Clinical predictors of adverse cardiovascular events for acute pediatric drug exposures.

Context: Risk factors for adverse cardiovascular events (ACVE) from drug exposures have been well-characterized in adults but not studied in children. The objective of the present study is to describe the incidence, characteristics, and risk factors for in-hospital ACVEs among pediatric emergency department (ED) patients with acute drug exposures.Methods: This is a prospective cohort design evaluating patients in the Toxicology Investigators Consortium (ToxIC) Registry. Pediatric patients (age <18 years) who were evaluated at the bedside by a medical toxicologist for a suspected acute drug exposure were included. The primary outcome was in-hospital ACVE (myocardial injury, shock, ventricular dysrhythmia, or cardiac arrest). The secondary outcome was in-hospital death. Multiple logistic regression analyses were performed to examine novel clinical risk factors and extrapolate adult risk factors (bicarbonate <20 mEq/L; QTc ≥500 ms), for the primary/secondary outcomes.Results: Among the 13,097 patients (58.5% female), there were 278 in-hospital ACVEs (2.1%) and 39 in-hospital deaths (0.3%). Age and drug class of exposure (specifically opioids and cardiovascular drugs) were independently associated with ACVE. Compared with adolescents, children under 2 years old (OR: 0.41, 95% CI: 0.21-0.80), ages 2-6 (OR: 0.37, 95% CI: 0.21-0.80), and ages 7-12 (OR: 0.51, 95% CI: 0.27-0.95) were significantly less likely to experience an ACVE. Serum bicarbonate concentration <20 mEq/L (OR: 2.31, 95% CI: 1.48-3.60) and QTc ≥ 500 ms (OR: 2.83, 95% CI: 1.67-4.79) were independently associated with ACVE.Conclusion: Previously derived clinical predictors of ACVE from an adult drug overdose population were successfully extrapolated to this pediatric population. Novel associations with ACVE and death included adolescent age and opioid drug exposures. In the midst of the opioid crisis, these findings urgently warrant further investigation to combat adolescent opioid overdose morbidity and mortality.

Effects of peripherally administered urotensin II and arginine vasotocin on the QT interval of the electrocardiogram in trout.

The QT interval of the electrocardiogram (ECG) is a measure of the duration of the ventricular depolarization and repolarization. In fish as in human, the QT interval is positively correlated with the RR interval of the ECG, a measure of the cardiac cycle length. Urotensin II (UII) is a neuropeptide that has been highly conserved from fish to human, and UII and its receptor (UT) are expressed in cardiovascular tissues including the heart. Although UII exerts potent cardiovascular actions, its possible effects on the QT interval have never been investigated. The goal of the present study was to provide insight into the potential effect of UII on the QT interval in an established in vivo trout model. To this end, the effects of UII on dorsal aortic blood pressure (PDA), RR, QT intervals and corrected QT (QTc) for RR interval, were investigated after intra-arterial (IA) injection of 5, 50 and 100 pmol UII. The effects of UII were compared to those of two structurally UII-related peptides (URPs), URP1 and URP2, and to those of arginine vasotocin (AVT), homolog of the mammalian arginine vasopressin. IA injection of vehicle or 5 pmol UII had no effect on the various parameters. At the 50-pmol dose, UII evoked its usual increase in PDA with a peak value observed 15 min after the injection (+22% from baseline, P<0.001). This hypertensive effect of UII was accompanied by a significant increase in the RR interval (+18%, P<0.001), i.e. a bradycardia, and these effects remained constant until the end of the recording. The highest dose of UII evoked similar hypertensive and bradycardic effects. Of interest, the QT interval did not change during the bradycardic action of UII (50 and 100 pmol) but the QTc interval significantly decreased. In trout pre-treated with urantide, a peptidic antagonist of UT, the hypertensive and bradycardic actions of 50 pmol UII were reduced 3-fold and no change occurred in the QT and QTc intervals. In trout pre-treated with blockers of the autonomic nervous system, the hypertensive effect of UII was maintained but no change appeared in RR, QT and QTc intervals. IA injections of 50 pmol URPs were without action on the preceding parameters. IA administration of 50 pmol AVT provoked quite similar increase in PDA, and elevation of the RR interval to those evoked by IA injection of UII but, in contrast to UII, AVT injection induced a highly significant and sustained prolongation of the QT interval compared to baseline (+7%, P<0.001) without change in QTc. Our results are indicative of a lack of QT interval change during UII-evoked bradycardia but not after AVT-induced bradycardia and suggest for the first time that some compensatory mechanism specific for the UII peptide is working to stabilize the QT interval. Further research is needed to elucidate the mechanism involved in this action of UII. The potential for UII to prevent detrimental prolongation of cardiac ventricular repolarization might be questioned.

