Initial resuscitation
Airway — MDMA-associated hyponatremia frequently produces obtundation to a degree that necessitates endotracheal intubation [19,20]. Standard agents for rapid sequence intubation (RSI) may be used. Prophylactic agents to prevent elevations in intracranial pressure during RSI are unnecessary.
Breathing — Abnormalities of oxygenation are not expected with MDMA toxicity and should prompt consideration of another diagnosis or a separate concurrent problem (such as aspiration pneumonia).
Circulation — Severe hypertension from sympathomimetic use typically has a central and peripheral component. Treatment of the central component is accomplished with sedatives; benzodiazepines (eg, lorazepam, 1 to 2 mg IV push; may repeat until hypertension is controlled or patient is sedated) are appropriate first line agents. Hypertension refractory to aggressive benzodiazepine therapy is not typical, but can be treated with peripheral agents such as sodium nitroprusside (standard doses) or the alpha-adrenergic blocking agent phentolamine (1 to 5 mg IV).
Tachycardia alone, in the absence of hypertension, rarely requires treatment. In the unlikely event of a supraventricular tachycardia, adenosine or calcium channel blockers may be used.
The use of beta-blocking agents to control pulse or blood pressure in sympathomimetic poisoning is controversial. Pure beta-blocking agents, such as metoprolol, esmolol, or propranolol, may lead to unopposed alpha-adrenergic stimulation, may exacerbate coronary artery vasospasm, and increase lethality in animal studies [28-31].
Data relating to the use of the mixed alpha/beta antagonist labetalol is less clear. Proponents cite anecdotal data and a small experimental study that suggest labetolol is safe and effective [32-35]. Opponents emphasize that intravenous labetalol acts almost entirely as a beta blocking agent (ratio of beta to alpha blockade is 7:1), and increases mortality in an animal model of sympathomimetic poisoning [36-38].
Given the availability of other antihypertensive agents and the controversy that surrounds this issue, we suggest against the use of all beta blocking agents, including labetalol, in the treatment of hypertension associated with sympathomimetic poisoning. Otherwise, cardiac arrhythmias are managed according to current advanced cardiac life support (ACLS) protocols. (See "Overview of advanced cardiovascular life support in adults").
Indiscriminate fluid resuscitation should be avoided, as it may cause or exacerbate MDMA-associated hyponatremia. In the event the patient truly appears hypovolemic (as demonstrated by poor skin turgor or dry mucous membranes), normal saline may be administered until euvolemia is obtained. Tachycardia is NOT an appropriate surrogate endpoint for dehydration, as many patients with MDMA toxicity are tachycardic due to the sympathomimetic effects of the drug.
Gastrointestinal decontamination — For a recent ingestion (ie, less than one hour) of MDMA (3,4-methylenedioxymethamphetamine), a single dose of activated charcoal (AC) (1 g/kg; maximum dose 50 g) should be administered. Beyond one hour, drug absorption is usually complete and decontamination is not indicated. However, if a coingestant is suspected, decontamination after one hour may be beneficial [4,8]. (See "Decontamination of poisoned adults" and see "Enhanced elimination of poisons").
Charcoal should be withheld in patients who are sedated and may not be able to protect their airway, unless endotracheal intubation is performed first. However, endotracheal intubation should not be performed solely for the purpose of giving charcoal.
Cardiac effects — In addition to hemodynamic effects (see "Circulation" above), MDMA may produce cardiac ischemia. An electrocardiogram (ECG) should therefore be obtained in all patients with MDMA intoxication and cardiovascular symptoms. Chest pain associated with MDMA use should be evaluated and managed in a manner similar to that of cocaine-associated chest pain. Benzodiazepines (eg, lorazepam, 1 to 2 mg IV, repeat as needed) are an appropriate initial therapy for blood pressure control and agitation. Aspirin, nitroglycerin, and supplemental oxygen are all indicated. We recommend against the use of beta-blocking agents, including labetalol. (See "Circulation" above).
Psychomotor agitation — Psychomotor agitation should be treated with sedative medications. We prefer benzodiazepines as first-line agents, as they have an excellent safety profile and are readily available. Lorazepam (1 to 2 mg IV) has a rapid onset of sedative effects; repeat doses may be administered until agitation is controlled. Very high doses of benzodiazepines (ie, greater than 10 mg of lorazepam) may be required.
Butyrophenones (such as haloperidol and droperidol) interfere with heat dissipation, may prolong the QTc, and may reduce the seizure threshold. Given that hyperthermia and seizures are known consequences of MDMA toxicity, we suggest that butyrophenones not be used.
Minimizing stimuli, such as light and noise, is helpful. Physical restraint should be avoided, if possible, and should only be used until the patient can be chemically sedated. Antipsychotic agents are not indicated.
Hyperthermia — An accurate core body temperature should be obtained. Severe hyperthermia (temperature >41ºC; 107ºF) can be managed by immersion in an ice bath, if feasible, until the core temperature is reduced to 100ºF. The temperature may continue to drop slightly after exiting an ice bath, but this after-drop is typically mild. Moderate hyperthermia should be treated with other cooling measures, including cooling blankets and the combination of cool water mist with fanning. (See "Severe hyperthermia: Heat stroke and malignant hyperthermia").
If hyperthermia from serotonin syndrome is suspected, initial treatment with benzodiazepines and possibly cyproheptadine is appropriate [4,16]. If hyperthermia is refractory to these measures, intubation and paralysis should be strongly considered. (See "Serotonin syndrome").
Hyponatremia and seizure — Although the etiology of MDMA-induced hyponatremia is likely multifactorial, the syndrome of inappropriate antidiuretic hormone secretion (SIADH) probably plays a central role [20]. Unless the patient is hypovolemic, management consists of fluid restriction. Fluid restriction generally results in a resolution of hyponatremia within 12 to 24 hours [21].
