血管性假血友病因子和细胞间黏附分子-1在急性呼吸窘迫综合征中的动态变化及早期诊断的意义

目的检测血管性假血友病因子、可溶性细胞间黏附分子-1浓度变化，以研究其在ARDS早期诊断中的意义。方法以ELISA法检测非ARDS组和ARDS组于0、2、3、5和7d血浆vWF和slCAM-l浓度。结果ARDS组vWF和sICAM-1浓度高于非ARDS组，前四个时点的中性粒细胞活化计数ARDS组高于非ARDS组。血浆vWF和sICAM-1水平具有相关性。结论血浆vWF和sICAM-1浓度及中性粒细胞活化计数在ARDS的早期即升高，对ARDS早期诊断有预警作用。     

ARDS in patients with thermal injury

Objective: To determine the time to onset of the adult respiratory distress syndrome (ARDS) in patients with thermal injury requiring mechanical ventilation. Secondarily, to consider the burn-related risk factors, demographics, incidence, and mortality for ARDS in this population.¶Design: Retrospective chart review; ARDS defined according to the American-European Consensus Conference and the Lung Injury Severity Score definitions.¶Setting: Regional, tertiary referral, adult burn unit in a university teaching hospital.¶Patients and participants: Patients with thermal injury requiring mechanical ventilation, admitted between 1 January 1991 and 28 February 1995.¶Interventions: None.¶Measurements and results: Of 469 consecutive admissions, 126 (26.9 %) received intubation and mechanical ventilation. ARDS was defined according to the American-European Consensus and Lung Injury Severity Score (score > 2.5) definitions. The mean time to onset of ARDS from admission to the burn unit was 6.9 ± 5.2 and 8.2 ± 10.7 days when defined by the American-European Consensus and Lung Injury Severity Score definitions respectively (p = 0.41). Of the intubated patients, 53.6 and 45.2 % developed ARDS according to the American-European Consensus and Lung Injury Severity Score definitions, respectively (p = 0.19). Using multivariate logistic analysis, only age proved to be an independent risk factor for the development of ARDS (p = 0.03), although there was a trend toward an increased incidence of inhalation injury in patients with ARDS. Mortality was not significantly greater (41.8 vs 32.2 %) in those with ARDS compared to those without (p = 0.27).¶Conclusions: According to the American-European Consensus Conference and the Lung Injury Severity Score definitions, ARDS is common in the adult burn population and has a delayed onset compared to most critical care populations. We found age to be a major predisposing factor for ARDS.     

Increased plasma levels of heparin-binding protein in patients with acute respiratory distress syndrome

Introduction

Heparin-binding protein (HBP) is an antimicrobial protein stored in neutrophil granules and plays a role in endothelial permeability regulation. The aim was to assess the diagnostic and prognostic value of measuring HBP in patients with acute lung injury (ALI)/acute respiratory distress syndrome (ARDS).

Methods

Plasma HBP was collected from 78 patients with ALI/ARDS, 28 patients with cardiogenic pulmonary edema (CPE) and 20 healthy volunteers at enrollment. Levels of HBP were measured by ELISA.

Results

Patients with ALI/ARDS had significantly higher median levels of HBP compared with patients with CPE (17.15 (11.95 to 24.07) ng/ml vs. 9.50 (7.98 to 12.18) ng/ml, P <0.001) at enrollment. There was no significant difference between CPE patients and healthy subjects in terms of HBP value (P = 0.372). The HBP levels of nonsurvivors was significantly higher than that of survivors (23.90 (14.81 to 32.45) ng/ml vs. 16.01 (10.97 to 21.06) ng/ml, P = 0.012) and multivariate logistic regression showed HBP (odds ratio =1.52, P = 0.034) was the independent predictor for 30-day mortality in patients with ALI/ARDS.

Conclusions

Plasma HBP levels of ALI/ARDS patients were significantly higher than that of CPE patients. HBP was a strong prognostic marker for short-term mortality in ALI/ARDS.     

