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Allopurinol for preventing mortality and morbidity in newborn infants with suspected hypoxic-ischaemic encephalopathy (Review) Chaudhari T, McGuire W

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2008, Issue 2 http://www.thecochranelibrary.com

Allopurinol for preventing mortality and morbidity in newborn infants with suspected hypoxic-ischaemic encephalopathy (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

TABLE OF CONTENTS HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.1. Comparison 1 Allopurinol versus control (placebo or no drug), Outcome 1 Death during the neonatal period and infancy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.2. Comparison 1 Allopurinol versus control (placebo or no drug), Outcome 2 Death or severe neurodevelopmental disability.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.3. Comparison 1 Allopurinol versus control (placebo or no drug), Outcome 3 Severe quadriplegia in surviving infants. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.4. Comparison 1 Allopurinol versus control (placebo or no drug), Outcome 4 Seizures during the neonatal period. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.5. Comparison 1 Allopurinol versus control (placebo or no drug), Outcome 5 Abnormalities on brain imaging. WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .


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[Intervention Review]

Allopurinol for preventing mortality and morbidity in newborn infants with suspected hypoxic-ischaemic encephalopathy Tejasvi Chaudhari2 , William McGuire1 1 Centre

for Reviews and Dissemination, Hull York Medical School, York, UK. 2 Centre for Newborn Care, The Canberra Hospital, Canberra, Australia Contact address: William McGuire, Centre for Reviews and Dissemination, Hull York Medical School, University of York, York, Y010 5DD, UK. [email protected]. Editorial group: Cochrane Neonatal Group. Publication status and date: Edited (no change to conclusions), published in Issue 11, 2010. Review content assessed as up-to-date: 3 December 2007. Citation: Chaudhari T, McGuire W. Allopurinol for preventing mortality and morbidity in newborn infants with suspected hypoxic-ischaemic encephalopathy. Cochrane Database of Systematic Reviews 2008, Issue 2. Art. No.: CD006817. DOI: 10.1002/14651858.CD006817.pub2. Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT Background Delayed neuronal death following a perinatal hypoxic insult is due partly to xanthine oxidase-mediated production of cytotoxic free radicals. Evidence exists that allopurinol, a xanthine-oxidase inhibitor, reduces delayed cell death in animal models of perinatal asphyxia and in human patients with other forms of organ reperfusion injury. Objectives To determine the effect of allopurinol on mortality and morbidity in newborn infants with suspected hypoxic-ischaemic encephalopathy. Search methods The standard search strategy of the Cochrane Neonatal Review Group was used. This included searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 4, 2007), MEDLINE (1966 - December 2007), EMBASE (1980 - December 2007), conference proceedings, and previous reviews. Selection criteria Randomised or quasi-randomised controlled trials that compared allopurinol administration vs. placebo or no drug in newborn infants with suspected hypoxic-ischaemic encephalopathy. Data collection and analysis The standard methods of the Cochrane Neonatal Review Group were used, with separate evaluation of trial quality and data extraction by two authors. Data were synthesised using a fixed effects model and reported using typical relative risk, typical risk difference and weighted mean difference. Allopurinol for preventing mortality and morbidity in newborn infants with suspected hypoxic-ischaemic encephalopathy (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Main results Three trials in which a total of 114 infants participated were identified. In one trial, participants were exclusively infants with severe encephalopathy. The other trials also included infants with mild and moderately-severe encephalopathy. These studies were generally of good methodological quality, but were underpowered to detect clinically important effects of allopurinol on mortality and morbidity. Meta-analysis did not reveal a statistically significant difference in the risk of death during infancy [typical relative risk 0.92 (95% confidence interval 0.59 to 1.45); typical risk difference -0.03 (95% confidence interval -0.16 to 0.11)], nor in the incidence of neonatal seizures [typical relative risk 0.93 (95% confidence interval 0.75 to 1.16); typical risk difference -0.05 (95% confidence interval -0.21 to 0.11)]. Only one trial assessed neurodevelopment in surviving children and did not find a statistically significant effect. Authors’ conclusions The available data are not sufficient to determine whether allopurinol has clinically important benefits for newborn infants with hypoxicischaemic encephalopathy and, therefore, larger trials are needed. Such trials could assess allopurinol as an adjunct to therapeutic hypothermia in infants with moderate and severe encephalopathy and should be designed to exclude clinically important effects on mortality and adverse long-term neurodevelopmental outcomes.

