Implications of the HELIX trial for treating infants with hypoxic ischaemic encephalopathy in low-to-middle-income countries
Joanne O. Davidson,1 Malcolm Battin,2 Alistair J. Gunn.1
1. Fetal Physiology and Neuroscience Group, Department of Physiology, Faculty of Medical and Health Sciences, The University of Auckland, 85 Park Road, Grafton, Auckland, 1142, New Zealand
2. Newborn Services, Auckland City Hospital, Auckland, New Zealand
Funding: The authors are supported by funding from the Health Research Council of New Zealand (grant numbers 17/601, 20/030).
Competing interests: The authors declare that there are no conflicts of interest.
Corresponding author:
Professor Alistair J. Gunn Department of Physiology,
Faculty of Medical and Health Sciences, The University of Auckland,
Private Bag 92019, Auckland 1023, New Zealand,
Phone: (+649) 373 7599, Email: [email protected]
Perinatal hypoxia-ischaemia (HI) is the single most common trigger of perinatal brain injury, and contributes to over two million deaths worldwide each year, of which about 96% were from low- and middle-income countries (LMICs) (1, 2). In high income countries (HICs) there is compelling evidence that therapeutic hypothermia for infants with HI encephalopathy (HIE) reduces grey and white matter lesions (3, 4) and improves survival without disability (5-7). In view of the differing populations, risks and medical systems it cannot be assumed that even such a simple and low cost treatment would be suitable for LMICs (8). Supporting this concern, the HELIX study, a large, well-designed and executed randomized controlled trial of therapeutic hypothermia for HIE in LMICs, found that treatment did not reduce the combined outcome of death or disability at 18 months of age and increased mortality (9), The authors concluded that therapeutic hypothermia should not be offered to infants with neonatal encephalopathy in LMICs, even when tertiary level neonatal intensive care support is available.
The study raises two important questions: 1) why therapeutic hypothermia was not beneficial in this setting despite a high level of neonatal care and 2) how to reduce the burden of injury for affected infants in the future. We propose that better targeting of treatment may enable benefit even in this setting.
It is important to appreciate that some findings of the CoolCap study, carried out in multiple HICs, were surprisingly consistent with HELIX. Secondary analysis of Coolcap suggested that not all infants benefited from therapeutic hypothermia and that the benefit was closely associated with body weight (10). In the normothermic control group, there was a significantly higher rate of unfavourable outcome in infants in the top 25th percentile for body weight than in the bottom 25th percentile. Strikingly, therapeutic hypothermia was associated with a much greater reduction in rate of unfavourable outcomes in the top 25th percentile than in the bottom 25th percentile. Interestingly, acute complications of labour were reported in 85% of infants in the top 25th percentile but only 71% of those in the bottom 25th percentile. These data suggest
that therapeutic hypothermia was most beneficial in a subset of infants who were larger and more likely to have had acute complications during labour rather than infants who were smaller and more likely to have had repetitive hypoxic insults in labour (10). Consistent with this interpretation, a recent study showed that perinatal sentinel events were associated with less severe brain injury on MRI after treatment with therapeutic hypothermia, and improved motor and language outcomes at 18-36 months (11).
In the HELIX study there was a notably low burden of perinatal sentinel events (8% and 13%, in the hypothermia and normothermia groups respectively) (9), compared to approximately 25% or more in studies of HIE from HICs (10, 12), denoting a correspondingly high proportion of injury evolving over the course of labour. Consistent with this, nearly three quarters of infants in both groups were already having seizures at randomisation, suggesting that secondary deterioration was already beginning at birth, when preclinical studies suggest that therapeutic hypothermia is no longer effective (13). Furthermore, MRI demonstrated a high burden of white matter injury (88% and 77%) but low burden of basal ganglia and thalamic injury (21 % and 26 %), highly consistent with that seen in preclinical studies of labour-like brief-repeated hypoxia in near-term fetal sheep (14), which are associated with early onset of seizures (15).
Together these data suggest that infants with lower birth weight often have injury evolving before birth, over the course of labour. These observations strongly infer that although the proportion of injury evolving in labour is higher in LMIC’s there is no intrinsic biological difference between HIE in LMIC and HICs. Thus, we suggest that it would be reasonable to consider a trial of treatment targeted to the subset of infants most likely to benefit from therapeutic hypothermia – larger infants who have had an acute sentinel event during birth but not smaller infants who have likely had prolonged or repetitive hypoxic insults before birth.
This would help make better use of scarce resources.
Next, it is striking that the risk of adverse outcomes after standard treatment with hypothermia has fallen from about 45% in the original trials to about 29% in a recent large randomized controlled trial (16). This change is likely multifactorial, but one potential contributor may be earlier treatment now that therapeutic hypothermia is routine practice. Multiple studies across species and different models have consistently shown that treatment with hypothermia is most efficacious the earlier it can be started in the latent phase after acute HI (13). Although the window of opportunity for therapeutic hypothermia was up to about 6 hours after an acute ischaemic insult, the therapeutic window has not been established after labour-like hypoxia (14). Unfortunately, preclinical models, such as repeated umbilical cord occlusion in fetal sheep, show considerable variability, making them poorly suited for neuroprotection studies (14).
Although there has never been a controlled clinical trial of the timing of initiation of therapeutic hypothermia, in a cohort of 76 infants recruited using the CoolCap/TOBY protocols treatment before 3 hours of age was associated with improved psychomotor developmental index scores (Bayley Scales of Infant Development II) at 18 months compared with cooling from 3 to 6 hours (17). Moreover, there is evidence that infants with HIE born in a centre that offers therapeutic hypothermia onsite have improved seizure-free survival, presumptively due to earlier initiation of treatment (18). Hypothermia was initiated in HELIX at a median of 4.30 h after birth (interquartile range 1.09–6.00), similarly to previous trials. It is plausible that treatment needs to be initiated significantly earlier than this to achieve benefit when injury has evolved in labour. We suggest that key studies should include documentation of the antecedent fetal heart rate patterns (12) and early EEG recordings in high-risk infants to determine the precise onset of seizures in LMICs.
An important strength of the HELIX trial was that only 5% of control infants experienced pyrexia, with a core body temperature greater than 38°C, compared with 38% of control infants
in NICHD, 31% in CoolCap and 14% in TOBY (10, 19, 20). Pyrexia was associated with approximately a 4-fold increase in the risk of death or disability per 1°C increase in body temperature (19). Thus, it is likely that maintenance of normothermia in control infants would partially attenuate the apparent benefit after therapeutic hypothermia, although it is highly improbable that it explains the complete lack of effect in HELIX.
Thayyil and colleagues reasonably call for therapeutic hypothermia to be stopped in LMICs in light of the increased risk of death in their study. However, there are no other proven neuroprotective strategies for HIE. Even the most promising neuroprotectant, erythropoietin, seemed to be less effective than therapeutic hypothermia in a low resource setting (21).
Therefore, we respectfully suggest that rather than abandoning hypothermia completely it would be better to focus on highly targeted studies to identify infants who may benefit and strategies to enable earlier treatment.
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