Isoflurane Inhalation: Indications, Dosage, Precautions, Adverse Effects
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Isoflurane Inhalation - Product Information

Manufacture: Fresenius Kabi USA, LLC
Country: Canada
Condition: Anesthesia
Class: Analgesics
Form: Liquid solution, Inhaler
Ingredients: Isoflurane

Summary Product Information

Route of Administration Dosage Form / Strength Clinically Relevant Nonmedicinal Ingredients
Inhalation Liquid / 99.9% None

Indications and Clinical Use

Isoflurane is indicated for:

  • induction and maintenance of general anesthesia.

Geriatrics (> 65 years of age)

The minimum alveolar concentration (MAC) of Isoflurane decreases with increasing patient age. The dose should be adjusted accordingly. See table in DOSAGE AND ADMINISTRATION.

Pediatrics (0 - 16 years of age)

With the exception of neonates, Isoflurane MAC decreases with increasing age. See table in DOSAGE AND ADMINISTRATION.

Contraindications

Isoflurane is contraindicated in patients:

  • with known hypersensitivity to Isoflurane or to other halogenated inhalational anesthetics.
  • with a history of hepatitis due to a halogenated inhalational anesthetic or in whom liver dysfunction, jaundice or unexplained fever, leucocytosis, or eosinophilia has occurred after a previous halogenated anesthetic administration (see WARNINGS AND PRECAUTIONS).
  • with known or suspected genetic susceptibility to malignant hyperthermia, or with a history of malignant hyperthermia (see WARNINGS AND PRECAUTIONS).
  • in whom general anesthesia is contraindicated.

Warnings and Precautions

Serious Warnings and Precautions

  • Isoflurane should be administered only by persons trained in the administration of general anesthesia.
  • Facilities for maintenance of a patent airway, artificial ventilation, oxygen enrichment, and circulatory resuscitation must be immediately available.
  • Isoflurane may trigger Malignant Hyperthermia in susceptible individuals and fatal outcomes have been reported (see Malignant Hyperthermia section below).
  • Isoflurane use may lead to Perioperative Hyperkalemia in patients with neuromuscular disorders (see Hyperkalemia section below).

General

Deliver Isoflurane from a vaporizer specifically designed and designated for use with Isoflurane. Monitoring of end-tidal concentration may be considered.

The safety of repeated anesthesia with Isoflurane has not been studied. As with all halogenated anesthetics, repeated anesthesia within a short period of time should be approached with caution.

Patients should be advised that performance of activities requiring mental alertness and motor coordination, such as driving a vehicle or operating machinery, may be impaired for at least 24 hours following administration of general anesthesia.

The following reactions have been reported following occupational exposure to isoflurane: dyspnea, bronchospasm, stridor, cough, dizziness, paresthesia, hepatic reactions, flushing, rash, contact dermatitis, erythema, periorbital edema, eye irritation, conjunctival hyperemia, and headache. See ADVERSE REACTIONS, Post-Market Adverse Drug Reactions.

Cardiovascular

Isoflurane can increase cerebral blood flow and hence intracranial pressure (ICP), and therefore should be used with special care in patients with pre-existing increases in intracranial pressure. In patients with or at risk for elevations of ICP, Isoflurane should be administered cautiously and in conjunction with ICP-reducing measures (e.g., optimized hyperventilation).

Isoflurane causes a dose-dependent reduction in systemic vascular resistance and blood pressure. Particular care must be taken when selecting the dosage for patients who are hypovolemic, hypotensive, or otherwise hemodynamically compromised, for example, due to concomitant medications. Excessive decreases in blood pressure may be related to depth of anesthesia and respond to reducing the inspired concentration of Isoflurane.

In patients with coronary artery disease, maintenance of normal hemodynamics is important in order to avoid myocardial ischemia. Isoflurane can cause dose dependent coronary vasodilation and has been shown to divert blood from collateral-dependent myocardium to normally perfused areas in an animal model (“coronary steal”). The extent to which coronary steal occurs in patients with steal-prone coronary anatomy is unclear. Isoflurane should be used with caution in such patients.

Caution should be exercised when administering Isoflurane to susceptible patients. Isoflurane can prolong the QT interval in adults and children. This effect is exacerbated by some of the patient’s disease conditions or concomitant peri -operative medications. Isolated post-market cases of cardiac arrhythmia associated with the QT prolongation have been reported. There are very rare reports of torsade de pointes.

