Document: Invite

Comments:

ALS-06-v1

RECOVER 2.0 Worksheet

QUESTION ID: ALS-06

PICO Question:
In cats and dogs with CPA and non-shockable arrest rhythms (P) does administration of no epinephrine (I) compared to administration of epinephrine (C) improve outcome (O)?

Outcomes:
Favorable neurologic outcome, surrogate marker(s) of perfusion, survival to discharge, ROSC

Prioritized Outcomes (1= most critical; final number = least important):

Favorable neurologic outcome
Survival to discharge
ROSC
Surrogate markers of perfusion

Domain chairs: Gareth Buckley, Elizabeth Rozanski; this evidence summary by Jamie Burkitt

Evidence evaluators: Mariko St James, Jake Wolf

Conflicts of interest: None reported

Search strategy: See attached document

Evidence Review:

Add rows to the table to incorporate all outcomes evaluated as part of the evidence review and all study types. You can use this template to add a new outcome by copying and pasting it to the end of the table. Once you have completed your review, please delete this template from the document.

Study Design

Reduced Quality Factors

0 = no serious, - = serious,

- - = very serious

Positive Quality Factors

0 = none, + = one, ++ = multiple

Dichotomous Outcome Summary

Non-Dichotomous Outcome Summary

Brief description

Overall Quality

High, moderate, low,
very low, none

No of studies

Study Type

RoB

Indirectness

Imprecision

Inconsistency

Large Effect

Dose-Response

Confounder

# Intervention with Outcome

# Control with Outcome

RR (95% CI)

Outcome: Favorable Neurologic Outcome

- -

Low

OBS

- -

Very low

Outcome: Survival to Discharge

- -

Low

OBS

- -

Very low

Outcome: ROSC

- -

Moderate

OBS

- -

Very low

PICO Question Summary

Introduction

Low-dose epinephrine (0.01 mg/kg) is recommended during advanced life support CPR for non-shockable rhythms in dogs and cats.1 However, there is little evidence to support the use of epinephrine in dogs and cats undergoing CPR for non-shockable rhythms outside the research setting. In particular, there is little and conflicting evidence regarding the impact of epinephrine use on the most critical outcomes of favorable neurologic outcome and survival to hospital discharge. This PICO question investigated the utility of epinephrine for non-shockable arrest rhythms in dogs and cats.

Consensus on science

We identified 2 clinical trials and 8 observational studies that addressed the PICO question.

Outcome 1: Favorable Neurologic Outcome:

For the most critical outcome of FNO, 1 clinical trial (PARAMEDIC2; low quality evidence downgraded for very serious indirectness) reported results over 3 papers.2–4 This trial evaluated the use of low-dose epinephrine compared to placebo in 8,014 adult human beings experiencing out-of-hospital cardiopulmonary arrest that did not respond to initial CPR and defibrillation if appropriate; 79% of people initially had a non-shockable rhythm (unclear if this was from time of first responder arrival or if this was at time of randomization/inclusion). The PARAMEDIC2 trial found no treatment benefit of epinephrine compared to placebo for FNO at hospital discharge or at 6 months. Six observational studies were identified (very low-quality evidence, downgraded for serious risk of bias, very serious indirectness, serious imprecision, and very serious inconsistency) that addressed the PICO question for the outcome of FNO.5–10 The largest of these studies included 383,811 adult human beings experiencing out-of-hospital cardiac arrest, 93% of which had a non-shockable rhythm at time of inclusion.10 This large observational study found no benefit to FNO with epinephrine treatment at 1 month, with the exception of the group in which CPR lasted for 15-19 minutes, in which epinephrine improved FNO compared to non-treatment (OR 1.327, 95% CI 1.017-1.733). The next largest study included 110,239 adults experiencing OHCA, 100% of whom had a non-shockable rhythm; this study found an association between epinephrine use and FNO at the earlier of 1 month or hospital discharge.7 Using propensity matching, the improvement in FNO with epinephrine was not appreciated in patients with PEA (7431 pairs; OR 1.26, 95% CI 0.86-1.85), but was noted in patients with asystole (8906 pairs; OR 2.89, 95% CI 1.42-6.05). However, the only relevant study identified that evaluated IHCA included 6033 adults undergoing in-hospital arrest, 77% of whom had a non-shockable rhythm.6 In this study of IHCA, epinephrine administration was negatively associated with FNO (i.e., receiving epinephrine was associated with a worse neurologic recovery than not receiving it) at discharge; authors noted concern for confounding by indication for these unexpected results, though most other studies on this subject are in a different patient set (OHCA victims).

