Clinical Toxicology (2012), 50: 458–470
`Copyright © 2012 Informa Healthcare USA, Inc.
`ISSN: 1556-3650 print / 1556-9519 online
`DOI: 10.3109/15563650.2012.702218
`
`REVIEW ARTICLE
`
` The clinical toxicology of gamma-hydroxybutyrate,
`gamma-butyrolactone and 1,4-butanediol
`
` LEO J SCHEP 1 , KAI KNUDSEN 2 , ROBIN J SLAUGHTER 1 , J ALLISTER VALE 3 , and BRUNO MÉGARBANE 4
`
` 1 National Poisons Centre, Department of Preventive and Social Medicine, University of Otago, Dunedin, New Zealand
` 2 Department of Anesthesia and Intensive Care Medicine, Surgical Sciences, Blå Stråket 5, Sahlgrenska University Hospital,
`Gothenburg, Sweden
` 3 National Poisons Information Service (Birmingham Unit) and West Midlands Poisons Unit, City Hospital, Birmingham, UK; School of
`Biosciences and College of Medical and Dental Sciences, University of Birmingham, Birmingham,UK
` 4 Hôpital Lariboisière, Réanimation Médicale et Toxicologique, INSERM U705, Université Paris-Diderot, Paris, France
`
` Introduction. Gamma-hydroxybutyrate (GHB) and its precursors, gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD), are drugs of
`abuse which act primarily as central nervous system (CNS) depressants. In recent years, the rising recreational use of these drugs has led
`to an increasing burden upon health care providers. Understanding their toxicity is therefore essential for the successful management of
`intoxicated patients. We review the epidemiology, mechanisms of toxicity, toxicokinetics, clinical features, diagnosis, and management
`of poisoning due to GHB and its analogs and discuss the features and management of GHB withdrawal. Methods. OVID MEDLINE
`and ISI Web of Science databases were searched using the terms “ GHB, ” “ gamma-hydroxybutyrate, ” “ gamma-hydroxybutyric acid, ”
` “ 4-hydroxybutanoic acid, ” “ sodium oxybate, ” “ gamma-butyrolactone, ” “ GBL, ” “ 1,4-butanediol, ” and “ 1,4-BD ” alone and in combination
`with the keywords “ pharmacokinetics, ” “ kinetics, ” “ poisoning, ” “ poison, ” “ toxicity, ” “ ingestion, ” “ adverse effects, ” “ overdose, ” and
` “ intoxication. ” In addition, bibliographies of identifi ed articles were screened for additional relevant studies including nonindexed reports.
`Non-peer-reviewed sources were also included: books, relevant newspaper reports, and applicable Internet resources. These searches
`produced 2059 nonduplicate citations of which 219 were considered relevant. Epidemiology. There is limited information regarding
`statistical trends on world-wide use of GHB and its analogs. European data suggests that the use of GHB is generally low; however, there
`is some evidence of higher use among some sub-populations, settings, and geographical areas. In the United States of America, poison
`control center data have shown that enquiries regarding GHB have decreased between 2002 and 2010 suggesting a decline in use over
`this timeframe. Mechanisms of action. GHB is an endogenous neurotransmitter synthesized from glutamate with a high affi nity for GHB-
`receptors, present on both on pre- and postsynaptic neurons, thereby inhibiting GABA release. In overdose, GHB acts both directly as a
`partial GABA b receptor agonist and indirectly through its metabolism to form GABA. Toxicokinetics. GHB is rapidly absorbed by the
`oral route with peak blood concentrations typically occurring within 1 hour. It has a relatively small volume of distribution and is rapidly
`distributed across the blood – brain barrier. GHB is metabolized primarily in the liver and is eliminated rapidly with a reported 20 – 60
`minute half-life. The majority of a dose is eliminated completely within 4 – 8 hours. The related chemicals, 1,4-butanediol and gamma
`butyrolactone, are metabolized endogenously to GHB. Clinical features of poisoning. GHB produces CNS and respiratory depression
`of relatively short duration. Other commonly reported features include gastrointestinal upset, bradycardia, myoclonus, and hypothermia.
