Protracted immune disorders at one year after ICU discharge in patients with septic shock.

BACKGROUND: Sepsis is a leading cause of mortality and critical illness worldwide and is associated with an increased mortality rate in the months following hospital discharge. The occurrence of persistent or new organ dysfunction(s) after septic shock raises questions about the mechanisms involved in the post-sepsis status. The present study aimed to explore the immune profiles of patients one year after being discharged from the intensive care unit (ICU) following treatment for abdominal septic shock. METHODS: We conducted a prospective, single-center, observational study in the surgical ICU of a university hospital. Eighty-six consecutive patients admitted for septic shock of abdominal origin were included in this study. Fifteen different plasma biomarkers were measured at ICU admission, at ICU discharge and at one year after ICU discharge. Three different clusters of biomarkers were distinguished according to their functions, namely: (1) inflammatory response, (2) cell damage and apoptosis, (3) immunosuppression and resolution of inflammation. The primary objective was to characterize variations in the immune status of septic shock patients admitted to ICU up to one year after ICU discharge. The secondary objective was to evaluate the relationship between these biomarker variations and patient outcomes. RESULTS: At the onset of septic shock, we observed a cohesive pro-inflammatory profile and low levels of inflammation resolution markers. At ICU discharge, the immune status demonstrated decreased but persistent inflammation and increased immunosuppression, with elevated programmed cell death protein-1 (PD-1) levels, and a counterbalanced resolution process, with elevated levels of interleukin-10 (IL-10), resolvin D5 (RvD5), and IL-7. One year after hospital discharge, homeostasis was not completely restored with several markers of inflammation remaining elevated. Remarkably, IL-7 was persistently elevated, with levels comparable to those observed after ICU discharge, and PD-1, while lower, remained in the elevated abnormal range. CONCLUSIONS: In this study, protracted immune disturbances were observed one year after ICU discharge. The study results suggested the presence of long-lasting immune illness disorders following a long-term septic insult, indicating the need for long-term patient follow up after ICU discharge and questioning the use of immune intervention to restore immune homeostasis after abdominal septic shock.

Reversal of neutrophil-to-lymphocyte count ratio in early versus late death from septic shock.

INTRODUCTION: Septic shock is one of the most frequent causes of admission to the intensive care unit (ICU) and is associated with a poor prognosis. Early and late death in septic shock should be distinguished because they may involve different underlying mechanisms. In various conditions, the neutrophil-to-lymphocyte count ratio (NLCR) has been described as an easily measurable parameter to express injury severity. In the present study, we investigated whether the timing of death was related to a particular NLCR. METHODS: We conducted a prospective, single-center, observational study that included consecutive septic shock patients. Severity scores, early (before day 5) or late (on or after day 5 of septic shock onset) ICU mortality, and daily leukocyte counts were collected during the ICU stay. We assessed the association between leukocyte counts at admission and their evolution during the first 5 days with early or late death. The association between patient characteristics (including cell counts) and prognosis was estimated using Cox proportional cause-specific hazards models. RESULTS: The study included 130 patients who were diagnosed with abdominal (n = 99) or extra-abdominal (n = 31) septic shock. The median (interquartile range) NLCR was 12.5 (6.5-21.2) in survivors and 6.2 (3.7-12.6) in nonsurvivors (p = 0.001). The NLCR at admission was significantly lower in patients who died before day 5 than in survivors (5 [3.5-11.6] versus 12.5 [6.5-21.2], respectively; p = 0.01). From day 1 to day 5, an increased NLCR related to an increase in neutrophil count and a decrease in lymphocyte count was associated with late death (+34.8 % [-8.2 to 305.4] versus -20 % [-57.4 to 45.9]; p = 0.003). Those results were present in patients with abdominal origin sepsis as well as in those with extra-abdominal sepsis, who were analyzed separately. CONCLUSIONS: In the present study, a reversed NLCR evolution was observed according to the timing of death. Septic shock patients at risk of early death had a low NLCR at admission, although late death was associated with an increased NLCR during the first 5 days.

Local and systemic innate immune response to secondary human peritonitis.

