Possible nociceptive structures in the sacroiliac joint cartilage: An immunohistochemical study.

The sacroiliac joint (SI joint) is a known source of low back pain. In the absence of validated physical signs and imaging studies, the diagnosis of SI joint pain can be secured by positive response to SI joint intra-articular infiltration with local anesthetics. The current anatomical and histological knowledge concerning intra-articular structures of the sacroiliac joint is insufficient to explain the efficacy of this infiltration. Consequently, this study was undertaken to detect the intra-articular presence of substance P and calcitonin gene-related peptide (CGRP) positive nerve fibers, providing indirect evidence of nociceptive innervation of the SI joint. Free-floating sections, obtained from iliac and sacral cartilage and subchondral bone of the SI joint and adjacent ligamentous tissue, of 10 human cadavers were studied immunohistochemically. Tissue of nine human cadavers showed the presence of substance P and CGRP immunoreactivity in the superficial layer of sacral and iliac cartilage, and the surrounding ligamentous structures. Subchondral bone reacted weakly to the antisera used. These findings support the view that the SI joint may be capable of intra-articular nociception and may explain the positive response to the intra-articular deposition of local anesthetic.

Intravenous magnesium for complex regional pain syndrome type 1 (CRPS 1) patients: a pilot study.

OBJECTIVES: To explore the feasibility of intravenous magnesium administration as a potential candidate intervention for a large size trial in Complex Regional Pain Syndrome Type 1 (CRPS 1). DESIGN: Randomized clinical trial. SETTING: Outpatient pain clinic. PATIENTS: Ten CRPS 1 patients. INTERVENTIONS: Eight patients received 70 mg/kg magnesium sulphate infusions in 4 hours for 5 days. For blinding purposes, 2 patients received equal amount NaCl 0.9% solutions (data not analyzed or presented). Interventions were accompanied by standardized physical therapy. OUTCOME MEASURES: Pain was assessed using an 11-point Box scale (three times daily for a week) and the McGill Pain Questionnaire. Skin sensitivity was measured with the Semmes Weinstein Monofilaments, (other) impairments with the Impairment Level Sumscore. In addition, functional limitations (Radboud Skills Questionnaire, questionnaire rising and sitting down) and quality of life (Short Form-36 [SF-36], EuroQol) were evaluated. Assessments were performed at baseline, 1, 3, 6, and 12 weeks after intervention. RESULTS: Mild systemic side effects were experienced and the infusions were locally well tolerated. Pain was significantly reduced at all follow up compared with baseline (T1: P = 0.01, T3: P = 0.04, T6: P = 0.02, T12: P = 0.02). McGill sensory subscale improved significantly at T1 (number of words chosen: P = 0.03 and pain rating index: P = 0.03). Impairment level (P = 0.03) and quality of life (EuroQol P = 0.04, SF-36 physical P = 0.01) were significantly improved at T12. No improvement was found for skin sensitivity and functional limitations. CONCLUSION: Intravenous magnesium significantly improved pain, impairment and quality of life and was well tolerated. The results of this pilot study are encouraging and suggest that magnesium IV as a treatment in CRPS 1 should be further explored in a large size formal trial design.

Development of a symptoms questionnaire for complex regional pain syndrome and potentially related illnesses: the Trauma Related Neuronal Dysfunction Symptoms Inventory.

