potential pitfalls of propofol target controlled infusion delivery related

Review

Potential pitfalls of propofol target controlledinfusion delivery related to its pharmacokineticsand pharmacodynamics

Agnieszka Bienert1, Pawe³ Wiczling2, Edmund Grzeœkowiak1,

Jacek B. Cywiñski3, Krzysztof Kusza4

1Department of Clinical Pharmacy and Biopharmacy, Karol Marcinkowski University of Medical Sciences,

Marii Magdaleny 14, PL 61-861 Poznañ, Poland

2Department of Biopharmaceutics and Pharmacodynamics, Medical Univeristy of Gdañsk, Hallera 107,

PL 80-401, Gdañsk, Poland

3Departments of General Anesthesiology and Outcome Research, Cleveland Clinic, 9500 Euclid Avenue,

Cleveland, Ohio 44195, USA

4Department of Anesthesiology and Intensive Therapy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus

University in Toruñ, Marii Sk³odowskiej-Curie 9, PL 85-094 Bydgoszcz, Poland

Correspondence: Agnieszka Bienert, e-mail: [email protected]

Abstract:

Target controlled infusion (TCI) devices are increasingly used in clinical practice. These devices unquestionably aid optimization ofdrug dosage. However, it still remains to be determined if they sufficiently address differences in pharmacological make up of indi-vidual patients. The algorithms guiding TCI pumps are based on pharmacological data obtained from a relatively small number ofhealthy volunteers, which are then extrapolated, on the basis of sophisticated pharmacokinetic and pharmacodynamic modeling, topredict plasma concentrations of the drug and its effect on general population. One has to realize the limitation of this approach: thesemodels may be less accurate when applied to patients in extreme clinical conditions: in intensive care units, with a considerable lossof blood, severe hypothermia or temporary changes in the composition of plasma, e.g., hypoalbuminemia. In the future, data ob-tained under these “extreme” clinical circumstances, may be used to modify the dosage algorithms of propofol TCI systems to matchthe clinical scenario.

Key words:

propofol, TCI systems, pharmacokinetics, pharmacodynamics

Introduction

Anesthetic management may influence the patient’spost-procedural quality of life and state of health forlong years following the anesthesia. In particular, re-

cent investigations focus on the effect of the depth ofanesthesia and postoperative cognitive function, aswell as long term mortality and morbidity [19, 40].This aspect may be particularly important during totalintravenous anesthesia (TIVA) when target controlledinfusion (TCI) models are used for direct dosing of

782 Pharmacological Reports, 2012, 64, 782�795

Pharmacological Reports2012, 64, 782�795ISSN 1734-1140

Copyright © 2012by Institute of PharmacologyPolish Academy of Sciences

the anesthetic agent without assessing the end effectsof the delivered drugs on the central nervous system.TCI models were developed on the basis of data fromhealthy volunteers and may not be uniformly applica-ble to all clinical situations, ultimately resulting in un-der- or overdosing of the anesthetic; both situationswith non-trivial consequence.

Although not very frequent, awareness under generalanesthesia has quite dramatic impact on the postopera-tive quality of life and psychosocial outcomes, whichhas been described in numerous prospective and retro-spective studies [13, 26, 47]. According to the Declara-tion of Helsinki, published by the European Society ofAnesthesiology (ESA) in 2010, the speciality of Anes-thesiology and Intensive Care guards the patient’s safetyand their quality of life after the surgery and anesthesia[27]. In view of that fact, the Declaration by itself em-phasises the role of education and the need to improveanesthesiologists’ knowledge and qualifications in orderto reduce perioperative morbidity and mortality [27].

For thorough understanding of the pharmacokineticsand pharmacodynamics of anesthetics, especially theserelated to the limitations of propofol, TCI model is abso-lutely crucial to provide safe patient care. Also, under-standing depth-of-anesthesia monitoring techniques, andtheir applicability for different anesthethics cannot beunderestimated. At present, there is no medical evidencethat the routine use of devices to monitor the depth ofanesthesia (BIS, entropy, SFX, AEP – auditory evokedpotential) is a reliable protection from intraoperativeawareness [6, 27]. Furthermore, due to the human cir-cadian rhythm, sex, concomitant diseases, includingthese found in patients with extreme obesity and geriat-ric age, the pharmacodynamics of anesthetics, includingpropofol, may vary. This understanding should be ourcontribution to reduction of long term morbidity and pe-rioperative mortality, with particular emphasis placed onpatients’ quality of life after anesthesia. Elements ofclinical pharmacology, which are part of the trainingcurricula, are frequently omitted in everyday education.In consequence, in clinical practice anesthesiologists un-dergoing training do not fully understand the differencesbetween the patient’s clinical state related to infusion ofan anesthetic and the state of expected depression of thecentral nervous system in the anesthetized patient [31].

