a b s t r a c t

Background: Epinephrine is recommended for the treatment of non-shockable out of hospital cardiac arrest (OHCA) to obtain return of spontaneous circulation (ROSC). Epinephrine efficiency and safety remain under de- bate.

Objective: We propose to describe the association between the Cumulative dose of epinephrine and the failure of ROSC during the first 30 min of Advanced life support .

Methodology: A retrospective observational cohort study using the Paris SAMU 75 registry including all non-trau-

matic OHCA. All OHCA receiving epinephrine during the first 30 min of ALS were enrolled. Cumulative epineph- rine dose given during ALS to ROSC was retrieved from medical reports.

Results: Among 1532 patients with OHCA, 776 (51%) had initial Non-shockable rhythm. Fifty-four patients were excluded for missing data.

The mean value of cumulative dose of epinephrine was 10 +- 4 mg in patients who failed to achieve ROSC (ROSC-) and 4 +- 3 mg (p = 0.04) for those who achieved ROSC.

ROC curve analysis indicated a cut-off point of 7 mg total cumulative epinephrine associated with ROSC- (AUC = 0.89 [0.86-0.92]).

Using Propensity score analysis including age, sex and no-flow duration, association with ROSC- only remained sig- nificant for epinephrine N 7 mg (p <=10-3, OR [CI95] = 1.53 [1.42-1.65]).

Conclusion: An association between total cumulative epinephrine dose administered during OHCA resuscitation and ROSC- was reported with a threshold of 7 mg, best identifying patients with refractory OHCA. We suggest using this threshold in this context to guide the termination of ALS and early decide on the implementation of Extracorporeal life support or organ harvesting in the first 30 min of ALS.

(C) 2018

Introduction

Clinical practice on cardiopulmonary resuscitation (CPR) is regularly updated in the guidelines for basic life support (BLS) and Advanced Life Support which are published every 5 years by the American Heart Association or the European Resuscitation Council [1,2]. Despite recent progress, outcome after cardiac arrest remain poor, with survival rates between 8.2 and 22% and 6 to 11% for hospitalized and critically ill patients respectively [3-6]. Unfortunately, despite recommendations and progress of cares during the last 20 years, survival rate of out-of-hos- pital cardiac arrest (OHCA) do not overcome 10% [7,8]. Resuscitation fail- ure constrains emergency medical services (EMS) dispatched to the scene to decide between the termination of ALS, the implementation of

? The authors declare no competing interests.

* Corresponding author.

E-mail address: [email protected] (R. Jouffroy).

extracorporeal life support (ECPR) in- or out-of-hospital, or organ dona- tion after eligibility. In fact, a positive association was described between the early onset of ECPR and better outcomes in refractory OHCA [9].

The early objective of CPR is to obtain the return of spontaneous cir- culation (ROSC). The incidence of ROSC in OHCA varies from 30 to 80% in the literature [10-12]. Despite reported significant associations, the achievement of ROSC does not always predict long-term survival and the neurological outcome.

Initial Shockable rhythms have a less pronounced association with time to obtain ROSC [9]. In case of asystole, epinephrine is recom- mended in association with CPR [13]. The duration of ALS remains under debate [14,15]. In France, refractory cardiac arrest is defined as the absence of ROSC after at least 30 min of normothermal CPR [15]. Negatives effects of prolonged CPR and potential deleterious effects of epinephrine were observed [16-18].

To our knowledge, no study has focused on the cumulative dose of epinephrine associated with the failure to obtain ROSC during the first 30 min of ALS.

https://doi.org/10.1016/j.ajem.2018.05.055

0735-6757/(C) 2018

388 R. Jouffroy et al. / American Journal of Emergency Medicine 37 (2019) 387–390

Methods and patients

Methods

We conducted a retrospective analysis of out-of-hospital cardiac ar- rest (OHCA) registry data between January 1, 2007 and December 31, 2013 covering the whole population of Paris and involving all consecu- tive non-traumatic OHCA patients with resuscitation attempts.

