Tomohito Sadahiro

Usefulness of plasma exchange plus continuous hemodiafiltration to reduce adverse effects associated with plasma exchange in patients with acute liver failure.

ObjectiveTo efficiently remove middle-molecular-weight substances such as hepatic toxins and minimize adverse effects associated with plasma exchange implementation, we have performed plasma exchange slowly in combination with continuous hemodiafiltration. This study was designed to determine the usefulness of plasma exchange with continuous hemodiafiltration in reducing the adverse effects associated with implementation of plasma exchange alone. DesignA retrospective clinical study. SettingUniversity teaching hospital. PatientsThe study involved 90 patients with liver failure who had been treated with plasma exchange in our department over the past 12 yrs. We examined these patients by dividing them into two groups (48 patients treated with plasma exchange alone and 42 patients treated with plasma exchange plus continuous hemodiafiltration at the time of plasma exchange implementation). Measurements and Main Results Baseline blood Na+ concentration, HCO3− concentration, and colloid osmotic pressure were followed after implementation of plasma exchange to compare the frequency of development of three adverse effects (hypernatremia, metabolic alkalosis, and sharp decrease in colloid osmotic pressure) in the two groups. Hypernatremia was found in 26.7% of treatments in the group with plasma exchange alone and 3.3% in the group of plasma exchange plus continuous hemodiafiltration, and metabolic alkalosis was found in 30.6% of treatments in the group with plasma exchange alone and 4.9% in the group of plasma exchange plus continuous hemodiafiltration; both percentages were significantly higher in the group with plasma exchange alone (p < .001). A sharp decrease in colloid osmotic pressure occurred in 13.3% of treatments in the group with plasma exchange alone but was not observed at all in the patients treated with plasma exchange plus continuous hemodiafiltration. ConclusionsWe conclude that adverse effects associated with plasma exchange for artificial liver support for liver failure can be alleviated with use of plasma exchange plus continuous hemodiafiltration instead of plasma exchange alone.

Gram-negative bacteremia induces greater magnitude of inflammatory response than Gram-positive bacteremia

IntroductionBacteremia is recognized as a critical condition that influences the outcome of sepsis. Although large-scale surveillance studies of bacterial species causing bacteremia have been published, the pathophysiological differences in bacteremias with different causative bacterial species remain unclear. The objective of the present study is to investigate the differences in pathophysiology and the clinical course of bacteremia caused by different bacterial species.MethodsWe reviewed the medical records of all consecutive patients admitted to the general intensive care unit (ICU) of a university teaching hospital during the eight-year period since introduction of a rapid assay for interleukin (IL)-6 blood level to routine ICU practice in May 2000. White blood cell count, C-reactive protein (CRP), IL-6 blood level, and clinical course were compared among different pathogenic bacterial species.ResultsThe 259 eligible patients, as well as 515 eligible culture-positive blood samples collected from them, were included in this study. CRP, IL-6 blood level, and mortality were significantly higher in the septic shock group (n = 57) than in the sepsis group (n = 127) (P < 0.001). The 515 eligible culture-positive blood samples harbored a total of 593 isolates of microorganisms (Gram-positive, 407; Gram-negative, 176; fungi, 10). The incidence of Gram-negative bacteremia was significantly higher in the septic shock group than in the sepsis group (P < 0.001) and in the severe sepsis group (n = 75, P < 0.01). CRP and IL-6 blood level were significantly higher in Gram-negative bacteremia (n = 176) than in Gram-positive bacteremia (n = 407) (P < 0.001, <0.0005, respectively).ConclusionsThe incidence of Gram-negative bacteremia was significantly higher in bacteremic ICU patients with septic shock than in those with sepsis or severe sepsis. Furthermore, CRP and IL-6 levels were significantly higher in Gram-negative bacteremia than in Gram-positive bacteremia. These findings suggest that differences in host responses and virulence mechanisms of different pathogenic microorganisms should be considered in treatment of bacteremic patients, and that new countermeasures beyond conventional antimicrobial medications are urgently needed.

Continuous Hemodiafiltration with PMMA Hemofilter in the Treatment of Patients with Septic Shock

Septic shock is the most severe form of sepsis. It is widely accepted that cytokines play pivotal roles in the pathophysiology of septic shock. We reported previously that continuous hemodiafiltration (CHDF) using a polymethylmethacrylate (PMMA) membrane hemofilter removed various cytokines from blood continuously and efficiently, mainly by adsorption to membrane matrix of the hemofilter. Furthermore, in April 2000, we introduced to clinical practice a rapid assay system that determines blood levels of IL (interleukin)-6 in approximately 30 min. This enabled us to routinely measure blood IL-6 as an index of cytokine cascade activation in critically ill patients for real-time clinical monitoring of hypercytokinemia. The aim of the present cohort study was to evaluate the clinical efficacy of PMMA-CHDF in septic shock, a typical condition associated with hypercytokinemia. Forty-three patients with septic shock were assessed by monitoring of blood IL-6 level with a rapid assay system and immediate initiation of critical care including PMMA-CHDF for cytokine removal. Following initiation of PMMA-CHDF, early improvement of hemodynamics was noted, as well as an increase in urine output. PMMA-CHDF treatment improved both hypercytokinemia (assessed by measurement of blood IL-6 level) and dysoxia (assessed by measurement of blood lactate level). The present findings suggest that cytokine-oriented critical care using PMMA-CHDF might be an effective strategy for the treatment of septic shock.