The lack of understanding of the aforementionedissues by anesthesia providers can cause potentialcomplications related to the maintenance of too lightor too deep plane of anesthesia which potentially canhave long-term consequences [25].

The significance of pharmacokinetic

and pharmacodynamic parameters in

intravenous anesthesia

Pharmacokinetic and pharmacodynamic modelling(PK/PD) of drugs consists of a mathematical descrip-tion of the relation between the dose and the concen-tration of a therapeutic substance (and its metabolites)in the organism as well as the relation between theconcentration of the therapeutic substance and its ef-fect on an end organ. It also describes the interactionof drug concentration and response of the organism tothe drug as a function of time. In other words, phar-macokinetics describes what happens to the drug inthe organism, i.e., the processes of distribution, me-tabolism and excretion as well as absorption for extra-vascular administration. When the drug is adminis-tered intravenously, the process of absorption is omit-ted because the drug directly enters the blood,whereas in extra vascular administrations such as sub-cutaneous, oral or intramuscular, the substance firstmust be absorbed into the blood from the place of ad-ministration. Pharmacodynamics describes how thedrug affects the organism and how those effectschange in time. The knowledge of these processes andpractical application of the pharmacokinetics andpharmacodynamics principles are necessary to assurethat the patient receives an optimal dose of drugs atthe right time. The anesthesiologist’s task is to ensurean appropriate depth of anesthesia and to achieve sta-ble dynamics of the circulatory system in response tothe surgical and perioperative stress. A particularlydesirable characteristic of an anesthetic is its titratibil-ity, i.e., the immediate effect after administration andabsence of accumulation, the risk of which increasesespecially in prolonged surgical procedures. Precise,quantitative understanding of all the processes thedrug undergoes within a body and what clinical effectthey cause is possible only on the basis of PK/PDmodels. They allow accurate description of both rapidchanges, which take place within seconds or minutesafter administration of the drug, and slow processes,which take hours or days to complete. Also, they givea possibility to understand and quantify the observedclinical effects (e.g., the onset, duration, offset anddepth of anesthesia).

Drugs are not evenly and simultaneously distrib-uted in the whole organism. The tissues where thedrug is distributed at the same rate and concentration

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Potential pitfalls of propofol target controlled infusion deliveryAgnieszka Bienert et al.

are called compartments. The three-compartmentmodel of distribution is commonly used in anesthesiato describe the pharmacokinetics of anesthetic agents.The central compartment is the one to which the drugis administered, i.e., the blood and tissues which arevery rich in blood vessels. Its volume, marked as Vc isimportant when specifying induction doses of drugs.As the volume of the central compartment decreases,the required dose of the drug necessary to obtaina specific effect is reduced. The drug will havea higher concentration due to the fact that initially it isdistributed in a smaller volume. This phenomenoncan be observed for propofol in geriatric patients. Thereduced volume of the central compartment requiresa smaller induction dose of the drug. For anestheticdrugs, two peripheral compartments are usually iden-tified (VT,1 and VT,2). These are peripheral tissues intowhich the drug penetrates quickly (VT,1) and slowly(VT,2). A frequently used pharmacokinetic parameteris the volume of distribution at steady state (Vss),which is the sum of all volumes to which the drug isdistributed (Vss = Vc + VT,1+VT,2). Figure 1 shows anexample scheme of a three-compartment model ofpropofol. The distinction of individual compartmentsentails the need of a mathematical description of themigration of drug molecules between the compart-ments and its elimination from the organism. Theseprocesses may be described by means of elimination(Cl) and distribution (Q) clearance. The clearance re-fers to the rate of a process and it is defined as the vol-ume from which total elimination or total distributionof the drug takes place per unit of time. Similarly, rateconstants may be used to describe drug migration,

elimination, distribution or redistribution. Likewiseclearance, they refer to the rate of a process and aredefined as the quotient of the corresponding clearanceand compartment volume. The rate constant is insepa-rable from the biological half-life, which provides in-formation about the time necessary for concentrationor quantity of the drug to be reduced by half of its ini-tial value. The biological half-lives are very often dis-tinguished in relation to each phase that can be distin-guished in a semi-logarithmic diagram. In a three-compartment model, three phases can be observed,which are named with consecutive letters of the Greekalphabet (a, b, g, etc.).

