Glasgow Meeting - May 2003

Frank Engbers, Leiden University Medical Center, NL.

The delivery of Intravenous anaesthesia by rate-adjustable infusion pumps is, in terms of equipment progress, extremely old fashioned. Using a computer to adjust the infusion rate to compensate for the distribution of the drug was developed for scientific purposes already some 20 years ago. These systems allowed for the first time to clinically work with (calculated) blood concentrations and potentially close the increasing gap between clinical practice and published scientific data where drug effects are related to blood concentration. It took the commercial interest and financial power of a pharmaceutical company as AstraZeneca to introduce the technique in clinical practice. At this moment in most parts of the world, except in North America Target Controlled Infusion for AZ propofol using the Diprifusor is available. This strong relationship between drug and device has initially helped the development of TCI by providing the proper studies to prove efficacy and safety of drug and system- [1]. Now with the availability of generic propofol in many countries also the drawback of this relationship becomes clear. The prefilled syringe necessary for using TCI offers several advantages but its high price forces many anaesthesiologists to fall back to manual controlled infusion. From a user perspective it is very promising that equipment manufacturers now also have shown interest in the development of Target Controlled Infusion. Braun and Fresenius have recently introduced systems with which it is possible to use Target Controlled Infusion without dependence on the Diprifusor technology. AneoAB has integrated the TCI technology using the Diprifusor into their TIVA workplace. The implementation of TCI in these systems and their capabilities is quite different.

What the near future will bring for Intravenous anaesthesia and Target Controlled Infusion may become clear by a closer look at what is or will become available at this moment.

Aneo TIVAS (http://www.aneo.se)

The main objective of Aneo was to build an Intravenous Anesthesia Machine. Because no nitrous oxide or inhalation anaesthetics needs to be delivered by the system a relative simple and cost effective ventilator could be used. For the intravenous part two Graseby infusion pumps are incorporated in the system. One of the pumps has the proven Diprifusor technology implemented and the other will be able to use the Remifusor once it becomes available. The advantage is that there is a worldwide, large experience with the Diprifusor. Fail-safe double processor technology, automated syringe and drug dilution recognition undoubtedly contribute to patient safety. Disadvantage is that for TCI, the system is only capable of using relative expensive prefilled syringes from AZ and that the implementation of new developments such as effect site control or patient maintained anaesthesia and implementation of specific pharmacokinetic parameters for patient groups is dependent on the original developer. The integration of the pumps is limited. There is no central control of the infusion pumps so for example patient characteristics must be entered in both pumps separately. The system is CE marked and commercially available in Europe

Braun OTCI( http://www.protiva-partner.com)

Braun was the first developer of a CE marked system that was capable of delivering TCI (or Optimized Target Controlled Infusion:OTCI as it is called by Braun) without using the Diprifusor technology. Because there is no syringe recognition implemented any 1% Propofol theoretically can be used. It allows a centralised control of different infusion pumps. OTCI can be combined with 2 rate adjusted infusions, controlled from the central unit. Implementation of other drugs in TCI mode once the TCI application is registered for that drug is relative easy. Although the system has many possibilities and a nice big screen for information display and control, the user interface still has some hurdles that makes its use less then intuitive. The system is CE marked and commercially available at this moment. Braun has announced the integration of the system in an anaesthesia machine to create an Intravenous Anaesthesia Workstation (PROTIVA).

Fresenius (http://www.fresenius-vial.fr)

Just recently Fresenius developed a dedicated two channel TCI system, Orchestra. It hosts a whole lot of functions that until now where only available in research system such as effect TCI[2], mixing manual delivery with TCI and possibility to use the implemented pharmacokinetic model to 'trace' the manual infusion. This offers possibilities to use information provided by pharmacokinetic models without actually driving a syringe pump. The modularity of the system allows transportation of the pump from one to another TCI base station and still continue in TCI mode. This could be valuable if the same drug will be used after the operation for example on the ICU, a recovery area or on a postoperative anaesthesia care unit or is started before the operation. The system has many possibilities but this of course also increases the risk of misuse. Application of model steered systems introduce their own typical errors and mishaps[3]. The more possibilities and complexity is put in a technical device the more the risk of human error increases. The current system is CE marked for research purposes. It holds pharmacokenetic models for Propofol(both Marsh and Schnider kinetics), Remifentanil and Sufentanil. Drugs can be delivered both in TCI mode and effect TCI mode. The system may offer what real TIVA enthusiasts now are doing with research systems. Anaesthesia however is usually not delivered by pharmacology experts. Differences between Effect Compartment Control and normal TCI, differences between pharmacokinetic sets(e.g. Marsh and Schnider[4]),  may confuse the every day user and lead to dangerous situations. Although effect compartment control has been used with research systems in many patients there are still some theoretical pitfalls associated with this kind of control that need some further study. Hopefully Fresenius will restrict the full capabilities of the system when it is commercially released until prospective studies have shown the efficacy and safety of certain combinations of drug/ kinetic sets and control mode.