Endocrine and Metabolism

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 features such as high core body temperature, muscle rigidity, tachycardia, tachypnea, cyanosis, arrhythmias, and unstable blood pressure. 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 decrease the patient’s body temperature to normal, respiratory and circulatory support as indicated, and management of electrolyte-fluid-acid-base derangements. Renal failure may appear later, and urine flow should be sustained if possible. A number of fatal outcomes from malignant hyperthermia have been reported with isoflurane. See CONTRAINDICATIONS.

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 intraoperatively and postoperatively. 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.

Hematologic

Intraoperative elevation of blood glucose and white blood count may occur. The effect of general anesthetics on blood glucose should be taken into consideration in the management of diabetic patients.

Hepatic/Biliary/Pancreatic

Isoflurane is contraindicated in patients with a history of hepatitis due to a halogenated inhalational anesthetic or in whom liver dysfunction, jaundice or unexplained fever, leucocytosis, or eosinophilia has occurred after a previous halogenated anesthetic administration.

Cases of mild, moderate, and severe postoperative hepatic dysfunction or hepatitis with or without jaundice, including fatal hepatic necrosis and hepatic failure, have been reported with Isoflurane. As with other halogenated anesthetics, Isoflurane may cause sensitivity hepatitis in patients who have been sensitized by previous exposure to a halogenated anesthetic. Such reactions may also occur after the first exposure to Isoflurane.

Although the mechanism by which this occurs is still unclear, data from studies on halothane suggests that metabolism by cytochrome P450 2E1 (CYP2E1) catalyzes formation of trifluoroacetylated haptens, which may be implicated as target antigens in the mechanism of halothane-induced hepatitis. Although other halogenated anesthetics are believed to be metabolized to a much lesser degree by the CYP2E1 system (20% by halothane compared to 0.2% isoflurane), the reported hepatic injuries share similarities with that associated with halothane.

In patients with pre-existing hepatic abnormalities or under treatment with drugs known to cause hepatic abnormalities, clinical judgment should be exercised and appropriate alternative general anesthesia should be considered. Specialized care is recommended when a patient presents with any postoperative hepatic dysfunction after receiving a halogenated inhalational anesthetic.

Psychiatric

Isoflurane may cause a decrease in intellectual function as well as changes in mood for several days after general anesthesia.

Respiratory

Isoflurane inhibits spontaneous respiration, which is enhanced with concurrent use of other inhalational and intravenous anesthetics. Respiration must be closely monitored and supported by assisted or controlled ventilation when necessary. Excessive respiratory depression may be related to depth of anesthesia and responds to decreasing the inspired concentration of Isoflurane.

Sensitivity/Resistance

Allergic-type hypersensitivity reactions, including anaphylaxis, have been reported with Isoflurane. Manifestations of such reactions have included hypotension, rash, difficulty breathing and cardiovascular collapse. Symptomatic management, as appropriate, is recommended as per standard of care.

Sexual Function/Reproduction

Isoflurane exerts a relaxant effect on uterine smooth muscle. Blood loss during intrauterine procedures is increased when halogenated agents such as Isoflurane are used for anesthesia.

Special Populations

Pregnant Women

The safety of Isoflurane anesthesia to mother and fetus has not been studied. Isoflurane should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and fetus.

Women in Labour and Delivery

Safety and efficacy of Isoflurane administration during labour and vaginal delivery have not been adequately studied. Isoflurane should not be used unless the potential benefit justifies the potential risk.

Cesarean Section

The use of Isoflurane as part of general anesthesia for elective cesarean section has been described in the literature. Isoflurane should be used only if the potential benefit justifies the potential risk.

Isoflurane exerts a relaxant effect on uterine smooth muscle. This can lead to increased blood loss in situations where uterine muscle contraction aids hemostasis, such as in obstetric surgery and in patients undergoing intrauterine procedures.

Nursing Women

Because there is insufficient information regarding the excretion of Isoflurane in human milk, the potential risks and benefits for each specific patient should be carefully considered before Isoflurane is administered to nursing women.

Pediatrics (0 - 16 years of age)

With the exception of neonates, Isoflurane MAC decreases with increasing age. See table in DOSAGE AND ADMINISTRATION.

Geriatrics (> 65 years of age)

With adults, Isoflurane MAC decreases with increasing age. See table in DOSAGE AND ADMINISTRATION.

Monitoring and Laboratory Tests

All patients anesthetized with Isoflurane should be continuously monitored (e.g., monitoring of the electrocardiogram, blood pressure, oxygen saturation, and end tidal CO2). Respiration must be monitored closely and supported when necessary.

