2016 Volume 39 Issue 9 Pages 1455-1460
To compare the effects of intrathecal dexmedetomidine and intrathecal morphine as supplements to bupivacaine in cesarean sections under spinal anesthesia. Full-term parturients (n=120) undergoing elective cesarean sections under spinal anesthesia were randomly allocated into three groups: Group B received 10 mg bupivacaine, Group BD received 10 mg bupivacaine plus 5 µg dexmedetomidine, and Group BM received 10 mg bupivacaine plus 100 µg morphine. The onset and regression time of sensory and motor blockade, postoperative analgesia, and side effects were recorded. Group BD showed quicker onset time and a longer sensory and motor blockade than other groups (BD vs. B and BD vs. BM, p<0.05). The mean time of sensory regression to the S1 segment was 253.21±42.79 min in group BD, 192.50±40.62 min in group BM and 188.33±37.62 min in group B (p<0.001). Group BD showed an analgesia duration (time to requirement of first rescue analgesic) (17.59±6.23 h) similar to that of group BM (16.78±5.90 h) but longer than that of group B (3.53±1.68 h) (p<0.001). The incidence of pruritus was significantly higher in group BM compared with groups BD and B (p<0.001). Less shivering was observed in group BD than in groups BM and B (p=0.009). So intrathecal dexmedetomidine (5 µg) prolonged the motor and sensory blockade, provided a similar analgesic effect and reduced pruritus and shivering compared with morphine (100 µg) in cesarean sections.
Supplementary drugs are often used for local intrathecal anesthetics to improve anesthesia, achieve better analgesic effects, and reduce the required dose of local anesthetics. Intrathecal opioids are often used for postoperative analgesia in cesarean sections. Intrathecal 0.2 mg morphine produced up to 20 h analgesia for cesarean sections,1) and 5–25 µg intrathecal fentanyl provided 1–4 h analgesia and shortened the onset of sensory and motor block while it prolonged the action time.2) However, opioids are consistently associated with the following side effects: itching, drowsiness, respiratory depression, nausea and vomiting or urinary retention.
The α2 agonist clonidine has been used as an intrathecal supplement to local anesthetics, and this supplement increases anesthetic effects, reduces the amount of local anesthetics,3–5) and prolongs the extent of sensory and motor block.6,7) Dexmedetomidine is a new type of α2 adrenoreceptor agonist similar to clonidine, and the α2/α1 selectivity of this drug is eight times higher than that of clonidine. Most clinical studies of intrathecal-α2 adrenoreceptor agonists have been associated with clonidine,8,9) while published studies on the use of intrathecal dexmedetomidine are scarce. Some studies have shown that the intrathecal administration of dexmedetomidine increases anesthetic effects,10–12) provides stable hemodynamic conditions, and improves the quality of intraoperative and prolongs postoperative analgesia with minimal side effects.13,14)
There are no such studies that compare the intrathecal administration of dexmedetomidine with intrathecal morphine during cesarean sections. Hence, the aim of the present study was to investigate and compare intrathecal morphine and dexmedetomidine as adjuvants to bupivacaine to examine their effects on efficacy, post-operative analgesia, side effects and neonatal conditions in cesarean sections.
We conducted a one center, double-blinded, randomized clinical trial at Shenzhen Maternity and Child Care Hospital (China). After receiving the approval of the ethics committee, written informed consent was obtained the day prior to surgery. We followed the recommendations of Consolidated Standards of Reporting Trials (CONSORT) to report randomized, controlled clinical trials.15) The trial was registered with the Chinese Clinical Registry Center (Registration no. ChiCTR-TRC-14005227). Patients (American Society of Anesthesiology (ASA) physical status I and II, full-term gestation) presenting for elective cesarean sections were enrolled in the present study. The patients were recruited between July 2014 and March 2015. Patients refusing spinal anesthesia (SA), presenting any contraindication to regional anesthesia, presenting with allergies to local anesthetics or showing any major co-morbidity were excluded from the present study.
Randomization and allocation were realized using a computer-generated random number assignment prior to the start of the study and sealed in envelopes opened prior to entry in the study. Both the patients and operators (anesthetists, intraoperative and postoperative observers and recorders) were unaware of the group allocation. A nurse not involved in the study prepared the medication solution, and attached numbers 1–3. The original bupivacaine solution was 0.75% isobaric, the original morphine solution was 10 mg/mL, and the original dexmedetomidine solution was 0.1 mg/mL. All solutions were diluted to 2 mL using saline. Group BD received 2 mL of 0.5% bupivacaine containing 5 µg of dexmedetomidine (n=40); Group BM received 2 mL of 0.5% bupivacaine containing 100 µg of morphine (n=40); and Group B received 2 mL of 0.5% bupivacaine alone (n=40). According to previous reports, intrathecal dexmedetomidine (3–10 µg) was safely used clinically.10,11,13) In the present study, 5 µg of dexmedetomidine was used to supplement the local anesthetics. The patients would be ruled out when spinal anesthesia failed or surgery was too long, resulting in the use of other unpredicted sedation methods or analgesics or transformed to general anesthesia.
