RECOVER 2.0 Worksheet

QUESTION ID: MON-09

PICO Question:
In cats and dogs in CPA (P), does the identification and treatment of (arterial or venous) calcium disorders during CPR (I) compared to not addressing calcium disorders (C) improve ... (O)?

Outcomes:
Favorable neurologic outcome,Survival to Discharge,ROSC

Prioritized Outcomes (1= most critical; final number = least important):

1.Favorable neurologic outcome

2.Survival to Discharge

3.ROSC

4.

5.

Domain chairs: Selena Lane, Ben Brainard, Dan Fletcher

Evidence evaluators: Kenneth Joubert, Stefania Grasso

Conflicts of interest:

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 outcome

0

Outcome: Survival to discharge

0

Outcome: ROSC

0

PICO Question Summary

Introduction

Calcium is important for myocardial function and vasomotor tone. Alterations in plasma calcium concentrations during CPA could result in a decreased chance of ROSC and survival if adequate myocardial contractility cannot be generated to maintain spontaneous circulation. This PICO question investigated the question of whether management of plasma calcium concentration abnormalities during CPR impacts outcome.

Consensus on science

No studies were identified that addressed the PICO question for any of the outcomes of interest. Studies were therefore examined to determine (1) if hypocalcemia occurs during CPR and if those changes are associated with outcome, and (2) if administration of calcium during CPR is associated with improved outcomes. 1. Hypocalcemia during CPR and its effect on outcome: Multiple studies have documented decreased plasma calcium concentrations in patients in CPA. Although the mechanism is unclear, there is some evidence that ionized calcium complexes with lactate as progressive lactic acidosis develops during CPA.1 Gando et al. showed a significant correlation between transport time to the hospital and plasma ionized calcium concentrations in 30 human patients with OHCA, suggesting that decreases in ionized calcium concentrations in patients in CPA are progressive over time (r = -0.371, P < 0.05).2 In a study of 22 patients with traumatic CPA and OCCPR, 12 (55%) had documented ionized hypocalcemia.3 Multiple experimental studies in dogs and swine have documented statistically significant decreases in plasma ionized calcium during CPR that persist in the PCA period.4–8 Ionized hypocalcemia has also been documented by Hopper et al. in 18% of dogs and cats in a clinical setting during CPR (mean 1.21, range 0.68 – 1.59 mmol/L, reference 1.1 – 1.5 mmol/L).9 Two observational studies in people investigated the association between serum calcium concentrations and outcomes in human patients in CPA.10,11 In a study of 1552 adult people with OHCA, ionized calcium concentration at catheter placement was not associated with favorable neurologic outcome.11 Univariate analysis of these data showed that plasma ionized calcium concentrations at catheter placement were associated with ROSC (OR of no ROSC 0.580 per mmol/L, 95% CI 0.347–0.971, P = 0.038), but in a multivariate analysis, only pH and PCO2 (but not ionized calcium) showed an independent association with ROSC. In a retrospective observational study of 33 adult people that achieved ROSC, the lowest serum ionized calcium concentration in the first 48 hours post ROSC was lower in patients with poor neurologic outcome than in patients with good neurologic outcome (0.96 ± 0.06 versus 1.02 ± 0.06 mmol/L, P = 0.011).10 Neither of these studies investigated the effect of treating hypocalcemia on outcome. 2: Calcium administration during CPR The routine administration of calcium during cardiopulmonary resuscitation has not been shown to improve the frequency of ROSC,2,3,12–17 favorable neurologic outcomes11 or survival to hospital discharge.13,18 In addition, some studies have documented increased mortality in patients in CPA treated with calcium.19,20 However, 2 studies have demonstrated improved outcomes in hyperkalemic human patients in CPA treated with calcium.21,22 Early studies suggested some benefit to the administration of calcium to adults and animals, but the evidence overall does not support routine administration of calcium in people in CPA. A retrospective study including 480 people with OHCA showed that calcium administration was associated with ROSC in patients with PEA (11% developed a perfusing rhythm after administration) but not in patients with asystole or ventricular fibrillation.23 In contrast, in a clinical trial in patients with OHCA in PEA, frequency of ROSC was similar for patients that received calcium (8/48) to those that did not receive calcium (2/42, P = 0.07).24[EF1] In addition, a retrospective study including 210 people with asystole or PEA showed a lower frequency of ROSC with calcium administration (8% in those with asystole and 16% for those with PEA) in a pre-hospital setting compared to those that did not (33% for those in asystole, P < 0.002; and 44% for PEA, P < 0.02).14 Another prospective, randomized, blinded clinical trial of 70 people found that calcium chloride administered during refractory asystole in pre-hospital cardiac arrest did not improve ROSC (5.1% in calcium group versus 14.7% in saline group, P=0.37).25 A multicenter, randomized, controlled clinical trial including 773 people experiencing in-hospital cardiac arrest showed that calcium administration during CPR was associated with non-survival at 1 hour after CPR (17.3% non-survivors versus 7.1 survivors, P<0.001). Likewise, an experimental study in 16 dogs showed that calcium administration during CPR for PEA was not more effective than placebo in achieving ROSC (4/11 in calcium group, 4/9 placebo group, P > 0.05).26 A larger experimental study in 40 dogs with PEA showed that calcium administration during CPR was not more effective than placebo for ROSC (6/10 versus 2/10, P > 0.05).17

