pk e pd nell'obesità per firenze 20 maggio

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:20-40%• 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

Benzodiazepine

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

0

1

2

3

4

5

6

7

8

9

Vd centrlt/kg

HL el hr CL totml/kg/mi

HL el hrper os

obesi

normali

* *

*

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 normaliAbernethy 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.

0

100

200

300

400

500

600

Vd CL Hl elim

alprazolam obesi

alprazolam norm

triazolam ,obesi

triazolam norma

* *

*

*

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)

propofol

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


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 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 × h-• Adulto 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

0

5

10

15

20

25

30

t 1/2 alfa t 1/2 beta t 1/2gamma Vd

Vd Vd ss Cl

obesi

normali

min

min

hr

lt

Lt/kg

Ml/min/kg

Tutto NS

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 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

0

5

10

15

20

25

Vd Cl Hl term

propofol

Tps

CL ml/kg

ml/min

lT/kg

Hr

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

Fenitoina

Dati cinetici per la fenitoina;in dose singola;da Abernethy Arch Neurol 1985,42:468-71

0

10

20

30

40

50

60

70

80

90

t 1/2 beta Vd Cl Vd/TBW

normali

obesi²hr

Lt/kg

LT/hr*10

Lt/kg

*

*

*

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)

Thiopental

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

0

5

10

15

20

25

30

Vd Lt/kg tbw Cl tot ml/kg/h HL el hr

obese

nonobese

Dose induzione TPS:mg/tbw

obesi Non obesi

Jung 3.9 5.1

Dundee

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!

Anestetici inalatori

Volumi di distribuzione ml di vapore /kg e Clearance di trasporto dal compart centrale al periferico ml vapore/kg/minWissing 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

500

1000

1500

2000

2500

3000

3500

4000

4500

Vd centr Vd peri Vd ss CL traspcentr-perif

desflurane

isoflurane

sevoflurane

*10

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

0.00

0.02

0.05

0.08

0.11

0.14

0.17

K 1-2 K 2-1

desflurane

isoflurane

sevoflurane

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

• 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

1

6

11

16

21

26

31

min

aperturaocchi

strettamano

estubaz nome datanascita

desflurane

sevoflurane

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

0

100

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500

600

sec

ripresaresp

spont

apertocchi

estubaz orient freeairway

sevoflurane

desflurane

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

isof

propof

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

0

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8

10

12

14

16

ap occhi estubaz dicenome

mobilità PaO2<95

desflurane

isoflurane

propofol

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

0

1

2

3

4

5

6

7

min

fine op-ap occhi estubaz

desfluranesevoflurane

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 della pervietà

Vie aeree

Minor rischio inalaz

+ precoce ripresa della funz resp

Migliore ossigenaz

+ precoce ripresaCardio vascolare e resp

+ rapida uscita dalla sala op

+ turnover

+ efficienza

fentanile

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). 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

Relazione non lineare fra PE Shafer e TBW;l’equazione mostrata puo essere usata per migliorare l’accuratezza della predicibilità dellla conc plasmatica del fentanylShibutani 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

TBW

•Pharmacokinetic mass-Shafer =• 52/(1 + PE-Shafer-reg) = 52/Correction factor; •i.e., 52/[1 + (196.4 ´ e-0.025kg - 53.66)/100].



•Pharmacokinetic mass-Shafer =• 52/(1 + PE-Shafer-reg) = 52/Correction factor; •i.e., 52/[1 + (196.4 ´ e-0.025kg - 53.66)/100].



• 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 esemplificativiShibutani 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

Estensione al postop

Shibutani K, Inchiosa MA Jr., Sawada K, Bairamiam M.Pharmacokinetic mass of fentanyl for postoperative analgesia in lean and obese patients.Brit J.Anesth 95.377-683: 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 95.377-683: 2005

(A) Non-linear relationship between postoperative analgesic dosingrequirements for fentanyl and total body weight (TBW). The equation forthis relationship was: dose (mg h1)=167·e0.011 TBW+149 (coefficient ofdetermination=0.551; P<0.001). (B) Linear relationship between analgesicdose for fentanyl and pharmacokinetic mass (PK mass). The equation forthis 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 predictedfrom 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 numbersfor 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

remifentanil

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 remifentanilEgan TD,Huizinga B,Gupta SK,Jaarsma RL,Sperry RJ,Yee JB,Muir KT.Remifentanil Pharmacokinetics in Obese versus Lean Patients Anesthesiology89:562-73, 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, 1998Slepchenko 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

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I grafici delle stime delle singole variabiliCon 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

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

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

• 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 98:65-73, 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

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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.

Messaggio da portare a casa per il sufentanil

• Dose iniziale o livello TCI calcolato sul TBW

• Mantenimento calcolato sul IBW

alfentanil

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×min-

1 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.


• 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 non-

opioid (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


• 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.

Miorilassanti

vecuronium

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.

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Principali tempi di ripresa dopo vecuronium 0.1 mg/kgSchwartz 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.

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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)

BMIBSAsomma di pieghe cutanee subscapularis and suprailiac /BSA.

•

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

% IBWKirkegaard-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

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

Duration of action of vecu according to anthropometric variablesKirkegaard-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)

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 cisatracurium on morbidly obese women. Anesth Analg. 2004 Oct;99(4):1090-4

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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 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 atracurium-induced neuromuscular block. Anesth Analg 1996; 83:1076-80

Total body weight/surface area kg/m2Kirkegaard-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 weightKirkegaard-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 atracurium-induced 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 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 la dose di atrac di 2.3 mg per ogni

10 kg di peso>70 kg• 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 DPEffect 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 DPEffect 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.

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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

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• 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 la dose di atrac di 2.3 mg per ogni 10 kg di peso>70 kg

• 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.

Succinilcolina

Velocità di Desaturazione in paz normali,obesi e patologicamente obesi. Jense HG,Dubin SA,Silverstein PI., ,O'Leary-Escolas 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

Rocuronium

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.

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•0.6 mg/ kg rocu,•6 obesi vs 6 controli •Anest bilanciata .

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

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Leykin morbid obesity class (BMI 43.8 ± 2.1) Puhringer moderate obesity class (BMI 33.5 ± 4.4).

Messaggio da portare a casa per il 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

Anestetici locali

Lidocaina

PK della lidocaina Abernethy DR,GReenblatt DJ.Lidocaine disposition in obesity.J.Cardiol 1984;53:1183-6.

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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 half-life, 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 half-time 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. Pharmacodynamicinteraction between propofol and remifentanil regarding hypnosis,tolerance of laryngoscopy, bispectral index, andelectroencephalographic 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.

Bouillon TW, Bruhn J, Radulescu L, et al. Pharmacodynamic

interaction between propofol and remifentanil regarding hypnosis,tolerance of laryngoscopy,

bispectral index, andelectroencephalographic approximate entropy.

Anesthesiology. 2004;100:1353-1372.

Bouillon TW, Bruhn J, Radulescu L, et al. Pharmacodynamicinteraction between propofol and remifentanil regarding hypnosis,tolerance of laryngoscopy, bispectral index, andelectroencephalographic approximate entropy. Anesthesiology. 2004;100:1353-1372.

Bouillon TW, Bruhn J, Radulescu L, et al. Pharmacodynamicinteraction between propofol and remifentanil regarding hypnosis,tolerance of

laryngoscopy, bispectral index, andelectroencephalographic approximate entropy. Anesthesiology. 2004;100:1353-

1372.



1372.

• 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.



1372.• 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.



1372.• 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: [email protected]. 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


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.

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 qui

• • AB - The effects of age, sex, and obesity on the kinetics of single intravenous (iv)

and oral doses of midazolam were evaluated in healthy volunteers who received 2.5-5 mg of iv midazolam on one occasion and 5-10 mg orally on another. Kinetics were determined from multiple plasma midazolam concentrations measured during 24 h after dosage. Midazolam elimination half-life (t1/2) after iv dosage was significantly prolonged in elderly (aged 60-74 yr) versus young (24-33 yr) males (5.6 vs. 2.1 hours, P less than 0.01) and total clearance was significantly reduced (4.4 vs. 7.8 ml X min-1 X kg-1, P less than 0.01), leading to increased systemic availability of the oral dose (50% vs. 41%, P less than 0.05). However total volume of distribution calculated by the area method (Vd) (1.6 vs. 1.3 1/kg) and protein binding (3.5 vs. 3.4% unbound) did not differ between groups. Among women there were no significant differences between elderly (64-79 yr) and young (23-37 yr) volunteers in t1/2 (4.0 vs. 2.6 h), clearance (7.5 vs. 9.4 ml X min-1 X kg-1), Vd (2.1 vs. 2.0 1/kg), protein binding (3.7% vs. 3.7% unbound), or oral bioavailability (38% vs. 36%). In obese volunteers (mean weight 117 kg; 173% of ideal weight) versus control subjects of normal weight (66 kg, 95% of ideal weight) matched for age, sex, and smoking habits, midazolam Vd was increased significantly (311 vs. 114 1, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS).

• The effect of age and sex on the disposition of single intravenous doses of midazolam is very similar to that reported previously for other benzodiazepines biotransformed by hepatic microsomal oxidation. 5‑7,26‑32 Midazolarn elimination half‑life was prolonged significantly and total clearance significantly decreased in elderly as opposed to young males. The larger midazolam Vd in the elderly male group was mainly attributable to the greater body weight and the slightly greater degree of adiposity of the elderly male volunteers. Furthermore, volumes of distribution were larger in women than in men regardless of age. In female subjects, however, there were no significant differences between young and elderly groups in any of the kinetic variables, although elimination halflife tended to be longer and total clearance tended to be lower in elderly as opposed to young women. The agerelated decrement in midazolam clearance‑with age effects generally more pronounced in men than in womenis consistent with that previously reported from our laboratory in studies of other oxidized benzodiazepines including diazepam, desmethy1diazepam, desalkylflurazepam, clobazam, triazolam, and alprazolam, as well as for the marker compound antipyrine ......

• In all subjects, oral midazolam was absorbed rapidly from the gastrointestinal tract, with the overall time of peak concentration at 0.85 h after dosage. This is consistent with the highly lipophilic properties of midazolam, causing a rapid rate of absorption similar to that observed with diazepam and desmethyidiazepam." Half‑life of midazolam elimination after oral dosage was highly consistent with that observed after intravenous administra

• tion, indicating that elimination half‑life is independent of route of administration. Overall absolute systemic availability of midazolam averaged 4 1 %. The incomplete systemic availability is due at least in part to first pass hepatic extraction, although incomplete absorption may

• contribute. Systemic availability of oral midazolam was significantly greater in elderly as opposed to young male volunteers, probably because of the decreased total metabolic clearance and decreased first pass hepatic extraction of midazolam in the elderly male group. Overall, systemic availability was related inversely to total metabolic clearance, with greater values of clearance associated with lesser systemic availability.

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.• 12 obese patients, pair-matched with 12 normal subjects, received a

single 1 mg oral dose of alprazolam. Nine similar subject pairs received a single 0.5 mg oral dose of triazolam. Oral volume of distribution (Vd) was much greater in obese than control subjects for alprazolam (mean 114 vs 73L, p less than 0.001), but there was no difference between the 2 groups for triazolam (117 vs 116L). Apparent oral clearance (not corrected for body weight) of alprazolam was lower, although not significantly so, in obesity (66 vs 88 ml/min), but for triazolam it was much lower in the obese (340 vs 531 ml/min, p less than 0.005). Elimination half-life, which is dependent on both Vd and clearance, was prolonged in obesity for alprazolam (22 vs 11h, p less than 0.001) due to the increase in Vd, and also for triazolam (4.1 vs 2.6 h, p less than 0.025) because of the decreased clearance. Plasma protein binding was unchanged in obese compared with control subjects for both alprazolam and triazolam.

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.• During long term administration alprazolam

should therefore take longer to reach steady-state concentrations in obese patients but the final levels achieved should be no different than for patients of normal bodyweight, provided dosage is adjusted for ideal rather than total bodyweight. In contrast, triazolam has impaired clearance in obesity. However, if given once-daily it still would not accumulate with long term dosing due to its short half-life relative to the interval between doses.

