Objective: Better understanding of the pathophysiology of critical illness has led to an increase in clinical trials designed to improve the clinical care and outcomes of patients with life-threatening illness. Knowledge of basic principles of clinical trial design and interpretation will assist the clinician in better applying the results of these studies into clinical practice. Data sources: We review selected clinical trials to highlight important design features that will improve understanding of the results of critical care clinical trials designed to improve clinical care of the critically ill. Results: Trial design features such as patient selection, bias, sample size calculation, selection of subjects and controls, and primary outcome measure may influence the results of a critical care clinical trial designed to test a therapy targeting improved clinical care. In conjunction with trial design knowledge, understanding the size of the anticipated treatment effect, the importance of any clinical end point achieved, and whether patients in the trial are representative of typical patients with the illness will assist the reader in determining whether the results should be applied to specific patients or usual clinical practice. Conclusions: Better understanding of important aspects of trial design and interpretation, such as whether patients enrolled in both intervention arms were comparable and whether the primary outcome of the trial is clinically important, will assist the bedside clinician in determining whether to apply the findings from the clinical study into clinical practice.
Cell-based therapies with embryonic or adult stem cells, including induced pluripotent stem cells, have emerged as potential novel approaches for several devastating and otherwise incurable lung diseases, including emphysema, pulmonary fibrosis, pulmonary hypertension, and the acute respiratory distress syndrome. Although initial studies suggested engraftment of exogenously administered stem cells in lung, this is now generally felt to be a rare occurrence of uncertain physiologic significance. However, more recent studies have demonstrated paracrine effects of administered cells, including stimulation of angiogenesis and modulation of local inflammatory and immune responses in mouse lung disease models. Based on these studies and on safety and initial efficacy data from trials of adult stem cells in other diseases, groundbreaking clinical trials of cell-based therapy have been initiated for pulmonary hypertension and for chronic obstructive pulmonary disease. In parallel, the identity and role of endogenous lung progenitor cells in development and in repair from injury and potential contribution as lung cancer stem cells continue to be elucidated. Most recently, novel bioengineering approaches have been applied to develop functional lung tissue ex vivo. Advances in each of these areas will be described in this review with particular reference to animal models.
Development of primary graft dysfunction (PGD) is associated with poor outcomes after transplantation. We hypothesized that Receptor for Advanced Glycation End-products (RAGE) levels in donor lungs is associated with the development of PGD. Furthermore, we hypothesized that RAGE levels would be increased with PGD in recipients after transplantation.
We measured RAGE in bronchoalveolar lavage fluid (BALf) from 25 donors and 34 recipients. RAGE was also detected in biopsies (TBBX) from recipients with and without PGD.
RAGE levels were significantly higher in donor lungs that subsequently developed sustained PGD vs transplanted lungs that did not display PGD. Donor RAGE level was a predictor of recipient PGD (odds ratio = 1.768 per 0.25 ng/ml increase in donor RAGE level). In addition, RAGE levels remained high at 14 days in those recipients that developed severe graft dysfunction.
Recipients may be at higher risk for developing PGD if they receive transplanted organs that have higher levels of soluble RAGE prior to explantation. Moreover, the clinical and pathologic abnormalities associated with PGD post-transplantation are associated with increased RAGE expression. These findings also raise the possibility that targeting the RAGE signaling pathway could be a novel strategy for treatment and/or prevention of PGD.
Purpose: Gastric fundoplication (GF) for gastroesophageal reflux disease (GERD) may protect against the progression of chronic rejection in lung transplant (LT) recipients. However, the association of GERD with acute rejection episodes (ARE) is uncertain. This study sought to identify if ARE were linked to GERD in LT patients.
Methods: This single-center retrospective observational study, of patients transplanted from January 1, 2000, to January 31, 2009, correlated results of pH probe testing for GERD with ARE (≥International Society for Heart and Lung Transplantation A1 or B1). We compared the rates of ARE among patients with GERD (DeMeester Score > 14.7) versus without GERD as number of ARE per 1,000 patient-days after LT. Patients undergoing GF prior to LT were excluded.
Results: The analysis included 60 LT subjects and 9,249 patient-days: 33 with GERD versus 27 without GERD. We observed 51 ARE among 60 LT recipients. The rate of ARE was highest among patients with GERD: 8.49 versus 2.58, an incidence density ratio (IDR) of 3.29 (P = .00016). Upon multivariate negative binomial regression modeling, only GERD was associated with ARE (IDR 2.15; P = .009). Furthermore, GERD was associated with multiple ARE (36.4% vs 0%; P < .0001) and earlier onset compared with patients without GERD: ARE proportion at 2 months was 0.55 versus 0.26 P = .004).
Conclusion: In LT recipients, GERD was associated with a higher rate, multiple events, and earlier onset of ARE. The efficacy of GF to reduce ARE among patients with GERD needs further evaluation.
Both HIV-1 infection and chronic alcohol abuse adversely affect lung health. For example, through multiple mechanisms, chronic alcohol abuse increases one's susceptibility to pneumonia, particularly pneumonia caused by certain serious pathogens. Similarly, pneumonia caused by opportunistic pathogens is very common in HIV-infected patients, at least in part because HIV-1 attacks the immune cells of the lungs and interferes with their functions. Alcohol abuse also increases the risk of developing acute respiratory distress syndrome, a serious acute lung condition; however, the association of this syndrome with HIV-1 infection remains unclear. Chronic lung conditions potentially caused or exacerbated by chronic alcohol abuse include asthma, emphysema, or chronic bronchitis, although the findings to date are equivocal. However, growing evidence indicates that HIV-1 infection increases the risk of chronic pulmonary diseases such as emphysema, lung cancer, and excessive blood pressure in the vessels supplying the lung (i.e., pulmonary hypertension). Both alcohol abuse and HIV infection can impair lung function through various mechanisms, including increasing oxidative stress and enhancing antioxidant deficits, preventing full activation of the lung's immune cells, and contributing to zinc deficiency. However, the interactions between alcohol abuse and HIV-1 infection in contributing to the range of lung disorders have not been studied in detail.