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ALS-02-v1

RECOVER 2.0 Worksheet

QUESTION ID: ALS-02

PICO Question:
In cats and dogs with a shockable rhythm that are being defibrillated (P), does the use of amiodarone (I) compared to not using amiodarone (C) improve outcome?

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 (Fletcher), Jake Wolf

Evidence evaluators: Alexander Thomson, Joseph DeFulio

Conflicts of interest: None

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
3	CT	0	-	0	0	0	0	0					Moderate
2	OS	0	-	-	0	0	0	0					Very low
0	ES
Outcome: Survival to discharge
3	CT	0	-	0	0	0	0	0					Moderate
8	OS	0	-	-	-	0	0	0					Low
4	ES	0	-	-	-	0	0	0					Low
Outcome: ROSC
1	CT	0	-	0	0	0	0	0					Moderate
2	OS	0	-	0	0	0	0	0					Very low
7	ES	0	-	-	-	0	0	0					Very low
Outcome: Surrogate markers of perfusion
0	CT
0	OS
11	ES	0	-	-	-	0	0	0					Very low

PICO Question Summary

Introduction

The gold-standard for treatment of PVT and VF is basic life support and defibrillation. However, the role of adjunctive therapies for shock-resistant PVT or VF is unclear. Current veterinary guidelines state that in dogs with shock-resistant PVT or VF, amiodarone may be considered.1 In human medicine, the role of antiarrhythmics (amiodarone, lidocaine, bretylium, nifekalant, etc.) during CPR remains unclear. This PICO question investigated whether amiodarone is efficacious as adjunctive therapy in dogs and cats with shockable arrest rhythms.

Consensus on science

Outcome 1: Favorable neurologic outcome

For the most critical outcome of favorable neurologic outcome, 3 clinical trials in adult humans (moderate quality of evidence downgraded for serious indirectness) and 2 observational studies, one in children and one in adult humans, were identified (very low quality of evidence downgraded for serious indirectness and imprecision).2–6 The clinical trials were double-blinded and evaluated adults with non-traumatic out-of-hospital cardiac arrest and shock-refractory VF or PVT (defined as persistent or recurrent shockable rhythms after one or more shocks anytime during resuscitation). Patients were randomized to receive amiodarone, lidocaine, or placebo following vasopressor administration. Neither amiodarone nor lidocaine resulted in a more favorable neurologic outcome compared to placebo.2–4 The observational studies found no difference between lidocaine and amiodarone for favorable neurologic outcome with refractory PVT or VF; however, no control group was used in these studies.5,6 One study showed increased defibrillation success after 3 shocks in patients receiving amiodarone compared to patients receiving lidocaine.6

Outcome 2: Survival to discharge

For the second most critical outcome of survival to discharge, the same 3 clinical trials in adults were identified. In addition, 8 observational studies in humans (very low quality of evidence downgraded for serious indirectness) and four experimental studies in pigs (low quality of evidence downgraded for serious indirectness and imprecision) were identified.5–16 One of the clinical trials showed that for witnessed arrests, patients administered lidocaine or amiodarone had significantly higher survival to discharge when compared to placebo.3 Additionally, lidocaine and amiodarone recipients required fewer shocks, but there was no difference in survival to discharge.2 Furthermore, one study showed that amiodarone or lidocaine administered intravenously, but not intraosseously, was associated with significantly improved survival to discharge compared to placebo.4 Many of the observational studies lacked a control population, complicating their interpretation. Many of these studies compared antiarrhythmics to one another (lidocaine versus amiodarone, nifekalant versus amiodarone); the majority found no difference in survival to discharge between different antiarrhythmics. Interestingly, in a study of adults with non-traumatic cardiac arrest, Huang et al. found that survival to ICU admission, survival to discharge, and 1-year survival were highest when patients with refractory shockable rhythms were given both lidocaine and amiodarone.12 Survival to discharge was less likely in those only administered amiodarone, lower still in those only administered lidocaine, and lowest in those receiving neither. Ji et al. demonstrated higher ROSC and 24 hour survival, decreased number of shocks, lower defibrillation energy, epinephrine dose, and duration of CPR in pigs with refractory shockable rhythms administered amiodarone or nifekalant when compared to saline.13 Similarly, Zoerner et al. found greater 3-hour survival in pigs administered amiodarone in a hemorrhagic shock VF model.16 However, Karlis et al. found higher survival with nifekalant compared to amiodarone and saline and no difference in 48 hour survival between the control and amiodarone groups.15 Similarly, Glover et al. found no difference in survival between amiodarone and placebo. 14

