Hypothermia for moderate or severe neonatal encephalopathy in low-income and middle-income countries (HELIX): a randomised controlled trial in India, Sri Lanka, and Bangladesh,The Lancet Global Health

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Hypothermia for moderate or severe neonatal encephalopathy in low-income and middle-income countries (HELIX): a randomised controlled trial in India, Sri Lanka, and Bangladesh
The Lancet Global Health ( IF 19.9 ) Pub Date : 2021-08-03 , DOI: 10.1016/s2214-109x(21)00264-3
Sudhin Thayyil ₁ , Stuti Pant ₁ , Paolo Montaldo ₁ , Deepika Shukla ₁ , Vania Oliveira ₁ , Phoebe Ivain ₁ , Paul Bassett ₂ , Ravi Swamy ₃ , Josephine Mendoza ₁ , Maria Moreno-Morales ₁ , Peter J Lally ₁ , Naveen Benakappa ₄ , Prathik Bandiya ₄ , Indramma Shivarudhrappa ₅ , Jagadish Somanna ₄ , Usha B Kantharajanna ₄ , Ankur Rajvanshi ₄ , Sowmya Krishnappa ₄ , Poovathumkal K Joby ₃ , Kumutha Jayaraman ₆ , Rema Chandramohan ₆ , Chinnathambi N Kamalarathnam ₆ , Monica Sebastian ₇ , Indumathi A Tamilselvam ₆ , Usha D Rajendran ₆ , Radhakrishnan Soundrarajan ₆ , Vignesh Kumar ₆ , Harish Sudarsanan ₆ , Padmesh Vadakepat ₈ , Kavitha Gopalan ₆ , Mangalabharathi Sundaram ₉ , Arasar Seeralar ₉ , Prakash Vinayagam ₉ , Mohamed Sajjid ₉ , Mythili Baburaj ₁₀ , Kanchana D Murugan ₉ , Babu P Sathyanathan ₁₁ , Elumalai S Kumaran ₁₁ , Jayashree Mondkar ₁₂ , Swati Manerkar ₁₂ , Anagha R Joshi ₁₂ , Kapil Dewang ₁₂ , Swapnil M Bhisikar ₁₂ , Pavan Kalamdani ₁₂ , Vrushali Bichkar ₁₂ , Saikat Patra ₁₂ , Kapil Jiwnani ₁₂ , Mohammod Shahidullah ₁₃ , Sadeka C Moni ₁₃ , Ismat Jahan ₁₃ , Mohammad A Mannan ₁₃ , Sanjoy K Dey ₁₃ , Mst N Nahar ₁₄ , Mohammad N Islam ₁₄ , Kamrul H Shabuj ₁₃ , Ranmali Rodrigo ₁₅ , Samanmali Sumanasena ₁₅ , Thilini Abayabandara-Herath ₁₅ , Gayani K Chathurangika ₁₅ , Jithangi Wanigasinghe ₁₆ , Radhika Sujatha ₁₇ , Sobhakumar Saraswathy ₁₇ , Aswathy Rahul ₁₇ , Saritha J Radha ₁₇ , Manoj K Sarojam ₁₇ , Vaisakh Krishnan ₁₈ , Mohandas K Nair ₁₈ , Sahana Devadas ₁₉ , Savitha Chandriah ₁₉ , Harini Venkateswaran ₃ , Constance Burgod ₁ , Manigandan Chandrasekaran ₃ , Gaurav Atreja ₁ , Pallavi Muraleedharan ₃ , Jethro A Herberg ₂₀ , W K Kling Chong ₂₁ , Neil J Sebire ₂₂ , Ronit Pressler ₂₃ , Siddarth Ramji ₂₄ , Seetha Shankaran ₂₅ ,