Treatment recommendation

In dogs and cats in CPA, we suggest monitoring of plasma ionized calcium during CPR. (weak recommendation, expert opinion) In dogs and cats in CPA with documented hypocalcemia (ionized calcium < 0.8 mmol/L), we suggest administration of 10% calcium gluconate (50 mg/kg IV over 2-5 minutes) or 10% calcium chloride (15 mg/kg IV over 2-5 minutes). (weak recommendation, expert opinion) In dogs and cats in CPA, we recommend against routine administration of calcium in patients in the absence of documented hypocalcemia or other specific indications (eg, calcium channel blocker overdose). (strong recommendation, very low quality of evidence)

Justification of treatment recommendation

There is limited evidence that ionized hypocalcemia impacts outcomes in people with CPA, and there are no studies in dogs or cats evaluating the impact of hypocalcemia during CPR on outcomes. However, plasma ionized calcium plays crucial roles in maintaining vascular tone and cardiac contractility, and it is likely that significant ionized hypocalcemia could reduce the likelihood of ROSC. Therefore, the committee suggests that measurement of plasma ionized calcium concentrations may be useful during CPR, and suggests that substantial ionized hypocalcemia (< 0.8 mEq/L) be treated with intravenous calcium.

Knowledge gaps

A placebo-controlled clinical trial of treatment of hypocalcemia in dogs and cats during CPR is considered by the committee to be a moderate level knowledge gap. To date there are no trials in humans or animals investigating the potential outcome benefits of treatment of documented hypocalcemia during CPA.

References:

1. Cairns CB, Niemann JT, Pelikan PC, Sharma J. Ionized hypocalcemia during prolonged cardiac arrest and closed-chest CPR in a canine model. Ann Emerg Med. 1991;20(11):1178-1182.

2. Gando S, Tedo I, Tujinaga H, Kubota M. Variation in serum ionized calcium on cardiopulmonary resuscitation. J Anesth. 1988;2(2):154-160.

3. Schnüriger B, Talving P, Inaba K, et al. Biochemical profile and outcomes in trauma patients subjected to open cardiopulmonary resuscitation: a prospective observational pilot study. World J Surg. 2012;36(8):1772-1778.

4. Bleske BE, Song J, Chow MS, Kluger J, White CM. Hematologic and chemical changes observed during and after cardiac arrest in a canine model--a pilot study. Pharmacotherapy. 2001;21(10):1187-1191.

5. Niemann JT, Cairns CB. Hyperkalemia and ionized hypocalcemia during cardiac arrest and resuscitation: possible culprits for postcountershock arrhythmias? Ann Emerg Med. 1999;34(1):1-7.

6. Youngquist ST, Heyming T, Rosborough JP, Niemann JT. Hypocalcemia following resuscitation from cardiac arrest revisited. Resuscitation. 2010;81(1):117-122.

7. Best R, Martin GB, Carden DL, Tomlanovich MC, Foreback C, Nowak RM. Ionized calcium during CPR in the canine model. Ann Emerg Med. 1985;14(7):633-635.

8. Salerno DM, Elsperger KJ, Helseth P, Murakami M, Chepuri V. Serum potassium, calcium and magnesium after resuscitation from ventricular fibrillation: a canine study. J Am Coll Cardiol. 1987;10(1):178-185.

9. Hopper K, Borchers A, Epstein SE. Acid base, electrolyte, glucose, and lactate values during cardiopulmonary resuscitation in dogs and cats. J Vet Emerg Crit Care (San Antonio). 2014;24(2):208-214.

