Clinical trial of tin mesoporphyrin to prevent neonatal hyperbilirubinemia.

OBJECTIVE: To assess the efficacy of the heme oxygenase inhibitor, tin mesoporphyrin (SnMP), to reduce total bilirubin (TB) levels. STUDY DESIGN: Masked, SnMP (4.5 mg kg(-1)), placebo-controlled, multicenter trial of single intramuscular injection to newborns ⩾35 weeks gestational age whose predischarge screening transcutaneous bilirubin (TcB) was >75th percentile. RESULTS: Two hundred and thirteen newborns (median age 30 h) were randomized to treatment with SnMP (n=87) or 'sham' (n=89). We found that the duration of phototherapy was halved. Within 12 h of SnMP administration, the natural TB trajectory was reversed. At age 3 to 5 days, TB in the SnMP-treated group was +8% but sixfold lower than the 47% increase in the sham-treated group (P<0.001). At age 7 to 10 days, mean TB declined 18% (P<0.001) compared with a 7.1% increase among controls. No short-term adverse events from SnMP treatment were noted other than photoreactivity due to inadvertent exposure to white light phototherapy. CONCLUSION: Early, predischarge SnMP administration decreased the duration of phototherapy, reversed TB trajectory and reduced the severity of subsequent hyperbilirubinemia.

Transcutaneous bilirubin levels in newborns <35 weeks' gestation.

OBJECTIVE: In infants <35 weeks' gestation, we sought to define the transcutaneous bilirubin (TcB) levels at which a total serum bilirubin (TSB) level suggesting the need for phototherapy is unlikely to occur and a TSB measurement can, therefore, be avoided. STUDY DESIGN: Nursing staff performed 896 TcB measurements within 1 h of a TSB on 225 neonates 26 0/7-34 6/7 weeks' postmenstrual age (PMA). Generalized linear models were fit with generalized estimating equations (GEEs) to model the probability of having a TSB level at or above the phototherapy initiation cutpoint as a function of the TcB; these methods allow for multiple tests per infant. RESULTS: The mean difference between TcB and TSB measurements was <1 mg dl(-1) for each PMA category. When the TcB was at least 3 mg dl(-1) below the TSB cutpoint for phototherapy, there was a ⩾98% probability that the TSB was not at, or above, the recommended phototherapy level. The single exception to this was a phototherapy level of 6 mg dl(-1) for infants of 28 0/7-29 6/7 weeks' PMA, where a TcB of 4 mg dl(-1) below the phototherapy level (ie a TcB ⩽2 mg dl(-1)) was necessary to achieve ⩾98% probability. CONCLUSION: Our data support the use of routine TcB screening for infants 28-34 6/7 weeks' gestation. TcB screening in the neonatal intensive care unit can identify infants who require a TSB to confirm or exclude the need for phototherapy.

Tin-mesoporphyrin in the treatment of refractory hyperbilirubinemia due to Rh incompatibility.

We describe the use of tin-mesoporphyrin (SnMP) in the treatment of an infant with Rh hemolytic disease. The infant's hyperbilirubinemia responded to phototherapy but every time the phototherapy was discontinued, the serum bilirubin rebounded and repeat phototherapy was necessary. A single intramuscular dose of SnMP on day 18 eliminated the need for further phototherapy and allowed us to discharge this infant.

An approach to the management of hyperbilirubinemia in the preterm infant less than 35 weeks of gestation.

We provide an approach to the use of phototherapy and exchange transfusion in the management of hyperbilirubinemia in preterm infants of <35 weeks of gestation. Because there are limited data for evidence-based recommendations, these recommendations are, of necessity, consensus-based. The recommended treatment levels are based on operational thresholds for bilirubin levels and represent those levels beyond which it is assumed that treatment will likely do more good than harm. Long-term follow-up of a large population will be needed to evaluate whether or not these recommendations should be modified.

Transcutaneous bilirubin levels in an outpatient and office population.

