Moderate hypothermia was first used in patients who remained comatose after cardiac arrest in clinical trials in the late 1950s [1,2]. These early studies, basically large case series with historical controls, enrolled only patients with in-hospital arrest (cardiopulmonary resuscitation (CPR) outside the hospital was only introduced in the early 1960s) and maintained temperatures of 30-34°C for a period of 36-72 h in their patients. At that time, the side-effects of hypothermia were difficult to manage, and the potential indication (in-hospital arrest) was not applicable to large numbers of patients. Thus, in spite of the initially positive results, the treatment was abandoned for a prolonged period of time, with interest being rekindled only in the 1980s by the positive results of numerous animal studies. This renewed interest led to the implementation of a number of small clinical trials in the 1990s, enrolling a total of 195 patients (Fig. 1). All of these studies reported that hypothermia was a feasible treatment in the ICU setting, and most reported improved outcomes compared to historical controls [3-8].
Subsequently, three randomized-controlled clinical trials were performed (Fig. 2 and Table 1). The first, a small clinical feasibility trial including 30 patients with both witnessed and unwitnessed cardiac arrests and an initial rhythm of asystole or pulseless electrical activity (PEA), reported improved neurological outcome in patients treated with hypothermia, but the study was underpowered to detect statistical significance; survival rates were 19% vs. 0% for hypothermia vs. controls, P = 0.15 .
The results of two larger, multi-centred trials were published early in 2002 [9,10]. Bernard and colleagues  included 77 patients in whom cooling was initiated very early, during the ambulance transport to the hospital following CPR. Target temperature was 33°C for a period of 12 h. The rate of good neurological outcome (no or moderate disability) was 49% (21/43 patients) in the hypothermia group vs. 26% (9/34 patients) in the controls (P = 0.046). The rate of survival was also higher in the hypothermia group but this difference did not reach statistical significance (21/43 vs. 11/34, P = 0.145). After adjustment for case mix, the odds ratio for good outcome for hypothermia patients vs. controls was 5.25 (95% CI 1.47-18.76, P = 0.011).
The second, larger study was carried out in Europe by the therapeutic Hypothermia after Cardiac Arrest (HACA) group, and enrolled 273 patients . Rates of good neurological outcome were 55% (75/136 patients) vs. 39% (54/137 patients; risk ratio (RR) 1.40, 95% CI 1.08-1.81) and mortality rates 41% vs. 55% (RR 0.74, 95% CI 0.58-0.95) for hypothermia patients vs. controls, respectively. In this study, cooling was initiated after a median of 105 min and maintained for 24 h, with a target temperature of 32-34°C. These results were achieved in spite of the fact that target temperatures were reached only after an average period of 8 h after restoration of spontaneous circulation (ROSC).
The patients included in the two multi-centred studies all had witnessed cardiac arrests, with maximum intervals of 5-15 min from collapse to arrival of the ambulance and start of resuscitation. In addition, the initial rhythm had to be ventricular fibrillation (VF) or ventricular tachycardia (VT), and patients were excluded if the interval from collapse to ROSC was longer than 60 min. Patients with persistent hypotension (mean arterial pressure (MAP) <60 mmHg  or systolic pressure <90 mmHg ) or persistent hypoxia (oxygen saturation <85%) were excluded from the studies. In the end, this meant that only about 10% of screened cardiac arrest patients met the eligibility criteria. Thus, it remains to be determined whether these findings apply to patients with other initial rhythms, and especially to those with unwittnessed arrests.
However, preliminary evidence suggests that hypothermia may also have protective effects in patients with witnessed arrests and an initial rhythm of asystole or PEA [9,12]. These patients have a poorer prognosis than patients who still have cardiac electrical activity (VT or VF) upon arrival of the ambulance; the reason for this is that VT and VF are easier to reverse than asystole, and because the presence of asystole or PEA may signify graver myocardial injury, or the presence of severe additional morbidity (e.g. massive pulmonary embolism) as the underlying cause of the cardiac arrest. However, in cases where ROSC is achieved, it seems plausible, based on the mechanisms underlying hypothermia's protective effects, that efficacy would depend on the duration of oxygen deprivation and speed of reperfusion rather than on the type of arrhythmia causing the interruption of brain perfusion.
In a small single-centre feasibility study in patients with asystole (n = 24) or PEA (n = 6), the rate of survival was 19% (3/16), with long-term good outcome in 13% (2/16) patients . In another retrospective study, Polderman and colleagues  reported data, from four hospitals, in patients with witnessed cardiac arrest and with an initial rhythm of asystole or PEA, who had reached the hospital alive and were subsequently treated with hypothermia. In this study, the rates of initial favourable neurological outcome were 40% (33/82), with 33% (27/82) being alive with no or minor neurological impairment at 6 months. These numbers were significantly higher than in historical controls from the four participating centres .
