S. Sujanthy Rajaram
Janice L. Zimmerman
Ethanol, illicit drugs, and prescription drugs used for nonmedical purposes are a significant medical as well as social problem. The 2005 National Survey on Drug Use and Health found that 22.7% of Americans, or 55 million individuals, were binge drinkers, which includes 16 million heavy drinkers (five or more drinks on the same occasion at least 5 different days in the prior 30 days) (1). Pain relievers were used nonmedically by 4.7 million Americans, and 3.5 million used stimulants or cocaine. Casual or habitual use of these drugs contributes to acute and chronic illness. Substance abuse also underlies many forms of injury, including vehicular accidents, falls, near-drowning, thermal injuries, homicide, and suicide. Other critical illnesses may be impacted by either substance use or substance withdrawal. This chapter will cover acute toxicity and withdrawal syndromes related to ethanol, cocaine, opioids, and other selected drugs likely to be of importance to the critical care practitioner.
Ethanol
Alcohol abuse and alcoholism (a dependence on alcohol) are major social, economic, and public health problems throughout the world. Alcoholism is the third leading cause of death in the United States and it reduces life expectancy by 10 to 12 years. Men who imbibe more than 14 drinks per week or four drinks at one time or women who have more than seven drinks per week or three drinks at one time are at risk for alcohol abuse and dependence (a standard drink is one 12-ounce beer or wine cooler, one 5-ounce glass of wine, or 1.5 ounces of 80-proof distilled spirits).
Ethanol is rapidly absorbed in unaltered form from the stomach and small intestine. The presence of food (especially milk and fatty foods) in the stomach delays absorption, whereas the presence of water enhances absorption. Ethanol diffuses freely into body tissues. It is primarily metabolized in the liver. Less than 10% is excreted by the lungs or kidneys or through the skin. Several hepatic enzyme systems independently metabolize ethanol to acetaldehyde. The primary degradation pathway is in the hepatic cytosol by alcohol dehydrogenase, with nicotinamide adenine dinucleotide (NAD) as a cofactor. Acetaldehyde generated by this process is in turn metabolized through the Krebs cycle to carbon dioxide and water with 7 kcal/g liberated in this process. Most people can metabolize about 150 mg of ethanol per kilogram body weight per hour. This is equivalent to about 12 ounces of beer or 1 ounce of 90-proof whiskey.
Acute Toxicity
Common features of acute ethanol intoxication are shown in Table 67.1. Intoxication with ethanol depends on the rate of rise of the blood alcohol level and the length of time the level is maintained. Blood alcohol levels of 20 to 30 mg/dL are often associated with a mild euphoria, delayed reaction time, decreased inhibition, and alteration in judgment. Most people exhibit gross intoxication at levels above 150 mg/dL. Obtundation often develops at levels above 300 mg/dL, and death may result from respiratory depression, aspiration, or cardiovascular collapse when levels exceed 400 to 500 mg/dL (2).
Ethanol is a sedative-hypnotic drug and exerts its primary effects on the central nervous system (CNS). Patients can present with altered consciousness, agitation, euphoria, slurred speech, ataxia, stupor, and coma. Awareness of the environment (e.g., heat or cold exposure) and perception of pain are diminished. Ethanol may depress the respiratory center and lead to hypoventilation and respiratory arrest. Although seizures are more common in alcohol withdrawal, they may also occur with acute intoxication.
Acute ethanol intoxication is often associated with an increased heart rate and cardiac output, whereas prolonged intoxication may be associated with depressed myocardial contractility (3). Acute intoxication can also be associated with a variety of cardiac arrhythmias, especially atrial fibrillation (“holiday heart” syndrome). Cutaneous vessels dilate, whereas splanchnic vessels constrict. Increased sweating associated with cutaneous vasodilation may account for the decrease in core temperature often associated with acute ethanol intoxication.
Metabolic problems related to alcohol ingestion can be life threatening. Alcohol enhances the urinary excretion of phosphate and magnesium that can result in clinically significant hypophosphatemia and hypomagnesemia. The chronic alcoholic patient often has decreased glycogen stores, and because alcohol also inhibits hepatic gluconeogenesis, profound hypoglycemia may occur. A variety of acid-base disturbances are seen in acute alcoholic intoxication. Depression of the respiratory center in the severely intoxicated person may result in respiratory acidosis. Nausea and vomiting may cause hypokalemia and metabolic alkalosis. The presence of a significant metabolic acidosis or elevated lactate should prompt a search for conditions other than alcohol intoxication.
|
Table 67.1 Clinical manifestations of alcohol intoxication |
|
|
Ethanol ingestion may cause acute gastritis and gastrointestinal (GI) bleeding. Alcoholics have an increased incidence of peptic ulcer disease and pancreatitis. Acute alcohol intoxication may precipitate alcoholic hepatitis in the chronic user. All bone marrow cell lines are suppressed by alcohol ingestion. Suppression of antidiuretic hormone by ethanol causes diuresis and may lead to profound hypovolemia, especially if there is associated nausea, vomiting, or diarrhea.
Assessment and Treatment of Acute Intoxication
Treatment of acute ethanol intoxication is primarily supportive, but a careful examination is needed to detect complications. The first priority is assessment and stabilization of the airway and ventilation. The respiratory rate, depth of respirations, SpO2, mental status, gag reflex, and presence of vomitus should be rapidly evaluated. An arterial blood gas should be obtained if hypoventilation is a concern but is not obvious on clinical examination. Intubation is indicated in the obtunded or comatose patient who is unable to protect his or her airway and when aspiration has occurred or is likely. Positive pressure ventilation should be instituted to correct alveolar hypoventilation and hypoxemia. If the patient presents with altered mental status, 50 to 100 mg of thiamine and 25 g of glucose should be administered intravenously. If the patient responds to the administration of glucose or if blood glucose levels are low, a continuous infusion of glucose should be given. Intravenous naloxone may be administered if concomitant opioid use is suspected. Hypotension should be treated initially with volume resuscitation. GI bleeding should be considered in the hypotensive patient and further assessment may include a rectal examination and insertion of a nasogastric tube. GI decontamination is of limited utility because the majority of alcohol is already absorbed. Ethanol is not adsorbed by activated charcoal, but charcoal may be administered if ingestion of other toxic drugs is suspected. Hypothermia should be corrected. Fluid, electrolyte, and acid-base disturbances are corrected, depending on the clinical presentation. A creatine phosphokinase (CPK) level may be warranted in the patient with trauma or prolonged muscle compression to evaluate for rhabdomyolysis. An ethanol blood level may be helpful in documenting the severity of intoxication and estimating the duration of impairment. A low ethanol level in the setting of a patient with a depressed level of consciousness should prompt an evaluation for other etiologies. A chest radiograph is often necessary to assess for evidence of aspiration or other complications such as pneumonia. Consider obtaining computed tomography of the head if there is any suspicion of subdural hematoma or other intracranial injury. Hemodialysis has been used in cases of massive ethanol ingestion (4).
The chronic alcoholic may also develop alcoholic ketoacidosis (5). This condition is typically preceded by binge drinking followed by a period of abstinence for 1 to 3 days with nausea, vomiting, and insufficient nutrient intake. The liver produces excessive ketones in response to starvation, which results in an anion gap acidosis. Pancreatitis is frequently present in these patients. The blood glucose may be low or high in this setting but is rarely above 300 mg/dL unless chronic glucose intolerance is present. The condition responds to volume replacement and administration of glucose. Insulin is not needed. Thiamine should be administered before glucose to avoid precipitation of acute beriberi and Wernicke-Korsakoff syndrome.