With drugs used in anesthesiology, there is a delaybetween the effect of the drug and its concentrationobserved in the blood. This leads to a hysteresis loopwhen the correlation between the drug concentrationin the blood and pharmacological effect is presentedin a diagram (Fig. 2). In order to account for this de-lay, the presence of a hypothetical compartment, i.e.,biophase compartment, is postulated. It refers to theplace of effect of the drug (biophase), to which thedrug is distributed and which is in equilibrium withthe drug concentration in the blood. The applicationof drug concentrations in the biophase leads to theachievement of direct dependence between the con-centration and therapeutic effect, which usually hasthe form of a sigmoid curve described with the Hillequation (Figs. 1 and 2). The Hill equation is charac-terized by three parameters: the maximum effect(Emax); the concentration, which leads to the effectequal to a half of the maximum effect (EC50); and the


Compartment

Fig. 1. The schematic diagram of a typi-cal PK/PD model of propofol. It is usedto describe propofol concentrationand anesthetic effect. VC, VT,1, andVT,2 denote the volume of the central,slow and fast distribution compart-ment; Cl, Q1 and Q2 denote the elimi-nation and distribution clearances; ke0is the distribution rate to the biophasecompartment; Emax denotes the maxi-mum effect; EC50 is the concentrationleading to the half-maximum effect;and g is the Hill coefficient

Hill coefficient which determines the slope of the re-lationship between the effect and concentration (g).

Time to peak effect (tpeak effect) is the pharmacody-namic parameter, which enables prediction how muchtime is necessary for a particular hypnotic or opioidagent to achieve its peak effect after a single dose. Forexample, it is about 1–2 minutes for remifentanil and5–6 minutes for sufentanil. In clinical practice itmeans that when a stress-inducing surgical or anes-thesiological manipulation is planned, it is recom-mended to administer sufentanil somewhat soonerthan remifentanil. The time necessary for concentra-tion of the drug in the biophase to achieve its peakvalue after administration of a specific dose (tpeak)does not always correspond to peak effect time, be-cause the relationship between the effect and concen-tration is sigmoidal (Fig. 2). The plateau phase, i.e.,further increase in the concentration, does not lead tointensification of the clinical effect. Moving around

the range of supramaximal concentrations, within therange of the plateau phase, the peak effect can actu-ally be observed immediately after administration ofthe drug, although it will not reach its peak concentra-tion in the brain yet, it will be high enough to have itsmaximum possible effect. The introduction of theconcept of biophase compartment also contributed tomore precise specification of the volume of distribu-tion used to calculate induction doses of drugs. Theinduction dose of the drug is calculated according tothe formula (Dind = C•Vd): it depends on the drug con-centration (C) one wants to achieve in a specific vol-ume of distribution (Vd). However, the volume of dis-tribution changes over time, initially Vd is low (equalto the volume of the central compartment), becausethe drug penetrates only into the tissues which are richin blood vessels. However, with time it is widely dis-tributed to the deep compartments, which results inthe volume of distribution reaching high values at



Fig. 2. A typical concentration-timeprofile of propofol in the blood and bio-phase (A), the relationship betweenpropofol concentration in the bloodand biophase and the anesthetic ef-fect (B), and the resulting time courseof the anesthetic effect (C). The simu-lation was based on the modelpresented in Figure 1 with the followingparameters: Cl – 1.44 l/min; Q1 – 2.25 l/min; Q2 – 0.92 l/min; VC – 9.3 l; VT,1 –44.2 l; VT,2 – 266 l; keo – 0.2 min-1; Emax– 80; g – 3; EC50 – 2.5 mg/l. The infusionrate and duration was 0.2 mg/min/kgand 100 min

steady state and sometimes exceeding volume of thebody. Therefore, the concept of the volume of distri-bution at the time of peak drug concentration in thebiophase was introduced. The induction dose shouldbe calculated on the basis of this value as it is moreprecise than the volume of the central compartment.

On the other hand, a pharmacokinetic parameterwhich is useful in describing the rate of patient’s awak-ening is context sensitive half-time (CSHT), i.e., theperiod of time after which the drug concentration dropsby half after finishing the infusion. This concept wasintroduced by Hughes et al. in 1992 and later it was ex-tended by the time necessary for the concentration todrop by 10, 20 or 30%, because the idea is to character-ize the drop in drug concentration to the level corre-sponding with awakening. Effect-site decrement timecurves, which are widely discussed in literature, de-scribe the time necessary for a particular decrease indrug concentration after stopping its infusion account-ing for the time of infusion [22, 23, 39, 64].

The pharmacokinetic and

pharmacodynamic parameters

of propofol

Propofol is a small lipophilic particle, which stronglybinds to proteins and penetrates into erythrocytes. Inthe plasma, more than 98% of propofol is bound,mainly by albumins, red blood cells, and lipid frac-tions [21, 29, 35]. The percentage of free fraction de-pends on the total concentration of propofol in theblood. For total concentrations under 2 µg/ml an in-crease in the free fraction was observed along witha drop in the concentration of propofol. When the to-tal concentration is very low, even as much as 100%of propofol may be unbound. For concentrationshigher than 2 µg/ml, the free fraction is constant andequals about 2% [18]. Only unbound drug is responsi-ble for the pharmacological effect: therefore, the non-linear binding of the drug in the blood may influencethe clinical effect.

