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Abstract

Background:

Many patients present to emergency departments (EDs) with an altered state of consciousness. Fast exclusion of gamma hydroxybutyrate (GHB)-associated intoxication in these patients may optimize diagnostic and therapeutic algorithms and decisions in the ED.

Methods:

Between January and March 2014, a novel enzymatic test system was used to quantify GHB in blood and urine samples of suspected intoxicated patients in the ED of the University Hospital. The underlying causes for suspected intoxication and the diagnostic and therapeutic measures were documented and analysed retrospectively.

Results:

GHB measurements were performed in 13 patients with suspected ingestion during a 3-month study period. GHB was positive in six patients showing serum levels between 61.8 mg/l and 254.8 mg/l, and GHB was tested negative in seven patients with a range of 0.3–6.2 mg/l (upper reference limit 6.1 mg/l). Additional intoxication was found in five of six GHB positive (83%, alcohol n = 2 and other drugs n = 5) and in six of seven negative-tested patients (86%, alcohol n = 5 and other drugs n = 1).

Conclusion:

GHB quantification in the ED provides specific additional information for intoxication, which can lead to more precise diagnostic and therapeutic decisions and may also be important for legal aspects. We believe that GHB analysis in unconscious patients with suspected intoxication may improve the efficient treatment of intoxicated patients.

Keywords

Gamma hydroxybutyrate emergency department intoxication laboratory investigation decision-making

Introduction

Many patients present to emergency departments (EDs) with an altered state of consciousness.¹ There are many causes for disorders of consciousness, which require fast and effective diagnostic measures.^1,2 Despite neurological, respiratory or metabolic disorders, a large number of patients suffer from intoxications.^1

–4 Gamma hydroxybutyrate (GHB) is increasingly misused but also endogenously produced at low levels in the central nervous system.^5
–7 Characteristic clinical symptoms associated with GHB ingestion vary in a dose-dependent manner (Table 1).^8,9

Table 1.

GHB-associated symptoms.^8,9

Dose (g)	Pharmacological issue	Symptoms
0.5–1.5	Stimulation of body own GHB receptor	Sedation, anxiolysis and euphoria
1.5–3.0	Agonism of GABAB receptor	Aphrodisiac effect and drive disorder
≥3		Sickness (malaise), vomiting, myoclonus, bradycardia, amnesia, motor disorders, unconsciousness and coma

GHB: gamma hydroxybutyrate; GABAB: γ-aminobutyric acid class B.

The half-life of GHB ranged from 30 to 45 min, resulting in a typical ‘switch off/on’ phenomenon: GHB-intoxicated people can suddenly awake from coma. GHB is metabolized by dehydration and oxidation to succinic acid, followed by entry in the citric acid cycle or by beta oxidation and release as carbon dioxide and water.¹⁰ Since the 1990s, GHB and its precursors (gamma butyrolactone and 1,4-butandiol) are used as drugs and in order to commit sexual offence or property crimes. In Germany, a significant increase of GHB intoxications is observed during the recent years.^2,11 Therefore, fast detection of GHB within the ED drug screening may have diagnostic or therapeutic consequences and may be cost-efficient.³ GHB detection may help to prevent unnecessary cerebral imaging procedures or hospitalization. In situations, where forced administration in the context of sexual offenses or robbery is assumed, a positive result should initiate further forensic investigations. However, after ingestion, the time slot for GHB detection is narrow because of the short half-life in vivo (blood sample: 6 h and urine samples: up to 12 h).^12
–14 For forensic purposes, a qualitative detection of GHB uptake can be provided even after several weeks by hair analysis.^15,16 Immunologic detection is not appropriate for GHB.^17,18 Thus a suitable clinical chemical detection method is still an obstacle of its widespread availability.

The aim of this retrospective single-centre study was to evaluate a novel and rapidly applicable GHB method for clinical decision-making in suspected GHB-intoxicated ED patients.

