Target-Controlled Infusion: A Mature Technology

Abstract

Target-controlled infusions (TCIs) have been used in research and clinical practice for >2 decades. Nonapproved TCI software systems have been used during the conduct of almost 600 peer-reviewed published studies involving large numbers of patients. The first-generation pumps were first approved in 1996, and since then an estimated 25,000 units have been sold and used. Second-generation pumps were first approved in 2003. During 2004 to 2013, >36,000 units were sold. Currently, TCI systems are approved or available in at least 96 countries. TCI systems are used to administer propofol and opioids for IV sedation and general anesthesia for millions of patients every year. In countries where TCI systems are approved, nonapproved software is still commonly used in studies of the pharmacology of hypnotics and opioids, because research software offers greater flexibility than approved TCI systems. Research software is also readily integrated into data management modules. Although TCI is a part of established practice around the world, TCI devices have not received regulatory approval in the United States. In the United States, TCI administration of propofol and opioids for sedation and anesthesia is only possible using research software in IRB-approved research studies.

Full text

Copyright © 2015 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited.
70 www.anesthesia-analgesia.org January 2016
•
Volume 122
•
Number 1
Copyright © 2015 International Anesthesia Research Society
DOI: 10.1213/ANE.0000000000001009
T
arget-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 avail-
able, 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 stan-
dard 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 rst generation of standalone TCI systems. These sys-
tems were designed to specically administer the Diprivan®
(AstraZeneca, Maccleseld, 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 clini-
cal 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 elec-
tronic record of details indispensable for PK and pharmacody-
namic (PD) studies. They also allow the user to implement, and
use, modied 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 tech-
nology and practice have spread, both geographically and
within current sedation and anesthesia practice for the facil-
itation 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 identied 14 groups that have developed 1 or more TCI
software programs or prototypes. These systems will be dis-
cussed 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 pro-
grams 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 pro-
grams we identied, listed in order of the rst 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 set-
tings. 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 publica-
tion dates. Table 1 summarizes the 14 nonapproved systems
developed by academic laboratories worldwide (Europe,
Target-controlled infusions (TCIs) have been used in research and clinical practice for >2
decades. Nonapproved TCI software systems have been used during the conduct of almost 600
peer-reviewed published studies involving large numbers of patients. The rst-generation pumps
were rst approved in 1996, and since then an estimated 25,000 units have been sold and
used. Second-generation pumps were rst approved in 2003. During 2004 to 2013, >36,000
units were sold. Currently, TCI systems are approved or available in at least 96 countries. TCI
systems are used to administer propofol and opioids for IV sedation and general anesthesia for
millions of patients every year. In countries where TCI systems are approved, nonapproved soft-
ware is still commonly used in studies of the pharmacology of hypnotics and opioids, because
research software offers greater exibility than approved TCI systems. Research software is
also readily integrated into data management modules. Although TCI is a part of established
practice around the world, TCI devices have not received regulatory approval in the United
States. In the United States, TCI administration of propofol and opioids for sedation and anes-
thesia is only possible using research software in IRB-approved research studies. (Anesth
Analg 2016;122:70–8)
Target-Controlled Infusion: A Mature Technology
Anthony R. Absalom, MBChB, FRCA, MD,* John (Iain) B. Glen, BVMS, PhD, FRCA,† Gerrit J. C. Zwart, MD,*
Thomas W. Schnider, MD, PhD,‡§ and Michel M. R. F. Struys, MD, PhD, FRCA (Hons)*∥
From the *Department of Anesthesiology, University of Groningen,
University Medical Center Groningen, Groningen, The Netherlands;
†Glen Pharma, Knutsford, Cheshire, United Kingdom; ‡Department of
Anesthesiology, Intensive Care, Rescue and Pain Medicine, Kantonsspital
St. Gallen, St. Gallen, Switzerland; §Faculty of Medicine, Anesthesiology,
University of Berne, Berne, Switzerland; and ∥Department of Anesthesia,
Ghent University, Gent, Belgium.
Accepted for publication July 27, 2015.
Funding: None.
Conict of Interest: See Disclosures at the end of the article.
Supplemental digital content is available for this article. Direct URL citations
appear in the printed text and are provided in the HTML and PDF versions of
this article on the journal’s website (www.anesthesia-analgesia.org).
Reprints will not be available from the authors.
Address correspondence to Anthony R. Absalom, MBChB, FRCA, MD,
Department of Anesthesiology, University Medical Center Groningen,
P.O. Box 30.001, Groningen 9700 RB, The Netherlands. Address e-mail to
a.r.absalom@umcg.nl.
REVIEW ARTICLE
E