• The distribution volume changes related to obesity depend on numerous factors, one of them being the increase of adipose mass. In obese patients, changes in distribution volume correlate with the lipophilicity of the agent. Propofol is highly lipophilic, with an octanol:buffer partition ratio of 15 (Phosphate buffer 10-2 M at pH 7.4, measured in our laboratory), similar to that of alprazolam, which is 18. This lipophilicity index is lower than that of midazolam (34), thiopental (89), and diazepam (309). Thiopental, midazolam, and diazepam display an increase in Vss in obese patients, and this increase in Vss remains significant even after correction for total body weight. However, although alprazolam volume of distribution in obese patients is greater than in control subjects, correction for total body weight results in no difference between the subjects groups. Propofol, with a similar octanol:buffer partition ratio, behaves like alprazolam as far as distribution is concerned, although the octanol:buffer partition ratio is perhaps not the more relevant parameter to estimate in vivo lipid solubility. The distribution volumes may be affected by numerous factors, including relative tissue affinity; therefore, pharmacologic agents demonstrate inconsistent changes as a result of their relative tissue affinities.

•

• In normal-weight patients, propofol clearance is very high, and calculated values usually exceed hepatic blood flow estimated from physiologic values. Although evidence of extrahepatic mechanisms' involvement in propofol total body clearance is increasing, the very high hepatic extraction of propofol has been confirmed by Lange et al., and the liver remains the main site of metabolism for propofol. As a consequence, propofol hepatic clearance is heavily dependent on hepatic blood flow. In obese patients, propofol clearance is correlated to body weight (), and may reach very high values. Increases in blood volume, cardiac output, and splanchnic blood flow have been observed as a consequence of obesity.** However, direct evidence of an enhancement of hepatic blood flow is lacking in the obese population. No significant differences were observed in the systemic clearance of lidocaine, a highly extracted drug with a systemic clearance that closely parallels hepatic blood flow, when obese patients were compared to normal-weight patients. Similarly, midazolam clearance after either intravenous or oral administration was not modified by obesity, and midazolam systemic availability remained constant. These findings indicate that functional hepatic blood flow is not substantially modified in obese subjects. The liver of obese subjects is significantly larger than that of normal-weight subjects because of an increase in the number and size of parenchymal cells. Nevertheless, obesity is associated with a number of pathologic conditions, mainly fatty infiltration of the liver, which may compromise hepatic function even when liver function tests are normal. Propofol is primarily biotransformed via hepatic phase 2 conjugation pathways, its main metabolites being propofol glucuronide, 1 and 4 quinol glucuronides, and 4 quinol sulfate. Oxazepam and lorazepam are two benzodiazepines primarily eliminated in the form of glucuronide. Their clearance was, respectively, 3.1 and 1.6 times greater in obese subjects than in control patients. The influence of obesity on drug metabolism depends heavily on the metabolic pathway considered. It seems that drugs that undergo phase 1 metabolism are unaffected by obesity, as well as those that undergo acetylation, which is a phase 2 metabolic reaction. Most phase-2 reactions of glucuronidation and sulfation are enhanced. Acetaminophen, as well as propofol in this study, display a progressively increasing clearance with increasing body weight, which implies that conjugative drug metabolizing processes may, in some way, be related to body weight. The possible role of extrahepatic conjugation in this process remains to be discovered.

• As a consequence of the simultaneous increase in the Vss and the clearance, propofol elimination half life was not prolonged in obese patients, and there were no signs of propofol accumulation in those subjects, nor of any prolongation of the duration of action. Obese patients opened their eyes when blood propofol concentration reached 1 mg × l-1. This value of propofol concentration when opening eyes on verbal command has already been widely reported in other categories of patients.

Mediane e range delle variabili farmacocinetiche per

deflurane,isoflurane e sevoflurane: K12 microcost per il trasporto dal compart centrale al perif,K 21 dal perif al centraleCL c clearance di trasp .dal centrale al perifV1 volume di distribuz del compart centrale,V2 del compart perif,VSS vol di distribuz allo steady state.volumi espressi in ml per volume inalato rispetto al pesoWissing 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

• Apparent volumes of distribution were clearly smaller for desflurane than for sevoflurane and isoflurane ( and ). This was most pronounced for the peripheral volume. Distribution from the central to the peripheral compartment was much more rapid for isoflurane than for sevoflurane and was slowest for desflurane, whereas the redistribution (k21) was only slightly greater for desflurane and sevoflurane than for isoflurane, and not significantly so. This minor difference may be explained by a 30% longer mean duration of isoflurane anaesthesia (). Duration of anaesthesia significantly decreased the apparent k21 and, to a lesser extent, increased the apparent V1 in the ANCOVA (). It may be that k21 reflects the effect of a third compartment which has increasing relevance as the duration of anaesthesia increases. Minor differences in baseline characteristics between treatment groups, however, are not expected to invalidate comparisons, because the pharmacokinetic differences between agents estimated by ANCOVA as a parametric approach () gave results very similar to the Hodges-Lehmann estimator (). The equilibrium constant (k12/k21) was about 2.5 times smaller for desflurane than for sevoflurane and isoflurane ( and ), confirming the less extensive distribution of desflurane. This could be a disadvantage for isoflurane with respect to the control of the anaesthesia, because pronounced distribution into peripheral compartments causes a continuous large uptake and thus slower saturation of the central compartment. In contrast, the slower distribution of desflurane (small Cl12) supports the more rapid saturation of the central compartment. The specific distribution behaviour thus turns out to be a relevant parameter besides the concentration of agent, cardiac output and physicochemical properties, including solubility in blood, which determine the wash-in behaviour and the intraoperative control of an inhalational anaesthetic. Cl12 of sevoflurane is two times that of desflurane. Its uptake with respect to the end-tidal concentration was about twice as high than that of desflurane. High uptake and high clearance into the periphery become important in the control of 'Low and Minimal Flow' anaesthesia, in which, compared with high-flow applications, the capacity for agent delivery is close to the uptake by the patient (determined by the concentration range of the vaporiser and fresh gas flow: 1 litre min-1 in low-flow and 0.5 litre min-1 in minimal-flow applications). Because of limited agent delivery in these circumstances, rapid distribution to the periphery considerably reduces the velocity of the concentration changes in the central compartment and makes it difficult to increase the depth of anaesthesia by increasing anaesthetic concentrations. In recovery, our data indicate that, during the wash-out period until extubation, pulmonary elimination of isoflurane and sevoflurane is less than that of desflurane ().

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

• ABSTRACT: The pharmacokinetic characteristics of desflurane, isoflurane and

sevoflurane (16 patients for each anaesthetic) were estimated from measurements of inspired and end-expired agent concentrations and ventilation, obtained during routine anaesthesia in patients undergoing maxillofacial surgery (mean age 38 yr, duration of anaesthesia approximately 2 h). A two-compartment model described the data adequately. Although isoflurane and sevoflurane have almost the same tissue/blood partition coefficients, significant differences between substances were observed for the peripheral volume of distribution (medians and ranges: desflurane, 612 (343–1850) mlvapour kgbw -1; isoflurane, 4112 (1472–9396) mlvapour kgbw-1; sevoflurane, 1634 (762–8843) mlvapour kgbw-1) and the transport clearance from the central to the peripheral compartment (desflurane, 7.0 (4.4–11.1) mlvapour kgbw-1 min-1; isoflurane, 30.7 (15.9–38.7) mlvapour kgbw-1 min-1; sevoflurane, 13.0 (9.8–22.4) mlvapour kgbw-1 min-1). Thus, during clinical anaesthesia the important characteristics of the compounds could be obtained and compared between substances from simple data.

•

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• ABSTRACT: Background. The concept of an 'inhalation bolus' can be used to optimize

inhaled drug administration. We investigated the depth of anaesthesia, haemodynamic stability, and recovery time in morbidly obese patients resulting from bispectral indexÔ (BISÔ)-guided sevoflurane or desflurane administration and BIS-triggered inhalation boluses of sevoflurane or desflurane combined with titration of remifentanil.

• Methods. Fifty morbidly obese patients undergoing laparoscopic gastroplasty received either BIS-guided sevoflurane or desflurane anaesthesia in combination with a remifentanil target-controlled infusion. Intraoperative haemodynamic stability and BIS control were measured. Immediate recovery was recorded.

• Results. Intraoperatively, the BIS was between 40 and 60 for a greater percentage of time in the sevoflurane (78 (13)% of case time) than in the desflurane patients (64 (14)% of case time), owing to too profound anaesthesia in the desflurane patients at the start of the procedure. However, fewer episodes of hypotension were found in the desflurane group, without the occurrence of more hypertensive episodes. During immediate recovery, eye opening, extubation, airway maintenance, and orientation occurred sooner in the desflurane group.

• Conclusions. Immediate recovery was significantly faster in the desflurane group. Overall hypnotic controllability measured by BIS was less accurate with desflurane. Overall haemodynamic controllability was better when using desflurane. Fewer episodes of hypotension were found in the desflurane group. The use of the inhalation bolus was found to be appropriate in both groups without causing severe haemodynamic side effects. Minimal BIS values were significantly lower after a desflurane bolus.

•

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.

• Recovery from anesthesia might be compromised in obese patients. Because of its pharmacological properties, desflurane might allow rapid postoperative recovery for these patients. We compared postoperative recovery for 36 obese patients randomized to receive either desflurane, propofol, or isoflurane to maintain anesthesia during laparoscopic gastroplasties. Anesthesia was induced with propofol and succinylcholine IV and was maintained with rocuronium, alfentanil, inhaled nitrous oxide, and the study drug. Immediate recovery (i.e., times from the discontinuation of anesthesia to tracheal extubation, eye opening, and the ability to state one's name) was measured. At the time of postanesthesia care unit (PACU) admission, arterial saturation and the ability of patients to move were recorded. In the PACU, intermediate recovery was measured by using sedation and psychometric evaluations, 30, 60, and 120 min postoperatively. Data were compared between groups by using the Kruskal-Wallis and c2 tests. Results were reported as means ± SD. P < 0.05, compared with desflurane, was considered significant. Immediate recovery occurred faster, and was more consistent, after desflurane than after propofol or isoflurane (times to extubation were 6 ± 1 min, 13 ± 8 min [P < 0.05, compared with desflurane], and 12 ± 6 min [P < 0.05, compared with desflurane], respectively). At PACU admission, SpO2 values were significantly higher and patient mobility was significantly better after desflurane than after isoflurane or propofol. Sedation was significantly less pronounced with desflurane at 30 and 120 min postoperatively. In morbidly obese patients, postoperative immediate and intermediate recoveries are more rapid after desflurane than after propofol or isoflurane anesthesia. This advantage of desflurane persists at least for 2 h after surgery and is associated with both an improvement in patient mobility and a reduced incidence of postoperative desaturation.

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• On the day before surgery, the patients underwent a baseline psychometric evaluation by using the Mini-Mental State examination (temporospatial orientation, anterograde and retrograde memory, attention, word fluency, and concentration) . Premedication was with oral hydroxyzine 1 mg/kg and oral cimetidine 800 mg, administered 1 h before the induction of anesthesia. Standard monitoring was used, including bispectral index (BIS) recording (Aspect Medical Systems) via two bipolar electroencephalographic leads (FpZ-At1 and FpZ-At2).

• After adequate denitrogenation , anesthesia was induced using a propofol target-controlled infusion (TCI) (DiprifusorÒ; Astrazeneca, Rueil-Malmaison, France) to reach an initial blood concentration of 8 mg/mL, which was modified immediately after tracheal intubation as described below. After loss of consciousness was obtained, succinylcholine 1.2 mg/kg was given IV to facilitate orotracheal intubation. After tracheal intubation, ventilation with 50% nitrous oxide in oxygen was delivered via a closed system, with a fresh gas flow of 1 L/min, and was controlled to achieve an end-tidal carbon dioxide pressure of 30–35 mm Hg. Patients were then randomly allocated to receive either desflurane (12 patients), propofol (12 patients), or isoflurane (12 patients). The propofol TCI used for induction was then stopped in both the desflurane and isoflurane groups and continued in the propofol group. Desflurane, propofol, and isoflurane were titrated continuously to maintain the BIS between 45 and 55 throughout the surgical procedure. Immediately after tracheal intubation, patients were given a 50-mg bolus of rocuronium and an infusion of alfentanil. Additional rocuronium boluses were used to keep the train-of-four below 2 throughout the surgical procedure. The alfen tanil infusion was delivered via a computer-controlled pump by using a program based on pharmacokinetic data reported by Maître et al. . A constant plasma target level of alfentanil (50 ng/mL) was maintained from tracheal intubation to gastric banding fixation .

