Anestesia generale in day
surgery
Anestesia generale in day
surgery
tecniche e farmacitecniche e farmaci
Claudio MelloniCl...
Requirements of GA for ambulatory surgeryRequirements of GA for ambulatory surgery
psychological and pharmacological prepa...
Essential intraoperative monitoringEssential intraoperative monitoring
guidelinesguidelines
continuous presence of trained...
Choice of technique I
• surgical requirements
• anaesthetic considerations
• patient's physical status
• Patient preferenc...
Choice of technique II
• Intraop optimal conditions
• Fast recovery of consciousness
• Minimal,if any,sedative residual ef...
DebateDebate
Gas vs TIVAGas vs TIVA
GasGas
advantagesadvantages
induction without
vein
induction without
vein
easy mainten...
DebateDebate
TIVATIVA
AdvantagesAdvantages
no pollutionno pollution
smooth
emergence...
smooth
emergence...
postop.analges...
Basic physico-chemical
properties of modern inhalational
agents:
• Low blood/ gas solubilities
»fast induction and emergen...
Inhalation
induction
• Ideal characteristics for an inhaled agent
useful for induction:
• Low blood gas solubility
• Pleas...
Characteristics of inhaled
anesthetics
Decomposesnone2,424150,20,75197,4haloth
Stablemoder
ate
1,917556.51,68184,5enflur
a...
Rate of equilibration between alveolar concentration and
inspired concentration
NN
NN
NN
2O
N2O
sevofluran
e
Fa/Fi
0.4
0.6...
The interaction between fentanyl and
isoflurane(BJA 1998,81,38-50)
Interaction between remifentanil and isofluraneIsoflurane
concentration reduction by increasing remifentanil whole blood
c...
Sebel PS., Glass PSA,Fletcher JE,Murphy
M,Gallagher C,Quill T.Reduction of rhe Mac of
desflurane with fentanyl. Anesthesio...
Sevoflurane Mac awake reduction by fentanyl
Katoh T,Iked K. The Effects of Fentanyl on Sevoflurane Requirements for Loss o...
Context sensitive half time of opioids(influence of P450
3A4 on alfentanil)
Inhalational anesthesia vs TIVAInhalational anesthesia vs TIVA
similarities...similarities...
parameterparameter inhalatio...
Plasma alfentanil vs propofol blood concentrations for
95% probability of no response to surgical stimulation(Vuyk
et al.P...
PharmacodynamicsPharmacodynamics
assumptionsassumptions
MEACMEAC
fent:0.6
ng/ml
fent:0.6
ng/ml
Resp
depression
Resp
depres...
Vuyk J,Mertens MJ,Olofsen E
Propofol Anesthesia and Rational Opioid
Selection: Determination of Optimal EC50-EC95
Propofol...
time
Propofol blood concOpioid blood concentration
Three dimensional planes in the
graphs from Vuyk et al.
manual opioid infusion schemesmanual opioid infusion schemes
from many sources...from many sources...
drugdrug plasma targ...
Practical pharmacokinetics as applied to our
daily anesthesia practice
Fiset, Pierre.Can J Anesth 1999 / 46 / R122-R126
Bekke AY, Berklay P, Osborn I,Bloo M, Yarmush J,
Turndorf H. The Recovery of Cognitive Function After
Remifentanil- Nitrou...
Bekke et al The Recovery of Cognitive Function After Remifentanil- Nitrous Oxide Anesthesia Is Faste
than After an Isoflur...
Physiological Effects of Remifentanil and
Alfentanil in Healthy Volunteers
Anesthesiology
90:718-26, 1999
• Background: Th...
remi
alf
remi
alf
Beers R,Calimlim JR, Uddoh E,Esposito B,
Camporesi EM.A Comparison of the Cost-
Effectiveness of Remifentanil Versus Fenta...
Rosenberg et al.Cost comparison:a desflurane
versus a propofol based general anesthetic
technique.AA 1994;79:
0
20
40
60
8...
Chung F. Recovery pattern and home readiness
after ambulatory surgery. Anesth Analg 1995;
80:896-902
• Despite increased u...
Laparscopy,general surg,orthopedic surg
Anesthesia and factors
associated with PONV
Anesthesia and factors
associated with PONV
GA> regGA> reg
etomidate,ketamine,...
