E   Editorial
Think Before You Administer: Is Routine
Benzodiazepine Premedication Before Endoscopy
in Adults Necessary?
John C. Alexander, MD, MBA, and Girish P. Joshi, MBBS, MD, FFARCSI
See Article, p 741
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GLOSSARY
PostopQRS = Postoperative Quality of Recovery Scale
S
edation and analgesia are commonly admin-
istered during gastrointestinal endoscopy to
promote patient comfort and cooperation and
to facilitate performing the procedure. Propofol has
become the standard of care because it allows for
rapid recovery without residual psychomotor effects
as well as optimizes patient satisfaction and proce-
dure acceptability. Usually, a low dose of midazolam
and/or opioid (eg, fentanyl) are combined with pro-
pofol. Midazolam is typically administered before
transferring the patient to the procedure room to
reduce anxiety. In addition, midazolam may reduce
propofol dose requirements and the risk of propofol-
induced cardiorespiratory complications. Opioids not
only provide analgesia but also reduce propofol dos-
ing and patient movement.1
In this issue of Anesthesia & Analgesia, Gurunathan
et al2 assessed the effects of adding midazolam (0.04
mg/kg, up to 5 mg) to a propofol and opioid sedation
regimen on the quality of recovery after colonoscopy.
The investigators used the Postoperative Quality of
Recovery Scale (PostopQRS)—a validated multidi-
mensional survey-based tool—to assess postoperative
recovery in the domains of physiological, emotive,
From the Department of Anesthesiology and Pain Management, University
of Texas Southwestern, Dallas, Texas.
Accepted for publication February 24, 2020.
Funding: None.
Conflicts of Interest: See Disclosures at the end of the article.
Reprints will not be available from the authors.
Address correspondence to Girish P. Joshi, MBBS, MD, FFARCSI, Depart-
ment of Anesthesiology and Pain Management, University of Texas South-
western Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390. Address
e-mail to girish.joshi@utsouthwestern.edu.
Copyright © 2020 International Anesthesia Research Society
DOI: 10.1213/ANE.0000000000004784
738 www.anesthesia-analgesia.org September 2020 • Volume 131 • Number 3
Copyright © 2020 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited.
nociceptive, cognitive, and activities of daily living.
The study found that there was no difference between
the midazolam and placebo groups in the cognitive
domain of PostopQRS on postprocedure day 3. Also,
the overall recovery, including nociceptive, emotive,
and activities of daily living, was similar with or with-
out midazolam. With respect to immediate recovery,
there were no differences in the time to eye opening
and hospital discharge. Finally, patient and endosco-
pist satisfaction were similar between groups. Because
there appeared to be neither benefits nor harm, the
authors concluded that the anesthesiologist should
determine the use of midazolam.
So, what should an anesthesiologist do? The out-
comes of the present study could readily support the
view that midazolam should not be used at all for colo-
noscopy because no benefit was shown. Alternatively,
midazolam use is justified as there was lack of
demonstrated harm. A nuanced answer, then, requires
one to address the following questions based on a crit-
ical evaluation of the literature:
• Does midazolam premedication in adults pro-
vide significant benefits such as reduced anxiety,
amnesia, improved cardiorespiratory status, or
improved patient satisfaction?
• Alternatively, does it increase the incidence of car-
diorespiratory depression and airway obstruc-
tion either during or after short procedures?
• Does it hinder recovery and delay discharge
home after short ambulatory procedures?
• Does low-dose midazolam cause any potential
harm in specific at-risk populations such as the
elderly and the obese with obstructive sleep
apnea or hypoventilation syndrome?
 EE EDITORIAL
The primary outcome of the study by Gurunathan
et al2 was to assess for cognitive impairment—a sub-
ject that has received increasing attention in recent
years—because it is associated with increased mor-
bidity and mortality.3 Although not observed in
this study, benzodiazepine administration has been
shown to increase emergence delirium and cogni-
tive dysfunction.3 The lack of cognitive dysfunction
observed in the present study may be due to its limita-
tion of substantial study subject attrition for cognitive
assessment, possibly because cognitively impaired
patients were reluctant to undergo evaluation.
The differences in the findings of this study and
previous reports may also be due to the variability in
tools used to assess postoperative cognitive dysfunc-
tion.4 The present study did not report differences
between younger and older patients, which might
have provided interesting insights on the differing
effects of midazolam based on age, as reported in
others studies. A recent study observed that even a 2
mg intravenous dose of midazolam in older adults is
associated with measurable deficits by cognitive test-
ing and functional imaging changes.5
Another study in colonoscopy patients reported
that the administration of adjuvants (eg, fentanyl or
midazolam) with propofol resulted in better operat-
ing conditions and shorter endoscopy time but also
increased the time to achieve cognitive recovery.6
This was especially pronounced in patients who took
preoperative psychotropic medications or received
>2 mg midazolam, who tended to display more
clinically significant cognitive decline.6 It should be
noted that antidepressant use has been on the rise for
decades; currently 1 in 8 adolescents and adults take
them, but this increases to 1 in 5 adults over 60 years.7
Additionally, older patients are at a higher baseline
risk of postoperative cognitive dysfunction which,
when coupled with higher rates of use of psychotro-
pic medications, may further increase the risk of post-
operative cognitive dysfunction in this population.