The systems described above are in their early stages of development and may have been changed in the mean while. Please contact the manufacturers for an updated picture. Apart from commercial developments there are developments in research institutes. Without trying to be comprehensive a few main lines of investigation can be distinguished.

Closing the loop

Getting the anesthetist out of the control loop has been the wish of many control engineers working in this area. If the effect of the drug can be measured than the drug delivery can be adjusted by a controlling device. This is relative simple with muscle relaxant drugs. With anaesthetics the difficulty is that the measured effect is generally a population measurement which is used as a surrogate for adequate anaesthesia in the individual patient. Nevertheless it is proven to be possible to use Bispectral Index or Auditory evoked potentials to automatically adjust the output of a pharmacokinetic model for propofol and steer an infusion pump[5,6 ,7]. The question if these systems give a real added value to the practicing anaesthetist(and thus the patient) still needs to be answered. For research purposes they are however very useful because they deliver the drug in an unbiased way. One of the problems of the close loop systems is that they cannot foresee what the surgeon is going to do with the patient in terms of surgical stimulation. To solve this problem it has been suggested to monitor the brain of the surgeon in addition to the brain of the patient.

To my knowledge there is only one research system that tries to incorporate the surgical events into a open controlling loop: Toolbox[8]. To differentiate surgical stimulation in different group of patients is a challenging task but modern communication- and computer-technologies together with this new pump technology might help in de future to produce the large and accurate numbers that are necessary to identify anaesthesia requirements of specific patients in specific situations.

Identification of pharmacodynamic differences between male and females have been shown up as a side product of a large study involving the BIS as a dose guiding instrument[10]. Another form of closing the loop is by putting the patient in the control loop. This can be done the old fashioned way : delivering intermittent boluses as in patient controlled analgesia(PCA), or by letting the patient adjust the target of a TCI system: Patient Maintained Analgesia(PMA)[11,12], Patient Maintained Sedation(PMS)[13], premedication or even anti nausea or anti pruritus therapy could benefit from this technique. The target of such a system could be either the calculated blood or the calculated effect site. Numerous studies have shown that using targets instead of fixed boluses reduces onset time, side effects and complications. Already there are research systems that can be changed from a 'normal' TCI system to be used during surgery by the anaesthesiologist to a patient maintained system in the postoperative period.

Optimising Pk/Pd

Compartmental models are oversimplifications of reality. Dynamic phenomena as drug mixing cannot be described by simple compartmental models while they most likely rely on physiologic parameters such as cardiac output[14]. Parameters of compartmental models are derived in healthy patients that stayed within normal physiological limits. In order to describe the increasingly older and sicker patient population that comes to the operation theatre more accurately in terms of Pk/Pd properties, more elaborate models might be necessary. Whether these models will be pure recirculatory, physiologic or hybrids with compartimental models is still under investigation. The development of non invasive new monitoring that is able to measure (regional) blood flow instead of blood pressure may help to develop or even clinically utilize such models. There are many recent pharmacodynamic studies on the interaction of drugs. It is possible with the new development of multichannel infusion pumps to use the interaction models to supply the user with relevant data. Adjusted concentration response curves by self-learning systems will help the anaesthesiologist to individualise TCI targets.

Conclusion

Development of TCI until now has been driven mainly by the pharmaceutical industry with the consequence that the drug-TCI combination until now was well studied before released. Drugs with relative long terminal elimination half-lives and large distribution volumes are considered by the 'experts' to benefit most of target controlled infusion. However, future IV drug development for anaesthesia will most likely go towards a profile like that from Remifentanil: short elimination half live with small distribution that will give an early steady state and hence a constant and short context sensitive half live. The author does not share the view that the pharmacokinetic properties alone determine the usefulness of the TCI mode for a drug. The possibility for fast change and implementation of population pharmacokinetics will increase the controllability of the anaesthetic process. The real question is do we need this technology to deliver anaesthesia. The answer is probably not. In terms of direct measurable patient outcome the numbers will never be large enough the prove the importance of these developments in pump technology. But the same is most likely true for advances in vaporizers technology, ventilators and monitoring devices. It is however obvious that these pump systems will allow to connect research to practice and vice versa. This will broaden our knowledge of the drugs we use and stimulate useful research. It will furthermore enhance the possibilities to extend the intraoperative drug administration to the period after (and before?) the anaesthesia. Common sense dictates that all this certainly will be beneficial for our patients.

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