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 Table of Contents  
ORIGINAL ARTICLE
Year : 2015  |  Volume : 4  |  Issue : 4  |  Page : 250-255

Indomethacin dose-interruption and maternal chorioamnionitis are risk factors for indomethacin treatment failure in preterm infants with patent ductus arteriosus


Department of Pediatrics, Division of Neonatology, McMaster University, Hamilton, Ontario, Canada

Date of Web Publication16-Oct-2015

Correspondence Address:
Muzafar Gani Abdul Wahab
Department of Pediatrics, Division of Neonatology, McMaster University Medical Centre, HSC.-4F, 1280 Main Street West, Hamilton, Ontario L8S 4K1
Canada
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2249-4847.165688

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  Abstract 

Background: Indomethacin has been used as the primary pharmacotherapeutic agent for the closure of patent ductus arteriosus (PDA) in preterm infants. However, it is commonly observed that infants often respond differently to indomethacin treatment with some requiring multiple courses of the drug and subsequently surgical ligation. Objectives: To explore common variables that could be associated with failure of a primary course of indomethacin for PDA in preterm infants.Methods: We examined 83 preterm infants who received intravenous indomethacin for PDA treatment from 2010 to 2013. We identified those who failed primary pharmacotherapy and required subsequent courses or surgical ligation. A number of perinatal/neonatal variables in the infants with and without primary indomethacin failure were compared initially for univariate analysis. Following the univariate analysis, those variables which had a significant difference between the two groups were selected to carry out logistic regression analysis to find out independent risk factors for indomethacin failure. Results: Of 77 infants analyzed, 36 (46.7%) had a primary indomethacin failure and nine infants (11.7%) underwent surgical ligation. Univariate analysis revealed that infants with primary indomethacin failure were significantly more preterm, were more likely to be males, did not receive a complete course of antenatal corticosteroids, their mothers had clinical chorioamnionitis and indomethacin dose interruption was documented during clinical care. The multivariate logistic regression analysis showed that dose interruption (odds ratio [OR]: 27.14; 95% confidence interval [CI]: 5.94, 124.07) and clinical chorioamnionitis (OR: 7.80; 95% CI: 1.73, 35.00) were independent risk factors for indomethacin failure. Conclusion: Indomethacin dose interruption and clinical chorioamnionitis appear to be independent risk factors for primary indomethacin failure in preterm infants.

Keywords: Chorioamnionitis, dose-interruption, indomethacin, patent ductus arteriosus


How to cite this article:
Mitra S, Wahab MG. Indomethacin dose-interruption and maternal chorioamnionitis are risk factors for indomethacin treatment failure in preterm infants with patent ductus arteriosus. J Clin Neonatol 2015;4:250-5

How to cite this URL:
Mitra S, Wahab MG. Indomethacin dose-interruption and maternal chorioamnionitis are risk factors for indomethacin treatment failure in preterm infants with patent ductus arteriosus. J Clin Neonatol [serial online] 2015 [cited 2019 Sep 19];4:250-5. Available from: http://www.jcnonweb.com/text.asp?2015/4/4/250/165688


  Introduction Top


Patent ductus arteriosus (PDA) is one of the most controversial topics in the management of preterm infants. It is a well-known fact that more preterm the infant is, more likely it is that the infant would have a persistent and often clinically significant PDA that would require treatment.[1] Indomethacin has been used as the primary pharmacotherapeutic agent for the closure of a hemodynamically significant PDA. However, it is commonly observed that infants with similar gestational age and clinical profile often respond differently to Indomethacin treatment with some requiring multiple courses of the drug and subsequently surgical ligation. Over the last few years, management of PDA in preterm infants has undergone a paradigm shift. Moving away from the prophylactic or early interventional approach, a number of Neonatal Intensive Care Units (NICUs) have adopted a more conservative, individualized and targeted approach to the management of the patent duct in a premature infant.[2] The adjunctive perinatal and neonatal management strategies have also undergone significant changes over the last few years. Therefore, a number of antenatal and postnatal factors may affect the infant's response to indomethacin treatment for PDA.

