Ethylene Glycol and Methanol

Methanol and ethylene glycol are toxic alcohols that have similar properties in overdose. Toxicity can occur through ingestion, inhalation, or dermal absorption. Cardiopulmonary and central nervous system (CNS) symptoms are common, and both agents can produce an anion gap metabolic acidosis and an osmolar gap. However, absence of an osmolar gap or anion gap does not exclude a toxic ingestion. The osmolar gap may be normal if all alcohol is metabolized to acid metabolites, and an anion gap may be normal if metabolism of alcohol has not yet produced acid metabolites (e.g., concomitant ethanol ingestion or early presentation). If toxic alcohol ingestion is suspected, regardless of whether the patient is symptomatic, blood should be immediately sent for serum methanol, ethylene glycol, and ethanol levels, and definitive treatment initiated based on the clinical history and acid-base status. Significant toxicity is associated with methanol and ethylene glycol levels greater than 50 mg/dL. The severity of pH, serum bicarbonate, and anion gap abnormalities appears to be directly correlated with the likelihood of survival.

Ethylene glycol is found in antifreeze and deicing solutions. Ethylene glycol causes acidemia as a result of metabolism by alcohol dehydrogenase to glycolic and oxalic acid. Oxalate crystals in the urine may be detected with a Wood’s lamp or on microscopic examination, but they may not be present in the majority of exposed patients. Three classic phases of ethylene glycol toxicity have been described: neurologic, cardiopulmonary, and renal. During the first 0.5 to 12 hours after ingestion, ethylene glycol produces transient inebriation without the usual odor of ethanol, along with GI symptoms (nausea, vomiting). After toxic metabolites form (4 to 12 hours after ingestion), a metabolic acidosis develops along with CNS depression. The CNS symptoms may progress to coma associated with hypotonia, hyporeflexia, and occasionally seizures, meningismus, and cerebral edema. In the second stage (12 to 24 hours after ingestion), tachycardia and hypertension often occur along with progression of metabolic acidosis. Hypoxia may result from aspiration, heart failure, or acute respiratory distress syndrome. Death is most common in this stage. In the third stage (24 to 72 hours after ingestion), oliguria, flank pain, acute tubular necrosis, and renal failure develop.

Methanol is found in windshield washer fluid, solvents, and bootleg whiskey. It is metabolized by alcohol dehydrogenase to formaldehyde, which is then metabolized by aldehyde dehydrogenase to formic acid. Uncoupling of the mitochondrial oxidative metabolism produces lactic acid. The metabolic derangements are caused by lactic and formic acid; the latter is responsible for ocular disturbances. When methanol is ingested, peak levels occur within 30 to 60 minutes but there is often a latent period of about 24 hours (range 1 to 72 hours) before the development of toxic symptoms or metabolic acidosis. GI (abdominal pain, nausea, vomiting), CNS (dizziness, headache, seizures, coma), and ocular toxicities (blurred vision, photophobia, retinal edema, disc hyperemia, blindness) are seen.

Practice guidelines are available for the treatment of ethylene glycol and methanol intoxication.19,20 If the patient has symptoms and is significantly acidemic, sodium bicarbonate may be administered as a temporizing measure to enhance formate and oxalate elimination by ion trapping. Fluid overload and hyperosmolarity may become significant problems as a result of bicarbonate administration. Hydration is helpful because ethylene glycol is well excreted by the kidney as long as renal function is maintained. The definitive treatment of intoxication with methanol or ethylene glycol is inhibition of the alcohol’s metabolism and hemodialysis to remove the alcohol and toxic metabolites and to correct metabolic abnormalities. Hemodialysis should be considered for the following conditions: deteriorating vital signs despite intensive supportive care, significant metabolic acidosis (pH < 7.25 to 7.3), blood level of methanol or ethylene glycol higher than 25 mg/dL, or any evidence of renal failure or electrolyte imbalances unresponsive to conventional therapy.^19,20

Antidotal treatment of significant poisoning involves inhibition of alcohol dehydrogenase to prevent metabolism of the alcohols to toxic metabolites with ethanol or fomepizole. Ethanol (IV or oral) allows preferential metabolism of ethanol over methanol and ethylene glycol. Ethanol should be administered to maintain a blood level of 100 to 150 mg/dL. A loading dose should be followed by a maintenance infusion according to the established dosing requirements for nondrinkers, drinkers, and during hemodialysis (Table 68.3).²¹ Problems encountered during ethanol administration include CNS depression, hypoglycemia, dehydration, and fluctuating serum concentrations. A second IV line using 0.9% sodium chloride may be necessary to avoid development of hyponatremia because of the large free water content and significant hypertonicity (1713 mOsm/L) of 10% ethanol solution. Advance notice should be given to the pharmacy to allow sufficient time to locate enough ethanol for administering and preparing the solution. If IV ethanol is not available, oral ethanol can be used.

Fomepizole, a competitive inhibitor of alcohol dehydrogenase, is approved for use in ethylene glycol and methanol overdose.²² It is easier to administer than ethanol, does not cause sedation, and is associated with fewer severe and serious adverse events.²³ Fomepizole administration should be considered instead of ethanol if the patient develops altered consciousness, seizures, or a significant metabolic acidosis. Although fomepizole appears to be equally effective, there are no data to demonstrate its comparative efficacy or cost-effectiveness. Administration of ethanol or fomepizole should continue after dialysis until the serum ethylene glycol or methanol concentration is undetectable or less than 20 mg/dL or acidosis is resolved and the patient is asymptomatic. In the absence of renal dysfunction and a significant metabolic acidosis, the use of fomepizole potentially could obviate the need for hemodialysis, even though the serum ethylene glycol or methanol concentration exceeds 50 mg/dL.²⁴ If patients with high serum concentrations of ethylene glycol are not treated with hemodialysis, then their acid-base balance should be monitored closely and hemodialysis instituted if a metabolic acidosis develops.¹⁹

Additional therapeutic measures for ethylene glycol ingestions may include thiamine 100 mg IV and pyridoxine 50 mg every 6 hours until the ethylene glycol level is zero and no acidosis persists. If the patient becomes hypocalcemic as a result of precipitation of calcium oxalate crystals, calcium should be replaced. In methanol overdose, it may be reasonable to also administer IV folate (folinic or folic acids) at 50 to 75 mg IV every 4 hours for at least 24 hours to provide the cofactor for enhancing formic acid elimination.

Isopropyl Alcohol

Isopropyl alcohol may also be ingested, particularly by chronic alcoholics with no access to ethanol. It is found in rubbing alcohol and some hand sanitizers in high concentrations. Oral absorption occurs rapidly (within 0.5 hour), and it undergoes metabolism to acetone, carbon dioxide, and water. Symptoms may include severe abdominal pain, GI bleeding, nausea, and vomiting. Isopropyl alcohol is two to three times more potent than ethanol as a CNS depressant, and acetone is comparable with ethanol. Patients frequently present with headache, lethargy, ataxia, or coma. Respiratory depression occurs secondary to the CNS depression. Laboratory findings include an osmolar gap without a metabolic acidosis. Patients may, however, have a fruity odor on their breath from acetone, and ketonemia and ketonuria may also be present. Treatment is supportive with fluid administration for significant dehydration. Hemodialysis should be considered when isopropyl alcohol levels exceed 400 to 500 mg/dL, evidence of hypoperfusion exists, coma is present, or a failure to respond to supportive therapy is noted.

