Farmacocinetica e
farmacodinamica nell’obesità
Claudio Melloni
Direttore Anestesia e Rianimazione
Ospedale di Faenza (RA)
Considerazioni generali
• Abbreviazioni
• LBM massa magra;cioè tessuti non grassi;99 % dei
tessuti metabolici
– (for men: ...
IBW Peso ideale
• ideal body weight (IBW) basato sulla
formula della Metropolitan Life Insurance
Co
• IBW (females) = 100 ...
Nomogramma della relazione fra altezza peso e
sesso e LBW:i punti indicano il peso ideale della
LBW per ciascuna altezza
Nomogramma che mette in relazione TBW,altezza
e sesso rispetto al peso da usare per calcolare la
dose
Considerazioni generali
• Vd:Volume di distribuzione =dose carico
• CL:dose di mantenimento
• Farmaci lipofilici :alti
Vd:...
Hankin ME, Munz K, Steinbeck AW. Total body
water content in normal and obese women. Med J
Aust 1976; 2:533-7

• Il conten...
Andersen T, Christoffersen P, Gluud C. The liver
in consecutive patients with morbid obesity. Int
J Obesity 1984; 8:107-15...
Fattori principali che influenzano la
distribuzione tissutale dei farmaci

• la composizione corporea
• Il flusso ematico ...
Benzodiazepine
Variabili cinetiche per il midazolam
Greenblatt DJ, Abernathy DR, Locniskar A, Harmatz JS, Limjuco RA, Shader RI. Effect o...
Midazolam nell’obeso
• Il Vd tot è aum.poichè la Cl in rapporto al
peso è minore;ma quella totale no
• Hl el è allungata
–...
Cinetica di alprazolam e triazolam negli obesi e nei paz
normali
Abernethy DR, Greenblatt DJ, Divoll M, Smith RB, Shader R...
Messaggio da portare a casa con le BDZ
• Dose iniziale rapportata al tbw
• Infusione continua:dose rapportata all‘IBW
BDZ e obesità
•
•
•
•
•

Tutte le BDZ sono altamente lipofile
Vd ampi,+ dei normali
Anche se le Cl sono simili ai normali
...
propofol
Schüttler, Jürgen, M.D.*; Ihmsen, Harald, Population
Pharmacokinetics of Propofol : A Multicenter Study
Anesthesiology.92:...
Schüttler, Jürgen, M.D.*; Ihmsen, Harald,
Population Pharmacokinetics of Propofol : A
Multicenter Study Anesthesiology.92:...
Schüttler, Jürgen, M.D.*; Ihmsen, Harald,
Population Pharmacokinetics of Propofol : A
Multicenter Study Anesthesiology.92:...
Schüttler, Jürgen, M.D.*; Ihmsen, Harald,
Population Pharmacokinetics of Propofol : A
Multicenter Study Anesthesiology.92:...
Velocità di infusione del propofol per mantenere una

concentrazione di 1 microg/ml per 2 h
Schüttler, Jürgen, M.D.*; Ihms...
Servin F,Farinotti R,Haberer JP,Desmonts
JM.Propofol Infusion for Maintenance of Anesthesia
in Morbidly Obese Patients Rec...
Servin F,Farinotti R,Haberer JP,Desmonts JM.Propofol
Infusion for Maintenance of Anesthesia in Morbidly Obese
Patients Rec...
CL propofol correlata al BW
Vss propofol correlato al BW
Dati per il propofol da Servin F,Farinotti R,Haberer JP,Desmonts JM.Propofol
Infusion for Maintenance of Anesthesia in Mor...
Concetto di Peso corretto
• Il peso utilizzato per il calcolo della velocità di
infusione si è basato su una formula empir...
insomma
• Dose iniziale normalizzata :vedi formule di
Servin
• Mantenimento in accordo con quella
iniziale
• Quindi;gli ob...
Concentrazioni plasmatiche di
propofol al risveglio(microgr/lt)
obesi

Non obesi

Servin

1

1

Kakinohana

1.49-1.69

1.4...
Messaggio da portare a casa:propofol
• Dose iniziale e mantenimento basate sul
peso corretto
• Ma ……….titolare con BIS o s...
Fenitoina
Dati cinetici per la fenitoina;in dose singola;da
Abernethy Arch Neurol 1985,42:468-71

90

Lt/kg

80
70
60

*

50
40
30
2...
Messaggio da portare a casa per la
fenitoina
• Poichè negli obesi t ½ beta allungato,Vd
aumentato,e dunque la distribuzion...
Thiopental
Wada DR,Björkman S, Ebling WF,Harashima H,
Harapat SR,Stanski DR.Computer Simulation of the
Effects of Alterations in Bloo...
Jung D, Mayersohn M, Perrier D, Calkins J, Saunders
R: Thiopental disposition in lean and obese patients
undergoing surger...
Dose induzione TPS:mg/tbw
obesi

Jung

Dundee

Non obesi

3.9

5.1
Messaggio da portare a casa per il pentotal

• Non somministrare la dose bolo secondo il
pso totale!
• Ridurre la dose ini...
Anestetici inalatori
Volumi di distribuzione ml di vapore /kg e Clearance di
trasporto dal compart centrale al periferico ml vapore/kg/min
Wiss...
Microcostanti per il trasporto dal compart. centrale
al perif. e dal periferico al centrale
Wissing H,Kuhn I,Rietbrock S, ...
Strum EM, Szenohradszki J, Kaufman WA, et al. Emergence
and recovery characteristics of desflurane versus
sevoflurane in m...
Tempi di ripresa dopo la sospensione della
erogazione degli anestetici
Strum EM, Szenohradszki J, Kaufman WA, et al. Emerg...
Tempi di ripresa precoci(sec) dopo anest con remif +
desflurane o sevoflurane
De Baerdemaeker LEC,Struys MMRF,Jacobs S,Den...
Juvin P., Vadam C., Malek L., Dupont H., Marmuse J.P,
Desmonts J-M. Postoperative recovery after desflurane,
propofol or i...
Livelli di sedazione postop valutati con l’Observers assessment of
alertness sedation score dopo anestesia con desflurane
...
Tempi di ripresa precoci,punteggio mobilità al risveglio e
desaturazione arteriosa dopo desflurane,isoflurane o
propofol i...
Arain SR,Barth CD,Shankar H,Ebert TJ. Choice
of volatile anesthetic for the morbidly obese
patient:sevoflurane or desflura...
Arain SR,Barth CD,Shankar H,Ebert TJ. Choice of
volatile anesthetic for the morbidly obese
patient:sevoflurane or desflura...
Differenze di metodologia fra gli
studi
•

Arain SR,Barth CD,Shankar
H,Ebert TJ. Choice of volatile
anesthetic for the mor...
Biotrasformazione degli anestetici
inalatori:fluoruri
agente

autore

obesi

nonobesi

Enflurane
isoflurane

Strube 1987

...
Livelli di fluoruri ionici in 17 pazienti obesi e 7
non obesi durante e dopo anestesia alotanica
Bentley JB, Vaughan RW, G...
Livelli nel siero di bromuri dopo 2 h di alotano,17
obesi e 7 non obesi Bentley JB, Vaughan RW, Gandolfi AJ, Cork RC.
Halo...
Casati A, Bignami E, Spreafico E, Mamo D. Effects of
obesity on wash-in and wash-out kinetics of
sevoflurane. Eur J Anaest...
Messaggio da portare a casa con sevorane
e desflurane
• Il desflurane presenta vantaggi più teorici
che reali
• Probabilme...
Vantaggi ipotizzabili da un risveglio più rapido
• minore solub sangue/gas desf 0.45 e sevo 0.65, isoflurane 1.4 ,
haloth ...
Vantaggi di una ripresa rapida

+ precoce protezione

+ precoce ripresa
della pervietà
Cardio vascolare e resp

Vie aeree
...
fentanile
BentleyJB, Borel JD,Gillespie TJ.Fentanyl
pharmacokinetics in obese and nonobese
patients.Anesthesiology 1981.55;A177.

• ...
Shibutani K, Inchiosa MA Jr., Sawada K, et al.
Accuracy of pharmacokinetic models for predicting
plasma fentanyl concentra...
Cp di Shafer sovrastima la Cpm nel gr.obesi( O), molto meno nel
gruppo L(lean,magri)
Shibutani K, Inchiosa MA Jr., Sawada ...
Analisi di regressione tra gli errori di performance con il
modello di Shafer(sopra) e quello di Scott(sotto).
Shibutani K...
Relazione non lineare fra PE Shafer e TBW;l’equazione
mostrata puo essere usata per migliorare l’accuratezza della
predici...
Shibutani K, Inchiosa MA Jr., Sawada K, et al. Accuracy of pharmacokinetic models
for predicting plasma fentanyl concentra...
Shibutani K, Inchiosa MA Jr., Sawada K, et al. Accuracy of pharmacokinetic models
for predicting plasma fentanyl concentra...
Shibutani K, Inchiosa MA Jr., Sawada K, et al. Accuracy of pharmacokinetic models
for predicting plasma fentanyl concentra...
Shibutani K, Inchiosa MA Jr., Sawada K, et al. Accuracy of pharmacokinetic models
for predicting plasma fentanyl concentra...
Fattori di correzione e massa farmacocinetica per alcuni pesio
esemplificativi
Shibutani K, Inchiosa MA Jr., Sawada K, et ...
Estensione al postop
Shibutani K, Inchiosa MA Jr., Sawada K, Bairamiam
M.Pharmacokinetic mass of fentanyl for postoperative
analgesia in lean a...
Shibutani K, Inchiosa MA Jr., Sawada K, Bairamiam
M.Pharmacokinetic mass of fentanyl for postoperative
analgesia in lean a...
Che cosa è il concetto di massa
farmacocinetica
• we described a non-linear dosing weight adjustment
(pharmacokinetic mass...
(A) Nomogram for the relationship between analgesic dosing
weight for fentanyl, i.e. pharmacokinetic mass (PK mass),
and t...
Pharmacokinetic mass (PK) weights for selected total body
weights.PK mass is calculated from the formula: PK
mass=52/[1+(1...
Messaggio da portare a casa per il
fentanyl nell’analgesia postop

• Dose carico e di mantenimento
basata sulla massa farm...
remifentanil
Minto CF,Schnider TW, Shafer SL.Pharmacokinetics
and Pharmacodynamics of Remifentanil II. Model
Application .Anesthesiolog...
Calcolo della dose bolo di remifentanil per ottenere un 50% di
depressione EEG in funzione della LBM ed età

.

Minto CF,S...
Calcolo della dose di mantenimento di remifentanil per ottenere
un 50% di depressione EEG in funzione della LBM ed età

.
...
Velocità di infusione del remifentanil per mantenere
una depressione del 50% dell’EEG in funzione
dell’età per un individu...
Farmacocinetica del remifentanil
Egan TD,Huizinga B,Gupta SK,Jaarsma RL,Sperry RJ,Yee JB,Muir KT.Remifentanil
Pharmacokine...
Il gruppo obesi raggiunge conc sostanzialmente +
alte sia di picco che di livello successivo
Volumi di distribuzione e clearances del
remifentanil nei soggetti obesi e in quelli normali
Parametri farmacocinetici del remifentanil nei soggetti
obesi e in quelli normali e del sufentanil negli obesi:dati
da Ega...
I grafici delle stime delle singole
variabili
Con la covariate rivelano che esistono
valide Relazioni con il LBM
Gli emitempi contesto sensitivi (50 e 80 %) non
sono significativamente differenti fra paz obesi
e magri

;il remif sembra...
La simulazione del dosaggio basata sul TBW determina
concentrazioni eccessive nell’obeso.Bolo di 1 MIcrogr/ml
seguito da i...
Messaggio da portare a casa per il
remifentanil
• Quanto premesso significa che tutti I pazienti devono
essere dosati sull...
sufentanil
Slepchenko G,Simon N,Goubaux B,Levron JC. Le Moing
JP,Raucoules-Aimé M.Performance of Target-controlled
Sufentanil Infusio...
Correlazione fra concentrazione predetta e misurata per il
sufentanil Slepchenko G,Simon N,Goubaux B,Levron JC. Le Moing J...
Rapporto Cm/Cp per il sufentanil
Slepchenko G,Simon N,Goubaux B,Levron JC. Le Moing JP,Raucoules-Aimé M.Performance
of Tar...
Relazione fra Median Performance error e BMI per il
sufentanilSlepchenko G,Simon N,Goubaux B,Levron JC. Le Moing JP,Raucou...
Conclusioni
• Usando i dati farmacocinetici descritti da
GEpts il TCI con sufentanil si comporta
bene anche negli obesi;
•...
Dati farmacocinetici del sufentanil,normalizzati
per IBW
Schwartz AE, Matteo RS, Ornstein E, Young WL, Myers KJ: Pharmacok...
Relazioni del sufent Vd tot con % IBW e
eliminazione con Vdtot/IBW
Schwartz AE, Matteo RS, Ornstein E, Young WL, Myers KJ:...
Schwartz AE, Matteo RS, Ornstein E, Young WL, Myers
KJ: Pharmacokinetics of sufentanil in obese patients.
Anesth Analg 73:...
Messaggio da portare a casa per il
sufentanil
• Dose iniziale o livello TCI calcolato sul
TBW
• Mantenimento calcolato sul...
alfentanil
Maitre PO, Vozeh S, Heykants J, Thomson DA, Stanski DR:
Population pharmacokinetics of alfentanil: The average
dose-plasma...
In generale:
• Cl ridotta:45% da 321 a 179 ml/min
• T ½ beta quasi doppio :da 92 a 172
min….
Messaggio da portare a casa per
l’alfentanil
• Dose iniziale ridotta
• Dose di mantenimento ridotta
Feld J M,Laurito CE, Beckerman M,Vincent J, Hoffman
WE.Non-opioid analgesia improves pain relief and decreases
sedation af...
Feld J M,Laurito CE, Beckerman M,Vincent J, Hoffman
WE.Non-opioid analgesia improves pain relief and
decreases sedation af...
Feld J M,Laurito CE, Beckerman M,Vincent J, Hoffman
WE.Non-opioid analgesia improves pain relief and decreases
sedation af...
Feld J M,Laurito CE, Beckerman M,Vincent J, Hoffman
WE.Non-opioid analgesia improves pain relief and
decreases sedation af...
Christofferson E, Dahlström B, Rawal N, Sjöstrand U, Arvill A,
Rydman H. Comparison of intramuscular and epidural
morphine...
Bennett R, Batenhorst R, Graves DA, Foster TS,
Griffen WO, Wright BD. Variation in postoperative
analgesic requirements in...
VanDercar DH, Martinez AP, De Lisser EA. Sleep
apnea syndromes: a potential contraindication
for patient-controlled analge...
Miorilassanti
vecuronium
Schwartz AE, Matteo RS, Ornstein E, Halevy JD, Diaz J.Pharmacokinetics and
pharmacodynamics of vecuronium in the obese sur...
Principali tempi di ripresa dopo vecuronium 0.1 mg/kg
Schwartz AE, Matteo RS, Ornstein E, Halevy JD, Diaz J.Pharmacokineti...
Schwartz AE, Matteo RS, Ornstein E, Halevy JD, Diaz J.Pharmacokinetics and
pharmacodynamics of vecuronium in the obese sur...
Kirkegaard-Nielsen H,Helbo-Hansen HS, Toft P,Severinsen
IK.Anthropometric Variables as Predictors for Duration of Action o...
Kirkegaard-Nielsen H,Helbo-Hansen HS, Toft P,Severinsen
IK.Anthropometric Variables as Predictors for Duration of Action o...
% IBW
Kirkegaard-Nielsen H,Helbo-Hansen HS, Toft P,Severinsen IK.Anthropometric Variables as Predictors for
Duration of Ac...
(Subscapularis+ suprailiac skinfolds)/surface area (mm/m2)
Kirkegaard-Nielsen H,Helbo-Hansen HS, Toft P,Severinsen IK.Anth...
Kirkegaard-Nielsen H,Helbo-Hansen HS, Toft P,Severinsen
IK.Anthropometric Variables as Predictors for Duration of Action o...
Duration of action of vecu according to anthropometric variables
Kirkegaard-Nielsen H,Helbo-Hansen HS, Toft P,Severinsen I...
Vecu
• Durata di azione= 0.291 * dose vecuronium
micrograms -1.88 min.
• Opp Dur az=0.18*%IBW+12.66
• From this equation i...
Messaggio da portare a casa per il
vecuronium

