High-Dose Insulin Euglycemic Therapy in Concomitant Beta-Blocker and Calcium Channel Blocker Overdose

Abstract

Beta-blockers and calcium channel blockers are among the most commonly used drugs in the adult population, and the National Poison Data System annual reports note 11 075 beta-blocker overdoses and 6256 calcium-channel blocker overdoses in 2022. Poisoning with these medications presents clinically with profound bradycardia, depression of myocyte contractility, and vasodilation resulting in hemodynamic instability often refractory to initial vasopressor treatment. Herein we present a case of concomitant beta-blocker and calcium-channel blocker overdose with hypotension refractory to vasopressors successfully managed with high-dose insulin euglycemic therapy. Close monitoring is required to prevent adverse effects from therapy, which are predictable: hypokalemia and hypoglycemia often result from the use of up to hundreds of units of insulin per hour, as was done in this case. Frequent monitoring is required to safely utilize high-dose insulin euglycemic therapy, which has a good safety profile when appropriate monitoring is utilized.

Introduction

Beta-blockers and calcium-channel blockers are among the most commonly used drugs in the adult population, and the National Poison Data System annual reports note 11 075 beta-blocker overdoses and 6256 calcium-channel blocker overdoses in 2022. ¹ Beta-blockers competitively block beta-adrenergic receptors, with resultant blunting of multiple metabolic and cardiovascular effects of circulating catecholamines. Calcium-channel blockers produce blockades at the trans-membrane receptor that open the L-type calcium channel, inhibiting downstream calcium release and thus slowing the depolarization of the sinoatrial node and inhibiting myocyte and vascular smooth muscle contraction. ² Poisoning with these medications can thus present clinically with profound bradycardia, depression of myocyte contractility, and vasodilation resulting in hemodynamic instability often refractory to initial vasopressor treatment. Herein, we present a case of concomitant beta-blocker and calcium-channel blocker overdose with hypotension refractory to vasopressors successfully managed with high-dose insulin euglycemic therapy.

Case Presentation

A 55-year-old male with a past medical history of HIV, bipolar 2 disorder, insomnia, substance use disorder, and a prior suicide attempt presented to the Emergency Department with auditory hallucinations of voices threatening to kill him. Subsequent collateral history from a friend indicated that the patient had called the friend to report that he would be committing suicide by overdose just prior to presenting to the ED. A review of his personal belongings revealed multiple empty medication bottles including dapsone, amlodipine, carvedilol, diazepam, methocarbamol, zolpidem, ezetimibe, and Triumeq: in total the patient had access to 60 days of a 90 day supply of dapsone 100 mg, 60 days of a 90 day supply of carvedilol 6.125 mg, an unknown quantity of amlodipine 5 mg, approximately 10 pills of diazepam 5 mg, and unknown quantities of methocarbamol, zolpidem, Triumeq, and ezetimibe. The patient progressively became somnolent refractory to multiple empiric doses of naloxone, ultimately rapidly becoming unresponsive and hypotensive, requiring vasopressors and intubation for airway protection.

The patient was afebrile, with heart rate 64 beats/min, blood pressure 70/50 mmHg, respiratory rate 12 breaths/min, and SpO₂ 95% on RA. He was obtunded, with pupils minimally reactive to light, and otherwise normal physical exam. Complete blood count was unremarkable, comprehensive metabolic panel notable for mild acute kidney injury. Urine drug screen was positive for cannabinoids and benzodiazepines. Ethanol, acetaminophen, and salicylate serum levels were negative. Arterial blood gas yielded pH 7.34, PaCO₂ 45 mm Hg, PaO₂ 211 mm Hg, and bicarbonate concentration of 23.9 mM with methemoglobin of 24.2%. ECG demonstrated normal sinus rhythm with corrected QT interval of 453. Chest x-ray was without consolidation or pleural effusion, with no acute abnormality.

