Translational research in sepsis - an ultimate challenge?

In the era of evidence-based medicine, large, randomized, controlled, multicenter studies represent the "summit of evidence". In contrast to specialties like cardiology, the majority of randomized, controlled trials in critical care medicine, however, have failed to demonstrate a survival benefit; notably, despite encouraging results from experimental and phase-II clinical studies. The difficulty in translating our theoretical knowledge into successful multicenter randomized, controlled trials and subsequent treatment recommendations may represent one reason, why the mortality of septic shock still averages between 40-60%, although our knowledge about the underlying pathophysiology has considerably increased and international guidelines have widely been implemented. The present article elucidates some of the difficulties in translating research from bench to bedside

Comparison of an automatic analysis and a manual analysis of conjunctival microcirculation in a sheep model of haemorrhagic shock

Life-threatening diseases of critically ill patients are known to derange microcirculation. Automatic analysis of microcirculation would provide a bedside diagnostic tool for microcirculatory disorders and allow immediate therapeutic decisions based upon microcirculation analysis

Comparison of first-line and second-line terlipressin versus sole norepinephrine in fulminant ovine septic shock

The Surviving Sepsis Guidelines suggest the use of vasopressin in case of catecholamine-refractory septic shock. Terlipressin (TP) as a V-1-selective AVP analogue is a potential alternative, though data regarding the first-line administration in septic shock are scarce. The present study explored and compared the effects of first-line vs. second-line infusion of TP or sole norepinephrine regarding organ function, fluid and norepinephrine requirements and survival in fulminant ovine septic shock. Peritoneal sepsis was induced in 23 ewes after laparotomy and faecal withdrawal from the caecum. After onset of shock, causal and supportive sepsis therapy (antibiotics, peritoneal lavage, fluids and open-label norepinephrine) was performed in all animals. Concurrently, animals were randomized to receive 0.9% sodium chloride (control group) or TP (2 mu g.kg(-1).h(-1), first-line group) after shock onset. In the second-line TP group, TP (2 mu g.kg(-1).h(-1)) was started once norepinephrine requirements exceeded 0.5 mu g.kg(-1).min(-1). No significant differences were found between groups regarding survival, haemodynamics as well as fluid-and catecholamine-requirements. Kidney function and electron microscopic kidney injury were comparable between groups. In the present model of fulminant ovine septic shock, first-line TP infusion had no significant effect on fluid and norepinephrine requirements or organ dysfunction as compared to second-line TP infusion or placebo

A new complimentary web-based tool for manual analysis of microcirculation videos: validation of the capillary mapper against the current gold standard AVA 3.2

OBJECTIVE: The aim of the current study was to compare a newly developed web-based freely accessible software program for manual analysis of the microcirculation, the Capillary Mapper (CM), with AVA 3.2 software (AVA; MicroVision Medical B.V., Amsterdam, The Netherlands), which is the current gold standard for analysis of microcirculation videos. METHODS: A web-based software program was developed, which enables manual analysis of videos of the microcirculation to be carried out according to recommendations of the 2018 consensus conference. A set of 50 high quality microcirculation videos was analyzed with AVA and CM with respect to total vessel density, perfused vessel density, proportion of perfused vessels, and the microvascular flow index. RESULTS: Comparison of the mean values derived from manual analysis with CM and AVA revealed no significant differences in microcirculatory variables. Analysis according to Bland and Altman revealed an acceptable bias between manual analysis with the CM and AVA for all variables tested with sufficient limits of agreement. The analysis of intraclass correlation showed "excellent" agreement for all microcirculatory variables analyzed. CONCLUSIONS: The newly developed CM was successfully validated for manual analyses of microcirculation videos against the current gold standard, the software AVA 3.2

Components of the Plasminogen Activation System Promote Engraftment of Porous Polyethylene Biomaterial via Common and Distinct Effects

Rapid fibrovascularization is a prerequisite for successful biomaterial engraftment. In addition to their well-known roles in fibrinolysis, urokinase-type plasminogen activator (uPA) and tissue plasminogen activator (tPA) or their inhibitor plasminogen activator inhibitor-1 (PAI-1) have recently been implicated as individual mediators in non-fibrinolytic processes, including cell adhesion, migration, and proliferation. Since these events are critical for fibrovascularization of biomaterial, we hypothesized that the components of the plasminogen activation system contribute to biomaterial engraftment. Employing in vivo and ex vivo microscopy techniques, vessel and collagen network formation within porous polyethylene (PPE) implants engrafted into dorsal skinfold chambers were found to be significantly impaired in uPA-, tPA-, or PAI-1-deficient mice. Consequently, the force required for mechanical disintegration of the implants out of the host tissue was significantly lower in the mutant mice than in wild-type controls. Conversely, surface coating with recombinant uPA, tPA, non-catalytic uPA, or PAI-1, but not with non-catalytic tPA, accelerated implant vascularization in wild-type mice. Thus, uPA, tPA, and PAI-1 contribute to the fibrovascularization of PPE implants through common and distinct effects. As clinical perspective, surface coating with recombinant uPA, tPA, or PAI-1 might provide a novel strategy for accelerating the vascularization of this biomaterial

Continuous terlipressin versus vasopressin infusion in septic shock (TERLIVAP): a randomized, controlled pilot study

Introduction Recent clinical data suggest that early administration of vasopressin analogues may be advantageous compared to a last resort therapy. However, it is still unknown whether vasopressin and terlipressin are equally effective for hemodynamic support in septic shock. The aim of the present prospective, randomized, controlled pilot trial study was, therefore, to compare the impact of continuous infusions of either vasopressin or terlipressin, when given as first-line therapy in septic shock patients, on open-label norepinephrine requirements. Methods We enrolled septic shock patients (n = 45) with a mean arterial pressure below 65 mmHg despite adequate volume resuscitation. Patients were randomized to receive continuous infusions of either terlipressin (1.3 mu g.kg(-1).h(-1)), vasopressin (.03U.min(-1)) or norepinephrine (15 mu g.min(-1); n = 15 per group). In all groups, open-label norepinephrine was added to achieve a mean arterial pressure between 65 and 75 mmHg, if necessary. Data from right heart and thermo-dye dilution catheterization, gastric tonometry, as well as laboratory variables of organ function were obtained at baseline, 12, 24, 36 and 48 hours after randomization. Differences within and between groups were analyzed using a two-way ANOVA for repeated measurements with group and time as factors. Time-independent variables were compared with one-way ANOVA. Results There were no differences among groups in terms of systemic and regional hemodynamics. Compared with infusion of .03U of vasopressin or 15 mu g.min(-1) of norepinephrine, 1.3 mu g.kg(-1).h(-1) of terlipressin allowed a marked reduction in catecholamine requirements (0.8 +/- 1.3 and 1.2 +/- 1.4 vs. 0.2 +/- 0.4 mu g.kg(-1).min(-1) at 48 hours; each P < 0.05) and was associated with less rebound hypotension (P < 0.05). At the end of the 48-hour intervention period, bilirubin concentrations were higher in the vasopressin and norepinephrine groups as compared with the terlipressin group (2.3 +/- 2.8 and 2.8 +/- 2.5 vs. 0.9 +/- 0.3 mg.dL(-1); each P < 0.05). A time-dependent decrease in platelet count was only observed in the terlipressin group (P < 0.001 48 hours vs. BL). Conclusions The present study provides evidence that continuous infusion of low-dose terlipressin - when given as first-line vasopressor agent in septic shock - is effective in reversing sepsis-induced arterial hypotension and in reducing norepinephrine requirements