Plasma angiopoietin 2 concentrations are related to impaired lung function and organ failure in a clinical cohort receiving high-dose interleukin 2 therapy.

INTRODUCTION: The pathophysiology and therapeutic options in sepsis-induced lung injury remain elusive. High-dose interleukin 2 therapy (HDIL-2) is an important protocol for advanced malignancies but is limited by systemic inflammation and pulmonary edema that is indistinguishable from sepsis. In preclinical models, IL-2 stimulates angiopoietin 2 (AngP-2) secretion, which increases endothelial permeability and causes pulmonary edema. However, these relationships have not been fully elucidated in humans. Furthermore, the relevance of plasma AngP-2 to organ function is not clear. We hypothesized that plasma AngP-2 concentrations increase during HDIL-2 and are relevant to clinical pathophysiology. METHODS: We enrolled 13 subjects with metastatic melanoma or renal cell carcinoma admitted to receive HDIL-2 and collected blood and spirometry data daily. The plasma concentrations of AngP-2 and IL-6 were measured with enzyme-linked immunosorbent assay. RESULTS: At baseline, the mean AngP-2 concentration was 2.5 (SD, 1.0) ng/mL. Angiopoietin 2 concentrations increased during treatment: the mean concentration on the penultimate day was 16.0 (SD, 4.5) ng/mL and increased further to 18.6 (SD, 4.9) ng/mL (P < 0.05 vs. penultimate) during the last day of therapy. The forced expiratory volume in 1 s decreased during treatment. Interestingly, plasma AngP-2 concentrations correlated negatively with forced expiratory volume in 1 s (Spearman r = -0.78, P < 0.0001). Plasma AngP-2 concentrations also correlated with plasma IL-6 concentrations (r = 0.61, P < 0.0001) and Sequential Organ Failure Assessment scores (r = 0.68, P < 0.0001). CONCLUSIONS: Plasma AngP-2 concentrations increase during HDIL-2 administration and correlate with pulmonary dysfunction. High-dose IL-2 may serve as a clinical model of sepsis and acute lung injury. Further investigation is warranted.

Renin-angiotensin system activation correlates with microvascular dysfunction in a prospective cohort study of clinical sepsis.

INTRODUCTION: Microvascular dysregulation characterized by hyporesponsive vessels and heterogeneous bloodflow is implicated in the pathogenesis of organ failure in sepsis. The renin-angiotensin system (RAS) affects the microvasculature, yet the relationships between RAS and organ injury in clinical sepsis remain unclear. We tested our hypothesis that systemic RAS mediators are associated with dysregulation of the microvasculature and with organ failure in clinical severe sepsis. METHODS: We studied 30 subjects with severe sepsis, and 10 healthy control subjects. Plasma was analyzed for plasma renin activity (PRA) and angiotensin II concentration (Ang II). Using near-infrared spectroscopy, we measured the rate of increase in the oxygen saturation of thenar microvascular hemoglobin after five minutes of induced forearm ischemia. In so doing, we assessed bulk microvascular hemoglobin influx to the tissue during reactive hyperemia. We studied all subjects 24 hours after the development of organ failure. We studied a subset of 12 subjects at an additional timepoint, eight hours after recognition of organ failure (early sepsis). RESULTS: After 24 hours of resuscitation to clinically-defined endpoints of preload and arterial pressure, Ang II and PRA were elevated in septic subjects and the degree of elevation correlated negatively with the rate of microvascular reoxygenation during reactive hyperemia. Early RAS mediators correlated with microvascular dysfunction. Early Ang II also correlated with the extent of organ failure realized during the first day of sepsis. CONCLUSIONS: RAS is activated in clinical severe sepsis. Systemic RAS mediators correlate with measures of microvascular dysregulation and with organ failure.

The use of MDCT-based computer-aided pathway finding for mediastinal and perihilar lymph node biopsy: a randomized controlled prospective trial.

BACKGROUND: Mediastinal and perihilar lymph node samples can be acquired safely through the transbronchial approach during a bronchoscopic examination that is usually required as part of the evaluation of suspected lung cancer. Typically, needle aspiration samples are performed and needle cores can be sampled if the operator is confident that the needle is within the lymph node target, partly because of the risk of bleeding if a large blood vessel is sampled during core biopsy, especially in the perihilar region. Many bronchoscopists have difficulty assessing the three-dimensional (3D) positioning for needle sampling during these procedures, especially when relying on multidetector-row computerized tomography (MDCT) images displayed two-dimensionally seen prior to and usually during the procedure. OBJECTIVE: We have developed and evaluated a process model and associated software for providing interactive 3D displays of the MDCT data for procedure planning and real-time virtual bronchoscopic pathfinding for these procedures. METHODS: We undertook a prospective randomized clinical study for evaluating the computer-aided pathfinding assistance in mediastinal lymph node biopsies in 87 consenting subjects. RESULTS: We demonstrate that the addition of this computer-aided pathfinding improved operator performance in perihilar and paratracheal lymph node sampling (100 vs. 69%) but not in subcarinal sampling (82 vs. 85%). Overall success with lymph node sampling is 92% using the computer-aided method and 77% using standard clinical practice. CONCLUSIONS: The type of computer-aided pathway assistance described here, using 3D MDCT scanning information obtained before the procedure, but interacting with real-time bronchoscopic images during the bronchoscopic procedure, should improve the confidence of most bronchoscopists in performing these procedures, with improved clinical outcomes, and will add to the personalization of medicine through imaging.

Impairments in microvascular reactivity are related to organ failure in human sepsis.

Severe sepsis is a systemic inflammatory response to infection resulting in acute organ dysfunction. Vascular perfusion abnormalities are implicated in the pathology of organ failure, but studies of microvascular function in human sepsis are limited. We hypothesized that impaired microvascular responses to reactive hyperemia lead to impaired oxygen delivery relative to the needs of tissue and that these impairments would be associated with organ failure in sepsis. We studied 24 severe sepsis subjects 24 h after recognition of organ dysfunction; 15 healthy subjects served as controls. Near-infrared spectroscopy (NIRS) was used to measure tissue 1) microvascular hemoglobin signal strength and 2) oxygen saturation of microvascular hemoglobin (StO2). Both values were measured in thenar skeletal muscle before and after 5 min of forearm stagnant ischemia. At baseline, skeletal muscle microvascular hemoglobin was lower in septic than control subjects. Microvascular hemoglobin increased during reactive hyperemia in both groups, but less so in sepsis. StO2 at baseline and throughout ischemia was similar between the two groups; however, the rate of tissue oxygen consumption was significantly slower in septic subjects than in controls. The rate of increase in StO2 during reactive hyperemia was significantly slower in septic subjects than in controls; this impairment was accentuated in those with more organ failure. We conclude that organ dysfunction in severe sepsis is associated with dysregulation of microvascular oxygen balance. NIRS measurements of skeletal muscle microvascular perfusion and reactivity may provide important information about sepsis and serve as endpoints in future therapeutic interventions aimed at improving the microcirculation.