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Inhalation Anesthetic
Action And Clinical Pharmacology: Enflurane is an inhalation anesthetic. Induction and recovery from anesthesia with enflurane are rapid. Enflurane does not appear to stimulate excessive salivation or tracheabronchial secretions, or affect bronchomotor tone. Pharyngeal and laryngeal reflexes are readily obtunded. The level of anesthesia changes rapidly, which would be predicted based upon its Oswald partition coefficients.

Enflurane reduces ventilation as depth of anesthesia increases. This is a result of a decrease in tidal volume with rate of respiration remaining essentially constant. Enflurane provokes a sigh response reminiscent of diethyl ether.

There is a decrease in blood pressure with induction of anesthesia, followed by a return to near normal with surgical stimulation. A slight fall in cardiac output, stroke volume, and peripheral resistance, and an increase in central venous pressure may occur. Progressive increases in depth of anesthesia produce corresponding increases in hypotension. ECG monitoring and recording indicate that the cardiac rhythm remains remarkably stable. Elevation of CO2 level in arterial blood does not alter cardiac rhythm.

While enflurane has been shown to sensitize the myocardial conduction system to epinephrine in the dog and may produce serious arrhythmias, studies in cats and man indicate that there is a certain margin of safety in the administration of epinephrine-containing solutions during enflurane anesthesia. Enflurane anesthesia has been used in medical conditions involving high levels of endogenous catecholamines, as well as surgical procedures involving carefully administered quantities of epinephrine-containing solutions. On the basis of this experience, up to 10 mL of 1:100 000 or 1:200 000 epinephrine-containing solution alone or in conjunction with lidocaine 0.5 to 2.0% may be injected s.c. at a rate of not more than 10 mL/10-minute period and no more than 30 mL/h. The concomitant administration of lidocaine enhances the safety of the use of epinephrine during enflurane anesthesia. This effect of lidocaine is dose related. More dilute solutions and reduced dosages should be used in highly vascular areas. All customary precautions in the use of vasoconstrictor substances should be observed, including monitoring of respiration, blood pressure and pulse. Epinephrine should be used in association with enflurane only in patients who have adequate pulmonary function to ensure optimal pulmonary ventilation and should not be used in patients with pre-existing cardiac disease who cannot tolerate the tachycardia or hypertension which may result from the administration of exogenous catecholamines, or in patients with hyperthyroidism.

Muscle relaxation in man may in certain cases be adequate for intra-abdominal operations at normal levels of anesthesia. Should greater relaxation be necessary, minimal doses of muscle relaxants may be used. Nondepolarizing muscle relaxants are markedly potentiated by enflurane. All commonly used muscle relaxants are compatible with enflurane. Neostigmine does not reverse the direct relaxant effect of enflurane.

Enflurane 0.25 to 1.0% (average 0.5%) provides analgesia equal to that produced by 30 to 60% (average 40%) nitrous oxide for vaginal delivery. With either agent, patients remain awake, cooperative and oriented. These anesthetic approaches produce normal Apgar scores and comparable maternal blood losses. Neither enflurane nor nitrous oxide when used for obstetrical analgesia alters BUN, creatinine, uric acid or osmolality. The only difference in the use of these two agents for obstetrical analgesia appears to be higher inspired oxygen concentration that may be used with enflurane.

Analgetic doses of enflurane (e.g. 0.5 to 0.8%) do not significantly depress the frequency of contraction of human uterine muscle. Force of contraction remains at more than 80% of normal. Higher concentrations (1.5 to 3.0%) depress both rate and contractility. Intrauterine manipulations for versions and extractions are easily done at higher concentrations because of the profound uterine relaxation. Blood loss in patients anesthetized for therapeutic abortion with 1.0% enflurane in 70% nitrous oxide is 24 mL greater than blood loss in patients receiving paracervical block anesthesia. Uterine bleeding may be increased when enflurane is used in anesthetizing concentrations for vaginal delivery or delivery by Cesarean section. However, unless the enflurane concentration exceeds 2 to 3%, the uterine muscle remains responsive to oxytocic administration. Babies delivered per vagina or by Cesarean section under nitrous oxide-enflurane anesthesia usually have normal Apgar scores.

