Total Plasma Concentrations Of Ropivacaine Research Articles

Systemic Ropivacaine Concentrations Following Local Infiltration Analgesia and Femoral Nerve Block in Older Patients Undergoing Total Knee Arthroplasty.

The study examined the pharmacokinetic profile of fixed formulation mixtures comprising 225 mg of ropivacaine for local infiltration analgesia with or without epinephrine, and femoral nerve block in older patients presenting for orthopedic surgery and explored potential influences of block type, age, and body weight on this profile. Twenty four patients scheduled for total knee arthroplasty were randomly assigned to three groups: femoral nerve block, local infiltration analgesia with epinephrine and local infiltration analgesia without epinephrine. Blood samples were collected at 10, 30, 60, and 120 min following the block and total plasma concentrations of ropivacaine were quantified by high performance liquid chromatography. The mean individual peak total plasma concentrations of ropivacaine in local infiltration analgesia with and without epinephrine, and femoral nerve block group were 0.334, 0.490 and 0.545 μg mL-1 (p = 0.16). Local infiltration with epinephrine group had significantly lower plasma ropivacaine concentrations at 30, 60 and 120 minutes. The plasma ropivacaine concentrations exceeded 2.2 μg mL-1 in one patient. Age, but not body weight, had a moderate correlation with peak plasma ropivacaine concentration (r = 0.37, p = 0.08). Administration of a fixed 225 mg dose of ropivacaine for local infiltration analgesia with epinephrine and femoral nerve block results in plasma ropivacaine concentrations below the toxicity threshold, indicating their safety. The use of local infiltration analgesia with epinephrine provides a greater safety margin, as local infiltration analgesia without epinephrine may lead to ropivacaine concentrations associated with symptoms of local anesthetic toxicity.

Population pharmacokinetics of ropivacaine used for local infiltration anaesthesia during primary total unilateral and simultaneous bilateral knee arthroplasty

BackgroundRopivacaine is commonly used in local infiltration anaesthesia (LIA) as pain management after total knee arthroplasty (TKA). Although considered safe, no studies evaluated the pharmacokinetics of high-dose ropivacaine infiltration in simultaneous bilateral TKA. MethodsWe studied 13 patients undergoing unilateral and 15 undergoing bilateral TKA. Standard LIA technique was used with ropivacaine 0.2%, 200 ml (400 mg) injected peri-articularly in each knee. Free and total plasma concentrations of ropivacaine were measured within 24 h using liquid chromatography–mass spectrometry. A population pharmacokinetic model was built using non-linear mixed-effects models. ResultsPeak free ropivacaine concentration was 0.030 (0.017–0.071) μg ml−1 (mean [99% confidence interval]) vs 0.095 (0.047–0.208) μg ml−1, and peak total ropivacaine concentration was 0.756 (0.065–1.222) μg ml−1vs 1.695 (0.077–3.005) μg ml−1 for unilateral and bilateral TKA, respectively. The pharmacokinetics was ascribed a one-compartment model with first-order absorption. The main identified covariates were protein binding, allometrically scaled body weight on clearance and volume, and unilateral or bilateral surgery on volume. ConclusionsThis is the first study to investigate the pharmacokinetics of free and total ropivacaine after unilateral and bilateral TKA. A population model was successfully built and peak free ropivacaine concentration stayed below previously proposed toxic thresholds in patients undergoing unilateral and bilateral TKA receiving LIA with high-dose ropivacaine. Clinical trial registrationClinicalTrials.gov Identifier: NCT04702282

Ropivacaine, Interleukin-6 and Tumor Necrosis Factor Alpha Plasma Levels during Intermittent Epidural and Continuous Wound Infusion of Ropivacaine for Analgesia after Hysterectomy or Myomectomy: An Observational Study

