Vetflurane

Vetflurane (isoflurane, USP) may be used for induction and maintenance of general anesthesia. Adequate data have not been developed to establish its application in obstetrical anesthesia.

Premedication

Premedication should be selected according to the need of the individual patient, taking into account that secretions are weakly stimulated by Vetflurane (isoflurane, USP), and the heart rate tends to be increased. The use of anticholinergic drugs is a matter of choice.

Inspired Concentration

The concentration of isoflurane being delivered from a vaporizer during anesthesia should be known. This may be accomplished by using:

1. Vaporizers calibrated specifically for isoflurane;
2. Vaporizers from which delivered flows can be calculated, such as vaporizers delivering a saturated vapor, which is then diluted. The delivered concentration from such a vaporizer may be calculated using the formula:

% isoflurane = 100 P_vF_v/F_T (P_A - P_V)

Where: :

P_A = Pressure of atmosphere
P_V = Vapor pressure of isoflurane
F_V=Flow of gas through vaporizer (mL/min)
F_T = Total gas flow (mL/min)

Isoflurane contains no stabilizer. Nothing in the agent alters calibration or operation of these vaporizers.

Induction

Induction with isoflurane in oxygen or in combination with oxygen-nitrous oxide mixtures may produce coughing, breath holding, or laryngospasm. These difficulties may be avoided by the use of a hypnotic dose of an ultra-short-acting barbiturate. Inspired concentrations of 1.5 to 3.0% isoflurane usually produce surgical anesthesia in 7 to 10 minutes.

Maintenance

Surgical levels of anesthesia may be sustained with a 1.0 to 2.5% concentration when nitrous oxide is used concomitantly. An additional 0.5 to 1.0% may be required when isoflurane is given using oxygen alone. If added relaxation is required, supplemental doses of muscle relaxants may be used.

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

Known sensitivity to Vetflurane (isoflurane, USP) or to other halogenated agents. 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, isoflurane 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.) 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 the CO₂ absorption system (hot canister). PaO₂ and pH may decrease, and hyperkalemia and a base deficit may appear. Treatment includes discontinuance of triggering agents (e.g., isoflurane), 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 derangements. (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.

Since levels of anesthesia may be altered easily and rapidly, only vaporizers producing predictable concentrations should be used. Hypotension and respiratory depression increase as anesthesia is deepened.

Increased blood loss comparable to that seen with halothane has been observed in patients undergoing abortions.

Vetflurane (isoflurane, USP) markedly increases cerebral blood flow at deeper levels of anesthesia. There may be a transient rise in cerebral spinal fluid pressure, which is fully reversible with hyperventilation.

PRECAUTIONS

General

As with any potent general anesthetic, Vetflurane (isoflurane, USP) should only be administered in an adequately equipped anesthetizing environment by those who are familiar with the pharmacology of the drug and qualified by training and experience to manage the anesthetized patient.

Regardless of the anesthetics employed, maintenance of normal hemodynamics is important to the avoidance of myocardial ischemia in patients with coronary artery disease ^4,5,6,7.

Vetflurane (isoflurane, 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 canister 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 Vetflurane (isoflurane, USP).

As with other halogenated anesthetic agents, Vetflurane (isoflurane, USP) may cause sensitivity hepatitis in patients who have been sensitized by previous exposure to halogenated anesthetics (see CONTRAINDICATIONS).

REFERENCES

4. S. Reiz, et al, Anesthesiology 59:91-97, 1983

5. S. Slogoff and A.S. Keats, Anesthesiology 70:179-188, 1989

6. K.J. Tuman, et al, Anesthesiology 70:189-198, 1989

7. D.T. Mangano, Editorial Views, Anesthesiology 70:175-178, 1989

Laboratory Tests

Transient increases in BSP retention, blood glucose and serum creatinine with decrease in BUN, serum cholesterol and alkaline phosphatase have been observed.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Swiss ICR mice were given isoflurane to determine whether such exposure might induce neoplasia. Isoflurane was given at ½, ⅛ 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, which were given the same background gases, but not the anesthetic.

Pregnancy

Pregnancy Category C

Isoflurane has been shown to have a possible anesthetic-related fetotoxic effect in mice when given in doses 6 times the human dose. There are no adequate and well-controlled studies in pregnant women. Isoflurane should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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 isoflurane is administered to a nursing woman.

Adverse reactions encountered in the administration of Vetflurane (isoflurane, USP) are in general dose dependent extensions of pharmacophysiologic effects and include respiratory depression, hypotension and arrhythmias.

Shivering, nausea, vomiting and ileus have been observed in the postoperative period.

As with all other general anesthetics, transient elevations in white blood count have been observed even in the absence of surgical stress. See WARNINGS for information regarding malignant hyperthermia and elevated carboxyhemoglobin levels.

During marketing, there have been rare reports of mild, moderate and severe (some fatal) postoperative hepatic dysfunction and hepatitis.

Vetflurane (isoflurane, 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 Vetflurane (isoflurane, USP). Due to the spontaneous nature of these reports, the actual incidence and relationship of Vetflurane (isoflurane, 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.