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Comments:

ALS-08-v1

RECOVER 2.0 Worksheet

QUESTION ID: ALS-08

PICO Question:
In cats and dogs with CPA (P) does the use of high dose epinephrine (0.1mg/kg IV) (I) compared to standard dose epinephrine (0.01mg/kg IV) (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 completed by Jamie Burkitt)

Evidence evaluators: Lindsey Strang, Erik Zager

Conflicts of interest: None reported

Search strategy: See attached document

Evidence Review:

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

2	EXPT	0	- -	0	0	0	0	0	Very low
Outcome: Survival to Discharge

- -

Low quality

EXPT

- -

Very low quality

Outcome: ROSC

- -

Very low

EXPT

Low

PICO Question Summary

Introduction

Limited evidence is available to determine the ideal dose of epinephrine during CPR in dogs and cats. Experimental and limited clinical evidence have suggested that high-dose epinephrine (~ 0.1 mg/kg) may improve chances of ROSC but may worsen survival or neurologic outcome when compared to low- (standard-) dose epinephrine (~ 0.01 mg/kg).1 Examination of literature surrounding this PICO question aimed to determine whether there is a benefit to routine use of high-dose epinephrine (as opposed to low-dose) in CPR in dogs and cats.

Consensus on science

Outcome 1: Favorable neurologic outcome

For the most critical outcome of favorable neurologic outcome, we identified 4 clinical trials (low quality of evidence, downgraded for very serious indirectness) and 2 experimental studies (very low quality of evidence, downgraded for very serious indirectness) that addressed the PICO.2–7 All 4 clinical trials investigated OHCA in human adults; the largest included 3327 people and all 4 combined contained ~5500 subjects. None of the 4 trials showed improvement in neurologic outcome at discharge when comparing high-dose epinephrine to standard, low-dose epinephrine. One trial containing only 816 people suggested a trend toward worse FNO with high-dose epinephrine.2 Both experimental studies that addressed FNO were in swine, and neither found a difference in FNO at 24 hours when comparing high-dose to standard-dose epinephrine; both studies used 0.2 mg/kg as “high dose” and 0.02 mg/kg as “low dose.”

Outcome 2: Survival to discharge

For the next most critical outcome of survival to discharge, we identified 6 clinical trials (low quality of evidence, downgraded for very serious indirectness) and 3 experimental studies (very low quality of evidence, downgraded for very serious indirectness) that addressed the PICO question.2–10 The 2 clinical trials here that were not listed under FNO were small, and together contributed only ~600 additional people, 68 of which were pediatrics with IHCA. Five of 6 trials found no benefit to high-dose epinephrine compared to low-dose epinephrine on survival to discharge. One trial in children with IHCA showed worse neurologic status at 24 hours post-CPR with high-dose compared to low-dose epinephrine, and no children in the high-dose group survived to discharge compared to 4 children in the low-dose epinephrine group.8 Three experimental studies, 2 in swine and 1 in dogs found no improvement in 24-hour survival (swine) or 2-hour survival (dogs) when high-dose was compared to low-dose epinephrine.6,7,10

Outcome 3: ROSC

We identified 6 clinical trials (very low quality of evidence, downgraded for very serious indirectness and serious inconsistency) and 6 experimental studies (low quality of evidence, downgraded for serious indirectness) that addressed the next critical outcome of ROSC.2–13 Two of the clinical trials, one of which was the largest trial including 3327 adults with OHCA found that high-dose epinephrine improved ROSC compared to low-dose epinephrine, while the other 4 trials failed to find a difference.2,5 Of the 6 experimental trials, none found an improvement in ROSC with use of high-dose compared to low-dose epinephrine; 3 studies were performed in dogs and one in cats. Despite this, 2 of the canine studies found that ROSC was achieved more quickly with high-dose epinephrine than with low-dose epinephrine.10,13

Treatment recommendation

We recommend against the routine use of high-dose epinephrine during CPR in dogs and cats (strong recommendation, low quality of evidence).

Justification of treatment recommendation

There is no evidence for the routine use of high-dose epinephrine to improve neurologic outcome or survival in dogs, cats, or other species, and some limited information in people suggests worse neurologic outcome and short-term (24h) survival with high doses. There is inconsistent evidence for improvement in ROSC with use of high-dose epinephrine in people, and no evidence for improvement in ROSC in experimental models in dogs, cats, or swine.

