortality during initial hospital stay Clinical assessment,no risk of bias Study population RR 0.95 (0.52 to 1.72)

250

(2 studies) ⊕⊕⊕⃝ moderate

152 per 1000

144 per 1000

(79 to 261) Moderate

153 per 1000

145 per 1000

(80 to 263)

4

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Surgical closure of the

PDA

following treatment failure with paracetamol or ibuprofen Surgery Study population RR 0.5 (0.05 to 5.32)

90

(1 study) ⊕⊕⊕⃝ moderate1

44 per 1000

22 per 1000

(2 to 236) Moderate

44 per 1000

22 per 1000

(2 to 234) Severe IVH (Grade III- IV) Ultrasound Study population RR 1 (0.3 to 3.37)

250

(2 studies) ⊕⊕⊕⃝ moderate

40 per 1000

40 per 1000

(12 to 135) Moderate

41 per 1000

41 per 1000

(12 to 138) Necrotizing enterocolitis Clinical assessment and radiography Study population RR 1.5 (0.43 to 5.18)

250

(2 studies) ⊕⊕⊕⃝ moderate

32 per 1000

48 per 1000

(14 to 166) Moderate

35 per 1000

52 per 1000

(15 to 181) Oliguria (< 1 cc/kg/hr) Measurement of urine output Study population See comment

250

(2 studies) ⊕⊕⊕⃝ moderate2 Risks were calculated from pooled risk differences

72 per 1000

48 per 1000

(-8 to 112) Moderate

5

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

56 per 1000

38 per 1000

(-6 to 87) Serum levels of creatinine after treatment (mmol/L) Serum samples The mean serum levels of creatinine after treatment mmol/ l in the intervention groups was

1.05 lower

(5.32

lower to

3.21

higher)

250

(2 studies) *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

1 Small sample size

2 Small sample size

6

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

B A C K G R O U N D Description of the condition The ductus arteriosus connects the pulmonary artery to the descending aorta (Clyman 2000). Normal fetal circulation is dependent on the placenta and the patency of the ductus arteriosus (PDA) (Mathew 1998). During fetal life it diverts most of the combined ventricular output away from the lungs (Clyman 2000). Following birth, and with the separation of the placenta and initiation of breathing, the circulation changes and the ductus closes (Mathew 1998). In full term newborns this happens within 24 to 48 hours after birth (Clyman 2000). In preterm newborns the ductus frequently fails to close. As a result, 70% of infants born before 28 weeks postmenstrual age (PMA) require medical or surgical closure of the PDA (Clyman 2000). The failure of the ductus arteriosus to constrict after birth is due to lower intrinsic tone, less ductal muscle fibre and fewer subendothelial cushions in preterm as compared to term infants (Hammerman 1995). The immature ductus arteriosus has higher sensitivity to the vasodilating effects of prostaglandins and nitric oxide (Hammerman 1995). This is aggravated by haemodynamic derangements due to respiratory distress syndrome and surfactant therapy (Hammerman 1995). The clinical consequences of a PDA are related to the degree of left to right shunting through the ductus. Despite the ability of the left ventricle, in preterm infants, to increase its output in the face of a left to right shunt, blood flow distribution to vital organs is altered due to a drop in diastolic pressure and localized vasoconstriction (Clyman 2000). The presence of a PDA is associated with reduced middle cerebral artery blood flow velocity (Weir 1999). The haemodynamic instability caused by the left to right shunt has been associated with gastrointestinal, cerebral and renal effects including spontaneous intestinal perforation and necrotizing enterocolitis (NEC), intraventricular haemorrhage (IVH), decreased kidney function and bronchopulmonary dysplasia (BPD) and, if not managed, may lead to death.

In the two Cochrane reviews of prophylactic use of ibuprofen and indomethacin to close a PDA in preterm infants, the spontaneous closure rate in the control group was 58% and 57% respectively (Fowlie 2010; Ohlsson 2011).

Description of the intervention A PDA can be treated surgically or medically with one of two prostaglandin inhibitors, indomethacin or ibuprofen. Surgical closure of a symptomatic PDA improves haemodynamics and lung compliance (Naulty 1978). However, medical treatment is still considered the treatment of choice because of the risks related to the surgery. In a large Canadian cohort (n = 3779) of very lowbirth-weight infants, 28% required treatment for a PDA; 75% were treated with indomethacin alone, 8% with surgical ligation alone, and 17% required both indomethacin and surgical ligation (Lee 2000). Infants with lower birth weights were more likely to be treated surgically (Lee 2000). Prostaglandins play a significant role in keeping the ductus arteriosus patent (Mathew 1998). Inhibiting prostaglandin synthesis with non-selective blockers of both cyclooxygenase (COX) 1 and 2 is effective for the non-surgical closure of PDA (Clyman 2000). However, indomethacin use is associated with transient or permanent derangement of renal function, NEC, gastrointestinal haemorrhage or perforation, alteration of platelet function and impairment of cerebral blood flow or cerebral blood flow velocity (Edwards1990; Ohlsson 1993; Seyberth 1983; Wolf

1989).

Ibuprofen, a propionic acid derivative and non-selective COX inhibitor, is as effective as indomethacin in closing a PDA and reduces the risk of NEC (Ohlsson 2015). There is less evidence of transient renal insufficiency following treatment with ibuprofen compared to indomethacin (Ohlsson 2015).

Another non-steroidal anti-inflammatory drug, mefenamic acid, has been reported to close a PDA (Sakhalkar 1992), but no randomised controlled trials have been reported (Ohlsson 2011; Ohlsson 2015).

In the sheep fetus, Peterson (Peterson 1985) showed that acetaminophen has potent activity on the ductus arteriosus and produces a constriction in therapeutic analgesic quantities. In humans, Simbi 2002 reported on a pregnant woman near term who took nimesulide 400 mg and acetaminophen 500 mg twice daily for three days as a medication for pain. The women noticed diminished fetal movements and one day later ultrasound confirmed lack of fetal movements and breathing. A constricted ductus arteriosus was confirmed by fetal echocardiography. Following cesarean section the male infant presented with severe mixed acidosis. An echocardiogram showed an almost completely constricted ductus arteriosus. Following intensive care the infant improved and was discharged home on day 12 after birth. At three months follow-up the infant was doing well. Either nimesulide or acetaminophen, or both, could be responsible for ductal closure in this case. The complications associated with the use of indomethacin and possibly ibuprofen have encouraged the search for an alternative drug to treat a PDA. In 2011 paracetamol was suggested as an alternative (Hammerman 2011). Hammerman reported on five preterm infants (PMA 26 to 32 weeks at birth and postnatal age of 3 to 35 days) with large, haemodynamically significant PDAs (Hammerman 2011). The infants had failed or had contraindications for treatment with ibuprofen. All infants were treated with oral paracetamol 15 mg/kg per dose every 6 hours. The treatment resulted in ductal closure in all infants within three days. No side effects were observed. The authors suggested that paracetamol could offer important therapeutic advantages over nonsteroidal anti-inflammatory drugs (NSAIDs) (indomethacin and ibuprofen) as paracetamol has no peripheral vasoconstrictive effect, can be given to infants with clinical contraindications to NSAIDs, and appears to be effective after ibuprofen treatment

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Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

failure (Hammerman 2011).

Paracetamol is used to treat pain in infants. At the Astrid Lindgren Children’s Hospital in Stockholm, Sweden, it is used for postoperative pain. An intravenous dose of paracetamol of 7.5 mg/kg every 8 hours for infants with a PMA of 28 to 32 weeks; 7.5 mg/ kg every 6 hours for infants with a PMA of 33 to 36 weeks, and

10 to 15 mg/kg every 6 hours for infants with a PMA of 37 weeks

or more is described in their protocol (Bartocci 2007). In a survey of intravenous paracetamol use in neonates and infants under one year of age by UK anaesthetists, maintenance doses were either 7.5 mg/kg or 10 mg/kg with a dosing interval of six or eight hours in preterm infants (Wilson-Smith 2009). In a study of the pharmacokinetics of intravenous acetaminophen, conducted in Australia, the postoperative dose given every 6 hours was 10 mg/kg for infants with a PMA of 28 to 32 weeks; 12.5 mg/kg for infants of a PMA of 32 to 36 weeks and 15 mg/kg for infants ≥36 weeks. Following the study the unit continues to use the reported doses based on PMA (Palmer 2008). Unconjugated hyperbilirubinaemia impacts upon clearance of paracetamol (Palmer 2008). Acetaminophen-induced hepatic failure with encephalopathy has been described in a term newborn who received oral acetaminophen every four hours by the parents following circumcision (Walls 2007).

How the intervention might work Paracetamol is an analgesic, antipyretic derivative of acetanilide with weak anti-inflammatory properties and is used as a common analgesic in all age groups, but may cause liver, blood cell and kidney damage (Drug Information Portal 2012). In low concentrations paracetamol stimulates and in high concentrations inhibits the synthesis of prostaglandins. In vivo (in adults) 500 mg of paracetamol causes a pronounced reduction of prostacyclin synthesis but has no effect on thromboxane synthesis (Grèen 1989). Because in vitro paracetamol is a weak inhibitor of both COX 1 and COX 2, the possibility exists that it inhibits a so far unidentified form of COX, perhaps a COX 3 (Botting 2000). In a murine model paracetamol was found to be less potent than indomethacin for construction of the mouse ductus arteriosus in vitro (El-Khuffash

2014).

Since the report in 2011 by Hammerman and co-workers (Hammerman 2011) there have been many case series of treatment of a PDA with paracetamol in preterm infants. In five recent case series (Kessel 2014; Nadir 2014; Sinah 2013; Terrin 2014; Yurttutan 2013) a total of 38 infants with different contraindications for the use of ibuprofen or indomethacin were included. Paracetamol was administered orally, intravenously or via nasogastric tube and the dose and duration of treatment varied; orally 15 mg/kg 8 hourly for 48 hours (Sinah 2013); 15 mg/kg 6 hourly for 3 days (Yurttutan 2013); 15 mg/kg 6 hourly for up to 7 days (Nadir 2014); via nasogastric tube 15 mg/kg 6 hourly for 3 to 7 days (Kessel 2014); or intravenously 7.5 to 15 mg/kg every 4 to 6 hours, with a maximum daily dose of 60 mg/kg (duration of treatment 3 days in 5 of 7 cases) (Terrin 2014). In these case reports the PDA closed in 33 of the 38 cases treated with paracetamol (86%). Kessel and co-workers (Kessel 2014) measured plasma paracetamol concentrations before the fifth dose and ninth dose and 24 hours after the last dose. Most measured paracetamol blood concentrations were comparable to those recommended for pain and fever control (10 to 20 mg/ml) (Arana 2001).

In the most recently published case series, El-Khuffash and coworkers (El-Khuffash 2014) retrospectively evaluated the clinical effectiveness of paracetamol on the closure of a PDA, and prospectively examined its effect on the in vitro term and preterm murine ductus arteriosus. A total of 21 infants were included in the study from the Mount Sinai Hospital, Toronto, Ontario, Canada and the Rotunda Maternity Maternity Hospital, Dublin, Ireland. At the Canadian site paracetamol was either given orally as a short course (15 mg/kg 6 hourly for 48 hours) or a long course of 15 mg/kg 6 hourly for 7 days. At the Irish site paracetamol was given intravenously, 15 mg/kg 6 hourly for a minimum of 48 hours until PDA closure was confirmed on echocardiography or up to a maximum of 6 days. In both centres, the decision to administer paracetamol treatment to neonates with a haemodynamically significant PDA was after failure of two courses of either ibuprofen or indomethacin or if there were contraindications to medical treatments (El-Khuffash 2014). No changes in PDA haemodynamics were seen in the five infants treated with a short course of paracetamol. In six of the seven infants treated with a long course the PDA closed. In eight of the nine infants treated with intravenous paracetamol the PDA closed (El-Khuffash 2014). Paracetamol drug levels were not ascertained. The authors concluded that the efficacy of paracetamol on PDA closure may depend on the duration of treatment and the mode of administration (El-Khuffash 2014). The inhibitory effect of paracetamol on prostaglandin E2 (PGE2) may not be present at lower gestational ages (El-Khuffash 2014). Recently there have been concerns raised that prenatal or neonatal exposure, or both, to paracetamol could have adverse effects on brain development. Viberg and co-workers (Viberg 2014) examined whether neonatal paracetamol exposure in mice could affect the development of the brain, manifested as adult behaviour and cognitive deficits, as well as changes in the response to paracetamol. Ten day-old mice were administered a single dose of paracetamol (30 mg/kg body weight) or repeated doses of paracetamol (30 +

30 mg/kg body weight, 4 hours apart). Concentrations of parac-

etamol and brain-derived neurotrophic factor (BDNF) were measured in the neonatal brain and behavioural testing was done when animals reached adulthood. Acute neonatal exposure to paracetamol (2 x 30 mg) resulted in altered locomotor activity on exposure to a novel home cage arena and failure to acquire spatial learning in adulthood, without affecting thermal nociceptive responding or anxiety-related behaviour. However, mice exposed to paracetamol (2 x 30 mg) as neonates failed to exhibit paracetamol-induced antinociceptive and anxiogenic-like behaviour in adulthood. The

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Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

authors suggested that behavioural alterations in adulthood may, in part, be due to paracetamol-induced changes in BDNF levels in key brain regions at a critical time during development. They concluded that in mice exposure to and presence of paracetamol during a critical period of brain development can induce longlasting effects on cognitive function and alter the adult response to paracetamol in mice (Viberg 2014).

In an ecological study conducted in humans and using countrylevel data for the period 1984 to 2005, prenatal use of paracetamol was correlated with autism or autism spectrum disorder (ASD) (Bauer 2013). To explore the relationship of early neonatal paracetamol exposure to autism and ASD, population weighted average male autism prevalence rates for all available countries and US states were compared to male circumcision rates, a procedure for which paracetamol has been widely prescribed since the mid- 1990s. For studies including boys born after 1995, there was a strong correlation between country-level autism and ASD prevalence in males and a country’s circumcision rate (r = 0.98) (Bauer

2013).

It is therefore of extreme importance that infants enrolled in trials of paracetamol either for pain relief or for closure of a PDA be followed long-term with conventional developmental tests and tests to diagnose autism and ASD (American Psychiatric Association

2013).

Why it is important to do this review Currently there are at least three ongoing trials on this topic (NCT01938261; NCT01291654; NCT02002741). It is likely that several trials will be conducted in the near future and, with regular updates, this review will track the progress of the research in a timely fashion. It is expected that paracetamol will be compared with oral or intravenous ibuprofen or intravenous indomethacin for the efficacy of closing a PDA. In view of recent findings in mice of adverse effects on brain development following neonatal exposure to paracetamol and an association of neonatal exposure to paracetamol and autism or ASD it is important that long-term follow-up is included in individual studies and in this systematic review.

O B J E C T I V E S To determine the efficacy and safety of intravenous or oral paracetamol compared with placebo or no intervention, intravenous indomethacin, intravenous or oral ibuprofen, or with other cyclooxygenase inhibitors for closure of a PDA in preterm or low-birthweight infants.

Primary objectives

1. To determine the efficacy and safety of intravenous or oral

paracetamol compared with placebo or no intervention for closure of a PDA in preterm or low-birth-weight infants

2. To determine the efficacy and safety of intravenous or oral

paracetamol compared with intravenous indomethacin, for closure of a PDA in preterm or low-birth-weight infants

3. To determine the efficacy and safety of intravenous or oral

paracetamol compared with intravenous ibuprofen for closure of a PDA in preterm or low-birth-weight infants

4. To determine the efficacy and safety of intravenous or oral

paracetamol compared with oral ibuprofen for closure of a PDA in preterm or low-birth-weight infants

5. To determine the efficacy and safety of intravenous or oral

paracetamol compared with other cyclo-oxygenase inhibitors (separate analyses for different cyclo-oxygenase inhibitors) for closure of a PDA in preterm or low-birth-weight infants Secondary objectives

1. To determine in subgroup analyses the efficacy and safety of

paracetamol for closure of a PDA in relation to postnatal ages of < 7 days, 7 to 14 days and > 14 days at the time of administration of the first dose of paracetamol.

2. To determine in subgroup analyses the efficacy and safety of

paracetamol for closure of a PDA in relation to the following criteria:

i) gestational age (< 28 weeks, 28 to 32 weeks, 33 to 36

weeks); ii) birth weight (< 1000 g, 1000 to 1500 g, 1501 to 2500 g).

M E T H O D S Criteria for considering studies for this review Types of studies We considered randomised and quasi-randomised controlled trials for inclusion.

Types of participants Infants born preterm (< 37 weeks PMA) or with low birth weight (< 2500 g at birth) who had an echocardiographic diagnosis of a PDA regardless of their postnatal age were included. In the Cochrane review of ibuprofen for the treatment of a PDA all 20

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Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

included studies made the diagnoses of a PDA by echocardiography (Ohlsson 2015), and it is likely that would be the case in studies of the effectiveness of paracetamol in closing a PDA. Types of interventions Paracetamol (given via any route for the purpose of closure of PDA) in any dose versus placebo or no intervention or versus another prostaglandin inhibitor were included. If the intention for administration of paracetamol was not closure of PDA, the study would be excluded. Only data from the first course of paracetamol were included if the study reported on more than one course. Studies that used any therapeutic regimen of paracetamol were included.

