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Using dexamethasone as an adjuvant to levobupivacaine in epidural anesthesia to change the pain intensity and duration in painless labor

Background and Objective: This is a randomized controlled trial aiming at comparing the effectiveness of levobupivacaine alone versus a levobupivacaine with dexamethasone in the epidural injection for painless labor. Patients and Methods: This is a comparative randomized controlled double-blinded clinical trial with 49 patients were included in this study, all of them were primigravidas and were during vaginal delivery with a cervical dilatation ≥4 cm. Patients were included randomly in one of two groups either Group C (26 cases) with epidural levobupivacaine 0.125% in normal saline or Group D (23 cases) with epidural levobupivacaine 0.125% in normal saline combined with dexamethasone 8 mg. The duration of a second dose request, total dose given, neonatal outcome and adverse effects of epidural were recorded. Results: Group D showed a longer duration of analgesia than Group C (80.5 ± 12.39 min in Group D vs. 61.75 ± 10.74 min in Group C) with a P < 0.05 (0.001). Furthermore, the patients in Group D received smaller dose of levobupivacaine than those in Group C with a statistically significant difference (90.87 ± 33.42 vs. 127.21 ± 40.68 mg with P = 0.002). There were no statistical differences between the two groups regarding hemodynamics, pain score, neonatal outcome, and complications. Conclusion: Dexamethasone in epidural analgesia for painless labor has a prolonged duration of analgesia with no complications for both the mother and the infant.


Introduction
Labor pain is one of the most painful situations in female life. It is considered to be more painful than cancer pain and as painful as amputation of a digit without anesthesia. [1] The increased knowledge of physiology and pharmacology nowadays greatly controls this type of pain and improves the quality of labor hours. [2] Different techniques were applied such as intravenous (IV) opioids, inhaled anesthetics, neuroaxial analgesia, and even alternative medicine (for instance: acupuncture and transcutaneous electrical nerve stimulation). However, each one of the above techniques has its own limitations that restrict its use as a standard single and optimum method for pain relief. [3] There is a claim that epidural analgesia will prolong the labor duration. However, there is a recent research that found that pain relief will cause normal labor course if there is a pain relief without interruption. [4] Moreover, studies concluded Using dexamethasone as an adjuvant to levobupivacaine in epidural anesthesia to change the pain intensity and duration in painless labor This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

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How to cite this article: Ali HM, Wahdan A. Using dexamethasone as an adjuvant to levobupivacaine in epidural anesthesia to change the pain intensity and duration in painless labor. Saudi J Anaesth 2018; 12:209-14. Saudi Journal of Anesthesia / Volume 12 / Issue 2 / April-June 2018 that using 0.125% levobupivacaine in epidural during labor will cause significant labor pain relief with fewer incidences of complications than conventional bupivacaine with less cardiac and neurotoxic adverse effects. [5][6][7] However, the practitioners still looking for a safe medication with prolonged duration to be used in painless labor in obstetric anesthesia practice. Over the last two decades, there were many modifications in regional anesthesia technique to achieve this target, with the advent of several newer and safer local anesthetic agents.
Dexamethasone was proven to be very effective in prolonging the duration of peripheral nerve blocks. Likewise, it improves the quality of the sensory block. [8] The mechanism of action is by decreasing inflammation, delaying impulses in C-fibers, and stopping the ectopic nerve discharge of the nerves. [9] Moreover, these effects have shown a great safety profile with no reported complications. [10][11][12] This study hypothesizes that adding dexamethasone to the levobupivacaine injected in the epidural catheter during painless labor will augment the analgesic effect of levobupivacaine regarding both quality and quantity. Furthermore, it will neither increase the time to delivery nor the fetal outcome.

