Atropine, calcium, calcium-channel blockers, beta-adrenergic-receptor blockers, oxygen, morphine, vasodilators, and potent diuretics are frequently used in advanced cardiac life support (ACLS). Since the last AHA conference on ACLS standards, little controversy has arisen regarding the use of oxygen, morphine, vasodilators, or potent diuretics. In 1979, a full vagolytic dose of atropine was recommended for use early in the course of asystolic or bradycardiac arrest. Since then reports suggest that this higher dose of atropine may be of some limited value in treating this highly resistant form of arrest. The routine use of calcium for asystole, bradycardiac arrest, and electromechanical dissociation has come under intense scrutiny. Studies have failed to demonstrate improved survival and have found potentially deleterious levels of serum calcium when calcium was administered according to AHA standards. It is also possible that postanoxic cerebral injury is exacerbated by the use of calcium. No controversy exists, however, concerning the use of calcium for the moribund patient with possible hypocalcemia or with an excess of calcium-channel blockers. The use of calcium-channel blockers has been advocated to prevent or retard the intracellular accumulation of calcium, which may cause irreversible postanoxic tissue damage. Calcium-channel blockers may also be useful in preventing or decreasing cerebral and coronary arteriospasm. These drugs have antianginal properties that may decrease ischemia. The antiarrhythmic effect of verapamil is particularly useful in the treatment of uncomplicated paroxysmal supraventricular tachycardia. Verapamil and diltiazem slow conduction through the atrioventricular node and may be used to slow the ventricular response in atrial fibrillation and flutter.(ABSTRACT TRUNCATED AT 250 WORDS)

The Cardiovascular Pharmacology II panel met during the AHA National Conference on Standards and Guidelines for CPR and emergency cardiac care to consider the use of catecholamines, pressor agents, digitalis, and corticosteroids during advanced cardiac life support. During cardiac arrest, catecholamines and pressor agents have been shown to improve the rate of success of resuscitation. The useful properties of these drugs are mediated by strong alpha-adrenergic stimulation resulting in improved coronary perfusion. beta-Adrenergic stimulation during cardiac arrest is unimportant for resuscitation and potentially harmful. Studies have not demonstrated a difference between mixed agonists and alpha-agonists with respect to overall outcome. Consequently, the panel recommended that epinephrine continue to be the primary vasopressor for use during cardiac arrest. For cardiovascular support in the hemodynamically unstable patient, the panel recommended that drugs be chosen for specific pharmacologic actions that will allow the needed physiologic manipulation guided by objective hemodynamic measurements. The panel found that digitalis preparations and corticosteroids have very limited use in emergency cardiac care.

The proper management of patients with acute myocardial infarction changes frequently as new data develop in this complex area. The present recommendations concerning the use of oxygen and morphine and the treatment of hypotension and congestive heart failure require little change save the addition of new agents. However, considerable new data have been derived in the area of limitation of myocardial infarct size. Several studies suggest that the early administration of beta-blockers or intravenous nitroglycerin may benefit patients with acute infarction. We must seriously consider whether the data supporting the use of these agents justify a recommendation that they be used routinely for patients with acute infarction. The role of thrombolytic agents, although widely used already, must also be addressed as data supporting its use build. Additionally, there are suggestive data that the aggressive treatment of hypertension is beneficial, and this approach may well merit advocacy. The prophylactic use of lidocaine and the ubiquitous use of nitrates necessitate reevaluation, although presently both agents are widely used. The aggressive use of electrical therapy for supraventricular arrhythmias and the lack of indication for the treatment of asymptomatic bradycardia with atropine in patients with acute infarction must be added to the previous National Conference standards.

Hemodynamic effects of intravenous administration of amrinone include increases in dP/dt, cardiac output, and stroke work with decreases in left ventricular filling pressure and systemic vascular resistance. Unlike other injectable positive inotropic agents, it does not increase myocardial oxygen consumption, a distinct advantage in patients with coexisting ischemic disease. Amrinone does not have deleterious effects on atrioventricular conduction and appears to have little arrhythmogenic potential. Side effects of intravenous administration are generally minor but include a reversible thrombocytopenia. Additional studies conducted in short-term low-output states are needed to define more completely its role in the treatment of this condition.