Outcome 2: Survival to Discharge:

For the second most critical outcome of survival to discharge, we identified 2 clinical trials (low quality evidence, downgraded for very serious indirectness, imprecision, and inconsistency) that addressed the PICO question. The clinical trial PARAMEDIC2 (see above) found that epinephrine improved survival to discharge and to 12 months compared to placebo.2,4 In a smaller clinical trial of 601 adults with OHCA (only 48% of which had non-shockable rhythms) there was no improvement in survival to discharge with epinephrine compared to placebo.11 Eight observational studies (very low quality evidence downgraded for very serious indirectness, serious imprecision, and inconsistency) showed mixed results regarding epinephrine use and survival to discharge for adults suffering OHCA, 68-100% of whom had non-shockable rhythms. The 2 largest studies in adults (383,811 and 110,239 subjects) suffering OHCA, 93-100% of whom had non-shockable rhythms, both showed improvement in survival to 1 month (or discharge, if earlier, in Tomio) with epinephrine compared to no epinephrine.7,10 Four smaller observational studies, all in adult OHCA with 68-92% non-shockable rhythms, showed mixed results with the largest (41,383 people in Fujii) showing a 1-month survival benefit with epinephrine and the 3 others (total fewer than 7,000 people) showing either no survival benefit (2 studies) or worse survival (1 study) with epinephrine use compared to none.8,9,12,13 The single study in adult IHCA (6033 subjects) found a negative association between the use of epinephrine and survival to discharge and 30 days.6 Finally, the single pediatric study in 3961 children, 92% of which had non-shockable rhythms, found no treatment benefit with epinephrine at 1 month.5

Outcome 3: Return of Spontaneous Circulation:

For the outcome of ROSC, both clinical trials and 7/8 above observational studies found treatment benefit with epinephrine compared to placebo or none, respectively.

Treatment recommendation

We recommend the use of epinephrine for non-shockable rhythms during CPR in dogs and cats (strong recommendation, low quality of evidence).

Justification of treatment recommendation

The largest clinical trial and two very large observational studies totaling nearly half a million adult human beings support the use of epinephrine in patients in cardiopulmonary arrest with non-shockable rhythms.

Knowledge gaps

There were no studies identified in dogs and cats in the clinical setting to support or reject the use of epinephrine during CPR for non-shockable rhythms. Given the evidence available, the committee believes that a placebo-controlled trial of vasopressor administration in dogs and cats with non-shockable arrest rhythms is not justifiable. However, a trial comparing vasopressors strategies could be of value.

References:

1. Fletcher DJ, Militello R, Schoeffler GL, Rogers CL. Development and evaluation of a high-fidelity canine patient simulator for veterinary clinical training. J Vet Med Educ. 2012;39(1):7-12.

2. Perkins GD, Ji C, Deakin CD, et al. A randomized trial of epinephrine in out-of-hospital cardiac arrest. New England Journal of Medicine. 2018;379(8):711-721.

3. Perkins GD, Kenna C, Ji C, et al. The influence of time to adrenaline administration in the Paramedic 2 randomised controlled trial. Intensive Care Med. 2020;46(3):426-436.

4. Haywood KL, Ji C, Quinn T, et al. Long term outcomes of participants in the PARAMEDIC2 randomised trial of adrenaline in out-of-hospital cardiac arrest. Resuscitation. 2021;160:84-93.

5. Matsuyama T, Komukai S, Izawa J, et al. Pre-Hospital Administration of Epinephrine in Pediatric Patients With Out-of-Hospital Cardiac Arrest. J Am Coll Cardiol. 2020;75(2):194-204.

