TOXICOLOGY REVIEW
| INTERESTING TOXICOLOGY CASES IN ACIDOSIS —Kent R. Olson, MD, Clinical Professor of Medicine, Pharmacy, and Pediatrics, University of California, San Francisco, School of Medicine, and Medical Director, California Poison Control System, San Francisco |
| Metabolic acidosis: case—man, 44 yr of age, found unconscious with suicide note and half-empty bottle of alcohol; physical examination reveals tachycardia and slightly elevated respiratory rate; PCO 2 , 22 mEq/L; bicarbonate low; anion gap, ≈16 mEq/L, but pH elevated (clue to diagnosis); blood alcohol level insufficient to induce coma |
 | Common causes: salicylates—hyperventilation increases pH of blood; MUDPILES mnemonic—methanol; uremia; diabetic ketoacidosis (DKA); phenformin and paraldehyde (no longer used); isoniazid and iron; lactic acid; ethylene glycol; salicylates |
| Diagnosis: salicylate level confirms diagnosis of salicylate poisoning; mixed acid-base abnormalities typical in cases of salicylate intoxication; primary respiratory alkalosis due to hyperventilation accompanies underlying metabolic acidosis; intoxication sometimes caused by long-term use of salicylates (consider in patients taking salicylates regularly and who present with confusion and metabolic acidosis) |
| Osmolar gap: case—male, found comatose with significant metabolic acidosis (pH, 6.9; bicarbonate, 5 mEq/L); anion gap, 37 mEq/L; blood glucose (BG), 166 mg/dL; serum urea nitrogen (BUN) and creatinine slightly elevated; measured osmolality, 331 mOsm/kg H2 O), with osmolar gap of 23 mOsm/kg H2 O; no evidence of ethanol ingestion |
| Calculation: expected osmolality—multiply sodium level by 2, and add BUN and BG in millimoles to get total osmolality (normally 290-300 mOsm/kg H2 O); conditions that affect levels of sodium, BUN, or BG affect total but not osmolar gap); osmolar gap—subtract expected osmolality from measured osmolality; causes of osmolar gap— exogenous substance with osmotic activity; all alcohols elevate osmolality (ethanol most common cause); sources of error—specimen stored in tube coated with chemicals that have osmotic activity (use plain serum tube with red top); specimens drawn at different times (ie, baseline could change, resulting in inaccurate calculation of gap); use of vaporization method to measure osmolality (drives off volatile alcohols, possibly resulting in normal-appearing gap) |
| Diagnosis: methanol poisoning, resulting in severe acidosis and osmolar gap |
| Ethylene glycol and methanol: methanol raises osmolar gap; formaldehyde (metabolite of methanol) also has osmotic activity; formaldehyde metabolized to formic acid, causing metabolic acidosis (also may cause blindness, brain damage, and coma); formic acid increases anion gap but not osmolar gap; therefore, osmolar gap and anion gap vary significantly, depending on time since ingestion; case—patient taken to emergency department (ED) after drinking antifreeze (witnessed by girlfriend); very large osmolar gap but no anion gap (ie, acidosis had not yet developed); ethanol treatment initiated to inhibit metabolism of ethylene glycol (eventually eliminated through urine) and to avoid development of acidosis; diagnosis—if level of ethylene glycol not immediately available, calculate osmolar gap (large gap in cases of ethylene glycol poisoning); anion gap elevated only if sufficient time has passed for metabolism to occur; low level of lactate (in patient with high anion gap) important clue pointing to ethylene glycol poisoning; other diagnostic clues include sheets of crystals (calcium oxalate) in urine and fluorescence of urine under Wood’s lamp (but fluorescence not specific to ethylene glycol poisoning); methanol may also cause visual disturbances; differential diagnosis—patients with alcoholic ketoacidosis also have high osmolar and anion gaps and low levels of lactate; ketone bodies present as β-hydroxybutyrate, not detected by test for ketones; anion gap improves within hours when patient treated with fluids, dextrose, and vitamins; level of alcohol often low (patient in gastrointestinal [GI] distress and possibly starvation state) |
| Ibuprofen: case—girl, 15 yr of age, found comatose with blood pressure (BP) of 92/34 mmHg, heart rate of 120 beats/ min, and slightly elevated respiratory rate; pH of blood, 7.16; Pco2 , 27 mEq/L; anion gap, 20 mEq/L; negative findings for salicylates, methanol, and ethylene glycol; BUN, creatinine, and BG within normal levels; patient intubated after becoming more obtunded, and treated with intravenous (IV) fluids and bicarbonate; acidosis resolved over 12 hr; after reviving, patient admitted to ingesting 500 tablets of ibuprofen; toxicity—ingestion of large quantities may cause acidosis (ibuprofen and naproxen derived from propionic acid); upset stomach common with moderate overdose; severe overdose may result in coma, seizures, adult respiratory distress syndrome (ARDS), severe hypotension, or acute renal failure; treatment mostly supportive, with patients typically recovering in 12 to 24 hr |
