Conflict of Interest Declaration
The ILCOR Continuous Evidence Evaluation process is guided by a rigorous ILCOR Conflict of Interest policy. The following Task Force members and other authors were recused from the discussion as they declared a conflict of interest: None applicable
The following Task Force members and other authors declared an intellectual conflict of interest and this was acknowledged and managed by the Task Force Chairs and Conflict of Interest committees: None applicable
CoSTR Citation
Lee H, Costa-Nobre D, Katheria A, Mausling R, Nakwa F, Schmölzer G, Weiner G, Liley HG on behalf of the Neonatal Life Support Task Force* International Liaison Committee on Resuscitation
Therapeutic hypothermia in limited resource settings (NLS #5701) [Internet] Brussels, Belgium: International Liaison Committee on Resuscitation (ILCOR) Neonatal Life Support Task Force, 2023 December 16th. Available from: http://ilcor.org
* Task Force members (in addition to Drs Lee, Costa-Nobre, Schmölzer, Weiner and Liley); Davis PG, Dawson JA, de Almeida MF, el-Naggar W, Fabres G, Fawke J, Foglia E, Guinsburg R, Isayama T, Kawakami M, Madar J, McKinlay C, Siguira T, Solevåg AL, Rüdiger M, Trevisanuto D, Wyckoff MH
Methodological Preamble and Link to Published Systematic Review
The continuous evidence evaluation process for the production of Consensus on Science with Treatment Recommendations (CoSTR) started with a systematic review of neonatal life support (Lee, 2022, 42022360554 – PROSPERO citation) conducted by ILCOR taskforce with support from David Honeyman, librarian at the University of Queensland, Brisbane, Australia, and with involvement of clinical content experts. After the completion of the systematic review, the search was performed again July 4, 2023 and no relevant studies were deemed applicable to add to the meta-analyses. The justifications and evidence to decision highlights section of this CoSTR are based on the systematic review and meta-analysis. These data were taken into account when formulating the Treatment Recommendations.
Systematic Review
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Therapeutic Hypothermia in Limited Resource Settings
PICOST
The PICOST (Population, Intervention, Comparator, Outcome, Study Designs and Timeframe)
Population: For late preterm and term infants (34+0 or more weeks’ gestation) with moderate/ severe hypoxic ischemic encephalopathy (HIE) managed in low resource settings
Intervention: Therapeutic hypothermia to a specified target temperature for a defined duration
Comparators: Standard care
Outcomes: Primary outcome is death or neurodevelopmental impairment (NDI) at 18 months to 2 years (critical), secondary outcomes are: death at hospital discharge (critical), neurodevelopmental impairments at 18 months to 2 years (critical), cerebral palsy (critical), blindness (critical), deafness (critical), persistent pulmonary hypertension of the newborn, or other adverse outcome (as defined by authors). Neurodevelopmental impairment was defined as abnormal motor, sensory or cognitive function using an appropriate standardized test (as noted by authors). Subgroups were limited to “active” vs. “non-active” methods of therapeutic hypothermia.
Study Designs: Randomized controlled trials (RCTs) and non-randomized studies (non-randomized controlled trials, interrupted time series, controlled before-and-after studies, cohort studies) were eligible for inclusion. Unpublished studies (e.g. conference abstracts, trial protocols) were excluded. Outcomes from observational studies were assessed if there were fewer than 3 included RCTs.
Timeframe: All years and all languages were included as long as there was an English abstract.
Search strings were developed for the following databases, and databases were searched from their inception date until September 15, 2022: MEDLINE (OVID interface), Embase (OVID interface), Cochrane Central Register of Controlled Trials, and any other database used that was unique to the PICOST.
An updated search was performed on July 4, 2023. One study identified in the updated search provided a secondary analysis of an already-included study.
The review was registered with PROSPERO CRD42022360554.
Risk of bias, using the Cochrane Risk of Bias 2 instrument (https://methods.cochrane.org/bias/resources/rob-2-revised-cochrane-risk-bias-tool-randomized-trials) was assessed for each outcome, but it is summarized for each comparison, because no important differences in risk of bias scores were found between outcomes.
