Vinod K. Bhutani

Predictive ability of a predischarge hour-specific serum bilirubin for subsequent significant hyperbilirubinemia in healthy term and near-term newborns

Objective. To assess the predictive ability of a universal predischarge serum bilirubin measurement to screen for risk of subsequent significant hyperbilirubinemia in the direct Coombs negative healthy term and near-term newborn during the first postnatal week. Methods. Total serum bilirubin (TSB) levels were obtained at the time of the routine metabolic screen in all term and near-term newborns cared for in the Pennsylvania Hospital Well Baby Nursery (n = 13 003). Postnatal age (in hours) at the time of TSB measurement was recorded. A percentile-based bilirubin nomogram for the first week was constructed from hour-specific predischarge and postdischarge TSB values of newborns (n = 2840; median BW = 3230 g and median gestational age = 39 weeks) who met classification criteria for healthy newborns (excluding those with a positive direct Coombs test or those requiring phototherapy before age 60 hours) and who were enrolled in a hospital supervised home or outpatient follow-up program. The accuracy of the predischarge TSB as a predictor of subsequent degree of hyperbilirubinemia was determined. Results. The study patients in the nomogram were racially diverse. Nearly 60% were breastfed. Predischarge, 6.1% of the study population (172/2840) had TSB values in the high-risk zone (≥95th percentile) at 18 to 72 hours; of these, 39.5% (68/172) remained in that zone (likelihood ratio [LR] = 14.08, sensitivity = 54%; specificity = 96.2%, probability = 39.5%). Predischarge, 32.1% of the population (912/2840) had TSB values in the intermediate-risk zone. In a clinically significant minority of these newborns (58/912 or 6.4%), the postdischarge TSB moved into the high-risk zone (LR of this move: 3.2 from the upper-intermediate zone and .48 from the lower-intermediate risk zone). The predischarge TSB in 61.8% of the newborns (1756/2840) was in the low-risk zone (<40th percentile) and there was no measurable risk for significant hyperbilirubinemia (LR = 0, sensitivity = 100%; specificity = 64.7%; probability = 0%). Conclusions. An hour-specific TSB before hospital discharge can predict which newborn is at high, intermediate or low risk for developing clinically significant hyperbilirubinemia (specifically defined as TSB levels ≥95th percentile for age in hours). Risk designation and subsequent increases or decreases of in TSB can be easily monitored on an hour-specific percentile based predictive bilirubin nomogram. A predischarge TSB measured as a universal policy would facilitate targeted intervention and follow-up in a safe, cost-effective manner. In conjunction with bilirubin practice parameter of the American Academy of Pediatrics, it could reduce the potential risk for bilirubin-induced neurologic dysfunction.

Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomised trial

BACKGROUND Opioid analgesia is commonly used during neonatal intensive care. We undertook the Neurologic Outcomes and Pre-emptive Analgesia in Neonates (NEOPAIN) trial to investigate whether pre-emptive morphine analgesia decreases the rate of a composite primary outcome of neonatal death, severe intraventricular haemorrhage (IVH), and periventricular leucomalacia (PVL) in preterm neonates. METHODS Ventilated preterm neonates (n=898) from 16 centres were randomly assigned masked placebo (n=449) or morphine (n=449) infusions. After a loading dose (100 microg/kg), morphine infusions (23-26 weeks of gestation 10 microg kg(-1) h(-1); 27-29 weeks 20 microg kg(-1) h(-1); 30-32 weeks 30 microg kg(-1) h(-1)) were continued as long as clinically justified (maximum 14 days). Open-label morphine could be given on clinical judgment (placebo group 242/443 [54.6%], morphine group 202/446 [45.3%]). Analyses were by intention to treat. FINDINGS Baseline variables were similar in the randomised groups. The placebo and morphine groups had similar rates of the composite outcome (105/408 [26%] vs 115/419 [27%]), neonatal death (47/449 [11%] vs 58/449 [13%]), severe IVH (46/429 [11%] vs 55/411 [13%]), and PVL (34/367 [9%] vs 27/367 [7%]). For neonates who were not given open-label morphine, rates of the composite outcome (53/225 [24%] vs 27/179 [15%], p=0.0338) and severe IVH (19/219 [9%] vs 6/189 [3%], p=0.0209) were higher in the morphine group than the placebo group. Placebo-group neonates receiving open-label morphine had worse rates of the composite outcome than those not receiving open-label morphine (78/228 [34%] vs 27/179 [15%], p<0.0001). Morphine-group neonates receiving open-label morphine were more likely to develop severe IVH (36/190 [19%] vs 19/219 [9%], p=0.0024). INTERPRETATION Pre-emptive morphine infusions did not reduce the frequency of severe IVH, PVL, or death in ventilated preterm neonates, but intermittent boluses of open-label morphine were associated with an increased rate of the composite outcome. The morphine doses used in this study decrease clinical signs of pain but can cause significant adverse effects in ventilated preterm neonates.