Smoking,von Willebrand factor and ADAMTS-13 in healthy males

While von Willebrand factor (vWF) has been reported to be elevated in smokers, there are no reports on the effects of smoking on its cleaving protease ADAMTS-13, particularly in subjects of Arab ethnicity. This study was conducted to determine the effects of smoking on vWF and ADAMTS-13 antigen and activity levels in Arab males. Venous blood samples from 80 smoking (at rest) and 80 non-smoking healthy males were collected after asking subjects to fast and refrain from smoking for 8 hours. Similar sampling was done for 40 smokers (acute smokers), who were asked to smoke one cigarette immediately before blood collection. Plasma was used to measure ADAMTS-13 antigen and activity levels, as well as vWF antigen and collagen binding activity levels using commercial ELISA kits. Compared to non-smokers, ADAMTS-13 and vWF activities were significantly lower in smokers at rest (p < 0.05). Acute smokers had significantly higher levels of vWF activity and ADAMTS-13 antigen and activity levels (p < 0.01), compared to smokers at rest. Our results suggest that high vWF activity is accompanied by an increase in ADAMTS-13 activity as a natural physiological mechanism to degrade the elevated vWF molecules. If not followed by a subsequent smoke, the activities of both proteins subside. It is possible that the repeated increase in vWF and constant degradation by ADAMTS-13 results in lower overall levels of both proteins in smokers (at rest) compared to nonsmokers who do not experience a similar (repeated) injury to the endothelium.     

脓毒症患者血管性假血友病因子、血栓调节蛋白变化及乌司他丁的干预作用

目的观察脓毒症患者血管内皮细胞(VEC)分泌血管性假血友病因子(vWF)、血栓调节蛋白(TM)的变化及乌司他丁的干预作用。方法选择脓毒症患者56例,分为治疗组(n=27)及乌司他丁组(n=29),两组均给予常规治疗,乌司他丁组加用乌司他丁静脉注射每12小时1次,连续10天;选取健康体检者作为对照组(n=20)。检测研究对象治疗前后外周血血清vWF、TM的水平;利用脓毒症患者血清作用于体外培养的VEC株(CRL-1730),检测培养上清液中可溶性vWF、TM的水平,并观察乌司他丁对培养上清液中vWF、TM水平的影响。结果治疗前,治疗组vWF、TM水平分别为(126.6±19.3)%,(29.8±5.6)μg/L;乌司他丁组vWF、TM水平分别为(128.3±6.3)%,(31.7±2.1)μg/L,两组患者vWF、TM水平与对照组比较均升高(均P0.05);治疗后,两组患者vWF、TM水平均下降,治疗组vWF、TM水平分别为(102.6±31.3)%,(18.9±3.6)μg/L;乌司他丁组vWF、TM水平分别为(80.6±26.3)%,(15.1±4.3)μg/L,治疗后乌司他丁组与治疗组比较差异有统计学意义(均P0.05);体外实验中,经乌司他丁干预后,细胞培养上清液中vWF、TM水平明显下降,分别为(67.1±21.6)%,(13.3±2.5)μg/L,与治疗组比较差异有统计学意义(均P0.01)。结论脓毒症患者存在VEC的损伤,乌司他丁对脓毒症患者的VEC损伤有保护作用。     

Pulmonary function and health-related quality of life in a sample of long-term survivors of the acute respiratory distress syndrome

Objective: We performed a follow-up cohort analysis in order to delineate the correlation between pulmonary function (PF) and health-related quality of life (HRQL) in patients after ARDS.¶Design: Follow-up cohort study.¶Setting: A 20-bed ICU of a university teaching hospital.¶Patients: A cohort of 50 long-term survivors of ARDS.¶Measurements and results: Measurements of PF (FVC, FEV₁, TLC, D_LCO) and HRQL (SF-36 Health Status Questionnaire) were made 5.5 years (median value) after discharge from the ICU. Impairments in PF (defined as PF results below 80 % of the predicted value) were frequent but generally mild. Twenty patients had a single PF impairment (with limitations in FEV1/FVC ratio in 12 patients being the most common), four patients had two (with D_LCO and FEV1/FVC ratio impairment the most common) and three patients had pathologic results in three PF tests (FEV₁/FVC ratio, TLC and capillary pO₂ during exercise in one case, FVC, TLC and capillary pO₂ during exercise in the second patient and FVC, TLC and D_LCO in the third). Compared to normal controls, survivors of ARDS showed impairments in all SF-36 health dimensions (p < 0.001). Patients with multiple (> 1) PF impairments described the lowest HRQL with major limitations in all SF-36 categories (p < 0.037) including physical and mental summary scores (36.5 vs 46.9, p = 0.037 and 31.3 vs 51.4, p = 0.003) when compared to patients with no or only one PF impairment.¶Conclusions: Long-term survivors of ARDS have a significant reduction in HRQL and the presence of multiple PF impairments is associated with maximal decrements in HRQL.     

