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Reply to Letter: Regarding "Effect of adrenaline on survival in out-of-hospital cardiac arrest: A randomised double-blind placebo-controlled trial"
... The original authors reached similar conclusions when they re-analyzed their data using a Bayesian approach (OR 2.1, 95%CI 0.7-6.3). [35] Like any post hoc analysis, the clinical significance of these arguments must be interpreted with caution, especially in light of the non-statistically signifi cant trend towards decrease in neurological performance found in this study and conflicting evidence from very large prospective cohort studies. [18] The opportunity cost of administering epinephrine must also be considered. ...
BACKGROUND:
Epinephrine is recommended in advanced cardiac life support guidelines for use in adult cardiac arrest, and has been used in cardiopulmonary resuscitation since 1896. Yet, despite its long time use and incorporation into guidelines, epinephrine suffers from a paucity of evidence regarding its influence on survival. This critical review was conducted to address the knowledge deficit regarding epinephrine in out-of-hospital cardiac arrest and its effect on return of spontaneous circulation, survival to hospital discharge, and neurological performance.
METHODS:
The EMBASE and MEDLINE (through the Pubmed interface) databases, and the Cochrane library were searched with the key words “epinephrine”, “cardiac arrest” and variations of these terms. Original research studies concerning epinephrine use in adult, out-of-hospital cardiac arrest were selected for further review.
RESULTS:
The search yielded nine eligible studies based on inclusion criteria. This includes five prospective cohort studies, one retrospective cohort study, one survival analysis, one case control study, and one RCT. The evidence clearly establishes an association between epinephrine and increased return of spontaneous circulation, the data were conflicting concerning survival to hospital discharge and neurological outcome.
CONCLUSIONS:
The results of this review exhibit the paucity of evidence regarding the use of epinephrine in out of hospital cardiac arrest. There is currently insufficient evidence to support or reject its administration during resuscitation. Larger sample, placebo controlled, double blind, randomized control trials need to be performed to definitively establish the effect of epinephrine on both survival to hospital discharge and the neurological outcomes of treated patients.
METHODS: The EMBASE and MEDLINE (through the Pubmed interface) databases, and the Cochrane library were searched with the key words "epinephrine", "cardiac arrest" and variations of these terms. Original research studies concerning epinephrine use in adult, out-of-hospital cardiac arrest were selected for further review. RESULTS: The search yielded nine eligible studies based on inclusion criteria. This includes five prospective cohort studies, one retrospective cohort study, one survival analysis, one case control study, and one RCT. The evidence clearly establishes an association between epinephrine and increased return of spontaneous circulation, the data were conflicting concerning survival to hospital discharge and neurological outcome. CONCLUSIONS: The results of this review exhibit the paucity of evidence regarding the use of epinephrine in out of hospital cardiac arrest. There is currently insufficient evidence to support or reject its administration during resuscitation. Larger sample, placebo controlled, double blind, randomized control trials need to be performed to defi nitively establish the effect of epinephrine on both survival to hospital discharge and the neurological outcomes of treated patients.
The International Liaison Committee on Resuscitation (ILCOR) now recommends therapeutic hypothermia (TH) (33 °C for 12-24 hours) as soon as possible for patients who remain comatose after resuscitation from shockable rhythm in out-of-hospital cardiac arrest and that it be considered for non shockable rhythms. The optimal timing of TH is still uncertain. Laboratory data have suggested that there is significantly decreased neurological injury if cooling is initiated during CPR. In addition, peri-arrest cooling may increase the rate of successful defibrillation. This study aims to determine whether paramedic cooling during CPR improves outcome compared standard treatment in patients who are being resuscitated from out-of-hospital cardiac arrest.
This paper describes the methodology for a definitive multi-centre, randomised, controlled trial of paramedic cooling during CPR compared with standard treatment. Paramedic cooling during CPR will be achieved using a rapid infusion of large volume (20-40 mL/kg to a maximum of 2 litres) ice-cold (4 °C) normal saline.The primary outcome measure is survival at hospital discharge. Secondary outcome measures are rates of return of spontaneous circulation, rate of survival to hospital admission, temperature on arrival at hospital, and 12 month quality of life of survivors.
This trial will test the effect of the administration of ice cold saline during CPR on survival outcomes. If this simple treatment is found to improve outcomes, it will have generalisability to prehospital services globally.