Types of outcome measures Primary outcomes

• Failure of PDA closure after the first course of paracetamol

treatment (closure and failure of closure confirmed by echocardiographic criteria)

• Neurodevelopmental outcome (neurodevelopmental

outcome assessed by a standardized and validated assessment tool or a child developmental specialist, or both) at any age reported (outcome data will be grouped at 12, 18, 24 months if available)

• Autism or autism spectrum disorder (ASD) in childhood

(American Psychiatric Association 2013); this outcome was added at the full review stage Secondary outcomes

• All-cause mortality during initial hospital stay

• Neonatal mortality (death during the first 28 days of life)

• Infant mortality (death during the first year of life)

• Re-opening of the ductus arteriosus (defined as

echocardiographic evidence of closure followed by re-opening of PDA at later stage)

• Surgical closure of the PDA

• Treatment with indomethacin, ibuprofen or other

prostaglandin inhibitor to close the PDA following treatment failure

• Duration of ventilator support (days)

• Duration of need for supplementary oxygen (O2) (days)

• Pulmonary haemorrhage (blood stained liquid flowing from

the trachea of the infant)

• Pulmonary hypertension (defined as an increased mean

pulmonary arterial pressure of 25 mmHg at rest) (Van Loon

2011)

• Bronchopulmonary dysplasia (BPD) at 28 days (defined as

O2 requirement at 28 days postnatal age in addition to compatible clinical and roentgenographic findings)

• BPD at 36 weeks PMA (defined as O2 requirement at 36

weeks PMA in addition to compatible clinical and roentgenographic findings)

• BPD defined according to the new criteria: mild BPD

defined as a need for supplemental O2 for ≥28 days but not at

36 weeks’ PMA or discharge, moderate BPD as O2 for ≥28 days

plus treatment with < 30% O2 at 36 weeks’ PMA, and severe BPD as O2 for ≥28 days plus ≥30% O2 or positive pressure, or both, at 36 weeks’ PMA (Ehrenkranz 2005)

• Intraventricular haemorrhage (IVH) (Grade I-IV)

• Severe IVH (Grade III-IV)

• Periventricular leukomalacia (PVL)

• Necrotizing enterocolitis (NEC) (any stage)

• Intestinal perforation

• Gastrointestinal bleed

• Retinopathy of prematurity (ROP) (according to the

international classification of ROP); any stage and stage ≥3

• Decreased urine output (defined as < 1 cc/kg/hr) during

treatment

• Sepsis (clinical symptoms and signs of sepsis and a positive

blood bacterial culture); this outcome was added at the full review stage

• Serum or plasma levels of creatinine (mmol/L) after

treatment

• Serum or plasma levels of aspartate transaminase (AST)

(IU/L) following treatment

• Serum or plasma levels of alanine transaminase (ALT) (IU/

L) following treatment

• Number of infants with AST or ALT levels > 100 IU/mL

• Serum bilirubin (mmol/L) following treatment

• Hyperbilirubinaemia (serum bilirubin level higher than the

exchange level according to the postnatal age and body weight)

• Incidence of liver failure; evidence of acute liver injury

combined with either severe coagulopathy (International Normalized Ratio (INR) > 2.0 or prothrombin time (PT) > 20 seconds) or encephalopathy with moderate coagulopathy (INR ≥1.5 or PT ≥15 seconds) (Sundaram 2011)

• Duration of hospitalisation (total length of hospitalisation

from birth to discharge home or death) (days)

• Other side effects reported by the authors (not pre-

specified) Search methods for identification of studies See: Cochrane Review Group search strategy. Electronic searches We used the standard search strategy of the Cochrane Neonatal Review Group as outlined in the Cochrane Library. This included electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL, Cochrane Library), MEDLINE (1966 to De-

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Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

cember2013),EMBASE(1980toDecember2013)andCINAHL (1982 to December 2013). Ms Colleen Ovelman, Trials Search Co-ordinator, Cochrane Neonatal Review Group, conducted the searches modified as needed for the different databases. For MED- LINE the following search string was used: (paracetamol OR acetaminophen) AND (patent ductus arteriosus or PDA) AND ((infant, newborn[MeSH] OR newborn OR neonate OR neonatal OR premature OR low birth weight OR VLBW OR LBW or infan* or neonat*) AND (randomised controlled trial [pt] OR controlled clinical trial [pt] OR Clinical Trial[ptyp] OR randomised [tiab] OR placebo [tiab] OR clinical trials as topic [mesh: noexp] OR randomly [tiab] OR trial [ti]) NOT (animals [mh] NOT humans [mh])). Relevant reviews related to the topic were identified. No language restrictions were applied.

We conducted electronic searches of abstracts from the meetings of the Pediatric Academic Societies 2000 to 2013 and the Perinatal Society of Australia and New Zealand 2000 to 2013. We searched the following clinical trials registries for ongoing or recently completed trials: clinicaltrials.gov; controlled-trials.com; anzctr.org.au; who.int/ictrp in December 2013. We searched the Web of Science for articles quoting identified RCTs in December

2013.

We searched the first 200 hits on Google ScholarT M to identify grey literature. We limited the Google ScholarTM to the first 200 hits as in our experience the yield is poor after 200 hits. We repeated the search of MEDLINE in August 2014 and did not identify any new trials.

Searching other resources We performed manual searches of the reference lists of full-text versions of eligible articles (RCTs and reviews) identified in the primary search of the literature.

Data collection and analysis Standard methods of The Cochrane Collaboration and its Neonatal Review Group were used.

Selection of studies Two review authors independently assessed study eligibility for inclusion in this review according to the pre-specified selection criteria.

Data extraction and management Tworeviewauthorsindependentlyextracteddatafromthe full-text articles using a specifically designed spread sheet and customized form to manage information. We used these forms to decide trial inclusion and exclusion, extract data from eligible trials, and for requesting additional published information from authors of the original report. We entered and cross-checked data using RevMan

5.3 software (RevMan 2014). We compared the extracted data

for any differences. If noted, we resolved differences by mutual discussion and consensus. We contacted the authors of the two identified trials and we obtained unpublished data from the Oncel group (Oncel 2013) and the Dang group (Dang 2013). Assessment of risk of bias in included studies The following headings and associated questions (based on the questions in the ’Risk of bias’ table) were evaluated by the two review authors and entered into the ’Risk of bias’ table. Selection bias (random sequence generation and allocation concealment) Adequate sequence generation?

For each included study, we categorized the risk of selection bias. Low risk: adequate (any truly random process e.g. random number table; computer random number generator).

High risk: inadequate (any non random process e.g. odd or even date of birth; hospital or clinic record number). Unclear risk: no or unclear information provided. Allocation concealment?

For each included study, we categorized the risk of bias regarding allocation concealment.

Low risk: adequate (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes). High risk: inadequate (open random allocation; unsealed or nonopaque envelopes; alternation; date of birth). Unclear risk: no or unclear information provided. Blinding?

Performance bias For each included study, we categorized the methods used to blind study personnel from knowledge of which intervention a participant received. As our study population consisted of neonates they would all be blinded to the study intervention. Low risk: adequate for personnel (a placebo that could not be distinguished from the active drug was used in the control group). High risk: inadequate, personnel aware of group assignment. Uncelar risk: no or unclear information provided.

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Detection bias For each included study, we categorized the methods used to blind outcome assessors from knowledge of which intervention a participant received. As our study population consisted of neonates they would all be blinded to the study intervention. Blinding was assessed separately for different outcomes or classes of outcomes. We categorized the methods used with regards to detection bias. Low risk: adequate, follow-up was performed with assessors blinded to group.

High risk: inadequate, assessors at follow-up were aware of group assignment.

Unclear risk: no or unclear information provided. Incomplete data addressed?

Attrition bias For each included study and for each outcome, we describe the completeness of data including attrition and exclusions from the analysis. We noted whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total number of randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information was reported or supplied by the trial authors, we planned to re-include missing data in the analyses. We categorized the methods with respect to the risk of attrition bias. Low risk: adequate (< 10% missing data).

High risk: inadequate (> 10% missing data).

Unclear risk: no or unclear information provided. Free of selective reporting?

Reporting bias Foreach includedstudy, we describe howwe investigatedthe riskof selective outcome reporting bias and what we found. We assessed the methods as follows.

Low risk: adequate (where it is clear that all of the study’s prespecified outcomes and all expected outcomes of interest to the review have been reported).

High risk: inadequate (where not all the study’s pre-specified outcomes have been reported; one or more reported primary outcomes were not pre-specified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported).

Unclear risk: no or unclear information provided (the study protocol was not available).

Free of other bias?

Other bias For each included study, we describe any important concerns we have about other possible sources of bias (for example, whether there was a potential source of bias related to the specific study design or whether the trial was stopped early due to some datadependent process). We assessed whether each study was free of other problems that could put it at risk of bias. Low risk: no concerns of other bias raised.

High risk: concerns raised about multiple looks at the data with the results made known to the investigators; difference in number of patients enrolled in abstract and final publications of the paper. Unclear: concerns raised about potential sources of bias that could not be verified by contacting the authors.

Overall risk of bias We made explicit judgements about whether studies were at high risk of bias, according to the criteria given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We planned to assess the likely magnitude and direction of the bias and whether we considered it was likely to impact on the findings. We planned to explore the impact of the level of bias through undertaking sensitivity analyses, see ’Sensitivity analysis’. We usedthe GRADEapproach (Guyatt 2011; Schünemann2009) in order to assess the quality of the body of evidence relating to the following key outcomes for the only comparison of ’oral paracetamol versus oral ibuprofen’.

1. Failure of ductal closure after the first course of treatment.

2. All-cause mortality during initial hospital stay.

3. Surgical closure of the PDA following treatment failure with

paracetamol or ibuprofen.

4. Severe IVH (Grade III-IV).

5. NEC.

6. Oliguria (< 1 cc/kg/hr)

7. Serum levels of creatinine after treatment (mmol/L).

We used GRADEprofiler (GRADEpro 2014) to import data from Review Manager 5.3 (RevMan 2014) in order to create a ’Summary of findings’ table. A summary of the intervention effect and a measure of quality for each of the above outcomes was produced using the GRADE approach. The GRADE approach uses five considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the quality of the body of evidence for each outcome. The evidence can be downgraded from ’high quality’ by one level for serious (or by two levelsfor very serious) limitations, depending on assessments for risk of bias, indirectness of evidence, serious inconsistency, imprecision of effect estimates or potential publication bias.

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Measures of treatment effect We analysed treatment effects in the individual trials using RevMan 5.3 (RevMan 2014).

Dichotomous data We reported dichotomous data using risk ratio (RR) and risk difference (RD) with respective 95% confidence intervals (CI). For those outcomes with a statistically significant RD for the pooled estimate from the meta-analysis, we calculated the number needed to benefit (NNTB) or number needed to harm (NNTH) and respective 95% CI.

Continuous data We reported continuous data using mean difference (MD) with 95% CI. If the authors had reported continuous data as median and range we would have estimated the mean and variance from the median, range and the size of the sample according to the formulas by Hozo 2005.

Unit of analysis issues The unit of randomisation was the individual infant. We did not include cross-over or cluster randomised trials as those trial designs are unlikely for the intervention studied in this review. No crossoverorclusterrandomisedtrialswere identified. Aninfantwasonly consideredonce evenifthe infantmayhave beenrandomisedtwice by investigators. We planned to contact the authors in order to provide data resulting from the first randomisation. If we could not separate data from the first randomisation, the study was planned to be excluded.

Dealing with missing data We requested additional data from the authors of each included trial when data on important outcomes were missing or needed clarification. We did receive clarifying information from the authors of both included trials (Dang 2013; Oncel 2013). The authors clarified that all the analyses that were published or they provided us with were intention-to-treat analyses. Assessment of heterogeneity We used RevMan 5.3 software to assess the heterogeneity of treatment effects between trials. We used the following two formal statistics described below.

1. The Chi2 test, to assess whether observed variability in

effect sizes between studies was greater than would be expected by chance. Since this test has low power when the number of studies included in the meta-analysis is small, we set the alpha probability at the 10% level of significance.

2. The I2 statistic to ensure that pooling of data was valid. We

graded the degree of heterogeneity as: none, low, moderate, and high for values of < 25%, ≥25% to 49%, 50% to 74%, and ≥ 75% respectively (Higgins 2003). There was no evidence of statistically significant heterogeneity for any of the analyses for which results from both the included trials were included (I2 = 0 % for most analyses, and all results for I2 < 25%, that is none). Assessment of reporting biases We identified the study protocols for both the trials we selected for inclusion (see the table ’Characteristics of included trials’). We planned to assess reporting and publication bias by examining the degree of asymmetry of a funnel plot in RevMan 5.3 provided that a sufficient number of studies (n = 10) were available (RevMan 2014). However, this was not feasible as only two trials were included in any one meta-analysis (Dang 2013; Oncel 2013). Data synthesis We performed statistical analyses according to the recommendations of the Cochrane Neonatal Review Group (http://neonatal.cochrane.org/en/index.html). We analysed all infants randomised on an intention-to-treat basis. We analysed treatment effects in the individual trials. We used a fixed-effect model in the meta-analysis to combine the data. Where substantial heterogeneity existed, the potential cause of heterogeneity would have been examined in subgroup and sensitivity analyses. There was no heterogeneity between the included study results (I2 < 25%). When we judgedmeta-analysistobe inappropriate, we plannedtoanalyse and interpret individual trials separately. For estimates of typical RR and RD, we used the Mantel-Haenszel method. For measured quantities, we used the inverse variance method. We would have used the standardized mean difference (SMD) to combine trials that measured the same outcome but used different scales. Subgroup analysis and investigation of heterogeneity The following subgroup analyses were pre-specified:

• gestational age (< 28 weeks, 28 to 32 weeks, 33 to 36

weeks);

• birth weight (<1000 g, 1000 to 1500 g, 1501 to 2500 g).

Subgroup analyses to determine the efficacy and safety of paracetamol for closure of a PDA in relation to postnatal ages of < 7 days, 7 to 14 days and > 14 days at the time of administration of the first dose of paracetamol.

The data from the two included studies were not suitable for subgroup analyses according to the pre-specified categories.

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Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Sensitivity analysis A sensitivity analysis was planned to be performed to determine if the findings were affected by including only studies of adequate methodology, defined as adequate randomisation and allocation concealment, blinding of intervention and measurement, and < 10% losses to follow-up.

The two studies were of equal quality.

R E S U L T S Description of studies Results of the search The literature searches in December 2013 identified three published studies (Dang 2013; Oncel 2013; Zarkesh 2013) and three ongoing studies (NCT01938261; NCT01291654; NCT02002741). The study by Zarkesh 2013 has been published in abstract form only and awaits further classification, leaving two studies for inclusion in this review.

Included studies For details see the table ’Characateristics of included studies’. Dang 2013 was a single centre study conducted in Changchun, China.

• Objective: to evaluate the efficacy and safety profiles of oral

paracetamol to those of standard ibuprofen for PDA closure in preterm infants.

• Population: preterm infants with PMA ≤34 weeks with

echocardiographically confirmed PDA; postnatal age ≤14 days.

• Intervention or contrast: the paracetamol group received 15

mg/kg of paracetamol orally every 6 hours for 3 days; the ibuprofen group received oral ibuprofen at an initial dose of 10 mg/kg followed by 5 mg/kg after 24 and 48 hours.

• Outcomes assessed, primary outcome: rates of ductal

closure after treatment confirmed by daily cardiography during treatment; secondary outcomes: oliguria (urine output < 1 cc/kg/ hr), IVH, tendency to bleed, NEC, hyperbilirubinaemia, serum creatinine, death, BPD, PVL, NEC, ROP, sepsis.

• Notes: we contacted the authors in January 2014 to obtain

unpublished information regarding outcomes, and we received information in April 2014.

Oncel2013 wasasingle centre studyconductedin Ankara, Turkey.

• Objective: to compare the efficacy and safety oral

paracetamol and oral ibuprofen for the pharmacological closure of PDA in preterm infants.

• Population: preterm infants PMA ≤30 weeks, birthweight

≤1250 g with echocardiographically confirmed significant PDA; postnatal age 48 to 96 hours.

• Intervention or contrast: the paracetamol group received 15

mg/kg of paracetamol orally every 6 hours for 3 days; the ibuprofen group received oral ibuprofen at an initial dose of 10 mg/kg followed by 5 mg/kg after 24 and 48 hours.

• Outcomes assessed, primary outcome: rates of ductal

closure after treatment by echocardiography performed by a cardiologist who was blinded to the treatment group; secondary outcomes: all-cause mortality during initial hospital stay, neonatal mortality (first 28 days of life), infant mortality, reopening of the ductus arteriosus, surgical closure of the PDA, duration of ventilatory support, duration of need for supplementary oxygen, pulmonary haemorrhage, pulmonary hypertension, BPD (at 28 days and at 36 weeks PMA, severe BPD at 36 weeks PMA), IVH (all grades and Grade III-IV), PVL, NEC, intestinal perforation, gastrointestinal bleeding, ROP (any stage, stage ≥3, ROP requiring laser treatment), oliguria (urine output < 1 cc/kg/hr), serum levels after treatment of creatinine, bilirubin, aspartate transaminase, alanine transaminase, liver failure, duration of hospital stay, sepsis.

• Notes: we contacted the authors and received unpublished

information regarding several of the outcomes listed above, we received information in January 2014. The published report includes 80 patients who actually received the intervention whereas from the authors we received information on all outcomes for all 90 enrolled patients.

Excluded studies No study was excluded but the study by Zarkesh 2013 was published in abstract form only and is awaiting classification before it can be included or excluded. There are at least three ongoing trials (NCT01938261; NCT01291654; NCT02002741) that we identified in clinical trials registries.

Risk of bias in included studies For details see Figure 1 (’Risk of bias’ graph) and Figure 2 (’Risk of bias’ summary).

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Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Figure 1.

Risk of bias graph: review authors’ judgements about each risk of bias item presented as percentages across all included studies.

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Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Figure 2.

Risk of bias summary: review authors’ judgements about each risk of bias item for each included study.

The randomisation sequence was computer generated in both studies.

Allocation Both studies used sequentially numbered, sealed opaque envelopes for the allocation to the two treatment groups. Blinding In both studies (Dang 2013; Oncel 2013) the two study drugs were administered at different time points after the initial dose. Both studies administered paracetamol 15 mg/kg every 6 hours for 3 days and ibuprofen was given at an initial dose of 10 mg/ kg followed by 5 mg/kg after 24 and 48 hours. No placebo was administered at time points when no active drug was administered in one of the treatment groups, to try and mask what drug was given. Therefore, healthcare providers and researchers were not blinded to group allocation of the infants. Dang 2013 states “doctors and nurses were not blind”. Oncel 2013 reports “....the intervention was not completely blinded because of the different number of doses per day of the drugs. However, the most important outcome-PDA closure-was made by a cardiologist, who was blinded to the treatment groups”.

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Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Incomplete outcome data Outcome data reported for all pre-set outcomes and for all enrolled infants.

Selective reporting The protocols for both studies were available to us as the trials were registered in the Chinese Clinical Trial Register (Dang 2013) and at ClinicalTrials.gov (Oncel 2013). We found no indication of selective reporting.

Other potential sources of bias There were no other sources of bias identified. We considered the overall risk of bias in the two studies to be low. Effects of interventions See: Summary of findings for the main comparison Oral paracetamol compared to oral ibuprofen for patent ductus arteriosus in preterm or low-birth-weight infants Oral paracetamol versus oral ibuprofen (Comparison 1) Primary outcomes Failure of PDA closure after the first course of paracetamol treatment (closure and failure of closure confirmed by echocardiographic criteria) (Outcome 1.1) See Analysis 1.1. Figure 3 Figure 3.

Forest plot of comparison: 1 Oral paracetamol versus oral ibuprofen, outcome: 1.1 Failure of ductal closure after the first course of treatment. Both studies (n = 250 infants) reported on this outcome. There was no significant difference between the paracetamol and the ibuprofen groups in failure of PDA closure (typical RR 0.90, 95%

0.67 to 1.22; typical RD -0.04, 95% CI -0.16 to 0.08; I2 = 0%

for RR and I2 = 23% for RD).

Neurodevelopmental outcome (neurodevelopmental outcome assessed by a standardized and validated assessment tool or a child developmental specialist, or both) at any age reported (outcome data will be grouped at 12, 18, 24 months if available) No study has reported on this outcome.