INTRODUCTION: Our aim was to describe inflammatory cytokines response in the peritoneum and plasma of patients with peritonitis. We also tested the hypothesis that scenarios associated with worse outcome would result in different cytokine release patterns. Therefore, we compared cytokine responses according to the occurrence of septic shock, mortality, type of peritonitis and peritoneal microbiology. METHODS: Peritoneal and plasma cytokines (interleukin (IL) 1, tumor necrosis factor α (TNFα), IL-6, IL-10, and interferon γ (IFNγ)) were measured in 66 patients with secondary peritonitis. RESULTS: The concentration ratio between peritoneal fluid and plasma cytokines varied from 5 (2 to 21) (IFNγ) to 1310 (145 to 3888) (IL-1). There was no correlation between plasma and peritoneal fluid concentration of any cytokine. In the plasma, TNFα, IL-6, IFNγ and IL-10 were higher in patients with shock versus no shock and in nonsurvivors versus survivors (P ≤0.03). There was no differential plasma release for any cytokine between community-acquired and postoperative peritonitis. The presence of anaerobes or Enterococcus species in peritoneal fluid was associated with higher plasma TNFα: 50 (37 to 106) versus 38 (29 to 66) and 45 (36 to 87) versus 39 (27 to 67) pg/ml, respectively (P = 0.02). In the peritoneal compartment, occurrence of shock did not result in any difference in peritoneal cytokines. Peritoneal IL-10 was higher in patients who survived (1505 (450 to 3130) versus 102 (9 to 710) pg/ml; P = 0.04). The presence of anaerobes and Enterococcus species was associated with higher peritoneal IFNγ: 2 (1 to 6) versus 10 (5 to 28) and 7 (2 to 39) versus 2 (1 to 6), P = 0.01 and 0.05, respectively). CONCLUSIONS: Peritonitis triggers an acute systemic and peritoneal innate immune response with a simultaneous release of pro and anti-inflammatory cytokines. Higher levels of all cytokines were observed in the plasma of patients with the most severe conditions (shock, non-survivors), but this difference was not reflected in their peritoneal fluid. There was always a large gradient in cytokine concentration between peritoneal and plasma compartments highlighting the importance of compartmentalization of innate immune response in peritonitis.

Radiomic analysis of abdominal organs during sepsis of digestive origin in a French intensive care unit.

BACKGROUND: Sepsis is a severe and common cause of admission to the intensive care unit (ICU). Radiomic analysis (RA) may predict organ failure and patient outcomes. The objective of this study was to assess a model of RA and to evaluate its performance in predicting in-ICU mortality and acute kidney injury (AKI) during abdominal sepsis. METHODS: This single-center, retrospective study included patients admitted to the ICU for abdominal sepsis. To predict in-ICU mortality or AKI, elastic net regularized logistic regression and the random forest algorithm were used in a five-fold cross-validation set repeated 10 times. RESULTS: Fifty-five patients were included. In-ICU mortality was 25.5%, and 76.4% of patients developed AKI. To predict in-ICU mortality, elastic net and random forest models, respectively, achieved areas under the curve (AUCs) of 0.48 (95% confidence interval [CI], 0.43-0.54) and 0.51 (95% CI, 0.46-0.57) and were not improved combined with Simplified Acute Physiology Score (SAPS) II. To predict AKI with RA, the AUC was 0.71 (95% CI, 0.66-0.77) for elastic net and 0.69 (95% CI, 0.64-0.74) for random forest, and these were improved combined with SAPS II, respectively; AUC of 0.94 (95% CI, 0.91-0.96) and 0.75 (95% CI, 0.70-0.80) for elastic net and random forest, respectively. CONCLUSIONS: This study suggests that RA has poor predictive performance for in-ICU mortality but good predictive performance for AKI in patients with abdominal sepsis. A secondary validation cohort is needed to confirm these results and the assessed model.

Factors associated with septic shock and mortality in generalized peritonitis: comparison between community-acquired and postoperative peritonitis.

