Effect of a preemptive femoral nerve block on cytokine release and hyperalgesia in experimentally inflamed skin of human volunteers.

BACKGROUND AND OBJECTIVES: Tissue injury is associated with the local release of inflammatory and nociceptive mediators and the development of hyperalgesia. It is unclear whether interrupting neuronal signaling using regional anesthetic techniques at the time of the injury modifies local nociceptive and inflammatory processes. The aim of this study was to determine whether a peripheral nerve block at the time of tissue injury could modify the development of wound hyperalgesia and the local release of inflammatory and nociceptive mediators. METHODS: Twelve healthy volunteers participated in this controlled, crossover, randomized study. A femoral nerve block or a sham block was established before inducing an experimental UVB burn on the thigh. Twenty-four hours later, the interstitial wound fluid was sampled, and mechanical and heat pain thresholds were assessed. Wound fluid concentrations of an array of cytokines, chemokines, nerve growth factor, prostaglandin E2, and substance P were determined. RESULTS: Skin inflammation was associated with the release of inflammatory and nociceptive mediators and resulted in significant tissue hyperalgesia (P < 0.001). However, the presence of a fully established peripheral nerve block at the time of tissue injury did not alter the development of hyperalgesia after regression of the block. Similarly, the presence of a peripheral nerve block did not modify the release of inflammatory or nociceptive mediators. CONCLUSIONS: These findings suggest that a preemptive, single-shot peripheral nerve block minimally affects wound hyperalgesia and inflammation. Continuous nerve block techniques may be better suited to alter nociceptive and inflammatory events in wounds beyond the duration of the block.

A randomized trial of maximum cephalad sensory blockade with single-shot spinal compared with combined spinal-epidural techniques for cesarean delivery.

BACKGROUND: Previous studies have shown more extensive cephalad sensory blockade in women receiving combined spinal-epidural (CSE) anesthesia compared with single-shot spinal (SSS) anesthesia for elective cesarean delivery. It has been postulated that introduction of the epidural needle during CSE disturbs the negative pressure in the epidural space, resulting in relatively greater cerebrospinal fluid (CSF) pressure and increased spread of intrathecal local anesthetic. We tested the hypothesis that CSE results in more extensive cephalad sensory blockade than SSS anesthesia and that loss-of-resistance during initiation of CSE anesthesia increases CSF pressure compared with SSS. METHODS: Thirty parturients scheduled for elective cesarean delivery were enrolled in this randomized, double-blind study. Patients received either SSS or CSE anesthesia with equal doses of intrathecal anesthetic (hyperbaric bupivacaine 12 mg, fentanyl 10 microg and morphine 200 microg). Before the intrathecal injection, the CSF pressure was measured with a fiberoptic pressure sensor. Maximum cephalad sensory blockade to pinprick, cold and touch was measured. The total dose of phenylephrine required to maintain baseline arterial blood pressure was also recorded. RESULTS: There were no significant differences in the median (interquartile range) pinprick sensory block height [T4 (T4-2) vs T3 (T4-1)] or CSF pressures [6 (4-12) vs 9 (8-12) mm Hg] between the SSS and CSE groups. There were no significant correlations between CSF pressure and block height or total dose of phenylephrine. CONCLUSION: The SSS and CSE techniques inserted in the lateral decubitus position resulted in similar extent of sensory blockade and CSF pressure. These findings suggest that altering the intrathecal dose is not necessary and that any difference in intrathecal pressure associated with initial placement of an epidural needle in the epidural space during CSE anesthesia is clinically inconsequential.

Variability of target-controlled infusion is less than the variability after bolus injection.

BACKGROUND: Target-controlled infusion (TCI) drug delivery systems deliver intravenous drugs based on pharmacokinetic models. TCI devices administer a bolus, followed by exponentially declining infusions, to rapidly achieve and maintain pseudo-steady state drug concentrations in the plasma or at the site of drug effect. Many studies have documented the prediction accuracy of TCI devices. The authors' goal was to apply linear systems theory to characterize the relation between the variability in concentrations achieved with TCI devices and the variability in concentrations after intravenous bolus injection. METHODS: The authors developed a mathematical model of the variability of any arbitrary method of drug delivery, based on the variability with intravenous bolus injection or the variability with an arbitrary infusion regimen. They tested the model in a simulation of 1,000 patients receiving propofol by simple bolus injection, conventional infusion, or a TCI device. The authors then examined an experimental data set for the same behavior. RESULTS: The variability of any arbitrary infusion regimen, including TCI, is bounded by the variability after bolus injection. This is observed in the simulation and experimental data sets as well. CONCLUSION: TCI devices neither create nor eliminate biologic variability. For any drug described by linear pharmacokinetic models, no infusion regimen, including TCI, can have higher variability than that observed after bolus injection. The median performance of TCI devices should be reasonably close to the prediction of the device. However, the overall spread of the observations is an intrinsic property of the drug, not the TCI delivery system.

Role of nitric oxide in heparin-induced attenuation of hypoxic pulmonary vascular remodeling.

Heparin and nitric oxide (NO) attenuate changes to the pulmonary vasculature caused by prolonged hypoxia. Heparin may increase NO; therefore, we hypothesized that heparin may attenuate hypoxia-induced pulmonary vascular remodeling via a NO-mediated mechanism. In vivo, rats were exposed to normoxia (N) or hypoxia (H; 10% O(2)) with or without heparin (1,200 U x kg-1 x day-1) and/or the NO synthase (NOS) inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME; 20 mg x kg-1 x day-1) for 3 days or 3 wk. Heparin attenuated increases in pulmonary arterial pressure, the percentage of muscular pulmonary vessels, and their medial thickness induced by 3 wk of H. Importantly, although L-NAME alone had no effect, it prevented these effects of heparin on vascular remodeling. In H lungs, heparin increased NOS activity and cGMP levels at 3 days and 3 wk and endothelial NOS protein expression at 3 days but not at 3 wk. In vitro, heparin (10 and 100 U x kg-1 x ml-1) increased cGMP levels after 10 min and 24 h in N and anoxic (0% O2) endothelial cell-smooth muscle cell (SMC) coculture. SMC proliferation, assessed by 5-bromo-2'-deoxyuridine incorporation during a 3-h incubation period, was decreased by heparin under N, but not anoxic, conditions. The antiproliferative effects of heparin were not altered by L-NAME. In conclusion, the in vivo results suggest that attenuation of hypoxia-induced pulmonary vascular remodeling by heparin is NO mediated. Heparin increases cGMP in vitro; however, the heparin-induced decrease in SMC proliferation in the coculture model appears to be NO independent.