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Medicine, Surgery

Sevoflurane, Surgical Anesthetic

Introduction

Boston; early demonstration of ether as surgical anesthesia
Boston; early demonstration of ether as surgical anesthesia

Sevoflurane is a general anesthetic used to bring about total but reversible unconsciousness in patients, usually for the purpose of surgery. It is a clear, colorless, non-corrosive, non-flammable and non-explosive volatile (easily vaporized) liquid administered with the aid of an anesthesia machine which vaporizes the drug and mixes it with oxygen, ambient air, and often nitrous oxide.

Sevoflurane is the most commonly used of the modern volatile anesthetics, chiefly because it is least irritating to mucous membranes during induction. Together with desflurane, sevoflurane has replaced isoflurane and halothane as the modern inhalation anesthetics of choice, with much of the clinical research performed demonstrating their superiority of performance in patient emergence, orientation, postoperative cognition, and psychomotor function recovery, including time to sitting and ambulation. Further, it facilitates more predictable extubation (removal of airway tube) times and significantly better postoperative modified Aldrete scores in outpatients (assessing level of consciousness, respiratory status, circulatory status, pain and nausea on a 1-10 scale); and it has a lower potential for hepatic injury compared to isoflurane, halothane, and other traditional general anesthetics.

Sevoflurane’s characteristic low solubility and sweet fragrance facilitate rapid mask induction; the low blood solubility also expedites “wash-out” (elimination via lungs) and therefore recovery 1. Sevoflurane produces dose-dependent central nervous, cardiovascular and respiratory depressant effects similar to other general anesthetics, but overall has a more favorable cardiovascular profile 2. It is degraded by carbon dioxide absorbents (soda lime in delivery apparatus) to nephrontoxic halo-alkenes (kidney-poisoning halogen-substituted alkenes) in rats, although renal (kidney) toxicity has not been observed in humans, perhaps because sevoflurane undergoes minimal intrarenal defluorination (removal of fluorine; formation of fluorine ions), despite elevated plasma fluoride levels after its delivery. Compared with other inhalation anesthetics, negligible quantities of carbon monoxide are generated from this degradation process 3.

Sevoflurane has been shown to attenuate the endocrine stress response better, and interfere with cellular immunity less, than common intravenously administered anesthetics 4.

Fun Fact

The Environmental Protection Agency has classified sevoflurane as a greenhouse gas, with a global warming potential of 345 (carbon dioxide equivalency).

History, Development

Sevoflurane first appeared in the literature in 1971, developed by scientists at Baxter Laboratories. It was first introduced into clinical practice in Japan in 1990. Abbott Laboratories holds the rights for sevoflurane in the US and several other countries.

Trade Names

  • US: Ultane
  • Canada: Sevorane

Clinical Use

General Anesthetic Procedure

  • Preanaesthetic assessment – an interview to determine anesthetic case plan
  • Administration of general anesthetic(s)
    • Induction (begins stage 1)
    • Stages of anesthesia
      • Stage 1 – between induction and loss of consciousness
      • Stage 2 – period following loss of consciousness: respirations and heart rate may become irregular, with uncontrolled movements, vomiting, breath holding, and pupillary dilation possible
      • Stage 3 – skeletal muscles relax; patient’s breathing becomes regular. Eye movements slow, then stop, and surgery can begin.
        • rolling eye balls, ending with fixed eyeballs
        • loss of corneal and laryngeal reflexes
        • pupils dilate and loss of light reflex
        • intercostal paralysis, shallow abdominal respiration, dilated pupils
      • Stage 4 – lethal overdose; stage 4 is undesirable
    • Maintenance
  • Use of analgesia (reducing pain signal transmissions to reduce heart rate and blood pressure responses to surgery), muscle relaxers/neuromuscular blockers, mechanic ventilation, and intubation
  • Cardiorespiratory monitoring throughout procedure
    • Airway management
    • Fluid management
  • Postoperative pain relief

It is generally believed that general anesthesia is now at least ten times safer than it was before 1980, with current rates estimated to be three to five deaths per million administrations. However, such data is not officially required or collected, let alone compiled and published, so the actual death rate is unknown.

