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Monday, June 1, 2015

It's 5 O'Clock in the ED Somewhere: An Intoxicating Review of Antidotal Ethanol

https://s-media-cache-ak0.pinimg.com/236x/7a/38/b1/7a38b11da26f5c814475f2eb4d80a718.jpgSay you have a patient who consumed almost an entire gallon of antifreeze over a span of 24 hours. Even Animal House’s Blutowski would be concerned, given that an adult who inadvertently sips 10-30 mL of antifreeze should be referred to the emergency department for evaluation of potential toxicity [1]. Initial lab results reveal an ethylene glycol (EG) level of 76 mg/dL, arterial pH of 6.9, and a serum bicarbonate level of 7 mmol/L. The medical team requests treatment with fomepizole, however due to its recent stint on ASHP’s National Drug Shortage List [2], you're forced to create a good old-fashioned intravenous ethanol cocktail.

The use of ethanol as an antidote for methanol and EG poisonings was first documented in the 1940s and 1960s, respectively [3]. Toxicity occurs secondary to accumulation of toxic metabolites formed by the enzymes alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (Figure 1). Although clinical presentation may vary between individuals, acute EG intoxication often progresses through three distinct stages: central nervous system depression (0.5-12 hours post ingestion), followed by cardiopulmonary dysfunction (12-24 hours), and lastly renal dysfunction (24-72 hours) [4]. Profound metabolic acidosis arises from accumulation of glycolic acid and oxalic acid, which may trigger hyperventilation (Kussmaul breathing) as a compensatory mechanism. Furthermore, visual disturbances and blindness have been reported in patients with severe methanol poisoning.

Management generally consists of supportive care (e.g. intravenous fluids, correction of electrolyte abnormalities and acidemia, etc.), the use of antidotes to antagonize ADH and prevent the formation of toxic metabolites, and hemodialysis. Hemodialysis fosters the removal of parent compounds as well as their toxic metabolites and is considered a key element in the treatment of severe EG and methanol intoxication. This may allow for a shorter duration of antidotal therapy and a reduction in hospital length of stay [4].

When should antidotal therapy be initiated following EG or methanol ingestion? [3,5,6,7]
  1. Serum EG or methanol level >20 mg/dL
  2. Documented history of recent ingestion of toxic alcohol and osmole gap >10 mOsm/L
  3. Clinical suspicion of toxic alcohol poisoning with at least 2 of the following criteria: 
    •  Arterial pH <7.3  
    • Serum bicarbonate level <20 mmol/L
    • Serum osmole gap >10 mOsm/L
    • Calcium oxalate crystallization
Evidence regarding criteria for initiation of hemodialysis is more limited, and often based on clinical experience. Some criteria previously reported include an initial EG/methanol level >50 mg/dL, severe metabolic acidosis, renal failure, visual disturbances (methanol ingestion), and deterioration of vital signs or electrolyte imbalances unresponsive to conventional care [4].

Ethanol vs. Fomepizole
Since its approval in 2000, fomepizole has been touted as a safer, more practical antidote, which has subsequently led to a decreased usage of ethanol in the clinical setting. Nonetheless, practitioners should be aware of the evidence (albeit very limited) comparing these two antidotal agents given the recent shortage of fomepizole.
  • To date, no prospective randomized trials have directly compared the efficacy of ethanol to fomepizole
  • Neither ethanol nor fomepizole affect the toxic metabolites already present in the body
  • Fomepizole has a higher potency to inhibit ADH, with a slightly longer duration of action
  • An observational cohort study of 172 hospitalized patients found that the administration of ethanol was associated with a higher rate of adverse drug events (ADE) compared with fomepizole (57% versus 12%). Central nervous system depression was the most frequent ADE reported (48% ethanol vs. 2% fomepizole) [8].
  • Unlike ethanol, fomepizole does not require serum concentration monitoring
  • The acquisition cost of fomepizole is much greater than ethanol, however this may be negated by ICU costs should intravenous ethanol be required

Ethanol is a pharmacokinetic nightmare
A summary of in vitro experiments using human liver cells found the affinity of ethanol for alcohol dehydrogenase is 67 times that of ethylene glycol and 15.5 times that of methanol [9,10,11]. At least a 1:4 molar ratio of ethanol to EG/methanol is required for sufficient saturation of ADH to prevent further metabolism of EG and methanol to their toxic metabolites. To achieve this ratio, a goal serum ethanol concentration of 100-150 mg/dL should be targeted [12].

