Action of drugs in patients early after cardiac surgery: I. comparison of isoproterenol and dopamine

Dopamine and isoproterenol were each administered in two different doses to 12 patients with coronary artery disease in the period immediately after open heart surgery. The two doses of dopamine resulted in respective increases in cardiac output of 23 and 43 percent and reductions in systemic vascular resistance of 23 and 32 percent; neither dose significantly altered heart rate. The two doses of isoproterenol caused respective increases of 23 and 37 percent in cardiac output and 18 and 28 percent in heart rate and reductions in systemic vascular resistance of 22 and 29 percent. We conclude that lack of chronotropic effect of dopamine as compared with isoproterenol may make the former the agent of choice in patients requiring inotropic agents for their care in the early period after cardiac surgery.     

Electrophysiologic evaluation of encainide with use of monophasic action potential recording

The electrophysiologic effects of encainide in the intact dog heart were evaluated with the use of monophasic action potential and His bundle recordings. Eight mongrel dogs were given 2.7 mg/kg body weight of encainide in two intravenous infusions. Plasma concentration, blood pressure, surface electrocardiogram, atrial and His bundle electrograms, right atrial and ventricular monophasic action potentials and the right atrial and ventricular effective and functional refractory periods were recorded before and 15 to 45 minutes after each infusion. Basic cycle length and A-H, H-V, QRS and Q-T_C intervals were significantly prolonged after administration of the drug. The refractory periods and the monophasic action potential durations were significantly increased in both the atrium and the ventricle although the increases were more pronounced in the atrium. It is concluded that encainide is a class I antiarrhythmic agent with properties very similar to those of quinidine.     

Circulatory effects of tazolol in experimental myocardial infarction.

The hemodynamic effects of tazolol, a new long-acting beta-stimulating drug, were studied in dogs with acute pump failure caused by experimental myocardial infarction and the results were compared with the actions of isoproterenol given in small and large doses. Tazolol produced a significant and sustained increase in cardiac output and stroke volume, while causing a decrease in peripheral resistance and mean aortic pressure. Heart rate was only modestly increased. Compared with isoproterenol at equivalent doses. tazolol appeared to cause less S-T segment elevation at the margin of infarction. The increase in double product (systolic pressure X heart rate) produced by tazolol was also considerably less than that of isoproterenol. Tazolol may prove to be a useful addition to the drugs available for the treatment of myocardial failure of various causes. It is now being studied in patients with heart failure due to coronary artery disease.     

Afterload reduction in the management of postinfarction ventricular septal defect

The primary goal in the medical management of ventricular septal defect complicating myocardial infarction is to support cardiac function and control symptoms, if possible, for a period of 4 to 6 weeks. If the patient survives this period, surgical correction of the defect is technically easier and safer. In many cases, however, cardiac function is severely compromised, intractable biventricular failure develops, early operation is necessary and the likelihood of successful repair is diminished.

We recently treated two such patients by means of afterload reduction with nitroprusside. In one patient, sublingually administered isosorbide dinitrate was later used, and prolonged survival was achieved after surgery. Hemodynamic investigations in both cases demonstrated that nitroprusside improved cardiac output without necessarily decreasing mean arterial pressure. The effect of nitroprusside on pulmonary blood flow and left to right shunt was variable: One patient demonstrated a decrease in the ratio of pulmonary to systemic blood flow, and the other did not. We conclude that afterload reduction with either intravenous or oral agents is a potentially useful measure in the management of patients with ventricular septal defect complicating myocardial infarction.     

Antiarrhythmic and circulatory effects of astra W36095: A new lidocaine-like agent

Although lidocaine is an effective antiarrhythmic agent, it must be administered parenterally and its duration of activity is short. Astra W36095 has a basic chemical structure similar to that of lidocaine but has a plasma half-life of 8 to 12 hours after administration to conscious dogs. Ventricular arrhythmias were produced in unanesthetized dogs, using ameroid constrictors on the proximal left anterior descending and circumflex coronary arteries. Stable ectopic beats were completely suppressed with plasma levels of 15 to 30 μg/ml of W36095. The duration of effect was 0.25 to 5 hours. In anesthetized dogs, an effective antiarrhythmic concentration of W36095 produced some depression of cardiac function. Thus, W36095 appears to be a long-acting, orally absorbed antiarrhythmic agent requiring clinical trials and metabolic studies. In addition, the arrhythmia model provides a sensitive method for studying new antiarrhythmic drugs.     

