Na Cui

Restriction of third-generation cephalosporin use decreases infection-related mortality.

ObjectiveTo determine the effect of restriction of third-generation cephalosporin use on antibiotic resistance and the outcome of patients with infection. DesignA prospective, before–after comparative study. SettingA general intensive care unit with 14 beds at a university-affiliated teaching hospital. PatientsAll patients admitted to the intensive care unit within 2 yrs. InterventionsA new antibiotic treatment strategy was implemented during phase II. All patients with confirmed or suspected Gram-negative bacterial infections were treated mainly with antibiotics other than third-generation cephalosporins. Measurements and Main ResultsAntibiotic resistance among common Gram-negative bacilli and infection-related hospital mortality during phase I were compared with phase II. A 26.6% reduction in third-generation cephalosporin use (from 168.2 ± 48.0 to 123.5 ± 39.3 g/month, p = .021), accompanied by a 277.7% increase in cefepime use (from 10.3 ± 19.2 to 38.9 ± 31.7 g/month, p = .014) occurred in phase II compared with phase I. This was accompanied by a significant decrease in reduced susceptibility of Gram-negative bacilli to third-generation cephalosporins (p < .05), mainly because of the improved susceptibility of Escherichia coli and Klebsiella species (p < .05). Infection-related hospital mortality was significantly lower in phase II (19.3% vs. 36.3%, p = .014). Multiple logistic regression analysis demonstrated lower respiratory tract infection, the status of immunocompromise, and continuous veno-venous hemofiltration as independent risk factors for infection-related hospital mortality (p < .05), whereas infection with E. coli or Klebsiella species (p = .039) and restriction of third-generation cephalosporin use (p = .025) were associated with a significantly lower mortality rate. ConclusionsRestriction of third-generation cephalosporin use may improve the antibiotic susceptibility and reduce infection-related hospital mortality in critically ill patients.

Dexamethasone Suppressed LPS-Induced Matrix Metalloproteinase and Its Effect on Endothelial Glycocalyx Shedding

The aim of this study is to determine the mechanism of sepsis-induced vascular hyperpermeability and the beneficial effect of glucocorticoid in protecting vascular endothelium. Male Sprague-Dawley rats were given either a bolus intraperitoneal injection of a nonlethal dose of LPS (Escherichia coli 055:B5, 10 mg/kg, Sigma) or vehicle (pyrogen-free water). Animals of treatment groups were also given either dexamethasone (4 mg/kg, 30 min prior to LPS injection) or the matrix metalloproteinases (MMPs) inhibitor doxycycline (4 mg/kg, 30 min after LPS injection). Both activities and protein levels of MMP-2 (p < 0.001) and MMP-9 (p < 0.001) were significantly upregulated in aortic homogenates from LPS-treated rats, associated with decreased ZO-1 (p < 0.001) and syndecan-1 (p = 0.011) protein contents. Both dexamethasone and doxycycline could significantly inhibit MMPs activity and reserve the expressions of ZO-1 and syndecan-1. The inhibition of MMPs by dexamethasone was significantly lower than that by doxycycline, while the rescue of syndecan-1 expression from LPS-induced endotoxemic rat thoracic aorta was significantly higher in the dexamethasone-treated compared to the doxycycline-treated (p = 0.03). In conclusion, activation of MMPs plays important role in regulating ZO-1 and syndecan-1 protein levels in LPS mediated endothelial perturbation. Both dexamethasone and doxycycline inhibit activation of MMPs that may contribute to the rescue of ZO-1 and syndecan-1 expression.

Prognostic value of extravascular lung water and its potential role in guiding fluid therapy in septic shock after initial resuscitation.

