Continuing Education Activity

Halothane is a medication previously used for induction and maintenance of general anesthesia. After its large impact on medicine and anesthesia specifically, it has since fallen out of practice due to its side effect profile. This activity describes the indications, action, and contraindications for halothane as a general anesthetic. This activity will also highlight the mechanism of action, adverse event profile, and shortcomings pertinent to members of the interprofessional team.

Objectives:

• Identify the etiology of halothane toxicity.
• Review the history, physical, and evaluation of halothane toxicity.
• Outline the treatment and management options available for halothane toxicity.
• Describe interprofessional team strategies for improving care coordination and communication to advance the care of halothane toxicity and improve outcomes.

Introduction

"Few drugs have excited such widespread interest and stimulated as much clinical and laboratory investigation as halothane." —Editorial, Brit. J. Anaesth. (1962).[1]

Halothane is a clear, heavy, and colorless liquid with a sweet and non-irritating odor. Halothane’s structure is that of an alkane. It has primarily been used clinically as an inhalational anesthetic. Ether and chloroform were rapidly replaced by halothane upon its introduction in 1956. Halothane is associated with a lower risk of nausea and vomiting than fluorinated methyl ethyl ether agents.[2] Due to its favorable side effect profile, halothane became the standard of practice, used in almost every operating room and for the comparison of other inhalational anesthetics as they came to the market. 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.[3] Although widely replaced by isoflurane or sevoflurane, halothane is the last common non-ether anesthetic used in the operating room. Halothane is the most soluble of the currently used anesthetic agents, indicating that the equilibration of inspired/brain partial pressures is the greatest. Although this property would seem to improve the safety profile of halothane, halothane is also the most potent of inhalational anesthetics.[4][5]

Cardiorespiratory instability (i.e., hypotension, bradycardia), sensitizing the myocardium to catecholamine-induced arrhythmias, and mild liver dysfunction are relatively common side effects of halothane. Arrhythmias are especially common in neonates and children after the administration of halothane, particularly bradyarrhythmias.[6] Additional adverse effects of halothane include hepatotoxicity (type 1) and hepatitis (type 2), which will be the focus of this activity. Type 1 hepatotoxicity is a transient, benign liver injury that is self-limiting; this differs from Type 2 hepatotoxicity, which is fulminant liver damage that can lead to liver failure, associated with a high mortality rate.

Etiology

Clinicians no longer commonly use halothane in today's operating rooms in developed countries. However, underserved communities and countries with fewer resources may not have access to other options, making halothane toxicity an ongoing concern. Obesity and non-alcoholic fatty liver disease positively correlate with hepatic dysfunction; therefore, it is no surprise that halothane toxicity is more prevalent in this cohort.[7][8] Apart from the liver dysfunction associated with obesity predisposing patients to halothane’s adverse effects, halothane also accumulates in the adipose tissue. Delayed excretion and theoretically prolonged exposure to potentially reactive halothane metabolites are also thought to increase the obese patient’s risk.[9]

Evidence implicates an imbalance between oxygen supply and demand in the development of halothane-induced liver injury. Rats treated with phenobarbitone, inducing hypoxia without anesthesia, exhibited centrilobular necrosis similar to that seen with halothane exposure.[10][11]

Genetic susceptibility also associates with halothane hepatitis in several studies. The extent of halothane metabolized, particularly through the reductive pathway, differs due to one’s genetics.[12][13] A case series of three closely related women suggested further genetic contributions to halothane hepatitis susceptibility.[13] Please refer to the pathophysiology and pharmacokinetics sections for additional information.

Epidemiology

Hepatotoxicity due to halothane administration is relatively common and is a major factor in its rapidly declining use. Type 1 hepatotoxicity has an incidence of 20% to 30%. A comprehensive report in 1969 demonstrated an incidence of type 2 hepatotoxicity (hepatitis) of 1 case per 6000 to 20000 cases, with fatal cases occurring approximately once in 35000 patients following a single exposure to the anesthetic.[6][14][15] This incidence of fatal cases increases to approximately 1 in 1000 patients following multiple exposures.[16][17][18] Following this study was a large-scale review in the United Kingdom, which showed similar results.[19] To put this into perspective, there is only a single case of hepatotoxicity confirmed after the administration of desflurane and 2 cases per 1 million after enflurane. By the 1970s, halothane was the most common cause of drug-induced liver failure.[20][21]

Halothane-induced hepatotoxicity has a female to male ratio of two to one.  Younger patients are less likely to be affected; 80% of the cases are typically in patients 40 years or older. Other risk factors include obesity and underlying liver dysfunction.[3][19][22] Medications such as phenobarbital, alcohol, and isoniazid may play a role in affecting CYP2E1 metabolism, increasing one’s risk.[23][24][25]