A number of studies have tried to look into different variables associated with indomethacin failure. A PubMed/MEDLINE search (Search details: ("Ductus Arteriosus, Patent" [Mesh] AND "Infant, Newborn" [Mesh]) AND "Indomethacin" [Mesh]) yielded 660 articles out of which 9 articles have tried to explore risk factors associated with indomethacin failure and persistent ductus in the past decade.[3],[4],[5],[6],[7],[8],[9],[10],[11] The antenatal factors that have been studied include exposure to antenatal betamethasone, gestational diabetes, preeclampsia, chorioamnionitis.[9] Out of these lack of antenatal steroids was found to be a significant risk factor for pharmacotherapeutic failure.[9] In a recent study by Arayici et al., histological chorioamnionitis was found to be an important risk factor for persistent PDA.[12] Among the postnatal factors, the most commonly studied factors include birth weight, gestational age, sex, race, postnatal age at indomethacin treatment, respiratory distress syndrome, excess fluid administration, platelet counts and treatment with furosemide, caffeine and phototherapy.[8-11,13-15] However, almost all these studies included a population dating back to 2009 or earlier except one by Sallmon et al. which included a population between 2005 and 2010.[3] With the advent of ibuprofen, the research focus has largely shifted away from indomethacin in the past few years. For example a recent study by Bas-Suárez et al. has looked into factors associated with failure of prostaglandin inhibitors in PDA, but in their study neonates from 2006 to 2009 received indomethacin and neonates thereafter (2009–2012) received ibuprofen.[16] Similar studies in recent times by Dani et al. and Alyamac Dizdar et al. have focused on factors related to ibuprofen failure.[17],[18] However, for institutions that continue to use indomethacin, it is important to identify the factors associated with indomethacin failure, especially with the currently adopted conservative management protocols. With this background, we conducted a study to explore common variables that could be associated with failure of a primary course of indomethacin for hemodynamically significant PDA in the preterm population in a tertiary care center.


  Methods Top


Design and data sources

We performed a single-center retrospective study of infants who received indomethacin for treatment PDA at McMaster Children's Hospital, Hamilton, Ontario, Canada. Data was collected for the period between 2010 and 2013. Infants who have received Indomethacin during the period were identified using the Canadian Neonatal Network database. Subsequently, details regarding perinatal and neonatal variables were obtained using medical records and electronic lab results. This study was approved by the Hamilton Integrated Research Ethics Board.

Infants admitted to the NICU during the study period and meeting both the following criteria were included in the study: (i) Neonates who completed a primary course of indomethacin for a significant PDA, and (ii) also required a second course of indomethacin or surgical ligation following a primary course of indomethacin. Infants who did not receive all three doses of indomethacin to complete a primary course were excluded. Those eligible infants who died during the NICU stay were also excluded from the final analytical sample.

Definitions

A complete course of indomethacin was defined as three doses of indomethacin (0.2 mg/kg/dose) infused over 20 min at 12 hourly intervals in accordance with the hospital policy. Failure of primary course of indomethacin was defined as infants requiring more than one full course of indomethacin for closure of PDA or received one full course of indomethacin followed by surgical ligation for the closure of PDA. Infants who did not require more than one course of indomethacin during their hospital stay were deemed as those who did not have primary indomethacin failure. The decision to treat PDA was at the discretion of the attending neonatologist in the presence of clinical symptoms attributable to PDA along with fulfilment of predefined echocardiographic criteria. The clinical criteria include any two of the following:

  • FiO2 requirement >30% to maintain target SpO2 between 91% and 95%
  • Escalation of ventilator parameters from baseline to maintain normal pCO2 levels
  • Feeding intolerance – defined as inability to increase feeds as per institutional feeding guidelines due to increased residuals/abdominal distension
  • Need for inotropes for hypotension management.


The echocardiographic criteria include presence of two or more of the following:[19]

  • Transductal PDA diameter >1.4 mm/kg
  • Unrestrictive pulsatile transductal flow (PDA maximum velocity [Vmax] <2.0 m/s)
  • Mild-to-moderate left heart volume loading (left atrium/aorta [LA/Ao] ratio >1.4)
  • Increased pulmonary perfusion, that is, mean and end-diastolic flow velocity in the left pulmonary artery 0.42 and 0.20 m/s, respectively
  • Increased left ventricular output (LVO) and consistent peripheral hypoperfusion in the superior vena cava (SVC), that is, LVO/SVC flow ratio 4.


Antenatal and postnatal variables

The antenatal variables that were studied included (i) complete course of antenatal steroids; (ii) clinical chorioamnionitis in the mother. Definition of variables: Clinical chorioamnionitis was defined as presence of maternal fever >38°C and >2 of following: Maternal heart rate >100/min; fetal heart rate >160/min; uterine tenderness; foul smelling amniotic fluid and maternal leukocytosis (>15,000/cumm).[20] Complete course of antenatal steroids were defined as two doses of betamethasone (12 mg each) given 24 h apart or four doses of dexamethasone (6 mg each) given intramuscularly 12 h apart to the mother with the last dose being given at least 24 h prior to delivery.[21] The postnatal variables included (i) gestational age; (ii) birth weight; (iii) sex; (iv) presence of respiratory distress syndrome requiring surfactant therapy; (v) prophylactic indomethacin administration; (vi) postnatal age at the start of primary course of indomethacin; (vii) any interruption in the dosage schedule during the primary course; (viii) total fluid intake at start of therapy; (ix) blood culture positive sepsis receiving antibiotics at start of treatment; (x) platelet counts at the start of the primary indomethacin course; whether the baby was receiving; (xi) caffeine citrate; (xii) phototherapy at the start of the primary course. An interruption in dosage was defined as any deviation from the prescribed frequency of doses in a complete course of indomethacin as defined above. Only cases, where the course was completed in spite of interruption, were included for analysis.

