Less invasive lumbopelvic fixation technique using a percutaneous pedicle screw system for unstable pelvic ring fracture in a patient with severe multiple traumas.

Pelvic ring fractures are defined as life-threatening injuries that can be treated surgically with external or internal fixation. The authors report on an 81-year-old woman with an unstable pelvic fracture accompanying multiple traumas that was successfully treated with a less invasive procedure. The patient was injured in a traffic accident and sustained a total of 20 fractures, including pelvic ring, bilateral rib, and lumbar transverse processes fractures, and multiple fractures of both upper and lower extremities. The pelvic ring fracture was unstable with fractures of the bilateral sacrum with right sacroiliac disruption, right superior and inferior pubic rami, left superior pubic ramus, and ischium. During emergency surgery, bilateral external fixation was applied to the iliac crest to stabilize the pelvic ring. Second and third surgeries were performed 11 and 18 days after the first emergency surgery, respectively, to treat the multiple fractures. At the third surgery, the pelvic ring fracture was stabilized surgically using a less invasive posterior fixation technique. In this technique, 2 iliac screws were inserted on each side following an 8-cm midline posterior incision from the S-1 to S-3 spinous process, with the subcutaneous tissue detached from the fascia of the paraspinal muscles. The S-2 spinous process was removed and 2 rods were connected to bilateral iliac screws to stabilize the bilateral ilium in a switchback fashion. A crosslink device was applied to connect the 2 rods at the base of the S-2 spinous process. Following pelvic fixation, percutaneous pedicle screws were inserted into L-4 and L-5 vertebral bodies on both sides, and connected to the cranial rod connecting the bilateral iliac screws, thus completing the lumbopelvic fixation. The postoperative course was favorable with no postoperative complications. At the 10-month follow-up, bone union had been achieved at the superior ramus of the pubis, the patient did not complain of pain, and her activities of daily life returned to preinjury status. Unstable pelvic ring fractures need to be sufficiently stabilized for good surgical outcome. However, to avoid postoperative complications, a less invasive treatment is preferred, particularly in cases with poor general condition. This procedure is less invasive and provides sufficient stabilization to the unstable pelvic ring fracture, and thus is the ideal surgical procedure for such cases.

The effects of early high-volume hemofiltration on prolonged cardiac arrest in rats with reperfusion by cardiopulmonary bypass: a randomized controlled animal study.

BACKGROUND: It is not yet clear whether hemofiltration can reduce blood cytokine levels sufficiently to benefit patients who suffer prolonged cardiac arrest (CA) treated with cardiopulmonary bypass (CPB). We sought to assess effects of high-volume and standard volume continuous veno-venous hemofiltration (CVVH) on blood cytokine levels and survival in a rat model of prolonged CA treated with CPB. METHODS: Sprague-Dawley male rats were subjected to 12 min of asphyxia to induce CA. CPB was initiated for resuscitation of animals and maintained for 30 min. Twenty-four rats were randomly assigned into three groups: without CVVH treatment (sham); standard volume CVVH at a filtration rate of 35-45 mL/kg/h; and high-volume hemofiltration (HVHF, 105-135 mL/kg/h). Hemofiltration was started simultaneously with CPB and maintained for 6 h. Plasma TNFα and IL-6 levels were measured at baseline, 0.5, 1, 2, 3, and 6 h after reperfusion. Survival time, neurological deficit score, and hemodynamic status were assessed. RESULTS: All animals survived over 6 h and died within 24 h. There were no significant differences in survival time (log-rank test, sham vs. CVVH; p = 0.49, sham vs. HVHF; p = 0.33) or neurological deficit scores (ANOVA, p = 0.14) between the groups. There were no significant differences in blood cytokine levels between the groups. Mean blood pressure in sham group animals increased to 1.5-fold higher than baseline levels at 30 min. HVHF significantly reduced blood pressure to 0.7-fold of sham group (p < 0.01). CONCLUSIONS: There was no improvement in mortality, neurological dysfunction, TNFα, or IL-6 levels in rats after prolonged CA with CPB on either hemofiltration group when compared to the sham group.

Developing dual hemofiltration plus cardiopulmonary bypass in rodents.

