Substances Included Synonyms

Therapeutic Toxic Class

A)

B)

C)

D)

Specific Substances

A)

1) 4-Hydroxybutyrate
2) Cherry menth (slang term for gamma hydroxybutyric acid)
3) Easy lay (slang term for gamma hydroxybutyric acid)
4) Everclear (slang term for gamma hydroxybutyric acid)
5) Fantasy (slang term for gamma hydroxybutyric acid)
6) Gamma Hydrate
7) Gamma Hydroxybutyrate sodium
8) Gamma-oh (slang term for gamma hydroxybutyric acid)
9) Gamma-oh (slang term for gamma hydroxybutyric acid (france)
10) Georgia home boy (slang term for gamma hydroxybutyric acid)
11) GHB (synonym)
12) GBH (slang term for gamma hydroxybutyric acid)
13) Goop (slang term for gamma hydroxybutyric acid)
14) Great hormones at bedtime (slang term for gamma hydroxybutyric acid)
15) G-riffick (slang term for gamma hydroxybutyric acid)
16) Grievous bodily harm (slang term for gamma hydroxybutyric acid)
17) Hydro (slang term for gamma hydroxybutyric acid) (new york)
18) Jib (slang term for gamma hydroxybutyric acid)
19) Jolt (slang term for gamma hydroxybutyric acid) (pennsylvania)
20) Liquid E (slang term for gamma hydroxybutyric acid)
21) Liquid X (slang term for gamma hydroxybutyric acid)
22) Liquid ecstasy
23) Organic quaalude (slang term for gamma hydroxybutyric acid)
24) Oxybutyrate
25) Salty water (slang term for gamma hydroxybutyric acid)
26) Scoop (slang term for gamma hydroxybutyric acid)
27) Sleep-500 (slang term for gamma hydroxybutyric acid)
28) Soap (slang term for gamma hydroxybutyric acid)
29) Sodium oxybate
30) Somatomax pm
31) Somatomax (slang term for gamma hydroxybutyric acid)
32) Sodium oxybate (Sodium salt)
33) Sodium oxybutyrate
34) Somsanit (Germany)
35) NSC 84223 (Sodium salt)
36) Vita-g (slang term for gamma hydroxybutyric acid)
37) Water (slang term for gamma hydroxybutyric acid)
38) Wy-3478 (Sodium salt)
39) CAS 502-85-2 (Sodium salt)

1) 1,2-butanolide
2) 2(3H)-furanone, dihydro
3) 3-hydroxybutyric acid lactone
4) 4-Butanolide
5) 4-Butyrolactone
6) 4-Hydroxybutanoic acid lactone
7) Butyrolactone
8) Butyrolactone gamma
9) Dihydro-2(3H)-furanone
10) Gamma butyrolactone
11) Gamma hydroxybutyric acid lactone
12) GBL

1) 1,4-B
2) 1,4-BD
3) 1,4-butylene glycol
4) 1,4-dihydroxybutane
5) 1,4-tetramethylene glycol
6) 2(3H)-Furanone di-dihydro
7) BD
8) butanediol
9) tetramethylene glycol

Available Forms Sources

A)

1) Brand names of GHB include (JEF Reynolds , 1990):

1) Gamma-OH (Cernep Synthelabo of France; Netherlands)
2) Somsanit (Kohler of Germany)

2) Names GHB has been illegally marketed under include (CDC, 1990):

1) 4-Hydroxybutyrate
2) Gamma Hydrate
3) Gamma Hydroxybutric Acid
4) Gamma Hydroxybutyrate Sodium
5) Gamma-OH
6) Oxybutyrate
7) Sodium Oxybate
8) Somatomax PM

3) Slang terms that have been used to describe Gamma Hydroxybutyric Acid (Williams, 1998):

1) Alcover
2) Cherry menth
3) Easy lay
4) Everclear
5) Fantasy
6) G
7) Gamma-OH
8) GBH
9) GHB
10) Georgia home boy
11) Great hormones at bedtime
12) Grievous bodily harm
13) G-riffick
14) Jolt
15) Lemons
16) Liquid E
17) Liquid Ecstasy
18) Liquid X
19) Organic Quaalude
20) Scoop
21) Soap
22) Salty water
23) Water
24) Zonked

4) Gamma butyrolactone is a precursor in the synthesis of gamma hydroxybutyric acid:

a) It may be marketed under numerous brand names as a herbal growth hormone stimulator. The brand name Renewtrient has been implicated in one case report of toxicity (LoVecchio et al, 1998).
b) Gamma butyrolactone can also be found in "acetone-free" nail polish remover. Two case reports of toxicity similar to GHB have been reported following ingestion of this product in an adult and a toddler (Rambourg-Schepens et al, 1997). Similar toxicity was reported in two children following exposure to an acetone-free nail polish remover (Finelle(R) nail polish remover) containing 75% GBL (LeBlanc & Blais, 2000). Although the product is no longer produced, the authors note that a similar product could still be commercially available.
c) Products containing gamma butyrolactone are marketed under various brand names and can include the following ((Anon, 1999)) Viswanathan, et al, 2000):

1) Beta-Tech
2) Blue Nitro
3) Blue Nitro Vitality
4) Firewater
5) GH Revitalizer
6) Gamma G
7) Insom-X
8) Invigorate
9) Jolt
10) Longevity
11) Re Active
12) Remforce
13) Renewtrient
14) Rest-EZE
15) Revivarant
16) Revivarant G
17) Thunder
18) Verve

d) Gamma-valerolactone (GVL) is a congener of gamma butyrolactone (GBL) and can be found on internet "recipes" as a primary ingredient for synthesis of gamma hydroxyvalerate (GHV), a methylated congener of GHB which has been reported to produce GHB-like effects. Based on the hypothesis that GVL undergoes in vivo biotransformation to GHV, animal studies were conducted to determine if GVL produced similar GHB-like toxicity. The findings suggested that in mice GVL has less toxicity than 1,4-BD based on a lack of seizure activity and no loss of the righting reflex in male CD-1 mice (Quang et al, 2001a).

5) 1,4-butanediol found in a "pine-needle oil" spray was responsible for 2 overdoses in adults with symptoms similar to gamma hydroxybutyrate (GHB) intoxication (Dyer et al, 1997c). It is metabolically oxidized to GHB and has the same expected clinical course following overdose.

a) Products containing 1,4-butanediol (BD) are marketed under various brand names and can include the following (H Lindsay , 1999; (Anon, 1999)):

1) Amino Flex
2) Biocopia
3) Borametz
4) BVM
5) Cherry FX Bomb
6) Dormir
7) Enliven
8) GHRE
9) Inner G
10) Lemon FX Drop
11) NRG3
12) Orange FX Rush
13) Rest-Q
14) Pine Needle Extract
15) Promusol
16) Revitalize Plus
17) Rejov-at-nite
18) Rejoov
19) Serenity
20) SomatoPro
21) Thunder Nectar
22) Weight Belt Cleaner
23) X-12
24) Zen

B)

1) GHB

a) GHB was banned from sale and distribution in the United States in the early 1990's.
b) Despite the ban on the sale and manufacture of GHB by the US FDA, mail order kits and most recently access through the internet have resulted in easy access to this agent (Osterhoudt & Henretig, 2003; Henretig et al, 1998). The kits are sold inexpensively and provide detailed instructions to manufacture the drug at home.
c) ADULTERATION - A report of ingredient substitution in the home manufacture of GHB has resulted in transient hematuria. Adulteration should be considered with the use of noncommercial products (Wiley et al, 1998).

2) GAMMA BUTYROLACTONE (GBL)

a) GBL (marketed under various brand names), a precursor in the synthesis of GHB, and an alleged herbal "growth hormone stimulator", produces an intoxication similar to GHB. GBL is also found in some nail polish removers that are labeled "acetone-free" and in cyanoacrylate glue.
b) Health food products used as sleep aids may contain gamma butyrolactone (GBL) or 1,4-butanediol (BD) which produce similar effects as GHB. Manufacturers may be renaming their products and substituting 1,4-BD or GBL.

3) 1,4-BUTANEDIOL

a) 1,4-BD is marketed as a sleep aid, muscle builder, and party drug, and is metabolized to GHB.
b) PRODUCT RECALL (TOY BEADS) - 1,4-butanediol (BD) was found in toy beads manufactured in Hong Kong. The product had been marketed as Bindeez(TM) in the United Kingdom and as Aqua Dots(TM) in the United States. Tests to confirm the presence of 1,4-BD in the toy beads were done after two children presented with symptoms similar to those seen in GHB exposures (ie, decreased consciousness, nausea, vomiting, hypotension, bradycardia). In both cases, it was identified that the child had ingested the toy beads prior to symptom onset. An international recall of the product has been done (Gunja et al, 2008).

C)

1) GAMMA HYDROXYBUTYRIC ACID

a) In Europe, GHB has been used experimentally to treat posthypoxic cerebral edema and ethanol withdrawal (Gallimberti et al, 1989) and as an anesthetic adjunct (CDC, 1990; Addolorato et al, 1997). It has been called "a natural growth hormone" for strength training/body building (Gilmore et al, 1991).

1) Withdrawal symptoms were reported in a patient after abusing GHB that was prescribed for the treatment of alcohol addiction (Hernandez et al, 1998). Please refer to the GHB-WITHDRAWAL management for further information.

b) In July 2002, the United States FDA approved the use of sodium oxybate (Xyrem(R)) to treat cataplexy, a sudden loss of muscle tone associated with narcolepsy ((Anon, 2002)).

1) Sodium oxybate (Xyrem(R)) is a Schedule III controlled substance. In addition, its distribution is governed by the FDA's Subpart H regulations. The manufacturer has worked closely with the FDA, DEA, and law enforcement agencies to develop strict distribution and risk-management controls designed to restrict access to Xyrem(R) to the intended patient population ((Anon, 2002)).

2) CONSUMER ALERTS/LEGISLATIVE ACTION/USA

a) GHB

1) Federal legislation took effect March 13, 2000, making GHB a schedule I agent and GHB under IND or NDA use a schedule III agent (DEA, 2000). Due to the fluctuating legal status of GHB, Orphan Medical (1-888-80RPHAN) maintains the current legislative status of GHB by state. In addition, this legislation makes the manufacture, distribution, and possession of GHB illegal. It also bans the manufacture, distribution, and possession of gamma butyrolactone and 1,4-butanediol when they are intended for human consumption (Engel, 2000).
2) Since 1990, the DEA has reported 68 deaths related to the use of GHB (Teter & Guthrie, 2001).

b) GAMMA BUTYROLACTONE

1) As of January 1999, the US FDA has alerted consumers NOT to purchase or consume products containing gamma butyrolactone (GBL), which may be labeled as dietary supplements, based on reports of serious health problems associated with its use. The FDA has also asked companies that manufacture these products to voluntarily recall them ((Anon, 1999)). Some products remain available labeled as "solvents".

c) 1,4-BUTANEDIOL

1) As of May 1999, the US FDA has alerted consumers of GBL-related products, one of which is 1,4-butanediol (BD) which may cause symptoms similar to GHB or GBL, and the effects are considered as potentially life-threatening (a Class I Health Hazard). Health authorities believe that manufacturers may be relabeling health food products or substituting 1,4-BD for GBL (Anon, 1999a).
2) In January 2000, the FDA announced a recall of 1,4-BD products. It is uncertain, at the time of this update, whether nutritional supplement manufacturers will comply ((Anon, 2000)). If these products are marketed as "dietary supplements" they are protected under the Dietary Supplement Health and Education Act which was created as a potential loophole for "natural" products, and thereby, 1,4-BD is protected from violation of the Controlled Substance Analogue Enforcement Act (Shannon & Quang, 2000).

Overview

Life Support

A)

Clinical Effects

0.2.1)

A) USES: Gamma hydroxybutyric acid (GHB) is used as a treatment for cataplexy symptoms in patients with narcolepsy. GHB and other substances that are metabolized to GHB are used as drugs of abuse. Gamma butyrolactone (GBL) (marketed under varius brand names), a precursor in the synthesis of GHB, and an alleged herbal "growth hormone stimulaor", produces an intoxication similar to GHB.
B) PHARMACOLOGY: GHB is a structural analog of the neurotransmitter gamma-amino butyric acid (GABA) with agonist activity at both GABA (B) and GHB receptors. It is rapidly absorbed and has a rapid onset of action.
C) TOXICOLOGY: GHB is believed to be a neuromodulator in the CNS where high affinity to specific GHB receptor occurs. It readily crosses the blood-brain barrier, resulting in general anesthesia and respiratory depression.
D) EPIDEMIOLOGY: Illicit use of GHB and its related compounds is fairly common in some areas of the US and may occur in several settings: in the recreational setting of raves and night clubs; in the athletic setting of bodybuilding gyms and fitness centers (used because it is alleged to stimulate growth hormone release); in the home consumer setting of individuals seeking its "natural health benefit," and in the criminal setting of drug-facilitated sexual assault.
E) WITH THERAPEUTIC USE

1) Nausea, headache, dizziness, nasopharyngitis, somnolence, vomiting, and urinary incontinence are the most commonly observed adverse events following therapeutic doses of sodium oxybate.

F) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: Following doses of 30 mg/kg, hallucination, abrupt onset of sleep, enuresis, myoclonic movements, and euphoria will occur, which start about 15 minutes after ingestion; delirium and agitation are also common. Vomiting is seen in 30% to 50% of patients.
2) SEVERE TOXICITY: Commonly present with bradycardia, myoclonic movements, unconsciousness, delirium, and coma, which occur about 30 to 40 minutes after oral overdose and recover within 2 to 4 hours, with complete resolution of symptoms within 8 hours. Hypothermia and mild acidosis may also develop. Seizures have been reported, but are rare. Cheyne-Stokes respiration and loss of proactive reflexes occur. Severe alkaline corrosive burn of the gastrointestinal tract may occur following ingestion of improperly prepared illicit GHB, but is rare.
3) ONSET: Rapid after IV injection (within 2 to 15 minutes) and oral ingestion (within 15 to 30 minutes). Concurrent alcohol ingestion may delay onset of symptoms from 1,4-BD, due to competition with alcohol dehydrogenase for metabolism to GHB.
4) DURATION: Coma typically lasts 1 to 2 hours, with full recovery by 8 hours; dizziness may linger for up to 2 weeks. Acute symptoms have resolved within 8 hours after doses of 1/4 teaspoon to 4 tablespoons. Concurrent alcohol ingestion may prolong the duration of effect from 1,4-BD.
5) WITHDRAWAL: A withdrawal syndrome similar to ethanol/sedative/hypnotic withdrawal has been reported in patients after abrupt cessation of long term, frequent (multiple times daily) use. Refer to the GHB-WITHDRAWAL management for further information.

0.2.3)

A) Significant respiratory depression may occur in comatose patients. Bradycardia with increases or decreases in blood pressure may be anticipated.

0.2.4)

A) Nystagmus, miosis and mydriasis may be seen.

0.2.20)

A) Sodium oxybate is classified as FDA pregnancy category C. GHB does cross the placenta, but no overt effects have been noted in the fetus. GHB has been used as an obstetric anesthetic.

Laboratory Monitoring

A)

B)

C)

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Treatment is symptomatic and supportive. Most patients will not require airway management but require monitoring and positioning such that if they vomit they do not aspirate. Treat seizures with benzodiazepines and barbiturates.

B) MANAGEMENT OF SEVERE TOXICITY

1) Protect the airway and assist ventilation if needed. Note that patients who required intubation are often awake and extubated within a few hours.

C) DECONTAMINATION

1) PREHOSPITAL: Do not give charcoal or induce vomiting because of the risk of rapid loss of consciousness and loss of airway protective reflexes, which may lead to pulmonary aspiration.
2) HOSPITAL: The small amount of GHB usually ingested is rapidly absorbed, so gastric lavage, and activated charcoal are of doubtful benefit and not recommended.

D) AIRWAY MANAGEMENT

1) Endotracheal intubation should be considered in any patient with an unprotected airway.

E) ANTIDOTE

1) There is no antidote. Flumazenil and naloxone are not clinically effective.

F) ENHANCED ELIMINATION

1) There is no role for enhanced removal procedures such as dialysis and hemoperfusion.

G) PATIENT DISPOSITION

1) OBSERVATION CRITERIA: Because symptoms typically resolve within few hours, stable patients can be discharged within 4 to 8 hours.

H) PITFALLS

1) Most patients recover within a few hours with only supportive care; aggressive treatment is generally not warranted.

I) PHARMACOKINETICS

1) Rapidly absorbed; onset of action is 15 minutes. Peak level occurs within 25 to 45 minutes after oral ingestion. The volume of distribution is variable. Hepatic metabolism. Virtually no protein binding. Half-life is 20 to 50 minutes; the drug is completely eliminated in 4 to 6 hours. GBL and 1,4-butanediol are both metabolized to GHB.

J) DIFFERENTIAL DIAGNOSIS

1) The diagnosis should be suspected in any patient who presents with abrupt onset of coma and recovers rapidly within a few hours. Overdose with short acting benzodiazepines or barbiturates, or ethanol may present in a similar fashion.

K) WITHDRAWAL SYMPTOMS

1) Withdrawal symptoms may be experienced by chronic GHB (or prodrugs of GHB) users. Refer to the GHB-WITHDRAWAL management for further information.

Range Of Toxicity

A)

B)

Clinical Effects

Summary Of Exposure

A)

B)

C)

D)

E)

1) Nausea, headache, dizziness, nasopharyngitis, somnolence, vomiting, and urinary incontinence are the most commonly observed adverse events following therapeutic doses of sodium oxybate.

F)

1) MILD TO MODERATE TOXICITY: Following doses of 30 mg/kg, hallucination, abrupt onset of sleep, enuresis, myoclonic movements, and euphoria will occur, which start about 15 minutes after ingestion; delirium and agitation are also common. Vomiting is seen in 30% to 50% of patients.
2) SEVERE TOXICITY: Commonly present with bradycardia, myoclonic movements, unconsciousness, delirium, and coma, which occur about 30 to 40 minutes after oral overdose and recover within 2 to 4 hours, with complete resolution of symptoms within 8 hours. Hypothermia and mild acidosis may also develop. Seizures have been reported, but are rare. Cheyne-Stokes respiration and loss of proactive reflexes occur. Severe alkaline corrosive burn of the gastrointestinal tract may occur following ingestion of improperly prepared illicit GHB, but is rare.
3) ONSET: Rapid after IV injection (within 2 to 15 minutes) and oral ingestion (within 15 to 30 minutes). Concurrent alcohol ingestion may delay onset of symptoms from 1,4-BD, due to competition with alcohol dehydrogenase for metabolism to GHB.
4) DURATION: Coma typically lasts 1 to 2 hours, with full recovery by 8 hours; dizziness may linger for up to 2 weeks. Acute symptoms have resolved within 8 hours after doses of 1/4 teaspoon to 4 tablespoons. Concurrent alcohol ingestion may prolong the duration of effect from 1,4-BD.
5) WITHDRAWAL: A withdrawal syndrome similar to ethanol/sedative/hypnotic withdrawal has been reported in patients after abrupt cessation of long term, frequent (multiple times daily) use. Refer to the GHB-WITHDRAWAL management for further information.

Vital Signs

3.3.1)

A) Significant respiratory depression may occur in comatose patients. Bradycardia with increases or decreases in blood pressure may be anticipated.

3.3.2)

A) WITH POISONING/EXPOSURE

1) CASE SERIES: In a case series involving 120 cases of overdose with GHB alone, out of 42 patients in whom respiratory rate was recorded, 4 patients (10%) had bradypnea (less than 10 breaths/minute). Out of 45 patients in whom oxygen saturation was reported, (13%) had hypoxemia (less than 95% oxygen saturation) (Galicia et al, 2011).

3.3.3)

A) HYPOTHERMIA: Anesthesia patients became hypothermic unless warmed with blankets (Vickers, 1969).

1) CASE SERIES: In a case series involving 120 cases of overdose with GHB alone, out of 21 patients in whom temperature was reported, 3 patients (14%) had hypothermia (body temperature less than 35 degrees Celsius)(Galicia et al, 2011)
2) Mild hypothermia was observed frequently in patients following GHB overdose. In a retrospective review, 31% (22 of 88 patients) had an initial temperature of 35 degrees Celsius or less (Chin et al, 1998).
3) Hypothermia was reported in 2 children (33.3 and 35 degrees Celsius, respectively) following unintentional exposure to GHB (Suner et al, 1997). Both children had been placed in the snow during resuscitation efforts.

B) ANIMAL DATA: Hyperthermia was reported in animals after low doses (5 to 10 mg/kg) and hypothermia after high doses (300 to 500 mg/kg) (Kaufman et al, 1990).

3.3.4)

A) Mild hypertension may occur with intravenous use (Geldenhuys et al, 1968a).
B) Hypotension is common in GHB or GHB analog exposure (Gunja et al, 2008).

3.3.5)

A) BRADYCARDIA occurs commonly after intravenous use (Vickers, 1969) and has been reported following ingestion (Gunja et al, 2008; Yambo et al, 2004; Osterhoudt & Henretig, 2003; Rambourg-Schepens et al, 1997; Suner et al, 1997) .

Heent

3.4.1)

A) Nystagmus, miosis and mydriasis may be seen.

3.4.3)

A) Nystagmus may be seen (Price et al, 1981).
B) CASE SERIES: In a case series involving 120 cases of overdose with GHB alone, out of 50 patients who had pupil size reported, 10 patients (20%) had miosis and 18 patients (36%) had mydriasis (Galicia et al, 2011).

Cardiovascular

3.5.2)

A) HYPOTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) CASE SERIES: In a case series involving 120 cases of overdose with GHB alone, out of 78 patients in whom blood pressure was reported, 2 patients (3%) had hypotension (systolic less than 90 mmHg)(Galicia et al, 2011).
b) INCIDENCE: In a retrospective case series (88 patients) of self-reported GHB ingestions, 10 (11%) patients had hypotension (a SBP of 90 mmHg or less) (Chin et al, 1998). All cases included coingestion of alcohol or another drug; 6 patients also had concurrent bradycardia.
c) CASE REPORT: A 2-year-old boy experienced hypotension, sinus bradycardia, and decreased consciousness after an exposure to 1,4-BD. It was determined the exposure was a result of the child ingesting toy beads that contained 1,4-BD (marketed as Bindeez(TM) in the United Kingdom and Aqua Dots(TM) in the United States). Seven hours after presentation, the boy became cooperative and alert (Gunja et al, 2008).
d) PEDIATRIC EXPOSURE: Gamma-Butyrolactone (GBL): A 9-month-old boy ingested GBL by briefly sucking on 2 "acetone-free" nail polish remover pads (GBL concentration 84%) for less than 1 minute. Upon presentation, the patient had hypotension, bradycardia, and was in shock. He was treated with supportive care and made a full recovery 8 hours after ingestion (Savage et al, 2007).

B) ORTHOSTATIC HYPOTENSION

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Orthostatic hypotension was noted in one patient after 2.5 grams IV (Takahara et al, 1977).

C) BRADYCARDIA

1) WITH THERAPEUTIC USE

a) Mild bradycardia is usually seen when used in anesthesia (Vickers, 1969).

2) WITH POISONING/EXPOSURE

a) CASE SERIES: In a case series involving 120 cases of overdose with GHB alone, out of 100 patients in whom pulse was recorded, 17 patients (23%) had bradycardia (heart rate less than 60 beats per minute)(Galicia et al, 2011)
b) Mild bradycardia is seen in overdose (Osterhoudt & Henretig, 2003; Dyer JE, 1990a; Normann S, 1990). Significant bradycardia may occur following overdose (Yambo et al, 2004; Suner et al, 1997).
c) CASE SERIES: In a retrospective case series of self-reported GHB ingestions, 36% (32 of 88 patients) developed bradycardia (Chin et al, 1998). Only 1 patient required atropine (a single dose) for a heart rate of 24 BPM. In addition, bradycardia was associated with decreased levels of consciousness. Median initial Glasgow comma scale was 4 in bradycardic patients versus 9.5 for patients without bradycardia.
d) CASE REPORT: A 9-year-old boy was found pulseless and apneic with a sinus rhythm of 20 bpm after an unintentional ingestion of GHB added to a soft drink. Following supportive care, the child was discharged without sequelae on hospital day 5 (Suner et al, 1997).
e) CASE REPORT: Two children (2-year-old and 10-year-old) experienced sinus bradycardia and decreased consciousness after an exposure to 1,4-BD. It was determined the exposure was a result of ingesting toy beads that contained 1,4-BD (marketed as Bindeez(TM) in the United Kingdom and Aqua Dots(TM) in the United States). Both children regained alertness within hours of presentation (Gunja et al, 2008).
f) PEDIATRIC EXPOSURE: Gamma-Butyrolactone (GBL): A 9-month-old boy ingested GBL by briefly sucking on 2 "acetone-free" nail polish remover pads (GBL concentration 84%) for less than 1 minute. Upon presentation, the patient had hypotension and bradycardia, and was in shock. He was treated with supportive care and made a full recovery 8 hours after ingestion. In vivo, GBL is metabolized into Gamma Hydroxybutyrate (GHB) (Savage et al, 2007).
g) PEDIATRIC EXPOSURE: 1,4-butanediol: A 7-year-old girl presented with critical bradycardia during an acute hypoxic event after swallowing 80 Bindeez toy beads coated with 1,4-butanediol. The patient was treated with supportive care and extubated less than 24 hours after admission to the hospital (Runnacles & Stroobant, 2008).

D) ATRIAL FIBRILLATION

1) WITH POISONING/EXPOSURE

a) Mild tachycardia (rate 100 to 120 BPM) and atrial fibrillation were reported in a 25-year-old man after ingesting GHB. A drug screen and alcohol level were negative. The atrial fibrillation resolved spontaneously within 30 minutes and the patient remained in normal sinus rhythm until discharge 24 hours later (Dribben & Kirk, 2001).

