JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY 2016, 67, 4, 617-624

www.jpp.krakow.pl

E. DEFLANDRE1, V. BONHOMME2, A.-C. COURTOIS3, S. DEGEY4, R. POIRRIER5, J.-F. BRICHANT6

INFLUENCE OF PREMEDICATION WITH ALPRAZOLAM

ON THE OCCURENCE OF OBSTRUCTIVE APNEAS.
A PROSPECTIVE RANDOMIZED DOUBLE-BLIND STUDY

1Department of Anesthesia, Clinique Saint-Luc, Bouge, Belgium & Cabinet Medical ASTES,

Jambes, Belgium & University of Liege, Liege, Belgium; 2University Department of Anesthesia and ICM,
CHR Citadelle and CHU Liege, Liege, Belgium & CHU Sart-Tilman, Domaine du Sart-Tilman, Liege, Belgium;
3Department of Physical Medicine and Functional Readaptation, CHRH, Huy, Belgium; 4Cabinet Medical ASTES, Jambes,

Belgium; 5Department of Neurology, CHU Liege, Liege, Belgium & CHU Sart-Tilman - Domaine du Sart-Tilman, Liege, Belgium;
6Department of Anesthesia and ICM, CHU Liege, Liege, Belgium & CHU Sart-Tilman - Domaine du Sart-Tilman, Liege, Belgium

Postoperative development or worsening of obstructive sleep apnea is a potential complication of anesthesia. The
objective of this study was to study the effects of a premedication with alprazolam on the occurrence of apneas during
the immediate postoperative period. Fifty ASA 1 – 2 patients undergoing a colonoscopy were recruited. Patients with a
history of obstructive sleep apnea (OSA) were excluded. Recruited patients were randomly assigned to one of two
groups: in Group A, they received 0.5 mg of alprazolam orally one hour before the procedure; and in Group C, they
received placebo. Anesthesia technique was identical in both groups. Patients were monitored during the first two
postoperative hours to establish their AHI (apnea hypopnea index, the number of apneas and hypopneas per hour). Nine
patients were excluded (4 in group A and 5 in group C) due to technical problems or refusal. Interestingly, premedication
by alprazolam did not change intra-operative propofol requirements. During the first two postoperative hours, the AHI
was significantly higher in group A than in group C (Group A: 20.33 ± 10.97 h–1, C: 9.63 ± 4.67 h–1). These apneas did
not induce significant arterial oxygen desaturation, or mandibular instability. Our study demonstrates that a
premedication with 0.5 mg of alprazolam doesn’t modify intra-operative anesthetic requirements during colonoscopy,
but is associated with a higher rate of obstructive apneas during at least three and a half hours after ingestion. No severe
side effects were observed in our non-obese population. Our results must be confirmed on a larger scale.

K e y w o r d s : alprazolam, obstructive, sleep apnea, postoperative complications, hypopnea, anesthesia, perioperative period