Patients and Methods
After approval of the local ethical committee of the Cairo University, faculty of medicine ((N-39-2015) and clinical trial registration (NCTR: 02665936), thorough and detailed explanation to the patients and signing consents, 49 patients were recruited in this parallel prospective double-blinded controlled trial. The study was conducted in the Obstetrics Department in the Cairo university teaching hospital in the period between first of January 2015 to last of March 2016. The inclusion criteria were patients aging between 21 and 35 years of age scheduled for normal vaginal delivery, with cervical dilatation 4 cm or more, and American Society of Anesthesiologists (ASA) II. Exclusion criteria were patient refusal, history of allergy to any medications to be used, coagulopathy, ASA III or more and spine deformity or any other contraindications to neuroaxial blocks. Effacement was assessed but neither included in inclusion nor exclusion criteria.
Any patients after assignment experienced failed epidural, fetal distress, shift to cesarean section (whatever the course) were considered a dropout. Patients were assigned either to Group C or Group D randomly using a closed envelope technique. All patients who were included were connected to routine monitors (noninvasive blood pressure, pulse oximetry, electrocardiography, and cardiotocography), a venous access was inserted and a coload of lactated Ringer in a volume of 15 ml/kg was given over 20 min. In a sitting position and after all aseptic precautions and thorough sterilization, skin was infiltrated by 2% lidocaine at the L2/L3 or L3/L4 intervertebral space then 17-gauge epidural needle (Perifix ® , Braun, Germany) was advanced using loss of resistance to reach the epidural space (either median or Para-median), the catheter (19-gauge) was then introduced 3-5 cm in the epidural space, the needle then was removed and the catheter was fixed over the patient's back. There was no preference regarding the patient position, site of the needle, the level of the needle, the direction of the needle, or the method that was used to identify the epidural space (saline or air). Before injecting the test dose (3 ml of lidocaine 1%), the catheter was aspirated to roll out blood or cerebrospinal fluid. The patient was asked to lay supine with 15° tilt to the left to avoid aortocaval syndrome. The blood pressure and heart rate (HR) were then measured every 5 min for 20 min and ten every 15 min till the delivery.
Epidural levobupivacaine 0.125% (Chirocaine ® 2.5 mg/ml Abbott) in normal saline in a total volume 15 ml was injected in Group C in 5 ml increments every 5 min, while epidural levobupivacaine 0.125% (Chirocaine ® ) in normal saline combined with dexamethasone 8 mg in a total volume 15 ml were injected in Group D in 5 ml increments every 5 min. The medications in the syringes were loaded by a pharmacist who was blinded to the study and was checked and marked by anesthetist on the spot who was not blinded to the patients, and then the syringes were endorsed to another anesthetist who was blinded to the patient. And was the one who gave the medications to the patients and follow them up. The patients were monitored for pain and upon her request in case of reappearance of pain (visual analog scale [VAS] more than 4) further dose of 0.125% levobupivacaine was given in a volume of 10 ml over 10 min.
The pain was assessed using VAS from 0 (no pain) to 10 (worst pain). Increments of levobupivacaine were given if the score is ≥4.
The level of sensory block was evaluated by loss of pinprick sensation (20-gauge hypodermic needle). The test is performed every 2 min till loss of discrimination to pinprick and then every 30 min until its full recovery. Time needed for sensory block at the level of T10 was recorded and the highest sensory level as well. Motor blockade is assessed using a modified Bromage scale (0 = no motor block, 1 = hip blocked, 2 = hip and knee blocked, 3 = hip, knee and ankle blocked). Mean arterial blood pressure, HR, and oxygen saturation were evaluated every 5 min during the first 15 min and every 15 min afterward.
Saudi Journal of Anesthesia / Volume 12 / Issue 2 / April-June 2018 The primary outcome was duration of analgesia (calculated from the time of pain relief [VAS <4] to the time to the first top-up dose), secondary outcomes were volume and dose of levobupivacaine till labor, Apgar score in 1 and 5 min, umbilical vein blood gas analysis, and maternal satisfaction score (0 = poor, 1 = fair, 2 = good, and 3 = excellent). [13] The end point of the study was neonate delivery; time to delivery in this study was not measured.
Expected side effects were monitored and recorded such as nausea and vomiting, itching, dizziness, bradycardia or tachycardia, and hypotension. Each of the above was managed accordingly as for bradycardia below 60 beats/min atropine 0.6 mg was given, mean blood pressure <25% from the baseline treated by ephedrine increments of 10 mg, vomiting treated by metoclopramide 10 mg slowly IV.

Sample size
We were planning a study of a continuous response variable from independent control and experimental subjects with 1 control per experimental subject. In previous studies, [14] the response of the patients to pain relief (VAS score) within each subject group was normally distributed with standard deviation (SD) 7.8. If the true difference in the experimental and control means is 7, we will need to study 20 experimental subjects and 20 control subjects to be able to reject the null hypothesis that the population means of the experimental and control groups are equal with probability (power) 0.98. The Type I error probability associated with this test of this null hypothesis is 0.5. A total number of 25 patients in each group were arranged to compensate for possible dropouts. A total number of 50 patients were randomly divided into two groups.

Statistical analysis
It was done using SigmaStat software version 3.1 (Systat Software, Inc., Point Richmond, CA, USA). Patients and obstetric data were collected and presented as the mean ± SD or median (range). The analysis was carried out using the unpaired Student's t-test for comparison of data between the two groups and with Chi-square tests for dichotomous data. P < 0.05 was considered statistically significant.

Results
Seventy-two patients were assessed for eligibility in delivery ward in Cairo university teaching hospital from first of January 2015 to last of March 2016, 13 were excluded because of patient's refusal or falling under the exclusion criteria [ Figure 1]. 10 cases were dropped out because of failed epidural or shifted to cesarean section whatever the causes the remained cases were assigned randomly to Group C (23 cases) and Group D (26 cases). No statistical differences were noticed regarding demographic data between the two groups (the patient age, body mass index, gestational age cervical dilation before analgesia, and the cervical effacement) [ Table 1].
There was a statistical difference between both groups regarding the mean duration of analgesia after the first bolus and the total dose given all through the course of delivery with P < 0.05. It was 80.5 ± 12.39 min and 90.87 ± 33.42 mg in Group D versus 61.75 ± 10.74 min and 127.21 ± 40.68 mg in Group C. This shows that adding dexamethasone not only increases the duration of the analgesia of the loading dose but also decreases the dose of the levobupivacaine over the duration of the labor [   cases (8.69%) in Group D. Moreover, shivering was recorded in three cases (11.53%) in Group C and only one case (4.34%) in Group D. The complications in both groups were mild, tolerable, and did not need any medications, only were treated with reassurance [ Table 6].
In both groups, maternal satisfaction was achieved in all patients with no major complaints.
Vital signs in both groups (blood pressure, HR, and oxygen saturation) showed no statistical differences [ Figures 2-4].

