Compound 347

Compound 347 (enflurane, USP) may be used for induction and maintenance of general anesthesia. Enflurane may be used to provide analgesia for vaginal delivery. Low concentrations of enflurane (see DOSAGE AND ADMINISTRATION) may also be used to supplement other general anesthetic agents during delivery by Cesarean section. Higher concentrations of enflurane may produce uterine relaxation and an increase in uterine bleeding.

The concentration of Compound 347 (enflurane, USP) being delivered from a vaporizer during anesthesia should be known. This may be accomplished by using:

1. vaporizers calibrated specifically for enflurane;
2. vaporizers from which delivered flows can easily and readily be calculated.

Preanesthetic Medication

Preanesthetic medication should be selected according to the need of the individual patient, taking into account that secretions are weakly stimulated by enflurane and that enflurane does not alter heart rate. The use of anticholinergic drugs is a matter of choice.

Surgical Anesthesia

Induction may be achieved using enflurane alone with oxygen or in combination with oxygen-nitrous oxide mixtures. Under these conditions some excitement may be encountered. If excitement is to be avoided, a hypnotic dose of a short-acting barbiturate should be used to induce unconsciousness, followed by the enflurane mixture. In general, inspired concentrations of 2.0 to 4.5% enflurane produce surgical anesthesia in 7 to 10 minutes.

Maintenance

Surgical levels of anesthesia may be maintained with 0.5 to 3.0% enflurane. Maintenance concentrations should not exceed 3.0%. If added relaxation is required, supplemental doses of muscle relaxants may be used. Ventilation to maintain the tension of carbon dioxide in arterial blood in the 35 to 45 mm Hg range is preferred. Hyperventilation should be avoided in order to minimize possible CNS excitation.

The level of blood pressure during maintenance is an inverse function of enflurane concentration in the absence of other complicating problems. Excessive decreases (unless related to hypovolemia) may be due to depth of anesthesia and in such instances should be corrected by lightening the level of anesthesia.

Analgesia

Enflurane 0.25 to 1.0% provides analgesia for vaginal delivery equal to that produced by 30 to 60% nitrous oxide. These concentrations normally do not produce amnesia. See also the information on the effects of enflurane on uterine contraction contained in the CLINICAL PHARMACOLOGY section.

Cesarean Section

Enflurane should ordinarily be administered in the concentration range of 0.5 to 1.0% to supplement other general anesthetics. See also the information on the effects of enflurane on uterine contraction contained in the CLINICAL PHARMACOLOGY section.

Seizure disorders (see WARNINGS).

Known sensitivity to Compound 347 (enflurane, USP) or other halogenated anesthetics.

Known or suspected genetic susceptibility to malignant hyperthermia.

WARNINGS

Perioperative Hyperkalemia

Use of inhaled anesthetic agents has been associated with rare increases in serum potassium levels that have resulted in cardiac arrhythmias and death in pediatric patients during the postoperative period. Patients with latent as well as overt neuromuscular disease, particularly Duchenne muscular dystrophy, appear to be most vulnerable. Concomitant use of succinylcholine has been associated with most, but not all, of these cases. These patients also experienced significant elevations in serum creatinine kinase levels and, in some cases, changes in urine consistent with myoglobinuria. Despite the similarity in presentation to malignant hyperthermia, none of these patients exhibited signs or symptoms of muscle rigidity or hypermetabolic state. Early and aggressive intervention to treat the hyperkalemia and resistant arrhythmias is recommended, as is subsequent evaluation for latent neuromuscular disease.

Malignant Hyperthermia

In susceptible individuals, enflurane anesthesia may trigger a skeletal muscle hypermetabolic state leading to high oxygen demand and the clinical syndrome known as malignant hyperthermia. The syndrome includes nonspecific features such as muscle rigidity, tachycardia, tachypnea, cyanosis, arrhythmias and unstable blood pressure. (It should also be noted that many of these nonspecific signs may appear with light anesthesia, acute hypoxia, etc. The syndrome of malignant hyperthermia secondary to enflurane appears to be rare; by March 1980, 35 cases had been reported in North America for an approximate incidence of 1:725,000 enflurane anesthetics.) An increase in overall metabolism may be reflected in an elevated temperature (which may rise rapidly early or late in the case, but usually is not the first sign of augmented metabolism) and an increased usage of CO₂ absorption system (hot cannister). PaO₂ and pH may decrease, and hyperkalemia and a base deficit may appear. Treatment includes discontinuance of triggering agents (e.g., enflurane), administration of intravenous dantrolene sodium, and application of supportive therapy. Such therapy includes vigorous efforts to restore body temperature to normal, respiratory and circulatory support as indicated, and management of electrolyte-fluid-acid-base derangement. (Consult prescribing information for dantrolene sodium intravenous for additional information on patient management.) Renal failure may appear later, and urine flow should be sustained if possible.