It is possible that midazolam may have minimal
effects on cognitive function after a diagnostic endo-
scopic procedure compared with a therapeutic endo-
scopic procedure requiring general anesthesia or a
more invasive surgical procedure.
It is also important to note that subjects with
prior cognitive decline or memory impairment were
excluded from the present study by Gurunathan et
al,2 and thus the effects of midazolam on postpro-
cedure cognitive function in this patient population
remain unknown. However, with the aging world
population, the prevalence of patients with cognitive
impairment presenting for diagnostic and therapeu-
tic gastrointestinal endoscopies will increase. While
in a rigorous study, even subtle cognitive impairment
September 2020 • Volume 131 • Number 3 www.anesthesia-analgesia.org 739
Copyright © 2020 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited.
can be identified by experienced research personnel,
it may be overlooked in a busy endoscopic practice.
Given these unknowns and the lack of any clinical
benefits, routine use of midazolam seems unjustified.
The current study observed that both groups
approached 100% patient satisfaction whether or not
midazolam was administered. In contrast, a previous
study found higher patient satisfaction for fentanyl/
propofol sedation for colonoscopy if preprocedure
midazolam was included.8 Another recent study
noted patient preference for propofol sedation over
midazolam/fentanyl sedation.9 Thus, it appears that
propofol, rather than midazolam, is the main con-
tributor to patient satisfaction. It is generally assumed
that midazolam premedication would reduce prepro-
cedure anxiety and, thus, improve patient satisfac-
tion. However, several studies have concluded that
benzodiazepine premedication may not necessarily
reduce anxiety or improve patient experience.10,11
In the present study by Gurunathan et al,2 the
midazolam group did require lower propofol doses,
which may exert clinical benefits such as reduced
occurrence of hypotension or airway obstruction, but
these were not reported. Given this, we cannot draw
any conclusions from this study on this end point.
Nevertheless, combining propofol, midazolam, and
fentanyl would have at least additive cardiorespira-
tory depressive effects and, thus, may increase the
potential cardiorespiratory complications. Several
studies have shown evidence of dose-dependent air-
way obstruction under propofol sedation,12–14 and a
recent study comparing obstruction patterns with
different sedatives showed higher levels of obstruc-
tion with midazolam compared to either propofol or
dexmedetomidine.15 The evidence-based guidelines
of the Society of Anesthesia and Sleep Medicine con-
cluded that patients with obstructive sleep apnea may
be at an increased risk for adverse respiratory events
after propofol sedation.16 This risk is further exacer-
bated with depressant drugs with additive effects
such as midazolam, opioids, ketamine, and dexme-
detomidine. Therefore, it was recommended that ben-
zodiazepine sedation should be used with caution.16
In the present study by Gurunathan et al,2 the mid-
azolam group had delayed recovery in the level of
consciousness and response to verbal command at 15
minutes, but this resolved after 1 hour. While a seem-
ingly minor difference, a 15-minute delay in recovery
for each patient may significantly reduce the effi-
ciency of a busy endoscopy facility. Thus, the addition
of preprocedure midazolam should be avoided if one
anticipates rapid postprocedure discharge.
Additionally, preoperative midazolam reliably
causes anterograde amnesia and thus has been reported
to impair patients’ recall of their interactions with their
 Midazolam Premedication For Endoscopy
anesthesiologist.17 While this does not worsen clini-
cal outcomes, such gaps in memory may mask from
patients the integral role of anesthesiologists in their
care and undermine this doctor–patient relationship.
Although not assessed in this study by Gurunathan
et al,2 the need for addition of opioids to propo-
fol sedation for colonoscopy is also questionable.
Addition of an opioid to propofol has been reported
to improve conditions of esophageal instrumentation
during upper endoscopy.18 In contrast to upper gas-
trointestinal endoscopy where insertion of endoscope
may cause retching, the insertion of the colonoscope
is usually well tolerated, and the stimulating portions
of the procedure relate to gas insufflation and scope
manipulation around colic flexures can be adequately
managed with propofol alone. Because gas insuffla-
tion and abdominal compression during colonoscopy
have been shown to increase the risk of aspiration,19
preservation of airway reflexes would be beneficial,
which would be achieved by avoiding deep sedation
that is more likely with combinations of midazolam,
fentanyl, and propofol.
In summary, given the modest advantages and sig-
nificant potential adverse effects of a benzodiazepine,
its routine use before endoscopy should be avoided.
This recommendation is in line with the enhanced
recovery protocols published by several prominent
professional societies emphasizing avoidance of rou-
tine benzodiazepine premedication. Finally, future
studies should more formally assess the differential
effects of each component of the propofol–opioid–
midazolam combinations in procedures of varying
invasiveness and in subpopulations at higher risk for
complications. E
DISCLOSURES
Name: John C. Alexander, MD, MBA.
Contribution: This author helped write and revise the
manuscript.
Conflicts of Interest: J. C. Alexander has received honoraria
from Pacira Pharmaceuticals.
Name: Girish P. Joshi, MBBS, MD, FFARCSI.
Contribution: This author helped write and revise the
manuscript.
Conflicts of Interest: G. P. Joshi has received honoraria from
Baxter Pharmaceuticals and Pacira Pharmaceuticals.
This manuscript was handled by: Jean-Francois Pittet, MD.
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