TOXICOLOGY

Editor: Alice Kennedy, MD
Faculty Editors: Rebecca E. Bruccoleri, MD and Saralyn R. Williams, MD

Management of Specific Overdoses

Author: Lauren Chan, MD

There are 5 main classes of drugs/toxins that induce bradycardia and hypotension (ABCDO): - Alpha-2 agonist - Beta-blockers - Calcium channel blockers - Digoxin and cardiac glycosides - Organophosphates (Acetylcholinesterase inhibitors)

Alpha-2 Agonists

Background

Examples: clonidine, dexmedetomidine, guanfacine, methyldopa, tizanidine
Mechanism: centrally acting inhibition of norepinephrine release → ↓ noradrenergic activity

Evaluation

Physical Exam: early/transient HTN, attenuated sympathetic response (decreased HR, BP), opioid toxidrome (pinpoint pupils, CNS depression, respiratory depression)
Laboratory abnormalities: None associated with overdose
EKG: sinus bradycardia

Management

IVF and high dose naloxone 10mg IVP followed by 5 mg/hr if there is no response
Naloxone may reverse the CNS and respiratory depression as well as hypotension
Vasopressors such as norepinephrine/epinephrine are used if naloxone does not work

Beta Blockers (BB's)

Background

Mechanism: competitively block catecholamines at beta-adrenergic receptors → ↓ inotropy and chronotropy; impaired gluconeogenesis and glycogenolysis
Lipophilic BB's (propranolol, metoprolol): cross the blood brain barrier → CNS depression
Membrane stabilizing BB's (propranolol): QRS prolongation, dysrhythmias, and seizures
Sotalol: potassium channel blocking properties → QTc prolongation and dysrhythmias

Evaluation

Physical Exam: CNS depression, seizures, myocardial depression, respiratory depression
Laboratory abnormalities: Hypoglycemia or normoglycemia
ECG: Sinus bradycardia, AV block (low grade), QRS widening (propranolol), QTc prolongation (sotalol)

Management

IVF, calcium gluconate 3 g
Glucagon 10 mg over 10 min and infusion 3-5 mg/hr (need infusion since half-life is 6 min)
Vomiting can occur if administered too fast
Epinephrine or norepinephrine should be first line vasopressors
Atropine 0.5-1mg q3-5min
Intralipid infusion if refractory HoTN or patient codes from a lipophilic BB (e.g. propranolol)
Intralipid (Lipid Emulsion) 20% infusions: 1.5 cc/kg bolus followed by 0.25 cc/kg/min for 60 minutes (for 70 kg adult: 1 liter over 1 hour) for refractory hypotension or if patient codes), max dose is 10 ml/kg or 1200 ml whichever is greater however, there is limited guidance on a max dose - if using lipid emulsion therapy, please call Toxicology or Poison Control immediately
BB induced arrhythmias: sodium bicarbonate (adjunct QRS widening) and Mg for QTc prolongation induced Torsades de pointes
Significant sotalol toxicity: hemodialysis

Calcium Channel Blockers (CCB's)

Background

Two categories: Dihydropyridines (DHP) and non-dihydropyridines (Non-DHP)
DHP (amlodipine, nifedipine): peripheral > central channels, selectivity is lost in overdose
Non-DHP (diltiazem, verapamil): primarily cardiac calcium channels

Mechanism: - DHP: arterial vasodilation → reflex tachycardia - Non-DHP: peripheral vasodilation, decreased inotropy, bradycardia; calcium mediated insulin inhibition in the pancreas → hyperglycemia

Evaluation

Physical Exam: Markedly preserved mental status until patient is about to code
Labs: hyperglycemia (elevated serum glucose concentrations are associated with severe overdose and sequelae)
EKG: bradyarrhythmia, high-degree heart block (3rd degree)

Management

IVF, vasopressors if needed
Bradycardia: atropine 0.5-1mg q3-5min (not effective for second- or third-degree block), calcium gluconate 3g, and glucagon 10 mg over 10 min followed by infusion 3-5 mg/h

