By Singh, Daljit; Kumar, Praveen; Narang, Anil
Abstract
Background. Phenobarbital is one of the oldest, cheapest and most easily available cerebro-protective drugs for the hypoxic brain. It has multiple actions that could be of benefit to the asphyxiated brain. However, its potential has not been fully explored.
Objective. To study the effect of phenobarbital given within six hours of life to term and near-term asphyxiated neonates, on mortality, neurological abnormality at discharge and seizures.
Methods. This was a randomized controlled trial set in a tertiary care referral perinatal centre. Asphyxiated neonates (gestational age ≥ 34 weeks) manifesting with hypoxic ischemic encephalopathy (HIE) in the first six hours of life were randomized to receive either injection of phenobarbital 20 mg/kg IV or to the control group. The primary outcome was death or abnormal neurological examination at discharge while seizures, need for ventilation and multi-organ dysfunction were secondary outcomes.
Results. Twenty-five babies received phenobarbital and 20 were in the control group. The mortality (20% vs. 15%) and abnormal neurological outcome at discharge (30% vs. 53%, p = 0.15) were statistically not different between the two groups. In the phenobarbital group, 8% of neonates developed seizures while 40% of babies in the control group developed seizures (p = 0.01, relative risk (RR) = 0.20 (0.05-0.84)). Phenobarbital was well tolerated and did not increase the need for respiratory support.
Conclusions. Phenobarbital in the dose of 20 mg/kg IV given within six hours of life to term and near-term neonates with HIE, significantly decreased the incidence of neonatal seizures and was well tolerated. However, it did not alter the mortality and neurologic outcome at discharge.
Keywords: Newborn, outcome, phenobarbital, hypoxic ischemic encephalopathy
Introduction
Hypoxic ischemic encephalopathy (HIE) is one of the major causes of morbidity and mortality in term and near-term newborns [1]. In the long run, perinatal asphyxia is responsible for 10-20% of all cases of cerebral palsy [2-4]. There are multiple mechanisms by which neuronal necrosis occurs, and is perpetuated in birth asphyxia. Of them, reperfusion and reoxygenation contribute substantially to birth asphyxia-related brain injury [5].
Reperfusion and reoxygenation leads to excessive production of free radicals. Free radicals can damage or kill cells via several pathways, which include lipid peroxidation of membranes, inactivation of enzymes and DNA and RNA alterations [6]. Of the multitude of drugs, including free radical scavengers, which have been tried in birth asphyxia, phenobarbital is one of the cheapest and most readily available. Apart from its free radical scavenging action, phenobarbital has the additional advantage of controlling seizures, reducing cerebral metabolic rate, inhibiting lipid peroxidation and stabilizing cell membranes [7]. However this drug has not been adequately studied for its potential prophylactic role in the management of birth asphyxia [8]. The aim of this randomized controlled trial was to determine whether intravenous phenobarbital given within six hours of life to term and near-term neonates with HIE would decrease adverse outcomes (death or abnormal neurological examination at discharge).
Methods
Babies with gestational age ≥ 34 weeks were eligible for inclusion if they developed features of encephalopathy in the form of alterations of tone, deep tendon reflexes, primitive reflexes and sensorium (Sarnat and Sarnat [9]) within the first six hours of life, in the settings of low Apgar score (≤6 at 1 min of age) and evidence of fetal distress (fetal bradycardia and/or meconium- stained amniotic fluid and/or cord arterial blood pH ≤ 7.15). Babies with major congenital malformations, meningitis, intracranial hemorrhage and whose mothers were receiving phenobarbital during the last week prior to delivery were excluded.
The study was conducted over a period of 10 months. The enrolled neonates were randomly assigned to treatment or control groups with the help of computer generated random numbers. The assignment was concealed in serially numbered opaque envelopes that were opened only at the time of randomization. The babies in the treatment group were administered an injection of phenobarbital 20 mg/kg IV over 20 minutes within the first six hours of life with monitoring of respiration, heart rate and blood pressure. The babies in the control group did not receive any drug. The rest of the management in both groups was as per the standard protocol for the management of HIE. Seizures were diagnosed clinically by the bedside nurses and physicians who were present round the clock. It was not possible to record electroencephalograms in the neonatal intensive care unit (NICU). If a baby developed seizures in any of the groups, they were managed with additional phenobarbital. Cerebrospinal fluid examination was performed between 10 and 12 hours of life to rule out meningitis and measure products of lipid peroxidation and anti- oxidant enzymes.