Noninvasive measurement of total serum bilirubin in a multiracial predischarge newborn population to assess the risk of severe hyperbilirubinemia.

Background. Jaundice in near-term and term newborns is a frequent diagnosis that may prompt hospital readmission in the first postnatal week. Hyperbilirubinemia, when excessive, can lead to potentially irreversible bilirubin-induced neurotoxicity. Predischarge risk assessment (at 24–72 hours of age) for subsequent excessive hyperbilirubinemia is feasible by a laboratory-based assay of total serum bilirubin (TSB). Hypothesis. Noninvasive, transcutaneous, point-of-care measurement of transcutaneous bilirubin (TcB) predischarge by multiwavelength spectral analysis, using a portable BiliCheck device (SpectRx Inc, Norcross, GA), is clinically equivalent to measurement of TSB in a diverse, multiracial term and near-term newborn population and predictive of subsequent hyperbilirubinemia. Methodology. We evaluated a hand-held device that uses multiwavelength spectral reflectance analysis to measure TcB (BiliCheck). The study population (490 term and near-term newborns) was racially diverse (59.1% white, 29.5% black, 3.46% Hispanic, 4.48% Asian, and 3.46% other) and was evaluated at 2 separate institutions using multiple (11) devices. The postnatal age ranged from 12 to 98 hours and the ranges of birth weights and gestational ages were 2000 to 5665 g and 35 to 42 weeks, respectively. All transcutaneous evaluations were performed contemporaneously and paired with a heelstick TSB measurement. All TSB assays were performed by high performance liquid chromatography, as well as by diazo dichlorophenyldiazonium tetrafluoroborate techniques. Results. TSB values ranged from .2 to 18.2 mg/dL (mean ± standard deviation: 7.65 ± 3.35 mg/dL). The overall correlation of TSB (by high performance liquid chromatography technique) to TcB (by BiliCheck devices) was linear and statistically significant (r = .91;r 2 = .83; TcB = .84; TSB = +.75; standard error of regression line = 1.38; P< .001; n = 490 infants; 1788 samples). Similar regression statistics were evident in subset populations categorized by race (white: r = .91 [n = 289 infants]; black: r = .91 [n = 145 infants]) as well as by gestation (term: r = .91 [n = 1625 samples]; near-term:r = .89 [n = 163 samples]). Intradevice precision was determined to be .59 mg/dL (2–3 measurements per infant with 1 device; n = 210 infants; 510 samples in a separate subset). Interdevice evaluation of 11 devices determined the precision to be .68 mg/dL (2–4 devices used for measurements per patient). In 23 of 419 of the study population infants who were in the 24- to 72-hour age range, the predischarge TSB values designated them to be at high risk for subsequent excessive hyperbilirubinemia (above the 95th percentile track on the hour-specific bilirubin nomogram). For these infants, the paired BiliCheck TcB values were all above the 75th percentile track (negative predictive value = 100%; positive predictive value = 32.86%; sensitivity = 100%; specificity = 88.1%; likelihood ratio = 8.43). Conclusions. Our data demonstrate the accuracy and reproducibility of the predischarge BiliCheck measurements in term and near-term newborn infants of diverse races and ethnicities. Infants with predischarge BiliCheck values above the 75th percentile of hour-specific TSB values on the bilirubin nomogram may be considered to be at high risk for subsequent excessive hyperbilirubinemia. Further studies are needed to assess the efficacy of this technique in preterm infants, those undergoing phototherapy, and those with TSB values of ≥15 mg/dL (≥256 μmol/L).