Hypotension + Bradycardia

High dose insulin/euglycemic therapy (HIE) - High-dose insulin 0.5-1 unit/kg bolus followed by 0.5-1 unit/kg/hour infusion titrated to up to 10 units/kg/hour. Call Toxicology immediately if exceeding 3 units/kg/hour - Give with dextrose. Titrate insulin like a pressor. Blood pressure may take up to 20 minutes to change - May increase contractility through increasing the cardiac utilization of glucose. Not likely to help with vasodilation or bradycardia

Vasopressors (norepinephrine or epinephrine): may consider phenylephrine for DHP induced vasoplegic shock with tachycardia

Intralipid should be used in code/refractory hypotensive situations for lipophilic CCB's (verapamil, amlodipine, diltiazem) - 20% infusions: 1.5 cc/kg bolus followed by 0.25 cc/kg/min for 60 minutes (for 70 kg adult: 1 liter over 1 hour) for refractory hypotension or if patient codes), max dose is 10 ml/kg or 1200 ml whichever is greater however, there is limited guidance on a max dose - if using lipid emulsion therapy, please call Toxicology or Poison Control immediately

Methylene blue for refractory distributive shock can be considered, but consult Toxicology prior to using

Digoxin and Cardiac Glycosides

Background

Examples: Digoxin, yellow oleander, lanatoside C, foxglove, lily of the valley, bufo toads
Mechanism: blockade of Na/K ATPase → increased intracellular calcium → increased contractility and may delay after depolarizations/shorten repolarization of the atria and ventricles → trigger arrhythmias; increased vagal tone

Evaluation

Physical Exam: lethargy, nausea, vomiting, reported yellow halos in visual fields (chronic)
Labs: hyperkalemia (marker of acute toxicity but not the cause; correlates with mortality)
EKG: any abnormality (though Afib RVR is unlikely, more likely to have a regular pulse due to 3rd degree block in the setting of Afib), biventricular tachycardia is classic but rarely seen

Management

Digoxin Fab Fragments

Number of vials = [(serum level times the weight of the patient)/100] rounded up. Empiric treatment 10 vials.
In acute on chronic toxicity or chronic toxicity, please contact the Poison Center or Medical Toxicology for guidance as less vials may be recommended to try to avoid adverse events from worsening heart failure or atrial fibrillation
Unclear dosing for natural toxins (often empirically 10 vials for an adult)

Indications: hemodynamic instability, significant unstable arrhythmia, end organ damage secondary to hypoperfusion (renal failure), or potassium ≥5.0 mEq/L

It can also be indicated for patients with high post distribution digoxin levels even if they are asymptomatic. However, please contact Poison Control/Toxicology for guidance.
Atropine 0.5-1mg q3-5min: severe symptomatic bradycardia when digoxin fab fragments are not available
Given the sensitivity of the myocardium with digoxin, pacers can trigger significant dysrhythmias and only recommended if no access to digoxin fab fragments or fab fragment failure

Acetylcholinesterase Inhibitors

Background

Examples: Organophosphates (e.g. insecticides), carbamates, physostigmine, rivastigmine, donepezil
Mechanism: Inhibition of the breakdown of acetylcholine → ↑ acetylcholine stimulation of muscarinic and nicotinic receptors

Evaluation

Physical Exam

Muscarinic (DUMBBELS): Diarrhea/Diaphoresis, Urination, Miosis, Bronchorrhea/Bronchospasm, Bradycardia, Miosis, Emesis, Lacrimation, Salivation

Nicotinic: fasciculations, muscle weakness, and/or muscle paralysis

Intermediate syndrome: neurologic syndrome after resolution of cholinergic excess, decreased DTR, proximal muscle weakness, respiratory insufficiency, neck flexion weakness, CN abnormalities

Laboratory abnormalities: Standard lab tests are not helpful
EKG: sinus bradycardia, QTc prolongation

