Unconscious Museum Worker:
Further History & Discussion

Francis DeRoos
Ed Boyer

Int J Med Toxicol 1998; 1(2):16

These case conferences are supported by a grant from Orphan Medical, Inc.

See also CASE PRESENTATION - 1998 1(1):3, CASE DISCUSSION - 1998 1(1):4

With his belongings, in addition to the rum, was a bottle of laboratory grade chloroform. He had obtained the chloroform several years earlier when he was working for a natural history museum and used it to prepare bones and other specimens. He also admitted to ingesting 4 bottles of Visine®eyedrops, approximately 4 hours prior to presentation. He had read a True Crimes book in which someone committed murder using Visine®. He also acknowledged ingesting most of the chloroform/rum mixture prior to being found by paramedics.

Hospital Course

Atropine (1 mg IV) was administered to treat bradycardia with improvement in heart rate to 70 beats/min. Gastrointestinal decontamination included aspiration of gastric contents (50 mL) and administration of activated charcoal via nasogastric tube. A loading dose of 140 mg/kg N-acetylcysteine (NAC) was also given via the NG tube.

During the first 12 hours of hospitalization he developed hypotension with systolic blood pressure ranging from 80-90 mmHg. This was treated successfully with normal saline and Trendelenburg positioning. By 20 hours after his hospitalization the patient was responding to verbal stimuli and he was extubated 30 hours after presentation. Oral N-acetylcysteine (70 mg/kg) therapy was continued for a total of 21 doses over 4 days. Initial hepatic enzymes included an ALT 40 U/L, AST 28 U/L, and an alkaline phosphatase of 71 U/L. These increased dramatically to a peak of ALT 582 U/L and AST 236 U/L by hospital day 4. At that time his coagulation profiles were PT/PTT 14.3/34.8 with an INR of 1.5. By the sixth hospital day all his laboratory values had normalized and he was discharged to a psychiatric facility.

Chloroform and tetrahydrozoline were found in the patient’s initial serum and urine, respectively with gas chromatography/mass spectroscopy.


Chloroform - Chloroform is a volatile chlorinated hydrocarbon first synthesized in 1831 and gained popularity as an inhalational anesthetic after 1947.(Simpson) By 1912 its association with intraoperative sudden death and peripartum jaundice lead to its ban. Recently, it has been proposed as a potential topical analgesic in the treatment of postherpetic neuralgia.(King) In industry it is used as a solvent, degreaser, and synthetic intermediate. (Pohl, Kim)

Chloroform has rapid pulmonary and gastrointestinal absorption with peak serum concentrations reached in less than one hour. There is no transdermal absorption. Chloroform is highly lipophilic and accumulates in adipose. It is metabolized by the liver into two hepatotoxins namely trichloromethane free radical and phosgene.(see later discussion) As with most other halogenated inhalational anesthetics, chloroform is rapidly eliminated through the pulmonary system with an elimination half life of about 1.5 hours. (Davison)

Chloroform possesses significant CNS, cardiac, hepatic and renal toxicity. The CNS and respiratory depression is potent and rapid in onset which made it an ideal agent for inhalational anesthesia. Its dysrhythmogenic potential was observed by early anesthetists who described bradycardia and occasionally sudden death in some chloroform treated patients. In 1911 Levy began publishing his work which convincingly demonstrated that low concentrations of chloroform altered myocardial tissue and rendered it more predisposed to dysrhythmias. (Levy 1911, Levy 1913)

Mechanistically, chloroform decreases the threshold for depolarization of heterotopic foci within the ventricular myocardium. (Schechter) When exposed to chloroform, a single ectopic ventricular focus discharges to produce an extrasystolic beat, which in turn depolarizes additional ectopic sites, thereby inducing fibrillation. Catecholamines and hypoxia both potentiate this effect and can precipitate fibrillation in chloroform sensitized tissue. (Schechter)

While the CNS depression and myocardial sensitization occur acutely following exposure, chloroform hepatotoxicity develops 24 to 72 hours later. In 1883, Lyman observed that of chloroform-related patient deaths, about 10 % occurred “several days” postoperatively and they all had symptoms of nausea, vomiting and jaundice. (Lyman)

The mechanism of chloroform hepatotoxicity involves the generation of free radical intermediates and glutathione depletion. Mixed function oxygenases metabolize chloroform into the trichloromethane free radical. This reacts with water to produce trichloromethanol which in turn hydrolyzes into phosgene. (Pohl, Wang) Both the trichloromethane radical and phosgene are hepatotoxic.

