Abstract
BackgroundTherapeutic hypothermia reduces death and disability after moderate or severe neonatal encephalopathy in high-income countries and is used as standard therapy in these settings. However, the safety and efficacy of cooling therapy in low- and middle-income countries (LMICs), where 99% of the disease burden occurs, remains unclear. We will examine whether whole body cooling reduces death or neurodisability at 18–22 months after neonatal encephalopathy, in LMICs.MethodsWe will randomly allocate 408 term or near-term babies (aged ≤ 6 h) with moderate or severe neonatal encephalopathy admitted to public sector neonatal units in LMIC countries (India, Bangladesh or Sri Lanka), to either usual care alone or whole-body cooling with usual care. Babies allocated to the cooling arm will have core body temperature maintained at 33.5 °C using a servo-controlled cooling device for 72 h, followed by re-warming at 0.5 °C per hour. All babies will have detailed infection screening at the time of recruitment and 3 Telsa cerebral magnetic resonance imaging and spectroscopy at 1–2 weeks after birth. Our primary endpoint is death or moderate or severe disability at the age of 18 months.DiscussionUpon completion, HELIX will be the largest cooling trial in neonatal encephalopathy and will provide a definitive answer regarding the safety and efficacy of cooling therapy for neonatal encephalopathy in LMICs. The trial will also provide important data about the influence of co-existent perinatal infection on the efficacy of hypothermic neuroprotection.Trial registrationClinicalTrials.gov, NCT02387385. Registered on 27 February 2015.
Highlights
Therapeutic hypothermia reduces death and disability after moderate or severe neonatal encephalopathy in high-income countries and is used as standard therapy in these settings
Every year, approximately one million babies die in lowand middle-income countries (LMIC) due to neonatal encephalopathy – a condition arising from an unexpected lack of cerebral blood flow and oxygen supply to the fetal brain at the time of birth [1]
Preclinical data suggest that the brain injury is worse and the neuroprotective effect of hypothermia in neonatal encephalopathy is lost in the presence of co-existent infection, with gram-negative organisms [13]
Summary
This is a multi-country two arm unblinded pragmatic randomised controlled trial of whole-body cooling along with usual supportive care vs. usual care alone. Blood gas analysis and amplitude integrated electroencephalogram may be performed as a part of the clinical care, they will not form part of the eligibility criteria, as these investigations are not widely available in LMICs. accurate Apgar scores are often not available when babies are born at home or in other hospitals and transferred to the recruiting centres, and often not collected beyond 5 min after birth. The inclusion criteria from the highincome country cooling trials are inappropriate for LMICs. our inclusion criteria are primarily based on a structured neurological examination using modified Sarnat staging. Evidence of moderate or severe encephalopathy at < 6 h of age on a structured clinical examination based on modified Sarnat staging (Table 1). Clinical outcomes (before discharge from hospital) Mortality from any cause before discharge from hospital Major intracranial haemorrhage on cranial ultrasound Gastric bleeds (fresh blood > 5 mL from nasogastric tube) Persistent hypotension (mean blood pressure < 25 mmHg despite maximum inotropic support) Pulmonary haemorrhage (copious bloody secretions with clinical deterioration requiring change(s) in ventilatory management) Persistent pulmonary hypertension (severe hypoxemia disproportionate to the severity of lung disease with a significant pre- and post-ductal saturation difference on pulse oximetry) Prolonged blood coagulation requiring blood products
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