Development Of Multiple Organ Dysfunction Syndrome Research Articles

Attenuation of Sepsis‐Induced Organ Injury in Mice by Vitamin C

Multiple organ dysfunction syndrome (MODS) is the principal cause of death in patients with sepsis. Recent work supports the notion that parenteral vitamin C (VitC) is protective in sepsis through pleiotropic mechanisms. Whether suboptimal levels of circulating VitC increase susceptibility to sepsis-induced MODS is unknown. Unlike mice, humans lack the ability to synthesize VitC because of loss of L-gulono-γ-lactone oxidase (Gulo), the final enzyme in the biosynthesis of VitC. To examine whether physiological levels of VitC are required for defense against a catastrophic infection, we induced sepsis in VitC sufficient and VitC deficient Gulo(-/-) mice by intraperitoneal infusion of a fecal stem solution (FIP). Some VitC deficient Gulo(-/-) mice received a parenteral infusion of ascorbic acid (AscA, 200 mg/kg) 30 minutes after induction of FIP. We used molecular, histological, and biochemical analyses to assess for MODS as well as abnormalities in the coagulation system and circulating blood cells. FIP produced injury to lungs, kidneys and liver (MODS) in VitC deficient Gulo(-/-) mice. MODS was not evident in FIP-exposed VitC sufficient Gulo(-/-) mice and attenuated in VitC deficient Gulo(-/-) mice infused with AscA. Septic VitC deficient Gulo(-/-) mice developed significant abnormalities in the coagulation system and circulating blood cells. These were attenuated by VitC sufficiency/infusion in septic Gulo(-/-) mice. VitC deficient Gulo(-/-) mice were more susceptible to sepsis-induced MODS. VitC sufficiency or parenteral infusion of VitC, following induction of sepsis, normalized physiological functions that attenuated the development of MODS in sepsis.

Systemic Inflammatory Responses and Multiple Organ Dysfunction Syndrome Following Skin Burn Wound and Pseudomonas aeruginosa Infection in Mice

Burn wound-related sepsis is associated with the development of systemic inflammatory response syndrome and multiple organ dysfunction syndrome (MODS). This study is aimed at investigating the development and progression of SIS and MODS in a mouse model of skin burn sepsis. C57BL/6J mice were randomly divided into the sham, burn, Pseudomonas, and burn/Pseudomonas groups. The back skin of the sham, burn, and burn/Pseudomonas groups was burned about 10% of total area with using 37°C or 98°C water for 8 s, respectively, followed by inoculating with Pseudomonas aeruginosa. The Pseudomonas group was infected with P. aeruginosa without burn injury. Their body weights, mortality, organ histology, and function as well as systemic inflammation were measured longitudinally. The burn/Pseudomonas mice lost more body weights than did mice from the other groups and had a significantly higher mortality rate (P < 0.05). The burn/Pseudomonas mice exhibited significantly higher levels of bacterial loads in different organs and serum endotoxin, interleukin 1β, interleukin 6, tumor necrosis factor α, and C-reactive protein than those in mice from the other groups (P < 0.05). The burn/Pseudomonas mice also displayed more severe liver, lung, and kidney tissue damage and impaired organ functions, particularly at 72 h after inoculation than did the burn and Pseudomonas groups of mice. Our data indicate that burn and P. aeruginosa infection induced severe sepsis and rapidly progressed into systemic inflammatory response syndrome and MODS in mice.

Tumor Necrosis Factor-α Levels Early in Severe Acute Pancreatitis

One of the most important cytokines in pathogenesis of acute pancreatitis is tumor necrosis factor (TNF)-α. The aim of our study was to determine whether the plasma levels of TNF-α in patients with severe acute pancreatitis (SAP) on admission correlate with severity and outcome of SAP. Blood samples were obtained from 100 patients with SAP. Patients were divided into 2 groups according to severity: SAP group (n=69) and SAP-induced multiple organ dysfunction syndrome (MODS) group (n=31). Survivors were patients who were alive 90 days after taking the blood sample for cytokine measurement (53/100). Blood sample for cytokine measurement was drawn immediately after admission. TNF-α was measured by commercial ELISA test in plasma. When comparing SAP group with SAP-induced MODS group, we found that mean values of TNF-α on admission were 191.5-fold lower in group with SAP-induced MODS (P<0.01). When comparing nonsurvivors with survivors, we found that mean values of TNF-α on admission were 63-fold higher in survivors (P<0.01). At cut-off level of 7.95 pg/mL sensitivity was 83.9% and specificity was 72.5%. Patients with TNF-α level lower than 7.95 pg/mL had 3.2-fold higher probability to develop SAP with MODS. At cut-off level of 10.5 pg/mL sensitivity was 83% and specificity was 77.4%. Patients with TNF-α level higher than 10.5 pg/mL had 4.8-fold higher probability to survive. TNF-α is good predictor of severity and outcome. Low TNF-α concentration in patients with SAP predicts development of MODS and fatal outcome.