| Acetaminophen: woman, 28 yr of age, found comatose with 2 empty bottles of acetaminophen (extra strength Tylenol; ≈150 g); patient tachycardic with significant acidosis (pH, 7.03; bicarbonate, 4 mEq/L; anion gap, 25 mEq/L); laboratory tests negative for aspirin but measured acetaminophen at 850 µg/mL; normal level of aspartate aminotransferase (AST), but high level of lactate; acute ingestion likely, but acidosis unexplained; tests for ethanol, methanol, and ethylene glycol had negative findings; patient later developed injury to liver and renal failure (consistent with acute acetaminophen overdose); toxicity—significant metabolic acidosis may occur after ingestion of massive quantities of acetaminophen, but mechanism unclear; condition tends to resolve in ≈24 hr; treatment with N-acetylcysteine (Mucomyst) may prevent injury to liver; high levels of acetaminophen may also result in coma or hypotension |
| Valproic acid (Depakote): case—ataxic child, 2 yr of age and obtunded woman, 25 yr of age; child has sodium level of 152 mEq/L, moderate acidosis, and elevated level of ammonia; woman hypotensive, with more significant acidosis, hypoglycemia, and mild hypocalcemia; toxicity—resulting metabolic dysfunction includes hypoglycemia, hypocalcemia, elevated ammonia, and encephalopathy (may resemble Reye’s syndrome); level of sodium increases as sodium divalproex dissociates; coma and (more rarely) cerebral edema may develop; treatment—consider hemodialysis when level of valproic acid \>600 to 800 µg/mL |
| Caustic substances: case 1—man ingested drain cleaner containing 9% sulfuric acid; evidence of significant burns included drooling and pain in mouth and chest; endotracheal tube placed shortly after arrival in ED; initial anion gap \>40 mEq/L, bicarbonate <5 mEq/L, but lactate only ≈2 mg/dL (acidosis caused by sulfate, not lactate); case 2—woman ingested toilet bowl cleaner containing ≈9% hydrochloric acid; patient presented with severe pain; elevated creatine kinase (CPK) indicated significant damage to tissue; although blood chemistry showed evidence of significant acidosis, anion gap smaller than expected; elevated level of chloride masks low level of bicarbonate, resulting in anion gap that appears normal |
| Cyanide: Laotian girl, 5 yr of age, brought to ED in lethargic state; history of nausea and vomiting; physical examination revealed moderate hypertension and tachycardia, but otherwise unremarkable; earlier, family had eaten “wild root,” collected from marina (no problems when eaten on previous occasions); later, all members experienced nausea and vomiting; child’s condition worsened, with dilated pupils, shallow respiration, severe acidosis (pH 6.3), and Pco2 of 21 mEq/L; child then had tonic-clonic seizure; other possible ingestions—family member taking “chest medicine” (isoniazid suspected, but family could not confirm) |
| Isoniazid: common cause of significant metabolic acidosis and seizures (often isolated and brief); toxicity associated with high levels of lactate; treat with IV vitamin B6 (gram-for-gram dose, if ingested quantity known; otherwise initial dose of 5 g); seizures often respond to benzodiazepines; vitamin B6 helps prevent additional seizures |
| Other causes of seizures: cocaine and amphetamines; tricyclic antidepressants; bupropion; tramadol; diphenhydramine; phenothiazines and newer antipsychotic agents; selective serotonin reuptake inhibitors (SSRIs) at high doses; bupropion can cause seizures even at low doses if patient has risk factors |
| Case (continued): vitamin B6 given empirically while waiting for identification of medication; identified as erythromycin (ie, not responsible for condition); further investigation returned to root as source of possible cyanide poisoning; patient’s cyanide level elevated; plant identified as pampas grass, which, although generally edible, produces cyanogenic glycosides at certain times of year; compounds hydrolyzed in stomach and released over several hours; child recovered with supportive care and cleared cyanide without receiving antidote |
