- Email: [email protected]
Thrombolysis During Resuscitation for Out-of-Hospital Cardiac Arrest Caused by Pulmonary Embolism Increases 30-Day Survival
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Thrombolysis During Resuscitation for Outof-Hospital Cardiac Arrest Caused by Pulmonary Embolism Increases 30-Day Survival
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Findings From the French National Cardiac Arrest Registry
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François Javaudin, MD; Jean-Baptiste Lascarrou, MD; Quentin Le Bastard, MD; Quentin Bourry, MD; Chloé Latour, MD;
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Hugo De Carvalho, MD; Philippe Le Conte, MD, PhD; Joséphine Escutnaire, PhD; Hervé Hubert, PhD;
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Emmanuel Montassier, MD, PhD; Brice Leclère, MD; on behalf of the GR-RéAC*
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76 BACKGROUND: Pulmonary embolism (PE) represents 2% to 5% of all causes of out-of-hospital cardiac arrest (OHCA) and is associated with extremely unfavorable prognosis. In PE-related OHCA, inconsistent data showed that thrombolysis during cardiopulmonary resuscitation may favor survival.
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This was a retrospective, observational, multicenter study from July 2011 to March 2018. All adults with OHCA, treated by a mobile ICU and with a diagnosis of PE confirmed on hospital admission, were included. The primary end point was 30-day survival in a weighted population. METHODS:
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Of the 14,253 patients admitted to hospitals, 328 had a final diagnosis of PE and 246 were included in the analysis. In the group that received thrombolysis during resuscitation (n ¼ 58), 14 (24%) received alteplase, 43 (74%) received tenecteplase, and one (2%) received streptokinase. Thirty-day survival was higher in the thrombolysis group than in the control group (16% vs 6%; P ¼ .005; adjusted log-rank test) but the good neurologic outcome was not significantly different (10% vs 5%; adjusted relative risk, 1.97; 95% CI, 0.70-5.56). Median duration of stay in the ICU was 1 (0-5) day for the thrombolysis group and 1 (0-3) day for the control group (P ¼ .23).
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RESULTS:
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In patients with OHCA with confirmed PE and admitted with recuperation of spontaneous circulation in the hospital, there was significantly higher 30-day survival in those who received thrombolysis during cardiopulmonary resuscitation compared with patients who did not receive thrombolysis. CHEST 2019; -(-):---
CONCLUSIONS:
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cardiopulmonary resuscitation; out-of-hospital cardiac arrest; pulmonary embolism; thrombolytic therapy
KEY WORDS:
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103 ABBREVIATIONS:
BLS = basic life support; CPC = Glasgow-Pittsburgh Cerebral Performance Category; CPR = cardiopulmonary resuscitation; CTPA = CT pulmonary angiography; IPTW = inverse probability of treatment weighting; MICU = mobile ICU; OHCA = out-of-hospital cardiac arrest; PE = pulmonary embolism; RéAC = French National OHCA Registry; ROSC = return of spontaneous circulation AFFILIATIONS: From the Department of Emergency Medicine (Drs Javaudin, Le Bastard, Bourry, Latour, De Carvalho, Le Conte, and Montassier), University Hospital of Nantes, France; Microbiotas,
Hosts, Antibiotics, and Bacterial Resistances (MiHAR) (Drs Javaudin, Le Bastard, Montassier, and Leclère), University of Nantes, Nantes, France; the Medical ICU (Dr Lascarrou), University Hospital of Nantes, Nantes, France; Public Health Department EA 2694 (Drs Escutnaire and Hubert), University of Lille, Lille University Hospital, Lille, France; and the Department of Epidemiology and Medical Evaluation (Dr Leclère), University Hospital of Nantes, Nantes, France. Q4
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Out-of-hospital cardiac arrest (OHCA) accounts for 600,000 deaths each year in industrialized countries.1,2 OHCA can be of cardiac or noncardiac origin.3 Pulmonary embolism (PE) represents 2% to 5% of OHCA and is associated with very unfavorable prognosis.4-9 Thrombolytic therapy during resuscitation in allcause OHCA has been evaluated by four randomized controlled trials that did not demonstrate improvement in survival.4,10-12 But it should be noted that the TROICA (Thrombolysis in Cardiac Arrest) trial was stopped in the interim analysis because of futility.4 A higher proportion of any intracranial hemorrhage was also reported in patients who received thrombolytic therapy; indeed, in the TROICA trial the rate of intracranial hemorrhage in the tenecteplase group was about five times higher but without an increase in symptomatic intracranial hemorrhage and major nonintracranial hemorrhage.4 Thrombolysis reduces mortality, decreases the risk of developing chronic thromboembolic pulmonary
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hypertension, and improves the quality of life in patients with massive PE.13,14 A meta-analysis has also suggested that thrombolysis reduces mortality in patients with submassive PE, but with increased major bleeding complications including intracranial hemorrhage.15 In OHCA caused by PE (PE-related OHCA), inconsistent data have indicated that thrombolysis during resuscitation could favor the return of spontaneous circulation (ROSC) and survival.5,16,17 The most recent American Heart Association18 and European Resuscitation Council19 guidelines therefore recommended that thrombolysis be used when cardiac arrest is suspected as being caused by PE, even if robust evidence is lacking. The objective of the present study was first to evaluate whether thrombolysis during cardiopulmonary resuscitation (CPR) was effective in the case of PErelated OHCA, before evaluating its effectiveness in suspected PE. To do this, we analyzed a large observational, multicenter cohort to assess whether thrombolysis during resuscitation improved 30-day survival in PE-related OHCA.
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Methods Study Design We performed a retrospective cohort study analysis based on data extracted from the French National OHCA Registry (RéAC) from July 2011 to March 2018. RéAC is a cohort that includes all OHCA managed by mobile ICUs (MICUs) in France. A MICU consists of an ambulance driver, a nurse, and a senior emergency physician as a minimum team. A detailed description of the emergency medical system in France has been previously published.20 The RéAC form meets the requirements of the French Emergency Medical Service organizations and is structured according to the Utstein universal style.21 Data are then entered in the secured RéAC database (www. registreac.org).22 The present study was approved by the French Advisory Committee on Information Processing in Health Research (CCTIRS) and the French National Data Protection Commission (CNIL; authorization No. 910946). It was approved as a
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*Collaborators from the GR-RéAC are listed in the Acknowledgments. FUNDING/SUPPORT: The French National Out-of-Hospital Cardiac 157 Arrest Registry (RéAC) is supported by the French Society of Emer158 gency Medicine (SFMU), a patient foundation, the Fédération Française de Cardiologie, the Mutuelle Générale de l’Education Nationale 159 Q18 (MGEN), the University of Lille, and the Institute of Health Engi160 Q5 Q6 neering of Lille. 161 CORRESPONDENCE TO: François Javaudin, MD, SAMU 44, 1 quai Moncousu, 44093 Nantes Cedex 01, France; e-mail: francois.javaudin@ 162 Q7 chu-nantes.fr 163 Copyright Ó 2019 American College of Chest Physicians. Published by 164 Elsevier Inc. All rights reserved. 165 DOI: https://doi.org/10.1016/j.chest.2019.07.015 156
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medical assessment registry without requirement for patient consent.22
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Patient Population
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We selected from the RéAC database all OHCAs that occurred in adults ($ 18 years of age), managed by a MICU, and with a diagnosis of pulmonary embolism confirmed on hospital admission. We excluded all other causes of OHCA and patients who had ROSC prior to mobile ICU management because they could not receive thrombolysis during CPR. Patients were classified in two groups: those who received thrombolytic therapy during CPR and those who did not. Following the initial treatment out of the hospital by MICU, the therapies initiated in the ICUs were left to the discretion of the physicians in charge (including initial or complementary thrombolytic therapy).