After administration of a single dose, the pharma-cokinetics of propofol is well described by three-compartment model, with the biological half-lives oft0.5, a = 1.8, t0.5, b = 34 and t0.5, g = 180 min, respectively[64]. The elimination half-lives of b and g phases arerelatively long, but the clinical effect of the drug can

be observed for a relatively short time. The correla-tion between the time of infusion and offset of thedrug effect is better described by the CSHT. For pro-pofol the time is shorter than 25 min for an infusionlasting up to 3 h and it is 50 min for a prolonged infusion[64]. The following pharmacokinetic parameters for pro-pofol were obtained for surgical patients in multi-centerstudies [55], based on the three-compartment model: thevolumes of the central compartment (VC) and the slow(VT,1) and fast (VT,2) distribution compartments were 9.3 l,44.2 l and 266 l, respectively; The elimination clear-ance (Cl) and distribution clearances (Q1 and Q2)were 1.44, 2.25 and 0.92 l/min, respectively, for a 70kg adult. However, in patients over 70 years old, a lin-ear decrease in propofol elimination clearance wasobserved along with their age [55].

The pharmacokinetics of propofol in patients in in-tensive care units (ICU), who undergo prolonged in-fusions, is slightly different. Above all, the propofolvolume of distribution at steady state increases. Ac-cording to the literature, the volume of distribution atsteady state is 23.8 l/kg of body mass for an infusionlasting 72 h [4]. For a shorter infusion lasting up to 24 h,the value of 499 l was obtained, i.e., about 7 l/kg fora 70 kg individual. This is about two or three timesmore than for a short infusion during anesthesia [20,37, 57]. The volume of the central compartment isabout 31 l for an infusion lasting up to 24 h. A similarvalue (27.2 l) was obtained in another group of pa-tients for an infusion lasting 98 h on average [9]. Alsothe volume of the peripheral compartment for propo-fol increases during a prolonged infusion and makesabout 801 l [9], as compared with the values of about113 –158 l obtained during general anesthesia [11,38]. In different studies the clearance of propofol dur-ing a prolonged infusion was 1.57, 2.11 and 2.55 l/min[5, 9, 36]. The value of propofol clearance for opera-tive procedures is 1.70 l/min [11] – 2.08 l/min [55].The distribution clearance of propofol during a pro-longed infusion is about 2.70 l/min [9]. The terminalbiological half-life of propofol (t0.5,g) depends on thereturn of its molecules from the tissues with poor bloodsupply. In patients subjected to several-day sedationwith propofol it ranges between 23.5 and 31.3 h [37].During a prolonged infusion lasting more than threedays, the concentration of triglycerides in the patient’splasma must be monitored due to the risk of hypertri-glyceridemia [37].

The pharmacokinetic parameters of propofolchange with patient’s age as well: children require


higher induction and maintenance doses of propofolper kg of body mass due to the higher volume of dis-tribution and drug clearance (Tab. 1) [5, 28, 33, 41,52]. In a geriatric population, the elimination of pro-pofol is slower, which is related mainly to the reducedhepatic flow and cardiac output. The total clearancedecreases by about 28% in patients over 60 years ascompared with patients younger than 60 [57]. Thevolume of the vessel rich compartment and the rate ofdrug distribution into that compartment are also re-duced. The volume of the central compartment isabout 0.32 l/kg of body mass in patients aged 65–80years as compared with the value of about 0.40 l/kg ofbody mass observed in patients aged 18–35 years[37]. Thus, the concentration of propofol will changemore rapidly in geriatric patients. Increasing the rateof infusion of propofol in a 75-year-old patient causesits concentration in the plasma to rise by about20–30%, as compared with a younger person. Thisfact is the reason why the dose of propofol adminis-tered to geriatric patients needs to be reduced byabout 30–75%. In elderly patients, the post-infusionelimination of the drug is also prolonged. After finish-ing an infusion lasting one hour, the value of theCSHT parameter is only slightly different. However,after four hours of continuous infusion in an 80-year-old patient, it is twice as high as in a 20-year-old [51].As far as pharmacodynamics is concerned, the valueof EC50 for loss of consciousness falls by about 50%between the age of 25 and 75 years (2.35 vs. 1.25 mg/l).However, greater sensitivity to the hypnotic effect ofpropofol is not coupled by the changes in the blood –effect site equilibration half-life, which remains con-stant with age (t0.5 (ke0) = 2.3 min.). The sensitivity todepressant effect of propofol on blood pressure is also

enhanced in elderly patients. The EC50 for hypoten-sion after propofol administration equals 2.09 mg/l forpatients aged 70–85 years, whereas for patients aged20–39 years it reaches the value of about 4.61 mg/l.Also, the cardiodepressive effect of propofol is slightlydelayed when compared with younger patients: t0.5(ke0) in an 80-year-old patient is about 10.22 min, ascompared with the value of 5.68 min. in a 25-year-oldperson [63].