PLAIN LANGUAGE SUMMARY Allopurinol for preventing mortality and morbidity in newborn infants with suspected hypoxic-ischaemic encephalopathy There is insufficient evidence to determine whether giving allopurinol to newborn infants with suspected hypoxic-ischaemic encephalopathy and, therefore, is beneficial.Newborn infants who have been deprived of oxygen before, during, or after delivery (perinatal asphyxia) are at high risk of dying or developing brain damage. Studies using animal models suggest that allopurinol (a drug commonly used for preventing gout) can reduce the level of brain damage following perinatal asphyxia. Three small randomised controlled trials that examined whether giving allopurinol to newborn infants following perinatal asphyxia affected their outcomes were identified. None of these trials provided any evidence of benefit. Larger trials are needed to exclude important effects on survival and disability.

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 (Gonzalez 2006; Vannucci 1997; 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 (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 (Beveridge 2006; Evans 2001;

Hunt 2002; Jacobs 2007; 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 (Jacobs 2007; Edwards 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 and its metabolic product, oxypurinol, reduce free radical formation and limit the degree of postasphyxia 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 (Johnson 1991; Sisto 1995). In newborn infants


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with severe respiratory failure needing treatment with extracorporeal membrane oxygenation, high-dose allopurinol reduces freeradical production and injury (Marro 1997). In infants with hypoplastic left heart syndrome who undergo cardiac surgery using deep hypothermic circulatory arrest, pretreatment with allopurinol reduces post-operative adverse cardiac and neurological outcomes (Clancy 2001). The most commonly reported adverse effects of allopurinol 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 hypoxicischaemic encephalopathy. The following subgroup analyses were planned: 1. Trials that assessed allopurinol as a sole therapy. 2. Trials of allopurinol as an adjunct to another therapy. 3. Trials where participants were predominantly (more than 80%) infants with moderate or severe encephalopathy (Sarnat 1976).

METHODS

Criteria for considering studies for this review

L), and/or clinical or electro-encephalographic (multi-channel or amplitude integrated) evidence of neonatal encephalopathy (MacLennan 1999).

Types of interventions Allopurinol vs. placebo or no drug administered within six hours of delivery. A minimum or maximum dose or duration of treatment was not pre-specified. Allopurinol could have been given in conjunction with another intervention provided both treatment and control groups received 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 in survivors (assessed aged greater than, or equal to, 12 months of age) defined as any one or combination of the following: non-ambulant cerebral palsy, severe developmental delay assessed using validated tools, auditory and visual impairment (each component analysed individually as well as part of the composite outcome). 3. 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 enteral tube feeding (days after birth), and/or incidence of continued enteral 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.

Types of studies Controlled trials using either random or quasi-random patient allocation.

Types of participants Term and near-term newborn infants [infants greater than 34 weeks’ gestation] 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/

Search methods for identification of studies The standard search strategy of the Cochrane Neonatal Review Group was used. This consisted of searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 4, 2007), MEDLINE (1966 - December 2007) and EMBASE (1980 - December 2007). The electronic search used 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 were limited with the relevant search filters for clinical


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trials. No language restriction was applied. References in previous reviews and studies were examined. Abstracts presented at the Society for Pediatric Research and European Society for Pediatric Research between 1990 and 2007 were searched. Trials reported only as abstracts were eligible if sufficient information was 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 were searched for completed or ongoing trials.

Data collection and analysis 1. The title and abstract of all studies identified by the above search strategy were screened and the full articles for all potentially relevant trials obtained. The full text of any potentially eligible reports was re-assessed and those studies that did not meet all of the inclusion criteria were excluded. Any disagreements were discussed until consensus was achieved. 2. The criteria and standard methods of the Cochrane Neonatal Review Group were used to independently assess the methodological quality of any included trials in terms of allocation concealment, blinding of parents or carers and assessors to intervention, and completeness of assessment in all randomised individuals. Additional information from the trial authors was requested to clarify methodology and results as necessary. 3. A data collection form was used to aid extraction of relevant information from each included study. Each review author extracted the data separately. Any disagreements were discussed until consensus was achieved. If data from the trial reports were insufficient, the investigators were contacted for further information. 4. Outcomes for categorical data are 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 was used. 5. The treatment effects of individual trials and heterogeneity between trial results was examined by inspecting the forest plots. The impact of heterogeneity in any meta-analysis was assessed using a measure of the degree of inconsistency in the studies’ results (I 2 statistic). If statistical heterogeneity was noted, the possible causes (for example, differences in study quality, participants, intervention regimens, or outcome assessments) were explored using posthoc subgroup analyses. A fixed effects model for meta-analyses was used.

