THE CODE STROKE THAT WASN’T Amy Gutman MD Director of Emergency Medicine

OBJECTIVES Case presentation Protocol review Assessment & management

CASE PRESENTATION 911 call for “Stroke” at local SNF 85 yo female, last seen well at breakfast 3 hours earlier Normally with dementia, but otherwise neurologically intact Now with AMS, slurred speech

PMH / SOCIAL PMH Alzheimer's Hypertension Hypercholesterolemia Social 40+ PYH, quit x 20 years, (-) ETOH / drugs Full Code

MEDICATIONS Haloperidol 5mg po prn Metoprolol XL 50mg po BID Atorvastatin 40mg po qDay Aspirin 81mg po qDay

INITIAL ASSESSMENT Elderly female, drooling, minimally responsive but maintaining airway ABC Maintaining airway, adequate respirations, diminished distal pulses Vitals HR 28 RR 10 BP 60/P Sat 92% ra

EMS AMS PROTOCOL

SECONDARY SURVEY Stroke Scale Face symmetrical Speech slurred Both arms weak Glucose 58

EKG

ON SCENE Problems identified Treatments initiated AMS Bradycardia Hypotension Treatments initiated 1 IV & 200cc NS 1 amp dextrose 4mg naloxone Cardiac monitor Medical control – called to notify of “Code Stroke 5 minutes out” At EMS arrival patient remained altered, hypotensive & bradycardic Let’s discuss…

AMS, BRADYCARDIA, HYPOTENSION What is the priority? Once bradycardia & hypotension identified, it’s difficult but important to address both simultaneously Equally important to start putting together a differential diagnosis as the shock is not going to kill this patient…it’s what’s CAUSING the shock that’s going to kill the patient!

AMS MNEMONIC – AEIOU TIPS A Alcohol, acidosis, arrythmia E Encephalopathy, electrolytes, endocrine, environmental I Insulin O Opiates, oxygen (hypoxia) U Uremia T Trauma, toxins I Infection, increased ICP P Psychosis, poisoning (CO, cyanide), porphyria S Stroke, shock, seizure But…What Causes AMS, Bradycardia & Hypotension? CVA w/ increased ICP Infection Cardiogenic shock Potassium Toxin

AMS, BRADYCARDIA, HYPOTENSION DDX CAUSE DIFFERENTIAL MANAGEMENT Beta Blocker Hypoglycemia Glucagon, Insulin + glucose, pressors Calcium Channel Blocker High lactate, hyperglycemia Calcium, pressors, insulin + glucose Cardiac glycosides (digitalis) Ventricular arrythmia, high digoxin level, hyperkalemia Digibind Class IC Antiarrhythmic (propafenone) Wide-complex bradycardia Inotropes, vasopressors, NaHCO3, pacemaker Clonidine Opiod-like symptoms (miosis, bradypnea) Naloxone Cyanide Metabolic acidosis, high lactate Hydroxocobalamin Organophosphates Muscarinic toxidrome Atropine, 2PAM

BRADYCARDIA MANAGEMENT https://www.aclsmedicaltraining.com/adult-bradycardia-algorithm/

HYPOTENSION CAUSES https://www.cvphysiology.com/Blood%20Pressure/BP030

MANAGEMENT: VOLUME, RATE OR PUMP? https://accessemergencymedicine.mhmedical.com/content.aspx?sectionid=41069038&bookid=521

VASOPRESSORS & INOTROPES Inotropy Myocardial contractility Chronotropy Heat rate Inotropic agents primary increase heart rate Vasopressor agents (to varying degrees) increase HR, SVR & CO https://umem.org/educational_pearls/2506/

VASOPRESSORS & INOTROPES Alpha-1 Increase arterial tone / MAP & venous tone Augment cardiac preload  Beta-1  Increase inotropy, chronotropy & arterial tone / SVR Beta-2 & Dopamine Vasodilation increases increases perfusion to cardiac, renal & GI tissues V1 Increase arterial vasoconstriction /  MAP https://umem.org/educational_pearls/2506/

