Comparative Analysis of Duration of Postoperative Analgesia between Levobupivacaine and Levobupivacaine with Clonidine after Ultrasound-Guided Transversus Abdominis Plane Block in Patients Undergoing Lower Segment Cesarean Section.

BACKGROUND: Transversus abdominis plane (TAP) block in cesarean section is carried out by local anesthetics such as bupivacaine or ropivacaine with a limited duration of analgesia. The addition of adjuvants such as clonidine and dexmedetomidine has increased the duration of postoperative analgesia. AIMS SETTINGS AND
DESIGN: The aim of this study was to compare the duration of postoperative analgesia between clonidine and levobupivacaine (0.25%) versus levobupivacaine (0.25%) alone in the bilateral TAP block after lower segment cesarean section (LSCS).
MATERIALS AND METHODS: In this prospective randomized double-blind interventional study, 100 parturients undergoing elective LSCS were included in the study. Patients were randomly divided to receive either 20-ml levobupivacaine 0.25% (Group A; n = 50) or 20-mL levobupivacaine (0.25%) +1-μg/kg clonidine bilaterally (Group B; n = 50) in TAP block in a double-blind fashion. The total duration of analgesia, patient satisfaction score, postoperative visual analog scale score, total requirement of analgesics in the first 24 h, and the side effects of clonidine were observed. STATISTICAL ANALYSIS: Statistical tests were conducted using SPSS. P < 0.05 was considered as statistically significant.
RESULTS: A total of 92 patients were analyzed. Duration of analgesia was significantly longer in Group B (17.94 ± 0.76 h) compared to Group A (7.16 ± 0.41 h) (P < 0.001). Mean consumption of tramadol was 197.77 ± 14.90 mg and 8.889 ± 28.77 mg in Groups A and B (P < 0.001), respectively. All patients in Group B were extremely satisfied while those in Group A were satisfied (P < 0.01). None of the patients experienced hypotension or bradycardia.
CONCLUSION: The addition of clonidine 1 μg/kg to 20-ml levobupivacaine 0.25% in TAP block bilaterally for cesarean section significantly increases the duration of postoperative analgesia, decreases postoperative rescue analgesic requirement, and increases maternal comfort compared to 20 ml of levobupivacaine 0.25% alone.

INTRODUCTION

Cesarean delivery is one of the most commonly performed surgical procedures, and postoperative pain is a great concern for women.[1] Its severity may impair early postoperative maternal rehabilitation and recovery.[2] Opioids and nonsteroidal anti-inflammatory drugs, as components of a multimodal analgesic regimen, are used to achieve effective analgesia. However, both systemic and neuraxial opioid administrations are associated with frequent dose-dependent adverse effects, including nausea, vomiting, pruritus, sedation, respiratory depression, and hyperalgesia,[3] and may be transferred across the breast milk to the baby. Thus, alternatives such as peripheral nerve block or wound infiltration have been suggested. Various trials have demonstrated the efficacy of transversus abdominis plane (TAP) block as a component of multimodal postoperative analgesia after cesarean section[4] and lower abdominal surgeries.[5] TAP block is a regional anesthetic technique that blocks the abdominal wall neural afferents (T7-L1) and significantly reduces the pain associated with lower abdominal surgery. Local anesthetic agents are injected into the neurofascial plane between the internal oblique and transversus abdominis muscle. The block, first described by Rafi in 2001,[6] is a simple and safe technique for analgesia after cesarean section, whether guided by anatomic landmarks or by ultrasound. TAP block in cesarean section is carried out by local anesthetics such as bupivacaine or ropivacaine with a limited duration of action.[7] Levo isomers have less systemic toxicity than the racemic compounds[8] and have frequently been used for TAP block.[14] Additives to local anesthetics such as opioids and ketamine and α2-agonists such as clonidine and dexmedetomidine have been successfully used in peripheral nerve blocks and field blocks to increase the duration of postoperative analgesia.

