Biventricular function in exercise during autonomic (thoracic epidural) block.

BACKGROUND: Blockade of cardiac sympathetic fibers by thoracic epidural anesthesia (TEA) was previously shown to reduce right and left ventricular systolic function and effective pulmonary arterial elastance. At conditions of constant paced heart rate, cardiac output and systemic hemodynamics were unchanged. In this study, we further investigated the effect of cardiac sympathicolysis during physical stress and increased oxygen demand. METHODS: In a cross-over design, 12 patients scheduled to undergo thoracic surgery performed dynamic ergometric exercise tests with and without TEA. Hemodynamics were monitored and biventricular function was measured by transthoracic two-dimensional and M-mode echocardiography, pulsed wave Doppler and tissue Doppler imaging. RESULTS: TEA attenuated systolic RV function (TV S': - 21%, P < 0.001) and LV function (MV S': - 14%, P = 0.025), but biventricular diastolic function was not affected. HR (- 11%, P < 0.001), SVI (- 15%, P = 0.006), CI (- 21%, P < 0.001) and MAP (- 12%, P < 0.001) were decreased during TEA, but SVR was not affected. Exercise resulted in significant augmentation of systolic and diastolic biventricular function. During exercise HR, SVI, CI and MAP increased (respectively, + 86%, + 19%, + 124% and + 17%, all P < 0.001), whereas SVR decreased (- 49%, P < 0.001). No significant interactions between exercise and TEA were found, except for RPP (P = 0.024) and MV E DT (P = 0.035). CONCLUSION: Cardiac sympathetic blockade by TEA reduced LV and RV systolic function but did not significantly blunt exercise-induced increases in LV and RV function. These data indicate that additional mechanisms besides those controlled by the cardiac sympathetic nervous system are involved in the regulation of cardiac function during dynamic exercise. Trial registration Clinical trial registration: Nederlands Trial Register, NTR 4880 http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=4880 .

Thoracic Epidural Anesthesia Reduces Right Ventricular Systolic Function With Maintained Ventricular-Pulmonary Coupling.

BACKGROUND: Blockade of cardiac sympathetic fibers by thoracic epidural anesthesia may affect right ventricular function and interfere with the coupling between right ventricular function and right ventricular afterload. Our main objectives were to study the effects of thoracic epidural anesthesia on right ventricular function and ventricular-pulmonary coupling. METHODS: In 10 patients scheduled for lung resection, right ventricular function and its response to increased afterload, induced by temporary, unilateral clamping of the pulmonary artery, was tested before and after induction of thoracic epidural anesthesia using combined pressure-conductance catheters. RESULTS: Thoracic epidural anesthesia resulted in a significant decrease in right ventricular contractility (ΔESV25: +25.5 mL, P=0.0003; ΔEes: -0.025 mm Hg/mL, P=0.04). Stroke work, dP/dtMAX, and ejection fraction showed a similar decrease in systolic function (all P<0.05). A concomitant decrease in effective arterial elastance (ΔEa: -0.094 mm Hg/mL, P=0.004) yielded unchanged ventricular-pulmonary coupling. Cardiac output, systemic vascular resistance, and mean arterial blood pressure were unchanged. Clamping of the pulmonary artery significantly increased afterload (ΔEa: +0.226 mm Hg/mL, P<0.001). In response, right ventricular contractility increased (ΔESV25: -26.6 mL, P=0.0002; ΔEes: +0.034 mm Hg/mL, P=0.008), but ventricular-pulmonary coupling decreased (Δ(Ees/Ea) = -0.153, P<0.0001). None of the measured indices showed significant interactive effects, indicating that the effects of increased afterload were the same before and after thoracic epidural anesthesia. CONCLUSIONS: Thoracic epidural anesthesia impairs right ventricular contractility but does not inhibit the native positive inotropic response of the right ventricle to increased afterload. Right ventricular-pulmonary arterial coupling was decreased with increased afterload but not affected by the induction of thoracic epidural anesthesia. CLINICAL TRIAL REGISTRATION: URL: http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2844. Unique identifier: NTR2844.

Effect of increasing age on the haemodynamic response to thoracic epidural anaesthesia: an observational study.

BACKGROUND: Sympathetic blockade with thoracic epidural anaesthesia (TEA) results in circulatory changes and may directly alter cardiac function. Ageing is associated with an impairment of autonomic nervous system control and a deterioration of myocardial diastolic performance. OBJECTIVES: We postulated that haemodynamic changes induced by TEA could vary with age. DESIGN: An observational study. SETTINGS: Tertiary, university hospital. PATIENTS: Thirty-five patients scheduled for pulmonary surgery and TEA stratified into three age groups: 18 to 45 years; 46 to 65 years; and at least 66 years. INTERVENTIONS: Cardiac performance was evaluated in awake patients using transthoracic echocardiography (TTE) at baseline and 45 min after institution of TEA. Intravenous volume loading was used to preserve preload. MAIN OUTCOME MEASURES: Tissue Doppler imaging (TDI) and other derived indices from TTE were used to quantify biventricular systolic and diastolic function. RESULTS: Baseline systolic and diastolic left ventricular function and right ventricular diastolic function decreased with age. After TEA, mean arterial pressure (MAP) decreased (91.2 vs. 79.2 mmHg; P < 0.001) and cardiac index increased (2.7 vs. 3.0 l min m; P = 0.005), although heart rate and Doppler-derived indices of left ventricular contractility remained unchanged. Right ventricular ejection indices increased and TDI-derived measures of diastolic performance increased for the left ventricle (LV) as well as the right ventricle (RV). With the exception of Tricuspid Annular Plane Systolic Excursion (TAPSE), which increased with increasing age (R = 0.53; P = 0.003), TEA effects on biventricular function were not influenced by age. CONCLUSION: When preload is preserved with volume loading, TEA predominantly causes systemic vasodilatation and increases global haemodynamic performance. Indices of left ventricular systolic function do not change, whereas left ventricular and right ventricular diastolic function appears to improve. The effects of TEA on right ventricular systolic function are inconclusive. Although increasing age causes a consistent decline of baseline diastolic function, the cardiovascular response to TEA is not impaired in the elderly. TRIAL REGISTRY NUMBER: EudraCT 2009-010594-20.

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.

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.

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 microg/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 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.