Pharmacokinetic and pharmacodinamic sedation.pdf

7/26/2019 Pharmacokinetic and pharmacodinamic sedation.pdf

1/15

Clin Pharmacokinet 2006; 45 (9): 855-869REVIEWARTICLE 0312-5963/06/0009-0855/$39.95/0

2006 Adis Data Information BV. All rights reserved.

Pharmacokinetic andPharmacodynamic Characteristicsof Medications Used forModerate SedationTong J. Gan

Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina, USA

Contents

Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8551. Optimal Sedation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8562. Pharmacokinetic Properties of Sedative Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 857

2.1 Midazolam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8572.2 Propofol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8592.3 Ketamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8602.4 Sevoflurane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8602.5 AQUAVAN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 860

3. Relationship between Pharmacokinetic Parameters and Pharmacodynamic Effects . . . . . . . . . . . . 861


4. Drug Combinations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8635. Safety Issues and Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 863


6. Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8656.1 Midazolam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8656.2 Propofol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8656.3 Sevoflurane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8666.4 AQUAVAN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 866

7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 866

The ability to deliver safe and effective moderate sedation is crucial to theAbstractability to perform invasive procedures. Sedative drugs should have a quick onset

of action, provide rapid and clear-headed recovery, and be easy to administer and

monitor. A number of drugs have been demonstrated to provide effective sedationfor outpatient procedures but since each agent has its own limitations, a thorough


2/15

856 Gan

knowledge of the available drugs is required to choose the appropriate drug, dose

and/or combination regimen for individual patients. Midazolam, propofol,

ketamine and sevoflurane are the most frequently used agents, and all have a quick

onset of action and rapid recovery. The primary drawback of midazolam is the

potential for accumulation of the drug, which can result in prolonged sedation and

a hangover effect. The anaesthetics propofol and sevoflurane have recently been

used for sedation in procedures of short duration. Although effective, these agents

require monitored anaesthesia care. Ketamine is an effective agent, particularly in

children, but there is concern regarding emergence reactions. AQUAVAN

injection (fospropofol disodium), a phosphorylated prodrug of propofol, is an

investigational agent possessing a unique and distinct pharmacokinetic and phar-

macodynamic profile. Compared with propofol emulsion, AQUAVANis asso-

ciated with a slightly longer time to peak effect and a more prolonged

pharmacodynamic effect. Advances in the delivery of sedation, including the

development of new sedative agents, have the potential to further improve the

provision of moderate sedation for a variety of invasive procedures.

The use of sedation for interventional procedures ate for moderate sedation during interventional pro-

cedures.[3,6,9,13-15] These agents have distinct phar-has become commonplace in a number of settings,

macokinetic and pharmacodynamic properties thatincluding endoscopic procedures (e.g. colonoscopy,

affect how they may be optimally used, either alonebronchoscopy, gastroscopy), cardiac catheterisation,

or in combination with other agents.outpatient oral/maxillofacial surgery and the emer-

This article reviews the individual sedationgency department.[1-3]For example, the increase in

profiles and pharmacokinetic and pharmacodynamicthe number of patients undergoing screening for

characteristics of the most commonly used agentscolorectal cancer by endoscopy has been accompa-

for moderate sedation during interventional proce-nied in most settings by an increased use of sedation

dures. These include the benzodiazepine midazo-for control of pain and discomfort during colonosco-lam, the sedative/hypnotic agents propofol andpy.[4]Agents that deliver moderate sedation are ap-ketamine, the inhalational agent sevoflurane and apropriate for these procedures because they providenovel sedative hypnotic in clinical development,quick recovery time, few sedation-related adverseAQUAVAN 1 (fospropofol disodium) injection.events and greater overall patient satisfaction.[5,6]

Important interactions of these agents with otherThe use of moderate sedation is also expanding tosedation agents are also presented to increase practi-include administration by nurse specialists and othertioners understanding and use of sedation tech-non-anaesthesiologists in the endoscopy setting, and

niques and to improve patient satisfaction and out-by the use of patient-controlled sedation (PCS).[7-11]

comes.Moderate sedation is defined as that level of

sedation in which patients are lethargic but respon-1. Optimal Sedation

sive to verbal or tactile stimulation and able to

maintain their own airway.[12] In the past, this has Physicians strive to provide an optimal level of

been referred to as procedural or conscious sedation. sedation for the individual patient and the particular

A number of drugs, including midazolam, propofol, procedure. The goal is to allow patients to tolerate

ketamine, fentanyl, remifentanil, meperidine and in- unpleasant procedures by relieving anxiety, discom-

haled anaesthetics, have properties that are appropri- fort and pain and to expedite completion of the

1The use of trade names is for product identification purposes only and does not imply endorsement.

2006 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2006; 45 (9)


3/15

PK/PD of Drugs for Moderate Sedation 857

procedure. To this end, sedative drugs need to be pharmacodynamic profiles of inhalational agents are

titrated to effect to reach an optimal level of sedation primarily determined by their physiochemical

and to avoid complications. The ability to achieve properties; common pharmacokinetic properties

the desired level of sedation is based on the charac- (e.g. protein binding, metabolism, renal excretion)teristics of the various sedative drugs. However, the have little impact on the pharmacodynamic profile

wide variability in the temporal and dose-related of the drug.[22] The physiochemical properties of

response to various sedation agents dictates careful sevoflurane are summarised in table II.

administration and monitoring of sedation in indi-

vidual patients. 2.1 Midazolam

The characteristics of an ideal agent for moderateMidazolam is highly lipophilic, resulting in rapidsedation have not been established by consensus

distribution into the CNS and adipose tissues.[17]opinion but are accepted to include rapid onset ofThese properties allow the drug to reach the site ofaction, quick recovery of cognitive and physicalaction rapidly, producing an onset of action in 12faculties following the procedure and a predictableminutes. However, the drug has a longer time topharmacokinetic/pharmacodynamic profile.[16]Eachpeak effect compared with propofol, making thisavailable sedation agent possesses characteristicsdrug less suitable for PCS.[39]Rapid recovery fromthat help dictate its best use and define its limita-sedation with midazolam results from the rapid re-tions.[17,18] A greater understanding of sedationdistribution of the drug from the brain to peripheralagents will help physicians choose the correct drug,tissues.[23] Although midazolam is well absorbeddose and combination to provide the best possibleafter oral administration, the relatively high first-sedation for their patients.pass hepatic metabolism of the drug results in oralThe availability of improved drug assay tech-bioavailability values ranging from 31% to 72%.[17]niques and pharmacokinetic modelling programmesThus, oral doses of midazolam are approximatelyand the introduction of reliable infusion systems has

twice those of the intravenous route.also led to an increased use of target-controlledMidazolam is eliminated by both hepatic andinfusions (TCIs) of anaesthetic agents.[19]TCI sys-

renal routes.[17]Hepatic metabolism is primarily viatems are pharmacokinetically based computer-con-oxidation to three metabolites (-hydroxymidazo-trolled infusion systems designed to automaticallylam, 4-hydroxymidazolam and ,4-hydroxymidazo-adjust the rate of infusion to maintain a desiredlam) that are subsequently excreted as glucuronide(target) concentration. These systems can also beconjugates.[17] Midazolam has a relatively highcombined into a patient-maintained sedation systemclearance rate that is partially dependent on hepaticin which target levels of the sedative agent areblood flow rate.[23]maintained via a computer-controlled infusion sys-

