Toxin-induced metabolic acidosis

1. Description of the problem

What every clinician needs to know

Metabolic acidosis is a common and serious presentation of several toxins. Toxin-induced metabolic acidosis can be due to multiple diverse pathways and can become become evident at various stages and time-frames of the poisoning. These include organic acid production through metabolic pathways, exogenous acid addition, tissue hypoperfusion, renal impairment and cytopathic pathways.

These variable pathways and presentations make the diagnosis and treatment challenging, and when a poisoning is suspected, consultation with a regional poison center and toxicologist is hightly recommended. There are numerous toxins that produce acid-base disturbances; however, we will only discuss the most common and serious toxins that result in a metabolic acidosis.

Clinical features of the condition

The clinical features of metabolic acidosis are similar regardless of the etiology. Depending on the toxin, type and amount of exposure, there may be other specific clinical features. These may include respiratory compensatory signs such as tachypnea and Kussmaul respirations.

• Hyperventilation (rapid shallow or Kussmaul respirations).

• Hypotension.

• Headache, altered mental status, seizures, coma.

• Nausea, vomiting, abdominal pain.

• Chest pain, cardiac dysrhythmias, palpations.

Key management points

Many poisoned patients are unable to provide a reliable history; therefore, laboratory and other ancillary testing is essential. Some patients will present with classic toxidromes (e.g. opioid, anticholinergic, cholinergic or sympathomimetic), others will have family or friends relay important information regarding recent activity and possible exposure. To adequately assess these patients, it is essential to use a systematic approach, as many different poisons will have subtle overlapping signs and symptoms.

Immediate supportive care

• Manage and protect the airway, intubate if necessary.

• Assess quality of respirations and provide additional support if needed.

• Rapidly establish two large peripheral intravenous (IV) lines and support hemodynamics.

Routine tests

• Point of care testing will provide a quicker result than central laboratory.

• ABG will provide insight to type and severity of acid-base disturbance.

• Comprehensive chemistry panel, including liver function tests, will provide information about electrolyte disturbances, renal function, glucose. An anion gap can also be calculated but the anion gap has limitations and should be adjusted for lactate and albumin. Hypoalbuminemia will LOWER the expected anion gap; therefore, an anion gap may be present within a “normal” range if the patient is hypoalbuminemic.

• Lactate. Can be from the venous or arterial blood gas, or capillary. May be helpful in determining type of toxin and severity.

• Electrocardiogram (ECG) to evaluate rhythm disturbances.

• Chest radiograph to assess for signs of pulmonary edema, aspiration, new infiltrate.

• Quantitative lab values of acetaminophen, aspirin, carboxyhemoglobin, ethylene glycol, methanol, or theophylline can help identify unknown cause of elevated anion gap or unmeasured ions.

• Routine serum and urine drug screens are rarely useful in the critically ill poisoned patient.

• With the advancement of toxicologic lab assays such as the toxic alcohol and glycol panel, the serum osmolar gap has become clinically less useful.

Identify major category of metabolic acidosis

• Anion gap or non-anion gap metabolic acidosis.

• Mixed metabolic-respiratory acid-base disorder.

2. Emergency Management

Stabilizing the patient

The immediate emergency management of the critically ill poisoned patient is similar to all emergency conditions. Priority must be applied to supportive care first by following the ABCs of resuscitation.

A patient who has had an environmental exposure needs to be decontaminated rapidly as per the policy and procedures of the Emergency Department. Appropriate personal protective equipment must be worn by the healthcare team to prevent cross contamination.

Management points not to be missed

Ethylene glycol (EG), Diethylene glycol (DEG), methanol

• Ethanol co-ingestion can delay metabolism (good) but make diagnostics more challenging. Methanol is metabolized slowly in the liver and commonly presents late with coma, bradycardia, profound acidosis.

• Suspect toxic alcohol or glycol and order serum laboratory tests.

• Antidote is fomepizole that competitively inhibits alcohol dehydrogenase.

• Ethanol infusion works through the same pathway but has central nervous system (CNS) depression at therapeutic levels.

• Dialysis.

Acetaminophen (APAP)

• N-Acetylcysteine (NAC) within 8 hours of ingestion.

• Supportive care.

Salicylates (ASA)

• Mixed metabolic acidosis and respiratory alkalosis.

• Urine alkalinization first line.

• Dialysis is most effective.

Metformin

• Supportive care, gastric decontamination if early after ingestion.

• Consider dialysis if serious lactic acidosis develops.

