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Cocaine and the Club Drugs

Samuel DeMaria, Jr, MD

Julia L. Weinkauf, MDThe Mount Sinai HospitalNew York, New York

The use of cocaine and other illicit club drugs has becomeincreasingly prevalent, especially amongst teenagers and young adults.

Anesthesiologists must deliver safe anesthetic care for surgery no matterthe status of the patient. Accordingly, acute and chronic effects ofcocaine and club drugs may make anesthetic care difficult. Ecstasy, inparticular, is the most commonly abused club drug and potentially one

of the most dangerous perioperatively. Familiarity with the drugs effectsis crucial to anesthesiologists who may encounter emergency casesinvolving substance abuse as an inciting or coincidental event. Cocainehas experienced resurgence in use recently and its acute and chroniceffects remain dangerous. Pitfalls to be aware of in both scheduled andemergency anesthetics must be appreciated.

Cocaine

Background

Cocaine has had a role in human culture for at least 5000 years. Thefirst evidence of use was by early Andean peoples, who chewed on thecoca plant leaves, resulting in a mild euphoria, easing hunger, andsymptoms of physical exertion. The Spanish arrived in South America inthe 16th century, and interest in the substance grew as they discoveredthe utility of coca as an exchange commodity for recruiting the nativeIndian laborers.1

INTERNATIONAL ANESTHESIOLOGY CLINICS

Volume 49, Number 1, 79101r 2011, Lippincott Williams & Wilkins

www.anesthesiaclinics.com | 79

REPRINTS: SAMUELDEMARIA, JR, MD, DEPARTMENT OFANESTHESIOLOGY, THEMOUNTSINAIHOSPITAL, NEWYORK,NY, E-MAIL: [email protected]

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Cocaine made its way to Europe via the Spanish. By the 1880s, ayoung neurologist named Sigmund Freud was advocating cocaine use asa cure for morphine addiction. Later, it became clear that treatingmorphine addiction with cocaine resulted simply in a patient addictedto both substances. Freud was blamed for unleashing the third scourgeof humanity, after alcohol and opiates.2 In the meantime, Freudhad introduced cocaine to Viennese ophthalmologist Karl Koller whonoted its numbing effects and used it to anesthetize eyes for surgery.He reported his findings to the Ophthalmologic Congress held inHeidelberg, Germany on September 15, 1884, causing a flurry of inves-tigations into the anesthetic utility of cocaine.

Cocaine has a renowned role in American history as an ingredientof the original Coca-Cola recipe. John Pemberton touted his new drinkas an intellectual beverageycontain(ing) theystimulant propertiesof the coca plantymakes not only an yinvigorating beverageybuta cure for all nervous affections. Whole coca leaves remainedan ingredient until 1901, when cocaine was increasingly recognizedas dangerous and addictive. Then owner Asa Candler arranged to

begin using a decocainized leaf, and shortly thereafter, launched arevision of Coca-Cola history, claiming that cocaine had never been aningredient.3

The role of cocaine as a drug of abuse escalated beginning in the1960s, and reached its peak in the late 1980s. In 1983, if the cocainetrade had been included in the Fortune 500 list of industries, it wouldhave ranked seventh in domestic sales, between the Ford MotorCompany and the Gulf Oil Corporation.1 Cocaine use resurged

beginning in the late 1990s. Today, some 0.7% adults use cocaineregularly in the US, with 1.7% of adults aged 18 to 25 years usingcocaine more than once per month.4 This makes cocaine abuse ofparticular importance to the anesthesiologist, as many anesthetics arelikely administered to cocaine users from whom a true history has not

been obtained. Furthermore, surgical trauma patients are particularlylikely to be recent users of cocaine, with one study finding that 38%oftrauma victims had serum or urine test positive for cocaine.5

Cocaine is obtained by processing coca leaves with an organicsolvent, yielding an alkaline coca paste of 80% pure cocaine. Passing thealkaloid through an acidic aqueous solution creates the water solublecrystalline form, cocaine hydrochloride, which can be ingested orally,intranasally, or by injection. The freebase form is created by dissolvingthe cocaine hydrochloride in an alkaline solution or in water and adding

baking soda. The precipitate forms a soft mass that dries into rocksor crack, and is smoked. Various substances then are used to cutthe pure form, including amphetamines, mannitol, lactose, dextrose,quinine, procaine, lidocaine, salicylamide, caffeine, talc, borax, Epsomsalts, plaster of Paris, and heroin.

80 DeMaria and Weinkauf

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Extremely rapid absorption occurs with both intravenous andinhalation (smoking) routes, with a rapid peak concentration in the

brain, and shorter behavioral and psychological effects. Snorting resultsin slower absorption, lower plasma levels, and longer effects. Because ofthese pharmacologic characteristics, cocaine is most addictive whensmoked or injected, giving a high of only approximately 30 minutes(compared with several hours from inhaling), thus quickly leading theuser to seek another dose.