Dosing

Adult

Anesthetic delivery, use 1.4-2.6%; or .07-1.4% with nitrous oxide

Pediatric

2.5-3.3%; or 2% with nitrous oxide

Interactions

Serious, life-threatening interactions are possible with a wide range of other drug/hormone treatments, such as:

  • Dopamine
  • Ephedrine
  • epinephrine and norepinephrine
  • methoxamine
  • phenylephrine
  • phenylpropanolamine

Adverse Side Effects

Mild to serious side effects are associated with sevoflurane, including:

  • Seizures in children and young adults with no prior histories
  • Cardiac arrest
  • Post-operative hepatic dysfunction and hepatitis (inflammation of liver), with and without jaundice
  • Malignant hyperthermia (drastic and uncontrolled increase in skeletal muscle oxidative metabolism, which overwhelms body’s capacity to supply oxygen, remove carbon dioxide, and regulate body temperature, eventually leading to circulatory collapse and death if not treated quickly)
  • Allergic reactions
  • Bradycardia (low heart rate)
  • Agitation
  • Respiratory irritation
  • Nephrotoxicity (kidney toxins)
  • Glycosuria (glucose in urine, resulting in water loss via higher osmotic pressure in lumen lowering reabsorption)
  • Proteinuria (protein in urine due to damaged glomeruli)

Contraindications

  • Malignant hyperthermia
  • Hypersensitivity, lack of ventilatory support

Cautions

  • Sevoflurane is a volatile liquid; use appropriate vaporizer for inhalation
  • Closely monitor patients w/:
    • Anemia (reduced hemoglobin levels in blood)
    • Hepatic impairment
    • Myxedema (form of edema – an abnormal fluid retention beneath skin)
    • Renal impairment

Pharmacology

  • Onset: 2-3 minutes
  • Metabolism: CYP2E1

Chemical Structure

Sevoflurane is a halogenated ether. Ethers are organic chemicals that contain an oxygen atom connected to two alkyl groups, such as diethyl ether. In halogenated ethers, one or more hydrogen atoms have been substituted with a halogen (fluorine, chlorine, bromine, or iodine).

Physical Properties

Boiling point: 58.6 °C (at 101.325 kPa)
Density: 1.517–1.522 g/cm³ (at 20 °C)
MAC (Minimum Alveolar Concentration): 2 vol % (decreases with age) (for 40 yo adult)
Molecular Weight: 200 u
Vapor pressure: 157 mmHg (20.9 kPa)197 mmHg (26.3 kPa)317 mmHg (42.3 kPa) (at 20 °C)(at 25 °C)(at 36 °C)
Blood:Gas Partition Coefficient: 0.68 (at 36 °C)
Oil:Gas Partition Coefficient: 47

Body Interactions and Physiological Mechanisms

General anesthetics have been widely used in surgery since 1846 when William Morton administered diethyl ether to a patient and performed a painless tooth extraction for the first time. It has been assumed that general anesthetics exert their effects (analgesia, amnesia, immobility) by modulating the activity of membrane proteins in neuronal membranes. However, despite voluminous investigation, the exact location and mechanism of this action are still largely unknown.

Chemical Structure of Common General Ansesthetics
1. ethanol, 2. Chloroform, 3. Diethylether, 4. Fluroxene, 5. Halothane, 6. Metheoxyflurane, 7. Enflurane, 8. Isoflurane, 9. Desflurane, 10. Sevoflurane; the chemical structure of general anesthetics are simple, making specific receptor targeting an unlikely explanation

Theories of Action

Lipid solubility – anesthetic potency correlation

The original mechanistic propositions were built on the observations made during the late 19th century that the anesthetic potency of a compound was positively correlated to its lipid solubility (lipophilicity). The conclusion drawn was that anesthetic dissolution in neuronal lipid bilayers caused neurons to malfunction, manifesting as the anesthetic effect. This general description was popular for over 60 years, but is now regarded as insufficient in accounting for these facts:

  1. Anesthetic stereoisomers have similar lipophilicity, but lack anesthetic effects
  2. Highly lipophilic drugs, expected to be anesthetics, have very different effects
  3. Anesthetic-induced changes to lipid bilayer density and fluidity can be mimicked through changes in temperature without anesthetic effects
  4. Cutoff effect