Bromsulfalein (BSP) retention is mildly elevated postoperatively in some cases.

Adverse Reactions

Adverse Drug Reaction Overview

Adverse event information is derived from controlled clinical studies of adult and pediatric patients exposed to Isoflurane. The studies were conducted using a variety of premedications, other anesthetics, and surgical procedures of varying length. In these controlled studies, Isoflurane was used in a total of 2830 cases: 2643 adults and 187 children 19 years of age or younger. The estimated frequencies for adverse events were based on various pooled data sets. Due to the differences in the sizes of the available pooled data sets, the denominators presented in the clinical trial adverse events table vary.

The most serious reported treatment-emergent adverse events in alphabetical order are apnea, atrioventricular block, bradycardia, bronchospasm, cardiac arrest, hepatic failure, hypercapnia, hyperkalemia, hypotension, hypoxia, malignant hyperthermia, respiratory depression, and ventricular arrhythmias including fibrillation.

The most frequent treatment-emergent adverse events (incidence > 10%) are white blood cell count increased, agitation, breath holding, cough, nausea, and chills/shivering.

All of the treatment-emergent adverse events listed in the table below may result in the need for clinical investigation and treatment.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

The following treatment-emergent adverse events were identified from controlled clinical studies of adult and pediatric subjects exposed to Isoflurane. The studies were conducted using a variety of premedications, other anesthetics, and surgical procedures of varying lengths.

System Organ Class (SOC) Adverse Reaction Frequency (%)
BLOOD AND LYMPHATIC
SYSTEM DISORDERS
White blood cell count
increased
> 10%
CARDIAC DISORDERS Ventricular arrhythmia
(intraoperative)
Induction
2% (45/2161)
Maintenance
3% (60/2253)
Nodal arrhythmia
(intraoperative)
Induction
4% (87/2161)
Maintenance
2% (38/2253)
Atrial arrhythmia
(intraoperative)
Induction
2% (35/2161)
Maintenance
2% (50/2253)
Arrhythmia
(postoperative)
1% (32/2830)
GASTROINTESTINAL
DISORDERS
Nausea (Recovery) 15% (436/2830)
Vomiting (Recovery) 10% (269/2830)
GENERAL DISORDERS AND
ADMINISTRATION SITE
CONDITIONS
Chills/shivering 14% (237/1691)
NERVOUS SYSTEM
DISORDERS
Agitation
(Excitement)
Induction
52% (267/515)
Data Not Available
Movement Data Not Available Maintenance
2% (52/2830)
PSYCHIATRIC DISORDERS Delirium 6% (176/2830)
RESPIRATORY, THORACIC,
AND MEDIASTINAL
DISORDERS
Breath holding Induction
24% (123/515)
Maintenance
1% (4/359)
Cough Induction
28% (145/515)
Maintenance
4% (15/359)
Laryngospasm Induction
8% (41/515)
Refer to Less
Common Clinical
Trial Adverse Drug
Reactions (< 1%)

Overall frequency of “White blood cell count increased” observed during clinical studies was very common. Increases in white blood cell count were reported to rise for all patients in the first 1 to 2 days and 3 to 5 days postoperatively.

The frequencies cannot be calculated from the database for the adverse events listed below.

GASTROINTESTINAL DISORDERS: Postoperative ileus

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS: Asthenia, fatigue

HEPATOBILIARY DISORDERS: Blood bilirubin increased, bromosulphthalein clearance decreased, alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, blood lactate dehydrogenase increased

METABOLISM AND NUTRITION DISORDERS: Blood glucose increased

MUSCULOSKELETAL, CONNECTIVE TISSUE AND BONE DISORDERS: Myalgia

NERVOUS SYSTEM DISORDERS: Ataxia, dizziness, drowsiness, intellectual function decreased

PSYCHIATRIC DISORDERS: Confusional state, nervousness

VASCULAR DISORDERS: Hypotension (intraoperative), hypertension (intraoperative)

Less Common Clinical Trial Adverse Drug Reactions (<1%)

GASTROINTESTINAL DISORDERS: Vomiting (induction), retching (induction and maintenance)

NERVOUS SYSTEM DISORDERS: Convulsive pattern on electroencephalogram, seizure

PSYCHIATRIC DISORDERS: Mood changes, nightmare

RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS: Laryngospasm (maintenance), secretions (induction)

SKIN AND SUBCUTANEOUS TISSUE DISORDERS: Diaphoresis (induction)

VASCULAR DISORDERS: Hypotension (postoperative), hypertension (postoperative)

Post-Market Adverse Drug Reactions

The following adverse events have been reported in the post-marketing experience, listed by MedDRA System Organ Class (SOC), then by Preferred Term in order of severity.

