Short- and long-term prognosis of acute critically ill patients with systemic rheumatic diseases: A retrospective multicentre study

Patients with systemic rheumatic disease (SRD) share the risks of multi-organ flare-up, cardiovascular diseases, and immunosuppression. Such situations can lead to an acute critical illness. The present study describes the clinical features of SRD patients admitted to the intensive care unit (ICU) and their short- and long- term mortality.We performed a multicentre retrospective study in 10 French ICU in Lyon, France. Inclusion criteria were SRD diagnosis and admission for an acute organ failure. The primary endpoint was ICU mortality.A total of 271 patients were included. SRD included systemic lupus erythematosus (23.2% of included patients), vasculitis (10.7%), systemic sclerosis (10.7%), idiopathic inflammatory myopathy (6.3%), and other connective tissue disorders (rheumatoid arthritis, Sjögren and Sharp syndromes; 50.9%). Initial organ failure(s) were shock (43.5% of included patients), acute kidney injury (30.5%), and acute respiratory failure (23.2%). The cause(s) of ICU admission included sepsis (61.6%), cardiovascular events (33.9%), SRD-flare up (32.8%), and decompensations related to comorbidities (28%). The ICU mortality reached 14.3%. The factors associated with ICU mortality were chronic cardiac failure, invasive ventilation and admission in ICU for another reason than sepsis or SRD flare-up. The median follow-up after ICU discharge was 33.6 months. During follow-up, 109 patients died. The factors associated with long-term mortality included age, Charlson comorbidity index, and ICU admission for sepsis or SRD flare-up.The ICU mortality of patients with SRD was low. Sepsis was the first cause of admission. Cardiovascular events and comorbidities negatively impacted ICU mortality. Admission for sepsis or SRD flare-up exerted a negative effect on the long-term outcome.     

Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine.

An American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference was held in Northbrook in August 1991 with the goal of agreeing on a set of definitions that could be applied to patients with sepsis and its sequelae. New definitions were offered for some terms, while others were discarded. Broad definitions of sepsis and the systemic inflammatory response syndrome were proposed, along with detailed physiologic parameters by which a patient may be categorized. Definitions for severe sepsis, septic shock, hypotension, and multiple organ dysfunction syndrome were also offered. The use of severity scoring methods when dealing with septic patients was recommended as an adjunctive tool to assess mortality. Appropriate methods and applications for the use and testing of new therapies were recommended. The use of these terms and techniques should assist clinicians and researchers who deal with sepsis and its sequelae.     

脓毒症的生物标记物的研究进展

脓毒症(sepsis)是由感染引起的全身性炎症反应综合征(SIRS),进一步发展将演变为严重脓毒症(severe sepsis)、脓毒症休克(septic shock)以及所导致的多器官功能障碍综合征(MODS),是危重病患者最常见的疾病和最主要的死亡原因,因而是当前重症监护病房(ICU)面临的巨大挑战.目前,诊断主要依靠非特异性的生理条件和培养的病原体检测.这导致诊断不明确,治疗的延误,抗生素的过度使用.脓毒血症需要新的生物标志物,可以帮助治疗决策和添加信息筛选、诊断、危险分层、对治疗的反应和监测.本文探讨一些临床研究较多及最新的生物标记物.     

Cumulative influence of organ dysfunctions and septic state on mortality of critically ill children

The interaction between sepsis and multiple organ dysfunction syndrome is poorly defined in children. We analyzed by Cox regression models the cumulative influence of organ dysfunctions, using the pediatric logistic organ dysfunction (PELOD) score, and septic state (systemic inflammatory response syndrome or sepsis, severe sepsis, and septic shock) on mortality of critically ill children. We included 593 children (mortality rate: 8.6%) from three pediatric intensive care units; 514 patients had at least a systemic inflammatory response syndrome and 269 had two or more organ dysfunctions. Hazard ratio of death significantly increased with the severity of organ dysfunction, as estimated by the PELOD score, and the worst diagnostic category of septic state. Each increase of one unit in the PELOD score multiplied the hazard ratio by 1.096 (p < 0.0001); hazard ratio of diagnostic category was 9.039 (p = 0.031) for systemic inflammatory response syndrome or sepsis, 18.797 (p = 0.007) for severe sepsis and 32.572 (p < 0.001) for septic shock. Cumulative hazard ratio of death = (hazard ratio of PELOD score) x (hazard ratio of diagnostic category). We conclude that there is a cumulative accrual of the risk of death both with an increasing severity of organ dysfunction and an increasing severity of the diagnostic category of septic state.     

