THE WESTE:RN Journal of MBdic
Refer to: Burns RS, Lerner SE, Corrado R, et al: Phencyclidine -States of acute intoxication and fatalities. West J Med 123:345-349, Nov 1975
Phencyclidine-
States of Acute Intoxication and Fatalities R. STANLEY BURNS, MD, STEVEN E. LERNER, MS, and ROBBIE CORRADO, PA San Francisco STUART H. JAMES, BS, Johnson City, New York SIDNEY H. SCHNOLL, MD, Philadelphia
Phencyclidine is now one of the most frequently used main ingredients of "street drug" preparations. Its effects are highly dose dependent and three varieties of acute intoxication have been seen clinically associated with different dosages and routes of administration. Most persons using phencyclidine smoke it sprinkled on parsley in low doses. The presence of horizontal and vertical nystagmus associated with hypertension in a patient who is agitated or comatose are diagnostic of a phencyclidine intoxicated state. Sensory isolation and intravenous administration of diazepam in the event of seizure activity have proved effective in the treatment of acute intoxicated states. Phencyclidine has pronounced behavioral toxicity and several deaths due to this agent have now been documented. It is unknown whether seizure activity or respiratory depression is the primary cause of death in pharmacological overdoses. PHENCYCLIDINE (SernylQ, Sernylan®) is 1-(1phencyclohexyl) piperidine hydrochloride (see Figure 1). It is a white crystalline solid which is soluble in water and alcohol. Synthesized by Parke, Davis and Company, phencyclidine was recommended for clinical trials in humans in 1957. Investigation of its effects in animals had shown a potent analgesic activity and potential use as a nonbarbiturate, nonnarcotic intravenously administered anesthetic agent was explored. Due to emergence reactions-agitation, From the Rock Medicine Section, Haight-Ashbury Free Medical Clinic, San Francisco (Dr. Burns, Mr. Lerner and Ms. Corrado); the Toxicology Department, Wilson Memorial Hospital, Johnson City, NY (Mr. James); and the Department of Psychiatry, University of Pennsylvania Medical School (Dr. Schnoll). Submitted March 26, 1975. Reprint requests to: Steven E. Lerner, MS, R. Stanley Burns, MD, & Associates, 350 Parnassus Avenue, Suite 304 A, San Francisco, CA 94117.
excitement, disorientation and hallucinatory phenomena-Parke, Davis and Company in 1965 requested that further human clinical investigation be discontinued. The structurally related anesthetic ketamine was subsequently developed. Since 1967, phencyclidine has been available for legitimate use only as an anesthetic or tranquilizing agent for primates. Currently, phencyclidine is considered a controlled dangerous substance under the Comprehensive Drug Abuse Prevention and Control Act of 1970. Phencyclidine made its first "street" appearance in San Francisco in 1967 -where it was being marketed as the "PeaCe Pill." Many persons experienced unexpected effects and phencyclidine gained a bad street reputation. It then began to appear in new guises and in combination with THE WESTERN JOURNAL OF MEDICINE
345
PHENCYCLIDINE
other drugs. Thirty different alleged street drugs analyzed during the years 1972 to 1974 contained phencyclidine.1 The most persistent misrepresentation of phencyclidine has been as THC (tetrahydrocannabinol). Most recently, phencyclidine has been sold on the West Coast as "crystal" or "crystal joints" (CJ's). Different patterns of phencyclidine use have emerged. First time use occurs with persons unknowingly or in an exploratory fashion smoking a cigarette made by sprinkling phencyclidine "crystals" on parsley. Although the occasional or recreational use pattern is seen, its development from this first time use is frequently interrupted by the experience of unexpected and unpleasant effects. However, several clusters of 10 to 20 persons who have shared phencyclidine daily for periods of two to six years have now been identified. Between July 1973 and February 1974 there were in excess of 1,300 mentions nationwide of phencyclidine in the Drug Abuse Warning Network (DAWN) system. Of 86 urine samples collected during 10 months by one California police agency in cases of suspected intoxication while driving or in public, 48 were positive for phencyclidine exclusively.2 Widespread use and availability both across the United States and Western Europe have also been reported by phencyclidine users during interviews.
Pharmacology Phencyclidine acts primarily on the central nervous system either by stimulation or depression. Its pharmacological action in animals is complex and dependent upon both the species and the dosages.3 The variability in activity makes it difficult to classify this agent. The effects of phencyclidine in humans, like-
Figure 1.-Phencyclidine (1-[1-phencyclohexyl] piperidine hydrochloride).
