Clinical Trial/Experimental Study Medicine ®

OPEN

Analgesia for spinal anesthesia positioning in

elderly patients with proximal femoral fractures
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Dexmedetomidine-ketamine versus dexmedetomidine-fentanyl

Ki Hwa Lee, MD, Soo Jee Lee, MD , Jae Hong Park, MD, Se Hun Kim, MD, Hyunseong Lee, MD,
∗
Dae Seok Oh, MD, Yong Han Kim, MD, Yei Heum Park, MD, Hyojoong Kim, MD, Sang Eun Lee, MD

Abstract
Elderly patients with femoral fractures are anticipated to endure the most pain caused by positional changes required for spinal
anesthesia. To improve pain relief, we compared the analgesic effects of intravenous dexmedetomidine-ketamine and
dexmedetomidine-fentanyl combinations to facilitate patient positioning for spinal anesthesia in elderly patients with proximal
femoral fractures. Forty-six patients were randomly assigned to two groups and received either 1 mg/kg of intravenous ketamine
(group K) or 1 mg/kg of intravenous fentanyl (group F) concomitant with a loading dose of dexmedetomidine 1 mg/kg over 10 minutes,
then dexmedetomidine infusion only was continued at 0.6 mg/kg/h for following 20 minutes, and titrated at a rate of 0.2 to 0.6 mg/kg/h
until the end of surgery. After completion of the infusion of either ketamine or fentanyl, the patients were placed in the lateral position
with the fracture site up. The pain score (0 = calm, 1 = facial grimacing, 2 = moaning, 3 = screaming, and 4 = unable to proceed
because of restlessness or agitation) was used to describe the pain intensity in each step during the procedure (lateral positioning, hip
flexion, and lumbar puncture), and quality score (0 = poor hip flexion, 1 = satisfactory hip flexion, 2 = good hip flexion, and 3 = optimal
hip flexion) was used to describe the quality of posture. Group K showed a median pain score of 0 (0-1), 0 (0–0) and 0 (0–0) in lateral
positioning, hip flexion and lumbar puncture, respectively, while group F showed a score of 3 (2.75–3), 3 (2–3) and 0 (0–1),
respectively. The pain score in lateral positioning (P < .0001) and hip flexion (P < .0001) was significantly lower in group K than group
F. Group K showed the significantly higher quality scores of spinal anesthesia positioning (P = .0044) than group F. Hemodynamic
adverse effects, such as bradycardia, hypotension, and desaturation, were not significantly different between the groups. The
administration of dexmedetomidine-ketamine showed a greater advantage in reducing pain intensity and increasing the quality with
patient positioning during spinal anesthesia in elderly patients with proximal femoral fractures, without any serious adverse effects.
Abbreviations: BIS = bispectral index, HR = heart rate, MBP = mean blood pressure, NRS = numerical rating scale, POD =
postoperative delirium, SD = standard deviation, SPO2 = peripheral pulse oximetry.
Keywords: analgesia, dexmedetomidine, fentanyl, ketamine, spinal anesthesia

Editor: Robert L. Barkin.

This work was supported by a grant from Research year of Inje University in 1. Introduction
20150690
The datasets generated during and/or analyzed during the current study are not Proximal femoral fractures are a critical cause of morbidity and
publicly available, but are available from the corresponding author on reasonable mortality in elderly patients.[1,2] Surgery has become the standard
request. treatment for femoral fractures.[3] Many studies have investigat-
The authors have no conflicts of interest to disclose. ed the relationship between anesthesia type and postoperative
The datasets generated during and/or analyzed during the current study are not outcomes. The excellent effect of spinal anesthesia in cases of
publicly available, but are available from the corresponding author on reasonable femoral fracture compared to that of general anesthesia has long
request. been controversial,[4] but spinal anesthesia was the preferred
Department of Anesthesiology and Pain Medicine, Inje University Haeundae Paik anesthetic technique with advantages in terms of one-month
Hospital, Haeundaegu, Busan, Republic of Korea.
∗
mortality and deep vein thrombosis, and spinal anesthesia was
Correspondence: Sang Eun Lee, Department of Anesthesiology and Pain mainly applied in elderly patients.[5]
Medicine, Inje University Haeundae Paik Hospital, 875 Haeundaero, Haeundaegu,
Busan 48108, Republic of Korea (e-mail: [email protected]).
For proximal femoral fractures, passive movement causes
severe pain when the affected patient is in the lateral position with
Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.
This is an open access article distributed under the terms of the Creative lumbar flexion.[6,7] It is a definite cause of discomfort and anxiety
Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is in conscious elderly patients, who are therefore more likely to
permissible to download, share, remix, transform, and buildup the work provided become agitated with screaming and uncontrolled movements.
it is properly cited. The work cannot be used commercially without permission Sufficient pain relief and adequate sedation in older patients can
from the journal.
lead to proper posture and successful spinal anesthesia in
How to cite this article: Lee KH, Lee SJ, Park J, Kim SH, Lee H, Oh DS, Kim
unfamiliar operating rooms. When trying to change the position
YH, Park YH, Kim H, Lee SE. Analgesia for spinal anesthesia positioning in
elderly patients with proximal femoral fractures: dexmedetomidine-ketamine of the patient on the operating table, much effort has been made
versus dexmedetomidine-fentanyl. Medicine 2020;99:20(e20001). to minimize pain. However, to date, few studies have compared
Received: 21 December 2019 / Received in final form: 24 March 2020 / analgesic methods for relieving pain.
Accepted: 24 March 2020 Elderly patients with femoral fractures can benefit from spinal
http://dx.doi.org/10.1097/MD.0000000000020001 anesthesia. However, postural changes that are essential for