Cocaine inhibits the cellular reuptake of the neurotransmittersdopamine (DA), norepinephrine, and serotonin (5-hydroxytryptamine),thereby increasing transmitter availability in the synaptic cleft, enhanc-ing activity. The reinforcing and addictive effects are thought to bea consequence of the DA activity in the mesocorticolimbic system, whichregulates reward neurophysiology. A powerful euphoric state is felt. Psy-chologic and physiologic tolerance develops after the first dose, resul-ting in tachyphylaxis of subjective effects, and the need for increasinglylarger doses to achieve the same euphoria as abuse continues.6

Adverse Effects

The effects of acute and chronic cocaine use involve most organsystems (Table 1).

Table 1. Adverse Effects of Cocaine Abuse

Organ System Acute Effects Chronic Effects

Neurologic SeizuresStrokeHemorrhage

Movement disorders

Hematologic ? Platelet aggregationProthrombotic state

ENT Midfacial necrosis

Pulmonary BronchospasmPulmonary hemorrhagePneumothoraxPulm infarction

Hypersensitivitypneumonitis

CavitationsPneumoniaPulm hypertension

Cardiovascular ArrhythmiasHypertensionCoronary

vasoconstrictionTachycardia

InfarctDissection

HypertrophyCardiomyopathyRisk of sudden deathAcceleratedAthersclerosis

MISC RhabdomyolysisRenal failureGI ischemia/hemorrhage

ENT, otolaryngological; GI, gastrointestinal; MISC, miscellanous.

Cocaine and the Club Drugs 81


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factor for ventricular dysrrhythmias, classically, torsades de pointes.Myocardial hypertrophy, in general, is an independent risk factor forsudden cardiac death. Cocaine users are at increased risk of suddendeath with a recent study reporting that 3% of all sudden deaths arecocaine related.12 Most deaths in this study were attributed tomyocardial infarction, but it is difficult to prove whether infarction oran arrhythmia was the primary cause.

Potential neurologic complications include stroke from vasospasticischemia, thrombosis, or cerebrovascular hemorrhage. Cocaine can alsoprecipitate seizures in previously unaffected patients, and lowers theseizure threshold in patients with epilepsy. Similarly, preexistingmovement disorders can be exacerbated by cocaine use, and new onsetmovement disorders can occur.13 Chronic cocaine use by inhalationleads to progressive ischemic necrosis of the midfacial structures.Reports ranging from simple nasal septal perforation to hard palatedestruction and maxilla and orbital wall destruction exist.

Direct adverse effects of cocaine use on the pulmonary systeminclude hypersensitivity pneumonitis (crack lung), pulmonary he-morrhage, cavitations, and pneumothorax. Cocaine can cause severe

bronchospasm and exacerbation of asthma by its irritant properties.Secondary pulmonary complications include predisposition to infection(tuberculosis, staphylococcus), pulmonary edema, pulmonary infarction,and pulmonary hypertension.14

The potential gastrointestinal complications of cocaine use are alsorelated to the intense vasoconstriction ischemia phenomenon, and includeischemia and necrosis of any part of the bowel or stomach, perforation,ulcer formation, and hemorrhage. It has also been suggested that thesympathomimetic effects of cocaine may act on medullary centers regulatinggastric motility, delaying gastric emptying, and increasing aspiration risk.15

The vasoconstrictive ischemic and thrombotic sequelae of cocaineuse can extend to any other organ systems. Thrombosis and ischemia ofany small or large artery is possible, with case reports of aorticthrombosis.16 Ischemia of the muscles in combination with direct toxi-city can lead to rhabdomyolysis. Renal failure associated with cocaine useis typically in the setting of rhabdomyolysis, but can also occur fromvasoconstriction, ischemia, and thrombosis.

Management

Traditionally, procedures on patients presenting for elective surgery

who were found to be recent users of cocaine (by history or presence ofurine cocaine metabolites) were cancelled and deferred until the patienthad no evidence of recent use, for fear of myocardial ischemia anddysrhythmias. Although there is no consensus and little evidence, a recentsurvey of anesthesia providers found that 30%believe it is prudent to wait



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until 7 days after a positive cocaine test before performing electiveprocedures.17 Some argue, however, that asymptomatic, clinically non-toxic patients (normal blood pressure, heart rate, ECG, temperature)may have elective surgeries performed without increased risk ofhemodynamic extremes, dysrrhythmias, or postoperative complication.18

Furthermore, most cocaine-related deaths are not owing to overdose, butto pathophysiology developed from long-term use; thus, the risk wouldnot decline by waiting for a negative test. Also, sudden death is not doserelated, and the best predictor of toxicity is confirmed history of use,rather than plasma levels.19 On the other hand, many case reports exist ofwhat seem to be complications from therapeutic cocaine use (primarilytopical use in otolaryngologic procedures), and complications unheralded

by symptoms in cocaine abusers. It is impossible to know, however,whether the complications were owing to chronically acquired pathologyand would have happened irrespective of recent use.

