1

[ Critical Care Original Research ] 56

2 57
3 58
4 59
5 60
6
7
Comparative Effectiveness of Amiodarone 61
62
8
9
Q27
and Lidocaine for the Treatment of 63
64
10 In-Hospital Cardiac Arrest 65
11 66
12 67
Q28 Deborah Wagner, PharmD; S. L. Kronick, MD; H. Nawer, PharmD; J. A. Cranford, PhD; S. M. Bradley, MD, PhD;
13 Q1 Q2 68
and R. W. Neumar, MD, PhD
14 69
15 70
16 BACKGROUND: American Heart Association Advanced Cardiac Life Support (ACLS) guide- 71
17 72
lines support the use of either amiodarone or lidocaine for cardiac arrest caused by ven-
18 73
tricular tachycardia or ventricular fibrillation (VT/VF) based on studies of out-of-hospital
19 74
cardiac arrest. Studies comparing amiodarone and lidocaine in adult populations with in-
20 75
21
hospital VT/VF arrest are lacking.
76
22 RESEARCH QUESTION: Does treatment with amiodarone vs lidocaine therapy have differential 77
23 associations with outcomes among adult patients with in-hospital cardiac arrest from VT/VF? 78
24 79
STUDY DESIGN AND METHODS: This retrospective cohort study of adult patients receiving
25 80
amiodarone or lidocaine for VT/VF in-hospital cardiac arrest refractory to CPR and defi-
26 81
brillation between January 1, 2000, and December 31, 2014, was conducted within American
27 82
28
Heart Association Get With the Guidelines-Resuscitation participating hospitals. The pri-
83
29 mary outcome was return of spontaneous circulation (ROSC). Secondary outcomes were 24 h 84
30 survival, survival to hospital discharge, and favorable neurologic outcome. 85
31 Q5 RESULTS: Among 14,630 patients with in-hospital VT/VF arrest, 68.7% (n ¼ 10,058) were 86
32 treated with amiodarone and 31.3% (n ¼ 4,572) with lidocaine. When all covariates were 87
33 statistically controlled, compared with amiodarone, lidocaine was associated with statistically 88
34 89
significantly higher odds of the following: (1) ROSC (adjusted OR [aOR], 1.15, P ¼ .01;
35 90
average marginal effect [AME], 2.3; 95% CI, .5-4.2); (2) 24 h survival (aOR, 1.16; P ¼ .004;
36 91
AME, 3.0; 95% CI, 0.9-5.1); (3) survival to discharge (aOR, 1.19; P < .001; AME, 3.3; 95% CI,
37 92
38
1.5-5.2); and (4) favorable neurologic outcome at hospital discharge (aOR, 1.18; P < .001;
93
39 AME, 3.1; 95% CI, 1.3-4.9). Results using propensity score methods were similar to those 94
40 from multivariable logistic regression analyses. 95
41 INTERPRETATION: Compared with amiodarone, lidocaine therapy among adult patients with 96
42 in-hospital cardiac arrest from VT/VF was associated with statistically significantly higher rates 97
43 of ROSC, 24 h survival, survival to hospital discharge, and favorable neurologic outcome. 98
44
CHEST 2022; -(-):--- 99
45 100
46 KEY WORDS: cardiology; cardiopulmonary arrest; cardiopulmonary resuscitation; drugs; 101
47 Q6 guidelines 102
48 103
49 ABBREVIATIONS: AME = average marginal effect; GWTG-R = Get CORRESPONDENCE TO: Deborah Wagner, PharmD; email: debbiew@ Q4104
50 With the Guidelines-Resuscitation; IHCA = in-hospital cardiac arrest; umich.edu 105
51 IPTW = inverse probability of treatment weighting; OHCA = out-of- Copyright Ó 2022 American College of Chest Physicians. Published by 106
hospital cardiac arrest; PSM = propensity score method; ROSC = re- Elsevier Inc. All rights reserved.
52 turn of spontaneous circulation; VF = ventricular fibrillation; VT = 107
DOI: https://doi.org/10.1016/j.chest.2022.10.024
53 ventricular tachycardia 108
54 Q3 AFFILIATIONS: From the Department of Pharmacy (D. W. and H. N.) 109
and Department of Emergency Medicine (S. L. K., J. A. C., and R. W.
55 110
N.), Michigan Medicine, and Allina Health (S. M. B.).