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spinal anesthesia are expected to cause severe pain. Dexmede- according to mean blood pressure (MBP), heart rate (HR) and
tomidine infusion is effective for alleviating anxiety and BIS until the end of surgery (Fig. 2).
providing sedation,[8] but dexmedetomidine alone is limited in The patients were placed in the lateral position, the fracture
controlling pain associated with postural changes. Ketamine and side up, followed by flexion of the hip and lumbar spine, after
fentanyl may be used in addition to dexmedetomidine for completion of the infusion of either ketamine or fentanyl. Lumbar
postural change-evoked pain. The combination of dexmedeto- puncture was performed at the L3–4, L4–5 or L5-S1 interspace
midine-ketamine or dexmedetomidine-fentanyl has become by another anesthesiologist who was not aware of which group to
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progressively utilized for painful procedures in children and which the patient belonged, and ropivacaine (10 to 15 mg) was
adults,[9,10] but there have been few studies on dexmedetomidine- injected intrathecally after confirmation of the free flow of
ketamine or dexmedetomidine-fentanyl use during spinal cerebrospinal fluid.
anesthesia in elderly patients. Hemodynamic parameters were recorded at a 5-minute
This study was performed to compare the analgesic effects of interval during anesthesia, and the data were collected during
dexmedetomidine-ketamine and dexmedetomidine-fentanyl in- the first 30 minutes from the start of either dexmedetomidine-
fusion on postural change-evoked pain for spinal anesthesia in ketamine or dexmedetomidine-fentanyl administration. A small
elderly patients with proximal femoral fractures. intravenous bolus of ephedrine 5 mg was administered in case of
hypotension (MBP < 60 mm Hg). Atropine 0.5 mg was intrave-
nously administered when HR was less than 50 beats per minute.
2. Methods If desaturation (SpO2 < 90%) was noted, supplemental oxygen
was provided at 6 L/min via facial mask. If the patient groaned
2.1. Study design and patient population
during the surgery, fentanyl 50 mg was intravenously adminis-
Forty-six patients were enrolled in this randomized, double-blind tered. A supplemental bolus of propofol 10 mg was repeatedly
study and underwent proximal femoral fracture surgery at our given as needed for the patients showing agitation that could
hospital from May 2014 to October 2016. This study was otherwise interrupt surgery.
approved by the Institutional Review Board of our institution
(129792–2014–027), and written informed consent was
2.4. Measurements
obtained from all patients.
The length of time taken for spinal anesthesia (i.e., the time from
lateral positioning until completion of the intrathecal ropivacaine
2.2. Criteria for inclusion and exclusion
injection) was recorded by a nurse who was blinded to the
Patients who were classified as American Society of Anesthesi- patients’ allocated treatment groups. Pain intensity was assessed
ologists physical status I-III, had proximal femoral fractures, and by an assessor, and quality scores representing the quality of
were aged over 70 years were included. Patients were excluded if spinal anesthesia were determined by the anesthesiologist who
they had hemorrhagic diathesis, bradycardia, atrioventricular conducted spinal anesthesia, both of whom were also blinded to
block, mental disorders, and any history of allergic reactions to the treatment allocation. The pain score (0 = calm, 1 = facial
the drugs used (dexmedetomidine, ketamine, fentanyl, and grimacing, 2 = moaning, 3 = screaming, and 4 = unable to
ropivacaine). proceed because of restlessness or agitation) was used to describe
the pain intensity in each step during the procedure (lateral
2.3. Preoperative preparations and anesthesia protocol positioning, hip flexion, and lumbar puncture), and quality score
(0 = poor hip flexion < 30 degrees, 1 = satisfactory hip flexion
The patients were randomly divided into 2 groups using a ≥30 and < 60 degrees, 2 = good hip flexion ≥ 60 and < 90
computer-generated allocation sequence; those in group K degrees, 3 = optimal hip flexion ≥90 degrees) was used to
received intravenous infusions of dexmedetomidine and keta- describe the quality of posture.
mine, while those in group F received intravenous infusions of
dexmedetomidine and fentanyl (Fig. 1). An anesthesiologist
2.5. Statistical analysis
evaluated the patient’s numerical rating scale (NRS) score the day
before surgery. No premedication was given to the patients. One The primary goal of this study was to compare the pain intensity
anesthesiologist prepared either ketamine (1 mg/kg) or fentanyl in the lateral positioning for spinal anesthesia between the 2
citrate (1 mg/kg) mixed with normal saline to form a total of 10 groups. In a pilot study of 10 patients per group, the sample size
ml, and dexmedetomidine (200 mg) mixed with normal saline to was estimated by comparing the proportion of patients with
form a total of 50 ml Upon arriving in the operating room, all severe pain scores (≥3) at the time of lateral positioning. It was
patients were monitored with electrocardiography, invasive estimated that at least 19 patients per group would be required,
arterial blood pressure, peripheral pulse oximetry (SpO2), and allowing a 5% a error and a 10% b error, and a 50% difference
bispectral index (BIS) monitoring. in the proportion of patients with severe pain. Assuming a drop-
Patients in groups K and F received intravenous ketamine (1 out rate of 15%, the final sample size was a set of 23 patients per
mg/kg) and fentanyl (1 mg/kg) via the syringe pump, respectively, group. The secondary goals were to compare the quality scores,
for 10 minutes and then discontinued. All patients were given adverse events, and hemodynamic changes. Data were analyzed
concomitantly dexmedetomidine with either ketamine or fenta- using MedCalc 19.2.0 (MedCalc Software, Ostend, Belgium).
nyl, and for the first 10 minutes a loading dose of dexmedeto- Parametric variables are described as the mean ± standard
midine (1 mg/kg) was administered via another syringe pump, and deviation (SD). Qualitative variables are described as a number
then the continuous infusion of dexmedetomidine only (0.6 mg/ (percentage) and median (interquartile range). Independent
kg/h) was maintained for following 20 minutes, and the infusion samples t-test, paired samples t-test, chi-squared test, Mann-
of dexmedetomidine was titrated at a rate of 0.2 to 0.6 mg/kg/h Whitney test, and repeated measures analysis of variance were

