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ISOFLURANE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Isoflurane is a clear, colorless, nonflammable liquid, used as a general inhalation anesthetic.

Specific Substances

    1) 2-CHLORO-2-(DIFLUOROMETHOXY)-1,1,1-TRIFLUOROETHANE
    2) ETHANE, 2-CHLORO-2-(DIFLUOROMETHOXY)-1,1,1-TRIFLUORO-
    3) FORANE
    4) ISF
    5) Pentaflouran
    6) R-E 235dal
    7) ISOFLURANE
    8) CAS 26675-46-7

Available Forms Sources

    A) FORMS
    1) Isoflurane is available in 100 mL and 250 mL bottles (Prod Info FORANE(R) inhalation liquid, 2010).
    B) USES
    1) Isoflurane is approved for induction and maintenance of general anesthesia (Prod Info FORANE(R) inhalation liquid, 2010).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: At normal anesthetic doses isoflurane has been associated with hypotension, dysrhythmias, seizures, nephrotoxicity, hepatotoxicity, malignant hyperthermia, and respiratory depression.
    B) WITH POISONING/EXPOSURE
    1) OVERDOSE: Isoflurane overdose may result in hypotension, coma, respiratory depression, apnea and seizures.
    0.2.4) HEENT
    A) WITH THERAPEUTIC USE
    1) Blurred or double vision may be a temporary effect of isoflurane anesthesia. Isoflurane lowers intraocular pressure.
    0.2.5) CARDIOVASCULAR
    A) WITH THERAPEUTIC USE
    1) Hypotension and dysrhythmias have been reported with the use of isoflurane. Isoflurane decreases total peripheral resistance and systemic arterial blood pressure in a dose-related fashion.
    0.2.6) RESPIRATORY
    A) WITH THERAPEUTIC USE
    1) Isoflurane causes respiratory depression, coughing, and laryngospasm in a dose-related fashion.
    0.2.7) NEUROLOGIC
    A) WITH THERAPEUTIC USE
    1) Isoflurane causes an increase in intracranial pressure during normocapnic ventilation. Isoflurane in combination with nitrous oxide for induction of anesthesia has been rarely associated with seizures.
    2) Isoflurane commonly causes symptoms of CNS depression including narcosis, drowsiness, dizziness, incoordination, weakness, thinking inabilities, and disorientation.
    0.2.8) GASTROINTESTINAL
    A) WITH THERAPEUTIC USE
    1) Nausea, vomiting, and postoperative ileus have been reported.
    0.2.10) GENITOURINARY
    A) WITH THERAPEUTIC USE
    1) Depresses renal blood flow, glomerular filtration rate, and urine flow similar to other general anesthetics. Fluoride effects have not been seen.
    0.2.12) FLUID-ELECTROLYTE
    A) WITH THERAPEUTIC USE
    1) Hyperkalemia may occur with malignant hyperthermia.
    0.2.15) MUSCULOSKELETAL
    A) WITH THERAPEUTIC USE
    1) Rhabdomyolysis may develop in patients with malignant hyperthermia.
    0.2.18) PSYCHIATRIC
    A) WITH POISONING/EXPOSURE
    1) Overdoses have been associated with disorientation.
    0.2.20) REPRODUCTIVE
    A) Isoflurane is classified as FDA Pregnancy Category C by the manufacturer. Teratogenic and fetotoxic effects have been observed in animal studies at high doses. Isoflurane should only be used during pregnancy if the potential maternal benefit outweighs the fetal risk. Isoflurane should only be used during pregnancy if the potential maternal benefit outweighs the fetal risk.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, the manufacturer does not report any carcinogenic potential with isoflurane.

Laboratory Monitoring

    A) Serum fluoride concentrations should be monitored in overdose cases.
    B) Monitor vital signs in all patients. Follow temperature and monitor for signs of fever possibly leading to malignant hyperthermia.
    C) A number of chemicals produce abnormalities of the hematopoietic system, liver, and kidneys. Monitoring complete blood count, urinalysis, and liver and kidney function tests is suggested for patients with significant exposure.
    D) A number of chemicals produce abnormalities of the hematopoietic system, liver, and kidneys. Monitoring urinalysis is suggested for patients with significant exposure.
    E) Monitor ECG for cardiac dysrhythmias following overdose.
    F) Monitor for respiratory depression.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) Ingestion of this inhalational anesthetic is unlikely but has occurred. Emesis is contraindicated due to rapid onset CNS depression. Absorption is rapid, gastric decontamination is unlikely to be useful unless performed very soon after ingestion.
    B) ACTIVATED CHARCOAL - May be of use if administered early and the patient's airway is protected.
    1) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    C) MALIGNANT HYPERTHERMIA - Administer dantrolene sodium in an initial recommended dose of 1 mg/kg by rapid IV. If symptoms persist or reappear, the dose may be repeated, to a cumulative dose of 10 mg/kg.
    1) Reversal is usually achieved with a cumulative dose of 2.5 mg/kg.
    2) Oral doses of 1 to 2 mg/kg QID for 1 to 3 days may be necessary to prevent the recurrence of the manifestations of malignant hyperthermia.
    3) Reducing body temperature with external cooling measures may be indicated.
    D) REFRACTORY SEIZURES: Consider continuous infusion of midazolam, propofol, and/or pentobarbital. Hyperthermia, lactic acidosis and muscle destruction may necessitate use of neuromuscular blocking agents with continuous EEG monitoring.
    E) HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; CHILD: begin infusion at 0.1 mcg/kg/min); titrate to desired response.
    F) METABOLIC ACIDOSIS - Treat acidosis (less than pH 7.1) with IV sodium bicarbonate.
    0.4.3) INHALATION EXPOSURE
    A) Care is symptomatic and supportive; there is no specific antidote.
    B) Administer 100 percent humidified supplemental oxygen with assisted ventilation as required.
    C) MALIGNANT HYPERTHERMIA -
    1) ADULTS AND CHILDREN - Administer dantrolene sodium in an initial dose of 1 mg/kg by rapid IV infusion.
    a) If symptoms persist or reappear, the dose may be repeated, to a cumulative dose of 10 mg/kg.
    b) Reversal is usually achieved with a cumulative dose of 2.5 mg/kg.
    c) Oral doses of 1 to 2 mg/kg QID for 1 to 3 days may be necessary to prevent the recurrence of the manifestations of malignant hyperthermia.
    2) Reduce body temperature with cooling blankets or ice, monitor serum potassium and CK levels.
    D) SEIZURES: Administer a benzodiazepine; DIAZEPAM (ADULT: 5 to 10 mg IV initially; repeat every 5 to 20 minutes as needed. CHILD: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed) or LORAZEPAM (ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist. CHILD: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue).
    1) Consider phenobarbital or propofol if seizures recur after diazepam 30 mg (adults) or 10 mg (children greater than 5 years).
    2) Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, and hypoxia.
    E) VENTRICULAR DYSRHYTHMIAS/SUMMARY: Institute continuous cardiac monitoring, obtain an ECG, and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders. Lidocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Amiodarone should be used with caution if a substance that prolongs the QT interval and/or causes torsades de pointes is involved in the overdose. Unstable rhythms require immediate cardioversion.
    F) HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; CHILD: begin infusion at 0.1 mcg/kg/min); titrate to desired response.
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    2) Isoflurane can produce systemic poisoning by absorption through intact skin. Carefully observe patients with dermal exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    3) Treatment should include recommendations listed in the INHALATION EXPOSURE section when appropriate.

