|Year : 2022 | Volume
| Issue : 2 | Page : 102-109
Spinal anesthesia for elective cesarean section – Comparison of levobupivacaine and ropivacaine with hyperbaric racemic bupivacaine
Melwin George1, Shalini Miriam Ipe2, Shaloo Ipe2, Saramma P Abraham2
1 Department of Critical Care Medicine, Rajagiri Hospital, Kochi, Kerala, India
2 Department of Anesthesiology, Malankara Orthodox Syrian Church Medical College, Ernakulam, Kerala, India
|Date of Submission||11-Mar-2022|
|Date of Decision||15-Jun-2022|
|Date of Acceptance||27-Jun-2022|
|Date of Web Publication||9-Aug-2022|
Department of Critical Care Medicine, Rajagiri Hospital, Aluva, Kochi, Kerala
Source of Support: None, Conflict of Interest: None
Background: Spinal anesthesia is a popular technique for cesarean section, the commonly used drug being hyperbaric bupivacaine. Levobupivacaine and ropivacaine are newer local anesthetics in the Indian market with similar sensory block profile, lesser cardiotoxicity, but shorter duration of motor block. Aim: To determine the efficacy and safety of hypobaric levobupivacaine and ropivacaine and to compare it with hyperbaric bupivacaine all with fentanyl for spinal anesthesia in elective cesarean section. Study Design: This was a prospective, randomized controlled, double-blinded study. Methodology: Ninety pregnant patients were allocated to three groups of 30 each. Group A (control) received 0.5% hyperbaric bupivacaine 1.8 ml with 25 μg fentanyl, Group B (study) received 0.5% levobupivacaine 1.8 ml with 25 μg fentanyl, and Group C (study) received 0.75% ropivacaine 1.8 ml with 25 μg fentanyl. The efficacy and safety were assessed and analyzed using SPSS version 22. Results: Our study showed that ropivacaine is noninferior to hyperbaric bupivacaine, with a similar efficacy of 96.7%. Hyperbaric bupivacaine and ropivacaine are superior to levobupivacaine with a success rate of 96.7% versus 80%, with a P = 0.02 for superiority (one-sided). Duration of motor block was shorter in levobupivacaine (P < 0.001) and ropivacaine (P = 0.016) groups compared to bupivacaine group. Mean duration of analgesia was shorter in levobupivacaine (P = 0.001) and ropivacaine (P = 0.010) groups when compared to bupivacaine group. Although the percentage of patients having hypotension were similar among the groups, episodes of intraoperative hypotension and the amount of ephedrine consumed were higher in ropivacaine group compared to bupivacaine group (P = 0.039). Conclusion: Ropivacaine 0.75% appeared noninferior to hyperbaric bupivacaine 0.5% in terms of efficacy and safety. Levobupivacaine 0.5% was found to be inferior to bupivacaine and ropivacaine in terms of efficacy.
Keywords: Bupivacaine, cesarean section, fentanyl, levobupivacaine, ropivacaine, spinal anesthesia
|How to cite this article:|
George M, Ipe SM, Ipe S, Abraham SP. Spinal anesthesia for elective cesarean section – Comparison of levobupivacaine and ropivacaine with hyperbaric racemic bupivacaine. Asian J Pharm Res Health Care 2022;14:102-9
|How to cite this URL:|
George M, Ipe SM, Ipe S, Abraham SP. Spinal anesthesia for elective cesarean section – Comparison of levobupivacaine and ropivacaine with hyperbaric racemic bupivacaine. Asian J Pharm Res Health Care [serial online] 2022 [cited 2022 Sep 27];14:102-9. Available from: http://www.ajprhc.com/text.asp?2022/14/2/102/353622
| Introduction|| |
Spinal anesthesia is the gold standard for cesarean section compared to general and epidural anesthesia. Hyperbaric bupivacaine 0.5% is commonly used for spinal anesthesia in cesarean section. However, bupivacaine is cardiotoxic and also produces motor blockade of prolonged duration. Levobupivacaine and ropivacaine are newer hypobaric long-acting local anesthetics, with claimed benefits of reduced cardiac toxicity and differential blockade on sensory and motor nerve fibers.,,, Fentanyl added to the local anesthetic improves the quality of intraoperative anesthesia, prolongs postoperative analgesia, and reduces the dose of local anesthetics needed. Our objective was to compare the efficacy and safety of hypobaric levobupivacaine and ropivacaine with fentanyl to hyperbaric bupivacaine with fentanyl in an attempt to use them as an alternative in spinal anesthesia for cesarean section.
