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The reported signs and symptoms of patients presenting to the ED with PCP and ketamine toxicity are variable. The variations are a result of differences in dosage, the multiple routes of administration, concomitant xenobiotic use, and other associated medical conditions. In accordance with their pharmacologic effect, ketamine toxicity produces signs and symptoms similar to PCP with a shorter duration of action. In addition, individual differences in xenobiotic susceptibility, the development of tolerance in chronic users, as well as contaminants in the drug manufacture, may account for erratic clinical findings.
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Body temperature is rarely affected directly by PCP and ketamine. In one large series, only 2.6% of patients demonstrated hyperthermia (> 101.8°F {38.8°C}).142 In an experimental animal model, PCP failed to increase body temperature.37,61 When hyperthermia does occur, all the known complications, including encephalopathy, rhabdomyolysis, myoglobinuria, acute kidney failure, electrolyte abnormalities, and liver failure, occur (Chap. 30).9,20,42,170
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Most PCP and ketamine toxic patients demonstrate mild sympathomimetic effects. PCP consistently increases both the systolic blood pressure (SBP) and diastolic blood pressure (DBP) in a dose-dependent fashion.37,61 Doses of 0.06 mg/kg of IV PCP increase the SBP and DBP by 8 mm Hg, whereas 0.25 mg/kg produce a 26 and 19 mm Hg increase in SBP and DBP, respectively. PCP also increases the heart rate, although it does so inconsistently.90 Likewise, ketamine produces mild increases in blood pressure, heart rate, and cardiac output via this same mechanism.52,133,197,212,222 In fact, tachycardia was the most common finding on physical examination in a case series of ketamine abusers presenting to the ED.220
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Cardiovascular catastrophes are rarely encountered in PCP toxicity.64,143 These complications may result from direct vasospasm,6,36 causing severe systemic hypertension, pulmonary edema, hypertensive encephalopathy,65 and cerebral hemorrhage.23 Hypertension, along with abnormal behavior, miosis, and nystagmus in children, strongly suggest toxicity due to a dissociative anesthetic.115
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The effect of PCP and ketamine on cardiac rhythm is controversial. Dysrhythmias are only observed in animals poisoned with very large doses of PCP. Ketamine both enhances and diminishes epinephrine-induced dysrhythmias in animals.22,62,91,116 The considerable experience in the use of ketamine anesthesia on humans undergoing surgery or cardiac catheterization has not demonstrated prodysrhythmic effects.69,159
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As these dissociative anesthetics were designed to maintain normal ventilation, hypoventilation is uncommon. In clinical studies, PCP increased the minute ventilation, tidal volume, and respiratory rate of volunteers.90 Clinically, in PCP-toxic patients, irregular respiratory patterns develop as tachypnea much more often than as bradypnea.9,142 Hypoventilation, when present, is usually secondary to the use of particularly high doses of PCP. Acute respiratory distress syndrome secondary to respiratory depression is also a rare occurrence. Large doses of PCP (20 mg/kg) administered to laboratory animals produced respiratory depression.37 Although respiratory depression in humans is an extremely rare event, it has been reported with fast or high-dose infusions of ketamine.84,222 In fact, ketamine has been successfully used to prevent intubation in patients with refractory asthma. Ketamine relaxes bronchial smooth muscles, decreases mean airway pressure and Paco2, and increases Pao2.75,178,202,222
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Most patients with PCP and ketamine toxicity brought to medical attention manifest diverse psychomotor abnormalities.13,19,29,72,108,220 As dissociative anesthetics, these xenobiotics impair response to external stimuli by separating various elements of the mind. Consciousness, memory, perception, and motor activity appear dissociated from each other. This dissociation prevents the user from attaining cognition and properly assembling all this information to construct a reality. Clinically, the person may appear inebriated, either calm or agitated, and sometimes violent. In large overdoses, the anesthetic effect causes patients to develop stupor or coma. In recreational use, “dissociatives” are not taken for these effects, but rather for so-called out-of-body experiences. In addition patients often have disordered thought processes (including disorientation as to time, place, and person) or amnesia, paranoia, and dysphoria.71
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The manifestations of PCP and ketamine toxicity are better illustrated by the results of their effects in controlled human studies. Volunteers who took oral doses of up to 7.5 mg/day of PCP or 0.1 mg/kg of ketamine exhibited clinical inebriation, but higher doses (PCP > 10 mg/day; ketamine 0.5 mg/kg) generally caused a more severe impairment of mental function.61,120 IV doses of 0.1 mg/kg of PCP17,58,131,158,181 and 0.5 mg/kg of ketamine120,168 cause diminution in all sensory modalities (pain, touch, proprioception, hearing, taste, and visual acuity) in a dose-dependent fashion. Both xenobiotics also cause feelings of apathy, depersonalization, hostility, isolation, and alterations in body image.17,58,74,109,137,156 The deficits in sensory modalities are evident prior to the development of the psychological effects of PCP, with pain perception disappearing first. This alteration in analgesic perception is caused by a blocking action on the thalamus and midbrain (Fig. 86–1).158