The systemic metabolism of enflurane in humans was measured in healthy female patients anesthetized with enflurane and undergoing routine gynecological procedures. In 7 patients, 85.1% of the administered enflurane was recovered; 82.7% as unchanged enflurane and 2.4% as nonvolatile fluorine-containing urinary metabolites. Of the urinary fluorine-containing metabolites, 0.5% was inorganic fluoride and 1.9% organic fluoride. Maximum inorganic fluoride excretion was attained in 7 hours, while maximum urinary organic fluoride excretion was attained on the second day. Although metabolism to the extent of at least 2.4% is attained, the degree is much less than that reported with halothane, methoxyflurane, fluroxene and trichloroethylene.

Serum inorganic fluoride was determined in 66 patients receiving enflurane. The patient population consisted of 23 males, 43 females, with a mean age of 53, age spread of 19 to 88, and a mean duration of anesthesia of 212 minutes. The mean serum inorganic fluoride levels in Ámol/L are as follows (the standard error of the mean was 0.03 to 2.6): before anesthesia (control) 1.54; 1 hour anesthesia 11.1; end of anesthesia 15.6; 24 hours postoperatively 7.6; 48 hours postoperatively 3.5.

These levels are well below the 50 Ámol/L threshold level which can produce minimal renal damage in normal subjects. However, patients chronically ingesting isoniazid or other hydrazine-containing compounds may metabolize greater amounts of enflurane. Although no significant renal dysfunction has been found thus far in such patients, peak serum fluoride levels can exceed 50 Ámol/L, particularly when anesthesia goes beyond 2 MAC hours. Depression of lymphocyte transformation does not follow prolonged enflurane anesthesia in man in the absence of surgery. Thus enflurane does not depress this aspect of the immune response.

Indications And Clinical Uses: May be used for induction and maintenance of general anesthesia. Enflurane may be used for analgesia in vaginal delivery. Enflurane may also be used for anesthesia during operative vaginal delivery or delivery by Caesarean section. However, as noted above, higher concentrations of enflurane may produce uterine bleeding.

Contra-Indications: Seizure disorders (see Warnings). Known sensitivity to enflurane or other halogenated anesthetics. tag_WarningWarnings

Manufacturers' Warnings In Clinical States: With increasing depth of enflurane anesthesia, CNS excitation occurs, manifested by a change in the EEG 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 EEG pattern associated with deep anesthesia is exacerbated by hyperventilation producing low arterial CO2 tension. The pattern serves as a warning that depth of anesthesia is excessive.

Cerebral blood flow and metabolism studies in normal volunteers during seizure patterns show no evidence of cerebral hypoxia, and recovery appears to be uncomplicated. Nevertheless, enflurane should not be used in patients with convulsive disorders.

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 anesthesia depth. With deep levels of anesthesia, more marked hypotension and respiratory depression are encountered.

The action of nondepolarizing relaxants is augmented by enflurane, so less than the usual amounts of those drugs should be used. The time for recovery from the myoneural effect of these relaxants is greater in the presence of enflurane than for other commonly used anesthetics.

Safety of repeat anesthesia with enflurane has not been established.

Epinephrine-containing solutions should be used in association with enflurane only in patients with adequate pulmonary function and should not be used in patients with pre-existing cardiac disease who cannot tolerate the tachycardia or hypertension which may result from the administration of exogenous catecholamines, or patients with hyperthyroidism.

Pregnancy: Safe use in pregnancy other than for analgesia for vaginal delivery or anesthesia during operative vaginal delivery or Cesarean section has not been established. Reproduction studies performed in rabbits and rats reveal no evidence of harm to the animal fetus. The relevance of these studies to the human is not known. There is no adequate experience in pregnant women who have received enflurane during the course of pregnancy (other than at term). Thus, safety to the fetus or pregnant mother has not been established.

