Xenon Anaesthesia

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Xenon Anaesthesia

• Dr Rishi Mehra
• 28.7.2003

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Introduction

• Chemical symbol Xe
• Trace gas, 1 part per 10 million by volume of dry
  air (0.0000086 percent)
• Belongs to noble gas group
• Unreactive, but capable of forming compounds -
  Xenon Hexafluroplatinate - Fluorine XeF2, XeF4

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Introduction

• Atomic No 54
• Atomic Weight 131.30
• Melting point - 111.9 ?C
• Boiling point - 107.1 ?C
• Critical Temperature 16.6 ?C
• Critical Pressure 58.2 ATM
• Non-flammable, does not support combustion

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Isotopes

• Natural xenon mixture of 9 stable isotopes-
  Xenon 124 136

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History of Xenon

• Xenon was first discovered by Sir William Ramsay
  in 1898
• Derived from the Greek word ?e??? xenos
  stranger

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History of Xenon

• First isolated following the discovery of Krypton
• Repeated fractionation of Krypton an extremely
  dense gas was obtained that was unable to be
  identified

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History of Xenon

• 1946 J.H. Lawrence- Studying effects of O2 and
  inert gases on mice- Found xenon has narcotic
  properties- Preliminary observations on the
  narcotic effect of xenon. J Physiol 1946
• 1950, Cullen Gross reported using xenon on two
  patients- 81 year old male, orchidectomy- 38
  year old female, 24 hrs post-partum

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History of Xenon

• FiO2 100 for 10 mins to denitrogenate
• 20 O2 and 80 xenon
• Time to loss of consciousness 3 mins for male,
  5 mins for female- At 10 mins, surgical incision
  made- 38 year old -gt Laryngeal spasm, treated
  with IV pethidine 50mg- 81 year old -gt no
  reaction

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History of Xenon

• On cessation of xenon- FiO2 100- Both
  patients eye opening 1 minute- Orientated to
  time, place and person within 2 mins
• Both patients maintained normal blood pressure,
  pulse rate and pulse character and had good
  colour throughout

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History of Xenon

• Work published in 1951- Cullen SC and Gross EG
  - The anaesthetic properties of xenon in human
  beingsScience 1951 113 580-2
• Concluded that Xenon is an inert gas capable of
  producing complete anaesthesia, although it may
  prove by virtue of its cost of manufacture not to
  be a satisfactory commercial agent.

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History of Xenon

• 1965 Eger and associatesMAC 71No syngergism
  found with other volatilesMAC awake 32 5
• 1973 Blood gas solubility coefficient 0.14
• 1997 Blood gas solubility coefficient argued to
  be lower- Goto T, Nakata Y mean coefficient
  0.112 (95 CI 0.104 0.119)

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Mechanism of action

• Unlike other volatile agents, no effects on GABAA
  receptor
• Xenon is a potent inhibitor of excitatory NMDA
  receptor
• NMDA has roles in- Memory- Pain pathways-
  Cell death, especially neural and cardiac tissue

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Mechanism of action

• Evidence for action at NMDA receptor first
  described in Nature 1998- Tested on hippocampal
  neurons that contained the NMDA receptor-
  Measured current generated by patch clamping-
  Initially NMDA agonist added- Followed by xenon

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Mechanism of action
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Mechanism of action

• Xenon 80 inspired concentration, with 20 O2
• Reduction in NMDA activated currents by 60
• No change to EC50 or Hill coefficient
• Strong support for non-competitive inhibition at
  NMDA receptors

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Mechanism of action

• NMDA antagonism common mechanism for ketamine and
  N2O
• Explains mechanism behind which xenon produces
  analgesia and amnesia

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Pharmacokinetics
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Pharmacokinetics
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Pharmacokinetics

• Overpressure cannot be used as MAC 63-71
• Hence no faster rise in FA/FI
• Argued that xenon may increase cardiac output-
  Theoretically increased uptake and slower rise in
  FA/FI- Argued that rate of rise so rapid that
  makes minimal difference

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Pharmacokinetics

• Nakata et al Comparison of inhalational
  inductions with xenon and isoflurane Acta
  Anaesthesiol Scand 1997 1157-1161-
  Equianaesthetic concentrations of 1MAC- Xenon
  induction 71 21 seconds- Isoflurane
  induction 147 59 seconds

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Pharmacokinetics

• Distribution- VRG 8 mins- Muscle Skin
  8-60 mins- Fatty tissue - gt 60 mins-
  Distribution not completed by 4 hours

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Pharmacokinetics
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Pharmacokinetics

• Metabolism- Inert gas hence not metabolised-
  Full outer valence, unreactive agent

