Suprane (Desflurane)

SUPRANE®

AstraZeneca

Desflurane

Inhalation Anesthetic

Action and Clinical Pharmacology:

Desflurane is a volatile inhalational anesthetic whose low solubility (blood/gas partition coefficient equals 0.42) permits rapid variation in anesthetic depth. If anesthesia is maintained with inflow rates of greater than 2 L/min, the alveolar concentration is usually within 10% of the inspired concentration. It is not necessary to deliver concentrations of desflurane far in excess of the desired end-tidal concentration (“overpressurization” technique) due to the low blood and tissue solubilities of desflurane and the resulting rapid equilibrium of alveolar concentration with inspired and delivered concentrations (see Warnings).

Since awakening is rapid, care should be taken that appropriate analgesia has been administered to the patient at the end of the procedure or early in the postanesthesia care unit.

MAC varies widely with age. In 45-year-old patients, MAC is 6% in 100% oxygen and 2.8% in 60% nitrous oxide (see Dosage).

Desflurane is not useful for mask induction as it causes an unacceptably high incidence of laryngospasm, coughing, secretions, breath holding and apnea (see Adverse Effects).

Approximately 0.02% of absorbed desflurane is metabolized. In normal volunteers, there was no increase in serum or urine fluoride concentrations. Studies in patients with chronic renal insufficiency and patients undergoing renal transplantation showed no effects on renal function. Hepatic dysfunction has been reported after desflurane use. A causal relationship may or may not exist.

Desflurane is a profound respiratory depressant, producing a progressive decrease in tidal volume and increase in arterial carbon dioxide tension. Apnea is common at concentrations above 1.5 MAC (Minimum Alveolar Concentration). This depression may be partly reversed by surgical stimulation. Nitrous oxide diminishes the inspired concentration of desflurane required to reach a desired level of anesthesia (see Dosage).

Desflurane potentiates the effect of depolarizing and nondepolarizing neuromuscular relaxants. When compared to nitrous oxide/opioid anesthesia, the requirements for depolarizing and nondepolarizing agents are reduced by 30% and 50%, respectively.

Desflurane, like other volatile anesthetics, induces malignant hyperthermia in genetically susceptible swine (see Precautions).

Hemodynamic Effects: Cardiovascular Effects: In healthy male volunteers, desflurane produced a progressive decrease in blood pressure (15% at 1.2 MAC), due mainly to vasodilation, and an increase in heart rate (15% at 1.2 MAC) when administered in oxygen or 60% nitrous oxide during controlled ventilation at normocapnia. The cardiac output was unchanged at 1.7 MAC in oxygen, but decreased 20% at 1.2 MAC in 60% nitrous oxide. Similar changes were seen during spontaneous ventilation.

Effect on Sympathetic Activity: Constant or slowly increasing concentrations of desflurane blunt or block sympathetic responses to noxious stimuli. The increased heart rate response to hypotension is reduced in this setting. However, rapid changes to concentrations above 6%, as well as rapid changes above 6% can result in tachycardia and hypertension. The physiology of this response is unknown. In unpremedicated volunteers, desflurane can unpredictably induce transient (approximately 4 minutes) increases in sympathetic activity, heart rate and blood pressure. The hemodynamic changes are more common at concentrations 6% and more severe with large (1%), sudden increments. A single clinical study of CABG patients showed similar effects (see Clinical Studies, Cardiovascular Surgery). This transient cardiovascular response can be blunted substantially by fentanyl (1.5 g/kg), alfentanil (10 or 20 g/kg), or clonidine 4 g/kg as a premedication. Esmolol decreases the heart rate, but not blood pressure. The sympathetic stimulation is not obtunded by i.v. or endotracheal lidocaine or by i.v. propofol.

Desflurane does not alter the human myocardial arrhythmogenic threshold for epinephrine (approximately 7 g/kg).

Clinical Studies: The safety and efficacy of desflurane have been established in large, multicentre clinical trials in adult outpatients (ASA I, II and III), in cardiovascular surgery (ASA II, III and IV) patients, in elderly (ASA II and III) patients and in pediatric (ASA I and II) patients.

