Toxicology

Toxicology Dalhousie Critical Care Lecture Series

Objectives
Discuss findings of sympathomimetic, anti-cholinergic, cholinergic and narcotic toxidromes
Discuss the essential investigations of a potential drug overdose.
Demonstrate the ability to calculate an anion gap, serum osmolality and osmolar gap. What is the significance of an elevated AG or osmolar gap?
Discuss the presentation and management of common overdoses including:
Toxic Alcohols
ASA
Tylenol
TCAs
Neuroleptic Malignant Syndrome and Serotonin syndrome
Which overdoses require nephrology consults for consideration of dialysis?

Overdose
Requires high index of suspicion
Non-specific symptoms
Tylenol O/D
Presents as other issues
AMI in setting of CO overdose

Overdose
Suspect in the setting of:
Altered LOC/coma
Trauma
Life threatening arrythmia
Unexpected clinical findings

Diagnosis - History
May be unreliable or incomplete
Things to consider
History of depression/prior overdose
Time of ingestion/last seen well
Pill bottles present at scene
Time of last refill
Medications of family memebers

Diagnosis - PE
Vitals
HR, BP, RR, Temp, O2 sat
Neuro
LOC, pupils
CVS
Arrythmias
Skin

Increased Osmolal Gap
Osmolarity = 2x[Na] + glc + urea
Osmolar gap = measured – calculated
normal = between 270 -290
Normal osmolar gap <10

Toxicology Critical Care Lecture Series

What is a toxidrome?
A collection of symptoms and signs that consistently occur after ingestion of a particular toxin or drug class or agent
Often identified with a basic history & physical examination
Rapid identification of the toxidrome saves time in evaluating and managing a poisoned patient

Anticholinergic
Mydriasis
Blurred vision
Fever
Flushed dry skin
Psycosis, coma
Seizures
Ileus
Urinary retention
Hypertension
Tachycardia
Eg. TCA, antihistamines, atropine, benztropine
Blind as a bat, hot as a hare, dry as a bone, red as a beet, mad as a hatter

Anticholinergic Toxidrome - Management
ABC, supportive care, consider GI decontamination
Benzodiazepines
Physostigmine – specific antidote.
May be used if
Severe agitation or psychosis unresponsive to other therapy
Sever peripheral and central anticholinergic features
NO history of seizures
Normal ECG especially QRS duration
NO co-ingestion of drugs altering intraventricular conduction
E.g. TCA’s
Cardio-respiratory monitoring and resus facilities in place

Cholinergic
Eg. organophosphates, nerve agents
DUMBELS
D-diaphoresis, diarrhea, decreased BP
U-urination
M-miosis
B-bronchorrhea, bronchospasm, brady
E-emesis, excitiation of skeletal muscle
L-lacrimation
S-salivation, seizures

Cholinergic Toxidrome - Management
ABC, supportive care
Decontamination procedures
Atropine
ACh antagonist
Antimuscarinic
Pralidoxime (2-PAM)
Regenerates Acetylcholinesterase
Removes phosphoryl group from enzyme
Must be given early before phosphorylation becomes irreversible (“aging”)

Sympathomimetic (adrenergic) toxidrome
Increased temp
Tachycardia
Hypertension
Dilated pupils
CNS excitiation
Seizures
Nausea/vomiting
Diaphoresis
Cocaine, MDMA (“ecstasy”), Amphetamines, Phencyclidine (PCP), Theophylline, Decongestants ( Ephedrine Pseudoephedrine Phenylpropanolamine), Caffeine (very large doses)

Adrenergic Toxidrome - Management
ABC, supportive care, consider GI decontamination
Investigations
Screen for other drugs & treatable toxins (eg, acetaminophen, salicylate)
Electrolytes (esp. sodium), urea, creatinine, blood sugar, anion gap.
CK levels to check for rhabdomyolysis
Consider cranial CT
EKG & Cardiac biomarkers (eg, CPK-MB, troponin)
Sedation – treats majority of effects
Benzodiazepines
Temperature control
Treat hypertension unresponsive to benzodiazepines
Nitroprusside
Nitroglycerine
Labetalol (avoid isolated  -blockade in mixed adrenergic agonist toxicity)

