A multifaceted investigation into molecular associations of chronic thromboembolic pulmonary hypertension pathogenesis.

PURPOSE: Chronic thromboembolic pulmonary hypertension is characterized by incomplete thrombus resolution following acute pulmonary embolism, leading to pulmonary hypertension and right ventricular dysfunction. Conditions such as thrombophilias, dysfibrinogenemias, and inflammatory states have been associated with chronic thromboembolic pulmonary hypertension, but molecular mechanisms underlying this disease are poorly understood. We sought to characterize the molecular and functional features associated with chronic thromboembolic pulmonary hypertension using a multifaceted approach. METHODS: We utilized functional assays to compare clot lysis times between chronic thromboembolic pulmonary hypertension patients and multiple controls. We then performed immunohistochemical characterization of tissue from chronic thromboembolic pulmonary hypertension, pulmonary arterial hypertension, and healthy controls, and examined RNA expression patterns of cultured lymphocytes and pulmonary arterial specimens. We then confirmed RNA expression changes using immunohistochemistry, immunofluorescence, and Western blotting in pulmonary arterial tissue. RESULTS: Clot lysis times in chronic thromboembolic pulmonary hypertension patients are similar to multiple controls. Chronic thromboembolic pulmonary hypertension endarterectomized tissue has reduced expression of both smooth muscle and endothelial cell markers. RNA expression profiles in pulmonary arteries and peripheral blood lymphocytes identified differences in RNA transcript levels related to inflammation and growth factor signaling, which we confirmed using immunohistochemistry. Gene expression data also suggested significant alterations in metabolic pathways, and immunofluorescence and Western blot experiments confirmed that unglycosylated CD36 and adiponectin expression were increased in chronic thromboembolic pulmonary hypertension versus controls. CONCLUSIONS: Our data do not support impaired clot lysis underlying chronic thromboembolic pulmonary hypertension, but did demonstrate distinct molecular patterns present both in peripheral blood and in pathologic specimens of chronic thromboembolic pulmonary hypertension patients suggesting that altered metabolism may play a role in chronic thromboembolic pulmonary hypertension pathogenesis.

Randomized Trial of Video Laryngoscopy for Endotracheal Intubation of Critically Ill Adults.

OBJECTIVE: To evaluate the effect of video laryngoscopy on the rate of endotracheal intubation on first laryngoscopy attempt among critically ill adults. DESIGN: A randomized, parallel-group, pragmatic trial of video compared with direct laryngoscopy for 150 adults undergoing endotracheal intubation by Pulmonary and Critical Care Medicine fellows. SETTING: Medical ICU in a tertiary, academic medical center. PATIENTS: Critically ill patients 18 years old or older. INTERVENTIONS: Patients were randomized 1:1 to video or direct laryngoscopy for the first attempt at endotracheal intubation. MEASUREMENTS AND MAIN RESULTS: Patients assigned to video (n = 74) and direct (n = 76) laryngoscopy were similar at baseline. Despite better glottic visualization with video laryngoscopy, there was no difference in the primary outcome of intubation on the first laryngoscopy attempt (video 68.9% vs direct 65.8%; p = 0.68) in unadjusted analyses or after adjustment for the operator's previous experience with the assigned device (odds ratio for video laryngoscopy on intubation on first attempt 2.02; 95% CI, 0.82-5.02, p = 0.12). Secondary outcomes of time to intubation, lowest arterial oxygen saturation, complications, and in-hospital mortality were not different between video and direct laryngoscopy. CONCLUSIONS: In critically ill adults undergoing endotracheal intubation, video laryngoscopy improves glottic visualization but does not appear to increase procedural success or decrease complications.