Copyright © 2015 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited.
TCI: A Mature Technology
January 2016
•
Volume 122
•
Number 1 www.anesthesia-analgesia.org 71
North America, South America, and Asia) over the past 33
years. The systems are listed in the order of rst 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 gures, will
be discussed in the following sections. There are large dif-
ferences 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.
Ofcially, 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 mili-
tary. 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 com-
panies produced and sold the rst-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 rst-generation TCI systems all incorporated a
Diprifusor™ module (AstraZeneca, Maccleseld, UK),
loaded with the mathematical (infusion) algorithms devel-
oped 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 rst-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 rst-generation TCI sys-
tems 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.
Second-Generation Systems
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
Table 1. The Nonapproved TCI Systems Developed by Academic Laboratories from 1982 to 2014
System Developers Institution
Publication dates
Total
publications
Software
availableFirst Last
CATIA, IVA-SIM Schwilden, Schüttler,
Stoeckel
University of Bonn 1982 2014 24 Open TCI
TIAC Ausems University of Leiden 1985 1992 10 No
CACI, CACI II Alvis, Jacobs, Reves University of Alabama,
Duke University
1985 2001 18 No
Unnamed Tackley Bristol Royal Inrmary 1989 1999 2 No
MINA, Infusion
Toolbox
Barvais Universite Libre de
Bruxelles
1989 2006 15 No
Diprifusor
prototypes
Kenny, White University of Glascow 1991 2013 43 Commercialized by
AstraZeneca
STANPUMP Shafer Stanford University 1990 2014 268 Open TCI
Leiden platform Engbers University of Leiden 1992 2003 13 No
PAMO Viviand Hôpital Nord 1997 2005 9 No
RUGLOOP Struys, de Smet Rijksuniversiteit Gent 1998 2014 93 Demed, Inc.
STELPUMP Coetzee University of
Stellenbosch
1999 2012 51 Open TCI
Bonn Platform Hoeft, Brauer University of Bonn 2006 2006 1 Commercialized by
B. Braun
AnestFusor Stutzin, Brinckmann,
Muñoz
University of Chile 2009 2014 7 No
Asan Pump Noh Asan University 2010 2013 5 http://www.
t4nm.org/
download_ap/370
TCI = target-controlled infusion.

Copyright © 2015 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited.
E
REVIEW ARTICLE
72 www.anesthesia-analgesia.org ANESTHESIA & ANALGESIA
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 gures. The remaining 5 companies that were pre-
pared to disclose their sales gures reported total sales of
almost 37,000 second-generation TCI pumps between 2004
and 2013.
Current Frequency of TCI Drug Administration
Sales gures provide data on the market penetration of a
technology, but actual use of a technology depends on more
Figure 1. Map of the world showing countries summarizing availability of target-controlled infusion (TCI) devices. Green indicates countries
for which availability and regulatory approval were conrmed by the companies responding to the survey. Red indicates a country where TCI
has not received regulatory approval (United States), and grey indicates countries for which availability and regulatory approval are uncertain.
Table 2. Summary of Models and Modes Available in Commercially Available TCI Systems
Manufacturer Pump name/s
Details of available pharmacokinetic models for TCI
Drug name Population PK model Plasma mode Effect-site mode
Arcomed
Volumed μVP7000
Propofol Adult Marsh et al.,
3
Schnider et al.
4,5
√ √
Syramed μSP6000 Remifentanil Adult Minto et al.
6,7
√ √
Fentanyl Adult Shafer et al.
8
√ √
Braun Infusomat Space Propofol Adult Marsh et al.,
3
Schnider et al.
4,5
√ √
Perfusor Space Remifentanil Adult Minto et al.
6,7
√ √
Bionet TCI pump Propofol Adult Schnider et al.
4,5
√ √
Aquafol Adult Jung et al.
9
√ √
Remifentanil Adult Minto et al.
6,7
√ √
Alfentanil Adult Maitre et al.
10
√
Sufentanil Adult Gepts et al.
11
√ √
CareFusion Alaris PK Propofol Adult Marsh et al.,
3
Schnider et al.
4,5
√ √
Propofol Pediatric Kataria et al.,
12
Paedfusor
13,14
√ √
Remifentanil Adult Minto et al.
6,7
√ √
Alfentanil Adult Maitre et al.
10
√ √
Sufentanil Adult Gepts et al.
11
√ √
Fresenius Kabi Base Primea Propofol Adult Marsh et al.,
3
Schnider et al.
4,5
√ √
Injectomat TIVA Remifentanil Adult Minto et al.
6,7
√ √
Sufentanil Adult Gepts et al.
11
√ √
Alfentanil Adult Scott and Stanski
15
√ √
Guangxi Veryark
Technology
Concert I Propofol Adult Marsh et al.,
3
Schnider et al.
4,5
√ √
Concert II Remifentanil Adult Minto et al.
6,7
√ √
TCI III-B Sufentanil Adult Gepts et al.
11
√ √
Concert-CL Alfentanil Adult Maitre et al.
10
√ √
Fentanyl Adult Shafer et al.
8
√ √
Midazolam Adult Greenblatt et al.
16
√ √
PK = pharmacokinetic; TCI = target-controlled infusion; TIVA = total IV anesthesia.

