Target-controlled infusion (TCI) systems have been in use for >2 decades. The history of the development of TCI and the underlying concepts is discussed in an accompanying article.1
Initially, only custom-made prototype systems were available, having been developed by different research groups who tended to use disparate names and acronyms to describe their systems. In 1996, a group of investigators proposed a standard nomenclature.2 It included the use of the generic term “target-controlled infusion” to describe this type of infusion system. This coincided with regulatory approval in Europe of the first generation of standalone TCI systems. These systems were designed to specifically administer the Diprivan® (AstraZeneca, Macclesfield, UK) formulation of propofol and only accepted syringes with the Diprivan label. After patent protection of Diprivan expired in Europe, a second generation of infusion pumps was introduced. These were termed “open TCI” pumps because they could use any syringe. The second generation of TCI pumps provided the user with the ability to administer a selection of drugs (e.g., propofol, remifentanil), using different pharmacokinetic (PK) models. In addition, the ability to target drug concentration in either the plasma (the original mode) or the effect site (e.g., the brain, based on the models of blood–brain equilibration) was introduced.
Since its introduction, TCI technology has transformed from a research tool in expert hands to a routine part of clinical anesthesia practice in many countries. However, the use of nonapproved software and prototypes did not stop with the introduction of commercial TCI systems. Several such programs also include data management modules that generate an electronic record of details indispensable for PK and pharmacodynamic (PD) studies. They also allow the user to implement, and use, modified or new PK/PD models. For these reasons, these systems are still commonly used during pharmacologic studies, even in countries where commercial TCI devices are available.
In this article, we describe the extent to which the technology and practice have spread, both geographically and within current sedation and anesthesia practice for the facilitation of different types of procedures.
NONAPPROVED TCI SOFTWARE, TCI PROTOTYPES
From a search of PubMed and Google Scholar (up to January 2015), book chapters, reference lists, and conference abstracts, we identified 14 groups that have developed 1 or more TCI software programs or prototypes. These systems will be discussed in the order in which they were completed, bearing in mind the fact that for many amateur programmers, the term “completed” is a relative concept and also that several programs evolved over time. The complete lists of peer-reviewed publications of studies in which these software or hardware systems were used for general anesthesia are provided in Supplemental Digital Content 1 (http://links.lww.com/AA/B240), which lists the references for the 14 nonapproved programs we identified, listed in order of the first publication. Several of the software programs are still commonly used. As can be seen in Appendices 1 and 2, the prototypes have been used for a wide variety of applications in a wide variety of settings. More than 50 studies have used prototypes for sedation, of which only 3 describe their use in critically ill patients. The dates that follow the system name are the range of publication dates. Table 1 summarizes the 14 nonapproved systems developed by academic laboratories worldwide (Europe, North America, South America, and Asia) over the past 33 years. The systems are listed in the order of first publication. Supplemental Digital Content 1 (http://links.lww.com/AA/B240) lists 559 references to studies conducted with these 14 TCI systems. Five of these systems are still used in clinical and basic research: IVA-SIM, STANPUMP, RUGLOOP, AnestFusor, and Asan Pump. Further information about the history of TCI development can be found in a companion article.1
APPROVED TCI SYSTEMS
An internet search was performed to identify the names and contact details of all commercial companies actively manufacturing and distributing TCI devices during the period 2004 to 2013. It is also based on the responses of medical device companies to a questionnaire requesting information about their systems (Appendix 1).
TCI devices are approved and/or sold in at least 96 countries (Fig. 1; for a full list of countries, see Appendix 2). Manufacturers, and, where available, sales figures, will be discussed in the following sections. There are large differences among the medical device companies in the TCI device proportions that constitute total infusion pump sales. Table 2 summarizes details of the drug models and modes available in each pump.
Officially, no TCI pumps have been sold in the United States. However, an initiative called Triservice Anesthesia Research Group Initiative on Total IV Anesthesia (TARGIT) was set up to promote the use of total IV anesthesia (TIVA) in the military. TCI pumps purchased in Europe have been used by U.S. military anesthesiologists outside the United States (Anthony Absalom, also a coauthor, personal communication, 2005).
