Anticoagulant therapy is indicated during pregnancy for the prevention and treatment of VTE, for the prevention and treatment of systemic embolism in patients with mechanical heart valves, and, in combination with aspirin, for the prevention of pregnancy loss in women with APLA and previous pregnancy losses. Several questions concerning anticoagulant therapy remain unanswered. Oral anticoagulants are fetopathic, but the true risks of the warfarin embryopathy and CNS abnormalities are unknown. There is some evidence that warfarin embryopathy occurs only when oral anticoagulants are administered between the 6th and the 12th weeks of gestation and that oral anticoagulants may not be fetopathic when administered in the first 6 weeks of gestation. Oral anticoagulant therapy should be avoided in the weeks before delivery because of the risk of serious perinatal bleeding caused by the trauma of delivery to the anticoagulated fetus. The safety of aspirin during the first trimester of pregnancy is still a subject of debate. There is a concern about the efficacy of unfractionated heparin in the prevention of arterial embolism in pregnant women with mechanical heart valves. Finally, the role of LMWH and heparinoids and appropriate dosing have still to be determined. Because it is safe for the fetus, heparin is the anticoagulant of choice during pregnancy for situations in which its efficacy is established. The evidence for the efficacy of heparin for the prevention and treatment of VTE disorders during pregnancy is based on level IV studies. There is some doubt that heparin is effective for the prevention of systemic embolism in patients with mechanical heart valves. Low doses of heparin or poorly controlled heparin therapy are not effective in preventing systemic embolism in patients with mechanical heart valves.

To critically appraise and summarize the trials examining the addition of continuous positive airway pressure (CPAP) or noninvasive positive pressure ventilation (NPPV) to standard therapy on hospital mortality, need for endotracheal intubation, and predischarge left ventricular function in patients admitted to the hospital with cardiogenic pulmonary edema with gas exchange abnormalities.

Multiple complications associated with mechanical ventilation mandate that clinicians expeditiously define and reverse the pathophysiologic processes that precipitate respiratory failure and then, detect the earliest point that a patient can breathe without the ventilator. Over the past decade, numerous laboratory and clinical studies have been reported that may inform transformation of the "art of weaning" to the science of liberation. We review these studies and use them to formulate a systematic approach to assure early, safe, and successful liberation of patients from mechanical ventilation.

The incidence of the sepsis syndrome has increased dramatically in the last few decades. During this time, we have gained new insights into the pathophysiologic mechanisms leading to organ dysfunction in this syndrome. Yet, despite this increased knowledge and the use of novel therapeutic approaches, the mortality associated with the sepsis syndrome has remained between 30% and 40%. Appropriate antibiotic selection and hemodynamic support remain the cornerstone of treatment of patients with sepsis. Recent studies have failed to demonstrate a global oxygen debt in patients with sepsis. Furthermore, therapy aimed at increasing systemic oxygen delivery has failed to consistently improve patient outcome. The primary aim of the initial phase of resuscitation is to restore an adequate tissue perfusion pressure. Aggressive volume resuscitation is considered the best initial therapy for the cardiovascular instability of sepsis. Vasoactive agents are required in patients who remain hemodynamically unstable or have evidence of tissue hypoxia after adequate volume resuscitation.

In recent years, considerable advances have been made in treating primary pulmonary hypertension (PPH). These have provided a series of therapeutic options, ranging from the oral administration of calcium channel blockers to the continuous infusion of prostacyclin and/or lung transplantation. These therapeutic advances have highlighted the need for the better understanding of etiology and pathogenesis. Among the key uncertainties, the following are defined as leading uncertainties: (1) the nature of the initiating lesion; (2) the shared pathogenetic mechanisms that culminate in the pathologic lesions of PPH; (3) the molecular genetic bases for familial PPH and for susceptibility to PPH; (4) understanding of the obliterative-proliferative occlusive process in the small muscular pulmonary arteries; and (5) redefinition of "primary" and "secondary," ie, a revised nomenclature of pulmonary hypertension. A revised classification based on etiology is presented.

Because of the lack of adequate animal models, much of our knowledge of the pathogenesis of primary pulmonary hypertension has come from clinical experiences. The clinical response to vasodilators, prostenoids, and anticoagulants as treatments appear to correlate with the pathologic changes of medial hypertrophy, intimal proliferation, and thrombosis. Endothelial dysfunction, as a primary abnormality in primary pulmonary hypertension, provides an explanation for the pathologic and clinical expression of the disease in its various forms. Other clinical features of the disease, such as age of onset and rapidity of progression, may be influenced by triggers of the disease process and underlying individual genetic susceptibility. As we have been able to correlate the spectrum of clinical observations with advances in vascular biology, newer, more focused and effective therapies should begin to emerge.

Primary pulmonary hypertension (PPH), also referred to as unexplained or idiopathic pulmonary hypertension, is the clinical term used to describe a condition in patients for which we can find no underlying cause. Patients with PPH not uncommonly also have evidence of immune dysregulation: autoimmune disorders, drug therapy, or HIV infections. We will review these associations and possible relevant abnormalities in immune regulation with regard to how they may play a role in the pathogenesis of PPH. Autoantibody-HLA correlations have been observed in several subsets of PPH patients. In addition, a familial form of PPH has been described and characterized with linkage to chromosome 2q31-q32. The identification of a specific gene for PPH and the subsequent understanding of its effects will help us identify the basic cause of PPH. Furthering our understanding regarding the role(s) and significance of immunogenetic as well as genetic aspects of the pathogenesis and pathophysiology of PPH should also lead to improved therapeutic modalities for PPH.