Propylene Glycol

Propylene glycol is another alcohol that can cause toxicity in critically ill patients receiving high doses of IV medications containing the alcohol as a solvent. Medications that contain propylene glycol include lorazepam, diazepam, phenobarbital, pentobarbital, nitroglycerin, phenytoin, esmolol, etomidate, and sulfamethoxazole/trimethoprim. Propylene glycol toxicity is more commonly observed with lorazepam because of the use of high doses in some patients, the frequency of use for sedation in ICUs, and the high concentration of propylene glycol—approximately 830 mg/mL.²⁵ Common manifestations of propylene glycol accumulation are anion gap metabolic acidosis and increased osmolar gap.²⁶ Additional toxicities include renal dysfunction, hemolysis, cardiac arrhythmias, seizures, and CNS depression or agitation. Clinical studies suggest that an elevated osmolar gap correlates with propylene glycol accumulation. Accumulation can occur when doses of lorazepam exceed 0.1 mg/kg/hour and when renal or hepatic insufficiency is present. Although toxicity is more common after long periods of lorazepam infusion (>3 days), toxicity has occurred with short-term, high-dose use. The treatment of choice is to stop the lorazepam infusion and sedate with an agent that does not contain propylene glycol. Hemodialysis removes propylene glycol but is usually not required unless severe renal dysfunction develops.

Acetaminophen

Acetaminophen (N-acetyl-p-aminophenol [APAP]) is present in a large number of prescription and over-the-counter medications and is frequently a coingestant with other drugs. In addition, unintentional overdoses result from patients unknowingly ingesting multiple products containing acetaminophen (particularly acetaminophen-narcotic combinations). Because APAP overdose may result in significant hepatotoxicity and even death that is preventable, it is important to recognize and initiate appropriate therapy. With higher doses of APAP, a greater proportion is hepatically metabolized by the cytochrome P-450 system of mixed function oxidases (CYP450) to the toxic metabolite, N-acetyl-p-benzoquinoneimine (NAPQI), which can result in cell injury and death. Hepatic glutathione facilitates detoxification and elimination of NAPQI with therapeutic doses of APAP, but glutathione supply is overwhelmed in APAP overdoses. The clinical course of APAP toxicity has been divided into stages on the basis of the development of hepatotoxicity (Table 68.4).²⁷

If possible, an estimate of the quantity and dosage form of APAP ingested and the time of ingestion should be obtained. In adults, hepatic toxicity can occur after ingestion of more than 7.5 to 10 g during 8 hours or less but has been reported with exposures of 4 g. The maximum daily dose of acetaminophen has been reduced to 3 g because of concerns for toxicity.²⁸ The risk of toxicity may be increased in patients with low glutathione stores (malnutrition, fasting state, chronic alcoholism) or induction of CYP450 enzymes (chronic alcoholism, phenytoin or carbamazepine use). For patients with a recent single, acute ingestion, an acetaminophen level should be obtained at least 4 hours after ingestion. Liver enzymes only need to be evaluated if the APAP level indicates potential toxicity or the clinical examination suggests hepatic injury. If the time of ingestion is unknown, an APAP level should be obtained on admission. An APAP level and liver function tests should be determined in patients presenting late, patients with multiple ingestions over time, or chronic ingesters of APAP.

Activated charcoal does adsorb acetaminophen, and it is reasonable to administer charcoal up to 2 hours after ingestion. Acetaminophen is absorbed rapidly from the GI tract, so later use of charcoal is not warranted unless gastric emptying is likely to be delayed. Administration of activated charcoal will not interfere with subsequent administration of oral N-acetylcysteine (NAC) therapy.

NAC is the antidote for APAP poisoning, but the optimal route and duration of treatment are still debated.²⁹ NAC limits toxicity by combining with NAPQI and by serving as a precursor of glutathione, which inactivates NAPQI. For patients with a single, acute ingestion of APAP, the serum acetaminophen level assessed at least 4 hours after ingestion is compared with the Rumack-Matthew nomogram. Treatment with NAC is initiated in the United States if the value falls above the lower possible hepatotoxicity line. Only the initial APAP level is used in making the decision to initiate or continue NAC treatment. Subsequent levels are unnecessary unless extended-release preparations are ingested (see following). The Rumack-Matthew nomogram is not useful for patients with multiple ingestions of APAP over time, chronic ingesters, or those ingesting extended-release forms (see following discussion). If acetaminophen levels are not available, NAC treatment should be initiated if more than 150 mg/kg or 10 g acetaminophen is ingested. For extended-release APAP, a second level 4 hours after an initial nontoxic level should be evaluated to assess for delayed absorption. If the second value is above the lower line on the Rumack-Matthew nomogram, NAC is initiated.

NAC is most effective in preventing toxicity if administered within 8 hours of ingestion. NAC therapy can be initiated pending results of the acetaminophen level if the patient is presenting late or APAP level results will be delayed. The oral regimen for NAC includes a loading dose of 140 mg/kg followed by 17 oral maintenance doses of 70 mg/kg administered 4 hours apart (72-hour regimen). Due to the odor of the oral form, a nasogastric tube may need to be placed for administration, and antiemetic therapy may be necessary to control vomiting that occurs in up to 50% of patients. If the patient vomits the loading dose or any maintenance dose within 1 hour of administration, the dose should be repeated. IV NAC is administered as a loading dose of 150 mg/kg over 60 minutes followed by 50 mg/kg infused over 4 hours and then 100 mg/kg infused over 16 hours (21-hour regimen). Anaphylactoid reactions may occur in 14% to 18% of patients with IV NAC. Oral and IV regimens of administering NAC are similar in efficacy.³⁰ However, the oral regimen may be more appropriate in patients who present later after ingestion (>18 hours) and when large amounts of APAP are ingested due to the higher dose of administered NAC.^31,32 If the patient has a serum APAP level in the potentially toxic range, the aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level should be evaluated daily. If abnormal, additional tests such as bilirubin, prothrombin time, creatinine, BUN, blood glucose, and electrolytes should also be obtained. In patients with elevated liver enzymes, NAC may be continued beyond the full course of therapy until transaminases are decreasing.

Chronic ingesters of APAP or patients with multiple ingestions over time are problematic when determining the need to administer NAC. Presentation beyond 24 hours after ingestion makes the APAP level essentially useless, and there are no established guidelines for administration of NAC in these circumstances. A marker of toxicity that may be useful is the evaluation of AST and ALT. If enzymes are elevated at the time of presentation (>50 IU/L) or the APAP level is greater than 10 µg/mL (>10 µmol/L), a course of NAC should be strongly considered.³³ A course of NAC should also be administered to patients with hepatic failure caused by APAP.

Patients with evidence of toxicity from APAP should be monitored for signs and symptoms of hepatic failure. This includes evaluating mental status and frequently assessing blood glucose. In cases in which fulminant hepatic failure develops, appropriate consultation with a hepatologist should be obtained. Transplant may be an option in severe cases.

Opioids

Illicit and prescription opioids can result in a toxidrome characterized by depressed level of consciousness, respiratory depression, and miosis. However, manifestations may be variable depending on the drug used and presence of other drugs or alcohol. Miosis is not seen with meperidine, propoxyphene, and tramadol toxicity. Additional clinical findings may include hypotension, pulmonary edema, bronchospasm (heroin), ileus, nausea, vomiting, and pruritus. Seizures may be a manifestation of toxicity with meperidine, propoxyphene, and tramadol. Methadone use is associated with QT interval prolongation and ventricular arrhythmias.

