toxicology journal club sept 2011

Effect of adrenaline on survival in out-of-hospital cardiac arrest:

Toxicology Journal Club

A randomised double-blind placebo-controlled trial

Resuscitation. 2011 Sep;82(9):1138-43. Epub 2011 Jul 2.

Juan Pablo Peña Diaz, MDMedicina de Urgencias

Effect of adrenaline on survival in out-of-hospital cardiac arrest

Juan Pablo Peña Diaz, MD / Medicina de UrgenciasToxicology Journal Club

Effect of adrenaline on survival in out-of-hospital cardiac arrest:

Ian G. Jacobs, Judith C. Finn, George A. Jelinek, Harry F. Oxer, Peter L. Thompson

Cardiovascular disease caused the dead of 15 million people in 1996 (29 % global mortality)

Ischemic Heart Disease: 7 million/people/year

Risk for Sudden Death: 5 to 7 times

Becker L, Larsen MP, Eisenberg MS. Incidence of cardiac arrest during self-transport for chest pain. Ann Emerg Med. 1996 Dec;28(6):612-6

Nichol G, Thomas E, Callaway CW, et al. Regional variation in out-of-hospital cardiac arrest incidence and outcome. JAMA 2008;300:1423–31.

Roger VL, Go AS, Lloyd-Jones DM, Adams RJ, Berry JD. Heart Disease and Stroke Statistics 2010 Update: A report from the American Heart Association. Circulation. 2011;123

Incidence in USA: 95.7 per 100,000 person years

AMI: 295.000 people die before hospital arrival (70%)

55% to 60% were attended by EMS

Commonest cardiac arrest rhythm:VF / VT (23% a 30%)

Survival to hospital discharge: < 7%

Becker L, Larsen MP, Eisenberg MS. Incidence of cardiac arrest during self-transport for chest pain. Ann Emerg Med. 1996 Dec;28(6):612-6.

Closed-chest cardiac massage. JAMA. 1960 Jul 9;173:1064-7.

Only Class I Evidence

Routine use of adrenaline (epinephrine) in treating cardiac arrest has been recommended for over half a century

First described in 1906:

JAMA. 1968 Jan 22;203(4):255-60.

Ann Emerg Med September 1984 (Part 2);13:840-843

We conclude that epinephrine produces a significant dose-dependent vasopressor response during CPR in human beings. This finding supports work in animal models and anecdotal reports in human beings, indicating that doses of epinephrine that are higher than those currently recommended may be needed during late CPR in human beings. Ann Emerg Med , September 1989;18:920-926

EMS setting

ObservationalProspective417: Adrenaline786: No Adrenaline

Authorized by Medical dispatcher

Resus, 1.995

Ann Emerg Med. 2007;50:635-642

Singapore EMS

ObservationalProspectiveBefore-after

October 2002 to October 20041.296 pts- 615 pre-epinephrine- 681 epinephrine phase

AIM: Evaluate the incremental benefitof introducing intravenous epinephrine in the out-of-hospitalsetting on the survival outcomes of cardiac arrest patients

There was no significant difference in survival to discharge, adjusted for rhythm; return of circulation or survival toadmission

There was a minimal increase in scene time in the epinephrine phase (10.3 minutes versus 10.7 minutes)

Conclusion: We were unable to establish a significant survival benefit with the introduction of IV epinephrine to an EMS system

ProspectiveRandomizedControlledNon Blinded

Objective: To determine whether removing intravenous drug administration from an ACLS protocol would improve survival to hospital discharge after out-of-hospital cardiac arrest.

JAMA. 2009;302(20):2222-2229

851 Pts- 418 in the ACLS with IV- 433 were in the ACLS with no access to IV drug administration group

- Survival to hospital discharge was 10.5% for the IV vs 9.2% for the no IV drug administration group (P=.61)- Hospital admission with ROSC 32% vs 21%, (P.001)- Survival with favorable neurological outcome 9.8% vs 8.1% (P=.45)- Survival at 1 year 10% vs8%(P=.53)

Despite adrenaline being universally considered “standard of care” in the treatment of cardiac arrest there has never been a randomized placebo-

controlled trial to establish its efficacy.

Methods

Study patients and setting:

All calls for ambulances throughout WA are received centrally and ambulances dispatched by the ambulance service communicationcentre located in Perth.

All ambulances in Perth and largerregional centres in WA are staffed by career PMDs where theirscope of clinical care is governed by specific SJA-WA clinical practiceguidelines.

The management of cardiac arrest is based on the recommendations of the Australian Resuscitation Council

- Defibrillation with a manual Defibrillator

- Securing the airway (TT or LMA)

- No drugs were administered

Study design

RandomizedDouble blindPlaceboControlled trial

Patients were randomized to receive:

- IV Adrenaline 1:1000 or- Placebo (sodium chloride 0.9%)

Out-of-hospital cardiac arrest patients attended by SJA-WA EMS

Study outcomes

* Primary endpoint: Survival to hospital discharge

** Secondary endpoints:- Pre-hospital ROSC (a period of sustained ROSC in the field for greater 30 s)- Cerebral Performance Category (CPC) at hospitalDischarge

I – normal functionII – mild to moderate disabilityIII – severe disabilityIV – vegetative state,V – dead