Anesthesia ProcedurePatients fasted overnight, and no preoperative medications were administered. Upon arrival in the operating room, pulse oximetry, electrocardiogram, and non-invasive blood pressure were monitored, and the baseline values were recorded. Oxygen (5 L/min) was delivered using a face mask until delivery. An intravenous catheter was placed, and the patients were preloaded with Lactated Ringer’s Solution (12–15 mL/kg) prior to the induction of spinal anesthesia.
SA was performed at the L3–4 intervertebral space with the patient in the lateral decubitus position. A 25 G pencil point spinal needle was introduced, and the correct position of the needle was confirmed based on the free flow of cerebrospinal fluid prior to withdrawing the stylet. The syringe containing the precise dose of medication was attached. The solution was injected at a rate of 0.1 mL/s. The needle was subsequently withdrawn, and the patient was immediately placed in the supine position with the uterus leftward. The time at which the drug administration was completed was recorded, and all durations were calculated considering the time of spinal injection as time zero.
Vital signs were monitored and recorded at 5-min intervals throughout the procedure. The onset of sensory blockade at the highest level was determined using the pinprick method (loss of pinprick sensation to a 23 G needle) every 2 min from the administration of the spinal anesthesia drug. Motor block was assessed using the Modified Bromage Scale16): Bromage 0, the patient is able to move the hip, knee and ankle; Bromage 1, the patient is unable to move the hip but is able to move the knee and ankle; Bromage 2, the patient is unable to move the hip and knee but is able to move the ankle; and Bromage 3, the patient is unable to move the hip, knee and ankle. The time from administration of the subarachnoid blockade to maximum motor blockade was recorded. Insufficient intraoperative analgesia, if any, was relieved (at the patient’s request) using an intravenous bolus injection of ketamine (1 mg/kg). All patients were pretreated with 6 mg of tropisetron to prevent nausea and vomiting. Hypotension (a decrease in systolic blood pressure of more than 30% from the baseline or a decrease below 90 mmHg) was treated with 10–15 mg ephedrine, and bradycardia (heart rate <50 beats per min) was treated with 0.3–0.5 mg atropine.
Surgeons assessed the extent of muscle relaxation: 0, good; 1, fair; and 3, poor. After delivery of the baby, blood samples were collected from the umbilical vein for blood gas analyses. The neonatal heartbeat, Apgar score at 1 and 5 min and neurologic and adaptive capacity score (NACS) at 2 and 24 h were recorded.
Sedation was assessed by Ramsay sedation scale, intraoperation and post operation. (Ramsay Sedation Scale: 1. Anxious, agitated; 2. Co-operative, oriented and tranquil; 3. Responding to commands; 4. Brisk response to glabellar tap; 5. Sluggish response to glabellar tap; 6. No response).
All side effects, such as insufficient analgesia, hypotension, bradycardia, nausea, vomiting, pruritus and shivering, dizziness, and respiratory depression (SpO2 <90% or respiratory rate <10 breaths/min) were recorded.
All patients received patient controlled intravenous analgesia (PCIA) through a pump after surgery. The pump contained 200 mL of 10 µg/mL fentanyl, with no background flow, a 4 mL bolus injection, and a 30 min locked time.
During the postoperative period, sensory and motor regression were recorded every 15 min until the sensory and motor blockade regressed to S1 and Bromage 0, respectively. The VAS (visual analog scale: 0, no pain; 10, most serious pain) was determined at 4, 8, 12, 24, and 48 h after drug administration. The postoperative analgesia duration was evaluated based on the time interval between subarachnoid injection and the need for first rescue analgesics.
Follow-up (neurological deficits secondary to spinal anesthesia) was conducted 48 h post-surgery. An anesthesiologist unaware of group allocation and blinded to the study drug recorded all observations.
Primary OutcomesThe primary endpoint was observed as the character of blockade and analgesic and sedation effects. The time from subarachnoid blockade administration to the time when the highest level of blockade was achieved was recorded as the onset of sensory block. The sensory regression time was defined as the time from subarachnoid drug administration to the time when the S1 level was achieved. Motor blockade was evaluated using the modified Bromage scale. The time from administration of the subarachnoid blockade to the time when the maximum motor blockade was achieved was recorded as the onset of motor blockade. Motor regression time was recorded every 15 min until the motor blockade regressed to Bromage 0.
