Geriatric Anesthesia

E ORIGINAL CLINICAL RESEARCH REPORT

Effect of Different Administration Routes of
Dexmedetomidine on Postoperative Delirium in Elderly
Patients Undergoing Elective Spinal Surgery: A
Prospective Randomized Double-Blinded Controlled Trial
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ORT
Jing-Yi Niu, MD,* Na Yang, MD,* Qing-Yu Tao, MD,* Yan He, MD,† Yong-Bo Hou, MD,†
Ren-De Ning, MD,‡ and Jun-Ma Yu, MD*

BACKGROUND: Intravenous dexmedetomidine has been reported to decrease the occurrence

of postoperative delirium (POD) in elderly patients. Nevertheless, some previous studies have
indicated that intratracheal dexmedetomidine and intranasal dexmedetomidine are also effec-
tive and convenient. The current study aimed to compare the effect of different administration
routes of dexmedetomidine on POD in elderly patients.
METHODS: We randomly allocated 150 patients (aged 60 years or more) scheduled for spinal
surgery to receive intravenous dexmedetomidine (0.6 μg/kg), intranasal dexmedetomidine (1
μg/kg) before anesthesia induction, or intratracheal dexmedetomidine (0.6 µg/kg) after anes-
thesia induction. The primary outcome was the frequency of delirium during the first 3 postop-
erative days. The secondary outcomes were the incidence of postoperative sore throat (POST)
and sleep quality. Adverse events were recorded, and routine treatment was performed.

From the *Department of Anesthesiology, The Third Affiliated Hospital
of Anhui Medical University (The First People’s Hospital of Hefei), Hefei,
Anhui, China; †Department of Anesthesiology, Wannan Medical College,
Wuhu, Anhui, China; and ‡Department of Orthopedics, The Third Affiliated
Hospital of Anhui Medical University (The First People’s Hospital of Hefei),
Hefei, Anhui, China.
Accepted for publication January 23, 2023.
Funding: Anhui Medical University Foundation for Clinical Science (No.
2021xkj223).
The authors declare no conflicts of interest.
Copyright © 2023 International Anesthesia Research Society
DOI: 10.1213/ANE.0000000000006464
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).
Trial registration: This study was registered at the Chinese Clinical Trial
Registry (ChiCTR2100046976) on June 6, 2021, and can be reached at https://
www.chictr.org.cn/showproj.aspx?proj=127689.
J.-Y. Niu and N. Yang contributed equally to this work.
Reprints will not be available from the authors.
Address correspondence to Jun-Ma Yu, MD, Department of Anesthesiology,
The Third Affiliated Hospital of Anhui Medical University (The First People’s
Hospital of Hefei), 390 Huaihe Rd, Hefei, Anhui 230061, China. Address
e-mail to majuny163@163.com.

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 Dexmedetomidine and Postoperative Delirium

RESULTS: Compared with the intranasal group, the intravenous group had a significantly lower
occurrence of POD within 3 days (3 of 49 [6.1%] vs 14 of 50 [28.0%]; odds ratio [OR], 0.17;
95% confidence intervals [CIs], 0.05–0.63; P < .017). Meanwhile, patients in the intratracheal
group had a lower incidence of POD than those in the intranasal group (5 of 49 [10.2%] vs 14
of 50 [28.0%]; OR, 0.29; 95% CI, 0.10–0.89; P < .017). Whereas, there was no difference
between the intratracheal and intravenous groups (5 of 49 [10.2%] vs 3 of 49 [6.1%]; OR, 1.74;
95% CI, 0.40–7.73; P > .017). The rate of POST was lower in the intratracheal group than that
in the other 2 groups at 2 hours after surgery (7 of 49 [14.3%] vs 12 of 49 [24.5%] vs 18 of 50
[36.0%], P < .017, respectively). Intravenous dexmedetomidine had the lowest Pittsburgh Sleep
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Quality Index score on the second morning after surgery (median [interquartile range {IQR}]: 4
[3–5] vs 6 [4–7] vs 6 [4–7], P < .017, respectively). Compared with the intranasal group, the
intravenous group had a higher rate of bradycardia and a lower incidence of postoperative nau-
sea and vomiting (P < .017). The intranasal group was associated with the highest incidence of
hypertension (P < .017).
CONCLUSIONS: For patients aged ≥60 years undergoing spinal surgery, compared with the
intranasal route of dexmedetomidine, intravenous and intratracheal dexmedetomidine reduced
the incidence of early POD. Meanwhile, intravenous dexmedetomidine was associated with bet-
ter sleep quality after surgery, and intratracheal dexmedetomidine resulted in a lower incidence
of POST. Adverse events were mild in all 3 administration routes of dexmedetomidine. (Anesth
Analg 2023;136:1075–83)