Autism or autism spectrum disorder (ASD) in childhood As defined by the American Psychiatric Association (American Psychiatric Association 2013).

No study has reported on this outcome.

Secondary outcomes All-cause mortality during initial hospital stay (Outcome 1.2) See Analysis 1.2 Both studies (n = 250 infants) reported on this outcome. There was no significant difference between the paracetamol and the ibuprofen groups in all-cause mortality during the initial hospital stay (typical RR 0.95, 95% CI 0.52 to 1.72; typical RD -0.01, 95% CI -0.10 to 0.08; I2 = 0% (none) for both RR and RD). Neonatal mortality (death during the first 28 days of life) (Outcome 1.3) See Analysis 1.3 One study (n = 90 infants) reported on this outcome. There was no significant difference between the paracetamol and the ibuprofen groups in neonatal mortality (RR 1.17, 95% CI 0.43 to 3.20; RD

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Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

0.02, 95% CI -0.12 to 0.17). The test for heterogeneity was not applicable.

Infant mortality (death during the first year of life) (Outcome 1.4) See Analysis 1.4 One study (n = 90 infants) reported on this outcome. There was no significant difference between the paracetamol and the ibuprofen groups in infant mortality (RR 1.14, 95% CI 0.45 to 2.89; RD 0.02, 95% CI -0.13 to 0.18). The test for heterogeneity was not applicable.

Re-opening of the ductus arteriosus (defined as echocardiographic evidence of closure followed by reopening of PDA at later stage) (Outcome 1.5) See Analysis 1.5 Both studies (n = 143 infants) reported on this outcome. There was no significant difference between the paracetamol and the ibuprofen groups in the risk of re-opening of the ductus arteriosus (typical RR 1.04, 95% CI 0.50 to 2.18; typical RD 0.01, 95% CI -0.11 to 0.13; I2 = 0% (none) for RR and I2 = 1% (none) for RD).

Surgical closure of the PDA following treatment failure with paracetamol or placebo (Outcome 1.6) See Analysis 1.6 One study (n = 90 infants) reported on this outcome. There was no significant difference between the paracetamol and the ibuprofen groups in surgical closure of the PDA following treatment failure (RR 0.50, 95% CI 0.05 to 5.32; RD -0.02, 95% CI -0.10 to 0.05). The test for heterogeneity was not applicable. Treatment with indomethacin, ibuprofen or other prostaglandin inhibitor to close the PDA following treatment failure with paracetamol or placebo This outcome was not reported in either of the two included studies.

Duration of ventilator support (days) (Outcome 1.7) See Analysis 1.7 One study (n = 90 infants) reported on this outcome. There was no significant difference between the paracetamol and the ibuprofen groups in the duration of ventilator support (mean difference (MD) -4.15 days, 95% CI -8.63 to 0.33). The test for heterogeneity was not applicable.

Pulmonary haemorrhage (blood stained liquid flowing from the trachea of the infant) (Outcome 1.8) See Analysis 1.8 One study (n = 90 infants) reported on this outcome. There was no significant difference between the paracetamol and the ibuprofen groups in the risk of pulmonary haemorrhage (RR 1.00, 95% CI 0.21 to 4.69; RD 0.00, 95% CI -0.10 to 0.10). The test for heterogeneity was not applicable.

Pulmonary hypertension (defined as an increased mean pulmonary arterial pressure of 25 mmHg at rest) (Outcome 1.9) See Analysis 1.9 One study (n = 90 infants) reported on this outcome. There was no significant difference between the paracetamol and the ibuprofen groups in pulmonary hypertension (RR 0.33, 95% CI 0.01 to 7.97; RD -0.02, 95% CI -0.08 to 0.04). The test for heterogeneity was not applicable.

Duration of need for supplementary oxygen (days) (Outcome 1.10) See Analysis 1.10, Figure 4 Figure 4.

Forest plot of comparison: 1 Oral paracetamol versus oral ibuprofen, outcome: 1.10 Duration for need of supplementary oxygen (days).

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Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

One study (n = 90 infants) reported on this outcome. There was a significant difference between the paracetamol and the ibuprofen groups in the duration of need of supplementary oxygen (O2) favouring the paracetamol treated group (MD -12.40 days, 95% CI -22.97 to -1.83). The test for heterogeneity was not applicable. Bronchopulmonary dysplasia (BPD) at 28 days (defined as O2requirement at 28 days postnatal age in addition to compatible clinical and roentgenographic findings) (Outcome 1.11) See Analysis 1.11 One study (n = 90 infants) reported on this outcome. There was no significant difference between the paracetamol and the ibuprofen groups in the risk of BPD at 28 days postnatal age (RR 0.79, 95% CI 0.46 to 1.35; RD -0.09, 95% CI -0.29 to 0.11). The test for heterogeneity was not applicable.

BPD at 36 weeks PMA (defined as O2requirement at 36 weeks PMA in addition to compatible clinical and roentgenographic findings) (Outcome 1.12) See Analysis 1.12 One study (n = 90 infants) reported on this outcome. There was no significant difference between the paracetamol and the ibuprofen groups in the risk of BPD at 36 weeks PMA (RR 0.71, 95% CI

0.38 to 1.30; RD -0.11, 95% CI -0.30 to 0.08). The test for

heterogeneity was not applicable.

Moderate to severe BPD according to the new criteria: moderate BPD defined as O2 for ≥28 days plus treatment with < 30% O2 at 36 weeks’ PMA; and severe BPD as O2 for ≥28 days plus ≥30% O2 or positive pressure at 36 weeks’ PMA, or both (Outcome 1.13) See Analysis 1.13 One study (n = 160 infants) reported on this outcome. There was no significant difference between the paracetamol and the ibuprofen groups (RR 0.80, 95% CI 0.22 to 2.87; RD -0.01, 95% CI -0.08 to 0.06). The test for heterogeneity was not applicable. Severe BPD defined according to the new criteria: severe BPD defined as O2 for ≥28 days plus ≥30% O2 or positive pressure at 36 weeks’ PMA, or both (Outcome 1.14) See Analysis 1.14 One study (n = 90 infants) reported on this outcome. There was no significant difference between the paracetamol and the ibuprofen groups in the risk of severe BPD (RR 0.63, 95% CI 0.32 to 1.23; RD -0.13, 95% CI -0.32 to 0.05). The test for heterogeneity was not applicable.

Intraventricular haemorrhage (IVH) (Grade I-IV) (Outcome 1.15) See Analysis 1.15 Both studies reported on this outcome, in 250 infants. There was no significant difference between the paracetamol and the ibuprofen groups in the risk of IVH (typical RR 0.92, 95% CI 0.73 to 1.15; typical RD -0.03, 95% CI -0.12 to 0.05; I2 = 0% (none) for RR and for RD).

Severe IVH (Grade III-IV) (Outcome 1.16) See Analysis 1.16 Both studies reported on this outcome, in 250 infants. There was no significant difference between the paracetamol and the ibuprofen groups in the risk of severe IVH (typical RR 1.00, 95% CI

0.30 to 3.37; typical RD 0.00, 95% CI -0.05 to 0.05; I2 = 0%

(none) for RR and for RD).

Periventricular leukomalacia (PVL) (Outcome 1.17) See Analysis 1.17 Both studies reported on this outcome, in 250 infants. There was no significant difference between the paracetamol and the ibuprofen groups in the risk of PVL (typical RR 1.00, 95% CI 0.36 to 2.76; typical RD -0.00, 95% CI -0.06 to 0.06; I2 = 0% (none) for RR and for RD).

Necrotizing enterocolitis (NEC) (any stage) (Outcome

1.18)

See Analysis 1.18 Both studies (n = 250 infants) reported on this outcome. There was no significant difference between the paracetamol and the ibuprofen groups in the risk of NEC (typical RR 1.50, 95% CI

0.43 to 5.18; typical RD 0.02, 95% CI -0.03 to 0.06; I2 = 0%

(none) for RR and for RD).

Intestinal perforation (Outcome 1.19) See Analysis 1.19 One study (n = 90 infants) reported on this outcome. Intestinal perforation did not occur in any patients in either of the two groups. The RR was not estimable and there was no significant difference between the paracetamol and the ibuprofen groups (RD 0.00, 95% CI -0.04 to 0.04). The test for heterogeneity was not applicable.

Gastrointestinal bleed (Outcome 1.20) See Analysis 1.20 Both studies (n = 250 infants) reported on gastrointestinal bleeding. There was no significant difference between the paracetamol

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Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

and the ibuprofen groups in the typical RR (typical RR 0.30, 95% CI 0.08 to 1.06; P = 0.06) but there was a significant difference in the typical RD (RD -0.06, 95% CI -0.11 to -0.00; P = 0.04) favouring paracetamol over ibuprofen (NNTB 17, 95% CI 9 to infinity; I2 = 0% (none) for RR and 5% (none) for RD). Retinopathy of prematurity (ROP) any stage (according to the international classification of ROP) (Outcome

1.21)

See Analysis 1.21 Both studies (n = 250 infants) reported on this outcome, in 250 infants. There was no significant difference between the paracetamol and the ibuprofen groups in the risk of developing ROP (typical RR 0.72, 95% CI 0.37 to 1.41; typical RD -0.04, 95% CI -0.12 to 0.04; I2 = 0% (none) for RR and for RD). ROP stage ≥3 (according to the international classification of ROP) (Outcome 1.22) See Analysis 1.22 One study (n = 90 infants) reported on this outcome. There was no significant difference between the paracetamol and the ibuprofen groups in the RR (RR 0.43, 95% CI 0.12 to 1.55) or in the RD (RD -0.09, 95% CI -0.22 to 0.04). The test for heterogeneity was not applicable.

ROP requiring laser therapy (Outcome 1.23) See Analysis 1.23 One study (n = 90 infants) reported on this outcome. There was no significant difference between the paracetamol and the ibuprofen groups in the risk of developing ROP requiring laser therapy (RR 0.43, 95% CI 0.12 to 1.55; RD -0.09, 95% CI -0.22 to 0.04). The test for heterogeneity was not applicable. Sepsis (clinical symptoms and signs of sepsis and a positive blood bacterial culture) (Outcome 1.24) See Analysis 1.24 One study (n = 90 infants) reported on this outcome. There was no significant difference between the paracetamol and the ibuprofen groups in the risk of sepsis (RR 1.08, 95% CI 0.57 to 2.03; RD 0.02, 95% CI -0.17 to 0.21). The test for heterogeneity was not applicable.

Oliguria (decreased urine output (defined as < 1 cc/kg/hr) during treatment) (Outcome 1.25) See Analysis 1.25 Both studies (n = 250 infants) reported on this outcome. Oliguria did not occur in any infant in the study by Oncel (Oncel 2013). There was no significant difference between the paracetamol and the ibuprofen groups in risk of oliguria (typical RR 0.67, 95% CI

0.25 to 1.79; typical RD -0.02, 95% CI -0.08 to 0.04; I2 test not

applicable for RR and 24% (none) for RD).

Serum or plasma levels of creatinine (mmol/L) after treatment (Outcome 1.26) See Analysis 1.26 Two studies (n = 250 infants) reported on this outcome. There was no significant difference between the paracetamol and the ibuprofen groups in creatinine levels (typical weighted mean difference (WMD) -1.05 mmol/L, 95% CI -5.32 to 3.21; I2 = 0% (none) for WMD).

Serum or plasma levels of aspartate transaminase (AST) (IU/L) following treatment (Outcome 1.27) See Analysis 1.27 One study reported on this outcome, in 90 infants. There was no significant difference between the paracetamol and the ibuprofen groups in the serum or plasma levels of AST (MD 4.20 IU/L, 95% CI -1.83 to 10.23). The test for heterogeneity was not applicable. Number of infants with AST or alanine amino transaminase (ALT) levels > 100 IU/mL No study reported on this outcome.

Serum or plasma levels of ALT (IU/L) following treatment (Outcome 1.28) See Analysis 1.28 One study reported on this outcome, in 90 infants. There was no significant difference between the paracetamol and the ibuprofen groups in the serum or plasma levels of ALT (MD 4.00 IU/L, 95% CI -3.58 to 11.58). The test for heterogeneity was not applicable. Serum bilirubin (mmol/L) following treatment (Outcome 1.29) See Analysis 1.29 One study reported on this outcome, in 90 infants. There was no significant difference between the paracetamol and the ibuprofen groups in the serum bilirubin (mmol/L) following treatment (MD -3.40 IU/L, 95% CI -15.74 to 8.94). The test for heterogeneity was not applicable.

Hyperbilirubinaemia (serum bilirubin level higher than the exchange level according to the postnatal age and body weight) (Outcome 1.30) See Analysis 1.30. Figure 5

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Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Figure 5.

Forest plot of comparison: 1 Oral paracetamol versus oral ibuprofen, outcome: 1.30 Hyperbilirubinaemia (serum bilirubin level higher than the exchange level according to the postnatal age and body weight.

One study reported on this outcome, in 160 infants. There was a significant difference in hyperbilirubinaemia favouring the paracetamol groups (RR 0.57, 95% CI 0.34 to 0.97; RD -0.15, -0.29 to -0.01; NNTB 7, 95% CI 3 to 100).

Duration of hospitalisation (total length of hospitalisation from birth to discharge home or death, in days) (Outcome 1.31) Analysis 1.31 One study reported on this outcome, in 90 infants. There was no significant difference between the paracetamol and the ibuprofen groups in the duration of hospitalisation (MD -6.50 days, 95% CI -21.42 to 8.42). The test for heterogeneity was not applicable. Incidence of liver failure; evidence of acute liver injury combined with either severe coagulopathy (International Normalized Ratio (INR) > 2.0 or prothrombin time (PT) > 20 seconds) or encephalopathy with moderate coagulopathy (INR ≥

1.5 or PT ≥15 seconds)

One study (n = 90 infants) reported on this outcome. Liver failure did not occur in any infant enrolled in the study. Other side effects reported by the authors (not prespecified) Oncel (Oncel 2013) reported that no other side effectswere noted. D I S C U S S I O N Summary of main results The two studies completed to date have compared oral paracetamol to oral ibuprofen. Both studies used oral paracetamol at the dose of 15 mg/kg every 6 hours for 3 days and the comparison group received oral ibuprofen at the initial dose of 10 mg/kg followed by 5 mg/kg after 24 and 48 hours.

There was no significant difference in the primary outcome of failure of PDA closure after the first course of paracetamol (closure and failure of closure confirmed by echocardiographic criteria), although the trend favoured paracetamol over ibuprofen. Of the many secondary outcomes two reached statistical significance. The duration of need for supplementary oxygen reported in one study (n = 90) was reduced in favour of paracetamol (MD -12 days, 95% CI -23 to -2 days). Hyperbilirubinemia (serum bilirubin level higher than the exchange level according to the postnatal age and body weight) reported in one study (n = 160) showed a RR of 0.57 (95% CI 0.34 to 0.97), a RD of -0.15 (95% CI -0.29 to -0.01) and NNTB of 7 (95% CI 3 to 100).

There were no concerns in the results for mortality or common adverse neonatal outcomes.

Overall completeness and applicability of evidence To date, 250 infants have been enrolled in two trials comparing the effectiveness and safety of paracetamol compared to ibuprofen for PDA closure in preterm infants. Larger trials are required to confirm the current promising evidence. Recently Viber and coworkers (Viberg 2014) reported that paracetamol administration during neonatal brain development affects cognitive function and alters its analgesic and anxiolytic response in adult male mice. The dose of paracetamol used in mice was similar to that used in the two studies included in this review. In view of the possible negative impact of paracetamol on the developing brain reported in mice (Viberg 2014), the long-term effects of paracetamol used for PDA closure or prevention and treatment of pain need to be studied carefully. In addition, in an ecological study conducted in humans and using country-level data for the period 1984 to 2005, postnatal use of paracetamol was associated with autism or autism spectrum disorder (ASD) (Bauer 2013).

There are at least three ongoing trials that should provide additional evidence regarding this topic. The researchers should be encouraged to include pharmacokinetic data to determine optimal dosing regimen, duration of treatment and mode of administration (El-Khuffash 2014). Long-term follow-up should be planned to at least 18 to 24 months and preferably to school age.

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Quality of the evidence Although healthcare providers and researchers were aware of group assignment, we considered the two included trials to be of good quality as the random sequence was computer generated and allocation to the two study groups was by opaque, sequentially numbered and sealed envelopes. In addition, we were able to obtain unpublished data from both studies (Dang 2013; Oncel 2013) enabling us to report outcomes on all randomised infants (intentionto-treat analyses). The quality of the evidence, using GRADE, was low for the outcome ’failure of ductal closure after the first course of treatment’ and moderate for six other important outcomes; ’allcause mortality during initial hospital stay’, ’ surgical closure of the PDA following treatment failure with paracetamol or ibuprofen’, ’severe IVH (Grade III-IV)’, ’necrotizing enterocolitis’, ’oliguria (< 1 cc/kg/hr)’, and ’serum levels of creatinine after treatment in mmol/L’.

Potential biases in the review process We are not aware of any biases in the review process. Agreements and disagreements with other studies or reviews We are not aware of any other published systematic reviews on the topic. Le and co-workers (Le 2015) recently published a narrative review of published case series and the two RCTs that we included (Dang 2013; Oncel 2013). They concluded: “Oral acetaminophen is an alternative to PDA therapy in preterm infants when indomethacin/ibuprofen is not effective or is contraindicated, and it may be considered before surgical ligation”. A U T H O R S ’ C O N C L U S I O N S Implications for practice Further research regarding the effectiveness and safety of paracetamol to close a PDA is needed before recommendations for practice can be stated.

Implications for research Additional larger trials are required to increase the precision of the point estimates for the primary and secondary outcomes included in this review. In view of the recent report in mice of adverse effects on the developing brain from paracetamol (Viberg 2014), and the association between postnatal use of paracetamol and autism and autism spectrum disorder (ASD) (Bauer 2013), long-term followup to 18 to 24 months postnatal age and preferably to school-age should be incorporated in any studies of paracetamol to close a PDA or to prevent or treat pain.

A C K N O W L E D G E M E N T S We are grateful to Ms Colleen Ovelman, Trials Search Co-ordinator, Cochrane Neonatal Review Group, who conducted the literature searches. We are thankful to Dr Mehmet Yekta Oncel, who provided us with unpublished data from their study (Oncel 2013). We are thankful to Dr Hui Wu, who provided us with unpublished information form their study (Dang 2013). R E F E R E N C E S References to studies included in this review Dang 2013 {published data only} Dang D, Wang D, Zhang C, Zhou W, Zhou Q, Wu H. Comparison of oral paracetamol versus ibuprofen in premature infants with patent ductus arteriosus: A randomized controlled trial. PLos ONE 2013;8(11):e77888. Oncel 2013 {published data only} Oncel MY, Yurttutan S, Erdeve O, Uras N, Altug N, Oguz SS, et al. Oral paracetamol versus oral ibuprofen in the management of patent ductus arteriosus in preterm infants: A randomized controlled trial. The Journal of Pediatrics 2013;13:S0022-3476(13)01394-2. doi: 10.1016/ j.jpeds.2013.11.008. [Epub ahead of print].