The VAS of skin incision, fetal delivery, the uterus being drawn outward, and peritoneum closer was recorded. The time from intrathecal drug administration to the first use of analgesics and the total volume of drug consumption of each patient were recorded.
Secondary OutcomesSecondary endpoints included side effects and newborn baby conditions.
Side effects such as pruritus, shivering, nausea, vomiting, hypotension, urinary retention, respiratory depression and dizziness were recorded during both the operation and post operation, and neurological complications were also recorded.
The potential of hydrogen (PH) of the umbilical vein, neonatal heartbeat, Apgar scores at 1 and 5 min and Neonatal Adaptive and Capacity Score (NACS)17) at 2 and 24 h were all recorded.
Statistical AnalysisStatistical analysis was conducted using SPSS software package version 19 (2010, IBM Corporation, Somers, NY, U.S.A.). To calculate the required sample size, a power analysis of (α=0.05, β=0.90) showed that 30 patients per study group were required to detect an increase of the 30 min difference between the median duration of spinal sensory blockade between the groups. The continuous variables are presented as the mean±standard deviation (S.D.), and the categorical variables are presented as absolute numbers and percentages. Probability values less than 0.05 were considered significant. For categorical covariates, the Chi-square (χ2) tests or Fisher’s exact tests were used as appropriate, with p-values reported at the 95% confidence interval (CI). ANOVA was used for the analysis of continuous variables (age, height, weight, and onset and regression time of the sensory and motor blockade). If the p-value indicated significance, then Turkey’s honest significant difference (HSD) post-hoc multi-comparison test was applied to evaluate the significance between each pair of groups.
In the present study, a total of 120 parturients were randomized, and 118 parturients were included in the final analysis. One parturient in group BD failed spinal anesthesia and changed to epidural anesthesia, and one parturient in group B eventually changed to general anesthesia because the surgery was complicated and lasted for 4 h. Both parturients were excluded from the present study.
Patient Demographics and Clinical Characteristics (Table 1)The demographic data are shown in Table 1. Three groups were comparable in terms of age, height, weight, gestation age, operation time and base line vital signs (p>0.05).
| BD (n=39) | BM (n=40) | B (n=39) | p Value | |
|---|---|---|---|---|
| Age (years) | 29.77±4.04 | 29.63±3.32 | 29.74±3.70 | 0.983 |
| Height (cm) | 160.00±4.59 | 159.00±4.30 | 160.03±3.94 | 0.480 |
| Weight (kg) | 75.44±7.93 | 74.08±7.65 | 74.05±5.66 | 0.620 |
| Gestational age (weeks) | 38.98±0.86 | 39.06±0.90 | 38.88±0.84 | 0.667 |
| Duration of surgery (min) | 40.51±7.99 | 39.45±8.75 | 38.41±7.62 | 0.524 |
| SAP (mmHg) | 119.08±14.09 | 119.42±14.11 | 117.64±11.03 | 0.817 |
| MAP (mmHg) | 83.77±9.82 | 84.80±9.69 | 84.46±8.33 | 0.882 |
| HR (beats/min) | 79.84±14.25 | 79.27±11.20 | 79.23±11.61 | 0.971 |
The values are presented as the mean±S.D. SAP: systolic arterial pressure. MAP: mean arterial pressure. HR: heart rate.
Sensory and motor blockade characteristics are shown in Table 2. The peak sensory and motor blockade levels were similar between groups. Group BD attained a significantly shorter onset time (p<0.05) and showed a longer duration of sensory and motor block than the other groups (p<0.001). The muscle relaxation score was comparable between groups.
| BD (n=39) | BM (n=40) | B (n=39) | p Value | |
|---|---|---|---|---|
| Peak sensory blockade | 5.54±1.12 | 5.75±1.01 | 5.69±1.08 | 0.664 |
| Peak motor blockade | 3 | 3 | 3 | — |
| Sensory onset time (min) | 6.46±1.35*,# | 7.82±2.31 | 7.43±2.23 | 0.010 |
| Motor onset time (min) | 4.87±1.36*,# | 5.95±2.01 | 5.89±1.89 | 0.012 |
| Sensory regression time (min) | 253.21±42.79**,## | 192.50±40.62 | 188.33±37.62 | <0.001 |
| Motor regression time (min) | 226.15±40.51**,## | 161.25±40.14 | 162.18±25.31 | <0.001 |
| Muscle relaxation score | 0.31±0.61 | 0.40±0.78 | 0.51±0.85 | 0.488 |
The values are presented as the mean±S.D., with the exception of the peak sensory level (median, interquartile range). * Compared with the control group, p<0.05. ** Compared with the control group, p<0.001. # Compared with group BM, p<0.05. ## Compared with group BM, p<0.001.
