Norihisa Yasuda

In vivo and in vitro effects of the anticoagulant, thrombomodulin, on the inflammatory response in rodent models.

Sepsis remains a major health threat in intensive care medicine. The physiological functions of the coagulation cascade extend beyond blood coagulation and play a pivotal role in inflammation. We investigated whether the use of recombinant thrombomodulin (rTM), which has activity comparable with antithrombin, tissue factor pathway inhibitor, and activated protein C, could inhibit secretion of cytokines and high-mobility group box 1 (HMGB1) protein, thus reducing lung damage in a rat model of LPS-induced systemic inflammation. Rats treated with an intravenous injection of either rTM or saline were injected concurrently with intravenous LPS. In addition, mouse macrophage RAW264.7 cells were stimulated with LPS, with or without simultaneous rTM treatment. Histological examination revealed marked reductions of interstitial congestion, edema, inflammation, and hemorrhage in lung tissue harvested 12 h after treatment with both agents compared with LPS administration alone. LPS-induced secretion of proinflammatory cytokines and HMGB1 protein was inhibited by treatment with rTM. The presence of HMGB1 protein in the lung was examined by immunohistochemistry; the number of HMGB1-positive cells was significantly lower in LPS-treated animals that also received rTM. In the in vitro studies, rTM administration inhibited the activation of nuclear factor-kappa B by inhibiting I kappa B phosphorylation. The anticoagulant rTM blocked the LPS-induced inflammatory response and protected against acute lung injury normally associated with endotoxemia in this rat sepsis model. Given these results, rTM is a strong candidate as a therapeutic agent for various systemic inflammatory diseases.

Removal of 17 Cytokines, HMGB1, and Albumin by Continuous Hemofiltration Using a Cellulose Triacetate Membrane: An Ex Vivo Study

BACKGROUND Hemofiltration is often used to treat critically ill patients with renal failure and septic shock. Although hemofiltration has been reported to remove humoral mediators such as cytokines, most studies have investigated the removal of only limited kinds of cytokines. Here, we assessed the removal of 17 cytokines, HMGB1, and albumin by continuous hemofiltration (CHF) with a cellulose triacetate membrane (2.1 m(2) or 1.1 m(2)). METHODS The subjects were six healthy volunteers. We collected 400 mL blood into containers with heparin. After adding 1 mg/mL lipopolysaccharide, the blood was incubated at 39°C for 12 h and then filtered through a closed hemofiltration circuit (1 or 2 L/h). Sixty and 240 min after beginning hemofiltration, samples were collected from the outlet (arterial) side, inlet (venous) side, and filtrate port. Blood levels of cytokines, HMGB1, and albumin were determined at each time point. RESULTS Increasing the flow rate significantly increased cytokine clearance. Increasing the membrane area of the hemofilter significantly changed the sieving coefficient of only five cytokines (IL-1β, IL-6, MCP-1, MIP-1β, HMGB1). For many cytokines, the sieving coefficient did not decline during the 240-min CHF procedure. CONCLUSION Although all 17 cytokines, HMGB1, and albumin were detected in the filtrate, the SC and clearance varied widely. For numerous cytokines, clearance increased with the higher filtration flow rate. We demonstrated that CHF removed many cytokines and HMGB1, but was inefficient at removing albumin.

The efficacy and safety of antithrombin and recombinant human thrombomodulin combination therapy in patients with severe sepsis and disseminated intravascular coagulation.

PURPOSE Recombinant human thrombomodulin (rhTM) is often used concomitantly with antithrombin (AT) to treat disseminated intravascular coagulation (DIC). This observational study aimed to investigate the efficacy and safety of AT+rhTM combination therapy. MATERIALS AND METHODS One hundred twenty-nine patients with severe sepsis and DIC participated in this study. Of these, 78 patients were treated with AT+rhTM (AT+rhTM group) and 51 patients were treated with AT alone (AT group). We compared coagulation and inflammation markers, Sequential Organ Failure Assessment score, and DIC score at day 0 (baseline) and day 7 between the 2 groups. Bleeding events and 28-day mortality were also compared. RESULTS Platelet counts and D-dimer levels at day 7 significantly improved in the AT+rhTM group compared with the AT group, and 28-day mortality was significantly lower in the AT+rhTM group than in the AT group (AT+rhTM: 15.4% vs AT: 29.4%). During the study period, the incidence of bleeding complications was similar in both groups (AT+rhTM: 6.4% vs AT: 7.8%). CONCLUSIONS Compared with AT monotherapy, combination therapy with AT and rhTM may be more effective in improving platelet counts and D-dimer levels, as well as reducing mortality, in patients with severe sepsis-associated DIC.

