Epidemiology of overdose episodes from the period prior to hospitalization for drug poisoning until discharge in Japan: An exploratory descriptive study using a nationwide claims database.

BACKGROUND: Little is known about the nationwide epidemiology of the annual rate, causative substance, and clinical course of overdose-related admission. We aimed to describe the epidemiology of overdose episodes from the period prior to hospitalization for drug poisoning until discharge to home. METHODS: We assessed all cases of admission due to overdose (21,663 episodes) in Japan from October 2012 through September 2013 using the National Database of Health Insurance Claims and Specific Health Checkups of Japan. RESULTS: The annual rate of overdose admission was 17.0 per 100,000 population. Women exhibited two peaks in admission rates at 19-34 years (40.9 per 100,000) and ≥75 years (27.8 per 100,000). Men exhibited one peak in the admission rate at ≥75 years (23.7 per 100,000). Within 90 days prior to overdose, ≥60% and ≥9% of patients aged 19-49 years received a prescription for benzodiazepines and barbiturates, respectively. In addition, 59% of patients aged ≥75 years received a prescription for benzodiazepines prior to overdose, 47% had a history of congestive heart failure, and 24% had a diagnosis of poisoning by cardiovascular drugs. The proportion of patients with recent psychiatric treatments decreased with age (65.1% in those aged 35-49 years and 13.9% in those aged ≥75 years). CONCLUSIONS: The findings emphasize the need for overdose prevention programs that focus on psychiatric patients aged 19-49 years who are prescribed benzodiazepines or barbiturates and on non-psychiatric patients aged ≥75 years who are prescribed benzodiazepines or digitalis.

Digoxin-specific Fab fragments as single first-line therapy in digitalis poisoning.

OBJECTIVE: Despite administration of Fab fragments in digitalis poisoning, high mortality rates are consistently reported. A previous study suggested that Fab fragments prescribed as first-line therapy might improve mortality rate. Our objective was to evaluate this approach. DESIGN: Retrospective chart review (January 1990 to January 2004). SETTING: University hospital intensive care unit. PATIENTS: Consecutive patients admitted for cardiac glycoside poisoning. INTERVENTION: First-line therapy with Fab fragments (with or without atropine) in either curative or prophylactic doses. MEASUREMENTS AND MAIN RESULTS: A total of 141 patients were admitted for digitalis poisoning of whom 66 received first-line Fab fragment therapy. Their median age was 74 years (25th to 75th percentiles: 51-83); 76% were women. Half were intoxicated by digitoxin and half by digoxin. Median serum concentration was 168 (108-205) ng/mL for digitoxin and 6.2 (4.3-13.5) ng/mL for digoxin. Conduction disturbances were reported in 45 cases (68%) and ventricular arrhythmia in six cases (9%). Fab fragments were administered as curative treatment in 21 patients (32%) and prophylactically in 45 patients (68%). The median cumulative dose was 4 (4-6) vials. No adverse effects were reported. Five patients (7.6%) died. CONCLUSIONS: First-line therapy with Fab fragments in patients with digitalis poisoning was associated with a low mortality rate.

Electrocardiographic abnormalities associated with poisoning.

This article will review the cardiovascular toxicities of various medications, stressing the electrocardiographic presentation--both rhythm and morphological issues--and emphasizing recognition and management issues. Cardiovascular toxins are grouped into categories causing similar electrocardiographic effects, including the potassium efflux blockers, sodium channel blockers, sodium-potassium adenosine triphosphatase blockers (ie, digitalis compounds), calcium channel blockers, and beta-adrenergic blockers. This article reviews the various electrocardiographic abnormalities associated with these 5 classes of agents, ranging from morphological abnormalities and conduction blocks to brady- and tachyarrhythmias.

Extrastimulus-related shortening of the first postpacing interval in digitalis-induced ventricular tachycardia: observations during programmed electrical stimulation in the conscious dog.

The effect of different modes of pacing on interval and configuration of the first postpacing QRS complex was studied during digitalis-induced ventricular tachycardia in the conscious dog. The effect of overdrive pacing was related to pacing rate; the longest pacing intervals resulted in prolongation of the first postpacing interval, while increasing the rate of overdrive pacing led to a progressive shortening of the first postpacing interval. When extrastimuli were introduced during fixed rate pacing, the duration of the first postpacing interval was found to be predominantly effected by the extrastimulus coupling interval. The importance of the last paced interval to the duration of the first postpacing cycle length was also observed when only a single or two extrastimuli were given. The duration of the first postpacing interval was found to be independent of the site site of stimulation. In contrast, the configuration of the first postpacing QRS complex was found to be related to the site of pacing; the first postpacing QRS complex originated close to the site of stimulation independent of the configuration of the tachycardia. In conclusion, it was found that during digitalis-induced ventricular tachycardia 1) the first postpacing interval is mainly, dependent on the interval of the last paced beat, 2) the length of the first postpacing interval is independent of the site of stimulation, but 3) the configuration of the first postpacing QRS complex is related to the site of stimulation. These findings may facilitate the understanding of complex ventricular arrhythmias observed during severe digitalis intoxication in human beings.

