Prognostic significance of urokinase-type plasminogen activator and its receptor in patients with systemic inflammatory response syndrome

BACKGROUND:

This study aimed to determine the plasma levels of urokinase-type plasminogen activator (uPA), urokinase-type plasminogen activator receptor (uPAR), D-dimer, IL-6 and TNF-α and observe the relations among uPA, uPAR, D-dimer, IL-6 and TNF-α in patients with systemic inflammatory response syndrome (SIRS).

METHODS:

A prospective, clinical case-control study was conducted in patients with SIRS at age of more than 55 years old treated during 2008-2010 at Wuhan Central Hospital. Venous blood samples were collected by routine venipuncture. Eighty-five patients were divided into two groups according to diagnostic criteria of SIRS: SIRS patients from intensive care units (n=50), and non-SIRS patients from medical wards (n=35). Thirty healthy blood donors who visited the General Health Check-up Division at Wuhan Central Hospital served as controls. Excluded from the study were (1) those patients with pregnancy; (2) those with cancer; (3) those died after admission into the ICU in 7 days; (4) those received cardiopulmonary resuscitation; (5) those who had previous blood system diseases; and (6) those with SIRS before admission into the ICU. The levels of uPA, uPAR, D-D, IL-6 and TNF-α in blood were detected by commercial enzyme-linked immunosorbent assay (ELISA) kit. The data were analyzed using SPSS version 17.0 and expressed as mean ± standard. Student''s t test and the Mann-Whitney U test were used in the analysis. The relations of uPA, uPAR and D-dimer, IL-6 TNF-α levels were analyzed using Spearman''s rank-order correlation coefficient test.

RESULTS:

The plasma levels of uPA, uPAR, D-dimer,IL-6 and TNF-α in the patients with SIRS were obviously higher than those in the non-SIRS patients and controls (P<0.001). Correlation analysis showed a positive correlation between uPAR and IL-6 levels (r=0.395, P=0.004) and between uPAR and TNF-α levels (r=0.606, P<0.001), but no correlation between uPAR and D-dimer levels (r=0.069, P=0.632). No correlation was observed between uPA, D-dimer, IL-6 and TNF-α levels (P>0.05). The establishment of ROC curve was based on the levels of uPAR, D-dimer, IL-6 and TNF-α in 24 hours for the diagnosis of multiple organ dysfunction syndrome (MODS), and the ROC areas under the curve were 0.76, 0.58, 0.86 and 0.83, respectively.

CONCLUSIONS:

uPA and uPAR play a major role in patients with SIRS in the process of coagulation disorder, but the mechanism of SIRS is not the same. uPAR may play a central role in the development of SIRS to MODS.KEY WORDS: Systemic inflammatory response syndrome, Multiple organ dysfunction syndrome, D-dimer, Interleukin-6, Tumor necrosis factor-alpha, Coagulant function     

全身炎症反应综合征患者血浆尿激酶型纤溶酶原激活物及其特异性受体动态变化的研究

目的 观察全身炎症反应综合征(SIRS)患者血浆尿激酶型纤溶酶原激活物(uPA)及其特异性受体(uPAR)的动态变化以及对预后的影响.方法 采用前瞻性病例对照研究设计方法,将85例住院患者按SIRS诊断标准分为SIRS组(50例)和非SlRS组(35例);SIRS组再按病情分为单纯SIRS组(26例)和合并多器官功能障碍综合征(MODS)组(24例),按预后分为生存组(35例)和死亡组(15例);另选择同期30例健康体检者作为对照.非SIRS组于入院当日,SIRS组于发生SIRS后的1、3、5、7 d,健康对照组于体检时采集空腹静脉血2 ml,用双抗体夹心酶联免疫吸附法(ELISA)测定血浆uPA和uPAR含量,并分析SIRS患者血浆uPAR含量与急性生理学与慢性健康状况评分系统I(APACHE I)评分的相关性.结果 单纯SIRS组、合并MODS组患者血浆uPA和uPAR含量均较非SIRS组和健康对照组显著升高[uPA(μg/L):1.208±0.264、1.120±0.276比0.744±0.190、0.782±0.257;uPAR(μg/L):3.704±1.018、4.970±1.284比1.892±0.476、1.823±0.797,均P＜0.01],且合并MODS组uPAR含量明显高于单纯SIRS组(P＜0.01).与生存组比较,死亡组5 d、7 d血浆uPA含量(μg/L)明显升高(5 d:1.177±0.185比0.856±0.223,7 d:1.377±0.185比0.836±0.223,均P＜0.01),1、3、5、7 d血浆uPAR含量(μg/L)显著增高(1 d:5.301±1.410比3.888±1.015,3 d:4.017±0.898比2.994±0.638,5 d:5.032±1.238比2.536±1.017,7 d:5.232±1.238比3.536±1.017,均P＜0.01).SIRS患者血浆uPAR含量与APACHE I评分呈显著正相关(r=0.640,P＜0.O1).结论 SIRS患者存在凝血功能障碍,血浆uPA、uPAR含量显著增高,uPAR含量的升高提示预后不良.     