Current concepts in the pathogenesis of chronic thromboembolic pulmonary hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by fibrotic obstruction of the proximal pulmonary arteries, and it is believed to result from incomplete thrombus resolution after acute pulmonary embolism. While treatment for this condition with surgery and medical therapy has improved outcomes, our understanding of the molecular mechanisms underlying CTEPH is incomplete. Numerous risk factors have been associated with the development of CTEPH, including but not limited to acquired thrombophilias and chronic inflammatory states. A minority of patients with CTEPH have an abnormal fibrin structure that may delay thrombus resolution. Recently, examination of resected scar material in patients with CTEPH has suggested that deficient angiogenesis may play a role in thrombus nonresolution, and there is increasing interest in factors that drive intravascular scar formation. An additional challenge in CTEPH research is understanding the etiology and implications of the small-vessel disease present in many patients. Future work will likely be directed at understanding the pathways important to disease pathogenesis through further examinations of resected tissue material, continued work on animal models, and genomic approaches to identify alterations in gene expression or gene variants that may distinguish CTEPH from other forms of pulmonary hypertension.

Severity of pulmonary hypertension and obesity are not associated with worse functional outcomes after pulmonary thromboendarterectomy.

Predictors of functional outcomes in patients with chronic thromboembolic pulmonary hypertension (CTEPH) undergoing pulmonary thromboendarterectomy (PTE) are important to identify preoperatively. We hypothesized that baseline severity of pulmonary hypertension and obesity would not be associated with 6-month functional outcomes after PTE. Clinical and hemodynamic data were collected on consecutive patients undergoing PTE from 2008 to 2014. Patients were stratified according to baseline pulmonary vascular resistance (PVR) and body mass index (BMI). Six-minute walk distance (6MWD), New York Heart Association functional class (FC), and echocardiography were assessed in each group at baseline and 6 months after PTE. Regression analyses were performed to evaluate for associations between functional outcomes and baseline PVR and BMI. Forty-two patients underwent PTE and had 6-month follow up data. In comparisons of patients with high and low baseline PVR, the baseline characteristics, distribution of disease, 6MWD, and FC were similar. Postoperative hemodynamics for both groups were similar. At 6 months, both groups achieved improvements in FC, and there were no between-group differences in the change in 6MWD or FC. In comparisons of obese and nonobese patients, perioperative and FC improvement were similar; however, obese patients achieved a greater improvement in 6MWD than nonobese patients (P = 0.04). In conclusion, our data suggest that baseline severity of CTEPH and obesity were not associated with worse functional outcome. Further studies are needed to confirm these results, as these findings could have implications for patient selection for PTE.

Randomized Trial of Apneic Oxygenation during Endotracheal Intubation of the Critically Ill.

RATIONALE: Hypoxemia is common during endotracheal intubation of critically ill patients and may predispose to cardiac arrest and death. Administration of supplemental oxygen during laryngoscopy (apneic oxygenation) may prevent hypoxemia. OBJECTIVES: To determine if apneic oxygenation increases the lowest arterial oxygen saturation experienced by patients undergoing endotracheal intubation in the intensive care unit. METHODS: This was a randomized, open-label, pragmatic trial in which 150 adults undergoing endotracheal intubation in a medical intensive care unit were randomized to receive 15 L/min of 100% oxygen via high-flow nasal cannula during laryngoscopy (apneic oxygenation) or no supplemental oxygen during laryngoscopy (usual care). The primary outcome was lowest arterial oxygen saturation between induction and 2 minutes after completion of endotracheal intubation. MEASUREMENTS AND MAIN RESULTS: Median lowest arterial oxygen saturation was 92% with apneic oxygenation versus 90% with usual care (95% confidence interval for the difference, -1.6 to 7.4%; P = 0.16). There was no difference between apneic oxygenation and usual care in incidence of oxygen saturation less than 90% (44.7 vs. 47.2%; P = 0.87), oxygen saturation less than 80% (15.8 vs. 25.0%; P = 0.22), or decrease in oxygen saturation greater than 3% (53.9 vs. 55.6%; P = 0.87). Duration of mechanical ventilation, intensive care unit length of stay, and in-hospital mortality were similar between study groups. CONCLUSIONS: Apneic oxygenation does not seem to increase lowest arterial oxygen saturation during endotracheal intubation of critically ill patients compared with usual care. These findings do not support routine use of apneic oxygenation during endotracheal intubation of critically ill adults. Clinical trial registered with www.clinicaltrials.gov (NCT 02051816).