Neurocrit Care DOI 10.1007/s12028-015-0184-z

ORIGINAL ARTICLE

Therapeutic Hypothermia After From a Non-Shockable Rhythm Improves Outcomes in a Regionalized System of Cardiac Arrest Care

1 2,3,4 2,3 5 Gene Sung • Nichole Bosson • Amy H. Kaji • Mark Eckstein • 6 3,7 3,7 David Shavelle • William J. French • Joseph L. Thomas • 4 2,3 William Koenig • James T. Niemann

Ó Springer Science+Business Media New York 2015

Abstract preexisting or death prior to initiation. The decision Objective Therapeutic hypothermia (TH) improves neu- to initiate TH was determined by the treating physician. rologic outcome in patients resuscitated from ventricular Measurements The primary outcome was survival with fibrillation. The purpose of this study was to evaluate TH good neurologic outcome defined by a cerebral perfor- effects on neurologic outcome in patients resuscitated from mance category of 1 or 2. a non-shockable out-of-hospital cardiac arrest rhythm. Main Results Of the 2772 patients treated for cardiac Design and Setting This is a retrospective cohort study of arrest during the study period, there were 1713 patients data reported to a registry in an emergency medical system resuscitated from cardiac arrest with an initial non-- in a large metropolitan region. Patients achieving field able rhythm and 1432 patients met inclusion criteria. The return of spontaneous circulation are transported to desig- median age was 69 years [IQR 59–82]; 802 (56 %) male. nated hospitals with TH protocols. TH was induced in 596 (42 %) patients. Survival with good Patients Patients with an initial non-shockable rhythm neurologic outcome was 14 % in the group receiving TH, were identified. Patients were excluded if awake in the compared with 5 % in those not treated with TH (risk Emergency Department or if TH was withheld due to difference = 8 %, 95 % CI 5–12 %). The adjusted OR for a CPC 1 or 2 with TH was 2.9 (95 % CI 1.9–4.4). Conclusion Analyzing the data collected from the reg- & Gene Sung [email protected] istry of the standard practice in a large metropolitan region, TH is associated with improved neurologic outcome in 1 Department of , Keck School of of the patients resuscitated from initial non-shockable rhythms in University of Southern California, 1520 San Pablo St, Ste a regionalized system for post-resuscitation care. 3000, Los Angeles, CA 90033, USA 2 Department of Emergency Medicine, Harbor-UCLA Medical Keywords Therapeutic hypothermia Á Cardiac arrest Á Center, Los Angeles Biomedical Research Institute at Harbor-UCLA, Torrance, CA, USA Resuscitation 3 David Geffen School of Medicine at UCLA, Los Angeles, CA, USA Introduction 4 Los Angeles County Emergency Medical Services Agency, Los Angeles, CA, USA 5 Therapeutic hypothermia (TH) is a proven intervention that Department of Emergency Medicine, Keck School of improves neurologic outcomes after successful resuscita- Medicine of the University of Southern California, Los Angeles, CA, USA tion from out-of-hospital cardiac arrest (OHCA) with initial shockable rhythm. [1, 2] The International Liaison 6 Department of , Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA Committee on Resuscitation supports the use of TH in patients after OHCA with an initial rhythm of ventricular 7 Department of Cardiology, Harbor-UCLA Medical Center, Los Angeles Biomedical Research Institute at Harbor-UCLA, fibrillation, and state that, while TH may be beneficial for Torrance, CA, USA other rhythms, further study is required in non-shockable 123 Neurocrit Care rhythms. [3] The proposed mechanism by which TH cardiac etiology with ROSC in the field to a cardiac arrest improves outcomes includes reducing cerebral reperfusion center with an institutionally approved hypothermia pro- injury by decreasing oxygen demand, glutamate release, tocol. Participating hospitals were encouraged to institute and production of free radicals. [1, 3] Cerebral reperfusion TH (target temperature 32–34 °C) within 6 h of ROSC and injury is applicable to all patients suffering cardiac arrest. to maintain it for a minimum of 20 h. The final decision to However, given the lower survival rates and higher initiate or withhold TH was guided by particular institu- potential for comorbidities in patients with non-shockable tional policy and at the discretion of the treating physician, rhythms, the degree to which TH may be beneficial for and TH was not initiated in the field. Six of the 33 cardiac these patients remains unclear. Small observational studies arrest centers have policies that specifically limit TH to that include patients with non-shockable rhythms demon- patients presenting with a shockable rhythm. strated safety and suggest that there may be a survival