The positive inotropic/vasodilator agent MDL 17,043 was evaluated to determine its usefulness for both short-term support of the failing circulation and long-term treatment of patients with congestive heart failure. Both intravenous and oral administration of MDL 17,043 significantly increased cardiac output, stroke volume, stroke work index, and heart rate, and significantly decreased pulmonary arterial wedge, right atrial, and mean arterial pressures as well as systemic and pulmonary arteriolar resistance. Such hemodynamic responsiveness persisted in patients on long-term oral therapy with MDL 17,043. When compared with dobutamine, the peak hemodynamic effects of MDL 17,043 were similar except for somewhat greater increases in heart rate with dobutamine and somewhat greater decreases in mean pulmonary arterial and wedge pressures with MDL 17,043. Both intravenous and oral MDL 17,043 elevated plasma renin activity. Oral doses were rapidly absorbed, and the drug had an elimination half-life of about 20 hr. Although the majority of patients showed clinical improvement at 1 month, this effect tended to wane over time leading to either recurrent heart failure or death. Mortality rates at 1 year are about 46% in class III patients and 97% in class IV patients on long-term oral MDL 17,043. The results of these studies suggest that MDL 17,043 may be useful in the short-term management of the failing circulation; however, its value in the long-term management of patients with chronic heart failure remains unclear and requires further studies for resolution.

Symptoms of dyspnea and fatigue limit effort tolerance in patients with chronic cardiac failure. These symptoms may be consequent to an abnormal cardiocirculatory response to the increased O2 demand that accompanies exercise as manifested by: reduced ability to augment cardiac output in response to increased left ventricular filling pressure, inadequate vasodilatory response in exercising limbs, the onset of lactate production by muscle at relatively low levels of work, and increased work of breathing that accompanies pulmonary venous hypertension and abnormal compliance of the lung secondary to left ventricular dysfunction. The clinical experience with new positive inotropic agents in the long-term treatment of patients with chronic cardiac failure is accumulating rapidly. Attention has focused on the ability of these agents to improve exercise performance, particularly their ability to increase the aerobic capacity. The experience to date suggest that beta-adrenergic receptor agonists offer little advantage in this regard while causing ventricular arrhythmias. On the other hand, the phosphodiesterase inhibitors, MDL 17,043 and MDL 19,205, and the bipyridine derivatives, amrinone and milrinone, may improve exercise performance in many patients and exert a sustained effect during long-term therapy. Placebo-controlled, randomized trials will need to be performed, however, to determine the ultimate efficacy and safety of these agents. The most meaningful results for analysis will be obtained when objective parameters of exercise performance, such as aerobic capacity and anaerobic threshold, are monitored that are free of patient or physician bias.

Coronary angiography has proved beyond doubt that complete coronary occlusion is the rule in the very early hours of infarction. The 60% to 80% rate of coronary recanalization after thrombolytic therapy has proved that thrombosis is a major component of the occlusion at the time when the procedure is performed a few hours after the onset of symptoms. However, the trigger for coronary thrombosis and the causes of failure of thrombolytic therapy are still a matter of speculation. The relatively rare occurrence of acute coronary occlusion in the life of an individual with even severe coronary disease can be explained on the basis of the necessity of either extremely powerful isolated stimuli, which only occurs rarely, or the casual simultaneous presence in one coronary arterial segment of multiple unfavorable events, such as plaque fissuring, enhanced reactivity of coronary smooth muscle to constrictor stimuli and displacement of the thrombotic-thrombolytic equilibrium toward thrombosis. Coronary artery constriction possibly caused by vasoconstrictor substances released by thrombus, represents the potential element of a vicious cycle causing persistent coronary occlusion and reocclusion when reflow occurs with thrombolysis.

To study the prevention of occlusion of aortocoronary-artery bypass grafts, we conducted a prospective, randomized, double-blind trial comparing long-term administration of dipyridamole (begun 2 days before operation) plus aspirin (begun 7 hr after operation) with placebo in 407 patients. Results at 1 month and at 1 year showed a reduction in the rate of graft occlusion in patients receiving dipyridamole and aspirin. On the basis of our clinical trial and our experimental studies in dogs and pigs, we describe four consecutive phases of aortocoronary artery bypass vein-graft disease: an early postoperative phase of platelet thrombotic occlusion, which is significantly prevented by platelet inhibitor therapy when started in the perioperative period; in addition, occlusion rates are presently decreasing, perhaps related to better surgical and technical experience; an intermediate phase of platelet-related intimal hyperplasia, within the first postoperative year, which is not prevented with platelet inhibitor therapy; a late phase of occlusion, toward the end of the first postoperative year, in which intimal hyperplasia or complicating platelet thrombi superimposed on the intimal hyperplasia may contribute to occlusion; platelet inhibitor therapy is of significant benefit in the prevention of this thrombotic type of occlusion; a phase of atherosclerotic disease, after the first postoperative year, in which the role of platelets and of platelet inhibitor therapy is under investigation.

