Heparin-induced thrombocytopenia.

Two patients with underlying thromboembolic disorders developed severe thrombocytopenia while receiving heparin sodium; one of these patients developed recurrence of the thrombocytopenia and possible heparin-induced pulmonary emboli when heparin was restarted. In a prospective study of patients receiving heparin in a coronary care unit (CCU), nine of 37 patients developed transient mild thrombocytopenia (platelet counts ranging from 88,000 to 150,000/cu mm). Heparin added to citrated platelet-rich plasma caused platelet aggregation in the two original patients. In three of six CCU patients tested, and in 17 of 87 other subjects, with maximum aggregation at concentrations of heparin likely to be present in vivo during therapy. We herein discuss evidence that suggests that heparin may cause or aggravate thrombosis by causing platelet aggregation. The occurrence of severe heparin-induced thrombocytopenia is well documented, and mild transient thrombocytopenia may be more common than has been recognized. Studies of heparin efficacy should take these responses into account.

Effects of actodigin on the heart.

Actodigin is a new semisynthetic cardiac glycoside reported to have a rapid onset and brief duration of action in dogs. Five patients with congestive heart failure in normal sinus rhythm were given incremental doses of actodigin. Overall, there was no significant change in heart rate, aortic or pulmonary artery pressure, systemic vascular resistance, cardiac index, and stroke volume. This lack of response to actodigin is consistent with previous reports of acute administration of other cardiac glycosides. Four patients with atrial fibrillation and a rapid ventricular rate were given similar doses of actodigin. The ventricular rate was readily controlled. After drug administration was stopped, the ventricular rate quickly returned toward predrug levels. Thus, the rapid onset and brief duration of action of actodigin may be useful in the initial management of atrial fibrillation.

The influence of metiamide on ouabain cardiotoxicity.

The effect of metiamide on the cardiotoxicity produced by ouabain was studied in pentobarbital-anesthetized cats. The onset of ouabain-induced ventricular tachycardia and fibrillation was significantly delayed in cats treated with metiamide as compared with cats that did not receive metiamide. Although the mechanism by which metiamide inhibits ouabain toxicity is speculative, the data suggest that histamine H2-receptor blocking agents may be useful as anti-arrhythmic drugs in digitalis cardiotoxicity.

The influence of heart rate on ouabain cardiotoxicity in cats with spinal cord transection.

The dose, serum level and ventricular content of ouabain needed to produce cardiotoxicity were examined in control cats, cats with transected spinal cords and cats with transected spinal cords whose heart rates were restored to control values by artificial pacing. The lethal dose of ouabain was higher in cats with transected spinal cords and not paced than it was in the control group. However, the lethal dose of ouabain in spinal-sectioned cats with ventricular pacing was no different from that in controls. However, in both groups of spinal-sectioned cats, death was associated with higher ventricular and serum levels of ouabain than in controls. The ventricular ouabain content of paced animals with transected spinal cords was higher than that of controls and lower than that of unpaced spinal cats. Thus, restoration of heart rate to control levels in spinal animals appeared to accelerate myocardial ouabain uptake. The lower myocardial ouabain content in the spinal-sectioned animals which were paced suggests that pacing sensitizes the heart to cardiotoxicity. Spinal section itself appears to decrease the sensitivity to ouabain partly through a decrease in cardiac rate and partly through a loss of neurogenic influence.

A role for environmental factors in the production of digitalis toxicity.

The purpose of our study was to learn whether changes in the external milieu could affect the lethality of ouabain. We found that guinea pigs experiencing restraint stress for the first time showed a greater susceptibility to the lethal effects of ouabain (175 microgram/kg IP) than non-stressed controls. Adaptation to the restraint procedure abolished this sensitization. This effect related to repeated experience with restraint and not to repeated human handling because repeatedly handled guinea pigs still showed sensitization to the lethal effect of ouabain (200 microgram/kg IP) when restrained for the first time. These data indicate that environmental factors will have to be considered in addition to changes in the internal milieu when trying to explain individual differences in sensitivity to toxicity while taking constant doses of digitalis.

Learned fear: a cause of arrhythmia onset in the presence of digitalis.

In earlier studies we have shown that guinea pigs exposed to signal-shock pairs develop digitalis toxicity earlier than control pigs on a test day when shocks are not delivered. Presenting subjects with signal-shock pairs is known to produce learned changes in autonomic tone thought to reflect fear. However, we were unable to find evidence of such changes in that model. A recent report extended our work on psychosomatic digitalis toxicity to the rabbit. Although that animal has been extensively used in studies of visceral learning, that study did not provide sufficient data to rigorously conclude that visceral learning had taken place. In this report, we show that rabbits which have learned that a signal accurately predicts the occurrence of shock develop digitalis-toxic arrhythmias more often during the signal and significantly earlier than other rabbits given prior exposure to equal numbers of signals and shocks, never explicitly paired. The use of this latter control group indicates that rabbits exposed to signal-shock pairs have learned to associate the signal with its consequences; independent evidence of learning exists in the fact that these rabbits showed a signal-locked bradycardia on their training day. However, bradycardia did not appear to be the mechanism for the early elicitation of digitalis toxicity on the test day when ouabain was infused during probes with the signal alone. These data may have clinical significance in their indication that factors in the external milieu can precipitate digitalis-toxic arrhythmias in individuals that would otherwise have no evidence of digitalis toxicity.