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CHEST-22-1157
111 and antiarrhythmic drugs that include amiodarone and 166
112 Take-home Points lidocaine. 167
113 168
Study question: Do the data in the GWTG-R pro- Current guidelines for VT/VF arrest recommend use
114 169
vide evidence to support the use of lidocaine in adult of either amiodarone or lidocaine, with no indication
115 170
116
IHCA? of preference.3 These recommendations are based on Q7 171
117 Results: Reconsideration for the use of lidocaine as a 172
three large randomized controlled trials comparing
118 preferred agent in adult IHCA should be considered lidocaine and amiodarone in the management of out- 173
119 based on the results of this study showing that of-hospital VT/VF arrest,4 ALIVE,5 and the 174
120 lidocaine was associated with statistically significant 175
Resuscitation Outcomes Consortium Amiodarone,
121 higher rates of ROSC, 24 h survival, survival to 176
Lidocaine, or Placebo Study (ROC-ALPS).6
122 hospital discharge, and favorable neurologic 177
Compared with placebo, there was evidence of
123 outcome. 178
124
improved survival to admission with use of either 179
Interpretation: The influence of lidocaine on
125
amiodarone or lidocaine. There were no differences 180
neurologic outcome should be a major consideration in survival to admission when comparing lidocaine
126 181
for use in adult IHCA. vs amiodarone.
127 182
128 183
Cardiac arrests occurring in the out-of-hospital setting
129 184
Sudden cardiac death claims > 350,000 lives annually in are often unwitnessed, with associated delay between
130 185
131
the United States.1 Nearly equal proportions of cardiac recognition of arrest, initiation of CPR, and 186
132 arrests occur out-of-hospital and in-hospital,2 but pharmacologic therapy. In comparison, IHCAs are often 187
133 studies of out-of-hospital cardiac arrest (OHCA) witnessed or monitored, with resulting rapid initiation 188
134 dominate guideline recommendations for management. of CPR and management. It is unknown if these 189
135 Differences in the patient populations and differences influence the relative effectiveness of 190
136 characteristics of in-hospital cardiac arrest (IHCA) may amiodarone and lidocaine for patients with IHCA, and 191
137 influence the effectiveness of therapies recommended prior studies of antiarrhythmic medication use for IHCA 192
138 based on the management of patients with OHCA. are lacking. Accordingly, using a large US national 193
139 Recommended treatments for cardiac arrest caused by registry of IHCA, our goal was to compare outcomes of 194
140 195
ventricular tachycardia or ventricular fibrillation (VT/ patients with IHCA caused by VT/VF treated with
141 196
VF) incorporate the use of defibrillation, vasopressors, amiodarone or lidocaine.
142 197
143 198
144 199
145 Study Design and Methods IHCA were identified. We excluded 159 patients with an arrest that 200
began in an outpatient or ambulatory care setting; 3,598 patients
146 Data Source and Patient Population 201
who did not receive defibrillation (standard treatment includes
147 The American Heart Association’s Get With the Guidelines- defibrillation for cardiac arrest caused by VT/VF); 14,827 patients 202
148 Resuscitation (GWTG-R) inpatient registry is a national, multicenter, who did not receive amiodarone or lidocaine; 4,522 patients who 203
prospective registry and quality improvement program for IHCA. received both antiarrhythmic therapies, as we would not be able to
149 204
Hospitals participating in the registry submit clinical information determine which antiarrhythmic was administered first or to which
150 regarding the medical history, hospital care, and outcomes of 205
antiarrhythmic the patient had or had not ultimately responded; 247
151 consecutive patients hospitalized for cardiac arrest using an online, 206
patients with missing data on amiodarone and lidocaine treatment;
152 interactive case report form and Patient Management Tool (IQVIA). and 1,106 patients with incomplete documentation. Our final 207
153 At participating hospitals, in-hospital adult resuscitation events for analytic cohort included 14,630 patients with IHCA secondary to 208
which an emergency resuscitation response was initiated and a VT/VF who received defibrillation and either lidocaine or
154 209
resuscitation record was completed are included in the database.7 amiodarone (Fig 1).
155 The variables used in the database are based on the Utstein-Style 210
156 Guidelines for Uniform Reporting of Laboratory CPR Research, and The primary outcome in this study was return of spontaneous 211
157 all data are evaluated for accuracy and compliance with guidelines circulation (ROSC). Secondary outcomes included 24 h survival 212
158 via data entry software and training and certification of data entry postarrest, survival to hospital discharge, and favorable neurologic 213
personnel.8 For data prior to October 1, 2010, IQVIA serves as the outcome. Favorable neurologic outcome was defined as cerebral
159 214
data collection (through their Patient Management Tool) and performance category at hospital discharge ¼ good cerebral
160 coordination center for the American Heart Association/American performance (conscious, alert, able to work, might have mild 215
161 Stroke Association GWTG programs. The University of Pennsylvania neurologic or psychologic deficit) or moderate cerebral disability 216
162 serves as the data analytic center and has an agreement to prepare (conscious, sufficient cerebral function for independent activities of 217
163 the data for research purposes. daily life; able to work in sheltered environment). 218
164 Within GWTG-R from January 2000 to December 2014, a total of Patient, event, and treatment characteristics were compared according 219
165 39,089 adult patients ($ 18 years of age) who experienced VT/VF to use of amiodarone and lidocaine using independent-group t tests 220

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CHEST-22-1157
221 276
39,089 Patients from 696 hospitals with index
222 277
IHCA with pulseless ventricular
223 tachycardia or ventricular 278
224 fibrillation that occurred between 279
225 January 1, 2000, and December 31, 2014 280
226 281
227 282
24,459 excluded
228 283
229 159 Arrest began in outpatient or 284
230 ambulatory care setting 285
231 3,598 No defibrillation shock provided 286
232 287
14,827 No treatment with amiodarone
233 288
or lidocaine
234 289
235 4,522 Treatment with amiodarone and 290
lidocaine
236 291
237 247 Missing data on amiodarone and 292
238 lidocaine 293
239 1,106 Incomplete documentation 294
240 295
print & web 4C=FPO

