Piramal
ISOFLURANE
Isoflurane Inhalation Anesthetic

 

 

Composition and Description

Isoflurane is a colourless non-flammable general inhalation anaesthetic which contains no additive or stabiliser. It is 1-chloro-2,2,2-trifluoroethyl difluoromethyl ether.

 

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Indications

General inhalation anaesthetic for use in induction and maintenance.

 

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Contraindications

Known sensitivity to isoflurane or to other halogenated agents.

Isoflurane should never be given to patients with known or suspected susceptibility to malignant hyperthermia.

Isoflurane must not be used in patients who have developed an icterus and/or fever of unknown origin, hepatic impairment or eosinphilia after administration of isoflurane or another halogenated anaesthetic.

 

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Precautions

Isoflurane is a profound respiratory depressant, this effect being accentuated by narcotic premedication or concurrent use of other respiratory depressants.
Isoflurane causes an increase in cerebral blood flow at deeper levels of anaesthesia, (1·5%), and this may give rise to an increase in cerebral spinal fluid pressure. Where appropriate, this can be prevented or reversed by hyper-ventilating the patient before or during anaesthesia. As with other halogenated anaesthetics, isoflurane must be used with caution in patients with increased intracranial pressure. Again, in such cases, hyperventilation may be necessary.

As with all halogenated anaesthetics, repeat anaesthesia within a short period of time should be approached with caution since the risk of hepatotoxicity is not fully understood. There is insufficient experience of use in repeated anaesthesia to make a definite recommendation in this regard.

Isoflurane has been reported to interact with dry carbon dioxide adsorbents during closed circuit anaesthesia, to form carbon monoxide. Inhalation of carbon monoxide may lead to formation of significant levels of carboxyhaemoglobin in exposed patients.

Carboxyhaemoglobin is toxic even in low concentrations and is not easily detected by standard anaesthesia monitors such as pulse oximeters. Direct measurement of carboxyhaemoglobin should be carried out in the event that a patient on closed circuit anaesthesia with an implicated agent develops oxygen desaturation which does not respond to the usual therapeutic measures. All necessary precautions should be taken to ensure that carbon dioxide adsorbents are not allowed to dry out.

Caution should be exercised when administering isoflurane to patients with pre-existing liver disease.

Isoflurane is a powerful systemic and coronary arterial dilator. The effect on systemic arterial pressure is easily controlled in the normal healthy patient and has been used specifically as a means of inducing hypotension. However, the phenomenon of "coronary steal" means that isoflurane should be used with caution in patients with coronary artery disease. In particular, patients with subendocardial ischaemia might be anticipated to be more susceptible.

Salivation and tracheo-bronchial secretions may be stimulated in children but pharyngeal and laryngeal reflexes are quickly diminished.

Because levels of anaesthesia can be altered easily and quickly with isoflurane, only vaporisers which produce a predictable concentration with a good degree of accuracy should be used. The degree of hypotension and ventilatory depression may provide some indication as to the level of anaesthesia. The level of anaesthesia may be changed quickly with isoflurane. Heart rhythm remains stable but spontaneous breathing should be monitored closely and supported where necessary.

It is recommended that vapour from this and other inhalational agents are efficiently extracted from the area of use.

Isoflurane should only be administered by, or in the presence of, anaesthetists with the appropriate anaesthesia and resuscitation equipment.

 

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Drug Interactions

Muscle Relaxants
Isoflurane produces sufficient muscle relaxation for some intra- abdominal operations. Isoflurane is compatible with all commonly used muscle relaxants, the effects of which may be markedly potentiated by isoflurane. The effect is most notable in non-depolarising agents, thus lower doses should be used in the presence of isoflurane. The effect of non-depolarising muscle relaxants can be counteracted by administering neostigmine as this has no effect on the relaxant properties of isoflurane.

Adrenaline
Administration of adrenaline (epinephrine) by any route during isoflurane anaesthesia may cause supraventricular or ventricular arrhythmias. Where adrenaline is used, the amount used should be limited to a maximum of 3µg/kg of bodyweight in patients with normal hearts, and less in those with rhythm disturbances. Concurrent use of other b-sympathomimetic drugs such as amphetamines may predispose to arrhythmias. If possible, interrupt treatment a few days before surgery.

Calcium Antagonists (and Other Vasodilators)
Isoflurane can cause marked hypotension in patients receiving concomitant therapy with calcium antagonists, especially those of the dihydropyridine class. Patients receiving chronic therapy with other vasodilators such as ACE inhibitors (eg captopril, enalapril, lisinopril) or a1-adrenoceptor antagonists (eg prazosin), may show unpredictable hypotension with any type of anaesthesia.

Monoamine oxidase inhibitors
Monoamine oxidase inhibitors have been shown to enhance the effects of general anaesthetics. If possible, patients should stop taking the MAOI drug at least 14 days before anticipated surgery.

Beta-blockers
Beta-blockers used in the peri-operative period will prevent, or reduce, any tendency for isoflurane to increae the heart rate. Thus, beta-blockade will normally tend to be cardioprotective. Should an increase in heart rate, or vasoconstriction, be required, appropriate sympathomimetics should be given by the anaesthetist. A full drug history should always be taken by the anaesthetist.

Isoniazid
Isoniazid induces enzymes. Patients receiving isoniazid may be more susceptible to hepatotoxicity from volatile anaesthetics. If possible cease isoniazid treatment one week before surgery.

Opioid analgesics

Opioid analgesics potentiate the respiratory depressant effect of isoflurane.

Pregnancy and Lactation
Reproduction studies have been carried out on rats and rabbits after repeated exposure to isoflurane at anaesthetic concentrations. In both species there was no effect on fertility, pregnancy or delivery. The viability of the offspring was unaffected.