Prescription opioids obtained from physicians or illicitly now account for almost 40% of all poisoning deaths in the United States and affect all age groups.³⁴ The agents most commonly involved in deaths include methadone, oxycodone, and hydrocodone.³⁵ Toxicity depends on the potency of the agent, dose ingested, tolerance of the individual, and concomitant use of other drugs. These prescription opioids have overshadowed deaths due to heroin. Heroin is rapidly absorbed by all routes of administration including IV, intranasal, intramuscular, subcutaneous, and inhalation, but most fatal overdoses occur with IV administration. IV fentanyl (sometimes extracted from analgesic patches) is also associated with fatalities. Diagnosis of an opioid overdose is made by characteristic clinical findings, exposure history, qualitative urine toxicology assay, and response to naloxone. Qualitative urine assays may not detect all opioid derivatives (e.g., fentanyl).

The immediate priorities in a patient with opioid toxicity are support of ventilation, correction of hypotension, and reversal of the toxic effects with an opioid antagonist. If reversal of respiratory depression cannot be accomplished quickly, intubation may be necessary. Isotonic fluids should be administered for hypotension. Naloxone, a potent competitive opioid antagonist, is the antidote for opioid toxicity. It can be administered intravenously, intramuscularly, subcutaneously, by sublingual injection, or through an endotracheal tube. The initial dose of naloxone in a suspected opioid overdose is 0.04 to 2 mg; the lower dose should be considered in patients suspected of chronic addiction to avoid precipitating acute withdrawal symptoms. The goal of therapy is to restore adequate spontaneous respirations rather than complete arousal. Doses of naloxone up to 10 to 20 mg may be required to reverse the effects of synthetic opioids such as pentazocine, methadone, and fentanyl. The effects of naloxone last approximately 60 to 90 minutes, necessitating continued observation of the patient for resedation. Patients may require continuous infusion of naloxone to maintain adequate respirations, particularly with long-acting opioids. The dose for infusion is typically one half to two thirds of the initial amount of naloxone that reversed the respiratory depression administered on an hourly basis. Adjustments of the dose should be made to achieve clinical end points and avoid withdrawal symptoms. Nalmefene, a long-acting opioid antagonist, has also been used to treat opioid overdoses, but prolonged withdrawal symptoms may be a concern.³⁶ Potential acetaminophen toxicity should be considered in patients ingesting opioids formulated with acetaminophen. Patients should also be observed for potential complications of opioid overdose including aspiration pneumonitis and noncardiogenic pulmonary edema. Noncardiogenic pulmonary edema is usually self-limited (24 to 36 hours) and managed with supportive care that may include intubation and mechanical ventilation.³⁷ Other complications that may be related to injection drug use include wound botulism, endocarditis, rhabdomyolysis, and compartment syndrome.

Salicylates

Salicylates should be considered as a potential toxin if a metabolic acidosis with an anion gap of unknown cause is present. The uncoupling of mitochondrial oxidative phosphorylation by salicylates results in metabolic acidosis and hyperthermia, and the stimulation of medullary respiratory centers results in tachypnea and respiratory alkalosis. Initial symptoms of toxicity include tinnitus and nausea or vomiting. Systemic acidosis promotes penetration of salicylate into the CNS, resulting in a depressed level of consciousness, coma, and seizures. Coagulopathy, transient hepatotoxicity, and hypoglycemia may also develop. Noncardiogenic pulmonary edema occurs more frequently in chronic salicylate toxicity than in acute overdose. The organ dysfunction and acid-base findings of salicylate intoxication can mimic sepsis and mislead clinicians.

Activated charcoal can be used for GI decontamination. Salicylates in large ingestions or enteric-coated forms can result in gastric concretions providing a depot for continued absorption; multiple doses of activated charcoal can be considered in this situation or when levels continue to rise despite other therapy.16,38 A salicylate ingestion is considered toxic if symptoms are present, if more than 150 mg/kg has been ingested, or if levels are higher than 35 mg/dL at 6 hours after ingestion. The Done nomogram was developed in pediatric ingestions and does not provide good clinical correlation with toxicity in adults. Acute intoxication with salicylate levels in excess of 35 mg/dL at 6 hours after ingestion should be treated with sodium bicarbonate to alkalinize the urine to a pH 7 to 8, which increases the renal clearance of salicylate metabolites through ion trapping.¹⁷ Hypokalemia will develop with correction of metabolic acidosis and must be corrected for urine alkalinization to be achieved. Alkalemia shifts the gradient of movement of salicylate from brain and tissues to blood.

Fluid status must be closely monitored, along with coagulation parameters, complete blood count, ABGs, electrolytes, and urine pH. Hemodialysis may be required for levels greater than 100 mg/dL in an acute ingestion, seizures, persistent alteration in mental status, refractory acidosis, persistent electrolyte abnormalities despite adequate therapy, or fluid overload resulting from sodium bicarbonate therapy. Additional indications for hemodialysis may include congestive heart failure (relative), noncardiogenic pulmonary edema, hepatotoxicity with coagulopathy, or renal insufficiency

Beta Blockers

β-Adrenergic blockers differ in their lipid solubility, oral availability, first-pass effect, protein binding, metabolism, β-1 selectivity, membrane stabilization, and intrinsic sympathomimetic activity. Clinical findings with beta-blocker toxicity include bradycardia, atrioventricular (AV) conduction abnormalities (QRS prolongation, first-degree AV block), and hypotension. The hypotension is primarily due to the negative inotropic effects of these agents. With the exception of sotalol, ventricular fibrillation and other arrhythmias are not usually seen. The more lipophilic β-adrenergic antagonists such as propranolol, metoprolol, acebutolol, and timolol can cause delirium, coma, and seizures. Hypoglycemia is rare in adults. Toxicity generally occurs within 6 hours of ingestion of immediate-release preparations. Ingestion of sotalol or extended-release preparations may result in delayed toxicity, and these patients should be observed for 24 hours or longer if absorption is delayed. Propranolol is associated with the highest mortality rate, which may reflect its greater toxicity attributable to membrane-stabilizing effects.⁴⁴ Bradyarrhythmias and asystole usually precede death.

GI decontamination with gastric lavage may be considered if there is a large ingestion of propranolol or other more toxic agent and the patient presents within the first hour, even if symptoms are absent. Because of the risk of vagal stimulation, pretreatment with atropine may be indicated. Orogastric lavage may also be a consideration in patients with significant symptoms if the drug is suspected to still be present in the stomach. Activated charcoal is another option for GI decontamination in patients who present early after ingestion. WBI may be considered in ingestions of sustained-release preparations. Extracorporeal removal is ineffective for lipid-soluble beta blockers because of the large volume of distribution. Hemodialysis may be rarely considered for atenolol, a water-soluble beta blocker.