Pharmacokinetics of ceftriaxone in patients undergoing continuous renal replacement therapy

Abstract Background: The duration of time for which the serum levels exceed the minimum inhibitory concentration (MIC) is an important pharmacokinetics (PK)/pharmacodynamics (PD) parameter correlating with efficacy for the antibiotic, ceftriaxone (CTRX). However, no reports exist regarding the PK or PD in patients undergoing continuous renal replacement therapy (CRRT). The purpose of this study was to examine the PK and safety of CTRX in patients undergoing CRRT in order to establish safer and more effective regimens. Methods: CTRX (1 g once a day) was intravenously administered four or more times to nine patients undergoing CRRT. Blood was collected after administration to measure CTRX concentrations in serum and the filtration fraction of CRRT by high-performance liquid chromatography. In addition to calculating PK parameters from serum CTRX, we (a) estimated by simulation CTRX concentrations when the dose interval was extended to once every 2 or 3 days, (b) calculated CTRX clearance via CRRT from CTRX concentrations in the filtration fraction, and (c) assessed the safety of CTRX use. Results: Total body clearance and the half-life of CTRX were 7.46 mL/min (mean) and 26.5 h, respectively, in patients undergoing CRRT. CTRX was found in the filtration fraction, and the estimated clearance by CRRT was about 70% of total body clearance. Simulations revealed that even when the dose interval is increased to 2 or 3 days, CTRX would retain its efficacy. Conclusions: Our findings suggest that, depending on the condition of patients undergoing CRRT, CTRX could be used safely against pathogens with a CTRX MIC ≤2 µg/mL, even when extending the dose interval.

Should Nicorandil Infusion Be Adapted in Dialysis‐Dependent Patients Undergoing Continuous Renal Replacement Therapy After Cardiac Surgery?

In this report, we studied whether plasma concentration of nicorandil is maintained effectively and safely in dialysis-dependent patients with stage 5 chronic kidney disease (CKD5D) undergoing continuous renal replacement therapy (CRRT). Participants consisted of 10 patients undergoing CRRT after cardiac surgery. CRRT was performed with an effluent flow rate of either 600 mL/h (low-flow group; n = 5) or 1800 mL/h (high-flow group; n = 5). Nicorandil was infused intravenously at 0.1 mg/kg/h for more than 15 h starting 8 h before and 7 h after the start of CRRT. Plasma nicorandil concentrations were measured from arterial blood lines 1 h before and 7 h after CRRT initiation. Nicorandil clearance by CRRT was also calculated 1 h after CRRT initiation. Nicorandil plasma concentrations before and 7 h after CRRT initiation were 68.0 ng/mL and 74.6 ng/mL, respectively. Nicorandil clearance 1 h after CRRT initiation was 20.2 mL/min. Increasing the effluent flow rate from 600 mL/h to 1800 mL/h tended to increase nicorandil clearance. When nicorandil was infused intravenously during CRRT at 0.1 mg/kg/h in patients with CKD5D, plasma nicorandil concentrations were maintained within an effective concentration range.

Continuous Renal Replacement Therapy Improves Septic Shock in Patients Unresponsive to Early Goal-Directed Therapy

