CONCEPTS, COMPONENTS, AND CONFIGURATIONS
Phencyclidine Overdose: An Emerging Concept of Management Regine Aronow, MD* Alan K. Done, MD t Detroit, Michigan
Emergency physicians should be prepared to treat overdosage from phencyclidine, a common street drug abused throughout North America. A dearth of laboratory resources to establish the diagnosis makes it essential that diagnoses include awareness of symptomatology. A specific therapeutic approach utilizing ion-trapping by continuous gastric sucUoning and acidification of urine and/or blood can be used successfully to treat these patients. Aronow R, Done AK: Phen-
cyclidine overdose: an emerging concept of management. JACEP 7:56-59, February 1978. drug abuse, phencyclidine; phencycfidine, overdose.
INTRODUC'nON There has been a recent nationwide effort to alert people generally, a n d emergency personnel in particular, to the overdosage problems caused by phencyclidine (PCP), a currently popular street drug of abuse. This has been accompanied by only vague and relatively ineffectual references 1-3 to m a n a g e m e n t , about which there is little in the medical literature. Our recent studies, presented elsewhere, 4 provide a rationale for t r e a t m e n t based upon detailed pharmacokinetic study, but the r e l e v a n t information has, as yet, received only limited dissemination. It seems desirable to b r i n g it specifically to the a t t e n t i o n of emergency physicians p e n d i n g further elaboration and the results of ongoing investigations. This report is intended to be a brief summary, h a v i n g practical and immediate usefulness to those who must t r e a t this most serious and unu s u a l type of poisoning. A d d i t i o n a l i n f o r m a t i o n a n d d o c u m e n t a t i o n will be available in a later publication.
PCP HISTORY Phencyclidine was investigated as an analgesic-anesthetic a g e n t in the late 1950s and early 1960s but was discarded for h u m a n use because of severe dysphoric effects. 5 Since 1967, it has been m a r k e t e d only as a sedative and tranquilizer for n o n h u m a n primates u n d e r the n a m e Sernylan. At about the same time, it appeared as a street drug in San Francisco. Although the ~'peace pill" did not g a i n p o p u l a r i t y t h e n , it was c o m m o n l y m i s r e p r e s e n t e d as o t h e r psychedelic compounds and has since become popular in its own right. Illicitly m a n u f a c t u r e d PCP has become a major drug of abuse at least in North America the last few years, especially in California, Michigan, Illinois a n d Ohio. Phencyclidine is found on the street in a variety of pill forms, capsules, dust (usually white), amorphous clumps and occasionally as a liquid. The doses From the Poison Control Center, and Division of Clinical Pharmacology and Toxicology't', Children's Hospital of Michigan*t and Department of Pediatrics*t and Pharmacology¢, Wayne State University, Detroit, Michigan. Supported in part by the National Insti-
7:2 (Feb) 1978
tute of Drug Abuse and the State of Michigan Department of Health. Address for reprints: Regine Aronow, MD, Director, Poison Control Center, Children's Hospital of Michigan, 3901 Beaubien Boulevard, Detroit, Michigan 48201.
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seem to range from 1 to 9 mg. It is used mixed w i t h s m o k i n g m a t e r i a l (tobacco, p a r s l e y or m a r i j u a n a ) , sniffed alone, ingested or m a i n l i n e d (less f r e q u e n t l y ) . P h e n c y c l i d i n e is k n o w n u n d e r a confusing variety of n a m e s (Table 1).
Pharmacology P h e n c y c l i d i n e is an arylcycloh e x y l a m i n e c o m p o u n d , closely related to the anesthetic a g e n t ketamine, and considered a sensory blocking a g e n t 2 It has a pKa apparently between 8.6 and 9.4, is highly lipid soluble and is metabolized by the liver with excretion in the urine of m a i n l y the mono-hydroxy-piperidine complex. 4,5 W i t h h i g h doses, much free drug is recoverable in the urine. 5 While it has been stated t h a t the half life is u n d e r one hour, this was with small doses which do not apply to the overdose s i t u a t i o n . % s However, u n i f o r m l y t h e d u r a t i o n of poisoning symptoms has heretofore been i n e x p l i c a b l y , l o n g - - a few to s e v e r a l days in m o s t i n s t a n c e s - even of acute overdose. An i m p o r t a n t a s p e c t of t h i s d r u g ' s p h a r m a c o l o g y r e l a t e s to i t b e i n g a w e a k e l e c t r o l y t e (base) r e a d i l y ionized in a n acid m e d i u m where it becomes trapped because of the i m p e n e t r a b i l i t y of m e m b r a n e s to ions.4, 9 T h i s h a s s e v e r a l conseq u e n c e s t h a t are g e r m a n e to the t h e r a p e u t i c a p p r o a c h h e r e i n described. 4 There is extensive secretion into the gastric acidity and t h e n recircul a t i o n after passage into the more alkaline intestine where less-ionized drug is reabsorbed. This, no doubt, accounts for the prolonged course, as well as the v a c i l l a t i n g clinical picture frequently observed. I o n - t r a p p i n g also occurs strikingly in the urine: the concentration i n u r i n e c a n be i n c r e a s e d from e q u i v a l e n c y w i t h blood to at least 200 t i m e s t h a t i n blood w h e n the u r i n e pH is reduced to below 5. 4 To our knowledge, this is the greatest a l t e r a t i o n of d r u g e x c r e t i o n y e t achieved t h r o u g h u r i n e pH m a n i p u l a t i o n s . W h e n t h e u r i n e is sufficiently acid, diuretics m a y f u r t h e r increase clearance of the drug, but have little effect when urine is not acidified. It is r e a s o n a b l e to a n t i c i p a t e that i n c r e a s i n g acidity of blood relative to cerebrospinal fluid, and the latter relative to i n t r a c e l l u l a r fluid, would also have desirable effects on the distribution of PCP t h r o u g h ion
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tive procedures (gastric s u c t i o n i n g a n d u r i n e a c i d i f i c a t i o n ) were so dramatic as to force the conclusion t h a t dialysis is likely to have a place o n l y in the t r e a t m e n t of p a t i e n t s with renal insufficiency (Table 2).
