Questions about the HELIX trial – Authors' reply

Thayyil, Sudhin; Bassett, Paul; Shankaran, Seetha

doi:10.1016/s2214-109x(21)00499-x

Cited by 5 publications

(5 citation statements)

References 10 publications

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“…A recent large randomized controlled trial of therapeutic hypothermia has shown that we cannot assume that standard interventions in HICs will work in the same way in LMIC settings; 27 evaluation of such interventions is essential before being introduced into new settings and prevention opportunities should remain a priority. 28 To calculate current global birth prevalence estimates, we restricted meta-analyses to regions with more than one birth year from 2010. No LMICs were able to participate in these analyses, so these primary findings are for high-income regions only.…”

Section: Discussionmentioning

confidence: 99%

“…A challenge for all is how to share knowledge, experiences, and lessons learnt to minimize this inevitable spike. A recent large randomized controlled trial of therapeutic hypothermia has shown that we cannot assume that standard interventions in HICs will work in the same way in LMIC settings; 27 evaluation of such interventions is essential before being introduced into new settings and prevention opportunities should remain a priority 28 …”

Section: Discussionmentioning

confidence: 99%

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Global prevalence of cerebral palsy: A systematic analysis

McIntyre

Goldsmith

Webb

et al. 2022

Develop Med Child Neuro

178

123

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Aim: To determine trends and current estimates in regional and global prevalence of cerebral palsy (CP).Method: A systematic analysis of data from participating CP registers/surveillance systems and population-based prevalence studies (from birth year 1995) was performed. Quality and risk of bias were assessed for both data sources. Analyses were conducted for pre-/perinatal, postnatal, neonatal, and overall CP. For each region, trends were statistically classified as increasing, decreasing, heterogeneous, or no change, and most recent prevalence estimates with 95% confidence intervals (CI) were calculated. Meta-analyses were conducted to determine current birth prevalence estimates (from birth year 2010).Results: Forty-one regions from 27 countries across five continents were represented. Pre-/perinatal birth prevalence declined significantly across Europe and Australia (11 out of 14 regions), with no change in postneonatal CP. From the limited but increasing data available from regions in low-and middle-income countries (LMICs), birth prevalence for pre-/perinatal CP was as high as 3.4 per 1000 (95% CI 3.0-3.9) live births. Following meta-analyses, birth prevalence for pre-/perinatal CP in regions from high-income countries (HICs) was 1.5 per 1000 (95% CI 1.4-1.6) live births, and 1.6 per 1000 (95% CI 1.5-1.7) live births when postneonatal CP was included.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Global prevalence of cerebral palsy: A systematic analysis

McIntyre

Goldsmith

Webb

et al. 2022

Develop Med Child Neuro

178

123

View full text Add to dashboard Cite

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“…It is unlikely that the lack of hypothermic neuroprotection seen in the HELIX trial 35 4 ), and the cooling device was the most efficient. Thus, 72% of the neonates reached the target temperature (Յ34 °C) by 6 hours in the HELIX trial compared with 53% in the NICHD NRN trial.…”

Section: Discussionmentioning

confidence: 99%

“…It is unlikely that the lack of hypothermic neuroprotection seen in the HELIX trial 35 can be explained by (1) delay in achieving target temperature, (2) use of simplified inclusion criteria for neonates born at home (ie, absence of cry by 5 minutes), (3) coexistent infection, or (4) lack of 1:1 nursing care. First, of all the major induced hypothermia trials, age at randomization (4.3 hours) was shortest in the HELIX trial (compared with age 4.8 hours in the Selective Head Cooling With Mild Systemic Hypothermia After Neonatal Encephalopathy [CoolCap] multicenter RCT, 2 age 4.3 hours in the NICHD NRN trial, 3 and age 4.7 hours in the Total Body Hypothermia [TOBY] trial 4 ), and the cooling device was the most efficient.…”

Section: Discussionmentioning

confidence: 99%

Whole-Body Hypothermia, Cerebral Magnetic Resonance Biomarkers, and Outcomes in Neonates With Moderate or Severe Hypoxic-Ischemic Encephalopathy Born at Tertiary Care Centers vs Other Facilities

