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How to avoid kernicterus
LETTERS
How to avoid kernicterus To the Editor: Johnson et al1 have performed a valuable service by reminding us that kernicterus is still occurring. They also point to lapses in physician management that might have contributed to these outcomes, and they outline an approach to making these lapses less likely. In the accompanying editorial, Poland suggests that the total serum bilirubin (TSB) level is a poor predictor of the risk of brain damage and that we would be better served by using measurements of bilirubin-albumin binding in the management of the jaundiced infant.2 We agree with Johnson et al1 that evidence-based, costeffective interventions to prevent kernicterus are needed. The data they present from the Pilot Kernicterus Registry, however, are not sufficient to conclude that the approach they recommend is either evidence-based or cost-effective. A key unknown quantity is the current incidence of kernicterus. Additional data, not included in their report, might help clarify the degree to which this can be estimated from the registry data. First, what is the denominator? That is, what period of time and what geographic area gave rise to these cases? Second, what are sources of error in the numerator? The most likely concern is underestimation. How was the Pilot Kernicterus Registry publicized? What proportions of the cases were previously published, contributed by colleagues, and identified through medical-legal consultation? How many cases were identified by more than one method? If most of the cases came to the authors’ attention from more than one source, this provides at least a hint of more complete ascertainment than if each case was reported from only one of many possible sources. There is also a possibility of overestimation of the numerator. Because there is no universally accepted “gold standard” for kernicterus (short of autopsy, perhaps), any possible set of diagnostic criteria must strike a balance between sensitivity and specificity. A very specific definition might require a bilirubin level of more than 30 to 40 mg/dL, acute symptoms, and all of the classic late sequelae and findings, including choreoathetoid cerebral palsy, upward gaze palsy, high-frequency sensorineural hearing loss, and increased signal intensity in the globus pallidus on T-2 weighted magnetic resonance images. Such a definition, however, would be insensitive, because children with bilirubin-induced brain damage who escaped the full-blown picture of classic kernicterus would be missed. Alternatively, a more sensitive case definition, like the one used by Johnson et al,1 would not require any particular degree of hyperbilirubinemia, and would include children with nonspecific impairments, like intellectual deficits. But in children meeting this more sensitive definition, some uncertainty remains about whether their handicaps are related to hyperbilirubinemia. 212 Letters
Because Johnson et al1 present data only in summary form, it is not possible for readers to review the details of the cases to determine how many of the inclusion criteria were present in each case. The interpretability of the data from the kernicterus registry would be enhanced if detailed data on each case were made available, or if at least the authors could divide their cases into definite, probable, and possible kernicterus cases, with clear, mutually exclusive criteria for each. We do not wish to imply that kernicterus is not occurring, nor that many of the cases reported by Johnson et al do not have it. However, to make recommendations that are evidencebased, it is important to evaluate the quality of the available evidence. Johnson et al1 also recognize the need for cost-effectiveness analyses of strategies to prevent bilirubin-related brain damage. We agree. Lack of data on the incidence of kernicterus will certainly hamper such analyses, but some estimate of costs and risks before widespread implementation of this approach would still be useful. Although the cost per infant of a