Coronary heart disease is a major public health issue, having 4 to 13 per 10,000 population experiencing a cardiac arrest per year (
). A recent multicenter study observed a median of 52 per 100,000 out-of-hospital--treated cardiac arrest population having a survival ranging from 3.0% to 16.3% ( 1 ). In patients with successful return of spontaneous circulation (ROSC), short-term prognosis has historically been poor, partially due to anoxic neurologic injury ( 2 ). Therapeutic hypothermia (TH) has been shown to reduce mortality and improve neurologic outcomes in patients with ROSC after cardiac arrest, both in controlled studies and in clinical practice ( 3 ). When compared with patients who do not receive TH, the number needed to treat to allow one more patient to be discharged with a Cerebral Performance Category (CPC) of 1 or 2 is estimated to be between 4 and 13 ( 4-7 ). 7
Post-cardiac arrest physiology is similar to severe sepsis and septic shock, with high levels of circulating cytokines, presence of endotoxin in plasma, increased vascular permeability and edema, free radical production, and apoptosis (
). This clinical state has been referred to as the 8 post-cardiac arrest syndrome, having four key components: ( a) post-cardiac arrest brain injury, ( b) post-cardiac arrest myocardial dysfunction, ( c) systemic ischemia/reperfusion response, and ( d) persistent precipitating pathology ( ). Because the 9 post-cardiac arrest syndrome has similar circulatory dysfunction as septic shock, guidelines have recommended hemodynamic optimization (HO) for post-cardiac arrest resuscitation similar to severe sepsis patients ( ). This recommendation was based on data extrapolated from the study on early goal-directed therapy (EGDT), demonstrating reduced in-hospital mortality from 46.5% to 30.5% in patients with severe sepsis and septic shock, with a decrease in cardiovascular collapse by approximately 50% in the EGDT-treated patients ( 9 ). 10
Implementation of complicated protocols is a challenge in most clinical settings. Although TH is a class IIa/IIb advanced cardiac life support recommendation for post-cardiac arrest care, these guidelines are not universally applied (
). Data suggest clinical use of TH as low as 30% in North America. Cited reasons for nonuse of TH were "not enough data," "not part of advanced cardiac life support guidelines," and "too technically difficult to use" ( 9 ). The ease and feasibility of rapid induction of TH outside research protocols were a point of concern. Other barriers included lack of familiarity and availability of treatment protocols ( 11 ). 12
Successful post-cardiac arrest care requires engagement of personnel from multiple disciplines. Performance measures must be sustainable without the need for additional resources. A care bundle strategy advocated by the Institute for Healthcare Improvement has proven to be effective in facilitating the adoption of treatment protocols into standard practice (
). In this study, we hypothesized that, by implementing a post-cardiac arrest care bundle that includes a number of quality indicators, achieving TH and HO is feasible as standard care in patients with ROSC after out-of-hospital cardiac arrest. 13, 14 METHODS
Design and setting
The study was a prospective observational cohort with historical control of patients presenting to the emergency department (ED) and admitted to the medical intensive care unit (MICU) of an academic tertiary-care medical center with ROSC after out-of-hospital cardiac arrest. Patients meeting study enrollment criteria from August 1, 2007, to July 31, 2009, were entered into a post-cardiac arrest registry approved by the institutional review board (IRB). Prior to patient enrollment, a post-cardiac arrest clinical pathway including a care bundle for TH and HO was approved at our institution, beginning August 4, 2008. The study period was divided in two phases: prebundle phase (retrospective, historical control), August 1, 2007, to August 3, 2008; and bundle phase (prospective, observational), August 4, 2008, to July 31, 2009.
The 51-bed ED includes approximately 70,000 annual adult and pediatric patient visits and 2,500 intensive care unit (ICU) admissions. Patient care is delivered by resident physicians under the supervision of emergency medicine attending physicians. Staffing for adult patient care includes two attending physicians, two to four resident physicians, 10 to 12 nurses, two respiratory therapists, and one pharmacist. Nurse-to-patient ratio ranges from 2:1 to 1:4, depending on the acuity of patients. The 46-bed MICU is divided in two multidisciplinary teams, each containing an attending intensivist, a critical-care fellow, four resident physicians, eight to 12 nurses, one to four respiratory therapists, one pharmacist, two case managers, and a nutritionist. Nurse-to-patient ratio ranges from 2:1 to 1:2.
