降低严重感染与感染性休克的病死率:机遇与挑战并存

严重感染(severe sepsis)与感染性休克(septic shock)是一种高患病率、高病死率、高治疗费用的临床综合征。虽然经过了多年的研究与实践探索,但严重感染与感染性休克的病死率一直居高不下,可高达40%左右,仍然是重症加强治疗病房(ICU)患者的首要致死原因。因此,目前在国际上,包括各级政府、医学专业组织和临床工作者已越来越重视这一问题。     

Prehospital hemodynamic optimisation is associated with a 30-day mortality decrease in patients with septic shock

IntroductionSeptic shock (SS) is characterized by low blood pressure resulting in organ failure and poor prognosis. Among SS treatments, in hospital studies reported a beneficial effect of early hemodynamic resuscitation on mortality rate.This study aims to investigate the relationship between prehospital hemodynamic optimisation and 30-day mortality in patients with SS.MethodsFrom April 6th, 2016 to December 31th, 2019, patients with SS requiring prehospital Mobile Intensive Care Unit intervention (mICU) were included. Prehospital hemodynamic optimisation was defined as a arterial blood pressure of >65 mmHg, or >75 mmHg if previous hypertension history, at the end of the prehospital stage.ResultsThree hundred thirty-seven patients were retrospectively analysed. The mean age was 69 ± 15 years, and 226 patients (67%) were male. One hundred and thirty-six patients (40%) had previous hypertension history. Pulmonary, digestive and urinary infections were the suspected cause of the SS in respectively 46%, 23% and 15% of the cases. 30-day overall mortality was 30%.Prehospital hemodynamic optimisation was complete for 204 patients (61%). Cox regression analysis reports a significant association between prehospital hemodynamic optimisation and 30-day mortality (HRa = 0.52 95%CI [0.31–0.86], p = 0.01).ConclusionIn this study, we report that prehospital hemodynamic optimisation is associated with a decrease in 30-day mortality in patients with SS cared for by a mICU in the prehospital setting. An individualized mean arterial pressure target, based on previous hypertension history, may be considered from the prehospital stage of SS resuscitation.     

Pulmonary contusion is associated with toll-like receptor 4 upregulation and decreased susceptibility to pseudomonas pneumonia in a mouse model

Pulmonary contusion is a major cause of respiratory failure in trauma patients. This injury frequently leads to immune suppression and infectious complications such as pneumonia. The mechanism whereby trauma leads to an immune-suppressed state is poorly understood. To further study this phenomenon, we developed an animal model of pulmonary contusion (PC) complicated by pneumonia and assessed the effect of PC and pneumonia on toll-like receptor expression in alveolar macrophages. Using a mouse model, PC was induced on the right lung, and pneumonia was induced with Pseudomonas aeruginosa (Pa) injected intratracheally 48 h after injury. Susceptibility to pneumonia was assessed by mortality at 7 days. Uninjured animals were used as controls. Bronchoalveolar lavage fluid and blood were assayed 48 h after injury and 24 h after Pa instillation to look at markers of systemic inflammation. Toll-like receptor expression in the initial inflammatory response was analyzed by flow cytometry. Unexpectedly, injured animals subjected to intratracheal injection of Pa at 48 h after PC demonstrated increased survival compared with uninjured animals. Bronchoalveolar lavage cytokine expression was increased significantly after Pa administration but not after PC alone. Toll-like receptor 4 expression on alveolar macrophages was significantly elevated in the injured group compared with sham but not in neutrophils. Animals subjected to PC are more resistant to mortality from infection with Pa and display an enhanced cytokine response when subsequently subjected to Pa. Increased expression of toll-like receptor 4 on alveolar macrophages and enhanced innate immunity are a possible mechanism of increased cytokine production and decreased susceptibility to pneumonia.     

Sustained high serum malondialdehyde levels are associated with severity and mortality in septic patients

Introduction

There is a hyperoxidative state in sepsis. The objective of this study was to determine serum malondialdehyde (MDA) levels during the first week of follow up, whether such levels are associated with severity during the first week and whether non-surviving patients showed higher MDA levels than survivors during the first week.

Methods

We performed an observational, prospective, multicenter study in six Spanish Intensive Care Units. Serum levels of MDA were measured in 328 patients (215 survivors and 113 non-survivors) with severe sepsis at days one, four and eight of diagnosis, and in 100 healthy controls. The primary endpoint was 30-day mortality and the secondary endpoint was six -month mortality. The association between continuous variables was carried out using Spearman’s rank correlation coefficient. Cox regression analysis was applied to determine the independent contribution of serum MDA levels on the prediction of 30-day and 6-month mortality. Hazard ratio (HR) and 95% confidence intervals (CI) were calculated as measures of the clinical impact of the predictor variables.

