Efficacy, Safety, and Pharmacokinetics of Levobupivacaine with and without Fentanyl after Continuous Epidural Infusion in Children: A Multicenter Trial

Background: Levobupivacaine, the levo-enantiomer of bupivacaine, is as potent as bupivacaine but less toxic. Therefore, the authors investigated the efficacy, safety, and pharmacokinetics of perioperative epidural levobupivacaine with and without fentanyl in children.

Methods: After Research Ethics Board approval and informed written consent, 120 healthy children aged 6 months to 12 yr who were scheduled to undergo urologic or abdominal surgery were randomized in a double-blinded and concealed manner to receive one of four epidural solutions as a continuous infusion for 24 h: 0.125% levobupivacaine; 0.0625% levobupivacaine; 1 [mu]g/ml fentanyl; or the combination, 0.0625 levobupivacaine and 1 [mu]g/ml fentanyl. After induction of anesthesia and tracheal intubation, a lumbar epidural catheter was sited, a loading dose was administered (0.75 ml/kg levobupivacaine, 0.175%), and the epidural infusion was commenced. The primary endpoint was the need for rescue analgesia (morphine) in the first 10 h after surgery. Pain, motor strength, and side effects were recorded for 24 h. Venous blood was collected from 18 children to determine the plasma concentrations of levobupivacaine and/or fentanyl before and 2, 4, 8, 16, 24, and 26 or 30 h after the start of the epidural infusion.

Results: Of the 114 children who were analyzed for intention to treat, a similar number of children in each group reached the 10-h mark. The time to the first dose of morphine in the first 10 h was less in the plain fentanyl group (P < 0.044). All other effects were similar among the four groups. The plasma concentration of levobupivacaine increased during the infusion period, reaching a maximum of 0.76 +/- 0.11 [mu]g/ml in the 0.125% group and 0.48 +/- 0.12 [mu]g/ml in the 0.0625% group by 24 h. The plasma concentration of fentanyl also increased steadily, reaching a maximum concentration of 0.37 +/- 0.11 ng/ml by 24 h.     

Pharmacokinetics of Bupivacaine during Postoperative Epidural Infusion: Enantioselectivity and Role of Protein Binding

Background: Changing plasma protein concentrations may affect the protein binding and pharmacokinetics of drugs in the postoperative period. This study examined the effect of postoperative increases (in response to surgery) in plasma [alpha]1-acid-glycoprotein (AAG) concentrations on the plasma concentrations of the enantiomers of bupivacaine during continuous epidural infusion of racemic bupivacaine for postoperative pain relief.

Methods: Six patients scheduled for total hip surgery with combined epidural and general anesthesia received a bolus dose of bupivacaine (65 mg) followed by constant-rate (8 ml/h) epidural infusion of 2.5 mg/ml bupivacaine for 48 h. Total and unbound plasma concentrations of the enantiomers of bupivacaine and plasma AAG concentrations during the 48-h epidural infusion were determined.

Results: Total plasma concentrations of the enantiomers of bupivacaine increased steadily during the infusion (P < 0.0001), whereas unbound concentrations did not change after 12 h (P > 0.1). Total plasma concentrations of S (-)-bupivacaine were higher than those of R (+)-bupivacaine (P < 0.02), whereas unbound concentrations of S (-)-bupivacaine were lower than those of R (+)-bupivacaine (P < 0.002). AAG concentrations initially decreased, but thereafter increased steadily (P < 0.0001). Consequently, free fractions of the enantiomers initially increased and then decreased with time (P = 0.0002). Free fractions of S (-)-bupivacaine were smaller than those of R (+)-bupivacaine (P = 0.0003).     

Pharmacokinetics and Analgesic Effect of Ropivacaine during Continuous Epidural Infusion for Postoperative Pain Relief

Background: The pharmacokinetics and clinical efficacy of ropivacaine (2.5 mg/ml) during a 24-h continuous epidural infusion for postoperative pain relief in 20 patients scheduled for abdominal hysterectomy were characterized using an open-label, increasing-dose design.

