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Toxicology Tales from the ED

Toxicology Tales from the ED. Amy Gutman MD EMS Medical Director Tobey Hospital prehospitalmd@gmail.com. DISCLOSURES. I have no financial disclosures or commercial endorsements to disclose. OVERVIEW. Four ED cases encountered over the past year Differential Diagnosis Epidemiology

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Toxicology Tales from the ED

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  1. Toxicology Tales from the ED Amy Gutman MD EMS Medical Director Tobey Hospital prehospitalmd@gmail.com

  2. DISCLOSURES • I have no financial disclosures or commercial endorsements to disclose

  3. OVERVIEW • Four ED cases encountered over the past year • Differential Diagnosis • Epidemiology • Pathophysiology • Emergency Management • Not a “traditional” toxicology lecture • Emergency care relevant to IM & pediatric office practices

  4. THE NOSEBLEED THAT LEAD TO HEMORRHAGIC SHOCK • 59 yo F with a “nosebleed that won’t stop”. Pressure & anterior nasal packing fail despite clear bleeding site at Kisselbock’s • After 3 hrs at home & 2 hrs of ED failed bleeding control she is tachycardic, hypotensive then has a syncopal event • Vitals:HR 130s & irregular, BP 74/42, Sat 92% ra • Differential diagnosis?

  5. HISTORY & EPIDEMIOLOGY OF WARFARIN TOXICITY • In 1900s bis-hydroxycoumarin discovered after cows eat spoiled sweet clover & die of massive hemorrhage • Warfarin derivatives used therapeutically as anticoagulants, commercially as rodenticides • ~3000 accidental exposures annually • 79% in <6yo children • In adults complications usually from incorrect dosing or diet / medication misadventures • 1%-8% toxicity risk for each year of therapy • Bleeding risk elevates as INR increases; 50% bleeding episodes occur w/ INR <4.0

  6. WARFARIN PATHOPHYSIOLOGY • Inhibits synthesis of vitamin K-dependent coagfactors II, VII, IX, X • No effect on established thrombus • Prevent progression / secondary thromboembolic complications • Metabolized by hepatic CP-450 isoenzymes to inactive metabolites • Abn metabolism alters physiology • Advanced age, hepatic dysfunction, diet, numerous meds • ½ life 20-60 hrs, effect duration 2–5 days, peak concentration 4 hrs

  7. EMERGENCY MANAGEMENT • Reversal & stabilization • Stable vs unstable? • Acute vs chronic? • Why anticoagulated? • Why reversal? • Exam: includes skin, neurological, rectal • Rads: If AMS or trauma obtain CT / US of affected area • Labs: • Type / cross, CBC, coags, LFTs, +/- tox screen • PT / INR (anticoagulant effect) • Vitamin K dependent factors • If critical need for anticoagulation (i.e. mechanical heart valve), heparin temporizes while warfarin reversed

  8. WARFARIN REVERSAL Ansell J. Pharmacology and management of the vitamin K antagonists: Chest 2008

  9. VITAMIN K1 MEPHYTON (PHYTONADIONE) • Fat soluble vitamin required for protein modification, blood coagulation, & metabolic pathways • Plant source (soy & green vegetables) • Overcomes competitive blocks • Clinical effect delayed for hours while liver synthesizes clotting factors & plasma factors II, VII, IX, X restored • IM, IV & PO equivalent, SQ not recommended

  10. FRESH FROZEN THERAPY • FFP contains plasma + coag factors • Free of RBCs, WBCs, PLTs • ABO compatible w/o rH considerations • In a 70 kg Patient: • 1 Unit (250cc) FFP increases factors 2.5% • 4 Units (1000cc) FFP increase factors 10% • 10% increase of factor levels required for clinically significant change in coagstatus, so usual dose is 4 units

  11. NOVEL REVERSAL AGENTS • Prothromin Complex Concentrate (PCC) • No thawing • Factors II, IX & X, minimal factor VII; new products include factor VII • Some contain protein C & S, antithrombinII or heparin • 4-factor products reverse coagulopathy within 30 mins • Must add FFP for F VII if 3-factor products (Prothrombinex-HT®) • Vitamin K1 to sustain reversal • Recombinant Factor VIIa (rFVIIa/ Novo7®) • No thawing • Less volume, ARDS, transfusion reactions & infection transmission • Vitamin K1 to sustaining reversal • Despite apparent advantages, no proven mortality benefit for rFVIIa or PCC > FFP