全身炎症反应综合征中血浆尿激酶型纤溶酶原激活物及其受体的表达

目的 探讨uPA,uPAR与D-D,IL-6及TNF-α之间的关系及其在SIRS中的作用.方法 采用前瞻性、临床病例对照研究,病例的收集均来源于武汉市中心医院2008年1月至2010年1月年龄＞55岁的就诊患者,标本的采集均为清晨空腹静脉血清,检测全身炎症反应综合征( SIRS)患者血中尿激酶型纤溶酶原激活物(uPA)及其受体(uPAR)、D-二聚体(D-D)、白细胞介素6(IL-6)和肿瘤坏死因子(TNF-α)含量.按SIRS诊断标准分为SIRS组:50例来源于重症医学科;非SIRS组35例来源于内科病房;另选30例体检科体检者作为健康对照组,均需排除:(1)孕产妇;(2)恶性肿瘤;(3)转入ICU后7d内死亡;(4)心肺复苏术后;(5)既往有血液系统疾病;(6)入住ICU时即有SIRS的患者.采用双抗体夹心酶联免疫吸附法(ELISA)测定血中uPA,uPAR,D-D,IL-6及TNF-α含量.数据均采用SPSS 17.0统计学软件进行分析:正态分布的计量资料以均数±标准差(-x±s)表示,独立样本t检验进行分析;非正态分布的计量资料以中位数表示,Mann-Whitney秩和检验;相关性分析采用Spearman秩相关检验;以24h血uPA、uPAR、IL-6和TNF-α作受试者工作特征曲线(ROC曲线),比较SIRS患者血uPA,uPAR,IL-6和TNF-α含量诊断MODS的应用价值.结果 SIRS组患者血uPA,uPAR,D-D,IL-6及TNF-α含量较非SIRS组和健康对照组均显著升高(均P＜0.01).uPA与IL-6、TNF-α不相关,uPAR与IL-6,TNF-α呈正相关(分别为r=0.395,P=0.004;r=0.606,P＜0.01).以uPA,uPAR,IL-6及TNF-α诊断MODS做ROC曲线,ROC曲线下面积(AUROC)分别为0.59,0.76,0.86,0.83.结论 uPA和uPAR参与了SIRS患者凝血功能障碍的过程,但在SIRS中起作用的途径机制并不完全相同.uPAR在SIRS向MODS的发展过程中起着一定作用.     

uPA、uPAR、PAI-1血浆含量与卵巢恶性肿瘤的相关性研究

目的：探讨尿激酶型纤溶酶原激活物（uPA）及其受体（uPAR）和抑制剂（PAI-1）血浆含量与卵巢恶性肿瘤之间的关系。方法：收集52例卵巢恶性肿瘤患者血液标本,以30例健康人作对照,用ELISA法分别检测uPA、uPAR和PAI-1的含量。结果：uPA、uPAR在卵巢恶性肿瘤各期之间均有极显著性差异（P〈0．01）,PAI-1在卵巢恶性肿瘤FIGO Ⅰ～Ⅲ期的含量逐渐升高,但在FIG0Ⅳ期时显著下降（P〈0．05）。患者组uPA、uPAR、PAI-1均较对照组升高,差异极显著（P〈0．01）。结论uPA、uPAR在卵巢恶性肿瘤患者可作为预后的判断指标,PAI-1与卵巢恶性肿瘤的分期有一定的相关性。     

The diagnostic and prognostic significance of monitoring blood levels of immature neutrophils in patients with systemic inflammation

IntroductionIn this cohort study, we investigated whether monitoring blood levels of immature neutrophils (myelocytes, metamyelocytes and band cells) differentiated patients with sepsis from those with the non-infectious (N-I) systemic inflammatory response syndrome (SIRS). We also ascertained if the appearance of circulating immature neutrophils was related to adverse outcome.MethodsBlood samples were routinely taken from 136 critically ill patients within 48 hours of ICU entry and from 20 healthy control subjects. Clinical and laboratory staff were blinded to each other’s results, and patients were retrospectively characterised into those with SIRS (n = 122) and those without SIRS (n = 14). The patients with SIRS were further subdivided into categories of definite sepsis (n = 51), possible sepsis (n = 32) and N-I SIRS (n = 39). Two established criteria were used for monitoring immature white blood cells (WBCs): one where band cells >10% WBCs and the other where >10% of all forms of immature neutrophils were included but with a normal WBC count. Immature neutrophils in blood smears were identified according to nuclear morphology and cytoplasmic staining.ResultsWith the first criterion, band cells were present in most patients with SIRS (mean = 66%) when compared with no SIRS (mean = 29%; P <0.01) and with healthy subjects (0%). The prevalence of band cells was higher in definite sepsis (mean = 82%) than in patients with possible sepsis (mean = 63%; P <0.05) or with N-I SIRS (mean = 39%; P <0.001), and they had a sensitivity of 84% and a specificity of 71% for the detection of definite sepsis. With the second criterion (that is, patients with normal WBC counts), we noted that immature neutrophils did not differentiate any of the patient groups from one another. Patients who died within 1 week of blood sample provision had higher levels of myelocytes and metamyelocytes (median = 9%; P <0.05) than patients who died at 2 to 4 weeks (median =0.5%).ConclusionsRaised blood levels of band cells have diagnostic significance for sepsis, provided that measurements are not confined to patients with normal WBC counts, whereas an increased prevalence of myelocytes and metamyelocytes may have prognostic application.     