Discussion
This study shows that adding dexamethasone to levobupivacaine in painless labor prolongs the analgesics duration and reduces the total levobupivacaine dose. Moreover, it showed a safety profile for both the mother There was no statistical difference between the two groups regarding the VAS before and after the epidural activation. Furthermore, no differences recorded regarding the highest level of the block.
Likewise, there were no differences between both groups neither in duration to reach the level of the T10 level or the duration to reach the highest level of the blockade. Moreover, both groups achieved almost the same highest level to be blocked [Tables 3 and 4].
Neonatal outcome was fair and showed no statistical differences regarding both Apgar score and fetal pH with excellent results [ Table 5].
The complications that were recorded were few in the form of nausea was recorded in four cases (15.38%) in Group C and three cases (13.04) in Group D, while vomiting was recorded in three cases (11.53%) in Group C and two Table 3: Visual analog score Group C Group D P Before the block 5 (6-9) 6 (6-9) 0.01 After the block Data are presented as median (range). † Statistically significant lower compared to before the block (P<0.05). Group C: Levobupivacaine 0.125%; Group D: Levobupivacaine 0.125% with dexamethasone 8 mg Data are presented as mean±SD. *Statistically significant higher compared to levopubivacaine Group C (P<0.05). Group C: Levobupivacaine 0.125%; Group D: Levobupivacaine 0.125% with dexamethasone 8 mg; SD: Standard deviation  and infant with infrequent and mild side effects that related conventionally to the procedure and not the added medications.
Several additives were tried to prolong the duration of local anesthetics and decrease the local anesthetics volume to achieve a better safety profile such as clonidine verapamil and dexmedetomidine. [15][16][17] Dexamethasone is an attractive choice because of it is efficacy, safety, familiarity, and low cost. The mode of action and molecular explanation are not clear. However, it showed a reliable effect when used perineural and intravenously. [18] Some authors claimed that the mechanism is related to its anti-inflammatory effect that blocks the transmission of nerve impulse in C-fibers by stopping the ectopic discharge of the nerves. [19] The reversibility of the dexamethasone action can raise the possible idea of membrane stabilization by modifications in potassium channels. [20] There is a great debate regarding the proper dose of dexamethasone for postoperative analgesia, and till now, there are no clear recommendations regarding this issue. In this study, the dose that was used was 8 mg as we considered that the dose in the epidural catheter, for any medication, usually is like the IV one. That is why we used 8 mg. the smaller dose may be ineffective; however, it needs further study and research. The results that were concluded in this study was agreed by Khafagy et al. [21] who tested dexamethasone versus fentanyl through epidural route regarding their effects as an adjuvant to local. However, the study was conducted on ninety patients underwent lower abdomen surgeries and not painless labor. Moreover, the dose of dexamethasone was 4 mg and fentanyl dose was 50 micrograms. The results showed favored response for both medications regarding their effect on postoperative analgesia and duration. Thomas et al. tested dexamethasone 5 mg with or without bupivacaine epidurally in patients having cholecystectomy and surprisingly found that dexamethasone has decreased postoperative pain either alone or with bupivacaine. [22] another study that tested dexamethasone through epidural route, but this time caudally, in pediatric patients, found the same results. However, further research is needed to create a formula regarding age, body weight, and type of surgery to calculate the proper dose of dexamethasone in pediatric patients. [23] Although there were many reviews and meta-analysis focused on the studies that were done regarding adjuvant injected in local nerve blocks, there is no meta-analysis or review that is focusing on the adjuvant used through epidural route. [24] On the other hand, some authors failed to find a prolonged analgesic effect of steroids postoperatively through epidural route. [25][26][27] One of them used methylprednisolone as an additive to bupivacaine for pain relief after lumbar discectomy and found no differences between it and bupivacaine alone. [25] Another one changed the route and made it through intrathecal route and found that it is not effective in analgesics duration. [26] Finally, there were no harms recorded in this study regarding the neonatal outcome, this result emphasized by the meta-analysis that was done on seven randomized controlled studies focused on the concentrations of epidural opioids and the neonatal outcome and found a favorable outcome. [28] There is a limitation in this study in the fact that it only tested one dose (8 mg) of dexamethasone and not different doses. Furthermore, it tested single shot over the whole procedure and not multiple shots. Moreover, time to delivery was not calculated because it was difficult to assess the start point of delivery. These points need further research and investigations.

Conclusion
In conclusion, dexamethasone in a dose of 8 mg as an additive to levobupivacaine through epidural route in painless labor will prolong the analgesic duration of levobupivacaine and decrease its dosage.
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Conflicts of interest
There are no conflicts of interest.