Thor Willy Ruud Hansen

Therapeutic Approaches to Neonatal Jaundice: An International Survey

Jaundice is one of the most common clinical phenomena in the neonatal period and a frequent indication for treatment with phototherapy, exchange transfusion, or drugs. The present study documents the variability in approaches to the treatment of this condition. A mail questionnaire was sent to neonatal units worldwide. One hundred and eight answers (49% response rate) were received from Europe (n=72), North America (n=28), Africa (n=7), and Asia (n=1). The neonatal intensive care units represented by the respondents had 31 ±18 beds [mean ±SD], and 638 ±519 admissions per year. All units offered phototherapy, 106/ 108 performed exchange transfusions, while 44/ 108 used some form of drug therapy. There was considerable variability among the units in their approaches to the jaundiced neonate. This applied to all aspects of care, including type of phototherapy lights used, practical implementation of phototherapy, use of fluid supplementation, and use of prophylactic phototherapy. The majority used written protocols for investigation and treatment of neonatal jaundice and would let their decision on whether to treat be influenced by the infants clinical state. There was great variability between units in the level of serum bilirubin that would trigger therapy. This applied across weight groups and to phototherapy as well as exchange transfusion. The significant heterogeneity in our approach to the treatment of jaundiced neonates suggests that our understanding of the biology of neonatal jaundice is inadequate and that further research will be necessary in order to provide a more solid biological foundation for therapy.

Bilirubin and Brain Toxicity

More than a century has passed since Hervieux first described yellow staining of the basal ganglia in association with neonatal jaundice (1). The term kernicterus was, however, first used by Schmorl in 1904 to describe the post-mortem finding of yellow staining of the basal ganglia in term infants whose cause of death was probably feto-maternal iso-immunization (2). This term has since been used to describe both the acute, often fatal condition in the newborn with substantial elevation of serum bilirubin levels, seizures, opisthotonus, and bleeding tendency, as well as the neurologic sequelae in survivors, consisting of choreoathetosis, asymmetric spasticity, paresis of upward gaze, and neurogenic hearing loss (3-7). Yellow staining of the brain has, in recent years, also been observed in infants dying without the clinical symptoms of kernicterus, and in whom only moderately elevated serum bilirubin values had been noted (8-10). Bilirubin has, in addition, been implicated in damage to cognitive functions (11, 12), but consensus is lacking regarding permanent damage to such functions (13, 14). The terms kernicterus and bilirubin encephalopathy have often been used interchangably, and without any clear definition of the terms. We suggest that bilirubin encephalopathy should be used in a broader sense so as to include all conditions in which bilirubin is known, or thought to be, the cause of brain toxicity. The term kernicterus would be reserved for cases exhibiting the classical acute symptoms described above, or surviving with the typical neurologic sequelae. During the past thirty years, considerable research has been carried out regarding the causes of hyperbilirubinemia and the mechanisms underlying bilirubin toxicity. Despite these efforts the basic mechanisms remain elusive. This research has been concentrated on three main areas. Firstly, the binding of bilirubin to albumin has been investigated in detail. Secondly, a number of studies have addressed the toxicity of bilirubin both in nervous tissue, and in other cell and organ systems. Finally, the mode of entry of bilirubin into the central nervous system has been examined.

Acute management of extreme neonatal jaundice : the potential benefits of intensified phototherapy and interruption of enterohepatic bilirubin circulation

Abstract Increasing numbers of neonates are being admitted to hospital because of extreme jaundice. Phototherapy should be very effective in such infants, because the efficacy of phototherapy is proportional to the concentration of bilirubin in the skin. Here, I report on four infants who were admitted for indirect serum bilirubin levels of >500 µmol/1 (»30mg/dl). In one of them, unrecognized Rhesus immunization was the main cause of hyperbilirubinemia, while in the other three increased enterohepatic circulation of bilirubin was thought to be an important contributory factor. In all four infants phototherapy (11–14 µW/cm2/nm) with whole body exposure plus ad lib feeding with milk were initiated immediately upon admission to the nursery. After 2h serum bilirubin values were reduced by 170–185 µmol/1 (10‐11mg/dl) in the first three infants, while in the fourth infant a reduction of 195 µmol/1 (11.3mg/dl) was seen in the 5h interval between the first and second bilirubin measurement. This experience suggests that in some infants with extreme jaundice, intensified phototherapy plus feeding with milk may be very effective in reducing serum bilirubin levels. Even if an exchange transfusion is performed, using this strategy in the waiting period may be beneficial, as both the rapid reduction in serum bilirubin levels as well as the conversion of significant amounts of bilirubin into water‐soluble isomers may reduce the risk of neurotoxicity.

Mechanisms of bilirubin toxicity: clinical implications.

