Multiple organ failure (MOF) is a major cause of morbidity and mortali ty in the critically ill patient. Emerging in the 1970s, the concept of MOF was linked to modern developments in intensive care medicine [1]. Although an uncontrolled infection can lead to MOF [2], such a phenomenon is not always found. A number of mediators and the persistence of tissue hypoxia have been incriminated in the development of MOF [3]. The gut has been cited as a possible \"moto r \" of MOF [4]. Nevertheless, our knowledge regarding the pathophysiology of MOF remains limited. Furthermore, the development of new therapeutic interventions aiming at a reduction of the incidence and severity of organ failure calls for a better definition of the severity of organ dysfunction/failure to quantify the severity of illness. Accordingly, it is important to set some simple but objective criteria to define the degree of organ dysfunction/failure. The evolution of our knowledge of organ dysfunction/failure led us to establish several principles: 1. Organ dysfunction/failure is a process rather than an event. Hence, it should be seen as a continuum and should not be described simply as \"present\" or \"absent~' Hence, the assessment should be based on a scale. 2. The time factor is fundamental for several reasons: (a) Development and similarly resolution of organ failure may take some time. Patients dying early may not have time to develop organ dysfunction/failure. (b) The time course of organ dysfunction/failure can be mult imodal during a complex clinical course, what is sometimes referred to as a \"multiple-hit\" scenario. (c) Time evaluation allows a greater understanding of the disease process as a natural process or under the influence of therapeutic interventions. The collection of data on a daily basis seems adequate. 3. The evaluation of organ dysfunction/failure should be based on a limited number of simple but objective variables that are easily and routinely measured in every institution. The collection of this information should not impose any intervention beyond what is routinely performed in every ICU. The variables used should as much as possible be independent of therapy, since therapeutic management may vary from one institution to another and even from one patient to another (Table 1). Until recently, none of the existing systems describing organ failure met these criteria, since they were based on categorial definitions or described organ failure as present or absent [5-7] . The ESICM organized a consensus meeting in Paris in October 1994 to create a so-called sepsis-related organ failure assessment (SOFA) score, to describe quantitatively and as objectively as possible the degree of organ dysfunction/failure over time in groups of patients or even in individual patients (Fig. 1). There are two major applications of such a SOFA score: 1. To improve our Understanding of the natural history of organ dysfunction/failure and the interrelation between the failure of the various organs.

The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine.

The discovery that mammalian cells have the ability to synthesize the free radical nitric oxide (NO) has stimulated an extraordinary impetus for scientific research in all the fields of biology and medicine. Since its early description as an endothelial-derived relaxing factor, NO has emerged as a fundamental signaling device regulating virtually every critical cellular function, as well as a potent mediator of cellular damage in a wide range of conditions. Recent evidence indicates that most of the cytotoxicity attributed to NO is rather due to peroxynitrite, produced from the diffusion-controlled reaction between NO and another free radical, the superoxide anion. Peroxynitrite interacts with lipids, DNA, and proteins via direct oxidative reactions or via indirect, radical-mediated mechanisms. These reactions trigger cellular responses ranging from subtle modulations of cell signaling to overwhelming oxidative injury, committing cells to necrosis or apoptosis. In vivo, peroxynitrite generation represents a crucial pathogenic mechanism in conditions such as stroke, myocardial infarction, chronic heart failure, diabetes, circulatory shock, chronic inflammatory diseases, cancer, and neurodegenerative disorders. Hence, novel pharmacological strategies aimed at removing peroxynitrite might represent powerful therapeutic tools in the future. Evidence supporting these novel roles of NO and peroxynitrite is presented in detail in this review.