E) ELECTROCARDIOGRAM ABNORMAL

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 12-year-old male developed cardiac dysfunction following an unintentional ingestion of GHB added to a soft drink. Effects included bradycardia, right bundle branch block pattern, and ST segment elevation. The child was given supportive care, and within 6 hours of admission the ECG had returned to normal (Suner et al, 1997).

1) Although further study is indicated, it is suggested that GHB may produce conduction disorders (Suner et al, 1997).

b) CASE SERIES: 5 of 7 patients developed U waves on their ECG following GHB exposure; 3 patients had significant abnormalities, which included first-degree heart block, right bundle branch block, and ventricular ectopy prompting lidocaine administration (Chin et al, 1998). The authors suggested a causal relationship with U waves and GHB toxicity.
c) Sinus bradycardia and slight QRS widening were reported after GBL poisoning (Rambourg-Schepens et al, 1997).

F) HYPERTENSIVE EPISODE

1) WITH THERAPEUTIC USE

a) Hypertension has been reported with intravenous use (Geldenhuys et al, 1968a).

G) CARDIAC ARREST

1) WITH POISONING/EXPOSURE

a) CASE REPORT: After ingesting 15 mL of 1,4-BD, a 22-year-old man and his girlfriend lost consciousness. He developed a seizure, vomiting, aspiration pneumonia, and cardiac/respiratory arrest (GHB blood level 220 mg/liter). He died the next day. Toxicology screen for other drugs of abuse was negative. His girlfriend recovered following several hours of ventilation (Theron et al, 2003).

H) CHEST PAIN

1) WITH POISONING/EXPOSURE

a) In an observational study involving 505 patients with known GHB consumption, the most common cardiovascular symptoms reported were chest pain and palpitation (Galicia et al, 2011).

Respiratory

3.6.2)

A) ACUTE RESPIRATORY INSUFFICIENCY

1) WITH POISONING/EXPOSURE

a) Difficulty breathing, depressed respirations, and apnea have been reported after oral or IV administration of GHB (Boyer et al, 2000; Li et al, 1998a; Dyer JE, 1990; Normann S, 1990; Vickers, 1969) and after ingestion of an organic inkjet cleaner containing 1,4-butanediol (Yambo et al, 2004). Dyspnea and cough are also commonly reported after GHB consumption (Galicia et al, 2011)
b) Cheyne-Stokes respiration was observed in 9.5% to 28% of cases (Dyer JE, 1990a). Patients (11/14 patients) may require intubation and artificial respiration (mean duration of ventilation was 10.6 hours) following severe overdose (Harraway & Stephenson, 1999).
c) CASE SERIES: In a case series involving 120 cases of overdose with GHB alone, out of 42 patients in whom respiratory rate was recorded, 4 patients (10%) had bradypnea (less than 10 breaths/minute). Out of 45 patients in whom oxygen saturation was reported, (13%) had hypoxemia (less than 95% oxygen saturation) (Galicia et al, 2011).
d) CASE REPORT: Respiratory arrest and coma was reported in a toddler following ingestion of 30 mL of GBL solvent (Higgins & Borron, 1996).
e) CASE REPORT: Respiratory arrest was reported twice in a 15-year-old girl following 2 separate episodes of GBL ingestion (ie, "Verve" and "Jolt"). The patient recovered following mechanical ventilation and was discharged in both cases within 48 hours of exposure; no permanent sequelae were reported (Winickoff et al, 2000).

B) APNEA

1) WITH POISONING/EXPOSURE

a) CASE REPORTS: Two children developed apnea following an unintentional ingestion of GHB contained in a soft drink. One child required immediate intubation and developed aspiration pneumonia. Both recovered with supportive care (Suner et al, 1997).
b) SODIUM OXYBATE: One patient became unresponsive with brief periods of apnea and incontinence (urine and feces) after ingesting approximately 150 g of sodium oxybate (more than 15 times the maximum recommended dose) (Prod Info Xyrem(R) oral solution, 2009).

C) ASPIRATION PNEUMONIA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: After ingesting 15 mL of 1,4-butanediol, a 22-year-old man and his girlfriend lost consciousness. He developed a seizure, vomiting, aspiration pneumonia, and cardiac/respiratory arrest (GHB blood level 220 mg/L). He died the next day. Toxicology screen for other drugs of abuse was negative. His girlfriend recovered following several hours of ventilation (Theron et al, 2003).

D) PULMONARY EDEMA

1) WITH POISONING/EXPOSURE

a) PEDIATRIC: A 3-year-old girl was found unresponsive after an unintentional ingestion of a chemical containing GBL. At presentation, she was comatose and hypoventilating, and had hyperglycemia, hypokalemia, and a coagulopathy. When intubation was initiated, secretions consistent with pulmonary edema were suctioned, and required controlled ventilation and inotropic support. Within 12 hours of presentation, the patient was clinically improving, and she was extubated the following day (Piastra et al, 2006).

E) NASOPHARYNGITIS

1) WITH THERAPEUTIC USE

a) SODIUM OXYBATE: In clinical trials (n=177), nasopharyngitis developed in 8% of narcoleptic patients receiving sodium oxybate (Prod Info Xyrem(R) oral solution, 2009).

F) RESPIRATORY ARREST

1) WITH POISONING/EXPOSURE

a) CHILD NEGLECT: Inadvertent exposure to GHB has occurred in children, and clinicians should consider such an exposure in the presence of toxic coma or respiratory arrest (Boyer et al, 2000).

Neurologic

3.7.2)

A) CENTRAL NERVOUS SYSTEM FINDING

1) WITH THERAPEUTIC USE

a) GHB has been used therapeutically to produce general anesthesia without analgesia, with a duration of about 1 to 2 hours (Snead, 1977; Vickers, 1969; Roth & Giarman, 1968; Steel, 1968; Besserman & Skolnik, 1964).

2) WITH POISONING/EXPOSURE

a) In an observational study involving 505 patients with known GHB consumption, the most common neurological symptoms reported were headache, instability, disorientation, dysarthria, and convulsions(Galicia et al, 2011).
b) Coma typically lasts 1 to 2 hours, with full recovery by 8 hours; dizziness may linger for up to 2 weeks (Dyer, 1991). Other authors have noted an inverse correlation between initial GCS scores and the time required to regain consciousness. Among patients who did not require intubation, the mean time to regain consciousness was between 2 and 3 hours, and intubated patients took approximately 4 to 5 hours (the difference may be reflective of sedative agents used during intubation) (Chin et al, 1998).
c) CASE SERIES: In a retrospective review, a marked decrease in level of consciousness was common following GHB overdose (Chin et al, 1998). Glasgow coma scores (GCS) were recorded in 86 of 88 patients, 28% (n=25) had an initial GCS of 3; 32% (n=28) ranged from 4 through 8; and 19% (n=17) had minimal alterations in consciousness with scores of 14 or 15.
d) CASE SERIES: Seven patients exposed to GHB developed loss of consciousness with marked respiratory depression (Li et al, 1998a). Extreme combativeness was noted on stimulation.
e) CASE SERIES: Three individuals experienced stupor following the use of GHB. One patient, a 17-year-old teenager, was stuporous, but became agitated and combative with stimulation. The authors indicated that lack of response to naloxone, a negative urine drug screen, mild bradycardia, and the clinical alternation between stupor and agitation are highly suggestive of GHB overdose by these patients (Osterhoudt & Henretig, 2003)
f) GAMMA BUTYROLACTONE

1) CASE REPORT: A 36-year-old man ingested 2 ounces of an alleged herbal growth hormone stimulator that contained GBL, a precursor in the synthesis of GHB, and developed CNS depression (LoVecchio et al, 1998). Symptoms of lethargy, diaphoresis, and vomiting occurred within 30 minutes of exposure and were similar to GHB.
2) CASE REPORT: A 2-year-old was found unresponsive with minimal respirations after ingesting 30 mL of a solvent used to remove methacrylate glues that contained GBL(Higgins & Borron, 1996). The patient required artificial ventilation, and awoke, spontaneously, 6 hours after admission.
3) CASE REPORT: A 21-year-old woman became unresponsive following the ingestion of "revivarant" (GBL) (Viswanathan et al, 2000). Glasgow coma scale was 6 on admission with intact deep tendon reflexes, but no Babinski reflexes bilaterally. The patient was unresponsive to naloxone, and following a 3-hour observation period, the patient awoke spontaneously and was alert and oriented and ambulating without difficulty.

g) 1,4-BUTANEDIOL

1) SUMMARY: The CNS depression observed following ingestion of this product is similar to GHB (Anon, 1999a). 1,4-BD and alcohol compete for aldehyde dehydrogenase (ADH) ,with alcohol having the greater affinity for ADH,; thus 1,4-BD metabolism is delayed in the presence of alcohol ingestion, increasing potential toxicity (Shannon & Quang, 2000).
2) CASE REPORT: A 26-year-old man ingested 1 to 2 capfuls of a product containing 1,4-BD along with excessive alcohol later that same day (Schneidereit et al, 2000). The patient did not experience his usual "high" until the following morning and became unconscious. Intubation for 5 hours was required with spontaneous awakening. It is speculated that the drug did not convert to GHB until the alcohol was fully metabolized.

B) COMA

1) WITH POISONING/EXPOSURE

a) GAMMA HYDROXYBUTYRIC ACID

1) CASE SERIES: In a case series involving 120 cases of overdose with GHB alone, out of 75 patients in whom Glasgow Coma Score (GCS) was reported, 28 patients (37%) has severely reduced consciousness (GSC less than 9) (Galicia et al, 2011).
2) CASE REPORT: Approximately 1 hour after an unintentional ingestion of GHB in a soft drink, 2 children were found unresponsive and had developed profound coma. Initial Glasgow coma scale score was 6 in each child. Following supportive care, both were discharged without permanent sequelae (Suner et al, 1997).
3) CASE REPORT: A 23-year-old woman was near comatose after coingesting a GHB (125 microgram/milliliter) solution, ethanol (134 mg/dL), and marijuana. After 45 minutes of unaltered near coma state, the patient suddenly woke despite no therapeutic measures and walked out of the hospital 15 minutes later (refusing further treatment/observation) (Louagie et al, 1997).
4) CASE REPORT: A 24-year-old woman was found unresponsive with suspected GHB ingestion 90 minutes prior to admission (Libetta, 1997). The patient's initial Glasgow coma score was 3 with shallow respirations and hypotension. Treatment included supplemental oxygen and 400 micrograms of naloxone IV plus an additional 400 micrograms IM; only her respirations improved to 16/minute with no change in mental status. Three hours after admission she was alert and oriented and was discharged within 8 hours of admission.

b) GAMMA BUTYROLACTONE

1) CASE REPORT: A 17-year-old man was found unconscious after ingesting 2.5 mL of GBL diluted in a soft drink. Following supportive care, he regained consciousness within 3 hours of admission (Hefele et al, 2009).
2) CASE REPORTS: Gamma-butyrolactone (GBL): A 45-year-old man collapsed and was unconscious after ingesting an estimated 50 mL GBL (equipotent to 385 mg/kg of GHB) requiring prehospital intubation. Upon admission, arterial blood gases revealed metabolic and respiratory acidosis. Sixteen hours later the patient awoke and was successfully extubated and completely recovered. The second patient was a young adult that was found unconscious with an empty bottle of GBL and had a combination metabolic lactic and respiratory acidosis. He was also intubated due to coma and respiratory depression. Following a brief period, the patient awoke and was easily extubated (van Vugt & Hofhuizen, 2012).
3) PEDIATRIC: A 14-month-old male ingested an unknown amount of "acetone-free" nail polish remover (Rambourg-Schepens et al, 1997). The patient quickly developed cyanosis and became comatose. Treatment included intubation with spontaneous respirations. The child awoke suddenly 5 hours after exposure with some residual confusion; 8 hours after the initial ingestion, he was fully awake and alert.
4) PEDIATRIC: A 9-month-old boy ingested Gamma-Butyrolactone (GBL) by briefly sucking on 2 "acetone-free" nail polish remover pads (GBL concentration 84%) for less than 1 minute. Within 15 minutes of ingestion, the patient vomited and became drowsy; 30 minutes after ingestion, his GCS was 3 and the patient was comatose. His condition improved with supportive care. At 60 minutes postingestion, the patient's GCS had improved to 6 and by 90 minutes postingestion, the patient's GCS was 12. The patient continued to progress into hyperalertness and extreme giddiness that lasted for several hours. The patient made a full recovery within 8 hours of ingestion (Savage et al, 2007).
5) PEDIATRIC: A 3-year-old girl was found unresponsive after an unintentional ingestion of a chemical containing GBL. The patient presented to the emergency department in a deep coma, with severe hyperglycemia (16.8 mmol/L), hypokalemia, pulmonary edema, hypoxemia, and a coagulopathy. With supportive care and intubation, the girl showed improved clinical status and alertness 12 hours after admission. She was extubated on day 2 and discharged with no lingering sequelae on day 3 of admission (Piastra et al, 2006).
6) ADULT: A 27-year-old man intentionally ingested 100 mL (equivalent to 71 mL pure GBL) of an "acetone-free" nail polish remover and became comatose within 45 minutes of exposure (Rambourg-Schepens et al, 1997). Intubation was required. The patient awoke suddenly 5 hours after ingestion and was agitated requiring sedation; 9 hours after initial exposure the patient was fully alert and oriented.