predischarge bilirubin measurement recommended by Johnson et al is not high, a strategy that identifies 60% of infants as requiring close follow-up to prevent bilirubin-induced brain damage has other costs and risks to consider. Besides the costs of additional follow-up visits, laboratory tests, and jaundice treatment, we are concerned about labeling large numbers of infants with normal bilirubin levels (by any usual definition) as being at increased risk of brain damage, especially because of a problem associated almost exclusively with breast-feeding. The lack of good evidence on incidence and on the costs and risks of treatment alternatives does not mean that we should ignore case reports of kernicterus3 or wait to attempt to reduce its frequency. In the absence of better data, we believe that infants with high bilirubin levels should be followed and treated as recommended by the American Academy of Pediatrics,4 and that system problems that make this difficult should be addressed. However, without interpretable data on the frequency of kernicterus, it is hard to know what level of “informed concern”1 about neonatal jaundice is appropriate. In the accompanying editorial, Poland2 asserts that “the total bilirubin has been shown beyond doubt not to estimate a person’s risk for devastating neurotoxicity.” We disagree. There is good evidence that the risk of severe neurologic abnormalities is not increased in infants with TSB levels of <25 mg/dL5,6 and that kernicterus does occur when TSB levels exceed 30 mg/dL. The fact that the vast majority of infants in the Pilot Kernicterus Registry had TSB levels >30 mg/dL (ie, in the top 0.01 percentile7) is consistent with this conclusion. Measures of bilirubin binding might be helpful in understanding why some infants with TSB levels >30 to 40 mg/dL get The Journal of Pediatrics • February 2003
kernicterus and others do not, or in identifying infants who have very high bilirubin levels but do not need an exchange transfusion. Such measurements, however, are irrelevant for the vast majority of jaundiced infants, who will never come close to exchange transfusion levels if they are followed and treated appropriately with phototherapy. The number of infants who require exchange transfusion has declined dramatically during the last few decades and the addition of new pharmacologic interventions8 could further reduce use of exchange transfusions. In view of this, it is likely that measurements of bilirubin binding will become less, rather than more, relevant in our management of the jaundiced newborn. Thomas B. Newman, MD, MPH Departments of Epidemiology and Biostatistics and Pediatrics School of Medicine, University of California San Francisco, CA 94143-0560 M. Jeffrey Maisels, MB, BCh Department of Pediatrics William Beaumont Hospital Royal Oak, MI 48073-6769 YMPD70 10.1067/mpd.2003.70
REFERENCES 1. Johnson LH, Bhutani VK, Brown AK. System-based approach to management of neonatal jaundice and prevention of kernicterus. J Pediatr 2002;140:396-403. 2. Poland RL. Preventing kernicterus: almost there. J Pediatr 2002; 140:385-6. 3. Newman TB, Maisels MJ. Less aggressive treatment of neonatal jaundice and reports of kernicterus: lessons about practice guidelines. Pediatrics 2000;105:242-5. 4. Maisels MJ, Baltz RD, Bhutani VK, Newman TB, Rosenfeld W, Stevenson DK, et al. Neonatal jaundice and kernicterus. Pediatrics 2001; 108:763-5. 5. Newman TB, Maisels MJ. Does hyperbilirubinemia damage the brain of healthy full-term infants? Clin Perinatol 1990;17:331-58. 6. Newman TB, Maisels MJ. Evaluation and treatment of jaundice in the term newborn: a kinder, gentler approach. Pediatrics 1992;89:809-18. 7. Newman TB, Escobar GJ, Gonzales V, Armstrong MA, Gardner M, Folck B. Frequency of neonatal bilirubin testing and hyperbilirubinemia in a large health maintenance organization. Pediatrics 1999;104:1198-203. 8. Kappas A, Drummond GS, Munson DP, Marshall JR. Sn-mesoporphyrin interdiction of severe hyperbilirubinemia in Jehovah’s Witness newborns as an alternative to exchange transfusion. Pediatrics 2001;108:1374-7.