Valproic acid (VPA)

• Gastric decontamination with activated charcoal if soon after ingestion. Multidose charcoal may be effective if sustained release preparations ingested.

• Whole bowel irrigation may be effective with multidose charcoal.

• Supportive care is cornerstone of therapy.

3. Diagnosis

Diagnostic criteria and tests

EG

• Ethanol co-ingestion can delay metabolism (good) but make diagnostics more challenging.

• High anion gap metabolic acidosis.

• Osmolar gap present (more than 10) especially later after ingestion. Less helpful now with timely toxic alcohol and glycol assays in the central laboratory.

• Altered mental status similar to ethanol intoxication – without characteristic odor on the breath – is an early sign.

• EG level measured in blood is confirmative.

• Renal failure is late consequence.

• Historic finding of calcium oxalate crystals in urine is nonspecific.

DEG

• Not as common or toxic as EG.

• High anion gap.

• Not as widely available for clinical detection as other toxic alcohol or glycol tests.

• High clinical suspicion needed for syndrome similar to EG toxicity with no EG level detected. Product label helpful if known ingestant.

Methanol

• Similar presentation to EG.

• Ethanol co-ingestion can delay metabolism (good) but make diagnostics more challenging. Methanol is metabolized slowly in the liver and commonly presents late with coma, bradycardia, profound acidosis.

• High anion gap metabolic acidosis.

• Osmolar gap present (more than 10) especially later after ingestion. Less helpful now with timely toxic alcohol and glycol assays in the central lab.

• Methanol level identified on toxic alcohol and glycol blood assay is confirmatory.

APAP

• If there is any suspicion that a significant APAP ingestion has occurred, a provisional diagnosis should be made and treatment started regardless of any measurable blood level of APAP.

• Even though they are not specific, transaminase levels can be helpful to follow hepatotoxicity; also follow renal function as acute kidney injury can also develop.

• If the time of a single ingestion is known, a serum APAP concentration can be plotted on the Rumack-Matthew nomogram as a guide to the likelihood of hepatotoxicity and an indication of NAC therapy.

• Abnormal prothrombin time and INR levels are predictive of mortality.

ASA

• Patients present with a mixed metabolic acidosis and metabolic alkalosis. ABG with complete metabolic panel is required immediately.

• ASA blood levels are readily available; however, levels are very dependent on chronic use and time after ingestion.

• Serum levels less than 6 hours post ingestion do not exclude the possibility of serious toxicity owing to the absorption-distribution phase.

• Chronic salicylism toxicity may be seen with levels of only 30-40 mg/d.

• Clinical presentation varies and ranges from nausea, vomiting, tinnitus, lethargy, ataxia to more severe presentations such as pulmonary edema, seizures, coma and cerebral edema.

Metformin

• Patients presenting with a recent, acute ingestion of metformin can have mild clinical findings; however, if the ingestion was large, they can rapidly decompensate over several hours.

• Tachycardia, tachypnea (with severe lactic acidosis), hypotension with symptoms similar to septic shock.

• Specific laboratory tests are to help identify the severity and presence of multiorgan involvement. These should include an arterial blood gas (ABG) to evaluate acid-base status; complete chemistry panel to assess renal function; and lactate, since lactic acidosis is a major contributor to the metabolic acidosis associated with metformin.

VPA

• Patients can present with CNS depression, cerebral edema, hypotension, lactic acidosis, elevated transaminases, hepatotoxicity and hyperammonemia. Thrombocytopenia may also be present.

• Plasma VPA levels above 180 mg/mL usually have some degree of lethargy or somnolence. VPA levels have little correlation with severity of intoxication and prognosis.

• Electrolyte abnormalities are common; hypernatremia, hypocalcemia and acute renal failure may also be present.

• ECG may demonstrate a variable heart block.

Normal lab values

EG

• Severe toxicity is rare with EG levels less than 20 mg/dL, and this value has been used as a guideline for treatment.

DEG

• Levels are not clinically available in most hospitals.

Methanol

• In acidotic patients, levels of 20 mg/dL or more have been used for guidelines as a threshold for treatment.

APAP

• If there is any suspicion that a significant APAP ingestion has occurred, a provisional diagnosis should be made and treatment started regardless of any measurable blood level of APAP.

• If the time of a single ingestion is known, a serum APAP concentration can be plotted on the Rumack-Matthew nomogram as a guide to the likelihood of hepatotoxicity and an indication of NAC therapy.

