desflurane 1000 MG/ML Inhalation Solution [Suprane]

INDICATIONS AND USAGE Desflurane, USP, liquid for inhalation a general anesthetic, is an inhalation agent indicated: • for induction and/or maintenance of anesthesia in adults ( 1.1 ) • for maintenance of anesthesia in pediatric patients following induction with agents other than Desflurane, USP, liquid for inhalation and intubation. 1.1 Induction of Anesthesia Desflurane USP, liquid for inhalation is indicated as an inhalation agent for induction of anesthesia for inpatient and outpatient surgery in adults. Desflurane, USP, liquid for inhalation is contraindicated as an inhalation agent for the induction of anesthesia in pediatric patients because of a high incidence of moderate to severe upper airway adverse events. 1.2 Maintenance of Anesthesia Desflurane USP, liquid for inhalation is indicated as an inhalation agent for maintenance of anesthesia for inpatient and outpatient surgery in adults and in pediatric patients. After induction of anesthesia with agents other than Desflurane USP, liquid for inhalation and tracheal intubation, Desflurane USP, liquid for inhalation is indicated for maintenance of anesthesia in infants and children. Desflurane USP, liquid for inhalation is not approved for maintenance of anesthesia in non-intubated children due to an increased incidence of respiratory adverse reactions, including coughing, laryngospasm, and secretions [ see Warnings and Precautions ( 5.3 ) and Clinical Studies ( 14.5 ) ] .

DOSAGE AND ADMINISTRATION Only persons trained in the administration of general anesthesia should administer Desflurane, USP, Liquid for Inhalation. Only a vaporizer specifically designed and designated for use with desflurane should be utilized for its administration. Facilities for maintenance of a patent airway, artificial ventilation, oxygen enrichment, and circulatory resuscitation must be immediately available. Desflurane, USP, Liquid for Inhalation is administered by inhalation. The administration of general anesthesia must be individualized based on the patient’s response. Hypotension and respiratory depression increase as anesthesia with Desflurane, USP, Liquid for Inhalation is deepened. The minimum alveolar concentration (MAC) of Desflurane, USP, Liquid for Inhalation decreases with increasing patient age. The MAC for Desflurane, USP, Liquid for Inhalation is also reduced by concomitant N 2 O administration (See Table 1 ) . The dose should be adjusted accordingly. The following table provides mean relative potency based upon age and effect of N 2 O in predominately ASA physical status I or II patients. Benzodiazepines and opioids decrease the MAC of Desflurane, USP, Liquid for Inhalation [See Drug Interactions (7.1, Table 3) ] . Desflurane, USP, Liquid for Inhalation also decreases the doses of neuromuscular blocking agents required [See Drug Interactions (7.2, Table 4) ] . The dose should be adjusted accordingly. Table 1 Effect of Age on Minimum Alveolar Concentration of Desflurane Mean ± SD (percent atmospheres) Age N O 2 100% N N 2 O 60%/40% O 2 2 weeks 6 9.2 ± 0 - - 10 weeks 5 9.4 ± 0.4 - - 9 months 4 10 ± 0.7 5 7.5 ± 0.8 2 years 3 9.1 ± 0.6 - - 3 years - - 5 6.4 ± 0.4 4 years 4 8.6 ± 0.6 - - 7 years 5 8.1 ± 0.6 - - 25 years 4 7.3 ± 0 4 4 ± 0.3 45 years 4 6 ± 0.3 6 2.8 ± 0.6 70 years 6 5.2 ± 0.6 6 1.7 ± 0.4 N = number of crossover pairs (using up-and-down method of quantal response) Desflurane, USP, Liquid for Inhalation should be administered only by persons trained in the administration of general anesthesia. It should only be administered using a vaporizer specifically designed and designated for use with desflurane. ( 2 ) The administration of general anesthesia must be individualized based on the patient’s response, including cardiovascular and pulmonary changes. ( 2 ) Desflurane, USP, Liquid for Inhalation should not be used as the sole agent for anesthetic induction in patients with coronary artery disease or where increases in heart rate or blood pressure are undesirable. ( 2.6 ) For dosing considerations in patients with intracranial space occupying lesions, see Full Prescribing Information. ( 2.7 ) 2.1 Preanesthetic Medication Issues such as whether or not to premedicate and the choice of premedication(s) must be individualized. In clinical studies, patients scheduled to be anesthetized with Desflurane, USP, Liquid for Inhalation frequently received IV preanesthetic medication, such as opioid and/or benzodiazepine. 