Digoxin Immune Fab therapy in the management of digitalis intoxication: safety and efficacy results of an observational surveillance study.

An observational surveillance study was conducted to monitor the safety and effectiveness of treatment with Digoxin Immune Fab (Ovine) (Digibind) in patients with digitalis intoxication. Before April 1986, a relatively limited number of patients received treatment with digoxin-specific Fab fragments through a multicenter clinical trial. Beginning with commercial availability in July 1986, this study sought additional, voluntarily reported clinical data pertaining to treatment through a 3 week follow-up. The study included 717 adults who received Digoxin Immune Fab (Ovine). Most patients were greater than or equal to 70 years old and developed toxicity during maintenance dosing with digoxin. Fifty percent of patients were reported to have a complete response to treatment, 24% a partial response and 12% no response. The response for 14% of patients was not reported or reported as uncertain. Six patients (0.8%, 95% confidence interval 0.3% to 1.8%) had an allergic reaction to digoxin-specific antibody fragments. Three of the six had a history of allergy to antibiotic drugs. Twenty patients (2.8%, 95% confidence interval 1.7% to 4.3%) developed recrudescent toxicity. Risk of recrudescent toxicity increased sixfold when less than 50% of the estimated dose of antibody was administered. A total of 215 patients experienced posttreatment adverse events. The events for 163 patients (76%) were judged to result from manifestations of underlying disease and thus considered unrelated to Fab treatment. Digoxin-specific antibody fragments were generally well tolerated and clinically effective in patients judged by treating physicians to have potentially life-threatening digitalis intoxication.

[Digitalis intoxication secondary to treatment with clarithromycin]. / Original Breve Intoxicación digitálica secundaria al tratamiento con claritromicina.

OBJECTIVE: The goal of this study was to investigate the percentage of patients concurrently receiving digoxin and clarithromycin who exhibited serum digoxin concentrations above the therapeutic range because of a likely interaction between both drugs, and whether digitalis intoxication ensued. METHOD: A descriptive, retrospective study carried out from January 2002 to December 2003 in all inpatients concurrently receiving digoxin and clarithromycin whose serum digoxin concentrations were monitored by the Pharmacy Department s Pharmacokinetics Section. RESULTS: Twenty-six patients having received digoxin and clarithromycin concurrently during their hospital stay were included in the study. Of these, 12 patients (46.2%) had serum digoxin concentrations above the therapeutic range: 7 received digoxin in doses unsuited for their age and/or renal function, and 2 fell short of the mean period of time considered adequate for an interaction to occur. Therefore, only 3 patients had serum digoxin concentrations above the therapeutic range, probably because of an interaction with clarithromycin, and all three had digitalis intoxication symptoms. CONCLUSIONS: According to the results of our study, 11.5% of patients concurrently receiving digoxin and clarithromycin had serum digoxin concentrations above the therapeutic range because of a likely interaction between these two drugs, with digitalis intoxication ensuing. Thus, we deem it necessary to monitor serum digoxin concentrations in patients receiving clarithtomycin.

Digitalis intoxication misdiagnosed as depression by primary care physicians.

Three cases are described in which digitalis intoxication was misdiagnosed as depression by primary care physicians. The authors discuss the potentially life-threatening consequences of such a misdiagnosis, guidelines for an accurate diagnosis, and the implications for medical education.

Digitalis toxicity: epidemiology and clinical use of serum concentration measurements.

Despite continuing advances in understanding of the basic pharmacology of the cardiac glycosides, digitalis intoxication remains a common clinical problem. Physician education programs and increasing use of serum or plasma concentration data have, however, been shown to be capable of substantially reducing the incidence of digitalis toxicity. Methodologic progress and availability of commercial radioimmunoassay kits have placed measurement of clinically relevant serum or plasma cardiac glycoside concentrations within the capability of most well equipped clinical laboratories. Extensive experience with serum digitalis levels now provides a basis for ongoing examination of the role of these measurements in clinical practice. Results of studies to date demonstrate that mean serum digoxin and digitoxin levels are significantly higher in patients with electrocardiographic evidence of toxicity compared with patients without such evidence. It must be emphasized, however, that because of overlap in serum digitalis levels between these two groups, sole dependence on these levels for established of a diagnosis of digitalis toxicity is not warranted. Multiple factors influence individual responses to cardiac glycosides, and serum concentration data must be interpreted in the over-all clinical context. Type and extent of underlying heart disease are important determinants of the clinical response to any given dose or concentration of cardiac glycoside. Knowledge of the serum digitalis concentration is likely to be helpful in the setting of suspected digitalis intoxication in the absence of an adequate history, or in the presence of fluctuating renal function, overt or suspected malabsorption, or uncertain bioavailability. More generally, such measurements may prove useful whenever an unanticipated response to digitalis is encountered, whether it be suspected toxicity or the absence of an expected therapeutic effect.