The influence of cycle length on the effective and functional refractory period of the human AV node.

The influence of atrial cycle length on the effective and functional refractory period of the human AV node and atrium is presented. In general, decrements in atrial cycle lengths resulted in a shortening of the refractory period of the atrium and the functional refractory period of the AV node. The effective refractory period of the AV node was not significantly prolonged. The physiologic significance of the effective and functional refractory periods of the AV node are discussed.

The role of shock predictability during aversive conditioning in producing psychosomatic digitalis toxicity.

Guinea pigs were subjected to Pavlovian fear conditioning (signaled shock) and then infused with a fast acting digitalis preparation on a day when all experimental stimuli except shock were delivered. A significant shortening in latency to the onset of life-threatening digitalis toxicity was found when comparisons were made to control pigs that had never been shocked. This effect was not found in other guinea pigs infused with ouabain after exposure to sessions of unsignaled shock. These experiments indicate that psychological factors, when divorced form physical factors, may produce lethal digitalis toxicity in an organism that would otherwise by asymptomatic. The data from these experiments suggest that the intense arousal associated with a signal that had previously been paired with shock is sufficient to precipitate cardiac arrhythmias in an animal with a predisposition to cardiac automaticity such as is produced by digitalis. Conversely, the less intense arousal associated with unsignaled shock is inadequate to produce this effect. This interpretation indicates that the state of an animal's health will affect its psychosomatic response to signaled or unsignaled shock.

Cholinergic activation produces psychosomatic digitalis toxicity.

The purpose of this study was first to develop an animal model for stress-induced digitalis toxicity in such a way that physical and psychological factors might be kept separate. The other purpose was to begin an analysis of the mechanism of this psychosomatic effect. To do this, free-ranging guinea pigs were subjected to repeated sessions of signaled shock (Pavlovian fear conditioning) or to signal alone. On a probe day in which signals were delivered as usual but shock was not administered, guinea pigs were infused i.v. with ouabain after an i.p. injection of either saline, atropine sulfate or atropine methylbromide. Saline-treated guinea pigs with prior fear conditioning became digitalis toxic at a significantly lower dose of the drug than control guinea pigs that had not had exposure to signaled shock. This effect was blocked by both atropine salts, indicating a cholinergic effector on the blood side of the blood-brain barrier responsible for early arrhythmogenesis in the fear-conditioned animals.

Stress-induced ventricular arrhythmias.

Restraint stress produced ventricular arrhythmias in seven of seven guinea pigs monitored by a Holter ECG recorder. Couplets and ventricular tachycardia, never seen in unrestrained guinea pigs, were noted in three. The arrhythmias were associated with high heart rates which showed no tendency to decrease during the restraint period.

A comparison of actodigin and ouabain in cats.

The effects of actodigin and ouabain at infusion rates which produce death in equivalent times were compared in anesthetized cats. Actodigin-induced ventricular tachycardia occurred sooner than that induced by ouabain. However, in animals in which the infusion of drug was stopped one minute after the onset of ventricular tachycardia, the arrhythmia terminated sooner in cats given actodigin than in those given ouabain. Actodigin produced a slower heart rate and greater prolongation of the PR interval than did ouabain suggesting a greater increase in vagal tone in the actodigin treated cats. Left ventricular pressure was not changed by either drug while peak dp/dt was increased after 30 min of the ouabain infusion but not significantly more than changes produced by actodigin. Thus, the use of actodigin may be limited by the early appearance of ventricular arrhythmias.

Neural basis for the genesis and control of digitalis arrhythmias.

The pharmacokinetics of ouabain associated with toxicity were studied in the cat and the guinea pig both in vivo and in vitro using ouabain-H3. After spinal cord transection a higher dose of ouabain was required to reach the lethal endpoint. This intervention also increased the myocardial and serum levels associated with toxicity were studied in the cat and the guinea pig both in vivo and in vitro using ouabain-H3. After spinal cord transection a higher dose of ouabain was required to reach the lethal endpoint. This intervention also increased the myocardial and serum levels associated with death. These findings were corroborated in experiments using digitoxin H3. In vitro, substantially higher ouabain tissue contents were associated with a lethal event. In addition, in cats and guinea pigs, the lethal myocardial ouabain content did not change when the infusion rate of ouabain was varied in vivo or the perfusate ouabain concentration was changed in vitro. In vivo, propranolol increases the myocardial ouabain content associated with death to in vitro levels. In vitro, the drugs prolongs the time to death by retarding the myocardial uptake of ouabain. These data suggest that the toxic effects of ouabain in the whole animal are largely neural and in the isolated heart, substantially myocardial.

Ouabain cardiotoxicity, a reassessment of methodology.

The capacity of ouabain (1 mug/kg/min and 2 mug/kg/min) to induce cardiotoxicity was explored in control cats and cats after spinal cord transection. In cats receiving 1 mug/kg/min, a higher dose of ouabain was needed to produce lethal arrhythmias in spinal cats compared to intact cats. However, in cats receiving 2 mug/kg/min, there was no difference in dose to death between intact and spinal cats. At death, the serum level and ventricular contents of ouabain was higher in animals with spinal cord transection regardless of the rate of ouabain infusion. Thus it appears that determination of the myocardial tissue digitalis concentration more accurately reflects the state of digitalis sensitivity than the administered dose. Additionally, seemingly paradoxical findings with regard to dose are explicable when serum and tissue concentration are simultaneously evaluated.