Intrathecal local anesthetics with or without adjuvants are commonly used for elective cesarean section. Many drugs such as opioids, neostigmine, $\alpha$${}_2$ adrenergic agonists, ketamine, midazolam have been used as adjuvants to local anesthetics in ordertoimprove the quality of spinal anesthesia. Dexmedetomidine is eight times more specific and highly selective $\alpha$${}_2$ 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.

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 $\epsilon$ = 1, error $\alpha$ = 0.01, partial $\eta$${}^2$ = 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 $\mu$g fentanyl (Group F) or 1.6–2.0 mL intrathecal ropivacaine 0.75% plus 10 $\mu$g dexmedetomidine (Dexdor® 100 $\mu$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${}_2$ saturation) were applied. The parturients were placed in the lateral decubitus position and the epidural space was identified at the L${}_2$ to L${}_3$ 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${}_4$ 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${}_8$, 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.

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%.

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 $\mathrm{>}$ 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${}_8$ 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.

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 $\mu$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 $\mu$g and the local anesthetic used was bupivacaine 0.5%. Only Sun et al. [2] administered 10 $\mu$g of intrathecal dexmedetomidine as adjuvant to bupivacaine. Similarly to the above-mentioned studies, the addition of 10 $\mu$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 $\pm$ 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 $\mu$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 $\pm$ 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.

In conlusion, it appears that the addition of 10 $\mu$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 $\mu$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.

t.i.d, three times daily; b.i.d, twice daily.

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 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.

Not applicable.

This research received no external funding.

The authors declare no conflict of interest.