Range Of Toxicity

    A) Human volunteers given isoflurane at 1 to 2 minimum alveolar concentration (MAC) for 6 to 7.5 hours did not show post-anesthetic evidence of significant liver or renal impairment. Ingestion of approximately 80 mL of isoflurane was fatal in an adult.

Clinical Effects

Summary Of Exposure

    A) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS: At normal anesthetic doses isoflurane has been associated with hypotension, dysrhythmias, seizures, nephrotoxicity, hepatotoxicity, malignant hyperthermia, and respiratory depression.
    B) WITH POISONING/EXPOSURE
    1) OVERDOSE: Isoflurane overdose may result in hypotension, coma, respiratory depression, apnea and seizures.

Vital Signs

    3.3.2) RESPIRATIONS
    A) WITH THERAPEUTIC USE
    1) Anesthetic concentrations cause decreased tidal volume while respiratory rate may increase or remain normal (Homi et al, 1972; Fourcade et al, 1971). Tachypnea may occur with malignant hyperthermia from isoflurane anesthesia (Prod Info FORANE(R) inhalation liquid, 2010).
    B) WITH POISONING/EXPOSURE
    1) Acute overdose may cause apnea (Prod Info FORANE(R) inhalation liquid, 2010).
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) Malignant hyperthermia has been associated with isoflurane anesthesia (McGuire & Easy, 1990; Johannesson et al, 1987; Thomas et al, 1987; Chalkiadis & Branch, 1990; Joseph et al, 1982; Chambers et al, 1994; Simons & Goldman, 1988; Jensen et al, 1986; Ong & Rosenberg, 1989; Boheler et al, 1982). The diagnosis of malignant hyperthermia can be confirmed by muscle biopsy.
    2) Anesthetic concentrations are usually associated with mild hypothermia (Dobkin et al, 1971; Pauca & Dripps, 1973).
    3.3.4) BLOOD PRESSURE
    A) WITH THERAPEUTIC USE
    1) Progressive increases in depth of anesthesia correspondingly decrease blood pressure (Homi et al, 1972; Pauca & Dripps, 1973; Dobkin et al, 1971).
    3.3.5) PULSE
    A) WITH THERAPEUTIC USE
    1) The hypercapnia associated with spontaneous ventilation during isoflurane anesthesia increases heart rate (Stevens et al, 1971; Tanaka et al, 1994).

Heent

    3.4.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Blurred or double vision may be a temporary effect of isoflurane anesthesia. Isoflurane lowers intraocular pressure.
    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) Blurred or double vision may be a temporary effect of isoflurane anesthesia (Prod Info Forane(R), isoflurane, 1990).
    2) Isoflurane lowers intraocular pressure (Earnshaw, 1984).
    3) Miosis occurs at anesthetic concentrations (Dobkin et al, 1971; Homi et al, 1972).

Cardiovascular

    3.5.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Hypotension and dysrhythmias have been reported with the use of isoflurane. Isoflurane decreases total peripheral resistance and systemic arterial blood pressure in a dose-related fashion.
    3.5.2) CLINICAL EFFECTS
    A) CARDIAC ARREST
    1) WITH THERAPEUTIC USE
    a) Cardiac arrest has been reported in post-marketing use of isoflurane; however, the causal relationship to isoflurane is not clear (Prod Info FORANE(R) inhalation liquid, 2010)
    B) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Isoflurane decreases total peripheral resistance and systemic arterial pressure in a dose-related fashion. Progressive increases in depth of anesthesia correspondingly decrease blood pressure (Homi et al, 1972; Pauca & Dripps, 1973; Dobkin et al, 1971).
    C) CONDUCTION DISORDER OF THE HEART
    1) WITH THERAPEUTIC USE
    a) Cardiac rhythm during isoflurane anesthesia is stable and isoflurane does not sensitize the heart to the effect of exogenous epinephrine (Homi et al, 1972; Pauca & Dripps, 1973; Dobkin et al, 1971; Johnston et al, 1976; Raj et al, 1976). Tachycardia may be seen.
    D) TACHYARRHYTHMIA
    1) WITH THERAPEUTIC USE
    a) The hypercapnia associated with spontaneous ventilation during isoflurane anesthesia further increases heart rate and cardiac output above awake levels (Stevens et al, 1971).
    b) Significant tachycardia has been reported with isoflurane in some patients. The tachycardia is not suppressed with increasing isoflurane concentrations (Dale & Brown, 1987; Eger, 1984; Tanaka et al, 1994).
    E) CARDIOMYOPATHY
    1) WITH THERAPEUTIC USE
    a) Isoflurane decreases cardiac index, stroke volume index, and myocardial oxygen consumption in children and adults (Reiz et al, 1984; Murray et al, 1992)
    F) MYOCARDIAL ISCHEMIA
    1) WITH THERAPEUTIC USE
    a) Isoflurane has been implicated in causing myocardial ischemia, but this effect appears to be limited to patients with coronary artery disease (Gross, 1989; Sahlman et al, 1989; Diana et al, 1993).
    b) Other studies have failed to confirm this effect (Slogoff et al, 1991).
    c) CASE REPORT: A 44-year-old man developed intraoperative ST depression during anesthesia with isoflurane. Changes resolved when halothane was substituted and recurred when isoflurane was resumed (Gross, 1989).
    G) MYOCARDIAL INFARCTION
    1) WITH THERAPEUTIC USE
    a) In a study of 1178 patients undergoing elective coronary artery bypass grafting, patients receiving isoflurane anesthesia (n=570) had a higher incidence of postoperative myocardial infarction, greater need for inotropic agents at the time of weaning from bypass, and higher postoperative mortality in hospital than did those receiving enflurane (n=608) (Inoue et al, 1990).

