Document: Invite

Comments:

ALS-08-v1

1 RECOVER 2.0 Worksheet

2 QUESTION ID: ALS-08

3 PICO Question:
In cats and dogs with CPA (P) does the use of high dose epinephrine (0.1mg/kg IV) (I) compared to standard dose epinephrine (0.01mg/kg IV) (C) improve outcome (O)

4 Outcomes:
Favorable neurologic outcome, Surrogate marker(s) of perfusion, Survival to Discharge, ROSC

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

6 Favorable neurologic outcome
7 Survival to discharge
8 ROSC
9 Surrogate markers of perfusion

10 Domain chairs: Gareth Buckley, Elizabeth Rozanski (this evidence summary completed by Jamie Burkitt)

11 Evidence evaluators: Lindsey Strang, Erik Zager

12 Conflicts of interest: None reported

13 Search strategy: See attached document

14 Evidence Review:

15 Study Design

16 Reduced Quality Factors

17 0 = no serious, - = serious,

18 - - = very serious

19 Positive Quality Factors

20 0 = none, + = one, ++ = multiple

21 Dichotomous Outcome Summary

22 Non-Dichotomous Outcome Summary

23 Brief description

24 Overall Quality

25 High, moderate, low,
very low, none

26 No of studies

27 Study Type

28 RoB

29 Indirectness

30 Imprecision

31 Inconsistency

32 Large Effect

33 Dose-Response

34 Confounder

35 # Intervention with Outcome

36 # Control with Outcome

37 RR (95% CI)

38 Outcome: Favorable neurologic outcome

39 4

40 CT

41 0

42 - -

43 0

44 0

45 0

46 0

47 0

48 Low

49 2	50 EXPT	51 0	52 - -	53 0	54 0	55 0	56 0	57 0	58 Very low
59 Outcome: Survival to Discharge

60 6

61 CT

62 0

63 - -

64 0

65 0

66 0

67 0

68 0

69 Low quality

70 3

71 EXPT

72 0

73 - -

74 0

75 0

76 0

77 0

78 0

79 Very low quality

80 Outcome: ROSC

81 6

82 CT

83 0

84 - -

85 0

86 -

87 0

88 0

89 0

90 Very low

91 6

92 EXPT

93 0

94 -

95 0

96 0

97 0

98 0

99 0

100 Low

101 PICO Question Summary

102 Introduction

103 Limited evidence is available to determine the ideal dose of epinephrine during CPR in dogs and cats. Experimental and limited clinical evidence have suggested that high-dose epinephrine (~ 0.1 mg/kg) may improve chances of ROSC but may worsen survival or neurologic outcome when compared to low- (standard-) dose epinephrine (~ 0.01 mg/kg).1 Examination of literature surrounding this PICO question aimed to determine whether there is a benefit to routine use of high-dose epinephrine (as opposed to low-dose) in CPR in dogs and cats.

104 Consensus on science

105 Outcome 1: Favorable neurologic outcome

106 For the most critical outcome of favorable neurologic outcome, we identified 4 clinical trials (low quality of evidence, downgraded for very serious indirectness) and 2 experimental studies (very low quality of evidence, downgraded for very serious indirectness) that addressed the PICO.2–7 All 4 clinical trials investigated OHCA in human adults; the largest included 3327 people and all 4 combined contained ~5500 subjects. None of the 4 trials showed improvement in neurologic outcome at discharge when comparing high-dose epinephrine to standard, low-dose epinephrine. One trial containing only 816 people suggested a trend toward worse FNO with high-dose epinephrine.2 Both experimental studies that addressed FNO were in swine, and neither found a difference in FNO at 24 hours when comparing high-dose to standard-dose epinephrine; both studies used 0.2 mg/kg as “high dose” and 0.02 mg/kg as “low dose.”

107 Outcome 2: Survival to discharge

108 For the next most critical outcome of survival to discharge, we identified 6 clinical trials (low quality of evidence, downgraded for very serious indirectness) and 3 experimental studies (very low quality of evidence, downgraded for very serious indirectness) that addressed the PICO question.2–10 The 2 clinical trials here that were not listed under FNO were small, and together contributed only ~600 additional people, 68 of which were pediatrics with IHCA. Five of 6 trials found no benefit to high-dose epinephrine compared to low-dose epinephrine on survival to discharge. One trial in children with IHCA showed worse neurologic status at 24 hours post-CPR with high-dose compared to low-dose epinephrine, and no children in the high-dose group survived to discharge compared to 4 children in the low-dose epinephrine group.8 Three experimental studies, 2 in swine and 1 in dogs found no improvement in 24-hour survival (swine) or 2-hour survival (dogs) when high-dose was compared to low-dose epinephrine.6,7,10

109 Outcome 3: ROSC

110 We identified 6 clinical trials (very low quality of evidence, downgraded for very serious indirectness and serious inconsistency) and 6 experimental studies (low quality of evidence, downgraded for serious indirectness) that addressed the next critical outcome of ROSC.2–13 Two of the clinical trials, one of which was the largest trial including 3327 adults with OHCA found that high-dose epinephrine improved ROSC compared to low-dose epinephrine, while the other 4 trials failed to find a difference.2,5 Of the 6 experimental trials, none found an improvement in ROSC with use of high-dose compared to low-dose epinephrine; 3 studies were performed in dogs and one in cats. Despite this, 2 of the canine studies found that ROSC was achieved more quickly with high-dose epinephrine than with low-dose epinephrine.10,13

111 Treatment recommendation

112 We recommend against the routine use of high-dose epinephrine during CPR in dogs and cats (strong recommendation, low quality of evidence).

