Kamal K. Mubarak

An Official American Thoracic Society Clinical Practice Guideline: Diagnosis, Risk Stratification, and Management of Pulmonary Hypertension of Sickle Cell Disease

BACKGROUND In adults with sickle cell disease (SCD), an increased tricuspid regurgitant velocity (TRV) measured by Doppler echocardiography, an increased serum N-terminal pro-brain natriuretic peptide (NT-pro-BNP) level, and pulmonary hypertension (PH) diagnosed by right heart catheterization (RHC) are independent risk factors for mortality. METHODS A multidisciplinary committee was formed by clinician-investigators experienced in the management of patients with PH and/or SCD. Clinically important questions were posed, related evidence was appraised, and questions were answered with evidence-based recommendations. Target audiences include all clinicians who take care of patients with SCD. RESULTS Mortality risk stratification guides decision making. An increased risk for mortality is defined as a TRV equal to or greater than 2.5 m/second, an NT-pro-BNP level equal to or greater than 160 pg/ml, or RHC-confirmed PH. For patients identified as having increased mortality risk, we make a strong recommendation for hydroxyurea as first-line therapy and a weak recommendation for chronic transfusions as an alternative therapy. For all patients with SCD with elevated TRV alone or elevated NT-pro-BNP alone, and for patients with SCD with RHC-confirmed PH with elevated pulmonary artery wedge pressure and low pulmonary vascular resistance, we make a strong recommendation against PAH-specific therapy. However, for select patients with SCD with RHC-confirmed PH who have elevated pulmonary vascular resistance and normal pulmonary capillary wedge pressure, we make a weak recommendation for either prostacyclin agonist or endothelin receptor antagonist therapy and a strong recommendation against phosphodiesterase-5 inhibitor therapy. CONCLUSIONS Evidence-based recommendations for the management of patients with SCD with increased mortality risk are provided, but will require frequent reassessment and updating.

A review of prostaglandin analogs in the management of patients with pulmonary arterial hypertension

Pulmonary arterial hypertension is a chronic, progressive disease characterized by elevation of pulmonary artery pressure and pulmonary vascular resistance that ultimately results in right ventricular failure and death. Multiple mechanisms are involved in the pathogenesis of pulmonary arterial hypertension, including prostacyclin, endothelin-1, and nitric oxide pathways amongst others. The first agent to be approved for the treatment of pulmonary arterial hypertension was synthetic prostacyclin (epoprostenol), followed by prostaglandin analogs (iloprost, treprostinil, and beraprost [Japan and Korea]), which act on prostaglandin receptors. This article reviews the physiology and pathophysiology of prostanoids, summarizes key clinical studies of prostaglandin analogs for the treatment of pulmonary arterial hypertension, and discusses important pharmacokinetic and pharmacodynamic distinctions between the various prostaglandin analogs. Different prostaglandin analogs have disparate binding affinities for the various prostaglandin receptors and different G-protein-coupled receptor interactions, which may result in varying clinical efficacy and safety depending on the target tissue. Differences in formulation, route of administration, effectiveness, and safety may all play a role in deciding which prostaglandin analog to prescribe for an individual patient. Head-to-head studies will be needed to confirm differences in efficacy and safety for the various prostaglandin analogs.

Exercise capacity and haemodynamics in patients with sickle cell disease with pulmonary hypertension treated with bosentan: results of the ASSET studies

