ALS-03-v1

RECOVER 2.0 Worksheet

QUESTION ID: ALS-03

PICO Question:
In cats and dogs with a shockable rhythm (P), does the use of beta blockers (I) compared to not using beta blockers (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: Rachel Stauffer, Christine Wong

Conflicts of interest: None

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
0	CT
2	OS	-	-	-	-	0	0	0				possible mild improved neuro outcome with tx	Very low
5	ES	0	-	-	0	0	0	0				improved neuro outcome with beta blockers	Very low
Outcome: Survival to discharge
0	CT
4	OS	–	–	-	-	0	0	0				possible mild improved survival with beta blockers	Very low
9	ES	-	–	0	0	0	0	0				Mild improved survival with beta blockers	Very low
Outcome: ROSC
0	CT
3	OS	-	-	-	-	0	0	0				Questionable improved ROSC with tx	Very low
15	ES	0	-	0	-	0	0	0				Slightly improved ROSC with treatment	Very low
Outcome: Surrogate markers of perfusion
0	CT
0	OS
12	ES	0	-	0	0	0	0	0				Improved markers with beta blocker treatment	Low

PICO Question Summary

Introduction

Refractory ventricular fibrillation and refractory pulseless VT (defined as a shockable rhythm resistant to 3 shocks) are believed to be at least partially due to high catecholamine tone resulting from severe stress. This may be compounded by the administration of exogenous catecholamines (such as epinephrine) during CPR. The peripheral vasoconstriction resulting from the alpha-1 effects of these catecholamines is believed to be beneficial during CPR, but the beta-1 effects may perpetuate refractory shockable rhythms. The use of beta-blockers has been proposed as a potential adjunctive therapy to mitigate these beta-1 effects and improve defibrillation success. Current veterinary guidelines do not make any recommendations on the use of beta-blockers during CPR.1

Consensus on science

Outcome 1: Favorable neurologic outcome For the most critical outcome of favorable neurologic outcome, there are 5 experimental studies in pigs and rats showing improvement in neurologic outcome scores with the use of beta blockers (very low quality of evidence downgraded for serious imprecision and serious indirectness).2–6 However, both studies in rats involved treatment with beta blockers prior to induction of ventricular fibrillation. Two small retrospective human observational studies failed to show statistically significant improvements in survival with good neurologic outcome in patients with refractory ventricular fibrillation treated with esmolol compared to those not receiving esmolol, but both were considered under-powered to detect a difference (very low quality evidence downgraded for serious risk of bias, serious indirectness, and serious imprecision).7,8 However one of these studies (Lee 2016)8 showed significantly higher rates of ROSC in the patients treated with esmolol. There are no clinical trials evaluating the use of beta blockers as adjunctive therapy in patients with refractory shockable rhythms. Outcome 2: Survival to discharge For the next most critical outcome of survival to discharge, 4 observational studies in people (very low quality of evidence, downgraded for serious risk of bias, serious indirectness, serious imprecision, and serious inconsistency) and 9 experimental studies in swine and rats (very low quality of evidence downgraded for serious risk of bias, serious indirectness, serious imprecision, and serious inconsistency) were identified. Of these, the highest quality evidence came from a large retrospective study of 8266 people older than 65 years of age, which found no difference in 30-day survival between those who had been prescribed a beta-blocker in the 90 days prior to CPA and those who had not been prescribed a beta-blocker.9 Of the other 3 studies, one showed no difference in 30-day, 3-month or 6-month survival between 16 patients with refractory VF receiving esmolol and 25 that did not receive esmolol.8 Another showed that of 28 human patients admitted to a hospital after OOH cardiac arrest, a significantly higher proportion (5/11) of the survivors to discharge had been on beta-blocker therapy than of non-survivors (1/17).10 The final study showed that patients with OOH CPA and refractory VF, 4/6 patients treated with esmolol had sustained ROSC while 8/19 not treated with esmolol had sustained ROSC, but due to the small number of patients included, no statistical analysis was done.7 In addition, 9 experimental studies in pigs and rats with refractory VF were identified that evaluated outcomes comparable to survival to discharge (very low quality of evidence, downgraded for serious risk of bias and serious indirectness). Of these, 7 found that animals treated with a beta-blocker had improved survival compared to controls.2,3,5,11–14 The other 2 found no difference in survival between animals treated with beta-blockers and controls.4,6 Outcome 3: ROSC Three observational human studies relevant to this outcome were identified (very low quality evidence, downgraded for serious risk of bias, serious indirectness, serious imprecision, and serious inconsistency). One showed that in 41 OOH CPA patients with refractory VF, 13/16 patients receiving esmolol achieved ROSC compared to 6/25 patients not receiving esmolol (P<0.001), while 9/16 patients receiving esmolol achieved sustained ROSC compared to 4/25 not receiving esmolol (P=0.007).8 A second study of 8266 patients with OOH CPA showed no difference in ROSC between patients on beta-blockers compared to those not on beta-blockers.9 Finally, the Driver (2014) study described in the section above did not provide a statistical analysis to compare ROSC rates due to the low number patients in the study.7 There were 14 experimental studies in swine and rats and 1 in dogs that examined the effect of beta-blockers on ROSC rates in animals with refractory VF (very low quality evidence, downgraded for serious indirectness and serious inconsistency). There are very heterogeneous study designs with some involving pre-treatment and many using concurrent interventions, but overall 9 of the studies showed improvements in the rates of ROSC in animals receiving beta-blockers compared to control animals.2,5,11,13–18 In one of those studies, CPR was administered in dogs 1 minute after induction of VF.18 Dogs pre-treated with propranolol followed by a propranolol CRI had improved rates of ROSC (10/10) compared to control dogs (7/10), and CPR duration was shorter in the dogs treated with propranolol (159 +/-27 seconds vs 205 +/- 57 seconds, P<0.05). The other 5 studies showed no difference in ROSC rates in animals treated with beta-blockers compared to control animals.3,4,6,12,19,20 No studies showed harm in the use of beta-blockers in patients with refractory VF. Outcome 4: Surrogate markers of perfusion Twelve experimental animal studies in pigs and rats that addressed this outcome were identified (low quality of evidence, downgraded for serious indirectness). Although the study designs were heterogenous, 10/12 studies showed a benefit in surrogate markers of perfusion or post-resuscitation tissue injury biomarkers with beta-blockers when combined with electrical defibrillation and BLS.2–6,12,13,15,16,19 One study in 16 pigs showed an improvement in ROSC rates and 4-hour survival in animals treated with esmolol at the beginning of CPR compared to controls, but no difference in CoPP and a lower maximum systolic arterial pressure after ROSC.11 Finally, a study in 20 piglets with 10 minutes of untreated VF followed by resuscitation with ECMO showed no difference in ROSC, cardiac output, CVP, arterial pressures, PAOP or other cardiac function parameters between piglets treated with beta-blockers and a placebo group.20