In obese patients (BMI > 35) it is recommended toconvert the induction dose of propofol to the idealbody mass (IBM), which is calculated for men andwomen according to the following formula:

Men: IBM (kg) = 49.9 + 0.89 x (height (cm) – 152.4)

Women: IBM (kg) = 45.4 + 0.89 x (height (cm) – 152.4)

or: IBW (kg) = height (cm) – x, where x = 100 for menand 105 for women [8].

In spite of its high lipophilicity propofol does notexhibit a strong tendency to accumulate in extremelyobese patients. Therefore, when maintaining anesthe-sia, it is possible to base it on the total body weight(TBW). However, this may lead to higher concentra-tions of the drug during emergence from anesthesiaand higher hemodynamic instability. Therefore, theadjustment of maintenance doses to the lean bodymass (LBM) is suggested or applying the formula:

IBW + 0.4 × kg body mass over IBW [8].

Propofol is predominantly metabolized in the liver.Initially it is oxidized to 1,4-di-isopropylquinol, thenglucuronidation takes place. Propofol and 1,4-di-isopropylquinol are coupled with glucuronic acid andproduce corresponding glucuronides: propofol glucu-ronide, quinol-1-glucuronide and quinol-4-glucu-



Tab. 1. The pharmacokinetic parameters of propofol for infants and children obtained on the basis of the three-compartment model [5, 28, 41,52, 57]

Kataria et al. [28] Allegaert et al. [5] Murat et al. [41] Saint-Maurice et al. [52] Adults [57]

Number of patients

Age (range)

Weight (kg, range)

Vc

(l/kg)

Vss

(l/kg)

Cl (l/min/kg)

53

3–11 y

15–61

0.52

9.7

0.034

9

4–25 days

0.9_3.8

0.34

3.7

0.014

12

1–3 y

8.7–18.9

0.95

8.17

0.049

10

4–7 y

17–24

0.72

10.9

0.031

29

43 (mean)

66 (mean)

0.12

3.4

0.028

Vc – the volume of central compartment, Vss – volume of distribution at steady state, Cl – clearance

ronide. In vitro studies indicate the involvement of theenzymes UDP-glucuronosyltransferase, particularly theisozyme 1A9 (UGT1A9), cytochrome P450 2B6(CYP2B6), 2C9 (CYP2C9), sulfotransferases (SULT)and DT-diaphorases (NQO1) [48]. The existence ofextrahepatic metabolism is also taken into considera-tion. Takata et al. suggested that the organs responsi-ble for its metabolism are the kidneys, small intestine,brain and lungs, where the kidneys were ascribed themost significant role [58, 60, 62]. Propofol has highhepatic extraction ratio. Therefore, there is a correla-tion between its elimination rate and the cardiac out-put and hepatic blood flow [45, 62].

Generally, propofol is a safe anesthetic agent.However, propofol infusion syndrome (PRIS) is a rareand potentially lethal adverse drug event associatedwith high doses (> 4 mg/kg per hour or > 67 µg/kg permin) and long-term (> 48 h) use of propofol. Also, itcan be observed with lower doses and after shorterduration of sedation. PRIS is characterized by severemetabolic acidosis, rhabdomyolysis, hyperkalemia,lipemia, renal failure, hepatomegaly, and cardiovascu-lar collapse. The physiopathology of PRIS mecha-nism remains unclear, however, a dysfunction ofmitochondrial respiratory chain could be involved andpotential genetic factor may account. The occurrenceof PRIS may be related to the existence of a geneticsusceptibility, such as an inborn error of mitochon-drial fatty acid oxidation [32, 48, 67].

The factors modifying the

pharmacokinetics and effect of propofol

In clinical conditions, numerous factors may changethe pharmacokinetics and end organ effect of propo-fol. Since propofol significantly binds to various com-ponents of the blood, in pathological states, such ashypoalbuminemia or anemia, an increase in the freefraction of the drug can be expected. Propofol hashigh hepatic extraction ratio: the free fraction is notcompensated by higher clearance and acceleratedelimination. In this situation, the total concentration atsteady state remains unchanged, but the concentrationof the unbound drug increases and its effect becomesintensified. This may be of clinical importance forhighly protein-bound drugs with narrow therapeuticindices, such as propofol. The situation is different in