  12. DISPOSITION • Initial INR 6 / hemoglobin 7 required 2.5mg po vitamin K, 4 units FFP, 1 unit PRBC • Hemorrhage controlled with bilateral RhinoRockets® • Admitted for 23 hrobs, warfarin held x 2 dosages • Determined pt accidentally doubling warfarin dosage due to pharmacy error

  13. THE CHILD WHO SWALLOWED “A FEW” OF GRANDMA’S PILLS • 21 mo F presents because “she wouldn’t wake up from her nap”. Parents earlier noted child playing with grandma’s pill bottles; Grandma counted pills & thinks “1 or 2” missing • Child floppy, minimally responsive, dilated pupils • ABCs – airway patent, hypoventilation, thready pulse • IO, O2, monitor • HR 68, BP 92 palp, Sat 85% ra, T 96 pr • Differential Diagnosis?

  14. PEDIATRIC POISONINGS • 6,000,000 potentially toxic ingestions yearly • Most common age group: 1-5 yo • Predominately accidental (toddlers), intentional (teens) • MCC fatal poisonings: • Iron • TCAs • Cardiovascular medications • Hypoglycemics • Hydrocarbons

  15. LETHALITY OF PEDIATRIC ODs

  16. PRESENTATION • AMS differential diagnosis • In non-diabetics, hypoglycemia usually asymptomatic until glucose <40 mg/dL • Weakness • Diaphoresis • Tachycardia • Tachypnea • Transient neurologic deficit • Pallor / Cyanosis • Seizure / Tremor / Jitteriness • Coma • Hypothermia

  17. PEDIATRIC HYPOGLYCEMIA DDX • Miscellaneous • Sepsis • Malnutrition • Renal / Liver Failure • Hyperinsulinemia • Beckwith-Weidman • β Cell Hyperplasia (Nesidioblastosis) • Toxicity: • ETOH, Salicylates, Methadone, Hypoglycemics • HPA Axis Abnormality • Inborn Errors of Metabolism: • Carnitine Deficiency • Fructosemia • Galactosemia • Glycogen-Storage Disease Type I • Maple Syrup Urine Disease

  18. HYPOGLYCEMIC AGENTS • 1st generation sulfonylureas (i.e. tolbutamide), very potent, ½ life 35-49 hrs • 2nd generation sulfonylureas (glipizide, glyburide, glimepiride) less potent, shorter ½ lives • Non-sulfonylureas: biguanides, a-glucosidase inhibitors • High dosages do not significantly decrease serum glucose • “Anti-hyperglycemics” not “hypoglycemics”

  19. SULFONYLUREA MOA • Sulfonamide derivatives w/o antibacterial activity • Bind to K+ receptors sensitive to β cell membrane ATP resulting in Ca++ influx, K+ efflux, membrane depolarization & insulin release • Decrease serum glucagon, potentiate insulin action in extra-pancreatic tissues • Effective if functional β cells

  20. EMERGENCY HYPOGLYCEMIA MANAGEMENT • ABC, IV, O2, Monitor • IV / IO dextrose / glucose • PO / IV glucagon • NPO if AMS • IV octreotide or diazoxide • Other than for glipizide (enterohepatic circulation) activated charcoal not beneficial >1 hr post ingestion • No role for hemodialysis

  21. MANAGEMENT OPTIONS • Dextrose (D-glucose) • Rapid serum glucose elevation • Monosaccharide absorbed from GIT then distributed to tissues • Glucagon • Polypeptide hormone from beef or pork pancreas Islets of Langerhans alpha cells • ½ life 3-6 min • Gluconeogenesis & lipolysis by inhibiting glycogen synthesis & enhancing glucose formation from proteins & fat stores • Glycogenolysis by increasing liver hydrolysis of glycogen to glucose

  22. MANAGEMENT OPTIONS • Diazoxide (Hyperstat) • Increases glucose by inhibiting pancreatic insulin release • Hyperglycemic effect within 1 hr, lasts 8 hrs • Octreotide(Sandostatin) • Acts on somatostatinreceptors • Hyperpolarization of β cells inhibits Ca++influx & insulin release

  23. DISPOSITION • If 1st gen sulfonylurea admit for minimum 24 hrs regardless of symptomatology • If 2nd gen sulfonylurea may discharge home if asymptomatic & euglycemic for 8-12 hrs • If AMS, lethargic or seizure, admit to PICU • Parental education!