2.2 Induction In adults, some premedicated with opioid, a frequent starting concentration was 3% Desflurane, USP, Liquid for Inhalation, increased in 0.5% to 1% increments every 2 to 3 breaths. End-tidal concentrations of 4% to 11%, Desflurane, USP, Liquid for Inhalation with and without N 2 O, produced anesthesia within 2 minutes to 4 minutes. When Desflurane, USP, Liquid for Inhalation was tested as the primary anesthetic induction agent, the incidence of upper airway irritation (apnea, breathholding, laryngospasm, coughing and secretions) was high. During induction in adults, the overall incidence of oxyhemoglobin desaturation (SpO 2 < 90%) was 6% [ See Adverse Reactions (6.1) ]. After induction in adults with an intravenous drug such as thiopental or propofol, Desflurane, USP, Liquid for Inhalation can be started at approximately 0.5 to 1 MAC, whether the carrier gas is O 2 or N 2 O/O 2 . Inspired concentrations of Desflurane, USP, Liquid for Inhalation greater than 12% have been safely administered to patients, particularly during induction of anesthesia. Such concentrations will proportionately dilute the concentration of oxygen; therefore, maintenance of an adequate concentration of oxygen may require a reduction of nitrous oxide or air if these gases are used concurrently. 2.3 Maintenance Surgical levels of anesthesia in adults may be maintained with concentrations of 2.5% to 8.5% Desflurane, USP, Liquid for Inhalation with or without the concomitant use of nitrous oxide. In children, surgical levels of anesthesia may be maintained with concentrations of 5.2% to 10% Desflurane, USP, Liquid for Inhalation with or without the concomitant use of nitrous oxide. During the maintenance of anesthesia with inflow rates of 2 L/min or more, the alveolar concentration of Desflurane, USP, Liquid for Inhalation will usually be within 10% of the inspired concentration [F A /F I , see Figure 2 in Clinical Pharmacology (12.3) ] . During the maintenance of anesthesia, increasing concentrations of Desflurane, USP, Liquid for Inhalation produce dose-dependent decreases in blood pressure. Excessive decreases in blood pressure may be due to depth of anesthesia and in such instances may be corrected by decreasing the inspired concentration of Desflurane, USP, Liquid for Inhalation. Concentrations of Desflurane, USP, Liquid for Inhalation exceeding 1 MAC may increase heart rate. Thus with this drug, an increased heart rate may not serve reliably as a sign of inadequate anesthesia. 2.4 Maintenance of Anesthesia in Intubated Pediatric Patients Desflurane, USP, Liquid for Inhalation is indicated for maintenance of anesthesia in infants and children after induction of anesthesia with agents other thanDesflurane, USP, Liquid for Inhalation, and tracheal intubation. Desflurane, USP, Liquid for Inhalation, with or without N 2 O, and halothane, with or without N 2 O were studied in three clinical trials of pediatric patients aged 2 weeks to 12 years (median 2 years) and ASA physical status I or II. The concentration of Desflurane, USP, Liquid for Inhalation required for maintenance of general anesthesia is age-dependent [See Clinical Studies (14.5) ] . Changes in blood pressure during maintenance of and recovery from anesthesia with Desflurane, USP, Liquid for Inhalation/N 2 O/O 2 are similar to those observed with halothane/N 2 O/O 2 . Heart rate during maintenance of anesthesia is approximately 10 beats per minute faster with desflurane than with halothane. Patients were judged fit for discharge from post-anesthesia care units within one hour with both Desflurane, USP, Liquid for Inhalation and halothane. There were no differences in the incidence of nausea and vomiting between patients receiving Desflurane, USP, Liquid for Inhalation or halothane. 2.5 Recovery The recovery from general anesthesia should be assessed carefully before patients are discharged from the post anesthesia care unit (PACU). 