| Mnemonics: MUDPILES does not identify important agents that cause metabolic acidosis; SALAD mnemonic— salicylates; alcohols (test for osmolality); lactic acid (normal or low level indicates non-lactate acidosis, eg, alcohols or ibuprofen); anuria (check levels of BUN and creatinine); DKA—(check BG) |
| Questions and answers: bedside toxicology screens—generally target drugs of abuse; good history and clinical assessment with simple laboratory tests often sufficient to make tentative diagnosis; false-negative results occur (eg, screens for opioids may miss methadone or fentanyl; screens for benzodiazepines may miss lorazepam [Ativan] or clonazepam [Klonopin]); occasionally, false-positive results occur (eg, pseudoephedrine may appear as methamphetamine); IV N- acetylcysteine—when repeated vomiting prevents use of oral Mucomyst, same drug can be given IV (but not approved for this purpose); new drug approved for IV use has shorter protocol (20 hr vs 36 hr or 72 hr), but more expensive; drugs have similar risk of causing hypotension (if given rapidly) or anaphylactoid reactions; pharmacokinetics of acetaminophen—half-life generally 4 to 5 hr; level possibly undetectable after ≈20 hr; in case of delayed presentation by patient with signs of liver injury, Mucomyst still beneficial; unless patient has no signs of acetaminophen poisoning or denies taking acetaminophen, give Mucomyst for 24 hr, then reassess patient |
| TOXICOLOGY LITERATURE REVIEW —Frank LoVecchio, DO, MPH, Banner Good Samaritan Center, Phoenix, Arizona |
| Ethylene glycol poisoning: data collected from poison control centers indicate fomepizole has surpassed ethanol as treatment for ingestion of ethylene glycol; fomepizole—expensive alternative to ethanol, but easy administration and dosing (15-mg/kg dose lasts 12 hr); ethanol—dosing partly dependent on history of alcohol use (ie, naïve, moderate, or chronic); risk for hypoglycemia in children and patients with decreased glycogen stores; crystals in urine—associated with ethylene glycol poisoning, but occur with other drugs as well (eg, acyclovir and indinavir); fluorescence—although associated with ingestion of ethylene glycol, decreases with increased acidity of urine; difficult to detect accurately without comparing to control specimen (consider looking for fluorescence around patient’s mouth or clothes as sign of ingestion); note—if ethylene glycol suspected, give 15 mg/kg fomepizole empirically while waiting for laboratory results |
| GI decontamination: cathartics have no proven benefit, and increase risk for death; single dose of charcoal most effective when given within 1 hr of ingestion; charcoal not effective in cases of lithium or iron poisoning; lavage no longer recommended; note—no controlled studies to determine whether GI decontamination benefits patient outcome; charcoal administration—study showed emergency medical system (EMS) personnel administered charcoal in ≈75% of cases in which patient received charcoal within 1 hr of overdose (ie, good idea to implement charcoal decontamination protocol with EMS); risks of decontamination—perforation of esophagus or spilling fluid into lungs may occur with lavage; aspiration may occur with administration of charcoal (study found 5% rate of aspiration without decontamination and 2% associated with decontamination); conclusions—avoid gastric emptying, with or without activated charcoal; consider giving activated charcoal alone (but, given time constraints and risk for aspiration, this may change) |
| Radiation exposure: distance—outcome improves with distance from source of exposure; lead also protective; effect— rapidly dividing cells (eg, bone marrow and intestinal mucosa) most vulnerable; exposure <1 Gy (100 rad) generally safe (but may increase risk for leukemia later in life); risk increases with increasing exposure to gamma radiation; decontamination—remove residue with soap and water or diluted (1:10) household bleach; evaluation— lymphocyte count 48 hr after exposure may aid in prognosis; patients with \>3000 cells/µL have good outcomes; 100% fatality in patients with <100 cells/µL; in cases of potential exposure of large number of people, get baseline measures of complete blood cell (CBC) count, then repeat in 2 days; treatment—although potassium iodide generally recommended, specific radionucleotide involved may affect treatment; after radiation exposure in Chernobyl, many children developed thyroid cancer; iodine deficiency may have predisposed thyroid glands of these children to take up radioactive element; treating with potassium iodide (130 mg in adults, for 5-7 days) may prevent uptake of radioactive iodine |
