Low Dose Hyperbaric Bupivacaine and Dexmedetomidine as an Adjuvant in Spinal Anaesthesia, Caesarean Section: A Randomized Controlled Trial

analgesic


Abstract
Background Alpha-2 agonist, e.g. dexmedetomidine, is a non-opioid adjuvant with a substantial role in extending the analgesic duration of the subarachnoid block. Here, we aim to test the e cacy of adding dexmedetomidine to hyperbaric bupivacaine in the caesarean delivery, targeting enhanced postoperative analgesia and more stable hemodynamics.
Continuous normally distributed data were expressed as mean and standard deviation. Ordinal data and continuous data not tting to the normal distribution curve were presented as medians (range) meanwhile categorical data were reported as percentage of the total number. Regarding the autonomic variables, we did a strati ed analysis to compare the mean change of these variables every 3 minutes till 60 minutes through a two-sample t-test (Welch t-test). All statistical analyses were performed using R software version 3.4.4 Results LD-DEX groups showed signi cant faster and prolonged sensory block (P-value < 0.05), stable maternal hemodynamic maintained by less amount of IV uids (P-value < 0.01), lower doses of ephedrine (P-value = 0.02), no signs of foetal distress, and low incidence of postoperative maternal shivering. As well, 3 hours cut off pain was more signi cant in LD-DEX group (P-value < 0.01).
Conclusion LD-DEX group provided an optimum intraoperative condition and postoperative analgesia with less maternal side effects and no neonatal risks, encouraging enhanced recovery and less hospital in-stay.

Background
Caesarean section (CS) is a life-saving surgical procedure, categorized as a major surgery that carries a direct twin maternal and perinatal threat with further consequences for later pregnancies. [1,2] There is unavailable crude difference in superiority between general anaesthesia (GA) and regional anaesthesia (RA) as special anaesthetic plans in coping with CS where selection is commonly dependant on anaesthetist's preference and local policy. [3] RA is, however, gaining more preference amongst anaesthetist, with facts from the United Kingdom, for example, showing that RA is utilized in 94.9% and 86.7% of elective and emergent CS, respectively. [4] In RA, the key problems relate to insu cient blockade and induced haemodynamic instability. Different additives have been tested, including opioids, ketamine, midazolam, and α2-agonists, with the aim of improving block quality and providing better postoperative analgesia along with the maintenance of stable haemodynamic during surgery. Consequently, even in the postoperative environment, all need careful supervision and treatment. [5,6] There was a growing interest in obstetric anaesthesia in the use of low-dose (LD) intrathecal hyperbaric bupivacaine "LD Scheme" (< 8 mg) relative to the traditional dose (≥ 8 mg). This is based on the assumption that an increased dose of local anaesthetic (LA) IT injection will lead to a higher level of blockage and, subsequently, to profound sympathectomy-induced hypotension (SIH). Both doses were comparable to the values studied using dose-response curve modeling by logistic regression given an effective dose in 50 percent of the population (ED50) and an effective dose in 95 percent of the population (ED95) respectively. [7,8] Alpha-2 agonists such as clonidine and dexmedetomidine (DEX) are non-opioid adjuvants with a signi cant role in extending the analgesic duration of the subarachnoid block, which reduces the need for postoperative opioid use.. [9][10][11] Several clinical trials have veri ed the analgesic advantages of neuraxial dexmedetomidine in non-obstetric settings. [12,13] While intrathecal (IT) clonidine has been shown to be a useful analgesic supplement for spinal anaesthesia (SA) in patients undergoing CS. [14,15] Animal studies showed a safe pro le for intrathecal injection of dexmedetomidine and no risk for induced neurotoxicity. [16,17] Our research suggested that the use of LD-scheme with hyperbaric bupivacaine and dexmedetomidine as an adjuvant would provide optimum intraoperative surgical conditions, strong postoperative analgesia and more stable hemodynamics.

