Supplemental Material Appendix A. Baseline Characteristics of Patients with Out-Of-Hospital

Supplemental Material Appendix A. Baseline characteristics of patients with out-of-hospital cardiac arrest according to initial rhythms and prehospital administration of epinephrine before propensity score matching (full version).

Pulseless

electrical

activity Asystole

Variable (n=44,454) (n=65,785) No epinephrine Epinephrine No epinephrine Epinephrine

(n=35,228) (n=9226) (n=54,969) (n=10,816)

n (%) n (%) D n (%) n (%) D

Year 2008 7199 (20.4) 1082 (11.7) 0.239 10,623 (19.3) 1273 (11.8) 0.210 2009 6644 (18.9) 1478 (16.0) 0.075 10,414 (18.9) 1619 (15.0) 0.106 2010 6917 (19.6) 1862 (20.2) 0.014 11,042 (20.1) 2232 (20.6) 0.014 2011 7137 (20.3) 2287 (24.8) 0.109 11,318 (20.6) 2676 (24.7) 0.099 2012 7331 (20.8) 2517 (27.3) 0.152 11,572 (21.1) 3016 (27.9) 0.159 Season

Spring 8953 (25.4) 2143 (23.2) 0.051 13,707 (24.9) 2,606 (24.1) 0.020 Summer 6863 (19.5) 1807 (19.6) 0.003 11,186 (20.4) 2,253 (20.8) 0.012 Fall 8434 (23.9) 2313 (25.1) 0.026 12,672 (23.1) 2,526 (23.4) 0.007 Winter 10978 (31.2) 2963 (32.1) 0.020 17,404 (31.7) 3,431 (31.7) 0.001 Prefecture

Hokkaido 1044 (2.96) 254 (2.75) 0.013 1563 (2.84) 450 (4.16) 0.072 Aomori 417 (1.18) 68 (0.74) 0.046 764 (1.39) 80 (0.74) 0.063 Iwate 361 (1.02) 146 (1.58) 0.049 783 (1.42) 245 (2.27) 0.063 Miyagi 645 (1.83) 144 (1.56) 0.021 1167 (2.12) 194 (1.79) 0.024 Akita 423 (1.20) 108 (1.17) 0.003 695 (1.26) 167 (1.54) 0.024 Yamagata 480 (1.36) 96 (1.04) 0.030 768 (1.40) 36 (0.33) 0.115 Fukushima 645 (1.83) 178 (1.93) 0.007 1020 (1.86) 160 (1.48) 0.029 Ibaraki 736 (2.09) 209 (2.27) 0.012 1442 (2.62) 211 (1.95) 0.045 Tochigi 710 (2.02) 53 (0.57) 0.128 1092 (1.99) 56 (0.52) 0.132 Gunma 698 (1.98) 57 (0.62) 0.121 1114 (2.03) 60 (0.55) 0.131 Saitama 1616 (4.59) 790 (8.56) 0.161 2539 (4.62) 1063 (9.83) 0.202 Chiba 1362 (3.87) 443 (4.80) 0.046 2418 (4.40) 434 (4.01) 0.019 Tokyo 3587 (10.2) 986 (10.7) 0.017 7366 (13.4) 1116 (10.3) 0.095 Kanagawa 2476 (7.03) 639 (6.93) 0.004 3655 (6.65) 799 (7.39) 0.029 Niigata 586 (1.66) 337 (3.65) 0.124 979 (1.78) 421 (3.89) 0.127