2.6 Use in Patients with Coronary Artery Disease In patients with coronary artery disease, maintenance of normal hemodynamics is important to prevent myocardial ischemia. A rapid increase in desflurane concentration is associated with marked increase in pulse rate, mean arterial pressure and levels of epinephrine and norepinephrine. Desflurane, USP, Liquid for Inhalation should not be used as the sole agent for anesthetic induction in patients with coronary artery disease or patients where increases in heart rate or blood pressure are undesirable. It should be used with other medications, preferably intravenous opioids and hypnotics [See Clinical Studies (14.2) ] . 2.7 Neurosurgical Use Desflurane, USP, Liquid for Inhalation may produce a dose-dependent increase in cerebrospinal fluid pressure (CSFP) when administered to patients with intracranial space occupying lesions. Desflurane, USP, Liquid for Inhalation should be administered at 0.8 MAC or less, and in conjunction with a barbiturate induction and hyperventilation (hypocapnia) until

WARNINGS AND PRECAUTIONS Malignant Hyperthermia: Malignant hyperthermia may occur, especially in individuals with known or suspected susceptibility based on genetic factors or family history. Discontinue triggering agents, administer intravenous dantrolene sodium, and apply supportive therapies. ( 5.1 ) Perioperative Hyperkalemia: Perioperative hyperkalemia may occur. Patients with latent or overt neuromuscular disease, particularly with Duchenne muscular dystrophy, appear to be most vulnerable. Early, aggressive intervention is recommended. ( 5.2 ) Respiratory Adverse Reactions in Pediatric Patients: - Not approved for maintenance of anesthesia in non-intubated children due to an increased incidence of respiratory adverse reactions. Monitor and treat accordingly. ( 5.3 ) - May cause airway narrowing and increased airway resistance in children with asthma or a history of recent upper airway infection. Monitor and treat accordingly.( 5.3 ) QTc Prolongation: Carefully monitor cardiac rhythm when administering desflurane to susceptible patients. ( 5.4 ) Interactions with Desiccated Carbon Dioxide (CO 2 ) Absorbents: May react with desiccated CO 2 absorbents to produce carbon monoxide. Replace desiccated CO 2 absorbent before administration of desflurane. ( 5.5 ) Hepatobiliary Disorders: May cause sensitivity hepatitis in patients sensitized by previous exposure to halogenated anesthetics. Approach repeated anesthesia with caution ( 5.6 ) Pediatric Neurotoxicity: In developing animals, exposures greater than 3 hours cause neurotoxicity. Weigh benefits against potential risks when considering elective procedures in children under 3 years old. ( 5.7 ) Postoperative Agitation in Children: May cause postoperative agitation during emergence from anesthesia in children. ( 5.9 ) 5.1 Malignant Hyperthermia In susceptible individuals, volatile anesthetic agents, including desflurane, may trigger malignant hyperthermia, a skeletal muscle hypermetabolic state leading to high oxygen demand. Fatal outcomes of malignant hyperthermia have been reported. The risk of developing malignant hyperthermia increases with the concomitant administration of succinylcholine and volatile anesthetic agents. Desflurane 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 [See Contraindications (4), Clinical Pharmacology (12.5)] . Signs consistent with malignant hyperthermia may include hyperthermia, hypoxia, hypercapnia, muscle rigidity (e.g., jaw muscle spasm), tachycardia (e.g., 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. Successful treatment of malignant hyperthermia depends on early recognition of the clinical signs. If malignant hyperthermia is suspected, discontinue all triggering agents (i.e., 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. 