UHPLC-MS/MS method for simultaneous quantification of doripenem, meropenem, ciprofloxacin, levofloxacin, pazufloxacin, linezolid, and tedizolid in filtrate during continuous renal replacement therapy.

BACKGROUND: Since severe infections frequently cause acute kidney injury (AKI), continuous renal replacement therapy (CRRT) is often initiated for regulation of inflammatory mediators and renal support. Thus, it is necessary to decide the antibiotic dosage considering the CRRT clearance in addition to residual renal function. Some of the hemofilters used in CRRT are known to adsorb antibiotics, and clearance of antibiotics may differ depending on the adsorptive characteristics of hemofilters. Although assay systems for blood and CRRT filtrate concentrations are required, no method for measuring antibiotics concentrations in filtrate has been reported. We developed a UHPLC-MS/MS method for simultaneous quantification of antibiotics commonly used in ICU, comprising carbapenems [doripenem (DRPM) and meropenem (MEPM)], quinolones [ciprofloxacin (CPFX), levofloxacin (LVFX) and pazufloxacin (PZFX)] and anti-MRSA agents [linezolid (LZD), and tedizolid (TZD)] in CRRT filtrate samples. METHODS: Filtrate samples were pretreated by protein precipitation. The analytes were separated with an ACQUITY UHPLC CSH C18 column under a gradient mobile phase consisting of water and acetonitrile containing 0.1% formic acid and 2 mM ammonium formate. RESULTS: The method showed good linearity over wide ranges. Within-batch and batch-to-batch accuracy and precision for each drug fulfilled the criteria of the US Food and Drug Administration guidance. The recovery rate was more than 87.20%. Matrix effect ranged from 99.57% to 115.60%. Recovery rate and matrix effect did not differ remarkably between quality control samples at different concentrations. CONCLUSION: This is the first report of a simultaneous quantification method of multiple antibiotics in filtrate of CRRT circuit.

Incidence, Outcome, and Risk Factors of Cardiovascular Surgery-Associated Disseminated Intravascular Coagulation: A Single-Center Retrospective Study.

Cardiovascular surgery is highly invasive, with a risk of postoperative coagulopathy due to various factors such as bleeding. Coagulopathy can progress to disseminated intravascular coagulation (DIC), which complicates various clinical conditions. However, no study to date has reported on DIC associated with cardiovascular surgery. Therefore, we investigated retrospectively the incidence, outcome, and risk factors of cardiovascular surgery-associated DIC in our institute. All patients who underwent cardiovascular surgery and were admitted to our intensive care unit between January 2016 and December 2017 were included in this study. The Japanese Association for Acute Medicine (JAAM) DIC score was calculated using our institute's database at the following time points: preoperatively, postoperative day 1 (POD1), POD3, and POD7. Data regarding surgery, 90-day mortality, and risk factors of DIC were also collected and analyzed by multiple regression. In total, 553 patients were considered eligible for analysis. Median age of eligible patients was 72 years, with a 90-day mortality rate of 1.4%. Patients with DIC at POD7 had higher Sequential Organ Failure Assessment (SOFA) score, preoperative JAAM DIC scores, and a longer anesthesia time than those without DIC. Female sex, preoperative DIC score, and anesthesia time were found to be risk factors for DIC.

Nasal pillow noninvasive ventilation versus high-flow nasal therapy after extubation in surgical intensive care patients: A propensity-matched cohort study.

OBJECTIVE: To evaluate the tolerability and efficacy of nasal pillow-noninvasive ventilation (NP-NIV) compared with high-flow nasal therapy (HFNT) in postsurgical patients. METHODS: This propensity score-matched retrospective study enrolled postoperative patients that received NP-NIV (NP-NIV group) or HFNT (HFNT group) in the intensive care unit. Data were collected from their medical records and the tolerability and respiratory status before and after extubation were compared between the two groups. RESULTS: The study enrolled 83 patients in the NP-NIV group and 27 patients in the HFNT group. After propensity score matching, there were 19 patients in each group. After matching, there were no significant differences in the baseline demographic and clinical characteristics before extubation. The tolerability was similar in both groups. When the NP-NIV group was compared with the HFNT group, the respiratory rate was significantly lower (median 16 [interquartile range, 14-17] versus median 19 [interquartile range, 18-26], respectively) and the partial pressure of arterial oxygen/fraction of inspired oxygen ratio was significantly higher (median 205 [174-256] versus median 155 [130-192], respectively) at 1 h after extubation. CONCLUSION: NP-NIV was equally well tolerated and provided better respiratory support than HFNT in postsurgical patients.