The primary goal of treatment is to reverse hypotension rather than to increase heart rate. Increases in heart rate do not always result in improvements in blood pressure. Although atropine is frequently administered for bradycardia, it is usually ineffective for beta–blocker and calcium channel blocker toxicity. Isotonic fluids can be administered for hypotension, but caution is warranted due to the negative inotropic effects of beta blockers on myocardial function. Pharmacologic interventions that have been used in beta–blocker overdoses include glucagon, calcium, catecholamines, insulin euglycemia therapy, and phosphodiesterase inhibitors.⁴³ IV lipid emulsion has recently been reported to be effective in refractory cases. Although clinical trials are lacking, glucagon is considered to be the appropriate initial intervention and is administered as 2 to 5 mg IV followed by a dose of 10 mg if necessary. If there is a positive clinical response, a continuous infusion (usually 2 to 10 mg/hour) is necessary owing to the short duration of action of glucagon. Glucagon is a chronotropic and inotropic agent that stimulates cyclic adenosine monophosphate (cAMP) by bypassing adrenergic receptors.⁴⁵ Adverse effects of glucagon include nausea, vomiting, hyperglycemia, and hypocalcemia.

Calcium salts should be considered as the next intervention for reversing hypotension that does not respond to glucagon if digoxin ingestion has been excluded.43,46 Calcium chloride 10% (1 g by slow IV push) may be administered initially, and up to 3 g is recommended. Calcium chloride is preferred over calcium gluconate because it contains three times the amount of elemental calcium. It is best administered through a central venous catheter to avoid the possibility of skin necrosis from extravasation. If access is limited, 10% calcium gluconate can be administered but an increased dose is required.

High-dose regular insulin infusions and glucose administration to maintain euglycemia have been shown to be effective in beta-blocker and calcium channel blocker toxicity.46,47 The beneficial effect may be caused in part by the metabolic effects of decreasing cardiac uptake of free fatty acids and increasing carbohydrate use. Reported insulin doses have been variable, but a reasonable initial dose is 0.5 units/hour with titration based on clinical response. It is also reasonable to administer a bolus insulin dose prior to initiation of the infusion. A glucose infusion should be initiated at the same time and a glucose bolus may also be needed. Careful monitoring of glucose and potassium is required.

Catecholamine infusions are frequently administered in beta-blocker toxicity concomitantly with other interventions. No agent is known to be more effective than others and response to various agents is often inconsistent in these clinical situations. Very large doses may be required because the β-adrenergic receptors are blocked; as a result, tachyarrhythmias can occur. The combination of dobutamine and norepinephrine may allow for titration of desired effects against cardiac output and blood pressure. Alternatively, phenylephrine may be used in conjunction with dobutamine. Epinephrine has been shown to be more effective than isoproterenol.⁴⁸ Infusion of any vasoactive agent should be started at usual doses and rapidly escalated to achieve a clinical response, but it should be stopped if there is a further fall in blood pressure or no beneficial effect.

Phosphodiesterase inhibitors such as milrinone and enoximone have been reported to be effective in some cases of human ingestions.43,46 These agents may be useful in patients who fail other pharmacologic interventions, although experience is limited and they may cause further hypotension through peripheral vasodilation. Invasive hemodynamic monitoring may be needed in some patients.

Recent reports suggest that a bolus administration of 20% lipid emulsion (100 mL) may be beneficial in beta–blocker and calcium channel blocker cardiovascular toxicity refractory to other interventions. An additional infusion of 0.25 mL/kg/minute has been used in some cases. The exact mechanism of effect is unknown, but it has been proposed that lipids serve as a “sink” for the toxin that reduces free drug levels and limits distribution to tissues. Another possibility is that the fatty acids of lipids improve inotropy by increasing intracellular calcium concentrations.⁴⁹

Ventricular pacing (transthoracic or transvenous) may be considered, but electrical capture is often unsuccessful. Even when pacing increases the heart rate, blood pressure often fails to improve. Intra-aortic balloon pump and cardiopulmonary bypass are potential options to maintain circulation until drug is metabolized in the unstable patient unresponsive to other interventions.

Calcium Channel Blockers

Calcium channel blockers selectively inhibit calcium movement in cardiac or vascular smooth muscle membranes during the slow inward phase of excitation-contraction. These agents have varying degrees of negative inotropic effect (verapamil), vasodilatory effect (nifedipine, diltiazem), depression of rate of discharge of the sinus node (verapamil, diltiazem), and slowed conduction through the AV node (verapamil, diltiazem). All are well absorbed with clinically significant protein binding (80%) and a large volume of distribution. All undergo extensive hepatic metabolism, many through the cytochrome P-450 system, and have varying degrees of active metabolites.

Signs and symptoms of toxicity occur within 6 hours for immediate release formulations but are delayed 6 to 18 hours for sustained-release preparations.⁵⁰ Gastric concretions often form, acting as a further reservoir for sustained absorption. Nausea, vomiting, and hypotension are usually accompanied by bradycardia with verapamil and diltiazem or reflex tachycardia with nifedipine. Conduction abnormalities associated with verapamil and diltiazem may include first-degree block, Wenckebach block, junctional rhythm, third-degree AV block, and AV dissociation. Hypoperfusion secondary to decreased cardiac output may lead to tissue ischemia and metabolic acidosis. The patient may present with CNS symptoms such as lethargy, confusion, and coma. Hyperglycemia can result from a decrease in insulin secretion and insulin resistance and may be a marker of severe exposure.

Activated charcoal is the preferred method of GI decontamination in recent ingestions. Because of the hepatic metabolism of calcium channel blockers, the parent and active metabolites exhibit enterohepatic circulation. However, once absorbed, calcium channel blockers decrease cardiac output and may lead to mesenteric ischemia and diminished bowel motility, which is a relative contraindication to MDAC. WBI may be considered for removing sustained-release preparations.

As with beta blockers, initial treatment of calcium channel blocker overdose should be aimed at treating hypotension and significant conduction defects. Interventions include the same pharmacologic interventions as for beta blockers with a change in order of administration. Calcium salts should be administered initially in toxicity due to calcium channel blockers.44,46 Repeat boluses of calcium may be needed every 10 minutes. If blood pressure improves with calcium, an infusion is usually needed owing to the transient effect of bolus doses of calcium. Doses up to 0.4 mL/kg/hour of 10% calcium chloride may be needed. Ionized calcium concentrations can be monitored, but high serum concentrations may be necessary for beneficial effects. Glucagon has also been reported to be beneficial in toxicity due to calcium channel blockers and it should be considered as a second intervention if there is no response to calcium.⁴⁵ Glucagon is dosed as in beta-blocker overdoses. A continuous infusion of glucagon can be titrated to maintain blood pressure, cardiac output, and sinus rhythm. Insulin-glucose infusions have also been evaluated as an adjunctive treatment in severe cases and should be considered if calcium and glucagon are ineffective.⁴⁷ As with beta-blocker overdose, large doses of catecholamines may be required. Administration of lipid emulsion can be considered in refractory cases.⁴⁹ Transthoracic or transvenous pacing may be considered but are often ineffective. Refractory hypotension may require intra-aortic balloon pump or cardiopulmonary bypass.

Digoxin

Cardiac glycosides inhibit active transport of Na⁺ and K⁺ across cell membranes by reversibly binding to a specific site on the Na⁺/K⁺-ATPase. The alterations in cardiac rate and rhythm occurring in digitalis toxicity can produce almost every type of arrhythmia. Toxicity results from the complex influence of digitalis on the electrophysiologic properties of the heart, as well as the cumulative result of the direct, vagotonic, and antiadrenergic actions of digitalis. Toxicity should be suspected if there is evidence of increased automaticity (ectopic rhythms) or depressed conduction (prolonged PR interval, AV node blockade, decreased QT interval). Early in acute intoxication, depression of sinoatrial (SA) or AV node function may be reversed by atropine, but atropine subsequently does not reverse the direct and vagomimetic actions of the drug. Noncardiac manifestations of acute digitalis intoxication include anorexia, confusion, nausea or vomiting, and increased K⁺ concentrations.

