bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nefopam, a Nonsedative Benzoxazocine Analgesic, Selectively Reduces the Shivering Threshold in Unanesthetized Subjects
Authors: Alfonsi Pascal , Adam Frederic , Passard Andrea , Guignard Bruno , Sessler Daniel I. , Chauvin Marcel 
Published: December 2003

Background
The analgesic nefopam does not compromise ventilation, is minimally sedating, and is effective as a treatment for postoperative shivering. The authors evaluated the effects of nefopam on the major thermoregulatory responses in humans: sweating, vasoconstriction, and shivering.

Methods
Nine volunteers were studied on three randomly assigned days: (1) control (saline), (2) nefopam at a target plasma concentration of 35 ng/ml (low dose), and (3) nefopam at a target concentration of 70 ng/ml (high dose, approximately 20 mg total). Each day, skin and core temperatures were increased to provoke sweating and then reduced to elicit peripheral vasoconstriction and shivering. The authors determined the thresholds (triggering core temperature at a designated skin temperature of 34 degrees C) by mathematically compensating for changes in skin temperature using the established linear cutaneous contributions to control of each response.

Results
Nefopam did not significantly modify the slopes for sweating (0.0 +/- 4.9 degrees C. microg-1. ml; r2 = 0.73 +/- 0.32) or vasoconstriction (-3.6 +/- 5.0 degrees C. microg-1. ml; r2 = -0.47 +/- 0.41). In contrast, nefopam significantly reduced the slope of shivering (-16.8 +/- 9.3 degrees C. microg-1. ml; r2 = 0.92 +/- 0.06). Therefore, high-dose nefopam reduced the shivering threshold by 0.9 +/- 0.4 degrees C (P < 0.001) without any discernible effect on the sweating or vasoconstriction thresholds.

Conclusions
Most drugs with thermoregulatory actions-including anesthetics, sedatives, and opioids-synchronously reduce the vasoconstriction and shivering thresholds. However, nefopam reduced only the shivering threshold. This pattern has not previously been reported for a centrally acting drug. That pharmacologic modulations of vasoconstriction and shivering can be separated is of clinical and physiologic interest.
Albumin and Hydroxyethyl Starch Modulate Oxidative Inflammatory Injury to Vascular Endothelium
Authors: Lang John D. , Figueroa Mario , Chumley Phillip , Aslan Mutay , Hurt John , Tarpey Margaret M. , Alvarez Beatriz , Radi Rafael , Freeman Bruce A. 
Published: December 2003

Background
Human serum albumin is used clinically to maintain colloid osmotic pressure and is viewed to serve an antioxidant role in the vascular compartment via binding of redox-active metal complexes, transport of nitric oxide, and the oxidant-scavenging reactions of the single thiol of human serum albumin, cys34. Because of these potentially desirable adjunctive actions, we evaluated the purity and thiol redox state and compared the relative effects of clinically available 25% human serum albumin preparations with a starch-derived colloid, 6% hydroxyethyl starch, in in vitro models of inflammatory vascular injury.

Methods
Bovine aortic endothelial cell responses to chemical, enzymatic, and cell-derived reactive inflammatory mediators in the presence of human serum albumin or hydroxyethyl starch were assessed.

Results
The cys34 thiol of fresh human serum albumin preparations was 70-85% oxidized and contained a population of human serum albumin (approximately 25% of total) having the cys34 resistant to reduction by 2-mercaptoethanol and NaBH4. Treatment of bovine aortic endothelial cells with human serum albumin dose-dependently protected from HOCl-mediated 14C-adenine release, with this protective effect of human serum albumin not dependent on protein thiol status. Addition of human serum albumin to cell media provided no protection from the cytotoxic actions of peroxynitrite and xanthine oxidase-derived reactive species. Binding of activated polymorphonuclear leukocytes to bovine aortic endothelial cells was significantly amplified by hydroxyethyl starch and inhibited by human serum albumin administration. The binding of neutrophil-derived myeloperoxidase to bovine aortic endothelial cells, a mediator of multiple oxidative and nitric oxide-consuming reactions, was also inhibited by human serum albumin and enhanced by hydroxyethyl starch.

