Femoral nerve catheter vs local infiltration for analgesia in fast track total knee arthroplasty: short-term and long-term outcomes.

BACKGROUND: The aim was to compare the effects on short-term and long-term pain and functional outcome of periarticular local anaesthetic infiltration (LIA) with LIA of the posterior knee capsule in combination with a femoral nerve block (FNB) catheter in patients undergoing total knee arthroplasty. METHODS: Eighty patients were randomised to one of two groups: Subjects in group LIA received periarticular LIA with ropivacaine 0.2% for postoperative analgesia; subjects in group FNB received LIA of the posterior capsule and a FNB catheter. The primary outcome parameter was functional capacity of the knee 12 months after surgery. Secondary parameters included mobility as determined by accelerometer data, pain, satisfaction with the analgesic regimen, hospital length of stay, and use of pain medication 3 and 12 months after surgery. RESULTS: There were no differences between groups in long-term functional capacity, patient satisfaction and hospital length of stay. In the first 2 days, subjects in group FNB had slightly lower pain scores and used less opioids, and subjects in group LIA had a higher level of accelerometer activity. Three and 12 months after surgery, subjects in group FNB had lower maximum pain scores and were less likely to use any pain medication 12 months after surgery. CONCLUSIONS: Both techniques were similar regarding long-term functional outcome. Subjects in group FNB had slightly lower pain scores and lower opioid consumption after operation, lower maximum pain scores at 3 and 12 months, and were less likely to use any pain medication at 12 months. CLINICAL TRIAL REGISTRATION: NCT01966263.

Pharmacokinetics of 400 mg ropivacaine after periarticular local infiltration analgesia for total knee arthroplasty.

BACKGROUND: Although considered safe, no pharmacokinetic data of high dose, high volume local infiltration analgesia (LIA) with ropivacaine without the use of a surgical drain or intra-articular catheter have been described. The purpose of this study is to describe the maximum total and unbound ropivacaine concentrations (Cmax , Cu max ) and corresponding maximum times (Tmax , Tu max ) of a single-shot ropivacaine (200 ml 0.2%) and 0.75 mg epinephrine (1000 µg/ml) when used for LIA in patients for total knee arthroplasty. METHODS: In this prospective cohort study, 20 patients were treated with LIA of the knee for primary total knee arthroplasty. Plasma samples were taken at 20, 40, 60, 90, 120, 240, 360 min and at 24 h after tourniquet release, in which total and unbound ropivacaine concentrations were determined. RESULTS: Results are given as median [IQR]. Highest ropivacaine concentration (Cmax ) was 1.06 µg/ml [0.34]; highest unbound ropivacaine concentration (Cu max ) was 0.09 µg/ml [0.05]. The corresponding time to reach the maximum concentration for total ropivacaine was 312 min [120] after tourniquet release, and for the unbound fraction 265 [110] min after tourniquet release. CONCLUSION: Although great inter-individual variability was found between the maximum ropivacaine concentrations, both maximum total and unbound serum concentrations of ropivacaine remained well below the assumed systemic toxic thresholds of 4.3 and 0.56 µg/ml.

Differences in maternal temperature during labour with remifentanil patient-controlled analgesia or epidural analgesia: a randomised controlled trial.

BACKGROUND: Epidural analgesia and remifentanil patient-controlled analgesia are two popular techniques for the treatment of labour pain, each with its own efficacy and toxicity. METHODS: Parturients requesting analgesia were randomly assigned to either patient-controlled intravenous remifentanil or epidural analgesia. Control patients consisted of parturients not requesting pain medication. The primary objective was to compare the incidence of maternal fever (temperature ⩾ 38°C); secondary outcomes included the incidence of low oxygen saturation, pain scores, nausea and vomiting, sedation scores, pruritus and neonatal outcome. RESULTS: Data from 140 parturients were analysed: 49 received remifentanil analgesia, 49 epidural analgesia and 42 no analgesia (controls). Fever (temperature ⩾ 38°C) developed in 10% of remifentanil patients compared to 37% of epidural patients and 7% of control patients (P<0.001). One or more hypoxaemic events (oxygen saturation <90% for at least 1 min) occurred in 48% of patients on remifentanil versus 15% of patients on epidural analgesia and 20% of control patients (P=0.003). Although pain intensity scores differed significantly between the two groups in favour of the epidural, mean satisfaction scores were similar in both analgesia groups (remifentanil 8.1 ± 1.2 vs. epidural 8.4 ± 1.2). Remifentanil analgesia was associated with a higher incidence of nausea and deeper levels of sedation. The differences in haemodynamic parameters between groups were small and clinically insignificant. CONCLUSIONS: During treatment of labour pain, epidural analgesia is associated with a higher incidence of maternal fever, while remifentanil analgesia results in more frequent and deeper hypoxaemic events.

