Toxic alcohols

1
Toxic alcohols

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• 91-01-22

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Methanol

• Methanol is a colorless, volatile, slightly
  sweet-testing alcohol.
• Certain products in home may contain high
  concentrations of methanol including antifreeze,
  windshield washer fluid, engine fuel, glass
  cleaners, lacquers, adhesives and inks.
• Industrially, the manufacture of plastics, films
  and dyes formalin and embalming fluid.

3
Methanol

• Methanol ingestion can result in serious sequelae
  such as permanent blindness, neurologic
  dysfunction, and death. Treatment delay is
  associtaed with increased morbidity.

4
Pharmoacology

• Rapidly absorbed from GI tract, blood levels peak
  30 to 60 mins after ingestion.
• A prolonged half-life of 24 to 30 hours, which
  may be extended by the concurrent ingestion of
  ethanol.
• In adults, the smallest lethal dose reported is
  15ml of 40 methanol, with as little as 4ml of
  pure methanol leading to blindness.

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Pharmacology

• As in child, 1.5ml of 100 methanol is sufficient
  to produce a toxic blood level of 20mg/dl, which
  requires therapy.
• Methanol has little toxicity less CNS depression
  and inebriation than ethanol. 90 is hepatically
  metabolized.

6
Pharmacology

• Methanol is oxidized by alcohol dehydrogenase to
  formaldehyde, which is then rapidly converted by
  aldehyde dehydrogenase to formic acid.
• Formic acid accounts for much of the anion-gap
  metabolic acidosis and ocular toxicity peculiar
  to methanol ingestion.
• Through a folate-dependent pathway, formic acidis
  degraded to carbon dioxide and water.

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Pathophysiology

• Optic neuropathy and putaminal necrosis are the
  two main complications of severe methanol
  poisoning.
• The primary sites of ocular injury are the
  retrolaminar optic nerve and retina.
  Histopathologic suggest that retinal cells
  develop intra-axonal swelling, calcium influx,
  mitochondrial destruction, and microtubular
  disruption.

8
Pathophysiology

• Formic acid has a high affinity for iron and
  inhibits mitochondrial cytochrome oxidase,
  halting cellular respiration.
• Lactate accumulation resulting from hypotension
  or seizures further compounds the metabolic
  acidosis caused by formate.
• Acidosis may accelerate this process, by
  enhancing nonionic diffusion of formic acid into
  neurons and further increaseing lactate.

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Pathophysiology

• This self-perpetuating cycle of acidosis, termed
  circulus hypoxicus, underscores the need for
  aggressive normalization of pH during therapy to
  accomplish ion-trapping of formate outside the
  CNS.

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Pathophysiology

• Necrosis of basal ganglia occurring in up to
  13.5 of pts. Also seen in the subcortical white
  matter, spinal cord anterior horn cells, and
  cerebellum.
• Why localization of neurologic damage to the
  basal ganglia is not known.
• High concentration of formate level
• Massive edema in MRI suggests possible localized
  disruption of the BBB

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Clinical features

• History may be unobtainable or unreliable.
• Consider in pts with altered mental status,
  visual complaints, or metabolic acidosis, or in
  those whose occupation may place them at high
  risk for exposure.
• Significant latency exists between the time of
  ingestion and onset of visual or metabolic
  disturbance. Typically 12- to 24- hrs.

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Clinical feature

• Once symptoms manifest, they are primarily
  neurologic, gastrointestinal, or ocular in
  nature.
• Visual disturbances are seen in 50 of pts, and
  their development may precede or parallel that of
  other clinical symptoms.

13
Clinical feature

• Pts may complain of cloudy, blurred, indistinct,
  or misty vision or may note yellow spots, or
  rarely photophobia.
• The most common acute field defect is a dense
  central scotoma. Some pts compare their visual
  symptoms to stepping out into a snowstorm a
  complaint unique to methanol ingestion.

14
Clinical feature

• Tachypnea heralds metabolic acidosis. Early
  tachycarida has been noted, but in general,
  cardiovascular abnormalities are unusual.
  Hypotension and bradycardia, when present, are
  preterminal findings.
• Historically, death was described in association
  with a peculiar, abrupt cessation of respiration,
  rather than with cardiovascular collapse. Rarely,
  multiple organ failure develops.