OBJECTIVE: To develop a questionnaire to evaluate symptoms of complex regional pain syndrome type I (CRPS-I), fibromyalgia, and repetitive strain injury to determine the test-retest reliability and investigate concurrence in the clinical manifestations of CRPS-I and fibromyalgia. DESIGN: The Trauma Related Neuronal Dysfunction Symptoms Inventory (TSI) was developed by determining the content validity and the practical use of the questionnaire. Furthermore, the test-retest reliability was assessed on 2 identical questionnaires filled out within a 7-day interval by CRPS-I and fibromyalgia patients. SETTING: Outpatient pain clinic of a Dutch medical center. PARTICIPANTS: CRPS-I (n=26; mean age, 54y) and fibromyalgia patients (n=42; mean age, 45.4y). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Test-retest reliability calculated with intraclass correlation (ICC). RESULTS: Reliability scores were good for the whole questionnaire, its categories, and domains (ICC>.75) for both CRPS-I and fibromyalgia patients. Sensory complaints (except for change in cold perception), motor complaints, and visceral complaints (diarrhea and incontinence) were reported by both CRPS-I and fibromyalgia patients. A change in cold perception, discoloration, change in skin temperature, change in sweating behavior, change in the severity of edema during exercise, and trophic changes of skin were reported significantly more often by CRPS-I patients, whereas complaints of the (upper and lower) back, constipation, urine retention, and experiencing a dry mouth were reported significantly more often by fibromyalgia patients. CONCLUSIONS: The TSI is a reliable instrument with good content validity, which can be used in the evaluation of similarities and differences between CRPS-I and fibromyalgia. The systematic evaluation of symptoms of CRPS-I and potentially related illnesses may provide a better basis for future research into the underlying mechanism(s).

Nociceptive nerve fibers in the sacroiliac joint in humans.

BACKGROUND AND OBJECTIVES: A positive response to sacroiliac joint intra-articular infiltration with local anesthetics is used to confirm sacroiliac joint pain. However, current anatomical and histological knowledge concerning the anatomy of pain perception within the sacroiliac joint intra- and peri-articular structures is insufficient to explain the efficacy of this infiltration, because of the use of unspecific histochemical visualization techniques. METHODS: In this study, immunohistochemistry for calcitonin gene-related peptide (CGRP) and substance P was used to trace nociceptive fibers and receptors in the anterior and interosseous sacroiliac ligaments obtained from 5 human cadavers without history of sacroiliac joint pain. RESULTS: Microscopic analysis of stained slides showed presence of CGRP and substance P immunoreactive fibers. Thick, wavy, formed bundles were observed in dense and loose connective tissue, whereas single, beaded nerve fibers, occasionally ramified, were observed more frequently in the dense connective tissue and next to blood vessels. Based on their morphologic features, these immunoreactive structures were classified as receptors type IV. Additionally, receptors type II were found in anterior and interosseous ligaments, which contained CGRP or substance P immunoreactive free nerve endings. CONCLUSIONS: We conclude that the presence of CGRP and substance P immunoreactive fibers in the normal anterior capsular ligament and interosseous ligament provides a morphological and physiological base for pain signals originating from these ligaments. Therefore, diagnostic infiltration techniques for sacroiliac joint pain should consider extra- as well as intra-articular approaches.

The efficacy of levobupivacaine, ropivacaine, and bupivacaine for combined psoas compartment-sciatic nerve block in patients undergoing total hip arthroplasty.

BACKGROUND AND OBJECTIVES: The aim of our study was to compare postoperative analgesic efficacy, and the extent of sensory and motor blockade of levobupivacaine, ropivacaine, and bupivacaine administered in a combined psoas compartment-sciatic nerve block (PCSNB) for total hip arthroplasty. METHODS: Forty-five patients undergoing total hip arthroplasty under general anesthesia combined with PCSNB, were randomly assigned to receive either 50 mL levobupivacaine 3 mg/mL, 50 mL ropivacaine 4.5 mg/mL or 50 mL bupivacaine 3 mg/mL with epinephrine. Postoperative, the pain intensity at rest, the degree of motor block (Modified Bromage Scale) and the extent of sensory block (pin prick test) were recorded at 4, 8, 12, 24, and 48 hours following initial injection in a double blind fashion. RESULTS: The postoperative pain intensity was low and did not differ between groups, except for a significantly lower pain intensity in group ropivacaine compared with group levobupivacaine at 4 hours. Five patients (11%), equally divided over three groups, needed parenteral rescue opiates postoperatively. The extent of sensory block was not different between the three groups. In each group the majority of patients showed no sensory block in dermatome L1. Group levobupivacaine initially showed the least motor impairment. Motor impairment was found to be significantly higher in bupivacaine group compared with both ropivacaine and levobupivacaine groups at 12 (P = 0.012) and 48 hours (P = 0.003). CONCLUSIONS: Levobupivacaine, bupivacaine and ropivacaine are equally effective for PCSNB in patients undergoing total hip arthroplasty. Residual pain may be due to the lack of sensory block in dermatome L1, suggesting that modification of this technique should be considered for this type of surgery.

