Effects Of Digitalis Research Articles

A patient-activated radio frequency pacemaker system: Therapy for recurrent ventricular tachycardia

amine stores, and in the former case a reduction in sympathetic nerve supply as well, 8 the intrinsic sympathetic support present in the human neonate's heart with sustained SVT and congestive heart failure may be even more diminished than that of the normal neonate's heart. In this setting the primary effect of digitalis (decreasing the ventricular threshold for fibrillation) may be unmasked, TM and the risk for fibrillation increased. Several if not all six of these conditions coexisted in our patient, but fortunately probably occur together rarely ~,~ in most infants with WPW. Although digoxin remains a useful drug in the management of PSVT in infants with WPW, these patients warrant in-hospital observation during the initiation and early phase of therapy. If digoxin does not control the PSVT at therapeutic doses (20 to 40 #g/kg total digitalizing dose) and therapeutic serum concentrations, electrophysiologic study to determine the mechanism of the arrhythmia and the site of and the effect of digoxin on the accessory connection (if present) should be performed, especially in an infant with congestive heart failure, prior to either increasing the digoxin dose or adding other medications which could aggravate the hemodynamic state. The electrophysiologic findings of very fast atrioventricular conduction with a short ERP of a demonstrable accessory connection, coupled to failure of digoxin, may indicate the need for other treatment, such as quinidine, propranolol, verapamil, ~2 or, rarely, surgery.

Effects of digitalis on subendocardial and subepicardial dysfunction during acute ischemia.

The effects of digitalis (ouabain infusion, priming dose of 10 micrograms/kg/min followed by 2.0 micrograms/kg/min) on subepicardial and subendocardial ischemic dysfunction during partial occlusion (59.4% reduction in coronary flow) and total coronary occlusion were evaluated in 14 dogs using pairs of ultrasonic crystals implanted in the epicardial and endocardial layers. After 30 minutes of partial coronary occlusion, systolic shortening in the ischemic zone decreased from 12.4 +/- 2.9% to -0.4 +/- 0.9% (p less than 0.001) in the epicardium and from 18.9 +/- 3.1% to -1.0 +/- 1.1% (p less than 0.001) in the endocardium. Ouabain infusion increased the systolic shortening from -0.4 +/- 0.9% to 10.6 +/- 3.1% (p less than 0.001) in the epicardium and from -1.0 +/- 1.1% to 17.2 +/- 3.4% (p less than 0.001) in the endocardium. The end-diastolic length did not change. In contrast, after 30 minutes of total coronary occlusion, systolic shortening in both epicardial and endocardial layers was replaced by systolic lengthening and remained unaffected by ouabain infusion in both layers. Systolic shortening in the nonischemic epicardial and endocardial layers increased consistently. We conclude that ouabain improves the contractile function of both ischemic epicardial and endocardial layers layers after partial coronary occlusion and does not worsen subendocardial ischemic dysfunction. After total coronary occlusion, however, the contraction of the ischemic zone is unaffected by ouabain.

What's New in Electrocardiography

The contents of this book were presented at an international work-shop of the same name; the aim was to bring together new information about the ECG and help the practicing physician update his or her knowledge about the 12-lead ECG as Continued from p 2597. a diagnostic, therapeutic, and prognostic tool. Some of the subjects include the prognostic value of the ECG, correlation with radionuclide findings during myocardial infarction, bundlebranch block, the short PR interval, pacemaker malfunction, the effects of aging, digitalis, and pulmonary embolism. Other interesting subjects are the diagnosis of myocardial infarction in pacemaker patients and in those with left bundle-branch block, differentiation between supraventricular and ventricular dysrhythmias, and a chapter on Torsade de Pointes. Wellens presents further documentation that a QR or R pattern in V, in patients having a right bundle-branch block during tachycardia helps to pinpoint the origin as ventricular, whereas if there is an

Effects of digitalis on the human sick sinus node after pharmacologic autonomic blockade