Background/Aims: The concentration-time profile of the long-acting local anesthetic ropivacaine after epidural (EP) administration at fixed time intervals or continuous subcutaneous (SC) infusion has not been fully evaluated. The objective of this work was to determine total plasma concentrations of ropivacaine and changes in cytokine interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) levels during EP and SC. Methods: In this prospective randomized controlled trial, 18 patients undergoing abdominal hysterectomy or myomectomy were randomly selected to receive ropivacaine either every 6 h via an EP catheter or by continuous wound infusion along the skin incision, after a bolus dose, for 48 h. Total plasma ropivacaine concentrations were measured before the bolus and 2, 4, 8, 24, 48, and 50 h after the bolus using high-performance liquid chromatography-UV and IL-6 and TNF-α levels were measured at 0, 8 and 24 h with ELISA and analyzed statistically. Results: During EP, mean ± SD ropivacaine concentrations were relatively stable up to 50 h postoperatively, that is, 239 ± 89 ng/ml, while during SC, initial concentrations between 2 and 8 h were comparatively lower (101.5 ± 42.9 ng/ml) than 24-50 h concentrations (437.1 ± 206 ng/ml). An increase in IL-6 levels was noted between 0 and 24 h during EP and SC, but TNF-α levels increased slightly, between 0 and 24 h, only during EP. Conclusion: Ropivacaine plasma concentrations with both EP and SC were found to be safe throughout the administration time interval. IL-6 levels increased during the same time interval, while TNF levels varied only slightly.

The efficacy of simultaneous bilateral axillary brachial plexus block under the guidance of neurostimulator or ultrasound: a prospective study.

This study was designed to investigate the risk of local anesthetic toxicity and efficacy of simultaneous bilateral axillary brachial plexus block performed under the guidance of ultrasound or a neurostimulator. One hundred and twenty patients who were anesthetized with bilateral axillary plexus block simultaneously between February 2012 and March 2014 were enrolled in the study. The patients were anesthetized under the guidance of a neurostimulator (group N, n=60) or ultrasound (group U, n=60). The block performance time, procedure-related pain, adverse events, total and free plasma concentrations of ropivacaine, and other data were recorded. The comparison was analyzed statistically. The block performance time, and onset of the sensory and motor block, of group N was longer than that of group U (p<0.001). The procedure-related pain of group N was more serious than that of group U (p<0.05). The patient satisfaction rate of group U was higher than that of group N (p<0.05). The total plasma concentrations of ropivacaine in group N were comparable to those of group U, except for the value at 50min after injection (p<0.05). The free plasma concentrations of ropivacaine of group N at 5min were significantly higher than that of group U (p<0.001). No apparent serious adverse events were observed perioperatively in both groups. Simultaneous bilateral axillary brachial plexus block guided by neurostimulator or ultrasound in bilateral distal upper extremity surgery seems to have a low risk of local anesthetic toxicity and to be effective. The ultrasound-guided block is superior in terms of providing the same degree of anesthesia with shorter duration, less pain, and faster onset of sensory and motor blockades, which is important in clinical practice.

Safety of blood reinfusion after local infiltration analgesia with ropivacaine in total knee arthroplasty

The authors hypothesized that it is safe to combine local infiltration analgesia (LIA) in total knee arthroplasty (TKA) with a retransfusion drain since ropivacaine concentrations would not exceed the arterial toxicity threshold concentrations of 4.3 mg/L for total and 0.56 mg/L for unbound ropivacaine. 22 patients scheduled for primary TKA were included. During surgery three peri-articular injections with ropivacaine (300 mg) were given. Plasma and shed blood samples were taken at 0, 1, 3, 6, 7, and 24 hours postoperatively. At 6 hours postoperatively, the total ropivacaine plasma concentration ranged from 0.26 to 1.53 mg/L and unbound ropivacaine from 0.03 to 0.12 mg/L. At 7 hours, the total ropivacaine plasma concentration ranged from 0.19 to 1.71 mg/L and unbound ropivacaine from 0.02 to 0.09 mg/L. In the collected shed blood, a total of 0.27 to 12.8 mg (median 3.73 mg) unbound ropivacaine was present. Reinfusion would lead to an addition of 3.73 mg (median) unbound ropivacaine that would be reinfused into the patient. The calculated (modeled) estimation regarding the maximum unbound ropivacaine plasma concentration showed a median value of 0.114 mg/L (IQR: 0.09, 0.12 mg/L). All concentrations were well below reported toxicity thresholds. The combination of LIA and reinfusion presented herein are considered safe. However, differences in pain protocol lead to changes in the safety evaluation. Compared with previous studies, the technique of administration is of greater importance for the effect on unbound ropivacaine because of unknown mechanisms.

Continuous Elastomeric Pump-Based Ropivacaine Wound Instillation after Open Abdominal Aortic Surgery: How Reliable Is the Technique?