Aspirin has been convincingly shown to reduce stroke and death in men with transient ischemic attacks (it may possibly be beneficial to women also), myocardial infarction and death in patients with unstable angina, thromboembolic complications associated with artificial heart valves in patients receiving oral anticoagulants (although gastrointestinal bleeding is prohibitive with this combination), and thrombotic occlusion of silicone rubber arteriovenous cannulae in uremic patients undergoing hemodialysis. In addition, aspirin may possibly decrease occlusion of saphenous vein aortocoronary grafts and venous thrombosis in men after hip replacement, although these reports require confirmation. Aspirin is ineffective in the secondary prevention of stroke and has unproven benefit in the secondary prevention of myocardial infarction. Dipyridamole in combination with oral anticoagulation decreases the thromboembolic complications associated with mechanical heart valves. The combination of aspirin and dipyridamole prevents both early and late occlusion of saphenous vein aortocoronary bypass grafts and protects renal function in patients with membranoproliferative glomerulonephritis. The relative importance of combining aspirin and dipyridamole compared with either agent used singly remains to be established. Sulfinpyrazone reduces the thrombotic occlusion of arteriovenous cannulae and early occlusion of saphenous vein aortocoronary grafts. The reported benefit in the secondary prevention of myocardial infarction is controversial.

There is evidence that aspirin is partially effective in the prophylaxis of various vasoocclusive disorders. This article reviews pharmacologic opportunities for improvement over and above the therapeutic effect of aspirin. It is concluded that several rational possibilities merit consideration, in particular, the use of combinations of drugs that affect the thrombotic process at different points. Such strategies will ultimately require validation by clinical trial.

Nonsteroidal anti-inflammatory drugs and sulfinpyrazone compete dose-dependently with arachidonate for binding to platelet cyclooxygenase. Such a process closely follows systemic plasma drug concentrations and is reversible as a function of drug elimination. Peak inhibition and extent of its reversibility at 24 hr varies consistently with individual pharmacokinetic profile. Inhibition of platelet cyclooxygenase activity by these agents is associated with variable effects on prostaglandin (PG) synthesis in the gastric mucosa and the kidney. Aspirin acetylates platelet cyclooxygenase and permanently inhibits thromboxane (TX) A2 production in a dose-dependent fashion when single doses of 0.1 to 2.0 mg/kg are given. Acetylation of the enzyme by low-dose aspirin is cumulative on repeated dosing. The fractional dose of aspirin necessary to achieve a given level of acetylation by virtue of cumulative effects approximately equals the fractional daily platelet turnover. Serum TXB2 measurements obtained during long-term dosing with 0.11, 0.22, and 0.44 mg/kg aspirin in four healthy subjects could be fitted by a theoretical model assuming identical acetylation of platelet (irreversible) and megakaryocyte (reversible) cyclooxygenase. For a given dose within this range, both the rate at which cumulative acetylation occurs and its maximal extent largely depend upon the rate of platelet turnover. Continuous administration of low-dose aspirin (20 to 40 mg/day) has no statistically significant effect on urinary excretion of either 6-keto-PGF1 alpha or 2,3-dinor-6-keto-PGF1 alpha, i.e., indexes of renal and extrarenal PGI2 biosynthesis in vivo. Whether a selective sparing of extraplatelet cyclooxygenase activity by low-dose aspirin will result in increased antithrombotic efficacy, fewer toxic reactions, or both remains to be established in prospective clinical trials.

Myocardial thallium-201 (201Tl) scintigraphy or radionuclide angiography performed in conjunction with exercise stress testing can provide clinically useful information regarding the functional significance of underlying coronary artery stenoses in patients with known or suspected coronary artery disease. Knowledge of type, location, and extent of myocardial 201Tl perfusion abnormalities or the severity of exercise-induced global and regional dysfunction has prognostic value. Risk stratification can be undertaken with either radionuclide technique by consideration of the magnitude of the ischemic response and may assist in the selection of patients for coronary artery bypass graft surgery (CABG). In patients with coronary artery disease, delayed 201Tl redistribution observed on exercise or dipyridamole 201Tl scintigraphy, particularly when present in multiple vascular regions and associated with increased lung 201Tl uptake, has been shown to be predictive of an adverse outcome, whereas patients with chest pain and a normal exercise 201Tl scintigram have a good prognosis with medical treatment. Similarly, a marked fall in the radionuclide ejection fraction from rest to exercise has been found to correlate with high-risk anatomic disease. In one published nonrandomized study, patients with coronary artery disease who demonstrated an abnormal ejection fraction response to exercise preoperatively had a better survival with CABG than with medical therapy. Another important application of radionuclide imaging in patients being considered for CABG (particularly those with a depressed resting left ventricular ejection fraction) is the determination of myocardial viability and potential for improved blood flow and enhanced regional function after revascularization. There are certain limitations of exercise 201Tl scintigraphy and radionuclide angiography that can be reduced by improved methods of quantitation of perfusion and function and further development of tomographic imaging approaches.