Table 1 THE MANY NAMES OF PHENCYCLIDINE Angel Dust Tranks Dust Sheets Crystal Surfer Crystal Joints Snorts Hog Scuffle CJ Cadillac KJ Cyclones PCP Soma Peace Mist Peace Weed Goon Supergrass TIC Superweed TAC Rocket Fuel Elephant Tranquilizer
Symptoms The symptoms are dose dependent. Overdose may result from onetime or from chronic use (Table 3).
Complications
Misrepresented & sold as: THC Mescaline Psilocybin
cannabinol cocaine amphetamine
MDA and other drugs. May be combined with LSD.
Table 2 MEAN PCP CLEARANCE RATE (MI Serum/Min) IN 3 PATIENTS WITH SEVERE POISONING Removal Method Urinary excretion at pH Plus furosemide diuresis
pH 66.5 5-6.5 5
Clearance Rate 4 20 53
4 . 5 - 5 ca100
Gastric drainage
30
Peritoneal dialysis
2
t r a p p i n g . While this p o s s i b i l i t y is still being explored, it certainly has been our clinical observation t h a t the m e n t a l and neurological status have improved d r a m a t i c a l l y , long before a n y such changes could be a t t r i b u t e d to increased excretion of the drug. P e r i t o n e a l d i a l y s i s , w i t h or w i t h o u t added a l b u m i n , p r o d u c e d d i a l y s a t e P C P l e v e l s w h i c h were s o m e w h a t g r e a t e r t h a n those in serum, 4 but the efficiency reflected in both m e a s u r e d drug clearance a n d clinical response did not ever rival gastric suctioning or urine acidification. The p o s s i b i l i t y of i m p r o v i n g dialysis by any permissible increase of acidity of the d i a l y s a t e has not been explored because the a l t e r n a -
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W i t h large doses of phencyclidine in our experience a n d t h a t of others,5,1° respiratory depression and even respiratory arrest requiring mechanical assistance up to several days have occurred. More commonly encountered is laryngeal stridor during periods of severe muscle contract i o n s a n d c o n v u l s i o n s , w h i c h may m a k e i n t u b a t i o n p a r t i c u l a r l y difficult2 ~ Increased blood pressure, with the k n o w n sympathomimetic effects of the drug, have occurred in bursts high enough to lead to intracerebral hemorrhage or, in a more sustained state, to h y p e r t e n s i v e encephalopathy. 12 Marked elevation of creatine p h o s p h o k i n a s e l e v e l s as well as myoglobinuria and renal failure have occurred. 13,14 These seem to be related to the i n t e n s i t y and d u r a t i o n of the isometric muscle contractions with possible added effect of the use of r e s t r a i n t s on the patient. H y p e r p y r e x i a also m a y occur. Presistent psychosis is seen, b u t it is u n c l e a r w h e t h e r this is due to the c o n t i n u e d presence of PCP, a n unm a s k i n g of basic personality pathology, or lasting physiological results of the phencyclidine overdose.
Treatment Low dose s y m p t o m a t o l o g y res u l t i n g from a limited exposure can u s u a l l y be h a n d l e d by p l a c i n g the p a t i e n t in a low sensory i n p u t environment (quiet and restricted light), 15 p e r f o r m i n g gastric lavage, a d m i n i s t e r i n g a saline, laxative (15 gm sodium sulfate) and, after one hour to allow for its absorption, continuous gastric drainage until a normal mental and neurological state is achieved. Vital signs should be monitored and careful a t t e n t i o n paid to fluid balance and the maint e n a n e e of a d e q u a t e u r i n a r y flow d u r i n g this period. The p a t i e n t t h e n m a y be put on oral c r a n b e r r y juice and 1 to 2 gm of ascorbic acid four t i m e s a day for the n e x t few days to promote 'acidification of the u r i n e
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Table 3 PHENCYCLIDINE OVERDOSE Dose 5mg Low Dose (For Adults)
Est. Serum Level 20-30 ng/ml
5-10 mg (0.1-0.2 mg/Kg) Moderate Dose
30-100 ng/ml
> 10 mg High Dose
100 ng/ml & up
Symptoms Psychological Changes EEG Findings Agitation & excitement Body image changes Slowed delta Gross incoordination Rhythmic theta Estrangement Blank stare appearance Disorganization of thought activity Catatonic rigidity Negativism & hostility Catalepsy Drowsiness & apathy Hypnagogic Unable to speak Pupils - reactive Feelings of inebriation Horizontal or vertical Amnesia may or may not nystagmus be present for the episode Loss of response to pinprick Flushing Diaphoresis Hyperacousis Coma or stupor (Same as low dose) Slowed delta Eyes remain open May have bursts Pupils in midposition reof theta activity active Nystagmus (any direction) Vomiting Hypersalivation Repetitive motor movements Myoclonous (shivering) Muscle rigidity on stimulation Flushing Diaphoresis Fever Decreased peripheral sensation (pain, touch, position) Hyperacousis Slow delta rhythm Coma (unusually proNo memory of episode Theta - - dysrhythmia longed 12 hrs to days) Eyes closed Pupil size varies - - reactive Hypertension Opisthotonic posturing Decerebrate positioning Repetitive motor movements Muscle rigidity Convulsions (0.5 to 1 mg/Kg) Absent peripheral sensation Decreased or absent deep sensation Decreased or absent gag & corneal reflexes Diaphoresis Hypersalivation Flushing Fever Prolonged recovery phase marked by alternating periods of sleep and waking, misperception, disorientation, "hallucinatory" phenomena and all the clinical picture of the lower dose states