• Even though they are not specific, transaminase levels can be helpful to follow hepatotoxicity; also follow renal function as acute kidney injury can also develop.

• Abnormal prothrombin time and INR levels are predicive of mortality.

ASA

• Levels are very dependent on chronic use and time after ingestion. Serum levels less than 6 hours post ingestion do not exclude the possibility of serious toxicity due to the absorption-distribution phase.

• Chronic salicylism toxicity may be seen with levels of only 30-40 mg/d.

• The following levels are based on 6 hours post ingestion and not chronic use. These are only guidelines: less than 50 mg/dL – asymptomatic; 51-110 mg/dL – mild to moderate toxicity; greater than 110 mg/dL – severe toxicity.

Metformin

• Blood metformin levels not routinely followed and do not correlate with outcome.

VPA

• Therapeutic plasma levels are 50-100 mg/L.

• Recommend serial serum VPA levels to identify peak concentration and demonstrate decline.

How do I know this is what the patient has?

For the majority of patients presenting with the common intoxications, the combination of a clinical toxidrome and laboratory findings will narrow the differential. Many of these have confirmatory laboratory values that can be obtained in a timely fashion. It is also very useful when family or other acquaintances provide corroborating data such as an empty medication container and a recent ingestion history.

What else could it be?

Any disease state that can produce metabolic acidosis should be considered in the differential diagnosis:

Diabetic ketoacidosis (DKA): Presence of hyperglycemia (usually), ketone production (always); history of diabetes is helpful but it may be the initial presentation. Several toxins also induce ketone production and thus need to be ruled out.

Severe sepsis or septic shock: Commonly presents with organ dysfunction. Metabolic acidosis is usually a combination of lactic acidosis and progressive renal and/or hepatic dysfunction.

Acute kidney injury: Severe AKI can present with metabolic acidosis; hyperkalemia is also commonly associated with this. AKI is associated with common toxins; therefore, the etiology must be rapidly determined.

Hyperchloremic metabolic acidosis presents with a normal anion gap and includes renal bicarbonate loss (type 2 proximal renal tubular acidosis [RTA]), gastrointestinal (GI) loss (diarrhea, pancreatic fistula), hypoaldosteronism (type 4 RTA) or iatrogenic in the form of large amounts of IV saline.

Are there specific confirmatory tests that I should perform?

Most of the toxins reviewed are able to be tested for in most hospital laboratories. However, some tests may need to be outsourced to specialized toxicology labs. It is essential that if a suspected clinical presentation of a patient is the result of an intoxication with any of these medications, immediate treatment with the antidote and other specific supportive care (e.g. bicarbonate infusion, hemodialysis) should be provided while the confirmatory tests are being performed.

The chance for a full recovery depends on how quickly appropriate treatment is initiated.

4. Specific Treatment

First line and other therapies

EG, DEG and methanol – anion gap metabolic acidosis

• CNS depressant – intubate earlier than later.

• Block metabolism of toxic metabolites by competitive inhibition of alcohol dehydrogenase with ethanol or fomepizole. Use cofactors folic or folinic acid, thiamine and pyridoxine to decrease optic toxicity.

• Bicarbonate therapy to prevent acidemia may help decrease toxic acids (formic, oxalic and glycolic) from entering the tissues (kidney, retina) and thus decrease end-organ damage. Paucity of data.

• Hemodialysis is the most effective treatment for all three.

• Gastric lavage and activated charcoal are not effective.

• Supportive care in ICU.

APAP – anion gap metabolic acidosis – late

• Treatment is supportive as multiorgan failure develops.

• Fulminant hepatic failure, acute kidney injury and lactic acidosis evolve over time.

• Treatment is combination of the antidote, NAC and aggressive, symptomatic and supportive care in an ICU. Cerebral edema, infection and multiorgan failure are common causes of mortality.

ASA – anion gap metabolic acidosis and respiratory alkalosis

• Hemodialysis is the treatment of choice and most effective if urine alkalinization is not working.

• Alkaline diuresis can aid in salicylate urinary excretion in properly functioning kidneys. Titrate IV sodium bicarbonate infusion to urinary pH of 7.5-8.5.

• Gastric lavage is not useful unless ingested within the hour and pill fragments still in stomach.

• Activated charcoal, if given early after ingestion, can delay absorption. Repeated doses more effective than single dose.

• May require intubation, supportive care in ICU.

