Efficacy of lipophilic vs lipophobic opioids in addition to hyperbaric bupivacaine for patients undergoing lower segment caeserean section.

BACKGROUND: Subarachnoid block is the preferred technique for providing anesthesia for patients undergoing cesarean section. Various pharmacological agents in added to local anesthetics (LA) modify their original effects in terms of block characteristics and quality of analgesia. However, there is ongoing debate about this practice of using adjuncts with LA. We tested whether addition of lipophilic versus lipophobic opioids to LA gives any clinical benefits to maternal and fetal outcome when used in these patients requiring spinal anesthesia. SUBJECTS AND METHODS: Sixty American Society of Anesthesiologists I and II parturients, undergoing elective cesarean section requiring subarachnoid block, were included in our study. The parturients were allocated randomly to three groups of 20 each to receive bupivacaine 12.5 mg (Group I), bupivacaine 12.5 mg + morphine 0.2 mg (Group II), bupivacaine 12.5 mg + fentanyl 25 μg (Group III), preservative free physiological saline 0.9% was added to all the solutions to achieve a total volume of 4 ml. The parameters studied were the time of onset, sensory level of the block achieved, total duration of analgesia, any need of rescue analgesics, maternal side effects, and fetal outcome.
RESULTS: Onset of block was early 4.30 ± 0.12 min in Group III as compared to Group I 4.64 ± 0.28 min and Group II 4.505 ± 0.22 min. Mean duration of analgesia (hours) was higher in Group II 15.91 ± 0.96 h as compared to Group I 1.95 ± 0.55 h and Group III 4.39 ± 0.2 h. Incidence of nausea, vomiting, and shivering was more in the control group as compared to study groups, whereas sedation and pruritus were seen more in the study groups. No adverse effects on fetus were seen with use of opioids and comparable Apgar scores were noted.
CONCLUSION: Addition of intrthecal fentanyl causes rapid onset of block whereas intrathecal morphine provides prolonged analgesia with comparable neonatal wellbeing.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

Present era in obstetric anesthesia shows increased popularity of regional anesthesia among obstetric anesthetist.[1] Regional anesthesia is more preferred technique because of lower risk of gastric aspiration, failed intubation various side effects of anesthetic drugs on fetus.[2] Neuraxial administration of opioids along with local anesthetics (LA) improves the quality of intraoperative analgesia provides sedation and postoperative pain relief for a longer duration.[3] Lipophilic opioids have a rapid onset of action (minutes) and short duration of action (1–4 h) with low risk of respiratory depression.[4] In contrast, the lipophobic opiate morphine has many beneficial effects of its own. Despite detailed characterization of opioid receptor systems at the cellular and even molecular level,[56] the mechanisms of LA-opioid interaction are still largely unknown.[7]

The combination of opioids with LA agents administered subarachnoidally in lower section cesarean section for block characteristics and intra- and post-operative analgesia seems promising. Although they have been used since decades, the issues regarding the proper opioid choice and dosage are still lacking. To the best of our knowledge, there is a paucity of studies comparing these opioids in a single study setting.

The present work studied the comparative evaluation of adding fentanyl and morphine to bupivacaine with the conventional dose of bupivacaine in patients undergoing lower segment cesarean section under spinal anesthesia along with neonatal outcome to confirm the best combination.

SUBJECTS AND METHODS

After approval of the Hospital Ethics Committee and written informed consent, 60 American Society of Anesthesiologists I and II parturients, undergoing elective cesarean section, were included in our study. Females with multiple pregnancies, pregnancy-induced hypertension, placenta previa, morbid obesity, fetal distress, and any contraindication to spinal analgesia were excluded from the study. The parturients were allocated randomly to three groups of 20 each using sealed envelopes. Group I was designated to be the control group. The spinal agents to be used were as follows;

Group I: Spinal analgesia with bupivacaine 12.5 mg

Group II: Spinal analgesia with bupivacaine 12.5 mg + morphine 0.2 mg

Group III: Spinal analgesia with bupivacaine 12.5 mg + fentanyl 25 µg.