241 296
242 14,630 Patients treated with amiodarone or 297
243 lidocaine 298
244 299
Figure 1 – IHCA ¼ in-hospital cardiac arrest. Q16 Q17
245 300
246 301
247 302
248 (for continuous variables) and c2 analysis (for binary variables). covariates.”12 PSM can potentially facilitate causal inference from 303
249 Unadjusted comparisons of ROSC, 24 h survival, survival to hospital observational (ie, nonrandomized) studies by balancing the 304
discharge, and favorable neurologic outcome at hospital discharge distribution of covariates between treatment groups.14 In the PSM
250 305
Q8 were assessed with c2 analysis. Multivariable logistic regression literature, the AME (ie, the risk difference between two groups) is
251 analysis and propensity score methods (PSMs) were used to test for referred to as the average treatment effect (ATE). Austin15 reviewed 306
252 associations between treatment drug (ie, amiodarone vs lidocaine) PSMs and their relative performance in scenarios such as the current 307
253 and ROSC, 24 h survival, survival to hospital discharge, and one in which the outcome variable is binary and the risk differences 308
254 favorable neurologic outcome at hospital discharge when other are the ATEs of interest. Results from simulations indicated that 309
covariates Table 3) were statistically controlled. Consistent with estimates of risk differences using inverse probability of treatment
255 310
previous studies based on the GWTG-R data, covariates in the risk- weighting (IPTW) with the PS showed lower SEs, approximately
256 311
adjusted analysis included age at admission, sex, race/ethnicity,9,10 correct CIs, and correct type I error rates compared with PS
257 preexisting conditions, event location, illness category, time of event matching, PS stratification, and covariate adjustment using the PS 312
258 (weekend vs weekday, daytime vs nighttime),7,11 event witnessed, score. Based on the results of Austin, IPTW was used to estimate 313
259 interventions already in place at the time of arrest (ECG; pulse risk differences between lidocaine and amiodarone on ROSC, 24 h 314
oximetry), and time to defibrillation. Average marginal effects survival, survival to hospital discharge, and favorable neurologic
260 315
(AMEs) of treatment, defined as the average difference between the outcomes. IPTW using the PS requires specification of a model for
261 amiodarone and lidocaine groups in the predicted probability of a the propensity score and a model for the treatment outcome, and we 316
262 given outcome with other covariates held constant, were calculated included all covariates in both models to facilitate comparisons with 317
263 and converted to percentages to gain perspective on the magnitude results from multivariable logistic regression analysis. 318
264 of treatment group differences. 319
An alpha level of 0.05 was used for all analyses, all hypothesis tests
265 PSMs were used in addition to multivariable logistic regression were two-sided, and P values for all test statistics were based on SEs 320
266 analysis.12,13 The PS was defined as “the conditional probability of adjusted for within-hospital nonindependence.16 Analyses were 321
Q9
267 assignment to a particular treatment given a vector of observed conducted with the 2017 Stata (Stata Corp) software package. 322
268 323
269 324
270
Results conditions (including diabetes mellitus, hepatic 325
271 Among 14,630 patients with VT/VF IHCA, 68.7% (n ¼ insufficiency, metabolic or electrolyte abnormality, 326
272 10,058) were treated with amiodarone and 31.3% (n ¼ metastatic or hematologic cancer, renal insufficiency, 327
273 4,572) were treated with lidocaine. Patients treated with respiratory insufficiency, and septicemia); were less 328
274 lidocaine were less likely to be male and more likely to likely to have events in the adult ICU and more likely 329
275 be White; had lower rates of several preexisting to have events in the ED, general inpatient area, and 330

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CHEST-22-1157
331 TABLE 1 ] --- 386
Q18 Q19

