中田 孝明

Background: Genetic variations contribute to septic shock mortality. To discover a novel locus, we performed in vitro genome-wide association studies (GWAS) and further tested the result in a cohort of septic shock patients. Methods: Two in vitro GWAS using a quantitative trait locus analysis of stimulated IL-6 production in lymphoblastoid cells from 60 individuals of European ancestry were performed. VPS13D rs6685273 was genotyped in European ancestry patients (n = 498). The VPS13D gene was silenced in vitro. Results: Two GWAS using lymphoblastoid cells identified the locus of VPS13D rs6685273 that was significant in the same direction in both GWAS. The VPS13D rs6685273 C allele was associated with increased IL-6 production. Patients with septic shock who had the VPS13D rs6685273 CC genotype had an increased 28-day mortality (p = 0.023) and more organ failure (p < 0.05) compared to the CT/TT genotypes. VPS13D in vitro gene silencing in the HeLa cell line increased IL-6 production. Furthermore, the rs6685273 genotype was associated with differential VPS13D splice variant expression. Conclusions: The VPS13D rs6685273 C allele was associated with increased IL-6 production in vitro. The patients with the VPS13D rs6685273 CC genotype had increased 28-day mortality and increased organ failure. VPS13D appears to regulate IL-6 production. (C) 2015 S. Karger AG, Basel

Subclavian arterial injury is rare and potentially life-threatening, particularly when it leads to arterial occlusion, causing limb ischemia, retrograde thromboembolization and cerebral infarction within hours after injury. Here we report a blunt trauma case with subclavian arterial injury, upper extremity ischemia, and the need for urgent treatment to salvage the limb and prevent cerebral infarction. A 41-year-old man had a left, open, mid-shaft clavicle fracture and left subclavian artery injury accompanied by a weak pulse in the left radial artery, decreased blood pressure of the left arm compared to the right, and left hand numbness. Urgent debridement and irrigation of the open clavicle fracture was followed by angiography for the subclavian artery injury. The left distal subclavian artery had a segmental dissection with a thrombus. Urgent endovascular treatment using a self-expanding nitinol stent successfully restored the blood flow and blood pressure to the left upper extremity. Endovascular treatment is a viable option for cases of subclavian artery injury where there is a risk of extremity ischemia and cerebral infarction.

Purpose: The final decision for discharge from the intensive care unit (ICU) is uncertain because it is made according to various patient parameters; however, it should be made on an objective evaluation. Previous reports have been inconsistent and unreliable in predicting post-ICU mortality. To identify predictive factors associated with post-ICU mortality, we analyzed physiological and laboratory data at ICU discharge. Methods: Patients admitted to our ICU between September 2012 and August 2013 and staying for critical care. 2 days were included. Sequential Organ Failure Assessment (SOFA) score; systemic inflammatory response syndrome score; white blood cell count; and serum C reactive protein, procalcitonin (PCT), interleukin-6 (IL-6), lactate, albumin, and hemoglobin levels were recorded. The primary end point was 90-day mortality after ICU discharge. Two hundred eighteen patients were enrolled (195 survivors, 23 non-survivors). Results: Non-survivors presented a higher SOFA score and serum PCT, and IL-6 levels, as well as lower serum albumin and hemoglobin levels. Serum PCT, albumin, and SOFA score were associated with 90-day mortality in multiple logistic regression analysis. Hosmer-Lemeshow test showed chi-square value of 6.96, and P value of 0.54. The area under the curve (95% confidence interval) was 0.830 (0.771-0.890) for PCT, 0.688 (0.566-0.810) for albumin, 0.861 (0.796-0.927) for SOFA score, and increased to 0.913 (0.858-0.969) when these were combined. Serum PCT level at 0.57 ng/mL, serum albumin at 2.5 g/dL and SOFA score at 5.5 predict 90-day mortality, and high PCT, low albumin and high SOFA groups had significantly higher mortality. Serum PCT and SOFA score were significantly associated with survival days after ICU discharge in Cox regression analysis. Conclusions: Serum PCT level and SOFA score at ICU discharge predict post-ICU mortality and survival days after ICU discharge. The combination of these two and albumin level might enable accurate prediction.

