Spinal anesthesia stands out as the preferred regional technique for cesarean sections owing to its ease of administration, rapid onset, and predictable outcomes. It ensures effective sensory and motor blockade in awake patients while minimizing the risk of drug transfer to the fetus.⁽¹⁾ Levobupivacaine, the pure S (-) enantiomer of racemic bupivacaine, offers reduced cardiac and central nervous system toxicity. Combining it with opioids like fentanyl enhances early onset, prolongs sensory and motor block, ensures stable hemodynamics, and minimizes side effects. Fentanyl's lipophilic properties improve blockade quality, extend analgesia duration, and reduce intraoperative nausea and vomiting. In the existing literature, there is a scarcity of studies that compare the fetomaternal outcome in cesarean section with varying doses of hyperbaric levobupivacaine combined with fentanyl as an adjuvant.

This study was designed to provide an impetus for further research with minimal pharmacological expenses, and better patient outcome.

Study Design: Aprospective, randomised and double-blind study.

Setting: The Department of Anaesthesia at Sri Guru Ram Das Institute of Medical Sciences and Research, Sri Amritsar, obtained approval from the Institutional Ethics Committee and collected written informed consent from participants.

Sample Size:The sample size calculation for this study was determined based on the findings of a prior investigation conducted by Gunsen I et al., which focused on a randomized comparison of various doses of intrathecal levobupivacaine combined with fentanyl for elective cesarean section. The primary outcome measure in both the previous study and our research is the mean arterial pressure. The prevalence of hypotension was observed to be 17%.

Epi Info™ software was used with acceptable margin alpha error of 5%. The sample size cameouttobe93. Taking the drop outrate of 10%, 105 patients were taken with 35 patients in each group.

This prospective, randomized ,double blind study was carried out on 105 patients posted for elective surgeries. After obtaining  approval from the Ethics Committee on 10 October ,2022 prior written informed consent was taken from all patients. The study protocol was registered with Clinical Trial registry of India (CTRI / 2023/08/056622) on 29/8/2023 .

The study enrolled patients aged 18 to 45 years, with ASA physical status 1 or 2, singleton pregnancy, term gestational age, and scheduled for elective cesarean section under spinal anesthesia. Exclusion criteria included patient refusal, height < 150 cm, drug allergies, maternal coagulopathy, cardiorespiratory, neurological, psychological, or endocrine disorders, and local sepsis. Out of 115 patients assessed for eligibility, 10 were excluded, with 3 not meeting inclusion criteria and 7 experiencing partial effects. The remaining 105 were randomly allocated into groups of 35 each using a computer-generated random number table. To ensure blinding, a consultant not involved in the study prepared the study drug solution. Both the anesthetists and patients were kept unaware of the study drug to ensure impartial administration and assessment.

STUDY PROTOCOL

Patients in Group A(n=35): received 7.5 mg hyperbaric levobupivacaine 0.5% plus 25µg of fentanyl intrathecally. Group B (n=35): received 8.5 mg hyperbaric levobupivacaine 0.5% plus 25µg of fentanyl intrathecally . Group C(n=35): received 10 mg hyperbaric levobupivacaine 0.5% plus 25µg of fentanyl intrathecally. Total volume of dose injected was 2.5ml.

TABLE1:GROUPS

All patients included in the study were fasted overnight and received anti-aspiration prophylaxis with oral ranitidine 150mg and metoclopramide 10mg the night before surgery. In the preoperative area, intravenous access was established, and preloading was performed with 15ml/kg of lactated Ringer's solution over 15 minutes. Upon arrival in the operating room, patients were connected to monitors for pulse rate, ECG, NIBP, and SpO2, and these parameters were recorded.

Under sterile aseptic precautions, in the left lateral position, spinal anesthesia was performed at the L3-L4 intervertebral space using a 25G Quincke's needle and midline approach. Following the spinal injection, the patient was repositioned to a supine posture with a wedge under the right flank, and oxygen was administered via a facemask at 4L/min. The initiation of spinal anesthesia marked the zero time. Sensory block level was assessed by pinprick at the mid-axillary line every minute until reaching T6, allowing surgery to commence. Motor block was evaluated using the modified Bromage scale, with onset defined as achieving Bromage grade 3. Maximum sensory block height, time to two-segment regression, and time to one-grade regression of motor block were recorded.

TABLE2:MOTORBROMAGESCORE

Maternal pulse rate and blood pressure were monitored at three-minute intervals for the first 15 minutes, followed by measurements every five minutes until the end of surgery. Subsequently, measurements were taken every 15 minutes for two hours in the Post-Anesthesia Care Unit (PACU), and then every four hours for up to 24 hours post-surgery.

