PEDIATRICS Vol. 111 No. 5 May 2003, pp. 1110-1112
EXPERIENCE AND REASON |
Unbound Bilirubin in a Term Newborn With Kernicterus
Department of Pediatrics
California Pacific Medical Center
San Francisco, California 94118
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Abbreviations: K, equilibrium association binding constant • ABR, auditory brainstem response • G6PD, glucose-6-phosphate dehydrogenase
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INTRODUCTION |
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 TOP INTRODUCTION CASE REPORTDISCUSSIONREFERENCES |
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In premature newborns, bilirubin-induced changes in the auditory brainstem response (ABR) begin at unbound (nonalbumin-bound or "free") bilirubin levels above .5 µg/dL,1 and kernicterus becomes likely at levels between
1 and 1.5 µg/dL (.017-.026 µmol/L).2,3 In term newborns, however, unbound bilirubin levels between .9 and 2 µg/dL, which would be associated kernicterus in premature newborns, produce only subtle, reversible changes in ABR wave latency and amplitude.4 Although the unbound bilirubin levels associated with kernicterus in term newborns are unknown, they clearly are greater than the levels associated with kernicterus in premature infants. This indicates that, as with the total bilirubin and total bilirubin/albumin ratio, the unbound bilirubin levels associated with kernicterus increase as birth weight and gestation increase.1,5
We have been using a Food & Drug Administration-approved method6 for measuring unbound bilirubin in jaundiced newborns as an adjunct to their clinical care since 1998. We use a weight-based unbound bilirubin reference value of 1.3 µg/dL/kg (the level of unbound bilirubin at which exchange transfusion should be considered) up to a maximum of 4 µg/dL to accommodate the need to increase the reference unbound bilirubin as birth weight increases and to incorporate the solubility limits of unbound bilirubin at ph 7.4 (4 µg/dL) into the reference criteria.1–5,7–9
We recently encountered a term, jaundiced newborn that developed acute shock and died, apparently from kernicterus. This report describes the infant’s clinical course and bilirubin-albumin binding data. This case provides insight into the levels of unbound bilirubin associated with kernicterus in term infants as well as the acute changes in distribution of the bilirubin load (miscible bilirubin pool) between the tissues and the vascular space following the onset of kernicterus.
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CASE REPORT |
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TOPINTRODUCTIONCASE REPORTDISCUSSIONREFERENCES |
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A 110-hour-old (4.5-day-old) Nigerian male newborn presented to the emergency department of our hospital with an 18-hour history of moaning and refusing to feed. He was born at 39 and 5/7 weeks gestation to a 34-year-old gravida 1 woman who had an unremarkable pregnancy except for a questionable bout of malaria during the first trimester in Nigeria. The remainder of her pregnancy was spent in the United States where she received good prenatal care. Her blood type was B positive with negative antibodies, and her vaginal group B streptococcus culture was negative before delivery. Vaginal delivery was uncomplicated with Apgar scores of 7 and 9 at 1 and 5 minutes, respectively. Birth weight was 2609 g (head circumference 34.5 cm, length 48 cm) and the physical examination was normal. The infant was discharged at 42 hours of age weighing 2524 g (weight loss 3.2%), "breastfeeding well," passing urine and stool, and had "mild jaundice," but the bilirubin was not measured. Verbal and written instructions were given to the mother to observe the infant for further jaundice and to call her private physician if the jaundice worsened. The infant was seen for a routine postpartum visit at
86 hours of age (3.5 days of age). At that visit the infant’s vital signs and physical examination were normal except for jaundice to the abdomen. He was observed to be breastfeeding well and making normal "cooing" sounds. The bilirubin was not measured, and the mother and infant were sent home with reassurance. Soon after returning home, the infant became fussy, refused to feed, and started "moaning". Overnight he became increasingly lethargic and eventually anuric. The following morning he was taken to the emergency department where the vital signs showed a heart rate of 150 beats per minute and a temperature of 37.3°C. His weight had decreased 9% from birth weight to 2400 g. He appeared dehydrated but otherwise responded appropriately and was admitted to the hospital. A sepsis evaluation was undertaken, including a lumbar puncture, which he tolerated well. Approximately 30 minutes after arrival he was given a bolus of normal saline, antibiotics were started, and he was able to breast feed. He appeared alert, but his axillary temperature had decreased to 33°C (confirmed