Cardioprotection via activation of protein kinase C-delta depends on modulation of the reverse mode of the Na+/Ca2+ exchanger.

BACKGROUND: Pretreatment with the volatile anesthetic sevoflurane protects cardiomyocytes against subsequent ischemic episodes caused by a protein kinase C (PKC)-delta mediated preconditioning effect. Sevoflurane directly modulates cardiac Ca2+ handling, and because Ca2+ also serves as a mediator in other cardioprotective signaling pathways, possible involvement of the Na+/Ca2+ exchanger (NCX) in relation with PKC-delta in sevoflurane-induced cardioprotection was investigated. METHODS AND RESULTS: Isolated right ventricular rat trabeculae were subjected to simulated ischemia and reperfusion (SI/R), consisting of superfusion with hypoxic glucose-free buffer for 40 minutes after rigor development, followed by reperfusion with normoxic glucose containing buffer. Preconditioning with sevoflurane before SI/R improved isometric force development during contractile recovery at 60 minutes after the end of hypoxic superfusion (83+/-7% [sevo] versus 57+/-2% [SI/R];n=8; P<0.01). Inhibition of the reverse mode of the NCX by KB-R7943 (10 micromol/L) or SEA0400 (1 micromol/L) during preconditioning attenuated the protective effect of sevoflurane. KB-R7943 and SEA0400 did not have intrinsic effects on the contractile recovery. Furthermore, inhibition of the NCX in trabeculae exposed to sevoflurane reduced sevoflurane-induced PKC-delta translocation toward the sarcolemma, as demonstrated by digital imaging fluorescent microscopy. The degree of PKC-delta phosphorylation at serine643 as determined by western blot analysis was not affected by sevoflurane. CONCLUSIONS: Sevoflurane-induced cardioprotection depends on the NCX preceding PKC-delta translocation presumably via increased NCX-mediated Ca2+ influx. This may suggest that increased myocardial Ca2+ load triggers the cardioprotective signaling cascade elicited by volatile anesthetic agents similar to other modes of preconditioning.

Diagnostic criteria for CRPS I: differences between patient profiles using three different diagnostic sets.

Complex Regional Pain Syndrome type I (CRPS I) is an illness which usually occurs due to major or minor tissue injury to the extremities. Because a unique pathophysiological mechanism for CRPS I has not yet been established, the diagnosis is based on observation and measurement of clinical symptoms and signs. In this study, a comparison was made between three sets of diagnostic criteria (the IASP, Bruehl et al. and Veldman et al.) based on patient reports and physicians' assessments of signs and symptoms associated with CRPS I, in 372 outpatients suspected of having CRPS I. Agreement between CRPS I diagnosis among the three sets was poor (kappa-range: 0.29-0.42), leading to positive CRPS I diagnoses according to Veldman et al.'s criteria in 218 cases (59%), according to the IASP in 268 cases (72%), and according to Bruehl et al. in 129 cases (35%). Significant differences in patient profiles were found between the diagnostic sets for the number of patients reporting continuing disproportionate pain, larger area affected than the initial trauma (both p<0.001), increase of symptoms due to exercise (p=0.009), edema (p=0.015), temperature asymmetry (p=0.015), hyperesthesia, allodynia (both p<0.001) and hyperalgesia (p=0.036). Similarly, significant differences emerged for physicians' observations of hyperesthesia and allodynia (both p<0.001). Highest combined values of sensitivity (SE) and specificity (SP) for the strongest cases of presence (n=108) or absence (n=62) of CRPS I were found for reported hyperesthesia (SE+SP:165%), allodynia (160%), observed color asymmetry (162%), hyperesthesia (157%), temperature asymmetry (154%) and edema (152%). The lack of agreement between the different diagnostic sets for CRPS I and the different clinical profiles that result from it may lead to different therapeutic and study populations, hampering adequate treatment and scientific development for this illness. We propose explicit reference to diagnostic criteria used in studies, and registration in trials of a broad variety of CRPS I features, as used in this study, to make subgroup phenotyping and post hoc analyses based on different diagnostic criteria possible.

