RECOVER 2.0 Worksheet

QUESTION ID: Newborn-28

PICO Question:
In newborn dogs and cats with ROSC that are spontaneously hypothermic (P), how does rewarming at a rate greater than 1 C/hour (I) compared with rewarming at a rate of 1 or less C/hour (C) improve outcome (O)?

Outcomes:
Surrogate marker(s) of perfusion,Histopathologic damage,Complications,Favorable neurologic outcome,Survival to Discharge

Prioritized Outcomes (1= most critical; final number = least important):

1. Favorable neurologic outcome

2. Survival to discharge

3. Complications

4. Surrogate markers of perfusion

5. Histopathologic damage

Domain chairs: Christopher Byers, Autumn Davidson, WS completed by Manuel Boller

Evidence evaluators: Katie Nash, Ladan Mohammad-Zadeh

Conflicts of interest: None

Search strategy: See attached document

Evidence Review:

Add rows to the table to incorporate all outcomes evaluated as part of the evidence review and all study types. You can use this template to add a new outcome by copying and pasting it to the end of the table. Once you have completed your review, please delete this template from the document.

Study Design

Reduced Quality Factors 0 = no serious, - = serious, - - = very serious

Positive Quality Factors 0 = none, + = one, ++ = multiple

Dichotomous Outcome Summary

Non-Dichotomous Outcome Summary Brief description

Overall Quality High, moderate, low, very low, none

No of studies

Study Type

RoB

Indirectness

Imprecision

Inconsistency

Large Effect

Dose-Response

Confounder

# Intervention with Outcome

# Control with Outcome

RR (95% CI)

Outcome: Favorable neurologic outcome: No evidence identified

0

NA

Outcome: Survival to discharge: No evidence identified

0

NA

Outcome: Complications: No evidence identified

1

ES

0

--

-

0

0

0

0

EEG power better with slow rewarming, but no impact on seizure burden. Could be secondary effect to prolonged protective effect of hypothermia with slow rewarming.

Very low

Outcome: Surrogate markers of perfusion: No evidence identified

0

NA

Outcome: Histopathologic damage

5

ES

0

--

-

0

0

0

0

No effect of slow rewarming on neuronal death, and white matter injury compared to fast rewarming after various lengths of TH

Very low

PICO Question Summary

Introduction

Newborn puppies and kitten are commonly hypothermic after birth and might be particularly vulnerable to low body temperature if undergoing resuscitative measures.[ Vassalo 2015] Establishing normothermia by utilizing passive and active temperature control measures is recommended during resuscitation of newborn puppies and kittens (see NB11) and infants.[ Wyckoff 2020] However, after a hypoxic-ischemic insult, evidence suggests that hypothermia is neuroprotective and that it should be maintained by active cooling (i.e., therapeutic hypothermia) or permissively in newborns with HIE (see NB27).( Wyckoff 2020, Greif 2024) The current RECOVER treatment recommendation in adult dogs and cats with ROSC is to suggest slow rewarming (0.25-0.5°C/hr) and recommends against fast rewarming (e.g., > 1°C/hr).( Fletcher 2012, Smarick 2012) The current question asks whether slow rewarming is beneficial over fast rewarming (e.g., > 1°C) in newborn puppies and kittens that experienced a significant hypoxic-ischemic insult at birth (e.g., CPA) and that are hypothermic.