Metformin – anion gap metabolic acidosis – lactic acidosis

• With significant ingestions, patients can rapidly decompensate. Rare in therapeutic dosages.

• Aggressive symptomatic care in an ICU environment.

• Hypotension requiring vasopressors, hypothermia, respiratory failure, altered mental status can mimic septic shock and can progress rapidly.

• Aggressive intravascular volume and emergent hemodialysis have been reported to be effective.

• GI decontamination with activated charcoal may be helpful in acute ingestion.

• Dextrose solutions if the patient is hypoglycemic.

VPA—anion gap metabolic acidosis

• With significant ingestions, patients can rapidly decompensate and cardiac arrest has been reported.

• Aggressive supportive care is initial step, with adequate intravascular volume replacement and vasopressor support if needed.

• Activated charcoal can be effective if given within the first hour of ingestion. Multidose charcoal administration has not been shown to be as effective unless used with whole bowel irrigation.

• Whole bowel irrigation may be used if large amounts of extended release preparations were ingested.

• Hemodialysis and hemoperfusion have been reported to be very effective in some cases, but data is limited.

• L-carnitine has been reported in small studies to be effective, with minimal side effects, but this therapy has not been validated in larger trials.

Drugs and dosages

Fomepizole

• Loading dose of 15 mg/kg followed by doses of 10 mg/kg every 12 hours for 4 doses, then 15 mg/kg every 12 hours until EG or methanol levels are below 20 mg/d and the patient is asymptomatic with normal pH.

• Doses should be given by IV infusion slowly over 30 minutes.

• Fomepizole is dialyzable and should be increased to every 4 hours during hemodialysis.

Ethanol

• Administered IV for titration purposes.

• Most effective when serum levels are 100 to 150 mg/dL.

Folinic acid

• 50 mg IV every 6 hours.

• Used as an adjunct for methanol (and potentially EG) poisoning.

Folic acid

• 50 mg IV every 6 hours.

• Used as an adjunct for methanol (and potentially EG) poisoning.

Thiamine

100 mg IV.

Used as an adjunct for methanol (and potentially EG) poisoning.

Pyridoxine

50 mg.

Used as an adjunct for methanol (and potentially EG) poisoning.

Sodium bicarbonate

• Various dosage regimens based on toxin.

• Usually an infusion is prepared by mixing 150mEq of sodium bicarbonate in a 1 liter bag of D5W.

• When adding the 150mEq of sodium bicarbonate, remove the same amount of volume from the 1 liter bag of D5W that will be added with the addition of the sodium bicarbonate BEFORE adding.

• Titrate to desired effect (eg, blood pH, urine pH).

• Infusion rates usually start at 100 to 200mL/h.

NAC

• Available for both PO and IV administration; same dosage for both.

• For full hepatic protection, administer within 8 h of APAP ingestion.

• 140 mg/kg in D5W over 60 min, then 70 mg/kg every 4 hours for a total of 12 maintenance doses (17 maintenance doses total for PO).

L-carnitine

• Prospective data lacking, all experience is from case reports for valproate toxicity.

• Some recommend giving when VPA levels are greater than 450 mg/L.

• Dosing should be in consultation with a medical toxicologist or poison control center.

Activated charcoal

• Optimal dose is unknown.

• Average adult dose is 50 to 100 g per dose PO.

• Need a protected airway.

WBI

• Used to prevent further absorption.

• Use osmotic cathartic such as polyethylene glycol electrolyte solution (PEG-ES) commonly know as GoLYTELY.

• Requires the placement of a nasogastric tube.

• Rate of PEG-ES administration in adults has been reported to be between 1500 to 2000 mL/h.

• Procedure is finished when clear liquid rectal effluent is observed.

• Usually takes 4 to 6 hours.

• Contraindications: bowel obstruction, GI bleed, airway at risk, intractable vomiting, hemodynamic instability.

• In 2004 the American Academy of Clinical Toxicology and the European Association of Poisons Centres and Clinical Toxicologists updated a position statement on WBI. Their recommendations reflect the lack of data in the literature supporting routine use; therefore it is NOT recommended for routine GI decontamination and should be considered in certain situations. Please consult a medical toxicologist or local poison center.

Refractory cases?

The treating physician should always reconsider the original diagnosis in refractory cases. Discussion with a medical toxicologist and poison center is essential.