197 198 199 200 201 202 203 204 205 206 207
Diagnosis of Pulmonary Embolism PE was diagnosed on hospital admission by CT pulmonary angiography (CTPA) (definite PE) or echocardiogram (probable PE). CTPA is the method of choice for imaging the pulmonary vasculature in patients with suspected PE.23-25 Echocardiographic examination is also recommended as part of the diagnostic workup in suspected PE with shock.24-26
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Outcomes
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The primary end point was 30-day survival, irrespective of GlasgowPittsburgh Cerebral Performance Categories (CPCs). The secondary end points were survival at 24 hours, length of stay in the ICU, and neurologic outcome (CPC). Outcomes were collected by blinded assessors.
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Statistical Analyses
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Continuous variables were reported as medians with interquartile range, and categorical variables were summed as patient counts and percentages.
223 224 225
To obtain unbiased estimations of the average treatment effects, we used inverse probability of treatment weighting (IPTW). This method was performed in two steps: first, an estimation of the propensity score of treatment (thrombolysis during cardiopulmonary resuscitation) with a logistic model, and then an estimation of the effect of treatment on 30-day survival, weighted on the propensity score. Since the study population was small, this conservative procedure was preferred to propensity score matching. The small sample size also forced us to carefully select the variables to be included in the propensity score calculation. Indeed, the inclusion of
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variables not or weakly correlated with the outcome (30-day survival) increases the variance of the effect and is related to low reduction of bias.27 The variables included for the propensity score were therefore limited to variables related to the outcome—whether or not related to exposure (thrombolysis during resuscitation). Observations with missing data for the variables included in the multivariate models were excluded (n ¼ 2).
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The primary end point was reported by Kaplan-Meier estimators, adjusted according to the IPTW method. The significance of the differences in survival between the two groups was measured with the log-rank test adapted to these estimators. Analyses were performed with R software 3.5.1 version and required the IPWsurvival library28 for survival analysis.
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Results
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Patient Characteristics
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From July 2011 to March 2018, 85,519 cardiac arrests were recorded in the RéAC database as reported in Figure 1. A total of 14,253 subjects were admitted to hospitals (admitted with ROSC or for extracorporeal membrane oxygenation). Of those, 328 (2.3%) presented with pulmonary embolism, with 82 excluded owing to ROSC (n ¼ 69; 21%) or unknown ROSC status (n ¼ 13;
239 240 241 242 243 244 245 246
3%) before MICU management on site. These subjects who achieved early ROSC (n ¼ 69) had a survival rate of 42% on day 30, and those whose ROSC status was not known had a survival rate of 23%. Finally, the population analyzed was composed of 58 patients in the thrombolysis group and 188 patients in the control group. The main characteristics of the study patients are reported in Table 1. The median age was 62 (48-73) years, with a male proportion of 48%. Most of the patients had a nonshockable rhythm when the mobile
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85,519 OHCA
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14,253 Admitted to hospital
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13,925 Excluded 1,195 Traumatic etiology 4,275 Acute coronary syndrome 1,234 Heart arrhythmia 265 Myocardiopathy 25 ARVD 804 Other cardiac etiologies 2,613 Respiratory etiology 581 Neurological etiology 1,818 Unknown etiology 1,115 Other etiology
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82 Excluded 69 ROSC before MICU arrival 13 ROSC status unknown on MICU arrival
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328 confirmed PE
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71,265 Excluded 1,696 Age <18 years 14 Age unknown 68,599 Died at the scene 658 Died during transport 298 Organ donation
58 Thrombolysis during CPR
188 No thrombolysis during CPR
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Figure 1 – Flow chart of patient inclusion. ARVD ¼ arrhythmogenic right ventricular dysplasia; OHCA ¼ out-of-hospital cardiac arrest; MICU ¼ mobile ICU; CPR ¼ cardiopulmonary resuscitation; PE ¼ pulmonary embolism; ROSC ¼ return of spontaneous circulation.
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TABLE 1
] Characteristics of Patients and Cardiac Arrest Management
Characteristic
334
Age, median (IQR), y
335
Male, No. (%)
336
Location, No. (%)
Q17
Fibrinolysis Group (n ¼ 58)
Control Group (n ¼ 188)
P Value
60.5 (45.5-69)
62.5 (50-73)
.33
30 (52)
87 (46)
386 387 388 389
.47
390 391
.42
337
Home/private place
36 (62)
133 (71)
338
Public place
14 (24)
33 (17)
393 394
339 340 341 342
Health facility
3 (5)
13 (7)
Other
5 (9)
9 (5)
21 (36)
68 (36)
392
395 396
Known medical history, No. (%)
397
> .99
343
Cardiovascular disease
344
Respiratory disease
4 (7)
29 (15)
.09
399
345
Diabetes
7 (12)
26 (14)
.73
400
346
Cancer
4 (7)
16 (9)
> .99
401
163 (87)
.67
402
51 (27)
.04
347
Bystander-witnessed cardiac arrest, No. (%)
49 (84)
348
Bystander-professional rescuers, No. (%)
24 (41)
Bystander-initiated CPR, No. (%)
35 (60)
122 (65)
.63
Estimated no-flow durationa > 5 min, No. (%)
14 (24)
54 (29)
.47
20 (13-31)
.98
349 350 351 352 353
Time between emergency call and MICU arrival at the scene, median (IQR), min
354
Defibrillation before MICU arrival at the scene, No. (%)
355
Initial cardiac rhythm recorded by MICU, No. (%)
398
19.5 (14-33)
403 404 405 406 407 408
5 (9)
8 (4)
.19
409
.01
410
356
Asystole
38 (66)
141 (75)
411
357
PEA
17 (29)
47 (25)
412
358
VF
3 (5)
0 (0)
359 360 361
b
Low-flow duration, median (IQR), min
35 (21-66)
24 (15-36)
Injection route, No. (%) Peripheral intravenous
363
Intraosseous
7 (12)
Central intravenous
0 (0)
2 (1)
8 (3-13)
5 (3-8)
365
Epinephrine dose during CPR, median (IQR), mg
366
Inotropic support, No. (%)
367 368 369
4 (7) 9 (16)
Endotracheal intubation by MICU, No. (%)
371 372
Death causes, No. (%) Irreversible coma
374
Cardiovascular failure
377 378
384
.14
421 422
8 (4)
.48
21 (11)
.38
187 (99)
> .99
20 (11)
.64
426 428
n ¼ 49
423 424 425
n ¼ 176
427
1 (2)
20 (11)
.052
24 (49)
74 (42)
.39
429 430
9 (5)
.73
0 (0)
1 (1)
> .99
Hypoxia
2 (4)
5 (3)
.65
18 (37)
55 (31)
.47
12 (7)
.31
Undetermined
383
419 420
.001
3 (6)
380 382
127 (68)
418
Septic shock
Multisystem organ failure
381
58 (100)
417
15 (8)
Hemorrhage
379
415 416
171 (91)
5 (9)
373
376
33 (57)
Defibrillation administered by MICU, No. (%)
ECMO, No. (%)
375
51 (88)
Amiodarone administration, No. (%)
370
< .001 .59
362 364
413 414
1 (2)
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P values were calculated by c test, Fisher’s exact test, or Mann-Whitney U test. CPR ¼ cardiopulmonary resuscitation; ECMO ¼ extracorporeal membrane oxygenation; IQR ¼ interquartile range; MICU ¼ mobile ICU; PEA ¼ pulseless electrical activity; VF ¼ ventricular fibrillation. a No-flow duration: time between collapse and initiation of basic life support (missing value, n ¼ 2). b Low-flow duration: time between initiation of basic life support and return of spontaneous circulation (missing value, n ¼ 14). 2
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ICU arrived at the scene (99%). The no-flow duration (time between collapse and initiation of basic life support [BLS]) was estimated to be more than 5 minutes in 28% of the cases. Twenty-six subjects (11%) were admitted to hospital without ROSC with the MICU, of whom 15 (6%) received extracorporeal membrane oxygenation and 11 (4%) underwent ROSC at the hospital.
