Hiroyuki Hirasawa

An initial comparison of intensive care in Japan, and the United States

ObjectiveThe objective of this study was to compare the utilization of, and outcome from, critical care services in selected medical centers providing secondary and tertiary care in the United States and Japan. DesignProspective data collection on 1,292 patients from each of the participating Japanese study hospitals in 1987 to 1989 and compared with the 5,030 patients in the United States 1982 Acute Physiology and Chronic Health Evaluation (APACHE II) database used to develop the APACHE II equation. Detailed organizational characteristics of the participating ICUs and hospitals were also obtained. SettingData collection took place in the ICUs of 13 U.S. hospitals and six Japanese hospitals. PatientsData were collected on consecutive, unselected patients from medical, surgical, and mixed medical/surgical critical care units, with a spectrum of medical and surgical diagnoses. Measurements and Main ResultsU.S. and Japanese ICUs have a similar array of diagnostic and therapeutic modalities. Only 2% (range 0.6 to 3.5) of beds in Japanese hospitals were designated to intensive care. The organization of the Japanese and U.S. ICUs varied by hospital. There were significantly fewer women admitted to Japanese ICUs and a substantially lower proportion of low-risk-of-death patients. Despite a rapidly aging population, there were relatively fewer elderly patients with chronic health ailments in the Japanese ICU population (8%) compared with the U.S. cohort (18%). ConclusionsIn this sample of hospitals, similar high-technology critical care is available in the United States and Japan. Variations in utilization between the two countries represent differences in case mix and bed availability. The APACHE II equation stratified patients in the Japanese patient cohort across the full spectrum of increasing severity of illness.

Blood Purification for Prevention and Treatment of Multiple Organ Failure

Abstract. Blood purification has been applied conventionally as an artificial kidney or artificial liver in the management of patients with multiple organ failure (MOF), and most blood purifications have been performed intermittently. Recent advances in medical engineering made it possible to perform such blood purifications continuously (i.e., 24 hours a day, 7 days a week if necessary) even in critically ill patients. This modality is referred to as continuous renal replacement therapy (CRRT) or continuous blood purification (CBP). Among many kinds of CBP, continuous hemodiafiltration (CHDF) is most useful for management of MOF, as it can be performed without serious or hazardous side effects, and improvement can be expected with it. Recently, CHDF and polymyxin B immobilized endotoxin adsorption columns were used for the prevention or treatment of MOF, with the expectation that such therapy can be effective as a countermeasure against the pathophysiologic causes of MOF. Our data and that of others clearly indicate that continuous blood purification, such as with CHDF and endotoxin adsorption, can remove or decrease the blood levels of humoral mediators, including proinflammatory cytokines, and can improve tissue oxygenation, especially oxygen consumption (VO 2 ) among critically ill patients including those with MOF. Blood purification is also useful in the careful management of fluid, electrolytes, and acid-base balance and for the removal of metabolic wastes. Blood purification is now considered to be one of the basic therapeutic tools of critical care, equal to nutritional support with total parenteral nutrition and respiratory support without a ventilator.

ABANDON THE MOUSE RESEARCH SHIP? NOT JUST YET!

ABSTRACT Many preclinical studies in critical care medicine and related disciplines rely on hypothesis-driven research in mice. The underlying premise posits that mice sufficiently emulate numerous pathophysiologic alterations produced by trauma/sepsis and can serve as an experimental platform for answering clinically relevant questions. Recently, the lay press severely criticized the translational relevance of mouse models in critical care medicine. A series of provocative editorials were elicited by a highly publicized research report in the Proceedings of the National Academy of Sciences (PNAS; February 2013), which identified an unrecognized gene expression profile mismatch between human and murine leukocytes following burn/trauma/endotoxemia. Based on their data, the authors concluded that mouse models of trauma/inflammation are unsuitable for studying corresponding human conditions. We believe this conclusion was not justified. In conjunction with resulting negative commentary in the popular press, it can seriously jeopardize future basic research in critical care medicine. We will address some limitations of that PNAS report to provide a framework for discussing its conclusions and attempt to present a balanced summary of strengths/weaknesses of use of mouse models. While many investigators agree that animal research is a central component for improved patient outcomes, it is important to acknowledge known limitations in clinical translation from mouse to man. The scientific community is responsible to discuss valid limitations without overinterpretation. Hopefully, a balanced view of the strengths/weaknesses of using animals for trauma/endotoxemia/critical care research will not result in hasty discount of the clear need for using animals to advance treatment of critically ill patients.