Physicians' assessments versus measured symptoms of complex regional pain syndrome type 1: presence and severity.

OBJECTIVE: To assess the validity of physician's judgements of symptoms associated with Complex Regional Pain Syndrome Type 1. METHODS: The validity of physicians' judgments was assessed using measurements with regard to presence and severity of pain, temperature and volume asymmetry, and reduction in active range of motion in 66 Complex Regional Pain Syndrome Type 1 outpatients. Measurements were performed using Visual Analog Scales and McGill (number of words chosen total) for pain, infrared thermography for temperature differences, water displacement volumeters for volume differences, and hand-held goniometers for active range of motion. Physicians were blind to the outcomes of the measurements. RESULTS: In general, physicians were capable of determining presence or absence of measured symptoms and indicate the direction of the symptom asymmetry. Establishing presence of temperature and volume asymmetries was, however, inadequate. Poor to moderate correspondence was found for the severity of individual symptoms between physicians' judgments and measurements. For the total number of assessments, correlation coefficients ranged from 0.39 for Volume to 0.68 for Pain. In general, lower correlations and percentages of association for Volume and Temperature were found. Monitoring changes between consecutive patient assessments showed poor correspondence between both assessment methods, with correlation coefficients ranging from 0.25 for Volume to 0.37 for Pain. CONCLUSIONS: We conclude that establishing the presence of Complex Regional Pain Syndrome Type 1 symptoms, except for temperature and volume asymmetries, and monitoring of disease progression based on these symptoms can be performed by clinical judgment. The severity of the individual symptoms evaluated in this study should be measured with reliable and valid measurement instruments.

Carbon monoxide production from five volatile anesthetics in dry sodalime in a patient model: halothane and sevoflurane do produce carbon monoxide; temperature is a poor predictor of carbon monoxide production.

BACKGROUND: Desflurane and enflurane have been reported to produce substantial amounts of carbon monoxide (CO) in desiccated sodalime. Isoflurane is said to produce less CO and sevoflurane and halothane should produce no CO at all.The purpose of this study is to measure the maximum amounts of CO production for all modern volatile anesthetics, with completely dry sodalime. We also tried to establish a relationship between CO production and temperature increase inside the sodalime. METHODS: A patient model was simulated using a circle anesthesia system connected to an artificial lung. Completely desiccated sodalime (950 grams) was used in this system. A low flow anesthesia (500 ml/min) was maintained using nitrous oxide with desflurane, enflurane, isoflurane, halothane or sevoflurane. For immediate quantification of CO production a portable gas chromatograph was used. Temperature was measured within the sodalime container. RESULTS: Peak concentrations of CO were very high with desflurane and enflurane (14262 and 10654 ppm respectively). It was lower with isoflurane (2512 ppm). We also measured small concentrations of CO for sevoflurane and halothane. No significant temperature increases were detected with high CO productions. CONCLUSION: All modern volatile anesthetics produce CO in desiccated sodalime. Sodalime temperature increase is a poor predictor of CO production.

Intrathecal administration of high-dose morphine solutions decreases the pH of cerebrospinal fluid.

Terminally ill patients suffering from intractable cancer pain are treated in our hospital on an outpatient basis with a percutaneous intrathecal (i.t.) catheter and a portable pump delivering morphine continuously. In a patient showing an increased demand of morphine the dose was raised from 1.5 to 2 mg/h, but pain intensity did not decrease. Subsequently a 1.5 ml dose of 5% lidocaine was administered; however, no motor or sensory block was observed. After controlling the catheter position and passage through the catheter, a sample of cerebrospinal fluid (CSF) was taken and the pH was measured. It was found to be outside the physiological range of 7.19 (normal range: 7.27-7.37), possibly explaining the decreased activity of the local anesthetic. The purpose of this study was to determine the influence of morphine, with or without sodium metabisulfite, on pH in vitro, using artificial CSF (ACSF) and on pH in vivo during i.t. administration of morphine. An in vitro model was used to measure pH changes by adding a morphine solution (concentrations of 0.5, 2, 5 and 10 mg/ml) with and without sodium metabisulfite to ACSF solutions (Elliott B). Fourteen patients were consecutively selected for continuous administration of morphine. An i.t. catheter was inserted, tunnelled and connected with an external pump (Provider 5500, Abbott, Chicago, IL). CSF was aspirated and pH was measured with a blood-gas system (Ciba-Corning 288, Medfield, USA). In vitro, morphine solutions with or without sodium metabisulfite added to an Elliott B solution (pH = 7.47, 37 degrees C) caused a concentration-related decrease in pH.(ABSTRACT TRUNCATED AT 250 WORDS)