Effects of low-dose intravenous immunoglobulin as the adjunctive therapy in septic shock patients with and without hypogammaglobulinemia: a retrospective cohort study.

BACKGROUND: Intravenous immunoglobulin (IVIG) therapy has a reported adjunctive effect in the treatment of sepsis, but in light of results from a large-scale randomized control trial (RCT), evidence for improved prognosis with IVIG therapy is currently deemed insufficient. In recent years, there have been many reports of low serum immunoglobulin G (IgG) as a poor prognostic factor in septic patients. Under Japan's national health insurance system, IVIG is administered for severe infections at a dose of 5 g/day for three days (total 15 g or 0.3 g/kg). At present, IVIG administration is not specifically formulated for septic patients with hypogammaglobulinemia. It is clinically significant to investigate whether serum IgG levels can serve as a biomarker to predict the efficacy of IVIG treatment for septic shock and help to identify those patients who might benefit from an adjunctive IVIG treatment. The purpose of this study was to compare the efficacy of this low-dose IVIG as an adjunctive therapy in septic shock patients with and without hypogammaglobulinemia. METHODS: In this retrospective cohort study, patients who received low-dose IVIG (5 g/day for 3 days) as adjuvant therapy for septic shock were enrolled. These patients were divided into two groups based on a median serum IgG level of 829 mg/dL (<830 mg/dL defined as hypogammaglobulinemia) prior to IVIG administration. To assess the efficacy of low-dose IVIG administration (0.3 g/kg), 28-day survival probability as the primary outcome, and the lengths of artificial ventilation and intensive care unit (ICU) stays as the secondary outcomes were compared using the Kaplan-Meier method, the log-rank test, the Wilcoxon or Mann-Whitney U test. RESULTS: A total of 80 patients with septic shock that underwent IVIG treatment in the ICU were enrolled. These patients were divided into two groups based on a median serum IgG level. Survival probabilities at 28 days were 90.0% and 85.0% in the high- and low-level groups, respectively, and there was no significant difference between the two groups (P=0.457). There are not also significant differences in median lengths of artificial ventilation (6 vs. 9 days, P=0.215) and ICU stays (10 vs. 12 days, P=0.199) after IVIG administration. Logistic regression revealed that these clinical outcomes were not associated with serum IgG after adjusting for confounding factors as the antibiotics. CONCLUSIONS: Serum IgG levels was not associated with the clinical outcomes by low-dose IVIG treatment. Our results suggest that the prognosis of low-dose IVIG as adjunctive therapy in patients with septic shock might be no different with and without hypogammaglobulinemia.

Pharmacokinetic and Adsorptive Analyses of Administration of Oral Voriconazole Suspension via Enteral Feeding Tube in Intensive Care Unit Patients.

For intensive care unit (ICU) patients, injectable voriconazole (VRCZ) is difficult to use because the patients often develop acute kidney injury. Since many ICU patients have consciousness disturbance, oral ingestion of tablet formulation is also difficult, and administration of a suspension via enteral feeding tube is required when using VRCZ. In this study, we investigated the in vitro adsorption property of oral VRCZ to feeding tube and performed pharmacokinetic analysis of VRCZ prepared by powdering and simple suspension for ICU patients. VRCZ was tube-administered to five ICU patients at a loading dose of 300 mg and plasma VRCZ concentrations before and at 1, 2, 4, 8, 12 h after the first dose were measured using HPLC. Pharmacokinetic parameters were calculated by non-compartmental model analysis. The recovery rate of VRCZ after infusion of the suspension through feeding tube was 89.8 ± 8.3%, but the cumulative rates after the first and second re-infusion were 102.7 ± 20.7 and 99.3 ± 10.3%, respectively, suggesting almost no residual drug in the tube after re-infusion. Metabolic phenotype was extensive metabolizer (EM) in two patients and intermediate metabolizer (IM) in three patients. The values of total clearance (CLtot/F) calculated by moment analysis were 0.51 and 0.55 L/h/kg in two EM patients, and 0.09, 0.29 and 0.31 L/h/kg in three IM patients. The CLtot/F was apparently lower in IM patients compared to EM. In conclusion, powdered and suspended VRCZ administered via enteral feeding tube showed pharmacokinetics depending on CYP2C19 gene polymorphism, similar to that observed in usual oral administration.