332 387
Treated With Lidocaine (n ¼ 4,572) Treated With Amiodarone (n ¼ 10,058) P Value
333 388
Age at admission, mean  SD, y 65.7  14.7 65.2  14.3 .09
334 389
335 Male 2,868 (62.7%) 6,478 (64.4%) .05 390
336 Race/ethnicity (White) 3,553 (77.7%) 7,541 (75.0%) .03 391
337 Preexisting conditions 392
338 Acute CNS nonstroke event 245 (5.4%) 537 (5.3%) .98 393
339 394
Acute stroke 148 (3.2%) 325 (3.2%) .99
340 395
Baseline depression in CNS function 389 (8.5%) 845 (8.4%) .88
341 396
Diabetes mellitus 1,240 (27.1%) 3,093 (30.8%) < .001
342 397
343 Heart failure this admission 892 (19.5%) 2,102 (21.8%) .13 398
344 Heart failure prior to this admission 1,023 (22.4%) 2,402 (23.9%) .09 399
345 Hepatic insufficiency 176 (3.9%) 494 (4.9%) .01 400
346 Hypotension or hypofusion 950 (20.8%) 2,224 (22.2%) .15 401
347 Major trauma 92 (2.0) 229 (2.3%) .39 402
348 403
Metabolic or electrolyte abnormality 557 (12.2%) 1,372 (13.7%) .04
349 404
Metastatic or hematologic cancer 284 (6.2) 750 (7.5%) .02
350 405
MI this admission 1,537 (33.6%) 3,218 (32.1%) .18
351 406
352 MI prior to admission 1,107 (24.2%) 2,281 (22.7%) .13 407
353 Pneumonia 371 (8.1) 911 (9.1%) .007 408
354 Renal insufficiency or dialysis 1,044 (22.9) 2,908 (29.0%) < .001 409
355 Respiratory insufficiency 1,374 (30.1) 3,451 (34.4%) < .001 410
356 411
Septicemia 349 (7.6) 1,053 (10.5%) < .001
357 412
Event locationa
358 413
Adult ICU 1,973 (43.2%) 5,091 (50.6%) < .001
359 414
360 Interventional area 325 (7.1%) 622 (6.2%) .09 415
361 ED 897 (19.6%) 1,404 (14.0%) < .001 416
362 General inpatient area, telemetry, or 1,044 (22.8%) 2,569 (25.5%) .005 417
363 step-down unit 418
364 Operating room 162 (3.5%) 127 (1.3%) < .001 419
365 Other 171 (3.7%) 242 (2.4%) < .001 420
366 b
Illness category (cardiac) 3,060 (66.9%) 6,650 (66.2%) .45 421
367 c 422
Event occurred on weekend (yes) 1,398 (30.6%) 2,971 (29.5%) .23
368 423
Event witnessedd (yes) 4,007 (87.7%) 8,804 (87.5%) .86
369 424
Time of cardiac arrest: daytime 3,158 (70.0%) 7,160 (71.7%) .03
370 425
371 ECG monitoringe (yes) 3,933 (86.0%) 8,794 (87.4%) .09 426
372 Pulse oximetry monitoringe (yes) 3,020 (66.1%) 7,219 (71.8%) < .001 Q20
427
373 Continuous vasopressor (yes) 1,196 (26.2%) 3,309 (32.9%) < .001 428
374 Mechanical ventilation (yes) 1,223 (26.8%) 3,118 (31.0%) < .001 429
375 Time to defibrillation, min 2.2 (3.9) 2.4 (4.2) .002 430
376 431
377 MI ¼ myocardial ischemia/infarction. 432
a
For the “event location” variable: Adult ICU includes the locations “Adult Coronary Care Unit (CCU),” “Adult ICU (includes medical, surgical, cardiovascular,
378 433
trauma, and burn ICUs),” and “All ICUs.” Interventional area includes the locations “Cardiac Catheterization Laboratory,” “Diagnostic/Intervention Area,”
379 and “Diagnostic/Intervention Area Including Catheter Lab.” 434
380 Other includes the locations “Delivery Suite,” “Neonatal ICU,” “Pediatric ICU,” “Post-Anesthesia Recovery Room (PACU),” “Rehab, Skilled Nursing or Mental 435
381 Health Unit/Facility,” “Same-day Surgical Area,” “Pediatric Cardiac Intensive Care Unit (PCICU),” “Unknown/Not Documented,” and “Other.” 436
b
For the “Illness category” variable, “Cardiac” includes “Medical-Cardiac” and “Surgical-Cardiac.” “Non-cardiac” includes “Medical-Noncardiac,” “Surgical-
382 437
Noncardiac,” “Obstetric,” “Trauma,” and “Other.”
383 c
Weekend was defined as the period from 11:00 PM Friday to 6:59 AM Monday. 438
384 d
In response to the question “Was the onset of the cardiopulmonary arrest directly observed by someone (family, lay bystander, employee, or health care 439
385 professional)?” 440
e
In response to the item “Intervention(s) ALREADY IN PLACE when the need for chest compressions and/or defibrillation was first recognized.”

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CHEST-22-1157
441 TABLE 2 ] --- 496
Q21

442 497
Treated With Lidocaine Treated With Amiodarone
443 (n ¼ 4,572) (n ¼ 10,058) P Value 498
444 499
Return of spontaneous circulationa (yes) 3,3530 (77.3%) 7,700 (76.6%) .47
445 500
24 h survivalb (yes) 2,898 (63.4%) 5,937 (59.1%) .001
446 501
447 Survival to hospital dischargec (yes) 2,168 (47.5%) 4,196 (42.0%) < .001 502
448 Favorable neurologic outcome at hospital 1,681 (39.6%) 3,083 (33.3%) < .001 503
449 discharged 504
450 a
Was ANY documented return of adequate circulation [ROSC] (in the absence of ongoing chest compressions return of pulse/heart rate by palpation, 505
451 auscultation, Doppler, arterial BP waveform, or documented BP) achieved during the event? 506
b Q22
452 Did patient survive 24 h from start of index CPA event?. 507
c
Did patient survive to hospital discharge?.
453 d 508
Defined as cerebral performance category at hospital discharge ¼ good cerebral performance (conscious, alert, able to work, might have mild neurologic
454 or psychologic deficit) or moderate cerebral disability (conscious, sufficient cerebral function for independent activities of daily life; able to work in sheltered 509
455 environment). Due to missing data, the total sample size for this variable was 13,494 (n ¼ 9,248 for treatment with amiodarone and n ¼ 4,246 for 510
456 treatment with lidocaine). 511
457 512
458 513
459 OR; were more likely to have events in the daytime; time to defibrillation. Statistically significant 514
460 515
and were less likely to have pulse oximetry monitoring correlates of higher odds of all four outcomes
461 516
(Table 1). included White race, myocardial infarction this
462 517
admission, cardiac illness category, ECG monitoring,
463 518
Results from unadjusted comparisons between the and year admitted. With all covariates statistically
464 519
lidocaine and amiodarone groups on the four outcomes controlled, compared with amiodarone, lidocaine was
465 520
(ROSC, 24 h survival, survival to discharge, and associated with statistically significantly higher odds
466 521
467
favorable neurologic outcome at hospital discharge of the following: (1) ROSC (aOR ¼ 1.15; P ¼ .01, 522
468 [defined as cerebral performance category at hospital AME, 2.3; 95% CI, .5-4.2); (2) 24 h survival (aOR, 523
469 discharge ¼ good cerebral performance (conscious, 1.16; P ¼ .004; AME, 3.0; 95% CI, 0.9-5.1); (3) 524
470 alert, able to work, might have mild neurologic or survival to discharge (aOR, 1.19; P < .001; AME, 3.3; 525
471 psychologic deficit) or moderate cerebral disability 95% CI, 1.5-5.2); and (4) favorable neurologic 526
472 (conscious, sufficient cerebral function for independent outcome at hospital discharge (aOR, 1.18; P < .001; 527
473 activities of daily life; able to work in sheltered 528
AME, 3.1; 95% CI, 1.3-4.9) (Fig 3).
474 environment]) are presented in Table 2. There was no 529
475 statistically significant difference between treatment Results from PSM analyses using IPTW were similar to 530
476 original results using multivariable logistic regression 531
groups on ROSC (absolute risk difference, 0.7; 95% CI,
477 analysis, although the risk differences from PSM 532
–1.2 to 2.7; P ¼ .47). However, treatment with
478 analyses were smaller in magnitude across all four 533
lidocaine was associated with statistically significantly
479 534
higher rates of 24 h survival (absolute risk difference, outcome measures. Compared with amiodarone, Q11