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In the group of patients who received thrombolysis during cardiopulmonary resuscitation, tenecteplase was the thrombolytic agent most used (n ¼ 43; 74%), with a median dose of 45 mg (minimum, 35; maximum, 50) known for 21 subjects; 14 subjects (24%) received alteplase (median dose, 50 mg [minimum, 50; maximum, 80] known for seven subjects) and one received streptokinase (2%; dose unknown). Patient characteristics and resuscitation treatment were balanced between the two groups except for initial rhythm recorded by medical team, low-flow duration (time between initiation of BLS and ROSC), and epinephrine dose during CPR.
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The most important variables associated with 30-day survival were as follows: professional rescuers as bystanders (52% for survivors vs 28%; P ¼ .02), estimated no-flow duration > 5 min (10% vs 29%; P ¼ .05) (time between collapse and initiation of BLS), epinephrine dose during CPR (2 vs 6 mg; P < .001), and inotropic support (38% vs 68%; P ¼ .006) (data detailed in e-Table 1).
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Primary and Secondary End Points
On day 30, there were 21 survivors (9%) including nine in the thrombolysis group (16%) and 12 in the control group (6%) (P ¼ .055; unweighted Fisher’s exact test). The population was successfully weighted (ie, standardized mean difference, < 0.1) on seven variables shown in Figure 2. Survival on day 30 was higher in the thrombolysis group than in the control group (P ¼ .005; adjusted log-rank test) on the weighted population (Figure 3). In the thrombolysis group six (10%) had a good neurologic outcome on day 30 (ie, CPC 1-2) vs nine (5%) in the control group (adjusted relative risk, 1.97; 95% CI, 0.70-5.56). In the thrombolysis group, there were four survivors among those who received alteplase (29%) and five among those who received tenecteplase (12%; P ¼ .20; unweighted Fisher’s exact Q11 test). Survival at 24 hours was 66% in the thrombolysis group and 63% in the control group (P ¼ .76). Median length of stay in the ICU was 1 (0-5) day for the thrombolysis group and 1 (0-3) day for the control group (P ¼ .23). Subjects in the thrombolysis group did not die of hemorrhage any more than those in the control group (6% vs 5%; P ¼ .73). On the other hand, irreversible coma appeared slightly less frequent as a cause of death in the thrombolysis group (2% vs 11%; P ¼ .05) (Table 1).
497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528
474
529
475
530
476
531
477
Bystander-professional rescuers
532
No flow duration >5min a
534
Medical history of cardiovascular or respiratory disease
536
Bystander-initiated CPR
538
Inotropic support
540
Age >60 years
542
478
533
479 480
535
481 482
537
483 484 485 486 487 488 490
493 494 495
543 544
0.0 print & web 4C=FPO
492
541
Epinephrine dose during CPR
489 491
539
0.1
0.2 0.3 Standardized Mean Difference Data unweighted
545
0.4
546 547 548
weighted
549 550
Figure 2 – Standardized mean difference before and after adjustment. See Figure 1 legend for expansion of abbreviation.
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Figure 3 – Adjusted Kaplan-Meier survival curves on weighted population.
606
70%
553
607
Thrombolysis No Yes
60%
554
Survival probability
555 556 557 558 559 560 561
50% 40%
617
P = .005
618 619 620
0
5
10 15 20 Days since cardiac arrest
25
30
621 622
No. at risk (adjusted sample)
568
623
569
Thrombolysis 242
84
56
36
32
32
23
570
No thrombolysis 247
43
16
7
7
3
2
624 625
571
626 627
573
Discussion
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We assessed thrombolysis during resuscitation for PErelated OHCA in a large prospective cohort. There was significantly higher 30-day survival in patients who received thrombolysis during CPR compared with patients who did not receive it.
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613 615
0%
567
577
611 612
20%
566
576
610
616
10%
565
575
609
30%
564
572
608
614
562 563
print & web 4C=FPO
551
PE-related OHCA is rare, representing 2.3% of all OHCA with ROSC managed by a mobile ICU in our cohort. This is comparable to other studies,5,6,8,9 with an incidence of 3.5% reported in the largest trial assessing thrombolysis during CPR, performed by Böttiger et al.4 They evaluated 30-day survival with a Kaplan-Meier survival model of patients who received either tenecteplase or placebo during resuscitation of a witnessed OHCA presumed to be cardiac in origin. They did not demonstrate a beneficial effect of thrombolysis under these conditions. However, of the 1,050 subjects included, only 37 had confirmed PE, with two of 15 survivors (13%) in the tenecteplase group vs 0 of 22 (0%) in the placebo group (relative risk, 7.19; 95% CI, 0.37139.9; P ¼ .31).4 Bougouin et al5 showed that thrombolysis was associated with improved survival rates on hospital discharge in patients with PE-related OHCA (adjusted OR, 12.5; 95% CI, 1.8-89.1; P ¼ .01). They analyzed the Sudden Death Expertise Center registry,29 which included 82 patients with suspected PE. In the observational study by Lederer et al,30 30-day survival after PE-related OHCA was 32% (n ¼ 6/19) in patients receiving recombinant tissue plasminogen activator. In another cohort of 42 subjects with in- or
6 Original Research
out-of-hospital cardiac arrest caused by PE, Kürkciyan et al9 showed a higher rate of ROSC (81% vs 43%; P ¼ .03) in patients who received recombinant tissue plasminogen activator (n ¼ 21). However, they did not provide survival data on hospital discharge. In a retrospective cohort, Janata et al31 found a higher proportion of survival at 24 hours in patients receiving thrombolysis (n ¼ 19/36 [53%] vs n ¼ 7/30 [23%]; P ¼ .01). The difference was not significant on hospital discharge (n ¼ 7/36 [19%] vs n ¼ 2/30 [7%]; P ¼ .15). Owing to methodologic limitations, the effect of thrombolytic therapy during CPR therefore remained unclear. We assessed 246 subjects with PE-related OHCA, 58 of whom received thrombolysis during cardiopulmonary resuscitation. Tenecteplase was used more frequently than alteplase, both of which were studied in pulmonary embolism32 and cardiac arrest due to suspected pulmonary embolism.17 We did not find any difference in survival rates between these two molecules. Therefore, in routine care, one or the other of these molecules could be used; nevertheless, tenecteplase is not yet approved by the Food and Drug Administration for this indication (PE). To the best of our knowledge, this is the largest prospective cohort. Q12 Moreover, we adjusted the two treatment groups before the survival analysis to place them in conditions similar to those of a randomized controlled trial. The survival rate was low in our study, about 9%. However, subjects who achieved ROSC before MICU arrival at the scene were excluded from the analysis because they were not eligible for thrombolysis during CPR. These subjects had
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Q13
a higher survival rate (42%), as well as subjects with unknown ROSC status (23%). In total, among all confirmed PE (n ¼ 328), the survival rate after admission to ICU was 16%. Compared with other PErelated OHCA studies, Kürkciyan et al9 had a survival rate of 12% in subjects who achieved ROSC, and for Bouguoin et al5 it was 22% in subjects admitted to the ICU. Determining the cause of an OHCA during resuscitation remains challenging. A diagnostic concordance study comparing the out-of-hospital physician’s presumed diagnosis and the diagnosis made in the hospital showed concordance in 74% of the cases.33 Regarding the diagnosis of PE-related OHCA outside the hospital (n ¼ 21/211), its sensitivity was low (43%) and its specificity was very high (94%).33 The factors associated with PErelated OHCA were previous thromboembolism and nonshockable rhythm. In this population with these two factors, the proportion of pulmonary embolism was 34% (sensitivity, 24%; specificity, 98%).34 The use of echocardiography during resuscitation could improve these results. Indeed, the presence of an acute pulmonary heart or a thrombus in the right cavities visualized on echocardiography guides the diagnosis of PE.35-37 American Heart Association and European Resuscitation Council guidelines therefore suggest the use of ultrasound during resuscitation for diagnostic and prognostic purposes.38,39 However, acute pulmonary heart can be related to acute circulatory failure and be nonspecific concerning pulmonary embolism, as highlighted.40
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groups to the initial cardiac rhythm recorded by the mobile ICU because there were no patients with ventricular fibrillation (VF) in the control group. Nevertheless, this imbalance was compensated by the fact that among the three subjects in VF in the thrombolysis group, only one survived to day 30; the other two died on day 0. In addition, this electric rhythm variable was not associated with the outcome in our cohort (ie, survival on day 30) (P ¼ .14) as well as defibrillation before MICU treatment on site (P ¼ .61). Second, an inherent limitation of this type of registry analysis is the lack of completeness of data, which may have resulted in our not being completely exhaustive in the selection of the population. The dose of fibrinolytic agent used was known in less than one-half of the subjects because of a lack of accuracy and completeness. The data only covered deaths caused by bleeding, but not all hemorrhage complications such as intracranial hemorrhage. Similarly, the method of confirming embolism, either by CTPA or echocardiogram, was not known for each patient. Last, we were not able to include all suspected PE-related OHCA because this variable is not clearly available in the registry. In our database there were a total of 1,300 adults who received thrombolysis during CPR, and 567 of them achieved ROSC (44%). However, this population was composed not only of suspected PE but also of suspected acute coronary syndrome, with a better prognosis.
