Toxicology

From Emergency Medicine 2009, sponsored by the University of California, Davis, Health System, Office of Continuing Medical Education, and Department of Emergency Medicine

Aaron Schneir, MD, Associate Professor, Department of Emergency Medicine,
University of California, San Diego, School of Medicine

Educational Objectives

The goal of this program is to improve the diagnosis and management of poisonings due to toxic alcohols, calcium channel blockers, and tricyclic antidepressants (TCAs), and toxicities that closely mimic other illnesses.

1.   Explain the pathophysiology of ethylene glycol and methanol toxicity.

2.   Describe the challenges and pitfalls in managing the patient with an acute verapamil overdose.

3.   Discuss the properties of TCAs, their effects, and appropriate treatment of overdoses.

4.   Differentiate tick paralysis from Guillain-Barré syndrome when evaluating a patient with toxic ascending pa­ralysis.

5.   Recognize the presentation of chronic salicylate poisoning.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any per­sonal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, Dr. Schneir and the planning committee reported nothing to disclose.

Acknowledgments

Dr. Schneir spoke at Emergency Medicine 2009, 32nd Annual University of California Davis Winter Conference, held February 9-13, 2009, in Olympic Valley, CA, and sponsored by the University of California, Davis, Health System, Office of Continuing Medical Education, and Department of Emergency Medicine. The Audio-Digest Foundation thanks Dr. Schneir and the University of California, Davis, Health System for their cooperation in the production of this program.

Toxicology’s Bad Boys: Ethylene Glycol, Verapamil, and Tricyclic Antidepressants

Toxic Alcohols

Introduction: parent compounds of ethlene glycol (EG) and methanol nontoxic but cause intoxication; converted to toxic metabolites by alcohol dehydrogenase (ADH) in body

Treatment: management of airway, breathing, and circulation (ABCs); ethanol or fomepizole therapy (to block me­tabolism of parent compound by ADH); immediate hemodialysis; replenishment of pyridoxine, thiamine, mag­nesium, and folate (cofactors in metabolism of EG and methanol; no evidence for effect on treatment, but beneficial for patients depleted in these vitamins)

Ethanol therapy: effective; inexpensive; causes central nervous system (CNS) depression; levels must be monitored (maintain level at 100 mg/dL)

Fomepizole therapy: oral or intravenous (IV) dosing; if patient presents during intoxication phase of EG (before toxic metabolites formed), continued fomepizole therapy precludes need for hemodialysis; hemodialysis re­quired due to long half-life of methanol; no need to monitor fomepizole levels; easy to use; does not cause CNS depression; expensive; limited availability

Challenges in management: inability to obtain levels within clinically useful time (£2 wk at speaker’s institution); must use nonspecific and imperfect surrogate markers for EG; methanol levels obtained somewhat faster (»6 hr at speaker’s institution); presentation on continuum; must initiate treatment without laboratory confirmation; specific treatment required

Surrogate markers for EG poisoning: intoxication; absence of lactic acidosis in setting of severe acidemia; contin­uum of toxicity  — hypocalcemia (not seen early on); progressive creatinine elevation; progressive acidosis (check serial chemistries); urine  — fluorescence (subjective; poor marker); significant amount of calcium oxalate crystals in urine (not present early on or in patients with renal failure); serum osmolarity  —  account for ethanol in calcula­tion of osmolar gap; enables calculation of amount of methanol or EG in urine; absence of gap does not exclude EG poisoning; most toxic metabolites not osmotically active; lactic acidosis  —  poor marker (one of metabolites of EG resembles lactate on analysis)

Management pitfalls: delayed recognition; failure to initiate treatment in timely manner; reliance on serum osmolar­ity; treating with ethanol or fomepizole only (hemodialysis required); sending for blood level without initiating treatment

Management pearls: if acidosis or creatinine elevation resolves without specific therapy (eg, through hydration alone), not likely to be caused by ingestion of significant amounts of toxic alcohol; severe acidosis or acidemia in setting of relatively normal cardiovascular status suggestive of EG or methanol poisoning

Alcoholic ketoacidosis: seen in same patients who use EG (alcoholics); often history of recent binging; nausea, vom­iting, and abdominal pain common; patients  —  typically present with severe metabolic acidosis and minimally al­tered consciousness; usually starving; have rapid recovery (with treatment, acidosis usually resolves within few hours)