Background: Early goal-directed therapy (EGDT) has been shown to improve patient outcomes. Treatment of patients unresponsive to the protocol, however, is difficult and the result is occasionally fatal. Recently, continuous renal replacement therapy (CRRT) has been used to treat acute kidney injury (AKI) to improve survival. We examined the effectiveness of CRRT in treating septic shock patients with concurrent AKI who are not amenable to EGDT. Methods: We studied 17 patients who underwent emergency surgery for intra-abdominal infection; these patients experienced AKI complications and did not respond to EGDT within 6 hrs after intensive care unit (ICU) admission. We treated patients with continuous venovenous hemodiafiltration (CVVHDF; dialysis = 900 ml/hr, filtration = 900 ml/hr, total hemopurification = 1800 ml/hr). We measured mean arterial pressure (MAP), central venous pressure (CVP), central venous oxygen saturation (ScvO 2 ), catecholamine index (CAI), and determined serum concentrations of lactate, interleukin-6 (IL-6), and high mobility group box-1 protein (HMGB-1) immediately before and 3, 6, 12, 24, 48 hrs after CRRT initiation. We also evaluated 28-day survival, ICU survival, and hospital survival. Results: CRRT duration was 6.5±4.2 days. MAP and ScvO 2 significantly increased with CRRT, while CAI and concentrations of lactate, IL-6, and HMGB-1 significantly decreased. After CRRT, no patients required intermittent hemodialysis in the ICU. Mean ICU stay was 15.1±10.4 days. ICU survival, 28-day survival, and hospital survival were 76.5%, 76.5%, and 70.6%, respectively. Conclusions: CRRT may be an effective treatment for seriously ill patients who have complications of AKI and are unresponsive to EGDT.

High efficiency removal of cytokines and HMGB-1 by continuous hemofiltration with a dual layered polyethersulfone membrane: An ex vivo study: Cytokine removal with a polyethersulfone membrane

Cytokines and high mobility group box chromosomal protein‐1 (HMGB‐1) play key roles in inflammatory conditions. While hemofiltration has been shown to remove cytokines, removal of cytokines and HMGB‐1 by hemofiltration using a polyethersulfone membrane has not been reported. This study aimed to test the hypothesis that the polyethersulfone membrane will achieve higher removal performance for substances including inflammatory cytokines compared to other hemofilters, while retaining low albumin removal capacity. Subjects were eight healthy volunteers. We collected 400 mL each of blood samples into containers with heparin and added 30 mg of lipopolysaccharide to spike cytokines and HMGB‐1. After incubation at 39ºC for 12 h, each blood sample was circulated through a hemofiltration circuit with a polyethersulfone hemofilter (2.1 m2 or 1.1 m2) at a filtration flow rate of 2 L/h. Measurement samples were collected from arterial, venous, and ultrafiltrate sampling points. Concentrations of cytokines (IL‐1ß, IL‐4, IL‐6, IL‐8, IL‐ 10, and tumor necrosis factor [TNF‐a]), HMGB‐1, and albumin were determined at each time point (1, 4, 8, 12, and 24h). High sieving coefficients (SCs) above 0.8 were obtained for all cytokines except for TNF‐a as well as HMGB‐1, whereas the SC for albumin was less than 0.04 with both hemofilters. The hemofilter with a larger membrane area achieved significantly higher clearances for TNF‐a and HMGB‐1, and slower decreases in SCs over time for IL‐1ß, IL‐6, IL‐8, TNF‐a, and albumin. Continuous hemofiltration with a polyethersulfone membrane achieved high efficiency removal of cytokines and HMGB‐1, without excessive removal of albumin.

Pharmacokinetic/Pharmacodynamic Analysis for Doripenem Regimens in Intensive Care Unit Patient

Doripenem (DRPM) is a broad-spectrum antibacterial agent often used as empirical therapy for critically ill patients, although there is a lack of studies validating the recommended dosage regimen for patients admitted to intensive care unit (ICU), based on pharmacokinetic (PK)/pharmacodynamic (PD) index. In this study, we estimated the free time above minimum inhibitory concentration (fT>MIC (%)) of DRPM using population PK analysis of 12 patients in ICU, and evaluated the validity of the dosage regimen stratified by creatinine clearance. Using a 2-compartment population PK model reported previously, the mean total clearance or distribution volume of DRPM estimated by Bayesian estimation was significantly lower or higher than that of based on population PK model. The estimated fT>MIC (%) of the recommended standard (normal renal function: 0.5 g every 8 h, moderate: 0.25 g every 8 h, severe renal impairment: 0.25 g every 12 h) and higher doses (normal: 1.0 g every 8 h, moderate: 0.5 g every 8 h, severe: 0.25 g every 8 h) against MICs of 0.5, 1 and 2 µg/mL exceeded 40% in all patients. When stratified by creatinine clearance, the PK/PD breakpoints estimated by Monte Carlo simulation in three grades of renal function tended to be higher than the previously reported PK/PD breakpoints for patients with urinary tract infection, an infection of lesser severity than ICU patients. These results suggest that the dosage regimen stratified by renal function derived from Japanese package insert may be sufficient to achieve effective treatment in ICU patients.