In our study, hypotension was characterized by a decrease in systolic blood pressure of more than 20% from the baseline value. It was managed with an intravenous bolus of phenylephrine at a dose of 100 µg. Maternal bradycardia was defined as a reduction of over 20% in the baseline pulse rate and was managed by administering intravenous atropine at a dosage of 0.01 mg/kg.

Complications like hypotension, nausea and vomiting, bradycardia, pruritis, respiratory depression, shivering were noted in both intraoperative and postoperative period. Respiratory depression was characterized as a respiratory rate below 8 breaths per minute and Sp02 less than 90%. Postoperative pain was assessed by numeric rating scale and if NRS >3 , Inj Diclofenac 75mg iv slowly was given as rescue analgesia according to the pain score. Shivering was treated with Inj tramadol @1mg/kg diluted in 100 ml normal saline. Neonatal assessment was conducted using APGAR scoring at the 1st and 5th minutes after delivery.

Table 3: NUMERICRATING SCALE

Neonatal assessment was conducted using APGAR scoring at the 1st and 5th minutes after delivery.

TABLE4:APGARSCORE

SAMPLE SIZE

The sample size calculation for this study was determined based on the findings of a prior investigation conducted by Gunsen I et al., which focused on a randomized comparison of various doses of intrathecal levobupivacaine combined with fentanyl for elective cesarean section. The primary outcome measure in both the previous study and our research is the mean arterial pressure. The prevalence of hypotension was observed to be 17%.Epi Info™ software was used with acceptable margin alpha error of 5%. The sample size came out to be 93. Taking the dropout rate of 10%, 105 patients will be taken with 35 patients in each group.

STATISTICAL ANALYSIS

The observed data’s was analyzed by SPSS version 21.0 software. The collected data was tabulated and expressed as mean, standard deviation, numbers and percentages. Continuous variables were compared with one way ANOVA. The comparison was done using chi Square as appropriate value reported at the 95% confidence interval. P value <0.05 was considered as statistically significantand p<0.001 as highly significant.

The study enrolled 105 patients. Demographic variables such as age, weight and height status were similar across all groups, as depicted in Table 5.

When comparing the hemodynamic changes among the three groups, both intraoperative and postoperative pulse rate and mean arterial pressure were similar, with no statistically significant differences except at 0, 3, 9, 12, 15, and 35 minutes intraoperatively. Regarding the spinal block characteristics, the results obtained are presented in Tables 6 and 7.

We noted a shorter onset time for sensory blockade in Group C. The mean onset time of sensory block in Group A, B, and C was 4.55±1.66197 mins, 3.9886±0.53290 mins, and 3.5514±0.89224 mins, respectively. The time taken for two-segment regression of sensory blockade in Group A, B, and C was 77.286±16.6867 mins, 82.571±14.1614 mins, and 91.571 ±10.6254 minutes, respectively.

In Group C, the mean onset time for motor block corresponding to grade 3 Bromage was 4.5006±1.01958 minutes, whereas in Group A and Group B, it was 5.66±1.929 minutes and 4.7114±0.65877 minutes, respectively, which was statistically significant (Table 7).

For rescue analgesia, the Numerical Rating Scale (NRS) was assessed. Intergroup comparisons between Group A vs. B and Group A vs. C were statistically significant, except for the comparison between Group B vs. C, which was statistically insignificant (p=0.25). The requirement for rescue analgesia was highest in Group A, comparable in Groups B and C. The effective analgesia period was longer in Group C, with a mean duration of 7.7029±9.07638 hrs, compared to Group B (6.0957±6.09 hrs), which was comparable with Group A (3.6014±4.70654 hrs), as shown in Table 8.

As depicted in Table 9, neonatal assessment via Apgar scoring and umbilical cord pH were comparable among the three groups, with scores exceeding 7 in all cases.

Table 10 presents the incidence of side effects, with higher occurrences of nausea and vomiting observed in Group C compared to Group A and B, which was statistically significant. The incidence of hypotension, bradycardia, pruritus, and shivering was higher in patients of Group C compared to those in Group A and B, although statistically insignificant except for vomiting, which showed significance with p<0.05.

TABLE5:DEMOGRAPHICDISTRIBUTION

TABLE6:CHARACTERISTICSOFSENSORYBLOCKADE

TABLE7:CHARACTERISTICSOFMOTORBLOCKADE

TABLE8: DURATION OF EFFECTIVE ANALGESIA

TABLE 9: APGARSCOREAT1 AND 5 MINUTES

TABLE10:SIDEEFECTS

                     FIGURE 1: COMPARISION BETWEEN MAPIN THE THREE GROUPS

FIGURE 2: COMPARISIONOFNRS IN THREE GROUPS

Adequate pain relief following caesarean section promotes emotional bonding with the child, promotes breast feeding, reduces the risk of developing deep vein thrombosis and pulmonary thromboembolism.² Spinal adjuvants prolong postoperative analgesia, mitigate intraoperative side effects of local anesthetics, and diminish the duration of motor block, facilitating early ambulation. Fentanyl, a synthetic opioid agonist, by acting on mu opioid receptors provides dense spinal blockade and local anaesthetic sparing effect. It can be used intrathecally in the range of 5 – 25 mcg.³

