Kimitaka Tajimi

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.

Association of body temperature and antipyretic treatments with mortality of critically ill patients with and without sepsis: multi-centered prospective observational study

IntroductionFever is frequently observed in critically ill patients. An independent association of fever with increased mortality has been observed in non-neurological critically ill patients with mixed febrile etiology. The association of fever and antipyretics with mortality, however, may be different between infective and non-infective illness.MethodsWe designed a prospective observational study to investigate the independent association of fever and the use of antipyretic treatments with mortality in critically ill patients with and without sepsis. We included 1,425 consecutive adult critically ill patients (without neurological injury) requiring > 48 hours intensive care admitted in 25 ICUs. We recorded four-hourly body temperature and all antipyretic treatments until ICU discharge or 28 days after ICU admission, whichever occurred first. For septic and non-septic patients, we separately assessed the association of maximum body temperature during ICU stay (MAXICU) and the use of antipyretic treatments with 28-day mortality.ResultsWe recorded body temperature 63,441 times. Antipyretic treatment was given 4,863 times to 737 patients (51.7%). We found that treatment with non-steroidal anti-inflammatory drugs (NSAIDs) or acetaminophen independently increased 28-day mortality for septic patients (adjusted odds ratio: NSAIDs: 2.61, P = 0.028, acetaminophen: 2.05, P = 0.01), but not for non-septic patients (adjusted odds ratio: NSAIDs: 0.22, P = 0.15, acetaminophen: 0.58, P = 0.63). Application of physical cooling did not associate with mortality in either group. Relative to the reference range (MAXICU 36.5°C to 37.4°C), MAXICU ≥ 39.5°C increased risk of 28-day mortality in septic patients (adjusted odds ratio 8.14, P = 0.01), but not in non-septic patients (adjusted odds ratio 0.47, P = 0.11).ConclusionsIn non-septic patients, high fever (≥ 39.5°C) independently associated with mortality, without association of administration of NSAIDs or acetaminophen with mortality. In contrast, in septic patients, administration of NSAIDs or acetaminophen independently associated with 28-day mortality, without association of fever with mortality. These findings suggest that fever and antipyretics may have different biological or clinical or both implications for patients with and without sepsis.Trial registrationClinicalTrials.gov: NCT00940654

M phase-specific expression and phosphorylation-dependent ubiquitination of the Clc-2 channel

Cl− channel activities vary during the cell cycle and are thought to play various roles including regulation of cell volume. We have shown previously that ClC-2 channels are directly phosphorylated and functionally regulated by the M phase-specific cyclin-dependent kinase p34cdc2/cyclin B. We investigate here to determine whether the expression levels of ClC-2 channel protein vary during the cell cycle. Immunoblot and immunocytochemical analyses of cells cycle-synchronized by serum depletion/replenishment reveal that ClC-2 channel protein is expressed predominantly at M phase in cells with two nuclei and a clear constriction ring, whereas RNA blot analysis shows that ClC-2 mRNA expression does not change during the cell cycle. Ubiquitin assays reveal that the ClC-2 channels are ubiquitinated at M phase, whereas the magnitude of ubiquitination is suppressed by incubation with olomoucine, an inhibitor of p34cdc2/cyclin B, and it is almost completely abolished in ClC-2 channels having an S632A mutation, which cannot be phosphorylated by p34cdc2/cyclin B, indicating that ubiquitination of ClC-2 channels requires phosphorylation by M phase-specific p34cdc2/cyclin B. Regulation at the post-transcriptional level, including phosphorylation-dependent ubiquitination, may contribute to M phase-specific expression of ClC-2 channels. Cell cycle-dependent regulation of expression at the protein level in addition to the regulation of function suggests that the ClC-2 channel plays a physiological role in the cell cycle.

Cl− channel blockers inhibit transition of quiescent (G0) fibroblasts into the cell cycle

Modulation of ion permeability during the cell cycle is one of the key events in cell cycle progression. We have compared the effects of K+ and Cl− channel blockers on the cell cycle in synchronous and asynchronous NIH3T3 cells. The Cl− channel blocker 5‐N‐2‐(3‐phenylpropylamino) benzoic acid (NPPB; 0.2 mM) inhibited entry into S phase in synchronous cells but not in asynchronous cells, while the K+ channel blocker 4‐aminopyridine (4‐AP) showed similar inhibitory effects in both conditions. In NIH3T3 cells synchronized by serum deprivation/replenishment, G0‐to‐G1 transition occurred within 8 h after serum addition, and the G1/S checkpoint at 10–14 h. NPPB applied only at 0–8 or 8–14 h after serum addition inhibited entry into S phase. Cl− permeability measured as 125I efflux increased at 4 and 10 h after serum addition. Ki‐67‐negative cells, which represent quiescent G0 phase cells, progressively decreased in number until 8 h after serum addition. The Cl− channel blockers (NPPB and 4,4′‐diisothiocyanatostilbene‐2,2′‐disulfonic acid [DIDS]) but not the K+ channel blocker (4‐AP) significantly decreased the rate of reduction in number of Ki‐67‐negative cells. These data indicate that an increase in Cl− permeability plays an important role in reentry of quiescent cells into the proliferating phase, in addition to the known effects on passage through the G1/S checkpoint.

