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ALS-07-v1
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RECOVER 2.0 Worksheet
QUESTION ID: ALS-07
PICO Question:
In cats and dogs with CPA (P) does administration of epinephrine at any other time interval (I) compared to administration of epinephrine 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):
- Favorable neurologic outcome
- Survival to discharge
- ROSC
- Surrogate markers of perfusion.
Domain chairs: Gareth Buckley, Elizabeth Rozanski; Jamie Burkitt performed this Evidence Summary
Evidence evaluators: Florian Sänger, Katherine Howie
Conflicts of interest: None declared
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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0 |
CT |
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1 |
OB |
0 |
- - |
0 |
0 |
+ |
+ |
0 |
NA |
NA |
NA |
Average dosing interval < 3 minutes significantly better survival w FNO – compared to 3-4, 4-5, >5 |
Low (humans, OHCA) |
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0 |
Expt |
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Outcome: Survival to Discharge |
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0 |
CT |
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3 |
OB |
0 |
- |
0 |
- - |
+ |
+ |
0 |
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Two large human studies, both adults (one IHCA, one OHCA): opposite findings. One large human ped, IHCA. |
Very low |
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0 |
Expt |
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Outcomes: ROSC, Surrogate markers of perfusion – no evidence identified for either outcome |
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0 |
N/A |
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PICO Question Summary
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Introduction |
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Human and veterinary CPR guidelines recommend a dosing interval of every 3 – 5 minutes for low-dose epinephrine during CPR.1,2 This recommendation is based largely on expert opinion and historically there have not been data to support one specific dosing interval over another. |
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Consensus on science |
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Outcomes 1 and 2: Favorable neurologic outcome and Survival to discharge
For the most critical outcome of favorable neurologic outcome, one observational study was identified that addresses the question (low quality outcome downgraded for serious indirectness, upgraded for large effect and dose-response effect).3 For the next most critical outcome of survival to hospital discharge, we identified three observational studies that address the question (very low quality evidence downgraded for serious indirectness and inconsistency, upgraded for large effect and dose-response effect).3–5 All studies were in people and all 3 averaged the epinephrine dosing interval over the course of the CPR effort, then analyzed categorized epinephrine dosing intervals and outcome. One study was in adults in out-of-hospital cardiac arrest, one was in adults in in-hospital cardiac arrest, and one was in in-hospital cardiac arrest in pediatric patients. 3–5 The most striking aspect of these studies taken together is the strongly positive effect of more frequent dosing interval demonstrated by Grunau in OHCA patients in contrast to the convincingly negative impact on outcome with more frequent dosing interval demonstrated in both the Warren and Hoymes studies in IHCA.
Outcomes 3 and 4: ROSC, Surrogate markers of perfusion
For the next important outcomes of ROSC and surrogate markers of perfusion, we identified no studies that addressed the PICO question.
Warren et al. showed in 20,909 adults with in-hospital cardiac arrest that compared to the reference average epinephrine dosing interval of 4 to < 5 minutes per dose, survival to hospital discharge was significantly higher in patients with an average epinephrine dosing period of 6 to <10 minutes per dose, with more positive impact on outcome the longer the interval was, up to a 9 to < 10 minute interval.5 Similarly, Hoyme et al. showed in 1630 pediatric patients with in-hospital cardiac arrest that compared to an average epinephrine dosing interval of 1 to 5 minutes, average intervals of > 5 to < 8 minutes and 8 minutes to < 10 minutes were associated with improved survival to discharge with a dose-response effect similar to that seen in Warren et al.4 These findings are contrary to those reported in Grunau et al. (2019), which showed that longer epinephrine dosing intervals were associated with lower hospital survival and lower survival with favorable neurologic status when compared to a < 3 minute average dosing interval in adults with out-of-hospital cardiac arrest, despite similar baseline characteristics in proportion of shockable rhythms, bystander CPR, interval between emergency call and emergency personnel arrival, and total dose of epinephrine administered.3 |
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Treatment recommendation |
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We suggest against changing the standard epinephrine dosing interval from every 3 – 5 minutes to any other dosing interval (weak recommendation, very low quality of evidence)
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Justification of treatment recommendation |
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There is conflicting evidence in the human literature, showing dramatically different effects in out-of-hospital (benefit of more frequent dosing) compared to in-hospital (benefit of less frequent dosing) cardiac arrest. The precise reason(s) for this difference are unclear and thus how to apply this information to the dog or cat at a veterinary hospital with cardiopulmonary arrest is unknown. Based on the inconsistency in the findings, we do not recommend a change from the current guidelines.
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Knowledge gaps |
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The appropriate dosing interval for epinephrine in dogs and cats in cardiopulmonary arrest is unknown.
It is unknown whether this interval may vary depending on lag time to start of high-quality CPR with ALS interventions.
The appropriate dosing interval of epinephrine in dogs and cats is considered a high-priority knowledge gap in the veterinary literature.
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References:
1. 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.