`Fatalities have been reported. Management of poisoning. Supportive care is the mainstay of management with primary emphasis on
`respiratory and cardiovascular support. Airway protection, intubation, and/or assisted ventilation may be indicated for severe respiratory
`depression. Gastrointestinal decontamination is unlikely to be benefi cial. Pharmacological intervention is rarely required for bradycardia;
`however, atropine administration may occasionally be warranted. Withdrawal syndrome . Abstinence after chronic use may result in a
`withdrawal syndrome, which may persist for days in severe cases. Features include auditory and visual hallucinations, tremors, tachycardia,
`hypertension, sweating, anxiety, agitation, paranoia, insomnia, disorientation, confusion, and aggression/combativeness. Benzodiazepine
`administration appears to be the treatment of choice, with barbiturates, baclofen, or propofol as second line management options.
` Conclusions. GHB poisoning can cause potentially life-threatening CNS and respiratory depression, requiring appropriate, symptom-
`directed supportive care to ensure complete recovery. Withdrawal from GHB may continue for up to 21 days and can be life-threatening,
`though treatment with benzodiazepines is usually effective.
`
` Keywords
` CNS/Psychological; Organ/tissue specifi c; Complications of poisoning; Pharmaceuticals; Gamma hydroxybutyrate;
`Gamma-butyrolactone; 1,4-butanediol
`
` Received 19 May 2012 ; accepted 4 June 2012.
`Address correspondence to Dr. Leo Schep PhD, National Poisons Centre,
`Department of Preventive and Social Medicine, University of Otago, PO
`Box 913, Dunedin, 9054 New Zealand. E-mail: leo.schep@otago.ac.nz
`
`458
`
`Clinical Toxicology Downloaded from informahealthcare.com by Sherry Mohr on 02/04/15
`
`For personal use only.
`
`PAR1036
`IPR of U.S. Patent No. 8,772,306
`Page 1 of 13
`
`

`
` Introduction
` Gamma-hydroxybutyrate (GHB) and its precursors, gam-
`ma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD),
`are drugs of abuse which act primarily as central nervous
`system (CNS) depressants (Fig. 1). Since the initial inves-
`tigations into gamma butyrolactone (GBL) in 1947 1,2 and
`GHB in 1960, 3 their biological, pharmacological, and
`toxicological properties have been studied extensively. 1,4-
`butanediol (1,4-BD) is an important industrial solvent and
`was discovered in 1890. 4
` GHB, commonly known as “ Liquid ecstasy, ” “ Gamma-O, ”
` “ G, ” “ Georgia Home Boy, ” “ Mils, ” “ Liquid X, ” and “ Liquid
`G, ” is a short-chain carboxylic acid neurochemical messen-
`ger that occurs within the mammalian CNS. GHB is both a
`metabolite and a precursor of the inhibitory neurotransmitter
`gamma-hydroxybutyrate (GABA) and acts as a neuromodu-
`lator in the GABA system (see below). 5 While endogenous
`concentrations of GHB function as a neuromodulator in
`various neurobiochemical pathways, supratherapeutic doses
`of GHB can readily cross the blood – brain barrier leading to
`profound CNS and respiratory depression.
` All three chemicals were shown to possess anesthetic
`properties and in the early-mid 1960 ’ s, GHB was fi rst trialed
`as clinical anesthetic agent. 6,7 However, many of the early
`studies demonstrated that it lacked analgesic and muscle
`relaxant properties and produced a number of adverse
`effects; it never became established as a general anesthetic
`agent. 8 Other research involving a single study with six sub-
`jects suggested that GHB administration was associated with
`an increased release of growth hormone and an increase in
`REM sleep. 9 Subsequently, GHB became popular at training
`gyms and fi tness centers as bodybuilders began to use it as
`
` Fig. 1. The chemical structures of gamma-butyrolactone, gamma-
`hydroxybutyric acid and 1, 4-butanediol.
`
`Copyright © Informa Healthcare USA, Inc. 2012
`
` The clinical toxicology of gamma-hydroxybutyrate 459
`
`a supplement, anticipating an increase in lean muscle mass
`due to increased growth hormone concentrations. It was
`also promoted in health stores for weight control and seda-
`tion. 10 However, as reports of adverse effects became more
`frequent, GHB was prohibited in 1990 in the United States
`of America. 11 The related chemicals GBL and 1,4-BD were
`substituted for GHB leading to predictable consequences
`and toxicity. 11,12
` The intoxicating properties of GHB (and GBL and 1,4-BD)
`led to them becoming popular as substances of abuse, mostly
`in some parts of Europe, the United States, and Australasia.
