Blood transfusion during cardiac surgery is associated with inflammation and coagulation in the lung: a case control study

Blood transfusion is associated with increased morbidity and mortality in cardiac surgery patients, but cause-and-effect relations remain unknown. We hypothesized that blood transfusion is associated with changes in pulmonary and systemic inflammation and coagulation occurring in patients who do not meet the clinical diagnosis of transfusion-related acute lung injury (TRALI). We performed a case control study in a mixed medical-surgical intensive care unit of a university hospital in the Netherlands. Cardiac surgery patients (n = 45) were grouped as follows: those who received no transfusion, those who received a restrictive transfusion (one two units of blood) or those who received multiple transfusions (at least five units of blood). Nondirected bronchoalveolar lavage fluid (BALF) and blood were obtained within 3 hours postoperatively. Normal distributed data were analyzed using analysis of variance and Dunnett's post hoc test. Nonparametric data were analyzed using the Kruskal-Wallis and Mann-Whitney U tests. Restrictive transfusion increased BALF levels of interleukin (IL)-1β and D-dimer compared to nontransfused controls (P < 0.05 for all), and IL-1β levels were further enhanced by multiple transfusions (P < 0.01). BALF levels of IL-8, tumor necrosis factor α (TNFα) and thrombin-antithrombin complex (TATc) were increased after multiple transfusions (P < 0.01, P < 0.001 and P < 0.01, respectively) compared to nontransfused controls, but not after restrictive transfusions. Restrictive transfusions were associated with increased pulmonary levels of plasminogen activator inhibitor 1 compared to nontransfused controls with a further increase after multiple transfusions (P < 0.001). Concomitantly, levels of plasminogen activator activity (PAA%) were lower (P < 0.001), indicating impaired fibrinolysis. In the systemic compartment, transfusion was associated with a significant increase in levels of TNFα, TATc and PAA% (P < 0.05). Transfusion during cardiac surgery is associated with activation of inflammation and coagulation in the pulmonary compartment of patients who do not meet TRALI criteria, an effect that was partly dose-dependent, suggesting transfusion as a mediator of acute lung injury. These pulmonary changes were accompanied by systemic derangement of coagulatio

Mechanisms of pulmonary dysfunction after on-pump and off-pump cardiac surgery: a prospective cohort study

BACKGROUND: Pulmonary dysfunction following cardiac surgery is believed to be caused, at least in part, by a lung vascular injury and/or atelectasis following cardiopulmonary bypass (CPB) perfusion and collapse of non-ventilated lungs. METHODS: To test this hypothesis, we studied the postoperative pulmonary leak index (PLI) for (67)Ga-transferrin and (transpulmonary) extravascular lung water (EVLW) in consecutive patients undergoing on-pump (n = 31) and off-pump (n = 8) cardiac surgery. We also studied transfusion history, radiographs, ventilatory and gas exchange variables. RESULTS: The postoperative PLI and EVLW were elevated above normal in 42 and 29% after on-pump surgery and 63 and 37% after off-pump surgery, respectively (ns). Transfusion of red blood cell (RBC) concentrates, PLI, EVLW, occurrence of atelectasis, ventilatory variables and duration of mechanical ventilation did not differ between groups, whereas patients with atelectasis had higher venous admixture and airway pressures than patients without atelectasis (P = 0.037 and 0.049). The PLI related to number of RBC concentrates infused (P = 0.025). CONCLUSION: The lung vascular injury in about half of patients after cardiac surgery is not caused by CPB perfusion but by trauma necessitating RBC transfusion, so that off-pump surgery may not afford a benefit in this respect. However, atelectasis rather than lung vascular injury is a major determinant of postoperative pulmonary dysfunction, irrespective of CPB perfusion