Methods: Through an epidural catheter inserted at T10-T12, a test dose of 7.5 mg ropivacaine was given 3 min before a bolus dose of 42.5 mg and immediately followed by a 24-h continuous epidural infusion with either 10 or 20 mg/h. Peripheral venous plasma samples were collected up to 48 h after infusion, and urinary excretion was followed up to the end of infusion. Postoperative pain at rest, on coughing, and at mobilization was assessed by means of a visual analog scale 2, 4, 6, 8, 12, and 24 h after the end of surgery. Sensory (pinprick) and motor block (modified Bromage scale) were assessed at the same intervals.

Results: The total plasma concentrations of ropivacaine increased markedly and consistently during the 24-h epidural infusion, in contrast to stable unbound concentrations. Both total and unbound plasma concentrations at the end of infusion were proportional to the total dose, although only the latter was proportional to the infusion rate. The total and unbound plasma clearance was independent of dose. Total mean clearance decreased on average by 21% (P < 0.001) during the last 12 h of epidural infusion, i.e., from 539+/-191 ml/min to 418+/-138 ml/min, indicating time-dependent kinetics. The unbound clearance also varied between estimates after 8 h of infusion and the end of treatment, i.e., a 5.3% decrease from 10.4+/-5.3 l/min to 9.5+/-3.9 l/min (P < 0.05). The unbound fraction of ropivacaine in plasma decreased during treatment, and this was related to the increase in alpha1 -acid glycoprotein concentration. Pain was generally well controlled, and median visual analog scale scores during mobilization were less than 30 mm in patients receiving ropivacaine at 20 mg/h.     

Continuous Infusion of Intraperitoneal Bupivacaine after Laparoscopic Surgery: A Randomized Controlled Trial

Background  A standard approach for postoperative analgesia in laparoscopic surgery is to infiltrate the incisions with local anesthetic in combination with systemic opioids. The intraperitoneal introduction of local anesthetic in this setting has the potential to provide appropriate analgesia without the side effects of systemic opioids. We performed a randomized clinical trial of the On-Q pump delivery system to determine the safety and efficacy of this device for this novel purpose. Methods  Thirty patients undergoing laparoscopic adjustable gastric banding were randomly assigned to one of two groups. The treatment group received On-Q pump systems filled with 0.375% bupivacaine, while the control group received pumps filled with 0.9% normal saline. The pump’s catheter was introduced intraperitoneally, and bupivacaine or saline was then delivered for the first 48 h after surgery. Patient’s subjective pain scores were evaluated at preset intervals. In addition, shoulder pain, morphine requirements, and anti-emetic requirements were tabulated. Results  A statistically significant decrease in patient’s subjective reports of pain by visual analog score was noted in the On-Q group 1.8 ± 1.93 vs. control 3.5 ± 2.4, p < 0.046 and remained significant until the end of the study (48 h). No statistical difference was noted in shoulder pain, morphine requirements, or anti-emetic requirements at any time point. Conclusion  Our trial was able to provide evidence of significant reduction in postoperative pain as measured by subjective pain scores with the use of continuous intraperitoneal bupivacaine using the On-Q pain pump system. Further investigation is warranted to evaluate the cost effectiveness of this technique.     

A Comparative Study of Sequential Epidural Bolus Technique and Continuous Epidural Infusion

Background: In this randomized, double-blind study, the authors compared the effectiveness of a sequential epidural bolus (SEB) technique versus a standard continuous epidural infusion (CEI) technique of local anesthetic delivery. Both techniques used the same hourly dose of local anesthetic.

Methods: Sixteen gynecologic patients undergoing abdominal surgery received postoperative epidural analgesia using 0.75% ropivacaine at a dose of 22.5 mg (3 ml) per hour. Patients were randomly assigned to one of two groups. In the SEB group (n = 8), patients received one third of the hourly dose every 20 min as a bolus. In the CEI group (n = 8), the hourly dose was administered as a continuous infusion. Analgesia was assessed by rest pain scored by a visual analog scale and pinprick to determine the number of separately blocked spinal segments on each side of the body. Doses of rescue medication for pain were also recorded.