The pharmacokinetic parameters of midazolamtem in response to patient demand.[20]Because of itsare variable and are dependent on the patient popu-short-acting pharmacokinetic profile, propofol haslation and the study design.[40,41]Age, bodyweight,become the most frequently infused drug via TCIand hepatic and renal function influence the elimina-and a proprietary system for propofol is available.[21]

tion of midazolam. In elderly and obese patients and

those with hepatic impairment, midazolam has a2. Pharmacokinetic Properties ofreduced clearance and prolonged half-life comparedSedative Agentswith those patients without these characteris-

Table I lists the pharmacokinetic and pharmaco- tics.[17,23,38,42]For example, in patients with cirrhosis,

dynamic properties of propofol, midazolam, the clearance of midazolam was halved and the half-

ketamine and AQUAVAN, a water-soluble life of the drug was doubled compared with patients

prodrug of propofol that is in clinical development with normal hepatic function.[38]Patients with renal

for moderate sedation during colonoscopy. The impairment have a higher free fraction of midazo-



4/15

858 Gan


T

ableI.Comparativepharmacokinetican

dpharmacodynamicparametersofmidazolam,propofol,AQUAVAN-produced

propofolandketamine[3,17,23-36]a

P

arameter

Mid

azolam

Propofolemulsion(Diprivan)

Propofolprodrug(AQUAVAN)

Ketamine(racemic)

C

ompartmentsofdistribution

Twocompartments

Threecompartments

Twocom

partments(prodrug)

Twocompartmentsor

m

odelling

Threecompartments

noncompartmental

(AQUAVA

N-derivedpropofol)

P

roteinbinding(%)b

95

97

9799

9799

7075

A

queoussolubility

Hig

h(atpH4)

M

etabolism

Hepatic(oxidation,

Hepatic

(hydroxylation,

Hepatic(hydroxylation,

Hepatic(dem

ethylation)

con

jugation)

conjugation)

conjugation)

D

oseb

bolus(mg/kg)

2.5

5mg

1.02.5

7.5,10.0,12.5

0.251.0

IVinfusiontargetplasma

35

35

concentration(g/mL)

V

ss(L/kg)c

13

.1b

4.52.1

12.44.6

2.13.3

b

t1/2

(min)[fast]

108

384b

4.70.8

2.51.2

711b

t1/2

(min)[intermediate]

58.217.9

26.39.3

130180b

t1/2(min)[terminal]

65119

4(residual)

543223

(residual)

C

L(L/h/kg)b

0.2

50.54

1.12.11

0.542.28

0.941.2

R

enalexcretion(%)

45

57b

>1

NR

2.3

P

harmacodynamicparameter

E

C50

31

ng/mL

3.00.7

g/mL

2.10.5

g/mL

NR

S

edationandrecoveryafterIVbolusadm

inistration

onsetofsedation(min)

1.0

2.5

b

2.11.2

2.0

d

0.5

durationofsedation(min)

10

20b

48b

NR

510b

timetofullyalert(min)

25

39b

14.46.5

11.0

d

NR

S

edationandrecoveryafterIVinfusiona

dministration

onsetofsedation(min)

8d(range421)

132

92

NR

timetofullyalert(min)

51.

66.6e

8226

12817

a

ValuesareexpressedasmeanSD

unlessspecifiedotherwise.

b

Range.

c

Assumesanaverageweightperpatientof70kg.

d

Median.

e

MeantimeSDtofullrecoveryand

discharge.

C

L=totalbodyclearance;EC50=blood

concentrationassociatedwithlossofconsciousnessin50%o

fpatients;IV=intravenous;NR

=notreported;t1/2

=initial

half-life;t1/2

=

intermediatehalf-life;t1/2=terminalhalflife;Vss=volumeofdistributionatstead

ystate.


5/15


phase of elimination (t1/2) of approximately 23

minutes that represents the distribution of the drug

into body tissues. The second phase is longer and

represents the metabolism of propofol (t1/2= 3060minutes), while the third much longer and highly

variable phase represents the slow elimination of the

drug from poorly perfused fat tissue (t1/2 = 245

hours).[17] As expected with a lipid-soluble com-

pound, propofol has a very large volume of distribu-

tion (Vd).[24,44]Propofol initially distributes to well

perfused tissue, then to lean tissue and finally to fat

Table II. Physical characteristics of sevoflurane and other inhala-

tion anaesthetic agents[22,37]

Parameter Sevoflurane Desflurane Nitrous oxide

Boiling point (C) 58.6 23.5 NR

Vapour pressure at 20C 157 669 NR

(mm Hg)

Potency (MAC)[38] 1.72.05 6 104

Partition coefficient (solubility)

oil : gas 47.253.4 18.7 1.4

blood: gas 0.68 0.42 0.47

MAC = minimum alveolar concentration (i.e. concentration that

produced immobility in 50% of individuals exposed to a noxious

stimulus); NR= not reported.

deposits.[24]

lam compared with healthy controls (6.5% vs 3.9%) Propofol is primarily (88%) eliminated as

because of a reduction in serum albumin concentra- sulphate and/or glucuronide conjugates in the urinetions.[17,23]This is significant because an increased with


6/15

860 Gan

significantly alter the pharmacokinetics of pro- 2.5 AQUAVAN

pofol.[44]

AQUAVAN, a new sedative/hypnotic agent, is

2.3 Ketamine a water-soluble prodrug of propofol that is currentlyin clinical development in the US. After intravenousKetamine is an antagonist of N-methyl-D-as-administration, propofol is released from thispartate (NMDA) receptors and is structurally relatedprodrug by the enzymatic action of alkaline phos-to phencyclidine.[47]The drug is highly lipid soluble,phatases in the vascular endothelium.[51]This actionresulting in extensive distribution to peripheral sitesprovides predictable and controlled release of pro-(including the CNS) as evidenced by its relativelypofol with a smooth rise to therapeutic plasma pro-large Vd.[48] The drug exhibits a biphasic plasmapofol concentrations. The pharmacokinetics ofconcentration-time curve characterised by a rapidAQUAVANare best described by a two-compart-elimination phase lasting approximately 45 minutes,ment model,[51]while AQUAVAN-delivered pro-which corresponds to the analgesia period (t1/210

pofol (once converted) is best described by a three-minutes). This is followed by a longer elimination compartment model.[26]The parent compound has ahalf-life that represents redistribution from the CNSrelatively fast distribution to the peripheral compart-and hepatic metabolism (t1/2 = 23 hours).[25]

ment, a small Vdand a short terminal half-life (t1/2=Ketamine is primarily eliminated via hepatic metab-3846 minutes), whereas AQUAVAN-deliveredolism with conversion to an active metabolitepropofol, as expected, is lipophilic and has large(norketamine). Elderly patients appear to have aperipheral compartments (as described previous-lower clearance and prolonged duration of actionly).[26,51]compared with younger adult patients.[49]There are

modest pharmacokinetic differences between the S+ Despite producing the same active compound,and R+ enantiomers, with the clearance of the S+ AQUAVAN-delivered propofol has a differentenantiomer being somewhat greater than that of the pharmacokinetic and pharmacodynamic profile thanR+ enantiomer.[25] propofol emulsion. For example, in experimental

animals AQUAVAN-delivered propofol had a2.4 Sevoflurane longer elimination half-life, a larger Vd, and a

delayed onset of action compared with propofolSevoflurane has a low blood : gas solubility thatemulsion.[52] Differences between propofol emul-produces a rapid uptake and elimination of thesion and AQUAVAN-delivered propofol were al-agent.[22,37]In healthy volunteers, the alveolar FA/FIso seen in healthy volunteers, although the type ofof sevoflurane (the rate at which fractional end-tidaldifferences varied from those seen in animals. Pro-alveolar concentration [FA] approaches the fraction-pofol from AQUAVAN had a longer residenceal inspired concentration [FI]) was 0.85 (i.e. wash-time, larger Vd, higher clearance and shorter elimi-in).[37]This increase was more rapid than that seen

nation half-life than propofol emulsion.[26]with isoflurane or halothane but somewhat slower