346
NOVEMBER 1975 * 123 * 5
wise, are highly dose dependent. In clinical trials, phencyclidine proved to have a unique spectrum of activity in anesthetic dosages (0.25 mg per kg of body weight, administered intravenously). An unresponsive state with complete anesthesia was induced, although the eyes remained open (blank stare) and the patient appeared to be awake. Neither hypotension nor respiratory depression was produced by phencyclidine in anesthetic dosages. Characteristically, a moderate hypertensive response associated with tachycardia and no significant change in respiratory function was observed. initial trials with the administration of higher dosages (0.5 to 1.0 mg per kg of body weight, given intravenously) showed the progressive development of severe agitation, muscle rigidity and generalized seizure activity. Respiratory depression was not seen in this dosage range.4
States of Acute Intoxication The temporal profile and unique spectrum of signs and symptoms associated with different dosage ranges and different routes of administration require description of three varieties or stages of acute intoxication. During the period April 1974 to June 1975, 55 cases of acute intoxication with phencyclidine by history were seen by the authors. Fifty-four cases represent acute intoxication states resulting from reported low to moderate doses of phencyclidine self-administered by inhalation (smoking) or insufflation ("snorting"). In one case a high dose was taken orally and the patient was comatose for a period of approximately 10 hours. Urine samples were obtained in 10 percent of the cases. Analysis by gas chromatography showed the presence of phencyclidine in all collected samples. The clinical findings in 44 cases of low dose acute intoxication and 10 cases involving a moderate dose have been summarized in Table 1. The single case involving a high oral dose has been combined with the findings from four similar cases and the composite clinical picture is also described in Table 1.5-8 The low dose state is characterized by mild agitation or excitement in a patient who is grossly ataxic and has a "blank stare" appearance. Catatonic rigidity (catalepsy) may be shown, with the patient unable to speak. However, in most cases the patient is communicative and on testing horizontal and vertical nystagmus is present. Loss of
PHENCYCLIDINE
TABLE 1.-Acute Intoxicated States
Route . . Estimated dose ...... Onset .............. Duration acute, symptoms ......... Time required to recover to normal . . State of consciousness .
Respirations Rate .....
..
Pattern .......
Circulation Blood pressure
.....
Pulse ......
..
High Dose (5 cases)-
Moderate Dose (10 cases)
Low Dose (44 cases)
Inhalation (smoking) 5-10 mg 2-3 minut .es
Inhalation or insufflation 10-20 mg 2-3 minutes
Oral 100+ mg (approx. for adults) 45 minutes
1-2 hours
Duration of coma h-I hour
Duration of coma 6-12 hours
4-8 hours
unable to speak; blank stare appearance; disoriented for time/place; anxious, fearful, agitated or may be mildly euphoric; resfiess or excited, may exhibit regressive or self-destructive behavior
8-24 hours Comatose or stuporous with open eyes, waking appearance; responds only to noxious stimuli (deep pain); followed by 1-2 hour period where signs and symptoms of low dose state are manifest; amnesia for period of coma/stupor
48-96 + hours Comatose, responding only to noxious stimuli; prolonged recovery period marked by alternating sleep and waking illusions, hallucinations, and clinical features of low dose state; amnesia for period of coma and prolonged recovery phase
16-24 (+) Normal
16-24 (+) Normal or Cheyne-Stokes
135-160 (+) 80-100 100-140(+)
135-160 (+) 80-100 100-140 (+)
18-28 (+) Normal or Cheyne-Stokes (adult); apnea (child) 120-200 60-110 80-100 (+)
Communicative, or may be
Pupils Size ..... ... Mid-position Light reflex ....... Normal Occular movements Eyelid position ..... Open/ptosis Nystagmus .......... Horizontal and vertical on testing Motor function ...... Ataxia (sensory); catatonic rigidity-catalepsy, facial grimacing; deep tendon reflexes (DTR's)-increased
Sensory function ..... Analgesia (pin prick) Autonomic function .. Vomiting (central)
Mid-position Normal or sluggish
Variable
Ptosis/closed Horizontal and/or vertical at rest Purposeless movements, repetitive; myoclonus (shivering) -trunk, extremities; clonic jerking extremities; muscle rigidity on stimulation; facial grimacing; deep tendon reflexes (DTR's) -increased
Closed Horizontal and/or vertical at
..
.
... .
rest Purposeless movements, muscle rigidity, opisthotonic
posturing (child), generalized seizure activity, deep tendon reflexes (DnTR's)-increased
...