IN THE ED Patient had seizure then intubated for airway protection Radiology: Optic nerve sheath US normal eFAST normal Head CT normal CXR CHF, cardiomegaly Cardiac US: Poor EF, right atrial collapse, global wall motion abnormality https://www.grepmed.com/images/1632; http://www.sonomojo.org/keeping-an-eye-on-intracranial-pressure-detecting-elevated-icp-using-ocular-ultrasound/

FURTHER STABILIZATION Central line placed Norepinephrine drip 2 liters lactated ringers Foley – good UOP ABG Combined respiratory alkalosis & metabolic acidosis Bradycardia resistant to medications Atropine, glucagon, insulin, glucose had little effect Transvenous pacemaker placed in ED http://www.tamingthesru.com/blog/procedural-education/transvenous-pacemaker-placement-part-1-the-walkthrough

THE “OH…BY THE WAY” SNF nurse called the ED 2 hours later with the “Oh…by the way…the patient likely also took her room-mates medications when she got up from the breakfast table. Actually…they sit together at breakfast a lot…..” Her room-mate’s medications? Metoprolol XL 100mg Metformin 500mg Warfarin 10mg po

SO…NOT A CODE STROKE!

METOPROLOL Selective β1 receptor blocker Lipophilic Decreases slope of phase 4 action potential Reduces Na+ uptake & prolongs phase 3 repolarization slowing down K+ release Lipophilic No sympathomimetic activity Weak membrane stabilizing activity Decreases HR, CO, BP & contractility https://commons.wikimedia.org/wiki/File:Cardiac_action_potential.png

BETA RECEPTORS B1 B2 B3 Cardiac, renal, adipose Smooth muscle (lungs, peripheral vasculature), cardiac Vasodilation, bronchodilation B3 Adipose, cardiac Thermogenesis, decrease contractility

CLINICAL SIGNS & SYMPTOMS Usually within 2 hours, but 95% within 6 hours of Ingestion Hypotension Bradycardia Arrythmias Seizures AMS Bronchospasm Hypoglycemia

SSX OF BETA BLOCKER OD Primary organ system affected is cardiovascular Hallmark of severe toxicity is bradycardia & shock Selectivity lost in large overdoses

WHY HYPOGLYCEMIA? Normally heart uses free fatty acids as primary energy source Switches to carbohydrates / glucose when “stressed” Glycogenolysis & gluconeogenesis inhibition reduce glucose availability In addition…this woman took her room-mate’s metformin!

WHY SEIZURES? Beta-blockers with sodium channel antagonism can cause a wide- complex bradycardia Wide-complex bradycardia contributes to seizure development In this patient, likely prolonged QT + hypoglycemia = seizure

POLYPHARMACY Haloperidol Metabolized by CYP450 Worsens AMS Increases metoprolol effects Glyburide Prolonged hypoglycemia Metformin Lactic acidosis Atorvastatin CYP450 inducer Worsens metoprolol effects Aspirin Cardioprotective – a positive for this patient Warfarin Vitamin K antagonist – made the central line interesting

POLYPHARMACY CONCERNS Majority of patient’s medications utilize CYP450 system She was on 2 medications that amplified the effects, increased the duration of action & decreased the elimination of metoprolol Haloperidol & atorvastatin Add in her room-mate’s medications (warfarin, glyburide, more metoprolol), & this is a recipe for disaster

BETA BLOCKER OD + POLYPHARMACY MANAGEMENT Airway stabilization IVF boluses Glucagon Calcium salts Vasopressors Insulin + glucose Lipid emulsion therapy Sodium bicarbonate + magnesium (occasionally)

SIMULTANEOUS ASSESSMENT & MANAGEMENT History is incredibly important Screening labs ABCs Intubated & mechanically ventilated Then address: Hypotension & bradycardia Hypoglycemia Seizures

GLUCAGON Activates adenylyl cyclase  increases CAMP  increased Ca++ available for muscle contraction (+) Inotropic & chronotropic effects Side effects: Nausea & vomiting from esophageal sphincter relaxation IV 0.05-0.15 mg/kg (3-10mg) bolus Effects of IV bolus within 1-2 minutes Duration of action 10-20 mins requires continuous infusion 1-10 mg/hr

INSULIN THERAPY Insulin facilitates cardiac utilization of glucose “Stress” substrate Glucagon, epinephrine & calcium all promote free fatty acid utilization 1 unit/kg IV bolus then 0.5-1.0 unit/kg/h continuous infusion