Clinical report from the pilot USA Kernicterus Registry (1992 to 2004)

To identify antecedent clinical and health services events in infants (⩾35 weeks gestational age (GA)) who were discharged as healthy from their place of birth and subsequently sustained kernicterus. We conducted a root-cause analysis of a convenience sample of 125 infants ⩾35 weeks GA cared for in US healthcare facilities (including off-shore US military bases). These cases were voluntarily reported to the Pilot USA Kernicterus Registry (1992 to 2004) and met the eligibility criteria of acute bilirubin encephalopathy (ABE) and/or post-icteric sequelae. Multiple providers at multiple sites managed this cohort of infants for their newborn jaundice and progressive hyperbilirubinemia. Clinical signs of ABE, verbalized by parents, were often inadequately elicited or recorded and often not recognized as an emergency. Clinical signs of ABE were reported in 7 of 125 infants with a subsequent diagnosis of kernicterus who were not re-evaluated or treated for hyperbilirubinemia, although jaundice was noted at outpatient visits. The remaining infants (n=118) had total serum bilirubin (TSB) levels >20 mg per 100 ml (342 μmol l−1; range: 20.7 to 59.9 mg per 100 ml). No specific TSB threshold coincided with onset of ABE. Of infants <37 weeks GA with kernicterus, 34.9% were LGA (large for gestational age) as compared with 24.7% of term infants (>37 weeks GA). Although >90% mothers initiated breast-feeding, assessment of milk transfer and lactation support was suboptimal in most. Mortality was 4% (5 of 125) in infants readmitted at age ⩽1 week. Along with a rapid rise of TSB (>0.2 mg per 100 ml per hour), contributing factors, alone or in combination, included undiagnosed hemolytic disease, excessive bilirubin production related to extra-vascular hemolysis and delayed bilirubin elimination (including increased enterohepatic circulation, diagnosed and undiagnosed genetic disorders) in the context of known late prematurity (<37 weeks), glucose 6-phosphate-dehydrogenase deficiency, infection and dehydration. Readmission was at age ⩽5 days in 81 of 118 (69%) infants and <10 days in 101 of 118 (86%) infants. TSB levels were ⩽35 mg per 100 ml (598 μmol l−1) in 46 (39%) infants, of whom one died before exchange transfusion, one was untreated and one was lost to follow-up. Timely and efficacious bilirubin reduction interventions defined by ‘crash-cart’ initiation of immediate intensive phototherapy and urgent exchange transfusion were accomplished in 11 of 43 infants, which were compared with 12 of 43 infants in whom a timely exchange sometimes could not be accomplished. No overt sequelae were found in 8 of 11 infants (73%) treated with a ‘crash-cart’ approach compared with none without sequelae when exchange was delayed by pre-admission delays, technical factors or need to transfer to a tertiary facility. None of the remaining 20 of 43 infants treated only with phototherapy escaped sequelae. Regardless of age at readmission and intervention, infants with peak measured TSB >35 mg per 100 ml had post-icteric sequelae (n=73). There was a narrow margin of safety between birthing hospital discharge or home birth and readmission to a tertiary neonatal/pediatric facility. Progression of hyperbilirubinemia to hazardous levels and onset of neurological signs were often not identified as infants care and medical supervision transitioned during the first week after birth. The major underlying root cause for kernicterus was systems failure of services by multiple providers at multiple sites and inability to identify the at-risk infant and manage severe hyperbilirubinemia in a timely manner.

Toward Understanding Kernicterus: A Challenge to Improve the Management of Jaundiced Newborns

PURPOSE. We sought to evaluate the sensitivity and specificity of total serum bilirubin concentration (TSB) and free (unbound) bilirubin concentration (Bf) as predictors of risk for bilirubin toxicity and kernicterus and to examine consistency between these findings and proposed mechanisms of bilirubin transport and brain uptake. METHODS. A review of literature was undertaken to define basic principles of bilirubin transport and brain uptake leading to neurotoxicity. We then reviewed experimental and clinical evidence that relate TSB or Bf to risk for bilirubin toxicity and kernicterus. RESULTS. There are insufficient published data to precisely define sensitivity and specificity of either TSB or Bf in determining risk for acute bilirubin neurotoxicity or chronic sequelae (kernicterus). However, available laboratory and clinical evidence indicate that Bf is better than TSB in discriminating risk for bilirubin toxicity in patients with severe hyperbilirubinemia. These findings are consistent with basic pharmacokinetic principles involved in bilirubin transport and tissue uptake. CONCLUSIONS. Experimental and clinical data strongly suggest that measurement of Bf in newborns with hyperbilirubinemia will improve risk assessment for neurotoxicity, which emphasizes the need for additional clinical evaluation relating Bf and TSB to acute bilirubin toxicity and long-term outcome. We speculate that establishing risk thresholds for neurotoxicity by using newer methods for measuring Bf in minimally diluted serum samples will improve the sensitivity and specificity of serum indicators for treating hyperbilirubinemia, thus reducing unnecessary aggressive intervention and associated cost and morbidity.