Methods

This descriptive investigation represents a consecutive case series of patients treated in the ED of the University Hospital of Leipzig, Germany, with more than 34,000 annual patient visits. During the study period (January to March 2014), the measurements were performed in residual blood or urine samples because of clinical indications. For GHB analysis, approximately 200 µl specimen was used. Rationales for GHB testing were unexplained coma, conspicuous behaviour and/or feared administration by a third party. The need for GHB testing were driven by the suspicions of the treating clinician. The clinical circumstances in the ED, the subsequent treatment and decision-making were recorded and analysed retrospectively. There were no additional blood samplings done for this investigation. The study was approved by the local ethical committee of the Medical Faculty of the University of Leipzig, Germany (DETECT-GHB-study, ref. no.: 276-14-25082014).

The GHB test (Buehlmann Laboratories AG, Germany) was applied to clinical chemistry analyser Cobas 6000 (Roche, Germany), and results were usually available within 1 h after blood collection. Calibration was performed according to manufacturer’s protocol and German regulatory guidelines for laboratory diagnostics.¹⁹ The kit is based on enzymatic detection, thereby using the transformation of GHB to succinic acid semialdehyde by recombinant GHB dehydrogenase, where NAD⁺ as a cofactor is reduced to nicotinamide adenine dinucleotide. The increase in absorbance at 340 nm is proportional to GHB concentration.¹⁷ The lower detection limit of the GHB kit is 2 mg/l and the lower limit of quantification is 5 mg/l, according to the information of the manufacturer. The 97.5th percentile in serum of blood donors who did not consume GHB is 6.1 mg/l. Other publications describe values up to 4–6 mg/l in control subjects.¹⁸

Results

During the study period, GHB measurement was performed in 13 patients (4 females and 9 males) with suspected intoxication. Mean age was 26.8 years (+/−5.4). An outline of the patients is given in Table 2. For detailed information see the following description for each patient.

Table 2.

Patient characteristics and laboratory findings.

No.	Age (years)	Sex	Indication	Clinical situation	GHB measure (mg/l), blood sample	Result interpretation	Alcohol test (g/l)	Conventional drug test (urine sample)	GHB result usefulness
1	28	m	Suspicion	Comatous state	128.1	Positive	n.d.	n.d.	Yes
2	26	m	Suspicion	Comatous state	195.8, 807 (U)	Positive	n.p.	THC, amphetamine, benzodiazepine, methamphetamines and MDMA	Yes
3	31	m	Suspicion	Collapsed and seizure	254.2	Positive	n.p.	THC, amphetamine and methamphetamines	Yes
4	26	m	Suspicion	Comatous state	254.8	Positive	0.56	THC, amphetamine and methamphetamines	Yes
5	35	m	Suspicion	Sleeping and vandalism	149.2	Positive	n.p.	amphetamine	Yes
6	21	m	Suspicion	Sleeping and vandalism	61.8	Positive	0.13	THC, amphetamine, methamphetamines and MDMA	Yes
7	37	m	Exclusion	Comatous state	6.2	Negative	5.9	Negative	Yes
8	26	f	Exclusion	Recurrent emesis after alcohol consumption	0.3	Negative	0.95	Negative	Yes
9	24	m	Exclusion	Apathy and emesis	3.3	Negative	<0.1	THC, amphetamine and methamphetamines	Yes
10	30	f	Suspected rape	Recurrent emesis after alcohol consumption	n.d.	Negative	0.97	Negative	Yes
11	18	f	Suspected rape	Sleeping and amnestic	0.8	Negative	1.18	Negative	Yes
12	25	f	Suspected rape	Hallucinations and suicidal	n.d. (U)	Negative	1.87	Benzodiazepines and tricyclic antidepressants	Yes
13	23	m	Suspected rape	Amnestic after alcohol consumption	1.4	Negative	n.p.	Negative	Yes

m: male; f: female; n.d.: not detectable; n.p.: not performed; U: urine sample; MDMA: 3,4-methylendioxy-N-methylamphetamin; GHB: gamma hydroxybutyrate.

Patient 1

A 28-year-old man was found insensible in front of a youth club. Friends reported that he had taken liquid ecstasy during the evening. After ED admission, the patient presented drowsiness alternating with aggressive and self-hazardous behaviour. Because of the strong suggestion of intoxication with GHB, we decided to abstain from extensive diagnostic measures. The patient was discharged from the ED in a stable cardiopulmonary condition after a few hours. GHB quantification in serum resulted in a clear positive finding (128 mg/l), which explained the symptoms and would have legitimized the clinical decision.