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Assessed for eligibility (n = 188)

Excluded (n = 142)
● Did not meet inclusion criteria (n = 55)
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● Declined to participate (n = 31)

● Other reasons (n = 56)

Enrollment Randomized (n = 46)

Allocation
Allocated to Group K (n = 23) Allocated to Group F (n = 23)
● Received allocated intervention (n = 22) ● Received allocated intervention (n = 21)
● Did not receive allocated intervention due to ● Did not receive allocated intervention due to
changes in surgical schedule (n = 1) changes in surgical schedule (n = 2)

Analysis
Analysed (n = 22) Analysed (n = 21)
● Excluded from analysis (n = 0) ● Excluded from analysis (n= 0)

Figure 1. CONSORT flow diagram.

Figure 2. Infusion plan. Intravenous ketamine (1 mg/kg) or fentanyl (1 mg/kg) was infused, concomitant with a loading dose of dexmedetomidine 1 mg/kg over 10
minutes. Then ketamine or fentanyl infusion was discontinued, and the infusion of dexmedetomidine was continued at 0.6 mg/kg/h for the next 20 min, and then
titrated at a rate of 0.2–0.6 mg/kg/h until the end of surgery. Group K = patients who received dexmedetomidine-ketamine, Group F = patients who received
dexmedetomidine-fentanyl. T0: at the beginning of infusion, T10: 10 min later, T30: 30 minlater, T100: at the end of surgery.

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used as appropriate to compare the two groups. A P value < .05 Table 2
was considered to indicate statistical significance. Pain scores related to positional changes during spinal anesthesia
procedures.
3. Results Group K (n = 22) Group F (n = 21) P value

A total of 46 patients were enrolled in this study, but 1 patient Lateral position [n, (%)]
from group K and 2 from group F were excluded from the data 0 15 (68.2) 0 (0)
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analysis due to changes in surgical schedules, respectively (Fig. 1). 1 5 (22.7) 0 (0)
2 2 (9.1) 5 (23.8)
The patients’ demographics and anesthetic characteristics are
3 0 (0) 16 (76.2)
described in Table 1. The time to surgery after trauma was 1 (1 to 4 0 (0) 0 (0)
2) day in group K and 2 (1 to 3.25) days in group F. The Median (interquartile range) 0 (0–1) 3 (2.75–3) < .0001
anesthesia time, the surgical procedure time, and dexmedetomi- Hip flexion [n, (%)]
dine infusion time were 117 ± 37, 64 ± 30 and 96 ± 23 minutes 0 17 (77.3) 1 (4.8)
(min), respectively, in group K, and 109 ± 27, 58 ± 25 and 88 ± 27 1 3 (13.6) 0 (0)
min, respectively, in group F. There were no statistically 2 1 (4.5) 6 (28.6)
significant differences in the anesthesia time, the surgical 3 1 (4.5) 14 (66.7)
procedure and dexmedetomidine infusion time between the 4 0 (0) 0 (0)
groups. Median (interquartile range) 0 (0–0) 3 (2–3) < .0001
Lumbar puncture [n, (%)]
The preoperative resting NRS score was not different between
0 17 (77.3) 11 (52.4)
the groups (3.9 ± 1.4 in group K, 3.3 ± 0.8 in group F). The 1 2 (9.1) 8 (38.1)
median pain score in lateral positioning, hip flexion, and lumbar 2 3 (13.6) 2 (9.5)
puncture was 0 (0–1), 0 (0–0) and 0 (0–0), respectively, in group 3 0 (0) 0 (0)
K and 3.0 (2.75–3), 3 (2–3), and 0 (0–1) in group F (Table 2). The 4 0 (0) 0 (0)
pain score in lateral positioning (P < .0001) and hip flexion Median (interquartile range) 0 (0–0) 0 (0–1) .1708
(P < .0001) was significantly lower in group K. The median
Pain scores (0 = calm, 1 = facial grimacing, 2 = moaning, 3 = screaming, 4 = unable to proceed
quality scores in spinal anesthesia positioning were 2 (1–3) in because of restlessness or agitation) were assessed in 3 sequential steps during positioning for spinal
group K and 1 (0.75–1) in group F (Table 3). Group K showed the anesthesia. Group F = patients who received dexmedetomidine-fentanyl, Group K = patients who
higher quality score in spinal anesthesia positioning (P < .0044). received dexmedetomidine-ketamine.
The median number of lumbar puncture attempts was 1 (1–2) in
group K, and 1 (1–1.25) and group F. The length of time needed They were not significantly different between the groups.
for spinal anesthesia was 5.8 ± 2.4 and 5.5 ± 2.0 minutes in Desaturation in this study was common, with a rate of 81.8%
groups K and F, respectively (Table 3). There were no statistically in group K and 66.7% in group F. Hemodynamic changes in
significant differences in the number of lumbar puncture attempts terms of the MBP, HR, SPO2, and BIS were recorded at a 5-
and the length of time needed for spinal anesthesia between the minute interval during the first 30 minutes from the beginning of
groups. dexmedetomidine administration with either ketamine or fenta-
Intraoperative hemodynamic adverse effects, including brady- nyl, as shown in Figures 3–5, respectively. No difference was
cardia, hypotension, and desaturation are shown in Table 4. found in the MBP, HR or SPO2 between the groups. The MBP
after 20 minutes (T20), 25 minutes (T25), and 30 minutes (T30)