  24. THE “HYPOGLYCEMIC” PATIENT WITH A NORMAL BLOOD GLUCOSE • Patient known to EMS & ED for multiple visits for hypoglycemia • Presents via ambulance with AMS. FSBG 120 “but we already gave an amp of D50because that what he always needs” • Patient remained altered during transport, did not respond as usual. Upon arrival, lethargic, maintaining gag, FSBG 135 • IV, O2, monitor placed & following noted:

  25. Vitals: HR 28, BP 64/34, T 98, Sat 82% NRB • Differential Diagnosis?

  26. DDX & EMERGENCYMANAGEMENT • Dependent on history + vitals • Bradycardia pathway if cannot obtain history

  27. PHARMACOLOGY • Beta Blockers • Lipophillic, large VOD • Wide variations in pharmakokinetics, but generally absorbed in GIT, eliminated hepatically or renally (atenolol, nadolol,esmolol) • Inhibit β adrenergic stimuli with (-) inotropy & chronotropy • Calcium Channel Blockers • Highly protein bound, large VOD • 1st pass effect via hepatic metabolism (low bioavailability) • Decreased calcium influx, causing (-) inotropy, chronotropy, dromotropy & vasodilation (decreased PVR)

  28. SIGNS & SYMPTOMS • Narrow therapeutic to toxic ratio • Most common features: hypotension + bradycardia • EKG: sinus bradycardia with PR prolongation • BBs > CCBs cause QRS prolongation • BBs cause additional symptoms due to effects on systemic beta receptors: • Bronchospasm • Hypoglycemia • Hyperkalemia • CNS toxicity

  29. EMERGENCY MANAGEMENT: GLUCAGON • Regulatory hormone with (+) inotropic & chronotropiceffects on myocardium via increasing cAMP • Effects independent of beta-adrenergic stimulation • Reverseshypotension, bradycardia& myocardial depression • Does not significantly reverse conduction disturbances (i.e. QRS prolongation)

  30. ADDITIONAL OD MANAGEMENT • Epinephrine • β adrenergic to treathypotension+ bradycardia • Calcium Gluconate or Chloride • 30 mL gluconate =1 gm of calcium • Rapid contractility improvement, limited effect on nodal depression or PVR • If critical hyperkalemia, chloride > gluconate • NaHCO3 • Treatment of QRS prolongation • Dopamine • a & β adrenergic actions • Magnesium • Hypocalcemia refractory to treatment if hypomagnesemia

  31. DISPOSITION • ABC, IV, O2, Monitor • RSI: vecuronium & etomidate • Ventilation with low PEEP • Atropine • External pacing • Central line • Glucagon • CaCl • MgSO4 • Epinephrine gtt • Med Flight to MGH • D/C at day 7…to be seen at Tobey 10 days later with ~ hypoglycemia!

  32. THE PLEASANT PATIENT WITH SUICIDAL IDEATION • 42 yo WF presents via police with SI. Arguing with husband, stated SI including driving off a cliff. Calm & forthcoming during interview, denying current SI • Toxscreen: negative • Crisis arrived 3 hrs after interview to find pt unresponsive, “twitchy” with “odd jerking motions”. Tech noted pt restless x 30-45 mins • MD called to room to find patient seizing • Airway controlled, ativangiven, placed on monitor • HR 120, BP 90/60, Sat 90%ra, T not done

  33. Differential Diagnosis?

  34. EMERGENCY MANAGEMENT • IV, O2, Monitor • 2 large bore IVs, 2 L NS bolus • 2 amps NaHCO3. then NaHCO3 drip • 2 grams MgSO4 • Partially awake intubation, followed by vecuronium • Ventilation w/ low PEEP • Dopamine

  35. DIFFERENTIAL DIAGNOSIS (AEIOU-TIPS) • CNS Catastrophe • Heatstroke • Metabolic: • Hyperkalemia • Hypocalcemia • Hyponatremia • Status Epilepticus • Arrythmias: • Sinus Brady • Heat Block • WPW • VF / VF / Torsades • OD: • Anticholinergic • Antidepressant • Antihistamine • Digitalis • INH • Local Anesthetic • Salicylate • TCA • Antiarrythmic • Withdrawal Syndromes • Metabolic Acidosis

  36. TCA PHARMACOLOGY • Extensively protein bound, large VOD • Hepatic metabolism, excreted as active metabolites with long ½ life • Toxic effects mediated through: • Anticholinergic • a1 blockade • Class 1a quinidine-like effects • Postganglionic norepinephrine reuptake blockade • Narrow therapeutic index

