Indications

Enflurane or 2-chloro-1,1,2,-trifluoroethyl-difluoromethyl ether (CHF2OCF2CHFCl)) is a halogenated inhaled anesthetic that can now be considered a chapter of the history of anesthesia. It was synthesized by Ross Terrell in 1963. It was approved by the Food and Drug Administration (FDA) for the induction and maintenance of general anesthesia (GA), becoming available in the United States in 1972. It was the most widely used inhalation between the late '60s and most of the '80s. However, its usage has decreased in favor of newer halogenated anesthetics such as isoflurane (enflurane is a structural isomer of isoflurane), sevoflurane, and desflurane which show a better pharmacokinetic profile (faster induction and emergence times) and are less burdened, compared to enflurane, with side effects, especially in terms of nephrotoxicity and pro-convulsant activity.[1] Enflurane has also been used to treat refractory status asthmasticus, though this indication is not FDA approved.[2]

Mechanism of Action

The mechanism of action of enflurane and other halogenated inhaled anesthetics is still poorly understood. The hypothesis is that these agents act on different ion channels within the nervous system by blocking excitatory channels and augmenting inhibitory channels. In particular, volatile anesthetics can depress ventral horn neurons, causing immobilization. For enflurane, 30% of depressant effects on the spinal cord are mediated by the gamma-aminobutyric acid type A (GABA-A) receptor, and glycine receptors mediate 20 % of the effects.[3]

Administration

Enflurane is a clear, colorless liquid at room temperature, requiring a vaporizer for administration, although it vaporizes quite readily. ZIts boiling point at 1 atmosphere is 56.5 degrees  Celsius. The patient then inhales it via a face mask. Enflurane is a non-flammable, nonexplosive liquid. The boiling point is 56.5 degrees C at 760 mm Hg, and the vapor pressure (in mm Hg) is 175 at 20 degrees C, 218 at 25 degrees C, and 345 at 36 degrees C. The delivery of continuous enflurane causes drug accumulation within the alveoli. Through gas exchange in the lungs, enflurane is carried on red blood cells and distributed to the rest of the body.[4] 

The minimal alveolar concentration (MAC) of enflurane is 1.68% in pure oxygen, 0.57 in 70% nitrous oxide with 30% oxygen, and 1.17 in 30% nitrous oxide with 70% oxygen. The MAC-Awake (the concentration at which appropriate voluntary responses to commands are lost; for example, the opening of the eyes) was 0.27 with slow alveolar washout and 0.20 with fast alveolar washout.[5] Blood-gas partition in adults is 2.07 and 1.78 in children, at 37 degrees.[6] The blood-gas partition correlates with serum albumin and triglyceride concentrations, which would explain the lower partition as children have less serum albumin and triglyceride. In particular, because the blood-gas partition coefficient is slightly lower than that of halothane, induction, and awakening are relatively slow. Certainly, induction and emergence times are slower than other halogenates, such as desflurane (blood-gas coefficient 0.47) or sevoflurane (0.65).

Induction. A hypnotic dose of a short-acting barbiturate or propofol followed by the mixture of the inhaled anesthetic with oxygen and air can be used to induce the loss of consciousness (LOC). In general, enflurane concentrations from 2.0% to 4.5% cause surgical anesthesia in 7 to 10 minutes. When using enflurane to induce LOC, the recommendation is to start the induction phase with enflurane at a concentration of 0.5% and gradually increase by another 0.5% every few respiratory acts until surgical anesthesia is reached. The concentration at this level must be less than 4%. The inhaled agent has a mild, sweet odor and may induce a mild stimulus to salivation or tracheobronchial secretions. Again, pharyngeal and laryngeal reflexes are readily obtunded.

Maintenance. Surgical anesthesia levels are maintainable with 0.5 to 3% enflurane concentrations. Maintenance concentrations should not exceed 3.0%.

Emergence. The concentration of enflurane can be reduced to 0.5% towards the end of the surgery or suspended at the beginning of the surgical suture.

Adverse Effects

Hemodynamic effects. The administration of enflurane has been known to decrease systemic vascular resistance.[7] This effect causes decreased blood pressure. Enflurane is also known to cause a concentration-dependent decrease in the heart and increased left atrial pressure. 

Respiratory effects. Inhaled anesthetics have been shown to have potent bronchodilator properties. Along with bronchodilation, inhaled anesthetics decrease airway responsiveness and reduce histamine-induced bronchospasm.[2] The exact mechanism leading to the dilation of the airway remains unknown at this time. However, the current theories are direct action on airway smooth muscle via diffusion to airway wall, systemic gas distribution via circulation, and central neurologic action.[8]

Neurological effects. Enflurane is known to increase cerebral blood volume in comparison to halothane.[9] The metabolism of enflurane has also been shown to increase cerebral blood flow, especially when anesthesia is at the level of frequent spikes and suppression on electroencephalogram (EEG).[10] As a result of the increased blood flow, enflurane has been demonstrated to decrease cerebral vascular resistance and cerebral metabolic rate for oxygen. The thought was that enflurane is pro-convulsant due to the GABA-ergic effect of inhaled anesthetics. On EEG, enflurane causes high-amplitude sharp waves, called paroxysmal epileptiform discharges. Researchers theorize that enflurane causes increased neuronal inhibition in the cortex, so any small amount of excitation would cause electrical discharges.[11]