Coagulofibrinolytic changes in patients with disseminated intravascular coagulation associated with post-cardiac arrest syndrome― Fibrinolytic shutdown and insufficient activation of fibrinolysis lead to organ dysfunction

IntroductionPost-cardiac arrest syndrome (PCAS) is often associated with disseminated intravascular coagulation (DIC), thus leading to the development of multiple organ dysfunction syndrome (MODS). The aim of this study was to examine the pathophysiological relationships between coagulation, fibrinolysis and fibrinolytic shutdown by evaluating the levels of coagulofibrinolytic markers, including soluble fibrin, thrombin-activatable fibrinolysis inhibitor (TAFI), tissue plasminogen activator-plasminogen activator inhibitor-1 complex (tPAIC), plasmin-alpha2 plasmin inhibitor complex (PPIC), neutrophil elastase and fibrin degradation product by neutrophil elastase (EXDP). Materials and MethodsFifty-two resuscitated patients were divided into two groups: 22 DIC and 30 non-DIC patients. ResultsThe levels of soluble fibrin, PPIC, tPAIC, EXDP and neutrophil elastase in the DIC patients with PCAS were significantly higher than those observed in the non-DIC patients. The values of the tPAIC and JAAM DIC scores were found to be independent predictors of increased SOFA scores in the DIC patients. The MODS patients demonstrated significantly higher levels of soluble fibrin and tPAIC; however, the levels of TAFI and EXDP were identical between the patients with and without MODS. In addition, positive correlations were observed between the levels of tPAIC and EXDP in the patients with non-MODS; however, no correlations were observed between these markers in the MODS patients. ConclusionsThrombin activation and fibrinolytic shutdown play important roles in the development of organ dysfunction in PCAS patients. Neutrophil elastase-mediated fibrinolysis cannot overcome the fibrinolytic shutdown that occurs in DIC patients with PCAS, thus resulting in the development of MODS.

Role of Fibrinolysis in Sepsis

Sepsis, defined as infection-induced systemic inflammatory response syndrome, invariably leads to hemostatic abnormalities ranging from insignificant coagulopathy to disseminated intravascular coagulation (DIC). The inflammation-induced activation of coagulation, the downregulation of physiologic anticoagulant pathways, and impairment of fibrinolysis play a pivotal role in the pathogenesis of microvascular fibrin thrombosis and multiple organ dysfunction syndrome (MODS) in DIC associated with sepsis. The balance between tissue plasminogen activator and plasminogen activator inhibitor-1 mainly regulates fibrinolytic activity. Thrombin-activatable fibrinolysis inhibitor and neutrophil elastase also modulate fibrinolysis. Dynamic changes in these molecules are deeply involved in the pathomechanisms of the impairment of fibrinolysis, leading to MODS in DIC associated with sepsis. Evidence indicates that physical entrapment of bacteria by fibrin at the site of infection may limit their capacity to disseminate into nearby tissues, organs, and systemic circulation. Under this circumstance, impairment of fibrinolysis has protective role in the host defense. Given the protective and pathologic potential of fibrinolysis during sepsis, therapeutics that control DIC as a systemic syndrome, while maintaining the host defense at the infectious foci, are required for the protection against both the development of MODS and for the host defense mechanisms.