5. Disease monitoring, follow-up and disposition

Monitoring

EG, DEG, methanol

EG and methanol poisoning are still common and even though an antidote is available, they still have a high morbidity and mortality due to their relative potency. Only small amounts ingested can cause profound acidosis, multiorgan failure and death. Successful treatment depends on early suspicion, early blockage of metabolic pathways, preferably with fomepizole (ethanol if not available), dialysis, and aggressive supportive care in an ICU.

Response to treatment is related to severity of acidosis and development of multiorgan failure. A more favorable outcome should be expected if treatment begins before acidosis develops.

APAP

If the antidote, NAC, is administered in a timely fashion, the outcome of APAP intoxication is usually good. In several large studies, no mortalities were reported if NAC was administered within 8 hours of an acute APAP overdose. Fulminant hepatic failure and death rarely occur in the setting of timely intervention and are usually associated with a delay in NAC administration.

ASA

Severe intoxication requires ICU admission and aggressive supportive care. Renal failure can be a complicating component. Even with aggressive, supportive care and hemodialysis, death may be unavoidable, especially if signs of multiorgan dysfunction are present.

Metformin

Based on timing and amount ingested. Disposition and prognosis depends on hemodynamics and presence of organ failure and acidosis. Patients should be monitored for at least 8 hours before being transferred or discharged and only if they are not acidotic and are clinically stable.

VPA

VPA intoxication can be life threatening and should be supported and monitored in the appropriate environment, usually an ICU. With appropriate supportive care, prognosis for a full recovery is good.

Incorrect diagnosis

Whenever a patient is unresponsive to the initial treatment plan, it is essential that the clinician review the probable differential diagnosis. Even though confirmatory test results (e.g. methanol level) may not be what the clinician suspected, it is important to understand that the clinical presentation and toxicity may not be reflected in these initial results. It is imperative to discuss the progress of the patient with a suspected serious intoxication with a medical toxicologist and poison center.

Follow-up

The medical toxicologist and poison center, if consulted, will initiate their own follow-up. If the ingestion was intentional, psychiatry will need to evaluate the patient after they have been stabilized. Other follow-up should be directed for more organ-specific injury resulting from the intoxication (e.g. nephrology for acute renal failure).

Pathophysiology

Metabolic acidosis resulting from a toxin arises from either an excess production (or addition) of an acid or decreased acid elimination. The pathways involved in this are several and usually include the liver and kidneys, and impaired hepatic or renal function can amplify the acidosis. One way of generalizing this further is to categorize the etiology based on the mechanism.

Excess acid addition

Toxins are themselves acidotic or are metabolized to acidic compounds.

• Methanol is hepatically converted by alcohol dehydrogenase into formaldehyde and then to formic acid. Both metabolites are toxic and disrupt oxidative phosphorylation.

• EG is metabolized by the liver into glycolic and oxalic acid. Propylene glycol is metabolized into lactate in the liver. This is one hypothesis of the acidosis seen during prolonged use; however, the concentrations required to cause this are very high.

• Salicylates are weak acids.

Toxins alter cellular energetics, resulting in a relative decrease in the amount of ATP production. This is accomplished by uncoupling oxidative phosphorylation or impairing the electron transport chain.

• APAP toxic metabolite NAPQI inhibits oxidative phosphorylation.

• Antiretroviral agents (not discussed) usually cause metabolic acidosis and lactic acidosis by uncoupling oxidative phosphorylation.

• VPA, iron and salicylates impair oxidative phosphorylation.

• Carbon monoxide, metformin, cyanide, hydrogen sulfide and formic acid (from methanol) all impair the function of the electron transport chain.

Toxins can cause a metabolic acidosis by inducing certain metabolic derangements.

• Formation of ketone bodies (acetoacetate, acetone, and beta-hydroxybutyrate). Alcohol ketoacidosis is one example.

• Lactate production from seizures either caused directly by the toxin (i.e. isoniazid) or indirectly by lowering the patient’s seizure threshold.

Impaired acid elimination

• Primarily results from impaired renal metabolism and/or clearance.

• Several toxins are also nephrotoxic and can cause AKI, resulting in accumulation of endogenous organic acids that may compound an exogenous inorganic source.

• Renal tubular acidosis can occur from chronic toluene exposure, most likely due to the toxic metabolite hippuric acid.

• Nontoxic EG is metabolized by hepatic enzymes into nephrotoxic metabolites such as oxalic acid.