Chronic: usually present as psychiatric problems Anxiety Acute anxiety or agitated state Severe depression Paranoid psychosis * F r o m a u t h o r s ' experience a n d adapted from Li den 1o a n d B u r n s 3
and, hence, i n c r e a s e d excretion of any r e m a i n i n g phencyclidine. The adolescent or adult patient with a history of chronic use, modo r a t e or h i g h - d o s e e x p o s u r e or symptomatology consistent with the l a t t e r should be placed on a n e n e r g e t i c r e g i m e to r e m o v e the phencyclidine t h r o u g h ion-trapping. C a u t i o n s h o u l d be exercised, however, with y o u n g pediatric p a t i e n t s who m a y become comatose w i t h a very small dose of PCP and are also a g r e a t e r r i s k from h y p e r o s m o l a l i t y caused by the t r e a t m e n t . U n f o r t u n a t e l y , few l a b o r a t o r y 7:2 (Feb) 1978
resources are available to establish the definitive diagnoses of PCP overdose. Where possible, such toxicological d e t e r m i n a t i o n s should be used. However, when a clear history implicates PCP or the patient's symptoms and electroencephalogram (EEG) are consistent with such a diagnosis, 1~,17 and toxicological confirmation cannot be immediately obtained, treatm e n t should be instituted. This reco m m e n d a t i o n is made in full recognition t h a t m a n y p a t i e n t s overdosed w i t h P C P m a y be p o l y d r u g users. R e v i e w i n g k n o w n pKas, it appears t h a t s a l i c y l a t e or p h e n o b a r b i t a l ,
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levels of which most hospital laboratories can run, are the only reas o n a b l y a n t i c i p a t e d d r u g s whose excretion would be adversely affected by t h e p u r p o s e f u l a c i d i f i c a t i o n of s e r u m and urine (Emergency Medicine, 8:197-207, 1976). If the p a t i e n t p r e s e n t s with resp i r a t o r y depression, in r e s p i r a t o r y arrest or with laryngeal stridor, int u b a t i o n and m a i n t e n a n c e of respira= tion come first. Convulsions may be controlled by t i t r a t i n g 10 mg doses of diazepam, cautiously. If the patient is extremely agitated, he should be p l a c e d i n a n a r e a of low s e n s o r y 58/35
i n p u t as q u i c k l y as possible. This may necessitate the use of earplugs to cut down the e v e r - p r e s e n t noise l e v e l s of most e m e r g e n c y d e p a r t ments. ~Talking down" has no role in h a n d l i n g these patients. Care m u s t be exercised to see t h a t the p a t i e n t does n o t i n j u r e h i m s e l f as he has, peripheral a n e s t h e s i a and is in a disassociative state. Gastric lavage w i t h at least a liter of h a l f s t r e n g t h saline should t h e n be i n s t i t u t e d even if the drug was s n o r t e d or smoked. T h e f i r s t syringeful of gastric content as well ns the first u r i n e should be sent or s a v e d for t o x i c o l o g i c a l a n a l y s i s . W h e n t h e l a v a g e is c o m p l e t e , a s a l i n e l a x a t i v e should be i n s t i l l e d t h r o u g h the tube. After its absorption, continuous suction m a y be instituted. Anticipate c o n t i n u i n g this for two to three days after the pat i e n t gains consciousness. Vital signs s h o u l d be monitored every 15 m i n u t e s while the p a t i e n t is c o m a t o s e a n d blood p r e s s u r e m o n i t o r e d t h r o u g h o u t the hospital course. Diazoxide (Hyperstat) may be used to control m a r k e d hypertension. Careful a t t e n t i o n m u s t be given to fluid balance so there will be good urine flow. Blood pH, blood gases and electrolytes m u s t be monitored with special, c o n c e r n a b o u t p o t a s s i u m . Hypokalemia will make it more difficult to acidify the urine. The goal now will be to reduce the urine pH to 5 or lower. An indwelling catheter should be in place so careful assessment of u r i n e flow and urine pH can be made. If a pH meter is available, it should be used. Otherwise fresh nitrazine paper can be used. There are various other ways to acidify urine, but we have used ammonium chloride (approximately •2.75 m E q / K g / d o s e ) iz/ c o n j u n c t i o n with ascorbic acid (2 gm/500 cc IV f l u i d q 6 h o u r s ) . The a m m o n i u m chloride is dissolved in 60 cc of saline and put down the gastric tube which is then clamped for one hour. This is repeated every six hours u n t i l the u r i n e pH is below 5. If the p a t i e n t vomits the dose, it is repeated. Once the desired urine pH is achieved, or t h e blood t o t a l c a r b o n d i o x i d e reaches 18-20 mEq/liter, repeat adm i n i s t r a t i o n of a m m o n i u m chloride is dictated by a rise in these indices. U s u a l l y two doses of a m m o n i u m chloride in conjunction with the int r a v e n o u s use of ascorbic acid has b r o u g h t the d e s i r e d r e s u l t . U p o n a c h i e v i n g a u r i n e pH below 5, furosemide (20-40 mg IM or IV) is