Simultaneous quantification of plasma levels of 12 antimicrobial agents including carbapenem, anti-methicillin-resistant Staphylococcus aureus agent, quinolone and azole used in intensive care unit using UHPLC-MS/MS method.

OBJECTIVES: Critically ill patients in intensive care unit (ICU) are susceptible to infectious diseases, thus empirical therapy is recommended. However, the therapeutic effect in ICU patients is difficult to predict due to fluctuation in pharmacokinetics because of various factors. This problem can be solved by developing personalized medicine through therapeutic drug monitoring. However, when different measurement systems are used for various drugs, measurements are complicated and time consuming in clinical practice. In this study, we aimed to develop an assay using ultra-high performance liquid chromatography coupled with tandem mass spectrometry for simultaneous quantification of 12 antimicrobial agents commonly used in ICU: doripenem, meropenem, linezolid, tedizolid, daptomycin, ciprofloxacin, levofloxacin, pazufloxacin, fluconazole, voriconazole, voriconazole N-oxide which is a major metabolite of voriconazole, and posaconazole. DESIGN & METHODS: Plasma protein was precipitated by adding acetonitrile and 50% MeOH containing standard and labeled IS. The analytes were separated with an ACQUITY UHPLC CSH C18 column, under a gradient mobile phase consisting of water and acetonitrile containing 0.1% formic acid and 2 mM ammonium formate. RESULTS: The method fulfilled the criteria of US Food and Drug Administration for assay validation. The recovery rate was more than 84.8%. Matrix effect ranged from 79.1% to 119.3%. All the calibration curves showed good linearity (back calculation of calibrators: relative error ≤ 15%) over wide concentration ranges, which allowed determination of Cmax and Ctrough. Clinical applicability of the novel method was confirmed. CONCLUSIONS: We have developed an assay for simultaneous quantification of 12 antimicrobial agents using a small sample volume of 50 µL with a short assay time of 7 min. Our novel method may contribute to simultaneous calculation of pharmacokinetic and pharmacodynamic parameters.

A new anticoagulation strategy using recombinant human thrombomodulin in patients on veno-venous extracorporeal membrane oxygenation: a retrospective study.

BACKGROUND: During veno-venous extracorporeal membrane oxygenation (VV-ECMO), systemic anticoagulation is required to prevent thrombotic complications within the circuit and oxygenator. The unfractionated heparin (UFH) is commonly administered as a standard anticoagulant, but in our institute recombinant human thrombomodulin (rhTM), instead of UFH, is used as an anticoagulant for VV-ECMO. In the present study, we reviewed whether rhTM could be applied effectively and safely as an anticoagulant agent during VV-ECMO. METHODS: All 15 patients with severe respiratory failure on VV-ECMO were analyzed retrospectively. The following data were collected: age, gender, underlying disease, APACHE-II score, SOFA score, Japanese association for acute medicine (JAAM) DIC score, the usage of anticoagulants, time course of coagulationrelated parameters during ECMO, hemorrhagic and thrombotic complications. RESULTS: The median age of the patients was 73 years. The median JAAM DIC score at day 0 was 5 points, indicating that 13 patients were diagnosed with DIC at the initiation of VV-ECMO. The total number of days of VV-ECMO runs combined was 193 days, with a median duration of VV-ECMO of 9 days. Among the 15 VV-ECMO runs, rhTM was used as monotherapy in 5 runs, and a combination of rhTM and (antithrombin) AT was used in 8 runs. UFH was used in combination with rhTM in only 2 runs. Median ACT and aPTT remained a little longer than normal range over the course of the 14 days of a VV-ECMO run. Bleeding events were observed in 6 cases (40%) and no major thromboses were observed in all patients. CONCLUSIONS: In this retrospective study, we analyzed 15 patients with severe respiratory failure who were administered rhTM as an anticoagulant during VV-ECMO and found that anticoagulation therapy with rhTM is maybe a feasible option which allows for effective and safe VV-ECMO.