Reply To the Editor: Drs Newman and Maisels have raised interesting questions about the commentary published by Johnson et al1 and about my associated editorial.2 They appear to believe that a bilirubin concentration <30 mg/dL could not cause brain damage in newborns. Yet, Johnson et al gave examples to the contrary. Seven infants with readmission bilirubin concentrations <30 mg/dL had signs of bilirubin toxicity, 4 with permanent sequelae. These were treated as “otherwise healthy” infants at discharge. Granted some had occult conditions such Letters
as sepsis and hemolysis, which made them more likely to suffer the neurotoxicity of bilirubin at concentrations <30 mg/dL. Furthermore, Newman and Maisels rely heavily on their previously published interpretation of the literature that a bilirubin concentration <25 mg/dL is safe for otherwise healthy newborns. Cases have been published1,3 that might refute this. The main problem with the concept of the “otherwise healthy newborn” is that we cannot always know when significant hemolysis, infection, or other modifying conditions exist, making it impractical to assume that a given infant fits the category. They also took issue with my statement that the total bilirubin concentration is not a very good indicator of risk for bilirubin toxicity. I provided references (refs 12-14 in my editorial),2 with evidence in support of that statement, but another might help. Amin et al4 have reported serial auditory brainstem responses (ABR) in premature infants and found that the peak unbound fraction of bilirubin correlated very well (P = .0002) with abnormal ABR results. The peak bilirubin:albumin molar ratio correlated fairly well (P = .01), and the peak total bilirubin concentration not at all (P = .29). The receiver operating characteristic curve for total bilirubin was far inferior to that of the unbound bilirubin in predicting neurotoxity. Their results are consistent with the findings of the 3 other studies I cited. This example illustrates a general principle: when a biologic effector molecule is highly protein bound (eg, calcium, thyroxine, phenytoin5), measuring the free or unbound concentration of the effector, not the total, correlates best with its action. These references support the strong statement I made against relying on total bilirubin to determine the risk of neurologic injury in an individual infant. Better measures have been identified. My point was that implementing the recommendations published by Johnson et al1 will go a long way toward eliminating bilirubin encephalopathy or kernicterus. However, continuing to rely on the total serum bilirubin concentration for treatment decisions will inevitably leave us with a residual incidence of this devastating form of brain injury. We cannot agree to the concept of an acceptable or irreducible incidence of kernicterus. We should apply already available scientific information to improve our ability to identify and treat infants at risk while avoiding the unnecessary treatment of those who are not. We could accomplish both aims by using the knowledge we have about bilirubin binding. Ronald L. Poland, MD Department of Pediatrics Children’s Hospital of New Mexico University of New Mexico Albuquerque, NM 87131-5313 YMPD72 10.1067/mpd.2003.72
REFERENCES 1. Johnson LH, Bhutani VK, Brown AK. System-based approach to management of neonatal jaundice and prevention of kernicterus. J Pediatr 2002;140:396-403.
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How to avoid kernicterus To the Editor: Johnson et al1 have performed a valuable service by reminding us that kernicterus is still occurring. They also point to lapses in physician management that might have contributed to these outcomes, and they outline an approach to making these lapses less likely. In the accompanying editorial, Poland suggests that the total serum bilirubin (TSB) level is a poor predictor of the risk of brain damage and that we would be better served by using measurements of bilirubin-albumin binding in the management of the jaundiced infant.2 We agree with Johnson et al1 that evidence-based, costeffective interventions to prevent kernicterus are needed. The data they present from the Pilot Kernicterus Registry, however, are not sufficient to conclude that the approach they recommend is either evidence-based or cost-effective. A key unknown quantity is the current incidence of kernicterus. Additional data, not included in their report, might help clarify the degree to which this can be estimated from the registry data. First, what is the denominator? That is, what period of time and what geographic area gave rise to these cases? Second, what are sources of error in the numerator? The most likely concern is underestimation. How was the Pilot Kernicterus Registry publicized? What proportions of the cases were previously published, contributed by colleagues, and identified through medical-legal consultation? How many cases were identified by more than one method? If most of the cases came to the authors’ attention from more than one source, this provides at least a hint of more complete ascertainment than if each case was reported from only one of many possible sources. There is also a possibility of overestimation of the numerator. Because there is no universally accepted “gold standard” for kernicterus (short of autopsy, perhaps), any possible set of diagnostic criteria must strike a balance between sensitivity and specificity. A very specific definition might require a bilirubin level of more than 30 to 40 mg/dL, acute symptoms, and all of the classic late sequelae and findings, including choreoathetoid cerebral palsy, upward gaze palsy, high-frequency sensorineural hearing loss, and increased signal intensity in the globus pallidus on T-2 weighted magnetic resonance images. Such a definition, however, would be insensitive, because children with bilirubin-induced brain damage who escaped the full-blown picture of classic kernicterus would be missed. Alternatively, a more sensitive case definition, like the one used by Johnson et al,1 would not require any particular degree of hyperbilirubinemia, and would include children with nonspecific impairments, like intellectual deficits. But in children meeting this more sensitive definition, some uncertainty remains about whether their handicaps are related to hyperbilirubinemia. 212 Letters
