Journal of Clinical Anesthesia (2007) 19, 397–404

Review article

Understanding modes of moderate sedation

during gastrointestinal procedures:
a current review of the literatureB
David A. Lubarsky MD, MBA (Professor and Chair) a,⁎,
Keith Candiotti MD (Associate Professor) b , Eric Harris MD (Assistant Professor) b
a
Department of Anesthesiology, Perioperative Medicine and Pain Management,
University of Miami Miller School of Medicine, Jackson Memorial Hospital, Miami, FL 33136, USA
b
Department of Anesthesiology, Perioperative Medicine and Pain Management,
University of Miami Miller School of Medicine, Miami, FL 33136, USA

Received 17 April 2006; revised 8 November 2006; accepted 9 November 2006

Keywords: Abstract Recommendations for routine screening for colorectal cancer with colonoscopy are likely to
Colonoscopy;
substantially increase the demand for provision of sedation for these procedures. Because of this bur-
Endoscopy;
geoning caseload and associated economic constraints, it is unlikely that anesthesiologists will be
Fospropofol disodium;
available for all such procedures, particularly those involving average-risk patients. Thus, sedative agents
Propofol;
that can be safely administered by nonanesthesiologists, appropriately trained in monitoring and managing
Rapid recovery;
the patient's airway, are desperately needed. New concepts in sedation for colonoscopy include enhanced
Sedation
mechanisms for drug delivery such as patient-controlled sedation/analgesia and target-controlled
infusion, along with the development of new drugs such as a modified cyclodextrin-based formulation
of propofol and fospropofol disodium (Aquavan Injection), a water-soluble prodrug of propofol.
© 2007 Elsevier Inc. All rights reserved.

1. Introduction early detection is essential. Widespread screening for

Colorectal cancer is associated with substantial morbidity
and mortality. It is the second leading cause of cancer-related
mortality in the United States [1], and it is associated with a
5-year survival rate of only 62% [2]. To improve survival,
☆
Financial support/Disclosures: Editorial support was provided by Nexus
Communications, Inc., through an unrestricted grant from MGI Pharma, Inc,
Bloomington, MN. Dr Lubarsky serves on an advisory board for MGI
PHARMA, Inc, and has received honoraria from MGI PHARMA, Inc.
⁎ Corresponding author. Tel.: +1 305 585 7037; fax: +1 305 545 6501.
E-mail address: lubarsky@miami.edu (D.A. Lubarsky).
colorectal cancer is currently the most effective method for
early detection. Screening is cost-effective and it has the
potential to improve patient outcomes [2]. Despite a recom-
mendation by the US Preventive Services Task Force that
adults 50 years or older be routinely screened with col-
onoscopy every 10 years, the use of screening tests among US
adults remains low [1]. In 2001, the Behavioral Risk Factor
Surveillance System estimated that only 47.3% of US adults
50 years or older had ever undergone lower endoscopy [1].
In 2002, 14.2 million colonoscopies were performed in
the U.S. [3]. Most of these procedures are performed with
sedation in patients who are at average risk of complications
associated with endoscopic sedation [4]. Risk stratification

