Nitin Seam

Effects of methylprednisolone infusion on markers of inflammation, coagulation, and angiogenesis in early acute respiratory distress syndrome.

Objective: Evaluate the effects of methylprednisolone on markers of inflammation, coagulation, and angiogenesis during early acute respiratory distress syndrome. Design: Retrospective analysis. Setting: Four intensive care units. Subjects: Seventy-nine of 91 patients with available samples enrolled in a randomized, blinded controlled trial. Interventions: Early methylprednisolone infusion (n = 55) compared with placebo (n = 24). Measurements and Main Results: Interleukin-6, tumor necrosis factor &agr;, vascular endothelial growth factor, protein C, procalcitonin, and proadrenomedullin were measured in archived plasma. Changes from baseline to day 3 and day 7 were compared between groups and in subgroups based on the precipitating cause of acute respiratory distress syndrome. Methylprednisolone therapy was associated with greater improvement in Lung Injury Score (p = .003), shorter duration of mechanical ventilation (p = .005), and lower intensive care unit mortality (p = .05) than control subjects. On days 3 and 7, methylprednisolone decreased interleukin-6 and increased protein C levels (all p < .0001) compared with control subjects. Proadrenomedullin levels were lower by day 3 with methylprednisolone treatment (p = .004). Methylprednisolone decreased interleukin-6 by days 3 and 7 in patients with pulmonary causes of acute respiratory distress syndrome but only at day 3 in those with extrapulmonary causes of acute respiratory distress syndrome. Protein C levels were increased with methylprednisolone on days 3 and 7 in patients with infectious and/or pulmonary causes of acute respiratory distress syndrome (all p < .0001) but not in patients with noninfectious or extrapulmonary causes of acute respiratory distress syndrome. Proadrenomedullin levels were decreased with methylprednisolone on day 3 in patients with infectious or extrapulmonary causes of acute respiratory distress syndrome (both p ⩽ .008) but not in noninfectious or pulmonary acute respiratory distress syndrome. Tumor necrosis factor, vascular endothelial growth factor, and procalcitonin were elevated but not differentially affected by methylprednisolone therapy. Conclusions: In early acute respiratory distress syndrome, administration of methylprednisolone was associated with improvement in important biomarkers of inflammation and coagulation and clinical outcomes. Biomarker changes varied with the precipitating cause of acute respiratory distress syndrome, suggesting that the underlying mechanisms and response to anti-inflammatory therapy may vary with the cause of acute respiratory distress syndrome.

Rapid induction of autoantibodies during ARDS and septic shock

BackgroundLittle is known about the induction of humoral responses directed against human autoantigens during acute inflammation. We utilized a highly sensitive antibody profiling technology to study autoantibodies in patients with acute respiratory distress syndrome (ARDS) and severe sepsis, conditions characterized by intensive immune activation leading to multiple organ dysfunction.MethodsUsing Luciferase Immunoprecipitation Systems (LIPS), a cohort of control, ARDS and sepsis patients were tested for antibodies to a panel of autoantigens. Autoantibody titers greater than the mean plus 3 SD of the 24 control samples were used to identify seropositive samples. Available longitudinal samples from different seropositive ARDS and sepsis patient samples, starting from within the first two days after admission to the intensive care, were then analyzed for changes in autoantibody over time.ResultsFrom screening patient plasma, 57% of ARDS and 46% of septic patients without ARDS demonstrated at least one statistically significant elevated autoantibody compared to the controls. Frequent high titer antibodies were detected against a spectrum of autoantigens including potassium channel regulator, gastric ATPase, glutamic decarboxylase-65 and several cytokines. Analysis of serial samples revealed that several seropositive patients had low autoantibodies at early time points that often rose precipitously and peaked between days 7-14. Further, the use of therapeutic doses of corticosteroids did not diminish the rise in autoantibody titers. In some cases, the patient autoantibody titers remained elevated through the last serum sample collected.ConclusionThe rapid induction of autoantibodies in ARDS and severe sepsis suggests that ongoing systemic inflammation and associated tissue destruction mediate the break in tolerance against these self proteins.

Temporal Changes in Microrna Expression in Blood Leukocytes from Patients with the Acute Respiratory Distress Syndrome

Background: MicroRNA (miRNA) control gene transcription by binding to and repressing the translation of messenger RNA (mRNA). Their role in the acute respiratory distress syndrome (ARDS) is undefined. Methods: Blood leukocytes from 51 patients enrolled in a prior randomized trial of corticosteroids for ARDS were analyzed. After screening eight patients with microarrays for altered miRNA expression, 25 miRNAs were selected for further analysis using RT-PCR in all 51 patients. Results: On day 0, the 51 patients had APACHE III score of 60.4 ± 17.7 and PaO2/FiO2 of 117 ± 49. 21 miRNA were expressed at increased levels in blood leukocytes at the onset of ARDS compared with healthy controls. These miRNA remained elevated at day 3 and increased further by day 7 (log2 fold change from 0.66 to 5.7 fold, P <0.05 compared to day 0). In a subgroup analysis (37 patients treated with corticosteroids and 14 treated with placebo), the interaction of miRNA expression over time and steroid administration was not significant suggesting that systemic corticosteroids had no effect on the miRNA detected in our study. In contrast, corticosteroids but not placebo decreased IL-6 and C-reactive protein at day 3 (P < 0.001) demonstrating an early systemic anti-inflammatory response whereas both treatment arms had decreased values by day 7 (P <0.001). Conclusions: Expression of miRNA is increased in blood leukocytes of patients with ARDS at day 0 and day 3 and rises further by day 7, when systemic inflammation is subsiding. These effects appear independent of the administration of steroids, suggesting different inflammatory modifying roles for each in the resolving phases of ARDS.