Data analysis

Variables of infants with and without primary indomethacin failure were compared initially for univariate analysis. The Chi-square test was used for analysis of categorical variables. For continuous variables, the Student's t-test (unpaired) was used for analysis of variables with normal distribution and the Mann–Whitney U-test for analysis of variables with skewed distribution. Following the univariate analysis, those variables which had a significant difference between the two groups were selected to carry out logistic regression analysis to find out independent risk factors for indomethacin failure. All data were entered into Excel spreadsheet and analyzed using Minitab 17 Statistical Software (2010). [Computer software]. State College, PA: Minitab, Inc. P <0.05 was considered to be statistically significant. Odds ratio (OR) and 95% confidence intervals (CIs) were calculated for independent factors in the regression analysis.


  Results Top


Eighty-three infants received indomethacin during the study period out of which six infants died during NICU stay. The remaining 77 infants formed the final analytical sample. The mean birth weight was 840 ± 246 g (mean ± standard deviation) and gestational age was 25 ± 2 weeks (23–31 weeks). The overall male: female ratio was 0.97 (38:39). Mean postnatal age at indomethacin treatment was 7.2 ± 3.8 days. Out of the 77 infants, 36 (46.7%) had primary indomethacin failure and nine infants (11.7%) underwent surgical ligation. None of the infants received prophylactic indomethacin nor received antibiotics for blood culture positive sepsis at the start of indomethacin treatment. The distribution of the cases according to their gestational age is shown in [Figure 1].
Figure 1: Distribution of indomethacin failure cases according to gestational age

Click here to view


Univariate analysis of the perinatal and neonatal variables revealed that infants with primary indomethacin failure were significantly more preterm with a lower birth weight, were more likely to be males, did not receive a complete course of antenatal corticosteroids, their mothers had documented clinical chorioamnionitis and indomethacin dose interruption was documented during clinical care (P < 0.05) [Table 1]. A total of 36 infants had documented dose interruption. In 20 of them (55.6%), doses were interrupted due to new onset oliguria (<1 ml/kg/h), nine infants (25%) had rising creatinine without oliguria and the rest seven (19.4%) developed thrombocytopenia (<100 × 109/L).
Table 1: Baseline variables and univariate analysis of risk factors for indomethacin failure

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Based on the results of the univariate analysis, multivariate logistic regression analysis was performed with the above-mentioned variables that were significant on univariate analysis. Gestational age and birth weight were found to be significantly correlated on linear regression (P < 0.0001; Pearson correlation coefficient: 0.75 [95% CI: 0.64–0.84]; r2 = 0.57). Hence, only gestational age was used as a covariate in the regression analysis instead of both gestational age and birth weight. The multivariate logistic regression analysis showed that dose interruption (OR: 27.14; 95% CI: 5.94, 124.07) and clinical chorioamnionitis (OR: 7.80; 95% CI: 1.73, 35.00) were independent risk factors for indomethacin failure in this population [Table 2].
Table 2: Multivariate logistic regression analysis of significant risk factors


Click here to view



  Discussion Top


Variation in response to indomethacin in preterm infants has always been an enigma to practicing neonatologists. As a result, there have been several attempts over the years to relate this variation to a number of perinatal and postnatal variables. However, logistic factors play an equally important role in the successful management of a preterm infant as does associated physiologic variables. This study is thefirst of its kind to test the interaction of operational factors like indomethacin dosage interruption with relevant physiologic variables to identify the risk factors for primary indomethacin failure in this changing era of conservative PDA management. Interestingly, we found that the presence of maternal clinical chorioamnionitis and interruption in indomethacin dosage were independent risk factors for primary indomethacin failure.

