Cardiovascular parameters and liver blood flow after infusion of a colloid solution and epidural administration of ropivacaine 0.75%: the influence of age and level of analgesia.

BACKGROUND AND OBJECTIVE: Lumbar epidural anaesthesia induces cardiovascular changes and decreases liver blood flow (Qh). We studied the effects of age on haemodynamics, blood volumes and Qh before and after epidural anaesthesia. METHODS: Thirty-six patients were enrolled as follows: group 1, 20-44 years; group 2, 45-70 years; group 3, >70 years. Using pulse dye densitometry, in addition to heart rate and arterial blood pressure (arterial BP), cardiac output, total blood volume, central blood volume and Qh were measured, before and after colloid infusion (500 ml hydroxyethyl starch, 6%) and after epidural administration of 15 ml of 0.75% ropivacaine. RESULTS: With age the level of analgesia [median (range)] increased from T7 (L2-T4) in group 1 to T4 (T10-C7) in group 3 (P = 0.04). After colloid infusion, heart rate (mean difference +/- SE; 2.1 +/- 0.7 beats min(-1)), systolic BP (4.1 +/- 2.2 mmHg) and Qh 162 ml min(-1) (ratio 0.90, 95% confidence interval 0.81-0.99) increased slightly but significantly, and were unaffected by age. Epidural anaesthesia induced a significant decrease in Qh (265 ml min(-1); ratio 1.20, 95% confidence interval 1.07-1.35) and arterial pressure (for systolic BP: P = 1 x 10(-7)). A significantly larger decrease in systolic BP occurred in the older, compared with the middle, age group (P = 0.04). Age did not affect epidural-induced changes in cardiac output, total and central blood volumes, and Qh. CONCLUSION: Age increases the level of analgesia after epidural ropivacaine and is associated with a more pronounced decrease in arterial pressure. A colloid preload mildly increases haemodynamics, but this insufficiently prevents younger and elderly patients from a decrease in Qh after lumbar epidural anaesthesia.

The effect of a long term epidural infusion of ropivacaine on CYP2D6 activity.

BACKGROUND: Ropivacaine and one of its metabolites, pipecoloxylidide, inhibit CYP2D6 in. human liver microsomes in vitro with K(i) values of 5 microM (1.4 mg/L) and 13 microM (3.6 mg/L), respectively. We investigated the effect of a 50 h continuous epidural infusion of ropivacaine 2 mg/mL at a rate of 14 mL/h on CYP2D6 activity. METHODS: Nineteen patients (41-85 yr) undergoing hip or knee replacement, all extensive metabolizers with respect to CYP2D6 activity, were included. Medications known to inhibit or be metabolized by CYP2D6, or known to be strong inhibitors/inducers of CYP1A2 or CYP3A4 were not allowed. Patients received 10 mg debrisoquine (a marker for CYP2D6 activity) before surgery and after 40 h epidural infusion. The metabolic ratio (MR) for debrisoquine hydroxylation was calculated as the amount of debrisoquine/amount of 4-OH-debrisoquine excreted in 0-10 h urine. RESULTS: The median (range) of MR before and after ropivacaine were 0.54 (0.1-3.4) and 1.79 (0.3-6.7), respectively. The Hodges Lehman estimate of the ratio MR after/MR before ropivacaine was 2.2 with a 95% confidence interval 1.9-2.7 (P < 0.001). CONCLUSION: A continuous epidural infusion of ropivacaine inhibits CYP2D6 activity in patients who are extensive metabolizers resulting in a twofold increase in the MR for debrisoquine hydroxylation. However, since none of the patients was converted into a functional poor metabolizer (MR >12.6), the effect on the metabolism of other drugs metabolized by CYP2D6 is unlikely to be of major clinical importance.

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.

Mixed-effects modeling of the influence of alfentanil on propofol pharmacokinetics.