We aimed at quantifying the impact of continuous wound infusion with ropivacaine 0.33% on morphine administration and subjective pain relief in patients after open abdominal aortic repair in a double-blind, placebo-controlled study. Before closing the abdominal wound, 2 multihole ON-Q® Soaker Catheters™ (I-Flow Corporation, Lake Forest, California, USA) were placed pre-peritoneally in opposite directions. Either ropivacaine 0.33% or saline 0.9% was delivered by an elastomeric pump at a rate of 2 mL/h for 72 hours in each of the catheters. Postoperative pain and morphine administration were assessed using the numerical rating scale (NRS) in 4-hour intervals. Total plasma concentrations of ropivacaine, unbound ropivacaine, and α1-acid glycoprotein (AAG) were measured daily. Mean arterial pressure, pulse rate, oxygen saturation, total amount of morphine administration, ventilation time, and length of stay in the intensive care unit (ICU) were recorded. At the end of the study period, the wound site and the condition of the catheters were assessed. The study was terminated prematurely due to a malfunction of the elastomeric balloon pump resulting in toxic serum levels of total ropivacaine in 2 patients (11.4 μmol/L and 10.0 μmol/L, respectively) on the second postoperative day. Six patients had been allocated to the ropivacaine group, and 9 patients had been allocated to the control group. Demographic and surgical data were similar in both groups. During the first 3 postoperative days, no difference between the ropivacaine and the control group was found in NRS (P = .15, P = .46, and P = .88, respectively) and morphine administration (P = .48). Concentrations of unbound serum ropivacaine (0.11 ± 0.08 μmol/L) were below toxic level in all patients. Continuous wound infusion of ropivacaine 0.33% 2 mL/h using an elastomeric system was not reliable and did not improve postoperative pain control in patients after open abdominal aortic surgery.

Stable plasma concentrations of unbound ropivacaine during postoperative epidural infusion for 24–72 hours in children

The aim of this open, non-controlled, multi-centre study was to evaluate the pharmacokinetics and safety of a 24-72 h continuous epidural ropivacaine infusion in children aged 1-9 yr. After induction of general anaesthesia, 29 ASA I-II children, scheduled for major surgery in dermatomes below T10 had lumbar epidural catheters placed. A bolus of ropivacaine, 2 mg kg(-1), was given over 4 min, followed immediately by an infusion of 2 mg mL(-1) ropivacaine 0.4 mg kg(-1) h(-1) for the next 24-72 h. Plasma concentrations of total ropivacaine (mean 0.83 and 1.06 mg L(-1) at 16-31 and 59-72 h, respectively) and alpha1-acid-glucoprotein (mean 13 and 25 micromol L(-1) at baseline and 59-72 h) increased over the course of the infusion. Plasma concentrations of unbound ropivacaine were stable throughout the epidural infusion (mean 0.021 range 0.011-0.068 and mean 0.016 range 0.009-0.023 mg L(-1) at 16-31 and 59-72 h, respectively) and were well below threshold levels associated with central nervous system toxicity in adults (0.35 mg L(-1)). Apparent unbound clearance (mean 346, range 86-555 mL min(-1) kg(-1)) showed no age-dependency. No signs of systemic toxicity or cardiovascular effects were observed. All patients received additional analgesics with morphine. Following a 24-72 h epidural infusion of ropivacaine 0.4 mg kg(-1) h(-1) in 1-9-yr-old children, the plasma concentrations of unbound ropivacaine were stable over time with no age-dependency.

Case report: Ropivacaine neurotoxicity at clinical doses in interscalene brachial plexus block

To describe a case of ropivacaine toxicity following an ultrasound guided interscalene block and discuss the possible mechanisms involved. A 76-yr-old woman with multiple myeloma was scheduled for open reduction and internal fixation following a pathological fracture of her left upper humerus. She developed central nervous system toxicity with ropivacaine 15 min after a carefully placed ultrasound-guided interscalene catheter. The dose of ropivacaine was within recommended limits and there was no evidence that the catheter was intravascular. Surgery proceeded uneventfully under general anesthesia. The interscalene catheter was left in situ for postoperative evaluation and intravascular injection was ruled out with a colour Doppler study. The total ropivacaine plasma concentration was 3.68 microgxmL-(1). Neurological evaluation, contrast computerized tomography and electroencephalogram were normal. The patient was discharged home with no sequelae. Advanced age, malnutrition, epinephrine and possible elevation of alpha-(1)-acid glycoprotein levels could have altered the pharmacokinetics of plasma ropivacaine and possibly contributed to delayed neurotoxicity. Local anesthetic toxicity is an uncommon but well documented complication of regional anesthesia. Careful monitoring and preparedness for managing complications during the conduct of regional anesthesia cannot be overemphasized. Experience from this case suggests that local anesthesia toxicity can happen within safe dose limits and without intravascular placement despite careful attention to needle and catheter placement, fractionated dosing and frequent aspirations.