Thayyil,

Montaldo,

Krishnan

et al. 2023

JAMA Netw Open

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ImportanceThe association between place of birth and hypothermic neuroprotection after hypoxic-ischemic encephalopathy (HIE) in low- and middle-income countries (LMICs) is unknown.ObjectiveTo ascertain the association between place of birth and the efficacy of whole-body hypothermia for protection against brain injury measured by magnetic resonance (MR) biomarkers among neonates born at a tertiary care center (inborn) or other facilities (outborn).Design, Setting, and ParticipantsThis nested cohort study within a randomized clinical trial involved neonates at 7 tertiary neonatal intensive care units in India, Sri Lanka, and Bangladesh between August 15, 2015, and February 15, 2019. A total of 408 neonates born at or after 36 weeks’ gestation with moderate or severe HIE were randomized to receive whole-body hypothermia (reduction of rectal temperatures to between 33.0 °C and 34.0 °C; hypothermia group) for 72 hours or no whole-body hypothermia (rectal temperatures maintained between 36.0 °C and 37.0 °C; control group) within 6 hours of birth, with follow-up until September 27, 2020.Exposure3T MR imaging, MR spectroscopy, and diffusion tensor imaging.Main Outcomes and MeasuresThalamic N-acetyl aspartate (NAA) mmol/kg wet weight, thalamic lactate to NAA peak area ratios, brain injury scores, and white matter fractional anisotropy at 1 to 2 weeks and death or moderate or severe disability at 18 to 22 months.ResultsAmong 408 neonates, the mean (SD) gestational age was 38.7 (1.3) weeks; 267 (65.4%) were male. A total of 123 neonates were inborn and 285 were outborn. Inborn neonates were smaller (mean [SD], 2.8 [0.5] kg vs 2.9 [0.4] kg; P = .02), more likely to have instrumental or cesarean deliveries (43.1% vs 24.7%; P = .01), and more likely to be intubated at birth (78.9% vs 29.1%; P = .001) than outborn neonates, although the rate of severe HIE was not different (23.6% vs 17.9%; P = .22). Magnetic resonance data from 267 neonates (80 inborn and 187 outborn) were analyzed. In the hypothermia vs control groups, the mean (SD) thalamic NAA levels were 8.04 (1.98) vs 8.31 (1.13) among inborn neonates (odds ratio [OR], −0.28; 95% CI, −1.62 to 1.07; P = .68) and 8.03 (1.89) vs 7.99 (1.72) among outborn neonates (OR, 0.05; 95% CI, −0.62 to 0.71; P = .89); the median (IQR) thalamic lactate to NAA peak area ratios were 0.13 (0.10-0.20) vs 0.12 (0.09-0.18) among inborn neonates (OR, 1.02; 95% CI, 0.96-1.08; P = .59) and 0.14 (0.11-0.20) vs 0.14 (0.10-0.17) among outborn neonates (OR, 1.03; 95% CI, 0.98-1.09; P = .18). There was no difference in brain injury scores or white matter fractional anisotropy between the hypothermia and control groups among inborn or outborn neonates. Whole-body hypothermia was not associated with reductions in death or disability, either among 123 inborn neonates (hypothermia vs control group: 34 neonates [58.6%] vs 34 [56.7%]; risk ratio, 1.03; 95% CI, 0.76-1.41), or 285 outborn neonates (hypothermia vs control group: 64 neonates [46.7%] vs 60 [43.2%]; risk ratio, 1.08; 95% CI, 0.83-1.41).Conclusions and RelevanceIn this nested cohort study, whole-body hypothermia was not associated with reductions in brain injury after HIE among neonates in South Asia, irrespective of place of birth. These findings do not support the use of whole-body hypothermia for HIE among neonates in LMICs.Trial RegistrationClinicalTrials.gov Identifier: NCT02387385

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“…The quest for such biomarkers is still mostly research based. While brain neuroimaging with MRI/MRS with lactate/NAA ratio in the thalamus or fractional anisotropy in the PLIC [4][5][6] before discharge is the gold standard to predict long-term neurodevelopment [7], it offers one snapshot in time as it is not available for dynamic real time measures or in the first day of life for decision making to enroll in trials. Recently, our group has reported the EEG based phase amplitude coupling (PAC) between slow and fast brain oscillations as a novel EEG marker of neural synchrony, which becomes dysregulated after injury.…”

Section: Introductionmentioning

confidence: 99%

Feasibility of EEG Phase-Amplitude Coupling to Stratify Encephalopathy Severity in Neonatal HIE Using Short Time Window

et al. 2022

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Goal: It is challenging to clinically discern the severity of neonatal hypoxic ischemic encephalopathy (HIE) within hours after birth in time for therapeutic decision-making for hypothermia. The goal of this study was to determine the shortest duration of the EEG based PAC index to provide real-time guidance for clinical decision-making for neonates with HIE. Methods: Neonates were recruited from a single-center Level III NICU between 2017 and 2019. A time-dependent, PAC-frequency-averaged index, tPACm, was calculated to characterize intrinsic coupling between the amplitudes of 12–30 Hz and the phases of 1–2 Hz oscillation from 6-h EEG data at electrode P3 during the first day of life, using different sizes of moving windows including 10 s, 20 s, 1 min, 2 min, 5 min, 10 min, 20 min, 30 min, 60 min, and 120 min. Time-dependent receiver operating characteristic (ROC) curves were generated to examine the performance of the accurate window tPACm as a neurophysiologic biomarker. Results: A total of 33 neonates (mild-HIE, n = 15 and moderate/severe HIE, n = 18) were enrolled. Mixed effects models demonstrated that tPACm between the two groups was significantly different with window time segments of 3–120 min. By observing the estimates of group differences in tPACm across different window sizes, we found 20 min was the shortest window size to optimally distinguish the two groups (p < 0.001). Time-varying ROC showed significant average area-under-the-curve of 0.82. Conclusion: We demonstrated the feasibility of using tPACm with a 20min EEG time window to differentiate the severity of HIE and facilitate earlier diagnosis and treatment initiation.

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Questions about the HELIX trial – Authors' reply

Cited by 5 publications

References 10 publications

Global prevalence of cerebral palsy: A systematic analysis

Global prevalence of cerebral palsy: A systematic analysis

Whole-Body Hypothermia, Cerebral Magnetic Resonance Biomarkers, and Outcomes in Neonates With Moderate or Severe Hypoxic-Ischemic Encephalopathy Born at Tertiary Care Centers vs Other Facilities

Feasibility of EEG Phase-Amplitude Coupling to Stratify Encephalopathy Severity in Neonatal HIE Using Short Time Window

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