Early changes of plasma angiopoietin-2 in patients with multiple trauma

BACKGROUND:

This study was undertaken to investigate the early changes of plasma levels of angiopoietin-2 (Ang-2) in patients with multiple trauma and the relations of plasma Ang-2, endothelial injury, and prognosis.

METHODS:

This study comprised 59 patients with multiple trauma who had been treated at the emergency department of Liao Cheng People’s Hospital from January 2008 to January 2010. Among them, 36 were male and 23 female. Their average age was 32.3±11.5 years. The 59 patients were divided into a severe trauma group (ISS≥16 points, 29 patients) and a slight trauma group (ISS<16 points, 30 patients) by injury severity score (ISS). Thirty healthy people aged more than 18 years with an average of 33.5±10.6 years served as controls (19 male and 11 female). Peripheral blood (10 mL) was collected within 10 minutes after the patients arrived at the emergency department, and plasma was separated from the blood. Enzyme-linked immunosorbent assay (ELISA) was applied to detect the levels of angiopoietin 2, thrombomodulin (TM), and Von willebrand factor (vWF).

RESULTS:

The level of Ang-2 in the severe trauma group (ISS score≥16 points) was significantly higher than that in the slight trauma group (ISS score<16 points) (P<0.05). The levels in the two groups were significantly higher than those in the control group (P<0.05). The levels of angiopoietin-2 in deaths were significantly higher than those in survivors (P<0.05). The levels of angiopoietin-2 were significantly correlated with the levels of vWF and TM (P<0.05).

CONCLUSIONS:

The plasma levels of Ang-2 are significantly higher after multiple trauma, and correlated with the degree of trauma severity. The levels of angiopoietin-2 are correlated with endothelial injury after multiple trauma, and are important values for the prognosis of patients with multiple trauma.KEY WORDS: Multiple trauma, Angiopoietin-2, Endothelial injury, Prognosis     

Acute Respiratory Distress Syndrome (ARDS) after trauma: Improving incidence,but increasing mortality

PurposeAcute Respiratory Distress Syndrome (ARDS) is an infrequent, yet morbid inflammatory complication in injury victims. With the current project we sought to estimate trends in incidence, determine outcomes, and identify risk factors for ARDS and related mortality.Materials & methodsThe national Trauma Quality Improvement Program dataset (2010–2014) was queried. Demographics, injury characteristics and outcomes were compared between patients who developed ARDS and those who did not. Logistic regression models were fitted for the development of ARDS and mortality respectively, adjusting for relevant confounders.ResultsIn the studied 808,195 TQIP patients, incidence of ARDS decreased over the study years (3–1.1%, p < 0.001), but related mortality increased (18.–21%, p = 0.001). ARDS patients spent an additional 14.7 ± 10.3 days in the hospital, 9.7 ± 7.9 in the ICU, and 6.6 ± 9.4 on mechanical ventilation (all p < 0.001). Older age, male gender, African American race increased risk for ARDS. Age, male gender, lower GCS and higher ISS also increased mortality risk among ARDS patients. Several pre-existing comorbidities including chronic alcohol use, diabetes, smoking, and respiratory disease also increased risk.ConclusionAlthough the incidence of ARDS after trauma appears to be declining, mortality is on the rise.     

Vascular endothelial markers, von Willebrand factor and thrombomodulin index, are specifically elevated in type 2 diabetic patients with nephropathy: comparison of primary renal disease

To elucidate the hypothesis that albuminuria in diabetic subjects reflects widespread vascular damage, plasma markers for vascular endothelial damage was measured in diabetic subjects with various degrees of albuminuria and compared to results in patients with primary renal disease. The groups consisted of 31 non-diabetic patient controls with normoalbuminuria, 109 type 2 diabetic patients with normo- micro- and macro-albuminuria, and 16 proteinuric patients with primary renal disease. Endothelial markers, plasma von Willebrand factor (vWF) and thrombomodulin (TM), were measured by enzyme-linked immunosolvent assay and enzyme immunoassay (EIA) methods, respectively. Plasma vWF levels were similar in controls (119+/-7%, mean+/-S.E.M.) and diabetic patients with normoalbuminuria (139+/-6), but significantly elevated in diabetic patients with microalbuminuria (174+/-11) and macroalbuminuria (204+/-17), while the level was not increased in patients with primary renal disease (124+/-11). Because plasma TM level was strongly affected by kidney function, TM index (TM (FU/ml)/serum creatinine (mg %)) was used as an endothelial marker. The TM index was substantially increased in diabetic patients with overt nephropathy compared with controls (5.29+/-2.98 vs. 2.35+/-0.85), whereas this was not observed in patients with primary renal disease (3.25+/-0.29). Both vWF and TM index were significantly higher in diabetic patients with retinopathy than in the patients without retinopathy. These results suggest that generalized vascular endothelial damage occurs in diabetic nephropathy including the microalbuminuric stage, which is not attributed to kidney damage per se.     

