RECOVER 2.0 Worksheet

QUESTION ID: ALS-19

PICO Question:
In cats and dogs with any cause of CPA (P) does any other atropine dosing interval (I) compared with atropine every 3-5 minutes (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):

1. Favorable neurologic outcome
2. Survival to discharge
3. ROSC
4. Surrogate markers of perfusion

Domain chairs: Gareth Buckley, Elizabeth Rozanski, Jake Wolf, final edits Dan Fletcher

Evidence evaluators: Nick Parkinson, Erin Binagia

Conflicts of interest: None

Search strategy: See attached 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 Neuro Outcome

1	CT	–	- -	–	0	0	0	0				there was no significant difference in outcome	Very low
Outcome: Survival to discharge
1	CT	–	- -	–	0	0	0	0				there was no significant difference in outcome	Very low
12	OB	0	–	–	-	0	0	0				Higher atropine doses associated with decreased survival to discharge	Very low
1	ES	0	–	–	-	0	0	0				Higher doses of atropine associated with higher mortality	Very low

Outcome: ROSC
1	CT	–	- -	–	0	0	0	0				there was no significant difference in outcome	Very low
5	OB	0	–	-	-	0	0	0				Atropine may be associated with ROSC; repeat dosing not evaluated	Very low
1	ES	0	–	–	-	0	0	0				Higher doses of atropine associated with higher mortality	Very low

Outcome: Surrogate markers - no evidence

PICO Question Summary

Introduction

Veterinary guidelines state that one may consider atropine administration at a dosing interval of every 3-5 minutes during CPR in patients with non-shockable arrest rhythms.1 There have been little data in veterinary medicine to support a specific dosing interval. The recommendation for atropine administration during CPR was removed from human CPR guidelines in 2010.2

Consensus on science

Outcome 1: Favorable Neurologic Outcome For the most critical outcome of favorable neurologic outcome, one clinical trial was identified (very low quality of evidence, downgraded for serious risk of bias, very serious indirectness, and serious imprecision). A study of 7,448 adults by the SOS-KANTO Study Group (2011) showed that epinephrine and atropine administration together resulted similar 30 day neurological outcome as epinephrine alone.3 Outcomes 2 and 3: Survival to Hospital Discharge and ROSC For the next most critical outcomes of survival to hospital discharge and ROSC, we identified 1 clinical trial (very low quality of evidence, downgraded for serious risk of bias, serious indirectness, and serious imprecision), 12 observational studies (downgraded for serious indirectness, serious imprecision, and serious inconsistency), and 1 experimental study (very low quality of evidence downgraded for very serious indirectness and imprecision).3–16 The clinical trial (adults with out-of-hospital cardiac arrest) and observational studies (5 in adults with out-of-hospital cardiac arrest, 1 in adults with in-hospital cardiac arrest, 1 in children with out-of-hospital cardiac arrest, and 5 in adults that either did not specify arrest location or included both in- and out-of-hospital cardiac arrest) were all in people. The experimental study was in mongrel dogs. Most studies evaluated the association of atropine administration with survival and did not specifically examine repeated atropine administration and its association with outcome. Chang et al. (2005) found in a study of 361 adults with out-of-hospital arrest in Taiwan that lower atropine dose was positively associated with survival to discharge.7 Similarly, a study of 159 adults who underwent CPR at a hospital in Pakistan found that a higher total atropine dose was associated with decreased survival to discharge (OR 0.68, 95%CI = 0.47 – 0.99, P=0.05).9 Agreeing with these findings, Dumot et al. (2001) found in a study of 445 adults who received advanced life support during CPR that atropine use was associated (p<0.01) with poor survival to discharge and administration of any atropine during resuscitation cut the survival rate in half.10 Additional atropine doses resulted in survival to hospital discharge rates of less than 5%. In this study, the number of atropine ampules administered to survivors was a quarter of that administered to non-survivors (0.4 v. 1.7 ampules). A study of 7,448 adults by the SOS-KANTO Study Group (2011) showed that epinephrine and atropine administration together resulted in higher ROSC than epinephrine alone for adults with asystole, but a similar 30 day neurological outcome was noted.3 However, in adults with pulseless electrical activity, the epinephrine with atropine group had a significantly lower survival than those who received epinephrine alone (P=0.02). In a study of adults with both in-hospital and out-of-hospital cardiac arrest by Stiell et al. (1995), no association was noted between atropine administration and ROSC or survival to discharge.15 However, administration of atropine during the fourth quartile of CPR was associated with improved ROSC. Behnke et al. (1995) showed in an experimental study in 75 mongrel dogs with an asphyxial model of pulseless electrical activity that the standard dose of atropine did not improve ROSC or survival compared with placebo and that higher doses of atropine tended to decrease ROSC.16

Treatment recommendation

We suggest against administering multiple doses of atropine (weak recommendation, very low quality of evidence).