Copeptin and arginine vasopressin concentrations in critically ill patients

CONTEXT: Determination of arginine vasopressin (AVP) concentrations may be helpful to guide therapy in critically ill patients. A new assay analyzing copeptin, a stable peptide derived from the AVP precursor, has been introduced. OBJECTIVE: Our objective was to determine plasma copeptin concentrations. DESIGN: We conducted a post hoc analysis of plasma samples and data from a prospective study. SETTING: The setting was a 12-bed general and surgical intensive care unit (ICU) in a tertiary university teaching hospital. PATIENTS: Our subjects were 70 healthy volunteers and 157 ICU patients with sepsis, with systemic inflammatory response syndrome (SIRS), and after cardiac surgery. INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASURES: Copeptin plasma concentrations, demographic data, AVP plasma concentrations, and a multiple organ dysfunction syndrome score were documented 24 h after ICU admission. RESULTS: AVP (P < 0.001) and copeptin (P < 0.001) concentrations were significantly higher in ICU patients than in controls. Patients after cardiac surgery had higher AVP (P = 0.003) and copeptin (P = 0.003) concentrations than patients with sepsis or SIRS. Independent of critical illness, copeptin and AVP correlated highly significantly with each other. Critically ill patients with sepsis and SIRS exhibited a significantly higher ratio of copeptin/AVP plasma concentrations than patients after cardiac surgery (P = 0.012). The American Society of Anesthesiologists' classification (P = 0.046) and C-reactive protein concentrations (P = 0.006) were significantly correlated with the copeptin/AVP ratio. CONCLUSIONS: Plasma concentrations of copeptin and AVP in healthy volunteers and critically ill patients correlate significantly with each other. The ratio of copeptin/AVP plasma concentrations is increased in patients with sepsis and SIRS, suggesting that copeptin may overestimate AVP plasma concentrations in these patients.     

A Review of GM-CSF Therapy in Sepsis

Determine what clinical role, if any, GM-CSF may have in the clinical treatment of sepsis in the adult patient.Advancements in the management of sepsis have led to significant decreases in early mortality; however, sepsis remains a significant source of long-term mortality and disability which places strain on healthcare resources with a substantial growing economic impact. Historically, early multiple organ failure (MOF) and death in patients with severe sepsis was thought to result from an exaggerated proinflammatory response called the systemic inflammatory response syndrome (SIRS).Numerous prospective randomized controlled trials (PRCTs) tested therapies aimed at decreasing the organ injury associated with an exaggerated inflammatory response. With few exceptions, the results from these PRCTs have been disappointing, and currently no specific therapeutic agent is approved to counteract the early SIRS response in patients with severe sepsis. It has long been recognized that there is a delayed immunosuppressive state that contributes to long-term morbidity. However, recent findings now support a concurrent proinflammatory and anti-inflammatory response present throughout sepsis. Multiple immunomodulating agents have been studied to combat the immunosuppressive phase of sepsis with the goal of decreasing secondary infection, reducing organ dysfunction, decreasing ICU stays, and improving survival. Granulocyte-macrophage colony stimulating factor (GM-CSF), a myelopoietic growth factor currently used in patients with neutropenia secondary to chemotherapy-induced myelosuppression, has been studied as a potential immune-activating agent.The applicability of GM-CSF as a standard therapy for generalized sepsis is still largely understudied; however, small-scale studies available have demonstrated some improved recovery from infection, decreased hospital length of stay, decreased days requiring mechanical ventilation, and decreased medical costs.     

