RECOVER 2.0 Worksheet

QUESTION ID: ALS-01

PICO Question:
In cats and dogs with a shockable rhythm that are being defibrillated (P), does the use of lidocaine (I) compared to not using lidocaine (C) result in improved 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 neurological outcome

2. Survival to discharge

3. ROSC

4. Surrogate marker of perfusion

Domain chairs: Gareth Buckley, Elizabeth Rozanski

Evidence evaluators: Asher Allison, Virginia Frauenthal

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 coutcome
2	CT	0	-	-	0	0	0	0				Point estimates showed benefit but not significant	Low
1	Obs	0	-	0	0	0	0	0					Very low
Outcome: Survival to discharge
5	CT	0	-	0	0	0	0	0					Moderate
4	Obs	0	-	0	0	0	0	0					Very low
Outcome: ROSC
5	CT	0	-	0	0	0	0	0					Moderate
5	Obs	0	-	0	0	0	0	0					Very low

PICO Question Summary

Introduction

Current veterinary and human CPR guidelines suggest that lidocaine may improve outcomes in patients with refractory shockable rhythms that do not respond to initial defibrillation.1,2 Further evidence in dogs suggests that lidocaine may increase the defibrillation threshold when a monophasic defibrillator is used, while a more recent study in pigs suggested that this increase in defibrillation threshold does not occur with biphasic defibrillation.3,4 This PICO question investigated the effects of lidocaine as an adjunctive therapy for refractory shockable rhythms on outcome.

Consensus on science

Outcome 1: Favorable neurologic outcome Two clinical trials and one observational study were found that addressed this outcome (low quality of evidence, downgraded for serious indirectness and imprecision). In a large, randomized, controlled clinical trial, 3026 adult human patients with refractory shockable rhythms (defined as shockable rhythms that persisted after 1 or more defibrillation attempts) were randomized to receive placebo, amiodarone or lidocaine.5,6 The investigators found no difference in functional neurologic outcome between the groups. A subgroup analysis of the same data evaluating patients that initially had non-shockable rhythms and converted to shockable rhythms also showed no difference in favorable neurologic outcomes between the groups.7 One retrospective study of 889 children less than 18 years of age with refractory shockable rhythms similarly showed no improvement in functional neurologic outcomes in the group receiving lidocaine compared to a placebo.8 Outcome 2: Survival to discharge Five clinical trials and 4 observational studies addressing this outcome were identified (moderate quality of evidence, downgraded for serious indirectness).5,7–14 Of these, one clinical trial, a re-analysis of a large clinical trial of 3026 adult human patients with refractory shockable rhythms showed improved survival to discharge in the patients that received intravenous lidocaine after 1 unsuccessful shock compared to controls (adjusted risk ratio 1.21, 95% CI 1.02–1.45), but not in patients receiving intraosseous lidocaine.10 In addition, a large, retrospective registry study of over 27,000 adult human patients showed an increased survival to discharge in patients that did not convert to a perfusing rhythm after a single shock who were administered lidocaine (odds ratio 1.88; 95% CI:1.40–2.53; P = 0.0001).13 Outcome 3: ROSC Five clinical trials and 6 observational studies addressing this outcome were identified (moderate quality of evidence, downgraded for serious indirectness).5–15 Of these, one clinical trial and 2 observational studies showed improvements in ROSC in patients receiving lidocaine compared to those that did not.10,13,15 These included the only veterinary observational study investigating this question.15 Outcome 4: Surrogate markers of perfusion No studies were identified that addressed this outcome for this PICO question.

Treatment recommendation

We suggest that intravenous lidocaine be administered to dogs (2 mg/kg) with refractory pulseless ventricular tachycardia or ventricular fibrillation after the initial shock has been unsuccessful (weak recommendation, moderate quality of evidence). We suggest that intravenous lidocaine not be administered in cats with refractory pulseless ventricular tachycardia or ventricular fibrillation after the initial shock has been unsuccessful (weak recommendation, moderate quality of evidence).