INTRODUCTION In clinical practice, anesthesiologists are aware of the risk of

apnea associated with the administration of opioids or muscle
Obstructive apnea is defined as an interruption of the airway relaxants (6). Although frequently omitted, premedication is a
flow during a minimum of ten seconds (1). Hypopnea is defined possible cause of obstructive apneas (7). Anxiolytic premedication
as a limitation of this airway flow during the same period (1). has been common practice in many centers (8). Benzodiazepines
The apnea hypopnea index (AHI) corresponds to the number of have long been used for this purpose (9), and alprazolam is one of
apnea and hypopnea per hour. The obstructive sleep apnea the numerous benzodiazepines that are commonly used in that
(OSA) syndrome is characterized by the repetitive occurrence of indication (10). In some countries, such as Belgium, alprazolam is
apneas or hypopneas during sleep. OSA is defined as mild when still widely used, including for outpatients. Dahmani et al. have
the AHI ranges between 5 and 15 events per hour, moderate already demonstrated that premedication with clonidine may have
when it ranges between 15 and 30 events per hour, or severe a better risk/benefit ratio (11), as do dexmedetomidine (12).
when AHI is higher than 30 events per hour) (2). Obstructive However, the effects of alprazolam on the occurrence of
sleep apnea is an independent risk factor for perioperative postoperative apnea, or the effects of those apneas on arterial
complications (2). Danger for the patient is particularly high oxygen saturation have never been assessed. Our primary
when it occurs on the ward, outside the post-anesthesia care unit, hypothesis was that alprazolam could jeopardize the upper airway
or worse, after hospital discharge (3, 4). The incidence of stability, and therefore favor the occurrence of obstructive apneas
obstructive apneas increases with the perioperative during the immediate postoperative period. To distinguish the
administration of several medications such as opioids, sedative effect of alprazolam from OSA pathophysiology, patients with a
agents, or neuromuscular blocking agents (5). known or suspected history of OSA were excluded from this study.
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MATERIALS AND METHODS In the endoscopy suit, patients were equipped with standard
monitoring, including electrocardiogram, non-invasive blood
This study has obtained the approval of our Institutional pressure, capnography, and a peripheral saturation in oxygen
Ethics Committee (Ethical Committee of Liege University (SpO2) sensor (Datex-Ohmeda, GE Healthcare, Fairfield,
Hospitals, Liege, Belgium, Chairperson: Prof Maurice Lamy, USA). A Bispectral Index® (BIS, Covidien, St. Ingbert,
Ref: 2007-110). EudraCT registered this study with the reference Germany) electrode was also placed on the forehead of all
number: 2007-002429-66. Informed consent was obtained from patients. An 18G IV line was inserted, and a Hartmann’s
all individual participants included in the study. solution (Baxter SA, Lessines, Belgium) was infused (rate: 200
ml h–1). Patients were also equipped with an oxygen face mask
Patients (Mallinckrodt, Covidien, St. Ingbert, Germany), and the oxygen
flow rate was 10 L min–1. This corresponds to the standard in
Fifty patients scheduled for day-care colonoscopy were our Institution.
recruited (Fig. 1). Exclusion criteria were patient’s refusal, During induction of anesthesia, patients received a single
patients with known obstructive sleep apnea (OSA) syndrome, intravenous bolus of ketamine (0.5 mg Kg–1). After that, a
and/or an ASA class ≥ 3. Patients in the first group (Group A) continuous infusion of propofol was adjusted to maintain a BIS
received an oral premedication, consisting in 0.5 mg of value between 70 and 80. This range was determined by a pre-
alprazolam one hour before colonoscopy. Patients in the second test on five patients (unpublished data). From a clinical point of
group (group C) received placebo. The placebo was an inactive view, sedation was targeted at a deep level, so that patients were
comparator indistinguishable from the alprazolam tablet. not responsive throughout the procedure. The respiratory rate
was measured using a capnograph, whose sampling line was
Experimental procedures inserted into the oxygen face mask. Throughout the procedure,
spontaneous ventilation was maintained in all patients.
A researcher who did not participate in managing anesthesia After colonoscopy, patients were admitted to the post-
and data recording prepared the randomization schedule using a anesthesia care unit (PACU) for two hours. They were monitored
computer-generated sequence. During the preoperative visit, a using a portable monitoring device (Somnolter®, Nomics SA,
second investigator recorded patient age, weight, height, neck 4031 Angleur, BELGIUM, www.nomics.be). This device is
circumference and airway difficult score (ADS), which is the validated as a portable device for diagnosing OSA (14-16). It
score for difficult intubation and ventilation used in our hospital consists in a SpO2 sensor, and two piezoelectric sensors placed
(13). This second investigator was blinded to between-group on the face of the patient. Those sensors measure mandibular
patient repartition. movement. This mandibular movement (JAWAC: JAW

Assessed for eligibility (n=50)

Excluded (n=0)

Randomized (n=50)

Group A (n=25) Group C (n=25)

These patients received oral These patients received oral
premedication, consisting of 0.5 premedication, consisting of
mg of alprazolam one hour placebo one hour before
before colonoscopy colonoscopy

Two hours stay in PACU in order to Two hours stay in PACU in order to
establish their AHI and to collect their establish their AHI and to collect their
SpO2 (n = 21). SpO2 (n = 20).

Four patients did not achieve this Five patients did not achieve this
monitoring for technical reasons (n=2) or monitoring for technical reasons (n=3) or
refusal of the patient to stay for two hours refusal of the patient to stay for two hours
in the PACU (n = 2). in the PACU (n = 2).

