Early-phase prothrombin time-international normalized ratio in acute liver injury indicates the timing of therapeutic intervention and predicts prognostic improvement.

AIM: We investigated whether an early-phase prothrombin time-international normalized ratio (PT-INR) is an interventional prognostic indicator for patients with acute liver injury, including acute liver failure. METHODS: This was a multicenter retrospective observational study. We included 595 patients with alanine aminotransferase levels ≥300 U/L due to acute liver injury who were admitted to Kagoshima University Hospital or other collaborative investigation organizations between January 1, 2010, and December 31, 2015. Patients with alanine aminotransferase levels ≥300 U/L and no previous liver disease were defined as having an acute liver injury. Acute liver failure was defined by PT-INR ≥1.5 with or without hepatic encephalopathy in acute liver injury patients. Data were obtained retrospectively from case reports and analyzed. RESULTS: The PT-INR on day 1 was the most accurate independent prognosis predictor in patients with acute liver injury and acute liver failure. On day 1, the transplant-free survival rates were significantly lower in patients with PT-INR ≥1.3. The transplant-free survival rates were also significantly higher in patients with acute liver injury and acute liver failure, in whom the PT-INR had recovered from ≥1.3 on day 1 to <1.3 by day 8. CONCLUSION: Early-phase changes in the PT-INR can predict the prognosis of patients with acute liver injury and acute liver failure. Furthermore, PT-INR ≥1.3 could be an interventional marker, whereas PT-INR <1.3 after 1 week could reflect prognostic improvement.

Acquisition and Analysis of Microcirculation Image in Septic Model Rats.

Background: Microcirculation is a vital sign that supplies oxygen and nutrients to maintain normal life activities. Sepsis typically influences the operation of microcirculation, which is recovered by the administration of medicine injection. Objective: Sepsis-induced variation and recovery of microcirculation are quantitatively detected using microcirculation images acquired by a non-contact imaging setup, which might assist the clinical diagnosis and therapy of sepsis. Methods: In this study, a non-contact imaging setup was first used to record images of microcirculation on the back of model rats. Specifically, the model rats were divided into three groups: (i) the sham group as a control group; (ii) the cecum ligation and puncture (CLP) group with sepsis; and (iii) the CLP+thrombomodulin (TM) group with sepsis and the application of TM alfa therapy. Furthermore, considering the sparsity of red blood cells (RBCs), the blood velocity is estimated by robust principal component analysis (RPCA) and U-net, and the blood vessel diameter is estimated by the contrast difference between the blood vessel and tissue. Results and Effectiveness: In the experiments, the continuous degradation of the estimated blood velocity and blood vessel diameter in the CLP group and the recovery after degradation of those in the CLP+TM group were quantitatively observed. The variation tendencies of the estimated blood velocity and blood vessel diameter in each group suggested the effects of sepsis and its corresponding therapy.

Early Elevation of Cell-Free DNA After Acute Mesenteric Ischemia in Rats.

BACKGROUND: Acute mesenteric ischemia (AMI) is challenging to diagnose in the early phase. We tested the hypothesis that blood levels of cell-free DNA would increase early after AMI. In addition, proteome analysis was conducted as an exploratory analysis to identify other potential diagnostic biomarkers. METHODS: Mesenteric ischemia, abdominal sepsis, and sham model were compared in Sprague-Dawley rats. The abdominal sepsis model was induced by cecum puncture and mesenteric ischemia model by ligation of the superior mesenteric artery. Blood levels of cell-free DNA were measured 2 h and 6 h after wound closure. Shotgun proteome analysis was performed using plasma samples obtained at the 2 h timepoint; quantitative analysis was conducted for proteins detected exclusively in the AMI models. RESULTS: Blood cell-free DNA levels at 2 h after wound closure were significantly higher in the AMI model than in the sham and the abdominal sepsis models (P < 0.05). Cell-free DNA was positively correlated with the pathologic ischemia severity score (correlation coefficient 0.793-0.834, P < 0.001). Derivative proteome analysis in blood at 2-h time point revealed higher intensity of paraoxonase-1 in the AMI models than in the abdominal sepsis models; the significantly high blood paraoxonase-1 levels in the AMI models were confirmed in a separate quantitative analysis (P = 0.015). CONCLUSIONS: Cell-free DNA was demonstrated to be a promising biomarker for the early diagnosis of mesenteric ischemia in a rat model of AMI. Paraoxonase-1 may also play a role in the differential diagnosis of mesenteric ischemia from abdominal sepsis. The current results warrant further investigation in human studies.