Functional changes of intestinal mucosal barrier in surgically critical patients

BACKGROUND:

The gut is capable of inducing multiple organ dysfunction syndrome (MODS). In the diagnosis and treatment of critical ill patients, doctors should pay particular attention to the protection or recovery of intestinal barrier function. However, no reliable diagnostic criteria are available clinically. This study aimed to assess the changes of intestinal mucosal barrier function in surgically critical ill patients as well as their significance.

METHODS:

Thirty-eight surgically critical ill patients were enrolled as a study group (APACHE II>8 scores), and 15 non-critical ill patients without intestinal dysfunction were selected as a control group (APACHE II<6). General information, symptoms, physical signs, and APACHE II scores of the patients were recorded. The patients in the study group were subdivided into an intestinal dysfunction group (n=26) and a non-intestinal dysfunction group (n=12). Three ml venous blood was collected from the control group on admission and the same volume of plasma was collected from the study group both on admission and in the period of recovery. The plasma concentrations of endotoxin, diamine oxidase (DAO), D-lactate, and intestinal fatty-acid binding protein (iFABP) were detected respectively. The data collected were analyzed by the SPSS 17.0 software for Windows.

RESULTS:

The levels of variables were significantly higher in the study group than in the control group (P<0.01). They were higher in the intestinal dysfunction group than in the non-intestinal dysfunction group (DAO P<0.05, endotoxin, D-lactate, iFABP P<0.01). In the non-intestinal dysfunction group compared with the control group, the level of endotoxin was not significant (P>0.05), but the levels of DAO, D-lactate and iFABP were statistically significant (P<0.05). The levels of variables in acute stage were higher than those in recovery stage (P<0.01). The death group showed higher levels of variables than the survival group (endotoxin and D-lactate P<0.01, DAO and iFABP P<0.05).

CONCLUSION:

The plasma concentrations of endotoxin, DAO, D-lactate, and intestinal fatty-acid binding protein (iFABP) could reflect a better function of the intestinal mucosa barrier in surgically critical ill patients.KEY WORDS: Intestinal mucosal barrier, Endotoxin, Diamine oxidase, D-lactate, Intestinal fatty-acid binding protein     

Therapeutic effect of recombinant tissue plasminogen activator on acute cerebral infarction at different times

BACKGROUND:

The study aimed to compare the therapeutic effect of recombinant tissue plasminogen activator (rt-PA) on the onset of acute cerebral infarction (ACI) at different time points of the first 6 hours.

METHODS:

A retrospective analysis was conducted in 74 patients who received rt-PA thrombolysis treatment within 4.5 hours after ACI and another 15 patients who received rt-PA thrombolysis treatment between 4.5–6 hours after ACI.

RESULTS:

National Institute of Health Stroke Scale (NIHSS) scores were statistically decreased in both groups (P>0.05) at 24 hours and 7 days after ACI. There was no significant difference in modified ranking scores and mortality at 90 days after the treatment between the two groups (P>0.05).

CONCLUSIONS:

The therapeutic effect and mortality of rt-PA treatment in patients with ACI between 4.5–6 hours after the onset of the disease were similar to those in patients who received rt-PA within 4.5 hours after the onset of this disease. Therefore, intravenous thrombolytic therapy for ACI within 4.5–6 hours after ACI was effective and safe.KEY WORDS: Acute cerebral infarction, Thrombolysis, Recombinant tissue type plasminogen activator     

Endothelial cell injury with inflammatory cytokine and coagulation in patients with sepsis

BACKGROUND:

Current studies on CD62P have focused mainly on cardiovascular diseases, while only few studies have evaluated the effects of CD62P on the development of sepsis and the association between endothelial cell injury with inflammation and coagulation. This study attended to explore the association between endothelial cell injury with inflammation and coagulation by evaluating the expression of soluble CD62P (s-CD62P) in plasma and its mechanism in patients with sepsis, thus to provide the evidence of effective treatment of sepsis with anti-adhesion therapy targeted CD62P.

METHODS:

A total of 70 critically ill patients with systemic inflammatory response syndrome (SIRS) admitted to intensive care unit (ICU) between September 2009 and February 2010 were enrolled for a prospective and control study. According to the diagnostic criteria of sepsis/SIRS, the patients were divided into two groups: a sepsis group (n=38) and a SIRS group (n=32). Another 20 healthy volunteers served as a control group. Patients in the sepsis group and SIRS group were matched by clinical signs of high blood pressure, diabetes and its complications. The demographics of the patients including age, sex, body mass index (BMI), smoking and alcohol addict were compared among the groups. Six mL peripheral blood samples were collected within 24-hour admission in ICU for enzymelinked immunosorbent assay (ELISA) to detect the plasma levels of s-CD62P, TNF-α, and hs-CRP. And variables of coagulation function such as platelet (PLT), prothrombin (PT), activated partial thromboplastin time (APTT), D-dimer and antithrombin-III (AT-III) were analyzed during 24 hours after admission to ICU. Meanwhile sequential organ failure assessment (SOFA) score of critically ill patients was evaluated. Data were expressed as mean±standard deviation and were statistically analyzed by using SPSS 17.0 statistical software. The differences in plasma levels of s-CD62P of patients in each group were analyzed by ANOVA and the Kruskal-Wallis test. The relations between s-CD62P and inflammatory cytokines as well as with coagulation were determined by Pearson’s product moment correlation coefficient analysis. Changes were considered as statistically significant if P value was less than 0.05.

