Mild induced hypothermia (MIH) was recently shown to improve neurological outcomes in patients who had sustained post-resuscitation encephalopathy secondary to cardiac arrest 123. Accordingly, this procedure has been recommended as part of the standard of care for out-of-hospital cardiac arrest 4. Nevertheless, the optimal technique for achieving MIH and its benefit/risk ratio in the target population remain controversial 5. Conventional techniques for effecting therapeutic hypothermia are cumbersome and time consuming, or they do not allow precise control of body temperature 6. Accordingly, we assessed the efficacy of and tolerance to a recently available endovascular cooling system in patients who were successfully resuscitated following out-of-hospital cardiac arrest.

All studied patients underwent MIH as part of their initial management using the CoolGard™ Thermal Regulation System (Alsius Corporation, Irvine, CA 92618, USA) connected to a balloon-equipped endovascular Icy™ catheter (Alsius Corp.) (single perfusion line with cooled normal saline) designed to be inserted in the inferior vena cava via the femoral vein. The decision regarding whether perform MIH was left to the discretion of the attending physician. Exclusion criteria were age above 85 years, a Glasgow Coma Scale score above 7 on admission, an in-hospital cardiac arrest, an estimated time of anoxia in excess of 40 min, and time from initiation of advanced cardiac life support (ACLS) to recovery of spontaneous circulation greater than 60 min. Because this observational study did not alter the standard of care in resuscitated patients after cardiac arrest in our institution, no informed consent was required.

Over a two-year period, 81 patients were admitted to the intensive care unit of our institution for management of resuscitated cardiac arrest. Among them, 10 patients (12%) sustained in-hospital cardiac arrest and were excluded. Among the 71 patients who sustained an out-of-hospital cardiac arrest, 31 patients (44%) had at least one exclusion criterion. The remaining 40 patients underwent MIH and constituted the study population.

Cardiac arrest was considered to be of cardiac origin in 31 patients (78%) and was deemed hypoxic in the nine remaining patients (three drownings, four hangings and two penetrative injuries). Among the 31 patients, the initial rhythm was ventricular fibrillation in 14, asystole in 23 and pulseless electric activity in the remaining three. Emergency angioplasty was performed in nine patients (23%), after initiation of MIH. The patients' characteristics are summarized in Table 1.

Mean interval between ACLS and initiation of MIH was 98 ± 54 min (range 45 to 300 min), and the target core temperature was reached after a mean interval of 296 ± 148 min (range 110 to 805 min) after cardiac arrest. Catheters were inserted successfully in all cases. The target temperature of 33°C was achieved after a mean period of 187 ± 119 min (range 30 to 600 min) after initiation of MIH (Table 1). In one patient, the intervals between cardiac arrest and initiation of MIH and between initiation of MIH and stabilization at the target temperature were 205 min and 600 min, respectively. This patient exhibited a relatively high body temperature on admission (37°7C), partly related to refractory myoclonus, and did not receive paralysis treatment. Once the target temperature was achieved, active cooling was performed for 37 ± 6 hours (range 20 to 48 hours).

Six patients (15%) died (four from cardiogenic shock and two from cerebral death) during MIH. Cardiac dysrythmia was observed in 11 patients (28%) during hypothermia, but this appeared to be unrelated to MIH. Dysrythmia consisted of ventricular fibrillation in two patients (who underwent defibrillation) and atrial fibrillation in the remaining nine patients (who received intravenous amiodarone, associated with correction of hypokalaemia in five of them).

Pancuronium bromide was administered to 19 patients (48%) to avoid excessive shivering during MIH. Among the 34 patients who completed the 36-hour period of MIH, hypothermia was maintained steadily in 31 patients (91%), with a core temperature maintained between 32.6°C and 33.4°C (Figure 2). In the three remaining patients, maximal temperature variations recorded around the target temperature were 1°C, 1.5°C and 2.6°C.