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given. F r e q u e n t l y , after t h e f i r s t diuresis the p a t i e n t ' s level of consciousness has m a r k e d l y improved. Occasionally, a second dose has been a d m i n i s t e r e d when the p a t i e n t ' s fluids and electrolytes are in balance. The ascorbic acid is c o n t i n u e d throughout the hospital stay, being administered orally when the gastric suctioning is discontinued. The pat i e n t is also encouraged to d r i n k several glasses of cranberry juice daily, which is excreted as hippuric acid. A p a t i e n t who is in a coma should be c o n t i n u e d on a course of u r i n a r y acidification for at least a week after consciousness has been regained. Patients requiring respiratory assistance, in deep coma, or status epilepticus should have their blood pH lowered more r a p i d l y so as to clear the central nervous system and s p i n a l fluid of p h e n c y c l i d i n e , We have used a m m o n i u m chloride int r a v e n o u s l y (2.75 m E q / k g as a 1%-2% c o n c e n t r a t i o n i n s a l i n e ) ( Q u a d r a t e -21.4% sol a m m o n i u m chloride) for this purpose. Precise and repeated m o n i t o r i n g of the patient's blood pH, blood gases, blood urea nitrogen (BUN), blood a m m o n i a levels and electrolytes m u s t be used d u r i n g this procedure. The EEG may be used to assist in the e v a l u a t i o n of the patient. Our experience 'indicates t h a t the E E G can predict the p a t i e n t ' s improved status before it is clinically evident. Manifestations or complications t h a t m a y r e q u i r e a d d i t i o n a l treatm e n t are generally m a n a g e d symptomatically. The use of b a r b i t u r a t e s is to be avoided as synergistic dep r e s s a n t effects m a y occur. Hypot e n s i o n m a y occur with the use of chlorpromazine. T h i s a p p r o a c h to t r e a t m e n t (ion-trapping to enhance the excretion of the drug) has been successful in every p a t i e n t in whom we have used it, including one who had been on r e s p i r a t o r y a s s i s t a n c e for n i n e days before the t h e r a p y was instituted. Patients recover from an extreme overdose in a p a t t e r n of cont i n u i n g i m p r o v e m e n t w i t h o u t the p r o l o n g e d v a c i l l a t i n g course s e e n while on supportive care alone.
REFERENCES 1. Phencyclidine Communication To Emergency Departments, National Institute of Drug Abuse, December, 1977.
2. Dorand R: Phencyclidine Ingestion: Therapy Review, South Med J 70:117119, 1977.
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3. Burns RS, Lerner SE: Management and Treatment of Acute Phencyclidine In. toxications, in Acute Drug Emergencies Bourne PG (ed), New York, Academic Press, 1976, pp 297-305. 4. Done AK, Aronow R, Miceli JN, Lia DCK: Pharmacokinetic Observations ia the Treatment of Phencyclidine Poison. ing, in Management of the Poisoned Patient p 79-95 Rumack BH, Temple AR (eds), Princeton New Jersey, Science Press, 1977, p 79-95. 5. Munch JC: Phencyclidine: pharmacol. ogy and toxicology. Bulletin on Narcotics 26:9-17, 1974. 6. Domino EF, Luby ED: Abnormal mental states induced by PCP as a model for schizophrenia, in Psychopathology and Psychopharmacology, Cole JO, Freedman AM, Friedhoff AJ, (eds), Baltimore Johns Hopkins University Press, 1972, pp 37-50. 7. Lin DCK, Fentiman AF Jr, Foltz RL, et al: Quantification of phencyclidine in body fluids by gas chromatology chemical ionization mass spectrometry and identification of two metabolites. Biomed Mass Spectrom 2:206-214, 1975. 8. Domino EF: Neurobiology of phencyclidine (Sernyl): A drug with an unusual spectrum of pharmacological activity. Int Rev Neurobiol 6:303-347, 1964. 9. Goldstein A, Aronow L, Kalman SM: Molecular mechanisms of drug action in Principles of Drug Action: The Basis of Pharmacology, ed 2. New York, John Wiley & Sons, 1974, pp 19~22. 10. Liden CB, Lovejoy FH, Costello CE: Phencyclidine: nine cases of poisoning. JAMA 234:513-516, 1975. 11. Burns RS, Lerner SE, Corrado R, et al: Phencyclidine - - states of acute intoxication and fatalities. West J Med 123:345-349, 1975. 12. Eastman JW, Cohen SN: Hypertensive crisis and death associated with phencyclidine poisoning. J A M A 231: 1270-1271, 1975. 13. Dandavino R, Friborg J, Beaudry C, et al: Un cas d'intoxication aigu~" a la phencyclidine avec atteinte musculaire importante et insuffisance r~nale aiguh'. L'Union Medicale du Canada 104:57~60, 1975. 14. Goode DJ, Meltzer HY: The role of isometric muscle tension in the production of muscle toxicity by phencyclidine and r e s t r a i n t stress. Psychopharmacologia 42:105-108, 1975. 15. Stein J: Phencyclidine-induced psychosis: the need to avoid unnecessary sensory influx. Milit Med 138-'590-591, 1973. 16. Rodin EA, Luby ED, Meyer JS: Electroencephalographic findings associated with sernyl infusion. Electroencephalogr Clin Neurophysiol 11:796-798, 1959. 17. Stockard JJ, Werner SS, Aalbers JA, et al: Electroencephal0graphic findings in phencyclidine intoxication. Arch Neurol 33:200-204, 1976.
