J. W. Van Kleef

Pharmacokinetics of lignocaine and bupivacaine in surgical patients following epidural administration. Simultaneous investigation of absorption and disposition kinetics using stable isotopes

SummaryThe pharmacokinetics of lignocaine (lidocaine) and bupivacaine following epidural administration were studied in 12 surgical patients using a stable isotope method. Shortly after epidural administration of the agent to be evaluated, a deuterium-labelled analogue was administered intravenously. Plasma concentrations of the unlabelled and the deuterium-labelled local anaesthetics were determined using gas chromatography and mass fragmentography. The pharmacokinetic behaviour of both agents was consistent with a 2- compartment open model and two parallel first-order absorption processes. The mean distribution and elimination half-lives were 12 minutes and 100 minutes for lignocaine, and 22 minutes and 143 minutes for bupivacaine. The mean volumes of the central compartment and the mean steady-state volumes of distribution were: lignocaine, 43L and 99L; bupivacaine, 33L and 68L. Total plasma clearances averaged 0.95 L/min (57 L/h) for lignocaine and 0.52 L/min (31.2 L/h) for bupivacaine. The half-lives, characterising the fast and slow absorption processes, were 9.3 and 82 minutes for lignocaine, and 7.0 minutes and 362 minutes for bupivacaine; the fractions of the doses absorbed in the fast and slow processes were lignocaine 0.38 and 0.58, bupivacaine 0.28 and 0.66, respectively. The results indicate that the local anaesthetics are completely absorbed from the epidural space into the general circulation. The initial absorption rates of both local anaesthetics appear to be similar, but, later, the absorption of bupivacaine proceeds much more slowly than the absorption of lignocaine.

Influence of hypoxic duration and posthypoxic inspired O2 concentration on short term potentiation of breathing in humans.

1. Short term potentiation (STP) of breathing refers to respiratory activity at a higher level than expected just from the dynamics of the peripheral and central chemoreceptors. In humans STP is activated by hypoxic stimulation. 2. To investigate the effects of the duration of hypoxia and the posthypoxic inspired O2 concentration on STP, the ventilatory responses to 30 s and 1, 3 and 5 min of hypoxia (end‐tidal PO2, P(ET.O2) approximately 6.5 kPa) followed by normoxia (P(ET.O2) approximately 14.5 kPa) and hyperoxia (P(ET.O2) approximately 70 kPa) were studied in ten healthy subjects. End‐tidal PCO2 (P(ET.CO2)) was clamped during hypoxic and recovery periods at 5.7 kPa. 3. Steady‐state ventilation (VE) was 13.7 +/‐ 0.6 l min‐1 during normoxia and increased to 15.5 +/‐ 0.3 l min‐1 during hyperoxia (P < 0.05) due to the reduced Haldane effect and some decrease in cerebral blood flow (CBF). 4. The mean responses following hypoxia reached normoxic baseline after 69, 54, 12 and 12 s when 30 s and 1, 3 and 5 min of hypoxia, respectively, were followed by normoxia. An undershoot of 10 and 20% below hyperoxic baseline was observed when 3 and 5 min of hypoxia, respectively, were followed by hyperoxia. Hyperoxic VE reached hyperoxic baseline after 9, 15, 12 and 9 s at the termination of 30 s and 1, 3 and 5 min of hypoxia, respectively. 5. Normoxic recovery from 30 s and 1 min of hypoxia displayed a fast and subsequent slow decrease towards normoxic baseline. The fast component was attributed to the loss of the hypoxic drive at the site of the peripheral chemoreceptors, and the slow component to the decay of the STP that had been activated centrally by the stimulus. A slow decrease at the termination of 30 s and 1 min of hypoxia by hyperoxia was not observed since this component was cancelled by the increase in ventilatory output due to the reduced Haldane effect and some decrease of CBF. 6. Decay of the STP was not apparent in the normoxic recovery from 3 and 5 min of hypoxia as a slow component since it cancelled against the slow ventilatory increase related to the increase of brain tissue PCO2 due to the reduction of CBF at the relief of hypoxia. The undershoot observed when hyperoxia followed 3 and 5 min of hypoxia reflects the stimulatory effects of hyperoxia on VE. 7. The manifestation of the STP as a slow ventilatory decrease depends on the duration of hypoxia and the subsequent inspired oxygen concentration. We argue that STP is not abolished by the central depressive effects of hypoxia, although the manifestation of the STP may be overridden or counteracted by other mechanisms.