A decrease in the activity of proprotein convertase subtilisin/kexin type 9 (PCSK9) increases the amount of low-density lipoprotein (LDL) receptors on liver cells and, therefore, LDL clearance. The clearance of lipids from pathogens is related to endogenous lipid clearance; thus, PCSK9 may also regulate removal of pathogen lipids such as lipopolysaccharide (LPS). Compared to controls, Pcsk9 knockout mice displayed decreases in inflammatory cytokine production and in other physiological responses to LPS. In human liver cells, PCSK9 inhibited LPS uptake, a necessary step in systemic clearance and detoxification. Pharmacological inhibition of PCSK9 improved survival and inflammation in murine polymicrobial peritonitis. Human PCSK9 loss-of-function genetic variants were associated with improved survival in septic shock patients and a decrease in inflammatory cytokine response both in septic shock patients and in healthy volunteers after LPS administration. The PCSK9 effect was abrogated in LDL receptor (LDLR) knockout mice and in humans who are homozygous for an LDLR variant that is resistant to PCSK9. Together, our results show that reduced PCSK9 function is associated with increased pathogen lipid clearance via the LDLR, a decreased inflammatory response, and improved septic shock outcome.

Purpose: Interleukin 6 (IL-6) is a proinflammatory cytokine produced during infections. We hypothesized that IL-6 levels in the cerebrospinal fluid (CSF) would be elevated in bacterial meningitis and useful for diagnosing and predicting neurologic outcomes. Materials and methods: For the differentiation of bacterial meningitis, serum and CSF samples were obtained from patients with an altered level of consciousness. Patients were classified into 3 groups: bacterial meningitis, nonbacterial central nervous system disease, and other site sepsis. Results: Of the 70 patients included in this study, there were 13 in the bacterial meningitis group, 21 in the nonbacterial central nervous system disease group, and 36 in the other site sepsis group. The CSF IL-6 level was significantly higher in the bacterial meningitis group than in the other 2 groups (P < .0001). Of the 5 CSF parameters assessed, CSF IL-6 level exhibited the largest area under the receiver operating characteristic curve (0.962), with a cut-off value of 644 pg/mL (sensitivity, 92.3%; specificity, 89.5%). To examine a potential association between a high CSF level and neurologic outcome, CSF IL-6 levels were divided into 4 quartiles, and each level was compared with the frequency of a good neurologic outcome. The frequency of a good neurologic outcome was significantly lower in the highest CSF IL-6 quartile than in the other 3 quartiles (odds ratio, 0.18; 95% confidence interval, 0.05-0.69; P = .013). Conclusions: Measurement of the CSF IL-6 level is useful for diagnosing bacterial meningitis. (C) 2014 Elsevier Inc. All rights reserved.

The major symptoms of median arcuate ligament syndrome, celiac axis stenosis, or occlusion compressed by the median arcuate ligament include eating-associated abdominal pain and weight loss. Because celiac stenosis increases retrograde collateral blood flow from the superior mesenteric artery to the celiac artery via the pancreaticoduodenal arcade, a pancreaticoduodenal artery aneurysm could occur at a low incidence rate. Rupture of the pancreaticoduodenal artery aneurysm and hemorrhagic shock are rare. In this report, we present 3 cases of patients who had been well with no abdominal symptoms until the day of admission, when they experienced sudden-onset intra-abdominal hemorrhage and shock. These 3 patients were admitted to the emergency department, and contrast-enhanced computed tomography and radiographic selective catheter angiography revealed intra-abdominal hemorrhage, stenosis of the celiac arteries, and dilated pancreaticoduodenal arcade. Case 1 demonstrated severe hemorrhagic shock, whereas case 2 demonstrated moderate shock. We treated ruptured pancreaticoduodenal artery aneurysms with coil embolization. Case 3 demonstrated complete celiac occlusion and moderate hemorrhagic shock, and no aneurysm was detected.

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&lt . 0.001, monocyte p&lt . 0.05). TREM-1 expression on neutrophils had a significant inverse correlation with serum IL-6 level (r= -0.64, p&lt . 0.0001). Plasma sTREM-1 level in septic patients was significantly higher than that in SIRS patients (p&lt . 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&lt . 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. © 2012 Elsevier Ltd.