Conclusions
Clinical human serum albumin preparations show modest intrinsic non-thiol-dependent antiinflammatory properties in vitro, a phenomenon that was not observed with hydroxyethyl starch.
Differential Activation of Mitogen-activated Protein Kinases in Ischemic and Anesthetic Preconditioning
Authors: da Silva Rafaela , Grampp Thomas , Pasch Thomas , Schaub Marcus C. , Zaugg Michael 
Published: December 2003

Background
Accumulating evidence pinpoints to the pivotal role of mitogen-activated protein kinases (MAPKs) in the signal transduction underlying cardiac preconditioning.

Methods
PD98059, an inhibitor of extracellular signal-regulated protein kinase (MEK-ERK1/2), and SB203580, an inhibitor of p38 MAPK, were used to evaluate the role of MAPKs with respect to postischemic functional recovery in isolated perfused rat hearts subjected to ischemic preconditioning (IPC) and anesthetic preconditioning (APC). Western blot analyses were used to determine the degree of ERK1/2 and p38 MAPK activation after the application of the preconditioning stimulus and after ischemia-reperfusion. Immunohistochemical staining served to visualize subcellular localization of activated MAPKs.

Results
PD98059 and SB203580 abolished postischemic functional recovery in IPC but not in APC. IPC but not APC markedly activated ERK1/2 and p38 MAPK, which were abrogated by coadministration of the specific blockers. Conversely, IPC and APC enhanced ERK1/2 activity after ischemia-reperfusion as compared to nonpreconditioned hearts, and IPC in addition enhanced p38 MAPK activity. Coadministration of PD98059 and SB203580 during IPC but not during APC inhibited postischemically enhanced MAPK activities. Moreover, chelerythrine and 5-hydroxydecanoate, effective blockers of IPC and APC, annihilated IPC- and APC-induced enhanced postischemic responses of MAPKs. Finally, administration of PD98059 during ischemia-reperfusion diminished the protective effects of IPC and APC. Immunohistochemistry revealed increased ERK1/2 activity primarily in intercalated discs and nuclei and increased p38 MAPK activity in the sarcolemma and nuclei of IPC-treated hearts.

Conclusions
Although MAPKs may orchestrate cardioprotection as triggers and mediators in IPC, they are devoid of triggering, but they may have mediator effects in APC.
Hyperoxic Ventilation Reduces 6-Hour Mortality at the Critical Hemoglobin Concentration
Authors: Meier Jens , Kemming Gregor I. , Kisch-Wedel Hille , Wölkhammer Stefan , Habler Oliver P. 
Published: December 2003

Background
Acute normovolemic hemodilution reduces the circulating erythrocyte mass and, thus, the hemoglobin concentration. After extreme acute normovolemic hemodilution to the critical hemoglobin concentration (Hbcrit), oxygen demand of the tissues is no longer met by oxygen supply, and death occurs with increasing oxygen debt. The aim of the current study was to investigate whether ventilation with 100% oxygen (fraction of inspired oxygen [FiO2] = 1.0; hyperoxic ventilation) initiated at Hbcrit could restore adequate tissue oxygenation and prevent death.

Methods
Fourteen anesthetized pigs ventilated with room air (FiO2 = 0.21) were hemodiluted by exchange of whole blood for 6% hydroxyethyl starch (200,000:0.5) until the individual Hbcrit was reached. Hbcrit was defined as the onset of oxygen supply dependency of oxygen consumption and was identified with indirect calorimetry. For the next 6 h, animals were either ventilated with an FiO2 of 0.21 (n = 7) or an FiO2 of 1.0 (n = 7).

Results
All animals in the 0.21 FiO2 group died within the first 3 h at Hbcrit (i.e., 6-h mortality 100%). Death was preceded by an increase of serum concentrations of lactate and catecholamines. In contrast to that, six of the seven animals of the 1.0 FiO2 group survived the complete 6-h observation period without lactacidosis and increased serum catecholamines (i.e., 6-h mortality 14%; FiO2 0.21 vs. FiO2 1.0, P < or = 0.05). After 6 h at Hbcrit, the FiO2 was reduced from 1.0 to 0.21, and five of the six animals died within the next 3 h.

