SUMMARY Muscular work requires the integration of cardiopulmonary mechanisms for gas exchange and 02 delivery. In patients with chronic cardiac failure, the response of these mechanisms may be impaired, and the pattern of 02 utilization (VO2) and gas exchange during exercise would thus provide an objective assessment of the severity of heart failure. Accordingly, rates of air flow, 0, uptake, CO, elimination and minute ventilation were determined during progressive treadmill exercise in 62 patients with stable heart failure. Exercise cardiac output, systemic 0, extraction and lactate production were measured directly in 40 patients with heart failure of varying severity. As the severity of heart failure increased from class A to D, there was a progressive decrease in exercise capacity (from 1157 4 154 to 373 ± 157 seconds) and maximum VO, (23 ± 3.1 to 8.4 ± 1.5 ml/min/kg). These decreases corresponded with the reduced maximum cardiac output and stroke volume during exercise. The appearance of anaerobic metabolism (580 ± 17 to 157 ± 7 seconds of exercise) and the corresponding anaerobic threshold (17 ± 0.34 to 7.1 i 1.5 ml/min/kg), determined noninvasively, were reproducible and correlated with the rise in mixed venous lactate concentration. No apparent untoward effects were experienced during or after the progressive exercise test. We conclude that the measurement of respiratory gas exchange and air flow during exercise is an objective, reproducible and safe noninvasive method for characterizing cardiac reserve and functional status in patients with chronic cardiac failure.AT REST, patients with heart disease often display normal cardiac performance. To elicit an abnormality in ventricular function, a physiologic stress, such as exercise, is required. This concept is well recognized clinically, when the severity of cardiac failure is traditionally evaluated in terms of information that relates levels of exertion with the appearance of breathlessness or fatigue. A more quantitative approach based on the pathophysiologic response to progressive exercise would be valuable for assessing the severity of cardiac disease and the functional capacity.Muscular work elicits a complex interplay of diverse physiologic mechanisms designed to ensure that 02 delivery is commensurate with 02 demand. The heart, lung and 02 carrying capacity of the blood participate in these adjustments. In patients with heart disease, cardiac output may not rise appropriately during exercise. The 02 delivery system is then compromised, and the aerobic capacity is thus reduced. Determination of 02 utilization during exercise, measured by the collection of expired air, provides an objective assessment of functional capacity in normal subjects and in patients with valvular heart disease.1-4 However, enthusiasm for using this method to evaluate patients with chronic failure irrespective of cause and severity is tempered by the relative uncertainty of correlating respiratory gas exchange with cardiac function, the perceived hazards of exposing the pat...

Severe sepsis leads to massive activation of coagulation and complement cascades that could contribute to multiple organ failure and death. To investigate the role of the complement and its crosstalk with the hemostatic system in the pathophysiology and therapeutics of sepsis, we have used a potent inhibitor (compstatin) administered early or late after Escherichia coli challenge in a baboon model of sepsis-induced multiple organ failure. Compstatin infusion inhibited sepsis-induced blood and tissue biomarkers of complement activation, reduced leucopenia and thrombocytopenia, and lowered the accumulation of macrophages and platelets in organs. Compstatin decreased the coagulopathic response by down-regulating tissue factor and PAI-1, diminished global blood coagulation markers (fibrinogen, fibrin-degradation products, APTT), and preserved the endothelial anticoagulant properties. Compstatin treatment also improved cardiac function and the biochemical markers of kidney and liver damage. Histologic analysis of vital organs collected from animals euthanized after 24 hours showed decreased microvascular thrombosis, improved vascular barrier function, and less leukocyte infiltration and cell death, all consistent with attenuated organ injury. We conclude that complement-coagulation interplay contributes to the progression of severe sepsis and blocking the harmful effects of complement activation products, especially during the organ failure stage of severe sepsis is a potentially important therapeutic strategy. (Blood. 2010;116(6):1002-1010) IntroductionSevere sepsis is a multistage, multifactorial, and life-threatening clinical syndrome that arises through the innate response to infection and can appear as a complication in conditions like trauma, cancer, and surgery. 1 Despite important strides made in understanding its pathophysiology, the sepsis-related mortality and morbidity rates still remain unacceptably high. Sepsis affects approximately 700 000 people and accounts for approximately 210 000 deaths per year 2 in the United States alone. In its most fulminant form, sepsis can produce cardiovascular collapse and death within hours. More common is the development of multiple organ failure (MOF) secondary to hypoperfusion and intravascular thrombosis. The MOF may run a protracted clinical course and eventually proves fatal in 30% to 40% of patients. The mechanisms responsible for the persistent and progressive organ failure are less understood. To examine this problem we have developed nonhuman primate models of Escherichia coli sepsis, which, depending on the bacterial dose, mimic the different pathophysiologic syndromes observed in clinical practice. 3 Challenge with 10 10 cfu/kg E coli (LD100) results in an explosive inflammatory and coagulopathic response leading to irreversible shock and death. The administration of a lower dose, 10 9 cfu/kg E coli (LD50), produces transient hypotension followed by MOF, which may progress and prove fatal in approximately 50% of the animals. The pathophysiology of the LD50 mo...