• Calcola la dose sull’IBW
• Monitorizza!!!!
CISATRACURIUM
Tempi di ripresa dopo cisatracurium 0.2 mg/kg
Leykin Y, Pellis T, Lucca M, Lomangino G, Marzano B, Gullo A.The effects of ...
Messaggio da portare a casa per il
cisatracurium
• Dose iniziale e supplementari basate
sull’IBW
Atracurium
Blobner M, Felber AR, Schneck HJ, Jelen-Esselborn S.
Dose-response relationship of atracurium in underweight, normal and
o...
Kirkegaard-Nielsen H, Lindholm P, Petersen HS, Severinsen
IK.Antagonism of atracurium-induced block in obese patients.Can
...
Kirkegaard-Nielsen H, Helbo-Hansen HS, Lindholm P, Severinsen IK,
Pedersen HS. Anthropometric variables as predictors for ...
Kirkegaard-Nielsen H, Helbo-Hansen HS, Lindholm P, Severinsen IK, Pedersen
HS. Anthropometric variables as predictors for ...
Total body weight/surface area kg/m2
Kirkegaard-Nielsen H, Helbo-Hansen HS, Lindholm P, Severinsen IK, Pedersen HS. Anthro...
Total body weight
Kirkegaard-Nielsen H, Helbo-Hansen HS, Lindholm P, Severinsen IK, Pedersen HS. Anthropometric
variables ...
Kirkegaard-Nielsen H, Helbo-Hansen HS, Lindholm P, Severinsen IK, Pedersen
HS. Anthropometric variables as predictors for ...
Beemer GH, Bjorksten AR, Crankshaw DP
Effect of body build on the clearance of atracurium: implication for drug
dosing.Ane...
Cl of atracurium vs LBW
Beemer GH, Bjorksten AR, Crankshaw DP
Effect of body build on the clearance of atracurium: implica...
Varin F, Ducharme J, Théorêt Y, et al. Influence of extreme obesity on
the body disposition and neuromuscular blocking eff...
Varin F, Ducharme J, Théorêt Y, et al. Influence of extreme obesity on the
body disposition and neuromuscular blocking eff...
Lavori di confronto
Vecu e atrac
Tempi di ripresa dopo vecu 0.1 mg/kg e ATRAC 0.5
mg/kg in paz obesi e normali
Weinstein JA, Matteo RS, Ornstein E, Schwart...
Weinstein JA, Matteo RS, Ornstein E, Schwartz AE,
Goldstoff M, Thal G. Pharmacodynamics of vecuronium
and atracurium in th...
Messaggio da portare a casa per atracurium
•

Ridurre modestamente la dose iniziale e quella di mantenimento secondo quant...
Succinilcolina
Velocità di Desaturazione in paz normali,obesi e
patologicamente obesi. Jense HG,Dubin SA,Silverstein PI., ,O'LearyEscolas...
Relazione fra desaturazione a SaO2 90% e % IBW
Cucuianu M, Popescu TA, Haragus S.
Pseudocholinesterase in obese and hyperlipemic
subjects.Clin Chim Acta. 1968 Oct;22(2):...
Kean KT, Kutty KM, Huang SN, Jain R.
A study of pseudocholinesterase induction in experimental
obesity.J Am Coll Nutr. 198...
Rose JB,Theroux MC,Katz M S.The Potency of
Succinylcholine in Obese Adolescents. Anesth
Analg 2000; 90:576–8
•

•

ABSTRAC...
Rose JB,Theroux MC,Katz M S.The Potency of Succinylcholine in Obese
Adolescents. Anesth Analg 2000; 90:576–8.

• ED50, ED9...
Messaggio da portare a casa per la
succinilcolina
• Somministrare la dose secondo il TBW
Rocuronium
Puhringer FK,Keller C;Kleinsasser A,Giesinger S,Benzer
A.Pharmacokinetics of rocuronum bromide in obese female patients.Eu...
Leykin Y, Pellis T, Lucca M, et al. The pharmacodynamic effects of
rocuronium when dosed according to real body weight or ...
Rocuronium 0.6 mg/kg
Leykin Y, Pellis T, Lucca M, et al. The pharmacodynamic effects of rocuronium when
dosed according to...
Confronto dei dati fra Leykin e Puhringher
Leykin morbid obesity class (BMI 43.8 ± 2.1)
Puhringer moderate obesity class (...
Messaggio da portare a casa per il
rocuronium
• Meglio somministrare secondo
IBW,specialmente in infusione
continua,ma dat...
Messaggio da portare a casa per tutti i
miorilassanti
• Non somministrare miorilassante a
demand dei chirurghi;potrebbero
...
Anestetici locali
Lidocaina
PK della lidocaina
Abernethy DR,GReenblatt DJ.Lidocaine disposition in obesity.J.Cardiol
1984;53:1183-6.

3,5

*

*

3
2,5...
Messaggio da portare a casa per gli AL
• I fattori che influenzano il dosaggio sono altri
che la dose totale:anatomia,sede...
Messaggi finali
• Da Casati
•
•

PER IL DOSAGGIO DEI FARMACI DIROFILICI BASTEREBBE
AGGIUNGERE 20% ALL’ IBW (per includere ...
FINE
Diapo da studiare
Tutte le seguenti……….
Minto CF, Schnider TW, Egan TD, et al. Influence of age
and gender on the pharmacokinetics and
pharmacodynamics of remifen...
Kapila A, Glass PSA, Jacobs JR, Muir KT, Hermann
DJ, Shiraishi M, Howell S, Smith RL: Measured
context-sensitive half-time...
Bouillon TW, Bruhn J, Radulescu L, et al. Pharmacodynamic
interaction between propofol and remifentanil regarding
hypnosis...
Pharmacodynamic
interaction between propofol and remifentanil
regarding hypnosis,tolerance of laryngoscopy,
bispectral ind...
Pharmacodynamic
interaction between propofol and remifentanil
regarding hypnosis,tolerance of laryngoscopy,
bispectral ind...
Bouillon TW, Bruhn J, Radulescu L, et al. Pharmacodynamic
interaction between propofol and remifentanil regarding hypnosis...
Bouillon TW, Bruhn J, Radulescu L, et al. Pharmacodynamic
interaction between propofol and remifentanil regarding hypnosis...
Bouillon TW, Bruhn J, Radulescu L, et al. Pharmacodynamic
interaction between propofol and remifentanil regarding hypnosis...
Bouillon TW, Bruhn J, Radulescu L, et al. Pharmacodynamic
interaction between propofol and remifentanil regarding hypnosis...
Bouillon TW, Bruhn J, Radulescu L, et al. Pharmacodynamic
interaction between propofol and remifentanil regarding hypnosis...
Bouillon TW, Bruhn J, Radulescu L, et al. Pharmacodynamic
interaction between propofol and remifentanil regarding hypnosis...
Bouillon TW, Bruhn J, Radulescu L, et al. Pharmacodynamic
interaction between propofol and remifentanil regarding hypnosis...
Bouillon TW, Bruhn J, Radulescu L, et al. Pharmacodynamic
interaction between propofol and remifentanil regarding hypnosis...
Bouillon TW, Bruhn J, Radulescu L, et al. Pharmacodynamic
interaction between propofol and remifentanil regarding hypnosis...
Bouillon TW, Bruhn J, Radulescu L, et al. Pharmacodynamic
interaction between propofol and remifentanil regarding hypnosis...
Bouillon TW, Bruhn J, Radulescu L, et al. Pharmacodynamic
interaction between propofol and remifentanil regarding hypnosis...
•
•
•

•

Electroencephalographic Assessment of Propofol—Remifentanil Interaction
The C50 of propofol for reduction of the...
Mertens MJ,Olofsen E,Engbers FHM,Burm AGL, Bovill JG,Vuyk J.Propofol
Reduces Perioperative Remifentanil Requirements in a ...
Mertens MJ,Olofsen E,Engbers FHM,Burm AGL, Bovill JG,Vuyk
J.Propofol Reduces Perioperative Remifentanil Requirements in a
...
Mertens MJ,Olofsen E,Engbers FHM,Burm AGL, Bovill JG,Vuyk
J.Propofol Reduces Perioperative Remifentanil Requirements in a
...
Mertens MJ,Olofsen E,Engbers FHM,Burm AGL, Bovill JG,Vuyk
J.Propofol Reduces Perioperative Remifentanil Requirements in a
...
Mertens MJ,Olofsen E,Engbers FHM,Burm AGL, Bovill JG,Vuyk
J.Propofol Reduces Perioperative Remifentanil Requirements in a
...
Mertens MJ,Olofsen E,Engbers FHM,Burm AGL, Bovill JG,Vuyk
J.Propofol Reduces Perioperative Remifentanil Requirements in a
...
Mertens MJ,Olofsen E,Engbers FHM,Burm AGL, Bovill JG,Vuyk
J.Propofol Reduces Perioperative Remifentanil Requirements in a
...
Mertens MJ,Olofsen E,Engbers FHM,Burm AGL, Bovill JG,Vuyk
J.Propofol Reduces Perioperative Remifentanil Requirements in a
...
Mertens MJ,Olofsen E,Engbers FHM,Burm AGL, Bovill JG,Vuyk
J.Propofol Reduces Perioperative Remifentanil Requirements in a
...
Mertens MJ,Olofsen E,Engbers FHM,Burm AGL, Bovill JG,Vuyk
J.Propofol Reduces Perioperative Remifentanil Requirements in a
...
Nieuwenhuijs DJF, Olofsen E, Romberg RR, et al.
Response surface modeling of remifentanil-propofol
interaction on cardiore...
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Pk e pd nell'obesità per firenze 20 maggio
Upcoming SlideShare
Loading in …5
×

Pk e pd nell'obesità per firenze 20 maggio

292 views
225 views

Published on

Pharmacokinetiscs and pharmacodynamics of anesthetic drugs in obese patients

Published in: Health & Medicine
0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total views
292
On SlideShare
0
From Embeds
0
Number of Embeds
0
Actions
Shares
0
Downloads
2
Comments
0
Likes
0
Embeds 0
No embeds

