Synbiotics modulate gut microbiota and reduce enteritis and ventilator-associated pneumonia in patients with sepsis: a randomized controlled trial.

BACKGROUND: Commensal microbiota deteriorate in critically ill patients. The preventive effects of probiotic/synbiotic therapy on microbiota and septic complications have not been thoroughly clarified in patients with sepsis. The objective of this study was to evaluate whether synbiotics have effects on gut microbiota and reduce complications in mechanically ventilated patients with sepsis. METHODS: Sepsis patients who were mechanically ventilated in the intensive care unit (ICU) were included in this randomized controlled study. Patients receiving daily synbiotics (Bifidobacterium breve strain Yakult, Lactobacillus casei strain Shirota, and galactooligosaccharides) initiated within 3 days after admission (the Synbiotics group) were compared with patients who did not receive synbiotics (the No-Synbiotics group). The primary outcome was infectious complications including enteritis, ventilator-associated pneumonia (VAP), and bacteremia within 4 weeks from admission. The secondary outcomes included mortality within 4 weeks, fecal bacterial counts, and organic acid concentration. Enteritis was defined as the acute onset of continuous liquid stools for more than 12 h. RESULTS: Seventy-two patients completed this trial; 35 patients received synbiotics and 37 patients did not receive synbiotics. The incidence of enteritis was significantly lower in the Synbiotics than the No-Synbiotics group (6.3% vs. 27.0%; p < 0.05). The incidence of VAP was also significantly lower in the Synbiotics than the No-Synbiotics group (14.3% vs. 48.6%; p < 0.05). The incidence of bacteremia and mortality did not differ significantly between the two groups. In the analysis of fecal bacteria, the number of Bifidobacterium and Lactobacillus in the Synbiotics group was significantly higher than that in the No-Synbiotics group. In the analysis of fecal organic acids, total organic acid concentration, especially the amounts of acetate, were significantly greater in the Synbiotics group than in the No-Synbiotics group at the first week (p < 0.05). CONCLUSIONS: Prophylactic synbiotics could modulate the gut microbiota and environment and may have preventive effects on the incidence of enteritis and VAP in patients with sepsis. TRIAL REGISTRATION: UMIN, R000007633 . Registered on 29 September 2011.

Adhesive strength of medical polymer on anodic oxide nanostructures fabricated on biomedical ß-type titanium alloy.

Anodic oxide nanostructures (nanopores and nanotubes) were fabricated on a biomedical ß-type titanium alloy, Ti-29Nb-13Ta-4.6Zr alloy (TNTZ), by anodization in order to improve the adhesive strength of a medical polymer, segmented polyurethane (SPU), to TNTZ. TNTZ was anodized in 1.0M H3PO4 solution with 0.5 mass% NaF using a direct-current power supply at a voltage of 20V. A nanoporous structure is formed on TNTZ in the first stage of anodization, and the formation of a nanotube structure occurs subsequently beneath the nanoporous structure. The nanostructures formed on TNTZ by anodization for less than 3,600s exhibit higher adhesive strengths than those formed at longer anodization times. The adhesive strength of the SPU coating on the nanoporous structure formed on top of TNTZ by anodization for 1,200s improves by 144% compared to that of the SPU coating on as-polished TNTZ with a mirror surface. The adhesive strength of the SPU coating on the nanotube structure formed on TNTZ by anodization for 3,600s increases by 50%. These improvements in the adhesive strength of SPU are the result of an anchor effect introduced by the nanostructures formed by anodization. Fracture occurs at the interface of the nanoporous structure and the SPU coating layer. In contrast, in the case that SPU coating has been performed on the nanotube structure, fracture occurs inside the nanotubes.

Outcome prediction model for severe traumatic brain injury.

