Cowboy Mac
Bluelighter
- Joined
- Jun 4, 2000
- Messages
- 3,084
It seems like a pertinent time to mention this. When babydoc and I went to reagent test pills in SA for the Enchanted Forest party we teamed up with a group of doctors from the Royal Adelaide Hospital. One of these doctors was Dr. David Caldicott, (aka drplatypus) who among many of our interesting conversations mentioned a GHB antidote called physostigmine. This was the first time I had heard about it, as all the literature I had read stated there was no antidote, however this is not the case. It seems the preferred (and possibly outdated) method is to intubate the person, and wait for the body to metabolise the GHB. The Royal Adelaide is a world leader in this area, and the paper that Dr. David Caldicott has written is copied below.
Original PDF can be downloaded here.[55kb]
Gamma-Hydroxybutyrate Overdose and Physostigmine: Teaching New Tricks to an Old Drug?
Gamma-hydroxybutyrate was introduced as an anesthetic agent in the 1960s and is still used in some countries, despite recognized disadvantages. More recently, it has emerged as a popular recreational drug. We report 3 cases of gamma-hydroxybutyrate overdose, the effects of which were reversed by the administration of low-dose intravenous physostigmine. The origins of this regimen and the case for physostigmine as a potential antidote are described.
[Caldicott DGE, Kuhn M. Gamma-hydroxybutyrate overdose and physostigmine: teaching new tricks to an old drug? Ann EmergMed. January 2001;37:99-102.]
Introduction
Gamma-hydroxybutyrate (GHB) is a water-soluble, naturally occurring, tetracarbon molecule. It has been used for anesthesia, as a treatment for narcolepsy, as an anabolic agent, and more recently as a drug of abuse.1,2 A number of overdose fatalities have been reported, with deaths occurring from profound respiratory depression.3 Simple overdoses can often be managed conservatively,1,2,4
but severe overdoses require endotracheal intubation and ventilation. Sedation may last up to 11 hours,5 and multiple simultaneous presentations may overwhelm emergency department resources.5,6We report the novel use of physostigmine, previously shown to be a safe and
efficacious reversal agent for GHB anesthesia,7,8 as an antidote for severe GHB overdose.
Case Reports
Case 1
A 19-year-old woman presented to the ED comatose and intermittently apneic. She had been systemically well earlier in the day, complaining only of residual pain from recent wisdom teeth extractions, for which she was taking acetaminophen and codeine. During a family reunion, her brother noticed that she was becoming increasingly unresponsive and telephoned the ambulance service. He reported a strong history of recreational drug abuse. In transit to the hospital, the patient’s status deteriorated, with periods of apnea and intermittent bradycardia, hypotension, and bizarre athetoid posturing. Naloxone, 0.8 mg, was administered intravenously without response. On arrival, the patient was apneic, with a Glasgow Coma Scale (GCS) score of 3; with aggressive stimulation, she resumed breathing, her GCS score improved to 10 (eyes [E] =3, verbal [V] =2, and motor [M] =5), and she had sporadic athetoid movements of her upper limbs. Her blood pressure was 130/95 mm Hg, pulse rate was 55 beats/min, respiratory rate was from 0 to 6 breaths/min, temperature was 35.6°C (96.1°F), and SaO2 was 90% on 10 L of oxygen. Her physical examination was otherwise normal. Her blood glucose level was 4.3 mmol/L, and arterial blood gases were unremarkable. A presumptive diagnosis of GHB overdose was made, and with the hope of avoiding endotracheal intubation, physostigmine, 2.0 mg, was administered intravenously over 2 to 3 minutes. Four minutes thereafter, the patient’s condition suddenly improved, with her GCS score increasing to 15. Her heart rate increased transiently to 110 beats/min and then decreased to 80 to 90 beats/min; cardiac monitoring and a subsequent ECG displayed a sinus rhythm without evidence of atrioventricular block. Her blood pressure remained stable, respiratory rate increased to 20 breaths/min, and SaO2 increased to 99%. On recovery, she admitted to having taken GHB earlier in the evening. She was observed for 6 hours and then discharged. A comprehensive urine toxicology screening revealed the presence of opiates, pseudoephedrine, tetrahydrocannibinoids, amphetamines, methamphetamines, and GHB.