Copyright © 2015 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited.
TCI: A Mature Technology
January 2016
•
Volume 122
•
Number 1 www.anesthesia-analgesia.org 73
than the availability of the equipment, the clinical work-
load, 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 approxi-
mately 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 pub-
lic holidays and during the summer vacation).
On the basis of the above ndings, 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 pro-
cedure requiring only induction of anesthesia, e.g., electro-
convulsive 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 tech-
nique 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 adminis-
tered 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 neurosurgi-
cal operating room, TCI is used almost exclusively.
During 2014, an additional 1029 patients received seda-
tion 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 anes-
thesia (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 dur-
ing from September 9 to 16, 2013.
19
During the course of the
Figure 2. Images of open target-controlled infusion devices sold between 2004 and 2013 by the companies to whom the questionnaire was
sent. A, Base Primea (Fresenius Kabi); (B) Injectomat TIVA (Fresenius Kabi); (C) Alaris PK (Carefusion); (D) Arcomed µSP 6000; (E) Arcomed
µVP 7000; (F) PION TCI pump (Bionet; withdrawn from market, no longer available); (G) Infusomat Space and Perfusor Space pumps (B.
Braun); and (H) Concert-CL (Veryark).

Copyright © 2015 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited.
E
REVIEW ARTICLE
74 www.anesthesia-analgesia.org ANESTHESIA & ANALGESIA
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 survey
19
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 remain-
ing 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 ther-
apeutic procedures, except for chronic pain procedures.
Frequency of TCI Use Within Europe
We were unable to nd 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 esti-
mate. 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, 2014
a
). If one ignores the health care activity
in the many nonnational health service hospitals in Britain
and Ireland and extrapolates these gures to the whole of
Europe (estimated population of 742,450,000 on December
1, 2014
a
), 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 speci-
cally 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 specically, 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 specied on the package insert.
The user interfaces of all devices display real-time informa-
tion 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 rst attended an educa-
tional session on the principles and practice of TCI.
With regard to education, some countries have now
included topics related to TCI in the anesthesiology exami-
nations syllabus. In Great Britain, training in anesthesiol-
ogy is regulated by the Royal College of Anaesthetists.
Examinees are given questions related to TCI in their writ-
ten 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 anesthesiologists
b
: Specic
topics included in the examination are as follows:
• PK modeling: types of models available: 1-, 2-, and
3-compartment models; noncompartmental; physi-
ological. 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 mainte-
nance 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
inuence of renal replacement therapies of commonly
used drugs.
In most countries of continental Europe, anesthesi-
ologists are required to sit and pass the examinations for
the European Diploma in Anaesthesia and Intensive Care
to obtain certication. 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 prac-
tice of, IV anesthesia. In general, the driving force behind
these societies has been a recognition of the fact that thor-
ough 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.isapon-
line.org/), Society for Intravenous Anaesthesia (http://
siva.ac.uk/joom2/), European Society for Intravenous
a
http://en.wikipedia.org/wiki/Demographics_of_Europe. Accessed January 5,
2015.
b
http://www.rcoa.ac.uk/exam-syllabus-and-regulations/examination-
syllabus. Accessed January 5, 2015.