Doppler‐defined pulmonary hypertension (PH) in sickle cell disease (SCD) is associated with 40% mortality at 40 months. To assess the effect of bosentan in SCD‐PH, two randomized, double‐blind, placebo‐controlled, 16‐week studies were initiated. Safety concerns are particularly relevant in SCD due to comorbid conditions. ASSET‐1 and ‐2 enrolled patients with pulmonary arterial hypertension (PAH) and pulmonary venous hypertension (PH), respectively. Haemodynamics and 6‐min walk distance (6MWD) were obtained at baseline and week 16. The studies were terminated due to slow site initiation and patient enrolment (n = 26). Bosentan appeared to be well tolerated. Although sample sizes were limited, in ASSET‐1 at baseline, 6MWD correlated with cardiac output (CO; P = 0·006) with non‐significant inverse correlations between 6MWD and pulmonary vascular resistance (PVR; P = 0·07) and between 6MWD and right atrial pressure (P = 0·08). In ASSET‐2 at baseline, there was a non‐significant correlation between 6MWD and CO (P = 0·06). Due to limited sample sizes, efficacy endpoints were not analysed. However, in both studies, non‐significant increases in CO were observed with bosentan compared to placebo. Similarly, non‐significant decreases in PVR were observed with bosentan. Limited data in SCD‐PH suggest that a low 6MWD predicts a low CO. Standard‐dose bosentan appears to be well tolerated. Further investigation is warranted. Clinicaltrials.gov registration numbers NCT00310830, NCT00313196, NCT00360087.

Mycobacterium-Mediated Chemokine Expression in Pleural Mesothelial Cells: Role of C-C Chemokines in Tuberculous Pleurisy

Pulmonary tuberculosis is characterized by granulomatous inflammation with an extensive infiltration of mononuclear phagocytes, but the mechanisms of phagocyte recruitment to the pleural space is unknown. In this study, pleural fluid from patients with tuberculosis contained significantly (P<.001) more biologically active MIP-1alpha and MCP-1 (C-C cytokines) than did effusions from patients with congestive heart failure. Antigenic MIP-1alpha and MCP-1 was detected by immunocytochemistry in pleural biopsy sections of patients with tuberculous pleurisy. In vitro, pleural mesothelial cells stimulated with bacille Calmette-Guérin (BCG) or interferon (IFN)-gamma produced MIP-1alpha and MCP-1. Reverse transcription-polymerase chain reaction studies confirmed that both BCG and IFN-gamma induced MIP-1alpha and MCP-1 expression in mesothelial cells, demonstrating that mesothelial cell-derived C-C chemokines play a biologically important role in the recruitment of mononuclear cells to the pleural space.

Pulmonary vasodilator testing and use of calcium channel blockers in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) encompasses a number of diseases responsible for a specific set of hemodynamic findings during right heart catheterization. During initial workup, pulmonary vasodilator testing is performed. A positive acute pulmonary vasodilator test predicts better survival and response to calcium channel blocker (CCB) therapy. There is lack of consensus on the preferred agent for determining acute pulmonary vasoreactivity. The ACCP guidelines and the 4(th) World Symposium on Pulmonary Hypertension support the use of intravenous epoprostenol or nitric oxide (NO) as the preferred agents for pulmonary vasodilator testing. A decrease in the mean pulmonary artery pressure by at least 10 mmHg to reach an absolute value of 40 mmHg or less without a decrease in cardiac output is currently considered a positive pulmonary vasodilator test. A positive test by the current recommended criteria is observed in about 10-15% of patients with idiopathic PAH. Approximately half of these patients will experience long-term benefits with CCBs. A positive test may select patients with an earlier or less aggressive form of disease, which may carry a better prognosis. A positive vasodilator test is observed very infrequently in patients with pulmonary arterial hypertension other than idiopathic PAH or anorexigen associated PAH. This article reviews the literature regarding pulmonary vasodilator testing and use of CCB therapy in patients with PAH, while identifying the gaps in knowledge concerning this diagnostic procedure.

Pleural mesothelial cell transformation into myofibroblasts and haptotactic migration in response to TGF-β1 in vitro

