Allopurinol for preventing mortality and morbidity in newborn infants with suspected hypoxic‐ischaemic encephalopathy
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To determine the effect of allopurinol on mortality and morbidity in term and near‐term newborn infants with suspected hypoxic‐ischaemic encephalopathy.
The following subgroup analyses are planned:
1. Trials that assessed allopurinol as a sole therapy.
2. Trials of allopurinol as an adjunct to an another therapy.
2. Trials where participants were predominantly (more than 80%) infants with moderate or severe encephalopathy (Sarnat 1976).
Background
Hypoxic‐ischaemic encephalopathy is a major cause of death and of disability in term and near‐term newborn infants worldwide. The severity of the encephalopathy predicts the risk of death and long‐term neurodisability (Vannucci 1990; Sarnat 1976). Brain damage following a perinatal hypoxic‐ischaemic insult occurs in two phases. Early cell death results from primary exhaustion of the cellular energy stores. A second phase of cell death occurs during reperfusion and reoxygenation several hours after the initial insult. The pathophysiology of late neuronal damage involves the production of cytotoxic free radicals (including hydrogen peroxide, superoxides, free iron and hydroxyl radicals) that damage cell lipids, proteins, and nucleic acids, and results in secondary energy failure, membrane dysfunction, and apoptosis (Inder 2000). The degree of secondary energy failure is predictive of mortality and neurodisability rates (Roth 1997). Various pharmacological and non‐pharmacological interventions that may limit free radical generation and minimise the extent of late cell death are the subject of other Cochrane reviews (Evans 2001; Hunt 2002; Jacobs 2003; Kecskes 2005; McGuire 2004). With the possible exception of therapeutic mild hypothermia, none of these interventions has yet been proven to limit brain damage in newborn infants with hypoxic‐ischaemic encephalopathy (Shankaran 2005; Edwards 2006; McGuire 2006).
In part, the production of cytotoxic free radicals is dependent on xanthine oxidase‐mediated metabolism of hypoxanthine (Warner 2004). Studies using animal models have found that the xanthine oxidase inhibitor allopurinol (via its metabolic product oxypurinol) reduces free radical formation and limits the degree of post‐asphyxia brain damage (Palmer 1990; Palmer 1991; Palmer 1993; Van Bel 1998). At high concentrations, allopurinol scavenges free radicals such as hydroxyl, chelates free iron, and inhibits lipid peroxidation and heat shock factor expression (Pacher 2006). Evidence from randomised controlled trials suggests that high‐dose allopurinol (above 10 milligrams per kilogram body weight) reduces reperfusion injury in adult patients who undergo coronary bypass surgery (Clancy 2001; Johnson 1991; Sisto 1995). In newborn infants with severe respiratory failure necessitating treatment with extracorporeal membrane oxygenation, high‐dose allopurinol reduces free‐radical production and injury (Marro 1997). Allopurinol pre‐treatment of infants with hypoplastic left heart syndrome who undergo cardiac surgery using deep hypothermic circulatory arrest reduces post‐operative adverse cardiac and neurological outcomes (Clancy 2001).
The most commonly reported adverse effects are skin rashes and hypersensitivity reactions (Vazquez‐Mellado 2001). Skin rashes may be more common in patients receiving ampicillin or amoxicillin concurrently with allopurinol. A very rare but severe hypersensitivity syndrome consisting of skin reactions (erythema multiforme, toxic epidermal necrolysis), fever, eosinophilia, and multiorgan failure has been described in patients with concomitant renal impairment or thiazide diuretic use (Arellano 1993; Kumar 1996).
Objectives
To determine the effect of allopurinol on mortality and morbidity in term and near‐term newborn infants with suspected hypoxic‐ischaemic encephalopathy.
The following subgroup analyses are planned:
1. Trials that assessed allopurinol as a sole therapy.
2. Trials of allopurinol as an adjunct to an another therapy.
2. Trials where participants were predominantly (more than 80%) infants with moderate or severe encephalopathy (Sarnat 1976).
Methods
Criteria for considering studies for this review
Types of studies
Controlled trials using either random or quasi‐random patient allocation.
Types of participants
Term and near‐term (greater than 34 weeks' gestation) newborn infants with suspected hypoxic‐ischaemic encephalopathy, defined as clinical evidence of cardiorespiratory or neurological depression (Apgar score less than 7 at five minutes and beyond after birth), and/or evidence of severe metabolic acidosis in intrapartum fetal, umbilical arterial cord, or very early neonatal blood samples (pH less than 7 or base deficit greater than 12 mmol/L), and/or clinical or electro‐encephalographic (multi‐channel or amplitude integrated) evidence of neonatal encephalopathy (MacLennan 1999).
