Effect of rewarming rate on outcomes for newborn infants who are unintentionally hypothermic after delivery (NLS 5700) TF SR

Conflict of Interest Declaration

No conflict of interest.

CoSTR Citation

Rüdiger M, Kawakami MD, Madar J, Finan E, Hooper S, Schmölzer G, Weiner G, Liley HG on behalf of the Neonatal Life Support Task Force* International Liaison Committee on Resuscitation. Effect of rewarming rate on outcomes for newborn infants who are unintentionally hypothermic after delivery. [Internet] Brussels, Belgium: International Liaison Committee on Resuscitation (ILCOR) Advanced Life Support Task Force, 2023 December xx. Available from: http://ilcor.org

* Task Force members (in addition to Drs Rüdiger, Kawakami, Madar, Schmölzer, Weiner and Liley); Costa-Nobre D, Davis PG, Dawson JA, de Almeida MF, el-Naggar W, Fabres G, Fawke J, Foglia E, Guinsburg R, Isayama T, Lee H, Madar J, McKinlay C, Siguira T, Solevåg AL, Trevisanuto D, Wyckoff MH

Methodological Preamble and Link to Published Systematic Review

Newborn infants are at high risk of becoming hypothermic during resuscitation and in the immediate newborn period. Previous evidence has demonstrated poor outcomes due to unintentional hypothermia.{Laptook 2018 53, Wilson 2016 61} As a result, clinicians strive to achieve normothermia during the resuscitation and stabilization phase however the preferred rate of rewarming for unintentionally hypothermic infants has remained unclear.

The most recent ILCOR systematic review of this topic was in 2015 (NLS 858) which concluded that; “The confidence in effect estimates is so low that a recommendation for either rapid rewarming (0.5°C/h or greater) or slow rewarming (0.5°C/h or less) of unintentionally hypothermic newborn infants (temperature less than 36°C) at hospital admission would be speculative”. {Perlman 2015 S204} In 2020, the Neonatal Life Support Task Force undertook an evidence update which concluded that there were sufficient new studies to consider updating the systematic review. {Wyckoff 2020 S185} The PICOST for the current review also considered additional outcomes as suggested in the evidence update.

The continuous evidence evaluation process for the production of Consensus on Science with Treatment Recommendations (CoSTR) started with a systematic review of rate of rewarming (PROSPERO 2022 CRD42022359005) conducted by Mario Rüdiger, Mandira Daripa Kawakami, John Madar, Emer Finan and Stuart Hooper. Evidence from neonatal literature was sought and considered by the Neonatal Life Support Task Force and clinical content experts. These data were taken into account when formulating the Treatment Recommendations.

Systematic Review

Rüdiger M, Kawakami MD, Madar J, Finan E, Hooper S. Effect of rewarming rate on outcomes for newborn infants who are unintentionally hypothermic after delivery.

PICOST (Population, Intervention, Comparator, Outcome, Study Designs and Timeframe)

Description: For newborn infants who are hypothermic (<36.0˚C) on admission (P), does rapid rewarming (I), compared with slow rewarming (C), change outcome (O)?

Population: Newborn infants who are hypothermic (<36.0˚C) on admission

Intervention: rapid rewarming (≥0.5°C/hour)

Comparison: slow rewarming (<0.5°C/hour)

Outcomes:

• Mortality rate [critical]

• Need for respiratory support during the first 48 hours of life [important]

• Hypoglycemia during the first week of life

• Convulsions/seizures during hospital stay

• Length of hospital stay [important]

• Neurodevelopmental impairment [critical]

In addition for preterm infants <34 weeks:

• Intraventricular hemorrhage (all grades- important; severe (III or IV -critical)

• Periventricular leukomalacia [critical]

• Necrotizing enterocolitis [important]

Study Design

Inclusion criteria: 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.

Exclusion criteria: Unpublished studies (e.g., conference abstracts, trial protocols), case series, case reports and animal studies were excluded.

Timeframe

Systematic Review search strategy: All years and all languages were included as long as there was an English abstract. The search strategy designed for the 2020 evidence update was re-run in July 2022 and updated in July 2023

PROSPERO registration:

The review was registered with PROSPERO 2022 CRD42022359005

Risk of Bias

In all cases bias was assessed by studies rather than by outcome because there were no meaningful differences in bias for the outcomes that were reported and available for assessment.

