Our study aimed at describing the short term outcomes and the factors associated with survival of new born infants with moderate to severe hypoxic ischemic encephalopathy treated with therapeutic hypothermia at St. Francis hospital Nsambya from June 2016 to February 2019.
The proportion of 84% newborn infants who were cooled and survived is high especially in a low resource setting. We attribute our high survival rates to the benefit therapeutic hypothermia has on newborn infants with moderate to severe HIE. Therapeutic hypothermia for newborn infants with moderate to severe HIE has been found to reduce mortality by 8-32 % (12, 15). It has also been found to reduce brain metabolic demands, by 5-7% for every 1oC drop in body temperature, reduce biosynthesis and release of excitatory amino acids. Similarly, therapeutic hypothermia has also been found to slow destructive enzymatic reactions, suppress free radical reactions, stabilize the cell membranes, slow deterioration of the blood-brain barrier, and reduce cerebral edema hence reducing intracranial pressure. These mechanisms have been found to reduce brain injury. (23-27). Different studies have shown different survival rates. Our findings are comparable to studies done in South Africa, United Kingdom and India with a survival rate of 89% (11) ,89% (28) and 87% (12, 21), though there was a difference in the cooling devices used and in the neonatal unit equipment.
The survival rate of 67% reported from a similar setting studies ( 30), differ from our findings The difference would be in the monitoring, in our setting the nurse to patient ratio was 1:4 compared to high nurse to patient ratio. Additionally availability of CPAP to appropriately managed respiratory distress and having mechanical ventilation may have been an added advantage, although very few babies were ventilated. Furthermore screening for infection and appropriate infection controls measures may have improved the outcome for these patients. On the other hand, in the study by Robertson and colleagues, there was an increased rate of sepsis and this could have resulted in higher mortality.
Factors associated with survival
Survival was related to a Thompson score of 7-10 at initiation of cooling and at 24 hours of cooling, Thompson score 11-14 at 24 hours, being born within the hospital providing cooling, and not needing a mechanical ventilator and inotropes. These factors may not be of a surprise for therapeutic hypothermia has been found to be more beneficial for the less encephalopathic babies (8, 9, 12, 15, 21). This could be attributed to the newborn infants in this group being less sick and probably having no multi organ damage due to the effect of hypoxia. It is known that the severity of hypoxia correlate the severity of cellular injury and destabilization of homeostasis hence, greater degree of depolarization leading to cytotoxic edema, increased accumulation of excitatory amino acids, free oxygen radicals, nitric acid and increased cell lysis. This reduces the benefits of hypothermia to avert these derangements. These findings are similar to other studies (8, 9, 11, 12, 31, 32).
The infants born within St. Francis hospital, Nsambya, had a better probability of survival as compared to the infants referred in from other health facilities. This could be attributed to having a neonatal resuscitation team for high risk deliveries and appropriate monitoring of labour and timely intervention in the intrapartum period. Furthermore these infants are born within the hospital providing cooling they are most likely not to suffer the temperature irregularities which worsen outcome following therapeutic hypothermia (27, 33) faced by the referred babies during transport to the hospital providing cooling. Our study showed that the median time to initiation of cooling for the newborn infants born within St. Francis Hospital, Nsambya was 1hour compared 4 hours for those who were referred in. (Additional file 1) Therapeutic hypothermia for newborn infants with moderate to severe HIE started within the first three hours has been associated with a better outcome in some studies.(34, 35). The difference in the outcome of the infants born within the hospital providing cooling and those referred to the cooling centre in the study of Kali and colleagues(11) could be due to the temperature control during transport to the cooling hospital, and initiation of cooling at the referral hospitals before transfer.
Duration of hospital stay
The median time to discharge for those who survived was 7 days, while the median time to death was 3 days. The majority of the infants 43/68(63%) who survived spent 6 to 10 days in the hospital while most infants 8/13(62%) died between the first and the third day of life. The shorter median time to death could have been influenced by the severity of the encephalopathy. Our study found that infants with a higher grade of encephalopathy were more likely to die as compared to infants with a lower grade of encephalopathy at initiation of cooling. On the other hand, the median time to discharge could have been influenced by a lower Thompson score at initiation of cooling for those who survived. Also, our hospital discharge protocol requires that all babies are discharged when either on full cup feeds or breast feeding and when the infants are clinically well. This could also influence a longer duration of hospital stay. The infant with the longest duration of hospital stay had other comorbidities, and a Thompson score of over 10 at initiation of cooling, hence a longer duration of hospital stay. The duration of hospital stay in our study is comparable to some studies.(28, 30, 36).
Return to full cup feeds or nutritive suckling for the participants who survived
The majority of the surviving infants 43/68(63%) attained full oral cup feeds or nutritive suckling between 5-8 days.
This is comparable to studies done elsewhere (11, 36). This similarity could be due to similarities in the NICU protocols on feeding. Our feeding protocol ensures that the babies are discharged only having attained full cup feeds or nutritive suckling. Therapeutic hypothermia has been found to improve neurological outcome (8-15) of which nutritive suckling is among.
Thompson score at discharge
The median Thompson score at discharge was 1, while the median Thompson score at death was 16. The infant with the Thompson score 7 at the time of death had completed cooling with an improving Thompson score but developed necrotizing enterocolitis with multiple gut perforation and died on day 5, hence a lower Thompson score than the median at death. The findings of our study is comparable to studies that report that most infants had normal neurology at discharge.(11, 28, 37). Similarly, the findings of our study are consistent with studies that have found that therapeutic hypothermia improves neurological outcome for infants with mild to moderate hypoxic ischaemic encephalopathy, but not with those who have severe encephalopathy.(8, 9, 11, 15, 21)
Strengths and Limitations of the study
This is one of the few studies in our setting to look at the short term outcome of newborn infants with moderate to severe HIE treated with Therapeutic hypothermia in our setting. The NICU protocol of St. Francis Hospital Nsambya ensures that newborn infants admitted for therapeutic hypothermia are investigated and managed for infections. This could have reduced the confounders. The protocol also ensures that additional life support like ventilator and inotropes where necessary was accorded to the newborn infant. There was a wide variety of data collection tools hence a minimal likelihood of having missing data.
We acknowledge some study limitations: The study was conducted in a health facility, clinical characteristics of babies referred in and the intrapartum, circumstances were based on the referral notes hence a difficulty in controlling referral bias. Secondarily this was a retrospective cohort study with its known study limitations. Metabolic cause of neonatal encephalopathy like some inborn errors of metabolism were not explored, this could have influenced some of the results. Lack of infant seizure monitor whilst being cooled hence infants with subclinical seizures could have been missed. We hence used a Thompson score of 7 as a cut off since it has been found to be a sensitive predictor of either an abnormal 6-hour EEG or moderate to severe encephalopathy (28).
What this study adds
Therapeutic Hypothermia is feasible in a resource poor setting under strict protocol. As such it can be taken up as a standard of care for all newborns with moderate to severe HIE. We therefore anticipate that the findings of this study could be used to inform clinicians, improve the existing cooling protocols and contribute to policy development regarding the uptake of therapeutic hypothermia for newborn infants with hypoxic ischaemic encephalopathy in low resource settings