KEY POINTS
• Questions: How effective are the different administration routes of dexmedetomidine on
postoperative delirium (POD) in elderly patients?
• Findings: This study found that compared with intranasal dexmedetomidine, both intrave-
nous and intratracheal dexmedetomidine resulted in lower incidence of early POD in elderly
patients after spinal surgery.
• Meaning: For patients aged ≥60 years undergoing spinal surgery, the IV route and intratra-
cheal route of dexmedetomidine were more helpful in reducing the incidence of early POD
than the intranasal route.

GLOSSARY
3D-CAM-CN = 3-Minute Diagnostic Interview for CAM-defined Delirium Chinese version; ANOVA
= analysis of variance; ASA = American Society of Anesthesiologists; CI = confidence interval;
CONSORT = Consolidated Standards Of Reporting Trials; HR = heart rate; IQR = interquartile
range; MAP = mean arterial pressure; OR = odds ratio; POD = postoperative delirium; PONV =
postoperative nausea and vomiting; POST = postoperative sore throat; PSQI = Pittsburgh Sleep
Quality Index; SD = standard deviation

D
elirium is a state of acute cerebral dysfunction
characterized mainly by disorders of atten-
tion and cognition.1 Postoperative delirium
(POD) is related to worse clinical prognosis, includ-
ing patient bed days, high health care costs, increased
mortality, and significant sequelae.2–4 Past studies
have demonstrated that older age groups and general
anesthesia are hazard factors for POD.5,6
Spine surgery is one of the most common surgical
procedures in elderly patients. Due to the influence of
postoperative pain, elderly patients often have obvi-
ous sleep disorder symptoms, including reduced sleep
time, increased awake time, and sleep fragmentation.7,8
It has been reported that sleeplessness on the first post-
surgical night is an early factor for predicting subse-
quent delirium.9 POD in elderly patients was reported
to have an incidence of up to 40.5% after spine surgery.10
Dexmedetomidine is a highly selective alpha-2
adrenoceptor agonist that has analgesic, sedative,
and anti-inflammatory functions. In rodent models,
dexmedetomidine reduces neuroinflammation by
inhibiting microglial activation and proinflamma-
tory cytokine expression.11,12 Akeju et al13 reported
that dexmedetomidine improved N3 sleep in a dose-
dependent manner, which was beneficial for improv-
ing neurocognitive function. In recent years, many
studies have revealed that intraoperative dexme-
detomidine reduces the incidence of POD in elderly
patients.14,15 However, dexmedetomidine was admin-
istered intravenously in these studies. Our previous
study indicated that the incidence and severity of
postoperative sore throat (POST) and anesthetic drug
requirements were significantly decreased for intratra-
cheal dexmedetomidine combined with ropivacaine.16
In addition, intranasal dexmedetomidine was found
to be effective, convenient, and well-tolerated, and the
intranasal availability was high.17,18 The absorption
and mechanism of dexmedetomidine differ across