Precautions: Bromsulfalein (BSP) retention is mildly elevated postoperatively in some cases. There is some elevation of glucose and WBC count intraoperatively. Glucose elevation should be considered in diabetic patients.

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 anesthesias.) 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. enflurane), administration of i.v. 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 i.v. for additional information on patient management.) Renal failure may appear later, and urine flow should be sustained if possible.

Adverse Reactions: Motor activity exemplified by movement of various muscle groups and/or seizures may be encountered with deep levels of enflurane anesthesia.

Hypotension, respiratory depression, arrhythmias, shivering, hyperthermia, nausea and vomiting have been reported.

Elevation of the WBC count has been observed. It has not been determined whether this is related to enflurane or to surgical stress.

Elevation of AST, LDH, alkaline phosphatase, and bilirubin, with or without frank jaundice, have been reported in the post-operative period following enflurane anesthesia in some patients. Hepatitis has been reported very rarely.

Delirium, hallucinations and hiccup occur rarely.

Symptoms And Treatment Of Overdose: Symptoms: Overdosage will generally produce marked hypotension and apnea in the absence of muscle relaxants. tag_Treatment

Treatment: In the event of overdosage, or what may appear to be overdosage, the following action should be taken: Stop drug administration. Establish that the airway is clear. Instigate assisted or controlled ventilation with pure oxygen as the circumstances dictate.

Similarly, motor activity and increased electrical and seizure-like activity in the EEG may be indicative of excessive levels of anesthesia. In the event that this occurs, it is recommended that the level of anesthesia be lowered. If motor activity does not cease, the administration of enflurane should be discontinued.

Dosage And Administration: The concentration of enflurane being delivered during anesthesia from a vaporizer should be known. This may be accomplished by using: (a) vaporizers calibrated specifically for enflurane; (b) vaporizers from which delivered flows can easily and readily be calculated.

Nothing is present in the agent to alter calibration or affect the operation characteristics of the vaporizer.

Preanesthetic Medication: Preanesthetic medication should be selected according to the needs of the individual patient, taking into account that secretions are weakly stimulated by enflurane and the heart rate remains constant. 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 CO2 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.

Enflurane, 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 sodalime 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 enflurane.

Administration Equipment: Enflurane may be administered from a flow-through type vaporizer manufactured and specifically calibrated for enflurane. Vaporizers which deliver saturated vapor at reasonable flows but are not specifically calibrated for enflurane may be used.

The actual concentration can also be calculaled by the following formula (1) where:

(1) Fv % Conc ( V V ) = ( Pv 760-Pv FT ) Legend: Pv=Vapor pressure of agent. Fv=Flow through vaporizer. FT=Total flow.

For all practical purposes, Diluent Flow and Total Flow can be considered the same. However, if Diluent Flow is accurately desired, it can be calculated by formula (2).

(2) FD=FT- ( 760 760-PV ) FV where FD=Diluent flow. Fv=Flow through vaporizer. Pv=Vapor pressure of agent. FT=Total flow.

Enflurane contains no stabilizer. Nothing is present in the agent to alter calibration or affect the operation characteristics of the vaporizer.

Keyed Bottle Collar (for use with key-fil vaporizer): Directions for Use: To attach a keyed bottle adaptor, remove cap and seal from anesthetic bottle. Check that the anesthetic bottle neck is not chipped or damaged. Match keyed bottle adaptor to keyed bottle collar and screw together until tight. Now connect the bottle to the vaporizer filler receptable.

Note that color of keyed bottle collar will match the color of the adpator.

(Refer to package insert for calculation of delivered enflurane concentration.)

Availability And Storage: Amber-colored bottles of 250 mL. No additives or stabilizers are present.