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Limitations
Conclusion
First, thrombolytic therapy during cardiopulmonary resuscitation was not assigned by random allocation. In our prospective cohort, we performed an IPTW survival analysis and made adjustments for selection bias and confounding factors. Under these conditions, the measured effect was considered comparable to randomized trials.41 However, we could not adjust the
We assessed thrombolysis during cardiopulmonary resuscitation for PE-related OHCA in a large prospective cohort. We found that thrombolysis during cardiopulmonary resuscitation was associated with higher 30-day survival in PE-related OHCA. A large randomized controlled trial is needed to confirm these results in case of OHCA presumed to be PE in origin.
751
705
752 753 754 755 756 757 758 759 760
706
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Acknowledgments
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Author contributions: F. J. and B. L. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. F. J. wrote the first draft of the paper, with all other authors making important critical revisions. All authors have read and approved the final version of the manuscript.
773 774 775 776 777 778 779 780
Q14
Role of sponsors: The authors declare that the funding sources had no role in the conduct, analysis, interpretation, or writing of this manuscript.
781 782 783 784 785 786 787 788 789 790 791 792 793 794 795 796 797 798 799 800 801 802 803 804 805 806 807 808 809 810 811 812 813 814 815 816 817 818 819 820 821 822 823 824 825
Financial/nonfinancial disclosures: None declared.
Q15
*GR-RéAC Collaborators:
---
Additional information: The e-Table can be found in the Supplemental Materials section of the online article.
References 1. Nichol G, Thomas E, Callaway C, et al. Regional variation in out-of-hospital cardiac arrest incidence and outcome. JAMA. 2008;300(12):1423-1431. 2. Ong M, Shin S, De Souza N, et al. Outcomes for out-of-hospital cardiac arrests across 7 countries in Asia: the Pan Asian Resuscitation Outcomes Study (PAROS). Recuscitation. 2015;96:100-108. 3. Engdahl J, Holmberg M, Karlson BW, Luepker R, Herlitz J. The epidemiology of out-of-hospital “sudden” cardiac arrest. Resuscitation. 2002;52(3):235-245. 4. Böttiger BW, Arntz H-R, Chamberlain DA, et al. Thrombolysis during resuscitation for out-of-hospital cardiac arrest. N Engl J Med. 2008;359(25): 2651-2662. 5. Bougouin W, Marijon E, Planquette B, et al. Pulmonary embolism related sudden cardiac arrest admitted alive at hospital: management and outcomes. Resuscitation. 2017;115:135-140. 6. Heradstveit BE, Sunde K, Sunde G-A, Wentzel-Larsen T, Heltne J-K. Factors complicating interpretation of capnography during advanced life support in cardiac arrest—a clinical retrospective study in 575 patients. Resuscitation. 2012;83(7):813-818. 7. Hess EP, Campbell RL, White RD. Epidemiology, trends, and outcome of out-of-hospital cardiac arrest of noncardiac origin. Resuscitation. 2007;72(2): 200-206. 8. Kuisma M, Alaspää A. Out-of-hospital cardiac arrests of non-cardiac origin: epidemiology and outcome. Eur Heart J. 1997;18(7):1122-1128. 9. Kürkciyan I, Meron G, Sterz F, et al. Pulmonary embolism as a cause of cardiac arrest: presentation and outcome. Arch Intern Med. 2000;160(10):1529-1535. 10. Böttiger BW, Bode C, Kern S, et al. Efficacy and safety of thrombolytic therapy after initially unsuccessful cardiopulmonary resuscitation: a
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prospective clinical trial. Lancet. 2001;357(9268):1583-1585. 11. Abu-Laban RB, Christenson JM, Innes GD, et al. Tissue plasminogen activator in cardiac arrest with pulseless electrical activity. N Engl J Med. 2002;346(20):1522-1528. 12. Fatovich DM, Dobb GJ, Clugston RA. A pilot randomised trial of thrombolysis in cardiac arrest (the TICA trial). Resuscitation. 2004;61(3):309-313. 13. Jerjes-Sanchez C, Ramirez-Rivera A, de Lourdes Garcia M, et al. Streptokinase and heparin versus heparin alone in massive pulmonary embolism: a randomized controlled trial. J Thromb Thrombolysis. 1995;2(3):227-229. 14. Sharifi M, Bay C, Skrocki L, Rahimi F, Mehdipour M; MOPETT Investigators. Moderate pulmonary embolism treated with thrombolysis (from the “MOPETT” Trial). Am J Cardiol. 2013;111(2):273-277. 15. Chatterjee S, Chakraborty A, Weinberg I, et al. Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis. JAMA. 2014;311(23):2414-2421. 16. Li X, Fu Q, Jing X, et al. A meta-analysis of cardiopulmonary resuscitation with and without the administration of thrombolytic agents. Resuscitation. 2006;70(1):31-36. 17. Logan JK, Pantle H, Huiras P, Bessman E, Bright L. Evidence-based diagnosis and thrombolytic treatment of cardiac arrest or periarrest due to suspected pulmonary embolism. Am J Emerg Med. 2014;32(7): 789-796. 18. Lavonas EJ, Drennan IR, Gabrielli A, et al. Part 10: Special circumstances of resuscitation: 2015 American Heart Association guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2015;132(18 suppl 2):S501S518. 19. Truhlár A, Deakin CD, Soar J, et al. European Resuscitation Council guidelines for resuscitation 2015: Section 4: Cardiac arrest in special circumstances. Resuscitation. 2015;95:148-201. 20. Adnet F, Lapostolle F. International EMS systems: France. Resuscitation. 2004;63(1): 7-9. 21. Jacobs I, Nadkarni V, Bahr J, et al. Cardiac arrest and cardiopulmonary resuscitation outcome reports: update and simplification of the Utstein templates for resuscitation registries: a statement for healthcare professionals from a task force of the International Liaison Committee on Resuscitation (American Heart Association, European Resuscitation Council, Australian Resuscitation Council, New Zealand Resuscitation Council, Heart and Stroke Foundation of Canada, InterAmerican Heart Foundation, Resuscitation Councils of Southern Africa). Circulation. 2004;110(21):33853387.
22. Hubert H, Tazarourte K, Wiel E, et al. Rationale, methodology, implementation, and first results of the French out-ofhospital cardiac arrest registry. Prehosp Emerg Care. 2014;18(4):511-519.
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23. Patel S, Kazerooni EA, Cascade PN. Pulmonary embolism: optimization of small pulmonary artery visualization at multi-detector row CT. Radiology. 2003;227(2):455-460.
