In the UK and other developed world settings, moderate-severe encephalopathy following perinatal asphyxia occurs in 1-2/1000 term births . There are major consequences for families and for society; approximately 25% of affected infants will die in the neonatal unit and 40% will develop cerebral palsy. Others will have long-term neurodevelopmental deficits that result in a difficult life and lost potential . Within the last decade, therapeutic hypothermia for infants with perinatal asphyxial encephalopathy has been studied in several randomised controlled trials (RCTs) in industrialized countries [3–6]. Meta-analyses of these trials show that therapeutic hypothermia increases survival with normal neurological function (pooled risk ratio of 1.53) with a number needed to treat of 8 (95% confidence interval (CI) 5 - 17) and in survivors reduces the rates of severe disability and cerebral palsy [7, 8]. Therapeutic hypothermia under intensive care settings appears safe . Therapeutic hypothermia is now widely offered to moderately or severely asphyxiated infants in high-income countries . In 2010 in the UK the National Institute for Health and Clinical Excellence (NICE) endorsed Therapeutic Hypothermia with Intracorporeal Temperature Monitoring for Hypoxic Perinatal Brain Injury (see website: http://www.nice.org.uk/nicemedia/live/11315/48809/48809.pdf)
The global burden of disease estimates indicate that perinatal asphyxia is a very significant problem in low and mid-resource settings ; for example in sub-Saharan Africa, neonatal encephalopathy related to perinatal asphyxia is ~10-20 times more common than in the developed world . Globally, perinatal asphyxia is responsible for 42 million disability life adjusted years, double that due to diabetes and three quarters of that due to HIV/AIDS . Almost one quarter of the world's 4 million annual neonatal deaths are caused by perinatal asphyxia  and 99% of these deaths occur in low and mid-resource settings. These intrapartum-related deaths account for as many deaths as does malaria but they are not addressed in any global health policy.
A safe and effective therapy for neonatal encephalopathy appropriate for low resource settings is likely to benefit millions of infants and families. There are, however, several compelling reasons why the efficacy and safety data on therapeutic hypothermia from high-income countries cannot be simply extrapolated to mid and low resource settings. For example (i) brain injury may be already established due to multiple antenatal insults (e.g. maternal malnutrition and other co-morbidities), (ii) prolonged obstructed labour, long delays in carrying out emergency caesarean sections, and lack of effective resuscitation and networks for neonatal transport may all reduce or nullify the therapeutic window for hypothermia . (iii) the incidence and profile of perinatal infections in this population is different. Cooling in the presence of infection might even be deleterious as hypothermia may impair innate immune function, including neutrophil migration and function , although it is reassuring that the neonatal cooling trials from industrialized countries did not show a higher incidence of sepsis in cooled infants. It is important to note that hypothermia during sepsis in adult patients has been associated with increased mortality and higher circulating levels of TNF-a AND IL-6 . One explanation for the higher morbidity and mortality associated with hypothermia in some clinical settings may be the prolongation of NF-KB activation and altered cytokine gene expression known to occur with moderate hypothermia . Furthermore, there is convincing experimental [17, 18] and epidemiological evidence [19, 20] suggesting that a 'dual hit' of infection and ischaemia results in disproportionately more severe brain injury and increases in the risk of cerebral palsy. It is likely that this 'dual hit' is one of the factors responsible for the poorer neurological outcome reported from low and mid-resource settings  and it is not known if therapeutic hypothermia would be neuroprotective in such situations. (iv) cooling may be unsafe in the presence of meconium aspiration and pulmonary hypertension where facilities for advanced multi-organ support may not be available; (v) the benefits of cooling may only be achieved in units with optimal neurological monitoring which may not be possible in low income settings. (vi) cooling equipment used in high income countries is expensive, requires maintenance support and has ongoing costs. There is therefore an important need for validation of 'low tech', safe and economical cooling methods.
Uganda was chosen as an optimal site for the pilot study because of the long tradition of research at Mulago Hospital and Makerere University. In 2006 the UCL Uganda Women's Health Initiative was set up between UCL and Mulago Hospital, Makerere University and Hospice Africa. Ten projects related to women's health were set up under the Uganda Women's Health initiative. One of the neonatal projects initially focused on training midwives in neonatal resuscitation, however MN was very keen to help the large number of infants with perinatal asphyxia admitted to the special care baby unit at Mulago each week. We set up a pilot randomized trial of therapeutic hypothermia in Mulago Hospital, Uganda to determine the feasibility of a larger RCT in this setting.
The aims of the pilot study were to determine:
(i) The feasibility of achieving consent, neurological assessment, randomisation and whole body cooling to a core temperature 33-34°C using a 'low tech' cooling method (water bottles) (already briefly reported )
(ii) The temperature profiles of encephalopathic infants randomized to standard care or standard care plus therapeutic hypothermia (already briefly reported )
(iii) The pattern, severity and evolution of brain tissue injury as seen on cranial ultrasound and relation with outcome
(iv) The feasibility of neurodevelopmental follow-up at 18-22 months of age