No notes for slide

Pk e pd nell'obesità per firenze 20 maggio

  1. 1. Farmacocinetica e farmacodinamica nell’obesità Claudio Melloni Direttore Anestesia e Rianimazione Ospedale di Faenza (RA)
  2. 2. Considerazioni generali • Abbreviazioni • LBM massa magra;cioè tessuti non grassi;99 % dei tessuti metabolici – (for men: 49.9 + 0.89 (height - 152.4) kg; for women: 45.4 + 0.89 (height - 152.4) kg). • IBW:Ideal body weight – IBW = [height (cm) - 100 - (height - 150)]/4 for men and IBW = [height - 100 - (height - 150)]/2 for women; excess weight = measured weight – IBW • LBM = 1.1 × weight - 128(weight/height)2 for men, and • • LBM = 1.07 × weight - 148(weight/height)2 for women CBW/corrected body weight,per es. – ideal body weight (IBW) + [0.4 * excess weight] IBW • Obesità prevede comunque un aumento della LBM:2040% • Es per me di LBM =1.1*100 –(128/100)2=1.1*100(128(100/173)2 =67!!!
  3. 3. IBW Peso ideale • ideal body weight (IBW) basato sulla formula della Metropolitan Life Insurance Co • IBW (females) = 100 lb + 5 lb per inch above 5 ft height • IBWmaschio=50kg+0.9 Kg/cm> 152.5 • IBW femmina=45.5kg +0.9 kg/cm>152.5 • Semplificazione massima: • statura in cm-100 (men) o 105 (women)
  4. 4. Nomogramma della relazione fra altezza peso e sesso e LBW:i punti indicano il peso ideale della LBW per ciascuna altezza
  5. 5. Nomogramma che mette in relazione TBW,altezza e sesso rispetto al peso da usare per calcolare la dose
  6. 6. Considerazioni generali • Vd:Volume di distribuzione =dose carico • CL:dose di mantenimento • Farmaci lipofilici :alti Vd:BDZ,sufent,verapamil • Ma nell’obeso notevoli variabilità. • Dati di letteratura non raramente discordanti……….
  7. 7. Hankin ME, Munz K, Steinbeck AW. Total body water content in normal and obese women. Med J Aust 1976; 2:533-7 • Il contenuto totale di H2O espresso in valore assoluto è significativamente aum nelle obese rispetto al gruppo di controllo,ma è invece minore se espresso in % del peso totale • Peso tot e contenuto totale di acqua sono correlati • I valori misurati e quelli calcolati di acqua tot corporea sono in accordo • Quindi le donne obese hanno acqua tot corporea nel range atteso ,cioè accumulano grasso,non acqua.
  8. 8. Andersen T, Christoffersen P, Gluud C. The liver in consecutive patients with morbid obesity. Int J Obesity 1984; 8:107-15. • • • • • • • • • Biopsie epatiche anormali:88% Istologia:normale 7 % Degenerazione grassa 85 % Degenerazioine grassa +lipogranulomi 54 % Necrosi focale 28% Lieve infiammazione parenchimale 33 % Proliferazione cell. Kupffer 49 % Lieve infiammazione portale 23 % Fibrosi portale 2 % • + sono obesi + sono le alterazioni
  9. 9. Fattori principali che influenzano la distribuzione tissutale dei farmaci • la composizione corporea • Il flusso ematico regionale • L’affinità del farmaco per le proteine plasmatiche • l’affinità del farmaco per I tessuti
  10. 10. Benzodiazepine
  11. 11. Variabili cinetiche per il midazolam Greenblatt DJ, Abernathy DR, Locniskar A, Harmatz JS, Limjuco RA, Shader RI. Effect of age, gender and obesity on midazolam kinetics. Anesthesiology 1984; 61:27-35 * 9 * 8 * 7 6 5 obesi normali 4 3 2 1 0 Vd centr lt/kg HL el hr CL tot ml/kg/mi HL el hr per os
  12. 12. Midazolam nell’obeso • Il Vd tot è aum.poichè la Cl in rapporto al peso è minore;ma quella totale no • Hl el è allungata – Allora;la dose singola ev deve essere aumentata. – Ma le dosi di mantenimento diminuite,ossia somministrate in base al IBW
  13. 13. Cinetica di alprazolam e triazolam negli obesi e nei paz normali Abernethy DR, Greenblatt DJ, Divoll M, Smith RB, Shader RI. The influence of obesity on the pharmacokinetics of oral alprazolam and triazolam. Clin Pharmacokinet. 1984;9:177- . 83 600 * 500 400 alprazolam obesi alprazolam norm triazolam ,obesi triazolam norma 300 200 100 * * * 0 Vd CL Hl elim
  14. 14. Messaggio da portare a casa con le BDZ • Dose iniziale rapportata al tbw • Infusione continua:dose rapportata all‘IBW
  15. 15. BDZ e obesità • • • • • Tutte le BDZ sono altamente lipofile Vd ampi,+ dei normali Anche se le Cl sono simili ai normali Hl prolungate Assorbimento dal tratto GI 40-50%;picco a 40-45 min(midaz) • Conseguenze pratiche; – dose iniziale aum – Dosi di mantenim ridotte(IBW)
  16. 16. propofol
  17. 17. Schüttler, Jürgen, M.D.*; Ihmsen, Harald, Population Pharmacokinetics of Propofol : A Multicenter Study Anesthesiology.92:727-38, 2000 • Il peso è una covariata fondamentale per V1,CL el,le CL intercompartimentali,V2 e V3 • La Cl el diminuisce proporzionalmente all’età • Il V1 diminuisce con l’età • Ma le forme delle correlazioni suggeriscono che il peso non viene incorporato nella formula in funzione lineare,ma come funzione con esponente <1 • V1 diminuisce con l’età con esponente neg < 1 • Cl1 diminusce linearmente > 60 anni
  18. 18. Schüttler, Jürgen, M.D.*; Ihmsen, Harald, Population Pharmacokinetics of Propofol : A Multicenter Study Anesthesiology.92:727-38, 2000
  19. 19. Schüttler, Jürgen, M.D.*; Ihmsen, Harald, Population Pharmacokinetics of Propofol : A Multicenter Study Anesthesiology.92:727-38, 2000 Per 70 kg: 250-300 mg/h Per 70 kg: 170-200 mg/h
  20. 20. Schüttler, Jürgen, M.D.*; Ihmsen, Harald, Population Pharmacokinetics of Propofol : A Multicenter Study Anesthesiology.92:727-38, 2000
  21. 21. Velocità di infusione del propofol per mantenere una concentrazione di 1 microg/ml per 2 h Schüttler, Jürgen, M.D.*; Ihmsen, Harald, Population Pharmacokinetics of Propofol : A Multicenter Study Anesthesiology.92:727-38, 2000 Dosi tot,inclusa quella induttiva: • • • • • Bambino: 3.7 mg × kg-1 × h-1 Adulto magro : 2.6 mg × kg-1 × hAdulto medio : 2.3 mg × kg-1 × h-1 Adulto obeso :1.9 mg × kg-1 × h-1 Anziano :1.5 mg × kg-1 × h-1
  22. 22. Servin F,Farinotti R,Haberer JP,Desmonts JM.Propofol Infusion for Maintenance of Anesthesia in Morbidly Obese Patients Receiving Nitrous Oxide A Clinical and Pharmacokinetic Study Anesthesiology 78:657-665, 1993 • • • • • 8 paz obesi patol Regime infusionale di propofol a gradini N2O/O2(66:34%). VD iniziale non modificato negli obesi Cl totale correlata al peso totale :25.4 ± 6.5 ml × kg-1 × min-1, • Vd ss correlato al peso 1.63 ± 0.54 l × kg-1
  23. 23. Servin F,Farinotti R,Haberer JP,Desmonts JM.Propofol Infusion for Maintenance of Anesthesia in Morbidly Obese Patients Receiving Nitrous Oxide A Clinical and Pharmacokinetic Study Anesthesiology 78:657-665, 1993 min 30 Ml/min/kg Tutto NS 25 lt 20 15 obesi normali 10 5 0 hr min t 1/2 alfa Lt/kg t 1/2 beta t 1/2 gamma Vd Vd Vd ss Cl
  24. 24. CL propofol correlata al BW
  25. 25. Vss propofol correlato al BW
  26. 26. Dati per il propofol da Servin F,Farinotti R,Haberer JP,Desmonts JM.Propofol Infusion for Maintenance of Anesthesia in Morbidly Obese Patients Receiving Nitrous Oxide A Clinical and Pharmacokinetic Study Anesthesiology 78:657-665, 1993 e per il pentotal da Wada DR,Björkman S, Ebling WF,Harashima H, Harapat SR,Stanski DR.Computer Simulation of the Effects of Alterations in Blood Flows and Body Composition on Thiopental Pharmacokinetics in Humans Anesthesiology. 87:884-99, 1997 CL ml/kg 25 20 15 Hr 10 5 ml/min lT/kg 0 Vd Cl Hl term propofol Tps
  27. 27. Concetto di Peso corretto • Il peso utilizzato per il calcolo della velocità di infusione si è basato su una formula empirica: (corrected weight = ideal weight + [0.4 X excess weight]) • Poichè non si sarebbe potuto escludere che,nei paz obesi la dose calcolata sul TBW avrebbe potuto causare deleteri effetti emodinamici • Peso corretto=IBW + 0.4*eccesso di peso
  28. 28. insomma • Dose iniziale normalizzata :vedi formule di Servin • Mantenimento in accordo con quella iniziale • Quindi;gli obesi hanno ricevuto meno propofol/kg a paragone dei sogg.normali se rapportato al peso
  29. 29. Concentrazioni plasmatiche di propofol al risveglio(microgr/lt) obesi Non obesi Servin 1 1 Kakinohana 1.49-1.69 1.49-1.69 Saijo 1.5 1.5
  30. 30. Messaggio da portare a casa:propofol • Dose iniziale e mantenimento basate sul peso corretto • Ma ……….titolare con BIS o similari
  31. 31. Fenitoina
  32. 32. Dati cinetici per la fenitoina;in dose singola;da Abernethy Arch Neurol 1985,42:468-71 90 Lt/kg 80 70 60 * 50 40 30 20 ² * hr * Lt/kg 10 0 normali obesi LT/hr*10 t 1/2 beta Vd Cl Vd/TBW
  33. 33. Messaggio da portare a casa per la fenitoina • Poichè negli obesi t ½ beta allungato,Vd aumentato,e dunque la distribuzione è aum, • Dose fenitoina=IBW +(1.33*(TBW-IBW)
  34. 34. Thiopental
  35. 35. Wada DR,Björkman S, Ebling WF,Harashima H, Harapat SR,Stanski DR.Computer Simulation of the Effects of Alterations in Blood Flows and Body Composition on Thiopental Pharmacokinetics in Humans Anesthesiology. 87:884-99, 1997 • • Vd 2.2 Lt/Kg,Cl el 0.22 lt/min,Hl term 9 h • Conc di picco + alte con CI basso • L’obesità influenza la conc per la differenza nel CO
  36. 36. Jung D, Mayersohn M, Perrier D, Calkins J, Saunders R: Thiopental disposition in lean and obese patients undergoing surgery. ANESTHESIOLOGY 56:269-274, 1982 30 25 20 obese nonobese 15 10 5 0 Vd Lt/kg tbw Cl tot ml/kg/h HL el hr
  37. 37. Dose induzione TPS:mg/tbw obesi Jung Dundee Non obesi 3.9 5.1
  38. 38. Messaggio da portare a casa per il pentotal • Non somministrare la dose bolo secondo il pso totale! • Ridurre la dose iniziale in accordo a???? l peso ideale???? • Attenzione alle dosi ripetute!
  39. 39. Anestetici inalatori
  40. 40. Volumi di distribuzione ml di vapore /kg e Clearance di trasporto dal compart centrale al periferico ml vapore/kg/min Wissing H,Kuhn I,Rietbrock S, Fuhr U. Br. J. Pharmacokinetics of inhaled anaesthetics in a clinical setting: comparison of desflurane, isoflurane and sevoflurane. BR J.Anaesth. 2000; 84:443-449 4500 4000 3500 3000 2500 desflurane isoflurane sevoflurane 2000 1500 1000 *10 500 0 Vd centr Vd peri Vd ss CL trasp centr-perif
  41. 41. Microcostanti per il trasporto dal compart. centrale al perif. e dal periferico al centrale Wissing H,Kuhn I,Rietbrock S, Fuhr U. Br. J. Pharmacokinetics of inhaled anaesthetics in a clinical setting: comparison of desflurane, isoflurane and sevoflurane. BR J.Anaesth. 2000; 84:443-449 0.17 0.14 0.11 desflurane isoflurane sevoflurane 0.08 0.05 0.02 0.00 K 1-2 K 2-1
  42. 42. Strum EM, Szenohradszki J, Kaufman WA, et al. Emergence and recovery characteristics of desflurane versus sevoflurane in morbidly obese adult surgical patients: a prospective, randomized study. Anesth Analg. 2004;99:18481853 • • • • • • 50 paz,desf vs sevo Bypass gastrointest per via laparotomica Premed con metoclopramide e midaz Catet peridurale Induz fent + propofol, IOT con succi Mantenim con 1 MAC aggiustato per età di DESF o SEVO • Fent;morf;AL per pd qb per stabilità press e FC • Monitoraggio BIS fra 40/60
  43. 43. Tempi di ripresa dopo la sospensione della erogazione degli anestetici Strum EM, Szenohradszki J, Kaufman WA, et al. Emergence and recovery characteristics of desflurane versus sevoflurane in morbidly obese adult surgical patients: a prospective, randomized study. Anesth Analg. 2004;99:1848-1853 31 26 21 min desflurane sevoflurane 16 11 6 1 apertura stretta occhi mano estubaz nome data nascita
  44. 44. Tempi di ripresa precoci(sec) dopo anest con remif + desflurane o sevoflurane De Baerdemaeker LEC,Struys MMRF,Jacobs S,Den lauwen NMM,Bossuyt GRPJ,Pattyn P,Mortier EP.Optimization of desflurane administration in morbidly obese patients: a comparison with sevoflurane using an 'inhalation bolus' technique . Br. J. Anaesth. 2003; 91:638-650 600 sevoflurane 500 desflurane sec 400 300 200 100 0 ripresa resp spont apert occhi estubaz orient free airway
  45. 45. Juvin P., Vadam C., Malek L., Dupont H., Marmuse J.P, Desmonts J-M. Postoperative recovery after desflurane, propofol or isoflurane anesthesia among morbidity obese patients: a prospective randomized study. Anesth Analg 2000; 91:714-9 • • • • • Gastroplast laparoscopica Propofol/scc/N2O/alfent TCI 50 Microgr/ml Rocu per miorisoluz BIS 3 gruppi/Propof Tci vs desf vs isof
  46. 46. Livelli di sedazione postop valutati con l’Observers assessment of alertness sedation score dopo anestesia con desflurane ,isoflurane ,propofol Juvin P., Vadam C., Malek L., Dupont H., Marmuse J.P, Desmonts J-M. Postoperative recovery after desflurane, propofol or isoflurane anesthesia among morbidity obese patients: a prospective randomized study. Anesth Analg 2000; 91:714-9 desf propof isof
  47. 47. Tempi di ripresa precoci,punteggio mobilità al risveglio e desaturazione arteriosa dopo desflurane,isoflurane o propofol in paz obesi operati di gastroplastica Juvin P., Vadam C., Malek L., Dupont H., Marmuse J.P, Desmonts J-M. Postoperative recovery after desflurane, propofol or isoflurane anesthesia among morbidity obese patients: a prospective randomized study. Anesth Analg 2000; 91:714-9 16 14 12 10 desflurane isoflurane propofol 8 6 4 2 0 ap occhi estubaz dice nome mobilità PaO2<95
  48. 48. Arain SR,Barth CD,Shankar H,Ebert TJ. Choice of volatile anesthetic for the morbidly obese patient:sevoflurane or desflurane.J.Clin Anesth. 2005.17:413-419 • Non ci sono differenze intra o postop quando i due anestetici vengono titolati con il BIS tra 40 e 50 intraop e a 60 negli ultimi 15 min di chirurgia. • Anest .midaz/propof/fent /cisatrac
  49. 49. Arain SR,Barth CD,Shankar H,Ebert TJ. Choice of volatile anesthetic for the morbidly obese patient:sevoflurane or desflurane.J.Clin Anesth. 2005.17:413-419 7 6 5 4 min desflurane sevoflurane 3 2 1 0 fine op-ap occhi estubaz
  50. 50. Differenze di metodologia fra gli studi • Arain SR,Barth CD,Shankar H,Ebert TJ. Choice of volatile anesthetic for the morbidly obese patient:sevoflurane or desflurane.J.Clin Anesth. 2005.17:413-419 • • • Fent Cisatrac IPPV fino alla fine • De Baerdemaeker LEC,Struys MMRF,Jacobs S,Den lauwen NMM,Bossuyt GRPJ,Pattyn P,Mortier EP.Optimization of desflurane administration in morbidly obese patients: a comparison with sevoflurane using an 'inhalation bolus' technique . Br. J. Anaesth. 2003; 91:638-650 • Remif • SIMV alla fine Ma una differenza di 2 min ha un senso clinicamente???? Poi arruolamento di obesi diversi:Arain media 118 kg p es.BMI 35-47 vs altri…………….
  51. 51. Biotrasformazione degli anestetici inalatori:fluoruri agente autore obesi nonobesi Enflurane isoflurane Strube 1987 22.7 6.5 enflurane Bentley 1979 28.0 +/- 1.9 17.3 +/- 1.3 halothane Bentley 1982 3.2 +/- 0.6 1.9 +/- 0.2 1,311 +/- 114 bromuri 0. 787 +/- 115 microM, sevoflurane Frink 1993 30 +/- 2 mumol/L 28 +/- 2 mumol/L sevoflurane Higuchi 1993 51 +/- 2.5 40 +/- 2.3
  52. 52. Livelli di fluoruri ionici in 17 pazienti obesi e 7 non obesi durante e dopo anestesia alotanica Bentley JB, Vaughan RW, Gandolfi AJ, Cork RC. Halothane biotransformation in obese and non-obese patients. Anesthesiology 1982; 57:94-7
  53. 53. Livelli nel siero di bromuri dopo 2 h di alotano,17 obesi e 7 non obesi Bentley JB, Vaughan RW, Gandolfi AJ, Cork RC. Halothane biotransformation in obese and non-obese patients. Anesthesiology 1982; 57:94-7
  54. 54. Casati A, Bignami E, Spreafico E, Mamo D. Effects of obesity on wash-in and wash-out kinetics of sevoflurane. Eur J Anaesthesiol. 2004;21:243- 5.
  55. 55. Messaggio da portare a casa con sevorane e desflurane • Il desflurane presenta vantaggi più teorici che reali • Probabilmente nell’uso di questi alogenati nella pratica clinica le differenze sono minime e riguardano i tempi di risveglio più precoci • Tanto poi dobbiamo fornire analgesia postop……………
  56. 56. Vantaggi ipotizzabili da un risveglio più rapido • minore solub sangue/gas desf 0.45 e sevo 0.65, isoflurane 1.4 , haloth 2. • Più precoce ripresa della pervietà delle vie aeree – Protezione dalla inalaz – Migliore ossigenazione • = rapida ripresa delle funzione cardiovas e resp • = precoce uscita dalla sala op • + precoce ripresa delle attività spontanee che richiedono coordinazione • maggiore sicurezza • Economicamente vantaggioso:turnover di sala op. • Desiderabile dal pdv del paz.