113 Justification of treatment recommendation

114 There is no evidence for the routine use of high-dose epinephrine to improve neurologic outcome or survival in dogs, cats, or other species, and some limited information in people suggests worse neurologic outcome and short-term (24h) survival with high doses. There is inconsistent evidence for improvement in ROSC with use of high-dose epinephrine in people, and no evidence for improvement in ROSC in experimental models in dogs, cats, or swine.

115 Knowledge gaps

116 There are no observational studies or clinical trials in the target species to investigate the possible utility of high-dose epinephrine in dogs and cats.

117 References:

118 1. Vandycke C, Martens P. High dose versus standard dose epinephrine in cardiac arrest - a meta-analysis. Resuscitation. 2000;45(3):161-166.

119 2. Callaham M, Madsen CD, Barton CW, Saunders CE, Pointer J. A randomized clinical trial of high-dose epinephrine and norepinephrine vs standard-dose epinephrine in prehospital cardiac arrest. JAMA. 1992;268(19):2667-2672.

120 3. Brown CG, Martin DR, Pepe PE, et al. A comparison of standard-dose and high-dose epinephrine in cardiac arrest outside the hospital. The Multicenter High-Dose Epinephrine Study Group. N Engl J Med. 1992;327(15):1051-1055.

121 4. Stiell IG, Hebert PC, Weitzman BN, et al. High-Dose Epinephrine in Adult Cardiac Arrest. New England Journal of Medicine. 1992;327(15):1045-1050.

122 5. Gueugniaud PY, Mols P, Goldstein P, et al. A comparison of repeated high doses and repeated standard doses of epinephrine for cardiac arrest outside the hospital. European Epinephrine Study Group. N Engl J Med. 1998;339(22):1595-1601.

123 6. Berg RA, Otto CW, Kern KB, et al. A randomized, blinded trial of high-dose epinephrine versus standard-dose epinephrine in a swine model of pediatric asphyxial cardiac arrest. Crit Care Med. 1996;24(10):1695-1700.

124 7. Berg RA, Otto CW, Kern KB, et al. High-dose epinephrine results in greater early mortality after resuscitation from prolonged cardiac arrest in pigs: a prospective, randomized study. Crit Care Med. 1994;22(2):282-290.

125 8. Perondi MBM, Reis AG, Paiva EF, Nadkarni VM, Berg RA. A comparison of high-dose and standard-dose epinephrine in children with cardiac arrest. N Engl J Med. 2004;350(17):1722-1730.

126 9. Choux C, Gueugniaud PY, Barbieux A, et al. Standard doses versus repeated high doses of epinephrine in cardiac arrest outside the hospital. Resuscitation. 1995;29(1):3-9.

127 10. Angelos MG, DeBehnke DJ. Epinephrine and high-flow reperfusion after cardiac arrest in a canine model. Ann Emerg Med. 1995;26(2):208-215.

128 11. Roberts D, Landolfo K, Dobson K, Light RB. The effects of methoxamine and epinephrine on survival and regional distribution of cardiac output in dogs with prolonged ventricular fibrillation. Chest. 1990;98(4):999-1005.

129 12. Schmitz B, Fischer M, Bockhorst K, Hoehn-Berlage M, Hossmann KA. Resuscitation from cardiac arrest in cats: influence of epinephrine dosage on brain recovery. Resuscitation. 1995;30(3):251-262.

130 13. Brunette DD, Jameson SJ. Comparison of standard versus high-dose epinephrine in the resuscitation of cardiac arrest in dogs. Ann Emerg Med. 1990;19(1):8-11.

131 Supplemental:

132 803: Berg RA, Otto CW, Kern KB, et al. A randomized, blinded trial of high-dose epinephrine versus standard-dose epinephrine in a swine model of pediatric asphyxia cardiac arrest. Crit Care Med 1996;24:1695-1700.

133 805: Perondi MBM, Reis AG, Paiva EF, et al. A comparison of high-dose and standard-dose epinephrine in children with cardiac arrest. N Engl J Med 2004;350:1722-1730.

134 1003: Callaham M, Madsen CD, Barton CW, et al. A randomized clinical trial of high-dose epinephrine and norepinephrine vs standard-dose epinephrine in prehospital cardiac arrest. JAMA 1992;268(19):2667-2672.

135 1004: Brown CG, Martin DR, Pepe PE, et al. A comparison of standard-dose and high-dose epinephrine in cardiac arrest outside the hospital. N Engl J Med 1992;327:1051-1055.

