1. Introduction
Intrathecal local anesthetics with or without adjuvants are commonly used for
elective cesarean section. Many drugs such as opioids, neostigmine,
adrenergic agonists, ketamine, midazolam have been used as
adjuvants to local anesthetics in ordertoimprove the quality of spinal
anesthesia. Dexmedetomidine is eight times more specific and highly selective
agonist than clonidine. Dexmedetomidine is metabolized in the
liver and has a distribution half-life of 6 to 8 min. It is highly lipophilic and
has, therefore, a high volume of distribution. When used intravenously,
dexmedetomidine produces sedation with preserved respiratory drive. Both
clonidine and dexmedetomidine have been extensively studied as adjuvants to spinal
local anesthetics, but trials in the obstetric population are scarce, due to the
demanding nature of obstetric anesthesia [1, 2].
This prospective, double blinded, randomized study explored whether intrathecal
dexmedetomidine as adjuvant to ropivacaine 0.75% provided improved quality of
anesthesia for cesarean section when compared to fentanyl. The primary outcome of
this study was the duration of motor and sensory block. Secondary outcomes
included neonatal Apgar scores in the first and fifth minute, additional
postoperative analgesia, time to first postoperative analgesic dose and maternal
satisfaction of overall anesthesia and analgesia.
2. Materials and methods
The regional Ethics Committee approved the study. Oral and written informed
consent was obtained from all the patients. The study was carried out in
accordance with the principles of the Helsinki Declarations.
Healthy parturients (ASA II), 37 weeks of gestation, scheduled for elective
Cesarean section, under combined spinal epidural anesthesia were included.
Exclusion criteria were: pre-eclampsia, eclampsia, Body Mass Index (BMI) 40,
age 18 years, height 150 cm or height 180 cm, gestational diabetes,
known cardiovascular disease of the mother, contraindication to neuraxial
blockade. Enrolled patients were excluded from the study if spinal anesthesia was
unsuccessful, if they had prolonged surgery 90 min or an estimated blood loss
more than 500 mL. They were also excluded if they required second operation for
postpartum hemorrhage.
The trial was performed from 2015 to 2018 as a single-center, prospective,
randomized, double blind controlled study. Sample size was calculated using
G*Power version 3.1.9.7 (Faul F. University of Kiel, Kiel, Germany) and the
following parameters: number of groups: 2, number of measurements: 9, correlation
among repeated measures = 0.5, non-sphericity correction = 1, error
= 0.01, partial = 0.06, power = 99%). Minimum sample
size per group was 20. The research staff (three Anesthesiologists with 10
years of experience in Obstetric Anesthesia) who enrolled the women and collected
study data were blinded to group assignment. Group assignment was done at the
time of enrolment by choosing an opaque serially numbered envelope. An
independent Anesthesiologist, who was blinded to the injected drug, recorded all
the parameters. The Obstetricians/Gynecologists were also blinded to anesthesia
technique.
Forty-six parturients were randomly assigned to two groups of 23.
Computer-generated random numbers were used for randomization of subjects.
Parturients received 1.6–2.0 mL intrathecal ropivacaine 0.75%
(Naropeine®, Astra Zeneca, Athens, Greece) plus 10 g
fentanyl (Group F) or 1.6–2.0 mL intrathecal ropivacaine 0.75% plus 10
g dexmedetomidine (Dexdor® 100 g/mL, Orion Pharma
Ltd, Reading, United Kingdom) (Group D). Ropivacaine doses were decided at the
anesthesiologists’ judgement and the dose was based on the parturients’ height.
Dexmedetomidine dose was decided after a small pilot study which was based on
recent literature [3].
All women eligible for the study were preloaded with 15 mL/kg Ringer’s Lactate
solution intravenously prior to spinal anesthesia and 500 mL hydroxyethyl starch
(Voluven®, Fresenius Kabi Hellas, Athens, Greece) according to
institutional guidelines. They were also pretreated with 4 mg intravenous
ondasetron. No other analgesic or sedative agent was used during surgery. Basic
monitoring probes (electrocardiography, non-invasive blood pressure, O
saturation) were applied. The parturients were placed in the lateral decubitus
position and the epidural space was identified at the L to L interspace. After lumbar puncture with a 26-gauge pencil-point needle, the
intrathecal drug was administered. The epidural catheter was placed as soon as
the spinal needle was withdrawn and the parturients were immediately positioned
supine with left lateral tilt. The operation started when the sensory block
reached T dermatome as determined by loss of sensation to pinprick.