AIM: Treatment of severe traumatic brain injury is aided by better prediction of outcomes. The purpose of the present study was to develop and validate a prediction model using retrospective analysis of prospectively collected clinical data from two tertiary critical care medical centers in Japan. METHODS: Data were collected from 253 patients with a Glasgow Coma Scale score of <9. Within 24 h of their admission, 15 factors possibly related to outcome were evaluated. The dataset was randomly split into training and validation datasets using the repeated random subsampling method. A logistic regression model was fitted to the training dataset and predictive accuracy was assessed using the validation data. RESULTS: The best model included the variables age, pupillary light reflex, extensive subarachnoid hemorrhage, intracranial pressure, and midline shift. The estimated area under the curve for the model development data was 0.957, with a 95% confidence interval of 0.926-0.987, and that for validation data was 0.947, with a 95% confidence interval of 0.909-0.980. CONCLUSION: Our predictive model was shown to have high predictive value. It will be useful for review of treatment, family counseling, and efficient allocation of resources for patients with severe traumatic brain injury.

Actual treatments for out-of-hospital ventricular fibrillation at critical care medical centers in Osaka: a pilot descriptive study.

AIM: Although advanced treatments are provided to improve outcomes after out-of-hospital ventricular fibrillation, including shock-resistant ventricular fibrillation, the actual treatments in clinical settings have been insufficiently investigated. The aim of the current study is to describe the actual treatments carried out for out-of-hospital ventricular fibrillation patients, including shock-resistant ventricular fibrillation patients, at critical care medical centers. METHODS: We registered consecutive adult patients suffering bystander-witnessed out-of-hospital cardiac arrest of cardiac origin, for whom resuscitation was attempted by emergency medical service personnel, who had ventricular fibrillation as an initial rhythm, and who were transported to critical care medical centers in Osaka from March 2008 to December 2008. This study merged data on treatments after transportation, collected from 11 critical care medical centers in Osaka with the prehospital Utstein-style database. RESULTS: During the study period, there were 260 bystander-witnessed ventricular fibrillation arrests of cardiac origin. Of them, 252 received defibrillations before hospital arrival, 112 (44.4%) were transported to critical care medical centers, and 35 had shock-resistant ventricular fibrillation. At the critical care medical centers, 54% (19/35), 40% (14/35), and 46% (16/35) of shock-resistant ventricular fibrillation patients were treated with extracorporeal life support, percutaneous coronary interventions, and therapeutic hypothermia, respectively, but their treatments differed among institutions. Some patients with prolonged arrest without prehospital return of spontaneous circulation who received advanced treatments had neurologically favorable survival, whereas approximately two-thirds of shock-resistant ventricular fibrillation patients with advanced treatments did not. CONCLUSION: This pilot descriptive study suggested that actual treatments for prehospital ventricular fibrillation patients differed between critical care medical centers. Further studies are warranted to evaluate the effectiveness of in-hospital advanced treatments for ventricular fibrillation including shock-resistant ventricular fibrillation.

Recombinant human soluble thrombomodulin in sepsis-induced disseminated intravascular coagulation: a multicenter propensity score analysis.

PURPOSE: Evidence of efficacy and safety of, and especially mortality related to, recombinant human thrombomodulin (rhTM) treatment for sepsis-induced disseminated intravascular coagulation (DIC) is limited. We hypothesized that patients with sepsis-induced DIC receiving treatment with rhTM would have improved mortality compared with those with similar acuity who did not. METHODS: This retrospective cohort study conducted in three tertiary referral hospitals in Japan between January 2006 and June 2011 included all patients with sepsis-induced DIC who required ventilator management. Primary endpoint was in-hospital mortality, with duration of intensive care unit treatment, changes in DIC scores and rate of bleeding complications as secondary endpoints. Regression technique was used to develop a propensity model adjusted for baseline imbalances between groups. RESULTS: Eligible were 162 patients with sepsis-induced DIC; 68 patients received rhTM and 94 did not. Patients receiving rhTM had higher severity of illness according to baseline characteristics. After adjusting for these imbalances by stratified propensity score analysis, treatment with rhTM was significantly associated with reduced in-hospital mortality (adjusted hazard ratio, 0.45; 95 % confidential interval, 0.26-0.77; p = 0.013). An association between rhTM treatment and higher numbers of intensive care unit-free days, ventilator-free days, and vasopressor-free days were observed. DIC scores were significantly decreased in the rhTM group compared with the control group in the early period after rhTM treatment, whereas the incidence of bleeding-related adverse events did not differ between the two groups. CONCLUSIONS: Therapy with rhTM may be associated with reduced in-hospital mortality in adult mechanically ventilated patients with sepsis-induced DIC.