Treatment recommendation

We suggest using 1-blocker therapy in dogs and cats with shockable rhythms that do not convert after the first defibrillation (weak recommendation, very low quality of evidence).

Justification of treatment recommendation

There are no clinical trials and few, very low-quality observational studies in people assessing the efficacy of beta-blockers in the treatment of patients with shockable arrest rhythms. There is 1 experimental study in dogs and 14 experimental studies in pigs and rats that utilized heterogeneous study designs but taken as a whole show either improvement or no difference in outcomes in animals treated with beta-blockers with experimentally induced VF. Notably in the one canine study, dogs pre-treated with propranolol had higher rates of ROSC and shorter duration of CPR. None of the studies evaluated showed a detrimental effect of beta-blocker administration in patients with VF. Most dogs and cats with naturally occurring shockable arrest rhythms develop them after initial non-shockable rhythms, which are commonly treated with epinephrine. [Hoehne, 2022] This suggests that 1 stimulation may be partially responsible for the progression to a shockable rhythm, increasing the likelihood that 1-blocker may be beneficial in these patients. Given the physiologic rationale for the use of  blockade in animals with refractory shockable arrest rhythms and the lack of evidence of harm across any of the studies evaluated, the panel concluded that the use of 1-blocker in patients with shockable rhythms that do not respond to an initial electrical defibrillation is reasonable. The panel also concluded that 1 specific blockade should be recommended rather than more generic  blockers (such as propranolol) because of concerns for potentially detrimental bronchoconstriction from 2-blockade.

Knowledge gaps

The optimal timing of 1-blocker administration, duration of 1-blocker therapy, and the specific optimal 1-blocker for use during CPR in dogs and cats are unknown. The potential efficacy of 1-blockers on outcome during CPR in dogs and cats is considered a moderate priority knowledge gap.

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. Huang L, Weil MH, Sun S, Tang W, Fang X. Carvedilol mitigates adverse effects of epinephrine during cardiopulmonary resuscitation. J Cardiovasc Pharmacol Ther. 2005;10(2):113-120.