1 Toyama 378 (1.07) 34 (0.37) 0.083 493 (0.9) 39 (0.36) 0.068 Ishikawa 295 (0.84) 60 (0.65) 0.022 401 (0.73) 81 (0.75) 0.002 Fukui 214 (0.61) 19 (0.21) 0.063 245 (0.45) 34 (0.31) 0.021 Yamanashi 176 (0.50) 133 (1.44) 0.096 310 (0.56) 190 (1.76) 0.112 Nagano 789 (2.24) 218 (2.36) 0.008 1140 (2.07) 216 (2.00) 0.005 Gifu 642 (1.82) 136 (1.47) 0.027 942 (1.71) 140 (1.29) 0.034 Shizuoka 1240 (3.52) 529 (5.73) 0.106 1977 (3.6) 592 (5.47) 0.090 Aichi 2510 (7.13) 735 (7.97) 0.032 2794 (5.08) 688 (6.36) 0.055 Mie 518 (1.47) 135 (1.46) 0.001 821 (1.49) 177 (1.64) 0.012 Shiga 388 (1.10) 76 (0.82) 0.028 589 (1.07) 70 (0.65) 0.046 Kyoto 806 (2.29) 156 (1.69) 0.043 1028 (1.87) 132 (1.22) 0.053 Osaka 2370 (6.73) 657 (7.12) 0.016 3122 (5.68) 679 (6.28) 0.025 Hyogo 1413 (4.01) 557 (6.04) 0.093 2108 (3.83) 628 (5.81) 0.092 Nara 297 (0.84) 110 (1.19) 0.035 501 (0.91) 153 (1.41) 0.047 Wakayama 331 (0.94) 70 (0.76) 0.020 516 (0.94) 97 (0.90) 0.004 Tottori 166 (0.47) 70 (0.76) 0.037 234 (0.43) 75 (0.69) 0.036 Shimane 182 (0.52) 125 (1.35) 0.087 282 (0.51) 176 (1.63) 0.108 Okayama 551 (1.56) 102 (1.11) 0.040 796 (1.45) 150 (1.39) 0.005 Hiroshima 815 (2.31) 87 (0.94) 0.108 1051 (1.91) 102 (0.94) 0.082 Yamaguchi 321 (0.91) 111 (1.20) 0.029 586 (1.07) 160 (1.48) 0.037 Tokushima 209 (0.59) 8 (0.09) 0.087 378 (0.69) 10 (0.09) 0.096 Kagawa 232 (0.66) 33 (0.36) 0.042 447 (0.81) 58 (0.54) 0.034 Ehime 502 (1.43) 74 (0.80) 0.059 763 (1.39) 83 (0.77) 0.060 Kochi 231 (0.66) 20 (0.22) 0.067 359 (0.65) 15 (0.14) 0.082 Fukuoka 1422 (4.04) 134 (1.45) 0.159 1740 (3.17) 104 (0.96) 0.155 Saga 237 (0.67) 5 (0.05) 0.103 343 (0.62) 3 (0.03) 0.105 Nagasaki 415 (1.18) 39 (0.42) 0.085 592 (1.08) 31 (0.29) 0.096 Kumamoto 463 (1.31) 97 (1.05) 0.024 629 (1.14) 119 (1.10) 0.004 Oita 294 (0.83) 34 (0.37) 0.060 479 (0.87) 51 (0.47) 0.049 Miyazaki 358 (1.02) 43 (0.47) 0.064 580 (1.06) 50 (0.46) 0.068 Kagoshima 380 (1.08) 45 (0.49) 0.067 852 (1.55) 83 (0.77) 0.073 Okinawa 297 (0.84) 66 (0.72) 0.015 506 (0.92) 138 (1.28) 0.034 Male sex 20,553 (58.3) 5676 (61.5) 0.065 31,439 (57.2) 6803 (62.9) 0.117 Age, years

<45 961 (2.73) 233 (2.53) 0.013 1932 (3.51) 369 (3.41) 0.006 45–64 5134 (14.6) 1482 (16.1) 0.041 7365 (13.4) 1593 (14.7) 0.038 65–74 6861 (19.5) 1853 (20.1) 0.015 9602 (17.5) 2116 (19.6) 0.054 75–84 12,326 (35.0) 3297 (35.7) 0.016 18,918 (34.4) 3781 (35.0) 0.011 85–94 9946 (28.2) 2361 (25.6) 0.060 17,152 (31.2) 2957 (27.3) 0.085 CPR by bystander 15,548 (44.1) 4213 (45.7) 0.031 26,501 (48.2) 5443 (50.3) 0.042

