A retrospective review of 10-year trends in general anesthesia for cesarean delivery at a university hospital: the impact of a newly launched team on obstetric anesthesia practice.

BACKGROUND: The indications for general anesthesia (GA) in obstetric settings, which are determined in consideration of maternal and fetal outcome, could be affected by local patterns of clinical practice grounded in unique situations and circumstances that vary among medical institutions. Although the use of GA for cesarean delivery has become less common with more frequent adoption of neuraxial anesthesia, GA was previously chosen for pregnancy with placenta previa at our institution in case of unexpected massive hemorrhage. However, the situation has been gradually changing since formation of a team dedicated to obstetric anesthesia practice. Here, we report the results of a review of all cesarean deliveries performed under GA, and assess the impact of our newly launched team on trends in clinical obstetric anesthesia practice at our institution. METHODS: Our original database for obstetric GA during the period of 2010 to 2019 was analyzed. The medical records of all parturients who received GA for cesarean delivery were reviewed to collect detailed information. Interrupted time series analysis was used to evaluate the impact of the launch of our obstetric anesthesia team. RESULTS: As recently as 2014, more than 10% of cesarean deliveries were performed under GA, with placenta previa accounting for the main indication in elective and emergent cases. Our obstetric anesthesia team was formed in 2015 to serve as a communication bridge between the department of anesthesiology and the department of obstetrics. Since then, there has been a steady decline in the percentage of cesarean deliveries performed under GA, decreasing to a low of less than 5% in the latest 2 years. Interrupted time series analysis revealed a significant reduction in obstetric GA after 2015 (P = 0.04), which was associated with decreased use of GA for pregnancy with placenta previa. On the other hand, every year has seen a number of urgent cesarean deliveries requiring GA. CONCLUSIONS: There has been a trend towards fewer obstetric GA since 2015. The optimized use of GA for cesarean delivery was made possible mainly through strengthened partnerships between anesthesiologists and obstetricians with the support of our obstetric anesthesia team.

Reliability of cardiac output measurements using LiDCOrapid™ and FloTrac/Vigileo™ across broad ranges of cardiac output values.

Knowing a patient's cardiac output (CO) could contribute to a safe, optimized hemodynamic control during surgery. Precise CO measurements can serve as a guide for resuscitation therapy, catecholamine use, differential diagnosis, and intervention during a hemodynamic crisis. Despite its invasiveness and intermittent nature, the thermodilution technique via a pulmonary artery catheter (PAC) remains the clinical gold standard for CO measurements. LiDCOrapid™ (LiDCO, London, UK) and FloTrac/Vigileo™ (Edwards Lifesciences, Irvine, CA) are less invasive continuous CO monitors that use arterial waveform analysis. Their calculations are based on arterial waveform characteristics and do not require calibration. Here, we evaluated LiDCOrapid™ and FloTrac/Vigileo™ during off-pump coronary artery bypass graft (OPCAB) and living-donor liver transplantation (LDLT) surgery. This observational, single-center study included 21 patients (11 OPCAB and 10 LDLT). We performed simultaneous measurements of CO at fixed sampling points during surgery using both devices (LiDCOrapid™ version 1.04-b222 and FloTrac/Vigileo™ version 3.02). The thermodilution technique via a PAC was used to obtain the benchmark data. LiDCOrapid™ and FloTrac/Vigileo™ were used in an uncalibrated fashion. We analyzed the measured cardiac index using a Bland-Altman analysis (the method of variance estimates recovery), a polar plot method (half-moon method), a 4-quadrant plot and compared the widths of the limits of agreement (LOA) using an F test. One OPCAB patient was excluded because of the use of an intra-aortic balloon pumping during surgery, and 20 patients (10 OPCAB and 10 LDLT) were ultimately analyzed. We obtained 149 triplet measurements with a wide range of cardiac index. For the FloTrac/Vigileo™, the bias and percentage error were -0.44 L/min/m2 and 74.4 %. For the LiDCOrapid™, the bias and percentage error were -0.38 L/min/m2 and 53.5 %. The polar plot method showed an angular bias (FloTrac/Vigileo™ vs. LiDCOrapid™: 6.6° vs. 5.8°, respectively) and radial limits of agreement (-63.9 to 77.1 vs. -41.6 to 53.1). A 4-quadrant plot was used to obtain concordance rates (FloTrac/Vigileo™ vs. PAC and LiDCOrapid™ vs. PAC: 84.0 and 92.4 %, respectively). We could compare CO measurement devices across broad ranges of CO and SVR using LDLT and OPCAB surgical patients. An F test revealed no significant difference in the widths of the LoA for both devices when sample sizes capable of detecting a more than two-fold difference were used. We found that both devices tended to underestimate the calculated CIs when the CIs were relatively high. These proportional bias produced large percentage errors in the present study.