These data should be interpreted with caution, as they were obtained in a selected group of patients in whom ROSC had been obtained and who had reached the hospital and ICU alive. In most centres, the overall percentage of patients with witnessed cardiac arrest who reach the hospital alive ranges from 8% to 40% ; this percentage is much lower in patients with an initial rhythm of PEA or asystole. Thus, patients with asystole/PEA who reach the ICU alive have already been ‘positively selected'. Nevertheless, these initial results do suggest that the prognosis of these patients, provided they have achieved ROSC and reached the hospital alive, is by no means hopeless, and that therapeutic hypothermia may be a valuable option also in this patient category.
Based on the currently available evidence, the most recent guidelines from the International Liaison Committee on Resuscitation recommend using hypothermia following cardiac arrest if the initial rhythm was VT or VF and considering its use for other rhythm disturbances .
A recently published meta-analysis concluded that for use of induced hypothermia in patients with witnessed VT/VF arrest, the number-needed-to-treat to allow one additional patient to leave the hospital with favourable neurologic recovery was 6, with a 95% CI of 4-13 . This number is very low compared to many other interventions in intensive care (and indeed other medical care area's). In addition, it should be realized that the cooling rates in these studies were relatively slow, with the time to target temperature <34°C ranging from 2.5 to 8 h [9-11]; it seems highly likely that outcomes could be further improved by the very early application of hypothermia, and perhaps by a longer duration of cooling treatment - although these issues need to be addressed in future studies [16-18].
Supporting evidence for the concept that hypothermia can provide protection from post-ischaemic injury comes from the field of perinatal asphyxia. Eight feasibility studies enrolling a total of 187 patients (118 of whom were cooled) and three randomized-controlled trials enrolling a total of 491 patients have assessed the efficacy of mild hypothermia to prevent or mitigate brain injury following perinatal asphyxia. Most of the non-randomized studies reported improvements in neurological outcome compared to historical controls, but these were underpowered to reach statistical significance. None reported significant adverse effects. The three RCTs all reported significant improvements in the outcome associated with cooling [19-21]. The smallest study enrolled 65 infants with perinatal asphyxia of ≥35 weeks of gestation in seven centres . Of these infants, 32 were cooled and 33 kept at normothermia. Infants were cooled within 6 h of birth to a rectal temperature of 33°C for a period of 48 h. Neurodevelopmental assessment was conducted at 12 months. In spite of the small number of patients there was a significantly lower number of patients with adverse outcome (death or severe motor disability) in the hypothermia group compared to the controls (84% vs. 52%, P < 0.02).
The second study, by Gluckman and colleagues , enrolled 234 infants with perinatal asphyxia in 25 centres; follow-up data at 18 months were available for 218 patients. Patients were cooled to 34-35°C within 5.5 h of birth. The rate of adverse outcome (death or severe disability) was 55% in cooled infants vs. 66% in controls. After adjustment for the initial severity of neurological injury, this difference just failed to reach statistical significance (P = 0.05, RR 0.57, 95% CI 0.32-1.01). However, in a predefined subgroup analysis of 172 infants with less severe electroencephalogram changes (indicating less severe degree of initial neurological injury), the rate of adverse outcome was 48% vs. 66% (P = 0.009, RR 0.42, 95% CI 0.22-0.80)*.
The third study, by Shankaran and colleagues, enrolled 208 infants with perinatal asphyxia in 15 centres. Infants were cooled within 6 h of birth to a temperature of 33.5°C for a period of 72 h. These authors reported significantly improved neurological outcome and reduced mortality in newborns treated with mild hypothermia (adverse outcome 44% vs. 62% for hypothermia vs. controls, P = 0.01, RR 0.72, 95% CI 0.54-0.95).
Only minor side-effects were reported in all three of these studies and the benefits were observed across the board in most participating centres. Taken together, the three studies indicate a number-needed-to-treat of 6 to achieve one additional case with favourable outcome. This is similar to the number for adult cardiac arrest patients, and it should be noted that in these studies also, target temperature was reached only after about 6 h. The reason in this case was the need to obtain informed consent, as well as logistical issues. Again, it seems likely that benefits could be significantly increased by earlier cooling, though this remains to be proven in future studies.
Of note, the studies using lower target temperatures (33-33.5°C) reported greater benefits in outcome than the study using somewhat higher temperatures (34-35°C), though the latter may have included more patients with more severe injuries.
