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.

Multiple organ failure (MOF) has reached epidemic proportions in most intensive care units and is fast becoming the most common cause of death in the surgical intensive care unit. Furthermore, in spite of the development of successive generations of new and more powerful antibiotics and increasing sophisticated techniques of organ support, our ability to salvage patients once MOF has become established has not appreciably improved over the last two decades. Clearly, new therapeutic strategies aimed at preventing or limiting the development of the physiologic abnormalities that induce organ failure are needed to improve survival in these critically ill patients. Based on our rapidly increasing knowledge of the mechanisms of MOF and the fruits of molecular biology, a number of new therapeutic approaches are in various stages of development. To effectively use these new therapeutic options as they become available, it is necessary to have a clear understanding of the pathophysiology of MOF. Thus, the goals of this review are to integrate the vast amount of new information on the basic biology of MOF and to focus special attention on the potential therapeutic consequences of these recent advances in our understanding of this complex and perplexing syndrome.

Multiple organ failure. Pathophysiology and potential future therapy.

A major problem in patients surviving thermal injury is the development of hypertrophic burn scars. The current study was performed to determine the factors associated with an increased risk of the development of hypertrophic burn scars. Fifty-nine children (mean age, 3 years; mean TBSA, 14%) and 41 adults (mean age, 37; mean TBSA, 21%) followed from 9 to 18 months formed the study group. The location as well as time required for the burns to heal were recorded in addition to the age and race of the patients. Sixty-three (26%) of the 245 burn areas, in these 100 patients, became hypertrophic. No correlation between patient age and the development of wound problems was found. Blacks had more wound problems than others, if the burn wound took longer than 10 to 14 days to heal. The most important indicator of whether wound problems would occur, in our series, was the time required for the burn to heal. If the burn wound healed between 14 and 21 days then one third of the anatomic sites became hypertrophic; if the burn wound healed after 21 days then 78% of the burn sites developed hypertrophic scars. Based upon these results we have developed a selective, individualized protocol for the use of prophylactic pressure therapy in patients with spontaneously healing burn wounds.

Hypertrophic burn scars: analysis of variables.

Traditionally, evaluation of intestinal function has been limited largely to monitoring gastric pH and intestinal motility. This clinical approach has led clinicians to equate normal intestinal motility with normal intestinal function and to assume that if stress-induced gastric bleeding can be prevented, all will be well. However, it is becoming increasingly clear that the gastrointestinal tract is not a passive organ and that intestinal dysfunction is not limited to ileus and upper gastrointestinal bleeding. Instead, the gastrointestinal tract is recognized as having important endocrine, metabolic, immunologic, and barrier functions, as well as its traditional role in nutrient absorption. Over the last 5 years, there has been a resurgence of interest in the role of intestinal barrier failure in the development of systemic infection and multiple organ failure in the critically ill or injured patient.

The Role of Intestinal Barrier Failure and Bacterial Translocation in the Development of Systemic Infection and Multiple Organ Failure

The current studies were performed to determine the influence of malnutrition alone or in combination with endotoxemia in promoting bacterial translocation from the gastrointestinal tract. Bacterial translocation did not occur in control, starved (up to 72 hours), or protein-malnourished (up to 21 days) mice not receiving endotoxin. Bacterial translocation to the mesenteric lymph nodes (MLNs) occurred in 80% of control mice 24 hours after receiving endotoxin (p less than 0.01). However, the combination of malnutrition plus endotoxin was associated with a higher incidence of translocation to the systemic organs (p less than 0.01), and higher numbers of bacteria per organ (p less than 0.01), than was seen in normally nourished mice receiving endotoxin. Additionally, mice that were protein malnourished were more susceptible to the lethal effects of endotoxin than were control animals, and the mortality rate was directly related to the degree of malnutrition (R2 = 0.93) (p less than 0.05). Histologically, endotoxin in combination with protein malnutrition resulted in mechanical damage to the gut mucosal barrier to bacteria. Thus, in the mice that were protein malnourished the spread of bacteria from the gut could not be controlled nor could translocated bacteria be cleared as well as normally nourished mice receiving endotoxin. These results support the concept that under certain circumstances the gut may serve as a clinically important portal of entry for bacteria.

The gut as a portal of entry for bacteremia. Role of protein malnutrition

Objective To determine whether gut-derived factors leading to organ injury and increased endothelial cell permeability would be present in the mesenteric lymph at higher levels than in the portal blood of rats subjected to hemorrhagic shock. This hypothesis was tested by examining the effect of portal blood plasma and mesenteric lymph on endothelial cell monolayers and the interruption of mesenteric lymph flow on shock-induced lung injury. Background Data The absence of detectable bacteremia or endotoxemia in the portal blood of trauma victims casts doubt on the role of the gut in the generation of multiple organ failure. Nevertheless, previous experimental work has clearly documented the connection between shock and gut injury as well as the concept of gut-induced sepsis and distant organ failure. One explanation for this apparent paradox would be that gut-derived inflammatory factors are reaching the lung and systemic circulation via the gut lymphatics rather than the portal circulation. Methods Human umbilical vein endothelial cell monolayers, grown in two-compartment systems, were exposed to media, sham-shock, or postshock portal blood plasma or lymph, and permeability to rhodamine (10K) was measured. Sprague-Dawley rats were subjected to 90 minutes of sham or actual shock and shock plus lymphatic division (before and after shock). Lung permeability, pulmonary myeloperoxidase levels, alveolar apoptosis, and bronchoalveolar fluid protein content were used to quantitate lung injury. Results Postshock lymph increased endothelial cell monolayer permeability but not postshock plasma, sham-shock lymph/plasma, or medium. Lymphatic division before hemorrhagic shock prevented shock-induced increases in lung permeability to Evans blue dye and alveolar apoptosis and reduced pulmonary MPO levels. In contrast, division of the mesenteric lymphatics at the end of the shock period but before reperfusion ameliorated but failed to prevent increased lung permeability, alveolar apoptosis, and MPO accumulation. Conclusions Gut barrier failure after hemorrhagic shock may be involved in the pathogenesis of shock-induced distant organ injury via gut-derived factors carried in the mesenteric lymph rather than the portal circulation.

Edwin A. Deitch

Papers

Multiple organ failure. Pathophysiology and potential future therapy.

Hypertrophic burn scars: analysis of variables.

The Role of Intestinal Barrier Failure and Bacterial Translocation in the Development of Systemic Infection and Multiple Organ Failure

The gut as a portal of entry for bacteremia. Role of protein malnutrition

Gut-derived mesenteric lymph but not portal blood increases endothelial cell permeability and promotes lung injury after hemorrhagic shock.