Multiple Organ Dysfunction Syndrome Score Research Articles

Effects of probiotic therapy in critically ill patients: a randomized, double-blind, placebo-controlled trial

Background:Multiple organ dysfunction syndrome (MODS) is a major cause of mortality in intensive care units. A breakdown in gut barrier function and immune dysfunction are associated with the onset of MODS. Probiotic bacteria have been shown to modulate intestinal barrier and immune function.Objective:This study assessed the efficacy of a probiotic compound in a viable and nonviable formulation in modulating intestinal permeability and immune function and preventing the onset of MODS in patients in the intensive care unit.Design:A double-blind, randomized controlled trial was conducted in the intensive care unit of a tertiary care teaching hospital. Twenty-eight critically ill patients admitted to the intensive care unit were randomly assigned to receive 1 of 3 treatments daily for 7 d: 1) placebo, 2) viable probiotics, or 3) equivalent probiotic sonicates. MODS scores and systemic concentrations of immunoglobulin (Ig) A and IgG were measured on days −1, 4, and 7, and intestinal permeability measurements were taken daily.Results:The patients responded to viable probiotics with a significantly larger increase in systemic IgA and IgG concentrations than in the patients who received placebo or sonicates (P< 0.05). MODS scores were not significantly affected by probiotic treatment. Over the study period, intestinal permeability decreased in most patients.Conclusion:Patients receiving viable probiotics show a greater enhancement in immune activity than do patients receiving either placebo or probiotic bacterial sonicates.

Copeptin and Arginine Vasopressin Concentrations in Critically Ill Patients

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. Our objective was to determine plasma copeptin concentrations. We conducted a post hoc analysis of plasma samples and data from a prospective study. The setting was a 12-bed general and surgical intensive care unit (ICU) in a tertiary university teaching hospital. Our subjects were 70 healthy volunteers and 157 ICU patients with sepsis, with systemic inflammatory response syndrome (SIRS), and after cardiac surgery. There were no interventions. Copeptin plasma concentrations, demographic data, AVP plasma concentrations, and a multiple organ dysfunction syndrome score were documented 24 h after ICU admission. 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. 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.

Regional Microvascular Function and Vascular Reactivity in Patients with Different Degrees of Multiple Organ Dysfunction Syndrome

The pathophysiology of multiple organ dysfunction syndrome (MODS) is believed to be related to that of microcirculatory dysfunction. We hypothesized that the severity of MODS is determined by measuring regional variables of microvascular function and vascular reactivity in critically ill patients. Therefore, we compared (a) reactive hyperemia response in the forearm using transcutaneous Po2/Pco2 electrodes and laser Doppler velocimetry, (b) microvascular permeability assessed by strain-gauge plethysmography in legs, and (c) variables derived from gastric tonometry in hemodynamically stable patients with moderate (n = 15) and severe (n = 15) MODS. There were no differences in systemic oxygen delivery, consumption, and oxygen extraction ratio between the groups. Mortality was 20% in patients with moderate MODS and 60% in patients with severe MODS (P = 0.025). Patients with a high MODS score had significantly larger arterial lactate concentrations (3.81 +/- 2.7 mmol/L) than patients with moderate MODS (1.66 +/- 0.82 mmol/L; P = 0.006). No significant differences in gastric pHi, gastric regional-to-arterial Pco2 difference, capillary filtration coefficient, isovolumetric venous pressure, and skin reactive hyperemia response were observed between patients with moderate and severe MODS. Once MODS is established, regional variables of microvascular function and vascular reactivity measured in this study do not reflect severity of organ dysfunction.

Damage Control Orthopaedics

In some groups of polytrauma patients, particularly those with chest injuries, head injuries, and those with mangled extremities, early total care of major bone fractures may be potentially harmful. Delaying all orthopaedic surgery, however, is also not always the best approach. In these situations, damage control orthopaedics, which emphasizes the stabilization and control of the injury rather than repair will add little additional physiologic insult to the patient and is a treatment option that should be considered.

