Nephrology Hypertension

Pharmacology and Toxicology: Treatment of Poisons - Isopropanol Intoxication

Does this patient have isopropanol intoxication?

Description of problem

There were 18,051 exposures to isopropanol and 1 death reported to the National Poison Data System (NPDS) in 2009. This represents 1.4% of all exposures reported (Figure 1). It has a lower associated mortality per exposure (0.01%) as compared to methanol (0.5%) or ethylene glycol(0.3%). The estimated minimum lethal dose for adults is approximately 100 ml. Patients have survived ingestions of over 1000 ml.

Figure 1.

Exposures and fatalities from toxins that are substantially removed by extracorporealtechniques.

Isopropanol reaches a peak serum level 15 to 30 minutes after ingestion. It is water-soluble and has a volume of distribution that is equal to total body water (0.6 L/kg). It has a molecular weight of 60 g/mole (Figure 2). Isopropanol is oxidized by alcohol dehydrogenase to acetone. The elimination half-life of isopropanol is 3 – 7 hours but is prolonged with ethanol co-ingestion. The elimination of acetone is much slower and is via excretion in the breath and urine.

Figure 2.

Characteristics of drugs and toxins that are amenable to removal with extracorporeal therapy.

What tests to perform?

Laboratory abnormalities

Anion gap

A high anion gap acidosis is rare following isopropanol ingestion since neither the parent compound nor its metabolites are organic acids. Therefore, a finding of a high serum or urine acetone level with an osmolar gap but without acidosis is suggestive of a recent isopropanol ingestion.

Osmolar gap

A serum level of isopropanol equal to 60 mg/dL will increase the serum osmolarity by 10 mOsm/kg (Figure 3). A high serum level should therefore produce a gap between the calculated serum osmolarity and that measured by freezing point depression.

Figure 3.

Osmolar contribution of various toxins and drugs.

Other lab abnormalities

Renal failure can occur in the setting of significant hypotension. However, acetone can also interfere with the creatinine assay. Hypoglycemia can result from the interference of gluconeogenesis by isopropanol.

How should patients with isopropanol intoxication be managed?

Diagnosis

Estimating serum levels in isopropanol

The alcohols will produce an osmolar gap when they are present in the serum in significant amounts. Although there are some cautions to be noted with its use, the osmolar gap can be used to estimate the serum concentration of the alcohols. If one keeps in mind that the osmolar gap may have fairly low specificity and sensitivity for the detection of alcohol intoxication due to variations in the normal gap in the general population, it can be helpful as a rapid way to estimate serum levels of the intoxicant. It should not be used as the sole criterion for deciding a treatment strategy in the case of a possible intoxication with one of the alcohols but it can be useful when other clinical data support the diagnosis.

Figure 3 describes the use of the osmolar gap to estimate the serum level of the alcohol intoxicant. An increase in the osmolar gap of 10 mOsm/L would be expected to be caused by a concentration of the drug listed in the figure. For example, if isopropanol were to cause an increase in the osmolar gap of 10 mOsm/L then the expected concentration of isopropanol would be 60 mg/dL. To estimate the concentration of the agent listed, the osmolar gap divided by 10 is multiplied by the factor listed in the table for the specific alcohol.

It is important to remember that a low gap does not always imply a low risk of intoxication. First, the gap will underestimate serum levels in some people who start out with a low serum osmolarity. Secondly, the gap will fall as the alcohol is metabolized and in the case of ethylene glycol and methanol, the metabolites are toxic and therefore a patient with a low gap may still have an indication for aggressive therapy including dialysis.

Emergency management

Supportive treatment

Supportive treatment includes airway protection and circulatory support. Metabolic abnormalities are less common than with either methanol or ethylene glycol intoxication. Circulatory support with fluids or vasoconstrictors is indicated in patients with hypotension. Inhibition of alcohol dehydrogenase is not indicated since acetone is less toxic than isopropanol.

Treatment

Isopropanol, like the rest of the alcohols, (e.g, ethanol, ethylene glycol, and methanol) has drug characteristics that allow for rapid removal with hemodialysis. They all have low molecular weights, are hydrophilic, have small Vd and rapidly equilibrate with the intravascular space. The drug characteristics of these compounds are listed in Figure 2. Ethanol toxicity usually does not require hemodialysis because most patients will recover with supportive measures alone.

Hemodialysis is very effective at clearing isopropanol. The clearance rate of isopropanol ranges between 200 – 250 ml/min depending on the filter and blood flow.

Hemodialysis for isopropanol - estimating dialysis time

Like all of the alcohols, isopropanol has a small Vd and rapid equilibration with the vascular space, its elimination therefore closely follows first order kinetics during dialysis.

The elimination of all the alcohols will follow the formula for first order kinetics:

C1/C0 = e-kt/V

If we determine a final concentration C1 that we want to achieve, we can solve for the time required for dialysis to achieve this final concentration:

t (min) = - ln (C1 /C0) x Vd(L) / k (L/min)

As an example, if a 100 Kg man has an isopropanol ingestion with a level of 1600 mg/dL and we want to perform dialysis with a membrane that can deliver a k = 0.3 L/min until his level is less than 400 mg/dL then

t = - ln ( 400/1600) 60 L / 0.3 L/min = 277 min = 4 hrs 37 min

It is important to note that this estimation does not take into account endogenous clearance of the alcohol and therefore will overestimate the time needed if the patient has significant renal clearance.

The indications for hemodialysis include those patients who have or are likely to develop the major sequelae of isopropanol ingestion. Hemodialysis is indicated for patients with an isopropanol level > 400 mg/dL who also have significant CNS depression, renal failure or hypotension. Hemodialysis will remove both isopropanol and acetone effectively.

What happens to patients with isopropanol intoxication?

Clinical and laboratory findings in isopropanol intoxication

Unlike ethylene glycol and methanol, most of the clinical effects in isopropanol intoxication are due to the parent compound. Acetone causes only mild central nervous system depression. The clinical signs of isopropanol intoxication will occur within an hour of ingestion and include effects on the central nervous system (CNS), gastrointestinal (GI) and cardiovascular systems (Figure 4). The CNS effects include ataxia, confusion, stupor and coma. The GI effects include nausea, vomiting, abdominal pain and gastritis. Patients with severe intoxication can present with hypotension due to cardiac depression and vasodilatation. Hypotension and coma are the strongest predictors of mortality. Many patients will have fruity breath from the acetone elimination via respiration.

Figure 4.

Clinical effects of isopropyl alcohol intoxication.

What is the evidence?

Abramson, S, Singh, AK. "Treatment of the alcohol intoxications: ethylene glycol, methanol and isopropanol". Current Opinion in Nephrology & Hypertension. vol. 9. 2000. pp. 695-701.

Kraut, JA, Kurtz, I. "Toxic alcohol ingestions: clinical features, diagnosis, and management". Clinical Journal of The American Society of Nephrology: CJASN. vol. 3. 2008. pp. 208-225.

Zaman, F, Pervez, A, Abreo, K. "Isopropyl alcohol intoxication: a diagnostic challenge". American Journal of Kidney Diseases. vol. 40. 2002. pp. E12.

Jammalamadaka, D, Raissi, S. "Ethylene glycol, methanol and isopropyl alcohol intoxication". American Journal of the Medical Sciences. vol. 339. 2010. pp. 276-281.

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