Background and Objective: Interleukin-8 (IL-8) is a central chemokine in acute respiratory distress syndrome (ARDS), and the IL-8 gene contains a functional single nucleotide polymorphism (SNP) -251A/T in its promoter region. We hypothesized that IL-8 -251A/T SNP is associated with PaO2/FiO(2) in critically ill patients. Methods: We conducted genetic-association studies in intensive care units at academic teaching centres using a derivation septic shock cohort (vasopressin and septic shock trial (VASST), n = 467) and a validation post-cardiopulmonary bypass surgery cohort (CPB, n = 739) of Caucasian patients. Patients in both cohorts were genotyped for IL-8 -251A/T. The primary outcome variable in both cohorts was the fraction of patients who had a PaO2/FiO(2) < 200. IL-8 mRNA expression was measured in genotyped lymphoblastoid cells in vitro. Results: The frequency of the patients with PaO2/FiO(2) < 200 was significantly greater in patients who had the AA genotype of -251A/T than in patients who had the AT or TT genotypes in both VASST (AA = 60.8% vs AT and TT = 53.8% and 48.0%, P = 0.038) and the CPB cohort (AA = 37.0% vs AT and TT = 27.0% and 26.0%, P = 0.039). Patients having the AA genotype had a higher probability to remain on mechanical ventilation (P = 0.047) in the first 14 days. Lymphoblastoid cells having the AA genotype had significantly higher IL-8 mRNA expression than cells having the AT or TT genotype (P = 0.022). Conclusions: Critically ill Caucasian patients who had the AA genotype of IL-8 -251A/T had an increased risk of PaO2/FiO(2) < 200. The AA genotype was associated with greater IL-8 mRNA expression than the AT or TT genotypes.

Introduction: Genetic variation in the Protein C gene (PROC) is associated with altered risk of adverse outcome for a number of diseases. Common single nucleotide polymorphisms (SNPs) in the promoter region and the adjacent 5' region of PROC are associated with Protein C expression. We tested the hypothesis that common SNPs (minor allele frequency >10%) between the frequently studied promoter SNPs -1654 (rs1799808) and -1641 (rs1799809), and the end of PROC intron 2 alter nuclear transcription factor binding. Materials and Methods: We used electrophoretic mobility shift assays with 25-mer oligonucleotides centered on each of the 10 SNPs assessed in this potential regulatory region of the Protein C gene to test for differential binding to nuclear factors isolated from Hep-G2 cells. Results: We found that the G-allele oligo of the intron 2 SNP rs2069915[G/A] bound nuclear factors more avidly than the A-allele (p = 1.9x10(-9), n = 24). Similarly, we found that the C-allele oligo of the intron 2 SNP rs2069916 [C/T] bound nuclear factors more avidly than the T-allele, (p = 3.7x10(-6), n = 19). Cold competition and supershift assays suggested that the protein differentially binding to the C-allele of rs2069916 was USF1. Notably, we observed minimal nuclear factor binding to oligos containing haplotypes of the previously reported -1654 and -1641 SNPs. Luciferase reporter assays that showed the A-T haplotype of rs2069915 and rs2069916 drives transcription significantly more than the C-G haplotype (t-test, P = 0.015, n = 12). Conclusion: Differential transcription factor binding occurs for common SNPs in the 5' intronic regions of PROC which may contribute to PROC regulation and reported PROC SNP - phenotype associations. (C) 2012 Elsevier Ltd. All rights reserved.

We hypothesized that lactate levels even within the normal range are prognostic and that low lactate levels predict a beneficial response to vasopressin infusion in septic shock. We conducted a retrospective analysis using the Vasopressin in Septic Shock Trial (VASST) as a derivation cohort (n = 665), then validated using another single-center septic shock cohort, St Paul's Hospital (SPH) cohort (n = 469). Lactate levels were divided into quartiles. The primary outcome variable was 28-day mortality in both cohorts. We used receiver operating characteristic (ROC) curve analysis to compare the prognostic value of lactate concentrations versus Acute Physiology and Chronic Health Evaluation II scores. We then explored whether lactate concentrations might predict beneficial response to vasopressin compared with noradrenaline in VASST. Normal lactate range is less than 2.3 mmol/L. At enrolment, patients in the second quartile (1.4 < lactate < 2.3 mmol/L) had significantly increased mortality and organ dysfunction compared with patients who had lactate <= 1.4 mmol/L (quartile 1) (P < 0.0001). Quartile 2 outcomes were as severe as quartile 3 (2.3 <= lactate < 4.4 mmol/L) outcomes. Baseline lactate values (area under the ROC curve = 0.63, 0.66; VASST, SPH) were as good as Acute Physiology and Chronic Health Evaluation II scores (area under the ROC curve = 0.66, 0.73; VASST, SPH) as prognostic indicators of 28-day mortality. Lactate concentrations of 1.4 mmol/L or less predicted a beneficial response in those randomized to vasopressin compared with noradrenaline in VASST (P < 0.05). Lactate concentrations within the "normal" range can be a useful prognostic indicator in septic shock. Furthermore, patients whose lactate level is less than or equal to 1.4 mmol/L may benefit from vasopressin infusion.

