Fatal Self-Poisoning With Massive Propranolol Ingestion in a Young Male Physician.

Suicidal intoxication from massive propranolol ingestion is rare. Surprisingly, no reported cases have involved physicians. The author herein reports a case of self-poisoning death due to ingestion of propranolol by a young male physician. A 31-year-old man with major depressive disorder was found dead in his dormitory room. Fifteen empty packages, each having contained ten 40-mg propranolol tablets, were found without any tablets leftover in his room. A suicide note was also found in his room. He was thus alleged to have ingested 6 g of propranolol for self-poisoning. Autopsy findings revealed approximately 150 mL of pink fluid with some partially dissolved pink tablets in the stomach. No anatomic cause of death was found, except for mild dilatation of cerebral ventricles. Toxicologic analysis revealed propranolol in his blood and gastric contents. The cause of death was attributed to acute cardiac arrest due to severe acute propranolol intoxication from self-poisoning caused by major depressive disorder possibly secondary to organic brain syndrome.

Dramatic resuscitation with Intralipid in an epinephrine unresponsive cardiac arrest following overdose of amitriptyline and propranolol.

Amitriptyline and propranolol are life threatening in overdose. The efficacy of intravenous lipid emulsion (ILE) in tricyclic antidepressant and propranolol overdose is unclear. We report a dramatic response to ILE following pulseless electrical activity arrest due to mixed amitriptyline and propranolol overdose.

Intravenous lipid emulsion for the treatment of drug toxicity.

Intravenous lipid emulsion (ILE) has emerged as a powerful antidote for the treatment of drug toxicity in the past decade. Initial efficacy of ILE was shown in the setting of local anesthetic systemic toxicity (LAST), but recent case reports suggest its consideration in a variety of other drug toxicities. In this review, we will summarize the experimental evidence as well as the clinical experience in using ILE as an antidote. Specifically, we will look at the evidence for using ILE in LAST as well as toxicity due to beta-blockers, calcium-channel blockers, and tricyclic antidepressants. We will also review the current dosing recommendations as well as potential side effects of ILE as an antidote.

A blinded, randomized, controlled trial of three doses of high-dose insulin in poison-induced cardiogenic shock.

BACKGROUND: High dose insulin (HDI) has proven superior to glucagon and catecholamines in the treatment of poison-induced cardiogenic shock (PICS) in previous animal studies. Standard recommendations for dosing of insulin vary and the optimal dose of HDI in PICS has not been established. Our hypothesis was a dose of 10 U/kg/hr of HDI would be superior to 1 U/kg/hr with cardiac output (CO) as our primary outcome measure in pigs with propranolol-induced PICS. METHODS: This was a blinded, prospective, randomized trial with 4 arms consisting of 4 pigs in each arm. The arms were as follows: placebo (P), 1 U/kg/hr (HDI-1), 5 U/kg/hr (HDI-5), and 10 U/kg/hr (HDI-10). Cardiogenic shock was induced with a bolus of 0.5 mg/kg of propranolol followed by an infusion of 0.25 mg/kg/min until the point of toxicity, defined as 0.75 x (HR x MAP) was reached. At this point the propranolol infusion was decreased to 0.125 mg/kg/min and a 20 mL/kg bolus of normal saline (NS) was administered. The protocol was continued for 6 hours or until the animals died. RESULTS: 2 pigs died in the P arm, 1 pig died each in the HDI-1 and HDI-5 arms, and all pigs lived in the HDI-10 arm. There was a statistically significant difference in dose by time interaction on CO of 1.13 L/min over the 6 hr study period (p = < 0.001). There was also a statistically significant difference in dose by time interaction on MAP, HR, and systemic vascular resistance (SVR). No statistically significant difference was found between any of the arms regarding glucose utilization. CONCLUSION: HDI was statistically and clinically significantly superior to placebo in this propranolol model of PICS. Furthermore a dose response over time was found where CO increased corresponding to increases in doses of HDI.

The effects of fructose-1,6-diphosphate on haemodynamic parameters and survival in a rodent model of propranolol and verapamil poisoning.