To study the effects of digitalis on the sinus node and the mechanisms involved, 16 patients with the sick sinus syndrome had electrophysiologic assessment of sinus nodal function during (1) control study, (2) after pharmacologic autonomic blockade with propranolol (0.2 mg/kg body weight and atropine sulfate 0.04 mg/kg intravenously), and (3) 10 minutes after 0.01 mg/kg of intravenous ouabain. The study was completed within 30 minutes of pharmacologic autonomic blockade. During the control study 50 percent of patients had an abnormal corrected sinus nodal recovery time or abnormal sinoatrial conduction time, or both. The effects of ouabain on sinus nodal function were compared with those after pharmacologic autonomic blockade. Ouabain significantly increased both intrinsic sinus cycle length (ouabain 975 ± 194 ms [mean ± standard deviation]; autonomic blockade 1,025 ± 218 ms, probability [p] < 0.001) and corrected sinus nodal recovery time (ouabain 615 ± 503 ms; autonomic blockade 575 ± 536 ms, p < 0.05). In contrast there was no significant change in sinoatrial conduction time after ouabain (ouabain 141 ± 56 ms; autonomic blockade 132 ± 45 ms; difference not significant). The effects of ouabain were similar in patients with both normal and abnormal sinus nodal function. These findings suggest that (1) digitalis in therapeutic doses has a depressant effect on intrinsic sinus nodal automaticity in patients with normal as well as abnormal sinus nodal function; (2) digitalis has no significant effects on sinoatrial conduction; and (3) the effects of digitalis on sinus nodal automaticity are primary and independent of its vagal and antiadrenergic effects.

The Use of Brain Digoxin Concentrations to Confirm Blood Digoxin Concentrations

Recent research suggests that the cardiotoxic as well as the neurotoxic effects of digitalis may be mediated by the central nervous system. Therefore brain regions implicated in the genesis of cardiac rhythm disorders were assayed for digoxin. An 125I-labeled radioimmunoassay was used to determine blood and tissue digoxin concentrations. Digoxin was found in the optic tract and optic chiasm in each of four persons who had been taking digoxin regularly. Digoxin is apparently concentrated from blood by the choroid plexus of the fourth ventricle but not by the choroid plexus of the lateral ventricle. However, digoxin was present in the area postrema and nucleus of the vagus only in the two digoxin overdose cases. Digoxin was not detected in any of the other brain regions analyzed. The presence of digoxin in the area postrema (the chemoreceptor trigger zone) and the nucleus of the vagus in the toxic but not in the therapeutic cases suggests a mechanism for the emesis and cardiac arrest brought about by digoxin toxicity in humans. The digoxin content of the medulla, especially the surface of the medulla under the obex, may be useful in confirmation of elevated blood digoxin concentrations.

Effects of chronic digitalization on cardiac and renal Na+ + K+-dependent adenosine triphosphate activity and circulating catecholamines in the dog.

To extend our understanding of the mechanism of action of digitalis drugs, we studied electrocardiograms (ECGs), renal function, plasma concentrations of catecholamines, and myocardial and renal Na+ + K+-dependent adenosine triphosphate (Na+ + K+ ATPase) activity in chronically digitalized dogs. Five healthy, male, mongrel dogs received a therapeutic regimen of digoxin (0.1 mg/kg on day 1 in three divided doses followed by 0.025 mg/kg per day) orally for 2-4 months. This resulted in plasma digoxin concentrations of 1.1 to 4.7 ng/ml as determined by radioimmunoassay. Six control dogs received daily gelatin capsules by mouth. ECGs monitored throughout the study showed no changes. Digitalized dogs had elevated plasma norepinephrine concentrations (347 vs. 137 pg/ml in controls) and no change in plasma epinephrine concentrations. Digitalized dogs had elevated glomerular filtration rates (0.74 vs. 0.94 ml/min per g of kidney) without significant changes in renal handling of electrolytes and water. All of the above studies were done without the aid of restraining drugs or infusions. The animals were killed with an overdose of pentobarbital for in vitro studies. In digitalized dogs, microsomal Na+ + K+ ATPase-specific activity was 26 to 33% lower in the renal cortex, medulla, and papilla, and 46% lower in the cardiac left ventricle than in control dogs. Digitalization did not alter the osmolalities of renal tissues. We conclude that chronic reduction Na+ + K+ ATPase activity by one-third dose does not cause abnormalities in renal handling of electrolytes and water, and inhibition of Na+ + K+ ATPase in the left ventricular muscle by one-half is associated with no obvious ECG changes in the dog. Further, elevated plasma norepinephrine concentrations may contribute to both the therapeutic and the toxic effects of digitalis.