Is antithrombin treatment of disseminated intravascular coagulation a quixotic goal

The development of disseminated intravascular coagulation (DIC) is associated with increased sepsis mortality. Antithrombin (AT) is one of several anticoagulants that have been studied in randomized trials of sepsis without benefit. In a recent study, Iba and colleagues reviewed data from patients who were treated for sepsis-related DIC with two lower doses of AT concentrate than studied in prior trials. Patients received 1,500 IU/day (n = 259) or 3,000 IU/day (n = 48) of AT for 3 days. All patients had baseline antithrombin activity <40% and there was no placebo group. The AT 3,000 group had higher 28-day survival as well as a higher rate of DIC resolution than the AT 1,500 group. Though intriguing, the study findings are limited by the non-randomized retrospective nature of the findings, which resulted in baseline differences in multiple confounders that affect mortality, as well as the lack of a placebo group to compare outcomes.

Ultrasound-guided Fine Needle Aspiration Biopsy of Pleural-based Intrathoracic Lesions.

BackgroundPleural-based intrathoracic lesions pose a diagnostic challenge. Image-guided percutaneous biopsy with fluoroscopy, computed tomography (CT) scan, and ultrasound (US) have been used to establish a diagnosis. We report the yield of US-guided fine needle aspiration biopsy (FNAB) of these lesions at our center. MethodsTwenty patients with pleural-based intrathoracic lesions underwent US-guided FNAB. All were considered to have an unresectable malignant process based on clinical evaluation. Nineteen patients had pleural-based parenchymal lesion and 1 had an anterior mediastinal mass touching the chest wall. ResultsTwenty patients underwent 21 US-guided FNAB procedures. A final diagnosis was established in all the patients: 19 malignancies and 1 benign lesion. US-guided FNAB established a diagnosis of malignancy in 17 of 19 patients (89.5%) in the first attempt. In 1 patient, a diagnosis of malignancy was made on a repeat US-guided FNAB, increasing the overall yield to 18 of 19 (95%). In 1 patient with a nondiagnostic US-guided FNAB, a diagnosis of malignancy was established with CT scan-guided FNAB. US-guided FNAB was able to diagnose 15 of 16 cases of non-small cell carcinoma and 3 of 3 (100%) small cell carcinoma. In 1 patient with benign lesion, US-guided FNAB showed pulmonary macrophages. This patient was diagnosed as having pneumonia after antibiotic therapy and repeat CT scan showed complete resolution. For a diagnosis of malignancy, US-guided FNAB had 94.7% sensitivity, 100% specificity, 95% diagnostic accuracy, 100% positive predictive value, and 50% negative predictive value. There were no major complications. ConclusionsUS-guided FNAB of pleural-based intrathoracic lesions is a rapid, simple, and safe procedure with a high yield for malignancy.

Metastatic endobronchial melanoma.

patients [1] . The most frequent nonpulmonary primary tumors with endobronchial metastases are breast, kidney and colon. Malignant melanoma is known to metastasize to the lung with isolated lung metastases found in 19% of patients with melanoma [2] . The radiographic characteristics of pulmonary melanoma are varied and include endobronchial masses, solitary or multiple pulmonary nodules and a miliary pattern. A 68-year-old male with a history of left thumb melanoma treated by amputation 12 years ago presented with a 6-month history of nonproductive cough. The patient denied hemoptysis, chest pain and weight loss. Physical examination, including skin exam, was normal. Chest Xray showed a right upper lung zone mass. Chest CT revealed the 6.3 ! 4.0 cm right upper lobe mass ( fig. 1 ) as well as multiple nodules in all lung lobes. Bronchoscopy revealed multiple pigmented lesions throughout the trachea ( fig. 2 ) and distal airways bilaterally, typical of endobronchial melanoma. Biopsies of the largest distal tracheal lesion as well as the right upper lobe lesion were performed. Biopsy specimens from both sites were human melanoma black 45 positive by immunohistochemistry. Endobronchial metastases from nonpulmonary primary malignancies are rare, occurring in less than 2% of Published online: January 5, 2007

A Longitudinal Regional Educational Model for Pulmonary and Critical Care Fellows Emphasizing Small Group- and Simulation-based Learning

Recent trends have necessitated a renewed focus on how we deliver formal didactic and simulation experiences to pulmonary and critical care medicine (PCCM) fellows. To address the changing demands of training PCCM fellows, as well as the variability in the clinical training, fund of knowledge, and procedural competence of incoming fellows, we designed a PCCM curriculum that is delivered regionally in the Baltimore/Washington, DC area in the summer and winter. The educational curriculum began in 2008 as a collaboration between the Critical Care Medicine Department at the National Institutes of Health and the Pulmonary and Critical Care Section of the Department of Medicine at MedStar Washington Hospital Center and now includes 13 individual training programs in PCCM, critical care medicine, and pulmonary diseases in Baltimore and Washington, DC. Informal and formal feedback from the fellows who participated led to substantial changes to the course curriculum, allowing for continuous improvement. The educational consortium has helped build a local community of educators to share ideas, support each others career development, and collaborate on other endeavors. In this article, we describe how we developed and deliver this curriculum and report on lessons learned.