Outcome 3: ROSC

For the next most important outcome of ROSC, we evaluated 1 clinical trial (low quality of evidence, downgraded for serious indirectness), 2 observational studies (very low quality of evidence, downgraded for serious indirectness) and 7 experimental studies (very low quality of evidence, downgraded for serious indirectness, serious imprecision, and serious inconsistency), 3 in dogs and 4 in swine. The clinical trial and 2 observational studies showed no difference in frequency of ROSC with the use of amiodarone in patients with refractory shockable rhythms.2,7,8 The experimental studies had heterogenous study designs, but overall 1 of 4 swine studies and 2 of 3 canine studies showed improvement in the frequency of ROSC in animals receiving amiodarone.13,17,18 The remainder of the studies showed no difference in ROSC between the amiodarone and control groups.15,16,19,20

Outcome 4: Surrogate markers of perfusion

For the outcome of surrogate markers of perfusion, 9 experimental studies were identified (very low quality of evidence, downgraded for serious indirectness, imprecision, and inconsistency). It is important to note that multiple experimental studies demonstrated lower coronary perfusion pressure in dogs and pigs administered amiodarone in the absence of concurrent vasopressor therapy13,18,19 The vasodilatory effects of amiodarone may be reduced when epinephrine is administered concurrently with amiodarone.17 It should also be noted that IV amiodarone does not appear to increase the defibrillation threshold, unlike oral amiodarone.21,22 Of the 9 studies, 4 were in dogs. Two showed improvement in surrogate markers of perfusion in dogs with refractory shockable rhythms with the addition of amiodarone, 1 showed no difference, and 1 showed worsened surrogate markers of perfusion.17–19,23

Treatment recommendation

If lidocaine is unavailable, we suggest that amiodarone may be administered intravenously (5 mg/kg) during CPR for PVT or VF refractory to the first shock in dogs (weak recommendation, very low quality of evidence).

We suggest that amiodarone may be administered intravenously (5 mg/kg) during CPR for PVT or VF refractory to the first shock in cats (weak recommendation, very low quality of evidence).

We recommend against the use of amiodarone formulations containing polysorbate-80 in dogs due to the adverse hemodynamic side effects of these formulations that have been documented (strong recommendation, moderate quality of evidence).

Justification of treatment recommendation

Clinical trials and observational studies in people and experimental studies in pigs and dogs found conflicting results for the efficacy of amiodarone for the treatment of refractory PVT and VF. Many of the observational studies lacked a placebo group (instead comparing lidocaine to amiodarone therapy), complicating their interpretation. There is very little evidence suggesting that amiodarone is superior to lidocaine in these studies. The evidence of profound adverse hemodynamic effects in dogs of amiodarone formulations containing polysorbate-80 indicates that these formulations should not be used during CPR in dogs.24 The alternative aqueous formulations of amiodarone are reportedly safer25, but they are pre-diluted to a low concentration, requiring infusion of large volumes (approximately 3.3 ml/kg) to achieve the recommended dose, which may be impractical during CPR. There is one case report of successful treatment of VT in a cat using the aqueous formulation of amiodarone.26 For these reasons, the committee suggests that amiodarone can be used for dogs and cats with PVT or VF refractory to an initial attempt at defibrillation, but if lidocaine is available, it is the more practical and safer drug in dogs.

Knowledge gaps

There are no controlled studies evaluating amiodarone administration in dogs and cats with spontaneous CPA and amiodarone has not been evaluated in cats. The optimal timing and dosage for amiodarone administration during CPR is unknown. Additionally, whether amiodarone should be administered concurrently with lidocaine to improve outcomes is unknown. Compared to human medicine, shockable rhythms in veterinary medicine appear less common.[ Hohene, in press] Therefore, the role of amiodarone for management of refractory pVT or VF is considered a low-priority knowledge gap in the veterinary literature.

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. Kudenchuk PJ, Leroux BG, Daya M, et al. Antiarrhythmic Drugs for Nonshockable-Turned-Shockable Out-of-Hospital Cardiac Arrest: The ALPS Study (Amiodarone, Lidocaine, or Placebo). Circulation. 2017;136(22):2119-2131.

3. Kudenchuk PJ, Brown SP, Daya M, et al. Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Cardiac Arrest. N Engl J Med. 2016;374(18):1711-1722.

4. Daya MR, Leroux BG, Dorian P, et al. Survival After Intravenous Versus Intraosseous Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Shock-Refractory Cardiac Arrest. Circulation. 2020;141(3):188-198.