Hydrocortisone Infusion for Severe Community-acquired Pneumonia

We hypothesize that hydrocortisone infusion in severe community-acquired pneumonia attenuates systemic inflammation and leads to earlier resolution of pneumonia and a reduction in sepsis-related complications. In a multicenter trial, patients admitted to the Intensive Care Unit (ICU) with severe community-acquired pneumonia received protocol-guided antibiotic treatment and were randomly assigned to hydrocortisone infusion or placebo. Hydrocortisone was given as an intravenous 200-mg bolus followed by infusion at a rate of 10 mg/hour for 7 days. Primary end-points of the study were improvement in Pa(O(2)):FI(O(2)) (Pa(O(2)):FI(O(2)) > 300 or >/= 100 increase from study entry) and multiple organ dysfunction syndrome (MODS) score by Study Day 8 and reduction in delayed septic shock. Forty-six patients entered the study. At study entry, the hydrocortisone group had lower Pa(O(2)):FI(O(2)), and higher chest radiograph score and C-reactive protein level. By Study Day 8, treated patients had, compared with control subjects, a significant improvement in Pa(O(2)):FI(O(2)) (p = 0.002) and chest radiograph score (p < 0.0001), and a significant reduction in C-reactive protein levels (p = 0.01), MODS score (p = 0.003), and delayed septic shock (p = 0.001). Hydrocortisone treatment was associated with a significant reduction in length of hospital stay (p = 0.03) and mortality (p = 0.009).

Discharge Decision-Making by Intensivists on Readmission to the Intensive Care Unit

Patients readmitted to the intensive care unit (ICU) have a significantly higher mortality rate. The role of intensivists in judging when to discharge patients from the ICU is very important. We undertook this study to evaluate the effect of the intensivists' discharge decision-making on readmission to ICU. The intensivists actively participated in the discharge decision-making, with the discharge guideline taken into consideration, in respect of group 1 patients, but not in respect of group 2. The readmission rate in group 1 was lower than that in group 2. The readmission in patients in each group was associated with higher mortality rates and longer lengths of stay at the ICU. Respiratory failure was the major cause of readmission. In the non-survivors out of the readmitted patients, the Acute Physiology and Chronic Health Evaluation (APACHE) scores on the initial discharge and readmission, the multiple organ dysfunction syndrome (MODS) scores on the initial admission, discharge and readmission were higher than the corresponding indices in the survivors. We conclude that the readmission rate was lower when intensivists participated in the discharge decision-making, and that APACHE and MODS scores on the first discharge and readmission were significant prognostic factors in respect of the readmitted patients.

Genomic polymorphism within interleukin-1 family cytokines influences the outcome of septic patients.

To determine the allele frequencies and genotype distribution of interleukin-1alpha, interleukin-1beta, and interleukin-1 receptor antagonist gene polymorphism in septic patients. Prospective, consecutive entry study of septic patients in a general intensive care unit. A 14-bed general intensive care unit of a university hospital. Sixty patients with diagnosis of sepsis, admitted to the intensive care unit between 1997 and 1999. None. The polymorphic regions within intron 6 of interleukin-1alpha gene containing variable numbers of a tandem repeat (VNTR) of 46 base pairs, and intron 2 of interleukin-1 receptor antagonist gene containing VNTR of 86 base pairs, were amplified by means of polymerase chain reaction. Alleles A1-4 and RN1-4 were identified according to the size of amplified DNA product. The region containing the AvaI polymorphic site at position -511 of interleukin-1beta gene was amplified by polymerase chain reaction and subsequently digested with AvaI restriction enzyme. The allele frequencies of interleukin-1 receptor antagonist RN2 and genotype RN2/2 were increased in 60 septic patients compared with normal controls (p <.01 and.05, respectively). Allele frequencies or genotype distribution of interleukin-1alpha VNTR gene polymorphism and interleukin-1beta AvaI polymorphism did not differ between septic patients and normal controls. In addition, genotypes A2/2, B2/2, and RN2/2 were associated with a significantly higher mortality rate (70% to 80%) in septic patients. Patients with any two of the three alleles (i.e., A2, B2, and RN2) suffered from much more severe sepsis (as measured by the Acute Physiology and Chronic Health Evaluation II and Multiple Organ Dysfunction Syndrome score) and a higher mortality rate (55% to 65%), whereas septic patients with genotypes A1/1, B1/1, or RN1/1 showed a much lower mortality rate (0% to 13%). Allele interleukin-1RN2, but not interleukin-1A or interleukin-1B gene polymorphism, was associated with susceptibility to sepsis. Alleles A2, B2, and RN2 might be important high-risk genetic markers for sepsis.