Justification of treatment recommendation

There is little evidence for administration of atropine in humans with CPA, which led to its removal from the 2010 American Heart Association’s Advanced Cardiac Life Support guidelines.2 There is even less information on dosing frequency or total dosage of atropine administration in humans, though some data suggest a higher dose of atropine is associated with decreased survival in people and dogs. In addition, although the pharmacokinetics of intravenous atropine in dogs and cats have not been well studied, there is evidence that at a dose of 0.03mg/kg IV, heart rate remains elevated in dogs for 30 minutes after administration.17 In humans, the half life of IV atropine is approximately 4 hours.18 This suggests that repeated doses of atropine in dogs and cats could result in excessive plasma concentrations, which could lead to detrimental effects on myocardial oxygen consumption in the PCA period. The applicability to dogs and cats with cardiopulmonary arrest, however, is unknown. Based on the findings in human medicine, we suggest a weak recommendation against repeated atropine administration during cardiopulmonary resuscitation in dogs and cats.

Knowledge gaps

The appropriate dosing interval for atropine in dogs and cats in cardiopulmonary arrest is unknown. The necessity of atropine administration during cardiopulmonary arrest in dogs and cats is also unknown. It is unknown whether atropine administration and dosing during cardiopulmonary arrest should be based on the underlying disease process (e.g., arrests precipitated by increased vagal tone) or arrest rhythm.

References:

1. Fletcher DJ, Boller M, Brainard BM, et al. RECOVER evidence and knowledge gap analysis on veterinary CPR. Part 7: Clinical guidelines: RECOVER clinical guidelines. J Vet Emerg Crit Care. 2012;22(s1):S102-S131.

2. Field JM, Hazinski MF, Sayre MR, et al. Part 1: Executive Summary. Circulation. 2010;122(18_suppl_3):S640-S656.

3. The Survey of Survivors After Out-of Hospital Cardiac Arrest. Atropine Sulfate for Patients With Out-of-Hospital Cardiac Arrest due to Asystole and Pulseless Electrical Activity. Circ J. 2011;75(3):580-588.

4. Coon GA, Clinton JE, Ruiz E. Use of atropine for brady-asystolic prehospital cardiac arrest. Ann Emerg Med. 1981;10(9):462-467.

5. Yano T, Kawana R, Yamauchi K, Endo G, Nagamine Y. The Additive Effect of Atropine Sulfate during Cardiopulmonary Resuscitation in Out-of-hospital Non-traumatic Cardiac Arrest Patients with Non-shockable Rhythm. Intern Med. 2019;58(12):1713-1721.

6. Robinson S, Swain AH, Hoyle SR, Larsen PD. Survival from out-of-hospital cardiac arrest in New Zealand following the 2005 resuscitation guideline changes. Resuscitation. 2010;81(12):1648-1651.

7. Chang MY, Lin M. Predictors of survival and hospital outcome of prehospital cardiac arrest in southern Taiwan. J Formos Med Assoc. 2005;104(9):639-646.

8. Erenler AK, Çelik S, Baydin A, et al. Outcomes of cardiopulmonary resuscitation in trauma patients in the Emergency Department. Eur Rev Med Pharmacol Sci. 2015;19(14):2567-2571.

9. Ishtiaq O, Iqbal M, Zubair M, Qayyum R, Adil M. Outcome of cardiopulmonary resuscitation - predictors of survival. J Coll Physicians Surg Pak. 2008;18(1):3-7.

10. Dumot JA, Burval DJ, Sprung J, et al. Outcome of adult cardiopulmonary resuscitations at a tertiary referral center including results of “limited” resuscitations. Arch Intern Med. 2001;161(14):1751-1758.

11. Moler FW, Donaldson AE, Meert K, et al. Multicenter cohort study of out-of-hospital pediatric cardiac arrest. Crit Care Med. 2011;39(1):141-149.

12. Holmberg MJ, Moskowitz A, Wiberg S, et al. Guideline removal of atropine and survival after adult in-hospital cardiac arrest with a non-shockable rhythm. Resuscitation. 2019;137:69-77.