Ambulatory Surgery: Desflurane was compared to isoflurane in multicentre studies (21 sites) of 792 ASA physical status I, II or III patients aged 18 to 76 years (median 32). Desflurane with or without nitrous oxide or other anesthetics was generally well tolerated. Patients receiving desflurane emerged significantly faster than those receiving isoflurane, and there were no differences in the incidence of nausea and vomiting.

Cardiovascular Surgery: Desflurane was compared to isoflurane, sufentanil or fentanyl for the anesthetic management of coronary artery bypass graft (CABG), abdominal aortic aneurysm, peripheral vascular and carotid endarterectomy surgery in 7 studies at 15 centres involving a total of 558 patients (ASA physical status II, III and IV).

Cardiac Studies: The effects of desflurane in patients undergoing CABG surgery were investigated in 3 studies.

Using echocardiography in addition to Holter monitoring to detect myocardial ischemia, 1 study compared desflurane with sufentanil in groups of 100 patients each. The opioid group received a small dose of thiopental, and sufentanil, 5 to 10 g/kg followed by an infusion of 0.07 g/kg/min, and no halogenated inhaled anesthetic. The desflurane group received no opioid for induction of anesthesia, and after i.v. thiopental had a rapid inhaled induction of anesthesia with desflurane concentrations exceeding 10% end-tidal. The desflurane group had increases in heart rate (HR) and mean arterial pressure (MAP) during induction of anesthesia and a 13% incidence of myocardial ischemia during induction of anesthesia which was greater than the zero incidence during induction in the sufentanil group. During the precardiopulmonary bypass period, more desflurane patients required cardiovascular adjuvants to control hemodynamics than the sufentanil patients. During maintenance of anesthesia, the sufentanil group had myocardial ischemia of greater duration and intensity than did the desflurane group. There were no differences in incidence of myocardial infarction or death between the 2 groups.

The second study compared desflurane with fentanyl in groups of 26 and 25 patients, respectively. The fentanyl group received 50 g/kg and no halogenated inhaled anesthetic. The desflurane group received fentanyl 10 g/kg and a maximum desflurane concentration of 6%. The groups did not differ in the incidence of ECG changes suggestive of ischemia, myocardial infarction, or death.

In the third study, investigators compared desflurane with isoflurane in groups of 57 and 58 patients, respectively. Both groups were given up to 10 g/kg fentanyl during induction of anesthesia. The mean end-tidal anesthetic concentrations prior to coronary bypass were 6% desflurane or 0.9% isoflurane. Desflurane and isoflurane provided clinically acceptable anesthesia prior to and after coronary bypass. A subanalysis was performed for data collected at one of the study centres. At this centre desflurane was administered to 21 patients and 20 patients received isoflurane. Both groups were given fentanyl 10 g/kg; during induction of anesthesia the maximum end-tidal anesthetic concentrations were 6% desflurane or 1.4% isoflurane. The groups had similar incidences of ischemia (as detected by Holter monitoring), myocardial infarction and death.

In the desflurane vs sufentanil study, investigators increased desflurane concentration rapidly to 10.2% end-tidal, without having administered any opioid, thereby increasing HR and MAP and observing a 13% incidence of myocardial ischemia in their patients with coronary artery disease. These rapid increases in desflurane concentration without pretreatment with an opioid, have been demonstrated to increase sympathetic activity, HR and MAP in volunteers. The other studies avoided these increases in HR and MAP by applying lower desflurane concentrations (less than 1 MAC), and by administering substantial doses of fentanyl (10 and 50 g/kg) as part of the induction technique.

Peripheral Vascular Studies: Four randomized, open-label trials were conducted to assess the hemodynamic stability of patients administered desflurane vs isoflurane for maintenance anesthesia in peripheral vascular surgeries.

In all patients, the volatile anesthetics were supplemented with fentanyl. Blood pressure and heart rate were controlled by changes in concentrations of the volatile anesthetics or opioids and cardiovascular drugs, if necessary. No differences were found in cardiovascular outcome (death, myocardial infarction, ventricular tachycardia or fibrillation, heart failure) for desflurane and isoflurane in these studies.

