The new england journal of medicine

case records of the massachusetts general hospital

Founded by Richard C. Cabot

Nancy Lee Harris, m.d., Editor Sally H. Ebeling, Assistant Editor
William F. McNeely, m.d., Associate Editor Stacey M. Ellender, Assistant Editor
Jo-Anne O. Shepard, m.d., Associate Editor Christine C. Peters, Assistant Editor

Case 30-2003: A 21-Year-Old Man with Sudden

Alteration of Mental Status
David N. Tancredi, M.D., and Michael W. Shannon, M.D.

presentation of case
Dr. Joshua N. Goldstein (Emergency Medicine): A 21-year-old man was brought to the From the Department of Emergency Med-
emergency department because of a sudden change in mental status. icine, Massachusetts General Hospital
(D.N.T.); the Department of Emergency
On the evening of admission, the patient had been consuming alcohol with friends. Medicine, Children’s Hospital (M.W.S.);
They noted that he had begun to act strangely, becoming uncommunicative and incon- and the Departments of Medicine (D.N.T.)
tinent of urine and stool, and thought that he might have had a brief seizure. They called and Pediatrics (M.W.S.), Harvard Medical
School — all in Boston.
an ambulance. When emergency medical services arrived, the patient was awake but un-
communicative and unable to follow commands. The glucose level in a finger-stick N Engl J Med 2003;349:1267-75.
blood sample was normal. An intravenous catheter was placed, and the patient was Copyright © 2003 Massachusetts Medical Society.

transported to the emergency department of this hospital.

On arrival, the patient was diaphoretic, alternately somnolent and agitated, and un-
able to follow commands. No seizure activity was noted. His eyes opened spontaneous-
ly. He spoke but produced only incomprehensible sounds. He withdrew inconsistently
from painful stimuli. As far as could be ascertained, he had been well previously and had
been taking no medications.
The temperature was 35.5°C, the blood pressure was 120/76 mm Hg, the heart rate
was 108 beats per minute, the respiratory rate was 36 breaths per minute, and oxygen
saturation was 100 percent while the patient was breathing room air.
Physical examination revealed no evidence of traumatic injury. The pupils were 5 mm
in diameter, round, and reactive to light. The gaze appeared intermittently disconju-
gate. There were no neck masses; palpation of the neck did not appear to be painful, and
the neck was fully mobile with no apparent stiffness or limited range of motion. The
lungs were clear on auscultation. The heart rate and rhythm were regular, and there were
no murmurs. The abdomen was soft, nondistended, and without palpable masses. The
extremities were warm and well perfused, and the patient moved them all equally well.
He was incontinent of stool, which was brown and negative for occult blood.
The patient was given oxygen by face mask. A cardiac monitor revealed sinus tachy-
cardia. Shortly after presentation, the patient was given 1.25 mg of intravenous droperi-
dol. Ten minutes later he appeared to be so somnolent that his ability to protect his air-
way was questioned. He suddenly awakened and became increasingly agitated, rapidly
reaching a level of agitation at which, even in restraints, he posed a risk to the staff and
to himself. Twenty minutes after admission, the trachea was intubated. A gastric tube

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 The new england journal of medicine