Efficacy and plasma levels of ropivacaine for children: controlled regional analgesia following lower limb surgery

Continuous regional analgesia (CRA) is considered a safe and efficacious technique for postoperative pain relief in children after lower limb surgery. We recently evaluated the feasibility of patient-controlled regional analgesia (PCRA) in a similar acute pain situation and we concluded that PCRA might be advantageous over CRA in terms of lower costs, risk of systemic toxicity while producing similarly adequate analgesia. We therefore prospectively compared both techniques in the paediatric population. In total, 30 children undergoing lower limb orthopaedic surgery were randomized to receive PCRA or CRA with ropivacaine 0.2%. Visual analogue scale scores, rescue analgesia, overall satisfaction, motor blockade and plasma ropivacaine concentrations were recorded for 48 h. Adequate analgesia was achieved with both techniques. No significant difference was noted for rescue analgesia, overall satisfaction and motor blockade. In contrast, children in the PCRA group received significantly less local anaesthetics than those in the CRA group. In addition, total plasma concentrations of ropivacaine were significantly reduced in the PCRA group as compared with the CRA group during the 48 h postoperative period. Both techniques are efficacious and satisfactory. However, PCRA with ropivacaine 0.2% can provide adequate postoperative analgesia for paediatric orthopaedic procedures with smaller doses of ropivacaine than CRA.

The Effect of Age on the Systemic Absorption and Systemic Disposition of Ropivacaine after Epidural Administration

Knowledge about the systemic absorption and disposition of ropivacaine after epidural administration is important in regard to its clinical profile and the risk of systemic toxicity. We investigated the influence of age on the pharmacokinetics of ropivacaine 1.0% after epidural administration, using a stable-isotope method. Twenty-four patients were enrolled in 1 of 3 groups according to age (group 1: 18-40 yr; group 2: 41-60 yr; group 3: > or =61 yr). Patients received 150 mg ropivacaine hydrochloride epidurally. After 25 min, patients received 50 mL 0.44 mg/mL deuterium-labeled ropivacaine (D3-ropivacaine) IV. Arterial blood samples were collected up to 24 h after epidural administration. Total plasma concentrations of ropivacaine and D3-ropivacaine were determined using liquid chromatography mass spectrometry. In the oldest patients, elimination half-life was significantly longer (ratio of the geometric means 0.60; 95% confidence interval, 0.37-0.99) and clearance was significantly decreased (mean difference, 194 mL/min; 95% confidence interval, 18-370 mL/min) compared with the youngest patients. The systemic absorption was biphasic. Absorption kinetics for ropivacaine (fractions absorbed: (F1, F2) and half-lives: (t(1/2),a1), t(1/2),a2) during the fast and slow absorption process: 0.27 +/- 0.08 and 0.77 +/- 0.12, respectively; 10.7 +/- 5.2 min and 248 +/- 64 min, respectively) were in the same range as for other long-acting local anesthetics. F1 was on average 0.11 (95% confidence interval, 0.002-0.22) higher in the youngest compared with the middle age group. Observed age-dependent pharmacokinetic differences do not likely influence the risk of systemic toxicity in the elderly after a single epidural dose of ropivacaine.

Continuous extrapleural infusion of ropivcicciine in children: is it safe?