CAP associated with a high Pneumonia Severity Index score, bacteremia, or an intense coagulation and inflammatory response requiring intensive care unit care were indicators of a high risk of death from severe sepsis. In patients with severe sepsis resulting from CAP, a readily identifiable disease, DrotAA, improved survival compared with placebo.

Studies that define natural responses to bacterial sepsis assumed new relevance after the lethal bioterrorist attacks with Bacillus anthracis (anthrax), a spore-forming, toxigenic gram-positive bacillus. Considerable effort has focused on identifying adjunctive therapeutics and vaccines to prevent future deaths, but translation of promising compounds into the clinical setting necessitates an animal model that recapitulates responses observed in humans. Here we describe a nonhuman primate (Papio c. cynocephalus) model of B. anthracis infection using infusion of toxigenic B. anthracis Sterne 34F2 bacteria (5 ؋ 10 5 to 6.5 ؋ 10 9 CFU/kg). Similar to that seen in human patients, we observed changes in vascular permeability, disseminated intravascular coagulation, and systemic inflammation. The lung was a primary target organ with serosanguinous pleural effusions, intra-alveolar edema, and hemorrhagic lesions. This animal model reveals that a fatal outcome is dominated by the host septic response, thereby providing important insights into approaches for treatment and prevention of anthrax in humans. (Am J Pathol

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IntroductionPROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) was a phase III, randomized, double blind, placebo controlled, multicenter trial conducted in patients with severe sepsis from 164 medical centers. Here we report data collected at study entry for 1690 patients and over the following 7 days for the 840 patients who received placebo (in addition to usual standard of care).MethodsNineteen biomarkers of coagulation activation, anticoagulation, fibrinolysis, endothelial injury, and inflammation were analyzed to determine the relationships between baseline values and their change over time, with 28-day survival, and type of infecting causative micro-organism.ResultsLevels of 13 of the 19 biomarkers at baseline correlated with Acute Physiology and Chronic Health Evaluation II scores, and nearly all patients exhibited coagulopathy, endothelial injury, and inflammation at baseline. At study entry, elevated D-dimer, thrombin–antithrombin complexes, IL-6, and prolonged prothrombin time were present in 99.7%, 95.5%, 98.5%, and 93.4% of patients, respectively. Markers of endothelial injury (soluble thrombomodulin) and deficient protein C, protein S, and antithrombin were apparent in 72%, 87.6%, 77.8%, and 81.7%, respectively. Impaired fibrinolysis (elevated plasminogen activator inhibitor-1) was observed in 44% of patients. During the first 7 days, increased prothrombin time (which is readily measurable in most clinical settings) was highly evident among patients who were not alive at 28 days.ConclusionAbnormalities in biomarkers of inflammation and coagulation were related to disease severity and mortality outcome in patients with severe sepsis. Coagulopathy and inflammation were universal host responses to infection in patients with severe sepsis, which were similar across causative micro-organism groups.

Although severe impairment on routine pulmonary function tests will identify patients with a high post-thoracotomy morbidity, cardiopulmonary complications often develop in patients with only a mild-to-moderate impairment in pulmonary function. To determine whether the preoperative exercise capacity can prospectively identify those at risk of developing complications, 22 patients scheduled for thoracotomy (mean age, 55.7 +/- 2 yr) underwent an incremental exercise test on a cycle ergometer to determine their maximal O2 uptake (VO2max) prior to thoracotomy. Routine pulmonary function tests were performed and postoperative forced expiratory volume in one second (FEV1) was predicted from split function perfusion lung scan in all subjects. Eleven of the 22 patients had no cardiopulmonary complications postoperatively. The age, history of prior cardiovascular disease, degree of impairment on routine pulmonary function tests, and predicted postoperative FEV1 were similar in those who did and those who did not experience complications. However, those without complications had a significantly higher VO2max than did those who experienced complications (22.4 +/- 1.4 versus 14.9 +/- 0.9 ml/kg/min, p less than 0.001). Only 1 of 10 patients with a VO2max greater than 20 ml/kg/min had a complication, whereas all 6 patients with a VO2max less than 15 ml/kg/min had a complication. We conclude that exercise testing is a useful adjunct in the evaluation of operative risk for thoracotomy.

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