Nawaporn L.�Nutchayavaree L.

Critical Appraisal: RCT

September 20^th, 2021

Section A: Is the basic study design valid for a randomised controlled trial?

Population: ��- All infants born at GA ≥ 36 weeks with a birth weight of ≥ 1.8 kg who were admitted to the neonatal unit within 6 h of birth AND �two criteria of eligibility�1. A need for continued resuscitation at 5 min of age or an Apgar score of < 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)�2. Evidence of moderate or severe encephalopathy at any time between 1 h and 6 h of age based on a structured clinical examination using modified Sarnat staging done by a certified examiner after admission to the neonatal unit�- 7 large public sector tertiary neonatal intensive care units in India, Sri Lanka and Bangladesh�- During Aug 15, 2015, and Feb 15, 2019

Intervention: therapeutic hypothermia��Comparator: no therapeutic hypothermia�

Outcomes:�Primary outcome: death or moderate or severe disability�Secondary outcomes:� - Short-term: death before hospital discharge, a major ICH on cranial ultrasonography, gastric bleeds, persistent hypotension, pulmonary haemorrhage, persistent pulmonary hypertension, prolonged blood coagulation requiring blood products, culture-proven EOS, NEC, cardiac arrhythmia, severe thrombocytopenia, persistent metabolic acidosis, pneumonia, renal failure, subcutaneous fat necrosis, an abnormal neurological examination at discharge, and duration of the hospital stay, all assessed at the time of hospital discharge� - Long-term: death from any cause at 18 months, severe disability among those who survived, and microcephaly, assessed at 18–22 months�

Randomisation:��- Ratio of 1:1 using web-based randomisation system (sealed envelope) using secure login�- Minimisation method: to control encephalopathy stage and study centre�- Each randomisation generated an automated e-mail to the team at Imperial College London, who then cross-checked the date and time of birth of the infant and adherence with the assigned group���

Allocation concealment:��- Masking the intervention was not possible�- The perinatal pathologist was masked to the treatment allocations�- The magnetic resonance biomarker analysis and neurodevelopmental outcome assessments were masked to the allocation�

- Intention-to-treat basis as the primary analysis

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Section B: Was the study methodologically sound?

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Perinatal pathologist

Neonatal neurologists and paediatric neuroradiologist Neurodevelopmental paediatricians

were “Blinded” to clinical information and treatment allocation

- All participating neonatal units had facilities for assisted ventilation, cardiovascular monitoring, and support; access to 3 Tesla MRI scanners; and were managed by a two-tier system of trainee doctors and neonatal consultants who were experienced in dealing with therapeutic hypothermia.

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- Daily encephalopathy staging until day 4 after birth, and again on day 7 after birth and at discharge�- Cerebral MRI 1–2 weeks after birth on a 3 Tesla scanner with the same protocol�- Research nurses maintained regular contact with the families after discharge�- Neurodevelopmental paediatrician assessed each infant at 18–22 months using the Bayley Scales of Infant Development (3^rd edition) and did a detailed neurological examination

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Section C: What are the results?

• Power of the study: 80%
• Outcomes:

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- Categorical outcomes using the χ² test or Fisher’s exact test for rarer outcomes

- Risk ratios (RRs) with corresponding 95% CIs for differences in outcomes between the study groups

- Mann-Whitney test to analyse continuous outcomes with a skewed distribution

- Log-rank test to compare survival times between the groups

- Ordinal logistic regression analysis was used to compare brain injury between the hypothermia and control groups

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• Protocol deviation
• 3 cases in hypothermia group:
• one infant did not receive hypothermia therapy
• another was over-cooled to 29·0°C for 3 h because of a machine malfunction
• a third had discontinuation of hypothermia because of suspected venous thrombosis and refractory hypotension.
• 10 cases in control group:
• 3 cases had at least one episode of a rectal temperature of more than 39°C (all died)
• 7 cases had rectal temperature between 38°C and (five died and two survived with a disability)

Section D: Will the results help locally?

Thank you