Per LA County EMS policy, resuscitation on scene to benefit in all rhythms. [4–8] The benefit was not consis- achieve ROSC prior to transport is encouraged. For tently seen when non-shockable rhythms were isolated, patients meeting criteria, termination of resuscitation in the causing some to question benefit in these cases, though field is supported by official policy since 2007. Termina- these results were possibly due to small sample size. [9–12] tion of resuscitation is based on medical futility determined While patients resuscitated after non-shockable cardiac by paramedics in consultation with the base hospital arrest rhythms may benefit from the neuroprotective physician and agreement of immediate family on scene. properties of cooling, hypothermia has known risks Since April 2011, all cardiac arrest centers have reported including dysrhythmias, coagulopathy, and infection. In their in-hospital mortality and neurologic outcome to a addition, it is resource intensive. Finally, there remains the single registry maintained by the LA County EMS Agency. possibility that TH may improve survival in this group of The database was queried from April 2011 through August patients without improving neurologic outcome, resulting 2013, representing all available data at the time of analysis. in more patients surviving severely dependent or moribund. Patients 18 years or older resuscitated from OOHCA with This study reports the results of the largest series of non- an initial non-shockable rhythm transported to a designated shockable rhythm patients in a registry of one of the largest cardiac arrest center were included. Non-shockable rhythm metropolitan regions in the world. It utilizes the regional- refers to the first rhythm noted by prehospital personnel ized care system for OHCA in Los Angeles County and its and includes PEA and asystole, as well as patients analyzed standard practices, with a centralized database of patient by an automated external defibrillator that advised no outcomes, to assess neurologic outcome in patients treated shock. Patients with traumatic cardiac arrest and with TH after successful resuscitation from OHCA with an patients <18 years of age were excluded. Additionally, initial rhythm of pulseless electrical activity (PEA) or patients who would not benefit from TH were excluded asystole compared to those patients not treated with TH. from the analysis in order to mitigate the selection bias toward or against TH given the observational design of the study. This included the following: patients awake and alert Materials and Methods in the emergency department, patients with prior coma, and patients who died prior to consideration for TH. (Fig. 1) Los Angeles County is a large metropolis with a population Finally, patients with termination of resuscitation in the of over 13 million. Emergency medical services (EMS) are field were not transported by protocol and, therefore, were provided by 32 municipal fire departments, one law not eligible for inclusion in the database. enforcement agency, and 25 private ambulance companies Study variables included age, gender, race/ethnicity, with over 3500 licensed paramedics throughout the county. initial cardiac rhythm, arrest location, witness, bystander Patients who call 911 are transported to one of 72 emer- CPR, vasopressor support, induction of hypothermia, rea- gency departments in the county. The LA County EMS son hypothermia was withheld (if applicable), and whether Agency provides oversight of providers operating within the patient received cardiac catheterization with or without the county, establishes protocols and procedures, and des- PCI. The primary outcome of the study was survival to ignates specialty care centers. This is a retrospective study hospital discharge with good neurologic outcome, as of data from a registry maintained by the LA County EMS defined by a cerebral performance category (CPC) score at Agency. The study was reviewed and approved with waiver hospital discharge of 1 or 2. A CPC of 1 corresponds to a of informed consent by the institutional review board. return to normal or mildly impaired cerebral function and The system of regionalized cardiac care in LA County, independence with activities of daily living. A CPC of 2 with 33 designated cardiac arrest receiving centers, has corresponds to moderate cerebral disability but sufficient been described previously. [13] Countywide protocols function to remain independent with activities of daily mandate transport of all OOHCA patients of presumed living. The CPC scores documented by physician 123 Neurocrit Care

calculated to evaluate each model. Mean CPC score out- comes among hospitals were compared with ANOVA.

