Multiple organ dysfunction syndrome: past,present and future

In the past, our approach to multiple organ failure in the injured or critically ill surgical patient was driven by attempts to simplify a complex process. Early studies focused on uncontrolled invasive infection (sepsis) as the driving force of multiple organ dysfunction syndrome (MODS). However, some patients with adequately controlled infection and those without sepsis nevertheless develop MODS and signs of systemic inflammation. This discrepancy led to investigations of systemic activation of inflammation by a wider variety of biological modulators than just infection. Despite the apparent involvement of biological modulators such as endotoxin, tumor necrosis factor, and interleukin-1 receptor in MODS, agents that neutralize these modulators have failed to thwart the progression of sepsis, septic shock, and organ failure. A new paradigm suggests that, in the critically ill patient at risk for organ failure, an integrated process propagates an excessive systemic inflammatory response and/or an inadequate compensatory anti-inflammatory response. Future studies should examine the balance between these two processes at the level of the individual patient with organ failure. Careful stratification of individual patient responses to inflammatory stressors may be an essential step for creating better strategies for therapeutic interventions that can restore balance between the pro-inflammatory and anti-inflammatory processes in the critically ill patient and possibly prevent organ failure.     

Effect of Neostigmine on Organ Injury in Murine Endotoxemia: Missing Facts about the Cholinergic Antiinflammatory Pathway

Electrical and pharmacologic stimulation of the efferent cholinergic antiinflammatory pathway suppress the systemic inflammatory response and can prevent lethal endotoxemia. Neostigmine, a cholinergic agent, has not been tested to determine if it can prevent histopathologic organ injury in endotoxemia. In the present study, the effects of neostigmine treatment on the histopathologic organ injury inflicted by Escherichia coli endotoxin in a mouse model of septic shock was investigated. Endotoxemia in mice caused weight loss and increased spleen, liver, and lung weight. When the organs were examined for histopathologic injury, endotoxemia increased interstitial inflammation in the lungs, liver injury, and organ injury in general terms; neostigmine, at a dose of 0.1 mg/kg, failed to attenuate these effects. Although the simultaneous administration of neostigmine at a dose of 0.3 mg/kg and endotoxin decreased interstitial inflammation in the lungs, vacuolar degeneration in the liver, and total liver injury, mortality was increased with this dose in the presence of endotoxemia. We conclude that neostigmine at a dose of 0.1 mg/kg was not protective against histopathologic organ injury in mice with endotoxemia, and a higher dose (0.3 mg/kg) was not tolerated probably owing to nonspecific parasympathetic action including cardiovascular effects. Further studies are required to determine the contribution of sites in the cholinergic antiinflammatory pathway.     

The cytokine network in the critically ill.

There is increasing experimental and clinical evidence that a number of cytokines play a major role in the response to injury and infection and in the development of organ damage in critically ill patients. Tumour necrosis factor (TNF) is now proposed to be a key mediator of organ injury during sepsis. It is elevated early in the course of septic shock and high levels correlate with unfavourable outcome. In animals it can produce the effects of endotoxin. The prophylactic administration of anti-TNF antisera protects mice and rabbits from lethal effects of lipopolysaccharide. Interleukin-1 (IL-1) is an endogenous pyrogen which induces leukocytosis and muscle catabolism. It causes hypotension and tachycardia by reducing smooth muscle contractility. IL-1 receptor blockers have been shown to diminish mortality in experimental endotoxic shock. Interleukin-6 (IL-6) is a pyrogen and lymphocyte activator. It is the major stimulus to acute phase protein production by the liver. A recently described neutrophil-activating peptide (Interleukin-8; IL-8) may be involved in the pathogenesis of ARDS. High blood levels of IL-8 have been found in patients with septic shock. Platelet-derived growth factor (PDGF) has been shown to stimulate TNF production, leukocyte chemotaxis and pulmonary vasoconstriction in response to endotoxin. Other cytokines and growth factors have not yet been studied in critical illness. The cytokine network can be either protective or damaging. Its activation during critical illness triggers complex and still poorly understood interactions. A better comprehension of its role in protection from infection and in the pathogenesis of multiple organ failure may allow therapeutic manipulations aimed at minimising adverse effects while retaining immunological protection.     

