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ALS-04-v1
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RECOVER 2.0 Worksheet
QUESTION ID: ALS-04
PICO Question:
In cats and dogs in CPA (P), does glucocorticoid use during CPR (I) versus not using glucocorticoids (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 neurologic outcome
2. Survival to discharge
3. ROSC
4. Surrogate marker(s) of perfusion
Domain chairs: Gareth Buckley, Elizabeth Rozanski, Jake Wolf, Dan Fletcher
Evidence evaluators: Steven Berkowitz, Janelle Wierenga, Jocelyn Patterson
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, |
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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 |
CT |
0 |
– |
– |
0 |
0 |
0 |
0 |
|
|
|
Better neuro outcome with steroids and AVP |
Very Low |
|
1 |
ES |
0 |
- - |
0 |
0 |
0 |
0 |
0 |
|
|
|
Improved neuro outcome in dogs with steroids |
Very Low |
|
Outcome: Survival to discharge |
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|
2 |
CT |
0 |
– |
– |
0 |
0 |
0 |
0 |
|
|
|
Better survival outcome with steroids and AVP |
Very low |
|
2 |
OB |
- |
– |
– |
0 |
0 |
0 |
0 |
|
|
|
Higher survival with steroid admin |
Very low |
|
Outcome: ROSC |
|||||||||||||
|
2 |
CT |
0 |
– |
– |
0 |
0 |
0 |
0 |
|
|
|
Better ROSC with steroids and AVP |
Very low |
|
2 |
OB |
- |
– |
– |
0 |
0 |
0 |
0 |
|
|
|
Higher ROSC with steroid admin |
Very low |
|
3 |
ES |
- |
- |
0 |
- |
0 |
0 |
0 |
|
|
|
2 showed no difference with steroids, 1 showed improved ROSC with high dose hydrocortisone |
Very low |
|
Outcome: Surrogate markers of perfusion |
|||||||||||||
|
2 |
CT |
0 |
– |
– |
– |
0 |
0 |
0 |
|
|
|
Better BP with steroids |
Very low |
|
0 |
OB |
|
|
|
|
|
|
|
|
|
|
|
|
|
2 |
ES |
- |
– |
– |
- |
0 |
0 |
0 |
|
|
|
No difference with steroids |
Very low |
PICO Question Summary
|
Introduction |
|
Glucocorticoid deficiency has been documented during and after CPA, prompting the question of the utility of glucocorticoid supplementation during CPR.1 The RECOVER 2012 veterinary CPR guidelines recommend against the routine use of glucocorticoids during CPR because of the weak evidence of benefit and the known potential for harm.2 Human guidelines state that glucocorticoids have an unclear benefit for out-of-hospital cardiac arrest. For in-hospital cardiac arrest in people, there is no recommendation for or against their use.3 Recommendations are currently based on a handful of studies in human medicine.
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Consensus on science |
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Outcome 1: Favorable neurologic outcome
For the most critical outcome of FNO, two clinical trials (very low-quality evidence, downgraded for serious indirectness, imprecision and inconsistency) and one experimental study (very low-quality evidence, downgraded for very serious risk of bias) were identified.4–6 Metzelopoulos et al. (2009) randomized 100 adults to either receive vasopressin and epinephrine every cycle for five cycles along with a single dose of methylprednisolone or to receive epinephrine alone. If ROSC was achieved, the patients in the experimental group also received “stress dose” hydrocortisone in the PCA period. There were no survivors with good neurological outcome in either group. Metzelopoulos et al. (2013) randomized 268 adults using the same study design as above and found better Cerebral Performance Category scores in the survivors in the experimental group compared to the placebo group. The one experimental study showed that dogs treated with therapeutic hypothermia and thiopental or therapeutic hypothermia, thiopental, phenytoin and methylprednisolone in the PCA period had lower neurologic deficit scores than dogs treated with only therapeutic hypothermia or maintained normothermic.6
Outcome 2: Survival to hospital discharge
For the next most critical outcome of survival to discharge, the same 2 clinical trials (very low-quality evidence, downgraded for serious indirectness, imprecision and inconsistency) and 2 observational studies were identified (very low quality downgraded for very serious indirectness and imprecision).7,8
The two clinical trials evaluating adults with in-hospital cardiac arrest described previously also evaluated survival to discharge. The earlier Metzelopoulos study reported improved survival to discharge in the group receiving methylprednisolone (9/48 in the experimental group, and 2/52 in the control group, P=0.02).4 The later study also demonstrated increased survival to discharge in the experimental group (29/130) compared to the control group (18/138). The observational studies were in adults and included both those with in-hospital and out-of-hospital cardiac arrest. Niimura et al. (2017) found in a study of 2233 adults with cardiac arrest that hydrocortisone administration (n=61) was associated with a higher survival to discharge when compared to no hydrocortisone administration (n=2172). However, the hydrocortisone group also had higher vasopressor and lidocaine dosages and a higher rate of mild hypothermia. Additionally, when propensity score matching was utilized, there was no significant difference in survival to discharge between the groups (p=0.08). White et al. (1979) performed a record review of 25 adults that had CPA, PEA, and were administered dexamethasone during CPR. In this group, they found high rates of survival to discharge (16%). However, no control group was examined. This group also included a large percentage (36%) who suffered CPA secondary to septic or hemorrhagic shock, making translation of these findings to other patient populations difficult.