3. Yang M, Hu X, Lu X, et al. The effects of α- and β-adrenergic blocking agents on postresuscitation myocardial dysfunction and myocardial tissue injury in a rat model of cardiac arrest. Transl Res. 2015;165(5):589-598.

4. Zhang Q, Li C. Combination of epinephrine with esmolol attenuates post-resuscitation myocardial dysfunction in a porcine model of cardiac arrest. PLoS ONE. 2013;8(12).

5. Xanthos T, Bassiakou E, Koudouna E, et al. Combination pharmacotherapy in the treatment of experimental cardiac arrest. Am J Emerg Med. 2009;27(6):651-659.

6. Li Z, Yuan W, Li J, et al. Selective beta-blocker esmolol improves cerebral cortex microcirculation in a swine ventricular fibrillation model. J Cell Biochem. 2019;120(3):3679-3688.

7. Driver BE, Debaty G, Plummer DW, Smith SW. Use of esmolol after failure of standard cardiopulmonary resuscitation to treat patients with refractory ventricular fibrillation. Resuscitation. 2014;85(10):1337-1341.

8. Lee YH, Lee KJ, Min YH, et al. Refractory ventricular fibrillation treated with esmolol. Resuscitation. 2016;107:150-155.

9. Czarnecki A, Morrison LJ, Qiu F, et al. Association of prior β-blocker use and the outcomes of patients with out-of-hospital cardiac arrest. Am Heart J. 2015;170(5):1018-1024.e2.

10. Jakobsson J, Nyquist O, Rehnqvist N, et al. Prognosis and clinical follow-up of patients resuscitated from out-of hospital cardiac arrest. Acta Med Scand. 1987;222(2):123-132.

11. Killingsworth CR, Wei CC, Dell’Italia LJ, et al. Short-acting β-adrenergic antagonist esmolol given at reperfusion improves survival after prolonged ventricular fibrillation. Circulation. 2004;109(20):2469-2474.

12. Jingjun L, Yan Z, Weijie, et al. Effect and mechanism of esmolol given during cardiopulmonary resuscitation in a porcine ventricular fibrillation model. Resuscitation. 2009;80(9):1052-1059.

13. Cammarata G, Weil MH, Sun S, et al. Beta1-adrenergic blockade during cardiopulmonary resuscitation improves survival. Crit Care Med. 2004;32(9 Suppl):S440-443.

14. Menegazzi JJ, Seaberg DC, Yealy DM, Davis EA, MacLeod BA. Combination pharmacotherapy with delayed countershock vs standard advanced cardiac life support after prolonged ventricular fibrillation. Prehosp Emerg Care. 2000;4(1):31-37.

15. Theochari E, Xanthos T, Papadimitriou D, et al. Selective beta blockade improves the outcome of cardiopulmonary resuscitation in a swine model of cardiac arrest. Ann Ital Chir. 2008;79(6):409-414.

16. Bassiakou E, Xanthos T, Koudouna E, et al. Atenolol in combination with epinephrine improves the initial outcome of cardiopulmonary resuscitation in a swine model of ventricular fibrillation. Am J Emerg Med. 2008;26(5):578-584.

17. Rittenberger JC, Menegazzi JJ, Callaway CW. Association of delay to first intervention with return of spontaneous circulation in a swine model of cardiac arrest. Resuscitation. 2007;73(1):154-160.

18. Salerno DM, Murakami M, Elsperger KJ. Effects of pretreatment with propranolol on potassium, calcium, and magnesium shifts after ventricular fibrillation in dogs. J Lab Clin Med. 1989;114(5):595-603.

19. Zoerner F, Lennmyr F, Wiklund L, Martijn C, Semenas E. Milrinone and esmolol decrease cardiac damage after resuscitation from prolonged cardiac arrest. Acta Anaesthesiol Scand. 2015;59(4):465-474.

20. Karlsen H, Bergan HA, Halvorsen PS, et al. Esmolol for cardioprotection during resuscitation with adrenaline in an ischaemic porcine cardiac arrest model. Intensive Care Med Exp. 2019;7(1):65.

Supplemental:

Outcome: Favorable neurologic outcome

0 Clinical Trials

2 Observational Studies

Lee et al., 2016: Refractory ventricular fibrillation treated with esmolol

● retrospective human trial of OOH patients with refractory VF (ventricular fibrillation that was resistant to ≥3 defibrillations, 3 mg of epinephrine, 300 mg of amiodarone, and no ROSC after >10 min of CPR). If initially had non-shockable rhythms were excluded. 16 got esmolol and 25 did not.

