Spinal anaesthesia is often used for both elective and emergency Caesarean section. Adding an opioid to the intrathecally administered local anaesthetic solution is a widely used method for improving the intraoperative and early postoperative quality of the subarachnoid block [1,2]. In recent years, opioids have been widely used for effective perioperative pain control when administered either intrathecally or as an adjunct to epidural local anaesthetics in patients undergoing Caesarean section. Intrathecal administration of local anaesthetics alone provides anaesthesia of shorter duration. Patients request analgesics earlier during the postoperative period and local anaesthetics alone are less effective in controlling the nausea–vomiting induced by surgical uterine manipulations than the combined intrathecal administration of local anaesthetic and opioid [3,4].
There are numerous studies on intrathecal morphine as an adjunct to hyperbaric bupivacaine for spinal anaesthesia in patients undergoing Caesarean section. Morphine is a highly ionized hydrophilic opioid, which provides a spinal analgesia of slow onset and long duration. In addition to the slow onset of analgesia, side-effects such as nausea and vomiting, pruritus and late respiratory depression limit its usefulness . Because of morphine's dose-limiting side-effects, numerous other opioids have been used intrathecally, including fentanyl, alfentanil and sufentanil. The addition of lipophilic opioids such as sufentanil to hyperbaric bupivacaine hastens the onset of spinal anaesthesia and improves both intraoperative and early postoperative analgesia .
This study aims to compare the quality of intraoperative anaesthesia, postoperative analgesia, the maternal and neonatal side-effects of 5 μg sufentanil or 0.2 mg morphine added to hyperbaric bupivacaine for spinal anaesthesia in patients undergoing Caesarean section.
After obtaining approval from the local Ethics Committee and written informed consent from each patient, 54 healthy (ASA I or II), full-term parturients scheduled for Caesarean section were included in the study. The indications for Caesarean section were either primary elective or repeat Caesarean section with no evidence of fetal distress in any of the patients. The inclusion criteria were parturients at term (gestation week 36–41), age ≥ 18 yr, height ≥ 150 cm, body weight ≤ 110 kg, singleton fetus and estimated fetal weight ≥ 2500g. Exclusion criteria were pre-eclampsia, and a history of allergies, sensitivity or any other form of reaction to local anaesthetics of the amide type. All patients were instructed on the use of the visual analogue scale (VAS) (0 = no pain, 10 = worst possible pain) on the day before operation. The parturients had nothing per os and were not given a premedication.
The patients were randomly assigned according to a computer-generated random number list into two groups of 27 patients each to receive either 0.2 mg (0.5 mL) morphine (Morphine group) or 5 μg (0.5 mL) sufentanil (Sufentanil group) as an adjunct to intrathecal bupivacaine 0.5% (2 mL). Patients taller than 165 cm were given an additional bupivacaine 0.5% 0.3 mL. The spinal anaesthetic technique was the same in all patients. Routine intraoperative monitoring devices (ECG, pulse oximetry, non-invasive blood pressure monitor, Datex-Ohmeda, Instrumentarium Corp., Helsinki, Finland) were attached. After insertion of a 16-G intravenous (i.v.) cannula, all patients were given 15 mL kg−1 balanced crystalloid solution infused over 10–15 min before intrathecal injection of the drugs. Spinal anaesthesia was induced with the patient in the sitting position. Lumbar puncture was performed at the L3–4 interspace with a 26-G spinal needle (Atraucan, B. Braun Melsungen, Brasil). The intrathecal injection was completed within 10 s after free flow of clear cerebrospinal fluid was observed. Neither the anaesthesiologist nor the patient were aware of group assignment and study solution.
Immediately after the intrathecal injection, the patients were placed in the supine position, with a wedge under the right hip to maintain left uterine displacement. Oxygen (5 L min−1) was given by facemask until delivery. Sensory block height was evaluated with bilateral pin-prick test at the midclavicular line and motor block was evaluated by Bromage scale (0 = none, 1 = ability to flex knees, but not the hips, 2 = unable to flex knees, but no problems with ankle movement, 3 = no movement possible in any lower extremity) every 2 min until skin incision. The operation started when sensory block level reached T4. The surgical technique was uniform for all patients and included exteriorization of the uterus. At delivery, blood samples were collected from the umbilical artery and vein for blood gas analyses (Stat Profile Nova 9, USA). Apgar scores was recorded at 1, 5 and 10 min. The neonate was also evaluated with the neurologic and adaptive capacity score (NACS) at 2 and 24 h after delivery.