Definitions
Moderate / severe hypoxic ischemic encephalopathy: Sarnat’s clinical staging system stages 2 or 3 or Thompson Score > 11, or as defined by authors. {Sarnat 1976 696, Thompson 1997 757}
Low resource setting (for study eligibility): any study conducted in low- and middle-income countries as designated by the World Bank; studies that were conducted in a low-resource setting in a high income country
Therapeutic hypothermia: intended therapy to maintain core temperature of ~33.5 degrees Celsius for defined duration (typically 72 hours)
Survival: survival to hospital discharge or as defined by authors
Neurodevelopmental impairment: graded by standardized testing, as defined by authors
Late preterm: 34+0 to 36+6 weeks gestation
Term: 37+0 and higher weeks gestation
Consensus on Science
The systematic review identified 21 RCTs involving 2145 infants with HIE. {Aker 2020 405, Aker 2022 32, Akisu 2003 45, Bharadwaj 2012 382, Catherine 2021 fmaa073, Chen 2018 1046, Das 2017 157, Gane 2014 134, Jose 2017 86, Joy 2013 17, Li 2009 147, Liao 2018 64, Lin 2006 180, Rakesh 2018 2418, Robertson 2008 801, Sun 2012 e316, Tanigasalam 2016 2545, Thayyil 2021 e1273, Yang 2020 300060520943770, Zhou 2010 367, Zou 2019 2332} The pre-specified outcomes included specification of the 18-24 month timeframe for later outcomes. Some studies reported on death or neurodevelopmental impairment at other timepoints after hospital discharge (for example, at 12 months). In order to account for those studies that had outcome assessment prior to 18 months, we distinguish the outcomes that were specific to the 18-24 month timeframe, and also present results that are more inclusive of reporting of outcomes outside that timeframe as “at follow up” more generally; these included studies that had follow-up at 6 months {Bharadwaj 2012 382},12 months {Gane 2014 134, Sun 2012 e316}, 15 months {Chen 2018 1046},18 months {Catherine 2021 fmaa073} and 30 months {Das 2017 157}. All studies included were conducted in low- and middle-income countries. No included studies were from high-income countries. Most studies were single center. Two were multi-center within one country {Li 2009 147, Zhou 2010 367}, and one was multi-center in several countries {Thayyil 2021 e1273}. Although the search intended to evaluate the population of late preterm and term (34+0 weeks and higher) infants, 15 of the included studies specified “term” infants as eligible at a minimum gestational age of 37 weeks or more. The other studies included 4 studies that had 36 weeks as the minimum gestational age, one study that had 35 weeks as the minimum gestational age, and one study without clear criteria for gestational age. Therefore, the data available for late preterm infants are very limited.
In term or late preterm infants with moderate or severe HIE in middle-or low-income countries, comparing use of therapeutic hypothermia to no therapeutic hypothermia:
For the critical combined outcome death or neurodevelopmental impairment at 18-24 months, there was probable clinical benefit (RR, 0.67; 95% CI, 0.45, 0.99; p = 0.04; I2 = 74%; absolute risk difference (ARD) 151 fewer infants per 1000 [95% confidence interval (CI) 252 fewer to 5 fewer]), moderate certainty evidence downgraded for risk of bias from five RCTs enrolling 813 participants. {Aker 2022 32, Li 2009 147, Thayyil 2021 e1273, Zhou 2010 367, Zou 2019 2332}
For the critical combined outcome death or neurodevelopmental impairment at follow up, there was possible clinical benefit (RR, 0.50; 95% CI, 0.35, 0.71; p = 0.0001; I2 = 80%; ARD 237 fewer infants per 1000 [95% CI from 308 fewer to 138 fewer]), low certainty evidence, downgraded for risk of bias and inconsistency, from nine RCTs enrolling 1168 participants. {Aker 2022 32, Bharadwaj 2012 382, Das 2017 157, Gane 2014 134, Li 2009 147, Sun 2012 e316, Thayyil 2021 e1273, Zhou 2010 367, Zou 2019 2332}
For the critical outcome death at 18-24 months, it was improbable that there was clinical benefit (RR, 0.89; 95% CI 0.55, 1.45; p = 0.65; I2 = 53%; ARD 28 fewer infants per 1000 [95% CI 115 fewer to 115 more]), moderate certainty evidence downgraded for risk of bias from five RCTs enrolling 813 participants. {Aker 2022 32, Li 2009 147, Thayyil 2021 e1273, Zhou 2010 367, Zou 2019 2332}
