Licensed to UpToDate Guest Pass

©2007 UpToDate ®

printer-friendly format

e-mail this to a colleague

New Search Contents My UpToDate Feedback Help Log Out

Your UpToDate guest pass will expire in 28 day(s). (12/19/2007) Click here to subscribe

Following is the full text, Medline abstracts, images and drug information of a topic review from UpToDate. Some of the regular features found in UpToDate, such as links to related topics and a simple but powerful search engine, are not incorporated here.

How to respect our copyright

Use of professional judgment

Methamphetamine intoxication

Edward W Boyer, MD, PhD Christina Hernon, MD

UpToDate performs a continuous review of over 375 journals and other resources. Updates are added as important new information is published. The literature review for version 15.3 is current through August 2007; this topic was last changed on September 13, 2007. The next version of UpToDate (16.1) will be released in March 2008.

INTRODUCTION — Methamphetamine is a sympathomimetic amine that belongs to a class of compounds, the phenethylamines, with a variety of stimulant, anorexiant, euphoric, and hallucinogenic effects. Methamphetamine was first synthesized in 1893. Thirty years later, pharmaceutical formulations were introduced as treatments for nasal congestion and asthma. Methamphetamine was widely used by German, Japanese, and American forces during World War II to increase alertness and decrease fatigue.

Methamphetamine is used clinically for treatment of Attention Deficit Disorder with Hyperactivity (ADHD), short-term treatment of obesity, and as an off-label treatment for narcolepsy. Recreational use of methamphetamine and other amphetamine-derived stimulants has reached epidemic proportions in the United States (US), southern Asia, the Philippines, and Japan. After cannabis, it is the most widely abused drug worldwide [1]. Approximately 5 percent of the US population are estimated to have used methamphetamine, with an estimated 300,000 new users each year [2,3].

Methamphetamine may be synthesized via simple reactions using readily available chemicals and over-the-counter cold medicines such as ephedrine and pseudoephedrine. Although some illicit methamphetamine is diverted pharmaceutical product, the majority of recreational methamphetamine is manufactured specifically for illicit use. The output of thousands of small laboratories in predominantly rural regions of the US has been supplanted by "superlabs" whose output is kilogram quantities. Clandestine methamphetamine synthesis carries significant risk of explosion or toxic exposure and is responsible for exposing many children to profoundly toxic products [4].

This topic review will discuss the toxicology, diagnosis, and management of acute methamphetamine intoxication. The general management of acute drug overdose and the management of other stimulants, such as cocaine, are discussed elsewhere. (See "General approach to drug intoxication in adults" and see "Cocaine: acute intoxication").

PHARMACOLOGY AND CELLULAR TOXICOLOGY — Phenethylamines comprise a class of central nervous system (CNS) stimulants (show figure 1). Various substitutions on the basic phenethylamine structure determine the degree of CNS penetration, likelihood of degradation by monoamine oxidase (MAO), receptor binding affinity, and the range of effects.

The prototypical phenylethylamine, is alpha methyl phenethylamine, which is contracted to give the common name amphetamine. Amphetamine possesses a methyl group at the alpha position of the carbon chain (show figure 2). Methamphetamine has a second methyl group (show figure 3), which increases lipophilicity and CNS activity. Methamphetamine exists in dextro- or levo- stereoisomers, with dextroamphetamine analogues conferring greater CNS stimulation.

• Methamphetamine-neurotransmitter interactions - The neurotransmitters norepinephrine, epinephrine, and serotonin are stored within cytoplasmic vesicles of presynaptic adrenergic neurons. These neurotransmitters are released into the synapse with nerve depolarization. Once in the synapse, the neurotransmitters bind to postsynaptic receptors and elicit neurochemical responses. Thereafter, they diffuse away from the postsynaptic receptor and are quickly degraded or undergo cellular reuptake and replaced into vesicles. Reuptake is mediated through adenosine triphosphate (ATP)-dependent or ion-dependent (Na+) neurotransmitter transporters, as well as by concentration gradient channels.

Methamphetamine lacks direct adrenergic effects, but is instead an indirect neurotransmitter. Methamphetamine is incorporated into cytoplasmic vesicles where it displaces epinephrine, norepinephrine, dopamine, and serotonin into the cytosol. As cytosolic concentrations rise, neurotransmitters diffuse out of the neuron and into the synapse where they activate postsynaptic receptors. Methamphetamine also inactivates neurotransmitter reuptake transporter systems.

The result of these two processes is a surge of adrenergic stimulation. The lone modulatory response to such stimulation is degradation by catechol o-methyl transferase (COMT), a slow, saturable degradation pathway.