High-throughput and wide-range simultaneous determination of linezolid, daptomycin and tedizolid in human plasma using ultra-performance liquid chromatography coupled to tandem mass spectrometry.

Several recent studies on pharmacokinetics of linezolid (LZD) and daptomycin (DAP) reported that plasma concentration was linked to efficacy and adverse effects, suggesting the usefulness of therapeutic drug monitoring (TDM). The usefulness of TDM for tedizolid (TZD) has not been reported, but a previous report showed individual differences in area under the curve depending on body weight. In intensive care unit (ICU) patients, pharmacokinetics was reported to fluctuate due to various factors. Here, we developed a high-throughput and wide-range simultaneous quantification method for LZD, DAP and TZD in human plasma using ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS). Plasma samples were pretreated by solid-phase extraction using Oasis® HLB µElution Plate. The assay fulfilled the requirements of US Food and Drug Administration and the European Medicines Agency for bioanalytical method validation. The assay for LZD, DAP and TZD showed good linearity over wide ranges of 100-100000, 150-150000 and 5-5000 ng/mL, respectively. Within-batch accuracy and precision as well as batch-to-batch accuracy and precision for all three drugs fulfilled the criteria of the above guidance. Extraction recovery rates were more than 92.2 % for LZD, 44.7 % for DAP, and 84.8 % for TZD. Matrix effect showed no remarkable differences among low, medium and high quality control samples for the three drugs. The maximum and trough concentrations of three patients each who received LZD, DAP or TZD in ICU were measured by the novel UPLC-MS/MS method. In all patients, the measured concentrations were within the ranges of the calibration curves, demonstrating the feasibility of clinical application of the novel method. In conclusion, we have succeeded to develop the first method for simultaneous quantification of plasma concentrations of LZD, DAP and TZD.

Population pharmacokinetic analysis of doripenem for Japanese patients in intensive care unit.

We aimed to construct a novel population pharmacokinetics (PPK) model of doripenem (DRPM) for Japanese patients in intensive care unit, incorporating the clearance of DRPM by continuous renal replacement therapy (CRRT). Twenty-one patients treated with DRPM (0.25 or 0.5 g) by intravenous infusion over 1 h were included in the study. Nine of the 21 patients were receiving CRRT. Plasma samples were obtained before and 1, 2, 4, 6 and 8 h after the first DRPM administration. PPK analysis was conducted by nonlinear mixed effects modeling using a two-compartment model. Total clearance (CLtotal) in the model was divided into CRRT clearance (CLCRRT) and body clearance (CLbody). The final model was: CLtotal (L h-1) = CLbody(non-CRRT) = 3.65 × (Ccr/62.25)0.64 in the absence of CRRT, or = CLbody(CRRT) + CLCRRT = 2.49 × (Ccr/52.75)0.42 + CLCRRT in the presence of CRRT; CLCRRT = QE × 0.919 (0.919 represents non-protein binding rate of DRPM); V1 (L) = 10.04; V2 (L) = 8.13; and Q (L h-1) = 3.53. Using this model, CLtotal was lower and the distribution volumes (V1 and V2) tended to be higher compared to previous reports. Also, Ccr was selected as a significant covariate for CLbody. Furthermore, the contribution rate of CLCRRT to CLtotal was 30-40%, suggesting the importance of drug removal by CRRT. The population analysis model used in this study is a useful tool for planning DRPM regimen and administration. Our novel model may contribute greatly to proper use of DRPM in patients requiring intensive care.

Veno-Venous Extracorporeal Membrane Oxygenation for Severe Pneumocystis jirovecii Pneumonia in an Immunocompromised Patient without HIV Infection.