`10,13 – 28 When taken recreationally, users may co-ingest GHB
`with other drugs of abuse including ethanol, 15,19,24,29 – 43 cannabis,
` 15,19,20,24,29 – 34,36,39,44 – 46 amfetamines, 15,19,20,24,29,32 – 34,36 – 39,44,47
`opioids, 15,19,20,25,32,36,48
`cocaine, 15,19,20,29,31,32,34,36 – 39,41,44,47
`benzodiazepines, 15,19,39,41,44,47 and other sedative or anesthetic
`drugs, 19,20,31,36,37,39 which may lead to a myriad of adverse
`clinical effects and social problems.
` Although GHB has also been implicated in sexual assaults
`as a “ date rape ” drug, 39,47,49 – 53 a recent review of the litera-
`ture suggested that GHB is rarely present in cases of drug-
`facilitated sexual assault. 54 The sodium salt of GHB, sodium
`oxybate, was also investigated for the treatment of cataplexy
`in patients with narcolepsy; an oral solution was approved
`in 2002 in the United States and in 2005 in Europe. 8,55 It
`has also been considered in Europe, particularly Italy, for the
`treatment of alcoholism. 56
` The aim of this paper is to review the epidemiology,
`mechanisms of toxicity, toxicokinetics, clinical features,
`diagnosis, and management of poisoning due to GHB and its
`precursors, GBL and 1,4-BD, and to review the features and
`management of the GHB withdrawal syndrome.
`
` Methods
` OVID MEDLINE (January 1950 – July 2011) and ISI Web
`of Science (1900 – July 2011) databases were searched using
`the terms “ GHB, ” “ gamma hydroxybutyrate, ” “ gamma-
`hydroxybutyric acid, ” “ 4-hydroxybutanoic acid, ” “ sodium
`oxybate, ” “ gamma-butyrolactone, ” “ GBL, ” “ 1,4-butanediol, ”
`and “ 1,4-BD ” alone and in combination with the keywords
` “ pharmacokinetics, ”
` “ kinetics, ”
` “ poisoning, ”
` “ poison, ”
` “ toxicity, ” “ ingestion, ” “ adverse effects, ” “ overdose, ” and
` “ intoxication. ” In addition, bibliographies of identifi ed arti-
`cles were screened for additional relevant studies including
`nonindexed reports. Non-peer-reviewed sources were also
`included: books, relevant newspaper reports, and applicable
`Internet resources. These searches produced 2059 nondu-
`plicate citations, which were then screened via their title or
`abstract (if available) for those referring specifi cally to the
`mechanisms of action, toxicokinetics, clinical features, and
`management of GHB toxicity and withdrawal in humans;
`219 were considered relevant.
`
` Epidemiology
` There are limited data regarding statistical trends on
`world-wide use of GHB and it analogs; nevertheless some
`
`Clinical Toxicology Downloaded from informahealthcare.com by Sherry Mohr on 02/04/15
`
`For personal use only.
`
`PAR1036
`IPR of U.S. Patent No. 8,772,306
`Page 2 of 13
`
`

`
`460
`
` L. J. Schep et al.
`
`tentative conclusion can be inferred from data, typically
`obtained from government and nongovernment organiza-
`tions, and poison center statistics. In Europe, there has been
`a fourfold increase in drug seizures by authorities over the
`2005 – 2009 period that, according to the UN Offi ce on Drugs
`and Crime, 57 account for almost 80% of the world total; in
`kilogram equivalents, seizures have increased from 156 in
`2005 to 675 in 2009. Nevertheless, when compared to sei-
`zures of other types of synthetic drugs, such as amfetamines
`and MDMA, the total number is still comparatively low. 58
`A recent publication from the European Monitoring Centre
`for Drugs and Drug Addiction investigating trends in GHB
`use in Europe, found there was limited information on the
`prevalence of use of GHB and its analogs but suggested its
`use is generally low; however, there is evidence of higher
`use among some sub-populations, settings, and geographical
`areas. 58 Another UN report suggests there is a growing con-
`cern in Europe, with an increasing number of people seeking
`treatment for addiction to GHB and GBL. 59
` Detection and seizures of both ketamine and GHB/GBL
`by the Australian Customs and Border Protection Service
`have steadily increased between 2002 and 2011. 60 The Aus-
`tralian National Drug Strategy Household Survey for 2010
`
`showed 0.8% of people aged 14 years or older had used
`GHB at some stage in their life. This was an increase from
`0.5% in 2004. 61 In contrast, rates of use in the United States,
`based on the American Association of Poison Control Cen-
`ters summary of GHB poison center enquiries, have declined
`from 1386 in 2002 62 to 546 for the year 2010. 63
`
` Mechanisms of action
` GHB is an endogenous neurotransmitter that is predomi-
`nantly distributed within discrete regions of the mamma-
`lian brain, 64 though it is also present in the blood, urine,
`and other peripheral tissues. 65 GHB is both a metabolite
`and a precursor of the inhibitory neurotransmitter gamma-
`hydroxybutyrate (GABA), 66 and acts as a neuromodulator
`in the GABA system. An overview of its biochemical path-
`way is presented in Fig. 2 with a detailed description in the
`Toxicokinetics section.