PONVPONV
Categories at riskCategories at risk
FemalesFemales young,pregnantyoung,pregnant
kinetosiskinetosis
certain opera...
PONVPONV
we know the risk factorswe know the risk factors
Preventive strategyPreventive strategy non emetogenic drugs...no...
Propofol & PONV
YES,>ondanse
tron (preop..)
Induz vs
intraop
Tps/isof vs
prop/N2O
major breast
surgery
Gan 1996
Fem outpts...
PONV prophylaxis and treatment
• Droperidol 10 microgr/kg ev/im++
• Ondansetron 4-8 mg ev(8 p.o.)++
• Dexamethasone 4 mg e...
How well do we manage pain?
• 77% of patients still experience pain
postoperatively:80% moderate-severe and
57% quote pain...
Acute Pain Management: Programs in U.S.
Hospitals and Experiences and Attitudes among
U.S. Adults
Anesthesiology
83:1090-1...
Song et al.
Titration of Volatile Anesthetics Using Bispectral
Index Facilitates Recovery after Ambulatory
Anesthesia Anes...
Song et al.
Titration of Volatile Anesthetics Using Bispectral Index
Facilitates Recovery after Ambulatory Anesthesia
Anes...
Song D, van Vlymen J, White PF.Is the
Bispectral Index Useful in Predicting Fast-Track
Eligibility After Ambulatory Anesth...
Dexter F, Tinker JH..
Comparison between desflurane and isoflurane
or propofol on time to following commands and
time to d...
Dexter F, Tinker JH..
Comparison between desflurane and isoflurane
or propofol on time to following commands and
time to d...
Dexter F, Tinker JH..
Comparison between desflurane and isoflurane
or propofol on time to following commands and
time to d...
Dexter F, Tinker JH..
Comparison between desflurane and isoflurane
or propofol on time to following commands and
time to d...
Dexter F, Tinker JH..
Comparison between desflurane and isoflurane
or propofol on time to following commands and
time to d...
Song et al.Remifentanil infusion facilitates early
recovery for obese outpatients undergoing
laparoscopic cholecystectomy....
Conclus from Song et al
• Variable rate infus of remif(0.09
microgr/kg/min) + sevo + N2O :
• 50% sevo %
• Contributed to a...
Joshi et al.Use of the Laryngeal Mask Airway as an
Alternative to the Tracheal Tube During
Ambulatory Anesthesia Anesth An...
Advantages of the LMA>TT
• increased speed and ease of placement by
inexperienced personnel;
• increased speed of placemen...
Advantages LMA>Face Mask
• easier placement by inexperienced
personnel;
• improved oxygen saturation;
• less hand fatigue;...
Disadvantages LMA> TT&FM
• lower seal pressures
• higher frequency of gastric insufflation.
• The only disadvantage compar...
In conclusionIn conclusion
for the success of day anesthesia & surgeryfor the success of day anesthesia & surgery
pk-pd
fo...
 ag in day surg tirrenia
 ag in day surg tirrenia
 ag in day surg tirrenia
 ag in day surg tirrenia
 ag in day surg tirrenia
 ag in day surg tirrenia
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anesthesia in day surgery ,presented to a course in Tirrenia,2002(???)

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ag in day surg tirrenia

  1. 1. Anestesia generale in day surgery Anestesia generale in day surgery tecniche e farmacitecniche e farmaci Claudio MelloniClaudio Melloni Bologna-FaenzaBologna-Faenza
  2. 2. Requirements of GA for ambulatory surgeryRequirements of GA for ambulatory surgery psychological and pharmacological preparationpsychological and pharmacological preparation rapid and predic table induc tion of anes thes iarapid and predic table induc tion of anes thes ia s mooth and reliable maintenanc es mooth and reliable maintenanc e hypnosis,amnesia,surgical anesthesiahypnosis,amnesia,surgical anesthesia c ardiov as c ular s tabilityc ardiov as c ular s tability ex cellent s urgic al conditionsex cellent s urgic al conditions prompt and c omplete recov ery of mentalfac ultiesprompt and c omplete recov ery of mentalfac ulties phys ic al c apability to return home safelyphys ic al c apability to return home safely mimimalpos top.s ide effectsmimimalpos top.s ide effects PONV,dizziness,pain...PONV,dizziness,pain... prompt return to normal ac tiv itiesprompt return to normal ac tiv ities
  3. 3. Essential intraoperative monitoringEssential intraoperative monitoring guidelinesguidelines continuous presence of trained anesthesia personnelcontinuous presence of trained anesthesia personnel continual assessment of ofcontinual assessment of of oxy genationoxy genation v entilationv entilation circulationcirculation tem peraturetem perature clinical asessment+ standards of careclinical asessment+ standards of care puls e oxy m etrypuls e oxy m etry capnographycapnography NIBPNIBP ECGECG FiO2FiO2 dis connect alarmdis connect alarm therm om etrytherm om etry
  4. 4. Choice of technique I • surgical requirements • anaesthetic considerations • patient's physical status • Patient preference. • The goal is to anaesthetize the patient for the shortest possible time with the lowest concentration of anaesthetic.