Vital signs were continuously monitored but recorded as baseline, 1 min
intervals until the fifth minute (starting from the administration of the
intrarthecal drug) and every ten minutes thereafter until the end of the
procedure. Vital signs were continuously recorded; only important anesthetic
timepoints have been included in Table 1, as all women remained practically
hemodynamically stable after 25 min of intrathecal drug administration. Mean
duration sensory block was recorded on regression to T, by evaluating
warm/cold sensation. Motor block was assessed using the Bromage Scale (1: unable
to remove feet or knees, 2: able to move feet only, 3: just able to move knees,
4: full flexion of knees and feet). Times from administration of the intrathecal
drug to maximum motor blockade were recorded and mean duration of motor block
overall was assessed by regression to Bromage 3. Hypotension (a decrease in
systolic blood pressure of more than 30% from the baseline or a decrease below
90 mmHg) was treated with 10 to 15 mg ephedrine and bradycardia (heart rate 60
beats per minute) was treated with 0.5 mg atropine. The Apgar scores were
evaluated at 1 and 5 min after delivery. Women’s satisfaction of the
anesthetic/analgesic technique was also evaluated on the first postoperative day
by a simple scale ranging from 0 (not satisfied at all) to 10 (very satisfied).
Time to first postoperative analgesic administration was recorded and included
paracetamol 500 mg t.i.d and subcutaneous morphine (1 mg/kg, according to ideal
body weight) b.i.d.
Table 1.Variability of mean arterial pressure and heart rate between
groups and time of first administration of analgesia.
|
Group |
Group F |
Group D |
Mean |
Standard deviation |
Mean |
Standard deviation |
Mean Arterial Pressure 1’ (mmHg) |
81.70 |
6.91 |
72.35 |
12.69 |
Mean Arterial Pressure 5’ (mmHg) |
80.85 |
5.82 |
78.90 |
5.68 |
Mean Arterial Pressure 15’ (mmHg) |
81.90 |
7.52 |
110.95 |
156.53 |
Mean Arterial Pressure 25’ (mmHg) |
75.10 |
9.19 |
73.10 |
11.12 |
Heart Rate 1’ (bpm) |
97.50 |
16.40 |
91.25 |
17.90 |
Heart Rate 5’ (bpm) |
94.35 |
17.25 |
86.75 |
14.39 |
Heart Rate 15’ (bpm) |
100.35 |
19.37 |
85.25 |
12.36 |
Heart Rate 25’ (bpm) |
100.95 |
12.31 |
92.95 |
26.62 |
1st administration of analgesia (min) |
382.50 |
192.94 |
501.05 |
352.60 |
Bpm, beats per minute. |
Statistical analysis was performed using SPSS Software version 25 (IBM Corp,
Armonk, NY, USA). The continuous variables were expressed in the form of mean
value and standard deviation, while the discrete ones in frequency and relative
frequency (%). The “Repeated Measures ANOVA” (RM-ANOVA) method was used to
compare the variability of the studied variables with the univariate approach.
The Two Independent Samples T-Test or the Mann-Withney Test (in case of
violation of the assumptions of the parametric statistical criterion) was used to
compare the mean values of two independent continuous variables. The Chi Square
Test was used to test the relationship between two categorical variables. The
significance level was set at 5%.
3. Results
Of the 46 parturients, six were excluded from the study. Two were in Group F:
both of them received additional local anesthetic via the epidural catheter due
to insufficient anesthesia. Four were in Group D: two underwent second operation
for postpartum hemorrhage, one underwent myomectomy (uterine fibroids were a
random intra-operative finding) in addition to cesarean section and in one there
was no aspiration of cerebrospinal fluid. Forty parturients completed the study
(Fig. 1).
Fig. 1.
Flow-chart of patient population. CBF, cerebrospinal
fluid.
There were no significant differences among groups in demographic data (Fig. 2),
clinical characteristics and duration of surgery (p 0.05). Mean
duration of motor block was significantly higher in Group D than in Group F
(163.75 min versus 124.75 min respectively, p = 0.013) (Fig. 3).
Regression of the sensory block to T was significantly prolonged for Group
D (158.50 min Group D versus 114.25 min in Group F, p = 0.021) (Fig. 4).
Fig. 2.
Age and BMI (Body Mass Index) of the groups.
Fig. 3.
Mean duration of motor block (min) of Groups F, D.
Fig. 4.
Mean duration of sensory block (min) of Groups F, D.
Regarding hemodynamic variables measured during the intra-operative period,
there were no significant differences between groups (Table 1). Additionally,
there were no statistically significant differences in neonatal Apgar scores
(first and fifth minute), need for additional postoperative analgesia and
maternal satisfaction of overall anesthesia/analgesia procedure (Figs. 5,6,7,8,9).
Mean time to first postoperative analgesic dose was 382.5 min for Group F and 501
min for Group D; although prolonged for Group D, time did not statistically
differ from Group F (p = 0.21, Table 1, Fig. 8). No significant
difference in the onset of anesthesia or in the highest level of sensory block
was observed.
Fig. 5.
Apgar scores 1’ of neonates of Groups F, D.
Fig. 6.
Apgar scores 5’ of neonates of Groups F, D.
Fig. 7.