the case of drugs with low hepatic extraction, wherean increase in the free fraction causes a parallel in-crease in clearance and decrease in total concentra-tion. As a result, the unbound drug concentration andthe effect of the drug remain unchanged. Approxi-mately a double increase in the propofol free fractionwas noted, with an unchanged total concentration inpatients undergoing the coronary artery bypass graftsurgery as a result of hypoalbuminemia [24]. Consid-erable changes in the pharmacokinetics of propofolwere also observed in patients qualified to groupsII–IV according to the ASA scale, who had severeburns accompanied by acute anemia and hypoalbumi-nemia [66]. They had a higher volume of the centralcompartment (48.4 l) in comparison with the controlgroup (27.6 l) as well as a higher central and periph-eral compartment clearance (4.2 l/min 3.6 l/min,respectively) as compared with the control group ofpatients without burns (1.7 l/min and 1.1 l/min, re-spectively). No definite cause of those changes wasidentified, though. It is known that in patients aftera severe, extensive burns, increased cardiac output oraltered levels of different blood components can beexpected for as long as several weeks or even months[66]. On the other hand, the pharmacokinetics andpharmacological effect of propofol was not observedto depend on the composition of plasma, including thelevel of proteins, hematocrit, erythrocytes or the levelof erythrocytes in the patients of groups I–III, accord-ing to the ASA scale, who underwent surgeries andwhose values of the abovementioned results were con-tained within the standard limits [11]. In intensive careunits (ICU), patients’ clearance of propofol may de-pend on the level of triglycerides in the plasma andbody temperature, though studies on the subject are notunequivocal. One of the reasons for that fact is a rela-tively small number of patients [9, 29]. In hemorrhagicshock, the elimination of propofol is slow, whereas thepharmacological effect is intensified [30, 42].

A significant role in accounting for those changesis ascribed to the impaired cardiac output [44]. In ICUpatients suffering from reduced myocardial contractil-ity, the clearance was slower by as much as 38% incomparison with critically ill patients without heartfailure. Simultaneously, the pharmacodynamics ofpropofol depended on the severity of the patient’sstate expressed according to the Sequential OrganFailure Assessment (SOFA) score. As the state ofhealth deteriorates, smaller doses of propofol werenecessary to obtain the same degree of sedation [45].


Recently, Wiczling et al. [65] have developed thePK/PD model of propofol in patients undergoingabdominal aortic surgery. The authors noted anincreased value of propofol metabolic clearance(2.64 l/min) coupled with decreased sensitivity to pro-pofol anesthesia. The obtained value of EC50 wasabout 2.19 mg/l, which was in agreement with theliterature values of 1.98 mg/l for ICU patients and1.84 mg/l for the patients with SOFA score equal 15[9, 42]. Propofol is also widely used during cancersurgery. It has been recently demonstrated that neoad-juvant chemotherapy before surgery significantly re-duces the EC50 of propofol for induction of anesthesia(EC50 was about 4.11 mg/l in the non-neoadjuvantgroup, whereas in the taxol- as well as cyclo-phosphamide-adriamycin-5-Fu groups they were 2.94and 2.91 mg/l, respectively) [68]. Further studies on

the pharmacokinetics and pharmacodynamics of pro-pofol are required in this group of patients, becauserecent literature data have suggested that anestheticdrugs may influence the patients’ long-term outcomeafter cancer surgery. It was shown on animals that,contrary to other studied agents, propofol did notincrease the tumor metastasis. Although human dataare more difficult to interpret, due to some beneficialeffects propofol may be expected to be increasinglyused in cancer surgery [58].

The animal research suggests that the time of theday may be a factor determining the effect of propofol[10, 14]. That supposition was not confirmed by thetests on critically ill patients exposed to propofol infu-sion for a prolonged time [9]. However, it is worth not-ing that severe disorders in the rhythms of essentialvital signs were observed in ICU patients [7, 9, 43].



Fig. 3. A comparison of the literaturepharmacokinetic models of propofol(Schnider [53], Bjornsson [12], Schut-tler [55], Marsh [34]) for a 40-year-oldmale adult of 70 kg and 170 cm. Thefollowing infusion was used for thesimulations: initial dose 2 mg/kg, rate ofinfusion 0.2 mg/min/kg and duration ofinfusion 200 min. The continuous linerepresents typical propofol concentra-tions, whereas the shaded area repre-sents the range of concentrationsfound across all the subjects in thestudied population. The dotted line rep-resenting a typical concentration of theSchnider model is presented for aneasy comparison

Pharmacokinetic models available in TCI

systems

TCI systems for dosage of propofol have been avail-able since 1997. The first systems included a Diprifu-sor® microprocessor (Astra Zeneca, UK), pro-grammed on the basis of the Marsh pharmacokineticmodel developed for adult patients. In the beginning,the dosage was based on the basis of simulated con-centration of the drug in the plasma. Then, after intro-ducing parameter ke0, describing the rate at which thedrug enters the biophase, i.e., the brain, the rate of in-fusion can also be adjusted to the current concentra-tion in the effector tissue. Diprifusor® was meant onlyfor one propofol preparation – Diprivan. So calledopen TCI systems, which are currently used, givea possibility to program the dosage of various intrave-nous drugs according to different pharmacokineticmodels. Two open TCI systems are available, i.e.,

Alaris Asena PKTM (Cardinal Health, Alaris Products,Basingstoke, UK) and Base PrimeaTM (Fresenius,France). Two models for adults (the Marsh andSchnider models) and the Kataria and Paedfusor mod-els for children are programmed in the former system.The Base Primera system offers a choice of two mod-els for adults, the modified Marsh model and theSchnider model [3]. Figures 3 and 4 show a compari-son of the pharmacokinetic models of propofol fromthe literature for an adult and for a child, respectively.An interpretation of those diagrams may be useful inclinical practice. The expected concentrations of pro-pofol after administration of a specific dose of thedrug to the patient, shown in Figure 4, are lower forthe Kataria model than for the Schnider and Paedfusormodels. Because of this, when using the Katariamodel, in order to achieve the same target concentra-tions, the infusion pump will administer higher dosesof the drug than the TCI system based on the Paedfu-sor model.


