Lessons to be learned from toxicological analyses in intoxicated patients and seized materials at an electronic music dance festival.

Medical problems related to illicit drug use are frequently encountered at electronic dance music (EDM) events. In this prospective study, the medical problems and toxicological analyses on intoxicated persons and seized materials are described jointly. The aim of this study is to find out to what extent these efforts may assist in developing prevention strategies and organising on-site care at EDM events. The most frequently encountered clinical presentation in the 121 included patients was: agitation/aggression (26%), drunkenness (25%), depressed level of consciousness (24%) and hallucinations (9%). Only five patients were transported by ambulance to a hospital. In 100 of the 121 included patients (83%) an ethanolemia of at least 0.50 g/L was measured (with ethanol as the only drug found in 47 cases). 3,4-methylenedioxymethamphetamine (MDMA) was detected in 54% of the blood samples, cocaine in 11%, gamma-hydroxybutyric acid (GHB) in 11%, amphetamine in 7%, ketamine in 6% and a new psychoactive substance (NPS) in 4%. Except for 8 MDMA-users poly drug use was found in all these cases. The 178 seized samples most frequently contained MDMA (31%), cannabis (28%) or no active substance (15%). In 11 samples (6%) an NPS was detected. Of particular interest was a tablet containing 4-chloromethamphetamine (a previously unknown neurotoxic NPS), 4-chloroamphetamine, para-methoxyamphetamine, para-methoxymethamphetamine and ethylone. Our data show that at EDM events ethanol and MDMA are still the party drugs causing most health hazards and that NPS only play a minor role. Regarding the toxicological efforts, we recommend to analyse all seized materials from an EDM event, but only blood samples from the most severely intoxicated patients.

Medical Emergencies Related to Ethanol and Illicit Drugs at an Annual, Nocturnal, Indoor, Electronic Dance Music Event.

Introduction Medical problems are frequently encountered during electronic dance music (EDM) events. Problem There are uncertainties about the frequencies and severity of intoxications with different types of recreational drugs: ethanol, "classical" illicit party drugs, and new psychoactive substances (NPS). METHODS: Statistical data on the medical problems encountered during two editions of an indoor electronic dance event with around 30,000 attendants were retrieved from the Belgian Red Cross (Mechelen, Belgium) database. Data on drug use were prospectively collected from the patient (or a bystander), the clinical presentation, and/or toxicological screening. RESULTS: In the on-site medical station, 487 patients were treated (265 in 2013 and 222 in 2014). The most frequent reasons were trauma (n=171), headache (n=36), gastro-intestinal problems (n=44), and intoxication (n=160). Sixty-nine patients were transferred to a hospital, including 53 with severe drug-related symptoms. Analysis of blood samples from 106 intoxicated patients detected ethanol in 91.5%, 3,4-methylenedioxymethamphetamine (MDMA) in 34.0%, cannabis in 30.2%, cocaine in 7.5%, amphetamine in 2.8%, and gamma-hydroxybutyric acid (GHB) in 0.9% of patients (alone or in combination). In only six of the MDMA-positive cases, MDMA was the sole substance found. In 2014, the neuroleptic drug clozapine was found in three cases and ketamine in one. Additional analyses for NPS were performed in 20 cases. Only in one agitated patient, the psychedelic phenethylamines 25B-NBOMe and 25C-NBOMe were found. CONCLUSIONS: At this particular event, recreational drug abuse necessitated on-site medical treatment in one out of 350 attendants and a hospital transfer in one out of 1,000. Ethanol remains the most frequently abused (legal) drug, yet classical illicit recreational drugs are also frequently (co-) ingested. The most worrying observation was high-risk poly-drug use, especially among MDMA users. Regarding NPS, the number of cases was low and the clinical presentations were rather mild. It should be stressed that these observations only apply to this particular event and cannot be generalized to other EDM events. Calle P , Sundahl N , Maudens K , Wille SMR , Van Sassenbroeck D , De Graeve K , Gogaert S , De Paepe P , Devriese D , Arno G , Blanckaert P . Medical emergencies related to ethanol and illicit drugs at an annual, nocturnal, indoor, electronic dance music event. Prehosp Disaster Med. 2018;33(1):71-76.

Abrupt awakening phenomenon associated with gamma-hydroxybutyrate use: a case series.