No clinically relevant advantage of intrathecal morphine in total hip arthroplasty?

Adding morphine to intrathecal bupivacaine provides sound analgesia, but is associated with side effects. The purpose of this study is to investigate if the contribution of intrathecal morphine to postoperative analgesia for total hip replacement outweighs its side effects in a modern multimodal setting. From November 2012 till January 2013 patients undergoing total hip arthroplasty (THA) under spinal anesthesia received either plain bupivacaine (group B) or bupivacaine + 0.1 mg morphine (group M). VAS pain scores, PCA morphine consumption and side effects (nausea, vomiting, pruritus) were registered. 60 patients in group B were compared to 36 patients in group M. Overall morphine consumption and pain scores were low, although they were slightly but significantly lower in group M. Intrathecal morphine was associated with significantly more pruritus. In this study, PCA morphine consumption and pain scores were low in THA with multimodal pain treatment, and the added analgesic value of intrathecal morphine did not outweigh the increased incidence of pruritus.

Start of insulin therapy in patients with type 2 diabetes mellitus promotes the influx of macrophages into subcutaneous adipose tissue.

AIMS/HYPOTHESIS: Insulin therapy in patients with type 2 diabetes mellitus is accompanied by weight gain characterised by an increase in abdominal fat mass. The expansion of adipose tissue mass is generally paralleled by profound morphological and inflammatory changes. We hypothesised that the insulin-associated increase in fat mass would also result in changes in the morphology of human subcutaneous adipose tissue and in increased inflammation, especially when weight gain was excessive. METHODS: We investigated the effects of weight gain on adipocyte size, macrophage influx, and mRNA expression and protein levels of key inflammatory markers within the adipose tissue in patients with type 2 diabetes mellitus before and 6 months after starting insulin therapy. RESULTS: As expected, insulin therapy significantly increased body weight. At the level of the subcutaneous adipose tissue, insulin treatment led to an influx of macrophages. When comparing patients gaining no or little weight with patients gaining >4% body weight after 6 months of insulin therapy, both subgroups displayed an increase in macrophage influx. However, individuals who had gained weight had higher protein levels of monocyte chemoattractant protein-1, TNF-α and IL-1ß after 6 months of insulin therapy compared with those who had not gained weight. CONCLUSIONS/INTERPRETATION: We conclude that insulin therapy in patients with type 2 diabetes mellitus improved glycaemic control but also induced body weight gain and an influx of macrophages into the subcutaneous adipose tissue. In patients characterised by a pronounced insulin-associated weight gain, the influx of macrophages into the adipose tissue was accompanied by a more pronounced inflammatory status. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00781495. FUNDING: The study was funded by European Foundation for the Study of Diabetes and the Dutch Diabetes Research Foundation.

Autophagy activity is up-regulated in adipose tissue of obese individuals and modulates proinflammatory cytokine expression.