Food-dependent, exercise-induced gastrointestinal distress

Among athletes strenuous exercise, dehydration and gastric emptying (GE) delay are the main causes of gastrointestinal (GI) complaints, whereas gut ischemia is the main cause of their nausea, vomiting, abdominal pain and (blood) diarrhea. Additionally any factor that limits sweat evaporation, such as a hot and humid environment and/or body dehydration, has profound effects on muscle glycogen depletion and risk for heat illness. A serious underperfusion of the gut often leads to mucosal damage and enhanced permeability so as to hide blood loss, microbiota invasion (or endotoxemia) and food-born allergen absorption (with anaphylaxis). The goal of exercise rehydration is to intake more fluid orally than what is being lost in sweat. Sports drinks provide the addition of sodium and carbohydrates to assist with intestinal absorption of water and muscle-glycogen replenishment, respectively. However GE is proportionally slowed by carbohydrate-rich (hyperosmolar) solutions. On the other hand, in order to prevent hyponatremia, avoiding overhydration is recommended. Caregiver's responsibility would be to inform athletes about potential dangers of drinking too much water and also advise them to refrain from using hypertonic fluid replacements

Opposing Effects of the Angiopoietins on the Thrombin-Induced Permeability of Human Pulmonary Microvascular Endothelial Cells

BACKGROUND: Angiopoietin-2 (Ang-2) is associated with lung injury in ALI/ARDS. As endothelial activation by thrombin plays a role in the permeability of acute lung injury and Ang-2 may modulate the kinetics of thrombin-induced permeability by impairing the organization of vascular endothelial (VE-)cadherin, and affecting small Rho GTPases in human pulmonary microvascular endothelial cells (HPMVECs), we hypothesized that Ang-2 acts as a sensitizer of thrombin-induced hyperpermeability of HPMVECs, opposed by Ang-1. METHODOLOGY/PRINCIPAL FINDINGS: Permeability was assessed by measuring macromolecule passage and transendothelial electrical resistance (TEER). Angiopoietins did not affect basal permeability. Nevertheless, they had opposing effects on the thrombin-induced permeability, in particular in the initial phase. Ang-2 enhanced the initial permeability increase (passage, P = 0.010; TEER, P = 0.021) in parallel with impairment of VE-cadherin organization without affecting VE-cadherin Tyr685 phosphorylation or increasing RhoA activity. Ang-2 also increased intercellular gap formation. Ang-1 preincubation increased Rac1 activity, enforced the VE-cadherin organization, reduced the initial thrombin-induced permeability (TEER, P = 0.027), while Rac1 activity simultaneously normalized, and reduced RhoA activity at 15 min thrombin exposure (P = 0.039), but not at earlier time points. The simultaneous presence of Ang-2 largely prevented the effect of Ang-1 on TEER and macromolecule passage. CONCLUSIONS/SIGNIFICANCE: Ang-1 attenuated thrombin-induced permeability, which involved initial Rac1 activation-enforced cell-cell junctions, and later RhoA inhibition. In addition to antagonizing Ang-1, Ang-2 had also a direct effect itself. Ang-2 sensitized the initial thrombin-induced permeability accompanied by destabilization of VE-cadherin junctions and increased gap formation, in the absence of increased RhoA activity

A group randomized trial of a complexity-based organizational intervention to improve risk factors for diabetes complications in primary care settings: study protocol

<p>Abstract</p> <p>Background</p> <p>Most patients with type 2 diabetes have suboptimal control of their glucose, blood pressure (BP), and lipids – three risk factors for diabetes complications. Although the chronic care model (CCM) provides a roadmap for improving these outcomes, developing theoretically sound implementation strategies that will work across diverse primary care settings has been challenging. One explanation for this difficulty may be that most strategies do not account for the complex adaptive system (CAS) characteristics of the primary care setting. A CAS is comprised of individuals who can learn, interconnect, self-organize, and interact with their environment in a way that demonstrates non-linear dynamic behavior. One implementation strategy that may be used to leverage these properties is practice facilitation (PF). PF creates time for learning and reflection by members of the team in each clinic, improves their communication, and promotes an individualized approach to implement a strategy to improve patient outcomes.</p> <p>Specific objectives</p> <p>The specific objectives of this protocol are to: evaluate the effectiveness and sustainability of PF to improve risk factor control in patients with type 2 diabetes across a variety of primary care settings; assess the implementation of the CCM in response to the intervention; examine the relationship between communication within the practice team and the implementation of the CCM; and determine the cost of the intervention both from the perspective of the organization conducting the PF intervention and from the perspective of the primary care practice.</p> <p>Intervention</p> <p>The study will be a group randomized trial conducted in 40 primary care clinics. Data will be collected on all clinics, with 60 patients in each clinic, using a multi-method assessment process at baseline, 12, and 24 months. The intervention, PF, will consist of a series of practice improvement team meetings led by trained facilitators over 12 months. Primary hypotheses will be tested with 12-month outcome data. Sustainability of the intervention will be tested using 24 month data. Insights gained will be included in a delayed intervention conducted in control practices and evaluated in a pre-post design.</p> <p>Primary and secondary outcomes</p> <p>To test hypotheses, the unit of randomization will be the clinic. The unit of analysis will be the repeated measure of each risk factor for each patient, nested within the clinic. The repeated measure of glycosylated hemoglobin A1c will be the primary outcome, with BP and Low Density Lipoprotein (LDL) cholesterol as secondary outcomes. To study change in risk factor level, a hierarchical or random effect model will be used to account for the nesting of repeated measurement of risk factor within patients and patients within clinics.</p> <p>This protocol follows the CONSORT guidelines and is registered per ICMJE guidelines:</p> <p>Clinical Trial Registration Number</p> <p>NCT00482768</p