c) 1,4-BUTANEDIOL

1) CASE REPORT: A 26-year-old man developed seizures, tachypnea (30 breaths/minute), bradycardia (48 BPM), and was comatose after ingesting an unknown amount of an organic inkjet cleaner containing 1,4-BD and butylene glycol. The patient had purchased the product as a sleep aid and antianxiety agent. Approximately 5 hours postingestion, the patient regained consciousness. He left the hospital against medical advice, but was clinically stable, alert, and oriented (Yambo et al, 2004).
2) PEDIATRIC EXPOSURE: A 20-month-old boy lapsed into a coma after ingesting an unknown quantity of toy beads coated with 1,4-Butanediol (Aqua Dots (TM)). Following supportive care, his mental status returned to normal (GSC of 15) and the patient was discharged 23 hours after ingestion (Ortmann et al, 2009).

d) SODIUM OXYBATE

1) CASE REPORT: One patient became unresponsive with brief periods of apnea and incontinence (urine and feces) after ingesting approximately 150 g of sodium oxybate (more than 15 times the maximum recommended dose) (Prod Info Xyrem(R) oral solution, 2009).

e) ABRUPT AWAKENING

1) CASE SERIES: A case series of 15 unconscious people who ingested GHB at a rave party (14 had coingestions of one or more other drugs) looked at the relationship between GHB plasma concentrations and time to awakening/Glasgow coma scores (GCS). All subjects had a GCS <8 at the start of monitoring. The median GHB plasma concentration at arrival was 212 mcg/mL (range 112 to 430 mcg/mL), and subjects maintained a GCS <8 for a median period of 90 minutes (range 30 to 105 minutes). Transition to wakefulness or a transition from a GSC <8 to a GCS >12 occurred quickly over a median time of 30 minutes (range 10 to 50 minutes), and the GHB plasma concentration was found to decrease only slightly over this transition period from a median concentration of 183 mcg/mL (range 100 to 321 mcg/mL) to 150 mcg/mL (range 78 to 256 mcg/mL). The authors concluded that coma from GHB ingestions can persist for long periods of time, after which subjects can awaken suddenly over about 30 minutes. This awakening was associated with only small changes in GHB plasma concentrations. Coingestion of other agents, primarily alcohol, was found to be a major confounder in this study(VanSassenbroeck et al, 2007).

C) SEIZURE

1) WITH POISONING/EXPOSURE

a) GAMMA HYDROXYBUTYRIC ACID

1) Several cases of generalized tonic-clonic seizures and uncontrollable shaking have been reported (Chin et al, 1992; Dyer JE, 1990a).
2) In a retrospective review, neurological events were uncommon. EMS or medical personnel observed no cases of seizure (Chin et al, 1998). However, in 2 cases, seizurelike activity was reported by bystanders prior to the arrival of paramedics.
3) CASE SERIES: In a retrospective review of 78 cases of GHB overdose, 9% developed seizures (Garrison & Muller, 1998).

b) 1,4 BUTANEDIOL

1) PEDIATRIC: A 10-year-old girl experienced a 4 minute generalized seizure after an exposure to 1,4-BD. She also had symptoms of bradycardia, vomiting, and decreased consciousness. It was determined that the exposure was a result of ingesting toy beads that contained 1,4-BD (marketed as Bindeez(TM) in the United Kingdom and Aqua Dots(TM) in the United States). The patient was observed in the emergency department, and she regained alertness within hours of presentation (Gunja et al, 2008).
2) CASE REPORT: A 39-year-old man developed a single witnessed tonic seizure episode (3 minutes) along with altered mental status and incontinence of stool following 7 days of ingesting 10 mL/day 1,4-BD to enhance sleep (Cisek, 2001). It is uncertain whether 1,4-BD or the conversion to GHB produced the seizure.
3) CASE REPORT: After ingesting 15 mL of 1,4-BD, a 22-year-old man and his girlfriend lost consciousness. He developed a seizure, vomiting, aspiration pneumonia, and cardiac/respiratory arrest (GHB blood level 220 mg/liter). He died the next day. Toxicology screen for other drugs of abuse was negative. His girlfriend recovered following several hours of ventilation (Theron et al, 2003).
4) CASE REPORT: A 26-year-old man developed seizures, tachypnea (30 breaths/minute), bradycardia (48 BPM), and was comatose after ingesting an unknown amount of an organic ink jet cleaner containing 1,4-BD and butylene glycol. The patient had purchased the product as a sleep aid and antianxiety agent. Approximately 5 hours postingestion, the patient regained consciousness. He left the hospital against medical advice, but was clinically stable, alert, and oriented (Yambo et al, 2004).

c) GAMMA BUTYROLACTONE

1) CASE REPORT: Gamma-Butyrolactone (GBL): A 39-year-old man experienced seizures during recovery when sedation was weaned following a substantial overdose of gamma-Butyrolactone, a precursor to GHB. The patient was treated with midazolam and successfully extubated 60 hours after ingestion (Roberts et al, 2011).

D) EXTRAPYRAMIDAL DISEASE

1) WITH POISONING/EXPOSURE

a) During onset of coma, after IV administration, random clonic movements of the limbs or face, orofacial dyskinesia, limb chorea, or dystonic foot posture may be seen (Price et al, 1981; Aldrete & Barnes, 1968).

E) ISCHEMIC STROKE

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 30-year-old man collapsed at a night club and was admitted with pinpoint pupils and a Glasgow Coma Score (GCS) of 3/15 requiring intubation and mechanical ventilation. A CT of the head showed a hyperdense basilar artery consistent with a thrombus. Within 2 hours of symptoms, intravenous thrombolytics were administered for presumed basilar artery ischemic stroke. Naloxone had no effect on consciousness level. Propofol needed to be increased to maintain sedation. About 24 hours later, propofol was discontinued and the patient was allowed to awaken and was extubated. An MRI was normal, with no evidence of infarction. The patient admitted to GHB use and a gas-chromatography mass spectrometry analysis of the urine confirmed GHB, cocaine and mephedrone. The patient was discharged to home with no neurologic deficits (Graham et al, 2012).

F) PSYCHOMOTOR AGITATION

1) WITH THERAPEUTIC USE

a) Hypomania, agitation, restlessness, hallucinations, and delusions were seen in 7% to 8% of anesthesia patients (Price et al, 1981; Steel, 1968) .

2) WITH POISONING/EXPOSURE

a) In a prospective observational study of patients (66 presentations in 47 patients) with histories and/or presentations suspicious for GHB intoxication, 40 of 66 presentations (61%) manifested 1 or more episodes of agitation with or without combativeness; 25 had agitation before or after somnolence, obtundation, stupor, and coma (SOSC), 10 had agitation alternating abruptly with SOSC, and 5 had agitation only. Of 40 presentations with agitation, 19 had stimulant cointoxicants (eg, methamphetamine, amphetamine, MDMA, cocaine) confirmed by screen (14) or history (5); 21 of 40 presentations with agitation were negative for stimulants by screen (12) or history (9). Bizarre behavior (eg, doing somersaults, snapping lips and tongue, spastic type movements and bizarre behavior and speech) or self-injurious behaviors (eg, beating his head with his fist, threw himself against a wall) were observed in 14 presentations. In 25 cases, GC/MS detected GHB; 4 of 12 cases with agitation screened negative for stimulants (Zvosec & Smith, 2005).
b) CASE REPORT: A 27-year-old man intentionally ingested 100 mL of "acetone-free" nail polish (equivalent to 72 mL pure GBL) and became comatose within 45 minutes of exposure. Five hours later he awoke abruptly with agitation and confusion necessitating sedation. The patient made a complete recovery (Rambourg-Schepens et al, 1997).
c) CASE REPORT: A 24-year-old man, with a history of Asperger's syndrome and recreational drug abuse, requested detoxication after a 19-month history of daily GBL use. After difficulty obtaining the drug, the patient began diluting the content of nail varnish remover pads with water and ingested 3 mL every 2 hours; he described withdrawal symptoms without frequent drug dosing. He became acutely psychotic about 5 hours after admission despite benzodiazepine therapy. The patient had persistent symptoms of agitation for days and required large doses of lorazepam and haloperidol. His clinical course was complicated by acute renal failure, hypoxia requiring ventilation, and aspiration pneumonia. The patient gradually improved and he was transferred to a psychiatric unit (Bhattacharya et al, 2011).
d) CASE SERIES: Li et al (1998) reported extreme combativeness in 7 GHB exposures when stimulated despite almost total respiratory depression. All patients required physical restraints to protect themselves and hospital personnel.

G) HEADACHE

1) WITH THERAPEUTIC USE

a) SODIUM OXYBATE: In clinical trials (n=177), headache developed in 22% of narcoleptic patients receiving sodium oxybate (Prod Info Xyrem(R) oral solution, 2009).

H) DROWSY

1) WITH THERAPEUTIC USE

a) SODIUM OXYBATE: In clinical trials (n=177), somnolence developed in 8% of narcoleptic patients receiving sodium oxybate (Prod Info Xyrem(R) oral solution, 2009).

I) DIZZINESS

1) WITH POISONING/EXPOSURE

a) Dizziness is commonly reported; may persist for up to 2 weeks after a dose (Chin et al, 1992; Dyer, 1991; Dyer JE, 1990a; Normann S, 1990) .

J) ATAXIA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: One teaspoonful of GHB resulted in the inability of a patient to rise, turn over, or move her extremities (Gilmore et al, 1991).

K) FATIGUE

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Fatigue and weakness lasting up to 3 days were reported after a 1 teaspoonful dose in an adult (Gilmore et al, 1991).

Gastrointestinal

3.8.2)

A) NAUSEA AND VOMITING

1) WITH THERAPEUTIC USE

a) In clinical trials (n=177), nausea (21%) and vomiting (8%) developed in narcoleptic patients receiving sodium oxybate (Prod Info Xyrem(R) oral solution, 2009).
b) INCIDENCE: Occurred in 3 of 10 cases of oral ingestion in adults (Chin et al, 1992); common when used orally to induce anesthesia during induction, and upon emergence from IV anesthesia (incidence greater than 50%) (Takahara et al, 1977; Brown, 1970; Vickers, 1969).
c) DOSE: Occurs after as little as 1 teaspoon (Chin et al, 1992; Gilmore et al, 1991; Dyer JE, 1990).
d) MECHANISM believed to be centrally mediated (Vickers, 1969).

2) WITH POISONING/EXPOSURE

a) Nausea and vomiting have been reported after ingestion of teaspoon amounts and IV administration. Excessive salivation has also been described.
b) CASE SERIES: In a retrospective review of self-reported GHB ingestion, vomiting was common. Vomiting appeared to be inversely related to initial GCS score with 85% of the reported cases having an initial GCS score of 8 or less (Chin et al, 1998). Typically, vomiting occurred as patients were regaining consciousness.
c) CASE SERIES: Of 78 cases of GHB overdose, 22% of cases reported vomiting following ingestion (Garrison & Muller, 1998).
d) CASE REPORT: Two children (2-year-old and 10-year-old) experienced decreased consciousness as well as multiple bouts of vomiting after an exposure to 1,4-BD. It was determined the exposure was a result of ingesting toy beads that contained 1,4-BD (marketed as Bindeez(TM) in the United Kingdom and Aqua Dots(TM) in the United States). Both children regained alertness within hours of presentation (Gunja et al, 2008).

B) EXCESSIVE SALIVATION

1) WITH THERAPEUTIC USE

a) Excessive salivation has been noted with therapeutic use (Steel, 1968).

C) BURN

1) WITH POISONING/EXPOSURE

a) Alkali burns of the esophagus occurred in a 19-year-old woman following the illicit manufacture of GHB (Dyer & Reed, 1997a). The patient developed mid-esophageal stricture and required repeated dilations over a 10-week period.
b) Home recipes of GHB start with GBL and the ring is opened by adding alkali, usually sodium hydroxide, which when heated forms GHB. If the sodium hydroxide is not completely consumed, the liquid will be strongly alkaline.

Genitourinary

3.10.2)

A) URINARY INCONTINENCE

1) WITH THERAPEUTIC USE

a) SODIUM OXYBATE: In clinical trials (n=177), urinary incontinence developed in 7% of narcoleptic patients receiving sodium oxybate (Prod Info Xyrem(R) oral solution, 2009).

2) WITH POISONING/EXPOSURE

a) Urinary incontinence and urgency have been reported in several cases of oral ingestion (Chin et al, 1992).
b) SODIUM OXYBATE: One patient became unresponsive with brief periods of apnea and incontinence (urine and feces) after ingesting approximately 150 g of sodium oxybate (more than 15 times the maximum recommended dose). The patient recovered without sequelae (Prod Info Xyrem(R) oral solution, 2009).