480
4.3; 95% CI, 2.2 to 6.5; P ¼ .001), survival to hospital lidocaine was associated with statistically significantly 535
481 536
discharge (absolute risk difference, 5.5; 95% CI, 3.4 to higher rates of the following: (1) ROSC (ATE, 2.3; P ¼
482 537
7.8; P < .001), and favorable neurologic outcome at .04; 95% CI, .1 to 4.2); (2) 24 h survival (ATE, 2.3; P ¼
483 538
484 hospital discharge (absolute risk difference, 6.3; .04; 95% CI, 0.1 to 4.5); (3) survival to discharge (ATE, 539
485Q10 95% CI, 3.9 to 8.6; P < .001) (Fig 2). 2.6; P ¼ .02; 95% CI, 0.5-4.6); and (4) favorable 540
486 neurologic outcome at hospital discharge (ATE, 2.2; P ¼ 541
487
The models were adjusted to minimize the influence .04; 95% CI, 0.1-4.3). Our PSM results seem similar to 542
488 of confounders from explaining the differences in those from other studies that found few differences 543
489 outcome. Results from multivariable logistic between estimates of the ATE based on multivariable 544
490 regression analyses are presented in Table 3. In fully modeling vs PSM.17,18 545
491 adjusted models, statistically significant correlates of 546
492 lower odds of all four outcomes included age, several 547
493 preexisting conditions (hypotension or hypoperfusion, Discussion 548
494 metastatic or hematologic cancer, renal insufficiency In a national cohort of nearly 15,000 patients with IHCA 549
495 550
or dialysis, sepsis, and continuous vasopressor), and caused by VT/VF, patient outcomes were compared

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551 Figure 2 – ROSC ¼ return to spon- A 606
552 taneous circulation. 607
90.0%
553 608

print & web 4C=FPO

80.0% 77.3% 76.6%
554 P = .001 609
555 70.0% 610
63.4%
556 59.1% P < .001 611
60.0%
557 612
47.5% P = .001
558 50.0% 613
42.0%
559 39.6% 614
40.0% 33.3%
560 615
561 30.0% 616
562 20.0% 617
563 618
10.0%
564 619
565 0.0% 620
ROSC 24 h Survival Survival to Favorable
566 621
Hospital Neurologic
567 Discharge Outcome 622
568 623
569 Lidocaine Amiodarone 624
570 625
571 626
572 B 627
573 90.0% 628
P = .01
574 79.0% 629
575 80.0% 76.1% 630
576 631
577 70.0% P = .001 632
578 62.5% 633
59.9%
579 60.0% 634
580 P < .001 635
581 50.0% 46.3%
P = .001 636
582 43.0% 42.5% 637
583 39.4% 638
40.0%
584 639
585 640
30.0%
586 641
587 642
20.0%
588 643
589 644
10.0%
590 645
591 646
592 0.0% 647
ROSC 24 h Survival Survival to Favorable
593 Hospital Neurologic 648
594 Discharge Outcome 649
595 650
596 Lidocaine Amiodarone 651
597 652
598 653
599 654
600 according to treatment with lidocaine or amiodarone. survival (AME, 3.1%). These observational findings 655
601 Adjusted results showed that use of lidocaine was warrant further investigation to ensure the optimal care 656
602 associated with statistically significantly higher rates of of patients experiencing in-hospital VT/VF arrest. 657
603 ROSC (AME, 2.3%), 24 h survival (AME, 3.0%), survival Amiodarone was introduced as the first-line 658
604 659
to discharge (AME, 3.3%), and favorable neurologic antiarrhythmic to be used in VT and VF with the 2000
605 660

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661 discharge or good neurologic function. ROSC with 716
662 ROSC 717
lidocaine, however, was significantly better than
663 718
placebo. Direct comparison between the two agents
664 719
found no difference for any outcomes. The ROC-
665 24 h Survival 720
ALPS trial of OHCA using the polysorbate-free
666 721
amiodarone also found no difference in survival to
667 722
668
discharge or neurologic state compared with 723
Survival to Discharge
669 lidocaine.6 ROSC, however, was higher in the 724
670 lidocaine group. Currently, the IV nonpolysorbate 725
671 amiodarone formulation is not available in the United 726
Favorable Neurologic Outcome
672 States. To the best of our knowledge, the current study 727
673 is the largest study to date of amiodarone and 728
print & web 4C=FPO