Management

Atropine: 1-2 mg (mild-moderate symptoms) vs 3-5mg (severe) IV repeated every 2-20 minutes or 1mg followed by doubling doses every 5 minutes until bronchorrhea is no longer present followed by an infusion 10-20% of the loading dose per hour (max 2 mg/hour)
Pralidoxime: 30mg/kg (max 2g) loading dose followed by 8-10 mg/kg/hr (max 650mg/hr); WHO dosing is 2000 mg bolus followed by 500 mg/hr infusion. Consult Poison Control/Medical Toxicology for acetylcholinesterase inhibitor use.
Seizures: Benzodiazepines
Secretions: Titrate atropine to dry secretions (can require large amounts i.e. 50 mg)
Bronchorrhea: Atropine as above

Alcohol

Background

One standard drink = 12oz regular beer = 5oz wine = 1.5oz 80% distilled spirit
Absorption primarily in duodenum/small intestine (80%) with 80-90% of absorption in <60 min in ideal conditions (i.e. empty stomach)
Mechanism: Metabolism via alcohol dehydrogenase. Withdrawal due to CNS overactivity from decreased inhibitory tone (GABA) and unregulated excess excitation (glutamate binding to NMDA, dopamine)

Evaluation

Intoxication: slurred speech, disinhibition, incoordination, unsteady gait, memory impairment, nystagmus, stupor, coma, hypotension, tachycardia
Wernicke encephalopathy (WE): encephalopathy, oculomotor dysfunction, gait ataxia, HA, n/v, hallucinations (12-24 hr after last drink), seizures (12-48 hr), DT (72-96 hr)
Labs: EtOH, Peth, UDS, hypoglycemia, hyperlactatemia, hypoK, hypoMg, hypoCa, hypophos

Management

Intoxication: supportive care
Withdrawal: thiamine, folate, multivitamin, IV fluid for intravascular depletion

Thiamine

Administer before glucose containing fluids - WE prevention: 100mg IV QD x3d - WE treatment (high risk): 500mg IV TID x3d followed by 250mg QD x3d, then 100mg QD

Psychomotor Agitation

Benzodiazepines (long-acting preferred) including diazepam, lorazepam, and chlordiazepoxide. Lorazepam for acute alcoholic hepatitis/liver dysfunction. - Diazepam: 5-10mg IV every 5-10min until appropriate sedation (severe) or per CIWA - Lorazepam: 2-4mg IV every 15-20min or per CIWA

Seizures

CIWA scoring and benzodiazepines. If history of DTs, consider phenobarbital taper. If status, consider escalation to Propofol

Opioids

Background

Examples: Natural opiates (morphine, codeine), semi-synthetic (hydrocodone, hydromorphone, oxycodone, oxymorphone, heroin, buprenorphine), synthetic (fentanyl, meperidine, tramadol)
Mechanism: Multiple receptors with wide range of clinical effects including sedation, analgesia, respiratory depression, GI dysmotility, bradycardia, miosis, anxiolysis

Evaluation

Intoxication: AMS, miosis, hypoventilation, decreased bowel sounds, seizures, coma
Withdrawal: mydriasis, yawning, piloerection, diaphoresis, rhinorrhea, increased BS
Laboratory abnormalities: None specific to opioid toxicity
EKG: QT prolongation (loperamide, methadone, very large doses of oxycodone), QRS widening (loperamide)

Management

Intoxication

Supplemental oxygenation/ventilation support, ACLS
Naloxone: IV preferable, but if no access, apneic, or critical condition, can use intranasal or IM. Switch to IV when able
IV: 0.4-2mg q2-3min. Consider initial lower dose (0.04-0.2mg) in patients with opioid dependence to avoid withdrawal or if concerned for concomitant stimulant overdose.
- If apneic, use higher doses
- If mildly bradypneic in a known chronic user, can try smaller doses repeated every 2 minutes until patient is breathing at a normal rate while using bag mask ventilation
Intranasal: 4 or 8mg as single dose in one nostril. Repeat q2-3min, alternating nostrils
Consider alternative etiologies of respiratory depression if no response after 10mg