Increasing depth of anesthesia with Compound 347 (enflurane, USP) may produce a change in the electroencephalogram characterized by high voltage, fast frequency, progressing through spike-dome complexes alternating with periods of electrical silence to frank seizure activity. The latter may or may not be associated with motor movement. Motor activity, when encountered, generally consists of twitching or “jerks” of various muscle groups; it is self-limiting and can be terminated by lowering the anesthetic concentration. This electroencephalographic pattern associated with deep anesthesia is exacerbated by low arterial carbon dioxide tension. A reduction in ventilation and anesthetic concentrations usually suffices to eliminate seizure activity. Cerebral blood flow and metabolism studies in normal volunteers immediately following seizure activity show no evidence of cerebral hypoxia. Mental function testing does not reveal any impairment of performance following prolonged enflurane anesthesia associated with or not associated with seizure activity.

Since levels of anesthesia may be altered easily and rapidly, only vaporizers producing predictable concentrations should be used. Hypotension and respiratory exchange can serve as a guide to depth of anesthesia. Deep levels of anesthesia may produce marked hypotension and respiratory depression.

When previous exposure to a halogenated anesthetic is known to have been followed by evidence of unexplained hepatic dysfunction, consideration should be given to use of an agent other than enflurane.

PRECAUTIONS

General

Compound 347 (enflurane, USP) should be used with caution in patients who by virtue of medical or drug history could be considered more susceptible to cortical stimulation produced by the drug.

Compound 347 (enflurane, USP), like some other inhalational anesthetics, can react with desiccated carbon dioxide (CO₂) absorbents to produce carbon monoxide which may result in elevated levels of carboxyhemoglobin in some patients. Case reports suggest that barium hydroxide lime and soda lime become desiccated when fresh gases are passed through the CO₂ absorber cannister at high flow rates over many hours or days. When a clinician suspects that CO₂ absorbent may be desiccated, it should be replaced before the administration of Compound 347 (enflurane, USP).

Laboratory Tests

Bromsulfthalein (BSP) retention is mildly elevated postoperatively in some cases. This may relate to the effect of surgery since prolonged anesthesia (5 to 7 hours) in human volunteers does not result in BSP elevation. There is some elevation of glucose and white blood count intraoperatively. Glucose elevation should be considered in diabetic patients.

Carcinogenesis/Mutagenesis

Swiss ICR mice were given enflurane to determine whether such exposure might induce neoplasia. Enflurane was given at 1/2, 1/8 and 1/32 MAC for four in-utero exposures and for 24 exposures to the pups during the first nine weeks of life. The mice were killed at 15 months of age. The incidence of tumors in these mice was the same as in untreated control mice who were given the same background gases, but not the anesthetic.

Exposure of mice to 20 hours of 1.2% enflurane causes a small (about 1/2 of 1.0%) but statistically significant increase in sperm abnormalities. In contrast to these results, in vitro approaches to the study of mutagenesis (Ames test, sister chromatid exchange test, and the 8-azaguanine system) have not shown a mutagenic effect of enflurane.

Pregnancy Category B

Reproduction studies have been performed in rats and rabbits at doses up to four times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to enflurane. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when enflurane is administered to a nursing woman.

1. Malignant hyperthermia (see WARNINGS).
2. Motor activity exemplified by movements of various muscle groups and/or seizures may be encountered with deep levels of Compound 347 (enflurane, USP) anesthesia, or light levels with hypocapnia.
3. Hypotension, respiratory depression, and hypoxia have been reported.
4. Arrhythmias, shivering, nausea and vomiting have been reported.
5. Elevation of the white blood count has been observed.
6. Mild, moderate and severe liver injury, including hepatic failure, may rarely follow anesthesia with enflurane. Serum transaminases may be increased and histologic evidence of injury may be found. The histologic changes are neither unique nor consistent. In several of these cases, it has not been possible to exclude enflurane as the cause or as a contributing cause to liver injury. The incidence of unexplained hepatotoxicity following the administration of enflurane is unknown, but it appears to be rare and not dose related.

Compound 347 (enflurane, USP) has also been associated with perioperative hyperkalemia (see WARNINGS).

Post-Marketing Events

The following adverse events have been identified during post-approval use of Compound 347 (enflurane, USP). Due to the spontaneous nature of these reports, the actual incidence and relationship of Compound 347 (enflurane, USP) to these events cannot be established with certainty.

Cardiac Disorders: Cardiac arrest

Hepatobiliary Disorders: Hepatic necrosis, Hepatic failure

In the event of overdosage, or what may appear to be overdosage, the following action should be taken:

Stop drug administration, establish a clear airway and initiate assisted or controlled ventilation with pure oxygen.