Combined nitroprusside-dopamine therapy in severe chronic congestive heart failure. Dose-related hemodynamic advantages over single drug infusions

To assess the circulatory effects of afterload reduction and inotropism individually and in combination as rational therapy for refractory heart failure, nitroprusside and dopamine were administered to 13 patients with severe cardiac decompensation. Dopamine at average doses of 3 and 7 microgram/kg per min produced increases in cardiac output and reductions in peripheral resistance. At doses of 15 microgram/kg per min, dopamine increased heart rate, peripheral arterial pressure and side effects. Nitroprusside alone decreased left-sided filling pressures and increased cardiac output. When the agents were administered together, the increases in cardiac output were significantly greater than with either agent alone and there was physiologic improvement in overall circulatory function. The relations among changes in afterload (systemic impedence), preload (filling pressures) and cardiac index help to explain the salutary effects of combined therapy in patients with refractory heart failure.     

Detection of ventricular arrhythmias in real-time with a portable analog computer

Recent studies on the occurrence of sudden death emphasize that many patients have ventricular premature contractions as prodromes of lethal arrhyhmlas. A portable, 6 ounce analog computer has been developed to detect tachycardias (heart rate 150 to 190 beats/min), bradycardias (heart rate less than 50 beats/min) and ventricular premature contractions. When preset limits are exceeded, acoustic warnings are sounded, and the patient may transmit his electrocardiogram by telephone, without additional equipment, to a receiving device that graphically reproduces the electrocardiogram in real-time. Hospital studies in 26 ambulatory patients with a variety of arrhythmias have been completed. Tachycardias and bradycardias were detected in every instance during 30 observation periods in six patients. Reproducible warnings were triggered in 19 of the 20 patients with ventricular premature contractions of various configurations during each of 5 observation periods (100 observations). In one patient, the electrical vector of the ventricular premature contraction closely resembled the normal QRS vector and was not detected. Appropriate electrode placement is essential to avoid initial Q waves and to maximize the difference between the vector of ventricular premature contraction and that of the normal QRS complex. No false positive acoustic alarms were sounded. Our results demonstrate that it is possible to detect ventricular premature contractions readily and reproducibly in ambulatory patients. Use of this detector may permit large scale monitoring of patients with a high risk of sudden death.     

Clinical electrophysiologic effects of encainide, a newly developed antiarrhythmic agent.

Encainide is a newly developed antiarrhythmic agent. With the use of intracardiac electrophysiologic techniques, its effects on the cardiac conduction system were examined in 10 patients with coronary artery disease. Five patients received 0.6 and five received 0.9 mg/kg body weight of encainide intravenously over 15 minutes. Plasma concentration, heart rate, blood pressure and conduction intervals (A-H, H-V, QRS and Q-T) were measured before, during and after encainide infusion. In addition, sinus nodal recovery time, Wenckebach cycle length, and atrial, atrioventricular (A-V) nodal and right ventricular refractory periods were measured before and after encainide infusion. The average peak plasma concentration was 0.49 +/- 0.35 microgram/ml (mean +/- standard error of the mean). Encainide significantly prologned H-V and QRS intervals in all patients by an average of 31 +/- 7 and 18 +/- 9 percent (standard deviation) (P less than 0.001), respectively. A minimal increase in the Q-T interval was also observed after encainide infusion (2 +/- 9 percent, P less than 0.01), but no significant changes were noted in heart rate, blood pressure, A-H interval, corrected sinus noal recovery time, Wenckebach cycle length or refractory periods of the atrium, A-V node or right ventricle. It is concluded that encainide significantly prolongs conduction in the His-Purkinje system without affecting conduction or refractoriness of other parts of the cardiac conduction system in man.     

Cost containment in medicine: Why cardiology?

In 1984, expenditures for health care in the United States were nearly $350 billion, more than 10% of the gross national product, and continued increases exceeding the general economic growth are projected. Cardiology and cardiovascular surgery represent a large part of this cost, reflecting the many new diagnostic and therapeutic procedures developed over the past 2 decades. Previous cost containment attempts failed because they provided no incentive to reduce spending for advanced technologies and procedures. A method of payment based on a case mix of 467 diagnosis related groups (DRGs), average duration of hospital stay and location of hospitals has been developed for Medicare. A 4-year trial using this method in New Jersey resulted in lower hospital costs per capita than in the rest of the country. In October 1983, a 3-year phase-in for all Medicare payments by the DRG method began. The 43 DRGs assigned to cardiology and cardiovascular surgery are among the highest-weighted for large reimbursement; thus, with the great number of aging patients with cardiac diagnoses, cardiology represents a very large share of the cost of medical care today. Because the quality of care can be determined and compared directly with costs, cardiology DRGs lend themselves to careful analysis. Three components will be examined. Coronary bypass surgery is the largest single reimbursement, thus the rationale for its use should be carefully studied. Coronary care units have markedly increased hospital costs for acute myocardial infarction, but have also improved care.(ABSTRACT TRUNCATED AT 250 WORDS)     