Narcotic
Hypothermia
Bradycardia
Hypotension
Respiratory depression
Constricted pupils
CNS depression

Opioid-Narcotic Toxidrome - Management
GI decontamination for oral ingestion
Naloxone
Specific antagonist
High doses may be needed for methadone & pentazocine
Short half-life compared to opioids
Infusion may be required
Pulmonary edema and seizures have been reported

Serotoninergic Toxidrome Eg. SSRI’s, MAOI’s, ecstasy Diarrhoea, trismus, myoclonus, tremor, rhabdo Other Normal/decreased (SIADH possible) Urination Increased Bowel sounds Increased Reflexes Normal/flushed/sweating Skin Normal Mucous membranes Normal/unreactive Pupils Agitated/irritable Mental status Physical examination Normal/decreased Blood pressure Increased Temperature Increased Heart rate Normal/increased Respiratory rate Vital Signs

Serotoninergic Toxidrome - Features
Mental status changes
Confusion (51%)
Agitation (34%)
Hypomania (21%)
Anxiety (15%)
Coma (29%)
Cardiovascular
Sinus tachycardia (36%)
Hypertension (35%)
Hypotension (15%)
Gastrointestinal
Nausea (23%)
Diarrhea (8%)
Abdominal pain (4%)
Salivation (2%)
Motor Abnormalities
Myoclonus (58%)
Hyperreflexia (52%)
Muscle rigidity (51%)
Restlessness (48%)
Tremor (43%)
Ataxia/incoordination (40%)
Shivering (26%)
Nystagmus (15%)
Seizures (12%)
Other
Diaphoresis (45%)
Unreactive pupils (20%)
Tachypnea (26%)
Hyperpyrexia (45%)
Sternbach H. The serotonin syndrome. Am J Psychiatry 1991;148:705-13 Mills KC. Serotonin syndrome. Am Fam Physician 1995;52:1475-82

Serotoninergic Toxidrome - Management
Stop intake of causative agent
Absorption
Gastric lavage in early acute ingestion (1hr)
Activated charcoal
Benzodiazepines
Others
Chlorpromazine
Diphenhydramine
? Serotonin antagonists e.g. cyproheptadine

Diagnosis - Investigation
Essential labs
CBC, lytes, BUN, Cr, BS
Ptt, INR, LFTs
ABG (calculate AG)
Serum osmo (calculate osmo gap)
ASA
Acetaminophen
Other
Drug levels
Urine

General Management
ABC
Consider thiamine, dextrose, naloxone if depressed GCS
Prevent further absorption
Decontaminate eyes, clothes, skin, hair if appropriate
Activated charcoal + sorbitol (if < 1 hour from ingestion)
Gastric lavage (if < 1 hour from ingestion and life-threatening drug or dose)
In general not used
Whole bowel irrigation for “body packing” illicit drugs
In general not used
Enhance elimination
Forced diuresis and urinary alkalinisation (salicylates and barbiturates)
Multiple dose activated charcoal 0.5 g/kg every 2-4 hours
binds toxin and interrupts enterohepatic recirculation
mainly life-threatening ingestion of carbamazepine, dapsone, phenobarbital, quinine or theophylline
Extracorporeal removal (for active metabolites, delayed toxicity or poor organ clearance)
Haemodialysis - low MW (<500 d), soluble, low Vd (< 1L/kg) e.g. methanol, ethylene glycol, salicylates, lithium
Haemoperfusion - e.g theophylline, phenobarbital, phenytoin, carbamazepine, paraquat
Haemofiltration for large Vd and extensive tissue bound toxins but removes virtually all drugs
Antidotes

Activated Charcoal
Universal absorbent
Produced by the controlled burning of various organic products at >600C, washed with inorganic acids and dried
Small particle with highly developed internal pore system
surface area of 50 gm AC = 10 football fields
Absorbs substances in varying degrees
If comes into contact with toxin in GI track prior to absorption, can bind and decrease systemic toxicity

General Treatment
Activated charcoal
Inert, non-toxic, non-specific adsorption
Risk of aspiration
Dose 1g/kg patients weight
Ineffective for alcohols or heavy metals
? Multi-dose charcoal
may cause GI dialysis for some drugs
Check with poison control!!!

