Effect of therapeutic hypothermia on the outcomes after out-of-hospital cardiac arrest according to initial ECG rhythm and witnessed status: A nationwide observational interaction analysis

doi:10.1016/j.resuscitation.2015.12.012

Resuscitation

Volume 100, March 2016, Pages 51-59

https://doi.org/10.1016/j.resuscitation.2015.12.012 Get rights and content

Abstract

Background

The use of mild therapeutic hypothermia (TH) in out-of-hospital cardiac arrest (OHCA) with shockable rhythms is recommended and widely used. However, it is unclear whether TH is associated with better outcomes in non-shockable rhythms.

Methods

This is a retrospective observational study using a national OHCA cohort database composed of emergency medical services (EMS) and hospital data. We included adult EMS-treated OHCA patients of presumed cardiac etiology who were admitted to the hospital during Jan. 2008 to Dec. 2013. Patients without hospital outcome data were excluded. The primary outcome was good neurological outcome at discharge; secondary outcome was survival to discharge. The primary exposure was TH. We compared outcomes between TH and non-TH groups using multivariable logistic regression, adjusting for individual and Utstein factors. Interactions of initial ECG rhythm and witnessed status on the effect of TH on outcomes were tested.

Results

There were 11,256 patients in the final analysis. TH was performed in 1703 patients (15.1%). Neurological outcome was better in TH (23.5%) than non-TH (15.0%) (Adjusted OR = 1.25, 95% CI 1.05–1.48). The effect of TH on the odds for good neurological outcome was highest in the witnessed PEA group (Adjusted OR = 3.91, 95% CI 1.87–8.14). Survival to discharge was significantly higher in the TH group (55.1%) than non-TH (35.9%) (Adjusted OR = 1.76, 95% CI 1.56–2.00).

Conclusions

In a nationwide observational study, TH is associated with better neurological outcome and higher survival to discharge. The effect of TH is greatest in witnessed OHCA patients with PEA as the initial ECG rhythm.

Introduction

Out-of-hospital cardiac arrest (OHCA) is a public health problem worldwide. The American Heart Association estimates that about 424,000 emergency medical service (EMS)-assessed OHCA episodes, or 134 per 100,000 persons, occur each year in the United States.¹ The incidence of EMS-assessed OHCA is estimated to be 86 per 100,000 person-years in Europe, and 53 per 100,000 person-years in Asia.² OHCA is also associated with high morbidity and mortality, pooled data showing that approximately 23.8% of the patients survive to hospital admission but only 7.6% of the patients survive to hospital discharge.³ The major cause of in-hospital mortality in patients who are resuscitated and survive to hospital admission is attributed to the post-cardiac arrest syndrome, composed of brain injury, myocardial dysfunction, systemic ischemia, and reperfusion response. Therapeutic hypothermia (TH) is a part of the recommended bundle of care that targets the post-cardiac arrest syndrome.⁴

Two randomized controlled trials5, 6 published in 2002 demonstrated the survival benefit of TH in comatose OHCA patients due to ventricular fibrillation (VF), which led the International Liaison Committee on Resuscitation in 2003 to recommend TH to comatose adult survivors of VF OHCA.⁷ However, a recent landmark study by Nielsen et al.⁸ calls into question the benefit of induced hypothermia compared to maintaining normothermia in post-OHCA patients, showing that many questions on TH are still unresolved.⁹ Nonetheless, TH is still widely used and the current guidelines recommend cooling comatose adult patients with return of spontaneous circulation (ROSC) to 32 °C to 34 °C for 12 to 24 h after VF OHCA (Class I, LOE B), and in-hospital cardiac arrest (IHCA) or after OHCA with an initial rhythm of pulseless electric activity (PEA) or asystole (Class IIb, LOE B).9, 10