OBJECTIVE: The use of transcutaneous bilirubin (TcB) measurements has been studied extensively in the newborn population, but there have been few studies in outpatient populations and none from the offices of practicing pediatricians. STUDY DESIGN: We performed TcB measurements on a mixed-race population of 120 jaundiced infants, ≥ 35 weeks of gestation, in two hospital-based outpatient clinics, a regional public health nurse follow-up program and two pediatric office practices. Three individual TcB readings were obtained from the mid-sternum, and the average and maximum values were recorded. RESULT: There was good correlation between the TcB and total serum bilirubin (TSB) measurements (r=0.78, P=0.0). 59% of TSB's were ≥15 mg dl(-1) and, although the number of false-negative readings increased when the TSB values exceeded 15 mg dl(-1), it was nevertheless possible to use TcB measurements to accurately predict the risk of TSB levels ≥ 15 mg dl(-1). CONCLUSION: In outpatient settings, a TcB measurement with the JM-103 provides a reliable screening method for the identification of hyperbilirubinemia even when the TSB level exceeds 15 mg dl(-1). Using the maximum of three independent measurements reduces the number of false negatives, but increases the number of false positives. The use of TcB measurements in an outpatient practice should be a valuable tool for the practitioner.

Routine transcutaneous bilirubin measurements combined with clinical risk factors improve the prediction of subsequent hyperbilirubinemia.

OBJECTIVE: To evaluate predischarge transcutaneous bilirubin (TcB) measurements combined with risk factors as predictors of the risk of a subsequent total serum bilirubin (TSB) >or=17 mg per 100 ml (291 micromol l(-1)). STUDY DESIGN: Routine TcB measurements are obtained daily for all infants in our well baby nursery. We performed a nested case-control study comparing all 75 infants who had been readmitted with TSB >or=17 mg per 100 ml (291 micromol l(-1)) between 1 February 2005 and 28 February 2007 with randomly selected controls that had not been readmitted. RESULT: Between 1 February 2005 and 28 February 2007, 11 456 infants were discharged from the well baby nursery. Seventy-five infants (0.65%) were readmitted at a mean age of 110+/-29.9 h with a TSB>or=17 mg per 100 ml (291 micromol l(-1)). All received phototherapy. Using logistic regression analysis, three variables were statistically significant for predicting cases: the maximum predischarge TcB percentile group (P<0.0001, adjusted odds ratio (AOR), >95th percentile 148; 95% confidence interval (CI) 21 to >999, AOR 76 to 95th percentile 15; 95% CI 3.1 to 70, AOR 50 to 75th percentile 6.1; 95% CI 1.3 to 28 compared with <50th percentile), exclusive breastfeeding (P<0.0001, AOR 11; 95% CI 3.7 to 34) and gestational age (P=0.0057, AOR 35 to 36 6/7 week 21; 95% CI 2.3 to 185, AOR 37 to 37 6/7 week 15; 95% CI 1.9 to 115, AOR 38 to 38 6/7 week 1.8; 95% CI 0.3 to 11, AOR 39 to 39 6/7 week 1.1; 95% CI 0.2 to 7 AOR >or=41 week 0.88; 95% CI 0.1 to 10 compared with 40 to 40 6/7 week infants). These three variables provided the best prediction of a case (c=0.885, area under the receiver operating characteristic curve) and this prediction was significantly better than the use of the clinical risk factors, gestation and exclusive breastfeeding, alone (c=0.770, P<0.001) or the TcB percentile grouping alone (c=0.766, P<0.001). Substituting the TcB rate of rise (c=0.903, P=0.316) or the last measured TcB (c=0.873, P=0.292) for the maximum TcB measurement did not significantly improve the predictors of a case. CONCLUSION: Combining predischarge TcB levels with two clinical risk factors-gestational age and exclusive breastfeeding-significantly improves the prediction of subsequent hyperbilirubinemia.

Randomized controlled trial of light-emitting diode phototherapy.

OBJECTIVE: We wished to compare the efficacy of light-emitting diode (LED) phototherapy with special blue fluorescent (BB) tube phototherapy in the treatment of neonatal hyperbilirubinemia. STUDY DESIGN: We randomly assigned 66 infants >or=35 weeks of gestation to receive phototherapy using an LED device or BB. In addition to phototherapy from above, all infants also received phototherapy from below using four BB tubes or a fiberoptic pad. RESULT: After 15+/-5 h of phototherapy, the rate of decline in the total serum bilirubin (TSB) was 0.35+/-0.25 mg/dl/h in the LED group vs 0.27+/-0.25 mg/dl/h in the BB group (P=0.20). CONCLUSION: LED phototherapy is as effective as BB phototherapy in lowering serum bilirubin levels in term and near-term newborns.

Does intensive phototherapy produce hemolysis in newborns of 35 or more weeks gestation?