• Vital signs were recorded before the induction of anesthesia. They were also recorded, as were alfentanil and propofol plasma concentrations or volatile end-tidal concentrations (Capnomac UltimaÒ; Datex, Helsinki, Finland), every 2 min until skin incision, every 1 min for 5 min after skin incision, and then every 15 min until the dressing was completed. BIS values were recorded continuously from the preoxygenation period until transfer to the postanesthesia care unit (PACU).

• After gastric banding fixation (approximately 45 min before the dressing), the alfentanil target concentration was set at zero, and propacetamol 2 g IV and nefopam 20 mg IV were administered. When the dressing was completed, the administration of anesthetics and nitrous oxide was discontinued. The times from study drug discontinuation to eye opening, extubation, and orientation (giving one's name on request) were recorded. Neostigmine 3 mg IV and atropine 1 mg IV were given systemically before tracheal extubation, 3 to 5 min after discontinuation of the anesthetic drugs.

• After extubation, the ability of the patients to move themselves was evaluated during transfer from the operating table to the bed (0 = needs help, no movement; 1 = needs help, moves only head; 2 = needs help, moves head and one leg; 3 = needs help, moves head and both legs; 4 = does not need help, able to move alone). Patients were then placed in a semirecumbent position and given oxygen 3 L/min, via a face mask, during transfer to the PACU. Vital signs were recorded at the time of PACU admission. Intermediate recovery was assessed 30, 60, and 120 min after extubation. This assessment included psychometric evaluation (Mini-Mental State examination), sedation scoring using a modified Observer's Assessment of Alertness/Sedation Scale (0 = asleep, not arousable; 1 = asleep but arousable; 2 = drowsy; 3 = awake but calm; 4 = awake, very aware) , pain scoring (10-cm visual analog scale, with 0 = no pain and 10 = worst pain), and recording of any nausea or vomiting. Postoperative analgesic requirements and the time to eligibility for PACU discharge, as determined by using the scoring system described by Aldrete and Kroulik , were also recorded. Postoperative recovery (i.e., from PACU admission to PACU discharge) was assessed by a single investigator blinded to the patient groups, whereas the single anesthesiologist who performed anesthesia (from denitrogenation to transfer to the PACU) was not blinded. Laboratory values, including serum electrolyte, hematocrit, creatinine, and liver function levels, were measured preoperatively and within 24 h after surgery.



study. Anesth Analg 2000; 91:714-9



study. Anesth Analg 2000; 91:714-9• The times from the end of administration of the study drug to extubation, eye opening, and orientation were significantly shorter in the desflurane group than in the propofol and isoflurane groups (). The ability of the patients to move was also significantly better with desflurane than with the other two medications; the postoperative mobility scores were 3 (range 2–4), 1 (range 0–3) (P < 0.05, compared with desflurane), and 1 (range 0–3) (P < 0.05, compared with desflurane) after desflurane, isoflurane, and propofol, respectively. At PACU admission, none of the desflurane-treated patients, compared with five of the propofol-treated patients and five of the isoflurane-treated patients, had SpO2 values of <95% (P < 0.05, compared with the desflurane group). The median (minimum–maximum) values of SpO2 were 97.5% (95%–99%), 95.5% (86%–98%), and 96% (84%–99%) after desflurane, isoflurane, and propofol, respectively. In the PACU, sedation was less pronounced after desflurane than after isoflurane or propofol, 30 and 120 min after surgery (). The results of postoperative psychometric evaluations () were similar in the three groups. The times to eligibility for PACU discharge (126 ± 56, 180 ± 72, and 198 ± 109 min after desflurane, isoflurane, and propofol, respectively) showed a trend toward shorter PACU stays for the desflurane group, compared with the two other groups, despite a lack of statistical significance.

• At none of the time points were there any differences among the three groups with respect to pain scores (), PACU analgesic requirements, or postoperative nausea and vomiting (PONV) incidences (). The amounts of IV fluids given during and after surgery and the incidences of the use of vasoactive drugs to maintain hemodynamic stability during the procedure were similar for the three groups (



study. Anesth Analg 2000; 91:714-9• This study demonstrates that, in morbidly obese patients, postoperative recovery occurs faster and is more constant after desflurane anesthesia than after isoflurane or propofol anesthesia. In agreement with previous studies , faster early recovery was demonstrated after desflurane, compared with isoflurane, in the present study. However, the magnitude of the advantage of desflurane over isoflurane was often smaller in those previous studies than in the present one . We also demonstrated that early recovery was faster and more predictable after desflurane than after propofol anesthesia, whereas previous studies, except one , found no difference in early recovery between these two drugs . However, most of those studies were performed in lean patients anesthetized for short times . The fact that our patients were obese and were anesthetized for more than two hours may explain our results. First, because of its low solubility, less desflurane needs to be released from the tissues and eliminated from the body at the end of prolonged anesthesia . This pharmacological advantage was suggested by clinical studies, in which anesthesia duration seemed to have little influence on recovery time after desflurane anesthesia . Second, propofol is a lipid-soluble anesthetic and may therefore have a prolonged effect in obese patients, whose proportion of fat in their total body weight is increased. Desflurane, in contrast, has very low solubility. This explanation remains controversial, because a pharmacokinetic study suggested that the propofol elimination half-life is not prolonged in obese patients, compared with lean subjects . The only study in which early recovery was also faster after desflurane than after propofol and isoflurane was conducted in our institution and involved prolonged anesthesia in elderly patients, who share with obese patients a high proportion of fat in their total body weight .

• Intermediate recovery, as assessed by sedation scores, was more rapid after desflurane than after propofol or isoflurane anesthesia in obese patients. Some previous studies performed with nonobese patients found no such advantage of desflurane . An advantage of desflurane was sometimes demonstrated but was small and short-lived . In the present study, the advantage of desflurane over propofol and isoflurane, in terms of sedation levels, was marked and lasted at least two hours.

• In previous studies performed with nonobese patients, the clinical relevance of the advantages of desflurane over other anesthetic regimens was not demonstrated . In the present study, the increase in the rapidity of early and intermediate recoveries with desflurane may be clinically significant. First, obese patients are at high risk of both aspiration and acute upper airway obstruction after tracheal extubation . Rapid early recovery may decrease these risks by improving active airway control by the patient and by permitting early efficient coughing. Consistent with this possibility, we found less hypoxemia at the time of PACU arrival for the desflurane group, compared with the propofol and isoflurane groups. Second, in contrast to previous studies, the improvement in intermediate recovery after desflurane was prolonged, being still perceptible two hours after surgery. This prolonged improvement might also have reduced the risk of postoperative respiratory complications. Third, the desflurane-treated patients were more successful in actively transferring from the operating table to the bed than were the patients in the other two groups. Despite the fact that the scores used in the present study have not been validated in the literature, this difference may also be of clinical relevance, because transferring from the operating table to the bed is often difficult, and it can require the help of several people or special lifting devices. More generally, our observations from this study suggest that obese patients anesthetized with desflurane can participate more effectively in their care (including physiotherapy), compared with those anesthetized with propofol or isoflurane. Lastly, the times to eligibility for PACU discharge showed a trend toward shorter PACU stays in the desflurane group, in agreement with a previous study performed with lean patients . However, the difference was not statistically significant in the present study, perhaps because of the small sample sizes.

• Our study was carefully designed to provide a valid comparison of the postoperative period after three different anesthetic regimens. Previous studies pursuing similar goals involved bolus opioid administration at undefined times, which might have resulted in interindividual differences in plasma opioid levels at the time of anesthesia discontinuation. These differences might have interfered with the assessment of recovery times. In the present study, the use of a TCI system to administer alfentanil ensured that alfentanil levels at anesthesia discontinuation and at extubation were similar for the three groups. Although such alfentanil concentrations were theoretical, it can be presumed that the potential effects of alfentanil on recovery times were similar in the three groups. Another problem with comparisons of postoperative recovery after different anesthetic regimens is the potential confounding influence of differences in the depth of anesthesia. To our knowledge, no previous studies comparing postoperative recovery after desflurane, propofol, and isoflurane have monitored the depth of anesthesia. In the present study, the depth of anesthesia was monitored continuously. The BIS values were similar between groups at the time of anesthesia discontinuation, establishing that the more rapid recovery in the desflurane group was not attributable to a lesser depth of anesthesia . However, this study can be criticized because of the lack of investigator blinding in the assessments of early recovery status (i.e., until PACU admission). However, all patients were undergoing identical surgical procedures performed by the same anesthesiologist and the same surgeon, the use of BIS values and the TCI system might have minimized investigator bias, and early recovery was assessed only by using objective end points. In addition, the postoperative period from PACU admission to PACU discharge was assessed by a single investigator blinded to the patient groups.

• The incidences of PONV were similar in the three groups. Propofol has intrinsic antiemetic properties, but the incidence of PONV after propofol or volatile anesthetic treatment remains controversial . In the present study, the concurrent administration of alfentanil and nitrous oxide might have blunted any beneficial effect of propofol in that respect. In addition, the incidence of PONV was low and, under these conditions, demonstration of a clinical advantage of one anesthetic over another is difficult.

• It is generally thought that the choice of anesthetic technique has little effect on significant or long-term outcomes (e.g., postoperative morbidity or economic costs). However, obese patients are at particular risk of early postoperative respiratory complications, so even slight improvements in early or intermediate recovery may be beneficial. In this respect, the more predictable and rapid recovery after desflurane demonstrated for our patients might have a significant beneficial effect on postoperative morbidity in the obese population. The clinical relevance of this early advantage of desflurane in obese patient is strengthened by its duration (at least two hours after surgery) and by the fact that it is associated with both a reduction in postoperative hypoxemia and an increase in patient mobility at the time of PACU admission.

Bentley JB, Vaughan RW, Miller MS, Calkins JM, Gandolfi AJ. Serum inorganic fluoride levels in obese patients during and after enflurane anesthesia. Anesth Analg 1979; 58:409-12

• AB - Serum ionic fluoride levels in 24 markedly obese patients (127.6 +/- 6.0 kg) and seven nonobese control subjects (67.3 +/- 1.2 kg) were compared during and following enflurane anesthesia (less than 2.0 MAC hr). Peak serum fluoride levels were higher (28.0 +/- 1.9 vs 17.3 +/- 1.3 micrometers/L, p less than 0.01) and the rate at which fluoride levels increased was more rapid (slope 5.6 vs 2.5 micrometers/L/hr) in obese patients than in control patients. No clinical evidence of nephrotoxicity was found in either group. Vasopressin resistance tests were not performed, and thus it is inknown whether subclinical nephrotoxicity occurred in either study group. Possible reasons for increased enflurane metabolism in obesity are discussed. These possibilities include differences in fluoride ion kinetics, hepatic delivery and penetration of volatile anesthetics, and altered hepatic microsomal enzyme activity. Obesity rather than weight is an important determinant of anesthetic biotransformation.

Bentley JB, Vaughan RW, Gandolfi AJ, Cork RC. Halothane biotransformation in obese and non-obese patients. Anesthesiology 1982; 57:94-7

• AB - Serum levels of inorganic fluoride, trifluoroacetic acid, and bromide ion were measured at various time intervals following two hours of halothane anesthesia in 17 morbidly obese and eight nonobese patients. Ionic fluoride, a marker of reductive halothane metabolism, increased in the obese but not the nonobese patients. This is of concern since reductive halothane metabolism is associated with hepatoxicity in animals. In addition, serum bromide levels were higher after 48 h in the obese patients compared to the nonobese patients (mean +/- SE, 1,311 +/- 114 vs. 787 +/- 115 microM, P less than 0.01). Sedative levels of bromide were not attained in any patient. Peak trifluoroacetic acid levels were similar in the two patient groups. Sex age, medication intake, and smoking history had no influence on the halothane metabolite levels found in this study.