Alcohol Withdrawal
Chronic excessive alcohol ingestion depresses central α and β receptors and potentiates the inhibitory neurotransmitter γ-aminobutyric acid (GABA). The brain adapts with a functional increase in N-methyl D-aspartate (NMDA) receptors, which are part of an excitatory system. When alcohol consumption stops, the excess excitatory receptors and removal of the inhibitory effects mediated by GABA contribute to the hyperadrenergic state that causes the symptoms seen in alcohol withdrawal.
Alcohol withdrawal syndromes occur in dependent patients during the initial period of abstinence. In hospitalized patients, symptoms of alcohol withdrawal may occur in up to 40% of those who drink excessive amounts of alcohol (6). Prevention of alcohol withdrawal syndromes has been shown to improve morbidity and mortality and shorten hospital and intensive care unit (ICU) length of stay (7). Four stages of alcohol withdrawal have been described (8), but symptoms are a continuum of neuropsychiatric and hemodynamic manifestations. Patients may manifest one or more of these syndromes on presentation or develop additional manifestations and progress from less severe to more severe stages while hospitalized (Table 67.2). A key distinction is to determine if the patient has an intact or altered sensorium.
|
Table 67.2 Stages of alcohol withdrawal and treatment |
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment of the severity of withdrawal is needed to determine appropriate treatment. Although the revised Clinical Institute Withdrawal Assessment-Alcohol Scale (CIWA-Ar) is often used for assessment, it has less applicability in critically ill patients (9). Patients with minor withdrawal symptoms can usually be treated with intravenous or oral benzodiazepines. Benzodiazepines act as an alcohol substitute to dampen the excitatory neuronal activity, and additional benefits include prevention of seizures and delirium tremens. The choice of benzodiazepine in hospitalized patients may depend on severity of hepatic dysfunction, desired duration of action, and available routes of administration. All benzodiazepines are effective when appropriate doses are used. Fixed dosing and symptom-triggered regimens have been used effectively. Fixed dosing may be more appropriate in critically ill patients until other conditions have stabilized. Treatment duration beyond 7 days is seldom required.
Although benzodiazepines are clearly superior to placebo in treating alcohol withdrawal, it is difficult to draw conclusions regarding the efficacy of benzodiazepines compared to β blockers, clonidine, carbamazepine, and valproic acid due to heterogeneity of clinical trials. Many trials are conducted in outpatients and have limited applicability to hospitalized and critically ill patients (10,11). Hallucinosis also responds well to benzodiazepines. Intravenous ethanol may be an option for alcohol withdrawal treatment or prophylaxis (12). However, it is not recommended for routine use due to dosing variability and lack of established efficacy (13). Other agents such as clonidine and β blockers have been reported to be effective for minor withdrawal symptoms but their use is less common. Clonidine and β blockers do not prevent the development of delirium. All patients with alcohol withdrawal should receive supportive measures in addition to pharmacologic intervention. Thiamine (vitamin B1) should be given intravenously or orally to prevent Wernicke encephalopathy. Magnesium sulfate may be needed to correct hypomagnesemia.
Seizures
Approximately 5% to 10% of patients with untreated mild alcohol withdrawal symptoms progress to seizures. Patients who have been drinking heavily for only a few years but have several detoxification admissions are at higher risk of seizures than patients with long drinking histories but fewer detoxification admissions. Previous nonalcohol-related admissions also increase the risk of alcohol withdrawal seizures. This association has been termed the “kindling effect.” According to the kindling hypothesis, each withdrawal episode is an irritative phenomenon to the brain. The accumulation of multiple episodes lowers the seizure threshold (14). Most alcohol withdrawal seizures are brief and self-limited in duration. Alcohol withdrawal seizures are usually generalized tonic-clonic but focal seizures may also occur. Multiple seizures (two to six episodes) occur in approximately 60% of patients and within a 12-hour period. It may be difficult to distinguish withdrawal seizures from a pre-existing seizure disorder or new onset of a nonalcohol-related seizure. Other causes of seizures such as hypoglycemia, metabolic abnormalities, trauma, infection, and other drug intoxication must be considered. A computed tomography (CT) scan of the head should be obtained for new-onset seizure, persistent neurologic deficits, or evidence or suspicion of trauma. Alcohol withdrawal seizures can be terminated with benzodiazepines (15). Intravenous lorazepam or midazolam is commonly used. If the seizure terminates without intervention, a benzodiazepine should be administered as soon as possible to prevent subsequent seizures. The risk of a recurrent seizure is 13% to 24% (16). Lorazepam (2 mg) significantly reduces the risk of recurrent seizure, whereas phenytoin has no effect (16,17). Less than 3% of patients develop status epilepticus and they should be treated with benzodiazepines or propofol. Phenytoin is not as effective.
Delirium Tremens
Delirium tremens (DT) is the most severe manifestation of alcohol withdrawal and these patients should be cared for in an ICU setting. Untreated DT carries a mortality of 15%, but mortality declines to 1% if treated. The accumulation of multiple prior withdrawal episodes leads to more severe DT with each episode (14). Patients with DT have more severe autonomic hyperactivity than milder stages of withdrawal and manifest delirium that may fluctuate. Some patients with severe withdrawal symptoms may need intubation during treatment. Fluid requirements may be increased due to increased insensible losses (fever, diaphoresis) and lack of oral intake. High-dose intravenous benzodiazepines (diazepam, lorazepam, midazolam) administered at frequent intervals or as a continuous infusion are needed to control the hyperadrenergic symptoms. Dosing should be individualized to achieve light somnolence (18). Benzodiazepines bind at the GABA–benzodiazepine receptor, and once these receptors are saturated, additional drug cannot bind. Patients may tolerate high doses of benzodiazepines but do not necessarily benefit from them (19). Caution is advised when administering high doses of intravenous lorazepam or diazepam over long periods of time as the propylene glycol diluent may result in a lactic acidosis (20). Daily dose reductions of 25% can be initiated after the second or third day of treatment. Propofol infusions may be useful for patients who are refractory to benzodiazepines. Propofol has dual activity similar to alcohol (GABA agonist and NMDA antagonist properties) that may explain its efficacy. Propofol has a rapid onset of action, sedation, and anticonvulsive properties (6,21). Other sedative-hypnotic drugs such as paraldehyde and barbiturates are effective in treating DT but are not commonly used. Neuroleptic agents are inferior to benzodiazepines and should not be used as single agents for treatment of DT (18). Neuromuscular blockers may be considered to control agitation when high-dose sedatives are not effective. Cardiac monitoring is necessary to detect arrhythmias early and institute therapy. Torsade de pointes may develop due to hypomagnesemia or prolongation of the QTc interval and should be treated aggressively with intravenous magnesium sulfate. Beta blockers may be needed to treat hypertension or tachycardia but they should not be administered to treat delirium. Propranolol may worsen delirium. Thiamine supplementation (100 mg/day) is recommended for 3 days.
DT usually lasts 2 to 5 days, but in 5% to 10% of cases, DT lasts greater than a week. Elderly alcoholics have a longer withdrawal period with more symptoms than younger alcoholics (23). A small percentage of patients remain delirious for several weeks and require continuing treatment. Be aware, however, that after head trauma, a subdural hematoma can evolve subacutely in the alcoholic patient. Repeat imaging of the brain may be warranted 7 to 10 days into a course of protracted delirium to rule out a slowly accumulating subdural hematoma (19).
Cocaine
Cocaine (benzoylmethylecgonine) is an alkaloid derived from leaves of Erythroxylon coca. It is the second most commonly used illicit drug and the most frequent cause of drug-related deaths. Eighteen- to twenty-five-year-olds are the most common users, although it is abused by younger and older individuals (1).