We believe that the monoclonal cell expansion in primary pulmonary hypertension is the result of autonomous growth of stem cell-like endothelial cells, whereas the polyclonal proliferation in secondary pulmonary hypertension occurs as a response of endothelial cells to exogenous stimuli (like viral infection or high shear stress). In this context, we propose that different transcriptional and translational events govern the growth and expansion of monoclonal when compared with polyclonal pulmonary endothelial cells. The availability of antibodies directed against specific tyrosine kinase proteins involved in vasculogenesis/angiogenesis now permits the identification and localization of the components of such a misguided angiogenesis cell proliferation program in the pulmonary hypertensive vascular lesions.

Our laboratory has focused on the increased activity of an endogenous vascular elastase in the pathobiology of pulmonary hypertension and on the mechanisms by which it is upregulated and by which it orchestrates abnormal remodeling of the vessel wall, specifically the induction of growth factors, the induction of the glycoprotein tenascin, which amplifies the proliferative response, and fibronectin, which is critical to the process of smooth muscle migration in the context of neointimal formation. We explore strategies by which targetting these processes might arrest progression or induce regression of pulmonary vascular disease associated with unexplained pulmonary hypertension.

The characteristic arteriopathy of primary pulmonary hypertension (PPH) with attendant endothelial dysfunction provides an opportunity for enhanced cellular activation in the lung. Data from many laboratories support the concept of altered eicosanoid metabolism in PPH. Rigorously quantitative measurements of the excretion of metabolites of thromboxane A2 and prostacyclin support persistent platelet activation and inadequate endothelial response in patients with PPH. Recent studies measuring excretion of prostaglandin D2 metabolites suggest that additional cell sources, such as activated tissue macrophages, may also play a role in the observed elevation in thromboxane excretion and possibly in the pathogenesis of the vascular remodeling. Additional research examining in vivo cell activation in patients receiving therapy with long-term infusion of prostacyclin may further our understanding of the pathogenesis of PPH.

Plasma serotonin levels are markedly elevated in patients with primary pulmonary hypertension (PPH) and platelet levels of serotonin are low. Furthermore, plasma serotonin levels remain elevated after bilateral lung transplantation, in the absence of any pulmonary hypertension. Dexfenfluramine can cause the anorexigen-induced form of PPH that is clinically and histologically indistinguishable from PPH. We find that dexfenfluramine releases serotonin from platelets and inhibits its reuptake. These observations suggest that serotonin might be involved in, or be a marker for, the mechanism responsible for both forms of PPH. Dexfenfluramine causes inhibition of voltage-sensitive potassium (Kv) channels, membrane depolarization, and calcium entry in pulmonary artery smooth muscle cells and vasoconstriction in isolated perfused rat lungs. We have recently found that dexfenfluramine also inhibits Kv channels in megakaryocytes, the stem cell for platelets. In smooth muscle cells, taken from the pulmonary arteries of PPH patients, Kv channels appear to be dysfunctional. The underlying defect in PPH is likely to be an abnormality of one or more Kv channels in both pulmonary artery smooth muscle cells and platelets. Relatively few patients exposed to dexfenfluramine develop PPH. The factors responsible for susceptibility might be a difference in expression of potassium channels and/or a decrease in the endogenous production of nitric oxide.

Fenfluramine derivatives (Fds) are a well-established risk factor for primary pulmonary hypertension (PPH). We compared 62 Fd-PPH patients (61 women) evaluated in our center between 1986 and 1997 with 125 sex-matched PPH patients nonexposed to Fd referred during the same period (control PPH). In the Fd-PPH group, 33 patients (53%) used dexfenfluramine alone, 7 patients (11%) used fenfluramine alone, and 5 patients (8%) used both drugs. In 17 cases (27%), Fd use was associated with that of amphetamines. Most of the exposed patients used Fd for at least 3 months (81%). The interval between the onset of dyspnea and that of drug intake was 49+/-68 months (27 days to 23 years). At the time of diagnosis, Fd-PPH and control PPH were similar in terms of New York Heart Association functional class and symptoms. The two groups significantly differed only in terms of age (50+/-12 vs 40+/-14 years) and body mass index (28+/-6 vs 23+/-4). The two groups displayed similar severe baseline hemodynamics (total pulmonary vascular resistance: 32+/-12 vs 31+/-12 IU/m2), but the percentage of responders to acute vasodilator testing was higher in control PPH (27% vs 10%, p < 0.01). As a result, more patients were treated with oral vasodilators in the control PPH group (36% vs 16%, p < 0.01) and long-term epoprostenol infusion was more frequently used in the Fd-PPH group (52% vs 31%, p < 0.01). Overall survival was similar in the two groups with a 3-year survival rate of 50%.

Primary pulmonary hypertension (PPH) is a rare disease that affects young people predominantly of female gender. Early epidemiologic studies have shown that the diagnosis is usually made 1 to 2 years after symptoms onset, and the mean survival is reduced to 2 to 3 years thereafter. New insights into the pathogenesis of PPH by epidemiologic studies may be obtained through the utilization of informatic technologies coupled to a clear definition of the disease. Early stages of precapillary pulmonary hypertension could be identified through screening tests like echocardiography in populations with higher incidence, such as familial PPH and the conditions associated with pulmonary hypertension. These latter conditions are hemodynamically and pathologically similar to the primary form, and they can give insight into several possible aspects of the pathogenesis of PPH. Prospective registries are very useful in coordinating the collection of epidemiologic data, and new technologies, such as informatics, may improve the management and the continuous updating of the databases.