5. Holmberg MJ, Ross CE, Atkins DL, et al. Lidocaine versus amiodarone for pediatric in-hospital cardiac arrest: An observational study. Resuscitation. 2020;149:191-201.

6. Wang CH, Chang WT, Huang CH, et al. Outcomes associated with amiodarone and lidocaine for the treatment of adult in-hospital cardiac arrest with shock-refractory pulseless ventricular tachyarrhythmia. J Formos Med Assoc. 2020;119(1 Pt 2):327-334.

7. Valdes SO, Donoghue AJ, Hoyme DB, et al. Outcomes associated with amiodarone and lidocaine in the treatment of in-hospital pediatric cardiac arrest with pulseless ventricular tachycardia or ventricular fibrillation. Resuscitation. 2014;85(3):381-386.

8. Pollak PT, Wee V, Al-Hazmi A, Martin J, Zarnke KB. The use of amiodarone for in-hospital cardiac arrest at two tertiary care centres. Can J Cardiol. 2006;22(3):199-202.

9. Amino M, Inokuchi S, Nagao K, et al. Nifekalant Hydrochloride and Amiodarone Hydrochloride Result in Similar Improvements for 24-Hour Survival in Cardiopulmonary Arrest Patients: The SOS-KANTO 2012 Study. J Cardiovasc Pharmacol. 2015;66(6):600-609.

10. Tagami T, Matsui H, Tanaka C, et al. Amiodarone Compared with Lidocaine for Out-Of-Hospital Cardiac Arrest with Refractory Ventricular Fibrillation on Hospital Arrival: a Nationwide Database Study. Cardiovasc Drugs Ther. 2016;30(5):485-491.

11. Tagami T, Matsui H, Ishinokami S, et al. Amiodarone or nifekalant upon hospital arrival for refractory ventricular fibrillation after out-of-hospital cardiac arrest. Resuscitation. 2016;109:127-132.

12. Huang CH, Yu PH, Tsai MS, et al. Acute hospital administration of amiodarone and/or lidocaine in shockable patients presenting with out-of-hospital cardiac arrest: A nationwide cohort study. Int J Cardiol. 2017;227:292-298.

13. Ji XF, Li CS, Wang S, Yang L, Cong LH. Comparison of the efficacy of nifekalant and amiodarone in a porcine model of cardiac arrest. Resuscitation. 2010;81(8):1031-1036.

14. Glover BM, Hu X, Aves T, et al. Dronedarone and captisol-enabled amiodarone in an experimental cardiac arrest. J Cardiovasc Pharmacol. 2013;61(5):385-390.

15. Karlis G, Iacovidou N, Lelovas P, et al. Nifekalant Versus Amiodarone in the Treatment of Cardiac Arrest: an Experimental Study in a Swine Model of Prolonged Ventricular Fibrillation. Cardiovasc Drugs Ther. 2015;29(5):425-431.

16. Zoerner F, Semenas E. Resuscitation with amiodarone increases survival after hemorrhage and ventricular fibrillation in pigs. J Trauma Acute Care Surg. 2014;76(6):1402-1408.

17. Wira C, Martin G, Stoner J, Margolis K, Donnino M. Application of normothermic cardiac arrest algorithms to hypothermic cardiac arrest in a canine model. Resuscitation. 2006;69(3):509-516.

18. Anastasiou-Nana MI, Nanas JN, Nanas SN, et al. Effects of amiodarone on refractory ventricular fibrillation in acute myocardial infarction: experimental study. J Am Coll Cardiol. 1994;23(1):253-258.

19. Stoner J, Martin G, O’Mara K, Ehlers J, Tomlanovich M. Amiodarone and bretylium in the treatment of hypothermic ventricular fibrillation in a canine model. Acad Emerg Med. 2003;10(3):187-191.

20. Wiesmann T, Freitag D, Dersch W, et al. Dantrolene versus amiodarone for cardiopulmonary resuscitation: A randomized, double-blinded experimental study. Sci Rep. 2017;7.

21. FRAME LH. The Effect of Chronic Oral and Acute Intravenous Amiodarone Administration on Ventricular Defibrillation Threshold Using Implanted Electrodes in Dogs. Pacing Clin Electrophysiol. 1989;12(2):339-346.

22. Fain ES, Lee JT, Winkle RA. Effects of acute intravenous and chronic oral amiodarone on defibrillation energy requirements. Am Heart J. 1987;114(1 PART 1):8-17.