Results

We found higher serum MDA in septic patients at day one (p < 0.001), day four (p < 0.001) and day eight (p < 0.001) of diagnosis than in healthy controls. Serum MDA was lower in surviving than non-surviving septic patients at day one (p < 0.001), day four (p < 0.001) and day eight (p < 0.001). Serum MDA levels were positively correlated with lactic acid and SOFA during the first week. Finally, serum MDA levels were associated with 30-day mortality (HR = 1.05; 95% CI = 1.02-1.09; p = 0.005) and six-month mortality (hazard ratio (HR) = 1.05; 95% CI = 1.02-1.09; p = 0.003) after controlling for lactic acid levels, acute physiology and chronic health evaluation (APACHE)-II, diabetes mellitus, bloodstream infection and chronic renal failure.

Conclusions

To our knowledge, this is the largest series providing data on the oxidative state in septic patients to date. The novel finding is that high serum MDA levels sustained throughout the first week of follow up were associated with severity and mortality in septic patients.     

腹腔镜手术对红细胞和淋巴细胞免疫功能的影响

目的探讨腹腔镜手术前后机体红细胞免疫和T淋巴细胞亚免疫功能的变化。方法以红细胞C3b受体花环率、红细胞免疫复合物花环率、肿瘤红细胞花环率及CD3，CD4，CD8细胞作为观测指标，测定该院60例腹腔镜手术患者的免疫指标变化，并与对照组进行比较。结果腹腔镜患者术后第1天的上述免疫指标虽有轻度障碍，但没有显著性意义，且术后第3天迅速恢复。结论腹腔镜患者手术前后红细胞免疫功能和T淋巴细胞亚群免疫功能没有明显障碍，是患者手术后能够迅速恢复的免疫依据。     

De-escalation of empirical therapy is associated with lower mortality in patients with severe sepsis and septic shock

Purposes

We set out to assess the safety and the impact on in-hospital and 90-day mortality of antibiotic de-escalation in patients admitted to the ICU with severe sepsis or septic shock.

Methods

We carried out a prospective observational study enrolling patients admitted to the ICU with severe sepsis or septic shock. De-escalation was defined as discontinuation of an antimicrobial agent or change of antibiotic to one with a narrower spectrum once culture results were available. To control for confounding variables, we performed a conventional regression analysis and a propensity score (PS) adjusted-multivariable analysis.

Results

A total of 712 patients with severe sepsis or septic shock at ICU admission were treated empirically with broad-spectrum antibiotics. Of these, 628 were evaluated (84 died before cultures were available). De-escalation was applied in 219 patients (34.9 %). By multivariate analysis, factors independently associated with in-hospital mortality were septic shock, SOFA score the day of culture results, and inadequate empirical antimicrobial therapy, whereas de-escalation therapy was a protective factor [Odds-Ratio (OR) 0.58; 95 % confidence interval (CI) 0.36–0.93). Analysis of the 403 patients with adequate empirical therapy revealed that the factor associated with mortality was SOFA score on the day of culture results, whereas de-escalation therapy was a protective factor (OR 0.54; 95 % CI 0.33–0.89). The PS-adjusted logistic regression models confirmed that de-escalation therapy was a protective factor in both analyses. De-escalation therapy was also a protective factor for 90-day mortality.

Conclusions

De-escalation therapy for severe sepsis and septic shock is a safe strategy associated with a lower mortality. Efforts to increase the frequency of this strategy are fully justified.     

Early dynamic left intraventricular obstruction is associated with hypovolemia and high mortality in septic shock patients

IntroductionBased on previously published case reports demonstrating dynamic left intraventricular obstruction (IVO) triggered by hypovolemia or catecholamines, this study aimed to establish: (1) IVO occurrence in septic shock patients; (2) correlation between the intraventricular gradient and volume status and fluid responsiveness; and (3) mortality rate.MethodWe prospectively analyzed patients with septic shock admitted to a general ICU over a 28-month period who presented Doppler signs of IVO. Clinical characteristics and hemodynamic parameters as well as echocardiographic data regarding left ventricular function, size, and calculated mass, and left ventricular outflow Doppler pattern and velocity before and after fluid infusions were recorded.ResultsDuring the study period, 218 patients with septic shock were admitted to our ICU. IVO was observed in 47 (22 %) patients. Mortality rate at 28 days was found to be higher in patients with than in patients without IVO (55 % versus 33 %, p < 0.01). Small, hypercontractile left ventricles (end-diastolic left ventricular surface 4.7 ± 2.1 cm²/m² and ejection fraction 82 ± 12 %), and frequent pseudohypertrophy were found in these patients. A rise ≥12 % in stroke index was found in 87 % of patients with IVO, with a drop of 47 % in IVO after fluid infusion.ConclusionLeft IVO is a frequent event in septic shock patients with an important correlation with fluid responsiveness. The mortality rate was found to be higher in these patients in comparison with patients without obstruction.     