Stimulated alpha- and beta-adrenergic receptors produce hypertension, tachycardia, hyperthermia, and vasospasm. Serotonergic activation contributes to alterations in mood as well as deranged responses to hunger and thirst. Dopamine receptor stimulation affects drug-craving and drug-seeking behavior, and psychiatric symptoms.

PHARMACOKINETICS AND METABOLISM — Methamphetamine is readily absorbed following administration via oral, pulmonary, nasal, intramuscular, intravenous, rectal, and vaginal routes. Body stuffing has been reported [5-7].

Methamphetamine is lipophilic, readily crosses the blood-brain barrier, and has a large volume of distribution (3 to 4 L/kg) [8]. Onset of action occurs within seconds after smoking or injection; effects may be observed within 5 minutes after intranasal use or within 20 minutes following oral ingestion [9]. Peak plasma concentrations are achieved approximately 30 minutes following intravenous or intramuscular administration and up to 2 to 3 hours after ingestion. Although methamphetamine has a plasma half-life of 12 to 34 hours, the duration of its effect commonly persists beyond 24 hours [10].

Elimination of methamphetamine occurs via several hepatic and renal pathways, including cytochrome CYP2D6. Polymorphisms of this cytochrome isoform have been implicated in cases of unanticipated toxicity [9]. Enzymatic degradation of methamphetamine results in active metabolites which may accumulate with repeated, frequent, or binge use. Renal elimination that is dependent upon urinary pH is related to methamphetamine's alkaline pKa of 9 to 10.

CLINICAL FEATURES OF OVERDOSE — Clinicians should consider the diagnosis of methamphetamine intoxication in any diaphoretic patient with hypertension, tachycardia, severe agitation, and psychosis.

History — Some patients may be unable to provide any history because of severe agitation. If possible, clinicians should identify the route of exposure to methamphetamine and the frequency of use, which can help distinguish among short-term, binge, and chronic abuse. Ascertaining the potential amounts of methamphetamine ingested, as well as the use of other illicit substances and coingestants (eg, heroin, benzodiazepines), can guide therapeutic interventions. In body stuffers (individuals who ingest methamphetamine to avoid arrest) and body packers (individuals who internally conceal large volumes of drug for transport), special attention should be paid to the number of packets ingested, their size, the wrapping used, the time since ingestion, and any abdominal complaints (eg, constipation, obstipation, distention, and vomiting). (See "Internal concealment of drugs of abuse (body packing)").

Methamphetamine can cause a host of respiratory, cardiac, vascular, otolaryngologic, neurologic, integumentary, psychiatric, infectious, traumatic, and dental maladies; when possible, a thorough review of systems is in order.

Physical examination — Patients with methamphetamine intoxication range from the virtually asymptomatic to those in sympathomimetic crisis with seizures, metabolic acidosis, and imminent cardiovascular collapse. Agitation, tachycardia, and psychosis are among the most frequent findings identified on presentation to the emergency department (ED) [11,12]. Life-threatening intoxication is characterized by hypertension, tachycardia, severely agitated delirium, hyperthermia, acidosis, and seizures. Prognostic factors for mortality include: coma, shock, body temperature >39ºC, acute renal failure, metabolic acidosis, and hyperkalemia (K 5.6 to 8.5 mmol/L) [13].

• General appearance - Methamphetamine abusers may appear malnourished, agitated, and disheveled [14]. Hypervigilance and akathisia may be present in mildly intoxicated patients, while patients with severe intoxication may exhibit abrupt changes in behavior, becoming extraordinarily violent. Excoriations on the skin and track marks suggest prolonged and intravenous use, respectively. Profound diaphoresis is common in moderate to severe intoxication.

• Vital signs - The severity of patient agitation sometimes prevents measurement of vital signs. Methamphetamine produces dose-dependent variations of pulse and blood pressure. At low doses (10 to 25 mg), elevations in heart rate and blood pressure may be insignificant [15]. At higher doses (30 to 40 mg), sympathomimetic stimulation may produce dramatic increases in heart rate, blood pressure, and respiratory rate [15]. Elevated temperature is common in moderate to severe intoxication while hypertensive crisis, hyperthermia, and refractory tachydysrhythmias are associated with severe intoxication.

• Cardiovascular - Tachycardia and hypertension are nearly universal among intoxicated patients irrespective of severity. Cardiac ischemia, myocardial infarction, and cardiomyopathy have been identified in acute and chronic users. In one retrospective, observational study of methamphetamine-exposed patients who presented to the emergency department complaining of chest pain, 25 percent had evidence of an acute coronary syndrome [16].