The correlation between animal study results and human reactions is not known, and insufficient data are present for humans and animals to estimate the risk of teratogenicity in children of women who receive isoflurane anaesthesia during pregnancy. Isoflurane is not recommended during the first trimester of pregnancy.

All anaesthetics should be avoided during pregnancy if possible. Unavoidable anaesthesia with isoflurane should be undertaken using due caution.

There is an increasing volume of information on the use of isoflurane in pregnancy and obstetrics anaesthesia and use in operative obstetrical interventions such as Caesarean section is established.

A suitable level of anaesthesia for Caesarean section can be maintained with 0·5-0·75% isoflurane in oxygen/nitrous oxide.

Increased blood loss has been observed, comparable with other volatile anaesthetics (eg halothane), in patients undergoing uterine curettage or other gynaecological surgical procedures.

Should isoflurane be administered during lactation, lactation is to be interrupted after the anaesthesia. Lactation can be restarted after the drug has been discharged from the circulation.

Driving: Use of Machinery
As with all general inhalation anaesthetics, it is advisable to allow 24 hours to elapse before driving or operating machinery.

 

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Dosage and Administration

Isoflurane has a slight pungent ethereal odour, which may limit the rate of gas induction but, despite this, induction and particularly recovery are rapid.

The use of isoflurane-specific vaporisers will facilitate accurate control of the administered concentration of anaesthetic.

The MAC (Minimum Alveolar Concentration) the standard measure of potency for anaesthetics, is 1.15% in pure oxygen, decreasing to 0.5% when given with 70% nitrous oxide, for middle-aged humans. There is an age-relationship: the MAC is significantly higher in children and is lower in the elderly:

AGE

Ave. Conc. In Ave. Conc.withOxygen

                                   

MAC Ave. Conc. with 75% N2O

up to 12 months 1.60 to 1.85%

0.49 to 0.69

1 to 5 years 1.50 to 1.60% 0.49 to 0.67
   

Ave. Conc. with70% N2O

                                                                       
Mid-twenties 1.25 to 1.30%

0.49 to 0.63

Mid-forties 1.10 to 1.20%

0.43 to 0.57

Mid-sixties 1.00 to 1.10% 0.33 to 0.41

 

Premedication
Premedication drugs should be selected according to the needs of the patient. The ventilatory depressant effect of isoflurane should be taken into account. Anticholinergic drugs (eg atropine, glycopyrrolate USP) may be used for their effects in drying oral secretions (antisialogogue) at the discretion of the anaesthetist, but they may enhance the weak effects of isoflurane in increasing heart rate.

Induction
As isoflurane has a mild pungency, inhalation should usually be preceded by the use of a short acting barbiturate, or other intravenous induction agent, to prevent coughing.

Salivation and coughing may be troublesome in small children induced with isoflurane. Alternatively, isoflurane with oxygen or with an oxygen/nitrous oxide mixture may be administered. It is recommended that induction with isoflurane be initiated at a concentration of 0·5%. Concentrations of 1·5-3·0% usually produce surgical anaesthesia in 7-10 minutes. Blood pressure decreases during induction but this may be compensated by surgical stimulation.

Maintenance
Adequate anaesthesia for surgery may be sustained with an inspired isoflurane concentration of 1·0% to 2·5% in an oxygen/70% nitrous oxide mixture. Additional inspired isoflurane (0·5% to 1·0%) will be required with lower nitrous oxide levels, or when isoflurane is given with oxygen alone or with air/oxygen mixtures. Blood pressure decreases during maintenance anaesthesia in relation to the depth of anaesthesia. That is, blood pressure is inversely related to the isoflurane concentration. Provided there are no other complicating factors this is probably due to peripheral vasodilation. Cardiac rhythm remains stable. Excessive falls in blood pressure may be due to the depth of anaesthesia and in such circumstances can be corrected by reducing the inspired isoflurane concentration.

Induced hypotension can be achieved by artificially ventilating patients with isoflurane 2·5-4·0%. Pre-treatment with Clonidine significantly decreases the isoflurane requirement for maintaining induced hypotension.

Recovery
The concentration of isoflurane can be reduced to 0.5% at the start of closing the operation wound, and then to 0% at the end of surgery, provided that the anaesthetist is satisfied that the effect of any neuromuscular blocking drugs has been reversed and the patient is no longer paralysed. After discontinuation of all anaesthetics, the airways of the patient should be ventilated several times with oxygen 100% until complete recovery.

 

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Side Effects and Adverse Reactions

Adverse reactions encountered with isoflurane are similar to those observed with other halogenated anaesthetics; these are hypotension, respiratory depression and arrhythmias. Other minor side effects encountered while using isoflurane are an increase in the white blood cell count (even in the absence of surgical stress) and also shivering, nausea and vomiting during the postoperative period. These side effects are only observed in a similar number of patients to other anaesthetics.

Increase in heart rate has been reported.

Rare cases of bronchospasm have been reported.

During marketing there have been rare reports of mild, moderate and severe (some fatal) post-operative hepatic dysfunction. The causal relationship is unknown.

 

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Overdose

Overdosing with isoflurane will result in marked depression of breathing, and a marked decrease in blood pressure, the latter being predominantly due to peripheral vasodilation rather than direct myocardial depression.

If it appears that an overdose has been administered, stop drug inspiration immediately, ensure a clear airway, and ventilate the lungs with oxygen. Institute assisted or controlled ventilation.

 

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Pharmaceutical Precaution

Store at controlled room temperature (15 to 30°C) with cap tightly closed and out of the reach of children. Expiry date 5 years. The product should not be used after the date indicated on the label.

 

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Package Information

Isoflurane is supplied in bottles of 100 ml or 250 ml.

 

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