Quick Test #66: Pharmacotherapy During Cardiopulmonary Resuscitation

AccessPharmacy's Quick Test lets you test your pharmacologic knowledge and anonymously compare your results to those of your peers. Sign up for our free AccessPharmacy e-newsletter and twice a month Quick Test will appear in your email inbox. Quick Test is developed by Terry L. Schwinghammer, PharmD, AccessPharmacy's Editor-in-Chief, from the site's online resources. Your results will be ranked against those of your peers. Quick Test posted on 9.30.11: Pharmacotherapy During Cardiopulmonary Resuscitation Pharmacologic Therapy   Sympathomimetics   The use of sympathomimetics is a major part of drug therapy in CPR. The primary goal of sympathomimetic therapy is to augment low coronary and cerebral perfusion pressures encountered during CPR. While chest compressions can provide some degree of blood flow to the brain and heart, it is only about 25% of that generally encountered under basal conditions. Animal studies have demonstrated that coronary perfusion pressures above 30 mm Hg are associated with improved survival. In humans, even with properly performed chest compressions, coronary perfusion pressures are only 10 to 15 mmHg, the systolic arterial pressure is rarely above 80 mmHg, the diastolic pressure is low, and the carotid mean pressure is rarely above 40 mm Hg. Epinephrine continues to be a drug of first choice for the treatment of VF, PVT, asystole, and PEA despite a paucity of evidence demonstrating improved survival in humans. Epinephrine is both an α-and β-receptor agonist, although its effectiveness is primarily through it's α effects. The β effects may in fact be harmful as β-stimulation increases myocardial oxygen demand and can increase the severity of postresuscitation myocardial dysfunction. This has led some investigators to evaluate simultaneous β-blocker administration in conjunction with sympathomimetic therapy using an animal model. Unfortunately, these studies have produced mixed results. Several studies have compared the effects of pure α1-agonists, such as phenylephrine and methoxamine, with epinephrine since these agents lack any β-activity. These studies have shown the use of α1-agonists to have no long-term survival advantage over epinephrine. One reason that selective α1-agonists are not superior to epinephrine is related to the α2 effects. Agents that have potent α2 effects (e.g., epinephrine and norepinephrine) may be more effective because the α2-adrenergic receptors lie extrajunctionally in the intima of the blood vessels, making them more accessible to circulating catecholamines—even in low-flow states that occur during CPR. Furthermore, during ischemia, the number of postsynaptic α1-receptors decreases, which suggests a greater role for α2-agonist activity during CPR. Several investigators have compared norepinephrine with epinephrine. Norepinephrine is a potent α-agonist (both α1 and α2) but also has β1-agonist effects. In the only large-scale randomized, double-blind, prospective trial that compared norepinephrine with epinephrine in the prehospital cardiac arrest setting, there were no significant differences in ROSC, hospital admission or discharge. A second, smaller study demonstrated higher resuscitation rates with norepinephrine compared to epinephrine (64% vs 32%) but no significant difference in hospital discharge. Consequently, epinephrine remains the first-line sympathomimetic for CPR. The recommended dose for epinephrine is 1 mg administered by IV or intraosseous (IO) injection every 3 to 5 minutes. This epinephrine dose was derived from animal studies (0.1 mg/kg in a 10 kg dog) and equates to approximately 0.015 mg/kg for a 70 kg human. Both animal and human studies have demonstrated a positive dose—response relationship with epinephrine suggesting that higher doses might be necessary to improve hemodynamics and achieve successful resuscitation. These results, however, have not been replicated in human studies. Collectively, these studies have shown that high-dose epinephrine may increase the initial resuscitation success rate but that overall survival is not significantly different. The discrepancy between animal and human studies may be due to the fact that most victims of cardiac arrest have coronary artery disease, a condition not present in an animal model. In a human model, however, atherosclerotic plaques can aggravate the balance between myocardial oxygen supply and demand. Moreover, the interval from arrest to treatment in animal studies is shorter than the interval frequently reported in human studies. Since time to CPR and defibrillation are crucial variables for success, prolonging this time period can lower resuscitation rates. Vasopressin   Vasopressin, also known as antidiuretic hormone, is a potent, nonadrenergic vasoconstrictor that increases blood pressure and systemic vascular resistance. Although it acts on various receptors throughout the body, its vasoconstrictive properties are due primarily to its effects on the V1 receptor. Measurement of vasopressin levels in patients undergoing CPR has shown a high correlation between the levels of endogenous vasopressin released and the potential for ROSC. In fact, in one study, plasma