Numerous observational studies have confirmed the improvement in neurological outcomes and survival in OHCA with shockable initial rhythms.11, 12 However, the initial rhythm in the majority of OHCA is PEA/asystole,² and the guidelines support the use of TH in non-shockable rhythms while recognizing and emphasizing the need for further studies. There are no randomized controlled trials that directly test the benefit of TH in non-shockable rhythms, and results of observational studies have been conflicting. Recent meta-analysis of observational studies have shown an association with improved outcomes, but state that the quality of the evidence is poor.13, 14

Further studies are needed to refine the details of TH, including the target population. In unwitnessed, non-shockable OHCA patients, it is debatable whether TH is associated with better outcomes. This study aimed to provide further evidence by comparing the effect of TH for the improvement of neurological outcome and survival to discharge in cardiac arrest patients, and the interaction effects of initial ECG rhythm and presence of witness on the effect of TH on outcomes.

Section snippets

Study setting and design

This is a retrospective observational study using a Korean national EMS-assessed OHCA cohort database, the Cardiovascular Disease Surveillance (CAVAS) project. The project started in 2006 and is sponsored by the National Emergency Management Agency and the Centers for Disease Control and Prevention of the Republic of Korea.15, 16, 17, 18, 19, 20 Data from EMS run sheets and hospital record reviews were used to form the database. Cases of OHCA were identified from the electronic EMS run sheets

Demographic findings

There were 11,335 adult OHCA patients of presumed cardiac origin who survived to hospital admission during the study period. Seventy-nine patients without neurological outcome data, 9 of whom underwent TH, were excluded from the study (Fig. 1). There were 11,256 patients in the final analysis, of whom 15.1% or 1703 patients were treated with TH, and 84.9% or 9553 patients formed the control group. The number of cases and the percentages of OHCA patients receiving TH increased yearly from 5.5%

Discussion

In the multifaceted approach to the care of patients with post cardiac arrest syndrome,⁴ TH is a treatment that has been shown to improve outcomes.4, 21 In this study, TH improved both neurological outcome and survival to discharge in OHCA patients in Korea. There was also an interaction effect that improvements to outcome were most pronounced in witnessed OHCA patients with PEA as their initial ECG rhythm.

Because of the relatively higher rate of survival compared to OHCA presenting with

Conclusion

In a nationwide observational study of OHCA and therapeutic hypothermia in Korea, therapeutic hypothermia use has been increasing every year and is associated with better neurological outcome and higher survival to discharge. The effect is greatest in witnessed patients with PEA as the initial ECG rhythm. More studies are needed to further elucidate the target population who will most benefit from TH.

Conflict of interest statement

The authors declare no conflict of interest relevant to this paper.

Acknowledgements

This study was supported by the National Emergency Management Agency of Korea and the Korea Centers for Disease Control and Prevention (CDC). The study was funded by the Korea CDC (2012–2014) (Grant Nos.: 2012-E33010-00; 2013-E33015-00; 2014-E33011-00).

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Cited by (18)