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Clinical features

• Prognosis correlate with the degree of acidosis,
  time to presentation, and initiation of treatment
  within 8 hrs of exposure.
• Pts surviving the acute phase of toxicity may be
  left with permanent blindness or neurologic
  deficts, such as parkinsonism, toxic
  encephalopathy, polyneuropathy, cognitive
  dysfunction, transverse myelitis, primitive
  reflexes, or seizures.

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Diagnostic strategies

• A severe anion gap metabolic acidosis is the
  hallmark of methanol ingestion.
• Another classic lab finding methanol toxicity is
  an elevated osmolal gap. (The normal osmolal gap
  is less than 10mosm/kg.)
• A toxic level of either methanol or ethylene
  glycol may be present with a gap of 10mosm/kg.

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Diagnostic strategies

• In addition to methanol, ethylene glycol, and
  isopropanol, other low-molecular-weight solutes
  may cause elevated osmolal gaps, such as ethanol,
  acetone, propylene glycol, mannitol, glycerol, or
  ethyl ether.
• In addition to severe acidosis, rhabdomyolysis,
  pancreatitis and hypomagnesemia, hypokalemia, and
  hypophophatemia are described.

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Differential considerations

• Altered mental status
• Hypoglycemia, head trauma, postictal state,
  carbon dioxide narcosis, hypoxia, infection,
  hepatic encephalopathy, other metabolic
  disorders, thiamine deficiency, endocrinopathy,
  and toxicant ingestion or exposure, etc.

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Differential considerations

• Elevated anion gap
• CO, alcoholism, toluene, methanol, uremia, DKA,
  paraldehyde, INH, iron, lactic aicdosis, ethylene
  glycol, salicylates, metformin, cyanide, cocaine,
  etc.
• Double gap (osmolal gap anion gap)
• DKA, AKA, acetonitrile, methanol, ethylene
  glycol, propylene glycol toxicity multiple organ
  failure, CRF, critical illness.

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21
Ethylene glycol

• Ethylene glycol is a viscous, colorless,
  odorless, slightly sweet-tasting liquid.
• Its primary utiliy is as a commercial antifreeze,
  due to it lowers freezing point of water.

22
Pharmacology

• Absorption of ethylene glycol is rapid after
  ingestion. Peak blood levels reaches within 1 to
  4 hrs.
• Unlike methanol and isopropanol, ethylene glycol
  is nonvolatile at room temperature therefore,
  absorption via inhalation is unlikely.

23
Pharmacology

• Half-lives range from 3 to 8.6 hrs.
• The toxic and lethal doses of 100 ethylene
  glycol have been reported as 0.2 and 1.4ml/kg.
• A total of 27 of ethylene glycol is excreted
  unchanged by the kidneys. The remainder is
  hepatically oxidized via alcohol dehydrogenase
  and other oxidative enzymes.

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Metabolism of ethylene glycol
Ethylene glycol
Glycoaldehyde
Glycolic acid
Pyridoxine
Thiamine
Glyoxylic acid
?-hydroxy-?-ketoadipate
Glycine
Oxalic acid
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Pathophysiology

• 2.3 of a dose of ethylene glycol is ultimately
  converted to oxalic acid, most of which is
  excreted in the urine.
• A fraction of oxalic acid combines with calcium
  to form calcium oxalate crystals, which then
  precipitate in renal tubules, brain and other
  tissues.

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Pathophysiology

• Histologically, proximal renal tubular dilation
  with hydropic change and vacuolar degeneration,
  intratubular crystal deposition, and edema of the
  interstitium are seen.

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Pathophysiology

• Neuropathologic changes include diffuse calcium
  oxalate deposition with petechial hemorrhages in
  the retina, brain, vessel walls and perivascular
  spaces.
• Similar chages have also been noted in the liver,
  spleen, pancreas, pleura, lungs, pericardium and
  blood vessel walls throughout the body.

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Pathophysiology

• Profound anion gap metabolic acidosis caused
  mainly by glycolic acid.
• An intermediary of glycolic acid metabolism,
  glyoxylic acid, can theoretically be shunted
  toward pyridoxine- or thiamine-dependent pathway,
  which generate nontoxic products.

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Clinical features

• 4 stages acute neurologic stage, cardiopulmonary
  stage, renal stage, and delayed neurologic
  sequlae stage.
• Pts may die in any stage of poisoning. Poor
  prognositc factors include hyperkalemia, severe
  acidosis, seizures and coma. Symptoms may be
  delayed for 4-8 hrs if ethanol is coingested.