Desflurane should not be used as the sole anesthetic in patients with coronary artery disease or in patients where increases in the heart rate or blood pressure are undesirable (see Warnings).

Geriatric Surgery: Desflurane plus nitrous oxide was compared to isoflurane plus nitrous oxide in a multicentre study (6 sites) of 203 ASA physical status II or III elderly patients, aged 57 to 91 years (median 71). Heart rate and arterial blood pressure remained within 20% of preinduction baseline values during administration of desflurane 0.5 to 7.7% (average 3.6%) with 50 to 60% nitrous oxide. Maintenance and recovery cardiovascular measurements did not differ from those during isoflurane plus nitrous oxide administration, nor did the postoperative incidence of nausea and vomiting. The most common cardiovascular adverse event was hypotension for both isoflurane (6%) as well as desflurane (8%).

Neurosurgery: Desflurane was studied in 38 patients aged 26 to 76 years (median 48 years), ASA physical status II or III undergoing neurosurgical procedures for intracranial lesions. Due to the limited number of patients studied, the safety of desflurane has not been established and is not recommended for use in neurosurgical procedures.

Pediatric Surgery: Desflurane was compared to halothane, with or without nitrous oxide, in 235 patients aged 2 weeks to 12 years (median 2 years), ASA physical status I or II. The concentration of desflurane required for maintenance of anesthesia is age dependent (see Dosage). Changes in blood pressure during maintenance of and recovery from anesthesia were similar between desflurane N 2O/O 2 and halothane/N 2O/O 2. Heart rate during maintenance of anesthesia was approximately 10 beats/min faster with desflurane than with halothane. There were no differences in the incidences of nausea and vomiting between desflurane and halothane.

Indications And Clinical Uses:

As an inhalation agent for maintenance of general anesthesia.

Desflurane is not recommended for mask induction of anaesthesia because of a high incidence of moderate to severe upper airway adverse events (see Adverse Effects).

Contra-Indications:

When general anesthesia is contraindicated. Known sensitivity to desflurane or other halogenated anesthetics. Patients in whom liver dysfunction, jaundice or unexplained fever, leukocytosis, or eosinophilia has occurred after a previous halogenated anesthetic administration (see Warnings). Known or suspected genetic susceptibility to malignant hyperthermia or in patients with a history of malignant hyperthermia (see Precautions).

Warnings in Clinical States:

Desflurane should be administered only by persons trained in the administration of general anesthesia, using a vaporizer specifically designed and designated for use with desflurane. Facilities for maintenance of a patent airway, artificial ventilation, oxygen enrichment and circulatory resuscitation must be immediately available. Hypotension and respiratory depression increase as anesthesia is deepened.

Respiration must be monitored closely and supported when necessary.

Desflurane is not recommended for mask induction as it causes a high incidence of laryngospasm, coughing, breath holding, apnea, increase in secretions and oxyhemoglobin desaturation (see Adverse Effects).

Since awakening is rapid, care should be taken that appropriate analgesia has been administered to the patient at the end of the procedure or early in the postanesthesia care unit. Rapid awakening with pain may be associated with agitation, particularly in pediatric patients.

As with other halogenated anesthetics, desflurane may cause sensitivity hepatitis in patients who have been sensitized by previous exposure to halogenated anesthetics (see Contraindications and Adverse Effects). In these patients, or in patients with pre-existing hepatic conditions, appropriate alternative therapy should be considered.

In healthy volunteers, in the absence of concomitant N 2O and/or opioid administration, sudden step increases in the end-tidal concentration of desflurane may cause transient increases in sympathetic activity with associated increases in heart rate and blood pressure. The hemodynamic changes are more common at concentrations 6% and more severe with large (1%), sudden increments. Without treatment, and without further increases in desflurane concentration, these increases in heart rate and blood pressure resolve in approximately 4 minutes. At the new, higher end-tidal desflurane concentration blood pressure is likely to be lower and heart rate higher than at the previous, lower steady-state desflurane concentration. The transient increases of heart rate and blood pressure are less if the end-tidal concentration of desflurane is increased in increments of 1% or less. However, if during the transiently increased heart rate and blood pressure the end-tidal concentration of desflurane is again rapidly increased, further increase of heart rate and blood pressure may result. Administration of sympatholytic drugs (fentanyl, alfentanil, esmolol, clonidine) prior to a sudden step increase of desflurane blunts or blocks the increase in heart rate and blood pressure. The sympathetic response is not obtunded by i.v. or endotracheal lidocaine or by i.v. propofol (see ).