Severe sepsis in community-acquired pneumonia: when does it happen, and do systemic inflammatory response syndrome criteria help predict course?

STUDY OBJECTIVES: Most natural history studies of severe sepsis are limited to ICU populations. We describe the onset and timing of severe sepsis during the hospital course for patients hospitalized with community-acquired pneumonia (CAP). We also determine the ability of the systemic inflammatory response syndrome (SIRS) and other proposed risk stratification scores measured at emergency department (ED) presentation to predict progression to severe sepsis, septic shock, or death. DESIGN: Retrospective analysis of a prospective observational outcome study from the Pneumonia Patient Outcomes Research Team (PORT). SETTING: Four academic medical centers in the United States and Canada between October 1991 and March 1994. PARTICIPANTS: The 1,339 patients hospitalized for CAP in the PORT study cohort, and a random subset of 686 patients for whom we had information for SIRS criteria. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: All subjects had infection (CAP). Severe sepsis was defined as new-onset acute organ dysfunction in this cohort, using consensus criteria. Severe sepsis developed in one half of the patients (n = 639, 48%), nonpulmonary organ dysfunction developed in 520 patients (39%), and septic shock developed in 61 subjects (4.5%). Severe sepsis and septic shock were present at ED presentation in 457 patients (71% of severe sepsis cases) and 27 patients (44% of septic shock cases), respectively. While SIRS was common at presentation (82% of the subset of 686 had two SIRS criteria), it was not associated with increased odds for progression to severe sepsis (odds ratios [ORs], 0.65 and 0.89 for two or more SIRS criteria and three or more SIRS criteria, respectively), septic shock (ORs, 0.80 and 0.55), or death (ORs, 0.65 and 0.39), with poor discrimination (all receiver operating characteristic [ROC] areas under the curve < 0.5). The pneumonia severity index was associated with severe sepsis (p < 0.001) with moderate discrimination (ROC, 0.63). CONCLUSIONS: Severe sepsis is common in hospitalized CAP patients, occurring early in the hospital course. SIRS criteria do not appear to be useful predictors for progression to severe sepsis in CAP.     

Neutrophil-endothelial cell interaction in critical illness

Sepsis syndrome frequently results in endothelial injury in many organ systems. To evaluate neutrophil-pulmonary endothelial cell interaction in the sepsis syndrome, we studied 39 critically ill patients prospectively and 20 normal volunteers. Thirteen patients with sepsis (mean age, 71.4 years), 14 patients in an intensive care unit control group (mean age 65.4 years), and 12 patients admitted with acute myocardial infarction (mean age, 66.8 years) were evaluated. Blood samples were drawn from septic patients within 24 hours and from ICU and MI patients within 72 hours of admission. All sepsis patients were culture positive, 6 of 13 from the blood. Both renal failure and ARDS developed in 54 percent of septic patients. 51Cr-labelled neutrophils were prepared and added to bovine pulmonary endothelial cell monolayers with and without added phorbol myristate acetate. Endothelial cells with adherent PMA and nonadherent PMN's, were harvested and radioactivity in each fraction measured with a gamma scintillation counter. Baseline and maximally stimulated (PMA, 3.0 ng/ml) neutrophil adherence to endothelial cells were similar in all patients groups. However, in septic patients, PMA-stimulated PMN adherence was reduced at lower doses, most significantly in those who developed ARDS within 24 to 48 hours of admission (p less than 0.05). Seventy-one percent of patients who developed ARDS had reduced stimulated adherence (PMA 1.0 ng/ml) compared to 22 percent of critically ill patients who did not. We conclude that diminished adherence of neutrophils to endothelium in response to low-level PMA stimulation is significantly more common in patients with sepsis who develop ARDS. Our findings suggest that PMN-endothelial cell interaction is altered by the time sepsis is clinically recognized but before the development of ARDS. We speculate that the observed reduction in adherence of the PMN to endothelial cells may be a consequence of down-regulation by mediators generated in the inflammatory response to sepsis and/or the need for active participation of septic endothelium in this interaction.     