The time course of plasma propofol concentra-than that seen with nitrous oxide and desflurane.[37]

tions is also different between propofol emulsionSimilarly, the washout of sevoflurane is faster than

and AQUAVAN-delivered propofol, the latterthat of isoflurane but slower than that of desflurane.

having lower peak concentrations and more pro-Elimination of the drug is primarily via the pulmo-

longed plasma concentrations (figure 2).[26] Dosenary route. A small proportion of the absorbed dose

escalation of AQUAVAN results in a less thanof sevoflurane (15%) is metabolised via cyto-

proportional increase in exposure to AQUAVAN-chrome P450 (CYP) 2E1, liberating inorganic fluo-

delivered propofol as measured by maximum plas-ride ions and hexafluoroisopropanol.[37] However,

ma concentration (Cmax) and area under the plasmasevoflurane undergoes minimal renal defluorina-

concentration-time curve (AUC).[53]

tion.[50]



7/15


tinct hysteresis between plasma concentrations and

CNS effects,[55] and the greater sensitivity to the

CNS depressant effects of midazolam among elder-

ly patients that is not explained by changes inpharmacokinetics.[55]In addition, midazolam has al-

so been shown to have both stimulatory and sedative

properties,[60,61]with stimulatory effects seen shortly

after infusion in small percentages of patients.[62]

This effect may explain why the drug is associated

with rebound adverse effects and tolerance.[60]

As noted earlier, protracted administration of

midazolam can produce prolonged sedation due to

accumulation of midazolam and its active metabo-

lite in adipose tissue from which it is slowly re-leased.[17,63]The risk of such accumulation is great-

est in patients with renal impairment but can also

occur in those with normal renal function. The

benzodiazepine antagonist flumazenil is effective

for reducing the residual effects (especially seda-

tion) of midazolam, although the duration of action

of a single dose of flumazenil may be shorter than

the hangover effect of midazolam.[64,65]

3.2 Propofol

Time (min)

P

ropofolconcentration(g/mL)

0 120

0

2

4

6

8

10

20 40 60 80 100

0.01

0.1

1

10

0 1440480 960

0

2

4

6

8

10

0.001

0.01

0.1

1

10

0 1440480 960

a

b

Fig. 2. Plasma concentration-time curve for (a) propofol emulsion

and (b) AQUAVAN-delivered propofol in healthy volunteers. The

insets show the complete plasma concentration-time courses (re-

produced from Fechner et al.,[26]with permission).

3. Relationship betweenThe plasma concentration of propofol required

Pharmacokinetic Parameters andfor sedation depends on the desired depth of seda-

Pharmacodynamic Effectstion and whether concomitant agents are used.[44]In

general, propofol produces sedation in a dose-de-

pendent fashion, with lower plasma concentrations3.1 Midazolam (0.51.5 g/L) needed for sedation and substantially

higher plasma concentrations (316 g/L) requiredfor surgical anaesthesia.[44]Loss of consciousness isMost, but not all, evidence suggests that there is a

typically reported at concentrations ranging fromwide range of midazolam blood levels associated

3.5 to 10.5 g/L.[24]There is also an inverse correla-with adequate sedation.[54-57]The level of sedationtion between plasma propofol concentrations andappears to correlate better to the level of receptor

mean EEG frequency, and a direct correlation withbinding,[57]although some have found the correla-

mean EEG amplitude.[24]However, there is substan-tion is relatively poor.[56]In addition, this correlation

tial variability in the concentrations of propofol atis likely to be impaired in those with alterations in

the site of a drug effect that induces loss of respon-benzodiazepine receptor density (e.g. alcoholics) as

siveness. The effect may be due to a complex inter-demonstrated by a decreased sensitivity to

action between the dose, rate of administration andbenzodiazepines in these patients.[58,59]Further com-

time of propofol induction, which may influence theplicating the pharmacokinetic/pharmacodynamic re-

rate of plasma effect-site equilibration.[24,66]

sponse of midazolam are the observations of a dis-



8/15

862 Gan

3.3 Ketamine two patients with 1.3%1.5% end-tidal sevoflurane

concentrations were responsive to voice at BISKetamine has general anaesthetic properties most

scores of 41 and 52.[71]prominently characterised by profound analgesia,

acting as an antagonist on the NMDA receptor.3.5 AQUAVAN

Unlike opioid analgesics, ketamine does not ad-

versely affect respiratory or cardiovascular stabili- In rats, AQUAVAN-delivered propofol was as-ty.[49]However, tachycardia was reported in 27.9% sociated with a delayed onset, a sustained durationof children sedated with ketamine and midazolam of action and greater potency compared with pro-who were undergoing minor surgical procedures.[67] pofol emulsion with respect to plasma concentra-The drug has a rapid onset of action (0.5 minute) and tion.[52] Initial studies in healthy volunteers founda short duration of action. The CNS depressant that propofol from AQUAVANhad a higher po-effects of ketamine are dose dependent, with con- tency than propofol emulsion with respect to plasmacentrations of 0.62.0 g/mL associated with gener- concentration and did not show a hysteresis between

al anaesthesia.[68] In children receiving postopera- plasma concentrations and effect.[26]However, an-tive analgesia and sedation following cardiac sur- other study found that when corrected for the braingery, the children were arousable when ketamine concentration of propofol, the pharmacodynamic ef-concentrations fell below 1.01.5 g/mL.[69] fect of AQUAVAN-delivered propofol was simi-

lar to that of propofol emulsion.[72]3.4 Sevoflurane

Fechner et al.[27]demonstrated in healthy volun-

teers that continuous infusions of AQUAVAN-Sevoflurane has been investigated for providing

produced, dose-dependent sedation, as measured bysedation because of its rapid onset and offset as well

the BIS and the Modified Observers Assessment ofas its non-pungent property, which makes inhalation

Alertness/Sedation (MOAA/S) scale. Probabilityof this agent tolerable. Sevoflurane produces dose-

curves from logistic regression analysis indicateddependent depressant effects on the central nervous,that an AQUAVAN-delivered propofol plasmarespiratory and cardiovascular systems.[37,50]In gen-

concentration of 1.85 g/mL or an initial intrave-eral, sedation with sevoflurane is associated withnous bolus dose of about 10 mg/kg of AQUAVANmore rapid recovery and faster return of cognitive

had the highest probability of producing an MOAA/function than with midazolam.[70]In a randomised,