When administered orally, ethanol is rapidly absorbed from the stomach within 5-10 minutes and reaches peak effect in 30-90 minutes; however, these parameters are highly variable and depend on the concentration of ethanol and the size/duration from last meal, chronic alcohol ingestion, nutritional status, and several other factors [13]. While intravenous ethanol has the advantage of complete absorption and may provide slightly easier titration, IV treatment requires ICU admission and frequent monitoring of serum ethanol levels (every 1-2 hours) [14].

Regardless of route of administration, the effect of ethanol on the CYP system may lead to unwanted drug interactions and pharmacokinetic tolerance after several days of administration [15].

Preparation and dosing
Commercial preparations of ethanol in 5% dextrose are no longer available for IV administration. A 10% sterile ethanol USP solution can be extemporaneously prepared by adding 55 mL or 110 mL of absolute ethanol to 500 mL or 1000 mL of D5W, respectively.

If any delay in preparing ethanol for IV use is expected, then oral ethanol should be initiated immediately. In addition to antidotal therapy, thiamine and pyridoxine should be administered daily to stimulate the conversion of glyoxylate to nontoxic metabolites.
 

Antidote
Loading dose
Maintenance dose
Adjustment for HD
Common ADEs
Ethanol
Oral
(20% ethanol [40 proof] in juice given orally or via NG tube)



4 mL/kg




Nondrinker:
0.4-0.7 mL/kg/hour

Chronic drinker:
0.8 mL/kg/hour

Nondrinker:
0.22 mL/kg/hour


Chronic drinker:
0.33 mL/kg/hour





Mental
status changes, hypoglycemia, liver toxicity, pancreatitis

IV
(10% solution in D5W) Central line preferred to reduce venous irritation

8 mL/kg over 20-60 min

Nondrinker:
 0.8-1.3 mL/kg/hour

Chronic drinker:
1.5 mL/kg/hour

Nondrinker:
2.5 mL/kg/hour

Chronic drinker:
3.5 mL/kg/hour



Antidote
Loading dose
Maintenance dose
Adjustment for HD
Common ADEs

Fomepizole (IV)

15 mg/kg

10 mg/kg q12h x 4 doses, then 15 mg/kg q12h until resolution of toxicity and EG level <20 mg/dL

Administer dose at initiation of HD is last dose given >6 hours ago

Increase dosing frequency to q4h

Alternative regimen: 1-1.5 mg/kg/hour continuous infusion


Headache (14%), nausea (11%), dizziness (6%), increased drowsiness (6%)

How long should antidotal therapy be administered?
Antidotal therapy should continue until serum EG/methanol level is <20 mg/dL and clinical manifestations of toxicity are resolved (e.g. resolution of metabolic acidosis and osmole gap, etc.). The half-lives of EG and methanol are dependent on both the presence of ADH blockade and hemodialysis.

EG follows zero-order kinetics with a half-life of 3-9 hours in the absence of treatment. This is extended to approximately 17 hours in the setting of ADH blockade [16,17,18]. Alternatively, methanol does not undergo significant renal elimination and is cleared more slowly than EG with a half-life of 30-54 hours in the setting of ADH blockade [19,20,21]. When hemodialysis is combined with antidotal therapy, half-lives of EG and methanol are both dramatically reduced to approximately 2.5-3.5 hours [21,22].

The bottom line…
  • Fomepizole is currently on ASHP’s national drug shortage list (a limited supply is available from Mylan for drop shipment only)
  • Ethanol is an effective alternative for the management of toxic EG or methanol ingestion but is associated with a greater number of adverse effects (e.g. altered mental status, hypoglycemia, hepatic toxicity) when compared with fomepizole
  • Ethanol dosing must be adjusted for patients with chronic alcohol consumption and in those receiving  hemodialysis
  • Serum ethanol levels should be monitored every 1-2 hours with a target concentration of 100-150 mg/dL
  • Continue antidotal ethanol until serum EG level is <20 mg/dL and clinical manifestations of toxicity are resolved