All OHCA patients who required epinephrine administration by prehospital mobile intensive care units (MICU) dispatched to scene were enrolled in the study. The study population included patients over 18 years who underwent OHCA from either cardiac or non-car- diac aetiology, excluding Traumatic causes. Patients older than 89 years were excluded considering the extremely bad prognosis and frequent early termination of CPR. Patients with missing data were excluded.

In France, the management of out-of-hospital emergencies is based on the emergency medical service, named SAMU (service d’aide medicale d’urgence). Identification of patients occurs through a phone call to the regulation call centre. When an OHCA is suspected, an emer- gency medical team (EMT) is dispatched to the scene, followed by a MICU.

No-flow duration corresponds to the time-lapse from collapse to the initiation of CPR and low-flow duration to the time from the initiation of CPR to ROSC.

Patients were categorized according to their initial rhythm: shock- able rhythm (ventricular fibrillation and pulseless ventricular tachycar- dia) or non-shockable rhythm (pulseless electrical activity, asystole, and unclassified rhythms that were not shockable). ROSC was defined as a palpable pulse in any vessel.

All patients in the study were treated according to the 2005 and 2010 guidelines from the European Resuscitation Council [13,19,20] in their French-adjusted version [21,22].

Cumulative epinephrine dose given during ALS until ROSC was re- trieved from medical reports.

Ethical approval for this study was provided by the local ethic com- mittee. Based on the French law, the review board considered that con- sent of patients was waived for participation in this observational study.

Analysis

Receiver operating characteristic curve analysis was used to determine the diagnosis performance of the cumulative epinephrine in- fusion for failure to obtain ROSC during the first 30 min of ALS. Analysis was stopped upon 30 min of ALS according to the French definition of refractory cardiac arrest [15].

We analysed the area under the curve (AUC) with a 95% confidence interval (CI) obtained after a resampling procedure based on a smoothed bootstrap due to the small size of the sample.

First, all variables for the primary outcome were analysed in a uni- variate model. Statistical significance of the variables was determined by Chi-square tests.

Then, a propensity score analysis including age, sex and no-flow du- ration was performed.

Data are presented as either absolute number (percentage), median with range or mean with standard deviation (SD).

Data analyses were performed using R^(C) version 3.2.3.

Results

A total of 1532 patients with OHCA were included between January 1, 2007 and December 31, 2013. Among these patients, 776 (51%) had an initial non-shockable rhythm and 756 (49%) had an Initial shockable rhythm (Fig. 1). Of the 776 patients, 54 patients had no available data on ROSC achievement and were excluded from the analysis. Table 1 gives an overview of the demographic and baseline clinical characteristics of patients with an initial non-shockable rhythm.

Among the 722 patients who had a non-shockable rhythm, 520 (72%) were male with a mean age of 61 +- 16 years (range = 21-89). No patient had Traumatic cardiac arrest or was over 89 years. Four-hundred and

Fig. 1. Flow chart of the study.

R. Jouffroy et al. / American Journal of Emergency Medicine 37 (2019) 387–390 389

Table 1 Demographics and clinical baseline characteristics of patients. The data are expressed as mean values with standard deviation (+-SD) and as absolute numbers with percentage.

Mean age (years)	61 +- 16
Male gender n (%)	536 (69%)
No-flow (minutes)	6 +- 7
Low-flow (minutes)	19 +- 13
First observed end-tidal CO2 (mm Hg)	36 +- 20

seventy-three patients (66%) achieved ROSC within the first 30 min of ALS (Table 2). The mean value of cumulative dose of epinephrine in the group of patients who failed to obtain ROSC (ROSC-) was 10 +- 4 mg, compared to a mean cumulative dose of epinephrine of 4 +- 3 mg (p = 0.04) in the group of patients who achieved ROSC (ROSC+) (Table 2).