Justification of treatment recommendation

No human study showed a clear survival to discharge benefit, and even large human studies had very small differences. One human paper14 reported improved rates of ROSC with the addition of lidocaine along with electrical defibrillation, although this did not translate to an improved survival to discharge. The available veterinary evidence is limited, although a retrospective paper15 reported a small subgroup of dogs receiving lidocaine who were more likely to survive to hospital discharge. Lidocaine was not identified as harmful in any study, and it is readily available so use in patients where the primary treatment (defibrillation) has been attempted several times and has been unsuccessful is reasonable. The use of intravenous lidocaine in cats is controversial due to their reported sensitivity to the central nervous system and cardiovascular effects.16 One study showed substantial cardiovascular effects of intravenous lidocaine infusions in cats during inhalant anaesthetic procedures and recommended against their use as an adjunctive therapy for this purpose.17 The sensitivity of cats to lidocaine has been postulated to be the result of the species’ reduced hepatic glucuronidation capacity.18 Given these potential detrimental effects and the limited evidence of efficacy, we have recommended against the use of this drug in cats during CPR.

Knowledge gaps

There are no studies in dogs or cats investigating the efficacy of lidocaine for the treatment of refractory shockable arrest rhythms. In addition, it is unknown in any species how many electrical defibrillations should be attempted before administering an anti-arrhythmic.

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. Panchal AR, Bartos JA, Cabañas JG, et al. Part 3: Adult Basic and Advanced Life Support: 2020 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2020;142(16_suppl_2):S366-S468.

3. Ujhelyi MR, Schur M, Frede T, et al. Mechanism of antiarrhythmic drug-induced changes in defibrillation threshold: role of potassium and sodium channel conductance. J Am Coll Cardiol. 1996;27(6):1534-1542.

4. Ujhelyi MR, Schur M, Frede T, Gabel M, Markel ML. Differential effects of lidocaine on defibrillation threshold with monophasic versus biphasic shock waveforms. Circulation. 1995;92(6):1644-1650.

5. 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.

6. Pollak PT, Spence JD. Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Cardiac Arrest. N Engl J Med. 2016;375(8):801-802.

7. 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.

8. 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.

9. Kovoor P, Love A, Hall J, et al. Randomized double-blind trial of sotalol versus lignocaine in out-of-hospital refractory cardiac arrest due to ventricular tachyarrhythmia. Intern Med J. 2005;35(9):518-525.

10. 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.

11. 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.

12. 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.

13. 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.

14. Herlitz J, Ekström L, Wennerblom B, et al. Lidocaine in out-of-hospital ventricular fibrillation. Does it improve survival? Resuscitation. 1997;33(3):199-205.

15. Hofmeister EH, Brainard BM, Egger CM, Kang SW. Prognostic indicators for dogs and cats with cardiopulmonary arrest treated by cardiopulmonary cerebral resuscitation at a university teaching hospital. J Am Vet Med Assoc. 2009;235(1):50-57.

16. Budde J, McCluskey D. Lidocaine, Local Anesthetic. In: Plumb’s Veterinary Drug Handbook. 10th ed. Wiley-Blackwell; 2023:756.

17. Pypendop BH, Ilkiw JE. Assessment of the hemodynamic effects of lidocaine administered IV in isoflurane-anesthetized cats. Am J Vet Res. 2005;66(4):661-668.

18. Steffey E, Booth N. Local Anesthetics. In: Veterinary Pharmacology and Therapeutics. 7th ed. Iowa State University Press; 1995:358-371.

Additional References:

Pypendop BH, Ilkiw JE. Assessment of the hemodynamic effects of lidocaine administered IV in isoflurane-anesthetized cats. Am J Vet Res. 2005 Apr;66(4):661-8. doi: 10.2460/ajvr.2005.66.661. PMID: 15900948.

Steffey EP, Booth NH. Local anesthetics. In: Adams HR, ed. Veterinary pharmacology and therapeutics. 7th ed. Ames, Iowa: Iowa State University Press, 1995;358–371.

Supplemental Information:

Outcome of key papers for this Question

OBS, CT

1130 – children < 18 years of age, refractory VT/PVT, retrospective registry study. Drug administered after 1 shock. 889 patients. Lidocaine was associated with increased ROSC (adjusted OR 2.02, 95% Cl 1.36-3) and 24 hour survival (adjusted OR 1.66, 95% CI 1.11-2.49), but not survival to discharge or FNO.

