EM CCM Conference: October 2013

BETA-BLOCKER TOXICITY

PRESENTED BY DR. KENDALL

SUMMARY BY DR. YOUN

The Case:

HISTORY: 91F with HTN, DM on carvedilol, labetalol BIBEMS for weakness, dizziness, and near-syncope.

VITALS: BP 76/38, HR 41

PRIMARY INTERVENTIONS: Intubation, fluids, atropine, dopamine drip, pacer pads applied

PHYSICAL:, anxious, decreasing mental status, progressive bradypnea, clear lungs, bradycardia, soft abdomen, LE edema

SECONDARY INTERVENTIONS: EKG, Labs, CXR

DDx: Ischemia/Infarction, Hyperkalemia, Toxicologic (CCB, BB, anti-dysrhythmics, cholinergics, digoxin, opiates, sympatholytics), Sarcoidosis, Amyloidosis, Hemochromatosis, Rheumatic fever, SLE, Myocarditis, Endocarditis, Lyme, Hypothyroidism, Sick sinus syndrome, Structural anomaly, Hypothermia

PERTINENT LABS: K 6.5, Cr 2.1, H/H 8/24.5, Lactate 3.5, AST/ALT 1091/1004

NEXT INTERVENTIONS: Glucagon 5mg IVP, Atropine 0.5mg IVP, Hyperkalemia treatment (Regular insulin 10U IVP, D50W 25mg IVP, NaHCO3 50 mEq IVP, Nebulized albuterol), Central venous access (R IJ Cordis), Arterial line, Levophed drip initiated in combination with Dopamine, then Insulin and D50 drips started.

CONSULTS: Cardiology, MICU, Poison Control Center

FINAL DISPOSITION: 91F with beta blocker toxicity resulting in cardiovascular collapse, admitted to MICU, with subsequent 5 day hospital course and eventual discharge.

BETA-BLOCKER TOXICITY EPIDEMIOLOGY:

– 23,902 cases in 2011, 10,485 single drug cases, 860 major/moderate toxicity, 9 deaths.

MECHANISM: L-type Ca channel in cardiac myocyte, with Ca involved in plateau phase of action potential

– Ca normally enters cell through L-type channel, stored in sarcoplasmic reticulum for release into actin-myosin complex

– Ca-channel blocker blocks this channel from allowing influx of Ca

– Beta-1 agonists bind to G protein, activing adenylate cyclase/cAMP cascade, which also allows for Ca influx into myocyte

– Beta-blocker inhibits binding to G protein, thus preventing downstream cascade

– Insulin

– Phosphodiesterase (PDE) promotes breakdown of cAMP

– PDE-inhibitor (milrinone, inamrinone) prevents breakdown of cAMP thus promoting further influx of Ca into cell

BETA-BLOCKER PROPERTIES:

– Lipid solubility – higher lipid solubility allows crossing blood-brain barrier, CNS effects

– Metabolism/Elimination

– Membrane Stabilizing Activity

– Formulation – Immediate release versions versus sustained-release formulations

EKG FINDINGS:

– Sinus bradycardia

– AV blocks/Junctional rhythms

– Ventricular escape rhythms

INITIAL TREATMENTS:

– Atropine (for undifferentiated symptomatic bradycardia)

– IV Fluids (for undifferentiated hypotension)

– Consider decontamination if acute ingestion, if concern for ongoing metabolism of medications (however, aspiration risk should be considered as well)

PHARMACOLOGIC MANAGEMENT:

– Glucagon – inotropic and chronotropic, activates adenyate cyclase, thus bypassing the beta-blocked G protein step of the pathway

No human studies, only animal studies and case reports
Bailey, systematic review – increases HR, questionable effect on CO or MAP
Bolus: 5-10 mg (150 mcg/kg), can repeat in 5-10 min
Infusion: 2-10 mg/hr (50-100 mcg/kg/hr)
Causes hyperglycemia and hypokalemia
Potent emetic