Case 2
A 28-year-old man was brought to the ED by friends with whom he had been dancing at a night club. They reported that approximately 21⁄2 hours before presentation, he had taken an unknown quantity of GHB and that he had become increasingly unresponsive during the hour before presentation. On arrival, his GCS score was 6 (E=1, V=1, and M=4); his gag reflex was absent. Monitoring revealed slow atrial fibrillation, with a rate of 50 to 90 beats/min, blood pressure of 145/95 mm Hg, respiratory rate of 0 to 8 breaths/ min, temperature of 35.8°C (96.4°F), and SaO2 of 99% on 10 L of oxygen. He was diaphoretic and had clenching of the fists while extending his arms. His blood glucose level was 5.8 mmol/L, arterial blood gas values were nondiagnostic, and blood alcohol level was 0.08 g/dL. A presumptive diagnosis of GHB overdose was made. A 1.0-mg bolus of physostigmine was administered intravenously without effect and then repeated 5 minutes later. Two minutes thereafter, the patient suddenly sat upright, became aggressive and abusive for 2 to 3 minutes, and then drifted back to sleep but was easily aroused with a GCS score of 11 (E=4, V=2, and M=5) and respiratory rate of 12 to 16 breaths/min. His heart rate, blood pressure, and SaO2 remained stable. His GCS score was 12 about 40 minutes later, when he was incontinent of feces. Five minutes thereafter, he was fully conscious (GCS score of 15) and apologetic. His heart rate spontaneously reverted from atrial fibrillation to sinus rhythm just before his admission for cardiac evaluation and he was discharged the next day without incident. A comprehensive urine toxicology screening revealed only the presence of tetrahydrocannibinoids and GHB.
Case 3
A 24-year-old man was found unconscious at a night club. A friend reported that the patient had used “fantasy” (GHB) approximately 1 hour earlier. In transit, the patient became incontinent of urine and was noted to have fluctuating consciousness, intermittently grinding his teeth and extending his upper limbs while clenching his fists. Naloxone, 0.4 mg, was administered intravenously without response. On arrival, the patient had a GCS score of 3 that increased to 8 with stimulation, blood pressure of 125/65 mm Hg, pulse rate of 72 beats/min, temperature of 34.9°C (94.8°F), and an SaO2 of 99% on 10 L of oxygen. His physical examination was otherwise normal. The patient’s blood glucose level was 5.9 mmol/L, arterial blood gas levels were unremarkable, and the blood alcohol level was undetectable. A diagnosis of GHB overdose was entertained, and the decision was made to administer physostigmine. Physostigmine was administered approximately every 3 minutes in 0.5-mg boluses to a total of 1.5 mg. Continuous monitoring did not reveal any apparent effect of physostigmine on heart rate, blood pressure, or SaO2. Approximately 10 minutes after the first dose of physostigmine, the patient’s condition suddenly improved, with the GCS score increasing to 10 (E=3, V=3, and M=6). Within 15 minutes, he had fully recovered and admitted to using GHB earlier in the evening. He was kept under observation for 51⁄2 hours and then discharged. Urine toxicology screening revealed cannibinoids, 3,4-methylenedioxymethamphetamine, and GHB.