First-Generation TCI Systems
Starting in 1996, 3 medical equipment manufacturing companies produced and sold the first-generation TCI systems: Graseby (part of Smiths Medical, Ashford, UK), Fresenius (Brésins, France) (later Fresenius-Kabi, Bad Homburg, Germany), and Alaris Medical Systems (Basingstoke, UK later Cardinal Health Inc., then Carefusion Inc., Basingstoke, UK). The first-generation TCI systems all incorporated a Diprifusor™ module (AstraZeneca, Macclesfield, UK), loaded with the mathematical (infusion) algorithms developed by the Glasgow group, and the Marsh PK model.3
These systems have received regulatory approval from >50 countries, including Japan, China, and most countries in South America. Approximately 25,000 modules have been provided to a widening group of medical device companies. On the basis of this, we assume that approximately 25,000 TCI pumps based on the Diprifusor model have been sold and used. Because these devices will only infuse Diprivan-labeled propofol, they are considered closed systems.
Of the 3 original companies, all 3 stopped marketing and selling their first-generation TCI pumps from 2004 to 2013. The primary reason was that customers did not want to be locked into a single supplier of propofol. All the companies continue to provide service and support for existing pumps.
Of the approximately 25,000 first-generation TCI systems sold, we estimate that 15,000 were sold before 2004 and 10,000 between 2004 and 2013. The principal medical device company actively marketing and selling Diprifusor-containing pumps is Terumo, Japan, with sales between 2004 and 2013 of 5600 units in Japan and 600 units in the rest of Asia and Europe.
We were able to trace and contact 7 commercial companies (Arcomed, Bionet, Braun, Carefusion, Fresenius, Terumo, Veryark) that actively manufactured and sold approved second-generation TCI pumps between 2004 and 2013 (among them the companies have marketed 13 models of TCI pump). The open TCI devices sold by these companies are shown in Figure 2. Of these 7 companies, 1 company declined to participate. Another company provided most of the information requested, but it declined to provide sales figures. The remaining 5 companies that were prepared to disclose their sales figures reported total sales of almost 37,000 second-generation TCI pumps between 2004 and 2013.
Current Frequency of TCI Drug Administration
Sales figures provide data on the market penetration of a technology, but actual use of a technology depends on more than the availability of the equipment, the clinical workload, and the choices of the users. Thus, we begin with an estimate of usage in the hospital where 2 of the authors work (University Medical Center Groningen [UMCG]) and thereafter discuss usage elsewhere.
University Medical Center Groningen
At the UMCG, TCI systems are used by anesthesiologists and specialist sedation nurse practitioners. To approximately estimate our use of TCI, we collected data from our hospital information system on all elective and emergency procedures during a representative week (November 24–30, 2014) and extrapolated to a whole year by multiplying by 48.5 (to adjust for reductions in elective activity during public holidays and during the summer vacation).
On the basis of the above findings, we estimate that at the UMCG, 23,600 patients per annum receive care from an anesthesiologist. Of these 1400 receive 1 or more drugs for sedation and 20,200 receive 1 or more drugs for general anesthesia. Of the patients receiving sedation, approximately 1000 (78%) receive an infusion of 1 or more drugs. In approximately 700 patients, the sedative drug (1 or more of propofol, remifentanil, or sufentanil) is administered by TCI.
Of the patients receiving general anesthesia, 18,100 require maintenance of anesthesia (patients undergoing a brief procedure requiring only induction of anesthesia, e.g., electroconvulsive therapy, were excluded) and are 3 years or older (3 years is the lower age limit for TCI propofol using the model proposed by Kataria et al.12 with which the pumps are programmed). For maintenance of anesthesia, IV anesthetic drug administration is used in approximately 75% of our patients and inhaled volatile agents in approximately 24% of our patients. For the remaining 1% of patients, the technique was not recorded. Among patients in whom anesthesia is maintained with IV agents, TCI is used in 66% of patients and non-TCI techniques (such as simple infusions or repeated boluses) in 34% of patients. An estimated 9100 patients receive 1 or more drugs by TCI (for maintenance of anesthesia) under the care of an anesthesiologist per annum. Drugs administered by TCI include propofol, remifentanil, and sufentanil. The patients receive these drugs by TCI for a wide range of procedures. The proportion of cases in which IV infusions are administered by TCI varies according to the surgical specialty and location. For example, in the radiology suite, TCI is used in approximately 33% of patients, whereas in the neurosurgical operating room, TCI is used almost exclusively.