When desflurane is used in the clinical setting, the following should be considered:

Desflurane should not be used as the sole anesthetic in patients with coronary artery disease or in patients where increases in heart rate or blood pressure are undesirable. Rapid inhaled induction of anesthesia with desflurane alone, without concomitant administration of an opioid, in patients with coronary artery disease, has been associated with an increased incidence of myocardial ischemia. Desflurane, when given in conjunction with opioids for maintenance of anesthesia in patients with coronary artery disease, has not produced an incidence of ischemia different from that produced by other anesthetics. Thus, when desflurane is to be used in patients with coronary artery disease, it should always be used in combination with other medications, such as i.v. opioids or hypnotics and it should not be used for induction (see).

When changing the depth of anesthesia, rapid increases in the end-tidal concentration of desflurane should be avoided and the end-tidal concentration increased in small increments of 1% or less. It is not necessary to deliver concentrations of desflurane far in excess of the desired end-tidal concentration (“overpressurization” technique) due to the low blood and tissue solubilities of desflurane and the resulting rapid equilibrium of alveolar concentration with inspired and delivered concentrations; thus the transient and self-limiting increases in heart rate and blood pressure may be avoided.

During maintenance of anesthesia, increases in heart rate and blood pressure occurring after rapid incremental increases in end-tidal concentration of desflurane may not represent inadequate anesthesia. The changes due to sympathetic activation resolve in approximately 4 minutes. Increases in heart rate and blood pressure occurring before or in the absence of a rapid increase in desflurane concentration, may be interpreted as light anesthesia. Thus, in such patients, incremental increases of 0.5 to 1% end-tidal desflurane may attenuate these signs of light anesthesia, as may concomitant administration of analgesics. Should raised heart rate and blood pressure persist, then other causes should be sought.

There are no data regarding the cardiovascular effects of desflurane in hypovolemic and hypotensive patients.

Precautions:

General: As with any inhalation agent, the use of desflurane proportionately decreases the concentration of all other gases administered concurrently, including O 2. For example, the addition of 10% desflurane to 70% N 2O and 30% O 2 reduces the O 2 concentration to 27%.

Nitrous oxide diminishes the inspired concentration of desflurane required to reach a desired level of anesthesia (see Dosage).

As with other rapidly acting anesthetic agents, rapid emergence with desflurane should be taken into account in cases where postanesthesia pain is anticipated. Care should be taken that appropriate analgesia has been administered to the patient at the end of the procedure or early in the postanesthesia care unit stay (see Warnings).

As with other halogenated anesthetic agents, there is some elevation of glucose intraoperatively. Glucose elevation should be considered in diabetic patients.

Desflurane can react with desiccated carbon dioxide (CO 2) absorbents to produce carbon monoxide which may result in elevated levels of carboxyhemoglobin in some patients. In clinical practice, cases of elevated carboxyhemoglobin have been reported in association with desflurane. Case reports suggest that barium hydroxide lime and sodalime become desiccated when fresh gases are passed through the CO 2 absorber cannister 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.

Geriatrics: The MAC in geriatric patients is approximately 70% of the adult dose in 100% oxygen and 40% the adult dose in 60% nitrous oxide (see Dosage).

Pregnancy: There are no adequate and well-controlled studies in pregnant women. Desflurane should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Obstetrics: Due to the limited number of patients studied, safety of desflurane in obstetrics has not been established at this time.

Children: The MAC of desflurane in pediatric patients is higher than that in young adults (see Dosage). Several publications in the literature have reported frequent agitation upon emergence from desflurane anesthesia in children. It is unknown whether this is related to desflurane or to the rapid transition from anesthesia to consciousness.