In this study, Different doses of levobupivacaine (7.5mg, 8.5 mg, 10 mg) with fentanyl 25 ug was used .We noted a higher incidence of hypotension in the levobupivacaine 10 mg group, despite this group offering superior anesthesia effectiveness and higher satisfaction levels for both patients and surgeons with spinal anesthesia compared to the other two groups.Levobupivacaine 7.5 mg combined with fentanyl 25 µg proved suitable due to its lower incidence of hypotension compared to the use of levobupivacaine 10 mg with fentanyl 25 µg. Additionally, there was a reduced requirement for rescue analgesia with both 10 mg and 8.5 mg of levobupivacaine compared to the combination with 7.5 mg of levobupivacaine plus fentanyl 25 µg. In our study, we found that adding 25 µg of fentanyl to levobupivacaine significantly improves the onset and duration of sensory blockade, with a p-value of 0.001, indicating statistical significance.

The density of the anesthetic solution and the position of the patient are the most important factors affecting intrathecal drug spread.⁴ Hyperbaric local anesthetics offer advantages over plain solutions, including a more predictable cephalad spread, prolonged duration of clinically effective block, and faster regression of sensory block and recovery from motor block.⁵ Sen et al.conducted a comparison between identical doses of hyperbaric and isobaric levobupivacaine.⁶ They observed that the speed of onset and offset of motor and sensory block was significantly faster with hyperbaric levobupivacaine. However, they found that hemodynamic parameters and the incidence of adverse effects were similar between the two formulations. Contrary to Sen et al.'s findings, a report by Van Gessel et al. indicated that the decrease in mean arterial pressure was significantly more pronounced in hyperbaric solutions (30%) compared to isobaric (18%) or hypobaric (14%) solutions.⁷ In another study, it was reported that the hyperbaric group exhibited a higher incidence of hypotension compared to the plain group.⁸

Incorporating an opioid with the local anesthetic can produce a local anesthetic-sparing effect, resulting in a quicker onset of sensory block and prolongation of its duration, while maintaining motor block unaffected. This approach also lowers the incidence of postoperative pain.The opioid interrupts pain transmission in the dorsal horn of the spinal cord, whereas the local anesthetic blocks conduction in both motor and sensory nerves.^9,10,11,12

In the initial study on levobupivacaine with fentanyl, Lee et al. compared the clinical efficacy, motor block, and hemodynamic effects of administering 2.6 mL of 0.5% levobupivacaine versus 2.3 mL of 0.5% levobupivacaine combined with fentanyl 15 µg during urological surgery.¹⁰ They demonstrated that levobupivacaine with fentanyl was more effective than levobupivacaine alone.The results indicated a quicker onset of both sensory and motor blockade with the addition of fentanyl.

As anticipated, the intensity of motor block was higher in groups receiving a higher dose of local anesthetic. This relationship was expected, as the lower incidence of complete motor block correlated with the lower dose of local anesthetic utilized.¹³  Bremerich et al. discovered that, in comparison to 7.5 mg of levobupivacaine, administering 10 and 12.5 mg of levobupivacaine extended the duration of effective postoperative analgesia to 81 and 96 minutes, respectively, as opposed to 45 minutes.¹⁴ Based on their findings, Bremerich et al. suggested a dose of 10 mg of levobupivacaine for parturients undergoing elective cesarean section with spinal anesthesia. They made this recommendation because parturients receiving 7.5 mg of levobupivacaine required additional intravenous opioid analgesics intraoperatively.In another study, Turkmen et al. compared the anesthetic effects of 7.5 mg of 0.5% bupivacaine and levobupivacaine, each combined with 15 µg fentanyl, in spinal anesthesia for cesarean section. The duration of analgesia was 118 minutes in the levobupivacaine with fentanyl group.

In our study, using a similar dose of fentanyl (25 µg), 10 mg of levobupivacaine provided analgesia for a duration of 7.7029 ± 9.07638 hours, while 8.5 mg provided analgesia for 6.0957 ± 6.09266 hours. The durations were statistically comparable between the two groups, with p=0.52.Therefore, we conclude that increasing the dose of levobupivacaine has extended the duration of postoperative analgesia.