Inhibition of neutrophil apoptosis after severe trauma is NFkappabeta dependent.

Systemic inflammation may inhibit neutrophil (PMN) apoptosis and promote multiple organ dysfunction syndrome. We hypothesize that severe trauma causes dysregulation of PMN apoptosis. Neutrophils were isolated from trauma patients (24-72 hours after injury; n = 16) and controls (healthy volunteers) and incubated for 18 hours. In separate experiments, control cells were treated +/- the nuclear factor kappa beta (NFkappabeta) inhibitor pyrrolidinithiocarbamate then incubated with 25% patient or control plasma. Apoptosis was quantified by enzyme-linked immunosorbent assay for histone-associated DNA and annexin V fluorescence-activated cell sorter. NFkappabeta activation was determined by Western blot for phosphorylated I kappabeta. Apoptosis was inhibited in trauma patient PMN. Neutrophil apoptosis correlated with multiple organ dysfunction syndrome score, Acute Physiology and Chronic Health Evaluation II, and platelet count. Patient plasma inhibited apoptosis and induced phosphorylation of I kappabeta in control cells. Inhibition of PMN apoptosis by patient plasma was blocked by pretreatment with pyrrolidinithiocarbamate. NFkappabeta-dependent inhibition of neutrophil apoptosis occurs after trauma. Early inhibition of PMN apoptosis is dependent on the magnitude of injury.

Relationships between T Lymphocyte Apoptosis and Anergy Following Trauma

Background. Severely injured trauma patients experience T cell depletion. A subset of these patients also develop T cell unresponsiveness (anergy), as characterized by the failure of their T cells to proliferate or to produce T lymphokines in response to a direct stimulus through the T cell receptor. We hypothesized that T cell apoptosis plays a role in the development of posttrauma T cell depletion and/or T cell anergy by deleting an activated T cell population. We found that moderately increased T cell depletion posttrauma is not innately deleterious or immediately responsible for anergy, but may predispose to later development of T cell anergy, possibly due to a more stringent requirement for activation of the remaining naive T cells.Methods. A total of 30 blunt trauma and burn patients were assessed twice weekly for the following parameters: (1) clinical outcome expressed as severity of organ dysfunction as measured by the multiple organ dysfunction syndrome score, (2) proliferative response of highly purified T cells to anti-CD3/anti-CD4, (3) level of apoptosis as determined by flow cytometric analysis of propidium iodide-stained monocyte reduced peripheral blood mononuclear cells, either unstimulated or in response to mitogenic challenge or Fas (CD95) stimulation.Results. A wide range of apoptosis levels are seen in the patients' T cells. Apoptosis is increased when all trauma patients' T cells are compared to T cells of normal volunteers. However, at the time a patients' T cells are anergic, there is no increased level of apoptosis. In fact, the point of maximum anergy (lowest proliferative response) correlates to diminished apoptotic response. Increased T cell apoptosis can be stimulated by anti-Fas antibody in trauma patients' responsive T cells but not in maximally anergic T cells. These data suggest that patients' T cell anergy is not an immediate result of apoptotic T cell depletion upon stimulation. However, patients who later develop T cell anergy have increased T cell apoptosis earlier in their clinical course than patients who never experience T cell anergy.Conclusions. Increased levels of apoptosis are not directly associated with negative trauma patient outcome nor the immediate cause of T cell anergy. However, unusually high levels of apoptosis and development of severe T cell depletion occurring before complete activation and expansion of the posttrauma T cell response may presage anergy and subsequent organ failure.