– High-dose insulin – because CCB and BB impair carbohydrate catabolism, leading to elevated lactate, metabolic acidosis à decrease insulin secretion and increase insulin resistance (CCB>BB)

Insulin as inotrope
Bolus: 1 U/kg with 25-50 mL D50W (likely will require dextrose infusion from outset)
Infusion: 1 U/kg/hr + dextrose 0.5g/kg/hr

– Catecholamines – first line is Dopamine, then consider vasopressin and epinephrine

– Calcium

Bolus: Ca CHLORIDE 10-20 mL (0.2 mL/g) or Ca GLUCONATE 30-60 mL (0.6 mL/kg)
Can repeat bolus 3-4 times q10-20 min, then check levels
Infusion: Ca CHLORIDE 0.4 mL/kg/hr or Ca GLUCONATE 1.2 mL/kg/hr

– Intravenous lipid emulsion – in animal models, propranolol > metoprolol

Bolus: 1.5 mL/kg over 2 min
Infusion: 1.5 mL/kg over 60 min

– PDE-inhibitors – inamrinone or milrinone

Can cause peripheral vasodilation, therefore worsen hypotension
Dosing challenge due to long half-life

ADDITIONAL CONSIDERATIONS:

– Transvenous pacing

– Intra-aortic balloon pump

– ECMO

– Hemodialysis

DISCUSSION:

– glucagon works faster than insulin, insulin takes approx 30 min for effect

– glucagon causes VOMITING!

– intralipid – case report data mostly, esp for verapamil

– hemodialysis – atenolol only

– recent study – pressors lower on list of treatment options because usually don’t work

– anecdotal success with epinephrine reported

– can do glucagon and insulin drips together as well (and very often may need to do so)

– need central line for dextrose infusion in order to support such a high insulin infusion

– pacing probably won’t work so if you know that it’s beta toxicity, better not to go with cordis since pt will need triple lumen; however you can also just change over wire if you start with cordis for pacing for undifferentiated bradycardia

REFERENCES:

Kerns, W. Management of Beta Adrenergic and Calcium Channel Antagonist Toxicity, Emerg Med Clin N Am 2007; (25): 309-331.

Holger, J. Insulin versus vasopressin and epinephrine to treat Beta blocker toxicity. Clinical Toxicology, 2007; (45), 396-401.

Harvey, M., Insulin versus Lipid Emulsion in a Rabbit Model of Severe Propranolol Toxicity: A Pilot Study. Critical Care Research and Practice, 2011, Article ID 361737.

Engebretsen, K., High-dose insulin therapy in beta-blocker and calcium channel-blocker poisoning. Clinical Toxicology, 2011, (49), 277-283.

Love, J., Electrocardiographic Changes Associated with Beta Blocker Toxicity. Annals of Emergency Medicine, 2002, (40:6) 603-610.

Bailey, B., Glucagon in beta Blocker and Calcium Channel Blocker Overdoses: A Systematic Review. Journal of Toxicology, Clinical Toxicology, 2003 (40:5) 595-602.

Browne, A., Intravenous Lipid Emulsion Does not Augment Blood Pressure Recovery in a Rabbit Model of Metoprolol Toxicity., J. Med Toxicol., 2010 (6): 373-378.

DeWitt, C., Pharmacology, Pathophysiology and Management of Calcium Channel Blocker and Beta blocker toxicity. Toxicol Rev, 2004: 23 (4): 223-238.

Bronstein, A. 2011 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 29th Annual Report., Clinical Toxicology, 2012, 50, 911-1164.

The views expressed on this blog are the author's own and do not reflect the views of their employer. Please read our full disclaimer here. Any references to clinical cases refer to patients treated at a virtual hospital, Janus General Hospital.

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Jay Khadpe MD

Editor in Chief of "The Original Kings of County" Assistant Professor of Emergency Medicine Assistant Residency Director SUNY Downstate / Kings County Hospital