Cocaine is available in two forms. Cocaine hydrochloride is prepared by dissolving alkaloidal cocaine in hydrochloric acid resulting in a white water-soluble powder, crystals, or granules. This form of cocaine is used intranasally (snorting), orally, or intravenously. The other available form of cocaine is free base or crack cocaine. Heating cocaine hydrochloride in sodium bicarbonate or ammonia makes the hard crystallized cocaine base called crack because of the popping sound it makes when heated (24). Smoking crack cocaine has become a widespread practice due to the rapid absorption across the alveolar surface. Both forms of cocaine are readily absorbed from all body mucosal surfaces. The peak effects of cocaine range from 1 to 90 minutes depending on the route of administration. Inhalational and intravenous use result in the most rapid peak effects and shortest duration of action. Cocaine is rapidly metabolized by hepatic and plasma cholinesterases and nonenzymatic hydrolysis to ecgonine methyl ester and benzoylecgonine, which are excreted in urine. The urinary excretion of unchanged cocaine ranges from 1% to 15%. The route of administration does not affect metabolic excretion patterns appreciably and half-lives of most metabolites range from 45 to 90 minutes (25). Subjective rating of euphoria declines within minutes after constant concentrations are achieved, demonstrating rapid desensitization and acute tolerance (26). Duration of positive urinary metabolites is somewhat dependent on the assay technique, the activity of plasma cholinesterases, and the duration and dosing of cocaine use.
Cocaine's lipophilic nature, compounded with rapid distribution into and out of the CNS, suggests a highly abusive profile (rush and crash) and increased incidence of kindling. The major neurochemical actions of cocaine are CNS stimulation with release of dopamine; inhibition of neuronal norepinephrine and dopamine uptake, resulting in generalized sympathetic nervous system stimulation; release of serotonin or blockade of serotonin reuptake; and inhibition of sodium current in neuronal tissue, resulting in a local anesthetic effect (27).
Toxicity
Numerous morbidities have been associated with acute and chronic cocaine use (Table 67.3). Complications of particular interest to intensivists are discussed below.
Cardiovascular
Cocaine increases the heart rate, blood pressure, and left ventricular contractility, leading to an increase in myocardial oxygen demand (28). The increased demand may combine with underlying coronary artery disease, vasoconstriction, platelet aggregation, or in situ thrombus formation to produce ischemia and infarction. Chronic cocaine use also accelerates atherosclerosis (29). Apart from structural changes in epicardial vessels, wall thickening is described in the intramyocardial small coronary arteries in people with cocaine-induced chest pain (30).
Chest pain is the most common cocaine-associated complication in patients who present for medical care. All patients presenting with chest pain should be questioned regarding cocaine use. Myocardial ischemia can occur with all routes of abuse with no relation to the dose or chronicity of use. The onset of chest pain often occurs temporally related to the use of cocaine. However, chest pain may occur hours to days after the last use of cocaine. Electrocardiograms are often abnormal in patients presenting with cocaine-associated chest pain (31,32). Myocardial infarction may be present with a normal or abnormal electrocardiogram. Conversely, electrocardiograms may suggest acute ischemia in the absence of infarction due to J-point elevation or repolarization changes (32). Cardiac troponins are more specific for assessing myocardial injury than creatine kinase-MB, which may be elevated due to skeletal muscle injury (33). Myocardial infarction is reported to occur in approximately 6% to 7% of patients and occurs with normal coronary arteries and in the presence of significant atherosclerotic disease (32,34,35). Periods of silent ischemia are common in chronic users of cocaine, as shown by Holter tests and during periods of withdrawal (36). Dilated cardiomyopathy, myocarditis, and congestive heart failure can occur secondary to chronic cocaine use (37).
|
Table 67.3 Clinical manifestations of cocaine use |
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Cocaine is arrhythmogenic when taken in large quantities because of catecholamine effects. The arrhythmias are usually transient and resolve when cocaine is metabolized. Sinus tachycardia, supraventricular tachycardia, atrial fibrillation, premature ventricular beats, ventricular tachycardia, ventricular fibrillation, bundle branch block, asystole, and torsade de pointes may occur.
Elevation of blood pressure occurs due to the acute effects of cocaine, but it is usually self-limited. Sustained elevations of blood pressure suggest the presence of chronic hypertension or another complication (e.g., intracranial process). The elevations of blood pressure may contribute to other catastrophic complications such as stroke and intracranial hemorrhage. Rupture of the ascending aorta in previously healthy men has been reported as well as aortic dissection (38).
Central Nervous System
In large doses, cocaine may cause a generalized impairment of neuronal impulse transmission leading to CNS depression, coma, respiratory depression, and respiratory arrest. At low doses, stimulation is the common feature of cocaine use. The euphoria produced by cocaine is the principal reason for its abuse. Excessive CNS stimulation can occur and is manifested by tremulousness, agitation, sleeplessness, paranoia, and frank psychosis. Aggressive and assaultive behavior can occur in cocaine overdose.
Seizures can be induced, even on the first exposure, because cocaine lowers the threshold for seizures. Cocaine-related seizures are usually brief and self-limited, occurring soon after taking cocaine, although the interval between last use of cocaine and onset of seizures can be several hours (39). Sustained or repeated seizure activity suggests an additional complication such as hyperthermia, intracranial hemorrhage, metabolic abnormality, or massive intake of cocaine.
Cocaine use is associated with ischemic cerebrovascular accidents as well as transient ischemic attacks (39,40,41). Radiologic studies have demonstrated cerebral vasoconstriction as well as vessel thrombosis with cocaine (41,42). Although most symptoms occur during or immediately after cocaine use, neurologic symptoms may occur within hours to several days after the last use. Subarachnoid, parenchymal, and intraventricular hemorrhage may occur within moments of drug use, possibly related to blood pressure elevation. Some patients have anatomic abnormalities such as vascular malformation or aneurysm that may be amenable to specific therapy (39,43,44). Cerebral atrophy, predominantly in the temporofrontal regions, has been noted in patients with chronic cocaine abuse (45).
Pulmonary
Pulmonary complications associated with cocaine are much less common than cardiovascular and cerebrovascular events but include a variety of conditions (46,47). Inhalation of cocaine, in contrast to IV use, has been demonstrated to cause bronchoconstriction (48). This response may be due to an irritant effect and may contribute to wheezing and exacerbations of asthma in cocaine users (49,50). Barotrauma (pneumothorax and pneumomediastinum) is reported secondary to snorting cocaine and crack inhalation (51). Noncardiogenic pulmonary edema may occur and is described more commonly with intravenous use of cocaine. Massive hemoptysis with diffuse alveolar hemorrhage is a rare complication of unknown etiology and has been reported with smoking free-base cocaine and other routes of abuse. Other rare pulmonary toxicities, more commonly reported after inhalation of cocaine, include interstitial pneumonitis, pulmonary infiltrates with peripheral and/or lung eosinophil prominence, and bronchiolitis obliterans (52). Septic pulmonary emboli and pulmonary vascular obstruction resulting from foreign body granulomas or angiothrombosis may develop as a consequence of IV cocaine use similar to IV heroin use (53).
Hyperthermia/Rhabdomyolysis
Hyperthermia may result from muscle hyperactivity or as a direct effect of cocaine on the hypothalamic temperature regulatory center. High ambient temperatures are associated with increased mortality from cocaine and hyperthermia is probably one of several factors that play a role (54). Cocaine impairs sweating and cutaneous vasodilation as well as heat perception under conditions of heat stress (55).
Cocaine-induced rhabdomyolysis is common and can lead to acute renal failure. Multiple factors such as hyperthermia, seizures, vasoconstriction with ischemia, excessive motor activity, concomitant use of other drugs, and even a direct toxic effect of cocaine may contribute to muscle injury. Myalgias and muscle tenderness are infrequently present. Seizures, hypotension or hypertension, arrhythmia, coma, and cardiac arrest identify a subgroup of patients who are prone to severe rhabdomyolysis (56,57).
