Original Article

Journal of Perinatology (2005) 25, 386–390. doi:10.1038/sj.jp.7211295 Published online 21 April 2005

Transient Bilirubin Encephalopathy and Apnea of Prematurity in 28 to 32 Weeks Gestational Age Infants

Sanjiv B Amin MD1, Lama Charafeddine MD2 and Ronnie Guillet MD, PhD2

  1. 1Department of Pediatrics (S.B.A), Division of Neonatology, University of Maryland, Baltimore, MD, USA
  2. 2Department of Pediatrics (L.C., R.G.), Division of Neonatology, Children's Hospital at Strong, Rochester, NY, USA

Correspondence: Sanjiv B. Amin, MD, University of Maryland School of Medicine, Division of Neonatology, 22, South Greene Street, N5W68, University Center, Baltimore, MD 21201, USA

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Abstract

OBJECTIVE:

 

Apnea of prematurity (AoP) is, in part, a reflection of brainstem-mediated respiratory control system maturation. We previously demonstrated changes in brainstem function in relation to hyperbilirubinemia (bilirubin encephalopathy, (BE)) as evaluated by auditory brainstem evoked responses (ABR) in infants 28 to 32 weeks gestational age (GA). We hypothesized that in this population, as bilirubin increases and causes auditory brainstem dysfunction, respiratory control system may also be adversely affected leading to increased frequency of AoP.

STUDY DESIGN:

 

We studied 100, 28 to 32 weeks GA infants and identified 66 with normal and 34 with abnormal ABR progression in temporal relation to hyperbilirubinemia (BE). The abnormal ABR progression was associated with elevated bilirubin, specifically elevated unbound bilirubin levels. A blinded, retrospective chart review quantified the amount of weekly apnea and bradycardia events during the hospital stay, total duration of methylxanthine treatment, total duration of mechanical ventilation, CPAP, and/or nasal cannula, and risk factors for apnea (sepsis, IVH grade >II, asphyxia). Since mechanical ventilation confounds the identification of apnea, infants requiring mechanical ventilation were excluded from further review (n=60; 21 with BE and 39 with normal ABR progression). Data from the remaining 40 infants were analyzed. Student's t-test was used to analyze continuous variables if the distribution was normal otherwise Wilcoxon-ranked-sum test was used. chi2 was used to analyze nominal variables. A pless than or equal to0.05 was considered significant.

RESULTS:

 

There was no difference in risk factors between infants with and without BE. BE was identified on day 3 (median; range 1 to 6 days). Patients with BE had significantly more apneic events (15 vs 2, p=0.0009), bradycardic events (14 vs 1, p=0.02), and required more prolonged treatment with CPAP (2.2 vs 0.5 days, p=0.007), nasal cannula (6.6 vs 2.2 days, p=0.02), and methylxanthines (9.5 vs. 1.9 days, p=0.002) than those with normal ABR progression. The difference in the incidence of apnea and bradycardia between infants with and without BE was most pronounced during the first week.

CONCLUSIONS:

 

Premature infants with transient bilirubin encephalopathy as defined by abnormal ABR progression in relation to hyperbilirubinemia have more concurrent apneic events and require more prolonged respiratory support and medications.

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INTRODUCTION

Apnea of prematurity (A.P.) is a manifestation of developmental immaturity of respiratory control mediated by the brainstem. Brainstem maturation may be evaluated by the progression of the auditory brainstem-evoked response (ABR).1, 2, 3, 4 The ABR in premature infants consists of a sequence of waves, wave I, III and V. Wave I represents the activity at the auditory nerve level while waves III and V represents the activity at the brainstem level.5, 6 In 28 to 32 weeks gestational age (GA) infants, ABR matures over the first postnatal week and is characterized by improving detectability of the response peaks and shortening of the absolute wave latencies.7 In addition, in premature infants, the waveform can be categorized depending on the replicability of the response and the presence of wave III and/or wave V. Response Type also demonstrates progressive improvement during the first postnatal week.7

Bilirubin has specific predilection for the auditory neural pathways, and therefore early detection of bilirubin-induced neuronal injury is possible using auditory brainstem responses (ABR).8, 9, 10, 11, 12 ABR changes induced by bilirubin progress from reversible prolongation of the absolute latencies of waves III and V to loss of wave amplitude and ultimately to the inability to detect an identifiable wave.8, 9, 10, 13 Reversible changes may persist for up to 24 hours after the decrease in serum bilirubin concentrations. Prolonged bilirubin toxicity may cause irreversible sensorineural hearing loss.14, 15, 16

Abnormal ABR progression (transient bilirubin encephalopathy) during the first week is associated with degree of hyperbilirubinemia and is better predicted by unbound bilirubin than total serum bilirubin.17 As bilirubin increases and transient brainstem dysfunction (bilirubin encephalopathy (BE)) occurs, the likelihood of A.P. may also increase in this population of infants with immature respiratory control. Our objective was to determine if premature infants with transient BE as defined by abnormal ABR progression in relation to hyperbilirubinemia have more concurrent apnea and bradycardia events as compared to premature infants without transient BE.