Discussion
GHB has respectable origins as an intravenous hypnotic agent.9 It did not, however, achieve widespread use because of its slow and unpredictable recovery rates.7,8 Henderson and Holmes7 found that physostigmine successfully and safely reversed the effects of GHB, with minimal adverse cholinergic effects. Despite the work of Henderson and Holmes,7 interest in GHB as an anesthetic agent diminished. Recently, GHB has emerged as a recreational drug, and increasing instances of severe overdose have created interest in finding a safe antidote. Although some authors1,2,10 advocate a conservative approach to the management of GHB overdose, they and others11 have noted that the work of Henderson and Holmes7 may indicate a role for physostigmine in the treatment of severely obtunded patients. Physostigmine is a well-known analeptic agent that causes generalized, nonspecific, central nervous system arousal.12 The mechanism of action by which physostigmine reverses GHB is unknown, but it is presumably through central nervous system stimulation because neostigmine (which does not cross the blood brain barrier) is ineffective in reversing the effects of GHB.8 Physostigmine has also been reported to reverse the effect of opiates.13 This effect may have played a role in the recovery of our first patient; however, she denied any opiate ingestion other than the codeine as prescribed, and therefore her obtundation was presumably related to GHB ingestion. Henderson and Holmes7 described a latent period of 2 to 10 minutes between the administration of physostigmine and the recovery of consciousness. This prolonged latent period has caused some to question whether the improvement in mental status after physostigmine administration might simply reflect the rapid recovery that is common after GHB intoxication. However, in the largest reported series of patients with GHB intoxication, 10 the mean time to regain consciousness was 146 minutes after ED presentation; the shortest interval was 16 minutes. Yet all 3 of our patients recovered within 25 minutes of their ED presentation, and conforming with Henderson and Holmes’ observations, all of our patients responded within 10 minutes after physostigmine administration. We therefore believe that physostigmine was instrumental in improving our patients’ levels of consciousness. The prolonged latent period did, however, appear to limit the utility of physostigmine for another patient treated in our ED. This 28-year-old woman presented with combined alcohol (blood alcohol level, 0.11 g/dL) and GHB intoxication. Her GCS score of 3 did not improve with stimulation. She was given 1.0 mg of physostigmine, but after several minutes had elapsed without response, the treating physician became concerned about airway compromise and elected to intubate her without administering drugs. We have subsequently concluded that those patients who remain obtunded despite stimulation may be at risk for airway compromise during the long latency period after physostigmine administration. We therefore recommend that these patients be intubated initially rather than treated with physostigmine. The subsequent role of physostigmine in reversing GHB overdose in intubated patients has yet to be evaluated. Traditional concerns regarding the use of physostigmine as an antidote relate to its previous use for tricyclic antidepressant (TCA) overdoses.12 However, a review of the relevant literature indicates that such concerns may not be well founded. Seizures occurred in 2 of 21 patients treated for TCA overdose in one series,14 but 1 of the 2 patients was subsequently shown to have had an acute cerebrovascular accident, and seizures are a relatively common complication of TCA poisoning alone.13 Adverse cardiac effects have been sporadically cited in conjunction with physostigmine treatment for TCA overdose, 15 but again, it is uncertain whether these complications were caused by the TCAs themselves. Conversely, extensive use of physostigmine as an antidote in other settings has proved to be safe.7Cholinergic symptoms were reported in 2 of the 21patients treated for TCA overdose14 but were of relatively minor significance. Two of our patients had cholinergic side effects: patient 1 had excessive lacrimation, an patient 2 had an episode of fecal incontinence. None of our patients manifested adverse cardiovascular sequelae or evidence of airway compromise caused by increased secretions. Nonetheless, to preempt cholinergic sequelae, pretreatment with atropine before physostigmine administration should be considered.7,8 GHB is an increasingly popular drug of abuse, the dangers of which are compounded by a misconception in the drug-abusing community that GHB is safe. It appears that physostigmine may effectively reverse the effects of GHB, obviating the need for intubation, particularly in those patients who are too obtunded to protect their airway, yet who require rapid sequence induction to facilitate intubation. Because GHB is often consumed in a group setting, the potential exists for several such patients to present simultaneously.5,6Were this to occur, an effective reversal agent might prove extremely useful.
References
OVERDOSE AND PHYSOSTIGMINE
Caldicott & Kuhn
1. Li J, Stokes SA, Woeckener A. A tale of novel intoxication: a review of the effects of gamma-hydroxybutyric acid with recommendations for management. Ann Emerg Med.1998;31:729-736.