Perioperative use

BLOOD AND LYMPHATIC SYSTEM DISORDERS: Carboxyhemoglobin increased

CARDIAC DISORDERS: Cardiac arrest, ventricular fibrillation, torsade de pointes, myocardial infarction, myocardial ischemia, atrioventricular block complete, atrioventricular block second degree, atrial fibrillation, electrocardiogram QT prolonged, atrioventricular block first degree, ventricular tachycardia, ventricular extrasystoles, tachycardia, bradycardia, cardiac output decreased

GASTROINTESTINAL DISORDERS: Pancreatitis

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS: Malignant hyperthermia, hypothermia

HEPATOBILIARY DISORDERS: Hepatic failure, hepatic necrosis, hepatitis fulminant, cholestatic hepatitis, hepatitis, hepatic steatosis, jaundice, gamma-glutamyltransferase increased

IMMUNE SYSTEM DISORDERS: Anaphylactic reaction

INJURY, POISONING, AND PROCEDURAL COMPLICATIONS: Unwanted awareness during anesthesia

METABOLISM AND NUTRITION DISORDERS: Hyperkalemia

MUSCULOSKELETAL, CONNECTIVE TISSUE AND BONE DISORDERS: Rhabdomyolysis

NERVOUS SYSTEM DISORDERS: Brain edema, intracranial pressure increased, migraine, myoclonus, nystagmus, pupils unequal, headache

PSYCHIATRIC DISORDERS: Withdrawal syndrome (following multi-day exposure; symptoms include seizure, hallucination, ataxia, agitation, confusion)

RENAL AND URINARY DISORDERS: Acute renal failure, oliguria

RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS: Apnea, hypoxia, bronchospasm, airway obstruction, respiratory depression, hypercapnia, stridor, hiccups

SKIN AND SUBCUTANEOUS TISSUE DISORDERS: Rash

VASCULAR DISORDERS: Flushing

Occupational Exposure

INJURY, POISONING, AND PROCEDURAL COMPLICATIONS: Dyspnea, bronchospasm, stridor, cough, dizziness, paresthesia, hepatic reactions, flushing, rash, contact dermatitis, erythema, periorbital edema, eye irritation, conjunctival hyperemia, headache

Drug Interactions

Serious Drug Interactions

  • In Patients with latent as well as overt muscular dystrophies, particularly Duchenne Muscular Dystrophy, concomitant use with succinylcholine is associated with hyperkalemia and cardiac arrhythmias (see WARNINGS AND PRECAUTIONS).

Overview

The minimum alveolar concentration (MAC) for Isoflurane is reduced by concomitant inhalational anesthetics, such as N2O, and intravenous anesthetics, such as opioids and benzodiazepines. Commonly used muscle relaxants are potentiated by Isoflurane.

Drug-Drug Interactions

The minimum alveolar concentration (MAC) for isoflurane is reduced by concomitant administration of intravenous anesthetics, such as opioids and benzodiazepines.

N2O also decreases the MAC of isoflurane (see DOSAGE AND ADMINISTRATION).

Opioids such as fentanyl and its analogues, when combined with isoflurane, may lead to a synergistic fall in blood pressure and respiratory rate.

Isoflurane decreases the required doses of neuromuscular blocking agents. Isoflurane potentiates all commonly used muscle relaxants, the effect being most profound with the nondepolarizing type. Therefore, less than the usual amounts of such agents should be used. In general, anesthetic concentrations of isoflurane at equilibrium reduce the ED95 of succinylcholine, atracurium, pancuronium, rocuronium and vecuronium by approximately 25 to 40% or more compared to N2O/opioid anesthesia. Neostigmine reverses the effects of nondepolarizing muscle relaxants, but does not reverse the direct neuromuscular depression of isoflurane.

Isoflurane is similar to sevoflurane in the sensitization of the myocardium to the arrhythmogenic effect of exogenously administered adrenaline. The threshold dose at which submucosally administered adrenaline produces multiple ventricular arrhythmias has been established at 5 µg/kg body weight.

Isoflurane may lead to marked hypotension in patients treated with calcium antagonists.

Concomitant use of beta blockers may exaggerate the cardiovascular effects of inhalational anesthetics, including hypotension and negative inotropic effects.