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Abnormal stereognosis and proprioception occur in a dose-dependent manner. This disturbed perception results in body image distortions described as “numbness,” “sheer nothingness,” and “depersonalization.” The decrease of proprioceptive sensation to gravity probably gives the sensation of “tripping” or “flying.” Because all sensory modalities are affected, visual, auditory, and tactile illusions and delusions are common. Hallucinations are typically auditory rather than visual, which are more common with LSD use. The hallucinogenic effects of ketamine on healthy human volunteers are linearly related to steady-state concentrations between 50 and 200 ng/mL.24 Most ketamine users report experiencing a “k-hole,” a slang term for the intense psychological and somatic state experienced while under the influence of ketamine. This experience varies with the individual, but can include buzzing, ringing or whistling sounds, traveling through a dark tunnel, intense visions, and out-of-body or near-death sensations.59
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The reaction to the misperceived or disconnected reality may result in unintentional actions and violent behavior. The hallmark of PCP toxicity is the recurring delusion of superhuman strength and invulnerability resulting from both its anesthetic and dissociative properties. There are case reports of patients presenting with trauma either from jumping from high altitudes, fighting large crowds or the police, or self-mutilation. The true extent and incidence of violence is probably less than previously suggested.25
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Typically, neurologic signs include horizontal, vertical, and/or rotatory nystagmus, ataxia, and altered gait. Initially, except for ataxia, motor movement is not impaired until the patient becomes unconscious. On physical examination, use of dissociative anesthetics typically produces relatively small pupils, nystagmus, and diplopia. In the largest case series reported to date, nystagmus and hypertension were noted in 57% of patients who had taken PCP.142 Smaller and more limited studies have found an incidence of nystagmus approximating 89%.19 In comparison, nystagmus was only found in 15% of patients with ketamine abuse.200 Other cerebellar manifestations were also encountered, most notably dizziness, ataxia, dysarthria, and nausea. A pooled data compilation of 35 reports demonstrated that emesis occurred 8.5% of the time.84 In fact, Internet chat groups devoted to substance abuse commonly direct users to “mix dissociatives with marijuana” for its antiemetic effect.
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Larger doses of PCP produce loss of balance and confusion, the latter characterized by inability to repeat a set of objects, frequent loss of ideas, blocking, lack of concreteness, and disordered linguistic expression.55,61,120,131,181 Similarly, ketamine users report a high incidence of incoordination, confusion, unusual thought content, and an inability to speak.59 In general, dissociative anesthetics stimulate the CNS but seizures rarely occur, except at high doses. The largest case series of PCP-toxic patients detected a 3.1% incidence of seizures.142
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Although PCP and ketamine toxic patients also present with motor disturbances, it is unclear to what extent PCP and ketamine are actually responsible for these manifestations. The most common of the reported disturbances are dystonic reactions: opisthotonos, torticollis, tortipelvis, and risus sardonicus (facial grimacing). Myoclonic movements, tremor, hyperactivity, athetosis, stereotypies, and catalepsy also occur.13,30,72,142 A slight increase in muscle tone results from a dopaminergic effect.131 Laryngospasm requiring intubation has been reported after the use of ketamine anesthesia. The incidence of this complication is less than 0.017%.83 By comparison, the incidence of laryngospasm following traditional general anesthesia is 2%.150
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Urological and Hepatobiliary
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Intense abdominal and pelvic pain is regularly reported in habitual ketamine users.160,232 In the majority of cases, the etiology is urologic. The first case series describing ketamine-associated urological dysfunction was reported in 2007. The patients’ symptoms consisted of severe lower urinary tract syndrome (LUTS): dysuria, frequency, urgency, urge incontinence, and painful hematuria (Fig. 86–2). When investigated by cystoscopy, patients with hematuria were frequently found to have ulcerative cystitis.184
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Subsequent reports have established LUTS as a complication in both recreational ketamine users as well as in a patient receiving ketamine therapeutically for chronic regional pain syndrome.39,89,103 The incidence of ketamine-induced urologic dysfunction is not well established. Studies from the United Kingdom report an incidence of 20%, whereas a study from Hong Kong reports the incidence of 32% and 92% in acute and chronic ketamine users respectively.139,227,232