` GHB is synthesized from glutamate, typically within
`GABA-releasing neurons, that are predominantly located
`in the hippocampus, cortex, thalamus, and amygdala. 67 – 69
`Upon depolarization, endogenously released GHB has a
`high affi nity for GHB-receptors, present both on pre- and
`
` Fig. 2. A summary of the metabolic pathway of gamma-hydroxybutyrate.
`
`Clinical Toxicology vol. 50 no. 6 2012
`
`Clinical Toxicology Downloaded from informahealthcare.com by Sherry Mohr on 02/04/15
`
`For personal use only.
`
`PAR1036
`IPR of U.S. Patent No. 8,772,306
`Page 3 of 13
`
`

`
`postsynaptic neurons. 70,71 . It acts principally upon G-protein
`coupled GHB receptors, possibly leading to the inhibition of
`GABA release. 70,71 GHB also acts to prevent dopamine neu-
`rotransmission within the substantia nigra and mesolimbic
`regions, 72,73 and it modulates the serotonin 74 and opioid 75
`systems. Additionally, GHB also modulates the release of
`growth hormone, 76 but lacks any anabolic effects. 77
` Endogenous concentrations of GHB, derived from postmor-
`tem samples, can range from 2 to 20 nmol/g, 64 though evidence
`with animal tissues suggests values may increase twofold over
`6 hours following death. 64 In contrast to endogenous concen-
`trations, exogenous sources of GHB, typically elevated to an
`excess of 1000 nmol/g tissue, can act directly as partial GABA b -
`receptor agonist and indirectly through its metabolism to form
`GABA 78 (see Fig. 2), both resulting in membrane hyperpolar-
`ization and subsequent CNS depression. 79
`
` Toxicokinetics
`in healthy
` GHB pharmacokinetics have been studied
`volunteers, 80 – 84 narcoleptics, 85,86 alcoholics, 87 and patients with
`liver impairment. 88 A further study monitored GHB kinetics
`following 1,4-butanediol administration to healthy volun-
`teers. 89 The pharmacokinetics do not appear to vary signifi -
`cantly among healthy human volunteers, narcoleptic patients,
`or alcohol-dependent patients. However, when healthy adult
`volunteers and patients with biopsy-proven liver cirrhosis were
`compared, there was a marked reduction in clearance following
`oral administration and signifi cant prolongation of elimination
`half-life. 88 A summary of kinetic parameters reported from
`these studies are presented in Table 1.