Therapeutic hypothermia in patients after cardiac arrest: A systematic review and meta-analysis of randomized controlled trials
2023, American Journal of Emergency Medicine
Targeted temperature management (TTM) with therapeutic hypothermia (TH) has been used to improve neurological outcomes in patients after cardiac arrest; however, several trials have reported conflicting results regarding its effectiveness. This systematic review and meta-analysis assessed whether TH was associated with better survival and neurological outcomes after cardiac arrest.
We searched online databases for relevant studies published before May 2023. Randomized controlled trials (RCTs) comparing TH and normothermia in post-cardiac-arrest patients were selected. Neurological outcomes and all-cause mortality were assessed as the primary and secondary outcomes, respectively. A subgroup analysis according to initial electrocardiography (ECG) rhythm was performed.
Nine RCTs (4058 patients) were included. The neurological prognosis was significantly better in patients with an initial shockable rhythm after cardiac arrest (RR = 0.87, 95% confidence interval [CI] = 0.76–0.99, P = 0.04), especially in those with earlier TH initiation (<120 min) and prolonged TH duration (≥24 h). However, the mortality rate after TH was not lower than that after normothermia (RR = 0.91, 95% CI = 0.79–1.05). In patients with an initial nonshockable rhythm, TH did not provide significantly more neurological or survival benefits (RR = 0.98, 95% CI = 0.93–1.03 and RR = 1.00, 95% CI = 0.95–1.05, respectively).
Current evidence with a moderate level of certainty suggests that TH has potential neurological benefits for patients with an initial shockable rhythm after cardiac arrest, especially in those with faster TH initiation and longer TH maintenance.
Effect of estimated glomerular filtration rate (eGFR) on incidence of out-of-hospital cardiac arrests: A case-control study
2019, Resuscitation
Citation Excerpt :
Generally, blood samples are drawn during the early CPR phase (within 5 min) after arrival at the ED in Korea.20 Detailed information about EMS characteristics, OHCA protocols, and ED characteristics has been reported previously.21,22 The primary outcome was the eGFR calculated from the serum creatinine level.
Serum creatinine levels in the post-resuscitative state have been associated with poor prognosis for out-of-hospital cardiac arrest (OHCA). Several studies have focused on kidney dysfunction in the general population, and the results suggested that serum creatinine level elevation or reduction of the estimated glomerular filtration rate (eGFR) are associated with increased risk of death and cardiovascular events. However, it is uncertain whether the serum creatinine levels or eGFR of OHCA patients are related to the incidence of OHCA. The aim of this study was to determine the association between eGFR and the incidence of OHCA.
This study was a case-control study performed using the Cardiac Arrest Pursuit Trial with Unique Registration and Epidemiologic Surveillance (CAPTURES) project dataset and the Korea National Health and Nutrition Examination Survey (KNHANES) dataset. Cases were defined as emergency medical service-treated adult OHCA patients with presumed cardiac etiology collected from the CAPTURES dataset. Four controls from the KNHANES dataset were matched to one case based on age, gender, and county. Multivariable conditional logistic regression analysis was conducted to evaluate the effect of eGFR on the incidence of OHCA.
A total of 1211 matched case-control pairs were included in the study analysis. We classified eGFR into 6 categories (≥90, 60–89, 45–59, 30–44, 15–29, and <15 mL/min/1.73 m²) according to the chronic kidney disease stage. Subjects with an eGFR ≥90 mL/min/1.73 m² were used as the reference group. In both the unadjusted and adjusted models, lower eGFR was significantly associated with OHCA incidence. The odds ratio (OR) for OHCA incidence increased sharply as the eGFR declined; the adjusted OR (95% CI) for OHCA incidence was 4.09 (2.81–5.95) with an eGFR of 60–89 mL/min/1.73 m², 36.59 (22.24–60.21) with an eGFR of 45–59 mL/min/1.73 m², 55.26(29.66–102.94) with an eGFR of 30–44 mL/min/1.73 m², 89.65 (37.25–215.79) with an eGFR of 15–29 mL/min/1.73 m², and 241.87 (73.49–796.01) with an eGFR of less than 15 mL/min/1.73 m².
In this study, we observed an association between reduced eGFR and the risk of OHCA incidence in a large, community-based population. Future prospective studies are needed to better understand how reduced renal function is associated with OHCA occurrence as well as the impact of intensive risk management and intervention of renal function on OHCA incidence.