● No difference in survival or neurological outcome at 30 days, 3 months, 6 months. Higher temporary ROSC, sustained ROSC, survival to ICU admission.

Driver et al., 2014: Use of esmolol after failure of standard cardiopulmonary resuscitation to treat patients with refractory ventricular fibrillation

● retrospective human trial of OOH patients with refractory VF (same definitions as Lee trial). 6 got esmolol, 19 did not.

● 3/6 esmolol patients and 2/19 controls survived with good neurologic outcome. 4/6 esmolol vs 8/19 control had sustained ROSC. Because of the small sample size no statistical analysis was done.

5 Experimental Studies

Huang et al., 2005: Carvedilol mitigates adverse effects of epinephrine during CPR

● Induced VF in 20 rats, randomized into four groups: placebo pretreatment and epi treatment, carvedilol pretreatment (15 min before VF) and placebo treatment, carvedilol pretreatment and epi treatment, and placebo pretreatment and treatment

● Carvedilol pretreatment reduced ventricular ectopy after ROSC, minimized lactate increases, and had increased CI 4 hours post. Longer survival and fewer postresuscitation neuro deficits

Yang et al., 2015: The effects of alpha and beta adrenergic blocking agents on postresuscitation myocardial dysfunction and myocardial tissue injury in a rat model of cardiac arrest

● 40 rats were randomized into 6 groups: placebo, epinephrine, epi pretreatment with prazosin, epi pretreated with yohimbine, epi pretreated with propranolol, and epi pretreated with prazosin and propranolol. Untreated VF for 8 minutes followed by CPR

● Better postresuscitation myocardial function and neuro deficits scores in epi pretreated with prazosin or propranolol (and decreased release of troponin I and NT-proBNP). Most significant improvement in rats treated with both prazosin and propranolol

Zhang et al., 2013: Combination of epinephrine with esmolol attenuates postresuscitation myocardial dysfunction in a porcine model of cardiac arrest

● 8 min of VF in 24 pigs followed by 2 minutes of BLS then randomized to three groups: epi and esmolol, epi, or saline

● Combo group had better CO, DO2, VO2, decreased cardiomyocyte apoptosis on histology

● Better neuro outcome based on CPC scores which was significant (6/8 for combo v 2/8 for epi and ⅜ for saline)

Xanthos et al., 2009: Combination pharmacotherapy in the treatment of experimental cardiac arrest

● VF in 60 piglets, untreated for 8 minutes then randomized to 4 groups: epi, epi and atenolol, epi and levosimendan, and epi and atenolol and levosimendan. Electrical defibrillation attempted 2 min after drug admin

● PR CO better in triple therapy, as was 48 hour survival, troponin I, serum astroglial protein, neuron specific enolase, and neuro alertness score

Li et al., 2018: Selective beta blocker esmolol improves cerebral cortex microcirculation in a swine ventricular fibrillation model

● VF for 8 minutes, CPR for 2 minutes and then randomized to: esmolol and epi, epi, and saline. Followed by electrical shock. This was repeated if ROSC not achieved (epi was repeated for first two groups, esmolol was not)

● Combo group had better neurological deficit scores, perfused vessel density, and microcirculatory flow than other groups. CPC better with combo but not significantly different between groups. Endothelial cell morphology remained intact in combo group but destroyed in epi alone.

Outcome: Survival to discharge

0 Clinical Trials

4 Observational Studies

Lee et al., 2016: Refractory ventricular fibrillation treated with esmolol

● retrospective human trial of OOH patients with refractory VF (ventricular fibrillation that was resistant to ≥3 defibrillations, 3 mg of epinephrine, 300 mg of amiodarone, and no ROSC after >10 min of CPR). If initially had non-shockable rhythms were excluded. 16 got esmolol and 25 did not.

● No difference in survival or neurological outcome at 30 days, 3 months, 6 months. Higher temporary ROSC, sustained ROSC, survival to ICU admission.

Driver et al., 2014: Use of esmolol after failure of standard cardiopulmonary resuscitation to treat patients with refractory ventricular fibrillation

● retrospective human trial of OOH patients with refractory VF (same definitions as Lee trial). 6 got esmolol, 19 did not.

● 3/6 esmolol patients and 2/19 controls survived with good neurologic outcome. 4/6 esmolol vs 8/19 control had sustained ROSC. Because of the small sample size no statistical analysis was done.