OBJECTIVE: Because there is some in vivo and in vitro evidence that standard phototherapy might produce hemolysis, we wished to know whether intensive phototherapy produces hemolysis. STUDY DESIGN: We measured end-tidal carbon monoxide (CO) concentration corrected for ambient CO (ETCOc) in 27 newborn infants > or =35 weeks gestation receiving intensive phototherapy (average irradiance 43 microW/cm2/nm). RESULTS: There was a steady decrease in the mean ETCOc over the course of the phototherapy. CONCLUSION: Intensive phototherapy did not produce hemolysis in infants > or =35 weeks gestation.

Jaundice in low birthweight infants: pathobiology and outcome.

Jaundice in preterm, as well as full term, infants results from (a) an increased bilirubin load in the hepatocyte, (b) decreased hepatic uptake of bilirubin from the plasma, and/or (c) defective bilirubin conjugation. Hyperbilirubinaemia in preterm infants is more prevalent, more severe, and its course more protracted than in term neonates.

Treatment of jaundice in low birthweight infants.

Exchange transfusion and phototherapy remain the staples of intervention for the jaundiced newborn. Clinical management of the jaundiced low birthweight infant is discussed.

The Bloxsom air lock: a historical perspective.

In 1950, Allan P. Bloxsom (1901-1991), a pediatrician at the St Joseph Hospital in Houston, introduced his positive pressure oxygen air lock (AL) for the delivery room resuscitation of the asphyxiated newborn. The infant's entire body was placed into a cylindrical steel chamber that was tightly sealed and infused with warmed humidified 60% oxygen. The positive pressure within the AL was cycled between 1 and 3 lb/in(2) at 1-minute intervals to simulate the intrauterine pressures during the second stage of labor. Bloxsom developed the AL device in response to his hypothesis that the contractions of labor help to "condition: the infant for extrauterine survival. Parmalee said that the AL "certainly locks the infant up, safe from meddlesome and unintelligent treatment." When clear plastic versions of the AL became commercially available, it received widespread use in delivery rooms and newborn nurseries throughout the United States. In 1953, Apgar and Kreiselman produced apnea in adult dogs using pentobarbital and a muscle relaxant, and found that the AL device was unsuccessful with the oxygenation and ventilation of the animals. In 1954, Townsend in Rochester, New York, reported on his experience with the AL in 150 premature infants. He concluded that the AL should be "more accurately referred to as an oxygenator" and that, "the truly apneic infant cannot be maintained in a acyanotic state by the AL." The AL was finally subjected to the scrutiny of a randomized, controlled clinical trial that was published in 1956. Reichelderfer and Nitowski at Johns Hopkins randomized 171 infants to receive care in the AL or in an Isolette. Routine resuscitation, including positive pressure ventilation, was administered, as needed, to both study groups before placement into the AL or Isolette (Air Shields Inc, Hatboro, PA). They did not find any differences in the outcomes of the 2 study groups. By the mid 1950s, new information linking oxygen therapy and retrolental fibroplasia, led to a rapid decline in the use of the AL, even before the publication of the randomized trial.

Prediction of hyperbilirubinemia in near-term and term infants.