1076 www.anesthesia-analgesia.org ANESTHESIA & ANALGESIA

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 E ORIGINAL CLINICAL RESEARCH REPORT
various routes of administration. Considering that the
intravenous administration can be rapidly absorbed
to achieve the peak plasma concentration, we postu-
lated that intravenous administration of dexmedeto-
midine would result in a lower incidence of POD than
intranasal or intratracheal administration in elderly
patients undergoing elective spinal surgery.
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METHODS
The present study was approved by the institutional
research ethics committee of the Third Affiliated
Hospital of Anhui Medical University (No. 2021-008-
01, approval on April 15, 2021) and was registered
before patient enrollment at the Chinese Clinical Trial
Registry (ChiCTR2100046976, principal investiga-
tor: Jun-Ma Yu; registration: https://www.chictr.org.
cn/showproj.aspx?proj=127689; date of registration:
June 6, 2021). With written informed consent by all
patients enrolled in this clinical trial before recruit-
ment, this trial was well completed from June 2021 to
March 2022 at the same hospital. The current research
was conducted in accordance with the Declaration of
Helsinki. In addition, this article adhered to the appli-
cable Consolidated Standards Of Reporting Trials
(CONSORT) guidelines.
Participants
The inclusion criteria were patients aged 60 years or
above, American Society of Anesthesiologists (ASA)
class I to III, and scheduled to undergo spinal sur-
gery with general anesthesia. The exclusion criteria
were as follows: consent form not confirmed; seri-
ous bradycardia (heart rate [HR] <50 bpm at rest);
body mass index ≥30 kg·m−2; preoperative Mini-Cog
score ≤2; serious cardiovascular, lung, kidney, or
liver diseases; known drug intolerance or allergy to
dexmedetomidine; history of traumatic brain injury
or neurosurgery; history of the use of psychotropic
drugs; allergic rhinitis and abnormal nasal structure;
chronic respiratory disease; transfer to the intensive
care unit without accomplishing decannulation after
operation.
Randomization and Blinding
A computer-generated randomization table was used
to assign the participants to 3 groups at a ratio of 1:1:1
in a blinded manner. Group allocation and study
number were kept in sealed envelopes by an anes-
thesia nurse who was not involved in the study. The
anesthesia nurse opened the sealed opaque envelopes
and prepared the experimental drugs according to
the randomization sequence before the induction of
anesthesia. Then, drugs were offered to the anesthe-
tists who performed perioperative anesthesia man-
agement. Study personnel, anesthetists, and patients
were blinded to the treatment group assignment
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throughout the study. In this way, the patients were
randomized to an IV group, an IN group, and an IE
group (defined below).
Intervention
Intervention and anesthesia induction were per-
formed by a senior anesthetist. For participants in the
IV group, a 0.6 μg/kg loading dose of dexmedetomi-
dine (Yangtze River Pharmaceutical [Group] Co, Ltd)
was administered with an injection pump 10 minutes
before induction of anesthesia. For those patients
in the IN group, intranasal dexmedetomidine was
administered in drops 30 minutes before anesthesia
induction. Undiluted dexmedetomidine (100 μg/mL)
was drawn with a 1-mL syringe at a dose of 1 μg/kg
and diluted to 1 mL with 0.9% normal saline. Patients
were asked to lie flat, and the same amount of drug
was dripped into the 2 nostrils (0.5 mL for each side)
within 1 minute. The induction of general anesthesia
was processed with etomidate (0.3 mg/kg) and suf-
entanil (0.3 μg/kg) followed by cisatracurium besilate
(0.2 mg/kg). After 3 minutes of assisted breathing, a
disposable laryngo-tracheal mucosal atomization
device was used to spray 5 mL of drug onto the tra-
cheal mucosa to allow surface anesthesia.16 The intra-
tracheal drug (diluted to 5 mL) used in the IV group,
and the IN group was 0.8% ropivacaine (40 mg). For
patients in the IE group, the intratracheal drug was
dexmedetomidine (0.6 µg/kg) mixed with 0.8% ropi-
vacaine (40 mg) diluted to 5 mL. Normal saline in the
same volume was administered in the same way for
patients in each group as the other 2 administration
routes. Tracheal intubations with internal diameters
of 7.0 mm and 6.5 mm were allocated to males and
females, respectively. All patients were successfully
intubated at 1 time and provided mechanical ven-
tilation. The end-expiratory carbon dioxide partial
pressures were maintained at 35 to 45 mm Hg. In
addition, cuff pressure was maintained at 15 to 25 mm
Hg using a manometer. Anesthesia was maintained
with intravenous remifentanil, intravenous propo-
fol, and inhalation of 1% sevoflurane. The anesthesia
depth was maintained at a BIS value between 40 and
60, and the nasopharyngeal temperature was main-
tained between 36.0 ℃ and 37.0 ℃. We standardized
the extubation protocol and extubated the patients’
tracheas after the surgery. Furthermore, we provided
postoperative analgesia for every patient with unified
patient-controlled intravenous analgesia.
Outcome Assessment
The incidence of delirium during the first 3 postop-
erative days was the primary outcome. The 3-Minute
Diagnostic Interview for CAM-defined Delirium
Chinese version (3D-CAM-CN) was used to evalu-
ate the state of delirium at 18:00–20:00 once a day.
www.anesthesia-analgesia.org 1077
 Dexmedetomidine and Postoperative Delirium
The 3D-CAM-CN, the partial details of which were
revised according to the population of China, has