  5. 5. Choice of technique II • Intraop optimal conditions • Fast recovery of consciousness • Minimal,if any,sedative residual effects • Minimal disturbance of cognitive postop.functions • No side effects during recovery;No ponv, • Fast discharge with early ambulation(???)
  6. 6. DebateDebate Gas vs TIVAGas vs TIVA GasGas advantagesadvantages induction without vein induction without vein easy maintenanceeasy maintenance easy recoveryeasy recovery familiar...familiar... disadvantagesdisadvantages pollutionpollution Ponv...Ponv... Point threePoint three
  7. 7. DebateDebate TIVATIVA AdvantagesAdvantages no pollutionno pollution smooth emergence... smooth emergence... postop.analgesiapostop.analgesia smooth induction (after i.v...). smooth induction (after i.v...). DisadvantagesDisadvantages know ledge of pk-pd know ledge of pk-pd less easyless easy less reversibleless reversible
  8. 8. Basic physico-chemical properties of modern inhalational agents: • Low blood/ gas solubilities »fast induction and emergence • No active metabolites • Recovery times not dependent from anesthesia duration
  9. 9. Inhalation induction • Ideal characteristics for an inhaled agent useful for induction: • Low blood gas solubility • Pleasant smell • Nonirritating for the airway • High potency • sevoflurane ??
  10. 10. Characteristics of inhaled anesthetics Decomposesnone2,424150,20,75197,4haloth Stablemoder ate 1,917556.51,68184,5enflur ane Stablemoder ate 1.423848.51.15184,5isoflur ane decomposesno0,6016058.52.0200sevofl urane stableno0,4739000 gas -8810544N2O stableyes0,4266323.56168desflu rane Soda limepungencyBlood/gas partition coeff. Vapor press. Boling point MACmwagent
  11. 11. Rate of equilibration between alveolar concentration and inspired concentration NN NN NN 2O N2O sevofluran e Fa/Fi 0.4 0.6 0.8
  12. 12. The interaction between fentanyl and isoflurane(BJA 1998,81,38-50)
  13. 13. Interaction between remifentanil and isofluraneIsoflurane concentration reduction by increasing remifentanil whole blood concentration Anesthesiology 85:721-8, 1996
  14. 14. Sebel PS., Glass PSA,Fletcher JE,Murphy M,Gallagher C,Quill T.Reduction of rhe Mac of desflurane with fentanyl. Anesthesiology 76:52-59, 1992
  15. 15. Sevoflurane Mac awake reduction by fentanyl Katoh T,Iked K. The Effects of Fentanyl on Sevoflurane Requirements for Loss of Consciousness and Skin Incision ANESTHESIOLOGY 1998; 88:5—6.
  16. 16. Context sensitive half time of opioids(influence of P450 3A4 on alfentanil)
  17. 17. Inhalational anesthesia vs TIVAInhalational anesthesia vs TIVA similarities...similarities... parameterparameter inhalation anesth.inhalation anesth. TIVATIVA cont.adm.cont.adm. yesyes yesyes methodmethod vaporizervaporizer syringe pumpsyringe pump titrationtitration yesyes yesyes how much?how much? MACMAC MIRMIR transporttransport airwayairway i.v.i.v. initinit overpressureoverpressure bolusbolus basal analgbasal analg N2O/titrationN2O/titration analgesicsanalgesics pre-intraop checkspre-intraop checksyesyes yesyes
  18. 18. Plasma alfentanil vs propofol blood concentrations for 95% probability of no response to surgical stimulation(Vuyk et al.Propofol Anesthesia and Rational Opioid Selection: Determination of Optimal EC50-EC95 Propofol— Opioid Concentrations that Assure Adequate Anesthesia and a Rapid Return of Consciousness Anesthesiology 87:1549-62, 1997
  19. 19. PharmacodynamicsPharmacodynamics assumptionsassumptions MEACMEAC fent:0.6 ng/ml fent:0.6 ng/ml Resp depression Resp depression >2 ng/ml>2 ng/ml MAC reduction MAC reduction CSHTCSHT RecoveryRecovery ED95 intraop for surgery/ED95 for recovery of consciousness & spont.resp.ED95 intraop for surgery/ED95 for recovery of consciousness & spont.resp.