Patient 2

Another 26-year-old man was found with reduced state of consciousness in front of a youth club. Friends told the police that he had taken crystal meth. The police found a small bottle with a clear fluid. The patient was aggressive and behaved erratically. After ED admission, conventional drug screening was positive for tetrahydrocannabinol (THC), amphetamines, benzodiazepines, methamphetamines and Ecstasy/3,4-methylendioxy-N-methylamphetamin (MDMA). Due to this polyintoxication and his unclear unconsciousness, the patient was admitted to the intensive-care unit (ICU). GHB level in serum was 196 mg/l. The result would have provided an explanation for the state of unconsciousness and one could have foregone hospitalization.

Patient 3

A 32-year-old male collapsed in the shower of a brothel and suffered a seizure. Bystanders reported that the patient had consumed one bottle of vodka and has taken ‘some kind of pill’ during the evening. After ED admission, the patient was not adequate on a cognitive level. Conventional drug screening was positive for amphetamines, methamphetamines and THC. The patient was discharged from ED in good conditions after he slept off his intoxication. GHB level in serum was 259 mg/l. The knowledge of the GHB intoxication would have legitimized the decision to wait for the resolve of the intoxication and avoid further laboratory and neurological diagnostic concerning epilepsy.

Patient 4

A 27-year-old man was admitted to the ED by emergency medicine service (EMS) with the suspicion of intoxication or drug abuse. He was found collapsed in front of a youth club and was immediately awake but not oriented after arrival of the EMS staff. After ED admission, the patient was not adequate with uncoordinated motor activity and grimaces but recovered very fast. Conventional drug screening was positive for amphetamines, methamphetamines and THC. Blood alcohol was 0.56 g/l. The patient was discharged from ED after a few hours in good clinical conditions. GHB measurement in serum was positive (255 mg/l). This result would have supported the decision to surrender cerebral imaging procedures and hospitalization.

Patient 5

A 36-year-old man was admitted by EMS after he had harassed passers-by. Shortly afterwards he fell asleep. After ED admission, the patient displayed sudden uncontrolled movements. The patient is known to abuse drugs, particularly GHB. Conventional drug screening was positive for amphetamines. The patient was discharged from ED without further cerebral imaging or other diagnostic procedures after recovery. GHB screening in serum was positive (149 mg/l). The result would have supported the decision to surrender further diagnostic steps or hospitalization.

Patient 6

A 31-year-old man was presented in ED by EMS after he had rioted in his shared flat. After he came home, at first he fell asleep and became aggressive shortly thereafter. Conventional drug screening was positive for amphetamines, methamphetamines, Ecstasy/MDMA and THC. Blood alcohol was 0.13 g/l. The patient was discharged from ED after he had slept off his intoxication. GHB screening in serum was positive (62 g/l). The result would have supported the decision to surrender further diagnostic steps or hospitalization.

Patient 7

A 37-year-old man collapsed in a train. At ED admission, the patient was unconscious with a Glasgow Coma Scale of 3. The airway was secured by immediate endotracheal intubation. The conventional drug screening was negative. Blood alcohol was 5.9 g/l. The patient was transferred to the ICU. The analysis for GHB in serum revealed a borderline positive result (6.2 mg/l). GHB could have been excluded as the major reason for coma and one may be able to have forgone hospitalization to ICU.

Patient 8

A 25-year-old woman presented by herself to the ED because of recurrent vomiting a few hours after alcohol consumption. She suspected a third-party administration of a drug. Conventional drug screening was negative. Blood alcohol was 0.95 g/l. The patient was discharged from the ED in good clinical conditions. GHB measurement in serum was negative (0.3 mg/l). These results speak against a date rape situation due to GHB and completed the ED conventional drug screening.

Patient 9

A 24-year-old man was admitted to the ED by an EMS. The patient was known to abuse crystal meth and THC. The patient had an episode of seizure and unconsciousness 2 years ago without further clarification. For the whole evening the patient had been sitting apathetic in his living room chair and had repeatedly vomited. After ED admission, he was not responsive but aggressive and then suffered a seizure. Conventional drug screening was positive for amphetamines, methamphetamines and THC but not for blood alcohol. The patient underwent cranial computed tomography (CCT) and was admitted to neurological ICU for surveillance due to the repeated seizures. GHB measurement in serum was negative. This result would have excluded GHB abuse in regards to the still present typical symptoms and would have supported the CCT and ICU surveillance.