was placed and 50 g of activated charcoal was ad-
ministered. A radiograph of the chest revealed that
the endotracheal tube was correctly placed and that
there were no obvious pulmonary lesions. His heart
rate became labile, dropping as low as 46 beats per
minute. Electrocardiography was performed (Fig.
1). Would anyone like to comment on the electro-
cardiogram?
Dr. Joshua Kosowsky (Emergency Department,
Brigham and Women’s Hospital): The electrocar-
diogram shows bradycardia, with a ventricular rate
of 66 beats per minute; no P waves are evident be-
fore the QRS complexes. These findings indicate the
presence of junctional bradycardia.
Dr. Goldstein: The blood pressure ranged from
150/60 mm Hg to 166/84 mm Hg. Transcutaneous
pacer pads were applied. He did not require trans-
cutaneous pacing. The pacer pads were left in place
while he was observed. The blood pressure remained
stable. The results of urinalysis were normal. Other
laboratory results and the results of toxicologic
screening are shown in Tables 1, 2, and 3. A com-
puted tomographic (CT) scan of the head showed
no extraaxial fluid collection, no midline shift, no
mass effect, no evidence of bleeding, and no focal
territorial infarction. No intracranial masses were
noted.
The emergency-medical-services personnel re-
ported that the patient’s friends had confirmed that
he had discussed having consumed laser-printer
toner-cartridge cleaner in order to augment the ef-
fect of alcohol. The Boston Poison Control Center
was contacted and reported that toner-cartridge
cleaner is metabolized to g-hydroxybutyrate. A urine
specimen was then sent to be analyzed for the pres-
ence of g-hydroxybutyrate.
Five hours after admission, the patient awoke
and was able to follow commands appropriately.
The trachea was extubated 30 minutes later. Seven
hours after admission, he disconnected himself
from the cardiac monitor and demanded to leave the
hospital. He was judged to have the capacity to make
his own decisions, and he decided to forego any fur-
ther evaluation.
Dr. Kosowsky: Was there any reason to keep him
in the hospital?
Dr. Goldstein: We did not have a formal diagno-
sis of g-hydroxybutyrate intoxication at the time,
since the results of urine screening for organic ac-
ids take a week to come back. The patient himself
could not provide any details regarding the sub-
stance he had ingested. Given his apparently new
junctional rhythm and his severe changes in men-
tal status only a few hours earlier, we were con-

I aVR V1 V4

II aVL V2 V5

III aVF V3 V6

V1

II

V5
25 mm/sec 10 mm/mV 100 Hz

Figure 1. Electrocardiogram Obtained Shortly after the Patient Arrived in the Emergency Department.
The ventricular rate is 66 beats per minute, the PR interval 121 msec, the QRS duration 96 msec, and the QT interval
388 msec. The findings indicate the presence of junctional rhythm with retrograde P waves.

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 case records of the massachusetts general hospital

cerned that there was another, unidentified inges-

Table 1. Laboratory Data on Arrival in the Emergency
tant. We believed that a period of further monitoring
Department.*
and an evaluation by the electrophysiology service
Variable Value were warranted if his junctional rhythm did not
Sodium (mmol/liter) 139 resolve.
Potassium (mmol/liter) 4.0 One week later, the results of the urine screen-
Chloride (mmol/liter) 106 ing were received. The level of g-hydroxybutyrate
Carbon dioxide (mmol/liter) 27.2
was markedly elevated.
Urea nitrogen (mg/dl) 16
Creatinine (mg/dl) 1.0 diagnosis and management
Glucose (mg/dl) 91
Dr. David N. Tancredi: This case presents a problem
White cells (per mm3) 8,000 that is familiar to emergency physicians: a change
Hematocrit (%) 43.4 in mental status in a young, otherwise healthy pa-
Hemoglobin (g/dl) 15.4 tient. The safety of the common practice of obser-
Red cells (per mm3) 4,970,000 vation and expectant management in cases of acute
Platelets (per mm3) 374,000 intoxication relies on timely identification of clini-
Mean corpuscular volume (µm3) 87 cally significant toxic exposures, coexisting condi-
Mean corpuscular hemoglobin (pg/red cell) 31.0 tions, injuries, or alternative causes of the change
Mean corpuscular hemoglobin 35.5 in mental status. In intoxicated patients, it is not un-
concentration (g/dl) usual to find multiple processes to account for cen-
Red-cell distribution width (%) 12.4 tral nervous system changes, such as hypoxia, trau-
Prothrombin time (sec) 12.8 matic injury, metabolic disorder, or seizure. In the
Activated partial-thromboplastin time (sec) 22.6 current case, we were initially uncertain about the
Creatine kinase isoenzymes (ng/ml) 2.9 toxicologic exposure. We therefore focused the early
Troponin T (ng/ml) <0.01 stages of the workup on the evaluation of causes of
Creatine kinase (U/liter) 408
change in mental status and coexisting conditions
that would pose an immediate threat to life or well-
* To convert the value for urea nitrogen to millimoles per being (Table 4).
liter, multiply by 0.357. To convert the value for creatinine
to micromoles per liter, multiply by 88.4. To convert the stabilization and sedation
value for glucose to millimoles per liter, multiply by
0.05551. Our first efforts were directed toward rapid assess-
ment and stabilization of the patient (Table 5). In-

Table 2. Results of Serum Toxicologic Screening.