ClinicalTrials.gov: NCT01172678.
Intravenous access and drug administration are included in advanced cardiac life support (ACLS) guidelines despite a lack of evidence for improved outcomes. Epinephrine was an independent predictor of poor outcome in a large epidemiological study, possibly due to toxicity of the drug or cardiopulmonary resuscitation (CPR) interruptions secondary to establishing an intravenous line and drug administration.
To determine whether removing intravenous drug administration from an ACLS protocol would improve survival to hospital discharge after out-of-hospital cardiac arrest.
Prospective, randomized controlled trial of consecutive adult patients with out-of-hospital nontraumatic cardiac arrest treated within the emergency medical service system in Oslo, Norway, between May 1, 2003, and April 28, 2008.
Advanced cardiac life support with intravenous drug administration or ACLS without access to intravenous drug administration.
The primary outcome was survival to hospital discharge. The secondary outcomes were 1-year survival, survival with favorable neurological outcome, hospital admission with return of spontaneous circulation, and quality of CPR (chest compression rate, pauses, and ventilation rate).
Of 1183 patients for whom resuscitation was attempted, 851 were included; 418 patients were in the ACLS with intravenous drug administration group and 433 were in the ACLS with no access to intravenous drug administration group. The rate of survival to hospital discharge was 10.5% for the intravenous drug administration group and 9.2% for the no intravenous drug administration group (P = .61), 32% vs 21%, respectively, (P<.001) for hospital admission with return of spontaneous circulation, 9.8% vs 8.1% (P = .45) for survival with favorable neurological outcome, and 10% vs 8% (P = .53) for survival at 1 year. The quality of CPR was comparable and within guideline recommendations for both groups. After adjustment for ventricular fibrillation, response interval, witnessed arrest, or arrest in a public location, there was no significant difference in survival to hospital discharge for the intravenous group vs the no intravenous group (adjusted odds ratio, 1.15; 95% confidence interval, 0.69-1.91).
Compared with patients who received ACLS without intravenous drug administration following out-of-hospital cardiac arrest, patients with intravenous access and drug administration had higher rates of short-term survival with no statistically significant improvement in survival to hospital discharge, quality of CPR, or long-term survival.
clinicaltrials.gov Identifier: NCT00121524.
The health and policy implications of regional variation in incidence and outcome of out-of-hospital cardiac arrest remain to be determined.
To evaluate whether cardiac arrest incidence and outcome differ across geographic regions.
Prospective observational study (the Resuscitation Outcomes Consortium) of all out-of-hospital cardiac arrests in 10 North American sites (8 US and 2 Canadian) from May 1, 2006, to April 30, 2007, followed up to hospital discharge, and including data available as of June 28, 2008. Cases (aged 0-108 years) were assessed by organized emergency medical services (EMS) personnel, did not have traumatic injury, and received attempts at external defibrillation or chest compressions or resuscitation was not attempted. Census data were used to determine rates adjusted for age and sex.
Incidence rate, mortality rate, case-fatality rate, and survival to discharge for patients assessed or treated by EMS personnel or with an initial rhythm of ventricular fibrillation.
Among the 10 sites, the total catchment population was 21.4 million, and there were 20,520 cardiac arrests. A total of 11,898 (58.0%) had resuscitation attempted; 2729 (22.9% of treated) had initial rhythm of ventricular fibrillation or ventricular tachycardia or rhythms that were shockable by an automated external defibrillator; and 954 (4.6% of total) were discharged alive. The median incidence of EMS-treated cardiac arrest across sites was 52.1 (interquartile range [IQR], 48.0-70.1) per 100,000 population; survival ranged from 3.0% to 16.3%, with a median of 8.4% (IQR, 5.4%-10.4%). Median ventricular fibrillation incidence was 12.6 (IQR, 10.6-5.2) per 100,000 population; survival ranged from 7.7% to 39.9%, with a median of 22.0% (IQR, 15.0%-24.4%), with significant differences across sites for incidence and survival (P<.001).
In this study involving 10 geographic regions in North America, there were significant and important regional differences in out-of-hospital cardiac arrest incidence and outcome.