Ethylene glycol

Nontoxic in its unmetabolized form, EG acts similarly to ethanol as a CNS depressant. In the liver, it is converted to toxic metabolites by alcohol dehydrogenase and aldehyde dehydrogenase. Glycolic acid is the major toxic metabolite and contributes to the severe anion gap metabolic acidosis. Oxalic acid is another metabolic byproduct that is excreted by the kidneys. Precipitation of calcium oxalate crystals contributes to acute renal failure in a dose-dependent fashion. By causing acute renal failure, ethylene glycol renal excretion in its unmetabolized form is decreased.

Diethylene glycol

DEG is a commonly used solvent with less toxic effects than EG; however, deaths do occur, depending on dose. DEG has been associated with multiple “famous” outbreaks worldwide such as the toxin in the Massengill antibiotic poison outbreak in 1937 and more recently a worldwide distribution of toothpaste contaminated with DEG manufactured in China.

DEG is hepatically metabolized through a different pathway than EG. One of the metabolites, 2-hydroxyethoxyacetic acid (HEAA), is a weak acid. Both unmetabolized DEG and HEAA can be renally reabsorbed, resulting in a progressive metabolic acidosis with the accumulation being a direct nephro- and hepatotoxin.

Methanol

Relatively nontoxic in its unmetabolized form, methanol acts similarly to ethanol as a CNS depressant. Metabolism in the liver is slow, allowing a latent period of 12-48 hours before toxic effects appear. In the liver, it is converted to toxic metabolites by alcohol dehydrogenase and aldehyde dehydrogenase.

Formic acid and formaldehyde are the toxic metabolites that interfere with oxidative phosphorylation. Formic acid causes retinal injury with optic disc hyperemia, edema and permanent blindness thought to be from direct mitochondrial toxicity.

Acetaminophen

The majority of APAP is metabolized in the liver to sulfate and glucuronide conjugates and then excreted by the kidneys. A small amount is metabolized by the hepatic cytochrome P450 mixed oxidase pathway to NAPQI, a toxic intermediate. NAPQI is quickly conjugated with hepatic glutathione, forming a nontoxic compound that is then excreted by the kidneys. With large doses of APAP, the hepatic pathways for sulfation and glucuronidation become saturated and more APAP is metabolized via cytocrome P450.

As hepatic glutathione stores are depleted by approximately 70%, NAPQI builds up and starts to react with the surrounding hepatocytes, causing direct hepatocellular centrilobular necrosis. It is thought that NAC prevents hepatotoxicity by repleting hepatic glutathione stores. Metabolic acidosis is the result of lactic acidosis and acute renal failure.

Salicylates

ASA has multiple cellular and systemic effects. It uncouples cellular oxidative phosphorylation, resulting in an increased production of endogenous acids such as lactic acid that lead to a metabolic acidosis. ASA directly stimulates the respiratory center of the medulla causing hyperventilation – this is dose dependent. ASA also directly stimulates the chemoreceptor trigger zone in the medulla, resulting in nausea and vomiting. Cyclooxygenase inhibition causes decreased production of thromboxanes, prostacyclin and prostaglandins.

Metformin

Metformin is renally excreted in its unmetabolized state. Thus it may accumulate in renal failure. The lactic acidosis associated with metformin is complex and not completely understood. Lactic acidosis is very rare when taken in therapeutic doses (five cases per 100,000 patient years); however, when lactic acidosis is present, two case series have reported a mortality of up to 48%.

Multiple case reports have supported the observation that serum metformin levels do not correlate with poor outcome. However, the underlying degree of health of the patient, presence of hepatic dysfunction and severity of lactic acidosis do seem to be important predictors of outcome.

Valproic acid

VPA is mostly metabolized in the liver by glucuronidation and oxidative pathways utilizing P450. These produce many active metabolites that are thought to be responsible for the wide variety of organ involvement.

One metabolite, 2-EN-VPA, is thought to mediate cerebral edema and since its half-life is long, may also be responsible for coma. 4-EN-VPA is thought to contribute to the reversible hepatotoxicity that results in elevated transaminases. Propionic acid metabolites are thought to contribute to the hyperammonemia by three different pathways. If these pathways are impaired, the ammonia level can rise enough to cause an encephalopathy.

Epidemiology

In 2009, the total number of poison center calls was almost 2.5 million, with almost 600,000 (24.1%) requiring management at a healthcare facility. Of those, 95,429 (3.9%) required ICU admission.

Ethylene glycol

EG poisoning is still relatively common worldwide and in the United States. Many cases are due to using EG as a cheap substitute for ethanol, less likely for suicide or homicide attempts. Some states have added compounds to make EG bitter to taste; however, follow-up studies have not shown an overall decrease in exposures, toxicity or death.

