Gamma-hydroxybutyric acid (GHB) is an intriguing, naturally-occurring, 4-carbon compound with a structure similar to gamma-aminobutyric acid (GABA). It is described as a neurotransmitter and as a regulator of energy metabolism. First synthesized in 1960, GHB initially was investigated as an anesthetic due to its rapid induction of deep coma with only minor cardiovascular and respiratory depressant effects. Its lack of analgesia and tendency to cause seizurelike activity soon dampened enthusiasm for its use. Purported to act as a fat-burner and growth hormone promoter, GHB enjoyed a resurgence in the late 1980s as a food supplement for body builders and dieters. The withdrawal of L-tryptophan from the market, a supplement with similar purported effects, spurred GHB use. Also used as a hallucinogenic, euphoric, and sleep aid, it was easily obtained at health food stores, gyms, and mail order outlets. This newfound popularity coincided with a rising tide of GHB-related morbidity that soon caught the attention of regional poison control centers. The FDA subsequently prohibited the sale and manufacture of GHB in 1990. Since then, GHB has continued to enjoy a more clandestine popularity as an illicit drug, particularly in the Southeast and Western US. It currently is prevalent in the dance music scene (at raves and nightclubs) as an alternative to Ecstasy and amphetamines and is often used in conjunction with alcohol. It has been implicated, with Rohipnol, as a "date rape" drug. GHB generally comes in pure powder form or mixed with water. Its highly-concentrated, street form is available as a liquid in small plastic bottles, the size and shape of hotel shampoo bottles. The bottles generally cost only $10 and usually contain about 10 "hits." GHB goes by many street names, including grievous bodily harm, scoop, liquid ecstasy, cherry meth, growth hormone booster, liquid x and Georgia homeboy. GHB is readily manufactured from its precursor, gamma-butyrolactone (also known as 2(3h)-furanose dihydro or GBL). GBL is a solvent found in floor cleaning products, nail polish, and super glue removers. Saponification of the lactone with sodium hydroxide in the form of lye results in nearly quantitative conversion. However, this method is not without its drawbacks. There are several case reports of caustic alkali ingestion from undissolved lye. GBL also undergoes conversion into GHB in-vivo (by an unknown mechanism) and, accordingly, is associated with many of the same symptoms. GBL presently is readily purchased over the Internet and at health food stores under several brand names, including Fire Water, Renewtrient, Revivarant or Revivarant G, Blue Nitro or Blue Nitro Vitality, GH Revitalizer, Gamma G, and Remforce. Several states have caught on to this practice and have banned these products. The FDA has issued a warning and notice requesting manufacturers to issue a recall of GBL-containing products on January 21, 1999. On January 28, 1999, the FDA issued a warning to consumers not to purchase or use GBL products. A ban of this product is imminent. In an effort to skirt FDA regulation, several manufacturers have begun marketing 1,4 butanediol (BD), a chemical structurally similar and in many cases clinically indistinguishable from GHB. The FDA has declared BD a Class I Health Hazard - a potentially life-threatening drug. GHB’s unique attributes do have some legitimate uses. In Europe it is still used as an anesthetic, for alcohol and opiate addiction therapy, and for narcolepsy therapy. Only this last indication is recognized by the U.S. FDA, which allows its use on an experimental basis in narcolepsy trials. Pathophysiology: GHB is found naturally in the CNS, with the highest concentrations in the basal ganglia. GHB binding sites are present in the cortex, midbrain, substantia nigra, basal ganglia and, most predominantly, in the hippocampus, where it appears to mediate intrinsic neurons. It also is found in the peripheral blood and readily crosses the blood-brain and placental barriers. It is rapidly absorbed after ingestion; it takes 20-30 minutes to reach a maximal plasma concentration after the ingestion of a 12.5 mg/kg dose and increases to 30-60 minutes with a dose of 50 mg/kg. The elimination half-life is 27 minutes and proceeds in a dose-dependent, saturable manner. Elimination is via expired carbon dioxide. The pharmacokinetics of GHB in alcoholics are similar to that of nonalcoholics, although the frequency of serious side effects are less in the alcoholics, suggesting a cross-tolerance between alcohol and GHB. Although readily detected in the urine and serum by gas chromatographic-mass spectrometric techniques,traditional hospital toxicology assays typically do not include GHB. CNS GHB has a myriad of neurological effects. It binds to GABA-B receptors in the brain, inhibits noradrenaline release in the hypothalamus and mediates the release of an opiatelike substance in the striatum. It produces a biphasic dopamine response, increasing release at high doses and inhibiting its release at lower doses. True to its body-building claims, it does show an increase in growth hormone in rats and in one small human study. However, no study has ever demonstrated weight loss or increased muscle growth. Although GHB traditionally has been considered a potent epileptogenic drug and has been noted to cause epileptiform electroencephalographs (EEGs) in animals, human studies have failed to demonstrate EEG changes associated with use. It is thought that a reemergence syndrome characterized by myoclonic jerks of the face and extremities may have been mistaken for evidence of seizures. CNS depression is the hallmark of GHB use. An oral dose of 10 mg/kg produces short-term amnesia and hypotonia and 20-30 mg/kg produces drowsiness and sleep. After the ingestion of approximately 50-70 mg/kg, profound hypnosis and then deep coma rapidly ensue. GHB rapidly initiates delta wave and REM sleep and produces moderate amnesia but does not produce analgesia or muscle relaxation. It decreases cerebral glucose metabolism and increases cerebral blood flow, yet reduces intracranial pressure. Myoclonic jerks and respiratory depression accompany the descent into anesthesia. A Glasgow Coma Score (GCS) of 3 is not uncommon. One peculiar characteristic of GHB toxicity, despite such profound CNS and respiratory depression, is that patients often demonstrate extreme combativeness and agitation. Several physicians have been surprised when the