Ultimately, it is reasonable to view chronic cocaine abuse as a riskfactor for the physiologic consequences of long-term use, and patientsshould have a preoperative evaluation of specific organ system complaints

before elective surgery. However, recent use alone should not necessarilybe a contraindication to surgery if the patient is asymptomatic with normalvital signs and ECG and a negative pertinent review of systems. Electivecases can be carried out at the discretion of the anesthesiologist andsurgeon, after a thorough discussion and consent by the patient.

In an emergency situation, perioperative management of the toxiccocaine abusing patient is guided predominantly by avoidance ofextremes in hemodynamics, to temper the potential acute cardiovas-cular consequences of sympathetic overdrive and vasospasm, as well asmanagement of any sequelae the patient may have developed withchronic use (Table 2).

Before induction, benzodiazepines are useful for anxiolysis and canalso have a mild effect on lowering blood pressure. A dexmedetomidineinfusion can also provide sedation and anxiolysis, and has demonstratedeffectiveness as a central sympatholysis agent of cocaines adverse

Table 2. Management Recommendations for Cocaine Users

Anxiolysis: benzodiazepines or dexmedetomidine

Induction: RSI with propofol or thiopentol and rocuronium

Maintenance: isoflurane, sevoflurane, or desflurane

Antihypertensive agents: benzodiazepines, nitroglycerin, phentolamine,

verapamil, dexmedetomidineMyocardial ischemia: Antihypertensives, aspirin

Ventricular dysrhythmias: sodium bicarbonate, ACLS

Other dysrhythmias: standard management

RSI indicates rapid sequence induction.



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hemodynamic effects.20 In addition to standard American Society ofAnesthesiologists monitors, a preinduction arterial cannula should beplaced for constant blood pressure monitoring. Also, should adysrrhythmia occur, invasive blood pressure monitoring is invaluablein assessing whether the patient has a stable perfusing rhythm, orwhether advanced life support is indicated.

Induction agents of choice are propofol or thiopental, both of whichhave been reported as safe in the cocaine toxic patient.21 Ketamineshould be avoided owing to its sympathomimetic properties, andpotential to precipitate myocardial depression in the setting ofexhausted catecholamine reserves. Regional anesthesia has been usedsafely in the cocaine using patient; however, the practitioner should erron the side of caution with respect to taking control of the airway owingto the potential adverse pulmonary effects of cocaine, and the potentialincreased risk of aspiration.

Owing to the potential for delayed gastric emptying, a rapid sequenceinduction should be used. Rocuronium may be preferable to succinylcholineto facilitate intubation owing to a theoretical concern of slowed metabolismof cocaine and succinylcholine from competition with plasma cholinesterase.

All halogenated inhaled anesthetics provide some myocardialprotection in the face of ischemia, with no clear benefit of any oneagent over the others.22 All inhaled agents sensitize the myocardium tocatecholamines, which could potentiate the dysrhythmogenic effects ofcocaine. Inhaled agents also have bronchodilating properties, which can

be beneficial as cocaine use can lead to bronchospasm, especially inpatients with asthma.

Hemodynamic stability should be achieved before induction to avoidexacerbation of sympathomimetic effects of laryngoscopy and intuba-tion. Though there has been much debate over the last 3 decades overthe use ofb-blockers in the setting of cocaine-induced hypertension andmyocardial ischemia, it now seems clear that they should be avoided.23

Unopposed a-mediated peripheral vasoconstriction with nonselectiveb-blockers is potentially catastrophic. Furthermore, propranolol has

been shown to exacerbate coronary vasoconstriction caused by cocaine.Labetalol, an agent with both a and b-blockade properties, does lower

blood pressure, but does not improve coronary blood flow, and shouldnot be a first-line agent. Verapamil and nitroglycerin have both beenshown to alleviate coronary vasospam. The a-agonist phentolamine alsodecreases coronary vasospasm. Dexmedetomidine has been postulatedto alleviate vasospasm via a central sympatholysis.

Consistent with the above evidence, the American Heart AssociationAcute Cardiac Care Committee scientific statement recommends the useof benzodiazepines and nitroglycerin for the treatment of myocardialischemia and hypertension in the setting of cocaine use, withphentolamine as the next drug of choice, followed by verapamil.24



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There is little evidence regarding the utility of various agents inpreventing hypertensive end organ damage to other systems susceptibleto the vasospastic effects of cocaine such as the brain and kidneys. Thus,it is reasonable to treat hypertension based on evidence in the setting ofimproving coronary blood flow detailed abovethat is, with benzodia-zepines, nitroglycerin, phentolamine, and verapamil on a case-by-case

basis. It should be noted that nitroglycerin should not be given toanyone with suspected intracranial pathology, at the risk of increasingcranial blood flow and raising intracranial pressure.