Knowledge gaps

There are no observational studies or clinical trials in the target species to investigate the possible utility of high-dose epinephrine in dogs and cats.

References:

1. Vandycke C, Martens P. High dose versus standard dose epinephrine in cardiac arrest - a meta-analysis. Resuscitation. 2000;45(3):161-166.

2. Callaham M, Madsen CD, Barton CW, Saunders CE, Pointer J. A randomized clinical trial of high-dose epinephrine and norepinephrine vs standard-dose epinephrine in prehospital cardiac arrest. JAMA. 1992;268(19):2667-2672.

3. Brown CG, Martin DR, Pepe PE, et al. A comparison of standard-dose and high-dose epinephrine in cardiac arrest outside the hospital. The Multicenter High-Dose Epinephrine Study Group. N Engl J Med. 1992;327(15):1051-1055.

4. Stiell IG, Hebert PC, Weitzman BN, et al. High-Dose Epinephrine in Adult Cardiac Arrest. New England Journal of Medicine. 1992;327(15):1045-1050.

5. Gueugniaud PY, Mols P, Goldstein P, et al. A comparison of repeated high doses and repeated standard doses of epinephrine for cardiac arrest outside the hospital. European Epinephrine Study Group. N Engl J Med. 1998;339(22):1595-1601.

6. Berg RA, Otto CW, Kern KB, et al. A randomized, blinded trial of high-dose epinephrine versus standard-dose epinephrine in a swine model of pediatric asphyxial cardiac arrest. Crit Care Med. 1996;24(10):1695-1700.

7. Berg RA, Otto CW, Kern KB, et al. High-dose epinephrine results in greater early mortality after resuscitation from prolonged cardiac arrest in pigs: a prospective, randomized study. Crit Care Med. 1994;22(2):282-290.

8. Perondi MBM, Reis AG, Paiva EF, Nadkarni VM, Berg RA. A comparison of high-dose and standard-dose epinephrine in children with cardiac arrest. N Engl J Med. 2004;350(17):1722-1730.

9. Choux C, Gueugniaud PY, Barbieux A, et al. Standard doses versus repeated high doses of epinephrine in cardiac arrest outside the hospital. Resuscitation. 1995;29(1):3-9.

10. Angelos MG, DeBehnke DJ. Epinephrine and high-flow reperfusion after cardiac arrest in a canine model. Ann Emerg Med. 1995;26(2):208-215.

11. Roberts D, Landolfo K, Dobson K, Light RB. The effects of methoxamine and epinephrine on survival and regional distribution of cardiac output in dogs with prolonged ventricular fibrillation. Chest. 1990;98(4):999-1005.

12. Schmitz B, Fischer M, Bockhorst K, Hoehn-Berlage M, Hossmann KA. Resuscitation from cardiac arrest in cats: influence of epinephrine dosage on brain recovery. Resuscitation. 1995;30(3):251-262.

13. Brunette DD, Jameson SJ. Comparison of standard versus high-dose epinephrine in the resuscitation of cardiac arrest in dogs. Ann Emerg Med. 1990;19(1):8-11.

Supplemental:

803: Berg RA, Otto CW, Kern KB, et al. A randomized, blinded trial of high-dose epinephrine versus standard-dose epinephrine in a swine model of pediatric asphyxia cardiac arrest. Crit Care Med 1996;24:1695-1700.

805: Perondi MBM, Reis AG, Paiva EF, et al. A comparison of high-dose and standard-dose epinephrine in children with cardiac arrest. N Engl J Med 2004;350:1722-1730.

1003: Callaham M, Madsen CD, Barton CW, et al. A randomized clinical trial of high-dose epinephrine and norepinephrine vs standard-dose epinephrine in prehospital cardiac arrest. JAMA 1992;268(19):2667-2672.

1004: Brown CG, Martin DR, Pepe PE, et al. A comparison of standard-dose and high-dose epinephrine in cardiac arrest outside the hospital. N Engl J Med 1992;327:1051-1055.

