Non-sepsis Patients Research Articles

Severe sepsis with Hafnia alvei and dual pulmonary infection with Mycobacterium tuberculosis and Pneumocystis carinii in a late presenter patient infected with HIV – case presentation

Once thought to be a simple commensal of the gastrointestinal tract, there is increasing evidence to suggest Hafnia alvei is a rare, but significant bacterium that may contribute to opportunistic infections in humans. Bacteremia and respiratory tract infections are the leading extraintestinal manifestations of Hafnia alvei as a pathogen. It can cause disease in immunocompromised patients and it is regularly resistant to multiple drugs. Patients with HIV may present with both TB and PCP and in these patients, TB seems to account for the most serious symptoms of their disease that require hospitalization. We report the case of a 36-years old patient admitted in our department in 23 October 2013, for persistent fever, headache, oral candidiasis, productive cough, weight loss and severe asthenia. He tested positive for HIV with a CD4 of 7 cells/µL and a viral load of 930,795 copies/mL. In the blood culture we isolated Hafnia alvei and the chest CT scan showed “a ground-glass aspect” suggestive for a Pneumocystis carinii pneumonia (PCP). The pneumological evaluation established the imagistic diagnostic of miliary tuberculosis and recommended treatment with tuberculostatic drugs and antibiotic. Severe sepsis has emerged as a common cause of hospital admission for those living with HIV/AIDS. Sepsis patients had significantly higher in-hospital mortality than did nonsepsis patients. Clinicians should be aware that patients with HIV/AIDS may present with concurrent pulmonary TB and PCP, especially in regions that are hyperendemic for TB.

GUIDELINE BUNDLES ADHERENCE AND MORTALITY IN SEVERE SEPSIS AND SEPTIC SHOCK: RESULTS OF A NATIONAL PATIENT SAFETY PROGRAM IN THE NETHERLANDS

IntroductionImplementation of Surviving Sepsis Campaign bundles have been associated with reduced mortality in severe sepsis and septic shock patients. Case-mix adjusted mortality evaluations have not been performed to compare hospitals...

Autophagy-Related IRGM Polymorphism Is Associated with Mortality of Patients with Severe Sepsis

ObjectiveAutophagy is the regulated catabolic process for recycling damaged or unnecessary organelles, which plays crucial roles in cell survival during nutrient deficiency, and innate immune defense against pathogenic microorganisms. Autophagy has been also reported to be involved in various conditions including inflammatory diseases. IRGM (human immunity-related GTPase) has an important function in eliminating Mycobacterium tuberculosis from host cells via autophagy. We examined the association between genetic polymorphism and clinical course/outcome in severely septic patients.MethodsThe study included 125 patients with severe sepsis/septic shock (SS) and 104 non-sepsis patients who were admitted to the intensive care unit (ICU) of Chiba University Hospital between October 2001 and September 2008 (discovery cohort) and 268 SS patients and 454 non-sepsis patients who were admitted to ICUs of five Japanese institutions including Chiba University Hospital between October 2008 and September 2012 (multi-center validation cohort). Three hundred forty seven healthy volunteers who consented to this study were also included. Genotyping was performed for a single-nucleotide polymorphism (SNP) within the coding region of IRGM, IRGM(+313) (rs10065172). Lipopolysaccharide challenge of whole blood from randomly selected healthy volunteers (n = 70) was performed for comparison of IRGM mRNA expression among different genotypes.ResultsNo significant difference in genotypic distributions (CC/CT/TT) at the IRGM(+313) locus was observed among the three subject groups (SS, non-sepsis, and healthy volunteers) in either cohort. When mortality were compared, no significant difference was observed in the non-sepsis group, while TT homozygotes exhibited a significantly higher mortality than the CC+CT genotype category in the SS group for both cohorts (P = 0.043, 0.037). Lipopolysaccharide challenge to whole blood showed a significant suppression of IRGM mRNA expression in TT compared with the CC+CT genotype category (P = 0.019).ConclusionsThe data suggest that the IRGM(+313), an autophagy-related polymorphic locus, influences outcome in severely septic patients, with the possible involvement of autophagy in sepsis exacerbation.

Thromboelastography in the evaluation of coagulation disorders in patients with sepsis.

Unbalanced hemostasis and disseminated intravenous coagulopathy serve as key participants in organ dysfunction and disability. In this study we evaluated the coagulation profiles of patients diagnosed with systemic inflammatory syndrome (SIRS)-sepsis and multiple organ dysfunction syndrome. We also researched coagulation in sepsis by comparing thromboelastography (TEG) data with those of nonsepsis patients to determine the usefulness of the TEG device. Data were collected from 55 anesthesiology and surgery intensive care unit (ICU) patients: 21 with SIRS-sepsis (Group S) and 34 patients without SIRS-sepsis (Group C). Blood samples were taken upon admission to the ICU (t1) and on day 3 of the ICU stay (t2). TEG data (R = reaction time, K = coagulation time, a = alpha angle, and MA = maximum amplitude) were recorded. TEG parameters were compared with routine coagulation and hemogram studies. The mean R value in Group C was higher than that of Group S at both t1 and t2. Group S had a significantly lower K value and higher alpha angle at t1 compared to Group C (P < 0.05). Hypercoagulability was observed in SIRS-sepsis patients in the ICU, as measured with TEG. We believe that TEG will be a useful tool in the evaluation of coagulation disorders developing in septic critically ill patients.