Cocaine predisposes to dysrhythmias by 2 mechanisms: the directeffects of cocaine on ion channel function, and indirectly via vasospasm andischemia. Both lidocaine and sodium bicarbonate have shown effectivenessin treating cocaine-induced ventricular dysrhythmias in animal models;however, the dose of lidocaine required is often above human toxic levels.The drug of choice for ventricular dysrhythmias caused by cocaines directeffect thus is sodium bicarbonate. With dysrhythmias suspected to besecondary to ischemia, treatment of the ischemic insult should be theprimary goal, with standard treatment of the arrhythmia and AdvancedCardiovascular Life Support (ACLS) initiated as appropriate.

Complications of cocaine ingestion during pregnancy include allof the previously discussed pathology in the mother, in addition topremature onset of labor, placental abruption, uterine rupture, and fetaldemise. Cocaine diffuses across placental membranes, and can causedirect vasoconstriction and ischemic effects to the fetus as well as indirecteffects through decreased uterine blood flow. Cocaine abuse symptomscan easily be mistaken for preeclampsia, with hypertension, proteinuria,and possibly convulsions being characteristic of either situation. Thereis no clear recommendation for either general or regional anesthesia inthese patients. Drawbacks to regional anesthesia include a potentiallycombative patient, an uncontrolled airway, and ephedrine-resistant hypo-tension. Drawbacks to general anesthesia include potential difficultysecuring the airway, the parturient missing the birth of her baby, andarrhythmias potentiated by inhaled anesthetics.25

The anesthesiologist obliged to anesthetize the acutely toxic cocaineabusing patient in an emergency must also be prepared to deal withother possible sequelae of cocaine abuse. Patients may have hyper-trophic or ischemic cardiomyopathies, or pulmonary hypertension fromchronic use. Seizures can occur and should be treated with benzodia-zepines or thiopental. Coagulopathies such as thrombocytopenia or aprothrombotic state should also be considered.

The Club Drugs

The use of illicit substances in large dance parties (raves) andnightclubs has become commonplace. Having now dispersed from rave



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subcultures, these drugs are widely available. Accordingly, the typicalclub drug user is harder to classify than during the 1990s. Although mostclub drugs are not new substances, their increased prevalence (lifetimerates of use among US college students irrespective of nightclubattendance ranges from 10% to 15% in one survey)26 makes themimportant. Also, the high likelihood of polysubstance intoxication, whetherthrough choice or through impurities in the drugs, makes toxidromesoften difficult to diagnose and treat. The most commonly used club drugsinclude methylenedioxymethamphetamine or Ecstasy, g-hydroxybuty-rate (GHB), ketamine, and flunitrazepam (Table 3).

Ecstasy

Background

Nearly 20 million people (or about 8.1%) over age 12 years usedillicit drugs in 2005 in the US. About 500,000 individuals took Ecstasy(3,4methylenedioxymethamphetamine or MDMA) at least once duringthe year before the survey.27 MDMA is available at approximately 70%of raves, with Europe the origin of most of the illicit drug trafficking.28

MDMA is known amongst users as XTC, X, E, and Adam.29 It was

patented in 1914 by Merck Pharmaceuticals as an appetite suppres-sant,30,31but later studied as a psychotherapeutic drug.32,33 Despite thispotential application, abuse of MDMA prompted the Drug Enforcement

Administration to issue a schedule I drug classification in the 1980s.MDMA is usually taken orally although it can be crushed and

snorted. It may also be dissolved for injection. As it is produced illegally,the purity of MDMA is variable and amphetamines and ketamine canoften be found in street pills.34 For this reason, any acute MDMAintoxication should be approached as polysubstance intoxication. The

concentration of MDMA itself may vary and accidental overdoses canoccur.MDMA structurally resembles mescaline and amphetamine, which

explains the mixture of psychedelic and stimulant effects, respectively.MDMA increases the release and decreases reuptake of serotonin andDA.35 The drug is metabolized through the cytochrome P450 2D6enzyme36 and 2D6 inhibitors (eg, cocaine, methadone, haloperidol,fluoxetine) may substantially increase side effects. Proserotonergic drugs(eg, fluoxetine, amphetamines, St Johns wort, tramadol, lithium) may

also increase the severity of side effects.

Adverse Effects

Effects are generally felt within 30 minutes of ingestion and can lastfor 8 hours.37 The drug produces euphoria, heightened alertness,



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Table3.