RESULTS

Description of studies

See: Characteristics of included studies. Three trials, in which a total of 114 infants participated, fulfilled eligibility criteria (Benders 2006; Gunes 2007; van Bel 1998). These studies were conducted between 1995 and 2005 in neonatal intensive care centres in The Netherlands and Turkey. Participants: The participants were term or near-term infants with suspected perinatal asphyxia and hypoxic-ischaemic encephalopathy. In one trial, only infants with severe encephalopathy, defined either clinically or on the basis of abnormal findings on amplitudeintegrated electroencephalography, were eligible to participate (Benders 2006). In the other trials, infants with mild and moderately-severe encephalopathy were also enrolled. Infants with major congenital anomalies or infections were excluded. Interventions: In all of the studies, infants received the intervention or control within four hours after birth. Allopurinol was given intravenously in total daily doses of 40 mg/kg of birth weight. Benders 2006 and van Bel 1998 continued treatment for one day. Gunes 2007 continued treatment for three days after birth. Outcomes: The trials reported mainly short-term outcomes including mortality, seizure frequency, neuro-imaging findings, and biochemical measures of hepatic and renal function. One study assessed neurodevelopmental outcomes in surviving infants aged 18 months (Gunes 2007).

Risk of bias in included studies Although small, the trials were generally of good methodological quality with adequate allocation concealment (randomisation in central pharmacy, computer generated sequence in sealed opaque envelopes). Only one trial did not blind caregivers or assessors (van Bel 1998). All trials achieved complete or near-complete followup and reported intention-to-treat analyses.

Effects of interventions ALLOPURINOL versus CONTROL (COMPARISON 1) Primary outcomes: Death and neurodisability Death during the neonatal period and during infancy (Outcome 1.1: three trials). Meta-analysis did not detect a statistically significant effect: typical relative risk 0.92 (95% confidence interval 0.59 to 1.45); typical risk difference -0.03 (95% confidence interval -0.16 to 0.11). There was no evidence of statistical heterogeneity. Death or severe neurodevelopmental disability in survivors (Outcome 1.2 and Outcome 1.3: one trial). Only Gunes 2007 reported on this outcome and no statistically significant effect was


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found: relative risk 0.73 (95% confidence interval 0.41 to 1.30); risk difference -0.14 (95% confidence interval -0.40 to 0.12). There was not a statistically significant difference in the rate of severe quadriplegia in surviving infants: relative risk 0.55 (95% confidence interval 0.24 to 1.25); risk difference -0.20 (95% confidence interval -0.46 to 0.06). Numerical data for statistical analyses were not available for neurosensory impairments or developmental indices. Cognitive and educational outcomes: Not assessed in any of the trials. Secondary outcomes: Neonatal morbidity Seizures in the neonatal period (Outcome 1.4: three trials). Meta-analysis did not detect a statistically significant effect: typical relative risk 0.93 (95% confidence interval 0.75 to 1.16); typical risk difference -0.05 (95% confidence interval -0.21 to 0.11). There was no evidence of statistical heterogeneity. Time to achieve full oral feeding: Not reported by any of the trials. Abnormalities on brain imaging (Outcome 1.5: one trial). Only Benders 2006 reported this outcome. No statistically significant difference in the incidence of brain abnormalities assessed in the early neonatal period with ultrasound was found [relative risk 1.12 (95% confidence interval 0.81 to 1.55; risk difference 0.10 (95% confidence interval -0.17, to 0.36)]. Surviving infants in each group were assessed with magnetic resonance imaging of the brain. No statistically significant difference in the incidence of abnormalities detected was found [relative risk 1.88 (95% confidence interval 0.56 to 6.31); risk difference 0.35 (95% confidence interval -0.25 to 0.95)]. Potential adverse effects of allopurinol: Not assessed in any of the trials. Subgroup analyses: 1. Trials that assessed allopurinol as a sole therapy: All of the included trials assessed allopurinol as a sole therapy. 2. Trials of allopurinol as an adjunct to an another therapy: None of the included trials assessed allopurinol in combination with another therapy. 3. Trials where participants were predominantly infants with moderate or severe encephalopathy: In Gunes 2007 and van Bel 1998, 30 to 40% of participants had mild encephalopathy on trial entry. Benders 2006 restricted participation to infants with severe encephalopathy, defined by the detection of a burst suppression pattern, or worse, on amplitude-integrated electroencephalography. This trial (N = 32) did not detect any statistically significant differences in mortality, seizure frequency, or incidence of abnormality on neuro-imaging (see outcomes 01:01, 01:04, 01:05).