0952-8180/$ – see front matter © 2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.jclinane.2006.11.006
398
for endoscopy is not well defined. However, most practi-
tioners agree that patients at average risk for developing
complications do not have risk factors such as cardiovascular
disease, pulmonary disease, or chronic airway obstruction
[4,5]. Sedation is routinely provided to patients during
colonoscopy and is considered the standard of practice in the
U.S. [6], where the performance of unsedated colonoscopy is
highly unusual. Cotton and colleagues [7] analyzed data
from 17,868 colonoscopies performed by 69 endoscopists
from 7 hospital centers across the U.S. between 1994 and
1998. They found that only 7% of endoscopists performed
more than 4% of their procedures in unsedated patients [7].
Although endoscopic procedures can be performed with-
out sedation, results of two studies showed that 16% to 56%
of such procedures are terminated because of pain [8,9]. An
important goal of colonoscopy is cecal intubation [7], and
without adequate sedation the endoscope is less likely to
reach that distance [9], increasing the possibility of missing
adenomatous polyps or tumors. Thus, moderate sedation with
or without supplemental analgesia is not only the standard of
practice in the U.S. for patients undergoing endoscopic
procedures, it is often necessary for successful completion of
the procedure [6,7]. Indeed, numerous clinical studies and
practice guidelines confirm the clinical benefit of adequate
levels of sedation/analgesia [10-13]. Although there are many
different techniques and medications to achieve sedation
during colonoscopy, the ideal amount of sedation for a patient
undergoing colonoscopy has not been established [14].
Current options for sedation include benzodiazepines (eg,
midazolam, diazepam), propofol, opioids (eg, fentanyl,
meperidine), ketamine, and inhaled anesthetics (eg, nitrous
oxide). Although dexmedetomidine has been suggested, one
report showed that dexmedetomidine was not successful for
moderate sedation during colonoscopy because of side
effects, hemodynamic instability, complicated administra-
tion, and prolonged recovery [15].
With the benefits of propofol as a sedating agent
appreciated widely outside the operating room, more
gastroenterologists are using this agent for endoscopic
procedures [16]. Gastroenterologists usually turn to anesthe-
siologists to provide sedation for these routine procedures
[4], but they are also advocating for the ability to provide
propofol-based sedation themselves [17-21]. In an ideal
situation, an anesthesiologist would be present during all
routine cases of colonoscopy so as to optimize sedation/
analgesia. However, the clinical merits and cost-effective-
ness of having an anesthesiologist during colonoscopy
involving patients who are at average risk of developing
sedation-related complications remain debatable [4].
Current guidelines of the ASA recommend that the
person responsible for monitoring patients who undergo
sedation be trained in recognizing complications associated
with sedation/analgesia and be competent to rescue the
patient from a deeper level of sedation [13]. In patients with
significant sedation-related risk factors (eg, potentially
difficult airway, severe obstructive pulmonary disease,
D.A. Lubarsky et al.
coronary artery disease, congestive heart failure, sleep
apnea), or if deep sedation is necessary to obtain adequate
procedural conditions, it is recommended that an anesthe-
siologist be consulted.
However, it is not feasible, and perhaps is even
unnecessary, for an anesthesiologist to be present during
colonoscopies involving average-risk patients. In most
average-risk patients receiving moderate sedation, the airway
is self-maintained and the skills of an anesthesiologist would
not be used.
Health care economics also influence the delivery of
moderate sedation. For example, policies in the U.S.
regarding payment of anesthesiologists during average-risk
colonoscopy vary across Medicare contractors [4]. In some
cases, Medicare may refuse to reimburse anesthesiologists
for sedation performed during colonoscopy. Moreover,
some insurers have questioned the separate reimbursement
for anesthesia coverage when the global reimbursement fee
for the endoscopic procedure includes administration of
sedation under the supervision of the gastroenterologist.
Many payors have taken a position on this subject similar to
that of the gastroenterology societies, in that anesthesiology
assistance is appropriate in high-risk cases but not in average-
risk cases [4]. As a result, the rates of using anesthesiologists
during average-risk colonoscopy vary in different regions
of the country and appear dependent on regional payor
policies [4].
2. Safety of current sedation regimens
for colonoscopy
Most endoscopic procedures occur at a moderate level
of sedation [14]. The goal is to relieve anxiety, discomfort,
and pain, and to provide amnesia while preserving
cardiopulmonary function [14]. Clinical practice guidelines
call for the careful titration of sedative medications using
small incremental doses [13]. However, the patients, their
accompanying support individual(s), the facility, and the
gastroenterologist all have incentives to move the pace of
sedation along. This attitude may lead to a false sense of
confidence and the administration of less safe, or larger,
doses of medication, which can result in unexpected or
prolonged apneic episodes and catastrophic consequences to
the patient.
Properties and dosing regimens culled from the gastro-
intestinal (GI) literature for the most commonly used drugs
for moderate sedation are summarized in Tables 1 and 2.
(Interestingly, the quoted side effects are not in total
accordance with those noted in the anesthesia literature.)
Many studies have compared these drugs, all of which
generally provide safe and effective sedation for colono-
scopy (Table 3).
There are a number of potential concerns/problems with
available sedative agents (Table 1). In fact, most complica-
Unmeet needs in moderate sedation for colonoscopy 399

Table 1 Commonly used drugs and effects in colonoscopy in the gastrointestinal (GI) literature
Drug Pharmacologic Pharmacologic Onset of Duration Adverse effects a
class effects action of action
Midazolam Benzodiazepine Sedation 1-5 min, 1-3 h Hypotension, hypoventilation, decreased tidal volume,
Amnesia peak 3-5 min increased respiratory rate, apnea, increased upper
Anxiolytic airway resistance
Diazepam Benzodiazepine Sedation 1-5 min 20-60 min Hypotension, hypoventilation, respiratory depression
Amnesia
Anxiolytic
Meperidine Opioid Sedation 5 min, 2-4 h Hypoventilation, hypotension, lower seizure threshold,
Analgesia peak 10 min respiratory depression, decreased tidal volume, nausea,
vomiting
Propofol Ultrashort-acting Sedation 30-60 s 3-10 min Dose-dependent hypotension, hypoventilation,
sedative hypnotic Hypnotic respiratory depression, pain at injection site
Droperidol Neuroleptic Neuroleptic 30 min 1-4 h Hypotension, tachycardia, hypoventilation, prolonged
Anxiolytic QT interval
Fentanyl Opioid Sedation b1 min, 30-60 min Hypoventilation, respiratory depression, decrease in
Analgesia peak 5-8 min tidal volume
a
Combinations are often more than additive (ie, synergistic) in the production of adverse respiratory depression. Adapted from Refs. [6,14,22].