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Introduction: Sepsis is a morbid cause of hospitalization, however, little is known about the relative proportion of hospital deaths that result from sepsis. We evaluated a multi-center sample of hospitalizations at 21 community medical centers in the Kaiser Permanente Northern California integrated healthcare delivery system between September 2010 and September 2012 to determine the proportion of all hospital deaths associated with sepsis. Methods: We retrospectively analyzed all hospitalizations that included non-obstetrical patients aged ≥18 years with overnight stays (or death at any time). We identified sepsis patients based on diagnosis coding and manually-collected data from regional sepsis quality improvement (QI) initiatives. We used QI data-available for 83.9% of sepsis patients-to categorize patients based on sepsis severity and their eligibility for, or use of, early goal-directed therapy (EGDT). Results: Over two years, a total of 345,264 patients met the study criteria including 42,457 (12.3%) hospitalized for sepsis-85.7% with the 038 ICD-9 diagnosis code. Mean age was 69.5 ± 16.9 for sepsis patients and 64.1 ± 17.5 years for others. Sepsis patients had higher comorbid disease burden, acute severity of illness, and predicted mortality (9.3% ± 12.6% versus 2.4% ± 5.5%, p<0.001) when compared with non-sepsis patients. They also had higher ICU utilization (31.8% versus 13.5%) and length of stay (6.7 versus 3.8 days) than other inpatients. Sepsis hospital mortality was 10.5%; 30-day mortality was 15.2%. Hospital mortality otherwise was 1.9%. More than 43% (n = 4,463) of all inpatient deaths were among sepsis patients. Most had sepsis present on admission (93.8%) and nearly 40% had severe sepsis or septic shock. Hospital mortality varied by severity strata; for example, 6.6% of patients with non-severe sepsis died compared with 17.8% of patients receiving EGDT. Hospital mortality was 26.2% to 33.6% among EGDT-eligible patients who did not receive EGDT (either based on clinician judgment, contraindications, patient refusal, or comfort care status). In terms of all sepsis deaths, each sepsis strata (non-severe sepsis, sepsis with intermediate lactate, and EGDT-eligible sepsis) contributed roughly equal numbers of deaths. This included 1,225 (31.9%) deaths among non-severe, 1,213 (31.6%) among intermediate lactate, and 1,397 (36.4%) among EGDT-eligible sepsis patients. Conclusions: In a multi-center study of community hospitals, >43% of patients dying in the hospital had sepsis. These sepsis deaths were roughly equally distributed across severity strata.

Hydroxyethyl starch (HES) versus other fluid therapies: effects on kidney function

Hydroxyethyl starches (HES) are synthetic colloids commonly used for fluid resuscitation to replace intravascular volume, yet they have been increasingly associated with adverse effects on kidney function. This is an update of a Cochrane review first published in 2010. To examine the effects of HES on kidney function compared to other fluid resuscitation therapies in different patient populations. We searched the Cochrane Renal Group's specialised register, the Cochrane Central Register of Controlled Trials (CENTRAL, in The Cochrane Library), MEDLINE, EMBASE, MetaRegister and reference lists of articles. The most recent search was completed on November 19, 2012. Randomised controlled trials (RCTs) and quasi-RCTs in which HES was compared to an alternate fluid therapy for the prevention or treatment of effective intravascular volume depletion. Primary outcomes were renal replacement therapy (RRT), author-defined kidney failure and acute kidney injury (AKI) as defined by the RIFLE criteria. Screening, selection, data extraction and quality assessments for each retrieved article were carried out by two authors using standardised forms.All outcomes were analysed using relative risk (RR) and 95% confidence intervals (95% CI). Authors were contacted when published data were incomplete.Preplanned sensitivity and subgroup analyses were performed after data were analysed with a random-effects model. This review included 42 studies (11,399 patients) including 19 studies from the original review (2010), as well as 23 new studies. Fifteen studies were excluded from the original review (nine retracted from publication due to concerns about integrity of data and six lacking individual patient creatinine data for the calculation of RIFLE criteria). Overall, there was a significant increase in the need for RRT in the HES treated individuals compared to individuals treated with other fluid therapies (RR 1.31, 95% CI 1.16 to 1.49; 19 studies, 9857 patients) and the number with author-defined kidney failure (RR 1.59, 95% CI 1.26 to 2.00; 15 studies, 1361 patients). The RR of AKI based on RIFLE-F (failure) criteria also showed an increased risk of AKI in individuals treated with HES products (RR 1.14, 95% CI 1.01 to 1.30; 15 studies, 8402 participants). The risk of meeting urine output and creatinine based RIFLE-R (risk) criteria for AKI was in contrast in favour of HES therapies (RR 0.95, 95% CI 0.91 to 0.99; 20 studies, 8769 patients). However, when RIFLE-R urine output based outcomes were excluded as per study protocol, the direction of AKI risk again favoured the other fluid type, with a non-significant RR of AKI in HES treated patients (RR 1.05, 95% CI 0.97 to 1.14; 8445 patients). A more robust effect was seen for the RIFLE-I (injury) outcome, with a RR of AKI of 1.22 (95% CI 1.08 to 1.37; 8338 patients). No differences between subgroups for the RRT and RIFLE-F based outcomes were seen between sepsis versus non-sepsis patients, high molecular weight (MW) and degree of substitution (DS) versus low MW and DS (≥ 200 kDa and > 0.4 DS versus 130 kDa and 0.4 DS) HES solutions, or high versus low dose treatments (i.e. ≥ 2 L versus < 2 L). There were differences identified between sepsis versus non-sepsis subgroups for the RIFLE-R and RIFLE-I based outcomes only, which may reflect the differing renal response to fluid resuscitation in pre-renal versus sepsis-associated AKI. Overall, methodological quality of the studies was good. The current evidence suggests that all HES products increase the risk in AKI and RRT in all patient populations and a safe volume of any HES solution has yet to be determined. In most clinical situations it is likely that these risks outweigh any benefits, and alternate volume replacement therapies should be used in place of HES products.

