Successful Pharmacologic Treatment of Massive Atenolol Overdose: Sequential Hemodynamics and Plasma Atenolol Concentrations

A 50-yr-old, 98-kg man with a history of depression, coronary artery disease, hypertension, and asthma was brought to the our institution's emergency department after having allegedly ingested 20 atenolol tablets (50 mg/tablet) 30 min earlier. On arrival, he was alert and cooperative. Blood pressure was 130/80 mmHg, heart rate was 72 beats/min, respiratory rate was 24 breaths/min, and tympanic temperature was 36.6 degrees Celsius. Physical examination was otherwise unremarkable. An electrocardiogram showed sinus rhythm with a ventricular rate of 72 beats/min. A chest roentgenogram was normal. Laboratory data revealed sodium 141 mmol/L, potassium 4.9 mmol/L, chloride 104 mmol/L, HCO³18 mmol/L, blood urea nitrogen 12 mg/dL (4.28 mmol/l), creatinine 1.2 mg/dL (106 micro mol/L), glucose 116 mg/dL (6.44 mmol/l), and hemoglobin 160 g/l. Routine toxicologic screening was negative. Gastric lavage was instituted without recovery of tablet fragments. An external pacemaker was applied. Electrocardiogram and oscillometric blood pressure monitoring were instituted, and for the next 90 min, a sinus rhythm at a rate of 60 beats/min and blood pressure between 110/70 mmHg and 120/80 mmHg were observed. Two hours after admission, the patient collapsed while having a bowel movement. Despite a total of 2 mg atropine, 1 mg glucagon, and 1,900 ml crystalloid, systolic blood pressure remained less than 80 mmHg. The electrocardiogram showed sinus rhythm at a rate between 40 and 50 beats/min. The level of consciousness varied from unresponsiveness to combativeness. Expiratory wheezes were heard, and the skin was cold and mottled. Three hours after admission, his trachea was intubated and he was transferred to the intensive care unit after receiving an additional dose of 2 mg atropine, 1 mg glucagon, 60 micro gram/min isoproterenol, and 13 micro gram/min norepinephrine. Arterial blood gas analysis from a sample taken immediately after intubation (manual ventilation with Ambu self insufflating bag, 6 l/min Oxygen²enrichment) revealed pH 6.85, Pa sub CO²74 mmHg, Pa^O2206 mmHg, and HCO³13 mmol/l). A catheter was inserted into the radial artery, and mechanical ventilation was started. Arterial blood gas analysis with the lungs ventilated at a respiratory rate of 16 breaths/min, tidal volume 900 ml, and FI^O21.0, revealed pH 7.23, P^CO233 mmHg, Pa^CO2136 mmHg, and HCO³14 mmol/l. A balloon-tipped pulmonary artery catheter was inserted. Pharmacologic management consisted of glucagon bolus doses, glucagon infusion, and isoproterenol infusion (Figure 1). Albuterol was given via a metered dosed inhaler and spacer. Three hours after intensive care unit transfer (6 h after hospital admission), the patient regained consciousness and expiratory wheezes were no longer present. The trachea was extubated the following morning. Recovery proceeded uneventfully, all drugs were discontinued over the next 12 h, and he was discharged to a psychiatric ward. Blood creatinine concentration remained between 0.9 and 1.7 mg/dl (79.5 and 150.2 micro mol/l, respectively) throughout the hospitalization. Creatinine clearance during the first 24 h was 68 ml/min. Atenolol plasma concentrations and hemodynamic profiles are summarized in Figure 1.

Plasma atenolol concentrations were determined by gas chromatography-mass spectrometry with selected-ion monitoring, by modification of a previously described assay [10]and using metoprolol as an internal standard. Briefly, plasma (100 micro liter) was added to a PTFE-lined screw-cap tube containing 900 of micro liter water, 25 ng metoprolol, and 0.36 g sodium chloride, followed by 100 micro liter 1 M NaOH, 50 micro Liter 2 M phosphate buffer (pH 11.5), and 10 ml methylene chloride. The mixture was vortexed for 30 s, shaken for 10 min, and centrifuged. The organic layer was evaporated to dryness under nitrogen, the residue dissolved in 100 micro liter ethyl acetate, and 25 micro liter pentafluoropropionic anhydride added. The reaction mixture was kept at 60 degrees Celsius for 30 min, evaporated to dryness under nitrogen, and reconstituted in 100 micro liter ethyl acetate, and 1-2 micro liter was injected into the gas chromatograph.

A Hewlett-Packard 5971A gas chromatograph-MSD equipped with a split-splitless injector was used with a 15 m x 0.32 mm x 0.25-micro DB-5 capillary column (J & W Scientific, Folsom, CA). The carrier gas was helium at 60 ml/min flow rate. Injector (splitless) and transfer line temperatures were 250 degrees Celsius and 260 degrees Celsius, respectively. The oven temperature was held at 50 degrees Celsius for 0.5 min, then increased to 250 degrees Celsius at 20 degrees Celsius per min. The dipentafluoropropionyl derivatives of metoprolol and atenolol were monitored at the base peak for each compound (ion at mass-to-charge ratio of 366). Atenolol was quantitated using a standard curve of the atenolol/metoprolol peak area ratio versus atenolol added (200-5,000 ng/ml), constructed with blank plasma spiked with known concentrations of atenolol. The standard curve was linear over this concentration range (r sup 2 = 0.996).