Side-effects of hypothermia
A detailed discussion of side-effects is beyond the scope of this review and this issue has been discussed elsewhere . Only the most important issues will be briefly addressed here.
It should be noted that the injured brain has a poor tolerance of disruptions in homoeostasis, and every effort should be made to prevent episodes of hypotension, hypovolaemia and hypoxia, as well as hypo- or hypercapnia, hyperglycaemia and electrolyte disorders. Hypothermia can lead to hypovolaemia and electrolyte disorders through hypothermia-induced (‘cold') diuresis and tubular dysfunction [17,22]. Hyperglycaemia can develop due to increased insulin resistance and decreased insulin secretion by the pancreatic islets . Accidental hyperventilation may occur if blood gasses are not temperature corrected. Numerous other side-effects may also develop . Of note, the side-effects that are usually most feared (arrhythmia's and bleeding) are in fact quite rare, or do not occur at all if mild hypothermia is used.
Although cooled patients are likely to develop bradycardia and changes in their electrocardiogram (increased PR and QT intervals, widening of the QRS-complex and in some cases so-called Osborne waves), no clinically significant arrhythmia's due to hypothermia will occur provided that the patients' core temperature remains higher than 30°C. The reason for this is that at temperatures above 30°C hypothermia actually has a membrane-stabilizing effect [16,23], which will tend to decrease the risk of arrhythmia rather than increasing it. This situation changes only when the core temperature drops below 28-30°C (normally 28°C, but this threshold may be slightly higher in the presence of electrolyte disorders and/or ischaemia).
At temperatures below 28°C, there is indeed a significant increase in the risk of hypothermia-induced severe arrhythmia's . In this situation, an additional problem is that once arrhythmia's do occur, they are more difficult to treat, because hypothermic myocardial tissue becomes less susceptible to anti-arrhythmic drugs. Thus core temperatures should always be maintained in the safe range, i.e. ≥30°C; but within the range of 30-36°C no hypothermia-induced arrhythmia will occur. Of note, none of the clinical hypothermia trials in patients with cardiac arrest, traumatic brain injury, stroke or neonatal asphyxia has reported significant arrhythmia problems.
Similarly, although hypothermia has a mild anticoagulatory effect, no major bleeding complications have been reported in any of the major hypothermia trials. Indeed, hypothermia's effects on coagulation may actually be beneficial in patients following myocardial infarction.
The most important long-term management problem during hypothermia may be the risk of infections, which is increased due to hypothermia's immune-suppressing effect. This can be counteracted with various preventive measures and perhaps antibiotic prophylaxis or early antibiotic treatment.
Few absolute counter-indications exist for therapeutic hypothermia in eligible patients following cardiac arrest. Although the side-effects can be significant, the potential benefits are likely to outweigh the risks in most situations in patients with witnessed VT/VF arrest. As explained above, arrhythmia should not be viewed as a counter-indication, as hypothermia will decrease rather than increase this risk, provided that the core temperature remains >30°C. The same applies to hypotension, which is frequently regarded as a counter-indication for cooling; in fact, hypothermia will increase average blood pressure, as well as decrease the metabolic rate and oxygen demand with an associated reduction in the workload of the heart. The only real counter-indications are severe active bleeding when the source of bleeding has not been brought under control, and perhaps severe sepsis (because immune-suppressing effect of hypothermia).
Other treatments to improve outcome in cardiac arrest
Hypothermia cannot be viewed in isolation but should be used in combination with a wide range of measures to improve outcome following cardiac arrest. This treatment should be provided not just in the ICU but throughout the chain of survival. One of the most important measures will be to improve the quantity (i.e. how often it is performed) and quality of bystander CPR, as well as the quality of CPR by the medical and nursing staff in the ER and ICU.
An important change in the latest European Resuscitation Council (ERC)/American Heart Association (AHA) guidelines is a greater emphasis on continuing chest compressions throughout various procedures, and resuming the compressions immediately after defibrillation even if the rhythm has been restored . This recommendation is applicable also in the ICU setting, and is based on observations that chest compressions are not harmful even in the presence of organized rhythm  and that in OHCA the pulse is rarely palpable immediately after successful shock [26,27]. In addition, various animal studies have shown that (adequate) coronary perfusion is restored relatively slowly after ROSC  and continuing chest compressions decreases the likelihood of new VF or asystole . Most of these findings are also applicable in the ICU setting.