Copyright © 2015 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited.
TCI: A Mature Technology
January 2016
•
Volume 122
•
Number 1 www.anesthesia-analgesia.org 75
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 pro-
vided those passing the tests with certicates as evidence
thereof.
CONCLUSIONS
Helmut Schwilden articulated the foundations for the prac-
tice of TCI >3 decades ago.
20
The basic principles, availability
of anesthetic and analgesic drugs suitable for use by continu-
ous 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, investiga-
tors 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 ani-
mal studies, where they are an important tool in PD studies.
TCI has now gained signicant traction in clinical prac-
tice and a place in the resident training programs in many
countries. Since 1996, >60,000 TCI pumps have been sold.
First-generation pumps were rst used in 1996 and con-
tinue to be used to this day. Second-generation pumps
were rst 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 inuence of enthusiastic users of TCI, these
gures are probably not representative of overall European
usage. The gures 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 afuent countries.
If one extrapolates the British and Irish gures 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 thera-
peutic 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
model
13
), TCI use is currently limited in the pediatric pop-
ulation. 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 pediat-
ric 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 ndings of early
studies, that anesthesiologists felt TCI was an excellent
tool that helped to facilitate smooth and accurate provi-
sion of anesthesia, are likely to apply just as well to anes-
thesiologists 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 suit-
able for these patient groups,
22,23
it is likely that the indi-
cations for TCI administration of drugs will increase. The
eld 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 sev-
eral 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 soft-
ware 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 pro-
vide 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 forward
20
and the
2 decades since it was rst approved, TCI has become a
mature technology.
E
APPENDIx 1
Contents of Questionnaire Sent to
Manufacturers of TCI Devices
1. Products
a. Which products have your company developed
for the administration of target-controlled infu-
sion (TCI)? (Please provide the product name,
date you started the development process, date of
regulatory approval, and date you launched the
product.)
c
http://www.eba-uems.eu/resources/PDFS/Training/Anaesthesiology-
syllabus.pdf. Accessed January 5, 2015.

Copyright © 2015 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited.
E
REVIEW ARTICLE
76 www.anesthesia-analgesia.org ANESTHESIA & ANALGESIA
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?
2. TCI product specications
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 param-
eters applied in your product.
b. How do your products deal with user attempts
to program the pumps with patient characteris-
tics 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 (xed keo or keo calculated using xed 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 (specically related to TCI)
dependent on some patents (company owned or
others)?
3. Safety assurance during development
a. Which regulatory process did you apply for develop-
ing and approving your TCI products?
b. Which notied body is responsible for the qual-
ity 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?
4. Safety assurance of the commercially available products
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 notied 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?
DISCLOSURES
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 nal manuscript.
Conicts 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 nal manuscript.
Conicts 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 develop-
ment of the Diprifusor TCI system. He was the owner and
a director of Glen Pharma Ltd, which traded as a consul-
tancy 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 orig-
inal data and approved the nal manuscript.
Conicts of Interest: The author declares no conicts of interest.
Appendix 2. Countries of the World Where TCI
Systems Are Approved and Sold
Algeria Hong Kong Paraguay
Andorra Hungary Peru
Argentina Iceland Philippines
Australia India Poland
Austria Indonesia Portugal
Bahrain Iran Puerto Rico
Bangladesh Ireland Qatar
Belgium Israel Reunion
Bolivia Italy Romania
Botswana Japan Russia
Brazil Jordan Saudi Arabia
Brunei Kuwait Serbia
Bulgaria Lebanon Singapore
Canada
a
Libya Slovakia
Cayman Islands Lithuania Slovenia
Chile Luxembourg South Africa
China Malaysia South Korea
Colombia Malta Spain
Croatia Martinique Swaziland
Cuba Mauritania Sweden
Cyprus Mexico Switzerland
Czech Republic Moldova Syria
Denmark Mongolia Taiwan
Ecuador Morocco Thailand
Egypt Namibia Tunisia
Estonia Netherlands Turkey
Finland New Caledonia UAE
France New Zealand Ukraine
French Polynesia Niger United Kingdom
Germany Norway Venezuela
Ghana Pakistan Vietnam
Greece Panama Zambia
TCI = target-controlled infusion.
a
In Canada, only partial approval has been granted (currently no active marketing).

