Early ascorbic acid administration prevents vascular endothelial cell damage in septic mice.

Oxidation of BH4, a cofactor of nitric oxide synthase (NOS), produces reactive oxygen species (ROS) through uncoupling of NOS and affects vascular endothelial dysfunction. Ascorbic acid (AsA) inhibits the oxidation of BH4 and reduces ROS. However, the kinetic changes of BH4 in sepsis and its effect on the kinetic changes in AsA administration therapy, as well as the appropriate timing of AsA administration for AsA therapy to be effective, are unclear. Mice with sepsis, induced by cecal ligation and puncture (CLP), were examined for the effect of AsA administration (200 mg/kg) on vascular endothelial cell dysfunction at two administration timings: early group (AsA administered immediately after CLP) and late group (AsA administered 12 h after CLP). Survival rates were compared between the early and late administration groups, and vascular endothelial cell damage, indicated by the dihydrobiopterin/tetrahydrobiopterin ratio, serum syndecan-1, and endothelial nitric oxide synthase, as well as liver damage, were examined. The early group showed significantly improved survival compared to the non-treatment group (p < 0.05), while the late group showed no improved survival compared to the non-treatment group. Compared to the non-treated group, the early AsA group showed less oxidation of BH4 in sepsis. Syndecan1, a marker of vascular endothelial cell damage, was less elevated and organ damage was reduced in the early AsA-treated group. In septic mice, early AsA administration immediately after CLP may protect vascular endothelial cells by inhibiting BH4 oxidation, thereby reducing organ dysfunction and improving survival.

Circulating Syndecan-1 as a Predictor of Persistent Thrombocytopenia and Lethal Outcome: A Population Study of Patients With Suspected Sepsis Requiring Intensive Care.

Background: Sepsis is defined as life-threatening organ dysfunction caused by dysregulated host responses to infection. Recent studies have suggested that endotheliopathy may be the common basis for multiple organ failure in sepsis. Under septic conditions, accumulation of proteases accelerates shedding of proteoglycans, such as syndecan-1, from the endothelial surface, resulting in augmented leukocyte adhesion to the vascular wall, enhanced vascular permeability, and intravascular coagulation. The purpose of this study was to determine the potential utility of syndecan-1 as a biomarker linking endotheliopathy to organ failure. Methods: One hundred patients with suspected infections who were admitted to the intensive care unit (ICU) at Kagoshima University Hospital were consecutively enrolled in the study. Serum syndecan-1 levels were measured using an in-house enzyme-linked immunosorbent assay. The difference between serum syndecan-1 levels in 28-day survivors and non-survivors was analyzed by the Mann-Whitney U-test. Receiver-operating characteristics curve analysis with area under the curve calculation was used to quantify the predictive performance of serum syndecan-1 for 28-day mortality. The correlations between serum syndecan-1 and coagulation markers were analyzed by Spearman's rank correlation test. Results: Serum syndecan-1 levels in non-survivors were significantly higher than those in survivors on Day 1 and Day 3 (P < 0.01). Among multiple organ failures, coagulation failure and renal failure were significantly correlated with serum syndecan-1. Spearman's rank correlation test indicated that serum syndecan-1 was weakly but significantly correlated with disseminated intravascular coagulation score (rho = 0.33, P < 0.01). Patients with serum syndecan-1 ≥21.4 ng/mL showed delayed recovery from thrombocytopenia relative to patients with serum syndecan-1 <21.4 ng/mL. Conclusions: Elevated circulating syndecan-1 on the first day of ICU admission was associated with persistent thrombocytopenia and lethal outcome in patients with suspected sepsis.

Circulating activated protein C levels are not increased in septic patients treated with recombinant human soluble thrombomodulin.

