Identification of risk for neonatal haemolysis.

AIM: To identify neonates at risk of haemolytic hyperbilirubinaemia through near-concurrent measurements of total serum/plasma bilirubin (TB) or transcutaneous bilirubin (TcB) and end-tidal breath carbon monoxide (CO), corrected for ambient CO (ETCOc), an index of bilirubin production and haemolysis. METHODS: Paired TB/TcB (mg/dL) and ETCOc (ppm) measurements were obtained in newborns (n = 283) at 20 to <60 hours of age in five nurseries. TB/TcB values were assigned TB/TcB percentile risk values using the Bhutani hour-specific nomogram. In infants having two serial TB/TcB measurements (n = 76), TB rate of rise (ROR, mg/dL/h) was calculated. RESULTS: For the entire cohort (n = 283), 67.1% and 32.9% had TB/TcB<75th and ≥75th percentile, respectively. TB/TcB (5.79 ± 1.84 vs 9.14 ± 2.25 mg/dL) and ETCOc (1.61 ± 0.45 vs 2.02 ± 1.35 ppm, p = 0.0002) were different between the groups. About 36.6% of infants with TB/TcB ≥75th percentile had ETCOc ≥ 2.0 ppm. In the subcohort of infants with serial TB/TcB measurements (n = 76), 44.7% and 55.3% had TB/TcB<75th and ≥75th percentile, respectively. TB/TcB (5.28 ± 1.97 vs 9.53 ± 2.78 mg/dL), ETCOc (1.72 ± 0.48 vs 2.38 ± 1.89 ppm, p = 0.05) and TB ROR (0.011 ± 0.440 vs 0.172 ± 0.471 mg/dL/h) were different between the groups. CONCLUSION: The combined use of TB/TcB percentile risk assessments and ETCOc measurements can identify infants with haemolytic hyperbilirubinaemia. The addition of TB ROR can identify those infants with elimination disorders.

Prevalence of Hypoalbuminemia and Elevated Bilirubin/Albumin Ratios in a Large Cohort of Infants in the Neonatal Intensive Care Unit.

OBJECTIVE: To provide descriptive data on serum albumin levels and the bilirubin to albumin (B/A) ratio in neonates admitted to the neonatal intensive care unit, assess the effect of gestational and chronological age on serum albumin and the B/A ratio, and evaluate the association between extreme values and mortality. STUDY DESIGN: Using a retrospective cohort design, we queried the Pediatrix clinical data warehouse for all infants born between 23 and 41 weeks of gestation from 1997 to 2014 who had a report of both a serum albumin and total serum bilirubin (TSB) level on the same day between birth and 14 days of life. RESULTS: There were 382 190 paired albumin and bilirubin levels across 164 401 neonates (15% of the 1 072 682 infants in the clinical data warehouse). Both gestational age and postnatal age were independent factors that influenced the values for serum albumin, TSB, and B/A ratio (ANOVA; P < .0001). TSB and B/A ratios values above birth weight-specific thresholds for exchange transfusions were uncommon (<6% of infants). Hypoalbuminemia (<2.5 mg/dL) was common (29% of infants). Neonates with serum albumin levels <2.5 g/dL or with B/A ratio levels exceeding exchange thresholds were at higher risk of death compared with infants who did not exceed these levels. This association was independent of other risk factors (estimated gestational age, birth weight, sex, and the presence of a major anomaly). CONCLUSION: Both gestational age and postnatal age influence TSB, albumin, and B/A ratios; hypoalbuminemia and extreme B/A ratios are associated with an increased risk of death.

Magnetic Resonance Imaging Abnormalities in Advanced Acute Bilirubin Encephalopathy Highlight Dentato-Thalamo-Cortical Pathways.

A distinct pattern of acute restricted diffusion on magnetic resonance imaging localized to key regions within the dentato-thalamo-cortical pathway was observed early in a term newborn during advanced stages of acute bilirubin encephalopathy. These findings demonstrate that vulnerability to bilirubin toxicity extends across specific neuroanatomic tracts.

Bilirubin Concentrations in Jaundiced Neonates with Conjunctival Icterus.

