Early recognition, treatment is critical for toxic alcohol ingestions.
Introduction
Toxic alcohol ingestions are potentially fatal and early recognition and treatment are critical. Importantly, a myriad of common household products like automotive antifreeze, cleaning solvents, and cooking fuels contain isopropyl alcohol, ethylene glycol and methanol. These products are inexpensive and easily accessible products and are consequently often involved in accidental and intentional overdoses alike.
The American Association Poison Control Center reported 6,739 cases including 12 deaths in the US in 2019 with a lethal dose as low as 1mg/kg.1 Alcohol abusers, suicidal patients, and children are high risk populations for fatal toxic alcohol ingestion. Children especially as they may be attracted to the sweet taste of these toxins and lethal doses are achieved with small ingestions.[9] Given the diagnostic difficulties and potential for critical illness, clinicians must maintain a high index of suspicion for these infamous “one-swallow-can-kill” toxins.
The Case
Chief complaint: Altered mental status
HPI: A 32-year-old-male with a past medical history of schizoaffective disorder, polysubstance abuse, and recent admission for suicide attempt and multiple traumatic injuries sustained after jumping from a window presents to the emergency department (ED) with altered mental status. The patient appeared intoxicated and was unable to provide any coherent history.
EMS reports that they were called by his girlfriend because the patient was not making any sense and acting bizarrely at home. In the field, the patient was found to be confused, hypertensive, and tachypneic. The patient’s girlfriend indicated that she last saw him normal at approximately 6AM before leaving for work. A prehospital stroke alert was activated by EMS and the patient was transported to the ED.
The patient was seen immediately upon arrival to the ED and sent for CT imaging where IV access and laboratory studies were also obtained. During this time, social work was able to contact the girlfriend who reported finding a letter written by the patient to his lawyer stating that he would not be appearing in court because his girlfriend was poisoning him. She denied this allegation and separately expressed concerns that he may have ingested something after finding an empty bottle of ibuprofen. The patient had also endorsed cocaine use to her prior to calling 911.
After CT, the patient’s mental status rapidly declined with increased respiratory effort and was not responding to painful stimuli requiring endotracheal intubation for airway protection.
Review of systems:
A complete review of systems was unable to be obtained due to altered mental status
Pertinent positives: confusion, suicidal ideation
Pertinent negatives: trauma
Past medical history: schizoaffective disorder, suicide attempt
Past surgical history: ORIF femur
Social history: polysubstance abuse
Family history: unable to be obtained due to altered mental status
Allergies: No known drug allergies
Physical exam: T 97.3F HR 93 BP 172/95 RR 27 SpO2 100% room air
Constitutional: Alert but disoriented
HENT: Normocephalic, atraumatic, dry mucous membranes
Eyes: Pupils equal round reactive to light, extraocular motions intact, sclera nonicteric
Neck: Supple, no nuchal rigidity
Lungs: Tachypneic but clear to auscultation, no wheezing or rales
Heart: Regular rate and rhythm, no murmur
Abdomen: Soft, nondistended, no tenderness to palpation
Extremities: Full range of motion in all extremities, symmetric pulses, no edema
Neuro: Alert and oriented to person only, intermittently follows simple commands, cranial nerves 2-12 intact, slurred speech, no facial asymmetry, 5/5 strength in all extremities, sensation intact to light touch
Skin: Warm and dry, no rash or lesions
Workup:
Imaging including CT angiogram of the head and neck and chest x-ray were unremarkable. Laboratory workup revealed several significant abnormalities. Serum lactate was elevated at 9.6 mmol/L. Arterial blood gas demonstrated metabolic acidosis with a pH 7.018 PaCO2 24mmHg PaO2 362mmHg bicarbonate 6 mmol/L and base excess -25.2. Electrolyte panel was significant for an anion gap 27, bicarbonate <5 mmol/L, and creatinine 1.67 mg/dL consistent with severe anion gap metabolic acidosis and acute kidney injury.
Complete blood count, hepatic panel, creatinine kinase, and urinalysis were unremarkable. Ethanol, tylenol, salicylate, and urine drug screen were all negative. Serum osmolality was elevated at 333 mOsm/kg. An osmolal gap of 39 was calculated. Toxic alcohol levels including ethylene glycol, methanol, and isopropyl alcohol were obtained and pending prior to the initiation of treatment given the high suspicion for lethal ingestion.
Treatment:
The patient was intubated for airway protection and ventilator settings maintained a high minute ventilation. Multiple infusions including IV crystalloid, bicarbonate, and fomepizole were initiated. IV thiamine and pyridoxine supplementation were also given. A trialysis catheter was inserted in the right internal jugular position and nephrology was consulted for hemodialysis. Poison control was contacted to help guide therapy and the patient was admitted to the medical intensive care unit.