Vomiting (central), hypersalivation
response to pin prick is observed. Most of these patients were seen at rock music events and were able to return with friends to their seats after an hour, although mild ataxia was still evident. The moderate dose state is marked by coma or stupor in which the eyes remain open associated with the presence of hypertension and the absence of respiratory depression. The pupils are midposition and reactive to light. Nystagmus at rest, repetitive motor movements, myoclonus (shivering) and muscle rigidity on stimulation are characteristic findings. Frequently vomiting and hypersalivation are part of the picture. Most pa-
Normal or sluggish
Vomiting (central), hypersalivation
tients are communicative and ambulatory within 30 minutes to an hour, although they manifest all the signs and symptoms of the low dose state on awakening. One to two hours of observation are required from the time of admission until the patient returns with friends to the auditorium or
stadium. The patient who has taken orally a high dose of phencyclidine either accidentally or as a suicide attempt usually presents at the emergency room. The two children included in this series presented with apnea, although in the adult patients where information is available respirations were normal THE WESTERN JOURNAL OF MEDICINE
347
PHENCYCLIDINE
and the blood pressure was normal or high. While pupil size varied, the pupillary light reflex was intact. Opisthotonic posturing was seen in one child over a six hour period, and generalized seizure activity has been observed in adult patients. Nystagmus at rest, vomiting and hypersalivation are, again, seen during the comatose period. The most characteristic feature of high dose oral ingestion is the prolonged recovery phase, marked by alternating periods of sleep and waking, misperceptions, disorientation, hallucinatory phenomena and the clinical picture of the low dose state. Patients have been comatose for periods of up to 12 hours and have required several days for recovery to normal.
Differential Diagnosis The low dose state is frequently interpreted as secondary to an unknown psychedelic drug. The absence of mydriasis and the presence of gross ataxia and horizontal and vertical nystagmus are diagnostic of a phencyclidine intoxication. The moderate dose state may be interpreted, initially, as a sedative-hypnotic overdose. However, the presence of hypertension and hyperreflexia (deep tendon reflexes or DTR'S) and the absence of prominent respiratory depression differentiate the phencyclidine intoxicated state from sedative-hypnotic overdose. Cases involving ingestion of high doses which present as undiagnosed coma may be difficult to differentiate from other causes. Again if hypertension is evident and there is no significant depression of respiration, sedative-hypnotic overdose can be ruled out. If, in addition, opisthotonic posturing is present in a child or seizure activity in an adult, a phencyclidine intoxication should be suspected. If a patient is in status epilepticus or in a postictal state, the underlying cause may be difficult to surmise. The characteristic prolonged recovery phase is diagnostic of phencyclidine intoxication.
Management, Treatment The key to management of the low dose acute intoxicated state is sensory isolation with observation at a distance. Exacerbation of clinical symptoms is seen even with minimal verbal or physical stimulation. The patient should be placed on a cushioned surface of the floor in a quiet room with a monitor present. Protection from self-harm may also be necessary. Most patients 348
NOVEMBER 1975 * 123 * 5
are able to be released to family or friends within one hour. In a patient who presents with the moderate dose state, respiratory status and blood pressure should be monitored, with close observation for clonic movements or muscle rigidity which usually precede seizure activity. Again, sensory stimulation should be controlled and minimized. On recovery from the short period of coma or stupor, the patient will require continued sensory isolation and protection from self-harm for approximately one hour. If seizure activity does intercede, judicious intravenous administration of diazepam (Valiums) in 2 to 3 mg increments is indicated. Respirations should be closely monitored postadministration. The general principles of management of coma would apply to high dose acute intoxication with phencyclidine. Closely monitoring respirations and blood pressure, and observing the patient for seizure activity or its prodromata would be indicated. Endotracheal intubation may be difficult and may precipitate laryngeal spasm. Gastric lavage is indicated in view of the large quantities of phencyclidine which have been recovered from the gastric contents in fatal cases. Diazepam carefully administered in increments of 2 to 3 mg intravenously with postadministration observation of respirations is indicated in the event of generalized seizure activity. Diazoxide was reported to be effective in lowering blood pressure during a hypertensive crisis thought to be secondary to phencyclidine.10 The patient may remain comatose for a period of 12 hours or more. The principles of sensory isolation and protection from self-harm apply to the prolonged recovery period which may last several days and require admission to a psychiatric unit.