| Methodology|| |
This prospective, double-blinded, randomized controlled study was conducted at a tertiary care teaching hospital. Pregnant patients selected for the study were randomly allocated to Group A, Group B, and Group C by computer-generated random number listing. The institute's ethics committee approved the study protocol (MOSC/ETHICS/24/2012), and written informed consent was obtained from the patients. The trial was registered with CTRI no CTRI/2020/12/030163. American Society of Anesthesiologists II pregnant patients, aged between 20 and 40 years, height 145–170 cm with singleton pregnancy for elective cesarean section were included in the study. Patient's refusal to take part in the study, those with local infection, those on anticoagulants, antiplatelets and those with allergy to the study drug or having any neurological deficit were excluded from the study. The details of the recruitment of the subjects are shown in a CONSORT diagram [Figure 1]. Patients were instructed to score the intensity of the pain on Verbal Numerical Rating Scale VNRS (0 – 10). 0 denoting no pain and 10 the worst imaginable pain. The procedure of subarachnoid block was explained. Patients were kept nil orally for 6 hrs and were premedicated with tablet ranitidine 150 mg PO the night before and on the morning of surgery.
Basal recording of electrocardiogram (ECG), oxygen saturation (SpO2), and noninvasive blood pressure (NIBP) was done. Oxygen was administered via Hudson face mask at 6 L/min. All patients were premedicated with 1 mg midazolam intravenously to allay anxiety., Patients were coloaded with 500 ml of Ringer lactate and maintained on 10 ml/kg/h. ECG, NIBP, and SpO2 were recorded at 2-min intervals for 20 min, at 10-min intervals throughout the surgery, and at 1-hr intervals up to 6 hrs postoperatively. Equal volumes of the study drug (2.3 ml) were prepared by an anesthesia colleague who was not involved in the study. The investigator, the obstetrician, and the neonatologist were blinded to the study drug used.
Under aseptic precautions, in the left lateral decubitus position, subarachnoid block was performed at L3–L4 space using 25-gauge Quincke spinal needle (Spinocan® BI BRAUN). After intrathecal drug placement, patients were immediately positioned supine with 15 uterine displacement (left lateral tilt). Intravenous ondansetron 4 mg was given after cord clamping. In Group A (the control group), 0.5% hyperbaric bupivacaine 1.8 ml with 25 μg fentanyl was given, and in the study groups; in Group B and Group C, 1.8 ml of 0.5% levobupivacaine with 25 μg fentanyl and 0.75% ropivacaine with 25 μg fentanyl, respectively, were given.
Time of onset of sensory block, maximum sensory level reached, and time taken to reach maximum sensory level were noted. Time of onset of sensory block was assessed as loss of pain to pinprick at T10 in the midclavicular line bilaterally using sterile 26G needle. To assess the duration of the sensory block, the two-segment regression time and time for regression to T10 from the maximum block height were used. Postoperatively, when the pain score was 3 or more on the Verbal Numerical Rating Scale, rescue analgesia was given (Verbal Numerical Rating Scale: 0 – no pain, 1–3 – mild pain, 4–6 – moderate pain, 7–10 – severe pain). The interval from onset of sensory block at T10 to time of rescue analgesia was taken as duration of analgesia.
Maximum degree of motor blockade achieved and time taken for that from subarachnoid blockade were noted. The duration of motor blockade was the time interval from the maximum degree of motor blockade to full recovery of motor power. Motor block was assessed using modified Bromage scale (1 – complete motor block, 2 – able to move feet only, 3 – able to move knees, 4 – weakness of hip flexion, 5 – no weakness of hip flexion, 6 – no weakness at all). Intraoperative hypotension episodes (systolic blood pressure <100 mmHg or 20% decrease from baseline) were treated with intravenous fluids and/or ephedrine. Bradycardia (heart rate <50/min) was treated with 0.2 mg glycopyrrolate given intravenously. Respiratory depression (respiratory rate <8/min or SpO2 <94%) was treated with oxygen supplementation or ventilatory support as needed. Surgery was started after 10 min when the upper sensory level reached T6 or above.
Pain was assessed at incision, extraction of the baby and peritoneal closure (when pain expected is maximum) as well as at any point when the patient complained of pain or discomfort or the VNRS score was 3 or more and the patient was given first rescue analgesia. Sedation, nausea, vomiting, and pruritus were noted up to 6 h postoperatively. Sedation was scored by Ramsay sedation scale (1 – anxious or agitated or both, 2 – cooperative and tranquil, 3 – responds to command only, 4 – brisk response to a light glabellar tap, 5 – sluggish response to a light glabellar tap, 6 – no response).