Kernicterus: Epidemiological Strategies for Its Prevention through Systems-Based Approaches

Kernicterus, thought to be due to severe hyperbilirubinemia, is an uncommon disorder with tragic consequences, especially when it affects healthy term and near-term infants. Early identification, prevention and treatment of severe hyperbilirubinemia should make kernicterus a preventable disease. However, national epidemiologic data are needed to monitor any preventive strategies. Recommendations are provided to obtain prospective data on the prevalence and incidence of severe hyperbilirubinemia and associate mortality and neurologic injury using standardized definitions, explore the clinical characteristics and root causes of kernicterus in children identified in the Kernicterus Pilot Registry, identify and test an indicator for population surveillance, validating systems-based approaches to the management of newborn jaundice, and explore the feasibility of using biologic or genetic markers to identify infants at risk for hyperbilirubinemia. Increased knowledge about the incidence and consequences of severe hyperbilirubinemia is essential to the planning, implementation and assessment of interventions to ensure that infants discharged as healthy from their birth hospitals have a safer transition to home, avoiding morbidity due to hyperbilirubinemia and other disorders.At a recent NIHCD-sponsored conference, key questions were raised about kernicterus and the need for additional strategies for its prevention. These questions and an approach to their answers form the basis of this report.

Vitamin E prophylaxis to reduce retinopathy of prematurity: A reappraisal of published trials

OBJECTIVE We conducted a meta-analysis of the published randomized clinical trials of vitamin E prophylaxis designed to reduce retinopathy of prematurity (ROP) to determine whether increased serum concentrations of vitamin E reduced the incidence of severe, threshold (Stage 3+) ROP in the very low birth weight (VLBW) infant subset. STUDY DESIGN Among the six trials considered eligible for analyses, the incidence for all stages of ROP and for Stage 3+ ROP was computed for all randomly assigned infants (intention-to-treat analysis) and for those infants completing the trials. Odds ratios (ORs) and pooled estimates for event rate reductions (and the respective 95% confidence intervals [CIs]) were calculated for these outcome end points. RESULTS There were 704 VLBW infants in the vitamin E prophylaxis groups and 714 in control groups; 536 (76.1%) infants in the vitamin E and 551 (77.2%) in the control groups completed the trials. In all trials the mean serum vitamin E concentrations were within or above the physiologic range in the vitamin-treated groups and at or below the physiologic ranges in the control groups. The overall incidence of any stage ROP was similar between the groups: 39.8% in the vitamin E group and 43.5% in the control group. The overall incidence for Stage 3+ ROP was lower in the vitamin E-treated groups than in the control group (2.4% in vitamin E vs 5.3% in control). The pooled OR for developing Stage 3+ ROP with vitamin E prophylaxis was 0.44 (95% CI, 0.21, 0.81, p < 0.02). The reciprocal of the pooled estimate of mean risk reduction (2.8%, 95% CI: 0.55%, 5.1%) for Stage 3+ ROP revealed that on average, vitamin E prophylaxis given to 35 VLBW infants would prevent one case of threshold, Stage 3+ ROP. CONCLUSIONS Considering that there was a 52% reduction in the incidence of Stage 3+ ROP, we suggest that the role of vitamin E in reducing severe ROP be re-evaluated. We could not assess the adverse effect rates from vitamin E therapy in the trials analyzed; therefore, we recommend a well-controlled and focused trial in which the issues of benefit, adverse effects, and cost can be assessed with vitamin E prophylaxis in extremely low birth weight (< 1000 gm) infants.

A Comparison of Alternative Risk-Assessment Strategies for Predicting Significant Neonatal Hyperbilirubinemia in Term and Near-Term Infants

