Modifications were made to the protocol in both the Objectives and Methods. For the Objectives, the inclusion criteria were modified to exclude infants < 35 weeks' gestation and cooling initiated after six hours. These modifications were made in order to streamline the review as data emerge on cooling in infants < 35 weeks' gestation and who undergo later cooling and to improve generalisability of results. As such, the Objectives were modified to remove the category "Inclusion criteria: term or late preterm (≥ 35 weeks' gestation) infants versus more preterm (< 35 weeks' gestation)" and the Methods section "Types of participants" was modified to include infants "35 weeks' gestation or greater." It is well‐described in animal models that the effectiveness of hypothermia is dramatically reduced when initiated after six hours of life (Gunn 1998), although studies are emerging (Li 2009) exploring the use of late hypothermia. As data emerge in this field, it is felt that this will warrant a separate review. Therefore, the Objectives were modified to remove the category "Timing of commencement of intervention (< three hours versus three to six hours versus more than six hours)". The Methods section "Types of interventions" was modified to include cooling initiated prior to six hours after birth. Given that infants undergoing head cooling with mild systemic hypothermia may have relatively higher core temperatures but lower intranasal and scalp temperatures than infants treated with whole body cooling, it is difficult to compare temperatures in these treatment modalities in a meaningful way. Therefore, the Objectives were modified to remove "Degree of cooling (core temperature ≤ 34.5 °C versus > 34.5 °C)." In addition, Objective 1 (Severity of HIE) was modified to include both clinical staging of encephalopathy and staging based on baseline aEEG findings.

Additional changes to the Methods included clarification of definitions for secondary outcomes, additions to secondary outcomes and changes in the pre‐specified outcomes reported. Definitions were clarified for "Any coagulopathy" and "Renal impairment." The outcome "Seizure" was modified to include both seizures during the initial hospitalisation and at follow‐up. Three additional outcomes were added, as they were felt to be clinically important.  These were 'outcome at six to seven years,' 'hepatic dysfunction,' and 'persistent pulmonary hypertension,' which also included the outcome 'requiring inhaled NO.  For 'outcome at six to seven years,' both mortality and multiple neurodevelopmental findings are reported. Additionally, the outcome 'days to sucking feeds' was modified to the more binary 'need for gavage feeds at time of discharge. The outcome 'diffusion weighted imaging (DWI) on early MRI (< day 4)' and 'basal ganglia, posterior limb of internal capsule (PLIC) and/or white matter (WM) injury, parasagittal neuronal necrosis on late MRI (> day 4) were replaced with 'MRI abnormalities (moderate or severe abnormalities in the basal ganglia or thalamus, severe white matter lesions or abnormalities in the posterior limb of the internal capsule).'