B) ACUTE RENAL FAILURE SYNDROME

1) WITH POISONING/EXPOSURE

a) GAMMA BUTYROLACTONE (GBL)

1) CASE REPORT: A 24-year-old man with a history of Asperger's syndrome and recreational drug abuse had a 19-month history of daily GBL use. After difficulty obtaining the drug, the patient began diluting the content of nail varnish remover pads with water and ingested 3 mL every 2 hours; he described withdrawal symptoms without the drug. Upon arrival, he was requesting detoxification and reported GBL use 3 hours prior to admission; routine labs were sent. He was started on benzodiazepines (chlordiazepoxide) and within 5 hours he became acutely psychotic with hypertension, tachycardia, and pyrexia. Labs were consistent with acute renal failure (urea 14.7; creatinine: 286; creatinine kinase: 858; and potassium 3.6). Treatment included IV rehydration with saline and a midazolam infusion. A renal ultrasound was normal. During the first night, the patient became suddenly hypoxic with respiratory depression, requiring mechanical ventilation. He continued to be agitated requiring large doses of lorazepam and haloperidol. Creatine kinase rose to 13,172 over 48 hours. Renal function normalized with treatment. His agitation gradually improved over several days and he was discharged to a psychiatric unit (Bhattacharya et al, 2011).

C) BLOOD IN URINE

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Two young adults developed painless hematuria following chronic exposure to "home brewed" GHB, which was ingested at bedtime 4 days per week for 2 months (Wiley et al, 1998). The authors discovered that the patients substituted swimming pool chlorine tablets (calcium hypochlorite) for the sodium hydroxide component that was specified in the GHB kit. Symptoms resolved in both individuals with drug cessation.

Acid-Base

3.11.2)

A) ACIDOSIS

1) WITH THERAPEUTIC USE

a) Metabolic acidosis has been noted when used as an anesthetic (Vickers, 1969).

2) WITH POISONING/EXPOSURE

a) CASE SERIES: In a retrospective review of self-reported GHB ingestion, 30 patients had ABG measurements; 9 (29%) cases had a pH of 7.30 or less (Chin et al, 1998). Twenty-one patients had a pCO2 of 45 mmHg or more. The relationship between the degree of acidosis and sedation were not well defined in this study.
b) CASE REPORTS: Gamma-butyrolactone (GBL): A 45-year-old man collapsed and was unconscious after ingesting an estimated 50 mL GBL (equipotent to 385 mg/kg of GHB) requiring prehospital intubation. Upon admission, arterial blood gases revealed metabolic and respiratory acidosis. Sixteen hours later the patient awoke and was successfully extubated and completely recovered. The second patient was a young adult that was found unconscious with an empty bottle of GBL and had a combination metabolic lactic and respiratory acidosis. He was also intubated due to coma and respiratory depression. Following a brief period, the patient awoke and was easily extubated (van Vugt & Hofhuizen, 2012).
c) CASE REPORT: Gamma-butyrolactone (GBL): A 39-year-old man developed coma, respiratory failure, and severe mixed respiratory and metabolic acidosis secondary to ingestion of a substantial quantity of gamma-butyrolactone, a precursor to GHB. On presentation to the ED he was immediately intubated and then sustained a cardiac arrest. Metabolic acidosis persisted postresuscitation. The patient's pH, measured several hours after ingestion, was 6.82 to 6.99, with an increased anion gap of 38 mEq/L and a minor contribution from lactate (26.1 to 44.1 mg/dL [2.9 to 4.9 mmol/L]). The patient was initiated on continuous venovenous hemodiafiltration approximately 8 hours after ingestion; his hemodynamic status quickly improved, and he recovered (Roberts et al, 2011).
d) PEDIATRIC EXPOSURE: Gamma-Butyrolactone (GBL): A 9-month-old boy ingested GBL by briefly sucking on 2 "acetone-free" nail polish remover pads (GBL concentration 84%) for less than 1 minute. Upon presentation, the patient had hypotension, bradycardia, and was in shock; blood gases revealed mild respiratory acidosis. He was treated with supportive care and made a full recovery 8 hours after ingestion (Savage et al, 2007).

Hematologic

3.13.2)

A) PORPHYRIA DUE TO TOXIC EFFECT OF SUBSTANCE

1) WITH THERAPEUTIC USE

a) GHB is considered unsafe for patients with porphyria; it has been shown to be porphyrinogenic in animals and in vitro systems (JEF Reynolds , 1990).

B) BLOOD COAGULATION DISORDER

1) WITH POISONING/EXPOSURE

a) GAMMA BUTYROLACTONE (GBL)

1) PEDIATRIC: A 3-year-old girl was found unresponsive after an unintentional ingestion of a chemical containing GBL. At presentation, she was comatose and hypoventilating, and had laboratory evidence of hyperglycemia, hypokalemia, and a coagulopathy. Coagulation screening showed an increased d-dimer (1743 nanograms/liter; normal less than 278 nanograms/liter), prothrombin activity 70%, activated partial thromboplastin time 24 seconds, fibrinogen 367 mg/dL, decreased antithrombin III (58%), and reduced protein C (55.3%). Within 12 hours of presentation, the patient was clinically improving, and she was extubated the following day. By day 3 of admission, the patient's hypercoagulability was decreased and she was discharged (Piastra et al, 2006).

Dermatologic

3.14.2)

A) EXCESSIVE SWEATING

1) WITH THERAPEUTIC USE

a) Profuse sweating was noted in some patients treated with GHB as an anesthetic (Aldrete & Barnes, 1968).

2) WITH POISONING/EXPOSURE

a) CASE SERIES: Of 78 cases of GHB overdose, diaphoresis was reported in 35% of cases (Garrison & Muller, 1998).

Musculoskeletal

3.15.2)

A) DECREASED MUSCLE TONE

1) WITH THERAPEUTIC USE

a) Hypotonia of skeletal muscles occurs by depressing the spinal cord (Vickers, 1969).

Endocrine

3.16.2)

A) HYPERGLYCEMIA

1) WITH THERAPEUTIC USE

a) A slight rise in blood sugar has been noted when the drug has been used as an anesthetic (Vickers, 1969).

2) WITH POISONING/EXPOSURE

a) The blood glucose in a 5 gram overdose reported by Dyer (1990) was 206 mg/dL, but the baseline for this patient was unknown.
b) CASE REPORT: A 3-year-old girl was found unresponsive after an unintentional ingestion of a chemical containing GBL. The patient had severe hyperglycemia (16.8 mmol/L), as well as pulmonary edema, hypoxemia, coagulopathy, hypokalemia, and coma. With supportive care and intubation, the girl made a full recovery and was discharged on day 3 of hospitalization (Piastra et al, 2006).

B) DISORDER OF ENDOCRINE SYSTEM

1) WITH POISONING/EXPOSURE

a) Growth hormone levels increased after injection of 2.5 grams of GHB in healthy adults, reaching a peak at 60 minutes postinjection (Takahara et al, 1977).

C) HYPERPROLACTINEMIA

1) WITH POISONING/EXPOSURE

a) Prolactin levels rose at 15 and 30 minutes after injection of 2.5 grams of GHB (Takahara et al, 1977).

Reproductive

3.20.1)

A) Sodium oxybate is classified as FDA pregnancy category C. GHB does cross the placenta, but no overt effects have been noted in the fetus. GHB has been used as an obstetric anesthetic.

3.20.2)

A) PLACENTAL BARRIER

1) GHB does cross the placenta, but the effect on the fetus is unknown. Fetal depression has not been a problem when used in obstetrics (Vickers, 1969).

B) ANIMAL STUDIES

1) SODIUM OXYBATE

a) RATS, RABBITS: Pregnant rats administered sodium oxybate in doses up to 1000 mg/kg (roughly equal to the maximum recommended dose in humans) and rabbits in doses up to 1200 mg/kg (approximately 3 times the maximum recommended dose in humans) throughout organogenesis did not deliver offsprings with increased incidence of malformations. Administration of oral sodium oxybate up to 1000 mg/kg/day during pregnancy and lactation in rats resulted in increased stillbirths, decreased offspring viability, and body weight gain. There was no evidence of pre- or postnatal developmental toxicity (Prod Info Xyrem(R) oral solution, 2012).

3.20.3)

A) LABOR ABNORMAL

1) Geldenhuys et al (1968) reported increased uterine contractions in obstetric patients given GHB for anesthesia (Geldenhuys et al, 1968).

B) LABOR AND DELIVERY

1) SODIUM OXYBATE

a) There are no adequate or well controlled studies of sodium oxybate use during human pregnancy. There is insufficient clinical experience with sodium oxybate in pregnancy to confirm its safety in that patient population. The manufacturer reports that infants exposed to sodium oxybate during obstetric anesthesia had stable cardiovascular and respiratory measures, but were very sleepy. Apgar scores were slightly decreased. Twenty minutes after injection, the rate of uterine contractions decreased. Placental transfer of the drug is described as rapid; umbilical vein levels were at most 25% of maternal plasma concentrations. Sodium oxybate was undetectable in infant's blood 30 minutes after delivery. The rate of elimination between a 2-day-old infant and a 15-year-old patient were reported as similar. The manufacturer recommends the use of sodium oxybate during pregnancy only if the potential maternal benefit outweighs the potential fetal risk (Prod Info Xyrem(R) oral solution, 2012).

C) PREGNANCY CATEGORY

1) SODIUM OXYBATE

a) Sodium oxybate is classified as FDA pregnancy category C (Prod Info Xyrem(R) oral solution, 2012).

3.20.4)

A) LACK OF INFORMATION

1) SODIUM OXYBATE

a) Lactation studies with sodium oxybate have not yet been conducted. It is not known whether sodium oxybate is excreted into human breast milk and the potential for adverse effects in the nursing infant from exposure to the drug are unknown. Due to the lack of safety information and because many drugs are excreted in breast milk, the manufacturer recommends using caution when administering sodium oxybate to a lactating woman (Prod Info Xyrem(R) oral solution, 2012).

3.20.5)

A) ANIMAL STUDIES

1) SODIUM OXYBATE

a) RATS: Administration of oral sodium oxybate 150, 300, or 1000 mg/kg/day in male and female rats prior to mating with continued use in females throughout early gestation had no adverse effects on fertility (Prod Info Xyrem(R) oral solution, 2012).

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS502-85-2 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) Not Listed

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor vital signs, mental status, and the ability to protect the airway.
B) Serum glucose, electrolytes, pulse oximeter, and ECG should be obtained as a part of the general assessment of the patient.
C) Serum levels are not routinely available or useful in patient management. A serum concentration greater than 50 mg/L is associated with loss of consciousness, and a concentration greater than 260 mg/L produces unresponsive coma. The duration of the detection of GHB in the blood and the urine is short (6 and 12 hours, respectively, after therapeutic doses).

4.1.2)

A) It has been reported that endogenous human levels of GHB are typically less than 10 mg/L in urine and less than 4 mg/L in blood/plasma. These levels can be 10 to 1000 fold higher after exogenous ingestion. Since GHB is rapidly metabolized and excreted, blood/plasma and levels can be comparable to endogenous levels within 8 to 12 hours after ingestion. In GHB-unrelated fatalities, GHB has also been found to be detected in post-mortem biological fluid (Elliott et al, 2004).
B) CASE SERIES - A case series of 15 unconscious subjects who ingested GHB at a rave party (14 had co-ingestions of one or more other drugs) looked at the relationship between GHB plasma concentrations and time to awakening/Glasgow coma scores (GCS). All subjects had a GCS of less than 8 at the start of monitoring. The median GHB plasma concentration at arrival was 212 mcg/mL (range: 112 to 430 mcg/mL), and subjects maintained a GCS of less than 8 for a median period of 90 minutes (range 30 to 105 minutes). Transition to wakefulness or a transition from a GSC of less than 8 to a GCS greater than 12 occurred quickly over a median time of 30 minutes (range 10 to 50 minutes), and the GHB plasma concentration was found to decrease only slightly over this transition period from a median concentration of 183 mcg/mL (range 100 to 321 mcg/mL) to 150 mcg/mL (range 78 to 256 mcg/mL). The authors concluded that coma from GHB ingestions can persist for long periods of time, after which subjects can awaken suddenly over about 30 minutes. This awakening was associated with only small changes in GHB plasma concentrations. Coingestion of other agents, primarily alcohol, was found to be a major confounder in this study (VanSassenbroeck et al, 2007).
C) POSTMORTEM GHB CONCENTRATIONS

1) A cut-off value for GHB in blood of 30 mcg/mL has bee proposed to discriminate between endogenous and exogenous GHB in postmortem specimens, provided there is little or no evidence of putrefaction and the postmortem interval is 48 hours or less (Moriya & Hashimoto, 2005).
2) To discriminate between endogenous formation and exposure, one study tested GHB in various postmortem biological fluids (cardiac blood, femoral blood, bile, and vitreous humor) in 71 autopsy cases in which GHB exposure could be excluded. GHB was present in cardiac blood in all cases, with a range of concentrations from 0.4 to 409 mg/L. Fourteen cases had concentrations in cardiac blood of greater than 50 mg/L. As there was no data to support GHB intoxication in any of these cases, this was considered to be postmortem formation of GHB. In 7 of these cases with cardiac blood GHB concentration of 55 to 409 mg/L, bile GHB concentration was 6.1 to 238 mg/L. In 5 cases cardiac blood GHB was 51 to 409 mg/L, compared with femoral blood concentrations of 17 to 44 mg/L. In 6 cases cardiac blood concentrations were 51 to 409 mg/L, compared with vitreous humor concentration of 3.9 to 21.4 mg/L. It was recommended to test for GHB in cardiac blood as a screening, and to confirm any result higher than 50 mg/L by a simultaneous analysis in femoral blood and vitreous humor, using a proposed cut-off in these specimens of 50 mg/L (Kintz et al, 2004).
3) Analysis of putrefied postmortem blood indicated that there was no observed relationship between endogenous GHB levels and concentrations of common putrefactive markers, such as tryptamine and phenyl-2-ethylamine. In addition, the authors proposed the possible influence of certain microorganisms (eg; Pseudomonas aeruginosa) on the production of GHB (Elliott et al, 2004).