Differences in tocopherol-lipid ratios in ARDS and non-ARDS patients

Plasma tocopherol, plasma total lipid levels and tocopherol-lipid ratio were measured every 6 h during 48 h in 12 critically ill patients and compared with those of a control group. The patients were divided into two groups. Group I comprised 6 critically ill patients with ARDS and group II comprised 6 severely ill patients without ARDS. The means for all observations of plasma tocopherol, total lipid levels and tocopherol-lipid ratio in groups I and II were significantly depressed relative to a control group (p<0.0001). The difference in the average tocopherol-lipid ratio between the three groups (p<0.0001) and between the groups I and II was statistically significant (p<0.0001). Our results indicated: (1) a decrease of vitamin E concentrations in the critically ill patients, particularly in ARDS patients; (2) the importance of the relationship between plasma tocopherol and plasma lipids levels in evaluating the deficiency in vitamin E which was evident in ARDS patients.     

严重肺挫伤患者冯·维勒布兰德因子,白介素8的动态变化及其意义

目的 通过检测严重肺挫伤患者血中冯·维勒布兰德因子(vWF),白介素8在受伤后不同时点的含量,揭示其动态变化规律及其临床价值.方法 将63例严重肺挫伤患者分成ARDS组和非ARDS组、生存组和死亡组、ISS评分<20分和ISS评分≥20分组,并引入正常对照组,使用ELISA法分别检测伤后24 h内、第3天、第5天、第7天时的血浆vWF和血清IL-8水平,观察其动态规律,并进行相关因素分析.结果 严重肺挫伤患者在各时点,血浆vWF和血清IL-8均高于正常对照组.严重肺挫伤并发ARDS组血浆vWF含量各时点逐渐升高,ARDS组在第5天、第7天血浆vWF含量显著高于非ARDS组(P<0.05).血清IL-8含量在第5天达到高峰后开始下降,两组之间在各时点差异具有统计学意义(P<0.05);死亡组血浆vWF与血清IL-8含量均显著高于生存组(P<0.05);ISS评分≥20分组血浆vWF和血清IL-8水平均在第5天达到高峰后开始回落,ISS评分<20分组在第3天达到高峰后回落.血浆vWF含量与血小板计数呈正相关,与氧合指数呈负相关.血清IL-8含量与白细胞计数、ISS评分呈正相关,与氧合指数呈负相关.结论 严重肺挫伤患者血中vWF和IL-8含量呈动态变化,反映了肺损伤的程度,并可以作为严重肺挫伤后并发ARDS的预测及预后判断指标.

Abstract：

Objective To study the clinical changes of von Willebrand factor( vWF) and interleukin-8 (IL-8) in patients with severe pulmonary contusion. Methods Sixty-three patients with severe pulmonary contusion were divided into three different classifications for the sake of comparison in different respects, namely (1) severe pulmonary contusion with ARDS group and severe pulmonary contusion without ARDS group, (2) survival group and non-survival group, and (3) ISS score <20 group and ISS scored 20 group. In addition, the normal control group was set up. The levels of plasma vWF and serum IL-8 were respectively detected by double-antibody sandwich enzyme-linked immunosorbent assay (ELISA) within 24 hours of injury and 1,3,5 and 7days after injury. The regularity of their changes was observed and the correlation factors were analyzed from the data. Results Compared with normal controls, the concentrations of plasma vWF and serum IL-8 were significantly increased in patients with severe pulmonary contusion in all intervals of detection. The concentrations of plasma vWF escalated gradually in severe pulmonary contusion with ARDS, and reached significantly higher levels in 5 days and 7 days after injury compared with those without ARDS group (P <0. 05). The increase in concentrations of serum IL-8 peaked in 5day after injury, and then declined. The levels of serum IL-8 were higher in patients with severe pulmonary contusion with ARDS group than those in this kind of patients without ARDS group. The levels of plasma vWF and serum IL-8 were higher in non - survival group than those in survival group (P < 0.05). The increase in levels of plasma vWF and serum IL-8 peaked and then declined in 5 days in ISS score 3:20 group, whereas it peaked and declined in 3 days after injury in ISS score < 20 group. The level of plasma vWF was positively correlated with platelets and negatively correlated with oxygenation index. The levels of serum IL-8 was positively correlated with white blood cell count and ISS score, and negatively correlated with oxygenation index. Conclusions The levels of plasma vWF and serum IL-8 were increased in patients with severe pulmonary contusion, reflecting the severity of pulmonary injury. The levels of plasma vWF and serum IL-8 were the sensitive markers for evaluating the severity of pulmonary injury and the prognosis of ARDS caused by severe pulmonary contusion.     

