SOFA and mortality endpoints in randomized controlled trials: a systematic review and meta-regression analysis.

BACKGROUND: The sequential organ failure assessment score (SOFA) is increasingly used as an endpoint in intensive care randomized controlled trials (RCTs). Although serially measured SOFA is independently associated with mortality in observational cohorts, the association between treatment effects on SOFA vs. effects on mortality has not yet been quantified in RCTs. The aim of this study was to quantify the relationship between SOFA and mortality in RCTs and to identify which SOFA derivative best reflects between-group mortality differences. METHODS: The review protocol was prospectively registered (Prospero CRD42016034014). We performed a literature search (up to May 1, 2016) for RCTs reporting both SOFA and mortality, and analyzed between-group differences in these outcomes. Treatment effects on SOFA and mortality were calculated as the between-group SOFA standardized difference and log odds ratio (OR), respectively. We used random-effects meta-regression to (1) quantify the linear relationship between RCT treatment effects on mortality (logOR) and SOFA (i.e. responsiveness) and (2) quantify residual heterogeneity (i.e. consistency, expressed as I 2). RESULTS: Of 110 eligible RCTs, 87 qualified for analysis. Using all RCTs, SOFA was significantly associated with mortality (slope = 0.49 (95% CI 0.17; 0.82), p = 0.006, I 2 = 5%); the overall mortality effect explained by SOFA score (R 2) was 9%. Fifty-eight RCTs used Fixed-day SOFA as an endpoint (i.e. the score on a fixed day after randomization), 25 studies used Delta SOFA as an endpoint (i.e. the trajectory from baseline score) and 15 studies used other SOFA derivatives as an endpoint. Fixed-day SOFA was not significantly associated with mortality (slope = 0.35 (95% CI -0.04; 0.75), p = 0.08, I 2 = 12%) and explained 3% of the overall mortality effect (R 2). Delta SOFA was significantly associated with mortality (slope = 0.70 (95% CI 0.26; 1.14), p = 0.004, I 2 = 0%) and explained 32% of the overall mortality effect (R 2). CONCLUSIONS: Treatment effects on Delta SOFA appear to be reliably and consistently associated with mortality in RCTs. Fixed-day SOFA was the most frequently reported outcome among the reviewed RCTs, but was not significantly associated with mortality. Based on this study, we recommend using Delta SOFA rather than Fixed-day SOFA as an endpoint in future RCTs.

Nitric Oxide Resistance Reduces Arteriovenous Fistula Maturation in Chronic Kidney Disease in Rats.

BACKGROUND: Autologous arteriovenous (AV) fistulas are the first choice for vascular access but have a high risk of non-maturation due to insufficient vessel adaptation, a process dependent on nitric oxide (NO)-signaling. Chronic kidney disease (CKD) is associated with oxidative stress that can disturb NO-signaling. Here, we evaluated the influence of CKD on AV fistula maturation and NO-signaling. METHODS: CKD was established in rats by a 5/6th nephrectomy and after 6 weeks, an AV fistula was created between the carotid artery and jugular vein, which was followed up at 3 weeks with ultrasound and flow assessments. Vessel wall histology was assessed afterwards and vasoreactivity of carotid arteries was studied in a wire myograph. The soluble guanylate cyclase (sGC) activator BAY 60-2770 was administered daily to CKD animals for 3 weeks to enhance fistula maturation. RESULTS: CKD animals showed lower flow rates, smaller fistula diameters and increased oxidative stress levels in the vessel wall. Endothelium-dependent relaxation was comparable but vasorelaxation after sodium nitroprusside was diminished in CKD vessels, indicating NO resistance of the NO-receptor sGC. This was confirmed by stimulation with BAY 60-2770 resulting in increased vasorelaxation in CKD vessels. Oral administration of BAY 60-2770 to CKD animals induced larger fistula diameters, however; flow was not significantly different from vehicle-treated CKD animals. CONCLUSIONS: CKD induces oxidative stress resulting in NO resistance that can hamper AV fistula maturation. sGC activators like BAY 60-2770 could offer therapeutic potential to increase AV fistula maturation.

Phenotypic fitness of primary endothelial cells cultured from patients with high cardiovascular risk or chronic kidney disease for vascular tissue engineering.

Vascular tissue engineering relies on the combination of patient-derived cells and biomaterials to create new vessels. For clinical application, data regarding the function and behavior of patient-derived cells are needed. We investigated cell growth and functional characteristics of human venous endothelial cells (HVECs) from coronary arterial bypass graft (CABG), chronic kidney disease (CKD), and control patients. HVECs were isolated from venous specimens that were obtained during elective surgical procedures by means of collagenase digestion. Gene expression, proliferation, migration, secretory functions, and thrombogenic characteristics were evaluated using high-throughput assays. A total of 48 cell batches (14 control, 19 CABG, and 15 CKD subjects) were assessed. Proliferation, population doubling times, and migration of HVECs derived from CABG and CKD patients did not differ from controls. Thrombomodulin expression was higher in CABG-HVECs compared with controls. HVEC-induced thrombin formation in plasma did not differ between groups, and the contact activation pathway was the major contributor to coagulation. Patient-derived HVECs were able to attach and survive on polycaprolactone scaffolds that were coated with fibrin. HVECs from cardiovascular-diseased and CKD patients showed comparable functional characteristics with HVECs derived from uncompromised patients. We, therefore, conclude that endothelial cells from aged patients with comorbidities can be safely used for isolation and in vitro expansion for vascular tissue engineering.