Urokinase-type plasminogen activator receptor as a predictor of poor outcome in patients with systemic inflammatory response syndrome

BACKGROUND:Urokinase-type plasminogen activator (uPA) and urokinase-type plasminogen activator receptor (uPAR) are known as important factors, which mediate a variety of functions in terms of vascular homeostasis, inflammation and tissue repair. However, their role in systemic inflammatory response syndrome (SIRS) has been less well studied. This study aimed to test the hypothesis that the abnormalities of fibrinolysis and degradation of extracellular matrix mediated by uPA and uPAR are directly related to the patients with SIRS. We therefore analyzed their role and clinicopathological significance in patients with SIRS.METHODS:A case-control study was conducted with 85 patients who were divided into two groups according to the diagnostic criteria of SIRS: SIRS group (n=50) and non-SIRS group (n=35). The SIRS group was divided into MODS group (n=26) and non-MODS group (n=24) by their severity, and survival group (n=35) and non-survival group (n=15) by their prognosis. Another 30 healthy adults served as normal controls. uPA and uPAR in plasma were detected by commercial enzyme-linked immunosorbent assay (ELISA) kits.RESULTS:The plasma level of uPA was lower in the SIRS group than in the non-SIRS group and controls (P<0.001 and P<0.001). It was lower in sepsis patients and the MODS group than in the non-sepsis patients and the non-MODS patients (all P<0.05). However, there was no difference in uPA level between survivors and non-survivors (P>0.05). The plasma level of uPAR increased in the SIRS group compared with the non-SIRS group and controls (P<0.001 and P<0.001). There was a significant elevation of uPAR in sepsis patients, MODS patients and non-survivors as compared with non-sepsis patients, non-MODS patients and survivors respectively (all P<0.05). Plasma uPAR levels were positively correlated with APACHE II score (r=0.575, P<0.001) and SOFA score (r=0.349, P=0.013). AUCs for the prediction of SIRS mortality were 0.67 and 0.51, respectively, for uPA and uPAR.CONCLUSION:uPAR could be a predictor of poor outcome in patients with SIRS.

Longer storage duration of red blood cells is associated with an increased risk of acute lung injury in patients with sepsis

BackgroundThe storage duration of red blood cells transfused to critically ill patients is associated with increased morbidity and mortality. Whether the association exists between storage duration of red blood cells transfused to patients with sepsis and the risk of developing ALI/ARDS is unknown. We aimed to determine the association of the storage duration of red blood cells transfused to patients with sepsis and risk of developing acute lung injury in the subsequent 96 hours, with comparator trauma and nonsepsis/nontrauma groups.MethodsWe conducted a retrospective observational study of 96 transfused, critically ill patients with sepsis, 176 transfused, critically ill patients with traumatic injury, and 125 transfused, critically ill nontrauma, nonsepsis patients. The primary outcome was the development of ALI/ARDS up to 96 hours after transfusion.ResultsIn 96 patients with sepsis, 49 (51%) patients developed ALI/ARDS. The median storage duration of transfused blood in the ALI/ARDS group was greater (24.5 days, interquartile range (IQR) 20–31) compared with the patients who did not develop ALI/ARDS (21 days, IQR 15–27, p = 0.018). Longer median storage duration was independently associated with an increased risk of developing ALI/ARDS in the subsequent 4 days (odds ratio 1.8, p = 0.028). The same association was not seen in the trauma or nonsepsis, nontrauma patients.ConclusionsTransfusion of blood with longer median storage duration to patients with sepsis is associated with a higher risk of developing ALI up to 4 days after transfusion. This same association is not seen in other critically ill patient populations.

