BMJ  2007;335:459-460 (8 September), doi:10.1136/bmj.39315.519201.BE

Editorials

Mild hypothermia for post cardiac arrest syndrome

Is recommended by evidence based guidelines yet uptake remains poor

Most people who have a cardiac arrest die. Many who are resuscitated subsequently die over the next few hours or days, and those who survive are at risk of cognitive dysfunction. This gloomy reality has prompted research into interventions to improve the prognosis of cardiac arrest; one of these interventions is the induction of mild hypothermia after spontaneous circulation has been restored.

Apart from patients resuscitated from a very brief cardiac arrest, most survivors will be comatose initially, and those without extensive comorbidity will be admitted to an intensive care unit. Unconscious, mechanically ventilated survivors of cardiac arrest account for one in 17 of all admissions to intensive care in the United Kingdom.¹ A third of these patients survive to hospital discharge. In one centre, two thirds of deaths in intensive care in initial survivors of cardiac arrest that occurred out of hospital, and a quarter of deaths after cardiac arrest that occurred in hospital, were attributed primarily to a neurological cause.²

Organ injury caused by ischaemia and hypoxia during prolonged cardiac arrest is compounded by reperfusion injury that occurs when a spontaneous circulation is restored. These insults trigger a systemic inflammatory response, similar to that associated with sepsis.³ The term post cardiac arrest syndrome describes this systemic response and associated multiple organ dysfunction.

Mild hypothermia is neuroprotective both before and after brain ischaemia through several mechanisms, including reduced production of excitotoxins and free radicals, suppression of apoptosis, and other anti-inflammatory actions.⁴ Animal studies show that hypothermia is more effective the earlier it is started after return of spontaneous circulation. Two randomised but unblinded clinical trials^{5 6} and a meta-analysis⁷ show improved survival and neurological outcome in adults who remained comatose after initial resuscitation from out of hospital ventricular fibrillation cardiac arrest, and who were cooled within minutes to hours after initial resuscitation. Patients were cooled to 33ºC⁶ or to 32-34ºC for 12-24 hours.⁵ Between four and 13 patients need to be treated for one extra survivor to leave hospital with good neurological function.⁷ None of the studies showed an increase in the number of survivors with poor neurological function.

Contraindications to inducing mild hypothermia include severe systemic infection, pre-existing coagulopathy (previous thrombolytic therapy is not a contraindication), and established multiple organ failure. Complications of mild hypothermia include increased infection, cardiovascular instability, coagulopathy, hyperglycaemia, increased plasma amylase, hypophosphataemia, and hypomagnesaemia.⁸ Most of these complications are easy to treat in the intensive care unit or can be reduced by raising the patient's temperature slowly by 1-2^oC.

Despite the evidence and inclusion in guidelines, the uptake of mild hypothermia by intensive care units around the world is poor.⁹ Some clinicians remain sceptical about the evidence—just two relatively small unblinded controlled trials; one used pseudorandomisation to allocate treatments,⁶ the other enrolled just 8% of all the patients assessed for eligibility.⁵

It is still not clear whether patients outside of the inclusion criteria used in the original trials would benefit from hypothermia (such as those with cardiac arrests occurring in hospital or non-ventricular fibrillation cardiac arrests). A randomised trial of hypothermia after resuscitation following in hospital cardiac arrest is ongoing (ClinicalTrials.gov identifier NCT00457431 [ClinicalTrials.gov] ).

An effective and easy method to initiate cooling is rapid infusion of cold (4°C) intravenous fluid.¹⁰ Cooling should start as soon as possible. This means that for cardiac arrests occurring out of hospital, cooling should ideally be started at the scene of the arrest or in the ambulance or, at the very latest, in the emergency department. A randomised controlled trial assessing long term survival after prehospital induction of hypothermia with cold intravenous fluid is about to start (ClinicalTrials.gov identifier NCT00391469 [ClinicalTrials.gov] ).

No consensus exists on the best way to maintain hypothermia, the optimum duration for hypothermia, or how best to rewarm the patient. In our experience, simple methods to maintain hypothermia—such as surface cooling with icepacks and fans—can work, but over-cooling and under-cooling are common. Intravascular cooling methods enable tighter temperature control, but insertion of large bore intravascular catheters has risks and the disposables are expensive.

Mild hypothermia is just one component of treatment for the post cardiac arrest syndrome. Other important components include early coronary reperfusion (percutaneous intervention or thrombolysis), controlled ventilation to achieve normal arterial blood oxygen and carbon dioxide tensions, cardiovascular support with vasoactive drugs, and, if necessary, an intra-aortic balloon pump, and intensive control of blood glucose. Evidence suggests that implementing a systematic treatment protocol after resuscitation improves outcomes.¹¹

Current guidelines recommend that unconscious adults with spontaneous circulation after out of hospital cardiac arrest should be cooled to 32-34ºC for 12-24 hours when the initial rhythm was ventricular fibrillation.¹² This treatment may be considered for unconscious adult patients with spontaneous circulation after out of hospital cardiac arrest with any other rhythm or after in hospital cardiac arrest. Many intensive care doctors, including ourselves, now cool most comatose patients admitted to intensive care after cardiac arrest.

¹ Southmead Hospital, North Bristol NHS Trust, Bristol BS10 5NB, ² Royal United Hospital, Bath BA1 3NG

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Competing interests: JS is vice chairman of the Resuscitation Council UK. JPN is chairman of the Resuscitation Council UK and co-chair of the International Liaison Committee on Resuscitation. JS and JPN are involved in writing international and national guidelines for cardiopulmonary resuscitation.

Provenance and peer review: Commissioned; not externally peer reviewed.

References

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3. Adrie C, Adib-Conquy M, Laurent I, Monchi M, Vinsonneau C, Fitting C, et al. Successful cardiopulmonary resuscitation after cardiac arrest as a "sepsis-like" syndrome. Circulation 2002;106:562-8.[Abstract/Free Full Text]
4. Gunn AJ, Thoresen M. Hypothermic neuroprotection. NeuroRx 2006;3:154-69.[CrossRef][Medline]
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6. Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002;346:557-63.[Abstract/Free Full Text]
7. Holzer M, Bernard SA, Hachimi-Idrissi S, Roine RO, Sterz F, Mullner M. Hypothermia for neuroprotection after cardiac arrest: systematic review and individual patient data meta-analysis. Crit Care Med 2005;33:414-8.[CrossRef][ISI][Medline]
8. Polderman KH. Application of therapeutic hypothermia in the intensive care unit. Opportunities and pitfalls of a promising treatment modality. Part 2: Practical aspects and side effects. Intensive Care Med 2004;30:757-69.[CrossRef][ISI][Medline]
9. Merchant RM, Soar J, Skrifvars MB, Silfvast T, Edelson DP, Ahmad F, et al. Therapeutic hypothermia utilization among physicians after resuscitation from cardiac arrest. Crit Care Med 2006;34:1935-40.[CrossRef][ISI][Medline]
10. Kim F, Olsufka M, Longstreth WT Jr, Maynard C, Carlbom D, Deem S, et al. Pilot randomized clinical trial of prehospital induction of mild hypothermia in out-of-hospital cardiac arrest patients with a rapid infusion of 4 degrees C normal saline. Circulation 2007;115:3064-70.[Abstract/Free Full Text]
11. Sunde K, Pytte M, Jacobsen D, Mangschau A, Jensen LP, Smedsrud C, et al. Implementation of a standardised treatment protocol for post resuscitation care after out-of-hospital cardiac arrest. Resuscitation 2007;73:29-39.[CrossRef][ISI][Medline]
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