Introduction: The aim of the present study was to investigate the relationship between the blood IL-6 level, the blood glucose level, and glucose control in septic patients.Methods: This retrospective observational study in a general ICU of a university hospital included a total of 153 patients with sepsis, severe sepsis, or septic shock who were admitted to the ICU between 2005 and 2010, stayed in the ICU for 7 days or longer, and did not receive steroid therapy prior to or after ICU admission. The severity of stress hyperglycemia, status of glucose control, and correlation between those two factors in these patients were investigated using the blood IL-6 level as an index of hypercytokinemia.Results: A significant positive correlation between blood IL-6 level and blood glucose level on ICU admission was observed in the overall study population (n = 153 r = 0.24, P = 0.01), and was stronger in the nondiabetic subgroup (n = 112 r = 0.42, P &lt 0.01). The rate of successful glucose control (blood glucose level &lt 150 mg/dl maintained for 6 days or longer) decreased with increase in blood IL-6 level on ICU admission (P &lt 0.01). The blood IL-6 level after ICU admission remained significantly higher and the 60-day survival rate was significantly lower in the failed glucose control group than in the successful glucose control group (P &lt 0.01 and P &lt 0.01, respectively).Conclusions: High blood IL-6 level was correlated with hyperglycemia and with difficulties in glucose control in septic patients. These results suggest the possibility that hypercytokinemia might be involved in the development of hyperglycemia in sepsis, and thereby might affect the success of glucose control. © 2012 Nakamura et al. licensee BioMed Central Ltd.

Introduction: The aim of the present study was to investigate the relationship between the blood IL-6 level, the blood glucose level, and glucose control in septic patients. Methods: This retrospective observational study in a general ICU of a university hospital included a total of 153 patients with sepsis, severe sepsis, or septic shock who were admitted to the ICU between 2005 and 2010, stayed in the ICU for 7 days or longer, and did not receive steroid therapy prior to or after ICU admission. The severity of stress hyperglycemia, status of glucose control, and correlation between those two factors in these patients were investigated using the blood IL-6 level as an index of hypercytokinemia. Results: A significant positive correlation between blood IL-6 level and blood glucose level on ICU admission was observed in the overall study population (n = 153; r = 0.24, P = 0.01), and was stronger in the nondiabetic subgroup (n = 112; r = 0.42, P < 0.01). The rate of successful glucose control (blood glucose level < 150 mg/dl maintained for 6 days or longer) decreased with increase in blood IL-6 level on ICU admission (P < 0.01). The blood IL-6 level after ICU admission remained significantly higher and the 60-day survival rate was significantly lower in the failed glucose control group than in the successful glucose control group (P < 0.01 and P < 0.01, respectively). Conclusions: High blood IL-6 level was correlated with hyperglycemia and with difficulties in glucose control in septic patients. These results suggest the possibility that hypercytokinemia might be involved in the development of hyperglycemia in sepsis, and thereby might affect the success of glucose control.

Purpose: Cytokines play pivotal roles in the pathophysiology of severe sepsis/septic shock, and continuous hemodiafiltration using a polymethylmethacrylate membrane hemofilter (PMMA-CHDF) removes cytokines efficiently and continuously, mainly through adsorption to a hemofilter membrane. The aim of this study was to investigate the clinical efficacy of enhanced intensity PMMA-CHDF in treating refractory septic shock. Methods: Seventy-two septic shock patients admitted to the intensive care unit (ICU) underwent critical care including PMMA-CHDF We employed enhanced intensity PMMA-CHDF to improve the cytokine removal rate by increasing the hemofilter membrane area in 10 refractory septic shock patients (enhanced intensity group, El group; 2 extracorporeal CHDF circuits using the hemofilter with a larger membrane area of 2.1 m(2)). Other patients undergoing conventional PMMA-CHDF and matched for severity with the El group, comprised a matched conventional group (MC group; using a PMMA membrane hemofilter with a membrane area of 1.0 m(2); n=15). The case-control comparison was performed between the 2 groups. Results: Enhanced intensity PMMA-CHDF significantly increased mean arterial pressure by 23.8% in 1 hour (p=0.037), decreased the blood lactate level by 28.6% in 12 hours (p=0.006), and reduced blood IL-6 level in 24 hours (p=0.005). The ICU survival rate in the El group was significantly better than that in the MC group (60% vs. 13.3%, p=0.028). Conclusion: Enhanced intensity PMMA-CHDF may improve hemodynamics and survival rate in patients with refractory septic shock.