Calcium Channel Blocker (CCB ) Toxicity

Similarities to tricyclic antidepressant (TCA) poisoning: high fatality rate; specific management required; both produce cardiac dysfunction and peripheral vasodilatation (bad combination); hemodialysis not helpful; in chil­dren, 1 or 2 pills highly toxic; severe cases may require cardiac bypass until toxicity cleared; newer antidote IV lipid emulsion (Intralipid) useful for both

Typical case: elderly patient comatose with bradycardia, hypotension, and no history of overdose; key  —  if patient hypotensive but not reflexively tachycardic, major clue to presence of b-blocker or CCB

Management: start with ABCs; give charcoal early if patient can tolerate it (if level of consciousness [LOC] altered, hold off due to risk for aspiration); IV fluids; atropine does not work well (speaker states if atropine works well, poisoning probably not due to CCB); calcium boluses (unknown how much to give; speaker generally raises cal­cium level to 17-18 mg/dL); vasopressor (eg, norepinephrine) or glucagon; insulin or glucose; options for further management  —  IV lpid emulsion; pacemaker; cardiac bypass; aortic balloon

Verapamil: while many emergency departments (EDs) moving away from activated charcoal for decontamination, speaker would use it in patient with verapamil poisoning who presented early; in patient who has ingested ex­tended-release preparation, decontamination must be very aggressive; speaker would add whole bowel irrigation; patient must be admitted

Calcium channel blockers: those that block L-type calcium channels  —  in myocardium, decrease  conduction, rate, and inotropy; cause vascular smooth muscle relaxation (peripheral vasodilation); extreme hyperglycemia common with severe CCB poisoning because these drugs prevent insulin release and greatly increase insulin resistance; di­hydropyridine CCBs  —mainly cause peripheral vasodilation and reflex tachycardia; distinction between types ob­scured in large overdoses

Insulin infusion for CCB poisoning: novel therapy, but well accepted by most toxicologists; dose of insulin given 0.5 to 1.0 unit/kg per hour; mechanism of action unclear, but studies show treatment effective; some research sug­gests that hyperglycemia early in course of CCB overdose predicts severity of patient’s illness

Pitfalls in management: failure to recognize; failure to initiate early aggressive decontamination (particularly with verapamil extended-release preparation); not using insulin or inadequate insulin dosing

TCA Poisoning

Presentation: patient appears poisoned with antimuscarinic agent; QRS prolongation (delay in depolarization; indi­cates sodium [Na+] channel blockade); generalized convulsion typical of TCA poisoning

Management: start with ABCs (rapid sequence intubation [RSI] with midazolam [eg, Versed]; induce mild hyper­ventilation to adjust pH to normal or slightly higher; give IV fluids; sodium bicarbonate to treat QRS prolongation); once airway secured, consider giving charcoal; differential diagnosis  —  other medications, eg, diphenhydramine, venlafaxine, bupropion, carbamazepine, disopyramide; however, initial treatment identical for all

Properties of TCAs: rapid absorption (patients become ill quickly); Na+ channel blockade; antimuscarinic effects; a₁-blockade; potassium (K+) channel blockade; reuptake inhibition;  g-aminobutyric acid (GABA) antagonism

Na+ channel blockade: manifests on electrocardiography (ECG) as QRS prolongation; can progress to ventricular dysrhythmias; treatment  —  NaHCO₃; main indication QRS prolongation (do not give prophylactically); lidocaine only other  applicable antidysrhythmic; avoid drugs with effects similar to TCAs, eg, procainamide

Antimuscarinic effects:  mydriasis; tachycardia; dry skin; confusion; helpful for making diagnosis

Classic signs on ECG that indicate TCA poisoning: sinus tachycardia; QRS prolongation; terminal rightward axis

a₁-blockade: decreases cardiac contractility, output, and conduction; causes peripheral vasodilation; treatment  —  fluids, vasopressor (eg, norepinephrine); NaHCO₃ may also be helpful

K+ channel blockade: effect  —  QT prolongation; in setting of acute poisoning, QT prolongation almost of no clini­cal significance (torsade extremely rare); however, avoid drugs that further prolong QT interval

Reuptake inhibition: therapeutic mechanism of TCAs; in overdose, causes tachycardia; norepinephrine preferred treatment; dopamine also used

GABA antagonism: effect  —  seizures (also caused by Na+ channel blockade); treatment  —  benzodiazepines; if pa­tient has multiple seizures, speaker recommends paralyzing patient to prevent increasing acidemia (makes Na+ channel blockade worse); sodium bicarbonate does not stop seizures

Drug levels: not useful; false-positive results common (indicate exposure to drug, not necessarily toxicity);  study showed serum drug levels do not correlate with severity of illness after overdose;  manage patients clinically, based on duration of QRS prolongation (predicts risk for convulsions and dysrhythmias)