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.     

Programmed death-1 levels correlate with increased mortality, nosocomial infection and immune dysfunctions in septic shock patients

Introduction

Septic shock remains a major health care problem worldwide. Sepsis-induced immune alterations are thought to play a major role in patients' mortality and susceptibility to nosocomial infections. Programmed death-1 (PD-1) receptor system constitutes a newly described immunoregulatory pathway that negatively controls immune responses. It has recently been shown that PD-1 knock-out mice exhibited a lower mortality in response to experimental sepsis. The objective of the present study was to investigate PD-1-related molecule expressions in septic shock patients.

Methods

This prospective and observational study included 64 septic shock patients, 13 trauma patients and 49 healthy individuals. PD-1-related-molecule expressions were measured by flow cytometry on circulating leukocytes. Plasmatic interleukin (IL)-10 concentration as well as ex vivo mitogen-induced lymphocyte proliferation were assessed.

Results

We observed that septic shock patients displayed increased PD-1, PD-Ligand1 (PD-L1) and PD-L2 monocyte expressions and enhanced PD-1 and PD-L1 CD4⁺ T lymphocyte expressions at day 1-2 and 3-5 after the onset of shock in comparison with patients with trauma and healthy volunteers. Importantly, increased expressions were associated with increased occurrence of secondary nosocomial infections and mortality after septic shock as well as with decreased mitogen-induced lymphocyte proliferation and increased circulating IL-10 concentration.

Conclusions

These findings indicate that PD-1-related molecules may constitute a novel immunoregulatory system involved in sepsis-induced immune alterations. Results should be confirmed in a larger cohort of patients. This may offer innovative therapeutic perspectives on the treatment of this hitherto deadly disease.     

Physical frailty and cognitive impairment is associated with diabetes and adversely impact functional status and mortality

Objectives: We investigated whether there was a higher prevalence of cognitive impairment (CI) and/or physical frailty (PF) in persons with diabetes compared to their non-diabetic counterparts, and the individual and combined impact of CI and PF on functional and mortality outcomes among diabetic older persons.

Method: Community-living diabetic and non-diabetic participants (N = 2696) aged 55 and above were assessed on CI (MMSE) and PF (CHS criteria) status. Among 486 diabetic persons, we estimated the odds ratio and 95% confidence intervals (OR, 95% CI) of association of CI and/or PF with prevalent IADL and ADL disability and mortality from 11 years of follow up.

Results: Diabetes was associated with significantly higher prevalence of CI and/or PF. Adjusted for sex, age, education, smoking, alcohol intake, physical activity, and BMI, diabetes was associated with higher prevalence of PF alone (OR = 2.24, 1.16–4.34) and PF with CI (OR = 2.01, 1.12–3.60), but not with CI alone (OR = 1.02, 0.73–1.44). In multivariable analyses of 486 diabetic older adults, compared to non-frail (NF) and cognitive normal (CN), CI alone was not significantly associated with IADL (OR = 1.06, 0.53–2.10), but PF alone was associated with considerably higher prevalence of IADL (OR = 6.72, 1.84–24.5). PF with CI was associated with the highest prevalence of IADL (OR = 17.8, 3.66–8.68) and ADL disability (OR = 93.8, 23.6–372.4). Whether singly or in combination, PF and/or CI were associated with worse hazard (HR) ratio for mortality outcomes: CI alone (HR = 2.72, 1.48–5.01), PF alone (HR = 4.30, 1.88–9.82) and CI with PF (HR = 8.41, 3.95–17.9).

Conclusion: Cognitive impairment and/or physical frailty are powerful prognostic factors identifying people with diabetes at high risk of mortality.     

