isoflurane (Rx)

1-10%

Nausea

Vomiting

Shivering

<1%

Dose-dependent hypotension

Arrhythmias

Malignant hyperthermia (rare)

Elevations in white blood count

May decrease creatinine and increase BUN

Ileus, severe (fatal)

Hepatic dysfunction (postoperative period) (rare)

Respiratory depression may occur (rare)

Contraindications

Hypersensitivity to isoflurane & halogenated agents

Genetic susceptibility to malignant hyperthermia

Patients in whom general anesthesia contraindicated

History of confirmed hepatitis due to a halogenated inhalational anesthetic or a history of unexplained moderate to severe hepatic dysfunction (eg, jaundice associated with fever and/or eosinophilia) after anesthesia with isoflurane or other halogenated inhalational anesthetics

Cautions

Caution in coronary heart disease

May decrease renal and hepatic blood flow

Postoperative hepatic dysfunction and hepatitis reported

Adequate data have not been developed to establish its application in obstetrical anesthesia

Should not be used as a sole agent of induction in patients with ventricular dysfunction

Therapy 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

All patients receiving the drug should be continually monitored (eg, monitoring of the electrocardiogram, blood pressure, oxygen saturation, and end tidal CO2)

The drug is a profound respiratory depressant; excessive respiratory depression may be related to depth of anesthesia and respond to decreasing the inspired concentration of isoflurane

The depressant effect is accentuated by concurrent use of opioids and other respiratory depressants; respiration should be closely monitored and assisted or controlled ventilation employed when necessary

With the exception of neonates, isoflurane MAC decreases with increasing age

QTc prolongation, with rare instances of torsade de pointes, reported; monitor QT interval when administering the drug to susceptible patients

Regardless of the anesthetics employed, maintenance of normal hemodynamics is important to the avoidance of myocardial ischemia in patients with coronary artery disease

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”); monitor for signs of inadequate myocardial perfusion via hemodynamic monitors (eg, ECG, blood pressure) during administration; consider additional cardiac monitoring in patients with known coronary artery disease, as clinically necessary

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, eg, due to concomitant medications

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

Allergic-type hypersensitivity reactions, including anaphylaxis, reported with therapy; manifestations of such reactions have included hypotension, rash, difficulty breathing and cardiovascular collapse

The drug markedly increases cerebral blood flow at deeper levels of anesthesia to produce a transient increase in intracranial pressure; in patients with or at risk for elevations of intracranial pressure (ICP), administer isoflurane in conjunction with ICP- reducing strategies, as clinically appropriate

The color indicator of most CO2 absorbents does not necessarily change as a result of desiccation; therefore, the lack of significant color change should not be taken as assurance of adequate hydration of the CO2 absorbent material; CO2 absorbents should be replaced routinely regardless of the state of color indicator following current manufacturer’s guidelines for use of anesthesiology equipment

Reactions reported following occupational exposure to the drug include dyspnea, bronchospasm, stridor, cough, dizziness, paresthesia, hepatic reactions, flushing rash, contact dermatitis, erythema, periorbital edema, eye irritation, conjunctival hyperemia, and headache

Hepatic reactions

• Cases of mild, moderate and severe postoperative hepatic dysfunction or hepatitis with or without jaundice, including fatal hepatic necrosis and hepatic failure, reported
• Such reactions can represent hypersensitivity hepatitis, a known risk of exposure to halogenated anesthetics, including isoflurane
• As with other halogenated anesthetic agents, the drug may cause sensitivity hepatitis in patients sensitized by previous exposure to halogenated anesthetics
• Clinical judgment should be exercised when isoflurane the drug is used in patients with underlying hepatic conditions or under treatment with drugs known to cause hepatic dysfunction
• As with all halogenated anesthetics, repeated anesthetics within a short period of time may result in increased effects, particularly in patients with underlying hepatic conditions, or additive effects in patients treated with drugs known to cause hepatic dysfunction
• Evaluate the need for repeated exposure in each individual patient and adjust the dose of isoflurane based on signs and symptoms of adequate depth of anesthesia if repeated exposure in a short period of time is clinically indicated

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; fatal outcomes of malignant hyperthermia have been reported
• Risk of developing malignant hyperthermia increases with concomitant administration of succinylcholine and volatile anesthetic agents; therapy can induce malignant hyperthermia in patients with known or suspected susceptibility based on genetic factors or family history, including those with certain inherited ryanodine receptor (RYR1) or dihydropyridine receptor (CACNA1S) variants
• Signs consistent with malignant hyperthermia may include hyperthermia, hypoxia, hypercapnia, muscle rigidity (eg, jaw muscle spasm), tachycardia (eg, particularly that unresponsive to deepening anesthesia or analgesic medication administration), tachypnea, cyanosis, arrhythmias, hypovolemia, and hemodynamic instability; skin mottling, coagulopathies, and renal failure may occur later in the course of the hypermetabolic process
• 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 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 (eg, isoflurane), administration of intravenous dantrolene sodium, and application of supportive therapy
• Successful treatment of malignant hyperthermia depends on early recognition of clinical signs; if malignant hyperthermia suspected, discontinue all triggering agents (eg, volatile anesthetic agents and succinylcholine), administer intravenous dantrolene sodium, and initiate supportive therapies
• Consult prescribing information for intravenous dantrolene sodium for additional information on patient management
• Supportive therapies include administration of supplemental oxygen and respiratory support based on clinical need, maintenance of hemodynamic stability and adequate urinary output, management of fluid and electrolyte balance, correction of acid-base derangements, and institution of measures to control rising temperature
• Renal failure may appear later, and urine flow should be sustained if possible; fatal outcome of malignant hyperthermia has been reported with isoflurane

Pediatric use

• During the induction of anesthesia, saliva flow and tracheobronchial secretion can increase and can be the cause of larynogospasm, particularly in children

Perioperative Hyperkalemia

• Inhaled anesthetics associated with rare increases in serum potassium levels that have resulted in cardiac arrhythmias and death in pediatric patients 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
• Elevated serum creatinine kinase levels and, in some cases, changes in urine consistent with myoglobinuria observed
• Despite similar presentation to malignant hyperthermia, none of affected patients exhibited signs or symptoms of muscle rigidity or hypermetabolic state
• Early and aggressive intervention to treat hyperkalemia and resistant arrhythmias recommended
• Evaluation for latent neuromuscular disease recomended

General anesthetics and sedation drugs in young children and pregnant women

• Brain development

  • Prolonged or repeated exposure may result in negative effects on fetal or young children’s brain development
  • Caution with use during surgeries or procedures in children younger than 3 yr or in pregnant women during their third trimester
  • Assess the risk:benefit ratio in these populations, especially for prolonged procedures (ie, >3 hr) or multiple procedures

Pregnancy

There are no adequate and well-controlled studies in pregnant women; in animal reproduction studies, embryofetal toxicity was noted in pregnant mice exposed to 0.075% (increased post implantation losses) and 0.3% isoflurane (increased post implantation losses and decreased live- birth index) during organogenesis

Lactation

Due to 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

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Volatile liquid inhalation anesthetic

Pharmacokinetics

Onset: Rapid (7-10 min)

Duration: Short (depends on blood concentration)

Minimum Alveolar Conc: 1.3%

Metabolism: Liver (0.2%)

Pharmacogenomics

Increased incidence of malignant hyperthermia with use of volatile anesthetics or depolarizing neuromuscular blockers in patients with gene mutations in ryanodine receptor (RYR1) or calcium channel alpha (1S)- subunit gene (CACNA1S)