WARNINGS
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.
Malignant Hyperthermia
In susceptible individuals, potent inhalation anesthetic agents may trigger a skeletal muscle hypermetabolic state leading to high oxygen demand and the clinical syndrome known as malignant hyperthermia. In genetically susceptible pigs, desflurane induced malignant hyperthermia. The clinical syndrome is signalled by hypercapnia, and may include muscle rigidity, tachycardia, tachypnea, cyanosis, arrhythmias, and/or unstable blood pressure. Some of these nonspecific signs may also appear during light anesthesia: acute hypoxia, hypercapnia, and hypovolemia.
Treatment of malignant hyperthermia includes discontinuation of triggering agents, administration of intravenous dantrolene sodium, and application of supportive therapy. (Consult prescribing information for dantrolene sodium intravenous for additional information on patient management.) Renal failure may appear later, and urine flow should be monitored and sustained if possible.
Respiratory Adverse Reactions in Pediatric Patients
SUPRANE (desflurane, USP) is not recommended for induction of general anesthesia via mask in children due to a high incidence of moderate to severe respiratory adverse reactions seen in clinical studies (see PRECAUTIONS– Pediatric Use).
SUPRANE 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 PRECAUTIONS– Pediatric Use).
Administration of Suprane
SUPRANE (desflurane, USP) 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.
PRECAUTIONS
During the maintenance of anesthesia, increasing concentrations of SUPRANE (desflurane, USP) produce dose-dependent decreases in blood pressure. Excessive decreases in blood pressure may be related to depth of anesthesia and in such instances may be corrected by decreasing the inspired concentration of SUPRANE.
Concentrations of desflurane exceeding 1 MAC may increase heart rate. Thus an increased heart rate may not be a sign of inadequate anesthesia.
In patients with intracranial space occupying lesions, SUPRANE (desflurane, USP) should be administered at 0.8 MAC or less, in conjunction with a barbiturate induction and hyperventilation (hypocapnia). Appropriate measures should be taken to maintain cerebral perfusion pressure (see CLINICAL STUDIES, Neurosurgery).
In patients with coronary artery disease, maintenance of normal hemodynamics is important to the avoidance of myocardial ischemia. Desflurane 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, Cardiovascular Surgery).
Inspired concentrations of SUPRANE (desflurane, USP) 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.
The recovery from general anesthesia should be assessed carefully before patients are discharged from the post anesthesia care unit (PACU).
SUPRANE (desflurane, USP), like some other inhalational anesthetics, can react with desiccated carbon dioxide (CO2) absorbents to produce carbon monoxide which may result in elevated levels of carboxyhemoglobin in some patients. Case reports suggest that barium hydroxide lime and soda lime become desiccated when fresh gases are passed through the CO2 absorber cannister at high flow rates over many hours or days. When a clinician suspects that CO2 absorbent may be desiccated, it should be replaced before the administration of SUPRANE (desflurane, USP).
As with other halogenated anesthetic agents, SUPRANE (desflurane, USP) may cause sensitivity hepatitis in patients who have been sensitized by previous exposure to halogenated anesthetics (see CONTRAINDICATIONS).
Drug Interactions
No clinically significant adverse interactions with commonly used preanesthetic drugs, or drugs used during anesthesia (muscle relaxants, intravenous agents, and local anesthetic agents) were reported in clinical trials. The effect of desflurane on the disposition of other drugs has not been determined.
Like isoflurane, desflurane does not predispose to premature ventricular arrhythmias in the presence of exogenously infused epinephrine in swine.
Benzodiazepines and Opioids (MAC Reduction)
Benzodiazepines (midazolam 25-50 µg/kg) decrease the MAC of desflurane by 16% as do the opioids (fentanyl 3-6µg/kg) by 50% (see DOSAGE AND ADMINISTRATION).
Neuromuscular Blocking Agents
Anesthetic concentrations of desflurane at equilibrium (administered for 15 or more minutes before testing) reduced the ED95 of succinylcholine by approximately 30% and that of atracurium and pancuronium by approximately 50% compared to N2O/opioid anesthesia. The effect of desflurane on duration of nondepolarizing neuromuscular blockade has not been studied.
DOSAGE OF MUSCLE RELAXANT CAUSING 95% DEPRESSION IN NEUROMUSCULAR BLOCKADE | Desflurane Concentration | Mean ED95 (µg/kg) |
| Pancuronium | Atracurium | Succinylcholine |
| 0.65 MAC 60% N2O/O2 | 26 | 123 | - |
| 1.25 MAC 60% N2O/O2 | 18 | 91 | - |
| 1.25 MAC O2 | 22 | 120 | 362 |
Dosage reduction of neuromuscular blocking agents during induction of anesthesia may result in delayed onset of conditions suitable for endotracheal intubation or inadequate muscle relaxation, because potentiation of neuromuscular blocking agents requires equilibration of muscle with the delivered partial pressure of desflurane.
Among nondepolarizing drugs, only pancuronium and atracurium interactions have been studied. In the absence of specific guidelines:
1. For endotracheal intubation, do not reduce the dose of nondepolarizing muscle relaxants or succinylcholine.
2. During maintenance of anesthesia, the dose of nondepolarizing muscle relaxants is likely to be reduced compared to that during N2O/opioid anesthesia. Administration of supplemental doses of muscle relaxants should be guided by the response to nerve stimulation.
Renal or Hepatic Insufficiency
Nine patients receiving SUPRANE (desflurane, USP) (N=9) were compared to 9 patients receiving isoflurane, all with chronic renal insufficiency (serum creatinine 1.5-6.9 mg/dL). No differences in hematological or biochemical tests, including renal function evaluation, were seen between the two groups. Similarly, no differences were found in a comparison of patients receiving either SUPRANE (desflurane, USP) (N=28) or isoflurane (N=30) undergoing renal transplant.