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Clinical features

• The acute neurologic stage, occurs 30 mins to 12
  hrs after ingestion.
• CNS depression, slurred speech, nystagmus,
  ataxia, and vomiting may be seen large
  ingesions, hallucinations, convulsions or coma
  may be present during the early phase.
• Ocular findings, similar to methanol intoxication
  are reported.

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Clinical features

• The cardiopulmonary stage, occurs 12 to 24 hrs
  after ingestion.
• Hypertension and tachycardia
• Tachypnea may reflect the metabolic acidosis or
  the onset of cardiogenic or noncardiogenic
  pulmonary edema.
• ARDS may be related to toxicity of glycolic and
  glyoxylic acids and the deposition of calcium
  oxalate within the lungs.

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Clinical features

• The renal stage, occurs 24 to 72 hrs after
  ingestion in about 67 pts.
• Awake pts may complain of flank pain or CP angle
  tenderness. Hematuria and proteinuria are common.
• The degree of acidosis, and glycolate levels
  correlate better with the development of renal
  failure.

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Clinical features

• The delayed neurologic sequelae stage, occurs 6
  to 12 days after ingestion and typically
  manifests as cranial neuropathy.
• Facial diplegia, occasionally with deafness is
  most frequently encountered other finding
  include dysarthria, dysphagia, tongue deviation,
  visual deterioration. Facial auditory nerve
  oxalosis
• Cognitive and motor deficit ataxia, chorea,
  personality changes are also reported.

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Diagnostic strategies

• Crystalluria is considered the hallmark of
  ethylene glycol ingestion, but less than half the
  pts have this finding.
• Other finding reflective of tubular dysfunction
  include decreased specific gravity, proteinuria,
  microscopic hematuria.

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Diagnostic strategies

• A qualitative but useful test in the ED involves
  examining voided urine for fluorescence with a
  Woods lamp.
• Gastric contents and pts skin or clothing may
  also fluoresce under Woods lamp exam.

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Diagnosis strategies

• One third of pts have hypocalcemia, which is most
  likely caused by calcium precipitation with
  oxalate. QT prolongation on ECG leads to the
  early diagnosis of hypocalcemia.
• Profound anion gap metabolic acidosis.
• An elevated osmolal gap as measured by freezing
  point depression is a clue to the diagnosis of
  ethylene glycol.

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Diagnosis strategies

• The CSF may be normal or may display a cloudy or
  bloody appearance, increased protein or most
  commonly, a PMN pleocytosis.
• Imaging studies show cerebral edema with
  decreased attenuation in the mediobasilar
  portions of the brain, typically with a return to
  isodensity within 1 wk. This does not necessarily
  correspond to the clinical picture.

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Differential considerations

• Classically, pts who ingest ethylene glycol
  appear intoxicated without the odor of ethanol,
  have an anion gap metabolic acidosis, increased
  osmolal gap, and calcium oxalate crystalluria.
• Renal toxicity antimicrobials, NSAID,
  acetaminophen, radiocontrast media, halogenated
  hydrocarbon, metals, antineoplastics, and
  myoglobin.

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Management

• Methanol and ethylene glycol ingestion are
  treated essentially the same.
• Specific blood levels that confirm the presence
  of these substances may not be readily available,
  and a delay in instituting therapy can lead to
  irreversible organ damage or death. Therefore,
  for any significant history of exposure,
  treatment should be initiated pending a
  confirmatory toxic alcohol blood level.

40
Management

• Gastic lavage is restricted to the pt who arrives
  in the ED within 30 to 60 mins of ingestion.
• 3 goal
• Correction of metabolic acidosis with bicarbonate
• Alcohol dehydrogenase blockade
• Removal of the parent alcohol and its metabolites
  by hemodialysis

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Management

• IV bicarbonate can be administered by
  intermittent boluses, an initial bolus followed
  by an infusion or infusion alone.
• Boluses of 1 to 2 mEq/kg to attain a target serum
  pH of 7.45 to 7.50 followed by an infusion of
  150mEq/L of 5 dextrose at 1.5 to 2 times the
  maintenance fluid rate are suggested.
• Early correction of metabolic acidosis is
  beneficail in reversing methanol-induced visual
  impairment.