Neonatal outcome was evaluated by the neonatologist at 1 min and 5 min using the APGAR scoring system. APGAR score of ≤7 at 5 min was taken as poor neonatal outcome. The need for neonatal resuscitation and intensive care unit (ICU) admission was considered.
Surgeons' subjective evaluation of quality of anesthesia (1 – poor, 2 – fair, 3 – good, 4 – excellent) was obtained. A subjective score of patient satisfaction for analgesia was procured on a 10-point scale (numerical rating scale (NRS) 1–10 [>8 – excellent, 6–7 – good, 4–5 – fair, <3 – poor, 0 – unequivocal]). Urinary retention could not be assessed as our patients were catheterized till 24 h postoperatively.
The efficacy of the drug was analyzed by Z-test followed by the superiority approach. All continuous variables were presented as mean ± standard deviation and median (range). The data were compared using analysis of variance and Chi-square test. When there were significant differences in the parameters in the initial analysis, post hoc analysis was carried out using Tukey's honest significant difference to find out the differences between the groups. A P < 0.05 was considered statistically significant. Data were analyzed using Statistical Package for the Social Sciences (SPSS Inc., Chicago, IL, USA) version 22. Considering the efficacy of local anesthetic as the primary outcome, the sample size calculated using power analysis and sample size software (PASS-13) was 88 to have a power of 90% and alpha error of 5%. The sample size was rounded to 90 with 30 patients in each group.
| Results|| |
Patient demographics (age, weight, height, and operative duration) were comparable across the groups. The study drug was considered effective if an upper sensory level of T6 or above was achieved and if intraoperative supplementation was not required for successful completion of surgery. Out of 90 pregnant patients enrolled for the study, eight were excluded during the course of the study. Four patients in Group B did not have adequate sensory block, and spinal anesthesia was converted to general anesthesia. One patient each in Group A and Group C and two patients in Group B needed supplemental anesthesia. The anesthetic outcome is presented in [Table 1]. The null hypothesis was that drugs in Group A and Group B are similar in efficacy. Since P value for superiority using Z-test (one-sided) was 0.02, the null hypothesis was rejected. An alternative hypothesis that A is superior to B was considered more probable. Group A and Group C had an equal success rate (96.7%), and hence, it is concluded that they are equally efficacious. Between Group C and Group B, the P value by Z-test is 0.02. Hence, the null hypothesis is rejected and the alternative hypothesis that Group C is superior to Group B is accepted.
The sensory and analgesia characteristics are mentioned in [Table 2]. Onset of sensory blockade, time to reach the maximum sensory level, and duration of the sensory blockade were similar in all the groups. The median maximum sensory level reached is T4 in all the three groups, with range being T6–T4 in Group A, T5–T2 in Group B, and T4–T2 in Group C [Table 2]. More than 50% of patients in Group A (51.7%) and Group C (55.2%) and 83.3% of the patients in Group B achieved a maximum sensory level of T4 [Graph 1]. Duration of analgesia was significantly prolonged in Group A (245.96 ± 35.99 min) compared to Group B (208.33 ± 44.54 min) (P = 0.001) and Group C (218.62 ± 21.91 min) (P = 0.010) [Table 2]. Duration of analgesia was similar between Group B and Group C.
The time to reach maximum degree of motor blockade was similar in all groups [Table 3]. 100% of the patients in Group A attained complete or near-complete motor block as against 87.5% in Group B and 82.7% in Group C. Duration of motor blockade was significantly prolonged in Group A (136.96 ± 18.87) compared to Group B (112.83 ± 21.57) (P < 0.001) and Group C (122.06 ± 19.84) (P = 0.016). However, there was no difference in duration of motor blockade between Group B and Group C (P = 0.132).
Hypotension was noticed in 55% (16/29) of patients in Group A, 29% (7/24) in Group B, and 48% (14/29) in Group C [Table 4]. Though, clinically, the incidence of hypotension seemed to be less in Group B, it was not statistically significant (P = 0.152). The quantity of ephedrine given for managing episodes of hypotension was 9.37 ± 4.36 mg, 10.28 ± 6.67 mg, 13.71 ± 4.93 mg in Group A, Group B, and Group C, respectively. Ephedrine consumption was significantly higher in Group C compared to Group A (P = 0.039). There was no significant difference in ephedrine consumption between Group A and Group B (P = 0.902) and Group B and Group C (P = 0.259) [Graph 2].