Autophagy, an evolutionary conserved process aimed at recycling damaged organelles and protein aggregates in the cell, also modulates proinflammatory cytokine production in peripheral blood mononuclear cells. Because adipose tissue inflammation accompanied by elevated levels of proinflammatory cytokines is characteristic for the development of obesity, we hypothesized that modulation of autophagy alters adipose tissue inflammatory gene expression and secretion. We tested our hypothesis using ex vivo and in vivo studies of human and mouse adipose tissue. Levels of the autophagy marker LC3 were elevated in sc adipose tissue of obese vs. lean human subjects and positively correlated to both systemic insulin resistance and morphological characteristics of adipose tissue inflammation. Similarly, autophagic activity levels were increased in adipose tissue of obese and insulin resistant animals as compared with lean mice. Inhibition of autophagy by 3-methylalanine in human and mouse adipose tissue explants led to a significant increase in IL-1ß, IL-6, and IL-8 mRNA expression and protein secretion. Noticeably, the enhancement in IL-1ß, IL-6, and keratinocyte-derived chemoattractant (KC) by inhibition of autophagy was more robust in the presence of obesity. Similar results were obtained by blocking autophagy using small interfering RNA targeted to ATG7 in human Simpson-Golabi-Behmel syndrome adipocytes. Our results demonstrate that autophagy activity is up-regulated in the adipose tissue of obese individuals and inhibition of autophagy enhances proinflammatory gene expression both in adipocytes and adipose tissue explants. Autophagy may function to dampen inflammatory gene expression and thereby limit excessive inflammation in adipose tissue during obesity.

Angiopoietin-like protein 4 is differentially regulated by glucocorticoids and insulin in vitro and in vivo in healthy humans.

OBJECTIVE: Angiopoietin-like protein 4 (Angptl4) is a circulating inhibitor of plasma triglyceride clearance via inhibition of lipoprotein lipase. The aim of the present study was to examine the regulation of Angptl4 by glucocorticoids and insulin in vivo in humans, since these factors regulate Angptl4 expression in vitro. RESEARCH DESIGN AND METHODS: In a randomized, placebo-controlled, double-blind, dose-response intervention study, 32 healthy males (age: 22 ± 3 years; BMI 22.4 ± 1.7 kg m⁻²) were allocated to prednisolone 30 mg once daily (n = 12), prednisolone 7.5 mg once daily (n = 12), or placebo (n = 8) for 2 weeks. Angptl4 levels and lipid metabolism were measured before and at 2 weeks of treatment, in the fasted state and during a 2-step hyperinsulinemic clamp. Additionally, human hepatoma cells were treated with dexamethasone and/or insulin. RESULTS: Compared to placebo, prednisolone treatment tended to lower fasting Angptl4 levels (P = 0.073), raised fasting insulin levels (P = 0.0004) and decreased fasting nonesterified fatty acid concentrations (NEFA) (P = 0.017). Insulin infusion reduced Angptl4 levels by 6 % (plasma insulin ~200 pmol/l, P = 0.006) and 22 % (plasma insulin ~600 pmol/l, P < 0.0001), which was attenuated by prednisolone treatment (P = 0.03). Prednisolone 7.5 mg and 30 mg dose-dependently decreased insulin-mediated suppression of lipolysis (by 11 ± 5 % and 34 ± 6 % respectively). Prednisolone 30 mg enhanced fasting triglyceride levels ( P = 0.028). Plasma Angptl4 was not related to prednisolone-induced changes in lipid metabolism. In human hepatoma cells, dexamethasone increased Angptl4 mRNA expression and protein secretion, whereas insulin had the opposite effect. CONCLUSIONS: Insulin lowers plasma Angptl4 levels in humans by lowering NEFA and by inhibiting Angptl4 expression and release. Glucocorticoids counteract insulin-mediated suppression of Angptl4.

A comparison of the efficacy of levobupivacaine 0.125%, ropivacaine 0.125% and ropivacaine 0.2%, all combined with sufentanil 0.5 microg/mL, in patient-controlled epidural analgesia after hysterectomy under combined epidural and general anesthesia.

UNLABELLED: We compared the relative potencies of ropivacaine and levobupivacaine in combination with sufentanil 0.5 microg/ml in postoperative epidural analgesia after abdominal hysterectomy. METHODS: In this randomized, prospective, double-blinded study we studied sixty-three patients scheduled for abdominal hysterectomy. They were randomly allocated to receive ropivacaine 0.2% with sufentanil 0.5 microg/ml (group 1), ropivacaine 0.125% with sufentanil 0.5 microg/ml (group 2) or levobupivacaine 0.125% with sufentanil 0.5 microg/ml (group 3) for postoperative pain relief. The primary outcome was the analgesic efficacy of levobupivacaine and ropivacaine in patient-controlled epidural analgesia, as assessed by the number of requests for epidural bolus injections. Secondary outcomes included local anesthetic consumption, numerical rating scale (NRS) scores and neural block characteristics, hemodynamic data and the incidence of side effects, in particular nausea, pruritus, hypotension and sedation. RESULTS: There was no difference between the groups in the number of epidural bolus requests. The hourly consumption of local anesthetic in mg/h in group 2 (8.5 +/- 1.5 mg/h) and group 3 (8.1 +/- 0.6 mg/h) was similar. However, patients in group 1 (13.1 +/- 1.6 mg/h) used significantly more local anesthetic compared to the other groups. CONCLUSIONS: In the context of this study there was no clinical difference in potency between epidural ropivacaine and levobupivacaine in a concentration of 0.125% combined with sufentanil 0.5 mg/mL because local anesthetic consumption was primarily driven by sufentanil. Increasing the concentration of ropivacaine to 0.2% did not result in better analgesia or reduction in sufentanil consumption.

