Implications of the HELIX trial for treating infants with hypoxic-ischaemic encephalopathy in low-to-middle-income countries

Davidson, John B.; Battin, Malcolm; Gunn, Alistair J.

doi:10.1136/archdischild-2021-323743

Cited by 10 publications

(4 citation statements)

References 21 publications

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“…Therefore, the authors made a strong recommendation to abandon the use of therapeutic hypothermia for newborns with HIE in low–middle‐income countries, but concerns have been raised on the generalisability to other settings in low–middle‐income countries such as South Africa where emerging evidence has pointed in favour of therapeutic hypothermia 27 . Some of the critical questions about the Helix trial findings include why therapeutic hypothermia was not effective in the three countries despite having neonatal care infrastructures almost similar to high‐income countries 28 . In line with a Cochrane review of 11 randomised trials on therapeutic hypothermia in high‐income countries, 29 a retrospective study in South Africa reviewed the outcomes of therapeutic hypothermia among 99 infants with HIE and reported reduction in mortality and that most infants with HIE who survived did not have major neurological impairments 30 .…”

Section: Discussionmentioning

confidence: 99%

“…TA B L E 2 (Continued) therapeutic hypothermia was not effective in the three countries despite having neonatal care infrastructures almost similar to highincome countries. 28 In line with a Cochrane review of 11 randomised trials on therapeutic hypothermia in high-income countries, 29 a retrospective study in South Africa reviewed the outcomes of therapeutic hypothermia among 99 infants with HIE and reported reduction in mortality and that most infants with HIE who survived did not have major neurological impairments. 30 While there is a need for low-and middle-income countries to further explore safe adoption of therapeutic hypothermia, measures should be taken to improve the quality of neonatal care including proper monitoring of labour and delivery, skilled neonatal resuscitation staff, timely referrals and well-functioning neonatal care facilities.…”

Section: Baseline Characteristics Of the Enrolled Newbornsmentioning

confidence: 99%

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High incidence of poor in‐hospital outcomes of term newborns with hypoxic–ischaemic encephalopathy admitted at a regional referral hospital in Dodoma, Tanzania

et al. 2022

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Aim: Hypoxic-ischaemic encephalopathy (HIE) is one of the leading causes of neonatal deaths and neurological impairment with the highest impact in resource-limited settings. This study aimed to determine the incidence of poor in-hospital outcomes and related factors among newborns with HIE in Tanzania.Methods: A prospective observational study in which 170 newborns with HIE (diagnosed using the Thompson clinical score) were followed from 1 September 2020 to 28 February 2021 at the neonatal ward of Dodoma Regional Referral Hospital in Dodoma, central Tanzania, until discharge or death. Clinical parameters were recorded. Multinomial logistic regression analysis was applied to determine factors associated with adverse outcomes.Results: Out of 170 newborns, 44.7% (76/170) had poor outcomes (death 27.1% (46/170); neurological deficits 17.6% (30/170)). Severe HIE (Thompson score > 14) (p < 0.0001), history of aspiration (adjusted odds ratio (AOR) = 3.06, 95% confidence interval (CI) [1.170, 8.014], p = 0.0226) and 5th-min APGAR of <7 (AOR = 2.88, 95% CI [1.133, 7.310], p = 0.0262) were associated with mortality. Severe HIE, delivery at other facilities (AOR = 3.106 CI [1.158, 8.332], p = 0.0244) and abnormal heart rate (<100 or ≥160 beats/min) on admission (AOR = 3.469 [1.200,10.030], p = 0.0216) predicted neurological impairment at discharge. Conclusion:Hypoxic-ischaemic encephalopathy is associated with a high incidence of poor outcomes in resource-limited settings. To improve outcomes newborns with severe HIE, history of aspiration, referred from other facilities, 5th-min APGAR score of <7 and abnormal heart rate need improved quality of neonatal care.