Cardiac troponin: a new serum marker of myocardial injury in sepsis

Objective: Echocardiogram-derived left ventricular ejection fraction (LVEF) is usually utilized to evaluate left ventricular function, including that of septic patients. However, LVEF is greatly influenced by afterload. The aim of this study was to test the hypothesis that troponin I, a serum marker of myocardial injury, may be able to detect left ventricular involvement by the septic process, being at least as sensitive an indicator of left ventricular dysfunction as LVEF in these patients.¶Design: Comparison of echocardiogram-derived LVEF with serum levels of troponin I in ten critically ill septic patients.¶Setting: General intensive care unit in a tertiary care private hospital.¶Patients: Ten critically ill septic patients with no previous documented heart disease.¶Measurements and results: Patients were simultaneously submitted to a two-dimensional echocardiogram and troponin I determinations. LVEFs and troponin I levels were analyzed in a two-by-two table in order to validate troponin I as a new biochemical marker of myocardial injury in sepsis. All the patients whose LVEF was < 0.5 had elevated troponin I levels (kappa = 0.61, p = 0.035).¶Conclusions: Identification of myocardial dysfunction in septic patients has been a challenging task. Troponin I, a serum marker of myocardial injury, may be of great help in the recognition of myocardial involvement by sepsis in a noninvasive and readily available way.     

急性心肌梗死患者组织因子及组织因子途径激活抑制物水平的变化

目的探讨急性心肌梗死(AMI)患者组织因子(TF)及组织因子途径激活抑制物(TF-PI)的变化及临床意义。方法用ELISA法分别检测50例AMI患者及20例健康对照的外周血TF及TFPI的抗原水平。比较15例支架手术患者冠状窦内及外周血的TFPI水平。比较并发糖尿病和/或高脂血症AMI患者与无并发症者的TFAg及TFPIAg水平。结果AMI患者的TFAg及TFPIAg较正常人均明显升高(P<0.01);支架患者冠状窦内的TFPI水平明显低于其外周血(P<0.01);有并发症患者的TF及TFPI水平均明显高于无并发症患者(分别为P<0.01和P<0.05)。结论AMI患者外周血凝血活性增高,并发糖尿病和/或高脂血症AMI患者的凝血活性较无并发症患者高,血栓形成使冠状动脉腔内的TFPI消耗而降低。     

Regional distribution of gas and tissue in acute respiratory distress syndrome. III. Consequences for the effects of positive end-expiratory pressure

Objective: To determine whether differences in lung morphology assessed by computed tomography (CT) affect the response to positive end-expiratory pressure (PEEP).¶Design: Prospective study over a 53-month period.¶Setting: Fourteen-bed surgical intensive care unit of a university hospital.¶Patients and participants: Seventy-one consecutive patients with early adult respiratory distress syndrome (ARDS).¶Measurements and results: Fast spiral thoracic CT was performed at zero end-expiratory pressure (ZEEP) and after implementation of PEEP 10 cmH₂O. Hemodynamic and respiratory parameters were measured in both conditions. PEEP-induced overdistension and alveolar recruitment were quantified by specifically designed software (Lungview). Overdistension occurred only in the upper lobes and was significantly correlated with the volume of lung, characterized by a CT attenuation ranging between –900 and –800 HU in ZEEP conditions. Cardiorespiratory effects of PEEP were similar in patients with primary and secondary ARDS. PEEP-induced alveolar recruitment of the lower lobes was significantly correlated with their lung volume (gas + tissue) at functional residual capacity. PEEP-induced alveolar recruitment was greater in the lower lobes with “inflammatory atelectasis” than in the lower lobes with “mechanical atelectasis.” Lung morphology as assessed by CT markedly influenced the effects of PEEP: in patients with diffuse CT attenuations PEEP induced a marked alveolar recruitment without overdistension, whereas in patients with lobar CT attenuations PEEP induced a mild alveolar recruitment associated with overdistension of previously aerated lung areas. These results can be explained by the uneven distribution of regional compliance characterizing patients with lobar CT attenuations (compliant upper lobes and stiff lower lobes) contrasting with a more even distribution of regional compliances observed in patients with diffuse CT attenuations.¶Conclusions: In patients with ARDS, the cardiorespiratory effects of PEEP are affected by lung morphology rather than by the cause of the lung injury (primary versus secondary ARDS). The regional distribution of the loss of aeration and the type of atelectasis –“mechanical” with a massive loss of lung volume, or “inflammatory” with a preservation of lung volume – characterizing the lower lobes are the main determinants of the cardiorespiratory effects of PEEP.     