Concomitant use of Monoamine Oxidase (MAO) inhibitors and inhalational anesthetics may increase the risk of hemodynamic instability during surgery or medical procedures.

CYP2E1 is the predominant CYP isoform responsible for isoflurane metabolism in vivo. Therapeutic products and other agents that increase the activity of cytochrome P450 isoenzyme CYP2E1, such as isoniazid and alcohol, may increase the metabolism of isoflurane and lead to significant increases in plasma fluoride concentrations. Moreover, CYP2E1 metabolic pathways may be involved in the rare hepatotoxic effects observed with halogenated anesthetics, therefore, a concomitant use of CYP2E1 inducers may potentiate this risk in susceptible patients. In contrast, disulfiram, a selective inhibitor of CYP2E1, prevents 80 90% of isoflurane metabolism.

Indirect-acting sympathomimetics (amphetamines and their derivatives, psychostimulants, appetite suppressants, ephedrine and its derivatives) increase the risk of perioperative hypertension. In patients undergoing elective surgery, treatment should ideally be discontinued several days before surgery.

Severe hypotension and delayed emergence from anesthesia with halogenated inhalational anesthetics have been reported in patients treated long-term with St John’s Wort.

Dosage and Administration

Dosing Considerations

Preanesthetic Medication

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

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 use of a hypnotic dose of an intravenous induction agent (e.g., propofol) or a short-acting barbiturate, preceding the Isoflurane mixture.

It should be considered that the risk of coughing, breath holding, laryngospasm, and bronchospasm during induction increases with the concentration of Isoflurane.

Recommended Dose and Dosage Adjustment

Dosage for induction and maintenance must be individualized and titrated to the desired effect according to the patient’s age, clinical status, and surgical requirements.

Induction

Inspired concentrations of 1.5 to 3.0% Isoflurane with a background of 50 to 70% nitrous oxide usually produce surgical anesthesia in 7 to 10 minutes. If nitrous oxide is not used, an additional 1.0 to 1.5% Isoflurane may be required for induction of anesthesia.

Maintenance

Surgical levels of anesthesia may be sustained with a 1.0 to 2.5% concentration when 50 to 70% nitrous oxide is used concomitantly. An additional 0.5 to 1.0% may be required when Isoflurane is given in oxygen alone. Additional relaxation may be produced with supplemental doses of muscle relaxants.

In the absence of other complicating problems, blood pressure during maintenance varies inversely with Isoflurane concentration. Hypotension may be related to depth of anesthesia and may respond to decreasing the inspired concentration of Isoflurane, if appropriate. Adequate depth of anesthesia should be maintained with Isoflurane and alternative anesthetics, as appropriate, to reduce the risk of unwanted awareness during surgery.

With the exception of neonates, minimum alveolar concentration (MAC) of Isoflurane decreases with increasing patient age.

Isoflurane MAC values according to age are shown below:

Age Average MAC Value In 100% Oxygen Average MAC Value In 30% Oxygen and 70% N2O
0 - 1 month 1.60 % -
1 - 6 months 1.87 % -
6 - 12 months 1.80 % -
1 - 5 years 1.60 % -
19 - 30 years 1.28 % 0.56 %
32 - 55 years 1.15 % 0.50 %
55 - 83 years 1.05 % 0.37 %

Administration

Isoflurane is administered by inhalation through a vaporizer specifically designed and designated for use with Isoflurane.

Maintenance

Isoflurane, 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. Barium hydroxide lime and sodalime become desiccated when fresh gases are passed through the CO2 absorber canister at high flow rates over many hours. The clinician must ensure the CO2 absorbent in use is adequately hydrated before using Isoflurane. 

The colour indicator of most CO2 absorbents does not necessarily change as a result of desiccation. Therefore, the lack of significant colour change should not be taken as an assurance of adequate hydration. CO 2 absorbents should be replaced routinely regardless of the state of the colour indicator, following current guidelines for use of anesthesiology equipment.

Administration Equipment

Isoflurane should be delivered from a vaporizer specifically designed and designated for use with Isoflurane. The delivered concentration of Isoflurane should be known. Isoflurane may be vaporized from a flow-through vaporizer specifically calibrated for Isoflurane.

Isoflurane contains no stabilizer and vaporization of Isoflurane does not leave a residual material which might alter the calibration or operation of a vaporizer.

Keyed Bottle Collar (for use with Key-fill 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 receptacle.