Conclusion
In anesthetized pigs submitted to lethal anemia, hyperoxic ventilation enabled survival for 6 h without signs of circulatory failure.
Sodium Bisulfite
Authors: Taniguchi Masahiko , Bollen Andrew W. , Drasner Kenneth 
Published: December 2003

Background
Neurologic deficits after apparent intrathecal injection of 3% Nesacaine-CE intended for epidural administration created concern about the potential toxicity of chloroprocaine and the preservative sodium bisulfite. Although bisulfite-free formulations of chloroprocaine were subsequently introduced into clinical practice, the relative toxicities of this anesthetic and preservative were never clearly established. The current studies used a relevant functional and histologic model to investigate the intrathecal neurotoxicity of these two compounds.

Methods
In the first experiment, rats implanted with intrathecal catheters were given one of two commercially available solutions of chloroprocaine, one of which contained sodium bisulfite; control animals received saline. Animals were assessed for sensory impairment 7 days after administration using the tail-flick test and were killed to obtain histologic specimens to quantify nerve injury. In the second experiment, identical methodology was used to investigate the effects of freshly prepared solutions of chloroprocaine, chloroprocaine with sodium bisulfite, sodium bisulfite, and saline.

Results
The two experiments yielded similar results. In experiment 1, tail-flick latencies and nerve injury scores after administration of plain chloroprocaine were significantly greater than those of chloroprocaine containing bisulfite. Injury scores for animals receiving chloroprocaine with bisulfite were elevated compared with those for animals given saline. In experiment 2, animals receiving plain chloroprocaine developed elevations in tail-flick latencies and nerve injury scores that were significantly greater than those for all other groups. Nerve injury scores with chloroprocaine containing bisulfite were greater than with saline or bisulfite alone. Tail-flick latencies and nerve injury scores with bisulfite alone were similar to those with saline.

Conclusions
Clinical deficits associated with unintentional intrathecal injection of chloroprocaine likely resulted from a direct effect of the anesthetic, not the preservative. The data also suggest that bisulfite can reduce neurotoxic damage induced by intrathecal local anesthetic.
Developmental Regulation of Codeine Analgesia in the Rat
Authors: Williams D. Glyn , Dickenson Anthony , Fitzgerald Maria , Howard Richard F. 
Published: December 2003

Background
Codeine analgesia is dependent on metabolism to morphine. Metabolic capability is genetically determined in rats and humans, and individuals can be classified as extensive or poor metabolizers, as determined by the extent of production of morphine. Codeine is often given to infants and children. The aim of this study was to investigate the effects of developmental age on codeine analgesia in rats.

Methods
The effects of codeine were compared with those of morphine using withdrawal reflex responses to mechanical stimuli (with and without inflammation) and to noxious heat in two strains of rats (Sprague-Dawley and Dark Agouti) that have been used to model human metabolic phenotypes because of marked differences in enzyme activity. Effects of the opioids were compared at 3, 10, and 21 days of age and in adult rats.

Results
Consistent age-related changes in the efficacy of codeine relative to morphine were noted for both strains of rats. For the extensive metabolizer (Sprague-Dawley) strain, codeine efficacy was substantially lower at 3 days of age (P < 0.001), but there was no difference between the effects of codeine and morphine for 10- and 21-day-old rats and adults (P > 0.05). Poor metabolizers (Dark Agouti strain) also had comparatively low efficacy for codeine compared with morphine in 3-day-old rats and in adults (P < 0.001). In 10- and 21-day-old Dark Agouti rats, there was no difference between either drug (P < 0.05).

Conclusions
Codeine analgesia is developmentally regulated, with low efficacy in the early postnatal period. Effects in the adult rat were not predictive of efficacy in development in either strain, which has important implications for further study and, possibly, for clinical use.
Chronic Pain Management
Authors: Fitzgibbon Dermot R. , Posner Karen L. , Domino Karen B. , Caplan Robert A. , Lee Lorri A. , Cheney Frederick W. 
Published: December 2003

Background
The practice of chronic pain management has grown steadily in recent years. The purpose of this study was to identify and describe issues and trends in liability related to chronic pain management by anesthesiologists.

Methods
Data from 5,475 claims in the American Society of Anesthesiologists Closed Claims Project database between 1970 and 1999 were reviewed to compare liability related to chronic pain management with that related to surgical and obstetric (surgical/obstetric) anesthesia. Acute pain management claims were excluded from analysis. Outcomes and liability characteristics between 284 pain management claims and 5,125 surgical/obstetric claims were compared.