7:2 (Feb) 1978
Phencyclidine Overdose: An Emerging Concept of Management Regine Aronow, MD* Alan K. Done, MD t Detroit, Michigan
Emergency physicians should be prepared to treat overdosage from phencyclidine, a common street drug abused throughout North America. A dearth of laboratory resources to establish the diagnosis makes it essential that diagnoses include awareness of symptomatology. A specific therapeutic approach utilizing ion-trapping by continuous gastric sucUoning and acidification of urine and/or blood can be used successfully to treat these patients. Aronow R, Done AK: Phen-
cyclidine overdose: an emerging concept of management. JACEP 7:56-59, February 1978. drug abuse, phencyclidine; phencycfidine, overdose.
INTRODUC'nON There has been a recent nationwide effort to alert people generally, a n d emergency personnel in particular, to the overdosage problems caused by phencyclidine (PCP), a currently popular street drug of abuse. This has been accompanied by only vague and relatively ineffectual references 1-3 to m a n a g e m e n t , about which there is little in the medical literature. Our recent studies, presented elsewhere, 4 provide a rationale for t r e a t m e n t based upon detailed pharmacokinetic study, but the r e l e v a n t information has, as yet, received only limited dissemination. It seems desirable to b r i n g it specifically to the a t t e n t i o n of emergency physicians p e n d i n g further elaboration and the results of ongoing investigations. This report is intended to be a brief summary, h a v i n g practical and immediate usefulness to those who must t r e a t this most serious and unu s u a l type of poisoning. A d d i t i o n a l i n f o r m a t i o n a n d d o c u m e n t a t i o n will be available in a later publication.
PCP HISTORY Phencyclidine was investigated as an analgesic-anesthetic a g e n t in the late 1950s and early 1960s but was discarded for h u m a n use because of severe dysphoric effects. 5 Since 1967, it has been m a r k e t e d only as a sedative and tranquilizer for n o n h u m a n primates u n d e r the n a m e Sernylan. At about the same time, it appeared as a street drug in San Francisco. Although the ~'peace pill" did not g a i n p o p u l a r i t y t h e n , it was c o m m o n l y m i s r e p r e s e n t e d as o t h e r psychedelic compounds and has since become popular in its own right. Illicitly m a n u f a c t u r e d PCP has become a major drug of abuse at least in North America the last few years, especially in California, Michigan, Illinois a n d Ohio. Phencyclidine is found on the street in a variety of pill forms, capsules, dust (usually white), amorphous clumps and occasionally as a liquid. The doses From the Poison Control Center, and Division of Clinical Pharmacology and Toxicology't', Children's Hospital of Michigan*t and Department of Pediatrics*t and Pharmacology¢, Wayne State University, Detroit, Michigan. Supported in part by the National Insti-
7:2 (Feb) 1978
tute of Drug Abuse and the State of Michigan Department of Health. Address for reprints: Regine Aronow, MD, Director, Poison Control Center, Children's Hospital of Michigan, 3901 Beaubien Boulevard, Detroit, Michigan 48201.
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seem to range from 1 to 9 mg. It is used mixed w i t h s m o k i n g m a t e r i a l (tobacco, p a r s l e y or m a r i j u a n a ) , sniffed alone, ingested or m a i n l i n e d (less f r e q u e n t l y ) . P h e n c y c l i d i n e is k n o w n u n d e r a confusing variety of n a m e s (Table 1).
Pharmacology P h e n c y c l i d i n e is an arylcycloh e x y l a m i n e c o m p o u n d , closely related to the anesthetic a g e n t ketamine, and considered a sensory blocking a g e n t 2 It has a pKa apparently between 8.6 and 9.4, is highly lipid soluble and is metabolized by the liver with excretion in the urine of m a i n l y the mono-hydroxy-piperidine complex. 4,5 W i t h h i g h doses, much free drug is recoverable in the urine. 5 While it has been stated t h a t the half life is u n d e r one hour, this was with small doses which do not apply to the overdose s i t u a t i o n . % s However, u n i f o r m l y t h e d u r a t i o n of poisoning symptoms has heretofore been i n e x p l i c a b l y , l o n g - - a few to s e v e r a l days in m o s t i n s t a n c e s - even of acute overdose. An i m p o r t a n t a s p e c t of t h i s d r u g ' s p h a r m a c o l o g y r e l a t e s to i t b e i n g a w e a k e l e c t r o l y t e (base) r e a d i l y ionized in a n acid m e d i u m where it becomes trapped because of the i m p e n e t r a b i l i t y of m e m b r a n e s to ions.4, 9 T h i s h a s s e v e r a l conseq u e n c e s t h a t are g e r m a n e to the t h e r a p e u t i c a p p r o a c h h e r e i n described. 4 There is extensive secretion into the gastric acidity and t h e n recircul a t i o n after passage into the more alkaline intestine where less-ionized drug is reabsorbed. This, no doubt, accounts for the prolonged course, as well as the v a c i l l a t i n g clinical picture frequently observed. I o n - t r a p p i n g also occurs strikingly in the urine: the concentration i n u r i n e c a n be i n c r e a s e d from e q u i v a l e n c y w i t h blood to at least 200 t i m e s t h a t i n blood w h e n the u r i n e pH is reduced to below 5. 4 To our knowledge, this is the greatest a l t e r a t i o n of d r u g e x c r e t i o n y e t achieved t h r o u g h u r i n e pH m a n i p u l a t i o n s . W h e n t h e u r i n e is sufficiently acid, diuretics m a y f u r t h e r increase clearance of the drug, but have little effect when urine is not acidified. It is r e a s o n a b l e to a n t i c i p a t e that i n c r e a s i n g acidity of blood relative to cerebrospinal fluid, and the latter relative to i n t r a c e l l u l a r fluid, would also have desirable effects on the distribution of PCP t h r o u g h ion
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tive procedures (gastric s u c t i o n i n g a n d u r i n e a c i d i f i c a t i o n ) were so dramatic as to force the conclusion t h a t dialysis is likely to have a place o n l y in the t r e a t m e n t of p a t i e n t s with renal insufficiency (Table 2).
