Pain can accentuate the body's stress response and adversely affect both endocrine and immune functions. Acute postoperative pain is also considered a risk factor for postoperative chronic pain,1,2 and it may increase postoperative morbidity and delay postoperative recovery. Thus, effective postoperative pain relief has a positive effect on the recovery of surgical patients.
Sufentanil is a selective μ-receptor agonist with a fast onset, short duration of action and a strong analgesic effect (12-fold greater intrinsic potency than fentanyl),3 making it ideal for intravenous patient-controlled analgesia (PCA). However, in common with other opioids, its side effects include respiratory depression, excess sedation, nausea, vomiting and constipation.4 The ideal method of providing postoperative analgesia is to use a combination of drugs that act on multiple anatomic and pharmacologic sites (multimodal therapy). This allows use of lower doses of opioids, which decreases the incidence of side effects. Dexmedetomidine is a highly selective α2 adrenergic receptor agonist that has sedative, analgesic and antianxiety actions, but does not cause respiratory depression.5 Although there are many studies in the literature reporting the use of dexmedetomidine to reduce the perioperative use of opioids,6–9 only a few have studied the use of dexmedetomidine in parturients.10
This prospective, randomised, double-blind, controlled study was designed to investigate whether the administration of dexmedetomidine immediately after delivery and for PCA can decrease postoperative sufentanil consumption and pain intensity after surgery. We also wished to explore the effect of dexmedetomidine on pain threshold (PTh) and pain tolerance threshold (PTTh) of parturients who undergo caesarean section.
Materials and methods
This trial was retrospectively registered at http://www.chictr.org on 24 July 2011 (registration number: ChiCTR-TRC-11001442). The study protocol (2010-05) was approved by the Ethics Committee of Obstetrics and Gynecology Hospital of Fudan University (Chair person: Dr Jinglei Wu) and informed consent was obtained from all parturients who participated in the study. Parturients undergoing elective caesarean delivery under spinal anaesthesia were recruited between January and June 2010. The inclusion criteria were age 18 to 40 years, height 155 to 170 cm and ability to understand verbal and written mandarin. Exclusion criteria included a long history of opioid analgesic use or NSAIDs, tranquilliser use, psychiatric disorders, preoperative heart rate (HR) less than 50 bpm with cardiac conduction or rhythm abnormalities, neuromuscular and endocrine diseases or allergic reactions to α2-adrenergic agonists, and any previous abdominal surgery including prior caesarean section. Individuals were subsequently excluded from the study if spinal anaesthesia was unsuccessful [no cerebrospinal fluid (CSF) or where an epidural catheter had to be used to achieve adequate anaesthesia], or who had prolonged surgery (>1 h), or an estimated intraoperative blood loss more than 500 ml or who required a second operation for postpartum haemorrhage. A computer-generated randomisation table was used to divide patients into three groups (40 per group).
Patients in Group 1 received 20 ml intravenous physiological saline immediately after delivery of the baby. Their PCA protocol (with a background infusion) consisted of 100 μg sufentanil diluted into 100 ml and administered at a continuous dose of 0.015 μg kg−1 h−1 and a bolus dose of 0.023 μg kg−1., with a lock-out of 8 min. Patients in Group 2 received 0.5 μg kg−1 intravenous dexmedetomidine diluted to 20 ml with physiological saline. The PCA protocol was the same as Group 1. Patients in Group 3 also received 0.5 μg kg−1 intravenous dexmedetomidine after delivery and their PCA protocol was 100 μg sufentanil and 300 μg dexmedetomidine diluted to 100 ml, with the continuous dose of sufentanil 0.015 μg kg−1 h−1 and dexmedetomidine 0.045 μg kg−1 h−1, and a bolus dose of sufentanil 0.023 μg kg−1 and dexmedetomidine 0.07 μg kg−1, with a lock-out of 8 min. The randomisation table was kept in the hospital pharmacy where the study medication and PCA solutions were prepared. The research staff who enrolled patients and collected study data were blinded to group assignment.
Parturients were seen before surgery. The method of measuring PTh and PTTh was explained and they were trained how to use the PCA pump. All patients also received instructions for using a 10-cm visual analogue score (VAS) (with 0, no pain; to 10, the worst imaginable pain). No premedication was administered. Upon arrival in the operating room, the individual rested in bed for 10 min, and then PTh and PTTh were measured using the microcurrent stimulation method11 by a PTh detector (EP601C PTh detector; Teaching Equipment Factory of Shanghai East China Normal University, Shanghai, China) on the left upper arm. Two electrodes were fixed over the deltoid muscle of the left upper arm 1.5 cm apart. The detector generates a 50-Hz electrical stimulation with 0.5-ms pulse width. The current intensity was increased gradually from 0 to 5 mA. The electrical PTh was reached when pain was first felt and electrical PTTh was reached when the pain became intolerable.