Early pulmonary immune hyporesponsiveness is associated with mortality after burn and smoke inhalation injury

This prospective study aims to address mortality in the context of the early pulmonary immune response to burn and inhalation injury. The authors collected bronchoalveolar lavage fluid from 60 burn patients within 14 hours of their injury when smoke inhalation was suspected. Clinical and laboratory parameters and immune mediator profiles were compared with patient outcomes. Patients who succumbed to their injuries were older (P = .005), had a larger % TBSA burn (P < .001), and required greater 24-hour resuscitative fluids (P = .002). Nonsurvivors had lower bronchoalveolar lavage fluid concentrations of numerous immunomodulators, including C5a, interleukin (IL)-1β, IL-1RA, IL-8, IL-10, and IL-13 (P < .05 for all). Comparing only those with the highest Baux scores to account for the effects of age and % TBSA burn on mortality, nonsurvivors also had reduced levels of IL-2, IL-4, granulocyte colony-stimulating factor, interferon-γ, macrophage inflammatory protein-1β, and tumor necrosis factor-α (P < .05 for all). The apparent pulmonary immune hyporesponsiveness in those who died was confirmed by in vitro culture, which revealed that pulmonary leukocytes from nonsurvivors had a blunted production of numerous immune mediators. This study demonstrates that the early pulmonary immune response to burn and smoke inhalation may be attenuated in patients who succumb to their injuries.     

Implementation of a bundle of quality indicators for the early management of severe sepsis and septic shock is associated with decreased mortality

OBJECTIVE: The purpose of this study was to examine the outcome implications of implementing a severe sepsis bundle in an emergency department as a quality indicator set with feedback to modify physician behavior related to the early management of severe sepsis and septic shock. DESIGN: Two-year prospective observational cohort. SETTING: Academic tertiary care facility. PATIENTS: Patients were 330 patients presenting to the emergency department who met criteria for severe sepsis or septic shock. INTERVENTIONS: Five quality indicators comprised the bundle for severe sepsis management in the emergency department: a) initiate central venous pressure (CVP)/central venous oxygen saturation (Scvo2) monitoring within 2 hrs; b) give broad-spectrum antibiotics within 4 hrs; c) complete early goal-directed therapy at 6 hrs; d) give corticosteroid if the patient is on vasopressor or if adrenal insufficiency is suspected; and e) monitor for lactate clearance. MEASUREMENTS AND MAIN RESULTS: Patients had a mean age of 63.8 +/- 18.5 yrs, Acute Physiology and Chronic Health Evaluation II score 29.6 +/- 10.6, emergency department length of stay 8.5 +/- 4.4 hrs, hospital length of stay 11.3 +/- 12.9 days, and in-hospital mortality 35.2%. Bundle compliance increased from zero to 51.2% at the end of the study period. During the emergency department stay, patients with the bundle completed received more CVP/Scvo2 monitoring (100.0 vs. 64.8%, p < .01), more antibiotics (100.0 vs. 89.7%, p = .04), and more corticosteroid (29.9 vs. 16.2%, p = .01) compared with patients with the bundle not completed. In a multivariate regression analysis including the five quality indicators, completion of early goal-directed therapy was significantly associated with decreased mortality (odds ratio, 0.36; 95% confidence interval, 0.17-0.79; p = .01). In-hospital mortality was less in patients with the bundle completed compared with patients with the bundle not completed (20.8 vs. 39.5%, p < .01). CONCLUSIONS: Implementation of a severe sepsis bundle using a quality improvement feedback to modify physician behavior in the emergency department setting was feasible and was associated with decreased in-hospital mortality.     

Low B and T lymphocyte attenuator expression on CD4+ T cells in the early stage of sepsis is associated with the severity and mortality of septic patients: a prospective cohort study

IntroductionB and T lymphocyte attenuator (BTLA) is an inhibitory receptor, whose primary role in CD4⁺ T cell is thought to inhibit cytokine production. We explore BTLA expression on CD4⁺ T cells in healthy controls and septic patients, and assess the correlation of BTLA expression on CD4⁺ T cells in the early stage of sepsis with the severity and mortality of septic patients in the emergency department (ED).Methods336 consecutive patients were included in this study. BTLA expression on CD4⁺ T cells was measured by flow cytometry within 24h of ED admission.ResultsOur results showed that the percentage of BTLA⁺/CD4⁺ T cells was high expression in healthy volunteers and it was statistically reduced in severe sepsis and septic shock compared with healthy controls(all P<0.01). The area under the receiver operating characteristic (AUC) curves of BTLA expression on CD4⁺ T cells was slightly lower than that of procalcitonin (PCT) and Mortality in Emergency Department Sepsis (MEDS) score. The percentage of BTLA⁺/CD4⁺T cells was lower in non-survivors than in survivors (P<0.01), and similar results were obtained when expressed as mean of fluorescence intensities (MFI) (P<0.01). Adjusted logistic regression analysis suggested that the percentage of BTLA⁺/CD4⁺ T cells was associated with 28-day mortality in septic patients (odds ratio (OR) = 0.394).ConclusionOur study shows that the percentage of BTLA⁺/CD4⁺ T cells was high in healthy volunteers. Furthermore, lower percentage of BTLA⁺/CD4⁺ T cells during the early stage of sepsis is associated with the severity and the mortality of septic patients.     