It is often observed in clinical practice that indomethacin doses are withheld due to poor urine output and resumed once the urine output has improved. In fact this renal effect of indomethacin along with its presumed role in increasing in the incidence of necrotizing enterocolitis have been cited as the reasons why ibuprofen should be considered as the drug of choice for PDA pharmacotherapy in the recent update of the Cochrane database of systematic reviews.[22] However, in institutions which continue to use indomethacin as the standard of care, this issue has largely remained unresolved in spite of infusing the drug over 20–30 min. The primary reason for this is dearth of good pharmacokinetic (PK)/pharamcodynamic (PD) studies to guide clinicians on how long to stagger the dosing interval in the face of a transient oliguria. This grey area in the clinical practice guidelines could potentially lead to situations where the plasma levels of indomethacin are subtherapeutic. In fact, PK/PD studies on indomethacin in preterm infants have shown that older the infant (>10 days), higher is the dose required to maintain a critical concentration and also infants with second-dose peak plasma indomethacin level <800 ng/ml required escalation of therapy to close the PDA.[23],[24] So the question is, is there any way to maintain therapeutic plasma levels without causing the untoward side effects? There have been studies which show that even infusing indomethacin over 20–30 min may also result in a hemodynamic compromise in the regional microcirculation. It has been shown by Austin et al. that indomethacin infusion over 30 min was associated with a significant reduction in time-averaged mean velocity, peak systolic velocity, and end diastolic velocity in both the anterior cerebral artery and middle cerebral artery.[25] In a recent study by Bhatt et al. in 2012, it was found that slow infusion of cyclooxygenase inhibitors were associated with significant reduction in regional cerebral (rSO2-C), renal (rSO2-R), and mesenteric (rSO2-M) tissue oxygenation measured by near-infrared spectroscopy.[26] Hence, dose interruption as a risk factor for indomethacin failure poses a unique question that needs to be addressed with future prospective trials.

Ductus arteriosus tone is maintained in the perinatal period by prostaglandins (PGE2) and prostacyclin and their production is mediated by cyclooxygenase enzyme.[27],[28],[29] Indomethacin targets this enzyme and downregulates prostaglandin production which facilitates ductus closure. However, perinatal inflammation in the form of chorioamnionitis may potentially alter PG levels and result in variable response to indomethacin as observed in our study. This hypothesis was further strengthened in a similar study by Kim et al., who not only showed that intrauterine inflammation was an independent risk factor for persistence of PDA, but also showed that cyclooxygenase-1 expression in the umbilical arteries and plasma 6-keto prostaglandin F1α levels were higher in nonresponders to indomethacin.[6]

Our univariate analysis revealed certain interesting observations. Firstly our success rate with the primary course of indomethacin was much lower (53.3%) as compared to a randomized trial by Van Overmeire et al. where the closure rate at day 6 was 73% in the early treatment group.[30] One possible explanation is that with the conservative approach of recent times, our mean postnatal age at treatment initiation was 7.2 ± 3.8 days as compared to 3.1 days in the early treatment group in the Van Overmeire et al. trial. This conforms to the observations by Shaffer et al. who suggested that older neonates require higher doses to maintain similar plasma levels of indomethacin.[23]

A number of other interesting findings were noted on univariate analyses that were subsequently not found to be independent risk factors on logistic regression. For example, female sex was found to be protective on univariate analysis. Higher incidence of PDA has also been previously reported in preterm males in observational studies. However no hypothesis for causality has been established.[31],[32] There has been some speculation that infants with lower platelet counts respond poorly to indomethacin treatment.[10],[33] The theory has also been refuted in a few other observation studies.[17],[18] We did not find any relation between platelet counts and primary indomethacin failure. Nor did we find any relation between the total fluid intake at the start of treatment and treatment failure which substantiate the increasingly acknowledged practice of not overtly restricting fluids during PDA treatment.[2]

We acknowledge the limitations of this being a retrospective study which brings in an inherent bias of variation in practice during the course of the study period. Hence we have tried to strike a balance between limiting our study period to as short as possible to ensure consistency of neonatal care versus obtaining a decent sample size to run a logistic regression with the most important covariates. However, this has led to a smaller sample size for the study and hence has limited our ability to test the effect of all potential variables using a regression model. Thus we selected only those variables that were most significantly different (P < 0.05) on univariate analysis to build our multivariable regression model. A prospective study of a similar nature, where all the variables are defined a priori, would lend more credibility to the study. Hence we would like to emphasize that our study only generates an important and previously unexplored hypothesis regarding the role of dosage interruption in treatment failure along with the association of the latter with maternal clinical chorioamnionitis This could pave the way for future prospective cohort studies to better analyze these interactions and also prospective randomized controlled trials to potentially find a solution to the problem associated with dose interruption.

Acknowledgments

We would like to thank Wendy Seidlitz (RN, BScN, MSc), Data Management Specialist, Hamilton Health Sciences for data collection.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflict of interest.

 
  References Top

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Arayici S, Kadioglu Simsek G, Oncel MY, Eras Z, Canpolat FE, Oguz SS, et al. The effect of histological chorioamnionitis on the short-term outcome of preterm infants 32 weeks: A single-center study. J Matern Fetal Neonatal Med 2014;27:1129-33.  Back to cited text no. 12
    
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Bell EF, Acarregui MJ. Restricted versus liberal water intake for preventing morbidity and mortality in preterm infants. Cochrane Database Syst Rev 2014;12:CD000503.  Back to cited text no. 13
    
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[PUBMED]    
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