[A Case of an EXIT (Ex-utero Intrapartum Treatment) Procedure for a Fetal Giant Oronasopharyngeal Tumor.]

We report successful anesthetic management of an EXIT (ex-utero intrapartum treatment) procedure for fetal giant oronasopharyngeal tumor. A 34-year-old nul- liparous woman was diagnosed as having a fetus with giant oronasopharyngeal tumor and scheduled for an EXIT procedure at 34 weeks of pregnancy. After induction of general anesthesia and tracheal intubation, 6% desflurane and a moderate dose of remifentanil infusion were started to provide anesthesia for both the mother and the fetus. To achieve sufficient uterine relaxation during an EXIT procedure, desflurane was gradually increased up to 10% and nitroglycerin infu- sion was added just before uterine incision. Maternal blood pressure was maintained with continuous infu- sion of phenylephrine. Fetal monitoring during an EXIT procedure was performed with an electrocar- diogram using needle electrodes in addition to trans- thoracic echocardiography. No additional anesthetics were necessary for fetal immobilization. After the completion of tracheostomy followed by the separation of the fetus, nitroglycerin and desflurane were discon- tinued and adequate uterine tone was soon obtained. Maintenance of anesthesia was achieved with propofol and remifentanil for the remaining of the operation. The postoperative course was uneventful. The impor- tance of preoperative detailed simulation and discussion about the procedure among multidisciplinary team members was reconfirmed.

Administration of hydrogen sulfide via extracorporeal membrane lung ventilation in sheep with partial cardiopulmonary bypass perfusion: a proof of concept study on metabolic and vasomotor effects.

INTRODUCTION: Although inhalation of 80 parts per million (ppm) of hydrogen sulfide (H2S) reduces metabolism in mice, doses higher than 200 ppm of H2S were required to depress metabolism in rats. We therefore hypothesized that higher concentrations of H2S are required to reduce metabolism in larger mammals and humans. To avoid the potential pulmonary toxicity of H2S inhalation at high concentrations, we investigated whether administering H2S via ventilation of an extracorporeal membrane lung (ECML) would provide means to manipulate the metabolic rate in sheep. METHODS: A partial venoarterial cardiopulmonary bypass was established in anesthetized, ventilated (fraction of inspired oxygen = 0.5) sheep. The ECML was alternately ventilated with air or air containing 100, 200, or 300 ppm H2S for intervals of 1 hour. Metabolic rate was estimated on the basis of total CO2 production (VCO2) and O2 consumption (VO2). Continuous hemodynamic monitoring was performed via indwelling femoral and pulmonary artery catheters. RESULTS: VCO2, VO2, and cardiac output ranged within normal physiological limits when the ECML was ventilated with air and did not change after administration of up to 300 ppm H2S. Administration of 100, 200 and 300 ppm H2S increased pulmonary vascular resistance by 46, 52 and 141 dyn·s/cm5, respectively (all P ≤ 0.05 for air vs. 100, 200 and 300 ppm H2S, respectively), and mean pulmonary artery pressure by 4 mmHg (P ≤ 0.05), 3 mmHg (n.s.) and 11 mmHg (P ≤ 0.05), respectively, without changing pulmonary capillary wedge pressure or cardiac output. Exposure to 300 ppm H2S decreased systemic vascular resistance from 1,561 ± 553 to 870 ± 138 dyn·s/cm(5) (P ≤ 0.05) and mean arterial pressure from 121 ± 15 mmHg to 66 ± 11 mmHg (P ≤ 0.05). In addition, exposure to 300 ppm H2S impaired arterial oxygenation (PaO2 114 ± 36 mmHg with air vs. 83 ± 23 mmHg with H2S; P ≤ 0.05). CONCLUSIONS: Administration of up to 300 ppm H2S via ventilation of an extracorporeal membrane lung does not reduce VCO2 and VO2, but causes dose-dependent pulmonary vasoconstriction and systemic vasodilation. These results suggest that administration of high concentrations of H2S in venoarterial cardiopulmonary bypass circulation does not reduce metabolism in anesthetized sheep but confers systemic and pulmonary vasomotor effects.