been confirmed as an efficient evaluation method for
delirium in Chinese patients undergoing surgery.19
Researchers who performed the delirium assessment
and postoperative follow-up underwent 4 weeks of
intensive training by psychiatrists before the trial
started (Supplemental Digital Content 1, Methods,
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http://links.lww.com/AA/E283).
The secondary outcome measures were the inci-
dence of POST and sleep quality. POST was recorded
at 2 hours and 24 hours after surgery. All patients were
assessed for the quality of sleep before the operation
and on the first, second, and third mornings (at 08:00–
09:00) after surgery by the Pittsburgh Sleep Quality
Index (PSQI).20 The PSQI contains 7 component scores
generated by 19 individual items. The 7 component
scores are summed to yield a global PSQI score, rang-
ing from 0 to 21. A global PSQI score ≥5 is consistent
with poor sleep quality, with a higher score indicat-
ing worse sleep quality. Furthermore, adverse events
were recorded from the start of study drug adminis-
tration until 2 hours after surgery, such as bradycardia
with an HR <50 bpm, tachycardia with HR >100 bpm,
hypotension with systolic blood pressure <90 mm Hg,
or a decrease >30% from baseline, hypertension with
systolic blood pressure >180 mm Hg, or an increase
>30% from baseline, early postoperative nausea and
vomiting (PONV), and dizziness occurring within 2
hours of surgery. We slowed down or stopped admin-
istration if there was a serious adverse event that was
unimproved after routine treatment. These patients
were excluded from the analysis of the results.
During the preoperative interview, a trained
investigator recorded the patient demographic data,
surgical diagnosis, and comorbidities and assessed
the ASA class. Preoperative cognitive function was
assessed with the Mini-Cog (score ranges from 0
to 5 and a score of 2 or less is considered cognitive
impairment).21 During the operation, the anesthetist
recorded the duration of the operation, the dura-
tion of extubation, and the intraoperative blood loss.
The patients’ mean arterial pressure (MAP) and HR
before drug administration (T0), 1 minute after induc-
tion (T1), 1 minute after superficial anesthesia (T2), 1
minute after intubation (T3), at the beginning of the
operation (T4), and 1 hour after the surgery started
(T5) were recorded.
Statistical Analysis
Data were analyzed using SPSS statistical soft-
ware version 25.0 (IBM). Continuous variables were
expressed as the mean (standard deviation [SD]) for
data with a normal distribution (evaluated with the
Shapiro−Wilk test), and nonnormally distributed data
were represented by the median and interquartile
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range (IQR). Categorical variables were summa-
rized as number and percentage. One-way ANOVA
was used to compare continuous data with a normal
distribution, and continuous data with a nonnormal
distribution were analyzed by the Kruskal−Wallis
rank-sum test. Categorical data were analyzed using
the χ2 test, and the P value was adjusted according
to Bonferroni method and fixed at 0.017 for pairwise
comparison. Statistical significance was defined as a
P value <.05.
The incidence of POD, POST, and adverse events
among the 3 groups was analyzed using the χ2 test
or Fisher exact test, and odds ratio (OR) and 95%
confidence interval (CI) were calculated by univari-
ate logistic regression. The PSQI score was analyzed
using the rank-sum test, and the median difference
(d) and 95% CI were calculated. Repeated measures
analysis of variance with Bonferroni correction was
applied to compare the MAP and HR at different time
points between groups.
Sample Size Estimation
Sample size was calculated based on a reported inci-
dence of POD (approximately 5.5%) in elderly patients
with intravenous dexmedetomidine.15 Combined
with the results of our pilot study, we assumed that
the incidence of POD was 5%, 30%, and 10% in the
IV group, IN group, and IE group, respectively. To
achieve 85% power and a 0.05 2-sided significance
level for the test, a total of 120 cases were needed,
as calculated using PASS 15.0. The sample size was
increased to 144 (48 in each group) to account for a
20% dropout rate. We ended up with 50 patients in
each group in the study.
RESULTS
A total of 180 patients were recruited, and among
them, 30 were excluded. One hundred fifty patients
were finally enrolled and randomized. One patient in
the IV group withdrew consent and refused the study
drug, and 1 patient in the IE group was lost to follow-
up due to early discharge during the study (Figure 1).
These baseline data (Table 1) were similar for all 3
groups, particularly with regard to the baseline Mini-
Cog scores associated with preoperative cognitive
function.
The incidence of POD in the IV group was signifi-
cantly lower than that in the IN group within 3 days (3
of 49 [6.1%] vs 14 of 50 [28.0%]; odds ratio [OR], 0.17;
95% CIs, 0.05–0.63; P < .017). Meanwhile, patients in
the IV group had a lower incidence of POD than those
in the IN group (5 of 49 [10.2%] vs 14 of 50 [28.0%];
OR, 0.29; 95% CI, 0.10–0.89; P < .017). However, there
was no difference between the IE and IV groups (5
of 49 [10.2%] vs 3 of 49 [6.1%]; OR, 1.74; 95% CI, 0.40–
7.73; P > .017) (Table 2; Figure 2).
ANESTHESIA & ANALGESIA
 E ORIGINAL CLINICAL RESEARCH REPORT
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Figure 1. Study flow chart. IV group: the patients received intravenous dexmedetomidine (0.6 µg/kg); IN group: the patients received intrana-
sal dexmedetomidine (l µg/kg); IE group: the patients received intratracheal dexmedetomidine (0.6 µg/kg).