OBJECTIVE: The purpose of this study was to determine whether end-tidal carbon monoxide (CO) corrected for ambient CO (ETCOc), as a single measurement or in combination with serum total bilirubin (STB) measurements, can predict the development of hyperbilirubinemia during the first 7 days of life. METHODS: From 9 multinational clinical sites, 1370 neonates completed this cohort study from February 20, 1998, through February 22, 1999. Measurements of both ETCOc and STB were performed at 30 +/- 6 hours of life; STB also was measured at 96 +/- 12 hours and subsequently following a flow diagram based on a table of hours of age-specific STB. An infant was defined as hyperbilirubinemic if the hours of age-specific STB was greater than or equal to the 95th percentile as defined by the table at any time during the study. RESULTS: A total of 120 (8.8%) of the enrolled infants became hyperbilirubinemic. Mean STB in breastfed infants was 8.92 +/- 4.37 mg/dL at 96 hours versus 7.63 +/- 3.58 mg/dL in those fed formula only. The mean ETCOc at 30 +/- 6 hours for the total population was 1.48 +/- 0.49 ppm, whereas those of nonhyperbilirubinemic and hyperbilirubinemic infants were 1.45 +/- 0.47 ppm and 1.81 +/- 0.59 ppm, respectively. Seventy-six percent (92 of 120) of hyperbilirubinemic infants had ETCOc greater than the population mean. An ETCOc greater than the population mean at 30 +/- 6 hours yielded a 13.0% positive predictive value (PPV) and a 95.8% negative predictive value (NPV) for STB >/=95th percentile. When infants with STB >95th percentile at <36 hours of age were excluded, the STB at 30 +/- 6 hours yielded a 16.7% PPV and a 98.1% NPV for STB >75th percentile. The combination of these 2 measurements at 30 +/- 6 hours (either ETCOc more than the population mean or STB >75th percentile) had a 6.4% PPV with a 99.0% NPV. Conclusions. This prospective cohort study supports previous observations that measuring STB before discharge may provide some assistance in predicting an infant's risk for developing hyperbilirubinemia. The addition of an ETCOc measurement provides insight into the processes that contribute to the condition but does not materially improve the predictive ability of an hours of age-specific STB in this study population. The combination of STB and ETCOc as early as 30 +/- 6 hours may identify infants with increased bilirubin production (eg, hemolysis) or decreased elimination (conjugation defects) as well as infants who require early follow-up after discharge for jaundice or other clinical problems such as late anemia. Depending on the incidence of hyperbilirubinemia within an institution, the criteria for decision making should vary according to its unique population.

Prediction of hyperbilirubinemia in near-term and term infants.

OBJECTIVE: The purpose of this study was to determine whether end-tidal carbon monoxide (CO) corrected for ambient CO (ETCOc), as a single measurement or in combination with serum total bilirubin (STB) measurements, can predict the development of hyperbilirubinemia during the first 7 days of life. METHODS: From nine multinational clinical sites, 1370 neonates completed this cohort study from February 20, 1998 through February 22, 1999. Measurements of both ETCOc and STB were performed at 30+/-6 hours of life; STB also was measured at 96+/-12 hours and subsequently following a flow diagram based on a table of hours of age-specific STB. An infant was defined as hyperbilirubinemic if the hours of age-specific STB was greater than or equal to the 95th percentile as defined by the table at any time during the study. RESULTS: A total of 120 (8.8%) of the enrolled infants became hyperbilirubinemic. Mean STB in breast-fed infants was 8.92+/-4.37 mg/dl at 96 hours versus 7.63+/-3.58 mg/dl in those fed formula only. The mean ETCOc at 30+/-6 hours for the total population was 1.48+/-0.49 ppm, whereas those of nonhyperbilirubinemic and hyperbilirubinemic infants were 1.45+/-0.47 and 1.81+/-0.59 ppm, respectively. Seventy-six percent (92 of 120) of hyperbilirubinemic infants had ETCOc greater than the population mean. An ETCOc greater than the population mean at 30+/-6 hours yielded a 13.0% positive predictive value (PPV) and a 95.8% negative predictive value (NPV) for STB > or =95th percentile. When infants with STB > or =95th percentile at <36 hours of age were excluded, the STB at 30+/-6 hours yielded a 16.7% PPV and a 98.1% NPV for STB >75th percentile. The combination of these two measurements at 30+/-6 hours (either ETCOc more than the population mean or STB >75th percentile) had a 6.4% PPV with a 99.0% NPV. CONCLUSIONS: This prospective cohort study supports previous observations that measuring STB before discharge may provide some assistance in predicting an infant's risk for developing hyperbilirubinemia. The addition of an ETCOc measurement provides insight into the processes that contribute to the condition but does not materially improve the predictive ability of an hours of age-specific STB in this study population. The combination of STB and ETCOc as early as 30+/-6 hours may identify infants with increased bilirubin production (eg, hemolysis) or decreased elimination (conjugation defects) as well as infants who require early follow-up after discharge for jaundice or other clinical problems such as late anemia. Depending on the incidence of hyperbilirubinemia within an institution, the criteria for decision making should vary according to its unique population.

Phototherapy--traditional and nontraditional.

An observation by an English nurse in 1956 led to the discovery that visible light could lower serum bilirubin levels in newborn infants, and subsequent research showed how photons of light energy are absorbed by the bilirubin molecule converting it into isomers that are readily excreted by the liver and the kidney. Understanding the dose-response effect and other factors that influence the way light works to lower bilirubin levels has led to the effective use of phototherapy and has eliminated the need for exchange transfusion in almost all jaundiced infants.