Methods
This was a prospective double-blind randomized controlled trial (RCT) including 40 parturient women scheduled for elective CS, it was retrospectively registered at clinicaltrial.gov (NCT03775655) also, it gained accreditation from the local ethical committee prior to starting the study and we are adherent to CONSORT statement. Participants were enrolled between September 2018 and January 2019 after obtaining written informed consent.
The study included full-term pregnant women aged 18-35 with singleton gestation and American Society of Anaesthesiologists (ASA) physical status classes I and II, excluding high risk pregnancies, patients with co-morbidities, and height more than 170 cm.

Study Intervention
Patients were given either 7 mg hyperbaric bupivacaine and 10 µg dexmedetomidine (LD-DEX) or 12 mg hyperbaric bupivacaine (Control group). All doses were diluted with saline to a total volume of 2.5 cm in an unlabelled syringe. The study medication was prepared with (A.H.Z) who was not involved in further perioperative care, data gathering or data analysis.

Anaesthetic and Perioperative Management
We standardized the anaesthetic technique for all participants. After an overnight fast, parturient was premedicated with intravenous (IV) ranitidine 50 mg, metoclopramide 10 mg given 30 minutes prior to the scheduled time for CS. Patients was instructed on the use of the Visual Analog Scale (VAS): zero = no pain and 10 = maximal unbearable pain.
Upon arrival to the operating room, Electrocardiogram (ECG), pulse oximetry (SpO 2 ) and non-invasive blood pressure (NIBP) was monitored. IV Lactated Ringer's solution of 500 ml was started, lumbar puncture was performed in the sitting position at the L 3 -L 4 level through a midline/ Para median approach using a 25G Quincke spinal needle preceded with local in ltration with 1 ml of lidocaine 2% using 27G insulin syringe needle. In case of failed block (failure of sensory level to reach T10 level after 15 minutes), conversion to general anaesthesia was done. In cases of inadequate block (sensory level reached higher than T10 level, but traction pain was perceived intra-operatively), fentanyl was administered by IV in incremental doses of 50 µg plus midazolam with maximum dose of 3 mg. With a persisted pain, conversion to general anaesthesia was done.
Hypotension, de ned as a decrease of systolic blood pressure by more than 30% from baseline or a fall below 90 mmHg, will be treated with incremental IV doses of ephedrine 6 mg and additional IV uid as required. Bradycardia, de ned as heart rate < 60 beat per minute (bpm), will be treated with IV atropine 0.5 mg. Postoperatively, patients received 30 mg of IV ketorolac.

Study Outcomes and data collection
The primary outcome was haemodynamic stability and total doses of IV uids and vasopressors, motor block density, the need of post-operative analgesia. Sensory level testing was, then, assessed by loss of pinprick sensation in each dermatomal level at mid-clavicular line every 2 min till the highest level was stabilized for four consecutive tests, every 10 minutes till the point of two segment regression of the block, and every 20 minutes till the recovery of S 1 dermatome. Motor block was, also, assessed using the modi ed Bromage scale [18]. The pain score was recorded initially every 1 h for 2 h, then every 2 h for the next 8 h and then after every 4 h till 24 h. When VAS score was above three, IV meperidine (Pethidine) 1 mg/kg was given as a rescue analgesic. Hemodynamic parameters (NIBP and heart rate (HR)) were recorded every three minutes during the whole operation. The total doses of uids and vasopressors were recorded at the end of operation. The level of sedation was assessed intra and post-operatively using the modi ed Ramsay Sedation Score [19]. The incidence of desaturation during surgery or PACU stay was recorded. However, nasal prongs were provided (Oxygen 2 L/min) when arterial oxygen saturation decreases to < 92%.
The incidence of other adverse effects, such as nausea, vomiting, shivering, pruritus, and respiratory depression was recorded. The Apgar scores of the new-born was assessed at 1 and 5 min after birth. All data were collected blindly by the assistant nurses.