Results

Of the 2772 patients treated for cardiac arrest during the study period, 893 (32 %) had an initial shockable rhythm and 166 (6 %) had an undocumented initial rhythm leaving 1713 consecutive patients resuscitated from cardiac arrest with an initial non-shockable rhythm. For these patients, the median age was 71 years [IQR 59–82] and 975 (57 %) were male. Overall, four-hundred and five (28 %) survived to hospital discharge and 176 (12 %) had documentation of good neu- rologic outcome. There were 33 survivors without documented CPC score and were not included in the analysis. Fig. 1 Study profile Of the 1713 patients presenting with an initial non- shockable rhythm, 86 were awake and 195 had prior coma assessment at the time of discharge were abstracted from or died, leaving 1432 that could have potentially benefitted the medical record. from TH. The overall characteristics of the study population Individual centers are responsible for reporting their data. are given in Table 1. TH was induced in 596 (42 %) Staff members charged with data entry abstract the data patients. Patient characteristics in the TH group and refer- points from the patient’s medical record, including prehos- ence group are given in Table 2. Of note, 159 (27 %) of pital care records. Greater than 90 % of staff responsible patients treated with TH and 169 (20 %) of patients who did for the data extraction and entry are registered nurses in the not receive TH, converted to a shockable rhythm and departments of emergency medicine, cardiology, and qual- received at least 1 shock during their resuscitation. For those ity improvement. Completeness and accuracy of the entered in the TH group, the target temperature of 33 °Cwas data is continually reviewed by the EMS Agency with ver- achieved 74 % of the time and ranged from 32 to 34 °C. ification performed during annual site visits. Bi-annual system-wide meetings are held for data review. Table 1 Patient characteristics (n = 1432) All data were entered into Microsoft Excel (Microsoft Characteristics Total Corporation, Redmond WA) and transferred to SAS 9.3 (SAS Institute, Cary, NC) for analysis. We report neuro- N (median) % (IQR*) logically intact survival as proportions with exact binomial Age 69 59–82 confidence intervals. Adjusted odds ratios (OR) and their Gender p values were calculated using logistic regression and the Female 629 44 Chi-square test. Variables in the regression (age, witness, Male 802 56 bystander CPR, rhythm, catheterization, PCI, and vaso- Race/ethnicity pressor support) were selected based on prior knowledge of Black 190 13 their contribution to cardiac arrest outcomes and entered Asian 177 12 simultaneously into the model. The generalized estimating Hispanic 331 23 equation was used to adjust for clustering by hospital. White 663 46 Additionally, a propensity score-adjusted model was per- Pacific Islander/Hawaiian 8 1 formed to confirm the results of the multivariable regression, Other/unknown 63 4 because of the large differences between the treatment Witnessed arrest 1165 81 groups. [14] A propensity score for receiving TH for each Bystander CPR 516 36 individual was calculated based on the following observed Pulseless electrical activity 632 44 covariates known to affect outcomes in cardiac arrest: age, Therapeutic hypothermia 596 42 witness, bystander CPR, initial rhythm, need for vasopressor support, and treatment hospital. This score was then used in Vasopressors 1194 84 a regression analysis to evaluate the association of TH with Catheterization performed 154 11 neurologic outcome, adjusting for the likelihood of receiving PCI performed 46 3 TH. The Hosmer–Lemeshow goodness-of-fit statistic was * Inter-quartile range 123 Neurocrit Care

Table 2 Patient characteristics by treatment group (n = 1423) Characteristics TH (n = 596) No TH (n = 827) N % N %

Age (median/IQR ) 68 57–77 73 60–84 Gender Female 239 40 386 47 Male 357 60 440 53 Race/ethnicity Black 91 15 94 11 Asian 62 10 115 14 Hispanic 147 25 183 22 White 275 46 386 47 Pacific Islander/Hawaiian 5 1 3 0 Other/unknown 16 3 46 6 Witnessed arrest 505 85 651 79 Bystander CPR 222 37 291 35 Pulseless electrical activity 255 43 373 45 Defibrillated at any point 159 27 169 20 Initial GCS after ROSC (median/IQR ) 3 3–3 3 3–3 Vasopressors 514 86 672 81 Catheterization performed 111 19 41 5 PCI performed 34 6 11 1 Inter-quartile range