ROC curve analysis indicated a cut-off point of 7 mg epinephrine in- fusion for ROSC^– patients in OHCA with initial Non-shockable rhythms. The corresponding AUC was 0.89 [0.86-0.92].

The statistical relationship between the cumulative dose of epineph- rine and ROSC was significant (p b 10^-3). This association was found for both the delivery of less (p b 10^-3) or more (p b 10^-3) than 7 mg of total cumulative dose of epinephrine. To compensate for the confound- ing effect of covariates, a propensity score analysis, including age, sex and no-flow duration, found a remaining association with ROSC^– only for a cumulative dose of epinephrine N 7 mg (p b 10^-3, OR [CI95] = 1.53 [1.42-1.65]).

Discussion

Our study attempted to identify a parameter for early identification of patients who will fail to obtain ROSC during OHCA resuscitation with non-shockable rhythm. The dose of epinephrine is a parameter that can be obtained simply and quickly during cardiopulmonary resuscitation.

Non-shockable rhythm is the most common presentation of OHCA with an increasing incidence [23] and has a negative prognosis value [19]. Epinephrine administration is the main therapeutic of OHCA with non-shockable rhythm. However, its efficacy and safety remain under debate [24-29]. Considering the administration of 1 mg epineph- rine every 4 min as recommended [1,2], 7 mg of epinephrine corre- sponds to the dose administered during 28 min of CPR. Interestingly, this time scale defines refractory CA [9]. Using this threshold, the AUC reached 89% to predict that patients who failed to obtain ROSC had re- ceived more than 7 mg epinephrine. Consequently, the AUC shows a probability of 11% to fail to obtain ROSC without having received more than 7 mg cumulative dose of epinephrine. Our work is a population study and lacks information on each individual. Our data found a high negative predictive value of 90% for ROSC failure using the cut-off of 7 mg epinephrine. However, the positive prediction value for ROSC failure when patients received N7 mg cumulative dose of epinephrine only reached 79%. This result suggests that a cumulative dose of epineph- rine N 7 mg is not a sufficient criterion to decide to terminate ALS,

Table 2

Demographic characteristics of patients. Data are expressed as mean value with minimal and maximal values and as absolute value with percentage.

Dose of epinephrine during the first 30 min of resuscitation

	N7 mg (n = 257)		<=7 mg (n = 465)
Age (years)		60 +- 16	62 +- 15
Gender (M:F)		184:73	336:129
ROSC + n (%)		53 (21%)	420 (90%)
ROSC – n (%)		204 (79%)	45 (10%)

implement extracorporeal life support or prepare for organ harvesting, as 20% patients achieved ROSC after they received N7 mg epinephrine. This decision is left to the physicians dispatched to the scene based on the patient’s general condition, clinical examination, the gathered infor- mation on his medical history and the no-flow duration. However, at that point, it is possible to start considering an alternative to CPR.

Further studies should be carried to confirm these values, but also to evaluate the cumulative dose of epinephrine that best predicts neuro- logical outcomes in determining cardiac arrest prognosis. We would ex- pect a low number of ROSC failure when patients are administered less than 7 mg total epinephrine, unless CPR is terminated for contraindica- tion (comorbidities, bad general condition) the most common being achievement of ROSC.

A recent study from Funada et al. [30] reported that only 0.23% OHCA patients with initial non-shockable rhythms who did not achieve ROSC in the prehospital setting had a cerebral performance category of 1-2 and that 1.1% survived. Recent studies highlighted the possibility to im- prove the prognosis of prolonged CA occurring both in-hospital [31] and out-of the hospital [32] when other measures such as ECPR are imple- mented early. [33]. The exact moment to terminate ALS or implement other measures remains unknown. Decision-making remains a team- work based on many criteria as the initial rhythm, ROSC in the field, and patient’s comorbidities. We suggest using the cumulated dose of epinephrine, as an early hallmark of poor outcome in OHCA with non- shockable rhythm to help the physician decide on alternatives in the case of refractory CA.

