George Nakos

Immunoparalysis in patients with severe trauma and the effect of inhaled interferon-gamma.

Objective To evaluate the local immune status in patients with severe trauma and the influence of interferon-&ggr; on patients with immunoparalysis. Patients Fifty-two mechanically ventilated patients with severe multiple trauma. Setting A 14-bed polyvalent intensive care unit. Interventions The local immune status was evaluated by examining bronchoalveolar lavage fluid. Subsequently, the patients were divided into two groups: immunoparalyzed (group 1) and nonimmunoparalyzed (group 2). Immunoparalysis was defined as a decreased level of human leukocyte antigen-DR expression of alveolar macrophages in <30%. Patients with immunoparalysis were treated with 100 &mgr;g of inhaled recombinant human interferon-&ggr;, three times daily (group 1a, 11 patients) or placebo (group 1b, ten patients). A second bronchoalveolar lavage fluid was obtained 3 days after the initiation of therapy. Measurements The alterations in human leukocyte antigen-DR expression, as well as in pro- and anti-inflammatory markers, such as platelet-aggregating factor, phospholipase A2, interleukin-1&bgr;, platelet-aggregating factor acetylhydrolase, and interleukin-10, were evaluated in the bronchoalveolar lavage fluids. Results In 21 of 52 (40%) patients, immunoparalysis was established. After interferon-&ggr; administration, the level of human leukocyte antigen-DR expression increased in group 1a from 17 ± 5% to 46 ± 9%. In parallel, platelet-aggregating factor and interleukin-1&bgr; as well as the specific activities of phospholipase A2 and platelet-aggregating factor acetylhydrolase significantly increased. In contrast, interleukin-10 decreased after interferon-&ggr; therapy. In group 1b, no statistically significant changes appeared in the levels of human leukocyte antigen-DR expression or in the concentrations of inflammatory mediators. The incidence of ventilator-associated pneumonia was significantly lower in group 1a than in group 1b. The administration of interferon-&ggr; did not affect the outcome of the patients. Conclusions A significant proportion of multiply injured patients developed immunoparalysis. The administration of interferon-&ggr; resulted in the recovery of levels of human leukocyte antigen-DR expression in alveolar macrophages, influenced the inflammatory reaction, and decreased the incidence ventilator-associated pneumonia, without affecting the patients’ outcome.

Phospholipases A2 and platelet-activating-factor acetylhydrolase in patients with acute respiratory distress syndrome

Objective:Phospholipases A2 (PLA2) comprise a family of enzymes probably implicated in the development of acute respiratory distress syndrome (ARDS). The aim was to investigate PLA2 activities and characteristics in bronchoalveolar lavage (BAL) fluid, BAL cells, and plasma from patients with ARDS by a fluorometric method. Design:Prospective, controlled study. Setting:Fourteen-bed polyvalent intensive care unit in a university hospital. Patients:A total of 31 mechanically ventilated patients, 20 with and 11 without ARDS, were studied. Intervention:BAL was performed by fiberoptic bronchoscopy in mechanically ventilated patients with a controlled mechanical ventilation mode. Measurements:PLA2 and platelet-activating-factor acetylhydrolase were determined in BAL fluid, cells, and plasma. For the classification of PLA2-specific inhibitors, Western blot analysis and their biochemical characteristics were used. Results:In ARDS patients, increased PLA2 levels were detected in BAL fluid, BAL cells, and plasma compared with the control patients. PLA2 in BAL fluid was mainly type IIA secretory and cytosolic types. In plasma, type IIA secretory and cytosolic and a Ca2+-independent PLA2 were found. In BAL cells, a cytosolic form, probably a Ca2+-independent intracellular form, and a low activity of type IIA secretory PLA2 was also observed. Total PLA2 activity correlated inversely with Pao2/Fio2 ratio and positively with the mortality rate. Patients with direct ARDS exhibited higher PLA2 activity compared with patients with indirect ARDS. Platelet-activating-factor acetylhydrolase activity was higher in BAL fluid and plasma, but it was lower in BAL cells. Conclusion:Ca2+-dependent, secretory, cytosolic, and Ca2+-independent forms of PLA2 and platelet-activating-factor acetylhydrolase could play important roles in the development or down-regulation of inflammation in ARDS, respectively.

Phospholipase A2 subclasses in acute respiratory distress syndrome

Phospholipases A2 (PLA2) catalyse the cleavage of fatty acids esterified at the sn-2 position of glycerophospholipids. In acute lung injury-acute respiratory distress syndrome (ALI-ARDS) several distinct isoenzymes appear in lung cells and fluid. Some are capable to trigger molecular events leading to enhanced inflammation and lung damage and others have a role in lung surfactant recycling preserving lung function: Secreted forms (groups sPLA2-IIA, -V, -X) can directly hydrolyze surfactant phospholipids. Cytosolic PLA2 (cPLA2-IVA) requiring Ca2+ has a preference for arachidonate, the precursor of eicosanoids which participate in the inflammatory response in the lung. Ca(2+)-independent intracellular PLA2s (iPLA2) take part in surfactant phospholipids turnover within alveolar cells. Acidic Ca(2+)-independent PLA2 (aiPLA2), of lysosomal origin, has additionally antioxidant properties, (peroxiredoxin VI activity), and participates in the formation of dipalmitoyl-phosphatidylcholine in lung surfactant. PAF-AH degrades PAF, a potent mediator of inflammation, and oxidatively fragmented phospholipids but also leads to toxic metabolites. Therefore, the regulation of PLA2 isoforms could be a valuable approach for ARDS treatment.

