Mitochondrial dysfunction in septic shock and multiple organ dysfunction syndrome

Sepsis is the leading cause of death in medical intensive care units. In most fatal cases of sepsis the patient experiences an insidious, progressive decline in vital organ function, i.e. multiple organ dysfunction syndrome (MODS), which is commonly associated with signs of accelerated anaerobic metabolism despite supernormal systemic oxygen delivery. Based on this clinical scenario, tissue hypoxia has long been considered the putative mechanism of MODS. However, efforts to enhance tissue oxygenation during severe sepsis have proved ineffective, and a growing body of evidence indicates that mitochondria contribute significantly to the pathogenesis of sepsis-induced MODS. In addition to dysregulation of oxygen metabolism ('cytopathic hypoxia'), sepsis-induced mitochondrial dysfunction contributes to organ injury through accelerated oxidant production and by promoting cell death. Advances in our understanding of the mechanisms of mitochondrial damage and in its detection could revolutionize the management of this devastating disease.     

Multiple organ dysfunction syndrome.

The multiple organ dysfunction syndrome (MODS), though newly described, has manifested itself in intensive care unit (ICU) patients for several decades. As the name implies, it is a syndrome in which more than one organ system fails. Failure of these multiple organ systems may or may not be related to the initial injury or disease process for which the patient was admitted to the ICU. MODS is the leading cause of morbidity and mortality in current ICU practice. While the pathophysiology of MODS is not completely known, much evidence indicates that, during the initial injury which precipitates ICU admission, a chain of events is initiated which results in activation of several endogenous metabolic pathways. These pathways release compounds which, in and of themselves, are usually cytoprotective. However, an over exuberant activation of these endogenous systems results in an inflammatory response which can lead to development of failure in distant organs. As these organs fail, they activate and propagate the systemic inflammatory response. No therapy has proven entirely efficacious at modulating this inflammatory response and the incidence and severity of MODS. In current ICU practice, treatment is focused on prevention and treating individual organ dysfunction as it develops. With increased understanding of the pathophysiology of MODS therapy will come newer modalities which inhibit or interfere with the propagation of the endogenous systemic inflammatory response. These newer therapies hold great promise and already some are undergoing clinical investigation.     

Absence of endogenous interleukin-10 enhanced organ dysfunction and mortality associated to zymosan-induced multiple organ dysfunction syndrome

Experimental evidence suggests that interleukin (IL)-10 plays a pivotal role in generalized inflammation. Here we investigate the effects of IL-10 gene deletion on the acute phase of the multiple organ dysfunction syndrome (MODS) caused by zymosan in the mouse. MODS was induced by zymosan administration (500 mg/kg, suspended in saline solution, i.p.) in IL-10 wild-type and knockout mice; sham groups were treated with vehicle. Mice were sacrificed 18 h after zymosan or saline administration. In another set of experiments, animals were monitored for 12 days to assess systemic toxicity and survival rate. Mice lacking IL-10 displayed increased peritoneal exudate volume and leukocytes. Also, we observed a significant increase in myeloperoxidase activity and lipid peroxidation in ileum and lung tissues, as well as augmented levels of TNF-alpha, IL-1beta and nitrogen-derived species in the plasma. With regard to organ injury, absence of IL-10 enhanced the renal, hepatocellular and pancreatic dysfunction caused by zymosan administration. All of these parameters significantly influenced the systemic toxicity and the overall survival at 12 days, which was significantly lower in IL-10 knockout mice. Therefore, this study demonstrates that the absence of endogenous IL-10 enhances the MODS induced by zymosan in mice.     