Recombinant human soluble thrombomodulin improves mortality and respiratory dysfunction in patients with severe sepsis.

BACKGROUND: Respiratory dysfunction associated with severe sepsis is a serious condition leading to poor prognosis. Activation of coagulation is a consequence of and contributor to ongoing lung injury in severe sepsis. The purpose of this study was to examine the efficacy of recombinant human soluble thrombomodulin (rhTM), a novel anticoagulant agent, for treating patients with sepsis-induced disseminated intravascular coagulation (DIC) in terms of mortality and respiratory dysfunction. METHODS: This study comprised 86 consecutive patients with sepsis-induced DIC who required ventilator management. The initial 45 patients were treated without rhTM (control group), and the following 41 patients were given rhTM (0.06 mg/kg/d) for 6 days (rhTM group). Patients were followed up for 90 days after study entry. Sequential Organ Failure Assessment (SOFA) score and lung injury score were recorded until 7 days after entry. RESULTS: The baseline characteristic of severity of illness was significantly higher in the rhTM group than in the control group. Nevertheless, 90-day mortality rate in the rhTM group was significantly lower than that in the control group (37% vs. 58%, p = 0.038). There was a significant difference in the serial change of SOFA score from baseline to day 7 between the two groups (p = 0.009). Both the respiratory component of the SOFA score and the lung injury score in the rhTM group were significantly lower compared with the control group (p = 0.034 and p < 0.001, respectively). CONCLUSIONS: rhTM may have a significant beneficial effect on mortality and respiratory dysfunction in patients with sepsis-induced DIC. LEVEL OF EVIDENCE: III, therapeutic study.

Treatment effects of recombinant human soluble thrombomodulin in patients with severe sepsis: a historical control study.

INTRODUCTION: Cross-talk between the coagulation system and inflammatory reactions during sepsis causes organ damage followed by multiple organ dysfunction syndrome or even death. Therefore, anticoagulant therapies have been expected to be beneficial in the treatment of severe sepsis. Recombinant human soluble thrombomodulin (rhTM) binds to thrombin to inactivate coagulation, and the thrombin-rhTM complex activates protein C to produce activated protein C. The purpose of this study was to examine the efficacy of rhTM for treating patients with sepsis-induced disseminated intravascular coagulation (DIC). METHODS: This study comprised 65 patients with sepsis-induced DIC who required ventilatory management. All patients fulfilled the criteria of severe sepsis and the International Society on Thrombosis and Haemostasis criteria for overt DIC. The initial 45 patients were treated without rhTM (control group), and the following 20 consecutive patients were treated with rhTM (0.06 mg/kg/day) for six days (rhTM group). The primary outcome measure was 28-day mortality. Stepwise multivariate Cox regression analysis was used to assess which independent variables were associated with mortality. Comparisons of Sequential Organ Failure Assessment (SOFA) score on sequential days between the two groups were analyzed by repeated measures analysis of variance. RESULTS: Cox regression analysis showed 28-day mortality to be significantly lower in the rhTM group than in the control group (adjusted hazard ratio, 0.303; 95% confidence interval, 0.106 to 0.871; P = 0.027). SOFA score in the rhTM group decreased significantly in comparison with that in the control group (P = 0.028). In the post hoc test, SOFA score decreased rapidly in the rhTM group compared with that in the control group on day 1 (P < 0.05). CONCLUSIONS: We found that rhTM administration may improve organ dysfunction in patients with sepsis-induced DIC. Further clinical investigations are necessary to evaluate the effect of rhTM on the pathophysiology of sepsis-induced DIC.

Incidence and outcomes of out-of-hospital cardiac arrest with shock-resistant ventricular fibrillation: Data from a large population-based cohort.