Coagulation on endothelial cells: the underexposed part of Virchow's Triad.

The process of thrombin generation involves numerous plasma proteases and cofactors. Interaction with the vessel wall, in particular endothelial cells (ECs), influences this process but data on this interaction is limited. We evaluated thrombin generation on EA.hy926, human coronary arterial ECs (HCAECs) and patient-derived human venous ECs (HVECs) by means of a modified calibrated automated thrombogram (CAT) method and especially looked into contribution of the intrinsic and extrinsic pathways. Thrombin generation was measured in presence of confluent ECs with normal pooled and factor XII-deficient (FXII-deficient) platelet-poor plasma, with/without active site inhibited factor VIIa (ASIS) to block the extrinsic pathway and corn trypsin inhibitor for blocking contact activation (intrinsic pathway). Fetal bovine serum (FBS) was removed from culture conditions as FXIIa from the serum retained on ECs apparently, thereby inducing strong contact activation. In serum-free conditions, EA.hy926 and patient-derived HVECs induced thrombin generation mainly via the contact activation pathway with minor influence of ASIS on peak height and very low thrombin generation curves in FXII-deficient plasma. HVECs derived from coronary arterial bypass graft (CABG) patients showed increased thrombin generation compared to control patients, which could be ascribed to increased contact activation. Contribution of the extrinsic pathway on patient-derived ECs was limited. We conclude that the CAT method in combination with serum-free cultured ECs offers a valuable high-throughput method to evaluate endothelial influences on thrombin generation, which appears to involve predominantly contact activation on ECs. Contact activation-mediated thrombin generation was increased on ECs from CABG patients compared to controls.

Prosthetic lower extremity hemodialysis access grafts have satisfactory patency despite a high incidence of infection.

INTRODUCTION: Prosthetic arteriovenous grafts (AVGs) in the lower extremity represent a useful alternative for hemodialysis vascular access when all upper limb access sites have been used or in some patients when freedom of both hands is necessary during dialysis. Reported complications include an increased risk of infection and limb ischemia. This study evaluated our experience with the patency outcomes and complication rates of polytetrafluoroethylene (PTFE) AVGs placed in the thigh. METHODS: A retrospective outcomes analysis was performed of all femoral AVGs inserted between January 1992 and July 2007. Data were obtained by review of medical records for patient demographics, comorbidities, and AVG-related outcomes. Patency, complication rates, and risk factors for infection were determined. RESULTS: A total of 153 prosthetic AVGs were placed in 127 patients (63 men). Mean patient age was 52.7 ± 16.3 years. Median follow-up was 25 months (range, 1-169 months). The most common underlying renal disease was glomerulonephritis in 27 (21%). Hypertension and coronary artery disease were common comorbidities, respectively, in 49 (39%) and 23 patients (18%). The primary and secondary AVG patency rates at 12 months were 53.9% and 75.3%, respectively, and 2- and 5-year patency rates were, respectively, 39.6% and 19.3% (primary) and 63.8% and 50.6% (secondary). The mean AVG survival for all cases was 31.6 months (range, 0-149 months). Surgical thrombectomy was required in 82 (54%), and 22 AVGs (14%) required surgical revision for stenosis. Infection occurred in 41 AVGs (27%), and limb ischemia occurred in 2 (1.3%). Statistical analysis did not reveal a significant risk factor for infection. CONCLUSIONS: Femoral AVGs are a suitable alternative to upper limb vascular access, with acceptable primary and secondary patency rates. Infection occurred in approximately one-quarter of cases, whereas steal was uncommon.

Histological features of human abdominal aortic aneurysm are not related to clinical characteristics.

BACKGROUND: Clinical presentation, maximal aortic diameter (Dmax), and growth rate are considered important clinical characteristics of the abdominal aortic aneurysm (AAA). Histologically, AAA is characterized by pathological changes of the media. In the present study, we investigated whether and how the histological features of AAA were related to clinical characteristics. METHODS: Clinical characteristics and anterior aneurysm wall biopsies were collected prospectively. Histological characteristics were determined by immunohistochemistry and morphometric analysis. RESULTS: Thirty-nine consecutive patients with elective or emergency aneurysm repair were included. AAA was located infra- or juxtarenal in 77% and 23%, respectively. Mean maximal aortic diameter was 67 mm with a mean growth rate of 6 mm/year. The histological features included a low elastin content, distorted elastin configuration, high collagen content, diminutive number of smooth muscle cells, and a high number of medial microvessels and inflammatory cells dominated by T cells. However, no intra- or interrelationship between histological and clinical characteristics was present. In particular, Dmax and clinical presentation were not related to media thickness or inflammatory cell count. CONCLUSIONS: We conclude that histologically AAA could not be classified in analogy to clinical characteristics. We suggest that progression of large AAA is mainly determined by parameters other than histological features of the diseased vessel wall.