6. Lundin A, Rylander C, Karlsson T, Herlitz J, Lundgren P. Adrenaline, ROSC and survival in patients resuscitated from in-hospital cardiac arrest. Resuscitation. 2019;140:64-71.

7. Tomio J, Nakahara S, Takahashi H, et al. Effectiveness of Prehospital Epinephrine Administration in Improving Long-term Outcomes of Witnessed Out-of-hospital Cardiac Arrest Patients with Initial Non-shockable Rhythms. Prehosp Emerg Care. 2017;21(4):432-441.

8. Fujii T, Kitamura T, Kajino K, et al. Prehospital intravenous access for survival from out-of-hospital cardiac arrest: propensity score matched analyses from a population-based cohort study in Osaka, Japan. BMJ Open. 2017;7(12):e015055.

9. Hayakawa M, Gando S, Mizuno H, et al. Effects of epinephrine administration in out-of-hospital cardiac arrest based on a propensity analysis. J Intensive Care. 2013;1(1):12.

10. Ono Y, Hayakawa M, Wada T, Sawamura A, Gando S. Effects of prehospital epinephrine administration on neurological outcomes in patients with out-of-hospital cardiac arrest. J Intensive Care. 2015;3(1):29.

11. Jacobs IG, Finn JC, Jelinek GA, Oxer HF, Thompson PL. Effect of adrenaline on survival in out-of-hospital cardiac arrest: A randomised double-blind placebo-controlled trial. Resuscitation. 2011;82(9):1138-1143.

12. Yamamoto R, Suzuki M, Hayashida K, et al. Epinephrine during resuscitation of traumatic cardiac arrest and increased mortality: a post hoc analysis of prospective observational study. Scand J Trauma Resusc Emerg Med. 2019;27(1):74.

13. Aoki M, Abe T, Oshima K. Association of Prehospital Epinephrine Administration With Survival Among Patients With Traumatic Cardiac Arrest Caused By Traffic Collisions. Sci Rep. 2019;9(1):9922.

Supplemental:

PaperID	Citation	N	Age	Scene	%NS Rthm	Epi Impv FNO	Epi Impv Surv-timept	Epi Impv ROSC	Comments
CT
2413	Perkins 2018 PARAMEDIC2	8014*	A	OHCA	79	NO - Discharge	YES - Discharge	YES	Baselines similar, including bystander CPR, rhythm
2414	Jacobs 2011	601	A	OHCA	48	N/A	No – Discharge	YES	Only 2 survivors had unfavorable neuro outcome – both got epi.
2437	Haywood 2021 PARAMEDIC2	8014*	A	OHCA	79	NO – 6 months	YES – to 12 months	N/A	Same subjects as 2413 Neuro: modified Rankin Scale score
2416	Perkins 2020 PARAMEDIC2	4810*	A	Wn’ed OHCA	75	NO - Discharge	NO – 30 days and Discharge	YES	Same subjects as 2413. Time to epi – the longer the CPR effort, the more beneficial epi is. Long-term outcomes not affected by epi.
OBS
2423	Lundin 2019	6033	A	IHCA – 81% witnessed	77	WORSE – Discharge	WORSE – 30 days and Discharge	WORSE w / epi for all rhythms	Table 2. Receiving epi was associated with worse everything.
2433	Tomio 2017	110,239	A	OHCA	100	YES – earlier of 1m or Discharge	YES – earlier of 1m or Discharge	N/A	Helped more in asystole than PEA
2445	Hayakawa 2013	633	A	OHCA – bystanders	~80	NO – 30 days	NO – 30 days	YES	Propensity analysis; some further analyses re: timing.
2446	Ono 2015	383,811	A	OHCA	93	NO* – 1 month	YES – 1 month	YES	*For CPR duration 15-19 minutes, epi improved FNO
2417	Matsuyama 2020	3961	P	OHCA	92	NO – 1 month	NO – 1 month	YES	All peds.
2436	Fujii 2017	41383	A	OHCA	92	YES – 1 month	YES – 1 month	YES	Table 3
2426	Aoki 2019	5204	>95% A	T-OHCA	92	N/A	NO – 1 month	YES	Figures 2 and 3. All traumatic OHCA, v few kids
2421	Yamamoto 2019	1030	A	T-OHCA	~68%	N/A	WORSE – 7 days	YES	All traumatic OHCA, as young as 15yo.

