Mild hypothermia during advanced life support: a preliminary study in out-of-hospital cardiac arrest

Out of hospital cardiac arrest (OHCA) is common and associated with a poor outcome, despite improvements in cardiopulmonary resuscitation (CPR) [1, 2]. Two major complications may occur after resuscitation from cardiac arrest. The first is postresuscitation disease, which occurs between 4 and 24 hours after resuscitation and is characterized by an ischaemia/reperfusion syndrome and a systemic inflammatory response syndrome [3]. The second complication is severe anoxic brain injury, which kills two-thirds of survivors [3, 4].

In a hospital setting, mild hypothermia induced 4 to 8 hours after OHCA improves the outcomes of comatose survivors in whom ventricular fibrillation (VF) is the initial rhythm [5, 6], and this strategy is currently recommended by the International Liaison Committee On Resuscitation [7]. Using external or endovascular cooling devices, it takes 219 to 480 minutes to achieve cooling to 33°C [6, 8, 9]. Infusion of cold crystalloids after hospital admission effectively lowers body temperature in resuscitated patients [10, 11]. However, studies of animal models of cardiac arrest suggest that the timing of induced hypothermia is a major determinant of survival [12, 13]. In an animal model early cooling resulted in significantly better neurological outcomes than did delayed cooling after return of spontaneous circulation (ROSC) or normothermic resuscitation [12]. In addition, a recent case report conducted by Bernard and coworkers [14] suggested that inducing cooling before ROSC may be advantageous.

In the present study we aimed to determine the feasibility, safety and effectiveness of cooling patients before ROSC during advanced life support (ALS) in the field before their arrival at the emergency department.

Thirty-three patients were included in this study (Figure 1). The baseline characteristics of the patients are shown in Table 1. In the 33 patients, the mean temperature decreased significantly (P < 0.0001) by -2.1°C ± 0.29°C after intravenous cooling to a median temperature of 33.3°C (32.3°C to 34.3°C). Twenty of the 33 (60.6%) were successfully resuscitated. The median time to reach mild hypothermia (<34°C) after ROSC was 16 minutes (11.5 minutes to 25.0 minutes). Eleven patients survived and were admitted to the ICU, where the endovascular cooling device was used. Boxplots of patients' body temperatures according to different resuscitation steps are shown in Figure 2. In this subgroup, temperatures before (step 0) and after (step 1) infusion of 4°C normal saline decreased significantly by -2.4°C ± 0.43°C (P < 0.0003). The temperatures in the kinetics curve revealed nonsignificantly passive rewarming, with a +0.26°C ± 0.35 of temperature variation (p = 0.48) between the end of cold normal saline infusion (step 1) and admission to the ICU (step 3). However, the patients' body temperatures were always significantly lower upon hospital admission (step 2; P < 0.004; temperature difference -1.13°C ± 0.28°C) and upon ICU admission (step 3; P < 0.02; temperature difference of -0.6°C ± 0.21°C) than their initial temperature before cooling (step 0).

Only one patient developed pulmonary oedema, which was characterized by clinical features as well as decreased pulsatile oxygen saturation; development of oedema prompted interruption of cold saline infusion after 1500 ml. There were no adverse events involving bleeding, and neither did any arrhythmia occur. Moreover, we did not observe any cases of re-arrest during transport to the hospital. There were no clinically relevant changes in the biological data recorded at the hospital (Table 1). Fluid loading did not induce haemodilution; the median haematocrit was 39.1% (36.4% to 40.7%). The pH of the arterial blood gas, 7.16 (7.02 to 7.23), exhibited a lactic acidaemia.

Finally, EMS personnel reported no technical difficulties in implementing the protocol.

At 6 months after OHCA, four patients survived, three with a favorable neurological outcome (CPC ≤ 2). The primary adverse effect was anterograde amnesia. The initial cardiac rhythms of these four patients were VFs in three patients and asystole in one.

This study shows that rapid infusion of 2 l of normal saline at 4°C in the field during ALS after OHCA and before ROSC was feasible, effective and safe in terms of decreasing body temperature before arrival at the hospital. We used a standard dose of 2 l instead of a weight-based dose in order to develop an easily managed protocol for treatment of OHCA patients in the field. With early cooling, we observed an ROSC rate of 60.6%; there were no adverse effects associated with the infusion of 2 l of ice-cold normal saline during ALS, except for oedema, which developed in one patient. The time from witnessed cardiac arrest to initial treatment, as well as delays from OHCA to CPR and to ROSC, were similar to those in previous reports [5, 6, 10, 11]. The no-flow time, which was 10 minutes (5 minutes to 14 minutes), was consistant with the criteria for inclusion in the HACA (Hypothermia After Cardiac Arrest) Study Group trial [6]. The median delay between the OHCA and ROSC (25 minutes [20.2 minutes to 37.5 minutes]) was comparable to that reported by Bernard and coworkers [10] (26 minutes [20.3 minutes to 34.5 minutes]) and Kliegel and colleagues [11] (20 minutes [13 minutes to 29 minutes]).