A randomised comparison of intravenous remifentanil patient-controlled analgesia with epidural ropivacaine/sufentanil during labour.

BACKGROUND: The µ-opioid agonist remifentanil has a rapid onset and offset and a short half-life making it an attractive option for intravenous patient-controlled labour analgesia. We aimed to compare the efficacy of intravenous remifentanil patient-controlled analgesia with epidural ropivacaine/sufentanil during labour. METHODS: Parturients were randomly assigned to receive intravenous patient-controlled analgesia with remifentanil (n=10) or epidural analgesia (n=10). Pain and satisfaction scores were assessed every hour by means of visual analogue scale, together with an observer sedation score. Side effects and neonatal outcome were noted. RESULTS: After one hour, visual analogue pain scores had decreased significantly in both groups (remifentanil: -3.8 ± 2.6, P<0.01; epidural -6.7 ± 2.0, P<0.01). The decrease in pain scores in the epidural group was significantly greater than the remifentanil group at all time intervals. The decrease in pain scores was sustained in the epidural group whereas in the remifentanil group pain scores increased over time. Oxygen saturation was significantly lower in the remifentanil group after one hour of treatment compared to the epidural group (95.2 ± 2.4% vs. 99.0 ± 1.1%, P<0.01). Patient satisfaction scores during and after delivery were similar in both groups. No differences were found in neonatal outcome. CONCLUSIONS: In the 20 patients recruited to this study, pain relief in labour with epidural ropivacaine/sufentanil was more effective than with intravenous remifentanil patient-controlled analgesia.

Oxidized LDL enhances pro-inflammatory responses of alternatively activated M2 macrophages: a crucial role for Krüppel-like factor 2.

OBJECTIVE: Macrophages are key players in atherogenesis because of their properties to form foam cells that produce a large variety of pro-inflammatory mediators. We addressed the potency of phenotypic different macrophages to accumulate oxidized LDL. METHODS AND RESULTS: Surprisingly, anti-inflammatory M2 macrophages but not pro-inflammatory M1 macrophages rapidly accumulated oxidized LDL. Simultaneously, expression of Krüppel-like factor 2, a nuclear transcription factor known to suppress inflammation in endothelial cells and monocytes, decreased and the functional phenotype of M2 macrophages shifted towards a pro-inflammatory profile, characterized by higher production of IL-6, IL-8 and MCP-1 and lower expression of IL-10 upon stimulation with LPS. In contrast, Krüppel-like factor 2 expression and the phenotype of M1 macrophages remained largely unchanged upon oxidized LDL exposure. Downregulation of Krüppel-like factor 2 expression of M2 macrophages using siRNA technology led to a significant increase of LPS-induced MCP-1 secretion. CONCLUSIONS: We show that (1) anti-inflammatory M2 macrophages are more susceptible to foam cell formation than pro-inflammatory M1 macrophages, (2) exposure to oxidized LDL renders M2 macrophages pro-inflammatory, and (3) Krüppel-like factor 2 is involved in the enhanced secretion of MCP-1 by M2 macrophages loaded with oxidized LDL. The phenotype switch of M2 macrophages from an anti- to a pro-inflammatory profile may play an important role in pathogenesis of atherosclerosis, and could represent a novel therapeutic target.

Obstetric analgesia: a comparison of patient-controlled meperidine, remifentanil, and fentanyl in labour.

