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Scientific Article | as coma, hypotonia, hyporeflexia, seizures, and meningismus, replace earlier symptoms. 3,8 Cerebral edema, secondary to direct cytotoxic damage as well as the deposition of calcium oxalate in the CNS, as verified in autopsy studies, contributes to CNS depression. 9 Stage 2: Cardiopulmonary (12-24 hours after ingestion) Symptoms during this phase 3 include shortness of breath and physical findings are consistent with congestive heart failure. 8,9 In serious cases, severe metabolic acidosis with compensatory hyperventilation can develop accompanied by multiple organ failure. Most deaths occur in this stage. 5 Stage 3: Renal (24-72 hours after ingestion) The third stage can include oliguria and flank pain indicative of acute tubular necrosis and renal failure. 5 The renal toxicity of EG is thought to be due to a combination of hydronephrosis from calcium oxalate crystals and a direct toxic effect from EG metabolites. 8 Tubular atrophy and interstitial fibrosis are poor prognostic indicators of renal function. 7 Recovery of renal function is typically complete but may require several months of hemodialysis. 3 Methanol: Clinical Features MTH is a highly toxic alcohol commonly found in a variety of commercial products such as windshield wiper fluid, gas line antifreeze, paint strippers, and industrial solvent. 3 Symptoms and signs of MTH intoxication usually are limited to the CNS, eyes, and gastrointestinal tract. Initial symptoms may appear as soon as 12 hours post-ingestion, but usually develop 24 hours after ingestion. 10 Initial symptoms may resemble these of ethanol intoxication including drowsiness, confusion, nausea, and vomiting. 3 It produces less euphoria than ethanol. 10 Visual disturbances range from blurred vision, photophobia, visual field defects, and blindness. 11 Fundoscopic exam may reveal hyperemia of the optic disc or papilledema. 11 There may be pupillary dilation and loss of the pupillary reflex. 10 Visual changes with MTH poisoning are due to microtubule and mitochondrial destruction in the retrolaminar optic nerve. 10 Severity of the visual abnormalities is directly correlated with the severity of the metabolic acidosis. 9 Severe poisoning is Figure 1. Toxic Metabolic Activation of Ethylene Glycol. Thiamine Magnesium a-Hydroxy-- β-Ketoadipate Other Pathways Oxalomalate Formate + Carbon Dioxide γ=Hydroxy-a-Ketoglutarate Ethylene Glycol Glycoaldehyde Glycolate (Glycolic Acid) Glyoxylate (Glyoxylic Acid) Oxalate Calcium Oxalate associated with cerebral edema, coma, and seizures. 11 Survivors may develop a parkinsonism-like syndrome which correlates with CT evidence of destruction in the putamen and subcortical white matter hemorrhage. 12 Survivors may have permanent blindness or neurological deficits. 2 Pharmacokinetics of ethylene glycol and methanol EG and MTH are rapidly absorbed after oral ingestion and both have a Alcohol Dehydrogenase* Aldehyde Dehydrogenase Calcium Pyridoxine Glycine * Conversion of ethylene glycol to glycoaldehyde is the rate-limiting step; alcohol dehydrogenase is inhibited by ethanol and 4-MP. This information was originally published in Emergency Medicine Reports. Reprinted with permission of AHC Media LLC, PO Box 740056, Atlanta, GA 30374. For subscription information, contact customer service at (800) 688-2421 13 . 20 West Virginia Medical Journal
| Scientific Article small volume of distribution (0.5- 0.8 L/kg). 9 The estimated minimum lethal adult dose of EG and MTH is 100 ml and 10 ml correspondingly. 3 Both undergo metabolism through hepatic alcohol dehydrogenase (ADH) to toxic metabolites as seen in Figure 1 and Figure 2. 13 With normal renal function, the elimination half life of EG is 3-8 hours and that of MTH is 14-30 hours. 9 If ADH is competitively blocked by another agent, such as ethanol or fomepizole, then metabolism is halted and the parent compounds are eventually renally eliminated unchanged. 14 Laboratory Abnormalities of ethylene glycol and methanol intoxications The Anion Gap Although determination of the anion gap is considered essential in the diagnosis of toxic alcohol ingestion, an anion gap acidosis will be observed only after the parent compound has been metabolized to its toxic by-products (approximately 3-6 hours depending on the elimination half life of the alcohol). 14 Glycolic acid and formic acid are largely responsible for the anion gap metabolic acidosis in the metabolism of EG and MTH respectively. 3 However, some of the acidosis stems from the production of lactate and is due to the reduction of nicotinamide adenine dinuleotide to nicotinamide adenine dinucliotide, reduced form. 3 Furthermore, the anion gap cannot be relied on as an accurate screening tool in cases where ethanol is a coingestant. 15 An ethanol level of greater than 100 mg/dl competitively inhibits ADH and will increase the elimination half life by fivefold or more. 14 All patients admitted with a diagnosis of EG or MTH intoxication had an elevated anion gap (Table 1). It is of interest that patient number nine presented with a very high ethylene glycol level with only a mild elevation of the anion gap; it is presumed that patient number nine presented very early in the course of toxicity given that there was not any evidence of other sources of intoxication. The Osmolar Gap The parent compound contributes to the osmolar gap because it is osmotically active and has a relatively small molecular weight. 3 Toxic acids generated by EG and MTH metabolism do not contribute to the osmolar gap; thus, the longer the delay in measurement of serum osmolarity from the time of ingestion, the more likely the osmolar gap may approach normal values. 14 Although it is conventionally believed that an OG of less than 10 mOsm/L is normal, other authors have found that the range of normal osmol values within the population is large (-5 to +15 mOsm/L). 16 Also, the value of the OG depends on the equation used to determine the gap; for example, the inclusion of ethanol in its determination lowers the traditionally accepted OG. 16 Further, other conditions such as alcoholic ketoacidosis, Figure 2. Toxic Metabolic Activation of Methanol. lactic acidosis, renal failure are associated with an elevated OG. 15 All patients admitted with EG or MTH poisoning had an elevated osmolar gap (except patient number nine where the OG data were unavailable, Table 1). Urinalysis Calcium oxalate deposition in tissues is one mechanism of toxicity, which contributes to hypocalcemia. Oxalate crystalluria is considered a hallmark of EG poisoning. 9 Up to 50% of patients with EG toxicity have calcium oxalate crystals in their urine and, if present, aides in diagnosis. 5 However, the absence of calcium oxalate crystaluria does not exclude EG poisoning. 8 Management of ethylene glycol and methanol poisoning The first approach to a patient suspected to have toxic alcohol poisoning is appropriate airway management, resuscitation and stabilization. 2 If toxic alcohol poisoning is suspected, poison control should be contacted and 1. Methanol alcohol dehydrogenase* Formaldehyde** aldehyde dehydrogenase 2. Formaldehyde Formic Acid + (Formate) 3. Formic acid Cofactor: tetrahydrofolate)++ Carbon Dioxide (Formate) and Water * The conversion of methanol to formaldehyde is the rate-limitng step. Alcohol dehydrogenase is inhibited by ethanol and 4-MP. ** Although the formaldehyde metabolite is quite toxic, in humans it has a very short half-life and does not significantly contribute to toxicity. + Accumulation of formate is responsible for metabolic acidosis and ocular toxicity in humans. ++ Hepatic metabolism of formate is a folate-dependent process; administration of exogenous folinic or folic acid may increse this conversion. This information was originally published in Emergency Medicine Reports. Reprinted with permission of AHC Media LLC, PO Box 740056, Atlanta, GA 30374. For subscription information, contact customer service at (800) 688-242113. September/October 2010 | Vol. 106 21
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