Bernadette Th. Veering

Maximum recommended doses of local anesthetics: A multifactorial concept

The current recommendations regarding maximum doses of local anesthetics presented in textbooks, or by the responsible pharmaceutical companies, are not evidence based (ie, determined by randomized and controlled studies). Rather, decisions on recommending certain maximum local anesthetic doses have been made in part by extrapolations from animal experiments, clinical experiences from the use of various doses and measurement of blood concentrations, case reports of local anesthetic toxicity, and pharmacokinetic results. The common occurrence of central nervous system toxicity symptoms when large lidocaine doses were used in infiltration anesthesia led to the recommendation of just 200 mg as the maximum dose, which has remained unchanged for more than 50 years. In most cases, there is no scientific justification for presenting exact milligram doses or mg/kg doses as maximum dose recommendations. Instead, only clinically adequate and safe doses (ranges) that are block specific are justified, taking into consideration the site of local anesthetic injection and patient-related factors such as age, organ dysfunctions, and pregnancy, which may influence the effect and the pharmacokinetics of the local anesthetic. Epinephrine in concentrations of 2.5 to 5 μg/mL should be added to the local anesthetic solution when large doses are administered, providing there are no contraindications for the use of epinephrine. As a rule, conditions (eg, end-stage pregnancy, high age in epidural, or spinal block) or diseases (uremia) that may increase the rate of the initial uptake of the local anesthetic are indications to reduce the dose in comparison to one normally used for young, healthy, and nonpregnant adults. On the other hand, the reduced clearance of local anesthetics associated with renal, hepatic, and cardiac diseases is the most important reason to reduce the dose for repeated or continuous administration. The magnitude of the reduction should be related to the expected influence of the pharmacodynamic or pharmacokinetic change.

The Effects of Age on Neural Blockade and Hemodynamic Changes After Epidural Anesthesia with Ropivacaine

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: ≥61 yr). After a test dose of 3 mL of prilocaine 1.0% with epinephrine 5 &mgr;g/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.

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 &agr;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). 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 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: ≥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: (t½,a1, t½,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.

Hemodynamic effects of central neural blockade in elderly patients

ly are now recognized as an increasing segment of the population. In one century the number of persons of 65 or older has increased three times perhaps because of better and more available medical care. By 2030, up to 20% of Western populations will be more than 65 yr of age.1 The oldest old (people aged 80 and over) are the fastest growing segment of the older population. Improvements in surgical techniques, anesthesia and intensive care units have made surgical interventions in more and more older and sicker patients possible. Over half of the population older than 65 yr will require surgical intervention at least once during the remainder of their lives and have surgery four times more often than the rest of the population.2 Accordingly, elderly patients will become a very large part of our anesthetic practice. The most common procedures, which are performed in the elderly, involve the cardiovascular system, the digestive system and musculoskeletal system. Regional anesthetic techniques (peripheral nerve blockade, central neural blockade) are frequently used in elderly patients, especially during orthopedic surgery, genito-urological, abdominal and gynecological procedures. Systemic hypotension and bradycardia are the most common cardiovascular disturbances associated with central neural blockade, with a particularly frequent incidence in the elderly.3 Systemic hypotension occurs from decreases in systemic vascular resistance and central venous pressure from sympathetic block with vasodilatation and redistribution of central blood volume to lower extremities and splanchnic beds.4 Marked hypotension may be especially harmful to elderly patients with limited cardiac reserve. Besides, elderly patients have decreased physiological reserve and an increased incidence of systemic disease. Normal aging is associated with a reduction in the baroreceptor-reflex mediated heart rate response to hypotensive stimuli.5 Consequently elderly patients may not respond with the same degree of sympathetic activity as younger patients. Decreased cardiac reserves, structural changes in the arterioles and changes in the autonomic nervous system with increasing age may also play a role. High levels of sensory anesthesia and increasing age appeared to be the two main risk factors for the development of hypotension after spinal anesthesia.6 In elderly patients both epidural and spinal anesthesia are associated with increased levels of analgesia.7–12 The level of analgesia increases with advancing age after lumbar epidural administration of a given dose (fixed volume and concentration) of a local anesthetic solution7–9 and following thoracic epidural administration of a fixed dose.11 Increased levels of analgesia with advancing age have been attributed to reduced leakage of local anesthetic solution, because of progressive sclerotic closure of intervertebral foramina. As the fatty tissue degenerates with advancing age, the epidural space becomes more compliant and less resistant; this may contribute to the greater longitudinal spread of injected solutions in elderly patients as well. In older patients the onset time to maximal caudad spread and motor blockade decrease together with an enhanced intensity of motor blockade following epidural administration of bupivacaine. The duration of sensory block is not, however, prolonged. Recently Simon et al.8 demonstrated that the increased levels of analgesia following epidural anesthesia with ropivacaine 1% are associated with a frequent incidence of bradycardia and hypotension, particularly in the elderly patients. With spinal anesthesia the clinical profile depends on the baricity of the solution. The effect of age on the maximal height of spinal analgesia with isobaric solutions is marginal.11 With hyperbaric local anesEDITORIAL 117

Population Pharmacokinetic–Pharmacodynamic Modeling of Epidural Anesthesia

Background:In previous studies, the authors reported on the absorption and disposition kinetics of levobupivacaine and ropivacaine. The current study was designed to develop a population pharmacokinetic–pharmacodynamic model capable of linking the kinetic data to the analgesic effects of these local anesthetics (i.e., sensory neural blockade). Methods:A disposition compartmental model was fitted to concentration data of the intravenously administered deuterium-labeled anesthetics, and a model consisting of two parallel absorption compartments and the identified disposition compartments was fitted to concentration data of the concomitantly epidurally administered unlabeled anesthetics. The epidural segments were modeled by individual central and peripheral absorption compartments and effect sites, which were fitted to the simultaneously acquired pinprick data. A covariate model incorporated the effects of age. Results:The threshold for epidural anesthesia increased from the lower to the higher segments. The central effect compartment equilibration half-lives were approximately 15 min for levobupivacaine and 25 min for ropivacaine. For levobupivacaine, age reduced the equilibration half-lives at all segments; for ropivacaine, age increased the anesthetic sensitivity at segments T12 and higher. Conclusions:A population pharmacokinetic–pharmacodynamic model was developed that quantitatively described sensory blockade during epidural anesthesia, including the effects of age. The model may be useful to individualize dose requirements, to predict the time course of sensory blockade, and to study new local anesthetics.

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 × 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.

Upper thoracic epidural anaesthesia: effects of age on neural blockade and cardiovascular parameters

Segmental dose reduction with increasing age after thoracic epidural anaesthesia (TEA) has been documented. We hypothesised that after a fixed loading dose of ropivacaine at the T3–T4 level, increasing age would result in more extended analgesic spread. In addition, other aspects of neural blockade and haemodynamic changes were studied.

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.

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 Ki values of 5 &mgr;M (1.4 mg/L) and 13 &mgr;M (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.