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NewsletterDrug UpdateA comparison of repeated high
doses and repeated standard doses of epinephrine for cardiac arrest
outside the hospital
Authors
Reference: N Engl J Med 1998; 339:1595-601.
Reviewer: Rose Christopherson, M.D. Portland VA Medical Center Oregon Health Science University Portland, OR
Background: A prospective randomized multicenter study was conducted to compare repeated high doses of epinephrine with repeated standard doses for out-of-hospital cardiac arrest. Methods: Adults who had out-of-hospital cardiac arrest were enrolled if their cardiac rhythm was ventricular fibrillation after 3 electrical cardioversion attempts, or if they had asystole or pulseless electrical activity at the time epinephrine was to be administered. A total of 3327 patients were randomized to receive up to 15 doses of either 5 mg or 1 mg of epinephrine. Time and route of dosing were determined according to current European Resuscitation Council or American Heart Association protocols. Results: Of 1677 patients randomized to the high-dose group, 40.4% had a return of spontaneous circulation, compared to 36.4% of 1650 patients in the standard-dose group (P = .02). However, 2.3 % of the high-dose group and 2.8 % of the standard-dose group survived to be discharged from the hospital (P = 0.34). Neurological status at discharge was similar in the 2 groups. Conclusions: Long-term survival after cardiac arrest outside the hospital was not better with high dose epinephrine than with standard 1-mg doses of epinephrine, when both were administered repeatedly according to standard protocols. Comment: Obviously, patients do not benefit from resuscitation that simply causes them to have vital signs long enough to be admitted to a hospital, where they subsequently die. This was what the high dose epinephrine seemed to produce, and as the authors concluded, this was not an important benefit. The results of this study are not precisely applicable to our practice, since this is a study of out of hospital cardiac arrests. Most perioperative cardiac arrests are witnessed, and have better outcomes than out of hospital arrests. There is some suggestion, however, that standard doses of epinephrine may be preferable in the kinds of arrests we deal with, from subgroup analyses. Among patients who had active compression-decompression ACLS, hospital discharge occurred for 3.6 % of standard dose and 1.7 % of high dose patients (P = 0.06). Among patients with coarse ventricular fibrillation, the standard dose group tended to do better (11.3 % discharged vs. 7.6 %, P = 0.34). And among patients with fine or medium ventricular fibrillation, 7.5 % of the standard dose patients vs. 4.9 % of high dose patients (P = 0.33) were discharged. These are the subgroups most similar to patients having witnessed, perioperative arrests. While none of these P values are less than 0.05, all of these tendencies favor the standard dose of epinephrine. This study at least shows that there is no proven benefit to higher doses of epinephrine when used in resuscitation, even though they may temporarily bring back a rhythm and pulse.
Human albumin administration
in critically ill patients: systematic review of randomized
controlled trials. Cochrane Injuries Group Albumin
Reviewers.
Reviewer: Sergio Gregoretti, M.D. Department of Anesthesiology University of Alabama at Birmingham Birmingham, AL
Introduction: Accepted indications for human albumin solutions are treatment of hypovolemia due to trauma or surgery, and correction of hypoproteinemia. Because human albumin is expensive and in limited supply, it is imperative that its use should be restricted to situations in which it has been shown effective. A meta-analysis of the existing literature was thus performed to determine if human albumin used in the treatment of critically ill patients has an effect on mortality. Methods: The trials included in the analysis met the following criteria. First, they were randomized trials in which the administration of albumin was compared with no albumin or with administration of crystalloids. Second, the randomized patients belonged to three broad groups: with hypovolemia from trauma or surgery, with burns, or hypoalbuminemia. Third, the mortality of the patients studied was known. No data were extracted on the causes or time of the deaths. Relative risk and risk differences for death for each trial and for the trials combined were calculated using standard statistical methods. Results: A total of 30 trials which met the study's inclusion criteria were identified. In six trials there were no deaths in either the albumin or the comparison groups. These trials were not further considered, leaving 24 trials available for analysis. In each of the three patient categories the risk of death in the albumin-treated group was higher than in the comparison group. The relative risk of death was 1.46, 2.4, and 1.69 for the patients with hypovolemia, burns, and hypoproteinemia, respectively. When all the trials were combined, the pooled relative risk of death in the albumin-treated patients was 1.68 and the pooled difference in the risk of death was 6%. This means that in a group of 100 patients treated with albumin there are going to be 6 deaths more than in a similar group not treated with albumin. Conclusions: This literature analysis found no evidence that albumin reduced mortality. Actually it strongly suggests that albumin might increase the risk of death in critically ill patients. The authors concede that caution must be exerted in interpreting these results. Nevertheless, they believe that a reasonable conclusion is that the use of human albumin should be reviewed. A strong argument could be made that albumin should not be used outside the context of randomized controlled trials with mortality as end-point. Comments: In 17 of the 24 trials reviewed