see also: [[Blood gas#osmolality and osmolar gap]], [[Solvents]] bookends: [Toxic Alcohols NEJM](bookends://sonnysoftware.com/pdf/DL/291413/1681805824/0), [goldfrank - toxic alcohols](x-devonthink-item://2F041FBD-FF1C-4E21-9CD5-5550C288F006?page=1447) > **ethylene glycol risk assessment:** > - Amount ingested > 1mL/kg is lethal dose > - Time of onset- peak toxicity within 1-4 hours since ingestion > - Co-ingestion of ethanol (prolongs time to toxicity) > - Serum osmolar gap >10 > - Serum ethylene glycol levels >50mg/dL > [!Key Points] > 1. Two broad groups of alcohols: scary [[Blood gas#HAGMA|high anion gap]] toxic alcohols ([[#Ethylene Glycol]] and [[#Methanol]], and less-scary [[#Ethanol]] and [[#Isopropyl alcohol]] > 2. methanol and ethylene glycol get metabolized into acids which lead to optic neuritis (methanol) ATN/ARF (ethylene glycol) requiring specific treatments, while isopropyl alcohol gets metabolized into acetone which generally requires supportive treatment only. > 3. ==The triad of acidosis, high osmolality and low or zero ethanol level is highly suspicious for a toxic alcohol ingestion.== > 4. The acidosis and osmolality in toxic alcohol poisoning are **inversely related**.  As the patient becomes more acidotic the osmolality decreases so that a normal osmolar gap does *not* rule out toxic alcohol poisoning. Think of their relationship like a pair of hockey sticks in a cross formation. > > Antidote:: [[#Ethanol treatment]], [[#fomepizole]] , [[#Indications for dialysis| haemodialysis]], [[HCO3 therapy]] > [!Goals of Management] > 1. **Block the toxic metabolites** with fomepizole or ethanol > 2. **Correct pH** to 7.2 with bicarb > 3. **Eliminate toxic metabolites** with dialysis (especially methanol) A delay in initiating treatment of toxic alcohol poisoning leads to worse outcomes. Do not wait for serum toxic alcohol levels to initiate treatment. ![[Pasted image 20230408205936.png]] ![[Pasted image 20230408211036.png]] ![[Pasted image 20230419174633.png]] # Clinical Signs 1. Tachyponea -- in absence of resp illness 2. visual changes -- "snowstorm" blurry vision for methanol. EOM paralysis is a late sign of ethylene glycol tox, rarely seen in ED 3. not appropriately sobering up 4. seizure with severe poisioning late in presentation > note that both methanol and ethylene glycol may cause ==elevated [[Lactic acidosis|lactate]]== # Ethylene Glycol > [!tip] Key features > metabolised by alcohol dehydrogenase to glycoaldehyde then broken down into **oxalic acid** and **glycolic acid** > causes renal failure, haematuria, hypocalcemia ## Risk assessment - Amount ingested > 1mL/kg is lethal dose - Time of onset- peak toxicity within 1-4 hours since ingestion - Co-ingestion of ethanol (prolongs time to toxicity) - Serum osmolar gap >10 - Serum ethylene glycol levels >50mg/dL ## Sources * antifreeze * degreasing agents * metal cleaners ## Clinical features * renal failure * [[Hypocalcemia]] with [[Long QT|prolonged QT interval]] * calcium is bound to oxalate and deposits in the kidneys causing renal failure and in the brain causing the late findings of parkinsonism and basal ganglia hemorrhages. * bilateral basal ganglia haemorrhages on CT is a late finding Note that urinary _calcium oxalate crystals_ have very poor sensitivity and specificity for ethylene glycol toxicity. The clinical picture of EG toxicity is typically divided into three stages: 1. **acute neurologic stage** 1. occurs over 30 minutes to 12 hours after ingestion 2. inebriation similar to ethanol. 3. In severe poisonings, CNS depression can progress to coma, hypotonia, and seizures. 4. Additional findings include nystagmus, ataxia, and myoclonic jerks. 