For the critical outcome death at follow up, clinical benefit or harm could not be excluded (RR, 0.62; 95% CI, 0.38, 1.01; P = 0.05; I2 = 64%; ARD 90 fewer infants per 1000 [95% CI, 148 fewer to 2 more]), low certainty evidence from nine RCTs enrolling 1168 participants. {Aker 2022 32, Bharadwaj 2012 382, Das 2017 157, Gane 2014 134, Li 2009 147, Sun 2012 e316, Thayyil 2021 e1273, Zhou 2010 367, Zou 2019 2332}
For the critical outcome death at hospital discharge, there was possible clinical benefit from the use of therapeutic hypothermia vs no therapeutic hypothermia in infants with HIE (RR, 0.70; 95% CI, 0.47, 1.02; P = 0.06; I2 = 54%; ARD 64 fewer infants per 1000 [95% CI, 114 fewer to 4 more]), moderate certainty evidence from fifteen RCTs enrolling 1488 participants. {Aker 2022 32, Akisu 2003 45, Bharadwaj 2012 382, Catherine 2021 fmaa073, Chen 2018 1046, Joy 2013 17, Liao 2018 64, Lin 2006 180, Rakesh 2018 2418, Robertson 2008 801, Sun 2012 e316, Tanigasalam 2016 2545, Thayyil 2021 e1273, Yang 2020 300060520943770, Zou 2019 2332}
For the critical outcome neurodevelopmental impairment at 18-24 months, there was possible clinical benefit (RR, 0.51; 95% CI, 0.39, 0.67; P < 0.0001; I2 = 0%; 127 fewer infants per 1000 [95% CI from 158 fewer to 86 fewer]), low certainty evidence, downgraded for risk of bias and inconsistency, from six RCTS enrolling 929 participants. {Aker 2022 32, Joy 2013 17, Li 2009 147, Thayyil 2021 e1273, Zhou 2010 367, Zou 2019 2332}
For the critical outcome neurodevelopmental impairment at follow up, there was possible clinical benefit (RR, 0.43; 95% CI, 0.34, 0.54; P < 0.0001; I2 = 0%; ARD 154 fewer infants per 1000 [95% CI, 178 fewer to 124 fewer]), low certainty evidence, downgraded for risk of bias and inconsistency, from twelve RCTs enrolling 1482 participants. {Aker 2022 32, Bharadwaj 2012 382, Catherine 2021 fmaa073, Chen 2018 1046, Das 2017 157, Gane 2014 134, Joy 2013 17, Li 2009 147, Sun 2012 e316, Thayyil 2021 e1273, Zhou 2010 367, Zou 2019 2332}
For the critical outcome cerebral palsy, there was clinical benefit (RR, 0.52; 95% CI, 0.37, 0.72; P < 0.0001; I2 = 0%; ARD 89 fewer infants per 1000 [95% CI from 117 fewer to 52 fewer]), high certainty evidence from six RCTs, enrolling 919 participants. {Aker 2022 32, Jose 2017 86, Li 2009 147, Sun 2012 e316, Thayyil 2021 e1273, Zhou 2010 367}
For the critical outcome blindness at follow up, there was probable clinical benefit (RR, 0.48; 95% CI, 0.22, 1.03; P = 0.06; I2 = 0%; ARD 28 fewer per 1000 [95% CI 41 fewer to 2 more]), moderate certainty evidence, downgraded for risk of bias, from four RCTs enrolling 718 participants. {Das 2017 157, Gane 2014 134, Jose 2017 86, Thayyil 2021 e1273}
For the critical outcome deafness at follow up, there was probable clinical benefit (RR, 0.42; 95% CI, 0.21, 0.82; P = 0.01; I2= 0%; ARD 42 fewer infants per 1000 [95% CI 57 fewer to 13 fewer]), moderate certainty evidence, downgraded for risk of bias, from four RCTs enrolling 718 participants. {Das 2017 157, Gane 2014 134, Jose 2017 86, Thayyil 2021 e1273}
For the critical outcome persistent pulmonary hypertension of the newborn (PPHN), clinical benefit or harm could not be excluded for the use of therapeutic hypothermia vs no therapeutic hypothermia in infants with HIE (RR, 1.31; 95% CI, 0.76 to 2.25; P = 0.33; I2 = 32%; 23 more patients/1000 [95% CI 18 fewer/1000 to 92 more/1000]), high certainty evidence from three RCTs, enrolling 564 participants. {Aker 2020 405, Tanigasalam 2016 2545, Thayyil 2021 e1273}
Subgroup analyses:
There were insufficient data to conduct the planned subgroup analysis. In particular, it was difficult to distinguish studies that used solely “passive” methods of cooling (removal of heat sources, clothing and coverings) from those that may have also used manually controlled “active” methods such as refrigerated gel packs and those that used both. Furthermore, both these methods may result in wider variation of core temperature than servo-controlled devices. The task force concluded that a more meaningful distinction was between studies that used servo-controlled vs non-servo-controlled methods of therapeutic hypothermia, and so this post-hoc subgroup analysis was conducted.