SummaryofClubDrugsWithCommonNamesandRelevantFeatures

MDMA

GHB

Ketamin

e

Flunitraz

epam

Streetname

Ecstasy,X,E,X

TC,

Adam

LiquidX,Liquid

Ecstasy,Scoop,

GrievousBodily

Harm,Georgia

Homeboy

K,SpecialK,

VitaminK,Kat,

Cat

Rohypnol,

Roofies,Rophies,

Circles,Rib,Rope,

R2

Durationof

action(h)

4-6

1-4

1-3

6-14

Peakeffect(h)

1-3

2-3

2

6-24

Form

Tabletorcapsule,

powder

Liquid

Liquid,powder

Tabletorpow

der

Dependence

No

Yes

No

Yes

Soughtafter

effects

Energy,self-

confidence,well

being,heighte

ned

mood,and

awareness

Euphoria,

decreasedanxie

ty,

relaxation

Relaxation,

positive

hallucinations

Euphoria,

decreaseda

nxiety,

increasedsocial

comfort

Adverse

effects

Anxiety,bruxism

,

psychosis,

cardiovascular

activation,

hyperthermia,

neurotoxicity

Sleepinduction,

unconsciousness,

agitation,

respiratory

depression,

bradycardia

Severehallucina

tions,

neardeath

experiences,

psychomotor

and

cognitiveimpairment,

anxiety,

dissociation,

flashbacks,de

lirium

Hypothermia,

hypotension

,

dizziness,

confusion,s

edation,

unconsciousness

Long-term

effects

Unknown;

possible

neurotoxicity

Unknown;likely

withdrawal

syndrome

Difficultiesin

cognition(attention,

learning,mem

ory)

Unknown;lik

ely

withdrawal

syndrome

GHBindicatesg-hydroxybutyrate;MDMA,3,4methylenedioxymethamphetamine.



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increased emotional lability, and sexual arousal.38 Serotonin stores aredepleted by MDMA and repeated doses are associated with increasedadverse effects with less desirable effects (eg, euphoria). Cardiovascularhyperactivation is common. Lethargy, fatigue, anorexia, psychosis, andmood disturbances (depression, anxiety) often follow chronic use andmay persist owing to drug-induced neuronal injury.39,40

The acute effects of MDMA intoxication are of greatest concern toanesthesiologists (Table 4). The spectrum of possible effects with MDMAabuse is broad.

Hyperthermia is a major cause of MDMA-related mortality4143 andtemperatures as high as 421C have been reported.44 The mechanism ofhyperthermia is likely central serotonergic overload in the hypothala-mus4547 but sustained muscular activity from dancing and a disregardof normal body signals such as thirst, compound any central effects.48,49

Whether MDMA can trigger malignant hyperthermia is unknown.As with cocaine intoxication, sympathetic stimulation increases myo-

cardial oxygen demand via tachycardia, vasoconstriction, and may resultin acute myocardial infarction and dilated cardiomyopathy.50 Significanthypotension and low cardiac output may also occur owing to catechola-mine depletion or autonomic dysregulation.51 Electrolyte disturbances arecommon. Hyponatremia, which results from excessive thirst from vigo-rous physical activity and a loss of normal physiologic cues, has beenassociated with seizures and altered mental status.52,53 Increased anti-diuretic hormone secretion from MDMA central effects may worsenhyponatremia.54 Hepatotoxicity is possible, with fulminant liver failurewell documented.55,56 Cerebrovascular events like subarachnoid hemor-rhage, cerebral infarct, and venous sinus thrombosis are relativelyuncommon.57 These neurological events are likely vasospastic in origin.

After MDMA use, depression, anxiety, myalgias, and fatigue may beobserved.58 These symptoms usually resolve without specific treatment.There is little evidence of a distinctive withdrawal syndrome that would

be amenable to specific treatment.

Management

The MDMA intoxicated patient may present with insult to multipleorgans. A directed history and physical examination is important, butnot always possible. As most urine toxicology screens will not detectMDMA, obtaining historical information is useful. On examination,particular attention should be paid to vital signs, with suspicion

heightened if the patient is severely hyperthermic.Anxiolysis with midazolam or diazepam may be useful and benzo-

diazepines raise the seizure threshold. Conversely, antipsychotics maylower the seizure threshold and should be avoided. Core bodytemperature should be monitored closely. Wide swings in hemodynamic



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parameters put the patient at risk for cardiomyopathy and coronary orcerebral vasospastic events.59,60 Invasive blood pressure monitoring isprudent. Hyponatremia, if corrected too aggressively, can lead todevastating neurological sequelae such as central pontine myelinolysis.Competing management strategies may be present when rhabdomyo-lysis (requiring generous hydration) and hyponatremia (requiringrelative dehydration) are present. Acidification of urine quickens MDMA

Table 4. Adverse Effects Associated With Acute 3,4MethylenedioxymethamphetamineIntoxication