Respiratory

    3.6.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Isoflurane causes respiratory depression, coughing, and laryngospasm in a dose-related fashion.
    3.6.2) CLINICAL EFFECTS
    A) ACUTE RESPIRATORY INSUFFICIENCY
    1) WITH THERAPEUTIC USE
    a) Isoflurane causes respiratory depression in a dose-related fashion, comparable to halothane. Lung compliance and functional residual capacity are slightly decreased during isoflurane anesthesia, while pulmonary resistance is increased (Fourcade et al, 1971; Rehder et al, 1974). Anesthetic concentrations cause decreased tidal volume while respiratory rate may increase or remain normal (Homi et al, 1972; Fourcade et al, 1971).
    B) APNEA
    1) WITH POISONING/EXPOSURE
    a) Acute overdose may cause apnea (Prod Info FORANE(R) inhalation liquid, 2010).
    C) COUGH
    1) WITH THERAPEUTIC USE
    a) Coughing may occur with isoflurane anesthesia (Prod Info FORANE(R) inhalation liquid, 2010).
    D) LARYNGEAL SPASM
    1) WITH THERAPEUTIC USE
    a) Laryngospasm may occur with isoflurane anesthesia (Prod Info FORANE(R) inhalation liquid, 2010)
    E) HYPERVENTILATION
    1) WITH THERAPEUTIC USE
    a) Tachypnea may occur with malignant hyperthermia from isoflurane anesthesia (Prod Info FORANE(R) inhalation liquid, 2010).
    F) UNEXPECTED THERAPEUTIC EFFECT
    1) WITH THERAPEUTIC USE
    a) Isoflurane produces bronchodilation and may be useful in the management of refractory status asthmaticus (Johnston et al, 1990; Bierman et al, 1986).

Neurologic

    3.7.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Isoflurane causes an increase in intracranial pressure during normocapnic ventilation. Isoflurane in combination with nitrous oxide for induction of anesthesia has been rarely associated with seizures.
    2) Isoflurane commonly causes symptoms of CNS depression including narcosis, drowsiness, dizziness, incoordination, weakness, thinking inabilities, and disorientation.
    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM DEFICIT
    1) WITH THERAPEUTIC USE
    a) Isoflurane commonly causes drowsiness, dizziness, incoordination, weakness, headaches, and disorientation (Prod Info Forane(R), isoflurane, 1990).
    b) Delirium and excitement may develop in the immediate postoperative period (Prithvi et al, 1976; Pauca & Dripps, 1973).
    2) WITH POISONING/EXPOSURE
    a) Isoflurane may cause dizziness, headache, and unconsciousness following acute overexposure (Prod Info FORANE(R) inhalation liquid, 2010).
    B) SEIZURE
    1) WITH THERAPEUTIC USE
    a) There are several reports of patients developing seizures during or immediately following isoflurane anesthesia (Harrison, 1986; Hymes, 1985; Poulton & Ellingson, 1984).
    b) Postoperative status epilepticus has been reported in patients receiving isoflurane and atracurium for neurosurgical procedures (Beemer et al, 1989).
    c) Seizures appear to be rare with isoflurane induction; however, the drug should be used cautiously in patients with a seizure history.
    C) RAISED INTRACRANIAL PRESSURE
    1) WITH THERAPEUTIC USE
    a) Isoflurane causes an increase in intracranial pressure during normocapnic ventilation. However, this increase may be corrected or prevented by hyperventilation or prior hypocapnia induction (Campkin & Flin, 1989) .
    b) The risk of isoflurane-induced increased intracranial pressure appears to be greater in neurosurgical patients who have some degree of midline shift on CT scan (Grosslight et al, 1985).
    D) SECONDARY PERIPHERAL NEUROPATHY
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 40-year-old woman who received isoflurane, fentanyl and vecuronium for 8 days to treat refractory status asthmaticus developed flaccid paralysis and sensory loss of all limbs (du Peloux Menage et al, 1992) The sensory loss resolved over 24 days while motor recovery was almost complete three months after the incident.
    E) DRUG WITHDRAWAL
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 7-year-old boy who received isoflurane for 4 days for sedation following a severe burn developed confusion, agitation, and apparent visual and auditory hallucinations for 5 days after isoflurane was discontinued (Hughes et al, 1993).
    F) UNEXPECTED THERAPEUTIC EFFECT
    1) WITH THERAPEUTIC USE
    a) Isoflurane has been used successfully in the treatment of refractory status epilepticus (Kofke et al, 1989).
    G) NEUROPATHY
    1) WITH THERAPEUTIC USE
    a) Electromyographic studies suggest that patients with myasthenia gravis are more sensitive to the neuromuscular depressant effects of isoflurane than are normal patients (Rowbottom, 1989; Nilsson & Muller, 1990).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) SEIZURES
    a) ANIMAL STUDIES: Four-week-old female mice showed disorientation and hypnosis, with convulsions seen at higher doses (Stevens et al, 1975).