Consensus on science

Outcome 1,2,4: Favorable neurologic outcome, survival to discharge, and surrogate markers of perfusion We identified no studies addressing the question for the critical outcome of favorable neurologic outcome and survival to discharge and the important outcome of surrogate markers of perfusion. Outcome 3: Complications For the important outcome of complications, we identified 1 ES (very low quality of evidence, downgraded for very serious indirectness and imprecision) pertinent to the PICO question.[ Davidson 2019) In an HIE model in near-term fetal lambs, cerebral ischemia of 30 minutes was followed by 48 hours of HYPOTHERMIA and either fast (5°C/h, n=8) or slow (0.2°C/h, n=8) rewarming. While seizure activity was extensive during ischemia and effectively suppressed during HYPOTHERMIA, rapid rewarming resulted in no significant effect on EEG-documented seizure burden (e.g., no rebound seizures).[ Davidson 2019] Outcome 5: Histopathologic damage For the important outcome of histopathologic damage, we identified 5 ES (very low quality of evidence, downgraded for very serious indirectness and imprecision) pertinent to the PICO question.[ Davidson 2019, Wang 2015, Wang 2016, Draghi 2019, McDouall 2024] The same near-term fetal HIE model described above was used in 3 studies examining the effect of slow (0.2 – 0.5°C/h) versus fast rewarming (4 – 5°C/h) on neuronal cell death and apoptosis as well as white matter changes (oligodendrocyte reduction, astrocytosis, microgliosis).[ Draghi 2019, Davidson 2019, McDouall 2024] For the majority of outcomes, slow rewarming had no protective effect over fast rewarming. Only 1 study found a reduction in astrocyte proliferation, a marker of brain injury, with slow rewarming.( Draghi 2019) It remains open whether this was a direct benefit of slow rewarming itself or due to the associated extension of hypothermia. Two studies were conducted in a newborn swine asphyxial cardiac arrest model, with animals undergoing CPR, 18 hours of hypothermia and rewarming at either 0.5°C/h (slow, n=8) or 4°C/h (fast, n=8).[ Wang 2015, Wang 2016] Fast rewarming did not lead to any differences in neuronal cell death, but was associated with increased apoptosis in the cortex but not in subcortical white matter.[ Wang 2015, Wang 2016].

Treatment recommendation

In newborn puppies and kittens that are hypothermic at birth and show evidence of hypoxic-ischemic injury, we suggest rewarming at a rate no faster than 1°C/h to achieve normothermia (35.0-37.2°C; 95-99°F) while avoiding accidental hyperthermia. (weak recommendation, very low quality of evidence) In newborn puppies and kittens that are hypothermic at birth without signs of hypoxic-ischemic encephalopathy, we suggest to actively rewarm newborns over 1-2 hours to reach normothermia (35.0–37.2°C; 95-99°F), avoiding accidental hyperthermia. (weak recommendation, expert opinion)

Justification of treatment recommendation

There are two scenarios in which rewarming is relevant in the context of newborn resuscitation of puppies and kittens. One concerns those animals with unintended hypothermia at birth that otherwise transition normally and for which establishing normothermia is important (see NB11). The other scenario concerns animals with acute signs of HIE, that are deliberately treated with permissive hypothermia for a period of time and might require rewarming by external heat administration at the end of that period to achieve normothermia (see NB27). The current PICO question primarily relates to the latter scenario. The studies identified report only lower priority outcomes and the study findings do not demonstrate consistent, if any benefit of slow over fast rewarming on the outcomes that were examined. This lack of differential effect occurred despite a 10-20 fold difference between slow and fast rewarming rates.[ Davidson 2019, Wang 2015, Wang 2016, Draghi 2019, McDouall 2024] Moreover, slower rewarming will lead to longer exposure to hypothermia, which could be the reason for the beneficial effects observed in some studies.[ Draghi 2019, Davidson 2019] Studies that did not qualify for inclusion in the evidence evaluation here, including one case report and one observational study without control group, reported risk of hypotension with rapid rewarming and the possibility for rebound seizure activity during rewarming.[ Thoresen 2000, Battin 2004] In addition, multiple experimental animal studies of HIE for other reasons than periparturient asphyxiation demonstrate harm with fast (i.e., > 1°C/h) rewarming rates.[ Lu 2014, Berger 2006, Suehiro 2003, Bisschops 2012, Zhu 2016, Suehiro 2001] For precautionary reasons, the recommendation for newborn infants undergoing TH is to rewarm over at least 4 hours, or at a rate of 0.5°C/h or less, which was the case in most clinical TH trials.[ Perlman 2010, Grief 2024, Thayyil 2021, Eicher 2005, Azzopardi 2009, Shankaran 2005, Jacobs 2011] Fast rewarming rates through external heat administration also carry the theoretical risk of overshoot hyperthermia. All taken together, the committee believes that it is prudent to avoid rapid rewarming of hypothermic newborn puppies and kittens with signs of acute HIE, and suggests a rewarming rate of 1°C/h or less. We did not systematically review the evidence on optimal rewarming rates for newborn puppies and kittens that are unintentionally hypothermic at birth but are otherwise normal or require only low levels of support. The most recent treatment recommendation for temperature management of newborn hypothermic infants emphasizes the need for establishing normothermia but does not stipulate any specific rewarming rate due to a lack of evidence.( Wyckoff 2020) Observational and interventional studies in newborn infants involving very-low-birthweight to normal full term infants and rewarming rates ranging from 0.1°C/h to 5°C/h did not document an association between rewarming rate and a variety of outcomes including mortality.[ Motil 1974, Rech Morassutti 2015, Feldman 2016, Jain 2021, Rossi 2023) One observational study identified an association between higher rewarming rates and the risk of hypothermia.( Rossi 2023) We did not identify any studies in newborn puppies and kittens pertaining to the topic. Thus, we recommend establishing normothermia over a few hours’ time and maintaining of normothermia (see NB11). Avoidance of hyperthermia with exposure to external heat sources through appropriate monitoring is of central importance, as temperature overshoot is likely the biggest risk with faster rewarming rates in otherwise normal newborns.( Christensen 2024)