Affiliation

Centre for Perinatal Neuroscience, Imperial College London, London, UK.
Statsconsultancy, Amersham, London, UK.
Perinatal Epidemiology Unit, Bengaluru, Karnataka, India.
Indira Gandhi Institute of Child Health, Bengaluru, Karnataka, India.
Perinatal Epidemiology Unit, Bengaluru, Karnataka, India; Indira Gandhi Institute of Child Health, Bengaluru, Karnataka, India; Institute of Obstetrics and Gynaecology and Government Hospital for Women and Children, Madras Medical College, Chennai, India.
Institute of Child Health, Madras Medical College, Chennai, India.
Perinatal Epidemiology Unit, Bengaluru, Karnataka, India; Institute of Child Health, Madras Medical College, Chennai, India.
Institute of Child Health, Madras Medical College, Chennai, India; Institute of Obstetrics and Gynaecology and Government Hospital for Women and Children, Madras Medical College, Chennai, India.
Institute of Obstetrics and Gynaecology and Government Hospital for Women and Children, Madras Medical College, Chennai, India.
Perinatal Epidemiology Unit, Bengaluru, Karnataka, India; Institute of Obstetrics and Gynaecology and Government Hospital for Women and Children, Madras Medical College, Chennai, India.
Barnard Institute of Radiology, Madras Medical College, Chennai, India.
Lokmanya Tilak Municipal Medical College, Mumbai, Maharashtra, India.
Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh.
National Institute of Neurosciences, Dhaka, Bangladesh.
University of Kelaniya, Colombo, Sri Lanka.
University of Colombo, Colombo, Sri Lanka.
Sree Avittom Thirunal Hospital and Government Medical College, Thiruvananthapuram, Kerala, India.
Institute of Maternal and Child Health, Government Medical College, Kozhikode, Kerala, India.
Vanivilas Hospital, Bangalore Medical College and Research Institute, Karnataka, India.
Section of Paediatric Infectious Disease, Imperial College London, London, UK.
Centre for Perinatal Neuroscience, Imperial College London, London, UK; Department of Neuroradiology, Great Ormond Street Hospital, London, UK.
Perinatal Pathology, National Institute for Health Research Biomedical Research Centre, Great Ormond Street Hospital for Children, University College London, London, UK.
Department of Neurophysiology, Great Ormond Street Hospital, London, UK.
Maulana Azad Medical College, New Delhi, India.
Neonatal-Perinatal Medicine, Wayne State University, Detroit, MI, USA.

Background

Although therapeutic hypothermia reduces death or disability after neonatal encephalopathy in high-income countries, its safety and efficacy in low-income and middle-income countries is unclear. We aimed to examine whether therapeutic hypothermia alongside optimal supportive intensive care reduces death or moderate or severe disability after neonatal encephalopathy in south Asia.

Methods

We did a multicountry open-label, randomised controlled trial in seven tertiary neonatal intensive care units in India, Sri Lanka, and Bangladesh. We enrolled infants born at or after 36 weeks of gestation with moderate or severe neonatal encephalopathy and a need for continued resuscitation at 5 min of age or an Apgar score of less than 6 at 5 min of age (for babies born in a hospital), or both, or an absence of crying by 5 min of age (for babies born at home). Using a web-based randomisation system, we allocated infants into a group receiving whole body hypothermia (33·5°C) for 72 h using a servo-controlled cooling device, or to usual care (control group), within 6 h of birth. All recruiting sites had facilities for invasive ventilation, cardiovascular support, and access to 3 Tesla MRI scanners and spectroscopy. Masking of the intervention was not possible, but those involved in the magnetic resonance biomarker analysis and neurodevelopmental outcome assessments were masked to the allocation. The primary outcome was a combined endpoint of death or moderate or severe disability at 18–22 months, assessed by the Bayley Scales of Infant and Toddler Development (third edition) and a detailed neurological examination. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, NCT02387385.

Findings

We screened 2296 infants between Aug 15, 2015, and Feb 15, 2019, of whom 576 infants were eligible for inclusion. After exclusions, we recruited 408 eligible infants and we assigned 202 to the hypothermia group and 206 to the control group. Primary outcome data were available for 195 (97%) of the 202 infants in the hypothermia group and 199 (97%) of the 206 control group infants. 98 (50%) infants in the hypothermia group and 94 (47%) infants in the control group died or had a moderate or severe disability (risk ratio 1·06; 95% CI 0·87–1·30; p=0·55). 84 infants (42%) in the hypothermia group and 63 (31%; p=0·022) infants in the control group died, of whom 72 (36%) and 49 (24%; p=0·0087) died during neonatal hospitalisation. Five serious adverse events were reported: three in the hypothermia group (one hospital readmission relating to pneumonia, one septic arthritis, and one suspected venous thrombosis), and two in the control group (one related to desaturations during MRI and other because of endotracheal tube displacement during transport for MRI). No adverse events were considered causally related to the study intervention.