Fig. 1. CONSORT flow chart (PACU,

Analyzed (n=21) Analyzed (n=20) post-anesthesia care unit; AHI, apnea
hypopnea index).
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ACtivity) correlates with the esophageal pressure during arrival in the PACU and 3) at PACU discharge by the
obstructive sleep apnea (14-16). The Somnolter® provides an anesthesiologist responsible for post-anesthesia care. Both
estimate of mandibular stability, expressed in percent. One practitioners were blind to group repartition. The overall patient
hundred percent corresponds to a fully closed mouth, and 0% to satisfaction regarding the whole procedure was evaluated upon
the largest mouth opening for a given patient. No calibration of patient discharge from the post-anesthesia care unit.
the device is needed. The software can distinguish obstructive
apneas from other mandibular movements such as speaking. In Statistical analysis
the post-anesthesia care unit, no oxygen was administered.
Somnolter®-recorded SpO2 and AHI were analyzed offline, Data were compiled into a computer file and compared
and the analyzing investigator was blind to group assignment. between groups. The normality of data distribution was
Analgesics consumption in the post-anesthesia care unit was evaluated using a Shapiro-Wilk test. Proportions were analyzed
also recorded. Any administration of paracetamol, ketorolac or using Fisher’s exact tests, and normally distributed data were
butylhyoscine bromure was also recorded. compared between groups using two-tailed unpaired t-tests. Data
The Lickert psychometric scale (17, 18) was used to estimate that did not show a normal distribution were assessed using
patient satisfaction and anxiety (Table 1). The anxiety level was Mann-Withney U tests, or Friedman tests as appropriate. A two-
assessed at three different time points: 1) before colonoscopy by tailed P value < 0.05 was considered as statistically significant.
the anesthesiologist in charge of providing anesthesia, 2) upon Data were analysed using XLSTAT for Mac® (version 2015.5.01,

Table 1. Psychometric Lickert’s scale used to appreciate anxiety and satisfaction of the patient. See text for explanations.

1 point 2 points 3 points 4 points

Anxiety and sedation Awake but not Very anxious and
Drowsy Awake and anxious
score anxious uncomfortable
Unsatisfied,
Satisfied, Satisfied, Satisfied,
he/she was too
Patient satisfaction but next time, he/she he/she would like but next time, he/she
anxious and would
on the whole would rather be the same would rather be
rather be
procedure premedicated more premedication next premedicated more
premedicated more
lightly time deeply
deeply next time

Table 2. Demographic, operating room and post-anesthesia care unit data. Reported values are means (S.D.), unless otherwise indicated.
Group A Group C Statistics P
(n = 21) (n = 20)
Age 55.1 (13) 49.7 (11.6) t(39) = 1.4 0.17
Male/female
5/16 11/9 0.03
(n)
BMI
24.9 (4) 24 (3.1) t(39) = 0.7 0.47
in Kg m–2
Neck circumference
36.5 (3.2) 36.9(3.9) t(39) = 0.4 0.7
in cm
Airway Difficult Score (ADS) U = 187.5,
6 (8 – 5) 6 (9 – 5) 0.34
[median (IQR)] Z = –0.6
Ketamine
27.9 (5.6) 31.5 (7.3) t(39) = 1.8 0.08
in mg
Ketamine
0.4 (0.1) 0.4 (0.1) t(39) = 2 0.15
in mg kg–1
Propofol consumption
236.4 (65.1) 291.4 (117.8) t(39) = 1.8 0.08
in mg
Propofol consumption
3.5 (1.2) 4.4 (2.4) t(39) = 2 0.16
in mg kg–1
Analgesic consumption
None None N/A N/A
in PACU
Anxiety upon arrival U = 106.5
2 (1 – 3) 3 (2 – 4) 0.01
in the operating room [median (IQR)] Z = –2.7
Anxiety upon arrival in PACU U = 189
2 (1 – 2) 2 (1 – 3) 0.34
[median (IQR)] Z = –0.5
Overall patient’s satisfaction U = 231
2 (2 – 2) 2 (1 – 2) 0.34
[median (IQR)] Z = –0.5

BMI, body mass index; IQR, interquartile range; PACU, post-anesthesia care unit.
620