DISCUSSION There are limited data available from three small randomised controlled trials that assessed the effect of allopurinol in newborn infants with suspected hypoxic-ischaemic encephalopathy. These trials did not find any evidence of an effect on mortality, seizure frequency, or the incidence of abnormalities on brain imaging during the neonatal period. The single trial that assessed neurodevelopmental outcomes beyond infancy found no evidence of effect (Gunes 2007). However, given the small number of infants who have participated in trials to date (N=114), clinically important beneficial or harmful effects of allopurinol have not yet been excluded. Much larger trials (multicentre and multinational), similar to the efforts undertaken to assess the effect of therapeutic hypothermia for infants with hypoxic-ischaemic encephalopathy, would be needed to detect modest but clinically important effect sizes. There are several reasons for considering that such trials may be justified. Allopurinol is a simple, relatively inexpensive intervention. The biological plausibility for preventing hypoxic-ischaemic injury has been well-established in pre-clinical studies and experiments using animal models (Warner 2004). The available data have not raised major safety concerns related to use in newborn infants. Trials in which other patient groups have participated have found some evidence of benefit in limiting tissue reperfusion injuries (Johnson 1991; Marro 1997; Sisto 1995). In newborn infants undergoing surgical correction of hypoplastic left heart syndrome during a period of planned hypothermia and circulatory arrest, allopurinol pre-treatment reduced a composite outcome of death or adverse neurological or cardiac outcomes (Clancy 2001). Mild systemic or head hypothermia may reduce mortality and morbidity in newborn infants with hypoxic-ischaemic encephalopathy (Jacobs 2007). Therefore, allopurinol or any other therapies that aim to minimise delayed neuronal damage following perinatal asphyxia could be assessed as an adjunct to hypothermia in future trials (Perlman 2006). Hypothermia is thought to prevent neuronal death by reducing cellular metabolic rates and inhibiting multiple cytotoxic pathways including the generation of free radicals and the accumulation of hypoxanthine (Vannucci 1997). It is not known whether adjunctive specific inhibition of these pathways with allopurinol is of any additional or synergistic value. Furthermore, the effect of hypothermia on the pharmacokinetics of allopurinol and oxypurinol has not been explored (McGaurn 1994; van Kesteren 2006). Several other generic issues relating to trials of interventions for newborn infants with hypoxic-ischaemic encephalopathy have been highlighted (Perlman 2006): 1. Inclusion criteria should be simple and pragmatic to allow the trial conclusions to be more widely generalisable, particularly to rural and remote settings, and middle- and low-income countries where the burden of hypoxic-ischaemic encephalopathy is great-


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est. Infants with either moderate or severe neonatal encephalopathy should be eligible to participate since evidence exists that therapeutic hypothermia benefits infants in both of these prognostic categories (Jacobs 2007). 2. The “therapeutic window” for minimising post-asphyxial secondary neuronal death is less than about six hours after birth (Inder 2000). Approaching parents about their infant’s participation in a clinical trial is very difficult during this time. Informing parents antenatally about the possible need for emergency intervention around the time of birth may help to increase recruitment rates without compromising parental understanding of the nature and purpose of the research. 3. Trials should assess more than short-term and surrogate outcomes. Since interventions that reduce mortality in infants with hypoxic-ischaemic encephalopathy may result in higher rates of adverse neurological outcomes, long-term follow up should be planned to assess the effect on neurodevelopmental and cognitive outcomes (Gonzalez 2006). A priori agreements between research groups on the use of standard neurodevelopmental assessments (as well as trial entry criteria and intervention dose and duration) would ease incorporation of data from future trials into meta-analyses to improve precision of effect size estimates.

AUTHORS’ CONCLUSIONS Implications for practice The currently available data are insufficient to determine whether allopurinol is beneficial as an adjunctive treatment for newborn infants with suspected hypoxic-ischaemic encephalopathy. Modest but important effect sizes have not been excluded.

Implications for research Further large trials to determine the effect of allopurinol on mortality and morbidity in newborn infants with suspected hypoxicischaemic encephalopathy may be justified. Such trials could evaluate allopurinol as an adjunct to therapeutic hypothermia and should be designed to assess the effect on mortality and long-term neurodevelopmental outcomes in infants with moderate and severe hypoxic-ischaemic encephalopathy.