`
` Absorption
` GHB is well absorbed orally. Peak blood concentrations
`occur 25 – 60 minutes post-ingestion. 80 – 82,84 – 88,90 The onset
`
` The clinical toxicology of gamma-hydroxybutyrate 461
`
`of clinical and electroencephalographic (EEG) effects typi-
`cally occur 15 – 20 minutes postexposure with peak effects at
`30 – 60 minutes postingestion. 80,83,91 Studies suggested that
`oral absorption of GHB is nonlinear with limited capacity
`at higher doses leading to an increased interval of time to
`achieve Tmax and a decrease in the normalized Cmax. 80 One
`study, for example, demonstrated that the average time to
`achieve peak concentration increased from 25 minutes at a
`dose of 12.5 mg/kg to 45 minutes at a dose of 50 mg/kg. 80
`Bioavailability was determined as 26% in one human study, 92
`though animal investigations suggested 50 – 94% values. 93,94
`Reduced bioavailability in humans is thought to be mainly
`due to more extensive fi rst pass metabolism. 92,94 The inges-
`tion of food with oral GHB has been shown to reduce mean
`peak plasma concentrations, increase median time to peak
`concentration, and decrease the area under the plasma con-
`centration-time curve. 81
` Like GHB, 1,4-BD is rapidly absorbed and promptly
`metabolized to GHB. Following the oral administration of
`25 mg/kg of 1,4-BD in healthy adult volunteers, the mean
`1,4-BD Cmax was reached at 24 ⫾ 12 minutes, with measur-
`able plasma GHB concentrations within 5 minutes postinges-
`tion and the mean Cmax at 39.4 ⫾ 11.2 minutes. 89
`
` Distribution
` Animal studies have shown that distribution occurs rapidly
`and appears to follow a two-compartment model. 93 Mean vol-
`umes of distribution have been reported to range from 192 to
`741 mL/kg when given to healthy volunteers 81,82,89 and from
`225.9 86 to 307 mL/kg 85 , when administered to narcoleptic
`patients. The volume of distribution was reduced from 225.9
`to 196.7 mL/kg after 8 weeks of GHB therapeutic adminis-
`tration. 86 Volumes of distribution do not appear to be signifi -
`cantly affected by gender or food. 81 Studies have shown that
`GHB crosses the placenta in animals 95 and humans, 96,97 and
`
` Table 1. A summary of the mean key pharmacokinetic parameters of GHB.
`
`Mean time to peak
`plasma concentration
`(min)
`
`Mean
`residence
`time (min)
`
`Mean apparent
`volume of distribution
`[Vz/F] (mL/kg)
`
`Mean clearance
`[CL/F](mL/min/kg)
`
`Mean elimination
`rate constant (h-1)
`
`Mean half-
`life (min)
`
`Reference
`
`25 *
`30 *
`45 *
`41.3
`60 *
`60 *
`45 *
`120 *
`42
`36
`36
`54
`43
`45 *
`45 *
`30 *
`45 *
`
`45
`53
`70
`73.2
` –
` –
` –
` –
` –
` –
` –
` –
` –
`77
`110
`68
`96
`
` –
` –
` –
`741
`202
`218
`192
`384
` –
` –
` –
` –
` 225.9
`198
`285
` –
` –
`
`14
`9
`7
`15.8
`3.8
`4.2
`3.7
`6.2
` –
` –
` –
` –
`
`4
`4.5
`4.1
`7.9
`5.3
`
` –
` –
` –
` –
` –
` –
` –
` –
`0.98
`1.01
`1.06
`1.23
` –
` –
` –
` –
` –
`
`20
`22
`23
`30
`39
`37
`34
`41
`44
`43
`40
`34
`43
`32
`56
`27
`35
`
`80
`80
`80
`82
`82
`82
`82
`82
`84
`84
`84
`84
`86
`88
`88
`87
`87
`
` * Median value.
`
`Copyright © Informa Healthcare USA, Inc. 2012
`
`Clinical Toxicology Downloaded from informahealthcare.com by Sherry Mohr on 02/04/15
`
`For personal use only.
`
`PAR1036
`IPR of U.S. Patent No. 8,772,306
`Page 4 of 13
`
`

`
`462
`
` L. J. Schep et al.