Results: The median number of blocked spinal segments was 19.5 (range, 18-24) in the SEB group and 11.5 (range, 10-18) in the CEI group (P < 0.001). The median difference in the number of blocked segments between the right and left sides was 0 (range, 0-1) in the SEB group and 2 (range, 0-6) in the CEI group (P < 0.04). No patients in the SEB group but one patient in the CEI group required rescue medication for pain. The visual analog scale pain score was 0 in both groups except for one patient in the CEI group during the study period.     

Continuous Epidural Analgesia in Prostatectomy: Comparison of Bupivacaine With and Without Adrenaline

Epidural analgesia is well-suited for lower abdominal surgery, especially on patients of advanced age groups. Bupivacaine (Marcain) has gradually become a well-established analgesic which is well-suited for epidural analgesia, being distinguished by its potency and prolonged action. As a rule, it has been recommended to add adrenaline to the analgesic solution to obtain the maximum period of action and to keep the plasma level of the analgesic as low as possible. However, since the addition of adrenaline per se involves a risk of untoward reactions, we were interested in investigating whether a clinical trial could demonstrate any difference between bupivacaine 0.5% with and without the addition of adrenaline. The trial was carried out double-blind in 50 consecutive prostatectomies performed under continuous epidural analgesia. The catheter was left in the epidural space for the first 24 postoperative hours, and during this period, the patients were kept free of pain by injection of the analgesic solution through the catheter as required. In this material, there was no difference with respect to effect, extent or duration of analgesia between the two groups.     

硬膜外连续泵注芬太尼与布比卡因用于分娩镇痛的临床研究

目的：探讨硬膜外泵注芬太尼与布比卡因用于分娩镇痛的有效性及安全药物剂量。方法：以０．１５％布比卡因为对照,比较０．０００５％至０．００１２％范围内四种不同浓度芬太尼与之混合硬膜外泵注的分娩镇痛效果。结果：选用０．０００８％与０．００１％两种浓度芬太尼与０．１５％布比卡因混合泵注时,镇痛作用起效快,镇痛时间明显延长,而且不增加副作用。结论：硬膜外连续泵注芬太尼与布比卡因用于分娩镇痛能明显改善镇痛效果,芬太尼使用浓度以限制在０．０００８％至０．００１％为宜。     

Epidural Analgesia with a Combination of Bupivacaine and Buprenorphine in Rats

We determined the analgesic effects of epidural administration of either bupivacaine at 62.5, 125, 250, and 500 μg/kg; buprenorphine at 5 and 10 μg/kg; and the combination of bupivacaine at 125 μg/kg and buprenorphine at 5 or 10 μg/kg, using the tail flick (TF) and colorectal distension (CD) tests in rats and compared the results with those obtained using morphine at 100 μg/kg. In both the TF and CD tests, all doses of bupivacaine alone produced potent anti‐nociceptive effects, although the effect rapidly diminished after 20–30 min of administration. The administration of buprenorphine at 10 and 5 μg/kg produced mild to moderate anti‐nociceptive effects in both the TF and CD tests, and the effects were relatively constant throughout the 2‐h experimental period. Combinations of 5 or 10 μg/kg of buprenorphine with 125 mg/kg of bupivacaine produced a significantly higher percentage of maximum possible analgesic effect (%MPE) than that of the calculated additive effect of each drug alone in the TF and CD tests. The analgesic effect of this combination was similar to that of morphine. Minimal ataxia was observed in rats administered this combination.     