BACKGROUND: Recombinant human soluble thrombomodulin (rTM) has been used for the treatment of disseminated intravascular coagulation in Japan, and an international phase III clinical trial for rTM is currently in progress. rTM mainly exerts its anticoagulant effects through an activated protein C (APC)-dependent mechanism, but the circulating APC levels after rTM treatment have not been clarified. This prospective observational study investigated plasma APC levels after rTM treatment. METHODS: Plasma levels of soluble thrombomodulin, thrombin-antithrombin complex (TAT), protein C, and APC were measured in eight septic patients treated with rTM. APC generation in vitro was assessed in the presence or absence of rTM. RESULTS: rTM significantly increased thrombin-mediated APC generation in vitro. In septic patients, soluble thrombomodulin levels were significantly increased during a 30-60-min period of rTM treatment and TAT levels were decreased. However, APC activity was not increased during the treatment period. CONCLUSIONS: Plasma APC activity is not increased in septic patients treated with rTM. It is possible that APC acts locally and does not circulate systemically.

Monitoring of Brain Oxygenation During and After Cardiopulmonary Resuscitation: A Prospective Porcine Study.

This study aimed to evaluate the usefulness of near-infrared time-resolved spectroscopy (TRS) for the monitoring of post-resuscitation encephalopathy. Cardiac arrest (CA) was induced in pigs by electrical stimuli; then, return of spontaneous circulation (ROSC) was achieved by direct current. The changes in cerebral oxygenation were analyzed by two methods: (1) the time-independent calculation based on the modified Beer-Lambert law (MBL), and (2) the curve-fitting method based on the photon diffusion theory (DT). The changes in reduced scattering coefficient (µs') in DT were also calculated. Post-resuscitation encephalopathy was evaluated by MRI findings. During CA, cerebral oxygen saturation (ScO2) decreased to the lowest level, and then gradually increased during the chest compression period. When ROSC was achieved, ScO2 (DT) increased further, but ScO2 (MBL) decreased transiently. This strange phenomenon disappeared when the scalp was peeled off and the probes were directly fixed to the cranial bone. In some cases, a sustained decrease in µs' was observed several hours after ROSC and, in such cases, MRI Diffusion Enhancement Image (DWI) showed findings suggestive of post-resuscitation encephalopathy. In conclusion, simultaneous monitoring of cerebral oxygenation with MBL and DT may provide more information about the vascular response of different layers. Also, the monitoring of µs' may help us to recognize the occurrence of post-resuscitation encephalopathy in real time.

Non-invasive Monitoring of Hepatic Oxygenation Using Time-Resolved Spectroscopy.

UNLABELLED: The aim of the present study was to investigate whether changes in hepatic oxygenation can be detected by time-resolved spectroscopy (TRS) placed on the skin surface above the liver. METHODS: With approval of the local Hospital Ethics Committee and informed consent, six healthy volunteers aged 28.8 (25-36) years, and five patients with chronic renal failure aged 70.6 (58-81) years were studied. In six healthy volunteers, following echography, TRS (TRS-10, Hamamatsu Photonics K.K., Hamamatsu, Japan) probes consisting of a near-infrared light (at 760, 800, 835 nm) emitter and a receiver optode, were placed 4 cm apart on the abdominal skin surface above the liver or at least 10 cm distant from the liver. In five patients with chronic renal failure, following echography, TRS probes were placed 4 cm apart on the skin surface above the liver during hemodialysis (HD). RESULTS: In six healthy volunteers, the values of abdominal total hemoglobin concentration (tHb) were significantly higher in the liver area than in the other area (80.6±26.81 vs 44.6±23.1 µM, p=0.0017), while the value of abdominal SO2 in the liver area was nearly the same as that in the other area (71.5±3.6 vs 73.6±4.6%, p=0.19). The values of mean optical pathlength and scattering coefficient (µ's) at 800 nm in the liver area were significantly different from those in the other area (21.3±4.9 vs 29.2±5 cm, p=0.0004, and 7.97±1.14 vs 9.02±0.51 cm(-1), p=0.015). One of five patients with chronic renal failure complained of severe abdominal pain during HD, and abdominal SO2 decreased from 53 to 22%; however, pain relief occurred following cessation of HD, and SO2 recovered to the baseline level. CONCLUSIONS: Our data suggest that the optical properties of the liver may be measured by the TRS placed on the skin surface, and the hepatic oxygenation may act as a non-invasive monitoring for early detection of intestinal ischemia.