Fig. 4. A comparison of the literaturepharmacokinetic models of propofol(Schnider [53], Kataria [28], Paedfusor[2]) for a 10-year-old male child of30 kg and 130 cm. The following infu-sion was used for the simulations: ini-tial dose 2 mg/kg, rate of infusion0.2 mg/min/kg and duration of infusion200 min. The continuous line repre-sents typical propofol concentrations,whereas the shaded area representsthe range of concentrations foundacross all the subjects in the studiedpopulation. The dotted line represent-ing a typical concentration of theSchnider model is presented for aneasy comparison

Differences between the Marsh and

Schnider models

The models were developed in different investiga-tions and for different populations. Therefore, theirapplication will lead to certain differences in the sug-gested rates of infusion of propofol. The differenceswill be evident within the first ten minutes in patientswith normal body mass and slight obesity. However,in patients with severe obesity, two models will pro-vide different infusion rates during the entire periodof anesthesia [3].

The Marsh model was suggested on the basis of re-search conducted on 3 groups of patients (6 patients ineach); they received three constant infusions of propo-fol administered at the rates of 3, 6 and 9 mg/kg/h, re-spectively. No detailed demographic characterizationof the volunteers was published. However, probablythere were few obese and elderly patients in the popu-lation. Later, Struys et al. suggested amending the ke0value of propofol and that model, known as the Marshmodified model, is applied in the TCI system of BasePrimea [3, 34].

The Schnider model was suggested on the basis ofinvestigation conducted on 24 volunteers of bothsexes (11 women and 13 men with the body massranging from 44 to 123 kg and age from 25 to 81years). The parameters of the model depended on thepatient’s age, total body mass, lean body mass andheight. The lean body mass was calculated on thebasis of the James formula, which works in patientswith slight or moderate obesity, but fails in patientswith severe (BMI > 40) or extreme obesity (BMI >50) [3, 53, 54].

The data available in the literature do not provideevidence of the advantage of either model. Most ex-perts think that anesthesiologists should apply the‘friendlier’ model. With currently available evidence,in most of the clinical situations, the safest options,and those most commonly chosen by clinicians, areeither of the Marsh in plasma mode or the Schnidermodel in effect-site mode. If the Marsh model is usedin effect-site targeting mode, then it should be usedwith the faster ke0 for propofol recommended byStruys and colleagues (1.2 min) [3]. In contrast to theSchnider model, the Marsh model does not allow forthe patient’s age, which is a disadvantage. Thus, inpractice when using the Marsh model in elderly pa-tients, the concentrations of propofol in the plasma

will actually be higher than expected, which may leadto hemodynamic instability. This may speak in favorof the Schnider model in a geriatric population. Fig-ure 5A shows differences in the values of concentra-tions of propofol in the plasma obtained for an infu-sion with the same parameters in a 40-year-old and an80-year-old patient, but described by means of differ-ent pharmacokinetic models. It is evident that theMarsh model does not allow for differences in age,because it assumes identical concentrations of thedrug, regardless of the age.

The application of TCI systems to patients with se-vere and extreme obesity still poses a problem. Clini-cal experiments with the Marsh model applied tothose patients show that the introduction of the pati-ent’s total body mass leads to hemodynamic instabil-ity during the induction of anesthesia. It is relatedwith the fact that in obese patients the volume of dis-tribution of the central compartment does not changeand patients are overdosed with the induction dosecalculated for the actual body weight. Therefore, it isrecommended to calculate induction doses per idealor fat-free body mass. The situation is even morecomplicated by the fact that the demand for propofolduring the maintenance of anesthesia increases pro-portionally to obesity, so maintenance doses shouldrather be adjusted to the total body mass. Thus, theanesthesiologist faces a difficult problem which bodymass should actually be entered to the TCI system.Many follow the recommendations suggested byServin et al. [56] and calculate the body mass on thebasis of the following formula:

IBM + 0.4 (TBW – IBM).