674 lidocaine use in adult patients with IHCA examining 729

675 the outcomes of ROSC, 24 h survival, survival to 730
0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4
676 731
Favors Amiodarone Favors Lidocaine hospital discharge, and neurologic outcome.
677 732
678 Figure 3 – ROSC ¼ return to spontaneous circulation. The current unadjusted analysis revealed no 733
679 difference between treatment groups in terms of 734
680 ROSC. Patients treated with lidocaine did have 735
681 update to the America Heart Association Advanced statistically significantly higher rates of survival to 736
682 737
Cardiac Life Support guidelines,19 replacing prior hospital discharge compared with patients treated
683 738
recommendations for lidocaine as first-line therapy.20-23 with amiodarone. However, following extensive risk
684 739
Until revised guidelines in 2018, which suggested that adjustment for potential confounders, lidocaine
685 740
686
either amiodarone or lidocaine may be used,3 treatment was associated with statistically
741
687 amiodarone remained a preferred therapy. This significantly higher odds of ROSC and continued to 742
688 preference was evident in the current study of patients be associated with statistically significantly higher 743
689 experiencing cardiac arrest between 2000 and 2014,24-26 odds of 24 h survival and survival to discharge 744
690 with 69% of patients receiving amiodarone and compared with amiodarone treatment. Our results 745
691 31% lidocaine. differ from the only studies we discovered of in- 746
692 hospital arrest from VT/VF. Neither Pollak et al30 747
693 Although studies comparing lidocaine and 748
nor Rea et al31 reported a difference for treatment
694 amiodarone in the management of adults with IHCA 749
with amiodarone compared with lidocaine for
695 are lacking, prior studies of pediatric populations have 750
survival at 24 h or survival to discharge or ROSC or
696 been completed. A 2014 study of IHCA in pediatric 751
24 h survival. These differences, however, may be
697 patients with VT/VF found that lidocaine was 752
due to the larger sample size used in our analysis.
698 associated with improved ROSC and 24 h survival but 753
One must also consider that local responses to Code
699 not survival to discharge.27 A more recent study by 754
700
Blue alerts within various institutions may be 755
Holmberg et al28 found no difference between agents
701 directed by an institution-specific protocol for 756
when compared in a propensity-matched study, again
702 medication administration that may preferentially 757
creating a lack of consensus for superiority of one
703 select one agent first over another. 758
agent over another. There have been no extensive
704 759
studies of antiarrhythmic use in adult patients with Results also showed that lidocaine compared with
705 760
706 IHCA. A 2018 systematic review by Ali et al29 amiodarone was associated with a statistically 761
707 included evidence for patients in any setting (in- significantly higher rate of favorable neurologic 762
708Q12 hospital and out-of-hospital) for all ages. They found outcome, as defined by the cerebral performance 763
709 14 randomized controlled trials and 18 observational categories “good cerebral performance” and “moderate 764
710 studies, but only one observational pediatric study cerebral disability” at discharge. There are several 765
711 reviewed earlier looked at in-hospital data. There was potential mechanisms for a positive association 766
712 no difference between either amiodarone or lidocaine between lidocaine post-ROSC outcomes in the absence 767
713 compared with placebo relative to survival to of an association with ROSC itself. One possibility is 768
714 769
715 770

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CHEST-22-1157
 825
824
823
822
821
820
819
818
817
816
815
814
813
812
811
810
809
808
807
806
805
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803
802
801
800
799
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789
788
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786
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784
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778
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776
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771
] Q23 Q24
8 Original Research

TABLE 3 ---
Q25

ROSC 24 h Survival Survival to Hospital Discharge Favorable Neurologic Outcome

aOR (95% CI) P Value aOR (95% CI) P Value aOR (95% CI) P Value aOR (95% CI) P Value
Age at admission .97 (.96 to.99) .001 .95 (.94 to .97) < .001 .91 (.89 to .92) < .001 .90 (.89 to .92) < .001
Female 1.18 (1.07 to 1.30) .001 1.04 (.96 to 1.12) .38 1.00 (.92 to 1.09) .94 .99 (.91 to 1.08) .87
January
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Race/ethnicity (white) 1.35 (1.22 to 1.49) < .001 1.34 (1.22 to 1.47) < .001 1.43 (1.29 to 1.59) < .001 1.40 (1.26 to 1.57) < .001
FLA 08,5.6.0

Preexisting conditions
2023.DTD

Acute CNS nonstroke event .97 (.80 to 1.17) .62 .92 (.79 to 1.08) .34 .95 (.78 to 1.15) .58 .83 (.69 to 1.01) .06
Acute stroke 1.08 (.86 to 1.36) .51 .76 (.61 to .93) .009 .73 (.59 to .91) .006 .54 (.42 to .69) < .001
For personal

Baseline depression in CNS function .99 (.86 to 1.14) .93 .99 (.88 to 1.12) .88 .81 (.70 to .94) .007 .53 (.44 to .63) < .001

CHEST5342_proof

Diabetes mellitus 1.02 (.94 to 1.12) .60 1.00 (.92 to 1.08) .99 .96 (.88 to 1.05) .36 .94 (.86 to 1.02) .15
use only. No other uses