GI decontamination in digoxin overdose consists of activated charcoal, if the timing is appropriate. Late administration of activated charcoal or MDAC may be considered due to enterohepatic metabolism of the drug.¹⁶ Steroid-binding resins such as cholestyramine and colestipol have also been used to prevent further absorption from the GI tract and reduce serum half-life in the same manner as charcoal. Forced diuresis, hemoperfusion, and hemodialysis are not effective in hastening the elimination of digoxin because of the large volume of distribution (4 to 10 L/kg). Only 1% of total body stores of digoxin is present in the serum; of that, 25% is protein bound.

The treatment for life-threatening digitalis toxicity is administration of digoxin-specific antibody fragments.⁵¹ Administration of digoxin-specific antibody fragments results in a sharp decrease in free digoxin levels, an increase in total serum digoxin, an increase in renal excretion of digoxin bound to Fab, and a decrease of serum potassium toward normal. The time to response is approximately 30 minutes (range 20 to 90 minutes). Indications for administration of digoxin-specific antibody fragments include severe ventricular arrhythmias, progressive bradyarrhythmias unresponsive to atropine, potassium concentration greater than 5 mEq/L in the setting of suspected digoxin toxicity, rapidly progressive cardiac or GI symptoms, an increasing potassium concentration, serum digoxin concentration greater than 15 ng/mL at any time or more than 10 ng/mL at steady state, ingestion of more than 10 mg of digoxin in a previously healthy adult, and to establish the diagnosis. In the event that digoxin-specific fragments are not immediately available, phenytoin (50 mg/minute up to 1000 mg) or lidocaine may be administered until control of the arrhythmia is achieved. Atropine may work for severe supraventricular bradyarrhythmias or varying degrees of AV block if administered early. Beta blockers may be used for supraventricular and ventricular tachycardias. Magnesium sulfate may be an effective temporizing measure for the treatment of ventricular arrhythmias in the absence of digoxin-specific antibodies, even in the presence of hypermagnesemia. All class Ia antiarrhythmic drugs are contraindicated. Isoproterenol should be avoided because there is an increased risk of ventricular ectopy in the presence of toxic digoxin levels. Transthoracic or transvenous pacing has limited value in this setting.⁵²

Hypokalemia, hyperkalemia, and hypomagnesemia can exacerbate digitalis cardiotoxicity and should be aggressively corrected. When hyperkalemia exists with toxic digoxin levels and ECG evidence of potassium toxicity, the serum potassium should be treated with conventional interventions if digoxin-specific Fab fragments are not immediately available. Calcium chloride, in the presence of digitalis toxicity, can theoretically be disastrous because intracellular hypercalcemia already exists. Intractable ventricular fibrillation or tachycardia may result.

After digoxin-specific antibodies have been administered, serum digoxin levels are no longer reliable because they represent free and bound digoxin. The digoxin-specific antibodies are effective even in anephric patients. In renal insufficiency, the Fab half-life is prolonged 10-fold with no change in volume of distribution. Fab concentrations remain detectable for 2 to 3 weeks. Although there is no dissociation of the complex in renal insufficiency, free digoxin levels rebound (redistribution from tissue sites) and Fab fragments leave the vascular space over 7 to 14 days.⁵³ During this time symptoms may recur and a second dose may be necessary.

Cyclic Antidepressants

Deaths caused by overdose with cyclic antidepressants are declining because of the increasing use of alternative antidepressants.⁴ The principal toxicities of cyclic antidepressants result from central and peripheral anticholinergic activity, α-adrenergic antagonism, and inhibition of norepinephrine reuptake. They also exert a membrane-depressant local anesthetic effect on the myocardium by blocking rapid sodium influx during phase 0 of the action potential. Primary toxicities include depressed level of consciousness, wide-complex arrhythmias, seizures, and hypotension. Acidosis, hypoxia, and seizures may increase the risk of wide-complex arrhythmias. Anticholinergic effects include mydriasis, fever, dry skin, delirium, agitation, tachycardia, ileus, and urinary retention. Life-threatening events usually occur within 6 hours of ingestion, most often in the first 2 hours.⁷⁶ Several electrocardiographic criteria have been proposed to predict complications: QRS duration greater than 0.1 second correlates with risk of seizures, QRS duration greater than 0.16 second correlates with increased risk of arrhythmias, and the presence of an R wave in lead aVR greater than 3 mm predicts seizures and arrhythmias.^77,78 However, the performance of these criteria in predicting complications including death is relatively poor.⁷⁹

If poisoning with a cyclic antidepressant is suspected, electrocardiographic monitoring should be instituted and IV access obtained. Intubation may be needed in patients with CNS depression who are unable to protect their airway. If wide-complex arrhythmias (or ECG changes described previously), hypotension, or seizures are present, stabilization requires immediate alkalinization of the blood and sodium loading with sodium bicarbonate.⁸⁰ Sodium bicarbonate should be administered in 50 to 100 mEq (1 to 2 mEq/kg) boluses to alkalinize the blood pH to 7.5 to 7.55. Clinical end points are normalization (narrowing) of the QRS complex, reestablishment of an adequate blood pressure, and termination of seizure activity. Alkalinization appears to decrease the free drug by increasing protein binding and shifting the concentration gradient away from tissues back into the main compartment. Sodium loading may have a greater benefit by overcoming the blockade of the myocardial sodium channels. The bolus doses of sodium bicarbonate should be immediately followed with a continuous infusion, which can be prepared by adding 150 mEq NaHCO₃ (sodium bicarbonate) to 1 L of D₅W. This should be titrated to the desired blood pH, QRS interval, and blood pressure. The infusion may be discontinued after 4 to 6 hours if the width of the QRS complex remains less than 100 ms without the administration of sodium bicarbonate. Hyperventilation to achieve blood alkalinization may be less effective but useful in patients who cannot tolerate the sodium and volume load or in those who develop pulmonary edema from treatment with sodium bicarbonate.^80,81 Hyperventilation without the administration of sodium bicarbonate may also be considered for patients with cerebral edema, head trauma, or poorly controlled congestive heart failure. Hypertonic saline has been effective in treating cardiac toxicity refractory to initial blood alkalinization.^82,83

If torsades de pointes is associated with QT prolongation, magnesium sulfate 1 to 2 g IV over 2 to 5 minutes should be administered.⁸⁰ Hypotension refractory to volume expansion is best treated with a direct-acting catecholamine such as norepinephrine or phenylephrine in the setting of depleted norepinephrine stores.⁸⁴ An inotropic agent such as dobutamine can be added if hypotension is the result of depressed myocardial contractility and decreased cardiac output. If hypotension remains refractory to fluids and vasopressors, the use of an intra-aortic balloon pump may be considered as a temporizing measure. Recently, IV lipid emulsion has been reported to successfully treat hemodynamic instability associated with cyclic antidepressant toxicity.^49,85

After the patient with a known or suspected cyclic antidepressant overdose has been stabilized and the airway protected, activated charcoal is indicated. Gastric lavage should only be performed if the patient is seriously ill and the ingestion occurred within 1 hour of presentation. A second dose of activated charcoal may be given in several hours if it seems plausible that the drug still remains in the GI tract in the case of a massive ingestion or hypotension. MDAC to enhance elimination is not warranted given the extremely large volume of distribution (10 to 50 L/kg) and the low-protein binding of cyclic antidepressants.¹⁶ Forced diuresis, hemodialysis, and hemoperfusion are ineffective. Physostigmine should also be avoided because of the potential anticholinergic toxicity of seizures and asystole.