Recent studies suggest that doses of epinephrine of 0.1 mg per kilogram of body weight or higher may improve myocardial and cerebral blood flow as well as survival in cardiac arrest. Such studies have called into question the traditional dose of epinephrine (0.007 to 0.014 mg per kilogram) recommended for advanced cardiac life support.
We randomly assigned 650 patients who had had cardiac arrest either in or outside the hospital to receive up to five doses of high-dose (7 mg) or standard-dose (1 mg) epinephrine at five-minute intervals according to standard protocols for advanced cardiac life support. Patients who collapsed outside the hospital received no advanced-life-support measures other than defibrillation before reaching the hospital.
There was no significant difference between the high-dose group (n = 317) and the standard-dose group (n = 333) in the proportions of patients who survived for one hour (18 percent vs. 23 percent, respectively) or who survived until hospital discharge (3 percent vs. 5 percent). Among the survivors, there was no significant difference in the proportions who remained in the best category of cerebral performance (90 percent vs. 94 percent) and no significant difference in the median Mini-Mental State score (36 vs. 37). The exploration of clinically important subgroups, including those with out-of-hospital arrest (n = 335) and those with in-hospital arrest (n = 315), failed to identify any patients who appeared to benefit from high-dose epinephrine and suggested that some patients may have worse outcomes after high-dose epinephrine.
High-dose epinephrine was not found to improve survival or neurologic outcomes in adult victims of cardiac arrest.
Epinephrine has been the mainstay for cardiac resuscitation for more than 30 years. Its vasopressor effect by which it increases coronary perfusion pressure is likely to favor initial resuscitation. Its beta-adrenergic action, however, may have detrimental effects on postresuscitation myocardial function when administered before resuscitation because it increases myocardial oxygen consumption. In the present study, our focus was on postresuscitation effects of epinephrine when this adrenergic agent was administered during cardiopulmonary resuscitation. Postresuscitation myocardial functions were compared with those of a selective alpha-adrenergic agent, phenylephrine, when epinephrine was combined with a beta 1-adrenergic blocking agent, esmolol, and saline placebo.
Ventricular fibrillation was induced in 40 Sprague-Dawley rats. Mechanical ventilation and precordial compression was initiated either 4 or 8 minutes after the start of ventricular fibrillation. The adrenergic drug or saline placebo was administered as a bolus after 4 minutes of precordial compression. Defibrillation was attempted 4 minutes later. Left ventricular pressure, dP/dt40, and negative dP/dt were continuously measured for an interval of 240 minutes after successful cardiac resuscitation. Except for saline placebo, comparable increases in coronary perfusion pressure were observed after each drug intervention. The number of countershocks required for restoration of spontaneous circulation was significantly greater for epinephrine-treated animals (10 +/- 8) when compared with phenylephrine-treated animals (1.8 +/- 0.4, P < .01) and with animals treated with epinephrine combined with esmolol (1.6 +/- 0.9, P < .01). After resuscitation, dP/dt40 and negative dP/dt were significantly decreased and left ventricular end-diastolic pressure was significantly increased in each animal when compared with prearrest levels. However, the greatest impairment followed epinephrine, and this was associated with significantly greater heart rate and the shortest interval of postresuscitation survival of 8 +/- 4 hours, whereas placebo controls survived for 12 +/- 11 hours. Phenylephrine-treated animals survived for 41 +/- 10 hours (P < .01 versus epinephrine), and animals that received a combination of epinephrine and esmolol survived for 35 +/- 11 hours (P < .01 versus epinephrine). When the duration of untreated cardiac arrest was increased from 4 to 8 minutes, the severity of postresuscitation left ventricular dysfunction was magnified, but disproportionate decreases in postresuscitation survival were again observed with placebo and epinephrine when compared with alpha-adrenergic agonists.
In an established rodent model after resuscitation following cardiac arrest, epinephrine significantly increased the severity of postresuscitation myocardial dysfunction and decreased duration of survival. More selective alpha-adrenergic agonist or blockade of beta 1-adrenergic actions of epinephrine reduced postresuscitation myocardial impairment and prolonged survival.
There is little evidence from clinical trials that the use of adrenaline (epinephrine) in treating cardiac arrest improves survival, despite adrenaline being considered standard of care for many decades. The aim of our study was to determine the effect of adrenaline on patient survival to hospital discharge in out of hospital cardiac arrest.