Withdrawal

COWs scoring and protocol
Symptom control: ondansetron (nausea, vomiting), loperamide (diarrhea), hydroxyzine (anxiety), methocarbamol (cramps), dicyclomine (abdominal cramps)
Acute, severe: methadone or buprenorphine, do NOT use for iatrogenic withdrawal (i.e following naloxone administration)
Buprenorphine 4-8mg sublingual. If symptoms persist after 60min, can give subsequent dose. Maximum 24mg in 24hr. Usually need to discuss with Psych to give.
Iatrogenic or patients trying to overcome addiction: clonidine 0.1-0.3mg q1h until symptom resolution (maximum 0.8mg/24hr) followed by taper

Sodium Channel Blockers

Background

Examples: Class I antiarrhythmics, tricyclic antidepressants (amitriptyline, imipramine) anticonvulsants (carbamazepine, lamotrigine), cocaine, insecticides
Mechanism: decreases depolarization of non-nodal cardiac myocytes
Consider other concomitant effects (e.g. TCA with anticholinergic and K channel blockade)

Evaluation

Pure Na channel blockade: classically bradycardia but sodium channel blocking drugs often have anticholinergic properties resulting in tachycardia
TCAs: typically tachycardia, cardiogenic shock, hypotension, AMS, seizures, respiratory depression, anticholinergic symptoms
Laboratory abnormalities: No specific abnormalities
EKG: QRS widening, QTc prolongation, ventricular dysrhythmia, new right axis deviation

Management

Sodium bicarbonate (mainstay): Initial 1-2mEq/kg bolus q5min until pH is 7.45 to 7.55 (QRS will hopefully narrow to < 120 msec) → infusion 150mEq in 1L D5W at 150ml/h (contact poison control or toxicology for guidance on discontinuation)
Indications: hypotension, QTC >100ms, QT prolongation
Goal pH: 7.5-7.55
Contact Poison Control or Toxicology for discontinuation guidance
Magnesium if arrhythmias refractory to sodium bicarb
IVF and vasopressor support as needed
TCA toxicity: consider lipid emulsion (discuss with Poison Control prior)
Intralipid infusions: 20% infusions: 1.5 cc/kg bolus followed by 0.25 cc/kg/min for 60 minutes (for 70 kg adult: 1 liter over 1 hour) for refractory hypotension or if patient codes), max dose is 10 ml/kg or 1200 ml whichever is greater however, there is limited guidance on a max dose.

Drug-Induced QTc Prolongation

Authors: Mohamed Salih, MD and Matthew Kern, MD

Background

QT is measured from the start of the Q-wave to the end of the T-wave (use the lead with the longest measurement)
The time of ventricular depolarization + repolarization
Prolongation is defined as QT > 440ms in males or >460ms in females
QTc is the corrected estimate of QT assuming a rate of 60 bpm since QT decreases with tachycardia and increases with bradycardia
QTcF (Fridericia) + QTcB (Bazett) are commonly included on ECG report (other formulas are available on MDCalc). QTcB often overestimates QT but is most accurate for bradycardia; QTcF is more accurate for tachycardia. "B for brady, F for fast".
Ventricular pacing and/or bundle branch block artificially prolongs QT
One quick correction is QT - (QRS - 120), then plug in the result to the correction formula
Can also use Mayo Clinic QTc Calculator to correct in cases of wide QRS or Afib (simply google this)
QTc > 500 ms increases risk of Torsades de pointes (TdP), a life-threatening wide complex VT (see "Wide Complex Tachycardias" in the Cardiology section for evaluation and management of TdP)

Two Main Causes of Prolonged QT

Congenital/Hereditary (long QT syndromes/channelopathies)
Acquired (Drug induced, anorexia, bradycardia, MI/BBB, hypothermia, hypothyroidism, hypokalemia, hypomagnesemia, hypocalcemia, increased ICP)

