Blood Propofol Concentrations: On Demand for

Pharmacokinetic/Pharmacodynamics Models and New

Measurement Automatic Technologies

S. Campos

, A. Silva

, P. G. de Pinho

and L. Antunes

Veterinary Sciences Department, Universidade de Trás-os-Montes e Alto Douro

Quinta de Prados, Apartado 1013, 5001-801 Vila Real, Portugal

Laboratory of Toxicology, Department of Biological Sciences, Faculty Pharmacy

Universidade do Porto, Porto, Portugal

Abstract. Propofol is a widespread anaesthetic agent in human medicine. It

allows the practice of total intravenous anaesthesia through the use of

sophisticated delivery systems due to its pharmacokinetic/ pharmacodynamics

properties.

Three New Zealand White rabbits were anaesthetized with three different

infusion rates (70, 100, 130 mg.kg

-1

) in a random order, during thirty

minutes each. Clinical parameters as well as arterial blood samples were

collected at specific time points. Rugloop II Vet software was used to storage

all data and to predict the propofol concentrations during the anaesthetic period.

A correlation analysis was done between real and predicted propofol

concentrations, in each infusion rate.

It was only observed a significant correlation between concentrations during the

lower infusion rate (70 mg.kg

-1

There is a lack of automatic devices and pharmacokinetic/pharmacodynamics

models that allow a real-time or predicted measurement of the propofol

concentrations in the patient, for veterinary medicine.

1 Introduction

During the last decades, the growing knowledge about the pharmacokinetic properties

of propofol allowed a continuous remodeling of pooled data, describing together

information of clinical trials and adequate modeling for the specie in which it is used

[6]; [7]. These characteristics are very well documented in humans and, in veterinary

medicine some research groups have already reported pharmacokinetic data for

propofol, especially in the dog and the cat [3]; [5]; [1]; [7].

From a pharmacokinetic point of view, propofol remains the best controllable

intravenous hypnotic, since it has a huge body uptake and a fast elimination due to a

large apparent volume of distribution and a high clearance [6].

Drug delivery systems, based on pharmacokinetic and pharmacodynamic

properties of propofol, were developed allowing a reasonable real-time estimation of

its plasma concentrations, during the anaesthetic period [6]; [9]. This can be equated

with the continuous measurement of end-tidal volatile anaesthetic agent concentration

Campos S., Silva A., G. de Pinho P. and Antunes L..

Blood Propofol Concentrations: On Demand for Pharmacokinetic/Pharmacodynamics Models and New Measurement Automatic Technologies.

DOI: 10.5220/0003880900180023

In Proceedings of the International Workshop on Veterinary Biosignals and Biodevices (VBB-2012), pages 18-23

ISBN: 978-989-8425-94-2

 2012 SCITEPRESS (Science and Technology Publications, Lda.)

that led to the concept of MAC (Minimum Alveolar Concentration) and provides the

best available method to monitor continuous brain concentration, nowadays.

Pharmacodynamic properties of propofol depend on its therapeutic plasma

concentrations. The knowledge of pharmacokinetic models allows a more accurately

prediction of the optimal dosage [9]. The required plasma concentration varies with

the desired pharmacological effect (sedation, induction or maintenance of

anaesthesia), the simultaneous use of other drugs (opioids, muscle relaxants), the type

of operation and the patient’s sensitivity to the drug (age, weight and pre-existing

diseases) [9]. So, the use of propofol demands a continuous titration of the drug

infusion rate to the desired pharmacological end point, however there is an absence of

a clinically useful method for measuring blood propofol concentrations.

In this study, an analysis over real propofol concentrations together with predicted

concentrations was performed using a rabbit model.

2 Methodology

2.1 Animals

All procedures were carried out under personal and project licenses approved by the

national regulatory office (Direcção Geral de Veterinária – DGV). Three healthy male

New Zealand White rabbits, approximately 2 months old, were used.