Addinsoft SARL®, Paris, France) and MedCalc® (version Patients premedicated with alprazolam were significantly
15.11.0 MedCalc Software bvba®, Ostend, Belgium). less anxious upon arrival in the operating room than patients
who received placebo (P = 0.01). On the opposite, anxiety was
similar in the two groups upon arrival in the post-anesthesia care
RESULTS unit (P = 0.34). The overall patient satisfaction concerning the
whole procedure did also not differ between groups (P = 0.34)
Nine patients were excluded from the study (4 in group A (Table 2).
and 5 in group C). Reasons for exclusion were related to
technical problems or refusal of the patient to stay for two hours
in the post-anesthesia care unit. Post hoc power calculation DISCUSSION
revealed a study power of 78% at detecting a clinically relevant
40% between-group difference in the incidence of apnea during The main result of the present study is that administration of
the first two postoperative hours, at a 0.05 a threshold. 0.5 mg of alprazolam one hour before colonoscopy significantly
Patient characteristics: age, body mass index (BMI), neck increases the number of apneas and hypopneas at least during
circumference, intubation and ventilation score were similar in the two hours after the completion of the procedure. However, this
two groups, except for the gender ratio (Table 2). There were increase is not associated with more frequent arterial oxygen
significantly more women in Group A than in Group C. There was desaturation episodes. It is worth to point out that our population
no statistically significant between-group difference regarding was not at risk of such events. None of the patients were obese
administered ketamine or propofol amounts. BIS values were nor had a history of OSA. Administrating the same alprazolam
comparable between the two groups (mean BIS (S.D.) was 74.52 premedication in patients with an increased risk of obstructive
(1.75) in Group A, and 74.95 (1.67) in Group C, Mann-Whitney apnea could lead to different results (19). Propofol and ketamine
U = 179, P = 0.417). No laryngeal device had to be inserted during were used to provide respectively anesthesia and anti-
colonoscopy. No patient requested the administration of analgesic nociception. This allowed avoiding opioid administration that
medications in the post-anesthesia care unit (Table 2). No could influence the occurrence of postoperative apneic events (6,
additional oxygen was necessary in the PACU. 20-22). Another reason for not observing desaturations can be
During the two hour stay in the post-anesthesia care unit, the related to the increased genioglossus activity associated with the
number of apneas and hypopneas was significantly higher in administration of ketamine (23). However, this property is
Group A than in Group C: median AHI (IQR) was 17.5 (11.45 – observed for much higher doses of ketamine (60 and 125 mg
30.29) in Group A, and 9.25 (7.32 – 10.74) in Group C, Mann- Kg–1) (23). Finally, ketamine could have some actions on delta-
Whitney U = 74, Z = –3.55, P = 0.0007) (Fig. 2). Subdividing and mu-opiod receptors, but without any influence on airway
the two hours spent in the PACU in four 30-minute periods patency (24, 25). Zirlik et al. have demonstrated that melatonin
allowed demonstrating that the difference in the absolute number and omentin seem to be involved in pathogenesis of OSA (26).
of apneas and hypopneas episodes became statistically Of note, the incidence of apneas and hypopneas tended to
significant between groups after 30 minutes (Table 3, Figs. 3 and increase with time in the PACU. However, this increase did not
4). Within-group comparisons did not reveal any significant reach the significance level. Hence, the risk of apnea and
change in the AHI across the 30-minute time points. hypopnea in alprazolam-premedicated patients more than
Peripheral oxygen saturation was similar in both groups at probably persists after PACU discharge, when patients are no
all times (Table 4). Similarly, in the post-anesthesia care unit, longer monitored.
there was no difference in mandibular stability between the two Other studies have investigated the perioperative effects of an
groups (Table 4). alprazolam premedication. Contrarily to our study, they were not

Fig. 2. Between-groups difference

in AHI values during the first two
hours after colonoscopy. Boxplots
represent median, IQR, maximum,
and minimum values.
AHI, apnea hypopnea index
(events/hour); IQR, interquartile
range.
 621

Table 3. Incidence of apnea and hypopnea in the post-anesthesia care unit. Data are means (S.D.).
Group A Group C
Statistics
(n = 21) (n = 20)
Total number of apneas and U = 75
35 18.5
hypopneas observed during 2 hours Z = –3.5
(21 – 53) (14.5 – 21.25)
[median (IQR)] P = 0.0008
U = 74
AHI over the 2 hours 17.5 9.25
Z = –3.5
[median (IQR)] (11.45 – 30.29) (7.32 – 10.74)
P = 0.0007
Number of apneas and hypopneas Friedmans test:
12 8
during first 30 minutes F = 3.20;
(5.5 – 18) (5 – 17)
[median (IQR)] P = 0.09
Number of apneas and hypopneas Friedmans test:
14 6
observed minutes 30 – 60 F = 8.88;
(6 – 29.5) (4 – 11)
[median (IQR)] P = 0.008
Number of apneas and hypopneas Friedmans test:
14 7
observed during minutes 60 – 90 F = 7.31;
(9.5 – 29) (2 – 12)
[median (IQR)] P = 0.014
Number of apneas and hypopneas Friedmans test:
22 11
observed during minutes 90 – 120 F = 5.21;
(10 – 30.5) (4 – 16)
[median (IQR)] P = 0.035
AHI, apnea/hypopnea index; IQR, interquartile range.