For subgroup analysis by servo-controlled vs non-servo-controlled methods, for the critical outcome death or neurodevelopmental impairment at follow up, the non-servo-controlled methods were more efficacious than servo-controlled (test for subgroup differences (random effects): χ2 = 22.43, df =1 (p < 0.0001)). For the critical outcome of death at follow up, the non-servo-controlled methods were more efficacious than servo-controlled (test for subgroup differences (random effects): χ2 = 14.80, df =1 (p = 0.0001)). For the critical outcome of death at hospital discharge, the non-servo-controlled methods were more efficacious than servo-controlled (test for subgroup differences (random effects): χ2 = 7.39, df =1 (p = 0.0065)). For all other outcomes, results of tests for subgroup differences were not statistically significant. However, heterogeneity in study design, meaning that factors other than method of cooling may have made a major contribution to the effect sizes for each subgroup.
For the servo-controlled studies, for the primary outcome of death or neurodevelopmental impairment at 18-24 months, clinical benefit or harm could not be excluded (RR, 0.73; 95% CI, 0.50, 1.07; P = 0.11; I2 = 74%). There was probable clinical benefit for the secondary outcomes of death or neurodevelopmental impairment at follow up (RR, 0.69; 95% CI, 0.48, 0.98; P = 0.037; I2 = 73%), neurodevelopmental impairment at 18-24 months (RR, 0.51; 95% CI, 0.36 to 0.72; P = 0.0002; I2 = 0.0%), neurodevelopmental impairment at follow up (RR, 0.48; 95% CI, 0.35, 0.65; P < 0.0001; I2 = 0.0%), and cerebral palsy (RR 0.46, 95% CI, 0.29 to 0.71, P = 0.0004, I2 = 0.0%). For the following outcomes, clinical benefit or harm could not be excluded: death at hospital discharge (RR, 1.17; 95% CI, 0.89, 1.54; P = 0.26; I2 = 42%), death at follow up (RR, 1.12; 95% CI, 0.90, 1.41; P = 0.30; I2 = 36%), blindness (RR 0.51, 95% CI 0.18, 1.47, P = 0.21, I2 = n/a), and deafness (RR, 0.51; 95% CI, 0.13, 2.01; P = 0.34; I2 = n/a).
For the non-servo-controlled studies, there was a probable clinical benefit for the primary outcome of death or neurodevelopmental impairment at 18-24 months (RR, 0.33; 95% CI, 0.12, 0.89; P = 0.029; I2 = n/a). There was additional probable clinical benefit for the secondary outcomes of death at hospital discharge (RR, 0.66; 95% CI, 0.50, 0.88; P = 0.0043; I2 = 14.90%), death at follow up (RR, 0.34; 95% CI, 0.19, 0.61; P = 0.0002; I2 = 0.0%), neurodevelopmental impairment at follow up (RR, 0.39; 95% CI, 0.28 to 0.54; P < 0.0001; I2 = 0.0%), neurodevelopmental impairment at 18-24 months (RR, 0.52; 95% CI, 0.36 to 0.77; P = 0.0009; I2 = 0.0%), death or neurodevelopmental impairment at follow up (RR, 0.30; 95% CI, 0.21, 0.44; P = <0.0001; I2 = 0.0%), and deafness (RR, 0.33; 95% CI, 0.11, 0.97; P = 0.04; I2 = 0.0%). Clinical benefit or harm could not be excluded for blindness (RR 0.33, 95% CI 0.11, 1.33, P = 0.13, I2 = 0.0%).
Treatment Recommendations
We suggest the use of therapeutic hypothermia in comparison with standard care alone for term (≥37+0 weeks gestational age) newborn infants with evolving moderate-to-severe hypoxic-ischemic encephalopathy in low- and middle-income countries in settings where a suitable level of supportive neonatal care is available (weak recommendation, low-certainty evidence).
For late preterm infants, 34+0 to 36+6 weeks gestational age infants, a recommendation cannot be made due to insufficient evidence.
Good practice statement: Cooling should only be considered, initiated, and conducted under clearly defined protocols with treatment in neonatal care facilities with the capabilities for multidisciplinary care and availability of adequate resources to offer intravenous therapy, respiratory support, pulse oximetry, antibiotics, anticonvulsants, transfusion services, radiology including ultrasound, and pathology testing. Treatment should be consistent with the protocols used in randomized clinical trials. Most protocols included commencement of cooling within 6 hours after birth, strict temperature control to specified range (typically 33°C to 34°C) and most commonly for a duration of 72 hours with rewarming over at least 4 hours. Adoption of hypothermia techniques without close monitoring, protocols, or without availability of comprehensive neonatal intensive care may lead to harm.