Knowledge gaps

The benefits and risks of fast versus slow rewarming after intended hypothermia in newborn puppies and kittens with HIE have not been studied and no safe protocols have been established. Of particular concerns would be the occurrence of hypoglycemia with prolonged hypothermia and slow rewarming, and the risk of seizure activity or hyperthermia with faster rewarming strategies.

Relevant literature (* pertinent to rewarming after intended hypothermia//TH/HIE; ** pertinent to non-intended hypothermia)

*Wang 2015 (1404): Rewarming from therapeutic hypothermia induces cortical neuron apoptosis in a swine model of neonatal hypoxic–ischemic encephalopathy.

EXP, Outcomes: histopath

Population: Piglets, male, 3-5 days old, hypoxic-ischemic injury by reduction of FiO2 to 10%, causing an SaO2 of 35% for 45 minutes, followed by room air, followed by asphyxiation by ET tube clamping for 7 minutes, followed by CPR

Intervention and comparator: normothermia post ROSC (38.5-39.5C), whole body hypothermia (34.0C), whole body hypothermia x 18 hrs and slow rewarming (0.5C/hr), whole body hypothermia x 18 hrs and fast rewarming (4C/hr). 8 piglets per group

Outcomes examined: apoptosis in motor and piriform cortex; neuronal cell death motor cortex and piriform cortex; surrogates (MAP, PaCO2, pH, electrolytes)

Results: Motor cortex: No diff in apoptosis between slow and fast rewarming. No change in neuronal death between slow and fast rewarming Similar findings in piriform cortex. More caspase activation with rapid rewarming than slow rewarming, and rewarming generally activates apoptosis (cell homogenate, so uncertain which cell type).

*Wang 2016 (1402): White matter apoptosis is increased by delayed hypothermia and rewarming in a neonatal piglet model of hypoxic ischemic encephalopathy.

EXP, histopath

Population: Piglets, male, 3-5 days old, hypoxic-ischemic injury by reduction of FiO2 to 10%, causing an SaO2 of 35% for 45 minutes, followed by room air, followed by asphyxiation by ET tube clamping for 7 minutes, followed by CPR

Intervention and comparator: normothermia post ROSC (38.5-39.5C), whole body hypothermia (34.0C), whole body hypothermia x 18 hrs and slow rewarming (0.5C/hr), whole body hypothermia x 18 hrs and fast rewarming (4C/hr). 8 piglets per group

Outcomes examined: apoptosis in white matter; cell death in white matter (TUNEL stain); surrogates (MAP, PaCO2, pH, electrolytes)

Results: Similar apoptotic profile counts between fast and slow rewarming (p=0.967) in striatal matter and hippocampus. Same for cell death as by TUNEL; no impact on caspase-3 in subcortical white matter (unlike in Wang 2015 for cortical grey matter). Apoptosis primarily in glia, given the absence of increased neuronal death in the areas examined. Overall, no effect of rewarming rate on apoptosis, but rewarming as such (regardless of rate) promoted white matter apoptosis.

*McDouall 2024: Slow rewarming after hypothermia does not ameliorate white matter injury after hypoxia-ischemia in near-term fetal sheep.

Population: Near-term fetal sheep (intrauterine, instrumeted) with HIE due to cerebral ischemia for 30 minutes.

Intervention and comparator: NT (n=8), hypothermia (3-72hrs) followed by spontaneous fast rewarming (n=8) in 1 hr (approx. 4C/h), or slow rewarming (0.5C/h) over 10 hours (n=8). Tissue harvested after 7 days.