Improving the Recognition of,and Response to In-Hospital Sepsis

Sepsis is an important cause of patient morbidity and mortality worldwide. Although the associated mortality seems to be decreasing, approximately 20 % of patients with organ dysfunction die in hospital. Since 1991 diagnostic criteria for sepsis focused on the systemic inflammatory response syndrome (SIRS). However, the utility of such criteria has been questioned, and alternative criteria have recently been proposed. It is likely that administration of early appropriate antibiotics and resolution of shock reduce sepsis-associated mortality. Accordingly, strategies need to be developed to improve the early recognition of, and response to patients with sepsis. Such system approaches may include improved acquisition and documentation of vital signs, enhanced recognition of shock, and integration of laboratory and microbiological results using clinical informatics. Hospitals should have guidelines for escalating care of septic patients, antibiotics stewardship programs, and systems to audit morbidity and mortality associated with sepsis.     

Prophylactic Use of Immunoglobulins in Cardiac Surgery

Cardiopulmonary bypass is associated with an injury that may cause pathophysiological changes in form of systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), and mediator induced multi organ failure (MIMOV). Systemic endotoxinaemia, release of proinflammatory cytokines, and interactions between neutrophils and endothelium have been reported to correlate with a high incidence of organ dysfunctions, infections and sepsis following cardiac surgery. This review discusses the dysregulation of immune response as a major reason for the higher susceptibility to infections following cardiac surgery, various treatment strategies to reduce CPB-induced inflammation, and especially the prophylactic use of immunoglobulins in cardiac surgery.     

Influence of systemic inflammatory response syndrome and sepsis on outcome of critically ill infected patients

The clinical significance of the systemic inflammatory response in infected patients remains unclear. We examined risk factors for hospital mortality in 3,608 intensive care unit patients included in the European Sepsis Study. Patients were categorized as having infection without or with (i.e., sepsis) systemic inflammatory response, severe sepsis, and septic shock, on the first day of infection. Hospital mortality varied from 25 to 60% according to sepsis stage, but did not differ between the first two categories (hazard ratio, 0.94; p = 0.55), whereas there was a grading of severity from sepsis to severe sepsis (1.53, p < 10-4) and septic shock (2.64, p < 10-4). Within each stage, mortality was unaffected by the number of inflammatory response criteria. Prognostic factors identified by Cox regression included comorbid conditions, severity of acute illness and acute organ dysfunction, shock, nosocomial infection, and infection caused by aerobic gram-negative bacilli, enterobacteria, Staphylococcus aureus, and infection from a digestive or unknown source. We conclude that whereas the categorization of infection by the presence of organ dysfunction or shock has strong prognostic significance, infection and sepsis have similar outcomes, unaffected by the presence or number of inflammatory response criteria. Refinement of risk stratification of patients presenting with infection and no organ dysfunction is needed.     

