ppr_278 289..

295

ORIGINAL ARTICLE

Effects of Intravenous Small Dose

Ketamine and Midazolam on
Postoperative Pain Following
Knee Arthroscopy

Buket Cagla Ozbakis Akkurt, MD*; Kerem Inanoglu, MD*;

Aydiner Kalaci, MD†; Selim Turhanoglu, MD*; Zeynel Asfuroglu, MD*;
Feray Tumkaya, MD*
*Department of Anesthesiology; †Department of Orthopedics, Mustafa Kemal University
Medical Faculty, Hatay, Turkey

䊏 Abstract whereas no difference was found between groups II and III.

Total meperidine consumption was significantly higher in
Background: The aim of this randomized, double blind,
group I (P = 0,001). Patient satisfaction was significantly
controlled study was to assess the effect of intravenous coad-
higher in group III compared with group I (P = 0.001), but no
ministration of small dose midazolam with ketamine on post-
difference was found between groups II and III (P = 0.3).
operative pain and spinal block level.
Conclusion: Ketamine improved the postoperative pain
Methods: Sixty patients undergoing arthroscopic knee
patient satisfaction, increased the maximal sensory level, and
surgery under spinal anesthesia were randomized into
was associated with lower sedation scores in the first 15
three groups: Group I (saline control); group II (ketamine
minutes after administration. Group I was also associated
0.15 mg/kg i.v.); and group III (ketamine 0.15 mg/kg +
with decreased total meperidine consumption and delayed
midazolam 0.01 mg/kg i.v.). Sedation scores, visual analogue
the time to first recue analgesic administration. Coadminis-
scores, time to first postoperative analgesic, total meperidine
tration of ketamine and midazolam did not provide any
consumption, patient satisfaction, sensory and motor block
further benefit over ketamine alone. 䊏
levels, and two segments regression times were assessed.
Results: Sedation scores were significantly lower in group I
Key Words: ketamine, postoperative pain, knee
when compared with groups II and III at 1, 3, 5, and 10
arthroscopy, randomized controlled trial, spinal anesthesia,
minutes after administration of the spinal anesthetic
preemptive analgesia
(P = 0.001). Sensory block was significantly higher in group III
(P = 0.001) in comparison with group II. Two segment regres-
sion time was significantly longer in group II than group I, INTRODUCTION
Address correspondence and reprint requests to: Buket Cagla Ozbakis Treatment of postoperative pain is an important and
Akkurt, MD, Mustafa Kemal University Medical Faculty—Anesthesiology, challenging issue in the field of anesthesia. There have
Bagriyanik Street, Hatay 31000, Turkey. E-mail: caglabuket@gmail.com.
Submitted: June 8, 2008; Accepted: January 28, 2009
been many studies concerning different methods for the
DOI. 10.1111/j.1533-2500.2009.00278.x management of postoperative pain. Currently there is
no method of preemptive analgesia accepted as optimal
© 2009 World Institute of Pain, 1530-7085/09/$15.00
for diminishing postoperative pain. The mechanisms
Pain Practice, Volume 9, Issue 4, 2009 289–295 responsible for postoperative pain are complex, but
290 • akkurt et al.
N-methyl-d-aspartate (NMDA) receptors are known to
play an important role. Ketamine, an NMDA receptor
blocker, has been used for analgesia for more than 30
years and its preemptive use for the reduction of post-
operative pain has gained popularity in recent years.
There are conflicting reports regarding the effect of
preoperative, perioperative or postoperative use of ket-
amine on postoperative pain relief. Although most
studies have supported the ability of ketamine to reduce
postoperative pain and morphine consumption,1–5 there
are studies where ketamine did not demonstrate these
benefits.6 Ketamine also has been administered intraspi-
nally, where its effect enhances the effect of epidural
anesthesia. It has been used alone or in combination
with other drugs, such as morphine and midazo-
lam.3,4,7–10 Fewer studies have shown that administration
of intravenous ketamine improved postoperative anal-
gesia after both spinal and epidural anesthesia.11,12
Midazolam is one of the clinically available water
soluble benzodiazepines and has been reported to have
an analgesic effect through neuraxial pathways.13 It has
been reported that the combination of epidural mida-
zolam with lidocaine improved the duration and quality
of the spinal anesthesia. Tripathi et al. has reported that
low dose of ketamine in combination with diazepam
significantly improves the quality of anesthesia compared
with diazepam alone after spinal block.12 However, it was
not clear whether these favorable effects could be attrib-
uted solely to ketamine or to the combination of both
drugs. To our knowledge, there are no published studies
reporting the effect of intravenous coadministration of
midazolam with ketamine with spinal anesthesia. In this