If the patient has had altered mental status, seizures, or cardiac arrhythmia, the patient should remain in the ICU for 12 hours after all supportive therapeutic interventions have been discontinued. If the patient remains asymptomatic with a normal ECG during this phase of observation, the patient may then be transferred for additional care.

Lithium

Although lithium is used to treat bipolar affective disorder and other psychiatric disorders, its narrow therapeutic index predisposes to toxicity.⁸⁶ After oral ingestion, lithium is absorbed within 1 to 2 hours, reaching peak blood levels in 2 to 4 hours with regular preparations or in 4 to 12 hours with sustained-release preparations. Lithium does not bind to plasma proteins and is excreted almost entirely by the kidneys. Toxicity may occur with acute, acute on chronic, or chronic ingestions. Drugs that increase lithium reabsorption (angiotensin-converting enzyme [ACE] inhibitors, thiazides, nonsteroidal anti-inflammatory drugs), sodium restriction, volume depletion, and intrinsic renal dysfunction increase the risk of toxicity. Lithium levels do not necessarily correlate with toxic symptoms. With an acute ingestion, the patient may be asymptomatic with a lithium level of 6 to 8 mmol/L. In chronic lithium ingestion, a high total-body lithium burden results in more immediate toxicity at lower serum levels.

The clinical presentation of patients with lithium toxicity varies with the type of ingestion. In an acute ingestion, nausea, vomiting, and diarrhea occur early with CNS symptoms developing later because of a delay in tissue distribution. In chronic ingestions, neurologic abnormalities are usually the major presenting manifestations. Patients with acute on chronic ingestions may manifest GI and neurologic symptoms. Neurologic abnormalities include tremor, hyperreflexia, agitation, fasciculations, clonus, and altered mental status. Confusion may be followed by lethargy, coma, and seizures. The tremor, hyperreflexia, and clonus usually precede altered mental status. Lithium can impair urine-concentrating ability in acute ingestions and cause nephrogenic diabetes insipidus and renal dysfunction in chronic ingestions that result in volume depletion. Although myocardial dysfunction and rhythm abnormalities have been reported in lithium toxicity, they occur infrequently. Lithium toxicity may produce flattened or inverted T waves and U waves on ECG.

Lithium toxicity is confirmed by assessment of the serum lithium level. A lithium level should be assessed immediately and 2 hours later to evaluate for increasing levels. Levels higher than 2.5 mmol/L in a chronic ingestion or higher than 4 mmol/L in an acute ingestion are potentially life-threatening. Renal function and volume status should also be assessed.

Management decisions in treating lithium toxicity may depend on the type of ingestion (acute versus chronic) and the product ingested (regular versus sustained-release). Lithium is not adsorbed by activated charcoal, but charcoal may be administered if other drugs are ingested or suspected. A forced diuresis is not effective in enhancing lithium excretion, but isotonic saline should be administered to replete and maintain intravascular volume and promote adequate urine output.⁸⁷ Diuretics can worsen lithium toxicity and should be avoided. WBI has been proposed for GI decontamination with acute or acute on chronic ingestions, ingestion of sustained-release products, or when serial lithium levels are rising. Despite lack of proven clinical benefit, this approach may be considered with appropriate precautions. Hemodialysis is effective in removing lithium, but controversy exists on the indications for treatment and duration of therapy. Proposed indications that have not been validated include renal dysfunction, severe neurologic dysfunction, inability to tolerate fluid replacement, lithium level higher than 4 mmol/L in an acute overdose, and lithium level higher than 2.5 mmol/L in chronic toxicity. The lithium level, duration of exposure, and severity of clinical symptoms should be balanced against risks of the procedure before initiating hemodialysis. Hemodialysis clears lithium only from the plasma, and a rebound increase can develop from drug redistribution. A lithium level should be assessed immediately after hemodialysis and 6 to 8 hours later. Repeat dialysis can be considered if the lithium level increases or neurologic toxicity persists at that time. Although a lithium level of 1 mmol/L is often recommended as the end point for hemodialysis, no systematic investigations have established the ideal end point for optimal outcome. Because of redistribution of lithium, improvement of neurologic toxicity lags behind the decrease in plasma level. Prolonged monitoring of lithium levels may be necessary, especially when sustained-release preparations are ingested. Continuous venovenous hemodiafiltration has also been used to remove lithium and may be associated with less rebound.⁸⁸ This technique results in a slower lithium clearance compared with hemodialysis and is not recommended if hemodialysis is available and can be tolerated. Sodium polystyrene sulfonate resin has been proposed to bind and remove lithium, but it is not currently recommended and may result in hypokalemia, hypernatremia, and fluid overload. Aminophylline and low-dose dopamine infusions have also been proposed to enhance lithium excretion, but no evidence of clinical efficacy exists and they should not be used.⁸⁷

Selective Serotonin Reuptake Inhibitors

Selective serotonin reuptake inhibitors (SSRIs) and related antidepressants are frequently prescribed for depression and other disorders. They have decreased lethality and fewer adverse cardiovascular effects compared with cyclic antidepressants.⁸⁹ Most fatalities involving SSRIs involve coingestion of other substances. Manifestations of an acute SSRI overdose may include nausea, vomiting, dizziness, blurred vision, and rarely CNS depression. Seizures and a wide QRS occur rarely but may be more likely with citalopram and bupropion, a unicyclic antidepressant. A syndrome characteristic of SSRIs is the serotonin syndrome, which may occur after a single dose, high dose, overdose, or when combined with other serotonergic agents.⁹⁰ The pathophysiology is related to excessive stimulation of central and peripheral serotonergic receptors. Clinical manifestations include altered mental status ranging from agitation to coma; autonomic dysfunction including diaphoresis, tachycardia, hyperthermia, unstable blood pressure, and diarrhea; and neuromuscular abnormalities that may range from tremors to myoclonus and rigidity.⁹¹ Severe cases may be complicated by rhabdomyolysis, renal failure, disseminated intravascular coagulation, or acute respiratory distress syndrome.

Management of an acute overdose of SSRIs is largely supportive. Gastric lavage is not warranted because of the low toxicity of these compounds, but use of activated charcoal may be considered. An ECG should be obtained to assess for the rare occurrence of a wide QRS complex or other electrocardiographic abnormality. Although clinical experience is limited, there are reports of sodium bicarbonate administration resulting in narrowing of the QRS complex. The treatment of serotonin syndrome is primarily supportive therapy after discontinuing the precipitating agents. Intubation and mechanical ventilation may be necessary for patients with significant alteration of mental status. Benzodiazepines are useful for control of agitation and external cooling for sustained hyperthermia. Rarely, neuromuscular blockers may be necessary for control of muscle rigidity or tremor. The syndrome usually resolves in 24 to 72 hours. Treatment of patients with serotonin antagonists has been proposed, but experience is limited to case reports. Cyproheptadine in varying dose regimens (12 to 32 mg/24 hour) has been most commonly recommended as a treatment option. Currently there is no role for the use of bromocriptine or dantrolene.⁹¹

Benzodiazepines

Although ingestions are relatively common, fatalities from benzodiazepines alone are uncommon. Benzodiazepine overdose results in a typical sedative-hypnotic toxidrome characterized by depressed level of consciousness, respiratory depression, hyporeflexia, and potentially hypotension and bradycardia. The clinical manifestations may be exacerbated by concomitant ingestion of other agents with sedating properties, such as ethanol, opioids, or antidepressants. Alprazolam is commonly seen in overdoses due to wide availability and may result in greater toxicity than other benzodiazepines.⁹² Flunitrazepam is a benzodiazepine not approved for use in the United States that has been associated with sexual assault. Diagnosis of benzodiazepine ingestion is primarily based on the history and clinical manifestations. Many benzodiazepines can be detected in qualitative urine toxicology assays, but a negative test does not rule out ingestion. If warranted, gas chromatography/mass spectrometry can be requested for definitive detection.