Preservative-free physiological saline 0.9% was added to all the solutions to achieve a total volume of 4 ml. All the subjects were advised tablet ranitidine 150 mg and tablet metoclopramide 5 mg a night before as well as 2 h before surgery. In the operating room, intravenous (IV) access was established with 18-gauge cannula and baseline vital signs, for example, pulse rate and noninvasive blood pressure (NIBP) were recorded. The parturients were then preloaded with 500 ml of Ringer's lactated solution. With the parturients in sitting position, spinal analgesia was administered at L3-4 space, using 25-gauge Quincke-Babcock spinal needle by anesthetist blind to the type of drug being used. On completion of the spinal injection, the parturients were placed supine on the table and a wedge was put under right hip to provide 15° lateral tilt. NIBP was monitored every 5 min until the end of surgery. The onset of sensory block was assessed by the loss of pinprick. Dermatomal level was assessed every 2 min until stabilized and time to reach maximum block height was noted. Furthermore, time of regression to T10 dermatome and time when patient demanded first rescue analgesia was noted.

Motor block was assessed by modified Bromage scale as follows: I - free movement of legs and feet; II - just able to flex knees with free movement of feet; III - unable to flex knees but with free movement of feet; and IV - unable to move legs and feet. Onset of motor block was assessed by time to reach Bromage II. Time to achieve complete motor block and its regression to Bromage I were noted. In the event of patient experiencing discomfort during surgery, a bolus of injection fentanyl 2 µg/kg IV was given as a rescue analgesic. If fall in NIBP was >30% of the base line, injection ephedrine was administered in repeated boluses. Injection Oxytocin 10 units in an infusion was administered after delivery of the baby.

The patients were also assessed for postoperative pain, nausea, vomiting, and shivering. A pediatrician assessed the neonatal Apgar score at 1, 5, and 10 min after delivery. Assessment of block characteristics and duration of analgesia were the primary outcome, and the intraoperative side effects and neonatal Apgar score were secondary outcome measures.

Statistical analysis

With α value determined at 0.05 and power of study at 80%, this study required 50 patients. Allowing for a dropout rate of 20%, 60 patients were recruited as sample size. Statistical analysis was performed for comparing groups using ANOVA F-test and pairwise comparison by Scheffe's test between the groups. The quantitative data on side effects of drugs under study were compared using Fisher exact test. P < 0.05 was considered statistically significant.

RESULTS

The demographic parameters were comparable among three groups [Table 1].

Table 1

Demographic profile of patients (mean±standard deviation)

The maximum block height achieved was T6 in Group I and Group III and T5 in Group II.

Time to achieve maximum sensory block height was 4.64 ± 0.28 min in Group I, 4.50 ± 0.22 in Group II, and 4.30 ± 0.12 min in Group III; however, no statistically significant difference was observed between the groups.

Regression time to T10 was 114.25 ± 6.54 in Group I, 119.25 ± 7.66 in Group III, and 148.50 ± 6.30 in Group II, which was significantly prolonged (P < 0.05) as compared to Groups I and III.

Duration of effective analgesia was significantly increased with the administration of morphine (15.91 h) and fentanyl, (4.39 h) as compared to control group (1.95 h) [Table 2].

Table 2

Characteristics of sensory block data presented as numbers or (mean±standard deviation)

Hypotension was observed in 15% patient in Group I and Group III and 10% in Group II.

None of the patients had bradycardia, respiratory depression in any of the groups.

Nausea and vomiting were observed maximum in Group I as compared to the Group II and Group III. However, pruritus was found 30% in Group III, 20% in Group II. None of the patients complained of pruritus in the control group.

Shivering was noted 30% in Group I, 20% in Group II, and 10% in Group III.

No patient had sedation in Group I, 5% in Group II followed by 30% in Group III. Statistically significant difference (P = 0.02) between Group I and Group II [Table 3].

Table 3

Frequency of intraoperative side effects

Additional analgesic requirement was needed in 15% patient in Group I.

No statistically significant difference as neonatal outcome was observed in terms of Apgar scores at 1, 5, and 10 min [Table 4].

Table 4

Neonatal outcome

DISCUSSION

The subarachnoid administration of opioids is based on the concept of multimodal analgesia acting at various levels of pain conduction. Our study demonstrated that spinal anesthesia for cesarean section with bupivacaine – fentanyl combination has the fastest onset of sensory block, but the onset of motor block is delayed as compared with bupivacaine-morphine. Doses of fentanyl 20–30 μg[8] and morphine 0.2 mg[9] have been used intrathecally in studies and have shown prolongation of analgesic effect of hyperbaric bupivacaine in a dose-dependent manner. Hence, a dose of 25 μg fentanyl versus 0.2 mg morphine was compared with heavy bupivacaine.