  20. 20. Vuyk J,Mertens MJ,Olofsen E Propofol Anesthesia and Rational Opioid Selection: Determination of Optimal EC50-EC95 Propofol—Opioid Concentrations that Assure Adequate Anesthesia and a Rapid Return of Consciousness Anesthesiology 87:1549-62, 1997
  21. 21. time Propofol blood concOpioid blood concentration Three dimensional planes in the graphs from Vuyk et al.
  22. 22. manual opioid infusion schemesmanual opioid infusion schemes from many sources...from many sources... drugdrug plasma target concentation(ngml) plasma target concentation(ngml) bolus(microgr/kg)bolus(microgr/kg) infusion rate (microgr/kg/min infusion rate (microgr/kg/min fentanylfentanyl 11 33 0.0200.020 fentanylfentanyl 44 1010 0.0700.070 alfentanilalfentanil 4040 2020 0.250.25 alfentanilalfentanil 160160 8080 1.001.00 sufentanilsufentanil 0.150.15 0.150.15 0.0030.003 sufentanilsufentanil 0.500.50 0.500.50 0.0100.010 remifentanilremifentanil 66 11 0.020.02 remifentanilremifentanil 12-2012-20 1-21-2 0.4-1.00.4-1.0
  23. 23. Practical pharmacokinetics as applied to our daily anesthesia practice Fiset, Pierre.Can J Anesth 1999 / 46 / R122-R126
  24. 24. Bekke AY, Berklay P, Osborn I,Bloo M, Yarmush J, Turndorf H. The Recovery of Cognitive Function After Remifentanil- Nitrous Oxide Anesthesia Is Faster than After an Isoflurane-Nitrous Oxide-Fentanyl Combination in Elderly Patients Anesth Analg 2000; 91:117–22 • We tested the hypothesis that remifentanil-nitrous oxide (N2O) anesthesia shortens postoperative emergence and recovery compared with an isoflurane-N2O-fentanyl combination in elderly patients undergoing spinal surgery. • 60 patients (>65 yr old) were randomly assigned to one of two groups for maintenance of anesthesia. After the induction with 3.6 ± 1.2 mg/kg IV thiopental and endotracheal intubation facilitated with 1.4 ± 0.5 mg/kg succinylcholine, patients were maintained with either 0.5%–1.5% isoflurane, 70% N2O, and up to 7 mg/kg fentanyl
  25. 25. Bekke et al The Recovery of Cognitive Function After Remifentanil- Nitrous Oxide Anesthesia Is Faste than After an Isoflurane-Nitrous Oxide-Fentanyl Combination in Elderly Patients Anesth Analg 2000; Isofl/fen Remif/N
  26. 26. Physiological Effects of Remifentanil and Alfentanil in Healthy Volunteers Anesthesiology 90:718-26, 1999 • Background: The subjective and psychomotor effects of remifentanil have not been evaluated. Accordingly, the authors used mood inventories and psychomotor tests to characterize the effects of remifentanil in healthy, non—drug-abusing volunteers. Alfentanil was used as a comparator drug. • Methods: Ten healthy volunteers were enrolled in a randomized, double-blinded, placebo- controlled, crossover trial in which they received an infusion of saline, remifentanil, or alfentanil for 120 min. The age- and weight-adjusted infusions
  27. 27. remi alf remi alf
  28. 28. Beers R,Calimlim JR, Uddoh E,Esposito B, Camporesi EM.A Comparison of the Cost- Effectiveness of Remifentanil Versus Fentanyl as an Adjuvant to General Anesthesia for Outpatient Gynecologic Surgery Anesth Analg 2000; 91:1420 • The unique pharmacokinetic properties of remifentanil make it a potentially useful adjuvant during general anesthesia for ambulatory surgery. Fentanyl, inexpensive and easy to administer, is the most common opioid used for this purpose. As an adjuvant to general anesthesia for outpatient gynecologic surgery, we questioned if remifentanil was cost-effective as an alternative to fentanyl. Thirty-four patients undergoing gynecologic laparoscopy or hysteroscopy were prospectively and randomly assigned to a standard practice (n = 18) or a study (n = 16) group. Standard practice patients received fentanyl(3 mg/kg) before induction; study patients received remifentanil by continuous infusion (0.5 mg×kg×min-1 at induction, then 0.2 mg×kg×min-1). Sevoflurane was titrated to a Bispectral index value of 40–55. • Fentanyl administered to studty pts for analgesia before awakening! the We investigated recovery profiles, patient and health care professional satisfaction, and drug costs . The incidence of rescue antiemetic treatment (2 of 16 vs 8 of 18; P = 0.013) and the nausea visual analog scale scores during second stage recovery (0.2 vs 0.6; P = 0.044) were more frequent in the study