Managing benzodiazepine ingestions should be guided by the clinical presentation of the patient. The airway is assessed and stabilized if necessary. Activated charcoal is the primary method of GI decontamination for recent ingestions. Supportive care with intubation and mechanical ventilation may be necessary for patients with significant toxicity. Hypotension usually responds to volume infusion.

Flumazenil is a competitive benzodiazepine receptor antagonist that will reverse the sedative effects of benzodiazepines. It may be a helpful diagnostic tool in evaluating an overdose patient but should not be routinely used as a substitute for adequate airway protection.⁹³ A dose greater than 1 mg is seldom necessary in overdose victims. The short half-life of flumazenil (0.7 to 1.3 hours) makes resedation likely because of the longer half-life of benzodiazepines. Continuous monitoring must be instituted if flumazenil is used to arouse the patient. Flumazenil use has been associated with seizures in patients with chronic benzodiazepine use and when cyclic antidepressants are present.⁹³ It is best to avoid flumazenil in those situations and in patients with a seizure disorder or when a drug capable of causing seizures has been ingested. Slow titration of flumazenil (0.1 mg/minute) and limiting the total dose to 1 mg may minimize the risk of seizures. If seizures occur with flumazenil, benzodiazepines (often in higher doses) may be effective.

Gamma Hydroxybutyrate

Gamma hydroxybutyrate (GHB), a naturally occurring substance found in the brain and peripheral tissues, is banned in the United States except for the treatment for narcolepsy. It is one of several agents characterized as a “date rape” drug and has been promoted to build muscle, improve performance, produce euphoria, induce fat loss, and enhance sleep. Several deaths have been attributed to GHB and related agents.⁹⁴ The drug is usually available as a colorless, odorless liquid with a mild, salty taste that is easy to mask in drinks. GHB is rapidly absorbed from the stomach (usually within 10 to 15 minutes) and readily crosses the blood-brain barrier. It is metabolized to carbon dioxide and water without active metabolites. Stimulatory effects occur from resulting increased dopamine levels in the brain and sedative effects by potentiation of endogenous opioids. The manifestations of GHB toxicity are dose related and include agitation, coma, seizures, respiratory depression, and vomiting.⁹⁵ Other effects include amnesia, tremors, myoclonus, hypotonia, hypothermia, decreased cardiac output, and bradycardia. Coma and respiratory depression may be potentiated by the concomitant use of ethanol. GHB is not routinely detected by urine toxicology assays but can be detected in plasma or urine by gas chromatographic and mass spectrophotometric techniques. Diagnosis is usually determined by the clinical course and history of exposure elicited after the patient recovers. Gamma butyrolactone (GBL), also known as 2(3H)-furanone dihydro, and 1,4-butanediol (BD), also called tetramethylene glycol, have been abused with the same adverse effects as GHB including death. Both agents are metabolized in the body to GHB.⁹⁴

No antidote for GHB, GBL, or BD exists. The primary management for ingestion of these drugs is supportive care with particular attention to airway protection and ventilation. In some cases, intubation and mechanical ventilation are required. Gastric lavage and activated charcoal are not indicated because of the small amounts involved and the rapid absorption. Naloxone and flumazenil are of no benefit. Patients with mild intoxication may be observed in the emergency department and released after symptoms resolve. A rapid recovery of consciousness from an obtunded condition is frequently observed. In patients requiring intubation and mechanical ventilation, symptoms can be expected to resolve within 2 to 96 hours unless complications such as aspiration or anoxic injury have occurred. The concomitant use of alcohol may prolong the CNS depression. Although physostigmine has been used to awaken patients with GHB intoxication, its use is not recommended.⁹⁶

A withdrawal syndrome has been described in patients who frequently ingest high doses of GHB (every 1 to 3 hours).⁹⁷ Mild symptoms such as anxiety, insomnia, nausea, vomiting, and tremors begin within 6 hours of the last dose and may progress to severe delirium with autonomic instability (usually mild) requiring hospitalization and sedation. The duration of symptoms requiring treatment may be as long as 2 weeks. Benzodiazepines are the initial choice for management, and high doses may be required. Propofol and barbiturates have also been used successfully.

Propofol

Propofol is a sedative-hypnotic used for general anesthesia, procedural sedation, more prolonged sedation in critically ill patients, and treatment of status epilepticus. It has also been implicated in abuse, accidental overdose, suicide, and even murder.⁹⁸ The critical care clinician should be aware of a potentially fatal toxicity associated with more prolonged infusions of propofol known as propofol-related infusion syndrome (PRIS).⁹⁹ The syndrome is usually associated with doses of propofol greater than 4 mg/kg/hour for longer than 48 hours’ duration. However, metabolic acidosis has been reported within 1 to 4 hours after the initiation of propofol infusion. Predisposing factors that have been associated with PRIS include young age, CNS or respiratory illness, vasopressor use, glucocorticoid use, greater severity of illness, sepsis, and impaired oxygen delivery. Mortality rates of 18% to 80% have been reported.⁹⁹ Clinical features of the syndrome can include refractory bradycardia progressing to asystole, other arrhythmias, myocardial failure, lactic acidosis, rhabdomyolysis, renal failure, and hypertriglyceridemia.¹⁰⁰ The pathophysiology is hypothesized to be related to mitochondrial utilization of free fatty acids and genetic predisposition.

Propofol infusions should be limited to less than 4 mg/kg/hour and no longer than 48 hours of infusion when possible. Prompt recognition of early signs of PRIS (elevated serum lactate, elevated creatine kinase, hypertriglyceridemia) is essential for successful intervention. Another clinical clue to possible PRIS is the unexplained need for increasing doses of pressor or inotropic agents. Management includes discontinuation of propofol and the use of alternative sedative agents. The most effective treatment for severe PRIS is cardiorespiratory support and hemodialysis or hemofiltration to decrease blood levels of metabolic acids and lipids.¹⁰⁰

Amphetamines/Methamphetamines

Amphetamines, methamphetamines, and related agents cause central and peripheral release of catecholamines, which result in a sympathomimetic/adrenergic toxidrome characterized by tachycardia, hyperthermia, diaphoresis, agitation, hypertension, and mydriasis. Hallucinations (visual and tactile) and acute psychoses are frequently observed. The clinical manifestations associated with abuse of these agents may last up to 24 hours due to the longer duration of pharmacologic effects. The acute adverse consequences are similar to those seen with cocaine abuse (see following) and include myocardial ischemia and arrhythmias, pulmonary hypertension, seizures, intracranial hemorrhage, stroke, hepatotoxicity, rhabdomyolysis, necrotizing vasculitis, and death.¹⁰¹ Chronic use of these drugs may result in dilated cardiomyopathy.¹⁰² Poor oral hygiene and severe dental caries (“meth mouth”) can be clues to chronic methamphetamine use.¹⁰³

Methamphetamine hydrochloride in a crystalline form called “ice,” “crank,” or “crystal” is one of the most popular drugs in this class. It has high purity and can be orally ingested, smoked, insufflated nasally, or injected intravenously. An amphetamine-like drug (3-4-methylenedioxymethamphetamine) is a designer drug commonly known as Ecstasy, XTC, or MDMA that acts as a stimulant and hallucinogen.¹⁰⁴ It results in serotonin release in the brain with inhibition of serotonin reuptake and has been reported to produce serotonin syndrome. Complications are usually a result of the drug effects and excessive physical activity. Complications include hyperthermia, hyponatremia (excessive water intake or syndrome of inappropriate antidiuretic hormone secretion), rhabdomyolysis, renal failure, cardiac collapse, cerebral infarction/hemorrhage, and multiple organ failure. MDMA and other amphetamines will usually be detected on qualitative toxicology assays of urine but false positives and negatives occur.