tions with colonoscopy are related not to procedure, but to consecutive patients receiving diazepam or midazolam plus
sedation and include cardiopulmonary events such as hypox- meperidine, found that 45% of patients had an oxygen
emia, hypoventilation, airway obstruction, apnea, arrhyth- saturation (SaO2) of less than 90% [14,44]. The rate of
mias, hypotension, and vasovagal episodes [14,37,38]. desaturation tended to be higher among patients undergoing
Although uncommon, serious cardiorespiratory complica- colonoscopy (54%) compared with those undergoing upper
tions, including death, can occur [39,40]. Data from the endoscopy (40%) [44]. These findings may explain the
American Society for Gastrointestinal Endoscopy's compu- increasing use of propofol, because the impression is that if
ter-based management system was used to review more than desaturation does occur with propofol, it will wear off
21,000 GI endoscopies in 1988, performed primarily with quickly and the patient will start to breathe again. A lower
sedation with either midazolam or diazepam [40]. The overall
complication rate was 13.5 events per 1,000 procedures, and Table 2 Dosing of commonly used drugs for procedural
the rate of serious cardiac or respiratory complications was sedation [14]
5.4 per 1000 [40]. Death was reported in 0.3 per 1,000
Drug Dosing guidelines
procedures [40]. There was no significant difference in the
rate of complications between patients receiving midazolam Midazolam Bolus 0.5-2 mg
and those receiving diazepam [40]. More recent data Incremental doses of 0.5-1 mg every 2 min
evaluating the safety and efficacy of meperidine and titrated to effect
Diazepam Bolus 2.5-5 mg
diazepam or meperidine and midazolam, when used for
Incremental doses of 2-5 mg every 5 min
moderate sedation during upper and lower GI endoscopic titrated to effect
procedures performed over a 12-year period, revealed no Meperidine Bolus 25 mg
deaths [41]. There were no episodes of cardiopulmonary Incremental doses of 25 mg every 2-3 min
arrest or pulmonary aspiration reported in this series [41]. The titrated to effect
most recent study using sedation-trained nurses administer- Fentanyl Bolus 100 μg
ing propofol to 36,743 patients at three centers with a limited Incremental doses of 100 μg titrated to effect
selection of busy endoscopists reported no fatalities or Propofol Bolus 1.0-2.5 mg/kg
intubations, and only 0.1% to 0.2% needing assisted Continuous infusion of 1-5 μg kg−1 h−1
ventilation [42]. We are not confident that such excellent titrated to effect
results will extrapolate to other centers without an ongoing Droperidol a Bolus 2.5 mg
a
study and the extensive training commitment present in these Cases of QT prolongation and/or torsade de pointes have been
three centers. Furthermore, the incidence and severity of reported in patients receiving droperidol at doses at or lower than
recommended doses. Some cases have occurred in patients with no
desaturation episodes (except those severe enough to require known risk factors for QT prolongation and some cases have been fatal.
assisted ventilation) were not reported. Because of its potential for serious proarrhythmic effects and death,
The incidence and severity of oxygen desaturation are droperidol should be reserved for use in the treatment of patients who
critical data. Oxygen desaturation is relatively common fail to show an acceptable response to other adequate treatments, either
during endoscopic procedures, although the effect appears to because of insufficient effectiveness or the inability to achieve an
effective dose due to intolerable adverse effects from those drugs.
be dose-dependent [43]. One older study, assessing 261
400 D.A. Lubarsky et al.

Table 3 Comparative studies on sedation efficacy during colonoscopy

Study Study Pa Sedation Drug Mean time to Time to full Time to Patient
design (n) administration sedation (min) recovery (min) discharge (min) satisfaction
(superior [sup])
Propofol vs benzodiazepines
Roseveare RCT 66 P/Al vs D/M PCS (P/Al) or Not addressed P/Al = 10, Not addressed P/Al = D/M
et al [23] physician (D/M) D = 40
Koshy et al Case 150 P/F vs Md/M Nurse anesthetist Not addressed P/F = M/Md Not addressed Not
[24] control addressed
Reimann RCT 79 P/Md vs Md/N Physician Not addressed P/Md = 5, ‡ P/Md = 17 ‡ P/Md N
et al [25] Md/N = 23 Md/N = 93 Md/N ⁎
Ng et al [26] RCT 88 P vs Md PCS (P) or Not addressed P sup to Md P = 43 Md = 61 P PCS N Md ‡
‡

anesthetist (Md)
Sipe et al RCT 80 P vs Md/M Nurse or P = 2.1 ‡ P = 14.4, ‡ P = 40.5 ‡ P N Md/M ⁎
[27] physician Md/M = 7.0 Md/M = 33.0 Md/M = 71.1
Ulmer et al [28] RCT 1000 P vs Md/F Nurse P = 2.1 ‡ P = 16.5, ‡ P = 36.5, † P = Md/F
Md/F = 6.1 Md/F = 27.5 Md/F = 46.1

Benzodiazepine vs benzodiazepine
Macken RCT 200 Md vs D Not stated Not addressed D = 31, Not addressed Not
et al [29] Md = 34 addressed
Zakko et al [30] RCT 100 Md vs D Gastroenterologist Not addressed Md = 22, D = 22 Not addressed Not
addressed

Propofol vs opioid
Moerman RCT 40 P vs R Anesthesiologist Not addressed R sup to P Not addressed P N R‡
et al [31]

Miscellaneous comparisons
Seifert et al RCT 239 P vs P/Md Physician Not addressed P = 19, ‡ Not addressed Not
[32] P/Md = 25 addressed
Morrow RCT 101 M/Md bolus vs Gastroenterologist Bolus = 3, ‡ Not addressed Not addressed Not
et al [33] M/Md titration Titration = 11 addressed
Paspatis RCT 120 P/Md vs Anesthesiologist Not addressed P/Md N Md/M ‡ Not addressed P/Md N
et al [34] Md/Me Md/M ⁎
Rudner RCT 100 P bolus/R vs Not stated Not addressed P/R = 8, ‡ Not addressed Not
et al [35] P bolus/F/Md P/F/Md = 31.2 addressed
Radaelli RCT 253 Md bolus vs Gastroenterologist Not addressed Md = Md/M Not addressed Md/M N M †
et al [36] Md/M bolus assistant
Al = alfentanil; D = diazepam; F = fentanyl; M = meperidine; Md = midazolam; N = nalbuphine; P = propofol; PCS = patient-controlled sedation; R =
remifentanil; RCT = randomized controlled trial.
⁎ P b 0.05 versus comparator.
†
P b 0.01 versus comparator.
‡
P b 0.001 versus comparator.