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24. Torbicki A, Perrier A, Konstantinides S, et al. Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). Eur Heart J. 2008;29(18):2276-2315.
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25. Konstantinides SV, Torbicki A, Agnelli G, et al; Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2014;35(43):3033-3073.
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26. Jaber WA, Fong PP, Weisz G, et al. Acute pulmonary embolism. J Am Coll Cardiol. 2016;67(8):991-1002.
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27. Brookhart MA, Schneeweiss S, Rothman KJ, Glynn RJ, Avorn J, Stürmer T. Variable selection for propensity score models. Am J Epidemiol. 2006;163(12):1149-1156. 28. Le Borgne F, Giraudeau B, Querard AH, Giral M, Foucher Y. Comparisons of the performance of different statistical tests for time-to-event analysis with confounding factors: practical illustrations in kidney transplantation. Stat Med. 2016;35(7):1103-1116. 29. Bougouin W, Lamhaut L, Marijon E, et al. Characteristics and prognosis of sudden cardiac death in Greater Paris: population-based approach from the Paris Sudden Death Expertise Center (ParisSDEC). Intensive Care Med. 2014;40(6): 846-854. 30. Lederer W, Lichtenberger C, Pechlaner C, Kroesen G, Baubin M. Recombinant tissue plasminogen activator during cardiopulmonary resuscitation in 108 patients with out-of-hospital cardiac arrest. Resuscitation. 2001;50(1):71-76. 31. Janata K, Holzer M, Kürkciyan I, et al. Major bleeding complications in cardiopulmonary resuscitation: the place of thrombolytic therapy in cardiac arrest due to massive pulmonary embolism. Resuscitation. 2003;57(1):49-55.
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33. Pokorna M, Necas E, Skripsky R, Kratochvil J, Andrlik M, Franek O. How accurately can the aetiology of cardiac arrest be established in an out-of-hospital setting? Analysis by “concordance in diagnosis crosscheck tables.” Resuscitation. 2011;82(4):391-397.
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32. Hao Q, Dong BR, Yue J, Wu T, Liu GJ. Thrombolytic therapy for pulmonary embolism. Cochrane Database Syst Rev. 2018;12:CD004437.
[
835 836
]
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881 882 883 884 885 886 887 888 889 890 891 892 893
34. Bougouin W, Marijon E, Planquette B, et al. Factors associated with pulmonary embolism-related sudden cardiac arrest. Circulation. 2016;134(25):2125-2127. 35. Breitkreutz R, Price S, Steiger HV, et al. Focused echocardiographic evaluation in life support and periresuscitation of emergency patients: a prospective trial. Resuscitation. 2010;81(11):1527-1533. 36. MacCarthy P, Worrall A, McCarthy G, Davies J. The use of transthoracic echocardiography to guide thrombolytic therapy during cardiac arrest due to massive pulmonary embolism. Emerg Med J. 2002;19(2):178-179.
37. Torbicki A, Galié N, Covezzoli A, et al. Right heart thrombi in pulmonary embolism: results from the International Cooperative Pulmonary Embolism Registry. J Am Coll Cardiol. 2003;41(12): 2245-2251. 38. Link MS, Berkow LC, Kudenchuk PJ, et al. Part 7: Adult Advanced Cardiovascular Life Support: 2015 American Heart Association guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2015;132(18 suppl 2):S444S464. 39. Soar J, Nolan JP, Böttiger BW, et al. European Resuscitation Council
guidelines for resuscitation 2015: Section 3: adult advanced life support. Resuscitation. 2015;95:100-147. 40. Aagaard R, Caap P, Hansson NC, Bøtker MT, Granfeldt A, Løfgren B. Detection of pulmonary embolism during cardiac arrest—ultrasonographic findings should be interpreted with caution. Crit Care Med. 2017;45(7):e695e702. 41. Austin PC. The use of propensity score methods with survival or time-to-event outcomes: reporting measures of effect similar to those used in randomized experiments. Stat Med. 2014;33(7):12421258.
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Thrombolysis During Resuscitation for Outof-Hospital Cardiac Arrest Caused by Pulmonary Embolism Increases 30-Day Survival
6 7 8 9 10 11 12 13
61 62 63 64 65 66 67 68
Findings From the French National Cardiac Arrest Registry
14
69
15 16
70 Q19
Q1
17 18
Q2 Q3
François Javaudin, MD; Jean-Baptiste Lascarrou, MD; Quentin Le Bastard, MD; Quentin Bourry, MD; Chloé Latour, MD;
71
Hugo De Carvalho, MD; Philippe Le Conte, MD, PhD; Joséphine Escutnaire, PhD; Hervé Hubert, PhD;
72 73
Emmanuel Montassier, MD, PhD; Brice Leclère, MD; on behalf of the GR-RéAC*
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21
76 BACKGROUND: Pulmonary embolism (PE) represents 2% to 5% of all causes of out-of-hospital cardiac arrest (OHCA) and is associated with extremely unfavorable prognosis. In PE-related OHCA, inconsistent data showed that thrombolysis during cardiopulmonary resuscitation may favor survival.
22 23 24 25 26
This was a retrospective, observational, multicenter study from July 2011 to March 2018. All adults with OHCA, treated by a mobile ICU and with a diagnosis of PE confirmed on hospital admission, were included. The primary end point was 30-day survival in a weighted population. METHODS:
27 28 29 30
Of the 14,253 patients admitted to hospitals, 328 had a final diagnosis of PE and 246 were included in the analysis. In the group that received thrombolysis during resuscitation (n ¼ 58), 14 (24%) received alteplase, 43 (74%) received tenecteplase, and one (2%) received streptokinase. Thirty-day survival was higher in the thrombolysis group than in the control group (16% vs 6%; P ¼ .005; adjusted log-rank test) but the good neurologic outcome was not significantly different (10% vs 5%; adjusted relative risk, 1.97; 95% CI, 0.70-5.56). Median duration of stay in the ICU was 1 (0-5) day for the thrombolysis group and 1 (0-3) day for the control group (P ¼ .23).
31
RESULTS:
32 33 34 35 36 37 38 39
In patients with OHCA with confirmed PE and admitted with recuperation of spontaneous circulation in the hospital, there was significantly higher 30-day survival in those who received thrombolysis during cardiopulmonary resuscitation compared with patients who did not receive thrombolysis. CHEST 2019; -(-):---
CONCLUSIONS:
40 41 42 43 44 Q8
47
50 51 52 53 54 55
81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 100 101 102
48 49
79 80
99
cardiopulmonary resuscitation; out-of-hospital cardiac arrest; pulmonary embolism; thrombolytic therapy
KEY WORDS:
45 46
77 78
103 ABBREVIATIONS:
BLS = basic life support; CPC = Glasgow-Pittsburgh Cerebral Performance Category; CPR = cardiopulmonary resuscitation; CTPA = CT pulmonary angiography; IPTW = inverse probability of treatment weighting; MICU = mobile ICU; OHCA = out-of-hospital cardiac arrest; PE = pulmonary embolism; RéAC = French National OHCA Registry; ROSC = return of spontaneous circulation AFFILIATIONS: From the Department of Emergency Medicine (Drs Javaudin, Le Bastard, Bourry, Latour, De Carvalho, Le Conte, and Montassier), University Hospital of Nantes, France; Microbiotas,
Hosts, Antibiotics, and Bacterial Resistances (MiHAR) (Drs Javaudin, Le Bastard, Montassier, and Leclère), University of Nantes, Nantes, France; the Medical ICU (Dr Lascarrou), University Hospital of Nantes, Nantes, France; Public Health Department EA 2694 (Drs Escutnaire and Hubert), University of Lille, Lille University Hospital, Lille, France; and the Department of Epidemiology and Medical Evaluation (Dr Leclère), University Hospital of Nantes, Nantes, France. Q4
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Out-of-hospital cardiac arrest (OHCA) accounts for 600,000 deaths each year in industrialized countries.1,2 OHCA can be of cardiac or noncardiac origin.3 Pulmonary embolism (PE) represents 2% to 5% of OHCA and is associated with very unfavorable prognosis.4-9 Thrombolytic therapy during resuscitation in allcause OHCA has been evaluated by four randomized controlled trials that did not demonstrate improvement in survival.4,10-12 But it should be noted that the TROICA (Thrombolysis in Cardiac Arrest) trial was stopped in the interim analysis because of futility.4 A higher proportion of any intracranial hemorrhage was also reported in patients who received thrombolytic therapy; indeed, in the TROICA trial the rate of intracranial hemorrhage in the tenecteplase group was about five times higher but without an increase in symptomatic intracranial hemorrhage and major nonintracranial hemorrhage.4 Thrombolysis reduces mortality, decreases the risk of developing chronic thromboembolic pulmonary
166
hypertension, and improves the quality of life in patients with massive PE.13,14 A meta-analysis has also suggested that thrombolysis reduces mortality in patients with submassive PE, but with increased major bleeding complications including intracranial hemorrhage.15 In OHCA caused by PE (PE-related OHCA), inconsistent data have indicated that thrombolysis during resuscitation could favor the return of spontaneous circulation (ROSC) and survival.5,16,17 The most recent American Heart Association18 and European Resuscitation Council19 guidelines therefore recommended that thrombolysis be used when cardiac arrest is suspected as being caused by PE, even if robust evidence is lacking. The objective of the present study was first to evaluate whether thrombolysis during cardiopulmonary resuscitation (CPR) was effective in the case of PErelated OHCA, before evaluating its effectiveness in suspected PE. To do this, we analyzed a large observational, multicenter cohort to assess whether thrombolysis during resuscitation improved 30-day survival in PE-related OHCA.