Copyright © 2015 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited.
TCI: A Mature Technology
January 2016
•
Volume 122
•
Number 1 www.anesthesia-analgesia.org 77
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 nal manuscript.
Conicts 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 nal manuscript.
Conicts 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 con-
sultancy fees in the eld 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.
ACkNOWLEDGMENTS
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).
REFERENCES
1. Struys MMRF, De Smet T, Glen JB, Vereecke HEM, Absalom
AR, Schnider TW. The history of target-controlled infusion.
Anesth Analg 2016;122:56–69
2. Glass PS, Glen JB, Kenny GN, Schüttler J, Shafer SL.
Nomenclature for computer-assisted infusion devices.
Anesthesiology 1997;86:1430–1
3. Marsh B, White M, Morton N, Kenny GN. Pharmacokinetic
model driven infusion of propofol in children. Br J Anaesth
1991;67:41–8
4. Schnider TW, Minto CF, Gambus PL, Andresen C, Goodale
DB, Shafer SL, Youngs EJ. The inuence of method of admin-
istration and covariates on the pharmacokinetics of propofol in
adult volunteers. Anesthesiology 1998;88:1170–82
5. Schnider TW, Minto CF, Shafer SL, Gambus PL, Andresen C,
Goodale DB, Youngs EJ. The inuence of age on propofol phar-
macodynamics. Anesthesiology 1999;90:1502–16
6. Minto CF, Schnider TW, Egan TD, Youngs E, Lemmens HJ,
Gambus PL, Billard V, Hoke JF, Moore KH, Hermann DJ, Muir
KT, Mandema JW, Shafer SL. Inuence of age and gender on
the pharmacokinetics and pharmacodynamics of remifentanil.
I. Model development. Anesthesiology 1997;86:10–23
7. Minto CF, Schnider TW, Shafer SL. Pharmacokinetics and
pharmacodynamics of remifentanil. II. Model application.
Anesthesiology 1997;86:24–33
8. Shafer SL, Varvel JR, Aziz N, Scott JC. Pharmacokinetics of
fentanyl administered by computer-controlled infusion pump.
Anesthesiology 1990;73:1091–102
9. Jung JA, Choi BM, Cho SH, Choe SM, Ghim JL, Lee HM, Roh
YJ, Noh GJ. Effectiveness, safety, and pharmacokinetic and
pharmacodynamic characteristics of microemulsion propofol
in patients undergoing elective surgery under total intravenous
anaesthesia. Br J Anaesth 2010;104:563–76
10. Maitre PO, Vozeh S, Heykants J, Thomson DA, Stanski DR.
Population pharmacokinetics of alfentanil: the average dose-
plasma concentration relationship and interindividual variabil-
ity in patients. Anesthesiology 1987;66:3–12
11. Gepts E, Shafer SL, Camu F, Stanski DR, Woestenborghs
R, Van Peer A, Heykants JJ. Linearity of pharmacokinet-
ics and model estimation of sufentanil. Anesthesiology
1995;83:1194–204
12. Kataria BK, Ved SA, Nicodemus HF, Hoy GR, Lea D, Dubois
MY, Mandema JW, Shafer SL. The pharmacokinetics of propo-
fol in children using three different data analysis approaches.
Anesthesiology 1994;80:104–22
13. Absalom A, Amutike D, Lal A, White M, Kenny GN. Accuracy
of the ‘Paedfusor’ in children undergoing cardiac surgery or
catheterization. Br J Anaesth 2003;91:507–13
14. Absalom A, Kenny G. ‘Paedfusor’ pharmacokinetic data set. Br
J Anaesth 2005;95:110
15. Scott JC, Stanski DR. Decreased fentanyl and alfentanil dose
requirements with age. A simultaneous pharmacokinetic
and pharmacodynamic evaluation. J Pharmacol Exp Ther
1987;240:159–66
16. Greenblatt DJ, Ehrenberg BL, Gunderman J, Locniskar A,
Scavone JM, Harmatz JS, Shader RI. Pharmacokinetic and
electroencephalographic study of intravenous diazepam, mid-