`
`also passes across the blood – brain barrier. 78,98 – 101 In-vitro
`studies indicate that GHB shows limited plasma protein
`binding. 80
`
` Metabolism
` GHB is primarily metabolized hepatically to succinic semi-
`aldehyde by means of NAD(P) ⫹ -linked oxidation by GHB
`dehydrogenase (Fig. 2). Succinic semialdehyde is metabo-
`lized primarily to succinic acid by succinic semialdehyde
`dehydrogenase 102 ; alternatively, it can also be metabolized
`to GABA by GABA transaminase. 103 Succinic acid enters
`the citric acid cycle and is ultimately metabolized to water
`and carbon dioxide. 40
` The related chemicals, 1,4-BD and GBL, are metabolized
`endogenously to GHB. 1,4-BD is metabolized by alcohol
`dehydrogenases to gamma-hydroxybutyraldehyde and then
`by aldehyde dehydrogenase to form GHB; ethanol can
`inhibit this metabolism as it acts as a competitive substrate
`to alcohol dehydrogenase, whereas fomepizole will also stop
`its metabolism by inhibiting alcohol dehydrogenase. 43,104 – 106
`GBL is converted to GHB by serum lactonase; this enzyme
`is not present in brain tissue. 107,108
`
` Elimination
` Exogenous GHB demonstrates rapid nonlinear elimination
`kinetics in both animals 93,95,98,100,109 and humans. 80,92 This
`is thought to be most likely due to saturatable metabolic
`pathways. 80 GHB is predominantly eliminated follow-
`ing the biotransformation pathway, as outlined in Fig. 2,
`to form GABA and ultimately enter the Krebs cycle; less
`than 2% of the parent drug is eliminated unchanged in
`the urine. 83,84,87 The reported half-life of GHB in kinetic
`studies in humans is generally consistent with mean values
`between 20 and 53 minutes, 80 – 82,84 – 89 with the majority
`of a dose being completely eliminated within 4 – 8 hours
`postingestion. 87,90 Mean clearance (CL/F) values range
`from 3.7 to 15.8 mL/min/kg in either fed or fasted healthy
`volunteers. 80 – 82
` Following the oral administration of 1,4-BD 25 mg/kg,
`the mean elimination half- life was reported to be 39.3 ⫾ 11
`minutes in healthy adult volunteers. 89
`
` Clinical features
`The majority of information regarding the features of
`GHB poisoning is obtained from case reports and case
`series; many of these did not have the diagnosis confi rmed
`analytically,
`instead
`relying on self-reporting which
`thereby limits their accuracy. Nevertheless, the majority of
`these papers did provide a relatively consistent toxidrome
`for GHB toxicity in humans. Mild clinical effects, such
`as short-term anterograde amnesia, hypotonia, and
`euphoria, are anticipated following the ingestion of GHB
`doses below 10 mg/kg. 40,110 At doses of 20 – 30 mg/kg,
`drowsiness, sleep, and myoclonus can occur, 40,111 whereas
`doses of 50 mg/kg may cause coma. 110,112,113 Doses
`
`in excess of 50 mg/kg may lead to the onset of coma,
`bradycardia, and/or respiratory depression. 40,110 – 113 Thus,
`patients may present with CNS Symptoms ranging from
`sudden drowsiness through to unresponsive and profound
`coma, depending on the dose ingested. 12,14,19,20,24,25,27,29 –
`33,35 – 43,45 – 47,106,110,114 – 149 symptoms typically occur within
`15 – 45 minutes, 12,30,41 and resolve within a relatively short
`interval of time; CNS depression usually persists for 1 – 3
`hours with patients making a complete recovery typically
`within 4 – 8 hours. 12,32,43,111,116 – 119,121,122,124,147,149
` In one case series of 88 patients who took GHB, the
`reported presenting Glasgow Coma Scale (GCS) scores
`were 3 in 25 patients (28%), 4 – 8 in 28 patients (33%),
`whereas 17 patients (19%) had a GCS score of 14 or 15. 32
`Other common neurological effects include ataxia, 29,45,115,
`119 – 121,131,149 disorientation, 30,38,136,144,149 dizziness, 20,120,123 –
`confusion, 20,45,124,125,136 hallucinations, 124,125,
` 125,132,144
`131,149 somnolence, 117,121,136,147 slurred speech, 115,131,149
`confusion, 12,20,149
`headache, 38,46
`dysarthria, 38,120
`incoordination, 115,124
`euphoria, 113,136
`amnesia, 120,136
`hypotonia, 12,24,41,45,110 hyporefl exia 118,133,139,143 tremor, 110,115
`and myoclonus. 19,110,117,120,150 Seizures or seizure-like
`activity have also been reported, 19,20,24,32,33,35 – 37,41,106,110,116,
`122,124,125,128,136,142,148 although, the majority of studies have
`shown seizures are uncommon. Some cases where seizures
`have been reported may have resulted from a misdiagnosis
`of myoclonus that was attributed to generalized seizures. 31
`Nevertheless, seizures may still occur secondary to hypoxia
`or due to coingested intoxicants.