The onset time of sensory block (time to reach L1 sensory block), time to T10 sensory block, time to highest sensory block, highest sensory block level, time to regression of sensory block to T10 level and time to resolution of motor blockade were recorded. Anaesthesia induction to delivery time, skin incision to delivery time, uterine incision to delivery time and duration of surgery were recorded.
Non-invasive systolic, diastolic and mean arterial pressures, heart rate (HR) and oxygen saturation were evaluated every 2 min during the first 20 min after subarachnoid block and then every 5 min throughout the operation. Hypotension was defined as a decrease in systolic arterial pressure of more than 30% or a systolic arterial pressure below 100 mmHg. Hypotension was treated by i.v. fluid loading and 5 mg ephedrine i.v. Bradycardia was defined as a HR below 55 beats min−1 and was treated with 0.01– 0.02 mg kg−1 atropine i.v. Maternal respiratory depression was defined as a respiratory rate less than 10 breaths min−1 or peripheral oxygen saturation less than 95%.
Intraoperative pain was assessed by VAS at skin incision, uterine incision, delivery, end of operation. Additional analgesic (fentanyl 50 μg) was given when required (VAS > 3). Intra- and postoperative occurrence of maternal side-effects such as nausea, vomiting, pruritus, or respiratory depression were recorded. Metoclopramide was given for vomiting or after two successive episodes of nausea. Pruritus was treated with 20 mg diphenhydramine i.v. Sedation was scored as follows every 15 min throughout the operation; 0 = awake, 1 = drowsy, 2 = asleep but rousable, 3 = unrousable. Urinary retention was not assessed since the patients had a urethral catheter for 24 h. In the postanaesthesia care unit, HR, mean arterial pressure, oxygen saturation and respiratory rate were continuously monitorized for 24 h. The time to the first postoperative request for an analgesic was also recorded.
The duration of postoperative analgesia was used as the main end-point for statistical analysis. A power analysis based on previous studies [4,7], in which the duration of postoperative analgesia was found to be 271 ± 66 min after 5 μg of intrathecal sufentanil and 585 ± 446 min after 0.2 mg of intrathecal morphine showed that two groups of 27 patients each would be required to demonstrate a 50% difference in postoperative analgesia duration with a Type I error of 0.05 and a Type II error of 0.1. Statistical analysis was performed with the SPSS (SPSS for Windows Release 10.0) statistical package. The results are presented as mean ± standard deviation, median (range), or frequencies as appropriate. Continuous variables were analyzed with t-test. Nominal or ordinal variables were analyzed by χ2 test and Fisher's exact test or U-test. P < 0.05 was considered statistically significant.
There were no significant differences among the groups with respect to patients characteristics, gestational age and parity of the patients (Table 1). Surgical variables such as spinal anaesthesia induction to delivery time, skin incision to delivery time, uterine incision to delivery time and duration of surgery were similar in both groups (Table 2).
There were no significant differences among the groups in the onset time of sensory block (time to reach L1 sensory block), time to T10 sensory block, time to highest sensory block, highest sensory block level, time to regression of sensory block to T10 level and time to resolution of motor blockade (P > 0.05) (Table 3). None of the patients received any supplemental analgesics or sedatives during the intraoperative period. The time to the first postoperative request for analgesics was significantly longer in the Morphine group (19.5 ± 4.7 h vs. 6.3 ± 5.2 h; (P < 0.05) (Table 3). Nineteen patients in the Morphine group (70%) and one patient in the Sufentanil group (3.6%) did not require additional analgesics during the first 24 postoperative hours.
All patients were haemodynamically stable during the perioperative period. The hypotensive response to the spinal block, as well as ephedrine requirements were similar in both groups (14.6 ± 6.6 mg vs. 15.7 ± 6.8 mg). Intraoperative nausea or vomiting is not observed in any patient. Intraoperative pruritus was observed in only two patients given intrathecal sufentanil. There were no significant differences in the incidence of postoperative nausea, vomiting or pruritus (Table 4). Respiratory parameters were stable and oxygen saturation values did not decrease to less than 97% in any patient, at any time during the study period (Table 4). There were no significant differences between the groups with respect to intraoperative sedation scores (Table 4).
Apgar scores at 1, 5, 10 min and NACS scores at 2, 24 h were not significantly different between the groups (Table 5). Umbilical arterial and venous blood gases were within normal limits and without significant differences between the groups (Table 5).