Frink EJ, Malan TP, Brown EA, Morgan S, Brown BR. Plasma inorganic fluoride levels with sevoflurane anesthesia in morbidly obese and nonobese patients. Anesth Analg 1993; 76:1333-7.• 74:

• Administration of several of the inhaled anesthetics result in plasma inorganic fluoride concentrations that are higher in obese compared to nonobese patients. Sevoflurane, a new inhaled anesthetic, is metabolized to inorganic fluoride; however, plasma inorganic fluoride levels with sevoflurane anesthesia in obese subjects have not been evaluated. We studied plasma inorganic fluoride concentrations during and after sevoflurane surgical anesthesia in morbidly obese (n = 13, body mass index > 35) and nonobese (n = 10) patients. Sevoflurane anesthesia in 60% nitrous oxide/40% oxygen was administered with a semiclosed circle absorption system. Mean anesthetic duration was 1.4 minimum alveolar anesthetic concentration (MAC) hours (sevoflurane MAC = 2.05%) for both groups. Pre- and postoperative blood urea nitrogen, creatinine, and liver function tests were evaluated. Venous blood samples were obtained during and after anesthesia for plasma inorganic fluoride analysis. In six morbidly obese and nonobese patients arterial blood samples were obtained during and after sevoflurane anesthesia for determining sevoflurane blood concentration. Plasma fluoride concentrations during and after anesthesia did not differ between morbidly obese and non-obese groups. Peak plasma inorganic fluoride ion concentrations were 30 +/- 2 mumol/L (mean +/- SEM) in obese and 28 +/- 2 mumol/L in nonobese patients 1 h after discontinuing anesthesia. The hourly rate of change of fluoride ion concentration in plasma during anesthesia was similar between the groups. The maximal recorded plasma fluoride concentrations were 49 mumol/L in an obese patient and 42 mumol/L in a nonobese patient. Pre- and postoperative hepatic and renal tests did not differ significantly in either group.(ABSTRACT TRUNCATED AT 250 WORDS).

Sollazzi L, Perilli V, Modesti C, et al. Volatile anesthesia in bariatric surgery. Obes Surg. 2001;11:623-626.

• Similarly, the results of the 50% and 80% decrement time simulations () suggest that for a given remifentanil plasma level, obese and lean patient groups would not exhibit widely different times to recovery, although remifentanil appears to be slightly shorter acting in the obese group. This may be a function of a larger absolute amount (not proportionally) of LBM in obese subjects compared to lean.

• The findings of this analysis are consistent with current knowledge regarding the effect of body weight on pharmacokinetics. There is mounting evidence to suggest that LBM is a better predictor of metabolic capacity than TBW. This is probably related to the fact that more than 90% of the body's metabolic processes are thought to occur in lean tissue.

• Does Size Matter? • EDITORIAL VIEW• • AUTHOR(S): Bouillon, Thomas, M.D.; Shafer, Steven L., M.D.• • This Editorial View accompanies the following article: Egan TD,

Talmage D, Huizinga B, Samir K, Jaarsma RL, Sperry RJ, Yee JB, Muir KT: Remifentanil pharmacokinetics in obese versus lean elective surgery patients. ANESTHESIOLOGY 1998; 89:562–73.

• Accepted for publication May 12, 1998.

• • Anesthesiology• 89:557-9, 1998

•INTRAVENOUS drugs used in anesthesia range from compounds with low margins of safety, such as opioids and hypnotics, to deadly poisons, such as muscle relaxants. During general anesthesia, patients often are paralyzed, their tracheas are intubated, their lungs are mechanically ventilated, and their vital signs are continuously scrutinized. In this environment, we rarely see injury from anesthetic drugs, because anesthesiologists have become highly skilled at titrating toxic drugs within their narrow therapeutic window and at managing the occasional toxic effects that develop. The therapeutic window for intravenous anesthetic drugs is diminished greatly in the awake, spontaneously breathing patient. Yet even during conscious sedation, the incidence of adverse events is very low when sedation is administered by an anesthesiologist. In this issue of the journal, Egan et al. use complex models to help us get the dose of remifentanil just right. Why should we care about getting the dose just right? We are clearly skilled at getting close to the right dose. Isn't “close” close enough?

• During general anesthesia, this is probably close enough. During conscious sedation, close may cross the line between hypoventilation and apnea. But why not do the best job we can? We want our patients to be unconscious, immobile, and hemodynamically stable during anesthesia. We want them to awaken promptly, yet comfortably, after anesthesia. Even if close is close enough, why not adjust the dose for weight, age, gender, organ function, and type of surgery? Much research has been done to understand how patient factors such as age, gender, and weight relate to the pharmacokinetics and pharmacodynamics of thiopental, fentanyl and alfentanil, sufentanil, propofol, and remifentanil, to give just a few examples.

• At a minimum, we should at least adjust adult doses to weight. Many package inserts, including those of propofol and remifentanil, explicitly provide per-kilogram adult-dosing guidelines. Doesn't this tell us that the drugs should be given per kilogram of body weight? That is the message, but it may be wrong.

• Egan et al. administered remifentanil to obese patients and nonobese control patients. To estimate pharmacokinetic parameters for an extended period, the authors chose a remifentanil dose that was large, 10 mg/kg during 1 min, but that had been well tolerated in his previous studies with nonobese persons. This dose proved to be a big mistake in large persons. Two of the first three patients had profound bradycardia associated with hypotension, necessitating a change in protocol to reduce the dose for subsequent patients. Yet this was a setting in which we think opioid overdoses are well tolerated: the paralyzed, intubated, and ventilated patient.

• Spontaneously breathing patients have little tolerance for opioid overdoses. Remifentanil is approved for use in conscious sedation. Dosing remifentanil according to the package insert recommendations of a 1 mg/kg bolus followed by a 0.05 mg × kg-1 × min-1 infusion may result in a profound overdose and injury in spontaneously breathing obese patients. So what options do we have?

• We can scale anesthetic drugs to lean body mass instead of weight. Lean body mass can be calculated from weight, in kilograms, and height, in centimeters, as follows: • LBM = 1.1 × weight - 128(weight/height)2 for men, and • LBM = 1.07 × weight - 148(weight/height)2 for women. • Scaling drugs to lean body mass instead of weight has been recommended for thiopental, methohexital, muscle relaxants, and propofol. However, the formula for lean body mass is complex, with implications for dosing that

are not immediately obvious. shows lean body mass as a function of weight (x axis) and height (different lines) for men (upper graph) and women (lower graph). The equation has an odd property: For every height there is weight associated with a peak lean body mass, beyond which, increases in weight are matched by a decrease in lean body mass. This is probably an artifact of the equation, so the relation beyond the peak lean body mass has been truncated from the lines shown in . This illustration also shows the ideal body weights for each height as a round dot on each curve, calculated from standard formulas (for men: 49.9 + 0.89 (height - 152.4) kg; for women: 45.4 + 0.89 (height - 152.4) kg).

• Let us assume that scaling to lean body mass, as suggested by Egan et al. and others, is a reasonable choice for intravenous anesthetic drugs. If this is true, shows that the problem with scaling to total body weight is asymmetrical. At weights less than ideal body weight (to the left of the dot on each line), total body weight is a good approximation of lean body mass, because small people do not have a lot of fat. Because total body weight and lean body mass are similar, either can be used to scale drug doses. When the total body weight exceeds ideal body weight (to the right of the dot on each line), total body weight increasingly overestimates lean body mass.

• The nomogram in can be used to estimate lean body mass from weight, height, and gender. Unfortunately, we cannot calculate the correct dose by multiplying the lean body mass by the recommended dose because recommended doses in package inserts and published guidelines are scaled to total body weight, not lean body mass. However, let us assume that scaling to lean body mass is appropriate for most intravenous drugs used in anesthesia and that the recommended doses, scaled to total body weight, are correct for persons of ideal body weight. Based on these assumptions, we can scale to produce a nomogram showing the weight we should enter into our calculations to accurately reflect the extent to which a patient's lean body mass is larger or smaller than the lean body mass in a person of ideal body weight. In this process, the curves in scale upward so that dots, showing ideal body weight, lie on the line of identity, as seen in .*

• shows the weight to use clinically with published doses scaled total body weight, as a function of patient sex, height, and total body weight. For example, if the patient is a 170-cm woman who weighs 90 kg, doses should be calculated as though the woman weighs 72 kg. When the remifentanil package insert calls an infusion of 1 mg × kg-1 × min-1, this patient should get 72 mg/min, not 90 mg/min. also illustrates that weight scaling is a problem for persons who are much heavier than ideal body weight. Below ideal body weight, the total body weight and the weight that should be used to scale by lean body mass are not very different.

• Another strategy is simply not to adjust weights in adults. For example, Gepts et al. concluded that weight did not affect the pharmacokinetics of sufentanil, implying that sufentanil doses should not be weight adjusted. In comparing individual volumes and clearances between obese patients and nonobese controls, Egan et al. did not identify any statistically significant differences provided the parameters were not normalized to weight. A NONMEM analysis identified an effect of lean body mass that was statistically significant, but the improvement was very small. Egan et al. recommend scaling to lean body mass, but they observe that not scaling at all did nearly as well. Either choice was acceptable, and either was preferable to scaling the remifentanil dose to total body weight.

• What can we conclude from Egan et al.'s article and other recent publications on pharmacokinetics? First, the tradition of scaling adult pharmacokinetic parameters to total body weight is not a priori correct. Whether pharmacokinetic parameters scale to weight is a hypothesis that can be tested before a decision is made on how to report pharmacokinetics. Second, scaling adult pharmacokinetics to lean body mass is also a hypothesis that can be tested. Egan et al. show how to do so: Study patients at the extremes of weight, and use formal statistical tests to prove (or disprove) the hypothesis. Third, the Food and Drug Administration and the pharmaceutical industry need to critically examine the assumptions underlying published dosing guidelines. Any choice (scaling to weight, lean body mass, ideal body weight, body surface area, or not scaling at all) represents an assumption about the relation between size and pharmacokinetics. The choice should be based on data, not tradition.

• Fourth, we must still administer our anesthetic drugs. Often we do not have information on how to best scale the dose to patient size. Egan et al. show that we cannot depend on published dosing information in obese persons. suggests a strategy for drug dosing when we are unsure about the true relation between size and pharmacokinetics. For persons smaller than ideal body weight, simply scale the dose to total body weight. For persons larger than ideal body weight, either scale the dose to ideal body weight or to ideal body weight plus some fraction of the difference between total weight and ideal body weight, as suggested by . also suggests that it is rarely appropriate to scale dose to a weight >80 kg in a woman or to 100 kg in a man.

• Size does matter. The Food and Drug Administration has been remiss in approving adult dosing recommendations scaled to weight without adequate scientific evidence that the pharmacokinetics are weight proportional. Fortunately, anesthesiologists reduce doses in obese persons based on experience and intuition alone. Still, the pharmaceutical industry, the Food and Drug Administration, and clinical investigators have an obligation to provide clinicians with the best possible dosing recommendations. We need to provide the scientific foundation to get the dose just right so we can help prevent the complications that arise when close isn't close enough.

• • homas Bouillon, M.D. •

Schwartz AE, Matteo RS, Ornstein E, Young WL, Myers KJ: Pharmacokinetics of sufentanil in obese patients. Anesth Analg 73:790-3, 1991

• ABSTRACT: The pharmacokinetics of sufentanil were determined in eight obese (94.1 ± 14 kg, mean ± SD) and eight control patients (70.1 ± 13 kg) anesthetized for neurosurgery. After induction of anesthesia, 4 microg/kg of sufentanil was administered in a single intravenous bolus. Multiple arterial samples were obtained at timed intervals over 6 h, and plasma concentrations of sufentanil were measured by radioimmunoassay. Calculation of pharmacokinetic variables from the derived compartmental models demonstrated an increased volume of distribution of sufentanil in the obese (9098 ± 2793 mL/kg ideal body weight, mean ± SD) when compared with a control group (5073 ± 1673 mL/kg ideal body weight) (P < 0.01) and a prolonged elimination half-life (208 ± 82 min vs 135 ± 42 min, P < 0.05). The total volume of distribution correlated linearly with the degree of obesity, as expressed in percent ideal body weight (r = 0.67). In contrast, plasma clearance was similar in both obese and control groups (32.9 ± 12.5 vs 26.4 ± 5.7 mL/kg ideal body weight). The high lipid solubility of sufentanil probably explains the altered pharmacokinetics of this opioid in obese patients.