Both T-helper-1- and T-helper-2-type lymphokines are depressed in posttrauma anergy.

We have previously shown that an intrinsic postinjury T-cell dysfunction defined as lack of proliferative response to direct stimulation through the T-cell receptor, referred to here as "anergy," occurs in a subgroup of patients with severe trauma and is associated with organ failure. It has been suggested recently that a dominance of T-helper-2 (Th2) lymphokine production might be responsible for immunosuppression and associated with poor patient outcome. Here, we hypothesize that anergy is associated with global failure of T lymphokine (T LK) production, suggesting that poor outcome is not the result of an excess of immunosuppressive T LK (i.e., interleukin (IL)-10) but rather results from lost T-cell regulatory networking. Purified T cells from 37 severely injured trauma patients were cultured and stimulated with alphaCD3/alphaCD4, and proliferation was assessed at 72 hours. Anergy is defined as occurring when the patient's T-cell proliferation to alphaCD3/alphaCD4 is less than 50% of the simultaneously run normal proliferation. Culture supernatants were assessed for T LK production by enzyme-linked immunosorbent assay. Clinical severity was measured by the multiple organ dysfunction syndrome (MODS) and Acute Physiology and Chronic Health Evaluation III scores. Anergy occurred in 20 of 37 patients, and it usually appeared at greater than 5 to 7 days after injury. There was a global reduction of T LK production during T-cell anergy (IL-2, 2.5%; interferon (IFN)gamma, 30.5%; IL-4, 11.8%; and IL-10, 16.9%) compared with increased or unchanged T LK production during the nonanergic state (IL-2, 83%; IFNgamma, 230%; IL-4, 110%; and IL-10, 307.9%; p < 0.01). There was a significant direct correlation between depressed IL-4 and depressed IFNgamma (r = 0.620, p < 0.001), indicating a diminished LK production of both types of T-helper cells (Th1 and Th2). Decreased IL-2 and IL-10 levels were also specifically correlated to each other during the anergic state (r = 0.91, p < 0.001). The average MODS score for patients during anergy was significantly higher (7.6) than their MODS score in the absence of anergy (4.0, p = 0.01). When IL-2 and IL-10 were measured simultaneously, a predominance of Th2 LK (IL-10) production would result in an IL-10/IL-2 ratio greater than 1. We found, however, that this ratio was not greater than 1 in 80% of assays in which T cells were anergic (p = 0.01). During T-cell anergy there is not a predominance of Th2 lymphokine production but rather a global depression of the T-cell lymphokine profile. Both depressed T-cell proliferation and depressed LK production correlate to poor clinical outcome.

Utility of illness severity scoring for prediction of prolonged surgical critical care.

To determine whether APACHE III and multiple organ dysfunction syndrome scores can predict a prolonged length of stay for critically ill surgical patients in the intensive care unit. Prospective, inception-cohort study. Surgical intensive care unit (SICU) of an urban, tertiary care hospital. 2,295 consecutive admissions for critical surgical illness, postoperative complications, or postoperative monitoring in 2,058 patients. Calculation of Acute Physiology and Chronic Health Evaluation (APACHE) II and APACHE III scores 24 hours after admission to the SICU. Serial quantitation of organ dysfunction for the duration of hospitalization according to the multiple organ dysfunction score. Patients were stratified by survival and time intervals for the duration of critical care, and followed until discharge or death. Hospital mortality and length of stay in the SICU. The mean APACHE II and APACHE III scores were 14.0 +/- 0.2 and 45.2 +/- 0.6 points, respectively (mean +/- SEM). The incidence of organ dysfunction was 43%, and the hospital mortality was 9.7%. The mean ICU length of stay was 6.1 +/- 0.2 days, but decreased progressively from 6.8 +/- 0.5 days in 1991 to 5.3 +/- 0.6 days in 1995 (p < 0.01) with no change in either illness severity or the number of admissions. By univariate analysis, increased length of stay in the ICU was associated with increasing APACHE scores, an increased incidence of emergency admissions, and the incidence and magnitude of organ dysfunction (all p < 0.01). Severity indices appeared to plateau in magnitude in patients whose ICU stay ultimately exceeded 21 days. By multivariate analysis of variance (MANOVA), independent predictors of a prolonged stay in the SICU were APACHE III (p = 0.0023), emergency admission (p = 0.0007), and the magnitude of organ dysfunction (p < 0.00001), but not APACHE II. Only an emergency admission (p = 0.0005) and the magnitude of organ dysfunction (p < 0.00001) predicted a prolonged stay independently in survivors. In contrast, only the admission APACHE III score(p = < 0.0001) and the magnitude of organ dysfunction (p = 0.0001) were independently predictive of mortality by MANOVA. The development of multiple organ dysfunction syndrome is a powerful predictor of a prolonged ICU course in critical surgical illness, even in survivors. Increased risk of a prolonged stay in the ICU plateaued at 21 days, making 21 days an appropriate definition of prolonged care for future studies. Predictive models should account for organ dysfunction and very long stays in future estimations. The combined use of APACHE III and the multiple organ dysfunction score may provide improved prediction of a prolonged stay in the ICU, but further enhancements are needed before prediction of outcome in individual patients is reliable.

