ISSN: 2455-3476

Global Journal of Anesthesiology

Review Article       Open Access      Peer-Reviewed

Therapeutic Hypothermia

Padmaja Durga*

Department of Anesthesia and Intensive Care, Nizam's Institute of Medical Sciences, Hyderabad, India

Author and article information

*Corresponding author: Padmaja Durga, Professor, [Cardiac and Neuroanesthesia], Department of Anesthesiology and Intensive Care, Nizam's Institute of Medical Sciences, Hyderabad-500082, India, Tel: 090-9440387299; E-mail: [email protected]
doi : 10.17352/2455-3476.000013
Submitted: 06 October, 2014 | Accepted: 29 August, 2015 | Published: 01 September, 2015
Keywords: Therapeutic Hypothermia; Mechanism; Clinical application; Evidence; Cooling methods; Practical aspects

Cite this as

Durga P (2015) Therapeutic Hypothermia. Glob J Anesth. 2015; 2(2): 25-35. Available from: 10.17352/2455-3476.000013

Copyright License

© 2015 Durga P. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Therapeutic hypothermia has been advocated for neuroprotection in cardiac arrest-induced encephalopathy, neonatal hypoxic-ischemic encephalopathy, traumatic brain injury, stroke, hepatic encephalopathy, and spinal cord injury, and as an adjunct to certain surgical procedures. In this review, we address physiological mechanism of hypothermia to mitigate neurological injury, the trials that have been performed for each of these indications, the strength of the evidence to support treatment with Evidence is strongest for prehospital cardiac arrest and neonatal hypoxic-ischemic mild/moderate hypothermia. Evidence is strongest for prehospital cardiac arrest and neonatal hypoxic-ischemic encephalopathy. For traumatic brain injury, a recent meta-analysis suggests that cooling may increase the likelihood of a good outcome, but does not change mortality rates. For many of the other indications, such as stroke and spinal cord injury, trials are ongoing, but the data is insufficient to recommend routine use of hypothermia at this time. Although induced hypothermia appears to be a highly promising treatment, it should be emphasized that it is associated with a number of potentially serious side effects, which may negate some or all of its potential benefits. Prevention and/or early treatment of these complications are the key to successful use of hypothermia in clinical practice.

Indexing and Abstracting

Introduction

Cardiac arrest is sudden circulatory standstill and is a common cause of death. Mortality ranges from 65-95% for out of hospital cardiac arrests and from 40- 50% for witnessed in- hospital arrests. Survivors have a high risk of significant neurological injury and only 10-20% are discharged with no significant neurological deficit [[2], but with inconclusive results. Even Peter Safar championed hypothermia [10]. Many of the mechanisms underlying hypothermia's effects have been derived from animal experiments, although many were subsequently confirmed in clinical studies.

Many studies have shown that hypothermia can prevent cell injury from apoptosis [[14]. The key destructive processes, such as calcium influx [16], are also blocked by hypothermia. Hypothermia suppresses ischemia-induced inflammatory reactions and release of pro-inflammatory cytokines [21],22]. These processes continue to last for hours to days after injury. Potentially, this would provide a significant time window for neuroprotective effects of therapeutic interventions such as hypothermia.

Current clinical applications of therapeutic hypothermia

The last decade has seen an overwhelming evidence for mild therapeutic hypothermia in various clinical situations. The evidence is discussed below and summarized in Table 1.

Table 1: Evidence for Clinical Application of TH.
Condition Level of Evidence Comments
Cardiopulmonary resuscitation Class I [32]. Indications
  • Witnessed arrest,
  • brief interval [15 min] until arrival of ambulance
  • VF, or VT upon arrival of ambulance
  • ROSC within 60 min
  • No refractory cardiac shock or persistent hypoxia,
  • Not responsive to verbal commands
Neurotrauma
Adult TBI		 Class III [60].
Class II [61].		 Reduces ICP Class II [b]
Decrease mortality and improve rates of good neurologic recovery.
Treatment should be commenced as soon as possible after injury
A temperature of 32 degrees -34 degrees C.
Pediatric TBI  Class III  [40]. Hypothermia initiated early will have a protective effect
Can be done safely. .Remains to be definitively tested
Stroke Class III b [88]. Evidence for severe MCA infarction.
Clipping of Aneurysm Class III [95]. IHAST2 (Intraoperative Hypothermia for Aneurysm Surgery Trial part 2) Did not improve the neurologic outcome Postoperative bacteremia was higher.
Neonatal Asphyxia Class I  [79,109]. Benefits of cooling on survival and neurodevelopment outweigh the short-term adverse effects