Characteristics of self-immolation attempts in Akita Prefecture, Japan

Akita Prefecture has had the highest suicide rate in Japan for the past 9 years. To obtain further information on suicide attempts by self-immolation in Akita, we performed a statistical analysis of patients in this prefecture who attempted to burn themselves. Over the past 6 years, 541 patients suffering from burns were transferred to medical emergency units. Of these, 35 (6.5%) attempted self-immolation, most of whom were between 20 and 60 years of age. Women over 50 years of age outnumbered men in the same age group. All 35 patients sustained flame burns. The total burn surface area (TBSA), burn index (BI), rate of inhalation injury, and mortality rate were all significantly higher in the patients who attempted self-immolation than in those with nonsuicidal burns. Most (68.6%) of the self-immolation attempts were made indoors. Because the Japanese are not generally a very religious people, training to help them cultivate a philosophy of life and educating them in moral science to help them form a personal view of life and death may be necessary to prevent suicides.

Extravascular lung water measured using single transpulmonary thermodilution reflects perioperative pulmonary edema induced by esophagectomy.

Pulmonary edema is the most frequent postoperative complication following esophagectomy for thoracic esophageal cancer. We enrolled 23 patients who underwent esophagectomy with extended lymph node dissection for thoracic esophageal cancer in a prospective observational clinical trial. We used the PiCCO device to measure extravascular lung water with the aim of determining whether it correlates with the respiratory index and whether it is predictive of pulmonary complications. Based on constant criteria, the tracheal tubes of 11 patients were removed on the morning of postoperative day 1 (extubation group), while 12 patients remained intubated (intubation group). These two groups significantly differed in that all patients in the extubation group recovered without any pulmonary complications, whereas 4 patients (33%) in the intubation group developed pulmonary complications. The extravascular lung water measured using PiCCO correlated significantly with the respiratory index. In the intubation group, both extravascular lung water and respiratory index were elevated 12 h after surgery and were even higher 24 h after surgery. The extravascular lung water measured using PiCCO reflects the level of postoperative pulmonary edema and predicts the pulmonary complications induced by esophagectomy with extended lymph node dissection.

Involvement of IL-18 and Soluble Fas in Patients with Postoperative Hepatic Failure

We measured the levels of tumor necrosis factor alpha (TNF-α), interleukins (IL)-6 and -18, and soluble Fas (sFas) in 11 patients with postoperative hepatic failure and assessed whether IL-18-mediated apoptosis is involved in the onset of liver dysfunction. The serum TNF-α, IL-18, and sFas levels were significantly higher in patients with sepsis as a complication than in those without sepsis. The TNF-α and IL-18 levels were significantly higher in nonsurvivors than in survivors. Significant correlations were observed between TNF-α and IL-6, between TNF-α and IL-18, and between TNF-α and sFas levels. These results showed that Fas-mediated hepatocyte apoptosis functions as an important mechanism responsible for the onset of postoperative hepatic failure in humans. They especially suggested that IL-18 and TNF-α function both as apoptosis-promoting factors and as apoptosis-inhibiting factors, depending on the conditions to which hepatocytes are subjected.

A Case Report of Hepatorenal Syndrome Treated With Plasma Diafiltration (Selective Plasma Filtration with Dialysis)

Abstract:  Plasma diafiltration (PDF) (selective plasma filtration with dialysis) is blood purification therapy in which simple plasma exchange is performed using a membrane plasma separator (Evacure EC‐2A) while dialysate flows outside of the hollow‐fibers. A 74‐year old man with hepatorenal syndrome underwent four sessions of PDF and three sessions of HDF. Finally he recovered from hepatorenal syndrome. In this therapy, the levels of total bilirubin, interleukin‐18, creatinine, and cystatin C were significantly reduced. On the other hand, there were no significant differences in the total protein and albumin levels before and after PDF. PDF may be one of the most useful blood purification therapies for hepatorenal syndrome in terms of medical economics.

Pharmacokinetics of Nafamostat Mesilate During Continuous Hemodiafiltration with a Polyacrylonitrile Membrane

Abstract: We studied the pharmacokinetics of nafamostat mesilate (NM) used as an anticoagulant in continuous hemodiafiltration (CHDF) with a polyacrylonitrile (PAN) membrane used as the hemofilter. Six patients undergoing CHDF for multiple organ dysfunction syndrome (MODS) were chosen as subjects. The inlet NM concentration measured 24 h after the start of CHDF was significantly greater than that after 1 h (P = 0.0431). No significant difference was observed between the outlet NM concentration and the ultrafilter concentration at 1 h or 24 h after the start of CHDF. However, concentrations at 24 h differed significantly from concentrations at 1 h at all sites. Significant correlation was observed between the dose of NM and the outlet NM concentration (P = 0.0475). No statistical correlation was observed between the dose of catecholamines and the outlet NM concentration (P = 0.0985). This study is the first to disclose a mild but significant time‐dependent serum NM concentration in patients with MODS.

A case report of pediatric fulminant hepatitis treated with plasma diafiltration.

Abstract:  Plasma diafiltration (PDF) is blood purification therapy in which simple plasma exchange is performed with a membrane plasma separator while dialysate flows outside the hollow fibers. A 14‐year‐old boy with fulminant hepatitis underwent two sessions of PDF and one session of hemodiafiltration. We infused filtered replacement fluid for artificial kidneys at a dialysate flow rate of 600 mL/h and a replacement flow rate of 450 mL/h. We infused fresh frozen plasma (1200 mL) and 25% albumin solution (50 mL) intravenously over 8 h. Each PDF session lasted 8 h. The patients total bilirubin, interleukin‐18, and cystatin C levels decreased with treatment, and he recovered from hepatic failure. PDF may be an extremely useful blood purification therapy for pediatric fulminant hepatitis in terms of both medical economics and cytokine removal.