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Section: Discussionmentioning

confidence: 99%

Section: Baseline Characteristics Of the Enrolled Newbornsmentioning

confidence: 99%

High incidence of poor in‐hospital outcomes of term newborns with hypoxic–ischaemic encephalopathy admitted at a regional referral hospital in Dodoma, Tanzania

et al. 2022

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“…TH has a high safety profile but has some limitations as noted above [ 198 ]. Critically, the recent HELIX trial showed that in low- and middle-income countries TH significantly increased mortality [ 18 ], likely because of a relatively higher proportion of injury evolving before birth [ 199 ].…”

Section: Therapeutic Potential Of Connexin and Pannexin Blockersmentioning

confidence: 99%

Connexins, Pannexins and Gap Junctions in Perinatal Brain Injury

et al. 2022

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Perinatal brain injury secondary to hypoxia-ischemia and/or infection/inflammation remains a major cause of disability. Therapeutic hypothermia significantly improves outcomes, but in randomized controlled trials nearly half of infants still died or survived with disability, showing that additional interventions are needed. There is growing evidence that brain injury spreads over time from injured to previously uninjured regions of the brain. At least in part, this spread is related to opening of connexin hemichannels and pannexin channels, both of which are large conductance membrane channels found in many brain cells. Opening of these membrane channels releases adenosine triphosphate (ATP), and other neuroactive molecules, into the extracellular space. ATP has an important role in normal signaling, but pathologically can trigger the assembly of the multi-protein inflammasome complex. The inflammasome complex promotes activation of inflammatory caspases, and release of inflammatory cytokines. Overall, the connexin hemichannel appears to play a primary role in propagation of injury and chronic disease, and connexin hemichannel blockade has been shown to be neuroprotective in multiple animal models. Thus, there is potential for some blockers of connexin or pannexin channels to be developed into targeted interventions that could be used in conjunction with or separate to therapeutic hypothermia.

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“…[3][4][5] While therapeutic hypothermia is standard of care and can reduce brain injury and mortality following birth asphyxia in high-income countries, 6 this was not observed in a large trial in the LMIC setting 7 where a lower incidence of sentinel events and higher seizure burden at randomization suggest an in utero injury evolving earlier over the course of labor. 8 Therapeutic agents that could be used prophylactically during labor, as well as immediately postnatally, may therefore be necessary to improve outcomes globally.…”

mentioning

confidence: 99%

Perinatal Azithromycin Provides Limited Neuroprotection in an Ovine Model of Neonatal Hypoxic-Ischemic Encephalopathy

Mike,

White,

Hutchings

et al. 2023

Stroke

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Background: Hypoxic-ischemic brain injury/encephalopathy affects about 1.15 million neonates per year, 96% of whom are born in low- and middle-income countries. Therapeutic hypothermia is not effective in this setting, possibly because injury occurs significantly before birth. Here, we studied the pharmacokinetics, safety, and efficacy of perinatal azithromycin administration in near-term lambs following global ischemic injury to support earlier treatment approaches. Methods: Ewes and their lambs of both sexes (n=34, 141–143 days) were randomly assigned to receive azithromycin or placebo before delivery as well as postnatally. Lambs were subjected to severe global hypoxia-ischemia utilizing an acute umbilical cord occlusion model. Outcomes were assessed over a 6-day period. Results: While maternal azithromycin exhibited relatively low placental transfer, azithromycin-treated lambs recovered spontaneous circulation faster following the initiation of cardiopulmonary resuscitation and were extubated sooner. Additionally, peri- and postnatal azithromycin administration was well tolerated, demonstrating a 77-hour plasma elimination half-life, as well as significant accumulation in the brain and other tissues. Azithromycin administration resulted in a systemic immunomodulatory effect, demonstrated by reductions in proinflammatory IL-6 (interleukin-6) levels. Treated lambs exhibited a trend toward improved neurodevelopmental outcomes while histological analysis revealed that azithromycin supported white matter preservation and attenuated inflammation in the cingulate and parasagittal cortex. Conclusions: Perinatal azithromycin administration enhances neonatal resuscitation, attenuates neuroinflammation, and supports limited improvement of select histological outcomes in an ovine model of hypoxic-ischemic brain injury/encephalopathy.

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Implications of the HELIX trial for treating infants with hypoxic-ischaemic encephalopathy in low-to-middle-income countries

Cited by 10 publications

References 21 publications

High incidence of poor in‐hospital outcomes of term newborns with hypoxic–ischaemic encephalopathy admitted at a regional referral hospital in Dodoma, Tanzania

High incidence of poor in‐hospital outcomes of term newborns with hypoxic–ischaemic encephalopathy admitted at a regional referral hospital in Dodoma, Tanzania

Connexins, Pannexins and Gap Junctions in Perinatal Brain Injury

Perinatal Azithromycin Provides Limited Neuroprotection in an Ovine Model of Neonatal Hypoxic-Ischemic Encephalopathy

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