2 Dispatch-assisted CPR 14,177 (40.2) 4151 (45.0) 0.096 26,000 (47.3) 5690 (52.6) 0.106 instruction AED by bystander 471 (1.34) 127 (1.38) 0.003 494 (0.90) 163 (1.51) 0.056 EMS call-contact interval, min ≤6 10,027 (28.5) 2094 (22.7) 0.132 11,953 (21.7) 1931 (17.9) 0.098 7−8 10,849 (30.8) 2804 (30.4) 0.009 15,695 (28.6) 2851 (26.4) 0.049 9−10 7483 (21.2) 2178 (23.6) 0.570 12,275 (22.3) 2445 (22.6) 0.007 ≥11 6869 (19.5) 2150 (23.3) 0.930 15,046 (27.4) 3589 (33.2) 0.127 Arrest had cardiac origin 21,972 (62.4) 6183 (67.0) 0.097 33,814 (61.5) 7345 (67.9) 0.134 Family member was a 23,666 (67.2) 6263 (67.9) 0.015 38,562 (70.2) 7661 (70.8) 0.015 bystander Airway management

Bag-valve mask 19,568 (55.5) 2960 (32.1) 0.487 31,600 (57.5) 3131 (28.9) 0.602 Laryngeal mask airway 1686 (4.79) 492 (5.33) 0.025 2390 (4.35) 540 (4.99) 0.031 Esophageal obturator 11,436 (32.5) 4377 (47.4) 0.309 17,011 (30.9) 5340 (49.4) 0.383 airway Tracheal intubation 2538 (7.20) 1397 (15.1) 0.254 3968 (7.22) 1805 (16.7) 0.295 Defibrillation attempted 1,819 (5.16) 994 (10.8) 0.208 2,162 (3.93) 943 (8.72) 0.198 CPR (EMS)-hospital arrival interval, min ≤17 11,908 (33.8) 888 (9.62) 0.613 16,137 (29.4) 857 (7.92) 0.572 18–22 8847 (25.1) 1868 (20.2) 0.116 13,629 (24.8) 2071 (19.1) 0.137 23–29 8261 (23.5) 2987 (32.4) 0.200 13,602 (24.7) 3320 (30.7) 0.133 ≥30 6212 (17.6) 3483 (37.8) 0.461 11,601 (21.1) 4568 (42.2) 0.466 Weekend/off-hour 23073 (65.5) 6127 (66.4) 0.019 38,713 (70.4) 7,463 (69.0) 0.031 Outcomes

Overall survival 2086 (5.92) 413 (4.48) 0.065 945 (1.72) 240 (2.22) 0.036 Neurologically intact 858 (2.44) 85 (0.92) 0.118 234 (0.43) 47 (0.43) 0.001 survival (CPC 1–2) EMS, emergency medical services; CPR, cardiopulmonary resuscitation; AED, automated external defibrillator;

CPC, Glasgow–Pittsburgh cerebral performance category score; D, absolute standardized difference.

3 Supplemental Material Appendix B. Characteristics of patients with out-of-hospital cardiac arrest according to initial rhythms and prehospital administration of epinephrine after propensity score matching (full version).