BACKGROUND: Emerging therapies for prolonged cardiac arrest (CA) include advanced circulatory interventions like emergency cardiopulmonary bypass (ECPB) and continuous venovenous hemofiltration (CVVHF). However, preclinical studies are limited because of the absence of a practical method of using CVVHF along with ECPB in rodents. METHODS: We modified a CA model with ECPB resuscitation to include the CVVHF circuit. Adult rats were cannulated via the femoral artery or vein and the jugular vein for the ECPB circuit. A new circuit for CVVHF was added to allow ECPB and CVVHF to be started simultaneously. CVVHF blood flow at 3 mL/min could be controlled with a screw clamp during ECPB. After cessation of ECPB, the CVVHF flow was maintained using a roller pump. The filtration rate was controlled at 40 mL/h/kg in the standard volume of CVVHF and 120 mL/h/kg in the high volume (HV) of CVVHF. The driving force of hemofiltration was evaluated by monitoring transmembrane pressure and filter clearance (FCL). RESULTS: Transmembrane pressure in both groups was stable for 6 h throughout CVVHF. FCL of blood urea nitrogen and potassium in the standard volume group was significantly less than the HV group (P < 0.01). FCL of blood urea nitrogen and potassium was stable throughout the CVVHF operation in both groups. CONCLUSIONS: We developed a method of CVVHF along with ECPB in rodents after CA. We further demonstrated the ability to regulate both standard and HV filtration rates.

Continuous hemodiafiltration with a cytokine-adsorbing hemofilter in patients with septic shock: a preliminary report.

BACKGROUND/AIM: We investigated the clinical efficacy of continuous hemodiafiltration (CHDF) with AN69ST hemofilter (AN69ST-CHDF) in patients with septic shock. MATERIALS AND METHODS: A prospective, multicenter, single-arm study was conducted. Patients with sepsis and shock defined by hyperlactemia were enrolled. The patients were treated with CHDF and in accordance with the Surviving Sepsis Campaign guidelines (SSCG). RESULTS: Thirty-four patients were enrolled. On ICU admission, the mean blood IL-6 level was 44,800 ± 77,700 pg/ml, and the mean blood lactate level was 69.0 ± 49.4 mg/dl. Both the mean blood IL-6 and lactate levels had significantly decreased to normal ranges after 72 h of AN69ST-CHDF. Though the mean APACHE II score was 32.7 ± 9.8, 28-day survival was 73.5%. CONCLUSION: The current study suggested that adding AN69ST-CHDF to the treatments outlined in the SSCG might lead to good outcomes for patients with septic shock, probably via the removal of cytokines from the bloodstream.

Efficacy of series double continuous hemodiafiltration using two polymethyl methacrylate membrane hemofilters for patients with hypercytokinemia.

Continuous hemodiafiltration using a hemofilter made from a membrane with cytokine adsorption properties is thought to be effective to remove cytokines in septic patients. In order to enhance cytokine removal capacity by increasing adsorption area, we devised a double polymethyl methacrylate continuous hemodiafiltration method, which involves serial connection of two polymethyl methacrylate membrane hemofilters, and we report clinical efficacy with this method. Of 74 patients who underwent continuous hemodiafiltration and had interleukin-6 blood levels measured during their ICU stay between March 2010 and June 2012, 13 patients with hypercytokinemia (interleukin-6 blood level >900 pg/mL) underwent series double continuous hemodiafiltration to be treated for hypercytokinemia. Cytokine reduction rate and clinical efficacy were compared between those 13 patients and those with a similar pathological condition who underwent continuous hemodiafiltration using the single polymethyl methacrylate membrane hemofilter. Interleukin-6 blood levels 6 h after continuous hemodiafiltration initiation increased in the single continuous hemodiafiltration group from 17040 ± 33660 pg/mL to 26290 ± 66250 pg/mL; however, interleukin-6 blood level significantly decreased in the series double continuous hemodiafiltration group from 20220 ± 29120 pg/mL to 6790 ± 10820 pg/mL. Interleukin-6 reduction rate during the period between initiation and 6 h after initiation of continuous hemodiafiltration was significantly higher in the series double continuous hemodiafiltration group(63.5 ± 38.9%) compared to that of the single continuous hemodiafiltration group (-342 ± 1306%)(P = 0.039). Series double continuous hemodiafiltration using two polymethyl methacrylate hemofilters with cytokine adsorbing capacity is effective to remove cytokine in hypercytokinemic septic patients.

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.

Tumor necrosis factor -308 polymorphism (rs1800629) is associated with mortality and ventilator duration in 1057 Caucasian patients.