Consensus on Science

The systematic review identified one RCT {Motil 1974 546} that enrolled 42 neonates but excluded two infants after randomization due to predefined reasons for study withdrawal, resulting in a sample for analysis of 40 infants for most outcomes. This study compared maximum temperature set points for the servo-controlled radiant warmers used for rewarming, but rates of rewarming depended on these set points. The study enrolled only (otherwise well) term newborn infants of normal birthweight. The review also included two observational studies enrolling a total of 280 neonates, one of which included only infants £28 weeks gestation and/or birth weight £1000 g {Rech Morassutti 557}, while the other enrolled only newborn infants <1500 g birthweight. {Rech Morassutti 2015 557}

For newborn infants who are unintentionally hypothermic after birth:

1. Mortality rate

For the critical outcome of mortality rate, clinical benefit or harm cannot be excluded for rapid compared to slow rates of rewarming (relative risk (RR) 1.09, 95% confidence interval (CI) 0.7-1.71, ARD 17 more infants per 1000 [95% CI from 58 fewer to 138 more]), low certainty evidence (downgraded for very serious imprecision) from 2 observational studies including 280 newborn infants. {Feldman 2016 295, Rech Morassutti 2015 557}

1. Hypoglycemia during the first week of life

For the important outcome of hypoglycemia, defined as glucose <30mg/dL (1.6 mmol/L), clinical benefit or harm cannot be excluded when comparing rapid to slow rates of rewarming ((RR 0.3, 95% CI 0.09-1.05), ARD 292 fewer infants per 1000 [95%CI from 379 fewer to 21 more]), very low certainty evidence (downgraded for serious indirectness and very serious imprecision) from one small randomized controlled trial, in which 8 newborn infants of 36 for whom the outcome was measured developed asymptomatic hypoglycemia during the first four hours from study enrolment. {Motil 1974 546}

For the important outcome of hypoglycemia, defined as glucose <47mg/dL (2.6 mmol/L), clinical benefit or harm cannot be excluded when comparing rapid to slow rates of rewarming ((OR 0.46, 95% CI 0.20-1.07), ARD 130 more infants per 1000 [95% CI from 211 fewer to 14 more]), very low certainty evidence (downgraded for serious indirectness and very serious imprecision) from one observational study, in which 47 newborn infants of 182 for whom the outcome was measured developed hypoglycemia. {Rech Morassutti 2015 557}

1. Convulsion/ seizures during hospital stay

For the important outcome of convulsion/seizures, clinical benefit/harm cannot be excluded when comparing rapid to slow rates of rewarming (RR 1.12, 95% CI 0.26 to 4.86, ARD 4 more infants per 1000 [95% CI from 27 fewer to 142 more]), low certainty evidence (downgraded for very serious imprecision) from one observational study including 182 newborn infants. {Rech Morassutti 2015 557}

1. Length of hospital stay

For the important outcome of length of hospital stay, clinical benefit or harm cannot be excluded (rapid rewarming group [median 62, IQR 26-89 days] compared to slower rewarming group [median 77, IQR 48- 108 days]; p=0.47), low certainty evidence (downgraded for very serious imprecision) from one observational study including 182 neonates. {Rech Morassutti 2015 557}

1. Intraventricular hemorrhage (all grades- important)

For the critical outcome of intraventricular hemorrhage, clinical benefit or harm cannot be excluded when comparing rapid with slow rates of rewarming (RR 1.18, 95% CI 0.81-1.72, ARD 47 more infants per 1000 [95% CI from 50 fewer to 188 more]), low certainty of evidence (downgraded for very serious imprecision) from 2 observational studies including 280 neonates. {Feldman 2016 295, Rech Morassutti 2015 557}

1. Necrotizing enterocolitis (NEC)

For the important outcome of necrotizing enterocolitis, clinical benefit or harm cannot be excluded when comparing rapid with slow rates of rewarming (RR 0.68, 95% CI 0.13 to 3.52, ARD 26 fewer infants per 1000 [95% CI from 70 fewer to 202 more]), low certainty evidence (downgraded for very serious imprecision) from one observational study in which NEC occurred in 6 of 98 included infants. {Feldman 2016 295}

1. Neurodevelopmental impairment

For the critical outcome of neurodevelopmental impairment, there were no data to assess the effect of rate of rewarming.

1. Periventricular leukomalacia

For the critical outcome of periventricular leukomalacia, there were no data to assess the effect of rate of rewarming.

1. Need for respiratory support during the first 48 hours after birth

For the important outcome of need for respiratory support during the first 48 hours after birth, there were no data to assess the effect of rate of rewarming.