Hydrogen sulfide improves survival after cardiac arrest and cardiopulmonary resuscitation via a nitric oxide synthase 3-dependent mechanism in mice.

BACKGROUND: Sudden cardiac arrest (CA) is one of the leading causes of death worldwide. We sought to evaluate the impact of hydrogen sulfide (H(2)S) on the outcome after CA and cardiopulmonary resuscitation (CPR) in mouse. METHODS AND RESULTS: Mice were subjected to 8 minutes of normothermic CA and resuscitated with chest compression and mechanical ventilation. Seven minutes after the onset of CA (1 minute before CPR), mice received sodium sulfide (Na(2)S) (0.55 mg/kg IV) or vehicle 1 minute before CPR. There was no difference in the rate of return of spontaneous circulation, CPR time to return of spontaneous circulation, and left ventricular function at return of spontaneous circulation between groups. Administration of Na(2)S 1 minute before CPR markedly improved survival rate at 24 hours after CPR (15/15) compared with vehicle (10/26; P=0.0001 versus Na(2)S). Administration of Na(2)S prevented CA/CPR-induced oxidative stress and ameliorated left ventricular and neurological dysfunction 24 hours after CPR. Delayed administration of Na(2)S at 10 minutes after CPR did not improve outcomes after CA/CPR. Cardioprotective effects of Na(2)S were confirmed in isolated-perfused mouse hearts subjected to global ischemia and reperfusion. Cardiomyocyte-specific overexpression of cystathionine gamma-lyase (an enzyme that produces H(2)S) markedly improved outcomes of CA/CPR. Na(2)S increased phosphorylation of nitric oxide synthase 3 in left ventricle and brain cortex, increased serum nitrite/nitrate levels, and attenuated CA-induced mitochondrial injury and cell death. Nitric oxide synthase 3 deficiency abrogated the protective effects of Na(2)S on the outcome of CA/CPR. CONCLUSIONS: These results suggest that administration of Na(2)S at the time of CPR improves outcome after CA possibly via a nitric oxide synthase 3-dependent signaling pathway.

Synergistic cytoprotection by co-treatment with dexamethasone and rapamycin against proinflammatory cytokine-induced alveolar epithelial cell injury.

BACKGROUND: One of the main pathophysiological manifestations during the acute phase of sepsis is massive production of proinflammatory mediators. Clinical trials involving direct suppression of inflammatory mediators to relieve organ dysfunction in sepsis have been extensively performed; however, the clinical outcomes of such trials remain far from satisfactory. Given the need for better sepsis treatments, we have screened various agents with anti-inflammatory properties for cytoprotective effects. In this study, we identified dexamethasone and rapamycin as clinically applicable candidates with favorable synergistic effects against inflammatory cytokine-induced cytotoxicity in vitro and further explored the molecular mechanisms underlying the augmented cytoprotective effects exerted by co-treatment with both drugs. METHODS: Human alveolar epithelial cell-derived A549 cells were stimulated with a mixture of inflammatory cytokines, TNF-alpha, IL-1beta, and IFN-gamma, which induce cellular injury, including apoptosis. This in vitro model was designed to simulate acute lung injury (ALI) associated with sepsis. The cells were co-treated with dexamethasone and rapamycin under cytokine stimulation. Conditioned medium and cell lysates were subjected to further analysis. RESULTS: Either dexamethasone or rapamycin significantly attenuated cytokine-induced cytotoxicity in A549 cells in a dose-dependent manner. In addition, the simultaneous administration of dexamethasone and rapamycin had a synergistic cytoprotective effect. The applied doses of dexamethasone (10 nM) and rapamycin (1 nM) were considerably below the reported plasma concentrations of each drug in clinical setting. Interestingly, distinct augmentation of both of c-Jun inhibition and Akt activation were observed when the cells were co-treated with both drugs under cytokine stimulation. CONCLUSIONS: A synergistic protective effect of dexamethasone and rapamycin was observed against cytokine-induced cytotoxicity in A549 cells. Augmentation of both of c-Jun inhibition and Akt activation were likely responsible for the cytoprotective effect. The combined administration of anti-inflammatory drugs such as dexamethasone and rapamycin offers a promising treatment option for alveolar epithelial injury associated with sepsis.