S score of 3, corresponding to a moderate level ofcomparative study in patients receiving sedation for

sedation.[27,28] Gibiansky et al.[53] found that thesurgery, 76% of patients receiving sevoflurane had

dose-response relationship for AQUAVAN-deliv-return of cognitive function 30 minutes postopera-

ered propofol was curvilinear, with a linear relation-tively compared with 35% of midazolam-treated

ship observed at doses up to 20 mg/kg.patients.[70]

The concentrations of sevoflurane required to A physiological model was used to compare the

produce sedation are variable. In patients who were pharmacokinetics and pharmacodynamics (BIS

slowly titrated to a moderate level of sedation with analysis) of propofol produced after intravenous

sevoflurane prior to surgery, there was a wide inter- infusion or bolus administration of AQUAVAN

and intraindividual variability between end-tidal with those of propofol emulsion.[73]This model took

sevoflurane concentrations and depth of sedation as into account the nonlinear protein binding of pro-

assessed by the bispectral index (BIS), a processed pofol and the metabolism of propofol in the liver and

EEG measure between 0 (no electrical activity) and other tissues (e.g. venous endothelium) prior to en-

100 (awake), which makes it difficult to predict tering into the systemic circulation. Compared with

depth of sedation.[71] For example, many patients a continuous infusion of propofol emulsion (50 mg/

with 1% end-tidal sevoflurane concentrations were minute), bolus injection of an equipotent dose of

unresponsive to voice at a BIS score of 98, whereas AQUAVANproduced an equivalent time to loss



9/15


of consciousness. However, AQUAVANwas as- meperidine) achieved a moderate level of sedation

sociated with a longer time to peak BIS and a more and measures of recovery that were comparable to

prolonged pharmacodynamic effect.[73] This was those of standard-dose propofol.[6]Benzodiazepines

probably related to a slower decrease in concentra- are frequently added to ketamine to reduce emer-tions of AQUAVAN-delivered propofol. In addi- gence reactions but may be associated with an in-

tion, AQUAVAN-delivered propofol plasma con- creased risk of hypoxaemia.[77]

centrations were predictive of effect-site concentra- Initial studies also suggest that AQUAVANcan

tions and clinical effect, although there were be effectively combined with other agents. Intrave-

concentration-related differences in the equilibra- nous bolus administration of AQUAVAN

tion time (Ke0= 1.2 minute1at AQUAVAN30 (7.512.5 mg/kg) following pretreatment with intra-

mg/kg dose) between plasma and effect-site concen- venous fentanyl (0.51.5 g/mL) induced sedationtrations.[73] adequate for colonoscopy within 2 minutes of ad-

ministration. Recovery to fully alert occurred within

11 minutes (median time) after end of procedure.[28]4. Drug Combinations

5. Safety Issues and Adverse EventsSedation regimens for moderate sedation fre-quently include the use of more than one agent, such

In addition to the normal concerns with overseda-as a hypnotic/anxiolytic (e.g. propofol, midazolam)

tion and the associated cardiopulmonary risks, ade-plus an opioid (e.g. fentanyl, remifentanil, meper-

quate and safe sedation in critically ill or high-riskidine) for the purpose of anaesthesia and analgesia.

patients is the primary measure of a good sedationThese combinations have been used with different

agent.[78]High-risk patients may include those withdegrees of patient satisfaction and procedural suc-

end-stage renal disease, chronic liver disease, orcess, and there are limited definitive data demon-

compromised cardiac or pulmonary function. Otherstrating the superiority of combination regimens

patient factors such as age and weight should also be

over single agents. For example, in a randomised taken into account when calculating dosage.study comparing propofol plus remifentanil with

Dexmedetomidine, a highly selective 2-adre-propofol alone in patients undergoing colonoscopy,noceptor agonist with sedative and analgesic effects

the addition of remifentanil resulted in a decreasedused for sedating patients in the intensive care

requirement for propofol.[74] However, patients inunit,[79]has a limited role in providing sedation and

the combination group experienced more respiratoryanalgesia for colonoscopy because of the drugs

and blood pressure depressant effects and had acomplicated administration regimen, prolonged re-

lower recovery and lower patient satisfaction thancovery time, pronounced haemodynamic instability

with propofol alone.and distressing adverse effects.[80]A dose sufficient

A number of trials have attempted to quantify theto produce sedation during colonoscopy results in

optimal concentrations of sedation agents that are

profound hypotension and bradycardia.[80]

used in combination (e.g. propofol emulsion/various

opioids),[75]or compared sets of different drug com-5.1 Midazolam

binations.[9] For example, low-dose midazolam

(0.03 mg/kg) plus a bolus dose of propofol (0.7 mg/ Since midazolam is highly protein bound, hy-

kg) followed by patient-controlled infusion of pro- poalbuminaemia may result in increased distribution

pofol (2 mg/kg/h) improved the levels of patient of the drug into the CNS, leading to increased seda-

acceptability and comfort during apicectomy com- tion effects.[17]The reduced clearance of midazolam

pared with the levels achieved with propofol in patients >65 years of age means that doses ap-

alone.[76] In another study, low-dose propofol (i.e. proximately half those used in younger patients are

mean 98mg for colonoscopy and 79mg for gastros- required to produce an equivalent level of seda-

copy) combined with midazolam and fentanyl (or tion.[17]

There are also a number of patient groups



10/15

864 Gan

(e.g. elderly, critically ill, those with hepatic dys- propofol is injected into the dorsum of the hand

function) who have decreased clearance of midazo- compared with the forearm or antecubital fossa.[86]It

lam. These patients should receive reduced doses has been suggested that the lipid solvent of propofol

and should be monitored for excessive seda- induces the release of bradykinin by activating thetion.[38,42] plasma kallikrein-kinin system, resulting in a modi-

fication of the local vein that increases the contact

between the aqueous phase of propofol and the free5.2 Propofolnerve endings of the vessel.[87]Concomitant use of a

Some of the limitations of propofol emulsion and local anaesthetic agent (e.g. lidocaine [lignocaine])its adverse effects include the risk of extraneous is commonly used to reduce local pain.[88]This canmicrobial contamination of the emulsion formula- include the administration of lidocaine immediatelytion, lipidaemia induced by repeated administration prior to propofol, the mixing of propofol with lido-of the agent over time, intravenous injection site caine or the use of topical EMLAcream (eutecticpain, oversedation and risk of hypotension/cardi- mixture of local anaesthetics).[86]Other methods ofopulmonary complications. Although short-term in- reducing local pain included administration of anfusions of propofol emulsion (3 days) have no opioid, metoclopramide, cold saline or topical nitro-effect on lipid levels, longer infusions produce pro- glycerin prior to propofol.[86]

gressive increases in serum lipid levels, particularlySeveral recent studies demonstrated the feasibili-

triglycerides.[44]Green discoloration of the urine canty and safety of propofol sedation administered by

also be seen after long-term administration, al-gastroenterologists, nurses and patients in short-

though its significance is not known.[81]There areterm endoscopic procedures.[8,9,89-92] For example,

also concerns about the safety of propofol for proce-nurse-administered propofol was associated with

dural sedation because of possible problems withfaster recovery, quicker discharge and better postop-

hypoxaemia, hypotension and decreased cardiacerative neuropsychological test scores than with

output when administered by non-anaesthesiolo- midazolam plus fentanyl in patients undergoing out-gists.[82] Propofol has well established respiratory

