Prophylactic intravenous ephedrine to minimize fetal bradycardia after combined spinal-epidural labour analgesia: a randomized controlled study.

BACKGROUND: The combined spinal-epidural (CSE) technique for relief of labour pain offers both rapid onset and superior first-stage analgesia. Nevertheless, the known increased risk for early profound fetal bradycardia (EPFB) following CSE continues to be a concern that often limits its use. The purpose of this study was to determine if giving prophylactic intravenous ephedrine at the time of CSE administration would reduce EPFB. METHODS: We conducted this clinical trial at a large community hospital and enrolled healthy patients requesting epidural analgesia for labour. Patients were randomly assigned to receive either normal saline placebo or ephedrine 10 mg iv at the time of CSE. The primary outcome of EPFB (defined as bradycardia < 90 beats·min(-1) for > two minutes and occurring within the first 30 min after CSE) was compared between groups. The secondary outcomes included the incidence of urgent cesarean delivery, the requirement for additional doses of ephedrine, maternal blood pressure, uterine hypertonus and tachysystole, and abnormal fetal heart rate (FHR) patterns before and after CSE. RESULTS: There were 299 women randomized to the ephedrine (EPH) group and 297 randomized to the normal saline placebo (NS) group. There was no difference between groups in the incidence of EPFB (2.7% EPH group vs 4.7% NS group; relative risk, 0.57; 95% confidence interval, 0.24 to 1.33; P = 0.184). There was also no difference between groups in the incidence of urgent cesarean delivery, uterine hypertonus, uterine tachysystole, and abnormal FHR patterns. CONCLUSIONS: We conclude that prophylactic intravenous ephedrine administration at the time of CSE during labour was ineffective at reducing the risk for EPFB associated with CSE. Nevertheless, a lower than expected rate of EPFB resulted in the trial being underpowered. This trial was registered at ClinicalTrials.gov, identifier: NCT02062801.

A randomized controlled comparison of epidural analgesia and combined spinal-epidural analgesia in a private practice setting: pain scores during first and second stages of labor and at delivery.

BACKGROUND: There has been no prospective evaluation of combined spinal-epidural (CSE) analgesia in a private practice setting and few studies have focused on pain relief during the second stage of labor and at delivery. In this randomized controlled trial, we compared verbal pain scores during the first and second stages of labor and at delivery in women receiving CSE or traditional epidural analgesia at a busy private maternity hospital. METHODS: Healthy, term parturients received epidural or CSE analgesia for labor pain upon request. Epidural analgesia was initiated with 0.125% bupivacaine plus 2 µg/mL fentanyl, 15 mL; CSE analgesia was initiated with intrathecal plain bupivacaine 3.125 mg plus 5 µg fentanyl. Thereafter, patient-controlled epidural analgesia with 0.125% bupivacaine plus 2 µg/mL fentanyl was used for maintenance analgesia in both groups. The primary outcome was an assessment of "typical" pain, using a verbal rating pain score from 0 to 10, made at the end of the first stage of labor and shortly after delivery. RESULTS: Data from 398 epidural and 402 CSE subjects were analyzed. The typical verbal rating pain score during the first stage was lower in the CSE group (mean: 1.4 vs 1.9; P < 0.001; 99.5% confidence interval [CI] for difference: -0.92, -0.14). Pain scores during the second stage of labor (1.7 vs 1.9; P = 0.17; 99.5% CI for difference: -0.82, 0.28) and at delivery (2.0 vs 2.0; P = 0.77; 99.5% CI for difference: -0.73, 0.59) were the same between groups. Fewer patients received an epidural top-up dose in the CSE group (16.4% vs 25.6%; P = 0.002; 99.5% CI for difference: -17.0%, -1.0%). Epidural catheters were replaced in 1.2% CSE vs 2% in the epidural group (P = 0.39; 99.5% CI for difference: -3.3%, 1.8%). CONCLUSIONS: Compared with traditional epidural labor analgesia, CSE analgesia provided better first-stage analgesia despite fewer epidural top-up injections by an anesthesiologist.

Extended-release epidural morphine (DepoDur) following epidural bupivacaine in patients undergoing lower abdominal surgery: a randomized controlled pharmacokinetic study.