  57. 57. Vantaggi di una ripresa rapida + precoce protezione + precoce ripresa della pervietà Cardio vascolare e resp Vie aeree + precoce ripresa della funz resp + rapida uscita dalla sala op Migliore ossigenaz + turnover Minor rischio inalaz + efficienza
  58. 58. fentanile
  59. 59. BentleyJB, Borel JD,Gillespie TJ.Fentanyl pharmacokinetics in obese and nonobese patients.Anesthesiology 1981.55;A177. • 10 microgr /kg • Non diff cinetiche fra obesi e non • Ma suggeriscono di somministrare il farmaco sulla base della LBW
  60. 60. Shibutani K, Inchiosa MA Jr., Sawada K, et al. Accuracy of pharmacokinetic models for predicting plasma fentanyl concentrations in lean and obese surgical patients: derivation of dosing weight (‘pharmacokinetic mass’). Anesthesiology. 2004;101:603-613 • • • • • • • Esistono 2 modelli principali per il dosaggio del fent e non sono stati testati nell’obeso Induz con fent 1–2 microg/kg, propofol 1.5 -2.5 mg/kg, sevoflurane 2%,atrac 0.5 mg/kg. Cont. infus fent: 0.05–0.07 microg×kg-1×min-1 * 60-75 min, poi 0.03–0.05 microgr×kg-1×min-1 * 1 -2 h, poi 0.02–0.03 microg×kg-1×min-1. Dose sempre aggiustata alla clinica Sospesa 30–40 min prima delle fine chir Confronto fra conc plasmatiche misurate e predette dai modelli. Risultati:il modello di Shafer overstima sistematicamente ,per paz di 140- 200 kg, I pesi da usare sono 100–108 kg • La massa farmacocinetica rappresenta il peso corporeo derivato dalla relazione non lineare fra l’errore di predizione dell’algoritmo di Shafer e il TBW e presenta una relazione lineare con la Cl
  61. 61. Cp di Shafer sovrastima la Cpm nel gr.obesi( O), molto meno nel gruppo L(lean,magri) Shibutani K, Inchiosa MA Jr., Sawada K, et al. Accuracy of pharmacokinetic models for predicting plasma fentanyl concentrations in lean and obese surgical patients: derivation of dosing weight (‘pharmacokinetic mass’). Anesthesiology. 2004;101:603-613
  62. 62. Analisi di regressione tra gli errori di performance con il modello di Shafer(sopra) e quello di Scott(sotto). Shibutani K, Inchiosa MA Jr., Sawada K, et al. Accuracy of pharmacokinetic models for predicting plasma fentanyl concentrations in lean and obese surgical patients: derivation of dosing weight (‘pharmacokinetic mass’). Anesthesiology. 2004;101:603-613
  63. 63. Relazione non lineare fra PE Shafer e TBW;l’equazione mostrata puo essere usata per migliorare l’accuratezza della predicibilità dellla conc plasmatica del fentanyl Shibutani K, Inchiosa MA Jr., Sawada K, et al. Accuracy of pharmacokinetic models for predicting plasma fentanyl concentrations in lean and obese surgical patients: derivation of dosing weight (‘pharmacokinetic mass’). Anesthesiology. 2004;101:603-613
  64. 64. Shibutani K, Inchiosa MA Jr., Sawada K, et al. Accuracy of pharmacokinetic models for predicting plasma fentanyl concentrations in lean and obese surgical patients: derivation of dosing weight (‘pharmacokinetic mass’). Anesthesiology. 2004;101:603-613 •Pharmacokinetic mass-Shafer = • 52/(1 + PE-Shafer-reg) = 52/Correction factor; •i.e., 52/[1 + (196.4 ´ e-0.025kg - 53.66)/100]. TBW
  65. 65. Shibutani K, Inchiosa MA Jr., Sawada K, et al. Accuracy of pharmacokinetic models for predicting plasma fentanyl concentrations in lean and obese surgical patients: derivation of dosing weight (‘pharmacokinetic mass’). Anesthesiology. 2004;101:603-613 •Pharmacokinetic mass-Shafer = • 52/(1 + PE-Shafer-reg) = 52/Correction factor; •i.e., 52/[1 + (196.4 ´ e-0.025kg - 53.66)/100]. TBW
  66. 66. Shibutani K, Inchiosa MA Jr., Sawada K, et al. Accuracy of pharmacokinetic models for predicting plasma fentanyl concentrations in lean and obese surgical patients: derivation of dosing weight (‘pharmacokinetic mass’). Anesthesiology. 2004;101:603-613 •Pharmacokinetic mass-Shafer = • 52/(1 + PE-Shafer-reg) = 52/Correction factor; •i.e., 52/[1 + (196.4 ´ e-0.025kg - 53.66)/100].
  67. 67. Shibutani K, Inchiosa MA Jr., Sawada K, et al. Accuracy of pharmacokinetic models for predicting plasma fentanyl concentrations in lean and obese surgical patients: derivation of dosing weight (‘pharmacokinetic mass’). Anesthesiology. 2004;101:603-613 • Insomma:da 52 a 100 kg la massa farmacocinetica cresce linearmente con pendenza 0.65. • quando il peso >140 kg;la curva si appiatta e basta correggere come fra 100 e 108
  68. 68. Fattori di correzione e massa farmacocinetica per alcuni pesio esemplificativi Shibutani K, Inchiosa MA Jr., Sawada K, et al. Accuracy of pharmacokinetic models for predicting plasma fentanyl concentrations in lean and obese surgical patients: derivation of dosing weight (‘pharmacokinetic mass’). Anesthesiology. 2004;101:603-613
  69. 69. Estensione al postop
  70. 70. Shibutani K, Inchiosa MA Jr., Sawada K, Bairamiam M.Pharmacokinetic mass of fentanyl for postoperative analgesia in lean and obese patients.Brit J.Anesth 95.377683: 2005 • • 69 paz con TBW fra 48 e181 kg. Fent intraop + postop evitando depress resp con misuraz delle conc plasmatiche di fent . – – – – • • • • Dose di partenza media 1 microg /kg/h( range of 0.5–2.0 ) Dosaggio successivo titolato dalle nurse asconda del dollore ,della possibilitàdi resp profondi e tossire,con pazienti capaci di rispondere prontamente al atto ed alla voce. Aggiustamenti manuali del 20-30% Sempre O2 suppl La dose media di fent necessaria per mantenere una valida analgesia nel postop (4 h) mostra una relaz non lineare con il TBW e invece lineare con la massa farmacocinetica dose (mg h1)=1.22·pharmacokinetic mass-7.5; r = 0.741, P<0.001. I valori corrispondenti sono fra TBW e Pk massa: TBW –massa PK 52 kg – 52 kg; 70 kg – 65 kg; 100 kg – 83 kg; 120 kg – 93 kg;140 kg – 99 kg; 160 kg – 104 kg; 180 kg – 107 kg; 200 kg – 109 kg. La conc plasmatica di fent necessaria per analg.vale approssimativamente 1.5 ng/ ml
  71. 71. Shibutani K, Inchiosa MA Jr., Sawada K, Bairamiam M.Pharmacokinetic mass of fentanyl for postoperative analgesia in lean and obese patients.Brit J.Anesth 95.377683: 2005 (A) Non-linear relationship between postoperative analgesic dosing requirements for fentanyl and total body weight (TBW). The equation for this relationship was: dose (mg h1)=167·e0.011 TBW+149 (coefficient of determination=0.551; P<0.001). (B) Linear relationship between analgesic dose for fentanyl and pharmacokinetic mass (PK mass). The equation for this relationship was: dose (mg h1)=1.22·pharmacokinetic mass–7.5; r = 0.741, P<0.001. The dashed lines represent –30% of the values predicted from the regression relationship.
  72. 72. Che cosa è il concetto di massa farmacocinetica • we described a non-linear dosing weight adjustment (pharmacokinetic mass), which proposes that the dose of fentanyl should be determined per kg of pharmacokinetic mass, rather than TBW. The relationship between pharmacokinetic mass and TBW is non-linear, and is shown as a nomogram • clearance was also measured in the previous study, and it had a similar non-linear relationship to TBW (Appendix Fig. A1B). Our previous findings suggested that pharmacokinetic mass is the dosing weight for fentanyl that reflects • the influence of TBW on clearance. The least-squares fit for this relationship indicates a dose of 1.22 microg h1 per unit of pharmacokinetic mass – 7.5. • If the relationship is forced through the origin, the sums of squares of deviations from linear regression is only increased by 0.7%, and the dose for postoperative analgesia is 1.12 mg h1 (or simply 1.1 mg h1) per unit of pharmacokinetic mass.
  73. 73. (A) Nomogram for the relationship between analgesic dosing weight for fentanyl, i.e. pharmacokinetic mass (PK mass), and total body weight (TBW). (B) Nomogram for the relationship between total body clearance of fentanyl (ml min1) and total body weight (TBW ).
  74. 74. Pharmacokinetic mass (PK) weights for selected total body weights.PK mass is calculated from the formula: PK mass=52/[1+(196.4·e0.025 TBW– 53.66)/100], as described in reference 2. The data are rounded to whole numbers for convenience; rounding errors are <1% in all cases. TBW, total body weight; PK mass, pharmacokinetic mass
  75. 75. Messaggio da portare a casa per il fentanyl nell’analgesia postop • Dose carico e di mantenimento basata sulla massa farmacocinetica; PK mass=52/[1+(196.4·e0.025 TBW– 53.66)/100], Ossia : 1.22 microg /h per unit of pharmacokinetic mass – 7.5; p es :obeso di 140 kg,la massa pkinetica vale 100 e la dose oraria è 115 microgr
  76. 76. remifentanil
  77. 77. Minto CF,Schnider TW, Shafer SL.Pharmacokinetics and Pharmacodynamics of Remifentanil II. Model Application .Anesthesiology 86:24-33, 1997 • • • • * Background: The pharmacokinetics and pharmacodynamics of remifentanil were studied in 65 healthy volunteers using the electroencephalogram (EEG) to measure the opioid effect. In a companion article, the authors developed complex population pharmacokinetic and pharmacodynamic models that incorporated age and lean body mass (LBM) as significant covariates and characterized intersubject pharmacokinetic and pharmacodynamic variability. In the present article, the authors determined whether remifentanil dosing should be adjusted according to age and LBM, or whether these covariate effects were overshadowed by the interindividual variability present in the pharmacokinetics and pharmacodynamics. Methods: Based on the typical pharmacokinetic and pharmacodynamic parameters, nomograms for bolus dose and infusion rates at each age and LBM were derived. Three populations of 500 individuals each, ages 20, 50, and 80 yr, were simulated base on the interindividual variances in model parameters as estimated by the NONMEM software package. The peak EEG effect in response to a bolus, the steady-state EEG effect in response to an infusion, and the time course of drug effect were examined in each of the three populations. Simulations were performed to examine the time necessary to achieve a 20%, 50%, and 80% decrease in remifentanil effect site concentration after a variable-length infusion. The variability in the time for a 50% decrease in effect site concentrations was examined in each of the three simulated populations. Titratability using a constant-rate infusion was also examined. Results: After a bolus dose, the age-related changes in V1 and ke0 nearly offset each other. The peak effect site concentration reached after a bolus dose does not depend on age. However, the peak effect site concentration occurs later in elderly individuals. Because the EEG shows increased brain sensitivity to opioids with increasing age, an 80-yr-old person required approximately one half the bolus dose of a 20-yr old of similar LBM to reach the same peak EEG effect. Failure to adjust the bolus dose for age resulted in a more rapid onset of EEG effect and prolonged duration of EEG effect in the simulated elderly population. The infusion rate required to maintain 50% EEG effect in a typical 80-yr-old is approximately one third that required in a typical 20-yr-old. Failure to adjust the infusion rate for age resulted in a more rapid onset of EEG effect and more profound steady-state EEG effect in the simulated elderly population. The typical times required for remifentanil effect site concentrations to decrease by 20%, 50%, and 80% after prolonged administration are rapid and little affected by age or duration of infusion. These simulations suggest that the time required for a decrease in effect site concentrations will be more variable in the elderly. As a result, elderly patients may occasionally have a slower emergence from anesthesia than expected. A step change in the remifentanil infusion rate resulted in a rapid and predictable change of EEG effect in both the young and the elderly. Conclusions: Based on the EEG model, age and LBM are significant demographic factors that must be considered when determining a dosage regimen for remifentanil. This remains true even when interindividual pharmacokinetic and pharmacodynamic variability are incorporated in the analysis.
  78. 78. Calcolo della dose bolo di remifentanil per ottenere un 50% di depressione EEG in funzione della LBM ed età . Minto CF,Schnider TW, Shafer SL.Pharmacokinetics and Pharmacodynamics of Remifentanil II. Model Application .Anesthesiology 86:24-33, 1997 20 40 60 80
  79. 79. Calcolo della dose di mantenimento di remifentanil per ottenere un 50% di depressione EEG in funzione della LBM ed età . Minto CF,Schnider TW, Shafer SL.Pharmacokinetics and Pharmacodynamics of Remifentanil II. Model Application .Anesthesiology 86:24-33, 1997
  80. 80. Velocità di infusione del remifentanil per mantenere una depressione del 50% dell’EEG in funzione dell’età per un individuo con LBM di 55
  81. 81. Farmacocinetica del remifentanil Egan TD,Huizinga B,Gupta SK,Jaarsma RL,Sperry RJ,Yee JB,Muir KT.Remifentanil Pharmacokinetics in Obese versus Lean Patients Anesthesiology 89:562-73, 1998 • Modello bicompartimentale • CL 3 l/min : 3.1 l/min obesi , 2.7 l/min Magri • + alta del flusso epatico (remi metab extraepatico ) • VD centr 7.5 l obesi e 6.8 magri • Vd perif 8.7 l obesi e 7.6 l magri(meno di quanto ci si sarebbe attesi da molecole liposolubili…………) • IL CONFRONTO FRA OBESI E MAGRI ns • Ma se I valori vengono normalizzati per il TBW emergono differenze significative
  82. 82. Il gruppo obesi raggiunge conc sostanzialmente + alte sia di picco che di livello successivo
  83. 83. Volumi di distribuzione e clearances del remifentanil nei soggetti obesi e in quelli normali
  84. 84. Parametri farmacocinetici del remifentanil nei soggetti obesi e in quelli normali e del sufentanil negli obesi:dati da Egan TD,Huizinga B,Gupta SK,Jaarsma RL,Sperry RJ,Yee JB,Muir KT.Remifentanil Pharmacokinetics in Obese versus Lean Patients Anesthesiology 99:562-73, 1998 Slepchenko G,Simon N,Goubaux B,Levron JC. Le Moing JP,Raucoules-Aimé M.Performance of Target-controlled Sufentanil Infusion in Obese Patients Anesthesiology 98:65-73, 2003 100 90 lt e lt/min 80 70 60 obesi remi magri remif obesi sufent 50 40 30 20 10 0 V1 V2 CL1 CL2
  85. 85. I grafici delle stime delle singole variabili Con la covariate rivelano che esistono valide Relazioni con il LBM
  86. 86. Gli emitempi contesto sensitivi (50 e 80 %) non sono significativamente differenti fra paz obesi e magri ;il remif sembra durare meno negli obesi
  87. 87. La simulazione del dosaggio basata sul TBW determina concentrazioni eccessive nell’obeso.Bolo di 1 MIcrogr/ml seguito da infusione di 0.5 microgr/kg/min per 15 min e poi 0.25 microgr/kg/min per altri 105 min
  88. 88. Messaggio da portare a casa per il remifentanil • Quanto premesso significa che tutti I pazienti devono essere dosati sulla base del LBM o IBW quindi: • • • • • Velocità di infusione di : 0.2–1 microg × kg-1 × min-1 IBW Dosi bolo: 0.25–1 microg/kg di IBW per la maggior parte delle applicazioni più comuni
  89. 89. sufentanil