Morphine is the most important analgesic drug used in the management of postoperative pain [8,9] and the discovery of opioid receptors in the substantia gelatinosa of the spinal cord pointed the way to new modes of administration [10,11]. Intrathecal morphine in doses of 0.1–0.2 mg and sufentanil 5–10 μg are commonly used in obstetric analgesia [9,11–13]. The addition of an opioid to the local anaesthetic has been widely studied in the management of spinal anaesthesia for Caesarean delivery, but there is no consensus yet about the optimal choice of opioid and dosage. In the present study, neither intrathecal morphine 0.2 mg nor intrathecal sufentanil 5 μg influenced time of onset and regression of sensory or motor block, but morphine prolonged the time to the first request for additional analgesia compared to sufentanil. Morphine and sufentanil were both associated with similar incidences of side-effects. This study showed that neither opioid had any gross effect on the neonate.
The intraoperative efficacy of intrathecal morphine has been described previously [10,11]. Nevertheless, its slow onset of action has raised doubts about its usefulness for Caesarean section where pain is visceral and caused mostly by peritoneal traction. In this study, none of the patients needed intraoperative supplementary analgesia. This confirms the quality of sensory blockade obtained with spinal anaesthesia.
Although intrathecal opioids are not known to cause significant haemodynamic changes , there have been some reports of significant hypotension after intrathecal fentanyl and sufentanil [15,16]. In Caesarean section, hypotension is the complication with the highest potential for causing detrimental effects to the fetus. In the present study, severe hypotension was not seen despite the high level of the sensory block (T4). This may be due to the prophylactic fluid therapy before and during subarachnoid block, as well as continuous left uterine displacement until delivery. In both groups, there was a similar decrease in systolic arterial pressure at the time of maximal sensory block height, which may be attributed to the sympathetic blockade induced by local anaesthetics.
Ummenhofer and colleagues  investigated the rate and extent of opioid distribution within cerebrospinal fluid, spinal cord, epidural space and systemic circulation after intrathecal injection in anaesthetized pigs. The investigators found that the integral exposure of the spinal cord (area under the opioid concentration curve in cerebrospinal fluid divided by dose) was higher with morphine than with alfentanil, fentanyl and sufentanil after intrathecal administration. Morphine's relatively low lipid solubility seems to be responsible for this observation, while it also accounts for the fact that morphine displays the greatest rostral spread. In contrast, the most highly lipid soluble drugs, fentanyl and sufentanil, have the most limited rostral spread, and their high volumes of distribution in the spinal cord, epidural space, and epidural fat result in very low integral exposure of the spinal cord. Ummenhofer and colleagues  reported the dose of intrathecal sufentanil that produces maximal analgesia (12.5 μg) to be 8–16 times less than a typical analgesic dose of intrathecal morphine (100–200 μg). Braga and colleagues , reported that intrathecal sufentanil doses of 5.0 and 7.5 μg added to hyperbaric bupivacaine increased the duration of analgesia compared with a dose of 2.5 μg or placebo in patients undergoing Caesarean section. The investigators reported no significant difference between the dose of 5.0 μg and 7.5 μg in terms of duration of analgesia (434 min and 427 min, respectively). In other studies, intrathecal doses of sufentanil higher than 10 μg did not provide any corresponding increase in analgesia . In the present study, 5 μg sufentanil provided effective analgesia only during the first 6 h postoperatively.
The low lipid solubility of morphine accounts for its slower onset but longer duration of action. Its duration of action after intrathecal administration is 12–24 h. The efficacy and safety of intrathecal 0.2 mg morphine combined with hyperbaric bupivacaine has been reported in earlier studies [6,11]. Abboud and colleagues  studied 35 patients undergoing Caesarean section with spinal anaesthesia using either 0.1 mg morphine, 0.25 mg morphine or saline as an adjuvant to hyperbaric bupivacaine. Morphine 0.1 and 0.25 mg provided excellent, long-lasting postoperative analgesia (27.7 ± 4.0 h and 18.6 ± 0.9 h, respectively). All patients in the saline group required additional subcutaneous morphine (8 mg) within 3 h after induction of spinal anaesthesia. In another placebo-controlled study, the effects of 0.2 mg morphine sulphate added to hyperbaric spinal bupivacaine were evaluated in 34 patients undergoing Caesarean section . The patients given morphine did not request additional analgesia for 27 ± 0.7 h, compared with 2 ± 0.3 h in the patients given saline.
In patients undergoing Caesarean section with spinal anaesthesia, intrathecal opioids may cause additional nausea, vomiting, pruritus, urinary retention and respiratory depression due to μ and κ opioid receptor activations . Nausea and vomiting due to uterine manipulations and peritoneal closure are frequent side-effects of Caesarean section. Adding an opioid to the local anaesthetic has been reported to decrease the incidence of intraoperative nausea and vomiting . In this study, no patient had intraoperative nausea or vomiting. Nausea and vomiting have been reported to occur far more frequently in the postoperative period . In this study, the incidence of postoperative nausea was found to be 29.6% in the Morphine group and 22.2% in the Sufentanil group.