randomized, double blind, controlled trial, we aimed to
investigate the effect of intravenous midazolam com-
bined with ketamine on postoperative pain and both
sensory and motor block following spinal anesthesia.
METHODS
Following approval from the ethics committee and
study-specific informed consent, 60 ASA physical status
I-II patients scheduled for arthroscopy under spinal
anesthesia were enrolled. Patients with a history of
chronic pain, long-term opioid consumption, hepatic,
renal, pulmonary, and cardiovascular system disorders
were excluded.
Patients were randomly assigned to three groups con-
taining 20 subjects in each. Patients were informed
about all study procedures and instructed in the use of
the Visual Analog Scale (VAS) before surgery after
written consent was obtained. None of the patients were
given premedication. Peripheral oxygen saturation
(SpO2), electrocardiogram, noninvasive arterial blood
pressure, and heart rate were recorded in the operating
room. Intravenous catheterization was performed with
a 20 g cannula in the left hand. All patients received a
10 mL/kg pre-load of ringer lactate solution before sub-
arachnoid block. Lumbar puncture was performed in
the sitting position with a 25 g Quincke-type spinal
needle at the L3–L4 interspace under aseptic conditions.
Spinal anesthesia was induced with 10 mg 0.5% hyper-
baric bupivacaine.
Patients were placed in the supine position immedi-
ately after the spinal block and the study solution was
administered slowly through the intravenous catheter.
Group I (control group, n = 20) received 1 mL + 1 mL
saline, group II (ketamine group, n = 20) was given
0.15 mg/kg ketamine + 1 mL saline, and group III (ket-
amine and midazolam group, n = 20) was given ket-
amine 0.15 mg/kg and midazolam 0.01 mg/kg and 1 mL
saline. The anesthesiologist providing perioperative and
postoperative follow-up of the patient was blinded and
not involved in the preparation or administration of
study solution. Hemodynamic parameters systolic arte-
rial blood pressure (SBP), diastolic arterial blood pres-
sure, mean arterial blood pressure, and heart rate were
recorded every 5 minutes before and after spinal block.
Hypotension was defined as systolic blood pressure
below 90 mm Hg or systolic blood pressure decreasing
more than 20% compared with the SBP immediately
before the spinal block. Intravenous ephedrine 5 mg was
administered for hypotension.
After the administration of the study drug, sedation
was assessed using a sedation scale (0, awake; 1, drowsy
but responsive to verbal orders; 2, drowsy but respon-
sive to physical stimulus; 3 sleepy but responsive to pain
stimulus) at the 1, 3, 5, 10, 15, 20, 25 and 30 minutes.
Sensory and motor block was assessed at 5, 10, and 15
minutes by pinprick testing and a modified Bromage
Scale (0, no motor loss; 1, inability to flex the hip; 2,
inability to flex the knee; 3, inability to flex the ankle),
respectively. Maximum block levels were recorded.
Offset time for regression of sensory and the motor
block was recorded. Complete motor recovery was
assumed when modified Bromage Scale was zero. After
spinal sensory block reached the maximum level, the
spinal block extent was examined every 5 minutes,
noting the time until it decreased by two dermatomal
levels: “two segment regression time” (TSRT). Begin-
ning from the TSRT, the intensity of the pain was
assessed every hour for 6 hours with a VAS (0–10 cm:
 Effects of Ketamine and Midazolam on Postoperative Pain • 291
0 = no pain, 10 = the worst pain possible). If the VAS
score was >4, then 0.4 mg/kg meperidine was given
intravenously and, if the score did not decrease within
10 minutes, an additional 0.2 mg/kg meperidine was
given. The total meperidine dose did not exceed a
maximum of 2 mg/kg in any 4 hours. The time for the
need of the first additional meperidine and total mep-
eridine consumption was recorded. The dose regimen
used in this study was based on results from previous
studies.
Adverse effects (pruritus, allergic reactions, nausea,
vomiting, and hallucinations) were recorded. Intrave-
nous metoclopramide was administered for nausea and
vomiting. Patients were discharged 6 hours after the
surgery and returned for a follow-up visit after two
days. Patients provided VAS scores and patient satisfac-
tion scores (0–3, categorical scale: 0 = not satisfied,
3 = very satisfied) at 48 hours after surgery.
Statistical analysis was performed with one-way
ANOVA test with Tukey’s posthoc test. Nonparametic
analyses were used as appropriate for categorical out-
comes. A P < 0.05 was assumed to be significant.
RESULTS
There were no important differences between the three
groups with regard to demographic characteristics
(Table 1). Each group contained 20 subjects (Figure 1:
CONSORT Diagram). Hemodynamic parameters were