RESULTS:

Compared with the control group and SIRS group, the sepsis group demonstrated significantly higher levels of s-CD62P, TNF-α and highly sensitive C-reactive protein (hs-CRP) (P<0.05). The plasma levels of D-dimer, PT, and APTT in the sepsis and SIRS groups were significantly higher than those in the control group, while the platelet count and the activity of AT-III were obviously lower (P<0.05). In the sepsis group, the plasma levels of hs-CRP and TNF-α were positively correlated with PT, APTT, and D-dimer, and negatively correlated with AT-III and PLT (P<0.05). The plasma levels of s-CD62P were significantly correlated with the plasma levels of TNF-α, hs-CRP, D-dimer, PT, and APTT, whereas they were correlated negatively well with PLT and AT-III (P<0.05).

CONCLUSIONS:

The concentration of plasma s-CD62P is elevated as a early biomarker in patients with sepsis, and it serves as one of the pathogenic factors responsible for endothelial cell damage. Coagulation and mediators of inflammation promote each other, aggravating the severity of sepsis. Plasma s-CD62P may be an important factor for the development of coagulation and inflammatory reaction.KEY WORDS: Sepsis, Endothelial cell injury, Plasma soluble CD62P, Inflammatory cytokine, Coagulation     

Effects of pulmonary stretch reflex on lung injury in rabbits with acute respiratory distress syndrome

BACKGROUND:

Pulmonary stretch reflex plays an important role in regulation of respiratory movement. This study aimed to evaluate the effect of pulmonary stretch reflex on lung injury in rabbits with acute respiratory distress syndrome (ARDS).

METHODS:

ARDS rabbits were given intratracheal infusion of hydrochloric acid and ventilated with neurally adjusted ventilatory assistance (NAVA) with a tidal volume (V_T) of 6 mL/kg and the electrical activity of diaphragm (EAdi)-determined positive end expiratory pressure. After isolation of the bilateral vagus nerve trunk, the rabbits were randomized into two groups: sham operation (SHAM) group (n=5) and bilateral vagotomy (VAG) group (n=5). Gas exchange and respiratory mechanics were detected at baseline, after lung injury and 1, 2, and 3 hours after ventilation respectively. Pulmonary permeability index, pathological changes and inflammatory response were also measured.

RESULTS:

Compared with the SHAM group, PaO₂/FiO₂ in the VAG group decreased significantly 2 and 3 hours after ventilation (P<0.05). There was no significant difference in PaCO₂ between the SHAM and VAG groups (P>0.05), and the VAG group had a high V_T, peak pressure (Ppeak), and mean pressure (Pm) compared with the SHAM group 1, 2, 3 hours after ventilation (P<0.05). Compared to the SHAM group, dead space fraction (V_D/V_T) and respiratory system elastance (Ers) in the VAG group increased (P<0.05) and static pulmonary compliance (Cst) decreased markedly (P<0.05) after ventilation for 3 hours. Lung wet/dry weight ratio (W/D) (8.4±1.2 vs. 6.6±1.0), lung injury score (6.3±1.8 vs. 3.8±1.3), tumor necrosis factor-α (TNF-α) (779±372 pg/mL vs. 355±130 pg/mL) and interleukin-8 (IL-8) (169±21 pg/mL vs. 118±17 pg/mL) increased significantly in the VAG group compared with the SHAM group (P<0.05).

CONCLUSION:

Lung injury is aggravated after bilateral vagotomy, demonstrating that pulmonary stretch reflex may have protective effect on the lung.KEY WORDS: Pulmonary stretch reflex, Vagus nerve, Lung injury, Acute respiratory distress syndrome, Electrical activity of diaphragm, Mechanical ventilation     

Evaluating the Value of uPAR of Serum and Tissue on Patients With Cervical Cancer