Other Toxicities
Intestinal ischemia, infarction, and perforation have been reported following ingested, intravenous, and inhaled cocaine (58,59). Patients may present with complaints of acute or chronic abdominal pain. Acute renal failure may be precipitated by rhabdomyolysis, but other etiologies may include accelerated hypertension and glomerulonephritis (60). Rare cases of renal infarction have also been reported.
Diagnosis of Acute Intoxication
Patients with cocaine intoxication may present with a variety of primary complaints such as altered mental status, chest pain, syncope, palpitations, seizures, or attempted suicide (61). Characteristic findings of CNS stimulation such as agitation, mydriasis, sweating, hypertension, and tachycardia are often present. However, the effects of other drugs, the presence of complications, and delays in presentation may obscure the typical sympathomimetic manifestations. Other medical conditions such as meningitis, encephalopathy, epilepsy with status, and thyrotoxicosis may mimic cocaine intoxication (27). Confirmation of acute or recent cocaine exposure is made by urine toxicology testing.
Treatment for Acute Intoxication
Benzodiazepines are the pharmacologic agents of choice for control of cocaine-induced agitation. The agitation and psychosis of cocaine overdose usually can be managed with titrated doses of IV diazepam, 5 to 20 mg; lorazepam, 2 to 4 mg; or midazolam, 5 to 10 mg slowly. Haloperidol is not recommended as a first-line agent because of the lack of experimental support (62) and potential to lower the seizure threshold. Adequate hydration and correction of electrolyte abnormalities are important.
Cardiovascular
No large clinical trials have evaluated treatment strategies for cocaine-associated ischemia. Treatment of cardiac toxicity due to cocaine is directed at reversing physiologic effects that cause ischemia or arrhythmias. Aspirin should be administered as an antiplatelet agent for suspected myocardial ischemia unless there is evidence of cerebral hemorrhage. Oxygen may also help to limit myocardial ischemia. Benzodiazepines and nitroglycerin are considered first-line agents for relief of chest pain, but small clinical studies have yielded conflicting results on the benefit of combining the agents (63,64). Benzodiazepines decrease the blood pressure and heart rate, thus decreasing myocardial oxygen demand, and nitroglycerin may dilate coronary arteries or relieve vasoconstriction. Alpha blockers such as phentolamine have been recommended as a second-line treatment for unrelieved pain, but are rarely needed (65). The use of β blockers in the management of myocardial ischemia is debated. There is a potential concern of worsening vasospasm or hypertension due to unopposed stimulation of α receptors. Intracoronary propranolol results in a small decrease in coronary artery diameter following intranasal cocaine, but β blockers are not administered by this route or as soon after cocaine use in most patients (66). However, β blockers have been used, particularly in the setting of myocardial infarction, without complications. Administration of β blockers might be avoided in patients manifesting acute sympathomimetic findings, but the benefits of these agents should be considered in other patients with ongoing myocardial ischemia.
Most patients with cocaine-associated chest pain will not have infarction. Patients can be managed in chest pain or observation units similar to other chest pain patients (67). Low-risk patients with normal cardiac markers can be risk stratified safely with stress testing.
Early therapy for cocaine-induced myocardial infarction should consist of oxygen, aspirin, and nitroglycerin as required for pain relief. If pain persists, patients with cocaine-induced myocardial infarction are candidates for reperfusion therapy. Primary percutaneous angiography is preferred in patients with evidence of ST-elevation myocardial infarction, especially when the diagnosis may be in doubt (65,68). Thrombolytic therapy has been safely used in cocaine-associated myocardial infarction and may be considered if invasive reperfusion is not available (69).
Arrhythmias associated with cocaine use are usually transient. Standard therapy should be considered for sustained arrhythmias unresponsive to control of pain and agitation. Although lidocaine is seldom used for ventricular arrhythmias, theoretical concerns of enhancing cocaine toxicity do not appear to be clinically significant (70).
Sustained hypertension in acute cocaine intoxication is not common due to the short physiologic effects of the drug. Control of agitation with benzodiazepines often results in resolution of hypertension. Intravenous labetalol is a reasonable option if the blood pressure needs to be lowered due to its α- and β-blocking effects. Cocaine-intoxicated patients should be considered to have acute elevations in blood pressure, and unless there is documentation or clinical evidence of long-standing hypertension, there should be little concern about cerebral hypoperfusion with immediate lowering of blood pressure to normal levels (71).
Central Nervous System
Seizures induced by cocaine are best controlled with IV benzodiazepines. Other standard antiepileptics can be added for refractory cases. If neuromuscular blockers are used, brain seizure activity may persist unrecognized and, hence, warrants continuous electroencephalographic monitoring.
Interventions for ischemic strokes associated with cocaine use should be carefully considered. Since the etiology may involve vasoconstriction as well as thrombosis, the decision to use thrombolytic agents in patients presenting within 3 hours of symptom onset may be more difficult. Vascular imaging, if readily available, may be helpful. Blood pressure is not usually severely elevated, but if sustained hypertension is present, current guidelines should be followed for lowering blood pressure. Neurosurgical consultation should be sought for intracranial hemorrhages to evaluate for possible interventions. Patients with subarachnoid hemorrhage should be evaluated for vascular malformations that may be amenable to treatment.
Pulmonary
Most pulmonary toxicities associated with cocaine are managed with usual care or supportive care (46,47). Bronchospasm and asthma should be treated with inhaled β agonists and corticosteroids if indicated. Pneumomediastinum can be followed without hospital admission for most patients. Small pneumothoraces may also resolve without intervention, whereas large pneumothoraces will require thoracostomy. Noncardiogenic pulmonary edema may require supplemental oxygen and mechanical ventilation but resolves within a few days unless other complications occur.
Hyperthermia/Rhabdomyolysis
Hyperthermia associated with cocaine use should be treated aggressively by rapid cooling (please see chapter discussing heat stroke). Control of coexisting agitation, psychosis, or seizures is essential to achieve and maintain cooling while avoiding brain, hepatic, and muscle cell destruction. There is no evidence that pharmacologic agents such as dantrolene are of benefit in cooling patients with life-threatening hyperthermia.
Patients with hyperthermia, severe agitation or motor activity, seizures, and obtundation should be evaluated for rhabdomyolysis. Aggressive fluid resuscitation to replete the intravascular volume and enhance urine output should often be initiated prior to definitive diagnosis. Serial tests of electrolytes, renal function, and creatine kinases are needed to monitor the severity and response of rhabdomyolysis.
Body Packers/Stuffers
Individuals may ingest packets of cocaine or any illicit drug for the purpose of transport or concealment. Body stuffers swallow small amounts of drug (wrapped or unwrapped) in order to avoid arrest. In this circumstance, drugs are not prepared for passage through the GI tract and drug is frequently absorbed. Due to the smaller quantities of drug, toxicity is usually mild (71). In contrast, body packers swallow larger quantities of drug in multiple packets that are specially prepared for smuggling to withstand transit through the GI tract. Abdominal radiographs often show the location of the packets and allow tracking as they move through the GI tract. However, a negative result on plain abdominal radiograph does not rule out body packing, and an abdominal CT scan may be needed to visualize the packets (72).
Most body packers are asymptomatic and can be managed conservatively until the packets have been completely evacuated (72,73). Activated charcoal given every 4 to 6 hours can reduce the lethality of oral cocaine. Whole bowel irrigation may assist with passage of the packets. Body packers with signs and symptoms of drug toxicity, in vivo degradation, or gastrointestinal obstruction require emergent surgical intervention (72).
Cocaine Withdrawal
Psychological and biochemical dependency on cocaine may be intense. Cocaine causes activation of the dopamine system and blocks dopamine uptake, especially in the pleasure centers of the brain (74). The brain becomes dopamine deficient, and even a short period of cocaine abstinence can result in a withdrawal state.