A detailed neurological examination was performed daily till the neonate was stabilized and recorded in a structured proforma according to the Sarnat and Sarnat staging system of HIE [9]. The discharge neurological examination was done as per the method described by Amiel-Tison [10]. It was considered abnormal if there were tone abnormalities, disturbances of cortical function and persistent abnormalities of neonatal reflexes. Cranial ultrasound examinations were done at the bedside on days 1, 3 and 7 using a 7.0 MHz probe. The discharge neurological examination and ultrasound examinations were done by neonatologists who were not aware of the group allocation. Administration of phenobarbital was not depicted in the routine nursing charts. The babies were followed up at three months of age. Informed parental consent was obtained before enrolment of the neonates and the institutional ethics committee approved the study.
Outcomes
The primary outcome variable was ‘adverse outcome’ which was defined as death or neurological abnormality at discharge. The secondary outcome variables were seizures, need for ventilation and multi-organ dysfunction.
Sample size
Estimating an incidence of 70% adverse outcome [11,12] among the asphyxiated neonates with HIE, 24 babies per group were required to detect a 50% difference in the primary outcome, with an α error of 0.05 and a power of 80%. Accounting for attrition, it was decided to recruit 60 babies.
Statistical analysis
Continuous, normally distributed variables between the two groups were analyzed using a two-tailed unpaired Student’s t-test. Continuous non-parametric data were analyzed using the MannWhitney ‘U’ test. Dichotomous categorical variables were analyzed using the Chi-square and Fisher’s exact tests. A post-hoc analysis was done for the group of babies with stage II (moderate) and stage III (severe) HIE.
Results
Sixty eligible neonates were randomized to phenobarbital and control groups. Of these, 15 were excluded because of CSF findings suggestive of meningitis (1) and intracranial bleed/traumatic lumbar puncture (14), leaving 25 babies in the phenobarbital group and 20 babies in the control group.
The mean age at administration of phenobarbital was 4.5 0.8 h. The mean birth weight, gestational age and severity of asphyxia as judged by Apgar scores during the first 10 minutes of life, need for intubation, and cord arterial pH were similar between the two groups (Table I). The severity of the neurological syndrome was similar at the time of entry into the study. The proportion of babies developing the various stages of HIE was distributed similarly in the two groups (Table II).
Table I. Baseline parameters.*
The survival rates at discharge were comparable between the two groups (80% vs. 85%). Five babies who died in the study group and the three who died in the control group, were comparable in their characteristics. Their mean gestation, weight, cord pH and median Apgar scores were similar. Four of the five in the phenobarbital group and two of the three in the control group had stage III HIE. All had myocardial dysfunction, hypotension and needed mechanical ventilation.
In the phenobarbital group, neurological examination was normal in 14 (70%) of the 20 babies discharged alive, while in the control group 8 (47%) of the 17 babies were neurologically normal at discharge (p = 0.15). There was no difference in the composite adverse outcome (death or abnormal neurological examination at discharge) in babies who received phenobarbital as compared to controls (44% in phenobarbital group vs. 60% in control group, p = 0.28, Table II).
In the phenobarbital group, only two neonates (8%) developed seizures while eight (40%) babies developed seizures in the control group (p = 0.01, odds ratio (OR) = 0.13 (0.01-0.83)). In the phenobarbital group, one baby had seizures at six hours of life and the other one at 60 hours of life. They were given an additional dose of phenobarbital. In the control group, four babies had seizures at six hours of life, another three babies by 24 hours and one baby had seizures at 36 hours of life. The control group babies also received phenobarbital for control of seizures. The four babies in the control group who developed se\izures by six hours of life received phenobarbital at a mean age of 5.6 0.6 h. Only one baby in the control group required a dose of phenytoin for controlling seizures while no baby needed this in the study group.
Table II. Mortality and neurologic outcomes.
Table III. Mortality and neurologic outcomes in the subgroup with moderate to severe HIE.
A post hoc analysis of the subgroup of babies with stage II and III HIE showed similar results. The incidence of seizures was significantly lower in the babies who received phenobarbital. Other outcomes were not different between the two groups (Table III).
There was no difference in the need for oxygen administration, need for ventilation, myocardial dysfunction, azotemia, coagulopathy, hospital-acquired sepsis and jaundice between the two groups.