Case reports mention a sudden awakening from GHB-associated coma but do not specify its time course. The aim of the present case series was to investigate the time course of the awakening from GHB intoxication and the relationship to plasma concentrations of GHB and the presence of other drugs. Unconscious (GCS or=12 was 30 minutes (range 10 to 50 minutes). A subgroup of five patients had a GCS of 3 upon arrival and remained at 3 for a median time of 60 minutes (range 30 to 110 minutes), while the median time for the transition between the last point with GCS 3 and the first with GCS 15 was 30 minutes (range 20 to 60 minutes). This case series illustrates that patients with GHB intoxications remain in a deep coma for a relatively long period of time, after which they awaken over about 30 minutes. This awakening is accompanied by a small change in GHB concentrations. A confounding factor in these observations is co-ingested illicit drugs.

Three cases of substitution errors leading to hyoscine hydrobromide overdose.

We report three patients with anticholinergic poisoning caused by the substitution of hyoscine hydrobromide for hyoscine butylbromide in preparations compounded by two different pharmacists. The patients took the preparations for gastrointes tinal discomfort and presented with altered mental status tachycardia, facial flushing, dilated pupils, and dry skin shortly after the ingestion. In one patient the intoxication was initially not recognized and he was treated as suffering from an acute cerebrovascular accident. Two patients experienced long-lasting effects such as decreased ability to concentrate, memory dis turbances, tremor, and photo- and phonophobia. It was obviously impossible to elucidate the exact nature of the relationship between the intoxication and these long-lasting complaints. Information from the Belgian poison control center revealed that cases of substitution error with hyoscine hydrobromide are not unique The Belgian authorities issued a warning to all pharmacists.

Characterization of the pharmacokinetic and pharmacodynamic interaction between gamma-hydroxybutyrate and ethanol in the rat.

It has been reported that ethanol enhances the hypnotic effect of gamma-hydroxybutyrate (GHB). In order to clarify the nature of this interaction we studied the pharmacokinetics and pharmacodynamics of combinations of GHB and ethanol in rats. Intraperitoneal injections of the GHB precursor gamma-butyrolactone (300 mg/kg) together with ethanol (3000 mg/kg) (n = 4) resulted in a longer "sleeping time" than the sum of the individual times (n = 8). Pharmacokinetic analysis of GHB concentrations with a two-compartment model with Michaelis-Menten (M-M) elimination in rats receiving a bolus of GHB (400 mg/kg, i.v.) in addition to steady-state ethanol concentrations (300-3000 microg/ml) (n = 12) or saline (n = 15) showed no marked differences in the area under the curve. The nature of the pharmacodynamic interaction was studied using isobolographs and an interaction model for the loss of the startle and righting reflex and a reaction to a painful tail clamp in rats receiving combinations of steady state concentrations of ethanol (1000-3000 microg/ml) and GHB (200-1400 microg/ml). For the righting reflex, synergy was observed at high ethanol concentrations (>2000 microg/ml) and additivity at lower concentrations. For the startle reflex, it was antagonistic at ethanol concentrations below 1000 microg/ml, and additivity was seen at higher concentrations. For the tail clamp reaction, a slight but significant antagonism was found at all combined concentrations. It is concluded that ethanol prolongs the sleeping time induced by GHB in the rat, which may not be due to a pharmacokinetic interaction. Pharmacodynamic interactions between GHB and ethanol in the rat occur, and the nature varies with the reflex studied and the concentration of ethanol used.

Tolerance to the hypnotic and electroencephalographic effect of gamma-hydroxybutyrate in the rat: pharmacokinetic and pharmacodynamic aspects.

Tolerance to gamma-hydroxybutyrate (GHB) has been suggested in illicit users and has been described for the hypnotic effect in the rat. The aim of this study was to investigate whether tolerance is also observed for the EEG effect, and whether the EEG can give insight into the pharmacodynamic aspects of GHB tolerance. In three series of experiments, rats were pre-treated with either the GHB precursor gamma-butyrolactone (GBL) or saline intraperitoneally twice daily. In the first series, a reduction in sleeping time was observed in the GBL pre-treated rats compared with controls. In the second series, a fast infusion of GHB (300 mg kg(-1) over 5 min) was given after 10 days pre-treatment. The GHB plasma concentration-time curves showed a slightly faster decrease in GHB concentration in the GBL pre-treated rats, suggesting a small induction of the GHB metabolism (V(max) = 2882 +/- 457 microg min(-1) kg(-1) vs 2205 +/- 315 microg min(-1) kg(-1), P < 0.01). In contrast to controls, GBL pre-treated rats did not lose righting reflex. In the third series, a slow infusion of 480 mg kg(-1) h(-1) was given after 7 days pre-treatment, which allowed fitting a sigmoid E(max) model to the EEG amplitude versus GHB plasma concentration curve. This showed reduced end-organ sensitivity to GHB in the GBL pre-treated rats (EC50 (concentration required to obtain 50% depression of the baseline effect) = 653+/- 183 microg mL(-1) vs 323 +/- 68 microg mL(-1), P < 0.001). In conclusion, chronic pre-treatment with gamma-butyrolactone in the rat results in a reduced sleeping time and this tolerance is reflected by the EEG. This can mainly be explained by reduced end-organ sensitivity.