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Pharmacokinetics

• Elimination- No renal or hepatic clearance- Low
  solubility of xenon provides rapid decline in
  ET-Xe- Study by H. Saito BJA 1997 Emergence
  times from xenon anaesthesia are independent of
  duration of anaesthesia 1997 79 595-599

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Pharmacokinetics

• Three groups of patients randomised- Xenon- N2O
  and isoflurane- N2O and sevoflurane
• Measured times taken for- Eye opening-
  Extubation- Orientation- Ability to count
  backwards from 10 to 1 within 15 seconds

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Pharmacokinetics

• Other factors- Age- Sex of patient- Body
  temperature- Pain amount of analgesia
• Matched for three groups

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Pharmacokinetics
XenonN2O-IsofluraneN2O-Sevoflurane
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Pharmacokinetics
XenonN2O-IsofluraneN2O-Sevoflurane
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Pharmacokinetics
XenonN2O-IsofluraneN2O-Sevoflurane
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Pharmacokinetics
XenonN2O-IsofluraneN2O-Sevoflurane
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Pharmacokinetics

• Conclusion No correlation with duration of
  anaesthesia and awakening timefor xenon
• Consistent with concept that lower soluble agents
  render emergence less dependent on the duration
  of anaesthesia

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Cardiovascular effects

• Cardiovascular physiology- Most research in
  animals- Xenon anaesthesia compared with TIVA in
  the pig- BJA 1997 78 pp326-327- Pigs
  cannulated with arterial lines swan-ganz
  catheters- Depth of anaesthesia monitored with
  spectral edge monitoring

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Cardiovascular effects
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Cardiovascular effects

• Human studies- Luttropp et al Anaesthesia
  1993 481045-1049 Effects of xenon in vivo
  using transoesophageal echo and haemodynamic
  measurements- ASA class I patients for
  abdominal surgery
• Induction with fentanyl, propofol and
  suxamethonium. Vecuronium added

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Cardiovascular effects

• After 10 mins for denitrogenation, 65 xenon
  administered- No change in MAP- Heart rate drop
  from 80 / min to 50-60 /min- Fractional area of
  short axis view of LV at level of papillary
  muscles unchanged- suggests that xenon has no
  effect on myocardial function

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Cardiovascular effects

• Conflicting studies on cerebral blood flow- Fink
  H Effects of xenon on cerebral blood flow and
  autoregulation BJA 2000 84 221-225-
  Autoregulation intact over ranges of MAP from
  60-120mmHg- ET Xe of 0.30, 0.50 and 0.70 showed
  no effect on regional CBF or sagittal sinus
  pressure

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Respiratory Effects

• Marked respiratory depressant
• Studies show a decrease in respiratory rate with
  an increase in tidal volume
• Appears feasable that could be used in
  spontaneously ventilating patients with no
  pulmonary disease

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Respiratory Effects

• Higher density and viscosity than N2O-
  Theoretically would cause an increase in airways
  resistance- Not studied in humans, but in pigs
  only- Airway resistance more than 50 increase
  in Xenon 70/O2 30 compared with N2O 70/O2 30

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Malignant hyperthermia

• Froeba et al Anesthesiology 2000 85
  712-716Xenon does not trigger MH in susceptible
  swine
• Main causative gene RYR1 encodes ligand gated
  calcium channel Ryanodine receptor located
  in sarcoplasmic reticulum membrane

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Malignant hyperthermia

• 9 Pigs, all purebred Pietrain swine
• All susceptible to MH due to RYR1 abnormalities
• Body temperature measured from a PA catheter and
  rectal probe
• Anaesthetised with pentobarbitone and
  buprenorphine
• Ventilated with 70 Xenon/30 O2 for 2 hours

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Malignant hyperthermia

• After 2 hours, xenon discontinued, swine woken up
• Swine left for 24 hours to recover
• Re-anaesthetised with halothane and suxamethonium
• After 15 mins, abrupt and progressive changes
  consistent with MH were observed in all animals
• Within 60 mins, all the pigs died

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CNS Effects

• Presence of excessive glutamate -gt cell death
• NMDA activation causes calcium influx
• Overactivation thought to be responsible for
  sustaining ongoing neuronal injury - stroke -
  head trauma - chronic neurodegenerative
  conditions

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CNS Effects

• Ma et al BJA Nov 2002 89 739-746
• - c-Fos marker of neuronal injury
• - c-Fos levels sampled in rats who were given
  excessive doses of NMDA agonist NMA at
  100mg/kg - c-Fos levels sampled in another
  group of rates who were given NMDA and xenon

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CNS Effects
C-Fos staining Group A NMDA and 30
oxygenGroup B NMDA and 70 xenon / 30 oxygen
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CNS Effects
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CNS Effects BIS monitoring