| Carbon monoxide (CO): poisoning may occur outdoors; many sources of CO occur indoors and outdoors; compound instantly binds to hemoglobin; treatment—victims of poisoning should receive O2 ; study (Weaver) concluded hyperbaric administration of O2 indicated in patients with loss of consciousness, cerebellar findings, persistent altered mental status, myocardial ischemia, seizures, or levels of CO \>25 mEq/L (but, study did not control for ingestion of alcohol or drugs that could have affected mental status) |
Educational Objectives
| The goal of this activity is to provide information and case examples on toxic ingestions and overdoses. After hearing and assimilating this program, the clinician will be better able to: |
| 1. Diagnose patients with metabolic acidosis from toxic ingestion and determine cause. |
| 2. Discuss the concept of osmolar gap and how it applies to diagnosing patients with metabolic acidosis. |
| 3. Identify and treat patients with ethylene glycol or methanol poisoning. |
| 4. Discuss advantages and disadvantages of different approaches to gastrointestinal (GI) decontamination. |
| 5. Assess and treat patients exposed to harmful levels of ionizing radiation. |
Discussed on This Program
Acetylcysteine (N-acetylcysteine) [Acetadote, Mucomyst, Mucosil-10, -20, Nacystelyn Dry Powder Inhaler (orphan)] Acetaminophen (several trade names and formulations) Acyclovir (acycloguanosine) [Zovirax] Bupropion HCl [Wellbutrin, Wellbutrin SR, Zyban] Clonazepam [Klonopin] Diphenhydramine HCl (several trade names) Erythromycin (several trade names) Fentanyl [ Sublimaze] Fomepizole (4-methylpyrazole; 4-MP) [Antizol] Ibuprofen (several trade names) Indinavir sulfate [Crixivan] Isoniazid (isonicotinic acid hydrazide; INH) [Isoniazid, Nydrazid] Lorazepam [Ativan, Lorazepam Intensol] Methadone HCl [Dolophine HCl, Methadone HCl Diskets, Methadone HCl Intensol, Methadose] Paraldehyde [Paral] Phenformin HCl [DBI] (available only under IND exemption) Pseudoephedrine HCl (several trade names) Tramadol HCl [Ultram] Valproic acid [Depacon, Depakene, Depakote, Depakote ER]
Suggested Reading
Buckley NA, Eddleston M: The revised position papers on gastric decontamination. Clin Toxicol (Phila) 43:129, 2005; Cardis E, et al: Risk of thyroid cancer after exposure to 131 I in childhood. J Natl Cancer Inst 97:724, 2005; Corley RA, McMartin KE: Incorporation of therapeutic interventions in a physiologically based pharmacokinetic modeling of human clinical case reports of accidental or intentional overdosing with ethylene glycol. Toxicol Sci 85:491, 2005; Crouch BI, Rusho WJ: Intravenous administration of N-acetylcysteine. Ann Emerg Med 46:207, 2005; Domachevsky L, et al: Hyperbaric oxygen in the treatment of carbon monoxide poisoning. Clin Toxicol (Phila) 43:181, 2005; Greene SL, et al: Acute poisoning: understanding 90% of cases in a nutshell. Postgrad Med J 81:204, 2005; Hess R, et al: Ethylene glycol: an estimate of tolerable levels of exposure based on a review of animal and human data. Arch Toxicol 78:671, 2004; Hovda KE, et al: Methanol and formate kinetics during treatment with fomepizole. Clin Toxicol (Phila) 43:221, 2005; Koga Y, et al: The irrationality of the present use of the osmole gap: applicable physical chemistry principles and recommendations to improve the validity of current practices. Toxicol Rev 23:203, 2004; Megarbane B, et al: Current recommendations for the treatment of severe toxic alcohol poisonings. Intensive Care Med 31:189, 2005; Tsai CL, et al: A patient-tailored N-acetylcysteine protocol for acute acetaminophen intoxication. Clin Ther 27:336, 2005; Weiner SW, Hoffman RS: Trends in clinical toxicology: advances that may change your practice. Basic Clin Pharmacol Toxicol 97:1, 2005; Zehtabchi S, et al: Does ethanol explain the acidosis commonly seen in ethanol-intoxicated patients? Clin Toxicol (Phila) 43:161, 2005.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial relationship with the manufacturer or provider of any commercial product or service discussed. For this issue, the faculty reported nothing to disclose.
Dr. Olson was recorded in San Francisco at Topics in Emergency Medicine, sponsored by University of California, San Francisco, School of Medicine, Division of Emergency Medicine, and held October 25-28, 2004; Dr. LoVecchio was recorded in Scottsdale, Arizona, at Emergency Medicine 2005: Moving Forward, sponsored by Mayo Clinic College of Medicine at Scottsdale, and held April 18-20, 2005. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.
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