小剂量持续静脉泵入对患者自控镇痛效果的影响

目的 :对患者自控镇痛 (PCA)使用或不使用背景灌注 (CI)两种镇痛模式进行观察比较。方法 :4 0例ASAⅠ或Ⅱ级腹部手术后患者 ,随机分为不使用背景灌注的PCA组与使用背景灌注的PCA +CI组 ,每组 2 0例 ,以吗啡作镇痛剂 ,观察两组的临床疗效 ,并测定血清吗啡浓度。结果 :两组在镇痛效果 (VAS均低 )及夜间睡眠上均满意 ;2 4小时吗啡总用量 (2 3 5 6± 13mg和 2 8 91± 13 88mg) ,最低有效吗啡血清浓度 (变化在 17 2～ 3 9 7ng/ml及 2 1 8～3 9 5ng/ml之间 )及HR、BP、RR、VT、SpO2 两组间变化相似 (P >0 0 5 ) ;而吗啡用量的个体差异较大 (3 5 6～ 4 9 76mg及 13 3 8～ 61 72mg) ;副作用恶心呕吐各为 4例和 6例 ,PCA +CI组 1例皮肤瘙痒 ,无临床呼吸抑制病例。结论 :PCA及PCA联合低剂量CI两种镇痛模式均是术后镇痛的安全有效方法。     

A Comparison of Epidural Morphine and Epidural Bupivacaine for Postoperative Pain Relief

In 32 patients subjected to total hip replacement, postoperative pain relief was achieved by random treatment with either 5 mg of morphine in 10 ml of saline (n = 15) or 6–8 ml of 0.5% bupivacaine with epinephrine (n = 17), both drugs administered by the lumbar epidural route. In an additional group of 10 patients, post-traumatic thoracic or post-operative abdominal pain was relieved first by 4–6 ml of 0.5% bupivacaine with epinephrine and subsequently by 5 mg of morphine in 10 ml of saline, both drugs being administered by the thoracic epidural route. The duration of analgesia was significantly longer, on average, with morphine (28 h) than with bupivacaine (4.3 h) when the drugs were given by the lumbar route. Thoracic administration of morphine also resulted in a significantly longer duration of pain relief (on average 9.8 h) than that of bupivacaine (3.8 h). Morphine gave satisfactory pain relief in all cases. It was not associated with motor block, loss of sensitivity to temperature, touch, or pin-prick, or any signs of sympathetic block, as was the case with epidural bupivacaine. Plasma concentrations of morphine were not detectable 8 h after injection, though the patients still had pain relief. One case of delayed severe respiratory depression occurred 6 h after morphine injection via the thoracic route. Epidural morphine analgesia should therefore be reserved for patients in whom continual surveillance is possible, at least until more is known about the pharmacokinetics of narcotics in the epidural and subarachnoid space.     

Continuous Infusion of Bupivacaine Following Total Knee Arthroplasty: A Randomized Control Trial Pilot Study

An RCT pilot-study was conducted to assess efficacy of a 48-h continuous local infiltration of intra-articular bupivacaine (0.5% at 2 cc/h) versus placebo (0.5% saline at 2 cc/h) in decreasing PCA morphine consumption following TKA. Secondary outcomes included 48-h VAS pain, opioid side effects, length of stay, and knee function scores up to 1-year postoperatively. Of 67 randomized patients, 49 completed the trial including 24 bupivacaine, and 25 placebo patients. Mean 48-h PCA morphine consumption did not differ significantly between treatment (39 mg ± 27.1) and placebo groups (53 mg ± 30.4) (P = .137). The intervention did not improve pain scores, or any other outcome studied. Given study results we would conclude that analgesia outcomes with a multimodal analgesia regimen are not significantly improved by adding 48 h of 0.5% bupivacaine infiltration at 2 cc/h.     

Epidural and Intrathecal n-Butyl-p-Aminobenzoate Solution in the Rat: Comparison with Bupivacaine

Background: Epidural administration of an aqueous suspension of n-butyl-p-aminobenzoate (BAB) to humans results in long-lasting sensory blockade without motor block. The dose-response of BAB administered epidurally and intrathecally as a solution was studied in rats to define the local anesthetic properties in an established animal model.

Methods: The time course of changes in tail withdrawal latency and motor function were determined in rats after epidural or intrathecal administration of solutions of BAB or bupivacaine. The dose-response relation was determined and median effective dose values were calculated.

Results: After epidural and intrathecal administration of BAB solutions, the onset and duration of the antinociceptive action were comparable to bupivacaine. Median effective dose values for tail-withdrawal latency of 6 s or more were significantly greater for BAB. After both routes of administration, BAB clearly affected motor function.     