number of oxygen desaturation events (b90%) have been
observed with propofol than with midazolam/meperidine
(12% vs 26%; P b 0.01) [45]. In addition, patients who are
ASA physical status III and IV are at greater risk for oxygen
desaturation (b90%) than those who are ASA physical
status I and II (3.6% vs 1.7%; P = 0.036) [46]. Misjudging
the depth of sedation with propofol is easier than with other
agents, and the risk of apnea is greater although prolonged
oxygen desaturation may occur less frequently.
The primary concerns with propofol are that it has a
narrow therapeutic window, it has the potential to cause
severe respiratory and cardiopulmonary complications, and it
requires the presence of an anesthesiologist or nurse
anesthetist [14,47,48]. Although the respiratory depressant
effect of propofol is dose-dependent and is most commonly
seen with deep sedation, even low-dose propofol used for
minimal-to-moderate sedation can decrease ventilatory drive
and produce hypoxemia [48]. Airway manipulations to
prevent or reverse airway obstruction may be required and
likely correspond to the depth of sedation and/or dose of
propofol during endoscopy [48-50].
The use of combination regimens increases the risk of
oversedation and cardiopulmonary complications. Indeed,
cardiopulmonary depression is the most clinically significant
complication of benzodiazepine/opioid and propofol/opioid
combinations [14,18]. For example, in the American Society
Unmeet needs in moderate sedation for colonoscopy
for Gastrointestinal Endoscopy study, 94% of patients who
experienced cardiopulmonary complications had received a
concomitant opioid, although only 65% of the total study
population had received an opioid [40].
Patient characteristics also influence the safety of sedative
regimens. Morbid obesity, older age, and underlying
cardiovascular, pulmonary, renal, hepatic, metabolic, and
neurologic disease are risk factors for the development of
hypoxemia [14,51]. Therefore, current ASA guidelines
recommend that physicians conduct a preprocedural evalua-
tion to become familiar with sedation-related aspects of a
patient's medical history and physical status, and how these
characteristics can influence the response to sedation/
analgesia [13].
3. Disadvantages of currently available agents
Because benzodiazepines are lipid-soluble (particularly
midazolam), repeat doses result in accumulation in adipose
tissue that is subsequently released, resulting in prolonged
effects. For example, Newcomer and colleagues [52] found
that 4% of patients had an unplanned work absence the day
after their colonoscopy. The most common reasons for
missing work were feeling sleepy and weak, or experiencing
abdominal pain and bloating.
There is interest in using propofol for colonoscopy
because it has properties (eg, fast onset and rapid recovery)
that render it an attractive alternative to benzodiazepines and
opioids as a sedative agent for colonoscopy [53]. However,
when used alone, propofol can cause deep sedation, resulting
in hypotension and respiratory depression [17,54]. For
example, a comparative study evaluating propofol versus
midazolam/meperidine for outpatient colonoscopy found
that those patients receiving propofol achieved a signifi-
cantly greater mean level of sedation than those receiving
midazolam/meperidine [27]. This increased sedation resulted
in fewer propofol-treated patients being able to assist with
the procedure (eg, changing position) [27]. It has been
suggested that a greater level of sedation also has the
potential to result in an increased risk of perforation because
patients are not able to report pain, an important warning
signal of impending perforation [27]. Only a small number of
GI physicians believe this theory, as there is no evidence to
support this claim.
Personnel administering propofol should be able to rescue
the patient from the next deeper level of sedation and should
be trained in the administration of general anesthesia [53]. As
a result, the ASA and the American Association of Nurse
Anesthetists issued a joint statement in 2004, that “whenever
propofol is used for sedation/analgesia, it should be
administered only by persons trained in the administration
of general anesthesia. This restriction is concordant with
specific language in the propofol package insert [55].” There
is controversy regarding the safety of propofol when
401
administered by nonanesthesiologists [56], which is why
nonanesthesiologists in general are reluctant to use it. These
clinicians are instead likely to continue to use sedatives with
which they are comfortable, such as a benzodiazepine with
an opioid [56,57].
3.1. Properties of an ideal agent
The ideal agent for sedation should have certain properties
to provide safe and effective minimal-to-moderate sedation.
These include a consistent and predictable pharmacokinetic/
pharmacodynamic profile, rapid onset of action, analgesic
and anxiolytic effects, immediate resolution of sedation
without any lingering effects on mental and psychomotor
function, amnestic period extending long enough for the
procedure, minimal associated risks or adverse effects, no
pain on injection, and no requirement for administration by
an anesthesiologist [53,58]. Although available agents have
some of these properties, none fulfill all of the criteria.
4. New Concepts in Sedation for Colonoscopy
New concepts in sedation for colonoscopy include
enhanced mechanisms for drug delivery such as target-
controlled infusion (TCI) and PCS along with the develop-
ment of new drugs such as a modified cyclodextrin-based
formulation of propofol and fospropofol disodium (Aquavan
Injection, MGI Pharma Inc., Bloomington, MN), a water-
soluble prodrug of propofol.
Because of its poor water solubility, propofol is formulated
as a lipid-based formulation. Cyclodextrins are widely used
as solubilizing agents in pharmaceutical practice to allow
compounds that are sparingly soluble in water to be
formulated in an injectable format [59]. A modified
cyclodextrin-based formulation of propofol (Fig. 1) has
been developed that may eliminate some of the formula-
tion-dependent problems of propofol, such as pain on
injection and the support of microbial growth [59-61]. It is
hypothesized that the cyclodextrin-based formulation of
propofol would be associated with similar sedative effects
compared with the currently marketed lipid formulation of
propofol, but producing less pain on injection. Results of a
single-center, double-blind, two-period, randomized, dose-
escalating trial in healthy volunteers found no differences in
sedative, hemodynamic, or respiratory effects [61]. How-
ever, patients receiving the cyclodextrin-based formulation
of propofol had statistically worse pain scores [61].
Fospropofol disodium (Aquavan Injection) is a novel
sedative/hypnotic, water-soluble prodrug of propofol with
pharmacokinetic and pharmacodynamic properties that differ
from those of propofol emulsion [62-64]. Aquavan is
hydrolyzed by alkaline phosphatase to release propofol
[62-65]. The pharmacokinetic profile of Aquavan is
characterized by avoidance of the high peak plasma
402 D.A. Lubarsky et al.

