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Out of hospital cardiac arrest is a devastating event and is associated with poor outcomes; however, therapeutic hypothermia (TH) is a novel treatment which may improve neurological outcome and decrease mortality. Despite this, TH is not uniformly implemented across Coronary Care and Intensive Care Units in Canada.
The purpose of this study was to compare cerebral recovery and mortality rates between patients in our Coronary Care Unit who received TH with a historical control group.
A retrospective chart review was performed of patients admitted to a tertiary care center with out-of-hospital cardiac arrest. Twenty patients who were admitted and cooled after December 2006 were compared with 29 noncooled patients admitted in the 5 years prior as a historical control group. The primary outcomes of interest were in-hospital mortality and neurological outcome.
Eleven of 20 (11/20, 55%) patients who were cooled as per protocol survived to hospital discharge, all having a good neurological outcome. Eleven of 29 (11/29, 38%) noncooled patients survived to hospital discharge (Odds Ratio: 0.50, 95% CI: 0.16- 1.60, P=0.26). Eleven of 20 patients who were cooled had a good neurological outcome (CPS I-II, 11/20, 55%), versus 7 of 29 (7/29, 24%) of noncooled patients (Odds ratio: 3.84, 95% CI: 1.13- 13.1, P=0.03). One hundred percent (11/11) of survivors in the cooled group had a good neurological outcome.
In our center, the use of TH in out-of-hospital cardiac arrest survivors was associated with improved neurological outcome.
Cardiac arrest is a devastating event for patients as the chance of survival is unlikely. In the past, supportive and expectant management have been the only therapeutic options for patients with return of spontaneous circulation (ROSC) after cardiac arrest. However, recent evidence suggests that the institution of rapid cooling to a core temperature of 32-34°C in survivors of ventricular fibrillation (VF) or pulseless ventricular tachycardia (VT) improves both neurological outcomes and survival.[1–9] Based on this evidence, recommendations have been made to incorporate therapeutic hypothermia (TH) into practice.
The mechanism of TH is not completely understood. TH is thought to reduce cerebral metabolic requirements, mitigate reperfusion injury and decrease free radical formation.[2,11,12] Regardless of mechanism, TH is an important therapeutic modality available in the management of the postcardiac arrest patient population. Despite this, the implementation of TH into practice has not been universal as studies have demonstrated systemic challenges to the implementation of TH as well as skepticism from physicians regarding the efficacy of this therapy.[6,12–14]
Further data on the use of TH in clinical practice is required to clarify the utility of this intervention. The goal of this paper is to determine the neurological outcome and survival in patients with out-of-hospital VF/VT cardiac arrest who received TH after the adoption of a TH protocol, compared to matched historical controls at a single Canadian academic center.
Research ethics approval was granted by the Queen Elizabeth II Health Sciences Centre (QEII) Research Ethics Board.
This is a retrospective, medical record review of patients admitted to the QEII HSC, Halifax, Nova Scotia, Canada. The QEII HSC is a tertiary care cardiac referral center for the Canadian provinces of Nova Scotia and Prince Edward Island.
We compared two cohorts of patients admitted with out-of-hospital cardiac arrest. First, a prospectively evaluated intervention group of patients managed with TH was assessed. This group included patients who suffered an out-of-hospital VF/VT cardiac arrest, had a ROSC, were admitted to our coronary care unit (CCU) from December 2006 to January 2008 and were managed with TH. A TH protocol, based on published algorithms and available evidence, was introduced to the QEII HSC in December 2006.[15,16,17] Education sessions were provided to attending and resident physicians, and to nursing staff. Nurse educators repeatedly reviewed and provided both formal and informal feedback on the use of TH. Data was collected prospectively and recorded in the QEII TH quality control registry.
As part of this protocol, TH was considered in patients with a primary cardiac arrest rhythm of VF or pulseless VT, time to advanced life support less than 15 minutes, ROSC within 60 minutes, and persistent coma after resuscitation. Exclusion criteria included immediately improving neurological status, arrest due to noncardiac factors, persistent shock despite the use of vasopressor medications, or a history of terminal illness.