Think of ABCDE for Common Medication Offenders

A: Anti"A"rrythmics (class IA (procainamide, disopyramide) and class III (amiodarone, sotalol, dofetilide))
Less clinical concern with amiodarone since its multiple mechanisms reduce risk of TdP despite QT prolongation
B: Anti"B"iotics: (azoles, macrolides, quinolones)
C: Anti"C"ychotics: 1st gen>2nd gen (chlorpromazine, haloperidol, risperidone)
D: Anti "D"epressants: SSRIs, TCAs
E: Anti"E"metics: Ondansetron, prochlorperazine, droperidol

Other high risk medications: methadone, Arsenic (chemo), quinines (antimalarials), hydroxychloroquine

Crediblemeds.org is a great resource to look up specific meds. It also shows risk of QT prolongation vs risk of inducing TdP (not always equal)
Special note on ondansetron (Zofran): Risk IV > PO/ODT. Risk is greater if using IV dose > 16mg, other concomitant QT prolonging meds, concomitant congenital and/or acquired QT prolongation condition.
Consider ECG if patient has these risk factors or if re-dosing within 2 hours.

Presentation

Most commonly asymptomatic
Possible palpitations, seizure, syncope, SCD

Evaluation

Check recent EKG
If patient is at high risk e.g. receiving antibiotics ± antiemetics while inpatient with QT >500, can monitor with EKG q 2-3 days
Include the most recent QTc in your handoff for crossover resident

Management

If Stable

Stop the offending medication (see ABCDE's above) if possible. Many meds have non-QT prolonging alternatives, e.g. scopolamine patch/alcohol wipe sniff for Zofran, doxycycline for azithromycin.
Aggressive electrolyte repletion (K and Mg especially)
Serial EKG monitoring ± monitor on telemetry

If Progression to TdP

Address ABCs
ACLS, defibrillation if pulseless
Empiric IV magnesium
STAT page cardiology for overdrive pacing and likely transfer to CCU
FYI: Most episodes of TdP self-terminate, but patients are likely to have multiple episodes. Up to 25% of TdP cases convert to VF.

Brown Recluse Bites (Loxoscelism)

Authors: Ashley Zeoli and Matthew Kern

Background

Only a handful of spiders are truly harmful to humans
The brown recluse (a member of the Loxosceles genus) is widespread in the South, West, and Midwest US
They are often found in homes (attics, basements, cupboards) and outdoors (rock piles and under tree bark)
Their numbers increase in association with humans (i.e. synanthropic)

Appearance/Identification

Three pairs of eyes, a monochromatic abdomen and legs, very fine hairs on legs
Using the "violin" pattern on its body is a poor way to identify this spider, as other harmless spiders can have similar markings
Loxoscelism is the medical manifestation of the brown recluse spider bite
Venom contains insecticidal toxins, metalloproteases, and phospholipases

Presentation

Bites are most common on the upper arm, thorax, or inner thigh

Local Signs

Usually painless, but can cause burning sensation with two small cutaneous puncture marks with surrounding erythema
Usually appears as a red plaque or papule with central pallor, sometimes with vesiculation
Usually self-resolves in 1 week
Skin necrosis (10-20% of cases):
Lesion can progress to necrosis overall several days
An eschar will form that eventually ulcerates
Usually will heal over several weeks to months

Systemic Signs (rare, but more common in children)

The degree of systemic effects does not correlate with the appearance of the bite
Symptoms develop over several days, and include nausea, vomiting, fever, rhabdomyolysis, malaise, acute hemolytic anemia, significant swelling from head/neck bites that can compromise the airway, DIC and renal failure. Myocarditis is a rare adverse effect that may occur.

Evaluation

Presumptive diagnosis is based clinical presentation of the bite/wound
DDx includes vasculitis, pyoderma gangrenosum, cellulitis, or other arthropod bites
Definitive diagnosis is based upon observing a spider bite in combination identification by an entomologist
Patients with local symptoms do not need any further workup
Patient with any systemic symptoms require lab evaluation for more serious disease:
CBC, UA to eval for "blood" without RBCs, CMP, CK
If anemia: Type and Screen, peripheral smear, reticulocyte count, LDH, haptoglobin, coags to evaluate for hemolysis or DIC

Please refer to physical handbook page 578 for flowchart on Brown Reclude Spider/Loxoscelism management.