  90. 90. Slepchenko G,Simon N,Goubaux B,Levron JC. Le Moing JP,Raucoules-Aimé M.Performance of Target-controlled Sufentanil Infusion in Obese Patients Anesthesiology 98:65-73, 2003 • • • • • • • • • Validazione nell’obeso di un protocollo TCI di sufentanil normalmente applicato a paz normali TCI prop e sufent 11 obesi con BMI> 45.0 ± 6.5 kg/m2 per gastroplast.laparoscopica TCI prop 3 microgr ml. TCI effetto sufent 0.4 ng/ml ;ma poi modificata intraop secondo clinica STANPUMP Results: Applied sufentanil target concentrations ranged from 0.3 to 0.65 ng/ml. The mean ± SD plasma sufentanil concentration measured during spontaneous ventilation was 0.13 ± 0.03 ng/ml. Median performance error (range) was -13% (-42 to 36%). Median absolute performance error was 26% (8–44%) during infusion and 17% (12–59%) for the 24 h after its completion. The pharmacokinetic sets used slightly overpredicted the concentrations, with a median divergence of -3.4% (-10.2 to 3.1%) during infusion. For body mass index greater than 40, the overestimation of plasma sufentanil concentrations was greater. A two-compartment model with proportional error for interindividual variability best fitted the data. The residual variability was modeled as an additive (0.016 ng/ml) or proportional error (23%). Clearance, central volume of distribution, intercompartmental clearance, and peripheral volume of distribution (coefficient of variation) were 1.27 l/min (23%), 37.1 l (20%), 0.87 l/min (44%), and 92.7 l (22%), respectively. Conclusion: The pharmacokinetic parameter set derived from a normal-weight population accurately predicted plasma sufentanil concentrations in morbidly obese patients.
  91. 91. Correlazione fra concentrazione predetta e misurata per il sufentanil Slepchenko G,Simon N,Goubaux B,Levron JC. Le Moing JP,Raucoules-Aimé M.Performance of Target-controlled Sufentanil Infusion in Obese Patients Anesthesiology 98:65-73, 2003
  92. 92. Rapporto Cm/Cp per il sufentanil Slepchenko G,Simon N,Goubaux B,Levron JC. Le Moing JP,Raucoules-Aimé M.Performance of Target-controlled Sufentanil Infusion in Obese Patients Anesthesiology 98:65-73, 2003
  93. 93. Relazione fra Median Performance error e BMI per il sufentanilSlepchenko G,Simon N,Goubaux B,Levron JC. Le Moing JP,Raucoules-Aimé M.Performance of Target-controlled Sufentanil Infusion in Obese Patients Anesthesiology 98:6573, 2003
  94. 94. Conclusioni • Usando i dati farmacocinetici descritti da GEpts il TCI con sufentanil si comporta bene anche negli obesi; • però la stima della concentrazione plasmatica cresce all’aumentare del BMI;quindi………….. • Il dosaggio dovrebbe essere un poco diminuito!
  95. 95. Dati farmacocinetici del sufentanil,normalizzati per IBW Schwartz AE, Matteo RS, Ornstein E, Young WL, Myers KJ: Pharmacokinetics of sufentanil in obese patients. Anesth Analg 73:790-3, 1991 35 * 30 25 20 15 obesi norm * 10 5 0 V d iniz V Tot Clp Hlel tot *10
  96. 96. Relazioni del sufent Vd tot con % IBW e eliminazione con Vdtot/IBW Schwartz AE, Matteo RS, Ornstein E, Young WL, Myers KJ: Pharmacokinetics of sufentanil in obese patients. Anesth Analg 73:790-3, 1991
  97. 97. Schwartz AE, Matteo RS, Ornstein E, Young WL, Myers KJ: Pharmacokinetics of sufentanil in obese patients. Anesth Analg 73:790-3, 1991 • Il fatto che Vd in ml/kg siano simili in obesi e normali suggeriscono che il farmaco è distribuito similmente nella massa in eccesso e nella LBmass • La dose carico percio potrebbe essere simile.ma la lenta eliminazione indica una riduzione durante il mantenimento (vedi il rischio ipossiemico nell’obeso….) • Comunque l’aum del Vd e del t ½ beta suggerisce che la cinetica nell’obeso è alterata e che il dosaggio debba essere ridotto.
  98. 98. Messaggio da portare a casa per il sufentanil • Dose iniziale o livello TCI calcolato sul TBW • Mantenimento calcolato sul IBW
  99. 99. alfentanil
  100. 100. Maitre PO, Vozeh S, Heykants J, Thomson DA, Stanski DR: Population pharmacokinetics of alfentanil: The average dose-plasma concentration relationship and interindividual variability in patients. ANESTHESIOLOGY 66:3-12, 1987 • No relaz fra Cl e BW • Stima del compart centrale • Vc in lt=VC * BW volume centrale (lt/kg)medio normalizzato per il peso • Implicaz:dose carico aggiustata al peso • Infusione di mantenim:non aggiustata al peso,ma riduz al crescere dell’età • Poichè la hl terminale è influenzata dall’età e un poco anche dal peso,considerare la durata e la dose di mantenim:::::vedi grafico • Variabilità interindividuale relativamente larga
  101. 101. In generale: • Cl ridotta:45% da 321 a 179 ml/min • T ½ beta quasi doppio :da 92 a 172 min….
  102. 102. Messaggio da portare a casa per l’alfentanil • Dose iniziale ridotta • Dose di mantenimento ridotta
  103. 103. Feld J M,Laurito CE, Beckerman M,Vincent J, Hoffman WE.Non-opioid analgesia improves pain relief and decreases sedation after gastric bypass surgery. Can J Anesth 2003 / 50 / 336-341 • 30 obesi (BMI > 50 kg×m-2) per bypass gastrico . • 2 gruppi: – fent+ sevo ,boli intermitt di fent 50 microg fentanyl fino a 6 microg×kg-1 di IBW (in kilograms)maschio = 50 ± 2.3 kg per 2.5 cm > 160 cm, femmine = 45.5 ± 2.3 kg per 2.5 cm > 160 cm. – Paz nel gruppo non oppioidi(sevoflurane):aggiunte – ketorolac, 30 mg iv a inizio e fine caso – clonidina, 300–500 mg iv nella prima ora di anest – lidocaina, 100 mg bolo induttivo +4 mg×min-1 nella I h,poi 3 mg×min1 for the seconda h e 2 mg×min-1 fino alla fine – ketamina, 0.17 mg×kg-1×hr-1 fino al max di 1 mg×kg-1 – magnesio solfato 80 mg×kg-1 totale – Metilprednisolone 60 mg iv bolo prima dell’inizio – Bis 40–60 durante CHIR.
  104. 104. Feld J M,Laurito CE, Beckerman M,Vincent J, Hoffman WE.Non-opioid analgesia improves pain relief and decreases sedation after gastric bypass surgery. Can J Anesth 2003 / 50 / 336-341 • Durata anest media 3.3 hr • MAP +bassa nel non-opioid (73 ± 6 mmHg) vs fentanyl (80 ± 7 mmHg, P < 0.05). • Meno ET sevoflurane per il mantenimento nonopioid (median = 1.0%, 25% range = 1.0%, 75% range = 1.5%) vs gruppo con fentanyl (median = 1.5%, 25% range = 1.4%, 75% range = 2.0%) (P < 0.001). • Tempo medio nella PACU:2 hr
  105. 105. Feld J M,Laurito CE, Beckerman M,Vincent J, Hoffman WE.Non-opioid analgesia improves pain relief and decreases sedation after gastric bypass surgery. Can J Anesth 2003 / 50 / 336-341
  106. 106. Feld J M,Laurito CE, Beckerman M,Vincent J, Hoffman WE.Non-opioid analgesia improves pain relief and decreases sedation after gastric bypass surgery. Can J Anesth 2003 / 50 / 336-341 • Allora nel gruppo trattato con analgesia preemptive e multimodale • Anestesia adeguata intraop e postop • Vantaggi: – – – – – • Meno stimolazione cardiovascolare intraop Meno sedazione postop Meno consumo di oppioidi Meno depress resp 0 intubati nel postop vs 2 nel gruppo oppioidi
  107. 107. Christofferson E, Dahlström B, Rawal N, Sjöstrand U, Arvill A, Rydman H. Comparison of intramuscular and epidural morphine for postoperative analgesia in the grossly obese. Influence on postoperative ambulation and pulmonary function. Anesth Analg 1984; 63:583-92 • • • • Studio randomizzato doppio cieco 30 obesi patol per gastroplastica ; Dosi equianalgesiche di morf. Morf epidurale >>>> im per: – capacità di sedere,alzarsi, camminare – PEF – ritorno motilità intestinale – Ricoveri + brevi!!!
  108. 108. Bennett R, Batenhorst R, Graves DA, Foster TS, Griffen WO, Wright BD. Variation in postoperative analgesic requirements in the morbidly obese following gastric bypass surgery. Pharmacotherapy 1982; 2:50-3 • • • • 10 paz obesi dopo chirurgia di bypass gastrico PCA con morfina Analgesia soddisfacente in tutti Dose tot di morfina nelle prime 36 h:66 mg,cioè 1.7 mg/hr. • Variabilità di 10 Volte:17.5-175 mg • Dose non relata a BSA,età,sesso;dose per iniezione,anestesia,ecc.
  109. 109. VanDercar DH, Martinez AP, De Lisser EA. Sleep apnea syndromes: a potential contraindication for patient-controlled analgesia. Anesthesiology 1991; 74:623-4.
  110. 110. Miorilassanti
  111. 111. vecuronium
  112. 112. Schwartz AE, Matteo RS, Ornstein E, Halevy JD, Diaz J.Pharmacokinetics and pharmacodynamics of vecuronium in the obese surgical patient.Anesth Analg. 1992 Apr;74(4):515-8. 1000 900 Calcolati su IBW 800 700 600 obese nonobese 500 400 300 200 100 0 Vd tot CL pl ml/min/kg HL el min
  113. 113. Principali tempi di ripresa dopo vecuronium 0.1 mg/kg Schwartz AE, Matteo RS, Ornstein E, Halevy JD, Diaz J.Pharmacokinetics and pharmacodynamics of vecuronium in the obese surgical patient.Anesth Analg. 1992 Apr;74(4):515-8. 80 Vecu 0.1 mg/kg Anest TPS /N2O/Haloth 7 obesi vs 6 norm 70 60 50 40 obesi norm 30 20 10 0 T1 50% T1 5-25% T1 25-75%
  114. 114. Schwartz AE, Matteo RS, Ornstein E, Halevy JD, Diaz J.Pharmacokinetics and pharmacodynamics of vecuronium in the obese surgical patient.Anesth Analg. 1992 Apr;74(4):515-8. • Poichè i parametri cinetici(VD,Vdss,Cl) sono simili fra obesi e non,ma la durata di azione è maggiore negli obesi per via dell’aumento della dose somministrata in accordo al TBW,gli AA raccomandano di somministrare vecu sec IBW. • Ma gli obesi erano (93.4 +/- 13.9 kg, 166% +/- 30% di IBW
  115. 115. Kirkegaard-Nielsen H,Helbo-Hansen HS, Toft P,Severinsen IK.Anthropometric Variables as Predictors for Duration of Action of Vecuronium-Induced Neuromuscular Block . Anesth Analg 1994; 79:1003– 6. • 67 femmine obese,,45–126 kg • Tps,fent,drop,N2O Variabili antropometriche studiate: (%IBW) BMI BSA somma di pieghe cutanee subscapularis and suprailiac /BSA. •
  116. 116. Kirkegaard-Nielsen H,Helbo-Hansen HS, Toft P,Severinsen IK.Anthropometric Variables as Predictors for Duration of Action of Vecuronium-Induced Neuromuscular Block . Anesth Analg 1994; 79:1003–6
  117. 117. % IBW Kirkegaard-Nielsen H,Helbo-Hansen HS, Toft P,Severinsen IK.Anthropometric Variables as Predictors for Duration of Action of Vecuronium-Induced Neuromuscular Block . Anesth Analg 1994; 79:1003–6 .
  118. 118. (Subscapularis+ suprailiac skinfolds)/surface area (mm/m2) Kirkegaard-Nielsen H,Helbo-Hansen HS, Toft P,Severinsen IK.Anthropometric Variables as Predictors for Duration of Action of Vecuronium-Induced Neuromuscular Block . Anesth Analg 1994; 79:1003–6
  119. 119. Kirkegaard-Nielsen H,Helbo-Hansen HS, Toft P,Severinsen IK.Anthropometric Variables as Predictors for Duration of Action of Vecuronium-Induced Neuromuscular Block . Anesth Analg 1994; 79:1003– 6
  120. 120. Duration of action of vecu according to anthropometric variables Kirkegaard-Nielsen H,Helbo-Hansen HS, Toft P,Severinsen IK.Anthropometric Variables as Predictors for Duration of Action of Vecuronium-Induced Neuromuscular Block . Anesth Analg 1994; 79:1003–6 • Durata di azione della dose induttiva (min.) = 0.112 * (Sub SF + Si SF) + 0.493 * BMI + 17.22 (r2 = 0.406, P = 0.0001), • Durata di azione della dose supplementare (min) = 0.174 * ([Sub SF + Si SF]/BSA) + 0.243 * BMI + 12.09 (r2 = 0.287, P = 0.0001).
  121. 121. Vecu • Durata di azione= 0.291 * dose vecuronium micrograms -1.88 min. • Opp Dur az=0.18*%IBW+12.66 • From this equation it appears that a reduction in duration of action by 1.8 min (the increase in duration of action when %IBW increases 10%) corresponds to a reduction in dose of vecuronium by 6.19 microg/kg • 162 microgr-(0.62* % IBW)
  122. 122. Messaggio da portare a casa per il vecuronium • Calcola la dose sull’IBW • Monitorizza!!!!
  123. 123. CISATRACURIUM
  124. 124. Tempi di ripresa dopo cisatracurium 0.2 mg/kg Leykin Y, Pellis T, Lucca M, Lomangino G, Marzano B, Gullo A.The effects of cisatracurium on morbidly obese women. Anesth Analg. 2004 Oct;99(4):1090-4 200 Cisatr 0.2 mg/kg Remifentanil propofol 180 160 140 120 * 100 obesi RBW obesi IBW normali RBW 80 60 40 20 0 onset sec dur 25%min dose mg
  125. 125. Messaggio da portare a casa per il cisatracurium • Dose iniziale e supplementari basate sull’IBW
  126. 126. Atracurium
  127. 127. Blobner M, Felber AR, Schneck HJ, Jelen-Esselborn S. Dose-response relationship of atracurium in underweight, normal and overweight patients. Anasthesiol Intensivmed Notfallmed Schmerzther. 1994 Oct;29(6):338-42. • ED 95 non è diversa fra pazienti sottopeso;normali e sovrappeso: 0.30 mg/kg • Dose necessaria per mantenere un blocco del 95% per 30 min eguale nei 3 gruppi; • Correlazione valida sia con LBW che IBW.
  128. 128. Kirkegaard-Nielsen H, Lindholm P, Petersen HS, Severinsen IK.Antagonism of atracurium-induced block in obese patients.Can J Anaesth. 1998 Jan;45(1):39-41 • Antagonismo con prostigmina 0.07 mg/kg restituisce alla norma la funzione neuromuscolare anche negli obesi con blocco nm mantenuto fra TOF 1-3.
  129. 129. Kirkegaard-Nielsen H, Helbo-Hansen HS, Lindholm P, Severinsen IK, Pedersen HS. Anthropometric variables as predictors for duration of action of atracurium-induced neuromuscular block. Anesth Analg 1996; 83:1076-80. • Reports concerning duration of action of atracurium in obese patients are conflicting. The aim of this study was to evaluate different anthropometric variables as predictors for duration of action of atracurium-induced block. We studied 127 female patients (total body weight 46–119 kg) anesthetized with midazolam, fentanyl, thiopental, nitrous oxide, and halothane. Twelve different anthropometric variables were evaluated as predictors for duration of action. Linear, least-square, regression analyses were used. There was a significant correlation between each of the 12 variables and the duration of action. The predictors with the greatest correlation coefficients for duration of action of the atracurium induction dose (0.5 mg/kg) were total body weight divided by surface area (r2 = 0.284, P < 0.0001), body mass index (r2 = 0.265, P < 0.0001), and total body weight (r2 = 0.264, P < 0.0001). The most significant predictors for the duration of action of the first supplemental atracurium dose (0.15 mg/kg) were total body weight divided by surface area (r2 = 0.170, P < 0.0001) and total body weight (r2 = 0.160, P < 0.0001). We propose that the atracurium dose should be reduced with 0.23 mg for each kilogram of total body weight above 70 kg. We conclude that the duration of action of atracurium block is prolonged in obese patients, and that atracurium dose in milligrams per kilogram of total body weight should be reduced in these patients. Total body weight divided by the surface area and total body weight were the best predictors for duration of action of atracurium-induced neuromuscular block.
  130. 130. Kirkegaard-Nielsen H, Helbo-Hansen HS, Lindholm P, Severinsen IK, Pedersen HS. Anthropometric variables as predictors for duration of action of atracuriuminduced neuromuscular block. Anesth Analg 1996; 83:1076-80
  131. 131. Total body weight/surface area kg/m2 Kirkegaard-Nielsen H, Helbo-Hansen HS, Lindholm P, Severinsen IK, Pedersen HS. Anthropometric variables as predictors for duration of action of atracurium-induced neuromuscular block. Anesth Analg 1996; 83:1076-80.
  132. 132. Total body weight Kirkegaard-Nielsen H, Helbo-Hansen HS, Lindholm P, Severinsen IK, Pedersen HS. Anthropometric variables as predictors for duration of action of atracurium-induced neuromuscular block. Anesth Analg 1996; 83:1076-80
  133. 133. Kirkegaard-Nielsen H, Helbo-Hansen HS, Lindholm P, Severinsen IK, Pedersen HS. Anthropometric variables as predictors for duration of action of atracuriuminduced neuromuscular block. Anesth Analg 1996; 83:1076-80 • • La durata di azione di atracurium è prolungata negli obesi TBW/BSA ,BMI e TBW sono gli indici predittivi migliori • La durata • Aumenta di 2.9 min per ogni 10 kg di aum del TBW • Allora propongono di diminuire di azione di atrac 0.5 mg/Kg di TBW=0.294 * TBW + 23.9 min 10 kg di peso>70 kg • • • • • • • • • • la dose di atrac di 2.3 mg per ogni Allora 80 kg atrac dose 37.7 90 Kg 41.4 100 kg 43.1 110 kg 45.8 120 kg 48.5 130 kg 51.2 140 kg 53.9 150 kg 56.6 . Per la prima dose supplementare diminuiamo la dose di 0.15 mg/kg di 0.7 mg (=6.6% di 10.5 mg) per ogni 10 kg TBW > 70 kg Only women were included in the present study.
  134. 134. Beemer GH, Bjorksten AR, Crankshaw DP Effect of body build on the clearance of atracurium: implication for drug dosing.Anesth Analg. 1993 Jun;76(6):1296-303 • La Cl di atracurium si correla bene con LBW, • … e meno bene con BSA,altezza e anche TBW,
  135. 135. Cl of atracurium vs LBW Beemer GH, Bjorksten AR, Crankshaw DP Effect of body build on the clearance of atracurium: implication for drug dosing.Anesth Analg. 1993 Jun;76(6):1296-303