BACKGROUND: To compare the analgesic efficacy of remifentanil with meperidine and fentanyl in a patient-controlled setting (patient-controlled analgesia, PCA). METHODS: Parturients (n=159) were randomly assigned to receive remifentanil (n=52), meperidine (n=53), or fentanyl (n=54). Pain scores and an observer sedation scores were assessed hourly. Fetal outcome was evaluated with Apgar score, cord blood gas analysis and the Neurologic and Adaptive Capacity Score. RESULTS: Pain scores decreased in all groups, the decrease varying from mild to moderate, average pain scores remaining above 4.5 cm in all groups. Remifentanil PCA was associated with the greatest decrease in pain scores, but the difference was significant only at 1 h. Pain scores returned towards baseline over time; 3 h after the initiation of treatment, pain scores no longer differed significantly from baseline values in any of the groups. Significantly more parturients receiving meperidine crossed over to epidural analgesia. Overall satisfaction scores were higher with remifentanil, but remifentanil produced more sedation and itching. More periods of desaturation (Sa(o(2)) <95%) were observed during administration of remifentanil and fentanyl. There were no significant differences in fetal outcome between the three groups. CONCLUSIONS: The efficacy of meperidine, fentanyl, and remifentanil PCA for labour analgesia varied from mild to moderate. Remifentanil PCA provided better analgesia than meperidine and fentanyl PCA, but only during the first hour of treatment. In all groups, pain scores returned to pre-treatment values within 3 h after the initiation of treatment.

Glycogen synthase 2 is a novel target gene of peroxisome proliferator-activated receptors.

Glycogen synthase 2 (Gys-2) is the ratelimiting enzyme in the storage of glycogen in liver and adipose tissue, yet little is known about regulation of Gys-2 transcription. The peroxisome proliferator-activated receptors (PPARs) are transcription factors involved in the regulation of lipid and glucose metabolism and might be hypothesized to govern glycogen synthesis as well. Here, we show that Gys-2 is a direct target gene of PPARalpha, PPARbeta/delta and PPARgamma. Expression of Gys-2 is significantly reduced in adipose tissue of PPARalpha-/-, PPARbeta/delta-/- and PPARgamma+/- mice. Furthermore, synthetic PPARbeta/delta, and gamma agonists markedly up-regulate Gys-2 mRNA and protein expression in mouse 3T3-L1 adipocytes. In liver, PPARalpha deletion leads to decreased glycogen levels in the refed state, which is paralleled by decreased expression of Gys-2 in fasted and refed state. Two putative PPAR response elements (PPREs) were identified in the mouse Gys-2 gene: one in the upstream promoter (DR-1prom) and one in intron 1 (DR-1int). It is shown that DR-1int is the response element for PPARs, while DR-1prom is the response element for Hepatic Nuclear Factor 4 alpha (HNF4alpha). In adipose tissue, which does not express HNF4alpha, DR-1prom is occupied by PPARbeta/delta and PPARgamma, yet binding does not translate into transcriptional activation of Gys-2. Overall, we conclude that mouse Gys-2 is a novel PPAR target gene and that transactivation by PPARs and HNF4alpha is mediated by two distinct response elements.

Avoidance of phrenic nerve paresis during continuous supraclavicular regional anaesthesia.

This study sought to determine whether it is possible reliably to avoid phrenic nerve block using the bent needle technique for continuous supraclavicular brachial plexus anaesthesia. In a prospective study, 100 patients undergoing a variety of upper extremity surgical procedures were studied. Ultrasound examinations of the patients' diaphragms were performed after insertion of an anaesthetic block, and were repeated a day later with the analgesic block working. Three phrenic nerve blocks were detected in different patients. Factors were identified in all three cases that we think contributed to the phrenic nerve blocks. We think it is possible to provide continuous supraclavicular regional anaesthesia and analgesia for a wide range of upper extremity operations without phrenic nerve blockade.

Lumbar epidural catheter insertion: the midline vs. the paramedian approach.