Derivation and Validation of the SWAP Score for Very Early Prediction of Neurologic Outcome in Patients With Out-of-Hospital Cardiac Arrest
2019, Annals of Emergency Medicine
Citation Excerpt :
Therefore, developing an assessment tool for patients who receive ongoing cardiopulmonary resuscitation (CPR) at EDs is necessary. Early assessment of prognosis is critical not only to determine which patients will benefit from intensive care, such as therapeutic hypothermia and extracorporeal CPR, but also to assess the effectiveness of interventional studies.5,6 Studies have reported several factors associated with the prognosis of out-of-hospital cardiac arrest, including age, witnessed arrest, bystander CPR, duration of no-flow or low-flow status, presence of shockable rhythm, and blood pH on admission.2,7-11
For patients with out-of-hospital cardiac arrest who receive cardiopulmonary resuscitation in an emergency department (ED), the early evaluation of their neurologic prognosis is essential for emergency physicians. The aim of this study is to establish a simple and useful assessment tool for rapidly estimating the prognosis of patients with out-of-hospital cardiac arrest after their arrival at an ED.
A total of 852 patients admitted from January 1, 2015, to June 30, 2017, were prospectively registered and enrolled in the derivation cohort. Multivariate logistic regression on this cohort identified 4 independent factors associated with unfavorable outcomes: initial nonshockable rhythm (odds ratio [OR] 3.40; 95% confidence interval [CI] 1.58 to 7.32), no witness of collapse (OR 3.19; 95% CI 1.51 to 6.75), older than 60 years (OR 3.65; 95% CI 1.64 to 8.09), and pH less than or equal to 7.00 (OR 3.27; 95% CI 1.42 to 7.54). The shockable rhythm–witness-age-pH (SWAP) score was developed and 1 point was assigned to each predictor.
For a SWAP score of 4, the specificity was 97.14% (95% CI 91.62% to 100%) for unfavorable outcomes in the derivation cohort. For validation, we retrospectively collected data for 859 patients with out-of-hospital cardiac arrest from January 1, 2012, to December 31, 2014. A SWAP score of 4 was 100% specific (95% CI 99.9% to 100%) for unfavorable outcomes in the validation cohort.
The SWAP score is a simple and useful predictive model that may provide information for the very early estimation of prognosis for patients with out-of-hospital cardiac arrest. Further research is required to integrate ultrasonographic findings and validate the SWAP score’s application in other populations.
Effect of target temperature management at 32–34 °C in cardiac arrest patients considering assessment by regional cerebral oxygen saturation: A multicenter retrospective cohort study
2018, Resuscitation
Citation Excerpt :
Conducting TTM at 32–34 °C for elderly patients [32], patients without diabetes [33], and patients with low GCS motor response [34] have been reported to be effective, but not for patients with traumatic brain injury (TBI) [35,36]. Conducting TTM in patients with in-hospital cardiac arrest [37,38] and those with initial non-shockable rhythms [39,40] still remains controversial. These findings indicate the potential effect of TTM at 32–34 °C in certain patient populations, although further evidence is required with regard to the characteristics of these patients.
Target temperature management (TTM) is used in comatose post-cardiac arrest patients, but the recommended temperature range is wide. This study aimed to assess the effectiveness of TTM at 32–34 °C while considering the degree of cerebral injury and cerebral circulation, as assessed by regional cerebral oxygen saturation (rSO₂).
This is a secondary analysis of prospectively collected registry data from comatose patients who were transferred to 15 hospitals in Japan after out-of-hospital cardiac arrest (OHCA) from 2011 to 2013. The primary outcome was all-cause mortality at 90 days after OHCA, and the secondary outcome was favorable neurological outcomes as evaluated according to the Cerebral Performance Category. We monitored rSO₂ noninvasively with near-infrared spectroscopy, which could assess cerebral perfusion and the balance of oxygen delivery and uptake.