Fig. 1 Modified cyclodextrin-based formulation of propofol [59-61].

concentrations seen with the lipid emulsion formulation of make any definite conclusions about the application of
propofol (Fig. 2) [49]. However, the elimination kinetics Aquavan in moderate sedation.
of Aquavan are similar to those of the lipid formulation of In PCS, the medication is self-administered by the patient
propofol and plasma concentrations are shifted in time in response to pain; therefore, the patient has to be conscious
reflective of propofol liberation from Aquavan [49]. enough to press the handheld button. Specialized pumps are
Results of the most recent dose-response study con- used that deliver a preset dose of medication in response to a
ducted in 127 patients with ASA physical status I, II, III, patient pressing a handheld button [67]. A lockout time is
and IV who were undergoing colonoscopy, found that a programmed into the pump to prevent the delivery of
6.5 mg/kg dose of Aquavan produced an acceptable safety additional doses until the previous dose has taken its full
profile while maintaining a minimal to moderate level of effect. When rapid-acting drugs such as propofol and
sedation in most patients [66]. Sedation success, defined as alfentanil are used for PCS, oversedation is unlikely to
completion of the procedure without the need for alternative occur [67].
sedative medication and without requiring manual/mechan- Target-controlled infusion systems of anesthetic agents
ical ventilation, was dose-dependent and was achieved in are pharmacokinetically based, computer-controlled infusion
24.0%, 34.6%, 69.2%, and 95.8% of patients who received systems designed to deliver intravenous (IV) drugs accord-
Aquavan doses of 2, 5, 6.5, and 8 mg/kg, respectively. The ing to the drug's pharmacokinetics, using an infusion pump
median time to discharge was 6.0, 4.0, 7.5, and 11.5 minutes
in the 2, 5, 6.5, and 8 mg/kg groups, respectively. Twenty-five
percent of patients in the 8 mg/kg group went into deep
sedation compared with 3.8% of patients in both the 5 mg/kg
and 6.5 mg/kg groups. No patient required manual or
mechanical ventilation, and there were no deaths. The most
common adverse events were burning sensation and pares-
thesia. The most common adverse events reported during
clinical trials are burning sensation, paresthesia, and pruritus
(J. Jones MD, oral communication, August 7, 2006). Similar
results were reported in a recently published double-blind,
randomized study in 314 patients undergoing colonoscopy
[52,53]. Aquavan 6.5 mg/kg was associated with a high level
of sedation success (87% of patients) and a high level of
physician- and patient-rated satisfaction. Aquavan-induced
sedation was reported as well tolerated, with paresthesia
being the most common treatment-related adverse event. We Fig. 2 Plasma concentration-time points of Aquavan-derived
must await the results of large clinical trials before we can propofol [49].
Unmeet needs in moderate sedation for colonoscopy
controlled by a computer [68]. Target-controlled infusion
systems use complex mathematical models to compute the
drug dosage and they may account for various patient
characteristics that alter drug disposition [68]. Because TCI
pumps frequently recalculate the appropriate dosage of drug
to be infused based on the computer's pharmacokinetic
simulation of the drug concentration, and gradually
decreases the rate of infusion, TCI pumps address the
limitations associated with delivery of drugs directly into the
circulation [68].
Propofol has become the most frequently infused drug via
TCI [68]. Results from a randomized, crossover trial com-
paring PCS using IV boluses of propofol and patient-
maintained sedation using TCI of propofol, found that the
mean time ± SD taken for titration to adequate sedation was
longer with TCI than with PCS (8.6 ± 3.7 vs 5.7 ± 3.1 min;
P b 0.005) [69]. Although both techniques provided moderate
sedation, two (9%) patients became oversedated during
PCS. Patient satisfaction was high with both techniques,
although most patients preferred PCS using TCI (65%
vs 30%; P b 0.05) [69].
5. Conclusions
Sedation and analgesia are routinely provided for most
patients undergoing colonoscopy in the United States, so as
to allow them to tolerate the procedure. An ideal agent for
procedural sedation is one that provides rapid, controlled