Table 1 THE MANY NAMES OF PHENCYCLIDINE Angel Dust Tranks Dust Sheets Crystal Surfer Crystal Joints Snorts Hog Scuffle CJ Cadillac KJ Cyclones PCP Soma Peace Mist Peace Weed Goon Supergrass TIC Superweed TAC Rocket Fuel Elephant Tranquilizer
Symptoms The symptoms are dose dependent. Overdose may result from onetime or from chronic use (Table 3).
Complications
Misrepresented & sold as: THC Mescaline Psilocybin
cannabinol cocaine amphetamine
MDA and other drugs. May be combined with LSD.
Table 2 MEAN PCP CLEARANCE RATE (MI Serum/Min) IN 3 PATIENTS WITH SEVERE POISONING Removal Method Urinary excretion at pH Plus furosemide diuresis
pH 66.5 5-6.5 5
Clearance Rate 4 20 53
4 . 5 - 5 ca100
Gastric drainage
30
Peritoneal dialysis
2
t r a p p i n g . While this p o s s i b i l i t y is still being explored, it certainly has been our clinical observation t h a t the m e n t a l and neurological status have improved d r a m a t i c a l l y , long before a n y such changes could be a t t r i b u t e d to increased excretion of the drug. P e r i t o n e a l d i a l y s i s , w i t h or w i t h o u t added a l b u m i n , p r o d u c e d d i a l y s a t e P C P l e v e l s w h i c h were s o m e w h a t g r e a t e r t h a n those in serum, 4 but the efficiency reflected in both m e a s u r e d drug clearance a n d clinical response did not ever rival gastric suctioning or urine acidification. The p o s s i b i l i t y of i m p r o v i n g dialysis by any permissible increase of acidity of the d i a l y s a t e has not been explored because the a l t e r n a -
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W i t h large doses of phencyclidine in our experience a n d t h a t of others,5,1° respiratory depression and even respiratory arrest requiring mechanical assistance up to several days have occurred. More commonly encountered is laryngeal stridor during periods of severe muscle contract i o n s a n d c o n v u l s i o n s , w h i c h may m a k e i n t u b a t i o n p a r t i c u l a r l y difficult2 ~ Increased blood pressure, with the k n o w n sympathomimetic effects of the drug, have occurred in bursts high enough to lead to intracerebral hemorrhage or, in a more sustained state, to h y p e r t e n s i v e encephalopathy. 12 Marked elevation of creatine p h o s p h o k i n a s e l e v e l s as well as myoglobinuria and renal failure have occurred. 13,14 These seem to be related to the i n t e n s i t y and d u r a t i o n of the isometric muscle contractions with possible added effect of the use of r e s t r a i n t s on the patient. H y p e r p y r e x i a also m a y occur. Presistent psychosis is seen, b u t it is u n c l e a r w h e t h e r this is due to the c o n t i n u e d presence of PCP, a n unm a s k i n g of basic personality pathology, or lasting physiological results of the phencyclidine overdose.
Treatment Low dose s y m p t o m a t o l o g y res u l t i n g from a limited exposure can u s u a l l y be h a n d l e d by p l a c i n g the p a t i e n t in a low sensory i n p u t environment (quiet and restricted light), 15 p e r f o r m i n g gastric lavage, a d m i n i s t e r i n g a saline, laxative (15 gm sodium sulfate) and, after one hour to allow for its absorption, continuous gastric drainage until a normal mental and neurological state is achieved. Vital signs should be monitored and careful a t t e n t i o n paid to fluid balance and the maint e n a n e e of a d e q u a t e u r i n a r y flow d u r i n g this period. The p a t i e n t t h e n m a y be put on oral c r a n b e r r y juice and 1 to 2 gm of ascorbic acid four t i m e s a day for the n e x t few days to promote 'acidification of the u r i n e
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Table 3 PHENCYCLIDINE OVERDOSE Dose 5mg Low Dose (For Adults)
Est. Serum Level 20-30 ng/ml
5-10 mg (0.1-0.2 mg/Kg) Moderate Dose
30-100 ng/ml
> 10 mg High Dose
100 ng/ml & up
Symptoms Psychological Changes EEG Findings Agitation & excitement Body image changes Slowed delta Gross incoordination Rhythmic theta Estrangement Blank stare appearance Disorganization of thought activity Catatonic rigidity Negativism & hostility Catalepsy Drowsiness & apathy Hypnagogic Unable to speak Pupils - reactive Feelings of inebriation Horizontal or vertical Amnesia may or may not nystagmus be present for the episode Loss of response to pinprick Flushing Diaphoresis Hyperacousis Coma or stupor (Same as low dose) Slowed delta Eyes remain open May have bursts Pupils in midposition reof theta activity active Nystagmus (any direction) Vomiting Hypersalivation Repetitive motor movements Myoclonous (shivering) Muscle rigidity on stimulation Flushing Diaphoresis Fever Decreased peripheral sensation (pain, touch, position) Hyperacousis Slow delta rhythm Coma (unusually proNo memory of episode Theta - - dysrhythmia longed 12 hrs to days) Eyes closed Pupil size varies - - reactive Hypertension Opisthotonic posturing Decerebrate positioning Repetitive motor movements Muscle rigidity Convulsions (0.5 to 1 mg/Kg) Absent peripheral sensation Decreased or absent deep sensation Decreased or absent gag & corneal reflexes Diaphoresis Hypersalivation Flushing Fever Prolonged recovery phase marked by alternating periods of sleep and waking, misperception, disorientation, "hallucinatory" phenomena and all the clinical picture of the lower dose states