BACKGROUND: The influence of alfentanil on the pharmacokinetics of propofol is poorly understood. Therefore, the authors studied the effect of a pseudo-steady state concentration of alfentanil on the pharmacokinetics of propofol. METHODS: The pharmacokinetics of propofol were studied on two occasions in eight male volunteers in a randomized crossover manner with a 3-week interval. While volunteers breathed 30% O2 in air, 1 mg/kg intravenous propofol was given in 1 min, followed by 3 mg.kg(-1).h(-1) for 59 min (sessions A and B). During session B, a target-controlled infusion of alfentanil (target concentration, 80 ng/ml) was given from 10 min before the start until 6 h after termination of the propofol infusion. Blood pressure, cardiac output, electrocardiogram, respiratory rate, oxygen saturation, and end-tidal carbon dioxide were monitored. Venous blood samples for determination of the blood propofol and plasma alfentanil concentration were collected until 6 h after termination of the propofol infusion. Nonlinear mixed-effects population pharmacokinetic models examining the influence of alfentanil and hemodynamic parameters on propofol pharmacokinetics were constructed. RESULTS: A two-compartment model, including a lag time accounting for the venous blood sampling, adequately described the concentration-time curves of propofol. Alfentanil decreased the elimination clearance of propofol from 2.1 l/min to 1.9 l/min, the distribution clearance from 2.7 l/min to 2.0 l/min, and the peripheral volume of distribution from 179 l to 141 l. Scaling the pharmacokinetic parameters to cardiac output, heart rate, and plasma alfentanil concentration significantly improved the model. CONCLUSIONS: Alfentanil alters the pharmacokinetics of propofol. Cardiac output and heart rate have an important influence on the pharmacokinetics of propofol.

Propofol reduces perioperative remifentanil requirements in a synergistic manner: response surface modeling of perioperative remifentanil-propofol interactions.

BACKGROUND: Remifentanil is often combined with propofol for induction and maintenance of total intravenous anesthesia. The authors studied the effect of propofol on remifentanil requirements for suppression of responses to clinically relevant stimuli and evaluated this in relation to previously published data on propofol and alfentanil. METHODS: With ethics committee approval and informed consent, 30 unpremedicated female patients with American Society of Anesthesiologists physical status class I or II, aged 18-65 yr, scheduled to undergo lower abdominal surgery, were randomly assigned to receive a target-controlled infusion of propofol with constant target concentrations of 2, 4, or 6 microg/ml. The target concentration of remifentanil was changed in response to signs of inadequate anesthesia. Arterial blood samples for the determination of remifentanil and propofol concentrations were collected after blood-effect site equilibration. The presence or absence of responses to various perioperative stimuli were related to the propofol and remifentanil concentrations by response surface modeling or logistic regression, followed by regression analysis. Both additive and nonadditive interaction models were explored. RESULTS: With blood propofol concentrations increasing from 2 to 7.3 microg/ml, the C(50) of remifentanil decreased from 3.8 ng/ml to 0 ng/ml for laryngoscopy, from 4.4 ng/ml to 1.2 ng/ml for intubation, and from 6.3 ng/ml to 0.4 ng/ml for intraabdominal surgery. With blood remifentanil concentrations increasing from 0 to 7 ng/ml, the C(50) of propofol for the return to consciousness decreased from 3.5 microg/ml to 0.6 microg/ml. CONCLUSIONS: Propofol reduces remifentanil requirements for suppression of responses to laryngoscopy, intubation, and intraabdominal surgical stimulation in a synergistic manner. In addition, remifentanil decreases propofol concentrations associated with the return of consciousness in a synergistic manner.

Occupational hazards of inhalational anaesthetics.