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Nausea, vomiting, and postoperative ileus have been reported.
    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting are common (Pauca & Dripps, 1973; Green & Jonsson, 1993; Prod Info FORANE(R) liquid for inhalation, 2006).
    B) DRUG-INDUCED ILEUS
    1) WITH THERAPEUTIC USE
    a) Postoperative ileus has been reported (Prod Info FORANE(R) liquid for inhalation, 2006).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER DAMAGE
    1) WITH THERAPEUTIC USE
    a) Although isolated reports of liver dysfunction with isoflurane have appeared, a causal relationship has not been established; it is felt that isoflurane is highly unlikely to be even rarely responsible for postoperative hepatotoxicity (Stoelting et al, 1987; Ray & Drummond, 1991).
    b) Several case reports describe hepatic dysfunction and fatal hepatic necrosis following isoflurane anesthesia (Gregoire & Smiley, 1986; Carrigan & Straughen, 1987; Brunt et al, 1991; Scheider et al, 1993).
    c) Hepatic failure and hepatic necrosis have been reported in post-marketing use of isoflurane; however, the causal relationship to isoflurane is not clear (Prod Info FORANE(R) inhalation liquid, 2010).
    B) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Isoflurane causes a transient increase in bromsulfalein (BSP) retention and a decrease in alkaline phosphatase levels (Prod Info FORANE(R) inhalation liquid, 2010). However, the occurrence of postoperative hepatic dysfunction is not associated with isoflurane (Stoelting et al, 1987).
    b) The administration of isoflurane 1 to 3% in 30% oxygen/70% nitrous oxide resulted in no significant increases in hepatic glutathione S-transferase (GST) concentrations in 17 patients (Allan et al, 1987).
    c) Human volunteers given isoflurane at 1 to 2 MAC for 6 to 7.5 hours did not show post-anesthetic evidence of significant liver impairment, as measured by alanine aminotransferase, aspartate aminotransferase, lactic dehydrogenase, blood urea nitrogen, and serum creatinine (Stevens et al, 1973).
    1) Bromsulfalein (BSP) retention was slightly increased 24 hours following anesthesia, although the values remained in the normal range.

Genitourinary

    3.10.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Depresses renal blood flow, glomerular filtration rate, and urine flow similar to other general anesthetics. Fluoride effects have not been seen.
    3.10.2) CLINICAL EFFECTS
    A) FLUOROSIS
    1) WITH THERAPEUTIC USE
    a) The metabolism of isoflurane into inorganic fluoride has not caused renal dysfunction. Elevated fluoride levels have been reported after prolonged use (Revell et al, 1988; Breheny, 1992).
    B) CRUSH SYNDROME
    1) WITH THERAPEUTIC USE
    a) Acute renal insufficiency may develop secondary to rhabdomyolysis in patients with malignant hyperthermia (Chalkiadis & Branch, 1990; Jensen et al, 1986).
    C) LACK OF EFFECT
    1) WITH THERAPEUTIC USE
    a) No residual renal depression or renal injury is seen following isoflurane anesthesia (Mazze et al, 1974).
    b) Human volunteers given isoflurane at 1 to 2 MAC for 6 to 7.5 hours did not show post-anesthetic evidence of significant renal impairment (Stevens et al, 1973).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) ACIDOSIS
    1) WITH THERAPEUTIC USE
    a) Severe metabolic acidosis may develop in patients with malignant hyperthermia (Johannesson et al, 1987; McGuire & Easy, 1990; Boheler et al, 1982; Joseph et al, 1982; Chambers et al, 1994).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) LEUKOCYTOSIS
    1) WITH THERAPEUTIC USE
    a) White blood cell counts may increase intra-operatively (Prod Info FORANE(R) liquid for inhalation, 2006).

Musculoskeletal

    3.15.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Rhabdomyolysis may develop in patients with malignant hyperthermia.
    3.15.2) CLINICAL EFFECTS
    A) RHABDOMYOLYSIS
    1) WITH THERAPEUTIC USE
    a) Muscle rigidity and rhabdomyolysis may develop in patients with malignant hyperthermia (McGuire & Easy, 1990; Johannesson et al, 1987; Thomas et al, 1987; Chalkiadis & Branch, 1990); (Joseph et al, 1982; Chambers et al, 1994; Simons & Goldman, 1988; Jensen et al, 1986; Ong & Rosenberg, 1989; Boheler et al, 1982).

Reproductive

    3.20.1) SUMMARY
    A) Isoflurane is classified as FDA Pregnancy Category C by the manufacturer. Teratogenic and fetotoxic effects have been observed in animal studies at high doses. Isoflurane should only be used during pregnancy if the potential maternal benefit outweighs the fetal risk. Isoflurane should only be used during pregnancy if the potential maternal benefit outweighs the fetal risk.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) MICE: Anesthetic-related fetotoxic effects have been observed in mice administered doses 6 times the human dose. Delayed ossification and increased cleft palate were observed in mice administered isoflurane 0.6% for 4 hours daily; lower doses were without adverse effect (Mazze, 1985).
    2) RATS: Fetotoxicity was observed in rats that inhaled 10,500 ppm for 6 hours on days 14 to 16 of pregnancy and 4,000 ppm for 3 hours during days 7 to 17 of pregnancy. Toxic physical effects were observed 21 days after birth with 12,000 ppm for 3 hours on days 17 to 20 of pregnancy. Craniofacial (including nose and tongue), musculoskeletal, and urogenital abnormalities were observed with 6,000 ppm for 4 hours during days 6 to 15 of pregnancy (RTECS , 1993).
    3) SHEEP: Fetal acidosis and a decline in cardiac index (from 391 to 292 mL/kg/min) were observed in sheep administered isoflurane during pregnancy (Biehl, 1983).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Isoflurane is classified as FDA Pregnancy Category C (Prod Info Terrell(TM) inhalation liquid, 2014).
    2) Isoflurane should only be used during pregnancy if the potential maternal benefit outweighs the fetal risk (Prod Info Terrell(TM) inhalation liquid, 2014).
    B) LACK OF EFFECT
    1) Isoflurane has been used in a small number of women as an anesthetic during labor without evident untoward effects (McLeod, 1985; Tunstall & Sheikh, 1989; Abboud et al, 1989).
    C) ANIMAL STUDIES
    1) MICE: Anesthetic-related fetotoxic effects have been observed in mice administered doses 6 times the human dose. Smaller litter size was observed in mice administered isoflurane 0.6% for 4 hours daily; lower doses were without adverse effect (Prod Info Terrell(TM) inhalation liquid, 2014).
    2) RATS: Fetotoxicity was observed in rats that inhaled 10,500 ppm for 6 hours on days 14 to 16 of pregnancy and 4,000 ppm for 3 hours during days 7 to 17 of pregnancy (RTECS , 1993).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Exercise caution when administering this drug to a woman who is breastfeeding (Prod Info Terrell(TM) inhalation liquid, 2014).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, the manufacturer does not report any carcinogenic potential with isoflurane.
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, the manufacturer does not report any carcinogenic potential with isoflurane (Prod Info FORANE(R) inhalation liquid, 2010)
    3.21.4) ANIMAL STUDIES
    A) NEOPLASIA
    1) Isoflurane was given to Swiss ICR mice at 1/2, 1/8, and 1/32 minimum alveolar concentration (MAC) for four in-utero exposures plus 24 exposures during the first 9 weeks of life. Compared to untreated control mice which received the same background gases, but not isoflurane, the incidence of tumors was the same (Prod Info FORANE(R) inhalation liquid, 2010).