Chronic: usually present as psychiatric problems Anxiety Acute anxiety or agitated state Severe depression Paranoid psychosis * F r o m a u t h o r s ' experience a n d adapted from Li den 1o a n d B u r n s 3
and, hence, i n c r e a s e d excretion of any r e m a i n i n g phencyclidine. The adolescent or adult patient with a history of chronic use, modo r a t e or h i g h - d o s e e x p o s u r e or symptomatology consistent with the l a t t e r should be placed on a n e n e r g e t i c r e g i m e to r e m o v e the phencyclidine t h r o u g h ion-trapping. C a u t i o n s h o u l d be exercised, however, with y o u n g pediatric p a t i e n t s who m a y become comatose w i t h a very small dose of PCP and are also a g r e a t e r r i s k from h y p e r o s m o l a l i t y caused by the t r e a t m e n t . U n f o r t u n a t e l y , few l a b o r a t o r y 7:2 (Feb) 1978
resources are available to establish the definitive diagnoses of PCP overdose. Where possible, such toxicological d e t e r m i n a t i o n s should be used. However, when a clear history implicates PCP or the patient's symptoms and electroencephalogram (EEG) are consistent with such a diagnosis, 1~,17 and toxicological confirmation cannot be immediately obtained, treatm e n t should be instituted. This reco m m e n d a t i o n is made in full recognition t h a t m a n y p a t i e n t s overdosed w i t h P C P m a y be p o l y d r u g users. R e v i e w i n g k n o w n pKas, it appears t h a t s a l i c y l a t e or p h e n o b a r b i t a l ,
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levels of which most hospital laboratories can run, are the only reas o n a b l y a n t i c i p a t e d d r u g s whose excretion would be adversely affected by t h e p u r p o s e f u l a c i d i f i c a t i o n of s e r u m and urine (Emergency Medicine, 8:197-207, 1976). If the p a t i e n t p r e s e n t s with resp i r a t o r y depression, in r e s p i r a t o r y arrest or with laryngeal stridor, int u b a t i o n and m a i n t e n a n c e of respira= tion come first. Convulsions may be controlled by t i t r a t i n g 10 mg doses of diazepam, cautiously. If the patient is extremely agitated, he should be p l a c e d i n a n a r e a of low s e n s o r y 58/35
i n p u t as q u i c k l y as possible. This may necessitate the use of earplugs to cut down the e v e r - p r e s e n t noise l e v e l s of most e m e r g e n c y d e p a r t ments. ~Talking down" has no role in h a n d l i n g these patients. Care m u s t be exercised to see t h a t the p a t i e n t does n o t i n j u r e h i m s e l f as he has, peripheral a n e s t h e s i a and is in a disassociative state. Gastric lavage w i t h at least a liter of h a l f s t r e n g t h saline should t h e n be i n s t i t u t e d even if the drug was s n o r t e d or smoked. T h e f i r s t syringeful of gastric content as well ns the first u r i n e should be sent or s a v e d for t o x i c o l o g i c a l a n a l y s i s . W h e n t h e l a v a g e is c o m p l e t e , a s a l i n e l a x a t i v e should be i n s t i l l e d t h r o u g h the tube. After its absorption, continuous suction m a y be instituted. Anticipate c o n t i n u i n g this for two to three days after the pat i e n t gains consciousness. Vital signs s h o u l d be monitored every 15 m i n u t e s while the p a t i e n t is c o m a t o s e a n d blood p r e s s u r e m o n i t o r e d t h r o u g h o u t the hospital course. Diazoxide (Hyperstat) may be used to control m a r k e d hypertension. Careful a t t e n t i o n m u s t be given to fluid balance so there will be good urine flow. Blood pH, blood gases and electrolytes m u s t be monitored with special, c o n c e r n a b o u t p o t a s s i u m . Hypokalemia will make it more difficult to acidify the urine. The goal now will be to reduce the urine pH to 5 or lower. An indwelling catheter should be in place so careful assessment of u r i n e flow and urine pH can be made. If a pH meter is available, it should be used. Otherwise fresh nitrazine paper can be used. There are various other ways to acidify urine, but we have used ammonium chloride (approximately •2.75 m E q / K g / d o s e ) iz/ c o n j u n c t i o n with ascorbic acid (2 gm/500 cc IV f l u i d q 6 h o u r s ) . The a m m o n i u m chloride is dissolved in 60 cc of saline and put down the gastric tube which is then clamped for one hour. This is repeated every six hours u n t i l the u r i n e pH is below 5. If the p a t i e n t vomits the dose, it is repeated. Once the desired urine pH is achieved, or t h e blood t o t a l c a r b o n d i o x i d e reaches 18-20 mEq/liter, repeat adm i n i s t r a t i o n of a m m o n i u m chloride is dictated by a rise in these indices. U s u a l l y two doses of a m m o n i u m chloride in conjunction with the int r a v e n o u s use of ascorbic acid has b r o u g h t the d e s i r e d r e s u l t . U p o n a c h i e v i n g a u r i n e pH below 5, furosemide (20-40 mg IM or IV) is