Pneumocystis jirovecii pneumonia (PJP) occurs in immunocompromised hosts and is classified as PJP with human immunodeficiency virus (HIV) infection (HIV-PJP) and PJP without HIV infection (non-HIV PJP). Non-HIV PJP rapidly progresses to respiratory failure compared with HIV-PJP possibly due to the difference in immune conditions; namely, the prognosis of non-HIV PJP is worse than that of HIV PJP. However, the diagnosis of non-HIV PJP at the early stage is difficult. Herein, we report a case of severe non-HIV PJP successfully managed with veno-venous extracorporeal membrane oxygenation (V-V ECMO). A 54-year-old woman with neuromyelitis optica was treated with oral corticosteroid, azathioprine, and methotrexate. She admitted to our hospital for fever, dry cough, and dyspnea which developed a week ago. On admission, she required endotracheal intubation and invasive ventilation for hypoxia. A chest computed tomography (CT) scan revealed ground-glass opacity and consolidation in the both lungs. Grocott staining and PCR analysis of bronchoalveolar lavage fluid indicated the presence of fungi and Pneumocystis jirovecii, respectively, whereas serum HIV-antibody was negative. The patient was thus diagnosed with non-HIV PJP and was treated with intravenous pentamidine and corticosteroid pulse therapy for PJP. However, hypoxia was worsened; consequently, V-V ECMO assistance was initiated on day 7. The abnormal chest CT findings and hypoxia were gradually improved. The V-V ECMO support was successfully discontinued on day 14 and mechanical ventilation was discontinued on day 15. V-V ECMO could be a useful choice for respiratory assistance in severe cases of PJP among patients without HIV infection.

High Efficiency Removal of Cytokines and HMGB-1 by Continuous Hemofiltration With a Dual Layered Polyethersulfone Membrane: An Ex Vivo Study.

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.

Development and validation of sensitive and selective quantification of total and free daptomycin in human plasma using ultra-performance liquid chromatography coupled to tandem mass spectrometry.

Recently, several studies on pharmacokinetics parameters of daptomycin reported that plasma trough concentration was linked to efficacy and adverse effects, suggesting the usefulness of therapeutic drug monitoring. Although some methods for determining total daptomycin concentration using liquid chromatography coupled to tandem mass spectrometry were established previously, no sensitive quantification method for free drug concentration was established. In this study, we aimed to develop a quantitative method of measuring both total and free daptomycin concentrations using ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS), by which both trough and maximum concentrations can be measured. Plasma samples were prepared by solid phase extraction. Free fractions were obtained by ultrafiltration. The assay fulfilled the requirements of US Food and Drug Administration and the European Medicines Agency for assay validation. The methods for total and free drug showed good fit over wide ranges of 0.5-200 and 0.04-40 µg/mL, with lower limits of quantitation of 0.5 and 0.04 µg/mL, respectively. Recovery rate of free daptomycin from ultrafiltration was approximately 100%. Extraction recovery rates of total and free drug measurements ranged from 57.1 to 67.4% and 54.6 to 62.3%, while matrix effect varied between 111.9 and 118.7% and 104.0 and 127.1%, respectively. The maximum and trough concentrations of total and free daptomycin in plasma from two patients in intensive care unit were successfully determined, demonstrating the feasibility of clinical application of the novel methods for determining plasma total and free daptomycin concentrations. In conclusion, we succeeded to develop a sensitive and selective method using UPLC-MS/MS for quantitative measurement of total and free daptomycin concentrations in plasma.

Vitamin E-Coated Polysulfone Membrane-Based Hemodiafiltration Attenuates Inflammation in a Rat Model of Lipopolysaccharide-Induced Systemic Inflammation.

BACKGROUND: Acute blood purification (ABP) therapy is used regularly in the clinical setting and reportedly alleviates organ failure associated with severe systemic inflammatory responses, leading to reduced mortality. The present study aimed to determine whether there is a difference in efficacy between polysulfone (PS) membranes, which are currently used regularly in the clinical setting, and vitamin E-coated polysulfone (VEPS) membranes, which are anticipated to exhibit the antioxidant and anti-inflammatory properties of vitamin E. METHODS: Male Wistar rats (n=15/group) were intravenously administered 10 mg/kg of lipopolysaccharide (LPS) to establish a systemic inflammatory response model. Six hours after LPS administration, hemodiafiltration (HDF) was performed for 30 minutes using a PS or VEPS membrane under general anesthesia. Blood was collected at various time points, lung tissue was evaluated histologically, and 24-hour survival was assessed. RESULTS: The rats in the VEPS group tended to have a higher survival rate than those in the PS group when undergoing HDF, although the difference was not significant. With respect to lung tissue, the inflammatory response was suppressed to a greater extent in the VEPS group than the PS group. Serum interleukin (IL)-6 levels were reduced at an early stage, plasma antioxidant activity was increased, and oxidative stress was reduced in the VEPS group compared to the PS group. CONCLUSION: Relative to PS membrane-based HDF, the survival rate tended to improve and inflammation was subdued earlier due to the antioxidant activity and early attenuation of inflammation associated with VEPS membrane-based HDF.