Additional postoperative analgesia for Groups F, D.
Fig. 8.
Time to first postoperative analgesic dose in minutes
for Groups F, D.
Fig. 9.
Maternal satisfaction of overall anesthesia/analgesia
process for Groups F, D.
4. Discussion
To our knowledge, this is the first study assessing the efficacy of
dexmedetomidine as adjuvant to ropivacaine for elective cesarean sections. Gupta
et al. [4] found that 5 g of intrathecal dexmedetomidine as
adjuvant to bupivacaine, is associated with prolonged motor and sensory block,
hemodynamic stability and reduced demand for rescue analgesics in 24 hours as
compared to fentanyl. Similarly, in the present study, time to first
postoperative analgesic dose was prolonged for parturients that received
dexmedetomidine, but not in a statistically significant way (p = 0.291).
Both Qi et al. [5] and Kamal et al. [6] concluded that
dexmedetomidine prolonged sensory and motor block without significantly
increasing side effects. The present study is in accordance with their results.
Mean duration of motor and sensory block was prolonged for women in Group D
(163.75 and 158.5 min respectively). Motor and sensory blockade was prolonged for
women who received intrathecal dexmedetomidine; these were the only results of
the present study that met statistically significant levels (p = 0.013
and p = 0.021 respectively/Figs. 3,4). Dexmedetomidine has been found
to be safe for the neonates when administered intrathecally [7]. Its safety has
also been demonstrated even when administered in larger doses [8, 9] (e.g., as
intravenous continuous infusions along with remifentanil or fentanyl for labor).
In the present study, Apgar scores did not differ between the groups; however,
the results fell short of meeting the statistically significant p value
of 0.05.
Only a few studies with dexmedetomidine as adjuvant to local anesthetics for
cesarean sections have been published so far [2, 4, 5, 6]. In some countries the
intrathecal use of dexmedetomidine for obstetric anesthesia is still off-label.
The usual dose of intrathecal dexmedetomidine, in these studies, was 5 g
and the local anesthetic used was bupivacaine 0.5%. Only Sun et al. [2]
administered 10 g of intrathecal dexmedetomidine as adjuvant to
bupivacaine. Similarly to the above-mentioned studies, the addition of 10
g of intrathecal dexmedetomidine significantly prolonged the mean duration
of sensory and motor block. It appears however that ropivacaine 0.75% has a more
favourable profile for the parturient when combined with dexmedetomidine.
Although in accordance with the results published by Qi et al. [5] and
Kamalet al. [6], as far as sensory block prolongation with
dexmedetomidine is concerned, it should be noted that in our study, sensory block
lasted fewer minutes. Similarly, mean duration of motor block was shorter for the
dexmedetomidine-ropivacaine group (163.75 min) when compared to
dexmedetomidine-bupivacaine groups (e.g., motor regression time of 226
40.51 min by Qi et al. [5], 265.42 min by Kamal et al. [6]).
In the present study, it is also worth mentioning that the addition of 10
g of intrathecal dexmedetomidine was not associated with remarkable
adverse effects (or hemodynamic instability. This is illustrated by the Apgar
scores and the positive feedback we received from women when asked of their
experience regarding anesthesia/analgesia. Mean time to first administration of
postoperative analgesic dose was 501.05 352.60 min; significantly longer
than times reported by previous authors.
The present study has several limitations: there is no control group and the
dose of ropivacaine 0.75% ranged from 1.6–2 mL according to the decision of the
anesthesiologist involved. As the child-bearing age advances in Europe, further
studies are needed to ensure the safety and efficacy of dexmedetomidine as
adjuvant to local anesthetic, in parturients with co-existing disease such as:
hypertension, pre-eclampsia, eclampsia and complex neurologic syndromes.
5. Conclusions
In conlusion, it appears that the addition of 10 g of dexmedetomidine to
1.6–2 mL of ropivacaine 0.75% significantly prolongs the mean duration of
sensory and motor block in elective cesarean sections. Patients on
dexmedetomidine remained pain-free longer postoperatively. Given the hemodynamic
stability and the lack of adverse effects in the parturient, 10 g of
additional dexmedetomidine intrathecally might be useful in cases where, further
surgical manipulations are about to take place during the cesarean section, such
as tubal ligation or excision of uterine fibroids.
Abbreviations
t.i.d, three times daily; b.i.d, twice daily.
Author contributions
AT and AM conceived and designed the project. TM and KT did the data collection,
data analysis and interpretation, ATG drafted the article and performed its
critical revision. All authors approved the final version of the manuscript to be
published.
Ethics approval and consent to participate
Ethics approval was obtained from Aretaieion University Hospital Ethics
Committee (approval no 17896). Oral and written consent was obtained from all
patients and is kept in their medical records.
Acknowledgment
Not applicable.
Funding
This research received no external funding.
Conflict of interest
The authors declare no conflict of interest.