Cost effectiveness and cost utility of acetylcysteine versus dimethyl sulfoxide for reflex sympathetic dystrophy.

OBJECTIVE: To determine the cost effectiveness and cost utility of acetylcysteine versus dimethyl sulfoxide (DMSO) for patients with reflex sympathetic dystrophy (RSD), from a societal viewpoint. DESIGN: An economic evaluation was conducted alongside a double-dummy, double-blind, randomised, controlled trial. Patients were followed for 1 year. The primary outcome measure was the Impairment-level Sum Score (ISS). Utilities were determined by the EuroQOL instrument (EQ-5D). Both cost-effectiveness and cost-utility analyses were performed. Differences in mean direct, indirect and total costs were estimated. Corresponding 95% confidence intervals were calculated by bootstrapping techniques. RESULTS: Both groups (DMSO, n = 64; acetylcysteine, n = 67) showed relevant improvement; no differences in effects were found. Only the total direct costs were significantly lower in the DMSO group for the period of 0-52 weeks. The incremental cost-effectiveness ratios showed that, in general, DMSO generated fewer costs and more effects compared with acetylcysteine. Post-hoc subgroup analyses on cost effectiveness suggested that patients with warm RSD could be best treated with DMSO and patients with cold RSD with acetylcysteine. These results were based on small subsamples. CONCLUSION: In general, DMSO is the preferred treatment for patients with RSD.

Impairment level SumScore for lower extremity Complex Regional Pain Syndrome type I.

OBJECTIVES: To construct a single indicator on impairment level for lower extremity Complex Regional Pain syndrome type I (CRPS I). DESIGN: The Impairment level SumScore (ISS) for upper extremity CRPS I was adapted to be used for lower extremity evaluation. Medline literature search and research findings were used to adapt the upper extremity version of the ISS, with emphasis on reliability, responsiveness and validity of measurement instruments. Where needed, additional patient data was gathered to evaluate these aspects for different measurement instruments. SETTING: An outpatient clinic of a university hospital in the Netherlands. PARTICIPANTS: Two groups consisting of 17 and 26 healthy volunteers, and two groups of respectively 40 and 18 lower extremity CRPS I patients according to Veldman's criteria. MAIN OUTCOME MEASURES: VAS and McGill pain scores, water displacement volumeter values, and physicians' and patients' assessment of CRPS I severity. RESULTS: A combination of measurements, incorporating pain (VAS and McGill), temperature (infrared thermometer), volume (water displacement volumeter) and active range of motion (universal goniometer), was converted in a single score ranging from 5 to 50. The reliability, as well as the responsiveness was adequate. CONCLUSIONS: The lower extremity ISS permits evaluation of the most prominent symptoms in CRPS I, and can be used to monitor changes in CRPS I.

Detection of carbon monoxide production as a result of the interaction of five volatile anesthetics and desiccated sodalime with an electrochemical carbon monoxide sensor in an anesthetic circuit compared to gas chromatography.