onset and recovery, analgesia, and no pain on injection, and
that can be safely administered by nonanesthesiologists.
Although there are many different medications available to
achieve sedation, none of the currently available sedative/
hypnotic agents completely fulfills these needs.
Propofol has been used increasingly for minimal-to-
moderate sedation because of its advantages over benzo-
diazepines and opioids. Propofol offers more rapid onset of
action than benzodiazepines or opioids, full relief from
discomfort, and rapid recovery to alertness without residual
sedative effects. However, propofol has a narrow therapeu-
tic window and has the potential to cause deep sedation.
New sedation agents and delivery systems under devel-
opment have the potential to improve the quality of
endoscopic sedation.
References
[1] Seeff L, Nadel M, Blackman D. Colorectal cancer test use among
persons aged N50 years—United States, 2001. MMWR Morb Mortal
Wkly Rep 2003;52:193-6.
[2] Hawk ET, Levin B. Colorectal cancer prevention. J Clin Oncol 2005;
23:378-91.
[3] Seeff LC, Richards TB, Shapiro JA, et al. How many endoscopies are
performed for colorectal cancer screening? Results from CDC's survey
of endoscopic capacity. Gastroenterology 2004;127:1670-7.
[4] Aisenberg J, Brill JV, Ladabaum U, Cohen LB. Sedation for
gastrointestinal endoscopy: new practices, new economics. Am J
Gastroenterol 2005;100:996-1000.
403
[5] Waring JP, Baron TH, Hirota WK, et al. Guidelines for conscious
sedation and monitoring during gastrointestinal endoscopy. Gastro-
intest Endosc 2003;58:317-22.
[6] Vicari JJ. Sedation and analgesia. Gastrointest Endosc Clin N Am
2002;12:297-311.
[7] Cotton PB, Connor P, McGee D, et al. Colonoscopy: practice variation
among 69 hospital-based endoscopists. Gastrointest Endosc 2003;57:
352-7.
[8] Rex DK, Lehman GA, Hawes RH, O'Connor KW, Smith JJ.
Performing screening flexible sigmoidoscopy using colonoscopes:
experience in 500 subjects. Gastrointest Endosc 1990;36:486-8.
[9] Rodney WM, Dabov G, Orientale E, Reeves WP. Sedation associated
with a more complete colonoscopy. J Fam Pract 1993;36:394-400.
[10] Hoffman MS, Butler TW, Shaver T. Colonoscopy without sedation.
J Clin Gastroenterol 1998;26:279-82.
[11] Rex DK, Imperiale TF, Portish V. Patients willing to try colonoscopy
without sedation: associated clinical factors and results of a
randomized controlled trial. Gastrointest Endosc 1999;49:554-9.
[12] Early DS, Saifuddin T, Johnson JC, King PD, Marshall JB. Patient
attitudes toward undergoing colonoscopy without sedation. Am J
Gastroenterol 1999;94:1862-5.
[13] American Society of Anesthesiology Task Force on Sedation and
Analgesia by Non-Anesthesiologists. Practice guidelines for sedation and
analgesia by non-anesthesiologists. Anesthesiology 2002;96:1004-17.
[14] Huang R, Eisen GM. Efficacy, safety, and limitations in current
practice of sedation and analgesia. Gastrointest Endosc Clin N Am
2004;14:269-88.
[15] Jalowiecki P, Rudner R, Gonciarz M, Kawecki P, Petelenz M,
Dziurdzik P. Sole use of dexmedetomidine has limited utility for
conscious sedation during outpatient colonoscopy. Anesthesiology
2005;103:269-73.
[16] Cohen LB, Wecsler JS, Gaetano JN, et al. Endoscopic sedation in the
Unites States: results from a nationwide survey. Am J Gastroenterol
2006;101:967-74.
[17] Cohen LB, Dubovsky AN, Aisenberg J, Miller KM. Propofol for
endoscopic sedation: a protocol for safe and effective administration
by the gastroenterologist. Gastrointest Endosc 2003;58:725-32.
[18] Heuss LT, Drewe J, Schnieper P, Tapparelli CB, Pflimlin E, Beglinger
C. Patient-controlled versus nurse-administered sedation with propofol
during colonoscopy. A prospective randomized trial. Am J Gastro-
enterol 2004;99:511-8.
[19] Heuss LT, Schnieper P, Drewe J, Pflimlin E, Beglinger C. Risk
stratification and safe administration of propofol by registered nurses
supervised by the gastroenterologist: a prospective observational study
of more than 2000 cases. Gastrointest Endosc 2003;57:664-71.
[20] Rex DK, Overley CA, Walker J. Registered nurse-administered
propofol sedation for upper endoscopy and colonoscopy: why?
When? How? Rev Gastroenterol Disord 2003;3:70-80.
[21] Rex DK, Overley C, Kinser K, et al. Safety of propofol administered
by registered nurses with gastroenterologist supervision in 2000
endoscopic cases. Am J Gastroenterol 2002;97:1159-63.