  29. 29. Rosenberg et al.Cost comparison:a desflurane versus a propofol based general anesthetic technique.AA 1994;79: 0 20 40 60 80 100 120 140 cost/hr cost wastetot.cost/hrduration totcost/hrt Pacustay prop/n2O desf/O2 * * * 0.09
  30. 30. Chung F. Recovery pattern and home readiness after ambulatory surgery. Anesth Analg 1995; 80:896-902 • Despite increased use of ambulatory surgery, few data exist regarding patient recovery patterns and home-readiness. We prospectively identified the pattern of home-readiness, the persistent symptoms after surgery, and the factors that delay discharge after home-readiness criteria are satisfied. Five hundred patients were scored by the same investigator using the Postanesthetic Discharge Scoring System (PADSS) every 30 min, commencing 30 min after surgery, until the PADSS score was > or = 9. The same investigator telephoned each patient 24 h after discharge to
  31. 31. Laparscopy,general surg,orthopedic surg
  32. 32. Anesthesia and factors associated with PONV Anesthesia and factors associated with PONV GA> regGA> reg etomidate,ketamine,(neostigmine),(N2O)etomidate,ketamine,(neostigmine),(N2O) PAINPAIN Sudden mov ementSudden mov ement Hy potensionHy potension Gastric distentionGastric distention
  33. 33. PONVPONV Categories at riskCategories at risk FemalesFemales young,pregnantyoung,pregnant kinetosiskinetosis certain operationscertain operations strabismus, inner ear,pelvic laparoscopic ... strabismus, inner ear,pelvic laparoscopic ... diabeticsdiabetics
  34. 34. PONVPONV we know the risk factorswe know the risk factors Preventive strategyPreventive strategy non emetogenic drugs...non emetogenic drugs... Antiemetic Prophylaxis Antiemetic Prophylaxis Selected at risk groupsSelected at risk groups Immediate treatmentImmediate treatment in case of occurrence..... in case of occurrence.....
  35. 35. Propofol & PONV YES,>ondanse tron (preop..) Induz vs intraop Tps/isof vs prop/N2O major breast surgery Gan 1996 Fem outpts laparoscopic surgery Mayot gynecol surg thyroidectomy Gynecol lap procedure YESintraopEnflur/N2O vs propof/N2O Ding 1993 YESPostop 0.1 ml/kg/h enfluraneMontgomery 1996 YESPostop,0.1 ml/kg/h Isof/N2OEwalenko 1996 NonepostopisoflCampbell 1991 effectsPropofol adm. Inh.agentAuthor
  36. 36. PONV prophylaxis and treatment • Droperidol 10 microgr/kg ev/im++ • Ondansetron 4-8 mg ev(8 p.o.)++ • Dexamethasone 4 mg ev+ • Ephedrine 10 mg iv? • Scopolamine 0.5 mg/62 hr patch ?? • Metoclopramide 10 mg iv +/- • Propofol 10-20 mg ev?? • ―setrons‖++
  37. 37. How well do we manage pain? • 77% of patients still experience pain postoperatively:80% moderate-severe and 57% quote pain as a primary concern or preop fear(Acute Pain Management: Programs in U.S. Hospitals and Experiences and Attitudes among U.S. Adults Anesthesiology,83:1090-1094, 1995)
  38. 38. Acute Pain Management: Programs in U.S. Hospitals and Experiences and Attitudes among U.S. Adults Anesthesiology 83:1090-1094, 1995• Two telephone questionnaire surveys • U.S. hospital participants: 100 teaching hospitals (acute care hospitals with a residency program and/or university affiliation), 100 nonteaching (community) hospitals with fewer than 200 beds, and 100 nonteaching (community) hospitals with 200 beds or more • interview regarding current and future pain management programs and related topics. • Adult participants in 500 U.S. households were interviewed on attitudes and experiences with postoperative pain and its management.