Pharmacokinetics of lidocaine and bupivacaine following subarachnoid administration in surgical patients: simultaneous investigation of absorption and disposition kinetics using stable isotopes

The pharmacokinetics of lidocaine and bupivacaine following subarachnoid administration were studied in 12 surgical patients using a stable isotope method. After subarachnoid administration of the agent to be evaluated, a deuterium-labelled analogue was administered intravenously. Blood samples were

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 clearance (349 ± 114 mL min−1) and volume of distribution at steady state (56 ± 14L), derived by compartmental analysis, were similar to those obtained by non-compartmental analysis. The absorption was bi-phasic. The fraction absorbed and half-life of the fast absorption process were 0.22 ± 0.06 and 5.2 ± 2.7 min, respectively. The 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.

Dutch case-control study of anaesthesia-related morbidity and mortality. Rationale and methods

To date, anaesthesia‐related mortality, morbidity and risk factors have almost exclusively been studied qualitatively rather than quantitatively. Therefore, knowledge of the relative risk associated with many anaesthesia‐related factors is still lacking. Recently, a quantitative study of the determinants and prevention of morbidity and mortality in anaesthesia was started in the Netherlands. Its objective is to study severe peri‐operative morbidity and mortality as a function of anaesthesia‐related risk factors. The study is designed as a case‐control study within a prospectively defined cohort. The cohort comprises all patients undergoing an anaesthetic procedure, either general, regional or a combination, in one of 61 hospitals between 1 January 1995 and 1 January 1997. A ‘case’ is a patient who dies within 24 h of undergoing an anaesthetic procedure or who remains comatose 24 h after an anaesthetic procedure. A ‘control’ patient is a randomly chosen patient who has undergone anaesthesia and is matched for gender and age. The present report discusses the study protocol.

Pharmacokinetics of Lidocaine and Bupivacaine Following Subarachnoid Administration in Surgical Patients: Simultaneous Investigation of Absorption and Disposition Kinetics Using Stable Isotopes

The pharmacokinetics of lidocaine and bupivacaine following subarachnoid administration were studied in 12 surgical patients using a stable isotope method. After subarachnoid administration of the agent to be evaluated, a deuterium-labelled analogue was administered intravenously. Blood samples were collected for 24 h. Plasma concentrations of the unlabelled and the deuterium-labelled local anesthetics were determined using a combination of capillary gas chromatography and mass fragmentography. Bi-exponential functions were fitted to the plasma concentration-time data of the deuterium-labelled local anesthetics. The progression of the absorption was evaluated using deconvolution. Mono- and bi-exponential functions were then fitted to the fraction absorbed versus time data. The distribution and elimination half-lives of the deuterium-labelled analogues were 25 ± 13 min (mean ± SD) and 121 ± 31 min for lidocaine and 19 ± 10 min and 131 ± 33 min for bupivacaine. The volumes of the central compartment and steady-state volumes of distribution were: lidocaine 57 ± 10 1 and 105 ± 25 1, bupivacaine 25 ± 6 1 and 63 ± 22 1. Total plasma clearance values averaged 0.97 ± 0.211/min for lidocaine and 0.56 ± 0.14 1/min for bupivacaine. The absorption of lidocaine could be described by a single first order absorption process, characterized by a half-life of 71 ± 17 min in five out of six patients. The absorption of bupivacaine could be described adequately assuming two parallel first order absorption processes in all six patients. The half-lives, characterizing the fast and slow absorption processes of bupivacaine, were 50 ± 27 min and 408 ± 275 min, respectively. The fractions of the dose, absorbed in the fast and slow processes, were 0.35 ± 0.17 and 0.61 ±0.16, respectively. The results indicate that both local anesthetics arc completely absorbed intact from the subarachnoid space into the general circulation.

Spinal Anesthesia with Hyperbaric Lidocaine and Bupivacaine: Effects of Epinephrine on the Plasma Concentration Profiles

The effects of epinephrine on the plasma concentration profiles and some derived pharmacokinetic parameters were studied after subarachnoid injection of hyperbaric lidocaine and bupivacaine solutions. Addition of epinephrine to the local anesthetic solution reduced the mean peak plasma concentration of lidocaine from 526 to 376 ng/ml, but did not significantly reduce the mean peak plasma concentration of bupivacaine (70 vs 56 ng/ml). Epinephrine did not affect the times at which the peak concentrations were reached, the terminal half-lives, or the total plasma clearances. The observed effects of epinephrine on the peak plasma concentrations are consistent with the vascular activity of lidocaine and bupivacaine, respectively.