The basic mechanism of kernicterus and bilirubin encephalopathy has not been unequivocally determined. Much knowledge has been gained about phenomena that contribute to bilirubin neurotoxicity, and this knowledge has implications for clinical practice. Conditions that impact on blood-brain barrier function, increase brain blood flow, or impact on bilirubin metabolism, including its transport in serum, should be avoided, if possible. Such conditions include drugs and drug stabilizers that compete with bilirubin binding to albumin, or that inhibit P-glycoprotein in the blood-brain barrier, prematurity/immaturity, and clinically significant illness in the infant that involves hemolysis, respiratory and metabolic acidosis, infection, asphyxia, hypoxia and (perhaps) hyperoxia, and hyperosmolality. If these conditions are not avoidable then there should be a more aggressive approach to the treatment of hyperbilirubinemia. The limits of tolerance for hyperbilirubinemia varies among neonates and there are no tools to determine with certainty when a particular infant is approaching the danger zone. Neurological symptoms in a jaundiced infant require extreme vigilance, and, in most cases, immediate intervention.

Brain Bilirubin Content Is Increased in P-Glycoprotein-Deficient Transgenic Null Mutant Mice

P-glycoprotein (P-gp), encoded by the mdr1a gene, is an ATP-dependent plasma membrane protein that is expressed in abundance on the blood-brain barrier (BBB). P-gp limits the CNS influx and retention of a variety of lipophilic compounds. We hypothesized that brain bilirubin content after an i.v. bilirubin infusion would be increased in P-gp-deficient mdr1a null mutant transgenic mice (mdr1a(-/-)) compared with controls. Eighteen mdr1a(-/-) null mutant and 18 P-gp-sufficient wild type mice (+/+) were anesthetized and 50 mg/kg bilirubin infused through the tail vein. Brain bilirubin content (mean ± SEM) 10 min after infusion was significantly higher in mdr1a(-/-) (18.1 ± 2.4 nmol/g) compared with (+/+) mice (10.4 ± 1.0 nmol/g). Brain bilirubin content declined 60 min after infusion but remained higher in mdr1a(-/-) (10.3 ± 1.4 nmol/g) compared with (+/+) mice (5.3 ± 0.9 nmol/g). Brain bilirubin clearance did not differ between groups (t1/2 ∼ 55 min). We conclude that P-gp-deficient mdr1a(-/-) mice have significantly higher brain bilirubin content compared with controls after an i.v. bilirubin load. These data suggest that 1) bilirubin is a substrate for P-gp and 2) the increased brain bilirubin content in mdr1a(-/-) mice is due to enhanced brain bilirubin influx. We speculate that BBB P-gp provides a protective effect against bilirubin neurotoxicity by reducing brain bilirubin influx.

Guidelines for the Management of Extremely Premature Deliveries: A Systematic Review.

BACKGROUND AND OBJECTIVES: Available data on survival rates and outcomes of extremely low gestational age (GA) infants (22–25 weeks’ gestation) display wide variation by country. Whether similar variation is found in statements by national professional bodies is unknown. The objectives were to perform a systematic review of management from scientific and professional organizations for delivery room care of extremely low GA infants. METHODS: We searched Embase, PubMed, and Google Scholar for management guidelines on perinatal care. Countries were included if rated by the United Nations Development Programme’s Human Development Index as “very highly developed.” The primary outcome was rating of recommendations from “comfort care” to “active care.” Secondary outcomes were specifying country-specific survival and considering potential for 3 biases: limitations of GA assessment; bias from different definitions of stillbirths and live births; and bias from the use of different denominators to calculate survival. RESULTS: Of 47 highly developed countries, 34 guidelines from 23 countries and 4 international groups were identified. Of these, 3 did not state management recommendations. Of the remaining 31 guidelines, 21 (68%) supported comfort care at 22 weeks’ gestation, and 20 (65%) supported active care at 25 weeks’ gestation. Between 23 and 24 weeks’ gestation, much greater variation was seen. Seventeen guidelines cited national survival rates. Few guidelines discussed potential biases: limitations in GA (n = 17); definition bias (n = 3); and denominator bias (n = 7). CONCLUSIONS: Although there is a wide variation in recommendations (especially between 23 and 24 weeks’ GA), there is general agreement for comfort care at 22 weeks’ GA and active care at 25 weeks’ GA.