Jakobsson et al., 1987: Prognosis and clinical follow up of patients resuscitated from OOH CA

● Retrospective evaluation of adults with OOHCA. 307 patients identified, 140 were defibrillated, and 28 patients were resuscitated. 22 patients had VF

● Significantly higher rate of beta-blocker use in survivors (5) than non-survivors (1)

Czarnecki et al., 2015: Association of prior beta blocker use and the outcomes of patients with OOHCA

● Observational study of adults over 65 with nontraumatic CA and attempted resuscitation. Compared patients prescribed beta blockers within 90 days with those without.

● 8266 patients examined and 2911 were prescribed a beta blocker. No difference in presenting rhythm, no difference in 30 day mortality

9 Experimental Studies

Li et al., 2018: Selective beta blocker esmolol improves cerebral cortex microcirculation in a swine ventricular fibrillation model

● VF for 8 minutes, CPR for 2 minutes and then randomized to: esmolol and epi, epi, and saline. Followed by electrical shock. This was repeated if ROSC not achieved (epi was repeated for first two groups, esmolol was not)

● Combo group had better neurological deficit scores, perfused vessel density, and microcirculatory flow than other groups. CPC better with combo but not significantly different between groups. No difference in survival

Killingsworth et al., 2004: Short acting beta adrenergic antagonist esmolol given at reperfusion improves survival after prolonged VF

● 8 minutes of VF in 16 pigs followed by external defibrillation. Esmolol or saline received at the start of CPR followed by ALS. Esmolol improved ROSC and 4 hour survival. Max SAP after ROSC lower in esmolol group. No difference in CPP or CPR time

Yang et al., 2015: The effects of alpha and beta adrenergic blocking agents on postresuscitation myocardial dysfunction and myocardial tissue injury in a rat model of cardiac arrest

● 40 rats were randomized into 6 groups: placebo, epinephrine, epi pretreatment with prazosin, epi pretreated with yohimbine, epi pretreated with propranolol, and epi pretreated with prazosin and propranolol. Untreated VF for 8 minutes followed by CPR

● Better postresuscitation myocardial function and neuro deficits scores in epi pretreated with prazosin or propranolol (and decreased release of troponin I and NT-proBNP, better CPP). Most significant improvement in rats treated with both prazosin and propranolol. Improved 72 hour survival in this group

Jingjun et al., 2009: Effect and mechanism of esmolol given during CPR in a porcine ventricular fibrillation model

● 40 pigs with untreated VF for 4 minutes then randomized to placebo or esmolol after two doses of epi. At post resuscitation 2 hours, 6 pigs randomly selected for second VF induction

● Esmolol decreased recurrent rate of VF, improves survival

Xanthos et al., 2009: Combination pharmacotherapy in the treatment of experimental cardiac arrest

● VF in 60 piglets, untreated for 8 minutes then randomized to 4 groups: epi, epi and atenolol, epi and levosimendan, and epi and atenolol and levosimendan. Electrical defibrillation attempted 2 min after drug admin

● PR CO better in triple therapy, as was 48 hour survival, troponin I, serum astroglial protein, neuron specific enolase, lactate, and neuro alertness score

Zhang et al., 2013: Combination of epinephrine with esmolol attenuates postresuscitation myocardial dysfunction in a porcine model of cardiac arrest

● 8 min of VF in 24 pigs followed by 2 minutes of BLS then randomized to three groups: epi and esmolol, epi, or saline

● No difference in survival

● Better neuro outcome based on CPC scores which was significant (6/8 for combo v 2/8 for epi and ⅜ for saline)

Huang et al., 2005: Carvedilol mitigates adverse effects of epinephrine during CPR

● Induced VF in 20 rats, randomized into four groups: placebo pretreatment and epi treatment, carvedilol pretreatment (15 min before VF) and placebo treatment, carvedilol pretreatment and epi treatment, and placebo pretreatment and treatment

● Carvedilol pretreatment reduced ventricular ectopy after ROSC, minimized lactate increases, and had increased CI 4 hours post. Lower diastolic pressures with pretreatment. Increased survival when combined with epinephrine

Cammarata et al., 2004: Beta 1 adrenergic blockade during CPR improves survival

● VF induced in 18 rats, untreated for 6 minutes, followed by precordial compression, MV, and defibrillation. Randomized to: esmolol or slaine during CPR. Defibrillation attempted after 12 minutes of VF