Limitations

There are several limitations to this retrospective and registry-based study. Despite organization similarities in pre-hospital settings, differ- ences in the management between medical teams may affect our results as therapeutics were left to the physician’s discretion and bedside judgment.

No-flow and low-flow are well known prognosis factors [15]. We did not include low-flow durations in the analyses because we considered it as an equivalent of our outcome (ROSC). In this study, we didn’t include data concerning ECPR candidates in non-shockable OHCA as we only fo- cused the ROSC.

The definition of refractory cardiac arrest, i.e. the absence of ROSC after at least 30 min of normothermal cardiopulmonary resuscitation [15], is only used in France, limiting the use of our results in others coun- tries. The herein results suggest that alternatives may be considered early, helped by the cumulative dose of received epinephrine. In France, in the context of refractory cardiac arrest, 3 options are considered: ECPR, Organ donation or termination of ALS [15]. We did not take into account the aetiology of cardiac arrest, another prognosis factor of ROSC [15]. In this study, our interest was focused on short-term progno- sis defined by ROSC and patients were not follow-up to evaluate long- term outcomes such as survival and Neurological sequelae. Nonetheless, ROSC remains the first step toward survival and neurological recovery. Finally, we studied patients from one city only (Paris), where a MICU or an EMT needs an average of 9 min to reach a patient [34]. Extrapolat- ing our results to other countries or Hospital systems may be questioned because of the differences in the organisations of emergency medical systems.

Conclusion

The cumulative dose of epinephrine during resuscitation of OHCA with non-shockable rhythms is associated with failure to obtain ROSC. We suggest that the cumulative dose of epinephrine may guide the phy- sician terminate ALS or early decide on the implementation of extracor- poreal life support or organ harvesting before 30 min of ALS.

Further prospective multicentre randomized studies are needed to validate this cut-off and assess a correlation between the cumulative

390 R. Jouffroy et al. / American Journal of Emergency Medicine 37 (2019) 387–390

dose of epinephrine, or the duration of low-flow, and neurological out- comes to guide the management of OHCA and help establish an interna- tional definition for refractory cardiac arrest.

Competing interests

All authors declare no competing interests.

Authors’ contribution

• Study concept and design: Jouffroy.
• Acquisition of data: Alexandre.
• Analysis and interpretation of data: Jouffroy.
• Drafting of the manuscript: Jouffroy, Saade.
• Critical revision of the manuscript for important intellectual content: Saade, Philippe, Carli, Vivien.

Funding/Support

None.

References

1. Nolan JP, Nadkarni VM, Billi JE, Bossaert L, Boettiger BW, Chamberlain D, et al. Part 2: in- ternational collaboration in resuscitation science. Resuscitation Oct. 2010;81(1):e26-31 Disponible sur http://linkinghub.elsevier.com/retrieve/pii/S030095721000448X. [Internet].[cite 10 mars 2017].
2. European Resuscitation Council Guidelines for Resuscitation 2015. Section 3. Adult advanced life support. – PubMed – NCBI. [Internet]. [cite 2 nov 2017]. Disponible sur https://www.ncbi.nlm.nih.gov/pubmed/26477701.
3. Hollingsworth JH. The results of cardiopulmonary resuscitation. A 3-year university hospital experience. Ann Intern Med Sept 1969;71(3):459-66.
4. Peterson MW, Geist LJ, Schwartz DA, Konicek S, Moseley PL. Outcome after cardio- pulmonary resuscitation in a medical intensive care unit. Chest Juill 1991;100(1): 168-74.
5. Landry FJ, Parker JM, Phillips YY. Outcome of cardiopulmonary resuscitation in the intensive care setting. Arch Intern Med Nov 1992;152(11):2305-8.
6. Rozenbaum EA, Shenkman L. Predicting outcome of Inhospital CArdiopulmonary re- suscitation. Crit Care Med Juin 1988;16(6):583-6.
7. Myat A, Song K-J, Rea T. Out-of-hospital cardiac arrest: current concepts. Lancet Lond

   Engl 10 Mars 2018;391(10124):970-9.