Idiopathic pulmonary fibrosis (IPF) is a disease of unknown etiology characterized by the development of subpleural foci of myofibroblasts that contribute to the exuberant fibrosis noted in the pulmonary parenchyma. Pleural mesothelial cells (PMC) are metabolically dynamic cells that cover the lung and chest wall as a monolayer and are in intimate proximity to the underlying lung parenchyma. The precise role of PMC in the pathogenesis of pulmonary parenchymal fibrosis remains to be identified. Transforming growth factor (TGF)-beta1, a cytokine known for its capacity to induce proliferative and transformative changes in lung cells, is found in significantly higher quantities in the lungs of patients with IPF. High levels of TGF-beta1 in the subpleural milieu may play a key role in the transition of normal PMC to myofibroblasts. Here we demonstrate that PMC activated by TGF-beta1 undergo epithelial-mesenchymal transition (EMT) and respond with haptotactic migration to a gradient of TGF-beta1 and that the transition of PMC to myofibroblasts is dependent on smad-2 signaling. The EMT of PMC was marked by upregulation of alpha-smooth muscle actin (alpha-SMA), fibroblast specific protein-1 (FSP-1), and collagen type I expression. Cytokeratin-8 and E-cadherin expression decreased whereas vimentin remained unchanged over time in transforming PMC. Knockdown of smad-2 gene by silencing small interfering RNA significantly suppressed the transition of PMC to myofibroblasts and significantly inhibited the PMC haptotaxis. We conclude that PMC undergo EMT when exposed to TGF-beta1, involving smad-2 signaling, and PMC may be a possible source of myofibroblasts in IPF.

Parenchymal trafficking of pleural mesothelial cells in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is characterised by myofibroblast proliferation leading to architectural destruction. Neither the origin nor the continued proliferation of myofibroblasts is well understood. Explanted human IPF lungs were stained by immunohistochemistry for calretinin, a marker of pleural mesothelial cells (PMCs). Chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF) lungs acted as controls. The number of PMCs per 100 nucleated cells and per photomicrograph was estimated along with the Ashcroft score of fibrosis. Mouse PMCs expressing green fluorescent protein (GFP) or labelled with nanoparticles were injected into the pleural space of mice given intranasal transforming growth factor (TGF)-&bgr;1. Mouse lungs were lavaged and examined for the presence of GFP, smooth muscle &agr;-actin (&agr;-SMA) and calretinin. Calretinin-positive PMCs were found throughout IPF lungs, but not in COPD or CF lungs. The number of PMCs correlated with the Ashcroft score. In mice, nanoparticle-laden PMCs were recoverable by bronchoalveolar lavage, depending on the TGF-&bgr;1 dose. Fluorescent staining showed &agr;-SMA expression in GFP-expressing PMCs, with co-localisation of GFP and &agr;-SMA. PMCs can traffic through the lung and show myofibroblast phenotypic markers. PMCs are present in IPF lungs, and their number correlates with IPF severity. Since IPF presumably begins subpleurally, PMCs could play a pathogenetic role via mesothelial–mesenchymal transition.

Prevalence of pulmonary hypertension in end-stage cystic fibrosis and correlation with survival

BACKGROUND Limited information is available about the prevalence of pulmonary hypertension diagnosed by right heart catheterization (RHC) in patients with cystic fibrosis being evaluated for lung transplantation. It is unclear whether there are factors that can predict the presence of pulmonary hypertension and whether the presence of pulmonary hypertension influences patient outcomes. METHODS The study included 57 unique and consecutive adult patients (33 women) with cystic fibrosis who underwent lung transplant evaluation at the University of Florida. RESULTS The average age at evaluation was 31.8 +/- 10 years. All patients were in New York Heart Association class III. The median (interquartile range) of mean pulmonary artery pressure (PAP) was 26 (24-30) mm Hg. Thirty-six patients (63.2%) had pulmonary hypertension (mean PAP >or= 25 mm Hg) and had a significantly higher degree of hypoxemia and oxygen requirements. Echocardiography evidenced limitations for the diagnosis of pulmonary hypertension. The 5-year mortality rate was similar in patients with or without pulmonary hypertension; however, it was higher in 7 patients identified by cluster analysis and in patients with a left ventricular ejection fraction < 55%. CONCLUSIONS More than half of our patients with cystic fibrosis and advanced lung disease have elevation of PAP, usually of mild degree. A lower left ventricular ejection fraction, but not the presence of pulmonary hypertension, was associated with worse outcomes.