The Discussion
Ethylene glycol is a toxic alcohol found in antifreeze, automobile coolants, and industrial solvents.[10] When ingested, it is rapidly absorbed by the gastric mucosa and processed by alcohol dehydrogenase and aldehyde dehydrogenase in the liver into its toxic byproducts glycolic acid, glyoxylic acid, and oxalic acid.4,5 Dermal and inhalant exposures will not cause toxicity. However, an ingestion as small as 1mL/kg should be considered lethal and clinical toxicity will develop rapidly.[6]
Recognition is the most critical step in treating ethylene glycol toxicity. Many patients will present to the emergency department able to report an ingestion of a substance known to contain ethylene glycol. However, in as little as 30 minutes after a significant ingestion, the toxins will cause central nervous system depression similar to ethanol intoxication which may not allow for this.[10]
Patients will appear inebriated with slurred speech, ataxia, nystagmus and may progress to seizures and coma.[10] Most poisoning deaths from ethylene glycol exposure occur 4-24 hours of ingestion where the cardiopulmonary systems are primarily affected resulting in hypertension or hypotension, hyperpnea, heart failure, acute respiratory distress syndrome (ARDS), hypocalcemia, arrhythmias, and myositis.[10] The subsequent 24-72 hours are characterized by profound renal failure with flank pain, oliguria, and hematuria.[4,10]
For those without a known ingestion, altered mental status with marked metabolic acidosis should prompt clinicians to consider a wide differential diagnosis including status epilepticus, profound shock, sepsis, ischemic bowel, diabetic ketoacidosis, alcoholic or starvation ketoacidosis, delirium tremens, and salicylate poisoning as possible explanations for these derangements.
Without a clear history of ingestion, a severe anion gap metabolic acidosis coupled with a high osmolar gap may be the only laboratory clue for ethylene glycol overdose.[5] However, this important clue may not be present in all clinical scenarios. For instance, anion gap acidosis may not be present immediately following ingestion as only the metabolites cause an acidosis.[10]
Additionally, if presentation is significantly delayed, an osmolal gap may not be present as only the parent alcohol compound is osmotically active and may have been completely metabolized.[10] Several other clinical and laboratory abnormalities may be present including acute kidney injury from nephrotoxic byproducts and hypocalcemia resultant from oxalate chelation which may cause tetany or prolonged QT. Lactate may also be falsely elevated as most lab tests are unable to differentiate between lactate, glycolate, and glyoxylate.[4]
Clinically, a compensatory hyperpnea will be present in the setting of severe metabolic acidosis caused by glycolic acid. Finally and maybe most interesting of all, urinary fluorescence may be seen. Most antifreezes have fluorescein additives to allow mechanics to more easily locate automotive leaks and can be seen under black light. This finding is transiently present in the urine within six hours of ingestion, but this finding lacks sensitivity and specificity for ethylene glycol ingestion.[7,10]
Once the toxidrome has been identified or a high clinical suspicion has been established, assessing airway, breathing, and circulation is priority. Securing the airway, as was necessary with our patient, may be warranted in severely intoxicated patients. Ventilatory settings should maintain high minute ventilation to prevent acidosis from worsening.[8]
There is no role for gastric decontamination given its rapid absorption in the stomach. The cornerstone of treatment is inhibition of alcohol dehydrogenase with either fomepizole or ethanol. These antidotes block the metabolism of ethylene glycol into glycolic and oxalic acid.[9] Treatment should not be delayed for confirmatory testing.[10] The American Academy of Clinical Toxicology’s minimum treatment threshold is 20 mg/dL, however there is not great literature to support this and is mainly a conservative number.[9]
Fomepizole is the preferred treatment regimen because it has fewer side effects than alcohol infusion though it is more expensive. The dosing regimen is 15mg/kg bolus followed by 10mg/kg twice daily until the ethylene glycol level falls below 20 mg/dL.8,9 Alcohol can be utilized where fomepizole is unavailable at a loading dose of 10mg/kg of a 10% ethanol solution over one hour followed by a 1mL/kg/hr infusion to a target blood alcohol level of 100mg/dL. This is difficult to maintain and should be administered via central line in an ICU setting due to the sedative and behavioral effects, multiple blood draws, frequent infusion titrations (decreased for an alcohol co-ingestion and increased after hemodialysis), and it may complicate overall fluid balance in the setting of acute kidney injury. Furthermore, alcohol infusions may not be appropriate for patients with history of gastrointestinal bleeding and first trimester pregnancy.[8]
After enzymatic blockade, direct elimination of ethylene glycol via hemodialysis becomes the mainstay of treatment. Hemodialysis is the most effective and rapid means of ethylene glycol elimination. Consultation with nephrology should not be delayed for confirmatory testing for a known ingestion or where high clinical suspicion exists.
