A case of fatal acebutolol poisoning: an illustration of the potential of molecular networking.

Acebutolol is a ß1-selective adrenergic receptor antagonist with moderate membrane-stabilizing activity and intrinsic sympathomimetic activity; accordingly, the drug is indicated in hypertension, angina pectoris, and arrhythmia. However, acebutolol's beta-blocking properties also extend the QRS and QTc intervals, and may predispose the patient to ventricular tachydysrhythmia. Here, we report autopsy and toxicological findings on a fatal case of acebutolol self-poisoning in a 70-year-old woman. Toxicological analyses of post-mortem samples (using a liquid chromatography high-resolution mass spectrometry (LC-HR-MS) method) highlighted high concentrations of acebutolol and its metabolite diacetolol in femoral blood (92.8 mg/L and 21.2 mg/L, respectively) and other matrices (cardiac blood, urine, bile, and gastric contents). A molecular networking approach provided useful information on acebutolol's metabolism and revealed the existence of an unknown phase II metabolite of acebutolol. Molecular networking also facilitated visualization of the complex LC-HR-MS/MS datasets and the sample-to-sample comparisons that confirmed massive acebutolol intoxication by ingestion.

Acebutolol overdose treated with hemodialysis and extracorporeal membrane oxygenation.

A case involving a 27-year-old woman who ingested an overdose of acebutolol is presented. Extracorporeal membrane oxygenation was initiated to stabilize the patient's condition before commencing hemodialysis. S-diacetolol (the N-acetelation product of acebutolol) was cleared with hemodialysis. It is suggested that extracorporeal membrane oxygenation may be of short-term benefit in the treatment of overdoses with beta-adrenergic agents such as acebutolol when accelerated clearance with hemodialysis is anticipated.

Toxicological findings in a fatal case of acebutolol self-poisoning.

A fatal case of acebutolol self-poisoning is presented. After single-step liquid-liquid alkaline extraction, acebutolol was identified by using an HPLC/DAD screening procedure. By means of a specific HPLC method, acebutolol was then quantified in a large range of postmortem samples. The blood acebutolol concentration was 34.7 micrograms/mL. The tissue distribution of the drug is discussed in the light of the existing literature.

Acebutolol overdose resulting in fatalities.

Two fatal cases of Acebutolol intoxication are presented that demonstrate its clinical characteristics and potential lethality. A review of the literature suggests that acebutolol is one of the most toxic beta blockers when taken as an overdose. In addition to demonstrating characteristics of membrane-stabilizing activity, both fatal cases demonstrate significant QTc prolongation and ventricular tachycardia. The latter findings suggest an impact on ventricular repolarization not seen with Propranolol intoxication. Clarification of these findings has important implications regarding identification and treatment of this potentially fatal intoxication.

[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.

[Nosocomial Aeromonas hydrophila pneumonia complicating toxic coma]. / Pneumopathie nosocomiale à Aeromonas hydrophila compliquant un coma toxique.

A 24-year-old male homosexual drug addict was admitted in coma and circulatory failure after a 10 g overdose of acebutolol. The usual resuscitative measures were undertaken, together with administration of adrenaline and gastric lavage. Six hours of external cardiac massage and pacing, and high catecholamine doses (36 mg.h-1 of adrenaline and 60 micrograms.kg-1 x min-1 of dobutamine) were required before the circulatory system became again spontaneously efficient. After this acute episode, the patient improved despite acute tubular necrosis. On the third day, bilateral alveolar and interstitial lesions were found on the chest film. Bronchoalveolar lavage and protected distal brushings were carried out. Both Aeromonas hydrophila and Staphylococcus aureus were found in the cultured brushings. Treatment with ceftriaxone, vancomycin and amikacin was introduced. This nosocomial pneumonia was very haemorrhagic, resulting in several bloody casts responsible for several episodes of atelectasis. The patient was definitely extubated on the 18th day, and left the ICU 23 days later without any sequela. His HIV status was negative. Four other infections with the same strain of Aeromonas hydrophila occurred at the same time as this patient's. The common source for this germ was found to be soft water. Several measures have since been undertaken: removal of a centralized water softener, filtration and higher chlorine content in the water circuit, and updating of intensive care protocols for disinfection of equipment.

[Acute poisoning with nifedipine and acebutol: two cases]. / Ostre zatrucie nifedypina i acebutolem--dwa przypadki.

