There is considerable evidence that mild therapeutic hypothermia after cardiac arrest is protective in preventing cerebral injury. Animal and human studies have demonstrated that hypothermia reduces brain metabolism and thus oxygen and ATP consumption [3, 4], reduces the release of excitotoxic glutamate via regulation of transmembrane electrolyte transport [5], protects against oxidative stress and lipid peroxidation [6, 7], and alters gene expression (see also reviews by Holzer [8], Liu and Yenari [9], and Yenari et al. [10]) to promote brain cell survival after cerebral ischemia. These physiologic effects were shown to have clinical significance with the publication in 2002 of two major clinical trials of therapeutic hypothermia in comatose survivors of cardiac arrest. These studies, by Bernard and colleagues [11] in Australia and by the Hypothermia after Cardiac Arrest Study Group [12] in Europe, showed that cooling these patients improved neurological outcomes and reduced rate of death.

Since the publication of these trials, numerous medical centers around the world have replicated the efficacy of therapeutic hypothermia in this patient population and also established its overall feasibility and safety [13–15] (see also review by Sagalyn et al. [16] and meta-analysis by Arrich et al. [17]). Followup from the European multicenter trial also included data from patients who had in-patient cardiac arrests and patients who initially had pulseless electrical activity (PEA) or nonventricular fibrillation or ventricular tachycardia rhythms. While return of spontaneous circulation (ROSC) was faster for in-hospital compared to out-of-hospital patients, there was no statistically significant difference in neurologic outcome or mortality in comparing hypothermia or normothermia within the in-hospital cohort. Within the PEA cohort, mortality was lower for patients who received therapeutic hypothermia [18].

This was a retrospective chart review study. In November 2007, a log was kept of every Code Blue on the medical center campus including the Emergency Department. After approval of study design from local IRB, each case was retrospectively reviewed from November 2007 to August 2010. Initial demographic information including age, gender, medical comorbidities, and events leading to the Code Blue alarm was obtained for each case. In those cases of documented cardiac arrest and loss of perfusing rhythm, information regarding the code was obtained including setting and location of the arrest; initial cardiac rhythm; medical cause of arrest if known at time of event or later; treatment during arrest including pharmacologic, electrical, and surgical intervention; duration of code; time at which spontaneous circulation returned; whether the patient survived the code; presence of coma after arrest. In those cases in which the patient was found to be in a coma, the chart was reviewed to determine if neurology service was consulted for possible cooling and any reason why they were not consulted was noted. Appropriate cases were reviewed for initiation of therapeutic hypothermia, and reasons for not starting protocol were also recorded. If started, the time of initiation in relation to return of spontaneous circulation was recorded, as was the cooling method, time at which goal temperature was achieved, total duration of cooling, rewarming time, complications related to cooling (defined as occurring during or up to one week after completion of rewarming), and any technical or unexpected difficulties were noted, including reasons for early termination of protocol. The lowest temperature recorded during treatment was also noted as measure of possible hypothermia overshooting. Cerebral Performance Categories (CPC) Scale scores of outcome (from 1 to 5, with 1 being conscious and alert with good cerebral performance, 2 being conscious with moderate cerebral disability, 3 being conscious with severe disability and dependent on others for activities of daily living, 4 being comatose or persistent vegetative state, and 5 being brain death or death from other causes) [22] were determined for all possible cases at hospital discharge, and, where appropriate, at six-month and two-year followup.

Inclusion criteria for initiation of cooling protocol included age greater than or equal to 18, woman with negative pregnancy test, and coma after cardiac arrest with no eye opening or response to noxious stimulation after resuscitation. Return of spontaneous circulation following loss of perfusing rhythm and subsequent stable cardiac rhythm was also required, with blood pressure greater than 90mmHg systolic. Any nonperfusing initial rhythm during cardiac arrest including ventricular fibrillation, ventricular tachycardia, PEA, or asystole was deemed appropriate for treatment upon return of spontaneous circulation. Exclusion criteria included noncomatose state or other reasons for coma beyond cardiac arrest, pregnancy, known advanced directive or goals of care that would preclude therapeutic hypothermia and prolonged life support measures, and known severe coagulopathy including administration of full dose tPA during arrest or active bleeding. Cooling was stopped if any of the exclusion criteria developed after initiation.

