Toxicology Tales from the ED

Amy Gutman MDEMS 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› Pathophysiology› Emergency Management

Not a “traditional” toxicology lecture

Emergency care relevant to IM & pediatric office practices

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?

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

WARFARIN PATHOPHYSIOLOGY

Inhibits synthesis of vitamin K-dependent coag factors 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

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

WARFARIN REVERSALINR BLEEDING PRESENT RECOMMENDATION

>Therapeutic - <5 No Lower warfarin dose, or omit dose & resume at low dose; no reduction if minimally elevated

>5-9 No Omit 1-2 doses, serial PT/INR, resume warfarin at lower dose; or omit dose & give 1-2.5mg vitamin K po

>9 No Hold warfarin, give 2.5-5 mg vitamin K po, serial PT/INR, administer more po vitamin K prn; If prosthetic heart valves, FFP > vitamin K

Any Serious or Life-threatening

Hold warfarin. Vitamin K 10mg IV. FFP. Consider PCC, rfVIIa

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

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

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 coag status, so usual dose is 4 units

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, antithrombin II 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

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 hr obs, warfarin held x 2 dosages

Determined pt accidentally doubling warfarin dosage due to pharmacy error

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?

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

LETHALITY OF PEDIATRIC ODs

MEDICATION / DRUG POTENTIALLY LETHAL DOSE (10KG)

Codeine 3 60mg tabletsDesipramine 2 75mg tabletsHydrocarbons 1 teaspoon (if aspirated)Imipramine 1 250mg tabletIron 2 adult strength tabletsLindane 2 teaspoonsTheophylline 1 500mg tabletVerapamil 1 240mg tabletMetoprolol 2 50mg tabletsSulfonylureas 2 5mg tablets

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

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

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”

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

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

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

MANAGEMENT OPTIONS

Diazoxide (Hyperstat)› Increases glucose by

inhibiting pancreatic insulin release

› Hyperglycemic effect within 1 hr, lasts 8 hrs

Octreotide (Sandostatin)› Acts on somatostatin

receptors› Hyperpolarization of β cells

inhibits Ca++ influx & insulin release

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!

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 D50 because 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:

• Vitals: HR 28, BP 64/34, T 98, Sat 82% NRB

• Differential Diagnosis?

DDX & EMERGENCY

MANAGEMENT

Dependent on history + vitals

Bradycardia pathway if cannot obtain history

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)

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

EMERGENCY MANAGEMENT: GLUCAGON

Regulatory hormone with (+) inotropic & chronotropic effects on myocardium via increasing cAMP

Effects independent of beta-adrenergic stimulation

Reverses hypotension, bradycardia & myocardial depression

Does not significantly reverse conduction disturbances (i.e. QRS prolongation)

ADDITIONAL OD MANAGEMENT

Epinephrine › β adrenergic to treat hypotension+ 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

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!

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

Tox screen: 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, ativan given, placed on monitor› HR 120, BP 90/60, Sat 90%ra, T not done

Differential Diagnosis?

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

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

TCA PHARMACOLOGY Extensively protein bound, large VOD

Hepatic metabolism, excreted as active metabolites with long ½ life

Toxic effects mediated through: › Anticholinergic› a 1 blockade › Class 1a quinidine-like effects › Postganglionic norepinephrine

reuptake blockade

Narrow therapeutic index

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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

ARRYTHMIAS Sinus tach 1st sign 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

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

aVR terminal 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

HYPOTENSION TCA anti–a adrenergic effects

Negative inotropy

Peripheral vasodilatation (decreased PVR)

Inhibition of Na+ flux into myocardium depresses inotropy

CLINICAL SSX

CARDIOVASCULAR CNS ANTICHOLINGERGIC

Sinus Tachycardia Drowsiness Dry MouthProlonged PR/ QRS/ QT

Opthalmoplegia Blurred Vision

ST Wave Abnormalities

Seizures* Dilated Pupils

Heart Blocks Pyramidal SSX Urinary Retention

Vasodilation Rigidity Absent Bowel Sounds

Hypotension Delirium PyrexiaCardiogenic Shock Respiratory

DepressionMyoclonic Twitching

VT / VF ComaAsystole

*Serotonin or norepinephrine mediated effects

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

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

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

REFERENCES www.emedicine.com~“INRReversal”, “Sulfonylurea Toxicity”, “TCA Overdose” 2011. Leissinger CA, 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.

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