ACKNOWLEDGEMENTS We thank Dr Zsuzsoka Kesckes for commenting on the review protocol.

REFERENCES

References to studies included in this review Benders 2006 {published data only} Benders MJ, Bos AF, Rademaker CM, Rijken M, Torrance HL, Groenendaal F, et al.Early postnatal allopurinol does not improve short term outcome after severe birth asphyxia. Archives of Disease in Childhood Fetal & Neonatal Edition 2006;91:F163–5. Gunes 2007 {published data only} Gunes T, Ozturk MA, Koklu E, Kose K, Gunes I. Effect of allopurinol supplementation on nitric oxide levels in asphyxiated newborns. Pediatric Neurology 2007;36:17–24. van Bel 1998 {published data only} Van Bel F, Shadid M, Moison RM, Dorrepaal CA, Fontijn J, Monteiro L, et al.Effect of allopurinol on postasphyxial free radical formation, cerebral hemodynamics, and electrical brain activity. Pediatrics 1998;101:185–93.

Additional references Arellano 1993 Arellano F, Sacristán JA. Allopurinol hypersensitivity syndrome: a review. Annals of Pharmacotherapy 1993;27: 337–43. Beveridge 2006 Beveridge CJ, Wilkinson AR. Sodium bicarbonate infusion during resuscitation of infants at birth. Cochrane Database of Systematic Reviews 2006, Issue 1.

Clancy 2001 Clancy RR, McGaurn SA, Goin JE, Hirtz DG, Norwood WI, Gaynor JW, et al.Allopurinol neurocardiac protection trial in infants undergoing heart surgery using deep hypothermic circulatory arrest. Pediatrics 2001;108:61–70. Coghlan 1994 Coghlan JG, Flitter WD, Clutton SM, Panda R, Daly R, Wright G, et al.Allopurinol pretreatment improves postoperative recovery and reduces lipid peroxidation in patients undergoing coronary artery bypass grafting. Journal of Thoracic and Cardiovascular Surgery 1994;107:248–56. Edwards 2006 Edwards AD, Azzopardi DV. Therapeutic hypothermia following perinatal asphyxia. Archives of Disease in Childhood Fetal & Neonatal Edition 2006;91:F127–31. Evans 2001 Evans DJ, Levene MI. Anticonvulsants for preventing mortality and morbidity in full term newborns with perinatal asphyxia. Cochrane Database of Systematic Reviews 2001, Issue 2. Gonzalez 2006 Gonzalez FF, Miller SP. Does perinatal asphyxia impair cognitive function without cerebral palsy?. Archives of Disease in Childhood Fetal & Neonatal Edition 2006;91: F454–9.


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Hunt 2002 Hunt R, Osborn D. Dopamine for prevention of morbidity and mortality in term newborn infants with suspected perinatal asphyxia. Cochrane Database of Systematic Reviews 2002, Issue 3. Inder 2000 Inder TE, Volpe JJ. Mechanisms of perinatal brain injury. Seminars in Neonatology 2000;5:3–16. Jacobs 2007 Jacobs S, Hunt R, Tarnow-Mordi W, Inder T, Davis P. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database of Systematic Reviews 2007, Issue 4. Johnson 1991 Johnson WD, Kayser KL, Brenowitz JB, Saedi SF. A randomized controlled trial of allopurinol in coronary bypass surgery. American Heart Journal 1991;121:20–4. Kecskes 2005 Kecskes Z, Healy G, Jensen A. Fluid restriction for term infants with hypoxic-ischaemic encephalopathy following perinatal asphyxia. Cochrane Database of Systematic Reviews 2005, Issue 3. Kumar 1996 Kumar A, Edward N, White MI, Johnston PW, Catto GR. Allopurinol, erythema multiforme, and renal insufficiency. BMJ 1996;312:173–4. MacLennan 1999 MacLennan A. A template for defining a causal relation between acute intrapartum events and cerebral palsy: international consensus statement. BMJ 1999;319:1054–9. Marro 1997 Marro PJ, Baumgart S, Delivoria-Papadopoulos M, Zirin S, Corcoran L, McGaurn SP, et al.Purine metabolism and inhibition of xanthine oxidase in severely hypoxic neonates going onto extracorporeal membrane oxygenation. Pediatric Research 1997;41:513–20. McGaurn 1994 McGaurn SP, Davis LE, Krawczeniuk MM, Murphy JD, Jacobs ML, Norwood WI, et al.The pharmacokinetics of injectable allopurinol in newborns with the hypoplastic left heart syndrome. Pediatrics 1994;94:820–3. McGuire 2004 McGuire W, Fowlie PW, Evans DJ. Naloxone for preventing morbidity and mortality in newborn infants of greater than 34 weeks’ gestation with suspected perinatal asphyxia. Cochrane Database of Systematic Reviews 2004, Issue 1. Pacher 2006 Pacher P, Nivorozhkin A, Szabo C. Therapeutic effects of xanthine oxidase inhibitors: renaissance half a century after the discovery of allopurinol. Pharmacological Reviews 2006; 58:87–114. Palmer 1990 Palmer C, Vannucci RC, Towfighi J. Reduction of perinatal hypoxic-ischemic brain damage with allopurinol. Pediatric Research 1990;27:332–6.