patient colonoscopy.[90]Similarly, PCS for colonos-depressant effects, particularly at anaesthetic doses

copy with propofol plus alfentanil produced fasterand when used in combination with opioids;[74,83,84]

recovery, quicker discharge and similar patient sat-however, comparative studies have found that pro-

isfaction than with physician-administered midazo-pofol does not induce greater changes in arterial

lam and meperidine.[9]blood gases than midazolam.[44]Propofol infusions

Propofol also appears to be a safe and effectivemay also decrease cardiac output, particularly insedation agent in critically ill or high-risk patients,conjunction with the coadministration of opioidsthose with end-stage renal disease and the elderly.[93](e.g. fentanyl).[16] Propofol-induced decreases inFor example, in high-risk patients (American Socie-blood pressure are generally dose- and infusion-rate

ty of Anesthesiologists [ASA] physical status III anddependent, an effect at least partially related toIV) undergoing colonoscopy, propofol produced ef-decreases in peripheral vascular resistance. Notwith-fective sedation, although there was an increasedstanding this reduction in arterial pressure, propofolrisk for clinically relevant short-term oxygentends to cause a modest decrease in heart rate.[44]

desaturation (


11/15


tion, time to full recovery and greater overall patient label, dose-ranging trial evaluating AQUAVANin

satisfaction than combination sedation with midazo- patients undergoing colonoscopy, transient, mild to

lam and meperidine.[95]In elderly patients undergo- moderate pelvic/perianal tingling, itching or burning

ing outpatient colonoscopy, patient-controlled ad- sensation was noted in 85% of patients.[28]

The useministration of propofol produced faster recovery of AQUAVAN in high-risk patients (e.g. bron-

time and significantly less hypotension than intrave- choscopy and intensive care unit sedation) is cur-

nous sedation with diazepam and meperidine.[10] rently under evaluation.

5.3 Ketamine 6. Drug Interactions

Ketamine has a narrow therapeutic window.6.1 MidazolamEmergence reactions such as disorientation, dream-

like experiences, vivid imagery, hallucinations and Midazolam is metabolised via CYP3A4 oxi-delirium are among the most important adverse re- dases. Therefore, coadministration of midazolam

actions. These reactions are particularly common in with CYP inhibitors (e.g. azole antifungals,adults.[77] These reactions are reduced when macrolide antibacterials, grapefruit juice) can resultketamine is used in conjunction with a benzodi- in excess sedation because of decreased clear-azepine or propofol. It can also increase the inci- ance.[97-99]For example, coadministration of intrave-dence of nausea and vomiting.[96] nous midazolam with azole antifungals (e.g.

itraconazole, fluconazole) decreased midazolam5.4 Sevoflurane

clearance by 5070%.[99] The interaction between

midazolam and azoles is even more pronouncedAs with other inhalational anaesthetics, sevoflu-

when midazolam is administered orally, which canrane can be associated with airway complications

result in 3- to 15-fold increases in midazolam drugsuch as breath holding, coughing, excitement and

exposure (as measured by the AUC).[99]This resultlaryngospasm.[37,50]Changes in haemodynamics are

may be explained by the potentially greater inhibito-generally small and the risk of fluoride-induced

ry effect of azoles on the CYP3A4-dependent, first-nephrotoxicity appears to be minimal. In a compara-

pass metabolism of midazolam that occurs predomi-tive trial in patients undergoing moderate sedation,

nantly in the gut mucosa,[100] resulting in slowersevoflurane was associated with significantly more

breakdown and clearance of midazolam adminis-disinhibition excitement (70%) than with propofol

tered by the oral route in the presence of antifungal(36%) or midazolam (5%).[71]

azoles.5.5 AQUAVAN

6.2 PropofolSome of the concerns associated with the use of

propofol emulsion may be mitigated with the use of Since propofol is metabolised via the CYP2C9

AQUAVAN, which has not been reported to in- pathway, drugs that inhibit this pathway theoretical-

duce injection site pain[73]and does not have safety ly could alter the clearance of propofol. However,

issues relating to lipid-containing formulation (con- coadministration of propofol with parecoxib, a

tamination, hyperlipidaemia). In healthy volunteers, COX-2-specific inhibitor that is a substrate for

AQUAVAN-delivered propofol was generally as- CYP2C9, demonstrated no effect on propofol

sociated with a haemodynamic profile similar to that pharmacokinetic parameters.[101] Propofol inhibits

produced by propofol emulsion except for an initial the metabolism of both alfentanil and sufentanil,

tachycardia in those receiving AQUAVAN.[73] producing increases in opioid concentrations of ap-

The onset of cardiovascular depression with proximately 15%.[75] Conversely, these agents in-

AQUAVANwas also delayed and smoother com- crease the Vdand reduce the clearance of propofol,

pared with propofol emulsion. In a phase II, open- resulting in increases in propofol concentrations of



12/15

866 Gan

approximately 20%.[102] Furthermore, combination Properties of an ideal agent for moderate sedation

of propofol and these opioids has synergistic seda- include rapid onset, rapid recovery, clear-headed

tive and analgesic effects, with fentanyl and al- recovery, ease of use, safety and no requirement for

fentanil concentrations of 3 ng/mL and 122 ng/mL, monitored anaesthesia care. The currently availablerespectively, reducing the propofol blood concentra- agents most commonly used in short-term moderatetion associated with loss of consciousness in 50% of sedation (e.g. midazolam, propofol, ketamine) arepatients (EC50) by 40%.[75] generally effective sedative agents and have some,

but not all, of these characteristics. For example, the6.3 Sevoflurane

benzodiazepine midazolam is an effective agent

The minimum alveolar concentration of sevoflu- when administered alone or in combination with

rane is reduced by the concomitant administration of other agents (e.g. opioids) for providing moderate

nitrous oxide and opioids. Sevoflurane also poten- sedation during short procedures. The primarytiates the pharmacological activity of neuromuscular drawback of this agent is the prolongation of seda-

blocking agents. Since sevoflurane is metabolised tion and hangover effects induced by the relativelyby CYP2E1, agents that induce this isozyme (isonia- long half-life of midazolam and its metabolites andzid, alcohol [ethanol]) may increase the metabolism their slow release from adipose tissue after repeatedof the drug.[37,50] administration.