急腹症合并感染性休克的相关因素分析及临床诊治对策

目的：探讨影响急腹症合并感染性休克的相关因素,并予以相对应的措施进行治疗.方法：回顾性分析40例急腹症合并感染性休克的患者,对其发生的相关因素进行分析,并比较治疗后的效果情况.结果：40例患者中有31例抢救成功,9例死亡,存活率为77.5％.患者发生急腹症合并感染性休克的影响因素有：高龄（≥60岁）、多种合并症（≥2种）、慢性疾病史、有创检查和治疗、器官衰竭个数多（＞2个）、全身炎症反应综合征、脏器功能衰竭综合征,低蛋白血症（P＜0.05）.与患者的性别、血培养、住院时间、静脉营养、手术治疗等无关（P＞0.05）,其中年龄、多种合并症、脏器功能衰竭综合征、全身炎症反应综合征是高危险因素.结论：密切注意急腹症合并感染性休克的影响因素,及时早期规范治疗,可提高急腹症合并感染性休克的临床效果,降低死亡发生率.     

Prevention of multiple organ dysfunction syndrome in patients with extensive deep burns

Multiple organ dysfunction (or failure) syndrone (MODS or MOFS) remains a hurdle for us to overcome before further improvement in the survival rate can be achieved in the patients with extensive deep bums. It is, however, generally recognized that MODS is the final result of the liberation and interplay of multiple inflammatory mediators or cytokines, and there is a two-hit phenomenon in its pathogenesis.     

The systemic inflammatory response syndrome

Sepsis and septic shock are the leading causes of death in intensive care units in developed countries despite recent advances in critical care medicine. Sepsis is the systemic inflammatory response to infection frequently associated with hypoperfusion followed by tissue injury and organ failure. The activation of monocytes/macrophages and neutrophils, with the consecutive release of pro-inflammatory mediators and activation of the coagulation cascade, seems to play a key role in the pathogenesis of sepsis. Elimination of the septic focus, anti-microbial therapy and supportive treatment are the cornerstones of sepsis therapy. In addition, the application of small doses hydrocortisone to patients with refractory septic shock and the treatment of patients with septic multiple organ failure with activated protein C are two adjunctive therapeutic strategies. Promising new experimental treatment options are interference with MIF, HMGB1, C5a or TREM-1 signal transduction pathways and an inhibition of apoptosis, which may further improve the prognosis of septic patients in the future.     

Sepsis, systemic inflammatory response, and multiple organ dysfunction: the mystery continues

Human sepsis is thought to be systemic inflammatory response syndrome (SIRS) that is activated by invasive infection. The multiple organ dysfunction syndrome (MODS) is the identified failure of critical organ function in patients that have sustained SIRS. Because SIRS and MODS are consequences of the excessive activation of inflammation, extensive research and numerous clinical trials have pursued treatments that would modify the inflammatory response. This presentation reviews the normal local mechanisms of inflammation and provides a theoretical framework for the transition of the inflammatory process to a systemic level. Clinical trials with biomodulators to block or inhibit inflammation have generally failed to improve the outcomes in patients with severe sepsis, septic shock, and MODS. The role of counter-inflammatory signaling and the newer concept of the cholinergic anti-inflammatory pathway are being investigated, and newer hypotheses are focusing upon the balancing of proinflammatory and counter-inflammatory mechanisms as important directions for newer therapies. It is concluded that failure to define novel and effective treatments reflects fundamental gaps in our understanding of inflammation and its regulation.     

Role of the neutrophil in septic shock and the adult respiratory distress syndrome.

The adult respiratory distress syndrome (ARDS) is a serious complication of many medical and surgical conditions, most of which do not involve direct pulmonary injury. In surgical practice, septic shock has long been recognised as an important cause of ARDS and it presents many management challenges. Endotoxin released from dead and dying Gram-negative bacteria induces a generalised inflammatory response that results in multiple organ dysfunction, the lung being just one target of this injurious process. In recent years, with the discovery of several key inflammatory mediators, many aspects of this complex condition have been elucidated. The neutrophil has emerged as the central effector cell and possesses a formidable armamentarium of cytokines, enzymes, and oxygen radicals that are capable of inflicting damage to cells. In this review I examine the mechanisms underlying the recruitment and activation of neutrophils in ARDS.     

Sepsis. What it is and how to recognize it.

Sepsis, shock, and resuscitation may result in various degrees of ischemia-perfusion injury that may produce widespread organ dysfunction through complex interactions and activation of host immunoinflammatory processes. As the pathophysiologic mechanisms of the inflammatory response are better defined, we may be able to modulate the generalized inflammatory state we know as sepsis and prevent the development of multiple organ failure syndrome. At present, however, the mainstay of therapy remains prompt resuscitation to eliminate regions of hypoperfusion and to limit as much as possible those factors that predispose to further organ injury while the source of inflammatory stimulation is being identified and controlled.     