/pdf/nitric-oxide-and-peroxynitrite-in-health-and-disease-3uuuqgfdcz.pdf

Nitric Oxide and Peroxynitrite in Health and Disease

Gut microbiota is an assortment of microorganisms inhabiting the length and width of the mammalian gastrointestinal tract. The composition of this microbial community is host specific, evolving throughout an individual's lifetime and susceptible to both exogenous and endogenous modifications. Recent renewed interest in the structure and function of this "organ" has illuminated its central position in health and disease. The microbiota is intimately involved in numerous aspects of normal host physiology, from nutritional status to behavior and stress response. Additionally, they can be a central or a contributing cause of many diseases, affecting both near and far organ systems. The overall balance in the composition of the gut microbial community, as well as the presence or absence of key species capable of effecting specific responses, is important in ensuring homeostasis or lack thereof at the intestinal mucosa and beyond. The mechanisms through which microbiota exerts its beneficial or detrimental influences remain largely undefined, but include elaboration of signaling molecules and recognition of bacterial epitopes by both intestinal epithelial and mucosal immune cells. The advances in modeling and analysis of gut microbiota will further our knowledge of their role in health and disease, allowing customization of existing and future therapeutic and prophylactic modalities.

Gut Microbiota in Health and Disease

ObjectiveTo develop an objective scale to measure the severity of the multiple organ dysfunction syndrome as an outcome in critical illness.DesignSystematic literature review; prospective cohort study.SettingSurgical intensive care unit (ICU) of a tertiary-level teaching hospital.PatientsAll patient

Multiple organ dysfunction score : a reliable descriptor of a complex clinical outcome

ContextEvaluation of trends in organ dysfunction in critically ill patients
may help predict outcome.ObjectiveTo determine the usefulness of repeated measurement the Sequential Organ
Failure Assessment (SOFA) score for prediction of mortality in intensive care
unit (ICU) patients.DesignProspective, observational cohort study conducted from April 1 to July
31, 1999.SettingA 31-bed medicosurgical ICU at a university hospital in Belgium.PatientsThree hundred fifty-two consecutive patients (mean age, 59 years) admitted
to the ICU for more than 24 hours for whom the SOFA score was calculated on
admission and every 48 hours until discharge.Main Outcome MeasuresInitial SOFA score (0-24), Δ-SOFA scores (differences between
subsequent scores), and the highest and mean SOFA scores obtained during the
ICU stay and their correlations with mortality.ResultsThe initial, highest, and mean SOFA scores correlated well with mortality.
Initial and highest scores of more than 11 or mean scores of more than 5 corresponded
to mortality of more than 80%. The predictive value of the mean score was
independent of the length of ICU stay. In univariate analysis, mean and highest
SOFA scores had the strongest correlation with mortality, followed by Δ-SOFA
and initial SOFA scores. The area under the receiver operating characteristic
curve was largest for highest scores (0.90; SE, 0.02; P<.001 vs initial score). When analyzing trends in the SOFA score
during the first 96 hours, regardless of the initial score, the mortality
rate was at least 50% when the score increased, 27% to 35% when it remained
unchanged, and less than 27% when it decreased. Differences in mortality were
better predicted in the first 48 hours than in the subsequent 48 hours. There
was no significant difference in the length of stay among these groups. Except
for initial scores of more than 11 (mortality rate >90%), a decreasing score
during the first 48 hours was associated with a mortality rate of less than
6%, while an unchanged or increasing score was associated with a mortality
rate of 37% when the initial score was 2 to 7 and 60% when the initial score
was 8 to 11.ConclusionsSequential assessment of organ dysfunction during the first few days
of ICU admission is a good indicator of prognosis. Both the mean and highest
SOFA scores are particularly useful predictors of outcome. Independent of
the initial score, an increase in SOFA score during the first 48 hours in
the ICU predicts a mortality rate of at least 50%.

https://jamanetwork.com/journals/jama/articlepdf/194262/JCE00056.pdf

Serial evaluation of the SOFA score to predict outcome in critically ill patients.