Schwartz AE, Matteo RS, Ornstein E, Young WL, Myers KJ: Pharmacokinetics of sufentanil in obese patients. Anesth Analg 73:790-3,

1991

alfentanil

• RUGLOOP is a general infusion-pump control and data-management system, written by T. De Smet and M. Struys, Ghent University, Belgium (more information: http://allserv.rug.ac.be/~mstruys). It is written in Visual C++ (Microsoft, Redmond, WA, USA) for Windows 2000 operating systems. It is able to deliver a computer-controlled infusion, targeting either the plasma or effect-site concentrations by using a combination of compartmental pharmacokinetic and effect-site models.

Adams JP, Murphy PG. Obesity in anaesthesia and intensive care. Br

J Anaesth 2000; 85:91-108

Ladergaard-Pederson MJ. Recovery from general anesthesia in obese patients. Anesthesiology

1981; 55:720.

Strube PJ, Hulands GH, Halsey MJ. Serum fluoride levels in morbidly obese patients: Enflurane compared with isoflurane anaesthesia. Anaesthesia 1987; 42:685-9

• Obese patients are known to metabolise anaesthetic agents more than patients of normal weight. The extent of this was investigated by the measurement of serum fluoride concentrations in 10 morbidly obese patients undergoing gastroplasty. Five were allocated to receive enflurane and five to receive isoflurane supplemented anaesthesia. The mean peak serum fluoride concentrations after enflurane anaesthesia were greater (22.7 mumol/litre, SE 2.9) than after isoflurane anaesthesia (6.5 mumol/litre, SE 0.6). The mechanisms and implications of this finding are discussed.

Feld, James M., MD; Laurito, Charles E., MD; Beckerman, Mihail, MD; Vincent, Joseph, MD; Hoffman, William E., PhD Non-opioid analgesia improves pain relief and decreases sedation after gastric bypass surgery. Can J Anesth 2003 /

50 / 336-341 • • : • Purpose: Several non-opioid drugs have been shown to provide analgesia during and

after surgery. We compared sevoflurane anesthesia with fentanyl analgesia to sevoflurane and non-opioid drug treatment for gastric bypass surgery and recovery.

• Methods: Thirty obese patients (body mass index > 50 kg×m-2) undergoing gastric bypass were randomized to receive sevoflurane anesthesia with either fentanyl or a non-opioid regimen including ketorolac, clonidine, lidocaine, ketamine, magnesium sulfate, and methylprednisolone. Morphine use by patient-controlled analgesia (PCA) pump and pain score measured by visual analogue scale were determined in the postanesthesia care unit (PACU) and for the first 16 hr after surgery. Sedation was evaluated in the PACU. Investigators assessing patient outcomes were blinded to the study group.

• Results: Fentanyl treated patients were more sedated in the PACU compared to the non-opioid group. Non-opioid treated patients required 5.2 ± 2.6 mg×hr-1 morphine by PCA during their stay in the PACU while patients anesthetized with fentanyl used 7.8 ± 3.3 mg×hr-1 (P < 0.05). Fentanyl and non-opioid treated patients showed no difference in pain score one or 16 hr after surgery.

• Conclusion: Our results show that non-opioid analgesia produced pain relief and less sedation during recovery from gastric bypass surgery compared to fentanyl.

•

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

• Ketamine is a unique anesthetic that may be best utilized as an analgesic adjuvant during anesthesia. In higher doses ketamine has undesirable side effects, including cardiovascular and metabolic stimulation and nightmares. However, low dose ketamine has less frequent incidence of adverse events and can obviate respiratory depression produced by opioids and produce opioid sparing for postoperative analgesia. This is consistent with the results of this study. It has been reported that fentanyl can activate N-methyl-D-aspartate (NMDA) mediated pain processes, enhancing pain sensitivity, and that this effect is reversed by ketamine pretreatment. In addition to possible analgesic and opioid sparing effects, ketamine has local anesthetic and anti-inflammatory properties. However, the clinical significance of ketamine mediated analgesia is controversial and there is concern for the cognitive and cardiovascular side effects of the drug.

•



• The use of clonidine with ketamine has been recommended because of the ability of a2-agonists to inhibit ketamine mediated sympathetic, cardiovascular and metabolic stimulations, nightmares and other undesirable side effects. Low dose clonidine is also reported to prolong postoperative analgesia with no clinically relevant side effects. Clonidine may act as a central or peripheral sympatholytic agent, resolving sympathetically mediated pain. In lower doses as used here, the sedative and hypotensive effects of clonidine are attenuated and act to offset the stimulating effects of ketamine.

•



• In addition to ketamine, magnesium is reported to enhance analgesia by blocking the NMDA receptor. Magnesium also has properties as a sympatholytic and has been promoted as a safe component for balanced general anesthesia. Although others reported that intraoperative magnesium treatment did not enhance postoperative analgesia, they did observe an inverse relationship between cerebrospinal fluid magnesium levels and postoperative analgesic consumption. The ability of magnesium and ketamine to inhibit NMDA receptor activity by separate mechanisms may explain why combinations of the drugs are more effective analgesics than either compound alone.

•



• The ability of lidocaine to improve bowel recovery after intra-abdominal surgery, decrease postoperative pain and decrease the hospital stay of patients undergoing abdominal surgery has been shown repeatedly. In part, the ameliorative action of lidocaine may be mediated by its ability to inhibit cytokine activity and inflammation in the gut. Lidocaine significantly inhibits gut fluid losses and colitis when administered topically or intravenously, perhaps by inhibition of intrinsic or extrinsic nerves in the gut wall. Lidocaine is reported to have significant analgesic effects that are distinct from that produced by morphine. It has been suggested that this analgesic effect of lidocaine may be important in its ability to decrease the requirement for inhalation anesthetics.

• Ketorolac is a non-steroidal anti-inflammatory drug that has been used to inhibit the inflammatory response to surgical trauma and



• improve postoperative analgesia. In addition, ketorolac was associated with decreased incidence of postoperative nausea and vomiting and provided an earlier discharge compared to patients receiving opioid drugs. Ketorolac provided similar postoperative pain relief to that of fentanyl and produced less nausea and sedation and an earlier return of bowel function after ambulatory surgery. Compared to morphine, ketorolac-induced analgesia develops more slowly but is longer lasting. This suggests an important role for ketorolac in the postoperative period for pain management.

• Analgesic effects have been reported for corticosteroids after general surgery and back surgery, but these results are controversial. Intramuscular betamethasone (12 mg), given before the start of ambulatory surgery for foot and hemorrhoid procedures, significantly reduced postoperative pain and nausea compared to a placebo. The use of perioperative opioids and local anesthetics were minimized in that study to reveal differences in postoperative analgesia. A significant analgesic effect of the steroid was revealed only after three to four hours postoperatively, perhaps related to a delayed effect of protein mediators. These results suggest that corticosteroids may reduce postoperative pain and nausea when given at the start of surgery.

• The hypothesis of this study was that anesthetic adjuvants that decrease pain by mechanisms separate from opioids could produce analgesia in lower doses when given together, producing less side effects and more rapid recovery compared to fentanyl. Although the non-opioid treatment decreased sedation during recovery from anesthesia and reduced morphine requirements in the PACU, it is unclear how each of the treatment compounds contributed to this effect. In contrast, fentanyl anesthesia may produce postoperative hyperalgesia and attenuate the effectiveness of morphine to relieve pain in the postoperative period. The non-opioid treatment in this study produced analgesia with stable blood pressure and heart rate during surgery and a rapid recovery. This is an advantage compared to fentanyl for gastric bypass surgery in patients that are at risk for respiratory depression.

Shenkman, Z.; Shir, Y.; Brodsky, J. B. PERIOPERATIVE MANAGEMENT OF THE OBESE PATIENT Br. J. Anaesth. 1993; 70:349-59• Systemic analgesia

• The use of opioid analgesics may be hazardous in the obese. The intramuscular route is not recommended as it is unpredictable and has been shown to provide poorer analgesia than other routes. If the intravenous route is to be used, then a patient-controlled analgesia system (PCAS) is probably the best option. PCAS has been shown to provide effective analgesia in the obese, although respiratory depression has been reported. Doses should be based on IBW. Supplemental oxygen and close observation, including pulse oximetry monitoring, are recommended.

• Postoperative epidural analgesia, using opioids or local anaesthetic solutions, may provide the most effective and safest analgesia for the obese patient. The epidural route for opioid administration is preferred over other routes because it produces less drowsiness, nausea and respiratory depression, earlier normalization of bowel motility, improved pulmonary function and reduced hospital stay. As a result of the potential for delayed onset respiratory depression, supplemental parenteral opioids should probably be avoided. Continuous epidural analgesia with local anaesthetics has been shown to have a beneficial effect on cardiovascular function, with a reduction in left ventricular stroke work, although an associated motor block will delay ambulation.

• All of the above regimens can be supplemented with oral analgesics such as paracetamol or non-steroidal anti-inflammatory drugs if appropriate.

• Considerations in obstetrics

• Drug handling in obesity• The physiological changes associated with obesity lead

to alterations in the distribution, binding and elimination of many drugs. The net phamacokinetic effect in any patient is often uncertain, making monitoring of clinical end-points (such as heart rate, arterial pressure and sedation) and serum concentrations of drugs more important than empirical drug dosing based on published data. For drugs with narrow therapeutic indices (e.g. aminophylline, aminoglycosides or digoxin), toxic reactions may occur if patients are dosed according to their actual body weight.

•

• Absorption• Oral absorption of drugs remains essentially unchanged in the obese patient. • Volume of distribution• Factors that affect the apparent volume of distribution (Vd) of a drug in the obese

include the size of the fat organ, increased lean body mass, increased blood volume and cardiac output, reduced total body water, alterations in plasma protein binding and the lipophilicity of the drug. Thiopental, for instance, has an increased Vd because of its highly lipophilic nature and also because of the increased blood volume, cardiac output and muscle mass. Therefore the absolute dose should be increased, even though on a weight-for-weight basis the dose required will be less than that for a lean individual. An increase in the volume of distribution will reduce the elimination half-life unless the clearance is increased. With thiopental and other lipophilic drugs (such as benzodiazepines or potent inhalational anaesthetic agents), effects may persist for some time after discontinuation.

• There may be variable effects of obesity on the protein binding of some drugs. The increased concentrations of triglycerides, lipoproteins, cholesterol and free fatty acids may inhibit protein binding of some drugs, and so increase free plasma concentrations. In contrast, increased concentrations of a1 acid glycoprotein may increase the degree of protein binding of other drugs (e.g. local anaesthetics), so reducing the free plasma fraction.

•

• Elimination• Although histological abnormalities of the liver are relatively common, hepatic clearance is usually

not reduced in the obese. Phase I reactions (oxidation, reduction and hydrolysis) are usually normal or increased in obesity, whereas metabolism of some drugs by phase II reactions (e.g. lorazepam) is consistently increased. Cardiac failure and reduced liver blood flow may slow the elimination of drugs that are rapidly eliminated by the liver (e.g. midazolam or lidocaine).

• Renal clearance increases in obesity because of the increased renal blood flow and glomerular filtration rate. In obese patients with renal dysfunction, estimates of the creatinine clearance from standard formulae tend to be inaccurate and dosing regimens for renally excreted drugs should be based instead on measured creatinine clearance.

• Inhalational anaesthetics• The traditional theory that slow emergence from anaesthesia in morbidly obese patients is a result

of delayed release of volatile agent from excessive adipose tissue has been challenged. Reductions in blood flow to the fat organ may limit the delivery of volatile agents to fat stores, with the slow emergence more probably resulting from increased central sensitivity. In fact, some studies demonstrate comparable recovery times in obese and lean subjects for anaesthesia lasting 2–4 h.