Risk prediction of biomarkers for early multiple organ dysfunction in critically ill patients.

BACKGROUND: Shock and organ damage occur in critically ill patients in the emergency department because of biological responses to invasion, and cytokines play an important role in their development. It is important to predict early multiple organ dysfunction (MOD) because it is useful in predicting patient outcomes and selecting treatment strategies. This study examined the accuracy of biomarkers, including interleukin (IL)-6, in predicting early MOD in critically ill patients compared with that of quick sequential organ failure assessment (qSOFA). METHODS: This was a multicenter observational sub-study. Five universities from 2016 to 2018. Data of adult patients with systemic inflammatory response syndrome who presented to the emergency department or were admitted to the intensive care unit were prospectively evaluated. qSOFA score and each biomarker (IL-6, IL-8, IL-10, tumor necrosis factor-α, C-reactive protein, and procalcitonin [PCT]) level were assessed on Days 0, 1, and 2. The primary outcome was set as MOD on Day 2, and the area under the curve (AUC) was analyzed to evaluate qSOFA scores and biomarker levels. RESULTS: Of 199 patients, 38 were excluded and 161 were included. Patients with MOD on Day 2 had significantly higher qSOFA, SOFA, and Acute Physiology and Chronic Health Evaluation II scores and a trend toward worse prognosis, including mortality. The AUC for qSOFA score (Day 0) that predicted MOD (Day 2) was 0.728 (95% confidence interval [CI]: 0.651-0.794). IL-6 (Day 1) showed the highest AUC among all biomarkers (0.790 [95% CI: 0.711-852]). The combination of qSOFA (Day 0) and IL-6 (Day 1) showed improved prediction accuracy (0.842 [95% CI: 0.771-0.893]). The combination model using qSOFA (Day 1) and IL-6 (Day 1) also showed a higher AUC (0.868 [95% CI: 0.799-0.915]). The combination model of IL-8 and PCT also showed a significant improvement in AUC. CONCLUSIONS: The addition of IL-6, IL-8 and PCT to qSOFA scores improved the accuracy of early MOD prediction.

Accuracy for Mortality Prediction With Additive Biomarkers Including Interleukin-6 in Critically Ill Patients: A Multicenter Prospective Observational Study.

OBJECTIVES: Several inflammation markers have been reported to be associated with unfavorable clinical outcomes in critically ill patients. We aimed to elucidate whether serum interleukin-6 concentration considered with Sequential Organ Failure Assessment score can better predict mortality in critically ill patients. DESIGN: A prospective observational study. SETTING: Five university hospitals in 2016-2018. PATIENTS: Critically ill adult patients who met greater than or equal to two systemic inflammatory response syndrome criteria at admission were included, and those who died or were discharged within 48 hours were excluded. INTERVENTIONS: Inflammatory biomarkers including interleukin (interleukin)-6, -8, and -10; tumor necrosis factor-α; C-reactive protein; and procalcitonin were blindly measured daily for 3 days. Area under the receiver operating characteristic curve for Sequential Organ Failure Assessment score at day 2 according to 28-day mortality was calculated as baseline. Combination models of Sequential Organ Failure Assessment score and additional biomarkers were developed using logistic regression, and area under the receiver operating characteristic curve calculated in each model was compared with the baseline. MEASUREMENTS AND MAIN RESULTS: Among 161 patients included in the study, 18 (11.2%) did not survive at day 28. Univariate analysis for each biomarker identified that the interleukin-6 (days 1-3), interleukin-8 (days 0-3), and interleukin-10 (days 1-3) were higher in nonsurvivors than in survivors. Analyses of 28-day mortality prediction by a single biomarker showed interleukin-6, -8, and -10 at days 1-3 had a significant discrimination power, and the interleukin-6 at day 3 had the highest area under the receiver operating characteristic curve (0.766 [0.656-0.876]). The baseline area under the receiver operating characteristic curve for Sequential Organ Failure Assessment score predicting 28-day mortality was 0.776 (0.672-0.880). The combination model using additional interleukin-6 at day 3 had higher area under the receiver operating characteristic curve than baseline (area under the receiver operating characteristic curve = 0.844, area under the receiver operating characteristic curve improvement = 0.068 [0.002-0.133]), whereas other biomarkers did not improve accuracy in predicting 28-day mortality. CONCLUSIONS: Accuracy for 28-day mortality prediction was improved by adding serum interleukin-6 concentration to Sequential Organ Failure Assessment score.