The study was approved by the

of the

and waiver (disclaim) of consent was granted

Study procedures

All out-of-hospital cardiac arrests attended between 11th August 2006 and 30th November 2009

Cardiac arrest from any causeUp 18 y.o.Resuscitation initiated by PMDs

Blinded selection of medication- Initiated after 3 shocks (VF/VT) or-After they got a vein access (PEA/Asys)* No other resuscitation drugs* No Tracheal Route permitted

After arrival to hospital, treating ED clinicians were unaware of drug assignment and managed the patient as per their usual clinical practice (Guidelines)

Data collection

Manually recorded by the paramedicClinically reviewed and data manually entered into theSPSS statistical packageThese form the WA Ambulance Service Cardiac Arrest RegistryCPC scores are derived from medical chart, the reviewer was blinded to the study group allocation

Statistical analysis

The sample size required for the study was 2213 patients per group

This was derived on a baseline survival to hospital discharge of 5% with an absolute improvement in survival of 2%, alpha 0.05 (two tailed) and power of 80%

A total patient enrollment of 5.000 was planned to account for losses to follow-up.

Patient and study characteristics were described using proportions and means, with differences assessed using Pearson’s chi-square and t-test (or Mann–Whitney) for categorical and continuous data respectively

Ambulance time intervals were described using means, medians and interquartile ranges (IQR).Odds ratios (OR) and 95% confidence intervals were derived for primary and secondary outcomes.

Logistic regression was used to adjust for potential confounders on the treatment effect of the studyDrug

It was planned ‘a priori’ to conduct subgroup analysis of primary and secondary outcomes by shockable versus non-shockable initial cardiac arrest rhythm

Analysis was performed on an intention to treat basis and per protocol basis using SPSS statistical software version 17

All statistical tests were two sided with a significance level of 0.05.

Study profile

Patients administered adrenaline the likelihood of achieving ROSC pre-hospital was 3.4 times greater than for those receiving placebo (23.5% versus 8.4%; OR 3.4; 95% CI 2.0–5.6)

Adrenaline was associated with a significant increase in the proportion of patients admitted from the ED to hospital (25.4% versus 13.0%; OR 2.3; 95% CI 1.4–3.6).

More than twice the number of patients who received adrenaline survived to hospital discharge, but this failed to reach statistical significance (4.0% versus 1.9%; OR 2.2; 95% CI 0.7–6.3)

Good neurological outcome (CPC 1 or 2) was achieved in 14 out of the 16 survivors. The two unfavourableneurological outcomes (one CPC = 3 and one CPC = 4) occurred in the adrenaline group.

Treatment effect of adrenaline on prehospitalROSC was more marked in non-shockable rhythms (OR 6.9; 95% CI 2.6–18.4) than shockable rhythms (OR 2.4; 95% CI 1.2–4.5)

Adjusted models

Little change in the effect of adrenaline on ROSC or survival to hospital discharge

The presence of an initial shockable rhythm was the only other factor associated with the likelihood of pre-hospital ROSC

A younger age and an initial shockable rhythm was also associated with improved survival to hospital discharge

Discussion

This is the 1st Placebo-RCT of Adrenaline in cardiac arrest

- Adrenaline resulted in a statistically significant increase in ROSC but not in the primary outcome of survival to hospital discharge

- For both shockable and non-shockable initial cardiacarrest rhythms we observed significantly better outcomes interms of ROSC and hospital admission with the use of adrenaline.

What this study demonstrates is that the administration of resuscitation drugs during out of hospital cardiac arrest is associated with improvements in short term survival.

This study “clearly demonstrates the superiority of adrenaline over placebo in achieving ROSC”

All the studies published to date have employed less robust study designs, used adrenaline doses much lower than recommended for cardiac arrest or compared larger doses of adrenaline against unproven standard dose adrenaline regimes.

This is an out-of-hospital study, the influence of post resuscitation care interventions (therapeutic hypothermia, managing underlying cause, organ perfusion and oxygenation) on survival to hospital discharge are recognised

Limitations

Failure to achieve an adequatesample size

Despite having obtained approvals for the study, the concerns of being involved in a trial in which the unproven “standard of care” was being withheld prevented four of the five ambulance servicesfrom participating

Adverse press reports questioning the ethics of conducting this trial, which subsequently led tothe involvement of politicians, further heightened these concerns.

The extensive barriers associated with trialling interventions deemed “standard of care” where clinical equipoise clearly exists serves only to ensure such interventions remain unproven

The findings of this study are clinically important in that it establishes efficacy for the continued use of adrenaline in cardiac arrest as currently recommended, however numerous questions remain unanswered …

What is the optimal dose ?

When is the moment for adrenaline during

cardiac arrest ?

Future Cardiology. July 2010, Vol. 6, No. 4, Pages 473-482Robert R Attaran & Gordon A Ewy

Vasopressor drugs will be more effective with wider adoption of strategies that delay the inevitable deterioration that accompanies untreated or suboptimally treated cardiac arrest.

Cardiac arrest survival rates are mutableResuscitation 82 (2011) 1257– 1258Michael R. Sayre

Measurement of survival to hospital discharge following out of-hospital cardiac arrest should be expected of all EMS systems.

EMS systems should publicly report their hospital discharge survival rates to their political leaders and the citizens they serve as well as the EMS professionals and hospital staffs caring for thosepatients.

Thank You !

toxicology journal club sept 2011

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