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  • Paolo Balzaretti
  • Commentaries

Adrenalin and vasopressin for cardiac arrest

  • 2/2019-giugno
  • ISSN 2532-1285
  • https://doi.org/10.23832/ITJEM.2019.025

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):
 
  1. Standard dose epinephrine (1 mg every 3 – 5 min) may be reasonable in patients with cardiac arrest (Class IIb – LoE B-R)
  2. High dose epinephrine (0,1 – 0,2 mg/kg) is not recommended for routine use in cardiac arrest (class III, LoE B-R)
  3. Vasopressin offers non advantage as a substitute for epinephrine in cardiac arrest (Class IIb, LoE B-R).
  4. Vasopressin in combination with epinephrine offers non advantage as a substitute for epinephrine in cardiac arrest (Class IIb, LoE B-R)
  5. 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):

  1. 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).
  2. 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

  1. Web-based Integrated 2015 & 2018 American Heart Association Guidelines for CPR and ECC. Part 7: Adult Advanced Cardiovascular Life Support. Available at: https://eccguidelines.heart.org/index.php/circulation/cpr-ecc-guidelines-2/part-7-adult-advanced-cardiovascular-life-support/. Accessed: 2019/05/04.
  2. Soara J, Nolan JP, Böttigerd BW, Perkins GD, Lott C, Carli P, Pellisi T, Sandroni C, Skrifvarsk MB, Smith GB, Sundem K, Deakin CD, on behalf of the Adult advanced life support section Collaborators. European Resuscitation Council Guidelines for Resuscitation 2015 Section 3. Adult advanced life support. Resuscitation 2015; 95: 100–147.
  3. Hagihara A, Hasegawa M, Abe T, Nagata T, Wakata Y, Miyazaki S. Prehospital epinephrine use and survival among patients with out-of-hospital cardiac arrest. JAMA. 2012 Mar 21;307(11):1161-8.
  4. Perkins GD, Ji C, Deakin CD, Quinn T, Nolan JP, Scomparin C, Regan S, Long J, Slowther A, Pocock H, Black JJM, Moore F, Fothergill RT, Rees N, O’Shea L, Docherty M, Gunson I, Han K, Charlton K, Finn J, Petrou S, Stallard N, Gates S, Lall R, for the PARAMEDIC2 Collaborators. A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest. N Engl J Med 2018; 379:711-21.
  5. Finn J, Jacobs I, Williams TA, Gates S, Perkins GD. Adrenalin and vasopressin for cardiac arrest. Cochrane Database Syst Rev 2019, Issue 1. Art. No.: CD003179.
  6. Holmberg MJ, Issa MS, Moskowitz A, Morley P, Welsford M, Neumar RW, Paiva EF, Coker A, Hansen CK, Andersen LW, Donnino MW, Berg KM; Advanced Life Support Task Force at the International Liaison Committee on Resuscitation (ILCOR). Vasopressors during adult cardiac arrest: A systematic reviewand meta-analysis. Resuscitation. 2019 Apr 10; 139:106-121.
  7. Haywood K, Whitehead L, Nadkarni VM, Achana F, Beesems S, Böttiger BW, Brooks A, Castrén M, Ong MEH, Hazinski MF, Koster RW, Lilja G, Long J, Monsieurs KG, Morley PT, Morrison L, Nichol G, Oriolo V, Saposnik G, Smyth M, Spearpoint K, Williams B, Perkins GD; COSCA COSCA(Core Outcome Set for Cardiac Arrest) in Adults: An Advisory Statement Fromthe International Liaison Committee on Resuscitation. Resuscitation. 2018; 127:147-163.