Unintentional lethal overdose with metildigoxin in a 36-week-old infant--post mortem tissue distribution of metildigoxin and its metabolites by liquid chromatography tandem mass spectrometry.

A massive lethal overdose with beta-metildigoxin in a 36-week-old infant is presented. Determination of beta-metildigoxin and its metabolites digoxin, digoxigenin and digoxigenin-monodigitoxosid is achieved by a liquid chromatographic mass spectrometric (LC-MS/MS) method. Measured concentrations for beta-metildigoxin and digoxin in peripheral blood were 40.2 ng/ml and 25.6 ng/ml, respectively. Tissue distribution showed highest concentrations in kidney tissue and gastric content. The metabolite digoxigenin-monodigitoxosid could be detected in heart blood, duodenal content, gastric content and fat tissue while the metabolite digoxigenin could only be detected in gastric content since the drug was given by a stomach tube.

Clinical signs of cardiovascular effects secondary to suspected pimobendan toxicosis in five dogs.

The purpose of this study was to review the medical records of dogs that were either suspected or known to have ingested large doses of pimobendan and to describe the clinical signs associated with pimobendan toxicosis. The database of Pet Poison Helpline, an animal poison control center located in Minneapolis, MN, was searched for cases involving pimobendan toxicosis from Nov 2004 to Apr 2010. In total, 98 cases were identified. Of those, seven dogs that ingested between 2.6 mg/kg and 21.3 mg/kg were selected for further evaluation. Clinical signs consisted of cardiovascular abnormalities, including severe tachycardia (4/7), hypotension (2/7), and hypertension (2/7). In two dogs, no clinical signs were seen. Despite a wide safety profile, large overdoses of pimobendan may present risks for individual pets. Prompt decontamination, including emesis induction and the administration of activated charcoal, is advised in the asymptomatic patient. Symptomatic and supportive care should include the use of IV fluid therapy to treat hypotension and address hydration requirements and blood pressure and electrocardiogram monitoring with high-dose toxicosis. Practitioners should be aware of the clinical signs associated with high-dose pimobendan toxicosis. Of the dogs reported herein, all were hospitalized, responded to supportive care, and survived to discharge within 24 hr of exposure.

An interesting case of cardiotoxicity due to bufotoxin (toad toxin).

Consumption of toads for their aphrodisiac effect is a common practice in Laos, China and in some parts of India. Toad secretions from parotid and skin contains toxin similar to cardiac glycosides. It results in bradycardia and cardiac dysfunction leading on to death in some cases. We report a case of toad poisoning in a young previously healthy male.

Treatment of chronically digoxin-poisoned patients with a newer digoxin immune fab--a retrospective study.

