Lung cancer is the most common cause of cancer death. The vast majority of patients present with non-small cell lung cancer (NSCLC) in advanced inoperable stages. The current first-line treatment for patients with advanced NSCLC includes chemotherapy and palliative radiotherapy, but most patients relapse and eventually succumb to the disease. Advances in our knowledge of cancer cell biology have led to the development of specific molecular-targeted therapeutic agents. Mutations in the epidermal growth factor receptor (EGFR) have been identified in NSCLC cells, and overexpression of the EGFR and its ligands is a common feature of many cancers; therefore, EGFR has become an attractive target for various antitumor strategies. Aberrant signaling from the EGFR is known to be important in the development and progression of NSCLC. Two oral EGFR inhibitors, gefitinib and erlotinib, are small-molecule agents that selectively inhibit the intracellular tyrosine kinase activity of the EGFR. Both have demonstrated antitumor activity in patients with advanced NSCLC who have failed all prior treatment regimens. In addition, the anti-EGFR monoclonal antibody cetuximab has shown promising activity in both first-line and second-line settings in patients with advanced NSCLC. Furthermore, patients with severe comorbidities who would not be eligible for systemic chemotherapy are candidates for these targeted therapies. Finally, these agents have also been shown to be effective for relieving symptoms, maintaining stable disease, and improving quality of life without the adverse events that may be associated with cytotoxic cancer therapies. This report will review the mechanism of action, indications, contraindications, patient selection, and efficacy and side effects of this new class of compounds. It is important for pulmonologists to be aware of this class of compounds, as they can provide benefit to patients with NSCLC who may not have been previously considered for antitumor therapy.

Exercise-induced bronchoconstriction (EIB) describes airway narrowing that occurs in association with exercise. EIB occurs in up to 90% of asthmatic patients and is estimated to occur in > 10% of the general population. Recent reviews have identified asthma as a risk factor for sudden death and have reported many deaths that have been attributed directly to EIB. We present a review of the literature related to EIB in athletes including sections discussing its pathogenesis, diagnosis, and treatment, and which athletes are most at risk for experiencing EIB.

A bronchopleural fistula (BPF) is a communication between the pleural space and the bronchial tree. Although rare, BPFs represent a challenging management problem and are associated with high morbidity and mortality. By far, the postoperative complication of pulmonary resection is the most common cause, followed by lung necrosis complicating infection, persistent spontaneous pneumothorax, chemotherapy or radiotherapy (for lung cancer), and tuberculosis. The treatment of BPF includes various surgical and medical procedures, and of particular interest is the use of bronchoscopy and different glues, coils, and sealants. Localization of the fistula and size may indicate potential benefits of surgical vs endoscopic procedures. In high-risk surgical patients, endoscopic procedures may serve as a temporary bridge until the patient's clinical status is improved, while in other patients endoscopic procedures may be the only option. Therapeutic success has been variable, and the lack of consensus suggests that no optimal therapy is available; rather, the current therapeutic options seem to be complementary, and the treatment should be individualized.

Patients requiring prolonged mechanical ventilation (PMV) are rapidly increasing in number, as improved ICU care has resulted in many patients surviving acute respiratory failure only to then require prolonged mechanical ventilatory assistance during convalescence. This patient population has clearly different needs and resource consumption patterns than patients in acute ICUs, and specialized venues, management strategies, and reimbursement schemes for them are rapidly emerging. To address these issues in a comprehensive way, a conference on the epidemiology, care, and overall management of patients requiring PMV was held. The goal was to not only review existing practices but to also develop recommendations on a variety of assessment, management, and reimbursement issues associated with patients requiring PMV. Formal presentations were made on a variety of topics, and writing groups were formed to address three specific areas: epidemiology and outcomes, management and care settings, and reimbursement. Each group was charged with summarizing current data and practice along with formulation of recommendations. A working draft of the products of these three groups was then created and circulated among all participants. The document was reworked with input from all concerned until a final product with consensus recommendations on 12 specific issues was achieved.

Although the blood supply has become safer with regard to transmission of infectious agents, attention should continue to focus on understanding and eliminating the other serious risks associated with transfusion. Transfusion-related acute lung injury (TRALI) is one such risk, only recently becoming recognized as an important and potentially preventable clinical syndrome. Strategies for prevention of TRALI, however, must rely on knowledge regarding its etiology and diagnosis, and significant gaps in our understanding of the syndrome currently exist. This review summarizes what is known and unknown about the incidence, severity, etiology, diagnosis, and prevention of TRALI and the potential consequences of these knowledge gaps.