References to studies awaiting assessment Zarkesh 2013 {published data only} Zarkesh MR, Nili F, Akbari Asbagh P, Nayeri FS, Naeem A. Prophylactic treatment with oral paracetamol for patent ductus arteriosus in preterm infants admitted in NICU Vali- Asr Hospital in 2012. Iranian Journal of Pediatrics 2013;23: S54–5.

References to ongoing studies NCT01291654 {published data only} NCT01291654. Paracetamol in the treatment of patent ductus arteriosus in the premature neonate. Clinicaltrials.gov/show/NCT01291654 (December 2013). NCT01938261 {published data only} NCT01938261. The preterm infants’ paracetamol study (PreParaS). Clinicaltrials.gov/show/NCT01938261 (December 2013).

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NCT02002741 {published data only} NCT02002741. Adding paracetamol to ibuprofen for treatment of patent ductus arteriosus in preterm infants. ClinicalTrials.gov/show/NCT02002741 (December 2013). Additional references American Psychiatric Association 2013 American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th Edition. Arlington, VA: American Psychiatric Association, 2013. Arana 2001 Arana A, Morton NS, Hansen TG. Treatment with paracetamol in infants. Acta Anaesthesiologica Scandinavica

2001;45:20–9. [PUBMED: 11152028 ]

Bartocci 2007 Bartocci M, Lundberg S. Intravenous paracetamol: the ’Stockholm protocol’ for postoperative analgesia of term and preterm neonates. Pediatric Anesthesia 2007;17(11): 1120–1.

Bauer 2013 Bauer AZ, Kriebel D. Prenatal and perinatal analgesic exposure and autism: an ecological link. Environmental Health 2013;12:1–13. [PUBMED: 10.1186/1476–069X– 12–41] Botting 2000 Botting RM. Mechanism of action of acetaminophen: is there a cyclooxgygenase 3?. Clinical Infectious Diseases 2000; 31 Suppl 5:S202–10.

Clyman 2000 Clyman R. Ibuprofen and patent ductus arteriosus. The New England Journal of Medicine 2000;343(10):728–30. Drug Information Portal 2012 U.S. National Library of Medicine. Acetaminophen/ Paracetamol.

Drug Information Portal (druginfo.nlm.nih.gov/drugportal) 2012. Edwards1990 Edwards AD, Wyatt JS, Richardson C, Potter A, Cope M, Delpy DT, et al. Effects of indomethacin on cerebral haemodynamics in very preterm infants. Lancet 1990;335 (8704):1491–5.

Ehrenkranz 2005 Ehrenkranz RA, Walsh MC, Vohr BR, Jobe AH, Wright LL, Fanaroff AA, et al. Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia. Pediatrics 2005;116(6):1353–60. El-Khuffash 2014 El-Khuffash A, Jain A, Corcoran D, Shah PS, Hooper CW, Brown N, et al. Efficacy of paracetamol on patent ductus arteriosus closure may be dose dependent: evidence from human and murine studies. Pediatric Research 2014;76(3):

238–44. [PUBMED: 24941212]

Fowlie 2010 Fowlie PW, Davis PG, McGuire W. Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants. Cochrane Database of Systematic Reviews 2010, Issue 7. [DOI: 10.1002/ 14651858.CD000174.pub2] GRADEpro 2014 [Computer program] McMaster University, 2014. GRADEpro. Version [20150131]. Hamilton, Ontario, Canada: McMaster University, 2014, 2014.

Grèen 1989 Grèen K, Drvota V, Vesterqvist O. Pronounced reduction of in vivo prostacyclin synthesis in humans by acetaminophen (paracetamol). Prostaglandins 1989;37(3):311–5. Guyatt 2011 Guyatt G, Oxman AD, Aklm EA, Kunz R, Vist G, Brozeka J. GRADE guidelines: 1. Introduction - GRADE evidence profiles and summary of findings tables. Journal of Clinical Epidemiology 2011;64(4):383–94.

Hammerman 1995 Hammerman C. Patent ductus arteriosus. Clinical relevance of prostaglandins and prostaglandin inhibitors in PDA pathophysiology and treatment. Clinics in Perinatology 1995;22(2):457–79.

Hammerman 2011 Hammerman C, Bin-Nun A, Markovitch E, Schimmel MS, Kaplan M, Fink D. Ductal closure with paracetamol: a surprising new approach to patent ductus arteriosus treatment. Pediatrics 2011;128(6):e1618–21. Higgins 2003 Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327 (7414):557–60.

Higgins 2011 Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011], The Cochrane Collaboration. Available from www.cochrane-handbook.org.

Hozo 2005 Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and variance from the median, range, and the size of a sample. BMC Medical Reseach Methodology 2005;20(5):13. Jobe 2001 Jobe AH, Bancalari E. Bronchopulmonary dysplasia. NICHD/NHLB/ORD Workshop summary. American Journal of Respiratory and Critical Care Medicine 2001;163: 1723–9.

Kessel 2014 Kessel I, Waisman D, Lavie-Nevo K, Golzman M, Lorber A, Rotschild A. Paracetamol effectiveness, safety and blood level monitoring during patent ductus arteriosus closure: a case series. Journal of Maternal-Fetal & Neonatal Medicine

2014;27(16):1719–21. [PUBMED: 24460433]

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Canadian NICU network 1996-1997. Pediatrics 2000;106 (5):1070–9.

Maisels 2003 Maisels MJ, Watchko JF. Treatment of jaundice in low birthweight infants. Archives of Disease in Childhood. Fetal and Neonatal Edition 2003;88:F459–63.

Mathew 1998 Mathew R. Development of the pulmonary circulation: metabolic aspects. In: Polin RA, Fox WW editor(s). Fetal and Neonatal Physiology. Vol. 1, Philadelphia: W.B. Saunders, 1998:924–9.

Nadir 2014 Nadir E, Kassem E, Foldi S, Hochberg A, Feldman M. Paracetamol treatment of patent ductus arteriosus in preterm infants. Journal of Perinatology 2014;34(10):748–9.

[PUBMED: 24854626]

Naulty 1978 Naulty CM, Horn S, Conry J, Avery GB. Improved lung compliance after ligation of patent ductus arteriosus in hyaline membrane disease. Journal of Pediatrics 1978;93(4): 682–4.

Ohlsson 1993 Ohlsson A, Bottu J, Govan J, Ryan ML, Fong K, Myhr T. Effect of indomethacin on cerebral blood flow velocities in very low birth weight neonates with patent ductus arteriosus. Developmental Pharmacology and Therapeutics 1993;20(1-2):100–6.

Ohlsson 2011 Ohlsson A, Shah SS. Ibuprofen for the prevention of patent ductus arteriosus in preterm and/or low birth weight infants. Cochrane Database of Systematic Reviews 2011, Issue

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Ohlsson 2015 Ohlsson A, Walia R, Shah SS. Ibuprofen for the treatment of patent ductus arteriosus in preterm or low birth weight (or both) infants. Cochrane Database of Systematic Reviews 2015, Issue 2. [DOI: 10.1002/14651858.CD003481.pub6;

PUBMED: 23633310]

Palmer 2008 Palmer GM, Atkins M, Anderson BJ, Smith KR, Culnane TJ, McNally CM, et al. I.V. acetaminophen pharmacokinetics in neonates after multiple doses. British Journal of Anaesthesia 2008;101(4):523–30. Peterson 1985 Peterson RG. Consequences associated with nonnarcotic analgesics in the fetus and newborn. Federation Proceedings 1985;44(7):2309–13.

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Sakhalkar 1992 Sakhalkar VS, Merchant RH. Therapy of symptomatic patent ductus arteriosus in preterms with mefenemic acid and indomethacin. Indian Pediatrics 1992;29(3):313–8. Schünemann 2009 Schünemann HJ. GRADE: From grading the evidence to developing recommendations. A description of the system and a proposal regarding the transferabiity of the results to clinical practice [GRADE: Von der Evidenz zur Empfehlung.: Beschreibung des Systems und Lösungsbeitrag zur Übertragbarkeit von Studienergebnissen]. Zeitschrift für Evidenz, Fortbildung und Qualität im Gesundheitswesen 2009;103(6):391–400. Seyberth 1983 Seyberth HW, Rascher W, Hackenthal R, Wille L. Effect of prolonged indomethacin therapy on renal function and selected vasoactive hormones in very-low-birth-weight infants with symptomatic patent ductus arteriosus. Journal of Pediatrics 1993;103(6):979–84.

Simbi 2002 Simbi KA, Secchieri S, Rinaldo M, Demi M, Zanardo V. In utero ductal closure following near-term maternal selfmedication with nimesulide and acetaminophen. Journal of Obstetrics and Gynaecology 2002;22(4):440–1. Sinah 2013 Sinah R, Negi V, Dalal SS. An interesting observation of PDA closure with oral paracetamol in preterm neonates. Journal of Clinical Neonatology 2013;2(1):30–2. [doi: 10.4103/2249–4847.109245] Sundaram 2011 Sundaram SS, Alonso EM, Narkewicz MR, Zhang S, Squires RH, Pediatric Acute Liver Failure Study Group. Characterization and outcomes of young infants with acute liver failure. The Journal of Pediatrics 2011;159(5):813–8. Terrin 2014 Terrin G, Conte F, Scipione A, Bacchio E, Conti MG, Ferro R. Efficacy of paracetamol for the treatment of patent ductus arteriosus in preterm neonates. Italian Journal of Pediatrics 2014;40:21.

Van Loon 2011 Van Loon RLE, Roofthooft MTR, Hillege HL, ten Harkel AD, Van Osch-Gevers M, Delhaas T, et al. Pediatric pulmonary hypertension in the Netherlands, Epidemiology and characterization during the period 1991 to 2005. Circulation 2011;124(16):1755–64.

Viberg 2014 Viberg H, Eriksson P, Gordh T, Fredriksson A. Paracetamol (acetaminophen) administration during neonatal brain development affects cognitive function and alters its analgesic and anxiolytic response in adult male mice. Toxicological Sciences 2014;138(1):139–47. [PUBMED: 24361869]

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Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Walls 2007 Walls L, Baker CF, Sarkar S. Acetaminophen-induced hepatic failure with encephalopathy in a newborn. Journal of Perinatology 2007;27(2):133–5.

Weir 1999 Weir FJ, Ohlsson A, Myhr TL, Fong K, Ryan ML. A patent ductus arteriosus is associated with reduced middle cerebral artery blood flow velocity. European Journal of Pediatrics 1999;158(6):484–7.

Wilson-Smith 2009 Wilson-Smith EM, Morton NS. Survey of i.v. paracetamol (acetaminophen) use in neonates and infants under 1 year of age by UK anesthetists. Pediatric Anesthesia 2009;19(4): 329–37.

Wolf 1989 Wolf WM, Snover DC, Leonard AS. Localized intestinal perforation following intravenous indomethacin in premature infants. Journal of Pediatric Surgery 1989;24(4): 409–10.

Yurttutan 2013 Yurttutan S, Oncel MY, Arayici S, Uras N, Altug N, Erdeve O, et al. A different first-choice drug in the medical management of patent ductus arteriosus: oral paracetamol. Journal of Maternal-Fetal & Neonatal Medicine 2013;26(8):

825–7. [DOI: 10.3109/14767058.2012.755162]

∗Indicates the major publication for the study

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Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

C H A R A C T E R I S T I C S O F S T U D I E S Characteristics of included studies [ordered by study ID] Dang 2013 Methods Randomised controlled trial conducted in the First Hospital of Jilin University. Study period 21 May 2012 to 30 March 2013 Participants Inclusion criteria: PMA ≤34 weeks; postnatal age < 14 days; echocardiographic diagnosis of haemodynamically significant PDA. Exclusion criteria were: congenital heart disease which required PDA to maintain blood flow; life-threatening infection; recent (within the previous 24 hr) intraventricular haemorrhage, Grade 3-4; urine output < 1 mL/kg/hr during the preceding 8 hr; serum creatinine > 88.4 mmol/L; platelet count of < 50 x 10 9/L; hyperbilirubinaemia requiring exchange transfusion; active necrotizing enterocolitis (NEC) and/or intestinal perforation; liver dysfunction Interventions Eighty infants received oral paracetamol at the dose of 15 mg/kg every 6 hr for 3 days, and 80 infants received oral ibuprofen at the initial dose of 10 mg/kg followed by 5 mg/kg after 24 and 48 hr. Between doses of oral ibuprofen, infants of the ibuprofen group received the same volume of dextrose 5% in water (D5W) as that given for drug administration in the paracetamol group. Whether a subject received a second course of treatment depended on echocardiography evaluation after the first course. If only minor ductal shunting was present after two courses without the need of respiratory support, no further treatment was given Outcomes Failure of PDA closure, all-cause mortality, re-opening of the ductus arteriosus, BPD (according to NICHD criteria: Jobe 2001), IVH (Grade I-IV; Grade I-II, Grade III-IV) , PVL (diagnosed by cranial MRI), NEC (Bell staging criteria - Grade IIa and above) , gastrointestinal bleed, ROP (any stage), oliguria (< 1 cc/kg/hr), sepsis (positive blood culture), hyperbilirubinaemia according to Maisels 2003 - a serum bilirubin level higher than the exchange transfusion level according to the postnatal age and body weight), serum creatinine (µmol/L) following treatment Notes In the report, although references were provided for BPD and hyperbilirubinaemia, it was not possible to ascertain exactly what criteria the authors applied. Sepsis was not defined. We wrote to the authors requesting clarification. We received a response and their definitions are included for the outcomes listed above Funded by Jilin Department of Health Risk of bias Risk of bias Bias Authors’ judgement Support for judgement Random sequence generation (selection bias) Low risk Computer-generated randomisation table (according to the published protocol) Allocation concealment (selection bias) Low risk “The participants were randomly assigned at a 1:1 ratio between oral paracetamol and

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Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Dang 2013 (Continued) ibuprofen groups by using cards in sealed opaque envelopes” Blinding of participants and personnel (performance bias) All outcomes High risk “...doctors and nurses were not blind” Blinding of outcome assessment (detection bias) All outcomes High risk “...doctors and nurses were not blind” Incomplete outcome data (attrition bias) All outcomes Low risk Results reported on an intention-to-treat basis which included patients who did not receive the complete course of treatment Selective reporting (reporting bias) Low risk The study was entered in the Chinese Clinical Trial Register (http://www.chictr.org/ cn/registration number: ChiCTR-TRC- 12002177) and approved by the Hospital Ethics Committee of the First Hospital of Jilin University. There does not appear to be any deviations in study conduct between the study protocol and the publication Other bias Low risk Appears free of other sources of bias Oncel 2013 Methods Randomised controlled trial conducted in the neonatal intensive care unit of Zekai Tahir Burak Maternity Teaching Hospital, Ankara,Turkey. Study period February to December

2012

Participants Ninty infants with a gestational age ≤30 weeks, birthweight ≤1250 g, postnatal age 48 to 96 hours, and 1 of the following echocardiographic criteria: a duct size > 1.5 mm, a left atrium-to-aorta ratio > 1.5, end diastolic reversal of blood flow in the aorta, or poor cardiac function in addition to clinical signs of a PDA Exclusion criteria were: the presence of major congenital abnormalities, right-to-left ductal shunting, life-threatening infection, Grade III or Grade IV IVH, urine output of less than 1 mL/kg/hr during the preceding 8 hours, serum creatinine level > 1.6 mg/dL, platelet count < 60 000/ mm3, liver failure, hyperbilirubinaemia requiring exchange transfusion, and persistent pulmonary hypertension Interventions Forty-five infants received oral paracetamol at a dose of 15 mg/kg every 6 hours for 3 days and 45 infants received oral ibuprofen at an initial dose of 10 mg/kg followed by

5 mg/kg at 24 and 48 hours. Both paracetamol and ibuprofen were administered via an

orogastric tube, which was flushed with 1 to 2 mL of sterile water to ensure delivery of the drug

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Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Oncel 2013 (Continued) Outcomes Failure of PDA closure, all-cause mortality, surgical closure of the PDA, duration of ventilator support, pulmonary haemorrhage, increase in grade of IVH, NEC, gastrointestinal bleed, ROP (requiring laser treatment), oliguria (not defined), sepsis (clinical symptoms and signs of sepsis and a positive blood bacterial culture), serum creatinine, bilirubin, AST and ALT, duration of hospitalisation Notes We contacted Dr Oncel and he provided us with data for additional outcomes not reported in the published paper. In addition he provided outcome data for all 90 randomised infants Risk of bias Risk of bias Bias Authors’ judgement Support for judgement Random sequence generation (selection bias) Low risk Sequential numbers were generated at the computer centre of the NICU (information provided by the authors) Allocation concealment (selection bias) Low risk The patients were randomly assigned to a treatment group by cards in sequentially numbered sealed opaque envelopes Blinding of participants and personnel (performance bias) All outcomes High risk Paracetamol and ibuprofen were given according to different schedules and therefore it is likely that healthcare providers were not blinded to the drug the infant was given. The authors write: “....the intervention was not completely blinded because of the different number of doses per day of the drugs. However, the most important outcome-PDA closure-was made by a cardiologist who was blinded to the treatment groups. Second, safety outcomes should have been defined more clearly before the study started to prevent overestimation in evaluation” Blinding of outcome assessment (detection bias) All outcomes High risk Paracetamol and ibuprofen were given according to different schedules and therefore it is likely that health care providers were not blinded to the drug the infant was given. The authors write: “....the intervention was not completely blinded because of the different number of doses per day of the drugs. However, the most important outcome-PDA closure-was made by a cardiologist who was blinded to the treatment groups. Second, safety outcomes

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Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Oncel 2013 (Continued) should have been defined more clearly before the study started to prevent overestimation in evaluation” Incomplete outcome data (attrition bias) All outcomes Low risk

90 infants were randomised, and we re-

ceived outcome data for the 10 infants (5 in ibuprofen group and 5 in paracetamol group) who died before the treatment was completed. Thus we received outcome data on an intention-to-treat basis for all 90 randomised infants Selective reporting (reporting bias) Low risk The trial was registered at ClinicalTrials. gov NCT01536158 and there does not seem to be any deviations between the protocol and the full publication Other bias Low risk Appears free of other bias Characteristics of studies awaiting assessment [ordered by study ID] Zarkesh 2013 Methods Infants were randomly assigned to two groups; the prophylaxis group and the control group Participants A total of 32 preterm infants (PMA < 32 weeks, body weight ≤1500 g) Interventions The prophylaxis group received oral paracetamol at a dose of 60 mg/kg/day, in 4 divided doses, for a period of 2 days starting during the first 24 hours of life. No placebo was given to the control group. Echocardiography was performed 24 to 36 hours after the last given dose to prophylaxis group and on the fourth to fifth day in the control group Outcomes Rate of ductal closure, need for later treatment with ibuprofen Notes To date (December 2013) this study has been published in abstract form only. The abstract does not report how many infants were assigned to each group, preventing us from incorporating the results of the study in our review If this study is published as a full report, we will need to make a deviation from our protocol and report separately on the prophylactic use of paracetamol for PDA

