Introduction:
Desflurane (halogenated entirely with fluorine), Halothane (halogenated with fluorine, chlorine, and bromine), Isoflurane (halogenated with fluorine and chlorine), and Sevoflurane (halogenated entirely with fluorine) halogenation improves the potency of the drug and is crucial to ensure nonflammability. Halothane was the first fluorinated inhaled anesthetic to achieve massive success, quickly replacing all other powerful and effective inhaled anesthetics. For over 50 years, halogenated inhalational anesthetics such as Halothane, Enflurane, Isoflurane, and Desflurane have been linked to idiosyncratic liver injury.
These agents produce anesthesia by inhibiting CNS (central nervous system) neurotransmission, but the exact mechanism is unknown. They are the most widely used inhalational anesthetics in surgery. Due to its potential to cause severe liver injury, which is uncommon in children, Halothane is now rarely used outside of pediatrics. Halothane was linked to the classic form of anesthetic-induced liver injury. There was initially strong opposition to accepting Halothane's hepatotoxicity, owing to its excellent safety record in other areas and the rarity of the hepatic reaction. However, Halothane had become the most common cause of idiosyncratic, drug-induced acute liver failure in the 1970s, with over 1000 cases of clinically diagnosed liver injury reported in the literature.
What Is the Underlying Mechanism for Hepatic Injury by Halothane?
A condition of Halothane hepatic injury was proposed based on its extensive metabolism (oxidation) by the liver's primary drug-metabolizing enzyme system, specifically the cytochrome P450, CYP 2E1. Furthermore, all halogenated anesthetics may interact with components of carbon dioxide absorbents, resulting in the formation of degradation products with their toxic potential. Halothane metabolism to a trifluoroacetylated reactive intermediate, followed by binding to intrahepatic cytosolic proteins, was thought to produce an antigenic molecule responsible for causing allergic and cytotoxic reactions. This proposed mechanism complements the allergic, clinical characteristics of Halothane hepatitis, which is characterized by an incubation period of a week after anesthesia, is associated with fever, rash, joint pain, and eosinophilia, and flares up with repeated exposure in a faster and frequently includes a more severe form of the injury.
Other halogenated anesthetics, such as Enflurane (1972), Isoflurane (1981), Desflurane (1993), and Sevoflurane (1995), have been introduced and have emerged as significant agents currently in use in the United States. These agents are less metabolized by the CYP 2E1 system (20 percent Halothane, three percent Sevoflurane, 2.4 percent Enflurane, 0.2 percent Isoflurane, and 0.01 percent Desflurane). Nonetheless, all agents have been connected to rare cases of acute liver injury. Moreover, the sequence of injury discussed with the newer halogenated anesthetics closely resembles that of Halothane hepatitis, and trifluoroacetyl adducts in liver tissue and antibodies are adducts in the serum of patients with hepatic injury from these other halogenated anesthetic agents. On the other hand, the histological and clinical sequence of Halothane hepatic injury mimics chloroform-induced liver damage, with centrolobular slightly dull necrosis, indicating that toxic byproducts of reductive Halothane metabolism may cause direct injury.
What Are the Predisposing Factors?
Most patients with severe hepatic damage have used one or more Halothane anesthetics in the past. Clinical trials document 92 and 96 percent of patients who have previously been exposed to Halothane. As the frequency of previous anesthetics increases, the asymptomatic time frame between exposure and clinical signs reduces. However, there is no evidence that a long interval between exposures minimizes the chance of developing a new 'hepatitis.'
Halothane hepatitis has been observed up to 28 years after initial exposure. Obese and female patients are more likely to experience severe hepatic toxicity. However, the occurrence is lower in children.Changing anesthetics to less metabolized substances, such as Isoflurane or Desflurane, may decrease the risk of a hepatotoxic reaction.
What Are the Diagnostic Methods?
Patients suffering from Halothane hepatitis or severe liver damage caused by other halogenated anesthetics develop antibodies against many of the liver trifluoroacetylated microsomal proteins. Employing purified trifluoroacetylated liver microsomal proteins, these antibodies can be detected using enzyme-linked immunoabsorbent assay (ELISA). According to published data, this technique has a sensitivity of 79 percent for classifying the etiology if anesthesia-induced damage is presumed.
What Is the Differential Diagnosis of Halothane-Induced Hepatotoxicity?
A clinical picture close to Halothane hepatitis can be attributed to shock or ischemia (decreased blood flow and oxygen), sepsis (body’s extreme response to infections), other distinctive forms of drug-induced liver injury, and acute viral infections or hepatitis due to herpes infection, complicating the differential diagnosis. Indeed, the several cases of significant liver injury reported in the literature attributed to halothane or other halogenated anesthetics most likely represent liver injury from shock and ischemia. In addition, rapid onset after surgery, high values for alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH), and successive rapid fall in serum enzymes all favor the diagnosis of ischemic hepatitis.
What Is the Management of Halogenated Anesthetic Agents?
The severity of the condition varies from mild and transient aminotransferase elevations without any symptoms or scientific evidence of liver damage to a self-limited symptomatic acute hepatitis-like reaction to severe liver failure. The intensity and outcome may be related to the patient's age, with the elderly being more severe and children being milder and less common.
Obesity may serve as both a risk factor and an indicator of outcome. Chronic liver injury from repetitive Halothane exposure has been presented in healthcare workers, but the damage does not seem to occur in chronic hepatitis if the exposure is stopped. Should warn with Halothane-induced hepatitis against using a fluorinated hydrocarbon anesthetic such as Isoflurane, Enflurane, Desflurane, or Sevoflurane in the long term.
Conclusion:
Mild hepatocellular injury is not uncommon in patients receiving Halothane anesthesia. This sort of damage is triggered by intraoperative hypoxia as well as anesthetic metabolism. Such changes are less common after Isoflurane and Enflurane. The formation of antibodies against trifluoroacetylated hepatocellular proteins causes Halothane hepatitis, an uncommon but severe form of liver damage. This injury occurs with Enflurane, Isoflurane, or Desflurane due to the significantly low metabolism levels. These halogenated anesthetics are not recommended for use in patients who have a history of unexplained liver damage following inhalation anesthesia due to the risk of cross-reactions.