PURPOSES To explore whether extravascular lung water (EVLW) provides a valuable prognostic tool guiding fluid therapy in septic shock patients after initial resuscitation. MATERIALS AND METHODS We performed a retrospective study of septic shock patients who achieved adequate initial fluid resuscitation with extended hemodynamic monitoring, analyzing the prognostic value of EVLW and whether fluid therapy for 24 (T24) or 24-48 hours (T24-48) after initial resuscitation with a recommended value of EVLW yielded a 28-day mortality advantage. RESULTS One hundred five patients with septic shock were included in this study, 60 (57.1%) of whom died after 28 days. For 48 hours after initial resuscitation, the daily fluid balance (DFB; T24: 2494 ± 1091 vs 1965 ± 964 mL [P = .011] and T24-48: 2127 ± 783 vs 1588 ± 665 mL [P < .001]) and daily maximum values of the EVLW index (EVLWImax; T24: 13.9 ± 3.7 vs 11.5 ± 3.2 mL/kg [P < .001] and T24-48: 14.4 ± 5.3 vs 12.0 ± 4.4 mL/kg [P < .001]) were significantly higher in nonsurvivors than in survivors. In multivariate regression analysis, the DFB (T24: odds ratio [OR] 1.001 [P = .016] and T24-48: OR 1.001 [P = .008]), EVLWImax (T24: OR 2.158 [P = .002] and T24-48: OR 3.277 [P = .001]), blood lactate (T24: OR 1.368 [P = .021] and T24-48: OR 4.112 [P < .001]), and central venous blood oxygen saturation (T24: OR 0.893 [P = .013] and T24-48: OR 0.780 [P = .004]) were all independently associated with the 28-day mortality. A receiver operating characteristic analysis revealed that area under the curve values of 0.82 (95% confidence interval, 0.74-0.91; P < .001) and 0.90 (95% confidence interval, 0.83-0.96; P < .001) for EVLWImax ≥ 12.5 mL/kg (T24 and T24-48) predicted a 28-day mortality with sensitivities of 88% (80%-96%) and 95% (90%-100%) and specificities of 60% (46%-74%) and 76% (63%-89%).The EVLWImax was correlated with DFB with Spearman ρ values of 0.497 (T24: P < .001) and 0.650 (T24-48: P < .001). Cox survival and regression analyses demonstrated that EVLWImax ≥ 12.5 mL/kg (T24 and T24-48) was associated with higher risk and increased mortality, with adjusted ORs of 4.77 (P < .001) and 10.86 (P < .001). CONCLUSIONS A higher EVLW in septic shock patients after initial resuscitation was associated with a more positive fluid balance and increased mortality, which is an independent predictor of the 28-day mortality in septic shock patients after initial resuscitation.

CD8 + T-cell counts: an early predictor of risk and mortality in critically ill immunocompromised patients with invasive pulmonary aspergillosis

IntroductionCritically ill immunocompromised (CIIC) patients with pulmonary infection are a population at high risk for invasive pulmonary aspergillosis (IPA). The host defenses are important factors to consider in determining the risk and outcome of infection. Quantification of changes in the status of host immunity could be valuable for clinical diagnosis and outcome prediction.MethodsWe evaluated the quantitative changes in key humoral and cellular parameters in CIIC patients with pulmonary infection and their potential influence on the risk and prognosis of IPA. We monitored the evolution of these parameters in 150 CIIC patients with pulmonary infection on days 1, 3 and 10 (D1, D3 and D10) following ICU admission. The primary outcome was 28-day mortality. Follow-up included 60- and 90-day mortality.ResultsAmong the 150 CIIC patients included in this study, 62 (41.3%) had microbiological evidence of IPA. Compared with patients without IPA, CD3+, CD8+, CD28+CD4+ and CD28+CD8+ CD28+CD8+ T-cell counts (D1, D3 and D10) and B-cell counts (D1 and D3) were significantly reduced in patients with IPA (P < 0.05). Multivariate regression analysis revealed that CD8+ (D3 and D10) (odds ratio (OR) 0.34, 95% confidence interval (CI) 0.23 to 0.46; OR 0.68, 95% CI 0.56 to 0.80), CD28+CD8+ (D3) (OR 0.73, 95% CI 0.61 to 0.86) and CD3+ (D10) (OR 0.81, 95% CI 0.63 to 0.98) T-cell counts were independent predictors of IPA in CIIC patients. Receiver operating characteristic analysis of immune parameters predicting 28-day mortality revealed area under the curve values of 0.82 (95% CI 0.71 to 0.92), 0.94 (95% CI 0.87 to 0.99), and 0.94 (95% CI 0.85 to 0.99) for CD8+ T-cell counts (D1, D3 and D10, respectively) and 0.84 (95% CI 0.75 to 0.94), 0.92 (95% CI 0.85 to 0.99) and 0.90 (95% CI 0.79 to 0.99) for CD28+CD8+ T-cell counts (D1, D3 and D10, respectively). Kaplan-Meier survival analysis provided evidence that CD8+ and CD28+CD8+ T-cell counts (<149.5 cells/mm3 and <75 cells/mm3, respectively) were associated with early mortality in CIIC patients with IPA (logrank test; P < 0.001).ConclusionsCD8+ and CD28+CD8+ T-cell counts were significantly lower in CIIC patients with IPA than in non-IPA patients. Lower CD8+ and CD28+CD8+ T-cell counts in CIIC patients with pulmonary infection were associated with higher risk and early mortality in IPA and may be valuable for clinical diagnosis and outcome prediction.