A review of septic shock

The mortality of septic shock, both in percentage of septic shock cases and total number of septic shock cases, has been increasing over the past several decades. This is despite major advances in diagnosis and treatment. The basic cause of traumatic and septic shock has only partially been elucidated. This review presents information about the basic cause and mechanism of septic shock as well as a new treatment based on this information. Data sources include research papers on the subject of septic shock from 1875 until the present. These papers numbered more than 10,000, most of which are not included in the reference list because many are duplicative. The main result of the review of literature is that all of a wide variety of treatments of septic shock have not resulted in a lowering of mortality, but in fact have increased it. Another toxin (in addition to endotoxin and its secondarily induced host mediators) is proposed. This toxin causes disseminated intravascular coagulation, which may obstruct the microcirculation of any and all organs, producing multiple organ failure by microclots. These microclots may be lysed by plasminogen activator and circulation to the organs restored.     

Cascade system activation in shock

Trauma and sepsis activate different cascade systems. Activation of the coagulation and clotting systems, of the kinin-kallekrein system and of the complement system are important etiological mechanisms behind development of the adult respiratory distress syndrome (ARDS) and multisystem organ failure (MOF) after extensive trauma or severe septic situations. Activation of complement with the release of anaphylatoxins and terminal complement complexes is associated with increased mortality and development of ARDS and MOF after major surgery and in situations of septic shock. The anaphylatoxins have potent vascular properties and they activate leukocytes. Their effects on the leukocytes lead to the release of free oxygen radicals, different lysosomal enzymes and cytokines, leukotrienes and histamine. All these inflammatory mediators may, if released in extensive amounts, induce microvascular injury and interstitial edema. If this process takes place in the lung, ARDS may develop and if other organs, i.e the liver and the kidneys, are involved, MOF may be the result.     

Poor outcome from peritonitis is caused by disease acuity and organ failure, not recurrent peritoneal infection.

OBJECTIVE: The purpose of the study is to determine whether organ failure develops in patients despite control of peritoneal infection and whether the process is, in part, neutrophil (polymorphonuclear leukocyte [PMN]) mediated. SUMMARY BACKGROUND DATA: Peritonitis generally responds to prompt surgical intervention and systemic antibiotics; however, some patients continue a septic course and progress to organ failure and death. METHODS: One hundred five consecutive patients with peritonitis between 1988 and 1996 who required operation and a postoperative hospital stay greater than 10 days were studied. Mice were injected with a monoclonal anti-PMN antibody 24 hours before cecal ligation and puncture (CLP) to deplete PMNs. RESULTS: Thirty-eight patients died, and all but 1 had identified organ failure. Seventy-seven patients had either pulmonary failure alone (25 patients) or as a component of multisystem organ failure (52 patients). All but one of these patients showed resolution of their intraperitoneal infection as evident by clinical course, abdominal computed tomographic scan, second-look laparotomy, or autopsy. Recurrent intra-abdominal infection developed in 15 patients, but only 1 had organ failure, and 2 died. At 18 hours after CLP, lung injury, PMN content, interleukin-1 mRNA expression, and liver injury were significantly reduced by anti-PMN treatment, whereas serum endotoxin levels actually increased. CONCLUSIONS: Disease acuity and organ failure, and not recurrent peritoneal infection, are the major causes of adverse outcome in patients with peritonitis. The authors' experimental data indicate that such organ injury is, in part, PMN mediated but not endotoxin mediated. Attraction of PMNs toward the site of primary infection, and thereby away from remote organs, is a logical future therapeutic approach in such patients who are critically ill with peritonitis.     