Sample size calculation and statistical analysis
Based on result of Kanazi et al [9], we calculated that 12 patients per group would provide 80% power to detect difference in the time to two segment regression with type I level of 5%. However, to compensate for possible dropouts, additional 40% was added and the nal sample size was 20 patients in each group.
Patient was randomly allocated to either groups LD-DEX group and control group, randomization done electronically.
All durations were calculated considering the time of spinal injection as time zero. Descriptive statistics were made for all variables. Continuous normally distributed data were expressed as mean and standard deviation (SD). Ordinal data and continuous data not tting to the normal distribution curve were presented as medians (range) meanwhile categorical data were reported as percentage of the total number. Regarding the autonomic variables (SBP, DBP, HR), the 2 groups were compared on baseline characteristics to ensure that there was no difference between the compared groups prior to our clinical testing. We then did a strati ed analysis to compare the mean change of these variables every 3 minutes till 60 minutes through a two-sample t-test (Welch t-test). All tests were two-sided with statistical signi cance below 0.05. All statistical analyses were performed using R software version 3.4.4 (R Foundation for Statistical Computing, Vienna, Austria). Our gures were generated using R package "ggplot2" [20].

Results
Two patients were excluded from the control group due to conversion to general anaesthesia, as shown in ow chart Fig. 1. Patients in the two groups didn't show statistical difference regarding baseline characteristics (P -value > 0.05). The mean height, and weight of LD-DEX group was 163.3 (3.8) cm, 70.2 (1.5) kg versus 164.4 (3.3) cm, 68.9 (2.7) kg for control group, respectively. Additionally, the preoperative vital signs of patients were comparable with no statistical signi cance. The mean HR was 102.7 (13.8) bpm versus 100.7 (17.4) bpm in LD -DEX group and control group respectively, while mean arterial pressure (MAP) was 90.2 (11.4) mmHg and 89.1 (13.5) mmHg in both groups respectively. However, the average duration of surgery in LD-DEX group was less than the control group (55.2 (13.3) min. and 65.2 (10.6) min respectively, P-value = 0.02) ( Table 1)

Sensory block and analgesia
Control group demonstrated a shorter time to reach the peak sensory block level -fast onset-and shorter duration of S1 dermatome pain perception and a lower postoperative analgesic effect with about 3-hours cut off pain value -in which VAS scores > 3-(P < 0.05 in all except duration of S1 dermatome pain perception P = 0.06). (Table 2)

Autonomic effects, uids and vasopressors
During sequential follow up of autonomic parameters, there were no signi cant difference between the two groups in the sixty minutes measurements. However, patients in LD-DEX group demonstrated signi cant increase in SBP at 12 minutes (P = 0.035), signi cant increase in DBP at 12 and 18 minutes (P = 0.039, P = 0.011) Fig. 3., and signi cant decrease in HR at 36 and 45 minutes (P = 0.006, P = 0.034).
( Fig. 2-4) More doses of ephedrine 22.6 (16.1) mg and IV uids 2361.1 (287.3) ml (P < 0.05) were used in control group just to maintain hemodynamic pro le of patients close to their preoperative data and LD-DEX group. (Table 2) Side effects and foetal characteristics Control group showed higher incidence of shivering (P < 0.05) than LD-DEX group while both groups showed equal incidence of nausea and vomiting. Traction pain, particularly during exteriorization of uterus was higher but not statistically signi cant in LD-DEX group (P-value = 0.13). All patients showed a sedation score < 2 at every time point with no need for oxygen supplementation all over the operation. In both groups, new-born have no signs of foetal distress, evidenced by Apgar score at 1 min. and 5 min (P > 0.05) ( Table 3).

