EM@3AM – Calcium Channel Blocker Toxicity

Author: Erica Simon, DO, MHA (@E_M_Simon, EM Chief Resident, SAUSHEC, USAF) and Daniel Sessions, MD (EM Associate Program Director, SAUSHEC, USA / Medical Toxicologist, South Texas Poison Center) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital) and Brit Long, MD (@long_brit, EM Attending Physician, SAUSHEC, USAF)

Welcome to EM@3AM, an emdocs series designed to foster your working knowledge by providing an expedited review of clinical basics. We’ll keep it short, while you keep that EM brain sharp.


A 78-year-old female, with a previous medical history of hypertension (diltiazem) and dementia (donepezil), presents to the ED with the chief complaint of weakness. The woman’s husband, her sole caregiver, reports the patient as “increasingly fatigued” since her morning awakening. Per the husband, the patient was without complaints prior to the onset of symptoms. The caregiver denies the observance of facial droop, motor difficulties, and slurred speech. He reports his spouse as without recent febrile illness, sick contacts, and changes in pharmaceutical therapy.

Initial VS: BP 124/88, HR 63, T 99.7F Oral, RR 14, SpO2 97% on room air.

Physical examination:
General: Thin, frail female appearing as stated age.
Neuro: GCS 15, no focal deficits.
CV: Regular rate and rhythm, no murmurs, rubs or gallops.
Pulm: Lungs CTAB.
Abdomen: Soft, non-tender, non-distended; no guarding, or rebound.

Upon completion of the physical examination, the patient suddenly slumps backwards on the stretcher.

Repeat VS: 82/64, HR 38, T 99.7F Oral, RR 14, SpO2 97% on room air.
Accucheck: 327 mg/dL

EKG: Sinus bradycardia, rate 37 bpm, QRS 200 msec, no acute ST-T wave changes

Bedside electrolyte assessment: Sodium 137 mmol/L, potassium 3.3 mmol/L, ionized calcium 0.8 mmol/L

What do you suspect as a diagnosis? What’s the next step in your evaluation and treatment?


Answer: Calcium Channel Blocker (CCB) Toxicity1-7

  • Epidemology:1 In 2015, the American Association of Poison Control Centers identified 1,253 persons with confirmed exposures to calcium channel blockers. Of these individuals, 958 required treatment at a healthcare facility, and 18 perished.
  • Pathophysiology and Clinical Presentation: Calcium is vital to a number of physiologic processes – an understanding of which yields insight regarding patient presentation and subsequent treatment:2
    • Cardiac:
      • Sinoatrial nodal and atrioventricular nodal tissue: slow inward calcium channels (and to a lesser extent, sodium channels) responsible for action potential generation.
      • Cardiac myocyte: calcium entry by L-type or voltage-gated calcium channels => calcium induced calcium release from intracellular organelles => excitation-contraction coupling.
    • Vascular:
      • Calcium required for the maintenance of vascular smooth muscle tone.
    • Metabolic:
      • Shock state induced by cardiac calcium insufficiency => increased free fatty acid metabolism and liver glycogenolysis.
      • Pancreatic β-islet cells: require calcium for insulin release. Insulin required for glucose uptake (cell specific: skeletal muscle, etc.). Lack of insulin => Krebs cycle shift to anaerobic metabolism (pyruvate production).
    • Presentation: bradycardia, conduction abnormalities, hypotension, possible shock, hyperglycemia, acidosis. (Note: patients with dihydropyridine CCB toxicity frequently present with reflex tachycardia – see below.)
  • Calcium Channel Blocker Classification:
    • Phenylalkylamine CCBs (verapamil) and benzothiazepine CCBs (diltiazem): bind to receptor sites in the pores of calcium channels and block them.3
      • Verapamil and diltiazem are responsible for the majority of cases of severe cardiovascular compromise.  These medications are commonly ingested in sustained release (SR) formulations => peak toxicity may be delayed for several hours, and the duration of toxicity prolonged secondary to continued GI absorption. Patients can appear clinically well for an extended period of time prior to sudden deterioration.
    • Dihydropyridine CCBs (amlodipine, nifedipine, etc.): enhance or inhibit the activation of voltage-gated calcium channels in heart and vascular smooth muscle by acting at allosteric modulatory sites outside of calcium channel pores.
      • As compared to verapamil and diltiazem, dihydropyridines display a lesser effect on cardiac myocytes: negative resting potential of cardiac myocytes => dihydropyridine dissociation.
      • Affect on vascular smooth muscle => vasodilatory shock and reflex tachycardia (compensation).
    • Summary of hemodynamic effects:4