A Thrombomodulin Promoter Gene Polymorphism, rs2239562, Influences Both Susceptibility to and Outcome of Sepsis.

Objective: Disseminated intravascular coagulation plays a key role in the pathophysiology of sepsis. Thrombomodulin is essential in the protein C system of coagulation cascade, and functional polymorphisms influence the human thrombomodulin gene (THBD). Therefore, we conducted a multicenter study to evaluate the influence of such polymorphisms on the pathophysiology of sepsis. Methods: A collaborative case-control study in the intensive care unit (ICU) of each of five tertiary emergency centers. The study included 259 patients (of whom 125 displayed severe sepsis), who were admitted to the ICU of Chiba University Hospital, Chiba, Japan between October 2001 and September 2008 (discovery cohort) and 793 patients (of whom 271 patients displayed severe sepsis), who were admitted to the five ICUs between October 2008 and September 2012 (multicenter validation cohort). To assess the susceptibility to severe sepsis, we further selected 222 critically ill patients from the validation cohort matched for age, gender, morbidity, and severity with the patients with severe sepsis, but without any evidence of sepsis. Results: We examined whether the eight THBD single nucleotide polymorphisms (SNPs) were associated with susceptibility to and/or mortality of sepsis. Higher mortality on severe sepsis in the discovery and combined cohorts was significantly associated with the CC genotype in a THBD promoter SNP (-1920*C/G; rs2239562) [odds ratio [OR] 2.709 (1.067-6.877), P = 0.033 and OR 1.768 (1.060-2.949), P = 0.028]. Furthermore, rs2239562 SNP was associated with susceptibility to severe sepsis [OR 1.593 (1.086-2.338), P = 0.017]. Conclusions: The data demonstrate that rs2239562, the THBD promoter SNP influences both the outcome and susceptibility to severe sepsis.

Distal pressure monitoring and titration with percent balloon volume: feasible management of partial resuscitative endovascular balloon occlusion of the aorta (P-REBOA).

INTRODUCTION: Resuscitative endovascular balloon occlusion of the aorta (REBOA) increases proximal arterial pressure, but may also induce life-threatening distal ischemia. Partial REBOA (P-REBOA) is thought to mitigate distal ischemia during aortic occlusion. However, feasible indicators of the degree of P-REBOA remain inconsistent. We hypothesised percent balloon volume could be a substitute for pressure measurements of gradients during P- REBOA. This study aimed to compare balloon volume and arterial pressure gradient, and analysed with intra-balloon pressure and balloon shape. METHODS: Proximal (carotid) and distal (femoral) arterial pressures were recorded and a 7-Fr REBOA catheter was placed in four swine. Total REBOA was defined as a cessation of distal pulse pressure and maximum balloon volume was documented. The balloon volume was titrated by 20% increments of maximum capacity to adjust the degree of P-REBOA. The distal/proximal arterial pressure gradient and the intra-balloon pressures were also recorded. The changes in shape and the cross-sectional area of the balloon were evaluated with computed tomography (CT) images. RESULTS: The proximal mean arterial pressure (MAP) plateaued after 60% balloon volume; meanwhile, distal pulse pressure was still left. The balloon pressure was traced with proximal MAP before contact with aortic wall. The balloon shape changed unevenly from "cone" to "spindle" shape, although the balloon cross-sectional area of the mid-segment linearly increased. CONCLUSION: Monitoring distal pressure and titrating percent balloon volume is feasible to manage P-REBOA. In this experiment, 60% balloon volume was enough inflation to elevate central pressure allowing distal perfusion. The intra-balloon pressure was not reliable due to the strong influence of proximal MAP and uneven change of the balloon shape.

Blood Interleukin-6 Levels Predict Multiple Organ Dysfunction in Critically Ill Patients.