Discussion
There is increasing evidence that free radical-mediated reactions, overstimulation by excitatory amino acids and intracellular calcium accumulation are the neurochemical processes that contribute to extension of brain damage after perinatal asphyxia [13-15]. A rational approach to the management of HIE may be directed to prevent or interrupt the biochemical processes initiated during asphyxia [15]. Barbiturates were one of the first agents investigated for the treatment of hypoxic-ischemic brain injury. Studies in asphyxiated human neonates using barbiturates have shown variable results [16-19]. A Cochrane meta-analysis concluded that there was a lack of studies of sufficient size and quality to demonstrate any differences in the risk of death or severe neuro-developmental disability [8]. The relative risk of seizures in this meta-analysis was 0.64 (0.37-1.13). The risk of death and severe disability were 1.06 (0.50-2.27) and 0.61 (0.30- 1.22), respectively.
Data from the present study indicate that early phenobarbital therapy is associated with a significant decrease in the incidence of neonatal seizures (p = 0.01) but that mortality and neurological outcome at discharge are not significantly influenced by phenobarbital therapy. There were no significant side-effects such as hypotension or increased need for ventilatory support. Hall et al. in a similar randomized trial, administered an injection of phenobarbital 40 mg/kg IV to term infants with severe birth asphyxia. They did not find significant effect on seizures; 60% of the treated infants developed seizures vs. 87% of the controls (p = 0.11) [16]. However, neurologic outcome was more likely to be normal (11/15) in the treatment group as compared to the control group (3/ 16) at three years of age (p = 0.003). Goldberg et al., in a randomized controlled trial that used thiopental infusion for 24 hours in babies with HIE, starting at a mean age of 2.3 hours, found no significant difference in the frequency of seizures between the two groups [17]. Early treatment with thiopental also did not improve neonatal mortality or neurologic outcome at 12 months of age. Ruth et al. gave phenobarbital for a period of five days to the study group and did not find any differences in the IQ of survivors at six years of age [18]. Vela et al. compared a 7-day course of phenobarbital with phenytoin but reported only the differences in seizure activity [19].
The reasons for the variability of results seen in different studies could be many. New knowledge of the nature of hypoxic ischemic reperfusion injury indicates that there is probably a ‘window of time’ (therapeutic window) after a hypoxic ischemic insult, during which neuroprotection could be effective. The duration of this therapeutic window is not exactly known but is thought to be in the area of six hours [20,21]. Also, there are a multitude of mechanisms and cascades that are initiated in asphyxia. Different mechanisms may be predominant with different causes of perinatal asphyxia. Hence, a single drug acting on a single step of a cascade may not be effective in all cases of asphyxia [22].
Seizures are associated with increased metabolic demands and may enhance neurologic injury in the hypoxic-ischemic injured brain by themselves [23]. Apart from its other potential actions, phenobarbital, by decreasing the incidence of neonatal seizures, may decrease the brain damage in HIE.
Limitations of our study
We were unable to do blinding for drug administration. However, personnel doing the discharge neurological examination and cranial ultrasound were blinded to the group allocation.
Ideally, long-term neuro-developmental outcome should be the primary outcome, but because of various constraints, we could not incorporate it into this study. Seizures were diagnosed clinically and EEGs could not be done in the NICU, potentially missing electrographic seizures.
Some babies in the control group received phenobarbital for treatment of seizures. However, all babies who received phenobarbital treatment did so at or beyond six hours of life, which probably is beyond the therapeutic window of effectiveness of these agents [20,21].
The sample size was calculated to pick up a 50% reduction in adverse outcomes. Retrospectively, it seems that was too much to expect. Smaller differences would have been missed by the current sample size. To detect a 25% reduction, one would need to recruit about 150 babies.
Conclusions
Phenobarbital given within six hours of life to term and near- term neonates with hypoxic ischemic encephalopathy significantly decreased the incidence of seizures and was well tolerated. The effects on mortality and neurological abnormality at discharge however, did not reach statistical significance. A large multi- centre trial of early phenobarbital therapy in severely asphyxiated neonates, where the drug is administered within first 2-3 hours of life and the primary outcomes are long-term neuro-developmental status, is warranted.
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DALJIT SINGH, PRAVEEN KUMAR, & ANIL NARANG
Neonatal Unit, Department of Pediatrics, Advanced Pediatrics Centre, PGIMER, Chandigarh, India
Correspondence: Dr Praveen Kumar, Associate Professor, Department of Pediatrics, PGIMER, Chandigarh-160012, India. Tel: +91 172 2747585 ext. 5308. Fax: +91 172 2744401. E-mail: [email protected]
Copyright CRC Press Dec 2005
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