Objective: Angiotensin II and its postreceptor signaling are crucial in regulating vasomotor tone. The objective of this study was to test the hypothesis that single nucleotide polymorphisms in angiotensin II pathway genes alter outcome of septic shock. Design: Genetic association study and in vitro experiment. Setting: Intensive care units at academic teaching centers. Patients: Derivation and validation septic shock cohorts (n = 589 and n = 616, respectively) and a coronary artery bypass surgery cohort (n = 551). Interventions: Patients with septic shock in the derivation cohort were genotyped for tag single nucleotide polymorphisms: angiotensin-converting enzyme (six single nucleotide polymorphisms), angiotensin II receptor type 1 (five single nucleotide polymorphisms), and angiotensin II type 1 receptor-associated protein (three single nucleotide polymorphisms), which is a negative regulator of angiotensin II receptor type 1. Patients in the septic shock replication cohort and the coronary artery bypass graft cohort were genotyped for the angiotensin II type 1 receptor-associated protein rs11121816. Measurements and Main Results: The primary outcome variable was 28-day mortality. Secondary outcome variables were blood pressure and heart rate. Angiotensin II type 1 receptor-associated protein messenger RNA expression was measured in genotyped lymphoblastoid cells in vitro. Patients with septic shock patients the GG genotype of angiotensin II type 1 receptor-associated protein rs11121816 had increased 28-day mortality in the derivation cohort (54.8% vs. 41.4%; adjusted hazard ratio, 1.46; 95% confidence interval, 1.09-1.93; p =.010 [all ethnicities]; p =.050 [white]) and in the replication cohort (43.8% vs. 32.3%; hazard ratio, 1.42; 95% confidence interval, 1.03-1.98; p =.035 [all ethnicities]; p =.037 [white]). Patients having the GG genotype had decreased mean arterial pressure (98.3% of other genotype, p =.058 [derivation cohort]; 97.7%, p =.00060 [replication cohort]) and increased heart rate (104.1%, p = .023 [derivation cohort], 102.9%, p = nonsignificant [replication cohort]). GG genotype patients undergoing coronary artery bypass grafting had decreased postoperative mean arterial pressure and increased postoperative heart rate (p < .05). GG genotype lymphoblastoid cells had 2.0-fold higher angiotensin II type 1 receptor-associated protein messenger RNA expression (p < .05). Conclusions: For angiotensin II type 1 receptor-associated protein, the negative regulator of angiotensin II receptor type 1, the GG genotype of rs11121816 was associated with increased angiotensin II type 1 receptor-associated protein expression, decreased blood pressure, and increased heart rate as well as increased 28-day mortality in septic shock. (Crit Care Med 2011; 39: 1641-1648)

Background: Vasopressin is an essential peptide hormone regulating cardiovascular homeostasis and an adjunctive vasopressor therapy for septic shock. Methods: We tested for association between single nucleotide polymorphisms (SNPs) in vasopressin pathway genes and altered outcome in derivation (n = 589) and replication (n = 616) cohorts of patients with septic shock. The primary outcome was 28-day mortality and the secondary outcome was vasopressin clearance. In a third cardiac surgical cohort (n = 977), we tested for locus-specific heritability of scrum sodium concentrations. Results: Of 17 tested tag SNPs in five vasopressin pathway genes (arginine vasopressin [AVP], arginine vasopressin receptor 1A and 1B [AVPR1A, AVPR1B], leucyl/cystinyl aminopeptidase [LNPEP], and oxytocin receptor [OXTR]), rs18059 in LNPEP (also known as vasopressinase) was associated with 28-day mortality in the derivation cohort (P = .037). Therefore, we resequenced the 160-kb haplotype block encompassing the LNPEP gene, including rs18059, and genotyped the 230 identified SNPs in the derivation cohort. The strongest signal was found for LNPEP rs4869317 (adjusted P = .044). The rs4869317 TT genotype was associated with increased 28-day mortality in the derivation cohort (51.0% [TT] vs 34.5% [AA/AT]; adjusted hazard ratio [HR], 1.58; 95% CI, 1.21-2.06; P = .00073) and the replication cohort (38.6% vs 29.6%; HR, 1.36; 95% CI, 1.03-1.80; P = .030). We found that the TT genotype was associated with increased plasma vasopressin clearance (P = .028), and the rs4869317 genotype accounted for 80% of the variance of serum sodium concentrations (locus-specific heritability) in cardiac surgical patients. Conclusions: The genetic variation in LNPEP (vasopressinase) is associated with 28-day mortality in septic shock and is associated with biologic effects on vasopressin clearance and serum sodium regulation. Further confirmation in additional cohorts is required. CHEST 2011; 139(5):1042-1049