BACKGROUND: Predicting multiple organ dysfunction (MOD) in the late phase of critical illnesses is essential. Cytokines are considered biomarkers that can predict clinical outcomes; however, their predictive value for late-phase MOD is unknown. This study aimed to identify the biomarker with the highest predictive value for late-phase MOD. METHODS: This observational study prospectively evaluated data on adult patients with systemic inflammatory response syndrome, those who presented to the emergency department or were admitted to intensive care units in five tertiary hospitals (n = 174). Seven blood biomarkers levels (interleukin-6 [IL-6], IL-8, IL-10, tumor-necrosis factor-α, white blood cells, C-reactive protein, and procalcitonin) were measured at three timepoints (days 0, 1, and 2). The area under the receiver operating characteristic curve (AUC) was analyzed to evaluate predictive values for MOD (primary outcome, MOD on day 7 [late-phase]; secondary outcome, MOD on day 3 [early-phase]). RESULTS: Of the measured 7 biomarkers, blood IL-6 levels on day 2 had the highest predictive value for MOD on day 7 using single timepoint data (AUC 0.825, 95% confidence interval [CI] 0.754-0.879). Using three timepoint biomarkers, blood IL-6 levels had the highest predictive value of MOD on day 7 (AUC 0.838, 95% CI 0.768-0.890). Blood IL-6 levels using three timepoint biomarkers had also the highest predictive value for MOD on day 3 (AUC 0.836, 95% CI 0.766-0.888). CONCLUSION: Of the measured biomarkers, blood IL-6 levels had the highest predictive value for MOD on days 3 and 7. Blood IL-6 levels predict early- and late-phase MOD in critically ill patients.

Multicenter study on the consciousness-regaining effect of a newly developed artificial liver support system in acute liver failure: An on-line continuous hemodiafiltration system.

AIM: Acute liver failure (ALF) patients with coma need to be revived not only for spontaneous recovery but also as a bridge to liver transplantation. We developed a new high-volume plasma purification system using an on-line continuous hemodiafiltration (CHDF) system, and evaluated its safety and efficacy in a multicenter study. METHODS: A single arm interventional study using the new apparatus was undertaken in the six major liver centers in Japan. The primary end-point was the proportion of patients who regained consciousness within 10 days, which was compared with a historical control (47%). Nine ALF patients were enrolled and treated with the new machine. One patient was excluded because of the need for artificial respiration support according to the established protocol. RESULTS: Seven of eight (87.5%) patients regained consciousness during the on-line CHDF session, with five of those seven waking within 4 days. After waking, one patient spontaneously recovered, three received liver transplantation, two died of liver failure, and one died of another disease. The plasma ammonia levels significantly decreased after the start of on-line CHDF from 182.5 ± 64.8 µg/dL (mean ± SD) on day 0 to 87.0 ± 38.9 µg/dL on the last day of the session (P < 0.001). Similarly, the plasma glutamine level also significantly decreased from 2069 ± 1234 µmol/L to 628 ± 193 µmol/L. Although seven severe adverse events occurred during on-line-CHDF, no causal relationship with liver support was recognized. CONCLUSIONS: The newly developed on-line CHDF system showed high efficacy for regain of consciousness and excellent therapeutic safety for managing ALF.

Serum levels of tau protein increase according to the severity of the injury in DAI rat model.

Traumatic brain injury (TBI) in the form of diffuse axonal injury (DAI) is difficult to diagnose in the early phase of the injury. Early diagnosis of DAI may provide opportunity for developing treatment and management strategies. Tau protein has been demonstrated to increase in the early phase of TBI with high diagnostic accuracy in patients with DAI. We tested the biological plausibility of tau protein using a rat DAI model by evaluating the association between serum tau levels and the severity of brain injury. DAI was induced in animals using the Marmarou model. After a survival of 60 minutes, rats were anesthetized and sacrificed after obtaining blood samples (5ml) from the heart. Eighteen rats were employed in the present study and were randomly subjected to sham-operated control (n=4), mild DAI (n=7), and severe DAI (n=7). Of seven severe DAI rats, two rats that had focal injury caused by skull fracture were excluded in the measurement of tau protein level. The serum levels of tau protein in the rat DAI model were found to increase significantly and consistently according to the severity of the injury. Rats with DAI showed significantly higher serum levels of tau protein compared to sham rats; the severe DAI rats had higher levels of tau than moderate DAI and sham rats (sham vs. mild,  P=0.02; mild vs. severe,  P=0.02). In conclusion, serum tau protein levels may be useful as a biomarker for diagnosing and estimating the severity of DAI in the early phase.

Investigation into Effect of Thrombomodulin Alfa for Septic Model Rats based on Microcirculation Image Analysis.