Palmer 1991 Palmer C, Smith MB, Williams GD. Allopurinol preserves cerebral energy metabolism during perinatal hypoxicischemic injury and reduces brain damage in a dose dependent manner. Journal of Cerebral Blood Flow and Metabolism 1991;11:S144–S149. Palmer 1993 Palmer C, Towfighi J, Roberts RL, Heitjan DF. Allopurinol administered after inducing hypoxia-ischemia reduces brain injury in 7-day-old rats. Pediatric Research 1993;33:405–11. Perlman 2006 Perlman JM. Intervention strategies for neonatal hypoxicischemic cerebral injury. Clinical Therapeutics 2006;28: 1353–65. Roth 1997 Roth SC, Baudin J, Cady E, Johal K, Townsend JP, Wyatt JS, et al.Relation of deranged neonatal cerebral oxidative metabolism with neurodevelopmental outcome and head circumference at 4 years. Developmental Medicine and Child Neurology 1997;39:718–25. Sarnat 1976 Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress. Archives of Disease in Childhood 1976;33: 696–705. Sisto 1995 Sisto T, Paajanen H, Metsa-Ketela T, Harmoinen A, Nordback I, Tarkka M. Pretreatment with antioxidants and allopurinol diminishes cardiac onset events in coronary artery bypass grafting. Annals of Thoracic Surgery 1995;59: 1519–23. Van Bel 1998 Van Bel F, Shadid M, Moison RM, Dorrepaal CA, Fontijn J, Monteiro L, et al.Effect of allopurinol on postasphyxial free radical formation, cerebral hemodynamics, and electrical brain activity. Pediatrics 1998;101:185–93. van Kesteren 2006 van Kesteren C, Benders MJ, Groenendaal F, van Bel F, Ververs FF, Rademaker CM. Population pharmacokinetics of allopurinol in full-term neonates with perinatal asphyxia. Therapeutic Drug Monitor 2006;28:339–44. Vannucci 1997 Vannucci RC, Perlman JM. Current and potentially new management strategies for perinatal hypoxic-ischemic encephalopathy. Pediatrics 1997;100:1004–14. Vazquez-Mellado 2001 Vazquez-Mellado J, Morales EM, Pacheco-Tena C, BurgosVargas R. Relation between adverse events associated with allopurinol and renal function in patients with gout. Annals of the Rheumatic Diseases 2001;60:981–3. Warner 2004 Warner DS, Sheng H, Batinic-Haberle I. Oxidants, antioxidants and the ischemic brain. Journal of Experimental Biology 2004;207:3221–312. ∗ Indicates the major publication for the study


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CHARACTERISTICS OF STUDIES

Characteristics of included studies [ordered by study ID] Benders 2006 Methods

Blinding of randomisation: yes. Blinding of intervention: yes. Complete follow-up: yes. Blinding of outcome measurement: yes.

Participants

Term newborn infants with evidence of perinatal asphyxia and severe neonatal encephalopathy (burst suppression pattern, or worse, on amplitude-integrated electroencephalogram)

Interventions

Allopurinol (40 mg/kg intravenously) in two doses, within 4 hours after birth and 12 hours later (N=17) versus placebo control (N=15)

Outcomes

Mortality, changes in amplitude-integrated electroencephalogram, abnormalities on brain ultrasound, and magnetic resonance imaging abnormal findings in surviving infants at discharge

Notes

The trial was stopped earlier than planned when an interim analysis had not detected any statistically significant effects

Risk of bias Item

Authors’ judgement

Description

Allocation concealment?

Yes

A - Adequate

Gunes 2007 Methods

Blinding of randomisation: yes. Blinding of intervention: yes. Complete follow-up: yes. Blinding of outcome measurement: yes.