Panel
Alcohols
Acetaminophen, the-
ophylline, salicylate
Barbiturates
Benzodiazepines
Tricyclic antidepressants
Compounds Included in Screen Result
Ethanol, isopropanol, and methanol Negative
Acetaminophen, theophylline, and salicylate Negative
Butalbital, carbamazepine, ibuprofen, pentobarbital, phenobarbital, phenytoin, Negative
and secobarbital
4-Hydroxyglutethimide, alprazolam, chlordiazepoxide, clonazepam, demox- Negative
epam, desalkylflurazepam, diazepam, flurazepam, glutethimide, lidocaine,
lorazepam, methaqualone, norchlordiazepoxide, nordiazepam, oxazepam,
quinidine, temazepam, and trazodone
Amitriptyline, chlorpheniramine, chlorpromazine, clomipramine, clozapine, Negative
cocaethylene, cocaine, cyclobenzaprine, pseudoephedrine, desipramine,
desmethylsertraline, dextromethorphan, diphenhydramine, disopyramide,
doxepin, doxylamine, fluoxetine, fluvoxamine, imipramine, meta-chloro-
phenylpiperazine, maprotilene, meperidine, mesoridazine, methadone,
nordoxepin, norfluoxetine, normaprotilene, normeperidine, norpropoxy-
phene, nortriptyline, norverapamil, oxycodone, paroxetine, pentazocine,
promazine, propoxyphene, propranolol, pyrilamine, sertraline, thiorida-
zine, trifluoperazine, trimipramine, venlafaxine, and verapamil