An 18-gauge intravenous cannula was inserted into a peripheral vein on the right arm. Standard monitoring including ECG, pulse oximetry and noninvasive blood pressure (NIBP) was commenced. NIBP was measured every 5 min during the operation and every 15 min for 24 h after the operation. All women received an intravenous preload of 6% hydroxyethyl starch (130/0.4) 500 ml at a rate of 20 ml min−1 before commencement of anaesthesia. A combined spinal-epidural anaesthesia (CSE) technique was used. The parturient was positioned in the right lateral decubitus position and the epidural space was identified at the L2 to L3 interspace. After lumbar puncture with a 26-gauge pencil-point needle, 1.5 ml (7.5 mg) 0.5% isobaric bupivacaine was injected. The epidural catheter was placed as soon as the spinal needle was withdrawn and parturients were immediately positioned supine with left lateral tilt. Surgery was begun when the sensory block reached T4 to T6 (determined by loss of sensation to pinprick). The epidural catheter was only used when the spinal anaesthesia did achieve an adequate effect or for prolonged surgery. Pain or discomfort during surgery and prior to delivery was managed by administering 5 ml 1% lidocaine via the epidural catheter. If the pain was not controlled after 15 min, another rescue dose was used. Sufentanil 5 μg was given intravenously if pain was reported after delivery. Parturients who needed epidural lidocaine or intravenous sufentanil were excluded. No other analgesic agent or sedative was used during surgery except for dexmedetomidine. Oxygen was administered at 5 l min−1 via a face-mask.
A baseline blood pressure recording was taken in the supine position on the operation bed before the measurement of PTh and PTTh and was calculated from the average of two readings taken 5 min apart. Hypotension (SBP <90 mmHg or more than 20% decline from the baseline) was treated with intravenous phenylephrine 0.1 mg. When the umbilical cord was clamped, the parturient received the study drug, which was administered intravenously over 15 min. After surgery, the parturient was sent to the recovery room, and 1 h after infusion of the study drug, PTh and PTTh were measured again and the level of sensory block was recorded. The PCA pump was then attached and the mother sent to the ward. The PCA was stopped 24 h after surgery.
Sedation was assessed using the Ramsay sedation scores (1, anxious patient; 2, cooperative and tranquil; 3, responding to command; 4, brisk response to stimulus; 5, sluggish response to stimulus; 6, no response to stimulus).12 The degree of satisfaction (0, very satisfied; 1, satisfied; 2, less satisfied; 3, not satisfied) was evaluated at 24 h after surgery. VAS, sedation scores and sufentanil consumption were recorded at 4, 8 and 24 h after surgery. The volume of lochia was recorded for the first 3 h postoperatively by weighing the sanitary napkins. The time to initiation of lactation (period from delivery to when the >10 ml of breast milk was expressed by massaging and compressing both breasts) was recorded. Blood samples were obtained prior to anaesthesia, 1 h after the study drug administration and 24 h after surgery for determination of serum cortisol concentration. Side effects such as hypotension (SBP <90 mmHg or DBP <60 mmHg), bradycardia (HR <60 bpm), hypoxaemia (SpO2 <90%), respiratory depression (respiratory rate <l0 breaths per minute lasting for more than 10 min) and nausea and vomiting were recorded during the period from the end of the surgery until the termination of the PCA regimen. Hypotension or bradycardia was treated with phenylephrine or atropine, respectively. Respiratory depression was treated with naloxone and oxygen.
The primary outcome was the total consumption of sufentanil. In the study by Lin et al.,13 the mean ± SD morphine consumption with and without dexmedetomidine was 32.8 ± 12.4 and 23 ± 10 mg, respectively, a 30% reduction of morphine use with dexmedetomidine. In our study, the hypothesis was that compared with Group 1, Group 3 would achieve a 30% reduction of sufentanil consumption, while Group 2 would achieve a 15% reduction. A power analysis suggested that with 32 individuals per treatment arm, we would have 80% power to detect differences among the means with a 0.05 significance level (two-tailed). Taking exclusions into account, we aimed to recruit 40 patients in each group. Statistical analysis was performed using SPSS 13.0 software (SPSS Inc., Chicago, Illinois, USA). Normally distributed data are expressed as mean ± SD, and skewed data distribution are expressed using median (interquartile range, IQR). Between-group comparisons were performed using repeated-measures analysis of variance (ANOVA). Bonferroni multiple comparisons were made for multiple comparisons. The intragroup comparisons were performed using Wilcoxon rank-sum test. A P value of less than 0.05 was considered significant.