Management of amphetamine intoxication is primarily supportive. Gastric lavage is not recommended because absorption after oral ingestion is usually complete when patients present. Activated charcoal may be considered if a recent oral ingestion is known to have occurred. Further interventions are dependent on patient complaints and clinical findings. A careful assessment for complications should be made including measurement of core temperature, obtaining an ECG, and evaluating laboratory data for evidence of renal dysfunction and rhabdomyolysis. IV hydration for possible rhabdomyolysis is warranted in individuals with known exertional activities pending creatine phosphokinase (CPK) results. Benzodiazepines, often in high doses, are used to control agitation. Haloperidol should be reserved for patients who do not have an adequate response to benzodiazepines. Seizures are best treated with benzodiazepines.

Cocaine

Cocaine abuse is a global problem that results in significant medical complications.¹⁰⁵ Cocaine hydrochloride is water soluble and can be injected intravenously, ingested, or snorted intranasally. Crack or rock cocaine is the alkaloid form primarily abused by inhalation. The onset, peak, and duration of physiologic effects of cocaine vary with the route of use, form of cocaine used, and concomitant use of other drugs.¹⁰⁵ Both forms of cocaine are absorbed from all mucosal surfaces and undergo hydrolysis by plasma and liver cholinesterases. The major metabolites, benzoylecgonine and ecgonine methyl ester, are excreted in the urine and can be detected by qualitative urine assays. The metabolites of cocaine may be detectable in urine for 24 to 36 hours after use, but prolonged detection can occur in frequent users of high doses.

Cocaine inhibits the presynaptic reuptake of biogenic amines such as norepinephrine, dopamine, and serotonin throughout the body including the CNS. Characteristic clinical findings of a sympathomimetic syndrome include tachycardia, mydriasis, hypertension, hyperthermia, diaphoresis, euphoria, and agitation. The sympathetic stimulation also results in multiple potential complications (Box 68.3). Complications such as myocardial ischemia or cerebral infarction may occur several days after the last use of cocaine. Complications of transporting cocaine in body cavities may include rupture of packets with drug absorption and bowel obstruction.

No specific antidote exists for cocaine. Treatment is primarily aimed at detecting complications, intervening as indicated, and preventing further injury. Benzodiazepines should be used liberally for control of agitation. Haloperidol is reserved for overt psychosis because of its potential for lowering the seizure threshold.

No large clinical trials have evaluated therapeutic strategies for myocardial ischemia resulting from cocaine use. Aspirin should be administered if the risk of intracranial hemorrhage is low because a significant number of patients have thrombotic occlusion as the cause of ischemia. Benzodiazepines and nitroglycerin are first-line agents for relief of chest pain, but small clinical studies have yielded conflicting results on the benefit of combining the agents.¹⁰⁶ α-Adrenergic blockers such as phentolamine and calcium channel blockers have been recommended as second-line treatment for unrelieved pain but are rarely necessary.¹⁰⁶ Beta blockers were often considered to be contraindicated in the management of potential ischemia related to cocaine because of the potential for unopposed α-adrenergic-mediated vasoconstriction leading to elevated blood pressures. However, beta-blocker use was not found to be detrimental in two retrospective studies of patients with recent cocaine use and may be beneficial in some patients.^107,108 It may be appropriate to avoid administration of beta blockers in patients manifesting acute sympathomimetic findings. In addition, routine use of IV beta blockers is no longer recommended for acute coronary syndromes. Reperfusion interventions, primarily percutaneous coronary interventions, should be considered for patients with myocardial infarction.¹⁰⁶ Ventricular arrhythmias are not common and may be related to cocaine blockade of myocardial sodium channels leading to QRS and QT interval prolongation. Wide complex arrhythmias may respond to treatment with sodium bicarbonate.¹⁰⁹ Class IA antiarrhythmic drugs such as procainamide should be avoided. Treatment of life-threatening arrhythmias should otherwise follow advanced life support guidelines.

Cerebral complications should be managed by standard interventions specific for the injury. Seizures are best managed with benzodiazepines. The reported incidence of underlying vascular malformations in intracranial hemorrhage has been variable, but if present these problems may require specific intervention. Severe hyperthermia is managed the same as heat stroke with either conductive or evaporative cooling.¹¹⁰ When there is suspicion of rhabdomyolysis, IV hydration should be instituted immediately pending assessment of renal function and CPK levels. Asymptomatic transporters of cocaine packets should be managed conservatively with activated charcoal, possible WBI, and supportive care. Surgery is reserved for patients exhibiting manifestations of cocaine poisoning or GI perforation or obstruction.¹¹¹ Contamination of cocaine with other drugs or fillers can result in toxicities that are not directly related to the effects of cocaine. Levamisole, an anthelminthic agent used in veterinary medicine, has been found in cocaine supplies and linked to the development of agranulocytosis.¹¹² Agranulocytosis resolves when drug use is discontinued. Retiform purpura and skin necrosis secondary to thrombotic vasculopathy have also been linked to cocaine contaminated with levamisole.^113,114 The potential for suicidal intent should be recognized in cocaine abusers, and psychiatric consultation may be appropriate after stabilization.

Mephedrone/Methylenedioxypyrovalerone (Bath Salts)

Mephedrone and 3.4-methylenedioxpyrovalerone (MDPV) are synthetic stimulants marketed in products sold as bath salts to avoid regulation. MDPV inhibits reuptake of dopamine and norepinephrine, and mephedrone may act as a monoamine reuptake inhibitor.¹¹⁵ Street names include Ivory Wave, Bliss, White Lightning, Vanilla Sky, Hurricane Charlie, White Knight, and others. The products have been ingested, snorted, smoked, and injected and are often used in combination with alcohol or other drugs. These agents are not detected by qualitative toxicology screens.

Clinical manifestations are similar to those of other stimulant drugs and include agitation, tachycardia, hyperthermia, hypertension, mydriasis, chest pain, palpitations, seizures, hallucinations, delusions, and paranoia.115,116 Symptoms may be prolonged for more than 24 hours after use of mephedrone despite a short expected half-life.¹¹⁶ Management includes IV benzodiazepines for significant agitation and psychotic symptoms. Symptoms may recur as sedation wears off, requiring repeat dosing. A thorough clinical evaluation is required to identify other complications such as rhabdomyolysis, myocardial ischemia, and organ dysfunction. Seizures are best treated with IV benzodiazepines.