Activated Charcoal
Binds most compounds; easier to remember what it doesn’t

Activated Charcoal
Big question in the use of AC is when to use it
Effectiveness is time dependent – the longer the time from ingestion, the less effective AC is
Toxin already absorbed or past pyloris
Effectiveness is lost between 1 and 2 hours

AC: problem
Patients with toxin ingestions will present to the ED >3 hours after poisoning
“should not be administered routinely”

Drugs and Extracorporeal Removal
Haemodialysis
M ethanol
Ethylene glycol
Salicylates
Lithium
Haemofiltration
Procainamide
Methotrexate
Haemoperfusion (Charcoal)
Theophylline
Carbamazepine
Amanita toxin (if early)
Aminoglycosides
Paraquat
Phenobarbital
Phenytoin
Sotalol

Urinary Alkalinisation
Fluoride
Isoniazid
Salicylic acid
Barbiturates
Methotrexate

Specific Ingestions

Acetaminophen
Peak plasma <1hr post ingestion
Metabolized in liver d/t glucuronidation
Toxic metabolite NAPQ1
NAPQ1 binds to hepatocytes and causes necrosis
Detoxified by glutathione & eliminated by kidneys
Toxic threshold adults - 7.5-10g

Acetaminophen
Phase I (<24 hrs):
Anorexia, malaise, N/V, diaphoresis
Phase II (24-48 hr):
RUQ pain,  LFTs, sx of phase I resolve
Phase III (48-96 hr)
Severe liver failure
Encephalopathy, coagulopathy,  BS
Pancreatitis
ARF
Phase IV (>4 days)
Death/full recovery/transplant

Acetaminophen
Limitations:
Requires time of ingestion
Very early or late ingestions
Chronic ingestions
Extended release preparations
At risk populations
ETOH abuse

Acetaminophen
Treatment
Activated charcoal
Given w/I 4-6 hr
Reduced absorption by 50-90%
NAC
Replete glutathione
combines directly with NAPQ1
Antioxident properties
vasodilatory properties
Treat:
Based on nomogram
Level >5 w/o ingestion time known
Evidence of hepatotoxicity or level unknown

Alcohols
Ethylene glycol, methanol, isopropanol
Lab:
Anion gap MA, elevated osmolar gap
Exceptions:
Normal AG
Not yet formed metabolites
Isopropanol ingestion
Sx may be delayed if co-ingested with ethanol

Ethylene Glycol
Oxalic acid  Ca oxalate  ARF
Hypocalcemia
Myocardial dysfunction (2 0  Ca)
100ml can be lethal
Ethylene glycol ETOH dehydrogenase Oxalic acid

Ethylene Glycol
Phase I (30min-12hr)
Inebriation, ataxia, seizures, AG-MA, OG, hypocalcemia, crystalluria, cerebral edema
Phase II (12-24hr)
Myocardial dysfunction, CHF
Phase III (2-3 days)
ARF

Methanol
150-240ml is lethal
Presents with:
Headache, inebriation
Dizziness, ataxia, confusion
Vision loss
Pancreatitis
Methanol ETOH dehydrogenase Formic Acid

Treatment
Inhibit alcohol dehydrogenase
Ethanol
Fomepizole
Removal of alcohol & it’s metabolites
Hemodialysis
Levels >50mg/dL
Significant MA
Evidence of end-organ damage

Isopropanol
Ketonuria
Absent AG or MA
Hemorrhagic gastritis
Generally just supportive care
Hemodialysis if:
Lethal ingestion (150-240ml)
Refractory shock/prolonged coma
Isopropanol ETOH dehydrogenasez Acetone

Salicylate Intoxication
Adult lethal dose - 10-30g
Sx include:
Tinnitus
Fever
Vertigo
Nausea/vomiting/diarrhea
AG MA & resp alkalosis
Altered LOC/coma
ARDS

Salicylate Treatment
Level check q2h until 2 values decreased from peak
Activated charcoal
?multiple dosing
Supplemental glucose
Alkalinization of serum & urine
Resp alkalosis not C/I to HCO3
Urine pH = 8
Dialysis

Salicylate Treatment
Hemodialysis Indications
Altered LOC
Pulmonary or cerebral edema
Renal failure
Fluid overload that prevents HCO3
Plasma level >7.2
Deterioration despite therapy

