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A slightly greater chance of being alive must be counterbalanced by a much greater probability that it is a life darkened by a serious disability
Synthesis and Commentary
Randomized Trial of Use epinephrine in patients with cardiac arrest »
More patients were alive 30 days after their heart was revived with adrenaline, but their risk of serious brain damage almost doubled ]. results, published in the New England Journal of Medicine. The discovery is expected to lead to a change in the guidelines for treating cardiac arrest, although the trial's lead author, Gavin Perkins of the University of Warwick, was reluctant to commit.
At a press conference at the Science Media Center in London Perkins said that he would need a broader review of findings from organizations such as the UK Resuscitation Council for make the change. The council said that he would consult widely, but expected a change in the guidelines.
Ambulance teams used epinephrine (known as epinephrine in the United States) for many years if cardiopulmonary resuscitation and defibrillation failed. It was introduced after animal experiments showed that the heart restarted but was never subjected to a randomized controlled trial. Observational studies have reported higher rates of return to circulation, but worse neurological outcomes.
The trial was held at five ambulance services in England. In total, nearly 8,000 people who had cardiac arrest and had previously undergone unsuccessful CPR and defibrillation were randomized to receive adrenaline or placebo. The main result was the 30 day survival rate
Patients who received epinephrine had more chance of being alive at 30 days , although the difference was not large: 3.2% vs. 2.4%, with an odds ratio of 1.39 (95% confidence interval: 1.06 to 1.82).
But the risk of disability was higher among the survivors of the epinephrine group, with 31% (39/126) of moderately severe or severe neurological insufficiency (modified Rankin scale 4 or 5), versus 17.8% (16/90) in the placebo group Only 9.5% of the adrenaline group had no disability, compared to 16.7% in the placebo group.
A slightly greater chance of being alive must be counterbalanced by a much greater likelihood that it will be a tarnished life a severe handicap
The results mean that a slightly greater chance of being born To be alive it must be balanced with a much greater probability that it is a life marked by a serious handicap.
The causes of disability remain unclear, but Perkins suggested two possibilities. Although adrenaline increases blood flow in major vessels, it reduces it in smaller ones, perhaps starving and causing injury.
Alternatively, the brain may be more sensitive to lack of blood than the heart. "Epinephrine can be restarting the heart at a time when the brain is already damaged," said co-author Jerry Nolan, a member of the Royal United Hospitals at Bath NHS Foundation Trust.
Perkins says: "Our own work with patients and the public before starting the trial has identified that brain-free survival is more important to patients than survival alone, and the results of the study show that". The trial will require close scrutiny by the community and the clinical guideline leaders, Jonathan Wyllie, President of the Board of Resuscitation (United Kingdom), said: "This study demonstrates the urgent need to conduct a resuscitation survey for consider treatments based on old data or long assumptions.If ever I need a resuscitation, I hope it's based on evidence like this rather than on a simple expert opinion. "[19659004] About 30,000 people have cardiac arrest outside UK hospitals each year. Of these, an estimated 15 to 18% receive adrenaline.
Introduction
Attempting to reduce the death and disability rate associated with cardiac arrest worldwide, 1.2 emergency medical workers have few effective treatments other than the usual. early onset of cardiopulmonary resuscitation (CPR) and immediate defibrillation.3 For over 50 years, treatment strategies have included the use of several drugs, but there is limited evidence that these treatments are effective.4 [19659004] Epinephrine (adrenaline) has potentially beneficial effects on cardiac arrest by constricting arterioles mediated by α-adrenergic receptors. This constriction increases the aortic diastolic pressure during CPR, thereby increasing coronary blood flow and increasing the likelihood of a return of spontaneous circulation.5
Potentially harmful effects in the heart are mediated by stimulation β-adrenergic, which causes arrhythmias and increases the oxygen demand of the myocardium and increases the risk of recurrent cardiac arrest6. In addition, α-adrenergic stimulation causes platelet activation, which promotes thrombosis7 and alters microvascular blood flow in the cerebral cortex, increasing the severity of cerebral ischemia during CPR and after [19659004] Previous studies comparing the standard dose of epinephrine (1 mg) to high doses of epinephrine (5 to 10 mg), epinephrine and vasopressin, or placebo n & # Did not show evidence of better results .9
Observational studies involving more than 500,000 patients reported higher rates of spontaneous recurrence but worse neurological outcomes in patients treated with epinephrine.10 The interpretation of these findings was limited by conflicting results and by the influence of unmeasured confounding factors.