5.2 Perioperative Hyperkalemia Use of inhaled anesthetic agents has been associated with rare increases in serum potassium levels that have resulted in cardiac arrhythmias and death in pediatric patients during the postoperative period. Patients with latent as well as overt neuromuscular disease, particularly Duchenne muscular dystrophy, appear to be most vulnerable. Concomitant use of succinylcholine has been associated with most, but not all, of these cases. These patients also experienced significant elevations in serum creatinine kinase levels and, in some cases, changes in urine consistent with myoglobinuria. Despite the similarity in presentation to malignant hyperthermia, none of these patients exhibited signs or symptoms of muscle rigidity or hypermetabolic state. Early and aggressive intervention to treat the hyperkalemia and resistant arrhythmias is recommended, as is subsequent evaluation for latent neuromuscular disease. 5.3 Respiratory Adverse Reactions in Pediatric Patients Desflurane is not approved for maintenance of anesthesia in non-intubated children due to an increased incidence of respiratory adverse reactions, including coughing, laryngospasm and secretions [See Clinical Studies (14.5) ] . Children, particularly if 6 years old or younger, who are under an anesthetic maintenance of desflurane delivered via laryngeal mask airway (LMA™ mask) are at increased risk for adverse respiratory reactions, e.g., coughing and laryngospasm, especially with removal of the laryngeal mask airway under deep anesthesia [See Clinical Studies (14.5) ] . Therefore, closely monitor these patients for signs and symptoms associated with laryngospasm and treat accordingly. When desflurane is used for maintenance of anesthesia in children with asthma or a history of recent upper airway infection, there is an increased risk for airway narrowing and increases in airway resistance. Therefore, closely monitor these patients for signs and symptoms associated with airway narrowing and treat accordingly . 5.4 QTc Prolongation QTc prolongation, associated with torsade de pointes, has been reported [See Adverse Reactions ( 6.2 )]. Carefully monitor cardiac rhythm when administering desflurane to susceptible patients (e.g., patients with congenital Long QT Syndrome or patients taking drugs that can prolong the QT interval). 5.5 Interactions with Desiccated Carbon Dioxide Absorbents Desflurane like some other inhalation anesthetics, can react with desiccated carbon dioxide (CO 2 ) absorbents to produce carbon monoxide that may result in elevated levels of carboxyhemoglobin in some patients. Case reports suggest that barium hydroxide lime and soda lime become desiccated when fresh gases are passed through the CO 2 canister at high flow rates over many hours or days. When a clinician suspects that CO 2 absorbent may be desiccated, it should be replaced before the administration of desflurane. 5.6 Hepatobiliary Disorders With the use of halogenated anesthetics, disruption of hepatic function, icterus and fatal liver necrosis have been reported; such reactions appear to indicate hypersensitivity. As with other halogenated anesthetic agents, desflurane may cause sensitivity hepatitis in patients who have been sensitized by previous exposure to halogenated anesthetics [See Contraindications (4) ] . Cirrhosis, viral hepatitis or other pre-existing hepatic disease may be a reason to select an anesthetic other than a halogenated anesthetic. As with all halogenated anesthetics, repeated anesthesia within a short period of time should be approached with caution. 5.7 Pediatric Neurotoxicity Published animal studies demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity increase neuronal apoptosis in the developing brain and result in long-term cognitive deficits when used for longer than 3 hours. The clinical significance of these findings is not clear. However, based on the available data, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately three years of age in humans. [See Use in Specific Populations ( 8.1 , 8.4 ), Nonc

CONTRAINDICATIONS The use of Desflurane, USP, Liquid for Inhalation is contraindicated in the following conditions: Known or suspected genetic susceptibility to malignant hyperthermia [See Warnings and Precautions (5.1), Clinical Pharmacology (12.5)] . Patients in whom general anesthesia is contraindicated. Induction of anesthesia in pediatric patients. Patients with known sensitivity to Desflurane, USP, Liquid for Inhalation or to other halogenated agents [See Warnings and Precautions (5.6) ] . Patients with a history of moderate to severe hepatic dysfunction following anesthesia with Desflurane, USP, Liquid for Inhalation or other halogenated agents and not otherwise explained [See Warnings and Precautions (5.6) ] . Patients with known or suspected genetic susceptibility to malignant hyperthermia ( 4 ) Patients in whom general anesthesia is contraindicated ( 4 ) Induction of anesthesia in pediatric patients ( 4 ) Patients with known sensitivity to halogenated agents ( 4 ) Patients with a history of moderate to severe hepatic dysfunction following anesthesia with halogenated agents and not otherwise explained. ( 4 )