A study was completed that administered halothane or enflurane during spontaneous ventilation to 50 children. The study found an incidence of cardiac arrhythmias of 72% in children who were administered halothane during spontaneous breathing and 32% during enflurane anesthesia with a p-value less than 0.05. This study also showed that 41.3% of those arrhythmias were of ventricular origin in the halothane group compared to only 2.8% in the enflurane group.[26]

Pathophysiology

Liver injury due to drugs often categorizes into two patterns: predominantly bile duct injury or predominantly hepatocyte injury, although liver injury often results in a combination of the two types. Halothane hepatic injury falls under the latter category of predominantly hepatocyte damage.[27][28][29]

Halothane hepatotoxicity can subdivide into two categories: type 1 (mild) and type 2 (fulminant). The causes of Type 1 and Type 2 hepatotoxicities are not fully understood but are believed to be completely separate disease processes.

Type 1 hepatotoxicity is much more common and has a self-limiting course. Although the mechanism of hepatotoxicity remains unknown, there is a hypothesis that when halothane is broken down via the cytochrome P450 system, it biotransforms into reactive intermediates. Halothane metabolism is in the range of 20 to 30% compared with 1% for sevoflurane. Metabolism via oxidation and reduction are simultaneous via CYP2E1/CYP2A6 and CYP3A4/CYP2A6 pathways, respectively, depending on oxygen tension.[30][31][32][33]

Type 1 hepatotoxicity is believed to be secondary to the 1% to 3% of halothane metabolized via the reductive pathway, leading to increased hepatocyte hypoxemia and subsequent injury. Free radical intermediates chlorotrifluoroethane (CTE) or chlorodifluoroethene (CDE) get created in the reductive pathway.[34][35] Although the free radicals are not the sole mechanism of injury, they are the cause of inactivation and destruction of CYP450, resulting in elevation of aminotransferase.[36]

Apart from type 1 hepatotoxicity, which occurs in approximately 20% to 30% of patients, halothane may also cause hepatitis (type 2 hepatotoxicity). The immune system has been determined to play an integral role in the development of halothane hepatitis. Liver trifluoroacetyl (TFA) protein adducts are created via the oxidative biotransformation of halothane, resulting in an antibody-mediated reaction that causes hepatitis.[36][37]

Cardiac instability, particularly in children, is another side effect limiting the use of halothane. Infants and children have a relatively higher parasympathetic tone compared with that of adults. This higher baseline tone, paired with halothane’s negative chronotropic properties, may induce bradycardia or asystole.[11]

Histopathology

A liver biopsy is an option in suspected cases of halothane hepatotoxicity. The liver biopsy most commonly shows centrilobular necrosis and yellow atrophy. However, these findings are equivalent to those of fulminant viral hepatitis making it hard to differentiate the two.[37][38]

Toxicokinetics

General anesthesia via halothane occurs via several ion channels, which ultimately depresses nerve conduction, breathing, and cardiac contractility. Halothane binds potassium channels in cholinergic neurons, producing an immobilizing effect. Hyperpolarization of NMDA and calcium channels also occur with halothane administration.

The association between repeat exposure to halothane and hepatotoxicity has led to the hypothesis of halothane itself inducing drug-metabolizing enzymes. Therefore, when recent administration of halothane has occurred, the liver is more susceptible to injury, as these enzymes may still undergo alteration. Microsomal enzyme induction in both adults and children has occurred with halothane use.[27][28][39][40]

History and Physical

Type 1 halothane hepatotoxicity can occur with or without prior exposure to halothane. It is seen in 20 to 30% of patients, indicated by a postoperative elevation in serum aminotransferases.[24][41] This hepatotoxicity is asymptomatic in most patients, but symptoms such as nausea, fever, and lethargy can present.  Symptoms can occur within hours after surgery and are typically self-limiting over 1 to 2 weeks.

Type 2 halothane hepatotoxicity (hepatitis) leads to necrosis and liver failure with a high mortality rate.[42] Within the first 2 to 14 days after halothane exposure, 75% of patients with type 2 hepatotoxicity present with a mix of jaundice, hepatomegaly, fever, anorexia, myalgias, nausea, diffuse rash, and encephalopathy. A hallmark clinical presentation is a mixture of a high fever, tender hepatomegaly, and jaundice starting two to three days post halothane exposure.

Evaluation

Postoperative hepatic dysfunction may have several etiologies. Therefore, halothane hepatotoxicity generally is a diagnosis of exclusion of other more common causes, e.g., infection, hypotension, or other medications.[16][41]

After a thorough history and physical exam, the next step in diagnosing halothane hepatotoxicity is to obtain laboratory studies. A complete blood count (CBC) with differential may show leukocytosis or eosinophilia. Serum transaminase and bilirubin levels become elevated in the majority of cases. Aminotransferase levels often return to normal without treatment in one to two weeks, especially in the case of type 1 hepatotoxicity.[43]

Halothane-related antibodies can present via an enzyme-linked immunosorbent. Most patients do not have an immune response to the liver trifluoroacetyl (TFA) protein byproducts. Molecular mimicry of TFA protein byproducts via the E2 subunit protein may increase one’s susceptibility to halothane hepatitis. 