During 2014, an additional 1029 patients received sedation under the direct care of a nurse sedation practitioner. Of these, all received propofol and remifentanil by TCI. Based on these estimates, it seems that approximately 10,800 patients receive 1 or more drugs for sedation or anesthesia by TCI per annum at the UMCG.
Great Britain and the Republic of Ireland
We were able to estimate TIVA and TCI usage in Great Britain and Ireland from the data acquired as part of the National Audit Project on accidental awareness during general anesthesia (NAP5).17,18 An essential part of this project involved a survey of the activity of anesthesiologists in all the United Kingdom and Irish National Health Service hospitals during from September 9 to 16, 2013.19 During the course of the survey, for each patient cared for by an anesthesiologist, details of the anesthetic technique and the diagnostic or therapeutic technique were recorded. Additional details relevant to IV anesthesia practice were kindly provided by one of the authors of the report (Dr. Mike Sury) on behalf of the NAP5 group.
The NAP5 activity survey19 estimated that 3,598,500 patients per annum are cared for by an anesthesiologist (in Great Britain and Ireland), among whom 3,075,400 received 1 or more anesthetic agents for sedation or general anesthesia. Of this group, 375,100 received an IV hypnotic agent for maintenance of sedation or anesthesia, although of these 10,800 received only intermittent propofol boluses and 61,300 received a mixed technique involving propofol (boluses or infusion) and an inhaled agent. Of the remaining 303,000 patients believed to have received TIVA or sedation, TCI was estimated to have been used in 237,000 patients (78%). This overall percentage was dependent on the clinical location where anesthesia was administered. For many surgical specialties, TCI was used in >90% of patients. However, similar to our experience at UMCG, in radiology suites, TCI was used in approximately 30% of cases. TCI was used during all recorded classes of diagnostic and therapeutic procedures, except for chronic pain procedures.
Frequency of TCI Use Within Europe
We were unable to find statistics to help estimate use of TCI in Europe. Thus, European usage can be estimated only by extrapolation. TCI usage varies within hospitals (based on the specialty and practitioner choice) and is likely to also vary among hospitals and among countries. Extrapolation on the basis of usage in 1 hospital is likely to give an unrealistic estimate. However, as shown earlier, the NAP5 data do give a reasonably reliable estimate for 2 countries (Great Britain and Ireland; with a combined estimated population of 68,709,600 on December 1, 2014a). If one ignores the health care activity in the many nonnational health service hospitals in Britain and Ireland and extrapolates these figures to the whole of Europe (estimated population of 742,450,000 on December 1, 2014a), then an estimated 2.6 million patients receive TCI administration of 1 or more drugs per annum in Europe.
For the purposes of this article, exact numbers are not particularly important. Based on the sales data, and also on the data from a few sources, TCI has become a routine part of anesthesia care in Europe. Thus, it is a mature technology.
Regulation and Education
There is no regulatory framework or legislation that specifically determines who may or may not use a TCI device. There is no regulatory requirement for the training required for competent use of TCI. Naturally, the restrictions that apply to the use of the drugs delivered by TCI do apply. TCI devices are programmed to only deliver agents in accordance with the approved details (as printed on the drug package insert). More specifically, TCI devices only deliver approved drugs, for approved indications, at approved doses, by approved routes of delivery. The infusion rates used by TCI are within the range of the infusion rates specified on the package insert.
The user interfaces of all devices display real-time information on the current rate of infusion in milliliters per hour and also in mass units (e.g., mg/kg/h). In this way, users can verify that the current dosage is appropriate and within approved dosage. To the best of our knowledge, any regulation of the use of TCI devices themselves depends on local arrangements. In the case of the UMCG, the department of anesthesiology requires all potential users to have first attended an educational session on the principles and practice of TCI.