rectally). The capillary refill time was 3 seconds, and additional warming measures were instituted and another saline bolus was given. Admission laboratory data then returned showing a white blood count of 2100/mm3 with 24% neutrophiles (absolute neutrophile count 504/mm3) and no band forms. The hematocrit was 34% and the platelet count 85 000/mm3. The serum chemistry panel revealed a sodium of 144 meq/L, creatinine of 0.1 mg/dL, glucose of 34 mg/dL, albumin of 2.8 g/dL, total bilirubin of 31.7 mg/dL, and the unbound bilirubin was 7.7 µg/dL. The spinal fluid glucose was 11 mg/dL, the protein 91 mg/dL, and the Gram-stain negative for bacteria. After the bilirubin value was reported, intravenous albumin and dextrose were given, but while arrangements were being made to transfer the infant to the newborn intensive care unit for an exchange transfusion, the infant suddenly became apneic, unresponsive, and developed seizures. The infant was resuscitated for several hours with mechanical ventilation, vasopressors, and blood components, but died 9 hours later without becoming stable enough to receive an exchange transfusion. Three hours after the initial arrest, the infant’s serum total bilirubin had fallen to 6.9 mg/dL, the albumin to 1.0 g/dL (despite administration of albumin), and the unbound bilirubin to 1.9 µg/dL. The total bilirubin and albumin were repeated and found to be correct. All cultures (blood, cerebral spinal fluid, and urine) were negative for bacteria. The red blood cell glucose-6-phosphate dehydrogenase (G6PD) test showed deficiency of the enzyme. Further history revealed no known drug or chemical exposure that might have induced hemolysis. Genetic analysis performed by Dr E. Beutler at Scripps Research Institute (La Jolla, CA) showed the infant to be hemizygous for G6PD A negative, confirming the diagnosis of G6PD deficiency, and homozygous for (Ta)6/(Ta)6, indicating that the infant did not have Gilbert’s disease.10 The carboxyhemoglobin level performed by Dr H. Vreman at Stanford University (Stanford, CA) was 0.57% (normal).11 At autopsy, kernicterus was present grossly and microscopically. There was inflammation in the spleen suggestive of infection, but no other evidence of infection or hemolysis was found in any of the other organ systems including the meninges. |
DISCUSSION |
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TOPINTRODUCTIONCASE REPORTDISCUSSIONREFERENCES |
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The sudden deterioration in this infant was presumed because of sepsis as supported by the neutropenia, thrombocytopenia, hypoglycorrhachia, and splenitis at autopsy. However, the lack of positive blood cultures and the absence of strong evidence for sepsis at autopsy suggest that acute bilirubin encephalopathy (kernicterus) played a significant role in the demise of this newborn. Although recovery from acute bilirubin encephalopathy is generally expected, bilirubin encephalopathy can be lethal.10,12
Before the infant’s acute deterioration, the unbound bilirubin concentration at the total bilirubin of 31.7 mg/dL and albumin of 2.8 g/dL (bilirubin/albumin molar ratio 1.25) was 7.7 µg/dL (2.9 µg/dL per kg) measured using an Arrows UB-analyzer (Arrows Co Ltd, Osaka, Japan)6 and corrected for rate limiting dissociation of bilirubin from albumin.13 This is the highest unbound bilirubin concentration measured in several hundred newborns at our institution over the last 3 years and well beyond both our 1.3 µg/dL per kg and 4 µg/dL reference value limits for unbound bilirubin.
The Table contains bilirubin binding and hearing screening data from 8 term newborns (including this patient) with total bilirubin levels between 28 and 34 mg/dL. The mean unbound bilirubin concentration for the group if this infant is excluded declines to 2.5 µg/dL and 0.7 µg/dL per kg. The only other infant with an unbound bilirubin concentration beyond 4 µg/dL (but still below the 1.3 µg/dL per kg reference value) had a "refer" hearing screening at the time of admission but passed the hearing screen after receiving an exchange transfusion. It should be noted that infants with unbound bilirubin levels above 1 µg/dL may have subtle bilirubin-induced ABR wave latency and amplitude changes that would have been detected by formal ABR testing4 but might still pass an Algo hearing screening test, which only looks for the presence of wave V. All the infants with total bilirubins above 30 mg/dL (except the reported case) received exchange transfusions according to the American Academy of Pediatrics guidelines.14 It is arguable whether the exchange transfusions were really needed in the infants with unbound bilirubin levels below both the reference levels of 4 µg/dL and 1.3 µg/dL per kg and who passed their hearing screen. Further study of the relationship between bilirubin binding and ABR changes might improve our ability to determine which infants with very high total bilirubins require exchange transfusion in addition to phototherapy.