Genotoxicity

    A) DNA single strand breaks in peripheral human lymphocytes immediately following anesthesia with isoflurane-nitrous oxide-oxygen has been reported. The DNA strand breaks appeared to be repaired by cellular repair systems within one day. However, the anesthesia could induce permanent DNA damage in patients with DNA repair defects(Reitz et al, 1993).
    B) In a study of 30 patients undergoing isoflurane anesthesia, sister chromatid exchanges in peripheral lymphocytes were significantly greater after anesthesia compared with before anesthesia in patients who smoked (Husum et al, 1984). This effect was not observed in non-smoking patients.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Serum fluoride concentrations should be monitored in overdose cases.
    B) Monitor vital signs in all patients. Follow temperature and monitor for signs of fever possibly leading to malignant hyperthermia.
    C) A number of chemicals produce abnormalities of the hematopoietic system, liver, and kidneys. Monitoring complete blood count, urinalysis, and liver and kidney function tests is suggested for patients with significant exposure.
    D) A number of chemicals produce abnormalities of the hematopoietic system, liver, and kidneys. Monitoring urinalysis is suggested for patients with significant exposure.
    E) Monitor ECG for cardiac dysrhythmias following overdose.
    F) Monitor for respiratory depression.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Monitor serum fluoride levels in overdose cases.
    2) Following isoflurane administration, plasma inorganic fluoride concentration increased from a mean of 3.5 to 43.2 micromoles/L in a study of 19 adult patients (Murray & Trinick, 1992).
    3) Monitor serum liver enzyme levels in overdose cases.
    4) Monitor serum kidney creatinine and creatinine kinase levels in overdose cases.
    5) A number of chemicals produce abnormalities of the hematopoietic system, liver, and kidneys. Monitoring complete blood count, urinalysis, and liver and kidney function tests is suggested for patients with significant exposure.
    4.1.3) URINE
    A) URINALYSIS
    1) A number of chemicals produce abnormalities of the hematopoietic system, liver, and kidneys. Monitoring urinalysis is suggested for patients with significant exposure.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) BLOOD PRESSURE - The depth of isoflurane anesthesia is inversely associated with blood pressure in the absence of other complications.
    b) RESPIRATIONS - Respiratory rate (respiratory failure) should be monitored during isoflurane anesthesia.
    c) ECG - Continuous cardiac monitoring is recommended for patients following overdose.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Serum fluoride concentrations should be monitored in overdose cases.
    B) Monitor vital signs in all patients. Follow temperature and monitor for signs of fever possibly leading to malignant hyperthermia.
    C) A number of chemicals produce abnormalities of the hematopoietic system, liver, and kidneys. Monitoring complete blood count, urinalysis, and liver and kidney function tests is suggested for patients with significant exposure.
    D) A number of chemicals produce abnormalities of the hematopoietic system, liver, and kidneys. Monitoring urinalysis is suggested for patients with significant exposure.
    E) Monitor ECG for cardiac dysrhythmias following overdose.
    F) Monitor for respiratory depression.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) Ingestion of this inhalation anesthetic is unlikely but has occurred. Because of the rapid absorption and rapid onset of CNS depression, prehospital decontamination is not recommended.
    6.5.2) PREVENTION OF ABSORPTION
    A) EMESIS/NOT RECOMMENDED
    1) Because of rapid absorption and onset of CNS depression, induced emesis is not recommended.
    B) ACTIVATED CHARCOAL
    1) May be of use if administered early and the patient's airway is protected.
    2) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    3) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) GENERAL TREATMENT
    1) Information on ingestions is limited. Treatment should include those methods listed under "INHALATION EXPOSURE", if appropriate.