Severe methamphetamine intoxication is associated with sudden cardiovascular collapse, particularly in agitated patients who require physical restraint for protection against injury to self and others, including law enforcement and clinicians. Severe agitation often presages cardiac arrest, which can occur with frightening rapidity, and has been observed after only a few minutes' struggle.

Cardiovascular collapse is postulated to arise from a combination of neurotransmitter depletion, metabolic acidosis, and dehydration. Toxic Exposure Surveillance Systems (TESS) data reported 3456 methamphetamine exposures that presented to medical care with consultation to the Poison Control Center System in 2005. Of these, there were 37 deaths and 207 life-threatening effects, as well as others with symptoms associated with significant morbidity [17]. These figures likely underestimate the number of severe exposures, due to under-reporting.

Valvular dysfunction may be related to the serotonergic effects of methamphetamine, while aortic dissection and rupture are more likely due to its vasospastic and hypertensive effects. Injection drug use increases the risk of infectious sequelae such as bacterial endocarditis.

• Head, eyes, ears, nose and throat (HEENT) - Common HEENT examination findings include minimally reactive mydriasis, mucosal injuries from insufflation (snorting), oropharyngeal burns in methamphetamine smokers, and gingival hypertrophy. Extensive tooth decay ("meth-mouth") is common in chronic methamphetamine abuse due to bruxism, decreased saliva production, and poor dental hygiene (show picture 1).

• Pulmonary - Increases in minute ventilation, respiratory rate, and tidal volume are often associated with severe intoxication. Illicit methamphetamine may contain pulmonary irritants that are directly toxic to the lung. Methamphetamine has been implicated in acute pulmonary edema [18], pulmonary hypertension [19,20], and, if smoked, thermal injury. Other pulmonary complications include: pneumothorax, pneumomediastinum, pneumonia, acute lung injury, and pulmonary hemorrhage. Similar injuries have been seen after inhalation of heroin and smoked cocaine (crack) [21]. (See "Pulmonary complications of cocaine abuse").

• Gastrointestinal - Methamphetamine can induce vomiting and diarrhea due to sympathomimetic stimulatory effects. Severe abdominal pain out of proportion to physical examination findings suggests methamphetamine-associated bowel ischemia [22], particularly in the setting of body packing and stuffing. Rectal exposure to methamphetamine occurs in cases of transport for distribution (ie, body packing) and rectal administration ("booty bumping") [23]. (See "Internal concealment of drugs of abuse (body packing)").

• Gynecologic/obstetric - Vaginal exposure to methamphetamine arises from body stuffing, body packing, or vaginal administration of the drug [7]. Among pregnant abusers, placental insufficiency, hemorrhage, and abruption is reported [24].

• Extremities - The extremities are a likely source of injury from burns or trauma, and stigmata of repeated intravenous injection (track marks) may be present.

• Dermatologic - Drug preparation may cause thermal or chemical burns, most commonly to the hands and face. Injection drug use may produce cellulitis, abscesses, and track marks. Protracted methamphetamine abuse is associated with formication ("crank bugs"), and many methamphetamine abusers suffer multiple small skin excoriations from unremitting picking. Jaundice may be due to hepatitis, while poor nutrition and vitamin deficiencies may cause skin changes (cracking, angular cheilitis, aphthous ulcers) or abdominal bleeding and bruising.

• Neurologic - Choreiform movement disorders are a relatively common finding in acute methamphetamine intoxication, and arise from derangements in dopaminergic neurotransmission [25]. Focal neurologic deficits may represent central nervous system ischemia, infarction, or hemorrhage. Seizures are associated with severe intoxication, typically within 24 hours of methamphetamine use. They are usually self-limited and brief [26,27].

• Psychiatric - Acute methamphetamine use can induce agitated delirium and paranoia. Binge or chronic methamphetamine use is strongly associated with a variety of psychiatric symptoms including paranoia and psychosis, but delusions, homicidal and suicidal ideation, mood disturbance, anxiety, and hallucinations also occur [28]. Suicidality, homocidality, psychosis, and abnormal behavior and movements are commonly seen in binge as well as chronic users. Psychiatric symptoms are often the chief complaint of patients presenting to the emergency or acute care setting.

DIFFERENTIAL DIAGNOSIS — Establishing the diagnosis of methamphetamine intoxication requires recognition of the sympathomimetic toxidrome, a condition characterized by signs of adrenergic excess, including: hypertension, tachycardia, hyperthermia, diaphoresis, minimally-reactive mydriasis, and agitation. The diagnosis of methamphetamine intoxication in patients with these findings is supported by a positive result on the amphetamine portion of a qualitative urine drug screen ("tox screen"). The differential diagnosis includes toxicologic and nontoxicologic etiologies.