Biochemical parameters of bronchoalveolar lavage fluid in fat embolism

ObjectiveTo identify diagnostic markers distinguishing between acute lung injury/acute respiratory distress syndrome (ALI/ARDS) due to fat embolism syndrome (FES) and that due to other causes, and to investigate whether phospholipase A2 and platelet-activating factor (PAF) play a role in the pathogenesis of ALI due to FES.Design and settingA prospective study in a 14-bed ICU.PatientsWe studied 13 patients with FES, 11 with ALI/ARDS from other causes (6 without trauma, ALI/ARDS group 1; 7 with trauma, ALI/ARDS group 2) and 5 without cardiopulmonary disease.Measurements and resultsWe compared broncholveolar lavage (BAL) fluid alterations in the respective groups. Total BAL protein in FES group was significantly higher compared to in ALI/ARDS group 1 and controls but ALI/ARDS group 2. Higher total phospholipids were found than in other groups. The alterations in individual phospholipid classes were similar to those in ALI/ARDS patients. However, total cholesterol, lipid esters, and monoglycerides were significantly higher in FES than in other groups. The level of PAF in FES was significantly higher and there was an inverse correlation between PAF and PAF-acetylhydrolase. Phospholipase A2 activity was significantly higher in both FES and ALI/ARDS groups than in control.ConclusionsThe levels of neutral lipids and especially cholesterol and cholesterol esters in BAL can be used to distinguish patients with FES from ALI/ARDS due to other predisposing factors. Phospholipase A2 may be involved in the development, and PAF-acetylhydrolase in the downregulation of inflammation in FES.

Recombinant human erythropoietin therapy in critically ill patients: a dose-response study [ISRCTN48523317].

IntroductionThe aim of this study was to assess the efficacy of two dosing schedules of recombinant human erythropoietin (rHuEPO) in increasing haematocrit (Hct) and haemoglobin (Hb) and reducing exposure to allogeneic red blood cell (RBC) transfusion in critically ill patients.MethodThis was a prospective, randomized, multicentre trial. A total of 13 intensive care units participated, and a total of 148 patients who met eligibility criteria were enrolled. Patients were randomly assigned to receive intravenous iron saccharate alone (control group), intravenous iron saccharate and subcutaneous rHuEPO 40,000 units once per week (group A), or intravenous iron saccharate and subcutaneous rHuEPO 40,000 units three times per week (group B). rHuEPO was given for a minimum of 2 weeks or until discharge from the intensive care unit or death. The maximum duration of therapy was 3 weeks.ResultsThe cumulative number of RBC units transfused, the average numbers of RBC units transfused per patient and per transfused patient, the average volume of RBCs transfused per day, and the percentage of transfused patients were significantly higher in the control group than in groups A and B. No significant difference was observed between group A and B. The mean increases in Hct and Hb from baseline to final measurement were significantly greater in group B than in the control group. The mean increase in Hct was significantly greater in group B than in group A. The mean increase in Hct in group A was significantly greater than that in control individuals, whereas the mean increase in Hb did not differ significantly between the control group and group A.ConclusionAdministration of rHuEPO to critically ill patients significantly reduced the need for RBC transfusion. The magnitude of the reduction did not differ between the two dosing schedules, although there was a dose response for Hct and Hb to rHuEPO in these patients.

Early changes of procalcitonin may advise about prognosis and appropriateness of antimicrobial therapy in sepsis

PURPOSE The objective of this study is to define if early changes of procalcitonin (PCT) may inform about prognosis and appropriateness of administered therapy in sepsis. METHODS A prospective multicenter observational study was conducted in 289 patients. Blood samples were drawn on day 1, that is, within less than 24 hours from advent of signs of sepsis, and on days 3, 7, and 10. Procalcitonin was estimated in serum by the ultrasensitive Kryptor assay (BRAHMS GmbH, Hennigsdorf, Germany). Patients were divided into the following 2 groups according to the type of change of PCT: group 1, where PCT on day 3 was decreased by more than 30% or was below 0.25 ng/mL, and group 2, where PCT on day 3 was either increased above 0.25 ng/mL or decreased less than 30%. RESULTS Death occurred in 12.3% of patients of group 1 and in 29.9% of those of group 2 (P < .0001). Odds ratio for death of patients of group 1 was 0.328. Odds ratio for the administration of inappropriate antimicrobials of patients of group 2 was 2.519 (P = .003). CONCLUSIONS Changes of serum PCT within the first 48 hours reflect the benefit or not of the administered antimicrobial therapy. Serial PCT measurements should be used in clinical practice to guide administration of appropriate antimicrobials.