BACKGROUND: Fructose-1,6-diphosphate (FDP) is a metabolite in the glycolytic pathway created from glucose. Exogenously administered FDP increases the yield of ATP from anaerobic glycolysis. FDP reduces ischaemic tissue area in experimentally-induced cerebral and myocardial infarction and improves haemodynamics post-cardiac bypass. We hypothesised that FDP improves haemodynamics in propranolol and verapamil poisoning. METHOD: Anesthetized Wistar rats were instrumented to record BP, heart rate (HR), cardiac output (CO) and QRS-duration. Propranolol or verapamil were infused continually. When BP dropped by 50%, propranolol-poisoned rats received one of 10% FDP125 mg/kg or 10% FDP250 mg/kg loading dose over 20 minutes followed by infusion 20 mg/kg/h. Verapamil-poisoned rats received the higher dosing regimen of FDP250. Controls received comparable volumes of 10% glucose. Haemodynamic time-points were compared for FDP to control by unpaired t-test or Mann-Whitney test as appropriate (p < 0.05). Survival was assessed using Kaplan-Meier survival analysis. RESULTS: FDP-treated animals survived significantly longer than glucose-treated controls at both doses in propranolol poisoning and in verapamil-poisoning. In propranolol poisoning, FDP250-treated animals showed a statistically significant increase in BP. However, there was no significant difference in cardiac output at this dose. There were also no significant differences in any haemodynamic parameters compared to control at the lower FDP dose in propranolol poisoning or in verapamil poisoning. CONCLUSION: FDP improved survival for both toxicants with an improvement in haemodynamics at the higher dose in propranolol poisoning. Future research could examine the efficacy of FDP in other beta-blocker and calcium channel-blocker poisoning as well as in concert with established inotropic therapies in drug-induced cardiovascular collapse.

Levosimendan does not improve cardiac output or blood pressure in a rodent model of propranolol toxicity when administered using various dosing regimens.

BACKGROUND: Levosimendan (CAS: 141505-33-1) is a myocardial calcium sensitizer that improves myocardial contractility in various forms of heart failure. It produces a moderate improvement in cardiac output (CO) without an improvement in blood pressure (BP) in verapamil and metoprolol poisoned rodents. AIM: To assess the effect of various levosimendan dosing regimens on hemodynamics in a rodent model of propranolol poisoning. METHOD: Male Wistar rats (350-450 g) were anesthetized, ventilated, and instrumented to record BP, heart rate (HR), and CO. Propranolol was infused continually. When BP dropped to 50% of baseline rats received 1 of 7 treatments: (1) 0.9% saline (control), (2) levosimendan 36 µg/kg loading dose then 0.6 µg/kg per min, (3) levosimendan 0.6 µg/kg per min, (4) epinephrine 0.5 µg/kg per min, (5) levosimendan 70 µg/kg loading dose then 1.2 µg/kg per min, (6) levosimendan 1.2 µg/kg per min, and (7) levosimendan 70 µg/kg loading dose alone. Hemodynamics were recorded every 10 minutes for 70 minutes. Cardiac output, mean arterial pressure, and HR for each group were compared with control. RESULTS: All groups had comparable baseline and maximal toxicity hemodynamics prior to initiation of treatment. Levosimendan did not improve CO or BP with any dosing regimen. Blood pressure tended to be lower than control for all doses of levosimendan. Epinephrine significantly improved BP but not CO compared to all other treatment groups. Survival did not differ between groups. CONCLUSIONS: Unlike in verapamil and metoprolol poisoning models, levosimendan did not improve CO or survival in propranolol poisoning. Epinephrine improved BP, but not CO, suggesting that its actions were due to peripheral vasoconstriction.

Severe propranolol and ethanol overdose with wide complex tachycardia treated with intravenous lipid emulsion: a case report.

BACKGROUND: Propranolol is a highly lipid-soluble beta-blocker. We describe a case of severe propranolol overdose, with atypical dysrhythmia--wide complex tachycardia--which was successfully treated with lipid emulsion. CASE REPORT: A 31-year-old woman ingested approximately 3.6 g of propranolol along with ethanol. Clinical manifestations of poisoning included coma, seizures, respiratory failure, hypoglycaemia, circulatory shock, and dysrhythmias. An ECG revealed nonspecific intraventricular conduction delay, followed by wide complex supraventricular tachycardia. Toxicological analysis of blood showed ethanol 2.42 g/L and propranolol 4.21 mg/L. The patient responded poorly to conventional therapy, so intravenous lipid emulsion was used. Apart from IV dopamine, the only treatment after the onset of wide complex tachycardia was 20% Intralipid. Transient improvement was noticed after the initial dose of 500 mL; during the infusion of further Intralipid, blood pressure returned to normal and sinus rhythm was re-established. CONCLUSION: We believe that lipid emulsion had a beneficial effect in the treatment of propranolol toxicity.

Brugada-pattern electrocardiogram in propranolol intoxication.

Brugada syndrome is characterized by the electrocardiographic (ECG) pattern of right bundle-branch block (RBBB) with a high take-off, coved ST-segment elevation in the precordial leads V1 to V3, and the risk of sudden cardiac death. Typically, there is no evidence of structural heart disease. In many cases, Brugada syndrome has been linked to a mutation of the gene SCN5A, which encodes for the fast cardiac sodium channel. In patients with the Brugada syndrome, pharmacologic sodium channel blockade can increase the degree of ST-segment elevation. Interestingly, even in patients with a normal baseline ECG and no clinical suggestion of the Brugada syndrome, toxic doses of class I antiarrhythmic agents as well as toxicities with several nonantiarrhythmic drugs that possess sodium channel blocking properties can induce the Brugada ECG abnormality. Specifically, the beta-receptor blocker propranolol, at high doses, binds to the cardiac sodium channels and inhibits sodium uptake. In this report, we describe a case of severe propranolol toxicity, which resulted in the Brugada ECG pattern in an otherwise healthy individual who had no clinical or ECG suggestion of the genetically determined Brugada syndrome.