[Second-degree atrioventricular block (Mobitz type II) probably exaggerated by dopamine during anesthetic management for a patient with ochronosis: a case report].

Ochronosis is a rare disease. Usually symptoms appear in the third, fourth, or later decade of life. The most common symptom is arthropathy, but cardiovascular system can be involved in this disease. A 71-year-old man with ochronosis was scheduled for total hip arthroplasty. Preoperatively, echocardiogram revealed aortic valve stenosis, mitral valve stenosis, and hypokinesis on antero-septal, lateral and posterior walls. Coronary angiogram revealed 50-75% stenosis of the left anterior descending coronary artery (segment 7) and 100% stenosis of the left circumflex artery (segment 15). Before the induction of general anesthesia, electrocardiogram showed first-degree atrioventricular block. After the induction of general anesthesia, blood pressure decreased markedly. Phenylephrine administration and rapid infusion of extracellular fluid failed to increase blood pressure. Thus, we started to administer dopamine at an infusion rate of 10 microg x kg(-1) x min(-1) which increased blood pressure effectively, but electrocardiogram showed second-degree atrioventricular block (Mobitz type II). We started rapid infusion of a plasma substitute, and gradually decreased the infusion rate of dopamine to 4 microg x kg(-1) x min(-1). Then electrocardiogram returned to first-degree atrioventricular block. We estimated that second-degree atrioventricular block in this patient might have been exaggerated by dopamine at least in part.

[Comparison of the effects of sevoflurane and propofol on changes in leukocyte-count induced by surgical stress].

BACKGROUND: It is well known that surgical stress causes granulocytosis and lymphopenia. However, effects of general anesthetics on changes in leukocyte-count induced by surgical stress are not still clear. METHODS: One hundred and sixteen patients undergoing elective surgery with general anesthesia were enrolled in this retrospective study. Patients were classified into two groups according to anesthetic agents used for maintenance of general anesthesia; sevoflurane group (n = 69) and propofol group (n = 47). Changes in leukocyte-count during surgery were compared between the two groups. RESULTS: In sevoflurane group, lymphocyte-count increased in the early period during surgery, but decreased later. However, lymphocyte-count continued to increase during surgery in propofol group. We found a significant difference in lymphocyte-count during surgery between sevoflurane group and propofol group. On the contrary, granulocyte- and monocyte-count increased during surgery in both groups. There were no significant differences in granulocyte- and monocyte-count during surgery between the two groups. CONCLUSIONS: There were significant differences in effects of sevoflurane and propofol on changes in lymphocyte-count induced by surgical stress. Results of this study imply the efficiency of propofol to prevent lymphopenia, which may play an important role in postoperative immunosuppression caused by surgical stress.

[Right bronchial intubation using a left-sided double-lumen tube in a patient with situs inversus].

A 74-year-old man was scheduled for resection of a pulmonary tumor in the left upper lobe. He had asymptomatic complete situs inversus, and therefore his left lung had three lobes whereas his right lung had two. Since the tumor had been growing through the left upper bronchus into the left main bronchus, it seemed that the use of a bronchial blocker in the left bronchus should be avoided. A 37-Fr left-sided double-lumen tube was rotated in the opposite direction (clockwise) and advanced easily into the right (anatomically left) main bronchus under fiberoptic guidance. One lung ventilation during the operation was performed successfully and there was no postoperative airway complication. Several ways of achieving one lung ventilation in patients with situs inversus are discussed in this report. The use of a bronchial blocker should be considered first-choice, but sometimes its use is inappropriate as in this case. Commercially available double-lumen tubes are not intended for use in cases of situs inversus. If a double-lumen tube is desired, intentional right bronchial insertion of a left-sided double-lumen tube seems to be an easy and reliable option.

[Tension pneumothorax associated with re-intubation through percutaneous tracheostoma site].