Foxglove tea poisoning.

Herbal teas occasionally produce toxic reactions. Unwitting use of the foxglove plant for brewing tea resulted in cardiac glycoside toxicity in an otherwise healthy man. Potentially toxic plants are omnipresent whereas herbal tea imbibing has had an enhanced popularity. Physicians will have increasing contact with patients who have inadvertently poisoned themselves with such concoctions.

Steady state serum digoxin concentration in relation to digitalis toxicity in neonates and infants.

Steady state serum digoxin concentrations were determined in 34 neonates and infants receiving standard maintenance doses of the drug. Digitalis intoxication, diagnosed by ECG criteria, occurred in four of 13 patients with a serum concentration above 2 ng/ml and not in any of 21 subjects with a serum digoxin concentration below this level. This association was found to be significant. It seems that the concept of increased tolerance to digoxin hitherto ascribed to infants is not tenable and that the monitoring of serum digoxin concentration is essential to treatment in this age group.

Recognition and management of digitalis toxicity.

The most important step in the management of toxicity due to any of the cardiac glycosides is its recognition. Despite the development of an accurate clinical assay for serum levels of digoxin greater than 20 years ago, digitalis toxicity remains common and difficult to confirm, even if suspected, due primarily to 2 factors. First, the signs and symptoms of digitalis toxicity, most commonly an abnormal electrocardiogram showing ventricular or atrial arrhythmias, with or without some degree of concurrent atrioventricular block, often also occur in patients with congestive heart failure (CHF) and underlying coronary atherosclerosis who are not receiving a cardiac glycoside. Second, due to digoxin's narrow therapeutic ratio, the marked degree of variability in the sensitivity of individual patients to its toxic effects, and the common problem of obtaining blood samples inappropriately during the early distribution phase following dosing, a serum digoxin concentration often does not serve as a reliable indicator of toxicity. Despite these difficulties in diagnosis, the management of digoxin toxicity has been made much more effective with the widespread availability of F(ab) fragments of anti-digoxin antibodies. This drug provides the clinician with a rapidly acting, safe antidote for all commonly used digitalis preparations. Conventional therapy for digoxin toxicity remains the maintenance of serum potassium levels greater than or equal to 4 mEq/liter, reversal of decompensated CHF or overt myocardial ischemia, attention to serum magnesium levels and the patient's acid-base status, appropriate antiarrhythmics in the event of ventricular arrhythmias, and a temporary pacemaker for high-grade atrioventricular block. Nevertheless, the high specificity and documented safety of the antibody preparation provides a needed safety net for the continuing use of cardiac glycosides as first-line inotropic agents in the modern therapy of chronic CHF.

A multipurpose catheter for electrophysiologic and hemodynamic monitoring plus atrial pacing.

A new multipurpose flow-directed pulmonary arterial catheter has been developed and evaluated in 30 patients with acute cardiopulmonary dysfunction. The catheter permits monitoring of the bipolar atrial electrogram, pulmonary arterial or wedge pressure, central venous pressure, and cardiac output, plus atrial pacing. The standard Swan-Ganz thermistor-equipped catheter was modified to incorporate two ring electrodes on the shaft at 25 and 26 cm from the tip. With the pair of electrodes positioned in the right atrium at the junction with the superior vena cava, stable electrograms of high quality were recorded in all 30 subjects, some for as long as six days. These high-fidelity atrial electrograms permitted rapid and accurate diagnosis of many complex dysrhythmias in these unstable patients. Because of the limited noise in the signal of the electrogram, continuous quantitative measurements of intervals by a computerized system was feasible. Furthermore, the stable intracavitary position of electrodes provided a reliable site for atrial pacing, with pacing thresholds (2 to 12 ma; average, 5 ma) that remained stable for up to four days. Atrial pacing was used to treat sinus bradycardia, atrial tachyarrhythmias, digitalis intoxication, and ventricular dysrhythmias.

Digitalis toxicity.

The principal causes of digitalis toxicity are overdose, reduced volume of distribution, reduced renal elimination, and increased myocardial sensitivity. The metabolic mechanism of digitalis toxicity is intense inhibition of sarcolemma Na-K ATPase, which leads to increases of intracellular Na+ and Ca2+ and arrhythmogenic membrane ionic currents. A variety of cellular electrophysiologic effects and effects on the nervous system are responsible for the array of clinical arrhythmias seen during digitalis toxicity, i.e., sinus bradycardia, atrioventricular block, nonparoxysmal atrioventricular junctional tachycardia, and ventricular tachycardia.