There was a single case of bradycardia in Group A, which got corrected by one dose of 0.2 mg glycopyrrolate given intravenously. Saturation remained within normal limits in all patients. Maternal effects such as nausea, vomiting, and pruritus were distributed equally among the groups. Patients in all three groups had a Ramsay sedation score of 2. The neonatal outcome assessed by APGAR score was satisfactory in all three groups. The surgeons rated the quality of anesthesia as excellent in 100% of cases in Group A, 83.3% in Group B, and 82.7% in Group C. The rating was good in the rest of the cases. 100% of patients in Group A, 91.6% in Group B, and 89.6% in Group C rated the quality of analgesia as excellent, while the rest of the patients in Group B and Group C rated it as good.
| Discussion|| |
Subarachnoid block is recognized as the choice of anesthesia in elective cesarean sections. The commonly used drug is hyperbaric bupivacaine with fentanyl. Hence, 9 mg hyperbaric bupivacaine with fentanyl 25 μg formed the control group. This study was to determine the efficacy and safety of levobupivacaine and ropivacaine with fentanyl (hypobaric solutions) in comparison to hyperbaric bupivacaine for spinal anesthesia in elective cesarean sections.
Richardson and Wissler had observed that the mean cerebrospinal fluid (CSF) density in term pregnant patients is 1.00030 ± 00004 and to say that a local anesthetic solution is hypobaric, and baricity should be <1.00018. McLeod determined the baricity of levobupivacaine (0.5%) as 1.00419 ± 0.00002 at 23°C and 1.00024 ± 0.00009 at 37°C and that of plain ropivacaine (0.75%) as 1.00380 ± 0.00003) at 23°C and 0.99953 ± 0.00014 at 37°C. The addition of fentanyl which is hypobaric (0.9933) will further decrease the baricity of the local anesthetic solutions. At a body temperature of 37°C and with the addition of 25 μg fentanyl, levobupivacaine and ropivacaine behave as hypobaric solutions.
Parpaglioni et al. found the minimum spinal anesthetic dose for cesarean section as 10.58 mg for levobupivacaine and 14.22 mg for ropivacaine. Choi et al. concluded that the dose of spinal local anesthetics can be brought down by the addition of fentanyl. The equipotent dose of ropivacaine compared to bupivacaine is considered to be 3:2 based on the studies conducted by Gautier et al. and Malinovsky et al., Hence, the doses chosen for the study were levobupivacaine 9 mg ± fentanyl 25 μg (similar to bupivacaine) and ropivacaine 13.5 mg ± 25 μg fentanyl.
Analysis was done using Z-test followed by superiority methods, based upon the Statistical Principles for Clinical Trials. It was shown that ropivacaine is noninferior to hyperbaric bupivacaine with a similar efficacy of 96.7%. Hyperbaric bupivacaine and ropivacaine are superior to levobupivacaine having a success rate of 96.7% versus 80%, with P value for superiority (one-sided) 0.02. Gautier et al. had conducted a similar study comparing plain solution of bupivacaine 8 mg, levobupivacaine 8 mg, and ropivacaine 12 mg, all with sufentanil 2.5 μg. The success rate was found to be 96.7%, 80.0%, and 86.7% for bupivacaine, levobupivacaine, and ropivacaine, respectively. Similar to their findings, in our study, levobupivacaine was found to be inferior to bupivacaine in terms of efficacy. However, they could not conclude the efficacy of ropivacaine in comparison to Bupivacaine. On the contrary, in our study, ropivacaine was found to be equally effective as hyperbaric bupivacaine. This could be attributed to the dose of local anesthetic and the adjuvant drug used (13.5 mg of ropivacaine instead of 12 mg and fentanyl 25 μg instead of sufentanil 2.5 μg). Nelson et al. compared intrathecal sufentanil to fentanyl for labor analgesia and found the potency ratio of sufentanil to fentanyl as 4.4:1. Our study used double the equipotent dose of fentanyl in comparison to sufentanil and also the quantity of ropivacaine used was higher (13.5 mg vs. 12 mg).