Recent studies have also shown that the short-6.4 AQUAVANacting agent propofol, an anaesthetic/hypnotic agent

Preliminary data indicate that coadministration used previously for deep sedation, can be used suc-of AQUAVANwith fentanyl provides satisfactory cessfully and safely for moderate sedation during asedation with an acceptable safety profile in patients variety of interventional procedures. Combinationsundergoing colonoscopy.[28] In the dose-ranging of propofol and other sedation agents can achievestudy of AQUAVANby Pruitt et al.[28] (931mg), hypoxaemia (1 g/kg. One episode of apnoeasion is limited by injection site pain, oversedationwas a serious adverse event requiring a 3-minuteand the risk of hypotension/cardiopulmonary com-interval of mechanical ventilation.[28]

plications. Possibly of most importance is the label-ling requirement for monitored anaesthesia care,7. Conclusionsmeaning that it is recommended to be administered

The increase in the total number of interventionalonly by physicians trained in anaesthesia care. The

procedures performed annually[4]has increased in-water-soluble prodrug of propofol, AQUAVAN,

terest in the types of sedation agents and protocolsmay have the potential to address some of these

that are amenable to short procedures and that alsolimitations and safety concerns.

achieve high levels of patient comfort and satisfac-In conclusion, there have been substantial ad-tion. This has been paralleled by an increased inter-

vances in the delivery of moderate procedural seda-est in the administration of moderate sedation agents

tion in recent years. The development of new seda-by non-anaesthesiologists and trained nurses, and

via patient-controlled devices.[7-11,103]

tive agents and improvements in techniques may



13/15


15. Stewart RD. Nitrous oxide sedation/analgesia in emergencyfulfil many unmet needs in the provision of moder-medicine. Ann Emerg Med 1985; 14: 139-48

ate sedation for invasive procedures. 16. Skues MA, Prys-Roberts C. The pharmacology of propofol. JClin Anesth 1989; 1: 387-400

17. Horn E, Nesbit SA. Pharmacology and pharmacokinetics of

Acknowledgements sedatives and analgesics. Gastrointest Endosc Clin N Am2004; 14: 247-68

Editorial assistance was provided on this manuscript 18. Karan SB, Bailey PL. Update and review of moderate and deepthrough an unrestricted grant from MGI Pharma. The author sedation. Gastrointest Endosc Clin N Am 2004; 14: 289-312is grateful for editorial assistance provided by Nexus Com- 19. Gepts E. Pharmacokinetic concepts for TCI anaesthesia. Anaes-

thesia 1998; 53 Suppl. 1: 4-12munications, Inc., North Wales, PA, USA.20. Rodrigo MR, Irwin MG, Tong CK, et al. A randomised cross-The author serves on the advisory board of MGI Pharma

over comparison of patient-controlled sedation and patient-and has received grant support related to research activities.maintained sedation using propofol. Anaesthesia 2003; 58:333-8

21. Egan TD. Target-controlled drug delivery: progress toward anReferencesintravenous "vaporizer" and automated anesthetic administra-

1. Bahn EL, Holt KR. Procedural sedation and analgesia: a reviewtion. Anesthesiology 2003; 99: 1214-9

and new concepts. Emerg Med Clin North Am 2005; 23:22. Behne M, Wilke HJ, Harder S. Clinical pharmacokinetics of

503-17 sevoflurane. Clin Pharmacokinet 1999; 36: 13-262. Javorski JJ, Hansen DD, Laussen PC, et al. Paediatric cardiac23. Fragen RJ. Pharmacokinetics and pharmacodynamics ofcatheterization: innovations. Can J Anaesth 1995; 42: 310-29

midazolam given via continuous intravenous infusion in inten-3. Cillo Jr JE. Propofol anesthesia for outpatient oral and maxil-

sive care units. Clin Ther 1997; 19: 405-19lofacial surgery. Oral Surg Oral Med Oral Pathol Oral Radiol

24. Kanto J, Gepts E. Pharmacokinetic implications for the clinicalEndod 1999; 87: 530-8use of propofol. Clin Pharmacokinet 1989; 17: 308-26

4. Heuss LT, Froehlich F, Beglinger C. Changing patterns of25. Persson J, Hasselstrom J, Maurset A, et al. Pharmacokineticssedation and monitoring practice during endoscopy: results of

and non-analgesic effects of S- and R-ketamines in healthya nationwide survey in Switzerland. Endoscopy 2005; 37:volunteers with normal and reduced metabolic capacity. Eur J161-6Clin Pharmacol 2002; 57: 869-755. Froehlich F, Schwizer W, Thorens J, et al. Conscious sedation

26. Fechner J, Ihmsen H, Hatterscheid D, et al. Comparativefor gastroscopy: patient tolerance and cardiorespiratory param-pharmacokinetics and pharmacodynamics of the new propofoleters. Gastroenterology 1995; 108: 697-704prodrug GPI 15715 and propofol emulsion. Anesthesiology6. Cohen LB, Hightower CD, Wood DA, et al. Moderate level2004; 101: 626-39sedation during endoscopy: a prospective study using low-

27. Fechner J, Ihmsen H, Schiessl C, et al. Sedation with GPIdose propofol, meperidine/fentanyl, and midazolam. Gas-15715, a water-soluble prodrug of propofol, using target-trointest Endosc 2004; 59: 795-803controlled infusion in volunteers. Anesth Analg 2005; 100:7. Kulling D, Bauerfeind P, Fried M, et al. Patient-controlled701-6analgesia and sedation in gastrointestinal endoscopy. Gas-

28. Pruitt RE, Cohen LB, Gibiansky E, et al. A randomized, open-trointest Endosc Clin N Am 2004; 14: 353-68label, multicenter, dose-ranging study of sedation with8. Heuss LT, Drewe J, Schnieper P, et al. Patient-controlled versusAQUAVANinjection (GPI 15715) during colonoscopy. In:nurse-administered sedation with propofol during colonosco-Digestive Disease Week; 2005 May 14-19, Chicago (IL), 2005py: a prospective randomized trial. Am J Gastroenterol 2004;

29. Greenblatt DJ, Ehrenberg BL, Culm KE, et al. Kinetics and99: 511-8EEG effects of midazolam during and after 1-minute, 1-hour,9. Bright E, Roseveare C, Dalgleish D, et al. Patient-controlledand 3-hour intravenous infusions. J Clin Pharmacol 2004; 44:sedation for colonoscopy: a randomized trial comparing pa-605-11tient-controlled administration of propofol and alfentanil with

30. Wehrmann T, Kokabpick S, Lembcke B, et al. Efficacy andphysician-administered midazolam and pethidine. Endoscopysafety of intravenous propofol sedation during routine ERCP: a2003; 35: 683-7prospective, controlled study. Gastrointest Endosc 1999; 49:10. Lee DW, Chan AC, Sze TS, et al. Patient-controlled sedation677-83versus intravenous sedation for colonoscopy in elderly pa-

31. Zakko SF, Seifert HA, Gross JB. A comparison of midazolamtients: a prospective randomized controlled trial. Gastrointestand diazepam for conscious sedation during colonoscopy in aEndosc 2002; 56: 629-32prospective double-blind study. Gastrointest Endosc 1999; 49:11. Irwin MG, Thompson N, Kenny GN. Patient-maintained pro-684-9pofol sedation. Assessment of a target-controlled infusion

32. Full prescribing information. Richmond (ON): Novex Pharma,system. Anaesthesia 1997; 52: 525-302000 [online]. Available from URL: http://www.apotex-12. American Society of Anesthesiologists. Practice guidelines forcorp.com/pdf/Midazolam%20Inj%20bio%20&%20PI.pdfsedation and analgesia by non anesthesiologists. Anesthesiolo-[Accessed 2005 Jun 20]gy 2005; 96: 1004-17

33. Wilson KE, Girdler NM, Welbury RR. Randomized, controlled,13. Gilger MA, Spearman RS, Dietrich CL, et al. Safety and effec-cross-over clinical trial comparing intravenous midazolam se-tiveness of ketamine as a sedative agent for pediatric GIdation with nitrous oxide sedation in children undergoingendoscopy. Gastrointest Endosc 2004; 59: 659-63dental extractions. Br J Anaesth 2003; 91: 850-614. Ristikankare M, Julkunen R, Mattila M, et al. Conscious seda-

tion and cardiorespiratory safety during colonoscopy. Gas- 34. Geisslinger G, Hering W, Kamp HD, et al. Pharmacokinetics of

trointest Endosc 2000; 52: 48-54 ketamine enantiomers. Br J Anaesth 1995; 75: 506-7