Renal and Hepatic Impairment: No dosage adjustments are required in these patients. Hepatic dysfunction has been reported after desflurane use (see Adverse Effects, Laboratory Findings). A causal relationship may or may not exist.

Neurosurgery: Due to the limited number of patients studied, the safety of desflurane has not been established and is not recommended for use in neurosurgical procedures (see , Clinical Studies).

Drug Interactions :

Benzodiazepines: Midazolam (25 to 50 g/kg) decreases the MAC of desflurane by 16%.

Opioids: Immediately following the administration of fentanyl (3 to 6 g/kg) the MAC of desflurane decreases by 50%.

Neuromuscular Relaxants: Desflurane potentiates the effect of depolarizing and nondepolarizing neuromuscular relaxants. When compared to nitrous oxide/opioid anesthesia, the requirements for depolarizing and nondepolarizing agents are reduced by 30% and 50%, respectively.

Other Drugs: The effects of desflurane on the disposition of other drugs has not been determined.

Pheochromocytoma/Neuroblastoma: There are insufficient data on the use of desflurane in patients with pheochromocytoma and neuroblastoma. Since desflurane can cause stimulation of the sympathetic nervous system, its use is not recommended in patients with these conditions (see Warnings).

Malignant Hyperthermia: In susceptible individuals, desflurane anesthesia may trigger a skeletal muscle hypermetabolic state leading to high oxygen demand and the clinical syndrome known as malignant hyperthermia. The clinical syndrome includes nonspecific features such as muscle rigidity, tachycardia, tachypnea, cyanosis, arrhythmias and unstable blood pressure. Some of these nonspecific signs may also appear during light anesthesia, acute hypoxia, hypercapnia and hypovolemia. An increase in overall metabolism may be reflected in an elevated temperature (which may rise rapidly early or late in the case, but usually is not the first sign of augmented metabolism) and an increased usage of the CO 2 absorption system (hot canister). PaO 2 and pH may decrease, and hyperkalemia and a base deficit may appear. Treatment includes discontinuation of desflurane, administration of i.v. dantrolene sodium, and application of supportive therapy. Such therapy includes vigorous efforts to restore body temperature to normal, respiratory and circulatory support as indicated, and management of electrolyte-fluid-acid-base derangements. (Consult prescribing information for dantrolene sodium i.v. for additional information on patient management.) Renal failure may appear later, and urine flow should be sustained if possible.

Drug Interactions :

Adverse event information is derived from controlled clinical trials. The studies were conducted using a variety of premedications, other anesthetics, and surgical procedures of varying length. Of the 1 843 patients exposed to desflurane in clinical trials, 1 209 were used in estimating the incidence of adverse reactions below. Of these, 370 adults and 152 children were induced with desflurane alone and 687 patients were maintained principally with desflurane. Frequencies reflect the percent of patients with the event and each patient was counted once for each type of adverse event. They are presented in alphabetical order within each body system.

Probably Causally Related: Incidence Greater than 1%. Induction (Use as a Mask Inhalation Agent): Adult Patients (n=370): coughing 34%, breath holding 27%, apnea 15%, increased secretions 9%, laryngospasm 8%, oxyhemoglobin desaturation (SpO 2 <90%) 8%, pharyngitis 4% (see Warnings). Pediatric patients (n=152): coughing 72%, breath holding 63%, laryngospasm 50%, oxyhemoglobin desaturation (SpO 2 <90%) 26%, increased secretions 21%, bronchospasm 3% (see Warnings).

Maintenance or Recovery: Adult and Pediatric Patients (n=687): Body as a Whole: headache 1%.

Cardiovascular: bradycardia 1%, hypertension 1%, nodal arrhythmia 1%, tachycardia 1%.

Digestive: nausea 27%, vomiting 16%.

Nervous System: increased salivation 1%.

Respiratory: apnea 7%, breath holding 2%, cough increased 4%, laryngospasm 3%, pharyngitis 1%.

Special Senses: conjunctivitis (conjunctival hyperemia) 2%.