individual suddenly awakens during an intubation attempt. The coma usually lasts from 1-4 hours and spontaneously resolves. Those patients intubated for respiratory depression typically have a longer time to recovery, but extubation within 8-10 hours is common; extubation in the ED has been described. The resolution is characteristically rapid and usually accompanied by myoclonic jerks and agitation. Cardiovascular (CV) GHB has been noted to cause bradycardia, decreased systemic vascular resistance, and hypotension. Pain or atropine rapidly causes an increase in heart rate and blood pressure. Studies of GHB infusion in hypovolemic shock have demonstrated an increase in mean arterial pressure and cardiac output when compared to a normal saline infusion. GHB also has been noted to have antidysrhythmic properties. Other effects One particularly fascinating property of GHB is its ability to prevent cell damage. Several studies have shown a reduction in oxygen requirements and a subsequent reduction in hypoxic cell damage. The exact mechanism of this tissue protective effect is unknown; however, several effects have been noted, including reductions in lipid peroxidation, lipolysis, free radical production, and a dampening of the inflammatory response. It has also been shown to be protective in radiation exposure. Benefit has been noted in a wide range of organ systems and in dozens of conditions, including hemorrhagic shock, sepsis, CVA, mesenteric ischemia, organ transplant, and MI. It is this last entity that has received the greatest attention. GHB has been found consistently to improve outcomes, including mortality, in several animal MI trials. However, its benefit in human MI trials has not yet been confirmed. The combination of its cell-protective and anesthetic properties has made GHB a candidate in certain types of surgery. Predominantly European literature has described its use in emergency laparotomy for hemorrhagic shock, aortic surgery, operations involving heart bypass, cataract surgery, labor, and many others. Its shortcomings as an anesthetic have led to a decline in its use in favor of more effective anesthetics. CNS Neurologic effects can range from mild (eg, nystagmus, dizziness, ataxia) to severe (eg, coma, respiratory failure, apnea, death). Typically, the patient experiences a short period of euphoria followed by a rapid and profound decline in the level of consciousness. Seizurelike activity and myoclonus commonly are reported. Pulmonary Respiratory depression Decreased respiratory rate Apnea Gastrointestinal (GI) Nausea Vomiting Physical: CNS The typical GHB ingestion presents with a profoundly depressed level of consciousness. A recent study noted that two-thirds of patients present with a GCS of less than 9, with a full one-third presenting with a GCS of 3. One unique aspect of GHB-induced coma is sporadic violent agitation, usually accompanying stimuli such as intubation attempts. The coma typically resolves completely and rapidly after a period of 1-4 hours. Seizurelike movements and myoclonus are common, particularly when descending into unconsciousness or on reemergence. Cardiovascular (CV) Approximately 36% of ingestions are accompanied by bradycardia. The bradycardia appears to be related to the depressed level of consciousness and is easily reversed with atropine. Hypotension accompanies about 10% of GHB ingestions. This usually is associated with coingestion of GHB and alcohol or another drug and usually is mild. If not readily resolved by stimulation or atropine administration, another ingestion or coingestion must be considered. Pulmonary Respiratory depression, evidenced by bradypnea to frank apnea, often occurs. Decreased breath sounds and rales may indicate aspiration. Gastrointestinal (GI) Nausea and vomiting are common with GHB ingestion and often accompany reemergence from unconsciousness. Prehospital Care: Prehospital personnel can contribute a great deal to an accurate diagnosis by obtaining a history of ingestion from the patient, friends, and bystanders and securing evidence of potential GHB ingestion (small shampoo bottles). Prehospital care primarily is supportive. Attention should be paid first and foremost to airway management and breathing. Oxygen should be administered and a patent airway established. Aspiration and cervical spine precautions should be observed. IV access should be established if possible. Naloxone should be considered for all comatose patients with any respiratory compromise. This may not be beneficial for GHB ingestions but is not considered to be detrimental. Intubation in the field should be reserved for severe, refractory, respiratory compromise and attempted only by experienced personnel when the airway is at risk. Emergency Department Care: ED management of GHB overdose is primarily supportive. Airway patency and aspiration precautions are of paramount importance. Consideration should be given to gastric lavage and/or activated charcoal if coingestion is suspected. Cardiac monitoring is indicated, given the relative frequency with which arrhythmias and conduction deficits have been noted. These interventions are of a limited benefit in isolated GHB ingestions due to the small amounts usually ingested (from one-fourth of a teaspoon to 4 tablespoons) and because of the rapidity of absorption (usually 10-15 minutes). If gastric lavage is deemed appropriate, the patient should be intubated prior to lavage to prevent potential aspiration. Symptomatic bradycardia that is unresponsive to stimulation should be treated with atropine. Given the usually benign course and rapid recovery of uncomplicated GHB intoxications, a conservative approach to intubation has been suggested. However, certain conditions necessitate intubation. If the history of GHB ingestion is unreliable in the presence of severe respiratory depression, hypoxia, or in preparation for lavage, rapid-sequence intubation should be performed. A sedative usually is not required, but neuromuscular blockade is recommended to avert the paradoxical agitation common with GHB. The reversal of GHB-induced CNS depression is a controversial issue. Although physostigmine has been shown to reverse sedation in clinical trials, most experts presently believe that the risks of its use (eg, bradycardia, asystole, seizures) outweigh the benefits in most GHB ingestions and that it should be reserved for selected cases, if used at all. ------------------ ~*P*L*U*R*~ Four Simple Words To Live By....