However, this formula seems to work only duringthe first 20–40 min of anesthesia and then the concen-trations remain lower than assumed. Figure 5B showsdifferences in the values of concentrations of propofolin the plasma for an infusion with the same parame-ters, in patients with the body mass of 70 and 120 kg,simulated with the application of different PK models.As can be seen, the Marsh model does not allow fordifferences in the pharmacokinetics of propofol inobese patients. In a study published in 2010, Cortinezet al. [17] suggested a pharmacokinetic model of pro-pofol, which characterized the dependence of thepharmacokinetics of propofol on the patient’s totalbody mass. The model was supposed to adjust thedosage of propofol to obese patients better than theJames formula suggested in the Schnider model. The



authors suggest applying this model in TCI systems.At present special care is recommended when apply-ing TCI systems to obese patients [3].

Although we may realize the limitations resultingfrom TCI systems, simultaneously we must rememberthat even if we ensured perfect precision, which wasclose to a direct measurement of the drug concentra-tion in the patient’s artery, their reaction to the drugmay still be different from our expectations. It is notonly individual variability in the PK parameters of theanesthetic that is a clinical problem, but it is also thepharmacodynamic variability, i.e., different responseto the drug, where its concentration is known and ex-pected. This is a separate issue.

Pediatric models

In order to make children sleep during anesthesia, in-haled drugs are mainly applied. However, recent stud-

ies show that TIVA with propofol may be a good al-ternative to children [15, 53, 54, 61]. Alaris® com-pany offers two pharmacokinetic models for children:Paedfusor and Kataria [2, 28, 33]. Both have beentested in clinical conditions. The minimum age limitfor the Paedfusor model is 1 year, where the child’slowest permissible body mass is 5 kg. The Katariamodel may be applied to children aged over 3 years,with the minimum body mass of 15 kg. Absalom et al.[1] estimated the mean error of the model pro-grammed in the Paedfusor, which was 4.1%. Thevalue was lower than the one for the Dipriphusor inadults [59]. The Paedfusor was validated in clinicalconditions in a group of 29 children aged 1–9 years,qualified for groups II and III according to the ASAscore, who underwent cardiac surgeries [1]. The pre-cision of Paedfusor deteriorates when the system doesnot dose propofol, e.g., after stopping the pump or im-mediately after reducing the target concentration. Inthose periods, the drug concentration measured in theplasma was on average by 20% higher than the con-centration simulated by the TCI pump [1]. The avail-


Fig. 5. The influence of age (A) andbody mass (B) on the propofol phar-macokinetics on the basis of selectedliterature models (Schnider [53],Schuttler [55], Marsh [34]). The simu-lations are for a (A) 40-year-old (con-tinuous line) and 80-year-old (dottedline) male adult of 70 kg and 170 cm;and for (B) a 40-year-old male adult of70 kg (continuous line) or 120 kg (dot-ted line) and 170 cm. The followinginfusion was used for the simulations:initial dose 2 mg/kg, rate of infusion0.2 mg/min/kg and duration of infusion200 min

able children pharmacokinetic models do not enablethe dosage of propofol on the basis of effectorconcentration, because the value of ke0 parameter inthis population has not been appropriately estimated[16, 33].

The dosage regimen of propofol 10-8-6 suggested toadults [50], which ensures keeping maintenance con-centrations at 3 µg/ml, leads to subtherapeutic concen-trations in children. It is the result of higher values ofthe central compartment volume and clearance ob-served in pediatric population (Tab. 1). McFarlan etal. [36] suggested a simple scheme of manual dosageof propofol to children.

We must not forget the fact that the pharmacoki-netic parameters of propofol change dynamically withage and children aged 2 and 12 years cannot betreated in the same way. Besides, high variability ofthe PK and PD of drugs can be observed in this popu-lation. As propofol anesthesia applied to children be-comes more popular, further research concerning op-timal dosage of the drug to this population of patientscan be expected. The studies by Rigouzzo et al. pub-lished in 2010 proved that in children aged between6 and 12 years the Schnider model, which is recom-mended to adults, may be more useful than classic pe-diatric models [49].

Summary

In our opinion the problems presented above and therelated areas of doubt concerning the appropriate se-lection of the system of TCI technologies in differentgroups of patients should indirectly increase alertnessduring TIVA. This applies especially to the group ofpatients who are at risk of perioperative complicationsresulting from the physical state of classes III and IVaccording to the ASA and to the group of patients whoare subjected to a one-time infusion of neuromuscularblocking drugs despite the monitoring of the neuro-muscular block. The continuous broadening and up-dating of the knowledge of clinical pharmacology ofpropofol may be an important extension of practicalskills of both the clinical pharmacist and anesthesiolo-gist. They are key people in the chain of safety linksimplemented according to the rule popularized in theJackson Reason’s ‘Swiss cheese’ model [45].

Acknowledgment:

One of the authors (Pawe³ Wiczling) was supported by a grant

from Iceland, Liechtenstein and Norway through the EEA Financial

Mechanism via Homing Program from the Foundation for Polish

Science.

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Received: November 10, 2011; in the revised form: March 22, 2012;

accepted: April 5, 2012.



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