Contribution of ambulatory electrocardiographic monitoring to antiarrhythmic management

To date, ambulatory electrocardiographic monitoring has contributed to our understanding of the occurrence and significance of arrhythmias. Our appreciation of the spontaneous variability of ventricular arrhythmias, the relations between symptoms and the occurrence of arrhythmias, and the use of ambulatory monitoring in documenting drug effect for new antiarrhythmic drugs and for defining relations among drug dose, plasma concentration and antiarrhythmic effect have contributed to our ability to make more rational recommendations for prescribing and monitoring drug therapy.Further work is necessary to define the occurrence of arrhythmias in normal persons and to determine the prognostic importance of arrhythmias in normal subjects and patients with heart disease other than coronary artery disease. Studies assessing the role of spontaneous variation have indicated the problems that can occur in attempting to evaluate antiarrhythmic drug therapy in individual patients. These variations are so great that it may not be practical to monitor antiarrhythmic drug therapy in certain patients.For patients with coronary artery disease, ambulatory electrocardiographic monitoring can identify those with frequent complex arrhythmias who are at high risk of subsequent sudden cardiac death. Such monitoring can document the effectiveness of antiarrhythmic drug therapy for ventricular irritability and define the dosing regimens or plasma concentrations that are effective for most patients. Ultimately, multicenter intervention trials must document whether or not such antiarrhythmic drug therapy can influence the outcome in the high risk patients identified with ambulatory electrocardiographic recordings. It will be important to determine whether any observed reduction in sudden death in these trials can be related to suppression of asymptomatic ventricular ectopy as determined with ambulatory electrocardiographic recordings.     

Pharmacologic therapy of ventricular arrhythmias

To treat patients with ventricular arrhythmias properly, one must characterize the arrhythmia, define the underlying heart disease and look for and treat reversible causes. When arrhythmias are suitable for pharmacologic suppression, it is necessary to predefine therapeutic goals, then carefully document that the drug accomplishes these goals. Knowledge of a drug's metabolism, excretion, active metabolites and plasma protein binding is often required for full understanding of its clinical effect. Pharmacokinetic principles require that antiarrhythmic drugs be given on a rigid schedule and that plasma drug levels be frequently determined. Use of compartment models and the principle of superposition can enable one to achieve and maintain therapeutic drug concentrations while avoiding toxic side effects. The drugs commonly used to treat arrhythmias, lidocaine, propranolol, procainamide, diphenylhydantoin and quinidine, as well as some newer agents, have specific pharmacokinetics and toxic effects that must be understood.     

Surgery for life-threatening ventricular tachyarrhythmias.

Among 203 left ventricular aneurysmectomies performed since 1970, the operative mortality rate was 18.7 percent. In 49 patients (24 percent), left ventricular aneurysmectomy was performed for refractory life-threatening ventricular arrhythmias. Eight additional patients had coronary bypass grafting without ventricular aneurysmectomy. One of these patients had bypass grafting followed later by ventricular aneurysmectomy. All 56 patients had underlying coronary artery disease. The operative mortality rate was 19.6 percent. In patients with a recent myocardial infarction, the rate was 60 percent, whereas it was 11 percent in patients with a remote myocardial infarction. Other high risk variables in these patients included coronary bypass grafting without myocardial resection, and an elevated left ventricular end-diastolic pressure. The late mortality rate was 17.9 percent, but only one of these deaths was sudden and unexpected. The 35 long-term survivors have been followed up for a mean of 40.7 months (range 7 to 92 months). Of these, 20 remain on antiarrhythmic medications for palpitation or documented ventricular premature complexes, whereas 15 are free of detectable rhythm disturbances and do not require antiarrhythmic agents. Only 4 of 35 (11 percent) have had recurrent documented ventricular tachycardia. Left ventricular aneurysmectomy may be performed for refractory ventricular tachyarrhythmias with an acceptable operative mortality, particularly if the patient has survived longer than 6 weeks after myocardial infarction. Although epicardial mapping techniques may be useful in localizing the reentrant pathway of the ventricular tachycardia, ventricular aneurysmectomy without mapping techniques produces a satisfactory clinical result in the vast majority of long-term survivors.     