Toxicologic conditions mimicking methamphetamine intoxication include (show table 1): adrenergic substances (eg, cocaine, phencyclidine [PCP]), theophylline, aspirin, monoamine oxidase inhibitors, serotonin syndrome, and anticholinergic poisoning. (See "Cocaine: acute intoxication" and see "Aspirin intoxication in adults" and see "Serotonin syndrome" and see "Anticholinergic poisoning" and see "Theophylline intoxication").

The prolonged duration of action of methamphetamine (approximately 20 hours) helps differentiate it from cocaine (duration of action 30 minutes) and PCP (duration of action less than 8 hours). The clinically distinct features of theophylline intoxication (tachycardia, unremitting vomiting, and widened pulse pressure) are confirmed by measurement of the serum theophylline concentration. Aspirin intoxication produces tinnitus and hyperpnea even in resting patients, as well as metabolic acidosis, hyperthermia, and elevated serum aspirin concentrations.

Monoamine oxidase inhibitor poisoning has a clinical appearance nearly identical to serotonin syndrome, and both share clinical features with methamphetamine toxicity. While the clinical manifestations of serotonin syndrome include agitation, tachycardia, and diaphoresis, they also include lower extremity tremor and clonus, which distinguish the condition from methamphetamine intoxication [29]. Patients with anticholinergic poisoning have anhidrosis, whereas methamphetamine intoxicated individuals are profusely diaphoretic. Furthermore, patients with the anticholinergic toxidrome feebly pick at objects and have a peculiar mumbling speech; methamphetamine produces wildly agitated delirium that often requires a combination of physical and chemical restraint.

Leading nontoxicologic mimics of methamphetamine intoxication include heat stroke, thyrotoxicosis, and pheochromocytoma. (See "Severe hyperthermia: Heat stroke and malignant hyperthermia" and see "Diagnosis of hyperthyroidism" and see "Clinical presentation and diagnosis of pheochromocytoma").

Diagnosis of heat stroke should have corroborating history, such as a hot environment, prolonged exercise or exertion, or decreased ability to regulate temperature. Associated medication (such as diuretics, antipsychotics, and some cardiovascular medications) or conditions (such as advanced age, intoxication, debility, and autonomic dysfunction) predispose certain patients to heat stroke. The degree of agitation in heat stroke is significantly less than that seen in methamphetamine intoxication.

While thyrotoxicosis may have several features consistent with methamphetamine intoxication, presence of goiter, thyroid artery bruit, exophthalmos, and pretibial edema are seen only in thyrotoxicosis. The associated agitation is also unlikely to be as severe as with methamphetamine. Pheochromocytoma usually produces intermittent hypertension, diaphoresis, vomiting, and diarrhea; duration of episodes is variable and may be associated with inciting stimulus.

LABORATORY EVALUATION

• General testing - Routine laboratory evaluation of the poisoned patient should include the following:

      -  Fingerstick glucose, to rule out hypoglycemia as the cause of any alteration in mental status

      -  Acetaminophen and salicylate levels, to rule out these common coingestions

      - Electrocardiogram (ECG), to rule out conduction system poisoning by drugs that effect the QRS or QTc intervals

      -  Pregnancy test in women of childbearing age

• Specific testing - Reliance upon qualitative toxicologic screens can be disastrous if care is delayed while awaiting test results. While urine drug tests may support the diagnosis of acute methamphetamine intoxication, the results of such a "tox screen" have little clinical utility.

The amphetamine portion of the tox screen is susceptible to both false positive and false negative results and must be interpreted in clinical context [30]. Drugs such as benzphetamine and bupropion may give positive results [31,32], as may selegiline following its metabolism to l-methamphetamine. Conversely, urine drug assays, which are dependent upon renal clearance, performed soon after use may fail to detect methamphetamine if insufficient time has elapsed for drug to accumulate in the urine [33]. Because urine tox screens contribute little to patient care, clinicians should not withhold immediate sedation for an acutely intoxicated individual while awaiting final test results.

Because dehydration, metabolic acidosis, hyperthermia, and rhabdomyolysis occur in a large proportion of methamphetamine users, we recommend the following tests also be obtained if methamphetamine intoxication is suspected:

      -  Basic serum electrolytes (ie, sodium, chloride, potassium, bicarbonate)       -  Serum lactate       -  Creatinine phosphokinase (CPK)       -  Hepatic transaminases (ie, ALT, AST)       -  Clotting times (ie, prothrombin time, activated partial thromboplastin time)       -  Renal function studies (ie, Creatinine, BUN)

An arterial blood gas may help to delineate the severity of acidosis identified by an elevated anion gap. Pelvic ultrasonography may be helpful in diagnosing placental abruption, but its sensitivity is limited and emergent obstetrical consultation is needed if this diagnosis is entertained. Additional studies, including echocardiography, chest and abdominal CT, and chest radiography, are obtained as needed to investigate other potential complications of methamphetamine abuse, such as cardiomyopathy, aortic dissection and rupture, pneumothorax, and stroke.