PURPOSE: Management of sepsis in critically ill patients remains difficult and requires prolonged intensive care. Genetic testing has been proposed as a strategy to identify patients at risk for adverse outcome of critical illnesses. Therefore, we wished to determine the influence of heredity on predisposition to poor outcome and on duration of ventilator support of intensive care unit (ICU) patients. METHODS: A study was conducted from July 2001 to December 2005 in heterogeneous population of patients from 12 US ICUs represented by the Genetic Predisposition to Severe Sepsis (GenPSS) archive. In 1057 Caucasian critically ill patients with SAPS II probability of survival of >0.2 in the US, six functional single nucleotide polymorphisms in relation to inflammatory cytokines and innate immunity (rs1800629, rs16944, rs1800795, rs1800871, rs2569190, and rs909253) were evaluated in terms of mortality and ventilator free days. RESULTS: The AA homozygote of TNF(-308) (rs1800629) was most over-represented in the deceased patient group (P=0.015 with recessive model). The carriage of the TNF(-308)*AA genotype showed significantly higher odds ratio of 2.67(1.29-5.55) (P=0.008) after adjustment with the covariates. However, the presence of 1, 2, or 3 acute organ dysfunctions was larger prognostic factors for the adverse outcome (OR(95%CI)=2.98(2.00-4.45), 4.01(2.07-7.77), or 19.95(4.99-79.72), P<0.001 for all). Kaplan-Mayer plot on ventilator duration of TNF(-308)*AA patient significantly diverged from that of TNF(-308)*(GG+GA) ((AA v GG+GA), Adjusted HR(95%CI)=2.53(1.11-5.79) with Cox regression, P=0.028). CONCLUSIONS: TNF(-308)*AA is significantly associated with susceptibility to adverse outcome and to longer ventilator duration. Therefore, heredity likely affects both predisposition to ICU prognosis as well as the resource utilization.

Correlation between high blood IL-6 level, hyperglycemia, and glucose control in septic patients.

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.

Treatment of septic shock with continuous HDF using 2 PMMA hemofilters for enhanced intensity.

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, EI group; 2 extracorporeal CHDF circuits using the hemofilter with a larger membrane area of 2.1 m2). Other patients undergoing conventional PMMA-CHDF and matched for severity with the EI group, comprised a matched conventional group (MC group; using a PMMA membrane hemofilter with a membrane area of 1.0 m2; 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 EI 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.

Association of angiotensin II type 1 receptor-associated protein gene polymorphism with increased mortality in 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.

Leucyl/cystinyl aminopeptidase gene variants in septic shock.

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 serum 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.

Outcome prediction in sepsis combined use of genetic polymorphisms - A study in Japanese population.

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, IL1ß -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 IL1ß -31) enabled more accurate prediction of ICU mortality (ROC-AUC=0.80). Significant association of two genetic polymorphisms, TNF -308 and IL1ß -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.

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.

Continuous hemodiafiltration using a polymethyl methacrylate membrane hemofilter for severe acute pancreatitis.

It has been reported that hypercytokinemia plays a pivotal role in the pathophysiology of severe acute pancreatitis (SAP). In our previous reports, continuous hemodiafiltration (CHDF) using a polymethyl methacrylate (PMMA) membrane hemofilter (PMMA-CHDF) was found to be capable of efficiently removing various cytokines from circulating blood. The present study was undertaken to evaluate the efficacy of PMMA-CHDF aimed at cytokine removal in the treatment of SAP. Patients with blood IL-6 level > or =400 pg/ml were considered indicated for initiation of PMMA-CHDF based on our previous data. Among the patients enrolled in the present study, there were significant differences in APACHE II sore, JMHLW (Japanese Ministry of Health, Labour, and Welfare) severity score, Ranson score, blood lactate level on ICU admission, and length of ICU stay between patients with blood IL-6 levels > or =400 pg/ml and patients with levels < 400 pg/ml. Using this PMMA-CHDF initiation criterion, PMMA-CHDF was performed on 82 SAP patients. Mean blood IL-6 level, which was 998 pg/ml on admission to the ICU, was significantly lower (335 pg/ml) after 3 days treatment of PMMA-CHDF (p < 0.01). In addition, heart rate, blood lactate level, and intra-abdominal pressure also decreased significantly (p < 0.01). At the time of weaning from PMMA-CHDF, blood IL-6 level had decreased to 99 pg/ml. The mortality rate among patients who received PMMA-CHDF was 6.1%, and significantly lower than that of patients before the introduction of PMMA-CHDF under non-renal indication (25.0%). These findings suggest that PMMA-CHDF is effective for treatment of SAP and that it can be expected to contribute to improving the outcome of SAP patients.

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 continuous hemodiafiltration with a cytokine-adsorbing hemofilter in the treatment of acute respiratory distress syndrome.