Circulating endothelin-1 and tumor necrosis factor-α: early predictors of mortality in patients with septic shock

Objectives: To determine the predictive value of early determination of tumor necrosis factor (TNF)-α, TNF-α 1 and 2 soluble receptors (sTNFR1 and sTNFR2) and endothelin-1 (ET-1) for mortality in patients with septic shock.¶Design: Prospective study.¶Setting: Intensive care unit of a university hospital.¶Patients: Twenty-one patients with septic shock.¶Interventions: None.¶Measurements and Results: Patients with septic shock had a pulmonary artery catheter inserted and blood samples drawn at time zero, 6, 12 and 24 h, simultaneously with hemodynamic assessments. Plasma levels of all markers were measured by ELISA. All patients were followed up to hospital discharge or death. Age and APACHE II scores were significantly higher in nonsurvivors (n = 11) than in survivors (n = 10). Hemodynamic assessments did not aid in the discrimination between the two groups of patients (P > 0.05). Levels of TNF-α were higher in nonsurvivors than in survivors at all time-points. sTNFR1 and sTNFR2 were also significantly elevated in nonsurvivors, but not in all measurements. Endothelin-1, however, was significantly higher in nonsurvivors than in survivors only at 6 h (P = 0.02). When both TNF-α and ET-1 were increased at early time-points, the best predictive values for mortality were obtained [positive and negative predictive values of 72 and 100 % at 6 h, odds ratio 3.0, 95 % CI (1.2–7.6)].¶Conclusions: Increased levels of TNF-α were consistently higher at all time-points in nonsurvivors with septic shock. ET-1 levels, however, appeared also to be an early and sensitive predictor of mortality. Very early determination of TNF-α and ET-1 in septic shock may help to identify patients at higher risk for adverse outcome.     

Plasma angiopoietin-2 as a potential causal marker in sepsis-associated ARDS development: evidence from Mendelian randomization and mediation analysis

Purpose

A causal biomarker for acute respiratory distress syndrome (ARDS) could fuel precision therapy options. Plasma angiopoietin-2 (ANG2), a vascular permeability marker, is a strong candidate on the basis of experimental and observational evidence. We used genetic causal inference methods—Mendelian randomization and mediation—to infer potential effects of plasma ANG2.

Methods

We genotyped 703 septic subjects, measured ICU admission plasma ANG2, and performed a quantitative trait loci (QTL) analysis to determine variants in the ANGPT2 gene associated with plasma ANG2 (p?<?0.005). We then used linear regression and post-estimation analysis to genetically predict plasma ANG2 and tested genetically predicted ANG2 for ARDS association using logistic regression. We estimated the proportion of the genetic effect explained by plasma ANG2 using mediation analysis.

Results

Plasma ANG2 was strongly associated with ARDS (OR 1.59 (95% CI 1.35, 1.88) per log). Five ANGPT2 variants were associated with ANG2 in European ancestry subjects (n?=?404). Rs2442608C, the most extreme cis QTL (coefficient 0.22, 95% CI 0.09–0.36, p?=?0.001), was associated with higher ARDS risk: adjusted OR 1.38 (95% CI 1.01, 1.87), p?=?0.042. No significant QTL were identified in African ancestry subjects. Genetically predicted plasma ANG2 was associated with ARDS risk: adjusted OR 2.25 (95% CI 1.06–4.78), p?=?0.035. Plasma ANG2 mediated 34% of the rs2442608C-related ARDS risk.

Conclusions

In septic European ancestry subjects, the strongest ANG2-determining ANGPT2 genetic variant is associated with higher ARDS risk. Plasma ANG2 may be a causal factor in ARDS development. Strategies to reduce plasma ANG2 warrant testing to prevent or treat sepsis-associated ARDS.