Levosimendan as a rescue drug in experimental propranolol-induced myocardial depression: a randomized study.

STUDY OBJECTIVE: Severe beta-blocker intoxication remains a clinical challenge despite a variety of treatment options. Because of its unique mechanism of action, the new calcium sensitizer levosimendan may provide more prominent cardiac support compared with current medications used to reverse negative inotropy. We hypothesize that levosimendan could reverse propranolol-induced severe negative inotropy in a porcine model of beta-blocker intoxication. METHODS: Twenty-four pigs were anesthetized and monitored. After severe propranolol intoxication was completed, animals were randomized into 3 groups. With a double-blind procedure, 9 animals received a 1.25-mg levosimendan bolus, followed by saline solution infusion, 9 animals received mean arterial pressure-targeted dobutamine infusion after saline solution bolus, and 6 animals received a saline solution bolus followed by saline solution infusion. Hemodynamic and laboratory data were collected during a follow-up period of 120 minutes. RESULTS: All 9 pigs in the levosimendan group survived. In contrast, 4 of 6 (67%) and 7 of 9 (78%) pigs died during the experiment in the placebo and the dobutamine groups, respectively. The levosimendan group showed improved change in the maximum positive slope of the left ventricular pressure, cardiac output, stroke volume, and mean arterial pressure compared with the dobutamine and the placebo groups. CONCLUSION: Levosimendan improved hemodynamic function and survival in this animal model of severe propranolol intoxication. The potential clinical application of levosimendan in propranolol intoxication warrants further investigation.

Extracorporeal life support in severe propranolol and verapamil intoxication.

Combined poisoning with calcium-channel blockers and beta-blockers is usually associated with severe heart failure. This report shows the effectiveness of emergency extracorporeal life support in treating life-threatening simultaneous propranolol and verapamil intoxication. A 15-year-old girl presented in cardiogenic shock after alcohol consumption and a propranolol and verapamil overdose; plasma concentrations: propranolol, 0.53 m/mL; verapamil, 1.06 mg/mL. She was successfully resuscitated with extracorporeal life support. Therapeutic plasma exchange was initiated. Extracorporeal support was discontinued 70 hours later. The patient made a full recovery. Simultaneous verapamil and propranolol overdoses can cause severe hemodynamic compromise and arrest of electrical and mechanical function of the heart. Emergency extracorporeal life support can successfully maintain vital organ blood flow and allows time for drug metabolism, redistribution, and removal. Therapeutic plasma exchange may reduce the time of emergency extracorporeal life support. Emergency extracorporeal life support should be considered early in cases of near-fatal intoxications with cardiodepressive drugs.

Insulin versus vasopressin and epinephrine to treat beta-blocker toxicity.

OBJECTIVE: We compared insulin and glucose (IN/G) to vasopressin plus epinephrine (V/E) in a pig model of beta-blocker toxicity. Primary outcome was survival over four hours. METHODS: Ten pigs received a 0.5 mg/kg bolus of propranolol IV followed by a continuous infusion. At the point of toxicity 20 ml/kg normal saline was rapidly infused and the propranolol drip continued at 0.125 mg/kg/min over four hours of resuscitation. Each pig was randomized to either IN/G or V/E. The V/E group began with epinephrine at 10 mcg/kg/min titrated up by 10 mcg/kg/min every 10 min to 50 mcg/kg/min or until baseline was obtained. Simultaneously, these pigs received vasopressin at 0.0028 units/kg/min, titrated upwards every 10 min to 0.014 units/kg/min or until baseline was obtained. The IN/G group began with a 2 units/kg/hr drip and increased by 2 units every 10 minutes to 10 units/kg/hr, or until baseline hemodynamics were obtained. CO, SVR, systolic blood pressure, HR, MAP, glucose, and potassium were monitored. Glucose was given for values <60 mg/dl. RESULTS: The study was terminated early due to marked survival differences after five pigs were entered in each group. All IN/G group pigs survived four hours. All V/E group pigs died within 90 min. CO in the IN/G group increased throughout the four hours, rising above pre-propranolol levels, while MAP, SBP, and SVR all trended slightly downward. CO in the V/E group dropped until death, while MAP, SBP, and SVR rose precipitously until 30-60 minutes when these dropped abruptly until death. Glucose was required in the IN/G group. CONCLUSION: In this swine model, IN/G is superior to V/E to treat beta-blocker toxicity. IN/G has marked inotropic properties while the vasopressor effects of V/E depress CO and contribute to death. Increasing SVR in this condition is detrimental to survival.