Elevated Mean Airway Pressure and Central Venous Pressure in the First Day of Mechanical Ventilation Indicated Poor Outcome

Objectives: The relationship between respiratory mechanical parameters and hemodynamic variables remains unclear. This study was performed to determine whether mean airway pressure and central venous pressure in the first day of mechanical ventilation are associated with patient outcomes. Design: Retrospective first 24-hour comparison during ICU stay. Setting: The Department of Critical Care Medicine of Peking Union Medical College Hospital. Patients: Patients with mechanical ventilation. Interventions: None. Measurements and Main Results: The clinical data of patients who received mechanical ventilation, especially respiratory and hemodynamic data, were collected and analyzed. In terms of the hemodynamic and perfusion data, the nonsurvivors group (177/2,208) had higher heart rate, respiratory rate, central venous pressure, and lactates and a lower perfusion index and P(v-a)CO2 (p < 0.05). In terms of respiratory condition, mean airway pressure, peak airway pressure, positive end-expiratory pressure, driving pressure, and inspiratory time/total respiration time of nonsurvivors were significantly higher, and arterial oxygen pressure and dynamic compliance worsened and were lower than the survivors (p < 0.05). Increased central venous pressure (odds ratio, 1.125; 95% CI, 1.069–1.184; p < 0.001) and elevated mean airway pressure (odds ratio, 1.125; 95% CI, 1.069–1.184; p < 0.001) were independently associated with 28-day mortality. The area under receiver operating characteristic demonstrated that central venous pressure and mean airway pressure were measured at 0.795 (95% CI, 0.654–0.757) and 0.833 (95% CI, 0.608–0.699), respectively. Based on the cutoff of central venous pressure and mean airway pressure, all of the participants were divided into the following groups: low central venous pressure and mean airway pressure, only high central venous pressure or mean airway pressure, or high central venous pressure and mean airway pressure. Post hoc tests showed significant differences among these three groups based on 28-day survival (log rank [Mantel-Cox], 131.931; p < 0.001). Conclusions: During the first 24 hours of mechanical ventilation, patients with elevated mean airway pressure and elevated central venous pressure had worse outcomes.

Impact of initial empirical antifungal agents on the outcome of critically ill patients with invasive candidiasis: analysis of the China-SCAN study

The effect of different empirical antifungal agents on the clinical outcome of critically ill patients with invasive candidiasis (IC) has not been fully elucidated. In this study, 136 patients with proven IC who received empirical therapy in the China-SCAN multicentre study were retrospectively analysed. Initial empirical antifungal monotherapy consisted of a triazole [fluconazole (n = 61), voriconazole (n = 20) or itraconazole (n = 12)] or an echinocandin (n = 43). Hospital mortality as the primary outcome and global responses (clinical and microbiological) were assessed. The results indicated that rates of hospital mortality (P = 0.006) and intensive care unit (ICU) mortality (P = 0.011) were significantly lower in patients treated with an echinocandin compared with those receiving fluconazole, voriconazole or itraconazole. Multivariate regression analysis indicated that the type of antifungal agent used in empirical therapy was an independent predictor of hospital mortality (P = 0.033). Initial empirical echinocandin treatment was associated with decreased hospital mortality compared with fluconazole [odds ratio (OR) = 0.22, 95% confidence interval (CI) 0.06-0.85; P = 0.028], voriconazole (OR = 0.11, 95% CI 0.02-0.56; P = 0.008) or itraconazole (OR = 0.12, 95% CI 0.02-0.72; P = 0.020). Similar findings were observed for the clinical success endpoint. This study demonstrated that the initial empirical antifungal agent was an independent predictor of hospital mortality in critically ill patients with IC. Empirical therapy with an echinocandin was associated with decreased hospital mortality and greater clinical success than empirical therapy with fluconazole, voriconazole or itraconazole.