Close correlation between development of MODS during the initial 72 h of hospitalization and hospital mortality in severe fever with thrombocytopenia syndrome

An emerging infectious disease was identified as severe fever with thrombocytopenia syndrome (SFTS) in central China since late March 2009. We found the patients with SFTS had severe clinical symptoms, and progressed rapidly to multiple organ dysfunction syndrome (MODS) with high fatality rate of 25%-30%. The aim of this study was to assess the significance of risk factors predicting the development of MODS and death in SFTS patients. Consecutive SFTS admissions between May 2009 and September 2011 were analyzed for parameters of organ function during hospitalization using Marshall scoring system for MODS, and platelet counts were recorded on admission and at 24, 48, 72 h and one week after admission. We investigated the kinetics of organ failures and analyzed the association between age, platelet count and development of MODS or death. A total of 92 SFTS patients were enrolled in this study. Among them, 32 patients with dysfunction of over 4 organs were identified, 45% of them died within 72 h, 72% died within 5 days, and 76% died within 7 days after admission. We also found cumulative Marshall score was significantly higher in death patients (11.76±2.05) than in survival patients (4.22±1.98) (P<0.001). In addition, SFTS patients had older age and lower platelet counts in MODS and death groups. Furthermore, we also observed that there was a close correlation between platelet count on admission and Marshall score (P<0.001). High Marshall score, advanced age and lower platelet counts were the main risk factors for the development of MODS, and those factors could predict mortality in SFTS patients, suggesting prompt treatment and close monitoring of severe complications, especially MODS, are of great importance in saving patients' lives.

Altered MARCH1 ubiquination-regulated dendritic cell immune functions during the early stage of zymosan-induced multiple organ dysfunction syndrome (MODS) in mice

Using a zymosan-induced mouse model of multiple organ dysfunction syndrome (MODS), we previously found profound increases in spleen immune cells’ expressions of ubiquitin and MHC-II molecules and increased CD11c+ dendritic cells (DCs) within 24h of zymosan injection. We postulated that the early stage of MODS altered DCs function via an ubiquitination-associated mechanism. We intraperitoneally injected zymosan into 100 male C57BL/6 mice (0.8mg/g) and randomly divided them into 5 groups based on the days after injection (20mice/group): 1d, 3d, 5d, 7d, and 10d. Mice were examined for spleen CD11c+ DC functions at the indicated days. Untreated mice were used for normal spleen tissue and T cell samples. By qPCR, IL-12 and TNF-α mRNA expressions in spleen CD11c+ DCs were significantly increased in MODS 1d mice; on subsequent days post-injection, these mRNA levels gradually returned to control levels. The same patterns were found for MODS mice DCs induction of untreated mouse T cells proliferation and IL-2 and IFN-γ mRNA expressions. When T cell functions were examined using MODS 1d DCs with and without MG132 treatment, an inhibitor of ubiquitinated protein degradation, T cell functional activities were enhanced by DCs treated with MG132. MODS 1d DCs also had significantly reduced MARCH1 mRNA expression, a key ubiquitin ligase that regulates DCs MHC-II expression. Silencing DCs MARCH1 expression with siRNA resulted in enhancing their induction of T cell functional activities. Using co-immunoprecipitation, Western blot, and flow cytometry assays, we deduced that MARCH1 ubiquitinated DC surface MHC-II molecules to regulate DC's immune functions in MODS mice. Our results suggest that aberrant degradation of spleen DCs MARCH1-mediated ubiquitinated proteins is involved during the earliest stage of MODS development.

A New Scoring System For Evaluation of Multiple Organ Dysfunction Syndrome in Premature Infants

The Neonatal Multiple Organ Dysfunction (NEO-MOD) scoring system is used to predict mortality in infants with multiple organ dysfunction syndrome (MODS). The NEOMOD scoring system was extended to include involvement of the microvascular system. This modified scoring system was developed to enable more accurate and earlier diagnosis of MODS in premature infants. To evaluate the modified NEOMOD scoring system in preterm infants with MODS and compare its effectiveness with the NEOMOD scoring system. This prospective study was performed in a tertiary neonatal intensive care unit. A total of 198 premature infants were enrolled. Infants were evaluated for development of MODS by using the modified NEOMOD scoring system until discharge or death according to clinical and laboratory findings. Infants who had organ dysfunction in 2 or more organ systems had MODS diagnosed. In the 160 infants (80.8%) with MODS, the gastrointestinal system, respiratory system, and hematologic system were involved most often. The gastrointestinal system, respiratory system, and acid-base metabolism were involved initially in 99.4%, 86.3%, and 26.3% of infants, respectively. The mean modified NEOMOD score for the infants who died in the first 28 days after birth was significantly higher than the mean score for infants who survived. The number of systems involved was also higher in infants who died. The modified NEOMOD scoring system is a safe and accurate tool for determining both mortality rate and dysfunction of multiple organ systems affecting mortality in pre-term infants.