Genetic polymorphisms have recently been found to be related to clinical outcome in septic patients. The present study investigated to evaluate the influence of genetic polymorphisms in Japanese septic patients on clinical outcome and whether use of genetic polymorphisms as predictors would enable more accurate prediction of outcome. Effects of 16 genetic polymorphisms related to pro-inflammatory mediators and conventional demographic/clinical parameters (age, sex, past medical history, and APACHE II score) on ICU mortality as well as disease severity during ICU stay were examined in the septic patients (n = 123) admitted to the ICU between October 2001 and November 2007 by multivariable logistic regression analysis. ICU mortality was significantly associated with TNF -308GA, IL1 beta -31CT/TT, and APACHE II score. Receiver-operating characteristics (ROC) analysis demonstrated that, compared with APACHE II score alone (ROC-AUC = 0.68), use of APACHE II score and two genetic parameters (TNF -308 and IL1 beta -31) enabled more accurate prediction of ICU mortality (ROC-AUC = 0.80). Significant association of two genetic polymorphisms, TNF -308 and IL1 beta -31, with ICU mortality was observed in septic patients. In addition, combined use of these genetic parameters with APACHE II score may enable more accurate prediction of outcome in septic patients. (C) 2010 Elsevier Ltd All rights reserved.

Objective: To determine whether central venous pressure and fluid balance after resuscitation for septic shock are associated with mortality. Design: We conducted a retrospective review of the use of intravenous fluids during the first 4 days of care. Setting: Multicenter randomized controlled trial. Patients: The Vasopressin in Septic Shock Trial (VASST) study enrolled 778 patients who had septic shock and who were receiving a minimum of 5 mu g of norepinephrine per minute. Interventions: None. Measurements and Main Results: Based on net fluid balance, we determined whether one's fluid balance quartile was correlated with 28-day mortality. We also analyzed whether fluid balance was predictive of central venous pressure and furthermore whether a guideline-recommended central venous pressure of 8-12 mm Hg yielded a mortality advantage. At enrollment, which occurred on average 12 hrs after presentation, the average fluid balance was +4.2 L. By day 4, the cumulative average fluid balance was +11 L. After correcting for age and Acute Physiology and Chronic Health Evaluation II score, a more positive fluid balance at both at 12 hrs and day 4 correlated significantly with increased mortality. Central venous pressure was correlated with fluid balance at 12 hrs, whereas on days 1-4, there was no significant correlation. At 12 hrs, patients with central venous pressure <8 mm Hg had the lowest mortality rate followed by those with central venous pressure 8-12 mm Hg. The highest mortality rate was observed in those with central venous pressure >12 mm Hg. Contrary to the overall effect, patients whose central venous pressure was <8 mm Hg had improved survival with a more positive fluid balance. Conclusions: A more positive fluid balance both early in resuscitation and cumulatively over 4 days is associated with an increased risk of mortality in septic shock. Central venous pressure may be used to gauge fluid balance <= 12 hrs into septic shock but becomes an unreliable marker of fluid balance thereafter. Optimal survival in the VASST study occurred with a positive fluid balance of approximately 3 L at 12 hrs. (Crit Care Med 2011; 39: 259-265)

Introduction: Interleukin 17A (IL17A) plays a key role in host defense against microbial infection including Gram-positive bacteria. Genetic factors contribute to the host defense, but the role of IL17A single nucleotide polymorphisms (SNPs) has not yet been investigated in severe sepsis. Therefore, we hypothesized that SNPs in the IL17A gene alter susceptibility to infection and clinical outcome of severe sepsis. Methods: We tested for the association of IL17A SNPs with susceptibility to infection and clinical outcome of severe sepsis using two cohorts of European ancestry (derivation cohort, St Paul's Hospital (SPH), n = 679; validation cohort, Vasopressin and Septic Shock Trial (VASST), n = 517). The primary outcome variable was susceptibility to Gram-positive bacterial infection. The secondary outcome variable was 28-day mortality. Results: Of four tested IL17A tag SNPs (rs4711998, rs8193036, rs2275913, rs1974226), rs1974226 SNP was associated with altered susceptibility to Gram-positive infection in the derivation SPH cohort (corrected P = 0.014). Patients having the rs1974226 GG genotype were more susceptible to Gram-positive infection, compared to AG/AA genotype in the two cohorts of severe sepsis (SPH, P = 0.0036, odds ratio (OR) 2.19, 95% confidence interval (CI) 1.28-3.72; VASST, P = 0.011, OR 1.95, 95% CI 1.16-3.27) and in the subgroup having lung infection (P = 0.017, OR 1.90, 95% CI 1.12-3.21). Furthermore, the IL17A rs1974226 G allele was associated with increased 28-day mortality in two cohorts (SPH, adjusted OR 1.44, 95% CI 1.04-2.02, P = 0.029; VASST, adjusted OR 1.67, 95% CI 1.17-2.40, P = 0.0052). Conclusions: IL17A genetic variation is associated with altered susceptibility to Gram-positive infection and 28-day mortality of severe sepsis.