MANAGEMENT

General approach and warning — Clinicians should consider the diagnosis of methamphetamine intoxication in any diaphoretic patient with hypertension, tachycardia, severe agitation, and psychosis. Control of agitation, correction of vital signs, control of hyperthermia, and fluid resuscitation, comprise the core of the management of acute methamphetamine intoxication.

The intensity of therapy depends upon the severity of illness, but cases of abrupt decompensation among conservatively treated patients highlight the need for immediate, aggressive intervention [13,34]. Interventions frequently must be initiated prior to confirmatory laboratory data or, in violent patients, even before vital signs are obtained.

Patients with acute methamphetamine intoxication may, without provocation, abruptly develop severe agitation and manifest extreme violence, placing themselves, their caretakers, and other patients at risk of major injury.

Sedation — Acutely intoxicated patients may be extremely agitated and pose a danger to themselves, other patients, and medical staff. Control of violent behavior is of critical importance. We treat severely intoxicated patients immediately with parenteral benzodiazepines (lorazepam 4 mg IV or diazepam 5 to 10 mg IV). The doses described here can be repeated every eight to ten minutes based on patient response; very large doses may be needed.

Benzodiazepines constitute extremely safe and effective first-line treatment for methamphetamine-related agitation. Atypical antipsychotic agents (eg, ziprasidone 10 mg), butyrophenones (eg, droperidol 10 mg or haloperidol 10 mg), or combinations of these agents can be used as adjunctive therapy when high doses of benzodiazepines do not adequately control symptoms. Although some studies support the use of butyrophenones [35-37], these agents may interfere with heat dissipation, lower the seizure threshold, and prolong the QTc interval [38].

Intravenous (IV) administration of sedatives and antipsychotics is strongly preferred, however, intramuscular (IM) injection may be used when IV access is unavailable. IM injection may provide sufficient sedation to allow definitive care, including placement of intravenous catheters.

Mildly intoxicated patients may benefit from a quiet environment with minimal sedation, while moderately ill patients should receive benzodiazepines. Lorazepam 1 to 2 mg or diazepam 2 to 5 mg may be adequate to sedate these patients, but should be repeated as needed. In animal models, benzodiazepines blunt the hyperadrenergic effects of methamphetamine, an outcome associated with increased survival.

Physical restraints are undesirable: patients who struggle against physical restraints undergo isometric muscle contractions that are associated with severe lactic acidosis, hyperthermia, sudden cardiac collapse, and death. Physical restraints should be replaced by chemical sedation as rapidly as possible.

Correction of vital signs — Severe hypertension, particularly if refractory to aggressive treatment with sedatives, may require treatment with vasodilators (eg, nitroprusside) or alpha-adrenergic antagonists (eg, phentolamine). The use of beta-adrenergic antagonists (beta-blockers), including labetolol, to manage hypertension should be avoided. Beta-blockers may lead to unopposed alpha-adrenergic agonism and vasospasm, and a paradoxical exacerbation of an already elevated blood pressure [39].

Hyperthermia — Control of hyperthermia (T 41.1ºC) involves eliminating excessive muscle activity. While benzodiazepines alone offer benefit to moderately ill patients, severely intoxicated hyperthermic patients may require paralysis with nondepolarizing agents, such as rocuronium and vecuronium, followed by endotracheal intubation and mechanical ventilation. Additional indications for endotracheal intubation include: refractory agitation; skeletal, cervical, or facial muscle rigidity; and worsening metabolic acidosis.

Succinylcholine is contraindicated because of the risk of rhabdomyolysis and associated hyperkalemic arrhythmias. Patients with increased respiratory rate and effort may benefit from the intravenous administration of 1 to 3 ampules sodium bicarbonate prior to intubation to treat a presumptive underlying metabolic acidosis, although the benefits of this therapy are unproven.

Paralyzed patients at risk for seizure should receive continuous bedside electroencephalography. Aggressive sedation, neuromuscular paralysis, and fluid resuscitation are used to control methamphetamine-induced hyperthermia, but these measures can be supplemented with external cooling blankets or evaporative cooling techniques. (See "Severe hyperthermia: Heat stroke and malignant hyperthermia").