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 The new england journal
Table 3. Results of Urine Toxicologic Screening.
Compound Result
Phencyclidine Negative
Barbiturates Negative
Cannabinoids Positive
Amphetamines Negative
Benzodiazepines Negative
Opiates Negative
Cocaine metabolites Negative
travenous access was obtained, and supplemental
oxygen was provided. A cardiac monitor was at-
tached. The airway was patent, and the patient was
able to phonate. It was not possible to test for a gag
reflex, because of his agitation. The presence of a
gag reflex, however, would not be sufficient proof of
his ability to protect his airway. In acutely intoxicat-
ed patients, airway reflexes and adequate respiratory
function may be normal in the presence of external
stimulation, only to diminish when such stimula-
tion is withdrawn. Because the patient was able to
breathe, we did not believe that immediate endotra-
cheal intubation was necessary. Instead, we planned
to observe him directly for changes in his respiratory
status and further changes in his mental status.
Empirical administration of a cocktail of intra-
venous dextrose, thiamine, and naloxone, common-
ly given to patients with altered mental status, was
considered, but it was thought that such an inter-
vention would be unhelpful in this case. Glucose is
often given because hypoglycemia is a common and
easily reversible cause of altered mental status, but
serum glucose levels in this patient were normal be-
fore admission and in the emergency department.
Thiamine is given in conditions in which its defi-
ciency would be suspected, such as malnutrition and
chronic alcoholism, in which the administration of
glucose could precipitate acute Wernicke’s enceph-
alopathy.1 This patient appeared well nourished and
at little risk for thiamine deficiency. Naloxone is giv-
en to reverse the effects of narcotics, but in the ab-
sence of respiratory depression, it would not be use-
ful. Flumazenil can reverse the sedating effects of
benzodiazepines, but its use was contraindicated
in this case because of the history of a possible sei-
zure. For agitation, the patient was given droperi-
dol, which is no longer available for this indication,
because a recent Food and Drug Administration
(FDA) warning implicated it in fatal arrhythmias.
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of medicine
Because agitation from intoxication or seizure may
occasionally abate in the absence of external stimu-
li, we attempted to minimize such stimuli and ob-
serve the patient’s response.
During the next few minutes, the patient, who at
one point had been unresponsive, became increas-
ingly agitated and began to thrash about wildly, pos-
ing a threat to his own safety and that of the staff,
and required restraints. The risks to such a patient
include not only traumatic injury but also cardiopul-
monary arrest. A number of case reports have doc-
umented sudden death in patients restrained for
agitated delirium, particularly in the context of stim-
ulant abuse.2 Early sedation is believed to be pro-
tective against sudden death. The need for rapid
chemical sedation is paramount and supersedes the
goal of minimizing the effects of sedation on airway
reflexes. Immediate endotracheal intubation per-
mits timely and adequate sedation without risking
compromise of respiratory status. It also facilitates
rapid workup, permitting the patient to leave the
emergency department safely for CT studies, and al-
lows expeditious gastrointestinal decontamination
in cases of suspected ingestion of toxic agents.
Endotracheal intubation in the emergency de-
partment setting is a safe procedure.3 As pretreat-
ment, the patient received lidocaine and a defas-
ciculating dose of vecuronium, since there was a
possibility of an intracranial lesion, in which case an
elevation in intracranial pressure from hypopharyn-
geal manipulation might prove harmful.4 The pa-
tient was given a benzodiazepine (midazolam) for
sedation; this medication provided several addition-
al benefits because of its antiepileptic properties and
its suitability for treatment of acute opioid or etha-
nol withdrawal and cocaine-induced coronary is-
chemia, which was considered possible in the light
of the patient’s electrocardiographic changes.5
provisional diagnosis
The findings on physical examination corroborat-
ed a provisional diagnosis of intoxication, without
necessarily ruling out all other causes of altered
mentation. The agitation, pupillary dilatation, and
diaphoresis suggested a sympathomimetic tox-
idrome (a set of findings corresponding to the pres-
ence of a specific class of toxic agents) of the type
that would be seen in, for example, amphetamine
toxicity. The electrocardiogram showed signs of in-
volvement of the cardiac conduction system, with a
junctional rhythm and retrograde atrial activation.
After stabilization and sedation, the patient was
september 25 , 2003
 case records of the massachusetts general hospital
Table 4. Potential Causes of Sudden Alterations
in Mental Status.
Hypoxia
Cardiovascular compromise
Infection: meningoencephalitis
Inflammatory states: cerebritis
Structural lesions of the central nervous system:
infarcts, hemorrhages, or masses
Metabolic disorder: hypoglycemia, hyponatremia,
diabetic ketoacidosis, or hyperosmolar coma
Seizure
Acute psychosis
Traumatic injury
Toxic exposure
Drug or alcohol withdrawal
able to undergo cranial CT scanning, which showed
no structural central nervous system lesions or signs
of trauma. Because the patient was not febrile and
because he did not have a history of illness before
the precipitous change in mental status, central
nervous system infection is an unlikely cause of his
symptoms. The results of routine laboratory analy-
sis were normal; there was no evidence of an anion
gap. Urine and serum toxicologic screening, valu-
able as a means of identifying potentially lethal com-
pounds, such as aspirin, methanol, or acetamino-
phen, revealed only cannabinoids.
The most important piece of information was
the patient’s statement that he had consumed laser-
printer toner-cartridge cleaner earlier that evening.
With help from the Boston Poison Control Center,
we were ultimately able to identify the product and
to ascertain that its toxicity was a result of its metab-
olism to g-hydroxybutyrate. Because a patient who
consumed this product might have consumed oth-
er drugs or household compounds as well, we as-
sumed from the outset that other toxic substances
could be involved. While this investigation was un-
der way, we made the decision to proceed with gas-
trointestinal decontamination.
gastrointestinal decontamination
The decision to proceed with gastric lavage and the
administration of activated charcoal must be based
on assessment of the probability of clinically sig-
nificant toxic exposure. Such a decision usually pre-
cedes availability of the results of comprehensive
serum toxicologic analysis. The use of gastric lavage
in cases of acute ingestion remains controversial.
The risks include aspiration, which can occur even
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Table 5. Diagnosis and Management of Sudden Alterations in Mental Status.
Establish intravenous access, administer supplemental oxygen, attach cardi-
ac monitor, and assess vital signs
Assess and correct airway and respiratory function
Assess and correct circulatory function (changes in blood pressure, heart
rate, or rhythm)