With regard to education, some countries have now included topics related to TCI in the anesthesiology examinations syllabus. In Great Britain, training in anesthesiology is regulated by the Royal College of Anaesthetists. Examinees are given questions related to TCI in their written and verbal accreditation examinations. TCI knowledge is explicitly mentioned as core competencies or knowledge in the syllabi of the Royal College of Anaesthetists for basic and intermediate training of anesthesiologistsb: Specific topics included in the examination are as follows:
- PK modeling: types of models available: 1-, 2-, and 3-compartment models; noncompartmental; physiological. PK parameters: volume of distribution, half-life and time constant, clearance.
- Context-sensitive half-time: comparison of drugs, e.g., propofol, fentanyl, and remifentanil.
- TCI in practice: accuracy, applicability, cost. Variations because of patient differences: predictable and unpredictable.
- Discusses the place of infusions compared with bolus doses and TCI, and the pharmacologic models and pump technology relevant to their use.
- TIVA and TCI: Demonstrate how a TCI system is set up and used to deliver both induction and maintenance levels of IV agents. Discuss the advantages and disadvantages of such a technique.
- PKs: Including TCI and effects of renal and/or hepatic impairment on drug disposition and elimination of influence of renal replacement therapies of commonly used drugs.
In most countries of continental Europe, anesthesiologists are required to sit and pass the examinations for the European Diploma in Anaesthesia and Intensive Care to obtain certification. These examinations have a strong emphasis on the pharmacology of the anesthetic agents but do not explicitly mention TIVA or TCI.c However, questions on TIVA and/or TCI are sometimes used, particularly in the oral section of the examination.
Over the years, several societies have been formed with the aim of promoting education related to, and good practice of, IV anesthesia. In general, the driving force behind these societies has been a recognition of the fact that thorough knowledge of the principles of PK/PD is essential for safe practice of IV anesthesia and in particular of TCI. The active and reputable societies include International Society for Anaesthetic Pharmacology (http://www.isaponline.org/), Society for Intravenous Anaesthesia (http://siva.ac.uk/joom2/), European Society for Intravenous Anaesthesia (http://www.eurosiva.eu/ and http://www.tivamerica.com/), and Asia Oceanic Community for Intravenous Anaesthesia (http://aociva.com/index.php). Many of these societies run practical workshops at their congresses, and some have provided written tests and provided those passing the tests with certificates as evidence thereof.
Helmut Schwilden articulated the foundations for the practice of TCI >3 decades ago.20 The basic principles, availability of anesthetic and analgesic drugs suitable for use by continuous infusion, and advances in computer technology have helped improve the popularity of the use of TCI for anesthetic agent administration, whether for induction or maintenance of anesthesia or simply for sedation or analgesia.
Software-only TCI platforms, mostly unapproved, have been widely used, mostly by research groups, and have become an essential tool in various avenues of research. Early studies were primarily characterizing the PK/PD of the drug being infused. There were no surprises: The PKs of anesthetic drugs when given by TCI looks like the PKs of anesthetic drugs given by conventional infusions (it would defy the fundamental principles of PKs if this were not the case). Once individual drugs had been studied, investigators used TCI to understand the combinations of plasma and effect-site concentrations of 2 different drugs and to facilitate study of the PK/PD interactions between the 2 agents. TCI is also used to provide stable concentrations to facilitate studies of monitors of anesthetic depth or simply to provide stable anesthesia to facilitate studies of unrelated phenomena. As a result of this broad range of clinical and research applications, TCI research software has been used in >500 clinical studies published in peer-reviewed journals. Nonapproved TCI systems are also commonly used in animal studies, where they are an important tool in PD studies.
TCI has now gained significant traction in clinical practice and a place in the resident training programs in many countries. Since 1996, >60,000 TCI pumps have been sold. First-generation pumps were first used in 1996 and continue to be used to this day. Second-generation pumps were first approved in 2003 and are commonly used in current practice. Commercially available TCI pumps are sold in most industrialized nations and in many low- and middle-income nations. Currently, they are available in >90 countries.
In the institution of 2 of the authors (UMCG), >10,000 patients receive 1 or more drugs by TCI per annum. Approximately a similar number receive TCI anesthesia in the St. Galen region of Switzerland (Thomas W. Schnider, also a coauthor, personal communication). Given the local presence and influence of enthusiastic users of TCI, these figures are probably not representative of overall European usage. The figures for Great Britain and Ireland may or may not be representative for Europe. Although proportional usage may be higher in a country such as Italy where TIVA is said to be popular (P. Martorano, personal communication), it is likely to be lower in some of the less affluent countries. If one extrapolates the British and Irish figures to the whole of Europe based on the relative populations, then the annual number of uses is in the region of 2.6 million, and the global usage may be approximately 5 million.