杀菌/通透性增加蛋白对内毒素休克大鼠微循环灌注的保护作用

目的 探讨杀菌／通透性增加蛋白（ＢＰＩ）对内毒素休克时血液动力学和内脏微徨灌注的保护作用及其机制。方法 采用大鼠内毒素休克模型,动态观察血液动力学、内脏微循环灌注量和血浆生物喋吟、一氧化氮（ＮＯ）水平的变化。结果 休克早期给予重组ＢＰＩ,可显著提高平均支流压、心脏指数及每搏输出量,明显改善肝、肾、小肠抽徨灌注量及动物预后（Ｐ〈０．０５～０．０１）,循环ＮＯ产生亦不同程度受到抑制。结论 早期应用ＢＰ     

Physiopathological alterations secondary to extracorporeal circulation in cardiac surgery

Cardiopulmonary bypass (CPB) is one of the methods used in myocardial revascularization and can be associated with adverse events that are uncommon, but CPB induces high morbidity and mortality. Cardiac surgery and CPB activate a systemic inflammatory response characterized by tissular lesions, cells movements and blood flow toward the interstice where the harmful stimulus has begun, under the influence of the mediators. The systemic inflammatory response may be initiated during cardiac surgery by a number of processes, including blood contact with the foreign surface of the CPB apparatus, development of ischemia and reperfusion injury, and presence of endotoxemia. In the course of cardiac surgery using CPB, all three processes are present and contribute concurrently to the systemic inflammatory response. The term "systemic inflammatory response syndrome" (SIRS) has been proposed to describe an entity that continually overlaps with normal postoperative physiology. A frequent complication of SIRS is the development of organ dysfunction, including acute lung injury, shock, renal failure, and multiple organ dysfunction syndrome. Finally, long-term survival in patients developing SIRS may also be adversely affected. The purpose of this review is to examine and understand the pathological mechanisms for inflammatory response that occur following cardiopulmonary bypass.     

Pathophysiologie der Sepsis Aktuelle Konzepte

Clinical manifestations of sepsis, such as systemic inflammatory response and multiple organ dysfunction syndrome, are considered to be the results of a decompensated host defense response. If tissue injury is sufficiently severe to overwhelm local defense mechanisms, systemic activation of these essentially protective mechanisms may lead to autodestructive ?host defense failure disease.“ This is not always caused by invading bacteria; sterile inflammation such as results from multiple trauma or pancreatitis can initiate a similar response. Evidence suggests that the activation of the macrophage/monocyte system that underlies the systemic inflammatory response may reflect one facet of a more generalized dysregulation of intercellular communication, as well as a dysfunction of such subcellular processes as signal transduction or stress gene expression. Alterations in signal transduction or stress gene expression can affect the host defense response to subsequent stressful events in either a negative or a positive sense. In particular, the sequential induction of acute phase and heat shock response may initiate programmed cell death, reflecting a potential molecular mechanism for the development of multiple organ dysfunction syndrome. The development of anti-inflammatory treatment strategies seems to be hampered by the discrepancy between locally protective and systemically deterimental properties of the host defense response.     

Multiple organ dysfunction syndrome: a narrative review

PURPOSE: To review multiple organ dysfunction syndrome with respect to: 1) clinical measurement systems; 2) molecular mechanisms; and 3) therapeutic directions based upon molecular mechanisms. METHODS: The Medline, Cochrane, and Best Evidence databases (1996 to 2000), conference proceedings, bibliographies of review articles were searched for relevant articles. Key index words were multiple organ failure, multiple system organ dysfunction, sepsis, septic shock, shock, systemic inflammatory response syndrome. Outcomes prospectively defined were death and physiological reversal of end organ failure. RESULTS: Multiple organ dysfunction/failure (MODS) is the most common cause for death in intensive care units. The recognition of this syndrome in the last 30 yr may be due to advances in early resuscitation unmasking these delayed sequelae in those that would have died previously. Multiple organ dysfunction occurs after shock of varied etiologies and may be the result of unbridled systemic inflammation. As yet, therapy directed to prevent or improve MODS has not dramatically altered outcomes. CONCLUSION: Multiple organ dysfunction may serve as useful measure of disease severity for risk adjustment and outcome marker for quality of care and therapy provided. Anesthesiologists treating shock patients will note the subsequent development of MODS in the critical care unit and may be required to provide anesthetic support to these patients.     

Splanchnic ischaemia and its role in multiple organ failure

Multiple organ failure remains the leading cause of death in the intensive care unit. Increasing numbers of investigators have focused their attention on the role of gastrointestinal tract in the pathogenesis of this syndrome. Their data indicate that inadequate gut perfusion leads to a measurable imbalance between oxygen delivery and the needs of the tissues, i.e., ischaemia. Gut ischaemia of sufficient duration impairs gastrointestinal tract barrier function, facilitating the passage of enteric bacterial endotoxin into the circulation. It has been hypothesized that production of tumor necrosis factor α, and other biologic mediators by endotoxin–stimulated macrophages, triggers a generalized and uncontrolled inflammatory response that ultimately leads to multiple organ failure.
Preliminary evidence suggests that survival can be improved significantly if gut ischaemia is promptly identifed and aggressively treated by administration of fluids and inotropic drugs, using gastric intramucosal pH as the therapeutic endpoint. Future studies are needed to determine whether additional treatment modalities can improve outcome once the inflammatory response has fully developed.     