similar between groups (Table 2). Sedation scores were
statistically significantly lower in the ketamine group
(group II) when compared with midazolam + ketamine
group (group III) at 1, 3, 5, and 10 minutes after spinal
block (P = 0.001, 0.001, 0.001, 0.001) but not after 15
minutes.
Motor block was significantly higher in group III five
minutes after block (P = 0.001) when compared with
group I, but the significance disappeared in later assess-
ments (Table 3). Sensory block was significantly higher at
all time points in group III in comparison with the other
two groups (P = 0.001, 0.001). When group II was com-
Table 1. Demographic Data (P > 0.05 in All Groups)
Group I Group II Group III
(Control) (Ketamine) (Ketamine + Midazolam)
n = 20 n = 20 n = 20
Gender M/F 10/10 11/9 9/11
Age-years 31–60 16–65 18–57
Weight (kg) 56–98 55–97 50–110
Height (cm) 166–178 160–186 160–183
pared with group I, sensory block was significantly
higher at 15 minutes after spinal block (P = 0.001)
(Table 3). Maximum sensory block, however, did not
show any significant difference between groups II and III,
but it was significantly higher when these groups were
compared with group I (P = 0.001, 0.001). Similarly,
maximum motor block was similar between groups II
and III (Table 3). The difference in VAS scores between
group II and III were not significant at 4, 5, 6, and 48
hours postoperatively, but they were significantly lower
at all of these time points compared with group I
(P = 0.001) (Figure 2). TSRT was significantly longer in
the ketamine group (group II) compared with the saline
group (group I), whereas no difference was found
between groups II and III (Table 4).
Total meperidine consumption was significantly
higher in group I than the other two groups (P = 0.001,
P = 0.001), but it was similar between group II and III
(Table 4). The time to administer the first additional
dose of analgesic was significantly longer in group III in
comparison with groups II and I (P = 0.001, P = 0.001)
(Figure 3). Patient satisfaction was found significantly
higher in group III compared with group I (P = 0.001)
and in group II compared with group I (P = 0.011), but
no difference was found between groups II and III
(P = 0.3).
DISCUSSION
In this randomized, double blind, controlled study, we
found that the administration of small doses of intrave-
nous ketamine and midazolam improved postoperative
pain, patient satisfaction, and second day VAS scores. It
was also associated with higher maximal sensory block
and lower sedation scores in the first 15 minutes follow-
ing administration, decreased total postoperative mep-
eridine consumption, and delayed the time of first
analgesic administration compared with saline controls
group, but the combination did not improve these
results significantly over the intravenous ketamine only
group. Coadministration of midazolam and ketamine
together increased the motor block levels in the first five
minutes, but this difference disappeared in subsequent
measurements. Study drugs did not have an effect on
the maximum motor block and sedation score after
20 minutes.
Midazolam, a benzodiazepine, binds to specific
receptor sites on GABA-A receptor complex (gamma
aminobutyric acid; GABA).1,14 It has been shown that
20% occupancy of a the receptor provides anxiolysis,
with 30–50% occupancy producing sedation.15 It has
292 • akkurt et al.
Figure 1. CONSORT diagram for the patients included to the study.
been suggested that GABA-A receptors in the dorsal
spinal horn are involved in pain transmission16 and that
inhibition of these receptors could reduce pain.2,17,18 Ket-
amine has been used as an analgesic for more than 3
years, but much of the knowledge about pharmacologi-
cal analgesic effects of ketamine are based on recent
studies.
Sajedi et al.19 have suggested that coadministration of
epidural midazolam with lidocaine could prolong the
durations of sensory and motor blocks of lidocaine in a
single administration. We also compared TSRT, postop-
erative motor and sensory block, and maximum motor
and sensory block. Despite nonneuraxial administra-
tion, significant differences in sensory block in the first
15 minutes after spinal anesthesia and motor block
within the first 10 minutes after spinal anesthesia in
ketamine+midazolam group were noted compared with
the ketamine group. TSRT and maximum sensory and
motor block did not differ significantly between these
two groups, but were significantly altered when these
groups were compared with the saline group. It is pos-
sible that this effect on TSRT might have been attributed
to or confounded by the higher sedation scores in the
two groups.
The effect of intravenous administration of mida-
zolam with ketamine specifically on spinal block has not
 Effects of Ketamine and Midazolam on Postoperative Pain • 293