TCI is used to provide sedation or anesthesia for patients undergoing a wide range of types of diagnostic and therapeutic procedures. Although current TCI devices do contain models for pediatric TCI propofol administration (validated for children as young as 3 years, in the case of the Kataria et al.’s model,12 and 1 year in the case of the Paedfusor model13), TCI use is currently limited in the pediatric population. Possible reasons include lack of knowledge of, or exposure to, the technique in children, concerns about the validity of the models in children, and fears that enabling the use of pumps programmed with both adult and pediatric models may compromise safety.
Currently, no data demonstrate that TCI administration of drugs is associated with better patient outcomes than manual administration.21 However, the findings of early studies, that anesthesiologists felt TCI was an excellent tool that helped to facilitate smooth and accurate provision of anesthesia, are likely to apply just as well to anesthesiologists currently practicing, judging by the growing popularity of TCI.
Although TCI is well established in many parts of the world, it remains an active area of research. With better insights into the pharmacologic modeling in patients at the extremes of physiology (the very young or old, and the obese), and recent publication of new models suitable for these patient groups,22,23 it is likely that the indications for TCI administration of drugs will increase. The field of IV anesthesia is advancing at such a pace that TCI systems have moved on from being seen as experimental and new and are now becoming an integral part of several new and exciting developments, such as computer-controlled anesthesia,24–26 and patient-maintained sedation and analgesia.27–29
In summary, nonapproved TCI prototypes and software platforms have been used in >500 published research studies involving large numbers of patients. Approved TCI systems are available in >90 countries. More than 60,000 units have been sold and are being used to provide TCI propofol-based IV sedation and anesthesia for millions of patients around the world every year. In the 3 decades since the principles were put forward20 and the 2 decades since it was first approved, TCI has become a mature technology.
Contents of Questionnaire Sent to Manufacturers of TCI Devices
TCI product specifications
- a. Which products have your company developed for the administration of target-controlled infusion (TCI)? (Please provide the product name, date you started the development process, date of regulatory approval, and date you launched the product.)
- b. In which countries are your products available? Please, specify per product, if appropriate.
- c. How many pumps have you sold in these countries over the past 10 years? (Please specify per country.)
- d. What is the percentage of TCI pumps compared with the overall sales of syringe pumps (for anesthesia)?
- e. Are you currently developing new TCI products?
- f. Are you planning to launch your product in new countries?
Safety assurance during development
- a. Which TCI models for which drugs and modes (plasma TCI versus effect-site TCI) do you have available? Please, provide us with the model parameters applied in your product.
- b. How do your products deal with user attempts to program the pumps with patient characteristics at the extremes of physiology (children, obese patients) to use with pharmacokinetic models that were developed in different populations, e.g., healthy adults?
- c. Specifically for propofol: How does your pump calculate the lean body mass for the Schnider model?
- d. Which algorithm approach did you use to calculate to infusion rates in plasma- and effect-site controlled TCI (fixed keo or keo calculated using fixed time-to-peak effect approach)?
- e. Do your products validate the infusion rate and drug concentration calculations with a parallel redundant calculation (e.g., 2 different algorithms, 2 central processing units or microprocessors). If not, how do you validate the concentrations online?
- f. Are the algorithms in the pump based on the publicly available algorithms (medical literature) or did you develop propriety algorithms independently?
- g. Is the pump technology (specifically related to TCI) dependent on some patents (company owned or others)?
Safety assurance of the commercially available products
- a. Which regulatory process did you apply for developing and approving your TCI products?
- b. Which notified body is responsible for the quality control of your TCI pumps before commercial launch? Please, specify per country or region.
- c. What is the regulatory process for approval of new pharmacokinetic models once the pump is on the market?
- a. Did you have any recalls of TCI pumps because of safety issues?
- b. Which reporting system are you using to assure the quality of your product?
- c. Which notified body is auditing your quality system?
- d. How do you categorize your quality reporting (e.g., device errors, complaints, feedback from customers)?