4.1.3)

A) A cut-off value for GHB in urine of 10 mcg/mL has been proposed to discriminate between endogenous and exogenous GHB in postmortem specimens, provided there is little or no evidence of putrefaction and the postmortem interval is 48 hours or less (Moriya & Hashimoto, 2005). GHB concentration can be 10 to 1000 fold higher after exogenous ingestion. Since GHB is rapidly metabolized and excreted, blood/plasma and urine levels can be comparable to endogenous levels within 8 to 12 hours after ingestion. In GHB-unrelated fatalities, GHB has also been found to be detected in postmortem biological fluid (Elliott et al, 2004).
B) The presence of GHB in urine does not necessarily indicate GHB ingestion. It was found that some GHB urine levels were elevated in GHB-unrelated fatalities; therefore, the use of urine levels to discriminate between endogenous formation and GHB exposure was not recommended (Kintz et al, 2004).
C) In vitro production of GHB in the urine may occur and cause artificially elevated concentrations in urine. Significant elevations of GHB were observed in many urine samples from users who reported they had never used GHB (n=31). Nine of the 31 samples had no detectable GHB at the beginning of the study; however, after all specimens were stored under refrigeration (5 degrees C) without preservative for 6 months, GC-MS testing of all samples revealed detectable levels of GHB. None of the samples exceeded the endogenous GHB level of 10 mcg/mL throughout the study period (LeBeau et al, 2007).

Methods

A)

1) 4-hydroxybutyrate can be extracted from plasma as 4-butyrolactone and subsequently analyzed using gas chromatography (GLC) (Van Der Pol et al, 1975).
2) Louagie et al (1997) described a method to determine GHB by gas chromatography-mass spectrometry after acetonitrile precipitation and derivation with N-methyl-N-trimethylsilyltrifluoroacetamide, using valproic acid as the internal standard.
3) LoVecchio et al (1998) described a method to detect GBL in urine using a gas chromatography and flame ionization detection.
4) Kohrs & Porter (1999) reported that the mass spectrometry assay for GHB used in either urine or serum studies is unable to differentiate between GHB and GBL.
5) Couper & Logan (2000) described a simple liquid-liquid extraction procedure to analyze GHB in biological fluids by gas chromatography-mass spectrometry. This method was able to detect GHB in both blood and urine in several case reports.
6) Gas chromatography-mass spectrometry methodology has been used successfully to detect 1,4-butanediol (BD) in human urine; one of the studies also found that 1,4-BD rapidly converts to GHB in vivo (Lewis-Younger et al, 2001; Gunja et al, 2008).
7) Gas chromatography-mass spectrometry has been used to detect GHB in postmortem biological fluids (cardiac blood, femoral blood, bile, and vitreous humor) (Kintz et al, 2004).

B)

1) Badcock & Zotti (1999) described a qualitative screening test (spot test) for GHB in urine which is rapid and sensitive. Results are obtained within 10 minutes, and are based on acid conversion to the corresponding butyrolactone and subsequent color formation (intense blue/green color indicates GHB) with nitroprusside in alkaline solution.
2) Laboratories that analyze urine samples for GHB include: National Medical Services (1-800-522-6671 or www.nmslab.com) and Elsohly Laboratories (662-236-2609 or www.elsohly.com) which tests for both GHB and Rohypnol. In general, samples should be collected as soon as possible in forensically acceptable sampling. Of note, blood sampling can be done, but is generally more expensive, requires rapid collection, and special handling.

C)

1) Robert et al (2001) reported the successful use of proton NMR spectroscopy in an unsuspected case of gamma hydroxybutyrate poisoning in a 55-year-old woman with coma and transient metabolic acidosis. High resolution NMR spectroscopy is used to detect and quantify low molecular weight metabolites in biological fluids such as plasma and urine.

D)

1) Capillary zone electrophoresis with indirect detection has been used to determine GHB in biological samples. The authors reported that this method offers a rapid, precise and accurate method for GHB determination of biological fluids following an overdose (Bortolotti et al, 2004).

Treatment

Life Support

A)

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients who require ventilator support or other intensive care measures should be admitted to an intensive care setting (CDC, 1990).
B) Health care personnel are encouraged to report cases of GHB-related illness to their regional poison control centers and state health departments (CDC, 1990).

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Any symptomatic patient should be monitored and observed until symptoms are resolved. Patients who are in stable condition and asymptomatic may be released from the emergency department within 4 to 8 hours (Li et al, 1998). Patients with a history of concurrent 1,4-butanediol and alcohol ingestion should be observed until blood alcohol concentrations are undetectable (Schneidereit et al, 2000).

1) CASE SERIES: In a cases series of 78 GHB overdose exposures, symptoms of decreased level of consciousness rapidly resolved (Garrison & Mueller, 1998). The mean time from arrival to the emergency department to becoming awake and alert was 1.9 hours, and mean time from arrival to discharge was 3.0 hours. Only 3 patients required hospital admission. Of 59 cases, 63% tested positive for ethanol.

B) Patients may require ventilator support or other intensive care measures (CDC, 1990). Chin et al (1998) observed that overdoses of GHB alone often resulted in spontaneous recovery and return of consciousness within a few hours (Chin et al, 1998). Patients should be referred for psychiatric and substance abuse counseling as appropriate.
C) Health care personnel are encouraged to report cases of GHB-related illness to their regional poison control centers and state health departments (CDC, 1990).

Monitoring

A)

B)

C)

Oral Exposure

6.5.1)

A) PREHOSPITAL: Do not give charcoal or induce vomiting because of the risk of rapid loss of consciousness and loss of airway protective reflexes, which may lead to pulmonary aspiration.

6.5.2)

A) The small amount of GHB usually ingested is rapidly absorbed, so gastric lavage, and activated charcoal are of doubtful benefit and not recommended.

6.5.3)

A) MONITORING OF PATIENT

1) Monitor vital signs, mental status, and the ability to protect the airway.
2) Serum glucose, electrolytes, pulse oximeter, and ECG should be obtained as a part of the general assessment of the patient.
3) Serum levels are not routinely available or useful in patient management. A serum concentration greater than 50 mg/L is associated with loss of consciousness, and a concentration greater than 260 mg/L produces unresponsive coma . The duration of the detection of GHB in the blood and the urine is short (6 and 12 hours, respectively, after therapeutic doses).
4) Patients with an initial GCS of 8 or less may develop more frequent episodes of bradycardia and emesis. Monitor neurological function and Glasgow coma scores (GCS) (Chin et al, 1998).
5) Initial GCS scores may be indicative of recovery time (the lower the score - the longer the time to regain consciousness) (Chin et al, 1998).

B) NALOXONE

1) Some of the effects of GHB are antagonized by naloxone in animals; efficacy in humans has not been demonstrated (Snead & Bearden, 1980).
2) Li et al (1998) reported no clinical response in 4 patients given naloxone following GHB intoxication.

a) The authors reported that naloxone has been shown to have equivocal results. In rodent studies it was found to be beneficial while it failed to reverse GHB-induced coma in both mice and human beings.

C) FLUMAZENIL

1) Flumazenil is a specific competitive antagonist at the benzodiazepine receptor and is not an effective reversal agent for GHB overdoses (Ragg, 1997; Williams, 1998). Its use can potentially make treatment of the myoclonic seizure-like activity more difficult because benzodiazepines are indirect gamma amino butyrate (GABA) agonists and their beneficial effects would be blocked by flumazenil (Williams, 1998).
2) PEDIATRIC: A 4-year-old boy was inadvertently exposed to an unknown amount of GHB and rapidly became unresponsive and required intubation for respiratory arrest (Boyer et al, 2000). Flumazenil and naloxone were given at the time of arrival to the emergency department; no response was noted. The patient was given supportive care and neurologically improved over 6 hours. Extubation was successful at this time. The patient was treated for a left-lower lobe aspiration pneumonia with no permanent neurological deficits reported.

D) PHYSOSTIGMINE

1) SUMMARY: Several case reports suggest that physostigmine may reverse the CNS depressant effects of GHB. There have been no controlled studies evaluating the efficacy and safety of physostigmine in this setting. Most patients with GHB overdose awaken spontaneously within a few hours of presentation and serious morbidity or mortality are unusual if adequate airway management and respiratory support is provided. Routine use of physostigmine is not recommended.
2) CASE REPORT: Two young adults ingested an unknown quantity of GHB and were comatose upon initial evaluation. Normal saline infusions were begun which were then followed by 2 milligrams physostigmine intravenously; within 5 minutes respirations began to increase and the patients regained consciousness soon after (Yates & Viera, 2000). No adverse effects were reported upon follow-up. It is not clear that physostigmine was responsible for awakening in these patients; routine use of physostigmine in GHB overdose is not recommended (Yates & Viera, 2000).
3) CASE REPORT: Physostigmine was used in 3 adults presenting with GHB overdose; Glasgow Coma Scale scores were between 3 to 6 on admission to the emergency department(Caldicott & Kuhn, 2001). Total doses of 1.0 to 2.0 milligram boluses of physostigmine were given; the patients became arousable with improved GCS within 5 to 10 minutes. Patients were observed for several hours and discharged without incident.
4) INSUFFICIENT EVIDENCE: Boyer et al (2001) stated that there is insufficient scientific evidence and limited studies (2 studies have been conducted which lacked placebo control) to support the use of physostigmine (which can further worsen bradycardia) in the management of GHB toxicity. The authors suggested that the risks currently outweigh the benefits (Boyer et al, 2001).

E) BACLOFEN

1) EXPERIMENTAL THERAPY

a) POTENTIAL TOXICITY OF COINGESTION

1) CASE REPORT: A 21-year-old woman with a 4-year history of GHB and amphetamine dependence had gone through detoxification but had begun to relapse and started using approximately 82 g of GHB on the weekends because she felt bored without the drug. She reported issues with decreased memory, disorganization, and forgetfulness. During her fourth GHB detoxification process, she was started on baclofen as an experimental treatment to assist with relapse prevention. She was receiving 40 mg/day and she remained abstinent for 2 months when she collapsed suddenly in front of staff and was unconscious. A 100 mL bottle of GHB was found in her pocket. She had short periods of apnea and only responded to painful stimuli. She was transferred to a general emergency department for a higher level of care and monitoring. Her vital signs were essentially normal upon admission and a chest x-ray was normal. She was observed for several hours and became alert and was transferred back to the addiction treatment center. In this case, the combined use of baclofen and GHB was characterized by a rapid onset of coma along with bradypnea with an essentially normal blood pressure and heart rate (Kamal et al, 2015).

F) EXPERIMENTAL THERAPY

1) ANIMAL DATA

a) Based on evidence that 1,4-butanediol (BD) undergoes biotransformation by hepatic alcohol dehydrogenase to GHB, CD-1 mice were pretreated with intraperitoneal injections of 4-methylpyrazole (4-MP, fomepizole) (25 milligrams/kilogram). The study found that 4-MP inhibited biotransformation of 1,4-BD to GHB as assessed by neuro exam at 10 minute intervals up to 60 minutes after being given 60 to 6000 milligrams/kilogram (Quang et al, 2000).
b) In a follow-up study, male CD-1 mice were given 4-MP (fomepizole) as both a pretreatment (25 milligrams/kilogram followed 5 minutes later with 1,4-BD (600 milligrams/kilogram IVP) and as an antidote (1,4-BD 600 milligrams/kilogram first, followed by 4-MP 25 milligrams/kilogram IVP). In each setting 4-MP was found to be effective in blocking in vivo biotransformation of 1,4-BD to GHB. Findings also indicated that the presence of 1,4-BD in blood concentrations resulted in normal neurological findings (i.e., righting reflex or rotarod test), while GHB concentrations resulted in neurological abnormalities (Quang et al, 2001).
c) A similar study, involving CD-1 mice who received 4-MP as antidotal therapy (25 mg/kg IVP) following 1,4-BD poisoning (600 mg/kg IVP), also showed that treatment with 4-MP was effective in attenuating the toxic effects of 1,4-BD by inhibiting its conversion in vivo to GHB (Quang et al, 2004).
d) CASE REPORT

1) A 43-year-old man with a history of regular GHB use, ingested 30 mL (approximately 3 grams) of a homemade 1,4-butanediol solution and developed 2 generalized seizures. Glasgow Coma Score on admission was 10. Based on an initial suspicion of a toxic alcohol ingestion, a loading dose of 10 mg/kg (700 mg) of fomepizole IV was given. The patient awoke to a normal mentation 3 hours after fomepizole was administered. A total dose of 2100 mg was administered over a 24 hour period. Given the generally short half-life of GHB and its analogs, the authors could not determine if fomepizole was beneficial in this case, and suggested further study (Megarbane et al, 2002). Since most patients recover from intoxication within 6 hours or less with basic supportive measures, routine use of fomepizole is not warranted.

