Cooling for newborns with hypoxic ischaemic encephalopathy

 

Abstract

Background

Newborn animal studies and pilot studies in humans suggest that mild hypothermia following peripartum hypoxia-ischaemia in newborn infants may reduce neurological sequelae without adverse effects.

Objectives

To determine the effect of therapeutic hypothermia in encephalopathic asphyxiated newborn infants on mortality, long-term neurodevelopmental disability and clinically important side effects.

Search methods

The standard search strategy of the Neonatal Review Group as outlined in The Cochrane Library (Issue 2, 2007) was used. Randomised controlled trials evaluating therapeutic hypothermia in term newborns with hypoxic ischaemic encephalopathy were identified by searching the Oxford Database of Perinatal Trials, the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2007), MEDLINE (1966 to June 2007), previous reviews including cross-references, abstracts, conferences, symposia proceedings, expert informants and journal hand searching.

Selection criteria

Randomised controlled trials comparing the use of therapeutic hypothermia with standard care in encephalopathic newborn infants with evidence of peripartum asphyxia and without recognisable major congenital anomalies were included. The primary outcome measure was death or long-term major neurodevelopmental disability. Other outcomes included adverse effects of cooling and 'early' indicators of neurodevelopmental outcome.

Data collection and analysis

Three review authors independently selected, assessed the quality of and extracted data from the included studies. Authors were contacted for further information. Meta-analyses were performed using relative risk and risk difference for dichotomous data, and weighted mean difference for continuous data with 95% confidence intervals.

Main results

Eight randomised controlled trials were included in this review, comprising 638 term infants with moderate/ severe encephalopathy and evidence of intrapartum asphyxia. Therapeutic hypothermia resulted in a statistically significant and clinically important reduction in the combined outcome of mortality or major neurodevelopmental disability to 18 months of age [typical RR 0.76 (95% CI 0.65, 0.89), typical RD -0.15 (95% CI -0.24, -0.07), NNT 7 (95% CI 4, 14)]. Cooling also resulted in statistically significant reductions in mortality [typical RR 0.74 (95% CI 0.58, 0.94), typical RD -0.09 (95% CI -0.16, -0.02), NNT 11 (95% CI 6, 50)] and in neurodevelopmental disability in survivors [typical RR 0.68 (95% CI 0.51, 0.92), typical RD -0.13 (95% CI -0.23, -0.03)]. Some adverse effects of hypothermia included an increase in the need for inotrope support of borderline significance and a significant increase in thrombocytopaenia.

Authors' conclusions

There is evidence from the eight randomised controlled trials included in this systematic review (n = 638) that therapeutic hypothermia is beneficial to term newborns with hypoxic ischaemic encephalopathy. Cooling reduces mortality without increasing major disability in survivors. The benefits of cooling on survival and neurodevelopment outweigh the short-term adverse effects. However, this review comprises an analysis based on less than half of all infants currently known to be randomised into eligible trials of cooling. Incorporation of data from ongoing and completed randomised trials (n = 829) will be important to clarify the effectiveness of cooling and to provide more information on the safety of therapeutic hypothermia, but could also alter these conclusions. Further trials to determine the appropriate method of providing therapeutic hypothermia, including comparison of whole body with selective head cooling with mild systemic hypothermia, are required.

 

Plain language summary

Cooling for newborns with hypoxic ischaemic encephalopathy

There is evidence that induced hypothermia (cooling) of newborn babies who may have suffered from a lack of oxygen at birth reduces death or disability, without increasing disability in survivors. This means that parents should expect that cooling will decrease their baby's chance of dying, and that if their baby survives, cooling will decrease his/her chance of major disability. A lack of oxygen before and during birth can destroy cells in a newborn baby's brain. The damage caused by the lack of oxygen continues for some time afterwards. One way to try and stop this damage is to induce hypothermia - cooling the baby or just the baby's head for hours to days. This treatment may reduce the amount of damage to brain cells. This review found that there is evidence from trials to show that induced hypothermia helps to improve survival and development at 18 months for term newborn babies at risk of brain damage. The results of ongoing trials may or may not confirm these favourable results. More research is also needed on the different methods of cooling.