党参合剂对多器官功能障碍综合征菌群失调及免疫功能的调整

目的研究党参合剂通过调整菌群失调,修复肠屏障功能,控制细菌、内毒素易位,提高机体免疫力,对多器官功能障碍大鼠肠源性感染及内毒素血症(IETM)进行防治。方法采用肠缺血再灌注的方法制造多器官功能障碍综合征(MODS)模型,分别以党参合剂、丽珠肠乐对动物进行灌胃治疗。取肠内容物、肝、脾、肠系膜淋巴结,门静脉血,分别做无菌培养,内毒素及sIgA的测定。结果各治疗组通过扶植肠道有益菌、抑制有害菌的生长繁殖并促进其排泄,保护肠黏膜屏障,明显降低了细菌易位,控制内毒素血症,改善了相关免疫指标。结论党参合剂从调整微生态失调的角度来防治MODS取得较好效果,优于丽珠肠乐。     

Interleukin 10 mitigates the development of the zymosan-induced multiple organ dysfunction syndrome in mice.

We investigated the effect of interleukin 10 on the development of zymosan-induced multiple organ dysfunction syndrome (MODS) and on plasma concentrations and production capacity of tumour necrosis factor (TNF)-alpha by peritoneal cells. Groups of C57BL/6 mice received a single intraperitoneal injection with zymosan, a cell wall component of Saccharomyces cerevisiae, at day 0. Daily doses of human recombinant interleukin 10 (IL-10: 10 or 50 microg/kg) were given intraperitoneally either starting directly before administration of zymosan (day 0), or 5 or 8 days after administration of zymosan. The animals were monitored for survival, condition, body weight and temperature. On day 12 all surviving animals were killed to obtain plasma, organs and peritoneal cells. Plasma concentrations of TNF-alpha and lipopolysaccharide-stimulated production of TNF-alpha by peritoneal cells were measured; organ weights were registered as an indicator for organ damage. IL-10 improves survival and clinical condition and also reduces organ damage, but only at the highest dose used and only when started simultaneously with the administration of zymosan. Circulating TNF-alpha concentrations 12 days after zymosan are not affected by any of the IL-10 schedules used. However, lipopolysaccharide-stimulated production of TNF-alpha by peritoneal cells is increased, in a dose- and time-dependent fashion. The anti-inflammatory cytokine IL-10 is able to attenuate the development of MODS in this model, but only when given simultaneously with zymosan, and in high dosages.     

Leukinferon in the treatment of patients with sepsis and multiple organ dysfunction syndrome]

Dynamics of clinical signs, blood formula and some cytokins in serum samples of the patients with sepsis complicated by multiorgan disfunction syndrome (as a rule kidney and liver were involved) were investigated. Etiotropic therapy was combined with immunocorrecting treatment with leukinferone Combined regime provided positive results in clinical symptoms, in lymphocytes number normalization (abs. and per cent), stimulated T lymphocytes differentiation and facilitated intoxication finishing according to LII). Immunocorrection practically had no effect on TNF-alpha, IL-1 alpha, IL-6, and stimulated IL-8 secretion more effectively than etiotropic therapy. IF-gamma level enhanced along with stopped IL-10 production. As a result ratio of IF-gamma/IL-10 enhanced from 0.56 to 1.0, in the case of etiotropic therapy this ratio diminished from 0.48 to 0.3. It is concluded that immunocorrecting therapy provided positive dynamics in the ration IF-gamma/IL-10, recurring cell immune reactions. The recurrence period was shortened and lethality level was substantially lower (2.5 times).     

Daily estimation of the severity of multiple organ dysfunction syndrome in critically ill children

Background

Daily evaluation of multiple organ dysfunction syndrome has been performed in critically ill adults. We evaluated the clinical course of multiple organ dysfunction over time in critically ill children using the Pediatric Logistic Organ Dysfunction (PELOD) score and determined the optimal days for measuring scores.

Methods

We prospectively measured daily PELOD scores and calculated the change in scores over time for 1806 consecutive patients admitted to seven pediatric intensive care units (PICUs) between September 1998 and February 2000. To study the relationship between daily scores and mortality in the PICU, we evaluated changes in daily scores during the first four days; the mean rate of change in scores during the entire PICU stay between survivors and nonsurvivors; and Cox survival analyses using a change in PELOD score as a time-dependent covariate to determine the optimal days for measuring daily scores.