Fig. 3. Between-groups difference

in the number of apnea and
hypopnea per period of 30 minutes
during the first two postoperative
hours. Data are expressed as mean
(S.D).
T0.30 - first thirty minutes spent in
PACU; T30.60 - period between
30 and 60 minutes spent in PACU;
T60.90 - period between 60 and 90
minutes spent in PACU: T90.120 -
period between 90 and 120
minutes spent in PACU; PACU,
post-anesthesia care unit.

necessarily designed to address the problem of postoperative colonoscopy. This is in line with the results of previous studies
apnea incidence and were not necessarily rid of the influence of (29-31). On the opposite, alprazolam administration did not alter
opioids or muscle relaxants (10, 12, 21, 27-30). None of these the anxiety level in the PACU, nor the overall patient
studies have studied the influence of alprazolam on the occurrence satisfaction. This is in accordance with the recent study of
of postoperative apneas. This point was the objective of our study. Maurice-Szamburski et al. (28, 32). Interestingly, the
Gentil et al. studied the effects of a premedication by premedication by alprazolam did not modify propofol
midazolam in an OSA patient population (70). They requirements to achieve the BIS target during colonoscopy.
demonstrated that midazolam did not increase the number of Our study shows that alprazolam administration increases the
apneas in the OSA group. Similarly to our results, they did not risk of obstructive apneas. Although our patient population was
evidence any significant difference in the incidence of peripheral not obese or suffering from OSA, this should prompt cautiousness
oxygen desaturation. Of note, however, this study was when administering an alprazolam premedication to them. Those
performed in only seven OSA patients. patients are particularly sensitive to drug-induced apneas, all the
Aside apnea/hypopnea findings, our study demonstrates that more if they do not have or use a CPAP (4, 19, 33, 34). According
alprazolam is effective at reducing patient anxiety before to Pawlik et al., clonidine could be an alternative in such a high-
622

Table 4. Peripheral saturation in oxygen (SpO2, %) and mandibular stability (%) during the perioperative period.

Group A Group C
Statistics
(n = 21) (n = 20)
U = 204
SpO2 before induction of anesthesia 96 96
Z = 0.16
[median (IQR)] (94.7 – 98) (95 – 97)
P = 0.87
U = 183
Maximal SpO2 in PACU 98 99
Z = 0.07
[median (IQR)] (97.8 – 99.3) (98 – 99.5)
P = 0.95
U = 207.5
Minimal SpO2 in PACU 91 91.5
Z = 0.07
[median (IQR)] (90 – 93) (90 – 95)
P = 0.95
U = 175.5
Mean SpO2 in PACU 95.17 94.28
Z = 0.97
[median (IQR)] (95.17 – 95.17) (92.46 – 95.98)
P = 0.33
U = 197
Number of events when SpO2 drop 4 5
Z = 0.34
below 94% in PACU [median (IQR)] (1 – 19.75) (0 – 18.5)
P = 0.73
Maximal MO in PACU t(39) = 0.47
95.88 (48) 90.78 (12.4)
[mean (S.D.)] P = 0.99
Minimal MO in PACU t(39) = 0.44
57.1 (28.3) 61.32 (32.8)
[mean (S.D.)] P = 0.78
Mean MO in PACU t(39) = 1.05
72.19 (22.4) 78.65 (16.7)
[mean (S.D.)] P = 0.89

IQR, interquartile range; PACU, post-anesthesia care unit; NS, not significant; MO, mouth opening

risk population (35). Hence, the choice of such premedication ACCP (American College of Chest Physicians), Madrid, March
should be weighed carefully, and should ideally be assessed in a 2014 and The Annual Congress of the American Society of
specifically dedicated study enrolling such patients (36, 37). Anesthesiologist, New Orleans, October 2014.
Readers should keep in mind that OSA is also correlated
with oxidative stress and thrombotic events that represent also a Acknowledgements: The authors want to acknowledge
risk of postoperative complications (38, 39). Recently, Sharman Sandrine REMY, Murielle KIRSCH, Gaetane HICK, Pol HANS,
et al. have demonstrated that repeated obstructions of the airway and Laurent CAMBRON as participating investigators.
do not lead to cardiovascular dysfunction in healthy individuals
(40). Hypoxemia could play a role in the development of Conflict of interests: None declared.
postoperative complications (41, 42).
This study has limitations. First, one may argue that a
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R e c e i v e d : June 19, 2016

A c c e p t e d : September 5, 2016

Author’s address: Dr. Eric Deflandre, Chaussee de Tongres, 29,

4000 Liege, Belgium.
E-mail: eric.deflandre@gmail.com