13. Herlitz J, Bång A, Gunnarsson J, et al. Factors associated with survival to hospital discharge among patients hospitalised alive after out of hospital cardiac arrest: change in outcome over 20 years in the community of Göteborg, Sweden. Heart. 2003;89(1):25-30.

14. van Walraven C, Stiell IG, Wells GA, Hébert PC, Vandemheen K. Do advanced cardiac life support drugs increase resuscitation rates from in-hospital cardiac arrest? The OTAC Study Group. Ann Emerg Med. 1998;32(5):544-553.

15. Stiell IG, Wells GA, Hebert PC, Laupacis A, Weitzman BN. Association of Drug Therapy with Survival in Cardiac Arrest: Limited Role of Advanced Cardiac Life Support Drugs. Acad Emerg Med. 1995;2(4):264-273.

16. Behnke DJD, Swart GL, Spreng D, Aufderheide TP. Standard and Higher Doses of Atropine in a Canine Model of Pulse less Electrical Activity. Acad Emerg Med. 1995;2(12):1034-1041.

17. Hendrix PK, Robinson E p. Effects of a selective and a nonselective muscarinic cholinergic antagonist on heart rate and intestinal motility in dogs. J Vet Pharmacol Ther. 1997;20(5):387-395.

18. Adams RG, Verma P, Jackson AJ, Miller RL. Plasma Pharmacokinetics of Intravenously Administered Atropine in Normal Human Subjects. J Clin Pharmacol. 1982;22(10):477-481.

Supplemental:

Outcome: Favorable neurologic outcome

0 Clinical Trials

0 Observational Studies

0 Experimental Studies

Outcome: Survival to Discharge

1 Clinical Trials

Coon et al (1981): Use of atropine for brady-asystolic prehospital cardiac arrest

● Prospective study in which people with PEA or asystole were either administered atropine (1 mg initially, repeated in 1 minute if no rhythm change) or non-atropine

● Not blinded, no placebo, the control group could receive calcium, steroid, isoproterenol, bicarbonate and atropine whereas study group received these only after atropine administration (all did receive initial dose of epinephrine and bicarbonate)

● Only 21 patients enrolled, only one patient survived to discharge

● Atropine made no difference in survival

12 Observational Studies

Yano et al (2019): The Additive Effect of Atropine Sulfate during Cardiopulmonary Resuscitation in Out-of-hospital Non-traumatic Cardiac Arrest Patients with Non-shockable Rhythm

● Retrospective observational study of patients over 5 year period

● Addition of atropine following epinephrine increased OR for survival to hospital admission for PEA and asystole when compared to epinephrine alone. However, only one patient had a good neuro outcome and 11 patients were alive and therefore binomial multivariate logistic regression analysis was not possible for 30 day survival or good 30 day neuro outcome

● More similar to atropine v. no atropine though repeat dosing was allowed and its inclusion up to 2 mg was potentially associated with predictor of survival to hospital admission

Robinson et al (2010): Survival from OHOCA in NZ following the 2005 resuscitation guideline changes

● Retrospective comparative study on OOHCA in NZ after removal of atropine for guidelines for CPR

● No significant difference in survival to hospital discharge following the change (increase in those who achieved ROSC)

● Improved survival to hospital admission but not to discharge

Chang et al (2005): Predictors of Survival and hospital outcome of prehospital cardiac arrest in southern Taiwan

● Retrospective review of OOHCA

● Lower atropine dose associated with survival to discharge

Erenler et al (2015): Outcomes of CPR in trauma patients in the ED

● Retrospective collection of data from trauma patients who required CPR

● No difference in survival with atropine administration

Ishtiaq et al (2008): Outcome of CPR - Predictors of survival

● All adult patients who underwent CPR in Pakistan

● Total atropine dose associated with decreased survival to discharge (p=0.05) during univariate logistic regression analysis

● Only 17 patients discharged alive from hospital

Duomo et al (2001): Outcome of adult CPR at a tertiary referral center including results of limited resuscitations

● Statistical analysis of 445 prospectively recorded resuscitation records of patients who received ALS

● Atropine use associated with poor immediate and hospital discharge survival on multivariate analysis (p<0.01)

● Administration of any atropine during resuscitation cut survival rate in half

● Additional atropine doses resulted in survival to hospital discharge of less than 5%

Moler et al (2011): Multicenter cohort study of OOH pediatric cardiac arrest

● retrospective cohort study at 15 clinical sites

● Multivariate analysis: administration of atropine associated with mortality

● No discussion about repeated dosages

Holmberg et al (2019): Guideline removal of atropine and survival after adult in-hospital cardiac arrest with non-shockable rhythm

● adults with in hospital cardiac arrest between 2006-2015 and asystole or PEA

● No change in survival after removal of atropine from guidelines in 2010

Herlitz et al (2003): Factors associated with survival to hospital discharge among patients hospitalized alive after OOHCA

● Retrospective analysis of prospectively recorded patient data in Sweden who experienced OOHCA

● Those who “required” atropine in the ED had a lower survival (p<0.01) in multivariate analysis

van Walraven et al (1998): Do Advanced cardiac life support drugs increase resuscitation rates from IHCA?