The clinical effects of cocaine withdrawal include depression, fatigue, irritability, sleep and appetite dysfunction, psychomotor agitation or retardation, and craving for more cocaine (25). A period of prolonged somnolence and decreased arousal can occur after binge use of cocaine and often necessitates evaluations to rule out complications associated with cocaine use (75). A supportive environment and professional drug counseling are warranted.
Opioids
Opioids include all drugs (synthetic as well as natural) that have morphine-like properties and/or bind to opioid receptors. There are at least five opioid receptors with various physiologic roles including analgesia, ventilatory depression, drug dependence, bradycardia, dysphoria, hallucinations, sedation, and miosis. Opioids are classified as receptor agonists or antagonists. Some have combined properties because they stimulate one type of receptor and antagonize another. A classification of opioids is found in Table 67.4. Opioid dependence is characterized by repeated self-administration of drug and encompasses physiologic dependence and addictive behavior. Exposure to opioids causes neural changes that produce tolerance, dependence, and withdrawal (76).
Toxicity
Although all opioids are associated with toxicity, heroin use has been increasing and the purity has increased, resulting in overdoses and fatalities (77). Heroin is rapidly absorbed by all routes of administration, including intravenous, intranasal, intramuscular, subcutaneous (skin popping), and inhalation. Most fatal overdoses occur with IV administration. Intravenous fentanyl extracted from analgesic patches is also associated with fatalities (78). Oral opioids are available illicitly or by prescription and toxicity depends on the potency of the agent, dose ingested, and tolerance of the individual. Codeine elixir (“syrup”) is abused by adolescents and young adults. The diagnosis of opioid toxicity is made by characteristic clinical findings, exposure history, qualitative toxicology assay, and response to naloxone. Qualitative urine assays may not detect all opioid derivatives (e.g., fentanyl).
Opioid intoxication is characterized by a clinical syndrome of 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 and propoxyphene toxicity. The primary toxic manifestations of opioids are mediated by the µ and κ receptors in the brain, which cause CNS depression. Common clinical effects of these drugs are shown in Table 67.5.
The most worrisome feature of CNS depression is hypoventilation. Tidal volume decreases first, and then respiratory rate falls. Although less common, seizures may be associated with meperidine, propoxyphene, and tramadol toxicity or result from hypoventilation and hypoxemia due to other opioids. Arteriolar and venous dilatation with opioid use can precipitate preload reduction, a fall in cardiac output, and hypotension.
|
Table 67.4 Classification of opioid agents |
|
|
An opioid-induced release of histamine from mast cells can precipitate bronchospasm, urticaria, and pruritus. Other respiratory complications include aspiration of gastric contents, noncardiogenic pulmonary edema, asthma exacerbation (heroin), pulmonary hypertension, acute respiratory distress syndrome, and septic pulmonary emboli (53,79). Intravenously injected illicit opioids may be mixed with microcrystalline cellulose, talc, or cellulose. These fillers are capable of producing angiothrombosis and a foreign body granulomatous reaction in the lung.
A pronounced decrease in gastrointestinal peristalsis and increased ileocecal and anal sphincter tone are responsible for the constipation frequently seen with opioid use. Urinary retention may be caused by increased detrusor muscle tone. Local infections, endocarditis, and other systemic infections are especially common in the IV user.
Treatment for Acute Intoxication
The most common cause of death in opioid overdose is ventilatory failure, and the immediate priority in acute opioid intoxication is airway management and ventilation. If reversal of respiratory depression cannot be accomplished quickly with naloxone, intubation may be necessary. Naloxone, a pure opioid antagonist, reverses all of the opioid-induced CNS and ventilatory depressant effects. The dose required to reverse opioid effects depends on the amount and type of opioid administered. The initial dose of naloxone is 0.4 to 2 mg; the lower dose should be administered initially in patients suspected of chronic addiction to avoid precipitating acute withdrawal symptoms. Additional doses of naloxone can be given based on the patient's response. Although intravenous administration is preferred, naloxone can be administered intramuscularly, by sublingual injection, or through an endotracheal tube. 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 in patients who have administered large quantities of opioids or opioids such as propoxyphene, pentazocine, methadone, and fentanyl. If CNS depression is not reversed by 20 mg of naloxone, alternate causes should be aggressively addressed (e.g., hypoglycemia, hypothermia, head trauma). Close observation of the patient after naloxone administration is warranted because its effects last approximately 60 to 90 minutes. The patient may require repeated bolus injections of naloxone or a continuous infusion to maintain adequate respirations, particularly with long-acting opioids. The dose for infusion is one half to two thirds of the initial naloxone dose that reversed respiratory depression given on an hourly basis. Adjustments of the dose should be made to achieve clinical end points and avoid withdrawal symptoms. Additional boluses may be required as the infusion is started. Nalmefene, a long-acting opioid antagonist, has also been used to treat opioid overdoses, but prolonged withdrawal symptoms are a concern (80).
|
Table 67.5 Clinical manifestations of opioid intoxication |
|
|
Isotonic fluids should be administered for hypotension due to opioids. Patients with significant opioid toxicity should be observed for other potential complications including aspiration pneumonitis and noncardiogenic pulmonary edema. Noncardiogenic pulmonary edema is usually self-limited (24–36 hours) and managed with supportive care that may include intubation and mechanical ventilation (81). Seizures unresponsive to naloxone should be treated with intravenous benzodiazepines. Refractory seizures may suggest either body packing or another complication. The potential for acetaminophen toxicity should be considered in patients ingesting opioids formulated with acetaminophen.
Acute Opioid Withdrawal
The chronic administration of exogenous opiates is thought to lead to diminished endogenous opioid peptides. When these exogenous opiates are discontinued, the patient can develop opioid withdrawal. The clinical manifestations of opioid withdrawal are outlined in Table 67.6. The onset of symptoms varies with the drug abused. Symptoms can begin within 6 to 12 hours of the last dose with short-acting opioids such as heroin and within 36 to 48 hours with long-acting opioids such as methadone. Opioid withdrawal is rarely life threatening and usually does not require intensive care.
|
Table 67.6 Clinical manifestations of opioid withdrawal |
|
|
If it is necessary to control withdrawal symptoms, most opioids in sufficient dosage will alleviate symptoms. Methadone, buprenorphine, and clonidine have been used to treat acute opioid withdrawal. In addition, methadone and buprenorphine have been used to treat opioid addiction chronically. Methadone can cause constipation, respiratory depression, dizziness, sedation, nausea, and diaphoresis. Oral buprenorphine use is restricted in the United States to qualified physicians who treat opioid dependence. It has low toxicity in high doses, partly because its µ-antagonistic effects limit the opioid effects of sedation, respiratory depression, and hypotension. Buprenorphine is more effective than clonidine and similar to methadone for management of opioid withdrawal (82).
Clonidine has also been used to suppress the autonomic effects of opioid withdrawal. Doses of 0.1 to 0.3 mg orally can suppress the signs and symptoms of opiate withdrawal within 24 hours and shorten acute withdrawal reactions by 3 to 4 days (83). Side effects are hypotension, drowsiness, dry mouth, and bradycardia.
Heroin Body Packers
Heroin body packers should be managed similar to cocaine body packers (see above). If there is evidence of systemic absorption from leaking packets, opioid toxicity should be treated with a continuous infusion of naloxone.
Amphetamines and Derivatives
Amphetamines, methamphetamines, and similar derivatives are the most commonly abused CNS stimulants along with cocaine. Although there are limited medical uses for these drugs (narcolepsy, attention deficit disorder, obesity), they are usually abused for the euphoric effects or to enhance performance. Amphetamines act by increasing release and inhibiting reuptake of dopamine and serotonin in the brain. Minor chemical substitutions can enhance the hallucinogenic properties of the drug. The ease of production of these drugs from readily available ingredients in clandestine laboratories has resulted in increased supply throughout the United States. Methamphetamine can be made from common ingredients such as rock salt, paint thinner, lantern fuel, battery acid, lye, ammonia, lithium, ether, rubbing alcohol, iodine, and cold medicines containing pseudoephedrine (84).