[22] Horn E, Nesbit SA. Pharmacology and pharmacokinetics of sedatives
and analgesics. Gastrointest Endosc Clin N Am 2004;14:247- 268.
[23] Roseveare C, Seavell C, Patel P, et al. Patient-controlled sedation and
analgesia, using propofol and alfentanil, during colonoscopy: a
prospective randomized controlled trial. Endoscopy 1998;30:768-73.
[24] Koshy G, Nair S, Norkus EP, Hertan HI, Pitchumoni CS. Propofol
versus midazolam and meperidine for conscious sedation in GI
endoscopy. Am J Gastroenterol 2000;95:1476-9.
[25] Reimann FM, Samson U, Derad I, Fuchs M, Schiefer B, Stange EF.
Synergistic sedation with low-dose midazolam and propofol for
colonoscopies. Endoscopy 2000;32:239-44.
[26] Ng JM, Kong CF, Nyam D. Patient-controlled sedation with propofol
for colonoscopy. Gastrointest Endosc 2001;54:8-13.
[27] Sipe BW, Rex DK, Latinovich D, et al. Propofol versus midazolam/
meperidine for outpatient colonoscopy: administration by nurses
supervised by endoscopists. Gastrointest Endosc 2002;55:815-25.
404
[28] Ulmer BJ, Hansen JJ, Overley CA, et al. Propofol versus midazolam/
fentanyl for outpatient colonoscopy: administration by nurses super-
vised by endoscopists. Clin Gastroenterol Hepatol 2003;1:425-32.
[29] Macken E, Gevers AM, Hendrickx A, Rutgeerts P. Midazolam versus
diazepam in lipid emulsion as conscious sedation for colonoscopy with
or without reversal of sedation with flumazenil. Gastrointest Endosc
1998;47:57-61.
[30] Zakko SF, Seifert HA, Gross JB. A comparison of midazolam and
diazepam for conscious sedation during colonoscopy in a prospective
double-blind study. Gastrointest Endosc 1999;49:684-9.
[31] Moerman AT, Foubert LA, Herregods LL, et al. Propofol versus
remifentanil for monitored anaesthesia care during colonoscopy. Eur J
Anaesthesiol 2003;20:461-6.
[32] Seifert H, Schmitt TH, Gultekin T, Caspary WF, Wehrmann T.
Sedation with propofol plus midazolam versus propofol alone for
interventional endoscopic procedures: a prospective, randomized
study. Aliment Pharmacol Ther 2000;14:1207-14.
[33] Morrow JB, Zuccaro G Jr, Conwell DL, et al. Sedation for colonoscopy
using a single bolus is safe, effective, and efficient: a prospective,
randomized, double-blind trial. Am J Gastroenterol 2000;95:2242-7.
[34] Paspatis GA, Manolaraki M, Xirouchakis G, Papanikolaou N,
Chlouverakis G, Gritzali A. Synergistic sedation with midazolam
and propofol versus midazolam and pethidine in colonoscopies: a
prospective, randomized study. Am J Gastroenterol 2002;97:1963-7.
[35] Rudner R, Jalowiecki P, Kawecki P, Gonciarz M, Mularczyk A, Petelenz
M. Conscious analgesia/sedation with remifentanil and propofol versus
total intravenous anesthesia with fentanyl, midazolam, and propofol for
outpatient colonoscopy. Gastrointest Endosc 2003;57:657-63.
[36] Radaelli F, Meucci G, Terruzzi V, et al. Single bolus of midazolam
versus bolus midazolam plus meperidine for colonoscopy: a prospec-
tive, randomized, double-blind trial. Gastrointest Endosc 2003;57:
329-35.
[37] Ristikankare M, Julkunen R, Mattila M, et al. Conscious sedation and
cardiorespiratory safety during colonoscopy. Gastrointest Endosc
2000;52:48-54.
[38] Bright E, Roseveare C, Dalgleish D, Kimble J, Elliott J, Shepherd H.
Patient-controlled sedation for colonoscopy: a randomized trial
comparing patient-controlled administration of propofol and alfentanil
with physician-administered midazolam and pethidine. Endoscopy
2003;35:683-7.
[39] Quine MA, Bell GD, McCloy RF, Charlton JE, Devlin HB, Hopkins
A. Prospective audit of upper gastrointestinal endoscopy in two
regions of England: safety, staffing, and sedation methods. Gut 1995;
36:462-7.
[40] Arrowsmith JB, Gerstman BB, Fleischer DE, Benjamin SB. Results
from the American Society for Gastrointestinal Endoscopy/U.S. Food
and Drug Administration collaborative study on complication rates and
drug use during gastrointestinal endoscopy. Gastrointest Endosc 1991;
37:421-7.
[41] Balsells F, Wyllie R, Kay M, Steffen R. Use of conscious sedation for
lower and upper gastrointestinal endoscopic examinations in children,
adolescents, and young adults: a twelve-year review. Gastrointest
Endosc 1997;45:375-80.
[42] Rex DK, Heuss LT, Walker JA, Qi R. Trained registered nurses/
endoscopy teams can administer propofol safely for endoscopy.
Gastroenterology 2005;129:1384-91.
[43] Froehlich F, Schwizer W, Thorens J, Kohler M, Gonvers JJ, Fried M.