Participants

Term newborn infants with evidence of perinatal asphyxia and mild to severe neonatal encephalopathy. Infants with suspected or confirmed congenital sepsis were excluded

Interventions

Allopurinol (40 mg/kg/day intravenously) in two doses, within 2 hours after birth and 12 hours later, then 12 hourly for a total of 3 days (N=30) versus normal saline placebo (N=30)

Outcomes

Mortality, neurodevelopment (assessed at aged greater than 12 months), frequency of neonatal seizures, duration of hospitalisation

Notes

2 infants in each group were lost to long-term follow up. All had mild neonatal encephalopathy

Risk of bias Allopurinol for preventing mortality and morbidity in newborn infants with suspected hypoxic-ischaemic encephalopathy (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

8

Gunes 2007

(Continued)

Item


Description


Yes

A - Adequate

van Bel 1998 Methods

Blinding of randomisation: yes. Blinding of intervention: no. Complete follow-up: yes. Blinding of outcome measurement: no.

Participants

Newborn infants (more than 34 completed weeks’ gestational age) with evidence of perinatal asphyxia and mild, moderate or severe neonatal encephalopathy within 2 hours after birth

Interventions

Allopurinol (40 mg/kg intravenously) in two doses, within 4 hours after birth and 12 hours later (N=11) versus control (N=11)

Outcomes

Mortality, incidence of seizures treated with anticonvulsants, biochemical assessments or renal and hepatic function

Notes Risk of bias Item


Description


Yes

A - Adequate


9

DATA AND ANALYSES

Comparison 1. Allopurinol versus control (placebo or no drug)

Outcome or subgroup title 1 Death during the neonatal period and infancy 2 Death or severe neurodevelopmental disability. 3 Severe quadriplegia in surviving infants 4 Seizures during the neonatal period 5 Abnormalities on brain imaging 5.1 Cranial ultrasound 5.2 Magnetic resonance imaging (surviving infants)

No. of studies

No. of participants

3

114

Risk Ratio (M-H, Fixed, 95% CI)

0.92 [0.59, 1.45]

1

56


0.73 [0.41, 1.30]

1

50


0.55 [0.24, 1.25]

3

114


0.93 [0.75, 1.16]

1 1 1

31 9

Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI) Risk Ratio (M-H, Fixed, 95% CI)

Subtotals only 1.12 [0.81, 1.55] 1.88 [0.56, 6.31]

Statistical method

Effect size

Analysis 1.1. Comparison 1 Allopurinol versus control (placebo or no drug), Outcome 1 Death during the neonatal period and infancy. Review:

Allopurinol for preventing mortality and morbidity in newborn infants with suspected hypoxic-ischaemic encephalopathy

Comparison: 1 Allopurinol versus control (placebo or no drug) Outcome: 1 Death during the neonatal period and infancy

Study or subgroup

Allopurinol

Control

n/N

n/N

13/17

10/15

57.0 %

1.15 [ 0.74, 1.79 ]

Gunes 2007

3/30

3/30

16.1 %

1.00 [ 0.22, 4.56 ]

van Bel 1998

2/11

5/11

26.8 %

0.40 [ 0.10, 1.64 ]

Total (95% CI)

58

56

100.0 %

0.92 [ 0.59, 1.45 ]

Benders 2006

Risk Ratio

Weight

M-H,Fixed,95% CI

Risk Ratio M-H,Fixed,95% CI

Total events: 18 (Allopurinol), 18 (Control) Heterogeneity: Chi2 = 2.28, df = 2 (P = 0.32); I2 =12% Test for overall effect: Z = 0.35 (P = 0.73)

0.1 0.2

0.5

Favours allopurinol

1

2

5

10

Favours control


10

Analysis 1.2. Comparison 1 Allopurinol versus control (placebo or no drug), Outcome 2 Death or severe neurodevelopmental disability.. Review:


Comparison: 1 Allopurinol versus control (placebo or no drug) Outcome: 2 Death or severe neurodevelopmental disability.