CONTEXT: Digoxin is used in the treatment of patients with cardiac dysfunction, though toxicity sometimes results from the use of this medication. In 1986, the US Food and Drug Administration (FDA) approved a digoxin immune Fab for the treatment of such patients. In 2001, the FDA approved a newer digoxin immune Fab, a digoxin-specific antibody (DSAb) known as DigiFab (Protherics Inc, Brentwood, Tennessee), though minimal literature exists on the clinical effects of this DSAb. OBJECTIVES: To characterize a cohort of patients presenting with chronic digoxin toxicity and to describe the clinical course of these patients with the use of DSAb. METHODS: A retrospective study included patients with life-threatening cardiotoxicity and serum digoxin level greater than 2 ng/mL who were treated at two US hospitals from 2003 to 2006. Trained investigators abstracted data from patients' medical records and assessed changes in clinical and laboratory parameters at regular intervals (0-4, >4-12, >12-24, and >24-72 hours) after treatment with DSAb. An expert panel reviewed electrocardiogram results to identify life-threatening manifestations of digoxin toxicity before and after DSAb treatment. Efficacy of treatment was assessed as rates of improvement in clinical parameters and cardiotoxic effects. Rates of adverse drug reactions were used to characterize safety. All data were analyzed with descriptive statistics. RESULTS: Fourteen patients (mean [SD] age, 71.3 [10.4] years) were treated for chronic digoxin toxicity. At presentation, 12 patients had a heart rate of less than 45 beats per minute, 1 had third-degree heart block, and 1 had asystole. Mean serum digoxin level was 3.6 ng/mL. Eleven patients had abnormal renal function. After administration of DSAb, clinical parameters improved in all patients. Within 24 hours, cardiotoxicity resolved in 7 of 9 evaluable patients. Two adverse drug reactions possibly related to DigiFab occurred, both of which resolved with conventional measures. Two patients died from conditions unrelated to treatment. CONCLUSION: The newer DSAb appears to be a safe and effective treatment for resolving digoxin toxicity in adults, as indicated by electrocardiogram and clinical assessments. Because patients with multiple comorbidities may be at greater risk for digoxin toxicity, they should be closely monitored during treatment with digoxin.

Retrospective review of digoxin exposures to a poison control system following recall of Digitek® tablets.

BACKGROUND: In April 2008, Digitek® digoxin tablets were recalled by the manufacturer as possibly containing double the labeled amount of drug. The recall to March 2006 involved 800 million tablets. OBJECTIVE: The aim of this study was to evaluate whether there was any increase in the number of calls to a poison control system, and any increase in the severity of exposures after the recall compared with before the recall. METHODS: A retrospective review of all digoxin exposures to a poison control system from March 2004 to February 2008 was conducted, with data extracted from an electronic database (California Poison Control System). Total numbers of exposures were identified. Cases with moderate, major, and death outcomes were also identified and tallied. Chi-squared analysis was performed. RESULTS: Prior to the recall, there were 679 digoxin exposures. 148 (22%) were listed with moderate, major, or death as outcome. After the recall, there were a total of 610 cases, 165 (27%) with moderate, severe, or death as outcome. There was a statistically significant increase in the total number of moderate, major, and death outcomes after the period of the manufacturing error compared with before (p = 0.028). CONCLUSION: During the period of manufacturing error, there was a statistically significant increase in digoxin exposures with moderate, major, or death outcomes. The recall of Digitek® tablets may have increased moderate, major, or death outcomes from digoxin exposures in a poison control system database.

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.

Assessment of digoxin antibody use in patients with elevated serum digoxin following chronic or acute exposure.

OBJECTIVE: To evaluate the use of antidotal therapy in patients with an elevated digitalis concentration following chronic or acute exposure. DESIGN AND SETTING: Retrospective review of patient records over 2 years in 20 city hospitals in France. PATIENTS: Overall 838 patients with an elevated serum digitalis concentration (digoxin > 1.95ng /ml or digitoxin > 23ng /ml) were included in the study. Of these, 67 (8%) had received antidotal therapy with Fab fragments. MEASUREMENTS AND RESULTS: The relationships between previously reported prognostic criteria and use of antidotal therapy were investigated. We identified five independent factors that were associated with the use of antidotal therapy: acute overdose (OR 15.74), Fab fragment availability in the hospital (11.06), serum potassium (1.81), and heart rate (0.96). Mortality was significantly lower in Fab-treated (6%, 4/67) than untreated patients (15%, 117/770). CONCLUSIONS: Antidotal therapy is underused in patients with an elevated digitalis concentration especially in patients with chronic digitalis exposure. These patients in our series presented a higher mortality rate than patients with acute poisoning. Although they were older and tended to have a history of cardiac disease, they did not differ from patients with acute poisoning with regard to the main severity criteria and prognostic factors. The use of identical criteria for antidotal treatment after acute and chronic poisoning should help optimize outcomes. Fab fragment availability is insufficient in France but ranks only second after type of poisoning (acute or chronic) in the multivariate association with Fab treatment.