Cardiopulmonary resuscitation [CPR]

Rationale: Neurological injury and cardiovascular instability are the major determinants of survival after cardiac arrest [24], and Australian study [[6,25]-[31], concluded that, with conventional cooling methods, patients in the hypothermia group were more likely to reach cerebral performance categories score (CPC) of one or two and were more likely to survive to hospital discharge compared to standard post-resuscitation care. There was no significant difference in reported adverse events between hypothermia and control across all studies. Class-I evidence supports the use of hypothermia in patients unresponsive to verbal commands following CPR with. witnessed arrest, brief interval (15 min) until arrival of ambulance, VF, or VT upon arrival of ambulance, ROSC within 60 min and no refractory cardiac shock or persistent hypoxia [[36]-[40],[27,43]-[46]. The clinical predictors of survival in patients treated with TH following cardiac arrest were VF on presentation (OR 14.9 p=0.002), pre-cardiac arrest aspirin use (OR 9.7 p=0.02), ROSC <20min (OR 9.4 p=0.003), absence of coronary artery disease (CAD) (OR 5.3 p=0.002) and preserved renal function [7], (Table 2).

Table 2: 2010 AHA guidelines for CPR. Recommendations for Hypothermia.
Recommendation Level of Evidence
Comatose [ie, lack of meaningful response to verbal commands] adult patients with ROSC after out-of-hospital VF cardiac arrest should be cooled to 32°C to 34°C (89.6°F to 93.2°F) for 12 to 24 hours. Class I, LOE B
Induced hypothermia also may be considered for comatose adult patients with ROSC after in-hospital cardiac arrest of any initial rhythm or after out-of-hospital cardiac arrest with an initial rhythm of pulseless electric activity or asystole. Class IIb, LOE B
Active rewarming should be avoided in comatose patients who spontaneously develop a mild degree of hypothermia (>32°C (89.6°F)) after resuscitation from cardiac arrest during the first 48 hours after ROSC. Class III, LOE C

Neurotrauma

Rationale: Traumatic brain injury initiates several secondary metabolic processes that can exacerbate the primary injury. Hypothermia may limit some of these deleterious metabolic responses [49]; however, clinical trials have provided conflicting results [50]-[56],[58],[61,65]-[68,72], though larger, Phase III studies have shown that it does not improve the neurologic outcome and may increase mortality. [74], but, currently, no large case series assess the value of this intervention in these individuals.

Recommendation: BTF/AANS guidelines task force has issued a Level III recommendation for optional and cautious use of hypothermia for adults with TBI [[61] but larger trials are required for inclusion in standard practice.

Neonatal Asphyxia

Rationale: Hypoxic-ischemic brain injury and hypoxic-ischemic encephalopathy (HIE]) remain a serious problem for both preterm and term neonates with the spectrum of injury ranging from neuronal injury to encephalopathy and death. Given that there is currently no other clinically proven treatment, introduction of TH may be beneficial.

Levels of evidence: Hypoxia ischaemia remains a significant cause of neonatal mortality and morbidity (Level 2c evidence). The trials of hypothermic neural rescue therapy for infants with neonatal encephalopathy that have recently been reported suggest that either selective head cooling [76]-[79] and other meta-analysis [83]-[86,88] and the 2007 American Stroke Associations Guidelines [91],[94], observed improved CBF in the ipsilateral frontal cortex, lower frequency of neurological deterioration and a greater incidence of long-term good outcomes and concluded that intraoperative hypothermia can reduce severity of ischemia induced by temporary cerebral vessel occlusion. A large prospective multi-center trial, the IHAST2 (Intraoperative Hypothermia for Aneurysm Surgery Trial part 2), on 1001 patients with good-grade patients concluded that mild intraoperative hypothermia did not improve the neurologic outcome after craniotomy [[97].