To the Editor: In contrast to bupivacaine, ropivacaine has not yet been shown to be suitable in the clinical context of continuous intercostal nerve blockade using an extrapleural catheter in children and young infants.1,2 After approval of the hospital’s Ethical Committee and obtaining parental consent, the pharmacokinetics of an extrapleural bolus of 0.5 mL·kg–1 ropivacaine 0.2% followed by a continuous extrapleural infusion at two different rates (0.2 mL·kg–1·hr–1 and 0.3 mL·kg–1·hr–1, resp.) for 48 hr were evaluated in two children undergoing cardiac surgery via a lateral thoracotomy (patient 1: male, four years old; patient 2: female, six years old). Anesthesia was performed according to our standard protocol and at the end of the operation an extrapleural catheter (20-gauge, multi-orifice, SIMS Portex Ltd., Hythe, UK) was placed as described earlier.3 The bolus of ropivacaine 0.2% was administered when the patients recovered from anesthesia (adequate reactions to verbal command) and the infusion was maintained for 48 hr. Total plasma concentrations of ropivacaine and plasma concentration of α1-acid glycoprotein were assessed at the hours t = 1/6, 1/3, 0.5, 1, 3, 6, 18, 30, 48, 50, 52 and 54. Total ropivacaine plasma concentration showed a first peak 30 min after the initial bolus. Its highest value was measured at the end of the continuous infusion (Figure) and exceeded the limit of 2.2 mg·L–1 that is accepted to be safe in terms of toxicity as described by Knudsen et al.4 The measured concentrations of α1-acid glycoprotein remained within the normal range. The capacity of α1-acid glycoprotein to buffer the free fraction of ropivacaine which, mainly, is responsible for toxic reactions in the context of a continuous infusion of local anesthetics was, therefore, not increasing. Thus, we may not assume a subsequent decrease in the unbound fraction of ropivacaine. Clinically, no pathological findings in terms of toxicity were found. Our preliminary results suggest that intercostal nerve block with an initial bolus of 0.5 mL·kg–1, followed by a continuous infusion through an extrapleural catheter of 2 mg·mL–1 ropivacaine at 0.2 mL·hr–1 and 0.3 mL·hr–1 over 48 hr is at the edge of being considered a safe technique for analgesia after lateral thoracotomy. More investigations also in terms of pharmacodynamics are needed to determine the optimal rate and concentration of ropivacaine administered through an extrapleural catheter in children.

Pharmacokinetics and efficacy of ropivacaine continuous wound instillation after joint replacement surgery

As continuous wound instillation with local anaesthetic has not been evaluated after hip/knee arthroplasties, our study was designed to determine whether this technique could enhance analgesia and improve patient outcome after joint replacement surgery. Thirty-seven patients undergoing elective hip/knee arthroplasties under spinal block were randomly assigned to two analgesia groups. Group M received continuous i.v. infusion of morphine plus ketorolac for 24 h. Then, a multi-hole 16 G catheter was placed subcutaneously and infusion of saline was maintained for 55 h. Group R received i.v. saline. Thereafter the wound was infiltrated with a solution of ropivacaine 0.5% 40 ml, then a multi-hole 16 G catheter was placed subcutaneously and an infusion of ropivacaine 0.2% 5 ml h(-1) was maintained for 55 h. Visual analogue scale scores were assessed at rest and on passive mobilization by nurses blinded to analgesic treatment. Total plasma ropivacaine concentration was measured. Group R showed a significant reduction in postoperative pain at rest and on mobilization, while rescue medication requirements were greater in Group M. Total ropivacaine plasma concentration remained below toxic concentrations and no adverse effects occurred. Length of hospital stay was shorter in Group R. Infiltration and wound instillation with ropivacaine 0.2% is more effective in controlling postoperative pain than systemic analgesia after major joint replacement surgery.

Pharmacokinetics of ropivacaine in uremic and nonuremic patients after axillary brachial plexus block.

Reports on the efficacy and pharmacokinetics of local anesthetics in uremic patients have been controversial. Our study involved 29 uremic and 28 nonuremic patients. We performed axillary block with ropivacaine 300 mg (50 mL). Venous blood samples were drawn for 24 h for assay of total and unbound plasma ropivacaine, 3-hydroxyropivacaine, pipecoloxylidide (PPX), and serum alpha(1)-acid glycoprotein (AAG). Block quality was similar in both groups. No toxicity occurred. Plasma clearance of ropivacaine was smaller and the area under the concentration-time curve of ropivacaine, 3-hydroxyropivacaine, and PPX larger in the uremic patients. The plasma concentration of PPX increased until 24 h in uremic patients whose AAG concentrations were also larger throughout the study. The free fraction of ropivacaine in plasma was smaller in the uremic group when measured 60 min and 12 h after the block, but the unbound concentration of ropivacaine was larger in the uremic group at 12 h. Enhanced absorption of ropivacaine into circulation, increased binding to AAG, and probably reduced urinary excretion of the metabolites lead to larger total plasma concentrations of ropivacaine and its main metabolites in uremic patients.