We investigated the relationship between the urokinase type plasminogen activator receptor (uPAR) in sera and tissues of patients with cervical cancer and the clinical and pathological features of the cancer. Immunohistochemistry (SABC method) was used to detect uPAR expression in cervical cancer and normal tissues; ELISA was employed to assay the uPAR levels in cervical cancer and normal tissues and the corresponding sera. The immunohistochemistry results showed that there were 37 cases of uPAR expression in 56 patients of cervical cancer with a positive expression rate of 66%, whereas there was no uPAR expression in normal cervical tissues. The uPAR levels in cancer tissue from patients with cervical cancer (70.92 ± 28.55 ng/100 mg protein) were significantly higher than those of adjacent tissues obtained from the cancer patients (11.01 ± 5.40 ng/100 mg protein) (P < 0.001). Furthermore, the tissue uPAR levels are correlated with the TNM stages, lymph node metastasis, and the degree of differentiation instead of tumor‐infiltrating and vessel thrombosis. Serum uPAR levels of patients (2.38 ± 0.29 ng/ml) were significantly increased compared with health control group (0.50 ± 0.16 ng/ml) (P < 0.001). Single‐factor analysis shows that the serum uPAR levels of preoperative patients are related with clinical grade, lymph node metastasis, vein embolism, and the depth of infiltration instead of tumor differentiation. We conducted multiple regression analysis and found that the factors affecting preoperative serum suPAR include clinical stage (P = 0.000), pelvic lymph node metastasis (P = 0.000), and depth of myometrial invasion (P = 0.001). The serum suPAR levels of patients with cervical cancer after surgery are significantly decreased compared with preoperation (P < 0.001). The uPAR levels of serum and tissue present a positive correlation (r = 0.705, P < 0.001). The soluble uPAR in serum (suPAR) may be a more convenient indicator to reflect the uPAR system activity in vivo. It could be a tumor marker for clinical diagnosis, treatment, and prognosis monitor of cervical cancer.     

Lung recruitment maneuver effects on respiratory mechanics and extravascular lung water index in patients with acute respiratory distress syndrome

BACKGROUND:

Animal experiments showed that recruitment maneuver (RM) and protective ventilation strategy of the lung could improve oxygenation and reduce extravascular lung water. This study was to investigate the effects of RM on respiratory mechanics and extravascular lung water index (EVLWI) in patients with acute respiratory distress syndrome (ARDS).

METHODS:

Thirty patients with ARDS were randomized into a RM group and a non-RM group. In the RM group, after basic mechanical ventilation stabilized for 30 minutes, RM was performed and repeated once every 12 hours for 3 days. In the non-RM group, lung protective strategy was conducted without RM. Oxygenation index (PaO₂/FiO₂), peak inspiratory pressure (PIP), Plateau pressure (Pplat), static pulmonary compliance (Cst) and EVLWI of patients before treatment and at 12, 24, 48, 72 hours after the treatment were measured and compared between the groups. Hemodynamic changes were observed before and after RM. One-way ANOVA, Student''s t test and Fisher''s exact test were used to process the data.

RESULTS:

The levels of PaO₂/FiO₂ and Cst increased after treatment in the two groups, but they were higher in the RM group than in the non-RM group (P<0.05). The PIP and Pplat decreased after treatment in the two groups, but they were lower in the RM group than in the non-RM group (P<0.05). The EVLWI in the two groups showed downward trend after treatment (P<0.05), and the differences were signifcant at all time points (P<0.01); the EVLWI in the RM group was lower than that in the non-RM group at 12, 24, 48 and 72 hours (P<0.05 or P<0.01). Compared with pre-RM, hemodynamics changes during RM were significantly different (P<0.01); compared with pre-RM, the changes were not significantly different at 120 seconds after the end of RM (P>0.05).

CONCLUSIONS:

RM could reduce EVLWI, increase oxygenation and lung compliance. The effect of RM on hemodynamics was transient.KEY WORDS: Lung recruitment maneuver, Acute respiratory distress syndrome, Respiratory mechanics, Extravascular lung water index, Hemodynamics, Lung protective ventilation, Oxygenation index     

Plasma adrenomedullin is associated with short-term mortality and vasopressor requirement in patients admitted with sepsis

Introduction

The incidence of death among patients admitted for severe sepsis or septic shock is high. Adrenomedullin (ADM) plays a central role in initiating the hyperdynamic response during the early stages of sepsis. Pilot studies indicate an association of plasma ADM with the severity of the disease. In the present study we utilized a novel sandwich immunoassay of bioactive plasma ADM in patients hospitalized with sepsis in order to assess the clinical utility.

Methods

We enrolled 101 consecutive patients admitted to the emergency department with suspected sepsis in this study. Sepsis was defined by fulfillment of at least two systemic inflammatory response syndrome (SIRS) criteria plus clinical suspicion of infection. Plasma samples for ADM measurement were obtained on admission and for the next four days. The 28-day mortality rate was recorded.

Results

ADM at admission was associated with severity of disease (correlation with Acute Physiology and Chronic Health Evaluation II (APACHE II) score: r = 0.46; P <0.0001). ADM was also associated with 28-day mortality (ADM median (IQR): survivors: 50 (31 to 77) pg/mL; non-survivors: 84 (48 to 232) pg/mL; P <0.001) and was independent from and additive to APACHE II (P = 0.02). Cox regression analysis revealed an additive value of serial measurement of ADM over baseline assessment for prediction of 28-day mortality (P < 0.01). ADM was negatively correlated with mean arterial pressure (r = -0.39; P <0.0001), and it strongly discriminated those patients requiring vasopressor therapy from the others (ADM median (IQR): no vasopressors 48 (32 to 75) pg/mL; with vasopressors 129 (83 to 264) pg/mL, P <0.0001).

Conclusions

In patients admitted with sepsis, severe sepsis or septic shock plasma ADM is strongly associated with severity of disease, vasopressor requirement and 28-day mortality.     