Outcome 3: ROSC
For the next most critical outcome of ROSC, the same 2 clinical trials (very low-quality evidence, downgraded for serious indirectness, imprecision and inconsistency) and 2 observational studies were identified (very low quality downgraded for very serious indirectness and imprecision).4,5,7,8 In addition 3 experimental trials were identified that address the question (very low quality of evidence, downgraded for serious indirectness, inconsistency, and imprecision).9–11 The two clinical trials evaluating adults with in-hospital cardiac arrest described previously also evaluated ROSC. The earlier Metzelopoulos study reported improved ROSC frequency in the group receiving methylprednisolone (39/48 [81%] in the experimental group, and 27/52 [52%] in the control group, P=0.003).4 The later study also demonstrated increased frequency of ROSC in the experimental group (109/130 [83.9%] vs 91/138 [65.9%]; odds ratio [OR], 2.98; 95% CI, 1.39-6.40; P = 0.005). Niimura et al. (2017) found in a study of 2233 adults with cardiac arrest that hydrocortisone administration (n=61) was associated with an increased frequency of ROSC when compared to no hydrocortisone administration (n=2172). However, the hydrocortisone group also had higher vasopressor and lidocaine dosages and a higher rate of mild hypothermia.8 White et al. (1979) performed a record review of 25 adults that had CPA, PEA, and were administered dexamethasone during CPR and found high rates of ROSC (52%), but no control group was examined. The 3 experimental studies were in pigs and rats, and had inconsistent results. Smithline (1993) found significantly higher frequency of ROSC in rats treated with mechanical ventilation, compressions, and standard ALS therapy administered high dose hydrocortisone (92%) compared to rats administered low dose hydrocortisone (50%) or placebo (50%). However, 2 other studies in swine showed no improvement in ROSC frequency with the use of hydrocortisone or methylprednisolone in addition to standard BLS and ALS therapy.9,11
Outcome 4: Surrogate Markers of Perfusion
For the outcome of surrogate markers of perfusion, the same 2 clinical trials described previously (very low-quality evidence, downgraded for serious indirectness, imprecision and inconsistency) and 2 of the previously described experimental studies (very low quality of evidence, downgraded for serious indirectness, inconsistency, and imprecision) addressed the question.4,5,9,11 The 2 clinical trials showed improved arterial blood pressure during CPR and shortly after ROSC in the patients receiving glucocorticoids, as did 1 of the 2 experimental studies in swine.
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|
Treatment recommendation |
|
We suggest against the routine administration of glucocorticoids during CPR (weak recommendation, very low quality of evidence).
In dogs and cats with vasopressor resistant hypotension at the time of CPA or with known or suspected hypoadrenocorticism, we suggest intravenous administration of glucocorticoids during CPR (weak recommendation, expert opinion).