5. Cerebral edema can develop from calcium oxalate crystal deposition and cytotoxic damage contributing to CNS depression 2. **cardiopulmonary stage** 1. occurs 12 to 24 hours after ingestion, with patients developing tachycardia with a severe metabolic acidosis and compensatory tachypnea. The acidosis occurs from the generation of glycolic acid. 2. Hypoxia with pulmonary edema and acute respiratory distress syndrome [[ARDS]] can cause hypoxia. 3. Multiorgan failure with circulatory collapse can occur, and most deaths ensue during this stage. 3. **renal stage** 1. The renal stage occurs 24 to 72 hours postingestion with the development of acute renal failure (ARF) from calcium oxalate crystal deposition. ## diethylene glycol * also some antifreeze productrs ## Toxicokinetics - Metabolism of EG primarily occurs in the liver via the conversion of ADH into glycoaldehyde, which is rapidly converted by ALDH into glycolate. Glycolate is further metabolized into ==glyoxylic acid== (glyoxylate) and ==oxalic acid== . - The conversion of glycolate into glyoxylate is slow, and the accumulation of glycolate generates a profound [[Blood gas#Metabolic acidosis]]. - A small amount of ==oxalate== will precipitate with calcium to form **calcium oxalate crystals**. These metabolic oxidation steps result in the conversion of NAD+ to NADH, which converts pyruvate to lactate and generates a **lactic acidosis**. - Calcium oxalate crystals precipitate in the proximal renal tubules and are the ==main contributing factor in the development of acute tubular necrosis and renal failure==. - Calcium oxalate deposits also occur in the brain, intestinal mucosa, lungs, heart, and spleen, although the contribution of these deposits to the clinical picture is less clear. - Further findings of EG toxicity include diffuse petechial hemorrhages in the heart, lungs, and brain, as well as the development of cerebral edema. - Myonecrosis and [[rhabdomyolysis]] can occur. - The chelation of calcium by oxalate can lead to systemic [[Hypocalcemia]]. # Methanol > [!doses] Approach > 1. Risk assessment > 2. Antidote — ethanol or fomepizole > 3. consult toxicologist * Clear, colourless ## Risk assessment - any ingestion >10mL can cause toxicity - 0.5mL/kg can be lethal ## Sources * home brew * model airplane fuel * windshield wiper fluid * de-icing products * paint remover * windex ## Tox kinetics * rapidly absorbed from Gi tract * peak concentration in 30-60 min * methanol itself has low toxicity, but its metabolism results in toxic metabolites (**formic acid**) → formate + H+ * metabolised in the liver by alcohol dehydrogenase into formaldehyde → aldehyde dehydrogenase → formic formic acid. * formic acid can combine with tetrahydrofolate to form 10-formyl THF * elmination zero order kinetics , at toxic concentrations elimination half life is nearly 24 hours ### formic acid and cellular respiration * formic acid accumulates due to slower metabolism. it binds iron, resulting in mitochondrial cytochrome oxidase inhibition, and interferes with oxidative metabolism in a manner similar to [[Cyanide]], [[carbon monoxide]], and Hydrogen sulfide. * interference of oxidative metabolism + acidosis promotes lactate production * decrased pH promotes formic acid diffusion across cell membranes, especially into CNS * results in **tissue hypoxia**, **inhibition of intracellular respiration** * other mechanisms include free radical formation, lipid peroxidation, and impairment of antioxidant reactions ### vision * ==formic acid uniquely targets the optic disc== of the retina and optic nerve. these cells are more susceptible to cellular hypoxia due to low levels of mitochodnria and cytochrome oxidase. results in decreased ATP --> myelin sheath damage, loss of vision. ### CNS * basal ganglia and subcortical white matter affected by formic acid similar to ocular toxicity. can