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

  • Review
  • Intervention

Authors


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.

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 hypoxic-ischaemic 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.

摘要

背景

Allopurinol預防疑似缺氧缺血性腦病變新生兒的死亡率和罹病率

出生前後發生缺氧造成的延遲性神經元死亡部分是由於黃嘌呤氧化脢產生的細胞毒性自由基引起。allopurinol為黃嘌呤氧化脢的抑制劑。有證據顯示,該藥對於動物出生前後缺氧模組和人類其他器官血液再灌注損傷上,可以減少延遲性細胞死亡。

目標

確定allopurinol對疑似缺氧缺血性腦病變的新生兒在死亡率和罹病率的影響。

搜尋策略

我們使用了Cochrane Neonatal Review Group 的標準蒐尋策略:包含the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 4, 2007), MEDLINE (1966 – December 2007), EMBASE (1980 – December 2007), 會議記錄和既往文獻回顧。

選擇標準

隨機或類隨機對照試驗比較疑似缺氧缺血性腦病變的新生兒接受allopurinol和安慰劑或不給藥的差別。

資料收集與分析

我們使用Cochrane Neonatal Review Group的標準方式,由兩個作者獨立評估試驗的品質和擷取數據。數據用固定效應模型(fixed effects model)運算,報告以典型相對風險、典型風險差和加權平均差呈現。

主要結論

收納3個試驗,共114名嬰兒。其中一個試驗,收入個案排除了嚴重腦病變者,其他兩個則包含由輕與中重度腦病變。這些試驗整體雖有好的方法學,但強度(power)不足以測定allopurinol對死亡率和發病率的臨床重要性。統合分析在嬰兒期死亡風險(0.92, 95%信賴區間0.59至1.45)、典型風險差( 0.03, 95%信賴區間 −0.16至0.11)或新生兒癲癇發作的發生率沒有顯著的差異(典型相對風險0.93,95%信賴區間0.75至1.16); 典型風險差  0.05,95%信賴區間 0.21至 0.11)。只有一個試驗評估存活腦病變兒童的神經發育,也沒有統計學意義效果。

作者結論

現有的數據不足以確定allopurinol對缺氧缺血性腦病的新生兒是否有臨床重要的好處,因此,較大的試驗是必要的。這些較大的試驗要能評估allopurinol作為中度和重度腦病變嬰幼兒低溫治療時的輔助治療,並且設計還要能排除對死亡率和神經長期發展不良結果的臨床重要影響。

翻譯人

本摘要由臺中榮民總醫院薛榮華翻譯。

此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。

總結

Allopurinol預防疑似缺氧缺血性腦病變新生兒的死亡率和發病率:沒有足夠的證據顯示,給予疑似缺氧缺血性腦病變新生兒allopurinol是有益的。出生前後發生缺氧的嬰兒是死亡或形成腦損傷的高危險群。動物模型研究顯示,用於防止痛風的allopurinol可以減少出生前後缺氧造成的腦損傷程度。這三個小型的隨機對照試驗檢視出生前後缺氧新生兒給予allopurinol的效果,但結果顯示沒有好處。目前尚需更大型的試驗來排除給予此藥物會對病嬰的生存和失能有重大影響。

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.

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