14/15

868 Gan

35. Hijazi Y, Boulieu R. Protein binding of ketamine and its active wide interpatient variability? Clin Pharmacol Ther 1988; 43:metabolites to human serum. Eur J Clin Pharmacol 2002; 58: 263-937-40 55. Albrecht S, Ihmsen H, Hering W, et al. The effect of age on the

36. Sipe BW, Rex DK, Latinovich D, et al. Propofol versus midazo- pharmacokinetics and pharmacodynamics of midazolam. Clinlam/meperidine for outpatient colonoscopy: administration by Pharmacol Ther 1999; 65: 630-9nurses supervised by endoscopists. Gastrointest Endosc 2002; 56. Short TG, Young KK, Tan P, et al. Midazolam and flumazenil55: 815-25 pharmacokinetics and pharmacodynamics following simulta-

37. Patel SS, Goa KL. Sevoflurane: a review of its pharmacodynam- neous administration to human volunteers. Acta Anaesthesiolic and pharmacokinetic properties and its clinical use in gener- Scand 1994; 38: 350-6al anaesthesia. Drugs 1996; 51: 658-700 57. Tolia V, Brennan S, Aravind MK, et al. Pharmacokinetic and

38. MacGilchrist AJ, Birnie GG, Cook A, et al. Pharmacokinetics pharmacodynamic study of midazolam in children during es-and pharmacodynamics of intravenous midazolam in patients ophagogastroduodenoscopy. J Pediatr 1991; 119: 467-71with severe alcoholic cirrhosis. Gut 1986; 27: 190-5 58. Volkow ND, Wang GJ, Hitzemann R, et al. Decreased cerebral

39. Cook LB, Lockwood GG, Moore CM, et al. True patient- response to inhibitory neurotransmission in alcoholics. Am Jcontrolled sedation. Anaesthesia 1993; 48: 1039-44 Psychiatry 1993; 150: 417-22

40. Maitre PO, Funk B, Crevoisier C, et al. Pharmacokinetics of 59. Abi-Dargham A, Krystal JH, Anjilvel S, et al. Alterations ofmidazolam in patients recovering from cardiac surgery. Eur J benzodiazepine receptors in type II alcoholic subjects mea-Clin Pharmacol 1989; 37: 161-6 sured with SPECT and [123I]iomazenil. Am J Psychiatry

41. Zomorodi K, Donner A, Somma J, et al. Population 1998; 155: 1550-5

pharmacokinetics of midazolam administered by target con- 60. Lau CE, Wang Y, Ma F. Pharmacokinetic-pharmacodynamictrolled infusion for sedation following coronary artery bypass modeling of the coexistence of stimulatory and sedative com-grafting. Anesthesiology 1998; 89: 1418-29 ponents for midazolam. Eur J Pharmacol 1998; 346: 131-44

42. Pentikainen PJ, Valisalmi L, Himberg JJ, et al. Pharmacokinet-61. Golparvar M, Saghaei M, Sajedi P, et al. Paradoxical reaction

ics of midazolam following intravenous and oral administra-following intravenous midazolam premedication in pediatric

tion in patients with chronic liver disease and in healthypatients: a randomized placebo controlled trial of ketamine for

subjects. J Clin Pharmacol 1989; 29: 272-7rapid tranquilization. Paediatr Anaesth 2004; 14: 924-30

43. Bell GD, Spickett GP, Reeve PA, et al. Intravenous midazolam62. Massanari M, Novitsky J, Reinstein LJ. Paradoxical reactions in

for upper gastrointestinal endoscopy: a study of 800 consecu-children associated with midazolam use during endoscopy.

tive cases relating dose to age and sex of patient. Br J ClinClin Pediatr (Phila) 1997; 36: 681-4

Pharmacol 1987; 23: 241-363. Bauer TM, Ritz R, Haberthur C, et al. Prolonged sedation due to

44. Fulton B, Sorkin EM. Propofol. An overview of its pharmacolo-accumulation of conjugated metabolites of midazolam. Lancet

gy and a review of its clinical efficacy in intensive care1995; 346: 145-7

sedation. Drugs 1995; 50: 636-5764. The Flumazenil in Intravenous Conscious Sedation with

45. Frenkel C, Schuttler J, Ihmsen H, et al. Pharmacokinetics and Diazepam Multicenter Study Group I. Reversal of centralpharmacodynamics of propofol/alfentanil infusions for seda-benzodiazepine effects by flumazenil after conscious sedation

tion in ICU patients. Intensive Care Med 1995; 21: 981-8produced by intravenous diazepam. Clin Ther 1992; 14: 895-

46. Servin F, Farinotti R, Haberer JP, et al. Propofol infusion for909

maintenance of anesthesia in morbidly obese patients receiv-65. Short TG, Galletly DC. Residual psychomotor effects followinging nitrous oxide: a clinical and pharmacokinetic study. Anes-

reversal of midazolam sedation with flumazenil. Anaesth In-thesiology 1993; 78: 657-65tensive Care 1989; 17: 290-7

47. Peyton SH, Couch AT, Bost RO. Tissue distribution of66. Doufas AG, Bakhshandeh M, Bjorksten AR, et al. Inductionketamine: two case reports. J Anal Toxicol 1988; 12: 268-9

speed is not a determinant of propofol pharmacodynamics.48. Xie H, Wang X, Liu G, et al. Analgesic effects andAnesthesiology 2004; 101: 1112-21pharmacokinetics of a low dose of ketamine preoperatively

67. Cheuk DK, Wong WH, Ma E, et al. Use of midazolam andadministered epidurally or intravenously. Clin J Pain 2003; 19:ketamine as sedation for children undergoing minor operative317-22procedures. Support Care Cancer 2005; 13: 1001-949. Tsui BC, Wagner A, Finucane B. Regional anaesthesia in the

68. Ketamine 2005 [online]. Available from URL: http://www.me-elderly: a clinical guide. Drugs Aging 2004; 21: 895-910

trohealthanesthesia.com/edu/ivanes/ketamine5.htm [Accessed50. Goa KL, Noble S, Spencer CM. Sevoflurane in paediatric anaes-2005 Aug 29]thesia: a review. Paediatr Drugs 1999; 1: 127-53

69. Hartvig P, Larsson E, Joachimsson PO. Postoperative analgesia51. Fechner J, Ihmsen H, Hatterscheid D, et al. Pharmacokineticsand sedation following pediatric cardiac surgery using a con-and clinical pharmacodynamics of the new propofol prodrugstant infusion of ketamine. J Cardiothorac Vasc Anesth 1993;GPI 15715 in volunteers. Anesthesiology 2003; 99: 303-137: 148-5352. Schywalsky M, Ihmsen H, Tzabazis A, et al. Pharmacokinetics

70. Ibrahim AE, Ghoneim MM, Kharasch ED, et al. Speed ofand pharmacodynamics of the new propofol prodrug GPIrecovery and side-effect profile of sevoflurane sedation com-15715 in rats. Eur J Anaesthesiol 2003; 20: 182-90pared with midazolam. Anesthesiology 2001; 94: 87-9453. Gibiansky E, Struys MM, Gibiansky L, et al. AQUAVAN

