Pharmacokinetics and efficacy of long-term epidural ropivacaine infusion for postoperative analgesia

The aim of this study was to evaluate the pharmacokinetics and efficacy of the new local anesthetic ropivacaine when used for epidural infusion for up to 72 h after major orthopedic surgery. Immediately after surgery, an epidural infusion of ropivacaine 2 mg/mL was begun at a rate of 6 mL/h in 11 patients. The infusion rate was then adjusted according to patient analgesic needs or side effects. Blood samples were taken during and after the infusion to determine total and unbound ropivacaine and alpha1-acid glycoprotein (AAG) concentrations. Patients were assessed regularly for sensory and motor block and pain using a visual analog scale (VAS) score (0-100 mm). Ten patients received 63-72 h of infusion. Total plasma concentrations of ropivacaine and binding protein (AAG) increased during the infusion such that free concentrations plateaued or began to fall over time. VAS values during mobilization were less than 40 mm in 93% of patients. The majority of patients had no measurable motor block once the surgical block had regressed. When epidural ropivacaine was titrated to achieve a stable sensory block, there was a low incidence of motor block, and free plasma ropivacaine levels were well below the toxic range. Implications: The pharmacokinetics of continuous epidural infusions of ropivacaine are described in patients for up to 72 h postoperatively. Clinical efficacy and side effects are also reported. An understanding of the plasma concentrations obtained and modes of elimination during prolonged epidural infusion is important for safe, routine clinical use in postoperative analgesia.     

Comparison of patient-assisted epidural analgesia with continuous-infusion epidural analgesia for postoperative patients

Number of electroconvulsive therapy (ECT) treatments administered and severity of psychopathology confound the interpretation of clinical studies that address the relationship between the rate of administration of ECT and cognitive morbidity occasioned by the treatment. A preclinical study was therefore conducted to address the issue. Three groups (n = 8/group) of adult male Sprague-Dawley rats received six electroconvulsive shocks (ECS) in daily ECS, 3 ECS/week, and 2 ECS/week schedules; a fourth group (control; n = 8) received only sham ECS. From days 2 to 7 after the conclusion of the ECS/sham ECS course, the rats were monitored for learning on the Hebb-Williams complex maze. The control, 2 ECS/week, and 3 ECS/week groups showed significant learning by days 3, 5, and 7, respectively, while the daily ECS group showed no significant learning during the assessment period. This indicates that even when the cumulative effect of ECS on learning is controlled for, more frequent ECS is associated with slower learning. Extrapolating to clinical settings, it is suggested that wider spacing of ECT may lessen ECT-induced cognitive morbidity.     

Intraoperative intravenous ketamine in combination with epidural analgesia: postoperative analgesia after renal surgery

We designed this double-blinded, randomized, controlled study to evaluate the effect of small-dose ketamine IV in combination with epidural morphine and bupivacaine on postoperative pain after renal surgery. An epidural catheter was inserted, and the administration of morphine and bupivacaine was started before surgery. Forty patients were assigned to one of two groups (ketamine or control). The ketamine group was administered a ketamine bolus and infusion during surgery. The median visual analog pain scale (VAS) scores at rest were significantly lower in the ketamine group during the first 6 h (P < 0.01). VAS pain scores on coughing were also significantly lower in the ketamine group (P < 0.01). Cumulative postoperative total analgesic consumption was less in the ketamine group on Days 1 and 2 (P < 0.001). The first analgesic demand time was shorter in the control group (9.2 +/- 11.5 min) than in the ketamine group (22.3 +/- 17.1 min) (P < 0.0001). The incidence of nausea and pruritus was more frequent in the control group (P < 0.05). In conclusion, postoperative analgesia was more effective when spinal cord and brain sensitization were blocked by a combination of epidural morphine/bupivacaine and IV ketamine. IMPLICATIONS: Renal nociception conducted multisegmentally by both the spinal nerves (T10 to L1) and the vagus nerve cannot be blocked by epidural analgesia alone. We demonstrated that IV ketamine had an improved analgesic or opioid-sparing effect when it was combined with epidural bupivacaine and morphine after renal surgery.     