     

Low plasma citrulline levels are associated with acute respiratory distress syndrome in patients with severe sepsis

Introduction

The role of nitric oxide synthase (NOS) in the pathophysiology of acute respiratory distress syndrome (ARDS) is not well understood. Inducible NOS is upregulated during physiologic stress; however, if NOS substrate is insufficient then NOS can uncouple and switch from NO generation to production of damaging peroxynitrites. We hypothesized that NOS substrate levels are low in patients with severe sepsis and that low levels of the NOS substrate citrulline would be associated with end organ damage including ARDS in severe sepsis.

Methods

Plasma citrulline, arginine and ornithine levels and nitrate/nitrite were measured at baseline in 135 patients with severe sepsis. ARDS was diagnosed by consensus definitions.

Results

Plasma citrulline levels were below normal in all patients (median 9.2 uM, IQR 5.2 - 14.4) and were significantly lower in ARDS compared to the no ARDS group (6.0 (3.3 - 10.4) vs. 10.1 (6.2 - 16.6), P = 0.002). The rate of ARDS was 50% in the lowest citrulline quartile compared to 15% in the highest citrulline quartile (P = 0.002). In multivariable analyses, citrulline levels were associated with ARDS even after adjustment for covariates including severity of illness.

Conclusions

In severe sepsis, levels of the NOS substrate citrulline are low and are associated with ARDS. Low NOS substrate levels have been shown in other disease states to lead to NOS uncoupling and oxidative injury suggesting a potential mechanism for the association between low citrulline and ARDS. Further studies are needed to determine whether citrulline supplementation could prevent the development of ARDS in patients with severe sepsis and to determine its role in NOS coupling and function.     

Expression patterns of plasma von Willebrand factor and serum interleukin-8 in patients with early-stage severe pulmonary contusion

BACKGROUND: von Willebrand factor (vWF) is only released from endothelial cells and platelets and is an in vivo and in vitro marker of endothelial injury in septic patients with acute lung injury (ALI). Interleukin-8 (IL-8), as a proinflammatory mediator causing recruitment of inflammatory cells, induces an increase in oxidant stress mediators and makes it as a key parameter for localized inflammation. However, it has not been well established whether the level of serum IL-8 is associated with the severity of lung injury and whether it is a prognosis marker for severe lung contusion. This study was to investigate the expression of plasma vWF and IL-8 and their association with the severity and outcomes of severe pulmonary contusion.METHODS: A total of 63 patients were divided into a severe pulmonary contusion with acute respiratory distress syndrome (ARDS) group and a non-ARDS group, or a survivor group and a non-survivor group, or an injury severity score (ISS) <20 group and an ISS ≥20 group. Another 20 healthy volunteers served as controls. The levels of plasma vWF and serum IL-8 were measured by enzyme-linked immunosorbent assay (ELISA) at 1, 3, 5 and 7 days after injury. The expression patterns of the plasma vWF and serum IL-8 were compared between different groups.RESULTS: The concentrations of plasma vWF and serum IL-8 were significantly increased in all severe pulmonary contusion patients at all time points in comparison with the control group. The concentrations of plasma vWF in patients with ARDS increased during the whole study period, but vWF in patients with non-ARDS increased gradually until day 5 and then decreased at day 7. The concentration of serum IL-8 showed a similar expression pattern in both groups, but the expression increased more significantly in the ARDS group than in the non-ARDS group. Interestingly, both plasma vWF and serum IL-8 levels steadily increased in the non-survivor group. Furthermore, the level of plasma vWF was higher in the ISS≥20 group than in the ISS<20 group. The level of serum IL-8 in the ISS≥20 group was consistently high, while that in the ISS<20 group peaked at day 3 and decreased at day 5. In addition, the level of plasma vWF was positively correlated with platelet count, but negatively correlated with oxygen index. The level of serum IL-8 was positively correlated with white blood cell count and ISS score, and inversely correlated with oxygen index.CONCLUSION: The elevated levels of plasma vWF and serum IL-8 in severe pulmonary contusion patients reflect the severity of pulmonary injury and patients outcomes, suggesting that the plasma vWF and serum IL-8 are sensitive markers for clinical evaluation of the severity of pulmonary injury and predication of patient prognosis.     