OBJECTIVES: To assess the total serum bilirubin (TSB) levels at which conjunctival icterus is observed in neonates of ≥34 weeks gestation during the first week of life. STUDY DESIGN: Two convenience samples of neonates were examined for conjunctival icterus within 4 hours of TSB measurements. A concurrent assessment of cephalopedal cutaneous icterus was performed and the TSB characterized using the Bhutani hour-specific risk zone nomogram. RESULTS: Two hundred forty neonates were studied of which 76 had conjunctival icterus. Conjunctival icterus was always accompanied by cutaneous jaundice to at least the chest and more often than not a TSB >14.9 mg/dL (255 umol/L) consistently in the 76th%-95th% to >95th% range on the Bhutani nomogram. Only a few infants with TSB in the range of 10-14.9 mg/dL (171-255 umol/L) had conjunctival icterus. CONCLUSIONS: Conjunctival icterus was observed in a subset of jaundiced neonates and associated with elevated hour-specific TSB levels frequently >95th% on the Bhutani nomogram. Conjunctival icterus is a sign of clinically relevant hyperbilirubinemia that merits a TSB measurement and evaluation of the infant.

ABO hemolytic disease of the newborn: a need for clarity and consistency in diagnosis.

The diagnosis of ABO hemolytic disease of the newborn (ABO HDN) has been the subject of considerable debate and clinical confusion. Its use as an overarching default diagnosis for hyperbilirubinemia in all ABO incompatible neonates regardless of serological findings is problematic and lacks diagnostic precision. Data on hemolysis indexed by carbon monoxide (CO) levels in expired air (ETCOc) and blood (COHbc) support an essential role for a positive direct antiglobulin test (DAT) in making a more precise diagnosis of ABO HDN. A working definition that includes ABO incompatibility, significant neonatal hyperbilirubinemia, and a positive DAT is needed to gain clarity and consistency in the diagnosis of ABO HDN. Absent a positive DAT, the diagnosis of ABO HDN is suspect. Instead, a negative DAT in a severely hyperbilirubinemic ABO incompatible neonate should trigger an exhaustive search for an alternative cause, a search that may require the use of targeted gene panels.

Little known and less understood: the benefits of a lower hematocrit (~40%) in reconstituted blood for double volume exchange transfusion.

A double volume exchange transfusion (DVET) is an important, if infrequently performed, intervention to acutely lessen the total serum bilirubin (TSB) and reduce the extravascular CNS bilirubin exposure when neonatal hyperbilirubinemia poses a neurotoxicity risk. The current analysis based on the seminal works of Valaes, and Sproul and Smith, predicts that a DVET blood product of lower hematocrit (~40%) via its greater plasma volume and corresponding higher albumin content optimizes the benefits of an DVET in several ways. First, by augmenting bilirubin clearance from the extravascular space and thereby further reducing the CNS bilirubin exposure, second, by favorably positioning the intravascular albumin-bilirubin binding capacity at DVET completion to accommodate additional bilirubin equilibration and rebound hyperbilirubinemia post-exchange, and third by correcting anemia if present.

Effect of nuclear factor κB inhibition on serotype 9 adeno-associated viral (AAV9) minidystrophin gene transfer to the mdx mouse.

Gene therapy studies for Duchenne muscular dystrophy (DMD) have focused on viral vector-mediated gene transfer to provide therapeutic protein expression or treatment with drugs to limit dystrophic changes in muscle. The pathological activation of the nuclear factor (NF)-κB signaling pathway has emerged as an important cause of dystrophic muscle changes in muscular dystrophy. Furthermore, activation of NF-κB may inhibit gene transfer by promoting inflammation in response to the transgene or vector. Therefore, we hypothesized that inhibition of pathological NF-κB activation in muscle would complement the therapeutic benefits of dystrophin gene transfer in the mdx mouse model of DMD. Systemic gene transfer using serotype 9 adeno-associated viral (AAV9) vectors is promising for treatment of preclinical models of DMD because of vector tropism to cardiac and skeletal muscle. In quadriceps of C57BL/10ScSn-Dmd(mdx)/J (mdx) mice, the addition of octalysine (8K)-NF-κB essential modulator (NEMO)-binding domain (8K-NBD) peptide treatment to AAV9 minidystrophin gene delivery resulted in increased levels of recombinant dystrophin expression suggesting that 8K-NBD treatment promoted an environment in muscle tissue conducive to higher levels of expression. Indices of necrosis and regeneration were diminished with AAV9 gene delivery alone and to a greater degree with the addition of 8K-NBD treatment. In diaphragm muscle, high-level transgene expression was achieved with AAV9 minidystoophin gene delivery alone; therefore, improvements in histological and physiological indices were comparable in the two treatment groups. The data support benefit from 8K-NBD treatment to complement gene transfer therapy for DMD in muscle tissue that receives incomplete levels of transduction by gene transfer, which may be highly significant for clinical applications of muscle gene delivery.