2. Li J, Stokes SA, Woeckener A. A tale of novel intoxication: seven cases of gamma-hydroxybutyric acid overdose. Ann Emerg Med. 1998;31:723-728.
3. Food and Drug Administration. Updates: injuries, deaths linked to GHB abuse. FDA Consumer. 1997;(May-June)31:4.
4. Ropero-Miller JD, Goldberger BA. Recreational drugs. Current trends in the 90s. Clin Lab Med. 1998;18:727-46.
5. Harraway T, Stephenson L. Gamma hydroxybutyrate intoxication: the Gold Coast experience. Emerg Med (Australia). 1999;11:45-48.
6. Eckstein M, Henderson SO, DelaCruz P, et al. Gamma hydroxybutyrate (GHB): report of a mass intoxication and review of the literature. Prehosp Emerg Care. 1999;3:357-361.
7. Henderson RS, Holmes CM. Reversal of the anaesthetic action of sodium gamma-hydroxybutyrate. Anaesth Intensive Care. 1976;4:351-354.
8. Holmes CM, Henderson RS. The elimination of pollution by a non inhalational technique. Anaesth Intensive Care. 1978;6:120-124.
9. Laborit H, Buchard F, Laborit G, et al. Emploi du 4-hydroxybutyrate en NA en anesthesie et en reanimation. Agressologie. 1960;1:549.
10. Chin RL, Sporer KA, Cullison B, et al. Clinical course of gamma-hydroxybutyrate overdose. Ann Emerg Med. 1998;31:716-722.
11. Viera AJ, Yates SW. Toxic ingestion of gamma hydroxybutyrate. South Med J. 1999;92:404-405.
12. Callaham M. Tricyclic antidepressant overdose. J Am Coll Emerg Phys. 1979;8:413-425.
13. Weinstock M, Davidson JT, Rosin AJ, et al. Effect of physostigmine on morphine-induced postoperative pain and somnolence. Br J Anaesth. 1982;54:429-433.
14. Newton RW. Physostigmine in the treatment of tricyclic antidepressant overdose. JAMA. 1975;231:941-943.
15. Pentel P, Peterson CD. Asystole complicating physostigmine treatment of tricyclic antidepressant overdose. Ann Emerg Med. 1980;9:588-590.
Original PDF can be downloaded here.[55kb]
Gamma-Hydroxybutyrate Overdose and Physostigmine: Teaching New Tricks to an Old Drug?
Gamma-hydroxybutyrate was introduced as an anesthetic agent in the 1960s and is still used in some countries, despite recognized disadvantages. More recently, it has emerged as a popular recreational drug. We report 3 cases of gamma-hydroxybutyrate overdose, the effects of which were reversed by the administration of low-dose intravenous physostigmine. The origins of this regimen and the case for physostigmine as a potential antidote are described.
[Caldicott DGE, Kuhn M. Gamma-hydroxybutyrate overdose and physostigmine: teaching new tricks to an old drug? Ann EmergMed. January 2001;37:99-102.]
Introduction
Gamma-hydroxybutyrate (GHB) is a water-soluble, naturally occurring, tetracarbon molecule. It has been used for anesthesia, as a treatment for narcolepsy, as an anabolic agent, and more recently as a drug of abuse.1,2 A number of overdose fatalities have been reported, with deaths occurring from profound respiratory depression.3 Simple overdoses can often be managed conservatively,1,2,4
but severe overdoses require endotracheal intubation and ventilation. Sedation may last up to 11 hours,5 and multiple simultaneous presentations may overwhelm emergency department resources.5,6We report the novel use of physostigmine, previously shown to be a safe and
efficacious reversal agent for GHB anesthesia,7,8 as an antidote for severe GHB overdose.
