The dose-response relationships of the direct scavenging activity of amide-based local anesthetics against multiple free radicals.

This study aimed to illustrate the dose-response relationships of the direct scavenging activity of amide-based local anesthetics against multiple free radicals in vitro. We have demonstrated that amide-type local anesthetics selectively and directly scavenge some free radicals. Three kinds of free radicals were eliminated by all the four local anesthetics examined. Mepivacaine, lidocaine, bupivacaine, and dibucaine scavenged hydroxyl radicals in dose-dependent manners. Ascorbyl free radicals were also scavenged in dose-dependent manners, and lastly singlet oxygen was scavenged in dose-dependent manners. Three other free radicals were not scavenged by all of the four local anesthetics; tert-butoxyl radical was scavenged by all the anesthetics examined but dibucaine, nitric oxide by mepivacaine but not by the other three, and tyrosyl radical by mepivacaine and lidocaine but not by the other two. Some free radicals (superoxide anion, tert-butyl peroxyl radical, DPPH) were not scavenged by any of the four local anesthetics. The local anesthetics were also shown to inhibit lipid peroxidation by TBARS assay. These results suggest that local anesthetics have antioxidant properties through their free radical scavenging activities.

Real-time monitoring of vitamin C levels in trauma patients by electron-spin resonance spectrometry.

BACKGROUND: In critically ill patients, healthy vitamin C levels are important to avoid an imbalance in reactive oxygen species. To achieve this, oxidative stress levels in emergency patients need to be accurately measured in real-time. However, normally, reactive oxygen/nitrogen species are short-lived, rendering measurement difficult; moreover, measurement of relatively stable antioxidants and other oxidative stress markers in real-time is challenging. Therefore, we used electron-spin resonance spectrometry (ESR) to assess vitamin C levels, clarify their relationship with patients' severity, and establish more effective vitamin C therapy in critically ill patients. METHODS: We studied 103 severely ill emergency patients and 15 healthy volunteers. Vitamin C radical (VCR/dimethyl sulfoxide [DMSO]) values were analyzed in arterial blood samples by ESR at admission and once daily thereafter during the acute recovery phase. Severity scores were calculated. The relationship between these scores and VCR/DMSO values and chronological changes in VCR/DMSO values were analyzed. RESULTS: Serum VCR/DMSO values were significantly lower in critically ill patients than in healthy volunteers (0.264 ± 0.014 vs. 0.935 ± 0.052, p < 0.05), particularly in the severe trauma group and the cardiopulmonary arrest/post-cardiac arrest syndrome group. VCR/DMSO values and various severity scores did not correlate at admission; however, they correlated with SOFA scores from days 2-6. VCR/DMSO values remained low from the first measurement day through Day 6 of illness. CONCLUSIONS: Vitamin C levels were low at admission, remained low with conventional nutritional support, and did not correlate with the initial patient's severity; however, they correlated with patients' severity after admission. Some patients had normal vitamin C levels. Therefore, vitamin C levels should be measured in real-time and supplemented if they are below normal levels. TRIAL REGISTRATION: Retrospectively registered.

General anesthesia with remimazolam for emergency cesarean section in a patient with acute infective endocarditis: a case report.

BACKGROUND: The anesthetic management of pregnant women with acute heart failure remains challenging with regard to maintaining the hemodynamic status of the mother and baby. The likelihood of decreased blood pressure is lower with remimazolam than with propofol. However, there is no report of general anesthesia with remimazolam for cesarean section. CASE PRESENTATION: The patient was a 34-year-old pregnant woman who was diagnosed with acute heart failure associated with infective endocarditis. We performed cesarean section under general anesthesia using remimazolam, with percutaneous cardiopulmonary support on standby. The mother's mean blood pressure was maintained above 65 mmHg during the surgery, without catecholamines or vasopressors. The infant's Apgar scores were 4 at 1 min and 7 at 5 min. CONCLUSION: Cesarean section was successfully performed under general anesthesia with remimazolam in a pregnant patient with acute heart failure. Further studies are needed to clarify the association between remimazolam and neonatal hypotension.

Sonographic diagnosis and evaluation in patients with superficial radial arteries.