References:
1.       Caravati EM, Erdman AR, Christianson G, et al. Ethylene glycol exposure: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol. 2005;43(5):327-45.
2.       http://www.ashp.org/menu/DrugShortages/CurrentShortages/Bulletin.aspx?id=1173. Accessed electronically 22 May 2015.
3.       Barceloux DG, Krenzelok EP, Olson K, et al. American Academy of Clinical Toxicology Practice Guidelines on the treatment of ethylene glycol poisoning. Ad Hoc Committee. J Toxicol Clin Toxicol. 1999;37:537–560.
4.       Rietjens SJ, de Lange DW, Meulenbelt J. Ethylene glycol or methanol intoxication: which antidote should be used, fomepizole or ethanol? Neth J Med. 2014;72(2):73-9.
5.       Brent J. Fomepizole for ethylene glycol and methanol poisoning. N Engl J Med. 2009;360:2216-23.
6.       Barceloux DG, Bond GR, Krenzelok EP, et al. American Academy of Clinical Toxicology practice guidelines on the treatment of methanol poisoning. J Toxicol Clin Toxicol. 2002;40:415-46.
7.       Megarbane B. Treatment of patients with ethylene glycol or methanol poisoning: focus on fomepizole. Open Access Emerg Med. 2010;2:67-75.
8.       Lepik KJ, Levy AR, Sobolev BG, et al. Adverse drug events associated with the antidotes for methanol and ethylene glycol poisoning: a comparison of ethanol and fomepizole. Ann Emerg Med. 2009;53:439–450.
9.       Li TK, Theorell H. Human liver alcohol dehydrogenase: inhibition by pyrazole and pyrazole analogs. Acta Chem Scand. 1969;23:892–902.
10.   Pietruszko R. Human liver alcohol dehydrogenase inhibition of methanol activity by pyrazole, 4-methylpyrazole, 4-hydroxymethylpyrazole and 4-carboxypyrazole. Biochem Pharmacol. 1975;24:1603–1607.
11.   Pietruszko R, Voigtlander K, Lester D. Alcohol dehydrogenase from human and horse liver—substance specificity with diols. Biochem Pharmacol. 1978;27:1296–1297.
12.   Jacobsen D, McMartin KE. Methanol and ethylene glycol poisonings: mechanism of toxicity, clinical course, diagnosis and treatment. Med Toxicol. 1986;1:309–334.
13.   Zakhari S. Overview: how is alcohol metabolized by the body? Alcohol Res Health. 2006;29:245–254.
14.   Julkunen RJ, Tannenbaum L, Baradna E, et al. First pass metabolism of ethanol: an important determinant of blood levels after alcohol consumption. Alcohol. 1985;2:437–441.
15.   Howland M. Antidotes in Depth. In: Hoffman RS, Howland M, Lewin NA, Nelson LS, Goldfrank LR. eds. Goldfrank's Toxicologic Emergencies, 10e. New York, NY: McGraw-Hill; 2015.
16.   Boyer EW, Mejia M, Woolf A, Shannon M. Severe ethylene glycol ingestion treated without hemodialysis. Pediatrics. 2001;107;172–173.
17.   Cheng JT, Beysolow TD, Kaul B, et al. Clearance of ethylene glycol by kidneys and hemodialysis. J Toxicol Clin Toxicol. 1987;25:95–108.
18.   Sivilotti MLA, Burns MJ, McMartin KE, Brent J. Toxicokinetics of ethylene glycol during fomepizole therapy: implications for management. Ann Emerg Med. 2000;36:114–124.
19.   Brent J, McMartin K, Phillips S, et al. Fomepizole for the treatment of methanol poisoning. N Engl J Med. 2001;344:424–429.
20.   Kraut JA, Jurtz  I. Toxic alcohol ingestions: clinical features, diagnosis, and management. Clin J Am Soc Nephrol. 2008;3:208–225.
21.   Palatnick W, Redman LW, Sitar DS, et al. Methanol half life during ethanol administration: implications for management of methanol poisoning. Ann Emerg Med. 1995;26:202–207.
22.   Eder AF, McGrath CM, Dowdy YG, et al. Ethylene glycol poisoning: toxicokinetic and analytical factors affecting laboratory diagnosis. Clin Chem. 1998;44:168-77.

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