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Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Characteristics of ongoing studies [ordered by study ID]

NCT01291654

Trial name or title Paracaetamol and patent ductus arteriosus (PDA) Methods Randomised controlled trial Participants Preterm infants with a haemodynamically significant PDA Interventions Group1:paracetamol orallyatadose of 15 mg/kg every6hoursx 3 days.Group2: indomethacin intravenously

0.2 mg/kg/dose for three doses

Outcomes Primary outcome: closure of the ductus within 3 days. Secondary outcomes: absence of peripheral vasoconstriction, Doppler flow velocity in the anterior cerebral artery, superior mesenteric artery and renal artery before and after pharmacological treatment, absence of hepatotoxicity Starting date February 6, 2011 Contact information Cathy Hammerman, Shaare Zedek Medical centre, Israel. cathy@cc.huji.ac.il Notes ClinicalTrials.gov identifier: NCT01291654

NCT01938261

Trial name or title The preterm infants’ paracetamol study (PreParaS) Methods Randomised controlled, double-blind trial Participants Preterm infants < 32 weeks PMA Interventions Paracetamol infusion solution 10 mg/mL (Perfalgan®) or placebo, 0.45% saline solution. The loading dose is 20 mg/kg, and the maintenance dose 7.5 mg/kg every 6 hours for 4 days Outcomes Primary outcome: ductus diameter mm/kg at postnatal age 5 days. Cumulative dose of morphine at postnatal age 5 days. Secondary outcomes: number of patients who received any treatment for PDA prescribed by an attending clinician, postnatal age at closure of PDA, left atrium to aorta ratio, number of apneic periods/day, cumulative NIAPAS screening score/day up to 5 days postnatal age, duration of mechanical ventilation, longterm morbidity diagnoses, deaths, paracetamol side effects, paracetamol serum concentrations (up to 5 days postnatal age) Starting date August 22, 2013 Contact information Outi Aikio, University of Oulu, Finland; outi.aikio@ppshp.fi Notes ClinicalTrials.gov identifier: NCT01938261

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Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

NCT02002741

Trial name or title Adding paracetamol to ibuprofen for treatment of patent ductus arteriosus in preterm infants Methods Randomised double blind controlled trial Participants Preterm infants born at 24 to 37 weeks PMA, diagnosis of haemodynamically significant PDA, medical staff decided to treat with ibuprofen Interventions Group 1: ibuprofen + paracetamol (Ibuprofen 10mg/kg once, then 5 mg/kg twice, every 24 hr for a total of 3 doses and intravenous paracetamol loading dose 20 mg/kg then 10 mg/kg every 6 hr for a total of 12 doses) Group 2: ibuprofen + placebo (ibuprofen 10mg/kg once, then 5 mg/kg twice, every 24 h for a total of 3 doses and placebo (NaCl 0.9%), intravenous, at equal volume to the paracetamol in the paracetamol arm, total of

12 doses given every 6 hr)

Outcomes Primary outcome: the incidence of patent ductus arteriosus closure 3 to 21 days after first dose of ibuprofen by echocardiography. The need for surgical ligation of PDA. Secondary outcomes: adverse effects until discharge home - renal and liver function, gastrointestinal complications Starting date February 2014 Contact information o hochwald@rambam.health.gov.il Notes ClinicalTrials.gov identifier: NCT02002741

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Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

D A T A A N D A N A L Y S E S Comparison 1. Oral paracetamol versus oral ibuprofen Outcome or subgroup title No. of studies No. of participants Statistical method Effect size

1 Failure of ductal closure after the

first course of treatment

2

250

Risk Ratio (M-H, Fixed, 95% CI)

0.90 [0.67, 1.22]

2 All-cause mortality during initial

hospital stay

2

250

Risk Ratio (M-H, Fixed, 95% CI)

0.95 [0.52, 1.72]

3 Neonatal mortality (deaths

during the first 28 days of life)

1

90

Risk Ratio (M-H, Fixed, 95% CI)

1.17 [0.43, 3.20]

4 Infant mortality (death during

the first year of life)

1

90

Risk Ratio (M-H, Fixed, 95% CI)

1.14 [0.45, 2.89]

5 Re-opening of the ductus

arteriosus

2

143

Risk Ratio (M-H, Fixed, 95% CI)

1.04 [0.50, 2.18]

6 Surgical closure of the PDA

following treatment failure with paracetamol or ibuprofen

1

90

Risk Ratio (M-H, Fixed, 95% CI)

0.5 [0.05, 5.32]

7 Duration of ventilator support

(days)

1

90

Mean Difference (IV, Fixed, 95% CI) -4.15 [-8.63, 0.33]

8 Pulmonary haemorrhage

1

90

Risk Ratio (M-H, Fixed, 95% CI)

1.0 [0.21, 4.69]

9 Pulmonary hypertension

1

90

Risk Ratio (M-H, Fixed, 95% CI)

0.33 [0.01, 7.97]

10 Duration for need of

supplementary oxygen (days)

1

90

Mean Difference (IV, Fixed, 95% CI) -12.40 [-22.97, -1.

83]

11 BPD at 28 days

1

90

Risk Ratio (M-H, Fixed, 95% CI)

0.79 [0.46, 1.35]

12 BPD at 36 weeks PMA

1

90

Risk Ratio (M-H, Fixed, 95% CI)

0.71 [0.38, 1.30]

13 Moderate to severe BPD

(according to the new criteria)

1

160

Risk Ratio (M-H, Fixed, 95% CI)

0.8 [0.22, 2.87]

14 Severe BPD (according to the

new criteria)

1

90

Risk Ratio (M-H, Fixed, 95% CI)

0.63 [0.32, 1.23]

15 Intraventricular haemorrhage

(grade I-IV)

2

250

Risk Ratio (M-H, Fixed, 95% CI)

0.92 [0.73, 1.15]

16 Severe IVH (Grade III-IV)

2

250

Risk Ratio (M-H, Fixed, 95% CI)

1.0 [0.30, 3.37]

17 Periventricular leukomalacia

2

250

Risk Ratio (M-H, Fixed, 95% CI)

1.0 [0.36, 2.76]

18 Necrotizing enterocolitis

2

250

Risk Ratio (M-H, Fixed, 95% CI)

1.5 [0.43, 5.18]

19 Intestinal perforation

1

90

Risk Ratio (M-H, Fixed, 95% CI)

0.0 [0.0, 0.0]

20 Gastrointestinal bleed

2

250

Risk Ratio (M-H, Fixed, 95% CI)

0.3 [0.08, 1.06]

21 Retinopathy of prematurity -

any stage

2

250

Risk Ratio (M-H, Fixed, 95% CI)

0.72 [0.37, 1.41]

22 Retinopathy of prematurity

stage =/> 3

1

90

Risk Ratio (M-H, Fixed, 95% CI)

0.43 [0.12, 1.55]

23 Retinopathy of prematurity

requiring laser therapy

1

90

Risk Ratio (M-H, Fixed, 95% CI)

0.43 [0.12, 1.55]

24 Sepsis

1

90

Risk Ratio (M-H, Fixed, 95% CI)

1.08 [0.57, 2.03]

25 Oliguria (<1cc/kg/h))

2

250

Risk Difference (M-H, Fixed, 95% CI) -0.02 [-0.08, 0.04]

26 Serum levels of creatinine after

treatment mmol/L

2

250

Mean Difference (IV, Fixed, 95% CI) -1.05 [-5.32, 3.21]

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Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

27 Serum levels of aspartate

transaminase (AST) IU/L

1

90

Mean Difference (IV, Fixed, 95% CI)

4.20 [-1.83, 10.23]

28 Serum levels of alanine

aminotransferase (ALT) (IU/L)

1

90

Mean Difference (IV, Fixed, 95% CI)

4.0 [-3.58, 11.58]

29 Serum bilirubin following

treatment (mmol/L)

1

90

Mean Difference (IV, Fixed, 95% CI) -3.40 [-15.74, 8.94]

30 Hyperbilirubinaemia (serum

bilirubin level higher than the exchange level according to the postnatal age and BW

1

160

Risk Ratio (M-H, Fixed, 95% CI)

0.57 [0.34, 0.97]

31 Duration of hospitalisation

(days)

1

90

Mean Difference (IV, Fixed, 95% CI) -6.5 [-21.42, 8.42] Analysis 1.1.

Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 1 Failure of ductal closure after the first course of treatment. Review:

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants Comparison:

1 Oral paracetamol versus oral ibuprofen

Outcome:

1 Failure of ductal closure after the first course of treatment

Study or subgroup Paracetamol Ibuprofen Risk Ratio Weight Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Dang 2013 35/80 42/80

82.4 %

0.83 [ 0.60, 1.15 ]

Oncel 2013 11/45 9/45

17.6 %

1.22 [ 0.56, 2.66 ]

Total (95% CI)

125

125

100.0 %

0.90 [ 0.67, 1.22 ]

Total events: 46 (Paracetamol), 51 (Ibuprofen) Heterogeneity: Chi2 = 0.81, df = 1 (P = 0.37); I2 =0.0% Test for overall effect: Z = 0.67 (P = 0.50) Test for subgroup differences: Not applicable

0.01

0.1

1

10

100

Favours [paracetamol] Favours [ibuprofen]

33

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Analysis 1.2.

Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 2 All-cause mortality during initial hospital stay.

Review:

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants Comparison:

1 Oral paracetamol versus oral ibuprofen

Outcome:

2 All-cause mortality during initial hospital stay

Study or subgroup Paracetamol Ibuprofen Risk Ratio Weight Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Dang 2013 10/80 12/80

63.2 %

0.83 [ 0.38, 1.82 ]

Oncel 2013 8/45 7/45

36.8 %

1.14 [ 0.45, 2.89 ]

Total (95% CI)

125

125

100.0 %

0.95 [ 0.52, 1.72 ]

Total events: 18 (Paracetamol), 19 (Ibuprofen) Heterogeneity: Chi2 = 0.26, df = 1 (P = 0.61); I2 =0.0% Test for overall effect: Z = 0.18 (P = 0.86) Test for subgroup differences: Not applicable

0.01

0.1

1

10

100

Favours [Paracetamol] Favours [Ibuprofen] Analysis 1.3.

Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 3 Neonatal mortality (deaths during the first 28 days of life). Review:

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants Comparison:

1 Oral paracetamol versus oral ibuprofen

Outcome:

3 Neonatal mortality (deaths during the first 28 days of life)

Study or subgroup Paracetamol Ibuprofen Risk Ratio Weight Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Oncel 2013 7/45 6/45

100.0 %

1.17 [ 0.43, 3.20 ]

Total (95% CI)

45

45

100.0 %

1.17 [ 0.43, 3.20 ]

Total events: 7 (Paracetamol), 6 (Ibuprofen) Heterogeneity: not applicable Test for overall effect: Z = 0.30 (P = 0.76) Test for subgroup differences: Not applicable

0.5

0.7

1

1.5

2

Favours [paracetamol] Favours [ibuprofen]

34

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Analysis 1.4.

Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 4 Infant mortality (death during the first year of life).

Review:

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants Comparison:

1 Oral paracetamol versus oral ibuprofen

Outcome:

4 Infant mortality (death during the first year of life)

Study or subgroup Paracetamol Ibuprofen Risk Ratio Weight Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Oncel 2013 8/45 7/45

100.0 %

1.14 [ 0.45, 2.89 ]

Total (95% CI)

45

45

100.0 %

1.14 [ 0.45, 2.89 ]

Total events: 8 (Paracetamol), 7 (Ibuprofen) Heterogeneity: not applicable Test for overall effect: Z = 0.28 (P = 0.78) Test for subgroup differences: Not applicable

0.01

0.1

1

10

100

Favours [paracetamol] Favours [ibuprofen]

35

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Analysis 1.5.

Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 5 Re-opening of the ductus arteriosus.

Review:

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants Comparison:

1 Oral paracetamol versus oral ibuprofen

Outcome:

5 Re-opening of the ductus arteriosus

Study or subgroup Paracetamol Ibuprofen Risk Ratio Weight Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Dang 2013 5/45 6/38

57.4 %

0.70 [ 0.23, 2.13 ]

Oncel 2013 7/29 5/31

42.6 %

1.50 [ 0.53, 4.19 ]

Total (95% CI)

74

69

100.0 %

1.04 [ 0.50, 2.18 ]

Total events: 12 (Paracetamol), 11 (Ibuprofen) Heterogeneity: Chi2 = 0.96, df = 1 (P = 0.33); I2 =0.0% Test for overall effect: Z = 0.11 (P = 0.91) Test for subgroup differences: Not applicable

0.01

0.1

1

10

100

Favours [paracetamol] Favours [ibuprofen] Analysis 1.6.

Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 6 Surgical closure of the PDA following treatment failure with paracetamol or ibuprofen. Review:

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants Comparison:

1 Oral paracetamol versus oral ibuprofen

Outcome:

6 Surgical closure of the PDA following treatment failure with paracetamol or ibuprofen

Study or subgroup Paracetamol Ibuprofen Risk Ratio Weight Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Oncel 2013 1/45 2/45

100.0 %

0.50 [ 0.05, 5.32 ]

Total (95% CI)

45

45

100.0 %

0.50 [ 0.05, 5.32 ]

Total events: 1 (Paracetamol), 2 (Ibuprofen) Heterogeneity: not applicable Test for overall effect: Z = 0.57 (P = 0.57) Test for subgroup differences: Not applicable

0.005

0.1

1

10

200

Favours [Paracetamol] Favours [Ibuprofen]

36

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Analysis 1.7.

Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 7 Duration of ventilator support (days).

Review:

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants Comparison:

1 Oral paracetamol versus oral ibuprofen

Outcome:

7 Duration of ventilator support (days)

Study or subgroup Paracetamol Ibuprofen Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI Oncel 2013

45

4.66 (3.99)

45

8.81 (14.8)

100.0 %

-4.15 [ -8.63, 0.33 ] Total (95% CI)

45

45

100.0 %

-4.15 [ -8.63, 0.33 ] Heterogeneity: not applicable Test for overall effect: Z = 1.82 (P = 0.069) Test for subgroup differences: Not applicable

-100

-50

0

50

100

Favours [Paracetamol] Favours [Ibuprofen] Analysis 1.8.

Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 8 Pulmonary haemorrhage. Review:

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants Comparison:

1 Oral paracetamol versus oral ibuprofen

Outcome:

8 Pulmonary haemorrhage

Study or subgroup Paracetamol Ibuprofen Risk Ratio Weight Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Oncel 2013 3/45 3/45

100.0 %

1.00 [ 0.21, 4.69 ]

Total (95% CI)

45

45

100.0 %

1.00 [ 0.21, 4.69 ]

Total events: 3 (Paracetamol), 3 (Ibuprofen) Heterogeneity: not applicable Test for overall effect: Z = 0.0 (P = 1.0) Test for subgroup differences: Not applicable

0.01

0.1

1

10

100

Favours [paracetamol] Favours [ibuprofen]

37

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Analysis 1.9.

Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 9 Pulmonary hypertension. Review:

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants Comparison:

1 Oral paracetamol versus oral ibuprofen

Outcome:

9 Pulmonary hypertension

Study or subgroup Paracetamol Ibuprofen Risk Ratio Weight Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Oncel 2013 0/45 1/45

100.0 %

0.33 [ 0.01, 7.97 ]

Total (95% CI)

45

45

100.0 %

0.33 [ 0.01, 7.97 ]

Total events: 0 (Paracetamol), 1 (Ibuprofen) Heterogeneity: not applicable Test for overall effect: Z = 0.68 (P = 0.50) Test for subgroup differences: Not applicable

0.01

0.1

1

10

100

Favours [paaracetamol] Favours [ibuprofen] Analysis 1.10.

Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 10 Duration for need of supplementary oxygen (days).

Review:

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants Comparison:

1 Oral paracetamol versus oral ibuprofen

Outcome:

10 Duration for need of supplementary oxygen (days)

Study or subgroup Paracetamol Ibuprofen Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI Oncel 2013

45

23.1 (16.7)

45

35.5 (32.1)

100.0 %

-12.40 [ -22.97, -1.83 ] Total (95% CI)

45

45

100.0 %

-12.40 [ -22.97, -1.83 ] Heterogeneity: not applicable Test for overall effect: Z = 2.30 (P = 0.022) Test for subgroup differences: Not applicable

-20

-10

0

10

20

Favours [paracetamol] Favours [ibuprofen]

38

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Analysis 1.11.

Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 11 BPD at 28 days. Review:

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants Comparison:

1 Oral paracetamol versus oral ibuprofen

Outcome:

11 BPD at 28 days

Study or subgroup Paracetamol Ibuprofen Risk Ratio Weight Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Oncel 2013 15/45 19/45

100.0 %

0.79 [ 0.46, 1.35 ]

Total (95% CI)

45

45

100.0 %

0.79 [ 0.46, 1.35 ]

Total events: 15 (Paracetamol), 19 (Ibuprofen) Heterogeneity: not applicable Test for overall effect: Z = 0.86 (P = 0.39) Test for subgroup differences: Not applicable

0.01

0.1

1

10

100

Favours [paracetamol] Favours [ibuprofen] Analysis 1.12.

Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 12 BPD at 36 weeks PMA. Review:

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants Comparison:

1 Oral paracetamol versus oral ibuprofen

Outcome:

12 BPD at 36 weeks PMA

Study or subgroup Paracetamol Ibuprofen Risk Ratio Weight Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Oncel 2013 12/45 17/45

100.0 %

0.71 [ 0.38, 1.30 ]

Total (95% CI)

45

45

100.0 %

0.71 [ 0.38, 1.30 ]

Total events: 12 (Paracetamol), 17 (Ibuprofen) Heterogeneity: not applicable Test for overall effect: Z = 1.11 (P = 0.27) Test for subgroup differences: Not applicable

0.01

0.1

1

10

100

Favours [Paraacetamol] Favours [Ibuprofen]

39

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Analysis 1.13.

Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 13 Moderate to severe BPD (according to the new criteria).