vasopressin concentrations were approximately three times as high in survivors compared with nonsurvivors, suggesting that vasopressin is released as an adjunct vasopressor to epinephrine in life-threatening events such as cardiac arrest. Vasopressin may have several advantages over epinephrine. First, the metabolic acidosis that frequently accompanies cardiac arrest can blunt the vasoconstrictive effect of adrenergic agents such as epinephrine. This effect does not occur with vasopressin. Second, the stimulation of β-receptors caused by epinephrine can increase myocardial oxygen demand and complicate the postresuscitative phase of CPR. Because vasopressin does not act on β-receptors, this effect does not occur with its use. Vasopressin also may have a beneficial effect on renal blood flow by stimulating V2-receptors in the kidney, causing vasodilation and increased water reabsorption. With regard to splanchnic blood flow, however, vasopressin has a detrimental effect when compared to epinephrine. Despite several theoretical advantages with vasopressin, clinical trials have not consistently demonstrated superior results over that achieved with epinephrine. In one large trial of out-of-hospital arrest, no significant differences were noted in ROSC, hospital admission rate or discharge rate. Although, when patients were stratified according to their initial rhythm, patients with asystole, had a significantly higher rate of hospital admission (29% vs 20%; P = 0.02) and discharge (4.7% vs 1.5%; P = 0.04) with vasopressin compared to epinephrine. In addition, a subgroup analysis of 732 patients who required additional epinephrine therapy despite the two doses of study drug revealed significant benefits in ROSC (37% vs 26%; P = 0.002), hospital admission rate (26% vs 16%; P = 0.002), and discharge rate (6.2% vs 1.7%; P = 0.002) with vasopressin. There was a trend, however, toward a poorer neurologic state or coma among the patients who survived to discharge and received vasopressin. The favorable results from the subgroup analysis led to a prospective study evaluating the combination of vasopressin and epinephrine versus epinephrine alone. In this study, patients were randomized to receive either 1 mg of epinephrine followed by 40 units of vasopressin (in less than 10 seconds) or 1 mg of epinephrine plus saline placebo. Unfortunately, there were no significant differences between the combination therapy group and epinephrine only group in any of the outcome measures studied (ROSC, survival to hospital admission, survival to hospital discharge, 1 year survival and good neurologic recovery at discharge). In contrast, a post-hoc subgroup analysis revealed a lower rate of survival (0% vs 5.8%, P = 0.02) with combination therapy when the initial rhythm was PEA. A second study evaluated combination therapy for in-hospital cardiac arrest. In this study, patients were randomized to receive either epinephrine alone or 20 units of vasopressin plus 1 mg of epinephrine and 40 mg of methylprednisolone (followed by hydrocortisone in the post-resuscitative phase). Vasopressin 20 units plus epinephrine 1 mg were repeated during each of 4 subsequent CPR cycles. This study marks the first to include corticosteroids as part of drug-therapy during CPR. The rationale is based on the hemodynamic effects of steroids alone with their potential to impact the intensity of the postresuscitation systemic inflammatory response and organ dysfunction. Significant benefits were observed in ROSC (81% vs 52%, P = 0.003) and survival to hospital discharge (19% vs 4%, P = 0.02) with combination therapy including corticosteroids. Future studies are required to determine the role of vasopressin and corticosteroids for cardiac arrest. Antiarrhythmics   The purpose of antiarrhythmic drug therapy following unsuccessful defibrillation and vasopressor administration is to prevent the development or recurrence of VF and PVT by raising the fibrillation threshold. Clinical evidence demonstrating improved survival to hospital discharge however is lacking. As the role of antiarrhythmics during CPR remains limited, only two individual agents are currently recommended in the 2005 AHA guidelines for CPR and ECC: amiodarone and lidocaine. The use of lidocaine has been beneficial in animal studies and in patients with arrhythmias following an acute myocardial infarction but its benefit in cardiac arrest remains questionable. In the only published case-control trial where patients were classified according to whether they received lidocaine, no significant difference was noted in ROSC, admission to the hospital, or survival to hospital discharge between groups. Similarly, a prospective study comparing the effectiveness of lidocaine with that of standard-dose epinephrine showed not only a lack of benefit with lidocaine but also a higher tendency to promote asystole. In contrast, a retrospective analysis in patients with VF indicated that lidocaine was associated with a higher rate of ROSC and hospitalization (P<0.01) but not an increase in the hospital discharge rate. Amiodarone is classified as a class III antiarrhythmic but possesses electrophysiologic characteristics of all four Vaughn Williams classifications. In a