Outcomes examined: Recovery of white matter: oligodendrocyte reduction (i.e., oligodendrocyte survival); myelin binding protein expression (MBP expression) and CNPase (i.e., both markers of myelination), glial protein expression as marker of astrocytosis (GFAP) and Iba-1 for microclia

Results: No difference in oligo reduction with fast versus slow rewarming (P>0.9), no difference in MBP (P>0.2), CNPase (P>0.3), GFAP (P>0.2), are fraction of GFAP (P>0.7). Overall slow rewarming was not associated with improved white matter outcomes (oligendrocyte preservation, astrocyte and microglia proliferation) when compared to fast, spontaneous rewarming, even after 72 hour of cooling.

*Davidson 2019: Limited benefit of slow rewarming after cerebral hypothermia for global cerebral ischemia in near-term fetal sheep.

Population: Near-term fetal sheep (intrauterine, instrumented) with HIE due to cerebral ischemia for 30 minutes.

Intervention and comparator: NT (n=8), hypothermia (approx. 32C) (3-48hrs) followed by spontaneous fast rewarming (n=8) in 1 hr (approx. 5C/h), or slow rewarming (0.2C/h) (n=7) over 24 hours, or hypothermia (72 h) with fast rewarming (to 39C). Tissue harvested after 7 days.

Outcomes examined: Neurophysiologic outcomes including seizure burden (on EEG) and suppression of EEG power

Results: Slower rewarming had significant positive impact on EEG power (P<0.05); no effect on seizure burden. No effect on neuronal survival beyond hypothermia.

*Draghi 2019: Differential effects of slow rewarming after cerebral hypothermia on white matter recovery after global cerebral ischemia in near-term fetal sheep.

Population: Near-term fetal sheep (intrauterine, instrumented) with HIE due to cerebral ischemia for 30 minutes.

Intervention and comparator: NT (n=8), hypothermia (3-48hrs) followed by spontaneous fast rewarming (n=8) in 1 hr (approx. 4C/h), or slow rewarming (0.2C/h) (n=8), or hypothermia (72 h) with fast rewarming. Tissue harvested after 7 days.

Outcomes examined: Recovery of white matter: oligodendrocyte reduction (i.e., oligodendrocyte survival); myelin binding protein expression (MBP expression) and CNPase (i.e., both markers of myelination), glial protein expression (GFAP).

Results: Overall slow rewarming did not improve oligo survival or myelination, or suppression of microgliosis compared to fast rewarming; reduced astrocytosis. Very slow rewarming was also associated with prolongation of hypothermia, which might explain the modest positive effect seen on astrocyte proliferation.

**Feldman 2016 (1407): Morbidity and mortality associated with rewarming hypothermic very low birth weight infants; OBS

Population: Very low birth weight infants with hypothermia (<36C) at admission to ICU, n=98, single centre

Intervention and comparator: No control group, logistic regression to associate rewarming rate with outcome; median rewarming rate 1.5C/hr; rewarming time 0.6-2.4 hr

Outcomes examined: mortality, bronchopulmonary dysplasia, intraventricular hemorrhage, necrotizing enterocolitis, retinopathy

Results: Temps 32.5-35.9; Prolonged rewarming time (but no rewarming rate!) was associated with an increase in mortality (OR 1.27, 95%CI 1.03-1.57); no association noted with other outcomes, and no association found if corrected for body weight.

**Rech Morassutti 2015 (1405): Association of Rewarming Rate on Neonatal Outcomes in Extremely Low Birth Weight Infants with Hypothermia, OBS

Population: Extremely low birth weight NB infants (n=182) with hypothermia (<36C) at admission to NICU.

Intervention and comparator: Rewarming rate dichotomized as => 0.5C/hr (rapid, n=73) or < 0.5C/hr (slow, n=109)

Outcomes examined: mortality, intraventricular hemorrhage, convulsions, late onset sepsis, hypoglycemia, respiratory distress syndrome (RDS), apnea of prematurity, duration of mechanical ventilation and supplemental oxygen, bronchopulmonary dysplasia (BPD), death/BPD, and length of hospitalization.

Results: No significant association between rewarming rate and any of the outcomes examined.

**Motil 1974 (1411): The effects of four different radiant warmer temperature set-points used for rewarming neonates, CT

Population: 42 healthy, newborn, term infants with variety of body temperatures (34.5 to 36.4C) after uncomplicate pregnancies and deliveries. Infants categorized to different temperature groups

Intervention and comparator: Exposure to 4 different radiant warmer settings, servo controlled to different skin temperature targets: 35, 36, 37, 38C. infants in different rectal temp cohorts evenly allocated to one of the radiant warmer target temps.