Clonidine added to bupivacaine-epinephrine-sufentanil improves epidural analgesia during childbirth

BACKGROUND AND OBJECTIVES: A double-blind study was conducted to assess the efficacy and the side effects of a low dose of clonidine added to an epidural injection of bupivacaine and epinephrine, with or without sufentanil. METHODS: One hundred healthy parturients (ASA 1) were randomly allocated into four groups according to the type of epidural analgesia administered. The bupivacaine/epinephrine (BE) group received a 10-mL standard injection of bupivacaine (B) 1.25 mg/mL and epinephrine (E) 1.25 microg/mL. In the bupivacaine/epinephrine/sufentanil (BES) group, 7.5 microg sufentanil (S) was added to the BE mixture. For the bupivacaine/ epinephrine/clonidine (BEC) group, 50 microg clonidine (C) was added to the BE mixture, whereas for the bupivacaine/epinephrine/sufentanil/clonidine (BESC) group, both sufentanil and clonidine were added to BE. Fetal heart rate was monitored by continuous cardiotocography. Duration of analgesia, method of delivery, and neonatal outcome (measured using APGAR score, peripheral oxygen saturation, and neurologic adaptive capacity score) and side effects of clonidine were observed. The parturients were routinely asked for their global appreciation of the epidural analgesia technique by visual analog score, 2 hours postpartum. RESULTS: The overall quality and duration of analgesia were superior in the BESC group compared with the other groups, as was the global appreciation by the parturient. The frequency of side effects in the clonidine groups was comparable, with the exception of hypotension and sedation. Hypotension was easily treated by fluids or ephedrine and caused no fetal distress. The level of sedation was mild, and all parturients aroused immediately after verbal commands. CONCLUSION: The addition of a low dose of clonidine to an epidural injection of bupivacaine with epinephrine and sufentanil provides better analgesia during labor, while keeping the side effects minimal and of minor clinical importance.     

Patient-controlled analgesia versus patient-controlled analgesia plus continuous infusion after hip replacement surgery

OBJECTIVE: To compare the efficacy and adverse effect profile of patient-controlled analgesia (PCA) versus PCA plus continuous infusion (PCACI) after hip replacement surgery. DESIGN: Prospective, randomized, open pilot study. SETTING: Large teaching institution. PARTICIPANTS: Thirty-four patients undergoing hip replacement or revision of hip replacement surgery. INTERVENTIONS: Patients were randomized to receive PCA morphine: 1 mg with 6-minute lockout, or PCACI, using the same dose, with a 0.5-1 mg/h continuous infusion. Pain intensity, sedation, narcotic use, injection/attempt ratio (I/A), and adverse effects were assessed. RESULTS: No significant differences in pain intensity were identified. Morphine use was not different between groups: PCA 61.8 +/- 35.0 and PCACI 74.2 +/- 54.9 mg (p =0.394). A trend toward an increased 12-hour I/A ratio was evident in the PCACI group: PCA 0.73 +/- 0.18 and PCACI 0.86 +/- 0.17 (p =0.073). Patient-reported adverse effects, sedation, and inability to sleep secondary to pain occurred similarly. Eight of 18 PCACI patients required discontinuation of either the continuous infusion mode or of PCA therapy entirely secondary to adverse effects. CONCLUSIONS: When compared with PCA therapy, PCACI was not associated with improved pain control and more patients receiving PCACI required discontinuation of therapy secondary to adverse effects.     

Epidural abscess following continuous epidural analgesia in two traumatized patients

We present a mutational analysis of the iduronate-2-sulfatase (IDS) gene of 36 Russian patients with Hunter syndrome. Among 29 mutant alleles, there were 19 missense mutations, 1 nonsense mutation, 6 mutations affecting splice sites, and 3 major structural alterations resulting in deletions. Of the 25 different mutations, 15 are novel and unique. Most of the missense mutations result in intermediate or severe phenotypes.     