Results

The overall mortality among the 1806 patients was 6.4%. A high PELOD score (≥ 20 points) on day 1 was associated with an odds ratio (OR) for death of 40.7 (95% confidence interval [CI] 20.3–81.4); a medium score (10–19 points) on day 1 was associated with an OR for death of 4.2 (95% CI 2.0–8.7). Mortality was 50% when a high score on day 1 increased on day 2. The course of daily PELOD scores differed between survivors and nonsurvivors. A set of seven days (days 1, 2, 5, 8, 12, 16 and 18) was identified as the optimal period for measurement of daily PELOD scores.

Interpretation

PELOD scores indicating a worsening condition or no improvement over time were indicators of a poor prognosis in the PICU. A set of seven days for measurement of the PELOD score during the PICU stay provided optimal information on the progression of multiple-organ dysfunction syndrome in critically ill children.Almost all patients in intensive care units (ICUs) have some organ dysfunction.^1–4 Adult and pediatric studies have shown that mortality increases with the number of organs involved.^2,4,5 Thus, multiple-organ dysfunction syndrome (dysfunction involving two or more organs) has been viewed as the inexorable pathway to death.⁶ Primary multiple-organ dysfunction syndrome (present at admission or occurring within the first week after admission to the ICU) accounts for 88% of children with the syndrome; secondary multiple-organ dysfunction syndrome is less common (12%) but is associated with higher morbidity and mortality.⁷Organ dysfunction scores were first developed for use in critically ill adults to describe and quantify the severity of organ dysfunction, not to predict mortality. Two scores have been proposed for critically ill children: the Pediatric Logistic Organ Dysfunction (PELOD) score and the Pediatric Multiple Organ Dysfunction Score (P-MODS).^8–10 These scores quantify organ dysfunction precisely and can be used as indicators of the severity of illness throughout the clinical course. They can also be used as baseline and outcome measures in clinical studies conducted in ICUs^11,12 and pediatric ICUs (PICUs).¹³The PELOD score calculated with data collected over the entire PICU stay has been validated (using the most abnormal value of each variable during the entire PICU stay).¹⁰ However, the PELOD score over the entire PICU stay cannot be calculated before discharge from the unit; therefore, it cannot be used to characterize and follow the severity of organ dysfunction on a daily basis. Measurements repeated daily may provide more useful information.¹⁴ The optimal period for measuring daily scores for multiple organ dysfunction in adults has been studied.^15–17 Indeed, trends in the Sequential Organ Failure Assessment score over the first 48 hours in the ICU was found to be a sensitive indicator of outcome, with decreasing scores associated with a decrease in mortality from 50% to 27%.¹⁷ Similar data for critically ill children are lacking.We conducted this study to describe the clinical course of multiple organ dysfunction over time as measured by the daily PELOD score. Because the time and effort necessary to ensure accurate daily assessments and data entry can be substantial,¹⁸ we also aimed to determine the optimal days for measuring daily scores during the PICU stay.     

年龄与老年高血压并发心力衰竭患者发生多器官功能衰竭的关系

目的:分析年龄对老年高血压患者伴发心力衰竭(CHF)后诱发多器官功能衰竭(MODSE)的关系,探讨年龄和CHF对老年高血压患者发生MODSE的预测值。方法:回顾性分析≥60岁高血压患者的19996例病历资料(男性13229例,女性6767例,平均年龄74.21±7.52),以10岁为界60~69岁、70~79岁、80~89岁和≥90岁划分年龄段,以69、79和89岁为分界点,分别分析各年龄段及各分界年龄上下老年高血压患者中因CHF并发MODSE的发生率。结果:①所有CHF患者中MODSE的发生率较非CHF患者升高(7.43%vs3.05%,χ2195.15,说明CHF是影响老年高血压患者出现MODSE的重要影响因素;②60~69岁、70~79,80~89岁和≥90岁发生CHF的比例分别10.60%vs18.88%vs30.11%vs60.57%,P<0.05,差异有统计学意义。4个年龄段发生MODSE分别为1.68%vs7.06%vs17.08%vs25.47%,P<0.05,有统计学差异。高血压患者中CHF的发生率与CHF中MODSE的发生率呈正相关r=0.696(P<0.01);年龄与老年高血压患者并发CHF的发生率以及年龄与CHF中MODSE发生率亦呈正相关r=0.987(P<0.01)。排除年龄因素的影响对CHF与MODSE的发生率进行偏相关分析表明r=-0.776(P>0.05),说明年龄是老年高血压患者并发CHF后出现MODSE的重要影响因素,且69岁以上各分界年龄上下之间差异最明显,具有统计学意义(P<0.05)。结论:年龄与CHF诱发老年高血压患者发生MODSE具有一定的早期预测值,69岁以上的高血压患者如合并CHF是发生MODSE的高危人群。     