1005: Choux C, Gueugniaud P, Barbieux A, et al. Standard doses versus repeated high doses of epinephrine in cardiac arrest outside the hospital. Resuscitation 1995;29:3-9.

1006: Stiell IG, Hebert PC, Weitzman BN, et al. High-dose epinephrine in adult cardiac arrest. N Engl J Med 1992;327:1045-1050.

1007: Gueugniaud P, Mols P, Goldstein P, et al. A comparison of repeated high doses and repeated standard doses of epinephrine for cardiac arrest outside the hospital. N Engl J Med 1998;339:1595-1601.

1016: Roberts D, Landolfo K, Dobson K, Light RB. The effects of methoxamine and epinephrine on survival and regional distribution of cardiac output in dogs with prolonged ventricular fibrillation. Chest 1990;98:999-1005.

1018: Schmitz B, Fischer M, Bockhorst K, et al. Resuscitation from cardiac arrest in cats: influence of epinephrine dosage on brain recovery. Resuscitation 1995;30:251-262.

1020: Brunette DD, Jameson SJ. Comparison of standard versus high-dose epinephrine in the resuscitation of cardiac arrest in dogs. Ann Emerg Med 1990;19:8-11.

1021: DeBehnke DJ, Angelos MG, Leasure JE. Use of cardiopulmonary bypass, high-dose epinephrine, and standard-dose epinephrine in resuscitation from post-countershock electromechanical dissociation. Ann Emerg Med 1992;21:1051-1057.

1022: Berg RA, Otto DW, Kern KB, et al. High-dose epinephrine results in greater early mortality after resuscitation from prolonged cardiac arrest in pegis: A prospective, randomized study. Crit Care Med 1994;22:282-290.

1023: Angelos MG, DeBehnke DJ. Epinephrine and high-flow reperfusion after cardiac arrest in a canine model. Ann Emerg Med 1995;26:208-215.

PaperID	Citation	N	Pop’n	Scene	HDE / LDE	HDE: Impv FNO	HDE: Impv Surv-timept	HDE: Impv ROSC	Comments
CT
805	Perondi 2004	68	P	IHCA	0.1mg/kg / 0.01 mg/kg	N/A	WORSE – 24h (UTE d/c)	NO	Sixty-eight kids; HDE worse survival 24h (& d/c)
1003	Callaham 1992	816	A	OHCA	15 / 1	NO (“trend” toward worse outcome)	NO	YES	P = 0.1 for worse FNO w HDE
1004	Brown 1992	1280	A	OHCA	.2mg/kg / .02mg/kg	NO	NO	NO	HDE showed some benefit specifically in PEA
1005	Choux 1995	536	A	OHCA	5 / 1	N/A	NO	NO	Neuro was evaluated but unclear that stats were done – not used for FNO
1006	Stiell 1992	650	A (16+)	About half/half OHCA / IHCA	7 / 1	NO - Discharge	NO - Discharge	NO
1007	Gueugniaud 1998	3327	A	OHCA	5 / 1	NO - Discharge	NO - Discharge	YES	HDE helped ROSC in asystole but not V-Fib
Expt
803	Berg 1996	30	Piglets	Expt	0.2mg/kg / 0.02mg/kg	NO	NO – 24 hour	NO
1016	Roberts 1990	24	Canine	Expt	.2 mg/kg / .02 mg/kg	N/A	N/A	NO	Tangential … ? No defib for 25min CC-CPR till then.
1018	Schmitz 1995	14	Feline	Expt	.2mg/kg / .02mg/kg	N/A*	N/A	NO	*MRI at 3 hours: no diff HDE / SDE. Time to ROSC same.
1020	Brunette 1990	25	Canine	Expt	0.014mg/kg / .071mg/kg	N/A	N/A	NO	ROSC faster w HDE than SDE.
1022	Berg 1994	30	Swine	Expt	0.2mg/kg / 0.02mg/kg	NO – 24 hour	NO – 24 hour	NO	HDE had worse survival in “ICU period” than SDE
1023	Angelos 1995	30	Canine	Expt	0.2mg/kg / 0.02mg/kg	N/A	NO – two hour	NO	More rapid ROSC w HDE, but no apparent comparison ROSC (Y vs N) between HDE & SDE

DMU Timestamp: July 13, 2023 21:18