Approach

The diagnosis of amphetamine toxicity is primarily clinical. Patients usually present with sympathetic nervous system hyperactivity and a history of legitimate (licit) or illicit drug use in the immediate past.

Initial impression

Patients with amphetamine toxicity will often present with agitated, irrational, restless, and aggressive behavior, and may show signs of hypervigilance, paranoia, and psychosis.[36] Control of behavioral disturbance may be necessary before accurate diagnosis and treatment can be attempted.[36][37] In the absence of a history from the patient or another reliable historian, psychostimulant toxicity is strongly suspected in any patient with this presentation.[36]

Another potential indicator of possible misuse of amphetamines is recent attendance at raves (youth parties with electronic dance music) and/or participation in vigorous club dancing. Club drug users are more likely to use multiple illicit substances, which may hinder a clear understanding of the clinical situation.[38][39][40] Rave attendees are more likely to report frequent use of MDMA.[40] Poor dentition ("meth mouth") may also provide clues to potential misuse of amphetamines.[41][42]

History

Significant risk for amphetamine overdose is imparted by known risk factors, such as exposure to high temperature, exercise, sweating and volume depletion, attendance at dance club or rave party, polydrug and alcohol usage, anxiety, depression, behavioral deviation or criminality, and ADHD.[29][31]

If the patient is cooperative, or a reliable history can be obtained from family or friends, a detailed drug history may reveal prior drug misuse, a known risk factor for amphetamine overdose. Questioning includes immediate and past use, type, route, amount, and time and potency (e.g., length and intensity of effect) of the ingested drug. Polydrug use is common (e.g., alcohol, cannabis, cocaine, and heroin), which may confuse and complicate the clinical picture.[25][43][44] All possibilities for drug misuse are investigated, including prescription medications.[38][39][40] It is very important to identify those patient medications that may interact with amphetamines to cause serotonin toxicity (e.g., serotonin-reuptake inhibitors, metoclopramide, sumatriptan, lithium, dextromethorphan).[27][45]

Symptoms such as palpitations and chest pain bear particular scrutiny. An overdose of amphetamines may increase myocardial oxygen demand (through increased heart rate, contractility, and wall tension), leading to increased risk of acute myocardial infarction, ischemia, and dysrhythmia.[37][46][47] Abdominal pain may suggest mesenteric ischemia or possible drug ingestion in bulk with gastrointestinal obstruction.[48] A headache may be the initial finding of subarachnoid hemorrhage or intracerebral bleeding. Pertinent findings from the medical history include exposure to hepatitis B, hepatitis C, or HIV (indirect indicators of high-risk lifestyle); traumatic physical injuries, which are common in the setting of drug misuse; and underlying (possibly untreated) psychiatric illness (e.g., anxiety, depression).

Examination

Objective signs may be the sole clues to amphetamine overdose if the patient is not cooperative or does not acknowledge psychostimulant use, or if corroborative history is not available. Signs of amphetamine intoxication include:[8][9][14][21][36]

  • Tachycardia

  • Hyperthermia (if >103°F [>39.5°C]) may indicate severe, life-threatening toxicity, and immediate cooling and sedation are necessary)

  • Volume depletion

  • Extreme agitation or acute behavioral disturbance

  • Seizures

  • Altered level of consciousness (e.g., disorientation, confusion, delirium)

  • Severe headache

  • Hypertension

  • Respiratory difficulties (e.g., tachypnea, dyspnea)

  • Chest pain or cardiac arrhythmias.

Flushed facial skin in the presence of pyrexia may be an early finding on exam, supporting the diagnosis of amphetamine toxicity. Volume depletion is typical of dancing activities or physical exertion in hot, crowded social venues. Paradoxically, stimulants may mask thirst and actually decrease fluid consumption, thereby exacerbating the degree of volume depletion.[49]

Behavioral and mental disturbance may be a manifestation of underlying psychiatric illness or hyperactivity of the sympathetic nervous system. Seizures may accompany hemodilution and hyponatremia with cerebral edema, as may headache. Respiratory symptoms (e.g., tachypnea) may occur in the context of cardiovascular compromise or as acute respiratory distress syndrome (ARDS). ARDS is a familiar sequel to hyperthermia with findings similar to those of heat stroke (high temperature, metabolic acidosis, renal failure). Tachycardia with or without arrhythmias, with increased cardiac workload, may lead to heart failure.[37][50][51][52][53]

Other signs may include:

  • Clenched jaw (trismus)

  • Muscle rigidity

  • Tremor or repetitive movements

  • Rapid speech

  • Pacing

  • Diaphoresis

  • Hallucinations or delusions

  • Dilated pupils that react sluggishly to light.

Long-standing regular drug use may be indicated by obvious signs of poor nutrition and evidence of needle marks or thrombophlebitis in the extremities. Signs of traumatic injury may also be present, as it is common in drug toxicity. Subarachnoid hemorrhage is an unusual but known presentation in amphetamine overdose, and mandates careful assessment of the eye grounds for papilledema and survey for focal neurologic signs.

Signs of serotonin toxicity

Serotonin toxicity may manifest clinically as the following:[27][45]

  • Agitation

  • Diaphoresis

  • Fever >100°F (38°C)

  • Tremor

  • Hyperreflexia

  • Hypertonicity

  • Spontaneous, induced, or ocular clonus.

Stimulation of the central nervous system may incite agitation and tremor. Clonus and bilateral Babinski signs also characterize serotonin toxicity, with neuromuscular findings typically more pronounced in the lower extremities.

Laboratory tests

Fingerstick glucose level is done immediately at the bedside to exclude hypoglycemia. Formal laboratory investigations may include:

  • Serum electrolytes, glucose, BUN, creatinine, liver function tests, prothrombin time, PTT, INR, creatine kinase, brain natriuretic peptide, and troponin[54]

  • Urinalysis (dipstick may cross-react positive for blood in rhabdomyolysis)[54]

  • Urine sample for drug screen (detects drug use over the past several days)[55]

  • Breath alcohol test or serum alcohol level.

Imaging

Depending on the presentation and findings, and in some cases intuition, the following imaging exams may be appropriate:

  • Chest x-ray if the patient has chest pain or dyspnea

  • Low-dose CT scan (LDCT) of the abdomen and pelvis (may reveal drug packages from body packing or body stuffing)[56]

  • CT or MRI of the head (in patients with severe headache, altered states of consciousness, seizures, or neurologic sign unexplained by serotonin toxicity); CT is more commonly the initial cranial imaging modality, because MRI is more difficult and time-consuming while trying to manage amphetamine overdose acutely, although it is better at identifying lesions at the gray-white interface

  • Cerebral angiography in patients younger than 40 years with nontraumatic intracerebral hemorrhage, as an increase in norepinephrine prompts cardiovascular effects, most notably hypertension, with risk of central nervous system hemorrhage and stroke.[2]

Other

ECG is routinely obtained in all patients. Patients with chest pain, tachycardia, or arrhythmia also undergo continuous cardiac monitoring.[21][37][46][47]

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