Justification and Evidence to Decision Framework Highlights
Therapeutic hypothermia is now considered standard care in high-income countries for the treatment of moderate-to-severe hypoxic ischemic encephalopathy term and near-tear infants. {Jacobs 2013 Cd003311} However, its safety and efficacy in low- and middle-income countries has been uncertain.
A 2020 Evidence Update found insufficient new evidence to change the 2015 CoSTR treatment recommendation: We suggest that newly born infants at term or near-term with evolving moderate-to-severe hypoxic-ischemic encephalopathy in low-income countries and/or other settings with limited resources may be treated with therapeutic hypothermia (weak recommendation, low-quality evidence). {Wyckoff 2015 S543, Wyckoff 2020 S185}
The topic was prioritized by the NLS Task Force after a publication of a large RCT in seven tertiary neonatal intensive care units in India, Sri Lanka and Bangladesh found that therapeutic hypothermia did not reduce the combined outcome of death or disability at 18 months after neonatal encephalopathy in low-income and middle-income countries, and significantly increased death alone. {Thayyil 2021 e1273}
For the primary (combined) outcome of death or neurodevelopmental impairment at 18-24 months moderate certainty evidence from five RCTs showed a clinically significant benefit from the use of the intervention. Although there was no benefit for the outcome of death at various time points, the neurodevelopmental outcomes were improved with the use of therapeutic hypothermia. Although the evidence for several important outcomes was of moderate certainty using GRADE criteria, it should be noted that none of studies was blinded. Furthermore, for the primary outcome of death and neurodevelopmental impairment, and other outcomes that concerned the critical outcome of death, there was high heterogeneity, suggesting the possibility of publication bias. Therefore, the task force concluded that the recommendation is based on low certainty evidence overall.
For the other five critical outcomes and one important outcome, therapeutic hypothermia also showed a benefit compared to standard care, although there was no improvement in death (at discharge, at follow up, or at 18 to 24 months) from the use of therapeutic hypothermia.
While our PICOST question pre-specified late preterm and term infants as the population of interest, most included studies (15 of 21) recruited term infants with gestational age 37 weeks or greater. In some low resource settings, the dating of pregnancy may not be as certain. Studies in high-income countries have not shown clear benefit for late preterm infants with the use of therapeutic hypothermia. The evidence from this review was not considered robust for therapeutic hypothermia in infants <37 weeks’ gestation, and hence the treatment recommendation is made only for term infants.
In reviewing the included studies, the descriptions of the care received, such as advanced respiratory support, point to many of the neonatal units being high-resourced services despite their location in low- or middle-income countries. Therefore, the safety and efficacy of therapeutic hypothermia in settings that cannot provide comprehensive intensive care remains uncertain, and hence a good practice statement specifying the need for such care has been made. The task force also considered that treatment should be consistent with the protocols used in the randomized clinical trials, i.e., cooling to commence within 6 hours after birth, strict temperature control to specified range (typically 33°C to 34°C) for specified duration (72 hours) and rewarming with close monitoring over at least 4 hours according to a protocol.
For many of the studies included in the review, there have been concerns raised concerning study methodology, the settings in which the studies were conducted, methods of patient selection, underlying heterogeneity, consistency of diagnosis, and the etiology of neonatal encephalopathy with potential variation amongst settings. {Krishnan 2021 }
For adverse outcomes there was heterogeneity and inconsistency of reporting among the included studies, precluding meta-analysis. The task force considered that publication bias might also be present. Most of the included studies were single center and, in all studies, neonatal intensive care was provided. Due to these concerns, the treatment is suggested rather than recommended and is conditional on the availability of neonatal intensive care.
In addition to the care in the birth period, adequate follow-up care both immediately after hospital discharge and long-term, to monitor and treat issues related to neurodevelopmental impairment is likely to be needed to ensure optimal outcomes and to monitor the effectiveness of treatment at each location. This follow-up should ideally include regular assessment using standard behavioral and neurodevelopmental tools, assessment of hearing and vision, and access to early intervention therapies.
Knowledge Gaps
Key gaps in knowledge include:
- minimum intensive care resources required for safety and effectiveness of therapeutic hypothermia in low- and middle-income countries.
- cost effectiveness of therapeutic hypothermia (using various methods and devices) in low- and middle-income countries.
- resource implications (including equipment, monitoring, nursing care and outcome measurement) for safe and effective care of infants receiving therapeutic hypothermia in low- and middle-income countries.
- strategies for optimal case recognition of infants who may benefit or may be harmed from therapeutic hypothermia in countries at all income levels.
Attachments: NLS 5701 Therapeutic hypothermia in limited resource settings Evidence to Decision Table
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