The primary functions of the gut are to absorb nutrients and exclude bacteria and their products. However, under certain circumstances the gut may lose its barrier function and serve as a reservoir for systemic microbial infections. These experiments were performed to determine the mechanisms whereby endotoxin causes bacteria to escape (translocate) from the gut. Bacteria translocated from the gut to the mesenteric lymph nodes of mice challenged with nonlethal doses of Escherichia coli 026:B6 or E. coli 0111:B4 endotoxin. Physical disruption of the gut mucosal barrier appears to be the primary mechanism whereby endotoxin promotes bacterial translocation. Mucosal injury and endotoxin-induced bacterial translocation were reduced by inhibition (allopurinol) or inactivation (tung-sten diet) of xanthine oxidase activity (P less than 0.01), but were not affected by the platelet-activation factor antagonists, SRI 63-441 or BN 52021. Because the inhibition or inactivation of xanthine oxidase activity reduced both the extent of mucosal injury and endotoxin-induced bacterial translocation, the effect of endotoxin on the gut appears to be mediated, at least to some degree, by xanthine oxidase-generated, oxygen-free radicals.

Inhibition of endotoxin-induced bacterial translocation in mice.

Reactive oxygen metabolites have been implicated as important mediators of inflammation-induced intestinal injury associated with ischemia (and reperfusion), radiation, and inflammatory bowel disease. Because the colonie mucosa may be subjected to significant oxidant stress during times of acute and chronic inflammation, knowledge of the oxidant defense mechanisms in the colon is of biologic and potential clinical importance. Therefore, the objective of this study was to quantify the specific activities of superoxide dismutase (SOD), catalase, and GSH peroxidase in the normal human colon. We found low, but significant, amounts of all three enzymes in the mucosa, submucosa, and muscularis/serosa of the human colon. However, the mucosal levels of SOD (3.6±0.3 units/mg protein), catalase (11±3 units/ mg), and GSH peroxidase (15.2±0.8 mU/mg) represented only 8%, 4%, and 40%, respectively, of those values determined for human liver. Colonic epithelial cells derived from mucosal biopsies exhibited significantly higher specific activities for SOD (12±0.5 units/mg) and catalase (26±6 units/mg) when compared to whole mucosa, suggesting most of the mucosal activity was associated with the epithelial cells and not the lamina propria. In a comparative study, we found that a human colonic carcinoma cell line (CaCo-2) contained significantly lower SOD (6 ±0.5 units/mg) and catalase (6±0.6 units/mg) activities when compared to colonic epithelial cells. Taken together, our data suggest that: (1) the colonic mucosa is relatively deficient in antioxidant enzymes when compared to liver, and (2) most of the protective enzyme activity is localized within the epithelium and not the mucosal interstitium.

Oxidant defense mechanisms in the human colon.