Once progressive rewarming was initiated, normothermia was achieved after a mean of 808 ± 365 min (range 420 to 1,800 min), close to the expected 800 min necessary at a warming rate of 0.3°C/hour. Post-rewarming 'rebound hyperthermia', defined as temperature of 38.5°C or greater, was observed in 25 patients (74%) during the first 24 hours that followed cessation of MIH (Figure 2). Catheters were withdrawn during the 24 hours following the end of MIH. None of the catheters were found to be colonized. No deep venous (particularly femoral) thrombosis was diagnosed both clinically and with routine ultrasound at the time of catheter removal.

Only few complications attributable to MIH were observed (Table 2). Haemorrhagic complications consisted mainly of nonserious bleeding related to the venous catheter insertion, which did not require blood transfusion. A single case of traumatic false aneurysm formation secondary to accidental puncture of a femoral artery was encountered (Table 2). Infectious complications were observed in 18 patients (45%), but no patient developed severe sepsis or septic shock. Five patients developed a nosocomial bacteraemia (Staphylococcus aureus in four cases), five patients (13%) were diagnosed with an early-onset nosocomial pneumonia (occurring within 72 hours after tracheal intubation; Table 2), six patients were diagnosed with an early-onset nosocomial bronchitis, and two patients were diagnosed with an urinary tract infection. During the study period, rates of infection in patients who did not undergo MIH in our intensive care unit were 12% for nosocomial pneumonia, 14% for bronchitis, 7% for nosocomial urinary tract infections and 2% for nosocomial bacteraemia. There was no apparent relationship between these documented bacterial infections during MIH and post rewarming 'rebound hyperthermia'.

Biological pancreatitis and seizures were not observed. When compared with baseline values obtained on admission, MIH presumably resulted in mild biological changes, with the exception of relevant hypokalaemia; 28% of patients had a potassium level below 3.5 mmol/l on admission, whereas this proportion reached 77% after 24 hours of MIH. Consequently, the mean potassium level significantly decreased after 24 hours of MIH compared with baseline (3.2 ± 0.6 mmol/l [range 2.2 to 4.6 mmol/l] versus 4.1 ± 0.8 mmol/l [range 2.8 to 6.6 mmol/l]; P < 0.0001). During the initial course of hypothermia, potassium was monitored closely and maintained within the normal range.

Among the 27 patients (67%) with a poor outcome, 24 patients died during their hospitalization (six patients during MIH and 18 patients after a decision to withdraw acute care) and three patients had moderate or severe neuromotor disability at hospital discharge. The remaining 13 out of the 40 patients had a favorable neurological outcome, with a CPC score of either 1 (n = 8) or 2 (n = 5) on day 28. Overall, 57% of patients who sustained a ventricular fibrillation, 17% of patients with asystole and 33% of patients with other pulseless electric activity had a favorable outcome. The estimated time of anoxia was shorter in the subset of patients with favorable outcome (7 ± 4 min versus 13 ± 9 min; P = 0.03). The time between initiation of ACLS and return of spontaneous circulation and the time between ACLS and initiation of MIH were similar between groups (Table 1). Similarly, the period required to achieve the target core temperature was similar between study groups (Table 1). MIH-attributed complications were equally distributed between patient groups (Table 2).

MIH is increasingly being used to provide protection for the brain against post-ischaemic injury 15. In various clinical circumstances, such as resuscitation following cardiac arrest, MIH may improve neurologic outcome when it is initiated quickly enough 1234. Clinical studies evaluating both the efficacy of and tolerance to recently available endovascular cooling systems are scarce 16.