Musculoskeletal

Rigidity and bruxism

Rhabdomyolysis

Extreme CPK elevations

Cardiovascular

Hypertension

Tachycardia

Increased myocardial O2demand

Myocardial infarction

Cardiomyopathy

Hypotension/cardiovascular collapse

Disseminated intravascular coagulation

Metabolic

Hyponatremia

Hyperkalemia

Hypermetabolic state

Pulmonary

Pneumothorax

Pneumomediastinum

Respiratory depression

Renal

Acute renal failure

Hepatic

Necrosis/steatohepatits

Fulminant hepatic failure

Neurological/cerebrovascular

Central thermogenesis

Hallucinations, derealization, depersonalization

Increased emotionality, heightened mood

AnxietySeizures

Subarachnoid hemorrhage

Cerebral infarction

Venous sinus thrombosis

CPK indicates creatine phosphokinase.



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elimination, but is contraindicated because of increased risk of metabolicacidosis and renal toxicity from rhabdomyolysis. An intra-arterial catheterallows for frequent blood samples to follow sodium levels.

A rapid sequence induction is generally indicated for intoxicatedpatients. Propofol and thiopental are appropriate induction agentsthough patients with extreme cardiovascular compromise may requireketamine. Etomidate has a stable hemodynamic profile and is also safe.Nondepolarizing neuromuscular blocking agents are not associatedwith malignant hyperthermia and may help slow heat production inhyperthermic patients. Succinylcholine is probably safe although thetrue risk of malignant hyperthermia is unknown with concomitant use ofMDMA. The serum potassium level should be reviewed, if available,

before succinylcholine administration, as these patients are at risk forhyperkalemia secondary to rhabdomyolysis.

If intraoperative hypertension and tachycardia require treatment,labetalol, because ofaandb-receptor antagonist effects, is a good choice.Pure b-blockade might worsen hypertension. Alternatively, nitroprussideor nitroglycerin may be useful in controlling hemodynamic instability ifthere is no suspicion of intracranial hypertension. If intraoperativehypotension is encountered, rapid infusions of crystalloid to a target of apresumed baseline pressure (presumed, as these patients may be veryhypertensive on initial examination) or the use of direct a-1 agonistsis reasonable. As these patients are generally young, the risk of fluidoverload and heart failure are seldom a reason to reduce crystalloidinfusions. Indirect agonists such as ephedrine should be avoided toprevent the potential catastrophe generated when an already exhaustedsympathetic nervous system is prompted to release catecholamines or thelikelihood of an unknown intensity of endogenous catecholamine release.

Hyperthermia must be treated promptly to avoid rhabdomyolysis anddisseminated intravascular coagulation.61 Cold fluids and active cool-ing are important measures. Dantrolene use is controversial as thedrug inhibits the release of calcium from sarcoplasmic reticulum andMDMA-induced hyperthermia is likely a central process.62 However,studies suggest that dantrolene may help exertional heat stroke, which issimilar to MDMA-induced hyperthermia. Dantrolene raises the calciumrequirements for excitation contraction coupling and may be of some

benefit.

GHB

Background

GHB is a central nervous system (CNS) suppressant used for itseuphoric and sedative effects.63 The drug is taken orally as a liquid,powder, tablet, or capsule and effects are apparent within minutes and



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last up to 4 hours. A salty liquid form is most common and is oftenmixed with alcohol as liquid ecstasy.

GHB was introduced in the 1960s as a treatment for alcoholwithdrawal.64 The Food and Drug Administration removed it from theretail market (it had been found in health food stores) in the early1990s.65 Although results in the treatment of alcohol withdrawal wereencouraging and Food and Drug Administration approval under thetrade name Xyrem occurred in 2002 (for cataplectic features ofnarcolepsy), misuse for its euphoric effects has limited the adoption ofGHB as a therapeutic agent. Misuse for purported anabolic properties

by athletes and bodybuilders have also become prevalent. In 2000, 60deaths were reported from overdose and GHB was reclassified as aschedule I controlled substance.

Restrictions on legal GHB have led to abuse of 2 substances thatconvert to GHB in the body: g-butyrolactone, whose street namesinclude Lactone, Renewtrient, Blue Nitro, and Verve, and 1,4-butanediol, also known as Pro-G, Thunder, and Pine NeedleExtract. Both substances are available as industrial solvents and can beeasily synthesized using internet recipes. A survey of 450 club drugusing homosexual men in New York city found that 29% had used GHBin the previous 4 months.66 Seven percent of young adults in treatmentfor substance abuse reported use of GHB at least once.67

The exact mechanism of action of GHB is still not clear. A naturallyoccurring analog, which is both a precursor and metabolite ofg-aminobutyric acid (GABA), it can bind to GABAB receptors, GHBreceptors, or both to have CNS inhibitor effects.68 An effect as aninhibitor of the dopaminergic system is suspected as well.69