• Bispectral Index (BIS) EEG derived parameter
  reflecting level of hypnosis in anaesthetised
  patients
• Exact algorithm for BIS not published
• Based on EEG data of patients receiving common
  anaesthetic agents e.g. isoflurane, propofol

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CNS Effects BIS monitoring

• Most agents affect GABAA receptor- suspected BIS
  monitoring for xenon would fail
• Goto et al International Anesthesiology Clinics
  2001 3 pp85-94
• Established that BIS monitoring unreliable for
  xenon vs isoflurane anaesthesia

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CNS Effects BIS monitoring
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CNS Effects

• In summary for CNS
• - Neuroprotective - Conflicting evidence, but
  majority of studies show no change to
  autoregulation - Unreliable BIS monitoring

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Costs of Xenon

• Xenon can only be produced by fractional
  distillation
• Expensive process, requiring energy- 1 Litre of
  xenon requires 220 watt-hours of energy- gt
  million times more energy than N2O production
• Multiple heating and cooling cycles to produce
  medical xenon (99.997)

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Costs of Xenon

• Current price (January 2003) 10 USD / Litre
• Pricing subject to market forces - 1988 - 4 USD
  / Litre - 1996 - 10 USD / Litre - 1998 - 18
  USD / Litre

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Costs of Xenon

• Thought that large amount of xenon is trapped-
  Gas hydrates in deep sea- compounds bound in
  polar ice sheets- bound in deep granite layers
• Potential at later stage to utilise this
• Two main areas of xenon use

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Uses of Xenon

• Non-medical - Lighting - Television industry
  (Plasma screens) - Subatomic particle
  detection - Aerospace industry
• Medical - Contrast imaging (e.g. CBF) -
  Improves quality of MRI - Radiographic
  imaging - Anaesthesia

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Uses of Xenon
Worldwide Xenon Supply 1999estimated 6,500,000
Litres
Source Hanne et Al Xenon, uptake and
costs International Anesthesiology Clinics
2001 3 pp43-61
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Costs of Xenon

• Methods to reduce costs include
• Decreasing consumption - careful denitrogenation
  of patient - priming anaesthetic circuit - use
  of closed system anaesthesia
• Recycling - Major way to reduce cost of xenon
  anaesthesia

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Costs of Xenon

• Argument that xenon does not have to be produced
  each time retrieved from waste anaesthetic gases
• Known as Recycling xenon

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Costs of Xenon

• Theoretically - Gas washed out from patient -
  Gas escaping via exhaust port - Gas remaining in
  machine after disconnection
• Above could be recycled
• Large amount of interest in recycling devices

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Costs of Xenon

• Current recycling devices- up to 90 of xenon
  used can be recovered, with a purity of 60
  Italy
• Burov et al Clinical and experimental study
  of  xenon anesthesia Journal of Anaesthesiology
  and Reanimatology (Russian publication!) June 1999

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Costs of Xenon

• - Gas mixture passes through several
• containers of absorbents (ie charcoal), is
• cooled via liquid nitrogen.
• - The cooled mixture is reheated xenon
• boils first
• Process repeated several times
• Claimed that 95 of xenon used is reclaimed at
  purity gt 99

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Costs of Xenon

• Also take into account - Cost of implementation
  of new technology
• Recycling technology used in association with
  very low flow circle systems or fully closed
  circle systems

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Cost of Xenon

• Recycling would recover most of the xenon used-
  Purity still not adequate
• Recycled gas would need off-site processing to
  increase purity

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Costs of Xenon

• Equipment Closed circuit e.g. Drager
  physioflex
• Computer controlled delivery system

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Costs of Xenon

• Combination of closed circle systems and xenon
  recycling units in use in Europe
• Recycling of expired air in recovery room!
• Use of these combinations has lowered costs

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Costs of Xenon

• Journal Clinical Anesth. 1999 11477-481 Cost
  analysis of Xenon Anesthesia
• 1999 Xenon Cost with recycling - 240 minute
  ananesthetic - Closed circle system - 167 USD

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Costs of Xenon

• Other factors
• - Country of purchase
• 2003 Jan. United States - 10 USD
• 2003 Jan. Russia - 4.80 USD( Source
  Anaesthesiology 2003 98pp 1-2 Will xenon be a
  stranger or a friend? The Cost, benefit and
  future of xenon anaesthesia. )

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Environmental Impact

• Xenon is a non-flurocarbon based anaesthetic
• All other inhalational agents carry fluorine,
  chlorine or bromine into the stratosphere
• Halogens react with ozone, degrading ozone in
  process
• Volatiles form a group known as H-CFCs, partly
  halogenated chloro-fluro-carbons

