Impact of increased mean arterial pressure on skin microcirculatory oxygenation in vasopressor-requiring septic patients : an interventional study

Background: Heterogeneity of microvascular blood flow leading to tissue hypoxia is a common finding in patients with septic shock. It may be related to suboptimal systemic perfusion pressure and lead to organ failure. Mapping of skin microcirculatory oxygen saturation and relative hemoglobin concentration using hyperspectral imaging allows to identify heterogeneity of perfusion and perform targeted measurement of oxygenation. We hypothesized that increasing mean arterial pressure would result in improved oxygenation in areas of the skin with most microvascular blood pooling. Methods: We included adult patients admitted to the intensive care unit within the previous 24 h with sepsis and receiving a noradrenaline infusion. Skin oxygen saturation was measured using hyperspectral imaging-based method at baseline and after the increase in mean arterial pressure by 20 mm Hg by titration of noradrenaline doses. The primary outcome was an increase in skin oxygen saturation depending upon disease severity. Results: We studied 30 patients with septic shock. Median skin oxygen saturation changed from 26.0 (24.5–27.0) % at baseline to 30.0 (29.0–31.0) % after increase in mean arterial pressure (p=0.04). After adjustment for baseline saturation, patients with higher SOFA scores achieved higher oxygen saturation after the intervention (r2=0.21; p=0.02). Skin oxygen saturation measured at higher pressure was found to be marginally predictive of mortality (OR: 1.10; 95% CI 1.00–1.23; p=0.053). Conclusions: Improvement of microcirculatory oxygenation can be achieved with an increase in mean arterial pressure in most patients. Response to study intervention is proportional to disease severity.publishersversionPeer reviewe

Tissue perfusion alterations correlate with mortality in patients admitted to the intensive care unit for acute pulmonary embolism

We aimed to assess the relationship between alterations of tissue perfusion parameters at admission (highly predictive of mortality in septic shock) and outcome in patients admitted to the intensive care unit (ICU) for acute pulmonary embolism (PE). We conducted a retrospective study to analyze the association between arterial lactate level, skin mottling and urinary output, and 28-day mortality. Over a 22-year period, 317 patients with PE were identified but we finally analyzed 108 patients whose main diagnosis for ICU admission was acute PE. At admission, the sequential organ failure assessment score was 2 (0–6) and the simplified acute physiology score II was 29 (16–43). Thirty patients (28%) received vasopressors and 37 patients (34%) received thrombolytic therapy. Day 28 mortality rate was 25% (n = 27). When compared to 28-day survivors, nonsurvivor patients had higher lactate level (4.5 [2.3–10.3] mmol/L vs 1.4 [1–2.9] mmol/L, P < .0001), more frequent mottling around the knee area (56% vs 25%, P = .003) and a lower urinary output (during the first 6 hours) (0.35 [0–1] mL/kg/h vs. 0.88 [0.62–1.677] mL/kg/h, P = .0002). Mortality increased with the number of tissue perfusion alterations present upon admission, 8% for none, 21% for 1, 28% for 2, and finally reached 85% for 3 tissue perfusion alterations (P < .0001). In a multivariate analysis, the relationship between the number of tissue perfusion alterations and 28-day mortality was maintained after adjustment on the presence of shock and right ventricular dilation at admission. In ICU patients admitted for acute PE, tissue perfusion alterations correlated with 28-day mortality independently of blood pressure and right ventricular dilation

The Weaning Index combining EtCO2 and respiratory rate early identifies Spontaneous Breathing trial failure. A pilot study

BACKGROUND: We aimed to evaluate the predictive value of the end-tidal CO2 (EtCO2) alone or combined with ventilation related parameters on spontaneous breathing trial (SBT) outcome on mechanically ventilated patients. METHODS: Prospective observational study in a medical ICU. Mechanically ventilated adult patients who met predefined criteria for weaning were included. Patients underwent a T-piece SBT for 30 minutes and the usual hemodynamic and respiratory clinical parameters including EtCO2 were recorded every 5 minutes. RESULTS: 280 patients were studied (age: 64±17 years, SAPS II: 44 [34-56]) during a first SBT and 76 patients during a second SBT. The Weaning Index, defined as the product of the respiratory rate and EtCO2, was a strong early predictive factor of SBT outcome; at 10 minutes, the area under the curve (AUC) was 86% ([80-90], P<0.0001) during the first SBT and 88% ([80-96], P<0.0001) during the second SBT. After 10 minutes of SBT, a Weaning Index >1100 identified patients that will not successfully complete the SBT at 30 minutes with a specificity of 98%. CONCLUSIONS: In unselected mechanically ventilated patients, the Weaning Index is helpful to early identify patients who will fail the SBT during a first and a second trial

D022 Natural CD4/CD25/Foxp3 regulatory t cells modulate post-ischemic inflammatory response: role in neovascularization