Table 1. Baseline Demographics and Clinical Characteristics

Characteristic IV group (n = 49) IN group (n = 50) IE group (n = 49) P value
Age, y 70.8 (6.6) 70.1 (6.4) 70.5 (7.1) .87
Height, cm 162.8 (7.0) 163.1 (6.6) 162.8 (7.3) .97
Bodyweight, kg 65.0 (10.2) 63.5 (9.4) 63.4 (12.1) .68
Female 27 (55.1) 25 (50.0) 26 (53.1) .88
Preoperative comorbidities
Hypertension 23 (46.9) 20 (40.0) 18 (36.7) .58
Diabetes 9 (18.4) 11 (22.0) 9 (18.4) .88
Coronary artery disease 4 (8.2) 2 (4.0) 3 (6.1) .64
Previous stoke 7 (14.3) 5 (10.0) 6 (12.2) .81
COPD 3 (6.1) 4 (8.0) 5 (10.2) .82
ASA class Ⅱ/Ⅲ 39/10 43/7 42/7 .62
Mini-Cog scorea 4 (3–5) 4 (3–5) 4 (3–5) .92
Preoperative PSQI scoreb 5 (4–6) 5 (4–6) 5 (4–6) .72
Duration of surgery, min 168.7 (44.3) 185.4 (54.3) 167.1(48.9) .13
Duration of extubation, min 10.2 (3.2) 11.4 (4.1) 11.0 (3.6) .26
Estimated blood loss, mL 170 (110–200) 200 (120–300) 170 (100–250) .08
Number of surgical segments 1 (1–2) 2 (1–2) 1 (1–2) .48
Data are in mean (SD), number (proportion), or median (IQR).
Abbreviations: ASA, American Society of Anesthesiologists; COPD, chronic obstructive pulmonary disease; IQR, interquartile range; PSQI, Pittsburgh Sleep Quality
Index; SD, standard deviation.
a
Score ranges from 0 to 5, a score of 2 or less is considered probable cognitive impairment, with higher score indicating better function.
b
Score ranges from 0 to 21, a score of 5 or more is consistent with poor sleep quality, with higher score indicating worse function.