Digitalis in Heart Failure

AFTER more than 200 years of clinical use, the role of digitalis therapy in the management of acute and chronic congestive heart failure and its effectiveness compared with vasodilator therapy is being questioned. This controversy results from the difficulty in demonstrating the salutary effect of digitalis on overall cardiac performance, although the positive inotropic effect of digitalis on left ventricular function, both in the normal and depressed ventricle, has been well established.^1,2Accordingly, we will review the evidence for the beneficial effects of digitalis in acute (eg, myocardial infarction) and chronic heart failure and the relation between digitalis therapy and vasodilator therapy in these conditions. Net cardiac pump performance results from the complex interaction of several opposing factors³(Figure). Cardiac output is determined by the heart rate, left ventricular filling volume or preload, left ventricular afterload or resistance to left ventricular ejection (approximated by systolic blood pressure), and

Systolic time intervals in chronic severe anaemia and effect of diuretic and digitalis.

Systolic time intervals were measured from simultaneous high speed recordings of the electrocardiogram, phonocardiogram, and carotid artery pulse in 15 men with chronic severe anaemia not in heart failure and with a normal heart size, and in 15 normal men. Heart rates, electromechanical systole (QS2), pre-ejection period index (PEPI), left ventricular ejection time index (LVETI), and the ratio of pre-ejection period to left ventricular ejection time (PEP/LVET) did not differ significantly in the two groups. After the intravenous administration of frusemide in 10 of the anaemic patients, the pre-ejection period index was prolonged, the PEP/LVET ratio increased, heart rate increased, and the left ventricular ejection time index shortened. Intravenous digoxin did not alter the QS2 interval and heart rate significantly in the anaemic subjects. Left ventricular function in chronic severe anaemia as measured by systolic time intervals does not differ from that of normal controls. The effect of frusemide on the systolic time intervals is explained as an effect of the fall in preload, bringing cardiac function further down on the ascending limb of the Frank-Starling curve. Other related studies are discussed.

Van Gogh's vision. Digitalis intoxication?

Vincent van Gogh, the Dutch postimpressionist painter, died in 1890. He was an uncommon man. Automutilation, depression, insanity, and suicide are part of his medical history. During the last few years of his life, his paintings were characterized by halos and the color yellow. Critics have ascribed these aberrations to innumerable causes, including chronic solar injury, glaucoma, and cataracts. Van Gogh may have been under the influence of digitalis intoxication and its side effects: xanthopsia and coronas. This hypothesis is based on his twice having painted his physician holding a foxglove plant; that this medicine was used in the latter part of the 19th century in the treatment of epilepsy; and that the toxic effects of digitalis may have, in part, dictated the artist's technique. (<i>JAMA</i>1981;245:727-729)

Van Gogh's Vision

Vincent van Gogh, the Dutch postimpressionist painter, died in 1890. He was an uncommon man. Automutilation, depression, insanity, and suicide are part of his medical history. During the last few years of his life, his paintings were characterized by halos and the color yellow. Critics have ascribed these aberrations to innumerable causes, including chronic solar injury, glaucoma, and cataracts. Van Gogh may have been under the influence of digitalis intoxication and its side effects: xanthopsia and coronas. This hypothesis is based on his twice having painted his physician holding a foxglove plant; that this medicine was used in the latter part of the 19th century in the treatment of epilepsy; and that the toxic effects of digitalis may have, in part, dictated the artist's technique.