Creation of the post-cardiac arrest care bundle
The post-cardiac arrest bundle and its elements were based on the American Heart Association (AHA) guidelines in collaboration with the International Liaison Committee on Resuscitation for cardiopulmonary resuscitation and emergency cardiovascular care (
). The AHA-recommended goals of postresuscitation care include optimizing hemodynamic, respiratory and neurologic support, identifying and treating reversible causes of arrest, monitoring temperature, and treating disturbances of temperature regulation and metabolism. These goals were accomplished via an institutional clinical pathway and implemented as standard care ( 9 Fig. 1A). Fig. 1: A, Clinical pathway for patients with ROSC after cardiac arrest. STEMI indicates ST-elevation myocardial infarction; PCI, percutaneous coronary intervention; DVT, deep vein thrombosis. B, Post-cardiac arrest bundle including TH and EGDT.
The pathway was developed and approved by a multidisciplinary committee with representation from emergency medicine, medical and surgical intensive care, cardiology, neurology, pharmacy, respiratory care, nursing, case management, and patient safety and reliability. For compliance measurements, a bundle of quality indicators was utilized based on accepted methodology of care bundle implementation (
). We identified a set of bundle elements based on evidence that when performed collectively and reliably may improve patient outcome after ROSC from cardiac arrest ( 15 Fig. 1B) ( ). The presence or absence of each component was documented. The approved clinical pathway was implemented on August 4, 2008. 5, 6, 10, 16 Patient selection and management
Patients were selected using criteria similar to the landmark clinical trials examining the efficacy of TH after cardiac arrest (
). 5, 6 Inclusion criteria
Emergency department records from August 1, 2007, to July 31, 2009, containing the diagnosis of "cardiac arrest" were evaluated. Eligible patients met the following criteria: (
a) 18 years or older; ( b) out-of-hospital nontraumatic cardiac arrest; ( c) documented ROSC after cardiopulmonary resuscitation; and ( d) remained comatose after ROSC. Exclusion criteria
Data of patients younger than 18 years or with initial temperature less than 30
oC, severe cardiogenic shock (despite epinephrine infusion), persistent life-threatening arrhythmia, pregnancy, primary coagulopathy, drug overdose, acute stroke, trauma, postsurgery, or existing terminal illness were excluded. Patient management
During the bundle phase, patients meeting criteria were on mechanical ventilation and received sedation and analgesia for ventilatory synchrony, as well as paralytic agents to avoid shivering. Cooling measures were initiated in the ED with infusion of 2 L (4°C) normal saline and by a surface cooling system (Medi-therm III; Gaymar Industries, Inc, Orchard Park, NY) with continuous rectal temperature monitoring. Additional cooling measures to reach therapeutic goals of 32°C to 34°C within 4 h included orogastric lavage and bladder irrigation with 4°C normal saline. Therapeutic hypothermia was maintained for 24 h. Controlled rewarming was initiated after 24 h, to target 36°C to 38°C within 8 to 12 h of rewarming and maintained. The surface cooling system was applied for a total of 48 h to include the induction, maintenance, and rewarming phases of TH. Continuous electroencephalography (EEG) monitoring was initiated and maintained for the same 48-h interval.
A standard triple-lumen central venous catheter or a catheter with continuous central venous oxygen saturation (Scvo
2) monitoring (PreSep; Edwards Lifesciences, Irvine, Calif) was inserted via the internal jugular or subclavian vein within 2 h of initiating TH. If Scvo 2 monitoring was not initiated, a central venous blood gas sample was obtained every 6 h to measure Scvo 2. Hemodynamic goals of central venous pressure (CVP) of greater than 12 mmHg, MAP of greater than 65 mmHg, and Scvo 2 of greater than 70% within 6 h and maintained were targeted with crystalloid infusion, transfusion of red blood cells when indicated, and administration of vasopressors and inotropes at the discretion of the treating physicians following the previous published protocol of EGDT in severe sepsis and septic shock patients ( ). Lactate levels were serially obtained to monitor for lactate clearance ( 10 ). 17
Treatment plans were discussed with the patient's family. The bundle was initiated by the ED treating team with respect to applying the surface cooling system, inducing TH, and inserting the central venous catheter for hemodynamic monitoring and optimization. After admission to the MICU, the ICU treating team continued the bundle with TH maintenance for 24 h and then rewarming. Hemodynamic CVP, MAP, and Scvo
2 goals were maintained. Central venous pressure and Scvo 2 monitoring was continued until vasoactive agents were discontinued and the patient was breathing spontaneously. Neurology consult was obtained to monitor and evaluate continuous EEG for possible seizure activity. Patients were discharged from the MICU when mechanical ventilation was withdrawn, TH had been discontinued, and temperature rewarmed to 36°C to 38°C, hemodynamically stable, and not requiring vasopressor therapy for greater than 24 h. Education and in-service on the bundle