Outcomes examined: cord blood analysis, including BG, respiratory rate, HR, activity

Results: No significant differences found (but likely low power), but more hypoglycemia with lower rewarming rates (36, 37C)

**Rossi 2023: Rewarming rate of hypothermic neonates in a low-resource setting: a retrospective single-center study, OBS

Population: All newborns admitted to NICU in a Tanzanian hospital, with either mod/sev HT (<36C), mild HT (26-36.4) (n=344) rewarmed with warmers or incubators, used in manual mode using manual thermometers for adjustment.

Intervention and comparator: different rewarming rate cohorts, median rewarming rate of 0.22C/hr, higher in mod/sev HT (0.24C/h) versus mild HT (0.1C/hr)

Outcomes examined: jaundice, respiratory distress, length of hospital stay

Results: No significant association between rewarming rate and outcomes

**Jain 2021 Slow Rewarming for Management of Moderate to Severe Hypothermia in Low-Birth-Weight Pre-term Neonates-An Open Label Randomized Controlled Trial. CT

Population: Hypothermic low-birth-weight, preterm infants, T>36C

Intervention and comparator: rapid (>0.5C/h, n=50) versus slow (<0.5C, n=50) rewarming; factually this was 0.7C/h in slow group and 5.1C/h in fast group, or rewarming to target in 20 mins versus 2 hrs.

Outcomes examined: [TOPS (temperature, oxygenation, perfusion and saturation) and MSNS (modified sick neonatal score)] at baseline, 6 and 24 h and mortality until discharge. Various other comorbidities.

Results: No difference in mortality (14% with fast, 10% with slow rewarming; P=0.538), no differences in any of the other morbidities (e.g., seizures, apnoea, IVH, NEC) but mostly as these were very rare or not occurring at all.

Additional articles and citations, not identified in literature search or not meeting criteria for inclusion in *evidence evaluation.

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 Sep 16;9(3):295-302. doi: 10.3233/NPM-16915143. PMID: 27589554.

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 Sep;167(3):557-61.e1-2. doi: 10.1016/j.jpeds.2015.06.008. Epub 2015 Jul 10. PMID: 26168772.

Motil KJ, Blackburn MG, Pleasure JR. The effects of four different radiant warmer temperature set-points used for rewarming neonates. J Pediatr. 1974 Oct;85(4):546-50. doi: 10.1016/s0022-3476(74)80467-1. PMID: 4443866.

Rossi E, Maziku DM, Leluko DE, Guadagno C, Brasili L, Azzimonti G, Putoto G, Pietravalle A, Cavallin F, Trevisanuto D. Rewarming rate of hypothermic neonates in a low-resource setting: a retrospective single-center study. Front Pediatr. 2023 May 9;11:1113897. doi: 10.3389/fped.2023.1113897. PMID: 37228438; PMCID: PMC10203202.

Jain P, Dalal JS, Gathwala G. Rapid vs. Slow Rewarming for Management of Moderate to Severe Hypothermia in Low-Birth-Weight Pre-term Neonates-An Open Label Randomized Controlled Trial. J Trop Pediatr. 2021 Jan 29;67(1):fmaa098. doi: 10.1093/tropej/fmaa098. PMID: 33381805.

McDouall A, Zhou KQ, Davies A, Wassink G, Jones TLM, Bennet L, Gunn AJ, Davidson JO. Slow rewarming after hypothermia does not ameliorate white matter injury after hypoxia-ischemia in near-term fetal sheep. Pediatr Res. 2024 Aug 5. doi: 10.1038/s41390-024-03332-y. Epub ahead of print. PMID: 39103629.

Davidson JO, Wassink G, Draghi V, Dhillon SK, Bennet L, Gunn AJ. Limited benefit of slow rewarming after cerebral hypothermia for global cerebral ischemia in near-term fetal sheep. J Cereb Blood Flow Metab. 2019 Nov;39(11):2246-2257. doi: 10.1177/0271678X18791631. Epub 2018 Aug 10. PMID: 30092709; PMCID: PMC6827112.

Draghi V, Wassink G, Zhou KQ, Bennet L, Gunn AJ, Davidson JO. Differential effects of slow rewarming after cerebral hypothermia on white matter recovery after global cerebral ischemia in near-term fetal sheep. Sci Rep. 2019 Jul 12;9(1):10142. doi: 10.1038/s41598-019-46505-0. PMID: 31300687; PMCID: PMC6626025.