BACKGROUND: The increasing survival rates after out-of-hospital cardiac arrests (OHCA) are due mainly to improvements in the first 3 steps of the chain of survival. The aim of this study was to describe the temporal trends of OHCA incidence and outcomes with shock-resistant ventricular fibrillation (VF) requiring advanced life support procedures. METHODS: All our subjects were persons aged 18 years or more who had suffered OHCA of presumed cardiac etiology, were witnessed by bystanders, treated by emergency medical service (EMS), and had VF as initial rhythm. Our study was conducted in Osaka Prefecture, Japan from May 1, 1998 through December 31, 2006. Data were collected by EMS personnel using an Utstein-style database. We evaluated the temporal trends of incidence and outcomes of shock-resistant VF. RESULTS: During the study period, there were 8782 witnessed OHCA cases of presumed cardiac etiology. Among them, 1733 had VF as an initial rhythm, 392 of whom were shock-resistant. While the age-adjusted annual incidence of witnessed VF increased from 2.0 to 3.3 per 100,000 inhabitants, that of shock-resistant VF underwent little change during the study period. The proportion of shock-resistant VF among witnessed VF decreased from 37.0% to 19.0%. Neurologically intact 1-month survival rates after shock-resistant VF remained low at 5.6% even in 2006. CONCLUSION: The actual incidence of shock-resistant VF has remained unchanged, and their outcomes continue to be dismal. Further efforts are required to reduce the mortality rates of such shock-resistant VF to achieve improved survival after OHCA.

Acute cerebral blood flow variations after human cardiac arrest assessed by stable xenon enhanced computed tomography.

In this study, changes in cerebral blood flow (CBF) during acute phase after cardiopulmonary arrest (CPA) were examined in patients using stable Xenon enhanced computed tomography (Xe-CT). All patients (8) were stabilized hemodynamically within 4 hours after admission, and Xe-CT was performed immediately after restoration of spontaneous circulation (ROSC) at 8, 24, 48, 96 and 168 hours after ROSC. The progress of patients was monitored in other hospitals and clinics after discharge. Neurological outcomes were evaluated using the Glasgow outcome scale (GOS) 6 months after admission, and scores were compared against changes in CBF. Patients were grouped by prognosis. Four patients belonged to Group A (good recovery) and Group B (2 severely disabled, 2 in persistent vegetative state). The pattern of change in CBF after ROSC was found to be significantly different between Groups A and B (p <0.05). The CBF ratio relative to normal controls was higher in Group B than Group A within 48 hours after ROSC. However, at 48, 96, and 168 hours after ROSC, the opposite was observed: The CBF ratio was significantly higher in Group A than Group B (p<0.05). Based on these results, we concluded that CBF in the patients who survived after CPA changed remarkable especially within the first week. Furthermore, patients with abnormally low CBF that returns to supernormal within the first 48 hours following CPA can be expected to recover well neurologically.

Mismatch recovery of regional cerebral blood flow and brain temperature during reperfusion after prolonged brain ischemia in gerbils.

BACKGROUND: Recovery of cerebral reperfusion after stroke or cardiac arrest can take a long time. We aimed to identify differences in the postischemic recovery of physiologic parameters between short and prolonged brain ischemia. METHODS: Eighteen Mongolian gerbils were assigned to one of three groups: 5-minute (G5), 15-minute (G15), or 30-minute (G30) ischemia. With the use of our original microspectroscopy system, global ischemic reperfusion was performed. We measured changes in regional cerebral blood flow (r-CBF), microvessel diameter, and brain temperature (BrT) simultaneously. We also monitored somatosensory evoked potentials (SEPs) to evaluate electrophysiologic response. RESULTS: Both G5 and G15 showed concurrent recovery of r-CBF and BrT with hyperemia and hyperthermia, respectively, 10 to 15 minutes after reperfusion. The increase in BrT was <1 degree C and recovered to baseline within 60 minutes after reperfusion. In G30, recovery of r-CBF was significantly delayed relative to that of BrT. The increase in BrT was >2 degrees C, peaking approximately 15 minutes after reperfusion, and then maintained increases of >1 degree C for 120 minutes. SEPs in G5 and G15 showed concomitant recovery with that of r-CBF, whereas SEP recovery in G30 was delayed relative to that of r-CBF, eventually disappearing. All except one of the G30 gerbils died within 24 hours, but all in G5 and G15 survived. CONCLUSIONS: These results suggest that mismatch recovery of r-CBF and BrT after prolonged ischemia initiates metabolic derangement in brain tissue, leading to the electrochemical dysfunction and mortality.