Early Postoperative Care of Liver Transplantation for Infants With Biliary Atresia During Pediatric Intensive Care Unit Stay

Subject

The aim of this study was to present our institutional experience with the pediatric intensive care unit (PICU) stays of liver recipients to understand prevention of complications.

Methods

This retrospective review included 22 infants who weighed 8.8 kg or less and underwent 23 transplantations. No grafts were from executed prisoners. We summarized the diagnosis, evaluation, medicine usage, and therapeutic intervention associated with subjects experiencing complications of rejection episodes, surgery, or infection during their ICU stay.

Results

There was one perioperative death from primary graft nonfunction. The most common postoperative complications were infections, gastrointestinal bleeding, and vascular complications. Rejection episodes occurred among 25% of patients. The most common isolated pathogenic bacteria was Staphylococcus epidermidis. Median initial ICU stay was 10 days. Mean requirement for artificial ventilation was 37.6 hour. Mean times of use of dobutamine, prostaglandin E1, and dopamine was 3.3, 7.5, and 8.8 days, respectively. Parenteral nutrition was started at a mean of 12 hours and oral food intake at a mean of 72 hours.

Conclusions

Although challenging, orthotopic liver transplantation (OLT) in small infants can be successfully performed with meticulous surgical technique and keen postoperative surveillance.     

Blood Levels of Bupivacaine After Single Dose, Supplementary Dose and During Continuous Infusion in Axillary Plexus Block

The material consisted of 25 patients undergoing orthopaedic or plastic surgery of the upper extremity, including seven cases of replantation surgery. The total doses of bupivacaine, 150–267 mg as a single dose, 280–440 mg as a supplementary dose and 247–629 mg as a continuous infusion, resulted in maximum venous concentrations of 0.68-3.33 μg/ml, 1.21-2.44 μg/ml and 0.51-1.89 μg/ml, respectively. These usually occurred 30–60 min after the injection of bupivacaine and always following the second injection when a supplementary dose was needed. The highest individual value noted occurred 15 min after single injection, possibly as a result of an exceptionally rapid absorption. Despite the high doses and the rather high venous peak concentration of bupivacaine in some of the patients, no toxic side-effects were observed during the block or during the recovery period.     

Systemic Toxicity of Levobupivacaine, Bupivacaine, and Ropivacaine during Continuous Intravenous Infusion to Nonpregnant and Pregnant Ewes

Background : Levobupivacaine, the single levorotatory isomer of bupivacaine, is now available for clinical use. This study was undertaken to determine whether pregnancy affects the systemic toxicity of levobupivacaine and to compare the systemic toxicity of levobupivacaine with that of bupivacaine and ropivacaine.

Methods : Chronically prepared nonpregnant and pregnant sheep were randomized to receive an intravenous infusion of 0.52% levobupivacaine, 0.52% bupivacaine, or 0.50% ropivacaine at a constant rate of 0.1 ml [middle dot] kg-1 [middle dot] min-1 until circulatory collapse. The investigators were blinded to the identity of the local anesthetic. Physiologic parameters, including cardiac rhythm, were monitored throughout the study. Arterial blood samples were obtained before infusion and at the onset of toxic manifestations. These were analyzed for total and free serum drug concentrations as well as arterial blood p H and gas tensions.

Results : The doses of all three drugs required to produce convulsions were lower in pregnant than nonpregnant animals. However, as the infusion continued, there were no significant differences between pregnant and nonpregnant ewes in the dose of drug required to produce more advanced manifestations of toxicity: hypotension, apnea, and circulatory collapse. The mean cumulative dose and serum concentration at each toxic manifestation was lowest for bupivacaine, intermediate for levobupivacaine, and highest for ropivacaine in both pregnant and nonpregnant animals. For all three local anesthetics, there were no significant differences between pregnant and nonpregnant ewes in total and free serum drug concentrations, except that at circulatory collapse, these were higher in pregnant animals.