Sepsis is life threatening organ dysfunction caused by microcirculatory dysfunction. With progression of sepsis, the patients are likely to develop septic shock which is associated with multi organ dysfunction. To treat sepsis and septic shock, Thrombomodulin alfa (TM alfa) was developed. Direct observation of the microcirculation may provide new and rich information in terms of the effect of TM alfa on sepsis. Thus we conducted rodent experiments in which we observed the microcirculation with a non-contact optical imaging setup and measured lactate value from collected blood. From the acquired motion pictures, we estimated the blood velocity. As a result, from experiments, the sham rats showed no significant change in both lactate value and the blood velocity during the observation. On the other hand, lactate value of the septic model rats increased and the blood velocity of them decreased. Lactate value of the septic model rats treated with TM alfa decreased after showing an increase while the blood velocity of them increased after showing a decrease. These findings suggest that microcirculatory alteration may be a sign of sepsis as well as septic shock progression and that the TM alfa may be effective for the treatment of sepsis and septic shock.

Shortening of low-flow duration over time was associated with improved outcomes of extracorporeal cardiopulmonary resuscitation in in-hospital cardiac arrest.

INTRODUCTION: Quality improvement in the administration of extracorporeal cardiopulmonary resuscitation (ECPR) over time and its association with low-flow duration (LFD) and outcomes of cardiac arrest (CA) have been insufficiently investigated. In this study, we hypothesized that quality improvement in efforts to shorten the duration of initiating ECPR had decreased LFD over the last 15 years of experience at an academic tertiary care hospital, which in turn improved the outcomes of in-hospital CA (IHCA). METHODS: This was a single-center retrospective observational study of ECPR patients between January 2003 and December 2017. A rapid response system (RRS) and an extracorporeal membrane oxygenation (ECMO) program were initiated in 2011 and 2013. First, the association of LFD per minute with the 90-day mortality and neurological outcome was analyzed using multiple logistic regression analysis. Then, the temporal changes in LFD were investigated. RESULTS: Of 175 study subjects who received ECPR, 117 had IHCA. In the multivariate logistic regression, IHCA patients with shorter LFD experienced significantly increased 90-day survival and favorable neurological outcomes (LFD per minute, 90-day survival: odds ratio [OR] = 0.97, 95% confidence interval [CI] = 0.94-1.00, P = 0.032; 90-day favorable neurological outcome: OR = 0.97, 95% CI = 0.94-1.00, P = 0.049). In the study period, LFD significantly decreased over time (slope - 5.39 [min/3 years], P < 0.0001). CONCLUSION: A shorter LFD was associated with increased 90-day survival and favorable neurological outcomes of IHCA patients who received ECPR. The quality improvement in administering ECPR over time, including the RRS program and the ECMO program, appeared to ameliorate clinical outcomes.

Organ ischemia during partial resuscitative endovascular balloon occlusion of the aorta: Dynamic 4D Computed tomography in swine.

Resuscitative endovascular balloon occlusion of the aorta (REBOA) increases proximal pressure, and simultaneously induces distal ischemia. We aimed to evaluate organ ischemia during partial REBOA (P-REBOA) with computed tomography (CT) perfusion in a swine model. The maximum balloon volume was recorded as total REBOA when the distal pulse pressure ceased. The animals (n = 4) were scanned at each 20% of the maximum balloon volume, and time-density curve (TDC) were analysed at the aorta, portal vein (PV), liver parenchyma, and superior mesenteric vein (SMV, indicating mesenteric perfusion). The area under the TDC (AUTDC), the time to peak (TTP), and four-dimensional volume-rendering images (4D-VR) were evaluated. The TDC of the both upper and lower aorta showed an increased peak and delayed TTP. The TDC of the PV, liver, and SMV showed a decreased peak and delayed TTP. The dynamic 4D-CT analysis suggested that organ perfusion changes according to balloon volume. The AUTDC at the PV, liver, and SMV decreased linearly with balloon inflation percentage to the maximum volume. 4D-VR demonstrated the delay of the washout in the aorta and retrograde flow at the inferior vena cava in the highly occluded status.

A 3-Species Aquatic Community Model for Ecological Risk Assessment Using Basic Ecotoxicity Data.

