Overdose

Management
Critical Decision-
Making in Toxicology
Carson R. Harris, MD
Director, Toxicology Section
Regions Hospital, Minnesota

Objectives

• Describe key issues in the management of

deadly ingestions

• Review the prognostic indicators of

acetaminophen toxicity

• Identify the acute and chronic complications

of methamphetamine abuse

• What are the indications and rationale for

administering sodium bicarbonate in
treating TCA overdose?

• When should a patient with acetaminophen-

induced hepatotoxicity be transferred for
consideration of liver transplant?

• List significant cardiovascular effects of

methamphetamine abuse.

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 The bad ones
• TCA

• Cardiovascular drugs

• Opiates
– Methadone
– Oxycontin
– ‘Tango and Cash’

• Acetaminophen

• Sympathomimetics

CA Overdose
• amitriptyline
• imipramine • Elavil
• doxepin • Tofranil
• desipramine • Adapin
• maprotiline • Ludiomil
• Surmontil
• clomipramine
• Anafranil
• protriptyline
• Vivactil
• amoxapine
• Norpramin
• trimipramine
• Asendin
• nortriptyline
• Pamelor

TCA Overdose

• Indications
– Depression
– Chronic pain syndromes
– OCD
– Panic and Phobic disorders
– Migraine prophylaxis
– Peripheral neuropathies

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 Antidepressants
• Mortality and Epidemiology
– 1977 TCA mortality - 15%
– Approximately 500,000 overdoses annually
– Replaced by analgesics as the leading cause of
death from overdose in US reported to the PC
– Female, age 20-29, single, employed, no history of
drug abuse
– 2005 antidepressants 3rd most common class of
drugs reported to PC
• 128 deaths
• Bupropion (35 deaths) > amitriptyline (21 deaths)

– Approximately 70% die pre-hospital

CA Overdose

• Acute Toxic Doses

– Fatal ingestions range 10-210 mg/kg
– 2-4 mg/kg is therapeutic
– Variable response
• 20 mg/kg is potentially fatal

CA - Pharmacokinetics

• Absorption
– Rapidly and completely absorbed
– Massive OD delays absorption
– Enterohepatic re-circulation secretes 30%
• Distribution
– Wide range in Vd (15-40 L/kg)
• Genetic variation
• Lipophilic
• Elderly has higher Vd

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 CA - Pharmacokinetics

• Distribution (cont’d)
– Tissue levels usually 10 times plasma levels
– Protein binding usually exceeds 90% with
some variations
• pH dependent
• Elimination
– Genetic component
– Metabolism influenced by other drugs

CA - Pathophysiology

• Therapeutic effects
– Not completely understood
– Blocks serotonin and NE uptake
– Anticholinergic effects
• Cardiac Effects
– Sinus tachycardia, dysrhythmias
• Na channel blockade – quinidine effect
– Hypotension
• Alpha adrenergic blockade and NE depletion
– Conduction delays / blocks

CA - Pathophysiology

• CNS
– Anticholinergic
• Excitation, confusion, hallucination,
ataxia
– Seizures
– Coma

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 CA - Pathophysiology

• Respiratory
– Pulmonary edema
– ARDS
– Aspiration pneumonia

• Gastrointestinal
– Delayed gastric emptying
– Decreased motility
– Prolonged transit time

TCA ECG Changes

• Prolongation of the QRS complex:

– Blockage of fast sodium channels slows phase 0
depolarization of the action potential.

– Ventricular depolarization is delayed, leading to a

prolonged QRS interval. Patients with QRS intervals
>100 ms are at risk for seizures and patient with QRS
intervals >160 ms are at risk for arrhythmias.

– QRS interval is evaluated best using the limb leads.

Action Potential

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 TCA ECG Changes

• R wave in aVR >3 mm:

– greater selectivity and toxicity to the distal conduction
system of the right side of the heart.
– effect can be observed as an exaggerated height of the
R wave aVR.
– may be more predictive of seizure and arrhythmia than
prolongation of the QRS.
• PPV 43% vs QRS >100 ms (35%)
• NPV 94% vs QRS >100 ms (92%)

CA Overdose

• R/S ratio >0.7 in aVR

– Arrhythmias and Seizures

ECG Parameter PPV NPV

RaVR > 3 mm 43% (13 /30) 94% (45/48)
R/S aVR > 0.7 46% (12/26) 92% (48/52
QRS interval >100 ms 35% (14/40) 92% (36/39)
• How do you treat this?

CA Toxicity Treatment

• ABCs
– Activated Charcoal: 30-50 gm
• Delayed gastric emptying

• Sodium Bicarbonate
– Dose
– Endpoint
• What is the mechanism of Sodium
Bicarbonate?

