“Few drugs have excited such widespread interest and stimulated as much clinical and laboratory investigation as halothane.”
Editorial, Brit. J. Anaesth. (1962)
History:
Halothane was synthesized by the British chemist Charles Suckling over 2 years of research and testing. Its required concentration for anesthesia was predicted, and the drug was tested by a well-known anesthesiologist, Michael Johnston, who recognized its superior properties compared with other anesthetics that were available at that time such as ether and chloroform. Development of halothane was considered as a great progress in anesthesiology, and it was introduced globally in 1956. Subsequently, several reports of postsurgical lethal hepatotoxicity in patients who were anesthetized with halothane emerged.
In addition, seeking an ideal drug that was associated with pleasant induction and rapid recovery, these reports led to the synthesis of new agents with greater efficacy and safety. Although halothane has several drawbacks, the lack of flammability and general smoothness of administration led to rapid, widespread use, which only changed with the growing popularity of sevoflurane in the 1990s
Aetiology
Halothane:
Potent volatile halogenated anesthetic widely used in major surgery between its introduction in 1956 and falling out of favor in the mid 1990s. Halothane must be administered in a controlled situation by a properly trained and credentialed anesthesiologist or nurse anesthetist and is typically given in concentrations up to 1% with oxygen.
Risk factors:
- Middle age, female sex predisposition
- Obesity
- Surgical risk factors: Coronary artery bypass graft (CABG), cholecyste-ctomy and cosmetic operations (mainly weight reducing surgeries including partial gastrectomy and liposuction)
Pathophysiology
Immune mediated hepatotoxicity:
~60-80% eliminated unchanged by the lungs, but a proportion is biotransformed by hepatic microsomal enzyme CYP 2E1 to a trifluoroacetic acid which can be detected in the urine, but which also can trifluoroacetylate hepatic proteins, some of which may be immunogenic and induce cytotoxic reactions.
- Type 1 HH (20-30% patients receiving halothane): Mild hepatitis associated with elevated transaminase levels and self-limiting symptoms
- Type 2 HH: Severe hepatotoxicity associated with acute fatal liver failure, resulting in death in most cases (50-80% mortality)
Clinical features
Type 1 HH:
Mild hepatitis associated with elevated transaminase levels and self-limiting symptoms
- Asymptomatic presentation (most patients)
- Symptoms cases: Nausea, fever, and lethargy (typically self-limiting over 1-2 weeks)
Type 2 HH:
Severe hepatotoxicity associated with acute fatal liver failure, resulting in death in most cases (50-80% mortality)
75% cases present within first 2-14 days after halothane exposure.
- Hallmark clinical feature: High fever, tender hepatomegaly, and jaundice starting 2-3 days post halothane exposure.
- Spectrum of presentation: Jaundice, hepatomegaly, fever, anorexia, myalgias, nausea, diffuse rash, and encephalopathy
Management
Halothane hepatitis is largely a diagnosis of exclusion, making its initial treatment similar to any other form of fulminant hepatitis. Depending upon each individual case, supportive therapy consists of:
- Fluid & electrolyte balance
- Correcting coagulation alterations
- Managing hypoglycemia
- Supporting ventilation
- Supporting hemodynamics
- Oral lactulose/restricting protein intake