Anaesthetic problems associated with the treatment of cardiovascular disease: I. Digitalis toxicity.

Digitalis intoxication is still a common clinical problem affecting a fifth to a quarter of all digitalized patients. In the surgical patients there are many factors - including fluid, electrolyte and acid-base disturbances, hypoxaemia, abnormal renal function and drug interactions - that can enhance the sensitivity of the heart to digitalis. Unfortunately, the cardiac as well as other systemic signs of digitalis toxicity are non-specific and the difference between therapeutic and toxic serum concentrations is ill-defined. Clinical acumen together with a knowledge of the preparation being used, its pharmacokinetics, factors that can enhance the sensitivity of the heart, and the serum concentration is still necessary in the diagnosis of toxicity. Whether to proceed with anaesthesia and operation in the toxic patient depends on the urgency of surgery. Elective surgery should be postponed until toxicity subsides. In an emergency, the urgency of the operation precludes any delay, and cardio-toxicity should be treated aggressively before, during and after operation. Treatment of digitalis toxicity should include the withdrawal of the cardiac glycoside and the elimination of all factors enhancing the toxic effects of digitalis. When the arrhythmia is causing haemodynamic instability or when there is ventricular irritability, treatment with anti-arrhythmic agents is indicated. Potassium chloride, lidocaine and diphenylhydantoin are the drugs of choice in the treatment of tachyarrhythmias and ventricular premature beats. Atropine can be used to counteract the vagal effect of digitalis in bradycardia and heart block. If atropine is ineffective, the placement of a temporary artificial pacemaker may be necessary. When congestive heart failure is a complication, the use of a vasodilator to decrease ventricu-lar preload and afterload will improve the mechanical efficiency of the heart, increase cardiac output and relieve pulmonary congestion.

Differing sensitivities of Purkinje fibers and myocardium to inhibition of monovalent cation transport by digitalis.

The extent of inhibition of monovalent cation active transport in Purkinje fibers and myocardium in response to toxic and inotropic doses of digitalis were studied in the dog to elucidate the factors underlying the different relative sensitivities of these tissues to the toxic arrhythmogenic effects of digitalis. Monovalent cation transport inhibition was assessed by measuring uptake of the K(+) analog Rb(+) in samples of myocardium and Purkinje fibers after in vitro ouabain exposure and after acute or chronic administration of digoxin in vivo. The active uptake of Rb+ was determined as the difference between total uptake and uptake in the presence of 1.0 mM ouabain. Mean active uptake of Rb(+) by Purkinje fibers from control hearts was 1.62+/-0.11 (SEM) nmol/mg wet wt per 15 min, significantly greater than the value of 0.49+/-0.05 for myocardium (P < 0.001). Concentration-effect curves for inhibition of monovalent cation active transport by in vitro exposure to graded concentrations of ouabain showed that the concentration for half-maximal inhibition of monovalent cation transport, IC(50), for Purkinje fiber transport was 0.4 muM, significantly less than the value of 1.4 muM for myocardial samples. Dogs were given toxic doses of digoxin (0.3 mg/kg i.v.). At onset of sustained ventricular tachycardia, they were killed and monovalent cation transport measured in myocardial and Purkinje fiber samples. Active Rb(+) uptake was inhibited by 44% in myocardial samples, whereas a significantly greater inhibition of 76% was noted in Purkinje fibers (P < 0.01). Similar data were obtained for both transmural myocardial biopsy samples and subendocardial trabecular samples obtained from regions adjacent to Purkinje fibers. Another group of dogs received a nontoxic dose of 0.02 mg/kg i.v. daily for 6 d. Myocardium showed a 17% reduction in Rb(+) active uptake compared to control animals receiving no drug, whereas Purkinje fiber transport was reduced in these dogs to a significantly greater extent averaging 44% (P < 0.001). Thus, both toxic and inotropic (non-toxic) doses of digoxin inhibited monovalent cation transport in Purkinje fibers to a greater extent than in myocardium. This difference in apparent sensitivity of monovalent cation transport to digoxin may contribute to the previously reported tendency of digitalis toxic arrhythmias to arise in Purkinje fibers.