Hemodialysis should be initiated immediately for a known ingestion with high anion gap metabolic acidosis or acute renal failure, an unknown ingestion with altered mental status along with a high anion gap metabolic acidosis and elevated osmolal gap, or with severe acidosis and high suspicion of ingestion.[8]
Hemodialysis should continue until serum ethylene glycol levels fall below 25mg/dL and is not necessary if initial levels are less than 20mg/dL. Concurrent fomepizole treatments should be increased as it is also dialyzable. Nephrology and medical toxicology consultations are necessary as strict cut off values for initiation of hemodialysis are unclear and may vary based on different sources.[3]
Beyond these modalities, aggressive IV fluid resuscitation, sodium bicarbonate infusion, and cofactor administration round out the treatment options for ethylene glycol overdose. Sodium bicarbonate and IV fluids are recommended as they will decrease the penetration of toxic metabolites into target tissues and promotes renal excretion.[10]
Sodium bicarbonate should be given as a 1-2mEq/kg IV bolus if pH <7.3 followed by an infusion at 150-250cc/hr with goal pH >7.35.8 Pyridoxine and thiamine administration are additionally given in order to further promote minor elimination pathways.[10]
Not all patients with ethylene glycol exposure will require treatment. Patients with unintentional ingestion who are asymptomatic with bicarbonate levels >20mmol/L at 4 hours post-exposure do not require treatment and can be safely discharged home.[9] Adults should also have a negative alcohol level in this scenario as toxicity will be delayed.
Our patient presented with several hallmarks of ethylene glycol toxicity. Chart review revealed prior suicidal attempts with ingestions making intoxication and overdose higher on our differential for his altered mental status. Further history provided by the patient’s girlfriend increased suspicions for ingestion.
Hyperpnea signaling severe acidosis and urine fluorescence were present clinically. Finally, the presence of high anion gap metabolic acidosis with elevated osmolal gap and acute kidney injury noted on laboratory workup clinched the diagnosis. Ethylene glycol level was confirmed in the medical intensive care unit at 81mg/dL. During the course of his admission, the patient regained full renal function following hemodialysis for one week and continued fomepizole treatment until his ethylene glycol level fell below 20 mg/dL. The patient was subsequently extubated with intact neurological function and later transferred to psychiatry for further behavioral health stabilization.
References
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- Keyes, DC. Ethylene Glycol Toxicity. Medscape. Dec 20, 2021. https://emedicine.medscape.com/article-814701-overview. Accessed Feb 22, 2022.
- Patocka J, Hon Z. Ethylene glycol, hazardous substance in the household. Acta Medica (Hradec Kralove). 2010;53(1):19-23. PMID: 20608228.
- Kraut JA, Kurtz I. Toxic alcohol ingestions: clinical features, diagnosis, and management. Clin J Am Soc Nephrol. 2008 Jan;3(1):208-25. doi: 10.2215/CJN.03220807. Epub 2007 Nov 28. PMID: 18045860.
- Sivilotti M. Methanol and ethylene glycol poisoning: Pharmacology, clinical manifestations, and diagnosis. In: Post TW, ed. UpToDate. UpToDate; 2022. Accessed Feb 22, 2022. https://www.uptodate.com/contents/methanol-and-ethylene-glycol-poisoning-pharmacology-clinical-manifestations-and-diagnosis
- Liesivuori J, Savolainen H. Methanol and formic acid toxicity: biochemical mechanisms. Pharmacol Toxicol. 1991 Sep;69(3):157-63. doi: 10.1111/j.1600-0773.1991.tb01290.x. PMID: 1665561.
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- Wallace KL, Suchard JR, Curry SC, Reagan C. Diagnostic use of physicians’ detection of urine fluorescence in a simulated ingestion of sodium fluorescein-containing antifreeze. Ann Emerg Med. 2001 Jul;38(1):49-54. doi: 10.1067/mem.2001.115531. PMID: 11423812.
- Sivilotti M. Methanol and ethylene glycol poisoning: Management. In: Post TW, ed. UpToDate. UpToDate; 2021. Accessed Feb 22, 2022.
- Barceloux DG, Krenzelok EP, Olson K, Watson W. American Academy of Clinical Toxicology Practice Guidelines on the Treatment of Ethylene Glycol Poisoning. Ad Hoc Committee. J Toxicol Clin Toxicol. 1999;37(5):537-60. doi: 10.1081/clt-100102445. PMID: 10497633.
- Gabow PA, Clay K, Sullivan JB, Lepoff R. Organic acids in ethylene glycol intoxication. Ann Intern Med. 1986 Jul;105(1):16-20. doi: 10.7326/0003-4819-105-1-16. PMID: 3717806.
- Barceloux DG, Bond GR, Krenzelok EP, Cooper H, Vale JA; American Academy of Clinical Toxicology Ad Hoc Committee on the Treatment Guidelines for Methanol Poisoning. American Academy of Clinical Toxicology practice guidelines on the treatment of methanol poisoning. J Toxicol Clin Toxicol. 2002;40(4):415-46. doi: 10.1081/clt-120006745. PMID: 12216995.
- Slaughter RJ, Mason RW, Beasley DM, Vale JA, Schep LJ. Isopropanol poisoning. Clin Toxicol (Phila). 2014 Jun;52(5):470-8. doi: 10.3109/15563650.2014.914527. Epub 2014 May 9. PMID: 24815348.