BACKGROUND/AIMS: In the pathophysiology of acute respiratory distress syndrome (ARDS), the increase in capillary and alveolar permeability caused by various humoral mediators and resultant pulmonary interstitial edema play major roles. In this study, the efficacy of continuous hemodiafiltration using a cytokine-adsorbing hemofilter with a membrane made of polymethylmethacrylate (PMMA-CHDF) in the treatment of ARDS patients was investigated. MATERIALS AND METHODS: Fifty-one patients with a diagnosis of ARDS complicated by renal failure and without prior steroid therapy were enrolled in this study. Changes in respiratory index (RI), positive end-expiratory pressure, central venous pressure (CVP) and blood levels of TNFalpha, IL-6 and IL-8 before/after blood purification for 3 days as well as the cumulative water balance during the 3-day treatment and 28-day cumulative survival rate were compared between 2 patient groups. One group underwent PMMA-CHDF and the other intermittent hemodialysis (IHD) without water removal for elimination of metabolites and continuous hemofiltration (CHF) for fluid management. RESULTS: Blood purification for 3 days significantly decreased blood levels of cytokines and successfully removed water without changing CVP in the PMMA-CHDF group, but not in the IHD+CHF group. Significant correlations between changes in blood levels of cytokines (IL-6 and IL-8) and changes in RI were demonstrated in the PMMA-CHDF group. The 28-day cumulative survival rate in the PMMA-CHDF group (68.8%) was significantly higher than that in the IHD+CHF group (36.8%). CONCLUSIONS: Cytokine removal therapy with PMMA-CHDF is expected to be useful as a new therapeutic modality in ARDS patients for non-renal indications.

Association between lymphotoxin-alpha (tumor necrosis factor-beta) intron polymorphism and predisposition to severe sepsis is modified by gender and age.

OBJECTIVE: To investigate the significance of functional polymorphisms of inflammatory response genes by analysis of a large population of patients, both with and without severe sepsis, and representative of the diverse populations (geographic diversity, physician diversity, clinical treatment diversity) that would be encountered in critical care clinical practice. DESIGN: : Collaborative case-control study conducted from July 2001 to December 2005. SETTING: A heterogeneous population of patients from 12 U.S. intensive care units represented by the Genetic Predisposition to Severe Sepsis archive. PATIENTS: A total of 854 patients with severe sepsis and an equal number of mortality, age, gender, and race-matched patients also admitted to the intensive care unit without evidence of any infection (matched nonseptic controls). MEASUREMENTS AND MAIN RESULTS: We developed assays for six functional single nucleotide polymorphisms present before the first codon of tumor necrosis factor at -308, IL1B at -511, IL6 at -174, IL10 at -819, and CD14 at -159, and in the first intron of LTA (also known as tumor necrosis factor-B) at +252 (LTA[+252]). The Project IMPACT critical care clinical database information management system developed by the Society of Critical Care Medicine and managed by Tri-Analytics and Cerner Corporation was utilized. Template-directed dye-terminator incorporation assay with fluorescence polarization detection was used as a high-throughput genotyping strategy. Fifty-three percent of the patients were male with 87.3% and 6.4% of Caucasian and African American racial types, respectively. Overall mortality was 35.1% in both severe sepsis and matched nonseptic control patients group. Average ages (standard deviation) of the severe sepsis and matched nonseptic control patients were 63.0 (16.05) and 65.0 (15.58) yrs old, respectively. Among the six single nucleotide polymorphisms, LTA (+252) was most overrepresented in the septic patient group (% severe sepsis; AA 45.6: AG 51.1: GG 56.7, p = .005). Furthermore, the genetic risk effect was most pronounced in males, age >60 yrs (p = .005). CONCLUSIONS: LTA(+252) may influence predisposition to severe sepsis, a predisposition that is modulated by gender and age. Although the genetic influences can be overwhelmed by both comorbid factors and acute illness in individual cases, population studies suggest that this is an influential biological pathway modulating risk of critical illnesses.

TNF-alpha contributes to axonal sprouting and functional recovery following traumatic brain injury.

In response to a central nervous system (CNS) injury, microglia and astrocytes release tumor necrosis factor-alpha (TNF-alpha). This proinflammatory cytokine has been implicated in both neuronal cell death and survival. Here, we show that TNF-alpha is involved in the recovery of neuromotor function following traumatic brain injury. Composite neuroscore and accel rotarod were employed to measure neuromotor function. TNF-alpha-deficient (TNF-alpha(-/-)) mice showed no improvement in their locomotor function up to 28 days following controlled cortical impact brain injury. Although collateral sprouting of the unlesioned corticospinal tract, as assessed by retrograde biotin dextran amine labeling, at the cervical spinal cord was observed following injury in the wild-type mice, such changes were not induced in the TNF-alpha(-/-) mice at 4 weeks after injury. These results provide evidence that TNF-alpha is involved in neuroanatomical plasticity and functional recovery following CNS injury.

Clinical application of cytokine-related gene polymorphism analysis using a newly developed DNA chip in critically ill patients.

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-1beta -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.