Therefore, the International Liaison Committee on Resuscitation, a consortium of seven major organizations involved in the field of resuscitation worldwide, called for the launch of a placebo-controlled trial to determine Epinephrine is safe and effective as a treatment for cardiac arrest.4
Subsequently, we began PARAMEDIC2 study (prehospital evaluation of the role of epinephrine: measurement of l / adrenaline. effectiveness of drug delivery in case of cardiac arrest) to determine if epinephrine is beneficial or harmful as a treatment for out-of-hospital cardiac arrest12.
Abstract of the study
Antecedents
The International Liaison Committee for Resuscitation, concerned about the use of epinephrine as a treatment for the arrest Heart failure outside the hospital, requested a placebo-controlled trial The use of epinephrine is safe and effective in these patients.
Methods
In a randomized double-blind trial with 8014 patients with cardiac arrest outside the UK hospital, paramedics at five ambulance services of the United States. parenteral adrenaline administered by the National Health Service (4015 patients) or saline placebo (3999 patients), with standard care.
The main result was the 30-day survival rate. Secondary endpoints included survival rate at discharge from the hospital with a favorable neurological outcome, as indicated by a score of 3 or less on the modified Rankin scale (ranging from 0 [sin síntomas] to 6 [muerte]). 19659004] Results
At 30 days, 130 patients (3.2%) in the epinephrine group and 94 (2.4%) in the placebo group were alive (unadjusted odds ratio for survival, 1.39, 95% confidence interval [IC] 1.06 to 1.82, p = 0.02)
There was no evidence of a significant difference in the proportion of patients who survived discharge from the hospital with a favorable neurological outcome (87 out of 4007 patients [2.2%] versus 74 out of 3994 patients [1.9%] unadjusted odds ratio, 1.18, 95% CI, 0, 86 to 1.61).
At the time of discharge to the hospital, severe neurological impairment (score 4 or 5 on the modified Rankin scale) occurred more alive in the epinephrine group than in the placebo group (39). of 126 patients [31.0%] vs. 16 of 90 patients [17.8%])
Survival with neurological outcome favorable to discharge from hospital
Distribution of patient scores on the scale of Rankin modified, ranging from 0 (without symptoms) to 6 (death) Survival at discharge from the hospital with a favorable neurological outcome, as indicated by a score of 3 or less on the scale of Rankin-modified, occurred in 87 of the 4007 patients (2.2%) in the epinephrine group and in 74 of 3994 patients (1.9%) of the placebo group However, severe neurological impairment (score 4 or 5) was more common in the epinephrine group than in the placebo group (39 of 126 patients [31,0%] vs 16 out of 90 patients [17,8%]) Patients who died before discharge were reported with a score of 6 on the scale. The data are presented in a log10 scale of percentages of patients and
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Conclusions In adults with cardiac arrest outside the hospital, the use of drugs was reported. Epinephrine resulted in a significantly higher 30-day survival rate than placebo, but there were no significant differences between the groups. favorable neurological outcome rate because more survivors had severe neurological damage in the epinephrine group. (Funded by the National Institute of Medical Research of the United States and others, the current number of controlled trials, ISRCTN73485024.) |
Discussion
A greater proportion of patients who survived with a severe neurological disability in the epinephrine group
In this trial, the use of epinephrine during resuscitation due to cardiac arrest outside the hospital resulted in a significantly higher survival rate at 30 days than placebo use. Patients in the epinephrine group had a higher rate of spontaneous circulation return, a higher frequency of transportation to the hospital, and a higher rate of intensive care unit treatment.