Management principles for TCA poisoning: onset of toxicity rapid; intubate patients early if ill; all ingestions do not require admission (if patient does not have altered LOC, respiratory depression, convulsion, QRS prolongation, dysrhythmia, or hypotension within »6 hr, he or she can be cleared medically and released)

Pitfalls in management of TCA poisoning: failure to recognize; failure to appreciate rapidity of toxicity (after ini­tial examination, patient must be placed on monitor; obtain serial ECGs and watch patient closely); relying on any­thing but clinical parameters; NaHCO₃ pitfalls  —  excessive administration (usually via continuous infusion) can lead to severe alkalemia; administration for QT prolongation (NaHCO₃ not for QT prolongation;  only for QRS pro­longation); contraindicated agents  — physostigmine; flumazenil

Toxicology Mimickers Relevant to Emergency Physicians

Case example 1: 6-yr-old girl with long hair; difficulty ambulating; previously healthy; no fever or incontinence; vi­tal signs normal; cranial nerve and neurologic examinations normal, except patient has 3/5 motor strength and are­flexic in lower extremities; periodic paralysis; K+ level normal

Differential diagnosis for ascending paralysis: Guillain-Barré syndrome (GBS); poliomyelitis; periodic paralysis; transverse myelitis; spinal cord lesions; toxic cause

Case management: patient’s cerebrospinal fluid (CSF) normal; patient admitted; while washing child’s hair, mother found engorged tick; patient diagnosed with tick paralysis; tick removed; within »12 hr, patient returned to normal and released

Tick paralysis: not common, but often missed (closely mirrors GBS); seasonal (spring and summer); pathophysiology  — engorged tick releases neurotoxin that causes problem at neuromuscular junction (motor changes only); mechanical removal best; generally occurs in young children (usually with long hair), although some cases reported in debilitated adults

GBS vs tick paralysis: similarities  —  ascending paralysis; areflexia; differences  —  GBS also produces sensory find­ings, elevated protein in CSF; time to recovery weeks to months with GBS, <24 hr after tick removed

Management of toxic ascending paralysis: take-home message  —  if considering GBS, do not accept diagnosis until presence of tick excluded

Case example 2: 24-yr-old woman with history of IV drug abuse (skin popping) presents with fatigue, dysphagia, and diplopia; patient reports feeling “weak”; vital signs normal; examination significant for ptosis and soft speech

Comments: when faced with patient who presents with cranial nerve changes, difficulty with speech and ptosis, think of descending paralysis; usually patient who reports “feeling weak” does not actually have physical motor weak­ness; however, burden on physician to do thorough neurologic examination (cranial nerve changes and ptosis often missed)

Differential diagnosis for descending paralysis: myasthenia gravis (MG); Miller-Fisher variant of GBS; brainstem cerebrovascular accident; toxic cause (botulism); case diagnosed as wound botulism

Botulism: produces classic descending paralysis; causes purely motor changes (if patient has sensory findings, re­lated to another condition); presents classically, but usually missed; types by incidence  — infants (<6 mo of age most common; do not yet have stomach acid or bile acids that would kill spores in, eg, raw honey); foodborne (eg, inadequate home canning); wound (often not found); therapeutic (inadvertent, eg, from cosmetic procedure)

Botulinum toxin: organisms  —  usually Clostridium botulinum; seven toxin types (A-G; all act similarly, but some more potent at different sites in body); depends on type of botulism and geographic location; common pathophysiology  —  prevents synaptic release of acetylcholine, leading to neuromuscular weakness; antimuscarinic effects (mydriasis; dry skin; dry mouth and difficulty speaking; constipation); tachycardia not common

Differentiating botulism from GBS and MG: finding of mydriasis in setting of descending paralysis strongly sug­gestive of botulism (not always present); sensory findings and/or elevated protein in CSF consistent with Miller-Fisher variant of GBS; ultimately, diagnosis made by identifying toxin

Importance of early treatment: must  initiate treatment before identifying toxin; get antitoxin therapy on board very quickly; the longer treatment delayed, the longer neuromuscular weakness present; if treatment not started early, patient may require intubation for 6 to 9 mo

Pitfalls: failure to recognize descending paralysis; not initiating antitoxin treatment early