Case Reports
Case 1
A 19-year-old woman presented to the ED comatose and intermittently apneic. She had been systemically well earlier in the day, complaining only of residual pain from recent wisdom teeth extractions, for which she was taking acetaminophen and codeine. During a family reunion, her brother noticed that she was becoming increasingly unresponsive and telephoned the ambulance service. He reported a strong history of recreational drug abuse. In transit to the hospital, the patient’s status deteriorated, with periods of apnea and intermittent bradycardia, hypotension, and bizarre athetoid posturing. Naloxone, 0.8 mg, was administered intravenously without response. On arrival, the patient was apneic, with a Glasgow Coma Scale (GCS) score of 3; with aggressive stimulation, she resumed breathing, her GCS score improved to 10 (eyes [E] =3, verbal [V] =2, and motor [M] =5), and she had sporadic athetoid movements of her upper limbs. Her blood pressure was 130/95 mm Hg, pulse rate was 55 beats/min, respiratory rate was from 0 to 6 breaths/min, temperature was 35.6°C (96.1°F), and SaO2 was 90% on 10 L of oxygen. Her physical examination was otherwise normal. Her blood glucose level was 4.3 mmol/L, and arterial blood gases were unremarkable. A presumptive diagnosis of GHB overdose was made, and with the hope of avoiding endotracheal intubation, physostigmine, 2.0 mg, was administered intravenously over 2 to 3 minutes. Four minutes thereafter, the patient’s condition suddenly improved, with her GCS score increasing to 15. Her heart rate increased transiently to 110 beats/min and then decreased to 80 to 90 beats/min; cardiac monitoring and a subsequent ECG displayed a sinus rhythm without evidence of atrioventricular block. Her blood pressure remained stable, respiratory rate increased to 20 breaths/min, and SaO2 increased to 99%. On recovery, she admitted to having taken GHB earlier in the evening. She was observed for 6 hours and then discharged. A comprehensive urine toxicology screening revealed the presence of opiates, pseudoephedrine, tetrahydrocannibinoids, amphetamines, methamphetamines, and GHB.
Case 2
A 28-year-old man was brought to the ED by friends with whom he had been dancing at a night club. They reported that approximately 21⁄2 hours before presentation, he had taken an unknown quantity of GHB and that he had become increasingly unresponsive during the hour before presentation. On arrival, his GCS score was 6 (E=1, V=1, and M=4); his gag reflex was absent. Monitoring revealed slow atrial fibrillation, with a rate of 50 to 90 beats/min, blood pressure of 145/95 mm Hg, respiratory rate of 0 to 8 breaths/ min, temperature of 35.8°C (96.4°F), and SaO2 of 99% on 10 L of oxygen. He was diaphoretic and had clenching of the fists while extending his arms. His blood glucose level was 5.8 mmol/L, arterial blood gas values were nondiagnostic, and blood alcohol level was 0.08 g/dL. A presumptive diagnosis of GHB overdose was made. A 1.0-mg bolus of physostigmine was administered intravenously without effect and then repeated 5 minutes later. Two minutes thereafter, the patient suddenly sat upright, became aggressive and abusive for 2 to 3 minutes, and then drifted back to sleep but was easily aroused with a GCS score of 11 (E=4, V=2, and M=5) and respiratory rate of 12 to 16 breaths/min. His heart rate, blood pressure, and SaO2 remained stable. His GCS score was 12 about 40 minutes later, when he was incontinent of feces. Five minutes thereafter, he was fully conscious (GCS score of 15) and apologetic. His heart rate spontaneously reverted from atrial fibrillation to sinus rhythm just before his admission for cardiac evaluation and he was discharged the next day without incident. A comprehensive urine toxicology screening revealed only the presence of tetrahydrocannibinoids and GHB.