Pruritus is a relatively minor, but common side-effect of central neuraxial opioid administration with an incidence of 50–90% . In contrast to the transient pruritus caused by highly lipid soluble opioids, morphine usually causes more severe and prolonged pruritus. Facial pruritus is mediated by opioid receptor action in the medulla, rather than by histamine discharge. Pruritus in regions other than the face has a segmental spread and its severity is dependent on the dose of the intrathecal opioid. The incidence of pruritus with epidural sufentanil is reported to be about 35–55%, while pruritus incidences of 90–100% have been reported with 1.5–10 μg intrathecal sufentanil for vaginal delivery. In one study, pruritus occurred with an incidence of 86% with intrathecally administered 10 μg sufentanil. The incidence decreased to 80% with the combination of sufentanil and bupivacaine . In the present study, the pruritus incidence was 62.9% in the Morphine group and 70.3% in the Sufentanil group. Most cases were mild and only three patients in the Morphine group required treatment. Sedation has been shown to be less with centrally administered opioids than when given parenterally . Sedation induced by opioids has generally not been reported except with doses exceeding those commonly used in current clinical practice . In this study, 62.9% of the patients in the Morphine group and 51.8% of the patients in the Sufentanil group were completely awake.
There are conflicting data on the incidence of late respiratory depression after intrathecal opioid administration. In a prospective study on 856 patients, there were eight cases of respiratory depression after 0.2 mg intrathecal morphine . Swart and colleagues  reported one case of respiratory depression 14 h after the administration of 0.1 mg intrathecal morphine in addition to bupivacaine in 30 patients undergoing Caesarean section with spinal anaesthesia. This respiratory depression was attributed more to postoperative parenteral opioid consumption (24 mg morphine) by patient-controlled analgesia than to the spinal opioid. In agreement with data from Abouleish and colleagues  in whose study 0.2 mg morphine was added to intrathecal hyperbaric bupivacaine, there was no case of respiratory depression in the Morphine group in our study. There are reports of high sensory block levels and respiratory depression after intrathecal administration of 10 μg sufentanil. Standl and colleagues  reported six cases of respiratory depression among 50 patients who were given 5 μg sufentanil intrathecally in addition to 2.5 mg bupivacaine for early postoperative pain management after major lower-limb surgery. These patients experienced a short episode of respiratory depression within 30 min of the intrathecal injection. The incidence of respiratory arrest after intrathecal opioid administration in obstetric patients was reported to be 0.02%. In this study, oxygen saturation levels were above 97% at all measurement times and there was no case of respiratory depression in either group. The inclusion of healthy parturients in the study, pregnancy induced central stimulation of the respiratory center and exclusion of any opioid administration during the postoperative period might have played a role in this result. However, the present study might have been underpowered to detect differences in the incidence of respiratory depression between the groups. We can therefore not state whether morphine or sufentanil is safer with respect to respiratory adverse events when given as an adjunct to intrathecal hyperbaric bupivacaine for Caesarean section. All patients receiving intrathecal morphine should be closely monitored in the first 24 h after surgery for potential side-effects such as respiratory depression. Future research must also focus on what is clinically significant respiratory impairment from intrathecal opioids and the optimal monitorization for these effects.
Although the Apgar scores at 1, 5, and 10 min shows the general well-being of the newborn, NACS is more sensitive for the assessment of adaptivity and the depressive effects of the drugs on newborn. In the present study, both groups demonstrated low NACS scores at 2 h after delivery, but there was a significant improvement at the 24 h NACS score. Dahlgren and colleagues  found no differences in umbilical cord blood gases or neonatal Apgar and NACS scores between groups given 2.5 or 5 μg of intrathecal sufentanil, fentanyl 10 μg or placebo when administered together with hyperbaric bupivacaine for Caesarean section. In this study, similar to the findings of Dahlgren and colleagues  umbilical cord blood gases, neonatal Apgar and NACS scores were similar between Morphine and Sufentanil groups.
In conclusion, this randomized, double-blind study comparing intrathecal morphine 0.2 mg and intrathecal sufentanil 5 μg added to hyperbaric bupivacaine for Caesarean section, showed that both techniques provided safe and effective anaesthesia, but that morphine increased the duration of postoperative analgesia without increasing maternal or neonatal side-effects.
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