Pulseless

electrical

activity Asystole

Variable (n=14,862) (n=17,812) No No

epinephrine Epinephrine D epinephrine Epinephrine D

(n=7,431) (n=7,431) (n=8,906) (n=8,906) n (%) n (%) n (%) n (%) Year 2008 948 (12.8) 918 (12.4) 0.012 1,054 (11.8) 1,100 (12.4) 0.016 2009 1,214 (16.3) 1,203 (16.2) 0.004 1,336 (15.0) 1,357 (15.2) 0.007 2010 1,525 (20.5) 1,491 (20.1) 0.011 1,891 (21.2) 1,851 (20.7) 0.011 2011 1,803 (24.3) 1,816 (24.4) 0.004 2,204 (24.8) 2,212 (24.8) 0.002 2012 1,941 (26.1) 2,003 (27.0) 0.019 2,421 (27.2) 2,386 (26.8) 0.009 Season

Spring 1,752 (23.6) 1,743 (23.5) 0.003 2,145 (24.1) 2,153 (24.2) 0.002 Summer 1,427 (19.2) 1,474 (19.8) 0.016 1,833 (20.6) 1,842 (20.7) 0.002 Fall 1,809 (24.3) 1,851 (24.9) 0.013 2,057 (23.1) 2,091 (23.5) 0.009 Winter 2,443 (32.8) 2,363 (31.8) 0.023 2,871 (32.2) 2,820 (31.7) 0.012 Prefecture

Hokkaido 212 (2.85) 216 (2.91) 0.003 334 (3.75) 385 (4.32) 0.029 Aomori 47 (0.63) 58 (0.78) 0.018 59 (0.66) 69 (0.77) 0.013 Iwate 106 (1.43) 110 (1.48) 0.004 178 (2.00) 181 (2.03) 0.002 Miyagi 104 (1.40) 123 (1.66) 0.021 156 (1.75) 159 (1.79) 0.003 Akita 77 (1.04) 84 (1.13) 0.009 124 (1.39) 136 (1.53) 0.011 Yamagata 72 (0.97) 86 (1.16) 0.018 21 (0.24) 34 (0.38) 0.026 Fukushima 150 (2.02) 142 (1.91) 0.008 120 (1.35) 134 (1.50) 0.013 Ibaraki 167 (2.25) 164 (2.21) 0.003 180 (2.02) 178 (2.00) 0.002 Tochigi 44 (0.59) 46 (0.62) 0.003 51 (0.57) 51 (0.57) 0.000 Gunma 53 (0.71) 51 (0.69) 0.003 53 (0.60) 55 (0.62) 0.003 Saitama 638 (8.59) 593 (7.98) 0.022 886 (9.95) 834 (9.36) 0.020 Chiba 366 (4.93) 369 (4.97) 0.002 402 (4.51) 366 (4.11) 0.020 Tokyo 954 (12.8) 850 (11.4) 0.043 1204 (13.5) 999 (11.2) 0.07 Kanagawa 573 (7.71) 523 (7.04) 0.026 702 (7.88) 660 (7.41) 0.018 Niigata 228 (3.07) 253 (3.4) 0.019 324 (3.64) 323 (3.63) 0.001 Toyama 22 (0.30) 33 (0.44) 0.024 33 (0.37) 35 (0.39) 0.004