Diethylene glycol

DEG is still used worldwide for a variety of reasons, usually as an inexpensive solvent or other component of chemical processing. It has been associated with multiple “famous” outbreaks worldwide such as the toxin in the Massengill antibiotic poison outbreak in 1937, and more recently a worldwide distribution of toothpaste contaminated with DEG manufactured in China. The last large outbreak was in 2008 in Nigeria, where at least 84 babies died due to the use of a teething mixture made with DEG.

Methanol

Used as windshield cleaning solution, solid fuel source for stoves, model airplane fuel and in many solvents, to name a few. A cheap alternative to ethanol, methanol has an ingestion profile similar to EG.

Acetaminophen

APAP has the highest associated mortality exposure, with 162 deaths attributed to APAP or APAP combination in 2009, most frequently due to intentional harm in young adults. The United States and the U.K. have the highest incidence of APAP overdose, with each experiencing 150-200 deaths per year.

Salicylates

In 2007, there were 63 deaths from ASA out of a total of 1,597 poisoning fatalities.

Metformin

Lactic acidosis is very rare when taken in therapeutic doses (five cases per 100,000 patient years); however, when lactic acidosis is present, two case series have reported a mortality of up to 48%.

Valproic acid

Toxic ingestions have been increasing since 1995, after the Food and Drug Administration approved its use for mood disorders. In 2005, 8,705 acute exposures occurred, with 404 major outcomes and 26 fatalities. The rate of exposure has doubled since 1995 and the rate of major outcomes and fatalities has increased more than three-fold.

Prognosis

EG, DEG, methanol

EG and methanol poisoning are still common and even though an antidote is available, they still have a high morbidity and mortality owing to their relative potency. Even small amounts ingested can cause profound acidosis, multiorgan failure and death. Successful treatment depends on early suspicion, early blockage of metabolic pathways preferably with fomepizole (ethanol if not available), dialysis and aggressive supportive care in an ICU.

Response to treatment is related to severity of acidosis and development of multiorgan failure. A more favorable outcome should be expected if treatment begins before acidosis develops.

Acetaminophen

If APAP overdose is treated within 8 hours of ingestion with NAC, prognosis is very good.

Salicylates

Acute ASA overdose has a mortality rate of about 2%. Chronic ASA poisoning has a much higher mortality rate, approaching 25%, usually owing to delayed presentation when symptoms are more severe. Overall the number of ASA poisonings has declined, partly because of the variety of other over-the-counter analgesics such as APAP and other NSAIDs.

With aggressive supportive critical care and hemodialysis in severe cases, most patients should be able to recover if treated before severe multiorgan failure develops.

Metformin

Lactic acidosis is very rare when taken in therapeutic doses (five cases per 100,000 patient years); however, when lactic acidosis is present, two case series have reported a mortality of up to 48%. Multiple case reports have supported the observation that serum metformin levels do not correlate with poor outcome. However, the general health of the patient, comorbities such as hepatic dysfunction, and severity of lactic acidosis are better predictors of outcome than plasma metformin levels, which may not be readily available.

Valproic acid

Depending on the level of toxicity and multiorgan involvement, most patients require ICU admission. Prognosis depends on the amount ingested, decontamination and elimination strategies used, and quality of supportive care. Patients suffering from severe poisonings can potentially recover without sequelae if adequately and aggressively treated.

What's the evidence?

Description of the problem

Judge, BS. “Metabolic acidosis: Differentiating the causes in the poisoned patient”. Med Clin North Am. vol. 89. 2005. pp. 1107-24. (Very good, detailed review about various toxins and how they are thought to cause metabolic acidosis.)

Emergency management

Lawrence, DT, Bechtel, L, Walsh, JP. “The evaluation and management of acute poisoning emergencies”. Minerva Med. vol. 98. 2007. pp. 543-68. (A very good, practical review and approach for diagnosing and management.)

Diagnosis

Jacobsen, D, McMartin, KE. “Methanol and ethylene glycol poisonings. Mechanism of toxicity, clinical course, diagnosis and treatment”. Med Toxicol. vol. 1. 1986. pp. 309-34. (A little dated, does not include the evidence-based usage of fomepizole; however, the workup of these toxic alcohols is still useful.)

Heard, KJ. “Acetylcysteine for acetaminophen poisoning”. N Engl J Med. vol. 359. 2008. pp. 285-92. (This is a nice, case-based review on the use of NAC for APAP poisoning.)