Fatalities Fifteen deaths associated with phencyclidine, and previously unreported, occurred in California between 1970 and 1975. Five of these deaths occurred during the period January 1974 to July 1975. In all cases analysis of body fluids for toxicology showed the presence of phencyclidine and the absence of any other chemical agent. Most of these deaths appear to represent accidents or suicides involving a pharmacological overdose. In some cases, however, the levels of phencyclidine in the blood and urine and the circumstances of
PHENCYCLIDINE
the death suggest that death resulted from the behavioral toxicity of phencyclidine. In the cases with high blood and urine levels, the associated presence of up to 185 mg of phencyclidine in the gastric contents points to an oral route of self-administration. In one case bloody fluid was noted in the mouth and nose which may have resulted from seizure activity. It is still unclear whether oral doses in the range of 150 to 200 mg or more, which were estimated to be involved in these cases, produce primary respiratory depression. Generalized seizure activity with postictal depression or hypoxia may be the precipitating factor in the death of these persons. Interviews with chronic, daily users of phencyclidine do not support the idea that tolerance develops to the behavioral effects of this agent. Behavioral toxicity is consistent with the lower blood and urine levels found in four cases where the immediate cause of death was asphyxiation on drowning. Chronic users report that friends have died while intoxicated by drowning, automobile accidents and fire. Gross ataxia, catatonic rigidity, misperception or analgesia may interfere with a person's ability to drive, swim, flee from a fire or sense imminent danger.
respiratory depression and seizure activity has yet to be documented with clinical findings in cases involving potentially lethal doses of the drug. Eastman and Cohen have recently reported a case involving a 13-year-old boy in which a hypertensive crisis was followed by an intracerebral hemorrhage and death.'0 There was no autopsy evidence of cerebral hemorrhage or hypertensive encephalopathy in the fatalities summarized. Potentiation of the stimulant or depressant effects of phencyclidine in huimans by other chemical agents is also an open question. While we have no familiarity with the intensity or spectrum of effects seen when phencyclidine is administered in comparable high doses, this becomes a critical question when central nervous system depressants are administered to control seizure activity. Judicious use of these agents would appear to be indicated. It is not clear whether symptomatic improvement consistently follows the use of the phenothiazines. In several cases, however, significant hypotension has resulted from the administration of therapeutic dosages of the phenothiazines. By 1964 more than 1,000 patients had received phencyclidine as an investigational drug and no evidence of acute cellular toxicity was reported."
Discussion
Conclusion
The central question of the occurrence of primary respiratory depression in fatal high dose phencyclidine ingestions in adults remains unanswered. Blood levels in fatal cases have been comparable to the level reported in one patient who presented with status epilepticus (0.70 mg per 100 ml)9 and the level in the single high dose case seen by the authors (0.37 mg per 100 ml). The former patient died four days after admission with autopsy evidence of severe anoxic encephalopathy and indications of progressive hepatic and renal failure. In the latter case no phencyclidine was detectable in the blood 71/2 hours after admission, although the patient remained comatose with no significant change in respiratory function or seizure activity for 10 hours. In a third case, where blood levels were not obtained, the patient also presented in status epilepticus. The 13 hour period of coma was marked by intermittent, generalized seizure activity with respiratory depression evident only after reiterative seizures. The information available is incomplete and the relationship between blood levels,
In contrast to its pronounced behavioral and central nervous system toxicity, phencyclidine parades as a "mild" psychedelic drug on the street. It has become one of the most frequently used main ingredients of street drug preparations. Further investigation of the cellular toxicity and neuropsychological dysfunction associated with chronic daily use of phencyclidine is indicated. REFERENCES 1. Radcliff BE: Personal communication 2. Reynolds P: Personal communication 3. Chen G, Ensor C, Russell D, et al: The pharmacology of l-(l-phenylcyclohexyl) piperidine HCL. J Pharmacol Exp Ther 127:241-250, May 1959 4. Greifenstein FE, Yoshitake J, DeVault M, et al: A study of a l-aryl cyclo hexyl amine for anesthesia. Anesth Analg 37:283294, Sep-Oct 1958 5. Liden CB, Lovejoy FH Jr, Costello CE: Phencyclidine (Sernylan) poisoning. J Pediatr 83:844-845, Nov 1973 6. Stein JI: Phencyclidine induced psychosis-The need to avoid unnecessary sensory influx. Military Med 138:590-591, Sep 1973 7. Highland General Hospital, Oakland, California: Personal communication 8. Davis W, Ezekiel G: Personal communication 9. Kessler GF Jr, Demers LM, Berlin C, et al: Phencyclidine and fatal status epilepticus. N Engl J Med 291:979, Oct 1974 10. Eastman JW, Cohen SN: Hypertensive crisis and death associated with phencyelidine poisoning. JAMA 231:1270-1271, Mar 24, 1975 11. Domino EF: Neurobiology of phencydidine (Sernyl), a drug with an unusual spectrum of pharmacological activity. Int Rev Neurobiol 6:303-347, 1964