Table 1
Patient demographics and spinal anesthetic characteristics. Table 3
Group K Group F Assessment of posture quality and difficulty performing a lumbar
(n = 22) (n = 21) P value puncture.

Age (years) 78.3 ± 6.5 79.6 ± 7.1 0.5352 Group K Group F

Male/female (n) 2/20 7/14 0.0535 (n = 22) (n = 21) P value
Height (cm) 156.5 ± 6.2 160.3 ± 7.1 0.0650 Quality scores of posture [n, (%)]
Weight (kg) 52.2 ± 8.7 55.8 ± 8.2 0.1723 0 3 (13.6) 5 (23.8)
ASA classification (1/2/3) (n) 0/15/7 0/9/12 0.1065 1 6 (27.3) 13 (61.9)
Time from trauma to surgery (days) 1 (1 to 2) 2 (1 to 3) 0.1012 2 5 (22.7) 3 (14.3)
Preoperative resting pain (NRS) 3.9 ± 1.4 3.3 ± 0.8 0.0936 3 8 (36.4) 0 (0)
Type of fracture 0.6289 Median (interquartile range) 2 (1–3) 1 (0.75–1) .0044
Femur neck fracture [n, (%)] 10 (45.5) 8 (38.1) The number of lumbar puncture attempts [n, (%)]
Intertrochanteric fracture [n, (%)] 12 (54.5) 13 (61.9) 1 16 (72.7) 16 (76.2)
Surgical techniques 0.4562 2 3 (13.6) 2 (9.5)
Hemiarthroplasty [n, (%)] 10 (45.5) 7 (33.3) 3 3 (13.6) 2 (9.5)
ORIF [n, (%)] 12 (54.5) 14 (66.7) 4 0 (0) 1 (4.8)
Anesthesia time (min) 117 ± 37 109 ± 27 0.4272 Median (interquartile range) 1 (1–2) 1 (1–1.25) .8738
Surgical procedure time (min) 64 ± 30 58 ± 25 0.4484 Time taken for spinal anesthesia (min) 5.8 ± 2.4 5.5 ± 2.0 .4562
Dexmedetomidine infusion time (min) 96 ± 23 88 ± 27 0.3429
Mean ± standard deviation. Quality scores of spinal anesthesia positioning (0 = poor hip flexion < 30
Mean ± standard deviation, median (interquartile range), ASA classification = American Society of degrees, 1 = satisfactory hip flexion ≥ 30 and < 60 degrees, 2 = good hip flexion ≥60 and < 90
Anesthesiologists classification, Group F = patients who received dexmedetomidine-fentanyl, Group degrees, 3 = optimal hip flexion ≥ 90 degrees) were assessed estimating the degree of hip flexion.
K = patients who received dexmedetomidine-ketamine, NRS = numerical rating scale, ORIF = open Group F patients who received dexmedetomidine-fentanyl, Group K patients who received
reduction and internal fixation. dexmedetomidine-ketamine.

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Table 4 who received intravenous propofol for the management of

Intraoperative hemodynamic adverse effects and perioperative agitation (P = .9734), and only 1 patient in group K was given
complications. additional fentanyl (P = .3286). The incidence of postoperative
delirium (POD)was noted in 5 patients in group F, 6 patients in
Group K (n = 22) Group F (n = 21) P value
group K (23.8% and 27.3%, P = .7971), and eleven patients
Bradycardia 18 (81.8) 14 (66.7) .2606 (25.6%) in total.
Hypotension 21 (95.5) 20 (95.2) .9734
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Desaturation 18 (81.8) 14 (66.7) .2606

PONV 4 (18.2) 2 (9.5) .6640 4. Discussion
Agitation 1 (4.5) 1 (4.7) .9734
Incomplete anesthesia 1 (4.5) 0 (0) .3286
Dexmedetomidine is widely used for proximal femoral fracture
Postoperative delirium 6 (27.3) 5 (23.8) .7971 surgery under spinal anesthesia in our institution because the
dexmedetomidine infusion provides sedation as well as analgesia
Data are presented as n (%). Bradycardia = Heart rate < 60 beats/min, Group F = patients who in elderly patients. Dexmedetomidine can also be used in patients
received dexmedetomidine-fentanyl, Group K = patients who received dexmedetomidine-ketamine,
Hypotension = mean blood pressure < 60 mm Hg or decrease in systolic blood pressure > 20%),
waiting for spinal anesthesia to reduce pain and anxiety.
PONV = postoperative nausea and vomiting. Movement-evoked pain in cases of femoral fracture for
positioning, however, is difficult to manage with dexmedetomi-
dine using a sole agent. Dexmedetomidine can be used in
was statistically lower than that at the beginning (T0) in both combination with ketamine or fentanyl. When considering the
groups. The HR at T15 began to become significantly lower than technique used to aid patient positioning for spinal anesthesia,
that at T0 in group K, while a significant reduction in the HR the intravenous agents used were ketamine and fentanyl.[7] Our
began at 20 minutes (T20) in group F. The BIS at T15 was 82 ± 9 results demonstrate that dexmedetomidine-ketamine had greater
and 75 ± 14 in groups K and F, respectively, which were benefits than dexmedetomidine-fentanyl in reducing the pain
significantly different (P = .0489). The MAP, HR, and BIS tended intensity and improving the quality of patient posture during
to significantly decrease over time (P < .001) in both groups. positional changes for spinal anesthesia in elderly patients with
Perioperative complications of dexmedetomidine with either proximal femoral fractures.
ketamine or fentanyl are shown in Table 4. There were four Ketamine, rather than fentanyl, resulted in reduced pain
patients (18.2%) and 2 patients (9.5%) in groups K and F, intensity and greater quality in lateral positioning and hip flexion
respectively, who complained of postoperative nausea and in this study, which suggests that ketamine (1 mg/kg over 10
vomiting (PONV, P = .6640). Both groups had one patient minutes) could produce better pain relief when compared to