` Agitation, bizarre behavior, and combativeness has
`been noted in some patients, either at presentation or upon
`wakening 12,19,20,24,29,31,36,38,42,46,115,119,120,122,124,127,129,136,
`142,144,145,147,149,150 ; this may also occur when intubation is
`attempted, or may also occur when the patient is in a deep
`coma. 31,119 Patients can also alternate between agitation and
`somnolence. 136,145
` Other less common neurological effects may include
`bruxism, 129 vertigo, 110 disinhibition, 38 increased sexual
`arousal, 132 delusions, 144 extrapyramidal side effects, 131
`dystonias, 131 and athetoid posturing. 129 Miosis is common 12,
`20,38,40,43,46,114,119,122,123,125,134,136,140,142 while mydriasis
`20,35,38,46,47,115,117,123,124 and horizontal and vertical gaze
`nystagmus 45,46,115,131,149 may also occur. Pupils may also be
`sluggish or nonreactive. 12,35,124,125,141
` Common cardiovascular effects include bradycardia, 19,20,
`24,30,35,37,38,43,110,115,116,120,122 – 124,126,127,129,130,133,135,136,140 – 143,
`147,149,150 and hypotension. 20,36,38,41,110,116,120,129,134,135,141,149
`Mild bradycardia without hemodynamic compromise is the
`most common cardiovascular effect; this is evident both
`following its use in anesthesia 151 and in recreational use. 32
`One case series of 88 overdose patients showed that 32
`(36%) developed bradycardia but only one case was deemed
`severe enough to require atropine. 32 In this case series,
`bradycardia was associated with decreased levels of con-
`sciousness; those with bradycardia had a mean GCS of
`4 whereas those without bradycardia had a mean initial
`GCS score of 9. 32 Hypotension is rare when GHB is the
`sole ingestant, 38 though it is reported more commonly
`
`Clinical Toxicology vol. 50 no. 6 2012
`
`Clinical Toxicology Downloaded from informahealthcare.com by Sherry Mohr on 02/04/15
`
`For personal use only.
`
`PAR1036
`IPR of U.S. Patent No. 8,772,306
`Page 5 of 13
`
`

`
`when taken with coingestants. 20,32 Conversely, tachycar-
`dia and hyper tension have also been reported. 35,36,45,119,120,
`122,124,136,140,147,149,152,153 ECG abnormalities occur occa-
`include U waves, 31
`sionally 36 and
`transient P-wave
`inversion, 154 elevation of the ST segments, 143 possible
`QRS widening, 12 QTc prolongation, 143 right bundle-branch
`block, 31,143 and fi rst-degree atrioventricular block. 31 Atrial
`fi brillation that spontaneously converted to sinus rhythm
`has also been reported, 32,129 while asystole may occur in
`severe cases. 35 Chest tightness 38,125 or palpitations 38 may
`also occur.
` The major respiratory effects of GHB include dose-
`related respiratory depression, 19,20,29,31,35,37,42,110,114,119,120,
`bradypnea, 12,30,33,36,38,118,120,123,129,133,134,138,
`122 – 124,136,141
`141,149 periodic (Cheyne – Stokes) respirations, 6,24,155 and
`apnea and respiratory failure. 14,24,27,31,33,43,110,114,122,125,12
`9,130,135,136,138,140,141,143,144,149 One case series reported 30
`patients that had arterial blood gases measured; 21 of these
`patients (70%) had a PCO 2 of 45 mmHg (6 kPa) or greater. 32
`The mean arterial pH in these 30 patients was 7.32 ⫾ 0.04;
`28 (93%) had a pH of less than 7.40 and 9 (30%) had a pH
`less than 7.30. 32 No cases of pulmonary aspiration were
`recorded in this series though this has been noted in other
`reports. 12,14,20,27,39,122,141 Tachypnea, 36 pneumothorax, 143 and
`cyanosis 12,35 have also been reported. Pulmonary edema has
`been documented during intoxication 114,156 and a common
`feature at autopsy. 48,120,139,157
` Hypothermia can also occur. 19,20,29,32,36,38,41,129,133,136,141
`143 144 149 One case series of 88 patients showed 48 had an
`initial temperature of 36 ° C or less and 22 patients had an ini-
`tial temperature of 35 ° C or less. 32 Hypothermia is normally
`not severe. 19,32
`include hyperglycemia, 114,122,140
`features
` Metabolic
`hypokalemia, 19,20,30,114
`and potentially hypernatremia
`if large doses of the sodium salt are ingested. 112 Ele-
`vated creatine kinase activity/rhabdomyolysis may also
`occur. 17,19,20,24,46,147
` Nausea and vomiting are common gastrointestinal symp-
`toms following oral or intravenous administration of
`GHB. 12,19,20,24,27,29,30,36,37,41,46,110,113,116,120 – 125,128,135,136,
`143,144,149,150,157 Two case series have noted vomiting in
`22% 44 and 30% 32 of presentations. In the latter series, vom-
`iting typically occurred during the fi nal emergence from
`unconsciousness, although sometimes occurred during other
`stages of intoxication. 32 Salivation, 24,158 abdominal pain, 144
`and incontinence of stool and urine may also occur. 20,120,124,
`125,129,136,143,147,148 Diaphoresis has also been reported. 29,31,44,
`119,120,136,147,149
` The majority of patients ingesting GHB recover with-
`out sequelae as long as they receive appropriate supportive
`care. 19,20,24,25,29,31,32,36 – 39,110,136,144 However, fatal outcomes
`have been recognized 14,15,27,39,42,48,120,139,157,159 – 165 ; typically
`these occur in a prehospital setting. Death is normally due to
`respiratory failure.