Enoximone in cardiac arrest caused by propranolol: two case reports.

We report two clinical cases of cardiac arrest, the former due to an adverse effect of intravenous (i.v.) propranolol in a patient with systemic sclerosis, the latter from a propranolol suicidal overdose. In both cases, conventional advanced life support (ALS) was ineffective but both patients eventually responded to the administration of enoximone, a phosphodiesterase III (PDE III) inhibitor. After the arrest, both patients regained consciousness and were discharged home. The chronotropic and inotropic effects of PDE III inhibitors are due to inhibition of intracellular PDEIII and are therefore unaffected by beta-blockers. These cases suggest that PDEIII inhibitors may be useful in restoring spontaneous circulation in cardiac arrest associated with beta-blocker administration when standard ALS is ineffective.

A comparison of vasopressin and glucagon in beta-blocker induced toxicity.

OBJECTIVE: We compared the efficacy of vasopressin and glucagon in a porcine model of beta-blocker toxicity. Our primary outcome was survival over 4 hours. METHODS: Sixteen pigs received a 1-mg/ kg bolus of propranolol IV followed by continuous infusion at 0.25 mg/kg/minute. Toxicity was defined as a 25% decrease in the product of heart rate (HR) and mean arterial pressure (MAP), at which point 20 mL/kg normal saline was rapidly infused. Each pig was randomly assigned to receive either vasopressin or glucagon after the saline bolus. The vasopressin group received a continuous infusion at 0.0028 U/kg/minute, titrated up to a maximum of 0.014 U/ kg/minute. The glucagon group received a 0.05-mg/kg bolus followed by continuous infusion at 0.15 mg/kg/hour. The HR, MAP, systolic BP (SBP), cardiac output (CO), glucose, and pH were monitored for 4 hours from toxicity or until death. RESULTS: One pig survived at 4 hours (vasopressin group). Analysis of the 4-hour Kaplan-Meier survival curves found no differences between the groups (log-rank test 0.059, p = 0.81). No overall differences were identified in MAP, systolic BP, cardiac output, glucose, pH, or HR. However, over the first hour MAP and SBP were significantly higher in the vasopressin group (p = 0.004, p = 0.006, respectively). CONCLUSION: In this beta-blocker toxicity model, there were no differences in the survival curves between vasopressin- and glucagon-treated pigs during a 4-hour analysis period. No overall differences were noted in MAP, systolic BP, CO, HR, pH, or glucose levels, although vasopressin treatment yielded higher MAP and systolic BP early in resuscitation.

The role of fat emulsion therapy in a rodent model of propranolol toxicity: a preliminary study.

INTRODUCTION: In animal models, lipid emulsion therapy has been shown to ameliorate toxicity from a number of lipid soluble agents. This preliminary study addresses the hypothesis that pretreatment with lipid emulsion protects against propranolol toxicity in rodents. METHODS: Ten spontaneously ventilating Rattus norvegicus rats were pretreated with either lipid emulsion or 0.9% normal saline before undergoing a constant infusion of propranolol until death. An electrocardiogram (ECG) sampling of heart rate and a QRS duration was performed at two-minute intervals until demise. RESULTS: There was no significant difference in lethal doses of propranolol between groups. Comparison of percent change in QRS prolongation and heart rate reduction was performed at 60% of the mean lethal dose in control animals. The percent change in QRS duration was reduced (from -0.9 to 17.3, p=0.016) in the intralipid pretreatment group. Attenuation of propranolol-induced bradycardia observed in the lipid emulsion group approached statistical significance (0% vs. 10.3%, p=0.06). INTERPRETATION: The results suggest that lipid emulsion may be effective in ameliorating propranolol toxicity in rats. Previous work gives reason to postulate a pharmacokinetic mechanism for this effect. The results represent encouraging exploratory work, and further work is planned to evaluate the role of lipid emulsion therapy in propranolol toxicity.

Unusual electrocardiographic changes with propranolol and diltiazem overdosage: a case report.

The therapeutic efficacy and safety of beta-adrenoreceptor-blocking drugs has been well established in patients with angina pectoris, cardiac arrhythmias, and hypertension and reducing the risk of mortality and nonfatal reinfarction on survival of acute myocardial infarction. The calcium antagonists are used for the treatment of patients with angina pectoris, long-term systemic hypertension, and the management of hypertensive emergencies and also for a multitude of other cardiovascular and noncardiovascular conditions. Because adverse cardiovascular effects can occur, however, patients being considered for combination treatment with propranolol and diltiazem must be selected carefully and observed closely. In this article, we present a suicidal case of drug overdose with propranolol and diltiazem with unusual electrocardiographic changes.