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.

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.

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.

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.

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.

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.

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.

Evaluation of antidotes against the acute cardiovascular toxicity of propranolol.

Rats anesthetized with pentobarbital and ventilated artificially were intoxicated with 1 mg/kg X min propranolol i.v. After 30 min heart rate, mean arterial blood pressure and peripheral resistance had dropped by about 50% and cardiac output by about 25% and were stable for up to 120 min. Isoprenaline proved to be the best antidote for the treatment of propranolol intoxication antagonizing the bradycardia by 76% and the hypotension completely. The antagonistic activities of orciprenaline and prenalterol were lower than those of isoprenaline. Dopamine, adrenaline and noradrenaline antagonized propranolol-induced hypotension but did not considerably influence the bradycardia whereas dobutamine was nearly ineffective in both respects. Glucagon and aminophylline displayed some chronotropic activity without influencing propranolol-induced hypotension. Calcium chloride, on the other hand, produced a moderate elevation of blood pressure but only a small chronotropic activity, and atropine was inactive in both respects. Isoprenaline also restored the cardiac function of propranolol-poisoned rats if administered by infusion and, furthermore, increased the lethal dose of propranolol from 77 to 165 mg/kg. The strong antagonistic activity of isoprenaline against propranolol-induced cardiovascular depression was also confirmed by experiments in pigs. In conclusion, isoprenaline is the most active antidote for the treatment of propranolol intoxication in the rat though the administration of massive doses are required. The vasodilatory effect of isoprenaline can be overcome by the additional administration of a vasoconstricting agent like dopamine.

Lipid solubility of a series of drugs and its relevance to fatal poisoning.

For 11 commonly used drugs, the n-octanol/water partition coefficient (pH 7.4 temperature 37 degrees C) and solubility in n-octanol were determined. The drugs tested were chlorpromazine, amitriptyline, trazodone, dextropropoxyphene, diltiazem, dibucaine, amethocaine, procaine, quinidine, acetylsalicylic acid and paracetamol. For eight of the drugs, the relative lipid saturation corresponding to a fatal plasma concentration was estimated from the two parameters determined above and the median fatal blood concentrations reported in the literature. For five of those eight drugs, the estimated relative saturation in the lipid phase fell within the range 0.001-0.004 which is close to relative saturation figures in aqueous and vapour phases already published for chemicals possessing a non-specific or physical mechanism of toxicity. Since this is determined largely by their lipid solubility, it is probable that accumulation in the lipid phase is an important determinant of the lethal toxicity of drugs and chemicals with a non-specific mechanism of toxicity.

A death investigation involving quinidine and propranolol.

A death attributed to quinidine-propranolol intoxication is described. Toxicological analysis of the tissues utilized thin layer (TLC) and gas-liquid (GLC) chromatography, ultraviolet (UV) spectrophotometry and gas chromatography-mass spectrometry (GC-MS). Tissue levels for both drugs, along with their chemical ionization mass spectra, are presented.

Reduced survival after isoprenaline/dopamine in d,l-propranolol intoxicated rats.

1. Respiratory and cardiovascular failure are principle toxic effects of beta-blocker overdose. Respiratory arrest is the primary cause of death in beta-blocker intoxicated rats. 2. The effect of beta-adrenoceptor agonists on respiratory and cardiovascular failure in beta-blocker overdose was investigated in a model of acute d,l-propranolol (30 mg kg-1 h-1) intoxication in spontaneously breathing rats. 3. Neither the aselective, hydrophilic beta-agonist isoprenaline (10, 25, 50 micrograms kg-1 min-1), nor the beta 1-selective, lipophilic beta-agonist flerobuterol (1, 3, 10 microgram kg-1 min-1) and the beta 2-selective, lipophilic beta-agonist clenbuterol (10, 25, 50 micrograms kg-1 min-1) had any beneficial effect on cardiovascular and respiratory variables or survival time in d,l-propranolol intoxicated spontaneously breathing rats. 4. Isoprenaline (10 micrograms kg-1 min-1) had no favourable effect on haemodynamic and respiratory variables in artificially ventilated d,l-propranolol intoxicated rats either. 5. Addition of dopamine to isoprenaline resulted in a significant reduction of survival time, primarily caused by a decreased in mean arterial blood pressure, in artificially ventilated d,l-propranolol intoxicated rats. Addition of glucagon to isoprenaline did not affect survival time. 6. Artificial ventilation is the most important supportive measure in d,l-propranolol intoxication in the rat.

Towards evidence based emergency medicine: best BETs from the Manchester Royal Infirmary. Glucagon for the treatment of symptomatic beta blocker overdose.

A short cut review was carried out to establish whether the intravenous glucagon can support blood pressure in beta blocker overdose. A total of 51 papers were found using the reported search, of which six presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results, and study weaknesses of these best papers are tabulated. A clinical bottom line is stated.

[Acute poisoning caused by beta blockers in the adult. Apropos of 7 cases]. / Intoxications aiguës par les bêtabloquants chez l'adulte. A propos de sept cas.

Although rare, acute poisoning with beta-blockers can be serious. Including the four personal cases of the authors, 40 cases of propranolol overdose have been published, with 8 deaths. Hypoglycaemia was not reported, but the association with alcohol can be very serious. One case of bronchospasm and one case of acute pulmonary oedema have been reported. Bradycardia is not the rule and widening of the QRS complex was reported in 4 cases. The other cases published are: 1) 10 cases with oxprenolol (including 5 cases of coma and 4 deaths), 2) 9 cases with acebutolol (2 deaths) including 5 with studies of the kinetics of the product (1 personal case), 3) 7 cases with pindolol (no bradycardia, good prognosis), 4) 6 cases (1 personal) with metoprolol (4 cases of massive ingestion with 1 death), 5) 3 cases with alprenolol (1 death), 6) 4 cases with sotalol (2 cases of turned apex, 1 death), 7) 1 case with atenolol. The authors discuss the practical management. They stress that glucagon is a much better form of treatment in severe cases than isopropylnoradrenaline, and that the crucial period is in the first few hours after the ingestion of the beta-blockers, i.e. usually before the patient's arrival at the hospital. The effectiveness of endocavity stimulation has not been demonstrated.

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.