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METHODS

All premature infants who were enrolled in our previously reported bilirubin – albumin binding variable study 17 were eligible for this nested case–control study as detailed below.

Transient Bilirubin Encephalopathy

The charts of 100, 28 to 32 weeks GA infants, admitted to the Neonatal Intensive Care Unit of Golisano Children's Hospital at Strong, Rochester, NY from July 1996 to July 1998 who participated in the transient BE study were examined retrospectively.

A detailed method involving ABR recording and analysis of ABR is described in our original BE study.17 As described previously, for each patient, sequential ABRs carried out in the first postnatal week were scored by the audiologists without knowledge of GA or serum bilirubin level. The waveforms and wave latency progressions were classified by the audiologists as normal or abnormal maturational progression. Normal progression was characterized by an improvement in Response Type (e.g. Type 2 to 1) or by shortening of the wave V latency. Conversely, abnormal ABR maturation was defined as a deterioration in Response Type (e.g. from Type 1 to 2) or prolongation of wave V latency compared to the previous ABRs. Transient BE was defined as a temporal association between abnormal ABR maturation and peak total serum bilirubin and unbound bilirubin. The unbound bilirubin was analyzed using the same aliquots of blood that was used to measure serum bilirubin in a subgroup of 31 of the 100 infants. BE was identified on a median age of 3 days (range 1 to 6 days). Infants received phototherapy based on institutional guidelines for the use of phototherapy in the management of hyperbilirubinemia in premature infants. None of these premature infants received exchange transfusion for hyperbilirubinemia.

Apnea of Prematurity

An independent investigator who was unaware of the ABR progression and was not a participant with the original study performed chart review and collected clinical data on the number of apnea and bradycardia episodes during each week of the hospital stay for each of the 100 subjects. In the NICU, all premature infants are routinely monitored for apnea and bradycardia using impedance technology. Episodes of apnea lasting longer than 20 seconds and bradycardia with heart rate <100/minute are detected by the cardiorespiratory monitor. The nurse confirms the events and records the heart rate and the occurrence of apnea in the infant's chart. For the purpose of this study, bradycardia was defined as a heart rate less than 80/minute. The initiation, use and discontinuation of respiratory support (nasal cannula, nasal continuous positive airway pressure (CPAP) and mechanical ventilation) and methylxanthines for the management of apnea and/or respiratory disease were at the discretion of the attending neonatologist.

Information on duration of mechanical ventilation, CPAP, nasal cannula (NC) and duration of methylxanthines (theophylline or caffeine) usage during the hospital stay were also collected for each of the 100 subjects. Additional data included clinical risk factors for apnea and bradycardia such as sepsis (culture proven or use of intravenous antibiotics for >7 days), IVH grades III and IV and asphyxia (Apgar <5 at 5 minutes). The study was approved by the University of Rochester Institutional Review Board.

Statistical Analysis

Statistical analysis was performed using Stata (Stata Corporation, College Station, TX, USA). Wilcoxon signed-rank test was used to test the null hypothesize that the median difference in occurrences of apnea during the 24-hours period before BE and during the 24-hours period after BE is equal to zero. Student's t-test was used to analyze continuous variables if the distribution was normal otherwise Wilcoxon ranked-sum test was used. chi2 was used to analyze nominal variables. A pless than or equal to0.05 was considered significant. Multiple regression analysis was performed to control for the confounding factors.

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RESULTS

Transient Bilirubin Encephalopathy

Of 100 subjects, 66 infants had normal ABR progression and 34 infants had abnormal ABR progression in temporal relation to hyperbilirubinemia (BE). In these 34 infants with abnormal ABR progression, peak bilirubin levels preceded (within 24 hours) the abnormality in ABR progression suggesting temporal relation to hyperbilirubinemia. 'There were no statistically significant differences in the mean birth weight and mean GA between infants with normal ABR progression and BE (Table 1). The wave V latencies and Response Types (ABR parameters) at the time of peak bilirubin measurements were significantly different (Table 1). The mean peak total bilirubin concentration during the first postnatal week for the 66 infants with normal ABR progression were not significantly different than the mean peak bilirubin concentration measured in the 24 hours preceding the ABR first showing abnormal progression in the other 34 infants (Table 1). The unbound bilirubin measurements were available for 31 out of 100 subjects. Compared to peak total serum bilirubin concentrations, the peak unbound bilirubin concentration measured in the 24 hours preceding the ABR first showing abnormal progression were significantly higher among infants with BE compared to mean peak unbound bilirubin concentration during the first postnatal week in infants with normal ABR progression (Table 1). This is highly suggestive that abnormal ABR progression is associated with bilirubin and best predicted by unbound bilirubin rather than the total bilirubin. There was no statistically significant difference in the incidence of clinical risk factors for apnea such as sepsis (5/31 vs 19/69), asphyxia (1/31 vs 4/69) and IVH grade >II (0/31 vs 1/69) between group of 31 infants with unbound bilirubin levels and group of 69 infants in whom the unbound bilirubin was not measured.