TH was initiated in the emergency department (ED) or CCU utilizing a pre-printed order sheet. Cooling options included the application of ice packs, and/or a cooling blanket, and/or cold normal saline (4 degrees Celsius) to a target temperature between 32-34 degrees Celsius. Medications were used to maintain a mean arterial pressure (MAP) greater than 75 and included norepinephrine, phenylephrine, and dopamine. Sedation was provided with infusions of propofol and midazalam, analgesia with fentanyl or morphine, and neuromuscular blockade with pancuronium or rocuronium.
Our comparative cohort consisted of out-of-hospital cardiac arrest patients admitted to our center in the 5 years preceding the implementation of the TH protocol. Patients were identified from a manual search of the admission logs of all admissions to the CCU and medical surgical intensive care units of the QEII HSC from January 2001 to December 2006. During this time, patients were not routinely cooled at our institution. Patients were included for analysis if they would have been an appropriate patient for TH had our protocol been in place at that time. Namely, we included patients with a primary cardiac arrest rhythm of VF or pulseless VT, time to advanced life support less than 15 minutes, ROSC within 60 minutes, and persistent coma after resuscitation. We also excluded patients who had an improving neurological status, arrest due to noncardiac factors, persistent shock despite the use of vasopressor medications, or a history of terminal illness.
The primary outcomes assessed were in-hospital mortality rate and cerebral outcome. Patients’ Glasgow-Pittsburg Cerebral Performance Category (GPCPC) was determined based on available documentation. A GPCPC of I or II was considered a "good" neurologic outcome in that a GPCPC I score indicates good cerebral performance and a GPCPC II score indicates moderate cerebral disability but able to live independently. A score of GPCPC III indicates severe cerebral disability with dependence on others for daily support. GPCPC score IV indicates coma or vegetative state and a patient unaware of their surroundings. GPCPC V score indicates brain death or death.
Other data included the CCU/ICU and hospital length of stay, cardiac interventions, cardiac arrest variables, and demographic data. We also recorded specific adverse events (seizures, bleeding, sepsis and acute kidney injury).
Data was collected by 2 independent persons and included patient demographics, pre-arrest status, resuscitation details, course in hospital, and discharge status. Data was analyzed with Chi-Squared analysis for discrete endpoints and Student t-test and Nonparametric Wilcoxon rank sum test for continuous variables. A Univariate analysis was performed to calculate Odds Ratios.
We identified 20 patients who underwent TH in our center between December 2006 and January 2008. Eighteen patients underwent TH for ROSC after a VF/VT cardiac arrest and 2 patients after a pulseless electrical activity (PEA) cardiac arrest.
A total of 223 potential cardiac arrest patients were identified by review of the CCU/ICU admission logs from January 2001-December 2006. Twenty-nine (29) patients met our inclusion criteria and underwent data abstraction. The majority of patients were excluded because they had had a PEA/Asystolic arrest (n=48), or had not actually had a cardiac arrest (n=43) at all. Other common reasons for exclusion included immediate improving neurological status (n=36) and having an in-hospital cardiac arrest (n=28). Also, some patients were excluded because they had been cooled in the intensive care unit (ICU) prior to the institution standardizing TH protocols and procedures in the CCU (n=20).
The patients in each group were similar at baseline [Table 1]. However, males composed a greater percentage of those patients who were underwent TH and there was a higher known history of coronary artery disease and suspected ischemia in the non-TH group.
All of the cooled patients were cooled using a cooling blanket (n=20), 15 used ice packs, and only two needed cold saline. Cooling time is shown in Table 2. The average time to reach target temperature was 3.4 hours. The mean time cooled was 24.1 hours and the mean time of passive rewarming was 8.9 hours.
Cardiac interventions provided to patients after admission are outlined in Table 3. There were similar rates of cardiac catheterization and the use of an ICD, although there was a trend for patients treated with TH to receive less PCI or thrombolytic medications.
Eleven of 20 (11/20, 55%) patients who were cooled survived to hospital discharge, compared to 11/29 (38%) of the noncooled patients (Odds ratio: 0.50, 95% CI: 0.16- 1.60, P=0.26; Risk reduction 17%, P=0.26) [Figure 1]. In addition, 11 of 20 patients who were cooled had a good neurological outcome (GPCPC I-II, 11/20, 55%; 11/11, 100% of survivors), versus 7 of 29 (7/29, 24%) of noncooled patients (Odds ratio: 3.84, 95% CI: 1.13-13.1, P=0.03; Risk Reduction 31%, P=0.03). We also found that patients had a similar CCU and hospital length of stay when treated with TH as compared to those who were not [Table 4].