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Administer high flow oxygen, establish airway and assist respirations as needed.
    6.7.2) TREATMENT
    A) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2010; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    B) MALIGNANT HYPERPYREXIA DUE TO ANESTHETIC
    1) SUMMARY - Isoflurane anesthesia has been associated with a skeletal muscle hypermetabolic state known as malignant hyperthermia. Dantrolene and ice may be of use.
    2) DANTROLENE SODIUM (ADULT AND PEDIATRIC) - Initial recommended dose is 1 mg/kg by rapid IV infusion. If symptoms persist or reappear, the dose may be repeated, to a cumulative dose of 10 mg/kg.
    a) Reversal is usually achieved with a cumulative dose of 2.5 mg/kg.
    b) Oral doses of 1 to 2 mg/kg four times daily for 1 to 3 days may be necessary to prevent the recurrence of the manifestations of malignant hyperthermia (Prod Info dantrolene sodium oral capsules, 2004; Cain & Bell, 1989).
    3) COOLING BLANKETS - Cooling blankets or other external cooling measures may be necessary to lower body temperature.
    C) CONDUCTION DISORDER OF THE HEART
    1) VENTRICULAR DYSRHYTHMIAS SUMMARY
    a) Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalemia, hypocalcemia, and hypomagnesemia). Lidocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Amiodarone should be used with caution if a substance that prolongs the QT interval and/or causes torsades de pointes is involved in the overdose. Unstable rhythms require immediate cardioversion.
    2) LIDOCAINE
    a) LIDOCAINE/INDICATIONS
    1) Ventricular tachycardia or ventricular fibrillation (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010; Vanden Hoek et al, 2010).
    b) LIDOCAINE/DOSE
    1) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010). Only bolus therapy is recommended during cardiac arrest.
    a) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010).
    2) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).
    c) LIDOCAINE/MAJOR ADVERSE REACTIONS
    1) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010).
    d) LIDOCAINE/MONITORING PARAMETERS
    1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).
    3) AMIODARONE
    a) AMIODARONE/INDICATIONS
    1) Effective for the control of hemodynamically stable monomorphic ventricular tachycardia. Also recommended for pulseless ventricular tachycardia or ventricular fibrillation in cardiac arrest unresponsive to CPR, defibrillation and vasopressor therapy (Link et al, 2015; Neumar et al, 2010). It should be used with caution when the ingestion involves agents known to cause QTc prolongation, such as fluoroquinolones, macrolide antibiotics or azoles, and when ECG reveals QT prolongation suspected to be secondary to overdose (Prod Info Cordarone(R) oral tablets, 2015).
    b) AMIODARONE/ADULT DOSE
    1) For ventricular fibrillation or pulseless VT unresponsive to CPR, defibrillation, and a vasopressor therapy give an initial dose of 300 mg IV followed by 1 dose of 150 mg IV. For stable ventricular tachycardias: Infuse 150 milligrams over 10 minutes, and repeat if necessary. Follow by a 1 milligram/minute infusion for 6 hours, then a 0.5 milligram/minute. Maximum total dose over 24 hours is 2.2 grams (Neumar et al, 2010).
    c) AMIODARONE/PEDIATRIC DOSE
    1) Infuse 5 milligrams/kilogram as a bolus for pulseless ventricular tachycardia or ventricular fibrillation; may repeat twice up to 15 mg/kg. Infuse 5 milligrams/kilogram over 20 to 60 minutes for perfusing tachycardias. Maximum single dose is 300 mg. Routine use with other drugs that prolong the QT interval is NOT recommended (Kleinman et al, 2010).
    d) ADVERSE EFFECTS
    1) Hypotension and bradycardia are the most common adverse effects (Neumar et al, 2010).
    4) PROCAINAMIDE
    a) PROCAINAMIDE/INDICATIONS
    1) An alternative drug in the treatment of PVCs or recurrent ventricular tachycardia when lidocaine is contraindicated or not effective. It should be avoided when the ingestion involves agents with quinidine-like effects (e.g. tricyclic antidepressants, phenothiazines, chloroquine, antidysrhythmics) and when the ECG reveals QRS widening or QT prolongation suspected to be secondary to overdose(Neumar et al, 2010; Vanden Hoek,TLet al,null).
    b) PROCAINAMIDE/ADULT LOADING DOSE
    1) 20 to 50 milligrams/minute IV until dysrhythmia is suppressed or toxicity develops from procainamide (hypotension develops or the QRS is widened by 50%), or a total dose of 17 milligrams/kilogram is given (1.2 grams for a 70 kilogram person) (Neumar et al, 2010).
    2) ALTERNATIVE DOSING: 100 mg every 5 minutes until dysrhythmia is controlled, or toxicity develops from procainamide (hypotension develops or the QRS is widened by 50%) or 17 mg/kg have been given (Neumar et al, 2010).
    3) MAXIMUM DOSE: 17 milligrams/kilogram (Neumar et al, 2010).
    c) PROCAINAMIDE/CONTROLLED INFUSION
    1) In conscious patients, procainamide should be administered as a controlled infusion (20 milligrams/minute) because of the risk of QT prolongation and its hypotensive effects (Link et al, 2015)
    d) PROCAINAMIDE/ADULT MAINTENANCE DOSE
    1) 1 to 4 milligrams/minute via an intravenous infusion (Neumar et al, 2010).
    e) PROCAINAMIDE/PEDIATRIC LOADING DOSE
    1) 15 milligrams/kilogram IV/Intraosseously over 30 to 60 minutes; discontinue if hypotension develops or the QRS widens by 50% (Kleinman et al, 2010).
    f) PROCAINAMIDE/PEDIATRIC MAINTENANCE DOSE
    1) Initiate at 20 mcg/kg/minute and increase in 10 mcg/kg/minute increments every 15 to 30 minutes until desired effect is achieved; up to 80 mcg/kg/minute (Bouhouch et al, 2008; Ratnasamy et al, 2008; Mandapati et al, 2000; Luedtke et al, 1997; Walsh et al, 1997).
    g) PROCAINAMIDE/PEDIATRIC MAXIMUM DOSE
    1) 2 grams/day (Bouhouch et al, 2008; Ratnasamy et al, 2008; Mandapati et al, 2000; Luedtke et al, 1997; Walsh et al, 1997).
    h) MONITORING PARAMETERS
    1) ECG, blood pressure, and blood concentrations (Prod Info procainamide HCl IV, IM injection solution, 2011). Procainamide can produce hypotension and QT prolongation (Link et al, 2015).
    i) AVOID
    1) Avoid in patients with QT prolongation and CHF (Neumar et al, 2010).
    5) TACHYCARDIA - Tanaka et al (1994) reported pre-medication with oral clonidine (3 to 4 micrograms/kilogram) and 2 mL of 4% lidocaine spray to the nasal mucosa, significantly blunted the circulatory responses to increasing isoflurane concentrations, thus minimizing isoflurance-induced tachycardia and hypertension (Tanaka et al, 1994).
    D) AIRWAY MANAGEMENT
    1) Isoflurane may cause respiratory failure. Administer oxygen and endotracheally intubate as clinically indicated.
    E) FLUID/ELECTROLYTE BALANCE REGULATION
    1) Fluid and electrolyte replacement may be necessary in cases of metabolic acidosis, hyperkalemia, and myoglobinemia.
    F) ACIDOSIS
    1) METABOLIC ACIDOSIS: Treat severe metabolic acidosis (pH less than 7.1) with sodium bicarbonate, 1 to 2 mEq/kg is a reasonable starting dose(Kraut & Madias, 2010). Monitor serum electrolytes and arterial or venous blood gases to guide further therapy.
    2) Repeat doses of no more than one-half the original amount may be given no more often than every 10 minutes if required. Monitor blood gases to adjust dose.
    G) HYPOTENSIVE EPISODE
    1) If possible, first decrease depth of isoflurane anesthesia if hypotension occurs (consider substituting another anesthetic agent).
    2) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    3) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    4) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    5) THORACIC EPIDURAL ANESTHESIA - concomitant with isoflurane may result in cardiovascular depression with decreased heart rate, mean arterial pressure, cardiac output and left ventricular contractility. Raner et al (1994) reported that exogenous dopamine effectively and dose-dependently counters the cardiovascular depression induced by the combination of thoracic epidural anesthesia and isoflurane (Raner et al, 1994).
    H) RHABDOMYOLYSIS
    1) SUMMARY: Early aggressive fluid replacement is the mainstay of therapy and may help prevent renal insufficiency. Diuretics such as mannitol or furosemide may be added if necessary to maintain urine output but only after volume status has been restored as hypovolemia will increase renal tubular damage. Urinary alkalinization is NOT routinely recommended.
    2) Initial treatment should be directed towards controlling acute metabolic disturbances such as hyperkalemia, hyperthermia, and hypovolemia. Control seizures, agitation, and muscle contractions (Erdman & Dart, 2004).
    3) FLUID REPLACEMENT: Early and aggressive fluid replacement is the mainstay of therapy to prevent renal failure. Vigorous fluid replacement with 0.9% saline (10 to 15 mL/kg/hour) is necessary even if there is no evidence of dehydration. Several liters of fluid may be needed within the first 24 hours (Walter & Catenacci, 2008; Camp, 2009; Huerta-Alardin et al, 2005; Criddle, 2003; Polderman, 2004). Hypovolemia, increased insensible losses, and third spacing of fluid commonly increase fluid requirements. Strive to maintain a urine output of at least 1 to 2 mL/kg/hour (or greater than 150 to 300 mL/hour) (Walter & Catenacci, 2008; Camp, 2009; Erdman & Dart, 2004; Criddle, 2003). To maintain a urine output this high, 500 to 1000 mL of fluid per hour may be required (Criddle, 2003). Monitor fluid input and urine output, plus insensible losses. Monitor for evidence of fluid overload and compartment syndrome; monitor serum electrolytes, CK, and renal function tests.
    4) DIURETICS: Diuretics (eg, mannitol or furosemide) may be needed to ensure adequate urine output and to prevent acute renal failure when used in combination with aggressive fluid therapy. Loop diuretics increase tubular flow and decrease deposition of myoglobin. These agents should be used only after volume status has been restored, as hypovolemia will increase renal tubular damage. If the patient is maintaining adequate urine output, loop diuretics are not necessary (Vanholder et al, 2000).
    5) URINARY ALKALINIZATION: Alkalinization of the urine is not routinely recommended, as it has never been documented to reduce nephrotoxicity, and may cause complications such as hypocalcemia and hypokalemia (Walter & Catenacci, 2008; Huerta-Alardin et al, 2005; Brown et al, 2004; Polderman, 2004). Retrospective studies have failed to demonstrate any clinical benefit from the use of urinary alkalinization (Brown et al, 2004; Polderman, 2004; Homsi et al, 1997).
    I) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).
    6.8.2) TREATMENT
    A) GENERAL TREATMENT
    1) Treatment should include recommendations listed in the INHALATION EXPOSURE section when appropriate.
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DERMAL DECONTAMINATION
    1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    6.9.2) TREATMENT
    A) SKIN ABSORPTION
    1) Some chemicals can produce systemic poisoning by absorption through intact skin. Carefully observe patients with dermal exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    B) GENERAL TREATMENT
    1) Treatment should include recommendations listed in the INHALATION EXPOSURE section when appropriate.
    C) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Enhanced Elimination