Apnea of Prematurity

Of 100 subjects, 60 subjects were mechanically ventilated (40 ventilated for respiratory distress syndrome, 10 ventilated for respiratory depression at birth and 10 ventilated for severe apnea) during the first postnatal week of life. In all, 54 out of 60 infants were ventilated from day 1. Among these 60 subjects, there was no difference in duration of mechanical ventilation between infants with normal ABR maturation (n=39, mean 2.7plusminus4.6 days) compared to infants with BE (n=21, mean 1.6plusminus2.8 days) (p=0.19). Since, mechanical ventilation confounds identification of apnea, infants on mechanical ventilation were excluded from further analysis.

Demographic profiles on the remaining 40 subjects are shown in Table 2. Of these 40 subjects, 13 infants had BE, while 27 infants had normal ABR maturation. There was no significant difference in GA, birth weight, or the incidence of clinical risk factors for apnea between the infants with BE and infants with normal ABR maturation (Table 2).


In 13 infants with transient BE, the number of apnea episode were greater during the 24-hours period after transient BE than 24-hours period before transient BE (p=0.04). Infants with BE had significantly more apnea and bradycardia events during the hospital stay compared to infants with normal ABR maturation (Table 3). On comparing weekly apnea and bradycardia events, the differences in the number of apnea and bradycardia events were most pronounced during the first week and were statistically significant only during the first two postnatal weeks between infants with and without BE (Table 3). These differences remained statistically significant when controlling for sepsis, asphyxia and IVH grades III and IV. During the course of their hospitalization, infants with BE also required significantly more prolonged respiratory support (NC and NCPAP) and were treated with methylxanthines longer than infants with normal ABR maturation. These differences remained statistically significant when controlling for sepsis, asphyxia and IVH grade >II.


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DISCUSSION

Our findings suggest that BE in premature infants, 28 to 32 weeks gestation manifests as an increased incidence of apnea and bradycardia, most pronounced during the first postnatal week. In addition, infants with BE require more prolonged respiratory support and respiratory stimulants. Although, there have been anecdotal reports of apnea occurring with acute bilirubin encephalopathy, this association has not been studied.18 We believe that this is the first clinical study associating apnea and bradycardia to acute BE in premature infants.

ABR has been studied in term and to a lesser extent in premature infants as a direct noninvasive neurophysiological assessment of reversible bilirubin neurotoxicity.9, 12, 13, 19 These studies have demonstrated reversible changes in ABR waves III and V latency induced by bilirubin. Both waves III and V reflect activity in the auditory nervous system at the brainstem level.5 As a result of the proximity of auditory neural system to cardiorespiratory center, ABR results may correlate with other brainstem functions such as control of heart rate and breathing. Henderson-Smart et al. have shown an association between abnormal brainstem function as evaluated by ABR and AoP.20 The inference is that if bilirubin rises and affects brainstem function, there will be an increase in the number of apneic and bradycardic episodes.

In general, the frequency of apnea and bradycardia decreases over time in both the groups. It is not clear whether this trend is due to therapeutic interventions or normal developmental maturation of the brainstem. However, the existence of significant differences in the incidence of apnea and bradycardia between the two groups during the first two postnatal weeks, with the most pronounced differences during the first postnatal week, strongly suggest an association between BE and apnea. Unfortunately, we did not perform sequential ABRs and analyze serum bilirubin levels beyond the first week to determine when bilirubin-induced ABR changes in infants with BE improve and with what consistency and completeness become similar to infants with normal ABR progression.

The retrospective design is the major limitation with our study. In addition, because of the retrospective nature and impedance technology used to monitor apnea, we could not differentiate between obstructive and central apnea. However, the chart review was performed by an investigator who was unaware of the study groups. Despite these limitations, our findings have clinical relevance and may provide the basis for future studies that will be required to determine a causal effect of bilirubin on apnea in premature infants. Our observation of increased AoP with degree of hyperbilirubinemia for infants of 28 to 32 weeks gestation may be generalizable and lead to a more function-based approach to the determination of safer levels of unbound bilirubin in infants of other GA groups, especially the very premature infants. Once threshold levels of total bilirubin or unbound bilirubin that result in brainstem dysfunction have been determined for different GA groups, a more rational basis for phototherapy can be developed. If the effect of bilirubin on apnea is causal then aggressive treatment of premature infants with elevated bilirubin levels to prevent bilirubin-induced brainstem dysfunction may decrease the incidence of apnea and bradycardia events.

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Acknowledgements

We thank all the neonatal intensive care unit nurses in monitoring the infants for apnea and bradycardia events during the course of the study. We thank Dr. Lois Johnson for her guidance during the preparation of this manuscript.