The Dynamics of Angiogenic Factors and Their Soluble Receptors in Relation to Organ Dysfunction in Disseminated Intravascular Coagulation Associated with Sepsis

We prospectively studied (1) the relationships between angiogenic factors, their soluble receptors and organ dysfunction and (2) the effects of disseminated intravascular coagulation (DIC)-induced platelet consumption, thrombin generation, and tissue hypoxia on the expression of the factors and receptors. Fifty patients with sepsis were classified into two subgroups: 37 patients with DIC and 13 patients without DIC. DIC patients showed higher Sequential Organ Failure Assessment (SOFA) scores, the prevalence of multiple organ dysfunction syndrome (MODS) and more increased soluble fibrin and lactate levels. We observed lower levels of vascular endothelial growth factor (VEGF), soluble VEGF receptor 2 (sVEGFR2), angiopoietin 1 (Ang1) and Ang1/Ang2, and higher sVEGFR1 and Ang2 levels in DIC patients, but not significant differences in soluble Tie2 expression during the study period. The levels of VEGF, sVEGFR1, and Ang2 in DIC patients correlated with the SOFA scores. Clear differences were observed in the levels of Ang2 in the DIC patients between survivors and nonsurvivors and between those with and without MODS. The area under receiver operating characteristic curves for predicting death and MODS by Ang2 were 0.710 and 0.784, respectively. The VEGF levels showed a marked correlation with the platelet counts. Soluble fibrin and lactate levels independently predicted increases in the levels of VEGF, sVEGFR1, and Ang2 in DIC patients. In conclusion, VEGF, sVEGFR1, Ang2, and Ang1/Ang2, especially Ang2, may have roles in the development of MODS in sepsis associated with DIC, and VEGF, sVEGFR1, and Ang2 serum levels correlated with the extent of DIC-induced platelet consumption, thrombin generation, and blood lactate levels.

Role of lipase-generated free fatty acids in converting mesenteric lymph from a noncytotoxic to a cytotoxic fluid

Recent studies have shown that mesenteric lymph plays a very important role in the development of multiple-organ dysfunction syndrome under critical conditions. Great efforts have been made to identify the biologically active molecules in the lymph. We used a trauma-hemorrhagic shock (T/HS) model and the superior mesenteric artery occlusion (SMAO) model, representing a global and a localized intestinal ischemia-reperfusion insult, respectively, to investigate the role of free fatty acids (FFAs) in the cytotoxicity of mesenteric lymph in rats. Lymph was collected before, during, and after (post) shock or SMAO. The post-T/HS and SMAO lymph, but not the sham lymph, manifested cytotoxicity for human umbilical vein endothelial cells (HUVECs). HUVEC cytotoxicity was associated with increased FFAs, especially the FFA-to-protein ratio. Addition of albumin, especially delipidated albumin, reduced this cytotoxicity. Lipase treatment of trauma-sham shock (T/SS) lymph converted it from a noncytotoxic to a cytotoxic fluid, and its toxicity correlated with the FFA-to-protein ratio in a fashion similar to that of the T/HS lymph, further suggesting that FFAs were the key components leading to HUVEC cytotoxicity. Analysis of lymph by gas chromatography revealed that the main FFAs in the post-T/HS or lipase-treated T/SS lymph were palmitic, stearic, oleic, and linoleic acids. When added to the cell culture at levels comparable to those in T/HS lymph, all these FFAs were cytotoxic, with linoleic acid being the most potent. In conclusion, this study suggests that lipase-generated FFAs are the key components resulting in the cytotoxicity of T/HS and SMAO mesenteric lymph.

