Case series of 226 γ-hydroxybutyrate-associated deaths: lethal toxicity and trauma.

γ-Hydroxybutyrate (GHB) and its prodrugs are drugs of abuse that were also sold as "dietary supplements." Users present to emergency departments with overdose, impaired driving, withdrawal, and associated trauma. We compiled a series of GHB-associated deaths to elucidate lethal risks, GHB concentrations, cointoxicants, products, uses, and medical interventions. Death records were reviewed for toxicology, autopsy findings, and history. Inclusion cutoffs were as follows: 5/10 mg/L of GHB (antemortem blood/urine) and 50/20/7 mg/L of GHB (postmortem blood/urine/vitreous). Of 226 deaths included, 213 had cardiorespiratory arrest and 13 had fatal accidents. Seventy-eight deaths (35%) had no cointoxicants. Sixteen deaths involved "supplements" and 1 involved pharmaceutical GHB (Xyrem, Jazz Pharmaceuticals, Palo Alto, CA). Postmortem blood GHB was 18 to 4400 mg/L (median, 347 mg/L) in deaths negative for cointoxicants. Cardiorespiratory arrest occurred prehospital in 100% of 184 cases with available history. Of 72 cases with antemortem adverse effects reported, medical assistance was delayed or absent in 66; of these, acute GHB ingestion was known in 51, including 40 left to "sleep off" adverse effects. Thirty others were left "sleeping" and found dead. γ-Hydroxybutyrate is lethal even without cointoxicants, directly and through fatal accidents. Medical interventions were frequently delayed or absent despite known GHB ingestion, and witnessed adverse events and cardiorespiratory arrest occurred prehospital. Education is needed about the lethality of GHB and the necessity for prompt medical intervention.

Systematic assessment of gamma hydroxybutyrate (GHB) effects during and after acute intoxication.

We adapted and tested a previously published questionnaire battery eliciting sensory and cognitive symptoms during (acute) and immediately after (post-acute) GHB intoxication. Studying 125 GHB users, we assessed the instrument's internal consistency using Cronbach's alpha (CA) and responsiveness to change comparing acute and post-acute symptoms. The final 14-item battery demonstrated good internal consistency (CA >or= 0.85, both acute and post-acute). The median symptom score (possible range 0-64) was 30 (acute) and 6 (post-acute; difference p < 0.001). This modified substance-specific symptom battery, which is easily administered, demonstrated excellent performance characteristics. It can be used to study GHB and, potentially, related drugs of abuse.

Trends in gamma-hydroxybutyrate (GHB) and related drug intoxication: 1999 to 2003.

STUDY OBJECTIVE: To analyze changes in gamma-hydroxybutyrate (GHB) case reporting, we review GHB or congener drug cases reported to the California Poison Control System, comparing these to other data sets. METHODS: We identified cases from the California Poison Control System computerized database using standardized codes and key terms for GHB and congener drugs ("gamma butyrolactone," "1,4-butanediol," "gamma valerolactone"). We noted California Poison Control System date, caller and exposure site, patient age and sex, reported coingestions, and outcomes. We compared California Poison Control System data to case incidence from American Association of Poison Control Centers and Drug Abuse Warning Network data and drug use prevalence from National Institute for Drug Abuse survey data. RESULTS: A total of 1,331 patients were included over the 5-year period (1999-2003). California Poison Control System-reported GHB exposures decreased by 76% from baseline (n=426) to the final study year (n=101). The absolute decrease was present across all case types, although there was a significant proportional decrease in routine drug abuse cases and an increase in malicious events, including GHB-facilitated sexual assault (P=.002). American Association of Poison Control Centers data showed a similar decrease from 2001 to 2003. Drug Abuse Warning Network incidence flattened from 2001 to 2002 and decreased sharply in 2003. National Institute for Drug Abuse survey time trends were inconsistent across age groups. CONCLUSION: Based on the precipitous decrease in California Poison Control System case incidence for GHB during 5 years, the parallel trend in American Association of Poison Control Centers data, and a more recent decrease in Drug Abuse Warning Network cases, a true decrease in case incidence is likely. This could be due to decreased abuse rates or because fewer abusers seek emergency medical care. Case reporting may account for part of the decrease in the incidence of poison center contacts involving GHB.

GHB urine concentrations after single-dose administration in humans.