Results
Claims related to chronic pain management increased over time (P < 0.01) and accounted for 10% of all claims in the 1990s. Compensatory payment amounts were lower in chronic pain management claims than in surgical/obstetric anesthesia claims from 1970 to 1989 (P < 0.05), but during the 1990s, there was no difference in size of payments. Nerve injury and pneumothorax were the most common outcomes in invasive pain management claims. Epidural steroid injections accounted for 40% of all chronic pain management claims. Serious injuries, involving brain damage or death, occurred with epidural steroid injections with local anesthetics and/or opioids and with maintenance of implantable devices.

Conclusions
Frequency and payments of claims associated with chronic pain management by anesthesiologists increased in the 1990s. Brain damage and death were associated with epidural steroid injection only when opioids or local anesthetics were included. Anesthesiologists involved in home care of patients with implanted devices such as morphine pumps and epidural injections or patient-controlled analgesia should be aware of potential complications that may have severe outcomes.
Influence of Lumbosacral Cerebrospinal Fluid Density, Velocity, and Volume on Extent and Duration of Plain Bupivacaine Spinal Anesthesia
Authors: Higuchi Hideyuki , Hirata Jyun-ichi , Adachi Yushi , Kazama Tomiei 
Published: December 2003

Background
The current study was designed to investigate the influence of lumbosacral cerebrospinal fluid (CSF) density, velocity, and volume on the extent and duration of plain bupivacaine spinal anesthesia.

Methods
Forty-one patients scheduled to undergo orthopedic surgery with spinal block were enrolled. Lumbosacral CSF volumes were calculated from low thoracic, lumbar, and sacral axial magnetic resonance images. CSF velocity at the L3-L4 level was derived from phase-contrast magnetic resonance images. Spinal anesthesia was performed in the lateral decubitus position. CSF (2 ml) was sampled to measure CSF density before injection of 3 ml plain bupivacaine (0.5%). Statistical correlation coefficients (rho) between CSF characteristics and measurements of spinal anesthesia were assessed by Spearman rank correlation. In addition, stepwise multiple linear regression models were used to select important predictors of measures of spinal anesthesia.

Results
There was a significant correlation between CSF density and peak sensory block level (rho = 0.33, P = 0.034). Lumbosacral CSF volume inversely correlated with peak sensory block level (rho = -0.65, P < 0.0001) and positively correlated with onset time of complete motor block (rho = 0.42, P = 0.008). CSF volume also inversely correlated with time required for regression of the sensory block to L1 (rho = -0.35, P = 0.026) and L2 (rho = -0.33, P = 0.039). There was a significant inverse correlation between peak diastolic CSF velocity and duration of motor blockade (rho = -0.44, P = 0.005). Multiple regression analysis revealed that weight and CSF volume significantly contributed to the peak sensory block level (R2 = 0.46).

Conclusions
These findings indicate that CSF density and volume influence the spread of spinal anesthesia with plain bupivacaine and that CSF volume also influences the duration of spinal anesthesia. CSF velocity might also influence the duration of plain bupivacaine spinal anesthesia.
Prediction of Postoperative Pain by Preoperative Nociceptive Responses to Heat Stimulation
Authors: Werner Mads U. , Duun Preben , Kehlet Henrik 
Published: December 2003

Background
Despite major advances in the understanding of the neurobiologic mechanisms of pain, the wide variation in acute pain experience has not been well explained. Therefore, the authors investigated the potential of a preoperatively induced heat injury to predict subsequent postoperative pain ratings in patients undergoing knee surgery.

Methods
Twenty patients were studied. The burn injury was induced 6 days before surgery with a contact thermode (12.5 cm2, 47 degrees C for 7 min). The sensory testing, before and 1 h after the injury, included pain score during induction of the burn, secondary hyperalgesia area, thermal and mechanical pain perception, and pain thresholds. Postoperative analgesia consisted of ibuprofen and acetaminophen. Pain ratings (visual analog scale) at rest and during limb movement were followed for 10 days after surgery.

Results
The burn injury was associated with development of significant hyperalgesia. There was a significant correlation between preoperative pain ratings during the burn injury and early (0-2 days, area under the curve) and late (3-10 days, area under the curve) postoperative dynamic pain ratings during limb movement.