167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 Q9
186 187 188 189 190
136
191
137
192
138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153
Methods Study Design We performed a retrospective cohort study analysis based on data extracted from the French National OHCA Registry (RéAC) from July 2011 to March 2018. RéAC is a cohort that includes all OHCA managed by mobile ICUs (MICUs) in France. A MICU consists of an ambulance driver, a nurse, and a senior emergency physician as a minimum team. A detailed description of the emergency medical system in France has been previously published.20 The RéAC form meets the requirements of the French Emergency Medical Service organizations and is structured according to the Utstein universal style.21 Data are then entered in the secured RéAC database (www. registreac.org).22 The present study was approved by the French Advisory Committee on Information Processing in Health Research (CCTIRS) and the French National Data Protection Commission (CNIL; authorization No. 910946). It was approved as a
154 155
*Collaborators from the GR-RéAC are listed in the Acknowledgments. FUNDING/SUPPORT: The French National Out-of-Hospital Cardiac 157 Arrest Registry (RéAC) is supported by the French Society of Emer158 gency Medicine (SFMU), a patient foundation, the Fédération Française de Cardiologie, the Mutuelle Générale de l’Education Nationale 159 Q18 (MGEN), the University of Lille, and the Institute of Health Engi160 Q5 Q6 neering of Lille. 161 CORRESPONDENCE TO: François Javaudin, MD, SAMU 44, 1 quai Moncousu, 44093 Nantes Cedex 01, France; e-mail: francois.javaudin@ 162 Q7 chu-nantes.fr 163 Copyright Ó 2019 American College of Chest Physicians. Published by 164 Elsevier Inc. All rights reserved. 165 DOI: https://doi.org/10.1016/j.chest.2019.07.015 156
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medical assessment registry without requirement for patient consent.22
194
Patient Population
196
195
We selected from the RéAC database all OHCAs that occurred in adults ($ 18 years of age), managed by a MICU, and with a diagnosis of pulmonary embolism confirmed on hospital admission. We excluded all other causes of OHCA and patients who had ROSC prior to mobile ICU management because they could not receive thrombolysis during CPR. Patients were classified in two groups: those who received thrombolytic therapy during CPR and those who did not. Following the initial treatment out of the hospital by MICU, the therapies initiated in the ICUs were left to the discretion of the physicians in charge (including initial or complementary thrombolytic therapy).
197 198 199 200 201 202 203 204 205 206 207
Diagnosis of Pulmonary Embolism PE was diagnosed on hospital admission by CT pulmonary angiography (CTPA) (definite PE) or echocardiogram (probable PE). CTPA is the method of choice for imaging the pulmonary vasculature in patients with suspected PE.23-25 Echocardiographic examination is also recommended as part of the diagnostic workup in suspected PE with shock.24-26
208 209 210 211 212 213 214
Outcomes
215
The primary end point was 30-day survival, irrespective of GlasgowPittsburgh Cerebral Performance Categories (CPCs). The secondary end points were survival at 24 hours, length of stay in the ICU, and neurologic outcome (CPC). Outcomes were collected by blinded assessors.
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Statistical Analyses
222
Continuous variables were reported as medians with interquartile range, and categorical variables were summed as patient counts and percentages.
223 224 225
To obtain unbiased estimations of the average treatment effects, we used inverse probability of treatment weighting (IPTW). This method was performed in two steps: first, an estimation of the propensity score of treatment (thrombolysis during cardiopulmonary resuscitation) with a logistic model, and then an estimation of the effect of treatment on 30-day survival, weighted on the propensity score. Since the study population was small, this conservative procedure was preferred to propensity score matching. The small sample size also forced us to carefully select the variables to be included in the propensity score calculation. Indeed, the inclusion of
226 227 228 229 230 231 232 233
276
variables not or weakly correlated with the outcome (30-day survival) increases the variance of the effect and is related to low reduction of bias.27 The variables included for the propensity score were therefore limited to variables related to the outcome—whether or not related to exposure (thrombolysis during resuscitation). Observations with missing data for the variables included in the multivariate models were excluded (n ¼ 2).
277 278 279 280 281 282
The primary end point was reported by Kaplan-Meier estimators, adjusted according to the IPTW method. The significance of the differences in survival between the two groups was measured with the log-rank test adapted to these estimators. Analyses were performed with R software 3.5.1 version and required the IPWsurvival library28 for survival analysis.
283 284 285 286 Q10
287 288
234
289
235
290
Results
236
Patient Characteristics
237 238
From July 2011 to March 2018, 85,519 cardiac arrests were recorded in the RéAC database as reported in Figure 1. A total of 14,253 subjects were admitted to hospitals (admitted with ROSC or for extracorporeal membrane oxygenation). Of those, 328 (2.3%) presented with pulmonary embolism, with 82 excluded owing to ROSC (n ¼ 69; 21%) or unknown ROSC status (n ¼ 13;
239 240 241 242 243 244 245 246
3%) before MICU management on site. These subjects who achieved early ROSC (n ¼ 69) had a survival rate of 42% on day 30, and those whose ROSC status was not known had a survival rate of 23%. Finally, the population analyzed was composed of 58 patients in the thrombolysis group and 188 patients in the control group. The main characteristics of the study patients are reported in Table 1. The median age was 62 (48-73) years, with a male proportion of 48%. Most of the patients had a nonshockable rhythm when the mobile
291 292 293 294 295 296 297 298 299 300 301
247
302
248
303
85,519 OHCA
249 250 251 252 253 254 255
14,253 Admitted to hospital
256 257 258 259 260 261 262 263 264 265 267
307 308 309 310 311
13,925 Excluded 1,195 Traumatic etiology 4,275 Acute coronary syndrome 1,234 Heart arrhythmia 265 Myocardiopathy 25 ARVD 804 Other cardiac etiologies 2,613 Respiratory etiology 581 Neurological etiology 1,818 Unknown etiology 1,115 Other etiology
312 313 314 315 316 317 318 319 320 321 322
82 Excluded 69 ROSC before MICU arrival 13 ROSC status unknown on MICU arrival
268 269 270 271 272 print & web 4C=FPO
273 275
305 306
328 confirmed PE
266
274
304
71,265 Excluded 1,696 Age <18 years 14 Age unknown 68,599 Died at the scene 658 Died during transport 298 Organ donation
58 Thrombolysis during CPR
188 No thrombolysis during CPR
323 324 325
Figure 1 – Flow chart of patient inclusion. ARVD ¼ arrhythmogenic right ventricular dysplasia; OHCA ¼ out-of-hospital cardiac arrest; MICU ¼ mobile ICU; CPR ¼ cardiopulmonary resuscitation; PE ¼ pulmonary embolism; ROSC ¼ return of spontaneous circulation.