Note that colour of keyed bottle collar will match the colour of the adaptor.

Overdosage

Overdosage with Isoflurane produces marked hypotension and may cause apnea. In the event of overdosage, or what appears to be overdosage, the following actions should be taken, as appropriate:

  1. Discontinue administration of Isoflurane.
  2. Establish a patent airway and initiate assisted or controlled ventilation with oxygen supplementation as needed.
  3. Maintain cardiovascular parameters within acceptable physiologic range.
For management of a suspected drug overdose, contact your regional Poison Control Centre.

Action and Clinical Pharmacology

Mechanism of Action

Isoflurane is an inhalation anesthetic whose low solubility (blood/gas partition coefficient equals 1.4), permits a rapid induction of and recovery from anesthesia. The mild pungency of isoflurane may limit the rate of induction, although excessive salivation or tracheobronchial secretions do not appear to be stimulated. The level of anesthesia may be changed rapidly with isoflurane. Pharyngeal and laryngeal reflexes are readily and easily obtunded. Isoflurane is a profound respiratory depressant. An increase in anesthetic dose will decrease tidal volume without changing respiratory rate. This depression is partially reversed by surgical stimulation, even at deeper levels of anesthesia. Isoflurane evokes a sigh response reminiscent of that seen with diethyl ether and enflurane.

Typically, blood pressure decreases with induction of anesthesia but may return toward normal with surgical stimulation. Progressive increases in depth of anesthesia correspondingly decrease blood pressure. Nitrous oxide diminishes the inspired concentration of isoflurane required to reach a desired level of anesthesia and has a favorable effect on the parameters of the anesthetic process. With controlled ventilation and normal PaCO2, cardiac output is maintained despite increasing depth of anesthesia primarily through an increase in heart rate which compensates for a reduction in stroke volume. The hypercapnia which attends spontaneous ventilation during isoflurane anesthesia further increases heart rate and raises cardiac output above awake levels.

The cardiac rhythm during isoflurane anesthesia is stable. In dog studies, isoflurane has not been found to sensitize the myocardium to exogenously administered epinephrine. Limited data indicate that subcutaneous injection of 0.25 mg of epinephrine (50 mL of 1:200,000 solution) does not cause ventricular arrhythmias in patients anesthetized with isoflurane. Doubling this dose will produce ventricular extrasystoles in about half of patients anesthetized with 1.25 MAC isoflurane.

Muscle relaxation usually is adequate for intra-abdominal operations at normal levels of anesthesia. All commonly used muscle relaxants are compatible with isoflurane. Complete paralysis can be attained with small doses of muscle relaxants. Isoflurane potentiates all commonly used muscle relaxants, the effect being most profound with nondepolarizing relaxants. Neostigmine reverses the effect of nondepolarizing muscle relaxants in the presence of isoflurane but does not reverse the direct neuromuscular depression of isoflurane.

Pharmacokinetics

Metabolism

CYP2E1 is the predominant CYP isoform responsible for isoflurane metabolism invivo.

The metabolism of isoflurane is low in miniature swine, black C-57 mice, and Fischer 344 rats. Less than half of one percent of the isoflurane taken up in humans can be recovered as metabolites.

In Fischer 344 rats, the peaks of inorganic fluoride ion occurred during the second 24 hours postanesthesia; all values had returned to baseline 2 to 3 days later (organic fluoride to inorganic fluoride ratio 0.53:1). Pre-treatment with phenobarbital did not change the fluoride values. Also in mice and rats, little or no skeletal deposition of fluoride ions did occur, suggesting low or no metabolism for isoflurane.

In miniature swine treated with subanesthetic doses, values indicated little or no metabolism of isoflurane.

In vitro studies confirmed the findings using livers from both untreated and phenobarbital pretreated mice and rats. When the liver homogenates were exposed to isoflurane, inorganic fluoride production was very low.

In three human volunteers given 0.9% (0.8 MAC) of isoflurane for an average of 2.8 hours, it was also found that the metabolism of isoflurane was low. The peaks occurred during the first postanesthetic day; by the third day all values had returned to preanesthetic levels. Tonic fluoride levels in urine rose from around 100 μM/day preanesthesia to a peak of around 400 μM and had returned to baseline levels on the fourth postanesthetic day.

Storage and Stability

Store between 15 °C and 30 °C.

Dosage Forms, Composition and Packaging

Isoflurane, USP (Isoflurane, 99.9%) is packaged in 100 and 250 mL amber-coloured bottles.