Conscious sedation for gastroscopy: patient tolerance and cardior-
espiratory parameters. Gastroenterology 1995;108:697-704.
[44] O'Connor KW, Jones S. Oxygen desaturation is common and
clinically underappreciated during elective endoscopic procedures.
Gastrointest Endosc 1990;36(3 Suppl):S2-S4.
[45] Riphaus A, Stergiou N, Wehrmann T. Sedation with propofol for
routine ERCP in high-risk octogenarians: a randomized, controlled
study. Am J Gastroenterol 2005;100:1957-63.
[46] Heuss LT, Schnieper P, Drewe J, Pflimlin E, Beglinger C. Safety of
propofol for conscious sedation during endoscopic procedures in high-
D.A. Lubarsky et al.
risk patients—a prospective, controlled study. Am J Gastroenterol
2003;98:1751-7.
[47] Vargo JJ. Propofol: a gastroenterologist's perspective. Gastrointest
Endosc Clin N Am 2004;14:313-23.
[48] Graber RG. Propofol in the endoscopy suite: an anesthesiologist's
perspective. Gastrointest Endosc 1999;49:803-6.
[49] Clarke AC, Chiragakis L, Hillman LC, Kaye GL. Sedation for
endoscopy: the safe use of propofol by general practitioner
sedationists. Med J Aust 2002;176:158-61.
[50] Sundman E, Witt H, Sandin R, et al. Pharyngeal function and
airway protection during subhypnotic concentrations of propofol,
isoflurane, and sevoflurane: volunteers examined by pharyngeal
videoradiography and simultaneous manometry. Anesthesiology
2001;95:1125-32.
[51] Faigel DO, Eisen GM, Baron TH, et al. Preparation of patients for GI
endoscopy. Gastrointest Endosc 2003;57:446-50.
[52] Newcomer MK, Shaw MJ, Williams DM, Jowell PS. Unplanned work
absence following outpatient colonoscopy. J Clin Gastroenterol 1999;
29:76-8.
[53] Chen SC, Rex DK. Review article: registered nurse-administered
propofol sedation for endoscopy. Aliment Pharmacol Ther 2004;19:
147-55.
[54] Karan SB, Bailey PL. Update and review of moderate and deep
sedation. Gastrointest Endosc Clin N Am 2004;14:289-312.
[55] Statement on safe use of propofol. October 27, 2004. Accessed January
26, 2005, at www.asahq.org/publicationsAndServices/standards/37.pdf.
[56] Bell GD. Premedication, preparation, and surveillance. Endoscopy
2002;34:2-12.
[57] Barawi M, Gress F. Conscious sedation: is there a need for
improvement? Gastrointest Endosc 2000;51:365-8.
[58] Skues MA, Prys-Roberts C. The pharmacology of propofol. J Clin
Anesth 1989;1:387-400.
[59] Sneyd JR. Recent advances in intravenous anaesthesia. Br J Anaesth
2004;93:725-36.
[60] Fulk C, Lund B, Mosher GL, et al. Preserved Formulations Containing
Captisol Brand of Sulfobutylether-beta-cyclodextrin. Accessed June
27, 2006, at www.cydexinc.com/maxdocs/preservativeposter2004.pdf.
[61] Egan TD, Kern SE, Johnson KB. Propofol in a modified cyclodextrin
formulation: first in man pharmacodynamics [Abstract]. Anesth Analg
2006;102:S297.
[62] Fechner J, Ihmsen H, Hatterscheid D, et al. Pharmacokinetics and
clinical pharmacodynamics of the new propofol prodrug GPI 15715 in
volunteers. Anesthesiology 2003;99:303-13.
[63] Gibiansky E, Struys MM, Gibiansky L, et al. AQUAVAN injection, a
water-soluble prodrug of propofol, as a bolus injection: a phase I dose-
escalation comparison with DIPRIVAN (part 1): pharmacokinetics.
Anesthesiology 2005;103:718-29.
[64] Struys MM, Vanluchene AL, Gibiansky E, et al. AQUAVAN injection,
a water-soluble prodrug of propofol, as a bolus injection: a phase I
dose-escalation comparison with DIPRIVAN (part 2): pharmacody-
namics and safety. Anesthesiology 2005;103:730-43.
[65] Fechner J, Ihmsen H, Schiessl C, et al. Sedation with GPI 15715, a
water-soluble prodrug of propofol, using target-controlled infusion in
volunteers. Anesth Analg 2005;100:701-6.
[66] Cohen LB, Wang C, Jones JB. AQUAVAN is safe and effective for
minimal to moderate sedation during colonoscopy. Park Ridge, IL:
American Society of Anesthesiologists, 2006. http://www.asaabstracts.
com/strands/asaabstracts/search.htm.
[67] Kulling D, Bauerfeind P, Fried M, Biro P. Patient-controlled analgesia
and sedation in gastrointestinal endoscopy. Gastrointest Endosc Clin N
Am 2004;14:353-68.
[68] Egan TD. Target-controlled drug delivery: progress toward an intra-
venous “vaporizer” and automated anesthetic administration. Anesthe-
siology 2003;99:1214-9.
[69] Rodrigo MR, Irwin MG, Tong CK, Yan SY. A randomised crossover
comparison of patient-controlled sedation and patient-maintained
sedation using propofol. Anaesthesia 2003;58:333-8.