多发伤患者早期血浆血管生成素2水平变化与内皮损伤和预后的关系

目的 探讨多发伤患者早期血浆血管生成素2(angiopoietin2,Ang2)的水平变化与血管内皮损伤和预后的关系及临床意义.方法 为前瞻性观察研究,选择2008年1月至2010年1月收入聊城市人民医院急诊科的多发伤患者59例,纳入标准:创伤至入院时间在1 h以内;年龄大于18周岁;既往身体健康,排除有心、脑、肝、肾等器质性疾病,糖尿病、高血压,肿瘤;急慢性感染性疾病;严重颅脑损伤(GCS<12分);两周前用过抗凝及溶栓类药物患者.共纳入59例患者包括男36例,女23例,年龄(32.3±11.5)岁.按创伤严重度评分(ISS)分为重伤组(ISS≥16分,29例),轻伤组(ISS<16分,30例)2组.另取30例健康人为健康对照组,均为接受体检的健康人.其中男19例,女11例,年龄均大于18周岁,年龄(33.5±10.6)岁.各组性别、年龄构成均具有可比性.患者到达急诊科后10 min内抽取外周静脉血 10 mL,分离血浆.应用酶联免疫吸附法(ELISA)测定血浆Ang2的水平.同时测定血浆冯·维勒布兰德因子(Von Willebrand factor,vWF)、血栓调节蛋白(thrembomodulin,TM)的水平.统计数据用均数±标准差(-x±s)表示,所有数据采用SPSS 13.0统计软件进行统计分析.应用单因素方差分析和两两比较的Q检验(Newman-Keuls法)比较分析各组Ang2的水平差异.采用成组资料t检验比较分析死亡和生存患者Ang2的水平.采用pearson相关分析法分析Ang2水平与血浆vWF,TM的相关性.以P<0.05为差异具有统计学意义.结果 重伤组(ISS≥16分)血浆Ang2水平明显高于轻伤组(ISS<16分)(P<0.05),两组均明显高于正常对照组(P<0.05).死亡组血浆Ang2水平明显高于生存组(P<0.05).创伤后Ang2水平变化与血浆vWF,TM水平均有明显相关性(P<0.05).结论 血浆Ang2水平在多发伤早期明显增高,和创伤严重程度相关,和创伤后内皮损伤相关,其对预后有重要的预测价值.

Abstract：

Objective To investigate the early changes of plasma levels of angiopoietin2 in patients with multiple trauma and the relationship between plasma levels of angiopoietin2 (Ang2) and endothelial injury as well as prognosis of patients in order to determine their clinical significance. Methods Patients with multiple trauma admitted to emergency department from January 2008 to January 2010 were enrolled. A total of 59 casualties met the criteria(admission within 1 h after trauma and age > 18 years), and were eligible for enrollment. Patients with heart, brain, liver, kidney and other organic diseases, diabetes, hypertension, tumor, acute and chronic infectious diseases , severe brain injury (CCS < 12 points) , anticoagulant and thrombolytic medicine used two weeks before trauma were excluded. Among 59 patients, 36 were males and 23 females. The average age was(32.3 ±11.5) years. Patients were divided into severe trauma group (ISS ≥16 points,n =29) , moderate trauma group (ISS < 16 points, n =30 ) judged by using injury severity score (1SS). Thirty healthy subjects were selected as controls, 19 male and 11 female, with age > 18 years and an average age of(33.5 ±10.6) years. All groups had comparable gender proportion and average age. The 10 mL peripheral blood sanple was collected within 10 minutes after arrival of patients to emergency department and the plasma was separated from blood. Enzyme-linked immunosorbent assay (ELISA) was used to detect the plasma levels of angiopoietin2, and the plasma levels of von Willebrand factor (vWF) and thrombomodulin (TM) were also detected. Data were expressed as mean ± standard deviation and were statistically analyzed by using SPSS version 13.0 statistical software. The differences in plasma levels of angiopoietin2 of patients in each group were analyzed by ANOVA and Newman-Keuls test. Levels of angiopoietin2 in fatal patients and survival patients were also compared by using t test. The relationships between angiopoietin2 and plasma levels of vWF as well as levels of TM were analyzed by Pearson correlation analysis. Changes were considered as statistically significant if P value was less than 0.05. Results The plasma levels of angiopoietin2 in severe trauma group (ISS scored 16 points) were significantly higher than those in moderate trauma group (ISS < 16 points) ( P < 0.05 ), and those in trauma patients of the two groups were both significantly higher than those in control group (P < 0.05). The plasma levels of angiopoietin2 in fatal patients were significantly higher than those in survivors (P < 0.05). Plasma levels of angiopoietin2 were significantly correlated with plasma levels of vWF and TM (P < 0.05). Conclusions The plasma levels of angiopoietin-2 significantly increase after multiple trauma, and correlate with the degree of trauma severity. The plasma levels of angiopoietin2 correlate with endothelial injury after multiple trauma, having important prognosis value in patients with multiple trauma.