Education on the clinical pathway and bundle was provided to physicians and nurses at the beginning of the bundle phase and throughout the implementation. Several tools were developed to facilitate adoption of the pathway, improve physician collaboration, and provide continuity of care for the patients as they transition from the ED to the ICU. These included treatment flow charts, physician order sets, and bundle compliance checklists. Similar tools had been successfully utilized in a prior bundle implementation process at our institution for severe sepsis (
). Additionally, all ED and MICU nursing and technician staff attended a 2-h in-service on the protocol and use of the surface cooling system and CVP and Scvo 13 2 continuous monitoring. Physicians, house staff, and nurses were also provided a 1-h lecture on TH and the pathway. A physician champion (H.B.N.), having clinical practice in emergency medicine and intensive care was available 24/7 to answer questions and assist in implementing the bundle both in the ED and MICU. Data collection
Demographics, initial cardiac arrest rhythm, hemodynamic variables, laboratories, and therapies were obtained. The Acute Physiology and Chronic Health Evaluation (APACHE) II score was computed from available data at MICU admission (
). Adverse events during the first 48 h, resource consumption, and in-hospital mortality were recorded. Cerebral Performance Category was obtained in survivors at hospital discharge ( 18 ). 19
The primary outcome was percentage compliance to the post-cardiac arrest bundle during the bundle phase. Trained data abstractors completed a bundle compliance checklist for each enrolled patient during the bundle phase. The physician champion for the bundle implementation verified the compliance checklist for correctness. The initiation of the bundle (or time 0) was indicated at the time of ROSC after cardiopulmonary resuscitation. Bundle elements evaluated included (
a) TH, ( b) CVP/Scvo 2 monitoring in 2 h, ( c) target temperature of 32°C to 34°C in 4 h, achieving goals of ( d) CVP greater than 12 mmHg, ( e) MAP greater than 65 mmHg, ( f) Scvo 2 greater than 70% in 6 h, ( g) TH maintained for 24 h, and ( h) decreasing lactate in 24 h.
Secondary outcomes included in-hospital mortality and neurological outcome (defined by CPC scale) in survivors.
Continuous data were reported as mean (SD). Categorical data were reported as frequency distribution. The unpaired Student
t test, chi-square, or Fisher exact test was used when appropriate for detecting differences between the bundle and prebundle phase. The outcome measurements included bundle percentage compliance, in-hospital mortality, and CPC scale. Statistical significance was defined as P < 0.05. Data analysis was performed using the SPSS 16.0 statistical software (SPSS Inc, Chicago, Ill). RESULTS
Two-hundred twenty-four patients presented to ED during the study period with out-of-hospital cardiac arrest, including 71 patients admitted to MICU after cardiopulmonary resuscitation and ROSC. Among the admitted patients, 55 patients met study enrollment criteria, with 26 patients in the prebundle phase (historical control) and 29 patients in the bundle phase included in the final analysis (
Fig. 2). Mean age of patients enrolled was 63 (SD, 13) years, with mean APACHE II score of 26.6 (SD, 6) and mean lactate concentration of 8.4 (SD, 5.0) mmol/L. There was no significant difference in patient age, sex, cardiac arrest rhythm, APACHE II score, temperature, lactate level, and MAP between bundle and prebundle patients ( Table 1). TABLE 1:
Baseline characteristics in bundle compared with prebundle patients
Fig. 2: Flow diagram of study enrollment.
During the bundle phase, time from ROSC to initiation of TH was 2.4 (SD, 1.9) h. Twenty-one patients (72%) in the treatment group achieved target temperature within 4 h, with overall mean time to target temperature of 3.5 (SD, 2.5) h. Twenty-six patients (90%) had TH maintained for 24 h, with overall mean time at target temperature of 26.4 (SD, 3.3) h (
Table 2 and Fig. 3). Of patients not at target temperature by 4 h, five achieved TH within 6 h, two died prior to achieving TH, and one remained normothermic despite cooling efforts because of a malfunctioning surface cooling system. Of the 26 patients who completed TH, only two patients had single temperature measurements greater than 34°C during the 24-h maintenance of TH, with temperatures of 35.5°C, 35.8°C, and 35.7°C. Their temperature returned within the therapeutic range during the remainder of the maintenance period. Figure 4 illustrates the mean temperature over 60 h in bundle compared with prebundle patients. TABLE 2:
Therapies and resource consumption in bundle compared with prebundle patients
Fig. 3: Compliance to individual elements of the bundle and percentageof the entire bundle completed during the bundle implementation period. Fig. 4: Mean temperature over 60 h in bundle compared with prebundle patients.