Gamma-hydroxybutyric acid (GHB) is used as an illicit drug and is implicated in drug-facilitated sexual assault, but it also has some therapeutic uses. Detection of GHB in urine is important for forensic testing and could be of clinical benefit in overdose management. Urine GHB concentration-time profiles have not been well-characterized or correlated with doses used therapeutically. GHB levels were measured by gas chromatography-mass spectrometry in urine collected over 24 h from 16 adults administered single doses of 50 mg/kg GHB (Xyrem) alone and combined with 0.6 g/kg ethanol. Peak GHB urine concentrations averaged 150-200 mg/L and occurred in the 0-3 h urine collection. Significant variability in GHB urine levels between individuals was observed. Caucasians had lower urine concentrations than other races/ethnicities (p = 0.03). Men had lower GHB levels than women in the first 3 h after dosing (p = 0.038). Coingestion of ethanol did not significantly affect renal clearance of GHB, but urine GHB concentrations were lower in the first 3 h when ethanol and GHB were coingested (p = 0.039). At a proposed cut-off of 10 mg/L to distinguish endogenous versus exogenous GHB levels, 12.5% of the samples collected from 3 to 6 h, 81.3% of samples collected from 6 to 12 h, and 100% of urine specimens collected from 12 to 24 h were below this level. We conclude that the detection time for GHB in urine may be shorter than the previously reported 12-h window in some people taking therapeutic doses of GHB.

Clinical Course of γ-Hydroxybutyrate Overdose.

STUDY OBJECTIVE: To describe the clinical characteristics and course of γ-hydroxybutyrate (GHB) overdose. METHODS: We assembled a retrospective series of all cases of GHB ingestion seen in an urban public-hospital emergency department and entered in a computerized database January 1993 through December 1996. From these cases we extracted demographic information, concurrent drug use, vital signs, Glasgow Coma Scale (GCS) score, laboratory values, and clinical course. RESULTS: Sixty-one (69%) of the 88 patients were male. The mean age was 28 years. Thirty-four cases (39%) involved coingestion of ethanol, and 25 (28%) involved coingestion of another drug, most commonly amphetamines. Twenty-five cases (28%) had a GCS score of 3, and 28 (33%) had scores ranging from 4 through 8. The mean time to regained consciousness from initial presentation among nonintubated patients with an initial GCS of 13 or less was 146 minutes (range, 16-389). Twenty-two patients (31%) had an initial temperature of 35°C or less. Thirty-two (36%) had asymptomatic bradycardia; in 29 of these cases, the initial GCS score was 8 or less. Ten patients (11%) presented with hypotension (systolic blood pressure≤90 mm Hg); 6 of these patients also demonstrated concurrent bradycardia. Arterial blood gases were measured in 30 patients; 21 had a Pco2 of 45 or greater, with pH ranging from 7.24 to 7.34, consistent with mild acute respiratory acidosis. Twenty-six patients (30%) had an episode of emesis; in 22 of these cases, the initial GCS was 8 or less. CONCLUSION: In our study population, patients who overdosed on GHB presented with a markedly decreased level of consciousness. Coingestion of ethanol or other drugs is common, as are bradycardia, hypothermia, respiratory acidosis, and emesis. Hypotension occurs occasionally. Patients typically regain consciousness spontaneously within 5 hours of the ingestion. [Chin RL, Sporer KA, Cullison B, Dyer JE, Wu TD: Clinical course of γ-hydroxybutyrate overdose. Ann Emerg Med June 1998;31: 716-722.].

Area-level socioeconomic status in relation to outcomes in gamma-hydroxybutyrate intoxication.

BACKGROUND: Area-level socioeconomic status (SES) may play an important role in drug abuse patterns, including related health outcomes. This may be particularly relevant for gamma-hydroxybutyrate (GHB), which is prototypical of "party" drug abuse. METHODS: We retrospectively reviewed GHB-related cases reported to the California Poison Control System (CPCS; January 1, 1999 through June 30, 2007). We limited analysis to CPCS calls containing a residential zip code (ZC). The CPCS data were extracted for key case characteristics, including the residential ZC. We linked cases to corresponding 2000 U.S. Census data for area-level measures of SES and demographics. We used multiple logistic regression analysis to test the associations between area-level SES and GHB case severity, taking into account area-level demographics and individual-level GHB high-risk behaviors. RESULTS: We analyzed 210 cases. Taking into account area-level demographics (age and racial mix; urbanicity) and GHB-related high-risk behaviors (use of GHB congeners; GHB-dependence; co-ingestion of other agents), we associated higher area-level SES with greater GHB case severity. There was 40% increased likelihood of major GHB adverse health outcomes for every $100,000 incremental increase in median home values (OR 1.41; 95% CI 1.1-1.8). For median annual household income (per $10,000), the association was similar (OR 1.39; 95% CI 1.0-1.9). CONCLUSION: Higher area-level SES is associated with greater GHB-related case severity. This study may serve as a model using a geographic information system (GIS) approach to study the population-based correlates of drugs of abuse reported through poison control surveillance.