Cardiac surgery

Transient cognitive deficits develop in 30–80% of patients undergoing cardiac surgery during the first postoperative month, with deficits persisting in 0–30% of patients. Intraoperative and brief postoperative cooling in patients undergoing cardiopulmonary bypass surgery was shown to reduce cognitive dysfunction [99]. The evidence supporting use of intraoperative hypothermia for intracerebral aneurysm surgery is class-IIb evidence. For cerebral- and spinal cord protection during thoraco-abdominal aortic aneurysm repair the evidence rates as class-III evidence [99].

Myocardial Infarction

TH has been shown in randomized clinical trials to improve neurologic outcomes following cardiac arrest due to acute myocardial infarction (AMI)Mild TH in combination with primary PCI is feasible and safe in patients resuscitated after cardiac arrest due to acute myocardial infarction [100,101]-[106]. Platelet count is decreased with impaired platelet function and also impaired coagulation cascade increasing risk of bleeding. No intervention is required if no active bleeding but cooling should be discontinued if bleeding present. It also causes reduction in white blood cell count with impaired neutrophil and macrophage function and suppression of pro-inflammatory mediator release resulting in increased risk of infection (mainly pneumonia & wound infections). Early antibiotic therapy improves outcome [[108], phenytoin, pentobarbital, verapamil, propanol and volatile anesthetics [reduced clearance], but in all likelihood applies to many other types of medication.

Monitoring of these complications is important as they can result in hazardous outcomes for patients. The failure to demonstrate positive effects of hypothermia in some clinical trials may be partly due to insufficient regard for side effects causing the negation of protective effects.

Practical Aspects of TH

Implementation of hypothermia requires planning, education, and integration of multiple services within an institution.

Patient Selection

Inclusion criteria: Patients who have been shown to benefit from induced hypothermia from the conditions mentioned earlier (Table 1).

Exclusion criteria: Exclusion criteria are in part based on theoretical increases in risk. Patients with recent major surgery within 14 days, systemic infection/sepsis, patients in a coma from other causes (drug intoxication, preexisting coma prior to arrest) known bleeding diathesis or with active ongoing bleeding, pulseless electrical activity (PEA), asystolic, or in-hospital arrest are not suitable candidates for TH. In neonates with HIE, TH may not be beneficial when cooling cannot be initiated within 6 hours of birth, birth weight is < 1800g, there are major congenital abnormalities including: suspected neuromuscular disorders, significant chromosomal abnormalities or life threatening abnormalities of the cardiovascular or respiratory systems infants with severe coagulopathy despite treatment, those requiring inspired oxygen over 80%, infant is ‘in extremis' and not expected to survive [110], or even on field [[112,114]. When using conventional surface cooling, sedation and paralysis with pharmacologic neuromuscular blockade is usually necessary. Many patients can have paralytic agents discontinued once the target core body temperature is achieved.

Supportive therapy: Skin care should be checked every 2-6 hours for thermal injury caused by cold blankets. Nutrition need not be provided to the patient during the initiation, maintenance, or rewarming phases of the therapy.

Controlled rewarming

The goal after rewarming is normothermia [ie, avoidance of hyperthermia]. Rewarming of the patient is begun 24 hours after the initiation of cooling. The rewarming phase may be the most critical, as constricted peripheral vascular beds start to dilate. Peripheral hyperemia may cause hypotension. The literature recommends rewarming slowly at a temperature of 0.3-0.5ºC every hour. Rewarming will take approximately 8 hours. The goal is to have the patient warm at about 0.3-0.5ºC per hour up to a target of 36°C. The paralytic agent and sedation are maintained until the patient's temperature reaches 35°C. If infusing, discontinue the paralytic agent first. The sedation may be discontinued at the practitioner's discretion. The patient is monitored for hypotension secondary to vasodilatation related to rewarming. Potassium infusions should be discontinued as hyperkalemia may occur when patients are rewarmed.