The protective effects of a phosphodiesterase 5 inhibitor,sildenafil, on postresuscitation cardiac dysfunction of cardiac arrest: metabolic evidence from microdialysis

Introduction

Recent experimental and clinical studies have indicated the cardioprotective role of sildenafil during ischemia/reperfusion injury. The aim of this study was to determine, by obtaining metabolic evidence from microdialysis, if sildenafil could reduce the severity of postresuscitation myocardial dysfunction and lead to cardioprotection through beneficial effects on energy metabolism.

Methods

Twenty-four male piglets were randomly divided into three groups: sildenafil (n = 8), saline (SA; n = 8) and sham operation (n = 8). Sildenafil pretreatment consisted of 0.5 mg/kg sildenafil administered once intraperitoneally 30 minutes prior to ventricular fibrillation (VF). The myocardial interstitial fluid (ISF) concentrations of glucose, lactate, pyruvate, glutamate and glycerol were determined by microdialysis before VF. Afterward, the piglets were subjected to 8 minutes of untreated VF followed by 15 minutes of open-chest cardiopulmonary resuscitation. ISF was collected continuously, and the experiment was terminated 24 hours after resuscitation.

Results

After 8 minutes of untreated VF, the sildenafil group exhibited higher glucose and pyruvate concentrations of ISF and lower lactate and glutamate levels in comparison with the SA group, and these data reached statistical significance (P < 0.05). Advanced cardiac life support was delivered to both groups, with a 24-hour survival rate showing a promising trend in the sildenafil group (7 of 8 versus 3 of 8 survivors, P < 0.05). Compared with the SA group, the sildenafil group had a better outcome in terms of hemodynamic and oxygen metabolism parameters (P < 0.05). Myocardial tissue analysis revealed a dramatic increase in the contents of ATP, ADP and phosphocreatine in the sildenafil group versus the SA group at 24 hours after return of spontaneous circulation (ROSC; P = 0.03, P = 0.02 and P = 0.02, respectively). Furthermore, 24 hours after ROSC, the sildenafil group had marked elevations in activity of left ventricular Na⁺-K⁺-ATPase and Ca²⁺-ATPase compared with the SA group (P = 0.03, P = 0.04, respectively).

Conclusions

Sildenafil could reduce the severity of postresuscitation myocardial dysfunction, and it produced better clearance of metabolic waste in the ISF. This work might provide insights into the development of a novel strategy to treat postresuscitation myocardial dysfunction.

Electronic supplementary material

The online version of this article (doi:10.1186/s13054-014-0641-7) contains supplementary material, which is available to authorized users.     

Effects of bone marrow-derived mesenchymal stem cells engraftment on vascular endothelial cell growth factor in lung tissue and plasma at early stage of smoke inhalation injury

BACKGROUND:

This study was undertaken to determine the effect of mesenchymal stem cells (MSCs) engraftment on vascular endothelial cell growth factor (VEGF) in lung tissue, plasma and extravascular lung water at early stage of smoke inhalation injury.

METHODS:

A rabbit smoke inhalation injury model was established using a home-made smoke inhalation injury generator, and rabbits were divided into two groups randomly: a control group (S group, n=32) and a MSCs treatment group (M group, n=32). 10 ml PBS was injected via the ear marginal vein immediately at injury into the S group. Third generation MSCs with a concentration of 1×10⁷/10 ml PBS were injected via the ear marginal vein immediately at injury into the M group. VEGF in peripheral blood and lung tissue were measured at 0 (baseline), 2, 4 and 6 hours after injection respectively and analyzed. The right lungs of rabbits were taken to measure lung water mass fraction.

RESULTS:

In the lung tissue, VEGF decreased gradually in the S group (P<0.05) and significantly decreased in the M group (P<0.05), but it increased more significantly than the values at the corresponding time points (P<0.05). In peripheral blood, VEGF increased gradually in the S group (P<0.05) and markedly increased in the M group (P<0.05), but it decreased more significantly than the values at corresponding time points (P<0.05).

CONCLUSION:

MSCs engraftment to smoke inhalation injury could increase VEGF in lung tissue, decrease VEGF in plasma and reduce extravascular lung water, indicating its protective effect on smoke inhalation injury.KEY WORDS: Mesenchymal stem cells, Smoke inhalation injury, Vascular endothelial cell growth factor, Extravascular lung water, Rabbit     

Midazolam and propofol used alone or sequentially for long-term sedation in critically ill,mechanically ventilated patients: a prospective,randomized study

Introduction

Midazolam and propofol used alone for long-term sedation are associated with adverse effects. Sequential use may reduce the adverse effects, and lead to faster recovery, earlier extubation and lower costs. This study evaluates the effects, safety, and cost of midazolam, propofol, and their sequential use for long-term sedation in critically ill mechanically ventilated patients.

Methods

A total of 135 patients who required mechanical ventilation for >3 days were randomly assigned to receive midazolam (group M), propofol (group P), or sequential use of both (group M-P). In group M-P, midazolam was switched to propofol until the patients passed the spontaneous breathing trial (SBT) safety screen. The primary endpoints included recovery time, extubation time and mechanical ventilation time. The secondary endpoints were pharmaceutical cost, total cost of ICU stay, and recollection to mechanical ventilation-related events.