BACKGROUND: The superficial radial artery (SRA) is a rare congenital anomaly in the forearm. However, it can be detected incidentally via trauma, intraoperative findings, angiography, or ultrasonography. In addition, intra-arterial infusion of intravenous medications and difficulties in radial artery catheterization may occur in cases of the SRA. METHODS: Between December 2016 and July 2020, anomalous branches of radial arteries were found incidentally in nine patients at the preoperative visit and identified during ultrasound-guided radial artery puncture in 21 patients when radial artery catheterization using the palpation method proved difficult. Ultrasound examinations were performed for diagnosis and evaluation of these 30 patients. RESULTS: All anomalous branches of the radial artery were SRAs; 11 (37%), 13 (43%), 6 (20%) were present on the right side, on the left side, and bilaterally, respectively. All SRAs ran close to the cephalic vein. The vascular diameters of the radial arteries were the smallest in the radial artery distal to the SRA bifurcation (followed by in the SRA) and the largest in the radial artery proximal to the bifurcation (p < .001). In two cases, color Doppler study revealed that both the blood flow and color Doppler signal of the SRA disappeared with compression of the radial artery proximal to the SRA bifurcation. CONCLUSIONS: Because the SRA runs very close to the cephalic vein, a tourniquet applied to the arm may easily lead to intravenous catheter misplacement into the SRA. In addition, the small radial artery distal to the SRA bifurcation causes difficulty in radial artery catheterization. Furthermore, SRA cases may have falsely normal Allen's test results. Therefore, the authors recommend that the SRA must be identified before vascular puncture for safe vascular catheterization in the forearm.

Application and Efficacy of Vitamin E-Bonded Polysulfone Membrane in Acute Blood Purification Therapy.

INTRODUCTION: Acute blood purification therapy (BPT) has been evaluated in the context of intensive care for serious conditions related to systemic inflammation, but its mechanism and efficacy are not fully understood. OBJECTIVE: This study examined the feasibility of using vitamin E-bonded polysulfone membranes (VEPS) for BPT in a LPS-induced rat model of systemic inflammation. METHODS: To evaluate the efficacy of BPT with a VEPS membrane, polysulfone (PS) membranes conventionally used in intensive care were bonded with the antioxidant vitamin E and used in a rat model of lipopolysaccharide (LPS)-induced systemic inflammation. BPT using a PS membrane (PS group) or a VEPS membrane (VEPS group) was performed 6 h after administration of LPS. Extracorporeal circulation was established in normal rats as a control (sham group). Survival rates, histology of lung specimens, and levels of myeloperoxidase (MPO) and high mobility group box-1 (HMGB-1) were examined in each group. RESULTS: Survival rates at 24 h after LPS administration were 100% in the VEPS group and 50% in the PS group. Pulmonary architecture was largely maintained and the level of infiltration of inflammatory cells remained moderate in the VEPS group. Levels of active MPO before and after BPT were significantly higher in the PS and VEPS groups than in the sham group, with no significant differences between the PS and VEPS groups. HMGB-1 levels were significantly elevated after BPT in the PS group. CONCLUSIONS: This study demonstrated that use of the VEPS membrane for BPT increased survival rate and reduced lung injury in a rat model of systemic inflammatory response syndrome (SIRS), suggesting the possible use of VEPS membranes in the treatment of serious conditions related to systemic inflammation.

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.

Dose-dependent scavenging activity of the ultra-short-acting ß1-blocker landiolol against specific free radicals.

Landiolol, a highly cardioselective ultra-short-acting ß1-blocker, prevents perioperative atrial fibrillation associated with systemic inflammation and oxidative stress. We evaluated the direct scavenging activity of landiolol against multiple free radical species. Nine free radical species (hydroxyl, superoxide anion, ascorbyl, tert-butyl peroxyl, tert-butoxyl, singlet oxygen, 2,2-diphenyl-1-picrylhydrazyl, nitric oxide, and tyrosyl radicals) were directly quantified using an X-band ESR spectrometer with the spin-trapping method. IC50 and reaction rate constants were estimated from the dose-response curve for each free radical. Landiolol scavenged six of the free radical species examined: hydroxyl radical (IC50 = 0.76 mM, k landiolol = 1.4 × 10|10 M|-1 s|-1, p<0.001), superoxide anion (58 mM, 2.1 M|-1 s|-1, p = 0.044), tert-butoxyl radical (4.3 mM, k landiolol/k CYPMPO = 0.77, p<0.001), ascorbyl free radical (0.31 mM, p<0.001), singlet oxygen (0.69 mM, k landiolol/k 4-OH |TEMP = 2.9, p<0.001), and nitric oxide (15 mM, 1.7 × 10 M|-1 s|-1, p<0.001). This study is the first to report that landiolol dose-dependently scavenges multiple free radical species with different reaction rate constants. These results indicate the potential clinical application of landiolol as an antioxidative and anti-inflammatory agent in addition to its present clinical use as an anti-arrhythmic agent.

Long-term delayed emergence after remimazolam-based general anesthesia: a case report.