A liver biopsy can be performed, which would show massive centrilobular liver necrosis.[38][41][42] However, this is not specific to halothane hepatitis. Eosinophilia occurs in 40% of cases of halothane hepatitis, which is congruent with an immuno-allergic mechanism. A subset of patients present with acute liver failure, hepatic encephalopathy, and elevated aminotransferases.[42][44] If the patient is in fulminant liver failure, other liver tests that are not specific to halothane hepatotoxicity may be abnormal, such as prolonged prothrombin time (PT) and/or a prolonged international normalized ratio (INR).

A case series focusing on children with reported halothane hepatitis demonstrated an incidence of halothane-related antibodies in six of the seven children studied, which is statistically similar to that of adults. This data suggests the validity of performing a similar workup in children.[45]

Treatment / 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 and electrolyte balance
• Correcting coagulation alterations
• Managing hypoglycemia 
• Supporting ventilation
• Supporting hemodynamics
• Oral lactulose/restricting protein intake

The treatment for both types of halothane hepatotoxicity is supportive measures.[46] There is minimal to no data to support glucocorticoids in the setting of halothane hepatotoxicity. However, a single case report shows complete resolution after glucocorticoid initiation, indicating steroids are still selectively used in practice.[47]

Type 2 halothane hepatitis is severe and requires close monitoring if suspected, as supportive care for these patients is much more intensive and needs to start immediately. A liver transplant is usually necessary once acute liver failure is imminent, despite best supportive measures.

Differential Diagnosis

Postoperative jaundice has a broad differential diagnosis that includes general surgery complications, bile-duct surgery or complications, sepsis, hepatotoxicity from other drugs, hemolysis, viral hepatitis, and hypoxic hepatic injury. Due to the broad differential diagnosis, halothane hepatitis remains a diagnosis of exclusion.[24][29][41][44]

There are not many randomized controlled trials comparing the development of halothane hepatitis as compared with hepatitis development from other inhalational agents due to the robust animal data behind halothane’s adverse side effect profile. Several major rat-based studies from the 1980s established the mechanism of injury, often referenced throughout the halothane literature.[10][11]

Prognosis

The prognosis of type 1 halothane hepatotoxicity is much better than that of type 2 hepatitis; it is often self-remitting over several weeks, leaving little to no long-term dysfunction in most cases.  Type 2 halothane hepatotoxicity has a 50% mortality rate once it has progressed to acute liver failure and as high as 80% if hepatic encephalopathy has developed.[46] Urgent liver transplantation is required if acute liver failure progresses.

Complications

In summary, halothane carries associations with two forms of hepatotoxicity: type 1 (benign) and type 2 (fulminant hepatitis). Type 1 is associated with increased serum aminotransferase levels with possible mild self-limiting symptoms. Type 2 halothane hepatotoxicity is associated with severe hepatitis, acute liver failure, and an elevated mortality rate. Another major complication of halothane is cardiac instability, particularly in children.

Deterrence and Patient Education

Patient education is not the most significant barrier in preventing halothane adverse effects such as hepatitis, as patients are not typically aware of the medications used for their anesthetic. The greatest risk factor is exposure to halothane, followed by previous exposure, obesity, and genetic susceptibility. Patients should receive education about weight management and personal/family history before being exposed to halothane.

Enhancing Healthcare Team Outcomes

In most cases, halothane toxicity presents after a few days or weeks. These patients often first present to the primary care provider or nurse practitioner, who must obtain a history of halothane use in the presence of liver dysfunction. A liver specialist and a gastroenterologist must be involved early in the care of these patients.

The most effective way of enhancing healthcare outcomes relative to halothane toxicity is to limit its use; this is particularly true in patients with prior exposure to halothane since the incidence of hepatic necrosis increases to 1 to 1000 with repeat exposure.[16] It is also vital to understand the additional increased effects of halothane on children and to use it as sparingly as possible in this population.[48] In situations where halothane is in use by necessity, protocols should be established that prioritize patient and health care worker education of the risks of halothane along with increasing specific monitoring to identify the development of liver dysfunction as soon as possible so that supportive care can initiate promptly. The pharmacist, anesthesiologist, and nurse anesthetist should collaborate on the dosing and administration of halothane and have the necessary supportive pharmacological agents ready in the event of toxicity. They should further urge the patient to wear an ID bracelet indicating an adverse reaction to halothane to avoid using the anesthetic in the future. Only through an interprofessional team approach can the morbidity of halothane toxicity be reduced. [Level 5]