2. Fletcher DJ, Boller M, Brainard BM, et al. RECOVER evidence and knowledge gap analysis on veterinary CPR. Part 7: Clinical guidelines: RECOVER clinical guidelines. Journal of Veterinary Emergency and Critical Care. 2012;22(s1):S102-S131.
3. Grunau B, Kawano T, Scheuermeyer FX, et al. The Association of the Average Epinephrine Dosing Interval and Survival With Favorable Neurologic Status at Hospital Discharge in Out-of-Hospital Cardiac Arrest. Ann Emerg Med. 2019;74(6):797-806.
4. Hoyme DB, Patel SS, Samson RA, et al. Epinephrine dosing interval and survival outcomes during pediatric in-hospital cardiac arrest. Resuscitation. 2017;117:18-23.
5. Warren SA, Huszti E, Bradley SM, et al. Adrenaline (epinephrine) dosing period and survival after in-hospital cardiac arrest: a retrospective review of prospectively collected data. Resuscitation. 2014;85(3):350-358.
Supplemental:
Outcome: Favorable neurologic outcome
0 Clinical Trials
1 Observational study:
Grunau et al. (2019): Average epi interval in human adult OHCA (N=15,909)
- post-hoc analysis of Resuscitation Outcomes Consortium continuous chest compression trial
- Compared with the reference dosing interval < 3 minutes, longer epinephrine dosing intervals were associated with lower survival with favorable neurologic status: dosing interval 3 to < 4 minutes, adjusted odds ratio 0.44 (95% confidence interval 0.32 to 0.60); 4 to < 5 minutes, adjusted odds ratio 0.26 (95% confidence interval 0.18 to 0.36); and ≥ 5 minutes, adjusted odds ratio 0.21 (95% confidence interval 0.15 to 0.30).
- Interval between the 911 call and first EMS arrival, the interval between the 911 call and first vasopressor, and the total dose of epinephrine - similar between groups.
- Effect persisted regardless of whether arrest was witnessed and regardless of arrest rhythm diagnosis (shockable v non-shockable)
- Large effect, dose-response effect: shorter epi interval better
0 Experimental studies
Outcome: Survival to hospital discharge
0 Clinical Trials
3 Observational studies:
Grunau et al. (2019): Average epi interval in human adult OHCA (N=15,909)
- post-hoc analysis of Resuscitation Outcomes Consortium continuous chest compression trial
- Similar relationships for epi dosing intervals and StHD as for FNO
- Interval between the 911 call and first EMS arrival, the interval between the 911 call and first vasopressor, and the total dose of epinephrine - similar between groups.
- Effect persisted regardless of whether arrest was witnessed and regardless of arrest rhythm diagnosis (shockable v non-shockable)
- Large effect, dose-response effect: shorter epi interval better
Warren et al (2014): Average epi dosing interval and StHD in human adult IHCA (N=20.909)
- Analysis of data from Get with the Guidelines-Resuscitation IHCA registry
- Compared to an epinephrine dosing period of 4 to <5 minutes per dose, survival to hospital discharge was significantly higher in patients with an epinephrine dosing period of 6 to <10 minutes per dose: for 6 to <7 min/dose, adjusted odds ratio [OR], 1.41 (95% CI: 1.12, 1.78); for 7 to <8 min/dose, adjusted OR, 1.30 (95%CI: 1.02, 1.65); for 8 to <9 min/dose, adjusted OR, 1.79 (95%CI: 1.38, 2.32); for 9 to <10 min/dose, adjusted OR, 2.17 (95%CI: 1.62, 2.92).
- True for shockable and non-shockable rhythms
- Large effect, dose-response effect: longer epi interval better
Hoyme et al (2017): Average epi dosing interval and StHD in pediatric IHCA (N=1630)
- Analysis of AHA Get with the Guidelines-Resuscitation registry data
- Adjusted OR for survival to hospital discharge for average dosing interval of >5–<8 min was 1.81 (95% CI 1.26–2.59) and for 8–<10min was 2.64 (95% CI 1.53–4.55)
- Also statistically significant improvement in OR for survival with longer average intervals between epi doses (longer interval better)
- For patients on or not on vasoactive infusions
- Large effect, dose-response effect: longer epi interval better
0 Experimental studies
2453 (both outcomes): Grunau B, Kawano T, Scheuermeyer FX, et al. The association of the average epinephrine dosing interval and survival with favorable neurologic status at hostpial discharge in out-of-hospital cardiac arrest. Ann Emerg Med 2019;74:797-806. Shorter better - OHCA
800 (StD): Hoyme DB, Patel SS, Samson RA, et al. Epinephrine dosing interval and survival outcomes during pediatric in-hospital cardiac arrest. Resuscitation 2017;117:18-23. – longer better – IHCA peds
Was this found in the lit search? It was a citation in Hoyme and appears compelling: Warren SA, Huszti E, Bradley SM, Chan PS, Bryson CL, Fitzpatrick AL, et al. Adrenaline (epinephrine) dosing period and survival after in-hospital cardiac arrest: a retrospective review of prospectively collected data. Resuscitation 2014;85:350–8. Very large study – significant and dose-dependent effect favoring longer dosing intervals. IHCA adults
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