Correct hypothermia or hyperthermia
Undertake directed physical examination with particular attention to any neu-
rologic deficit or evidence of traumatic injury
Give sedation as necessary for extreme agitation (early, if needed to permit
evaluation)
Administer empirically a cocktail of dextrose, thiamine, and naloxone if indi-
cated
Administer antibiotics or antivirals if there is a possibility of meningoenceph-
alitis (fever, nuchal rigidity, or rash) or sepsis
Perform CT scanning of the head to determine whether lesions or traumatic
injuries are present
Determine whether a metabolic abnormality is present
If there is the possibility or evidence of acute toxicity, give specific therapy
as indicated
Offer neurologic or psychiatric consultation as appropriate
in intubated patients, and traumatic injury to the
gastrointestinal tract. If gastric lavage is performed
within one hour after ingestion, a substantial frac-
tion of pharmacologically active substances, even
liquids, can be cleared from the gastrointestinal
tract.6 It is not clear whether the use of gastric lavage
changes patients’ outcomes.7 Nevertheless, the pau-
city of data on the efficacy of gastric lavage does not
indicate that it is ineffective. For possibly lethal in-
gestions or for ingestions that have occurred within
an hour before presentation, the American Acad-
emy of Clinical Toxicology recommends gastric
lavage as a means of gastrointestinal decontami-
nation.8
The use of activated charcoal to adsorb ingested
toxins is controversial in patients who present late
(more than an hour after ingestion). In this case, the
time of ingestion was not known, but the best infor-
mation available indicated that the ingestion may
have taken place more than one hour before arrival
at the hospital. The nature, amount, and lethality of
the ingestion were not immediately known. We de-
cided to administer activated charcoal (by nasogas-
tric tube), but we did not perform gastric lavage.
With supportive care, the patient’s delirium rap-
idly resolved. He was reevaluated and was found
to be neither suicidal nor acutely psychotic. The fol-
lowing morning, he demanded to go home and was
deemed capable and competent to leave. Thus, he
became one of the few patients with changes in
september 25, 2003 1271
 The new england journal
mental status whose course in the emergency de-
partment runs from intubation to discharge.
Dr. Melissa Lai (Emergency Medicine): Before the
patient was discharged, did his electrocardiograph-
ic changes resolve?
Dr. Goldstein: A second electrocardiogram, ob-
tained several hours after the first, showed no chang-
es. After his trachea was extubated, he disconnect-
ed himself from the cardiac monitor and refused
to undergo any further testing.
pathophysiology and management
of g-hydroxybutyrate intoxication
Dr. Michael W. Shannon: The most relevant clinical
features in this case of suspected ingestion of a tox-
ic agent were an agitated delirium, mild hypother-
mia, bradycardia, and a depressed level of conscious-
ness, which necessitated endotracheal intubation.
Five hours after presentation, consciousness rapidly
returned, and the patient’s trachea was promptly
extubated. He had no unusual odors, skin chang-
es, or other diagnostic findings. Urine toxicologic
screening was positive only for cannabinoids. On
consultation with a medical toxicologist, additional
laboratory tests were performed, and the results ul-
timately proved to be diagnostic of ingestion of
g-hydroxybutyrate or a related drug.
The case also sheds light on current patterns of
substance abuse, which change frequently, as indi-
cated by recent national reports of decreased use of
“crack” cocaine and increased use of heroin. The
drugs commonly used also vary highly from region
to region. There is relatively consistent use of eth-
anol and marijuana, which therefore must be con-
sidered in all cases of suspected drug abuse. In re-
cent years, two new substance-abuse trends have
emerged. First, there has been increasing abuse of
pharmaceutical agents, such as benzodiazepines
and opiates. Second, the introduction and growing
use of the Internet have prompted the creation of
Web sites that encourage the use of psychoactive
drugs.9
A number of dangerous drugs have recently be-
gun being abused and must be considered in the
evaluation and management of drug-overdose cas-
es. These agents, known as “club drugs,” include ke-
tamine, methylenedioxymethamphetamine (“ec-
stasy”), and g-hydroxybutyrate. Benzodiazepines
such as flunitrazepam have become popular because
of their prolonged duration of action. There has also
been increasing concomitant use of sildenafil (Vi-
agra) by those who seek to enhance their sexual ex-
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of medicine
perience. Used singly or in combination, these new
agents are creating novel profiles of intoxication.
g-Hydroxybutyrate is a substance of abuse that
is being used with increasing frequency nationwide.
It gained popularity in the 1980s as a growth hor-
mone secretagogue and bodybuilding drug. It was
soon found to produce alterations in mental status
and to enhance the effect of ethanol, and it rapidly
began appearing in clubs, at raves, and in other ven-
ues. Its effects on the central nervous system led to
its use as a chemical-submission drug (a “date rape”
drug), and in 1990 federal legislation criminalized
possession of this agent. Nonetheless, home man-
ufacture, which is relatively simple, has continued,
aided by information available on the Internet. In-
terestingly, g-hydroxybutyrate has been developed
and was recently approved by the FDA as a treatment
for narcolepsy.
Criminalization of the possession of g-hydroxy-
butyrate led to the development and use of its
congeners. The first such congener to appear was
g-butyrolactone. At the time, g-butyrolactone was
found in numerous over-the-counter products. How-
ever, its use has also been restricted recently by fed-
eral legislation. g-Valerolactone is a chemical that is
used as a solvent in industrial applications. It has ef-
fects on the central nervous system that are similar
to, though less than, those of g-hydroxybutyrate.
This patient almost certainly took 1,4-butanediol,
currently the most widely used of the g-hydroxybu-
tyrate congeners. It continues to be found in a wide
variety of products, particularly bodybuilding bev-
erages and soporific medications. As a solvent, it is
also a constituent of several cleaners, including com-
pact-disc and printer cleaners. Despite the growing
abuse of 1,4-butanediol and the associated risks
of illness and death,10 there are no effective feder-
al regulations limiting its manufacture and use. Col-
lectively, at least four drugs related to g-hydroxy-
butyrate are now being abused.
The structural relation among these agents is
depicted in Figure 2. g-Butyrolactone is converted
to g-hydroxybutyrate primarily through nonenzy-
matic hydrolysis. In contrast, butanediol must un-
dergo metabolism by alcohol dehydrogenase to
form g-hydroxybutyrate. The mechanism of action
of g-hydroxybutyrate is unclear. The original theo-
ries were that the agent acted at g-aminobutyric
acid receptors in the central nervous system, produc-
ing neurotoxic effects by this means alone. More re-
cent data strongly suggest the existence of a recep-
tor specific for g-hydroxybutyrate. We now believe
september 25 , 2003
 case records of the massachusetts general hospital