Methamphetamine in a crystalline form (commonly called ice, crank, glass, or crystal) is one of the most popular drugs in this class. It can be orally ingested, smoked, snorted, or injected intravenously. An amphetamine-like drug, 3–4-methylenedioxymethamphetamine, is a designer drug (commonly known as Ecstasy, XTC, or MDMA) that acts simultaneously as a stimulant and hallucinogen (85). It results in greater serotonin release in the brain with inhibition of serotonin reuptake. It is abused in pill or capsule forms that are orally ingested. MDMA use has been associated with rave parties and is more commonly abused by adolescents and young adults. Most amphetamines are detected on qualitative urine toxicology assays but a negative result does not rule out amphetamine intoxication or abuse.
Toxicity
In general, these drugs cause release of catecholamines, which result in a sympathomimetic/adrenergic syndrome. Compared to cocaine, the “high” and physiologic effects last longer (hours to several days depending on the agent used). The clinical presentation is characterized by tachycardia, hyperthermia, agitation, hypertension, and mydriasis. Hallucinations (visual and tactile), hypervigilance, and acute psychoses (often paranoia) are frequently observed. MDMA leads to increased verbosity and sociability. MDMA use is associated with bruxism that is often countered by sucking on a pacifier or lollipop. Amphetamine use is often associated with behaviors resulting in trauma and risky sexual encounters. The acute adverse medical consequences are similar to those seen with cocaine abuse (see above) and include myocardial ischemia and arrhythmias, seizures, intracranial hemorrhage, stroke, hyperthermia, rhabdomyolysis, necrotizing vasculitis, and death (86). Long-term use of these drugs may result in dilated cardiomyopathy and “meth mouth.” Meth mouth refers to a pattern of oral signs and symptoms of methamphetamine abuse, thought to include rampant caries and tooth fracture, leading to multiple tooth loss and edentulism (84). Burn injuries from methamphetamine laboratory explosions are associated with a higher incidence of inhalational injury and greater use of critical care resources (87).
Complications of MDMA use are usually a result of the drug effects and nonstop physical activity. The effects of MDMA last 4 to 6 hours. Medical complications include hyperthermia, hyponatremia, rhabdomyolysis, seizures, renal failure, arrhythmias, syncope, cerebral infarction/hemorrhage, hepatotoxicity, serotonin syndrome, and death (88). Hyponatremia and hepatoxicity are relatively unique with this agent and the mechanisms leading to these complications are unknown.
Management
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 electrocardiogram (ECG), searching for evidence of trauma, and evaluating laboratory data for evidence of renal or hepatic dysfunction and rhabdomyolysis. IV hydration for possible rhabdomyolysis is warranted in individuals with known exertional activities pending CPK results. Patients should be placed in a quiet, calm environment and benzodiazepines, often in high doses, are used for controlling agitation. Haloperidol should be reserved for patients who do not have an adequate response to benzodiazepines.
Withdrawal
Acute withdrawal from amphetamines is similar to cocaine and symptoms include fatigue, depression, anxiety, motor retardation, hypersomnia (followed by insomnia), increased eating, and drug craving (89). Although withdrawal is uncomfortable, the manifestations are not dangerous. Patients may become suicidal during withdrawal and should be evaluated for this possibility. Symptoms may persist for months.
γ-Hydroxybutyrate
γ-Hydroxybutyrate (GHB), a naturally occurring metabolite of GABA found in the brain, has limited clinical use in narcolepsy but is more commonly a drug of recreational abuse. It is one of several agents characterized as a “date rape” drug and it has been promoted to build muscle, improve performance, produce euphoria, and enhance sleep. 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 10–15 minutes) and readily crosses the blood–brain barrier where it interacts with GHB and γ-aminobutyric acid type B (GABAB) receptors. Stimulatory effects occur from resulting increased dopamine levels in the brain and sedative effects by potentiation of endogenous opioids. γ-Butyrolactone (GBL), also known as 2(3H)-furanone-di-hydro, and 1,4 butanediol (BD), also called tetramethylene glycol, have been abused with the same adverse effects as GHB (90). Both agents are metabolized systemically to GHB.
Acute Toxicity
The manifestations of GHB toxicity are dose related and include agitation, coma, seizures, respiratory depression, and vomiting. Other effects include amnesia, tremors, myoclonus, hypotonia, hypothermia, decreased cardiac output, and bradycardia. A dose of 20 to 30 mg/kg can produce euphoria and sleepiness and coma may result from doses of ≥40 to 60 mg/kg (91). Concomitant use of ethanol results in synergistic CNS and respiratory depressant effects. Deaths attributed to GHB and related agents usually result from respiratory depression, hypoxemia, or aspiration. GHB is not routinely detected by urine toxicology assays but can be detected in plasma or urine by gas chromatographic-mass spectrophotometric techniques. Rapid clearance precludes detection beyond 12 hours after a dose (91). Diagnosis is usually determined by the clinical course and history of exposure elicited after the patient recovers. A hallmark of GHB intoxication is rapid onset of toxicity and sudden, rapid recovery rather than a gradual recovery usually seen with ethanol or benzodiazepine intoxication.
Assessment and Treatment of Acute Intoxication
There is no antidote for GHB, GBL, or BD toxicity. The primary management for ingestion of these drugs is supportive care with particular attention to airway protection. In some cases, intubation and mechanical ventilation are required. Gastric lavage and activated charcoal are not warranted because of the small amounts involved and the rapid absorption. Naloxone and flumazenil are of no benefit. Atropine may be needed for symptomatic bradycardia. 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 in a few hours 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 reported to awaken patients with GHB intoxication, its use is not recommended (92).
γ-Hydroxybutyrate Withdrawal
A sedative withdrawal syndrome following high-dose frequent use (every 1–3 hours) of GHB, GBL, and BD has been described (91,93). 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. Patients may experience auditory, visual, and tactile hallucinations. 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 (91,93).
Phencyclidine
Phencyclidine (PCP) is a psychoactive drug used as a hallucinogen that can be administered by oral ingestion, nasal insufflation, smoking, or intravenous injection. PCP is a dissociative agent that blocks the NMDA receptors leading to an inhibition of sensory perception. Sympathomimetic effects result from inhibition of norepinephrine and dopamine reuptake.
Clinical Manifestations
Signs and symptoms reported with PCP use are variable depending on the route of abuse, susceptibility of the user, and concomitant drug use (94). Behavioral effects of PCP include coma, catatonia, psychosis, and confusion. Agitation may be intermittent and unexpected. Misperception of reality can lead to violent behavior, risk-taking behavior, and accidents resulting in trauma. Nystagmus (horizontal, vertical, and/or rotatory) and miosis are characteristic findings with PCP intoxication along with ataxia. Medical complications can include hyperthermia, rhabdomyolysis, and seizures. Dystonic reactions occur rarely. PCP is usually detected on urine qualitative toxicology tests.
Management
Management of a patient with PCP intoxication includes control of agitation using a quiet, nonstimulatory environment and benzodiazepines as needed. Haloperidol may be beneficial for frank psychosis. Physical restraints are often needed until adequate sedation is achieved. Tachycardia and hypertension, if present, usually respond to control of agitation. Activated charcoal does adsorb PCP but most patients present after GI absorption is complete following oral ingestion. Although urinary acidification enhances PCP excretion, that intervention is not recommended. The possibility of rhabdomyolysis should be evaluated and early fluid therapy should be considered while awaiting test results.
References
1. Department of Health and Human Services. Results from the 2005 National Survey on Drug Use and Health: national findings. http://www.drugabusestatistics.samhsa.gov/NSDUH/2k5NSDUH/2k5results.htm. Accessed March 22, 2008.