Acute intestinal failure in surgical patients: an audit of incidence, management and outcomes in an irish hospital, and compliance with ASGBI guidelines

Acute intestinal failure (AIF) is defined as an inability to tolerate 80% of nutritional requirements delivered enterally for a minimum of 48 h. In surgical patients it commonly relates to abdominal sepsis, intestinal obstruction, or ileus. The prevalence of AIF in surgical units in Ireland has not previously been studied. We retrospectively audited the general surgical and ICU departments in St James's Hospital over a 3-month period to identify patients with AIF and followed their management and outcomes focusing on the need for artificial nutrition and surgical intervention. Fifty-four surgical patients (11.4% of surgical emergency admissions) were diagnosed with AIF over the 3-month period. Of these, 30 (55.6%) required nutritional support; 26 (48.2%) had surgical ± radiological intervention and 6 (11.1%) had radiological intervention alone. Abdominal sepsis was present in 17 (31.5%) patients, a group that required significantly longer parenteral (14.6 vs. 6.7 days, p 0.029) and enteral (13.9 vs. 2.2 days, p 0.005) nutrition than AIF patients without abdominal sepsis. AIF also took longer to resolve in (5.8 vs. 4.2 days, p 0.024) in sepsis versus nonsepsis patients. The majority of patients (n = 43, 80%) were referred to clinical nutrition teams early after having symptoms for 3.77 days (range 1-21) and 72% had complete nutritional assessment clearly documented. AIF is common, and can often be treated conservatively. Early linkage with nutrition services is recommended. Early diagnosis of abdominal sepsis is important as this cohort of patients can be particularly difficult to manage.

Patterns and early evolution of organ failure in the intensive care unit and their relation to outcome

IntroductionRecognition of patterns of organ failure may be useful in characterizing the clinical course of critically ill patients. We investigated the patterns of early changes in organ dysfunction/failure in intensive care unit (ICU) patients and their relation to outcome.MethodsUsing the database from a large prospective European study, we studied 2,933 patients who had stayed more than 48 hours in the ICU and described patterns of organ failure and their relation to outcome. Patients were divided into three groups: patients without sepsis, patients in whom sepsis was diagnosed within the first 48 hours after ICU admission, and patients in whom sepsis developed more than 48 hours after admission. Organ dysfunction was assessed by using the sequential organ failure assessment (SOFA) score.ResultsA total of 2,110 patients (72% of the study population) had organ failure at some point during their ICU stay. Patients who exhibited an improvement in organ function in the first 24 hours after admission to the ICU had lower ICU and hospital mortality rates compared with those who had unchanged or increased SOFA scores (12.4 and 18.4% versus 19.6 and 24.5%, P < 0.05, pairwise). As expected, organ failure was more common in sepsis than in nonsepsis patients. In patients with single-organ failure, in-hospital mortality was greater in sepsis than in nonsepsis patients. However, in patients with multiorgan failure, mortality rates were similar regardless of the presence of sepsis. Irrespective of the presence of sepsis, delta SOFA scores over the first 4 days in the ICU were higher in nonsurvivors than in survivors and decreased significantly over time in survivors.ConclusionsEarly changes in organ function are strongly related to outcome. In patients with single-organ failure, in-hospital mortality was higher in sepsis than in nonsepsis patients. However, in multiorgan failure, mortality rates were not influenced by the presence of sepsis.

Steroidogenesis in the adrenal dysfunction of critical illness: impact of etomidate

IntroductionThis study was aimed at characterizing basal and adrenocorticotropic hormone (ACTH)-induced steroidogenesis in sepsis and nonsepsis patients with a suspicion of critical illness-related corticosteroid insufficiency (CIRCI), taking the use of etomidate-inhibiting 11β-hydroxylase into account.MethodThis was a prospective study in a mixed surgical/medical intensive care unit (ICU) of a university hospital. The patients were 62 critically ill patients with a clinical suspicion of CIRCI. The patients underwent a 250-μg ACTH test (n = 67). ACTH, adrenal steroids, substrates, and precursors (modified tandem mass spectrometry) also were measured. Clinical characteristics including use of etomidate to facilitate intubation (n = 14 within 72 hours of ACTH testing) were recorded.ResultsAt the time of ACTH testing, patients had septic (n = 43) or nonseptic critical illness (n = 24). Baseline cortisol directly related to sepsis and endogenous ACTH, independent of etomidate use. Etomidate was associated with a lower baseline cortisol and cortisol/11β-deoxycortisol ratio as well as higher 11β-deoxycortisol, reflecting greater 11β-hydroxylase inhibition in nonsepsis than in sepsis. Cortisol increases < 250 mM in exogenous ACTH were associated with relatively low baseline (HDL-) cholesterol, and high endogenous ACTH with low cortisol/ACTH ratio, independent of etomidate. Although cortisol increases with exogenous ACTH, levels were lower in sepsis than in nonsepsis patients, and etomidate was associated with diminished increases in cortisol with exogenous ACTH, so that its use increased, albeit nonsignificantly, low cortisol increases to exogenous ACTH from 38% to 57%, in both conditions.ConclusionsA single dose of etomidate may attenuate stimulated more than basal cortisol synthesis. However, it may only partly contribute, particularly in the stressed sepsis patient, to the adrenal dysfunction of CIRCI, in addition to substrate deficiency.