azolam, and placebo. Clin Pharmacol Ther 1989;45:356–65
17. Pandit JJ, Andrade J, Bogod DG, Hitchman JM, Jonker WR,
Lucas N, Mackay JH, Nimmo AF, O’Connor K, O’Sullivan EP,
Paul RG, Palmer JH, Plaat F, Radcliffe JJ, Sury MR, Torevell HE,
Wang M, Cook TM; Royal College of Anaesthetists; Association
of Anaesthetists of Great Britain and Ireland. 5
th
National Audit
Project (NAP5) on accidental awareness during general anaes-
thesia: protocol, methods, and analysis of data. Br J Anaesth
2014;113:540–8
18. Pandit JJ, Andrade J, Bogod DG, Hitchman JM, Jonker WR,
Lucas N, Mackay JH, Nimmo AF, O’Connor K, O’Sullivan EP,
Paul RG, Palmer JH, Plaat F, Radcliffe JJ, Sury MR, Torevell
HE, Wang M, Hainsworth J, Cook TM; Royal College of
Anaesthetists; Association of Anaesthetists of Great Britain and
Ireland. 5
th
National Audit Project (NAP5) on accidental aware-
ness during general anaesthesia: summary of main ndings
and risk factors. Br J Anaesth 2014;113:549–59
19. Sury MR, Palmer JH, Cook TM, Pandit JJ. The state of UK anaes-
thesia: a survey of National Health Service activity in 2013. Br J
Anaesth 2014;113:575–84
20. Schwilden H. A general method for calculating the dosage
scheme in linear pharmacokinetics. Eur J Clin Pharmacol
1981;20:379–86
21. Leslie K, Clavisi O, Hargrove J. Target-controlled infusion
versus manually-controlled infusion of propofol for general
anaesthesia or sedation in adults. Cochrane Database Syst Rev
2008:CD006059
22. Eleveld DJ, Proost JH, Cortínez LI, Absalom AR, Struys MM. A
general purpose pharmacokinetic model for propofol. Anesth
Analg 2014;118:1221–37
23. Cortínez LI, De la Fuente N, Eleveld DJ, Oliveros A, Crovari
F, Sepulveda P, Ibacache M, Solari S. Performance of propo-
fol target-controlled infusion models in the obese: pharma-
cokinetic and pharmacodynamic analysis. Anesth Analg
2014;119:302–10
24. Liu N, Chazot T, Hamada S, Landais A, Boichut N, Dussaussoy
C, Trillat B, Beydon L, Samain E, Sessler DI, Fischler M. Closed-
loop coadministration of propofol and remifentanil guided
by bispectral index: a randomized multicenter study. Anesth
Analg 2011;112:546–57
25. Le Guen M, Liu N, Bourgeois E, Chazot T, Sessler DI, Rouby JJ,
Fischler M. Automated sedation outperforms manual adminis-
tration of propofol and remifentanil in critically ill patients with
deep sedation: a randomized phase II trial. Intensive Care Med
2013;39:454–62
26. Dussaussoy C, Peres M, Jaoul V, Liu N, Chazot T, Picquet J,
Fischler M, Beydon L. Automated titration of propofol and

Copyright © 2015 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited.
E
REVIEW ARTICLE
78 www.anesthesia-analgesia.org ANESTHESIA & ANALGESIA
remifentanil decreases the anesthesiologist’s workload during
vascular or thoracic surgery: a randomized prospective study.
J Clin Monit Comput 2014;28:35–40
27. Pambianco DJ, Whitten CJ, Moerman A, Struys MM, Martin
JF. An assessment of computer-assisted personalized seda-
tion: a sedation delivery system to administer propo-
fol for gastrointestinal endoscopy. Gastrointest Endosc
2008;68:542–7
28. Pambianco DJ, Vargo JJ, Pruitt RE, Hardi R, Martin JF.
Computer-assisted personalized sedation for upper endos-
copy and colonoscopy: a comparative, multicenter randomized
study. Gastrointest Endosc 2011;73:765–72
29. O’Brien C, Urquhart CS, Allam S, Anderson KJ, Leitch JA,
Macpherson A, Kenny GN. Reaction time-monitored patient-
maintained propofol sedation: a pilot study in oral surgery
patients. Anaesthesia 2013;68:760–4