Review:

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants Comparison:

1 Oral paracetamol versus oral ibuprofen

Outcome:

13 Moderate to severe BPD (according to the new criteria)

Study or subgroup Paracetamol Ibuprofen Risk Ratio Weight Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Dang 2013 4/80 5/80

100.0 %

0.80 [ 0.22, 2.87 ]

Total (95% CI)

80

80

100.0 %

0.80 [ 0.22, 2.87 ]

Total events: 4 (Paracetamol), 5 (Ibuprofen) Heterogeneity: not applicable Test for overall effect: Z = 0.34 (P = 0.73) Test for subgroup differences: Not applicable

0.01

0.1

1

10

100

Favours [parexperimental] Favours [ibuprofecontrol] Analysis 1.14.

Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 14 Severe BPD (according to the new criteria).

Review:

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants Comparison:

1 Oral paracetamol versus oral ibuprofen

Outcome:

14 Severe BPD (according to the new criteria)

Study or subgroup Paracetamol Ibuprofen Risk Ratio Weight Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Oncel 2013 10/45 16/45

100.0 %

0.63 [ 0.32, 1.23 ]

Total (95% CI)

45

45

100.0 %

0.63 [ 0.32, 1.23 ]

Total events: 10 (Paracetamol), 16 (Ibuprofen) Heterogeneity: not applicable Test for overall effect: Z = 1.37 (P = 0.17) Test for subgroup differences: Not applicable

0.01

0.1

1

10

100

Favours [paracetamol] Favours [ibuprofen]

40

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Analysis 1.15.

Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 15 Intraventricular haemorrhage (grade I-IV).

Review:

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants Comparison:

1 Oral paracetamol versus oral ibuprofen

Outcome:

15 Intraventricular haemorrhage (grade I-IV)

Study or subgroup Paracetamol Ibuprofen Risk Ratio Weight Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Dang 2013 9/80 10/80

20.4 %

0.90 [ 0.39, 2.10 ]

Oncel 2013 36/45 39/45

79.6 %

0.92 [ 0.77, 1.11 ]

Total (95% CI)

125

125

100.0 %

0.92 [ 0.73, 1.15 ]

Total events: 45 (Paracetamol), 49 (Ibuprofen) Heterogeneity: Chi2 = 0.01, df = 1 (P = 0.94); I2 =0.0% Test for overall effect: Z = 0.74 (P = 0.46) Test for subgroup differences: Not applicable

0.2

0.5

1

2

5

Favours [paracetamol] Favours [ibuprofen] Analysis 1.16.

Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 16 Severe IVH (Grade III- IV).

Review:

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants Comparison:

1 Oral paracetamol versus oral ibuprofen

Outcome:

16 Severe IVH (Grade III-IV)

Study or subgroup Paracetamol Ibuprofen Risk Ratio Weight Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Dang 2013 3/80 3/80

60.0 %

1.00 [ 0.21, 4.81 ]

Oncel 2013 2/45 2/45

40.0 %

1.00 [ 0.15, 6.79 ]

Total (95% CI)

125

125

100.0 %

1.00 [ 0.30, 3.37 ]

Total events: 5 (Paracetamol), 5 (Ibuprofen) Heterogeneity: Chi2 = 0.0, df = 1 (P = 1.00); I2 =0.0% Test for overall effect: Z = 0.0 (P = 1.0) Test for subgroup differences: Not applicable

0.01

0.1

1

10

100

Favours [Paracetamol] Favours [Ibuprofen]

41

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Analysis 1.17.

Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 17 Periventricular leukomalacia.

Review:

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants Comparison:

1 Oral paracetamol versus oral ibuprofen

Outcome:

17 Periventricular leukomalacia

Study or subgroup Paracetamol Ibuprofen Risk Ratio Weight Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Dang 2013 6/80 5/80

71.4 %

1.20 [ 0.38, 3.77 ]

Oncel 2013 1/45 2/45

28.6 %

0.50 [ 0.05, 5.32 ]

Total (95% CI)

125

125

100.0 %

1.00 [ 0.36, 2.76 ]

Total events: 7 (Paracetamol), 7 (Ibuprofen) Heterogeneity: Chi2 = 0.43, df = 1 (P = 0.51); I2 =0.0% Test for overall effect: Z = 0.0 (P = 1.0) Test for subgroup differences: Not applicable

0.01

0.1

1

10

100

Favours [paracetamol] Favours [ibuprofen]

42

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Analysis 1.18.

Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 18 Necrotizing enterocolitis.

Review:

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants Comparison:

1 Oral paracetamol versus oral ibuprofen

Outcome:

18 Necrotizing enterocolitis

Study or subgroup Paracetamol Ibuprofen Risk Ratio Weight Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Dang 2013 3/80 2/80

50.0 %

1.50 [ 0.26, 8.74 ]

Oncel 2013 3/45 2/45

50.0 %

1.50 [ 0.26, 8.55 ]

Total (95% CI)

125

125

100.0 %

1.50 [ 0.43, 5.18 ]

Total events: 6 (Paracetamol), 4 (Ibuprofen) Heterogeneity: Chi2 = 0.0, df = 1 (P = 1.00); I2 =0.0% Test for overall effect: Z = 0.64 (P = 0.52) Test for subgroup differences: Not applicable

0.002

0.1

1

10

500

Favours [paracetamol] Favours [ibuprofen] Analysis 1.19.

Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 19 Intestinal perforation. Review:

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants Comparison:

1 Oral paracetamol versus oral ibuprofen

Outcome:

19 Intestinal perforation

Study or subgroup Paracetamol Ibuprofen Risk Ratio Weight Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Oncel 2013 0/45 0/45 Not estimable Total (95% CI)

45

45

Not estimable Total events: 0 (Paracetamol), 0 (Ibuprofen) Heterogeneity: not applicable Test for overall effect: not applicable Test for subgroup differences: Not applicable

0.01

0.1

1

10

100

Favours [paracetamol] Favours [ibuprofen]

43

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Analysis 1.20.

Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 20 Gastrointestinal bleed. Review:

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants Comparison:

1 Oral paracetamol versus oral ibuprofen

Outcome:

20 Gastrointestinal bleed

Study or subgroup Paracetamol Ibuprofen Risk Ratio Weight Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Dang 2013 2/80 8/80

80.0 %

0.25 [ 0.05, 1.14 ]

Oncel 2013 1/45 2/45

20.0 %

0.50 [ 0.05, 5.32 ]

Total (95% CI)

125

125

100.0 %

0.30 [ 0.08, 1.06 ]

Total events: 3 (Paracetamol), 10 (Ibuprofen) Heterogeneity: Chi2 = 0.23, df = 1 (P = 0.63); I2 =0.0% Test for overall effect: Z = 1.86 (P = 0.062) Test for subgroup differences: Not applicable

0.01

0.1

1

10

100

Favours [paracetamol] Favours [ibuprofen] Analysis 1.21.

Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 21 Retinopathy of prematurity - any stage.

Review:

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants Comparison:

1 Oral paracetamol versus oral ibuprofen

Outcome:

21 Retinopathy of prematurity - any stage

Study or subgroup Paracetamol Ibuprofen Risk Ratio Weight Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Dang 2013 7/80 9/80

50.0 %

0.78 [ 0.30, 1.99 ]

Oncel 2013 6/45 9/45

50.0 %

0.67 [ 0.26, 1.72 ]

Total (95% CI)

125

125

100.0 %

0.72 [ 0.37, 1.41 ]

Total events: 13 (Paracetamol), 18 (Ibuprofen) Heterogeneity: Chi2 = 0.05, df = 1 (P = 0.82); I2 =0.0% Test for overall effect: Z = 0.96 (P = 0.34) Test for subgroup differences: Not applicable

0.01

0.1

1

10

100

Favours [paracetamol] Favours [ibuprofen]

44

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Analysis 1.22.

Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 22 Retinopathy of prematurity stage =/> 3.

Review:

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants Comparison:

1 Oral paracetamol versus oral ibuprofen

Outcome:

22 Retinopathy of prematurity stage =/> 3

Study or subgroup Paracetamol Ibuprofen Risk Ratio Weight Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Oncel 2013 3/45 7/45

100.0 %

0.43 [ 0.12, 1.55 ]

Total (95% CI)

45

45

100.0 %

0.43 [ 0.12, 1.55 ]

Total events: 3 (Paracetamol), 7 (Ibuprofen) Heterogeneity: not applicable Test for overall effect: Z = 1.29 (P = 0.20) Test for subgroup differences: Not applicable

0.01

0.1

1

10

100

Favours [paracetamol] Favours [ibuprofen]

45

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Analysis 1.23.

Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 23 Retinopathy of prematurity requiring laser therapy. Review:

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants Comparison:

1 Oral paracetamol versus oral ibuprofen

Outcome:

23 Retinopathy of prematurity requiring laser therapy

Study or subgroup Paracetamol Ibuprofen Risk Ratio Weight Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Oncel 2013 3/45 7/45

100.0 %

0.43 [ 0.12, 1.55 ]

Total (95% CI)

45

45

100.0 %

0.43 [ 0.12, 1.55 ]

Total events: 3 (Paracetamol), 7 (Ibuprofen) Heterogeneity: not applicable Test for overall effect: Z = 1.29 (P = 0.20) Test for subgroup differences: Not applicable

0.01

0.1

1

10

100

Favours [paracetamol] Favours [ibuprofen] Analysis 1.24.

Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 24 Sepsis. Review:

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants Comparison:

1 Oral paracetamol versus oral ibuprofen

Outcome:

24 Sepsis

Study or subgroup Paracetamol Ibuprofen Risk Ratio Weight Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Oncel 2013 14/45 13/45

100.0 %

1.08 [ 0.57, 2.03 ]

Total (95% CI)

45

45

100.0 %

1.08 [ 0.57, 2.03 ]

Total events: 14 (Paracetamol), 13 (Ibuprofen) Heterogeneity: not applicable Test for overall effect: Z = 0.23 (P = 0.82) Test for subgroup differences: Not applicable

0.01

0.1

1

10

100

Favours [paracetamol] Favours [ibuprofen]

46

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Analysis 1.25.

Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 25 Oliguria (<1cc/kg/h)). Review:

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants Comparison:

1 Oral paracetamol versus oral ibuprofen

Outcome:

25 Oliguria (<1cc/kg/h))

Study or subgroup Paracetamol Ibuprofen Risk Difference Weight Risk Difference n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Dang 2013 6/80 9/80

64.0 %

-0.04 [ -0.13, 0.05 ] Oncel 2013 0/45 0/45

36.0 %

0.0 [ -0.04, 0.04 ]

Total (95% CI)

125

125

100.0 %

-0.02 [ -0.08, 0.04 ] Total events: 6 (Paracetamol), 9 (Ibuprofen) Heterogeneity: Chi2 = 1.32, df = 1 (P = 0.25); I2 =24% Test for overall effect: Z = 0.79 (P = 0.43) Test for subgroup differences: Not applicable

-1

-0.5

0

0.5

1

Favours [paracetamol] Favours [ibuprofen] Analysis 1.26.

Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 26 Serum levels of creatinine after treatment mmol/L.

Review:

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants Comparison:

1 Oral paracetamol versus oral ibuprofen

Outcome:

26 Serum levels of creatinine after treatment mmol/L

Study or subgroup Paracetamol Ibuprofen Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI Dang 2013

80

61.62 (14.53)

80

62.4 (15.24)

85.5 %

-0.78 [ -5.39, 3.83 ] Oncel 2013

45

74.25 (23.8)

45

76.9 (30)

14.5 %

-2.65 [ -13.84, 8.54 ] Total (95% CI)

125

125

100.0 %

-1.05 [ -5.32, 3.21 ] Heterogeneity: Chi2 = 0.09, df = 1 (P = 0.76); I2 =0.0% Test for overall effect: Z = 0.48 (P = 0.63) Test for subgroup differences: Not applicable

-10

-5

0

5

10

Favours [paracetamol] Favours [ibuprofen]

47

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Analysis 1.27.

Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 27 Serum levels of aspartate transaminase (AST) IU/L.

Review:

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants Comparison:

1 Oral paracetamol versus oral ibuprofen

Outcome:

27 Serum levels of aspartate transaminase (AST) IU/L

Study or subgroup Paracetamol Ibuprofen Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI Oncel 2013

45

44.3 (12.1)

45

40.1 (16.7)

100.0 %

4.20 [ -1.83, 10.23 ]

Total (95% CI)

45

45

100.0 %

4.20 [ -1.83, 10.23 ]

Heterogeneity: not applicable Test for overall effect: Z = 1.37 (P = 0.17) Test for subgroup differences: Not applicable

-100

-50

0

50

100

Favours [paracetamol] Favours [ibuprofen]

48

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Analysis 1.28.

Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 28 Serum levels of alanine aminotransferase (ALT) (IU/L).

Review:

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants Comparison:

1 Oral paracetamol versus oral ibuprofen

Outcome:

28 Serum levels of alanine aminotransferase (ALT) (IU/L)

Study or subgroup Paracetamol Ibuprofen Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI Oncel 2013

45

28.6 (18.5)

45

24.6 (18.2)

100.0 %

4.00 [ -3.58, 11.58 ]

Total (95% CI)

45

45

100.0 %

4.00 [ -3.58, 11.58 ]

Heterogeneity: not applicable Test for overall effect: Z = 1.03 (P = 0.30) Test for subgroup differences: Not applicable

-100

-50

0

50

100

Favours [paracetamol] Favours [ibuprofen] Analysis 1.29.

Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 29 Serum bilirubin following treatment (mmol/L).

Review:

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants Comparison:

1 Oral paracetamol versus oral ibuprofen

Outcome:

29 Serum bilirubin following treatment (mmol/L)

Study or subgroup Paracetamol Ibuprofen Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI Oncel 2013

45

66.7 (29)

45

70.1 (30.7)

100.0 %

-3.40 [ -15.74, 8.94 ] Total (95% CI)

45

45

100.0 %

-3.40 [ -15.74, 8.94 ] Heterogeneity: not applicable Test for overall effect: Z = 0.54 (P = 0.59) Test for subgroup differences: Not applicable

-100

-50

0

50

100

Favours [paracetamol] Favours [ibuprofen]

49

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Analysis 1.30.

Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 30 Hyperbilirubinaemia (serum bilirubin level higher than the exchange level according to the postnatal age and BW. Review:

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants Comparison:

1 Oral paracetamol versus oral ibuprofen

Outcome:

30 Hyperbilirubinaemia (serum bilirubin level higher than the exchange level according to the postnatal age and BW Study or subgroup Paracetamol Ibuprofen Risk Ratio Weight Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Dang 2013 16/80 28/80

100.0 %

0.57 [ 0.34, 0.97 ]

Total (95% CI)

80

80

100.0 %

0.57 [ 0.34, 0.97 ]

Total events: 16 (Paracetamol), 28 (Ibuprofen) Heterogeneity: not applicable Test for overall effect: Z = 2.07 (P = 0.039) Test for subgroup differences: Not applicable

0.01

0.1

1

10

100

Favours [parexperimental] Favours [ibuprofecontrol] Analysis 1.31.

Comparison 1 Oral paracetamol versus oral ibuprofen, Outcome 31 Duration of hospitalisation (days).

Review:

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants Comparison:

1 Oral paracetamol versus oral ibuprofen

Outcome:

31 Duration of hospitalisation (days)

Study or subgroup Paracetamol Ibuprofen Mean Difference Weight Mean Difference N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI Oncel 2013

45

59.3 (37.3)

45

65.8 (34.9)

100.0 %

-6.50 [ -21.42, 8.42 ] Total (95% CI)

45

45

100.0 %

-6.50 [ -21.42, 8.42 ] Heterogeneity: not applicable Test for overall effect: Z = 0.85 (P = 0.39) Test for subgroup differences: Not applicable

-100

-50

0

50

100

Favours [paracetamol] Favours [ibuprofen]

50

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

C O N T R I B U T I O N S O F A U T H O R S Both authors contributed to all sections of this review.

D E C L A R A T I O N S O F I N T E R E S T Arne Ohlsson - no conflict of interest to declare.

Prakeshkumar Shah - no conflict of interest to declare.

S O U R C E S O F S U P P O R T Internal sources

• Department of Pediatrics, Mount Sinai Hospital, Toronto, Ontario, Canada, Other.

External sources

• Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health,

Department of Health and Human Services, USA.

Editorial support of the Cochrane Neonatal Review Group has been funded with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN275201100016C.

D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W We made some minor wording changes to the primary outcome. We changed from ’Failure of PDA closure within a week of administration of the first dose of paracetamol (closure and failure of closure confirmed by echocardiographic criteria)’ to ’Failure of PDA closure after the first course of paracetamol (closure and failure of closure confirmed by echocardiographic criteria)’. We have added a few outcomes that the authors of the included studies reported on but that we had not anticipated. We have indicated this for the specific outcomes that were not pre-determined.

I N D E X T E R M S Medical Subject Headings (MeSH) Acetaminophen[∗administration&dosage; adverse effects]; Administration, Oral; DuctusArteriosus, Patent[∗drugtherapy];Ibuprofen [administration & dosage; adverse effects]; Indomethacin [administration & dosage]; Infant, Low Birth Weight; Infant, Premature; Oxygen Inhalation Therapy [utilization]; Randomized Controlled Trials as Topic

51

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

MeSH check words Humans; Infant, Newborn

52

Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low-birth-weight infants (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

February 2018  |  Volume 6  |  Article 25

1

Original Research published: 14 February 2018 doi: 10.3389/fped.2018.00025

Frontiers in Pediatrics  |  www.frontiersin.org

Edited by:

Giovanni Biglino, University of Bristol, United Kingdom Reviewed by:

Yogen Singh, Cambridge University Hospitals NHS Foundation Trust, United Kingdom Hopewell Nkosipendule Ntsinjana, University of the Witwatersrand, South Africa *Correspondence:

Maria Dolores Ruiz-González maesrugo17@hotmail.com Specialty section:

This article was submitted to Pediatric Cardiology, a section of the journal Frontiers in Pediatrics Received: 06 October 2017 Accepted: 25 January 2018 Published: 14 February 2018 Citation:

Tofe I, Ruiz-González MD, Cañete MD, Pino A, Rueda RL, Parraga MJ and Perez-Navero JL (2018) Efficacy of Paracetamol in Closure of Ductus Arteriosus in Infants under 32 Weeks of Gestation.

Front. Pediatr. 6:25.

doi: 10.3389/fped.2018.00025 E

Ines Tofe1, Maria Dolores Ruiz-González1*, Maria Dolores Cañete1,2, Asuncion Pino3, Rosa Lorena Rueda1, Maria Jose Parraga1 and Juan Luis Perez-Navero1 1 Hospital Reina Sofía de Córdoba, Cordova, Spain, 2 Instituto Maimonides de Investigación Biomédica de Cordoba (IMIBIC), Cordova, Spain, 3 Pediatrics, Hospital Alto Guadalquivir, Andújar, Spain Background: Standard medical treatment for patent ductus arteriosus (PDA) closure has been indomethacin/ibuprofen or surgical ligation. Up to date, new strategies have been reported with paracetamol. The aim of this study was to present our experience with intravenous paracetamol for closing PDA in preterm neonates presenting contraindication to ibuprofen or ibuprofen had failed and no candidates for surgical ligation because of huge instability.