The present study was planned to investigate whether the addition of 1.0 μg/kg clonidine bilaterally to 0.25% levobupivacaine in TAP block increases the duration of postoperative analgesia in lower uterine segment cesarean section or not compared to 0.25% levobupivacaine alone.

MATERIALS AND METHODS

After the Institutional Ethical Committee approval, this randomized, double-blind controlled trial was conducted in 100 parturients (American Society of Anesthesiologists' physical status Class II) scheduled to undergo elective or no urgent cesarean section (where no fetal or maternal compromise existed) through Pfannenstiel incision under spinal anesthesia (SA). The patients were recruited between November 2017 and June 2018.

Exclusion criteria

Patients who refused SA, had any contraindication to regional anesthesia, history of drug allergy or chronic pain, a coagulation disorder or infection at the needle insertion site, a body mass index of >30 kg/m2, or were unable to communicate were excluded from this study. Patients in whom SA was inadequate for the conduct of surgery were also excluded from the study.

Patients were divided into two equal groups of fifty each to receive either:

Group A (n = 50): TAP block with 20 mL of 0.25% levobupivacaine alone bilaterally

Group B (n = 50): TAP block with 20 mL of 0.25% levobupivacaine + 1.0 μg/kg clonidine bilaterally (total dose – 2.0 μg/kg).

Patients were allocated to the respective groups using a computer-generated random number table. Group allocation report was concealed in sealed, opaque envelopes that were opened in the operating theater just before the administration of SA. The study drug was prepared and coded by an anesthesiologist who not involved in the study. The patient and the anesthesiologist administering the TAP block and involved in data collection were also blinded to group assignment. The code was broken after the completion of the study and statistical analysis. After written informed consent, patients were made familiar with 10-cm visual analog scale (VAS) with 0 representing no pain and 10 representing worst imaginable pain before administering the block. Patients received a standard SA comprising hyperbaric 0.5% bupivacaine (1.8 ml) with 25-μg fentanyl. Bilateral ultrasound-guided TAP blocks were performed under all aseptic precautions, in the lumbar triangle of Petit bilaterally [Figure 1]. Once the surgery was over and the sensory block had receded to T10 level by pinprick, TAP block was given with an S-Nerve™ transportable ultrasound device (SonoSite, Bothell, WA, USA) using a linear array transducer (5–10 MHz) at the level of the anterior axillary line between the 12th rib and the iliac crest. The assigned drug was slowly injected under direct ultrasonographic guidance [Figure 2].

Figure 1

Ultrasound image of transversus abdominis plane. EO: External oblique, IO: Internal oblique, TA: Transversus abdominis

Figure 2

Ultrasound image during the initial injection of a small amount of local anesthetic

After completion of the surgical procedure and block, patients were transferred to the postanesthesia care unit. The duration of postoperative analgesia, defined as the time (in hours) from the giving of the TAP block to the time to the first analgesic request in the postoperative period, was recorded. The degree of pain was observed using the VAS in 2, 4, 6, 8, 12, 18, and 24 h. The time was noted when the patient demanded for the first dose of analgesia. The TAP block was deemed a failure if the patient requested analgesia within the first 2 h of administering the block, and the case was not included in analyses. Patients were given injection tramadol 100 mg slow intravenous (IV) injection on demand or if the VAS score was ≥4. Sedation was evaluated along with VAS using a four-point ordinal scale (1 = wide awake and alert, 2 = awake but drowsy, responding to verbal stimulus, 3 = arousable, responding to physical stimulus, and 4 = not arousable, not responding to physical stimulus). The presence of sedation was defined as a sedation score >1 at any postoperative time point. A four-point patient satisfaction score (1 = extremely satisfied, 2 = satisfied, 3 = dissatisfied, and 4 = extremely dissatisfied) was also noted. Other associated side effects such as dryness of the mouth, hypotension (systolic blood pressure <20% of baseline), nausea, vomiting, and bradycardia (heart rate <50/min) were also observed. A note was made of the total analgesic consumption in the first 24 h after the block. All the observations were made by an anesthesiologist who was unaware of group allocation and blind to the study drug.