BACKGROUND: Remimazolam is an ultra-short-acting benzodiazepine anesthetic that is antagonized by flumazenil, and it is typically expected to be applied in anesthesia with the purpose of ensuring early postoperative recovery. We report a case of long-term delayed emergence with re-sedation even after three times of flumazenil administration. CASE PRESENTATION: A 71-year-old man was scheduled for a robotic-assisted laparoscopic radical prostatectomy for prostate cancer. We used remimazolam for anesthetic induction and maintenance. The intraoperative bispectral index (BIS) was 30-50. Flumazenil was administered as patient emergence was delayed after surgery; however, re-sedation was observed. This finding persisted till 12 h after surgery, and the patient awakened on postoperative day 2. CONCLUSIONS: Remimazolam is a short-acting anesthetic, but long-term delayed emergence with re-sedation may occur even after flumazenil administration. Anesthesia using remimazolam requires anesthesia management that takes into account the individual differences in sensitivity and metabolism, with BIS as the indicator.

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.

Comparison of three obturator nerve block techniques for injectate spread into the obturator canal: a randomized controlled trial.

PURPOSE: The obturator nerve branches into the obturator canal; therefore, local anesthetic spread into the obturator canal predicts the success of the obturator nerve block (ONB). We compared three ONB techniques for the spread of local anesthetic mixed with contrast medium into the obturator canal. METHODS: We performed the ONB using the classical pubic approach (PA), inguinal approach (IA), or ultrasound-guided methodologic approach (UMA) in 143 patients undergoing transurethral resection of bladder tumors. The obturator nerve course and branching patterns of the UMA group were examined using ultrasound imaging. After injecting a local anesthetic mixed with a contrast medium, we evaluated its spread into the obturator canal using fluoroscopic imaging. P < 0.05 indicated statistical significance. RESULTS: Success rate of obturator canal enhancement was the greatest in the UMA group (84%; P < 0.001); the PA (42.6%; 20/47 patients) and IA (47.8%; 22/46 patients) groups did not differ significantly (P = 1.000). Both branches of the obturator nerve passed above the superior margin of the external obturator muscle (EOM), and the obturator canal was enhanced in 13 of 50 (26%) patients in the UMA group. The posterior branch of the obturator nerve passed between the superior and main fasciculi of the EOM in 37 of 50 patients (74%) in the UMA group; the obturator canal was enhanced in 29 of these 37 patients (78%). CONCLUSION: Local anesthetic spread into the obturator canal using the UMA was superior to that using the PA and IA. Both branches of the obturator nerve could be blocked using the UMA.

Influence of aging on the color visual field in humans: A cross-sectional study.

ABSTRACT: Age-related narrowing of the visual field is observed in the elderly, which leads to reduced cognitive and psychomotor functions. The aim of the present cross-sectional study was to determine the influence of aging on the visual field for color vision in humans, with respect to angular thresholds for object detection and color detection.The subjects were divided into the elderly group (mean 76.1-year-old [70-89]) and the control group (25.2 [18-47]). Visual fields for different colors (blue, green, yellow, and red) were measured by manual kinetic perimetry and evaluated in terms of 2 measures of visual-field width: angular thresholds for object detection and those for color detection.While angular thresholds for object detection were significantly wider than those for color detection in the control group (P < .001), there was no difference in the elderly group (P = .06). Moreover, angular thresholds for object detection were significantly wider in the control group than in the elderly group (P = .019), but angular thresholds for color detection were not significantly different between the 2 groups (P = .903).The observed age-related changes in angular thresholds for object detection in color vision may reflect an age-related reduction in rod function. Stable cone function might explain the preserved angular thresholds for color detection in the elderly.

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-Dose Vitamin C Preadministration Reduces Vancomycin-Associated Nephrotoxicity in Mice.

Vancomycin is recommended for treating severe infections caused by Gram-positive cocci, including methicillin-resistant Staphylococcus aureus. However, renal damage often occurs as a side effect because vancomycin is mainly excreted via the kidneys. The mechanism of vancomycin-associated nephrotoxicity is thought to involve the elevation of oxidative stress in the kidneys. Vitamin C (VC) has strong antioxidant properties; therefore, we evaluated the effect of high-dose VC preadministration on vancomycin-associated nephrotoxicity. Vancomycin was intraperitoneally injected into mice once daily for 7 d. Additionally, high-dose VC was intraperitoneally injected into mice at 30 min before vancomycin administration for 7 d. The plasma creatinine and urea nitrogen levels were increased by vancomycin treatment; however, high-dose VC preadministration suppressed the increase in these levels. Histological examination also revealed that high-dose VC preadministration reduced the characteristics of vancomycin-associated nephrotoxicity, such as dilated renal tubules with casts, the dilation of renal proximal tubules, and tubular epithelial desquamation. Furthermore, high-dose VC preadministration reduced the appearance of apoptotic cells presumably derived from the epithelial cells in the dilated proximal tubules. Thus, intraperitoneally injected high-dose VC preadministration reduced vancomycin-associated nephrotoxicity in mice. These novel findings may indicate that vancomycin-associated nephrotoxicity in humans may be reduced by high-dose VC preadministration.