Figure 3. Mean blood pressure (MBP) at a 5-minute interval during the first 30 Figure 4. Heart rate (HR) at a 5-minute interval during the first 30 min from the
min from the beginning of dexmedetomidine administration with either beginning of dexmedetomidine administration with either ketamine or fentanyl.
ketamine or fentanyl. Intravenous ketamine (1 mg/kg) or fentanyl (1 mg/kg) Intravenous ketamine (1 mg/kg) or fentanyl (1 mg/kg) was infused, concomitant
was infused, concomitant with a loading dose of dexmedetomidine 1 mg/kg with a loading dose of dexmedetomidine 1 mg/kg over 10 minutes. Then
over 10 min. Then ketamine or fentanyl infusion was discontinued, and the ketamine or fentanyl infusion was discontinued, and the infusion of
infusion of dexmedetomidine was continued at 0.6 mg/kg/h for the next 20 dexmedetomidine was continued at 0.6 mg/kg/h for the next 20 minutes.
minutes. There was no statistically significant difference in the MBP between There was no statistically significant difference in the HR between groups K and
groups K and F. The MBP at T20, T25 and T30 were significantly lower than F. The HR at T20, T25, and T30 were significantly lower than that at T0 in group
that at T0 in both groups. There were significant differences in the MBP K, while the HR at T15, T20, T25, and T30 were significantly lower than that at
between T10 and T15, and between T15 and T20 in group K, while significant T0 in group F. There was a significant difference in the HR between T15 and
differences were shown in the MBP between T10 and T15, between T15 and T20 in group K, while there were significant differences between T10 and T15,
T20, and between T20 and T25 in group F. There was a significant decrease and between T15 and T20 in group F. There was a significant decrease over
over time in each group (x: P < .001 in group K, #: P < .001 in group F). Data are time in each group (x: P < .001 in group K, #: P < .001 in group F). Data are
presented as the mean ± SD. Group K = patients who received presented as the mean ± SD. Group K = patients who received
dexmedetomidine-ketamine, Group F = patients who received dexmedeto- dexmedetomidine-ketamine, Group F = patients who received dexmedeto-
midine-fentanyl. †: P < .05 compared with baseline value, ‡: P < .05 compared midine-fentanyl. †: P < .05 compared with baseline value, ‡: P < .05 compared
with previous value. with previous value.

