Microcirculatory effects of the transfusion of leukodepleted or non-leukodepleted red blood cells in patients with sepsis: a pilot study

Introduction: Microvascular alterations impair tissue oxygenation during sepsis. A red blood cell (RBC) transfusion increases oxygen (O2)-delivery but rarely improves tissue O2 uptake in septic patients. Possible causes include RBC alterations due to prolonged storage or residual leukocyte-derived inflammatory mediators. The aim of this study was to compare the effects of two types of transfused-RBCs on microcirculation in septic patients. Methods: In a prospective randomized trial, 20 septic patients were divided into two separate groups and received either non-leukodepleted (n = 10) or leukodepleted (n = 10) RBC transfusions. Microvascular density and perfusion were assessed with sidestream dark-field (SDF) imaging sublingually, before and 1 hour after transfusions. Thenar tissue O2-saturation (StO2) and tissue haemoglobin index (THI) were determined with near-infrared spectroscopy (NIRS), and a vascular occlusion test was performed. The microcirculatory perfused boundary region was assessed in SDF images as an index of glycocalyx damage and glycocalyx compounds (syndecan-1, hyaluronan, heparan sulfate) were measured in the serum. Results: No differences were observed in microvascular parameters at baseline and after transfusion between the groups, except for the proportion of perfused vessels (PPV) and blood flow velocity, which were higher after transfusion in the leukodepleted group. Microvascular flow index in small vessels (MFI) and blood flow velocity exhibited different responses to transfusion between the two groups (P = 0.03 and P = 0.04, respectively), with a positive effect of leukodepleted RBCs. When looking at within-group changes, microcirculatory improvement was only observed in patients that received leukodepleted RBC transfusion as suggested by the increase in De Backer score (P = 0.02), perfused vessel density (P = 0.04), PPV (P = 0.01) and MFI (P = 0.04). Blood flow velocity decreased in the non-leukodepleted group (P = 0.03). THI and StO2-upslope increased in both groups. StO2 and StO2-downslope increased in patients who received non-leukodepleted RBC transfusions. Syndecan-1 increased after the transfusion of non-leukodepleted RBCs (P = 0.03). Conclusions: This study does not show a clear superiority of leukodepleted over non-leukodepleted RBC transfusions on microvascular perfusion in septic patients, although it suggests a more favourable effect of leukodepleted RBCs on microcirculatory convective flow. Further studies are needed to confirm these findings. © 2014 Donati et al.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Optimized EGFR blockade strategies in <i>EGFR</i> addicted gastroesophageal adenocarcinomas

Purpose: Gastric and gastroesophageal adenocarcinomas represent the third leading cause of cancer mortality worldwide. Despite significant therapeutic improvement, the outcome of patients with advanced gastroesophageal adenocarcinoma is poor. Randomized clinical trials failed to show a significant survival benefit in molecularly unselected patients with advanced gastroesophageal adenocarcinoma treated with anti-EGFR agents.Experimental Design: We performed analyses on four cohorts: IRCC (570 patients), Foundation Medicine, Inc. (9,397 patients), COG (214 patients), and the Fondazione IRCCS Istituto Nazionale dei Tumori (206 patients). Preclinical trials were conducted in patient-derived xenografts (PDX).Results: The analysis of different gastroesophageal adenocarcinoma patient cohorts suggests that EGFR amplification drives aggressive behavior and poor prognosis. We also observed that EGFR inhibitors are active in patients with EGFR copy-number gain and that coamplification of other receptor tyrosine kinases or KRAS is associated with worse response. Preclinical trials performed on EGFR-amplified gastroesophageal adenocarcinoma PDX models revealed that the combination of an EGFR mAb and an EGFR tyrosine kinase inhibitor (TKI) was more effective than each monotherapy and resulted in a deeper and durable response. In a highly EGFR-amplified nonresponding PDX, where resistance to EGFR drugs was due to inactivation of the TSC2 tumor suppressor, cotreatment with the mTOR inhibitor everolimus restored sensitivity to EGFR inhibition.Conclusions: This study underscores EGFR as a potential therapeutic target in gastric cancer and identifies the combination of an EGFR TKI and a mAb as an effective therapeutic approach. Finally, it recognizes mTOR pathway activation as a novel mechanism of primary resistance that can be overcome by the combination of EGFR and mTOR inhibitors

Homologous platelet-rich plasma for the treatment of knee osteoarthritis in selected elderly patients: an open-label, uncontrolled, pilot study

The objective of this study was to evaluate the safety and the effect of platelet-rich plasma (PRP) intra-articular injections obtained from blood donors (homologous PRP) on elderly patients with early or moderate knee osteoarthritis (OA) who are not candidates for autologous PRP treatment

Plasma Free Hemoglobin and Microcirculatory Response to Fresh or Old Blood Transfusions in Sepsis

