Halothane

Introduction

• Halothane is a halogenated alkane volatile anesthetic (Figure 1). It was the first non-flammable agent suitable for general use and replaced ether and chloroform due to ease of induction and titratable depth of anesthesia.³
• New agents have replaced halothane’s clinical use in high-income countries, but it remains an important anesthetic in low- and middle-income countries (LMICs).¹

History

• Halothane entered clinical practice in 1956, initially touted as a safer, more manageable alternative to the commonly used anesthetics of the time, ether and chloroform.¹
• The study of halothane helped confirm the Meyer-Overton correlation, which links lipid solubility to anesthetic potency.⁴
• Once in wide clinical use, increasing reports of halothane hepatitis and cardiac arrhythmias led to a decline in use in high-income countries and a transition to other volatile anesthetics with a better side effect profile.²

Physical Properties

• Halothane carries the chemical name 2-bromo-2-chloro-1,1,1-trifluoroethane and has a minimum alveolar concentration (MAC) of 0.75%
• The high blood/gas solubility of halothane compared to isoflurane and sevoflurane causes slower induction and emergence (Table 1).⁵

Pharmacology

• Halothane works by enhancing inhibitory neurotransmitters such as gamma-aminobutyric acid and glycine, while suppressing excitatory neurotransmitters such as N-methyl-D-aspartate, and inhibiting nicotinic acetylcholine receptors.³
• Halothane also activates K2P potassium channels, promoting neuronal hyperpolarization.⁴
• Halothane is more highly metabolized than other volatile anesthetics, generating trifluoroacetylated hepatocellular proteins that can lead to hepatotoxicity in some patients.⁵

Systemic Effects⁵

• Cardiovascular: Halothane causes myocardial depression, in turn decreasing cardiac output (CO) and mean arterial pressure. It does this by directly impairing contractility and is the volatile anesthetic associated with the greatest reduction in CO.
• Respiratory: It reduces tidal volume and minute ventilation. This can contribute to hypercapnia during spontaneous ventilation. The agent has a sweet, non-pungent odor, making it useful for inhalational induction.
• Neurologic: It increases cerebral blood flow while decreasing cerebral metabolic rate of oxygen consumption.
• Musculoskeletal: It provides skeletal muscle relaxation through central depression of spinal reflexes.

Adverse Effects

• Halothane hepatitis: Immune-mediated hepatic necrosis caused by antibodies against CYP2E1 byproducts
  • Type 1: Mild hepatitis and self-limited symptoms, including elevated transaminase levels and symptoms such as rash, arthralgias, lethargy, and nausea²
  • Type 2: Severe hepatotoxicity, liver failure, fatal in most cases²
  • The incidence of Type 2 halothane hepatitis has been reported to range from 1/6000 to 1/35,000 halothane exposures, with frequency increasing with each subsequent exposure.²
  • Female sex, middle age, obesity, and genetic predisposition are all risk factors for severe hepatotoxicity. Halothane use is not recommended in patients with a family history of Type 2 halothane hepatitis.²
• Cardiac arrhythmias: Halothane sensitizes the myocardium to catecholamines, which can predispose patients to ventricular arrhythmias and fibrillation.⁶
  • This risk of cardiac arrhythmias is increased in the setting of hypercarbia or in the presence of exogenous epinephrine.⁶
• Hypotension: Arises from direct negative inotropic action⁴
• Respiratory depression: There is a dose-dependent decrease in minute ventilation with subsequent hypercarbia contributing to arrhythmias.⁵
• Malignant hyperthermia: More potent activator of ryanidine receptor-mediated calcium release than other volatile anesthetics like sevoflurane or isoflurane, making it more likely to trigger malignant hyperthermia in at-risk patients.⁴
• Renal effects: It can cause transient decreases in renal blood flow and glomerular filtration rate.⁴
• Uterine effects: Uterine relaxation occurs in a dose-dependent manner, increasing postpartum bleeding risk.⁶

Availability in Resource-Limited Settings¹

• Halothane remained on the World Health Organization Essential Medicines List until 2025 and continues to be used in many hospitals in sub-Saharan Africa and parts of Asia.
• Piramal Pharma, the largest global manufacturer of halothane, ceased production in 2023, leading to sudden shortages and decreasing access to safe surgery and anesthesia in hospitals dependent on halothane.¹
• The sudden withdrawal of halothane production raises concerns for equitable access to safe anesthesia and surgery in LMICs, especially in cases requiring inhalational induction or general anesthesia.
• Replacing halothane is a complex task that will take substantial time, requiring investment in new equipment, new supply chains of volatile anesthetics, and additional anesthesia provider training on the use of alternative volatile anesthetics.¹
• In the short term, isoflurane can be used in halothane vaporizers because of their similar saturated vapor pressures, but there are significant safety concerns with this as a permanent solution. These include the inability to safely perform an inhalational induction with isoflurane, differences in MAC between halothane and isoflurane that lead to substantially lighter anesthesia with isoflurane in a halothane vaporizer at the same dial setting, and the unknown long-term compatibility of halothane vaporizer materials with isoflurane.¹