Treatment Recommendations

In newborn infants who are unintentionally hypothermic after birth, rewarming should be commenced, but there is insufficient evidence to recommend either rapid (≥0.5˚C /hour) or slow (<0.5˚C /hour) rates of rewarming. (Low certainty evidence)

Irrespective of the rewarming rate chosen, a protocol for rewarming should be used. Frequent or continuous monitoring of temperature should be undertaken while rewarming, particularly if using a supraphysiological set temperature point to accelerate the rewarming rate, due to potential risk of hyperthermia. In any hypothermic infant, monitoring of blood glucose should occur due to risk of hypoglycemia. (Good practice point)

Justification and Evidence to Decision Framework Highlights

The available evidence does not confirm clinical benefit or harm in either rewarming rate; however, the overall certainty of evidence was low with wide confidence intervals and small numbers.

We are aware of the increased risk of mortality associated with hypothermia. However, the included studies were too small to assess the impact of rewarming rate on mortality. The one included small RCT showed an association of slow rewarming with asymptomatic hypoglycemia. {Motil 1974 546} However, a larger observational study did not show any association with hypoglycemia although again, the total number of infants was low. {Rech Morassutti 2015 557} Finally, one observational study showed an association of rapid rewarming with a reduced rate of respiratory distress syndrome (RDS) in preterm infants. {Rech Morassutti 2015 557} However, numbers were small, the absolute risk difference is not shown, and the authors did not report whether this resulted in a clinical difference in need for respiratory support for RDS.

The task force considered that both intervention and control were acceptable and feasible. Two of the three included studies used servo-controlled devices to monitor and control the rate of rewarming. If servo-controlled devices (e.g. servo-controlled radiant warmers, incubators, or thermal mattresses) are demonstrated to improve outcomes of rewarming in future studies, the cost of these devices (capable of operating in servo-mode) and disposable temperature probes may have implications in resource limited settings.

The rate of rewarming varied widely in both the slow and rapid rewarming groups in the included studies. The task force noted that a safe maximum rate of rewarming has not been identified. Furthermore, none of the included studies reported hyperthermia as an outcome. However, one observational study that did not meet the inclusion criteria found that 43 (12.5%) of 344 included infants developed hyperthermia (>37.5˚C). {Rossi 2023 1113897} In this study, a rapid, compared to a slow rewarming rate was associated with hyperthermia (p=0.007). It is unclear whether this related to specific settings of the devices used for rewarming in this study (which were radiant warmers and incubators in manual mode), or to other characteristics of the included infants. Future studies should consider this important outcome.

Knowledge Gaps

Attachment: NLS 5700 Rapid vs slow rewarming for unintended hypothermia Et D

References

Feldman A, De Benedictis B, Alpan G, La Gamma EF, Kase J. Morbidity and mortality associated with rewarming hypothermic very low birth weight infants. J Neonatal Perinatal Med. 2016;9(3)295-302.

Laptook AR, Bell EF, Shankaran S, Boghossian NS, Wyckoff MH, Kandefer S, et al. Admission Temperature and Associated Mortality and Morbidity among Moderately and Extremely Preterm Infants. J Pediatr. 2018;19253-59.e2.

Motil KJ, Blackburn MG, Pleasure JR. The effects of four different radiant warmer temperature set-points used for rewarming neonates. J Pediatr. 1974;85(4)546-50.

Perlman JM, Wyllie J, Kattwinkel J, Wyckoff MH, Aziz K, Guinsburg R, et al. Part 7: Neonatal Resuscitation: 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Circulation. 2015;132(16 Suppl 1)S204-41.

Rech Morassutti F, Cavallin F, Zaramella P, Bortolus R, Parotto M, Trevisanuto D. Association of Rewarming Rate on Neonatal Outcomes in Extremely Low Birth Weight Infants with Hypothermia. J Pediatr. 2015;167(3)557-61.e1-2.

Rossi E, Maziku DM, Leluko DE, Guadagno C, Brasili L, Azzimonti G, et al. Rewarming rate of hypothermic neonates in a low-resource setting: a retrospective single-center study. Front Pediatr. 2023;111113897.

Wilson E, Maier RF, Norman M, Misselwitz B, Howell EA, Zeitlin J, et al. Admission Hypothermia in Very Preterm Infants and Neonatal Mortality and Morbidity. J Pediatr. 2016;17561-67.e4.

Wyckoff MH, Wyllie J, Aziz K, de Almeida MF, Fabres J, Fawke J, et al. Neonatal Life Support: 2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Circulation. 2020;142(16_suppl_1)S185-s221.