Synergistic effects of recombinant human soluble thrombomodulin and fluid-volume resuscitation in a rat lethal crush injury model.

Severe crush injury results in a high mortality rate because of acute circulatory failure and hyperkalemia. The purpose of this study was to evaluate whether administration of prophylactic-recombinant human soluble thrombomodulin (rhsTM) and/or fluid-volume resuscitation before reperfusion attenuates severe crush injury in rats. Both hindlimbs of anesthetized rats were compressed for 6 h under blocks weighing 3.5 kg each, followed by 3 h of reperfusion. In the first group, fluid resuscitation with normal saline (1 mL/kg/h) was performed throughout the experiment. In the second group, volume resuscitation treatment with normal saline (10 mL/kg/h) was initiated 60 min before the end of the crush period and was continued until the end of the experiment. In the third group, normal saline-resuscitation treatment plus rhsTM (3 mg/kg) was performed. In the fourth group, volume resuscitation treatment plus rhsTM was performed. Blood samples were collected 6 h after the end of the crush period. Complete blood count and platelets were measured. In addition, serum lactate, base deficit, serum potassium, creatine phosphokinase, blood urea nitrogen, creatinine, myoglobin, and some cytokines were evaluated. In another experiment, survival of each group was monitored for 72 h after the end of the crush period. Combined administration of rhsTM and volume resuscitation significantly decreased hemoconcentration and hyperkalemia. The serum interleukin-6 level and mortality were also significantly improved in the combination group compared with those in the other groups. We conclude that prophylactic combination of rhsTM administration and volume resuscitation may be an effective therapy for severe crush injury.

Enhanced expression of intracellular heme oxygenase-1 in deactivated monocytes from patients with severe systemic inflammatory response syndrome.

BACKGROUND: Monocyte deactivation is an important contributor to infectious susceptibility in critically ill patients. However, the mechanism of monocyte deactivation has not been fully elucidated. Recently, intracellular heme oxygenese-1 (HO-1), an anti-inflammatory heat-shock protein, was reported to be activated by Toll-like receptors (TLRs), and to inhibit inflammatory cytokine production such as that of TNF-alpha. In the present study, we evaluated the expression of intracellular HO-1 and TLRs in monocytes from patients with severe systemic inflammatory response syndrome (SIRS) and examined the role of HO-1 in monocyte deactivation. PATIENTS: Twenty-seven patients who fulfilled the criteria for severe SIRS and had a serum C-reactive protein (CRP) level >10 mg/dL were included in this study. The cause of SIRS was sepsis in 16 patients, trauma in 7, and other in 4. Expression of intracellular HO-1, surface TLR2 and TLR4, and intracellular cytokines (TNF-alpha, Interleukin-6) stimulated via TLR activation were measured in circulating monocytes by flow cytometry. Intracellular HO-1 expression was evaluated in normal monocytes stimulated with patient serum. Serum cytokine levels were also measured. Patient data were compared with data from healthy volunteers (n = 16). RESULTS: Cytoplasmic HO-1 was clearly detected by fluorescence microscopy. Expression of HO-1, TLR2, and TLR4 in monocytes was significantly enhanced in patients with severe SIRS compared with that in healthy volunteers, whereas intracellular TNF-alpha expression with peptidoglycan was significantly decreased (p < 0.05) in patients compared with that in healthy volunteers. HO-1 expression was significantly enhanced in normal monocytes stimulated with patient serum. Intracellular HO-1 levels were positively related to serum TNF-alpha levels in patients (r = 0.46). CONCLUSIONS: Expression of intracellular HO-1 and of TLRs was enhanced in deactivated monocytes from patients with SIRS. Increased production of intracellular HO-1 in response to serum factors may play a role in monocyte deactivation after systemic inflammation.