Although the onset of block with fentanyl was faster than morphine. The duration of analgesia was significantly prolonged in bupivacaine-morphine group as compared to other groups. Recent evidence suggests that bupivacaine also potentiates the binding of morphine to spinal opioid receptors, especially the highly dense k receptors, as the result of an associated conformational change in opioid receptors.[10] It is possible that this conformational change may be responsible for prolonging the inhibitory effect of opioids in the spinal cord.

Our results differ from Palmer et al. and by Milner et al. who concluded that although a dose of 0.1 mg intrathecal morphine provides optimal analgesia for postcesarean section parturients. However, in their none of their patients was completely pain-free and all patients requested additional IV analgesia.[11] In our study, we used 0.2 mg intrathecal morphine, just double the dose used in the above studies which could be the reason for prolonged analgesia.

In another study, Siti and Choy[12] compared the quality of postoperative analgesia between intrathecal fentanyl 25 mcg and intrathecal morphine 0.1 mg in patients undergoing cesarean section. They found that postoperative analgesia of intrathecal fentanyl was inferior to that of intrathecal morphine similar to our observation.

The side effect profile of this study revealed nausea and vomiting more in patients of control than study groups. Many studies on the use of intrathecal fentanyl have demonstrated decreased incidence of intraoperative nausea and vomiting. We found reduction in the incidence of nausea, vomiting, and shivering by the addition of fentanyl to bupivacaine, which is in accordance with the findings of Rudra et al.[13]

Pregnant women seem to be more susceptible to pruritus after neuraxial opioid administration than other populations, with incidence of 60–100%.[14] This increased incidence may be due to an interaction of estrogen with opioid receptors,[15] but it was more pronounced in the fentanyl group. The results published by other authors are comparable pruritus has previously been reported as the most common adverse effect of intrathecal fentanyl. The incidence of pruritus with the administration of opioid into the subarachnoid space was reported to be 62% for morphine, 67% for fentanyl, and 80% for sufentanil.[16] In this study, the incidence of pruritus was 30% and 10% for Group III and Group II, respectively, and although the incidence was about thrice that of intrathecal fentanyl, the occurrences appeared as mild to the face and upper chest regions. However, most cases were tolerably mild and no patient required therapeutic intervention to alleviate the symptoms.

Respiratory depression caused by morphine is more prolonged and may occur much later up to 12 h. These are generally due to an effect of stimulation at the µ receptor.[17] The true incidence of respiratory depression is unknown; two large studies quote the incidence in obstetric population between 0.003% and 0.01%.[18] In our study, no evident respiratory depression, either immediate or delayed, was observed postoperatively, as preventive measures, all patients received oxygen via a facial mask and SpO2 was continuously monitored for at least 24 h. Although respiratory rate and monitoring oxygen saturation by pulse oximetry can detect respiratory depression, arterial blood gas analysis would have given better and accurate idea of it, which was not done in our case. Another reason could be the small sample size of the study to confirm this complication.

About 30% of the patients become drowsy but arousable with the intrathecal fentanyl as compared to those without fentanyl addition. However, there is report where fentanyl addition does not cause any change in the sedation.[10]

On the basis of our results, 0.2 mg morphine intrathecally provided excellent postoperative pain relief without any intolerable side effects in patients undergoing cesarean section. In addition, the overall patient satisfaction was significantly greater in the morphine group. In the existing literature, there are very few reports showing possible effects of low doses of opioids on the neonate outcome in terms of Apgar scores, and successful breast-feeding initiation within 24 h after birth, which was statistically comparable in all the groups demonstrating that both opioids seem safe for newborns.

The limitations of this study were that we did not consider relative density of an LA in relation to that of cerebrospinal fluid, which is one of the most important physical properties that affect the level of analgesia obtained after subarachnoid administration of the drug.[19] Secondarily, umbilical pH and blood gas status could not be done for evaluation of fetal outcome.

CONCLUSION

The study has established that LA can be safely administered with addition of both lipophilic or lipophobic opioids avoiding hemodynamic fluctuation and providing a stable peri- and post-operative period in the obstetric patients. In addition, the duration of sensory analgesia is significantly prolonged with addition of morphine ensuring neonatal well-beings.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.