The incidence of adverse events was similar in both groups. Four of 20 patients in the cooled group had complications, compared to three of 29 in the noncooled group (P=0.42).
We have found that TH improved neurological outcomes in survivors of cardiac arrest admitted to our center. We have also found that patients who were treated with TH had CCU length of stay and hospital length of stay that was similar to patients who were managed without TH in a retrospective cohort. In addition, although mortality was lower in patients who received TH, this was not statistically significant.
TH has been shown to improve outcomes after cardiac arrest with landmark randomized controlled trials that were published in the early portion of the past decade.[1,4] Bernard et al, first randomized a small number of patients to be cooled in a pilot study, and then completed a multicentered study of 77 patients that were randomized to normothermia or hypothermia and assessed neurological outcomes. Their findings were similar to ours in that they had improved neurological outcomes at time of hospital discharge but no statistically significant difference in mortality. The other landmark study in TH was published by Holzer et al, They randomized 175 patients to normothermia or hypothermia after out-of-hospital cardiac arrest and found that those patients who were cooled had improved neurological outcome and decreased mortality at 6 months follow-up.
More recent publications have looked at the effects of cooling on outcomes after the implementation in a non clinical trial setting, with similar results.[5,7–9] These studies found improved neurological outcomes, and in some a mortality benefit. TH has not been shown to improve either outcome in those patients cooled who had a PEA/asystolic arrest.
Our findings are similar to previous published literature[1,3,4,18] that demonstrated improved neurological outcomes. However, we did not show improved mortality, which has been demonstrated in some published studies.[1,4,18] A possible reason for the lack of significant difference in mortality could be the small sample size.
Despite the available information and recommendations by the multiple authorities, TH is has not been completely implemented as standard of care.[6,12–14] Specifically, in Canada, a 2006 survey demonstrated that less than half of emergency medicine physician respondents initiated TH when indicated after cardiac arrest. Stated reasons for lack of implementation have included lack of evidence, lack of resources, lack of institutional protocols and policies, and simply not considering the therapy.[6,12–14]
One concern with the use of TH may be that patients remain in hospital for a prolonged period of time. We have found no evidence that this was the case in our patients, as patents who received TH had the same CCU and hospital LOS as those who did not. Combined with the dramatic improvement in neurological outcomes with TH, consideration for rapid cooling of cardiac arrest victims should be considered in all VF/VT patients.
Our finding should be interpreted with consideration of the limitations of our study design. The most important limitation is the partial retrospective nature of our study. However, our TH intervention group's data was collected prospectively, and we are confident that our search and rigorous data extraction methods provide an accurate account of patients treated at our institution. Another limitation is the use of historical controls. During the study period, there may have been a change in practice toward more primary percutaneous coronary interventions. Although a change in patient population is possible during the study period, it is unlikely given the short duration of the study and that the regional referral system did not change. It is also possible that the determination of the GPCPC required subjective judgment. This was limited because the patients’ disposition was a large determinant of their neurological outcome.
We cannot determine the external validity of our study, as this was data from a single academic center with a relatively small number of patients. Although the results should be applicable in other academic centers with a relatively high volume of cardiac arrests, it is yet to be determined if the same can be said about smaller community hospitals. The small subject number likely limited our statistical analysis and explains why we failed to demonstrate a mortality benefit in the cooled group, where other studies have done so.[3,4,18] The lack of statistically significant mortality benefit may also be a consequence of the lack of longer term follow-up, such as 6 months or a year. Although it would have been ideal to show cooling as an independent predictor of improved outcome, our study was under-powered to do multivariate regression analysis.
Our findings support the use of TH in Canadian academic centers. TH has emerged as an effective treatment of comatose survivors of out-of-hospital cardiac arrest. We have found an improvement in neurological outcomes, and no increased incidence of adverse events, which supports TH as a beneficial therapeutic modality in this population with a guarded prognosis.
In conclusion, within the study's limitations, we found that cooling patients improved neurological outcomes after out-of-hospital VT/VF cardiac arrest at our institution.
Source of Support: Nil
Conflict of Interest: None declared.