We conducted a double blind randomised placebo-controlled trial of adrenaline in out-of-hospital cardiac arrest. Identical study vials containing either adrenaline 1:1000 or placebo (sodium chloride 0.9%) were prepared. Patients were randomly allocated to receive 1 ml aliquots of the trial drug according to current advanced life support guidelines. Outcomes assessed included survival to hospital discharge (primary outcome), pre-hospital return of spontaneous circulation (ROSC) and neurological outcome (Cerebral Performance Category Score - CPC).
A total of 4103 cardiac arrests were screened during the study period of which 601 underwent randomisation. Documentation was available for a total of 534 patients: 262 in the placebo group and 272 in the adrenaline group. Groups were well matched for baseline characteristics including age, gender and receiving bystander CPR. ROSC occurred in 22 (8.4%) of patients receiving placebo and 64 (23.5%) who received adrenaline (OR=3.4; 95% CI 2.0-5.6). Survival to hospital discharge occurred in 5 (1.9%) and 11 (4.0%) patients receiving placebo or adrenaline respectively (OR=2.2; 95% CI 0.7-6.3). All but two patients (both in the adrenaline group) had a CPC score of 1-2.
Patients receiving adrenaline during cardiac arrest had no statistically significant improvement in the primary outcome of survival to hospital discharge although there was a significantly improved likelihood of achieving ROSC.
Epinephrine is the recommended drug for use in resuscitation from all types of cardiac arrest. Experimental evidence has shown that the actions of epinephrine important for the restoration of spontaneous circulation are mediated by the alpha-adrenergic properties. The beta-adrenergic effects do not aid restoration of spontaneous circulation, nor do they aid defibrillation; however, beta-adrenergic stimulation does increase the oxygen consumption of the fibrillating myocardium, a potentially deleterious effect. The important factor in restoring spontaneous circulation appears to be development of adequate coronary blood flow by increasing coronary perfusion pressure (aortic diastolic minus right atrial pressure). Aortic diastolic pressure can be increased by any potent alpha-adrenergic agonist. Because phenylephrine and methoxamine do not have significant beta-adrenergic actions, they should be considered as alternatives to epinephrine for aid in restoring spontaneous circulation. Once spontaneous circulation is restored, alpha-and/or beta-adrenergic agonists may be needed for circulatory support. Which drugs will provide the best longterm survival has not been established.
A large proportion of cardiac arrests outside hospital are caused by ventricular fibrillation. Although it is frequently used, the exact role of treatment with adrenaline in these patients remains to be determined.
To describe the proportion of patients with witnessed out-of-hospital cardiac arrest found in ventricular fibrillation who survived and were discharged from hospital in relation to whether they were treated with adrenaline prior to hospital admission.
All the patients with out-of-hospital cardiac arrest found in ventricular fibrillation in Göteborg between 1981 and 1992 in whom cardiopulmonary resuscitation (CPR) was initiated by our emergency medical service (EMS). During the observation period, some of the EMS staff were authorized to give medication and some were not.
In all, 1360 patients were found in ventricular fibrillation and detailed information was available in 1203 cases (88%). Adrenaline was given in 417 cases (35%). Among patients with sustained ventricular fibrillation, those who received adrenaline experienced the return of spontaneous circulation more frequently (P < 0.001) and were hospitalized alive more frequently (P < 0.01). However, the rate of discharge from hospital did not differ significantly between the 2 groups. Among patients who converted to asystole or electromechanical dissociation, those who received adrenaline experienced the return of spontaneous circulation more frequently (P < 0.001) and were hospitalised alive more frequently (P < 0.001). However, the rate of discharge from hospital did not differ significantly between the 2 groups.
On the basis of 2 treatment regimens during a 12-year survey, we explored the usefulness of adrenaline in out-of-hospital ventricular fibrillation. Both patients with sustained ventricular fibrillation and those who converted to asystole or electromechanical dissociation had an initially more favourable outcome if treated with adrenaline. However, the final outcome was not significantly affected. This study does not confirm the hypothesis that adrenaline increases survival among patients with out-of-hospital cardiac arrest who are found in ventricular fibrillation.