Mutations in IRAK4 have been associated with recurrent Gram-positive infections in children. Given the central role of IRAK4 in innate immunity signaling, we hypothesized that common genetic variants of IRAK4 may be associated with prevalence of Gram-positive infection in critically ill adults. Haplotype clade tag single nucleotide polymorphisms (SNPs) of the IRAK4 gene were selected and genotyped in a cohort of 1,029 critically ill patients with systemic inflammatory response syndrome (SIRS). We found that a haplotype clade tagged by the A allele of the htSNP G29429A (Ala428Thr) was associated with increased relative risk of Gram-positive infection at admission to ICU (RR = 1.2, p < 0.05). Furthermore, the 29429A allele was associated with decreased lymphoblastoid cell response to CpG (as measured by IL-6 production) (raw values +/- 95% CI 40.3 +/- 32.3 vs. 85.8 +/- 29.4 pg/ml; log-transformed values +/- 95% CI 1.13 +/- 0.37 vs. 1.55 +/- 0.18, p < 0.04). We also found that IRAK4-deficient fibroblasts transfected with an IRAK4 expression plasmid containing the 29429A allele produced less IL-6 in response to lipopolysaccharide (p = 0.07). Our data suggest that the IRAK4 haplotype clade marked by 29429A (428Thr) alters susceptibility to Gram-positive bacteria, by decreasing cellular response to TLR ligands. Copyright (C) 2011 S. Karger AG, Basel

Rationale: The CysGlyGln haplotype of the beta(2)-adrenergic receptor gene (ADRB2) is functional and associated with altered responses to adrenergic agonists in patients with asthma. Whether this functional haplotype alters outcome in patients receiving adrenergic agonists in septic shock is unknown. Objectives: To determine whether genetic variation of ADRB2 influences outcome in septic shock. Methods: Two cohorts of patients with septic shock were studied: a single center (St. Paul's Hospital [SPH]) cohort (n = 589) and the Vasopressin and Septic Shock Trial (VASST) cohort (n = 616). The A allele of the rs1042717 G/A polymorphism is in complete linkage disequilibrium with the CysGlyGln haplotype of ADRB2; therefore, rs1042717 was genotyped. Modulation by norepinephrine and salbutamol of IL-6 production by stimulated in vitro lymphoblastoid cells was measured by genotype. Measurements and Main Results: Patients who had the AA genotype of rs1042717 displayed increased 28-day mortality in SPH (adjusted hazard ratio, 2.23; 95% confidence interval, 1.33-3.72; P = 0.0022), and this result was replicated in VASST (adjusted hazard ratio 2.82; 95% confidence interval, 1.56-5.09; P = 0.0006). This genotypic effect was eliminated in patients treated with acute low-dose corticosteroids. In all patients, the AA genotype was associated with more organ dysfunction. Patients with the AA genotype had a higher heart rate (SPH; P < 0.05; VASST; P < 0.05) and required a higher norepinephrine dose over Days I through 3 (VASST, P < 0.05). The AA genotype was associated with decreased norepinephrine and salbutamol inhibition of IL-6 production by stimulated lymphoblastoid cells in vitro (P < 0.05). Conclusions: The AA genotype of ADRB2 rs1042717, identifying homozygotes for the CysGlyGln haplotype, was associated with increased mortality and more organ dysfunction in septic shock.