    A) SUMMARY
    1) No studies have addressed the utilization of extracorporeal elimination techniques in poisoning with this agent.

Abstracts

Case Reports

    A) ADULT
    1) CARDIAC ARREST: Isoflurane was implicated increasing cardiac arrest in a Duchenne's muscular dystrophy patient following an orchidopexy procedure. Ten minutes after regaining consciousness from isoflurane-induces anesthesia, cardiac arrest occurred.
    a) After 2 hours of external cardiac compression, the patient was revived. Isoflurane was suspected of inducing rhabdomyolysis and hypokalemia resulting in cardiac failure (Chalkiadis & Branch, 1990).
    2) MYOCARDIAL ISCHEMIA: Isoflurane use in patients undergoing coronary artery bypass (CABG) is controversial because of possible myocardial ischemia induction (Dahlgren et al, 1989; Gross, 1989; Sahlman et al, 1989).
    a) One case of progressive ischemia occurred out of 9 patients administered isoflurane, 2.5% initially and 1.5% for maintenance, during CABG. Isoflurane was discontinued in this patient and the electrocardiogram normalized within 20 minutes.
    b) Although the number of patients examined was small, the mean ischemic score did not change in the majority of the patients (Dahlgren et al, 1989).
    3) SEIZURES: Postoperative seizure activity has occurred following isoflurane anesthesia (with thiopental, nitrous oxide, and oxygen) in a 69-year-old female who underwent surgery for arthroscopy (Harrison, 1986).
    a) Shortly after admission to the recovery room, the patient developed myoclonic-type movements of the arms and shoulders without rigidity, which responded to IV diazepam.
    b) However, within 30 minutes the patient developed upper extremity twitching which again responded to diazepam; a second bout of myoclonus was observed 30 minutes later which responded slowly to IV phenytoin.
    c) Following phenytoin administration, myoclonus could still be initiated by stimulation of the extremities. It is difficult to attribute seizure activity in this patient totally to isoflurane administration.

Range Of Toxicity

Summary

    A) Human volunteers given isoflurane at 1 to 2 minimum alveolar concentration (MAC) for 6 to 7.5 hours did not show post-anesthetic evidence of significant liver or renal impairment. Ingestion of approximately 80 mL of isoflurane was fatal in an adult.