cause putamen hypodensity, haemorrhages, and necrosis. * basal ganglia possibly more vulnerable to formic acid due to high metabolic activity and poor venous drainage ## Clinical features * early features similar to EtOH * GI irritation, inebriation, CNS depression * latent period of 12-24 hours before other features apparent * severe metabolic acidosis * coma * visual impairment‘snowstorm’ vision -- up to 1/3 suffer perminant visual impairment * initial high [[Blood gas#osmolality and osmolar gap|osmolar gap]] and low anion gap * as MeOH metabolised, osmolar gap decreases and anion gap increases * a severely poisone dpatient can present with normal AG and pH but elevated osmolar gap * co-ingestion of EtOh delays onset of toxicity ## Management - any delay can cause more severe toxicity - **No roll for activated charcoal** (doesn't absorb MeOH) - intermittent [[haemodialysis]] preferred modality - [dialysis](x-devonthink-item://2F041FBD-FF1C-4E21-9CD5-5550C288F006?page=1454) is definitive management, but if patient doesn't have any [[#Indications for dialysis]], then can do fomepizole or ethanol treatment - [[HCO3 therapy|bicarb]] correct acideaemia if pH <7.3 (bolus 1-2mL/kg 8.4% solution) - co-factors: IV folinic acid 30mg q6H for 48 hours may help in metabolism to non-toxic metabolites - ==Antidote== [[#Ethanol treatment]] or [[#fomepizole]] - alcohol dehydrogenase blocker > [!treatment] Indications for antidote therapy > documented history of ingestion AND OG >10 or raised anion gap > **OR** suspicion of ingestion AND at least two of pH <7.3, HCO3 <20, OG >10, visual disturbance > **OR** MeOH concentration >20mg/dL # Treatment ## Ethanol treatment - target serum ethanol concentration is 0.1 - 0.15% (22-33 mmol/L) - monitor glucose - continue until serum methanol is <6 mmol/L - Commercially available 40-43% preparations (e.g., Vodka) may be given orally (PO) or via a nasogastric tube - 10 mL vial of 96% ethanol for dilution and administration via intravenous infusion. - add 100 mL of 96% ethanol to 1000mL of 5% dextrose > [!doses] Ethanol Dose > Oral: > **loading dose** (over 30-60 minutes): 1.8 mL/kg of 40-43% ethanol (4 x 30 mL shots vodka in a 70 kg adult) > **Maintenance**: 0.4 mL/kg/hour of 40-43% ethanol (30 mL of vodka each hour in a 70 kg adult) > > IV: > 8 mL/kg over 30-60 min > Aim maintenance of serum ethanol concentration of 0.1-0.15 g/dL (100-150 mg/dL OR 22-33 mmol/L) > monitor hourly Alcohol dehydrogenase is not effectively blocked at serum ethanol concentrations < 0.1 g/dL (22 mmol/L) ## Fomepizole - **competitive inhiitor of alcohol dehydrogenase** - blocks first stage in metabolism of methanol and ethylene glycol to their respective toxic metabolites - toxic alcohols are then excreted unchanged in urine - preferred in children and pregnancy , as well as signfincant liver disease - better in patients with low GCS or on disulfram --> may contribute to severe disulfran reactions Adverse effects: - headache, nausea - phlebitis - eosinophilia, transamniitis > [!treatment] Fomepizole Dose > 1.5g/1.5 mL vial: (dilute in 100 mL 0.9% NaCl or 5% dextrose to avoid venous irritation) > Loading dose: 15mg/kg > maintenance dose: 10 mg/kg IV every 12 hours for 48 hours (4 doses) (Q4 hours if intermittent haemodialysis; Q8H if CVVHD) **Therapeutic endpoint:** Osmol gap <10, resolving acidosis, serum methanol or ethylene glycol concentration <20mg/dL # Indications for dialysis 1. Metabolic acidosis with evidence of end organ damage (ocular, renal, CNS) 2. Methanol >15 mmol/L 3. Ethylene glycol >6 mmol/L 4. Elevated osmolar gap if toxic alcohol levels not available See: [[haemodialysis|dialysis]] # Non-scary alcohols ## Isopropyl alcohol * hand sanitiser * rubbing alcohol - presents similarly to ethanol