Comparison of the inotropic action of digitalis and isoproterenol in younger and older individuals

The positive inotropic effects of digitalis (deslanoside C, 1.2 mg. intravenously) and isoproterenol (2 μg/minute intravenously) were compared in two groups of younger and older individuals using the systolic time interval method. Both groups responded in a completely comparable way to deslanoside C. However, after isoproterenol administration, the LVET of the older group was significantly shortened. Consequently, the PEP/LVET ratio did not change significantly. This difference is attributed to a lesser increase of the stroke volume in the older group.

Effects of ouabain on the electrophysiological properties of subendocardial Purkinje fibers surviving in regions of acute myocardial infarction

We compared the effects of ouabain 2.5 × 10 −8 M. on the electrophysiological properties of minimally-depressed subendocardial Purkinje fibers surviving in regions of acute myocardial infarction with its effects on subendocardial Purkinje fibers in adjacent normal regions and in anatomically identical regions of noninfarcted hearts. Experiments were carried out in vitro on left ventricular tissue preparations dissected from the hearts of dogs 24 hours after coronary artery ligation and from normal canine hearts. Ouabain had no effect on maximum diastolic potential, action potential upstroke, or V max of Purkinje fibers in normal or infarcted regions. It prolonged the action potential duration in infarcted but not in normal regions. In infarcted tissue preparations ouabain increased conduction velocity and failed to alter the effective and functional refractory periods, while in normal tissue preparations the drug did not affect conduction velocity or the effective refractory period but caused an increase in the functional refractory period. Ouabain did not cause spontaneous activity in normal tissue preparations. In infarcted preparations it resulted in spontaneous activity in six of eight preparations studied. This was due to the development of oscillatory afterpotentials in three preparations and phase 4 depolarization in one; in the other two preparations the mechanism was uncertain. Thus, Purkinje fibers surviving in infarcted regions are more sensitive than normal fibers to the direct electrophysiological effects of digitalis.

How do digitalis tolerance and toxicity change with age?

Digitalis is perhaps the fourth most frequently prescribed drug in the United States, but it has a low margin of safety. Abnormalities of the heart increase with age. For many cardiovascular conditions that may not respond to any other current treatment, digitalis compounds provide effective therapy. 9 Because the digitalis glycosides and related, compounds greatly increase the force of cardiac contrac9 tion, they are most useful in treating persons with congestive heart failure. The electrophysiological effects of digitalis are beneficial in reversing atrial fibrillation and most ventricular tachyarrhythmias of supraventricular origin. An estimated 5 percent of the population over age 65 are taking some form of digitalis. The most common forms are digoxin (Lanoxin) and digitoxin (Crystodigin, Purodigin). Toxicity to digitalis occurs at about 60 percent of the therapeutic dose. Consequently, it is not surprising that 20 to 30 percent of patients taking digitalis experience some adverse effects.

Effects of digitalis intoxication on the phosphoglucomutase and creatine phosphokinase of guinea pig livers.

A study was made of the behavior of the phosphoglucomutase (PGluM) and creatine phosphokinase (CPK) in the liver tissue of guinea pigs after chronic digitalis intoxication. It was found that the latter causes a statistically significant decrease of both enzymatic activities. The results obtained by the authors with this investigation, together with those of previous researchers, show that the toxic effect of digitalis on the enzymatic activities is not limited to the reported effect on the ATPase but also involves, at least at the doses and under the conditions used, other enzymatic activities.