OBJECTIVE. The purpose of this work was to compare the predictive accuracy of alternative risk-assessment strategies used to screen for the risk of significant neonatal hyperbilirubinemia. PATIENTS AND METHODS. We conducted a prospective cohort study of 823 term and near-term newborns admitted to the well-infant nursery at the Hospital of the University of Pennsylvania. Maternal, infant, and delivery risk factors for significant hyperbilirubinemia were obtained from chart review, structured interviews with parents, and nurse assessments before discharge. Transcutaneous bilirubin measurement was performed daily until discharge and once by a visiting home nurse between 3 and 8 days of life. We used the c statistic to compare the predictive accuracy of 3 risk-assessment strategies for estimating the risk of significant neonatal hyperbilirubinemia, defined as a bilirubin level that at any time after birth exceeded or was within 1 mg/dL (17 μmol/L) of the hour-specific phototherapy treatment threshold recommended by the American Academy of Pediatrics in 2004. The compared strategies included those that use (1) a predischarge bilirubin level (obtained before 52 hours) expressed as a risk zone on an hour-specific bilirubin nomogram, (2) clinical risk factors other than the predischarge bilirubin level, and (3) a combination of the predischarge bilirubin risk zone and additional clinical risk factors. RESULTS. Forty-eight patients (6%) developed significant neonatal hyperbilirubinemia. The predischarge (<52 hours) bilirubin level expressed as a risk zone on the bilirubin nomogram and a prediction model that combined multiple other clinical risk factors had similar accuracy for predicting significant hyperbilirubinemia. The only clinical risk factor that could be added to the predischarge risk zone to improve overall predictive accuracy was gestational age. The predischarge bilirubin risk zone and gestational age could be used to stratify patients into a large group (n = 523 [70%]) of infants with a very low (0.2%) risk of developing significant hyperbilirubinemia, a small group of infants (n = 127 [17%]) with a low (4%) risk of developing significant hyperbilirubinemia, and an even smaller group of infants (n = 100 [13%]) with a high (42%) risk of developing significant hyperbilirubinemia. CONCLUSIONS. An infants risk of developing significant hyperbilirubinemia can be simply and accurately assessed by using just the infants predischarge bilirubin level and gestational age.

Changes in Pulmonary Mechanics after the Administration of Surfactant to Infants with Respiratory Distress Syndrome

We assessed pulmonary mechanics in 35 premature infants with respiratory distress syndrome just before and one hour after the administration of 90 mg of surfactant to each infant. Transpulmonary pressure was measured between the airway opening and an esophageal balloon with use of a differential transducer, and flow rates were measured by a pneumotachometer. Values for pulmonary mechanics were then calculated by microcomputer processing. The administration of surfactant produced a large decrease (56 percent) in the mean (+/- SEM) ratio of alveolar to arterial oxygen, from 7.1 +/- 0.5 to 3.1 +/- 0.2 (P less than 0.0001)--a change that indicates improvement in gas exchange. Associated changes in pulmonary mechanics were not demonstrable when 10 of the infants were studied during continuous mechanical ventilation. However, in the 25 infants examined during spontaneous breathing with continuous positive airway pressures (identical airway pressures before and after treatment), large and consistent improvements in pulmonary mechanics were found after the administration of surfactant. Tidal volume increased by 32 percent (P less than 0.03), minute ventilation by 38 percent (P less than 0.02), dynamic compliance by 29 percent (P less than 0.004), and inspiratory flow rates by 54 percent (P less than 0.01). We conclude that significant improvement in pulmonary mechanics results from surfactant-replacement therapy for respiratory distress syndrome, but that these mechanical changes are apparent only during spontaneous respiration and can be masked if measurements are made during mechanical ventilation.

Neonatal hyperbilirubinemia and Rhesus disease of the newborn: incidence and impairment estimates for 2010 at regional and global levels

Background:Rhesus (Rh) disease and extreme hyperbilirubinemia (EHB) result in neonatal mortality and long-term neurodevelopmental impairment, yet there are no estimates of their burden.Methods:Systematic reviews and meta-analyses were undertaken of national prevalence, mortality, and kernicterus due to Rh disease and EHB. We applied a compartmental model to estimate neonatal survivors and impairment cases for 2010.Results:Twenty-four million (18% of 134 million live births ≥32 wk gestational age from 184 countries; uncertainty range: 23–26 million) were at risk for neonatal hyperbilirubinemia-related adverse outcomes. Of these, 480,700 (0.36%) had either Rh disease (373,300; uncertainty range: 271,800–477,500) or developed EHB from other causes (107,400; uncertainty range: 57,000–131,000), with a 24% risk for death (114,100; uncertainty range: 59,700–172,000), 13% for kernicterus (75,400), and 11% for stillbirths. Three-quarters of mortality occurred in sub-Saharan Africa and South Asia. Kernicterus with Rh disease ranged from 38, 28, 28, and 25/100,000 live births for Eastern Europe/Central Asian, sub-Saharan African, South Asian, and Latin American regions, respectively. More than 83% of survivors with kernicterus had one or more impairments.Conclusion:Failure to prevent Rh sensitization and manage neonatal hyperbilirubinemia results in 114,100 avoidable neonatal deaths and many children grow up with disabilities. Proven solutions remain underused, especially in low-income countries.