High-risk behaviors and hospitalizations among gamma hydroxybutyrate (GHB) users.

INTRODUCTION: Little is known about behaviors linked to gamma hydroxybutyrate (GHB) morbidity. METHODS: We surveyed 131 GHB users, using logistic regression to test the associations between the high risk behaviors and hospital treatment for GHB (26 [20%] of subjects). RESULTS: Increased risk of GHB hospital treatment was associated with: co-ingestion of ethanol (OR 5.2; 95% CI 1.7-16), driving under the influence of GHB (OR 3.2; 95%, CI 1.3-7.8),use of GHB to treat withdrawal symptoms (OR 2.9; 95% CI 1.1-7.9), and co-ingestion of ketamine (OR 2.7; 95% CI 1.1-6.7). CONCLUSION: Targeted prevention activities could focus on selected high-risk behaviors.

Gamma-hydroxybutyrate and ethanol effects and interactions in humans.

BACKGROUND: Gamma-hydroxybutyrate (GHB) is a common drug of abuse that can produce serious toxicity, particularly when used with other sedatives. We examined the individual and combined effects of GHB and ethanol in human volunteers. METHODS: Sixteen healthy adults (7 men) were given 50 mg/kg GHB (Xyrem), 0.6 g/kg ethanol in 2 doses, alone and combined in a double-blind, placebo-controlled, crossover study. Plasma concentrations, heart rate (HR), blood pressure (BP), and oxygen saturation (O2sat) were serially monitored for 24 hours. RESULTS: Adverse events included 2 instances of hypotension and 6 episodes of vomiting with GHB-plus-ethanol ingestion. Oxygen saturation was decreased by GHB and ethanol individually, and maximally decreased by the drugs combined (max -2.1% +/- 0.3%, P < 0.0001 vs placebo). Compared with baseline, systolic and diastolic BP were significantly decreased, and HR was increased by ethanol but not affected by GHB alone (maximum systolic BP change -15.7 +/- 3.0 mm Hg, P = 0.0006; maximum HR change 13.5 +/- 2.3 beats per minute, P = 0.006). Ethanol coingestion resulted in 16% higher GHB maximal plasma concentration and 29% longer elimination half-life, indicating possible enhanced bioavailability or reduced clearance of GHB caused by ethanol, however, these effects were not statistically significant. CONCLUSIONS: Modest doses of GHB do not affect hemodynamic function, but O2sat was decreased. Gamma-hydroxybutyrate-plus-ethanol resulted in more adverse effects, including gastrointestinal disturbances, hypotension, and decreased O2sat, but only minimal pharmacokinetic interactions were observed.

Gamma-hydroxybutyrate serum levels and clinical syndrome after severe overdose.

STUDY OBJECTIVE: We discuss a prospective case series of patients who present with a severe gamma-hydroxybutyrate intoxication with confirmatory serum and urine gamma-hydroxybutyrate levels. METHODS: Patients with a clinical suspicion of gamma-hydroxybutyrate-like drug overdoses and a Glasgow Coma Scale score of 8 or lower were identified from July 1998 through January 1999. Serial serum specimens and a single urine specimen were collected. The levels of gamma-hydroxybutyrate were performed by gas chromatography-mass spectrometry. RESULTS: All 16 suspected severe gamma-hydroxybutyrate overdose patients had significant serum or urine levels of gamma-hydroxybutyrate. Serum levels ranged from 45 to 295 mg/L, with a median of 180 mg/L (interquartile range [IQR] 235 to 118 mg/L). Patients who developed a Glasgow Coma Scale score of 3 had serum levels that ranged from 72 to 300 mg/L, with a median of 193 mg/L (IQR 242 to 124 mg/L). The time of awakening ranged from 30 minutes to 190 minutes, with a median of 120 minutes (IQR 150 to 83 minutes). Quantitative serum gamma-hydroxybutyrate levels did not correlate with the degree of coma or the time to awakening. Urine levels ranged from 432 to 2,407 mg/L, with a median of 1,263 mg/L (IQR 1,550 to 796 mg/L). Mild transitory hypoventilation occurred in 5 of the 16 patients. CONCLUSION: All of our patients with clinically suspected severe gamma-hydroxybutyrate overdose were confirmed to have significant serum and urine levels of exogenous gamma-hydroxybutyrate. They presented with severe coma that lasted 1 to 2 hours. Transient hypoventilation occurred in one third of these patients.