Grand mal convulsion and plasma concentrations after intravascular injection of ropivacaine for axillary brachial plexus blockade

We report a patient to whom ropivacaine 1.1 mg kg(-1) was administered for brachial plexus blockade and who developed grand mal convulsions because of inadvertent i.v. injection. No symptoms of cardiovascular toxicity occurred. Venous blood samples were taken 15, 45, 75 and 155 min after the injection. The measured total plasma concentrations of ropivacaine were 3.3, 1.6, 1.2 and 1.0 mg litre(-1) respectively. Initial plasma concentration after the end of the injection period was estimated at 5.75 mg litre(-1) using a two-compartment pharmacokinetic model.

Efficacy and uptake of ropivacaine and bupivacaine after single intra‐articular injection in the knee joint

The efficacy of ropivacaine 100 mg (5 mg ml(-1)), 150 mg (7.5 mg ml(-1)) and 200 mg (10 mg ml(-1)) and bupivacaine 100 mg (5 mg ml(-1)) given by intra-articular injection into the knee after the end of surgery was studied in 72 ASA I-II patients scheduled for elective knee arthroscopy under general anaesthesia in a randomized, double-blind study. Kapake (paracetamol 1 g and codeine 60 mg) was given as a supplementary analgesic. Pain scores were assessed 1-4 h after surgery and a verbal rating scale of overall pain severity was assessed on second postoperative day. Ropivacaine or bupivacaine concentrations were determined in peripheral venous plasma up to 3 h after injection in eight patients in each group. Verbal rating pain scores were lower with ropivacaine 150 mg compared with bupivacaine 100 mg (P<0.05). There was a tendency for lower analgesic consumption and pain scores with all doses of ropivacaine (not significant). The mean (SD) maximum total plasma concentrations of ropivacaine were 0.64 (0.25), 0.78 (0.43), and 1.29 (0.46) mg litre(-1) after 100, 150 and 200 mg. The corresponding unbound concentrations were 0.018 (0.009), 0.024 (0.020) and 0.047 (0.022) mg litre(-1). Both were proportional to the dose. The maximum total concentration after bupivacaine 100 mg was 0.57 (0.36) mg litre(-1). The time to reach maximum plasma concentration was similar for all doses and varied between 20 and 180 min. All concentrations were well below the threshold for systemic toxicity.

Anesthesia (3)

Epidural infusion of ropivacaine for postoperative analgesia after major orthopedic surgery. (Leiden University Medical Center, Leiden, The Netherlands) Anesthesiology 2000;93:395–403.This study evaluated the pharmacokinetics of ropivacaine administered by 72‐h epidural infusion to provide postoperative analgesia. Twenty‐eight patients scheduled for major orthopedic surgery during combined epidural and general anesthesia received a bolus dose of ropivacaine (50 or 70 mg), followed by constant‐rate (10 mL/h) epidural infusion of ropivacaine 2 mg/mL (Group 1) or 3 mg/mL (Group 2). Total and unbound plasma concentrations of ropivacaine and pipecoloxylidide and plasma concentrations of α1‐acid glycoprotein were determined. The urinary excretion of ropivacaine and major metabolites was measured. Results showed that total plasma concentrations of ropivacaine increased steadily during infusion and unbound ropivacaine concentrations reached average steady levels of approximately 0.06 and 0.07 mg/l. Total and unbound concentrations of pipecoloxylidide increased to 1.0 ± 0.4 and 0.4 ± 0.2 mg/l (Group 1) and 1.2 ± 0.4 and 0.5 ± 0.1 mg/l (Group 2) after 72 h infusion. α1‐Acid glycoprotein concentrations initially decreased, but thereafter increased steadily to approximately twice the baseline values. Conclude postoperative increases in plasma α1‐acid glycoprotein concentrations enhance the protein binding of ropivacaine and pipecoloxylidide, which causes divergence of total and unbound plasma concentrations.

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. 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.

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. (Anesth Analg 1997;85:1322-30)

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

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. 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. 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. The pharmacokinetics of ropivacaine were independent of dose, but total clearance decreased with time over 24 h. The consistent increase in total plasma concentration during the postoperative epidural infusion contrasted to much less variation in the unbound plasma concentrations of ropivacaine.