Early high-dose phenobarbital treatment for prevention of hypoxic-ischemic brain damage in very low birth weight infants

doi:10.1016/S0022-3476(88)80127-6

The Journal of Pediatrics

Volume 112, Issue 1, January 1988, Pages 81-86

https://doi.org/10.1016/S0022-3476(88)80127-6 Get rights and content

In a randomized prospective trial, we studied the effect of early high-dose phenobarbital treatment on the early (intraventricular hemorrhage) and late (neurodevelopmental abnormalities) manifestations of hypoxic-ischemic encephalopathy in preterm infants weighing 1500 g or less at birth. The first intravenous dose of 15 mg/kg was given at a mean age of 110 minutes, followed by 15 mg/kg after 4 hours and then by 5 mg/kg at 24-hour intervals for 5 days. The overall incidence of intraventricular hemorrhage was 32% in treated and 46% in control infants, a nonsignificant difference. An ultrasound brain scan at 9 months old revealed no significant difference in the incidence of ventricular dilatation between treated (19%) and control (29%) infants. At 27 months, a similar incidence of mild (10%) and severe (10%) neurodevelopmental handicaps was found in both treated and control groups. Since beneficial effects could not be documented by any of the criteria used, we conclude that routine administration of phenobarbital to low birth weight infants is not justified.

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Germinal matrix hemorrhage–intraventricular hemorrhage (GMH-IVH) is the most common variety of neonatal intracranial hemorrhage and is characteristic of the premature infant. This form of brain injury affects around 25% of all very low birthweight (<1500 g) premature infants, resulting in an increased risk for neurodevelopmental disability. Its occurrence can lead to impact on subsequent brain development because of destruction of the immature germinal cerebral region resulting in loss of progenitor cells, acceleration of white matter injury via pressure and oxidative stress, and direct parenchymal injury. Finally, hydrocephalus can complicate IVH, resulting in a further increased risk of neurodevelopmental disability. In this chapter, the neuropathology, pathogenesis, clinical features, diagnosis, prognosis, and management of IVH, and its complications will be reviewed. The prominent position of this lesion in neonatal medicine has been accompanied by a large increase in work from several disciplines. This chapter attempts to integrate this information in a meaningful way without oversimplifying a clearly complex problem.
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In infants with hypoxic-ischemic encephalopathy, cooling reduces death/neurodevelopmental impairment, whereas prophylactic anticonvulsants may not. This retrospective analysis shows no reduction in neurodevelopmental impairment (23% in prophylactic phenobarbital group vs 45% in controls, P = .3) but fewer clinical seizures in cooled infants who received prophylactic phenobarbital (15% vs 82% P < .0001).
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The ability to protect or rescue the central nervous system from hypoxic–ischaemic injury has yet to materialise into clinical reality. However, exciting advances have recently occurred in this field and in this article the mounting evidence for perinatal neuroprotective interventions is reviewed. A multi-modal approach is advocated, based on the recent findings that hypothermia is therapeutic for sufferers of perinatal asphyxia. As anaesthetic/sedative agents need to be co-administered available data to define the best putative protective adjunct to hypothermia is also reviewed.
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Prematurely born infants with intraventricular hemorrhage (IVH) suffer significant morbidity and mortality, particularly those infants with high grade hemorrhage. The more premature infants have a higher incidence, experiencing more severe IVH. Early onset IVH is also likely to be severe and to progress to a higher grade. The etiology of intraventricular hemorrhages is clearly multifactorial, with differing sets of risk factors for early onset and later occurring hemorrhage. Prevention reqires multilayered strategies, both prenatal and postnatal. These strategies are discussed in detail, highlighting unresolved controversies. Certain recommendations for prevention can be made. These include efforts to prevent preterm delivery, transfer of high risk mothers to tertiary care centers and antenatal maternal steroid use. Postnatally, the importance of optimal resuscitation and neonatal care practices is stressed, particulary those which minimize cerebral blood flow fluctuation. Postnatal indomethacin use should be considered in most infants. Further investigation of other strategies is necessary, including multicenter randomized trials to further evaluate antenatal pharmacologic agents, as well as the relative efficacy of different modes of delivery. The different risk factors for early onset versus later onset IVH must be more clearly delineated. Most importantly, any strategy must include sustained neurodevelopmental followup.

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^*: Supported by the Foundation for Pediatric Research, the Sigrid Juselius Foundation, and the Signe and Ane Gyllenberg Foundation.

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Early high-dose phenobarbital treatment for prevention of hypoxic-ischemic brain damage in very low birth weight infants*

J Pediatr

Lancet

Lancet

J Pediatr

Lancet

Lancet

Am J Obstet Gynecol

J Pediatr

Lancet

Hypoxic-ischemic brain injury in the newborn

Semin Perinatol

Incidence, severity, and timing of subependymal and intraventricular hemorrhages in preterm infants born in a perinatal unit as detected by serial real-time ultrasound

Pediatrics

Timing of neonatal cerebroventricular hemorrhage with ultrasound

Arch Dis Child

Obstetric management and intraventricular hemorrhage in very-low-birth-weight infants

Obstet Gynecol

Cerebral protection by barbiturate anesthesia

Arch Neurol