Because Johnson et al1 present data only in summary form, it is not possible for readers to review the details of the cases to determine how many of the inclusion criteria were present in each case. The interpretability of the data from the kernicterus registry would be enhanced if detailed data on each case were made available, or if at least the authors could divide their cases into definite, probable, and possible kernicterus cases, with clear, mutually exclusive criteria for each. We do not wish to imply that kernicterus is not occurring, nor that many of the cases reported by Johnson et al do not have it. However, to make recommendations that are evidencebased, it is important to evaluate the quality of the available evidence. Johnson et al1 also recognize the need for cost-effectiveness analyses of strategies to prevent bilirubin-related brain damage. We agree. Lack of data on the incidence of kernicterus will certainly hamper such analyses, but some estimate of costs and risks before widespread implementation of this approach would still be useful. Although the cost per infant of a predischarge bilirubin measurement recommended by Johnson et al is not high, a strategy that identifies 60% of infants as requiring close follow-up to prevent bilirubin-induced brain damage has other costs and risks to consider. Besides the costs of additional follow-up visits, laboratory tests, and jaundice treatment, we are concerned about labeling large numbers of infants with normal bilirubin levels (by any usual definition) as being at increased risk of brain damage, especially because of a problem associated almost exclusively with breast-feeding. The lack of good evidence on incidence and on the costs and risks of treatment alternatives does not mean that we should ignore case reports of kernicterus3 or wait to attempt to reduce its frequency. In the absence of better data, we believe that infants with high bilirubin levels should be followed and treated as recommended by the American Academy of Pediatrics,4 and that system problems that make this difficult should be addressed. However, without interpretable data on the frequency of kernicterus, it is hard to know what level of “informed concern”1 about neonatal jaundice is appropriate. In the accompanying editorial, Poland2 asserts that “the total bilirubin has been shown beyond doubt not to estimate a person’s risk for devastating neurotoxicity.” We disagree. There is good evidence that the risk of severe neurologic abnormalities is not increased in infants with TSB levels of <25 mg/dL5,6 and that kernicterus does occur when TSB levels exceed 30 mg/dL. The fact that the vast majority of infants in the Pilot Kernicterus Registry had TSB levels >30 mg/dL (ie, in the top 0.01 percentile7) is consistent with this conclusion. Measures of bilirubin binding might be helpful in understanding why some infants with TSB levels >30 to 40 mg/dL get The Journal of Pediatrics • February 2003
kernicterus and others do not, or in identifying infants who have very high bilirubin levels but do not need an exchange transfusion. Such measurements, however, are irrelevant for the vast majority of jaundiced infants, who will never come close to exchange transfusion levels if they are followed and treated appropriately with phototherapy. The number of infants who require exchange transfusion has declined dramatically during the last few decades and the addition of new pharmacologic interventions8 could further reduce use of exchange transfusions. In view of this, it is likely that measurements of bilirubin binding will become less, rather than more, relevant in our management of the jaundiced newborn. Thomas B. Newman, MD, MPH Departments of Epidemiology and Biostatistics and Pediatrics School of Medicine, University of California San Francisco, CA 94143-0560 M. Jeffrey Maisels, MB, BCh Department of Pediatrics William Beaumont Hospital Royal Oak, MI 48073-6769 YMPD70 10.1067/mpd.2003.70
REFERENCES 1. Johnson LH, Bhutani VK, Brown AK. System-based approach to management of neonatal jaundice and prevention of kernicterus. J Pediatr 2002;140:396-403. 2. Poland RL. Preventing kernicterus: almost there. J Pediatr 2002; 140:385-6. 3. Newman TB, Maisels MJ. Less aggressive treatment of neonatal jaundice and reports of kernicterus: lessons about practice guidelines. Pediatrics 2000;105:242-5. 4. Maisels MJ, Baltz RD, Bhutani VK, Newman TB, Rosenfeld W, Stevenson DK, et al. Neonatal jaundice and kernicterus. Pediatrics 2001; 108:763-5. 5. Newman TB, Maisels MJ. Does hyperbilirubinemia damage the brain of healthy full-term infants? Clin Perinatol 1990;17:331-58. 6. Newman TB, Maisels MJ. Evaluation and treatment of jaundice in the term newborn: a kinder, gentler approach. Pediatrics 1992;89:809-18. 7. Newman TB, Escobar GJ, Gonzales V, Armstrong MA, Gardner M, Folck B. Frequency of neonatal bilirubin testing and hyperbilirubinemia in a large health maintenance organization. Pediatrics 1999;104:1198-203. 8. Kappas A, Drummond GS, Munson DP, Marshall JR. Sn-mesoporphyrin interdiction of severe hyperbilirubinemia in Jehovah’s Witness newborns as an alternative to exchange transfusion. Pediatrics 2001;108:1374-7.