Inducing mild hypothermia during ALS, as compared with post-ROSC early cooling [17, 18], may reduce the duration of cerebral ischaemic injury. In experimental models [12, 13, 19], the time to induce hypothermia was closely correlated with anoxic neurological injury. In the animal model described by Nozari and coworkers [19], 17 dogs had VF cardiac arrest with a no-flow of 3 minutes, followed by 7 minutes of CPR basic life support and 50 minutes of ALS. The dogs were randomly assiged to two treatment groups: an early hypothermia group (34°C), in which cooling was initiated at 10 minutes of VF during ALS, and a delayed hypothermia group, in which colling was initiated at 20 minutes of VF. In the early hypothermia group, seven out of nine dogs survived to 96 hours, five with good neurological outcome. In contrast, seven of eight dogs in the delayed hypothermia group died within 37 hours with multiple organ failure (P = 0.012) [19]. Consequently, a small reduction in the delay between cardiac arrest and therapeutic hypothermia may improve neurological outcome after resuscitation. The present study confirmed the feasibility and effectiveness of cooling with a rapid infusion of cold fluid, as was previously reported [10, 11, 17, 18]. Lowering temperatures by infusion of normal saline at 4°C was more effective in this study than in the other studies [10, 11, 17, 18]; we achieved a mean temperature decrease of 2.1°C ± 0.29°C and a median body temperature of 33.3°C (32.3°C to 34.3°C; step 1). Differences in the cooling protocol could account for this finding. Recently, Kämäräinen and coworkers [20] observed a decrease of 2.5°C (nasopharyngeal temperature) in five patients after paramedics infused 14 ml/kg of Ringer's acetate at 4°C during CPR; four patients died in the field.

Once the target temperature was reached, patients remained within the temperature range of 32°C to 34°C. Hypothermia induced in the field persisted from the end of infusion until admission to the ICU. However, rewarming was reported by Kliegel and colleagues [21], who proposed maintenance of mild hypothermia by repeated cold infusions. The consequences of these thermal deviations for cerebral metabolism remain unknown. Because the cerebral metabolic rate decreases by 6% to 7% for each 1°C decrease in temperature [22], it could be preferable to continue the 'cold chain' without interruption until admission to the ICU.

A major concern about rapidly infusing cold fluid in the field is the possibility of inducing pulmonary oedema in resuscitated patients. In the present study, initiating hypothermia during ALS before ROSC reduced volume infusion during resuscitation and possibly decreased the risk for development of pulmonary oedema. All patients except one received 2 l of cold fluid loading, and the median arterial oxygen tension/fraction of inspired oxygen ratio of patients who survived to ICU admission was 300 (159 to 403). This study confirms the safety of infusing a large volume of cold fluid, consistent with the findings of an echocardiographic study [23] and with those of other studies that tested the safety and effectiveness of this cooling procedure [10, 11, 17, 18]. Kim and coworkers [23] demonstrated that fluid loading with 2 l of normal saline at 4°C had no significant effect on left ventricular function, left atrial filling pressures, pulmonary artery pressure, or central venous pressure. Bernard [10] and Kliegel [11] and their colleagues did not observe pulmonary oedema after infusion of cold Ringer's solution in any of the 22 or 26 patients, respectively, included in their studies. However, these trials were conducted after hospital admission rather than before. In-field cooling was not associated with pulmonary oedema, as initially assessed by chest radiography, in the recent clinical trial conducted by Kim and coworkers [23]; however, only 12 patients out of 63 received the 2 l of cold normal saline after ROSC. Virkkunen and colleagues [18] also found no pulmonary oedema after prehospital infusion of cold Ringer's solution. In addition, we did not observe bleeding complications or metabolic disturbances in any patients included in the present study.

We are aware that this study has limitations. Specifically, there was no control group with which to compare changes in body temperature, renal function, or electrolyte disorders. However, the results of this feasibility study now make it ethically acceptable to conduct a larger, multicentre, randomized trial to assess whether prehospital induced cooling after OHCA confers neurological benefits.

We conclude that infusion of 2 l of normal saline at 4°C in the field during ALS to induce mild hypothermia in resuscitated OHCA patients is feasible, safe and effective. This approach could represent the earliest and most cost-effective neuroprotective strategy.