● Prospective cohort of patients undergoing cardiac arrest in hospital

● At 1 hour after survival, administration of atropine was associated with higher mortality (including when controlling for arrest rhythm; p<0.01)

SOS-KANTO Study Group (2011): Atropine sulfate for patients with OOHCA due to asystole and PEA

● Retrospective review of SOS-Kanto study

● Epi with atropine had significantly higher ROSC than epi alone, but similar 30 day neuro outcome. In PEA, the epi with atropine group had significantly lower 30 day survival than epi alone (p=0.02)

Stiell et al (1995): Association of drug therapy with survival in cardiac arrest

● Observational cohort study in two tertiary hospitals of adults who suffered either in or OOH cardiac arrest

● Univariate analysis revealed no association between atropine administration and resuscitation or discharge

● Administration of atropine during the fourth quartile of CPR was associated with initial resuscitation

1 Experimental Studies

Behnke et al (1995): Standard and Higher Doses of atropine in a canine model of PEA

● Experimental study in mongrel dogs in which asphyxial model of PEA created (75 dogs untreated PEA for 10 minutes)

● Randomized to receive placebo and one of four doses of atropine (single dose)

● All received mechanical external CPR and epinephrine every 3 minutes

● Standard dose atropine did not improve ROSC compared with placebo and increasing doses tended to decrease ROSC

Outcome: ROSC

1 Clinical Trials

Coon et al (1981): Use of atropine for brady-asystolic prehospital cardiac arrest

● Prospective study in which people with PEA or asystole were either administered atropine (1 mg initially, repeated in 1 minute if no rhythm change) or non-atropine

● Not blinded, no placebo, the control group could receive calcium, steroid, isoproterenol, bicarbonate and atropine whereas study group received these only after atropine administration (all did receive initial dose of epinephrine and bicarbonate)

● Only 21 patients enrolled, only one patient survived to discharge

● Atropine made no difference in survival

5 Observational Studies

Holmberg et al (2019): Guideline removal of atropine and survival after adult in-hospital cardiac arrest with non-shockable rhythm

● adults with in hospital cardiac arrest between 2006-2015 and asystole or PEA

● No change in ROSC after removal of atropine from guidelines in 2010

1 Experimental Studies

Behnke et al (1995): Standard and Higher Doses of atropine in a canine model of PEA

● Experimental study in mongrel dogs in which asphyxial model of PEA created (75 dogs untreated PEA for 10 minutes)

● Randomized to receive placebo and one of four doses of atropine (single dose)

● All received mechanical external CPR and epinephrine every 3 minutes

● Standard dose atropine did not improve ROSC compared with placebo and increasing doses tended to decrease ROSC

Robinson et al (2010): Survival from OHOCA in NZ following the 2005 resuscitation guideline changes

● Retrospective comparative study on OOHCA in NZ after removal of atropine for guidelines for CPR

● Trend towards higher ROSC without atropine use

Vanags et al (1989): Interventions in the therapy of electromechanical dissociation

● Adults with non-traumatic non-poisoning CPA with initial rhythm of EMD

● Atropine administered to 22% of patients

● Atropine associated with attainment of a pulse in EMD

SOS-KANTO Study Group (2011): Atropine sulfate for patients with OOHCA due to asystole and PEA

● Retrospective review of SOS-Kanto study

● Multivariate analysis showed that administration of atropine was independent predictor of ROSC with asystole but not with PEA

Stiell et al (1995): Association of drug therapy with survival in cardiac arrest

● Observational cohort study in two tertiary hospitals of adults who suffered either in or OOH cardiac arrest

● Univariate analysis revealed no association between atropine administration and resuscitation or discharge

● Administration of atropine during the fourth quartile of CPR was associated with initial resuscitation

Outcome: Surrogate markers of perfusion

0 Clinical Trials

0 Observational Studies

0 Experimental Studies