In the management of cardiac arrest there is ongoing controversy concerning the optimal dose of epinephrine. To obtain the best available evidence regarding the current optimal dose, we performed a meta-analysis. We searched the Medline database online and reviewed citations in relevant articles to identify studies that met preset inclusion criteria (prospective, randomized, double-blind). Five trials were identified. The pooled odds ratio for return of spontaneous circulation favours the experimental dose. The pooled odds ratio for hospital discharge failed to demonstrate a statistically significant beneficial effect of high and/or escalating doses of epinephrine in comparison with standard dose of epinephrine. The possibility that patients who have already sustained irreversible neurologic injury will be resuscitated carries potential adverse social and economic implications.
To relate the outcome of out-of-hospital cardiac arrest to whether medication with adrenaline (epinephrine) was given and whether patients were intubated.
A national survey in Sweden between 1990-1995 among patients suffering out-of-hospital cardiac arrest and in whom resuscitation was attempted. Sixty per cent of ambulance organisations in Sweden participated.
Prospective evaluation. Survival was defined as survival 1 month after cardiac arrest.
In all, 14065 patients were included in the evaluation. Of these, resuscitation was attempted in 10966 cases. Among these adrenaline (epinephrine) was given in 42.4 and 47.5% were intubated. In an univariate analysis treatment with adrenaline (epinephrine) and intubation was associated with a lower survival when all patients were evaluated. In a multivariate analysis including age, sex, place of arrest, bystander-CPR, initial arrhythmia, arrest being witnessed and aetiology, treatment with adrenaline (epinephrine) (OR 0.43, CI 0.27-0.66) and intubation (OR 0.71, CI 0.51-0.99) were both independent predictors of a lower chance of survival. When separately analysing patients with bystander witnessed cardiac arrest found in ventricular fibrillation and requiring more than 3 defibrillatory shocks neither treatment with adrenaline (epinephrine) nor intubation was associated with survival. Among patients with a non-shockable rhythm treatment with adrenaline (epinephrine) was a significant independent predictor for lower survival (OR 0.30, CI 0.07-0.82).
In a national survey in Sweden including 10966 cases of out-of-hospital cardiac arrest the outcome was related to whether medication with adrenaline (epinephrine) was given and whether patients were intubated. Neither in total nor in any subgroup did we find results indicating beneficial effects of any of these two interventions. Whether treatment with adrenaline (epinephrine) or intubation will increase survival after out-of-hospital cardiac arrest needs to be confirmed in prospective randomised trials.
Both epinephrine and vasopressin increase aortic and carotid arterial pressure when administered during cardiopulmonary resuscitation. However, we recently demonstrated that epinephrine reduces cerebral cortical microcirculatory blood flow. Accordingly, we compared the effects of nonadrenergic vasopressin with those of epinephrine on cerebral cortical microvascular flow together with cortical tissue Po2 and Pco2 as indicators of cortical tissue ischemia.
Randomized, prospective animal study.
University-affiliated research laboratory.
Domestic pigs.
The tracheae of ten domestic male pigs, weighing 40 +/- 2 kg, were noninvasively intubated, and the animals were mechanically ventilated. A frontoparietal bilateral craniotomy was created. Microcirculatory blood flow was quantitated with orthogonal polarization spectral imaging. Blood flow velocity in pial and cortical penetrating vessels measuring <20 microm was graded from 0 (no flow) to 3 (normal). Cerebral cortical tissue carbon dioxide and oxygen tensions (Pbco2 and Pbo2) were measured concurrently using miniature optical sensors. Ventricular fibrillation, induced with an alternating current delivered to the right ventricular endocardium, was untreated for 3 mins. Animals were then randomized to receive central venous injections of equipressor doses of epinephrine (30 microg/kg) or vasopressin (0.4 units/kg) at 1 min after the start of cardiopulmonary resuscitation. After 4 mins of cardiopulmonary resuscitation, defibrillation was attempted. Spontaneous circulation was restored in each animal. However, postresuscitation microvascular flows and Pbo2 were greater and Pbco2 less after vasopressin when compared with epinephrine. We observed that a significantly greater number of cortical microvessels were perfused after vasopressin.
Cortical microcirculatory blood flow was markedly reduced after epinephrine, resulting in a greater severity of brain ischemia after the restoration of spontaneous circulation in contrast to the more benign effects of vasopressin.