Incidence and impact of organ dysfunctions associated with sepsis

OBJECTIVE: To study the incidence and severity of organ dysfunction associated with sepsis. DESIGN: Comprehensive review of prospectively collected data from intensive care patients hospitalized between 1997 and 2001. SETTING: Thirty-five ICUs in nonuniversity and university hospitals located in the Paris area. PATIENTS: All patients hospitalized in the ICU for > 24 h meeting the criteria for severe sepsis (SS), either with only one organ dysfunction present during the ICU stay (SS1; n = 5,675) or with at least two organ dysfunction present during the ICU stay (SS2; n = 12,598), were compared to all other patients hospitalized for > 24 h in the ICU over the same time period (n = 47,637). INTERVENTIONS: None.Measurements and main results: We collected information on demographic characteristics, type of admission, underlying disease, organ dysfunction, organ support, McCabe and Charlson-Deyo scores, simplified acute physiology score II, length of stay, and outcome. The incidence of SS was 27.7% (8.6% for SS1 and 19.1 for SS2). Compared with non-SS patients, those with SS were significantly older, were more frequently men, required organ support more frequently, had higher severity scores, and stayed longer in the ICU and hospital. Respiratory and cardiovascular dysfunction and fungal infection were strong independent risk factors for death in SS patients, with 5.64-fold, 4.35-fold, and 2.0-fold increased risks, respectively. SS2 is significantly different from SS1: older age, more surgical stays and admission from external transfer, greater number of organ supports, site of infection (less pulmonary and urinary tract infections, and more abdominal and cardiovascular infections), type of bacteria (more methicillin-resistant Staphylococcus aureus, Pseudomonas, and fungus), ICU length of stay (20.4 d vs 11.6 d), hospital length of stay (33 d vs 27.9 d), ICU mortality (42.7% vs 5.5%), and hospital mortality (49% vs 11.3%). CONCLUSIONS: Our study identifies a subgroup of patients with an ICU stay > 24 h and SS with at least two organ dysfunctions. This group of patients requires special attention since their ICU mortality is > 40% and they occupy almost 40% of all ICU beds.     

综合医院危重症患者1735例死亡危险因素分析

目的探讨综合医院危重症患者死亡的危险因素,以提高诊治质量。方法回顾性分析2005年至2010年重症监护病房收治的1735例患者,其中198例于重症监护病房（ICU）死亡,135例出ICU后死亡,对198例患者各年龄段进行统计学分析,并调查疾病分布特点;对比ICU内、外器官功能衰竭数与死亡率,检验各种危险因素对死亡的影响。结果老年组死亡率明显高于非老年组,差异有统计学意义（P〈0.01）。随年龄增长,死亡率呈增高趋势;发生功能障碍器官数与死亡率密切相关,功能障碍器官数越多,死亡率越高;当有5个或5个以上器官发生功能障碍时,死亡率接近100%。当衰竭器官数≤3个时,ICU内死亡率明显低于ICU外死亡率（P〈0.01）。从器官功能障碍分布来看,心血管系统功能障碍发生率高达51.8%,死亡率却低;致死性最高的功能障碍器官是：血液（59.3%）、肾（58.7%）;ICU内、外致死的障碍功能器官不同。结论降低危重症患者死亡率首先要降低≥60岁老年人的死亡率,明确原发病和受损器官,积极控制疾病向多器官功能衰竭的发展,保护重要脏器功能在危重症患者治疗中占重要地位。     

Intensive care of the patient with cirrhosis

Acute deterioration of patients with cirrhosis manifests as multiple organ failure requiring admission to an intensive care unit. Precipitating events may be viral hepatitis, typically in Asia, and drug or alcoholic hepatitis and variceal hemorrhage in the West. Patients with cirrhosis in the intensive care unit have a high mortality, and each admission is associated with a mean charge of US $116,200. Prognosis is determined by the number of organs failing (sequential organ failure assessment [SOFA] score), the presence of infection, and the degree of liver dysfunction (Child-Turcotte-Pugh or Model for End-Stage Liver Disease scores). The most common organ failing is the kidney; sepsis is associated with further deterioration in liver function by compromise of the microcirculation. Care of these critically ill patients with impending multiple organ failure requires a team approach with expertise in both hepatology and critical care. Treatment is aimed at preventing further deterioration in liver function, reversing precipitating factors, and supporting failing organs. Liver transplantation is required in selected patients to improve survival and quality of life. Treatment is futile in some patients, but it is difficult to identify these patients a priori. Artificial and bioartificial liver support systems have thus far not demonstrated significant survival benefit in these patients.     