None of the prebundle patients received CVP/Scvo
2 monitoring and early HO. Twenty-five patients (86%) in the bundle phase received CVP/Scvo 2 monitoring within 2 h of initiating the bundle, with initial CVP of 13 (SD, 8) mmHg and Scvo 2 of 81% (SD, 12%) ( Table 1; Fig. 3). At 6 h, 21 (or 72%), 22 (76%), and 12 (41%) bundle patients met CVP, MAP, and Scvo 2 goals of HO, respectively ( Fig. 3). There was no significant difference in therapies for hemodynamic support during the first 6 h and up to 72 h in the ICU between the bundle and prebundle patients, with a trend toward more blood transfusion during the first 6 h in the bundle patients, most likely due to recommendations to maintain hemoglobin of greater than 10 g/dL in bundle patients ( Table 2). Twenty-four patients (83%) in the bundle phase had decreased lactate with resolving acidosis within 24 h.
Overall, 77% of the bundle elements were completed in all patients during the bundle phase (
Fig. 3). Bundle patients had less sepsis, as documented in the chart, during the first 48 h when compared with prebundle patients ( P = 0.03). There was no significant difference in other adverse events between the bundle and prebundle patients ( Table 3). In-hospital mortality in the bundle compared with prebundle patients was 55.2 vs. 69.2% ( P = 0.29) ( Fig. 5). In the bundle patients, those patients who received all elements of the care bundle had a mortality of 33.3% compared with 60.9% in those receiving some of the bundle elements ( P = 0.22). Cerebral Performance Category in survivors, determined by evaluation at hospital discharge, was 2.1 (SD, 1.1) in the bundle patients compared with 2.6 (SD, 1.4) in prebundle patients ( P = 0.33); with more bundle patients achieving CPC 1 or 2, 31% vs. 12% ( P = 0.08). TABLE 3:
Adverse events during the first 48 h after admission to the ICU in bundle compared with prebundle patients
Fig. 5: Mortality and neurologic outcome in prebundle compared withbundle patients. Cerebral Performance Category: 1 = good cerebral performance, 2 = moderate cerebral disability, 3 = severe cerebral disability, 4= coma, vegetative state. DISCUSSION
Despite the recent focus on chest compressions, survival after cardiac arrest remains in the 10% range for most institutions (
). The most common causes of mortality have not changed and remain to be postresuscitation encephalopathy and hemodynamic instability beyond the initial resuscitation ( 20 ). In one study, brain injury was the cause of death in 68% of out-of-hospital and in 23% of in-hospital cardiac arrests with ROSC ( 21 ). 22
Mild hypothermia has been shown to be neuroprotective. Exact mechanisms are unknown, but animal models have shown that cooling reduced cerebral metabolic demand, reduced production of excitatory amino acids and glutamate-mediated cell death, reduced formation of free radicals, inhibited inflammation and cytokine production, reduced disruption of the blood-brain barrier, increased cell membrane stabilization, and preserved cerebral autoregulation (
). Other theories include improved oxygen supply to ischemic areas of the brain and decreased intracranial pressure. Additionally, hemodynamic effects show a decrease in heart rate, increase in systemic vascular resistance, and decreased cardiac output, while maintaining stroke volume and MAP. 23
Although HO in post-cardiac arrest care has not been studied in prospective, randomized trials, targeting hemodynamic goals and increased blood flow in post-cardiac arrest patients is physiologically sensible, with potential for improved survival and neurologic outcome. Combining two intensive treatment strategies (TH and HO) that are relatively time-sensitive can be challenging. Several studies have demonstrated the feasibility and safety of combining a primary coronary percutaneous intervention protocol with the induction of mild hypothermia for patients with ST-elevation acute myocardial infarction (
). Other investigators have demonstrated that TH and HO can be implemented simultaneously with favorable outcome ( 24, 25 ). We further applied a care bundle approach with performance measurements for quality improvement in our implementation. 26, 27
Our study was nonrandomized because of the ethical constraints regarding withholding recommended treatments for post-cardiac arrest patients. We implemented the bundle and accepted the guideline recommendations as standard care. Thus, our IRB would not have approved a randomized study in which patients may not receive standard therapies. However, because our clinical pathway and bundle were not yet developed during the prebundle phase, implementation allowed us to make comparisons with historical control patients. We observed a 14% lower mortality during the bundle implementation phase compared with the prebundle period. As this was a feasibility study examining the implementation of a care bundle over a 1-year period, the sample size could not be powered to detect a statistical significance. To detect a significant 14% absolute reduction in mortality from our baseline prebundle mortality of 69%, achieving a type I error rate of 0.05 and power of 0.8, we would need a sample size of 188 patients in each group. We were more interested in showing the feasibility of implementing such bundle with improved compliance over time and thus did not