  • Evaluation and Treatment:
    • Assess the ABCs and obtain vital signs.
    • Obtain an EKG and initiate continuous cardiac monitoring.
    • Perform a thorough H&P: Question regarding specific medication(s) ingested (number of capsules/tablets and dose), sustained release formulations, time of ingestion, co-ingestions, and intent.
    • Laboratory evaluation and imaging:
      • ABG/VBG: acidosis demonstrated to worsen myocardial dysfunction secondary to calcium channel antagonism (hypothesis: increased drug binding at calcium channels).5
      • Accucheck: assess for hypoglycemia; essential evaluation for hyperinsulinemia euglycemia therapy (HIET) (detailed below).
      • BMP: evaluate renal function in the setting of hemodynamic compromise/hypoperfusion state. Hypokalemia is frequently present.
      • Consider serum acetaminophen, serum salicylates, serum ETOH, and a UDS if concern for co-ingestions.
      • Bedside ultrasound: useful adjunct for the evaluation cardiac function.2
  • Treatment:
    • Source control:
      • Gastric lavage: not routinely employed. Consult toxicology => may be considered in patients presenting within 1-2 hours of a “life threatening” ingestion.2
      • Activated charcoal: consider a single dose for patients presenting within 4 hours of the ingestion of a potentially toxic dose (immediate release formulations).4
      • Whole bowl irrigation: initiate following the ingestion of SR formulations in asymptomatic patients.
        • Symptomatic patients (bradycardia and/or hypotension) = not indicated given association with depressed GI function and ileus.4
    •  Hemodynamic support:
      • Consider initial therapy with IVF and atropine.
        • IVF therapy: 1-2 L titrated to response (avoid additional fluids as the majority of patients are euvolemic (iatrogenic pulmonary edema)).4
          • Note: IVR and atropine often fail to improve heart rate and blood pressure in significant overdose.2
        • Atropine: 0.02mg/kg (min 0.1mg, max 0.5mg)4
      • Hypotension, cardiogenic shock, or vasodilatory shock:
        • HIET:4 insulin 1 U/kg IV bolus
          • Follow with an insulin infusion of 1-10 U/kg/hr + 50% glucose infusion to maintain euglycemia (requires frequent accuchecks). May increase infusion by 0.5-1 U/kg/hr every 30-60 minutes.
        • Calcium:4,6 6-mL/kg (3-6g) bolus of 10% calcium gluconate, or 0.2 mL/kg (1-2g) 10% calcium chloride administered over 5 to 10 minutes.
          • Follow with a calcium gluconate infusion at 0.6-1.2 mL/kg/hour (0.2–0.4 mL/kg/hour 10% calcium chloride). Titrate to improved blood pressure or contractility.
          • Assess ionized calcium levels q 30 mins. Goal = 2x normal.
        • Epinephrine: 0.05-1 μg/kg/min to increase heart rate and contractility; titrated to effect.4,6
        • Norepinephrine to increase blood pressure.4,6
    •  Toxicity refractory to initial treatment:
      • Incremental increase in HIET up to 10U/kg/hr.
      • Lipid emulsion therapy:6    1.5 mL/kg of 20% lipid emulsion administered as a bolus; repeat up to two times as needed to achieve clinical stability.
        • Followed by infusion of 0.25mL/kg/min for 30-60 min.
      • In the absence of myocardial contractility dysfunction, consider pacemaker if bradycardia or high grade AV block.6
      • Consult for venoarterial extracorporeal membrane oxygenation (VA-ECMO) if available.6 
  • Disposition:
    • Symptomatic patients required ICU-level care. All asymptomatic patients in whom concern for ingestion of SR formulations exist = admission for 24 hour monitoring.4
  • Pearls:
    • Consult Poison Control at 1-800-222-1222 for expert opinion given low level of evidence for management.6
    • The extent of hyperglycemia and metabolic acidosis serve as a marker of the degree of calcium channel toxicity.7

 References:

  1. Mowry J, Spyker D, Brooks D, Zimmerman A, Schauben J. 2015 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 33rd Annual Reports. Available from: https://aapcc.s3.amazonaws.com/pdfs/annual_reports/2015_AAPCC_NPDS_Annual_Report_33rd_PDF.pdf
  2. Kerns W. Management of B-adrenergic blocker and calcium channel antagonist toxicity. In Emergency Medicine Clinics of North America. Philadelphia, Elsevier. 2007; 25(2):309-331.
  3. Catterall W, Swanson T. Structural basis for pharmacology of voltage-gated sodium and calcium channels. Mol Pharmacol. 2015; 88(1):141-150.
  4. Graudina A, Lee H, Druda D. Calcium channel antagonist and beta-blocker overdose: antidotes and adjunct therapies. Br J Pharmacol. 2016; 81(3):453-461.
  5. Smith H, Briscoe M. The relative sensitization by acidosis of five calcium channel blockers in cat papillary muscles. J Mol Cell Cardiol. 1985; 17:1709-1716.
  6. St. Onge M, Anseeuw K, Cantrell FL, et al. Experts consensus recommendations for the management of calcium channel blocker poisoning in adults. Crit Care Med 2017 Mar;45(3):e306-315.
  7. Kine J, Raymond R, Schroeder J, et al. The diabetogenic effects of acute verapamil poisoning. Toxicol Appl Pharmacol 1997; 145: 357-362.

 

For Additional Reading:

Core EM: Hyperinsulinemia Euglycemia Therapy (HIET) for BB and CCB Toxicity

Core EM: Hyperinsulinemia Euglycemia Therapy (HIET) for BB and CCB Toxicity

 

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