OH

OH
1,4-Butanediol

O 4-Methylpyrazole NAD
O Alcohol dehydrogenase

NADH
O
g-Butyrolactone
OH
H
g-Hydroxybutyraldehyde

Metabolism by
tissue lactonases
NAD
or nonenzymatic
hydrolysis Aldehyde dehydrogenase
NADH

O O g-Hydroxybutyrate O
dehydrogenase
HO b-Oxidation HO GABA transaminase NH2

OH OH OH
GABA transaminase GABA
Trans-4- g-Hydroxybutyrate
Succinic semialdehyde
hydroxycrotonic acid
reductase

NCS-382 CGP-35348 or SCH-50911

g-Hydroxybutyrate Receptor GABAB Receptor

Figure 2. g-Hydroxybutyrate and Related Compounds.

The illustration shows the structural relations among g-hydroxybutyrate and its congeners and the pathways that can be inhibited by available
drugs. g-Butyrolactone can be converted either enzymatically or nonenzymatically to g-hydroxybutyrate. 1,4-Butanediol, in contrast, requires
alcohol dehydrogenase and aldehyde dehydrogenase to be converted to g-hydroxybutyrate. The latter may be metabolized to trans-4-hydroxy-
crotonic acid or to g-aminobutyric acid (GABA). g-Hydroxybutyrate and trans-4-hydroxycrotonic acid are thought to act at a putative g-hydroxybuty-
rate receptor, and both g-hydroxybutyrate and GABA to act at the GABAB receptor. Knowledge of these pathways creates potential avenues for
intervention that can reduce the toxic effects of these agents. 4-Methylpyrazole has been shown to reduce the toxic effects of 1,4-butanediol.
NCS-382 is an antagonist at the g-hydroxybutyrate receptor, and CGP-35348 and SCH-50911 are potential GABAB-receptor antagonists. NAD
denotes nicotinamide adenine dinucleotide, and NADH reduced nicotinamide adenine dinucleotide.