Case 3
A 24-year-old man was found unconscious at a night club. A friend reported that the patient had used “fantasy” (GHB) approximately 1 hour earlier. In transit, the patient became incontinent of urine and was noted to have fluctuating consciousness, intermittently grinding his teeth and extending his upper limbs while clenching his fists. Naloxone, 0.4 mg, was administered intravenously without response. On arrival, the patient had a GCS score of 3 that increased to 8 with stimulation, blood pressure of 125/65 mm Hg, pulse rate of 72 beats/min, temperature of 34.9°C (94.8°F), and an SaO2 of 99% on 10 L of oxygen. His physical examination was otherwise normal. The patient’s blood glucose level was 5.9 mmol/L, arterial blood gas levels were unremarkable, and the blood alcohol level was undetectable. A diagnosis of GHB overdose was entertained, and the decision was made to administer physostigmine. Physostigmine was administered approximately every 3 minutes in 0.5-mg boluses to a total of 1.5 mg. Continuous monitoring did not reveal any apparent effect of physostigmine on heart rate, blood pressure, or SaO2. Approximately 10 minutes after the first dose of physostigmine, the patient’s condition suddenly improved, with the GCS score increasing to 10 (E=3, V=3, and M=6). Within 15 minutes, he had fully recovered and admitted to using GHB earlier in the evening. He was kept under observation for 51⁄2 hours and then discharged. Urine toxicology screening revealed cannibinoids, 3,4-methylenedioxymethamphetamine, and GHB.
Discussion
GHB has respectable origins as an intravenous hypnotic agent.9 It did not, however, achieve widespread use because of its slow and unpredictable recovery rates.7,8 Henderson and Holmes7 found that physostigmine successfully and safely reversed the effects of GHB, with minimal adverse cholinergic effects. Despite the work of Henderson and Holmes,7 interest in GHB as an anesthetic agent diminished. Recently, GHB has emerged as a recreational drug, and increasing instances of severe overdose have created interest in finding a safe antidote. Although some authors1,2,10 advocate a conservative approach to the management of GHB overdose, they and others11 have noted that the work of Henderson and Holmes7 may indicate a role for physostigmine in the treatment of severely obtunded patients. Physostigmine is a well-known analeptic agent that causes generalized, nonspecific, central nervous system arousal.12 The mechanism of action by which physostigmine reverses GHB is unknown, but it is presumably through central nervous system stimulation because neostigmine (which does not cross the blood brain barrier) is ineffective in reversing the effects of GHB.8 Physostigmine has also been reported to reverse the effect of opiates.13 This effect may have played a role in the recovery of our first patient; however, she denied any opiate ingestion other than the codeine as prescribed, and therefore her obtundation was presumably related to GHB ingestion. Henderson and Holmes7 described a latent period of 2 to 10 minutes between the administration of physostigmine and the recovery of consciousness. This prolonged latent period has caused some to question whether the improvement in mental status after physostigmine administration might simply reflect the rapid recovery that is common after GHB intoxication. However, in the largest reported series of patients with GHB intoxication, 10 the mean time to regain consciousness was 146 minutes after ED presentation; the shortest interval was 16 minutes. Yet all 3 of our patients recovered within 25 minutes of their ED presentation, and conforming with Henderson and Holmes’ observations, all of our patients responded within 10 minutes after physostigmine administration. We therefore believe that physostigmine was instrumental in improving our patients’ levels of consciousness. The prolonged latent period did, however, appear to limit the utility of physostigmine for another patient treated in our ED. This 28-year-old woman presented with combined alcohol (blood alcohol level, 0.11 g/dL) and GHB intoxication. Her GCS score of 3 did not improve with stimulation. She was given 1.0 mg of physostigmine, but after several minutes had elapsed without response, the treating physician became concerned about airway compromise and elected to intubate her without administering