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 TCA Toxicity Treatment

• Alkalinization
– Uncouple TCA from myocardial sodium
channels.
– Alkalinization may increase protein binding
• Increases the extracellular sodium
concentration
– Improves the gradient across the channel.

TCA Toxicity Treatment

• The initial bolus is 1-2 mEq/kg

• A constant infusion of sodium bicarbonate
– commonly accepted - without controlled
studies validating the optimum administration
– 100 - 150 mEq of sodium bicarbonate to each
liter of 5% dextrose
• solution is hypotonic or nearly isotonic.

TCA Toxicity Treatment

• What if NaHCO3 doesn’t work?

– may require treatment with lidocaine and/or
magnesium sulfate.
– Class Ia and Ic agents contraindicated
– Beta blockers and CCB
• Worsen or potentiate hypotension

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 TCA Toxicity Treatment

• Hypotension, Persistent
– Direct acting alpha agonists, such as
norepinephrine and phenylephrine
– Dopamine may not be as effective
• Require release of endogenous catecholamines
– Dopamine or dobutamine alone may result in
unopposed beta-adrenergic activity due to TCA
induced alpha blockade and, therefore, may
worsen hypotension.
– Vasopressin (ADH)

TCA Toxicity Treatment

• What about Seizures from TCA

– Usually brief (<1 min)
– Self-limiting
– Acidosis increase cardiovascular toxicity.
• Benzodiazepines
• Phenytoin is no longer recommended
– Limited efficacy and possible prodysrhythmic.
– Phenobarbital may be used as a long-acting
anticonvulsant.

TCA Toxicity Treatment

• Agitation from TCA

– Anticholinergic effects

– Benzodiazepines are also the treatment of choice

– Physostigmine is contraindicated in TCA overdoses

• May cause bradycardia and asystole in the setting of TCA
cardiotoxicity.

– Flumazenil is contraindicated even in the presence

of a benzodiazepine co-ingestion.
• Several case reports - seizures

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 TCA Overdose

• Emergency department discharge criteria

– At least 6 hour observation period
– No significant sign of toxicity during
observation period, including normal follow-up
ECG prior to discharge
– Accidental ingestion
– Appropriate follow-up measures in place
– Adequately supervised home environment

Acetaminophen

APAP
Paracetamol
Tylenol®
Non-aspirin

It’s Everywhere!

• Over 200 products

Tylenol Anacin 3 Tempra
Tylenol cold Goody’s Comtrex
Contac Severe Cold Junior Strength Tylenol Vicks Nyquil
Sinutab Sinus Theraflu Sine-off
Sinarest Robitussin Cold Panadol
Midol PMS Sudafed Sinus Vanquish
Vicks 44M Unisom Singlet
Pyrroxate Midol teen Coricidin
Dimetapp allergy Drixoral Cold Alka Seltzer Plus
Actifed Sinus Benadryl allergy Panex

• Analgesic
• Antipyretic

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 Pharmacokinetics
• Absorption
– Rapidly absorbed from the GI tract
– Peak concentration usually occurs between 60 and 120
minutes
– Peak plasma levels almost always occur within 4 hours
• Distribution
– Vd 1.0 - 2.0 L/Kg
– Approximately 20% protein bound
– Has been reported to cross the placenta
• Metabolism*
– Occurs via several pathways in the liver
• 4% biotransformed by C-P450 MFO system
– 2E1, 1A2, 3A4

• Excretion
– Kidneys
– Minimal excretion into breast milk

Pharmacokinetics

• *Adults
– Glucoronidation – 60%
– Sulfation 30%
– Renal 5%
– P450 5%
• Half life
– Average 2 hours
– range 0.9 to 3.25 hours
– No age related differences
– No change in patients with renal disease
– With liver dysfunction, may increase to 17 hours

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 Toxicity
• Factors involved in predicting hepatotoxicity
– Total quantity ingested
– Time from ingestion to treatment
– Age of the patient
– Alcoholism*
– Enzyme inducing medications (P4-CRISES)
– Rumack-Matthew nomogram

• Toxic dose
– In adults, threshold for liver damage is 150 to 250
mg/kg
– Children under 10 appear to be more resistant

Acetaminophen Overdose

• Assessing Toxicity
–Stages
• Stage I (0.5-24h): GI, Malaise, Diaphoresis
• Stage II (24-48 h): Resolution of GI, Increase
LFTs, coagulation abnormality
• Stage III (72-96 h): GI Sx return, FHF, Renal
abnormality
• Stage IV (4d – 2 wks): Resolution of
abnormal labs or Death in FHF, oliguric RF
can develop

