
I have no financial disclosures or commercial endorsements
to disclose

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

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?

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

Inhibits synthesis of vitamin Kdependent 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

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
INR
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 12.5mg 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

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

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

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

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

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?

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
MEDICATION / DRUG
POTENTIALLY LETHAL DOSE (10KG)
Codeine
3 60mg tablets
Desipramine
2 75mg tablets
Hydrocarbons
1 teaspoon (if aspirated)
Imipramine
1 250mg tablet
Iron
2 adult strength tablets
Lindane
2 teaspoons
Theophylline
1 500mg tablet
Verapamil
1 240mg tablet
Metoprolol
2 50mg tablets
Sulfonylureas
2 5mg tablets

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

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
›
›
›
›

1st generation sulfonylureas (i.e.
tolbutamide), very potent, ½ life 3549 hrs

2nd generation sulfonylureas
(glipizide, glyburide, glimepiride)
less potent, shorter ½ lives

Non-sulfonylureas: biguanides, aglucosidase inhibitors
› High dosages do not significantly
decrease serum glucose
› “Anti-hyperglycemics” not
“hypoglycemics”

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 extrapancreatic tissues

Effective if functional β cells

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

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

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

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!

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?

Dependent on
history + vitals

Bradycardia
pathway if
cannot obtain
history

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)

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

Regulatory hormone with (+)
inotropic & chronotropic effects on
myocardium via increasing cAMP

Effects independent of betaadrenergic stimulation

Reverses hypotension, bradycardia &
myocardial depression

Does not significantly reverse
conduction disturbances (i.e. QRS
prolongation)

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

ABC, IV, O2, Monitor

Central line
›
›
›
›
Glucagon
CaCl
MgSO4
Epinephrine gtt

RSI: vecuronium & etomidate

Ventilation with low PEEP

Atropine

Med Flight to MGH

External pacing

D/C at day 7…to be seen at
Tobey 10 days later with ~
hypoglycemia!

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?

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



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
en
1
isch
674
1024

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

Rapid onset of CNS & CV effects

Unlikely to develop life-threatening
events 6 hrs post ingestion

May appear to have a pure
anticholinergic toxidrome

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

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

TCA anti–a adrenergic effects

Negative inotropy

Peripheral vasodilatation
(decreased PVR)

Inhibition of Na+ flux into
myocardium depresses inotropy
CARDIOVASCULAR
CNS
ANTICHOLINGERGIC
Sinus Tachycardia
Drowsiness
Dry Mouth
Prolonged 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
Pyrexia
Cardiogenic Shock
Respiratory Depression
Myoclonic Twitching
VT / VF
Coma
Asystole
*Serotonin or norepinephrine mediated effects

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

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

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
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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.

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