The hemodynamic effects of ventilation are complex but can be grouped under four clinically relevant concepts. First, spontaneous ventilation is exercise, and critically ill patients may not withstand the increased work of breathing. Initiation of mechanical ventilatory support will improve oxygen delivery to the remainder of the body by decreasing oxygen consumption. To the extent that mixed venous oxygen also increases, Pao(2) will increase without any improvement in gas exchange. Similarly, weaning from mechanical ventilatory support is a cardiovascular stress test. Patients who fail to wean also manifest cardiovascular insufficiency during the failed weaning attempts. Improving cardiovascular reserve or supplementing support with inotropic therapy may allow patients to wean from mechanical ventilation. Second, changes in lung volume alter autonomic tone and pulmonary vascular resistance (PVR), and at high lung volumes compress the heart in the cardiac fossa. Hyperinflation increases PVR and pulmonary artery pressure, impeding right ventricular ejection. Decreases in lung volume induce alveolar collapse and hypoxia, stimulating an increased pulmonary vasomotor tone by the process of hypoxic pulmonary vasoconstriction. Recruitment maneuvers, positive end-expiratory pressure, and continuous positive airway pressure may reverse hypoxic pulmonary vasoconstriction and reduce pulmonary artery pressure. Third, spontaneous inspiration and spontaneous inspiratory efforts decrease intrathoracic pressure (ITP). Since diaphragmatic descent increases intra-abdominal pressure, these combined effects cause right atrial pressure inside the thorax to decrease but venous pressure in the abdomen to increase, markedly increasing the pressure gradient for systemic venous return. Furthermore, the greater the decrease in ITP, the greater the increase in left ventricular (LV) afterload for a constant arterial pressure. Mechanical ventilation, by abolishing the negative swings in ITP, will selectively decrease LV afterload, as long as the increases in lung volume and ITP are small. Finally, positive-pressure ventilation increases ITP. Since diaphragmatic descent increases intra-abdominal pressure, the decrease in the pressure gradient for venous return is less than would otherwise occur if the only change were an increase in right atrial pressure. However, in hypovolemic states, positive-pressure ventilation can induce profound decreases in venous return. Increases in ITP decrease LV afterload and will augment LV ejection. In patients with hypervolemic heart failure, this afterload reducing effect can result in improved LV ejection, increased cardiac output, and reduced myocardial oxygen demand.

Healthy individuals are able to tolerate profound, short-term decreases in hemoglobin levels and oxygen saturation without serious consequences, but critically ill patients in respiratory failure lack the necessary reserve capacity to preserve tissue oxygenation. The development of progressive anemia in ICU patients has led to much interest and debate about transfusion practices, yet optimal hemoglobin levels and how they should be achieved remain unclear. Animal and human studies regarding critical oxygen delivery provide the rationale for optimizing hemoglobin levels and supporting cardiovascular function during respiratory failure. Theoretically, the oxygen-carrying benefit of RBCs should hasten recovery from respiratory failure, and transfusions would therefore be expected to shorten the duration of mechanical ventilation. However, evidence to the contrary has been reported. Controversies related to transfusions and their inability to improve outcomes suggest that further research regarding transfusion alternatives is needed, especially in anemic patients with respiratory failure.

Anemia occurs in virtually all critically ill patients receiving long-term mechanical ventilation and has been associated with increased mortality and poor outcomes. Allogeneic RBC transfusions are routinely administered to critically ill anemic patients, especially during lengthy stays in ICUs or in long-term acute care facilities. Although RBC transfusions are a physiologically rational approach to raising hemoglobin levels, they may increase the risk of complications and have been associated with higher mortality in critically ill patients. Treatment with epoetin alfa, an erythropoiesis-stimulating agent, as a means of reducing transfusion requirements has been studied in the critically ill and in patients receiving long-term mechanical ventilation. Promising results have been reported, including a potential survival benefit, although larger and more definitive studies are needed in order to establish whether raising hemoglobin levels affects clinical outcomes in patients receiving mechanical ventilation.

The morbidity and mortality associated with respiratory failure is, to a certain extent, iatrogenic. Mechanical ventilation, although the mainstay of treatment for respiratory distress syndrome, can result in physical trauma to lung tissue (ventilator-induced lung injury [VILI]). Strategies to alleviate VILI are often termed lung-protective strategies and are aimed at reducing overstretching and shear stresses associated with repetitive alveolar collapse and reopening. Lower tidal volumes during ventilation, maintenance of positive-end expiratory pressure, and high-frequency ventilation are the best-studied lung-protective strategies that appear to reduce VILI. Faster withdrawal from mechanical ventilation could also improve outcomes and lower the costs associated with care. To enhance the success of weaning from mechanical ventilation, the cooperative efforts of physicians and respiratory therapists are needed. These efforts involve the initiation of spontaneous-breathing trials, implementation of systematic weaning protocols, and optimization of individual patient interventions.