Heart failure this admission .99 (.89 to 1.11) .74 1.00 (.90 to 1.11) .96 .97 (.88 to 1.08) .63 .95 (.85 to 1.06) .34
Heart failure prior to this admission .92 (.82 to 1.03) .15 .91 (.83 to 1.01) .08 .87 (.79 to .96) .006 .85 (.76 to .94) .002
Hepatic insufficiency .84 (.69 to 1.01) .07 .80 (.67 to .95) .01 .73 (.51 to .79) <.001 .63 (.50 to .79) < .001
Hypotension or hypofusion .69 (.62 to .77) < .001 .60 (.55 to .66) <.001 .57 (.51 to .63) < .001 .57 (.51 to .64) < .001
Major trauma .89 (.68 to 1.17) .42 .66 (.52 to .84) .001 .53 (.39 to .71) < .001 .52 (.37 to .73) < .001

without
28 November

Metabolic or electrolyte abnormality 1.14 (1.00 to 1.29) .046 1.01 (.91 to 1.14) .73 .95 (.84 to 1.08) .44 .94 (.82 to 1.07) .35
Metastatic or hematologic cancer .84 (.71 to .98) .03 .71 (.62 to .81) < .001 .65 (.56 to .75) < .001 .61 (.52 to .71) < .001
permission.2022

MI this admission 1.62 (1.46 to 1.80) < .001 1.49 (1.37 to 1.63) < .001 1.45 (1.33 to 1.58) < .001 1.43 (1.30 to 1.57) < .001
MI prior to admission 1.05 (.95 to 1.17) .34 1.05 (.95 to 1.16) .32 1.05 (.95 to 1.16) .33 1.01 (.91 to 1.12) .81
Copyright

Pneumonia 1.12 (.98 to 1.28) .11 1.18 (1.03 to 1.35) .02 1.08 (.93 to 1.25) .32 .93 (.80 to 1.09) .38
<.001 < .001 <.001 < .001

11:45

Renal insufficiency or dialysis .85 (.77 to .93) .71 (.66 to .77) .55 (.51 to .60) .56 (.51 to .61)
Preexisting conditions
©2023.

Respiratory insufficiency .97 (.88 to 1.07) .52 .90 (.83 to .99) .03 .82 (.75 to .91) < .001 .76 (.69 to .85) < .001
amElsevier

Septicemia .87 (.76 to .99) .04 .83 (.73 to .95) .006 .69 (.59 to .80) < .001 .70 (.59 to .82) < .001

EO:Inc.

Event location
Adult ICU . . . .
[
CHEST-22-1157
All rights reserved.

-#- CHEST - 2022

Interventional area .80 (.66 to .99) .03 0.85 (0.73 to 1.00) .05 1.00 (.86 to 1.17) .99 .95 (.81 to 1.12) .55
ED 1.00 (.87 to 1.16) .96 .88 (0.78 to .99) .03 1.21 (1.08 to 1.36) .001 1.13 (1.01 to 1.27) .03
General inpatient area 0.81 (.71 to .91) .001 0.82 (0.72 to .94) < .001 .94 (.84 to 1.05) .28 .95 (.85 to 1.06) .37
Operating room .79 (.59 to 1.04) .10 1.32 (1.02 to 1.70) .04 1.64 (1.24 to 2.18) .001 1.83 (1.27 to 2.45) < .001
Other 1.00 (.77 to 1.30) .99 1.18 (.93 to 1.51) .17 1.39 (1.10 to 1.75) .006 1.31 (1.03 to 1.65) .02
Illness category: cardiac 1.62 (1.46 to 1.79) <.001 1.91 (1.74 to 2.08) < .001 1.97 (1.80 to 2.16) <.001 2.06 (1.86 to 2.28) <.001

(Continued)
]

880
879
878
877
876
875
874
873
872
871
870
869
868
867
866
865
864
863
862
861
860
859
858
857
856
855
854
853
852
851
850
849
848
847
846
845
844
843
842
841
840
839
838
837
836
835
834
833
832
831
830
829
828
827
826
 Q26
881 that lidocaine could have been associated with earlier 936

*Due to missing data on covariates, sample sizes for multivariable analysis were as follows: return of spontaneous circulation (ROSC; n ¼ 13,953); 24 h survival (n ¼ 13,957); survival to discharge (n ¼ 13,957); and
P Value

.003
< .001

< .001

< .001
< .001
< .001
< .001
< .001
882 937
Favorable Neurologic Outcome

.04

.39
ROSC compared with amiodarone, which might
883 938
translate into better post-ROSC outcomes overall.
884 939
There is also evidence for neuroprotective effects of
885 940
1.43 (1.25 to 1.63)
1.14 (1.04 to 1.24)
1.51 (1.31 to 1.74)

1.03 (1.01 to 1.04)

1.18 (1.07 to 1.30)

.95 (.86 to 1.06)
.91 (.83 to .99)
lidocaine in animal models. This may be due to

.42 (.38 to .47)

.57 (.52 to .64)

.89 (.88 to .90)

886 941
aOR (95% CI)

lidocaine’s sodium channel inhibition, preservation of

887 942
888
adenosine triphosphate, and neuroinflammatory 943
889 reduction protecting against hypoxia and ischemia.32 944
890 However, it is not clear why the same apparent 945
891 treatment effect was not observed in OHCA studies 946
892 unless it is also dependent on time to treatment, 947
<.001
.001
< .001