Case example: 70-yr-old man with progressive altered LOC for »1 day; history of osteoarthritis; medications un­known; on examination  —  hypoxic, tachypneic, and diaphoretic; core temperature 100.8ºF; has supple neck and bi­basilar crackles; tachycardic; disoriented; no rigidity; laboratory findings  —  glucose 220 mg/dL arterial blood gases (pH 7.42, Pco₂ 24 mm Hg); slightly hypokalemic; wide anion gap metabolic acidosis; creatinine slightly ele­vated; white blood cell count »14,000/mL; urine positive for ketones and protein; lactate and international normal­ized ratio slightly elevated; findings classic for patient’s condition; obtain chest x-ray

Case management: at most hospitals, patient would be admitted for pneumonia; diagnosis salicylate (aspirin) poi­soning; seldom see chronic salicylate poisoning now, because patients use other drugs (eg, ibuprofen) to treat pain or rheumatoid arthritis; treatment  —  hydration with glucose and K+; external cooling; hemodialysis

Suggested Reading

Arnon SS et al: Human botulism immune globulin for the treatment of infant botulism. N Engl J Med 354:462, 2006; Boehnert MT, Lovejoy FH Jr: Value of the QRS duration versus the serum drug level in predicting seizures and ventricular arrhythmias after an acute overdose of tricyclic antidepressants. N Engl J Med 313:474, 1985; Bradberry SM et al: Management of the cardiovascular complica­tions of tricyclic antidepressant poisoning: role of sodium bicarbonate. Toxicol Rev 24:195, 2005; Brindley PG et al: Falsely elevated point-of-care lactate measurement after ingestion of ethylene glycol. CMAJ 176:1097, 2007; Burke MS et al: Ticks and tick paralysis: imaging findings on cranial MR. Pediatr Radiol 35:206, 2005; Centers for Disease Control and Prevention (CDC): Cluster of tick pa­ralysis cases--Colorado, 2006. MMWR Morb Mortal Wkly Rep 55:933, 2006; Chang GY, Ganguly G: Early antitoxin treatment in wound botulism results in better outcome. Eur Neurol 49:151, 2003; Dargan PI et al: An evidence based flowchart to guide the manage­ment of acute salicylate (aspirin) overdose. Emerg Med J 19:206, 2002; Edlow JA, McGillicuddy DC: Tick paralysis. Infect Dis Clin North Am 22:397, 2008; Foulke GE: Identifying toxicity risk early after antidepressant overdose. Am J Emerg Med 13:123, 1995; Glasser DS: Utility of the serum osmolal gap in the diagnosis of methanol or ethylene glycol ingestion. Ann Emerg Med 27:343, 1996; Harrigan RA, Brady WJ: ECG abnormalities in tricyclic antidepressant ingestion. Am J Emerg Med 17:387, 1999; Levine M et al: As­sessment of hyperglycemia after calcium channel blocker overdoses involving diltiazem or verapamil. Crit Care Med 35:2071, 2007; Li Z, Turner RP: Pediatric tick paralysis: discussion of two cases and literature review. Pediatr Neurol 31:304, 2004; Lund B et al: Efficacy of sustained low-efficiency dialysis in the treatment of salicylate toxicity. Nephrol Dial Transplant 20:1483, 2005; Marques M et al: Treatment of calcium channel blocker intoxication with insulin infusion: case report and literature review. Resuscitation 57:211, 2003; Martin C et al: Cranial nerve palsies and descending paralysis in a drug abuser resulting from wound botulism. Intensive Care Med 25:765, 1999; Needham GR: Evaluation of five popular methods for tick removal. Pediatrics 75:997, 1985; O'Malley GF: Emergency department management of the salicylate-poisoned patient. Emerg Med Clin North Am 25:333, 2007; Passaro DJ et al: Wound botulism associated with black tar heroin among injecting drug users. JAMA 279:859, 1998; Pellegrino B et al: Ethylene glycol intoxication: Dis­parate findings of immediate versus delayed presentation. W V Med J 102:32, 2006; Shepherd G, Klein-Schwartz W: High-dose insulin therapy for calcium-channel blocker overdose. Ann Pharmacother 39:923, 2005; Soghoian S et al: Ethylene glycol toxicity presenting with non-anion gap metabolic acidosis. Basic Clin Pharmacol Toxicol 104:22, 2009; Tebbutt S et al: Intralipid prolongs survival in a rat model of verapamil toxicity. Acad Emerg Med 13:134, 2006; Velez LI et al: Ethylene glycol ingestion treated only with fomepizole. J Med Toxicol 3:125, 2007; Werner SB et al: Wound botulism in California, 1951-1998: recent epidemic in heroin injectors. Clin Infect Dis 31:1018, 2000.