An accurate assessment of regional tissue oxygen delivery (DO(2)) may help the intensivist to attenuate end-organ damage in critically ill patients. Transport of oxygen from the ambient air to the mitochondria occurs by convection and diffusion, and is tightly regulated by neural and humoral factors. This article reviews the basic principles of DO(2) and the abnormal oxygen supply-demand relationship seen in patients with shock. It also discusses approaches to monitoring DO(2), including clinical symptoms/signs, acid-base status, and gas exchange, which provide global assessment, as well as gastric tonometry, which may reflect regional DO(2). Some new experimental methods, such as near-infrared spectroscopy and positron emission tomography, are still in development but may in the future provide useful clinical devices for quantifying the adequacy of regional tissue oxygenation in critically ill patients.

Complex physiologic interactions exist between oxygenation, hemoglobin, and cardiac output (Qt) in critically ill patients with respiratory failure. When any or all of these three critical factors fail, clinicians are challenged to support oxygen delivery (DO(2)) in order to avoid tissue hypoxia, end-organ damage, and high mortality rates. Many of the interventions performed to improve DO(2), including mechanical ventilation, blood transfusions, fluid management, and invasive monitoring of cardiac function, are accompanied by serious risks that can exacerbate the pathology of DO(2). This article provides an overview of oxygenation, hemoglobin, and Qt in patients with respiratory failure and highlights some of the current research that seeks safe and effective ways to improve DO(2) in these patients.

Prolonged postoperative cognitive dysfunction (POCD) is reported to occur frequently after cardiac surgery. However, it is rarely assessed in routine clinical practice and receives little attention. Although the cerebral consequences of cardiopulmonary bypass have been measured clinically, insights into the resulting molecular and pathologic events within the brain have only begun to be investigated. POCD is likely to impair quality of life and constitutes a large burden on society when elderly patients prematurely lose their independence. Numerous studies have reported that neurocognitive deficit is associated with heightened mortality, increased length of hospital stay, and discharge to a nursing home. This is linked with a tremendous demand for health-care resources. Because of the magnitude of the clinical problem, serious consideration must be directed toward understanding its etiology and the development of neuroprotective strategies. Clearly identifying the mechanisms of POCD is challenging. The purpose of this review is to discuss recent developments in our understanding of the pathophysiologic mechanisms, prevention, and treatments that have been designed to ameliorate brain dysfunction after cardiac surgery.

Diastolic dysfunction is increasingly recognized as a cause of hemodynamic instability in the perioperative setting. Difficulty weaning from cardiopulmonary bypass and an increased need for inotropic support can occur in the absence of systolic impairment. Diastolic dysfunction can also impede hemodynamic stabilization and weaning progress in the mechanically ventilated critically ill patient. The use of transesophageal echocardiography in the ICU can assist in diagnosing the presence and progression of diastolic impairment, which may help to target therapeutic interventions that lead to positive outcomes. This review summarizes the conventional and new echocardiographic modalities for evaluating diastolic function in the perioperative setting.

Patients with acute coronary syndrome (ACS) are at high risk for recurrent coronary events, sudden death, and all-cause mortality. Conventional revascularization therapies reduce the risk of further ischemia but do not affect the underlying atherosclerotic disease. Statins have a proven record in the secondary prevention of coronary heart disease. Furthermore, statins have been shown to exert varying degrees of pleiotropic effects, which may stabilize vulnerable atherosclerotic plaques. A compelling body of evidence from randomized controlled trials demonstrates that high-dose, potent statin therapy initiated immediately after an acute coronary event can significantly reduce early as well as longer-term morbidity and mortality. Furthermore, high-dose, potent statin therapy displays a reasonable safety profile. National guidelines now recommend that in patients with ACS, statin therapy should be initiated in hospital prior to discharge, irrespective of baseline low-density lipoprotein cholesterol levels, to improve clinical outcomes. Every effort should be made to ensure all eligible patients with ACS are initiated and maintained on statin therapy.

