Adrenalin and vasopressin for cardiac arrest

Dott. Paolo Balzaretti

S.C. Medicina e Chirurgia d’Accettazione e d’Urgenza, A.O. “Ordine Mauriziano”, Torino

What we already know about this topic

For several reasons, management of patients with cardiac arrest has always been an actively debated field of Emergency Medicine and one of the subjects which has received great attention in the past years is vasopressor administration. The pathophysiological mechanism which underpinned the adoption of adrenaline in ALS guidelines is the vasoconstriction caused by the stimulation of alpha-adrenergic receptors located on vascular smooth muscle, which in turn increases aortic pressure and coronary perfusion.

Actually, American Heart Association (AHA) and European Resuscitation Council (ERC) guidelines, even if with different strengths of recommendation, list standard dose adrenaline (1 mg every 3 – 5 min) among the drugs to consider in patients with cardiac arrest (a synthesis of both documents statements about vasopressors is reported at the end of the review) (1,2).

Some concerns began to rise when an observational study by Hagihara et al. indicated an improved rate of return of spontaneous circulation with adrenaline, at the expanse of a lower 30-days survival and worst neurological outcomes (3). The latter observation could be related to vasoconstriction induced by epinephrine in the cerebral microcirculation. To clarify the issue, a large trial has been conducted and published recently (Perkins 2018) and its results have been incorporated in the systematic review we are going to summarize.

The Cochrane review

Title: Adrenalin and vasopressin for cardiac arrest

Authors: Finn J, Jacobs I, Williams TA, Gates S, Perkins GD.

Bibliographic citation: Cochrane Database Syst Rev 2019, Issue 1. Art. No.: CD003179.

Objective: to determine whether adrenaline or vasopressin, or both, administered during cardiac arrest, afford any survival benefit.

Included studies: randomized controlled trials

Primary outcome: survival to hospital discharge, survival to hospital admission, neurological outcome.

Secondary outcomes: return of spontaneous circulation.

Number of included studies: 26.

Quality of included studies: globally, risk of bias was poor, except for

Number of patients: 21.704.

Results:

Table 1. Standard dose adrenalin vs. placebo
Outcome	No. of studies / No. of patients	Risk ratio (95% C.I.)	Quality of evidence
Survival to hospital discharge	2 / 8538	1,44 (1,11 – 1,86)	Moderate (OHCA only)
Survival to hospital admission	2 / 8489	2,51 (1,67 – 3,76)	Moderate (OHCA only)
Favourable neurologic outcome*	2 / 8535	1,21 (0,90 – 1,62)
Return to spontaneous circulation	3 / 8663	2,86 (3,12 – 3,71)

Table 2. Standard dose adrenalin vs. high-dose adrenalin
Outcome	No. of studies / No. of patients	Risk ratio (95% C.I.)	Quality of evidence
Survival to hospital discharge	10 / 6274	1,10 (0,75 – 1,62)	Very low
Survival to hospital admission	5 / 5764	1,13 (1,03 – 1,24)	Very low (OHCA only)
Favourable neurologic outcome*	4 / 5803	0,91 (0,65 – 1,26)	Very low
Return to spontaneous circulation	13 / 7014	1,15 (1,02 – 1,29)	Very low

Table 3. Standard dose adrenalin vs. vasopressin
Outcome	No. of studies / No. of patients	Risk ratio (95% C.I.)	Quality of evidence
Survival to hospital discharge	6 / 2511	1,25 (0,84 – 1,85)	Very low
Survival to hospital admission	3 / 1953	1,27 (1,04 – 1,54)	Low (OHCA only)
Favourable neurologic outcome*	4 / 2406	0,82 (0,54 – 1,25)	Very low
Return to spontaneous circulation	6 7 2531	1,10 (0,90 – 1,33)	Very low

Table 4. Standard dose adrenalin vs. standard dose adrenalin and vasopressin
Outcome	No. of studies / No. of patients	Risk ratio (95% C.I.)	Quality of evidence
Survival to hospital discharge	3 / 3242	0,76 (0,47 – 1,22)	Very low
Survival to hospital admission	3 / 3249	0,95 (0,83 – 1,08)	Low (OHCA only)
Favourable neurologic outcome*	1 / 2887	0,65 (0,33 – 1,31)	Very low
Return to spontaneous circulation	3 /3249	0,97 (0,87 – 1,08)	Low

Tables 1 – 4. Results of the meta-analysis. In table 1, RR > 1 favours adrenaline. In tables 2 to 4, RR < 1 favours adrenaline. *: *CPC < 3 o mRS < 4. Abbreviations: RR = risk ratio, OCHA = out of Hospital Cardiac Arrest; CPC = Cerebral Performance Category; mRS = modified Rankin Score.

Comment and conclusions

According to this work, standard dose adrenaline increases the proportion of patients with return of spontaneous circulation, arrived alive to hospital and discharged alive from hospital, while has no impact on favorable neurological outcomes. Vasopressin has no meaningful impact either as a substitute or an adjunct to adrenaline in cardiac arrest. These results are confirmed by another recent systematic review conducted by an independent group (Holmberg 2019).

For comparison of standard dose epinephrine and placebo, 92% of patients come from a single trial, whose authors are involved also in the present systematic review (Perkins 2018); for other comparisons, sources of data are more balanced. There are some concerns about publication bias: indeed, no small studies with negative or non-significant results were included in the analysis.

Most data are related to out-of-hospital cardiac arrest: for this reason, applicability to in-hospital cardiac arrest is only partially warranted.

This study confirm the observation that adrenaline administration can actually increase the proportion of survivor patients developing severe neurological impairment; tacking into account that good neurologic outcome is considered important by patients and their relatives (Haywood 2018, Perkins 2018), more research is needed to better understand how patient’s preferences can taken into account in cardiac arrest decision making about vasopressor use.

Notes

Guidelines from AHA (1):

Standard dose epinephrine (1 mg every 3 – 5 min) may be reasonable in patients with cardiac arrest (Class IIb – LoE B-R)
High dose epinephrine (0,1 – 0,2 mg/kg) is not recommended for routine use in cardiac arrest (class III, LoE B-R)
Vasopressin offers non advantage as a substitute for epinephrine in cardiac arrest (Class IIb, LoE B-R).
Vasopressin in combination with epinephrine offers non advantage as a substitute for epinephrine in cardiac arrest (Class IIb, LoE B-R)
It may be reasonable to administer epinephrine as soon as feasible after the onset of cardiac due to an initial non-shockable rhythm.

Guidelines from ERC (2):

On the basis of expert consensus, for VF/pVT give adrenaline after the third shock once chest compressions have resumed, and then repeat every 3–5 min during cardiac arrest (alternate cycles).
For PEA, give adrenaline 1 mg as soon as venous or intraosseous access is achieved, and repeat every alternate CPR cycle (i.e. about every 3–5 min).

Bibliography

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