   Ong MEH, Perkins GD, Cariou A. Out-of-hospital cardiac arrest: prehospital manage- ment. Lancet Lond Engl 10 Mars 2018;391(10124):980-8.

8. Grunau B, Scheuermeyer FX, Stub D, Boone RH, Finkler J, Pennington S, et al. Poten- tial candidates for a structured Canadian ECPR program for out-of-hospital cardiac arrest. CJEM Nov 2016;18(6):453-60.
9. Reynolds JC, Frisch A, Rittenberger JC, Callaway CW. Duration of resuscitation efforts and functional outcome after out-of-hospital cardiac arrest: when should we change to novel therapies? Circulation 3 Dec 2013;128(23):2488-94.
10. Zhang W, Liao J, Liu Z, Weng R, Ye X, Zhang Y, et al. Out-of-hospital cardiac arrest with do-not-resuscitate orders signed in hospital: who are the survivors? Resusci- tation 6 Avr 2018;127:68-72.
11. Brinkrolf P, Metelmann B, Scharte C, Zarbock A, Hahnenkamp K, Bohn A. Bystander- witnessed cardiac arrest is associated with reported agonal breathing and leads to less frequent bystander CPR. Resuscitation 18 Avr 2018;127:114-8.
12. Nolan JP, Deakin CD, Soar J, Bottiger BW, Smith G, European Resuscitation Council. European Resuscitation Council guidelines for resuscitation 2005. Section 4. Adult advanced life support. Resuscitation Dec 2005;67(Suppl 1):S39-86.
13. Nagao K, Nonogi H, Yonemoto N, Gaieski DF, Ito N, Takayama M, et al. Duration of prehospital resuscitation efforts after out-of-hospital cardiac arrest. Circulation 5 Avr 2016;133(14):1386-96.
14. Recommandations sur les indications de l’assistance circulatoire dans le traitement des arrets cardiaques refractaires. Ann Fr Anesth Reanimation [Internet] 2009;28

    (2):182-6 [cite 10 mars 2017] Disponible sur: http://linkinghub.elsevier.com/ retrieve/pii/S0750765808006874.

    Kagawa E, Inoue I, Kawagoe T, Ishihara M, Shimatani Y, Kurisu S, et al. Assessment of outcomes and differences between in- and out-of-hospital cardiac arrest patients treated with cardiopulmonary resuscitation using extracorporeal life support. Resus- citation Aout 2010;81(8):968-73.