Cost-effectiveness and Impact

TH was found to significantly shorten ICU stay and time of mechanical ventilation in survivors after out-of-hospital cardiac arrest [117]. In 2010, 98.4% were practicing TH and 85.6% were using hypothermia as part of post-cardiac arrest management [118118. Binks AC, Murphy RE, Prout RE, Bhayani S, Griffiths CA, et al. (2010) Therapeutic hypothermia after cardiac arrest - implementation in UK intensive care units. Anaesthesia 65: 260-265.]. The practice of TH in India has not been surveyed.

Conclusion

A large body of evidence suggests that hypothermia can be used to prevent or limit damage to the injured brain and spinal cord, and perhaps the heart, in selected categories of patients. It is important to induce hypothermia as quickly as possible, as protection appears to be greater when cooling is initiated early (although benefits have been reported even when cooling was initiated many hours after injury). The induction of hypothermia will affect every organ in the body and it is important that anesthesiologists are aware of this and are able to distinguish physiological changes from pathophysiological side effects. Implementation of hypothermia requires planning, education, and integration of multiple services within an institution.

Appendix 1: Summary of Trials on Hypothermia for Cardaic Arrest.
Author /Year Methods Results Conclusion
Bernard Gary et al. [6]. Randomized, controlled trial.
Comatose patients after ROSCA from OHCA [VF/VT]. 77 patients-hypothermia [33 degrees C within 2 hours after ROSC for 12hrs] and normothermia. 		Good Outcome- Hypothermia-21/ 43 (49%): Normothermia -9/34 (26%) P=0.046).
Odds ratio for a good outcome with hypothermia -5.25 (95% C.I. 1.47 to 18.76; P=0.011).
No difference in the frequency of adverse events.		 Moderate hypothermia appears to improve outcomes.
HACA group [24]. Multicenter, randomized controlled trial
Patients resuscitated after cardiac arrest due to ventricular fibrillation Hypothermia- 32-340 for 24 hours] or normothermia. 		CPC 1 or2- Hypothermia 75/136 (55%): Normothermia 54/137 (39%) (RR, 1.40; 95% C.I. 1.08 to 1.81).
Mortality at 6mo- Hypothermia-56/137: Normothermia76/138 (RR-0.74: 95% C.I.-0.58 to 0.95).
No difference in complication rate between the two groups.		 Therapeutic mild hypothermia increased the rate of a favorable neurologic outcome and reduced mortality.
Belliard G et al.  [26]. Historical control [n=36] vs mild hypothermia [n=32 in out-of-hospital cardiac arrest due to VF. Historical controls [36] vs TH [32].
Survival was significantly higher in the hypothermia group (56% versus 36%). 		TH is efficient in significantly improving survival and neurological outcome of out-of-hospital cardiac arrest with VF.
Castrejon S et al. [25]. Randomised controlled trial - control group [28] Hypothermia [41]. Good neurological outcome.
At discharge-Hypothermia 18 (43.9%): Control 5 (17.9%) RR=2.46; 95% C.I. 1.11-3.98; P=.029).
At 6 months Hypothermia-19 (46.3%): Control 6 (21.4%) (RR=2.16; 95% C.I. 1.05-3.36; P=.038).		 Hypothermic treatment after cardiac arrest (VF/VT) helps improve the prognosis.
Holzer et al. [27]. Retrospective cohort study in unselected survivors of cardiac arrest.
Endovascular cooling 330C for 24hrs vs standard postresuscitation therapy. 		.Survival-Endovascular cooling group- (67/97 patients versus 466/941 patients; odds ratio 2.28, 95% CI, 1.45 to 3.57; P<0.001).
Good neurological outcome- Endovascular cooling-51/97 patients (53%) 320/941 (34%): control group (odds ratio 2.15, 95% CI, 1.38 to 3.35; P=0.0003; adjusted odds ratio 2.56, 1.57 to 4.17).