INTRODUCTION: The risk factors associated with poor outcome in generalized peritonitis are still debated. Our aim was to analyze clinical and bacteriological factors associated with the occurrence of shock and mortality in patients with secondary generalized peritonitis. METHODS: This was a prospective observational study involving 180 consecutive patients with secondary generalized peritonitis (community-acquired and postoperative) at a single center. We recorded peri-operative occurrence of septic shock and 30-day survival rate and analyzed their associations with patients characteristics (age, gender, SAPS II, liver cirrhosis, cancer, origin of peritonitis), and microbiological/mycological data (peritoneal fluid, blood cultures). RESULTS: Frequency of septic shock was 41% and overall mortality rate was 19% in our cohort. Patients with septic shock had a mortality rate of 35%, versus 8% for patients without shock. Septic shock occurrence and mortality rate were not different between community-acquired and postoperative peritonitis. Age over 65, two or more microorganisms, or anaerobes in peritoneal fluid culture were independent risk factors of shock. In the subgroup of peritonitis with septic shock, biliary origin was independently associated with increased mortality. In addition, intraperitoneal yeasts and Enterococci were associated with septic shock in community-acquired peritonitis. Yeasts in the peritoneal fluid of postoperative peritonitis were also an independent risk factor of death in patients with septic shock. CONCLUSIONS: Unlike previous studies, we observed no difference in incidence of shock and prognosis between community-acquired and postoperative peritonitis. Our findings support the deleterious role of Enterococcus species and yeasts in peritoneal fluid, reinforcing the need for prospective trials evaluating systematic treatment against these microorganisms in patients with secondary peritonitis.

Diastolic arterial blood pressure: a reliable early predictor of survival in human septic shock.

BACKGROUND: Emphasis in therapy of human septic shock is shifting towards reliable end points and predictors of survival. Rationale is to study whether the evolution of cardiovascular reactivity in view of the administered doses of norepinephrine is an early predictor of in-hospital survival and to determine the optimal threshold of norepinephrine therapy and its consequences on renal function. METHODS: Observational study of a prospective cohort of patients in septic shock, hospitalized in intensive care unit at least 24 hours before requiring norepinephrine. Excluded were patients requiring <72 hours of continuous norepinephrine (16 patients) or who received corticosteroids. Hemodynamic parameters (heart rate, blood pressure, urinary output, and temperature) were continuously monitored. RESULTS: Of 68 patients, 45 survived [intensive care unit stay of 24 (12-36) days, hospital stay of 36 (27-66) days], and 23 died 5 (3-10) days after septic shock onset and norepinephrine treatment. Multivariate analysis revealed four independent positive predictive factors of short-term (10 days) outcome: Simplified Acute Physiology Score (SAPS) II <50 [odds ratio (OR) 6.4, 95% confidence interval (95% CI) 1.3-30.7, p < 0.011], and on day 3 Logistic Organ Dysfunction System (LODS) score <6 (OR 29.1, 95% CI 2.7-314.3, p = 0.0056), norepinephrine concentration <0.5 mug/kg/min (OR 17.6, 95% CI 2.2-142.0, p < 0.0007), diastolic arterial pressure >50 mm Hg (OR 24.8, 95% CI 2.9-215.9, p < 0.004), but not systolic arterial pressure. CONCLUSIONS: Septic shock survival increases when dose of 0.5 mug/kg/min of norepinephrine continuously improves vascular tone within the first 48 hours, or when diastolic arterial pressure (>50 mm Hg) is restored. Norepinephrine has beneficial effects on renal function. Predictive value of LODS score on day 3 is demonstrated, while SAPS II is confirmed as the only reliable predictive factor in first 24 hours.

Adrenal response in patients with septic shock of abdominal origin: relationship to survival.

OBJECTIVE: To evaluate the prognostic value of adrenocortical response to corticotropin in septic shock patients operated on exclusively for an intra-abdominal source of infection. DESIGN AND SETTING: Prospective, observational, single-center study in a surgical intensive care unit of a university hospital PATIENTS: 118 consecutive septic shock patients undergoing laparotomy or drainage for intra-abdominal infection. MEASUREMENTS AND RESULTS: Baseline cortisol (t (0)) and cortisol response to corticotropin test (Delta) were measured during the first 24 h following onset of shock. The relationship between adrenal function test results and survival was analyzed as well as the effect of etomidate anesthesia. Cortisol plasma level at t (0) was higher in nonsurvivors than in survivors (33 +/- 23 vs. 25 +/- 14 microg/dl), but the response to corticotropin test did not differ between these two subgroups. ROC analysis showed threshold values for t (0) (32 microg/dl) and Delta (8 microg/dl) that best discriminated survivors from nonsurvivors in our population. We observed no difference in survival at the end of hospital stay using log rank test when patients were separated according to t (0), Delta, or both. In addition, adrenal function tests and survival did not differ in patients who received etomidate anesthesia (n = 69) during the surgical treatment of their abdominal sepsis. CONCLUSIONS: In this cohort of patients with abdominal septic shock baseline cortisol level and the response to corticotropin test did not discriminate survivors from nonsurvivors. No deleterious impact of etomidate anesthesia on adrenal function tests and survival was observed in these patients.