纳米党参合剂调整肠道微生态失衡防治多器官功能障碍综合征的研究

目的研究纳米党参合剂通过调整菌群失调,修复肠屏障功能,控制细菌、内毒素易位,对多器官功能障碍大鼠肠源性感染及内毒素血症(IETM)进行防治。方法采用肠缺血再灌注的方法制造多器官功能障碍综合征(MODS)模型,分别以纳米中药、常态中药对动物进行灌胃治疗。取肠内容物做无菌培养,内毒素、sIgA的测定,CD4+、CD8+T细胞计数。结果各治疗组通过扶植肠道有益菌、抑制有害菌的生长繁殖并促进其排泄,保护肠黏膜屏障,明显降低细菌易位,控制内毒素血症,改善相关免疫指标。结论党参合剂从调整微生态失调的角度来防治MODS取得较好效果,纳米中药效果更佳。     

Ulinastatin-mediated protection against zymosan-induced multiple organ dysfunction in rats

The purpose of this study was to evaluate the potential organ-protective activity of ulinastatin (a urinary trypsin inhibitor) and to investigate the underlying mechanism(s) in a rat model of multiple organ dysfunction syndrome (MODS). When adult Wistar rats were challenged intraperitoneally with yeast polysaccharide (zymosan), they developed biochemical and histological abnormalities similar to those seen in human MODS as compared with the controls. Among these abnormalities were: 1) significant increases in serum concentrations of tumor necrosis factor-alpha (TNF-α) and soluble intercellular adhesion molecule-1 (sICAM-1); 2) aberrant values in the liver and kidney function tests; and 3) presence of evident pathology in the major organs (i.e. liver, kidney and lung). In addition, zymosan challenge resulted in an increase in toll-like receptor-4 (TLR4) mRNA abundance in all three organs tested. Ulinastatin treatment significantly decreased the zymosan-induced elevation in serum concentrations of TNF-α and sICAM-1 and tissue abundance of TLR mRNA in the liver, kidney and lung, effectively attenuated the development of the polysaccharide-induced biochemical and histological abnormalities and successfully reduced the MODS-associated death. In conclusion, ulinastatin is able to protect multiple organs from yeast polysaccharide-induced damage and function failure, at least partially, through a TLR4-dependent mechanism, suggesting a therapeutic potential against MODS.     

伊曲康唑序贯疗法治疗老年MODS患者侵袭性肺部真菌感染14例

目的 观察伊曲康唑序贯疗法治疗老年多脏器功能障碍综合征（MODS）患者侵袭性肺部真菌感染的疗效。方法 回顾分析重症监护病房（ICU）中,老年MODS患者侵袭性真菌感染14例,最初应用伊曲康唑注射液7～14d,第1～2d,200mg,1次／12h,第3～14d,200mg,1次／d;然后,采用伊曲康唑胶囊或口服液序贯治疗,400mg／d剂量水平,疗程2—4周。结果 临床有效率85．7％,真菌清除率为92．9％,真菌清除平均天数为6．1d;患者28d生存率85．7％,不良反应发生率为42．9％。结论 对老年MODS合并侵袭性真菌感染患者在综合治疗的基础上,应用广谱抗真菌药物——伊曲康唑序贯疗法,是巩固疗效,防止复发值得推广的给药方式。临床应用伊曲康唑时,应注意适应证、药物不良反应及药物的相互作用。     