INSULIN THERAPY Adverse effects include hypoglycemia & hypokalemia Always give 0.5 gram/kg glucose when initial glucose <400 mg/dL Q30 minute monitoring of glucose & potassium Potassium drops precipitously when insulin pushes it into the cell

ADRENERGIC RECEPTOR AGONISTS Beta-adrenergic receptor agonists improve hypotension Norepinephrine, dopamine, epinephrine, isoproterenol Most effective is norepinephrine Works primarily on Beta 1 receptors Increases HR & BP

CALCIUM SALTS In refractory shock to increase inotropy Calcium chloride has 3 x more elemental calcium than calcium gluconate 10% gluconate 0.6 mL/kg over 5-10 mins Then 0.6-1.5 mL/kg/h 10% chloride 0.2 mL/kg over 5-10 minutes Then 0.2-0.5 mL/kg/h https://scholarblogs.emory.edu/curbsideconsult/2014/05/09/case-of-the-month-beta-blocker-overdose/

SODIUM BICARBONATE QRS interval >120 MS Dose 2-3 mEq/kg of 8.4% NaHCO3 May repeat boluses

TRANSVENOUS PACING Electrical capture & restoration of blood pressure https://emedtravel.wordpress.com/2012/04/13/%E2%99%A5-understanding-pacemakers-part-5-of-5/

PHOSPHODIESTERASE INHIBITORS (MILRINONE)? Limited data Inhibits breakdown of cAMP by PDE Maintains intracellular calcium levels (+) Inotropic effects No increase in myocardial oxygen demand or HR Continuous IV infusion of 0.5 micrograms/kg/min

NOT HELPFUL Atropine GI decontamination Muscarinic blocker Unlikely to help or harm GI decontamination Activated charcoal of limited benefit within 1-2 hours after ingestion Whole-bowel irrigation +/- benefit

LAST DITCH OPTIONS Hemodialysis not an option for metoprolol Lipid-bound Intralipid emulsion therapy Promising, but not standard of care For intractable hypotension / cardiogenic shock: ECMO Intra-aortic balloon pump

REFERENCES Wax PM et al. beta-blocker ingestion: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila) 2005; 43:131 Lyden AE, Cooper C, Park E. Beta-Blocker Overdose Treated with Extended Duration High Dose Insulin Therapy. J Pharmacol ClinToxicol 2014; 2:1015. http://www.jscimedcentral.com/Pharmacology/pharmacology-2-1015.pdf (Accessed on June 16, 2014). Shepherd et, al. “Treatment of poisoning caused by B-adrenergic and calcium-channel blockers”. Am J Health Syst. Pharm- Vol 63. Oct 1 2006. Bronstein AC, Spyker DA, Cantilena LR Jr, et al. 2006 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS). Clin Toxicol (Phila) 2007; 45:815. Bailey B. Glucagon in beta blocker and calcium channel blocker overdoses: a systematic review. Journal of Clinical Toxicology. 2003; 41 (5); 595-602. Love JN, Howell JM, Litovitz TL, Klein-Schwartz W. Acute beta blocker overdose: factors associated with the development of cardiovascular morbidity. J Toxicol Clin Toxicol 2000; 38:275. Leppikangas, et al. Levosimendan as a rescue drug in experimental propanolol-induced myocardial depression: a randomized study. Ann Emerg Med. 2009 Dec; 54(6): 811-817. Vucinić S, Joksović D, Jovanović D, et al. Factors influencing the degree and outcome of acute beta- blockers poisoning. Vojnosanit Pregl 2000; 57:619. Taboulet P, Cariou A, Berdeaux A, Bismuth C. Pathophysiology and management of self-poisoning with beta- blockers. J Toxicol Clin Toxicol 1993; 31:531.

SUMMARY prehospitalmd@gmail.com / PreparedRescuer.com When patient can’t give history, rely on what you see with your own eyes Start resuscitation in the field – if you cannot, notify medical control Don’t dismiss clinical clues because they do not “fit” your differential Beware polypharmacy – what you are seeing may be primary or secondary effects of a medical problem or a drug-interaction