No difference in the rate of complications except for bradycardia.		 Endovascular cooling improved survival and short-term neurological recovery. Temperature control was effective and safe with this device.
Oddo et al. [34]. Retrospective study,
Out-of-hospital cardiac arrest due to VF and non-VF rhythms.
therapeutic hypothermia [330 -55
Control 54. 		TH beneficial in short duration of cardiac arrest (<30 mins).
Cerebral Performance category 1 or 2.
VF with TH- 24 of 43 patients [55.8%] Control-. 11 of 43 patients (25.6%] p = .004].
Non VF- outcome poor: With TH - 5of 17 patients of Control - 0 of 14 p = .0.27). 		major benefit on patient outcome appeared to be related to the type and the duration of initial cardiac arrest.
Arrich et al. [33]. Multicentre data from European Cardiac Arrest Registry
650 patients from 19 sites. 		 462 [79%] treated with therapeutic hypothermia irrespective of the presenting rhythm.
VF group - Demonstrates a benefit in terms of neurological outcome at 6 months – CPC 1-2:45% in hypothermia group vs. 32% in normothermia group (ARR 13%; NNT = 7.6; P = 0.02).
Non-significant increase of favorable outcome in hypothermic patients in Asystole/ PEA groups: 35/124 (28%] in the hypothermic group; 14/73 (19%) in the normothermic group [ARR 9%; NNT = 11.1; P = 0.18).		  
Don CW et al. [119]. Retrospective.
Total of 491 consecutive adults with OHCA.
204 –before use of TH.
287 during use of TH.		 Compared to control pts with VF who received TH had improved survival [odds ratio, 1.71, 95% confidence interval, 0.85-3.46] and had favorable neurologic outcome (odds ratio, 2.62, 95% confidence interval, 1.1-6.27).
Benefit was not observed in patients whose initial. rhythm was PEA or asystole.		 TH associated with a significant improvement in neurologic outcomes in patients whose initial rhythm was VF, but not in patients with other rhythms.
OHCA-out of Hospital Cardiac Arrest: CPC-Cerebral Performance Category.
Appendix 2: Summary of Clinical trials for mild hypothermia in TBI.
Author/year Methods Results Conclusion
Clifton et al. [50] . RCT in 46 severe TBI pts
Hypothermia-32 to330 C
Study (n=24)Control (n = 23)		 Outcome GOS at 3 mo
Good recovery
C- 36.4/ H-52.2%, 		Hypothermia improved neurologic outcome with minimal toxicity
Marion et al. [54]. RCT 82 patients with severe TBI
Hypothermia -330C		 Outcome GOS-3,,6, 12 mo
Outcome at 12mo
.H- 62%/ vsC-38%
No improvement in pts with GCS 3 /4		 Moderate hypothermia for 24 hours in patients with GCSof 5 to 7 hastened neurologic recovery and improved outcome.
Jiang, Yu et al. [52]. RCT- 87pts of sev TBI
Hypothermia- 33-350C for 3-14 days, Rewarming-after normal ICP
Study- 43 patients. Control- 44 patients 		Outcome-GOS at 1yr
H- mortality-25.58% good recovery 46.51%
C- mortality-45.45% Good outcome-27.27% (p < 0.05)
Hypothermia markedly reduced ICP (p < 0.01)		 Hypothermia therapy significantly improves outcomes in patients with severe TBI.
Clifton et al. [53]. Multicenter RCT, 392 patients
,Hypothermia- 330 C within 8hr,		 Outcomr functional status 6 mo
Mortality” H-28%/ N- 27% (P=0.79).
H-longer hospital stay due to complications
Poor neurological outcome- 57% in both groups 		Treatment with hypothermia is not effective in improving outcomes in patients with severe brain injury.
Shiozaki et al.  [56]. Multicenter RCT
11 medical centers, 91 severe TBI patients ,ICP could be maintained below 25 mm Hg by conventional therapies