Persistent Elevation of Inflammatory Cytokines Predicts a Poor Outcome in ARDS: Plasma IL-1β and IL-6 Levels Are Consistent and Efficient Predictors of Outcome Over Time

Inflammatory cytokines have been related to the development of adult respiratory distress syndrome (ARDS), shock, and multiple organ dysfunction syndrome (MODS). We tested the hypothesis that unfavorable outcome in patients with ARDS is related to the presence of a persistent inflammatory response. For this purpose, we evaluated the behavior of inflammatory cytokines during progression of ARDS and the relationship of plasma inflammatory cytokines with clinical variables and outcome.We prospectively studied 27 consecutive patients with severe medical ARDS. Plasma levels of tumor necrosis factor alpha (TNF-alpha) and interleukins (ILs) 1 beta, 2, 4, 6, and 8 were measured (enzyme-linked immunosorbent assay [ELISA] method) on days 1, 2, 3, 5, 7, 10, and 12 of ARDS and every third day thereafter while patients were receiving mechanical ventilation. Subgroups of patients were identified based on outcome, cause of ARDS, presence or absence of sepsis, shock, and MODS at the time ARDS developed. Subgroups were compared for levels of plasma inflammatory cytokines on day 1 of ARDS and over time.Of the 27 patients, 13 survived ICU admission and 14 died (a mortality rate of 52%). Overall mortality was higher in patients with sepsis (86 vs 38%, p < 0.02). The mean initial plasma levels of TNF-alpha, IL-1 beta, IL-6, and IL-8 were significantly higher in nonsurvivors (p < 0.0001) and in those patients with sepsis (p < 0.0001). Plasma levels of IL-1 beta (p < 0.01) and IL-6 (p = 0.03) were more strongly associated with patient outcome than cause of ARDS (p = 0.8), lung injury score (LIS), APACHE II score, sepsis (p = 0.16), shock, or MODS score. Plasma levels of TNF-alpha, IL-1 beta, IL-6, and IL-8 remained significantly elevated over time (p < 0.0001) in those who died. Although it was the best early predictor of death (p < 0.001), plasma IL-2 > 200 pg/mL lost its usefulness after the first 48 h. A plasma IL-1 beta or IL-6 level > 400 pg/mL on any day in the first week of ARDS was associated with a low likelihood of survival.Our findings indicate that unfavorable outcome in acute lung injury is related to the degree of inflammatory response at the onset and during the course of ARDS. Patients with higher plasma levels of TNF-alpha, IL-1 beta, IL-6, and IL-8 on day 1 of ARDS had persistent elevation of these inflammatory cytokines over time and died. Survivors had lesser elevations of plasma inflammatory cytokines on day 1 of ARDS and a rapid reduction over time. Plasma IL-1 beta and IL-6 levels were consistent and efficient predictors of outcome.