Additional evidence on effect of speed of rewarming after cardiac arrest/brain injury/HIE:

Lu X, Ma L, Sun S, Xu J, Zhu C, Tang W. The effects of the rate of postresuscitation rewarming following hypothermia on outcomes of cardiopulmonary resuscitation in a rat model. Crit Care Med. 2014 Feb;42(2):e106-13. doi: 10.1097/CCM.0b013e3182a63fff. PMID: 24434470.

This study demonstrated that the severity of myocardial, cerebral injuries, and inflammatory reaction after cardiopulmonary resuscitation was reduced when mild therapeutic hypothermia was applied. A rewarming rate at 0.5-1°C/hr did not alter the beneficial effects of therapeutic hypothermia. However, a rapid rewarming rate at 2°C/hr abolished the beneficial effects of hypothermia.

Berger C, Xia F, Köhrmann M, Schwab S. Hypothermia in acute stroke--slow versus fast rewarming an experimental study in rats. Exp Neurol. 2007 Mar;204(1):131-7. doi: 10.1016/j.expneurol.2006.10.002. Epub 2006 Nov 16. PMID: 17112513. Slow rewarming after a period of hypothermia is superior to fast rewarming. It may blunt deleterious rebound effects such as overexpression of AQP4, sustain anti-inflammatory mechanisms and thereby preserve the neuroprotection delivered by hypothermia.

Suehiro E, Ueda Y, Wei EP, Kontos HA, Povlishock JT. Posttraumatic hypothermia followed by slow rewarming protects the cerebral microcirculation. J Neurotrauma. 2003 Apr;20(4):381-90. doi: 10.1089/089771503765172336. PMID: 12866817. This study provides additional evidence of the benefits of posttraumatic hypothermia followed by slow rewarming, demonstrating for the first time that the previously described neuroprotective effects extend to the cerebral microcirculation.

Bisschops LL, Hoedemaekers CW, Mollnes TE, van der Hoeven JG. Rewarming after hypothermia after cardiac arrest shifts the inflammatory balance. Crit Care Med. 2012 Apr;40(4):1136-42. doi: 10.1097/CCM.0b013e3182377050. PMID: 22020246. Complement activation occurs during rewarming from mild therapeutic hypothermia after cardiac arrest. Interleukin-6 increased already from 12 to 24 hrs, concomitantly with a significant increase in the temperature seen during this period of mild therapeutic hypothermia. The optimal rate of rewarming is unknown. Additional clinical studies are needed to determine the optimal rewarming rate and strategy.

Zhu SZ, Gu Y, Wu Z, Hu YF, Pan SY. Hypothermia followed by rapid rewarming exacerbates ischemia-induced brain injury and augments inflammatory response in rats. Biochem Biophys Res Commun. 2016 May 20;474(1):175-181. doi: 10.1016/j.bbrc.2016.04.095. Epub 2016 Apr 20. PMID: 27107700. These results indicated that HTRR significantly impaired neurovascular unit and augmented proinflammatory response in stroke.

Suehiro E, Povlishock JT. Exacerbation of traumatically induced axonal injury by rapid posthypothermic rewarming and attenuation of axonal change by cyclosporin A. J Neurosurg. 2001 Mar;94(3):493-8. doi: 10.3171/jns.2001.94.3.0493. PMID: 11235956. The results of this study show that rapid rewarming exacerbates traumatically induced axonal injury, which can be significantly attenuated by administering CsA.

Justification for slower rewarming (0.5C/hr in newborns as used in RCTs):

Thoresen M, Whitelaw A. Cardiovascular changes during mild therapeutic hypothermia and rewarming in infants with hypoxic-ischemic encephalopathy. Pediatrics. 2000 Jul;106(1 Pt 1):92-9. doi: 10.1542/peds.106.1.92. PMID: 10878155. Reduction in MAP during rewarming when using the overhead heater at higher output.

Battin, Malcolm, et al. “Rebound Seizures During Rewarming.” Pediatrics (Evanston), vol. 114, no. 5, 2004, pp. 1369–1369, https://doi.org/10.1542/peds.2004-1695. Letter to the editor, on a report of an occurrence of rebound seizure during rewarming after TH.

Hyperthermia in puppies with inadequate monitoring during external heat administration (case series):

Christensen BW, Erb HN. An investigation of the discrepancy between set and actual temperature of neonatal incubators: concern for hypothermia and hyperthermia. J Am Vet Med Assoc. 2023 Sep 27;262(1):68-71. doi: 10.2460/javma.23.07.0382. PMID: 37758187.