 

摘要

背景

缺血缺氧性腦病新生兒的降溫療法

新生兒動物的研究以及小規模對人的研究提示，新生兒周產期缺氧缺血隨後的輕度體溫過低可減少神經學後遺症而無不良影響。

目標

為確定治療性降低體溫對窒息性腦病變新生兒的死亡率、長期神經發育殘障和臨床重要副作用的影響。

搜尋策略

應用在Cochrane圖書館(2007年第2期)中所敘述的新生兒評價組的標準檢索法。利用搜尋牛津周產期試驗數據庫、Cochrane對照試驗中心註冊資料庫(CENTRAL，Cochrane圖書館，2007年第2期)、MEDLINE(1966年至2007年6月)、含參考文獻的回顧綜述、摘要、學術會議、討論會論文集、專家信息以及雜誌手工檢索，來確定評估低溫療法治療足月新生兒缺血缺氧性腦病變的結果。

選擇標準

納入對腦病變新生兒(這些新生兒有周產期窒息的證據但無可以識別的先天異常)應用治療性降低體溫與標準治療進行比較的隨機對照試驗。主要結論指標是死亡或長期重要神經發育殘障。其它結論包括降溫的不良影響以及影響神經發育結果的“早期”指標。

資料收集與分析

三位檢閱人員獨立選擇、評估納入研究的品質和提取數據。與研究作者聯繫以獲得進一步的信息。二分類數據應用相對危險度和風險差、連續數據用加權均數差，以及95％可信區間進行統合分析。

主要結論

本評價納入八項隨機對照試驗，含638名中度/重度腦病變且有分娩時窒息證據的足月嬰兒。治療性降低體溫使18月齡時死亡率或併有重要神經發育殘疾的結果有統計學意義和臨床重要性的減少[典型RR 0.76 (95% CI 0.65, 0.89)，典型RD −0.15 (95% CI −0.24，−0.07)，NNT 7 (95% CI 4，14)]。降溫還使存活者的死亡率[典型RR 0.74 (95% CI 0.58，0.94)，典型RD −0.09 (95% CI −0.16，−0.02)，NNT 11 (95% CI 6，50)]和神經發育殘疾[典型RR 0.68 (95% CI 0.51，0.92)，典型RD −0.13 (95% CI −0.23，−0.03)，NNT 8 (95% CI 4，33)]有統計學意義的減少。降低體溫的不良影響包括，強心類藥物(inotrope)支持的需要有臨界意義增加以及血小板減少症顯著增加。

作者結論

納入系統評價的八項隨機對照試驗(n = 638)的證據表明，治療性降溫對缺血缺氧性腦病變的足月新生兒是有利的。降溫減少了死亡率而不增加存活者的重要殘疾。降溫對存活和神經發育的好處超過短期的不良影響。然而，本評價所包含的分析是基於目前已知隨機分到合格降溫試驗全部嬰兒的一半不到。將正在進行和已完成隨機試驗的數據(n = 829)結合進來，對於闡明降溫的效果和提供治療性降低體溫的安全性是重要的，但也可能改變以上結論。需要通過進一步的試驗，確定提供治療性降低體溫的合適方法，包括對全身與選擇性頭部降溫結合輕微全身降溫的比較。

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

有證據表明，誘導出生時缺乏氧氣的新生嬰兒低溫(降溫)可減少死亡或傷殘，而不會增加有殘疾的倖存者。這意味著，家長會期望降溫會減少他們的嬰兒死亡機會，而如果他們的嬰兒能存活，降溫將減少他/她的發生殘疾的機會。出生之前和生產期間缺乏氧氣可以破壞新生嬰兒的大腦細胞。這種缺氧造成的損害會繼續之後一段時間。其中一個試圖制止這種損害的方法是誘發低溫，把嬰兒或僅是嬰兒的頭降溫幾個小時到幾天。這種治療可減少腦細胞損害的量。這次回顧發現，有證據表明，誘發低溫有助於改善有腦損傷風險的新生兒存活率和18個月內發展狀況。正在進行試驗的結果可能會或可能不會確認這些有利的結果。還需要更多的研究，針對不同的降溫方法做進一步探討分析。