Reply To the Editor: Drs Newman and Maisels have raised interesting questions about the commentary published by Johnson et al1 and about my associated editorial.2 They appear to believe that a bilirubin concentration <30 mg/dL could not cause brain damage in newborns. Yet, Johnson et al gave examples to the contrary. Seven infants with readmission bilirubin concentrations <30 mg/dL had signs of bilirubin toxicity, 4 with permanent sequelae. These were treated as “otherwise healthy” infants at discharge. Granted some had occult conditions such Letters
as sepsis and hemolysis, which made them more likely to suffer the neurotoxicity of bilirubin at concentrations <30 mg/dL. Furthermore, Newman and Maisels rely heavily on their previously published interpretation of the literature that a bilirubin concentration <25 mg/dL is safe for otherwise healthy newborns. Cases have been published1,3 that might refute this. The main problem with the concept of the “otherwise healthy newborn” is that we cannot always know when significant hemolysis, infection, or other modifying conditions exist, making it impractical to assume that a given infant fits the category. They also took issue with my statement that the total bilirubin concentration is not a very good indicator of risk for bilirubin toxicity. I provided references (refs 12-14 in my editorial),2 with evidence in support of that statement, but another might help. Amin et al4 have reported serial auditory brainstem responses (ABR) in premature infants and found that the peak unbound fraction of bilirubin correlated very well (P = .0002) with abnormal ABR results. The peak bilirubin:albumin molar ratio correlated fairly well (P = .01), and the peak total bilirubin concentration not at all (P = .29). The receiver operating characteristic curve for total bilirubin was far inferior to that of the unbound bilirubin in predicting neurotoxity. Their results are consistent with the findings of the 3 other studies I cited. This example illustrates a general principle: when a biologic effector molecule is highly protein bound (eg, calcium, thyroxine, phenytoin5), measuring the free or unbound concentration of the effector, not the total, correlates best with its action. These references support the strong statement I made against relying on total bilirubin to determine the risk of neurologic injury in an individual infant. Better measures have been identified. My point was that implementing the recommendations published by Johnson et al1 will go a long way toward eliminating bilirubin encephalopathy or kernicterus. However, continuing to rely on the total serum bilirubin concentration for treatment decisions will inevitably leave us with a residual incidence of this devastating form of brain injury. We cannot agree to the concept of an acceptable or irreducible incidence of kernicterus. We should apply already available scientific information to improve our ability to identify and treat infants at risk while avoiding the unnecessary treatment of those who are not. We could accomplish both aims by using the knowledge we have about bilirubin binding. Ronald L. Poland, MD Department of Pediatrics Children’s Hospital of New Mexico University of New Mexico Albuquerque, NM 87131-5313 YMPD72 10.1067/mpd.2003.72
REFERENCES 1. Johnson LH, Bhutani VK, Brown AK. System-based approach to management of neonatal jaundice and prevention of kernicterus. J Pediatr 2002;140:396-403.
213