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Three Part Question

In [patients receiving cardiopulmonary resuscitation following cardiac arrest], is [the use of adrenaline beneficial] in [improving long-term survival]?

Search Strategy

Ovid MEDLINE(R) 1946 to December Week 4 2012
({(CPR.mp. OR exp cardiopulmonary resuscitation/OR internal cardiac massage.mp. OR chest compressions.mp.) AND (adrenaline.mp. OR exp epinephrine/) AND (survival.mp. OR mortality.mp.)} LIMIT to (human)) 209 records.

The Cochrane Library issue 12 of 12 2012

MeSH descriptor: (Cardiopulmonary Resuscitation) explode all trees AND MESH descriptor: (Epinephrine) this term only 23 records no unique data.

Search Outcome

wo hundred and nine papers were found of which 202 were irrelevant or of insufficient quality for inclusion. The remaining seven papers are shown in the table

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Hagihara et al 2012 Japan	417,188 OHCAs occurring between 2005-2008 in Japan with or without use of adrenaline in the pre-hospital phase.	Retrospective cohort study with concurrent control group	Return of spontaneous circulation before hospital arrival	No adrenaline: 5.7%, Adrenaline: 18.5% (p=0.001, OR 2.36)	Observational study, not random allocation, subject to selection bias and confounding factors. In-hospital resuscitation data not used, 1-month survival influenced by in-hospital care which varies between centres.
			1-month survival	No adrenaline: 4.7%, Adrenaline 5.3% (OR 0.46)
			Survival with Cerebral Performance Category (CPC) 1 or 2	No adrenaline: 2.2%, Adrenaline 1.4% (OR 0.36)
Herlitz et al 1995 Sweden	1203 patients either received adrenaline or not, following OHCA with VF on first ECG recording. Took place in Goteborg (Sweden) between October 1980 to December 1992. 417 (35%) patients received adrenaline.	Retrospective cohort study with concurrent control group	ROSC	No adrenaline: 21%, Adrenaline: 37% (p=0.001)	Patient demographics differed between two groups. Long-term survival not given and neurological status was not indicated or assessed in those that were discharged. Small sample size with potential for type 2 error. Long study period with changes in equipment and protocol. Could not account for quality of post resuscitation care. No randomisation thus subject to selection bias.
			Hospitalised alive	No adrenaline: 22%, Adrenaline: 31% (p=0.01)
			Discharged alive	No adrenaline: 6%, Adrenaline: 9%
Holmberg et al 2002 Sweden	10,966 cases of OHCA over a 5 year period. 42.4% treated with adrenaline	Prospective observational cohort study	1-month survival	No adrenaline: 6.3%, Adrenaline: 3.4% (p<0.0001)	No detailed information concerning neurological status at discharge, and ROSC. Significant differences between two study groups with no randomisation, thus can’t assume two groups are comparable. No control over correct indication for adrenaline, ambulance crew proficiency and compliance to guidelines. No information concerning post-resuscitation care.
Jacobs et al 2011 Australia	534 OHCA of which 262 in placebo group and 272 in adrenaline (given according to Australian Resuscitation Council recommendations). Groups matched for baseline characteristics.	Placebo controlled RCT	Survival to hospital discharge	Placebo: 1.9% (n=5), Adrenaline: 4% (11). (OR 2.2, 95% CI 0.7-6.3)	Underpowered study with regard to survival to hospital discharge. Quality and timing of CPR and adrenaline administration not possible. Paramedic participation was voluntary thus only 40% of possible patients recruited.
			Pre-hospital ROSC (>30s)	Placebo: 8.4% (22), Adrenaline 23.5% (64). (OR 3.4, 95% CI 2.0-5.6)
			CPC at hospital discharge	2 patients in the adrenaline group had CPC score below 1-2.
Olasveengen et al 2012 Norway	848 OHCA with 387 (45.6%) given adrenaline vs. 481 (54.4%) no adrenaline given.	Retrospective analysis of RCT	Admission to hospital alive with ROSC	No adrenaline: 27%, Adrenaline: 48% (OR 2.5, p<0.001)	Confounders not fully adjusted as time points for adrenaline administration and ROSC unreliable. Single centre study.
			Discharge from hospital	No adrenaline: 13%, Adrenaline: 7% (OR 0.5, p=0.006)
			Favourable neurological outcome (CPC 1-2)	No adrenaline: 11%, Adrenaline 5% (OR 0.4, p=0.001)
			Survival at 1 year	No adrenaline: 12%, Adrenaline: 6% (OR 0.5, p=0.004)
Ong et al 2007 Singapore	1296 OHCA. Two phase study. Phase I [pre-adrenaline: paramedics untrained to use adrenaline pre-hospitably (615 patients). Phase II [adrenaline phase]: Paramedics trained to use adrenaline pre-hospitably (of 681 patients 301 receive adrenaline).	Prospective observational cohort study	Survival to hospital discharge (>30 days post arrest)	Pre-adrenaline: 1%, Adrenaline: 1.6% (OR 1.7, 95% CI 0.6-4.5) [Adjusted for rhythm: OR 2.0, 95% CI 0.7-5.5]	Not a randomised placebo controlled RCT. Low rate of successful IV drug delivery. Variation in post-resuscitation care and quality of EMS care, paramedics inexperienced in endotracheal intubation and cannulation (and thus adrenaline administration). Only studied single dose adrenaline.
			CPC 1-2 at discharge	Pre-adrenaline: 80% (n=4), Adrenaline: 81.8% (n=9)
Väyrynen et al 2007 Finland	984 OHCA with initial rhythm being pulseless electrical activity (PEA)	Retrospective observational cohort study	Short term survival rate (hospital admission alive)	No adrenaline: 62.8%, Adrenaline: 28.2% (OR 0.23, p<0.0001)	Only focused on PEA arrests. Range of other factors studied not purely adrenaline. No information on neurological outcome. No randomisation. Difficult to apply results to all EMS systems as protocols vary.
			Long term survival rate (>30 days post arrest)	No adrenaline: 20.9%, Adrenaline: 5.5% (OR 0.22, p<0.0001)