1132/1137 (same paper) – ALPS trial, 3026 adult patients, randomized to amiodarone, lidocaine or placebo. No increase in survival to discharge or FNO with either amiodarone or lidocaine.

1136 – subgroup analysis of data from ALPS trial of patients with initially non-shockable rhythm that converted to shockable. No statistically significant improvement in ROSC, 24 hour survival, S2D or FNO with either amiodarone or lidocaine, but point estimates of survival were higher (not statistically significant).

1125 – sotalol vs lidocaine for >= 4 shocks resistant VF. No difference between sotalol and lidocaine, in S2D, overall very low S2D rates (3-7%).

1156 – ALPS trial re-analysis comparing IV vs IO administration of amiodarone, lidocaine and placebo for recurrent/resistant VF/VT (>= shock). Original trial showed no benefit of either drug. This re-analysis showed improved S2D with both lidocaine and amiodarone when given IV but not when given IO. (3019 patients, most had IV access, 661 had IO access).

1157 – pediatric registry study, no difference in FNO, S2D, ROSC between amiodarone and lidocaine. No placebo group.

1133 – 347 patients, OOH CPR, resistant to 3 shocks, clinical trial, amiodarone vs lidocaine. ROSC Amiodarone 2.49 (1.28–4.85), p = 0.007, no difference in S2D.

1134 – registry study, 27,463 patients, amiodarone, lidocaine or combined therapy improved 1 year survival (Relative to those given neither medication, odds ratios for 1-year survival via multiple regression analysis were 1.84 (95% CI: 1.58–2.13; p b 0.0001) for amiodarone, 1.88 (95% CI:1.40–2.53; p b 0.0001) for lidocaine, and 2.18 (95% CI: 1.71–2.77; p b 0.0001) for dual agent use.

1127 – retrospective, 1127 patients with sustained VF, lidocaine increases ROSC but not S2D

74 - Prognostic indicators for dogs and cats with cardiopulmonary arrest treated by cardiopulmonary cerebral resuscitation at a university teaching hospital. Hofmeister 2009. Successful cases were more likely to have received lidocaine, small study, not designed to look at this particularly.

Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Cardiac Arrest (Kudenchuk,, 2016). This prospective study compared amiodarone, lidocaine and placebo in out of hospital arrests, where patients had received at least one shock, and had shock-resistant VF, or pVT. Neither lidocaine or amiodarone was better than placebo with ROSC, neurological outcome or survival to discharge.

Antiarrhythmic Drugs for Nonshockable-Turned-Shockable Out-of-Hospital Cardiac Arrest: The ALPS Study (Amiodarone, Lidocaine, or Placebo). (Kudenchuk 2020). This study was a sub-group analysis of the ALPS study that initially were unshockable, but became shockable. There was no significant difference in outcome, but the authors perceived a trend towards improved survival in this group with historically dismal outcomes following with lidocaine or amiodarone.

Randomized double-blind trial of sotalol versus lignocaine in out-of-hospital refractory cardiac arrest due to ventricular tachyarrhythmia ( Kovoor 2005)- this is small number study of shock resistant VF that received sotalol or lidocaine, there was no benefit to either therapy.

Survival After Intravenous Versus Intraosseous Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Shock-Refractory Cardiac Arrest.Daya 2020; this is a larger study comparing lidocaine, amiodarone and placebo, both with IV and IO. There was no benefit to therapy; although overall IV was perceived as better than IO.

Lidocaine versus amiodarone for pediatric in-hospital cardiac arrest: An observational study. Holmberg, 2020. This study compared amiodarone and lidocaine, there was no control group, and no clear difference between groups.

Effect of epinephrine and lidocaine therapy on outcome after cardiac arrest due to ventricular fibrillation Weaver 1990 Lidocaine and epinephrine were not helpful although it was suggested this was due to delay in defibrillation attempts.

Lidocaine in out-of-hospital ventricular fibrillation. Does it improve survival? Herlitz 1997 Lidocaine improved rate of ROSC/admission, but not discharge

Prognostic indicators for dogs and cats with cardiopulmonary arrest treated by cardiopulmonary cerebral resuscitation at a university teaching hospital. Hofmeister 2009. Successful cases were more likely to have received lidocaine, small study, not designed to look at this particularly.