10. Akasaka T, Watanabe T, Mukai-Yatagai N, et al. Neurological Prognostic Value of Adjusted Ca(2+) Concentration in Adult Patients with Out-of-Hospital Cardiac Arrest. Int Heart J. 2020;61(2):295-300.

11. Corral Torres E, Hernández-Tejedor A, Suárez Bustamante R, de Elías Hernández R, Casado Flórez I, San Juan Linares A. Prognostic value of venous blood analysis at the start of CPR in non-traumatic out-of-hospital cardiac arrest: association with ROSC and the neurological outcome. Crit Care. 2020;24(1):60.

12. van Walraven C, Stiell IG, Wells GA, Hébert PC, Vandemheen K. Do advanced cardiac life support drugs increase resuscitation rates from in-hospital cardiac arrest? The OTAC Study Group. Ann Emerg Med. 1998;32(5):544-553.

13. Stiell IG, Wells GA, Hebert PC, Laupacis A, Weitzman BN. Association of Drug Therapy with Survival in Cardiac Arrest: Limited Role of Advanced Cardiac Life Support Drugs. Academic Emergency Medicine. 1995;2(4):264-273.

14. Stueven H, Thompson BM, Aprahamian C, Darin JC. Use of calcium in prehospital cardiac arrest. Ann Emerg Med. 1983;12(3):136-139.

15. REDDING JS, PEARSON JW. Evaluation of drugs for cardiac resuscitation. Anesthesiology. 1963;24:203-207.

16. Marill KA, Salcido DD, Sundermann ML, Koller AC, Menegazzi JJ. Energy conserving chemical defibrillation of ventricular fibrillation: A randomized two phase controlled blinded trial. Resuscitation. 2016;103:41-48.

17. Redding JS, Haynes RR, Thomas JD. Drug therapy in resuscitation from electromechanical dissociation. Crit Care Med. 1983;11(9):681-684.

18. Urban P, Scheidegger D, Buchmann B, Barth D. Cardiac arrest and blood ionized calcium levels. Ann Intern Med. 1988;109(2):110-113.

19. Anton-Martin P, Moreira A, Kang P, Green ML. Outcomes of paediatric cardiac patients after 30 minutes of cardiopulmonary resuscitation prior to extracorporeal support. Cardiol Young. 2020;30(5):607-616.

20. Lasa JJ, Alali A, Minard CG, et al. Cardiopulmonary Resuscitation in the Pediatric Cardiac Catheterization Laboratory: A Report From the American Heart Association’s Get With the Guidelines-Resuscitation Registry. Pediatr Crit Care Med. 2019;20(11):1040-1047.

21. Gilroy BA, Rockoff MA, Dunlop BJ, Shapiro HM. Cardiopulmonary resuscitation in the nonhuman primate. J Am Vet Med Assoc. 1980;177(9):867-869.

22. Wang CH, Huang CH, Chang WT, et al. The effects of calcium and sodium bicarbonate on severe hyperkalaemia during cardiopulmonary resuscitation: A retrospective cohort study of adult in-hospital cardiac arrest. Resuscitation. 2016;98:105-111.

23. Harrison EE, Amey BD. The use of calcium in cardiac resuscitation. Am J Emerg Med. 1983;1(3):267-273.

24. Stueven HA, Thompson B, Aprahamian C, Tonsfeldt DJ, Kastenson EH. The effectiveness of calcium chloride in refractory electromechanical dissociation. Ann Emerg Med. 1985;14(7):626-629.

25. Stueven HA, Thompson B, Aprahamian C, Tonsfeldt DJ, Kastenson EH. Lack of effectiveness of calcium chloride in refractory asystole. Ann Emerg Med. 1985;14(7):630-632.

26. Blecic S, De Backer D, Huynh CH, et al. Calcium chloride in experimental electromechanical dissociation: a placebo-controlled trial in dogs. Crit Care Med. 1987;15(4):324-327.

Supplemental:

Akasaka 2020: Retro observational study at 2 centers, 190 patients with ROSC after OHCA, 33 patients met inclusion criteria. Serum Ca++ q 4hrs for 48 hours after ROSC. Lowest serum Ca++ during 48 hours post ROSC was associated with poor neurologic outcome (0.96 ± 0.06 versus 1.02 ± 0.06 mmol/L, P = 0.011).

Torres 2020: Prospective observational study of 1552 adults with OOHCPA, 58.4% ROSC, 24.68% good neurologic recovery at 30 days

[EF1]for “Steven 1985” and since the next Steven 1985 includes the paper title, I chose the other Steven 1985 paper “the effectiveness of…”