Of the 120 parturients, four withdrew from the study. Two were in Group 1: one patient who received local anaesthetics via epidural catheter because of insufficient anaesthesia and another patient whose intraoperative haemorrhage exceeded 500 ml. The other two were in Group 3; in one, there was no CSF on aspiration and another needed a second operation because of a postpartum haemorrhage. Thus, 116 parturients completed the study (Fig. 1). There were no significant differences in demographic data and general conditions between the three groups (Table 1). The median (IQR) levels of sensory block measured when the parturients entered the recovery room were T7 (T7 to T8), T6 (T6 to T8) and T7 (T6 to T8) for Groups 1, 2 and 3, respectively. There was no difference between the three groups.
PTh was different among three groups (overall ANOVA, P = 0.038). As compared with Group 1 (1.49 ± 0.49 mA), PTh was significantly increased at 1 h after drug administration in Group 2 (1.59 ± 0.45 mA) (P = 0.043) and Group 3 (1.74 ± 0.37 mA) (P = 0.022). PTTh was different among three groups (overall ANOVA P = 0.017). The PTTh at 1 h after drug administration in Group 1 (2.42 ± 0.62 mA) was lower than that in Group 2 (2.57 ± 0.46 mA) (P = 0.012) and in Group 3 (2.56 ± 0.48 mA) (P = 0.019). However, there was no difference in PTh and PTTh 1 h after bolus injection of study drug between Group 2 and Group 3. In Group 2 and Group 3, PTh and PTTh was increased 1 h after drug administration compared with their own baseline values (P < 0.05, Table 2).
There were no differences in VAS scores between Group 1 and Group 2 at 4, 8 and 24 h after surgery. VAS scores in Group 3 were lower than those in Group 1 at 4 h (P < 0.001), 8 h (P < 0.001) and 24 h (P = 0.002) after surgery. Parturients in Group 2 had higher VAS scores than those in Group 3 at 4 h (P < 0.001), 8 h (P < 0.001) and 24 h (P = 0.004) after operation (Fig. 2), while the satisfaction score were higher in Group 3 than those in other two groups (Table 3).
The total amount of sufentanil consumption over the 24 h after surgery in Group 3 (43.9 ± 19.2 μg) was lower than that in Group 1 (54.5 ± 23.9 μg; P = 0.023) and Group 2 (56.3 ± 20.6 μg; P = 0.013) (Fig. 3). Serum cortisol concentrations were increased 1 h after dexmedetomidine/physiological saline injection compared with the baseline before anaesthesia in all three groups, but there was no difference in serum cortisol levels among the three groups. The median (IQR) time to initiation of lactation was 56 (40 to 64) hr in Group 1, 56 (38 to 62) h in Group 2 and 55 (43 to 68) h in Group 3; there was no difference between the three groups. The amount of lochia and the time to initiation of lactation were the same in three groups. The RSS score was 2 at each time point, and no adverse reactions such as hypotension, bradycardia (HR <60 bpm), hypoxaemia and respiratory depression were observed in any of the three groups after injecting the initial study drug. Two parturients in Group 1, one in Group 2 and two in Group 3 experienced nausea. The incidence of nausea in three groups was not different. There was no vomiting in the three groups.
In this prospective study, we found that intravenous injection of a loading dose of dexmedetomidine immediately after delivery increased the PTh and PTTh values of parturients 1 h after injecting the initial study drug. We also found that adding dexmedetomidine to PCA reduced the consumption of sufentanil, enhanced analgesic effect and improved maternal satisfaction. Moreover, the addition of dexmedetomidine had no effect on the time to initiation of lactation and the amount of lochia.