Percutaneous tracheostomy (PT) has become popular recently, but occasionally cannula exchange can be difficult and hazardous. A 55-year-old woman with pontine hemorrhage was admitted to our ICU after oral intubation. On the 3 rd day, PT was performed with no complication to prepare for prolonged airway management. On the 14 th day, surgical removal of the pontine hematoma was scheduled. Since our neurosurgeon requested a prone position with maximal neck anteflexion, she was re-intubated orally and the tracheostomy cannula was removed during the operation. At the end of the operation, the tracheostoma had already been narrowed and re-insertion of a narrower tracheostomy cannula was unsuccessful even with bronchoscopic guidance. Following several attempts, her Spo2 gradually decreased and her blood pressure dropped. A chest X-ray showed right pneumothorax and a chest drainage tube was inserted. Posterior tracheal wall injury was suspected, though the exact injury site was not identified bronchoscopically. She was treated conservatively because no air leak was observed after advancing the oral tube. Three weeks later, surgical tracheostomy was performed without major abnormal findings. A small tracheostoma characteristic of PT might be associated with an increased risk of delayed airway complication. Cannula exchange should be performed more carefully after PT compared with surgical tracheostomy.

[How should we perform acute normovolemic hemodilution during radical prostatectomy? Comparison with a mathematical model].

BACKGROUND: Although allogenic blood transfusion has become safer than ever, there still exist some risks such as infection and immunomodulation. The importance of autologous blood transfusion is emphasized. METHODS: Fourteen cases of radical prostatectomy performed with the use of acute normovolemic hemodilution (ANH) were examined retrospectively. The efficacy of ANH was evaluated in comparison with a mathematical model. RESULTS: The average blood loss was 1321 ml and the average blood volume collected during ANH was 637 ml. In no cases, allogenic blood transfusion was necessary. According to a mathematical model, however, the actual blood loss was smaller than the calculated allowable blood loss in all the cases, which implied allogenic blood transfusion would have been avoidable even without ANH. It was also suggested that only a limited efficacy was obtained due to a relatively small blood volume collected during ANH. CONCLUSIONS: Our way of performing ANH was considered suboptimal in that no efficacy was found as to avoidance of allogenic blood transfusion and the extent of ANH was not sufficient to prepare for unexpected massive blood loss. It seemed necessary to reconsider the indications for ANH to increase the efficacy. The importance of the informed consent was also recognized.

[Anesthetic management of a hemophilia A patient with HIV infection: a case report].

A 40-year-old male with hemophilia A was scheduled for right total knee arthroplasty. He was HIV positive probably due to receiving infected blood products previously. We performed the pharmacokinetic study of factor VIII in advance, which showed the increased factor VIII activity 1.6% by an injection of one unit. kg-1 of factor VIII and the half-life of about 16 hours. To keep the factor VIII activity over 100% in the perioperative period, 3000 units of recombinant factor VIII was injected one hour before the induction of anesthesia followed by continuous infusion at 125 units per hour. The factor VIII activity before the induction was 110.6%. The operation was successful and there was no sign of bleeding tendency. The factor VIII activity after the operation, however, was unexpectedly low (73.1%), and it was necessary to increase the infusion rate to 150 units per hour. The factor VIII activity was kept over 80% until POD 7 with the continuous infusion and over 60% until POD 21 with intermittent administration. Factor VIII was discontinued on POD 21 without any sign of bleeding tendency after the postoperative rehabilitation. Although this patient was HIV positive, his immune system was well controlled with HAART and there was no difficulty in the anesthetic management. To prevent accidental infection to the medical staff, we again recognized the importance of standard precautions.

[Successful anesthetic management of patients with poor ventricular function using the phosphodiesterase III inhibitor, olprinone, during major cardiovascular procedures].

We administered olprinone, a newly developed phosphodiesterase III inhibitor, commencing before induction of general anesthesia to patients with poor ventricular function during major cardiovascular procedures. Case 1 patient underwent off-pump CABG for acute myocardial infarction. Although he was in a shock state, olprinone improved the contractility of viable myocardium, increased the cardiac index, and decreased the pulmonary artery pressure. Case 2 patient underwent off-pump CABG for unstable angina. Olprinone significantly increased the cardiac index and the mixed venous oxygen saturation. Case 3 patient underwent graft replacement for rupture of a dissected descending aorta. Although he showed ischemic cardiomyopathy with diffuse hypokinetic left ventricle, olprinone drastically improved the contractility of the heart. Olprinone was very effective for improving ventricular dysfunction; its institution prior to induction of anesthesia made successful anesthetic management possible without resorting to a mechanical assist device like the intra-aortic balloon pump.