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Management

• To prevent further production of the toxic and
  acidic metabolites of methanol and ethylene
  glycol, metabolism of the parent compounds must
  be blocked.
• Ethanol or fomepizole (Antizol)
• Symptomatic adult or child, or in asymptomatic pt
  with methanol or ethylene glycol levels gt20 mg/dl.

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Management
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Management

• If ethanol is used to block ADH, the goal is to
  maintain the blood ethanol level between 100 and
  150 mg/dl, which will completely saturate alcohol
  dehydrogenase.

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Management

• Fomepizole
• 15 mg/kg followed by 10 mg/kg q12h for 4 doses.
• Ease of administration, predictable
  pharmacokinetics, improved pt safety profile
• Side effects headache, nausea, dizziness,
  inflammation at site of infusion, rash
  eosinophilia, mild transaminase elevation.

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Management

• Indications of hemodialysis
• Metabolic acidosis, renal compromise, visual
  symptoms, deterioration despite intensive
  supportive care, electrolyte imbalances
  unresponsive to conventional therapy.
• gt25mg/dl of blood level
• Endpoint undetectable serum ethylene glycol or
  methanol concentration and disappearance of
  acid-base abnormalities and signs of systemic
  toxicity.

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Management

• 50mg of leucovorin (folinic acid) should be given
  IV q4h to pts with methanol toxicity.
• Empiric administration of thiamine 100mg IV q6h
  and pyridoxine 50mg q6h for 2 days with ethylene
  glycol toxicity.

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49
Isopropyl alcohol

• Isopropyl alcohol (isopropanol) is a clear,
  colorless liquid with a slightly bitter taste.
• It is the second most commonly ingested alcohol
  after ethanol.
• Sources rubbing alcohol, skin and hair products,
  nail polish removers, disinfectants, antifreezes.

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Pharmacology

• Absorption of isopropanol is rapid and complete.
  Kidney excrete 20 as unchanged isopropanol.
  Remaining 80 is metabolized in the liver to
  acetone by ADH.
• Acetone is primarily excreted by the kidneys with
  small amounts expired through the lungs.

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Pathophysiology
Isopropanol
Alcohol dehydrognease
Acetone
Kidneys lung (minor)
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Pathophysiology

• Isopropanol and acetone are potent CNS
  depressants, but the mechanism of action is
  unclear.
• Acetone does not be shunted into the formation of
  acetoacetate or ß-hydroxybutyrate therefore the
  finding of ketosis without acidosis is
  characteristic of isopropyl ingestion.

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Clinical findings

• Intoxication may be suspected based on apparent
  inebriation with the odor of acetone rather than
  ethanol on the breath.
• Headache, dizziness, neuromuscular
  incoordination, confusion, nystagmus, respiratory
  depression, loss of DTR, corneal or protective
  airway reflexes.
• GI irritation abdominal pain, nausea and vomit

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Clinical findings

• Hypotension signifies severe poisoning, with the
  mortality rate as 45 with this finding.
• Sinus tachycardia
• Characteristically, metabolic acidosis is not
  present with isopropanol intoxication unless
  accompanied by hypotension, GI bleeding, or
  coingestants.

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Diagnostic strategies

• Isopropanol levels
• The most common lab abnormality is ketosis with
  little or no acidosis and normal blood glucose
  level acetone is uncharged, so it doesnt
  elevate the anion gap.
• Both isopropanol and acetone contribute to the
  increased osmolal gap.

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Diagnositic strategies

• Pseudo renal failure isolated false elevation of
  Cr with a normal BUN. This results from
  interference of acetone and acetoacetate by the
  colorimetric method of creatinine determination.

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Differential considerations

• High or rising Cr and normal BUN, acute
  rhabdomyolysis should also be considered other
  substances that falsely elevate creatinine are
  cimetidine and nitroethane.
• Ketosis DKA, AKA, cyanide, or starvation ketosis.

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Management

• Unless large amounts have been ingested very
  recently, neither gastric emptying nor charcoal
  administration is warranted.
• ADH blockade is not indicated.
• Hypotension should be managed with fluids and
  vasopressors. Dialysis is indicated in vital sign
  deterioration.

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Management

• Some authors also recommend dialysis for
  isopropanol levels gt400 mg/dl.
• Hemodynamically stable without coma during the
  first 6 hrs will be at low risk.
• Care is supportive and includes rewarming,
  administration of thiamine, evaluation for
  hypoglycemia, and monitoring for GI bleeding.