Chloroform depletes glutathione by at least three mechanisms. First the sulfur group of glutathione, which is an excellent free radical scavenger, is oxidized by the trichloromethane radical. Second, phosgene undergoes nucleophilic attack twice by glutathione to form diglutathionlydithiocarbonate which cannot be hydrolyzed to regenerate glutathione. (Pohl) Finally, chloroform may impair glutathione reductase and limit the cells ability to regenerate glutathione reserves. (el-Shewany) When cellular glutathione is depleted, free radicals attack lipid olefins and phosgene forms adducts with cellular macromolecules. (Pohl, DeCurtis) Hepatocyte damage ensues, and depending upon the degree of injury, liver failure and death can result.

Glutathione depletion appears to play a critical role in both chloroform and acetaminophen hepatotoxicity. Since NAC is effective in the prevention and treatment of acetaminophen hepatotoxicity, it is logical to explore whether it may also be beneficial in preventing hepatic injury from chloroform. Although animal studies support this, limited data exist to support NAC’s use in a patient with chloroform ingestion. (Flanagan, Rao)

We initiated NAC therapy with a 140 mg/kg oral loading dose within five hours of the chloroform ingestion and continued oral NAC (70 mg/kg Q4hrs). Although initially normal, the transaminases began rising within 48 hours and peaked on day 3 with an ALT of 582. NAC therapy was continued until there was a demonstrable improvement in this transaminitis. In total, 21 doses NAC therapy were given.

Historically deaths have been reported with chloroform ingestions of volumes of 30 mL to 180 mL and no survivors with ingestions greater than 120 mL of chloroform (Board, Bridgman, Piersol, Schroeder, Rao) Based on this it appears that early NAC therapy was instrumental in preventing severe hepatotoxicity in our patient.

Tetrahydrozoline - The other significant compound ingested was tetrahydrozoline. Tetrahydrozoline, an imidazoline, is an alpha adrenergic agonist commonly used in over-the-counter medications for the treatment of ocular irritation and nasal congestion. It’s systemic toxicity closely resembles other imidazolines such as clonidine, guanfacine and guanabenz. It is rapidly absorbed from the GI tract and toxicity develops within 30 to 90 minutes. Initially peripheral alpha adrenergic agonism may manifest with hypertension and tachycardia. However, this is typically short-lived as the central sympatholytic effects ensue. This central alpha adrenergic agonism impairs sympathetic outflow from the medulla resulting in hypotension and bradycardia. CNS and respiratory depression and miosis also classically occur.

Treatment recommendations for patients with imidazoline overdoses include atropine for bradycardia, dopamine for blood pressure support and endotracheal intubation if needed. Most pediatric patients exposed to these agents respond well to simple tactile stimulation to maintain adequate ventilations. Naloxone has also been recommended as an antidote for respiratory depression. Unfortunately, it’s clinical efficacy is variable and some patients fail to respond at all. (Neimann, Kulig, Knopp, Banner) Tolazoline, an alpha adrenergic antagonist, has also been proposed as treatment of patients with imidazoline poisoning.Unfortunately there is very little clinical experience with this “antidote” and its clinical utility is unclear. (Schieber, Anderson )

Specific Pharmacologic Considerations in this Case

This patient’s clinical presentation was challenging because although he presented with bradycardia resulting from the tetrahydrazoline, he was at risk of developing tachydysrhythmias secondary to the chloroform.Oxygenation and atropine were used to treat the bradycardia. Oxygen is essential since hypoxia enhances chloroform-induced myocardial irritability.(Davison) These modalities were effective and eliminated the need for catecholamine pressors or a pacemaker, both of which may precipitate ventricular fibrillation in chloroform-sensitized myocardium.

Chloroform’s potential to sensitize myocardium became much more concerning as our patient became hypotensive from the combined effects of the chloroform and tetrahydrozoline. Catecholamines with prominent beta adrenergic stimulation, such as dopamine, dobutamine and epinephrine, could have precipitated ventricular fibrillation.We were very conservative with this patient, treating his hypotension with fluids and Trendelenburg positioning and closely monitored him for signs of hypoperfusion. If a pressor would have been used we would have selected Neo-Synephrine since it is a pure peripheral alpha-1 agonist with minimal cardiac effects. Fortunately, it was not needed.

One possible alternative would be to block or minimize the dysrhythmogenic potential of chloroform with a beta adrenergic antagonist. A small dose of propranolol has been clinically successful in treating dysrhythmias produced by a chloral hydrate overdose. In our patient the combination of early bradycardia and subsequent hypotension eliminated any opportunity to use a beta adrenergic antagonist.


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Int J Med Toxicol 1998; 1(2):16

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