Study or subgroup

Gunes 2007

Total (95% CI)

Allopurinol

Control

n/N

n/N

Risk Ratio

Weight

11/28

15/28

100.0 %

0.73 [ 0.41, 1.30 ]

28

28

100.0 %

0.73 [ 0.41, 1.30 ]

M-H,Fixed,95% CI


Total events: 11 (Allopurinol), 15 (Control) Heterogeneity: not applicable Test for overall effect: Z = 1.06 (P = 0.29)

0.1 0.2

0.5

1

Favours allopurinol

2

5

10

Favours control

Analysis 1.3. Comparison 1 Allopurinol versus control (placebo or no drug), Outcome 3 Severe quadriplegia in surviving infants. Review:


Comparison: 1 Allopurinol versus control (placebo or no drug) Outcome: 3 Severe quadriplegia in surviving infants

Study or subgroup

Gunes 2007

Total (95% CI)

Allopurinol

Control

n/N

n/N

Risk Ratio

Weight

6/25

11/25

100.0 %

0.55 [ 0.24, 1.25 ]

25

25

100.0 %

0.55 [ 0.24, 1.25 ]

M-H,Fixed,95% CI


Total events: 6 (Allopurinol), 11 (Control) Heterogeneity: not applicable Test for overall effect: Z = 1.44 (P = 0.15)

0.001 0.01 0.1 Favours allopurinol

1

10 100 1000 Favours control


11

Analysis 1.4. Comparison 1 Allopurinol versus control (placebo or no drug), Outcome 4 Seizures during the neonatal period. Review:


Comparison: 1 Allopurinol versus control (placebo or no drug) Outcome: 4 Seizures during the neonatal period

Study or subgroup

Allopurinol

Control

n/N

n/N

Risk Ratio

Weight

Benders 2006

16/17

14/15

35.5 %

1.01 [ 0.84, 1.21 ]

Gunes 2007

19/30

20/30

47.8 %

0.95 [ 0.66, 1.38 ]

van Bel 1998

5/11

7/11

16.7 %

0.71 [ 0.33, 1.57 ]

Total (95% CI)

58

56

100.0 %

0.93 [ 0.75, 1.16 ]

M-H,Fixed,95% CI


Total events: 40 (Allopurinol), 41 (Control) Heterogeneity: Chi2 = 1.20, df = 2 (P = 0.55); I2 =0.0% Test for overall effect: Z = 0.62 (P = 0.53)

0.1 0.2

0.5

Favours allopurinol

1

2

5

10

Favours control


12

Analysis 1.5. Comparison 1 Allopurinol versus control (placebo or no drug), Outcome 5 Abnormalities on brain imaging. Review:


Comparison: 1 Allopurinol versus control (placebo or no drug) Outcome: 5 Abnormalities on brain imaging

Study or subgroup

Allopurinol

Control

n/N

n/N

Risk Ratio

Weight

15/17

11/14

100.0 %

1.12 [ 0.81, 1.55 ]

17

14

100.0 %

1.12 [ 0.81, 1.55 ]

3/4

2/5

100.0 %

1.88 [ 0.56, 6.31 ]

4

5

100.0 %

1.88 [ 0.56, 6.31 ]

M-H,Fixed,95% CI


1 Cranial ultrasound Benders 2006

Subtotal (95% CI) Total events: 15 (Allopurinol), 11 (Control) Heterogeneity: not applicable Test for overall effect: Z = 0.70 (P = 0.48)

2 Magnetic resonance imaging (surviving infants) Benders 2006

Subtotal (95% CI) Total events: 3 (Allopurinol), 2 (Control) Heterogeneity: not applicable Test for overall effect: Z = 1.02 (P = 0.31)

0.001 0.01 0.1 Favours allopurinol

1

10 100 1000 Favours control

WHAT’S NEW Last assessed as up-to-date: 3 December 2007.

Date

Event

Description

5 October 2010

Amended

Contact details updated.


13

HISTORY Protocol first published: Issue 4, 2007 Review first published: Issue 2, 2008

Date

Event

Description

13 December 2007

Amended

Converted to new review format.

CONTRIBUTIONS OF AUTHORS Tejesvi Chaudhari and William McGuire developed the protocol, performed undertook the electronic and hand searches, screened the title and abstract of all studies identified, and the full text of potentially relevant reports. Each author independently assessed the methodological quality of the included trials, extracted the relevant information and data, and completed the final review.

DECLARATIONS OF INTEREST None.

SOURCES OF SUPPORT Internal sources • ANU Medical School, Canberra, Australia.

External sources • No sources of support supplied

DIFFERENCES BETWEEN PROTOCOL AND REVIEW None

INDEX TERMS


14

Medical Subject Headings (MeSH) Allopurinol [adverse effects; ∗ therapeutic use]; Free Radical Scavengers [adverse effects; ∗ therapeutic use]; Hypoxia-Ischemia, Brain [complications; ∗ drug therapy; mortality]; Infant, Newborn; Randomized Controlled Trials as Topic

MeSH check words Humans


15