Adrenergic drugs have been the primary agents studied and utilized in all types of cardiac arrest. Epinephrine is the predominant adrenergic drug and remains the recommended agent. The mechanism of action of adrenergic therapy in cardiac resuscitation has been convincingly shown to be primarily alpha adrenergic receptor-mediated vasoconstriction in the peripheral arterial system resulting in increased aortic pressure and thus increased coronary perfusion pressure. In addition to epinephrine, several other pure alpha-adrenergic or mixed alpha- and beta-adrenergic agents have been studied. However, none of these agents has been shown to increase ROSC or long-term survival as compared with epinephrine.
The appropriate dosage of adrenergic drugs during cardiac arrest is the subject of ongoing controversy. Although based on early animal studies and on very limited anecdotal clinical evidence, an epinephrine dose of 1 mg was the standard recommendation for many years. Laboratory investigations and clinical reports in the 1980s suggest that substantially higher doses were required for optimal beneficial effect. These studies led to large, randomized, controlled clinical trials in the early 1990s that showed variable effects on the rate of ROSC but failed to show improvement in survival to hospital discharge or neurologic outcome. 6 Although no benefit was demonstrated, no adverse results were identified with the use of higher doses of epinephrine. Still, there have been anecdotal complaints from intensivists that the temporary ROSC achieved unnecessarily diverts intensive care resources for futile situations. The American Heart Association has left the option of using higher doses of epinephrine open to the clinician's discretion in the clinical arena. 6
Although adrenergic therapy has been the pharmacologic cornerstone of vasoconstrictor therapy, there are nonadrenergic agents capable of producing significant arterial vasoconstriction; these could prove beneficial in the treatment of cardiac arrest. The most promising nonadrenergic agent is vasopressin. Laboratory studies and early clincial reports have shown favorable effects as compared with epinephrine. Linder et al reported a small randomized clinical study comparing intravenous vasopressin (40 U) with intravenous epinephrine (1 mg) and showed a significant increase in initial ROSC, hospital admission, and 24-h survival. 7 There was also a trend toward improved survival to hospital discharge. Another nonadrenergic agent that has undergone only limited laboratory investigation is angiotensin II. The use of nonadrenergic vasoconstrictor agents either alone or in conjunction with adrenergic vasoconstrictor agents may prove to be more effective than adrenergic therapy alone.
Release and accumulation of adenosine in ischemic tissues and adenosine's role as a depressant of cardiac pacemaker automaticity has been more clearly defined in recent years. There is limited clinical evidence to suggest that aminophylline can reverse these effects (by acting as an adenosine antagonist) and may be useful in the treatment of bradydysrhythmias associated with myocardial ischemia. Clinical studies have shown favorable initial response to aminophylline bolus, but long-term survival does not appear to be affected.89 Laboratory studies have shown no apparent benefit of aminophylline in cardiac arrest. Thus, adenosine antagonism remains an unproven therapy. However, given the dismal prospects for survival associated with bradyasystolic arrest, a clinician could not be faulted for administering aminophylline in such a setting, especially if there was no response to standard therapy. However the caveat noted earlier for high-dose epinephrine would apply here also.
Amiodarone is an antiarrhythmic agent with a complex electropharmacologic profile that has been used for long-term control of a variety of atrial and ventricular dysrhythmias. Despite its reportedly limited effect on ventricular effective refractory period after acute intravenous administration, it has been shown to be effective in the treatment of acute unstable ventricular dysrhythmias refractory to lidocaine and procainamide. In a randomized, double-blind, multicenter clinical trial, two amiodarone regimens (low-dose and high-dose) were compared to a standard bretylium regimen in 302 patients with refractory, hemodynamically unstable ventricular tachycardia and ventricular fibrillation. 10 The high-dose amiodarone regimen (an initial rapid infusion of 150 mg over 10 min, followed by 1 mg/min for 6 h and 0.52 mg/h thereafter to 48 h) was equivalent to bretylium in terms of suppression of subsequent unstable ventricular dysrhythmias and showed a better side-effect profile. Amiodarone is, therefore, an emerging antiarrhythmic agent in the treatment of acute ventricular dysrhythmia, especially those cases that are refractory to more traditional antiarrhythmic therapy.
Clinical studies have shown improved survival with magnesium supplementation in the setting of acute myocardial infarction. The cardioprotective effects of magnesium are thought to be related to suppression of automaticity, coronary vasodilation, platelet inhibition, and inhibition of calcium influx. Although an association between hypomagnesemia and cardiac dysrhythmias has been recognized, the value of magnesium in the treatment of acute, life-threatening ventricular dysrhythmias has not been established. Thel et al reported a randomized, double-blind, placebo-controlled clinical trial of magnesium administration in 156 in-hosptial cardiac arrest patients.11 Administration of magnesium (initial 2 g bolus during cardiac arrest followed by an infusion of 8 g over 24 h) showed no difference in ROSC, survival to 24 h, survival to hospital discharge, or Glasgow Coma Scale score on discharge as compared with placebo. However, among survivors to hospital discharge (21 percent in each group), quality of life assessed by Karnofsky performance status was better in the magnesium group, and no adverse effects of magnesium administration were noted. Thus, the use of magnesium in cardiac arrest remains incompletely defined. Magnesium administration during cardiac arrest seems acceptable based on clinical judgment, especially in cases of suspected hypomagnesemia or refractory cardiac arrest.
Recommended routes for the administration of resuscitation drugs include intravenous, endotracheal, and intraosseous routes. Intravenous administration is considered optimal, with central venous delivery preferred over peripheral venous delivery provided that there is no delay in gaining central venous access. Intracardiac drug injection has largely been discouraged. Central arterial administration of medications has received little attention but may be a useful alternative, especially for delivery of vasoconstrictor agents, which have their effector sites in the peripheral arterial system.
Catheterization to measure arterial pressure during cardiac arrest is becoming a more accepted intervention to help guide resuscitative efforts. Thoracic aortic catheterization via a femoral artery approach allows for both pressure monitoring and homogeneous arterial drug administration. When aortic arch and central venous routes of epinephrine administration were compared in a laboratory model, aortic arch delivery resulted in a more rapid increase in CPR diastolic aortic pressure, a greater magnitude of aortic pressure increase, and a maximal response consistently seen within 30 to 50 s of injection. 12 The rapidity of initial and maximal aortic pressure response suggests that adrenergic therapy could be rapidly adjusted based on a parameter reflecting vital organ perfusion. Thus, thoracic aortic catheterization allows for both rapid delivery of vasoconstrictor agents to effector sites and rapid assessment of therapeutic effect, such that therapy can be rapidly titrated on an individual basis. The major limitation of this route is the need to establish central arterial access.
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