Discussion
Along the past time, researchers are addressing the optimal conditions of parturient female to provide an optimum intraoperative condition with stable hemodynamic, good postoperative analgesia and early ambulation with minimal maternal and foetal side effects targeting enhanced recovery after CS. According to our results, LD-DEX group showed better sensory block, longer postoperative analgesia, less dense motor block with earlier ambulation, stable maternal hemodynamic maintained by lower amounts uids and ephedrine, and less shivering with no neonatal side effects.
Ginosar et.al., reported ED50 of hyperbaric bupivacaine ranges from 4.8 mg to 9.8 mg and the ED95 ranges from 8.8 mg to 15 mg [8]. Meanwhile we used, throughout our study hyperbaric bupivacaine at dose of 7 mg and 10 µg dexmedetomidine as LD-DEX group versus 12 mg as control group. Dexmedetomidine proved to enhance sensory block and post-operative analgesic effect of IT hyperbaric bupivacaine (P < 0.05 in all except duration of S1 dermatome pain perception P = 0.06). that was supported by other reports in literature. [21][22][23][24] The mechanism of action of dexmedetomidine could be due to binding to pre-synaptic C-bres and post-synaptic dorsal horn neurons which causes decreased release of C-bres neurotransmitters and hyperpolarization of post-synaptic dorsal horn neurons. [25,26] Regarding motor block, our results showed a weak degree of block 2 degree according to modi ed Bromage score [18] which is suitable for that LD of hyperbaric bupivacaine and help early ambulation postoperative and regaining the muscle power which is reported to be 206 (60.9) min. and came parallel to 331 (35) min. that is reported by Shukla et.al., using 15 mg hyperbaric bupivacaine and about 221.1 (1.37) min as reported by Fyneface-Ogan et.al., [27,28] That decreased dose resulted in more stable maternal hemodynamic pro le and subsequently, less IV uids and ephedrine than used for control group to be maintained, which came parallel to what is reported by Al-Mustafa and colleagues [29] and El-lakany [22]. Follow up of BP measurements, there was an initial increase in BP lasting for 12 minutes followed by hypotensive episodes with well response to IV uids and ephedrine. However, that biphasic response had no effect on mean blood pressure which also approved by Kanazi et.al. [30] taking in consideration different populations of reported studies and different doses of hyperbaric bupivacaine that is used which was 12.5 mg, 17.5 mg, respectively and 7 mg in our study. That 12 minute-hypertensive episode would allow a good time for co-loading and delivery of the foetus decreasing episodes of foetal hypoperfusion due to decreased blood pressure.
As well, shivering in LD-DEX group showed a good pro le with incidence of 5% which is much lower (P < 0.05) and came parallel to reports by Abdelhamid and El-lakany [22], Y. Sun et.al., [31] and K. Nasseri et.al., [32] Regarding nausea with or without vomiting there is no difference in incidence and is well corelated to episodes of hypotension and peritoneal traction parallel to outlined by Kang et.al. [33] We encountered several limitations in this study. Firstly, intravenous uid regimen was not standardized during the surgical procedure and was left up to judgement of the attending anaesthesiologist. However, that had no potential impact on our outcomes. The second limitation was the use of lower concentrations of LA. Nonetheless, the dose of LA and not the volume or concentration is the major determining factor in block height and motor block. [34] Finally, sample size was calculated based on two segment regression as the primary outcome which found to be statistically insigni cant, hence, conclusions for others outcomes should be interpreted cautiously.

Conclusion
We conclude that LD-DEX scheme (10 µg dexmedetomidine + 7 mg hyperbaric bupivacaine) is an e cient option for intrathecal injection in patients scheduled for elective caesarean section as it provides better sensory block, more stable maternal hemodynamic with less vasopressors and uids, good postoperative analgesia, early ambulation and less hospital in-stay. Ethics approval and consent to participate An ethical approval was obtained from a local ethical committee with number of 050220181 and a photocopy of the approval is available upon request.

Consent for publication
Not applicable, we do not make it as we will not include any personal data throughout our publication.

Availability of data and materials
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. The sequential changes in SBP measurements represented in mean with 95% con dence interval.  The sequential changes in DBP measurements represented in mean with 95% con dence interval. At 3 min. after SA induction mean DBP was 73.8 in LD-DEX group and 69.9 in control group. After 30 min.
mean DBP was 60.2 in LD-DEX group and 59.1 in control group After 60 min. from induction the mean DBP was 62.1 in LD-DEX group and 63.3 in control group.