- e. How many reports did you archive per year and per category (listed in d) since the launch and during the past 2 years?
Appendix 2. Countries of the World Where TCI Systems Are Approved and Sold
Name: Anthony R. Absalom, MBChB, FRCA, MD.
Contribution: This author helped write the manuscript.
Attestation: Anthony R. Absalom attests to the integrity of the original data and approved the final manuscript.
Conflicts of Interest: The department where Anthony R. Absalom works has received unrestricted research grants from Dräger Medical (Lübeck, Germany) and Carefusion, Inc. (United Kingdom). He is a paid consultant for Janssen (Belgium) and is an editor of the British Journal of Anaesthesia.
Name: John (Iain) B. Glen, BVMS, PhD, FRCA.
Contribution: This author helped write the manuscript.
Attestation: John (Iain) B. Glen attests to the integrity of the original data and approved the final manuscript.
Conflicts of Interest: John (Iain) B. Glen is a former employee of ICI, Zeneca, and AstraZeneca (retired 2000) and was closely involved in the clinical validation and commercial development of the Diprifusor TCI system. He was the owner and a director of Glen Pharma Ltd, which traded as a consultancy between 2000 and 2010, and worked with AstraZeneca, GlaxoSmithKline, NeuroSearch, LaboPharm, Claris Life Sciences, CareFusion, and Fresenius Kabi. Since 2010, he has been paid by Anaesthesia Technology Ltd. for documentation related to Diprifusor development.
Name: Gerrit J. C. Zwart, MD.
Contribution: This author helped write the manuscript.
Attestation: Gerrit J. C. Zwart attests to the integrity of the original data and approved the final manuscript.
Conflicts of Interest: The author declares no conflicts of interest.
Name: Thomas W. Schnider, MD, PhD.
Contribution: This author helped write the manuscript.
Attestation: Thomas W. Schnider attests to the integrity of the original data and approved the final manuscript.
Conflicts of Interest: Thomas W. Schnider is a paid consultant for Codan Medical (Switzerland).
Name: Michel M. R. F. Struys, MD, PhD, FRCA (Hons).
Contribution: This author helped write the manuscript.
Attestation: Michel M. R. F. Struys attests to the integrity of the original data and approved the final manuscript.
Conflicts of Interest: Michel M. R. F. Struys is co-owner of RUGLOOP, a software for target-controlled infusion. His department has received noneducational grants and consultancy fees in the field of medical device technology from Dräger Medical (Lübeck, Germany), Fresenius Kabi (Germany), Baxter (Chicago, IL). He is an editor of the British Journal of Anaesthesia.
This manuscript was handled by: Steven L. Shafer, MD.
The authors thank the following for their assistance with the preparation of this manuscript: Mr. Kiyoung Lee (Director, Bionet, Korea), Mr. Christian Hauer (President Medical Device Division, Fresenius Kabi, Germany), Mr. James Green (Product Manager, B. Braun Medical, Germany), Ms. S. Burmeister (Director Customer Advocacy International, Carefusion, United Kingdom), Mr. Hitoshi Kuboki (Deputy Product Manager/GHPC/Terumo Corporation, Terumo, Japan), Mr. Nick Syrett (Global Project Manager Anaesthesia, AstraZeneca, United Kingdom), Mr. Jeff Mak (Guangxi Veryark, China), Prof. Makoto Ozaki (Tokyo, Japan), Prof. Johan Coetzee (Stellenbosch, South Africa), Dr. Frank Engbers (Leiden, The Netherlands), Prof. Steven L. Shafer (Stanford, California), Prof. Jürgen Schüttler (Erlangen, Germany), Dr. Harhald Ihmsen (Erlangen, Gemany), Dr. Pablo Sepulveda (Santiago, Chili), and Prof. Luc Barvais (Brussels, Belgium).
a http://en.wikipedia.org/wiki/Demographics_of_Europe. Accessed January 5, 2015.
b http://http://www.rcoa.ac.uk/exam-syllabus-and-regulations/examination- syllabus. Accessed January 5, 2015.
c http://http://www.eba-uems.eu/resources/PDFS/Training/Anaesthesiology-syllabus.pdf. Accessed January 5, 2015.
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