the patients treated with albumin had a higher mortality than the patients who did not receive albumin. In seven trials mortality was less in the patients who received albumin. In each of these trials, analyzed alone, the difference in mortality between treatments did not reach statistical significance. If, however, all the studies are combined, the end result is that albumin treatment is associated with a slight increased risk in mortality. First of all, is it legitimate to combine results of studies so different in patient population, design and endpoints? As eyebrow arising as it may seem, apparently it is. From each study the authors extracted only the mortality, thus making differences among studies unimportant. If the results of this study are valid, how should they be interpreted? I think few would take issue with the finding that albumin does not improve mortality. In a way this information was already contained in the trials reviewed, which overall did show albumin to be of little advantage over other, less expensive treatments. The fact that albumin treatment was associated with an increase in mortality is more problematic. In a later correspondence the authors stated that "the trials were included in the analysis only if the treatment (albumin) group differed from the comparison group only in the treatment of interest; any difference in mortality would thus be attributed to albumin or the play of chance". Since the authors collected mortality data regardless of the time of death, in several instances the deaths recorded occurred well after the randomized protocol was completed. During this time interval it is reasonable to expect in these critically ill patients new morbid events and additional treatments. Although initially the two groups of patients were well matched and they differed indeed only in the albumin treatment, over time the groups' profile may have changed so as to make any comparison difficult, if not meaningless. The authors' position that the only difference in treatment between the groups of patients, from the randomization until their demise or discharge, was the administration of albumin is open to criticism. Since the patients most likely received a variety of treatments in addition to albumin during the hospitalization, my bias is that the difference in mortality found between the groups is indeed the play of chance. Because of this criticism, the authors' recommendation that albumin should be used exclusively in randomized trials seems unjustifiably strong. Nevertheless, I found this study a powerful incentive to re-assess my own indications for the use of albumin.
New Uses For
Phosphodiesterase Inhibitors
References
Takeuchi K, et al. Vesnarinone and amrinone reduce the systemic inflammatory response syndrome. J Thorac Cardiovasc Surg 117:375-382, 1999
Reviewer: Mark A. Chaney, M.D.
Comments: The hemodynamic effects of phosphodieserase inhibitors are well known. Selective phosphodieserase inhibition creates increased cyclic adenosine monophosphate levels in myocardium and vascular endothelium which leads to positive inotropic effects and vasodilation. Stroke volume and cardiac output increase, intracardiac filling pressure and systemic vascular resistance decrease, and heart rate and myocardial oxygen consumption remain unchanged. However, recent investigations reveal that phosphodiesterase inhibitors also possess antiinflammatory properties which may benefit patients exposed to cardiopulmonary bypass. The systemic inflammatory response syndrome occurs in patients during and after cardiopulmonary bypass. It involves activation of many complex and interrelated pathways that affect platelets, white blood cells, complement activation, endotoxin release, cytokine production, etc. creating changes in coagulation, fibrinolysis, and vascular permeability, among others. These alterations may affect postoperative morbidity by causing major organ dysfunction. Thus, therapies modulating the systemic inflammatory response are desirable yet not available for routine use at the present time. Recent investigation suggests that phosphodiesterase inhibitors may be useful. Phosphodiesterase inhibitors possess diverse immunomodulating properties and affect production of pro - and antiinflammatory cytokines by endotoxemia-stimulated monocytes in both human and experimental models. They decrease myocardial inflammation and T-cell activity in experimental myocarditis. Some investigators have speculated that the antiinflammatory actions of phosphodiesterase inhibitors may be responsible for the clinical improvements in cardiac function observed at concentrations that are not inotropic. The exact mechanism of action is still uncertain yet likely involves increased intracellular levels of cyclic adenosine monophosphate (increased levels of which have been shown to inhibit lipopolysacchride-mediated tumor necrosis factor gene transcription). It is apparent that important differences exist in varied cell types with regard to phosphodiesterase isoform content (phosphodiesterase III or IV) and the sensitivity of these isoforms to phosphodiesterase inhibitors. The first referenced study reveals that milrinone diminishes endotoxemia and subsequent acute-phase response in adult patients following cardiopulmonary bypass. The second referenced study shows that vesnarinone and amrinone prevent or reduce many aspects of acute endotoxemia (fever, acidosis, cardiac dysfunction, death) in a rabbit model of experimentally induced endotoxemia. In conclusion, because of their ability to modulate several aspects of the inflammatory response, phosphodieserase inhibitors may benefit patients exposed to cardiopulmonary bypass in ways other than hemodynamic. Mark A. Chaney, M.D. Assistant Professor of Anesthesiology Loyola University Medical Center Foster G. McGaw Hospital Maywood, IL
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