Intrathecal anaesthesia is the first choice for parturients without contradictions who select caesarean section. As parturients are at a high risk of a difficult airway, sedatives and tranquillisers are seldom used during caesarean section. However, a certain degree of sedation can increase the comfort of parturients receiving combined epidural spinal anaesthesia.14 Compared with other sedatives, dexmedetomidine has better properties,15 such as light sedation and less likelihood of respiratory depression.16 The recommended loading dose of dexmedetomidine is 0.5 to 1 μg kg−1 in nonpregnant women. In addition, a case report has shown that a 0.5 μg kg−1 loading dose of dexmedetomidine reduced the labour pain of a 31-year-old parturient.17 The duration of caesarean section operations is relatively short (30 to 45 min), so we selected a loading dose of 0.5 μg kg−1. The onset time for dexmedetomidine is approximately 15 min, with a distribution half-life approximately 6 min and an elimination half-life approximately 2 h.18 Thus, we elected to measure PTh and PTTh 1 h after study drug infusion. A previous study demonstrated that morphine could be used in combination with dexmedetomidine for postoperative analgesia during general anaesthesia,13 and that satisfactory analgesia could be achieved when a continuous dose of 0.05 μg kg−1 h−1 of dexmedetomidine was used intravenously within 4 to 24 h after surgery. In this study, we used isobaric bupivacaine for spinal anaesthesia. The effective duration of spinal anaesthesia is 2 to 4 h, so the PCA was started 1 h after study drug administration with a dexmedetomidine dose of 0.045 μg kg−1 h−1.
The study by Nielsen et al.19 showed that the preoperative PTh correlated significantly with post-caesarean pain score (VAS) at rest and on mobilisation and the preoperative electrical PTh seems to predict the intensity of postoperative pain. There was no difference in preoperative PTh and PTTh in our three groups. We found that the loading dose of dexmedetomidine can increase PTh and PTTh values of parturients, and dexmedetomidine can enhance the analgesic effect of sufentanil, reducing the consumption of sufentanil. This is the first reported study that measured PTh and PTTh in pregnancy. It is probable that dexmedetomidine increased the PTh and PTTh of the parturients, thus relieving the intensity of postoperative pain and reducing the consumption of sufentanil. However, a single dose of dexmedetomidine did not improve postoperative analgesia at 4, 8 and 24 h after surgery. The most probable explanation is that the increase of PTh and PTTh by a single dose could not last long enough nor be strong enough to affect postoperative pain scores and opioid consumption. Another possibility is that the analgesic effect of spinal anaesthesia using bupivacaine may override the analgesia derived from a single dose of dexmedetomidine. Thus, the parturients in Group 2 that had higher PTh and PTTh did not have lower pain scores and opioid consumption. However, the continuous dosing by PCA did show benefit of reducing postoperative analgesia and sparing opioid.
Our study found that sufentanil consumption was reduced by 20% in the parturients who received sufentanil and dexmedetomidine in their PCA, compared with the other two groups, indicating that dexmedetomidine plays a role in the course of clinical analgesic treatment by binding central and peripheral α2 receptors and reducing the consumption of opioid. The VAS was below four in all three groups, reaching the level of satisfactory analgesia. The VAS was even lower and the rate of analgesic satisfaction was even higher in parturients who received sufentanil and dexmedetomidine in the PCA than in patients in the other two groups, indicating that dexmedetomidine can be beneficial as an adjuvant for postoperative intravenous analgesia in parturients who undergo caesarean section.
Patient haemodynamics were stable in all three groups, and the RSS score was 2 at all time-points. No adverse reactions such as hypotension, bradycardia and hypoxia were observed after surgery in the dexmedetomidine group. This might due to the lower dose of dexmedetomidine than previous studies.
Cortisol is one of the hallmark hormones of the stress response.20 Our study showed that cortisol levels were slightly increased 1 h after drug administration in three groups compared with the baseline; this may be due to surgical stimulation. There was no significant difference between the three groups. This may be because caesarean section is a pelvic procedure in the lower abdomen and spinal anaesthesia may completely block the sympathetic pathway, thus inhibiting the stress response. The cortisol level was not increased 24 h after surgery, most likely because postoperative analgesia was satisfactory.
There are some limitations in the present study. We did not have a group that received a physiological saline bolus and sufentanil/dexmedetomidine PCA to test whether the dexmedetomidine bolus in Group 3 had any clinical benefit. However, this will be further investigated in future studies. We did not measure the concentration of dexmedetomidine in the breast milk due to limit of detection technology. We only studied the time until initiation of lactation, but breastfeeding success rates or the degree of infant exposure to dexmedetomidine through the expressed milk was not evaluated. The time until initiation of lactation after operation was 55 to 56 h; however, the infusion of dexmedetomidine ended 24 h after surgery. According to dexmedetomidine's pharmacokinetics (t1/2 = 2 h), its concentration in breast milk was probably extremely low in our study. Hypotension was defined as an SBP below 90 mmHg; however, others have used a definition of lower than 100 mmHg or a 20% drop from baseline. Furthermore, blood pressure was measured less frequently than in other studies. Our results should only be applied to parturients undergoing elective caesarean delivery after an otherwise uneventful pregnancy. In addition, the study was not powered for maternal and neonatal safety. Therefore, further research is needed to confirm the safety of dexmedetomidine in parturients and neonates.