Interpretation

Therapeutic hypothermia did not reduce the combined outcome of death or disability at 18 months after neonatal encephalopathy in low-income and middle-income countries, but significantly increased death alone. Therapeutic hypothermia should not be offered as treatment for neonatal encephalopathy in low-income and middle-income countries, even when tertiary neonatal intensive care facilities are available.

Funding

National Institute for Health Research, Garfield Weston Foundation, and Bill & Melinda Gates Foundation.

Translations

For the Hindi, Malayalam, Telugu, Kannada, Singhalese, Tamil, Marathi and Bangla translations of the abstract see Supplementary Materials section.

中文翻译：

低收入和中等收入国家中度或重度新生儿脑病的低温治疗 (HELIX)：印度、斯里兰卡和孟加拉国的一项随机对照试验

背景

尽管低温治疗可减少高收入国家新生儿脑病后的死亡或残疾，但其在低收入和中等收入国家的安全性和有效性尚不清楚。我们的目的是研究低温治疗与最佳支持性重症监护是否可以减少南亚新生儿脑病后的死亡或中度或重度残疾。

方法

我们在印度、斯里兰卡和孟加拉国的七个三级新生儿重症监护病房进行了一项多国开放标签、随机对照试验。我们纳入了妊娠 36 周或之后出生的患有中度或重度新生儿脑病且需要在 5 分钟时继续复苏或在 5 分钟时阿普加评分低于 6 分的婴儿（对于在医院出生的婴儿），或两者兼有，或 5 分钟内没有哭闹（对于在家出生的婴儿）。使用基于网络的随机化系统，我们将婴儿分配到一组，使用伺服控制冷却装置接受 72 小时的全身低温（33·5°C），或在出生后 6 小时内接受常规护理（对照组）。所有招募地点均配备有创通气、心血管支持以及 3 台 Tesla MRI 扫描仪和光谱学设施。不可能掩盖干预措施，但参与磁共振生物标志物分析和神经发育结果评估的干预措施却被掩盖了分配。主要结局是 18-22 个月时死亡或中度或重度残疾的综合终点，通过贝利婴幼儿发育量表（第三版）和详细的神经学检查进行评估。分析是按意向治疗进行的。该试验已在 ClinicalTrials.gov 注册，NCT02387385。通过贝利婴幼儿发育量表（第三版）和详细的神经学检查进行评估。分析是按意向治疗进行的。该试验已在 ClinicalTrials.gov 注册，NCT02387385。通过贝利婴幼儿发育量表（第三版）和详细的神经学检查进行评估。分析是按意向治疗进行的。该试验已在 ClinicalTrials.gov 注册，NCT02387385。

发现

我们在2015年8月15日至2019年2月15日期间筛查了2296名婴儿，其中576名婴儿符合纳入条件。排除后，我们招募了 408 名符合条件的婴儿，其中 202 名被分配到低温组，206 名被分配到对照组。低温组 202 名婴儿中的 195 名（97%）婴儿和对照组 206 名婴儿中的 199 名（97%）婴儿有主要结局数据。低温组中有 98 名 (50%) 婴儿和对照组有 94 名 (47%) 婴儿死亡或患有中度或重度残疾（风险比 1·06；95% CI 0·87–1·30；p=0 ·55）。低温组有 84 名婴儿 (42%) 死亡，对照组有 63 名婴儿 (31%; p=0·022) 死亡，其中 72 名 (36%) 和 49 名 (24%; p=0·0087) 婴儿死亡新生儿住院。报告了五例严重不良事件：三例发生在低温组（其中一例因肺炎而再次入院，1 例为化脓性关节炎，1 例疑似静脉血栓形成），对照组有 2 例（1 例与 MRI 期间的饱和度降低有关，另一例与 MRI 运输过程中气管内导管移位有关）。没有不良事件被认为与研究干预有因果关系。