• Obese patients may be more susceptible to the ill-effects of altered hepatic metabolism of volatile agents. Plasma concentrations of bromide, a marker of reductive and oxidative metabolism of halothane, are increased in obese patients. Increased reductive metabolism may be an important factor in the development of liver injury after exposure to halothane, and this may be more likely in obese individuals at risk from hypoxaemia and reduced liver blood flow. Concentrations of inorganic free fluoride ions are higher in obese patients following exposure to halothane or enflurane, increasing the risk of nephrotoxicity. This does not appear to be the case with sevoflurane, despite its significant hepatic metabolism. Fluoride concentrations are not significantly increased after isoflurane anaesthesia,

Marik P, Varon J. The obese patient in the ICU. Chest 1998; 113:492-8

• :

• AB - Data from recent surveys indicate that a staggering 34.9% of US adults are overweight. Obese adults are at in increased risk for many chronic medical conditions, and this increases the likelihood of admission to an ICU. The critically ill obese patient presents the ICU team with many unique problems. Obesity may result in significant alterations of pulmonary and cardiac function, as well as the handling of many drugs. An appreciation of these and other changes is essential in the management of the obese ICU patient. The purpose of this article is to review some of the basic concepts related to the treatment of obese patients in the ICU.

Cheymol G. Clinical pharmacokinetics of drugs in obesity: an update. Clin Pharmacokinet 1993; 25:103-

14:

• AB - Obesity is common enough to constitute a serious medical and public health problem. Drug prescription for obese patients is difficult since dosages based on pharmacokinetic data obtained in normal-weight individuals could induce errors. In obese patients, physiopathological modifications are likely to affect drug tissue distribution and elimination. Body constitution is characterised by a higher percentage of fat and a lower percentage of lean tissue and water. Although the cardiac output and total blood volume are increased, the blood flow per gram of fat is less than in nonobese individuals. Histological hepatic alterations are commonly reported in morbidly obese individuals. A higher glomerular filtration rate is also observed. Most of the pharmacokinetic information concerning obesity deals with distribution. Published data concerning molecules with moderate and weak lipophilicity are homogeneous. In obese compared with normal weight individuals, the total volume of distribution (Vd) is moderately increased (aminoglycosides, caffeine) or similar (H2-blockers, neuromuscular blockers), but the Vd corrected by kilogram of actual bodyweight is significantly smaller. These drugs distribute to a limited extent in excess bodyweight. For highly lipophilic drugs, despite this common characteristic, discrepancies in distribution in obesity exist between drugs belonging to different pharmacological classes. Some drugs show a clear augmentation of Vd and elimination half-life (benzodiazepines, carbamazepine, trazodone, verapamil, sufentanil), indicating a marked distribution into adipose tissue. For others, Vd and Vd/kg are decreased (cyclosporin, propranolol), suggesting that factors other than lipid solubility intervene in tissue distribution. As a general trend, the total clearance (CL) of drugs metabolised by oxidation, conjugation or reduction, and also of drugs with flow-dependent hepatic clearance, is not diminished in obesity. Usually CL is identical in obese and nonobese individuals, sometimes it is increased in obesity (enflurane, halothane, prednisolone, some benzodiazepines). With some drugs a significant reduction in CL is observed in obese individuals (methylprednisolone, propranolol). Renal clearance of aminoglycosides and cimetidine increases in obese individuals. Practical guidelines for dosage adjustment are proposed. For drugs with distribution restricted to lean tissues, the loading dose should be based on the ideal bodyweight of patients. For drugs markedly distributed into fat tissue the loading dose is based on total bodyweight. Adjustment of the maintenance dose depends on possible changes in CL. In some cases (atracurium, prednisolone) dosage adjustment does not follow these recommendations, owing to pharmacodynamic data.

Cheymol G. Effects of obesity on pharmacokinetics: implications for drug therapy. Clin Pharmacokinet 2000; 39:215-31

• AB - Obesity is a worldwide problem, with major health, social and economic implications. The adaptation of drug dosages to obese patients is a subject of concern, particularly for drugs with a narrow therapeutic index. The main factors that affect the tissue distribution of drugs are body composition, regional blood flow and the affinity of the drug for plasma proteins and/or tissue components. Obese people have larger absolute lean body masses as well as fat masses than non-obese individuals of the same age, gender and height. However, the percentage of fat per kg of total bodyweight (TBW) is markedly increased, whereas that chrome P450 isoforms are altered, but no clear overview of drug hepatic metabolism in obesity is currently available. Pharmacokinetic studies provide differing data on renal function in obese patients. This review analyses recent publications on several classes of drugs: antibacterials, anticancer drugs, psychotropic drugs, anticonvulsants, general anaesthetics, opioid analgesics, neuromuscular blockers, beta-blockers and drugs commonly used in the management of obesity. Pharmacokinetic studies in obesity show that the behaviour of molecules with weak or moderate lipophilicity (e.g. lithium and vecuronium) is generally rather predictable, as these drugs are distributed mainly in lean tissues. The dosage of these drugs should be based on the ideal bodyweight (IBW). However, some of these drugs (e.g. antibacterials and some anticancer drugs) are partly distributed in adipose tissues, and their dosage is based on IBW plus a percentage of the patient's excess bodyweight. There is no systematic relationship between the degree of lipophilicity of markedly lipophilic drugs (e.g. remifentanil and some beta-blockers) and their distribution in obese individuals. The distribution of a drug between fat and lean tissues may influence its pharmacokinetics in obese patients. Thus, the loading dose should be adjusted to the TBW or IBW, according to data from studies carried out in obese individuals. Adjustment of the maintenance dosage depends on the observed modifications in clearance. Our present knowledge of the influence of obesity on drug pharmacokinetics is limited. Drugs with a small therapeutic index should be used prudently and the dosage adjusted with the help of drug plasma concentrations.

Blouin RA, Kolpek JH, Mann HJ. Influence of obesity on drug disposition. Clin Pharm 1987;

6:706-14

• AB - Physiologic changes associated with obesity and their effects on the distribution, protein binding, metabolism, and renal excretion of drugs are described. Changes in the volume of distribution correlate with drug lipophilicity. Drugs that have a high affinity for adipose tissue have an increased volume of distribution, whereas the distribution of drugs that have low partition coefficients is not altered substantially. Albumin and total protein concentrations are comparable in lean and obese subjects, but concentrations of alpha 1-acid glycoprotein are increased. Consequently, protein binding of acidic drugs is unchanged, but the free fraction of basic drugs may be decreased. Changes in hepatic drug clearance are complex. Phase 1 reactions and acetylation, a Phase 2 reaction, appear to be unaffected by obesity, but activity of Phase 2 glucuronidation and sulfation pathways is enhanced. Available physiologic and pharmacokinetic data on the effect of obesity on systemic clearance of highly extracted drugs are conflicting. Both glomerular filtration and tubular secretion appear to be increased in obese individuals, and tubular secretion may be disproportionately increased compared with filtration. Clearance of drugs that depend on glomerular filtration for elimination is consistently higher in obese subjects. Differences among patient populations, other conditions associated with obesity, and the small study populations described to date may account for some discrepancies in reported results. Awareness of the physiologic effects of obesity is essential for ensuring appropriate drug therapy in obese patients.

Mayersohn M, Calkins JM, Perrier DG, et al. Thiopental kinetics in obese patients.

Anesthesiology 1981; 55:178A.

Wasan KM, Lopex-Berestein G. The influence of serum lipoproteins on the pharmacokinetics and pharmacodynamics of lipophilic drugs and drug carriers. Arch Med Res 1993; 24:395-401

• AB - One of the most ambitious goals in the therapy of human diseases is developing targeted drug delivery which would allow an effective concentration of drug to reach diseased sites while sparing non-diseased tissues. One of the most extensively researched approaches in controlled drug delivery has been the incorporation of drugs into lipid carriers or phospholipid vesicles, known as liposomes. However, the behavior of lipophilic drugs and liposomes within the circulating blood remains unknown. Several laboratories have demonstrated that the pharmacokinetics, tissue distribution, and pharmacological activity of a number of drugs incorporated into liposomes are influenced by their interaction with serum lipoproteins. This chapter will examine the influence of serum lipoproteins on the pharmacokinetics and pharmacodynamics of lipophilic drugs and drug carriers.

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.

Vecu 0.1 mg/kg Anest TPS /N2O/Haloth7 obesi vs 6 normThe effect of obesity on the disposition and action of vecuronium was studied in 14 surgical patients. After induction of anesthesia with thiopental and maintenance of anesthesia by inhalation of nitrous oxide and halothane, seven obese patients (93.4 +/- 13.9 kg, 166% +/- 30% of ideal body weight, mean +/- SD) and seven control patients (60.9 +/- 12.3 kg, 93% +/- 6% of ideal body weight) received 0.1 mg/kg of vecuronium. Plasma arterial concentrations of muscle relaxant were determined at 1, 3, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 210, 240, 300, and 360 min by a spectrofluorometric method. Simultaneously, neuromuscular blockade was assessed by stimulation of the ulnar nerve and quantification of thumb adductor response. Times to 50% recovery of twitch were longer in the obese than in the control patients (75 +/- 8 versus 46 +/- 8 min) as were 5%-25% recovery times (14.9 +/- 4.0 versus 10.0 +/- 1.7 min) and 25%-75% recovery times (38.4 +/- 13.8 versus 16.7 +/- 10.3 min). However, vecuronium pharmacokinetics were similar for both groups. When the data were calculated on the basis of ideal body weight (IBW) for obese and control patients, total volume of distribution (791 +/- 303 versus 919 +/- 360 mL/kg IBW), plasma clearance (4.65 +/- 0.89 versus 5.02 +/- 1.13 mL.min-1.kg IBW-1), and elimination half-life (119 +/- 43 versus 133 +/- 57 min) were not different between groups.(ABSTRACT TRUNCATED AT 250 WORDS)

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• The results of the study show that among the anthropometric variables, %IBW, BMI, and the sum of

subscapularis and suprailiac skin folds divided by the surface area are the best predictors for duration of action of vecuronium-induced neuromuscular block. Vecuronium dosage should therefore be based on one of these variables. We propose to use %IBW, as it is easy to calculate and does not involve measurement of skin folds, which is bothersome and unpleasant for the patient.

• According to the regression analyses duration of action of induction dose equals 0.18 multiplied by %IBW plus 12.66. To calculate how much we have to reduce the dose of vecuronium in obese patients to obtain similar duration of action in normal weight and obese patients, we need to know how dosage influences the duration of action. This has been studied by Feldman and Liban . Regression analyses of their data indicate that duration of action bears a linear relationship to dosage, with the regression equation: duration of action equals 0.291 multiplied by the dose of vecuronium in micrograms minus 1.88 min. 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 mg/kg. On condition that the induction dose of vecuronium based on body weight alone is 100 mg/kg, the induction dose of vecuronium in micrograms per kilogram corrected for %IBW therefore equals 162 mg/kg minus 0.62 mg/kg multiplied by %IBW. As the volume of distribution corrected for IBW for drugs with low lipid solubility is similar in females and males , the dosage regimen may also be used for males, provided that the formula for calculation of %IBW for males, 110 lb + 5 lb per inch above 5 ft height, is used . It is not possible to perform similar calculations for correction of the supplemental doses, as no dose-duration studies are available. However, we propose to reduce the supplemental doses proportionally, as the elimination half-life of vecuronium is unaffected by body weight . Many factors other than body composition influence the duration of action of vecuronium, and the duration of action in the obese as well as in the non-obese is associated with large individual variability. Although it is impossible to predict the exact duration of action, we find it important to correct the dose of vecuronium according to %IBW in the obvious obese patient when a short procedure is planned.

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• , There is conflicting evidence on the duration of action of atracurium in obese

patients. Cisatracurium is one of the stereoisomers of atracurium. We investigated the neuromuscular effects of cisatracurium in morbidly obese patients. Twenty obese female patients (body mass index >40) were randomized in two groups. Group I (n = 10) received 0.2 mg/kg of cisatracurium on the basis of real body weight (RBW), whereas in Group II (n = 10) the dose was calculated on ideal body weight (IBW). In a control group of 10 normal weight female patients (body mass index 20-24), the dose of cisatracurium was based on RBW. Neuromuscular transmission was monitored using acceleromyography of the adductor pollicis, and anesthesia was induced and maintained with remifentanil and propofol. Onset time was comparable between Group I and the control group (132 s versus 135 s; P = ns). The duration 25% was longer in Group I than in the control group (74.6 min versus 59.1 min; P = 0.01) and in the control group compared with Group II (45.0 min; P = 0.016). In conclusion, the duration of action of cisatracurium was prolonged in morbidly obese patients when dosed according to RBW compared with a control group of normal weight patients. Duration was also prolonged in the control group patients compared with morbidly obese patients to whom the drug was administered on the basis of IBW.