THE WESTERN JOURNAL OF MEDICINE
349
Refer to: Burns RS, Lerner SE, Corrado R, et al: Phencyclidine -States of acute intoxication and fatalities. West J Med 123:345-349, Nov 1975
Phencyclidine-
States of Acute Intoxication and Fatalities R. STANLEY BURNS, MD, STEVEN E. LERNER, MS, and ROBBIE CORRADO, PA San Francisco STUART H. JAMES, BS, Johnson City, New York SIDNEY H. SCHNOLL, MD, Philadelphia
Phencyclidine is now one of the most frequently used main ingredients of "street drug" preparations. Its effects are highly dose dependent and three varieties of acute intoxication have been seen clinically associated with different dosages and routes of administration. Most persons using phencyclidine smoke it sprinkled on parsley in low doses. The presence of horizontal and vertical nystagmus associated with hypertension in a patient who is agitated or comatose are diagnostic of a phencyclidine intoxicated state. Sensory isolation and intravenous administration of diazepam in the event of seizure activity have proved effective in the treatment of acute intoxicated states. Phencyclidine has pronounced behavioral toxicity and several deaths due to this agent have now been documented. It is unknown whether seizure activity or respiratory depression is the primary cause of death in pharmacological overdoses. PHENCYCLIDINE (SernylQ, Sernylan®) is 1-(1phencyclohexyl) piperidine hydrochloride (see Figure 1). It is a white crystalline solid which is soluble in water and alcohol. Synthesized by Parke, Davis and Company, phencyclidine was recommended for clinical trials in humans in 1957. Investigation of its effects in animals had shown a potent analgesic activity and potential use as a nonbarbiturate, nonnarcotic intravenously administered anesthetic agent was explored. Due to emergence reactions-agitation, From the Rock Medicine Section, Haight-Ashbury Free Medical Clinic, San Francisco (Dr. Burns, Mr. Lerner and Ms. Corrado); the Toxicology Department, Wilson Memorial Hospital, Johnson City, NY (Mr. James); and the Department of Psychiatry, University of Pennsylvania Medical School (Dr. Schnoll). Submitted March 26, 1975. Reprint requests to: Steven E. Lerner, MS, R. Stanley Burns, MD, & Associates, 350 Parnassus Avenue, Suite 304 A, San Francisco, CA 94117.
excitement, disorientation and hallucinatory phenomena-Parke, Davis and Company in 1965 requested that further human clinical investigation be discontinued. The structurally related anesthetic ketamine was subsequently developed. Since 1967, phencyclidine has been available for legitimate use only as an anesthetic or tranquilizing agent for primates. Currently, phencyclidine is considered a controlled dangerous substance under the Comprehensive Drug Abuse Prevention and Control Act of 1970. Phencyclidine made its first "street" appearance in San Francisco in 1967 -where it was being marketed as the "PeaCe Pill." Many persons experienced unexpected effects and phencyclidine gained a bad street reputation. It then began to appear in new guises and in combination with THE WESTERN JOURNAL OF MEDICINE
345
PHENCYCLIDINE
other drugs. Thirty different alleged street drugs analyzed during the years 1972 to 1974 contained phencyclidine.1 The most persistent misrepresentation of phencyclidine has been as THC (tetrahydrocannabinol). Most recently, phencyclidine has been sold on the West Coast as "crystal" or "crystal joints" (CJ's). Different patterns of phencyclidine use have emerged. First time use occurs with persons unknowingly or in an exploratory fashion smoking a cigarette made by sprinkling phencyclidine "crystals" on parsley. Although the occasional or recreational use pattern is seen, its development from this first time use is frequently interrupted by the experience of unexpected and unpleasant effects. However, several clusters of 10 to 20 persons who have shared phencyclidine daily for periods of two to six years have now been identified. Between July 1973 and February 1974 there were in excess of 1,300 mentions nationwide of phencyclidine in the Drug Abuse Warning Network (DAWN) system. Of 86 urine samples collected during 10 months by one California police agency in cases of suspected intoxication while driving or in public, 48 were positive for phencyclidine exclusively.2 Widespread use and availability both across the United States and Western Europe have also been reported by phencyclidine users during interviews.
Pharmacology Phencyclidine acts primarily on the central nervous system either by stimulation or depression. Its pharmacological action in animals is complex and dependent upon both the species and the dosages.3 The variability in activity makes it difficult to classify this agent. The effects of phencyclidine in humans, like-
Figure 1.-Phencyclidine (1-[1-phencyclohexyl] piperidine hydrochloride).