BACKGROUND AND OBJECTIVE: The purpose of this study was to compare the characteristics of epidural catheter insertion via the midline or the paramedian approach with regard to ease of catheter insertion, incidence of paraesthesias and efficacy of epidural block. In addition to the type of approach, the prognostic value of Patients characteristics variables with regard to the incidence of paraesthesias was assessed. METHODS: Thirty patients scheduled for surgery under epidural anaesthesia were randomly assigned to one of two groups of 15 patients each. Epidural anaesthesia was performed via a midline or paramedian approach using loss of resistance to saline. Variables measured were: time needed to identify the epidural space, time needed for and ease of epidural catheter insertion and the incidence of paraesthesias. After completion of these observations, epidural anaesthesia was established with 150 mg ropivacaine 1%. Efficacy of the epidural block was assessed by the need for intraoperative analgesics and by the patient on a three-point scale (good/fair/poor). RESULTS: Quality of sensory blockade was adequate in both groups. Catheter insertion was significantly faster using the paramedian approach. The difference between the two approaches with regard to the incidence of paraesthesias was not significant, however, there was a trend towards more paraesthesias in the midline group. In the multivariate analysis, type of approach was an independent significant predictor of paraesthesias and we found a trend towards a higher incidence of paraesthesias in female patients. CONCLUSIONS: Catheter insertion was faster in the paramedian group and we found a trend towards a higher incidence of paraesthesias with the midline approach.

Transient neurological symptoms with subarachnoid lidocaine: effect of early mobilization.

BACKGROUND AND OBJECTIVE: Although lidocaine has been used extensively for spinal anaesthesia since 1949, it has been associated with transient neurological symptoms only in the past 10 yr. It has been suggested that early ambulation after spinal anaesthesia, as opposed to traditional 24 h recumbency, might be the causative factor for the development of transient neurological symptoms. The purpose of this study was to examine the effect of early ambulation on the incidence of transient neurological symptoms after single injection spinal anaesthesia with lidocaine 2%. METHODS: Sixty patients undergoing minor surgery under spinal anaesthesia were included. All patients received lidocaine 60 mg. After the establishment of successful subarachnoid block, patients were randomly allocated to two groups of 30 patients. Patients in Group 1 were ambulated as soon as possible, whereas patients in Group 2 were kept recumbent until 6 h after subarachnoid injection. Two days after surgery patients were contacted by a blinded observer and interviewed of transient neurological symptoms using a standardized questionnaire. Patients were asked to express the intensity of pain/discomfort on a verbal rating scale from 0 (no pain) to 10 (worst pain imaginable). RESULTS: There was no significant difference in the incidence of transient neurological symptoms (23% vs. 27%). In all patients, symptoms resolved completely within 6-24 h. The median pain score was 5 (range 2-8) in Group 1 and 7 (range 1-8) in Group 2. CONCLUSIONS: Under the conditions of this study, there is no correlation between the time of ambulation after spinal anaesthesia with lidocaine and the incidence of transient neurological symptoms.

Effect of age on the clinical profile and systemic absorption and disposition of levobupivacaine after epidural administration.

BACKGROUND: Pharmacokinetic and/or pharmacodynamic changes, which may occur with increasing age, could alter the clinical profile of the new local anaesthetic levobupivacaine. We investigated the effect of age on the absorption and disposition kinetics and the neural block characteristics after epidural administration of levobupivacaine 0.75%. METHODS: Thirty-one patients were enrolled in one of three age groups (Group 1, 18-44 yr; Group 2, 45-70 yr; Group 3, >70 yr). Twenty-five minutes after epidural administration of levobupivacaine (127.5 mg), they received approximately 25 mg deuterium-labelled levobupivacaine (D(3)-levobupivacaine) intravenously. Arterial blood samples were collected until 24 h after the epidural administration. Plasma concentrations were determined using liquid chromatography mass spectrometry. Plasma concentration-time data were analyzed by compartmental and non-compartmental analysis. Assessments of analgesia and motor block were made at set intervals until complete regression of the block. RESULTS: The upper levels of analgesia in the two oldest groups of patients were 3 dermatomes (95% confidence interval (95% CI): 0.5-5.0 dermatomes) higher than in the youngest group. The fraction absorbed (F(1)) was 0.07 (95% CI: 0.02-013) smaller and the absorption half-life (t(1/2,a1)), characterizing the initial fast absorption phase, 3.6 min (95% CI: 0.8-6.4) shorter in the oldest group compared with the youngest group. CONCLUSIONS: Age influences the pharmacokinetics, in particular the early absorption kinetics, and the neural block characteristics after epidural administration of levobupivacaine. Changes in the upper level of analgesia are best explained by anatomical considerations and possibly pharmacodynamic changes in the elderly.