YKL-40 identified by proteomic analysis as a biomarker of sepsis.

To investigate changes in protein expression by proteomic analysis in the sera of patients with sepsis and to identify new biomarkers of sepsis. A total of 45 consecutive patients with severe sepsis or septic shock (sepsis group), 22 healthy volunteers, and 23 patients undergoing off-pump coronary artery bypass grafting (control group). Serum samples from eight patients of each group underwent proteomic analysis involving removal of 12 major proteins and subsequent reversed-phase high-performance liquid chromatography fractionation and one-dimensional electrophoresis. The intensity of 41 bands (with 12 proteins identified) increased and that of 42 bands (with 22 proteins identified) decreased in the sepsis group. Results of proteomic analysis successfully validated by Western blotting and/or enzyme-linked immunosorbent assay for three proteins (YKL-40, lipocalin 2, and S100A9) increased in the sepsis group as well as two proteins (retinol-binding protein, vitamin D-binding protein) decreased. Serum YKL-40 levels (sYKL-40) on intensive care unit (ICU) admission were assessed by enzyme-linked immunosorbent assay between the two groups; resulting YKL-40 was significantly higher in the sepsis group (P < 0.001). Furthermore, sYKL-40 on ICU admission was significantly higher in patients with positive blood culture (P < 0.005), patients with septic shock (P < 0.05), and patients requiring continuous hemodiafiltration (P < 0.05) or hydrocortisone replacement therapy (P < 0.005) during subsequent treatment. A positive correlation between sYKL-40 and blood IL-6 level on ICU admission was noted in the sepsis group (r = 0.465, P < 0.01). YKL-40 identified by proteomic analysis is considered as a biomarker of sepsis. However, further investigation is needed to clarify its roles and clinical usefulness as a biomarker.

Treatment of Severe Sepsis and Septic Shock by CHDF Using a PMMA Membrane Hemofilter as a Cytokine Modulator

It has been reported that various types of blood purification intended for the removal of humoral mediators, such as cytokines, were performed in patients with severe sepsis/septic shock. While high-volume hemofiltration, hemofiltration using high cut-off membrane filters, and direct hemoperfusion with a polymyxin-B immobilized column are widely used in the treatment of severe sepsis/septic shock, we perform continuous hemodiafiltration using a polymethylmethacrylate membrane hemofilter (PMMA-CHDF), which shows an excellent cytokine-adsorbing capacity, for the treatment of severe sepsis/septic shock. In our previous study, it was found that PMMA-CHDF could efficiently remove various pro-inflammatory cytokines such as TNFalpha, IL-6 and IL-8 from the bloodstream, resulting in early recovery from septic shock. Furthermore, PMMA-CHDF could remove anti-inflammatory cytokines such as IL-10 from bloodstream, suggesting that it might improve immunoparalysis as well. These findings suggest that PMMA-CHDF is useful for the treatment of patients with severe sepsis/septic shock as a cytokine modulator.

Efficacy of combination therapy of antiviral and immunosuppressive drugs for the treatment of severe acute exacerbation of chronic hepatitis B

BackgroundPatients with severe exacerbation of chronic hepatitis B, sometimes developing into fulminant liver failure, are at high risk for mortality even with antiviral therapy. The efficacy of immunosuppressive therapy in clinically severe exacerbation of chronic hepatitis B has not been well demonstrated. In this study, we evaluated the efficacy of the early introduction of immunosuppressive therapy in combination with antiviral therapy in such patients.MethodsForty-two patients, 29 men and 13 women, were defined as having severe exacerbation of chronic hepatitis B based on our uniform criteria, and were enrolled in this study. Sixteen patients between 1982 and 1996 were analyzed retrospectively. We defined the criteria of severe disease in 1997, and then began to introduce sufficient doses of corticosteroids prospectively. Nucleoside analogs were administered in combination with corticosteroids after 1999. Twenty-six patients between 1997 and 2007 were analyzed prospectively.ResultsIn the retrospective study between 1982 and 1996, four of 16 (25%) patients recovered. In the prospective study between 1997 and 2007, 17 of 26 (65%) patients recovered; 15 of 17 patients treated with corticosteroids with or without antiviral drugs within 10 days after the diagnosis of severe disease recovered, none of five treated similarly but later than 10 days after the diagnosis recovered, and two of three treated with antiviral drugs recovered.ConclusionsThe early introduction of sufficient doses of corticosteroids and nucleoside analogs could be one option for reversing the potential deterioration of patients with clinically severe, life-threatening exacerbation of chronic hepatitis B.