CLINICAL PHARMACOLOGY 12.2 Pharmacodynamics Changes in the clinical effects of desflurane rapidly follow changes in the inspired concentration. The duration of anesthesia and selected recovery measures for desflurane are given in the following tables: In 178 female outpatients undergoing laparoscopy, premedicated with fentanyl (1.5 mcg/kg to 2 mcg/kg), anesthesia was initiated with propofol 2.5 mg/kg, desflurane/N 2 O 60% in O 2 or desflurane/O 2 alone. Anesthesia was maintained with either propofol 1.5 mg/kg/hr to 9 mg/kg/hr, desflurane 2.6% to 8.4% in N 2 O 60% in O 2 , or desflurane 3.1% to 8.9% in O 2 . Emergence and Recovery After Outpatient Laparoscopy 178 Females, Ages 20 to 47 Times in Minutes: Mean ± SD (Range) Induction: Propofol Propofol Desflurane/N 2 O Desflurane/O 2 Maintenance: Propofol/N 2 O Desflurane/N 2 O Desflurane/N 2 O Desflurane/O 2 Number of Pts: N = 48 N = 44 N = 43 N = 43 Median age 30 (20 to 43) 26 (21 to 47) 29 (21 to 42) 30 (20 to 40) Anesthetic time 49 ± 53 (8 to 336) 45 ± 35 (11 to 178) 44 ± 29 (14 to 149) 41 ± 26 (19 to 126) Time to open eyes 7 ± 3 (2 to 19) 5 ± 2 Differences were statistically significant (p < 0.05) by Dunnett’s procedure comparing all treatments to the propofol-propofol/N 2O (induction and maintenance) group. Results for comparisons greater than one hour after anesthesia show no differences between groups and considerable variability within groups. (2 to 10) 5 ± 2 (2 to 12) 4 ± 2 (1 to 11) Time to state name 9 ± 4 (4 to 22) 8 ± 3 (3 to 18) 7 ± 3 (3 to 16) 7 ± 3 (2 to 15) Time to stand 80 ± 34 (40 to 200) 86 ± 55 (30 to 320) 81 ± 38 (35 to 190) 77 ± 38 (35 to 200) Time to walk 110 ± 6 (47 to 285) 122 ± 85 (37 to 375) 108 ± 59 (48 to 220) 108 ± 66 (49 to 250) Time to fit for discharge 152 ± 75 (66 to 375) 157 ± 80 (73 to 385) 150 ± 66 (68 to 310) 155 ± 73 (69 to 325) In 88 unpremedicated outpatients, anesthesia was initiated with thiopental 3mg/kg to 9 mg/kg or desflurane in O 2 . Anesthesia was maintained with isoflurane 0.7% to 1.4% in N 2 O 60%, desflurane 1.8% to 7.7% in N 2 O 60%, or desflurane 4.4% to 11.9% in O 2 . Emergence and Recovery Times in Outpatient Surgery 46 Males, 42 Females, Ages 19 to 70 Times in Minutes: Mean ± SD (Range) Induction: Thiopental Thiopental Thiopental Desflurane/O 2 Maintenance: Isoflurane/N 2 O Desflurane/N 2 O Desflurane/O 2 Desflurane/O 2 Number of Pts: N = 23 N = 21 N = 23 N = 21 Median age 43 (20 to 70) 40 (22 to 67) 43 (19 to 70) 41 (21 to 64) Anesthetic time 49 ± 23 (11 to 94) 50 ± 19 (16 to 80) 50 ± 27 (16 to 113) 51 ± 23 (19 to 117) Time to open eyes 13 ± 7 (5 to 33) 9 ± 3 Differences were statistically significant (p < 0.05) by Dunnett’s procedure comparing all treatments to the thiopental-isoflurane/N 2O (induction and maintenance) group. Results for comparisons greater than one hour after anesthesia show no differences between groups and considerable variability within groups. (4 to 16) 12 ± 8 (4 to 39) 8 ± 2 (4 to 13) Time to state name 17 ± 10 (6 to 44) 11 ± 4 (6 to 19) 15 ± 10 (6 to 46) 9 ± 3 (5 to 14) Time to walk 195 ± 67 (124 to 365) 176 ± 60 (101 to 315) 168 ± 34 (119 to 258) 181 ± 42 (92 to 252) Time to fit for discharge 205 ± 53 (153 to 365) 202 ± 41 (144 to 315) 197 ± 35 (155 to 280) 194 ± 37 (134 to 288) Recovery from anesthesia was assessed at 30 minutes, 60 minutes, and 90 minutes following 0.5 MAC desflurane (3%) or isoflurane (0.6%) in N 2 O 60% using subjective and objective tests. At 30 minutes after anesthesia, only 43% of patients in the isoflurane group were able to perform the psychometric tests compared to 76% in the desflurane group (p < 0.05). Recovery Tests: Percent of Preoperative Baseline Values 16 Males, 22 Females, Ages 20 to 65 Percent: Mean ± SD 60 minutes