Materials and methods: We conducted a retrospective case series study in a neonatal intensive care unit from a tertiary hospital. 9 preterm infants ≤32 weeks of gestational age with hemodynamically significant PDA (hsPDA) were enrolled. They received 15 mg/ kg/6h intravenous paracetamol for ductal closure. Demographic data and transaminase levels before and after treatment were collected.

results: 30 preterm babies were diagnosed of hsPDA. 11/30 received ibuprofen with closure in 81.1%. 9 received intravenous paracetamol mainly due to bleeding disorders or thrombocytopenia. Successful closure on paracetamol was achieved in seven of nine babies (77.7%). There was a significant increase in transaminase levels in two patients. They required no treatment for normalization.

conclusion: Paracetamol is an effective option in closure PDA. It should be a firstline therapeutic option when there are contraindications for ibuprofen treatment. Transaminases must be checked during treatment.

Keywords: patent ductus arteriosus, paracetamol, preterm, treatment, ibuprofen

INTRODUCTION

Closure of ductus arteriosus after birth is very important for circulation adaptation to the extrauterine life. Patent ductus arteriosus (PDA) in extremely premature infants is associated with morbidities such as necrotizing enterocolitis, bronchopulmonary dysplasia (BPD), and neurodevelopmental disabilities (1). Standard medical treatment for PDA closure has been indometacin/ibuprofen or surgical ligation. Adverse events have been reported with NSAIDs (2), and surgical ligations have been associated with a higher incidence of BPD, retinopathy of prematurity, and neurodevelopmental disorders (3).

Hammerman et al. reported for the first time the use of paracetamol for closing PDA (4). Since then, many studies have reported similar efficiency of paracetamol to COX-inhibitors for closing PDA and less adverse events (5).

Tofe et al.

Acetaminophen as an Alternative Drug for Closing PDA

Frontiers in Pediatrics  |  www.frontiersin.org

February 2018  |  Volume 6  |  Article 25

The aim of this study was to present our experience with intravenous (iv) paracetamol for closing PDA in preterm neonates presenting contraindication to ibuprofen or ibuprofen had failed and had feeding intolerance.

MATERIALS AND METHODS

We conducted a retrospective case series study of 30 preterm infants of ≤32 weeks of gestational age (GA) with hemodynamically significant PDA (hsPDA) from May 2015 to January 2017. The medical records were retrospectively evaluated. We collected the percentage of spontaneous closure, the percentage of patients who received ibuprofen versus paracetamol or surgical ligation. Ibuprofen was given intravenously at a regimen of 10, 5, and 5 mg/ kg/day [for 3 days, respectively. Pedea (orphan drug) 5 mg/ml]. Nine premature infants received paracetamol (Paracetamol B. Braun 10 mg/ml), 15 mg/kg iv administration every 6 h. All had hsPDA clinically diagnosed and confirmed by means of echo- Doppler cardiography.

Echocardiography criteria of hsPDA were a ductal diameter ≥1.5 mm, a left atrium to aortic root ratio >1.5, and diastolic aortic retrograde flow. Bidimensional color Doppler echocardiography with Philips HD7 GE Healthcare multifrequency 8 MHz sector probe was used. Daily echocardiographic examination was conducted. If ductus closure was confirmed by echocardiography, treatment was discontinued. The study was carried out in accordance with the recommendations of RSUH Ethics and Research Committee.

Primary reason for using paracetamol was failure to response to ibuprofen administration or the presence of absolute contraindications for ibuprofen (bleeding, platelet count ≤ 60,000, intraventricular hemorrhage, and pulmonary hemorrhage). Demographic features (GA, gender, birth weight, height, head circumference, Apgar score, delivery mode, antenatal steroids, MgSO4, age treatment/days of treatment, primary reason to use paracetamol, main outcome, adverse events, surgery, and invasive ventilation), antenatal exposure to steroids and magnesium sulfate, postnatal age at diagnosis, age at first paracetamol dose, duration of treatment, response to treatment, and need of surgical ligation were noted. Before and 24 h after the end of paracetamol treatment, liver function tests were performed in all patients. In all cases, a written informed consent was obtained.

RESULTS

Between May 2015 and January 2017, there were a total of

30 preterm infants who had significant PDA. 11/30 received

ibuprofen, and 3/30 had a spontaneous closure (10%) with GA 28, 28, and 29 weeks. 7 died (4 under ibuprofen treatment, two received no treatment, and one underwent PDA ligation), and nine patients received iv paracetamol (5 of them of ≤28 weeks of GA). Results among the nine patients who underwent paracetamol were as follows: mean GA was 28 weeks ranging from 25 to 32 weeks and mean birth weight was 1,052 g ranging from 560 to 1,860 g. 3 preterm were male. All the patients had received antenatal steroids, and five of them have been exposure to antenatal magnesium sulfate as neuroprotection. Table  1 describes main clinical findings among infants who received paracetamol.

In all patients, due to feeding intolerance and clinic instability, iv paracetamol was started after obtaining informed consent signature. Complete closure was observed in 7/9 (77.7%). The mean postnatal age at the first iv paracetamol dose was 4 days, ranging from 2 to 35 days. In eight of nine patients, the treatment was started in the first week of life. In eight infants, ibuprofen was contraindicated, and in one of them, the ibuprofen treatment had failed. One patient was treated for 2 days due to an elevation in liver transaminases, but ductus was closed so treatment was discontinued. Values were normalized 5  days later. Three patients were treated for 3 days, one for 4 days, and 2 for 6 days. Two patients needed two courses; one of them received acetaminophen for 3 days. In that case, ductus persisted opened even though ibuprofen was administered in a second course because there were no contraindications. Finally, baby went to surgical ligation on 16th day of life. One patient was successfully treated on the third day of life, but on the 16th day of life, ductus was reopened and a second course was conducted with definitively ductal closure after 48 h.

Table 2 shows transaminases levels before and after treatment with paracetamol.

DISCUSSION

Hammerman et al. reported for the first time several case reports on premature infants who received paracetamol achieving ductal closure (4). Since then, 24 case reports series have been reported and 6 randomized control trials (RCTs) showing paracetamol utility for ductal closure with similar results comparing to ibuprofen/indomethacin and fewer adverse events. Prostaglandins are relevant in PDA. Indomethacin and ibuprofen inhibit cyclooxygenase (COX3) in a no selective manner. How paracetamol acts for closing PDA still remains unclear, but it is known that it inhibits prostaglandin synthetase (5). Alternatively, paracetamol has been proposed to selectively inhibit a central isoform of COX3, but the existence of a functional human COX3 has been questioned (6).

Oncel et al. used paracetamol in 10 premature infants under than 30 weeks of GA with a 100% of effectiveness. Nevertheless, other authors did not achieve same striking results (7–9). The most common dosage is 15 mg/k/dose/q6h.

A report on high level of transaminases caused by iv paracetamol treatment for PDA closure in premature infants found that a lower dose of paracetamol also is effective (10, 11). Therefore, the dose and dose interval of iv paracetamol treatment might require revision.

One of our patient received paracetamol on day 35 of life and ductus was closed, even though the most studies state that the earliest beginning of treatment is the most effective. Some studies reported up to a 71.6% of ductal closure when it is administered after 20 days of life (11–17).

Among 13 observational studies published, paracetamol was orally given (18–22) (112 premature infants), and in 12

Table 2 | Liver tests before and 24 h after the end of paracetamol treatment.

AST (U/L)

before

AST (U/L)

after

ALT (U/L)

before

ALT (U/L)

after

1

31

34

8

10

2

27

24

6

7

3

6/9 10/6 20/24 39/26

4

17

13

25

26

5

30/20 16/41 6/36 11/31

6

41

2,624

7

355

7

34

117

8

10

8

177

166

67

68

9

28

21

7

13

Table 1 | Demographic characteristics among infants treated with paracetamol and main outcomes. GA (w) Gender Birth weight (g) Height (cm) Head circumference (cm) Apgar 1′/5′ Delivery mode (C/V) Antenatal steroids MgSO4 pre Age treatment/ days of treatment Primary reason use paracetamol Main outcome Adverse events Surgery Invasive ventilation

1

28

M

716

33.5

23

8/8 C

1

Yes 7/4 Thrombocytopenia, bleeding No closed No Yes Yes

2

29

M

1,000

35

26

7/9 C

1

No 4/6 Bleeding Closed No No Yes

3

25

F

560

31

22

4/7 C

1

Yes 4/6; 7/6 Fail ibuprofen, intraventricular hemorrhage No closed (2 courses) No Yes Yes

4

29

F

1,120

37

26

6/7 C

1

Yes 2/3 Intraventricular hemorrhage Closed No No Yes

5

27

F

930

38

24

5/7 C Partial No 2/3; 16/3 Intraventricular hemorrhage Closed (2 courses) No No Yes

6

31

M

1,860

42

32

5/6 C

0

No 3/2 Thrombocytopenia, coagulopatía Closed

AST↑

ALT↑

No Yes

7

32

F

1,495

41

29

7/8 C

1

No 5/3 Thrombocytopenia, pulmonary hemorrhage Closed

AST↑

No Yes

8

28

F

1,060

36

26

7/9 C

2 courses

Yes 35/6 Thrombocytopenia Closed No No Yes

9

26

F

731

30

22.5

4/7 C

1

Yes 3/3 Thrombocytopenia, intraventricular hemorrhage Closed No No Yes Echocardiography criteria of hsPDA were a ductal diameter ≥1.5 mm, a left atrium to aortic root ratio >1.5, and diastolic aortic retrograde flow. Bidimensional color Doppler echocardiography with Philips HD7 GE Healthcare multifrequency 8 MHz sector probe was used.

C, cesarean section; hsPDA, hemodynamically significant patent ductus arteriosus; V, vaginal delivery.

3

Tofe et al.

Acetaminophen as an Alternative Drug for Closing PDA

Frontiers in Pediatrics  |  www.frontiersin.org

February 2018  |  Volume 6  |  Article 25

observational studies, paracetamol was given iv (150 premature infants) with a closing average up to a 72.2% in oral route versus 66% with iv paracetamol. Of the six RCTs, just one compared indomethacin and ibuprofen (9, 23–25) with no statistical significant differences. We have reported a higher average ductal closure probably because paracetamol was given earlier, in the first week of life. Only one patient had received ibuprofen first. Other observational studies show that paracetamol is more effective when there has been no exposure to ibuprofen and less effective when it is administered later (23, 26). In fact, one of our patients with no ductal closure after paracetamol who underwent surgical ligation had received ibuprofen first. Average of spontaneous ductal closure is higher at higher GAs. The small sample size is a limitation for our study, and four of nine patients who received paracetamol were of ≥29  weeks of GA. Nonetheless, the median GA among our 30 premature infants with hsPDA and spontaneous closure was 28 weeks, so we truly believe that the spontaneous closure among our population cannot be due to higher GAs.

The single adverse event we noticed was a transient elevation in liver enzymes in two patients as previously has been reported in literature, and they required no treatment. Our patients had oral feeding intolerance, so we use iv route. In our opinion, the oral route probably does not represent the optimal choice for ELBW infants. In these patients, gut immaturity together with oral feeding intolerance typical of ELBW can lead to unpredictable and possibly too low intestinal drug absorption.

Since 2012, MgSO4 (magnesium sulfate) have been used as a neuroprotector agent among premature infants under

31 + 6 weeks of GA. 5 out of nine premature infants received

MgSO4 as neuroprotection. del Moral et al. (27) related prenatal exposure to MgSO4 with higher incidence of hemodynamically significant persistent ductus arteriosus. Functional closure of the ductus after birth is primarily due to smooth muscle constriction, owing an increase in intracellular calcium concentration (27). Magnesium acts as a calcium antagonist, blocking calcium ion entry into the smooth muscles. More studies are probably needed to investigate the relationship between prenatal magnesium sulfate and PDA in premature infants. Some epidemiological studies suggest a link between early exposure to paracetamol and risk of asthma and other atopic diseases (28). Moreover, one study among 64,322 infants whose mother received acetaminophen

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Acetaminophen as an Alternative Drug for Closing PDA

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February 2018  |  Volume 6  |  Article 25

during pregnancy reported a higher incidence of attention deficit syndrome and hyperactivity (29).

CONCLUSION

Our results highlight that paracetamol could become not only an alternative treatment in closing PDA but also the treatment of choice in several scenarios. Nevertheless, one of the main limitations of this study is that it is a case series report with fewer subjects. More studies are needed to know long-term consequences of using paracetamol for closing PDA and to answer important questions about the optimal dose, the best route of administration, safety and the implications for neurodevelopmental, and longterm consequences.

AUTHOR CONTRIBUTIONS

IT: patient recruitment after informed consent was signed up, review of the charts, review of the literature, and writing of the manuscript. MR: review literature and patient recruitment and made corrections. MC: establish the protocol and writing of the special informed consent for an off-label indication treatment. AP: review of the charts. RR: patient recruitment. MP: corrections.

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pregnancy, behavioural problems and hyperkinetic disorders. JAMA (2014) 168:313–20. doi:10.1001/jamapediatrics.2013.4914 Conflict of Interest Statement: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Year : 2013 | Volume : 59 | Issue : 4 | Page : 312-

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Oral paracetamol in treatment of closure of patent ductus arteriosus in preterm neonates B Jasani, N Kabra, RN Nanavati Department of Neonatology, Seth GS Medical College and KEM Hospital, Acharya Donde Marg, Parel, Mumbai, Maharashtra, India Correspondence Address:

B Jasani Department of Neonatology, Seth GS Medical College and KEM Hospital, Acharya Donde Marg, Parel, Mumbai, Maharashtra India Abstract We herewith report a case series of six premature neonates with hemodynamically significant paten ductus successfully treated with oral paracetamol. This is a first case series describing the use of oral paracetamol treatment patent ductus in preterm neonates from India. Further prospective randomized-controlled trials are needed to evaluate the efficacy and safety of oral paracetamol in the treatment of patent ductus in preterm neonates.

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Jasani B, Kabra N, Nanavati R N. Oral paracetamol in treatment of closure of patent ductus arteriosus in preterm neonates.J Postgrad Med 2013;59:312-314 How to cite this URL:

Jasani B, Kabra N, Nanavati R N. Oral paracetamol in treatment of closure of patent ductus arteriosus in preterm neonates. J Postgrad Med [serial online] 2013 [cited 2019 Jul 4 ];59:312-314 Available from: http://www.jpgmonline.com/text.asp?2013/59/4/312/123164 Full Text Introduction Persistent patent ductus arteriosus (PDA) renders the preterm neonates vulnerable to pulmonary over-circulation with diminished systemic blood flow. The increase in pulmonary blood flow in the setting of prematurity can lead to pulmonary edema, loss of lung compliance, and deterioration of respiratory status, which ultimately leads to the development of chronic lung disease. Therapeutic medical interventions that are most commonly used for closure of a hemodynamically significant patent ductus arteriosus (hsPDA) are cyclooxygenase inhibitors, mainly indomethacin and intravenous/oral ibuprofen. Overall the efficacy of both these drugs in the treatment of PDA is similar and is about 60 to 70%. [1],[2] . However, these drugs can cause undesired side effects such as peripheral vasoconstriction, gastrointestinal perforations, weakened platelet aggregation, and hyperbilirubinemia [3],[4] . Intravenous indomethacin and intravenous ibuprofen are expensive and not readily available. A drug like oral paracetamol, if successful, would not only eliminate these adverse effects but can also offer a cheaper and better alternative. Recently serendipitously it was found that oral paracetamol therapy may be effective in the closure of

4/7/2019 Journal of Postgraduate Medicine: Oral paracetamol in treatment of closure of patent ductus arteriosus in preterm neonates : <b>B Jasani,… www.jpgmonline.com/printarticle.asp?issn=0022-3859;year=2013;volume=59;issue=4;spage=312;epage=314;aulast=Jasani 2/3 PDA in preterm neonates, who do not respond to traditional drugs [5] . We herewith report a case series, which provides further evidence of efficacy of oral paracetamol in the closure of hsPDA in preterm neonates. Case Report [Table 1] summarizes the characteristics of neonates who had hsPDA and were treated with oral paracetamol. The baseline characteristics (birth weight, gestational age); age at presentation, echocardiographic findings and response to therapy is also narrated.{Table 1} All of the six neonates had hsPDA that was confirmed by echocardiography. Three neonates did not respond to Indomethacin and one to ibuprofen treatment. In two others treatment with indomethacin/ibuprofen was contraindicated. In general contraindications for indomethacin or ibuprofen treatment includes: Renal failure, hyperbilirubinemia and severe thrombocytopenia.

Treatment with oral paracetamol (Crocin drops 100 mg/ml, Glaxo Smithkline Consumer Healthcare, India) was started in these cases at a dose of 15 mg/kg every 6 h after echocardiographic confirmation of hsPDA. Repeat echocardiographic evaluation was performed on Day 3 of treatment. In the event of evidence of a persistent hsPDA, duration of therapy was extended up to 7 days. Further follow-up echocardiography was performed on completion of 7 days of therapy.

A total of six preterm neonates birth weight (range: 1040 to 1235 g), gestational age (range: 28.56 to 31.14 weeks) who admitted in neonatal intensive care unit of a level III tertiary unit are reported in this case series. Out of the six babies four babies had respiratory distress syndrome and all of them received natural surfactant. The age at administration of surfactant was 5.87 ± 1.25h. Two neonates with hsPDA in addition also had sepsis. Median age at paracetamol administration was 128 hours (range 62-214 h). The median duration of therapy was 82.5 h. (range 56-102 h) and median age at closure of ductus was 209.5h (range 130-210 h). Complete closure was observed in 6/6 (100%) of babies. None of the babies had any adverse effect. Pre and post-treatment levels of liver enzymes were normal in all neonates.