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329 330
331 332 333
TABLE 1
] Characteristics of Patients and Cardiac Arrest Management
Characteristic
334
Age, median (IQR), y
335
Male, No. (%)
336
Location, No. (%)
Q17
Fibrinolysis Group (n ¼ 58)
Control Group (n ¼ 188)
P Value
60.5 (45.5-69)
62.5 (50-73)
.33
30 (52)
87 (46)
386 387 388 389
.47
390 391
.42
337
Home/private place
36 (62)
133 (71)
338
Public place
14 (24)
33 (17)
393 394
339 340 341 342
Health facility
3 (5)
13 (7)
Other
5 (9)
9 (5)
21 (36)
68 (36)
392
395 396
Known medical history, No. (%)
397
> .99
343
Cardiovascular disease
344
Respiratory disease
4 (7)
29 (15)
.09
399
345
Diabetes
7 (12)
26 (14)
.73
400
346
Cancer
4 (7)
16 (9)
> .99
401
163 (87)
.67
402
51 (27)
.04
347
Bystander-witnessed cardiac arrest, No. (%)
49 (84)
348
Bystander-professional rescuers, No. (%)
24 (41)
Bystander-initiated CPR, No. (%)
35 (60)
122 (65)
.63
Estimated no-flow durationa > 5 min, No. (%)
14 (24)
54 (29)
.47
20 (13-31)
.98
349 350 351 352 353
Time between emergency call and MICU arrival at the scene, median (IQR), min
354
Defibrillation before MICU arrival at the scene, No. (%)
355
Initial cardiac rhythm recorded by MICU, No. (%)
398
19.5 (14-33)
403 404 405 406 407 408
5 (9)
8 (4)
.19
409
.01
410
356
Asystole
38 (66)
141 (75)
411
357
PEA
17 (29)
47 (25)
412
358
VF
3 (5)
0 (0)
359 360 361
b
Low-flow duration, median (IQR), min
35 (21-66)
24 (15-36)
Injection route, No. (%) Peripheral intravenous
363
Intraosseous
7 (12)
Central intravenous
0 (0)
2 (1)
8 (3-13)
5 (3-8)
365
Epinephrine dose during CPR, median (IQR), mg
366
Inotropic support, No. (%)
367 368 369
4 (7) 9 (16)
Endotracheal intubation by MICU, No. (%)
371 372
Death causes, No. (%) Irreversible coma
374
Cardiovascular failure
377 378
384
.14
421 422
8 (4)
.48
21 (11)
.38
187 (99)
> .99
20 (11)
.64
426 428
n ¼ 49
423 424 425
n ¼ 176
427
1 (2)
20 (11)
.052
24 (49)
74 (42)
.39
429 430
9 (5)
.73
0 (0)
1 (1)
> .99
Hypoxia
2 (4)
5 (3)
.65
18 (37)
55 (31)
.47
12 (7)
.31
Undetermined
383
419 420
.001
3 (6)
380 382
127 (68)
418
Septic shock
Multisystem organ failure
381
58 (100)
417
15 (8)
Hemorrhage
379
415 416
171 (91)
5 (9)
373
376
33 (57)
Defibrillation administered by MICU, No. (%)
ECMO, No. (%)
375
51 (88)
Amiodarone administration, No. (%)
370
< .001 .59
362 364
413 414
1 (2)
431 432 433 434 435
P values were calculated by c test, Fisher’s exact test, or Mann-Whitney U test. CPR ¼ cardiopulmonary resuscitation; ECMO ¼ extracorporeal membrane oxygenation; IQR ¼ interquartile range; MICU ¼ mobile ICU; PEA ¼ pulseless electrical activity; VF ¼ ventricular fibrillation. a No-flow duration: time between collapse and initiation of basic life support (missing value, n ¼ 2). b Low-flow duration: time between initiation of basic life support and return of spontaneous circulation (missing value, n ¼ 14). 2
385
436 437 438 439 440
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ICU arrived at the scene (99%). The no-flow duration (time between collapse and initiation of basic life support [BLS]) was estimated to be more than 5 minutes in 28% of the cases. Twenty-six subjects (11%) were admitted to hospital without ROSC with the MICU, of whom 15 (6%) received extracorporeal membrane oxygenation and 11 (4%) underwent ROSC at the hospital.
442 443 444 445 446 447 448 449 450
In the group of patients who received thrombolysis during cardiopulmonary resuscitation, tenecteplase was the thrombolytic agent most used (n ¼ 43; 74%), with a median dose of 45 mg (minimum, 35; maximum, 50) known for 21 subjects; 14 subjects (24%) received alteplase (median dose, 50 mg [minimum, 50; maximum, 80] known for seven subjects) and one received streptokinase (2%; dose unknown). Patient characteristics and resuscitation treatment were balanced between the two groups except for initial rhythm recorded by medical team, low-flow duration (time between initiation of BLS and ROSC), and epinephrine dose during CPR.
451 452 453 454 455 456 457 458 459 460 461 462 463 464 465
The most important variables associated with 30-day survival were as follows: professional rescuers as bystanders (52% for survivors vs 28%; P ¼ .02), estimated no-flow duration > 5 min (10% vs 29%; P ¼ .05) (time between collapse and initiation of BLS), epinephrine dose during CPR (2 vs 6 mg; P < .001), and inotropic support (38% vs 68%; P ¼ .006) (data detailed in e-Table 1).
466 467 468 469 470 471 472 473
496
Primary and Secondary End Points
On day 30, there were 21 survivors (9%) including nine in the thrombolysis group (16%) and 12 in the control group (6%) (P ¼ .055; unweighted Fisher’s exact test). The population was successfully weighted (ie, standardized mean difference, < 0.1) on seven variables shown in Figure 2. Survival on day 30 was higher in the thrombolysis group than in the control group (P ¼ .005; adjusted log-rank test) on the weighted population (Figure 3). In the thrombolysis group six (10%) had a good neurologic outcome on day 30 (ie, CPC 1-2) vs nine (5%) in the control group (adjusted relative risk, 1.97; 95% CI, 0.70-5.56). In the thrombolysis group, there were four survivors among those who received alteplase (29%) and five among those who received tenecteplase (12%; P ¼ .20; unweighted Fisher’s exact Q11 test). Survival at 24 hours was 66% in the thrombolysis group and 63% in the control group (P ¼ .76). Median length of stay in the ICU was 1 (0-5) day for the thrombolysis group and 1 (0-3) day for the control group (P ¼ .23). Subjects in the thrombolysis group did not die of hemorrhage any more than those in the control group (6% vs 5%; P ¼ .73). On the other hand, irreversible coma appeared slightly less frequent as a cause of death in the thrombolysis group (2% vs 11%; P ¼ .05) (Table 1).
497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528
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529
475
530
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Bystander-professional rescuers
532
No flow duration >5min a
534
Medical history of cardiovascular or respiratory disease
536
Bystander-initiated CPR
538
Inotropic support
540
Age >60 years
542
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533
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535
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Epinephrine dose during CPR
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0.1
0.2 0.3 Standardized Mean Difference Data unweighted
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0.4
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weighted
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Figure 2 – Standardized mean difference before and after adjustment. See Figure 1 legend for expansion of abbreviation.
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Figure 3 – Adjusted Kaplan-Meier survival curves on weighted population.