Patient 10

A 31-year-old woman was presented to the ED after she celebrated with friends. It was reported that she started to vomit 2 h after she had two drinks. Her husband reported that she was not vigilant, had a strange behaviour and was amnestic. There was a suspicion that somebody might have instilled a date rape drug. After ED admission, the patient was in a normal mental state. Conventional drug screening was negative. Blood alcohol was 0.97 g/l. The patient was hospitalized due to distinct elevations for creatine kinase, myoglobine and transaminases, a cause could not be revealed during the further hospital stay. GHB revealed a negative result in serum. This result speaks against the suspicion of a date rape situation and completed the conventional drug screening.

Patient 11

An 18-year-old girl was presented to the ED by her mother after an episode of marihuana and alcohol abuse. She had a loss of memory for a couple of hours and was found asleep. According to information given by a girlfriend, there occurred a sexual intercourse with an unknown man during the period of unconsciousness. Conventional drug screening was negative, also for blood alcohol. GHB quantification in serum revealed a negative result. The result gave no indication for a date rape situation.

Patient 12

A 25-year-old woman was brought to the ED with hallucinations in an agitated state accompanied by a male person, who posed as a doctor. The patient was under the influence of alcohol and showed suicidal tendencies. The patient was transferred to the psychiatric clinic in good cardiopulmonary conditions. GHB quantification was done to exclude drug abuse as the reason for the acute psychiatric state, an intended abuse or third-party administration. The result in urine was negative and would have supported the decision to transfer the patient to the psychiatric clinic.

Patient 13

A 23-year-old patient presented himself to the ED in the morning with memory loss since 1 a.m. He had spent his evening with some colleagues and his brother, enjoying three beers. They took him home at 2.30 a.m., but the patient has had no memory for this situation. There were no clinical or laboratory striking features. The patient was informed about safety precautions concerning drinks in the public and left the ED well. Serum GHB concentration was 1.4 mg/l, and there was no indication for a third-party administration.

Discussion

We show the results of a novel and rapidly applicable GHB test for serum or urine GHB quantification in patients with suspected GHB intoxication in a consecutive single-centre case series.

An altered mental state is common in patients presenting to the ED.¹ Unconsciousness is defined as a lack of awareness and response to external stimuli. Often these patients cannot be roused. In the ED, many causes for disorders of consciousness have to be promptly elucidated by the physicians in charge, and the underlying pathology has to be detected using well-defined and effective diagnostic steps.^1,2 The emergency situation in these patients differs from case to case, and the emergency physician has to use diagnostic procedures in order to make a conclusive decision for the further ED or hospital treatment.¹ In a single-centre retrospective study, we found a marked increase in the ED admission rate due to overdose of GHB in the years 2011 and 2012. GHB was, with 2.3%, one of the most common agents of self-poisoning with acute intoxication.²⁰ However, the lack of appropriate laboratory detection methods may have influenced the true incidence of intoxication with GHB.²⁰ Even if fatal cases are rare, intoxication should be quickly identified.^18,21
–23 It depends on the level of training how reliable symptoms for GHB intoxication are recognized.⁸ In comparison to these results, the most important step is to consider GHB as a differential diagnosis, as it is a currently more frequent used drug. In turn, when ED physicians get more familiar with the clinical profile of GHB due to the ability to measure its concentration, the results could save costs in terms of other unnecessary diagnostic measures.²¹

Beside the obligation to give every patient the optimal emergency care, there are several ramifications concerning occupancy of structures like radiation-based cerebral imaging procedures and the associated costs, which have to be considered. Intensive-care measures, such as intubation of GHB-related cases, increase the mean length of stay and the rate of hospital admissions.³

The wide range of diagnostic options for patients suffering from confusion and also for patients, who fear the forced administration of any substance, already includes various laboratory measurements and different drug-screening methods. However, the different diagnostic possibilities must be implemented efficiently. Considering the therapeutic and diagnostic relevance and the rising incidence of GHB misuse, the drug would have been included in the conventional urine-based immunological drug screening very fast.^4,11,24 But as mentioned before, this was hindered by methodical pitfalls and complexities.