4 Ishikawa 43 (0.58) 51 (0.69) 0.014 77 (0.86) 68 (0.76) 0.011 Fukui 9 (0.12) 17 (0.23) 0.026 27 (0.30) 30 (0.34) 0.006 Yamanashi 81 (1.09) 99 (1.33) 0.022 123 (1.38) 147 (1.65) 0.022 Nagano 171 (2.30) 187 (2.52) 0.014 159 (1.79) 186 (2.09) 0.022 Gifu 112 (1.51) 122 (1.64) 0.011 100 (1.12) 125 (1.40) 0.025 Shizuoka 412 (5.54) 418 (5.63) 0.004 474 (5.32) 493 (5.54) 0.009 Aichi 577 (7.76) 507 (6.82) 0.036 560 (6.29) 492 (5.52) 0.032 Mie 121 (1.63) 104 (1.40) 0.019 129 (1.45) 143 (1.61) 0.013 Shiga 56 (0.75) 67 (0.90) 0.016 52 (0.58) 59 (0.66) 0.010 Kyoto 117 (1.57) 142 (1.91) 0.026 92 (1.03) 126 (1.41) 0.035 Osaka 572 (7.70) 527 (7.09) 0.023 603 (6.77) 559 (6.28) 0.020 Hyogo 418 (5.63) 453 (6.10) 0.02 506 (5.68) 513 (5.76) 0.003 Nara 82 (1.10) 85 (1.14) 0.004 116 (1.30) 128 (1.44) 0.012 Wakayama 50 (0.67) 61 (0.82) 0.017 77 (0.86) 83 (0.93) 0.007 Tottori 43 (0.58) 56 (0.75) 0.022 53 (0.60) 56 (0.63) 0.004 Shimane 90 (1.21) 85 (1.14) 0.006 108 (1.21) 129 (1.45) 0.021 Okayama 64 (0.86) 83 (1.12) 0.026 104 (1.17) 120 (1.35) 0.016 Hiroshima 74 (1.00) 75 (1.01) 0.001 65 (0.73) 88 (0.99) 0.028 Yamaguchi 68 (0.92) 88 (1.18) 0.026 108 (1.21) 136 (1.53) 0.027 Tokushima 10 (0.13) 7 (0.09) 0.012 5 (0.06) 8 (0.09) 0.012 Kagawa 26 (0.35) 28 (0.38) 0.004 33 (0.37) 52 (0.58) 0.031 Ehime 57 (0.77) 60 (0.81) 0.005 62 (0.70) 62 (0.70) 0.000 Kochi 11 (0.15) 19 (0.26) 0.024 15 (0.17) 13 (0.15) 0.006 Fukuoka 112 (1.51) 113 (1.52) 0.001 76 (0.85) 100 (1.12) 0.027 Saga 5 (0.07) 4 (0.05) 0.005 2 (0.02) 3 (0.03) 0.007 Nagasaki 37 (0.50) 34 (0.46) 0.006 26 (0.29) 25 (0.28) 0.002 Kumamoto 72 (0.97) 85 (1.14) 0.017 100 (1.12) 92 (1.03) 0.009 Oita 18 (0.24) 27 (0.36) 0.022 36 (0.40) 47 (0.53) 0.018 Miyazaki 40 (0.54) 33 (0.44) 0.013 44 (0.49) 40 (0.45) 0.007 Kagoshima 32 (0.43) 38 (0.51) 0.012 55 (0.62) 67 (0.75) 0.016 Okinawa 38 (0.51) 55 (0.74) 0.029 92 (1.03) 117 (1.31) 0.026 Male sex 4,551 (61.2) 4,538 (61.1) 0.004 5,569 (62.5) 5,547 (62.3) 0.005 Age, years

<45 168 (2.26) 188 (2.53) 0.018 281 (3.16) 316 (3.55) 0.022 45–64 1,161 (15.6) 1,162 (15.6) <0.001 1277 (14.3) 1,303 (14.6) 0.008 65–74 1,491 (20.1) 1,492 (20.1) <0.001 1691 (19.0) 1,699 (19.1) 0.002 75–84 2,737 (36.8) 2,666 (35.9) 0.020 3182 (35.7) 3,122 (35.1) 0.014 85–94 1,874 (25.2) 1,923 (25.9) 0.015 2474 (27.8) 2,466 (27.7) 0.002 CPR by bystander 3,282 (44.2) 3,358 (45.2) 0.021 4,368 (49.1) 4,466 (50.2) 0.022 Dispatch-assisted CPR 3,199 (43.1) 3,303 (44.5) 0.028 4603 (51.7) 4628 (52.0) 0.006