a priori seek IRB approval for long-term patient follow-up. Although our results did not reach statistical significance, the mortality benefit may be clinically relevant and comparable to the mortality reduction observed in the index multicenter randomized trial examining the benefit of TH after ventricular fibrillation (VF) ( ). 6
We included patients with arrest rhythm of asystole and pulseless electrical activity as well as VF. Previous studies showed that TH was not associated with a significant reduction in mortality in patients with non-VF arrest rhythm (
). We included patients with non-VF arrest in our implementation per guideline recommendation that "cooling may also be beneficial for other (non-VF) rhythms" ( 7 ). Almost one third of the bundle patients did not achieve 9 a priori-determined time to target temperature of 4 h. Although the optimal time to achieve TH has not been defined, studies suggest a therapeutic window for TH exists ( ). Although we did not collect specific data regarding barriers to achieving the target temperature within the determined time period, our observation was that they were predominantly logistical. Delay to initiation of TH included ( 28 a) the surface cooling system residing in the hospital central supply, requiring time to obtain the system for each usage; ( b) initiating the protocol concurrent to other high-acuity ED patient care such as activation of trauma, stroke, or cardiac team; ( c) unfamiliarity of staff with a new cooling technology; and ( d) unfamiliarity with a new therapeutic strategy.
Cooling technologies can be external (surface) or internal. In most clinical trials examining the benefit of TH, external cooling methods have been used (
). Techniques included the application of ice packs to specialized cooling blankets or gel pads. Internal cooling systems use an endovascular device placed via a central venous catheter to cool blood as it circulates around the catheter. Different technologies for rate of cooling, effectiveness of maintaining target temperature, and development of complications have been compared. However, outcome studies comparing cooling techniques are lacking. We utilized a surface cooling system already familiar to both ED and ICU staff because of its ease of use, safety, reliability, and low cost. Additionally, other cooling measures, such as intravenous infusion of 4°C normal saline, and gastric and bladder irrigation were performed while the surface cooling system was initiated. These efforts resulted in an average cooling rate of 1.1°C (range, 0.3°C-2.5°C) per hour. No complication related to the cooling technique was observed. 29
Knowledge translation literature enumerates several specific barriers to TH implementation, including the fact that TH is a prolonged therapy requiring collaboration of many different caregivers, inertia of previous practice, difficulty in changing physician behaviors, perceived difficulties in providing the technology or therapies, lack of detailed protocols, and cross-disciplinary hurdles (
). Similarly, barriers to implementing best practices for severe sepsis, which similarly has hemodynamic monitoring requirements, include lack of nursing staff, inability to insert a central venous catheter to monitor CVP, and patient selection ( 12 ). A care bundle includes an evidence-based checklist of easily remembered items that must be completed over a defined period. It provides a forcing function for the multidisciplinary team to deliver consistent patient care and overcome barriers ( 30, 31 ). Examples of conditions for which care bundles have been developed include ventilator-associated pneumonia, central line insertion, severe sepsis, heart failure, stroke, and surgical site infections ( 32 ). With respect to the 13, 14, 33, 34 post-cardiac arrest syndrome, the implementation of a hospital-wide TH protocol has been shown to facilitate standardized care for post-cardiac arrest patients ( ). In this study, we showed that treatment of the 27, 35 post-cardiac arrest syndrome can be accomplished via a care bundle with elements for the completion of both TH and HO. CONCLUSIONS
Barriers exist to best practices for post-cardiac arrest patients and are similar to barriers observed in implementing intensive treatment protocols for other critical illnesses. These barriers include clinicians' impression that these therapies are technically difficult to use, unfamiliarity with therapies, and protocol lack. A care bundle approach has been shown to improve the process of care and improve outcome. In our study, we showed that a post-cardiac arrest care bundle including elements to accomplish TH and early HO can be implemented as standard care with similar clinical benefit as shown in previous clinical trials. Most importantly, the bundle served as a tool to facilitate collaborations and effective transition of care between the ED and ICU for a very-high-risk patient population.
The authors thank the emergency medicine and medical intensive care physicians, nurses, respiratory therapists, and staff for their contributions to this study.
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