TCA Intoxication
Rapidly absorbed - peak dose 2-8h
T1/2 - 24-72hr
Enterohepatic recirculation
Delayed absorption d/t anticholinergic effects

TCA - Clinical Presentation
Cardiac
Inhibits fast Na channels - slowed depolarization
QRS prolongation
Reentry arrhythmias - V-tach, torsade
Hypotension, Decreased CO
CNS
Delerium, seizures, coma
Anticholinergic
 temp, flushed, dilated pupils, ilieus, urinary retention, sinus tach

TCA - Treatment
ABCs
Activated charcoal - ?multidose
Gastric decontamination
NaHCO3 - most effective therapy!
D/t raised pH and serum [Na]
Recommend for QRS >100msec
Push amps for arrhythmias
Do not give dilantin for seizures!
No role for dialysis!!!!

B-Blocker Overdose
Most are symptomatic within 4 hours of ingestion
Asymptomatic pts with a normal EKG after 6hrs generally don’t need ICU
SX:
Hypotension
Bradycardia/A-V block
CHF
Bronchospasm
Decreased LOC, seizures, coma

 -blocker Treatment
ABCs
Activated charcoal
Temporary pacing/vasopressors prn
Glucagon
+ve inotropic and chronotropic effect d/t increased AMP and intracell Ca
5-10mg bolus followed by 1-10mg/h gtt
High dose insulin/glucose drip
**Atenolol is dialyzable**

Ca channel Blocker OD
Selectively inhibit the movement of Ca through cardiac and vascular smooth mm
Present with
Hypotension
Bradycardia/conduction delays
Confusion/ altered LOC

Ca Channel Treatment
ACBs
Activated charcoal
?Gastric lavage
Ca gluconate
Glucagon
Insulin/glucose infusion

CO poisoning
Seen with:
smoke inhalation
SA with car exhaust
poorly vented wood or gas stoves
CO binds Hg 240X> then O 2
Causes tissue hypoxia
Serum CO up to 5-10% in smokers or large cities

CO poisoning
Presentation
5-10% CO
H/A, mild dyspnea
10-30%
H/A, dizziness, weakness, N/V, dyspnea, cardiac ischemia
>50%
Coma, seizures, cardiovascular collapse, death
10-30% survivors have delayed neuro deficits

CO poisoning - Diagnosis
High index of suspicion
Serum CO level
Measured by co-oximeter of an ABG
Pulse oximetry can’t distinguish carboxyHg from oxyHg
PO2 on ABG may be normal since it represents dissolved oxygen
CT head may specifically demonstrate globus pallidus abnormalities

CO Poisoning - Treatment
ABCs
100% FiO2
T1/2 R/A - 5-6hr
T1/2 100% - 40-90min
Hyperbaric O2
T1/2 - 15-30 min
If accessible, suggested for:
CO>25%
Loss of consciousness, EKG changes, chest pain
pH<7.1

Antidotes Naloxone Opioids Atropine, pralidoxime Organophosphates Methylene blue Methaemoglobinaemia Ethanol/fomepizole, folate Methanol Pyridoxine Isoniazid Deferoxamine Iron Dextrose, glucagon, ocreotide Hypoglycaemic agents Dimercaprol, EDTA, penicillamine Arsenic, copper, gold, lead, mercury Ethanol/fomepizole, thiamine, pyridoxine Ethylene Glycol Digoxin-specific antibodies Digoxin Amyl nitrite/sodium nitrite/thiosulphate ( Taylor Cyanide Antidote Package) hydroxycobalamin Cyanide Oxygen Carbon Monoxide Flumazenil Benzodiazepines Atropine Anticholinesterases Physostigmine Anticholinergics N-acetylcysteine Acetaminophen Antidote Toxin/effect

Summary
Familiarity with toxidromes will allow you to assess and manage unconscious overdose/poisoning victims
Supportive care and decontamination is the mainstay of most treatments
Calculation of the anion gap and osmolar gap will allow you to identify and treat toxic alcohol ingestions prior to end organ damage
In known overdoses and poisonings early involvement of a toxicologist/poison control is very helpful to direct specific antidote therapies

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Toxicology

by Andrew Ferguson on Mar 04, 2008

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