In this paper the case of intoxication in two women (19-year-old and 23-year-old), who in suicide attempts ingested at the same time different doses of nifedipine and acebutol. In 23-year-old woman 4 hours post ingestion cardiorespiratory arrest was stated. Resuscitation procedures were ineffective, she died. Acebutol concentration in postmortem blood was 24.1 mg/l and nifedipine-1.8 mg/l. The second one (19-year-old) was treated successfully, only mild cardiac disturbances were observed. Acebutol concentration in blood was 1.8 mg/l, nifedipine was not stated.

A case of acebutolol intoxication.

A case of a nonfatal acebutolol intoxication in a 15 year old female is described. Ingestion of 7600 mg acebutolol resulted in a plasma acebutolol concentration of 15 mg/1 one hour after ingestion. The patient remained conscious, had a severe hypotension and the electrocardiogram showed a 1st degree AV-block and severe intraventricular conduction disturbances at a rate of 70 bpm. After the administration of calcium gluconate and plasma the blood pressure gradually increased to normal values in 2 hours time. Plasma halflife of acebutolol was 8 hours. Pathophysiology of acebutolol intoxication is discussed.

[Lethal intoxication by acebutolol (author's transl)]. / Tödliche Vergiftung mit Acebutolol (Prent).

Report on suicidal intoxication by acebutolol (prent). Thin-layer and gas chromatography as well as spectrophotometry were used to show the presence of and to determine acebutolol and its aniline derivative arising from hydrolysis in all tissues. The highest concentrations were found in urine and liver.

Acebutolol-induced ventricular tachycardia reversed with sodium bicarbonate.

BACKGROUND: Acebutolol is a unique beta blocker that possesses cardioselectivity, partial agonist activity, and membrane stabilizing activity. Sodium bicarbonate is used to reverse the cardiotoxic effects of other drugs with membrane stabilizing activity. There have been no reported cases of acebutolol-induced ventricular dysrhythmias treated successfully with bolus sodium bicarbonate. CASE PRESENTATION: A 48-year-old man ingested approximately 6.4 g of acebutolol with ethanol (blood ethanol 61 mmol/L). There were no other coingestants identified. One hour after presentation, the patient had a cardiac arrest with the monitor showing ventricular tachycardia. Sodium bicarbonate 50 mEq intravenous push converted the patient to sinus rhythm and the blood pressure improved to 129/90 mm Hg. CONCLUSION: This case demonstrates a temporal relationship between bolus sodium bicarbonate administration and the termination of acebutolol-induced ventricular tachycardia.

[Intoxication by beta-blockers in children and adolescents (author's transl)]. / Vergiftungen mit beta-rezeptorenblockern bei Kindern und Jugendlichen.

After ingestion of beta-blocking agents 20 out of 77 children and adolescents developed clinical symptoms. 11 cases resulted from suicidal attempts. A 15 year old girl died. Neurological signs (12) predominated. Cardiovascular signs (10) were especially seen after suicidal ingestion of beta-blocking agents. Infants frequently showed hypoglycemia or symptoms based on hypoglycemia (6). After elimination from the gastrointestinal tract patients require intensive monitoring as well as symptomatic treatment. Treatment with atropin often gave insufficient results. However, treatment with glucagon was successful. Secondary detoxication generally is not required and must be evaluated after pharmacokinetic data. Forced diuresis is not indicated.

[Intoxication with beta-receptor blockers (author's transl)]. / Intoxikation mit Beta-Rezeptorenblockern.

Beta-blockers are increasingly often used with suicidal intent, but are also sometimes swallowed accidentally by small children. Beta-blockers available in the Federal Republic of Germany differ in their pharmacodynamics and pharmacokinetics. After analysing 49 cases of intoxication, no certain relationship was found between the different substances and specific symptoms. Cardiovascular signs such as sinus bradycardia, arrhythmia, hypotension (30 cases), as well as dizziness and drowziness (17) were the most frequent ones. Loss of consciousness and hallucination (13), as well as seizures (3), also occurred frequently. Hypoglycaemia or symptoms due to it (12) were noted especially in young children. In addition to primary removal of the drug, repeated administration of charcoal and sodium sulphate are recommended with most of the drugs for interrupting the enterohepatic circulation. Administration of atropine for bradycardia and hypotension was usually not effective. Dopamine is recommended; glucagon for definite signs of shock. Haemodialysis is indicated only in exceptional instances and is effective for only a few of the drugs. Forced diuresis should not be practised.

Electrocardiographic changes associated with beta-blocker toxicity.