that g-hydroxybutyrate acts both at that specific re-
ceptor and at the GABAB receptor.11
Intoxication by g-hydroxybutyrate, butanediol,
and other related drugs produces a diagnostic tox-
idrome (Table 6). Several studies12,13 have found
that 30 to 35 percent of overdose victims have brady-
cardia, mild hypothermia, or both. Central nervous
system effects are striking and include inebriation,
often with an agitated delirium. Myoclonus or frank
seizures may occur. Severe intoxication produces
coma and apnea. The coma of g-hydroxybutyrate is
unique, in that it resolves rapidly with a prompt re-
turn to alertness. Amnesia for recent events is com-
mon. Recently, a g-hydroxybutyrate dependence

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 The new england journal of medicine

syndrome has been described in chronic g-hydroxy-

butyrate users, in which abrupt abstinence leads to
signs of acute withdrawal.14,15
1,4-Butanediol has two characteristic properties
that distinguish it from its metabolite, g-hydroxy-
butyrate. Because both of these substances have
neurotoxic effects, an overdose of 1,4-butanediol
typically produces a more prolonged period of coma
than an overdose of g-hydroxybutyrate or g-butyro-
lactone. Even more important is the effect of con-
comitant ingestion of ethanol and 1,4-butanediol.
Ethanol competitively inhibits alcohol dehydrogen-
ase, temporarily halting the metabolism of 1,4-
butanediol. Thus, there may be an initial depression
of mental status due to the combination of ethanol
and butanediol, followed by a period of improved
alertness as the ethanol is metabolized, followed in
turn by the development of coma as alcohol dehy-
drogenase freely metabolizes the 1,4-butanediol
to g-hydroxybutyrate.16 Because of this possibility
of a delayed effect, patients with 1,4-butanediol in-
toxication should undergo a prolonged period of
observation.
Treatment of g-hydroxybutyrate overdose con-
sists primarily of supportive care. The bradycardia
typically does not require treatment. Short-term en-
dotracheal intubation may be necessary in persons
with a depression in mental status. Although myoc-
lonus requires no specific therapy, frank seizures
should be treated with short-acting benzodiaz-
epines.
Recently, in an effort to improve the treatment of
overdoses of this drug, several novel therapies have
been developed. Specific g-aminobutyric acid–recep-
tor antagonists, such as NCS-382, and g-hydroxy-
butyrate–receptor antagonists, such as CGP-35348
and SCH-50911, have also been created; preliminary
data from our laboratory have shown their ability to
attenuate the toxic effects of g-hydroxybutyrate on
Table 6. Clinical Features of g-Hydroxybutyrate
Intoxication.
Bradycardia
Hypothermia
Agitated delirium
Myoclonus or seizures
Coma followed by rapid emergence
Amnesia
Syndrome of g-hydroxybutyrate dependence or with-
drawal
the central nervous system.11,17 A promising treat-
ment for 1,4-butanediol toxicity has appeared in the
form of 4-methylpyrazole (fomepizole), an alcohol
dehydrogenase inhibitor. Currently approved for
use in methanol and ethylene glycol toxicity, fo-
mepizole has been shown in animal models to re-
duce the neurotoxicity of butanediol.
Dr. Malini K. Singh (Emergency Medicine): During
the lucid phase of the biphasic toxic effects of con-
comitant ethanol and butanediol ingestion, could
a patient appear well enough to be discharged, only
to enter into a coma after discharge? How long
should such a patient be observed before discharge?
Dr. Shannon: A patient may appear well enough
to be discharged only to have recurrent mental-sta-
tus depression. Observation in the emergency de-
partment for two to six hours should be sufficient.
When either g-hydroxybutyrate alone or 1,4-butan-
ediol alone has been ingested, we feel comfortable
discharging patients as soon as they become lucid.
final diagnosis
Ingestion of 1,4-butanediol, resulting in g-hydroxy-
butyrate intoxication.
We are indebted to Dr. David F. Brown (Emergency Medicine),
who played a key part in identifying this case and organizing this
conference.

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