Antipyretics have no role in the management of acute methamphetamine intoxication: increased body temperature arises from muscular activity, not an alteration in the hypothalamic temperature set point.

Fluid resuscitation — The profuse diaphoresis, neuromuscular activity, hyperthermia, and hyperpnea of acute methamphetamine intoxication can lead to severe dehydration. Treatment consists of immediate, aggressive fluid resuscitation with normal saline. Because patients who have engaged in binge methamphetamine abuse can have insensible fluid losses of several liters, an initial fluid bolus of two liters of normal saline given through a 14 gauge intravenous catheter should be administered over approximately 30 minutes.

After initial resuscitation is completed, normal saline should be administered at rates of 500 to 1000 mL/hour until a urine output of one mL/Kg per hour is achieved. Although central lines are seldom used in these patients, a central venous pressure of approximately 7 mmHg may serve as an alternative goal of resuscitation.

If severe metabolic acidosis (pH <7.1) or rhabdomyolysis are present, we suggest intravenous sodium bicarbonate. Bicarbonate solution should be isotonic (eg, 3 ampules bicarbonate in 5 percent dextrose with water) and administered at a rate of 200 mL/hour. (See "Approach to the adult with metabolic acidosis" and see "Clinical features and prevention of heme pigment-induced acute tubular necrosis", section on Prevention of acute renal failure).

Sudden cardiac arrest — Despite appropriate and expeditious management, some patients with severe methamphetamine intoxication will sustain sudden cardiovascular collapse. No predisposing factors rigorously predict collapse, but the clinician should anticipate clinical deterioration and cardiac arrest in any wildly agitated patient, particularly those requiring physical restraints to maintain patient safety [40].

Patients placed in physical restraints can suffer sudden cardiac arrest due to a combination of dehydration, depletion of adrenergic neurotransmitters, and metabolic acidosis. Contributing factors to metabolic acidosis may include excessive muscular activity and increased ATP hydrolysis from methamphetamine-induced increases in metabolism. The multifactorial nature of cardiovascular collapse makes successful resuscitation notoriously difficult, even when arrest is witnessed [40]. In addition to airway control with endotracheal intubation, therapy is directed toward:

• Fluid resuscitation with large volumes of normal saline.

• Correction of metabolic acidosis with sodium bicarbonate.

• Administration of vasoactive amines to overcome neurotransmitter depletion.

Intravenous fluids should be administered until circulation is restored. Specific guidelines for fluid administration in methamphetamine-associated cardiovascular collapse are lacking, but a useful starting point is a bolus of 2 liters of normal saline (or 20 mL/kg in a child) administered over 30 minutes, followed by repeat boluses as needed to overcome insensible losses. Treatment of metabolic acidosis consists of fluid resuscitation, as described above, and administration of sodium bicarbonate, 1 to 3 ampules administered intravenously.

A direct-acting vasopressor, such as norepinephrine, is preferred for management of shock associated with methamphetamine intoxication. Continuous norepinephrine administration should be titrated to a systolic blood pressure greater that 90 mmHg and a urine output greater than 1 mL/Kg per hour. The use of direct-acting vasopressor amines, such as norepinephrine and epinephrine, is postulated to be more effective at reestablishing effective vascular tone than indirect vasopressors, such as dopamine, which require neuronal uptake and conversion to norepinephrine.

Hyperkalemic cardiac arrest may occur in acute methamphetamine intoxication; patients with a suggestive electrocardiogram may benefit from standard treatment with calcium and insulin with dextrose. (See "Clinical manifestations and treatment of hyperkalemia").

Gastrointestinal (GI) decontamination — Activated charcoal is rarely indicated due to the route of administration (eg, intranasal, inhalation, injection). If methamphetamine has been ingested, the greatest benefit of activated charcoal occurs if administered within one to two hours of ingestion [41]. Activated charcoal should not be given to a patient with a declining mental status, severe agitation requiring sedation, or at risk of seizure. If given, the standard dose is 1 mg/kg (maximum of 50 g).

In the case of a single large recent ingestion, body packing or stuffing, or a slow-release mechanism (ie, "parachuting," in which the drug is folded into plastic or paper before swallowing allowing for gradual absorption), GI decontamination with whole bowel irrigation using agents such as polyethylene glycol may be useful [5,42]. We suggest such treatment be done in consultation with a medical toxicologist or poison control center since individuals who have gastrointestinal exposure to methamphetamine (eg, body stuffers) and abdominal pain may deserve immediate laparotomy to prevent bowel ischemia from local vasoconstriction. Gastric lavage is unlikely to be of benefit, and is discouraged.