CD4+ and CD8+ T lymphocytes control revascularization after vascular occlusion. T cell activation is mediated by two major costimulatory signalings: the B7/CD28 and the CD40-CD40 ligand pathways. Interestingly, CD28 interactions with the structurally related ligands B7-1 and B7-2 are also required for the generation and homeostasis of CD4+CD25+ regulatory T cells (Treg), whichactively maintain immunological tolerance to self and nonself antigens. We hypothesized that naturally arising Treg modulate the immuno-inflammatory response to ischemic injury, and subsequently vessel growth.Ischemia was induced by right femoral artery ligation in CD28-deficient mice (n=10 per group). After 21 days of ischemia, CD28 deficiency showed a profound reduction in Treg number and upregulated post-ischemic inflammatory response and neovascularization. Similarly, injection of splenocytes isolated from CD28-/- mice in Rag1-/- mice with hindlimb ischemia increased angiographic score, foot perfusion, and capillary density by 2.2-, 2.3- and 1.1-fold, respectively, compared to PBS-injected Rag1-/- mice. These effects were associated with enhanced accumulation of CD3-positive T cells and Mac-3 positive macrophages in the ischemic leg of Rag1-/- mice treated with CD28-/- splenocytes. Interestingly, cotransfer of Treg with CD28-/- splenocytes in Rag1- /- mice abrogated activation of neovascularization induced by CD28-/- splenocytes. Inflammatory cells accumulation was also decreased in Rag1-/- transplanted with both Treg and CD28-/- splenocytes compared to mice receiving CD28-/- splenocytes only. In contrast, treatment of C57Bl/6 Wild-Type mice with an anti- CD25 antibody (PC61) markedly reduced endogenous Treg levels in blood and spleen. At day 14 of ischemia, inflammatory response and neovascularization were markedly increased in anti-CD25 treated Wild-Type mice compared to untreated mice. These results provide new insights into the immunoregulation of post-ischemic neovascularization

Reversible Microvascular Hyporeactivity to Acetylcholine During Diabetic Ketoacidosis

OBJECTIVES: Metabolic acidosis is commonly observed in critically ill patients. Experimental studies suggested that acidosis by itself could impair vascular function, but this has been poorly investigated in human. DESIGN: Prospective observational study. SETTING: Medical ICU in a tertiary teaching hospital. PATIENTS: To assess the relationship between metabolic acidosis severity and microvascular reactivity, we included adult diabetic patients admitted in ICU for ketoacidosis. Microvascular response to acetylcholine iontophoresis was measured at admission (baseline) and after correction of metabolic acidosis (24 hr). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Thirty-nine patients with diabetic ketoacidosis were included (68% male), with a median age of 43 (31-57) years. At admission, microvascular reactivity negatively correlated with acidosis severity (R = -0.53; p < 0.001). Microvascular response was strongly depressed at pH less than 7.20 (area under the curve, 1,779 [740-3,079] vs 12,944 [4,874-21,596] at pH > 7.20; p < 0.0001). In addition, acidosis severity was significantly correlated with capillary refill time (R = 0.50; p = 0.02). At H24, after rehydration and insulin infusion, clinical and biological disorders were fully corrected. After acidosis correction, microvascular reactivity increased more in patients with severe baseline acidosis (pH < 7.20) than in those with mild baseline acidosis (area under the curve, +453% [213%-1,470%] vs +121% [79%-312%]; p < 0.01). CONCLUSIONS: We identified an alteration of microvascular reactivity during metabolic acidosis in critically ill patients with diabetic ketoacidosis. Microvascular hyporeactivity recovered after acidosis correction

Deficient CD40-TRAF6 signaling in leukocytes prevents atherosclerosis by skewing the immune response toward an antiinflammatory profile

The CD40–CD40 ligand (CD40L) signaling axis plays an important role in immunological pathways. Consequently, this dyad is involved in chronic inflammatory diseases, including atherosclerosis. Inhibition of CD40L in apolipoprotein E (Apoe)–deficient (Apoe−/−) mice not only reduced atherosclerosis but also conferred a clinically favorable plaque phenotype that was low in inflammation and high in fibrosis. Blockade of CD40L may not be therapeutically feasible, as long-term inhibition will compromise systemic immune responses. Conceivably, more targeted intervention strategies in CD40 signaling will have less deleterious side effects. We report that deficiency in hematopoietic CD40 reduces atherosclerosis and induces features of plaque stability. To elucidate the role of CD40–tumor necrosis factor receptor-associated factor (TRAF) signaling in atherosclerosis, we examined disease progression in mice deficient in CD40 and its associated signaling intermediates. Absence of CD40-TRAF6 but not CD40-TRAF2/3/5 signaling abolishes atherosclerosis and confers plaque fibrosis in Apoe−/− mice. Mice with defective CD40-TRAF6 signaling display a reduced blood count of Ly6Chigh monocytes, an impaired recruitment of Ly6C+ monocytes to the arterial wall, and polarization of macrophages toward an antiinflammatory regulatory M2 signature. These data unveil a role for CD40–TRAF6, but not CD40–TRAF2/3/5, interactions in atherosclerosis and establish that targeting specific components of the CD40–CD40L pathway harbors the potential to achieve therapeutic effects in atherosclerosis