Results

The incidence of agitation following cessation of sedation in group M-P was lower than group M (19.4% versus 48.7%, P = 0.01). The mean percentage of adequate sedation and duration of sedation were similar in the three groups. The recovery time, extubation time and mechanical ventilation time of group M were 58.0 (interquartile range (IQR), 39.0) hours, 45.0 (IQR, 24.5) hours, and 192.0 (IQR, 124.0) hours, respectively; these were significantly longer than the other groups, while they were similar between the other two groups. In the treatment-received analysis, ICU duration was longer in group M than group M-P (P = 0.016). Using an intention-to-treat analysis and a treatment-received analysis, respectively, the pharmaceutical cost of group M-P was lower than group P (P <0.01) and its ICU cost was lower than group M (P <0.01; P = 0.015). The proportion of group M-P with unbearable memory of the uncomfortable events was lower than in group M (11.7% versus 25.0%, P <0.01), while the proportion with no memory was similar (P >0.05). The incidence of hypotension in group M-P was lower than group (P = 0.01).

Conclusion

Sequential use of midazolam and propofol was a safe and effective sedation protocol, with higher clinical effectiveness and better cost-benefit ratio than midazolam or propofol used alone, for long-term sedation of critically ill mechanically ventilated patients.

Trial registration

Current Controlled Trials ISRCTN01173443. Registered 25 February 2014.     

Pro-adrenomedullin,pro-endothelin-1, procalcitonin,C-reactive protein and mortality risk in critically ill children: a prospective study

Introduction

We tested the hypothesis that higher mid-regional pro-adrenomedullin (MR-proADM), carboxy-terminal pro-endothelin-1 (CT-proET-1), procalcitonin (PCT) and C-reactive protein (CRP) plasma concentrations would be associated with increased prediction of mortality risk scores.

Methods

Prospective observational study set in two pediatric intensive care units (PICUs). Two-hundred-thirty-eight patients were included. MR-proADM, CT-proET-1, PCT and CRP levels were compared between children with PRISM III and PIM 2 > p75 (Group A; n = 33) and the rest (Group B; n = 205).

Results

Median (range) MR-proADM levels were 1.39 nmol/L (0.52–12.67) in group A versus 0.54 (0.15–3.85) in group B (P < 0.001). CT-proET-1 levels were 172 pmol/L (27–500) versus 58 (4–447) (P < 0.001). PCT levels were 7.77 ng/mL (0.34–552.00) versus 0.28 (0.02–107.00) (P < 0.001). CRP levels were 6.23 mg/dL (0.08-28.25) versus 1.30 mg/dL (0.00-42.09) (P = 0.210). The area under the ROC curve (AUC) for the differentiation of group A and B was 0.87 (95% CI:0.81–0.821) for MR-proADM, 0.86 (95% CI:0.79–0.92) for CT-proET-1 and 0.84 (95% CI:0.74–0.94) for PCT. A MR-proADM > 0.79 nmol/L had 93% sensitivity and 76% specificity to differentiate groups, whereas a CT-proET-1 > 123 pmol/L had 77% sensitivity and 84% specificity, and a PCT concentration > 2.05 ng/mL had 80% sensitivity and specificity.

Conclusions

In critically ill children, high levels of MR-proADM, CT-proET-1 and PCT were associated with increased prediction of mortality risk scores. MR-proADM, CT-proET-1 and PCT concentrations higher than 0.80 nmol/L, 123 pmol/L and 2 ng/mL, respectively, could be used by clinicians to identify critically ill children at higher prediction of risk death scores.     

Effect of Zhenwu Tang Granule on pressure-overloaded left ventricular myocardial hypertrophy in rats

BACKGROUND:

In the perspective of traditional Chinese medicine, few studies have focused on the compound preparations though there are many investigations. The present study was undertaken to investigate the effect of Zhenwu Tang Granule on chronic pressure-overloaded left ventricular hypertrophy in rats.

METHODS:

The study was performed at the laboratory of Guangzhou Institute of Respiratory Disease. Male SD rats were divided randomly into 3 groups: sham operation group (n=8), operation group (n=15) and traditional Chinese medicine (TCM) group (n=15). The model of myocardial hypertrophy was made by gradually constricting the abdominal aorta. Sixteen weeks later, cardiac ultrasonography was performed in all groups in order to ascertain post-operational left ventricular (LV) hypertrophy. And Zhenwu Tang Granule was added at a dose of 12 g/kg in the mixed feedstuff for 8 weeks in the TCM group. In the 24th week, weight, structure as well as function of the heart in each group were measured by high-frequency ultrasonography, and Masson’s staining was performed on the cardiac muscles. Meanwhile, total collagen volume fraction (CVF-T) and non-coronary vessel collagen volume fraction (CVF-NV) were analyzed.