Reduction of Plasma Gelsolin Levels Correlates with Development of Multiple Organ Dysfunction Syndrome and Fatal Outcome in Burn Patients

BackgroundDepletion of the circulating actin-binding protein, plasma gelsolin (pGSN) has been described in critically ill surgical patients. We hypothesized that the extent of pGSN reduction might correlate with different outcome of burn patients. The study was performed to evaluate the prognostic implications of pGSN levels on the development of multiple organ dysfunction syndrome (MODS) and fatal outcome in a group of severely burn patients.Methods and Findings95 patients were included, and they were divided into three groups with different burn area: group I (n = 33), group II (n = 32) and group III (n = 30). According to whether there was development of MODS or not, patients were divided into MODS group (n = 28) and none-MODS group (n = 67); then the patients with MODS were further divided into non-survivor group (n = 17) and survivor group (n = 11). The peripheral blood samples were collected on postburn days (PBD) 1, 3, 7, 14, and 21. The levels of pGSN were determined and T cells were procured from the blood. The contents of cytokines (IL-2, IL-4 and IFN-γ) released by T cells were also measured. The related factors of prognosis were analyzed by using multivariate logistic regression analysis. The results showed that pGSN concentrations, as well as the levels of IL-2 and IFN-γ, decreased markedly on PBD 1–21, whereas, the levels of IL-4 increased markedly in all burn groups as compared with normal controls (P<0.05 or P<0.01), and there were obviously differences between group I and group III (P<0.05 or P<0.01). The similar results were found in MODS patients and the non-survivor group as compared with those without MODS and the survival group on days 3–21 postburn (P<0.05 or P<0.01). Moreover, as the pGSN levels decreased, the incidence of septic complication as well as MODS remarkably increased.ConclusionspGSN levels appear to be an early prognostic marker in patients suffering from major burns.

Clinical relevance of single nucleotide polymorphisms of the high mobility group box 1 protein gene in patients with major trauma in Southwest China

High-mobility group box protein 1 (HMGB1) is a pivotal late mediator involved in the development of sepsis and multiple organ dysfunction syndrome (MODS) in critically ill patients. While several single nucleotide polymorphisms (SNPs) have been demonstrated to be critical determinants for outcome of critically ill patients, little is known about the clinical relevance of SNPs of the HMGB1 gene up to date. A total of 3 tag SNPs of the HMGB1 gene were selected using HapMap database and linkage disequilibrium analysis. The tag SNPs were genotyped using a pyrosequencing methodology in 556 unrelated patients with major trauma. Peripheral whole blood samples obtained immediately after admission were determined for HMGB1 production in response to exvivo lipopolysaccharide (LPS) stimulation. The rs2249825 SNP and the haplotype TCG were significantly associated with LPS-induced HMGB1 production by peripheral blood leukocytes. There were also significant differences in sepsis morbidity rate and MOD scores among patients with different genotypes of the rs2249825. In addition, the patients with the wild-type haplotype TCG had a lesser sepsis morbidity rate and MOD scores than those without the TCG haplotype. A total of 3 SNPs might act as tag SNPs for the entire HMGB1 gene. The rs2249825 and the haplotype TCG might be used as relevant risk estimate for the development of sepsis and MODS in patients with major trauma.

Extravascular Lung Water Correlates Multiorgan Dysfunction Syndrome and Mortality in Sepsis

BackgroundThis study was designated to investigate whether increased extravascular lung water index (EVLWI) may correlate multiple organ dysfunction syndrome (MODS) and mortality in sepsis.MethodsWe designed a prospective cohort study in an intensive care unit of a tertiary care hospital. Sixty-seven patients with severe sepsis were included. Data were used to determine an association between EVLWI and the development of MODS and mortality. These connections were determined by the multiple logistic regression, plotting the receiver operating characteristic (ROC) curve and by Spearman test.ResultsEVLWI levels were higher in MODS patients on day 1 (median (IQR), 18(12.8–23.9) ml/kg, n = 38, p<0.0001) than in those without (median (IQR), 12.4 (7.9–16.3) ml/kg, n = 29) and day 3 (median (IQR), 17.8 (11.2–22.8) ml/kg, n = 29, p = 0.004) than in those without (median (IQR), 12.4 (8.0–16.3) ml/kg, n = 29). EVLWI was used as an independent predictor of the development of MODS (odds ratio, 1.6; p = 0.005; 95% confidence interval, 1.2∼2.2) during ICU stay. The area under the ROC curve showed that EVLWI levels could predict MODS (0.866) and mortality (0.881) during ICU stay. Meanwhile, the higher of SOFA score, the more EVLWI was found on day 1 (r = 0.7041, p<0.0001) and day 3 (r = 0.7732, p<0.0001).ConclusionsIncreased EVLWI levels correlates development of MODS and mortality during the patients' ICU stay. Further more, the potential of novel treatment in severe sepsis with lung injury may develop.

