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Association Between Prompt Defibrillation and Epinephrine Treatment With Long-Term Survival After In-Hospital Cardiac Arrest

and for the American Heart Association’s Get With the Guidelines–Resuscitation Investigators
Originally publishedhttps://doi.org/10.1161/CIRCULATIONAHA.117.030488Circulation. 2018;137:2041–2051

Abstract

Background:

Prior studies have reported higher in-hospital survival with prompt defibrillation and epinephrine treatment in patients with in-hospital cardiac arrest (IHCA). Whether this survival benefit persists after discharge is unknown.

Methods:

We linked data from a national IHCA registry with Medicare files and identified 36 961 patients ≥65 years of age with an IHCA at 517 hospitals between 2000 and 2011. Patients with IHCA caused by pulseless ventricular tachycardia or ventricular fibrillation were stratified by prompt (≤2 minutes) versus delayed (>2 minutes) defibrillation, whereas patients with IHCA caused by asystole or pulseless electric activity were stratified by prompt (≤5 minutes) versus delayed (>5 minutes) epinephrine treatment. The association between prompt treatment and long-term survival for each rhythm type was assessed with multivariable hierarchical modified Poisson regression models.

Results:

Of 8119 patients with an IHCA caused by ventricular tachycardia or ventricular fibrillation, the rate of 1-year survival was higher in those treated with prompt defibrillation than with delayed defibrillation (25.7% [1466 of 5714] versus 15.5% [373 of 2405]; adjusted relative risk [RR], 1.49; 95% confidence interval [CI] 1.32–1.69; P<0.0001). This survival advantage persisted at 3 years (19.1% versus 11.0%; adjusted RR, 1.45; 95% CI, 1.23–1.69; P<0.0001) and at 5 years (14.7% versus 7.9%; adjusted RR, 1.50; 95% CI, 1.22–1.83; P<0.0001). Of 28 842 patients with an IHCA caused by asystole/pulseless electric activity, the rate of 1-year survival with prompt epinephrine treatment was higher than with delayed treatment (5.4% [1341 of 24 885] versus 4.3% [168 of 3957]; adjusted RR, 1.20; 95% CI, 1.02–1.41; P=0.02), but this survival benefit was no longer present at 3 years (3.5% versus 2.9%; adjusted RR, 1.17; 95% CI, 0.95–1.45; P=0.15) and at 5 years (2.3% versus 1.9%; adjusted RR, 1.18; 95% CI, 0.88–1.58; P=0.27).

Conclusions:

Prompt defibrillation for IHCA caused by ventricular tachycardia or ventricular fibrillation was associated with higher rates of long-term survival throughout 5 years of follow-up, whereas prompt epinephrine treatment for asystole/pulseless electric activity was associated with greater survival at 1 year but not at 3 or 5 years. By quantifying the greater survival associated with timely defibrillation and epinephrine administration, these findings provide important insights into the durability of survival benefits for 2 process-of-care measures in current resuscitation guidelines.

Introduction

Clinical Perspective

What Is New?

  • In a large, national registry of patients with in-hospital cardiac arrest, we found that prompt defibrillation (within 2 minutes) for shockable in-hospital cardiac arrests was associated with a 49% greater likelihood of survival at 1 year, a benefit that persisted at 3 and 5 years.

  • Prompt epinephrine treatment (within 5 minutes) for nonshockable in-hospital cardiac arrests was associated with a 20% greater survival at 1 year but was not sustained at 3 or 5 years of follow-up.

What Are the Clinical Implications?

  • These findings provide important insights into the durability of associations with greater survival for 2 process-of-care measures in current resuscitation guidelines.

  • Although causal conclusions cannot be drawn from observed associations, early defibrillation and epinephrine administration might have contributed to improved long-term survival in patients with in-hospital cardiac arrest.

  • These findings underscore the importance of large-scale implementation of programs to reduce delays in treatment during acute resuscitation.

In-hospital cardiac arrest (IHCA) affects 200 000 patients in the United States annually and has significant morbidity and mortality.1,2 In shockable rhythms secondary to pulseless ventricular tachycardia (VT) or ventricular fibrillation (VF), prompt defibrillation (≤2 minutes) is associated with higher rates of survival to discharge compared with delayed defibrillation.3 Similarly, early administration of epinephrine in nonshockable arrests caused by asystole or pulseless electric activity (PEA) is associated with greater odds of survival to discharge.4 Consequently, clinical guidelines recommend prompt defibrillation for all patients with cardiac arrest presenting with shockable rhythms and epinephrine administration within 3 to 5 minutes for those presenting with nonshockable rhythms.5,6 However, prior studies have focused only on in-hospital survival. Whether these process measures are associated with long-term survival is largely unknown but important to understand because the survival advantage with prompt defibrillation or epinephrine treatment may attenuate over time. This is especially important for patients with IHCAs resulting from nonshockable rhythms because these rhythms make up >75% of all IHCAs but have in-hospital survival rates of only 15%.2

To better understand the impact of these process measures on long-term outcomes, we leveraged data from a large national registry of patients with IHCA linked with Medicare inpatient claims files to examine long-term survival according to the promptness of defibrillation and epinephrine administration in patients with an IHCA resulting from shockable and nonshockable rhythms, respectively. Quantifying the long-term survival benefit associated with timely defibrillation and epinephrine administration can provide important insights into the durability of survival benefits for 2 process-of-care measures in current resuscitation guidelines.

Methods

The data, analytical methods, and study materials will be made available to other researchers for purposes of reproducing the results once required permission is obtained from the Get With The Guidelines (GWTG)–Resuscitation registry.

Data Sources and Linkage

We used data from American Heart Association’s GWTG-Resuscitation registry, which is a large, prospective, quality-improvement registry of IHCAs. The design of this registry has been described in detail previously.7 Briefly, all patients with an IHCA, defined as absence of a palpable central pulse, apnea, and unresponsiveness and without do-not-resuscitate orders, are enrolled by trained personnel at participating hospitals. Multiple case-finding methods are used, including centralized collection of cardiac arrest flow sheets, reviews of hospital paging system logs, routine checks of code carts, pharmacy tracer drug records, and hospital billing charges for resuscitation medications.7 The data are entered into a secured electronic database, which uses standardized definitions for patient variables and outcomes based on Utstein-style templates for reporting cardiac arrest data.8,9 To ensure accuracy and completeness of the data, further measures are undertaken that include rigorous certification of hospital staff, use of standardized software with internal checks, and periodic reabstraction and audits of collected data.7

To obtain information on long-term survival, we used data that have been previously linked with the use of a deterministic algorithm between GWTG-Resuscitation and Medicare inpatient files.10 Briefly, patient-level data from GWTG-Resuscitation were linked to Medicare inpatient files using 6 identifiers: the dates of hospital admission and discharge, the patient’s age and sex, the admitting hospital (deidentified), and the diagnosis and procedure codes in the International Classification of Diseases, Ninth Revision, Clinical Modification related to cardiac arrest and resuscitation procedures.10,11 For each linked patient, Medicare denominator files from 2000 through 2012 were obtained.

Study Population

Because we were interested in examining long-term survival, the study cohort included 162 831 IHCA events in adult patients from 517 hospitals within GWTG-Resuscitation between January 1, 2000, and December 31, 2011, to allow at least 1 year of long-term follow-up (Figure 1). We excluded 70 444 IHCA events occurring in patients <65 years of age, leaving 92 387 Medicare-eligible patients. For patients with a recurrent cardiac arrest during the same hospitalization, only the index cardiac arrest event was included (10 647 recurrent arrest events excluded). Of the remaining 81 740 patients, 52 727 patients were successfully linked to Medicare claims data. Because we were interested in examining the association between prompt and delayed treatment for IHCA, 6604 patients with IHCAs that occurred outside intensive care units, monitored units, or nonmonitored floors were excluded because these hospital areas (eg, operating rooms) have response times and outcomes that are uniquely different from those of inpatient units. In addition, 1199 patients with inconsistent (eg, time to defibrillation <0 or >30 minutes) or missing (n=1164) information on time to defibrillation and 7765 patients with inconsistent (eg, time to epinephrine administration <0 or >30 minutes) or missing (n=7171) information on time to epinephrine were excluded. Finally, 81 patients with an IHCA caused by asystole or PEA who received vasopressin as the initial treatment were excluded, as well as 117 patients with missing survival information. Our final study cohort included a total of 36 961 patients from 517 hospitals linked to Medicare inpatient files.

Figure 1.

Figure 1. Study cohort. ED indicates emergency department; ICD-9, International Classification of Diseases, Ninth Revision; IHCA, in-hospital cardiac arrest; OR, operating room; and VA, Veterans Administration.

Independent Variable and Outcomes

The primary independent variable was prompt versus delayed treatment for IHCA. Treatment times for defibrillation and epinephrine are documented at the minute level within GWTG-Resuscitation. For patients with a shockable IHCA caused by VF/VT, prompt treatment was defined as the time from initial arrest to first defibrillation of ≤2 minutes.3 For patients with a nonshockable IHCA resulting from asystole/PEA, prompt treatment was defined as the time from initial arrest to first epinephrine administration of ≤5 minutes.6

The primary outcomes of interest were survival at 1, 3, and 5 years from the index IHCA, which was determined from Medicare denominator files. For 3-year and 5-year survival, only patients with an IHCA in GWTG-Resuscitation between 2000 and 2009 and between 2000 and 2007 were analyzed to enable 3 and 5 years of vital status follow-up, respectively.

Statistical Analysis

Baseline characteristics between patients with prompt and delayed treatment for each rhythm type (shockable, nonshockable) were compared by use of the Student t test or Mann-Whitney U test for continuous variables and the χ2 or Fisher exact test for categorical variables. Survival curves with Kaplan-Meier estimates were then constructed for each rhythm type to examine unadjusted rates of survival.

To assess the associations between prompt treatment and long-term survival for each rhythm type, hierarchical multivariable modified Poisson regression models were constructed.1214 We used modified Poisson regression to correct for overestimation of estimates of effect observed with odds ratios when the outcome rate exceeds 10%.15 Instead, Poisson models yield relative risk estimates obtained from a Poisson distribution.1214 Moreover, our models were hierarchical models, with site as a random effect and patient-level factors as fixed effects. Specifically, they modeled as fixed effects age, sex, race, time to start of cardiopulmonary resuscitation, location of cardiac arrest, and the following coexisting conditions and events present within 24 hours before the cardiac arrest: heart failure, myocardial infarction, diabetes mellitus, renal insufficiency, hepatic insufficiency, respiratory insufficiency, acute stroke, pneumonia, hypotension, sepsis, major trauma, metabolic or electrolyte abnormality, metastatic or hematologic malignancy, and presence of an implantable cardioverter-defibrillator. In addition, the models were adjusted for interventions in place at the time of cardiac arrest (mechanical ventilation, continuous intravenous vasopressor, and hemodialysis), the time of day (daytime [7 am–10:59 pm] versus nighttime [11 pm–6:59 am]) and day of the week (weekday versus weekend; weekend versus holiday) of the cardiac arrest, and calendar year of admission (to account for temporal trends). In effect, use of hierarchical models facilitated within-hospital comparisons of patients with early and delayed treatment. Model performance was assessed with the c statistic. To further examine the effect of time to treatment and survival, we conducted sensitivity analyses wherein times to defibrillation were categorized as ≤1, 2, and >2 minutes and times to epinephrine were categorized as ≤3, 4 to 5, and >5 minutes.

All study analyses were performed with SAS 9.4 (SAS Institute, Cary, NC) and R version 2.15.0.16 All analyses were evaluated with a 2-sided significance level of 0.05. The institutional review board at Saint Luke’s Mid America Heart Institute approved the study, deemed it exempt from further review, and waived the requirement for informed consent because the study involved deidentified data.

Results

Of 36 961 patients with an IHCA, 8119 (22.0%) had an initial cardiac arrest rhythm that was shockable, and 28 842 (78.0%) had a nonshockable cardiac arrest rhythm. Among patients with a shockable IHCA, 2959 (36.4%) had an initial cardiac arrest rhythm of pulseless VT, and 5160 (63.6%) had VF. Median time to defibrillation was 1.0 minute (interquartile range, 0.0–3.0 minutes), and 5714 patients (70.4%) received prompt defibrillation (≤2 minutes), whereas 2405 (29.6%) received delayed defibrillation (>2 minutes). Patients with prompt defibrillation were younger and more likely to have an IHCA in intensive care units and during daytime hours, to have a myocardial infarction during the index hospitalization, and to have respiratory insufficiency and hypotension and be on mechanical ventilation or continuous intravenous vasopressor at the time of cardiac arrest (Table 1).

Table 1. Patient Characteristics for Shockable In-Hospital Cardiac Arrests, by Promptness of Defibrillation

CharacteristicPrompt Defibrillation (≤2 min) (n=5714), n (%)Delayed Defibrillation (>2 min)(n=2405), n (%)P Value
Age, mean±SD, y76.2±7.077.0±7.4<0.001
Male sex3432 (60.1)1407 (58.5)0.19
Race0.07
 White4703 (82.3)1948 (81.0)
 Black548 (9.6)272 (11.3)
 Other147 (2.6)50 (2.1)
 Unknown316 (5.5)135 (5.6)
Initial cardiac rhythm0.38
 Ventricular tachycardia2100 (36.8)859 (35.7)
 Ventricular fibrillation3614 (63.2)1546 (64.3)
Location of cardiac arrest<0.001
 Intensive care unit3708 (64.9)1015 (42.2)
 Telemetry-monitored unit1447 (25.3)844 (35.1)
 Nonmonitored unit559 (9.8)546 (22.7)
Time of cardiac arrest
 Daytime (7 am–10:59 pm)/nighttime (11 pm–6:59 pm)3977 (69.6)/1737 (30.4)1558 (64.8)/847 (35.2)<0.001
 Weekend or holiday1795 (31.4)797 (33.1)0.13
Time to cardiopulmonary resuscitation, min<0.001
 04209 (86.5)1837 (80.7)
 1366 (7.5)158 (6.9)
 >1293 (6.0)280 (12.3)
Cardiac diagnosis
 Congestive heart failure during admission1597 (27.9)661 (27.5)0.67
 Previous congestive heart failure1774 (31.0)759 (31.6)0.65
 Myocardial infarction during admission1802 (31.5)505 (21.0)<0.001
 Previous myocardial infarction1624 (28.4)574 (23.9)<0.001
Present within 24 h of in-hospital cardiac arrest
 Renal insufficiency1820 (31.9)815 (33.9)0.07
 Hepatic insufficiency237 (4.1)84 (3.5)0.17
 Respiratory insufficiency2114 (37.0)819 (34.1)0.01
 Hypotension1390 (24.3)484 (20.1)<0.001
 Septicemia585 (10.2)243 (10.1)0.86
Coexisting medical illnesses
 Diabetes mellitus1888 (33.0)829 (34.5)0.21
 Baseline depression in central nervous system function636 (11.1)259 (10.8)0.64
 Acute stroke204 (3.6)103 (4.3)0.12
 Acute nonstroke central nervous system event337 (5.9)132 (5.5)0.47
 Pneumonia640 (11.2)301 (12.5)0.09
 Major trauma83 (1.5)37 (1.5)0.77
 Metabolic or electrolyte abnormality770 (13.5)318 (13.2)0.76
 Metastatic or hematologic malignancy482 (8.4)214 (8.9)0.50
 Implantable cardioverter-defibrillator143 (2.5)58 (2.4)0.81
Interventions in place at time of cardiac arrest
 Intravenous vasopressor1730 (30.3)497 (20.7)<0.001
 Mechanical ventilation1780 (31.2)451 (18.8)<0.001
 Dialysis194 (3.4)75 (3.1)0.52

Among patients with a nonshockable IHCA, 13 746 (47.7%) had an initial rhythm of asystole and 15 096 (52.3%) had PEA. Median time to epinephrine administration was 2.0 minutes (interquartile range, 0.0–4.0 minutes). A total of 24 885 patients (86.3%) received prompt epinephrine treatment (≤5 minutes) compared with 3957 (13.7%) with delayed (>5 minutes) epinephrine treatment. Patients with prompt epinephrine treatment were younger, were more likely to arrest in intensive care units and during daytime hours, and were more likely to have a myocardial infarction during the hospitalization, as well as renal insufficiency, respiratory insufficiency, sepsis, and metabolic and electrolyte abnormalities at the time of their cardiac arrest (Table 2).

Table 2. Patient Characteristics for Nonshockable In-Hospital Cardiac Arrests, by Promptness of Epinephrine Administration

Baseline CharacteristicPrompt Epinephrine(≤5 min) (n=24 885), n (%)Delayed Epinephrine(>5 min) (n=3957), n (%)P Value
Age, mean±SD, y77.4±7.578.0±7.6<0.001
Male sex13 521 (54.3)2154 (54.4)0.91
Race0.07
 White18 793 (75.5)3008 (76.0)
 Black4142 (16.6)665 (16.8)
 Other729 (2.9)86 (2.2)
 Unknown1221 (4.9)198 (5.0)
Initial cardiac rhythm<0.001
 Asystole11 716 (47.1)2030 (51.3)
 Pulseless electric activity13 169 (52.9)1927 (48.7)
Location of cardiac arrest<0.001
 Intensive care unit14 138 (56.8)1077 (27.2)
 Telemetry-monitored unit5668 (22.8)1359 (34.3)
 Nonmonitored unit5079 (20.4)1521 (38.4)
Time of cardiac arrest<0.001
 Daytime (7 am–10:59 pm)15 918 (64.0)2326 (58.8)
 Nighttime (11 pm–6:59 am)8967 (36.0)1631 (41.2)
 Weekend or holiday8367 (33.6)1381 (34.9)0.11
Time to cardiopulmonary resuscitation, min<0.001
 022 452 (91.0)3108 (79.8)
 11231 (5.0)236 (6.1)
 >1992 (4.0)553 (14.2)
Cardiac diagnosis
 Congestive heart failure during admission5410 (21.7)826 (20.9)0.22
 Previous congestive heart failure6404 (25.7)1054 (26.6)0.23
 Myocardial infarction during admission4464 (17.9)562 (14.2)<0.001
 Previous myocardial infarction4818 (19.4)795 (20.1)0.28
Present within 24 h of in-hospital cardiac arrest
 Renal insufficiency9436 (37.9)1388 (35.1)<0.001
 Hepatic insufficiency1265 (5.1)154 (3.9)0.001
 Respiratory insufficiency11 340 (45.6)1425 (36.0)<0.001
 Hypotension7136 (28.7)772 (19.5)<0.001
 Septicemia4321 (17.4)496 (12.5)<0.001
Coexisting medical illnesses
 Diabetes mellitus8074 (32.4)1282 (32.4)0.95
 Baseline depression in central nervous system function3664 (14.7)569 (14.4)0.57
 Acute stroke1155 (4.6)172 (4.3)0.41
 Acute nonstroke central nervous system event1832 (7.4)243 (6.1)0.01
 Pneumonia4227 (17.0)670 (16.9)0.93
 Major trauma589 (2.4)80 (2.0)0.18
 Metabolic or electrolyte abnormality4268 (17.2)540 (13.6)<0.001
 Metastatic or hematologic malignancy3297 (13.2)528 (13.3)0.87
 Implantable cardioverter-defibrillator413 (1.7)60 (1.5)0.51
Interventions in place at time of cardiac arrest
 Intravenous vasopressor7249 (29.1)486 (12.3)<0.001
 Mechanical ventilation7496 (30.1)442 (11.2)<0.001
 Dialysis891 (3.6)92 (2.3)<0.001

Rates of prompt defibrillation and prompt epinephrine treatment increased over the study period from 65% to 75% and 81% to 90%, respectively (P for trend for both <0.001; Table I in the online-only Data Supplement).

Survival to Discharge

Prompt defibrillation and epinephrine administration in shockable and nonshockable IHCA, respectively, were associated with greater unadjusted rates of return to spontaneous circulation, 24-hour survival, survival to discharge with good neurological status, and overall survival to discharge compared with delayed treatment, with a larger magnitude of differences between prompt and delayed defibrillation in shockable IHCA than between prompt and delayed epinephrine administration in nonshockable IHCA (Table 3).

Table 3. Unadjusted Short-Term Survival Rates Among Patients With In-Hospital Cardiac Arrests Receiving Prompt Versus Delayed Treatment

Shockable (Ventricular Fibrillation or Ventricular Tachycardia)Nonshockable (Asystole or Pulseless Electric Activity)
Prompt Defibrillation (≤2 min)(n=5714), n (%)Delayed Defibrillation (>2 min) (n=2405), n (%)P ValuePrompt Epinephrine (≤5 min) (n=24 885), n (%)Delayed Epinephrine (>5 min)(n=3956), n (%)P Value
Survived initial arrest4151 (72.6)1325 (55.1)<0.00112 167 (48.9)1674 (42.3)<0.001
Survival 24 h after in-hospital cardiac arrest3459 (60.5)1038 (43.2)<0.0016938 (27.9)990 (25.0)<0.0001
Survival to discharge2247 (39.3)580 (24.1)<0.0012588 (10.4)322 (8.1)<0.0001
Survival to discharge with Cerebral Performance Category 1*1290 (22.6)320 (13.3)<0.0011000 (4.0)132 (3.3)0.04
Survival to discharge with Cerebral Performance Category 1 or 2*1977 (34.6)498 (20.7)<0.0011923 (7.7)247 (6.2)0.001

*Multiple imputation was used to impute 5.1% missing Cerebral Performance Category status data for shockable in-hospital cardiac arrest and 1.7% missing Cerebral Performance Category status for nonshockable in-hospital cardiac arrest.

Long-Term Survival

Among patients with a shockable IHCA, 1839 (22.7%) were alive at 1 year, and 1205 (16.8%) and 742 (12.8%) were alive at 3 and 5 years, respectively. Kaplan-Meier survival curves, stratified by the promptness of defibrillation, are displayed in Figure 2. Patients with prompt defibrillation had a higher unadjusted rate of 1-year survival compared with those with delayed defibrillation (25.7% [1466 of 5714] versus 15.5% [373 of 2405]). After risk adjustment, prompt defibrillation was associated with a 49% higher likelihood of being alive at 1 year after a shockable IHCA (adjusted relative risk [RR], 1.49; 95% confidence interval [CI], 1.32–1.69; P<0.0001). This survival advantage persisted at 3 years (19.1% [974 of 5089] versus 11.0% [231 of 2091]; adjusted RR, 1.45; 95% CI,: 1.23–1.69; P<0.0001) and at 5 years (14.7% [614 of 4175] versus 7.9% [128 of 1625]; adjusted RR, 1.50; 95% CI, 1.22–1.83; P<0.0001), with large absolute survival differences throughout (Table 4). The C statistic of the adjusted models ranged from 0.75 to 0.79 for the 3 survival time points. Sensitivity analyses show a graded increase in long-term survival with decreasing time to defibrillation, with survival benefits associated with time to defibrillation of ≤1 and 2 compared with >2 minutes extending to 5 years of follow-up (Table 5). Long-term survival with prompt defibrillation in shockable IHCA was not different by location of IHCA (Table II in the online-only Data Supplement).

Table 4. Long-Term Survival for In-Hospital Cardiac Arrests, by Timeliness of Treatment

Shockable (Ventricular Fibrillation or Ventricular Tachycardia)Nonshockable (Asystole or Pulseless Electric Activity)
Unadjusted Rate of Survival, n (%)Adjusted RR* (95% CI)P ValueUnadjusted Rate of Survival, n (%)Adjusted RR* (95% CI)P Value
Prompt Defibrillation (≤2 min)Delayed Defibrillation (>2 min)Prompt Epinephrine (≤5 min)Delayed Epinephrine (>5 min)
1-y survival1466/5714 (25.7)373/2405 (15.5)1.49 (1.32–1.69)<0.00011341/24 885 (5.4)168/3957 (4.2)1.20 (1.02–1.41)0.02
3-y survival974/5089 (19.1)231/2091 (11.0)1.45 (1.23–1.69)<0.0001733/20 868 (3.5)100/3476 (2.9)1.17 (0.95–1.45)0.15
5-y survival614/4175 (14.7)128/1625 (7.9)1.50 (1.22–1.83)<0.0001380/16 281 (2.3)54/2782 (1.9)1.18 (0.88–1.58)0.27

CI indicates confidence interval.

*Relative risks were calculated with hierarchical multivariable modified Poisson regression model adjusted for site as a random effect (hierarchical level) and patient factors included in Tables 1 and 2 as fixed effects.

For 3- and 5-year survival, only patients with an in-hospital cardiac arrest in Get With the Guidelines–Resuscitation between 2000 and 2009 and between 2000 and 2007 were analyzed to ensure 3 and 5 years of vital status follow-up, respectively.

Table 5. Long-Term Survival for In-Hospital Cardiac Arrests, by Timeliness of Treatment

Shockable (Ventricular Fibrillation or Ventricular Tachycardia)Nonshockable (Asystole or Pulseless Electric Activity)
Unadjusted Rate of Survival, n (%)Adjusted Relative Risk* (95% CI)P ValueUnadjusted Rate of Survival, n (%)Adjusted Relative Risk* (95% CI)P Value
Defibrillation ≤1 min (Group 1)Defibrillation 2 min (Group 2)Defibrillation >2 m (Group 3)Epinephrine ≤ 3 m (Group 1)Epinephrine 4–5 m (Group 2)Epinephrine > 5 m (Group 3)
1-y survival1245/4761 (26.2)221/953 (23.2)373/2405 (15.5)Group 1 vs 31.51 (1.33–1.71)<0.00011151/20 217 (5.7)190/4668 (4.1)168/3957 (4.2)Group 1 vs 31.27 (1.07–1.50)0.006
Group 2 vs 31.43 (1.21–1.68)<0.0001Group 2 vs 30.99 (0.82–1.19)0.89
3-y survival832/4262 (19.5)142/827 (17.2)231/2091 (11.0)Group 1 vs 31.46 (1.24–1.71)<0.0001627/16 856 (3.7)106/4012 (2.6)100/3476 (2.9)Group 1 vs 31.24 (0.99–1.55)0.06
Group 2 vs 31.40 (1.14–1.72)0.001Group 2 vs 30.97 (0.75–1.25)0.80
3-y survival533/3505 (15.2)81/670 (12.1)128/1625 (7.9)Group 1 vs 31.52 (1.24–1.85)<0.0001333/13 100 (2.5)47/3181 (1.5)54/2782 (1.9)Group 1 vs 31.29 (0.96–1.75)0.10
Group 2 vs 31.40 (1.07–1.84)0.01Group 2 vs 30.84 (0.57–1.22)0.35

CI indicates confidence interval.

*Relative risks were calculated with hierarchical multivariable modified Poisson regression model adjusted for site as a random effect (hierarchical level) and patient factors included in Tables 1 and 2 as fixed effects.

For 3- and 5-year survival, only patients with an in-hospital cardiac arrest in Get With the Guidelines–Resuscitation between 2000 and 2009 and between 2000 and 2007 were analyzed to ensure 3 and 5 years of vital status follow-up, respectively.

Figure 2.

Figure 2. Survival curves for patients with pulseless ventricular tachycardia or ventricular fibrillation arrests according to promptness of defibrillation.Inset, Survival curves during the first year. P values were obtained with the log-rank test.

Among patients with a nonshockable IHCA, 1509 (5.2%) were alive at 1 year, 833 (3.4%) at 3 years, and 434 (2.3%) at 5 years. Kaplan-Meier survival curves for these patients, stratified by promptness of epinephrine treatment, are displayed in Figure 3. Patients with prompt epinephrine treatment had a higher rate of 1-year survival compared with those with delayed treatment (5.4% [1341 of 24 885] versus 4.3% [168 of 3957]). After risk adjustment, prompt epinephrine treatment was associated with a 20% higher likelihood of being alive at 1 year after a nonshockable IHCA (adjusted RR, 1.20; 95% CI, 1.02–1.41; P=0.02). However, there were no significant differences in survival with prompt versus delayed epinephrine treatment at 3 years (3.5% [733 of 20 868] versus 2.9% [100 of 3476]; adjusted RR, 1.17; 95% CI, 0.95–1.45; P=0.15) and 5 years (2.3% [380 of 16 281] versus 1.9% [54 of 2782]; adjusted RR, 1.18; 95% CI, 0.88–1.58; P=0.27; Table 4). The C statistic of the adjusted models ranged from 0.73 to 0.78 for the 3 survival time points. In sensitivity analyses, only times to epinephrine of ≤3 minutes were associated with a higher likelihood of 1-year survival (adjusted RR, 1.27; 95% CI, 1.07–1.50; P=0.006), and there were no significant differences in survival at 3 or 5 years in comparisons of times to epinephrine of ≤3, 4 to 5, and >5 minutes (Table 5). Long-term survival with prompt epinephrine in nonshockable IHCA was not different by location of IHCA (Table II in the online-only Data Supplement).

Figure 3.

Figure 3. Survival curves for patients with asystole or pulseless electric activity arrests according to promptness of epinephrine administration.Inset, Survival curves during the first year. P values were obtained with the log-rank test.

Discussion

In this large, multicenter national registry of IHCA, we found that patients with shockable arrests caused by VT or VF who received prompt defibrillation had a 53% greater likelihood of survival at 1 year, a benefit that was sustained through 5 years of follow-up. Furthermore, there was a graded inverse association between times to defibrillation and long-term survival. For patients with nonshockable arrests caused by asystole or PEA, long-term survival was low overall (with only 5.2% alive at 1 year and 2.3% at 5 years), and prompt epinephrine administration was associated with improved survival only at 1 year, not at 3 and 5 years. Collectively, our study findings provide important insights into the durability of survival benefits observed during the index hospitalization when patients with IHCA are treated with prompt defibrillation or epinephrine.

Single-center studies in patients with shockable arrests have previously reported a strong inverse relationship between time to defibrillation and survival to discharge, but these studies were limited by small numbers and did not examine long-term survival.1719 Similarly, a prior GWTG-Resuscitation analysis of 6789 patients reported a 2.08-times greater odds of in-hospital survival with prompt defibrillation compared with delayed defibrillation in patients with a shockable IHCA.3 However, the association between prompt defibrillation and long-term survival for patients with IHCA is unknown, which has limited our understanding of the survival implications of this resuscitation process measure. Leveraging linked data between a national IHCA registry and Medicare files, we found that prompt defibrillation was associated with an 8% to 10% higher rate of unadjusted absolute survival and a >50% greater likelihood of survival after adjustment that was consistent throughout 5 years of follow-up.

Early defibrillation is associated with shorter duration of arrests, and prior work has shown that it is associated with improved neurological and functional outcomes on discharge.3 Improved neurological outcomes and consequently better cerebral performance category scores on discharge are also associated with improved long-term survival in patients with IHCA.10 Higher rates of survival on discharge with good neurological status with early defibrillation in patients with shockable IHCA might be the potential downstream mechanism explaining improved long-term survival with this process measure. Although decreasing time to administration of epinephrine has also been emphasized in resuscitation guidelines, the long-term survival implication of this resuscitation process measure also has not been well understood. For out-of-hospital cardiac arrests, shorter times to epinephrine are associated with higher rates of return to spontaneous circulation20,21 but not survival.20 Patients with nonshockable IHCAs have low rates of in-hospital and long-term survival,2,10,22 and our study found overall 1-year survival rates of only 5.2%. Hence, there is great interest in identifying process measures that could improve survival for patients with nonshockable cardiac arrests. Although a previous GWTG-Resuscitation analysis found that patients with faster times to epinephrine had higher rates of in-hospital survival,4 there is evidence of hospital-level variability in times to epinephrine administrations, with >1 in 10 patients receiving epinephrine after 5 minutes of IHCA.23 Our study suggests that the survival benefit associated with prompt times to epinephrine extends up to a year after an IHCA and appears localized in those patients treated within the first 3 minutes. However, this survival benefit was not sustained at 3 and 5 years of follow-up, thus underscoring the continued need to identify resuscitation strategies that have durable long-term survival benefits in patients with IHCA caused by asystole and PEA. The lack of significant difference in survival at 3 and 5 years between patients receiving prompt and delayed epinephrine in nonshockable IHCA is likely the result of the small differences in absolute survival at 1 year of follow-up. The absolute differences in survival at 1, 3, and 5 years between prompt and delayed epinephrine administration groups in nonshockable arrests were 1.2%, 0.6%, and 0.4%, respectively, whereas the absolute differences in survival for patients with prompt and delayed defibrillation for VT/VF arrests were 10.2%, 8.1%, and 6.8%, respectively.

The recent Institute of Medicine report emphasized an urgency for new research to identify effective cardiac arrest treatment strategies that could be efficiently translated into care delivery to achieve better patient outcomes.24 Our results suggest that efforts to target reduction of times to defibrillation in shockable arrests can potentially achieve large benefits in survival, both short term and long term. These measures may include training nurses who are not certified in acute cardiac life support to defibrillate, increasing access to defibrillation devices in nonmonitored hospital areas, identifying obstacles in achieving prompt times to defibrillation, and providing routine feedback to hospital staff on their times to defibrillation. There is some evidence from single-center experiences in the United States and Germany of increased in-hospital survival in patients with IHCA after implementation of hospital-wide programs encouraging early defibrillation, a benefit achieved mainly as a result of improvement in survival of VT/VF arrests.25,26 The findings from this study underscore the potential for large-scale implementation of programs to reduce delays in defibrillation treatment because they may improve both short- and long-term survival in patients with IHCA.

Our study should be interpreted in context of the following limitations. Our study was observational in nature, and the possibility for unmeasured confounding remains, despite adjustment for a number of demographic, comorbidity, and cardiac arrest characteristics. In addition, we could not account for care received by patients during follow-up, which could also affect their long-term survival. It is possible that the survival benefits associated with prompt defibrillation and epinephrine treatment are not causal and reflect unmeasured aspects of cardiopulmonary resuscitation quality that correlated strongly with prompt treatment times. Therefore, hospitals should work toward improving the totality of acute resuscitation care, including the provision of high-quality chest compressions with minimal interruptions. Second, our study included only data from hospitals voluntarily participating in the GWTG-Resuscitation registry, so our results might not be generalizable to nonparticipating hospitals. Nonetheless, GWTG-Resuscitation includes information submitted by >500 different large and small hospitals, and there is no reason to expect that the association between prompt versus delayed treatment and survival would differ in nonparticipating hospitals. We also excluded patients <65 years of age because long-term outcomes were not available for these patients, which could affect the generalizability of our findings to younger patients. Among Medicare-eligible patients, 29 013 patients were excluded because of an inability to link patients in GWTG-Resuscitation with Medicare inpatient files. From our prior work, common reasons for nonlinkage included10 admission to a non-Medicare hospital such as Veteran’s Administration hospitals, lack of fee-for-service Medicare insurance, very low number of patients with IHCA enrolled from a particular hospital to facilitate a conclusive linkage, or lack of qualifying International Classification of Diseases, Ninth Revision diagnoses or procedure codes for cardiac arrest in Medicare files to complete linkage. Exclusion of these patients, however, was unlikely to cause significant bias to the results because most patient characteristics were similar in both groups (Table III in the online-only Data Supplement). Similarly, patient characteristics of those with nonshockable IHCA excluded secondary to missing time to epinephrine administration were also similar to those of the final patient cohort. Because treatment received in an index IHCA event would influence subsequent outcomes, for patients with recurrent arrests, we included only the index arrest events. Furthermore, we were unable to assess the impact of prompt treatment on cardiovascular cause of death because neither GWTG-Resuscitation nor Medicare inpatient files collect information on cause of death. Finally, times to treatment were based on reported times of cardiac arrest, defibrillation, and epinephrine administration recorded in patient charts, and there is the possibility of inaccurate documentations of times. Any misclassification in times would be expected to be nondifferential and would have biased our results toward the null, which could have affected our analyses of epinephrine treatment.

Conclusions

We found that prompt defibrillation was associated with substantially higher survival at 5 years for patients with a shockable IHCA, with a graded inverse relationship between treatment time and survival. Prompt epinephrine administration in nonshockable IHCAs was associated with higher survival at 1 year, but this survival advantage did not persist at 3 and 5 years. By quantifying the greater long-term survival associated with timely defibrillation and epinephrine administration, these findings provide important insights into the durability of survival benefits for 2 process-of-care measures in current resuscitation guidelines.

Appendix

GWTG-Resuscitation Investigators: Besides author Paul S. Chan, MD, MSc, members of the GWTG-Resuscitation Adult Task Force include Anne Grossestreuer, PhD, Beth Israel Deaconess Medical Center, Harvard Medical School; Ari Moskowitz, MD, Massachusetts General Hospital; Dana P. Edelson, MD, MS, University of Chicago; Joseph P. Ornato, MD, Virginia Commonwealth University; Mary Ann Peberdy, MD, DACC, Virginia Commonwealth University; Matthew M. Churpek, MD, MPH, PhD, University of Chicago; Michael C. Kurz, MD, MS-HES, University of Alabama at Birmingham; Monique Anderson Starks, MD, Duke Clinical Research Institute; Patricia Kunz Howard, PhD, RN, University of Kentucky; Saket Girotra, MBBS, SM, University of Iowa Carver College of Medicine; Sarah M. Perman, MD, MSCE, University of Colorado; and Zachary D. Goldberger, MD, MS, University of Washington.

Footnotes

http://circ.ahajournals.org

The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.117.030488/-/DC1.

Contact the Get With The Guidelines (GWTG)–Resuscitation registry at .

Krishna K. Patel, MD, Department of Cardiovascular Research, Mid America Heart Institute, Saint Luke’s Hospital of Kansas City, University of Missouri-Kansas City, 4401 Wornall Road, 9th Floor Cardiovascular Research, Kansas City, MO 64111. E-mail

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