  136. 136. Varin F, Ducharme J, Théorêt Y, et al. Influence of extreme obesity on the body disposition and neuromuscular blocking effect of atracurium. Clin Pharmacol Ther 1990; 48:18-25. • - The pharmacokinetics and pharmacodynamics of atracurium, a nondepolarizing neuromuscular blocking agent, were compared between morbidly obese patients and nonobese patients. Atracurium besylate (0.2 mg/kg) was administered intravenously as a bolus to patients who had received anesthesia. The force of contraction of the adductor pollicis was measured and plasma samples were collected for a 2-hour period. The concentrations of atracurium and its major end product, laudanosine, were determined by use of a chromatographic method. The pharmacokinetic-pharmacodynamic relationship was characterized by use of several models. No difference was observed between obese patients and nonobese patients in atracurium elimination half-life (19.8 +/- 0.7 versus 19.7 +/- 0.7 minutes), volume of distribution at steady state (8.6 +/- 0.7 versus 8.5 +/- 0.7 L), and total clearance (444 +/- 29 versus 404 +/- 25 ml/min). However, if values were expressed on a total body weight basis, there was a difference between obese and nonobese patients in the volume of distribution at steady state (0.067 versus 0.141 L/kg) and total clearance (3.5 +/0.2 versus 6.6 +/- 0.5 ml/min/kg). Although atracurium concentrations were consistently higher in obese patients than in nonobese patients, there was no difference in the time of recovery from neuromuscular blockade between the two groups. Consequently, the median effective concentration was higher in obese than in nonobese patients (470 +/- 46 versus 312 +/- 33 ng/ml).
  137. 137. Varin F, Ducharme J, Théorêt Y, et al. Influence of extreme obesity on the body disposition and neuromuscular blocking effect of atracurium. Clin Pharmacol Ther 1990; 48:18-25. 20 18 16 14 12 Ma se divisi per TBW VD:0.67 obesi vs 0.141 non obesi total clearance:3.5 +/- 0.2 versus 6.6 +/- 0.5 ml/min/kg). obesi non obesi 10 8 6 4 2 0 Vdss lt Cl tot lt/min Hl el min
  138. 138. Lavori di confronto Vecu e atrac
  139. 139. Tempi di ripresa dopo vecu 0.1 mg/kg e ATRAC 0.5 mg/kg in paz obesi e normali Weinstein JA, Matteo RS, Ornstein E, Schwartz AE, Goldstoff M, Thal G. Pharmacodynamics of vecuronium and atracurium in the obese surgical patient Anesth Analg. 1988 Dec;67(12):1149-53 160 140 120 100 vecu obes vecu contr atrac obes atrac norm min 80 60 40 20 0 5-25% 25-75% T1 50% T1 75% T1 100%
  140. 140. Weinstein JA, Matteo RS, Ornstein E, Schwartz AE, Goldstoff M, Thal G. Pharmacodynamics of vecuronium and atracurium in the obese surgical patient Anesth Analg. 1988 Dec;67(12):1149-53 • Per il vecu esistono correlaz e regress altam signif fra durate cliniche e IBW o % grasso calcolate sec formula ….) • RI 25-75 cresce di 0.6 min per ogni punto % di aum di IBW e 1.1 per ogni punto % di aum di grasso • Nessuna correlaz per atrac
  141. 141. Messaggio da portare a casa per atracurium • Ridurre modestamente la dose iniziale e quella di mantenimento secondo quanto proposto nella tabella di Kirkegaard-Nielsen H, Helbo-Hansen HS, Lindholm P, Severinsen IK, Pedersen HS. Anthropometric variables as predictors for duration of action of atracurium-induced neuromuscular block. Anesth Analg 1996; 83:1076-80 • La durata di azione di atrac 0.5 mg/Kg di TBW=0.294 * TBW + 23.9 min • Aumenta di 2.9 min per ogni 10 kg di aum del TBW • Allora propongono di diminuire 10 kg di peso>70 kg • • • • • • • • • • la dose di atrac di 2.3 mg per ogni Allora 80 kg atrac dose 37.7 90 Kg 41.4 100 kg 43.1 110 kg 45.8 120 kg 48.5 130 kg 51.2 140 kg 53.9 150 kg 56.6 . Per la prima dose supplementare diminuiamo la dose di 0.15 mg/kg di 0.7 mg (=6.6% di 10.5 mg) per ogni 10 kg TBW > 70 kg Only women were included in the present study.
  142. 142. Succinilcolina
  143. 143. Velocità di Desaturazione in paz normali,obesi e patologicamente obesi. Jense HG,Dubin SA,Silverstein PI., ,O'LearyEscolas U.Effect of Obesity on Safe Duration of Apnea in Anesthetized Humans . Anesth Analg 1991; 72:89–93 Preossigenazione per 5 min o fino a N2<5%. Induzione anest e miorisoluzione
  144. 144. Relazione fra desaturazione a SaO2 90% e % IBW
  145. 145. Cucuianu M, Popescu TA, Haragus S. Pseudocholinesterase in obese and hyperlipemic subjects.Clin Chim Acta. 1968 Oct;22(2):151-5 It was found that serum pseudocholinesterase increases not only in obese subjects but also in hyperlipemic patients with normal body weight. A good statistical correlation was found between serum pseudocholinesterase on one hand, and both serum cholesterol and the logarithm of serum triglycérides concentration, on the other. It cannot be stated whether increased pseudocholinesterase activity should be correlated with a possible role of the enzyme in the metabolism of lipids or with an unspecific and rather general stimulation of protein synthesis in the liver of obese and hyperlipemic subjects.
  146. 146. Kean KT, Kutty KM, Huang SN, Jain R. A study of pseudocholinesterase induction in experimental obesity.J Am Coll Nutr. 1986;5(3):253-61 Liver pseudocholinesterase (PChE) activity was significantly higher in genetically obese (ob/ob) mice than in lean littermates as early as 23 days after birth. By cytochemical electron microscopy, increased staining for PChE was observed in the rough endoplasmic reticulum of ob/ob mice. Albino mice with different diets showed that high-protein diets produced the greatest increase in PChE activity in the liver compared to carbohydrate or high fat. Mice fed a normal mouse diet ad lib had significantly higher liver PChE activity than those fed a restricted diet of 2 g of a normal mouse chow per day. In albino mice liver PChE activity varied directly with the protein content in the diet. These studies suggest that liver PChE induction is a function of the level of protein in the diet.
  147. 147. Rose JB,Theroux MC,Katz M S.The Potency of Succinylcholine in Obese Adolescents. Anesth Analg 2000; 90:576–8 • • ABSTRACT: We constructed a single-dose response curve for succinylcholine in 30 obese adolescents during thiopental-fentanyl anesthesia administration by using 100 mg/kg, 150 mg/kg, or 250 mg/kg IV. The maximal response (percent depression of neuromuscular function) of the adductor pollicis to supramaximal train-of-four stimuli was recorded by using a Datex (Helsinki, Finland) relaxograph. Linear regression and inverse prediction were used to determine doses of succinylcholine to produce 50% (ED50), 90% (ED90), and 95% (ED95) depression of neuromuscular function. The ED50, ED90, and ED95 were 152.8 mg/kg (95% confidence interval: 77.8–299.5), 275.4 mg/kg (95% confidence interval: 142–545.7), and 344.3 mg/kg (95% confidence interval: 175.3–675.3), respectively. This ED50 is similar to the dose reported for similarly aged, nonobese adolescents, 147 mg/kg. The previously reported ED95 for succinylcholine in nonobese adolescents, 270 mg/kg, is within the 95% confidence interval generated for ED95 in our study. Implications: The potency estimates for succinylcholine in obese (body mass index > 30 kg/m2) adolescents are comparable to those in similarly aged nonobese adolescents when dosing is calculated based on total body mass and not lean body mass. When a rapid sequence induction of anesthesia is considered in an obese adolescent, the dose of succinylcholine should be based on actual (not lean) body mass.
  148. 148. Rose JB,Theroux MC,Katz M S.The Potency of Succinylcholine in Obese Adolescents. Anesth Analg 2000; 90:576–8. • ED50, ED90, and ED95 with lower and upper 95% confidence intervals in microg/kg are 152.8 (77.8 and 299.5), 275.4 (142 and 545.7), and 344.3 (175.3 and 675.3), respectively • the potency of SCH in obese adolescents, as estimated by the ED50 of 158 mg/kg, is similar to the value of 147 mg/kg reported previously for lean adolescents • . The ED95 of SCH in lean adolescents, 270 mg/kg, occurs within the 95% confidence intervals generated for obese adolescents in the present study . • Of further interest is our finding that PCHE levels may be increased in obese adolescents. We have no explanation for this observation; however, similar results have been noted in studies of obese adults
  149. 149. Messaggio da portare a casa per la succinilcolina • Somministrare la dose secondo il TBW
  150. 150. Rocuronium
  151. 151. Puhringer FK,Keller C;Kleinsasser A,Giesinger S,Benzer A.Pharmacokinetics of rocuronum bromide in obese female patients.Eur J Anesth.1999;16:507-10. 250 •0.6 mg/ kg rocu, •6 obesi vs 6 controli •Anest bilanciata . 200 Tutto NS 150 obese non obese 100 50 0 Vdss ml/kg Hl dist min HL el min MRTmin CL ml/kg/min
  152. 152. Leykin Y, Pellis T, Lucca M, et al. The pharmacodynamic effects of rocuronium when dosed according to real body weight or ideal body weight in morbidly obese patients. Anesth Analg 2004; 99:1086-9. • 12 paz femmine obese (body mass index >40 kg/m(2)) • Per laparoscopic gastric banding • Gruppo 1 (n = 6) 0.6 mg/kg rocuronium RBW • Gruppo 2 (n = 6) 0.6 mg/kg rocuronium IBW • Gruppo controllo 6 paz normali operati per chir laparoscopica • Acceleromiografia dell’ adductor pollicis • remifentanil /propofol.
  153. 153. Rocuronium 0.6 mg/kg Leykin Y, Pellis T, Lucca M, et al. The pharmacodynamic effects of rocuronium when dosed according to real body weight or ideal body weight in morbidly obese patients. .Anesth Analg 2004; 99:1086-9 90 80 70 60 50 obesi RBW obesi IBW normali RBW 40 30 20 10 0 onset sec dur 25%min dose mg RI 25-75% min
  154. 154. Confronto dei dati fra Leykin e Puhringher Leykin morbid obesity class (BMI 43.8 ± 2.1) Puhringer moderate obesity class (BMI 33.5 ± 4.4). 100 90 obesi RBW Leykin 80 obesi RBW Puhringer obesi IBW Leykin 70 normali RBW Leykin 60 normali RBW Puhringer 50 40 30 20 10 0 onset sec dur 25% min dose mg RI 25-75% min
  155. 155. Messaggio da portare a casa per il rocuronium • Meglio somministrare secondo IBW,specialmente in infusione continua,ma dati scarsi…..
  156. 156. Messaggio da portare a casa per tutti i miorilassanti • Non somministrare miorilassante a demand dei chirurghi;potrebbero richiederne molto di più per le difficoltà tecniche legate all’intervento(esposizione) più che per reali necessità di miorisoluzione….. • Monitorizzare almeno semiquantitativamente
  157. 157. Anestetici locali Lidocaina
  158. 158. PK della lidocaina Abernethy DR,GReenblatt DJ.Lidocaine disposition in obesity.J.Cardiol 1984;53:1183-6. 3,5 * * 3 2,5 2 obesi non obesi 1,5 1 0,5 0 Hl el hr CL lt/min Vd tot lt *100 Vd/TBW
  159. 159. Messaggio da portare a casa per gli AL • I fattori che influenzano il dosaggio sono altri che la dose totale:anatomia,sede,difficoltà ecc • Prudenza nei blocchi centrali • Dosi ev basati su IBW ???
  160. 160. Messaggi finali • Da Casati • • PER IL DOSAGGIO DEI FARMACI DIROFILICI BASTEREBBE AGGIUNGERE 20% ALL’ IBW (per includere la LBM) Per il dosaggio dei farmaci lipofilici…………….
  161. 161. FINE
  162. 162. Diapo da studiare Tutte le seguenti……….
  163. 163. Minto CF, Schnider TW, Egan TD, et al. Influence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil. I. Model development. Anesthesiology. 1997;86:10-23 • .
  164. 164. Kapila A, Glass PSA, Jacobs JR, Muir KT, Hermann DJ, Shiraishi M, Howell S, Smith RL: Measured context-sensitive half-times of remifentanil and alfentanil. ANESTHESIOLOGY 83:968-75, 1995 • BACKGROUND: The context-sensitive half-time, rather than the terminal elimination halflife, has been proposed as a more clinically relevant measure of decreasing drug concentration after a constant infusion of a given duration. The context-sensitive half-time is derived from computer modelling using known pharmacokinetic parameters. The modelled context-sensitive half-time for a 3-h infusion of alfentanil is 50-55 min and is 3 min for remifentanil. The terminal elimination half-life is 111 min for alfentanil and 12-30 min for remifentanil. It has not been tested whether the modelled context-sensitive half-time reflects the true time for a 50% decrease in drug concentration or drug effect. METHODS: Thirty volunteers received a 3-h infusion of remifentanil or alfentanil at equieffective concentrations. Depression of minute ventilation to 7.5% ETCO2 was used as a measure of drug effect. Minute ventilation response was measured, and blood samples for drug concentration were taken during and after drug infusion. The recovery of minute ventilation (drug effect) and decrease in blood drug concentration was plotted, and the time for a 50% change was determined. RESULTS: The measured pharmacokinetic context-sensitive halftime for remifentanil after a 3-h infusion was 3.2 +/- 0.9 min, and its pharmacodynamic offset was 5.4 +/- 1.8 min. Alfentanil's measured pharmacokinetic context-sensitive half-time was 47.3 +/- 12 min, and its pharmacodynamic offset was 54.0 +/- 48 min. The terminal elimination half-life modelled from the volunteers was 11.8 +/- 5.1 min for remifentanil and 76.5 +/- 12.6 min for alfentanil. CONCLUSIONS: The measured context-sensitive half-times were in close agreement with the context-sensitive half-times previously modelled for these drugs. The results of this study confirm the value of the context-sensitive half-time in describing drug offset compared to the terminal elimination half-life.
  165. 165. Bouillon TW, Bruhn J, Radulescu L, et al. Pharmacodynamic interaction between propofol and remifentanil regarding hypnosis,tolerance of laryngoscopy, bispectral index, and electroencephalographic approximate entropy. Anesthesiology. 2004;100:1353-1372. • • • • Background: The purpose of this investigation was to describe the pharmacodynamic interaction between propofol and remifentanil for probability of no response to shaking and shouting, probability of no response to laryngoscopy, Bispectral Index (BIS), and electroencephalographic approximate entropy (AE). Methods: Twenty healthy volunteers received either propofol or remifentanil alone and then concurrently with a fixed concentration of remifentanil or propofol, respectively, via a target-controlled infusion. Responses to shaking and shouting and to laryngoscopy were assessed multiple times after allowing for plasma effect site equilibration. The raw electroencephalogram and BIS were recorded throughout the study, and AE was calculated off-line. Response surfaces were fit to the clinical response data using logistic regression or hierarchical response models. Response surfaces were also estimated for BIS and AE. Surfaces were visualized using three-dimensional rotations. Model parameters were estimated with NONMEM. Results: Remifentanil alone had no appreciable effect on response to shaking and shouting or response to laryngoscopy. Propofol could ablate both responses. Modest remifentanil concentrations dramatically reduced the concentrations of propofol required to ablate both responses. The hierarchical response surface described the data better than empirical logistic regression. BIS and AE are more sensitive to propofol than to remifentanil. Conclusions: Remifentanil alone is ineffective at ablating response to stimuli but demonstrates potent synergy with propofol. BIS and AE values corresponding to 95% probability of ablating response are influenced by the combination of propofol and remifentanil to achieve this endpoint, with higher propofol concentrations producing lower values for BIS and AE.
  166. 166. Pharmacodynamic interaction between propofol and remifentanil regarding hypnosis,tolerance of laryngoscopy, bispectral index, and electroencephalographic approximate entropy. Anesthesiology. 2004;100:1353-1372.
  167. 167. Pharmacodynamic interaction between propofol and remifentanil regarding hypnosis,tolerance of laryngoscopy, bispectral index, and electroencephalographic approximate entropy. Anesthesiology. 2004;100:1353-1372.