• Patients were positioned in the 30° reverse Trendelenburg position and breathed 100% O2 for 5 min. Cricoid pressure was applied and anesthesia was subsequently induced with remifentanil 0.25 mg × kg-1 × min-1 and propofol 2 mg/kg and maintained by continuous infusion of remifentanil 0.25–0.50 mg × kg-1 × min-1 and propofol 4–6 mg × kg-1 × h-1. Ventilation was controlled with 50% air in oxygen and end-tidal

• Obes Surg. 2000 Aug;10(4):353-60.• Related Articles, Links

• Total intravenous anesthesia with midazolam, remifentanil, propofol and cistracurium in morbid obesity.

Alvarez AO, Cascardo A, Albarracin Menendez S, Capria JJ, Cordero RA.

IMETCO, "Arturo Onativia Hospital", Buenos Aires, Argentina. [email protected]

BACKGROUND: According to physical impairments of massive obesity, cardiac, respiratory and gastrointestinal physiology must be considered as much as pharmacokinetic behavior. Anesthetic management of morbidly obese patients has to be carefully planned, in order to minimize the increased risks of aspirative pneumonitis, hemodynamic instability and delay in recovery. The ideal anesthesia should provide a smooth and quick induction, allowing rapid airway control, prominent hemodynamic stability, and rapid emergence from anesthesia. To approach these ideal conditions, a Total Intravenous Anesthesia (TIVA) with midazolam, remifentanil, propofol and cisatracurium was designed and analyzed. METHODS: 10 consenting morbidly obese patients scheduled for elective Laparoscopic Adjustable Gastric Banding participated in the study. TIVA with midazolam, remifentanil, propofol and cisatracurium was used in all cases. Time to loss of consciousness, tracheal intubation, perianesthetic physiological parameters and complications, incidence of awareness with recall, recovery times, postoperative analgesia and costs of drugs were evaluated. RESULTS: The analyzed data showed adequate time and physiological conditions for induction and tracheal intubation, stable maintenance with easy handling of deepness, low incidence of perianesthetic complications, excellent recovery performance and institutional efficiency. CONCLUSIONS: TIVA with midazolam, remifentanil, propofol and cisatracurium was found to be effective, secure, predictable and economic for the anesthetic management of morbidly obese patients.

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

• Nessuna diff nella ripresa(tof 0.70) da TOF 0.10 fra pz sovrappeso e normali dopo neostigmina 0.07 mg/kg dopo anest bilanciata fent/tps/aloth 0.5%

• NB.non erano veramente obesi……………….

• PURPOSE: To investigate the relationship between total body weight (TBW) or body mass index (BMI) and atracurium reversal time. METHODS: The study population comprised 25 patients with TBW < 80 kg and 25 patients with TBW > or = 80 kg anaesthetised with midazolam, thiopentone, fentanyl, nitrous oxide and halothane. Neuromuscular block was induced with 0.5 mg.kg-1 atracurium and maintained with doses of 0.15 mg.kg-1. Neuromuscular transmission was recorded using train-of-four (TOF) nerve stimulation and mechanomyography. Neostigmine, 0.07 mg.kg-1, was administered when the first twitch in TOF had recovered to 10% of control. Reversal time was defined as: time from administration of neostigmine until TOF ratio recovered to 0.70. RESULTS: There was no difference in reversal time between patients with TBW < 80 kg (7.2 +/- 2.6 min, mean +/- SD), and patients with TBW > or = 80 kg (6.9 +/- 3.6 min). When patients were grouped according to BMI there was no difference in reversal time between groups with low BMI (6.9 +/- 2.6 min) or high BMI (7.1 +/- 3.6 min). There was, furthermore, no difference in reversal time between the 15 patients in the study population with the smallest TBW or BMI and the 15 patients with the greatest TBW or BMI. There was no correlation between TBW or BMI and reversal time. CONCLUSION: When atracurium-induced neuromuscular block is antagonised with 0.07 mg.kg-1 neostigmine. TBW or BMI have no influence on reversal time.


To determine factors that influenced the clearance (Cl) of atracurium, 80 adult patients of varying body build were given an atracurium infusion according to a predetermined profile, which was scaled by lean body mass (LBM). Cl was estimated at 50-60 min by the constant infusion rate required to maintain the steady-state plasma concentrations. The efficacy of scaling the absolute Cl estimate by body build variables, in which the absolute Cl estimate is divided by the body build variable to achieve similar scaled estimates in all patients, was assessed by the bias and precision of the individual scaled Cl estimates to those in patients with a "normal" body build (23%-27% body fat). The efficacy of scaling the dose of atracurium by differing body build variables to achieve similar plasma concentrations was also assessed by bias and precision, in which the plasma concentrations from an infusion scaled by other body build variables were generated by linear simulation. Body size, as quantified by LBM, total body mass (TBW), height, and body surface area, had a significant influence on Cl, with the effect best described by LBM (respective R2, 0.487, 0.368, 0.265, 0.445). No other factors could be identified, including blood pH, serum creatinine, and drugs given during the peroperative period. The efficacy of scaling Cl by TBW (absolute Cl estimate divided by patient TBW) to achieve similar estimates in all patients was poor; Cl.TBW estimates varied inversely with patient body fat content and resulted in obese patients having smaller estimates, a mean bias of -29%, compared with those in patients with a normal body build (P = 0.002).(


• The mean Cl of atracurium in the 80 patients was 291 ± 76 mL/min. The individual Cl estimates were related significantly to patient body build variables; absolute Cl estimates increased with increasing size of the patient. The relationship between Cl estimates and the body build variables TBW, LBM, Ht, and BSA were best described by a linear relationship with a respective R2 of 0.368, 0.487, 0.265, 0.368 (all variables; P < 0.001). The relationship with LBM best accounted for the variability in the absolute Cl estimates. Without adjusting for body size, the overall variability of the Cl estimates (coefficient of variation) was 26.1%; with a linear relationship to LBM, this index of variability decreased to 18.8%, whereas with a linear relationship with BSA it decreased to 19.6%, with TBW to 20.9%, and with Ht to 22.5%. shows the regression relationship between Cl of atracurium and LBM.


• LBM best described the influence of body build and size. The efficacy of scaling Cl by TBW was poor due to the inability of TBW to account for the extremes of body build. Our findings are consistent with those of Varin et al. , who found that the absolute Cl of atracurium or Cl scaled by ideal body weight was similar in nonobese and morbidly obese patients. Scaling Cl by TBW introduced a twofold difference in their Cl.TBW estimates . These results, together with our own, suggest that the more the body build of an individual differs from the mean of the population, the more absurd are Cl estimates scaled by TBW. By contrast, scaling Cl by LBM or BSA minimizes the influence of body build and size.


• Scaling the dose of atracurium by LBM resulted in similar plasma concentrations in patients of varying body build. This is prima facie evidence that dosing with LBM is optimal for atracurium. The more the body build of an individual differs from "normal" the greater the advantage of dosing with LBM by comparison with TBW. LBM has been shown previously to correlate better than TBW with the dose of d-tubocurarine required to produce 90%–95% twitch depression . Similarly, dose of halothane, thiopental ketamine, and succinylcholine correlate better with LBM than TBW .

• total free body water and the extracellular fluid volume in which competitive neuromuscular blocking drugs are distributed do not correlate linearly with BSA .


• These results, together with our own, suggest that the more the body build of an individual differs from the mean of the population, the more absurd are Cl estimates scaled by TBW. By contrast, scaling Cl by LBM or BSA minimizes the influence of body build and size.

• These findings have practical implications for the dosing of atracurium in clinical practice. The patient body build variable that best describes the influence of body build on the pharmacokinetic variables of that drug should be used to scale dosage, if the pharmacodynamics of the drug are independent of body build. This applies to atracurium, as we have shown that its pharmacodynamics are not influenced by body build and size . Traditionally, dosage of atracurium and other competitive neuromuscular blocking drugs are scaled by TBW. We investigated the efficacy of using different patient variables to scale drug dosage by simulating the plasma concentrations of atracurium that would have been achieved. These simulations are based on the assumption that the pharmacokinetics of atracurium are linear over the concentration range simulated. If we double the infusion rate of atracurium we would expect that the plasma concentration would also double. This basic assumption, which underlies all dosage regimens, has been verified for atracurium .

• The results of our dosage simulations were consistent with the efficacy of the patient body build variables in describing the influence of body build and size on Cl. Simulated dosage with TBW suggested that lean patients would be underdosed and obese patients overdosed. Obese patients would receive at least 40% more drug than was required. Fisher et al. observed that "fat people require larger amounts of drug than is usual, but in fact require much less on a body weight basis".

• Scaling the dose of atracurium by LBM resulted in similar plasma concentrations in patients of varying body build. This is prima facie evidence that dosing with LBM is optimal for atracurium. The more the body build of an individual differs from "normal" the greater the advantage of dosing with LBM by comparison with TBW. LBM has been shown previously to correlate better than TBW with the dose of d-tubocurarine required to produce 90%–95% twitch depression . Similarly, dose of halothane, thiopental ketamine, and succinylcholine correlate better with LBM than TBW .

• The alternative dosing regimens we investigated, such as dosing by BSA or giving a fixed dose to all adult patients, did not seem to offer any significant advantage. BSA has been used previously to calculate drug dosage in pediatrics and in spinal anesthesia . Simulated dosing of atracurium by BSA was superior to TBW in allowing for variation in body build, but its major limitation seemed to be a tendency to overdose the obese group of patients (>43% body fat). This contrasts with the observation of Tseuda et al. that the pancuronium requirements for morbidly obese and nonobese patients were similar when corrected for BSA. Theoretically, BSA may not be an accurate guide to dosage of competitive neuromuscular blocking drugs in obese patients, inasmuch as total free body water and the extracellular fluid volume in which competitive neuromuscular blocking drugs are distributed do not correlate linearly with BSA . Administration of a fixed dose of atracurium would improve dosing accuracy compared with dosing based on TBW. A fixed dose avoids the marked under- and overdosage in patients at the extremes of body size and partially justifies the clinical practice of administering similar doses of neuromuscular blocking drugs to all adult patients (for example, 30–40 mg of atracurium for intubation). However, the method is associated with the poorest precision, as the interpatient variability in plasma concentrations is greatest with administration of a fixed dose, and can not be recommended.

• The previous lack of interest in the use of LBM as a basis for scaling pharmacokinetic variables or drug dosing may have been due to the perceived difficulty of estimating LBM in routine clinical practice. Precise estimation of LBM requires sophisticated, and hence impractical, measurement techniques, such as estimation of patient total body water, total content of potassium, body density or uptake of inert gases . Alternative methods, based on skinfold thickness, are also impractical and subject to several potential sources of error . Anthropometric methods are more suited to routine clinical use and are used extensively to estimate BSA . Various numerical indices based on patient physical measurements have been described for estimating LBM. In military personnel, Ht2 has been found to correlate well with LBM estimated from body density . Allen et al. reported that TBW and Ht3 could be used as a readily available method to estimate blood volume and adiposity. In this study we used the method of James to calculate LBM. This method is based on (TBW/Ht)2, and can be used to estimate LBM in neonates, children, and adults. This method has comparable accuracy with skinfold thickness measurement techniques .

• The significance of our findings is emphasized by the large variability in body build in adult patients presenting for routine surgery. Adult patients can have a fat content ranging from 15%–80% of total body weight . The routine use of TBW to scale clearance and probably other pharmacokinetic variables, and for dosing of atracurium, should be questioned. Alternative body build variables, such as LBM, seem to be more efficacious and should be used particularly at the extremes of body build.


28 neurosurgical patientsvecuronium (0.1 mg/kg), the time to go from 5 to 25% of recovery of

twitch response was statistically significantly longer (14.6 +/- 7 minutes, mean +/- SD) than it was in nonobese control patients (6.9 +/- 2 minutes). Similarly, with vecuronium times for recovery from 25 to 75% were longer (33 +/- 15 minutes) in obese patients than in control patients (13.2 +/- 2 minutes), as was time to 75% recovery, 82 +/- 30 minutes in obese patients, 50 +/- 9 minutes in controls. In contrast, obese patients given atracurium (0.5 mg/kg) exhibited no difference in recovery indexes or recovery times when compared to control patients of normal weight. The prolonged duration of action of vecuronium in obese patients is most likely related to impaired hepatic clearance and/or an overdose effect with recovery occurring during the distribution phase. That the duration of action of atracurium is not prolonged in the obese is believed due to this relaxant's not depending on organ function for elimination.