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Figure 6. Bispectral index (BIS) at a 5-min interval during the first 30 min from
Figure 5. Pulse oximetry saturation (SpO2) at a 5-min interval during the first
the beginning of dexmedetomidine administration with either ketamine or
30 min from the beginning of dexmedetomidine administration with either
fentanyl. Intravenous ketamine (1 mg/kg) or fentanyl (1 mg/kg) was infused,
ketamine or fentanyl. Intravenous ketamine (1 mg/kg) or fentanyl (1 mg/kg) was
concomitant with a loading dose of dexmedetomidine 1 mg/kg over 10 min.
infused, concomitant with a loading dose of dexmedetomidine 1 mg/kg over 10
Then ketamine or fentanyl infusion was discontinued, and the infusion of
minutes. Then ketamine or fentanyl infusion was discontinued, and the infusion
dexmedetomidine was continued at 0.6 mg/kg/h for the next 20 minutes. The
of dexmedetomidine was continued at 0.6 mg/kg/h for the next 20 minutes.
BIS at T15 was 82 ± 9 and 75 ± 14 in groups K and F, respectively, and there
There was no statistically significant difference in the SPO2 between groups K
was a statistically significant difference between groups K and F (P = .0489).
and F. Data are presented as the mean ± SD. Group K = patients who received
The BIS at T5, T10, T15, T20, T25, and T30 were significantly lower than those
dexmedetomidine-ketamine, Group F = patients who received dexmedeto-
at T0 in both groups. There was a significant difference in the BIS between T0
midine-fentanyl.
and T5, and between T5 and T10 in group K, while there was a significant
difference between T0 and T5 in group F. The BIS tended to decrease over
time, and there was a significant decrease over time in both groups (x: P < .001
fentanyl (1 mg/kg over 10 minutes). Intravenous ketamine in group K, #: P < .001 in group F). Data are presented as the mean ± SD
provides longer postoperative analgesia, reduces postoperative Group K = patients who received dexmedetomidine-ketamine,
∗
Group F =
patients who received dexmedetomidine-fentanyl. : P < .05 compared with
analgesic consumption and may be useful in acute pain group F, †: P < .05 compared with baseline value, ‡: P < .05 compared with
management.[11,12] Due to the advantages of dexmedetomidine, previous value.
which attenuates the cardiostimulatory effects and adverse effects
of ketamine on the central nervous system, the dexmedetomidine-
ketamine combination also showed better analgesia and
hemodynamic parameter stability, with better recovery pro- This study was designed to compare the effect of ketamine
files.[13,14] The dexmedetomidine-midazolam-fentanyl combina- infusion (1 kg/mg over 10 minutes) and fentanyl infusion (1 mg/kg
tion showed a similar analgesic effect and a better sedative effect over 10 minutes) instead of a single bolus. Fentanyl is most
than the dexmedetomidine-ketamine combination.[15] The dex- commonly used for perioperative pain control, and analgesic
medetomidine-fentanyl combination seemed to provide better action can occur as soon as 1 to 2 minutes after the intravenous
sedation, stable hemodynamics, and postoperative pain relief administration of fentanyl.[19] Many studies have reported that
than the midazolam-fentanyl combination during tooth extrac- the analgesic and side effects of fentanyl and ketamine are
tion.[16] Therefore, the appropriate combination of dexmedeto- correlated with plasma concentration.[20] The infusion of a drug
midine and adjuvant drugs with the careful adjustment of their slowly reaches the target plasma concentration compared to a
doses is required to achieve adequate analgesia and sedation. single bolus injection, with a slower onset and fewer side
The analgesic effect of ketamine compared to fentanyl in effects.[21] Opioids should be administered in the most favorable
elderly patients have been unreported in the literature. The doses for patients over 70 years old, that is, starting from
previous studies failed to show differences of analgesic effect approximately 25% to 50% of the approved starting dose in
between intravenous ketamine (0.5 mg/kg) and fentanyl (1 mg/kg) adults, and then slowly titrated to minimize negative con-
in children following adenotonsillectomy, and between intrana- sequences.[22] In this study, the average age of the patients was
sal ketamine (1.5 mg/kg) and fentanyl (2 mg/kg) in children 78.3 ± 6.5 and 79.6 ± 7.1 in groups K and F, respectively, and we
presenting with acute extremity.[17,18] This result may be infused the study drugs over 10 minutes to minimize adverse
interpreted as a difference in morphine equivalent dose between effects, such as respiratory depression, hypotension, and
ketamine and fentanyl. Considering that ketamine 0.3 mg/kg has bradycardia. However, desaturation frequently occurred, when
analgesic effects similar to morphine 0.1 mg/kg, which is dexmedetomidine was administered concomitant with fentanyl
equivalent to fentanyl 1 mg/kg, the morphine equivalent dose or ketamine in elderly patients (Table 4). Planning anesthesia and
of ketamine (1 mg/kg) in this study may be superior to that of analgesia techniques for senior patients with multiple comorbid-
fentanyl (1 mg/kg). However, the opioid requirement decreases ities would be a great burden on anesthesiologists, taking into
with age in the elderly patients, and the dose of fentanyl (1 mg/kg) account the risk of respiratory depression and hemodynamic
was administered rather than higher doses, in order to help adverse effects, caused by dexmedetomidine-ketamine or dex-
reduce pain and improve the anesthesia posture, with fewer side medetomidine-fentanyl. This result suggests that precaution
effects. should be taken when administering dexmedetomidine concomi-