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 Acetaminophen Overdose

– APAP Levels
– AST
– Baseline CBC
– Creatinine, BUN, blood sugar, electrolytes
– PT/INR
– AST, ALT
• repeat q 24 hours
• elevations typically seen 24-36 hours post
ingestion

Acetaminophen Overdose

• Acetaminophen Levels
– 4-hour
– Extended release products
• AST
– 24-36 hours
• INR predictive of FHF
– >2 at 24 hr, >4 at 48 hr, or >6 at 36
• Persistent acidosis = poor prognosis (pH
<7.3)
• Elimination half-life > 4 hours

Others
• Need for inotropic support

• Age over 45 years

• Elevated serum phosphorus level >2.5 mg/dL.

Chung, et.al. Liver Transpl. 2003 Mar;9(3):248-53.
– Reliability questioned. Ng, et.al. Liver Transpl. 2004
Jan;10(1):158-9.

• Arterial blood lactate level

– Increased sensitivity of KCH criteria from 76% to 91%
and lowered negative likelihood ratio from 0.25 to 0.10.
Bernal, et al. Lancet. 2002 Feb 16;359(9306)

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 The Antidote

• N-Acetylcysteine (NAC)
– Protects the liver
– Increase synthesis of glutathione
– Provides sulfation for APAP
– Bind and detoxify NAPQI
– Decreases chance of cerebral edema
– Hepatic microcirculation effects
– Free radical scavenger

NAC

• Acute Overdose
– Administer within 8 hours
– 140 mg/kg oral loading plus 70 mg/kg maintenance q
4 hr for 17 doses
– Dilute to 5% solution and mix with juice or soda
• Repeat if emesis within 1 hour
– Antiemetics

NAC

• The Abbreviated NAC Treatment

– Oral: 24 hours of treatment
• If APAP <2 and transaminases <2-3 times normal,
D/C treatment
• Exclude pregnancy, initial APAP levels >300
– Oral: 36 hours
• D/C treatment if above criteria met

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 NAC

– IV NAC – Recently APPROVED in US

– If Oral/Inhaled Prep is used:
• Must show adequate attempt at antiemetic Rx
• 20-hr protocol
– 150 mg/kg over 30 minutes, 50 mg/kg over 4 hrs,
100 mg/kg over 16 hours (may be given as
boluses q2-4 h )
– Reactions
• 48-Hr Protocol
– 140 mg/kg over 30-45 minutes, 70 mg/kg q4 hr

Acetadote

• 24 hours of Acetadote for a 70 kg patient

costs $430 wholesale, compared with $18
for generic NAC
• Pharmacy legal issues

NAC
• If hepatotoxicity develops then standard
course of treatment is recommended.
• No magic to 20 hours, 24 hours or 72 hours
– Late presenters and FHF patients may be treated
for > 72 hours
• Relatively free of side effects when given
orally
• Emesis may occur
– extremely offensive sulfur odor
– Ondansetron or metoclopramide

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 Treatment
• Hemodialysis
– Limited benefit
– Damage occurs quickly
• Hemoperfusion
– No benefit
• Peritoneal dialysis
– No benefit
• MARS – Molecular Adsorbant Recirculating
System (liver dialysis)
– Limited use in toxin-induced HF

Criteria for liver transplant

• Metabolic acidosis (pH<7.31) on day 2+

after adequate fluid resuscitation
• Combination of
– PT >100 secs (INR >6.5)
– serum creatinine >3.9 mg/l, and
– Grade III to IV encephalopathy.

Points to remember

• APAP is present in many poly drug overdoses

• No symptoms may be present…screen
• 150 mcg/ml at 4 hours is a “treat” level
• NAC loading dose is 140 mg/kg
• NAC maintenance doses are 70 mg/kg
• Once NAC is started, DO NOT DC (or Consult
Toxicology or PC
• Metoclopramide 0.1-1.0 mg/kg is very effective in
controlling nausea/vomiting associated with APAP
toxicity

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 Methamphetamine

Glass
Crystal
Ice
Crank
Speed

Meth Use in the USA

• An estimated 12.3 million Americans

(5% of the adult population) have used
meth at least once
• An estimated 600,000 people are weekly
users.
• Today about half the meth in the United
States is made in Mexico, smuggled
across the border and ferried around
the country in cars with secret
BMJ 2005;331:476 (3 September)
compartments.

The Meth Problem

• Of 500 law enforcement agencies surveyed

in 45 states
– 58% cited meth as their biggest drug problem
– 19 % cited Cocaine
– 17% labeled marijuana
– 3% rated heroin
– Areas with the biggest Meth Problem
• West Coast and Upper Midwest.
• Northeast, only 4 % of counties rated meth as their
biggest drug problem
– 46% cited heroin as the top problem
– 21 percent cited cocaine.