  168. 168. Bouillon TW, Bruhn J, Radulescu L, et al. Pharmacodynamic interaction between propofol and remifentanil regarding hypnosis,tolerance of laryngoscopy, bispectral index, and electroencephalographic approximate entropy. Anesthesiology. 2004;100:1353-1372.
  169. 169. Bouillon TW, Bruhn J, Radulescu L, et al. Pharmacodynamic interaction between propofol and remifentanil regarding hypnosis,tolerance of laryngoscopy, bispectral index, and electroencephalographic approximate entropy. Anesthesiology. 2004;100:1353-1372.
  170. 170. Bouillon TW, Bruhn J, Radulescu L, et al. Pharmacodynamic interaction between propofol and remifentanil regarding hypnosis,tolerance of laryngoscopy, bispectral index, and electroencephalographic approximate entropy. Anesthesiology. 2004;100:1353-1372.
  171. 171. Bouillon TW, Bruhn J, Radulescu L, et al. Pharmacodynamic interaction between propofol and remifentanil regarding hypnosis,tolerance of laryngoscopy, bispectral index, and electroencephalographic approximate entropy. Anesthesiology. 2004;100:1353-1372.
  172. 172. Bouillon TW, Bruhn J, Radulescu L, et al. Pharmacodynamic interaction between propofol and remifentanil regarding hypnosis,tolerance of laryngoscopy, bispectral index, and electroencephalographic approximate entropy. Anesthesiology. 2004;100:13531372.
  173. 173. Bouillon TW, Bruhn J, Radulescu L, et al. Pharmacodynamic interaction between propofol and remifentanil regarding hypnosis,tolerance of laryngoscopy, bispectral index, and electroencephalographic approximate entropy. Anesthesiology. 2004;100:13531372.
  174. 174. Bouillon TW, Bruhn J, Radulescu L, et al. Pharmacodynamic interaction between propofol and remifentanil regarding hypnosis,tolerance of laryngoscopy, bispectral index, and electroencephalographic approximate entropy. Anesthesiology. 2004;100:13531372.
  175. 175. Bouillon TW, Bruhn J, Radulescu L, et al. Pharmacodynamic interaction between propofol and remifentanil regarding hypnosis,tolerance of laryngoscopy, bispectral index, and electroencephalographic approximate entropy. Anesthesiology. 2004;100:13531372.
  176. 176. Bouillon TW, Bruhn J, Radulescu L, et al. Pharmacodynamic interaction between propofol and remifentanil regarding hypnosis,tolerance of laryngoscopy, bispectral index, and electroencephalographic approximate entropy. Anesthesiology. 2004;100:13531372. • • • • • • • • This investigation was intended to quantify interaction between propofol and remifentanil on ablating response to a primarily hypnotic endpoint, loss of response to shaking and shouting, and a hypnotic—analgesic endpoint, the loss of response to laryngoscopy, while concurrently quantifying the interaction of propofol and remifentanil on two electroencephalographic measures of drug effect, BIS and AE. The major results are as follows: 1. The interaction between propofol and remifentanil is synergistic for loss of response to shaking and shouting and for loss of response to laryngoscopy. 2. Remifentanil is not hypnotic in clinically relevant concentrations. 3. Remifentanil concentrations of 4 ng/ml reduce the propofol concentration associated with loss of response to shaking and shouting and to laryngoscopy by approximately two thirds. Further increases in remifentanil only modestly reduce the propofol concentration required to ablate the response to either stimulus. 4. Propofol was equipotent in its effect on BIS and AE, with or without remifentanil. 5. The interaction between propofol and remifentanil on BIS and AE was additive, but in the clinical range (< 8 ng/ml), remifentanil had little effect on either electroencephalographic measure of drug effect. 6. The combination of propofol and remifentanil chosen to ablate response has a large effect on the concurrent electroencephalographic measure of drug effect. 7. The new hierarchical model provides a better prediction of the likelihood of response than the empirical model described by Minto.
  177. 177. Bouillon TW, Bruhn J, Radulescu L, et al. Pharmacodynamic interaction between propofol and remifentanil regarding hypnosis,tolerance of laryngoscopy, bispectral index, and electroencephalographic approximate entropy. Anesthesiology. 2004;100:13531372. • • • • • • • Clinical Assessment of Propofol—Remifentanil Interaction The synergy between opioids and propofol is well established. In this light, our findings of a synergistic interaction on loss of response to shaking and shouting and loss of response to laryngoscopy are hardly surprising. Only two other studies specifically investigating the interaction between propofol and remifentanil with regard to clinical endpoints are available for comparison. Roepcke et al. investigated the interaction of propofol and remifentanil to maintain a BIS between 45 and 55 during orthopedic surgical procedures. Propofol was administered with a TCI device at predetermined concentrations between 1.5 and 6 mg/ml and supplemented with the corresponding remifentanil concentration via TCI to maintain the target BIS. The data were analyzed with an isobolographic analysis, and a synergistic interaction was found similar to that reported here. Mertens et al. investigated the interaction of propofol and remifentanil on tolerance of laryngoscopy, intubation, adequate anesthesia, and awakening. They concluded that the interaction is synergistic, but additive in the clinical range. Their results for loss of response to laryngoscopy are similar to ours. In their study, the C50 of propofol for tolerance to laryngoscopy decreased was 6 mg/ml in absence of remifentanil, which decreased to 2 mg/ml when the remifentanil concentration was 3.4 ng/ml. Our corresponding results are 6.62 mg/ml propofol (TCI predictions) in the absence of remifentanil and 2 mg/ml propofol at a remifentanil target concentration of 3.5 ng/ml. As judged from , the interaction between remifentanil and propofol, although synergistic over the entire range of propofol concentrations, may seem additive for propofol concentrations between 2 and 6 mg/ml propofol, and thus, the findings reported by Mertens et al. are consistent with our results. Our estimates of the C50 of propofol alone for attenuation of response to noxious stimulation are less than some previously reported estimates. For example, Kazama et al. estimated that the C50 to blunt response to laryngoscopy was 9.8 mg/ml, which was confirmed as being 10.9 mg/ml in a subsequent study by the same authors. As reported by Kazama et al. and by Zbinden et al., the C50 for laryngoscopy is similar for that to incision. Therefore, it is also relevant that Smith et al. reported that the C50 of propofol for skin incision in the absence of opioids was 15.2 mg/ml. In contrast, our values for the C50 of propofol to ablate response to laryngoscopy range from a low of 3.2 mg/ml () to a high of 8.44 mg/ml (, C50 propofol ´ preopioid stimulus for the model using TCI concentrations). We do not have a ready explanation for this discrepancy. It could relate to laryngoscopic technique, but we were able to visualize vocal cords in every laryngoscopy, so in our view, the technique was adequately vigorous. Nevertheless, the data suggest that our laryngoscopy technique was less stimulating than that of other investigators, resulting in a lower estimate of the C50 of propofol. The hypnotic properties of remifentanil and other opioids have been investigated. Jhaveri et al. concluded that the median effective concentration of remifentanil for loss of consciousness equals 54 ng/ml, and therefore, remifentanil is not suitable as a sole induction agent. We calculated the C50 of remifentanil at approximately 19 ng/ml, much lower, but still clearly outside the clinically used range. This agrees with the findings of Vuyk et al. as well, who concluded that alfentanil was not suitable as a sole induction agent. Although remifentanil is not a hypnotic in the clinically relevant concentration range, it profoundly decreases the propofol concentration for loss of response to shaking and shouting. Without remifentanil, 8.6 mg/ml propofol is needed to ablate response to shaking and shouting in 95% of patients (hierarchical model, TCI concentrations, calculated from ). This is reduced to only 0.88 mg/ml in presence of 6 ng/ml remifentanil, a concentration of remifentanil that does not cause unconsciousness during monoadministration. A similar relation exists with regard to laryngoscopy. In the absence of remifentanil, 15 mg/ml propofol is needed to ensure a 95% probability of no response to laryngoscopy. In presence of 6 ng/ml remifentanil, the propofol concentration associated with 95% probability of no response decreases to 2.5 mg/ml. These data is similar to data from interaction studies between propofol and fentanyl (corrected for relative potency of the fentanyl), as well as isoflurane and remifentanil. The SEs of the parameter estimates for the Minto empirical model with TCI concentrations were modest (), suggesting that there was enough data relative to the numbers of parameters in the model to estimate the parameters accurately. However, we found that our data set was very sensitive to initial estimates. Some initial estimates produced reasonable estimates of SEs but had objective functions approximately 10 points higher than those in and . When we used starting estimates that produced the best fits, as determined from the objective function, the estimates of SEs became exceedingly small. Our guess is that the small SEs are NONMEM's representation of the same dependence on starting estimates, in that very small changes in the estimates produce significantly worse fits, thus leading to very small SEs. We also note that the coefficient variations on most of the parameters in and are reasonable. This means that although the subjects differ from each other, the response of the typical patient (e.g., and ) is a useful starting point for titration. We also note the high coefficient variation values (about 100%) for the estimates of the steepness of the propofol concentration—versus—probability of no response relation with the hierarchical model. When the slopes become quite steep (e.g., 5 and 7 for the TCI and Bayesian models, respectively), they can vary considerably without being clinically distinguishable.
  178. 178. Bouillon TW, Bruhn J, Radulescu L, et al. Pharmacodynamic interaction between propofol and remifentanil regarding hypnosis,tolerance of laryngoscopy, bispectral index, and electroencephalographic approximate entropy. Anesthesiology. 2004;100:13531372. • • • • • Choice of Models for Clinical Assessment The parameters for the hierarchical model are interesting in comparison with those of the Minto empirical model. First, the C50 of remifentanil has been reduced from approximately 19 in the empirical model () to approximately 1 ng/ml in the hierarchical model (). This is because the model estimates something that remifentanil can do: attenuate the intensity of noxious stimulation, rather than something remifentanil cannot do: prevent response to noxious stimulation. The model thus directly reports the “take home” message: Only a modest amount of remifentanil is required to blunt response to noxious stimulation. Our estimate that 1 ng/ml remifentanil reduces the propofol dose by 50% is similar to the estimate of Lang et al. that the minimum alveolar concentration (MAC) of isoflurane is 50% reduced by a remifentanil concentration of 1.37 ng/ml. The model also estimates a steepness parameter for remifentanil slightly less than 1. This indicates that increasing the opioid beyond the C50 does continue to produce increased opioid drug effect but that the incremental benefit relative to the increase in concentration is modest. This is exactly the message from careful analysis of the empirical model as well, but it does not emerge from simple analysis of the parameters of the empirical model (). The C50 values for propofol in the hierarchical model are higher than those estimated with the Minto model. For the hierarchical model, the propofol C50s are, by definition, the hypnotic concentration associated with 50% probability of no response when the preopioid stimulus intensity equals 1 and no opioid is present. This is approximately the level of intensity of stimulation associated with laryngoscopy. The propofol C50 for hypnosis in the absence of opioids is the C50 value times the prestimulus intensity of shaking and shouting, which is approximately 0.5. This can be seen in the bottom two graphs of , which are the propofol concentration—versus—probability of no response curves for hypnosis (left) and laryngoscopy (right) in the absence of opioid. It is interesting that the “preopioid stimulus,” the only parameter that differs between the model for no response to shouting and shaking, and the model for no response to laryngoscopy suggest that the level of arousal associated with shaking and shouting is 0.5, whereas the level associated with laryngoscopy is 1.0. We speculated that perhaps this parameter could be set arbitrarily to 1.0 for the first model and could thus be interpreted as “stimulation level relative to shaking and shouting.” However, this significantly reduced the NONMEM objective function, indicating that this parameter cannot arbitrarily be set to one for a particular stimulus-response pair. We have two possible explanations for why the preopioid stimulus for shaking and shouting is half of that for laryngoscopy, rather than, say, a tenth. One possibility is that the baseline stimulus of simply being alive is only slightly less than 0.5, and thus, shaking and shouting is adding only slightly to the baseline stimulus level (e.g., baseline = 0.4, shaking and shouting = +0.1), while laryngoscopy adds several-fold more input (e.g., +0.5). Alternatively, shouting and shaking as practiced by the assessor (S. L. S.) may have been quite noxious and thus benefited from the analgesic properties of remifentanil. This is the first introduction of the hierarchical model. We expect that as experience with this model grows, it will become clearer how to interpret the preopioid stimulus estimated by the model. The model could be expanded by adding another input for strictly hypnotic drug effect to equation 4:
