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ALS-09-v1
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RECOVER 2.0 Worksheet
QUESTION ID: ALS-09
PICO Question:
In cats and dogs with CPA associated with high vagal tone (P) does not using atropine (I) compared with using atropine (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 neurological outcome
2. Survival to discharge
3. ROSC
4. Surrogate marker(s) of perfusion
Domain chairs: Gareth Buckley, Elizabeth Rozanski, final edits Dan Fletcher
Evidence evaluators: Igor Yankin, Janelle Wierenga
Conflicts of interest: None
Search strategy: See attached document
Evidence Review:
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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, |
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No of studies |
Study Type |
RoB |
Indirectness |
Imprecision |
Inconsistency |
Large Effect |
Dose-Response |
Confounder |
# Intervention with Outcome |
# Control with Outcome |
RR (95% CI) |
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Outcome: Favorable neurologic outcome |
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2 |
Obs |
- |
-- |
- |
0 |
0 |
0 |
0 |
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Very low |
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Outcome: Suvival to discharge |
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4 |
Obs |
- |
-- |
- |
0 |
0 |
0 |
0 |
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Very low |
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Outcome: ROSC |
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4 |
Exp |
- |
- |
0 |
0 |
0 |
0 |
0 |
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Low |
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3 |
Obs |
- |
-- |
- |
0 |
0 |
0 |
0 |
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Very low |
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PICO Question Summary
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Introduction |
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Atropine, a parasympatholytic, is recommended to prevent CPA in patients with bradycardia secondary to high vagal tone. The RECOVER 2012 guidelines also suggest that it can be considered during CPR in dogs and cats with non-shockable arrest rhythms, particularly in animals with high vagal tone as a suspected trigger for arrest.1 However, atropine has been removed from human CPR guidelines, and the evidence is primarily supportive of atropine as part of treatment of bradycardia, rather than as part of CPR. This question investigates whether atropine is beneficial in dogs and cats with high vagal tone preceding CPA.
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Consensus on science |
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Outcome 1: Favorable neurologic outcome
There are 2 retrospective observational studies of humans with non-shockable arrest rhythms (very low quality of evidence, downgraded for serious risk of bias and very serious indirectness), neither of which showed an association between atropine administration and favorable neurologic outcome.2,3
Outcome 2: Survival to discharge
A total of 4 retrospective observational studies of humans with non-shockable arrest rhythms (very low quality of evidence, downgraded for serious risk of bias and very serious indirectness) examined the association of atropine administration with survival to discharge. The 2 previously mentioned studies showed no association between atropine administration and this outcome. 2,3 One of the additional studies showed an association between atropine administration and reduced likelihood of survival to discharge using a multi-variate analysis for in-hospital CPA (odds ratio 0.21, 95% CI 0.055 – 0.81).4 The other study showed a survival to discharge benefit associated with administration of epinephrine and/or atropine, but did not examine the effects of the 2 drugs independently.5
Outcome 3: ROSC
Four experimental animal studies in dogs were identified that examined the outcome of ROSC (low quality of evidence, downgraded for serious risk of bias and serious inconsistency). The most direct evidence involved an asphyxial PEA arrest model in 75 dogs that received chest compressions, epinephrine every 3 minutes, and a single injection of one of four doses of atropine or placebo.6 Dogs receiving standard dose atropine (0.04 mg/kg IV) had comparable ROSC rates to dogs receiving placebo. ROSC rates were lower for dogs receiving higher doses of atropine (0.1, 0.2, and 0.4 mg/kg IV). In another experimental study of 40 dogs with induced asphyxia arrests leading to PEA treated with chest compressions and ventilation, dogs receiving an alpha-adrenergic agonist had significantly higher ROSC rates than dogs given saline placebo, but dogs treated with atropine or calcium chloride had similar ROSC rates to placebo controls.7 However, a study of PEA induced by asphyxia in dogs showed that dogs receiving epinephrine and atropine (0.025mg/kg IV) had higher rates of ROSC than dogs receiving epinephrine and D5W (10/11 vs 8/12, P < 0.01).8 Finally, in a study of bradycardic arrests induced in dogs using digoxin and propranolol, administration of atropine prior to the arrest prevented CPA.9
Three retrospective observational studies in people with non-shockable arrest rhythms (very low quality of evidence, downgraded for serious risk of bias and very serious indirectness) examined the association of atropine with ROSC.2–4 Of these, only one showed an association with increased ROSC in patients with asystole (odds ration 1.6, 95% CI 1.4–1.7, P<0.0001).2
The outcome of surrogate markers of perfusion was not assessed because adequate evidence was identified to answer the PICO question for the higher priority outcomes. |
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Treatment recommendation |
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We suggest that atropine (0.04 mg/kg IV) may be administered once during CPR for dogs and cats with non-shockable arrest rhythms (weak recommendation, low quality of evidence).
We recommend that if atropine is used, it is given as early as possible in the CPR effort (strong recommendation, very low quality of evidence).