Other effects. Along with the mentioned effect, enflurane can also cause cardiac arrhythmias, postoperative nausea and vomiting, respiratory irritation, and agitation (emergence delirium) or postoperative delirium.[12][13]

Contraindications

Like many inhaled anesthetics, enflurane is contraindicated for a patient with a personal history or family history of malignant hyperthermia. Depending on hospital policy, either the machine will be cleaned so there would be no lingering traces of any inhaled gas in the machine, or a different machine used only for patients with malignant hyperthermia will be in the operating room.

Generally, it is contraindicated in pregnancy or during breastfeeding and in patients with convulsive disorders.

Monitoring

There are no specific guidelines for monitoring enflurane. However, the American Society of Anesthesiologists (ASA) guidelines recommend monitoring consciousness, pulmonary ventilation, oxygenation, and hemodynamics.[14] Intraoperatively, the patient is monitored using pulse oximetry, electrocardiography, continuous blood pressure device, temperature monitor, inspired and expired oxygen levels, inspired and expired volatile anesthetic levels, carbon dioxide levels, and airway pressure. If the surgery requires patient paralysis, peripheral nerve stimulation will be used. Though not in the recommendations, anesthesiologists have used the bispectral index (BIS) to monitor the depth of anesthesia to prevent intraoperative awareness.[15][16]

Toxicity

Like many inhaled anesthetics, enflurane has associated adverse effects. Amongst the effects are hepatotoxicity, nephrotoxicity, and neurotoxicity. 

Hepatotoxicity. Enflurane has shown minor elevations in serum aminotransferase levels (5- to 50-fold) 1 to 2 weeks after surgery and anesthesia. Furthermore, jaundice has been reported 2 to 21 days following surgery.[1] There is also an elevation in alkaline phosphatase and gamma-glutamyl transpeptidase levels. In rare instances, enflurane causes a rash and eosinophilia after a day of fever. The mechanism of injury is thought to be similar to halothane-associated hepatotoxicity. Enflurane is metabolized by liver enzyme CYP2E1 to trifluoroacetate reactive intermediate, which binds to several proteins.[17]

Nephrotoxicity. Nephrotoxicity from enflurane use is associated with high doses of the drug. This anesthetic can cause significant renal structure damage and transient renal functional impairment. However, there is a greater potential for toxicity when there is already renal impairment. The mechanism of injury appears to be due to increased concentration from an enflurane metabolite, inorganic fluoride. Approximately 2.4% are fluorinated urinary metabolites, of which 0.5% as fluorine inorganic and 1.9% as organic fluorine. Along with decreased ability to eliminate inorganic fluoride, there is an increased urine flow rate and more significant damage in the proximal convoluted tubule cells.[18]

Neurotoxicity. Currently, no anesthetic is contraindicated for pregnancy due to neurotoxicity. However, there is very limited research on the effects of volatile anesthetics on developing brains. Exposure to volatile anesthetic theoretically causes acute neurotoxicity and later defects in learning and memory during the postnatal period.[19] Other subtle neurotoxicity includes abnormal fear response and social interactions. The theorized mechanism of injury includes reactive oxygen species stress, growth or nutrient signaling, and direct neuronal modulation.[20] 

Early studies have shown potential neurotoxicity via N-methyl-D-aspartate (NMDA) receptor antagonism and potentiation of GABA signal transduction.[21] A different study showed that volatile anesthetics induce interleukin 6 (IL-6) mRNA. The cytokine may affect neuronal precursor cells, which would later cause learning impairments in the fetus.[22]

Enhancing Healthcare Team Outcomes

Enflurane is rarely the anesthetic of choice any longer due to newer agents with faster induction and emergence times and fewer adverse events. Enflurane administration should only be done by trained anesthesiologists or healthcare professionals certified in anesthesia to maintain patient safety. It is essential to encourage anyone involved in the patient's direct care to speak up about any concerns they have about the patient's safety. Having an interprofessional team meeting with the surgeon, anesthesiologist, and all patient care personnel involved directly with the specific patient will help improve surgical outcomes. This can be included in the pre-surgical "time out," where everyone on the surgical and anesthesia team ensures complete agreement on what will happen in the upcoming procedure.[23] 

Communication between surgeons and anesthesiologists is required to determine the timing of emergence from the anesthesia.[24] Following the surgery, anesthesia personnel can give a thorough hand-off to nurses in the post-anesthesia care unit to help with the emergence of enflurane; these nurses can monitor the patient post-operatively and report any concerns to the clinician on-duty or the surgeon and/or anesthesia personnel who performed the procedure. Interprofessional care coordination and communication are vital to the proper use of anesthetics and optimal patient outcomes. [Level 5]