The systemic absorption and disposition of levobupivacaine 0.5% after epidural administration in surgical patients: a stable-isotope study.

BACKGROUND AND OBJECTIVE: Absorption and disposition kinetics can be studied with a stable-isotope method. The aim of this study was to validate a stable-isotope method for levobupivacaine and to derive the relevant pharmacokinetics after epidural administration. METHODS: Eight volunteers (18-32 yr) received approximately 23 mg of both levobupivacaine and deuterium-labelled levobupivacaine simultaneously by intravenous infusion. Venous blood samples were taken for 8 h. Fifteen patients (23-85 yr) received 19 mL levobupivacaine 0.5% (including a 3 mL test dose) epidurally and, 25 min later, approximately 25 mg deuterium-labelled levobupivacaine (D3-levobupivacaine) intravenously. Arterial blood samples were collected for 24 h. Plasma concentrations were determined using liquid chromatography-mass spectrometry. Plasma concentration-time data were analysed by compartmental and non-compartmental analysis. RESULTS: Based on the ratio of the normalized areas under the curve of unlabelled and deuterium-labelled levobupivacaine in volunteers, as determined by both compartmental (mean ratio: 1.02, 90% CI: 1.00-1.04) and non-compartmental analysis (mean ratio: 1.02, 90% CI: 1.00-1.03) the two formulations were considered equivalent. In surgical patients the elimination half-life (mean +/- SD: 196 +/- 65 min), total body clearanc (349 +/- 114 mL min(-1)) and volume of distribution at steady state (56 +/- 14 L), derived by compartmental analysis, were similar to those obtained by non-compartmental analysis. The absorption was bi-phasic. The fractio absorbed and half-life of the fast absorption process were 0.22 +/- 0.06 and 5.2 +/- 2.7 min, respectively. Th values for the slow absorption process were 0.84 +/- 0.14 and 386 +/- 91 min, respectively. CONCLUSIONS: D3-levobupivacaine is pharmacokinetically equivalent to unlabelled levobupivacaine and can be used to study the absorption and disposition kinetics after perineural administration of levobupivacaine in a single experiment.

The place of ropivacaine in anesthesia.

Ropivacaine has two advantages over bupivacaine. It provides more differential block when given epidurally, allowing for a better separation between sensory and motor block. This feature can be used to its advantage in obstetrics and in postoperative epidural pain relief. Ropivacaine has a lower systemic toxicity than both racemic and levobupivacaine. Especially its better cardiotoxic profile has been well documented and is an important advantage when using techniques with a potential for high plasma concentrations. Ropivacaine is less potent than bupivacaine and has a shorter duration of action. The magnitude of this potency difference however is not clearly quantified and differs with varying techniques. In some studies, the potency difference amounts up to 50% whereas in other studies the difference is negligible. The lower systemic toxicity of ropivacaine compared to bupivacaine is not offset by a lower potency, as ropivacaine in a 50% higher dose is still less cardiotoxic.

Clinical application of ropivacaine in obstetrics.

Ropivacaine is a new long-acting local anesthetic which is a pure (S)-(-)-enantiomer, with an efficacy profile similar to that of bupivacaine. Compared in equal doses, ropivacaine shows more separation between sensory and motor blockade than bupivacaine. Moreover, ropivacaine has a lower systemic toxicity than bupivacaine. In obstetrics, ropivacaine and bupivacaine have been compared for Cesarean section and for epidural pain relief during labor and delivery. For Cesarean section, both drugs provide similar analgesia when given in equal doses, but motor block is less pronounced with ropivacaine. Neonatal outcome as determined by Apgar scores and Neurological Adaptive Capacity Scores (NACS) is also similar. For epidural pain relief during labor and delivery, both drugs are equally effective, either when given alone or in combination with opioids; a meta-analysis of six studies showed that compared to bupivacaine, the use of ropivacaine is associated with significantly less motor block and instrumental deliveries.