Manuscripts:

Clinical Trials:

(Perkins et al 2018; paper 2413): Perkins GD, Ji C, Deakin CD, et al. A randomized trial of epinephrine in out-of-hospital cardiac arrest. N Engl J Med 2018;379(8):711-721. – PARAMEDIC2 trial;

(Jacobs et al 2011; paper 2414): Jacobs IG, Finn JC, Jelinek GA, et al. Effect of adrenaline on survival in out-of-hospital cardiac arrest: A randomized double-bling placebo-controlled trial. Resuscitation 2011;821138-1143.

(Haywood et al 2021; paper 2437): Haywood KL, Ji C, Quinn T, et al. Long term outcomes of participants in the PARAMEDIC2 randomised trial of adrenaline in out-of-hospital cardiac arrest. Resuscitation 2021;160:84-93.

(Perkins et al 2020; paper 2416): Perkins GD, Kenna C, Ji C, et al. The influence of time to adrenaline administration in the Paramedic 2 randomised controlled trial. Intensive Care Med 2020;46:426-436.

Observational:

(Lundin A et al 2019; paper 2423): Lundin A, Rylander C, Karlsson T, et al. Adrenaline, ROSC and survival in patients resuscitated from in-hospital cardiac arrest. Resuscitation 2019;140:64-71. – For nonshockable rhythms epi was associated with better ROSC, but negatively associated with 30 day survival. Those that lived to 30 days had good neuro outcome in general.

(Tomio et al 2017; paper 2433): Tomio J, Nakahara S, Takahashi H, et al. Effectiveness of prehospital epinephrine administration in improving long-term outcomes of witnessed out-of-hospital cardiac arrest patients with initial non-shockable rhythms. Prehosp Emerg Care 2017;21:432-441.

(Hayakawa et al 2013, paper 2445): Hayakawa M, Gando S, Mizuno H, et al. Effects of epinephrine administration in out-of-hospital cardiac arrest based on a propensity analysis. J Intensive Care 2013;1:12. DOI: https://doi.org/10.1186/2052-0492-1-12

(Ono et al 2015, paper 2446): Ono Y, Hayakawa M, Wada T, et al. Effects of prehospital epinephrine administration on neurological outcomes in patients with out-of-hospital cardiac arrest. J Intensive Care 2015:3:29. DOI: 10.1186/s40560-015-0094-3

(Matsuyama et al 2020, paper 2432): Matsuyama T, Komukai S, Izawa J, et al. Pre-hospital administration of epinephrine in pediatric patients with out-of-hospital cardiac arrest. J Am Coll Cardiol 2020;75:194-204.

(Fujii et al 2017, paper 2436): Fujii T, Kitamura T, Kajino K, et al. Prehospital intravenous access for survival from out-of-hospital cardiac arrest: propensity score matched analyses from a population-based cohort study in Osaka, Japan. BMJ Open 2017;7:e015055

(Aoki et al 2019, paper 2426): Aoki M, Abe T, Oshima K. Association of prehospital epinephrine administration with survival among patients with traumatic cardiac arrest caused by traffic collisions. Sci Rep 2019;9:9922. DOI: 10.1038/s41598-019-46460-w

(Yamamoto et al 2019, paper 2421): Yamamoto R, Suzuki M, Hayashida K, et al. Epinephrine during resuscitation of traumatic cardiac arrest and increased mortality: a post hoc analysis of prospective observational study. Scand J Trauma Resusc Emerg Med 2019;27(1):74. DOI: 10.1186/s13049-019-0657-8

DMU Timestamp: July 13, 2023 21:18