Group BD showed postoperative analgesic effects similar to group BM, associated with longer time to first analgesics and smaller total opioid volume at 24 and 48 h, compared with the control group (p<0.001). Sedation score was comparable between groups.
| BD (n=39) | BM (n=40) | B (n=39) | p Value | ||
|---|---|---|---|---|---|
| VAS | Skin incision | 0 | 0 | 0 | — |
| Fetal delivery | 0.44±0.64 | 0.40±0.55 | 0.38±0.81 | 0.935 | |
| Uterus outward | 0.31±0.57 | 0.35±0.58 | 0.33±0.62 | 0.950 | |
| Close peritoneal | 0.26±0.44 | 0.28±0.45 | 0.33±0.48 | 0.741 | |
| Post-operative | 4 h | 0.38±0.59* | 0.43±0.59* | 0.82±0.79 | 0.007 |
| 8 h | 0.69±0.73* | 0.80±0.82* | 1.2±0.86 | 0.015 | |
| 12 h | 2.77±1.2* | 2.78±1.21* | 3.51±1.55 | 0.020 | |
| 24 h | 3.51±1.52* | 3.60±1.13* | 4.41±1.35 | 0.006 | |
| 48 h | 2.51±1.32 | 2.50±1.34 | 3.03±1.31 | 0.130 | |
| Sedation score (intraoperative) | 2.20±0.41 | 2.05±0.22 | 2.05±0.22 | 0.196 | |
| (postoperative 4 h) | 2.70±0.86 | 2.45±0.51 | 2.25±0.44 | 0.089 | |
| Time to first analgesics (h) | 17.59±6.23** | 16.78±5.90** | 3.53±1.68 | <0.001 | |
| Total volume of 24 h analgesics (mL) | 16.79±4.75** | 18.75±4.70** | 56.92±14.02 | <0.001 | |
| Total volume of 48 h analgesics (mL) | 103.46±20.16** | 115.55±32.03** | 150.12±31.06 | <0.001 | |
The values are presented as the mean±S.D. * Compared with the control group, p<0.05. ** Compared with the control group, p<0.001.
Shivering was significantly reduced in the BD group compared with the other groups (p<0.001). Pruritus was much less in the BD and B groups than in the BM group (p=0.009). No respiratory depression, urinary retention or nerve system complications were observed.
| Side effects | BD (n=39) | BM (n=40) | B (n=39) | p Value | |||
|---|---|---|---|---|---|---|---|
| No. | % | No. | % | No. | % | ||
| Additional analgesics | 1 | 2.6 | 2 | 5 | 4 | 10.3 | 0.339 |
| Hypotension | 15 | 38.5 | 16 | 40 | 12 | 30.8 | 0.661 |
| Bradycardia | 3 | 7.7 | 2 | 5 | 1 | 2.6 | 0.573 |
| Nausea/Vomiting | 5 | 12.8 | 9 | 22. 5 | 4 | 10.3 | 0.278 |
| Shivering | 3*,# | 7.7 | 12 | 30 | 14 | 35.9 | 0.009 |
| Pruritus | 0## | 0 | 13** | 32.5 | 1 | 2.6 | <0.001 |
* Compared with the control group, p<0.05. ** Compared with the control group, p<0.001. # Compared with group BM, p<0.05. ## Compared with group BM, p<0.001.
There was no significant difference between the three groups concerning the Apgar score, umbilical vein PH, or neonatal heartbeat (p>0.05). NACS was comparable between the groups.
| BD (Mean±S.D.) | BM (Mean±S.D.) | B (Mean±S.D.) | p Value | |
|---|---|---|---|---|
| One-minute Apgar | 8.51±0.76 | 8.63±0.90 | 8.74±0.82 | 0.470 |
| Five-minutes Apgar | 9.64±0.49 | 9.83±0.38 | 9.64±0.49 | 0.119 |
| Umbilical vein PH | 7.30±0.08 | 7.34±0.11 | 7.33±0.08 | 0.159 |
| Heart rate | 136.33±10.98 | 142.40±11.46 | 140.20±11.78 | 0.062 |
| NACS at 2 h | 35.56±1.71 | 35.83±1.68 | 36.03±1.48 | 0.457 |
| NACS at 24 h | 38.13±1.26 | 38.05±1.32 | 38.12±1.28 | 0.718 |
PH: Potential of hydrogen. NACS: Neurological and adaptive capacity score.