Jense HG,Dubin SA,Silverstein PI., ,O'Leary-Escolas U.Effect of Obesity on Safe Duration of Apnea in Anesthetized Humans . Anesth Analg 1991; 72:89–93

• • ABSTRACT: Obese patients have a decreased functional residual capacity and,

hence, a reduced oxygen supply during periods of apnea. To determine whether obese patients are at greater risk of developing hypoxemia during induction of anesthesia than patients of normal weight, 24 patients undergoing elective surgical procedures were studied. Group 1 (normal) were within 20% of their ideal body weight. Group 2 (obese) were more than 20% but less than 45.5 kg over ideal body weight. Group 3 (morbidly obese) were more than 45.5 kg over ideal body weight. Patients were preoxygenated for 5 min or until expired nitrogen was <5%. After induction of anesthesia and muscle relaxation the patients were allowed to remain apneic until arterial saturation as measured by pulse oximetry reached 90%. The time taken for oxygen saturation to decrease to 90% was 364 ± 24 s in group 1, 247 ± 21 s in group 2, and 163 ± 15 s in group 3; these times are significantly different at P < 0.05 between groups. Regression analysis of the data demonstrated a significant negative linear correlation (r = -0.83) between time to desaturation and increasing obesity. These results show that obese patients are at an increased risk of developing hypoxemia when apneic.

•

Bentley JB, Borel JD, Vaughan RW, Gandolfi AJ.Weight, pseudocholinesterase activity, and succinylcholine requirement. Anesthesiology. 1982

Jul;57(1):48-9.

Puhringer FK, Keller C, Kleinsasser A, et al. Pharmacokinetics of rocuronium bromide in obese patients. Eur J Anaesthesiol 1999; 16:507-10.

• 0.6 mg kg-1 rocuronium,• 6 obesi vs 6 controli • balanced anaesthesia. • Venous plasma concentrations were determined by high-pressure liquid

chromatography before administration of rocuronium, at 1, 2, 4, 6, 8, 10, 15, 20, 25, 30, 35, 40, 48, 60, 75, 120, 180, 240, 300, 360 and 420 min after administration of rocuronium and at recovery of single twitch to 25% and 75% of control twitch heigh

• Onset time was shorter (NS) in the obese compared with normal weight (obese weight: 65 +/- 16, normal weight: 100 +/- 39 s, mean +/- SD). Duration 25% (obese weight: 29.5 +/- 5.3, normal weight: 28.4 +/- 5.3 min) and spontaneous recovery time (obese weight: 12.6 +/- 2.7, normal weight: 12.5 +/- 2.3 min) did not show any differences between the two groups.

• The pharmacokinetics of rocuronium were comparable in the two groups. The volume of distribution at steady state Vss (mL kg-1) was 208 +/- 56 in normal weight and 169 +/- 37 in obese weight. Distribution (T1/2 alpha) and elimination half-life (T1/2 beta) as well as mean residence time were 15.6 +/- 3.7, 70.3 +/- 23.9 and 53.2 +/- 9.8 min in normal weight and 16.9 +/- 3.8, 75.5 +/- 25.5 and 51.1 +/- 18.9 min in obese weight, respectively. Also, no differences were observed in plasma clearance (3.89 +/- 0.58 in normal weight and 3.62 +/- 1.42 mL kg-1 min-1 obese weight). This study indicates that the pharmoacodynamics and pharmacokinetics of rocuronium are in female patients not altered by obesity.

Puhringer FK, Khuenl-Brady KS, Mitterschiffthaler G. Rocuronium bromide: time-course of action in

underweight, normal weight, overweight and obese patients. Eur

J Anaesthesiol 1995; 12(suppl. 11):107-10.

• The pharmacokinetics of rocuronium bromide are similar to those of vecuronium, although with minor volume of distribution and no active metabolites . Puhringer et al. showed that obese patients receiving rocuronium had a slightly longer duration of action compared with normal weight patients, but this finding did not achieve statistical significance, whereas in another study by the same authors there was no difference in duration between two similar groups . To the contrary, in a study by our group we demonstrated, with statistical significance, a considerably prolonged duration of action after administration of rocuronium in morbidly obese patients compared with NBW patients (55.5 minutes versus 24.4 minutes). The reason for the difference observed between our study and Puhringer et al.'s is probably related to the obesity class to which the patients belonged. In our study patients belonged to the morbid obesity class (BMI 43.8 ± 2.1) whereas in Puhringer et al.'s to the moderate obesity class (BMI 33.5 ± 4.4). Accordingly the total dose of rocuronium administered was significantly larger in our patients, thereby explaining the statistical difference that Puhrigner et al. were not able to meet.

Spoelders K, van Duffel L, Vandermeersch E, Adriaenssens G, Van de Velde M. Recovery of neuromuscular block in morbidly obese patients following an infusion of rocuronium.Acta Anaesthesiol Belg. 2001;52(3):293-5.• :

Oberg B,Poulsen TD.Obesity:an anesthetic challenge.Acta Anesthesiol.Scand.1996;40;191-

200.

Domande corso ECM

• 1) le benzodiazepine ;in generale,nell’obeso devono essere somministrate in dose:

• A)iniziale proporzionale al peso totale,ma poi ridotta nel mantenimento;

• B)ridotta sia nella dose iniziale che nel mantenimento;

• C)poichè sono altamente lipofile,devono essere somministrate in aumento nella dose iniziale e nel mantenimento

• Risposta esatta a)

Domande per ecm

• La dose di propofol da somministrare nell’obeso è stata individuata come:

• A)2 mg/kg *(TBW-IBW)

• B) 2 mg/kg* TBW(peso totale)• C) 2 mg/kg * IBW(peso ideale)• D) 2 mg/kg* Peso corretto(che è

=IBW + 0.4 * eccesso di peso)• Risposta esatta :d)

Domande per ecm

• Le concentrazioni plasmatiche da impostare su una pompa TCI nella sedazione per un obeso sono:

• A)superiori a quelle dei pazienti normopeso

• B)inferiori a quelle dei pazienti normopeso

• C)eguali a quelle dei pazienti normopeso

• Risposta esatta:c)

Domande per ecm

• Le durate di azione di vecuronium e atracurium somministrati a 2ED 95 µkg /di TBW si comportano differentemente in pazienti normali e obesi:

• a)vero:il vecuronium dura molto di più dell’atracurium

• B)falso:le durate di azione sono simili• C)vero per il vecuronium e falso per

l’atracurium

Domande per ecm

• La dose di succinilcolina da somministrare nell’obeso per intubazione(1 mg/kg):

• A) È da ridurre,somministrando una dose in base al peso ideale e non al tbw

• B)è da somministrare la dose piena in relazione al peso totale tbw

• C)poichè le pseudocolinesterasi sono aumentate ,s i puo aumentare la dose > 1 mg/kg

• The simulations we made in this study show that elderly individuals should receive one half the bolus dose and one third the infusion rate of young individuals. These conclusions depend on both pharmacokinetic and pharmacodynamic factors. The reduction in the volumes, clearances, and ke0 that occur in the elderly result in little change in the Vdpe. The decreased bolus requirement in the elderly is due to the age-related decrease in EC50 found using the EEG model of drug effect. The lower infusion rate requirement in the elderly is a result of the age-related decrease in both metabolic clearance and EC50. Although the time to the peak effect site concentration is almost twice as long in the elderly as the young, the bolus and infusion simulations ( and ) revealed a rapid onset (and more prolonged duration) of EEG effect in the elderly, when the dose was not adjusted for age. These findings are explained by the sigmoid Emax model. The age-related changes in pharmacokinetics and pharmacodynamics, together with the relative overdose, result in effect site concentrations that increase more quickly and stay higher (relative to the EC50) for a much longer period. The adjustment of bolus and infusion rates according to the nomograms presented resulted in a similar distribution of peak EEG effect after a bolus, steady-state EEG effect after an infusion, and time course of EEG effect in all age groups. ………………………

• 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.

Egan TD,Huizinga B,Gupta SK,Jaarsma RL,Sperry RJ,Yee JB,Muir KT.Remifentanil Pharmacokinetics in Obese versus Lean Patients Anesthesiology89:562-73, 1998

• ABSTRACT: • Background: Remifentanil is a short-acting opioid whose pharmacokinetics have been

characterized in detail. However, the impact of obesity on remifentanil pharmacokinetics has not been specifically examined. The goal of this study was to investigate the influence of body weight on remifentanil pharmacokinetics.

• Methods: Twelve obese and 12 matched lean subjects undergoing elective surgery received a 1-min remifentanil infusion after induction of anesthesia. Arterial blood samples were collected for determination of remifentanil blood concentrations. Each subject's pharmacokinetic parameters were estimated by fitting a two-compartment model to the concentration versus time curves. Nonlinear mixed-effects population models examining the influence of lean body mass (LBM) and total body weight (TBW) were also constructed. Clinical simulations using the final population model were performed.

• Results: The obese patient cohort reached substantially higher remifentanil concentrations. The individual pharmacokinetic parameters of a two-compartment model were not significantly different between the obese versus lean cohorts (unless normalized to TBW). The final population model scaled central clearance and the central and peripheral distribution volumes to LBM. The simulations illustrated that remifentanil pharmacokinetics are not grossly different in obese versus lean subjects and that TBW based dosing in obese patients can result in excessively high remifentanil concentrations.

• Conclusions: The essential findings of the study are that remifentanil's pharmacokinetics are not appreciably different in obese versus lean subjects and that remifentanil pharmacokinetic parameters are therefore more closely related to LBM than to TBW. Clinically this means that remifentanil dosing regimens should be based on ideal body weight (or LBM) and not TBW.

•

Song D,Whitten CW,White PF. Remifentanil Infusion Facilitates Early Recovery for Obese Outpatients Undergoing Laparoscopic Cholecystectomy Anesth Analg 2000; 90:1111–3

• sevo vs remif con dosi salvataggio di sevo o remif con fent

Tempi di ripresa dopo anest con sevoflurane o remifentanilSong D,Whitten CW,White PF. Remifentanil Infusion Facilitates Early Recovery for Obese Outpatients Undergoing Laparoscopic Cholecystectomy Anesth Analg 2000; 90:1111–3

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risveglio estubaz arrivo Pacu orientamento

remifentanil

sevoflurane

Degenza Pacu e dimissione =

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



• Pharmacokinetic mass-Shafer = 52/(1 + PE-Shafer-reg) = 52/Correction factor; i.e., 52/[1 + (196.4 ´ e-0.025kg - 53.66)/100].

• Pharmacokinetic mass-Shafer increases exponentially as TBW increases (). When TBW exceeds 140 kg, increases in pharmacokinetic mass appear less, implying that increases of metabolism and distribution may be small beyond this body weight.

• Pharmacokinetic mass was derived similarly from the Scott and Stanski model. PE-Scott is close to zero at body weight of 82 kg. Therefore, 82 kg was used as a reference body weight in calculating pharmacokinetic mass. The formula for pharmacokinetic mass derived from the Scott-Stanski model (“pharmacokinetic mass-Scott”) is as follows, and the curve in relationship to TBW is shown in : Pharmacokinetic mass-Scott = 82/(1 + PE-Scott-reg); i.e., 82/[1 + (266.8 ´ e-0.025kg - 34.74)/100].

• Pharmacokinetic mass-Shafer and pharmacokinetic mass-Scott have similar profiles and similar absolute relationships to TBW. Between body weights of 52 kg and 100 kg, both pharmacokinetic mass curves have almost identical linear slopes of approximately 0.65. When TBW exceed 140 kg, both of the pharmacokinetic mass curves flatten considerably.

pk e pd nell'obesità per firenze 20 maggio

Health & Medicine

measured weight ibw

ibw females

ibw femmina

sono obesi

women excess weight

weight 148weightheight2

weight 128weightheight2

women cbwcorrected body