EARLY ELEVATION IN RANDOM PLASMA IL-6 AFTER SEVERE INJURY IS ASSOCIATED WITH DEVELOPMENT OF ORGAN FAILURE

Excessive proinflammatory activation after trauma plays a role in late morbidity and mortality, including the development of multiple organ dysfunction syndrome (MODS). To date, identification of patients at risk has been challenging. Results from animal and human studies suggest that circulating interleukin 6 (IL-6) may serve as a biomarker for excessive inflammation. The purpose of this analysis was to determine the association of IL-6 with outcome in a multicenter developmental cohort and in a single-center validation cohort. Severely injured patients with shock caused by hemorrhage were evaluated within a multicenter developmental cohort (n = 79). All had blood drawn within 12 h of injury. Plasma IL-6 was determined by multiplex proteomic analysis. Clinical and outcome data were prospectively obtained. Within this developmental cohort, a plasma IL-6 level was determined for the subsequent development of MODS by developing a receiver operating curve and defining the optimal IL-6 level using the Youden Index. This IL-6 level was then evaluated within a separate validation cohort (n = 56). A receiver operating curve was generated for IL-6 and MODS development, with an IL-6 level of 350 pg/mL having the highest sensitivity and specificity within the developmental cohort. IL-6 was associated with MODS after adjusting for Acute Physiology and Chronic Health Evaluation, Injury Severity Score, male sex, and blood transfusions with an odds ratio of 3.9 (95% confidence interval, 1.33 - 11.19). An IL-6 level greater than 350 pg/mL within the validation cohort was associated with an increase in MODS score, MODS development, ventilator days, intensive care unit length of stay, and hospital length of stay. However, this IL-6 level was not associated with either the development of nosocomial infection or mortality. Elevation in plasma IL-6 seems to correlate with a poor prognosis. This measurement may be useful as a biomarker for prognosis and serve to identify patients at higher risk of adverse outcome that would benefit from novel therapeutic interventions.

System biology of multiple organ dysfunction: formation of a ceramide-enriched macro-domain in SIRS/sepsis

Generation of bioactive lipids such as ceramide (Cer) and the formation of Cer-enriched macrodomains are regarded as mediators of SIRS and the development of multiple organ failure. Therefore, we addressed the question of whether there is a difference in the plasma activity of the secreted isoform of the Cer-forming enzyme sphingomyelinase (SMPD1) in patients with various degrees of SIRS/sepsis of different origin as well as in a murine loss of function model. We found plasma activity in critically ill patients (median 262.3 pmol/ml*hour) was significantly higher than age-matched controls (123.6). In patients with fatal outcome, activity increased (+77.4) in comparison with survivors (-252.1). A severity-dependent increase was also analyzed in patients with multiple organ dysfunction syndrome (MODS) following elective cardiac surgery. Beyond immunological detection of increased pSMPD1 in septic patients, we found an increase in Cer-enriched macrodomains in endothelial cells after stimulation with patients' plasma, endotoxin, or TNF. We also found formation of Cer-enriched macrodomains by immunostaining using specific antibodies directed against Cer, CD14, and Fas. In a loss of function model, we identified 315 transcripts differentially regulated in circulating white blood cells, liver, and lung by use of microarray technology as well as in the cytokine pattern/organ function parameters following polymicrobial cavity infection. Furthermore, host responses in knockout mice were more pronounced with respect to bacterial load in lung, liver, and blood, plasma cytokine levels, thrombocytopenia as well as delayed migration of neutrophils into hepatic tissue. In conclusion, the results provide demonstration of a biofunctional relevant activity of SMPD1 resulting in altered signal transduction in SIRS, which may contribute to the development of MODS.