Under the protocol, surface cooling—with ice packs placed under the axilla and near the neck, torso, and limbs—was initiated once patient was hemodynamically stable after acute treatment for cardiac arrest and if there were no other clear contraindications to initiation of hypothermia. This was done to prevent delay in initiation of cooling. The neurology consult service would then evaluate the patient and history and recommend whether cooling should continue or be discontinued. If cooling was to be continued, a cooling blanket or suit was deployed and nursing staff, primary physicians, and neurology service would work together to achieve goal temperature of 33°C as quickly as possible, ideally within 8 hours of return of spontaneous rhythm. Temperature was then maintained at 32°C to 33°C, and temperature sensing was done with a Foley catheter bladder probe when possible, otherwise, rectal temperatures were recorded. All patients were mechanically ventilated, and midazolam and fentanyl were used for sedation. Vecuronium was sometimes used as a paralytic and to help control shivering, and EEG monitoring was placed if there was concern for seizures under discretion of neurology consult service. All other ICU management and treatment plans were continued as deemed appropriate by the critical care team. Twenty-four hours after initiation of therapeutic hypothermia, passive rewarming was initiated using normal blankets and the removal of cooling measures, with goal of reaching 37°C at a rate of 0.3–0.5°C increase per hour. Paralytics and then sedation would then be discontinued as appropriate, and any subsequent hyperthermia was treated with cooling blanket and antipyretics.

Baseline demographics and characteristics of cardiac arrest are summarized for the 80 cardiac arrests involving 70 unique surviving patients in Table 1. The overall mean age of these cases was 70.7 years, and 95% were men. Ninety-three percent of these arrests occurred in-hospital, and the initial perfusing rhythm was PEA or asystole in 94% of cases and ventricular tachycardia or fibrillation in 6%. Although comparisons were limited by small sample size, return of spontaneous circulation occurred faster in patients who were not in a coma after arrest (F = 29.6,P = 3.9 × 10⁻⁹). The 17 patients who were in a coma after arrest and did not undergo therapeutic cooling also had a higher rate of unfavorable CPC at discharge compared to the other groups (P = 7.6 × 10⁻⁵) and between the comatose survivor groups at six months after arrest (P = 0.05).

Amongst the 51 cardiac arrests in which the survivor was not comatose afterwards, 14 were treated with attempted electrical cardioversion (27%) and one patient received full-dose tPA (2%). In one case, a chest tube was placed due to hemothorax. Neurology was consulted in one case for consideration of therapeutic hypothermia but patient was noted to be moving extremities and was not comatose; the service was consulted for six other patients later in their hospital course typically for prognosis or management of other complications. Of note, one patient was initially noted to not be in a coma by primary team but was noted to be comatose by neurology service 72 hours after arrest and has since remained in persistent vegetative state.

Of the 18 cardiac arrests in which the survivor was comatose but not cooled, one patient was treated with attempted electrical cardioversion (6%) and three with full-dose tPA (17%). One patient was taken to the operating room urgently for cardiac surgery and was placed on extracorporeal membrane oxygenation. Neurology service was consulted for five cases regarding initiation of therapeutic hypothermia and two times for other reasons including prognosis. The reasons why patients were not cooled are listed in Figure 1. Of note, neurology was not called initially by primary team for one patient due to prolonged duration of code (30 minutes before ROSC); that patient was later declared brain dead by neurology service. In addition, one patient was felt to have a focal examination concerning for focal cerebral process after cardiac arrest rather than global hypoxia and so neurology service advised against cooling; that patient remained neurologically devastated and was eventually transitioned to hospice care and died one month later.

Amongst the 11 cases where cooling was initiated, 3 were treated with attempted electrical cardioversion (28%), and 2 were treated with bedside cardiac massage. Two were treated with bedside cardiac massage. Table 2 displays data specific to this group of patients, including description of discharge and six-month outcomes and details regarding cessation of cooling therapy in three cases. For the 8 patients that completed the cooling protocol, mean time to initiation of cooling protocol was 3.7 hours (range 2 to 6 hours) and mean time to goal temperature of 33°C after ROSC was 8.8 hours (range 3 to 17 hours). Cooling was continued for an average of 23.6 hours (range 22 to 24 hours). Rewarming occurred over an average of 13.9 hours (range 4 to 24 hours). Five of these 8 patients had favorable CPC score of 1 or 2 after 72-hour evaluation (63%) and three expired before discharge (38%). Three patients continued to have CPC score of 1 or 2 at six months after cardiac arrest (38%). Complications noted during therapeutic cooling or during the subsequent week after cardiac arrest included cardiac arrhythmia requiring treatment with medication in 3 patients (38%), pneumonia in 3 patients (38%), another infection in 1 patient (13%), and deep venous thrombosis or subsegmental pulmonary embolus in 2 patients (25%). There were no instances of acute kidney injury, skin breakdown or rash, or bleeding or hemorrhage during this same time period.