Regarding the secondary outcomes, fewer cases
had POST in the IE group than those in the IV group
and IN group at 2 hours after surgery (7 of 49 [14.3%]
vs 12 of 49 [24.5%] vs 18 of 50 [36.0%]; P < .017,
respectively). The IV group had the lowest PSQI score
among the 3 groups on the second morning after sur-
gery (median [IQR]: 4 [3–5] vs 6 [4–7] vs 6 [4–7]; P <
.017, respectively) (Table 2).
For safety analysis, compared with the IN group,
the IV group had a higher rate of bradycardia and a

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 Dexmedetomidine and Postoperative Delirium

Table 2. Primary and Secondary Outcomes

IV group IN group IE group IV versus IN OR IE versus IN OR IE versus IV OR
Outcomes (n = 49) (n = 50) (n = 49) (95% CI) (95% CI) (95% CI)
Primary outcome
POD 3 (6.1) 14 (28.0) 5 (10.2) 0.17 (0.05–0.63)a 0.29 (0.10–0.89)a 1.74 (0.40–7.73)
Secondary
outcomes
POST
At 2 h 12 (24.5) 18 (36.0) 7 (14.3) 0.58 (0.24–1.38) 0.30 (0.11–0.80)a 0.44 (0.14–0.94)a
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At 24 h 6 (12.2) 7 (14.0) 4 (8.2) 0.86 (0.27–2.76) 0.55 (0.15–2.00) 0.64 (0.17–2.41)

PSQI score
1st morning 7 (6–9) 8 (6–9) 8 (6–8) 0 (−1 to 0)b 0 (−1 to 0)b 0 (−1 to 1)b
2nd morning 4 (3–5) 6 (4–7) 6 (4–7) −1 (−2 to −1)b,a 0 (−1 to 0)b 1 (1–2)a,b
3rd morning 4 (3–5.5) 5 (4–5) 4 (3–5) 0 (−1 to 0)b 0 (−1 to 0)b 0 (−1 to 0)b
Data are in number (proportion), median (IQR), or odds ratio (95% CI).
Abbreviations: CI, confidence interval; IQR, interquartile range; POD, postoperative delirium; POST, postoperative sore throat; PSQI, Pittsburgh Sleep Quality Index.
a
P < .017.
b
Data are median difference (95% CI).