Management

Local Signs

Wound care (soap/water, elevation)
Pain management
Tetanus vaccine/prophylaxis if indicated
Antibiotics only if signs of concurrent cellulitis

Skin Necrosis

Symptomatic and supportive care
Surgical intervention can worsen cosmetic outcomes and is rarely indicated in the acute care setting. Skin grafting is occasionally needed for a very large ulcerative wound that is not healing. Infection is rare. Furthermore, the ulcerative base of the wounds often have a yellow stringy material that is not pus or infection. Please call Toxicology with any questions regarding brown recluse bites

Systemic Signs

Targeted at treatment of symptoms that develop (Consult toxicology) - Hemolytic anemia: generally, transfuse to keep hgb > 9-10. However, the rapidity of hemolysis is more important than the hgb for determining when to transfuse but almost always the threshold is higher than other forms of anemia. - Rhabdomyolysis: LR for UOP >200-300cc/hr - If patient develops chest pain: obtain EKG and check a troponin; if either is abnormal please obtain echo and call Toxicology as heart effects (i.e. myocarditis) is something we have been seeing at VUMC - DIC: supportive care

Toxidrome Overview

Author: Quinton Taylor

Toxidrome	Agent	Symptoms	Antidote
Cholinergic	Insecticides (e.g. organophosphates), physostigmine, neostigmine, pyridostigmine, pilocarpine, nerve agents (e.g. Sarin)	Muscarinic: Defecation, Urination, Miosis, Bradycardia, Bronchosecretions, Emesis, Lacrimation, Salivation, Sweating (DUMBBELSS) Nicotinic: Mydriasis, Tachycardia, Weakness, Hypertension, Fasciculations (MTWtHF)	Atropine (with pralidoxime if organophosphate poisoning)
Anticholinergic	Antihistamines, antipsychotics, antidepressants (TCAs), antiparkinsons, atropine, scopolamine	Hyperthermia, dry skin, mydriasis, delirium, hallucinations, tachycardia, urinary retention, seizures ("Hot as a hare, red as a beet, dry as a bone, blind as a bat, mad as a hatter")	Supportive care, consider physostigmine with toxicology
Sympathomimetic	Cocaine, amphetamines, bath salts, synthetic cannabinoids, sedative/hypnotic withdrawal, pseudoephedrine, caffeine	Hyperthermia, mydriasis, diaphoresis, tachycardia, arrhythmias, hypertension, seizures	None, supportive care; benzodiazepines as needed*
Opioid	Morphine, heroin, hydromorphone, fentanyl	Miosis, hypoventilation, somnolence, comatose, bradycardia, hypotension	Naloxone
Sedative-hypnotic	Benzos, barbiturates, alcohol, zolpidem	CNS depression, confusion, stupor, coma	None, supportive care only
Hallucinogenic	Phencyclidine, LSD, MDMA "Ecstasy"	Hallucinations, depersonalization, agitation, mydriasis (usually), tachycardia, hypertension, nystagmus	None, supportive care only
Serotonin syndrome	SSRIs, SNRIs, MOAIs	Hyperreflexia, myoclonus, diaphoresis, flushing, diarrhea, hyperthermia, tachycardia, confusion, agitation, coma	Supportive care; benzodiazepines as needed*; contact toxicology prior to using cyproheptadine

*for treatment of seizures, tachycardia, hypertension, agitation, and hyperthermia

General Workup

ABCs, evaluate vital signs, mental status, pupil size, skin temperature and moisture
Pulse ox, continuous cardiac monitoring, EKG, blood glucose
Beta blocker (hypo or normoglycemia) and CCB (hyperglycemia) toxicity
UDS, acetaminophen/salicylate level, ethanol levels UA, BMP, LFT, blood gas

General Management

Decontamination for topical exposures
Antidotes if known ingestions/fits appropriate toxidrome
Supportive care
Discuss with Toxicology for possible ways to enhance elimination of the toxin (e.g. diuresis, alkalinization, dialysis, etc.)