Previous publications therefore regularly report of retrospective quantification at the next working day or later, when the result does not influence early decision-making in the ED.

Since the measurement of GHB now became robust and fast in blood and urine samples, the expenses for the measurement seem to be the limitation for this diagnostic option. One could restrict the measurement to very few cases. But this restriction is time consuming and depends on the experience level of the emergency physician. Furthermore there is also the risk that intoxication may be overlooked due to unspecific symptoms or situations, when ingestion is not expected. It is essential that every ED should develop guidelines to recognize these patients and decide about the significance of the diagnostics. A cost calculation depends on the availability of the analyser, the frequency of calibration and quality control testing on the laboratory side. In the ED, it depends on the individual indication for GHB quantification and the saved cost for further diagnostic or therapeutic steps. This should has to be revealed in further studies.

In line with previous investigations, all positive-tested samples in this investigation showed a GHB level higher than 50 mg/l, therefore these tests are doubtless positive (cut-off 6.1 mg/l^18,21,25). In all cases, testing would have revealed relevant information for the ED treatment and decision-making (Table 3).

Table 3.

Intoxication with GHB?

No	Yes
Intubation, if indicated	Watchful waiting
Cerebral imaging, if indicated	Symptomatic therapy
Hospitalization (ICU admission), if indicated	Prevention of self-harm
Expected date rape situation: no further investigation	Back up samples for forensic reasons

GHB: gamma hydroxybutyrate; ICU: intensive-care unit.

Particularly avoidance of hospital admission, cerebral imaging procedures and immediate airway management led to an increase in efficiency and a decrease in costs in early ED and hospital management. Furthermore, the clinical course and behaviour of patients could be predicted better. In cases where third-party administration was suspected, the negative results are important when obtained within the diagnostic window.

Ethanol proportionally enhances GHB results. At up to 3‰ blood alcohol, GHB is measured below 10 mg/l, and the highest result in the investigation of the manufacturer was approximately 15 mg/l at 5‰ blood alcohol. None of the other drugs tested revealing interference. From our point of view, since all positive results were >50 mg/l, the influence of blood alcohol for the identification of intoxicated patients is not relevant. For example, the slightly positive test result for patient 7 was very likely caused by interference with the very high blood alcohol concentration.

On the other side, the question of third-party administration combined with alcohol intake can lead to uncertain situations, especially when the implied administration is some hours ago. Slightly positive results would be hard to interpret.

The second critical point is the short half-life in vivo. Since the serum specimen of patients 11 and 13 were obtained between 3 h and 8 h past a possible forced administration, the negative test result could be due to the short diagnostic window. The other way round can testing be meaningful in these cases anyway, because if for some reason there is a positive result, the intoxication is proven.

Taken together, knowledge of typical signs and symptoms, knowledge of the rising rate of misuse and real-time measurement of GHB in an ED will help to optimize patient care in unconscious ED patients.

There are several limitations of this investigation. The results are from a single centre and it included a small number of patients. However, this consecutive cases series of 13 patients within a narrow timeline provides an impression of the local situation. The relatively strict criteria for the measurement (ordering by senior physicians) biases for cases were the results seem to be positive. The efficacy in a larger and wider selected set of patients remains unclear, and a large multicentre using this GHB test kit should be recommended. Particularly for negative results, the narrow time frame could be a sticking point in the interpretation and the resulting conclusions. Furthermore positive test results – especially in connection with an alleged rape – cannot be considered as evidence in court.

Based on our experience, we recommend that acute care facilities should familiarize themselves with this new diagnostic option for GHB quantification in patients presenting with symptoms of GHB misuse and establish ED protocols to decide about quantification.

Conclusion

Fast GHB quantification in the ED offers additional information, which can influence further diagnostic or therapeutic decision-making and may lead to a more efficient patient care.

Footnotes

Authors’ note

TD, AW and MB collected the data, performed the analysis and wrote the manuscript. AR-Z, LW, SP, CH, JT and AG helped draft the manuscript and participated in study design and coordination. All authors read and approved the final manuscript.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This project was funded solely by departmental resources.

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