Differential pattern of cell-surface and soluble TREM-1 between sepsis and SIRS

OBJECTIVE Triggering receptor expressed on myeloid cells-1 (TREM-1) was reported to play a key roll in amplification of production of inflammatory cytokines. TREM-1 is suggested to be a specific biomarker for sepsis for this reason, but the clinical significance of TREM-1 has not been elucidated. We investigated TREM-1 expression on the cell-surface, and plasma levels of soluble TREM-1 (sTREM-1) in patients with non-infectious systemic inflammatory response syndrome (SIRS) and sepsis admitted to the ICU. METHODS Thirty-five patients with SIRS and 21 patients with sepsis admitted to ICU were subjected to the study. TREM-1 expressions on the surfaces of monocytes and neutrophils were measured by flow cytometry. Plasma sTREM-1 level and serum interleukin (IL)-6 level were measured. RESULTS Septic patients had decreased TREM-1 expression, clearly on neutrophils or to a lesser extent on monocyte compared to SIRS patients on ICU admission (neutrophils p<0.001, monocyte p<0.05). TREM-1 expression on neutrophils had a significant inverse correlation with serum IL-6 level (r=-0.64, p<0.0001). Plasma sTREM-1 level in septic patients was significantly higher than that in SIRS patients (p<0.05). Plasma sTREM-1 level positively correlated with severity score and non-survivors had increased plasma sTREM-1 level compared to survivors in all SIRS/sepsis patients (p<0.05). CONCLUSIONS Patients with sepsis had increased soluble TREM-1 and decreased TREM-1 expression on neutrophil compared to SIRS patients. sTREM-1 may be useful to evaluate disease severity and outcome of patients with SIRS or sepsis.

Non-Renal Indications for Continuous Renal Replacement Therapy: Current Status in Japan

Continuous renal replacement therapy (CRRT) has been extensively used in Japan as renal support for critically ill patients managed in the ICU. In Japan, active research has also been conducted on non-renal indications for CRRT, i.e. the use of CRRT for purposes other than renal support. Various methods of blood purification have been attempted to remove inflammatory mediators, such as cytokines, in patients with severe sepsis or septic shock. In these attempts, efficacy was demonstrated for continuous hemodiafiltration(CHDF) using a polymethyl methacrylate (PMMA) membrane hemofilter which is capable of adsorbing and removing various cytokines, plasma diafiltration, and online CHDF. Furthermore, a recently developed cytokine-adsorbing column is now under clinical evaluation. Definite evidence for the efficacy of CRRT for non-renal indications has not been established. In evaluating the efficacy of CRRT for non-renal indications, it is essential to focus on patients subjected to be studied, such as severe sepsis or septic shock, and to evaluate its indication, commencement, termination of therapy and also its therapeutic effects based on analysis of blood levels of the target substances to be removed (e.g. cytokines). IL-6 blood level appears to be useful as a variable for this evaluation. It is expected that evidence endorsing the validity of these methods now being attempted in Japan will be reported near future.

The effects of body temperature control on cytokine production in a rat model of ventilator-induced lung injury

BACKGROUND AND PURPOSE Injurious ventilation with high peak inspiratory pressure (PIP) is known to cause systemic inflammatory response through cytokine production. This study was performed to examine whether body temperature could regulate cytokine production in ventilator-induced lung injury (VILI) model. METHODS After performing anesthesia, tracheostomy, and catheter insertion, rats were ventilated with 17cmH(2)O of PIP in the low-pressure (LP) group or 35cmH(2)O in the high-pressure (HP) group. Then, each group was divided into three subgroups; hyperthermia (39 degrees C), normothermia (37 degrees C), and hypothermia (34 degrees C) group. Six groups were observed for 6h. RESULTS Plasma levels of pro-inflammatory cytokines, TNF-a and IL-6 at 1h after the start of observation were highest in 39 degrees C-HP group and were lowest in 34 degrees C-HP group. Furthermore, sustained high plasma levels of IL-6 were observed only in 39 degrees C-HP group. In contrast, plasma levels of anti-inflammatory cytokine, IL-10 at 1h were highest in 34 degrees C-HP group, and lowest in 39 degrees C-HP group. CONCLUSION The body temperature significantly affects cytokine production in a model of VILI. Body temperature control may be a potentially effective therapeutic modality to regulate cytokine production in VILI.

Efficacy of high-flow dialysate continuous hemodiafiltration in the treatment of fulminant hepatic failure

We compared the clinical efficacy of high-flow dialysate continuous hemodiafiltration (HFCHDF) performed as artificial liver support (ALS) in fulminant hepatic failure (FHF) with those of conventional ALS techniques. Ninety patients were divided into non-HFCHDF and HFCHDF groups. Rate of recovery from coma was significantly higher in the HFCHDF group (70.2%) than in the non-HFCHDF group (44.2%) (p<0.01). The excellent recovery rate from coma achieved in patients with FHF by HFCHDF may be due to its enhanced capacity for liver support enabling efficient removal of substances causing hepatic coma from blood. HFCHDF should thus be useful for ALS.