Electrophysiologic effect of digitalis on sinoatrial nodal function in children

Despite the prevalence of digitalis usage in children, the electrophysiologic effects of digitalis on sinoatrial (S-A) nodal function is unknown in this age group. The purpose of this study was to determine the effect of digitalis on sinoatrial conduction time as well as on S-A nodal automaticity. Ten subjects (mean age 10.5 years) underwent electrophysiologic assessment of S-A nodal function before and 30 minutes after administration of ouabain (0.01 mg/kg). Total S-A conduction time increased in each subject and the mean value after ouabain (182 msec ± 13 standard errors of the mean [SEM]) was significantly higher ( P < 0.01) than before (149 msec ± 11). The sinus cycle length was variable after ouabain ( P > 0.1). The corrected sinus nodal recovery time also was variable ( P > 0.1), decreasing substantially in three subjects. Mechanisms of the effect of digitalis on the S-A node and atrium are proposed and discussed. It is concluded that digitalis prolongs the S-A conduction time in children with normal S-A nodal function. By prolonging the S-A conduction time, digitalis may artifactually shorten corrected S-A nodal recovery time in some patients.

Effect of digitalis on salivary electrolytes of infants

Effect of digitalis on salivary electrolytes of infants

Ischemic-induced alterations in cardiac sensitivity to digitalis

Intravenous infusion of acetylstrophanthidin to 6 dogs, after a 60 min left anterior descending coronary artery occlusion, was associated with a 43.0 ± 10.5% decrease in the dose of digitalis needed to produce ventricular arrhythmias as compared to the pre-ischemic dose (97.5 ± 8.0 μg/kg). Reperfusion of the ischemic region for 2 h after a 90 min occlusion resulted in a 54.4 ± 6.7% decrease in the arrhythmogenic dose. Direct intracoronary infusions of digitalis into the ischemic region, after a 90 min coronary occlusion followed by 2 h of reperfusion, was associated with a 47.7 ± 6.4% decrease in the dose of digitalis needed to produce arrhythmias. The pre-ischemic (control) arrhythmogenic dose of digitalis via the intracoronary infusion method was 1.5 ± 0.3 μg/kg (ean ± S.E.M. of 7 dogs). Sodium pump activity, estimated from the ouabain-sensitive 86Rb uptake in sodium-loaded loaded ventricular slices, was significantly higher in slices obtained from the ischemic regions (6.84 ± 0.30 nmoles 86Rb/mg dry wt. (ean ± S.E.M.), than from the non-schemic regions (3.43 ± 0.64 nmoles 86 Rb/mg dry wt.) . Sensitivity of the sodium pump activity to the inhibitory effect of ouabain was also increased in the ischemic regions as indicated by a shift in the log dose-response curve to the left. Thus, it appears that there is an increase in myocardial sensitivity to the toxic efect of digitalis after temporary ischemia and it appears to be related to an increase in the sensitivity of the Na +,K +-ATPase or sodium pump to the inhibitory effect of digitalis.

Effect of digitalis on diminished baroreceptor sensitivity in diabetics.

The baroreceptor sensitivity was estimated in 50 normal controls (Group A) and in 50 diabetics of comparable age (Group B). The technique used was infusion of angiotensin (0.5 microgram/min) and measurement of the bradycardic response resulting from the increase of blood pressure. The slope was used as an index of baroreceptor sensitivity. Diabetics had significantly lower baroreceptor sensitivity and a higher resting heart rate. Sensitivity decreased with age in both groups. The reproducibility of the method was excellent. Deslanoside-C (0.8 mg) significantly increased the baroreceptor sensitivity in 11 normal controls and 9 diabetics. Very low sensitivity was found in 26 diabetics who had no evidence of orthostatic hypotension, neuropathy, or retinopathy. However all 17 patients with the above findings had very low sensitivity.