2. Johnston RE, Reier CE. Acute respiratory effects of ethanol in man. Clin Pharmacol Ther. 1973;14:503.
3. Friedman HS, Lieber CS. Cardiotoxicity of alcohol. Cardiovasc Med. 1977;2:111.
4. Marc Aurcle J, Schreier GE. The dialysance of ethanol and methanol: a proposed method of treatment for massive intoxication by ethyl or methyl alcohol. J Clin Invest. 1960;39:802.
5. Wrenn KD, Slovis CM, Minion GE, et al. The syndrome of alcoholic ketoacidosis. Am J Med. 1991;91:119.
6. Sharma AN, Hoffman RS. Withdrawal syndromes. In: Brent J. (ed) Critical Care Toxicology: Diagnosis and Management of the Critically Poisoned Patient. Philadelphia: Elsevier Mosby; 2005:363–371.
7. Spies C, Tonnesen HS, Andreasson S. Perioperative morbidity and mortality in chronic alcoholic patients. Alcohol Clin Exp Res. 2001;25:164s–170s.
8. Victor M, Adams RD. The effect of alcohol on the nervous system. Res Publ Assoc Res Nerv Ment Dis. 1953;32.
9. Sullivan JT, Sykora K, Schneiderman J, et al. Assessment of alcohol withdrawal: the revised Clinical Institute Assessment for Alcohol scale (CIWA-Ar). Br J Addict. 1989;84:1353.
10. Ntais C, Pakos E, Kyzas P, et al. Benzodiazepines for alcohol withdrawal. Cochrane Database Syst Rev. 2005;3:CD005063.
11. Polycarpou A, Papanikolaou P, Ioannidis JPA, et al. Anticonvulsants for alcohol withdrawal. Cochrane Database Syst Rev. 2005;3:CD005064.
12. Dissanaike S, Halldorsson A, Frezza EE, et al. An ethanol protocol to prevent alcohol withdrawal syndrome. J Am Coll Surg. 2006;203:186–191.
13. Hodges B, Mazur JE. Intravenous ethanol for the treatment of alcohol withdrawal syndrome in critically ill patients. Pharmacotherapy. 2004;24:1578.
14. Lechtenberg R, Worner TM. Relative kindling effect of detoxification and non-detoxification admissions in alcoholics. Alcohol. 1991;26:221.
15. Brathen G, Ben-Menachem F, Brodtkorb E, et al. EFNS guideline on the diagnosis and management of alcohol-related seizures: report of an EFNS task force. Eur J Neurol. 2005;12:575.
16. Hillbom M, Pieninkeroinen I, Leone M. Seizures in alcohol dependent patients. Epidemiology, pathophysiology and management. CNS Drugs. 2003;17:1013.
17. D'Onofrio G, Rathlev NK, Ulrich AS, et al. Lorazepam for the prevention of recurrent seizures related to alcohol. N Engl J Med. 1999;340:915.
18. Mayo-Smith MF, Beecher LH, Fischer TL, et al. Management of alcohol withdrawal delirium, an evidence-based practice guideline. Arch Intern Med. 2004;164:1405.
19. Miller FT. Protracted alcohol withdrawal delirium. J Subst Abuse Treat. 1994;11:127.
20. Wilson KC, Reardon C, Theodore AC, et al. Propylene glycol toxicity: a severe iatrogenic illness in ICU patients receiving IV benzodiazepines. Chest. 2005;128:1674.
21. McCowan C, Marik P. Refractory delirium tremens treated with propofol. Crit Care Med. 2000;28:1781–1784.
22. Cuculi F, Kobza R, Ehmann T, et al. ECG changes amongst patients with alcohol withdrawal seizures and delirium tremens. Swiss Med Wkly. 2006;136:223.
23. Brower KJ, Mudd S. Severity and treatment of alcohol withdrawal in elderly vs younger patients. Alcohol Clin Exp Res. 1994;18:196.
24. Olmedo R, Hoffman RS. Cocaine. In: Brent J. (ed) Critical Care Toxicology: Diagnosis and Management of the Critically Poisoned Patient. Philadelphia: Elsevier Mosby; 2005:3785–3797.
25. Hall WC, Talbert RL. Cocaine abuse and its treatment. Pharmacotherapy. 1990;10:47.
26. Ambre JJ, Belknap SM, Nelson J. Acute tolerance to cocaine in humans. Clin Pharmacol Ther. 1988;44:1.
27. Mueller PD, Olson KR. Cocaine. Emerg Med Clin North Am. 1990;8:481.
28. Lange RA, Hills LD. Cardiovascular complications of cocaine use. N Engl J Med. 2001;345:351–358.
29. Eichhorn EJ, Peacock E, Grayburn PA, et al. Chronic cocaine abuse in association with accelerated atherosclerosis in human coronary arteries. J Am Coll Cardiol. 1992;19:105A.
30. Majid PA, Patel B. An angiographic and histologic study of cocaine induced chest pain. Am J Cardiol. 1990;65:812.
31. Zimmerman JL, Dellinger RP, Majid PA. Cocaine associated chest pain. Ann Emerg Med. 1991;20:611–615.
32. Gitter MJ, Goldsmith SR, Dunbar DN, et al. Cocaine and chest pain: clinical features and outcome of patients hospitalized to rule out myocardial infarction. Ann Intern Med. 1991;115:277–282.
33. Hollander JE, Levitt A, Young GP, et al. Effect of recent cocaine use on the specificity of cardiac markers for diagnosis of acute myocardial infarction. Am Heart J. 1998;135:245–252.
34. Hollander JE, Hoffman RS, Gennis P, et al. Prospective multicenter evaluation of cocaine associated chest pain. Acad Emerg Med. 1994;1:330–339.
35. Kontos MC, Jesse RL, Tatum JL, et al. Coronary angiographic findings in patients with cocaine-associated chest pain. J Emerg Med. 2003;24:9–13.
36. Nademanee K, Gorelick DA, Josephson MA, et al. Myocardial ischemia during withdrawal. Ann Intern Med. 1989;111:876.
37. Kloner RA, Hale S, Alker K, et al. The effects of acute and chronic cocaine use on the heart. Circulation. 1992;85:407–419.
38. Barth CW III, Bray M, Roberts WC. Rupture of the ascending aorta during cocaine intoxication. Am J Cardiol. 1986;57:496.
39. Lowenstein DH, Massa SM, Rowbothem MC. Acute neurological and psychological complications associated with cocaine. Am J Med. 1987;87:841.
40. Kaku DA. Emergence of recreational drug use as a risk factor for stroke in young adults. Ann Intern Med. 1990;113:821.
41. Levine SR, Brust JCM, Futrell N. Cerebrovascular complications of the use of the “crack” form of alkaloidal cocaine. N Engl J Med. 1990;323:699.
42. Kaufman MJ, Levin JM, Ross MH, et al. Cocaine-induced cerebral vasoconstriction detected in humans with magnetic resonance angiography. JAMA. 1998;279:376–380.
43. Oyesiku NM, Colohan ART, Barrow DL, et al. Cocaine-induced aneurysmal rupture: an emergent negative factor in the natural history of intracranial aneurysms? Neurosurgery. 1993;32:518–526.
44. Fessler RD, Esshaki CM, Stankewitz RC, et al. The neurovascular complications of cocaine. Surg Neurol. 1997;47:339–345.
45. Leone AP, Dhuna A. Cerebral atrophy in habitual cocaine abusers: a planimetric CT study. Neurology. 1991;41:34.
46. Haim DY, Lippmann ML, Goldberg SK, et al. The pulmonary complications of crack cocaine. A comprehensive review. Chest. 1995;107:233–240.