< .001
< .001
< .001
< .001
< .001
P Value
.01

.72
Survival to Hospital Discharge

893 which could be more delayed in OHCA. 948

894 949
895
Limitations of the current study include that it was 950
1.35 (1.18 to 1.55)
1.15 (1.06 to 1.26)
1.41 (1.24 to 1.61)

1.02 (1.01 to 1.04)

1.19 (1.08 to 1.30)

.98 (.89 to 1.08)

an observational analysis with potential for residual

.90 (.82 to .98)

.43 (.40 to .48)

.60 (.54 to .66)

.89 (.88 to .91)

896 951
aOR (95% CI)

897 confounding. The data used in the current study 952

898 came only from hospitals participating in the 953
899 GWTG-R registry and may not generalize to other 954
900 patients at other hospitals due to lack of time stamps 955
901 for administration. Also, data were not available on 956
902 957
.002
.001

< .001
< .001

<.001
.004

underlying reasons for hospital admission, etiology of

P Value
.05
.02

.46

.01

903 958
the cardiac arrest, whether the cardiac arrest was
904 959
medical or surgery related, duration of CPR,
905 960
24 h Survival

1.17 (1.03 to 1.34)

1.13 (1.05 to 1.23)
1.22 (1.08 to 1.39)
1.05 (0.95 to 1.16)

1.02 (1.00 to 1.03)

1.16 (1.05 to 1.28)

hemodynamic parameters at ROSC, Acute Physiology

.93 (.86 to 1.00)

.49 (.45 to .54)

.74 (.67 to .81)

.91 (.90 to .93)

906 961
and Chronic Health Evaluation II score, targeted
aOR (95% CI)

907 962
908
temperature management, or the amount of drug 963
909 administered. In addition, data regarding preexisting 964
910 administration of either lidocaine or amiodarone are 965
911 not available within the GWTG-R reporting and 966
favorable neurologic outcome (n ¼ 13,957). aOR ¼ adjusted OR; MI ¼ myocardial infarction.

912 cannot be ruled out as a possible contributing factor 967

.001

.001

< .001
< .001
P Value
.14
.13
.23

.02

.55

.01

913 for either success or failure. For example, it is 968

914 plausible that choice of treatment was dependent on 969
915 certain conditions that respond better to that 970
1.24 (1.09 to 1.41)
1.13 (1.02 to 1.26)

1.04 (1.02 to 1.05)

1.15 (1.03 to 1.30)

1.12 (.97 to 1.29)
1.06 (.97 to 1.15)
.93 (.86 to 1.02)

.97 (.87 to 1.08)

916 971
.85 (.78 to .94)

.94 (.93 to .95)

ROSC

treatment drug, resulting in better outcomes. This is

aOR (95% CI)

917 972
in addition to the lack of documentation or oral
918 973
agents such as mexiletine or other antiarrhythmic
919 974
agents prior to the event.
920 975
921 976
922 Interpretation 977
Treatment drug: lidocaine vs amiodarone

923 978
Among adult patients with IHCA secondary to VT/VF
924 979
who received defibrillation, treatment with lidocaine
925 980
was associated with differences in ROSC, 24 h
926 981
survival, rates of survival to hospital discharge, and
927 982
Pulse oximetry monitoring
Event occurred weekend

favorable neurologic outcomes compared vs treatment

Continuous vasopressor
Time of arrest: daytime

928 983
] (Continued)

Mechanical ventilation

with amiodarone. Further study of treatment specific

Time to defibrillation

929 984
930 to IHCA is needed to inform optimal management 985
Event witnessed

ECG monitoring

Year admitted

931 and guidelines for cardiac arrest in this setting. In 986

932 addition, data on underlying reasons for hospital 987
933 admission may inform the treatment decisions 988
TABLE 3

934 undertaken by inpatient teams or underlying 989

935 pathology leading to the arrest. 990

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991 Acknowledgments
992
Author contributions: D. W. is the
993 guarantor of the content of the manuscript.
994 All authors provided substantial contribution
to the conception or design of the work or the
995 acquisition, analysis, or interpretation of data
996 for the content contained in the manuscript;
997 and contributed to drafting, revising, and/or
critically reviewing the manuscript for
998 important intellectual content. All authors
999 provided final approval of the version to be
1000 published and agreed to be accountable for all
aspects of the work in ensuring that questions
1001 related to the accuracy or integrity of any part
1002 of the work are appropriately investigated
1003 and resolved.
1004
Q13 Funding/support: The authors have reported
1005 to CHEST that no funding was received for
this study.
1006
Q14 Financial/nonfinancial disclosures: None
1007
declared.
1008
Q15 American Heart Association’s GWTG-R
1009 Collaborators: The American Heart
1010 Association’s GWTG-R Investigators
1011 included D. W., S. L. K., H. N., J. C., S. B., and
R. N. GWTG-R Adult Research Task Force
1012 members: Anne Grossestreuer, PhD; Ari
1013 Moskowitz, MD; Dana Edelson, MD; Joseph
1014 Ornato, MD; Mary Ann Peberdy, MD;
Matthew Churpek, MD, MPH, PhD; Michael
1015 C. Kurz, MD; Monique Anderson Starks,
1016 MD; Paul Chan, MD; Saket Girotra, MBBS,
1017 SM; Sarah Perman, MD, MSCE; and Zachary
Goldberger, MD.
1018
1019
1020 References
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1021
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1101 American Heart Association’s for the for shockable cardiac arrest: a systematic lidocaine, or both, outcomes for 1108
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