In terms of the initiation of the cooling protocol from time of ROSC, our average of 3.7 hours is comparable to another series from a community hospital [20] and the average time to goal temperature of 8.8 hours was also comparable to previous reports, which ranged from 5.0 to 9.2 hours [15, 18, 20]. Given that most of the arrests were in-hospital, it would be hoped that time to initiation would be even shorter. However, there was no association with time from ROSC to initiation of protocol or time to goal temperature and CPC score at discharge, although the small sample size likely contributed to the lack of statistical significance.

In comparing the survivors of cardiac arrest, there was a significantly faster ROSC in the cases where the survivor was not in a coma afterwards. Although this data was not available in all cases, faster return of circulating rhythm was also associated with higher probability for favorable CPC given that more patients who were not in a coma were neurologically intact at discharge and at six months compared to the patients who were comatose. Although these noncomatose survivors were similar in age and comorbidities, and had high rates of initial PEA or asystole during arrest compared to the comatose survivors, there was a trend towards a higher proportion of primary cardiac etiologies (P = 0.07). Similarly, only one patient out of 18 arrests in the noncooled comatose survivor group was treated with electrical cardioversion, compared to more than 25% of the arrests in the noncomatose and cooled comatose survivor groups, suggesting increased evolution of rhythm to ventricular fibrillation or tachycardia in these latter arrests. Thus, there were some differences in the baseline characteristics in these patient groups which likely affected the duration of arrest. This also meant that, as expected, patients with longer periods of impaired cerebral perfusion were more likely to become comatose.

We should also point out that, within this sample, 38 patients did not survive the arrest itself and overall 65 patients (65%) died before hospital discharge. This rate is higher than reported in previous registries of in-hospital cardiac arrest [1, 2] and may be related to the large majority of patients having an initial rhythm at time of arrest of PEA or asystole (94% overall), which is associated with poorer outcome and has been noted to be the predominant initial rhythm in other in-hospital arrest series as well [24, 25]. Among patients who received cooling, 2 died within the following six months (18%). These observations are also in line with a recent study that demonstrated decreased chances of good outcome from cooling in patients with such nonshockable rhythms [26]. It is possible that patients in the latter category may have more severe disease, but this study did not suggest that such patients were harmed by cooling.

Of the 18 cases in which the survivor was comatose and therapeutic hypothermia was not initiated, these patients were not felt to be candidates for therapeutic hypothermia due to change in goals of care status, hemodynamic instability, or severe coagulopathy and hemorrhage. There were 2 cases where patients might have benefitted from cooling and neurology was not consulted initially. These cases occurred before a formal cooling protocol was adopted by our hospital and relevant staff were educated in its implementation. Since staff training occurred, no further cases were identified. Moving forward, one way to prevent this in the future would be to have every case in which the patient was comatose after cardiac arrest discussed with the on-call neurologist, even in cases where there is a clear contraindication. Other measures to improve our current protocol might include providing a dedicated neurology code pager in code blue protocols and staff training and reorientation at regular intervals.

At our institution, hypothermia was instituted using surface cooling methods and cooling blankets or suits. While our time to target temperature was comparable to previously published studies, it might be possible to further shorten the cooling time by induction with chilled intravenous saline solution. Further, there has also been some concern that surface cooling has been associated with overshooting of goal temperatures which could lead to higher complication rates. Studies have shown that endovascular catheter-assisted hypothermia allows for better control of temperature and faster cooling rates [27]. As such, the incorporation of endovascular cooing catheters might help achieve cooling at a faster rate and prevent overshooting of mild hypothermia goals. However, placement of these catheters requires a trained physician and this can often delay the initiation of cooling if the physician is not readily available [28]. Many community hospitals, including ours, do not always have such trained individuals on staff. Thus, our experience demonstrates that it is still possible to implement a cooling protocol where advanced technologies are not available. It should be noted that, in our series, there were two cases of overshooting beyond 32°C but both of these patients had a favorable CPC score at discharge.

Complications that were noted during the cooling phase and in the week after induction of hypothermia included pneumonia, cardiac arrhythmia requiring administration of medication, deep venous thrombosis, and, in one case, subsegmental pulmonary embolus. It is unclear whether these complications were necessarily related to cooling, as these are also common complications that occur in noncooled cardiac arrest patients. However, a recent study of therapeutic cooling in stroke patients did report a somewhat higher incidence of pneumonia that did not adversely affect eventual patient outcome [29]. Our rates were similar to those described by Prior and colleagues in their series at a community-based hospital [20]. There were no complications associated with rewarming, and although one patient was warmed faster than expected, this was likely related to underlying fever leading to rapid increase in temperature once therapeutic hypothermia was completed.