Haemostasis Change in Intensive Care Patients with Severe Sepsis and Patients with Organ Failure without Sepsis

Abstract 1233 Introduction:Despite recent advances in understanding the pathophysiology of sepsis, multiple organ failure remains one of the leading causes of death in intensive care units (ICUs). A wide range of coagulation abnormalities have been observed in patients diagnosed with severe sepsis (SS). Its magnitude in relationship to organ failure without sepsis is less well documented. In this study, we examined and compared the results of plasma levels of coagulation tests and thrombin generation (calibrated automated thrombography (CAT) in patients with sepsis, patients with organ failure (OF) without sepsis and controls. We investigated whether the CAT and procoagulant phospholipids would be good prognostic markers and whether these markers would show a significant correlation with coagulation disorders. Patients and Methods:21 patients with severe sepsis, 24 non-sepsis patients with organ failure were compared with 30 healthy subjects as controls. The delay between the onset of SS or OF and blood sampling was less than 12 hours. Analytical determinations of prothrombin time, activated partial thromboplastin time, and the levels of factors V,VII,VIII,X antithrombin, fibrinogen, protein C, protein S, D-Dimers were analysed using the STA-R analyser (Diagnostica Stago, France), Tissue factor activity (TFa) and thrombomodulin activity (TMa) were measured with two home-test. Free tissue factor pathway inhibitor (fTFPI), Soluble endothelial protein C receptor (sEPCR), and soluble thrombomodulin antigen were measured by ELISA assays (Diagnostica Stago, France). CAT was performed on PPP using PPP-reagent 5pM (Thrombinoscope, The Netherlands). Procoagulant phospholipids (PPL) were evaluated using the STA Procoag PPL assay (Diagnostica Stago, France). Results:The mean levels of factors V, VII, X, antithrombin, protein S, protein C, sEPCR were decreased in both SS and OF (p<0.001) compared with controls. Protein S, factor VII and X were significantly lower in the SS group than in the OF group (p<0.05). Factor VIII, D-Di, and fibrinogen level were increased in SS and OF groups (p<0.001). Activity and antigen thrombomodulin were significantly higher in SS and OF groups (p<0.01) than in healthy subjects, with no difference between patients groups. TFa was strongly increased in SS and OF (p<0.001) and not compensated by any increase in TFPI. We also observed that TF/fTFPI ratio were significantly increased in the SS and OF groups (p<0.001). Elevated thrombin generation was observed in patients with SS and OF. In particular lag-time and time to peak were prolonged (p<0.05), peak thrombin was significantly decreased only in SS group. However the mean total amount of thrombin generated in the groups of patients by endogenous Thrombin Potential (ETP) was equivalent to healthy controls. Procoagulant phospholipids were significantly higher in SS and OF groups than controls (p<0.001 and p<0.05 respectively). Non-surviving patients showed higher ETP, D-Di, TFa, PPL than survivors in both groups (p<0.05). No difference in fTFPI levels were observed between patients with negative outcome and survivors in the two groups of patients. IL-6 levels as inflammatory status were higher in SS and OF than in healthy controls, with a more pronounced increase in SS group. The levels of IL-6 were more important in non-survivors compared with survivors (p<0.05). Conclusion:This study suggests that severe septic and non septic patients with organ failure have similar coagulation abnormalities independently of the triggering event. Marked TFa generation was not adequately balanced by TFPI and inflammation may synergistically play a role in the pathogenesis of OF and death. Thrombin generation results showed that while the total amount of thrombin generated (ETP) was unchanged the initiation of thrombin generation was delayed and peak thrombin was reduced. This could be explained by the decreased levels of FVII, X, II causing a delay in the generation of thrombin. PPL and TGT may be useful in determining clinical outcome in patients and perhaps as a predictive parameter for an increased risk of bleeding or thrombotic complications in these patients. Their role to develop useful new markers in the management of patients remains to be defined. Disclosures:Van Dreden:Diagnostica Stago: Employment. Woodhams:Diagnostica Stago: Employment. Lenormand:Hospital: Employment. Vasse:hospital: Employment.

The correlation of serum interleukin-6, interleukin-10 and tumor necrosis factor-α concentrations and the prognosis of sepsis in children