346
NOVEMBER 1975 * 123 * 5
wise, are highly dose dependent. In clinical trials, phencyclidine proved to have a unique spectrum of activity in anesthetic dosages (0.25 mg per kg of body weight, administered intravenously). An unresponsive state with complete anesthesia was induced, although the eyes remained open (blank stare) and the patient appeared to be awake. Neither hypotension nor respiratory depression was produced by phencyclidine in anesthetic dosages. Characteristically, a moderate hypertensive response associated with tachycardia and no significant change in respiratory function was observed. initial trials with the administration of higher dosages (0.5 to 1.0 mg per kg of body weight, given intravenously) showed the progressive development of severe agitation, muscle rigidity and generalized seizure activity. Respiratory depression was not seen in this dosage range.4
States of Acute Intoxication The temporal profile and unique spectrum of signs and symptoms associated with different dosage ranges and different routes of administration require description of three varieties or stages of acute intoxication. During the period April 1974 to June 1975, 55 cases of acute intoxication with phencyclidine by history were seen by the authors. Fifty-four cases represent acute intoxication states resulting from reported low to moderate doses of phencyclidine self-administered by inhalation (smoking) or insufflation ("snorting"). In one case a high dose was taken orally and the patient was comatose for a period of approximately 10 hours. Urine samples were obtained in 10 percent of the cases. Analysis by gas chromatography showed the presence of phencyclidine in all collected samples. The clinical findings in 44 cases of low dose acute intoxication and 10 cases involving a moderate dose have been summarized in Table 1. The single case involving a high oral dose has been combined with the findings from four similar cases and the composite clinical picture is also described in Table 1.5-8 The low dose state is characterized by mild agitation or excitement in a patient who is grossly ataxic and has a "blank stare" appearance. Catatonic rigidity (catalepsy) may be shown, with the patient unable to speak. However, in most cases the patient is communicative and on testing horizontal and vertical nystagmus is present. Loss of
PHENCYCLIDINE
TABLE 1.-Acute Intoxicated States
Route . . Estimated dose ...... Onset .............. Duration acute, symptoms ......... Time required to recover to normal . . State of consciousness .
Respirations Rate .....
..
Pattern .......
Circulation Blood pressure
.....
Pulse ......
..
High Dose (5 cases)-
Moderate Dose (10 cases)
Low Dose (44 cases)
Inhalation (smoking) 5-10 mg 2-3 minut .es
Inhalation or insufflation 10-20 mg 2-3 minutes
Oral 100+ mg (approx. for adults) 45 minutes
1-2 hours
Duration of coma h-I hour
Duration of coma 6-12 hours
4-8 hours
unable to speak; blank stare appearance; disoriented for time/place; anxious, fearful, agitated or may be mildly euphoric; resfiess or excited, may exhibit regressive or self-destructive behavior
8-24 hours Comatose or stuporous with open eyes, waking appearance; responds only to noxious stimuli (deep pain); followed by 1-2 hour period where signs and symptoms of low dose state are manifest; amnesia for period of coma/stupor
48-96 + hours Comatose, responding only to noxious stimuli; prolonged recovery period marked by alternating sleep and waking illusions, hallucinations, and clinical features of low dose state; amnesia for period of coma and prolonged recovery phase
16-24 (+) Normal
16-24 (+) Normal or Cheyne-Stokes
135-160 (+) 80-100 100-140(+)
135-160 (+) 80-100 100-140 (+)
18-28 (+) Normal or Cheyne-Stokes (adult); apnea (child) 120-200 60-110 80-100 (+)
Communicative, or may be
Pupils Size ..... ... Mid-position Light reflex ....... Normal Occular movements Eyelid position ..... Open/ptosis Nystagmus .......... Horizontal and vertical on testing Motor function ...... Ataxia (sensory); catatonic rigidity-catalepsy, facial grimacing; deep tendon reflexes (DTR's)-increased
Sensory function ..... Analgesia (pin prick) Autonomic function .. Vomiting (central)
Mid-position Normal or sluggish
Variable
Ptosis/closed Horizontal and/or vertical at rest Purposeless movements, repetitive; myoclonus (shivering) -trunk, extremities; clonic jerking extremities; muscle rigidity on stimulation; facial grimacing; deep tendon reflexes (DTR's) -increased
Closed Horizontal and/or vertical at
..
.
... .
rest Purposeless movements, muscle rigidity, opisthotonic
posturing (child), generalized seizure activity, deep tendon reflexes (DnTR's)-increased
...