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The symptoms of ketamine–induced urologic dysfunction are secondary to an inflammatory process that reduces bladder size. Initial urinalyses are typically sterile. Patients develop diminished voiding capacity of 20 to 200 mL, decreased bladder compliance, and detrusor overactivity as measured by urodynamic testing. A thickened bladder wall, a small bladder volume, and perivesicular stranding are usually detected by ultrasonography and computerized tomography (CT) of the lower urologic tract.139 Cystoscopy demonstrates an erythematous bladder mucosa with various degrees of ulcerations. Bladder biopsies confer epithelium denudation and ulcerative cystitis. There is a marked lymphocytic infiltration with a variable number of eosinophils and fibrosis as well as squamous metaplasia and nephrogenic metaplasia. The exact mechanism by which ketamine or one of its metabolites causes the destruction of the urinary tract remains unknown.39,40,227,232
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The pathology of ketamine-induced urologic dysfunction is not confined to the lower urinary tract. Upper urinary tract involvement is variable. A lower incidence of 13% has been reported in the United Kingdom compared with 51% in Hong Kong. The lower incidence is thought to be due to patients in the United Kingdom seeking medical attention earlier than those living in Hong Kong. IV urography and urography by CT reveal unilateral or bilateral ureteric narrowing. Bilateral hydronephrosis was reported in 44% to 50% of patients, and renal impairment has also been described.139,147 Biopsy of the ureter in a patient who underwent right nephrectomy with an ileal conduit anastomosis to the left renal pelvis demonstrated nephrogenic metaplasia throughout the ureter extending to the renal pelvis as well as ulceration with associated inflammatory changes, as described the bladder biopsies.99
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Intense abdominal pain in frequent ketamine users is also suggested to be hepatobiliary in nature. Case series of patients who used ketamine illicitly or therapeutically report abnormal liver function tests and biliary tract abnormalities.129,162,183 CT revealed common bile duct dilation with a smooth tapered end, a condition that mimics benign cystic dilation of the bile ducts. Endoscopic retrograde cholangiopancreatography and hepatobiliary iminodiacetic acid studies concur with these findings, suggesting gallbladder wall dyskinesia. These biliary abnormalities are noted to subside with cessation of ketamine use.128
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The acute psychosis observed during the recovery phase of PCP anesthesia limits its clinical use. This bizarre behavior, characterized by confusion, vivid dreaming, and hallucinations, is termed an “emergence reaction.” These reactions occur most frequently in middle-aged men, with a reported incidence of 17% to 30%.90,114 The most violent emergence reactions follow an IV dose of approximately 0.25 mg/kg of phencyclidine.61 The mildest degrees of agitation produced by PCP resemble the effects of ethanol intoxication.
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These same postanesthetic reactions also limit the clinical use of ketamine. The incidence of emergence reactions following ketamine administration may approximate 50% in adults and 10% in children.83 Patients older than 10 years of age, women, persons who normally dream frequently, have a prior personality disorder, or both, premorbid denial of presence of illness or anosognosia (denial of the presence of an illness), and paranoia incur the greatest risk.83,144 The incidence of the occurrence of emergence reactions appears to be exacerbated when dissociative anesthetics are rapidly IV administered, as well as in patients exposed to excessive stimuli during recovery. Although it has not been proved in a controlled study, reducing external stimuli during the recovery phase might reduce emergence reactions.
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Ironically, the very characteristics thought to make PCP ideal for anesthesia—the preservation of muscle tone and cardiopulmonary function—magnify the difficulties in managing an individual who manifests dysphoria after an overdose. The course of delirium, stupor, and coma associated with PCP and ketamine is extremely variable, although the manifestations are much milder and shorter acting following ketamine use.
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Cholinergic and Anticholinergic Effects
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Both cholinergic and anticholinergic clinical manifestations occur in the PCP- or ketamine-toxic patient. Miosis or mydriasis, blurred vision, profuse diaphoresis, hypersalivation, bronchospasm, bronchorrhea, and urinary retention may occur.13,19,127,141,142 Clinically, ketamine stimulates salivary and tracheobronchial secretions, both of which are equally and effectively inhibited by atropine and glycopyrolate.152 Furthermore, in a randomized, double-blind trial, after infusion of 1.5 mg/kg of ketamine in healthy volunteers, physostigmine decreased nystagmus, blurred vision, and the time to recovery. However, nausea and vomiting were more frequent.211