606
70%
553
607
Thrombolysis No Yes
60%
554
Survival probability
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50% 40%
617
P = .005
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0
5
10 15 20 Days since cardiac arrest
25
30
621 622
No. at risk (adjusted sample)
568
623
569
Thrombolysis 242
84
56
36
32
32
23
570
No thrombolysis 247
43
16
7
7
3
2
624 625
571
626 627
573
Discussion
574
We assessed thrombolysis during resuscitation for PErelated OHCA in a large prospective cohort. There was significantly higher 30-day survival in patients who received thrombolysis during CPR compared with patients who did not receive it.
578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605
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0%
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611 612
20%
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10%
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609
30%
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562 563
print & web 4C=FPO
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PE-related OHCA is rare, representing 2.3% of all OHCA with ROSC managed by a mobile ICU in our cohort. This is comparable to other studies,5,6,8,9 with an incidence of 3.5% reported in the largest trial assessing thrombolysis during CPR, performed by Böttiger et al.4 They evaluated 30-day survival with a Kaplan-Meier survival model of patients who received either tenecteplase or placebo during resuscitation of a witnessed OHCA presumed to be cardiac in origin. They did not demonstrate a beneficial effect of thrombolysis under these conditions. However, of the 1,050 subjects included, only 37 had confirmed PE, with two of 15 survivors (13%) in the tenecteplase group vs 0 of 22 (0%) in the placebo group (relative risk, 7.19; 95% CI, 0.37139.9; P ¼ .31).4 Bougouin et al5 showed that thrombolysis was associated with improved survival rates on hospital discharge in patients with PE-related OHCA (adjusted OR, 12.5; 95% CI, 1.8-89.1; P ¼ .01). They analyzed the Sudden Death Expertise Center registry,29 which included 82 patients with suspected PE. In the observational study by Lederer et al,30 30-day survival after PE-related OHCA was 32% (n ¼ 6/19) in patients receiving recombinant tissue plasminogen activator. In another cohort of 42 subjects with in- or
6 Original Research
out-of-hospital cardiac arrest caused by PE, Kürkciyan et al9 showed a higher rate of ROSC (81% vs 43%; P ¼ .03) in patients who received recombinant tissue plasminogen activator (n ¼ 21). However, they did not provide survival data on hospital discharge. In a retrospective cohort, Janata et al31 found a higher proportion of survival at 24 hours in patients receiving thrombolysis (n ¼ 19/36 [53%] vs n ¼ 7/30 [23%]; P ¼ .01). The difference was not significant on hospital discharge (n ¼ 7/36 [19%] vs n ¼ 2/30 [7%]; P ¼ .15). Owing to methodologic limitations, the effect of thrombolytic therapy during CPR therefore remained unclear. We assessed 246 subjects with PE-related OHCA, 58 of whom received thrombolysis during cardiopulmonary resuscitation. Tenecteplase was used more frequently than alteplase, both of which were studied in pulmonary embolism32 and cardiac arrest due to suspected pulmonary embolism.17 We did not find any difference in survival rates between these two molecules. Therefore, in routine care, one or the other of these molecules could be used; nevertheless, tenecteplase is not yet approved by the Food and Drug Administration for this indication (PE). To the best of our knowledge, this is the largest prospective cohort. Q12 Moreover, we adjusted the two treatment groups before the survival analysis to place them in conditions similar to those of a randomized controlled trial. The survival rate was low in our study, about 9%. However, subjects who achieved ROSC before MICU arrival at the scene were excluded from the analysis because they were not eligible for thrombolysis during CPR. These subjects had
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Q13
a higher survival rate (42%), as well as subjects with unknown ROSC status (23%). In total, among all confirmed PE (n ¼ 328), the survival rate after admission to ICU was 16%. Compared with other PErelated OHCA studies, Kürkciyan et al9 had a survival rate of 12% in subjects who achieved ROSC, and for Bouguoin et al5 it was 22% in subjects admitted to the ICU. Determining the cause of an OHCA during resuscitation remains challenging. A diagnostic concordance study comparing the out-of-hospital physician’s presumed diagnosis and the diagnosis made in the hospital showed concordance in 74% of the cases.33 Regarding the diagnosis of PE-related OHCA outside the hospital (n ¼ 21/211), its sensitivity was low (43%) and its specificity was very high (94%).33 The factors associated with PErelated OHCA were previous thromboembolism and nonshockable rhythm. In this population with these two factors, the proportion of pulmonary embolism was 34% (sensitivity, 24%; specificity, 98%).34 The use of echocardiography during resuscitation could improve these results. Indeed, the presence of an acute pulmonary heart or a thrombus in the right cavities visualized on echocardiography guides the diagnosis of PE.35-37 American Heart Association and European Resuscitation Council guidelines therefore suggest the use of ultrasound during resuscitation for diagnostic and prognostic purposes.38,39 However, acute pulmonary heart can be related to acute circulatory failure and be nonspecific concerning pulmonary embolism, as highlighted.40
695 696 697 698 699 700 701 702 703 704
groups to the initial cardiac rhythm recorded by the mobile ICU because there were no patients with ventricular fibrillation (VF) in the control group. Nevertheless, this imbalance was compensated by the fact that among the three subjects in VF in the thrombolysis group, only one survived to day 30; the other two died on day 0. In addition, this electric rhythm variable was not associated with the outcome in our cohort (ie, survival on day 30) (P ¼ .14) as well as defibrillation before MICU treatment on site (P ¼ .61). Second, an inherent limitation of this type of registry analysis is the lack of completeness of data, which may have resulted in our not being completely exhaustive in the selection of the population. The dose of fibrinolytic agent used was known in less than one-half of the subjects because of a lack of accuracy and completeness. The data only covered deaths caused by bleeding, but not all hemorrhage complications such as intracranial hemorrhage. Similarly, the method of confirming embolism, either by CTPA or echocardiogram, was not known for each patient. Last, we were not able to include all suspected PE-related OHCA because this variable is not clearly available in the registry. In our database there were a total of 1,300 adults who received thrombolysis during CPR, and 567 of them achieved ROSC (44%). However, this population was composed not only of suspected PE but also of suspected acute coronary syndrome, with a better prognosis.
716 717 718 719 720 721 722 723 724 725 726 727 728 729 730 731 732 733 734 735 736 737 738 739 740 741 742 743 744 745 746 747 748 749 750
Limitations
Conclusion
First, thrombolytic therapy during cardiopulmonary resuscitation was not assigned by random allocation. In our prospective cohort, we performed an IPTW survival analysis and made adjustments for selection bias and confounding factors. Under these conditions, the measured effect was considered comparable to randomized trials.41 However, we could not adjust the
We assessed thrombolysis during cardiopulmonary resuscitation for PE-related OHCA in a large prospective cohort. We found that thrombolysis during cardiopulmonary resuscitation was associated with higher 30-day survival in PE-related OHCA. A large randomized controlled trial is needed to confirm these results in case of OHCA presumed to be PE in origin.
751
705
752 753 754 755 756 757 758 759 760
706
761
707
762
708
763
709
764
710
765
711
766
712
767
713
768
714
769
715
770
7
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Acknowledgments
772
Author contributions: F. J. and B. L. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. F. J. wrote the first draft of the paper, with all other authors making important critical revisions. All authors have read and approved the final version of the manuscript.
773 774 775 776 777 778 779 780
Q14
Role of sponsors: The authors declare that the funding sources had no role in the conduct, analysis, interpretation, or writing of this manuscript.
781 782 783 784 785 786 787 788 789 790 791 792 793 794 795 796 797 798 799 800 801 802 803 804 805 806 807 808 809 810 811 812 813 814 815 816 817 818 819 820 821 822 823 824 825
Financial/nonfinancial disclosures: None declared.
Q15
*GR-RéAC Collaborators:
---
Additional information: The e-Table can be found in the Supplemental Materials section of the online article.
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