Modern Lipid Hypothesis

One major modern hypothesis builds off the lipophilicity-potency correlation, but suggests a different interaction effect on the neuronal lipid bilayer, namely a redistribution of membrane lateral pressures. Cantor, using lattice statistical thermodynamics, has suggested the following account 5:

General anesthesia likely involves inhibition of the opening of the ion channel in a postsynaptic ligand-gated membrane protein. If channel opening increases the cross-sectional area of the protein more near the aqueous interface than in the middle of the bilayer, then the anesthetic-induced increase in lateral pressure near the interface will shift the protein conformational equilibrium to favor the closed state, since channel opening will require greater work against this higher pressure.

Membrane Protein Hypothesis of General Anesthetic Action

General anesthetics may also interact with hydrophobic protein sites of certain proteins, rather than or in addition to the indirect path via membrane bilayer gate disruption. In this model, anesthetics alter the functions of signaling proteins, and perhaps even bind directly to ligand-gated ion channels, making them much more selective than the lipid hypothesis suggests.

Sevoflurane specific Actions

Metabolism

  • Sevoflurane is metabolized by cytochrome P450 2E1, to hexafluoroisopropanol (HFIP) with release of inorganic fluoride and CO2. Once formed, HFIP is rapidly conjugated with glucuronic acid and eliminated as a urinary metabolite. No other metabolic pathways for sevoflurane have been identified. In-vivo metabolism studies suggest that approximately 5% of the sevoflurane dose may be metabolized 6.
  • Cytochrome P450 2E1 is the principal isoform identified for sevoflurane metabolism and this may be induced by chronic exposure to isoniazid and ethanol. This is similar to the metabolism of isoflurane and enflurane and is distinct from that of methoxyflurane, which is metabolized via a variety of cytochrome 450 isoforms. The metabolism of sevoflurane is not inducible by barbiturates. As shown in Figure 5, inorganic fluoride concentrations peak within 2 hours of the end of sevoflurane anesthesia and return to baseline concentrations within 48 hours post-anesthesia in the majority of cases (67%). The rapid and extensive pulmonary elimination of sevoflurane minimizes the amount of anesthetic available for metabolism 6.

Elimination

  • Up to 3.5% of the sevoflurane dose appears in the urine as inorganic fluoride. Studies on fluoride indicate that up to 50% of fluoride clearance is nonrenal (via fluoride being taken up into the bone) 6.

References

1. Torri G, Casati A, Comotti L, et al. Wash-in and wash-out curves of sevoflurane and isoflurane in morbidly obese patients. Minerva Anestesiol. 2002;68(6):523-527. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12105408 [Accessed May 9, 2010].

2. Ebert TJ, Harkin CP, Muzi M. Cardiovascular responses to sevoflurane: a review. Anesthesia & Analgesia. 1995;81(6):S11. Available at: http://www.anesthesia-analgesia.org/content/81/6/S11.abstract [Accessed May 9, 2010].

3. Patel SS, Goa KL. Sevoflurane. A review of its pharmacodynamic and pharmacokinetic properties and its clinical use in general anaesthesia. Drugs. 1996;51(4):658-700. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8706599 [Accessed May 9, 2010].

4. Zhang Xiulai, Haiyan Zhou, Yi Wang, Gang Chen, Lingling Fang. Comparison of Propofol and Sevoflurane Anesthesia on Human Cellular Immunity in Patients Undergoing Total Hip Arthroplasty. Priory.com. Available at: http://www.priory.com/anaesthesia/propofol_and_sevoflurane.htm [Accessed May 9, 2010].

5. Cantor RS. The Lateral Pressure Profile in Membranes: A Physical Mechanism of General Anesthesia. Biochemistry. 1997;36(9):2339-2344. Available at: http://dx.doi.org/10.1021/bi9627323 [Accessed May 9, 2010].

6. Human Presecription Drug Label: Sevoflurene. Daily Med.nlm.nih.gov. Available at: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=6401#nlm34090-1 [Accessed May 9, 2010].

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