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given. F r e q u e n t l y , after t h e f i r s t diuresis the p a t i e n t ' s level of consciousness has m a r k e d l y improved. Occasionally, a second dose has been a d m i n i s t e r e d when the p a t i e n t ' s fluids and electrolytes are in balance. The ascorbic acid is c o n t i n u e d throughout the hospital stay, being administered orally when the gastric suctioning is discontinued. The pat i e n t is also encouraged to d r i n k several glasses of cranberry juice daily, which is excreted as hippuric acid. A p a t i e n t who is in a coma should be c o n t i n u e d on a course of u r i n a r y acidification for at least a week after consciousness has been regained. Patients requiring respiratory assistance, in deep coma, or status epilepticus should have their blood pH lowered more r a p i d l y so as to clear the central nervous system and s p i n a l fluid of p h e n c y c l i d i n e , We have used a m m o n i u m chloride int r a v e n o u s l y (2.75 m E q / k g as a 1%-2% c o n c e n t r a t i o n i n s a l i n e ) ( Q u a d r a t e -21.4% sol a m m o n i u m chloride) for this purpose. Precise and repeated m o n i t o r i n g of the patient's blood pH, blood gases, blood urea nitrogen (BUN), blood a m m o n i a levels and electrolytes m u s t be used d u r i n g this procedure. The EEG may be used to assist in the e v a l u a t i o n of the patient. Our experience 'indicates t h a t the E E G can predict the p a t i e n t ' s improved status before it is clinically evident. Manifestations or complications t h a t m a y r e q u i r e a d d i t i o n a l treatm e n t are generally m a n a g e d symptomatically. The use of b a r b i t u r a t e s is to be avoided as synergistic dep r e s s a n t effects m a y occur. Hypot e n s i o n m a y occur with the use of chlorpromazine. T h i s a p p r o a c h to t r e a t m e n t (ion-trapping to enhance the excretion of the drug) has been successful in every p a t i e n t in whom we have used it, including one who had been on r e s p i r a t o r y a s s i s t a n c e for n i n e days before the t h e r a p y was instituted. Patients recover from an extreme overdose in a p a t t e r n of cont i n u i n g i m p r o v e m e n t w i t h o u t the p r o l o n g e d v a c i l l a t i n g course s e e n while on supportive care alone.
REFERENCES 1. Phencyclidine Communication To Emergency Departments, National Institute of Drug Abuse, December, 1977.
2. Dorand R: Phencyclidine Ingestion: Therapy Review, South Med J 70:117119, 1977.
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3. Burns RS, Lerner SE: Management and Treatment of Acute Phencyclidine In. toxications, in Acute Drug Emergencies Bourne PG (ed), New York, Academic Press, 1976, pp 297-305. 4. Done AK, Aronow R, Miceli JN, Lia DCK: Pharmacokinetic Observations ia the Treatment of Phencyclidine Poison. ing, in Management of the Poisoned Patient p 79-95 Rumack BH, Temple AR (eds), Princeton New Jersey, Science Press, 1977, p 79-95. 5. Munch JC: Phencyclidine: pharmacol. ogy and toxicology. Bulletin on Narcotics 26:9-17, 1974. 6. Domino EF, Luby ED: Abnormal mental states induced by PCP as a model for schizophrenia, in Psychopathology and Psychopharmacology, Cole JO, Freedman AM, Friedhoff AJ, (eds), Baltimore Johns Hopkins University Press, 1972, pp 37-50. 7. Lin DCK, Fentiman AF Jr, Foltz RL, et al: Quantification of phencyclidine in body fluids by gas chromatology chemical ionization mass spectrometry and identification of two metabolites. Biomed Mass Spectrom 2:206-214, 1975. 8. Domino EF: Neurobiology of phencyclidine (Sernyl): A drug with an unusual spectrum of pharmacological activity. Int Rev Neurobiol 6:303-347, 1964. 9. Goldstein A, Aronow L, Kalman SM: Molecular mechanisms of drug action in Principles of Drug Action: The Basis of Pharmacology, ed 2. New York, John Wiley & Sons, 1974, pp 19~22. 10. Liden CB, Lovejoy FH, Costello CE: Phencyclidine: nine cases of poisoning. JAMA 234:513-516, 1975. 11. Burns RS, Lerner SE, Corrado R, et al: Phencyclidine - - states of acute intoxication and fatalities. West J Med 123:345-349, 1975. 12. Eastman JW, Cohen SN: Hypertensive crisis and death associated with phencyclidine poisoning. J A M A 231: 1270-1271, 1975. 13. Dandavino R, Friborg J, Beaudry C, et al: Un cas d'intoxication aigu~" a la phencyclidine avec atteinte musculaire importante et insuffisance r~nale aiguh'. L'Union Medicale du Canada 104:57~60, 1975. 14. Goode DJ, Meltzer HY: The role of isometric muscle tension in the production of muscle toxicity by phencyclidine and r e s t r a i n t stress. Psychopharmacologia 42:105-108, 1975. 15. Stein J: Phencyclidine-induced psychosis: the need to avoid unnecessary sensory influx. Milit Med 138-'590-591, 1973. 16. Rodin EA, Luby ED, Meyer JS: Electroencephalographic findings associated with sernyl infusion. Electroencephalogr Clin Neurophysiol 11:796-798, 1959. 17. Stockard JJ, Werner SS, Aalbers JA, et al: Electroencephal0graphic findings in phencyclidine intoxication. Arch Neurol 33:200-204, 1976.
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