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 Meth MN trends -Adolescent
• More prevalent among a younger
population in 2004.
– 18-34 year-old
• Growing abuse High School Students
• Latest scourge bedeviling Native
Americans - Second only to marijuana

Organ Toxicity from Meth

• Central nervous system toxicity

• Cardiovascular toxicity

• Pulmonary toxicity
• Renal toxicity
• Hepatic toxicity
• Maternal-Fetal Effects

Cardiovascular Toxicity from Meth

• Arrhythmic sudden death

– Ventricular tachycardia/fib
• Myocardial infarction
• Myocardial ischemia
• Cardiomyopathy
• Myocardial rupture
• Fibrosis
• Hypertension
• Tachycardia

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 Cardiovascular Effects and Treatment

• Hypertensive Episode
– Generally transient and may not require Rx unless severe.
– IV Benzos often effective in treating hypertension
– Nitroprusside if unresponsive to benzodiazepines
– Phentolamine if refractory

• Tachyarrhythmia
– Generally does require Rx if hemodynamic compromise develops.
– Benzodiazepines
– If not working, may try Esmolol.
• Reminder: may be hazardous in patients with bronchospastic disease
(asthmatics, COPD) or myocardial depression.

Pulmonary Toxicity from Meth

• Increased breathing rate

• Lungs are vulnerable to IV and
inhaled illicit drugs
• Acute pulmonary congestion /
Pulmonary edema
• Increase in pulmonary infections
– pneumonia
• Barotrauma
• Pulmonary embolism of particulate
matter
• Chronic obstructive lung disease

Renal / Hepatic Toxicity from Meth

• Renal failure
– Becoming more frequent
– May be strong vascular
component
– Often chronic and irreversible
• Hepatic failure
– Liver failure
– Hepatitis B, C

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 Skin Toxicity from Meth Abuse

• Formication
• Skin abscesses

Meth Mouth

• Gum disease, broken and

cracked jaw, tooth decay
• Contributors to tooth
decay/enamel erosion
– Absence of saliva
– Acidic nature of Meth (smoked)
– Poor nutrition
• Eat nothing or eat junk food –
awake for days
• Drink lots of high-caffeine,
high-sugar beverages
– Bruxism
– Lack of dental hygeine

Acute Psychological Effects

• Increases • Decreases
– Confidence – Boredom
– Alertness – Loneliness
– Mood – Timidity
– Sex drive
– Energy
– Talkativeness

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 Meth Chronic Psychological Effects

- Confusion - Irritability
- Concentration - Paranoia
- Hallucinations - Panic reactions
- Fatigue - Depression
- Memory loss - Anger
- Insomnia - Psychosis

Acute Meth Psychosis

• Extreme Paranoid Ideation

• Well Formed Delusions
• Hypersensitivity to Environmental Stimuli
• Stereotyped Behavior “Tweaking”
– Panic, Extreme Fearfulness
– High Potential for Violence

Treatment of Meth Psychosis

• Typical ER Protocol for Meth Psychosis

(HAC cocktail or B-52) – can be repeated
on the ward
– Haloperidol - 5mg
– Ativan 2 mg
– Cogentin - 1 mg or Benadryl 25-50 mg
– Quiet, Dimly Lit Room
– Restraints

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 Meth “Withdrawal”

- Depression - Paranoia
- Fatigue - Cognitive Impairment
- Anxiety - Agitation
- Anergia - Confusion

• Duration: 2 Days - 2 Weeks

Treatment of Meth “Withdrawal”

• Hospitalization/Residential Supervision if:

– Danger to Self or Others, or, so
Cognitively Impaired as to be Incapable of
Safely Traveling to and from Clinic.
– Otherwise Intensive Outpatient Treatment

Methamphetamine Withdrawal

• Relatively safe, not directly life-threatening.

• Severe depression and suicide attempts
• Anxiety, lethargy, apathy, abdominal cramps,
gastroenteritis, headache, diaphoresis, and dyspnea
may result.
• Symptoms peak 2 to 3 days after abrupt
discontinuation.

– Tapering of the drug dose is not necessary

during withdrawal.

• Withdrawal may coincide with development of

psychosis. It may take as long as 8 weeks for
suppressed REM (rapid eye movement) sleep to return
to normal

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 Summary

• Highly addictive – “poor man’s cocaine”

• Affects nearly every organ system in the body
• May lead to death or chronic medical problems
• [Easily manufactured and concealed]
• Dangerous lab chemical
• Increasing use by surburbia (Supermoms)

Questions???

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