Thus, similar to the findings of Ben David et al. , we observed early regression of surgical anesthesia and an increased requirement for analgesic supplementation when utilizing levobupivacaine 5 mg in combination with fentanyl 25 µg.¹⁵ Furthermore, Guasch et al. established that the necessity for rescue analgesia was elevated in the cohort receiving 5 mg of levobupivacaine with 25 µg fentanyl, mirroring our findings in the 7.5 mg levobupivacaine group.¹⁶ Chu et al. investigated the use of 0.5% hyperbaric bupivacaine combined with various doses of fentanyl (7.5, 10, 12.5, and 15 µg) for spinal anesthesia.¹⁷  While all patients in the 12.5 and 15 µg fentanyl groups reported excellent intraoperative and postoperative analgesia, 7.5 µg fentanyl did not result in significant clinical effects. Additionally, Goel et al. conducted a comparison of three different doses of intrathecal fentanyl (7.5, 10, or 12.5 µg) in conjunction with low-dose bupivacaine to determine the minimum effective dose of intrathecal fentanyl.¹⁸ Taking into account these studies, we opted to utilize 25 µg of fentanyl, as Goel et al. revealed that the group receiving 7.5 µg of fentanyl had a notably higher rate of failed blocks, nearly 27%.

Hypotension is associated with the extent of sympathetic block. A decrease in the concentration of the anesthetic solution results in reduced drug penetration into the nerves, potentially leading to a less intense sympathetic block.^19,20 Moreover, opioids contribute to a diminished sympathetic block, leading to a decreased occurrence of hypotension. Parpaglioni et al. found that the percentage of patients experiencing hypotension was 38.5% in the levobupivacaine-alone group. Another investigation by the same authors demonstrated that the proportions of patients exhibiting hypotension were 43.3% in the levobupivacaine group and 20.4% in the levobupivacaine with sufentanil group.In our study, we observed that the incidence of hypotension rose with the increasing dose of levobupivacaine combined with fentanyl, with the highest occurrence seen in the 10 mg levobupivacaine group compared to the 8.5 mg and 7.5 mg groups.

Prabha et al. conducted a comparative study wherein they administered 8.75 mg of 0.5% bupivacaine and 12.5 µg of fentanyl intrathecally to Group B, and 8.75 mg of 0.5% levobupivacaine with 12.5 µg of fentanyl to Group L, comprising 20 patients each for cesarean section.²¹ The study observed stable hemodynamics and prolonged sensory blockade in the Levobupivacaine plus fentanyl group.In this study, neonatal assessment using the APGAR score at the 1st and 5th minute revealed scores exceeding 8 in both groups, indicating that the addition of fentanyl to levobupivacaine did not induce significant neonatal depression.Our study produces similar results to the study mentioned above.

The analgesic advantages of intrathecal opioids must be weighed against their side effects, including nausea, vomiting, sedation, and itching, all of which are dose-dependent. Specifically, higher opioid doses correlate with heightened itching.²² In our study, the occurrence of itching was minimal, and no intervention was required. When assessing other side effects, we observed a higher incidence of nausea and/or vomiting, bradycardia, and hypotension with 10 mg of levobupivacaine compared to 8.5 mg, with the lowest incidence in the 7.5 mg group. However, there was no statistically significant difference among the groups.Nausea or vomiting subsequent to spinal anesthesia can be attributed to hypotension or the administration of fentanyl.In the current study, the increased occurrence of nausea may be associated with the higher prevalence of hypotension observed with levobupivacaine 10 mg, while the lowest incidence was noted with 7.5 mg (11% and 9% incidence, respectively).Brizzi et al. illustrated that in the spinal group receiving 7.5 or 8 mg of levobupivacaine and 5 µg sufentanil, the incidences of vomiting and bradycardia were 12% and 24%, respectively.²³ We observed fewer adverse effects such as nausea, vomiting, and hypotension compared to the study by Brizzi et al. This difference could be attributed to the utilization of different opioids or variations in the doses of the block tailored to the initial demand for postoperative analgesia.

In this comparative study of three different doses of levobupivacaine with fentanyl, it was found that 10 mg of levobupivacaine combined with 25 µg fentanyl provided rapid and effective induction of surgical anesthesia for elective cesarean section. However, the incidence of maternal hypotension was higher in this group compared to the other two. On the other hand, 8.5 mg and 7.5 mg of levobupivacaine combined with 25 µg fentanyl were deemed more suitable as they resulted in a lower incidence of hypotension than the 10 mg dose. Additionally, the postoperative analgesic requirement was comparable between the 10 mg and 8.5 mg levobupivacaine groups . Therefore, based on our findings, we suggest that the combination of 8.5 mg of levobupivacaine with 25 µg fentanyl may be the preferred minimum effective dose for achieving better fetomaternal outcomes in cesarean sections compared to the other two groups. This combination offers fewer side effects while providing effective postoperative analgesia .

LIMITATION

The pain threshold varies from person to person. The tools used to quantify pain were subjective for better assessment more large-scale trials and researches need to be conducted in future.

FINANCIAL SUPPORT AND SPONSORSHIP

Nil

CONFLICTS OF INTEREST

There are no conflicts of interest

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