Types of interventions
Allopurinol versus placebo or no drug administered within six hours of delivery. A minimum or maximum dose or duration of treatment will not be pre‐specified. Allopurinol may be given in conjunction with another intervention provided both treatment and control groups receive the intervention.
Types of outcome measures
Primary outcomes: Death and neurodisability
1. Death during the neonatal period and during infancy.
2. Death or severe neurodevelopmental disability defined as any one or combination of the following: non‐ambulant cerebral palsy, developmental delay (developmental quotient less than 70), auditory and visual impairment. Each component will be analyzed individually as well as part of the composite outcome.
3. Neurodevelopmental outcomes in survivors aged greater than, or equal to, 12 months of age measured using validated assessment tools such as Bayley scales.
4 Cognitive and educational outcomes in survivors aged more than five years old (intelligence quotient and/or indices of educational achievement measured using a validated assessment tool, including school examination results).
Secondary outcomes: Neonatal morbidity
1. Seizures in the neonatal period, either apparent clinically or detected by electro‐encephalographic recordings.
2. Time to achieve full oral feeding independent of enteric tube feeding (days after birth), and/or incidence of continued enteric tube feeding at four weeks after birth.
3. Cortical, white matter, or basal ganglia abnormalities on brain imaging (magnetic resonance, computed tomography, or ultrasound)
4. Potential adverse effects of allopurinol (skin rashes, hypersensitivity reactions) that necessitates discontinuation of therapy.
Search methods for identification of studies
The standard search strategy of the Cochrane Neonatal Review Group will be used. The search strategy will include searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2007), MEDLINE (1966 ‐ June 2007), and EMBASE (1980 ‐ June 2007) via the OVID interface using the following text words and MeSH terms: [Infant, Newborn OR Asphyxia Neonatorum/ OR Hypoxia, Brain/ OR Brain Ischemia/ OR infant OR neonat*] AND [Allopurinol/ OR Free Radical Scavengers/ OR Free Radicals/ OR Antioxidants/]. The search outputs will be limited with the relevant search filters for clinical trials. No language restriction will be applied.
References in previous reviews and studies will be examined. The abstracts presented at the Society for Pediatric Research and European Society for Pediatric Research between 1990 and 2007 will be searched by hand. Trials reported only as abstracts will be eligible if sufficient information is available from the report, or from contact with the authors, to fulfil the inclusion criteria. The UK National Research Register (http://www.nrr.nhs.uk), and Current Controlled Trials (http://www.controlled‐trials.com) websites will be searched for completed or ongoing trials.
Data collection and analysis
1. The title and abstract of all studies identified by the above search strategy will be screened and the full articles for all potentially relevant trials obtained. Two review authors will re‐assess independently the full text of any potentially eligible reports and exclude those studies that do not meet all of the inclusion criteria. The authors will resolve any disagreements by discussion with Zsuzsoka Kecskes until consensus is achieved.
2. The criteria and standard methods of the Cochrane Neonatal Review Group will be used to assess the methodological quality of any included trials in terms of allocation concealment, blinding of parents or caregivers and assessors to intervention, and completeness of assessment in all randomised individuals (classified as "yes", "no", or "can't tell"). Additional information will be requested from the trial authors to clarify methodology and results if necessary.
3. Two review authors will use a data collection form to aid extraction of relevant information from each included study. Each review author will extract the data separately. Any disagreements will be resolved by discussion with the third author until consensus is achieved. If data from the trial reports are insufficient, the trialists will be contacted for information.
4. Outcomes for categorical data will be presented as relative risk, risk difference, and number needed to treat, with respective 95% confidence intervals. For continuous data, the weighted mean difference with 95% confidence interval will be used.
5. A fixed effects model for meta‐analyses will be used. The treatment effects of individual trials and heterogeneity between trial results will be examined by inspecting the forest plots. The impact of heterogeneity in any meta‐analysis will be quantified using a measure of the degree of inconsistency in the studies' results (I‐ squared statistic). If statistical heterogeneity is detected, the possible causes (for example, differences in study quality, participants, intervention regimens, or outcome assessments) will be explored using post hoc sensitivity analyses.