Comment(s)

Adrenaline has long been used following cardiac arrest; however, data from both observational studies and randomised clinical trials (RCT) suggest its use is not beneficial, and more worryingly, may be associated with reduced long-term survival. Its ‘de facto’ use in CPR is contrary to the available evidence. A Cochrane Review is planned, the results of which could influence current guidelines; however, most beneficial would be a well-designed, multicentre placebo controlled RCT to determine if adrenaline is beneficial or harmful in the treatment of cardiac arrest.

Editor Comment

CPC, cerebral performance category; CPR, cardiopulmonary resuscitation; EMS, emergency medical services; IV, intravenous; OHCA, out-of-hospital cardiac arrest; PEA, pulseless electrical activity; RCT, randomised clinical trial; ROSC, return of spontaneous circulation; VF, ventricular fibrillation.

Clinical Bottom Line

The evidence is strong for improved short-term survival when adrenaline is administered during CPR (ROSC and/or survival to hospital admission), but may be associated with worse long-term survival and neurological outcome.

References

1. Hagihara A, Hasegawa M, Abe T. Prehospital epinephrine use and survival among patients with out-of-hospital cardiac arrest. JAMA 2012;307:1161–8.
2. Herlitz J, Ekström L, Wennerblom B. Adrenaline in out-of-hospital ventricular fibrillation. Does it make any difference? Resuscitation 1995;29:195–201.
3. Holmberg M, Holmberg S, Herlitz J. Low chance of survival among patients requiring adrenaline (epinephrine) or intubation after out-of-hospital cardiac arrest in Sweden. Resuscitation 2002;54:37–45.
4. Jacobs IG, Finn JC, Jelinek GA, et al. Effect of adrenaline on survival in out-of-hospital cardiac arrest: A randomised double-blind placebo-controlled trial. Resuscitation 2011;82:1138–43.
5. Olasveengen TM, Wik L, Sunde K, et al. Outcome when adrenaline (epinephrine) was actually given vs. not given - post hoc analysis of a randomized clinical trial. Resuscitation 2012;83:327–32.
6. Ong ME, Tan EH, Ng FS et al. Survival outcomes with the introduction of intravenous epinephrine in the management of out-of-hospital cardiac arrest. Ann Emerg Med 2007;50:635–42.
7. Väyrynen T, Kuisma M, Määttä T, et al. Who survives from out-of-hospital pulseless electrical activity? Resuscitation 2008;76:207–13.