The primary outcome measure in this study was duration of postoperative analgesia. The secondary outcome measures included total analgesic consumption in the first 24 h after the block, patient satisfaction, and possible clonidine side effects (dryness of the mouth, sedation, hypotension, and bradycardia).

For the purposes of sample size calculation based on 20 pilot cases done before the study, the duration of analgesia in Group A was 6.5 ± 1.1 h and 12.5 ± 4.5 h in Group B. Sample size calculation based on these data had indicated that at least 25 patients in each group will be required to demonstrate a clinically significant difference (4 h) in the duration of postoperative analgesia with an α = 0.05 and a power of 99%. However, 50 patients were recruited in each trial arm in an attempt to collect data on side effects [Figure 3].

Figure 3

Consort trial diagram

Statistical analysis

The data were compiled, tabulated, and statistically analyzed using SPSS version 24 (IBM, Chicago, IL, USA). Unpaired Student's t-test was used for analysis of the duration of analgesia at the time of administration of injection tramadol. For analysis of nonparametric variables, such as the level of sedation and patient satisfaction score, Mann–Whitney U-test was used. Results were presented as mean ± standard deviation. P < 0.05 has been considered statistically significant.

RESULTS

One hundred patients were enrolled and randomized for the study. Two patients from Group A and one patient from Group B were excluded from the study after randomization due to the conversion to general anesthesia. Baseline clinical characteristics are given in Table 1.

Table 1

Baseline clinical characteristics

Groups were comparable in terms of age, weight, duration of surgery, and body mass index. Intraoperative blood pressure and heart rate were significantly lower in Group B than Group A, but it is in the physiological range. The triangle of Petit was located easily on palpation; the TAP block performed without complication in all patients. The TAP blocks failed in three patients in Group B and in two patients in Group A. These patients were excluded from the analysis. Thus, a total of 46 patients each were analyzed in Groups A and B.

Ninety-two patients were analyzed. Postoperative clinical outcome parameters were compared in Table 2.

Table 2

Postoperative outcome parameters

Duration of analgesia was significantly longer in Group B (17.94 ± 0.76 h) compared to Group A (7.16 ± 0.41 h) (P < 0.001). Mean consumption of tramadol was 197.77 ± 14.90 mg and 8.889 ± 28.77 mg in Groups A and B (P < 0.001), respectively. All patients in Group B were extremely satisfied (P < 0.01) while those in Group A were satisfied. In Group B, 13 (28%) patients were sedated but arousable (P = 0.01) compared to 9 (19.5%) in Group A. In Group B, 19 (42.2%) patients complained of dry mouth compared to 14 (31.1%) in Group A (P = 0. 274). None of the patients experienced hypotension or bradycardia.

DISCUSSION

This randomized, double-blind, controlled trial demonstrated that the addition of clonidine to levobupivacaine in single-shot TAP block for cesarean section under SA prolongs analgesia by 10–12 h and reduces overall postoperative analgesic requirements by more than 190 mg compared to levobupivacaine alone. Although long-acting neuraxial or patient-controlled epidural/IV opioids produce effective analgesia, they are frequently associated with nausea, vomiting, and pruritus, which reduce overall patient satisfaction.[9] In addition, hydrophilic opioids such as morphine may cause delayed maternal respiratory depression due to the rostral spread.[10] The use of neuraxial opioids may be limited by logistic issues and/or the presence of medical contraindications.[1112] Systemically administered lipophilic opioids such as pethidine may be secreted in breast milk and cause transient adverse neurobehavioral effects in the neonate.[13] Given these issues, there is considerable potential for a regional technique such as TAP blockade to provide effective and long-lasting postcesarean section analgesia. Many previous investigators have reported the analgesic benefit of TAP block in patients undergoing a wide variety of lower abdominal surgeries,[45] including cesarean section.[141516] Belavy et al.[14] and McDonnell et al.[15] investigated the effect of TAP block with 0.5% ropivacaine 20 ml bilaterally in patients undergoing cesarean section and reported improved postoperative pain scores, reduced postoperative opioid consumption, and higher patient satisfaction. In a recent study, Eslamian et al. concluded that bilateral TAP block with 0.25% bupivacaine decreases postoperative pain and analgesic consumption with a longer time to the first analgesic rescue.[17] A meta-analysis by Abdallah et al. concluded that TAP block can provide effective analgesia when spinal morphine is contraindicated or not used in patients undergoing lower segment cesarean section under SA.[7] A study by John et al. showed that the TAP block as a part of a multimodal analgesic regimen definitely has a role in providing superior analgesia in the postoperative period. However, adjunct fentanyl to local anesthetic bupivacaine was found to have no added advantage when quality and duration of analgesia were compared.[18]