Matrix metalloproteinase-9 as new biomarkers of severity in multiple organ dysfunction syndrome caused by trauma and infection

Multiple organ dysfunction syndrome (MODS) is an important cause of morbidity and mortality in intensive care unit. A severe insult in the form of infection or trauma primes the host immune system so that a subsequent, relatively trivial insult produces systemic inflammation response syndrome, which can lead to MODS and death. Matrix metalloproteinase-9 (MMP-9) is stored in the tertiary granules of polymorphonuclear leukocytes. These cells are key effectors in acute inflammatory diseases, such as sepsis and MODS. Endotoxin leads to rapid release of MMP-9 from these granules in vitro and in vivo. However, the role of this enzyme in MODS, and whether it is associated with organ injury at the early stage of MODS remains unclear. This present work may study role of MMP-9 with the MODS rats that caused by trauma and infection and investigate the mechanism of organ injury at the early stage of MODS. Here, we developed a rat model for MODS caused by trauma and infection and analyzed the dynamic level of MMP-9 and determined the relationship between MMP-9 level and early phase of organ injury in MODS rat. The histological changes in pulmonary, renal, and hepatic tissue were observed by light microscope. The expressions of plasma MMP-9 proteins were detected by an enzyme linked immunosorbent assay and its levels in the pulmonary, renal, and hepatic tissue were detected by using immunohistochemistry, respectively. The results indicated that there were no significant improvements in histopathology of rats in control group. However, the pulmonary, renal, and hepatic damage were serious in MODS groups. The concentration of MMP-9 in plasma and tissues of MODS rats increased markedly at the early stage and were higher than that of the control group. Moreover, the MMP-9 level in plasma positively correlated with the levels of pulmonary, renal, and hepatic tissue. This study clearly shows that MMP-9 is good biomarker to predict the severity of injury organ at the early phase of MODS.     

Accessing autonomic function can early screen metabolic syndrome

Background

Clinical diagnosis of the metabolic syndrome is time-consuming and invasive. Convenient instruments that do not require laboratory or physical investigation would be useful in early screening individuals at high risk of metabolic syndrome. Examination of the autonomic function can be taken as a directly reference and screening indicator for predicting metabolic syndrome.

Methodology and Principal Findings

The EZSCAN test, as an efficient and noninvasive technology, can access autonomic function through measuring electrochemical skin conductance. In this study, we used EZSCAN value to evaluate autonomic function and to detect metabolic syndrome in 5,887 participants aged 40 years or older. The EZSCAN test diagnostic accuracy was analyzed by receiver operating characteristic curves. Among the 5,815 participants in the final analysis, 2,541 were diagnosed as metabolic syndrome and the overall prevalence was 43.7%. Prevalence of the metabolic syndrome increased with the elevated EZSCAN risk level (p for trend <0.0001). Moreover, EZSCAN value was associated with an increase in the number of metabolic syndrome components (p for trend <0.0001). Compared with the no risk group (EZSCAN value 0–24), participants at the high risk group (EZSCAN value: 50–100) had a 2.35 fold increased risk of prevalent metabolic syndrome after the multiple adjustments. The area under the curve of the EZSCAN test was 0.62 (95% confidence interval [CI], 0.61–0.64) for predicting metabolic syndrome. The optimal operating point for the EZSCAN value to detect a high risk of prevalent metabolic syndrome was 30 in this study, while the sensitivity and specificity were 71.2% and 46.7%, respectively.

Conclusions and Significance

In conclusion, although less sensitive and accurate when compared with the clinical definition of metabolic syndrome, we found that the EZSCAN test is a good and simple screening technique for early predicting metabolic syndrome.     

Reduction of plasma gelsolin levels correlates with development of multiple organ dysfunction syndrome and fatal outcome in burn patients

Background

Depletion 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 Findings

95 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.

Conclusions

pGSN levels appear to be an early prognostic marker in patients suffering from major burns.