Vomiting (central), hypersalivation
response to pin prick is observed. Most of these patients were seen at rock music events and were able to return with friends to their seats after an hour, although mild ataxia was still evident. The moderate dose state is marked by coma or stupor in which the eyes remain open associated with the presence of hypertension and the absence of respiratory depression. The pupils are midposition and reactive to light. Nystagmus at rest, repetitive motor movements, myoclonus (shivering) and muscle rigidity on stimulation are characteristic findings. Frequently vomiting and hypersalivation are part of the picture. Most pa-
Normal or sluggish
Vomiting (central), hypersalivation
tients are communicative and ambulatory within 30 minutes to an hour, although they manifest all the signs and symptoms of the low dose state on awakening. One to two hours of observation are required from the time of admission until the patient returns with friends to the auditorium or
stadium. The patient who has taken orally a high dose of phencyclidine either accidentally or as a suicide attempt usually presents at the emergency room. The two children included in this series presented with apnea, although in the adult patients where information is available respirations were normal THE WESTERN JOURNAL OF MEDICINE
347
PHENCYCLIDINE
and the blood pressure was normal or high. While pupil size varied, the pupillary light reflex was intact. Opisthotonic posturing was seen in one child over a six hour period, and generalized seizure activity has been observed in adult patients. Nystagmus at rest, vomiting and hypersalivation are, again, seen during the comatose period. The most characteristic feature of high dose oral ingestion is the prolonged recovery phase, marked by alternating periods of sleep and waking, misperceptions, disorientation, hallucinatory phenomena and the clinical picture of the low dose state. Patients have been comatose for periods of up to 12 hours and have required several days for recovery to normal.
Differential Diagnosis The low dose state is frequently interpreted as secondary to an unknown psychedelic drug. The absence of mydriasis and the presence of gross ataxia and horizontal and vertical nystagmus are diagnostic of a phencyclidine intoxication. The moderate dose state may be interpreted, initially, as a sedative-hypnotic overdose. However, the presence of hypertension and hyperreflexia (deep tendon reflexes or DTR'S) and the absence of prominent respiratory depression differentiate the phencyclidine intoxicated state from sedative-hypnotic overdose. Cases involving ingestion of high doses which present as undiagnosed coma may be difficult to differentiate from other causes. Again if hypertension is evident and there is no significant depression of respiration, sedative-hypnotic overdose can be ruled out. If, in addition, opisthotonic posturing is present in a child or seizure activity in an adult, a phencyclidine intoxication should be suspected. If a patient is in status epilepticus or in a postictal state, the underlying cause may be difficult to surmise. The characteristic prolonged recovery phase is diagnostic of phencyclidine intoxication.
Management, Treatment The key to management of the low dose acute intoxicated state is sensory isolation with observation at a distance. Exacerbation of clinical symptoms is seen even with minimal verbal or physical stimulation. The patient should be placed on a cushioned surface of the floor in a quiet room with a monitor present. Protection from self-harm may also be necessary. Most patients 348
NOVEMBER 1975 * 123 * 5
are able to be released to family or friends within one hour. In a patient who presents with the moderate dose state, respiratory status and blood pressure should be monitored, with close observation for clonic movements or muscle rigidity which usually precede seizure activity. Again, sensory stimulation should be controlled and minimized. On recovery from the short period of coma or stupor, the patient will require continued sensory isolation and protection from self-harm for approximately one hour. If seizure activity does intercede, judicious intravenous administration of diazepam (Valiums) in 2 to 3 mg increments is indicated. Respirations should be closely monitored postadministration. The general principles of management of coma would apply to high dose acute intoxication with phencyclidine. Closely monitoring respirations and blood pressure, and observing the patient for seizure activity or its prodromata would be indicated. Endotracheal intubation may be difficult and may precipitate laryngeal spasm. Gastric lavage is indicated in view of the large quantities of phencyclidine which have been recovered from the gastric contents in fatal cases. Diazepam carefully administered in increments of 2 to 3 mg intravenously with postadministration observation of respirations is indicated in the event of generalized seizure activity. Diazoxide was reported to be effective in lowering blood pressure during a hypertensive crisis thought to be secondary to phencyclidine.10 The patient may remain comatose for a period of 12 hours or more. The principles of sensory isolation and protection from self-harm apply to the prolonged recovery period which may last several days and require admission to a psychiatric unit.