G) AIRWAY MANAGEMENT

1) Endotracheal intubation should be considered in any patient with an unprotected airway.

H) BRADYCARDIA

1) Most patients with bradycardia do not require treatment. Treat hemodynamically significant bradycardia with atropine. Assure adequate oxygenation and manage the patient's airway as clinically indicated.
2) Bradycardia seen when GHB is used as an anesthetic was controlled with atropine in some cases (Vickers, 1969; Aldrete & Barnes, 1968), and not in others (Steel, 1968).
3) Atropine was used successfully to treat symptomatic bradycardia (Chin et al, 1998).
4) ATROPINE/DOSE

a) ADULT BRADYCARDIA: BOLUS: Give 0.5 milligram IV, repeat every 3 to 5 minutes, if bradycardia persists. Maximum: 3 milligrams (0.04 milligram/kilogram) intravenously is a fully vagolytic dose in most adults. Doses less than 0.5 milligram may cause paradoxical bradycardia in adults (Neumar et al, 2010).
b) PEDIATRIC DOSE: As premedication for emergency intubation in specific situations (eg, giving succinylchoine to facilitate intubation), give 0.02 milligram/kilogram intravenously or intraosseously (0.04 to 0.06 mg/kg via endotracheal tube followed by several positive pressure breaths) repeat once, if needed (de Caen et al, 2015; Kleinman et al, 2010). MAXIMUM SINGLE DOSE: Children: 0.5 milligram; adolescent: 1 mg.

1) There is no minimum dose (de Caen et al, 2015).
2) MAXIMUM TOTAL DOSE: Children: 1 milligram; adolescents: 2 milligrams (Kleinman et al, 2010).

I) SEIZURE

1) SUMMARY

a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).

2) DIAZEPAM

a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .

3) NO INTRAVENOUS ACCESS

a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).

4) LORAZEPAM

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).

5) PHENOBARBITAL

a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).

6) OTHER AGENTS

a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):

1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

7) In monkeys phenytoin increases GHB-induced myoclonus (Snead, 1978); benzodiazepines and barbiturates are preferred for the treatment of seizures.

Enhanced Elimination

A)

1) There is no role for enhanced removal procedures such as dialysis and hemoperfusion.
2) Continuous venovenous hemodiafiltration was used to correct severe metabolic acidosis in one incidence where a 39-year-old male developed severe, persistent metabolic acidosis after cardiopulmonary resuscitation secondary to ingestion of a substantial quantity of gamma-Butyrolactone, a precursor to GHB (GHB serum level 60 to 90 minutes post ingestion was 2,498 mg/L (24 mmol/L). Once stabilized, the patient's acidosis persisted despite standard care but resolved after continuous venovenous hemodiafiltration was initiated. The patient also experienced seizures when weaned from sedation when extubated but eventually made a full recovery (Roberts et al, 2011).

Abstracts

Case Reports

A)

1) ADULT

a) GAMMA HYDROXYBUTYRIC ACID (GHB)

1) A male adult was seen in the emergency department approximately 2 hours after ingesting approximately 15 grams of GHB. The patient was unresponsive to pain. Symptomatic care was administered and the patient was discharged asymptomatic (Dyer JE, 1990).
2) An estimated 5 g of GHB in a 23-year-old produced vomiting and unconsciousness. The patient was found 2.5 hours postingestion and brought to the emergency department comatose with a depressed mental status and responsive only to pain. Clinical signs included a blood pressure of 159/90 mmHg, a heart rate of 60 beats/minute, respirations 20/minute, and pupils sluggishly reacting and 6 mm in diameter. The patient was treated symptomatically, and discharged asymptomatic, 10 hours postingestion (Dyer JE, 1990).
3) A 39-year-old woman developed a "high" sensation, pressured speech, ebullience, intense drowsiness, confusion, difficulty breathing, and arm twitching after ingestion of her fourth 1/2 teaspoon dose during a day (Chin et al, 1992) She was found hallucinating. Twitching continued for 45 minutes. After admission she alternated between wakeful and sleepy states, with irregular leg twitching. Laboratory values were within normal limits. The patient was discharged without sequelae after an overnight hospitalization.
4) A 28-year-old woman ingested an unknown amount of GHB along with mixed drinks. She was observed to be confused, shaking uncontrollably, and banging her head on a wall, followed by a seizure and coma (Chin et al, 1992). Prolonged apneic periods were noted upon arrival to the ED. Treatment included gastric lavage, activated charcoal, intubation, and mechanical ventilation. Recovery was complete.

b) GAMMA BUTYROLACTONE (GBL)

1) CASE REPORT: A 39-year-old man developed coma, respiratory failure and severe mixed respiratory and metabolic acidosis secondary to ingestion of a substantial quantity of gamma-butyrolactone, a precursor to GHB (GHB serum level 60 to 90 minutes postingestion was 2498 mg/L [24 mmol/L]). The patient was immediately intubated upon arrival to the ED. Labs and vital signs at admission were as follows: BP 178/80, GCS 3 of 15, pH 6.75, pCo2 70 mmHg, pO2 483 mmHg, base excess -23 mEq/L and lactate was 26.1 mg/dL (2.9 mEq/L). Shortly after, he developed cardiopulmonary arrest and was successfully resuscitated. Several hours after ingestion, the patient's acidosis persisted. His pH measured 6.82 to 6.99 with an increased anion gap of 38 mEq/L and a minor contribution from lactate (26.1 to 44.1 mg/dL [2.9 to 4.9 mmol/L]). Peak Troponin I and creatinine were also 0.26 ng/mL and 1.63 mg/dL (144 mmol/L), respectively. The patient was initiated on continuous venovenous hemodiafiltration approximately 8 hours after ingestion and his hemodynamic status quickly improved. The patient also experienced seizures when weaned from sedation prior to extubation, but eventually made a full recovery (Roberts et al, 2011).

Range Of Toxicity

Summary

A)

B)

Therapeutic Dose

7.2.1)

A) SODIUM OXYBATE: Indicated for the treatment of cataplexy in narcolepsy: Initial dose: 4.5 g per night divided into 2 equal doses of 2.25 g; maximum: 9 g/day (Prod Info Xyrem(R) oral solution, 2012).

7.2.2)

A) SODIUM OXYBATE: Safety and efficacy have not been established in pediatric patients (Prod Info Xyrem(R) oral solution, 2012).

Minimum Lethal Exposure

A)

1) GAMMA HYDROXYBUTYRIC ACID (GHB)

a) Deaths have been reported following GHB exposure, especially if alcohol and other drugs have been coingested (Jones, 2001; Teter & Guthrie, 2001).
b) CASE SERIES: In a case series involving 226 deaths attributed to GHB use, postmortem GHB plasma levels were detected in the following four groups:

1) Drug-caused deaths without cointoxicants (n=64): 18 to 4400 mg/L, Mean 544 (+/- 161)
2) Death with involvement of one or more depressant cointoxicants (n=62): 9 to 2300 mg/dL, Mean 404 (+/- 112)
3) Death with involvement of one or more stimulant cointoxicants (n=20): 23 to 2900 mg/dL, Mean 525 (+/- 277)
4) Death with involvement of one or more stimulant and depressant cointoxicants (n=29): 67-1680 mg/dl, Mean 451 (+/-167)

c) SURVEILLANCE STUDY: A descriptive surveillance study was conducted to evaluate the clinicopathologic features of GHB-related fatalities using autopsy and investigative reports. During the study period, 20 (GHB/GBL/BD) fatalities were reported with most being young males; the youngest victim was 15 years old. The findings indicated that coingestants were found in 80% of the fatalities with alcohol being present in 60% of the cases.

1) Deaths were often due to respiratory compromise secondary to aspiration of gastric contents, positional asphyxia, or pulmonary edema. Some deaths were associated with traumatic injury or accident, which may have been due to rapid loss of consciousness. Of note, 35% of the cases had cardiomegaly or left ventricular hypertrophy; the authors suggested further evaluation of these findings (Dyer & Haller, 2001).

2) 1,4-BUTANEDIOL

a) CASE REPORT: After ingesting 15 mL of 1,4-butanediol, a 22-year-old man lost consciousness and developed a seizure, vomiting, aspiration pneumonia, shock, and cardiac/respiratory arrest (GHB blood level 220 mg/L). He died the next day. Toxicology screen for other drugs of abuse was negative (Theron et al, 2003).

Maximum Tolerated Exposure

A)

1) In general, single doses of GHB can result in the following: 10 mg/kg causes amnesia and hypotonia; 20 to 30 mg/kg causes miosis, drowsiness, euphoria, vertigo, and somnolence; greater than 30 mg/kg causes myoclonic movements, and hallucinations; 50 mg/kg causes loss of consciousness (patients are usually still arousable); 60 to 70 mg/kg results in coma or unconsciousness (unarousable); greater than 70 mg/kg causes cardiorespiratory depression and death (Yambo et al, 2004; Couper & Logan, 2001).

B)

1) GHB

a) Intravenous injection of 2.5 g of GHB produced sleep within 5 to 20 minutes, with a sleep duration of 30 to 150 minutes (Takahara et al, 1977).
b) Doses of 20 to 30 g per 24 hours of the sodium salt have been taken without serious ill effects (Vickers, 1969).
c) In a case series of GHB ingestion, doses of 0.25 teaspoonful up to 30 g produced symptoms; 1 teaspoonful to 6 produced coma and 3 to 4 teaspoonfuls produced seizures (Dyer JE, 1990a).
d) 60 to 70 mg/kg may result in unarousable coma (Vickers, 1969).
e) A dose of "1 level teaspoonful" induced ataxia within a few minutes and headache, fatigue, weakness, and nausea for the next 3 days (Gilmore et al, 1991).
f) DRIVING IMPAIRMENT: In a case series of suspected drug-impaired drivers, the findings indicated that there was evidence of a dose- or concentration-dependent increase in impairment while taking GHB (Couper & Logan, 2001).

2) GAMMA BUTYROLACTONE

a) CASE REPORTS: Gamma-butyrolactone (GBL): A 45-year-old man collapsed and was unconscious after ingesting an estimated 50 mL GBL (equipotent to 385 mg/kg of GHB) requiring prehospital intubation. Upon admission, arterial blood gases revealed metabolic and respiratory acidosis. Sixteen hours later the patient awoke and was successfully extubated and completely recovered (van Vugt & Hofhuizen, 2012).
b) CASE REPORT: A 17-year-old man was found unconscious after ingesting 2.5 mL of GBL diluted in a soft drink. Following supportive care, he regained consciousness within 3 hours of admission (Hefele et al, 2009).

3) SODIUM OXYBATE

a) SODIUM OXYBATE: One patient became unresponsive with brief periods of apnea and incontinence (urine and feces) after ingesting approximately 150 g of sodium oxybate (more than 15 times the maximum recommended dose). The patient recovered without sequelae (Prod Info Xyrem(R) oral solution, 2009).