The new guidelines also recommend a 30 : 2 rather than a 15 : 2 ratio for chest compressions vs. breaths/ventilations . This is based on numerous animal studies showing that the blood flow in coronary and cerebral arteries is much better maintained with a 30 : 2 than a 15 : 2 ratio ; the importance of chest compressions is further underscored by observations that in unwitnessed arrests and/or arrests in patients in whom no bystander CPR has been performed, performing CPR for 2-3 min rather than immediate defibrillation improves the rates of successful defibrillation .
Several studies have suggested that a stronger emphasis on continuous chest compressions as recommended in the new guidelines can markedly improve outcome. In a before-after study by Rea and colleagues , rates of hospital survival increased from 32.8% to 45.5% (P < 0.01) and the number of patients discharged home from 25.6% to 36.6% (P < 0.05) after implementation of the new guidelines.
In this regard, it should be realized that we may often be doing a poorer job than we think; Abella and colleagues  studied physician and nurse performance during in-hospital CPR and reported that no chest compressions were given for 24% of the time . The performance outside the hospital may be even worse, with studies showing that in out-of-hospital CPR no chest compressions were given for up to 50% of the time [32,33]. There are many more of such examples in the literature. This is also important for the application of hypothermia, because the better the initial situation and degree of reversibility is, the greater the efficacy of treatments like hypothermia can potentially be. If few patients reach the hospital alive and if many of those who do have suffered had long interruptions of circulation without proper CPR, the potential efficacy of hypothermia to reverse this situation will decrease significantly even if it is induced quickly and used as effectively as possible.
Most studies show that hypothermia is most effective in patients with mild-to-moderate post-hypoxic injury; the degree of hypoxic injury can be moderated by effective CPR provided that this takes place throughout the rescue chain, and thus the potential efficacy of hypothermia crucially depends on what happens before.
Implementation rates for therapeutic hypothermia are still relatively low, especially in the United States where usage of hypothermia ranges from 10% to 35% [34,35]. In Europe, an average of 60% of ICUs currently uses hypothermia for some categories of cardiac arrest patients in Europe . In a survey by Merchant and associates, a number of different reasons were given for this, ranging from practical implementation issues, to fear of side-effects, to perceived lack of effective cooling methods and to discussions about the available evidence. Some of those surveyed indicated that hypothermia was too dangerous or difficult to apply in a general hospital or that the initial favourable results could not be easily reproduced.
However, a number of before-after studies have recently been published, showing a doubling of favourable outcome in patients with witnessed cardiac arrest and an initial VT/VF rhythm after the implementation of a range of measures, including but not limited to hypothermia.
Oddo and colleagues  reported an increase in favourable outcome from 14% to 42%; Busch and colleagues  from 32% to 59%; Kette and colleagues  from 15% to 41%; and Sunde and colleagues  from 26% to 56%.
Such data suggest that good outcomes could be achieved in 50% or more of patients with witnessed VT/VF arrest if our organizations are improved and the most effective treatments are used. These should include, but not be limited to, hypothermia.
A detailed discussion of cooling methods and devices is also beyond the scope of this review. However, one easy method to facilitate the induction of hypothermia is the rapid infusion of cold fluids. A number of studies have now shown that this is a safe and highly effective method to facilitate the induction of hypothermia [41-45]; in addition, this method can be easily applied outside the intensive care setting, i.e. in the ambulance, ER, catheterization lab or elsewhere.
Summary and conclusions
Hypothermia can improve neurological outcome after post-anoxic injury. It is the most promising development in the field of neurocritical care in many years. In patients with witnessed cardiac arrest and an initial rhythm of VT/VF, the number-needed-to-treat is 6; early induction of hypothermia may further improve outcome. Hypothermia is still underused in ICU's worldwide, and efforts should focus on improving implementation rates. Hypothermia treatment should not be viewed in isolation, but rather in the context of a ‘treatment bundle,' which together can significantly improve outcome after witnessed cardiac arrest. In some centres, favourable outcomes of 50-60% are now routinely achieved in this category of patients, and we should strive to emulate these successes. Rapid induction of hypothermia and proper management of side-effects will be key elements of a successful strategy, and rapid infusion of cold fluids should be a part of the treatment plan.
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* This type of selection of less severely injured infants, with a better initial chance of favourable neurological outcome, is in many ways comparable to the selection of patients in the larger studies in cardiac arrest patients [10,11], where those with an initial rhythm other than VT/VF and those with persistent hypoxia or hypotension were excluded; the category of patients who have the best prognosis a priori are those where the effects of a treatment will most easily be demonstrated and will reach statistical significance with the smallest number of patients. This principle is used in many study areas both inside and outside of critical care; many large multi-centre studies typically enrol between 10% and 30% of initially screened patients.