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Justification of treatment recommendation |
|
The literature on the use of glucocorticoids during CPR is confounded by the use of multiple interventions (e.g., vasopressin, thiopental, phenytoin, cyclosporine, therapeutic hypothermia and others) in addition to glucocorticoids in the experimental group, making development of a clinical guideline on the use of glucocorticoids during CPR challenging. In addition, there is little consistency between studies in the type and dose of glucocorticoid used during CPR. Given the lack of evidence of a benefit that can be attributed to glucocorticoids and the potential harm of the use of glucocorticoids, especially in patients with poor perfusion, the committee decided that the weak evidence of benefit was outweighed by the potential detrimental effects of glucocorticoids. However, in cases in which absolute or relative hypoadrenocorticism is suspected to be a precipitating cause of the arrest, it is reasonable to administer glucocorticoids.
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Knowledge gaps |
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The specific effects on outcome of glucocorticoid administration in dogs and cats during CPR are unknown. A single intervention clinical trial investigating this question would be a valuable addition to the literature. The dosage and optimal glucocorticoid drug to use during CPR are also unknown. The effects of glucocorticoids on outcome during CPR is considered a moderate priority knowledge gap in the veterinary literature. |
1. Hékimian G, Baugnon T, Thuong M, et al. Cortisol levels and adrenal reserve after successful cardiac arrest resuscitation. Shock. 2004;22(2):116-119.
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. 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.
4. Mentzelopoulos SD, Zakynthinos SG, Tzoufi M, et al. Vasopressin, epinephrine, and corticosteroids for in-hospital cardiac arrest. Arch Intern Med. 2009;169(1):15-24.
5. Mentzelopoulos SD, Malachias S, Chamos C, et al. Vasopressin, steroids, and epinephrine and neurologically favorable survival after in-hospital cardiac arrest: a randomized clinical trial. JAMA. 2013;310(3):270-279.
6. Ebmeyer U, Safar P, Radovsky A, et al. Thiopental combination treatments for cerebral resuscitation after prolonged cardiac arrest in dogs. Exploratory outcome study. Resuscitation. 2000;45(2):119-131.
7. White BC, Petinga TJ, Hoehner PJ, Wilson RF. Incidence, etiology, and outcome of pulseless idioventricular rhythm treated with dexamethasone during advanced CPR. Journal of the American College of Emergency Physicians. 1979;8(5):188-193.
8. Niimura T, Zamami Y, Koyama T, et al. Hydrocortisone administration was associated with improved survival in Japanese patients with cardiac arrest. Sci Rep. 2017;7(1):17919.
9. Gonzalez R, Urbano J, Botran M, et al. Adrenaline, terlipressin, and corticoids versus adrenaline in the treatment of experimental pediatric asphyxial cardiac arrest. Pediatr Crit Care Med. 2014;15(6):e280-287.
10. Smithline H, Rivers E, Appleton T, Nowak R. Corticosteroid supplementation during cardiac arrest in rats. Resuscitation. 1993;25(3):257-264.
11. Chonde M, Flickinger KL, Sundermann ML, et al. Intra-Arrest Administration of Cyclosporine and Methylprednisolone Does Not Reduce Postarrest Myocardial Dysfunction. Biomed Res Int. 2019;2019:6539050.
Supplemental:
Outcome: Favorable neurologic outcome
2 Clinical Trials
Metzelopoulos (2009): Vasopressin, epi, and corticosteroids for in hospital cardiac arrest
● placebo controlled trial of 100 patients with cardiac arrest in Greece
● Received either vasopressin plus epinephrine every cycle for 5 cycles with a dose of methylprednisolone. Post resuscitation treatment with hydrocortisone. Or placebo group (no vasopressin or steroids during CPR), then subdivided to either receive steroids or not post-CPR
● More frequent ROSC and improved survival to discharge (all control patients died before discharge, 2 survived from experimental study–1 with severe and 1 with moderate cerebral disability)
● Makes it very difficult to analyze outcome since both groups may have received steroids at some point during hospitalization
Metzelopoulos (2013): Vasopressin, steroids, and epi and neurologically favorable survival after in hospital cardiac arrest
● Placebo controlled study (same design as above) that included 268 patients
● Higher ROSC and survival to discharge with better CPC score for study groups