  179. 179. • • • • Electroencephalographic Assessment of Propofol—Remifentanil Interaction The C50 of propofol for reduction of the BIS was almost identical to that for AE with both monoadministration and the propofol—remifentanil interaction model, indicating that both measurements are nearly interchangeable measures of propofol drug effect. The C50 values for both propofol and remifentanil are in good agreement with those published previously. Initial studies of the BIS showed that it worked well when propofol was the primary anesthetic agent but did not work well for anesthetics that combined nitrous oxide with high-dose opioids. For this reason, we integrated the synergistic response surface of the hierarchical model with the additive response surface of the electroencephalographic model to explore the influence of the anesthetic combination on the electroencephalographic measure of drug effect. The results ( and ) show that electroencephalographic measures alone are not adequate to predict the probability of response but must be interpreted in light of the drug concentration used to achieve the electroencephalographic response. For example, at 16 ng/ml remifentanil and 0.11 mg/ml propofol, the probability of response to shouting and shaking is 95%, but the calculated BIS is 54 (). However, at a remifentanil concentration of 4 ng/ml and a propofol concentration of 1.25 mg/ml, the probability of no response to shouting and shaking is 95%, and the calculated BIS is 72. Similarly, at a propofol concentration of 4.7 mg/ml, in the absence of remifentanil, there is a 95% chance of response to laryngoscopy (), even though the calculated BIS is 46. However, at a propofol concentration of 2.5 mg/ml and a remifentanil concentration of 6 ng/ml, there is a 95% chance of no response, and the calculated BIS is 54. This analysis emphasizes that BIS (and, presumably, most other electroencephalographic measures used to assess anesthetic depth) are measures of hypnotic drug effect, and the brain's response to both the drugs and the surgical stimulus and are not measures of the brain's likelihood of response to noxious stimulation. Because electroencephalographic response does not measure an intrinsic state of the brain, interpretation of electroencephalographic measures requires consideration of the drugs used. In summary, response surface methodology has demonstrated that propofol and remifentanil are synergistic for the clinical endpoints of no response to shouting and shaking and no response to laryngoscopy and have additive effects on two electroencephalographic measures of drug effect, the BIS and AE. This should caution the reader against using BIS or other measurements of anesthetic depth without considering the relative contributions of a hypnotic and an opioid to the anesthetic state. These models may have applicability in designing anesthetic regimens and closed-loop control of anesthesia administering both an opioid and a hypnotic using electroencephalographic measures of drug effect.
  180. 180. Mertens MJ,Olofsen E,Engbers FHM,Burm AGL, Bovill JG,Vuyk J.Propofol Reduces Perioperative Remifentanil Requirements in a Synergistic Manner. Response Surface Modeling of Perioperative Remifentanil— Propofol Interactions Anesthesiology, 99:347-59, 2003 • • • • • • • • • * Staff Anesthesiologist, † Research Associate, ‡ Professor of Anesthesiology and Head of the Anesthesia Research Laboratory, § Professor of Anesthesiology. Received from the Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands. Submitted for publication December 3, 2001. Accepted for publication April 1, 2003. Supported by GlaxoSmithKline BV, Zeist, The Netherlands. Presented in part at the annual meeting of the European Society of Anaesthesiologists, in Gothenburg, Sweden, October 4, 2001. Address reprint requests to Dr. Mertens: Department of Anesthesiology, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, The Netherlands. Address electronic mail to: m.j.mertens@lumc.nl. Individual article reprints may be purchased through the Journal Web site, www.anesthesiology.org. ABSTRACT: Background: Remifentanil is often combined with propofol for induction and maintenance of total intravenous anesthesia. The authors studied the effect of propofol on remifentanil requirements for suppression of responses to clinically relevant stimuli and evaluated this in relation to previously published data on propofol and alfentanil. Methods: With ethics committee approval and informed consent, 30 unpremedicated female patients with American Society of Anesthesiologists physical status class I or II, aged 18–65 yr, scheduled to undergo lower abdominal surgery, were randomly assigned to receive a target-controlled infusion of propofol with constant target concentrations of 2, 4, or 6 mg/ml. The target concentration of remifentanil was changed in response to signs of inadequate anesthesia. Arterial blood samples for the determination of remifentanil and propofol concentrations were collected after blood—effect site equilibration. The presence or absence of responses to various perioperative stimuli were related to the propofol and remifentanil concentrations by response surface modeling or logistic regression, followed by regression analysis. Both additive and nonadditive interaction models were explored. Results: With blood propofol concentrations increasing from 2 to 7.3 mg/ml, the C50 of remifentanil decreased from 3.8 ng/ml to 0 ng/ml for laryngoscopy, from 4.4 ng/ml to 1.2 ng/ml for intubation, and from 6.3 ng/ml to 0.4 ng/ml for intraabdominal surgery. With blood remifentanil concentrations increasing from 0 to 7 ng/ml, the C50 of propofol for the return to consciousness decreased from 3.5 mg/ml to 0.6 mg/ml. Conclusions: Propofol reduces remifentanil requirements for suppression of responses to laryngoscopy, intubation, and intraabdominal surgical stimulation in a synergistic manner. In addition, remifentanil decreases propofol concentrations associated with the return of consciousness in a synergistic manner.
  181. 181. Mertens MJ,Olofsen E,Engbers FHM,Burm AGL, Bovill JG,Vuyk J.Propofol Reduces Perioperative Remifentanil Requirements in a Synergistic Manner. Response Surface Modeling of Perioperative Remifentanil—Propofol Interactions Anesthesiology, 99:347-59, 2003 • • • The C50 of remifentanil for laryngoscopy and intubation decreased with increasing propofol concentrations. For laryngoscopy and intubation, the data were best characterized by a synergistic model (). The addition of the interaction term in the response surface model resulted in a reduction in the AIC (from 62.41 to 59.51 for laryngoscopy and from 39.21 to 34.95 for intubation). Introduction of intraindividual variability did not result in a further reduction in the AIC. As blood propofol concentrations increased from 2 to 7.3 mg/ml, the C50 of remifentanil decreased from 3.8 ng/ml to 0 ng/ml for laryngoscopy and from 4.7 ng/ml to 1.2 ng/ml for intubation ( and ). For skin incision and the opening of the peritoneum, the configuration of the data did not allow modeling. In 3 of 29 patients, the data set for intraoperative stimuli did not allow modeling. The concentration—effect relation of remifentanil for intraabdominal stimuli could therefore not be determined in these 3 patients. In 17 patients, no overlap existed between response and nonresponse data. Because the lowest measured plasma remifentanil concentration at which no response occurred and the highest blood remifentanil concentration at which a response was noted differed only marginally in these patients, the C50 of remifentanil was determined as the midrange between the lowest measured blood remifentanil concentration at which no response occurred and the highest blood remifentanil concentration at which a response was noted. If in any patient no responses occurred, even when the actual measured blood remifentanil concentration was below the detection limit, the C50 of remifentanil was set to 0 ng/ml. The measured blood propofol concentration remained stable throughout the surgical procedure in most patients (). The remifentanil concentration—effect relations for the intraabdominal part of the surgical procedure in the individual patients of the three groups are shown in , , . Results are presented in . The C50 of remifentanil versus mean blood propofol concentration relation for the intraabdominal part of surgery as determined over all patients is presented in . The C50 of remifentanil for suppression of responses to intraabdominal surgical stimuli decreased with increasing propofol concentrations. The data were best characterized by a synergistic model. The addition of the interaction term in the model resulted in a reduction in the AIC from 82.07 to 79.96. Because C50,rem and Î of the nonadditive model were very large, the model described in equation 9 was fitted to the data. The parameters (± SE) describing the curve are C50,prop = 9.02 ± 2.47 mg/ml and ΢ = 0.557 ± 0.306. Introduction of intraindividual variability did not result in a further reduction in the AIC. As mean blood propofol concentrations increased from 2 to 9 mg/ml, the C50 of remifentanil for intraabdominal stimuli decreased from 6.3 to 0 ng/ml (). Remifentanil significantly affected the blood propofol concentration at which the patients regained consciousness. According to the response surface modeling technique described by Bol et al., the interaction between propofol and remifentanil was judged to be synergistic for the probability of unconsciousness (). Introduction of intraindividual variability did not result in a further reduction in the AIC. With blood remifentanil concentration increasing from 0 to 10 ng/ml, the C50,prop for return of to consciousness decreased from 3.5 mg/ml to 0.4 mg/ml (). For this unimodal end point, the response surface modeling technique described by Minto et al. proved also adequate. The additive model with the lowest AIC is a model in which gprop and grem are identical. Introduction of intraindividual variability did not result in a further reduction in the AIC. Because the addition of the interaction term b2,U50 (see Appendix) in the model resulted in a reduction in the AIC from 48.152 to 46.409, the interaction between propofol and remifentanil for the probability of unconsciousness based on the response surface modeling technique described by Minto et al. was also judged synergistic. The parameters (± SE) describing the response surface are E0 = 0, Emax = 1, C50,prop = 3.40 ± 0.75 mg/ml, C50,rem = 8.91 ± 2.35 ng/ml, gprop = 4.29 ± 0.98, grem = 4.29 ± 0.98, and b2,U50 = 1.69 ± 0.42. The C50 of propofol decreased from 3.4 mg/ml to 0.5 mg/ml as blood remifentanil concentrations increased from 0 to 8 ng/ml. The model described in equation 2 was selected as the final model for the return to consciousness because its AIC was lower than that for the model described by
  182. 182. Mertens MJ,Olofsen E,Engbers FHM,Burm AGL, Bovill JG,Vuyk J.Propofol Reduces Perioperative Remifentanil Requirements in a Synergistic Manner. Response Surface Modeling of Perioperative Remifentanil—Propofol Interactions Anesthesiology, 99:347-59, 2003
  183. 183. Mertens MJ,Olofsen E,Engbers FHM,Burm AGL, Bovill JG,Vuyk J.Propofol Reduces Perioperative Remifentanil Requirements in a Synergistic Manner. Response Surface Modeling of Perioperative Remifentanil—Propofol Interactions Anesthesiology, 99:347-59, 2003
  184. 184. Mertens MJ,Olofsen E,Engbers FHM,Burm AGL, Bovill JG,Vuyk J.Propofol Reduces Perioperative Remifentanil Requirements in a Synergistic Manner. Response Surface Modeling of Perioperative Remifentanil—Propofol Interactions Anesthesiology, 99:347-59, 2003 • • • Laryngoscopy and Intubation In keeping with the observations of Vuyk et al. on the interactions between propofol and alfentanil, the interactions between propofol and remifentanil for suppression of responses to laryngoscopy and intubation were best described by a synergistic interaction model. For laryngoscopy, the C50,rem and Î estimated with the model described by Bol et al. were very large, whereas for intubation, C50,rem, C50,prop, and Î were several orders of magnitude larger than the concentrations encountered in this study. Therefore, these effects were modeled with the modified models (equations 2 and 3, respectively). Similarly, Vuyk et al. have demonstrated that propofol decreases alfentanil requirements for suppression of responses to laryngoscopy and intubation in a synergistic manner. Remifentanil concentrations required to suppress responses to intubation are higher at any given propofol concentration compared to those required to suppress responses to laryngoscopy. This indicates that tracheal intubation is a stronger stimulus than laryngoscopy. The C50 of propofol for laryngoscopy in the absence of remifentanil, determined as the intercept of the interaction model with the x-axis (), is 7.3 mg/ml. Because the interaction model for suppression of responses to intubation did not cross the x-axis in the concentration range studied (), the C50 of propofol alone for intubation could not be determined. These findings are in accordance with the findings of Kazama et al., who determined the C50s of propofol for laryngoscopy and intubation at 9.8 and 17.4 mg/ml, respectively.
  185. 185. Mertens MJ,Olofsen E,Engbers FHM,Burm AGL, Bovill JG,Vuyk J.Propofol Reduces Perioperative Remifentanil Requirements in a Synergistic Manner. Response Surface Modeling of Perioperative Remifentanil—Propofol Interactions Anesthesiology, 99:347-59, 2003 • Return of Consciousness • The propofol C50 for return of consciousness of 3.5 mg/ml corresponds well with the reported propofol concentrations at which consciousness was lost in 50% of the patients of 3.4 mg/ml. However, the C50,prop for return of consciousness determined in our study is lower than the C50,prop for return of consciousness of approximately 4 mg/ml determined in a similar study after total intravenous anesthesia with propofol and alfentanil. It is conceivable that 0.2 mg/kg morphine administered 30 min before the end of surgery to provide adequate initial postoperative pain control after remifentanil anesthesia may have lowered the concentration at which patients regained consciousness and delayed the return of consciousness in our study group.
  186. 186. Mertens MJ,Olofsen E,Engbers FHM,Burm AGL, Bovill JG,Vuyk J.Propofol Reduces Perioperative Remifentanil Requirements in a Synergistic Manner. Response Surface Modeling of Perioperative Remifentanil—Propofol Interactions Anesthesiology, 99:347-59, 2003
  187. 187. Mertens MJ,Olofsen E,Engbers FHM,Burm AGL, Bovill JG,Vuyk J.Propofol Reduces Perioperative Remifentanil Requirements in a Synergistic Manner. Response Surface Modeling of Perioperative Remifentanil—Propofol Interactions Anesthesiology, 99:347-59, 2003
  188. 188. Mertens MJ,Olofsen E,Engbers FHM,Burm AGL, Bovill JG,Vuyk J.Propofol Reduces Perioperative Remifentanil Requirements in a Synergistic Manner. Response Surface Modeling of Perioperative Remifentanil—Propofol Interactions Anesthesiology, 99:347-59, 2003
  189. 189. Mertens MJ,Olofsen E,Engbers FHM,Burm AGL, Bovill JG,Vuyk J.Propofol Reduces Perioperative Remifentanil Requirements in a Synergistic Manner. Response Surface Modeling of Perioperative Remifentanil—Propofol Interactions Anesthesiology, 99:347-59, 2003 • • Based on the results of this study and our clinical experience, we recommend a minimum effect site propofol concentration of 2.0 mg/ml in combination with an effect site remifentanil concentration of 6.3 ng/ml in female patients with American Society of Anesthesiologists physical status I or II in the absence of premedication and significant muscle relaxation. These “optimal” effect site concentrations can be used as guidelines during target-controlled infusion. The actual target concentrations during anesthesia will have to be titrated to the desired effect. Dosing guidelines to rapidly achieve these adequate effect site concentrations without target controlled infusion are given in . A “low” target propofol concentration of 2.0 mg/ml in combination with a relatively higher remifentanil concentration of 6.3 ng/ml should only be used in the absence of significant muscle relaxation. When maximum muscle relaxation is required for surgery, we advise use of a target propofol concentration of 3 mg/ml or greater to reduce the risk of awareness. To avoid unrecognized awareness, premedication will further increase the margin of safety. None of the patients in our study had recall of any perioperative event. Patients in group A (the lowest target propofol concentration of 2.0 mg/ml) were hemodynamically stable, and the mean intraoperative Bispectral Index value was 59 (). Because the level of intraoperative neuromuscular blockade was maintained at a train-of-four level of 1–3, patients were able to move in response to inadequate anesthesia at all times.
  190. 190. Nieuwenhuijs DJF, Olofsen E, Romberg RR, et al. Response surface modeling of remifentanil-propofol interaction on cardiorespiratory control and bispectral index. Anesthesiology. 2003;98:312-322.

×