Enhanced elimination — Urine acidification, formerly used to promote the elimination of methamphetamine, is no longer recommended. The administration of acidic intravenous fluids may exacerbate life-threatening metabolic acidosis.

PEDIATRIC CONSIDERATIONS

Pediatric exposure — Pediatric exposure to methamphetamine may be intentional (typically seen in adolescents), or unintentional (in neonates, infants, or children). Presentation and management of methamphetamine-related illness in adolescents is largely similar to that of adults, but with an increased need for attention to social ramifications.

In children and infants, inadvertent exposure to methamphetamine is increasing [43]. Although sympathomimetic and neuropsychiatric manifestations of methamphetamine exposure should be similar in a pediatric patient, inadvertent exposure may be difficult to diagnose for several reasons. Caregivers may not be forthcoming about access to this illicit substance, and the most frequent signs and symptoms noted in pediatric patients exposed to methamphetamine are nonspecific.

Agitation, tachycardia, and crying are the most common symptoms of exposure in young children, followed by vomiting with or without abdominal pain, hyperthermia, ataxia, mydriasis, seizures, and roving eye movements.

Evaluation often includes an extensive workup to exclude other neurologic or abdominal pathologies. Methamphetamine poisoning has even been mistaken for scorpion envenomation (Centuroides sculpturatus) with administration of antivenin [43]. Additionally, caustic ingestion/injury in the pediatric patient should prompt consideration for methamphetamine exposure; such presentations may be more common among children living in methamphetamine-production sites [44]. Once methamphetamine exposure is suspected, we recommend that routine laboratory work and an electrocardiogram be performed to evaluate for rhabdomyolysis and methamphetamine-induced ischemia.

Symptoms may persist up to 24 hours, and ongoing management may require frequent vital signs, telemetry monitoring, sedation, aggressive cooling measures, control of hypertension with rapid-acting agents, and intravenous fluid hydration to maintain urine output of one to two mL/minute to prevent myoglobinuric renal failure. Hospitalization should continue until appropriate social and child protection services are enlisted.

Special attention should be given to children living at methamphetamine-manufacturing sites or meth labs. These children are particularly vulnerable to child abuse, neglect, serious injury, exposure to toxic chemicals, and malnutrition [45]. They are often discovered after an in-home fire or explosion, and the number of children found at these sites has more than doubled in recent years [46]. Any child brought from such an environment requires initial decontamination to prevent healthcare worker exposure to toxic chemicals.

Pregnancy and lactation — Methamphetamine demonstrates teratogenic and embryocidal effects in mammals. Prenatal exposure to methamphetamine has been linked to growth restriction, low birth weight, and withdrawal symptoms in the perinatal period. There is an increased risk of perinatal complication, such as placental hemorrhage, in methamphetamine-exposed mothers. Amphetamines, including methamphetamine, are excreted into breast milk. (See "Substance abuse in pregnancy", section on Methamphetamine).

PITFALLS IN MANAGEMENT

• Failure to respect agitation - Uncontrolled agitation results in hyperthermia, acidosis, rhabdomyolysis, and sudden cardiovascular collapse. Control of agitation and chemical sedation is a clinical priority.

• Failure to respect hyperthermia - Hyperthermia is strongly associated with mortality and morbidity if not rapidly corrected.

• Failure to recognize rhabdomyolysis - A frequent complication of methamphetamine intoxication, rhabdomyolysis contributes to renal failure and hyperkalemia.

• Failure to consider associated illness - Methamphetamine-intoxicated patients are frequently the victims of traumatic injury. In addition, methamphetamine users may suffer from a range of complications, including: intracranial hemorrhage, myocardial infarction, aortic dissection, pulmonary edema or hemorrhage, endocarditis, injection site abscess, and placental abruption.

• Failure to note risk of contamination - Methamphetamine synthetic labs are often contaminated with toxic chemicals. Patients who work in or have contact with such labs may need decontamination to prevent poisoning patients and staff.

• Failure to appreciate the risk of violence - Methamphetamine-intoxicated patients can demonstrate a striking degree of violence. The use of physical and chemical restraints, personnel, and police is often required to ensure the safety of care providers and other patients.

SUMMARY AND RECOMMENDATIONS

Assessment

• Methamphetamine is a sympathomimetic with a variety of stimulant, anorexiant, euphoric, and hallucinogenic effects. Methamphetamine is readily absorbed following administration via oral, pulmonary, nasal, intramuscular, intravenous, rectal, and vaginal routes. The pharmacology and kinetics of methamphetamine are discussed in the text. (See "Pharmacology and cellular toxicology" above and see "Pharmacokinetics and metabolism" above).