RESULTS:

There was an increase in the weight of the heart in the operation group, with the left ventricule dominated (P<0.05). The heart was enlarged, with diastolic interventricular septal distance (IVSd) and left ventricular posterior wall distance (LVPWd) dominated (P<0.01). There was a significant decrease in the cardiac function (P<0.05). The weight (P<0.01) and volume of the heart decreased in the TCM group compared with the operation group, with IVSd and systolic left ventricular posterior wall dominated (P<0.01). And the cardiac function was improved (P<0.05). Significant interstitial and collagen hyperplasia was shown in the operation group based on pathological analysis, and various improvements were proved in the TCM group, i.e. there was a significant decrease in CVF-T and CVF-NV (P<0.01) compared with the operation group; but no difference (P>0.05) was found when compared with the pseudo-operation group.

CONCLUSION:

Zhenwu Tang Granule could reduce the weight and volume of the heart, improve the cardiac function, inhibit hyperplasia of collagen, and reverse myocardial hypertrophy in rats with pressure-overloaded left ventricular hypertrophy.KEY WORDS: Zhenwu Tang Granule, Heart failure, Ventricular remodeling, Hypertrophy, Pressure load, Masson stain, Myocardial collagenous fiber, Abdominal aorta constriction     

Protective effect of glutamine in critical patients with acute liver injury

BACKGROUND:

Glutamine (Gln) supplementation is known to decrease oxidative stress and inflammatory response, enhance resistance to infectious pathogens, shorten hospital stay, and decrease medical costs of patients. This study was undertaken to evaluate the relationship between the effect of early parenteral glutamine (Gln) supplement on acute liver injury (ALI) and heat shock protein 70 (HSP-70) expression in critical patients.

METHODS:

Forty-four patients who had been admitted to the emergency intensive care unit (EICU) of Nanjing First Hospital Affiliated to Nanjing Medical University were randomly divided into a control group (n=22) and a Gln group (n=22). The patients of the two groups received enteral and parenteral nutrition. In addition, parenteral Gln 0.4 g/kg per day was given for 7 days in the Gln group. Serum HSP-70 and Gln were measured at admission and at 7 days after admission. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBiL), serum levels of HSP-70 and Gln, mechanical ventilation (MV) time, ICU stay, peripheral blood of TNF-α, IL-6, CD3, CD4 and CD4/CD8 levels were also measured in the two groups.

RESULTS:

In the Gln group, the levels of serum HSP-70 and Gln were significantly higher after Gln treatment than those before the treatment (P<0.01). HSP-70 level was positively correlated with the Gln level in the Gln group after administration of parenteral Gln (P<0.01). The levels of serum ALT, AST, TBiL and TNF-α, IL-6 were lower in the Gln group than in the non-Gln group (P<0.01). MV time and ICU stay were significantly different between the two groups (P<0.05). The levels of CD3, CD4 and CD4/CD8 were significantly higher in the Gln group than in the control group after treatment (P<0.05).

CONCLUSION:

Parenteral Gln significantly increases the level of serum HSP70 in critically ill patients. The enhanced expression of HSP70 is correlated with improved outcomes of Gln-treated patients with acute liver injury.KEY WORDS: Glutamine, Heat shock protein, Critically ill patients, Acute liver injury     

Therapeutic effects of smecta or smectite powder on rats with paraquat toxication

BACKGROUND:

The plasma concentration of paraquat is closely related to the prognosis of patients with paraquat toxication, and the most common cause of death from paraquat poisoning is multiple organ failure (MOF). This study aimed to evaluate therapeutic effect of smecta on the plasma concentrations of paraquat and multi-organ injury induced by paraquat intoxication in rats.

METHODS:

A total of 76 healthy adult SD rats were randomly divided into group A (control group, n=6), group B (poisoned group, n=30) and group C (smecta-treated group, n=30). Rats in groups B and C were treated intragastrically with PQ at 50 mg/kg, and rats in group A was treated intragastrically with saline (1 mL). Rats in group C were given intragastrically smecta at 400 mg/kg 10 minutes after administration of PQ, while rats in other two groups were treated intragastrically with 1 mL saline at the same time. Live rats in groups B and C were sacrificed at 2, 6, 24, 48, 72 hours after administration of PQ for the determination of paraquat plasma concentrations and for HE staining of the lung, stomach and jejunum. The rats were executed at the end of trial by the same way in group A.

RESULTS:

The plasma concentration of paraquat (ng/mL) ranged from 440.314±49.776 to 4320.6150±413.947. Distinctive pathological changes were seen in the lung, stomach and jejunum in group B. Lung injuries deteriorated gradually, edema, leukocyte infiltration, pneumorrhagia, incrassated septa and lung consolidation were observed. Abruption of mucosa, hyperemic gastric mucosa and leukocyte infiltration were obvious in the stomach. The hemorrhage of jejunum mucosa, the abruption of villus, the gland damage with the addition of inflammatory cell infiltration were found. Compared to group B, the plasma concentration of paraquat reduced (P<0.01) and the pathological changes mentioned above were obviously alleviated in group C (P<0.05, P<0.01).

CONCLUSION:

Smecta reduced the plasma concentration of paraquat and alleviated pathologic injury of rats with PQ poisoning.KEY WORDS: Smecta, Paraquat, Pathological change, Therapeutic injury