● Esmolol treated: fewer shocks before resuscitation, improved ROSC, improved duration of survival, improved contractile and LV diastolic functions

Menegazzi et al., 2000: Combination pharmacotherapy with delayed countershock vs standard advanced cardiac life support after prolonged VF

● 56 pigs shocked into VF, untreated for 8 minutes, then basic CPR for 1 minutes. Randomized to: epi, lidocaine, bretylium, propranolol, and U-74389G; epi; lidocaine and bretylium; propranolol, U-74389G; saline; standard ACLS

● Higher ROSC and one hour survival in Group 1 compared to standard

Outcome: ROSC

0 Clinical Trials

3 Observational Studies

Lee et al., 2016: Refractory ventricular fibrillation treated with esmolol

● retrospective human trial of OOH patients with refractory VF (ventricular fibrillation that was resistant to ≥3 defibrillations, 3 mg of epinephrine, 300 mg of amiodarone, and no ROSC after >10 min of CPR). If initially had non-shockable rhythms were excluded. 16 got esmolol and 25 did not.

● No difference in survival or neurological outcome at 30 days, 3 months, 6 months. Higher temporary ROSC, sustained ROSC, survival to ICU admission.

Driver et al., 2014: Use of esmolol after failure of standard cardiopulmonary resuscitation to treat patients with refractory ventricular fibrillation

● retrospective human trial of OOH patients with refractory VF (same definitions as Lee trial). 6 got esmolol, 19 did not.

● 3/6 esmolol patients and 2/19 controls survived with good neurologic outcome. 4/6 esmolol vs 8/19 control had sustained ROSC. Because of the small sample size no statistical analysis was done.

Czarnecki et al., 2015: Association of prior beta blocker use and the outcomes of patients with OOHCA

● Observational study of adults over 65 with nontraumatic CA and attempted resuscitation. Compared patients prescribed beta blockers within 90 days with those without.

● 8266 patients examined and 2911 were prescribed a beta blocker. No difference in presenting rhythm, no difference in 30 day mortality, or ROSC

15 Experimental Studies

Yang et al., 2015: The effects of alpha and beta adrenergic blocking agents on postresuscitation myocardial dysfunction and myocardial tissue injury in a rat model of cardiac arrest

● 40 rats were randomized into 6 groups: placebo, epinephrine, epi pretreatment with prazosin, epi pretreated with yohimbine, epi pretreated with propranolol, and epi pretreated with prazosin and propranolol. Untreated VF for 8 minutes followed by CPR

● No difference in ROSC

Killingsworth et al., 2004: Short acting beta adrenergic antagonist esmolol given at reperfusion improves survival after prolonged VF

● 8 minutes of VF in 16 pigs followed by external defibrillation. Esmolol or saline received at the start of CPR followed by ALS.

● Esmolol improved ROSC and 4 hour survival. Max SAP after ROSC lower in esmolol group. No difference in CPP or CPR time

Li et al., 2018: Selective beta blocker esmolol improves cerebral cortex microcirculation in a swine ventricular fibrillation model

● VF for 8 minutes, CPR for 2 minutes and then randomized to: esmolol and epi, epi, and saline. Followed by electrical shock. This was repeated if ROSC not achieved (epi was repeated for first two groups, esmolol was not)

● No difference in ROSC

Theochari et al., 2008: Selective beta blockade improves the outcome of CPR in a swine model of cardiac arrest

● 14 pigs with VF induced and untreated for 5 minutes. Randomized into saline or esmolol. All then received epi and ALS

● Improved ROSC and CPP in esmolol group at 6 minutes and beyond

Zoerner et al., 2015: Milrinone and esmolol decrease cardiac damage after resuscitation from prolonged cardiac arrest

● 26 piglets with 12 min VF followed by 8 min CPR. Randomized to vasopressin, esmolol, and milrinone (at 13 and 18 minutes, followed by esmolol CRI during 180 minute reperfusion) versus vasopressin and saline

● No difference in ROSC

Karlsen et al., 2019: Esmolol for cardioprotection during resuscitation with adrenaline in an ischaemic porcine cardiac arrest model

● MI induced in 20 piglets, followed by 10 minutes of VF. Resuscitation with ECMO and randomized to esmolol or saline before epi.