Fatalities Fifteen deaths associated with phencyclidine, and previously unreported, occurred in California between 1970 and 1975. Five of these deaths occurred during the period January 1974 to July 1975. In all cases analysis of body fluids for toxicology showed the presence of phencyclidine and the absence of any other chemical agent. Most of these deaths appear to represent accidents or suicides involving a pharmacological overdose. In some cases, however, the levels of phencyclidine in the blood and urine and the circumstances of
PHENCYCLIDINE
the death suggest that death resulted from the behavioral toxicity of phencyclidine. In the cases with high blood and urine levels, the associated presence of up to 185 mg of phencyclidine in the gastric contents points to an oral route of self-administration. In one case bloody fluid was noted in the mouth and nose which may have resulted from seizure activity. It is still unclear whether oral doses in the range of 150 to 200 mg or more, which were estimated to be involved in these cases, produce primary respiratory depression. Generalized seizure activity with postictal depression or hypoxia may be the precipitating factor in the death of these persons. Interviews with chronic, daily users of phencyclidine do not support the idea that tolerance develops to the behavioral effects of this agent. Behavioral toxicity is consistent with the lower blood and urine levels found in four cases where the immediate cause of death was asphyxiation on drowning. Chronic users report that friends have died while intoxicated by drowning, automobile accidents and fire. Gross ataxia, catatonic rigidity, misperception or analgesia may interfere with a person's ability to drive, swim, flee from a fire or sense imminent danger.
respiratory depression and seizure activity has yet to be documented with clinical findings in cases involving potentially lethal doses of the drug. Eastman and Cohen have recently reported a case involving a 13-year-old boy in which a hypertensive crisis was followed by an intracerebral hemorrhage and death.'0 There was no autopsy evidence of cerebral hemorrhage or hypertensive encephalopathy in the fatalities summarized. Potentiation of the stimulant or depressant effects of phencyclidine in huimans by other chemical agents is also an open question. While we have no familiarity with the intensity or spectrum of effects seen when phencyclidine is administered in comparable high doses, this becomes a critical question when central nervous system depressants are administered to control seizure activity. Judicious use of these agents would appear to be indicated. It is not clear whether symptomatic improvement consistently follows the use of the phenothiazines. In several cases, however, significant hypotension has resulted from the administration of therapeutic dosages of the phenothiazines. By 1964 more than 1,000 patients had received phencyclidine as an investigational drug and no evidence of acute cellular toxicity was reported."
Discussion
Conclusion
The central question of the occurrence of primary respiratory depression in fatal high dose phencyclidine ingestions in adults remains unanswered. Blood levels in fatal cases have been comparable to the level reported in one patient who presented with status epilepticus (0.70 mg per 100 ml)9 and the level in the single high dose case seen by the authors (0.37 mg per 100 ml). The former patient died four days after admission with autopsy evidence of severe anoxic encephalopathy and indications of progressive hepatic and renal failure. In the latter case no phencyclidine was detectable in the blood 71/2 hours after admission, although the patient remained comatose with no significant change in respiratory function or seizure activity for 10 hours. In a third case, where blood levels were not obtained, the patient also presented in status epilepticus. The 13 hour period of coma was marked by intermittent, generalized seizure activity with respiratory depression evident only after reiterative seizures. The information available is incomplete and the relationship between blood levels,
In contrast to its pronounced behavioral and central nervous system toxicity, phencyclidine parades as a "mild" psychedelic drug on the street. It has become one of the most frequently used main ingredients of street drug preparations. Further investigation of the cellular toxicity and neuropsychological dysfunction associated with chronic daily use of phencyclidine is indicated. REFERENCES 1. Radcliff BE: Personal communication 2. Reynolds P: Personal communication 3. Chen G, Ensor C, Russell D, et al: The pharmacology of l-(l-phenylcyclohexyl) piperidine HCL. J Pharmacol Exp Ther 127:241-250, May 1959 4. Greifenstein FE, Yoshitake J, DeVault M, et al: A study of a l-aryl cyclo hexyl amine for anesthesia. Anesth Analg 37:283294, Sep-Oct 1958 5. Liden CB, Lovejoy FH Jr, Costello CE: Phencyclidine (Sernylan) poisoning. J Pediatr 83:844-845, Nov 1973 6. Stein JI: Phencyclidine induced psychosis-The need to avoid unnecessary sensory influx. Military Med 138:590-591, Sep 1973 7. Highland General Hospital, Oakland, California: Personal communication 8. Davis W, Ezekiel G: Personal communication 9. Kessler GF Jr, Demers LM, Berlin C, et al: Phencyclidine and fatal status epilepticus. N Engl J Med 291:979, Oct 1974 10. Eastman JW, Cohen SN: Hypertensive crisis and death associated with phencyelidine poisoning. JAMA 231:1270-1271, Mar 24, 1975 11. Domino EF: Neurobiology of phencydidine (Sernyl), a drug with an unusual spectrum of pharmacological activity. Int Rev Neurobiol 6:303-347, 1964
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