The patient was transferred to ICU with rapidly increasing vasopressor requirements refractory to IV glucagon, IV calcium, and gastrointestinal decontamination with 50 g activated charcoal and whole bowel irrigation with polyethylene glycol electrolyte lavage solution, eventually requiring norepinephrine, epinephrine, phenylephrine, and vasopressin. High-dose euglycemic insulin therapy was initiated along with methylene blue infusion to address methemoglobinemia secondary to dapsone toxicity and provide further hemodynamic support. The patient improved on high-dose insulin euglycemic therapy (HIET) and methylene blue infusion from a hemodynamic perspective, with discontinuation of both in the 48- to 72-hour period as his acute intoxication resolved, without adverse events as a result of therapy despite infusion of hundreds of units of insulin per hour. The patient remained intubated after admission given ongoing central nervous system (CNS) depression in the setting of polysubstance overdose with several agents capable of crossing the blood brain barrier with toxidromes consistent with said CNS depression. He was initially without hypoxia despite being COVID-positive on admission; however, he developed Acute Respiratory Distress Syndrome (ARDS). Focus shifted as the patient was successfully treated for his polyoverdose to respiratory support for ARDS and COVID pneumonia. Ongoing goals of care discussion noted that remaining intubated was not aligned with the patient’s wishes. The patient’s family then proceeded with comfort care measures, and the patient expired.

Discussion

Beta-blockers and calcium-channel blockers are among the most commonly used drugs in the adult population, and the National Poison Data System annual reports note 11 075 beta-blocker overdoses and 6256 calcium-channel blocker overdoses in 2022. ¹ Beta-blockers competitively block beta-adrenergic receptors, decreasing cyclic adenosine monophosphate production with resultant blunting of multiple metabolic and cardiovascular effects of circulating catecholamines. Calcium-channel blockers produce blockades at the trans-membrane receptor that open the L-type calcium channel, inhibiting downstream calcium release and thus slowing the depolarization of the sinoatrial node and inhibiting myocyte and vascular smooth muscle contraction. ² Poisoning with these medications can thus present clinically with profound bradycardia, depression of myocyte contractility, and vasodilation resulting in hemodynamic instability. This case highlights an example of concomitant overdose with both calcium-channel blocker (amlodipine) and beta-blocker (carvedilol), wherein these mechanisms acted synergistically to create a profound hemodynamic instability refractory to vasopressors.

Depending on the particular agents involved, additional effects such as corrected QT interval prolongation in the case of sotalol or CNS depression with propranolol may be observed. Because of these possible additional effects, an effort should be made to identify which agents were involved in an overdose. Additionally, it should be identified whether any of them were extended-release formulations in order to determine the role for gastrointestinal detoxification.

Treatment begins with a trial of IV glucagon to directly increase adenylyl cyclase activity independent of beta-receptor stimulation and IV calcium to increase extracellular concentration to promote influx and improve conduction disturbances. Gastrointestinal detoxification is indicated with activated charcoal within 1 to 2 hours of ingestion and with whole bowel irrigation in the event of a large ingestion of extended-release formulations. ³ If hypotension proves refractory to these first-line treatments, HIET is initiated, using insulin to stimulate phosphatidylinositol-3-kinase which increases myocardial contractility via both calcium-dependent and calcium-independent mechanisms. ⁴ Insulin also addresses the calcium channel blocker interference with insulin secretion and glucose catabolism, helping to reduce lactic acidemia and metabolic acidosis. HIET begins with a 1 unit/kg bolus of insulin, followed by 1 unit/kg/h drip titrated every 30 to 60 minutes to end organ perfusion with a relative maximum of 10 units/kg/h. This is accompanied by a dextrose infusion with frequent glucose checks and prn dextrose as needed to prevent hypoglycemia, as well as potassium repletion to counter intracellular shift.^5,6 This monitoring is crucial to prevent adverse effects from therapy, which is predictable based on the pathophysiology behind the intervention. ⁷ Methylene blue, classically known for its role in treating methemoglobinemia, can also play a role in calcium-channel blocker overdose as adjunct therapy, as it inhibits guanylate cyclase thus inhibiting nitric oxide synthesis and decreasing vasodilation.

Clinical Pearls

1. Hypotension in the setting of multidrug overdose should raise suspicion for beta-blocker and calcium-channel blocker toxicity.

2. HIET should be initiated promptly in the event of refractory hypotension in this patient population.

3. Frequent monitoring is required to safely utilize HIET, which has a good safety profile when appropriate monitoring is utilized.