Temple, AR. “Acute and chronic effects of aspirin toxicity and their treatment”. Arch Intern Med. vol. 141. 1981. pp. 364-9.

Chang, CT, Chen, YC, Fang, JT, Huang, CC. “Metformin-associated lactic acidosis: case reports and literature review”. J Nephrol. vol. 15. 2002. pp. 398(Case report on presentation, diagnosis, and treatment of metformin poisoning.)

Spiller, HA, Krenzelok, EP, Klein-Schwartz, W. “Multicenter case series of valproic acid ingestion: serum concentrations and toxicity”. J Toxicol Clin Toxicol. vol. 38. 2000. pp. 755-60(One of the larger case series of valproic acid toxicity reported. )

Specific treatment

Brent, J, McMartin, K, Phillips, S. “Fomepizol for the treatment of ethylene glycol poisoning. Methylpyrazole for Toxic Alcohols Study Group”. N Engl J Med. vol. 340. 1999. pp. 832-8. (Classic paper describing the efficacy of fomepizole for the treatment of EG poisoning.)

Barceloux, DG, Bond, GR, Krenzelok, EP, Cooper, H, Vale, JA. “American Academy of Clinical Toxicology practice guidelines on the treatment of methanol poisoning”. J Toxicol Clin Toxicol. vol. 40. 2002. pp. 415-46. (Guidelines utilizing fomepizole for treatment of methanol poisoning.)

Heard, KJ. “Acetylcysteine for acetaminophen poisoning”. N Engl J Med. vol. 359. 2008. pp. 285-92. (This is a nice, case-based review on the use of NAC for APAP poisoning.)

Temple, AR. “Acute and chronic effects of aspirin toxicity and their treatment”. Arch Intern Med. vol. 141. 1981. pp. 364-9. (This is a classic, yet still relevant review of the differences of acute and chronic aspirin toxicity in regard to clinical presentation and treatment.)

Harvey, B, Hickman, C, Hinson, G, Ralph, T, Mayer, A. “Severe lactic acidosis complicating metformin overdose successfully treated with high-volume venovenous hemofiltration and aggressive alkalinization”. Pediatr Crit Care Med. vol. 6. 2005. pp. 598-601. (One of a few reports of the successful use of dialysis to treat rare but life-threatening lactic acidosis associated with metformin poisoning.)

Al Aly, Z, Yalamanchili, P, Gonzalez, E. “Extracorporeal management of valproic acid toxicity: a case report and review of the literature”. Semin Dial. vol. 18. 2005. pp. 62(Review of case reports of using dialysis for treating valproic acid toxicity)

Disease monitoring, follow-up, and disposition

Seidowsky, A, Nseir, S, Houdret, N. “Metformin-associated lactic acidosis: A prognostic and therapeutic study”. Crit Care Med. vol. 37. 2009. pp. 2191-6. (Recent retrospective study describing one center's 10-year experience with metformin poisoning-associated lactic acidosis, intentional vs incidental, and the outcomes associated with each. Study found increased mortality in the incidental group and that metformin levels did not correlate with mortality.)

Bronstein, AC, Spyker, DA, Cantilena, LR. “2009 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 27th Annual Report”. Clin Toxicol (Phila). vol. 48. 2010. pp. 979-1178. (Very detailed annual report from all poison centers in the United States.)

Bronstein, AC, Spyker, DA, Cantilena, LR. “2007 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 25th Annual Report”. Clin Toxicol (Phila). vol. 46. 2008. pp. 927-1057. (Very detailed annual report from all the poison centers in the United States.)

Lai, MW, Klein-Schwartz, W, Rodgers, GC. “2005 Annual Report of the American Association of Poison Control Centers' National Poisoning and Exposure Database”. Clin Toxicol (Phila). vol. 44. 2006. pp. 803-932. (Very detailed annual report from all poison centers in the United States.)

Larson, AM, Polson, J, Fontana, RJ. “Acetaminophen-induced acute liver failure: results of a multicenter, prospective study”. Hepatology. vol. 42. 2005. pp. 1364-72. (Recent large epidemiology-based trial with detailed outcomes of APAP poisoning.)

Isbister, GK, Balit, CR, Whyte, IM, Dawson, A. “Valproate overdose: a comparative cohort study of self poisonings”. Br J Clin Pharmacol. vol. 55. 2003. pp. 398-404. (A case-based review of the epidemiology of valproate poisonings.)

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