Farmacocinetica e farmacodinamica nell'obesità: considerazioni su anestetici e sedativi

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: 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!!!

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)

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:BDZ,sufent,verapamil
• Ma nell’obeso notevoli variabilità.
• Dati di letteratura non raramente
discordanti……….

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.

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

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

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

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

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

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
Hl prolungate
Assorbimento dal tratto GI 40-50%;picco a
40-45 min(midaz)
• Conseguenze pratiche;
– dose iniziale aum
– Dosi di mantenim ridotte(IBW)

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

Schüttler, Jürgen, M.D.*; Ihmsen, Harald,
Population Pharmacokinetics of Propofol : A
Multicenter Study Anesthesiology.92:727-38, 2000

Schüttler, Jürgen, M.D.*; Ihmsen, Harald,
Population Pharmacokinetics of Propofol : A

Per 70 kg:
250-300 mg/h

Per 70 kg:
170-200 mg/h

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

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

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

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

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

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

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

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

Messaggio da portare a casa:propofol
• Dose iniziale e mantenimento basate sul
peso corretto
• Ma ……….titolare con BIS o similari

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

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)

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

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

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 iniziale in accordo a???? l
peso ideale????
• Attenzione alle dosi ripetute!

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

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

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

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

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

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

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

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

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

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

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…………….

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

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

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

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.

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……………

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.

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

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

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

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

Analisi di regressione tra gli errori di performance con il
modello di Shafer(sopra) e quello di Scott(sotto).

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

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

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].

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

Fattori di correzione e massa farmacocinetica per alcuni pesio
esemplificativi

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

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.

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.

(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

).

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

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

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.

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

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

Velocità di infusione del remifentanil per mantenere
una depressione del 50% dell’EEG in funzione
dell’età per un individuo con LBM di 55

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

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 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

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 durare meno negli obesi

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

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

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.

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

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

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

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!

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

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

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.

sufentanil
• Dose iniziale o livello TCI calcolato sul
TBW
• Mantenimento calcolato sul IBW

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

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 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.

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

WE.Non-opioid analgesia improves pain relief and decreases
sedation after gastric bypass surgery. Can J Anesth 2003 / 50
/ 336-341

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

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!!!

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.

VanDercar DH, Martinez AP, De Lisser EA. Sleep
apnea syndromes: a potential contraindication
for patient-controlled analgesia. Anesthesiology
1991; 74:623-4.

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

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%

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

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.
•

Vecuronium-Induced Neuromuscular Block . Anesth Analg 1994;
79:1003–6

% 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

.

(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

Vecuronium-Induced Neuromuscular Block . Anesth Analg 1994; 79:1003–
6

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).

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)

vecuronium

• Calcola la dose sull’IBW
• Monitorizza!!!!

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

cisatracurium
• Dose iniziale e supplementari basate
sull’IBW

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.

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.

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.

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

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.

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

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.

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,

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

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).

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

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, 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%

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

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.

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

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):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.

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.

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.

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

Messaggio da portare a casa per la
succinilcolina
• Somministrare la dose secondo il TBW

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

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.

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

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

rocuronium
• Meglio somministrare secondo
IBW,specialmente in infusione
continua,ma dati scarsi…..

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

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

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 ???

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…………….

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 remifentanil.
I. Model development. Anesthesiology. 1997;86:10-23

• .

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.

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.

Pharmacodynamic
interaction between propofol and remifentanil
regarding hypnosis,tolerance of laryngoscopy,
bispectral index, and
electroencephalographic approximate entropy.
Anesthesiology. 2004;100:1353-1372.

interaction between propofol and remifentanil regarding hypnosis,tolerance of
laryngoscopy, bispectral index, and
electroencephalographic approximate entropy. Anesthesiology. 2004;100:1353-1372.

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.

•
•

•

•

•

•

•

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.

•
•

•

•

•

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:

•
•
•

•

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.

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.

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 Î¢ = 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

2003

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.

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.

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.

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.

Farmacocinetica e farmacodinamica nell'obesità: considerazioni su anestetici e sedativi

Farmacocinetica e farmacodinamica nell'obesità: considerazioni su anestetici e sedativi

Empfohlen

Empfohlen

Weitere ähnliche Inhalte

Was ist angesagt?

Was ist angesagt? (20)

Andere mochten auch

Andere mochten auch (17)

Ähnlich wie Farmacocinetica e farmacodinamica nell'obesità: considerazioni su anestetici e sedativi

Ähnlich wie Farmacocinetica e farmacodinamica nell'obesità: considerazioni su anestetici e sedativi (20)

Mehr von Claudio Melloni

Mehr von Claudio Melloni (20)

Kürzlich hochgeladen

Kürzlich hochgeladen (20)

Farmacocinetica e farmacodinamica nell'obesità: considerazioni su anestetici e sedativi