Adverse Effects

The sedative effects of GHB appear within 15 minutes of ingestion

and make it popular with users seeking rapid euphoric effects or tofacilitate sexual assaults (ie, a date rape drug). A mellow and sociableexperience is often described. Severity is generally related to dosageand concurrent use of other substances. Low-dose GHB may leadto drowsiness/loss of consciousness and visual disturbances. Higherdoses may cause confusion, seizures, respiratory arrest, bradycardia,hypothermia, and coma.70 When mixed with other sedatives such asalcohol, these effects are more pronounced. Sudden awakening andrebound agitation is characteristic of overdose though the mechanism is

unclear.Physical dependence has been reported with GHB and its

precursors and may develop rapidly in every day users.71 Withdrawalfrom GHB is similar to that of alcohol and can last from 3 to 12 days.72,73

Concomitant ethanol abuse is common and may confound or worsen



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GHB withdrawal. Symptoms include tremors, insomnia, anxiety, anddiaphoresis. Milder symptoms occur in the first 24 hours. Forty-eight to72 hours after the last GHB dose, severe symptoms can ensue such asincreasing tachycardia and hypertension, hallucinations, confusion,delirium, seizures, and possibly death.74 Adverse effects of GHBintoxication are summarized in Table 5.

Management

The acutely intoxicated patient may require emergency supportivecare and establishment of a definitive airway prehospitalization. Patientsknown to have used GHB should be managed as if they are alsointoxicated with alcohol and it is likely that minimum alveolar

concentration requirements are reduced. In patients who chronicallyabuse GHB, signs of withdrawal intraoperatively or postoperativelyshould be treated aggressively with drugs that increase the seizurethreshold (eg, midazolam). If aspiration is suspected in the patient whopresents with respiratory failure and hypoxia, intensive care and

Table 5. Adverse Effects Associated With Acute g-Hydroxybutyrate Intoxication

Musculoskeletal

HypotoniaCardiovascular

Hypotension

Bradycardia

Metabolic

Purported benefits on sleep and anabolic processes

Hypothermia

Pulmonary


Cheyne stokes respirationRenal

Unknown

Hepatic

Likely induces P450 enzymes, unknown

Neurological/psychiatric

Amnesia

Somnolence/coma

Nausea/vomiting

DizzinessConfusion

Seizures

Withdrawal: insomnia, anxiety, tremor

Aggression upon sudden awakening from overdose



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continued mechanical ventilation may be indicated as well as a taperingschedule of long-acting benzodiazepines.

Ketamine

Background

Ketamine is a potent anesthetic induction agent. It causes loss ofconsciousness with little cardiorespiratory depression and providesprofound analgesia. It was first used as a replacement for phencyclidineas an anesthetic in the 1960s, but like phencyclidine it also leads to vividand unpleasant dreams and hallucinations.75 However, ketamine hasreemerged as a useful drug in anesthesiology where its role as an

analgesic particularly for children and at low doses in adults (especiallyfor endoscopy) makes it a useful adjunct.76 Use in the psychiatriccommunity for antidepressant effects has also reemerged.77 Abuse hassteadily risen over the past decade and ketamine is often combined withMDMA. Effects generally last from 1 to 3 hours so frequent redosing iscommon. It is available as a liquid or powder and can be abused orally,intravenously, intramuscularly, or via inhalation (smoked or snorted).78

Ketamine is an N-methyl-D-aspartate receptor antagonist, whichcauses noncompetitive antagonism of glutamate in the CNS.79 A dual

anesthetic/hallucinogenic nature comes from the composition as a chiralcompound, with 2 enantiomers that have different effects. S-ketamineproduces anesthetic effects and R-ketamine acts as a hallucinogen.In addition to its N-methyl-D-aspartate effects, ketamine causes amoderate sympathomimetic action via increased catecholamine outflowand possibly decreased reuptake.80

Adverse Effects

Blockade of the NMDA receptor leads to feelings of relaxation at lowdoses and to dissociative or psychotic states, hallucinations, visualdisturbances, and derealization or out of body experiences at highdoses (the k-hole).81 Nystagmus is a key physical feature of intoxication,which may help distinguish ketamine intoxication from use of other drugs.Severe agitation and hyperexcitability may also be observed and patientsmay be aggressive, agitated, and uncontrollable.82 Table 6 demonstratessome of the adverse effects of ketamine intoxication.

ManagementManagement of the acutely intoxicated patient who presents for

surgery is generally supportive. Most patients are young and toleratesympathomimetic activation well. Acute agitation and psychosis maymake procedures in an awake patient difficult. One or several doses of a



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benzodiazepine such as midazolam or diazepam are generally required.Inclusion of antipsychotic drugs such as haloperidol is appropriate de-pending on the degree of psychiatric impairment. High-dose ketamineintoxication may obtund a patient severely and aspiration precautionsshould be taken. Polydrug use should be assumed, especially if symp-toms and signs persist an hour after the last ingestion.