We recommend against administering repeated doses of atropine during CPR for dogs and cats with non-shockable arrest rhythms (strong recommendation, very low quality of evidence).
We recommend the use of atropine (0.04 mg/kg IV) in dogs and cats with bradycardia causing hemodynamic compromise to attempt to prevent progression to CPA (strong recommendation, expert opinion).
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Justification of treatment recommendation |
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The evidence surrounding the potential benefit of atropine during CPR for patients with non-shockable arrest rhythms is conflicting and extremely limited. Although the majority of studies showed no difference in outcomes in these patients with administration of atropine, one observational study in humans demonstrated an association between atropine administration and reduced likelihood of survival to discharge2, and one experimental dog study also showed a potential benefit.8 Given the very limited evidence of harm associated with standard dose atropine, the committee suggests that the use of atropine in dogs and cats with non-shockable arrest rhythms may be considered, especially if the arrest was preceded by bradycardia due to high parasympathetic tone.
There is convincing evidence that higher doses of atropine are associated with worse outcomes in dogs compared to placebo control.6 Atropine is partially metabolized by the liver and excreted in the urine, does not reach peak plasma concentrations for 3-4 minutes after administration, and has a long half-life. Therefore, we recommend against giving more than one dose of atropine during CPR because multiple doses are likely to lead to accumulation, effectively equivalent to administering a higher dose. Given that the physiologic rationale for the use of atropine is the potential that high vagal tone may have contributed to the arrest, we recommend that atropine be given as early in the CPR attempt as possible.
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Knowledge gaps |
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The incidence of vagally mediated arrests in dogs and cats is unknown, but is assumed to be relatively high in hospitalized patients. There are no studies evaluating the utility of atropine in dogs and cats with high vagal tone and/or bradycardia at the time of the arrest, The majority of the studies included either experimentally induced arrest in healthy dogs, or OOH arrest, with long response times and generally dismal outcomes.
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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. 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.
3. 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.
4. Nguyen D, Kritek PA, Greco SA, Prutkin JM. Bradycardia at the onset of pulseless electrical activity arrests in hospitalized patients is associated with improved survival to discharge. Heliyon. 2020;6(2):e03491.
5. Kaki AM, Alghalayini KW, Alama MN, et al. An audit of in-hospital cardiopulmonary resuscitation in a teaching hospital in Saudi Arabia: A retrospective study. Saudi J Anaesth. 2017;11(4):415-420.
6. 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.
7. Redding JS, Haynes RR, Thomas JD. Drug therapy in resuscitation from electromechanical dissociation. Crit Care Med. 1983;11(9):681-684.
8. Blecic S, Chaskis C, Vincent JL. Atropine administration in experimental electromechanical dissociation. Am J Emerg Med. 1992;10(6):515-518.
9. Rials SJ, Tse WW. Effects of atropine on the cardiac arrest induced by propranolol and digitoxin in dogs. J Electrocardiol. 1982;15(3):277-284.
Supplemental:
Articles reviewed-
ROSC
experimental studies
DeBehnke 1995- PEA in dogs induced by hypoxemia were treated with compression/epinephrine and placebo or accelerating doses of atropine. No difference in outcome or survival with a trend toward decreasing survival at higher doses -75 dogs.- this is strong article supporting lack of utility for atropine.
Redding, 1983- PEA was induced, atropine atropine alone did not lead to ROSC, although a pure Alpha agonist (without atropine) was. Study population dogs
BLECIC 1992- A similar hypoxemia model of PEA demonstrated increased ROSC with atropine. Dogs
RIALS, 1982- In dogs pre-treated with digoxin and propranolol, atropine prevented an arrest.
In dogs that had arrested, atropine did not reverse the arrest alone.
Observational studies
(SOS-KANTO)[ 1960] asystole, epi+atropine better ROSC 1.6 (95% confidence interval (CI) 1.4–1.7, P<0.0001) but similar FNO; PEA same FNO and ROSC but lower 30 day survival 0.4 (95%CI 0.2–0.9, P=0.016).
Yano [1961]- OOH arrest, non shockable, retrospective, atropine + epi, overall no difference between groups in FNO, S2D, ROSC. Slight survival to admission (e.g., ROSC) benefit of a dose of 1-2mg (rather than higher or lower) in multivariate analysis.
Kaki [1814] – large retrospective in Saudi Arabia; low overall survival and a multitude of confounding factors. Unable to fully assess significance, very poor quality study. Possible
Nguyen [1821] – reduced S2D, no difference in ROSC
Good Neurological outcome-
SOS-Kanto- no effect on neurological outcome of atropine administration
Hospital discharge
SOS-Kanto- no effect on neurological outcome of atropine administration
Other- Case reports
Two cases reports in a dog and a foal, support [1][2]atropine use in suspect vagal arrests, although a multitude of other interventions were performed.
Markers of perfusion
None specifically evaluated
[1]Also not sure why these case reports are listed under clinical trials?
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