OBJECTIVES: There is a continuing risk of production of toxic levels of carbon monoxide (CO) as a result of interaction of volatile anesthetics and desiccated strong base carbon dioxide absorbents like soda lime. The aim of this study is to establish the reliability of detection of CO levels by an electrochemical carbon monoxide sensor compared to gas chromatography. METHODS: Completely desiccated sodalime was conducted through a circle anesthesia system connected to an artificial lung. For different rates of CO production, a low flow anesthesia with a oxygen/nitrous oxide mixture was maintained using five volatile anesthetics. For quantification of CO production, a portable gas chromatograph (GC) was connected to this setup, as well as a Bedfont EC40 electrochemical carbon monoxide sensor (ES) with a claimed reliable sensitivity of 0-200 parts per million (ppm) and a maximum detection range of more than 5500 ppm. To assess the agreement between the GC and ES measurements the intra class correlation coefficient (ICC) and the 95% limits of agreement were calculated. Bland and Altman scatterplots were made to visualize the difference between measurements. RESULTS: For concentrations up to 200 ppm, no significant differences between the GC and ES mean CO measurements were found in the halothane experiments. However CO was not accurately measured at every moment during these experiments by the ES. For concentrations above 200 ppm the results of the two instruments differed significantly. The ES malfunctioned when exposed to sevoflurane and desiccated sodalime. CONCLUSIONS: From these data we conclude that the ES can only be used as an indicator of CO production. When this sensor is used with sevoflurane and desiccated sodalime it is not capable of normal operation. The use of a strong base free carbon dioxide absorbent is therefore recommended.

Psychotropic drugs and the perioperative period: a proposal for a guideline in elective surgery.

Evidence-based guidelines for the perioperative management of psychotropic drugs are lacking. The level of evidence is low and is based on case reports, open trials, and non-systematic reviews. However, the interactions and effects mentioned indicate that patients who use psychotropics and require surgery have an enhanced perioperative risk. A group of clinicians from several clinical disciplines determined which risks should be considered in an integrated preoperative assessment, as well as how psychotropics might interfere with these risks. The risks that should be considered in the perioperative period are the extent of the surgery, the patient's physical state, anesthesia, the direct and indirect (Phase I and II) effects of psychotropics, risk of withdrawal symptoms, and risk of psychiatric recurrence or relapse. Because of new drug developments, the risk of interactions increases. The literature has not provided articles that systematically address these risks. On the basis of a systematic analysis of the available literature guided by the formulated perioperative risks, a proposal for the perioperative management of psychotropics was formulated. Patients who use lithium, monoamine oxidase inhibitors, tricyclics, and clozepine have serious drug-drug interactions, with increased physical risks, including withdrawal, and therefore qualify for American Society of Anesthesiologists (ASA) Classification 3. From the perspective of the physical risk, they require discontinuation. However, from the perspective of the risk of withdrawal and psychiatric relapse and recurrence, these patients deserve intensive, integrated anesthetic/psychiatric management. For patients on selective serotonin reuptake inhibitors (SSRIs) who are mentally and physical stable (ASA Classification 2), the risk of withdrawal seems to justify their continuation. Yet, patients on SSRIs with higher physical or psychiatric risks should be seen in consultation. Both the physical and psychiatric risks of patients who use antipsychotics and other antidepressants should be regarded as enhanced. From a physical perspective, they qualify for ASA Classification 2. From the perspective of withdrawal and psychiatric recurrence or relapse, they should be seen by (their) psychiatrists. Preoperative assessment clinics offer the opportunity to assess and evaluate these risks in order to deliver patient-tailored integrated care. Authors propose a model for quality management.

Induced nitric oxide impairs relaxation but not contraction in endotoxin-exposed rat pulmonary arteries.

BACKGROUND: Many patients with severe acute lung injury do not respond to nitric oxide (NO) inhalational therapy with alleviation of pulmonary arterial hypertension and hypoxemia, so this treatment remains controversial. MATERIALS AND METHODS.: We investigated in endotoxin-exposed Wistar rat pulmonary arteries whether endogenous NO alters contractile and relaxing responses, by electrochemical NO and isometric force measurements. RESULTS: Receptor-independent contraction was similar in control and endotoxin-exposed arteries, while thromboxane analogue (TxA)-dependent contraction was less in the latter. Neither non-selective NO synthase (NOS) inhibition by N(G)-nitro-l-arginine (l-NA) or selective inducible-NOS2 inhibition by aminoguanidine (AG) improved TxA-induced contraction in endotoxin-exposed arteries. Acetylcholine-induced relaxation was impaired in endotoxin-exposed pulmonary arteries, despite a comparable acetylcholine-induced NO release in control arteries. Additionally, NO solution-induced relaxation of endotoxin-exposed arteries was impaired, but could be improved by l-NA or AG. Application of a phosphodiesterase-insensitive cyclic guanosine monophosphate analogue induced similar relaxation in both control and endotoxin-exposed arteries. CONCLUSIONS: Endotoxin-associated NOS2-derived NO is thus associated with impaired NO-mediated relaxation, but does not underlie reduced receptor-mediated pulmonary contractile responses. An increased phosphodiesterase activity may underlie the former, so this route can be explored to replace or improve the effect of inhalational NO therapy in severe sepsis-induced acute lung injury in patients.