Relationship between HMGB1 content and MHC-II expression in circulating monocytes and spleen of mice challenged with zymosan

To observe the regularity of change in high mobility group protein box 1 (HMGB1) content in serum and spleen of mice with multiple organ dysfunction syndrome (MODS), to analyze the correlation between HMGB1 content and major histocompatibility complex (MHC)-II---I-A(b) expression on monocytes in blood and spleen, and to explore the effect of HMGB1 on immune function of circulating monocytes and splenocytes. One hundred 8-week-old male 57BL/6 mice were randomly divided into normal group and experimental group subdivided into 8 subgroups: 3, 8, 12 hours, 1, 2, 3, 5-7 days and 10-12 days post zymosan injection (PZI). MODS model was replicated by injecting zymosan into the peritoneal cavity. At each time point, blood and spleen were collected to detect HMGB1 content and the rate of I-A(b) positive monocytes. In normal and PZI 3-hour, 8-hour mice, serum HMGB1 was not detected, but it significantly increased at PZI 12 hours. In spleen of normal mice, there was low level of HMGB1 expression. In zymosan-treated mice, HMGB1 started to rise in spleen at PZI 3 hours. Subsequently, HMGB1 content in both serum and spleen significantly increased, and it reached the peak level in 1-2 days, decreased in 5 days, and then increased in 10-12 days. The number of I-A(b) positive monocytes in circulating blood and spleen decreased at 1-2 days (t equal to 9.589, 4.432, P <0.01) and 10-12 days following the challenge, forming a two trough like decrease, just corresponding with two-peak increase of HMGB1. However, at 3 hours after zymosan challenge, I-A(b) expression on circulating monocytes was downregulated (t =5.977, P less than 0.01), while that in spleen upregulated (t equal to 4.814, P less than 0.01). In mice with MODS, up-regulated HMGB1 expression can regulate I-A(b)expression on monocytes to depress their ability of presenting antigen, which results in immune disturbance contributing development of MODS.

Disfunción mitocondrial en sepsis, impacto y posible papel regulador del factor inducible por hipoxia (HIF-1α)

There is a direct correlation between the development of the multiple organ dysfunction syndrome (MODS) and the elevated mortality associated with sepsis. The mechanisms responsible for MODS development are being studied, however, the main efforts regarding MODS evaluation have focused on oxygen delivery optimization and on the modulation of the characteristic inflammatory cascade of sepsis, all with negative results. Recent studies have shown that there is development of tissue acidosis, even when there are normal oxygen conditions and limited presence of tissue cellular necrosis or apoptosis, which would indicate that cellular energetic dysfunction may be a central element in MODS pathogenesis. Mitochondrias are the main source of cellular energy, central regulators of cell death and the main source for reactive oxygen species. Several mechanisms contribute to mitochondrial dysfunction during sepsis, that is blockage of pyruvate entry into the Krebs cycle, oxidative phosphorylation substrate use in other enzymatic complexes, enzymatic complex inhibition and membrane damage mediated by oxidative stress, and reduction in mitochondrial content. Hypoxia-inducible factor-1α (HIF-1α) is a nuclear transcription factor with a central role in the regulation of cellular oxygen homeostasis. Its induction under hypoxic conditions is associated to the expression of hundreds of genes that coordinate the optimization of cellular oxygen delivery and the cellular energy metabolism. HIF-1α can also be stabilized under normoxic condition during inflammation and this activation seems to be associated with a prominent pro-inflammatory profile, with lymphocytes dysfunction, and to a reduction in cellular oxygen consumption. Further studies should establish a role for HIF-1α as a therapeutic target.

Systemic inflammatory response syndrome outcome in surgical patients.

The problems of inflammation and infection as a leading cause of organ dysfunction and failure is a major problem after injury or operations. When systemic inflammatory response syndrome (SIRS) progress to multiple organ failure (MOF), the mortality reach up to 30-80% depending on the number of failed organs. Recent discoveries and improvement in patient care, a reasonable question then arises, are the incidence of MOF decreasing? The literature suggests a decrease in mortality of patients with severe organ failure and a decrease in elective surgical mortality in patients. This is prospective study of 50 patients who underwent surgical procedure. They were followed up till date of termination with daily SIRS monitoring, development of MODS and MOF. Risk factors for MOF are addressed. There are total 31 patients who develop SIRS, of whom 7 patients develop severe sepsis and 4 went into MOF. Early detection of SIRS helps us to prevent multiple organ dysfunction syndrome (MODS)/MOF, leading to lesser hospital stay and better outcome.