large, randomized, double-blind trial in out-of-hospital cardiac arrest secondary to VF or PVT (also known as the ALIVE trial), patients were randomized to receive either amiodarone 300 mg or placebo. Recipients of amiodarone were more likely to be resuscitated and survive to hospital admission than were recipients of placebo (44% and 34%, respectively; P = .03). There was no difference in survival to hospital discharge (amiodarone, 13.4% vs placebo, 13.2%; P = NS). This was the first trial to demonstrate the benefit of an antiarrhythmic agent over placebo in patients with out-of-hospital cardiac arrest. A subsequent trial (known as the ALIVE trial) compared amiodarone 5 mg/kg with lidocaine 1.5 mg/kg in patients with out-of-hospital cardiac arrest due to VF. In this trial, amiodarone was associated with a relative improvement of 90% in survival to hospital admission compared with lidocaine [22.8% vs 12%; OR 2.17 (95% CI 1.21-3.83); P = 0.009]. Similar to the ARREST trial, there was no difference in survival to hospital discharge (amiodarone, 5% vs lidocaine, 3%; P = .34). Amiodarone and lidocaine have also been compared following in-hospital cardiac arrest secondary to VF or PVT. In a multicentered, retrospective review, 194 patients who received amiodarone (n = 74), lidocaine (n = 79), or both (n = 41) were evaluated. The rate of survival at 24 hours was 55%, 63%, and 50% for patients receiving amiodarone, lidocaine, or both, respectively (P = 0.39). There was no difference in survival to hospital discharge (39% for amiodarone, 45% for lidocaine, and 42% for patients receiving both agents; P = 0.72). After adjusting for multiple covariates, Cox regression analysis revealed higher mortality for those patients who received amiodarone (as opposed to lidocaine) [survival to 24 hours: hazard ratio was 3.15 (95% CI, 1.68-5.92), P<0.001; survival to hospital discharge: hazard ratio was 3.25 (95% CI, 1.22-8.65), P = 0.02] and in those patients with VF/PVT as the initial rhythm (as opposed to bradycardia followed by VF/PVT) [survival to 24 hours: hazard ratio was 3.36 (95% CI, 1.98-5.71), P<0.001; survival to hospital discharge: hazard ratio was 3.6 (95% CI, 1.2-10.6), P = 0.021]. The mean initial dose of amiodarone, though, was 190 mg, and only 25% of patients received the recommended dose of 300 mg. Additionally, the time to first dose of antiarrhythmic was significantly longer in the amiodarone group than in the lidocaine group (14 minutes vs 6 minutes, P<0.001). While these differences could have biased the results in favor of lidocaine, they provide a real-world experience with the use of amiodarone. Further large-scale trials are needed to determine the preferred antiarrhythmic for both in-hospital and out-of-hospital cardiac arrest. In the meantime, amiodarone remains the preferred antiarrhythmic during cardiac arrest according to the 2005 AHA guidelines for CPR and ECC with lidocaine considered as an alternative. Thrombolytics   Since most cardiac arrests are related to either MI or PE, several investigators have evaluated the role of thrombolytics during CPR. While these studies have demonstrated successful use of thrombolytics, few have shown improvements to hospital discharge. In the largest published randomized controlled trial to date, tenecteplase was compared with placebo for out-of-hospital cardiac arrest. Unfortunately, enrollment was stopped early due to futility in meeting their primary endpoint, 30 day survival. Survival in the tenecteplase and placebo groups, respectively, was 15% and 17% (P = 0.36). Potential reasons for failure in this study include the lack of antiplatelet and antithrombin medications and decreased delivery of the thrombolytic to the coronary arteries (where the clots exist) due to impaired flow and perfusion. Of note, intracranial hemorrhage occurred with significantly greater frequency with tenecteplase versus placebo (2.7% vs 0.4%, P = 0.006). The role of thrombolytics as part of CPR will require further study. Magnesium   While severe hypomagnesemia has been associated with VF/PVT, clinical trials have not demonstrated any benefit with the routine administration of magnesium during a cardiac arrest. Two observation trials though have shown an improvement in ROSC in patients with arrests associated with torsades de pointes. Therefore, magnesium administration should be limited to these patients. Figure 18-2. Treatment algorithm for adult cardiopulmonary arrest: advanced cardiac life support (ACLS) About AccessPharmacy | Core Curriculum | Subscription Information | Advisory Board | Contact Us | Help | Privacy Notice | Terms of Use | Notice | Additional Credits and Copyright Information Copyright © 2011 The McGraw-Hill Companies, Inc. All rights reserved. Any use is subject to the Terms of Use and Notice. For further information about this newsletter, contact onlinecustomer_service@mcgraw-hill.com. You have received this message because you opted-in to receive information and special offers from McGraw-Hill Professional. We hope you enjoyed receiving this message. However, if you would like to unsubscribe from receiving emails from McGraw-Hill Professional, please follow this link. 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