SIH--a novel lipophilic iron chelator--protects H9c2 cardiomyoblasts from oxidative stress-induced mitochondrial injury and cell death.

Recent evidence suggests that oxidative stress is a common denominator in many aspects of cardiovascular pathogenesis. Free cellular iron plays a crucial catalytic role in the formation of highly toxic hydroxyl radicals, and thereby it may aggravate the contribution of oxidative stress to cardiovascular disease. Therefore, iron chelation may be an effective therapeutic approach, but the progress in this area is hindered by the lack of effective agents. In this study, using the rat heart myoblast-derived cell line H9c2, we aimed to investigate whether the novel lipophilic iron chelator salicylaldehyde isonicotinoyl hydrazone (SIH) protects the cells against hydrogen peroxide (H2O2)-induced cytotoxicity. Exposure of cells to 100 micromol/l H2O2 has within 4 h induced a complete dissipation of their mitochondrial membrane potential (DeltaPsim). Co-treatment with SIH dose-dependently reduced (EC50=0.8 micromol/l) or even completely abolished (3 micromol/l) this collapse. Furthermore, the latter SIH concentration was capable to fully prevent alterations in cell morphology, and inhibited both apoptosis (annexin-V staining, nuclear chromatin shrinkage, TUNEL positivity) and necrosis (propidium iodide staining), even 24 h after the H2O2 exposure. In comparison, deferoxamin (a commercially available hydrophilic iron chelator used in clinical practice and most previous studies) was cytoprotective only at three-order higher and clinically unachievable concentrations (EC50=1300 micromol/l). Thus, in this study, we present iron chelation as a very powerful tool by which oxidative stress-induced myocardial damage can be prevented.

Impact of anesthesia management characteristics on severe morbidity and mortality.

BACKGROUND: Quantitative estimates of how anesthesia management impacts perioperative morbidity and mortality are limited. The authors performed a study to identify risk factors related to anesthesia management for 24-h postoperative severe morbidity and mortality. METHODS: A case-control study was performed of all patients undergoing anesthesia (1995-1997). Cases were patients who either remained comatose or died during or within 24 h of undergoing anesthesia. Controls were patients who neither remained comatose nor died during or within 24 hours of undergoing anesthesia. Data were collected by means of a questionnaire, the anesthesia and recovery form. Odds ratios were calculated for risk factors, adjusted for confounders. RESULTS: The cohort comprised 869,483 patients; 807 cases and 883 controls were analyzed. The incidence of 24-h postoperative death was 8.8 (95% confidence interval, 8.2-9.5) per 10,000 anesthetics. The incidence of coma was 0.5 (95% confidence interval, 0.3-0.6). Anesthesia management factors that were statistically significantly associated with a decreased risk were: equipment check with protocol and checklist (odds ratio, 0.64), documentation of the equipment check (odds ratio, 0.61), a directly available anesthesiologist (odds ratio, 0.46), no change of anesthesiologist during anesthesia (odds ratio, 0.44), presence of a full-time working anesthetic nurse (odds ratio, 0.41), two persons present at emergence (odds ratio, 0.69), reversal of anesthesia (for muscle relaxants and the combination of muscle relaxants and opiates; odds ratios, 0.10 and 0.29, respectively), and postoperative pain medication as opposed to no pain medication, particularly if administered epidurally or intramuscularly as opposed to intravenously. CONCLUSIONS: Mortality after surgery is substantial and an association was established between perioperative coma and death and anesthesia management factors like intraoperative presence of anesthesia personnel, administration of drugs intraoperatively and postoperatively, and characteristics of delivered intraoperative and postoperative anesthetic care.