71. Ibrahim AE, Taraday JK, Kharasch ED. Bispectral index moni-injection, a water-soluble prodrug of propofol, as a bolustoring during sedation with sevoflurane, midazolam, and pro-injection: a phase I dose-escalation comparison withpofol. Anesthesiology 2001; 95: 1151-9DIPRIVAN (part 1): pharmacokinetics. Anesthesiology 2005;

103: 718-29 72. Levitt DG, Schnider TW. Human physiologically based54. Oldenhof H, de Jong M, Steenhoek A, et al. Clinical pharmacokinetic model for propofol. BMC Anesthesiol 2005;

pharmacokinetics of midazolam in intensive care patients, a 5: 1-29



15/15


73. Struys MM, Vanluchene AL, Gibiansky E, et al. AQUAVAN tion by nurses supervised by endoscopists. Clin Gastroenterolinjection, a water-soluble prodrug of propofol, as a bolus Hepatol 2003; 1: 425-32injection: a phase I dose-escalation comparison with

91. Seifert H, Schmitt TH, Gultekin T, et al. Sedation with propofolDIPRIVAN (part 2): pharmacodynamics and safety. Anesthe-plus midazolam versus propofol alone for interventional endo-siology 2005; 103: 730-43

scopic procedures: a prospective, randomized study. Aliment74. Moerman AT, Struys MM, Vereecke HE, et al. Remifentanil Pharmacol Ther 2000; 14: 1207-14used to supplement propofol does not improve quality of

92. Koshy G, Nair S, Norkus EP, et al. Propofol versus midazolamsedation during spontaneous respiration. J Clin Anesth 2004;and meperidine for conscious sedation in GI endoscopy. Am J16: 237-43

Gastroenterol 2000; 95: 1476-975. Vuyk J. Clinical interpretation of pharmacokinetic and pharma-

codynamic propofol-opioid interactions. Acta Anaesthesiol 93. Knibbe CA, Zuideveld KP, DeJongh J, et al. PopulationBelg 2001; 52: 445-51 pharmacokinetic and pharmacodynamic modeling of propofol

for long-term sedation in critically ill patients: a comparison76. Kucukyavuz Z, Cambazoglu M. Effects of low-dose midazolambetween propofol 6% and propofol 1%. Clin Pharmacol Therwith propofol in patient-controlled sedation (PCS) for2002; 72: 670-84apicectomy. Br J Oral Maxillofac Surg 2004; 42: 215-20

94. Heuss LT, Schnieper P, Drewe J, et al. Safety of propofol for77. Mason KP, Michna E, DiNardo JA, et al. Evolution of a protocolconscious sedation during endoscopic procedures in high-riskfor ketamine-induced sedation as an alternative to general

anesthesia for interventional radiologic procedures in pediatric patients: a prospective, controlled study. Am J Gastroenterolpatients. Radiology 2002; 225: 457-65 2003; 98: 1751-7

78. Walder B, Tramer MR. Analgesia and sedation in critically ill 95. Weston BR, Chadalawada V, Chalasani N, et al. Nurse-adminis-patients. Swiss Med Wkly 2004; 134: 333-46 tered propofol versus midazolam and meperidine for upper

endoscopy in cirrhotic patients. Am J Gastroenterol 2003; 98:79. Bhana N, Goa KL, McClellan KJ. Dexmedetomidine. Drugs2440-72000; 59: 263-8

96. Badrinath S, Avramov MN, Shadrick M, et al. The use of a80. Jalowiecki P, Rudner R, Gonciarz M, et al. Sole use ofketamine-propofol combination during monitored anesthesiadexmedetomidine has limited utility for conscious sedationcare. Anesth Analg 2000; 90: 858-62during outpatient colonoscopy. Anesthesiology 2005; 103:

269-7397. Eilers H, Niemann C. Clinically important drug interactions

81. Motsch J, Schmidt H, Bach A, et al. Long-term sedation with with intravenous anaesthetics in older patients. Drugs Agingpropofol and green discolouration of the liver. Eur J Anaes- 2003; 20: 969-80thesiol 1994; 11: 499-502

98. Dresser GK, Spence JD, Bailey DG. Pharmacokinetic-pharma-82. Koch ME, Gevirtz C. Propofol may be safely administered by codynamic consequences and clinical relevance of cytochrometrained nonanesthesiologists. Con: Propofol: far from harm- P450 3A4 inhibition. Clin Pharmacokinet 2000; 38: 41-57less. Am J Gastroenterol 2004; 99: 1208-11

99. Yuan R, Flockhart DA, Balian JD. Pharmacokinetic and phar-83. Godambe SA, Elliot V, Matheny D, et al. Comparison of

macodynamic consequences of metabolism-based drug inter-propofol/fentanyl versus ketamine/midazolam for brief ortho-

actions with alprazolam, midazolam, and triazolam. J Clinpedic procedural sedation in a pediatric emergency depart-

Pharmacol 1999; 39: 1109-25ment. Pediatrics 2003; 112: 116-23

100. Paine MF, Shen DD, Kunze KL, et al. First-pass metabolism of84. Sternlo JE, Sandin RH. Recurrent respiratory depression aftermidazolam by the human intestine. Clin Pharmacol Ther 1996;total intravenous anaesthesia with propofol and alfentanil.60: 14-24Anaesthesia 1998; 53: 378-81

101. Ibrahim A, Park S, Feldman J, et al. Effects of parecoxib, a85. Grauers A, Liljeroth E, Akeson J. Propofol infusion rate doesparenteral COX-2-specific inhibitor, on the pharmacokineticsnot affect local pain on injection. Acta Anaesthesiol Scandand pharmacodynamics of propofol. Anesthesiology 2002; 96:2002; 46: 361-3

88-9586. Bryson HM, Fulton BR, Faulds D. Propofol: an update of its usein anaesthesia and conscious sedation. Drugs 1995; 50: 513-59 102. Vuyk J. Pharmacokinetic and pharmacodynamic interactions

between opioids and propofol. J Clin Anesth 1997; 9: 23S-6S87. Nakane M, Iwama H. A potential mechanism of propofol-induced pain on injection based on studies using nafamostat 103. Vargo JJ. Propofol may be safely administered by trainedmesilate. Br J Anaesth 1999; 83: 397-404 nonanesthesiologists. Pro: Propofol demystified: it is time to

change the sedation paradigm. Am J Gastroenterol 2004; 99:88. Scott RP, Saunders DA, Norman J. Propofol: clinical strategies1207-8for preventing the pain of injection. Anaesthesia 1988; 43:

492-4

89. Chen SC, Rex DK. Review article: registered nurse-adminis-Correspondence and offprints: Dr Tong J. Gan, Departmenttered propofol sedation for endoscopy. Aliment Pharmacol

Ther 2004; 19: 147-55 of Anesthesiology, Duke University Medical Center, 3094

Erwin Road, Durham, NC 27710, USA.90. Ulmer BJ, Hansen JJ, Overley CA, et al. Propofol versus

midazolam/fentanyl for outpatient colonoscopy: administra- E-mail: [email protected]


Pharmacokinetic and pharmacodinamic sedation.pdf

Documents

Transcript of Pharmacokinetic and pharmacodinamic sedation.pdf