Comparative study of postoperative analgesia with methadone and fentanyl in continuous peridural perfusion

OBJECTIVE: To determine whether continuous epidural perfusion of fentanyl, which is more liposoluble than methadone, provides a similar level of analgesia with fewer side effects than methadone administered by the same route for postoperative pain. PATIENTS AND METHODS: Prospective double blind study of 40 patients, randomly assigned to two groups. Group F (n = 20) received 300 micrograms-1200 micrograms/24 h in epidural perfusion. Group M (n = 20) received 9 mg-18 mg/24 h in epidural perfusion. In both cases treatment was for pain in the first 72 h after abdominal surgery. Analgesia quality was evaluated on a visual analog (VAS) scale from 1 to 10 at rest and moving. Need for complementary analgesia was also recorded, as were side effects related to the technique. RESULTS: Quality of analgesia was good and similar which both drugs. Postoperative pain did not surpass 3 on the VAS at rest or 4.5 while moving, although group F patients' need for complementary analgesia was significantly greater (p < 0.05). The incidence of hypoxemia was greater in group M than in group F (p = 0.05). CONCLUSIONS: Continuous epidural perfusion of fentanyl provides good analgesia and is associated with less hypoxemia than is methadone.     

The epidural use of morphine and alpha 2-agonists for postoperative analgesia

Three protocols of postoperative pain relief after gastric surgery were used in 60 male patients: regular intramuscular morphine, epidural morphine, and epidural morphine with 0.1 mg of clonidine. Pain relief was more effective with the epidural route of administration. Addition of clonidine in a daily dose of 0.1 mg allowed a twofold decrease of epidural morphine dose, involving lesser hyperdynamic postoperative cardiovascular changes and complete elimination of psychotic complications and delirium in alcohol-dependent patients.     

Epidural fentanyl, adrenaline and clonidine as adjuvants to local anaesthetics for surgical analgesia: meta-analyses of analgesia and side-effects

BACKGROUND: The risk/benefit ratio of adding fentanyl, adrenaline and clonidine to epidural local anaesthetics for improving intraoperative analgesia is unclear. This meta-analysis was performed to clarify this issue. METHODS: Trials retrieved by search were considered if they were prospective, controlled, epidural analgesia (without combining general anaesthesia) was planned and occurrence of pain during surgery or side-effects were reported. Papers entered meta-analysis if they reached a predefined minimum quality score. Pooled odds ratios (OR) and confidence intervals (CI) were computed. P < 0.05 was considered as significant. RESULTS: Eighteen trials were included in the analysis for fentanyl. Fentanyl decreased the likelihood of pain (OR = 0.21, 95% CI = 0.15-0.30, P < 0.001) and increased the incidence of pruritus (OR = 5.59, 95% CI = 3.12-10.05, P < 0.001) and sedation (OR = 1.88, 95% CI = 1.19-2.98, P = 0.003), compared to control (local anaesthetic without fentanyl). Fentanyl had no effect on respiratory depression, nausea, vomiting and Apgar score. One case of respiratory depression of a newborn was observed. Because of the very low number of trials selected, evaluation of adrenaline and clonidine was not feasible. CONCLUSION: The analysis of current literature shows that the addition of fentanyl to local anaesthetics for intraoperative epidural analgesia is safe and advantageous. The reduction in the incidence of pain during surgery is quantitatively high and therefore clinically significant. Side-effects are mild. Randomized, controlled trials have to be performed in order to clarify the role of adrenaline and clonidine as epidural adjuvants for surgical analgesia.     

Obstetric analgesia using continuous epidural perfusion of bupivacaine, adrenaline, and fentanyl

OBJECTIVES: To determine the efficacy and complications of continuous epidural perfusion of bupivacaine, adrenaline and fentanyl in the relief of pain during first and second stage labour during vaginal birth. PATIENTS AND METHODS: Between January 1990 and March 1993 we used continuous epidural perfusion for control of pain during labor in 1307 women. The solution administered through an epidural catheter and maintained until expulsion was one 10 ml bolus of bupivacaine 0.25% with adrenaline 1:200,000 and fentanyl 25 micrograms followed by continuous perfusion of bupivacaine 0.0625% with adrenaline 1:200,000 and fentanyl 2 micrograms/ml at an infusion rate of 12 ml/h. When analgesia was insufficient, a bolus of local anesthetic was administered or a pudendal block was carried out. RESULTS: Ninety-two percent of the birthing women reported good analgesic effect during the first stage; for 7% the effect was fair and for 0.55% it was poor. During the second stage 88% reported satisfactory analgesia, and 8% fair or poor. Assessment was not possible for the remaining women, who underwent cesarean sections. Complications were few and easily controllable. CONCLUSIONS: Maintenance of epidural perfusion with 0.0625% bupivacaine with adrenaline 1:200,000 and fentanyl 2 micrograms/ml provides sufficient analgesia during all stages of childbirth.     