Objective To investigate the correlation of serum concentrations of interleukin(IL)-6,IL-10 and tumor necrosis factor(TNF)-α and the prognosis of sepsis in children.Methods Fifty-seven septic patients in PICU were enrolled in the study,of whom 44 patients survived(sepsis survival group),13 patients died(sepsis dead group).Another 65 cases of non-sepsis patients served as control(non-sepsis group).The critical illness score,the number of damaged organs,and serum levels of IL-6,IL-10,TNF-α,IL-6/IL-10,TNF-α/IL-10 in each group were compared.Results The critical illness score was decreased and the number of damaged organs was more in sepsis dead group than those in non-sepsis group and sepsis survival group.Compared with non-sepsis group and sepsis survival group,the expression of IL-6 and IL-10 increased,TFN-α/IL-10 ratio significantly decreased in sepsis dead group(P ＜ 0.05),but the difference between the sepsis survival group and non-sepsis group was not statistically significant(P ＞ 0.05).The serum levels of TNF-α and IL-6/IL-10 ratio showed no significant difference among three groups(P ＞ 0.05).Conclusion In sepsis patients,the serum concentrations of IL-6,IL-10 are higher and the TNF-α/IL-10 ratio is smaller,the prognosis is worse. Key words: Cytokines; Inflammatory Mediators; Anti-inflammatory Media; Interleukin-6; Interleukin-10; tumor necrosis factor-α; Sepsis; Children

Diagnostic Accuracy of HMGB-1, sTREM-1, and CD64 as Markers of Sepsis in Patients Recently Admitted to the Emergency Department

The objectives were to evaluate the diagnostic accuracy for sepsis in an emergency department (ED) population of the cluster of differentiation-64 (CD64) glycoprotein expression on the surface of neutrophils (nCD64), serum levels of soluble triggering receptor expressed on myeloid cells-1 (s-TREM-1), and high-mobility group box-1 protein (HMGB-1). Patients with any of the following as admission diagnosis were enrolled: 1) suspected infection, 2) fever, 3) delirium, or 4) acute hypotension of unexplained origin within 24 hours of ED presentation. Levels of nCD64, HMGB-1, and s-TREM-1 were measured within the first 24 hours of the first ED evaluation. Baseline clinical data, Sepsis-related Organ Failure Assessment (SOFA) score, Acute Physiology and Chronic Health Evaluation (APACHE II) score, daily clinical and microbiologic information, and 28-day mortality rate were collected. Because there is not a definitive criterion standard for sepsis, the authors used expert consensus based on clinical, microbiologic, laboratory, and radiologic data collected for each patient during the first 7 days of hospitalization. This expert consensus defined the primary outcome of sepsis, and the primary data analysis was based in the comparison of sepsis versus nonsepsis patients. The cut points to define sensitivity and specificity values, as well as positive and negative likelihood ratios (LRs) for the markers related to sepsis diagnosis, were determined using receiver operative characteristics (ROC) curves. The patients in this study were a prespecified nested subsample population of a larger study. Of 631 patients included in the study, 66% (95% confidence interval [CI] = 62% to 67%, n = 416) had sepsis according with the expert consensus diagnosis. Among these sepsis patients, SOFA score defined 67% (95% CI = 62% to 71%, n = 277) in severe sepsis and 1% (95% CI = 0.3% to 3%, n = 6) in septic shock. The sensitivities for sepsis diagnosis were CD64, 65.8% (95% CI = 61.1% to 70.3%); HMGB-1, 57.5% (95% CI = 52.7% to 62.3%); and s-TREM-1, 60% (95% CI = 55.2% to 64.7%). The specificities were CD64, 64.6% (95% CI = 57.8% to 70.8%), HMGB-1, 57.8% (95% CI = 51.1% to 64.3%), and s-TREM-1, 59.2% (95% CI = 52.5% to 65.6%). The positive LR (LR+) for CD64 was 1.85 (95% CI = 1.52 to 2.26) and the negative LR (LR-) was 0.52 (95% CI = 0.44 to 0.62]; for HMGB-1 the LR+ was 1.36 (95% CI = 1.14 to 1.63) and LR- was 0.73 (95% CI = 0.62 to 0.86); and for s-TREM-1 the LR+ was 1.47 (95% CI = 1.22 to 1.76) and the LR- was 0.67 (95% CI = 0.57 to 0.79). In this cohort of patients suspected of having any infection in the ED, the accuracy of nCD64, s-TREM-1, and HMGB-1 was not significantly sensitive or specific for diagnosis of sepsis.

Circulating soluble urokinase plasminogen activator receptor is stably elevated during the first week of treatment in the intensive care unit and predicts mortality in critically ill patients

IntroductionsuPAR is the soluble form of the urokinase plasminogen activator receptor (uPAR), which is expressed in various immunologically active cells. High suPAR serum concentrations are suggested to reflect the activation of the immune system in circumstances of inflammation and infection, and have been associated with increased mortality in different populations of non-intensive care patients. In this study we sequentially analyzed suPAR serum concentrations within the first week of intensive care in a large cohort of well characterized intensive care unit (ICU) patients, in order to investigate potential regulatory mechanisms and evaluate the prognostic significance in critically ill patients.MethodsA total of 273 patients (197 with sepsis, 76 without sepsis) were studied prospectively upon admission to the medical intensive care unit (ICU), on Day 3 and Day 7, and compared to 43 healthy controls. Clinical data, various laboratory parameters as well as investigational inflammatory cytokine profiles were assessed. Patients were followed for approximately one year.ResultsUpon admission to the ICU suPAR serum concentrations were elevated in critically ill patients as compared with healthy controls. In sepsis patients suPAR levels were higher than in non-sepsis patients (with or without systemic inflammatory response syndrome (SIRS)). During the first week after admission to the ICU serum suPAR concentrations remained stably elevated. suPAR serum concentrations measured upon admission were closely and independently correlated to various laboratory parameters, specifically biomarkers of inflammation (tumor necrosis factor (TNF), C-reactive protein (CRP)), hepatic and renal dysfunction. High suPAR levels at admission and at Day 3 were a strong independent predictor for both ICU and long-term mortality in critically ill patients.ConclusionsIn sepsis and non-sepsis patients suPAR serum concentrations are increased upon admission to the ICU, likely reflecting the activation state of the immune system, and remain stably elevated in the initial course of treatment. Low suPAR levels are a positive predictor of ICU- and overall survival in critically ill patients, including sepsis and non-sepsis patients. Aside from its value as a promising new prognostic biomarker, both experimental and clinical studies are required in order to understand the specific effects and regulatory mechanisms of suPAR in SIRS and sepsis, and may reveal new therapeutic options.