2.2 Anaesthetic Protocol

Anaesthesia was induced with a dose of 20 mg.kg

-1

propofol (Propofol Lipuro®, B.

Braun Melsungen, Germany) intravenously, using a syringe pump (Asena GH, Alaris

Medical Systems) controlled by the Rugloop II software (developed by Tom DeSmet

(Demed Engineering, Gent, Belgium)) at an infusion rate of 200 ml.h

-1

. Following

blind orotracheal intubation with a cuffed endotracheal tube with 2.5 mm in internal

diameter, propofol started to be administered according to an infusion scheme in

which three infusion rates were used in every animal: each infusion (70, 100 and 130

mg.kg

-1

) was maintained during thirty minutes. The order of the administration

rates chosen for each animal was random.

Monitoring of anaesthesia included cardio-respiratory parameters (heart rate (HR),

mean arterial blood pressure (MABP), arterial blood oxygen (SpO

) and respiratory

rate (RR)), temperature (T), clinical evaluation of depth of anaesthesia (DoA) and the

Index of Consciousness (IoC).

Anaesthetic monitoring included cardio-respiratory monitoring provided by a

Datex S/5 Anaesthetic station (Datex Ohmeda, Helsinki, Finland) which included:

pulse-oxymetry and pulse rate monitored with the probe placed in the ear, invasive

mean arterial blood pressure (MBAP), inspired and end-tidal concentrations of

oxygen and carbon dioxide. The animals were under mechanical ventilation with

100% oxygen, with ventilation parameters set to maintain the end-tidal CO

(ETCO

)

between 35 and 45 mmHg. At the end of the infusion scheme fresh gas flow rate was

increased to 5 L.min

-1

of 100% oxygen until the rabbits regained swallowing reflexes

and at this point extubation was performed. Animals were considered recovered from

anaesthesia when they exhibited an alert stance and had regained ambulation and

limbs coordination.

2.3 Data Acquisition

Data were stored using the Rugloop II Vet software that was also used as software to

predict the propofol concentrations at the different time points. This software uses the

Beths’ pharmacokinetic/ pharmacodynamics parameters for propofol in order to

predict its concentration in blood.

2.4 Blood Sampling

Arterial blood samples were collected before the beginning of anaesthesia and at three

time points in each infusion rate (20, 25 and 30 minutes after the start of the infusion

rate) and in the totally recovered animals (Figure 1). This infusion scheme was

designed to achieve a steady-state, based on pharmacokinetic data of clearance from

Cockshott et al. [3].

Fig. 1. Schematic representation of blood samples (S) collection. S

represents the baseline

sample; S

, S

and S

represent the blood sample collection of each infusion rate. S

is collected

20 minutes after the beginning of each infusion rate; S

is collected 5 minutes after S

and S

collected 5 minutes after S

. S

rec

is the blood sample collection from recovered animals.

2.5 Propofol Quantification in Blood Serum

Propofol concentrations were determined by Gas Chromatography/ Ion Trap - Mass

Spectrometry (GC/IT-MS) in rabbit serum. This method was adapted from that

previously described by Guitton et al. 1995, used to quantify propofol in human blood

[4].

2.6 Statistical Analysis

Statistical analyses were performed by using Excel® and GraphPad Prism®

(GraphPad Prism, version 5.00 for Windows, GraphPad Software, San Diego,

California, USA, and www.graphpad.com). A Kolmogorov-Smirnov test [8] was used

to test data for normality.

Recovery

Third infusion rate

First infusion rate

Second infusion rate

rec

30 min. 30 min.

30 min.

Undetermined

Pearson and Spearman Rank correlation analysis were used to study the

correlation between real propofol concentrations and the propofol concentrations

calculated by Rugloop II.

3 Results and Discussion

In this study, three rabbits weighing 2.79±0.25 Kg were successfully anaesthetized

with three different propofol infusion rates (70, 100 and 130 mg.kg

-1

) in a

randomized order, during thirty minutes.