Time of onset of sensory blockade, time to reach the maximum sensory level, and duration of sensory blockade were similar in all the groups. This agrees with the study done by Gautier et al. comparing plain solutions of bupivacaine, levobupivacaine, and ropivacaine. In comparison to hyperbaric bupivacaine, the duration of analgesia was shorter in levobupivacaine and ropivacaine groups (245.96 ± 35.99 vs. 208.33 ± 44.54 and 218.62 ± 21.91, respectively) [Table 2]. Since the same dose of fentanyl was used in all three groups, the difference in the duration of analgesia can be attributed to the effect of the local anesthetic solutions used. The longer duration of analgesia offered by hyperbaric bupivacaine is advantageous.
In our study where we had compared hypobaric ropivacaine and hyperbaric bupivacaine, the sensory level attained with ropivacaine was higher. Forty-five percent of patients in ropivacaine attained a maximum sensory level of T2 to T3 as against none in the hyperbaric bupivacaine group attaining a level above T4. The higher level of the sensory blockade is likely to be due to hypobaricity of ropivacaine plus fentanyl solution as it enters the CSF. In a study done to know the effect of posture and baricity on intrathecal drug spread for elective cesarean section, Hallworth et al. and Loubert et al. demonstrated that decreasing baricity is associated with higher sensory level, increasing hypotension, and concomitant increase in ephedrine usage.,
The time to reach the maximum degree of motor block was similar in all three groups. 100% of patients attained complete or near-complete motor block in the hyperbaric bupivacaine group as against 87.5% in levobupivacaine and 82.7% in ropivacaine groups. Duration of motor block was prolonged in the hyperbaric bupivacaine group compared to levobupivacaine and ropivacaine groups [Table 3]. The shorter duration of motor block associated with ropivacaine can be explained by its differential sensory motor-blocking property., This property of ropivacaine is advantageous since it can help in early mobilization of patients.
Although it appeared that the incidence of hypotension was less in the levobupivacaine group, there was no significant statistical difference between the three groups. Oğün et al.'s study demonstrated a similar incidence of hypotension between ropivacaine and bupivacaine. The number of patients having hypotension in the ropivacaine group (48%) was comparable to the hyperbaric bupivacaine group (55%), but the number of episodes of hypotension was more with ropivacaine necessitating the use of repeated doses of ephedrine. This is contradictory to the findings in the study done by Gautier et al. where plain solutions of ropivacaine and bupivacaine were compared and it was found that there was no difference in episodes of hypotension and ephedrine consumption. The higher level of sensory blockade attained with hypobaric ropivacaine plus fentanyl probably explains the increased episodes of hypotension and ephedrine consumption in this group. In the study done by Gautier et al., they used 12 mg of ropivacaine, whereas, in our study, we used 13.5 mg. They also had given 5 mg of ephedrine concomitantly along with the intrathecal injection of local anesthetic. Respiratory parameters remained within normal limits in all patients. The incidence of maternal side effects such as nausea, vomiting, and pruritus was minor and distributed equally among the groups. All the patients were tranquil and cooperative as assessed by Ramsay sedation score.
Neonatal safety was assured by satisfactory APGAR scores at 1 min and 5 min in all three groups. None of the babies needed active resuscitation or ICU admission.
Surgeons and patients rated the quality of anesthesia as “excellent” for those who received hyperbaric bupivacaine. There was a subtle difference in patient satisfaction and surgeons' rating in the levobupivacaine and ropivacaine groups as compared to hyperbaric bupivacaine group. However, all had rated anesthesia as either “excellent” or “good.”
| Conclusion|| |
Hyperbaric bupivacaine plus fentanyl with its efficacy, better hemodynamic stability, and longer duration of analgesia can still be recommended as the spinal anesthetic of choice in cesarean section compared to agents such as hypobaric 0.5% levobupivacaine and 0.75% ropivacaine with fentanyl. 0.75% Ropivacaine is shown to have a noninferior profile compared to hyperbaric bupivacaine. Levobupivacaine 0.5% was found to be inferior to hyperbaric bupivacaine and ropivacaine in terms of efficacy.
We would like to acknowledge Department of Anesthesiology and Department Obstetrics and Gynecology, MOSC Medical College, Kolenchery, Kerala; Dr. Tarun Sebastian Joseph, Department of Gastroenterology, Rajagiri Hospital, for helping in manuscript formation; Dr. Kiran, Department of Anesthesiology, MOSC Medical College, Kolenchery, for helping proofreading of article file; and Aesmira Life Science and Neon Labs for giving sample medicines during our pilot study.
Financial support and sponsorship
Drugs from Aesmira Life Sciences and Neon Labs supported the study.
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]