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) CONCENTRATION LEVEL

a) SUMMARY - In general, GHB concentrations above 50 milligrams/liter frequently result in sedation, drowsiness and dizziness (Couper & Logan, 2001).
b) Peak blood concentrations of 0.87 and 1.15 millimoles/liter occurred at 1.5 to 2 hours following oral doses of 75 to 100 milligrams/kilogram in humans (Hoes et al, 1980).
c) SYMPTOMS OBSERVED AT VARIOUS CONCENTRATION LEVELS

1) A blood level of 3.2 mg/L for GHB was reported in an adult female who was confused, agitated, and appeared to be hallucinating and having seizures within 8 hours (approximate time level was obtained) of a reported sexual assault (Couper & Logan, 2000).
2) A blood level of 34 mg/L produced incoherence and erratic driving in an adult charged with DUI (Couper & Logan, 2000).
3) At plasma levels less than 0.5 millimole/liter (52 milligrams/liter), patients awakened (Helrich et al, 1964).
4) A blood level of 130 mg/L and a urine level of 1.6 g/L produced confusion, ataxia, and combativeness in a 16-year-old male who recovered without sequelae (Couper & Logan, 2000).
5) GHB at concentrations of 221 mg/L, 339 mg/L and 2.2 g/L in blood, serum and urine, respectively were reported in a male bodybuilder found unconscious (Couper & Logan, 2000).
6) Plasma concentrations greater than 2.5 millimoles/liter (260 milligrams/liter) were associated with coma, unresponsive to noxious stimuli and abolished pharyngeal and laryngeal reflexes (Helrich et al, 1964).

d) FATALITIES

1) Deaths have been reported following GHB exposure, especially if alcohol and other drugs have been coingested (Jones, 2001; Teter & Guthrie, 2001).
2) CASE SERIES: In a case series involving 226 deaths attributed to GHB use, postmortem GHB plasma levels were detected in the following four groups:

a) Drug-caused deaths without cointoxicants (n=64): 18 to 4400 mg/L, Mean 544 (+/- 161)
b) Death with involvement of one or more depressant cointoxicants (n=62): 9 to 2300 mg/dL, Mean 404 (+/- 112)
c) Death with involvement of one or more stimulant cointoxicants (n=20): 23 to 2900 mg/dL, Mean 525 (+/- 277)
d) Death with involvement of one or more stimulant and depressant cointoxicants (n=29): 67-1680 mg/dl, Mean 451 (+/-167)

e) GBL CASE REPORT: A 39-year-old man survived a substantial overdose of gamma-Butyolactone, a precursor to GHB. The specific amount ingested is unknown; however, plasma levels taken 60 to 90 minutes after ingestion revealed a GHB level of 2,498 mg/dl (Roberts et al, 2011).
f) 1,4 BUTANEDIOL CASE REPORT: After ingesting 15 mL of 1,4-butanediol, a 22-year-old male lost consciousness and developed a seizure, vomiting, aspiration pneumonia, shock, and cardiac/respiratory arrest (GHB blood level 220 mg/L). He died the next day. Toxicology screen for other drugs of abuse was negative (Theron et al, 2003).

2) POSTMORTEM SAMPLES

a) GHB

1) SUMMARY - Gamma-hydroxybutyrate is a product of postmortem decomposition, leading to falsely elevated postmortem blood concentrations; one study recommended obtaining urine levels as the preferred methodology in GHB related deaths (Timby et al, 2000). However, other studies have suggested that the presence of GHB in urine does not necessarily indicate GHB ingestion. It was found that some GHB urine levels were elevated in GHB-unrelated fatalities; therefore, the use of urine levels to discriminate between endogenous formation and GHB exposure was not recommended (Kintz et al, 2004).
2) It has been reported that endogenous human levels of GHB are typically less than 10 mg/L in urine and less than 4 mg/L in blood/plasma. These levels can be 10- to 1000-fold higher after exogenous ingestion. Since GHB is rapidly metabolized and excreted, blood/plasma and urine levels can be comparable to endogenous levels within 8 to 12 hours after ingestion. In GHB-unrelated fatalities, GHB has been detected in postmortem biological fluid (Elliott et al, 2004).
3) To discriminate between endogenous formation and exposure, one study tested GHB in various postmortem biological fluids (cardiac blood, femoral blood, bile, and vitreous humor) in 71 autopsy cases in which GHB exposure could be excluded. GHB was present in cardiac blood in all cases, with a range of concentrations from 0.4 to 409 mg/L. Fourteen cases had concentrations in cardiac blood of greater than 50 mg/L. As there was no data to support GHB intoxication in any of these cases, this was considered to be postmortem formation of GHB. In 7 of these cases with cardiac blood GHB concentration of 55 to 409 mg/L, bile GHB concentration was 6.1 to 238 mg/L. In 5 cases cardiac blood GHB was 51 to 409 mg/L, compared with femoral blood concentrations of 17 to 44 mg/L. In 6 cases cardiac blood concentrations were 51 to 409 mg/L, compared with vitreous humor concentration of 3.9 to 21.4 mg/L. It was recommended to test for GHB in cardiac blood as a screening and to confirm any result higher than 50 mg/L by a simultaneous analysis in femoral blood and vitreous humor, using a proposed cut-off in these specimens of 50 mg/L (Kintz et al, 2004).
4) In 25 autopsy cases, endogenous GHB levels in postmortem cerebrospinal fluid (1.8 +/- 1.5 mcg/mL, n=9), vitreous humor (0.9 +/- 1.7 mcg/mL, n=8), bile (1.0 +/- 1.1 mcg/mL, n=9), and urine (0.6 +/- 1.2 mcg/mL, n=12) were significantly lower (P <0.005-0.05) than levels found in femoral venous blood (4.6 +/- 3.4 mcg/mL, n=23). Endogenous GHB levels were similar in femoral venous blood, other blood samples and pericardial fluid. It is proposed that cut-off limits of 30 mcg/mL for blood and 10 mcg/mL for urine may be used to discriminate between exogenous and endogenous GHB in decedents when there is little or no putrefaction (Moriya & Hashimoto, 2005).
5) SURVEILLANCE STUDY - A descriptive surveillance study was conducted to evaluate the clinicopathologic features of GHB-related fatalities using autopsy and investigative reports. During the study period, 20 (GHB/GBL/BD) fatalities were reported with most being young males; the youngest victim was 15 years old. Postmortem blood levels ranged from 140 to 2900 milligrams/liter. Alcohol was the primary coingestant (60% of deaths) with plasma levels ranging from 10 to 170 milligrams/deciliter; stimulants were reported in 4 cases (Dyer & Haller, 2001).
6) CASE REPORTS - Postmortem GHB blood concentrations have ranged from 27 to 121 mg/L in GHB-related deaths. A study of non-GHB-related deaths also found postmortem GHB levels in 15 of 20 autopsy specimens, ranging from 3.2 to 168 mg/L, using GC-MS or GC with flame ionization detection, suggesting that GHB is a normal product of postmortem decomposition. None was found in postmortem urine of unexposed individuals (Fieler et al, 1998).
7) CASE REPORTS - Postmortem GHB blood concentrations ranged from 52 to 121 milligrams/liter in three cases (Teter & Guthrie, 2001).
8) OTHER - Timby et al (2000) reported the following postmortem GHB concentration ranges in 4 cases: 11.5 to 170 micrograms/gram in blood and 258.3 to 620 micrograms/gram in urine.
9) CASE REPORT - Postmortem GHB blood concentration was 34.5 mg of GHB per 100 mL of blood (34.5%) (Jones, 2001).

b) 1,4-BUTANEDIOL

1) CASE REPORT - A 40-year-old female was found dead after ingesting an unknown amount of 1,4-butanediol (BD); several bottles of commercially prepared product were found in the home (Kraner et al, 2000). Toxicology screen revealed no drugs of abuse. The following postmortem GHB and BD levels were assayed by GC/MS (which are reportedly similar to other GHB fatalities):

1) BD - 7.6 mcg/mL blood; 12.3mcg/mL vitreous; 146 mcg/mL urine, and none detected in bile
2) GHB - 280 mcg/mL blood; 324 mcg/mL vitreous; 6171 mcg/mL urine, and 218 mcg/mL bile

Workplace Standards

A)

1) Not Listed

B)

1) Not Listed

C)

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
5) MAK (DFG, 2002): Not Listed
6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

D)

1) Not Listed

Toxicity Information

7.7.1)

A) 1,4-BD-

1) LD50- (INTRAPERITONEAL)RAT:

a) 327 mg/kg ((RTECS, 2000))

B) GHB

1) LD50- (INTRAPERITONEAL)MOUSE:

a) 4200 mg/kg ((RTECS, 2000))

2) LD50- (SUBCUTANEOUS)MOUSE:

a) 4500 mg/kg ((RTECS, 2000))

Pharmacology Toxicology

Pharmacologic Mechanism

A)

1) GHB is a naturally occurring, water-soluble four carbon molecule. It is formed from the precursor molecule, gamma-butyrolactone (GBL) and is metabolized to succinic semialdehyde and gamma-aminobutyric acid (GABA) (Li et al, 1998a). The greatest concentration in humans is in the basal ganglia.
2) NARCOLEPSY - The sleep inducing properties seem to be due to conversion of the lactone (gamma hydroxybutyrolactone) to the free acid (Roth & Giarman, 1968). Orphan Medical, Inc., has studied GHB for the treatment of narcolepsy ((Anon, 2000)). Kalra & Hart (1992) examined the effects of GHB and found that deeper sleep (delta stages 3 and 4) was increased and light sleep (delta stage 1) was decreased during therapy. The number of nocturnal awakenings was also noted to decrease. The overall, benefits appear to be consolidation of sleep with a promotion of REM sleep (Mamelak et al, 1986).
3) GHB may produce a general anesthesia by a general suppressant action on the entire cerebrospinal axis, and muscular relaxation by an action on the spinal cord rather than a direct action on the neuromuscular junction (Doherty et al, 1975).
4) It was available as a food supplement for body builders. Promotional information claim GHB has anabolic effects by stimulating growth hormone release (Dyer, 1991).
5) GHB (an inhibitory neurotransmitter that regulates dopaminergic neurons) acts as a central nervous system depressant and has euphoria-inducing capabilities (Tunnicliff, 1997).

a) GHB administered to animals can result in a reduction in dopaminergic activity in the basal ganglia (possibly due to the inhibition of dopamine-releasing nerve cells by GHB) or it can stimulate dopamine release. GHB appears to alter dopaminergic activity, but the direction is dependent on several undefined variables (Tunnicliff, 1997).
b) The exact mechanism of GHB action in the central nervous system is unknown, but GHB is structurally related to GABA, which is a precursor in GHB formation. GHB has high-affinity brain receptors and undergoes synthesis, release, uptake, and degradation within the CNS; the exact location of the biosynthetic pathway of GHB inside the cell (cytosol vs. mitochondria) has not been fully determined (Teter & Guthrie, 2001).

1) GHB has been shown to have affinity to two receptor sites in the central nervous system (GHB-specific receptor and the GABA(B) receptor) (Tunnicliff, 1997). GHB mediates the accumulation of dopamine by increasing the activity of tyrosine hydroxylase. GHB can also inhibit the release of newly synthesized dopamine and decrease the firing rate of dopaminergic neurons in the substantia nigra with maximal inhibition within 8 minutes. The end result is a tissue accumulation of dopamine in the brain (Teter & Guthrie, 2001).

a) The release of dopamine in the striatum may also be accompanied by the release of endogenous opioids. The exact interaction between GHB and the opioid system is not understood, but the administration of naloxone or nalorphine, opioid receptor antagonists, can block some of the effects of GHB (Teter & Guthrie, 2001).

B)

1) Conversion of 1,4 butanediol to tetrahydrofuran can occur by dehydrolysis ((Anon, 2000)). Tetrahydrofuran can be converted to gammabutyrolactone via oxidation. Likewise, oxidation and dehydrolysis can convert 1,4 butanediol directly to gammabutyrolactone.

Toxicologic Mechanism

A)

B)

1) In this study, several drugs were tested to evaluate their efficacy in exerting a protective effect on GHB-induced mortality in mice. Mice were treated with a lethal dose of GHB (7 g/kg, administered intragastrically). Various doses of each of the following drugs were administered intraperitoneally to 10 mice: SCH 50911, a GABA(B) receptor antagonist (75,150, and 300 mg/kg); bicuculline, a GABA(A) receptor antagonist (2, 4, 6, and 8 mg/kg); flumazenil, a benzodiazepine receptor antagonist (1, 3, and 10 mg/kg); NCS-382, the putative GHB receptor antagonist (50 and 200 mg/kg); naltrexone, the opioid receptor antagonist (3 and 10 mg/kg); taurine (250 and 750 mg/kg). Mortality rates were obtained every hour for the first 9 hours and then at 12, 18, and 24 hours after GHB injection. All mice from the control group (treated with saline only) died within 24 hours of GHB injection. SCH 50911 (75 mg/kg) exerted a partial protection on GHB-induced mortality (5 of 10 mice died within 8 hours and 1 additional mouse died before final observation). SCH 50911 (150 and 300 mg/kg) produced greater protection on GHB-induced mortality (0 of 10 and 2 of 10 mice died in the 150 and 300 mg/kg groups, respectively). In contrast, bicuculline, flumazenil, NCS-382, naltrexone, and taurine did not exert any protective effect on GHB-induced mortality (9 to 10/10 mice died in each treatment group). The authors suggested an involvement of the GABA(B) receptor in the mediation of the lethal effects of GHB (Carai et al, 2005)

Physicochemical

Molecular Weight

A)

Animal Toxicology

Clinical Effects

11.1.6)

A) In cats, the EEG is strongly similar to epilepsy (Vickers, 1969).

References

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GAMMA HYDROXYBUTYRIC ACID AND RELATED AGENTS

Classification | Detailed evidence-based information

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Specific Substances

Available Forms Sources

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Treatment Overview

Range Of Toxicity

Summary Of Exposure

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Heent

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Monitoring Parameters Levels

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Case Reports

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Minimum Lethal Exposure

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

Workplace Standards

Toxicity Information

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Toxicologic Mechanism

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General Bibliography