` GHB use alongside other CNS depressant drugs
`may increase toxicity by producing synergistic CNS
`depression. 15,166 and coingestants may also contribute to
`fatalities involving GHB. 15,39,48,164,165
`
`Copyright © Informa Healthcare USA, Inc. 2012
`
` The clinical toxicology of gamma-hydroxybutyrate 463
`
` Diagnosis
`A diagnosis of GHB intoxication is typically made
`on the basis of the patient’s history and presentation.
`However, as such symptoms are not specifi c, it may be
`diffi cult to differentiate GHB poisoning from other sedative-
`hypnotic intoxications, especially if no history of GHB use
`is available to the clinician. 29
` A number of analytical methods to detect GHB, both in
`urine and serum, have been utilized; including gas or liquid
`chromatography coupled with electron capture and fl ame
`ionization, mass spectrometric detection, liquid chromatog-
`raphy-mass spectrometry (LCMS), and ultraviolet-visible
`spectrophotometry. 29,47,115,146,149,167 – 174 However,
`serum
`or urine concentrations cannot be readily assayed in most
`hospital laboratories. Interpretation of serum or urine con-
`centrations may also be diffi cult due to confounding factors
`such as the rapid metabolism and elimination of GHB, the
`presence of endogenous GHB, spontaneous GHB-to-GBL
`interconversion, and possible erroneous results from collec-
`tion and storage of samples. 172,175 – 179 Interpretation is also
`complicated by the poor correlation between plasma/urine
`concentrations and clinical effects. 29 Analytical assessment
`should not therefore be considered a routine component of
`diagnosis.
`
` Management
` Decontamination
`The effi cacy of activated charcoal or gastric lavage following
`GHB ingestion has not been assessed formally. Decontami-
`nation is unlikely to be benefi cial in the majority of cases
`because of the drug ’ s rapid absorption, particularly when
`consumed in a liquid form. Additionally, as patients typi-
`cally do well with supportive care, the risk of adverse effects
`from decontamination likely outweighs any benefi t. Gastric
`lavage and activated charcoal are therefore not indicated for
`sole GHB ingestions. However, activated charcoal may have
`a role in patients who have taken coingestants for which
`activated charcoal is an appropriate treatment. Activated
`charcoal (50 – 100 g) should only be considered in patients
`who are alert, stable, and cooperative, or have a protected
`airway. It must be administered cautiously, because of the
`risk of coma and/or loss of airway protective refl exes and
`pulmonary aspiration. 40,180
`
` Supportive care
`Supportive care is the mainstay of management, with pri-
`mary emphasis on respiratory and cardiovascular support.
`Initial treatment includes securing intravenous access and
`continuous cardiac and blood pressure monitoring along
`with pulse oximetry and arterial blood gas monitoring.
` Airway protection including rapid sequence induction with
`endotracheal intubation and/or assisted ventilation is indicated
`in patients unable to maintain an airway or in the situation
`of hypercarbia or hypoxia unresponsive to oxygen adminis-
`tration. GHB is commonly associated with vomiting 32 and,
`
`Clinical Toxicology Downloaded from informahealthcare.com by Sherry Mohr on 02/04/15
`
`For personal use only.
`
`PAR1036
`IPR of U.S. Patent No. 8,772,306
`Page 6 of 13
`
`

`
`464
`
` L. J. Schep et al.
`
`in the presence of loss of protective airway refl exes, this
`may increase the risk of pulmonary aspiration, therefore
`intubation would be additionally recommended in this situ-
`ation. 181 Occasionally some patients may become agitated or
`combative when intubation is attempted, even in the state of
`deep coma 31,119 ; sedation in incremental doses or paralysis
`may be r