BACKGROUND AND OBJECTIVES: The primary objective was to compare the serum pharmacokinetic profile of a single dose of extended-release epidural morphine (EREM) administered alone versus 15 to 60 mins after an analgesic epidural dose of bupivacaine. METHODS: This multicenter study enrolled 144 patients, 18 years or older, with scheduled lower abdominal surgery under general anesthesia. Patients were randomly assigned to a single 15-mg dose of EREM; the same dose administered 15, 30, or 60 mins after epidural bupivacaine (20 mL 0.25%); or epidural placebo (normal saline) administered 15, 30, or 60 mins after bupivacaine. Postoperatively, fentanyl patient-controlled analgesia was offered for breakthrough pain. Multiple serum samples were analyzed for morphine and morphine metabolites. Safety and efficacy were assessed. RESULTS: The mean maximum serum concentration and area under the concentration-time curve for morphine and metabolites were not significantly different when EREM was administered alone versus 15, 30, or 60 mins after bupivacaine. Median time to maximum serum concentration and median apparent terminal elimination half-life were also comparable. Total fentanyl patient-controlled analgesia consumption was comparable among all EREM groups (with/without prior bupivacaine) but significantly (P < 0.05) lower compared with the bupivacaine + placebo group. Nausea, vomiting, and dizziness were consistently more frequent in groups receiving EREM after bupivacaine versus EREM alone. CONCLUSIONS: The pharmacokinetic and efficacy profiles of a single 15-mg dose of EREM were not significantly altered when administered 15, 30, or 60 mins after an analgesic epidural dose of bupivacaine.

Pharmacokinetics of extended-release epidural morphine sulfate: pooled analysis of six clinical studies.

PURPOSE: A pooled analysis of six clinical studies was conducted to describe the pharmacokinetics of extended-release epidural morphine sulfate. METHODS: Data from six clinical studies evaluating extended-release epidural morphine sulfate in volunteers and abdominal or hip surgery patients were pooled and analyzed. Participants age 18 years or older received extended-release epidural morphine sulfate (2.5-40 mg) within 30 minutes of surgery initiation. Most participants received a test dose of 1.5% lidocaine with 1:200,000 epinephrine for epidural space identification 15 minutes before study drug administration. Blood samples were generally collected at 0.5, 2, 4, 8, 12, 18, 24, and 48 hours postinjection. RESULTS: Standard epidural morphine sulfate exhibited a spike in drug release, producing higher peak concentrations (C(max)) than 5-mg extended-release epidural morphine sulfate, which produced more prolonged serum morphine concentrations. Using labeled doses of extended-release epidural morphine sulfate (10-20 mg), the C(max) was comparable to that for 5-mg standard epidural morphine sulfate, whereas the apparent terminal elimination half-life and area under the serum concentration-time curve were twofold to fourfold greater and consistent with dose-proportional exposure. The mean dose-normalized C(max) for extended-release epidural morphine sulfate was 25% higher for women versus men. Administering extended-release epidural morphine sulfate 15 minutes after the test dose mitigated any pharmacokinetic interaction. Extended-release epidural morphine sulfate demonstrated dose- related reductions in postoperative fentanyl consumption and pain intensity. CONCLUSION: A pooled analysis of six studies revealed that extended-release epidural morphine sulfate provided a more prolonged release of morphine compared with standard epidural morphine sulfate. Extended-release epidural morphine sulfate displayed a consistent pharmacokinetic profile among adults, with only slight variability between men and women in C(max), which appeared to be mainly caused by differences in body weight.

Respiratory compromise after MgSO4 therapy for preterm labor in a woman with myotonic dystrophy: a case report.

BACKGROUND: MgSO4 is widely used for tocolysis. Serious complications are rare as long as dosing is carefully monitored. Adverse effects in muotonic dustrophy have not been previously described. CASE: A 35-year-old woman, gravida 1, para 0, was hospitalized with suspected mild myotonic dystrophy, polyhydramnios and preterm labor at 33 weeks. MgSO4 infusion rapidly resulted in respiratory compromise. Muscular strength returned to baseline after the infusion was stopped. Mother and infant proved to have myotonic dystrophy. CONCLUSION: The choice of tocolytic medication in maternal myotonic dystrophy is problematic. Beta-2 sympathomimetics have been reported to precipitate myotonia. This case illustrates the potential for MgSO4 to cause respiratory embarrassment. Indomethacin may be the tocolytic of choice in myotonic dystrophy.