● Makes it very difficult to analyze outcome since both groups may have received steroids at some point during hospitalization (compared placebo group as a whole, some of whom received steroids, to study group)
0 Observational Studies
1 Experimental Studies
Ebmeyer (2000): Thiopental combination treatments for cerebral resuscitation after prolonged cardiac arrest in dogs
● 24 dogs with VF for 12.5 min, reversed with brief bypass, controlled ventilation. Four groups:
○ 1: normothermia throughout
○ 2: mild hypothermia from reperfusion to 2 h
○ 3: hypothermia with thiopental over 6 hours
○ 4: hypothermia with lower thiopental dose over 90 min with phenytoin and methylprednisolone
○ All dogs survived. Better neuro scores in groups 3 and 4
Outcome: Survival to discharge
3 Clinical Trials
Metzelopoulos (2009): Vasopressin, epi, and corticosteroids for in hospital cardiac arrest
● placebo controlled trial of 100 patients with cardiac arrest in Greece
● Received either vasopressin plus epinephrine every cycle for 5 cycles with a dose of methylprednisolone. Post resuscitation treatment with hydrocortisone. Or placebo group (no vasopressin or steroids during CPR), then subdivided to either receive steroids or not post-CPR
● More frequent ROSC and improved survival to discharge (all control patients died before discharge, 2 survived from experimental study–1 with severe and 1 with moderate cerebral disability)
● Makes it very difficult to analyze outcome since both groups may have received steroids at some point during hospitalization
Metzelopoulos (2013): Vasopressin, steroids, and epi and neurologically favorable survival after in hospital cardiac arrest
● Placebo controlled study (same design as above) that included 268 patients
● Higher ROSC and survival to discharge with better CPC score for study groups
● Makes it very difficult to analyze outcome since both groups may have received steroids at some point during hospitalization (compared placebo group as a whole, some of whom received steroids, to study group)
2 Observational Studies
White (1979): Incidence, etiology, and outcome of pulseless idioventricular rhythm treated with dexamethasone during advanced CPR
● Record review for humans that had CPR and PIVR (wide, slow bizarre QRS complex) - no control group
● 458 cases, 25 of whom were treated with dexamethasone (high rate of septic or hemorrhagic shock in this study - 36%)
● ROSC in 52% with 16% survived to discharge “neurologically intact”
Niimura (2017): Hydrocortisone administration was associated with improved survival in Japanese patients with cardiac arrest
● 2233 adults with cardiac arrest in hospital or out of hospital based on insurance codes
● Grouped into hydrocortisone (61) and no hydrocortisone group (2172)
● Higher survival to discharge in hydrocortisone group {survival discharge rate (13/61 [21.1%] vs. 240/2172 [11.0%], adjusted odds ratio: 4.2, 95% CI: 1.60–10.98, p=0.004).
● Higher vasopressor, lidocaine, and hypothermia in hydrocortisone group
● Inverse probability of treatment weighting (p=0.077) and 1:1 matched cohort using propensity score matching method (p=0.083) approached significant between study and control, but did not reach significance
**Tsai (2007): The effect of hydrocortisone on the outcome of out-of-hospital cardiac arrest patients: a pilot study
- Prospective, non-randomized trial 97 patients with OOHCA, 36 received hydrocortisone, 61 did not
- Family chose whether to enrol
- No difference in FNO or S2D (very small number)
- Higher frequency of ROSC (90% vs 50%, P=0.045)
** NOT GRADED
0 Experimental Studies
Outcome: ROSC
2 Clinical Trials
Metzelopoulos (2009): Vasopressin, epi, and corticosteroids for in hospital cardiac arrest
● placebo controlled trial of 100 patients with cardiac arrest in Greece
● Received either vasopressin plus epinephrine every cycle for 5 cycles with a dose of methylprednisolone. Post resuscitation treatment with hydrocortisone. Or placebo group (no vasopressin or steroids during CPR), then subdivided to either receive steroids or not post-CPR
● More frequent ROSC and improved survival to discharge (all control patients died before discharge, 2 survived from experimental study–1 with severe and 1 with moderate cerebral disability)
● Makes it very difficult to analyze outcome since both groups may have received steroids at some point during hospitalization
Metzelopoulos (2013): Vasopressin, steroids, and epi and neurologically favorable survival after in hospital cardiac arrest
● Placebo controlled study (same design as above) that included 268 patients
● Higher ROSC (91/138 vs 109/130 , p=0.003). and survival to discharge (18/138 vs 29/130, no stats… Fisher Exact P=.0541) with better CPC score for study groups