Probiotic/Synbiotic Therapy for Treating Critically Ill Patients from a Gut Microbiota Perspective

The gut is an important target organ for stress caused by severe insults such as sepsis, trauma, burn, shock, bleeding and infection. Severe insult to the gut is considered to have an important role in promoting infectious complications and multiple organ dysfunction syndrome. These are sequelae of interactions between deteriorated intestinal epithelium, the immune system and commensal bacteria. The gut is the “motor” of multiple organ failure, and now it is recognized that gut dysfunction is a causative factor in disease progression. The gut flora and environment are significantly altered in critically ill patients, and the number of obligate anaerobes is associated with prognosis. Synbiotic therapy is a combination of probiotics and prebiotics. Probiotic, prebiotic and synbiotic treatment has been shown to be a promising therapy to maintain and repair the gut microbiota and gut environment. In the critically ill, such as major abdominal surgery, trauma and ICU patients, synbiotic therapy has been shown to significantly reduce septic complications. Further basic and clinical research would clarify the underlying mechanisms of the therapeutic effect of probiotic/synbiotic treatment and define the appropriate conditions for use.     

Sepsis syndrome, the adult respiratory distress syndrome, and nosocomial pneumonia. A common clinical sequence

Systemic sepsis and pneumonia are common predisposing factors for ARDS, which can serve as the initial manifestation of the multisystem organ failure syndrome. Primary pneumonia that necessitates ICU admission leads to ARDS in approximately 10% of patients. Systemic infection can also lead to ARDS, but when bacteremia alone is present, the risk is low (probably less than 5%). If the septic syndrome with a hemodynamic and end-organ response develops, the ARDS may follow in as many as 40% of patients. When multiple risk factors for acute lung injury are present, the risk of developing ARDS rises dramatically. The septic syndrome, acute lung injury, and multiorgan failure are closely tied to one another because bacterial cell walls can activate inflammatory mediators, such as interleukin-1 and tumor necrosis factor, which can in turn lead to the septic syndrome and inflammatory injury to the lung. Clinical features, more than serum markers, have been the best predictors of whether lung injury will follow sepsis, indicating that the mere presence of mediators alone cannot cause ARDS and that there are individual susceptibility factors in the effects of these mediators. With the advent of monoclonal antibodies and new anti-inflammatory drugs, prevention of progression from sepsis to multiorgan failure may become possible. Pneumonia is the most common infection that complicates ARDS once it is established, and the mortality rate may approach 90%. The existence of acute lung injury, its predisposing conditions, coexisting illnesses, and the therapeutic interventions used for patients with lung injury all can interfere with lung host defenses and set the stage for bacterial infection of the already-injured lung. This infection appears to add to the propagation of the multiple system organ failure that has already begun. In the future, it may become possible to prevent this infection, which would be a welcome development, because currently, we are stymied in our efforts to diagnose and treat pneumonia in the setting of acute lung injury. Preventive efforts will follow from an understanding of the pathogenesis of pneumonia and in the future may include topical antibiotics, selective digestive decontamination, and prophylactic passive immunotherapy.     

Immunologic alterations and the pathogenesis of organ failure in the ICU

Rapid and marked alterations of innate and adaptive immunity typify the host response to systemic infection and acute inflammatory states. Immune dysfunction contributes to the development of organ failure in most patients with critical illness. The molecular mechanisms by which microbial pathogens and tissue injury activate myeloid cells and prime cellular and humoral immunity are increasingly understood. An early and effective immune response to microbial invasion is essential to mount an effective antimicrobial response. However, unchecked and nonresolving inflammation can induce diffuse vasodilation, increased capillary permeability, microvascular damage, coagulation activation, and organ dysfunction. Control of the inflammatory response to limit tissue damage, yet retain the antimicrobial responses in critically ill patients with severe infection, has been sought for decades. Anti-inflammatory approaches might be beneficial in some patients but detrimental in others. It is now clear that a state of sepsis-induced immune suppression can follow the immune activation phase of sepsis. In carefully selected patients, a better therapeutic strategy might be to provide immunoadjuvants to reconstitute immune function in intensive care unit (ICU) patients. Proresolving agents are also in development to terminate acute inflammatory reactions without immune suppression. This brief review summarizes the current understanding of the fundamental immune alterations in critical illness that lead to organ failure in critical illness.