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.

Pharmacokinetics of ceftriaxone in patients undergoing continuous renal replacement therapy.

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.

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.

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.

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-1ß, IL-6, MCP-1, MIP-1ß, 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.

Effect of hemopurification rate on doripenem pharmacokinetics in critically ill patients receiving high-flow continuous hemodiafiltration.

  Hemopurification is an effective therapy for acute kidney injury, defined as creatinine clearance less than 30 ml/min, which occurs frequently in the intensive care unit. These critically ill patients often have severe infectious complications and are thus often treated with antibiotics. However, the effect of hemopurification on the pharmacokinetics of antibiotics is not well understood. In this study, we investigated the pharmacokinetics of doripenem (DRPM) in critically ill patients with accompanying renal dysfunction undergoing continuous hemodiafiltration by high-volume filtration/high-flow dialysis (high-flow CHDF) and compared it to the pharmacokinetics of DRPM during conventional CHDF. We studied 8 patients (2 in the high-flow group and 6 in the conventional group) in whom DRPM was administered while performing CHDF for acute kidney injury. DRPM (250 mg) was intravenously infused over 1 h. For the conventional group, CHDF was performed at a blood flow rate (Q(B)) of 100 ml/min, dialysate flow rate (Q(D)) of 500 ml/h, and filtration flow rate (Q(F)) of 300 ml/h. For the high-flow group, CHDF was performed at a blood flow rate (Q(B)) of 100 ml/min, dialysate flow rate (Q(D)) of 1500 ml/h, and filtration flow rate (Q(F)) of 900 ml/h. For both groups, a polysulfonehemofilter with a membrane area of 1.0 m(2) was used. Mean half-life, total body clearance, and clearance via hemodiafiltration of DRPM were 2.9 h, 118 ml/min, and 41.9 ml/min, respectively, in the high-flow group, and 7.9 h, 58 ml/min, and 13.5 ml/min in the conventional group. Clearance via hemodiafiltration increased approximately 3-fold by tripling the hemopurification rate. Therefore, CHDF parameters greatly affected DRPM pharmacokinetics in patients receiving CHDF. These results suggest that clearance via hemodiafiltration increases proportionally to the hemopurification rate. Thus, it is reasonable to conclude that DRPM dose must be increased to 1.0-1.5 g/day when performing high-flow CHDF.

Effective control of paroxysmal tachycardia with landiolol hydrochloride during cesarean section in a patient with hypertrophic obstructive cardiomyopathy.

Hypertrophic obstructive cardiomyopathy (HOCM) involves marked hypertrophy of cardiac muscle, resulting in myocardial ischemia and arrhythmia because of left ventricular diastolic dysfunction. In perioperative management of HOCM, hemodynamic stabilization is required, by prevention of arrhythmia and tachycardia and maintenance of preload and afterload. Here, we describe anesthesia management during cesarean section in a patient complicated by HOCM. The patient was a 27-year-old woman who underwent elective cesarean section scheduled at 36 weeks of pregnancy given her history of HOCM. She was managed with spinal anesthesia with monitoring of invasive blood pressure and arterial pressure cardiac output. Administration of landiolol hydrochloride was initiated, because of paroxysmal tachycardia after delivery. Approximately 5 min after initiation of administration, her heart rate decreased gradually and blood pressure rose. Circulatory dynamics stabilized and landiolol was discontinued 3 h after she was admitted to the intensive care unit. Her circulatory dynamics remained stable after discontinuation of landiolol, and she was moved to a general ward on the following day. She was discharged on postoperative day 14, with her child.