23. Arredondo MT, Guillen SG, Quinteiro RA. Effect of amiodarone on ventricular fibrillation and defibrillation thresholds in the canine heart under normal and ischemic conditions. Eur J Pharmacol. 1986;125(1):23-28.

24. Masini E, Planchenault J, Pezziardi F, Gautier P, Gagnol JP. Histamine-releasing properties of Polysorbate 80 in vitro and in vivo: correlation with its hypotensive action in the dog. Agents Actions. 1985;16(6):470-477.

25. Levy NA, Koenigshof AM, Sanders RA. Retrospective evaluation of intravenous premixed amiodarone use and adverse effects in dogs (17 cases: 2011-2014). J Vet Cardiol Off J Eur Soc Vet Cardiol. 2016;18(1):10-14.

26. Berlin N, Ohad DG, Maiorkis I, Kelmer E. Successful management of ventricular fibrillation and ventricular tachycardia using defibrillation and intravenous amiodarone therapy in a cat. J Vet Emerg Crit Care San Antonio. Published online 2020.

Additional References:

Masini E, Planchenault J, Pezziardi F, Gautier P, Gagnol JP. Histamine-releasing properties of Polysorbate 80 in vitro and in vivo: correlation with its hypotensive action in the dog. Agents Actions. 1985; 16: 470–477.

Levy NA, Koenigshof AM, Sanders RA. Retrospective evaluation of intravenous premixed amiodarone use and adverse effects in dogs (17 cases: 2011-2014). J Vet Cardiol. 2016 Mar;18(1):10-4. doi: 10.1016/j.jvc.2015.10.009. Epub 2016 Jan 21. PMID: 26803199.

Berlin N, Ohad DG, Maiorkis I, Kelmer E. Successful management of ventricular fibrillation and ventricular tachycardia using defibrillation and intravenous amiodarone therapy in a cat. J Vet Emerg Crit Care (San Antonio). 2020 Jul;30(4):474-480. doi: 10.1111/vec.12960. Epub 2020 May 13. PMID: 32400960

Supplemental Information:

Outcome: Favorable neurologic outcome

3 Clinical Trials

Kudenchuk et al., 2016: Amiodarone, lidocaine, or placebo in OOHCA

● Randomized, double blind trial of adults with non-traumatic OOHCA and shock refractory VF or PVT (shock refractory: persistent or recurrent shockable rhythm after one or more shocks anytime during resuscitation)

● Patients then randomized to receive amiodarone, lidocaine, or placebo after a vasopressor

● Neither amiodarone nor lidocaine resulted in a higher survivor or favorable neuro outcome than placebo

● With witnessed arrest, lidocaine and amiodarone had significantly higher survival than placebo

Kudenchuk et al., 2017: Antiarrhythmic drugs for nonshockable turned shockable OOHCA

● Adults with nontraumatic OOHCA and VF/PVT anytime after one or more shocks randomized to placebo, lidocaine, or amiodarone

● 3026 with VF/PVT and 1063 with nonshockable turned shockable

● Non-statistically significant increase in survival (and improved neuro outcome) with amiodarone or lidocaine compared to placebo

● Active-drug recipients in this cohort required fewer shocks, supplemental doses of their assigned drug, and ancillary antiarrhythmic drugs than recipients of a placebo

● Survival approached significance (p 0.08) for nonshockable turned shockable rhythms with amiodarone compared to placebo

Daye et al., 2020: Survival after IV versus IO amiodarone, lidocaine, or placebo in OOH shock-refractory cardiac arrest

● Same study population as previous study

● Amiodarone and lidocaine associated with more favorable neuro outcome when administered IV, but not IO when compared to placebo (as was survival to discharge and survival to hospital admission)

2 Observational Studies

Holmberg et al., 2020: Lidocaine versus amiodarone for pediatric in hospital cardiac arrest: an observational study

● From registry, included children with IHCA with an initial or subsequent shockable rhythm and then matched based on a propensity score

● No difference between lidocaine and amiodarone for survival, ROSC, or favorable neuro outcome

Wang et al., 2020: Outcomes associated with amiodarone and lidocaine for the treatment for adult IHCA with shock refractory pulseless ventricular tachyarrhythmia

● Included 130 patients with IHCA and VF/pVT requiring more than one defibrillation attempt

● No control group. No difference in ROSC, survival or favorable neuro outcome for lidocaine v amiodarone. Amiodarone group experienced a higher likelihood of terminating VF/pVT within three shocks

0 Experimental Studies

Outcome: Survival to discharge