A meta-analysis of randomized trials has demonstrated that the addition of clonidine to local anesthetics significantly prolongs the duration of the motor block and postoperative analgesia when used for peripheral nerve and plexus blocks.[19] Singh et al. concluded that the addition of clonidine 1 μg/kg to 20-ml bupivacaine 0.25% in TAP block bilaterally for cesarean section provides 17–19 h of postoperative analgesia, decreases postoperative analgesic requirement, and increases maternal comfort compared to 20 ml of bupivacaine 0.25% alone with minimal side effects.[20] The reason for the prolonged effect seen with clonidine is not clear because α2-adrenoreceptors are not present on the axon of the normal peripheral nerve.[21] Laboratory studies have suggested that clonidine exerts an effect directly on the nerve fiber, as a result of a complex interaction between clonidine and axonal inotropic, metabolic, or structure proteins (receptors).[22232425] Another hypothesis that may explain prolonged analgesia with clonidine is the systemic absorption of the drug from TAP.[26]

This may explain sedation in 13 of the 46 patients in this group. Furthermore, many were delivered at odd hours in the night. Although the patients were drowsy, they were responding to verbal commands and were able to breastfeed the babies. Thus, even with the use of clonidine, sedation did not in any way pose a clinical problem. Long hours of fasting and prolonged labor pains may have also contributed to dryness of the mouth, which was comparable in the two groups. However, other systemic side effects of clonidine such as bradycardia and hypotension were not observed.

Compared with bupivacaine, levobupivacaine is thought to be less toxic to the cardiovascular systems.[27] The quality of sensory and motor block appears to be similar in most studies after equal doses of levobupivacaine and bupivacaine.[2829] The minimum effective local anesthetic concentration of levobupivacaine for motor block is significantly greater than that of bupivacaine, indicating that levobupivacaine is less potent at motor block than bupivacaine when administered in epidural analgesia for labor.[30] At this similar dose, levobupivacaine showed significantly less myocardial contractility and atrioventricular conduction depressant effect than bupivacaine.[31] Levobupivacaine reversibly blocks the transmission of action potential in sensory, motor, and sympathetic nervous fibers by inhibiting the passage of sodium through voltage-sensitive ion channels in the neuronal membrane. Whereas the inhibitory action is intended to be localized at the site of administration, excessive doses or accidental intravascular injection may lead to activity at the level of other ion channels in the excitable tissues, followed by unwanted central nervous and cardiovascular adverse effects. The current pharmacodynamic evidence from animal and human studies suggests that levobupivacaine has a potentially greater margin of safety than the racemic bupivacaine. Hence, we used levobupivacaine as the local anesthetic which causes less motor blockade and comparatively safer drug than its congener bupivacaine.

Limitations of study

There are a number of limitations of this study. First, the study was not large enough to assess safety. Second, there is a risk of inadvertent peritoneal puncture with this block, however, small. We, however, have not encountered this complication in the TAP blocks; we perform under ultrasonography guidance. Finally, we have not performed a dose response study to determine whether a lower dose of clonidine would provide same results.

CONCLUSION

We conclude that the addition of clonidine 1 μg/kg to 20 ml levobupivacaine 0.25% in TAP block bilaterally for cesarean section provides 17–19 h of postoperative analgesia, decreases postoperative analgesic requirement, and increases maternal comfort compared to 20 ml of levobupivacaine 0.25% alone with minimal side effects.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.