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tant with other drugs, and further studies on the combination of was a significant decrease over time in the MBP and HR in both
sedative and analgesic agents are needed. groups, and the BP and HR began to decline after 15 minutes
The positioning of femoral fracture patients for spinal anesthesia compared to the baseline or previous values (Figs. 3 and 4). The
is regularly problematic because even minimal overriding of the intravenous infusion of dexmedetomidine was initiated with a
fracture ends is extremely painful.[23] There are several strategies to loading dose (1 mg/kg) over 10 minutes, followed by a
reduce postural pain during spinal anesthesia in these patients. The maintenance infusion (0.6 mg/kg) in this study. Our results are
administration of opioids, the femoral nerve block (FNB), and the consistent with that dexmedetomidine resulted in a decrease in
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fascia iliaca compartment block can be used for analgesia.[6] the BP and HR due to presynaptic a2 receptors reducing
However, the degree of pain relief differs according to the norepinephrine release, inhibiting central sympathetic outflow.[8]
concentration of opioids and local anesthetics.[7,23] There are There was a significant decrease over time in the BIS in both
several studies on FNB for suppressing pain during postural groups. In addition, there was a statistically significant difference
changes in patients with femoral fractures, and the comparative in the BIS at T15 between groups K and F, and the values were 82
effects of FNB and fentanyl were not consistent in these studies. The ± 9 and 75 ± 14 (P = .0489), respectively. This should be
FNB was more advantageous than the intravenous administration cautiously interpreted, considering ketamine significantly in-
of fentanyl to facilitate a sitting position,[24] while it was not creased the BIS, despite cortical depression by dexmedetomi-
superior to intravenous fentanyl for lateral positioning.[7] dine,[15,16,27] and deepening sedation.[28] As ketamine is known
However, these 2 studies had some differences in the final patient to increase the activity of the electroencephalography towards
position (sitting vs lateral position) and in the fracture site (femoral higher frequencies and desynchronization, an elevated BIS value
shaft vs proximal femur), which could have led to different results. may reflect greater cortical activity rather than consciousness.[29]
All patients included in this study had proximal femoral fractures. There are some limitations to this study. First, the patients’
FNB was thought to be less effective than intravenous analgesics, subjective expression of pain and satisfaction were not taken into
considering that the proximal femur is innervated by the lateral account. The analgesic effect was assessed by the evaluator based
femoral nerve, the femoral nerve, the obturator nerve, the on objective expressions, such as the facial expressions or voice of
genitofemoral nerve, and sciatic nerve. In addition, it may be the patient. This study failed to show the difference in difficulty of
more difficult to perform FNB without an expert, and its onset spinal anesthesia which was demonstrated by the number of
would be slower than 15 minutes. The time to induce anesthesia lumbar puncture attempts and the length of time needed for
with FNB is significantly longer than that with the intravenous spinal anesthesia, despite the differences in both pain score and
administration of opioids.[6] We assumed that the intravenous quality of positioning. This might indicate the degree of hip
administration of analgesics would be easier and less invasive than flexion was inadequate to assess the overall quality of
the FNB. Therefore, we provided either intravenous dexmedeto- positioning. Further investigation is needed for the clinical
midine-ketamine or dexmedetomidine-fentanyl administration to relevance between postural change evoked pain and difficulty of
produce analgesic and sedative effects. spinal anesthesia. Second, BIS was measured, instead of a clinical
This is the first clinical study to compare the feasibility and sedation level, such as the modified observer’s assessment
analgesic effect of ketamine and fentanyl concomitant with a alertness/sedation scale, to minimize painful or verbal stimulation
loading dose of dexmedetomidine for sedation. Recently, of the elderly patients. BIS value paradoxically increases as deeper
prophylactic low-dose dexmedetomidine appreciably decreased planes of anesthesia are achieved by infusion of ketamine which
the incidence of delirium after noncardiac surgery and hip stimulates the activity of encephalogram. BIS can also greatly
arthroplasty.[24,25] Patients with a proximal femoral fracture are change with time, which leads to misinterpretation of the
usually elderly, and a significant proportion of these patients have sedation status. Third, the infusion of sedatives before spinal
comorbidities and are at an increased risk for POD. The rate of anesthesia prevented the anesthesiologist from accurately
POD in this study was 25.6%, which is similar to the incidence of measuring the patient’s level of motor and sensory blockade.
POD reported in other studies.[26] Although ketamine stimulates Fourth, the dose of analgesics previously administered before
the central nervous system and raises the intracranial pressure, surgery was not taken into account, although the preoperative
which can cause delirium-like symptoms, no difference was found resting NRS score was not different between the groups (3.9 ± 1.4
in the incidence of POD between the groups (27.3% in group K, in group K vs 3.3 ± 0.8 in group F). Fifth, the dose and infusion
23.8% in group F). One groaning patient in group K was duration of fentanyl and ketamine were arbitrary for researchers
diagnosed with inadequate anesthesia during surgery and given and determined based on the convenience of study within the
an additional 50 mg of intravenous fentanyl. There was one scope of clinical use. The results of this study may be interpreted
agitated patient in each group who once received 10 mg of as the pharmacodynamic and pharmacokinetic differences
intravenous propofol. Pain, discomfort, and anxiety in elderly between ketamine and fentanyl in elderly patients. Further
patients can generate agitated screaming and uncontrolled studies are needed to clarify the doses of fentanyl and ketamine.
movement. Adequate sedation with dexmedetomidine-ketamine The conclusion that dexmedetomidine-ketamine is superior to
can provide sufficient pain relief during positional changes and dexmedetomidine-fentanyl is difficult to generalize through this
lead to successful spinal anesthesia. study. However, it is of value in this study that dexmedetomidine-
In this study, bradycardia, hypotension, and desaturation were ketamine helps to suppress postural pain and improve postural
common complications during the entire anesthesia, which may maintenance in elderly patients with hip fractures. Providing
be relevant to spinal anesthesia itself under continuous longer time for drug action after the infusion of ketamine and
dexmedetomidine infusion, but their incidences with the fentanyl may also affect the results.
administration of dexmedetomidine-ketamine were not signifi- In conclusion, the concomitant administration of dexmedeto-
cantly different from those with the administration of dexme- midine and ketamine can be an effective and excellent method for
detomidine-fentanyl. There was no difference in the MBP, HR, or suppressing the pain of postural changes for spinal anesthesia in
SPO2 between groups K and F. This study also shows that there elderly patients with proximal femoral fractures and for