Acute yellow oleander (Thevetia peruviana) poisoning: cardiac arrhythmias, electrolyte disturbances, and serum cardiac glycoside concentrations on presentation to hospital.

OBJECTIVE: To describe the cardiac arrhythmias, electrolyte disturbances, and serum cardiac glycoside levels seen in patients presenting to hospital with acute yellow oleander (Thevetia peruviana) poisoning and to compare these with published reports of digitalis poisoning. DESIGN: Case series. SETTING: Medical wards of Anuradhapura District General Hospital, Sri Lanka, and coronary care unit of the Institute of Cardiology, National Hospital of Sri Lanka, Colombo, the national tertiary referral centre for cardiology. PATIENTS: 351 patients with a history of oleander ingestion. MEASUREMENTS: ECG and blood sample analysis on admission. RESULTS: Most symptomatic patients had conduction defects affecting the sinus node, the atrioventricular (AV) node, or both. Patients showing cardiac arrhythmias that required transfer for specialised management had significantly higher mean serum cardiac glycoside and potassium but not magnesium concentrations. Although there was considerable overlap between groups, those with conduction defects affecting both sinus and AV nodes had significantly higher mean serum cardiac glycoside levels. CONCLUSIONS: Most of these young previously healthy patients had conduction defects affecting the sinus or AV nodes. Relatively few had the atrial or ventricular tachyarrhythmias or ventricular ectopic beats that are typical of digoxin poisoning. Serious yellow oleander induced arrhythmias were associated with higher serum cardiac glycoside concentrations and hyperkalaemia but not with disturbances of magnesium.

Arrhythmias in patients with drug toxicity, electrolyte, and endocrine disturbances.

The common rhythm disturbances related to electrolyte imbalance are due predominantly to abnormalities of potassium. An understanding of the mechanism underlying these abnormalities is facilitated by a brief review of normal electrical activity during impulse propagation in cardiac tissue. Also discussed are the actions of all cardioactive and antiarrhythmic drugs on membrane permeability to ions. Lastly, the nonspecific arrhythmias associated with endocrine disturbances are outlined.

Digitalis sensitivity of Na+,K(+)-ATPase, myocytes and the heart.

Cardiac Na+,K(+)-ATPase, the receptor molecule for digitalis glycosides, have isoforms with different intrinsic affinities for the glycosides. Expression of these isoforms are under developmental and hormonal regulation. Switching in isoforms to those with lower intrinsic affinity may decrease digitalis sensitivity of the heart. In addition to the intrinsic affinity of the cardiac Na+,K(+)-ATPase for the glycoside, increases in the rate of Na+ influx and decreases in extracellular K+ concentrations increase glycoside sensitivity of the heart and also reduces the margin of safety by reducing reserve capacity of the sodium pump. Reserve capacity of the sodium pump is also reduced by pathological conditions or aging, resulting in reduced margin of safety for the glycoside. Events that follow sodium pump inhibition also affect sensitivity of the heart to digitalis toxicity. These are hypercalcemia and magnesium depletion. It is now feasible to predict digitalis sensitivity of the heart, not empirically but based on the understanding of the mechanisms responsible for the positive inotropic and toxic actions of the glycoside.

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.

Poisoning by antidysrhythmic drugs.

This article discusses the management of antidysrhythmic drug overdoses in children and adolescents.

The use of central nervous system manifestations in the early detection of digitalis toxicity.

Cardiac glycosides have been used therapeutically for more than 3000 years. They have been the treatment of choice for congestive heart failure for many decades, and recently their clinical utility has been redefined. Despite increased telemetry and development of a sensitive radioimmune assay of serum digoxin levels and the availability of digoxin immune Fab fragments (Digibind) to treat digitalis-induced life-threatening dysrhythmias, toxicity remains a serious and common problem. A body of literature, old and new, speaks to the clear but potentially unrecognized role that digitalis-induced central nervous system symptoms can play in the early detection and management of digitalis toxicity.

Bidirectional tachycardia a study of five cases.

Five patients with bidirectional tachycardia due to digitalis toxicity associated with severe organic heart disease were studied. The origin of the abnormal rhythm was established with the aid of His bundle recordings in three cases and by indirect clues in the others two. In three cases the origin of bidirectional tachycardia was suprahisian while in two patients it was infrahisian. In one patient the transition from junctional to ventricular tachycardia could be observed. Bidirectional tachycardia appears to be a complex arrhythmia in which similar electrocardiographic configuration can be due to different mechanism. Digitalis toxicity was often a causal factor.