Anaesthetic induction was smooth in all animals, without any excitatory

movements and was achieved with a propofol bolus of 20 mg.kg

-1

. Due to the

randomization of the infusion schemes, the same infusions and its duration did not

produce the same propofol plasma concentrations.

The duration of the infusions was stipulated based on pharmacokinetic data of

propofol in rabbits from Cockshott et al. [3]. A ten minute steady-state at the end of

each infusion rate was produced, according to data from these authors. Table 1 shows

the infusion schemes that were made for each rabbit.

Table 1. Propofol infusion schemes order and respective rabbit.

Rabbit(s)

Infusion scheme

(mg.kg

-1

)

1 and 2

70→130→100

100→70→130

As it can be observed in the graphs, the propofol concentrations predicted by the

software are underestimated when compared with the real propofol concentrations,

particularly at high infusion rates. This is especially important due to the dose-

dependent effects of anaesthetics that should be precisely measured in the blood and

automatically adjusted to the desired level of anaesthetic depth and hemodynamic

answers of the animal. Besides, it was only observed a very significant correlation

(r=0,833; P=0,0083) between real propofol concentrations and predicted

concentrations during the lowest infusion rate (70 mg.kg

-1

). The other two infusion

rates did not show significant correlations. This indicates that the pharmacokinetic/

pharmacodynamic parameters incorpored in VET Rugloop II are not adequate for

estimation of propofol concentrations when infusion rates above 70 mg.kg

-1

are

used, in rabbits. This can be justified because the pharmacokinetic/

pharmacodynamics parameters from the VET Rugloop II are based on the Beths

model for dogs, which are suited for other species [2].

Despite many advantages over traditional volatile anaesthetic techniques, propofol

total intravenous anaesthesia makes up a small percentage of general anaesthetics

administered. One of the reasons for this is the absence of a clinically useful method

for measuring blood propofol concentrations.

The knowledge of the real propofol plasma concentration achieved at each study

moment may allow a more precise analysis of the effects of propofol on clinical signs

R130

100

120

140

Infusion rate

Real PC

Predicted PC

Rabbit 3

Infusion rate (mL.h

-1

)

Propofol concentration (

g.mL

-1

)

Fig. 2. Graphic representations of real propofol plasma concentration, predicted propofol

concentration and for infusion rate to rabbit 1, 2 and 3. In the x-axis is represented each blood

sample collection (S1- sample 1; S2 – sample 2 and S3 – sample 3) for each propofol infusion

70S1

70S2

70S3

R10

100

120

140

Real PC

Predicted PC

Infusion rate

Rabbit 1

Infusion rate (mL.h

-1

)

Propofol concentration (

g.mL

-1

)

R70

R130S

R100S3

100

120

140

Real PC

Predic ted PC

Infusion rate

Rabbit 2

Infusion rate (mL.h

-1

)

Propofol concentration (

g.mL

-1

)

rate (R70 – infusion rate of 70 mg.Kg

-1

; R130 – infusion rate of 130 mg.Kg

-1

and R100 –

infusion rate of 100 mg.Kg

-1

of the anaesthetized animals. This is particular important attending to the different

animal species that demand the development of pharmacokinetic/pharmacodynamic

models for each one of them, in order to respond to the individual variance between

species.

In conclusion, regarding the intravenous anaesthesia in the veterinary medicine

there is a huge lack in the offer of devices and pharmacokinetic/pharmacodynamics

models that allow an accurate and real-time measurement (predicted or real) of the

intravenous anaesthetics in the animal, for immediate adjustment of the anaesthetic

plane.

Acknowledgements

This investigation was supported by FEDER funds through the COMPETE Program,

and by national funds from Portuguese Foundation for Science and Technology,

under the project COMPETE: FCOMP-01-0124-FEDER-009497 PTDC/CVT/

099022/2008).and personal grant from FCT: SFRH/BD/72360/2010.

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