136 1005: Choux C, Gueugniaud P, Barbieux A, et al. Standard doses versus repeated high doses of epinephrine in cardiac arrest outside the hospital. Resuscitation 1995;29:3-9.

137 1006: Stiell IG, Hebert PC, Weitzman BN, et al. High-dose epinephrine in adult cardiac arrest. N Engl J Med 1992;327:1045-1050.

138 1007: Gueugniaud P, Mols P, Goldstein P, et al. A comparison of repeated high doses and repeated standard doses of epinephrine for cardiac arrest outside the hospital. N Engl J Med 1998;339:1595-1601.

139 1016: Roberts D, Landolfo K, Dobson K, Light RB. The effects of methoxamine and epinephrine on survival and regional distribution of cardiac output in dogs with prolonged ventricular fibrillation. Chest 1990;98:999-1005.

140 1018: Schmitz B, Fischer M, Bockhorst K, et al. Resuscitation from cardiac arrest in cats: influence of epinephrine dosage on brain recovery. Resuscitation 1995;30:251-262.

141 1020: Brunette DD, Jameson SJ. Comparison of standard versus high-dose epinephrine in the resuscitation of cardiac arrest in dogs. Ann Emerg Med 1990;19:8-11.

142 1021: DeBehnke DJ, Angelos MG, Leasure JE. Use of cardiopulmonary bypass, high-dose epinephrine, and standard-dose epinephrine in resuscitation from post-countershock electromechanical dissociation. Ann Emerg Med 1992;21:1051-1057.

143 1022: Berg RA, Otto DW, Kern KB, et al. High-dose epinephrine results in greater early mortality after resuscitation from prolonged cardiac arrest in pegis: A prospective, randomized study. Crit Care Med 1994;22:282-290.

144 1023: Angelos MG, DeBehnke DJ. Epinephrine and high-flow reperfusion after cardiac arrest in a canine model. Ann Emerg Med 1995;26:208-215.

145 PaperID	146 Citation	147 N	148 Pop’n	149 Scene	150 HDE / 151 LDE	152 HDE: 153 Impv FNO	154 HDE: 155 Impv Surv-timept	156 HDE: 157 Impv ROSC	158 Comments
159 CT
160 805	161 Perondi 2004	162 68	163 P	164 IHCA	165 0.1mg/kg / 166 0.01 mg/kg	167 N/A	168 WORSE – 24h (UTE d/c)	169 NO	170 Sixty-eight kids; HDE worse survival 24h (& d/c)
171 1003	172 Callaham 1992	173 816	174 A	175 OHCA	176 15 / 1	177 NO (“trend” toward 178 worse outcome)	179 NO	180 YES	181 P = 0.1 for worse FNO w HDE
182 1004	183 Brown 1992	184 1280	185 A	186 OHCA	187 .2mg/kg / 188 .02mg/kg	189 NO	190 NO	191 NO	192 HDE showed some benefit specifically in PEA
193 1005	194 Choux 1995	195 536	196 A	197 OHCA	198 5 / 1	199 N/A	200 NO	201 NO	202 Neuro was evaluated but unclear that stats were done – not used for FNO
203 1006	204 Stiell 1992	205 650	206 A (16+)	207 About half/half OHCA / IHCA	208 7 / 1	209 NO - Discharge	210 NO - Discharge	211 NO
212 1007	213 Gueugniaud 1998	214 3327	215 A	216 OHCA	217 5 / 1	218 NO - Discharge	219 NO - Discharge	220 YES	221 HDE helped ROSC in asystole but not V-Fib
222 Expt
223 803	224 Berg 1996	225 30	226 Piglets	227 Expt	228 0.2mg/kg / 229 0.02mg/kg	230 NO	231 NO – 24 hour	232 NO
233 1016	234 Roberts 1990	235 24	236 Canine	237 Expt	238 .2 mg/kg / 239 .02 mg/kg	240 N/A	241 N/A	242 NO	243 Tangential … ? No defib for 25min CC-CPR till then.
244 1018	245 Schmitz 1995	246 14	247 Feline	248 Expt	249 .2mg/kg / 250 .02mg/kg	251 N/A*	252 N/A	253 NO	254 *MRI at 3 hours: no diff HDE / SDE. Time to ROSC same.
255 1020	256 Brunette 1990	257 25	258 Canine	259 Expt	260 0.014mg/kg / .071mg/kg	261 N/A	262 N/A	263 NO	264 ROSC faster w HDE than SDE.
265 1022	266 Berg 1994	267 30	268 Swine	269 Expt	270 0.2mg/kg / 271 0.02mg/kg	272 NO – 24 hour	273 NO – 24 hour	274 NO	275 HDE had worse survival in “ICU period” than SDE
276 1023	277 Angelos 1995	278 30	279 Canine	280 Expt	281 0.2mg/kg / 282 0.02mg/kg	283 N/A	284 NO – two hour	285 NO	286 More rapid ROSC w HDE, but no apparent comparison ROSC (Y vs N) between HDE & SDE

DMU Timestamp: July 13, 2023 21:18