15. Avalli L, Maggioni E, Formica F, Redaelli G, Migliari M, Scanziani M, et al. Favourable survival of in-hospital compared to out-of-hospital refractory cardiac arrest patients treated with extracorporeal membrane oxygenation: an Italian tertiary care Centre experience. Resuscitation Mai 2012;83(5):579-83.
16. Dumas F, Bougouin W, Geri G, Lamhaut L, Bougle A, Daviaud F, et al. Is epinephrine during cardiac arrest associated with worse outcomes in resuscitated patients? J Am Coll Cardiol 9 Dec 2014;64(22):2360-7.
17. Nolan JP, Hazinski MF, Billi JE, Boettiger BW, Bossaert L, de Caen AR, et al. Part 1: ex- ecutive summary: 2010 international consensus on cardiopulmonary resuscitation and Emergency Cardiovascular Care Science with treatment recommendations. Re- suscitation Oct 2010;81(Suppl 1):e1-25.
18. Perkins GD, Olasveengen TM, Maconochie I, Soar J, Wyllie J, Greif R, et al. European resuscitation council guidelines for resuscitation: 2017 update. Resuscitation Fevr 2018;123:43-50.
19. doi: 10.1016/j.annfar.2007.09.010-2_AFAR_Prise-en-charge-de-l1arret-cardiaque-1. pdf [Internet]. [cite 5 nov 2017] 2007;26:1008-19 Disponible sur: http://sfar.org/ wp-content/uploads/2015/10/2_AFAR_Prise-en-charge-de-l%C2%B9arret- cardiaque-1.pdf.
20. Recommandations pour la prise en charge de l’arret cardiaque – Rapport_ANM_30_01_07.pdf [Internet]. 2007;26:1008-19 [cite 5 nov 2017]. Disponible sur: http://www.cfrc.fr/documents/Rapport_ANM_30_01_07.pdf? PHPSESSID=62b42ed2ef1a6ff3bd0aa57f2fb9cfea.
21. Sandroni C, Cavallaro F, Antonelli M. Therapeutic hypothermia: is it effective for non-VF/VT cardiac arrest? Crit Care Lond Engl 19 Mars 2013;17(2):215.
22. Lindner KH, Dirks B, Strohmenger HU, Prengel AW, Lindner IM, Lurie KG. Randomised comparison of epinephrine and vasopressin in patients with out-of- hospital ventricular fibrillation. Lancet Lond Engl 22 Fevr 1997;349(9051):535-7.
23. Olasveengen TM, Sunde K, Brunborg C, Thowsen J, Steen PA, Wik L. Intravenous drug

    administration during out-of-hospital cardiac arrest: a randomized trial. JAMA 25 Nov 2009;302(20):2222-9.

    Gueugniaud PY, Mols P, Goldstein P, Pham E, Dubien PY, Deweerdt C, et al. A com- parison of repeated high doses and repeated standard doses of epinephrine for car- diac arrest outside the hospital. European Epinephrine Study Group. N Engl J Med 26 Nov 1998;339(22):1595-601.

24. Tang W, Weil MH, Sun S, Noc M, Yang L, Gazmuri RJ. Epinephrine increases the se- verity of postresuscitation myocardial dysfunction. Circulation 15 Nov 1995;92(10): 3089-93.
25. Angelos MG, Yeh ST, Aune SE. Post-cardiac arrest hyperoxia and mitochondrial func- tion. Resuscitation Dec 2011;82(Suppl 2):S48-51.
26. Ristagno G, Sun S, Tang W, Castillo C, Weil MH. Effects of epinephrine and vasopres- sin on cerebral microcirculatory flows during and after cardiopulmonary resuscita- tion. Crit Care Med Sept 2007;35(9):2145-9.
27. Funada A, Goto Y, Tada H, Teramoto R, Shimojima M, Hayashi K, et al. Duration of cardiopulmonary resuscitation in patients without prehospital return of spontane- ous circulation after out-of-hospital cardiac arrest: results from a severity stratifica- tion analysis. Resuscitation Mars 2018;124:69-75.
28. Cardarelli MG, Young AJ, Griffith B. Use of extracorporeal membrane oxygenation for adults in cardiac arrest (E-CPR): a meta-analysis of observational studies. ASAIO J Am Soc Artif Intern Organs 1992 Dec 2009;55(6):581-6.
29. Morimura N, Sakamoto T, Nagao K, Asai Y, Yokota H, Tahara Y, et al. Extracorporeal cardiopulmonary resuscitation for out-of-hospital cardiac arrest: a review of the Jap- anese literature. Resuscitation Janv 2011;82(1):10-4.
30. Ishaq M, Pessotto R. Might rapid implementation of cardiopulmonary bypass in pa- tients who are failing to recover after a cardiac arrest potentially save lives? Interact Cardiovasc Thorac Surg Oct 2013;17(4):725-30.
31. Pochmalicki G, Le Tarnec J-Y, Franchi J-P, Empana J-P, Genest M, Foucher R, et al. Management of sudden death in a semi-rural district, Seine-et-Marne: the DEFI 77 study. Arch Mal Coeur Vaiss Oct 2007;100(10):838-44.