Cooling was maintained for a median time of 23 h (IQR Table 3 Primary reason given for no therapeutic hypothermia 19–24). For patients that did not receive TH, the reason was (n = 827) undocumented in one-third and less than half had docu- Reason given Frequency Percent mentation of a known contraindication to cooling, Table 3. Survival with good neurologic outcome occurred in 14 % in Bleeding complications 60 5 the group receiving TH, compared with 5 % in the group not and/or dysrhythmia 45 4 treated with TH (risk difference = 8 %, 95 % CI 5–12 %). Temperature less than 35 °C192 The adjusted OR for a CPC 1 or 2 with TH was 2.9 (95 %CI 32 3 1.9–4.4) compared to patients not receiving TH, adjusted for Drug-induced coma 7 1 age, witnessed arrest, bystander CPR, arrest rhythm (PEA or Chronic renal disease 31 3 asystole), vasopressor support, treatment in the cath lab, Non-shockable rhythm 48 4 whether PCI was performed, and clustering by hospital Withdrawal of care 159 14 (Table 4). Frequency of adverse events from TH is in Table 5. Other 66 6 The propensity score analysis, which included a variable Missing 366 33 representing the probability of the patient receiving TH, given the age of the patient, whether the arrest was wit- nessed and bystander CPR was performed, the initial Discussion presenting rhythm, need for vasopressor support, and the hospital at which the patient was treated, yielded identical In the LA County regional system for OHCA care, TH results to the regression analysis. The overall survival improved overall survival and survival with good neuro- increased from 16 % without TH to 30 % with TH (risk logic outcome in patients resuscitated from cardiac arrest difference = 14 %, 95 %CI 10–19 %), as well as an with an initial non-shockable rhythm. To our knowledge, increase in the proportion of patients who survived with this is the largest cohort to date evaluating use of TH for CPC 3 or 4–13 % with TH versus 9 % without TH (risk patients with non-shockable cardiac arrest rhythms and the difference = 4 %, 95 % CI 1–7 %). first to report the results from the general practice of TH in