  37. SIGNS & SYMPTOMS • Rapid onset of CNS & CV effects • Unlikely to develop life-threatening events 6 hrs post ingestion • May appear to have a pure anticholinergic toxidrome

  38. ARRYTHMIAS • Sinus tach 1stsign of toxicity • Class 1A antiarrhythmic effect decreases Na+ influx through fast Na+channels • Decreased phase 0 slope prolongs QRS / QT / PR • Delays myocardial & conducting tissue depolarization

  39. WIDE QRS W / R-R PRIME • QRS >0.16 with predicts seizures / arrhythmias > drug levels • >130 msec, 90% required mechanical ventilation • >120 msec, 1/3 seized • >160 msec, 75% VT / VF • aVRterminal R >3mm better predictor of seizures or arrhythmias than QRS duration Right axis shift in last 40ms of QRS, deep S wave in lead 1, large R wave in aVr suggestive of TCA cardiotoxitiy

  40. HYPOTENSION • TCA anti–aadrenergic effects • Negative inotropy • Peripheral vasodilatation (decreased PVR) • Inhibition of Na+ flux into myocardium depresses inotropy

  41. CLINICAL SSX *Serotonin or norepinephrine mediated effects

  42. MANAGEMENT • ABC, IV x 2, O2, Monitor, EKG • Correcting hypotension, hypoxia, acidosis reduces cardiotoxicity & arrhythmias • Unlike pure anticholinergic toxicity, no physostigmine (decreases seizure threshold, arrythmogenic) • ICU admission • Many common meds have “TCA-Like” toxicity

  43. ALKALINIZATION WITH NAHCO3 • QRS >100 ms, seizures, acidosis, hypotension, ventricular arrhythmias, cardiac arrest • Corrects acidosis by increasing extracellular Na+ • Narrows QRS • Stabilizes Na+ channels • Raises BP even if no acidosis • Increases TCA plasma protein binding • Improves inotropy

  44. DISPOSITION • Patient decompensated en route to Boston • At MGH, placed on epinephrine gtt, Swan-Ganz placed, intralipids started • Hemodialysis initiated when creatinine bumped to 5 & potassium elevated • After 4 days in the ICU, extubated • OD cocktail: amitriptyline, flexeril, diphenhydramine • Discharged to psychiatric rehab on day 7 of hospital stay

  45. REFERENCES • www.emedicine.com~“INRReversal”, “Sulfonylurea Toxicity”, “TCA Overdose” 2011. • LeissingerCA, Blatt PM, Hoots WK, et al. Role of prothrombin complex concentrates in reversing warfarin anticoagulation: A review of the literature. Am J Hematol. 2008;83:137-43 • Weber JE, Jaggi FM, Pollack, CV. Anticoagulants, antiplatelet agents, and fibrinolytics. In: Tintinalli JE, Kelen GD, Stapczynski JS, eds. Emergengy Medicine: A Comprehensive Study Guide. 6th ed. McGraw-Hill; 2004: 1354-60 • Hirsh J, Guyatt G, Albers GW, et al. Executive Summary: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2008;133:72S-3S • Poison Control Center Data. 2010 • AHA Cardiovascular Care Recommendations; Warfarin reversal: consensus guidelines, on behalf of the Australasian Society of Thrombosis & Haemostasis. Circulation. 2010. • Baker R. Wood; the Warfarin Reversal Consensus Group recommendations. MJA 2004; 181 (9): 492-497 • Bonow RO, Carabello BA, Chatterjee K, et al. 2008 Focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease”. Circulation 2008; 118(15):e523-661. • Tintanelli. “Emergency Medicine”. 2009. • www.cdc.gov~Poisoning statistics 2010. • www.aapcc.org~American Association of Poison Control Website. 2011. • www.toxicology.org~Toxicologyand Critical Care Management Updates. 2011 • Carr D. Successful resuscitation of a doxepin overdose using intravenous fat emulsion (IFE). Clinical Toxicology 2009; 47(7): 710.

  46. CONCLUSIONS • Review of the epidemiology, pathophysiology, differential diagnosis & emergency management of four common overdoses • Implications for internal medicine & pediatrics • Importance of a broad differential diagnosis & early recognition and aggressive emergency management • Questions? • Thank you for your time ~ find me nights at Tobey ED or at Amy.Gutman72@gmail.com

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