STUDY OBJECTIVE: We sought to characterize the ECG changes associated with symptomatic beta-blocker overdose. METHODS: The study population consisted of a prospective cohort of patients reporting to 2 regional poison centers with beta-blocker overdose. Each patient received an ECG on presentation and a structured follow-up. The inclusion criteria for symptomatic overdose included heart rate of less than 60 beats/min or systolic blood pressure of less than 90 mm Hg; symptoms consistent with decreased end-organ perfusion; therapeutic intervention with cardioactive medication; and corroboration by 2 of the authors that this was a clear-cut case of symptomatic beta-blocker overdose with cardiovascular toxicity. Exclusion criteria included cardioactive coingestants, age younger than 6 years, and no available ECG. RESULTS: Of 167 patients, 13 were determined to have symptomatic exposures. First-degree heart block (>200 ms) was the most common ECG finding (10/12) and also had the greatest likelihood ratio (5.31) when comparing those with symptomatic exposures with those with asymptomatic exposures. Comparing the asymptomatic with the symptomatic groups, the mean PR interval was 167 ms (95% confidence interval [CI] 162 to 171 ms) versus 216 ms (95% CI 193 to 238 ms), the mean QRS interval was 89 ms (95% CI 87 to 91 ms) versus 112 ms (95% CI 92 to 132 ms), the mean QTc interval was 422 ms (95% CI 417 to 428) versus 462 ms (95% CI 434 to 490 ms), and the mean heart rate was 72 beats/min (95% CI 69 to 74 beats/min) versus 66 beats/min (95% CI 59 to 73 beats/min). Two cases of symptomatic acebutolol exposure appeared unique by demonstrating disproportionate prolongation of the QTc interval, an RaVR height of 3 mm or greater, and associated ventricular tachydysrhythmia. CONCLUSION: The majority of clinically significant beta-blocker intoxications demonstrate negative dromotropic effects on ECG. Several ECG differences in acebutolol intoxication might reflect unique pathophysiologic processes relative to other beta-blockers.

Survival following massive overdose of adrenergic blocking agents (acebutolol and labetalol).

Massive overdosage of adrenergic blocking drugs is associated with severe morbidity and a high mortality rate. We report the case of a 24-year-old medical intern who ingested 9.6 g acebutolol, 7.2 g labetalol and 0.625 g trimipramine in an attempted suicide. Blood samples drawn on admission were shown to contain markedly elevated plasma levels of acebutolol and its major metabolite and of labetalol. The patient was deeply comatose on admission. The heart rate was 60 min-1 (sinus rhythm) and the blood pressure was clinically unrecordable. Atropine, isoproterenol and dopamine initially had no effect on either heart rate or blood pressure. Only following the administration of inordinately large doses of isoproterenol and dopamine, together with glucagon was a clinical response obtained. The patient remained haemodynamically dependent on dopamine for 12 h and isoproterenol for 65 h. The total dose of isoproterenol administered was 260 mg, two thirds of this during the first 12 h. The patient left hospital well after 7 days but was readmitted after 26 days because of intestinal obstruction due to ischemic bowel necrosis.

[Antidotal treatment of acebutolol poisoning]. / Zur Antidot-Behandlung der Acebutolol-Vergiftung.

In rats, the intravenous infusion with acebutolol lead to a dose dependent decrease of arterial blood pressure, heart rate, cardiac output and total peripheral resistance, to sinus bradycardia, widening of the QRS complex, 1st and 2nd degree AV-block and intraventricular conductance disturbances. Nine possible antidotes were administered i.v. to rats which had been infused with 2 mg/kg X min acebutolol for 60 min. Isoprenaline proved the best antidote against acebutolol antagonizing the bradycardia by 88% and the hypotension completely. The activities of orciprenaline and prenalterol were lower than those of isoprenaline. Dopamine, epinephrine and norepinephrine antagonized acebutolol-induced hypotension, but did not influence considerably the bradycardia. Glucagon, on the other hand, antagonized the acebutolol-induced bradycardia by 47% but exerted only a small activity on the hypotension. Aminophyllin and calcium were nearly ineffective as antidotes against acebutolol. Isoprenaline and dopamine infused simultaneously restored heart rate, arterial blood pressure and cardiac output of acebutol-poisoned rats. The survival time of rats infused with 4 mg/kg X min acebutolol was doubled by the additional infusion of 0.2 mg/kg X min isoprenaline. The antagonistic activity of a treatment with isoprenaline and dopamine against the cardiovascular toxicity of acebutolol was confirmed in rabbits.