Patterns and mechanisms of early Pliocene warmth

About five to four million years ago, in the early Pliocene epoch, Earth had a warm, temperate climate. The gradual cooling that followed led to the establishment of modern temperature patterns, possibly in response to a decrease in atmospheric CO2 concentration, of the order of 100 parts per million, towards preindustrial values. Here we synthesize the available geochemical proxy records of sea surface temperature and show that, compared with that of today, the early Pliocene climate had substantially lower meridional and zonal temperature gradients but similar maximum ocean temperatures. Using an Earth system model, we show that none of the mechanisms currently proposed to explain Pliocene warmth can simultaneously reproduce all three crucial features. We suggest that a combination of several dynamical feedbacks underestimated in the models at present, such as those related to ocean mixing and cloud albedo, may have been responsible for these climate conditions

Attenuation of Skeletal Muscle and Renal Injury to the Lower Limb following Ischemia-Reperfusion Using mPTP Inhibitor NIM-811.

INTRODUCTION: Operation on the infrarenal aorta and large arteries of the lower extremities may cause rhabdomyolysis of the skeletal muscle, which in turn may induce remote kidney injury. NIM-811 (N-metyl-4-isoleucine-cyclosporine) is a mitochondria specific drug, which can prevent ischemic-reperfusion (IR) injury, by inhibiting mitochondrial permeability transition pores (mPTP). OBJECTIVES: Our aim was to reduce damages in the skeletal muscle and the kidney after IR of the lower limb with NIM-811. MATERIALS AND METHODS: Wistar rats underwent 180 minutes of bilateral lower limb ischemia and 240 minutes of reperfusion. Four animal groups were formed called Sham (receiving vehicle and sham surgery), NIM-Sham (receiving NIM-811 and sham surgery), IR (receiving vehicle and surgery), and NIM-IR (receiving NIM-811 and surgery). Serum, urine and histological samples were taken at the end of reperfusion. NADH-tetrazolium staining, muscle Wet/Dry (W/D) ratio calculations, laser Doppler-flowmetry (LDF) and mean arterial pressure (MAP) monitoring were performed. Renal peroxynitrite concentration, serum TNF-alpha and IL-6 levels were measured. RESULTS: Less significant histopathological changes were observable in the NIM-IR group as compared with the IR group. Serum K+ and necroenzyme levels were significantly lower in the NIM-IR group than in the IR group (LDH: p<0.001; CK: p<0.001; K+: p = 0.017). Muscle mitochondrial viability proved to be significantly higher (p = 0.001) and renal function parameters were significantly better (creatinine: p = 0.016; FENa: p<0.001) in the NIM-IR group in comparison to the IR group. Serum TNF-alpha and IL-6 levels were significantly lower (TNF-alpha: p = 0.003, IL-6: p = 0.040) as well as W/D ratio and peroxynitrite concentration were significantly lower (p = 0.014; p<0.001) in the NIM-IR group than in the IR group. CONCLUSION: NIM-811 could have the potential of reducing rhabdomyolysis and impairment of the kidney after lower limb IR injury