<div><p>Background</p><p>Free hemoglobin (fHb) may induce vasoconstriction by scavenging nitric oxide. It may increase in older blood units due to storage lesions. This study evaluated whether old red blood cell transfusion increases plasma fHb in sepsis and how the microvascular response may be affected.</p><p>Methods</p><p>This is a secondary analysis of a randomized study. Twenty adult septic patients received either fresh or old (<10 or >15 days storage, respectively) RBC transfusions. fHb was measured in RBC units and in the plasma before and 1 hour after transfusion. Simultaneously, the sublingual microcirculation was assessed with sidestream-dark field imaging. The perfused boundary region was calculated as an index of glycocalyx damage. Tissue oxygen saturation (StO₂) and Hb index (THI) were measured with near-infrared spectroscopy and a vascular occlusion test was performed.</p><p>Results</p><p>Similar fHb levels were found in the supernatant of fresh and old RBC units. Despite this, plasma fHb increased in the old RBC group after transfusion (from 0.125 [0.098–0.219] mg/mL to 0.238 [0.163–0.369] mg/mL, p = 0.006). The sublingual microcirculation was unaltered in both groups, while THI increased. The change in plasma fHb was inversely correlated with the changes in total vessel density (r = -0.57 [95% confidence interval -0.82, -0.16], p = 0.008), De Backer score (r = -0.63 [95% confidence interval -0.84, -0.25], p = 0.003) and THI (r = -0.72 [95% confidence interval -0.88, -0.39], p = 0.0003).</p><p>Conclusions</p><p>Old RBC transfusion was associated with an increase in plasma fHb in septic patients. Increasing plasma fHb levels were associated with decreased microvascular density.</p><p>Trial Registration</p><p>ClinicalTrials.gov <a href="https://www.clinicaltrials.gov/ct2/show/NCT01584999" target="_blank">NCT01584999</a></p></div

Patient characteristics for the two groups.

<p>RBCs = red blood cells; SAPS II = Simplified Acute Physiology Score II; ICU = Intensive Care Unit; SOFA = Simplified Organ Failure Assessment.</p><p>Data are expressed as median (interquartile range) unless stated otherwise. Sepsis, severe sepsis, septic shock are reported as independent categories.</p><p>^aThese data have been already presented in [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0122655#pone.0122655.ref016" target="_blank">16</a>] as “non-leukodepleted group”.</p><p>^bnumber of patients; dose in μg/kg*min [median (interquartile range)].</p><p>Patient characteristics for the two groups.</p

Hematologic, hemodynamic and gas exchange variables in the two groups (baseline and 1 hour after transfusion).

<p>^aThese data have been already presented in [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0122655#pone.0122655.ref016" target="_blank">16</a>] as “non-leukodepleted group”.</p><p>^bpre vs. post, Wilcoxon matched-pairs signed rank test.</p><p>^c between-group comparison of delta [after-before] values, Mann-Whitney U test.</p><p>^ddp<0.01</p><p>^dddp<0.001, vs. fresh RBCs group at the same time point, Mann-Whitney U test.</p><p>Data are expressed as median (interquartile range).</p><p>RBCs = red blood cells; Hb = haemoglobin; Hct = haematocrit; HR = heart rate; MAP = mean arterial pressure; T = body temperature; WBC = white blood cell count; PLT = platelet count; BE = base excess; Lac = arterial lactate levels.</p><p>Hematologic, hemodynamic and gas exchange variables in the two groups (baseline and 1 hour after transfusion).</p

Correlation analysis between the change in plasma fHb (X axis) and changes in: (A) total small vessel density, (B) perfused vessel density, (C) De Backer score, (D) tissue haemoglobin index, (E) tissue oxygen saturation (Y axis).

<p>Correlation analysis between the change in plasma fHb (X axis) and changes in: (A) total small vessel density, (B) perfused vessel density, (C) De Backer score, (D) tissue haemoglobin index, (E) tissue oxygen saturation (Y axis).</p

Changes in plasma free haemoglobin after blood transfusion in the two groups.

<p>(A) Individual changes in plasma free haemoglobin after blood transfusion in the two groups; **p<0.01, Wilcoxon matched-pair signed rank test. (B) Delta values (after-before transfusion) of plasma free haemoglobin in the two groups. *p<0.05, Mann-Whitney U test. Open circles indicate patients in the fresh RBC group, full circles patients in the old RBC group.</p

Plasma free haemoglobin, sublingual microvascular parameters and NIRS-derived variables in the two groups (baseline and 1 hour after blood transfusion).

<p>^aThese data have been already presented in part in [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0122655#pone.0122655.ref016" target="_blank">16</a>] as “non-leukodepleted group”.</p><p>^bpre vs. post, Wilcoxon matched-pairs signed rank test.</p><p>^cbetween-group comparison of delta [after-before] values, Mann-Whitney U test.</p><p>Data are expressed as median (interquartile range).</p><p>RBCs = red blood cells; MFI = microvascular flow index; TVD = total vessel density; PVD = perfused vessel density; PPV = proportion of perfused vessels; HI = flow heterogeneity index; THI = tissue hemoglobin index; StO2 = tissue oxygen saturation; AUC StO2 = area under the curve of the StO2 (reactive hyperemia following the vascular occlusion test); PBR = perfused boundary region. MFI, TVD, PVD, PPV and HI were calculated in small vessels (diameter <20 μm).</p><p>Plasma free haemoglobin, sublingual microvascular parameters and NIRS-derived variables in the two groups (baseline and 1 hour after blood transfusion).</p