Inflammatory cytokines, C reactive protein, and procalcitonin as early predictors of necrosis infection in acute necrotizing pancreatitis.

BACKGROUND: Infection of necrosis is a major risk factor in patients with acute pancreatitis. Systematic use of broad spectrum antibiotics has been recommended in these patients but may induce serious side effects. To better target patients in whom antibiotic prophylaxis could be beneficial, we evaluated whether early serum profiles of interleukin 6 (IL-6), tumor necrosis factor (TNF-alpha, C reactive protein (CRP) and procalcitonin (PCT) help to discriminate between patients who eventually develop infection of necrosis and those who do not. METHODS: Forty-eight patients with acute pancreatitis and a computed tomography (CT) severity index score of more than 3 were prospectively screened. They were then separated into infected and non-infected groups according to the occurrence of infected pancreatic necrosis. The severity of illness was assessed with Ranson's classification and Simplified Acute Physiologic Score II. Serum levels of IL-6, TNF-alpha, CRP, and PCT were measured during the first 3 days after admission. CT-guided fine needle aspiration of pancreatic necrosis was performed to prove infection when sepsis of abdominal origin was suspected. Using the methodology of receiver operating curves, we determined the presence of a threshold for markers that would be predictive of the development of infected necrosis. RESULTS: PCT and IL-6 were higher in the serum of patients who eventually developed infection of necrosis (P < 0.003 and < 0.04, respectively). No difference was noted between the 2 groups for TNF- alpha and CRP. The combination of IL-6 < 400 pg/l and PCT < 2 ng/L best identified patients who were not at risk for necrosis infection. The negative predictive value for these thresholds was 91%, whereas sensitivity and specificity were 75% and 84%. CONCLUSIONS: PCT and IL-6 serum levels were elevated very early in patients who eventually developed necrosis infection. A combination of PCT and IL-6 thresholds could be helpful in identifying a subgroup of patients in whom antibiotic prophylaxis is likely to be ineffective.

Erythromycin improves the quality of EGD in patients with acute upper GI bleeding: a randomized controlled study.

BACKGROUND: The diagnostic and therapeutic value of EGD in patients with upper GI bleeding is often limited by the presence of residual blood or clots. When infused before EGD, erythromycin, a potent gastrokinetic drug, might improve the quality of EGD in patients with upper GI bleeding. The aim of this study was to assess the effect of erythromycin on the quality of the EGD in patients with acute upper GI bleeding. METHODS: Forty-one patients admitted to the intensive care unit because of acute upper GI bleeding were included in a randomized, endoscopist-blinded, controlled trial, comparing erythromycin (3 mg/kg intravenously over 30 minutes) to no treatment (control patients). EGD was performed 30 to 90 minutes after the end of the infusion. The primary study outcome was quality of EGD examination, as evaluated on a scale of 0 to 3, and the need to perform a second diagnostic EGD within the next 8 days. Secondary outcomes were efficiency of the endoscopic hemostatic therapy and intensity of esophagogastroduodenal contractions, as evaluated on a scale of 0-3. RESULTS: The characteristics of the patients and lesions found by EGD were similar in both groups. Quality of the EGD examination was significantly better in the erythromycin group (n = 19) compared with the control group (n = 22) (2.5 [0.8] vs. 1.5 [1.3]; p = 0.02). Three patients receiving erythromycin required a second EGD compared with 10 control patients (p = 0.089). Erythromycin did not interfere with the performance of EGD or the efficiency of hemostatic procedures. The intensity of gastroduodenal contractions was similar in both groups. No adverse event was observed. CONCLUSIONS: In patients with acute upper GI bleeding, infusion of erythromycin before endoscopy significantly improved the quality of EGD and tended to reduce the need for second-look endoscopy.