Model for action of local anaesthetics

Sodium channels in nerve membranes are postulated to be surrounded by lipid molecules in the gel (or crystalline) phase. Addition of local anasethetics triggers a change in the surrounding lipids to the fluid, liquid crystalline phase, allowing the sodium channel to close with resulting local anaesthesia. The experimental evidence for this model is discussed.     

Recent advances in the pharmacokinetics of local anaesthetics. Long-acting amide enantiomers and continuous infusions

The most widely used long-acting amide local anaesthetic is bupivacaine, a racemic mixture of 2 stereoisomers. However, there is evidence that the use of single enantiomer compounds offers advantages over racemic agents. Ropivacaine, the recently introduced propyl homologue of bupivacaine, is a pure S-(-)-enantiomer. It is associated with a reduced incidence of both cardiovascular and central nervous system toxicity, a concern with racemic bupivacaine, in preclinical studies. The relevant pharmacokinetic differences include a lower lipid solubility, a slightly higher plasma clearance and shorter elimination half-life (t 1/2 beta) compared with racemic bupivacaine, with a similar degree of plasma protein binding. More recently levobupivacaine, the pure S-(-)-enantiomer of bupivacaine, has been produced. Stereoselective differences have been observed between the 2 enantiomers and the racemic mixture, with levobupivacaine exhibiting a slightly higher degree of plasma protein binding, a lower volume of distribution, a higher plasma clearance, and a shorter t 1/2 beta than the R-(+)-enantiomer. In common with ropivacaine, levobupivacaine has been shown to have a reduced incidence of toxicity in comparison the R-(+)-enantiomer in preclinical studies, explained in part by a reduced affinity to both brain and myocardial tissue. Racemic bupivacaine is increasingly administered by continuous infusion to provide prolonged postoperative analgesia. The pharmacokinetic profile of the drug administered in this manner has only recently been elucidated and indicates a slow rise in total plasma concentration with increasing duration of infusion, mitigated by changes in plasma protein concentrations during the postoperative period. This appears to be the predominant reason why complications related to systemic toxicity are rarely observed with this technique. However, continuous administration of individual enantiomers may potentially serve as a safer option in the future.     

Postoperative hypoxaemia: continuous extradural infusion of bupivacaine and morphine vs patient-controlled analgesia with intravenous morphine

We carried out a randomized prospective study in 60 patients who had undergone major abdominal surgery for cancer. For postoperative pain control, 30 patients received continuous extradural infusion of 0.125% bupivacaine 12.5 mg h-1 and morphine 0.25 mg h-1 (EXI group) and 30 received patient-controlled analgesia (PCA) with intravenous morphine (1 mg bolus, 5-min lock-out and maximum dose 20 mg 4h-1). Both groups had general anaesthesia. The two groups were compared for postoperative pain scores, satisfaction, sedation and oxygen saturation. Oxygen saturation was recorded continuously the night before surgery and for two consecutive postoperative nights. Episodes of moderate desaturation (90% > SpO2 85%) were more frequent in the EXI group than in the PCA group (P < 0.05). Pain scores were lower in the EXI group compared with the PCA group at rest and while coughing (P < 0.05). No significant difference was found for patient sedation and satisfaction.     

Midazolam for caudal analgesia in children: comparison with caudal bupivacaine

In a randomized, double-blind study we have examined the analgesic efficacy of caudal administration of midazolam, bupivacaine, or a mixture of both drugs in 45 children, undergoing inguinal herniotomy. They were allocated randomly into three groups (n = 15 in each) to receive a caudal injection of either 0.25% bupivacaine 1 ml.kg-1 with or without midazolam 50 micrograms.kg-1 or midazolam 50 micrograms.kg-1 with normal saline 1 ml.kg-1. There were no differences in quality of pain relief, postoperative behaviour or analgesic requirements between the midazolam group and the other two groups. Times to first analgesic administration (paracetamol suppositories) were longer (P < 0.001) in the bupivacaine-midazolam group than in the other two groups. Further, the bupivacaine-midazolam group received fewer (P < 0.05) doses of paracetamol than the bupivacaine group. Side effects such as motor weakness, respiratory depression or prolonged sedation were not observed in patients who received caudal epidural midazolam only. We conclude that caudal midazolam in a dose of 50 micrograms.kg-1 provides equivalent analgesia to bupivacaine 0.25%, when administered postoperatively in a volume of 1 ml.kg-1 for children following unilateral inguinal herniotomy.     