We stratified 431 study patients into three groups according to rSO₂ on hospital arrival: rSO₂ ≤40% (n = 296), rSO₂ 41–60% (n = 67), and rSO₂ ≥61% (n = 68). Propensity score analysis revealed that TTM at 32–34 °C decreased all-cause mortality in patients with rSO₂ 41–60% (average treatment effect on treated [ATT] by propensity score matching [PSM] −0.51, 95%CI −0.70 to −0.33; ATT by inverse probability of treatment weighting [IPW] −0.52, 95%CI −0.71 to −0.34), and increased favorable neurological outcomes in patients with rSO₂ 41–60% (ATT by PSM 0.50, 95%CI 0.32–0.68; ATT by IPW 0.52, 95%CI 0.35–0.69).
TTM at 32–34 °C effectively decreased all-cause mortality in comatose OHCA patients with rSO₂ 41–60% on hospital arrival in Japan.
Cooling methods of targeted temperature management and neurological recovery after out-of-hospital cardiac arrest: A nationwide multicenter multi-level analysis
2018, Resuscitation
Citation Excerpt :
This result indicated that even prolonged resuscitation cannot justify the futility of aggressive post-cardiac arrest management. TTM showed less significant improvement or no improvement in neurological outcomes in OHCA patients with a shockable rhythm or patients with diabetes [26,27]. Outcomes may be affected according to the cooling methods for patients with specific conditions; however, the studies were not adjusted for the cooling methods.
The purpose of this study was to determine whether the cooling method used for target temperature management (TTM) was associated with neurological recovery after out-of-hospital cardiac arrest (OHCA).
From January 2008 to December 2016, adult OHCA patients who survived to hospitalization without any traumatic etiology and who received TTM were included. Patients who did not have information about neurological status at hospital discharge or who did not have information on target temperature management were excluded. Cooling methods were classified into four groups: (1) external device cooling (EDC) using a pad with cooling device, (2) external conventional cooling (ECC) such as ice water, fans, and simple blankets, (3) Intravascular cooling (IVC) using an intravascular cooling catheter, and (4) intracavitary cooling (ICC) using ice water for washing cavitary organ. The outcomes were good cerebral performance scale (CPC) score 1 or 2 and survival to discharge. In multivariate logistic regression analysis, the adjusted odds ratios (AORs) and the 95% confidence intervals (CIs) were calculated (reference = ECC). Finally, we used a GLIMMIX procedure with group-level variables (hospitals) to create a multilevel model for adjusting the clustering factor of patients being treated in the same hospital.
The final analysis included a total of 4246 eligible patients (ECC 1386, EDC 2107, IVC 376, ICC 377). Good neurologic recovery was 20.7% for all (ECC 17.4, EDC 23.1%, IVC 26.9%, and ICC 13.3%, p < .001). The survival rate was 46.4% for all (ECC 45.4%, EDC 48.5%, IVC 50.5%, ICC 34.2%, p < .001). There were no significant differences (AOR and 95% CI) in the multi-level analysis for good neurological recovery between cooling methods compared with ECC; EDC 1.20 (0.95–1.52), IVC 1.43 (0.90–2.27), and ICC 0.71 (0.46–1.10). The ICC group had a lower survival to discharge rate compared with ECC; EDC 0.97 (0.83–1.15), IVC 0.96 (0.78–1.19), and ICC 0.63 (0.43–0.85).
The cooling methods for TTM did not show any significant difference in neurological recovery in multi-level logistic regression analysis. Only intracavitary cooling resulted in a lower survival to discharge than external surface cooling.
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^☆: A Spanish translated version of the abstract of this article appears as Appendix in the final online version at http://dx.doi.org/10.1016/j.resuscitation.2015.12.012.

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Clinical paperEffect of therapeutic hypothermia on the outcomes after out-of-hospital cardiac arrest according to initial ECG rhythm and witnessed status: A nationwide observational interaction analysis☆

Abstract

Background

Methods

Results

Conclusions

Introduction

Section snippets

Study setting and design

Demographic findings

Discussion

Conclusion

Conflict of interest statement

Acknowledgements

Resuscitation

Resuscitation

Resuscitation

Resuscitation

Resuscitation

Resuscitation

Resuscitation

Resuscitation

Resuscitation

Resuscitation

Resuscitation

Resuscitation

J Cardiothorac Vasc Anesth

Heart disease and stroke statistics—2014 update: a report from the American Heart Association

Circulation

Clinical paper
Effect of therapeutic hypothermia on the outcomes after out-of-hospital cardiac arrest according to initial ECG rhythm and witnessed status: A nationwide observational interaction analysis☆