A simplified ecosystem model, the Aquatic Tritrophic Ecological Risk Assessment Model (A-TERAM), for the ecological risk assessment of chemicals is presented. The A-TERAM comprises a linear grazer food chain with 3 trophic levels (the algae-Daphnia-fish system). The model simulates the seasonal patterns of abundance at each level observed in the field, and it translates the direct toxic effects of chemicals on algae or Daphnia to implications for fish via ecological interactions; thus, the A-TERAM evaluates ecological risk in terms of the annual population growth rate of fish. The model also incorporates toxicokinetics for fish. The minimum input data required for the A-TERAM are basic ecotoxicity endpoints (algal growth inhibition median effect concentration [EC50] or no-observed effect concentration, Daphnia immobility EC50, and fish acute mortality median lethal concentration); however, additional ecotoxicity data (Daphnia reproduction test, fish early life test, and fish reproduction test) are also relevant for improving simulations. Comparisons made across 496 chemicals (255 nonagricultural chemicals and 241 agrochemicals) indicated that the A-TERAM, in comparison with the conventional predicted-effect concentration/predicted-no-effect concentration method, tended to evaluate higher risk to chemicals that are highly bioaccumulative and toxic to fish by 2 orders of magnitude at the largest but lower or comparable risk to chemicals that are toxic only to algae or Daphnia. Environ Toxicol Chem 2020;39:1086-1100. © 2020 SETAC.

Population Pharmacokinetic Analysis of Meropenem in Critically Ill Patients With Acute Kidney Injury Treated With Continuous Hemodiafiltration.

BACKGROUND: The aim of this study was to conduct a population pharmacokinetic (PK) analysis of meropenem and to explore the optimal dosing strategy for meropenem in critically ill patients with acute kidney injury receiving treatment with continuous hemodiafiltration (CHDF). METHODS: Blood samples were obtained on days 1, 2, and 5 after the start of meropenem administration, immediately before dosing, and at 1, 2, 6, and 8 hours after dosing. Population PK model analysis was performed and concentration-time profiles were simulated using the Nonlinear Mixed Effects Model software. RESULTS: Twenty-one patients receiving CHDF in our intensive care unit were enrolled and 350 serum concentration-time data points were obtained. The PKs of meropenem were best described using a 2-compartment model. Typical total and intercompartmental clearance values were 4.22 L/h and 7.84 L/h, respectively, whereas the central and peripheral compartment volumes of distribution were 14.82 L and 11.75 L, respectively. Estimated glomerular filtration rate was identified as a significant covariate of meropenem total clearance. In simulations of patients with renal failure receiving CHDF, the dose was affected by estimated glomerular filtration rate; a dose of 0.5 g every 8 hours or 1 g every 12 hours showed the probability of target attainment of achieving 100% time above the minimum inhibitory concentration for bacteria with a minimum inhibitory concentration ≤2 mg/L. CONCLUSIONS: A population PK model was developed for meropenem in critically ill patients with acute kidney injury receiving CHDF. Our results indicated that a meropenem dosage of 0.5 g every 8 hours or 1 g every 12 hours was suitable in this population and for susceptible bacteria.

Case Report: Sustained mitochondrial damage in cardiomyocytes in patients with severe propofol infusion syndrome.

Introduction: Propofol infusion syndrome (PRIS) is rare but a potentially lethal adverse event. The pathophysiologic mechanism is still unknown. Patient concerns: A 22-year-old man was admitted for the treatment of Guillain-Barré syndrome. On day six, he required mechanical ventilation due to progressive muscle weakness; propofol (3.5 mg/kg/hour) was administered for five days for sedation. On day 13, he had hypotension with abnormal electrocardiogram findings, acute kidney injury, hyperkalemia and severe rhabdomyolysis. Diagnosis and interventions: The patient was transferred to our intensive care unit (ICU) on suspicion of PRIS. Administration of noradrenaline and renal replacement therapy and fasciotomy for compartment syndrome of lower legs due to PRIS-rhabdomyolysis were performed. Outcomes: The patient gradually recovered and was discharged from the ICU on day 30. On day 37, he had repeated sinus bradycardia with pericardial effusion in echocardiography. Cardiac 18F-FDG PET on day 67 demonstrated heterogeneous 18F-FDG uptake in the left ventricle. Electron microscopic investigation of endomyocardial biopsy on day 75 revealed mitochondrial myelinization of the cristae, which indicated mitochondrial damage of cardiomyocytes. He was discharged without cardiac abnormality on day 192. Conclusions: Mitochondrial damage in both morphological and functional aspects was observed in the present case. Sustained mitochondrial damage may be a therapeutic target beyond the initial therapy of discontinuing propofol administration.