In conclusion, the combination use of sufentanil and dexmedetomidine for PCA can reduce sufentanil consumption, enhance the analgesic effect and improve parturients’ satisfaction compared with sufentanil PCA alone. Although the use of dexmedetomidine bolus immediately after delivery can increase parturients’ PTh and PTTh, it has not shown any clinical benefit in postoperative pain management in the current study.
Acknowledgements relating to this article
Assistance with the study: the authors would like to thank Dr Wei Jiang and Dr Guiling Li, from Department of Gynecology, for their assistance with the study.
Financial support and sponsorship: none.
Conflicts of interest: none.
1. Perkins FM, Kehlet H. Chronic pain as an outcome of surgery. A review of predictive factors. Anesthesiology
2. Callesen T, Bech K, Kehlet H. Prospective study of chronic pain after groin hernia repair. Br J Surg
3. Scott JC, Cooke JE, Stanski DR. Electroencephalographic quantitation of opioid effect: comparative pharmacodynamics of fentanyl and sufentanil. Anesthesiology
4. Gadsden J, Hart S, Santos AC. Postcesarean delivery analgesia. Anesth Analg
5. Ebert TJ, Hall JE, Barney JA, et al. The effects of increasing plasma concentrations of dexmedetomidine in humans. Anesthesiology
6. Arain SR, Ruehlow RM, Uhrich TD, Ebert TJ. The efficacy of dexmedetomidine versus morphine for postoperative analgesia after major inpatient surgery. Anesth Analg
7. Bulow NM, Barbosa NV, Rocha JB. Opioid consumption in total intravenous anaesthesia is reduced with dexmedetomidine: a comparative study with remifentanil in gynecologic videolaparoscopic surgery. J Clin Anesth
8. Ayoglu H, Yapakci O, Ugur MB, et al. Effectiveness of dexmedetomidine in reducing bleeding during septoplasty and tympanoplasty operations. J Clin Anesth
9. Al-Zaben KR, Qudaisat IY, Al-Ghanem SM, et al. Intraoperative administration of dexmedetomidine reduces the analgesic requirements for children undergoing hypospadius surgery. Eur J Anaesthesiol
10. El-Tahan MR, Mowafi HA, Al Sheikh IH, et al. Efficacy of dexmedetomidine in suppressing cardiovascular and hormonal responses to general anaesthesia for caesarean delivery: a dose-response study. Int J Obstet Anesth
11. Aasvang EK, Hansen JB, Kehlet H. Can preoperative electrical nociceptive stimulation predict acute pain after groin herniotomy? J Pain
12. Yazigi A, Abou-Zeid H, Srouji T, et al. The effect of low-dose intravenous ketamine on continuous intercostal analgesia following thoracotomy. Ann Card Anaesth
13. Lin TF, Yeh YC, Lin FS, et al. Effect of combining dexmedetomidine and morphine for intravenous patient-controlled analgesia. Br J Anaesth
14. Cheng YJ, Wang YP, Fan SZ, Liu CC. Intravenous infusion of low dose propofol for conscious sedation in cesarean section before spinal anesthesia. Acta Anaesthesiol Sin
15. Yoshida Y, Nakazato K, Takemori K, et al. The influences of propofol and dexmedetomidine on circadian gene expression in rat brain. Brain Res Bull
16. Venn RM, Bradshaw CJ, Spencer R, et al. Preliminary UK experience of dexmedetomidine, a novel agent for postoperative sedation in the intensive care unit. Anaesthesia
17. Palanisamy A, Klickovich RJ, Ramsay M, et al. Intravenous dexmedetomidine as an adjunct for labor analgesia and cesarean delivery anesthesia in a parturient with a tethered spinal cord. Int J Obstet Anesth
18. Bhana N, Goa KL, McClellan KJ. Dexmedetomidine. Drugs
19. Nielsen PR, Nørgaard L, Rasmussen LS, Kehlet H. Prediction of postoperative pain by an electrical pain stimulus. Acta Anaesthesiol Scand
20. Desborough JP. The stress response to trauma and surgery. Br J Anaesth