The present study showed that the CoolGard™ Thermal Regulation System, connected to an Icy™ catheter inserted in the femoral vein, allowed the target temperature of 33°C to be attainted after a mean of 187 min (Table 1). This intravascular cooling system appeared to induce hypothermia faster than external devices, because a similar target temperature was obtained after means of 480, 301 and 287 min using external cooling techniques (cold air mattress, ice packs and cooling blankets, respectively) 11017. External cooling systems usually allow body temperature to be decreased at a rate of 0.3 to 0.5°C/hour 18, whereas the endovascular device used in our patients induced hypothermia at a mean rate of 1.1 ± 0.4°C/hour without use of additional external device. Paralytic drug therapy, frequently used in our patients, presumably accelerated the cooling rate by avoiding excessive shivering. Using the same endovascular cooling device, Georgiadis and coworkers 19 recently reported a mean cooling rate of 1.4 ± 0.6°C/hour. In keeping with previous reports, the present study suggests that intravascular cooling systems allow induction of moderate hypothermia more rapidly than various external techniques.

Because the protective effects of MIH appear to be greater when it is initiated early 20, investigators have recently proposed that ice cold intravenous fluid be administered to reduce the time needed to reach the target temperature 3621. In 22 patients who sustained an out-of-hospital cardiac arrest, Bernard and coworkers 3 lowered body temperature by 1.6°C over 25 min by rapidly infusing 30 ml/kg of crystalloid at 4°C, without noticeable adverse effect. Similarly, Polderman and coworkers 6 recently reported mean decreases in core temperature of 2.3°C and 4.0°C over 30 min and 60 min, respectively, in 134 patients undergoing MIH. Although more rapid than the endovascular device evaluated in the present study, rapid infusion of refrigerated saline does not allow one to maintain induced hypothermia steadily at the predefined target temperature. Accordingly, this approach appears to be a promising additional means to induce hypothermia rapidly, but it should be combined with another system once the target temperature has been reached 6.

In the present study, the target temperature of 33°C was reached in all patients and maintained steadily over a mean of 36 hours in all but three patients (91%). In contrast, external cooling systems such as cooling blankets, ice packs, cold lavage, or cooling helmet failed to achieve the target temperature in a substantial proportion of patients in whom MIH was indicated 11017. In a landmark clinical study, Holzer and coworkers 1 reported that external cooling using packs of ice allowed attainment of the target temperature of 33°C in only 30% of patients hospitalized after cardiac arrest. Furthermore, with regard to temperature variation with time, MIH was fairly stable over time (37 ± 6 hours) in our patients (Figure 2), whereas core temperature was found to be less stable in studies using external cooling techniques 11017.

Although slow rewarming is widely advocated, because rapid increase in body temperature after MIH may offset its potential beneficial effects on brain injury 11, no precise recommendation is currently available regarding the optimal rewarming technique 4. In 74% of our patients, we observed an increase in body temperature to 38.5°C or greater during the first 24 hours that followed progressive rewarming (Figure 2). This finding is in keeping with that reported by McIntyre and coworkers 18, who observed 'rebound hyperthermia' resulting from rapid rewarming after MIH induced to manage severe head trauma with associated brain oedema. Importantly, this rebound hyperthermia was associated with an increase in intracranial pressure. Brain oedema secondary to postanoxic injury after a cardiac arrest may potentially be worsened by the hyperthermia that was noted in a substantial proportion of our patients after slow rewarming. This phenomenon frequently observed after rewarming has not yet been clearly explained, and may be secondary to sustained cytokine release related to ischaemia/reperfusion cerebral injuries. In the present study, prolonged use of the cooling system (with a target temperature of 37°C) appears to be an effective approach to avoiding post-rewarming rebound hyperthermia in patients who underwent MIH after cardiac arrest. Nevertheless, efficacy of and tolerance to such prolonged use of this external cooling system require further study.