Medical problems related to recreational drug use at nocturnal dance parties.

During 'I love techno' (edition 2001), an indoor rave party attended by 37 000 people, data about medical problems (especially drug-related problems) were collected. To place these data in a wider perspective, a similar registration was done during 'De Nacht', a traditional New Year's Eve dance party held at the same location and attended by 12 000 people. Furthermore, a prospective study on the time course of the level of consciousness (Glasgow Coma Score) and blood concentrations of illicit drugs, especially gamma-hydroxybutyrate was set up. The results revealed that during 'I love techno' the incidence of medical problems was high (66.5/10 000 attendees), but not higher than during 'De Nacht' (70.0/10 000 attendees). At 'I love techno', however, mainly illicit drugs were used, more frequently leading to severe drug-related medical problems. The observations in patients with a drug-related medical problem who had taken gamma-hydroxybutyrate showed that for a given level of consciousness the gamma-hydroxybutyrate concentrations may show important differences, that the transition from coma (Glasgow Coma Score < or =7) to full recovery (Glasgow Coma Score 15) takes only 30-60 min (and only a small decrease in gamma-hydroxybutyrate concentrations), and that the time it takes before a comatose patient reaches the above-mentioned 'transition area' may be a few hours.

Dried blood spot punches for confirmation of suspected γ-hydroxybutyric acid intoxications: validation of an optimized GC-MS procedure.

BACKGROUND: γ-hydroxybutyric acid (GHB), notorious as a club- and date-rape drug, was quantified in dried blood spots (DBS) by punching out a disc, followed by 'on-spot' derivatization and analysis by GC-MS. RESULTS: A homogenous distribution in DBS was demonstrated and accurate results were obtained when analyzing a disc punched out from a 20-35 µl spot, regardless the hematocrit of the blood sample. Validation based on US FDA and European Medicines Agency guidelines was performed, with a calibration range covering 2-100 µg/ml. CONCLUSION: A sensitive GC-MS method for GHB analysis in DBS was successfully optimized and validated. The successful analysis of DBS collected from GHB abusers suggests the routine applicability of the DBS sampling technique for GHB analysis in toxicological cases.

Influence of hypovolemia on the pharmacokinetics and electroencephalographic effect of gamma-hydroxybutyrate in the rat.

BACKGROUND: Hypovolemia alters the effect of propofol in the rat by influencing the pharmacokinetics and the end organ sensitivity. We now studied the effect of hypovolemia on the anesthetic gamma-hydroxybutyrate (GHB) because in contrast with propofol it increases blood pressure. METHODS: Thirty-two rats were randomly assigned to undergo moderate hypovolemia or a control procedure. Each rat received either an infusion of sodium-GHB (390 mg x kg(-1) x 5 min(-1)) or the same volume of an equimolar solution of sodium chloride (6.9%). Plasma samples were taken for GHB assay (high-performance liquid chromatography) and the electroencephalography and blood pressure values were recorded. A two-compartment model with Michaelis-Menten elimination was fitted to the concentration-time data and a sigmoid E(max) model to the electroencephalographic effect effect site concentration curve allowing the study of the end organ sensitivity. RESULTS: Plasma concentration-time curves and the total volume of distribution in hypovolemic and normovolemic rats were comparable with only small but significant differences in central volume of distribution and the intercompartmental clearance. There was no significant difference either in the distribution from the plasma to the brain (k(e0)) or in the end organ sensitivity (EC50 = 335 +/- 76 microg/ml in control vs. 341 +/- 89 microg/ml in hypovolemic rats). GHB temporarily increased mean arterial pressure in both groups, which cannot be explained by the sodium salt alone. CONCLUSIONS: Hypovolemia does not influence the overall concentration-time curve of GHB and induces no changes in the electroencephalographic effect of GHB in the rat. This difference with propofol may be due to the fact that it increases blood pressure but also due to its different pharmacokinetic properties.