Background Previously, we showed that mesenteric lymph generated following hemorrhagic shock increases endothelial cell permeability and contributes to lung injury. It has also been shown that lymph produced at the site of burn injury plays a role in altering pulmonary vascular hemodynamics. In addition, previous experimental work has suggested that organs and tissues distant from the injury site may contribute to pulmonary dysfunction. One explanation would be that gut-derived inflammatory factors (in addition to those produced locally at the site of injury) are reaching the pulmonary circulation, where they exert their effects via the gut lymphatics. Hypotheses The 2 hypotheses herein were that (1) gut-derived factors carried in the mesenteric lymph of rats generated following thermal injury will contribute to lung injury and (2) intestinal bacterial overgrowth will potentiate the degree of burn-induced lung injury. These hypotheses were tested by examining the effect of mesenteric lymph flow interruption prior to thermal injury on burn-induced lung injury in rats with a normal intestinal bacterial flora and in rats with intestinal Escherichia coli overgrowth. These rats were termed E coli –monoassociated rats. Methods Normal intestinal bacterial flora and monoassociated male Sprague-Dawley rats were subjected to sham burn, 40% total body surface area burn, or lymphatic division plus burn. After 3 hours, 10 mg of Evans blue was injected to measure lung permeability. After the rats were killed, a bronchoalveolar lavage was performed and the fluid analyzed spectrophotometrically. Bronchoalveolar lavage fluid protein content, pulmonary myeloperoxidase activity, and alveolar apoptosis served to further quantitate lung injury. Results Both normal intestinal bacterial flora and monoassociated-burned rats exhibited significant increases in lung permeability, bronchoalveolar lavage fluid protein content, myeloperoxidase activity, and alveolar apoptosis. The combination of monoassociation and thermal injury resulted in even further increases in lung injury over thermal injury alone. Lymphatic division prior to thermal injury ameliorated burn-induced increases in lung permeability, bronchoalveolar lavage fluid protein content, pulmonary myeloperoxidase accumulation, and alveolar apoptosis in both normal intestinal bacterial flora and monoassociated rats. Conclusions The results of this study support the hypothesis that gut-derived factors carried in the mesenteric lymph contribute to burn-induced lung injury and may therefore play a role in postburn respiratory failure and suggest that intestinal bacterial overgrowth primes the host such that when animals are exposed to a second stimulus (such as thermal injury) an exaggerated response occurs.

https://jamanetwork.com/journals/jamasurgery/articlepdf/390454/ssi9016.pdf

Gut-Derived Mesenteric Lymph A Link Between Burn and Lung Injury

Previously we have shown that under certain conditions, bacteria can pass through the intact epithelial mucosa to the mesenteric lymph nodes (MLN), liver, spleen, and bloodstream to cause infection, a process termed bacterial translocation. To extend these studies, we determined the influence of protein malnutrition and endotoxemia on bacterial translocation in burned (25% TBSA) and unburned mice. The results of these experiments documented that protein malnutrition did not promote bacterial translocation from the gut in either burned or unburned animals, although it did disrupt the normal indigenous gut flora. In contrast, a nonlethal dose of endotoxin (IP) promoted bacterial translocation to the mesenteric lymph nodes in burned and unburned mice, but only in burned mice did the bacteria translocate from the gut to other systemic organs (p less than 0.01). Furthermore, the mortality rate of mice receiving only endotoxin or burn was less than 10%, while the combination of endotoxin plus a thermal injury increased the mortality rate to 100% (p less than 0.01). These studies support the concept that bacteria may translocate from the gut to other organs and be a potential source of lethal infections after thermal injury.

Endotoxin but not malnutrition promotes bacterial translocation of the gut flora in burned mice.

Recent animal studies indicate that immediate enteral feeding may be beneficial in patients with major burns. Yet, largely because of the fear of complications, immediate enteral feeding is not commonly performed in patients with major burns until after the resuscitation period. The purpose of this study was to evaluate the safety and efficacy of immediate enteral tube feedings in patients with burns larger than 20% of their body surface area. The daily intake of enteral feedings begun immediately (less than 6 hours) after burn was measured during the first 7 days after burn in 106 consecutive patients with a mean +/- SD burn size of 40% +/- 21%. The incidence of complications related to enteral feeding was low; aspiration pneumonia did not occur. Vomiting was the major complication observed and occurred 21 times in 16 patients during the 745 study days (2.8% daily incidence). The mean number of calories absorbed enterally increased daily and met the patient's calculated resting energy expenditure (REE) on day 3 after burn (99% +/- 7% REE). The results of this study indicate that immediate enteral feeding is a safe and effective method of delivering nutritional support to burn victims with major burns.

Edwin A. Deitch

Papers

Inhibition of endotoxin-induced bacterial translocation in mice.

Oxidant defense mechanisms in the human colon.

Gut-Derived Mesenteric Lymph A Link Between Burn and Lung Injury

Endotoxin but not malnutrition promotes bacterial translocation of the gut flora in burned mice.

Immediate enteral feeding in burn patients is safe and effective.