Seizures are treated with benzodiazepines and (if necessary) appropriate correction of the patient's serum sodium. Persistent seizures resulting from severe hyponatremia (less than 115 mEq/L) can be treated with hypertonic saline (3 percent or 513 mEq/L) [20,22]. One treatment approach for such patients is as follows. First, 100 mL of hypertonic saline are given by IV infusion over 10 minutes. This is followed by a second dose of 100 mL of hypertonic saline given over 50 minutes. No additional saline treatment (hypertonic or normal) is given in the acute setting, and serum sodium levels are monitored closely, to avoid an overly rapid correction, which can induce osmotic demyelination syndrome [39]. (See "Treatment of hyponatremia").
The mechanism of MDMA-induced seizures makes phenytoin an illogical treatment choice, and we do not recommend its use. Seizures that occur in the setting of drug intoxication typically result from an altered balance of excitatory and inhibitory neurotransmitters. This mechanism is distinct from that of patients with a known seizure disorder, who generally have electrical instability in a discrete area of brain tissue amenable to treatment with sodium channel blocking agents, such as phenytoin.
Serotonin syndrome — Benzodiazepines, with or without cyproheptadine, remain the mainstay of treatment. Patients with significant hyperthermia as part of a severe serotonin syndrome require aggressive treatment. The management of serotonin syndrome is discussed elsewhere. (See "Serotonin syndrome").
Disposition — Patients with severe toxicity, including cardiotoxicity, hypertensive emergency, severe neurologic symptoms, hyperthermia, serotonin syndrome, and hyponatremia/hypoosmolality should be managed in an intensive care setting. Patients with mild symptoms and no evidence of end-organ toxicity may be discharged after their symptoms resolve, usually within six to eight hours.
SUMMARY AND RECOMMENDATIONS — MDMA (3,4-methylenedioxymethamphetamine) continues to gain popularity as a drug of abuse, particularly among adolescent and young adult party-goers at "raves" and "circuit parties," due to its capacity to elicit feelings of euphoria, wakefulness, intimacy, and disinhibition. A summary table to facilitate emergent management is provided (show table 1).
Pharmacology and presentation
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Peak effects of MDMA toxicity occur within two hours of ingestion and typically last four to six hours. Concentrations of MDMA contained in illicitly produced pills vary widely. Major toxicity and death may occur after ingestion of a single tablet. (See "Pharmacology and cellular toxicology" above and see "Kinetics" above).
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MDMA intoxication can cause a myriad of dangerous effects including severe hypertension, hyperthermia, delirium, psychomotor agitation, and profound hyponatremia. Potential life-threatening complications of these effects include intracranial hemorrhage, myocardial infarction, aortic dissection, disseminated intravascular coagulation, rhabdomyolysis, seizure, and serotonin syndrome. (See "Clinical features" above).
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The differential diagnosis for MDMA intoxication includes other sympathomimetic drugs of abuse, such as cocaine, amphetamine, and methamphetamine, and anticholinergic toxicity. Hypoglycemia, electrolyte disorders, intracranial hemorrhage, and infection should also be considered. (See "Differential diagnosis" above).
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Patients with hyperthermia and alterations in mental status who do not have a history strongly suggestive of MDMA or other drug intoxication should undergo lumbar puncture to rule out an infection of the central nervous system (CNS). (See "Hyperthermia and related effects" above).
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Routine laboratory evaluation of the poisoned patient should include the following (see "Laboratory evaluation" above):
- Fingerstick glucose - Acetaminophen and salicylate levels - Electrocardiogram (ECG) - Pregnancy test in women of childbearing age
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For patients in whom significant toxicity related to use of MDMA is suspected, the clinician should also obtain the following (see "Laboratory evaluation" above):
- Basic serum electrolytes; if hyponatremia is present, a serum osmolality is recommended - Creatine kinase and urine myoglobin - Serum creatinine - Serum aminotransferase concentrations - Coagulation studies (ie, aPTT, PT, INR, platelet count, d-dimer)
Treatment
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MDMA-associated hyponatremia frequently produces obtundation to a degree that necessitates endotracheal intubation. No induction or paralytic agent commonly used for rapid sequence intubation (RSI) is contraindicated in the setting of MDMA intoxication. (See "Initial resuscitation" above).
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We recommend severe hypertension and psychomotor agitation be treated with benzodiazepines (eg, lorazepam, 1 to 2 mg IV push; may repeat until hypertension is controlled or patient is sedated). (Grade 1C). Refractory hypertension may be treated with nitroprusside or phentolamine. We avoid beta-blocking agents, including labetalol, in the treatment of sympathomimetic poisoning because they may lead to unopposed alpha-adrenergic stimulation and a paradoxical increase in blood pressure. (See "Psychomotor agitation" above).
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For a recent ingestion (ie, less than one hour) of MDMA, we suggest a single dose of activated charcoal (1 g/kg; maximum dose 50 g) be administered. (Grade 2C). Charcoal should be withheld in patients who are sedated and may not be able to protect their airway, unless endotracheal intubation is performed first. However, endotracheal intubation should not be performed solely for the purpose of giving charcoal. (See "Gastrointestinal decontamination" above).
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Butyrophenones (such as haloperidol and droperidol) interfere with heat dissipation, may prolong the QTc, and may reduce the seizure threshold. We suggest butyrophenones not be used to sedate patients with MDMA toxicity. (Grade 2C). (See "Psychomotor agitation" above).
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Seizures, hyperthermia, and serotonin syndrome should be treated in standard fashion. (See "Status epilepticus in adults", and see "Severe hyperthermia: Heat stroke and malignant hyperthermia" and see "Serotonin syndrome").
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