The peripheral perfusion index and transcutaneous oxygen challenge test are predictive of mortality in septic patients after resuscitation

Introduction

The peripheral perfusion index (PI) is a noninvasive numerical value of peripheral perfusion, and the transcutaneous oxygen challenge test (OCT) is defined as the degree of transcutaneous partial pressure of oxygen (PtcO₂) response to 1.0 FiO_2. The value of noninvasive monitoring peripheral perfusion to predict outcome remains to be established in septic patients after resuscitation. Moreover, the prognostic value of PI has not been investigated in septic patients.

Methods

Forty-six septic patients, who were receiving PiCCO-Plus cardiac output monitoring, were included in the study group. Twenty stable postoperative patients were studied as a control group. All the patients inspired 1.0 of FiO₂ for 10 minutes during the OCT. Global hemodynamic variables, traditional metabolic variables, PI and OCT related-variables were measured simultaneously at 24 hours after PiCCO catheter insertion. We obtained the 10min-OCT ((PtcO₂ after 10 minutes on inspired 1.0 oxygen) - (baseline PtcO₂)), and the oxygen challenge index ((10min-OCT)/(PaO₂ on inspired 1.0 oxygen - baseline PaO₂)) during the OCT.

Results

The PI was significantly correlated with baseline PtcO₂, 10min-OCT and oxygen challenge index (OCI) in all the patients. The control group had a higher baseline PtcO₂, 10min-OCT and PI than the septic shock group. In the sepsis group, the macro hemodynamic parameters and ScvO₂ showed no differences between survivors and nonsurvivors. The nonsurvivors had a significantly lower PI, 10min-OCT and OCI, and higher arterial lactate level. The PI, 10min-OCT and OCI predicted the ICU mortality with an accuracy that was similar to arterial lactate level. A PI <0.2 and a 10min-OCT <66mmHg were related to poor outcome after resuscitation.

Conclusions

The PI and OCT are predictive of mortality for septic patients after resuscitation. Further investigations are required to determine whether the correction of an impaired level of peripheral perfusion may improve the outcome of septic shock patients.     

High central venous oxygen saturation in the latter stages of septic shock is associated with increased mortality

Introduction  

Current guidelines recommend maintaining central venous oxygen saturation (ScvO₂) higher than 70% in patients with severe sepsis and septic shock. As high levels of ScvO₂ may reflect an inadequate use of oxygen, our aim was to evaluate the relation between maximal ScvO₂ levels (ScvO_2max ) and survival among intensive care unit (ICU) patients with septic shock.     

Elevated plasmatic level of soluble IL-7 receptor is associated with increased mortality in septic shock patients

Purpose

Adjunctive immunoadjuvant therapies are now proposed in the treatment of septic patients that develop immune dysfunctions. However, a prerequisite is to identify patients at high risk of death that would benefit from such therapy. Knowing that rhIL-7 is a putative candidate for septic shock treatment, we evaluated the association between increased plasmatic level of soluble CD127 (sCD127, IL-7 receptor alpha chain) and mortality after septic shock.

Methods

sCD127 plasmatic level was measured in 70 septic shock patients sampled at day 1–2 (D1) and day 3–4 (D3) after the onset of shock and 41 healthy volunteers.

Results

Compared with survivors, non-survivors presented with significantly higher sCD127 concentrations at D1 and D3 (p < 0.001 and p = 0.002). At D1, the area under the receiver operating characteristic curve for sCD127 level association with mortality was 0.846 (p < 0.0001). Kaplan–Meier survival curves illustrated that mortality was significantly different after stratification based on D1 sCD127 level (log rank test, hazard ratio 9.10, p < 0.0001). This association was preserved in multivariate logistic regression analysis including clinical confounders (age, SAPS II and SOFA scores, odds ratio 12.71, p = 0.003). Importantly, patient stratification on both D1 sCD127 value and SAPS II score improved this predictive capacity (log rank test, p = 0.0001).

Conclusions

Increased sCD127 plasmatic level enables the identification of a group of septic shock patients at high risk of death. After confirmation in a larger cohort, this biomarker may be of interest for patient stratification in future clinical trials.