Role of Triggering Receptor Expressed on Myeloid Cell-1 Expression in Mammalian Target of Rapamycin Modulation of CD8+ T-cell Differentiation during the Immune Response to Invasive Pulmonary Aspergillosis

Background: Triggering receptor expressed on myeloid cell-1 (TREM-1) may play a vital role in mammalian target of rapamycin (mTOR) modulation of CD8+ T-cell differentiation through the transcription factors T-box expressed in T-cells and eomesodermin during the immune response to invasive pulmonary aspergillosis (IPA). This study aimed to investigate whether the mTOR signaling pathway modulates the proliferation and differentiation of CD8+ T-cells during the immune response to IPA and the role TREM-1 plays in this process. Methods: Cyclophosphamide (CTX) was injected intraperitoneally, and Aspergillus fumigatus spore suspension was inoculated intranasally to establish the immunosuppressed IPA mouse model. After inoculation, rapamycin (2 mg·kg−1·d−1) or interleukin (IL)-12 (5 &mgr;g/kg every other day) was given for 7 days. The number of CD8+ effector memory T-cells (Tem), expression of interferon (IFN)-&ggr;, mTOR, and ribosomal protein S6 kinase (S6K), and the levels of IL-6, IL-10, galactomannan (GM), and soluble TREM-1 (sTREM-1) were measured. Results: Viable A. fumigatus was cultured from the lung tissue of the inoculated mice. Histological examination indicated greater inflammation, hemorrhage, and lung tissue injury in both IPA and CTX + IPA mice groups. The expression of mTOR and S6K was significantly increased in the CTX + IPA + IL-12 group compared with the control, IPA (P = 0.01; P = 0.001), and CTX + IPA (P = 0.034; P = 0.032) groups, but significantly decreased in the CTX + IPA + RAPA group (P < 0.001). Compared with the CTX + IPA group, the proportion of Tem, expression of IFN-&ggr;, and the level of sTREM-1 were significantly higher after IL-12 treatment (P = 0.024, P = 0.032, and P = 0.017, respectively), and the opposite results were observed when the mTOR pathway was blocked by rapamycin (P < 0.001). Compared with the CTX + IPA and CTX + IPA + RAPA groups, IL-12 treatment increased IL-6 and downregulated IL-10 as well as GM, which strengthened the immune response to the IPA infection. Conclusions: mTOR modulates CD8+ T-cell differentiation during the immune response to IPA. TREM-1 may play a vital role in signal transduction between mTOR and the downstream immune response.

Initial therapeutic strategy of invasive candidiasis for intensive care unit patients: a retrospective analysis from the China-SCAN study

BackgroundTo investigate the impact of initial antifungal therapeutic strategies on the prognosis of invasive Candida infections (ICIs) in intensive care units (ICUs) in China.MethodsA total of 306 patients with proven ICIs in the China-SCAN study were analyzed retrospectively. Empiric, pre-emptive, and targeted therapy were adopted based on starting criteria including clinical, microbiological, and other conventional prediction rules. The primary outcome was hospital mortality and the secondary endpoints were duration days in ICU and duration days in hospital. The global responses (clinical and microbiological) at the end of the empirical therapy were also assessed.ResultsA total of 268/306 (87.6%) ICI patients received antifungal therapy, including 142/268 (53.0%) initial empirical therapy, 53/268 (19.8%) initial pre-emptive therapy, and 73/268 (27.2%) initial targeted therapy. Compared with the initial empirical antifungal therapy and targeted antifungal therapy, patients with initial pre-emptive antifungal therapy had significantly less clinical remission [11/53 (21.2%) vs. 61/142 (43.3%) vs. 22/73 (30.1%), P = 0.009], higher ICU [26/53 (57.8%) vs. 42/142 (32.2%) vs. 27/73 (43.5%), P = 0.008] and hospital mortality [27/53 (60.0%) vs. 43/142 (32.8%) vs. 29/73 (46.8%), P = 0.004] and more microbiological persistence [9/53 (17.0%) vs. 6/142 (4.2%) vs. 9/73 (12.3%), P = 0.011]. Kaplan-Meier survival analysis revealed that ICI patients with initial pre-emptive antifungal therapy and targeted antifungal therapy were associated with reduced hospital duration compared with patients with initial empirical antifungal therapy after confirmation of fungal infection (log-rank test: P = 0.021). Multivariate regression analysis provided evidence that initial empirical antifungal therapy was an independent predictor for DECREASING the hospital mortality in ICI patients on ICU admission and at ICI diagnosis (odds ratio 0.327, 95% confidence interval 0.160–0.667, P = 0.002; odds ratio 0.351, 95% confidence interval 0.168–0.735, P = 0.006).ConclusionsThe initial therapeutic strategy for invasive candidiasis was independently associated with hospital mortality. Prompt empirical antifungal therapy could be critical to decrease early hospital mortality.Trial registrationClinicaltrials.gov NCT01253954 (retrospectively registration date: December 3, 2010)