Early Hypothermia in Severely Injured Trauma Patients Is a Significant Risk Factor for Multiple Organ Dysfunction Syndrome but Not Mortality

To evaluate the relationship of early hypothermia to multiple organ failure and mortality in a prospectively-collected database of severely injured trauma patients. This prospective observational study was performed at 7 level I trauma centers over a 16-month period. Severely injured trauma patients with signs of hypoperfusion (eg, base deficit, hypotension) and need for blood transfusion during their early hospital course were followed for 24 hours with near infrared spectroscopy-derived tissue oxygen saturation (StO2) and other variables for 28 days to evaluate outcomes including multiple organ dysfunction syndrome (MODS) and death. Early hypothermia was defined as the presence of a temperature <35°C [corrected] anytime within the first 6 hours of hospitalization. Comparisons between groups were made using the Wilcoxon Two-Sample test for continuous variables and either the Fisher exact or chi2 test for categorical variables. Multivariate logistic regression was utilized to understand the effect of hypothermia on outcome (MODS and mortality). Hypothermia was very common in this cohort of patients, present in 43% of patients enrolled (155/359). Hypothermic patients were 3 times more likely than normothermic patients to develop MODS (21% vs. 9%, P = 0.003). Hypothermic patients did not have an increased incidence of mortality (16% vs. 12%, P= 0.2826). Base deficit in hypothermic patients did not discriminate between patients who did or did not develop MODS (9.8 +/- 4.6 mEq/L vs. 9.4 +/- 4.4 mEq/L). In contrast, base deficit in hypothermic patients discriminated with respect to mortality (14.6 +/- 7.2 mEq/L versus 9.5 +/- 4.5 mEq/L; P 0.0021), but this effect was not observed in normothermic patients [corrected]. Significant predictors of MODS using multivariate analysis included minimum StO2 (P= 0.0014) and hypothermia (P = 0.0371). Predictors for mortality using multivariate analysis included minimum StO2 (P= 0.0021) and base deficit (P= 0.0454), but not hypothermia (P= 0.5289). Hypothermia remained a significant risk factor for MODS when systolic blood pressure, volume of fluid, and volume of blood infused were included in the multivariate model. Hypothermia is common in severely injured trauma patients (nearly half of patients in this series) and is a significant risk factor for MODS but not mortality. The predictive value of base deficit for development of MODS is blunted in the presence of hypothermia. A low StO2 value predicts MODS and mortality in trauma patients and is a durable measure in both normothermic and hypothermic patient groups.

Innate Immune Responses to Danger Signals in Systemic Inflammatory Response Syndrome and Sepsis

The systemic immune response induced by non-infectious agents is called systemic inflammatory response syndrome (SIRS) and infection-induced systemic immune response is called sepsis. The host inflammatory response in SIRS and sepsis is similar and may lead to multiple organ dysfunction syndrome (MODS) and ultimately death. The mortality and morbidity in SIRS and sepsis (i.e. critical illness) remain high despite advances in diagnostic and organ supporting possibilities in intensive care units. In critical illness, the acute immune response is organized and executed by innate immunity influenced by the neuroendocrine system. This response starts with sensing of danger by pattern-recognition receptors on the immune competent cells and endothelium. The sensed danger signals, through specific signalling pathways, activate nuclear transcription factor kappaB and other transcription factors and gene regulatory systems which up-regulate the expression of pro-inflammatory mediators. The plasma cascades are also activated which together with the produced pro-inflammatory mediators stimulate further the production of inflammatory biomarkers. The acute inflammatory response underlies the pathophysiological mechanisms involved in the development of MODS. The inflammatory mediators directly affect organ function and cause a decline in remote organ function by mediating the production of nitric oxide leading to mitochondrial anergy and cytopathic hypoxia, a condition of cellular inability to use oxygen. Understanding the mechanisms of acute immune responses in critical illness is necessary for the development of urgently needed therapeutics. The aim of this review is to provide a description of the key components and mechanisms involved in the immune response in SIRS and sepsis.