Cerebral oxygen desaturation caused by the prone

Figure 2. Daily rate of delirium. Data are expressed as number (pro-
portion). The incidence of delirium is highest on the first day after
surgery.
lower incidence of PONV (P < .017). The IN group
had the highest incidence of hypertension among the
3 groups (P < .017) (Supplemental Digital Content
2, Table S1, http://links.lww.com/AA/E284), and
all adverse reactions were relieved with routine
treatment. Furthermore, the trend of hemodynamic
changes among the 3 groups during intubation and
surgery can be found in Supplemental Digital Content
3, Figure S1, http://links.lww.com/AA/E285.
DISCUSSION
This study found that compared with intranasal dex-
medetomidine, intravenous and intratracheal dex-
medetomidine reduced the incidence of early POD.
Meanwhile, intravenous dexmedetomidine was
associated with better sleep quality after surgery,
and intratracheal dexmedetomidine reduced the inci-
dence of POST 2 hours after surgery. Adverse events
of all 3 administration routes of dexmedetomidine
were mild.
There is an increasing frequency of spinal surgery
as the population ages, and degenerative diseases
with painful manifestations become more prevalent.
position in elderly patients undergoing spine sur-
gery is considered to be associated with a higher inci-
dence of delirium.22 The current study found a high
rate of delirium in the IN group even higher than
the reported rates in a previous retrospective study
that did not use dexmedetomidine.23 The possible
reason is that the older spine patients in our study
had more preoperative comorbidities. Furthermore,
47% of patients with delirium have been reported to
have purely hypoactive features, and this subtype of
delirium is often underrecognized.24 Although the
CAM was credited to be the most effective measure,
there exists a shortage in the consistency of diag-
nostic standards even after sufficient training.25 We
used a delirium assessment method that had been
rigorously validated in the Chinese population. The
3D-CAM-CN was proven to have high sensitivity and
specificity, especially in patients with mild cognitive
impairment.19
A previous study showed that dexmedetomidine
can synergistically decrease the rate of delirium in
terms of neuroprotection, renoprotection, pulmonary
protection, anti-inflammation, natural sleep, pain
relief, and other aspects.26 However, in our study, dif-
ferent administrations of dexmedetomidine resulted
in different results. Compared with the IN group,
both the IV group and the IE group had a decreased
incidence of POD within 3 days after surgery. Elderly
patients have an increased sensitivity to anesthetic
drugs due to their decreased reserve capacity of car-
diovascular structure and function. Some adverse
effects of higher doses of anesthetic drugs may be
catastrophic in the geriatric age group. Keshri et al27
reported that a loading dose of 0.5 µg/kg intravenous
dexmedetomidine has the minimum side effects in
reducing the hemodynamic stress response in geri-
atric patients undergoing spine surgery when com-
pared with 1 µg/kg dexmedetomidine. The dose