● Makes it very difficult to analyze outcome since both groups may have received steroids at some point during hospitalization (compared placebo group as a whole, some of whom received steroids, to study group)
2 Observational Studies
White (1979): Incidence, etiology, and outcome of pulseless idioventricular rhythm treated with dexamethasone during advanced CPR
● Record review for humans that had CPR and PIVR (wide, slow bizarre QRS complex) - no control group
● 458 cases, 25 of whom were treated with dexamethasone (high rate of septic or hemorrhagic shock in this study - 36%)
● ROSC in 52% with 16% survived to discharge “neurologically intact”
Niimura (2017): Hydrocortisone administration was associated with improved survival in Japanese patients with cardiac arrest
● 2233 adults with cardiac arrest in hospital or out of hospital
● Grouped into hydrocortisone (61) and no hydrocortisone group (2172)
● Higher ROSC in hydrocortisone group, but not the focus of the study
● Higher vasopressor, lidocaine, and hypothermia in hydrocortisone group
3 Experimental Studies
Gonzalez (2014): Adrenaline, terlipressin, and corticoids versus adrenaline in the treatment of experimental pediatric asphyxial cardiac arrest
● 49 piglets in which asphyxial cardiac arrest was induced, followed by manual compressions and MV
● Randomized (if they did not achieve ROSC after three minutes with compressions) to epi v. epi plus terlipressin plus hydrocortisone
● 14% achieved ROSC with only compressions, 14% additional achieved ROSC
● 25% with epi and 9% with study achieved ROSC (p=0.1367) - no higher ROSC
Smithline (1993): Corticosteroid supplementation during cardiac arrest in rats
● 8 min cardiac arrest induced in rats via KCl infusion and chest restriction
● Received either placebo, low dose hydrocortisone, or high dose hydrocortisone along with MV, compressions, and ACLS administration
● Significantly higher ROSC in high dose hydrocortisone group (92% v. 50% v 50%)
Chonde (2019): Intra-arrest administration of cyclosporine and methylprednisolone does not reduce postarrest myocardial dysfunction
● 11 swine with induced ventricular fibrillation via a transthoracic shock
● After 8 min, CPR started and administered either placebo or cyclosporine and methylprednisolone 2 min after initiation of CPR
● Not a primary focus of study, but no difference in ROSC
Outcome: Surrogate markers of perfusion
2 Clinical Trials
Metzelopoulos (2009): Vasopressin, epi, and corticosteroids for in hospital cardiac arrest
● placebo controlled trial of 100 patients with cardiac arrest in Greece
● Received either vasopressin plus epinephrine every cycle for 5 cycles with a dose of methylprednisolone. Post resuscitation treatment with hydrocortisone. Or placebo group (no vasopressin or steroids during CPR), then subdivided to either receive steroids or not post-CPR
● Makes it very difficult to analyze outcome since both groups may have received steroids at some point during hospitalization
● Improved BP during CPR and within 15-20 min after ROSC, decreased vasopressor needs
Metzelopoulos (2013): Vasopressin, steroids, and epi and neurologically favorable survival after in hospital cardiac arrest
● Placebo controlled study (same design as above) that included 268 patients
● Makes it very difficult to analyze outcome since both groups may have received steroids at some point during hospitalization (compared placebo group as a whole, some of whom received steroids, to study group)
● Improved BP during CPR and after ROSC. No difference in lactate, acid base status, or use of other vasopressors
0 Observational Studies
2 Experimental Studies
Gonzalez (2014): Adrenaline, terlipressin, and corticoids versus adrenaline in the treatment of experimental pediatric asphyxial cardiac arrest
● 49 piglets in which asphyxial cardiac arrest was induced, followed by manual compressions and MV
● Randomized (if they did not achieve ROSC after three minutes with compressions) to epi v. epi plus terlipressin plus hydrocortisone
● No difference in surrogate markers of perfusion that were analyzed
Chonde (2019): Intra-arrest administration of cyclosporine and methylprednisolone does not reduce postarrest myocardial dysfunction
● 11 swine with induced ventricular fibrillation via a transthoracic shock
● After 8 min, CPR started and administered either placebo or cyclosporine and methylprednisolone 2 min after initiation of CPR
● Improved MAP and decreased vasopressor requirement in study group, no difference in myocardial dysfunction 12 hours after ROSC
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