Table 2. Hemodynamic Data (mean 1 SD) 4.5

4
Group I Group II Group III
(n = 20) (n = 20) (n = 20) 3.5

Before spinal block 3

SBP: mm Hg 143 1 16 144 1 17 141 1 22 VAS 2.5
DBP: mm Hg 93 1 8 89 1 13 85 1 11
HR: beat/min. 83 1 14 79 1 9 80 1 13 2
5 min. after spinal block
SBP: mm Hg 139 1 13 147 1 19 139 1 22 1.5
DBP: mm Hg 86 1 8 86 1 15 83 1 9 1
HR: beat/min. 90 1 12 85 1 8 85 1 16
10 min. after spinal block 0.5
SBP: mm Hg 135 1 12 138 1 21 135 1 15
0
DBP: mm Hg 82 1 8 82 1 12 80 1 9 3 4 5 6 48
HR: beat/min. 85 1 12 79 1 10 81 1 14
15 min. after spinal block Time after operation (h)
SBP: mm Hg 135 1 11 139 1 19 132 1 13
Ketamine Ketamine-Midazolam Saline
DBP: mm Hg 83 1 10 80 1 14 80 1 8
HR: beat/min. 82 1 12 76 1 10 77 1 13
30 min. after spinal block Figure 2. Visual Analog Scale (VAS) scores.
SBP: mm Hg 130 1 9 128 1 17 126 1 13
DBP: mm Hg 83 1 8 75 1 15 75 1 8
HR: beat/min. 79 1 12 69 1 8 73 1 11
45 min. after spinal block 200
SBP: mm Hg 129 1 6 126 1 21 124 1 8
DBP: mm Hg 80 1 7 76 1 12 75 1 6
HR: beat/min. 79 1 7 71 1 9 71 1 11

HR, heart rate; SBP, systolic blood pressure; DBP, diastolic blood pressure. 150

Table 3. Motor Block, Sensory Block Levels and

Sedation Scores at 5 minutes and Patient Satisfaction 100
(mean 1 SD)

Group I Group II Group III

(n = 20) (n = 20) (n = 20)
50
Sensory block (min. 5) 7.30 1 2.36 9.60 1 0.82 10.2 1 0.44*
Sensory block (min. 10) 6.20 1 1.93 8.4 1 1.23 9.55 1 0.94
Motor block (min. 5) 1.70 1 0.73* 2.35 1 0.81 2.60 1 0.68
Motor block (min. 10) 2.50 1 0.60 2.85 1 0.36 2.80 1 0.61
Maximum Motor Block 5.2 1 1.19 6.5 1 1.57 8.60 1 1.14 0
Sedation scale (5 minutes) 0.00 1 0.00* 0.85 1 0.48 1.65 1 0.74 Ketamine Ketamine-Midazolam Saline
Patient satisfaction (24 hours) 1.65 1 0.58* 2.15 1 0.48 2.40 1 0.50
Figure 3. Time to first analgesic administration (minutes).
* P < 0.05.