1080 www.anesthesia-analgesia.org ANESTHESIA & ANALGESIA

Copyright © 2023 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited.
 E ORIGINAL CLINICAL RESEARCH REPORT
of intratracheal dexmedetomidine was 1 µg/kg for
patients aged 20 to 65 in our previous study,16 and
the intratracheal route of dexmedetomidine is rapidly
absorbed through the bronchial and alveolar capillary
network.28 Considering its safety and effectiveness in
elderly patients aged 60 years or above in this study,
the final dose for the IV route and intratracheal route of
dexmedetomidine is equal to 0.6 µg/kg. A pharmaco-
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kinetic and pharmacodynamic study with intranasal
or intravenous dexmedetomidine (1 µg/kg)29 found
that the IV route had a conspicuously faster onset
time than the intranasal-drop route. Moreover, the
intranasal bioavailability was estimated to be 40.7%29
or 82%.17 Therefore, we increased the dose of intrana-
sal dexmedetomidine (1 µg/kg) to increase systemic
absorption to mimic the concentration resulting from
intravenous infusion. We hypothesized that the main
possible reasons for our primary outcome are as fol-
lows: the absorption rate and bioavailability of the
intratracheal and intravenous routes were both supe-
rior to those of the intranasal route. The mechanisms
of the delirium-sparing effect might be related to the
reduced stress response and consumption of gen-
eral anesthetic during surgery. Several studies have
shown that dexmedetomidine attenuates the surgical
stress response by reducing the levels of serum cate-
cholamines, cortisol, and inflammatory cytokines,30,31
and dexmedetomidine reduces the consumption of
opioids and anesthetics.32 In addition, we found that
the highest incidence of delirium occurred on the first
day after surgery (Figure 2), which was consistent
with the view that the rate of delirium is highest dur-
ing the early postoperative period.33
In line with a previous report,16 this study con-
firmed that intratracheal dexmedetomidine reduced
the incidence of sore throat at 2 hours after surgery.
This was probably because dexmedetomidine pro-
longed the duration of ropivacaine and improved
the efficacy of postoperative local analgesia.34 We
speculate that dexmedetomidine may work primar-
ily through a perineural mechanism when used as
an adjuvant to local anesthesia, and systemic action
might explain other clinical effects.35 Patients assume
the supine position the night after spinal surgery, and
intravenous fluids are required because of the 6-hour
fast after general anesthesia. Postoperative pain and
the use of opioids are also important factors in post-
operative sleep disorders.8,36 Therefore, all 3 groups
had poor sleep patterns on the first night after surgery
in our current study. The highest incidence of delir-
ium on the first day might have been associated with
this reduced sleep quality. Wu et al37 found that sleep
architecture and subjective sleep quality can be ame-
liorated by dexmedetomidine infusion at a low dose
through an increased percentage of N2 sleep and a
June 2023 • Volume 136 • Number 6
Copyright © 2023 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited.
decreased percentage of stage N1 sleep. We observed
that intravenous dexmedetomidine significantly
improved sleep quality on the second night after
surgery, which might be associated with a reduced
stress response and improved postoperative analge-
sia. Moreover, the IV group and the IE group exhib-
ited more stable hemodynamics during intubation
and surgery (Supplemental Digital Content 3, Figure
S1, http://links.lww.com/AA/E285). Notably, the
development of POD and hemodynamic variables
had a significant correlation,38 which may explain our
primary outcome in another aspect.
In terms of safety, intravenous dexmedetomidine
increased the risk of bradycardia compared with
the intranasal group, but all cases of bradycardia
were relieved after atropine treatment, and no epi-
sode of bradycardia requiring special treatment was
observed. Although it has been reported that dex-
medetomidine can reduce the incidence of PONV,39
we found that there was a higher incidence rate of
hypertension and PONV in the IN group. However,
the PONV was mild and relieved spontaneously.
Transient hypertension caused by surgical stress
also decreased rapidly with increased analgesia and
sedation. Therefore, all 3 routes of dexmedetomidine
administration are safe.
Several weaknesses should be considered in the
current study. First, as a single-center study of spinal
surgery patients, there may be a limit for generalized
application. Second, delirium was assessed only once
a day, and we did not further record its subtypes and
severity. Third, only a single dose of dexmedetomidine
might have a reduction in the efficacy in ameliorating
delirium, and the doses of the 3 groups need to be fur-
ther explored. Fourth, the patients’ level of education
may have influenced the Mini-Cog score. Finally, the
investigation period of different administrations of dex-
medetomidine on POD in elderly patients was main-
tained merely 3 days after surgery, and more studies
should be performed to explore the long-term effect.
In conclusion, for patients aged ≥60 years under-
going spinal surgery, compared with intranasal
dexmedetomidine (1 µg/kg), both intravenous dex-
medetomidine (0.6 µg/kg) and intratracheal dexme-
detomidine (0.6 µg/kg) resulted in a lower incidence
of POD within 3 days. Meanwhile, intravenous dex-
medetomidine improved sleep quality, and intra-
tracheal dexmedetomidine reduced the incidence of
POST 2 hours after surgery. All 3 administrations of
dexmedetomidine were found to be safe. E
ACKNOWLEDGMENTS
We acknowledge the assistance of American Journal Experts
(AJEs) for English language editing and Editage for plagia-
rism checking.
www.anesthesia-analgesia.org 1081
 Dexmedetomidine and Postoperative Delirium
DISCLOSURES
Name: Jing-Yi Niu, MD.
Contribution: This author helped design the study, analyzed
part of the data, and wrote the original draft.
Name: Na Yang, MD.
Contribution: This author participated in the conceptualiza-
tion of the study and data curation and wrote the original draft.
Name: Qing-Yu Tao, MD.
Contribution: This author helped with data collection and data
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analysis.
Name: Yan He, MD.
Contribution: This author helped with patient recruitment and
data curation.
Name: Yong-Bo Hou, MD.
Contribution: This author took part in patient recruitment and
formal analysis.
Name: Ren-De Ning, MD.
Contribution: This author conducted the study and revised
part of the manuscript.
Name: Jun-Ma Yu, MD.
Contribution: This author helped design the study, reviewed
and revised the manuscript, and took leadership responsibility
for this study.
This manuscript was handled by: Robert Whittington, MD.
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