Splanchnic hypoperfusion and distant organ injury]

Acute respiratory distress syndrome (ARDS) and multiple organ failure (MOF) are the most common causes of death in surgical intensive care units. A variety of stimuli, such as major surgery, trauma, shock, thermal injury, acute pancreatitis, and ischemia-reperfusion injury, initiate a systemic inflammatory response that contributes to the development of these complications. Splanchnic hypoperfusion is a common clinical event in critically ill patients. Recently, measurement of the adequacy of gut circulation has been demonstrated as an excellent tool for prediction of outcome in these patients. The emphasis of this review is on events associated with intestinal ischemia-reperfusion and subsequent distant organ injury.     

Technical advances in renal replacement therapy

Critically ill patients are subject to several risk factors for organ injury: surgical intervention, trauma, rhabdomyolysis, hemodynamic instability, organ hypoperfusion, bacteremia and endotoxemia, sepsis and septic shock. These conditions may cause acute kidney injury (AKI), myocardial dysfunction, liver failure, coagulation abnormalities, acute lung injury (ALI), adult respiratory distress syndrome (ARDS), bone marrow depression, loss of acid/base homeostasis, and finally, brain dysfunction. The resulting picture of multiple organ dysfunction syndrome (MODS) is a lethal clinical entity that is refractory to all therapies in the majority of cases. According to the "humoral theory of sepsis", soluble substances circulate in blood and participate in the generation of the different disorders of MODS; thus, AKI is not the only clinical disorder observed in intensive care unit (ICU) patients nor is it an isolated syndrome. Current extracorporeal management of such patients focuses mainly on renal replacement therapy (RRT). Nevertheless, in recent years, technical evolution of extracorporeal devices led to the potential creation of multiple organ support therapy (MOST) in order to provide a comprehensive replacement of multiorgan dysfunction: hence, other organs (liver, heart, lungs) and syndromes (abdominal sepsis, septic shock) can today be consistently supported and bridged. The technical advances of extracorporeal equipment, moreover, might allow today the design of a dedicated pediatric RRT device in order to treat patients below 10 kg, with the safety and adequacy standards that are currently granted to the adult population. This review will describe the technical evolution of MOST machines and current literature available on MOST.     

The effects of nitric oxide inhalation on respiratory mechanics and gas exchange during endotoxaemia in the pig

Background : In the adult respiratory distress syndrome, nitric oxide (NO) inhalation improves oxygenation through reducing ventilation-perfusion mismatching, but detailed information on the pulmonary effects of NO inhalation in septic shock is scarce. The present study investigated the effects of inhaled NO on alveolar dead space (Vdalv) and venous admixture as well as on respiratory system compliance (Crs) and respiratory system resistance (Rrs) in a porcine model of septic shock. Protective effects of NO are discussed.
Methods : Thirteen anaesthetised and ventilated pigs were given an infusion of endotoxin for an observation time of 220 min to induce acute lung injury (ALI). In the NO-early group (n=6), an inhalation of 60 ppm NO was started simultaneously with the endotoxin infusion and continued for 190 min. In 7 control/NO-late animals, 60 ppm NO was administered for 30 min following 190 min of endotoxin infusion. Haemodynamics, single-breath CO₂-, pressure-, and flow signals were recorded.
Results : Endotoxin induced haemoconcentration, pulmonary vasoconstriction, and a decrease in Crs, while venous admixture, Vdalv, and Rrs increased. In the NO-early group, the pulmonary vasoconstriction was attenuated, no increase in pulmonary venous admixture or in Vdalv was seen before cessation of NO, and the improvements in oxygenation outlasted the NO inhalation. In the control/NO-late group, the NO inhalation reversed the changes in dead space and venous admixture. NO had no effect on the changes in respiratory mechanics.
Conclusion : In porcine ALI, 60 ppm NO diminishes pulmonary vasoconstriction and improves gas exchange by reducing pulmonary venous admixture and alveolar dead space, but does not prevent a fall in Crs. NO inhalation may help prevent longlasting pulmonary failure.