Hypoxia-induced endothelial CX3CL1 triggers lung smooth muscle cell phenotypic switching and proliferative expansion

Distal arterioles with limited smooth muscles help maintain the high blood flow and low pressure in the lung circulation. Chronic hypoxia induces lung distal vessel muscularization. However, the molecular events that trigger alveolar hypoxia-induced peripheral endothelium modulation of vessel wall smooth muscle cell (SMC) proliferation and filling of nonmuscular areas are unclear. Here, we investigated the role of CX3CL1/CX3CR1 system in endothelial-SMC cross talk in response to hypoxia. Human lung microvascular endothelial cells responded to alveolar oxygen deficiency by overproduction of the chemokine CX3CL1. The CX3CL1 receptor CX3CR1 is expressed by SMCs that are adjacent to the distal endothelium. Hypoxic release of endothelial CX3CL1 induced SMC phenotypic switching from the contractile to the proliferative state. Inhibition of CX3CR1 prevented CX3CL1 stimulation of SMC proliferation and monolayer expansion. Furthermore, CX3CR1 deficiency attenuated spiral muscle expansion, distal vessel muscularization, and pressure elevation in response to hypoxia. Our findings indicate that the capillary endothelium relies on the CX3CL1-CX3CR1 axis to sense alveolar hypoxia and promote peripheral vessel muscularization. These results have clinical significance in the development of novel therapeutics that target mechanisms of distal arterial remodeling associated with pulmonary hypertension induced by oxygen deficiency that is present in people living at high altitudes and patients with obstructive lung diseases.

A lost guidewire.

Sir, Central venous cannulation is one of the most common procedures performed in any intensive care unit. The incidence of mechanical complications i.e., pneumothorax, arterial injury etc., are reduced with an experienced operator and routine use of ultrasound guidance for insertion of the catheter.[1] Various complications related to guidewire can happen during the insertion process e.g., kinking, loss, breakage, and knotting of guidewire. Some guidewire problems e.g., breakage or loss can lead to adverse consequences.[2] Here, we describe a case where a guide wire was lost during insertion of a femoral central line and was not recognized until several hours later. A 46-year-old woman was diagnosed with severe community acquired pneumonia, respiratory failure, septic shock, and acute renal failure. In the emergency room, a right subclavian vein central venous line was placed and after initial volume resuscitation, vasopressors were started. She was intubated, placed on mechanical ventilation and transferred to the medical intensive care unit. Over the next 24-h, a left peripherally inserted central venous catheter and a right femoral central venous line were placed to obtain adequate access for monitoring and treatment. A routine chest X-ray performed 18 h after the placement of the right femoral central venous line, detected a guidewire lodged partly in the heart [Figure 1 and Figure 2a, arrowhead]. With bedside ultrasonography, the guidewire could be traced in the inferior vena cava (IVC) up to the level of the renal veins [Figure 2b, sagittal plane view of IVC with guidewire (arrow); Figure 2c shows transverse section of IVC at the confluence of hepatic veins, with guidewire (arrow); Figure 2d shows transverse section of IVC at the level of renal veins showing guidewire (arrow)]. She was taken to the interventional radiology suite where under fluoroscopic guidance, the right femoral catheter was carefully removed. The proximal straight end of the guidewire was found inside the tip of the central venous catheter. It was grasped and removed uneventfully with a steady gentle pull. Figure 1 Chest X-ray showing misplaced guide wire Figure 2 (a) Chest X-ray showing a guide wire lodged partly in the heart (arrowhead); (b) longitudinal view of inferior vena cava (IVC) with guide wire (arrow); (c) transverse section of IVC at the confluence of hepatic veins, with guidewire (arrow); (d) transverse ... Loss of the guidewire inside the vessel is a serious complication of central venous line placement. In this case report, the guidewire was lost during insertion and not recognized by an operator, judged competent in a residency training setting to perform the procedure independently, until many hours later. Similar complications have been reported in literature.[3,4] Serious consequences include perforation of vascular and cardiac structures. Difficult management issues arise as it often involves transport of clinically unstable patients outside intensive care unit environment for removal of the guidewire. We believe that the complication happened due to failure to adhere to good practice, e.g., withdrawing the guidewire until the proximal end comes out of the catheter port and holding the guidewire while advancing the catheter beyond the skin entry site. A meticulous attention to standard precautions can prevent this untoward and avoidable complication.