[Successful management of a patient for cardiac surgery with difficulty in weaning from cardiopulmonary bypass by using both isosorbide dinitrate and olprinone hydrochloride].

A 57-year-old man with mitral stenosis underwent mitral valve plasty under general anesthesia. He had a history of cerebral infarction. Although he was with atrial fibrillation, his left ventricular function was good. Preoperative coronary angiography revealed no significant coronary stenosis. Induction of anesthesia and the surgical procedure had been uneventful, but the patient had difficulty to wean the patient from cardiopulmonary bypass because of unexpected low cardiac output syndrome. O1-prinone hydrochloride, a newly developed phosphodiesterase III inhibitor, was initiated in addition to high doses of dopamine and dobutamine. This increased the amplitude of the electrocardiogram and caused ST elevation of the lead II. A full dose of isosorbide dinitrate was administered intravenously to differentiate coronary artery spasm from coronary air embolism. This drastically improved the ventricular function and mixed venous oxygen saturation, and weaning from CPB was finally accomplished. The heart showed hypercontraction and inotropes were tapered gradually without further cardiac events. Although there are various etiologies for low cardiac output syndrome after CPB, the possibility of myocardial ischemia must be the first consideration. Full pharmacological support must be tried before initiating a mechanical assist modality. Coronary dilators, nitrates in particular, and phosphodiesterase III inhibitors are promising agents in such cases.

[Changes in whole blood ionized magnesium concentration during cardiac surgery employing St. Thomas' cardioplegic solution].

BACKGROUND: Although there is growing evidence to suggest that magnesium supplementation to patients undergoing cardiac surgery is beneficial, the way to administer magnesium is not established. Moreover in Japan St Thomas' cardioplegic solution, containing a high level of magnesium is widely used and the effect of such magnesium-rich cardioplegic solutions on blood magnesium concentration has not been well defined. METHODS: We measured ionized magnesium concentrations (iMg) during cardiac surgery employing St Thomas' solution. Patients were divided into four groups. Group 1 patients were adults and group 2 were children, both of whom received St. Thomas' solution. Group 3 patients underwent cardiopulmonary bypass but did not receive any cardioplegic solution. Group 4 patients underwent off-pump coronary artery bypass grafting. RESULTS: In cardioplegia group (group 1 and 2) iMg was higher than the normal reference range at periods of rewarming, immediately postbypass, and at the end of the operation. iMg at immediately postbypass was related to the total amount of cardioplegic solution. In non-cardioplegia group (group 3 and 4) progressive decrease of iMg was observed throughout the operation. CONCLUSION: Because magnesium in cardioplegic solutions has substantial effect on perioperative iMg, it is crucial to measure iMg to avoid overdose of magnesium when magnesium-rich cardioplegic solutions are employed.

Analysis of cytotoxicity induced by proinflammatory cytokines in the human alveolar epithelial cell line A549.

Epithelial cell injury under hyperinflammatory conditions is critical in the development of septic acute lung injury (ALI). The aim of the present study is to analyze the cytotoxic effects of a mixture of proinflammatory cytokines in the human alveolar epithelial cell line A549. The cytotoxicity of proinflammatory cytokines were assessed in A549 cells by measuring lactate dehydrogenase released into the culture medium and by crystal violet staining of surviving cells. Activation of the caspase-dependent apoptotic pathway was evaluated by monitoring cleavage of cytokeratin 18 by caspases using enzyme-liked immunosorbent assay (ELISA). To estimate the cytotoxic signaling pathways responsible for epithelial injury, agents with antiinflammatory or antioxidative properties were extensively screened for cytoprotective effects in the inflammation-associated epithelial injury model. The present study revealed that inflammatory cytokines exerted cytotoxicity in A549 cells. A mixture of interleukin-1beta (IL-1ß), tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ), designated as cytomix, augmented cytotoxicity compared with each individual cytokine. Treatment with glucocorticoid (dexamethasone), tetracycline-derived antiinflammatory antibiotics (minocycline or doxycycline), angiotensin II receptor blockers (losartan or telmisartan), or antioxidants (dimethyl sulfoxide, catalase) attenuated cytomix-induced cytotoxicity, including caspase activation. These results implied that inflammatory cytokines alone could cause alveolar epithelial injury in the pathophysiology of septic ALI. Caspase-dependent apoptosis was speculated to be one mechanism responsible for the cytokine-induced cytotoxicity. Agents with antiinflammatory or antioxidative properties such as glucocorticoid, tetracycline-derived antibiotics, angiotensin II receptor blockers, or direct antioxidants showed substantial effect in attenuating cytokine-induced cytotoxicity and may be candidates for treatment options.