● No difference in ROSC

Jingjun et al., 2009: Effect and mechanism of esmolol given during CPR in a porcine ventricular fibrillation model

● 40 pigs with untreated VF for 4 minutes then randomized to placebo or esmolol after two doses of epi. At post resuscitation 2 hours, 6 pigs randomly selected for second VF induction

● No difference in ROSC

Xanthos et al., 2009: Combination pharmacotherapy in the treatment of experimental cardiac arrest

● VF in 60 piglets, untreated for 8 minutes then randomized to 4 groups: epi, epi and atenolol, epi and levosimendan, and epi and atenolol and levosimendan. Electrical defibrillation attempted 2 min after drug admin

● Improved ROSC with intervention

Menegazzi et al., 2000: Combination pharmacotherapy with delayed countershock vs standard advanced cardiac life support after prolonged VF

● 56 pigs shocked into VF, untreated for 8 minutes, then basic CPR for 1 minutes. Randomized to: epi, lidocaine, bretylium, propranolol, and U-74389G; epi; lidocaine and bretylium; propranolol, U-74389G; saline; standard ACLS

● Higher ROSC and one hour survival in Group 1 compared to standard, but not propranolol alone

Zhang et al., 2013: Combination of epinephrine with esmolol attenuates postresuscitation myocardial dysfunction in a porcine model of cardiac arrest

● 8 min of VF in 24 pigs followed by 2 minutes of BLS then randomized to three groups: epi and esmolol, epi, or saline

● No effect on ROSC

Huang et al., 2005: Carvedilol mitigates adverse effects of epinephrine during CPR

● Induced VF in 20 rats, randomized into four groups: placebo pretreatment and epi treatment, carvedilol pretreatment (15 min before VF) and placebo treatment, carvedilol pretreatment and epi treatment, and placebo pretreatment and treatment

● Improved ROSC

Bassiakou et al., 2008: Atenolol in combination with epinephrine improves the initial outcome of CPR in a swine model of VF

● VF induced in 20 piglets, untreated for 8 minutes. Attempted resuscitation with precordial compression, mechanical ventilation, and electrical defibrillation. Randomized to receive saline and epi or atenolol and epi during CPR. Defibrillation attempted after 10 minutes of VF

● Improved ROSC in atenolol group

Cammarata et al., 2004: Beta 1 adrenergic blockade during CPR improves survival

● VF induced in 18 rats, untreated for 6 minutes, followed by precordial compression, MV, and defibrillation. Randomized to: esmolol or slaine during CPR. Defibrillation attempted after 12 minutes of VF

● Esmolol treated: improved ROSC

Rittenberger et al., 2007: Association of delay to first intervention with ROSC in a swine model of cardiac arrest

● Retrospective analysis of 271 swine resuscitation attempts with VF. Five groups: immediate countershock, CPR with standard dose drugs, CPR alone, CPR and high dose epi, and CPR with propranolol, epi, and vasopressin

● Time to first drug and CPR with propranolol, epi, and AVP were predictors of ROSC

Salerno et al., 1989: Effects of pretreatment with propranolol on potassium, calcium and magnesium shifts after VF in dogs

● 40 dogs for VF and were either pretreated with saline, pretreated with propranolol then received either CRI of propranolol or saline. VF for one minute followed by CPR and external defibrillation

● Improved ROSC with treatment group (10/10 v 7/10). Less severe K, Mg, and BG changes with propranolol administration

Outcome: Surrogate markers of perfusion

0 Clinical Trials

0 Observational Studies

Experimental Studies

Huang et al., 2005: Carvedilol mitigates adverse effects of epinephrine during CPR

● Induced VF in 20 rats, randomized into four groups: placebo pretreatment and epi treatment, carvedilol pretreatment (15 min before VF) and placebo treatment, carvedilol pretreatment and epi treatment, and placebo pretreatment and treatment

● Carvedilol pretreatment reduced ventricular ectopy after ROSC, minimized lactate increases, and had increased CI 4 hours post. Lower diastolic pressures with pretreatment

Yang et al., 2015: The effects of alpha and beta adrenergic blocking agents on postresuscitation myocardial dysfunction and myocardial tissue injury in a rat model of cardiac arrest

● 40 rats were randomized into 6 groups: placebo, epinephrine, epi pretreatment with prazosin, epi pretreated with yohimbine, epi pretreated with propranolol, and epi pretreated with prazosin and propranolol. Untreated VF for 8 minutes followed by CPR

● Better postresuscitation myocardial function and neuro deficits scores in epi pretreated with prazosin or propranolol (and decreased release of troponin I and NT-proBNP, better CPP). Most significant improvement in rats treated with both prazosin and propranolol