Management of intra-abdominal hypertension in patients with severe acute pancreatitis with continuous hemodiafiltration using a polymethyl methacrylate membrane hemofilter

Abstract:  To evaluate, with a prospective observational study, whether continuous hemodiafiltration using a polymethyl methacrylate membrane hemofilter (PMMA‐CHDF) is effective for prevention and treatment of  intra‐abdominal hypertension (IAH) and abdominal compartment syndrome (ACS) on patients with severe acute pancreatitis (SAP). The study was carried out in the general intensive care unit (ICU) of a university hospital. Seventeen consecutive patients with SAP were treated in the intensive care unit and underwent PMMA‐CHDF whether or not they had renal failure. Blood level of interleukin (IL)‐6, as an indicator of cytokine network activation, and intra‐abdominal pressure (IAP) were measured daily to investigate their time‐course of changes and the correlation between the two. The blood level of IL‐6 was high at 1350 ± 1540 pg/mL on admission to the ICU. However, it significantly decreased to 679 ± 594 pg/mL 24 h after initiation of PMMA‐CHDF (P < 0.05), and thereafter decreased rapidly. Mean intra‐abdominal pressure (IAP) on admission was high, at 14.6 ± 5.3 mm Hg, with an IAP of 20 mm Hg or over in 2 of 17 patients, showing that they had already developed IAH. The IAP was significantly lower (P < 0.05) 24 h after initiation of PMMA‐CHDF, and subsequently decreased. There was a significant positive correlation between blood level of IL‐6 and IAP, suggesting that PMMA‐CHDF improved vascular permeability through elimination of cytokines, and that it thereby decreased interstitial edema to lower IAP. Sixteen of the 17 patients were discharged from the hospital in remission from SAP without development of complications. Continuous hemodiafiltration using a polymethyl methacrylate membrane hemofilter appears to be effective for prevention and treatment of IAH in patients with SAP through the removal of causative cytokines of hyperpermeability.

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.

Nicotine enhances human vascular endothelial cell expression of ICAM-1 and VCAM-1 via protein kinase C, p38 mitogen-activated protein kinase, NF-κB, and AP-1

Investigation into the etiology of atherosclerosis has identified cigarette smoking as a major risk factor. Although it has been established that cellular adhesion molecule expression on endothelial cells is stimulated by nicotine, the mechanism by which this occurs is not clear. The aim of this study was to determine the effect of nicotine on the expression of the adhesion molecules, intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 inendothelial cells and to determine the involvement of imporcule tank known intermediaries, protein kinase C (PKC), p38 mitogen-activated protein kinase (p38 MAPK), and the transcription factors NF-κB and AP-1. Human umbilical vein endothelial cells (HUVEC) were exposed to 10−8M nicotine for up to 24 h. Expression of ICAM-1 and VCAM-1 and phosphorylation of p38 were examined by immunoblot. Electrophoretic mobility shift assay was performed to determine NF-κB and AP-1 activation. We observed that nicotine increased the expression of ICAM-1 and VCAM-1 with a peak at 6h.p38 MAPK was activated after 5 min exposure to 10−8 mol/L nicotine and returned to baseline levels by 30 min. Exposure of HUVEC to nicotine resulted in a 4.1-fold increase of PKC activity at 5 min, which subsequently returned to control levels by 15 min. Nicotine (10−8 mol/L) also increased NF-κB and AP-1 activity. Inhibitors of p38 MAPK, PKC, and NF-κB suppressed nicotine-stimulated expression of ICAM-1 and VCAM-1. Our results indicate that nicotine enhances the expression of ICAM-1 and VCAM-1 on the endothelial cell surface via a second messenger pathway which involves PKC and p38 MAPK-mediated activation of NF-κB and AP-1, resulting in increased expression of these cellular adhesion molecules.

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.

The Japanese guidelines for the management of sepsis

SummaryThis is a guideline for the management of sepsis, developed by the Sepsis Registry Committee of The Japanese Society of Intensive Care Medicine (JSICM) launched in March 2007. This guideline was developed on the basis of evidence-based medicine and focuses on unique treatments in Japan that have not been included in the Surviving Sepsis Campaign guidelines (SSCG), as well as treatments that are viewed differently in Japan and in Western countries. Although the methods in this guideline conform to the 2008 SSCG, the Japanese literature and the results of the Sepsis Registry Survey, which was performed twice by the Sepsis Registry Committee in intensive care units (ICUs) registered with JSICM, are also referred. This is the first and original guideline for sepsis in Japan and is expected to be properly used in daily clinical practice.This article is translated from Japanese, originally published as “The Japanese Guidelines for the Management of Sepsis” in the Journal of the Japanese Society of Intensive Care Medicine (J Jpn Soc Intensive Care Med), 2013; 20:124–73. The original work is at http://dx.doi.org/10.3918/jsicm.20.124.