Prognostic value of circulating amino-terminal pro-C-type natriuretic peptide in critically ill patients

IntroductionC-type natriuretic peptide (CNP) is a paracrine molecule which is mainly synthesized in the vasculature. High levels have been reported in sepsis, and CNP has been proposed as a biomarker predicting sepsis in traumatized patients. We aimed at evaluating the diagnostic and prognostic value of N-terminal pro-CNP (NT-proCNP) for predicting sepsis, disease severity and mortality in critically ill medical patients.Methods273 critically ill patients (197 patients with sepsis or septic shock, 76 without evidence of sepsis) and 43 healthy controls were consecutively included in a prospective clinical single-center non-interventional study at the Medical Intensive Care Unit, RWTH-University Aachen, Germany. Patients' outcome was followed for about 1 year. NT-proCNP serum concentrations were determined upon ICU admission, as well as in the mornings of day 3 and day 7 after admission. Intensive care treatment measures as well as routine and experimental laboratory parameters were recorded and analyzed.ResultsNT-proCNP serum concentrations upon admission to the ICU were elevated in critically ill patients as compared with healthy controls. Patients with sepsis had significantly higher NT-proCNP levels than non-sepsis patients. NT-proCNP was strongly associated with inflammatory parameters (i.e. C-reactive protein, procalcitonin and TNF-α), biomarkers of organ dysfunction and clinical composite scores (APACHE-II, SOFA, SAPS2). NT-proCNP levels at admission and day 3 were found to be a strong predictive marker for ICU- and overall survival. Moreover, a decline of serum NT-proCNP after admission to the ICU was associated with reduced mortality. The predictive power of serum NT-proCNP was similar to 'conventional' prognostic tools such as clinical scores.ConclusionsNT-proCNP is significantly elevated in critically ill patients, with highest levels in sepsis. Inflammation as well as organ function are strongly associated with NT-proCNP serum concentrations. Low initial NT-proCNP levels and a decline during initial treatment indicate a favourable ICU- and long-term outcome.

Greater cardiac response of colloid than saline fluid loading in septic and non-septic critically ill patients with clinical hypovolaemia.

Background and objectiveThe haemodynamics of crystalloid and colloid fluid loading may depend on underlying disease, i.e. sepsis versus non-sepsis.Design and settingA single-centre, single-blinded, randomized clinical trial was carried out on 24 critically ill sepsis and 24 non-sepsis patients with clinical hypovolaemia, assigned to loading with normal saline, gelatin 4%, hydroxyethyl starch 6% or albumin 5% in a 90-min (delta) central venous pressure (CVP)-guided fluid loading protocol. Transpulmonary thermodilution was done each 30 min, yielding, among others, global end-diastolic volume and cardiac indices (GEDVI, CI).ResultsSepsis patients had hyperdynamic hypotension in spite of myocardial depression and dilatation, and greater inotropic/vasopressor requirements than non-sepsis patients. Independent of underlying disease, CVP and GEDVI increased more after colloid than saline loading (P < 0.018), so that CI increased by about 2% after saline and 12% after colloid loading (P = 0.029). The increase in preload-recruitable stroke work was also greater with colloids and did not differ among conditions.ConclusionFluid loading with colloids results in a greater linear increase in cardiac filling, output and stroke work than does saline loading, in both septic and non-septic clinical hypovolaemia, in spite of myocardial depression and presumably increased vasopermeability potentially decreasing the effects of colloid fluid loading in the former.Electronic supplementary materialThe online version of this article (doi:10.1007/s00134-010-1776-x) contains supplementary material, which is available to authorized users.