(HT group, 45 patients] [NT group, 46 patients)		 The incidences of pneumonia, meningitis, leukocytopenia, thrombocytopenia, hypernatremia, hypokalemia, and hyperamylasemia were significantly higher in the HT than in the NT group (p < 0.05). Mild hypothermia therapy conveys no advantage over normothermia.
Gal, Cundrle et al. [58]. RCT sev TBI, HT-15/ NT-15 No difference in the GOS between the HT and NY groups at 6 months (P value 0.0843) TH not beneficial
Polderman et al. [55]. Prospective clinical trial. 136 sev TBI patients. Hypothermia in pts with no response to barbiturate coma (n=64). Responders control-n=72 Mortality: H-62% vs C- 72%; (p<0.05).
Good neurological outcome H= 15.7% vs C- 9.7% (p<0.02)		 Hypothermia improve survival and neurological outcome.
Effective in treating refractory intracranial hypertension
Guy L. Clifton et al.  [64]. Multi center NABIS:H IIR
randomized clinical trial designed to enroll 240 patients		 Ongoing awaited
Jiang [59]. RCT, sev TBI with ICH TH improves the outcome, significantly decreases intracranial pressure,
associated with high incidence of pneumonia and hypokalemia		 Not conclusive
Appendix 3: Clinical Trials on Therapeutic Hypothermia for Neonatal Hypoxic Encephalopathy in Term Neonates.
Author/year Methods Results Conclusion
Eicher et al. [120]. Systemic cooling to 33 0 for 48hr, HT-32/NT-33
Outcome- rate of death and severe disability at 12mo		 Mortality: HT (10/32, 31%)/ NT (14/33, 42%), Sev disability: HT24%/ NT 64% The combined outcome of death or severe motor scores yielded fewer bad outcomes in the hypothermia group
CoolCap trial
Gluckman et al. [75]. 		Selective head cooling at 33-340C for 72 hrs, HT-116/ NT118, Outcome -Rates of death and severe disability at 18hr Severe disability or death at 18mo -HT- 59/108 (55%) NT-73/110 (66%) (odds ratio 0.61; 95% CI 0.34-1.09, p=0.1). induced head cooling is not definitively protective but it could safely improve survival without severe  neurodevelopmental disability in infants
NICHD trial
Shankaran et al.  [121].		 Systemic cooling to 33.50 C for 72 hr, HT-102/ NT 106, Outcome -Rates of death and severe and moderate disability at 18mo Severe disability: HT- [44%] /NT- (62%) (RR, 0.72; 95 % CI 0.54 to 0.95; P=0.01).
Mortality: HT-24%/NT-37% [RR 0.68; 95% CI 0.44 to 1.05; P=0.08] cerebral palsy: HT-19%NT-30% (RR 0.68; 95% CI 0.38 to 1.22; P=0.20). 		Whole-body hypothermia reduces the risk of death or disability in infants with moderate or severe hypoxic-ischemic encephalopathy.
Lin et al.  [122]. Selective cooling to 33-340 C for 72 hr, HT-32/ NT-30, Outcome: Head CT and neurological assessment at 7-10 days Hypoxic-ischemic changes on head CT HT- 4/30 cases NT-18/28 P<0.01]. NBNA score HT-32+/-2: NT-28+/-3 (P<0.01). Selective head cooling may be used as a neuroprotective therapy
Robertson et al. [123]. Systemic cooling to 33-340 C for 72 hr, HT-21/ NT-15, Outcome: Mortality, neurological assessment, and eizures Mortality-HT-7/21/NT-1/15 [More neonates in Sarnat stage 3 in HT [6] where mortality is 100%
 Feasible in low resource center
TOBY trial
Azzopardi et al. [77]. 		Systemic cooling to 33-340 C for 72 hr, HT-163/ NT-162, Outcome -Rates of death and severe disability at 18mo Mortality: HT- 42/NT 44
Neurological Disability: HT- 32 NT- 42 [RR outcome, 0.86; 95% (CI), 0.68 to 1.07; P=0.17]. Infants in the cooled group had an increased rate of survival without neurologic abnormality abd reduced risks of cerebral palsy 		TH did not significantly reduce the combined rate of death or severe disability but resulted in improved neurologic outcomes in survivors

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