Considering that the oral bioavailability of atenolol is approximately 40% of the ingested dose, peak plasma concentrations occur 1-2 h after oral administration, and the elimination half-life is 6-9 h [1]and extrapolating the measured plasma concentrations to the time of peak effect one would predict this patient had a peak atenolol plasma concentration of 10,000 ng/ml which also coincides with the predicted peak concentration after ingesting 1,000 mg of the drug. Therapeutic plasma concentrations of atenolol are 200-500 ng/ml. [1].

The usual clinical manifestations of beta-adrenergic blocker overdose include bradycardia, hypotension, low cardiac output, cardiac failure, and cardiogenic shock. [11]Bronchospasm [11]and respiratory depression [3,11]also may occur. Seizures and prolonged intraventricular conduction are thought to be the result of the local anesthetic properties of intoxication with certain beta-adrenergic blockers (propranolol, acebutolol, alprenolol, oxprenolol) but not atenolol. [1,11]Hypoglycemia is reported to be rare. [11].

Patients vary in their responses to beta-adrenergic blockers. As much as 4,000 mg/day of propranolol have been well tolerated, [4]whereas 40 mg of the same drug precipitated pulmonary edema in patients with occult cardiomyopathy. [11]In a previous report, an atenolol overdose of 5,000 mg resulting in a plasma concentration of 9,400 ng/ml, produced marked ventilatory depression requiring mechanical ventilation but only a sinus bradycardia to 59 beats/min, and hemodynamic stability was maintained without medication. [3]Hemodynamic instability, responsive to intravenous sympathomimetic or parasympatholytic support, was present in three cases of atenolol overdose, and another patient was treated with hemodialysis and pharmacologic support. [2]That case, complicated by hemodynamic instability and oliguria/anuria, apparently was unresponsive to pharmacologic support and cardiac pacing. [2]However, the hemodynamic data included only heart rate and blood pressure, the regime of isoproterenol and glucagon administration was unclear, and a single atenolol plasma concentration was reported (2,500 ng/ml), making it difficult to establish true unresponsiveness to conventional pharmacologic treatment. Additionally, hemodialysis requires large-bore vascular access and specialized personnel and may be complicated by hypotension, which is common in critically ill patients. [12,13].

Hemodynamic depression induced by beta-adrenergic blocker overdose usually is responsive to sympathomimetics, parasympatholytics, glucagon, phosphodiesterase inhibitors, and cardiac pacing. [11]However, our patient did not show hemodynamic improvement with 60 micro gram/min isoproterenol and 13 micro gram/min norepinephrine. Norepinephrine was chosen for its alpha-adrenergic effect to increase blood pressure and possibly improve myocardial perfusion. [11].

In addition to myocardial depression, the hypotension observed with beta-adrenergic blocker overdose is due in part to blockade of presynaptic beta²-adrenergic receptors that, when activated, increase neurotransmitter release in sympathetic nerve endings. [14]During massive atenolol overdose beta²-adrenergic blockade is likely to occur because the ratio of beta¹to beta²selectivity of atenolol is 5.5. [15]It is also reasonable to speculate that, in the presence of decreased myocardial contractility caused by beta-adrenergic blockade, the vagal stimulation or decreased venous return as a result of increased intra-abdominal pressure associated with defecation precipitated cardiovascular collapse, which, in the setting of coronary artery disease and possibly ventricular hypertrophy, resulted in myocardial ischemia and "stunning." [16]"Stunned" myocardium shows good responsiveness to adrenergic stimulation, [16]but the complete beta-adrenergic blockade present in this patient markedly shifted to the right the apparent dose-response relationship for beta-adrenergic agonists. [11]In a previous report, 115 mg isoproterenol were infused over 65 h to maintain hemodynamic stability. [17]In contrast, our patient showed marked hemodynamic improvement after the administration of glucagon.

Glucagon is probably the drug of choice to treat massive beta-blocker overdose. [11]A loading dose of up to 10 mg followed by up to 5 mg/h infusion may be required. [11]In the case we report, glucagon was titrated to effect, guided by sequential hemodynamic data. The activation of glucagon receptors, via G protein-mediated mechanisms, stimulates adenylyl cyclase, and increases intracellular cyclic adenosine monophosphate (cAMP) concentration independently of beta-adrenergic receptors. Phosphodiesterase inhibitors (amrinone, milrinone) also increase intracellular cAMP by blocking its degradation, but because cAMP production is not activated, it relies on modest basal activity of adenylyl cyclase, which results in modest cAMP production. [18]In dogs, both glucagon and amrinone improved the depressed ventricular performance induced by 10 mg/kg intravenous propranolol, but only glucagon reversed the bradycardia. [19].

In conclusion, aggressive pharmacologic management and cardiac pacing, in our opinion, should be the first choice to treat beta-blocker overdose. Glucagon appears to be particularly effective for this purpose. Hemodialysis should be reserved to remove minimally protein-bound, renally excreted beta-blockers in cases refractory to pharmacologic therapy. It remains to be seen if earlier detection and treatment of cardiorespiratory depression can prevent cardiovascular collapse in these patients.