Probably Causally Related: Incidence Less than 1% and Reported in 3 or More Patients, Regardless of Severity (n=1 843): Cardiovascular: arrhythmia, bigeminy, ECG abnormal, myocardial ischemia, vasodilation.

Nervous System: agitation, dizziness.

Respiratory: asthma, dyspnea, hypoxia.

Causal Relationship Unknown: Incidence Less than 1% and Reported in 3 or More Patients, Regardless of Severity (n=1 843): Body as a Whole: fever.

Cardiovascular: hemorrhage, myocardial infarct.

Metabolic and Nutrition: creatinine phosphokinase increased.

Musculoskeletal System: myalgia.

Skin and Appendages: pruritus.

See Precautions for information regarding pediatric use and malignant hyperthermia.

Laboratory Findings: Transient elevations in glucose and white blood cell count may occur as with the use of other anesthetic agents. Abnormal liver function tests were observed in <1% of patients. Hepatitis has been reported very rarely.

Symptoms And Treatment Of Overdose:

OverdoseSymptoms: Marked hypotension, tachycardia and apnea.Treatment

Treatment: Stop drug administration. Support respiration and circulation as required.

Dosage And Administration:

General: Deliver from a vaporizer specifically designed and designated for use with desflurane.

Premedication should be selected according to the need of the individual patient. There is no evidence of interaction between desflurane and commonly used anticholinergic drugs. Desflurane is potentiated by benzodiazepines and opioids (see Precautions, Drug Interactions).

Desflurane is not recommended for mask induction as it causes a high incidence of laryngospasm, coughing, secretions, breath holding, apnea, and increase in secretions and oxyhemoglobin desaturation (see Adverse Effects).

Maintenance: Adults: Surgical levels of anesthesia in adults may be maintained with concentrations of 2.5 to 8.5% desflurane with or without the concomitant use of nitrous oxide.

Children: Surgical anesthesia is maintained with concentrations of 5.2 to 10% desflurane in children with or without the concomitant use of nitrous oxide.

Geriatrics: Geriatric patients require approximately 70% the adult dose in 100% oxygen and approximately 40% the adult dose in 60% nitrous oxide.

Desflurane should not be used as the sole anesthetic in patients with coronary artery disease or in patients where increases in heart rate or blood pressure are undesirable. Rapid inhaled induction of anesthesia with desflurane alone, without concomitant administration of an opioid, in patients with coronary artery disease, has been associated with an increased incidence of myocardial ischemia. Desflurane, when given in conjunction with opioids for maintenance of anesthesia in patients with coronary artery disease, has not produced an incidence of ischemia different from that produced by other anesthetics. Thus, when desflurane is to be used in patients with coronary artery disease, it should always be used in combination with other medications, such as i.v. opioids or hypnotics and it should not be used for induction (see ).

When changing the depth of anesthesia, rapid increases in the end-tidal concentration of desflurane should be avoided and the end-tidal concentration increased in small increments of 1% or less. It is not necessary to deliver concentrations far in excess of the desired end-tidal concentration (“overpressurization” technique) due to the low blood and tissue solubilities of desflurane and the resulting rapid equilibrium of alveolar concentration with inspired and delivered concentrations; thus the transient and self-limiting increases in heart rate and blood pressure may be avoided.

During maintenance of anesthesia, increases in heart rate and blood pressure occurring after rapid incremental increases in end-tidal concentration of desflurane may not represent inadequate anesthesia. The changes due to sympathetic activation resolve in approximately 4 minutes. Increases in heart rate and blood pressure occurring before or in the absence of a rapid increase in desflurane concentration may be interpreted as light anesthesia. Thus, in such patients, incremental increases of 0.5 to 1% end-tidal desflurane may attenuate these signs of light anesthesia, as may concomitant administration of analgesics. Should raised heart rate and blood pressure persist, then other causes should be sought.

Availability And Storage:

Each bottle contains: desflurane 240 mL. Amber glass bottles of 250 mL. Store at or below 30°C.

SUPRANE® AstraZeneca Desflurane Inhalation Anesthetic

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