Zhang et al., 2013: Combination of epinephrine with esmolol attenuates postresuscitation myocardial dysfunction in a porcine model of cardiac arrest

● 8 min of VF in 24 pigs followed by 2 minutes of BLS then randomized to three groups: epi and esmolol, epi, or saline

● Combo group had better CO, DO2, VO2, decreased cardiomyocyte apoptosis on histology. Lactate and troponin decreased at several points for combo

Xanthos et al., 2009: Combination pharmacotherapy in the treatment of experimental cardiac arrest

● VF in 60 piglets, untreated for 8 minutes then randomized to 4 groups: epi, epi and atenolol, epi and levosimendan, and epi and atenolol and levosimendan. Electrical defibrillation attempted 2 min after drug admin

● PR CO better in triple therapy, as was 48 hour survival, troponin I, serum astroglial protein, neuron specific enolase, lactate, and neuro alertness score

Li et al., 2019: Selective beta blocker esmolol improves cerebral cortex microcirculation in a swine ventricular fibrillation model

● VF for 8 minutes, CPR for 2 minutes and then randomized to: esmolol and epi, epi, and saline. Followed by electrical shock. This was repeated if ROSC not achieved (epi was repeated for first two groups, esmolol was not)

● Combo group had better neurological deficit scores, perfused vessel density, and microcirculatory flow than other groups. CPC better with combo but not significantly different between groups. Endothelial cell morphology remained intact in combo group but destroyed in epi alone.

Theochari et al., 2008: Selective beta blockade improves the outcome of CPR in a swine model of cardiac arrest

● 14 pigs with VF induced and untreated for 5 minutes. Randomized into saline or esmolol. All then received epi and ALS

● Improved ROSC and CPP in esmolol group at 6 minutes and beyond

Killingsworth et al., 2004: Short acting beta adrenergic antagonist esmolol given at reperfusion improves survival after prolonged VF

● 8 minutes of VF in 16 pigs followed by external defibrillation. Esmolol or saline received at the start of CPR followed by ALS.

● Esmolol improved ROSC and 4 hour survival. Max SAP after ROSC lower in esmolol group. No difference in CPP or CPR time

Bassiakou et al., 2008: Atenolol in combination with epinephrine improves the initial outcome of CPR in a swine model of VF

● VF induced in 20 piglets, untreated for 8 minutes. Attempted resuscitation with precordial compression, mechanical ventilation, and electrical defibrillation. Randomized to receive saline and epi or atenolol and epi during CPR. Defibrillation attempted after 10 minutes of VF

● Improved ROSC in atenolol group, improved SAP, DAP, and CPP during CPR in this group and decreased HR postresuscitation. No difference in pressures between groups after 10 minutes post ROSC

Cammarata et al., 2004: Beta 1 adrenergic blockade during CPR improves survival

● VF induced in 18 rats, untreated for 6 minutes, followed by precordial compression, MV, and defibrillation. Randomized to: esmolol or slaine during CPR. Defibrillation attempted after 12 minutes of VF

● Esmolol treated: fewer shocks before resuscitation, improved ROSC, improved duration of survival, improved contractile and LV diastolic functions

Zoerner et al., 2015: Milrinone and esmolol decrease cardiac damage after resuscitation from prolonged cardiac arrest

● 26 piglets with 12 min VF followed by 8 min CPR. Randomized to vasopressin, esmolol, and milrinone (at 13 and 18 minutes, followed by esmolol CRI during 180 minute reperfusion) versus vasopressin and saline

● Troponin I lower in treatment group, had less norepi, greater diuresis. No difference in survival, CVP, PAOP, SAP, DAP, MAP, CI

Karlsen et al., 2019: Esmolol for cardioprotection during resuscitation with adrenaline in an ischaemic porcine cardiac arrest model

● MI induced in 20 piglets, followed by 10 minutes of VF. Resuscitation with ECMO and randomized to esmolol or saline before epi.

● No difference in ROSC, CO. Larger LVEDV and LVESV in control group. No differences in CVP, arterial pressures, PAOP, or other cardiac function parameters

Jingjun et al., 2009: Effect and mechanism of esmolol given during CPR in a porcine ventricular fibrillation model

● 40 pigs with untreated VF for 4 minutes then randomized to placebo or esmolol after two doses of epi. At post resuscitation 2 hours, 6 pigs randomly selected for second VF induction

● Esmolol decreased recurrent rate of VF, alleviated CaMKIIdelta hyperactivation, RyR2 hyper-phosphorylation, and flattened activation-recovery intervals