• Clinicians should consider the diagnosis of methamphetamine intoxication in any diaphoretic patient with hypertension, tachycardia, severe agitation, and psychosis. Patients with methamphetamine intoxication range from the virtually asymptomatic to those in sympathomimetic crisis with imminent cardiovascular collapse. (See "Clinical features of overdose" above).

• Methamphetamine can cause a host of respiratory, cardiac, vascular, otolaryngologic, neurologic, integumentary, psychiatric, infectious, traumatic, and dental maladies. These are discussed in detail in the text. Agitation, tachycardia, hypertension, and psychosis are among the most frequent findings. (See "Clinical features of overdose" above).

• In severe intoxication, prognostic factors for mortality include: coma, shock, body temperature >39ºC, acute renal failure, metabolic acidosis, and hyperkalemia (serum potassium 5.6 to 8.5 mmol/L). The clinician should anticipate clinical deterioration and cardiac arrest in any wildly agitated patient, particularly those requiring physical restraints to maintain patient safety. (See "Clinical features of overdose" above and see "Sudden cardiac arrest" above).

• The differential diagnosis includes a number of poisonings and medical conditions with characteristics of the sympathomimetic toxidrome, a condition characterized by signs of adrenergic excess. This broad differential is discussed in the text. (See "Differential diagnosis" above).

• Reliance upon qualitative toxicologic screens can be disastrous if care is delayed while awaiting test results. While urine drug tests may support the diagnosis of acute methamphetamine intoxication, the results of such a "tox screen" have little clinical utility. (See "Laboratory evaluation" above).

• Patients with acute methamphetamine intoxication may, without provocation, abruptly develop severe agitation and manifest extreme violence, placing themselves, their caretakers, and other patients at risk of major injury. (See "General approach and warning" above and see "Sedation" above).

Management

• The intensity of therapy depends upon the severity of illness, but patients can decompensate abruptly, highlighting the need for immediate, aggressive intervention, even in the absence of confirmatory laboratory data. Control of agitation, correction of vital signs, control of hyperthermia, and aggressive fluid resuscitation, comprise the core of management. Common management pitfalls are described above. (See "Sedation" above and see "Correction of vital signs" above and see "Hyperthermia" above and see "Fluid resuscitation" above and see "Pitfalls in management" above).

• Control of violent behavior is of critical importance. We suggest severely intoxicated patients be treated immediately with parenteral benzodiazepines (Grade 2B). Reasonable initial doses include lorazepam 4 mg IV or diazepam 5 to 10 mg IV. These doses can be repeated every eight to ten minutes based on patient response; very large doses may be needed. IV administration is strongly preferred; intramuscular (IM) injection may be used initially when IV access is unavailable.

• Atypical antipsychotic agents (eg, ziprasidone 10 mg), butyrophenones (eg, droperidol 10 mg or haloperidol 10 mg), or combinations of these agents can be used as adjunctive therapy when high doses of benzodiazepines do not adequately control symptoms. (See "Sedation" above).

• Severe hypertension, particularly if refractory to aggressive treatment with sedatives, may require treatment with vasodilators (eg, nitroprusside) or alpha-adrenergic antagonists (eg, phentolamine). The use of beta-adrenergic antagonists (beta-blockers), including labetolol, should be avoided. (See "Correction of vital signs" above).

• Control of hyperthermia (T 41.1ºC) involves eliminating excessive muscle activity. While benzodiazepines alone offer benefit to moderately ill patients, severely intoxicated hyperthermic patients may require paralysis with nondepolarizing agents, such as rocuronium and vecuronium, followed by endotracheal intubation and mechanical ventilation. Succinylcholine is contraindicated because of the risk of rhabdomyolysis and hyperkalemic arrhythmias. (See "Hyperthermia" above).

• The profuse diaphoresis, neuromuscular activity, hyperthermia, and hyperpnea of acute methamphetamine intoxication can lead to severe dehydration. Treatment consists of immediate, aggressive fluid resuscitation with normal saline. An initial fluid bolus of two liters of normal saline given through a 14 gauge intravenous catheter should be administered over approximately 30 minutes. (See "Fluid resuscitation" above).

• In children and infants, inadvertent exposure to methamphetamine is increasing and may be difficult to diagnose. Agitation, tachycardia, and crying are the most common symptoms of exposure in young children, followed by vomiting with or without abdominal pain, hyperthermia, ataxia, mydriasis, seizures, and roving eye movements. (See "Pediatric considerations" above).

Use of UpToDate is subject to the Subscription and License Agreement.