Occupational exposure to inhalational anaesthetics has often been associated with health hazards and reproductive toxicity, but the available evidence is weak and comes mostly from epidemiological studies that have been criticized. Studies based on registered data generally showed no association between occupational exposure to inhalational anaesthetics and reproductive effects. Animal studies also showed a lack of carcinogenicity, organ toxicity and reproductive effects with trace concentrations, as observed in operating rooms. The exception may be nitrous oxide, which in some, but not all, studies showed teratogenicity in rats chronically exposed to concentrations of 1000 p.p.m. and higher, such as may occur in unscavenged operating rooms lacking a mechanical ventilation system. Occupational exposure has also been associated with impairment of psychological functions, but these effects do not occur with trace concentrations. All in all, the scientific evidence for hazards is weak. Nonetheless, it is good practice to limit levels of exposure.

The epidural "top-up": predictors of increase of sensory blockade.

BACKGROUND: Extension of sensory blockade after an epidural top-up in combined spinal epidural (CSE) anesthesia is partly attributed to compression of the dural sac by the injected volume. This study investigated whether a volume effect plays a significant role when administering an epidural top-up after an initial epidural loading dose and assessed the predictive value of different factors with respect to the increase in sensory blockade. METHODS: After an epidural loading dose of 75 mg ropivacaine, 0.75%, 30 patients were randomly assigned to one of three groups. After the maximum level of sensory blockade (MLSB) had been established, patients received either an epidural top-up with 10 ml ropivacaine, 0.75% (group 1, n = 10) or saline (group 2, n = 10), or no epidural top-up (group 3, n = 10). Subsequently, sensory blockade was assessed at 5-min intervals for a further 30 min by a blinded observer. RESULTS: The MLSB increased significantly in the patients receiving an epidural top-up with ropivacaine but not in the patients receiving normal saline. Sensory block extension was inversely related to the number of segments blocked at the time of the epidural top-up, and female gender was associated with a smaller increase in MLSB. CONCLUSIONS: When using epidural ropivacaine, the extension of sensory blockade after administering an epidural top-up is caused by a local anesthetic effect and not by a volume effect. Under the conditions of this study, predictors of the increase in sensory blockade are the presence of ropivacaine in the top-up injectate, the number of segments blocked at the time of epidural top-up, and gender.

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 alpha1-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). CONCLUSIONS: The study confirmed that the pharmacokinetics of bupivacaine are enantioselective. During postoperative epidural infusion, changing plasma AAG concentrations affect the protein binding of both enantiomers of bupivacaine. Consequently, total plasma concentrations of the enantiomers increase with time, whereas unbound concentrations reach a plateau.

The effects of age on neural blockade and hemodynamic changes after epidural anesthesia with ropivacaine.

UNLABELLED: We studied the influence of age on the neural blockade and hemodynamic changes after the epidural administration of ropivacaine 1.0% in patients undergoing orthopedic, urological, gynecological, or lower abdominal surgery. Fifty-four patients were enrolled in one of three age groups (Group 1: 18-40 yr; Group 2: 41-60 yr; Group 3: > or=61 yr). After a test dose of 3 mL of prilocaine 1.0% with epinephrine 5 microg/mL, 15 mL of ropivacaine 1.0% was administered epidurally. The level of analgesia and degree of motor blockade were assessed, and hemodynamic variables were recorded at standardized intervals. The upper level of analgesia differed among all groups (medians: Group 1: T8; Group 2: T6; Group 3: T4). Motor blockade was more intense in the oldest compared with the youngest age group. The incidence of bradycardia and hypotension and the maximal decrease in mean arterial blood pressure during the first hour after the epidural injection (median of Group 1: 11 mm Hg; Group 2: 16 mm Hg; Group 3: 29 mm Hg) were more frequent in the oldest age group. We conclude that age influences the clinical profile of ropivacaine 1.0%. The hemodynamic effects in older patients may be caused by the high thoracic spread of analgesia, although a diminished hemodynamic homeostasis may contribute. IMPLICATIONS: Analgesia levels after the epidural administration of 15 mL of ropivacaine 1.0% increase with increasing age. This is associated with an increased incidence of hypotension in the elderly, although an effect of age on the hemodynamic homeostasis may have contributed. It appears that epidural doses should be adjusted for elderly patients.