Review of bilirubin neurotoxicity II: preventing and treating acute bilirubin encephalopathy and kernicterus spectrum disorders

The goal of this review was to summarize the available literature covering the safety profiles of oral doxycycline and minocycline. Scientific literature published between 1966 and August 2003 was searched using the MEDLINE, EMBASE, and Biosis databases (search terms: minocycline or doxycycline, each paired with adverse reaction, adverse event, and side effect, and doxycycline or minocycline with the limits English language, human, and clinical trials). Safety information was collected from case reports and clinical trials. Adverse event (AE) rates in the United States were calculated by comparing data from the MedWatch AE reporting program used by the US Food and Drug Administration (FDA) with the number of new prescriptions dispensed for each drug from January 1998 to August 2003. Between 1966 and 2003, a total of 130 and 333 AEs were published in case reports of doxycycline and minocycline, respectively. In 24 doxycycline clinical trials (n = 3833) and 11 minocycline trials (n = 788), the ranges in incidence of AEs were 0% to 61% and 11.7% to 83.3%, respectively. Gastrointestinal AEs were most common with doxycycline; central nervous system and gastrointestinal AEs were most common with minocycline. From January 1998 to August 2003, the FDA MedWatch data contained 628 events for doxycycline and 1099 events for minocycline reported in the United States. Approximately 47,630,000 doxycycline and 15,234,000 minocycline new prescriptions were dispensed in the United States during that period, yielding event rates of 13 per million for doxycycline and 72 per million for minocycline, based on FDA data. Between 1998 and 2003, doxycycline was prescribed 3 times as often as minocycline. The incidence of AEs with either drug is very low, but doxycycline had fewer reported AEs. Although more head-to-head clinical trials are needed for a direct comparison of AE frequency, these preliminary data from separate reports suggest the possibility that AEs may be less likely with doxycycline than minocycline.

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 micromol 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). 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 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 ( 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 infant's 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.

Hypoxia–ischemia before or around the time of birth occurs in approximately 2/1000 live births and is associated with a high risk of death or lifelong disability. Therapeutic hypothermia is now well established as standard treatment for infants with moderate to severe hypoxic–ischemic encephalopathy but is only partially effective. There is compelling preclinical and clinical evidence that hypothermia is most protective when it is started as early as possible after hypoxia–ischemia. Further improvements in outcome from therapeutic hypothermia are very likely to arise from strategies to reduce the delay before starting treatment of affected infants. In this review, we examine evidence that current protocols are reasonably close to the optimal depth and duration of cooling, but that the optimal rate of rewarming after hypothermia is unclear. The potential for combination treatments to augment hypothermic neuroprotection has considerable promise, particularly with endogenous targets such as melatonin and erythropoietin, and noble gases such as xenon. We dissect the critical importance of preclinical studies using realistic delays in treatment and clinically relevant cooling protocols when examining combination treatment, and that for many strategies overlapping mechanisms of action can substantially attenuate any effects.