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Table 4 Adjusted odds ratios for survival with good neurologic assessed at one year rather than at hospital discharge. There outcome were a significant number of deaths from any cause in both Adjusted odds ratio for good outcome groups during the one-year follow-up, which may or may (95 % CI)* not be related to the initial cardiac event. Similarly, a study by Dumas et al. found a hazard ratio for death of 0.89 Therapeutic hypothermia 2.9 1.9–4.4 (95 % CI 0.51–1.55) in patients resuscitated from PEA or Witnessed arrest 2.2 1.0–4.5 asystole who received TH compared to those not treated. Rhythm (PEA) 1.7 1.3–2.3 Over a period of nine years, only 261 patients with non- Bystander CPR 1.2 0.8–1.7 shockable rhythm were enrolled of whom 68 were cooled. Age (per year) 1.0 1.0–1.0 Several studies have demonstrated a benefit to TH Cath lab 1.3 0.5–3.4 across all ROSC patients irrespective of initial rhythm. [4– PCI 1.5 0.4–4.9 8, 19] Because of conflicting outcomes, some investigators Vasopressor 0.6 0.3–1.0 have questioned the use of TH in general. [20, 21] A recent *Adjusted odds ratio generated by the simultaneous entry of covari- randomized control study of adults resuscitated from car- ates in the logistic regression model diac arrest regardless of initial rhythm calls into question Hosmer–Lemeshow goodness-of-fit statistics p 0.2, Akaike Informa- whether it is the induced hypothermia or the careful tem- tion Criterion = 686 perature modulation alone that may prove beneficial. [22] In this study, patients were randomized to a target tem- perature of 36 or 33 °C and no difference in death or Table 5 Reported adverse events from TH neurologic outcome at 180 days was noted. Since the study Adverse event Frequency was powered to detect a 20 % difference in the groups for Shivering 53 the primary outcome of mortality, it does not eliminate the Electrolyte abnormality 50 possibility of a smaller but substantial benefit to TH. While Dysrhythmia 24 further study may be needed to determine the optimum Bleeding/coagulopathy 19 target temperature, hyperthermia is known to be detri- Infection 18 mental after cardiac arrest. [23] Post-cardiac arrest Aspiration 5 syndrome, including brain injury and reperfusion response, is common to all victims resuscitated from cardiac arrest. Thrombotic event 2 [24] It follows that interventions demonstrated effective for Ileus 1 one rhythm are likely generalizable to all cardiac arrest Decubitus 1 patients. Other 34 Our results support the use of TH in patients resuscitated from cardiac arrest with initial non-shockable rhythms, but have several limitations. Our study is retrospective and the the care of cardiac arrest patients in a large metropolitan validity of the results depends on the accuracy of the data region. Prior literature has been conflicting on the effec- entered in the registry by the cardiac arrest centers. tiveness of TH for these patients, possibly due to the Although all designated hospitals were required to meet limitations of small sample size. [15–17] In our cohort, TH criteria set by the LA County EMS Agency and were was used in 35 % of patients. subject to ongoing quality improvement, there was variety Lundbye et al. evaluated 100 patients with non-shock- in the institutional protocols and devices used for TH. able rhythms before and after implementation of TH However, this makes the results more generalizable to protocol and found TH improved both survival to hospital other systems with varying methods and target parameters discharge and neurologic outcome. [18] In contrast, two for cooling. The reason TH was withheld was missing in other studies found trends for benefit but did not reach one-third of patients. We were unable to adjust for down- statistical significance. Vaahersalo and colleagues time (time from cardiac arrest to ROSC), which is known prospectively evaluated the effect of TH on adult OHCA to affect outcomes [25], as this was missing a large number patients treated in intensive care units in Finland, where of patients and is likely to be inaccurate when reported national guidelines do not recommend TH for patients with [26–28]. In addition, there are other uncontrolled factors non-shockable cardiac arrest rhythms. While the authors that may contribute to patient outcomes that we did not found a 3.4 % reduction in poor neurologic outcome for measure in this study. In particular, selection bias is pos- patients with initial non-shockable rhythm, this difference sible due to the observational design of the study, despite did not reach statistical significance. The outcome in this exclusion of patients in whom TH was withheld for futility study differs from ours in that neurologic outcome was and adjustment for measured confounders. Although the 123 Neurocrit Care propensity score analysis helps account for large differ- 10. Oddo M, Schaller MD, Feihl F, Ribordy V, Liaudet L. From ences between groups, it too is limited by inclusion of only evidence to clinical practice: effective implementation of thera- peutic hypothermia to improve patient outcome after cardiac the known covariates. Use of additional interventions arrest. Crit Care Med. 2006;34:1865–73. varied between centers, however, we did adjust for hospital 11. Vaahersalo J, Hiltunen P, Tiainen M, et al. Therapeutic in order to partially account for clustering by center. hypothermia after out-of-hospital cardiac arrest in Finnish Misclassification bias is possible if paramedics misinter- intensive care units: the FINNRESUSCI study. Intensive Care Med. 2013;39:826–37. preted the initial presenting rhythm. Finally, the ability to 12. Dumas F, Grimaldi D, Zuber B, et al. Is hypothermia after cardiac obtain information regarding long-term follow-up was not arrest effective in both shockable and nonshockable patients? possible, as the database is limited to prehospital and Insights from a large registry. Circulation. 2011;123:877–86. inpatient data through hospital discharge only. 13. Bosson N, Kaji AH, Niemann JT, et al. Survival and neurologic outcome after out-of-hospital cardiac arrest: results one year after regionalization of post-cardiac arrest care in a large metropolitan area. Prehosp Emerg Care. 2014;18:217–23. Conclusion 14. Newgard CD, Hedges JR, Arthur M, Mullins RJ. Advanced statistics: the propensity score–a method for estimating treatment effect in observational research. Acad Emerg Med. 2004;11: Patients resuscitated from non-shockable cardiac arrest 953–61. rhythms may benefit from TH. In our cohort, TH was 15. Arrich J, Holzer M, Havel C, Mullner M, Herkner H. associated with improved neurologic function at hospital Hypothermia for neuroprotection in adults after cardiopulmonary discharge and our results support current international resuscitation. Cochrane Database Syst Rev. 2012;9:CD004128. 16. Kim YM, Yim HW, Jeong SH, Klem ML, Callaway CW. Does guidelines. therapeutic hypothermia benefit adult cardiac arrest patients presenting with non-shockable initial rhythms? A systematic Acknowledgments The authors would like to thank all the cardiac review and meta-analysis of randomized and non-randomized arrest center participants and the Los Angeles County EMS Agency studies. 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