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The total bilirubin spontaneously fell (verified by repeat analysis) to 6.9 mg/dL, the albumin to 1 g/dL (bilirubin/albumin molar ratio .7 vs 1.25 on presentation to the hospital), and the unbound bilirubin to 1.9 µg/dL following the acute onset of bilirubin encephalopathy, as has been described previously.15 This paradoxical decline in total bilirubin during acute bilirubin toxicity illustrates how rapidly the total bilirubin may change and how potentially misleading it can be as an indicator of the true bilirubin load, which is the primary determinant of the risk of kernicterus.16 Without knowledge of the admission laboratory values, the role of bilirubin toxicity in this infant would not have been apparent until autopsy.
The equilibrium association binding constant (K) for the infant at a total bilirubin of 6.9 mg/dL, albumin of 1 g/dL, and unbound bilirubin of 1.9 µg/dL is 110 L/µmol, similar to the mean K for the newborns in the Table . At this level of unbound bilirubin, subtle bilirubin-induced changes in the ABR would be expected although the total bilirubin is quite low.4 Furthermore, it can be shown that at this very low albumin the total bilirubin would only need to rise above 7.5 mg/dL for the unbound bilirubin to approach its solubility level of 4 µg/dL. At the infant’s initial albumin of 2.8 g/dL and a K of 110 L/µmol, the unbound bilirubin would reach 4 µg/dL at a total bilirubin of 20 g/dL and 1.3 µg/dL per kg at total bilirubin of 17 mg/dL. This case is a poignant example of the need to interpret the total bilirubin in the context of the albumin concentration and in particular the unbound bilirubin concentration.3,15,17
The course of the clinical events is consistent with the hypothesis that kernicterus in this particular infant began with the unbound bilirubin reaching its solubility limit. Bilirubin precipitation7–9 then damages the blood brain barrier subsequently allowing both albumin bound and unbound bilirubin to exit the vascular space. The fall in bilirubin/albumin molar ratio from 1.25 on admission to .7 in 3 hours suggests that more bilirubin than albumin exited the vascular space. However, the susceptibility of premature newborns to kernicterus at unbound bilirubin concentrations well below its theoretical solubility limits1,2 indicates that the pathogenesis of bilirubin toxicity is complex, and many factors such as the relative maturity of the central nervous system and tissue bilirubin levels may predispose an infant to kernicterus before the solubility of unbound bilirubin becomes a factor.1–3
For the total bilirubin to have reached 31.7 mg/dL with an unbound bilirubin of 7.7 g/dL an extremely large bilirubin load must have been present. The large bilirubin load does not appear because of greatly increased hemolysis, since the carboxyhemoglobin level was normal and the hematocrit 34%. This supports the hypothesis that poor hepatic conjugation and excretion of bilirubin may sometimes play an important role in kernicterus associated with G6PD deficiency, although the infant did not have Gilbert’s disease.
It is disconcerting that even with early postnatal hospital discharge follow-up, kernicterus still occurred. Clinicians caring for jaundiced newborns must deal not only with the inherent risk in not measuring bilirubin levels when newborns appear jaundiced, but also with the reality that total bilirubin levels alone can be quite misleading.3,15,17 The latter is caused in part by the significant variability in bilirubin-albumin binding,18 which reduces the correlation between the risk of bilirubin toxicity (bilirubin load) and the total bilirubin.
Newer methods for predicting bilirubin load such as the age-specific total bilirubin and end tidal carbon monoxide levels have been disappointing.16 Measuring the unbound bilirubin concentration and albumin concentration, and performing hearing screening can provide critically important additional information about the risk of bilirubin toxicity in jaundiced newborns. Furthermore, the unbound bilirubin along with the total bilirubin and albumin can be used to estimate the specific total bilirubin at which the unbound bilirubin level reaches reference levels (1.3 µg/dL per kg or its solubility limit of 4 µg/dL).9 Once that specific total bilirubin of concern has been identified by measuring bilirubin binding in addition to the total bilirubin, a more individualized and rational approach to newborn jaundice becomes possible. This case along with the considerable body of evidence documenting the potential usefulness of bilirubin binding measurements in jaundiced newborns indicates that further studies of bilirubin binding measurements in the jaundiced newborns are warranted.
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FOOTNOTES |
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Received for publication May 7, 2002; Accepted Sep 12, 2002.
Reprint requests to (C.E.A.) Division of Neonatology, Department of Pediatrics, California Pacific Medical Center, 3850 California St, San Francisco, CA 94118. E-mail: ligand{at}centurytel.net
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PEDIATRICS (ISSN 1098-4275). ©2003 by the American Academy of Pediatrics
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