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 INF alpha, 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. Copyright (C) 2010 S. Karger AG, Basel

まれな外傷性腎梗塞を経験したので報告する。症例は61歳，男性。工場内で作業中に約8mの高さから転落し受傷。軽度の肺挫傷，肝損傷および右肋骨骨折，右橈骨骨折，骨盤骨折，右大腿骨骨折があり，造影CT検査にて右腎臓の造影不良を認めた。血管造影検査を行ったところ右腎動脈が起始部で途絶しており，血行再建を目的に開腹術を施行した。しかし右腎臓の鬱血は高度であったため右腎を摘出した。術後，肺炎による人工呼吸管理が長期化し退院まで100日を要した。外傷性梗塞腎に対する血行再建の成績は悪く，本症例のような血行動態が安定している片側腎梗塞の場合は治療方針として保存的療法を第1選択にすべきと思われた。

Objectives: To investigate the usefulness of analysis of single nucleotide polymorphism (SNP) using a newly developed DNA chip assay involving single base extension(SBE) and subsequent hybridization in cytokine-related genes in critical care patients. Design and methods: Genotyping was performed in 76 ICU patients admitted to the ICU. First, the DNA samples from 58 patients were subjected to PCR and SBE conditioning for DNA. Second, another 18 patients were subjected to genotyping for SNPs in IL-6 -596G/A, -572C/G, -174G/C, TNF-alpha -308G/A, -238G/A, IL-1 beta -511C/T and -31T/C by both TaqMan and DNA chip method, and by DNA direct sequencing prospectively. Results: First, PCR and SBE condition were established with initial sample sets, which were consistent with results by TaqMan method. Second, no difference was observed between two assay methods in prospective validation set. Conclusions: The genotyping assay using the new chip was developed and its usefulness was confirmed. (C) 2009 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Introduction: Most patients with cardiac arrest (CA) admitted to hospitals after successful cardiopulmonary resuscitation (CPR) are discharged with various degree of neurological deficits. To determine predictor of neurological outcome early and accurately, and to determine cutoff values, serum levels of protein S-100B and neuron-specific enolase (NSE) within 24 h after CA were assessed. Methods and results: A multicenter prospective observational study was conducted between May 2007 and April 2008 at three medical institutions in Japan on 107 consecutive non-traumatic CA patients with return of spontaneous circulation after CPR. Based on "best-ever achieved" Glasgow-Pittsburgh cerebral performance categories (CPC) score within 6 months after CA, patients were classified into a "poor neurological outcome" group (CPC3 to CPC5) (n = 67) and "favorable neurological outcome" group (CPC1 and CPC2) (n = 13). Blood was sampled on admission, at 6 and 24 h after CA. Serum S-100B and NSE in "poor outcome" group were higher than those in "favorable outcome" group (P < 0.01). On ROC analysis, area under the curve of S-100B was 0.85, 0.94 and 1.0, respectively. These were greater than those of NSE at all sampling points. The "100%-specific" cutoff values of S-100B predictive of poor neurological outcome were 1.41, 0.21, and 0.05 ng/mL, respectively. These values corresponded to sensitivities of 20.9%, 62.8%, and 100%, respectively, each of which was higher than those of NSE. Conclusions: S-100B is more reliable as an early predictor of poor neurological outcome within 24 h after CA than NSE and can be applied clinically. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

Background. None of the parameters can predict the deterioration of sepsis early enough. A new predictor allowing earlier detection of changes in septic patients' condition is indispensable. Methods. We examined whether cytokine-related mRNA expression in peripheral leukocytes, cytokine blood level, and monocyte human leukocyte antigen (HLA)-DR expression rate could be useful predictors of deterioration of sepsis. Twenty septic patients were enrolled. mRNA expression levels were quantified using real-time reverse transcriptase-polymerase chain reaction and assessed by percent changes during the first 24 h. Cytokine blood levels on admission and day 3 and monocyte HLA-DR expression rate on day 3 were also measured. Correlations between each of these parameters, and between these parameters and outcome were analyzed. Results. Among seven kinds of cytokines studied, only IL-10 mRNA level showed significant difference between survivors and non-survivors (P < 0.05). Mortality rate of interleukin (IL)-10 mRNA level upregulated group was significantly higher than that of IL-10 mRNA level down-regulated group (P < 0.05). HLA-DR expression rate in non-survivors were significantly lower than that in survivors (P < 0.05). Although IL-10 blood level on day 3 significantly correlated with HLA-DR expression on day 3(r = 0.54, P < 0.05), IL-10 blood level on admission did not correlate with it. Contrarily, the degree of up-regulation of IL-10 mRNA expression during the first 24 h significantly correlated with the degree of diminished HIA-DR expression on day 3 (r = 0.78, P < 0.001). Conclusions. Up-regulated IL-10 mRNA expression and diminished HLA-DR expression could be indicators of poor outcome. Furthermore, IL-10 mRNA expression measurement could predict the onset of immunoparalysis indicated by diminished HLA-DR expression earlier than IL-10 blood level measurement, leading to earlier commencement of the treatment. (C) 2008 Elsevier Inc. All rights reserved.