A CO2 removal system using extracorporeal lung and renal assist device with an acid and alkaline infusion.

The patients with respiratory failure need high tidal volume by mechanical ventilation, which lead to the ventilator-induced lung injury. We developed an extracorporeal lung and renal assist device (ELRAD), comprising acid infusion, membrane lung, continuous hemodiafiltration and alkaline infusion. To evaluate this system, we conducted in vivo studies using experimental swine which were connected to the new system. In vivo experiments consist of four protocols; baseline = hemodiafiltration only (no O2 gas flow to membrane lung); membrane lung = "Baseline" plus O2 gas flow to membrane lung; "Acid infusion" = "Membrane lung" plus continuous acid infusion; ELRAD = "Acid infusion" plus continuous alkaline infusion. We changed the ventilatory rate of the mechanical ventilation to maintain PCO2 at 50-55 mmHg during the four protocols. The results showed that there was statistically no significant difference in the levels of pH, HCO3-, and base excess when each study protocol was initiated. The amount of CO2 eliminated by the membrane lung significantly increased by 1.6 times in the acid infusion protocol and the ELRAD protocol compared to the conventional membrane lung protocol. Minute ventilation in the ELRAD protocol significantly decreased by 0.5 times compared with the hemodiafiltration only protocol (P < 0.0001), the membrane lung (P = 0.0006) and acid infusion protocol (P = 0.0017), respectively. In conclusion, a developed CO2 removal system efficiently removed CO2 at low blood flow and reduced minute ventilation, while maintaining acid-base balance within the normal range.

Pharmacokinetics, Pharmacodynamics, and Safety of Nivolumab in Patients With Sepsis-Induced Immunosuppression: A Multicenter, Open-Label Phase 1/2 Study.

BACKGROUND: Sepsis often induces an immunosuppressive state, which is associated with high mortality rates. Immunostimulation may be beneficial for sepsis. We investigated the pharmacokinetics, pharmacodynamics, and safety of nivolumab, a human programmed death-1 immune checkpoint inhibitor approved for the treatment of several cancers. METHODS: In this multicenter, open-label phase 1/2 study, a single 480 or 960 mg nivolumab dose was intravenously infused into Japanese patients with immunosuppressive sepsis. Doses were selected to mimic the exposure achieved with the approved dosage for cancer patients (3 mg/kg every 2 weeks [Q2W]). RESULTS: Single 480 and 960 mg nivolumab doses were intravenously infused into five and eight patients, respectively. The maximum concentration after 480 mg (132 µg/mL) was similar to the predicted concentration at the end of infusion with 3 mg/kg Q2W (117 µg/mL). The concentration on Day 28 after 960 mg (33.1 µg/mL) was within the predicted trough concentration range for 3 mg/kg Q2W (90% prediction interval 19.0-163 µg/mL). Absolute lymphocyte counts and monocyte human leukocyte antigen-DR subtype expression levels appeared to increase over time. The incidences of adverse events (AEs) were 80% and 50% in the 480 mg and 960 mg groups, respectively. Drug-related AEs were observed in only one patient in the 480 mg group. No deaths related to nivolumab occurred. CONCLUSIONS: A single dose of 960 mg nivolumab appeared to be well tolerated and sufficient to maintain nivolumab blood concentrations. Both 480 mg and 960 mg nivolumab seemed to improve immune system indices over time. TRIAL REGISTRATION: JAPIC, JapicCTI-173600.

Changes in acute blood purification therapy in critical care: republication of the article published in the Japanese Journal of Artificial Organs.

Acute blood purification therapy is an essential artificial organ in critical care. In the review article, looking back on the history, we describe our present knowledge and techniques of acute blood purification therapy in critical care. The topics include continuous hemodiafiltration (CHDF), online HDF as an artificial liver support, blood purification therapy aiming to remove pathogenic substances of sepsis, a procedure for connecting a CRRT device into an extra-corporeal membrane oxygenation circuit, and replacement fluid for CHDF. We also raise remaining issues and clarify the future direction of acute blood purification therapy in critical care. This review was created based on a translation of the Japanese review written in the Japanese Journal of Artificial Organs in 2017 (Vol. 46, No. 1, pp. 67-70), with adding some references.