Conclusion
The results of this study suggest that the pain response to a preoperative heat injury may be useful in research in predicting the intensity of postoperative pain. These findings may have important implications to identify patients at risk for development of chronic pain and to stratify individuals for investigations of new analgesics.
Pharmacokinetic-Pharmacodynamic Modeling of Morphine-6-glucuronide-induced Analgesia in Healthy Volunteers
Authors: Romberg Raymonda , Olofsen Erik , Sarton Elise , den Hartigh Jan , Taschner Peter E. M. , Dahan Albert 
Published: December 2003

Background
Morphine-6-glucuronide (M6G) is a metabolite of morphine and a micro-opioid agonist. To quantify the potency and speed of onset-offset of M6G and explore putative sex dependency, the authors studied the pharmacokinetics and pharmacodynamics of M6G in volunteers using a placebo-controlled, randomized, double-blind study design.

Methods
Ten men and 10 women received 0.3 mg/kg intravenous M6G and placebo (two thirds of the dose as bolus, one third as a continuous infusion over 1 h) on separate occasions. For 7 h, pain tolerance was measured using gradually increasing transcutaneous electrical stimulation, and blood samples were obtained. A population pharmacokinetic (inhibitory sigmoid Emax)-pharmacodynamic analysis was used to analyze M6G-induced changes in tolerated stimulus intensity. The improvement in model fits by inclusion of covariate sex was tested for significance. P values less than 0.01 were considered significant. Taking into account previous morphine data, a predictive pharmacokinetic-pharmacodynamic model was constructed to determine the contribution of M6G to morphine analgesia.

Results
M6G concentrations did not differ between men and women. M6G caused analgesia significantly greater than that observed with placebo (P < 0.01). The M6G analgesia data were well described by the pharmacokinetic-pharmacodynamic model. The M6G effect site concentration causing a 25% increase in current (C25) was 275 +/- 135 nm (population estimate +/- SE), the blood effect site equilibration half-life was 6.2 +/- 3.3 h, and the steepness parameter was 0.71 +/- 0.18. Intersubject variability was 167% for C25 and 218% for the effect half-life. None of the model parameters showed sex dependency.

Conclusions
A cumulative dose of 0.3 mg/kg M6G, given over 1 h, produces long-term analgesia greater than that observed with placebo, with equal dynamics (potency and speed of onset-offset) in men and women. Possible causes for the great intersubject response variability, such as genetic polymorphism of the micro-opioid receptor and placebo-related phenomena, are discussed. The predictive pharmacokinetic-pharmacodynamic model was applied successfully and was used to estimate M6G analgesia after morphine in patients with normal and impaired renal function.
Effects of Perioperative Oral Amantadine on Postoperative Pain and Morphine Consumption in Patients after Radical Prostatectomy
Authors: Snijdelaar Dirk G. , Koren Gideon , Katz Joel 
Published: December 2003

Background
Amantadine is known to be a noncompetitive N-methyl-D-aspartate receptor antagonist and may be useful in preventing postoperative central sensitization, acute opioid tolerance, and opioid-induced hyperalgesia, thereby decreasing pain and analgesic requirements. The aim of this pilot study was to evaluate the effects of perioperative oral amantadine on postoperative pain and analgesic consumption.

Methods
Twenty-four patients scheduled to undergo radical prostatectomy were given oral amantadine before and after surgery in a randomized, double-blind, placebo-controlled manner. After surgery, patients received intravenous patient-controlled analgesia with morphine for 48 h. Wound pain intensity, sensitivity to mechanical pressure around the surgical wound, and incidence of bladder spasm pain were assessed. Blood samples were drawn for analysis of amantadine, morphine, and the morphine metabolites. Adverse effects and patient satisfaction were assessed.

Results
The cumulative morphine consumption was significantly lower in the amantadine group at all time points (except at 48 h), amounting to a 32% reduction over the 48-h period. Forty-eight hours after surgery, visual analog pain scores to pressure applied near the wound were significantly lower in the amantadine group than in the placebo group. In addition, the number of patients reporting bladder spasm pain was significantly lower in the amantadine group. Plasma concentration of morphine-3-glucuronide was significantly lower at the end of surgery in the amantadine group. Pharmacokinetic analyses showed that the plasma clearance of morphine at 22-24 h after surgery was also significantly lower in the amantadine group.

Conclusion
The results suggest that perioperative oral amantadine reduces postoperative opioid consumption by pharmacokinetic mechanisms, although additional pharmacodynamic interactions may also be involved.