Table 4. Two Segment Regression Time (TSRT), Total effect of midazolam.21–23 Although statistically not sig-
Meperidine Consumption, Time to First Additional nificant in the current study, the sensory and motor
Analgesic Administration blocks were intensified in the ketamine + midazolam
Group I Group II Group III
group. Whether this effect is a result of sedation or is
attributed to direct effect of intravenous midazolam is
TSRT (min.) 40 1 6 48 1 7 43 1 7
Total meperidine consumption (mg) 36 1 11 22 1 6 20 1 4
not known. However, it is unlikely that intravenous low
First analgesic (min.) 136 1 40 198 1 21 198 1 21 dose midazolam would have such an effect. Additional
study is warranted.
The effect of coadministration of intravenous mida-
zolam and ketamine in epidural anesthesia has been
been studied before, but it has been previously shown studied previously.1 Wang and colleagues reported that
that increased sedation has been associated with high preoperative epidural coadministration of low dose ket-
spinal block20 It has also been demonstrated that high amine with midazolam was more effective in relieving
spinal anesthesia increased sensitivity to the sedative postoperative pain than ketamine alone. In our study
294 • akkurt et al.
intravenous coadministration of ketamine and mida-
zolam did not provide significant reduction in total mep-
eridine consumption or lower VAS scores for pain when
compared with ketamine alone. On the other hand,
when these groups were compared with the control
group, we found statistically significant difference for
both groups.
Intravenous administration of ketamine has been
shown to improve postoperative pain after epidural
anesthesia and spinal anesthesia.11,12 Kararmaz et al.
studied the effect of intraoperative intravenous ket-
amine in renal surgery and found that postoperative
analgesia was more effective when central sensitization
were blocked by a combination of epidural morphine/
bupivacaine and intravenous ketamine.11 Hazama et al.
reported that preincisional administration of intrave-
nous ketamine reduced the postoperative pain in
patients undergoing abdominal hysterectomy.24 One
study using both intravenous ketamine and benzodiaz-
epine in spinal anesthesia was performed by Tripathi
et al. They concluded that low dose of ketamine in
combination with diazepam significantly improves
quality of anesthesia, gives better cardiovascular stabil-
ity without a significant increase in complication rate
and significantly improves patient satisfaction. In their
study, patients were divided into two groups. Group I
received only intravenous diazepam while group two
received combination of diazepam and ketamine.
However, in the mentioned study, it was not clear
whether the favorable results in the ketamine group
could be attributed to ketamine or to the combination of
the two drugs. Thus in the present study we aimed to
investigate whether coadministration of midazolam
improved the effects of ketamine. Contrary to the study
of Tripathi et al., our results suggest that the favorable
effects in the ketamine and midazolam group can be
attributed to ketamine and that coadministration of
midazolam with ketamine did not improve the results
significantly.
There have been a number of studies concerning the
effect of intrathecal ketamine on postoperative pain.4,7–
10,25–32 The results of these studies have been conflicting.
Hawskworth et al.33 studied the effect of intrathecal
ketamine on patients undergoing transurethral prostate
resection. The study was abandoned because of the high
incidence of side effects and 6 of the 10 patients
included in the study required general anesthesia. Wong
et al., on the other hand, suggested that addition of
ketamine to morphine significantly reduced the pain in
patients undergoing total knee replacement.6 A meta-
analysis performed by Ong et al.34 concluded that sys-
temic administration of NMDA receptor blockers
provided the least efficacy in preemptive analgesia.
To our knowledge, our study has been the first to
assess the effect of intravenous ketamine and ketamine +
midazolam combination on sensory motor block and
postoperative pain in spinal anesthesia. However, future
studies are required to make more precise and definitive
conclusions.
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