Outpatient ACL reconstruction using intraoperative local analgesia and oral postoperative pain medication

Thirty-five consecutive anterior cruciate ligament (ACL) reconstructions were performed in an ambulatory surgical unit using a bone-patellar tendon-bone autograft. Patients were evaluated postoperatively to determine the amount of pain medication used, the readmission rate, postoperative complications, and cost. Outpatient ACL reconstruction led to a savings of $4700 compared with the cost of performing the same procedure in a hospital operating room with an overnight admission. This study demonstrates that outpatient ACL reconstruction, using local analgesia intraoperatively and oral narcotic pain medication postoperatively, is a safe and cost-effective procedure with minimal to no morbidity.     

Postoperative patient-controlled epidural analgesia with opioid bupivacaine mixtures

PURPOSE: To determine the efficacy and safety of patient-controlled epidural analgesia of morphine or fentanyl in combination with bupivacaine for postoperative pain relief. METHODS: Forty ASA I-II patients scheduled for major abdominal surgery were studied. After insertion of a lumbar epidural catheter, patients were given a non-opioid general anaesthetic. After surgery patients complaining of pain, received a loading dose of 2 mg morphine (Group I) or 50 micrograms fentanyl (Group II). For continuing pain, 1 mg morphine in 4 ml bupivacaine 0.125% (0.25 mg.ml-1 morphine and 1 mg.ml-1 bupivacaine, Group I) or 20 micrograms fentanyl in 4 ml bupivacaine 0.125% (5 micrograms.ml-1 fentanyl and 1 mg.ml-1 bupivacaine Group II) were administered. Blood pressure, heart rate, respiratory rate and SpO2 were monitored. Assessments of pain (VAS), nausea-vomiting, motor block, pruritus and sedation were recorded for 24 hr. RESULTS: No difference in pain or sedation was observed between groups. The 24 hr postoperative opioid consumption was 15.50 +/- 7.53 mg morphine and 555.10 +/- 183.85 micrograms fentanyl. Total bupivacaine 0.125% consumption was 58.00 +/- 30.14 ml in Group I and 101.05 +/- 36.77 ml in Group II. One patient in Group II complained of motor weakness in one leg. The incidence of nausea (Group I 45%, Group II 10% P < 0.05) and pruritus (Group I 30%, Group II 5% P < 0.05) was less in patients receiving fentanyl. CONCLUSION: Both methods were effective in the prevention of pain but, because of fewer side effects, fentanyl may be preferable to morphine.     

Control of postoperative pain with intrapleural analgesia

INTRODUCTION: Personal experience in the treatment of postoperative pain using intrapleural analgesia applied on 50 patients chosen at random in a group of 90 after thoracotomy is reported. METHODS: At the end of operation a peridural catheter for continuative infusion was applied in the paravertebral socket by direct transfixion of chest wall. A local anaesthetic has been given (75 mg of bupivacaine 0.50%) through the catheter at 8 hours interval for three times at the most. The degree of analgesia has been valued immediately before and after medicine administration and during the 8 hours interval by recording the cardiocirculatory and haemogasanalytical parameters. The measurement of pain intensity has been achieved by visual analogous just an hour after operation and subsequently every 4 hours during the first post operative day and every 8 hours during the following days. RESULTS: Most of the examined patients (90%), reported a remarkable attenuation of pain, valued by achromatic grey test after 4 hours since the first giving. The catheter has always been removed during the 8th postoperative day and it did not cause intrapleural complications. The method used warrants a good level of analgesia, improving the respiratory per-formance and giving a rapid mobilization, essential items in the reduction of immediate post operative complications. CONCLUSIONS: The results confirm the validity of this treatment in the pain control of thoracothomized patients with a positive answer in 45 out of 50 examined patients without remarkable complications.