Inhaled hydrogen sulfide prevents endotoxin-induced systemic inflammation and improves survival by altering sulfide metabolism in mice.

AIMS: The role of hydrogen sulfide (H(2)S) in endotoxin (lipopolysaccharide [LPS])-induced inflammation is incompletely understood. We examined the impact of H(2)S breathing on LPS-induced changes in sulfide metabolism, systemic inflammation, and survival in mice. RESULTS: Mice that breathed air alone exhibited decreased plasma sulfide levels and poor survival rate at 72 h after LPS challenge. Endotoxemia markedly increased alanine aminotransferase (ALT) activity and nitrite/nitrate (NOx) levels in plasma and lung myeloperoxidase (MPO) activity in mice that breathed air. In contrast, breathing air supplemented with 80 ppm of H(2)S for 6 h after LPS challenge markedly improved survival rate compared to mice that breathed air alone (p<0.05). H(2)S breathing attenuated LPS-induced increase of plasma ALT activity and NOx levels and lung MPO activity. Inhaled H(2)S suppressed LPS-induced upregulation of inflammatory cytokines, while it markedly induced anti-inflammatory interleukin (IL)-10 in the liver. Beneficial effects of H(2)S inhalation after LPS challenge were associated with restored sulfide levels and markedly increased thiosulfate levels in plasma. Increased thiosulfate levels after LPS challenge were associated with upregulation of rhodanese, but not cystathionine-γ-lyase (CSE), in the liver. Administration of sodium thiosulfate dose-dependently improved survival after LPS challenge in mice. INNOVATION: By measuring changes in plasma levels of sulfide and sulfide metabolites using an advanced analytical method, this study revealed a critical role of thiosulfate in the protective effects of H(2)S breathing during endotoxemia. CONCLUSION: These observations suggest that H(2)S breathing prevents inflammation and improves survival after LPS challenge by altering sulfide metabolism in mice.

Nos3 protects against systemic inflammation and myocardial dysfunction in murine polymicrobial sepsis.

NO has been implicated in the pathogenesis of septic shock. However, the role of NO synthase 3 (NOS3) during sepsis remains incompletely understood. Here, we examined the impact of NOS3 deficiency on systemic inflammation and myocardial dysfunction during peritonitis-induced polymicrobial sepsis. Severe polymicrobial sepsis was induced by colon ascendens stent peritonitis (CASP) in wild-type (WT) and NOS3-deficient (NOS3KO) mice. NOS3KO mice exhibited shorter survival time than did WT mice after CASP. NOS3 deficiency worsened systemic inflammation assessed by the expression of inflammatory cytokines in the lung, liver, and heart. Colon ascendens stent peritonitis markedly increased the number of leukocyte infiltrating the liver and heart in NOS3KO but not in WT mice. The exaggerated systemic inflammation in septic NOS3KO mice was associated with more marked myocardial dysfunction than in WT mice 22 h after CASP. The detrimental effects of NOS3 deficiency on myocardial function after CASP seem to be caused by impaired Ca handling of cardiomyocytes. The impaired Ca handling of cardiomyocytes isolated from NOS3KO mice subjected to CASP was associated with depressed mitochondrial ATP production, a determinant of the Ca cycling capacity of sarcoplasmic reticulum Ca-ATPase. The NOS3 deficiency-induced impairment of the ability of mitochondria to produce ATP after CASP was at least in part attributable to reduction in mitochondrial respiratory chain complex I activity. These observations suggest that NOS3 protects against systemic inflammation and myocardial dysfunction after peritonitis-induced polymicrobial sepsis in mice.