Steven Tennenberg

Complement activation and lung permeability during cardiopulmonary bypass.

Pulmonary dysfunction after cardiopulmonary bypass has been attributed to the damaging effects of complement activation on the lung. To further explore this phenomenon, we measured plasma levels of activated complement components (radioimmunoassay), assessed neutrophil n-formyl-methionyl-leucyl-phenylalanine (FMLP) receptor status (radioligand saturation binding assay), and quantified pulmonary epithelial permeability as radioaerosol lung clearance of technetium 99m-labeled diethylenetriamine pentaacetic acid in a series of 8 patients undergoing cardiopulmonary bypass. Significant elevations of plasma C3adesArg, C4adesArg, and C5adesArg levels were seen just after CPB, indicating activation of both the classic and alternate complement pathways. Neutrophil activation was evident as increased expression of neutrophil FMLP surface receptors after bypass. Despite the presence of complement and neutrophil activation, increased pulmonary epithelial permeability was not seen. These data support the hypothesis that complement and neutrophil activation during cardiopulmonary bypass is not associated with acute lung injury, at least not pulmonary epithelial injury. One can therefore infer that increased pulmonary epithelial permeability in patients at high risk for and experiencing sepsis-induced and trauma-induced adult respiratory distress syndrome may be due to factors other than complement and neutrophil activation.

Increased pulmonary alveolar-capillary permeability in patients at risk for adult respiratory distress syndrome.

Two methods for predicting adult respiratory distress syndrome (ARDS) were evaluated prospectively in a group of 81 multitrauma and sepsis patients considered at clinical high risk. A popular ARDS risk-scoring method, employing discriminant analysis equations (weighted risk criteria and oxygenation characteristics), yielded a predictive accuracy of 59% and a false-negative rate of 22%. Pulmonary alveolar-capillary permeability (PACP) was determined with a radioaerosol lung-scan technique in 23 of these 81 patients, representing a statistically similar subgroup. Lung scanning achieved a predictive accuracy of 71% (after excluding patients with unilateral pulmonary contusion) and gave no false-negatives. We propose a combination of clinical risk identification and functional determination of PACP to assess a patients risk of developing ARDS.

Endothelium Down-Regulates Fas, TNF, and TRAIL-Induced Neutrophil Apoptosis

BACKGROUND Neutrophil (PMN) apoptosis regulates PMN functional longevity and is integral to the resolution of inflammation. We have recently shown that PMN contact with an endothelial monolayer down-regulates spontaneous PMN apoptosis. We sought to explore endothelial-mediated down-regulation of PMN apoptosis following mediator-induced apoptosis. We tested the three known membrane-initiated, receptor-ligand apoptotic pathways: Fas, tumor necrosis factor-alpha (TNF), and TNF-related apoptosis inducing ligand (TRAIL). METHODS PMNs were isolated from peripheral venous blood of healthy volunteers. PMNs were co-cultured in the absence and presence of a human coronary artery endothelial cell (HCAEC) monolayer for 4 h. PMNs were then stimulated with the pro-apoptotic agonists (agonistic anti-Fas IgM, TNF, and TRAIL) for one hour, followed by an assessment of apoptosis after 5 h. PMN apoptosis was measured using an acridine orange/ethidium bromide in situ fluorescent microscopy assay. Caspase 3 activity was assessed using a spectrophotometric assay. RESULTS In addition to spontaneous PMN apoptosis, endothelial co-culture resulted in significant increases in the percentages of normal cells and decreased percentages of apoptotic cells after stimulation with agonistic anti-Fas IgM, TNF and TRAIL. Endothelial co-culture did not alter PMN caspase 3 activity. CONCLUSION Endothelial-mediated down-regulation of PMN apoptosis is conferred after 4 h of co-culture. In addition to spontaneous apoptosis, endothelial contact down-regulated the three known membrane-initiated PMN apoptotic pathways: Fas, TNF, and TRAIL. These data imply that endothelial-mediated down-regulation of PMN apoptosis may involve defects in each apoptotic pathway or a single defect in a distal transduction or effector event common to all three pathways. Alterations in the activity of caspase 3 did not appear to serve as a mechanism for endothelial-mediated down-regulation of PMN apoptosis.

Vascular Catheter Tip Cultures for Suspected Catheter-Related Blood Stream Infection in the Intensive Care Unit: A Tradition Whose Time Has Passed?

BACKGROUND Catheter-related blood stream infections (CR-BSIs) are estimated to occur in 80,000 patients in intensive care units (ICUs) each year in the United States. We sought to determine the clinical utility of vascular catheter cultures in critically ill patients with suspected CR-BSI. METHODS We reviewed retrospectively all positive (≥15 colony forming units/roll) vascular catheter tip cultures (CTCs) documented over a four-year period in the ICUs of two hospitals. A CR-BSI was defined as matching positive blood and catheter cultures. The time interval between catheter removal and blood culture was recorded. RESULTS A total of 1,391 CTCs were obtained, of which 468 (34%) were positive and 143 (31% of the positive cultures) were associated with a diagnosis of CR-BSI. In 133 of these 143 cases (93%), the positive blood culture was obtained before or within 24 h after catheter removal and dictated antibiotic therapy. In only 10 of 143 cases (7%) did catheter removal and culture significantly (>1 day) precede the positive blood culture. In 55% of the CR-BSI cases, the catheter was removed empirically and close to the time of blood culture (-1.3±19.0 h). In the remaining 45%, the catheter was removed clinically (after a blood culture was positive), and this action was more remote in time (23.6±19.4 h; p<0.001 vs. empiric removal). Total microbiology laboratory costs for the CTCs were

A prospective randomized trial of an antibiotic- and antiseptic-coated central venous catheter in the prevention of catheter-related infections

75,300, and 600 microbiology technician hours were required. CONCLUSION In an ICU patient population, only about one-third of vascular catheter cultures were positive, and only about one-third of the positive CTCs were associated with CR-BSI. Ninety-three percent of all CR-BSIs were identified by bacteremia either before or coinciding with catheter removal, and the results of the blood culture dictated antimicrobial therapy. Because CTCs rarely changed therapy, they may not be appropriate in the management of suspected CR-BSI in the ICU setting.