Therapeutic Dose

    7.2.1) ADULT
    A) INDUCTION OF ANESTHESIA: Inspired 1.5% to 3% isoflurane produces surgical anesthesia within 7 to 10 minutes (Prod Info Terrell(TM) inhalation liquid, 2014).
    B) MAINTENANCE OF ANESTHESIA: Surgical anesthesia may be sustained using inspired 1% to 2.5% isoflurane used concomitantly with nitric oxide. An additional 0.5% to 1% may be needed when isoflurane is delivered with oxygen alone (Prod Info Terrell(TM) inhalation liquid, 2014).
    7.2.2) PEDIATRIC
    A) In children, the minimum anesthetic concentration of isoflurane in oxygen is 1.6% to 1.8% (Cameron et al, 1984).

Minimum Lethal Exposure

    A) GENERAL/SUMMARY
    1) The minimum lethal human dose has not been established.
    B) CASE REPORTS
    1) Ingestion of approximately 80 mL of isoflurane was fatal in a 37-year-old man (Dooper et al, 1988).

Maximum Tolerated Exposure

    A) CASE REPORTS
    1) VOLUNTEER STUDY: Human volunteers given isoflurane at 1 to 2 minimum alveolar concentration (MAC) for 6 to 7.5 hours did not show post-anesthetic evidence of significant liver or renal impairment, as measured by alanine aminotransferase, aspartate aminotransferase, lactic dehydrogenase, blood urea nitrogen, and serum creatinine (Stevens et al, 1973).
    2) FLUORIDE: Following isoflurane administration, plasma inorganic fluoride concentration increased from a mean of 3.5 to 43.2 micromoles/L in a study of 19 adult patients (Murray & Trinick, 1992).
    B) ANIMAL DATA
    1) Disorientation, hypnosis, and convulsions (in some) were observed in 4-week-old female mice following acute exposure to high intraperitoneal doses of isoflurane (Stevens et al, 1975).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CASE REPORT: The serum isoflurane level in an adult one hour after resuscitation from cardiac arrest, sustained after ingesting 80 mL, was 2 mcg/liter (Dooper et al, 1988).
    2) CASE REPORT: A case of a fatal abuse of isoflurane by an operating room assistant has been reported. Evidence at autopsy revealed death through functional asphyxiation. Oxazepam, prothipendyl, and metabolites of midazolam and prothiopendyl were also found in the urine. Post-mortem isoflurane concentrations in body fluids and tissues were as follows (Pavlic et al, 2002):
    1) URINE (mg/L): 4.4 +/- 0.14
    2) LIQUOR (mg/L): 6.3 +/- 0.27
    3) CARDIAC BLOOD (mg/L): 47.9 +/- 0.94
    4) GASTRIC CONTENTS (mg/kg): 252.7 +/- 16.05
    5) KIDNEY (mg/kg): 52.8 +/- 4.70
    6) LIVER (mg/kg): 999.8 +/- 89.99
    7) BRAIN (mg/kg): 306.9 +/- 9.55

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) References: RTECS, 2000 Stevens et al, 1975. Note: All values are from RTECS 2000 unless otherwise noted.
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 3030 mg/kg
    2) LD50- (ORAL)MOUSE:
    a) 5080 mg/kg
    b) 6740 mg/kg (Stevens et al, 1975)
    3) LD50- (INTRAPERITONEAL)RAT:
    a) 4280 mg/kg
    4) LD50- (ORAL)RAT:
    a) 4770 mg/kg

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Isoflurane is administered by inhalation and is a volatile halogenated anesthetic agent. Its anesthetic properties are similar to those of halothane. It has a minimum alveolar concentration (MAC) value ranging from 1.05% in the elderly to 1.87% in infants. Its uses include induction and maintenance of general anesthesia, although induction is more frequently accomplished using an intravenous anesthetic with isoflurane used for maintenance (JEF Reynolds , 2000).

Toxicologic Mechanism

    A) HEMODYNAMIC EFFECTS: Isoflurane has been reported to cause dose-dependent hemodynamic effects that include decreases in mean arterial pressure, cardiac output, left ventricular contractility, and systemic vascular resistance ((Raner et al, 1994).
    B) TACHYCARDIA: Significant increases in sympathetic nervous system activity and hemodynamic changes are associated with isoflurane anesthesia. Isoflurane-induced tachycardia is related to three factors: (1) decreased systemic vascular resistance; (2) less depression of baroreflex function than that seen with other volatile anesthetics, such as halothane or enflurane; and (3) depressed parasympathetic tone in comparison with sympathetic tone during isoflurane administration (Tanaka et al, 1994).
    1) Another potential source of tachycardia is a rapid increase in end-tidal concentration of isoflurane from 1.3% to 2.6% which has caused sympathetic activation and induced hemodynamic responses, including tachycardia and hypertension. Hyperdynamic circulation in normotensive and hypertensive patients has also been elicited by rapid administration of 5% isoflurane (Tanaka et al, 1994).
    C) AIRWAY IRRITATION: A 5% isoflurane administration causes stimulation of the nasal mucosa subsequently increasing expiratory time and decreasing respiratory frequency, both of which are considered to be defensive airway reflexes. This irritating effect of isoflurane on the airways also results in increased blood pressure and sympathetic efferent nerve activity, which could be another cause of tachycardia (Tanaka et al, 1994).
    1) Tanaka et al (1994) suggested if isoflurane stimulates airway receptors which then evokes adrenosympathetic reflexes, then isoflurane-induced tachycardia may be modulated by intervention within the reflex arc, e.g., with local anesthetics applied to the airways. A centrally acting alpha 2 agonist, such as clonidine, may suppress sympathetic reflexes, thus weakening the reflex and decreasing tachycardia(Tanaka et al, 1994).

Physicochemical

Physical Characteristics

    A) Isoflurane is a potent, nonflammable inhalation anesthetic that is a clear, colorless liquid with a slight pungent, ethereal odor. It is also used as a solvent and dispersant for fluorinated compounds (Budavari, 1996; JEF Reynolds , 2000).

Molecular Weight

    A) 184.50 (Budavari, 1996)

References

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