Regulation and prognostic relevance of serum ghrelin concentrations in critical illness and sepsis

IntroductionGhrelin has been recently identified as a mediator of various beneficial effects in animal models of sepsis. At present, no data are available concerning specific properties of ghrelin in critically ill patients from large cohorts. In order to identify possible pathogenic functions of ghrelin in critically ill patients and human sepsis from a clinical point of view, we aimed at analyzing ghrelin serum concentrations in a large cohort of well characterized patients with critical illness.MethodsA total of 170 critically ill patients (122 with sepsis, 48 without sepsis) were studied prospectively on admission to the Medical intensive care unit (ICU) and compared to 60 healthy controls. Careful assessment of clinical data, various laboratory parameters, metabolic and endocrine functions as well as investigational inflammatory cytokine profiles have been performed, and patients were followed for approximately three years.ResultsGhrelin serum concentrations are elevated in critically ill patients as compared to healthy controls, but do not differ between sepsis and non-sepsis patients. The underlying etiologies of critical diseases are not associated with ghrelin serum levels. Neither pre-existing diabetes mellitus nor body mass index is correlated to serum ghrelin concentrations. Ghrelin is not correlated to markers of inflammation or hepatic function in critically ill patients. In the subgroup of non-sepsis patients, ghrelin correlates inversely with renal function and markers of carbohydrate metabolism. High ghrelin levels are an indicator for a favourable prognosis concerning mortality at the ICU in sepsis patients. Furthermore, ghrelin is significantly associated with the necessity of ventilation in critically ill patients.ConclusionsGhrelin serum concentrations are elevated in all circumstances of critical disease, including sepsis and non-sepsis patients. High ghrelin levels are a positive predictor of ICU-survival in sepsis patients, matching previous results from animal models. Future experimental and clinical studies are needed to evaluate ghrelin as a novel prognostic tool in ICU patients and its potential therapeutic use in sepsis.

Analysis of Subendothelial Leukocyte Infiltration in the Trabecular Veins of Septic Spleen

The splenic white pulp (WP) consists of CD20-positive lymph follicles (LFs) and CD3-positive periarteriolar lymphoid sheaths. Atrophy of the WP associated with a prolonged period of sepsis is a well-known pathological finding at autopsy. On the other hand, dense subendothelial leukocyte infiltration in the trabecular veins is also commonly observed in autopsy specimens of septic spleen. However, the characteristics and significance of this finding have not yet been well studied. In this study, autopsy spleens obtained from 55 sepsis and 45 non-sepsis patients were compared to determine the clinicopathological characteristics of subendothelial leukocyte infiltration in the trabecular veins, and its pathological significance was discussed. Severe and mild subendothelial leukocyte infiltration in the trabecular veins was observed in 45.5% of sepsis patients, but was absent in non-sepsis patients. Several clinicopathological characteristics of subendothelial leukocyte infiltration were identified. Firstly, the majority of infiltrated cells were lymphocytes. Secondly, both incidence and degree of infiltration were decreased at the late phase of sepsis accompanied by atrophy of the WP. Thirdly, types and compositions of infiltrated leukocytes reflected the histological findings of the spleen. Thus, the percentage of CD20-positive cells in the infiltrating cells into the subendothelium was proportional to the relative size of the CD20-positive area in the specimen, and the percentage of MUM1-p-positive cells in the infiltrating cells was proportional to the frequency of appearance of MUM1-p-positive cells in the red pulp. The CD20-positive area approximated the relative size of the WP in the septic cases, while the frequency of appearance of MUM1-p-positive cells was indicative of the differentiation levels of LFs into plasma cells upon antigen stimulation. Lastly, the intense subendothelial infiltration of CD20-positive cells was specific for the early stage of sepsis, and the morphological characteristics of these CD20-positive cells suggested their association with the marginal zone. Based on these clinicopathological characteristics and the fact that leukocyte infiltration into the subendothelium of trabecular veins became undetectable as atrophy of the WP progressed, it was suggested that the infiltrating cells had migrated from the WP, and this cell infiltration is an early activated immunological reaction in the spleen. Furthermore, the presence of possible efflux or drainage routes in the subendothelial spaces of trabecular veins was suggested.

INCREASED PLASMA KYNURENINE VALUES AND KYNURENINE-TRYPTOPHAN RATIOS AFTER MAJOR TRAUMA ARE EARLY INDICATORS FOR THE DEVELOPMENT OF SEPSIS

Kynurenine, the major degradation product of tryptophan has been shown to directly damage tissues, but its possible contribution to posttraumatic morbidity is unknown. Here, we studied the kinetics of kynurenine in patients after major trauma and whether this correlates with the development of posttraumatic sepsis. Kynurenine and tryptophan levels of 60 multiple-injured patients with Injury Severity Score of more than 16 were quantified prospectively by high-performance liquid chromatography. Blood samples were obtained daily from admission until day 10 after admission. Significantly increased kynurenine values were detectable already at day 1 after admission in blood from patients who later developed sepsis, regardless of injury pattern (P < 0.01). In contrast, kynurenine values of nonsepsis patients remained low throughout the observation period. However, all patients exhibited significantly decreased tryptophan values versus healthy controls (P < 0.01). Moreover, significantly increased kynurenine-tryptophan ratios rapidly predicted subsequent sepsis, multiple organ failure, and death (P < 0.01). Both increased kynurenine values and kynurenine-tryptophan ratios predicted posttraumatic development of sepsis and organ failure. This ought to be validated in subsequent studies.