7
 Lee et al. Medicine (2020) 99:20 Medicine

maintaining stable sedation during the operation. The dexme- [11] Neuman MD, Silber JH, Elkassabany NM, et al. Comparative
effectiveness of regional versus general anesthesia for hip fracture
detomidine-ketamine combination may be useful for analgesia
surgery in adults. Anesthesiology 2012;117:72–92.
without serious adverse reactions; therefore, further studies are [12] Dahanl A, Olofsenl E, Sigtermans M, et al. Population pharmacokinetic
required to clarify the dose and infusion duration. —pharmacodynamic modeling of ketamine-induced pain relief of
chronic pain. Eur J Pain 2011;15:258–67.
[13] Levanen J, Makela M-L, Scheinin H. Dexmedetomidine premedication
Author contributions
attenuates ketamine-induced cardiostimulatory effects and postanes-
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Conceptualization: Ki Hwa Lee, Sang Eun Lee. thetic delirium. Anesthesiology 1995;82:1117–25.
[14] Kose EA, Honca M, Yılmaz E, et al. Comparison of effects of
Data curation: Hyojoong Kim.
dexmedetomidine-ketamine and dexmedetomidine-midazolam combi-
Formal analysis: Hyunseong Lee, Yong Han Kim. nations in transurethral procedures. Urology 2012;79:1214–9.
Investigation: Sang Eun Lee. [15] Chun EH, Han MJ, Baik HJ, et al. Dexmedetomidine-ketamine versus
Methodology: Ki Hwa Lee, Sang Eun Lee. Dexmedetomidine-midazolam-fentanyl for monitored anesthesia care
Software: Jae Hong Park. during chemoport insertion: a Prospective Randomized Study. BMC
anesthesiology 2015;16:49.
Supervision: Se Hun Kim. [16] Yu C, Li S, Deng F, et al. Comparison of dexmedetomidine/fentanyl with
Validation: Yei Heum Park. midazolam/fentanyl combination for sedation and analgesia during
Visualization: Dae Seok Oh. tooth extraction. Int J Oral Maxillofac Surg 2014;43:1148–53.
Writing – original draft: Ki Hwa Lee. [17] Taheri R, Seyedhejazi M, Ghojazadeh M, et al. Comparison of ketamine
and fentanyl for postoperative pain relief in children following
Writing – review and editing: Sang Eun Lee, Soo Jee Lee.
adenotonsillectomy. Pak J Biol Sci 2011;14:572.
[18] Frey TM, Florin TA, Caruso M, et al. Effect of intranasal ketamine vs
References fentanyl on pain reduction for extremity injuries in children: the PRIME
randomized clinical trial. JAMA Pediatr 2019;173:140–6.
[1] Roche J, Wenn RT, Sahota O, et al. Effect of comorbidities and [19] Stanley TH. The fentanyl story. J Pain 2014;15:1215–26.
postoperative complications on mortality after hip fracture in elderly [20] Jonkman K, Dahan A, van de Donk T, et al. Ketamine for pain.
people: prospective observational cohort study. BMJ 2005;331:1374. F1000Res 2017;6.
[2] Miller CP, Buerba RA, Leslie MP. Preoperative factors and early [21] Lötsch J. Pharmacokinetic–pharmacodynamic modeling of opioids. J
complications associated with hemiarthroplasty and total hip arthro- Pain Symptom Manage 2005;29:90–103.
plasty for displaced femoral neck fractures. Geriatr Orthop Surg Rehabil [22] Chau DL, Walker V, Pai L, et al. Opiates and elderly: use and side effects.
2014;5:73–81. Clin Interv Aging 2008;3:273–8.
[3] Lee DJ, Elfar JC. Timing of hip fracture surgery in the elderly. Geriatr [23] Sia S, Pelusio F, Barbagli R, et al. Analgesia before performing a spinal
Orthop Surg Rehabil 2014;5:138–40. block in the sitting position in patients with femoral shaft fracture: a
[4] Bech RD, Lauritsen J, Ovesen O, et al. The verbal rating scale is reliable comparison between femoral nerve block and intravenous fentanyl.
for assessment of postoperative pain in hip fracture patients. Pain Res Anesth Analg 2004;99:1221–4.
Treat 2015;2015:676212. [24] Mei B, Meng G, Xu G, et al. Intraoperative sedation with dexmede-
[5] Sandby-Thomas M, Sullivan G, Hall J. A national survey into the peri- tomidine is superior to propofol for elderly patients undergoing hip
operative anaesthetic management of patients presenting for surgical arthroplasty. Clin J Pain 2018;34:811–7.
correction of a fractured neck of femur. Anaesthesia 2008;63:250–8. [25] Su X, Meng Z-T, Wu X-H, et al. Dexmedetomidine for prevention of
[6] Yun M, Kim Y, Han M-K, et al. Analgesia before a spinal block for delirium in elderly patients after non-cardiac surgery: a randomised,
femoral neck fracture: fascia iliaca compartment block. Acta Anaes- double-blind, placebo-controlled trial. Lancet 2016;388:1893–902.
thesiologica Scandinavica 2009;53:1282–7. [26] Inouye SK, Westendorp RG, Saczynski JS. Delirium in elderly people.
[7] Iamaroon A, Raksakietisak M, Halilamien P, et al. Femoral nerve block Lancet 2014;383:911–22.
versus fentanyl: Analgesia for positioning patients with fractured femur. [27] Kim KH. Safe Sedation and Hypnosis using Dexmedetomidine for
Local Reg Anesth 2010;3:21. Minimally Invasive Spine Surgery in a Prone Position. Korean J Pain
[8] Bhana , Bhana N, Goa KL, et al. Dexmedetomidine. Drugs 2000;59: 2014;27:313–20.
263–8. [28] Sengupta S, Ghosh S, Rudra A, et al. Effect of ketamine on bispectral
[9] Tobias JD. Dexmedetomidine and ketamine: an effective alternative for index during propofol–fentanyl anesthesia: a randomized controlled
procedural sedation? Pediatric Critical Care Medicine 2012;13:423–7. study. Middle East J Anaesthesiol 2011;21:391–5.
[10] Erdil F, Demirbilek S, Begec Z, et al. The effects of dexmedetomidine and [29] Hans , Hans P, Dewandre PY, et al. Comparative effects of ketamine on
fentanyl on emergence characteristics after adenoidectomy in children. Bispectral Index and spectral entropy of the electroencephalogram under
Anaesth Intensive Care 2009;37:571–6. sevoflurane anaesthesia. Br J Anaesth 2005;94:336–40.