Reactive oxygen species precede protein kinase C-delta activation independent of adenosine triphosphate-sensitive mitochondrial channel opening in sevoflurane-induced cardioprotection.

BACKGROUND: In the current study, the authors investigated the distinct role and relative order of protein kinase C (PKC)-delta, adenosine triphosphate-sensitive mitochondrial K+ (mito K+(ATP)) channels, and reactive oxygen species (ROS) in the signal transduction of sevoflurane-induced cardioprotection and specifically addressed their mechanistic link. METHODS: Isolated rat trabeculae were preconditioned with 3.8% sevoflurane and subsequently subjected to an ischemic protocol by superfusion of trabeculae with hypoxic, glucose-free buffer (40 min) followed by 60 min of reperfusion. In addition, the acute affect of sevoflurane on PKC-delta and PKC-epsilon translocation and nitrotyrosine formation was established with use of immunofluorescent analysis. The inhibitors chelerythrine (6 microM), rottlerin (1 microM), 5-hydroxydecanoic acid sodium (100 microM), and n-(2-mercaptopropionyl)-glycine (300 microM) were used to study the particular role of PKC, PKC-delta, mito K+(ATP), and ROS in sevoflurane-related intracellular signaling. RESULTS: Preconditioning of trabeculae with sevoflurane preserved contractile function after ischemia. This contractile preservation was dependent on PKC-delta activation, mito K+(ATP) channel opening, and ROS production. In addition, on acute stimulation by sevoflurane, PKC-delta but not PKC-epsilon translocated to the sarcolemmal membrane. This translocation was inhibited by PKC inhibitors and ROS scavenging but not by inhibition of mito K+(ATP) channels. Furthermore, sevoflurane directly induced nitrosylation of sarcolemmal proteins, suggesting the formation of peroxynitrite. CONCLUSIONS: In sevoflurane-induced cardioprotection, ROS release but not mito K+(ATP) channel opening precedes PKC-delta activation. Sevoflurane induces sarcolemmal nitrotyrosine formation, which might be involved in the recruitment of PKC-delta to the cell membrane.

The cardioprotective effect of sevoflurane depends on protein kinase C activation, opening of mitochondrial K(+)(ATP) channels, and the production of reactive oxygen species.

UNLABELLED: Several studies suggest that the cardioprotective effect of sevoflurane depends on protein kinase C (PKC) activation, mitochondrial K(+)(ATP) channel (mitoK(+)(ATP)) opening, and reactive oxygen species (ROS). However, evidence for their involvement was obtained in separate experimental models. Here, we studied the relative roles of PKC, mitoK(+)(ATP), and ROS in sevoflurane-induced cardioprotection in one model. Rat trabeculae were subjected to simulated ischemia by applying metabolic inhibition (MI) through buffer containing NaCN, followed by 60-min reperfusion. Recovery of active force (F(a)) was assessed as percentage of pre-MI force. In time controls, F(a) amounted 60% +/- 5% at the end of the experiment. The recovery of F(a) after MI was reduced to 28% +/- 5% (P = 0.045 versus time control), whereas sevoflurane reversed the detrimental effect of MI (F(a) recovery, 67% +/- 8%; P = 0.01 versus MI). The PKC inhibitor chelerythrine, the mitoK(+)(ATP) inhibitor 5-hydroxy decanoic, and the ROS scavenger N-(2-mercaptopropionyl)-glycine all completely abolished the protective effect of sevoflurane (recovery of F(a), 31% +/- 8%, 33% +/- 8%, and 24% +/- 9% for chelerythrine, 5-hydroxy decanoic, and N-(2-mercaptopropionyl)-glycine, respectively). In conclusion, PKC activation, mitoK(+)(ATP) channel opening, and ROS production are all essential for sevoflurane-induced cardioprotection. These signaling events are arranged in series within a common signaling pathway, rather than in parallel cascades. Our findings implicate that the perioperative use of sevoflurane preserves cardiac function by preventing ischemia-reperfusion injury. IMPLICATIONS: Protein kinase C, mitochondrial K(+)(ATP) channels and reactive oxygen species act within one downstream signaling pathway in mediating the cardioprotective effect of sevoflurane.