poisoning only more severely with coma and cerebellar signs, and it has more of a predilection for hemorrhagic gastritis and pancreatitis. Don’t ignore abdominal complaints in patients with a history of alcohol misuse! - Isopropyl alcohol is about ==twice as inebriating as is ethanol (for any particular load or blood level)== and lasts twice as long. can cause haemorrhagic gastritis, pulm oedema, #hypoglycaemia , severe hypotension **ketosis** # Using Osmolar Gap Relative contribution of agents to the osmolar gap, ​in decreasing order for a fixed amount in the serum: - ​methanol - ethanol - ​acetone - ​isopropyl alcohol - ​ethylene glycol - ​propylene glycol > ​the concentration of a known toxic alcohol can be estimated from the osmolar gap > [!Definition] > multiply the osmolar gap by the molecular weight of the alcohol divided by 10 to get the concentration in mg/dL - the change in the osmolar gap is most helpful, not absolute single values - ​normal range of osmolar gap is -4 - +10 - ​the osmolar gap decreases as toxic alcohol metabolites increase - ​osmolar gap is of use in the detection of toxic alcohol poisoning ==only in the early phase== * ​**may be elevated in non toxicological causes** * alcoholic ketoacidosis (mechanism unexplained) * other organ failure # Related Questions ## blood gas - [ ] 5Q: [Altered level of consciousness](x-devonthink-item://D4C19F6F-0718-4AD7-BDC4-34B460451B98?page=9) -- [Answer](x-devonthink-item://736EC9CD-AC9C-4588-BA1E-F4AD190CBA47?page=17) ## charcoal - [ ] 6Q: [Altered consciousness and altered ECG](x-devonthink-item://554C45F7-8661-4467-BD61-8A79B6ECABF4?page=5) -- [Answer](x-devonthink-item://554C45F7-8661-4467-BD61-8A79B6ECABF4?page=6) ## ethylene glycol - [ ] 22Q: [Rural overdose](x-devonthink-item://1A2C485F-D4AD-4821-AFF2-452BA753717F?page=22) -- [Answer](x-devonthink-item://FD716379-1A77-4B5B-B257-1154995ECA6E?page=13) ## ethylene glycol toxicity - [ ] 23Q: [Unknown ingestion and seizure](x-devonthink-item://B9C99BB4-DAF8-4D15-BBD3-40E82B279902?page=0) -- [Answer](x-devonthink-item://DF848F67-27AB-450A-988B-159784B72957?page=0) ## pancreatitis - [ ] 39Q: [Pancreatitis](x-devonthink-item://554C45F7-8661-4467-BD61-8A79B6ECABF4?page=64) -- [Answer](x-devonthink-item://554C45F7-8661-4467-BD61-8A79B6ECABF4?page=66) - [ ] 40Q: [Pancreatitis](x-devonthink-item://F0498813-9350-484C-AD5B-6FF7C3AE9015?page=30) -- [Answer](x-devonthink-item://A491A3F6-FD6D-492F-BCBE-7F7BAE101EDF?page=30) - [x] 41Q: [Pancreatitis](x-devonthink-item://1EA9311E-0B9E-49F7-8D6E-4C4187A838C4?page=15) -- [Answer](x-devonthink-item://B1CB2E8F-5D04-49EE-8274-043871389D28?page=8) ## risk assessment - [ ] 45Q: [Eucalyptus oil ingestion](x-devonthink-item://1A2C485F-D4AD-4821-AFF2-452BA753717F?page=40) -- [Answer](x-devonthink-item://FD716379-1A77-4B5B-B257-1154995ECA6E?page=27) - [ ] 46Q: [Overdose](x-devonthink-item://FE3157C2-07B3-43F2-9ECE-AFACE1355E13?page=37) -- [Answer](x-devonthink-item://DDC959EB-0C1E-448A-8380-C397BF734322?page=18) - [ ] 47Q: [Schizophrenia and Agitation](x-devonthink-item://09CFA1A7-00F1-4151-979E-8F3984924D54?page=57) -- [Answer](x-devonthink-item://CF5E9C2B-42F9-4F9C-AC29-877E20134927?page=37) ## seizure - [ ] 60Q: [Amitriptyline Overdose](x-devonthink-item://7E9EF652-F67B-42C5-A536-2EE85BA1954F?page=45) -- [Answer](x-devonthink-item://2DE5FACA-6D8F-41A2-8EAA-8DFE1E76FA61?page=28) ## seizures - [ ] 63Q: [Unknown ingestion and seizure](x-devonthink-item://1EA9311E-0B9E-49F7-8D6E-4C4187A838C4?page=16) -- [Answer](x-devonthink-item://B1CB2E8F-5D04-49EE-8274-043871389D28?page=9) ## toxic alcohols - [x] DUPLICATE Q: [Altered level of consciousness](x-devonthink-item://D4C19F6F-0718-4AD7-BDC4-34B460451B98?page=9) -- [Answer](x-devonthink-item://736EC9CD-AC9C-4588-BA1E-F4AD190CBA47?page=17)