Discussion Traditional nonsteroidal anti-inflammatory drugs promote ductal constriction by inhibiting prostaglandin synthesis. Prostaglandin synthetase has two components, a cyclooxygenase and a peroxidase, that operate at distinct, active sites on the same protein with different catalytic activities. At the active cyclooxygenase site, arachidonic acid undergoes oxygenation and forms PGG2, which is then acted on by the peroxidase component of the enzyme, forming PGH2. Indomethacin and ibuprofen compete with the arachidonic acid substrate for the active cyclooxygenase site. Thus, the potency of these drugs is influenced by endogenous arachidonic acid levels. Paracetamol also inhibits prostaglandin synthetase activity. [6] . Although the precise mechanism of action of paracetamol in the closure of PDA in preterm remains uncertain, paracetamol seems to act at the peroxidase segment of the enzyme which indicates that paracetamol-mediated inhibition is facilitated by a reduction in the concentration of local peroxide. [7] There have been reports of paracetamol promoting ductal constriction, albeit mostly in pregnant animal models, [8],[9] and there has been one case report of human in utero ductal closure after maternal self-medication with a combination of nimesulide and acetaminophen. [10] In a recent case series by Hammerman et al., [5] paracetamol was given to two patients who did not respond to ibuprofen and to three patients with contraindications to treatment (hyperbilirubinemia, thrombocytopenia). Successful hsPDA closure was observed in all five preterm infants without any side effect. More recently two case reports of use of intravenous paracetamol have appeared in the literature. [11],[12] Extensive clinical experience with the use of paracetamol in neonates has been accumulated due to its widespread use in pain relief with minimal side effects. [13]

4/7/2019 Journal of Postgraduate Medicine: Oral paracetamol in treatment of closure of patent ductus arteriosus in preterm neonates : <b>B Jasani,… www.jpgmonline.com/printarticle.asp?issn=0022-3859;year=2013;volume=59;issue=4;spage=312;epage=314;aulast=Jasani 3/3 Further prospective randomized-controlled trials are needed to evaluate the efficacy and safety of oral paracetamol in the treatment of hsPDA in preterm neonates. Until results of such studies are available, it should be used with caution where established therapies fail or are contraindicated. Oral paracetamol therapy could have potentially several advantages: Inexpensive, easy availability no peripheral vasoconstrictive effect and it can be given orally to infants with clinical contraindications for nonsteroidal anti-inflammatory drugs (indomethacin/ibuprofen). Acknowledgment Authors thank the Dean Dr. Sandhya Kamath, Seth GS Medical College and KEM Hospital, Mumbai for permitting them to publish the manuscript.

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Ohlsson A, Walia R, Shah SS. Ibuprofen for the treatment of patent ductus arteriosus in preterm and/or low birth weight infants. Cochrane Database Syst Rev. 2010;4:CD003481.

2

Neumann R, Schulzke SM, Bührer C. Oral ibuprofen versus intravenous ibuprofen or intravenous indomethacin for the treatment of patent ductus arteriosus in preterm infants: A systematic review and meta-analysis. Neonatology. 2012;102:9-15.

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Zecca E, Romagnoli C, De Carolis M, Costa S, Marra R, De Luca D. Does ibuprofen increase neonatal hyperbilirubinemia? Pediatrics. 2009;124:480-4.

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Rheinlaender C, Helfenstein D, Walch E, Berns M, Obladen M, Koehne P. Total serum bilirubin levels during cyclooxygenase inhibitor treatment for patent ductus arteriosus in preterm infants. Acta Paediatr. 2009;98:36-

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Hammerman C, Bin-Nun A, Markovitch E, Schimmel MS, Kaplan M, Fink D. Ductal closure with paracetamol: A surprising new approach to patent ductus arteriosus treatment. Pediatrics 2011; 128:e1618-21.

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Green K, Drvota V, Vesterqvist O. Pronounced reduction of in vivo prostacyclin synthesis in humans by paracetamol. Prostaglandins. 1989;37:311-5.

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Lucas R, Warner TD, Vojnovic I, Mitchell JA. Cellular mechanisms of acetaminophen: Role of cyclo-oxygenase.

FASEB J. 2005;19:635-7.

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Momma K, Takao A. Transplacental cardiovascular effects of four popular analgesics in rats. Am J Obstet Gynecol. 1990;162:1304-10.

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Peterson RG. Consequences associated with nonnarcotic analgesics in the fetus and newborn. Fed Proc. 1985;44:2309-13.

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Simbi KA, Secchieri S, Rinaldo M, Demi M, Zanardo V. In utero ductal closure following near-term maternal self-medication with nimesulide and acetaminophen. J Obstet Gynaecol. 2002;22:440-5.

11

Oncel MY, Yurttutan S, Degirmencioglu H et al. Intravenous Paracetamol Treatment in the Management of Patent Ductus Arteriosus in Extremely Low Birth Weight Infants. Neonatology. 2012 Dec 19;103:166-9.

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Yurttutan S, Oncel MY, Arayýcý S, Uras N, Altug N, Erdeve O, Dilmen U. A different first-choice drug in the medical management of patent ductus arteriosus: Oral paracetamol. J Matern Fetal Neonatal Med. 2013 Jan

15. [Epub ahead of print].

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Wilson-Smith EM, Morton NS. Survey of i.v. paracetamol (acetaminophen) use in neonates and infants under 1 year of age by UK anesthetists. Paediatr Anaesth. 2009;19:329-37.

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Carta cientı´ficas Cierre de conducto arterioso con paracetamol: estudio piloto Ductus Arteriosus Closure With Paracetamol:

a Pilot Study Sr. Editor:

El conducto arterioso es frecuente en prematuros, con una incidencia de 1:2.500-5.000, y representa el 9-12% de las cardiopatı´as conge´nitas1. Se han utilizado diversos fa´rmacos para el cierre del conducto arterioso permeable hemodina´micamente significativo. El primero empleado con este fin fue la indometacina, con una tasa de e´xito del 70% y reapertura del 35%; sin embargo, por su elevado coste se han buscado otras opciones, como el ibuprofeno2; pero estas no son inocuas y se asocian con reduccio´n de la perfusio´n renal, mesente´rica y cerebral, adema´s, el ibuprofeno se asocia con hiperbilirrubinemia3. Recientemente se ha demostrado la utilidad del paracetamol para este fin, sin reportar toxicidad hasta el momento.

En este estudio se reporta el uso de paracetamol oral en prematuros, que ha resultado seguro y eficaz para el cierre del conducto arterioso permeable hemodina´micamente significativo. Se incluyeron pacientes prematuros de 30 a 36 semanas de gestacio´ n en sus primeros 10 dı´as de vida, con conducto arterioso permeable hemodina´micamente significativo, de acuerdo con alguno de los siguientes para´metros ecocardiogra´ficos Qp/Qs mayor 1,5/1 y/o relacio´n auricula izquierda/aorta mayor a 1,8 adema´s de soporte ventilatorio2. Se excluyeron pacientes con cardiopatı´as dependientes del ducto, hemorragia intraventricular, trombocitopenia, insuficiencia renal, hiperbilirrubinemia y enterocolitis necrosante. Se dividieron en 2 grupos sobre la base del peso, grupo I menor de 1 kg y grupo II mayores de 1 kg, ambos tratados con paracetamol a 15 mg/kg/dosis vı´a oral cada 6 h (total acumulado 60 mg/kg); 48 h despue´s de la primera dosis se realizo´ control ecocardiogra´fico. En caso de demostrar permeabilidad del ducto se administro´ un segundo ciclo farmacolo´gico, si el segundo tratamiento mostraba permeabilidad del ducto se procedı´a al cierre quiru´ rgico. Todos los pacientes se trataron el primer dı´a con lı´quidos totales a 70 ml/kg/dı´a, con incremento diario de 10 a

20 ml/kg/dı´a hasta un tope ma´ximo de 160 ml/kg/dı´a al final de

la primera semana de vida.

Se incluyeron 10 pacientes para tratamiento farmacolo´ gico, de los cuales se obtuvo el cierre en 6 pacientes con el primer ciclo farmacolo´gico, 4 pacientes fueron sometidos a un segundo ciclo, y se obtuvo el cierre solo en 1 caso y los 3 restantes se trataron con cirugı´a, con una tasa de e´xito final del 70%; el cierre fue mayor en mayores de 1 kg (6 pacientes). La relacio´n por sexo fue femenino 3:1 (75%). En la tabla se observa el taman˜o del ducto arterioso de

1 a 5 mm de dia´metro. Los datos ecocardiogra´ficos fueron: gasto

cardiaco en sı´stole, promedio 292,5 (rango, 143-440 mmHg); Qp/Qs, promedio 2 (rango, 1,1-3,5); aurı´cula izquierda/aorta, promedio 1,23 (rango, 1-1,8). Durante la aplicacio´n del fa´rmaco se monitorizo´ la funcio´n hepa´tica y el recuento plaquetario, sin observar cambios significativos.

Dos pacientes fallecieron: el paciente 4, por choque se´ptico, a las 48 h posteriores al te´rmino del ciclo, y el paciente 8 por choque hipovole´mico secundario al evento quiru´ rgico (tabla). La mortalidad no se relaciono´ con el empleo del fa´rmaco. El cierre farmacolo´ gico del ducto arterioso con paracetamol tiene un e´xito similar al de otros antiinflamatorios no esteroideos, con un porcentaje del 70%. Al igual que en este estudio, otros autores han descrito que el paracetamol tiene tasas de e´xito similares a otros fa´rmacos, como lo demuestra la revisio´ n realizada en Cochrane Plus de 2008, donde observan que la indometacina tiene una tasa de e´xito de aproximadamente un 70%2. Otro estudio, realizado por Jones et al4, compara la indometacina frente a ibuprofeno para conducto arterioso permeable hemodina´micamente significativo en pacientes prematuros, y sen˜ala que la indometacina es efectiva hasta un 70% en un primer ciclo y un 60% cuando requieren un segundo ciclo; con el ibuprofeno se ha observado una tasa de cierre del 75% y con segundo ciclo del 55%. En el estudio realizado por Ozmert et al5 se registro´ una tasa de e´xito del 71,4%5 con el empleo de paracetamol. Dichas tasas de e´xito son similares a las obtenidas en este trabajo. Algo importante que debemos sen˜alar es la aparente inocuidad del medicamento, ya que durante nuestro estudio no se documentaron complicaciones a corto y medio plazo. Esto se explica porque el fa´rmaco realiza su accio´ n a trave´s de la inhibicio´ n no selectiva de la ciclooxigenasa, Rev Esp Cardiol. 2015;68(5):441–451 Tabla Caracterı´sticas de los pacientes incluidos en el estudio Paciente Peso (kg) PCA (mm)

GCSI

Qp/Qs AI/Ao Ciclo 1 Ciclo 2 Qx Mortalidad

1

1,15

1

258

1,9

1,07

Exitoso

2

1,35

5

320

3,6

1,20

Exitoso

3

1,20

2

270

2,0

1,00

Exitoso

4

0,84

1

440

1,1

1,01

Exitoso Sı´

5

1,20

2

355

1,4

1,26

Exitoso

6

1,60

2

281

1,9

1,20

Exitoso

7

0,98

2

143

3,0

1,30

Sı´

8

0,97

3

273

1,2

1,80

Sı´ Sı´

9

1,20

3

168

1,5

1,90

Exitoso

10

1,30

2,5

210

1,9

2,10

Sı´ AI: aurı´cula izquierda; Ao: aorta; GCSI: gasto cardiaco en sı´stole; PCA: conducto arterioso permeable. 0300-8932/ 2014 Sociedad Espan˜ola de Cardiologı´a. Publicado por Elsevier Espan˜a, S.L.U. Todos los derechos reservados. Document downloaded from http://www.revespcardiol.org/, day 04/07/2019. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited. Document downloaded from http://www.revespcardiol.org/, day 04/07/2019. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited.

enzima encargada de la sı´ntesis de prostaglandinas, sin originar vasoconstriccio´ n y reduccio´ n de los flujos sanguı´neo renal, mesente´rico y cerebral6. Al ser un fa´rmaco de fa´cil acceso y de inocuidad demostrada en neonatos, con las propiedades para cierre de conducto arterioso permeable hemodina´micamente significativo, se espera que la estancia intrahospitalaria disminuya y con ello la morbilidad asociada.

Una limitacio´ n de este estudio es el nu´ mero reducido de pacientes, por lo que no es posible alcanzar conclusiones precisas, pero ha demostrado hasta el momento que el paracetamol es eficaz con pocos efectos secundarios; aunque es necesario que se continu´ e con estudios a largo plazo y con muestras mayores para mostrar con ma´s claridad este efecto farmacolo´gico, adema´s de analizar las complicaciones potenciales.

Rocı´o A. Pen˜a-Jua´rez*, Miguel A. Medina-Andrade, Marı´a T. Martı´nez-Gonza´lez, Antonio F. Gallardo-Meza, Daniel Cortez-Comparan y Miguel A. Pin˜a-Garay Divisio´n de Pediatrı´a, Hospital General de Occidente, Secretarı´a de Salud Jalisco, Zapopan, Jalisco, Me´xico

* Autor para correspondencia:

Correo electro´nico: alepejz@gmail.com (R.A. Pen˜a-Jua´rez). On-line el 16 de marzo de 2015

BIBLIOGRAFI´A

1. Garson A, Bricker T, Fisher D. The science and practice of Pediatric Cardiology. En:

Aortic stenosis valvular, supravalvular and fibromuscular subvalvular. Vol. I. 2 nd ed. Londres: Lea and Febiger; 1990. p. 1183.

2. Golombek SG, Sola A, Baquero H. Primer consenso clı´nico de SIBEN: enfoque

diagno´stico y terape´utico del ductus arterioso permeable en recie´n nacidos pretermino. An Pediatr Barc. 2008;69:454–81.

3. Coceani F, White E, Bodach E, Olley PM. Age-dependent changes in the response

of the lamb ductus arteriosus to oxygen and ibuprofen. Can J Physiol Pharmacol. 2009;57:825–31.

4. Jones LJ, Craven PD, Attia J, Thakkinstian A, Wright I. Network meta-analysis

of indomethacin versus ibuprofen versus placebo for PDA in preterm infants. Arch Dis Child Fetal Neonatal Ed. 2011;96:F45–52.

5. Ozmert M, Dogan M, Kucuktasci K. Paracetamol therapy for patent ductus

arteriosus in premature infants: a chance before surgical ligation. Pediatr Cardiol. 2014;35:276–9.

6. Lucas R, Warner TD, Vojnovic I, Mitchell JA. Mechanisms of acetaminophen: role

of cyclo oxigenase. FASEB J. 2005;19:630–5.

http://dx.doi.org/10.1016/j.recesp.2014.11.029 Revascularizacio´n endovascular carotı´dea realizada por un equipo multidisciplinar:

primera experiencia en Espan˜a Endovascular Carotid Revascularization Performed by a Multidisciplinary Team: First Experience in Spain Sr. Editor:

Las enfermedades cerebrovasculares son la segunda causa de muerte en nuestro paı´s y la enfermedad carotı´dea extracraneal es responsable de un tercio de los ictus isque´micos. La indicacio´ n para revascularizar una lesio´n carotı´dea depende del estado sintoma´tico del paciente y de su grado de gravedad obstructiva. La intervencio´n endovascular con stent es una forma o´ ptima de revascularizacio´n carotı´dea, con resultados a medio y largo plazo comparables con la endarterectomı´a1.

El cardio´logo intervencionista ha mostrado ser un profesional con habilidades o´ptimas para realizar con seguridad el implante de stent en la enfermedad carotı´dea2. Sin embargo, a diferencia de lo que sucede fuera de nuestras fronteras, en Espan˜a no ha habido implicacio´n de cardio´logos intervencionistas en este procedimiento3. La Unidad Endovascular del Hospital Virgen Macarena reu´ ne la atencio´ n endovascular a las enfermedades cardiovasculares. En su interior se ha creado un grupo multidisciplinar compuesto por cardio´ logos intervencionistas y neuro´logos para el tratamiento de la enfermedad carotı´dea, lo que constituye un modelo innovador en nuestro paı´s.

El rol del neuro´logo consiste en indicar el procedimiento, realizar el control clı´nico durante la intervencio´ n y efectuar el seguimiento. Los cardio´logos intervencionistas han participado en un programa dedicado de formacio´n para la revascularizacio´ n carotı´dea con stent, con tutorizacio´n inicial por un radio´logo intervencionista; adema´s fueron entrenados por un neurorradio´ logo intervencionista en el manejo de dispositivos para la resolucio´n de complicacio´n tromboembo´lica intracraneal. El motivo de este trabajo es presentar nuestra experiencia en la revascularizacio´ n con stent de la patologı´a carotı´dea extracraneal, ası´ como evaluar si las competencias obtenidas en cardiologı´a intervencionista pueden ser transferidas a este procedimiento para amortiguar la necesidad de una curva de aprendizaje.

Desde mayo de 2008 a abril de 2014 se revascularizo´ con stent a

300 pacientes con enfermedad carotı´dea; nuestra poblacio´n, con

una edad de 68,9 8,6 an˜os ha sido mayormente sintoma´tica (81,3%). El 53% de los pacientes tenı´a diagnosticada enfermedad en otro territorio vascular, fundamentalmente miembros inferiores (31%) y coronarias (23,7%).

El acceso fue mayoritariamente transfemoral (91%), aunque en los u´ ltimos 2 an˜os se ha comenzado con el acceso transradial derecho para el tratamiento carotı´deo ipsilateral. La tasa de arco ao´rtico hostil para el cateterismo carotı´deo fue del 26% y de enfermedad significativa (< 50%) de la caro´tida contralateral en el 48% de los pacientes.

En todas las intervenciones se planteo´ el uso de dispositivos de proteccio´ n cerebral, aunque en 11 (4%) no se logro´ te´ cnicamente. Se empleo´ proteccio´ n distal en dos tercios de los casos, principalmente cesta-filtro (56%), aunque tambie´ n balo´ n de oclusio´ n distal (11%). La proteccio´ n proximal se utilizo´ en

75 procedimientos (29%). En general, en caso de placas con alta

gravedad obstructiva y de caracterı´sticas hipo o anecoge´ nicas se opto´ por la proteccio´ n proximal y, ma´s recientemente, por la distal con balo´ n oclusor (figura).

La tasa global de e´xito del procedimiento, entendido como revascularizacio´n con estenosis residual < 50% y ausencia de eventos mayores (fallecimiento, ictus o infarto) en las primeras

24 h, fue del 98%: en 6 pacientes se produjo un evento clı´nico

mayor (1 ictus mayor, 4 menores y 1 infarto de miocardio sin elevacio´ n del segmento ST).

Pasada la fase periprocedimiento y durante los primeros 30 dı´as se produjeron 4 fallecimientos (3 casos por henorragia intracraneal debida, probablemente, a sı´ndrome de hiperperfusio´n, mientras que el cuarto se debio´ a trombosis probable del stent) y 4 ictus. Por tanto, de forma global, la tasa combinada de eventos neurolo´gicos (fallecimiento e ictus) a 30 dı´as de la intervencio´n fue del 4,3%. Estos resultados clı´nicos son similares a los obtenidos por otras series nacionales4 (tabla).

Con el fin de evaluar el impacto de nuestra curva de aprendizaje se compararon los resultados clı´nicos obtenidos en el primer tercio de nuestra experiencia (100 procedimientos iniciales) con las restantes 200 intervenciones. La tasa de e´xito del procedimiento fue Cartas cientı´ficas / Rev Esp Cardiol. 2015;68(5):441–451

442

Document downloaded from http://www.revespcardiol.org/, day 04/07/2019. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited. Document downloaded from http://www.revespcardiol.org/, day 04/07/2019. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited.