Interaction effects between hypothermia and diabetes mellitus on survival outcomes after out-of-hospital cardiac arrest

Resuscitation 90 (2015) 35–41

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Clinical Paper

Interaction effects between hypothermia and diabetes mellitus on survival outcomes after out-of-hospital cardiac arrest夽 Young Sun Ro a , Sang Do Shin b,∗ , Kyoung Jun Song b , Eui Jung Lee b , Yu Jin Lee b , Joo Yeong Kim c , Dayea Beatrice Jang a , Min Jung Kim a , So Yeon Kong d a

Laboratory of Emergency Medical Services, Seoul National University Hospital Biomedical Research Institute, Republic of Korea Department of Emergency Medicine, Seoul National University College of Medicine, Republic of Korea c Department of Emergency Medicine, Korea University Ansan Hospital, Republic of Korea d World Health Organization, International Agency for Research on Cancer, France b

a r t i c l e

i n f o

Article history: Received 26 October 2014 Received in revised form 5 February 2015 Accepted 6 February 2015 Keywords: Cardiac arrest Therapeutic hypothermia Diabetes mellitus Outcomes

a b s t r a c t Objectives: Mild therapeutic hypothermia (MTH) is the core hospital intervention to enhance neurological outcome after out-of-hospital cardiac arrest (OHCA). Diabetes mellitus (DM) has been known to be a harmful risk factor on survival after OHCA. This study aimed to investigate whether the effect of MTH on brain recovery after OHCA differed between patients with or without DM. Methods: We used a Korean national OHCA database composed of hospital and ambulance data. We included adult OHCA patients who survived to admission with presumed cardiac etiology during the study period from 2009 to 2013. We excluded cases without hospital outcome data. The primary exposure was MTH, which included all kinds of cooling methods that had been initiated within 6 h after return of spontaneous circulation. DM was coded positive when the patient had a clinical history diagnosed by a physician before an OHCA event. The endpoints were discharge with good neurological recovery (cerebral performance category 1 or 2) and survival to discharge. We compared outcomes between MTH vs. nonMTH groups using multivariable logistic regression with an interaction term between MTH and DM for calculating adjusted odds ratios (AORs) and 95% confidence intervals (CIs) after adjusting for potential confounders. Results: Among 9735 patients following OHCA survived to hospital admission with cardiac etiology, MTH was performed in 16.5%. History of DM was observed in 25.4% among MTH group and 27.4% in non-MTH group (p = 0.09). MTH group showed better outcomes than non-MTH group; 23.6% vs. 15.7% for good neurological recovery (p < 0.01). AOR (95% CI) of MTH for good neurological recovery for all study groups was 1.23 (1.03–1.47). In the interaction model, AOR (95% CI) of MTH for good neurological recovery was 1.40 (1.16–1.70) in patients without DM vs. 0.69 (0.46–1.04) in patients with DM. For survival to discharge, the effects of MTH were different in patients without DM (1.97 (1.70–2.29)) and patients with DM (1.23 (0.96–1.57)). Conclusion: DM modified the effect of MTH on survival and neurological outcomes for OHCA survivors. MTH is significantly associated with good neurological recovery in patients without DM, but not in patients with DM. © 2015 Elsevier Ireland Ltd. All rights reserved.

夽 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.2015.02.006. ∗ Corresponding author at: Department of Emergency Medicine, Seoul National University College of Medicine, 101 Daehak-Ro, Jongno-Gu, Seoul 110-744, Republic of Korea. E-mail addresses: [email protected] (Y.S. Ro), [email protected] (S.D. Shin), [email protected] (K.J. Song), [email protected] (E.J. Lee), [email protected] (Y.J. Lee), [email protected] (J.Y. Kim), [email protected] (D.B. Jang), [email protected] (M.J. Kim), [email protected] (S.Y. Kong). http://dx.doi.org/10.1016/j.resuscitation.2015.02.006 0300-9572/© 2015 Elsevier Ireland Ltd. All rights reserved.

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Y.S. Ro et al. / Resuscitation 90 (2015) 35–41

1. Introduction Out-of-hospital cardiac arrest (OHCA) is a significant global public health problem, and the overall burden continues to increase with cardiovascular comorbidities of aging population.1,2 Incidence of OHCA is increasing, and OHCA survival has not improved over the past several decades. Only a minority of patients was successfully resuscitated and survived with good quality of life despite the advances in resuscitation technology and systematic post-cardiac arrest care.2,3 Mild therapeutic hypothermia (MTH) is undoubtedly a novel intervention demonstrated to improved cerebral outcome after OHCA.4–6 MTH is becoming the standard of post-resuscitation treatment and recommended to be considered for any OHCA regardless of causes for patients who are unconscious after return of spontaneous circulation (ROSC).4 The exact mechanism of MTH is not clear, but previous studies have speculated it works through the modes of inhibiting ischemia-reperfusion injury, mitigating intracranial hypertension, reducing brain edema, and stimulating protective system.6–8 Diabetes mellitus (DM) increases the risk of developing sudden cardiac arrest, coronary artery disease, and ischemic stroke, and the associated mortality and morbidity is higher.9,10 DM is associated with higher risk for sudden cardiac arrest due to macrovascular process, and previous studies have found that the risk was not reduced with glycemic control.11–13 Among patients admitted to hospital after OHCA, DM is a strong predictor for lower survival rate and higher positive coronary angiography.14,15 The characteristics of OHCA patients are heterogeneous, and the potential risks and benefits of MTH intervention may not be the same across subgroups. The benefits of MTH intervention on the good neurological recovery for patients with or without DM have not been reported. This study aimed to investigate whether the interactive effect of MTH on brain recovery after OHCA was observed across patients with or without DM.

guidelines have been accepted as the standard practice by national organizations.

2.2. Data source This research was part of a population-based study, the Cardiovascular Disease Surveillance (CAVAS) project, which has been conducted since 2006 in collaboration with the National Emergency Management Agency (NEMA) and the Korea Centers for Disease Control and Prevention (CDC) of the Republic of Korea government. The CAVAS project has constructed a nationwide EMSassessed OHCA cohort, which was drawn from EMS run sheets for demographic and Utstein information. This cohort was followed by hospital medical record review for hospital resuscitation and post-resuscitation care and outcomes. All information from the EMS run sheets (patient records) is input by EMS providers immediately after the transport of OHCA patients and is stored in the NEMA electronic server. Medical record review experts from the Korean CDC visited all of the hospitals and captured the information for hospital care and outcome using an appropriately designed survey form. All of the items including definitions, inclusion and exclusion criteria, examples, and warnings are defined in the medical record review guidelines and was developed by the project quality management committee (QMC). All medical record reviewers are trained prior to joining the project by the QMC, which consists of emergency medicine physicians, epidemiologists, statistical experts, cardiologists, and medical record review experts. In order to acquire more knowledge and maintain supervised information procurement, the reviewers are to consult an emergency medicine physician from the QMC for clarification when they are unable to objectively define a coding element.

2.3. Study participants 2. Methods The study was approved by the institutional review board of the Seoul National University Hospital, and informed consent was waived. 2.1. Study setting The Korean emergency medical services (EMS), which is a single-tiered, government-based system, provides a basic-tointermediate level of ambulance services from sixteen provincial headquarters of the national fire department and supports a population of approximately 50 million.16,17 Ambulance crews can administer CPR at the scene and during transport with automatic external defibrillation and advanced airway management under direct medical control. Advanced cardiac life support is limited in most areas of the country, but it is available in emergency departments (EDs). The public access defibrillation program began in 2009, but it was not widely accepted until recently. The national government designated three levels to EDs according to the resources and functional requirements; level 1 (n = 19) and level 2 (n = 110) EDs have more resources and better facilities for emergency care and must be staffed by emergency physicians 24 h a day and 365 days a year, whereas level 3 EDs (n = 310) can be staffed by general physicians. The EMS Act indicated that the structural and functional status of all EDs should be evaluated every year by a public audit committee. CPR guidelines from international societies are generally accepted by the academic societies and are recommended in clinical practice. In recent years, the 2010 AHA

The data were extracted between January 2009 and December 2013. All adults who are older than 18 years and survived to admission with presumed cardiac etiology were included. Patients were excluded if they had unknown neurological status at hospital discharge. Patients were also excluded if they had an alert mental status at ED arrival through prehospital EMS resuscitation and successful defibrillation. Patients having an arrest of cardiac etiology were identified by medical record review. We presumed non-cardiac etiology if the medical record described the cause of cardiac arrest definitely as trauma, drowning, poisoning, burn, asphyxia, and hanging. Without definite non-cardiac etiology, we presumed it to be of cardiac etiology.

2.4. Outcomes measure The primary outcome was good neurological status, which was defined as having a cerebral performance categories (CPC) score of 1 (good recovery) or 2 (mild disability), and secondary outcome was survival to hospital discharge. The CPC score was categorized by medical record reviewers on the basis of discharge summary abstracts or documentations in medical records. Discharge summary abstracts or documentations were drafted by inpatient care doctors, and the summaries including the patient’s mental and physical status were usually reviewed and revised for greater validity by the hospital medical record review team because the summaries were utilized for national health insurance claim data after discharge.

Y.S. Ro et al. / Resuscitation 90 (2015) 35–41

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Fig. 1. Study population. OHCA, out-of-hospital cardiac arrest; ED, emergency department.

2.5. Variables DM variable was obtained from medical record review. DM was positive when the patient had a clinical history diagnosed by a physician before the arrest event. MTH was defined as a case receiving therapeutic hypothermia within 6 h after return of spontaneous circulation using methods such as external cooling (water, fanning, or ice padding), internal cooling (gastric lavage, bladder cooling, or intravascular cooling using a catheter) or mixed cooling. We regarded the case as part of the hypothermia-treated group if the hospital attempted the procedure for hypothermia regardless of the actual duration or early withdrawal due to death during induced hypothermia. We used the Utstein defined risk factors listed in the previous literature for co-variables, which included gender, age, witness status, pre-hospital defibrillation, location of the event (public vs. private vs. unknown), bystander CPR, elapsed time interval from call to ambulance arrival at the scene (EMS response time), elapsed time interval from arrival to departure from the scene (EMS scene time), elapsed time interval from departure from the scene to arrival at the ED (EMS transport time), and initial electrocardiogram (ECG) rhythm (ventricular fibrillation/ventricular tachycardia, pulseless electrical activity, and asystole). Additionally, we added the following covariates: comorbidities including hypertension, stroke, and heart disease (myocardial infarction and angina pectoris); level of ED (levels 1–3) adjusted for ED capacity; place of ROSC (prehospital vs. ED); and community urbanization (metropolitan vs. non-metropolitan) by a population of one million to adjust for geographical variation in community performance and resource factors. The use of an electronic database prevented skipped entries and missing data. Unknown data were categorized as unknown, and comorbidities including DM were treated as positive when there was description on medical records or drug was prescribed. 2.6. Statistical analysis Demographic findings and outcomes by MTH and DM were described. Continuous variables were compared using Wilcoxon rank sum test, and categorical variables were compared using chisquare test.

A multivariable logistic regression analysis was conducted to estimate the effect of MTH on good neurological recovery for all eligible study population and to calculate the adjusted odds ratios (ORs) and 95% confidence intervals (CIs) after adjusting for the 16 co-variables mentioned above. For survival to discharge outcomes, a multivariable logistic regression analysis was conducted for all OHCA patients survived to admission. We put an interaction term of MTH and DM to the multivariable logistic regression model to estimate the effect of MTH changes by DM status on the study outcomes. If there is an interactive effect between MTH and DM, the adjusted OR of MTH on the study outcomes would be different across patients with or without DM. We tested multicollinearity between co-variables in model. All statistical analysis was performed using SAS-Version 9.4 (SAS Institute Inc., Cary, NC, USA) software.

3. Results Among 119,077 EMS-assessed OHCA cases that occurred during the study period, 9735 (8.2%) adult OHCA cases who survived to hospital admission with cardiac etiology were analyzed (Fig. 1). The characteristics of the patients, community, EMS, and ED factors based on the Utstein criteria by MTH are shown in Table 1. MTH was performed in 16.5%. Significant differences were found by MTH for gender, age, a clinical history of hypertension and stroke, initial ECG, arrest place, witness, bystander CPR, prehospital defibrillation, EMS scene and transport time, ED level, and post-resuscitation care. History of DM was observed in 25.4% of those receiving MTH, compared with 27.4% of those not receiving MTH (p = 0.09). MTH group showed better outcomes than non-MTH group; 23.6% vs. 15.7% for good neurological recovery and 55.3% vs. 36.8% for survival discharge (both p values <0.01). Demographic findings by DM are demonstrated in Table 2. Good neurological recovery was observed in 17.0% of all, 19.2% of patients without DM (n = 7096), and 11.2% of patients with DM (n = 2639) (p < 0.01). Survival to discharge rates were 39.8% of all, 42.3% of patients without DM, and 33.2% of patients with DM (p < 0.01). After adjusting for other covariates, patients receiving MTH had a higher odds of making a good neurological recovery (adjusted OR 1.23 (95% CIs 1.03–1.47)) and for survival to hospital discharge

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Y.S. Ro et al. / Resuscitation 90 (2015) 35–41

Table 1 Demographics of adult cardiac OHCAs survived to admission by mild therapeutic hypothermia. Total

MTH (−)

N Total Sex Male Female Age, year Adult (19–64) Elderly (≥65) Median (IQR) Past medical history Diabetes mellitus Hypertension Heart Disease Stroke Initial ECG VF/VT PEA Asystole Community Rural Metropolitan Arrest place Public Private Other Witnessed status Yes Bystander CPR Yes Pre-hospital defibrillation Yes EMS response time, min 0–4 4–8 8–12 12–16 16– Median (IQR) EMS scene time, min 0–4 4–8 8–12 12–16 16– Median (IQR) EMS transport time, min 0–4 4–8 8–12 12–16 16– Median (IQR) ED level Level 1 Level 2 Level 3 Post-resuscitation care Reperfusion ECMO Outcome Prehospital ROSC Survival to discharge Good neurological recovery

%

9735

MTH (+)

p-value

N

%

N

%

8132

83.5

1603

16.5 <0.01

6555 3180

67.3 32.7

5357 2775

65.9 34.1

1198 405

74.7 25.3

5472 4263

56.2 43.8

4461 3671

54.9 45.1

1011 592

63.1 36.9

<0.01

62 (51–73)

63 (51–74)

<0.01†

58 (48–70)

2639 4123 1828 911

27.1 42.4 18.8 9.4

2232 3489 1504 797

27.4 42.9 18.5 9.8

407 634 324 114

25.4 39.6 20.2 7.1

914 843 7978

9.4 8.7 82.0

696 634 6802

8.6 7.8 83.6

218 209 1176

13.6 13.0 73.4

4367 5368

44.9 55.1

3810 4322

46.9 53.1

557 1046

34.7 65.3

2080 6607 1048

21.4 67.9 10.8

1613 5617 902

19.8 69.1 11.1

467 990 146

29.1 61.8 9.1

6661

68.4

5460

67.1

1201

74.9

1400

14.4

976

12.0

424

26.5

2316

23.8

1690

20.8

626

39.1

972 5940 2082 492 249

10.0 61.0 21.4 5.1 2.6

827 4931 1732 416 226

10.2 60.6 21.3 5.1 2.8

145 1009 350 76 23

9.0 62.9 21.8 4.7 1.4

0.09 0.01 0.11 <0.01 <0.01

<0.01

<0.01

<0.01 <0.01 <0.01 0.01

6 (5–8) 1993 4089 2407 849 397

6 (5–8) 20.5 42.0 24.7 8.7 4.1

1681 3451 1985 688 327

6 (4–9) 1463 4696 1963 731 882

20.7 42.4 24.4 8.5 4.0

312 638 422 161 70

6 (4–9) 15.0 48.2 20.2 7.5 9.1

1283 3885 1582 619 763

6 (4–9)

0.22† 0.05

6 (5–8) 19.5 39.8 26.3 10.0 4.4

<0.01† <0.01

6 (4–10) 15.8 47.8 19.5 7.6 9.4

180 811 381 112 119

6 (4–9)

11.2 50.6 23.8 7.0 7.4 0.02† <0.01

6 (5–9)

1765 6388 1582

18.1 65.6 16.3

1210 5365 1557

14.9 66.0 19.1

555 1023 25

34.6 63.8 1.6

1205 298

12.4 3.1

965 204

11.9 2.5

240 94

15.0 5.9

<0.01 <0.01

1735 3876 1657

17.8 39.8 17.0

1447 2990 1279

17.8 36.8 15.7

288 886 378

18.0 55.3 23.6

0.87 <0.01 <0.01

MTH, mild therapeutic hypothermia; ECG, electrocardiogram; VF, ventricular fibrillation; VT, ventricular tachycardia; EMS, emergency medical services; ED, emergency department; ECMO, extracorporeal membrane oxygenation; ROSC, return of spontaneous circulation. † Wilcoxon rank sum test.

(adjusted OR 1.72 (95% CIs 1.51–1.96)). DM was negatively associated with both good neurological recovery (adjusted OR 0.80 (95% CIs 0.67–0.95)) and survival to discharge (adjusted OR 0.86 (95% CIs 0.77–0.97)) (Table 3). After adjusting for other covariates in the interaction model, the adjusted OR of MTH for good neurological recovery was

different in patients without DM (adjusted OR 1.40 (95% CIs 1.16–1.70)) and patients with DM (adjusted OR 0.69 (95% CIs 0.46–1.04)). For survival to discharge, the adjusted OR (95% CIs) of MTH was 1.96 (1.69–2.27) in patients without DM whereas the effect was statistically non-significant in patients with DM with adjusted OR of 1.20 (95% CIs 0.94–1.53) (Table 4).

Y.S. Ro et al. / Resuscitation 90 (2015) 35–41

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Table 2 Demographics of adult cardiac OHCAs survived to admission by diabetes mellitus. Total

DM (−)

N Total Sex Male Female Age, year Adult (19–64) Elderly (≥65) Median (IQR) Past medical history Hypertension Heart Disease Stroke Initial ECG VF/VT PEA Asystole Community Rural Metropolitan Arrest place Public Private Other Witnessed status Yes Bystander CPR Yes Pre-hospital defibrillation Yes EMS time, min, Median (IQR) EMS response time EMS scene time EMS transport time ED level Level 1 Level 2 Level 3 Post-resuscitation care Hypothermia Reperfusion ECMO Outcome Prehospital ROSC Survival to discharge Good neurological recovery

%

9735

DM (+)

N

%

7096

p-value

N

%

2639 <0.01

6555 3180

67.3 32.7

4847 2249

68.3 31.7

1708 931

64.7 35.3

5472 4263

56.2 43.8

4375 2721

61.7 38.3

1097 1542

41.6 58.4

<0.01

62 (51–73)

59 (49–72)

<0.01†

68 (58–75)

4123 1828 911

42.4 18.8 9.4

2306 1192 566

32.5 16.8 8.0

1817 636 345

68.9 24.1 13.1

914 843 7978

9.4 8.7 82.0

734 614 5748

10.3 8.7 81.0

180 229 2230

6.8 8.7 84.5

4367 5368

44.9 55.1

3174 3922

44.7 55.3

1193 1446

45.2 54.8

2080 6607 1048

21.4 67.9 10.8

1651 4660 785

23.3 65.7 11.1

429 1947 263

16.3 73.8 10.0

6661

68.4

4852

68.4

1809

68.5

1400

14.4

1086

15.3

314

11.9

2316

23.8

1866

26.3

450

17.1

<0.01 <0.01 <0.01 <0.01

0.67

<0.01

0.87 <0.01 <0.01

6 (5–8) 6 (4–9) 6 (4–9)

6 (5–8) 6 (4–9) 6 (4–9)

0.10† 0.18† 0.93† <0.01

6 (5–8) 6 (4–9) 6 (4–9)

1765 6388 1582

18.1 65.6 16.3

1336 4656 1104

18.8 65.6 15.6

429 1732 478

16.3 65.6 18.1

1603 1205 298

16.5 12.4 3.1

1196 914 223

16.9 12.9 3.1

407 291 75

15.4 11.0 2.8

0.09 0.01 0.44

1735 3876 1657

17.8 39.8 17.0

1381 3000 1361

19.5 42.3 19.2

354 876 296

13.4 33.2 11.2

<0.01 <0.01 <0.01

DM, diabetes mellitus; ECG, electrocardiogram; VF, ventricular fibrillation; VT, ventricular tachycardia; EMS, emergency medical services; ED, emergency department; ECMO, extracorporeal membrane oxygenation; ROSC, return of spontaneous circulation. † Wilcoxon rank sum test.

4. Discussion This study found that the effect of MTH on neurological outcomes had an interaction with a history of DM for OHCAs that survived to hospital admission with presumed cardiac origin. The benefits of MTH on neurological and survival outcomes were not found for those who had a history of DM, but increased benefits were found in those who did not have a history of DM. These results emphasize the role of DM as a strong risk factor for poor neurological and survival outcomes when providing MTH to OHCA patients. MTH is the only evidence-based intervention to enhance brain recovery after resuscitation.4–6 One of the complications in hypothermia cooling is poor control of serum glucose.4 Moderate glycemic control and minimization of glycemic variations are recommended during post-resuscitation care because hyper-glycemia, hypo-glycemia and large glycemic variation are associated with poor neurological outcome.4,18 A history of DM was a risk factor for poor glucose control itself for critical ill patients.19 Hypoglycemia, one of complications for

glycemic control, occurred frequently for pre-existing DM patients and was associated with high mortality and poor neurological outcomes.14,19,20 Furthermore, hyperglycemia occurred frequently in diabetic patients and exacerbated ischemic brain injury in models of cerebral ischemia-reperfusion.21,22 Hyperglycemia resulting from post-resuscitation stress can increase oxidative stress and protein glycosylation, decrease blood insulin level, and exert systemic harmful effects. Hyperglycemia during the initial phase after cardiac arrest and hypoglycemia during the rewarming phase were independent risk factors that could negatively influence neurological outcome.18,20 MTH enhances neurological outcome with inhibiting ischemia-reperfusion injury for resuscitated OHCA patients; however, the effects might offset due to poor glucose control especially for DM patients. We observed different characteristics in patients with a history of DM from those without DM by being older and having a higher prevalence of previous myocardial infarction, angina pectoris, hypertension and stroke. Potential factors contributing to the increased risk of cerebro- and cardio-vascular disease observed in patients with DM include microvascular processes

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Table 3 Effects of hypothermia and diabetes mellitus on survival outcomes. Total

Outcome

N

N

%

Primary outcome: good neurologic recovery 9735 1657 Total MTH 8132 1279 No Yes 1603 378 DM 7096 1361 No 2639 296 Yes

Adjusteda

Unadjusted OR

95% CI

OR

95% CI

15.7 23.6

1.00 1.65

1.45

1.88

1.00 1.23

1.03

1.47

19.2 11.2

1.00 0.53

0.47

0.61

1.00 0.80

0.67

0.95

36.8 55.3

1.00 2.11

1.89

2.35

1.00 1.72

1.51

1.96

42.3 33.2

1.00 0.68

0.62

0.75

1.00 0.86

0.77

0.97

17.0

b

Secondary outcome: survival to discharge Total 9797 3938 MTH 8186 3044 No Yes 1611 894 DM No 7143 3047 Yes 2654 891

39.8

OR, odds ratio; 95% CI, 95% confidence interval; MTH, mild therapeutic hypothermia; DM, diabetes hypothermia. a Adjusted for hypothermia, diabetes mellitus, age, gender, hypertension, heart disease, stroke, primary ECG, community, arrest place, witness, bystander CPR, prehospital defibrillation, EMS response time, EMS scene time, EMS transport time, prehospital ROSC, and ED level. b Adjusted OR of MTH on survival to discharge was calculated for total of 9797 OHCA patients survived to admission.

Table 4 Effects of hypothermia in interaction model with diabetes mellitus. MTH Adjusted ORa Primary outcome: good neurologic recovery DM (−) 1.40 0.69 DM (+) Secondary outcome: survival to dischargeb DM (−) 1.96 DM (+) 1.20

95% CI 1.16 0.46

1.70 1.04

1.69 0.94

2.27 1.53

OR, odds ratio; 95% CI, 95% confidence interval; MTH, mild therapeutic hypothermia; DM, diabetes mellitus. a Adjusted for hypothermia, diabetes mellitus, age, gender, hypertension, heart disease, stroke, primary ECG, community, arrest place, witness, bystander CPR, prehospital defibrillation, EMS response time, EMS scene time, EMS transport time, prehospital ROSC, and ED level. b Adjusted OR of MTH on survival to discharge was calculated for total of 9797 OHCA patients survived to admission.

including autonomic nervous system dysfunction and abnormal cardiac repolarization, and macrovascular diseases such as coronary atherosclerosis, hypercoagulable status secondary to DM, and diabetic cardiomyopathy.12,14,23 It was known that glycemic control for DM patients significantly reduced the incidence of microvascular disease but had more limited effects on cardiovascular events including arrest.13 This pathophysiology of DM affects survival outcomes after cardiac arrest. DM was identified to be an independent risk factor for poor survival outcomes in this study. Both independent macro- and micro-vascular pathophysiologic mechanisms and poor control of serum glucose during therapeutic hypothermia might contribute to the poor outcomes. In this study, 16.5% of patients admitted after OHCA received MTH. Hospitals hardly provide post-resuscitation care including MTH unless there are resources, protocols and a dedicated multidisciplinary post-resuscitation care team with experiences and skills.17 4.1. Limitation This study has some limitations. We classified MTH to be a homogeneous group although there were differences in protocol

and methods for MTH provided by hospitals. Also, we had no information about the severity, type, and duration of diabetes, which might have different effect sizes on the study outcomes. Serum glucose level during MTH was not collected, which may be an important factor for the interaction between DM and MTH. While we tried to classify past medical history of survived patients to admission using medical record review, DM prevalence may have been underestimated. Furthermore, the effect size of MTH using logistic regression may have been overestimated with quite large outcomes (17% of good neurological recovery). Finally, we could not adjust for unmeasured bias. 5. Conclusion DM modified the effect of therapeutic hypothermia on good neurological recovery and survival outcomes for OHCA patients. Therapeutic hypothermia is significantly associated with survival with minimal neurological impairment in non-diabetes group, but not in diabetes group in Korea. Funding This study was supported by the National Emergency Management Agency of Korea and the Korea Centers for Disease Control and Prevention. The study was funded by the Seoul Metropolitan City Government (2008) and the Korea Centers for Disease Control and Prevention (2009–2013). Conflict of interest statement There are no conflicts of interest for all authors in this study. Acknowledgement This study was supported by the National Emergency Management Agency of Korea and the Korea Centers for Disease Control and Prevention. The study was funded by the Seoul Metropolitan City Government (2008) and the Korea Centers for Disease Control and Prevention.

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