  39. 39. Song et al. Titration of Volatile Anesthetics Using Bispectral Index Facilitates Recovery after Ambulatory Anesthesia Anesthesiology 87:842-8, 1997 -4 -2 0 2 4 6 8 10 12 14 % or min Gas % Mac/hr verb resp extub orient SEVO BIS sevocontr DESFL BIS desfl contr diff bis-contr desf diff bis-contr sevo
  40. 40. Song et al. Titration of Volatile Anesthetics Using Bispectral Index Facilitates Recovery after Ambulatory Anesthesia Anesthesiology 87:842-8, 1997
  41. 41. Song D, van Vlymen J, White PF.Is the Bispectral Index Useful in Predicting Fast-Track Eligibility After Ambulatory Anesthesia with Propofol and Desflurane? Anesth Analg 1998; 87:1245
  42. 42. Dexter F, Tinker JH.. Comparison between desflurane and isoflurane or propofol on time to following commands and time to discharge:a metanalysis. Anesthesiology 1995; 83,
  43. 43. Dexter F, Tinker JH.. Comparison between desflurane and isoflurane or propofol on time to following commands and time to discharge:a metanalysis. Anesthesiology 1995; 83,
  44. 44. Dexter F, Tinker JH.. Comparison between desflurane and isoflurane or propofol on time to following commands and time to discharge:a metanalysis. Anesthesiology 1995; 83,
  45. 45. Dexter F, Tinker JH.. Comparison between desflurane and isoflurane or propofol on time to following commands and time to discharge:a metanalysis. Anesthesiology 1995; 83,
  46. 46. Dexter F, Tinker JH.. Comparison between desflurane and isoflurane or propofol on time to following commands and time to discharge:a metanalysis. Anesthesiology 1995; 83,
  47. 47. Song et al.Remifentanil infusion facilitates early recovery for obese outpatients undergoing laparoscopic cholecystectomy.AA 2000,90:1111-3. 0 2 4 6 8 10 12 14 16 18 sevo% opioid intraop awake extub orient sevo remif * * * * mg min
  48. 48. Conclus from Song et al • Variable rate infus of remif(0.09 microgr/kg/min) + sevo + N2O : • 50% sevo % • Contributed to a more rapid emergence • Postop side effects not increased(PONV=) • PACU stay and discharge times =
  49. 49. Joshi et al.Use of the Laryngeal Mask Airway as an Alternative to the Tracheal Tube During Ambulatory Anesthesia Anesth Analg 1997; 85:573 0 20 40 60 80 100 120 140 160 180 fent mant PACU- stepdown PACU- ambul sore throat nausea LMA IOT microg min min % %
  50. 50. Advantages of the LMA>TT • increased speed and ease of placement by inexperienced personnel; • increased speed of placement by anaesthetists; • improved haemodynamic stability at induction and during emergence; • minimal increase in intraocular pressure following insertion; • reduced anaesthetic requirements for airway tolerance; • lower frequency of coughing during emergence; • improved oxygen saturation during emergence;
  51. 51. Advantages LMA>Face Mask • easier placement by inexperienced personnel; • improved oxygen saturation; • less hand fatigue; • improved operating conditions during minor paediatric otological surgery.
  52. 52. Disadvantages LMA> TT&FM • lower seal pressures • higher frequency of gastric insufflation. • The only disadvantage compared with the FM was that oesophageal reflux was more likely.
  53. 53. In conclusionIn conclusion for the success of day anesthesia & surgeryfor the success of day anesthesia & surgery pk-pd foundations pk-pd foundations clinical experience clinical experience organizationorganization continuous improvement continuous improvement pk/pd foundations pk/pd foundations technology?technology?

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