Eight patients receiving SUPRANE (desflurane, USP) were compared to six patients receiving isoflurane, all with chronic hepatic disease (viral hepatitis, alcoholic hepatitis, or cirrhosis). No differences in hematological or biochemical tests, including hepatic enzymes and hepatic function evaluation, were seen.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Animal carcinogenicity studies have not been performed with SUPRANE (desflurane, USP). In vitro and in vivo genotoxicity studies did not demonstrate mutagenicity or chromosomal damage by SUPRANE. Tests for genotoxicity included the Ames mutation assay, the metaphase analysis of human lymphocytes, and the mouse micronucleus assay.
Fertility was not affected after 1 MAC-Hour per day exposure (cumulative 63 and 14 MAC-Hours for males and females, respectively). At higher doses, parental toxicity (mortalities and reduced weight gain) was observed which could affect fertility.
Pregnancy
Teratogenic Effects
No teratogenic effect was observed at approximately 10 and 13 cumulative MAC-Hour exposures at 1 MAC-Hour per day during organogenesis in rats or rabbits. At higher doses increased incidences of post-implantation loss and maternal toxicity were observed. However, at 10 MAC-Hours cumulative exposure in rats, about 6% decrease in the weight of male pups was observed at preterm caesarean delivery.
Pregnancy Category B
There are no adequate and well-controlled studies in pregnant women. SUPRANE (desflurane, USP) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Rats exposed to desflurane at 1 MAC-Hour per day from gestation day 15 to lactation day 21, did not show signs of dystocia. Body weight of pups delivered by these dams at birth and during lactation were comparable to that of control pups. No treatment related behavioral changes were reported in these pups during lactation.
Labor and Delivery
The safety of desflurane during labor or delivery has not been demonstrated.
Nursing Mothers
The concentrations of desflurane in milk are probably of no clinical importance 24 hours after anesthesia. Because of rapid washout, desflurane concentrations in milk are predicted to be below those found with other volatile potent anesthetics.
Pediatric Use
SUPRANE (desflurane, USP) is approved for maintenance of anesthesia in infants and children after induction of anesthesia with agents other than SUPRANE, and tracheal intubation.
SUPRANE is not recommended for induction of general anesthesia via mask in children because of the high incidence of moderate to severe respiratory adverse reactions, including laryngospasm (50%), coughing (72%), breathholding (68%), increase in secretions (21%) and oxyhemoglobin desaturation (SpO2< 90%) (26%) seen in clinical studies.
SUPRANE is not approved for maintenance of anesthesia in non-intubated children due to an increased incidence of respiratory adverse reactions (see below).
In a clinical safety trial conducted in children aged 2 to 16 years (mean 7.4 years), following induction with another agent, SUPRANE and isoflurane (in N2O/O2) were compared when delivered via face mask or laryngeal mask airway (LMA) for maintenance of anesthesia, after induction with intravenous propofol or inhaled sevoflurane, in order to assess the relative incidence of respiratory adverse events.
MAINTENANCE IN NONINTUBATED PEDIATRIC PATIENTS(FACE MASK OR LMA USED; N=300) All Respiratory Events
(>1% of All Pediatric Patients) | | All Ages (N=300) | 2-6 yr (N=150) | 7-11 yr (N=81) | 12-16 yr (N=69) |
| Any respiratory events | 39% | 42% | 33% | 39% |
| Airway obstruction | 4% | 5% | 4% | 3% |
| Breath-holding | 3% | 2% | 3% | 4% |
| Coughing | 26% | 33% | 19% | 22% |
| Laryngospasm | 13% | 16% | 7% | 13% |
| Secretion | 12% | 13% | 10% | 12% |
| Non-specific desaturation | 2% | 2% | 1% | 1% |
SUPRANE was associated with higher rates (compared with isoflurane) of coughing, laryngospasm and secretions with an overall rate of respiratory events of 39%. Of the pediatric patients exposed to desflurane, 5% experienced severe laryngospasm (associated with significant desaturation; i.e. SpO2 of <90% for >15 seconds, or requiring succinylcholine), across all ages, 2-16 years old. Individual age group incidences of severe laryngospasm were 9% for 2-6 years old, 1% for 7-11 years old, and 1% for 12-16 years old. Removal of LMA under deep anesthesia (MAC range 0.6 – 2.3 with a mean of 1.12 MAC) was associated with a further increase in frequency of respiratory adverse events as compared to awake LMA removal or LMA removal under deep anesthesia with the comparator. The frequency and severity of non-respiratory adverse events were comparable between the two groups.
The incidence of respiratory events under these conditions was highest in children aged 2-6 years. Therefore, similar studies in children under the age of 2 years were not initiated.
Geriatric Use
The average MAC for SUPRANE (desflurane, USP) in a 70 year old patient is two-thirds the MAC for a 20 year old patient (see DOSAGE AND ADMINISTRATION).
Neurosurgical Use
SUPRANE (desflurane, USP) may produce a dose-dependent increase in cerebrospinal fluid pressure (CSFP) when administered to patients with intracranial space occupying lesions. Desflurane should be administered at 0.8 MAC or less, and in conjunction with a barbiturate induction and hyperventilation (hypocapnia) until cerebral decompression in patients with known or suspected increases in CSFP. Appropriate attention must be paid to maintain cerebral perfusion pressure (see CLINICAL STUDIES, Neurosurgery).
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