COPD is a major cause of death and disability worldwide. Treatment of COPD improves lung function but is unlikely to slow the steady downhill course of the disease or reduce mortality. In COPD, numerous abnormalities can be found outside the lung. These include systemic inflammation, cachexia, and skeletal muscle dysfunction. Thus, COPD has been called a systemic disease. Convincing data demonstrate that COPD causes neurohumoral activation. By precedents derived from chronic heart failure and other diseases characterized by neurohumoral activation, we propose that the negative consequences of neurohumoral activation, namely inflammation, cachexia, effects on ventilation, and skeletal muscle dysfunction, give rise to a self-perpetuating cycle that contributes to the pathogenesis of COPD, and which may involve respiratory muscle dysfunction as well as systemic inflammation. This concept may further help explain the increased cardiovascular morbidity and mortality in COPD patients. Currently, little is known about the effect of treatments directed at neurohumoral activation and COPD. As this aspect of COPD becomes better understood, new insights may direct novel therapeutic approaches.

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disorder of unknown etiology. The consensus statement released by the American Thoracic Society and European Respiratory Society has provided guidelines for the diagnosis, evaluation, and management of patients with IPF. These guidelines suggest the use of conventional treatment options including therapy with corticosteroids and immunosuppressive agents. The guidelines statement acknowledged the fact that there is little good-quality evidence to support the safety and efficacy of such therapies in patients with IPF. The statement was published in 2000 and was based on an extensive review of the literature up to and including December 1998. The goal of this review is to reexamine the treatment recommendations of the guidelines statement in the context of data that has since become available.

Idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP) is not well-understood. Current explanations of the natural history and pathogenesis of IPF/UIP are controversial, and ongoing research continues to investigate multiple hypotheses. A complete understanding of the natural history of IPF could potentially help to identify different mechanisms that are operative at the early, intermediate, and end stages of the disease. This knowledge could lead to the development of more effective therapeutic interventions that target stage-specific aberrant pathways involved in IPF/UIP pathogenesis.

Idiopathic pulmonary fibrosis (IPF) is a chronic disorder that is associated with a poorer prognosis than subacute idiopathic interstitial pneumonias (IIPs). IPF can be differentiated from other IIPs on the basis of its histologic pattern of usual interstitial pneumonia (UIP). Although a surgical lung biopsy specimen showing a UIP pattern is required for the definitive diagnosis of IPF, clinical criteria can be used in the absence of a lung biopsy specimen to make a likely diagnosis of IPF. The predictive value of these criteria largely depends on the expertise of the clinician and radiologist, but considerable interobserver variability exists even when evaluations are performed by experts in the field. Moreover, these criteria lead to misdiagnosis in about 25 to 35% of cases. Interobserver variability is reduced and diagnostic accuracy is improved in cases in which a diagnosis is made with a high degree of confidence. Diagnostic accuracy is also higher when the diagnosis is made by a core group of experts rather than by a referring center. The decision on whether or not to perform a surgical lung biopsy is difficult. It is clearly indicated in cases in which clinical or radiologic findings are atypical or when the diagnosis is made with a low degree of certainty.

The idiopathic interstitial pneumonias (IIPs) are a heterogeneous group of diffuse parenchymal diseases of unknown etiology. The pathologic classification of the IIPs has evolved considerably over the past 50 years and is based on the histopathologic pattern. A final, and clinically relevant, diagnosis often depends on integration of the histologic findings with the radiologic and clinical presentations. Specimens for histopathologic evaluation are best obtained by surgical wedge biopsy to allow the accurate recognition of the involvement patterns of these disorders. Two of the most common IIPs, idiopathic pulmonary fibrosis (IPF) and nonspecific interstitial pneumonia (NSIP), differ with respect to prognosis. Patients with IPF have a poorer prognosis than those with NSIP and most other IIPs. Within the NSIP diagnosis, a fibrotic pattern seems to be associated with a worse outcome than a cellular pattern. By distinguishing IPF from other clinicopathologic entities, clinicians should be better able to identify optimal treatment strategies and hopefully to improve patient outcomes.

Exaggerated vasospasm, platelet activation, and early graft occlusion are significant barriers to successful coronary artery bypass grafting (CABG). Interestingly, vascular smooth muscle and platelets are predominant sources of type-5 phosphodiesterase (PDE5) in the body, and this enzyme is specifically inhibited by PDE5 inhibitors (eg, sildenafil citrate). Together with endogenous nitric oxide, sildenafil can induce pulmonary and coronary vasodilation, precondition the myocardium, reduce platelet activation, and potentially reduce early graft occlusion. Currently, there are no published clinical trials investigating sildenafil in coronary surgery. Recent studies on the potential use of sildenafil strongly support its beneficial effects in a wide range of patients with cardiovascular diseases. Therefore, we sought to review the literature, explore the current hypothesis that the use of sildenafil in coronary surgery patients can be beneficial, and attempt to define its potential place in the setting of CABG.