Flunitrazepam

Background

Flunitrazepam is a drug abused for its sedative effects and also givenas a date rape drug.83 It was developed in 1975 by the Hoffman-LaRoche pharmaceutical company and given its trade name Rohypnol.Its street name, roofies, is perhaps the best-known moniker. Fluni-trazepam is approved as a sedative/hypnotic drug in Europe, South

America, Asia, and Australia where it is marketed as a sleep aid anda preoperative anxiolytic. Most of the available street drug in the US

Table 6. Adverse Effects Associated With Acute Ketamine Intoxication

Musculoskeletal

Occasional tonic-clonic movements

Cardiovascular

Hypertension

Tachycardia

Arrhythmias

Metabolic

None known

Pulmonary

Hypersalivation and increased bronchial secretions

Airway obstruction

Renal

None known

Hepatic

None known

Neurological/psychological

Hallucinations/disorientation

Psychoses

Dissociation/derealization

Near death experiences

Flashbacks

Nystagmus/diplopia

Increased intraocular pressure

Lowered seizure threshold



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is smuggled in from Mexico by way of mail or delivery services. Reportsof abuse have been common in Europe since the 1970s and in the 1990sthe drug emerged in the US.

The drug is taken orally in tablet or capsule form and through itsbenzodiazepine effects has muscle relaxant, sedative, anxiolytic, andamnestic qualities. Effects generally begin in 15 minutes, peak within anhour of ingestion and last up to 12 hours. This rapid onset of actioncompared with other commercially available benzodiazepines, makesthe drug desirable for a rapid high and as a date rape drug. A

benzodiazepine, flunitrazepam serves as a GABAA-receptor agonist thatincreases channel opening with subsequent chloride ion flux, neuronalmembrane hyperpolarization and CNS depression.

Adverse Effects

Adverse effects are dose related and revolve around potent CNSdepressant effects. Somnolence, confusion, stupor, and coma are alleffects of large doses. Respiratory depression may also be present whenother CNS depressants are used in conjunction such as alcohol andother benzodiazepines. Paradoxical reactions may occur with varyingincidence just as with all benzodiazepines, leading to hyperexcitable

Table 7. Adverse Effects Associated With Acute Flunitrazepam Intoxication

Musculoskeletal

Muscle relaxation

Tremors

Cardiovascular

Hypotension

Bradycardia

Metabolic

None knownPulmonary


Renal

None known

Hepatic

None known

Neurological/cerebrovascular

Relaxation/anxiolysis

DrowsinessAnterograde amnesia

Headaches

Confusion

Paradoxical excitability or aggression



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states and agitation. True overdose is heralded by slurred speech,respiratory depression, bradycardia, hypotension, and stupor or coma.The withdrawal profile is not unlike that of alcohol. Adverse effects arepresented in Table 7.

Management

Patients acutely intoxicated by or withdrawing from flunitrazepammay be managed similarly to those who have ingested any other CNSdepressant (ie, alcohol, benzodiazepines). Reversal with flumazenil ispossible but can precipitate seizures and withdrawal. A long-acting

benzodiazepine taper may be required postoperatively (clonazepam islong acting and tends to be most commonly used). Any rapid changes

in hemodynamic measurements intraoperatively may be due to with-drawal. In the case of young women and girls brought to the emergencyroom with or without signs of trauma, suspicion of rape should beentertained and the appropriate authorities notified.

Conclusions

Abuse of cocaine and the club drugs remain a problem in the US.Patients may present acutely intoxicated or withdrawing from thesesubstances. Often patients are brought to the attention of medicalpersonnel for reasons such as trauma related to risky behaviors whileunder the influence and the clouded sensorium produced by eitheracute intoxication with these agents or during withdrawal can make thediagnosis of underlying medical issues difficult. Management becomesdifficult when presenting signs and symptoms may be due to thedrug or from an injury (eg, head trauma) sustained while intoxicated.With cocaine, controversy still exists as to the correct timing ofabstention before an elective case can be performed, but evidence ofend organ damage is probably more important than the time since lastingestion.

Supportive care is generally all that is needed to affect a positiveoutcome when these patients present acutely intoxicated. Polysubstanceabuse should be assumed when abuse of one of the drugs is suspected andwhereas a typical drug user is now very difficult to identify given thewidespread use, young adults and teens remain a likely group. Alcohol iscommonly used along with the club drugs and confounds or exacerbatesthe toxidromes of these drugs. Also, these substances are not generallydetected by urine toxicology screens performed in the emergency room sohistorical information and clinical signs and symptoms remain paramount.

Anesthesiologists should keep this information in mind when taking care ofyoung intoxicated patients for emergency surgeries and remain vigilant forrapidly evolving adverse effects perioperatively.



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