5 instruction AED by bystander 84 (1.13) 98 (1.32) 0.017 120 (1.35) 130 (1.46) 0.010 EMS call-contact interval, min ≤6 1746 (23.5) 1,727 (23.2) 0.006 1,581 (17.8) 1,648 (18.5) 0.020 7−8 2,304 (31.0) 2,257 (30.4) 0.014 2,459 (27.6) 2,378 (26.7) 0.020 9−10 1,709 (23.0) 1,763 (23.7) 0.017 2012 (22.6) 2,041 (22.9) 0.008 ≥11 1,672 (22.5) 1,684 (22.7) 0.004 2,854 (32.1) 2,839 (31.9) 0.004 Arrest had cardiac origin 5,104 (68.7) 4,915 (66.1) 0.054 6,025 (67.7) 5,982 (67.2) 0.010 Family member was a 5,071 (68.2) 5042 (67.9) 0.008 6,356 (71.4) 6,294 (70.7) 0.015 bystander Airway management

Bag-valve mask 3,164 (42.6) 2,449 (33.0) 0.199 4,004 (45.0) 2,689 (30.2) 0.308 Laryngeal mask airway 400 (5.38) 394 (5.30) 0.004 410 (4.60) 458 (5.14) 0.025 Esophageal obturator 3,127 (42.1) 3,475 (46.8) 0.094 3,604 (40.5) 4315 (48.5) 0.161 airway Tracheal intubation 740 (9.96) 1,113 (15.0) 0.152 888 (9.97) 1444 (16.2) 0.186 Defibrillation attempted 492 (6.62) 788 (10.6) 0.142 432 (4.85) 789 (8.86) 0.159 CPR (EMS)-hospital arrival interval, min ≤17 1,016 (13.7) 745 (10.0) 0.113 1,051 (11.8) 728 (8.17) 0.121 18–22 1,722 (23.2) 1,537 (20.7) 0.060 1,975 (22.2) 1,789 (20.1) 0.051 23–29 2,292 (30.8) 2,480 (33.4) 0.054 2,717 (30.5) 2,901 (32.6) 0.044 ≥30 2,401 (32.3) 2,669 (35.9) 0.076 3,163 (35.5) 3,488 (39.2) 0.075 Weekend/off-hour 5,050 (68.0) 4,890 (65.8) 0.046 6419 (72.1) 6,128 (68.8) 0.072 Outcomes

Overall survival 220 (2.96) 334 (4.49) 0.081 93 (1.04) 212 (2.38) 0.103 Neurologically intact 58 (0.78) 73 (0.98) 0.022 20 (0.22) 43 (0.48) 0.044 survival (CPC 1–2) EMS, emergency medical services; CPR, cardiopulmonary resuscitation; AED, automated external defibrillator;

CPC, Glasgow–Pittsburgh cerebral performance category score; D, absolute standardized difference

6 Supplemental Material Appendix C. The associations between prehospital epinephrine administrations and the outcomes among the propensity-matched patients with out-of-hospital cardiac arrest (matched by a different set of random numbers).

Absolute risk reduction (%) Odds ratio (95% CI)

(95% CI) Unadjusted* Adjusted†

Pulseless electrical activity (7,424 pairs) 1.67 (1.05–2.29) Overall survival 1.62 (1.36–1.93) 1.60 (1.33–1.93) Neurologically intact survival 0.20 (-0.12–0.52) 1.25 (0.89–1.77) 1.25 (0.86–1.83) Asystole (8,930 pairs) Overall survival 1.25 (0.86–1.64) 2.39 (1.86–3.07) 2.40 (1.85–3.13) 0.22 (0.04–0.41) Neurologically intact survival 1.95 (1.15–3.30) 2.74 (1.35–5.57) *Bivariate analysis after propensity score matching.

†Adjusted for type of bystander (family or non-family), airway management (bag-valve mask, laryngeal mask airway, esophageal obturator airway, or tracheal intubation), attempts at defibrillation by emergency medical services, time of hospital admission (weekday daytime or weekend/off-hour), and time from onset of CPR by emergency medical services to hospital arrival (≤17, 18–22, 23–29, or ≥30 min) with a multivariate conditional logistic regression model. Presumed cause of arrest (cardiac or non-cardiac, excluding external causes) was also adjusted for in the pulseless electrical activity group.