P-Glycoprotein Expression in Mouse Brain Increases with Maturation

The mdr1a isoform of P-glycoprotein (Pgp) is an integral plasma membrane efflux pump expressed in adult brain capillary endothelial cells and astrocytes of the blood-brain barrier. We determined the developmental pattern of Pgp expression in brain tissue at embryonic day 16 (E16), day of life 0 (D0), day of life 7 (D7), day of life 21 (D21), and adults (Ad). The relative expression of Pgp mRNA and protein was indexed as a percent (mean ± SEM) of D0 levels. Pgp mRNA levels increased significantly (p < 0.01) with maturation (E16: 75 ± 8%; D21: 303 ± 37%, and Ad: 1,160 ± 120%). Similarly, Pgp protein expression was observed at E16 and increased significantly (p < 0.01) during development (E16: 52 ± 8%; D7: 187 ± 23%; D21: 440 ± 48%, and Ad: 441 ± 56%). This developmental pattern of enhanced blood-brain barrier Pgp expression with maturation was confirmed by immunohistochemistry. We conclude that (i) Pgp expression in mouse brain is limited during late embryogenesis and the newborn period; (ii) Pgp expression increases markedly with postnatal maturation, and (iii) by D21 brain Pgp protein expression approximates adult levels.

Deaths in a neonatal intensive care unit: a 10-year perspective.

Objective: To examine changes in the characteristics and management of infants dying in a regional neonatal intensive care unit in 1987–1988 vs. 1997–1998. Setting: The level III Neonatal Intensive Care Unit (NICU) at Rikshospitalet, Oslo, Norway, handles both regional and national referrals. Design/Methods: The study was retrospective and observational. Patients who died in the neonatal intensive care unit were identified using our own and the hospital’s data records. Charts were reviewed by the principal author. Results: The mortality rate relative to admissions decreased significantly from 1987–1988 to 1997–1998 (6.9% vs. 3.4%, p < .0001). Infants who died in 1997–1998 were more mature and had higher birth weights than those who died in 1987–1988 (34.0 ± 5.5 vs. 32 ± 6.0 wks gestational age [mean ± sd], p < .05; and 2186 ± 1207 vs. 1699 ± 1038 g, p < .05). There was a significantly higher proportion of infants with complex congenital malformations among those who died in 1997–1998 (54% vs. 28%, p < .005). Forgoing intensive care treatment was more commonly associated with the process of dying in 1997–1998 than 10 yrs earlier (63.5% vs. 22.8%, p < .0001). Parental involvement in the process leading to a decision to forgo life support was more frequently described in the charts from 1997–1998 (72.7% vs. 23.8%, p < .001). During the last time period, parents were also present at the time of death significantly more often. Conclusions: The mortality rate of sick infants decreased significantly between 1987–1988 and 1997–1998, showing the improvements in neonatal intensive care during that decade. In 1997–1998, congenital malformations had become the leading cause of death. Parental involvement in life-and-death questions seems to have become the rule, and almost two thirds of neonatal intensive care unit deaths followed a decision to forgo life support.

Bilirubin induces apoptosis and necrosis in human NT2-N neurons.

Studies on primary cultures of newborn rodent neurons have suggested that neuronal death induced by unconjugated bilirubin (UCB) is mainly apoptotic in nature. We exposed a human teratocarcinoma-derived cell line, NT2-N neurons, to different concentrations of UCB and albumin at a 1.5 molar ratio and used multiple, independent measures of cell damage to evaluate neuronal injury after 6, 24, and 48 h. Low doses of UCB (0.66, 2, and 5 μM) induced a moderate loss of 3–4[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazoliumbromide (MTT) cleavage accompanied by delayed morphologic changes consistent with apoptosis (2 and 5 μM). Moderate concentrations of UCB (10 and 25 μM) resulted in early (6 h) necrosis in a subset of neurons, while remaining neurons underwent progressive impairment of MTT cleavage and increasing lactate dehydrogenase (LDH) release accompanied by predominantly delayed apoptosis. High concentrations of UCB (100 μM) induced severe impairment of MTT cleavage, extensive LDH release, and morphologic changes consistent with necrosis within 6 h. Used as a positive control for apoptosis, 2 μM STS induced progressive impairment of MTT cleavage and morphologic changes consistent with apoptosis over the entire observation period. DNA electrophoresis at 48 h was compatible with apoptosis both after treatment with STS and UCB concentrations ≤25, but not at 100 μM. Cleavage of poly (ADP-ribose) polymerase (PARP) was only seen in neurons treated with low UCB concentrations and STS. We conclude that UCB induces early necrosis at high and moderate concentrations and predominantly delayed apoptosis at low and moderate concentrations in cultured human NT2-N neurons.

Kernicterus in term and near-term infants--the specter walks again.

Diagnostic and therapeutic intervention is common in newborns with neonatal jaundice, motivated by the fear of bilirubin‐associated brain damage, kernicterus. In recent years, a resurgence of kernicterus has been noted in countries in which this complication had essentially disappeared. Both early postnatal discharge and relaxation of attitudes to neonatal jaundice have been implicated. Guidelines for the management of neonatal jaundice show significant disparity, attesting to our inadequate understanding of the underlying biology. Aggressive guidelines expose infants to unnecessary risks, risks that are significant when it comes to exchange transfusion, and may also involve improper use of limited resources. Relaxed guidelines, on the other hand, may expose infants to increased risk of brain toxicity.