In the present study, we compared the use of intrathecal dexmedetomidine with intrathecal morphine for spinal anesthesia during cesarean sections. The results of the present study showed that the supplementation of spinal bupivacaine with 5 µg dexmedetomidine produced a similar analgesic effect as intrathecal morphine, associated with less pruritus and shivering. Sensory and motor blockade were prolonged with intrathecal dexmedetomidine compared with intrathecal morphine. No obvious neonatal side effects were observed in the three groups. We concluded that dexmedetomidine is an adequate alternative to opioids as an intrathecal additive in cesarean sections.
The blockade characteristics shown in Table 2 indicate that supplemental dexmedetomidine improves anesthesia effects and prolongs the anesthesia time compared with the use of bupivacaine alone, consistent with other reports.11–13,18) The mechanism by which intrathecal α2-adrenoceptor agonists prolong motor and sensory blockade through local anesthetics is not well understood. The prolongation of effects might result from synergism between the local anesthetic and the α2-adrenoceptor agonist.19) Intrathecal dexmedetomidine combined with spinal bupivacaine prolongs the sensory block through the suppression of C-fiber transmitter release and the hyperpolarization of post-synaptic dorsal horn neurons,15) while the prolongation of the motor block of spinal anesthetics might result from the binding of α2-adrenoceptor agonists to motor neurons in the dorsal horn.20,21) Most studies have indicated that intrathecal dexmedetomidine prolongs the sensory and motor blockade of local anesthetics, although a consensus regarding the onset time of these effects has not been reached. Some studies have demonstrated a faster onset time,10,22) while other studies have recorded no difference.23) The results of the present study showed that intrathecal dexmedetomidine has a rapid onset time of anesthesia.
In the present study, dexmedetomidine produced analgesic properties similar to morphine regarding the first rescue analgesics and total volume consumed during 24 and 48 h. Compared with the control group, the analgesic effect of intrathecal bupivacaine was prolonged through the intrathecal administration of 5 µg of dexmedetomidine or 100 µg morphine. However, there were no such comparative studies concerning dexmedetomidine and morphine, and some studies comparing intrathecal dexmedetomidine and fentanyl11–13,18,24) reported that dexmedetomidine produced better analgesic effects than fentanyl.
In terms of adverse effects, the most obvious benefit of dexmedetomidine is that this drug avoids the pruritus compared with morphine. Moreover, shivering, nausea and vomiting were also less in the dexmedetomidine group compared with the morphine group, consistent with other studies.25–28) The low incidence of shivering might reflect a decreased shivering threshold and a lower core temperature.29)
The most significant side effects reported for the use of intrathecal α2-adrenoreceptor agonists are bradycardia and hypotension. In the present study, the incidence of bradycardia was not significant. Previous studies have demonstrated that intrathecal dexmedetomidine at doses of 5 and 10 µg has no significant effect on blood pressure or heart rate.30) However, in the present study, the incidence of postoperative hypotension was mild but significant, and patients did not report any discomfort; therefore, no additional treatment was required.
Previous studies have also shown that intravenous dexmedetomidine has no adverse effect on parturients and neonates,31–33) similar results were also obtained in the present study. The results showed no difference in the Apgar score, heart rate or NACS compared with the control group. The α2-agonist clonidine was safely used as an intrathecal supplement in cesarean sections34,35); however, dexmedetomidine eliminates faster than clonidine in maternal circulation and much less in fetal circulation,36) thus, theoretically, dexmedetomidine is safer for babies than clonidine.
A limitation of the present study is that the formula of the postoperative analgesia pump did not consider differences in the weight of parturients and might affect the assessment of the analgesic effects. In addition, intrathecal dexmedetomidine in obstetric anesthesia is not widely used, thus the safety of the use of dexmedetomidine requires further study.
Intrathecal dexmedetomidine supplementation produced prolonged sensory and motor blockade and similar analgesic effects compared with supplementation using 100 µg of morphine. Furthermore, intrathecal dexmedetomidine additive produced less side effects compared with morphine, and there were no obvious side effects on neonates. Thus, these findings indicate that dexmedetomidine is a suitable alternative to intrathecal morphine in cesarean sections.
The research is supported by Shenzhen Health and Family Planning Commission (Project number: 201402062). The authors would like to thank our colleagues for help and support of the study.
The authors declare no conflict of interest.