Studies on circulatory response to hypoxia in the denervated transplanted human heart

The relative importance of centrally mediated reflex responses versus the release of circulating humoral substances in the heart's response to acute hypoxia was studied in the transplanted human heart with its residual innervated recipient atrium and denervated donor atrium. The sinus node rates of both the donor and recipient atria were compared by monitoring P wave activity on the standard electrocardiogram in six patients during control and hypoxic conditions. Breathing 13 per cent oxygen for 10 minutes resulted in an average oxygen saturation of 75 per cent and an oxygen tension (pO₂) of 40 mm Hg, and was associated with a 16 per cent (p 0&;#x030C;.05) increase in the recipient sinus node rate, but with no change in the donor sinus node rate. Pretreatment with atropine abolishes this increase in the innervated recipient sinus node. Breathing 10 per cent oxygen resulted in an oxygen saturation of 55 per cent and a pO₂ of 25 mm Hg, with an associated 10 per cent increase in both donor and recipient sinus node rate. These studies indicate that changes in heart rate during mild degrees of hypoxemia are mediated by a central reflex mechanism which leads to the release of normal vagal parasympathetic tone. The increase in heart rate that occurs in both the innervated and denervated sinus node rates during more severe degrees of hypoxia is probably due to the release of circulating humoral substances, since reinnervation has not been documented in the human cardiac allograft.     

Antiarrhythmic drug effect assessed from ventricular arrhythmia reduction in the ambulatory electrocardiogram and treadmill test: Comparison of propranolol,procainamide and quinidine

A 5 week study was performed in 17 patients with frequent ventricular ectopic complexes. The study design comprised an initial control period, 1 week each of treatment with propranolol (240 mg daily), procainamide (3.0 g daily) and quinidine (1.8 g daily) and a final control period. Twenty-four hour ambulatory electrocardiograms and maximal exercise tests were performed each week. For the group, the total number and qualitative types of ventricular ectopic complexes were similar during the two control periods; however, there were large variations among individual patients. Each drug reduced the total number of ventricular ectopic impulses and the percent of patients with each qualitative type. There was agreement between the ambulatory electrocardiogram and treadmill test in three quarters of the drug evaluations. Although it is possible to determine antiarrhythmic drug effects for a group, spontaneous variability In the occurrence of ventricular arrhythmias makes it difficult to evaluate the effects in individual patients.     

Electrophysiologic findings in patients with idiopathic hypertrophic subaortic stenosis

Thirteen patients with catheterization-proved idiopathic hypertrophic subaortic stenosis underwent intracardiac electrophysiologic study. There was a large incidence of arrhythmias and a strikingly large incidence of conduction system abnormalities among these patients. The P-A and A-H intervals were normal in all patients. Atrial pacing resulted in Mobitz type 1 block proximal to the His bundle at an abnormal rate (less than 140/min) in 2 of 12 patients (17 percent). H-V intervals were prolonged (greater than 50 msec) in 10 of 12 patients (83 percent) and were greater than 60 msec in 7 patients (58 percent). The atrial effective refractory period was prolonged in 3 of 12 patients and was markedly prolonged in 1 of them. Effective refractory period of the atrioventricular (A-V) node, determined in five patients, was prolonged in three. Dual responses of the A-V node to atrial extrastimuli were found in seven patients. Dual A-V nodal repsonses were evoked with propranolol in three patients and persisted in the other four patients with dual responses despite propranolol administration.     

Hypertrophic subaortic stenosis: Clinical and hemodynamic effects of long-term propranolol therapy

Thirteen patients with hypertrophic subaortic stenosis underwent right and transatrial septal left heart catheterization. Outflow obstruction was measured in the resting state and during a variety of stimulating maneuvers before and after the intravenous administration of 150 μg/kg of propranolol. The patients were then treated with orally administered propranolol and followed up for an average period of 17 months. Nine patients were available for a second catheterization, during which detailed hemodynamic measurements were repeated. Most patients had an initially favorable response to propranolol. However, 3 with an initially good response had a return of symptoms during the period of study. The initial clinical response appeared to correlate with the reduction of outflow obstruction seen after intravenous administration of propranolol. The long-term clinical course correlated with the hemodynamic findings at the second catheterization. The severity or lability of the outflow obstruction during the initial catheterization did not appear to have predictive value for the patient's response to long-term therapy. Propranolol had a favorable effect on the symptomatic state of the patients, but did not appear to change the course of the underlying disease.