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Environmental Impact

• Worldwide efforts aimed to decreased production
  and emission of CFCs and H-CFCs
• Brown et al Nature 1989 341 635-637
  Tropospheric lifetimes of halogenated
  anaesthetics
• Contribution of damage to ozone layer by
  volatiles 0.1 1.0 worldwide per annum

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Environmental Impact

• Aim was to cease CFC use by 2000- European
  union ceased consumption on Jan. 7, 1997
• Kyoto Climate Control Agreement- H-CFCs are
  specifically being targeted by Kyoto Protocol
• Agreement that by 2030 H-CFCs would be completely
  prohibited

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Environmental Impact

• Newer agents Desflurane and Sevoflurane are not
  H-CFCs, but FHCs (Fluorinated hydrocarbons)
• Less destruction of ozone as only contain
  fluorine
• Majority of global warming believe to arise from
  CO2

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Environmental Impact

• FHCs are 10 times more heat trapping than CO2
• (Source The United Nations Framework
  Convention on Climate Change, Feb. 17, 2003)
• 178 Signatories for Kyoto agreement

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Environmental Impact

• Xenon advocates propose xenon more
  environmentally friendly - non-degrading to
  ozone layer - no direct heat trapping effect
• No figures published to indicate production of
  CO2 per litre of xenon
• Hence may be worse environmentally

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Human trials

• Largest human trial of xenon Multicentre
  randomised comparison of the efficacy and safety
  of xenon vs isoflurane in patients undergoing
  elective surgery- Rossaint et al
  Anesthesiology Jan 2003 986-13

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Human trials

• 224 Patients, in six centres
• Randomly assigned to either isoflurane/N2O/O2 or
  xenon/O2
• Inclusion criteria - 18 years of age or
  older - ASA class I-III - elective surgery -
  planned duration of inhalational anaesthesia lt 2
  hours

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Human trials

• Exclusion criteria - ASA class IV, V -
  Emergency procedures - Increased intracranial
  pressure - SaO2 lt 90 on room air - AMI within
  6 months - CVA within 12 months - LFT
  abnormalities - Serum creatinine gt 2 x normal
  limits

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Human trials

• Exclusion criteria - Diabetes - Congestive
  cardiac failure - Adrenal insufficiency -
  Alcohol or drug abuse - Pregnant women /
  breastfeeding women

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Human trials

• Sample size determined for - a of 0.001 - Power
  of 90
• N 90 patients
• However underlying variability not known
• Decided to recruit 224 patients

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Human trials

• Protocol - Premedication with midazolam at
  discretion of individual anaesthetists -
  Anaesthesia induced with - Propofol
  1-2mg/kg - sufentanil 0.4mcg/kg -
  cisatracurium 0.2mg/kg - Each patient
  denitrogenated until ETO2 gt 90 via face-mask -
  Tracheal intubation

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Human trials

• Protocol continued - Closed envelopes opened,
  randomly assigning patients to 1 of 2 groups -
  Xenon 60 O2 40 - Isoflurane-N2O-O2 - ET
  Isoflurane 0.5 - N2O 60 - O2
  39.5 - Cisatracurium given as needed

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Human trials

• At the end of surgery - Neostigmine to reverse
  neuromuscular blockade if TOF ratio lt 0.7
• Each centre used own protocols for treatment of
  blood loss, fluid replacement
• No set requirements for arterial lines or CVCs

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Human trials

• Anaesthetic agents were discontinued when all
  surgical interventions (including bandaging)
  ceased
• Patients extubated when - Adequate spontaneous
  ventilation - ETCO2 between 40 50mmHg - Eye
  opening on command

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Human trials
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Human trials

• Anaesthetic circuit closed circuit (
  Physioflex
• Duration of anaesthesia 211 102 mins
• Xenon used 24.6 10.2 litres per patient
• Cost of xenon at USD 10 / litre 240 per
  patient
• No xenon recycling system used

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Human trials

• Hence costs could be reduced significantly if
  recycling system implemented- Current systems
  reclaim 90-95 of xenon used

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Human trials
P lt 0.01
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Human trials
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Human trials
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Human trials
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Summary

• Unanswered questions- Total number of patients
  treated lt 1000 worldwide- Relative paucity of
  data for humans in ASA IV and V patients
  Trauma settings Disease e.g IHD, COAD- Does
  faster offset equate with higher patient turnover?

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Summary

• 1 MAC 70 Xenon minimal discussion in
  literature about issues of awareness
• Cost analysis of xenon equipment
• Future xenon uses - Aerospace industry - Plasma
  display technology
• Does all of this equate to better patient
  outcomes?

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End