Propofol prevents lung injury following intestinal ischemia-reperfusion.

BACKGROUND The antioxidant properties of propofol have been shown to improve ischemia/reperfusion injury. We investigated whether anesthesia with propofol can ameliorate remote lung injury induced by intestinal ischemia-reperfusion (IIR). MATERIALS AND METHODS Thirty male Wistar rats were randomly allocated in three groups (n = 10 each): animals in group Sham were anesthetized with ketamine and xylazine and then laparotomy and sham IIR followed. Animals in group IIR received ketamine and xylazine and were then subjected to clamping of the superior mesenteric artery for 45 min and reperfusion for 4 h. Group IIR+P received anesthesia with propofol and then IIR was induced, as in group IIR. Blood samples for blood gases and malondialdehyde measurements were drawn at the end of reperfusion. Bronchoalveolar lavage fluid (BALF) was obtained to measure cell counts, total protein, and phospholipids levels. RESULTS Induction of IIR resulted in deteriorated oxygenation, acidemia, and inflammatory cells sequestration, along with increased BALF protein content and increased proportions of small surfactant aggregates. Anesthesia with propofol alleviated intestinal injury and efficiently prevented lipid oxidation. In group IIR+P inflammatory cell infiltration and pulmonary histologic changes were significantly limited. The increase in BALF total protein and the changes in surfactant aggregates were prevented, leading to normal systemic oxygenation. CONCLUSION Using propofol to induce and maintain anesthesia efficiently prevented IIR-induced lung injury. Systemic antioxidant protection, improvement of intestinal injury, inhibition of the inflammatory response, and preservation of the alveolar-capillary permeability seem to be crucial mediating mechanisms for this simple and clinically relevant intervention.

Inhaled NO and sildenafil combination in cardiac surgery patients with out-of-proportion pulmonary hypertension: acute effects on postoperative gas exchange and hemodynamics.

Background— The goal of this study was to examine the effects of coadministration of sildenafil and inhaled nitric oxide (iNO) in patients with out-of-proportion pulmonary hypertension who underwent cardiac valve replacement surgery. Methods and Results— Twenty consecutive cardiac surgery patients with out-of-proportion pulmonary hypertension were randomly assigned postoperatively into 2 groups: group A received 10 ppm of iNO followed by sildenafil (100 mg) orally 30 minutes later, and group B initially received sildenafil (100 mg) orally followed by 10 ppm of iNO 60 minutes later. Hemodynamic and gas exchange data were obtained at baseline, after administration of either iNO or sildenafil alone, and at 90 minutes from baseline. In group A, iNO resulted in a significant reduction in mean pulmonary artery pressure (MPAP) and pulmonary vascular resistance index (PVRI) (by 9.6% and 20.8%, respectively). In group B, sildenafil administration also resulted in a significant decrease in mean arterial pressure, MPAP, pulmonary artery occlusive pressure, PVRI, and systemic vascular resistance index but also in the PaO2/inspired fraction of oxygen ratio (by 18.7%, 22.0%, 15.7%, 31.6%, 21.3%, and 14%, respectively). In both groups, the coadministration of the 2 drugs resulted in a significant further reduction of mean arterial pressure, MPAP, pulmonary artery occlusive pressure, systemic vascular resistance index, and PVRI, whereas cardiac index and mixed venous oxygen saturation remained unchanged. The hypoxemia after sildenafil administration in group B improved after the coadministration of iNO, and thus PaO2/inspired fraction of oxygen returned to values near baseline. Conclusion— In this study, the postoperative coadministration of iNO and oral sildenafil in patients with out-of-proportion pulmonary hypertension undergoing cardiac surgery is safe and results in an additive favorable effect on pulmonary arterial pressure and pulmonary vascular resistance, without systemic hypotension and ventilation/perfusion mismatch.

Respiratory effects of tracheal gas insufflation in spontaneously breathing COPD patients

AbstractObjectiveTo evaluate the effect of tracheal gas insufflation (TGI) in spontaneously breathing, intubated patients with chronic obstructive pulmonary disease (COPD) undergoing weaning from the mechanical ventilation.DesignA prospective study in humans.SettingPolyvalent intensive care unit (14-bed ICU) in a 700-bed general university hospital.PatientsTwelve patients with chronic obstructive pulmonary disease (COPD) who required intubation and mechanical ventilation were studied. All patients met standard criteria for weaning from mechanical ventilation. Seven patients (group 1) had been transorally intubated during episodes of acute respiratory failure. Five patients, all men (group 2), had previously undergone tracheostomy and had a transtracheal tube in place.InterventionsIntratracheal, humidified, O2-mixture insufflation (TGI) was given via a catheter placed in distal or proximal position. Gas delivered through the intratracheal catheter was blended to match the fractional of inspired gas through the endotracheal tube. Continuous flows of 3 and 6 l/min in randomized order were used in each catheter position. Prior to data collection at each stage, an equilibration period of at least 30 min was observed, and thereafter blood gases were analyzed every 5 min. A new steady state was assumed to have been established when values of bothPaCO2 and