After Anesthesia 90 minutes After Anesthesia Maintenance: Desflurane/N 2 O Isoflurane/N 2 O Desflurane/N 2 O Isoflurane/N 2 O Confusion Visual analog scale (values from 0 to 100; 100 = baseline) 66 ± 6 47 ± 8 75 ± 7 Differences were statistically significant (p < 0.05) using a two-sample t-test 56 ± 8 Fatigue 70 ± 9 33 ± 6 89 ± 12 47 ± 8 Drowsiness 66 ± 5 36 ± 8 76 ± 7 49 ± 9 Clumsiness 65 ± 5 49 ± 8 80 ± 7 57 ± 9 Comfort 59 ± 7 30 ± 6 60 ± 8 31 ± 7 DSST DSST = Digit Symbol Substitution Test score 74 ± 4 50 ± 9 75 ± 4 55 ± 7 Trieger Tests Trieger Test = Dot Connecting Test 67 ± 5 74 ± 6 90 ± 6 83 ± 7 Desflurane was studied in twelve volunteers receiving no other drugs. Hemodynamic effects during controlled ventilation (PaCO 2 38 mmHg) were: Hemodynamic Effects of Desflurane During Controlled Ventilation 12 Male Volunteers, Ages 16 to 26 Mean ± SD (Range) Heart Rate (beats/min) Mean Arterial Pressure (mmHg) Cardiac Index (L/min/m 2 ) Total MAC Equivalent End-Tidal % Des/O 2 End-Tidal % Des/N 2 O O 2 N 2 O O 2 N 2 O O 2 N 2 O 0 0% / 21% 0% / 0% 69 ± 4 (63 to 76) 70 ± 6 (62 to 85) 85 ± 9 (74 to 102) 85 ± 9 (74 to 102) 3.7 ± 0.4 (3.0 to 4.2) 3.7 ± 0.4 (3.0 to 4.2) 0.8 6% / 94% 3% / 60% 73 ± 5 (67 to 80) 77 ± 8 (67 to 97) 61 ± 5 Differences were statistically significant (p < 0.05) compared to awake values, Newman-Keul’s method of multiple comparison. (55 to 70) 69 ± 5 (62 to 80) 3.2 ± 0.5 (2.6 to 4.0) 3.3 ± 0.5 (2.6 to 4.1) 1.2 9% / 91% 6% / 60% 80 ± 5 (72 to 84) 77 ± 7 (67 to 90) 59 ± 8 (44 to 71) 63 ± 8 (47 to 74) 3.4 ± 0.5 (2.6 to 4.1) 3.1 ± 0.4 (2.6 to 3.8) 1.7 12% / 88% 9% / 60% 94 ± 14 (78 to 109) 79 ± 9 (61 to 91) 51 ± 12 (31 to 66) 59 ± 6 (46 to 68) 3.5 ± 0.9 (1.7 to 4.7) 3.0 ± 0.4 (2.4 to 3.6) When the same volunteers breathed spontaneously during desflurane anesthesia, systemic vascular resistance and mean arterial blood pressure decreased; cardiac index, heart rate, stroke volume, and central venous pressure (CVP) increased compared to values when the volunteers were conscious. Cardiac index, stroke volume, and CVP were greater during spontaneous ventilation than during controlled ventilation. During spontaneous ventilation in the same volunteers, increasing the concentration of desflurane from 3% to 12% decreased tidal volume and increased arterial carbon dioxide tension and respiratory rate. The combination of N 2 O 60% with a given concentration of desflurane gave results similar to those with desflurane alone. Respiratory depression produced by desflurane is similar to that produced by other potent inhalation agents. The use of desflurane concentrations higher than 1.5 MAC may produce apnea. Figure 1. PaCO2 During Spontaneous Ventilation in Unstimulated Volunteers Figure 1 12.3 Pharmacokinetics Due to the volatile nature of desflurane in plasma samples, the washin-washout profile of desflurane was used as a surrogate of plasma pharmacokinetics. Desflurane is a volatile liquid inhalation anesthetic minimally biotransformed in the liver in humans. Less than 0.02% of the desflurane absorbed can be recovered as urinary metabolites (compared to 0.2% for isoflurane). Eight healthy male volunteers first breathed 70% N 2 O/30% O 2 for 30 minutes and then a mixture of desflurane 2%, isoflurane 0.4%, and halothane 0.2% for another 30 minutes. During this time, inspired and end-tidal concentrations (F I and F A ) were measured. The F A /F I (washin) value at 30 minutes for desflurane was 0.91, compared to 1.00 for N 2 O, 0.74 for isoflurane, and 0.58 for halothane (See Figure 2 ) . The washin rates for halothane and isoflurane were similar to literature values. The washin was faster for desflurane than for isoflurane and halothane at all time points. The F A /F AO (washout) value at 5 minutes was 0.12 for desflurane, 0.22 for isoflurane, and 0.25 for halothane (See Figure 3 ) . The washout for desflurane was more rapid than that for isoflurane and halothane at all elimination time points. By 5 days, the F A /F AO for desflurane is 1/20th of that for halothane or isoflurane. Figure 2. Desflurane Washin Figure 3. Desflurane Washout Figure 2 Figure 3 12.5 Pharmacogenomics RYR1 and CACNA1S are polymorphic genes and multiple pathogenic variants have been associated with malign