The present study showed that early-onset nosocomial infections were the most frequent complication observed over seven days after the initiation of MIH (Table 2). Comparison of rates of nosocomial infections between patients who underwent MIH and the remaining patients hospitalized in our intensive care unit over the same period revealed an increased rate of bacteraemia only (13% versus 2%). A significantly higher rate of nosocomial pneumonia during therapeutic hypothermia was reported only in one case-control study 22, but this finding was not confirmed by our study (13% versus 12%). Hypokalaemia was observed in the majority of our patients, but this was not associated with relevant arrhythmia (Table 2). A nonsignificant increase in white blood cells was observed during MIH (P = 0.02), whereas haemoglobin and platelet count remained unchanged. In a recent meta-analysis 23, only one clinical study identified a nonsignificant increase in haemorrhagic complications and sepsis in patients undergoing MIH when compared with normothermic patients 1. In our study, no complication related to insertion of the 35 cm femoral catheter was noted. Minor local complications such as bleeding at the puncture site have previously been reported in fewer than 10% of cases 1924.

The present observational study has several limitations. In the absence of randomization, the potential benefits of MIH in terms of neurological outcome cannot be evaluated in our study population. Similarly, reported complications in our patients cannot clearly be attributed to MIH. In addition, MIH was maintained for a mean of 37 ± 6 hours, whereas the International Liaison Committee on Resuscitation currently recommends a period of 24 hours 4. Nevertheless, the Committee emphasizes the fact that the optimum duration of hypothermia remains to be determined 4 and the potential benefits of applying MIH for longer than 24 hours require further investigation 25. Some of our patients who sustained a hypoxic cardiac arrest with asystole also underwent MIH, but they had a poor neurological outcome. According to the literature and the International Liaison Committee on Resuscitation recommendations, patients suffering out-of-hospital cardiac arrest secondary to asystole should not undergo MIH 26. Although MIH is currently recommended in witnessed cardiac arrest secondary to ventricular fibrillation or tachycardia 4, it may be performed in other categories of patients regardless of initial rhythm, provided that the cardiac arrest is witnessed and the prognosis is not hopeless because of associated comorbidities 11. Finally, physicians in charge of resuscitated patients who have suffered cardiac arrest recently reported fairly low rates of application of MIH 27. Incorporation of current resuscitation guidelines for MIH and future research aimed at improving cooling techniques may improve physicians' awareness and utilization of therapeutic hypothermia after out-of-hospital cardiac arrest 272829.

The present study demonstrated that the CoolGard™ system combined with the Icy™ venous catheter is efficient at inducing MIH and well tolerated. This intravascular cooling system allowed attainment of a target temperature of 33°C fairly rapidly and maintenance of MIH steadily over a period of 36 hours in all patients. This system was also consistently effective at progressive rewarming. Ease of use, efficacy and tolerance to this cooling system justify further studies to evaluate modalities for inducing MIH in various clinical settings, aiming to optimize the protective effect against post-ischaemic and traumatic brain injury. The efficacy and safety of prolonged use of this endovascular cooling system to avoid post-rewarming rebound hyperthermia remain to be investigated, as well as the potential relation between MIH and early-onset nosocomial infections.

• The Alsius CoolGard™ intravascular cooling system combined with the Icy™ venous catheter is a safe, efficient and well tolerated method for inducing MIH.

• This intravascular cooling system appears to be more efficient than conventional external cooling methods in tightly regulating body temperature (induction and stability of mild therapeutic hypothermia, as well as its reversal).

• The safety and efficiency of prolonged use (> 24 hours) of the present cooling system remain to be determined by further studies.

• The potential relation between mild therapeutic hypothermia and early-onset nosocomial infection remains to be investigated, especially regarding the development of bacteraemia.

• Incorporation of therapeutic hypothermia into resuscitation guidelines may increase physicians' awareness and yield improvements in the use of cooling systems in resuscitated patients after cardiac arrest.

ACLS = advanced cardiac life support; CPC = Pittsburgh Cerebral Performance Category; MIH = mild induced hypothermia.

The authors declare that they have no competing interests.

NP and JBA were responsible for the conception and design of the study, acquisition and interpretation of data, and writing of the manuscript. BF, AD and CE acquired data. PV was responsible for reviewing and writing of the manuscript.