Inhibition of the mTOR Pathway Exerts Cardioprotective Effects Partly through Autophagy in CLP Rats

Background Sepsis-induced myocardial dysfunction is a severe clinical problem. Recent studies have indicated that autophagy and myocardial energy depletion play a major role in myocardial dysfunction during sepsis, a mechanistic target of rapamycin (mTOR) as a master sensor of energy status and autophagy mediator; however, there are little data describing its role during sepsis in the heart. Methods Cecal ligation and puncture (CLP) or sham operation (SHAM) was performed in rats. After treatment, pathological changes were determined by H&E staining, cardiac functions by echocardiography, the distribution of microtubule-associated protein light chain 3 (LC-3) type II and hypoxia-inducible factor 1α (HIF-1a) by immunohistochemical staining, and autophagic vacuoles by transmission electron microscopy. Moreover, the mTOR signaling pathway and LC3II, p62, and HIF-1a expression were measured by western blotting. Results Rapamycin alleviated the pathological damage of myocardial tissue, attenuated cardiac dysfunction (left ventricular ejection fraction (LVEF), p < 0.05; fractional shortening (FS), p < 0.05), and reduced HIF-1a expression (p < 0.05). Expectedly, rapamycin decreased the activity of the mTOR pathway in both sham-operated rats (p < 0.0001) and CLP rats (p < 0.01). Interestingly, we also found inhibition of the mTOR pathway in CLP rats compared with sham-operated rats; phosphorylation of both mTOR (p < 0.001) and pS6K1 (p < 0.01) was significantly suppressed following CLP challenge. Furthermore, autophagic processes were elevated by CLP; the ratio of LC3II/LC3I (p < 0.05) was increased while p62 expression (p < 0.001) was decreased significantly; there were also more autophagic vacuoles in CLP rats; and rapamycin could further elevate the autophagic processes compared with CLP rats (LC3II/LC3I, p < 0.05; P62, p < 0.05). Conclusion Inhibition of the mTOR pathway has cardioprotective effects on myocardial dysfunction during sepsis induced by CLP, which is partly mediated through autophagy.

Invasive Fungal Disease in Critically Ill Patients at High Risk: Usefulness of Lymphocyte Subtyping

Objectives: This study aimed to investigate the distinguishing ability of lymphocyte subtyping for diagnosis and prognosis of invasive fungal disease (IFD). Methods: We assessed lymphocyte subtyping and evaluated the quantitative changes in key immunological parameters at intensive care unit (ICU) admission in critically ill patients at high risk and their potential influence on diagnosis and outcome of IFD. The primary outcome was 28-day mortality. Results: Among the 124 critically ill patients with mean Candida score 3.89 (0.76), 19 (15.3%) were in the IFD group. CD28+CD8+ T-cell counts (area under the curve [AUC] 0.899, 95% confidence interval [CI], 0.834-0.964, P < .001) had better distinguishing ability than other immune parameters for IFD diagnosis. The cutoff value of CD28+CD8+ T-cell counts at ICU admission for IFD diagnosis was 59.5 cells/mm3, with 83.3% sensitivity and 86.4% specificity. Multivariate logistic regression analysis identified CD28+CD8+ T-cell count <59.5 cells/mm3 (odds ratio 59.7, 95% CI, 7.33-486.9, P < .001) as an independent predictor for IFD diagnosis. CD28+CD8+ T-cell counts could also predict 28-day mortality (AUC 0.656, 95% CI, 0.525-0.788, P = .045). Kaplan-Meier survival analysis provided evidence that natural killer cell count <76.0 cells/mm3 (log-rank test; P = .001), CD8+ T-cell count <321.5 cells/mm3 (log-rank test; P = .04), and CD28+CD8+ T-cell count <129.0 cells/mm3 (log-rank test; P = .02) at ICU admission were associated with lower survival probabilities. Conclusion: CD28+CD8+ T-cell counts play an important role in early diagnosis of IFD. Low counts are associated with early mortality in critically ill patients at high risk of IFD. Our findings add evidence to the utility of lymphocyte subtyping in a diagnostic algorithm to better define IFD in critically ill patients at high risk.