drugs. We have subsequently concluded that those patients who remain obtunded despite stimulation may be at risk for airway compromise during the long latency period after physostigmine administration. We therefore recommend that these patients be intubated initially rather than treated with physostigmine. The subsequent role of physostigmine in reversing GHB overdose in intubated patients has yet to be evaluated. Traditional concerns regarding the use of physostigmine as an antidote relate to its previous use for tricyclic antidepressant (TCA) overdoses.12 However, a review of the relevant literature indicates that such concerns may not be well founded. Seizures occurred in 2 of 21 patients treated for TCA overdose in one series,14 but 1 of the 2 patients was subsequently shown to have had an acute cerebrovascular accident, and seizures are a relatively common complication of TCA poisoning alone.13 Adverse cardiac effects have been sporadically cited in conjunction with physostigmine treatment for TCA overdose, 15 but again, it is uncertain whether these complications were caused by the TCAs themselves. Conversely, extensive use of physostigmine as an antidote in other settings has proved to be safe.7Cholinergic symptoms were reported in 2 of the 21patients treated for TCA overdose14 but were of relatively minor significance. Two of our patients had cholinergic side effects: patient 1 had excessive lacrimation, an patient 2 had an episode of fecal incontinence. None of our patients manifested adverse cardiovascular sequelae or evidence of airway compromise caused by increased secretions. Nonetheless, to preempt cholinergic sequelae, pretreatment with atropine before physostigmine administration should be considered.7,8 GHB is an increasingly popular drug of abuse, the dangers of which are compounded by a misconception in the drug-abusing community that GHB is safe. It appears that physostigmine may effectively reverse the effects of GHB, obviating the need for intubation, particularly in those patients who are too obtunded to protect their airway, yet who require rapid sequence induction to facilitate intubation. Because GHB is often consumed in a group setting, the potential exists for several such patients to present simultaneously.5,6Were this to occur, an effective reversal agent might prove extremely useful.
References
OVERDOSE AND PHYSOSTIGMINE
Caldicott & Kuhn
1. Li J, Stokes SA, Woeckener A. A tale of novel intoxication: a review of the effects of gamma-hydroxybutyric acid with recommendations for management. Ann Emerg Med.1998;31:729-736.
2. Li J, Stokes SA, Woeckener A. A tale of novel intoxication: seven cases of gamma-hydroxybutyric acid overdose. Ann Emerg Med. 1998;31:723-728.
3. Food and Drug Administration. Updates: injuries, deaths linked to GHB abuse. FDA Consumer. 1997;(May-June)31:4.
4. Ropero-Miller JD, Goldberger BA. Recreational drugs. Current trends in the 90s. Clin Lab Med. 1998;18:727-46.
5. Harraway T, Stephenson L. Gamma hydroxybutyrate intoxication: the Gold Coast experience. Emerg Med (Australia). 1999;11:45-48.
6. Eckstein M, Henderson SO, DelaCruz P, et al. Gamma hydroxybutyrate (GHB): report of a mass intoxication and review of the literature. Prehosp Emerg Care. 1999;3:357-361.
7. Henderson RS, Holmes CM. Reversal of the anaesthetic action of sodium gamma-hydroxybutyrate. Anaesth Intensive Care. 1976;4:351-354.
8. Holmes CM, Henderson RS. The elimination of pollution by a non inhalational technique. Anaesth Intensive Care. 1978;6:120-124.
9. Laborit H, Buchard F, Laborit G, et al. Emploi du 4-hydroxybutyrate en NA en anesthesie et en reanimation. Agressologie. 1960;1:549.
10. Chin RL, Sporer KA, Cullison B, et al. Clinical course of gamma-hydroxybutyrate overdose. Ann Emerg Med. 1998;31:716-722.
11. Viera AJ, Yates SW. Toxic ingestion of gamma hydroxybutyrate. South Med J. 1999;92:404-405.
12. Callaham M. Tricyclic antidepressant overdose. J Am Coll Emerg Phys. 1979;8:413-425.
13. Weinstock M, Davidson JT, Rosin AJ, et al. Effect of physostigmine on morphine-induced postoperative pain and somnolence. Br J Anaesth. 1982;54:429-433.
14. Newton RW. Physostigmine in the treatment of tricyclic antidepressant overdose. JAMA. 1975;231:941-943.
15. Pentel P, Peterson CD. Asystole complicating physostigmine treatment of tricyclic antidepressant overdose. Ann Emerg Med. 1980;9:588-590.