A comparison of Depodur, a novel, single-dose extended-release epidural morphine, with standard epidural morphine for pain relief after lower abdominal surgery.

In this randomized, controlled, dose-ranging study, we evaluated the analgesic efficacy of a novel single-dose extended-release epidural morphine (Depodur) in patients undergoing lower abdominal surgery. Five-hundred-forty-one patients were randomly assigned to one of six epidural treatments administered approximately 30 min before surgery. The 6 treatments were 5 mg of standard epidural morphine sulfate (MS) (active comparator); 5 mg of single-dose extended-release epidural morphine (EREM) (dose control); and 10, 15, 20, and 25 mg of single-dose EREM. The main study objective was to assess the efficacy of single-dose EREM 10, 15, 20, or 25 mg versus single-dose EREM 5 mg for the management of postoperative pain. This was done by plotting a linear dose-response relationship to assess postoperative IV patient-controlled analgesia (PCA) fentanyl consumption for breakthrough pain for 48 h after surgery. Secondary safety and efficacy analyses compared the 10-, 15-, 20-, and 25-mg single-dose EREM groups with the 5-mg single-dose EREM group and compared each single-dose EREM group with 5 mg of MS. As shown by the dose-response relationship, there was a dose-related reduction in the use of postoperative IV fentanyl through 48 h (estimated slope, -22.2; P = 0.0002). Patients treated with 10, 20, and 25 mg of single-dose EREM used significantly less IV fentanyl (mean +/- sd: 995 +/- 987 microg, P = 0.0446; 972 +/- 982 microg, P = 0.0221; and 683 +/- 620 microg, P < 0.0001, respectively) through 48 h after surgery compared with the 5-mg single-dose EREM group (1218 +/- 894 microg). At 48 h postdose, significantly more single-dose EREM patients (13%) than MS patients (2%) had required no IV fentanyl (P < 0.01). Although all treatment groups had access to PCA fentanyl and there was more frequent PCA fentanyl use in the MS group, patients in the single-dose EREM 15, 20, and 25 mg groups reported significantly lower pain-intensity scores and greater satisfaction with their pain relief. Overall, single-dose EREM was well tolerated, with 97% of adverse events rated as mild to moderate. As expected, the adverse events reported were consistent with those of other epidural opioids (i.e., nausea, vomiting, pruritus, and hypotension). In conclusion, this controlled study demonstrated that single-dose EREM can provide up to 48 h of postoperative analgesia, but supplementation for breakthrough pain is still required in most patients. Within the context of this study, the side effect profile of single-dose EREM was acceptable and predictable.

Single-dose, sustained-release epidural morphine in the management of postoperative pain after elective cesarean delivery: results of a multicenter randomized controlled study.

In this multicenter, randomized, controlled study, we compared the analgesic efficacy and safety profile of a new single-dose extended-release epidural morphine (EREM) formulation (DepoDur) with that of epidural morphine sulfate for the management of postoperative pain for up to 48 h after elective cesarean delivery. ASA physical status I or II parturients (n = 75) were anesthetized with a combined spinal/epidural technique. Parturients received intrathecal bupivacaine 12-15 mg and fentanyl 10 mug for spinal anesthesia and a single epidural injection of either 5 mg of standard (conventional preservative-free) morphine or 5, 10, or 15 mg of extended-release morphine after cord clamping for postoperative pain control. Single-dose EREM 10 and 15 mg groups significantly decreased total supplemental opioid medication use and improved functional ability scores for 48 h after surgery compared with those receiving 5 mg of standard morphine. Visual analog scale pain scores at rest and with activity at 24 to 48 h after dosing were significantly better in the 10- and 15-mg single-dose EREM groups versus the standard morphine group. There were no significant differences between the two 5 mg (single-dose EREM and standard morphine) groups. Single-dose EREM was well tolerated, and most adverse events were mild to moderate in severity. Single-dose EREM is a potentially beneficial epidural analgesic for the management of post-cesarean delivery pain and has particular advantages over standard morphine for the period from 24 to 48 h after surgery.