However, although the survival rate was slightly better, the trial showed no evidence of a difference between the groups in the survival rate with a favorable neurological outcome. This result was explained by a higher proportion of patients who survived with a severe neurological handicap in the epinephrine group.
A meta-analysis of six randomized trials with 6174 patients in which the researchers compared the standard dose of epinephrine (1 mg) with high doses of epinephrine (5 to 10 mg) showed better rates of spontaneous circulation return and admission to the hospital with a high dose.
However, these data, combined with an increase in myocardial dysfunction after a return of spontaneous circulation with high doses of epinephrine, led to a decrease in survival rate. In the study on prehospital adrenaline for cardiac arrest (PACA), which compared the standard dose of epinephrine to placebo 18, the result was inconclusive, as only 10 had been recruited. % of patients expected and information on the distribution of treatment was not available for 10% of patients who were randomized.
The benefit of epinephrine for survival that we found in our study should be considered compared to other treatments the chain of survival.19
The number of patients who would need to be treated with epinephrine to prevent death after cardiac arrest was 112 compared with early detection of cardiac arrest (number needed to treat, 11), 20 CPR performed by one viewer (number needed to treat, 15), 21 and early defibrillation (needed number) to be treated, 5) .22
Reasons why the use of epinephrine does not not improved neurological outcome in this trial are uncertain. One explanation is that, although epinephrine increases macroscopic cerebral blood flow, paradoxically affects cerebral microvascular blood flow and, therefore, has the potential to worsen brain damage after the return of spontaneous circulation. 8.23
An alternative explanation is that the brain is more sensitive to ischemia and the reperfusion injury and less able to recover functionally after the restoration of the circulation than the heart and the others organs24,25. Specific therapies other than temperature management have not been shown to reduce the severity of brain damage after cardiac arrest.
Clinical decision-making must balance the burden and benefits of treatment. The treatment load is high in case of cardiac arrest, because resuscitation is an invasive procedure with significant risks of complications.26
If resuscitation is successful initially, most patients need to continue survival treatments. Treatments are withdrawn in one third of patients and one third of patients die 27, mainly because of the consequences of severe brain injury.
In these patients, the benefits of epinephrine that was identified in our trial is small since it would result in 1 additional survivor for every 112 patients treated . This number is less than the clinically important minimum difference that has been defined in previous studies29,30. Among survivors, almost twice the number in the epinephrine group as in the placebo group had severe neurological deterioration.
Our work with patients and the public before starting the trial identified survival with a favorable neurological outcome as a higher priority than survival alone. The primary endpoint for evaluation of cardiac arrest (COSCA) has been developed by patients and physicians16; the neurological outcome and quality of life related to health were considered priorities and survival as the most important results. Patients may be less willing to accept expensive treatments if the chances of recovery are low or the risk of survival with neurological deterioration is high.31,32
Our trial has several limitations .
According to the protocol, paramedics administered intermittent boluses of 1 mg epinephrine, while other strategies (for example, different doses or dosing intervals) may have produced different results . The previous administration of epinephrine could also have influenced the results, although the data on the benefits of early administration of the drug are contradictory.33-35
We do not collect any information about the results. information on the basic neurological status of patients, although the number of patients who had impaired neurological function prior to cardiac arrest were probably very small and balanced between the two groups.
The original protocol provided for a higher survival rate than observed. This result probably reflects the poor overall prognosis in patients who have no response to initial CPR and defibrillation, and is similar to the results of other studies.7,36
Information about CPR quality was limited to the first 5 minutes of cardiac arrest and involved less than 5% of enrolled patients. Although national guidelines indicate the care that patients receive after resuscitation, we have not ordered or controlled the observance of specific protocols.
| In conclusion in this randomized trial including patients with out-of-hospital cardiac arrest, the use of epinephrine resulted in a significantly higher survival rate at 30 days as the placebo use, but there were no significant differences between the groups in the group. favorable neurological outcome rate because more survivors had severe neurological involvement in the epinephrine group. |
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