47. Albertson TE, Walby WF, Derlet RW. Stimulant-induced pulmonary toxicity. Chest. 1995;108:1140–1149.
48. Tashkin DP, Kleerup KC, Koyal SN, et al. Acute effects of inhaled and i.v. cocaine on airway dynamics. Chest. 1996;110:904–910.
49. Osborn HH, Tang M, Bradley K, et al. New-onset bronchospasm or recrudescence of asthma associated with cocaine abuse. Acad Emerg Med. 1997;4:689–692.
50. Levine M, Iliescu ME, Margellos-Anast H, et al. The effects of cocaine and heroin use on intubation rates and hospital utilization in patients with acute asthma exacerbations. Chest. 2005;128:1951–1957.
51. Matthew E, Seaman M. Barotrauma related to inhalational drug abuse. J Emerg Med. 1990;8:141.
52. Forrester JM, Steele AW, Waldron JA, et al. Crack lung: an acute pulmonary syndrome with a spectrum of clinical and histological findings. Am Rev Respir Dis. 1990;142:462.
53. Zimmerman JL, Dellinger RP. Septic pulmonary emboli in the intravenous substance abuser. In: Dellinger RP, ed. The Substance Abuser: Problems in Critical Care. Philadelphia: J.B. Lippincott; 1987.
54. Marzuk PM, Tardiff K, Leon AC, et al. Ambient temperature and mortality from unintentional cocaine overdose. JAMA. 1998;279:1795–1800.
55. Crandall CG, Vongpatanasin W, Victor RG. Mechanism of cocaine-induced hyperthermia in humans. Ann Intern Med. 1992;136:785–791.
56. Dwelch R, Todd K. Incidence of cocaine associated rhabdomyolysis. Ann Emerg Med. 1991;20:154.
57. Brody S, Wrenn KD. Predicting the severity of cocaine associated rhabdomyolysis. Ann Emerg Med. 1990;19:1137.
58. Muniz AE, Evans T. Acute gastrointestinal manifestations associated with use of crack. Am J Emerg Med. 2001;19:61–63.
59. Feliciano DV, Ojukwu JC, Rozycki GS, et al. The epidemic of cocaine-related juxtapyloric perforations. Ann Surg. 1999;6:801–806.
60. Nzerue CM, Hewan-Lowe K, Riley LJ. Cocaine and the kidney: a synthesis of pathophysiologic and clinical perspectives. Am J Kid Dis. 2000;35:783–795.
61. Derlet RN, Albertson TE. ED presentation of cocaine intoxication. Ann Emerg Med. 1989;18:182.
62. Derlet RN, Albertson TE, Rice P. Effect of haloperidol in cocaine and amphetamine intoxication. J Emerg Med. 1989;7:633.
63. Baumann BM, Perrone J, Hornig SE, et al. Randomized, double-blind, placebo-controlled trial of diazepam, nitroglycerin, or both for treatment of patients with potential cocaine-associated acute coronary syndromes. Acad Emerg Med. 2000;7:878–885.
64. Honderick T, Williams D, Seaberg D, et al. A prospective, randomized, controlled trial of benzodiazepines and nitroglycerine or nitroglycerine alone in the treatment of cocaine-associated acute coronary syndromes. Am J Emerg Med. 2003;21:39–42.
65. Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction. J Am Coll Cardiol. 2002;40:1366–1374.
66. Lange RA, Cigarroa RG. Potentiation of cocaine-induced coronary vasoconstriction by beta-adrenergic blockade. Ann Intern Med. 1990;112:897.
67. Weber JE, Shofer FS, Larkin GL, et al. Validation of a brief observation period for patients with cocaine-associated chest pain. N Engl J Med. 2003;348:510–517.
68. Hollander JE. The management of cocaine induced myocardial ischemia. N Engl J Med. 1995;333:1267–1272.
69. Hollander JE, Burstein JL, Hoffman RS, et al. Cocaine-associated myocardial infarction. Clinical safety of thrombolytic therapy. Chest. 1995;107:1237–1241.
70. Shih RD, Hollander JE, Burstein JL, et al. Clinical safety of lidocaine in patients with cocaine-associated myocardial infarction. Ann Emerg Med. 1995;26:702–706.
71. Goldfrank LR, Hoffman RS. The cardiovascular effects of cocaine. Ann Emerg Med. 1991;20:165.
72. Traub SJ, Hoffman RS, Nelson LS. Body packing—the internal concealment of illicit drugs. N Engl J Med. 2004;349:2519–2526.
73. Das D, Ali B, Mackway-Jones K. Conservative management of asymptomatic cocaine body packers. Emerg Med J. 2003;20:172–174.
74. Dackis CA, Gold MS. New concepts in cocaine addiction: the dopamine depletion hypothesis. Neurosci Biobehav Rev. 1985;9:469.
75. Roberts JR, Greenberg MI. Cocaine washout syndrome. Ann Intern Med. 2000;132:679–680.
76. Fiellin DA, O'Connar PG. Office based treatment of opioid dependent patients. N Engl J Med. 2002;347:817–823.
77. Sporer KA. Acute heroin overdose. Ann Intern Med. 1999;130:584.
78. Tharp AM, Winecker RE, Winston DC. Fatal intravenous fentanyl abuse. Am J Forensic Med Pathol. 2004;25:178.
79. Wolff AJ, O'Donnell AE. Pulmonary effects of illicit drug use. Clin Chest Med. 2004;25:203.
80. Kaplan JL, Marx JA, Calabro JJ, et al. Double blind, randomized study of nalmefene and naloxone in emergency department patients with suspected narcotic overdose. Ann Emerg Med. 1999;34:42.
81. Sporer KA, Dorn E. Heroin-related noncardiogenic pulmonary edema. Chest. 2001;120:1628.
82. Growing L, Ali R, White J. Buprenorphine for the management of opioid withdrawal. Cochrane Database Syst Rev. 2006;2:CD002025.
83. Cuthill JD, Beroniade V. Evaluation of clonidine suppression of opiate withdrawal reactions: a multidisciplinary approach. Can J Psychiatry. 1990;35:377.
84. Curtis EK. Meth mouth: a review of methamphetamine abuse and its oral manifestations. General Dentistry. 2006;54:125–129.
85. de la Torre R, Farré M, Roset PN, et al. Human pharmacology of MDMA, pharmacokinetics, metabolism, and disposition. Ther Drug Monit. 2004;26:137.
86. Lineberry TW, Bostwick JM. Methamphetamine abuse: a perfect storm of complications, Mayo Clin Proc. 2006;81:77.
87. Santos AP, Wilson AK, Hornung CA, et al. Methamphetamine laboratory explosions: a new and emerging burn injury. J Burn Care Rehabil. 2005;26:228.
88. Kalant H. The pharmacology and toxicology of “ecstasy” (MDMA) and related drugs. CMAJ. 2001;165:917.
89. McGregor C, Srisurapanont M, Jittiwutikarn J, et al. The nature, time course, and severity of methamphetamine withdrawal. Addiction. 2005;100:1320.
90. Zvosec DL, Smith SW, McCutcheon JR, et al. Adverse events, including death, associated with the use of 1,4-butanediol. N Engl J Med. 2001;344:87–94.
91. Snead OC, Gibson KM. γ-Hydroxybutyric acid. N Engl J Med. 2005;352:2721–2732.
92. Traub SJ, Nelson LS, Hoffman RS. Physostigmine as a treatment for gamma-hydroxybutyrate toxicity: a review. J Toxicol Clin Toxicol. 2002;40:781.
93. Dyer JE, Roth B, Hyma BA. Gamma-hydroxybutyrate withdrawal syndrome. Ann Emerg Med. 2001;37:147–153.
94. McCarron MM, Schulze BW, Thompson GA, et al. Acute phencyclidine intoxication: incidence of clinical findings in 1,000 cases. Ann Emerg Med. 1981;10:237–242.