Multidetector computed tomographic pulmonary angiography in patients with a high clinical probability of pulmonary embolism.

UNLABELLED: ESSENTIALS: When high probability of pulmonary embolism (PE), sensitivity of computed tomography (CT) is unclear. We investigated the sensitivity of multidetector CT among 134 patients with a high probability of PE. A normal CT alone may not safely exclude PE in patients with a high clinical pretest probability. In patients with no clear alternative diagnosis after CTPA, further testing should be strongly considered. BACKGROUND: Whether patients with a negative multidetector computed tomographic pulmonary angiography (CTPA) result and a high clinical pretest probability of pulmonary embolism (PE) should be further investigated is controversial. METHODS: This was a prospective investigation of the sensitivity of multidetector CTPA among patients with a priori clinical assessment of a high probability of PE according to the Wells criteria. Among patients with a negative CTPA result, the diagnosis of PE required at least one of the following conditions: ventilation/perfusion lung scan showing a high probability of PE in a patient with no history of PE, abnormal findings on venous ultrasonography in a patient without previous deep vein thrombosis at that site, or the occurrence of venous thromboembolism (VTE) in a 3-month follow-up period after anticoagulation was withheld because of a negative multidetector CTPA result. RESULTS: We identified 498 patients with a priori clinical assessment of a high probability of PE and a completed CTPA study. CTPA excluded PE in 134 patients; in these patients, the pooled incidence of VTE was 5.2% (seven of 134 patients; 95% confidence interval [CI] 1.5-9.0). Five patients had VTEs that were confirmed by an additional imaging test despite a negative CTPA result (five of 48 patients; 10.4%; 95% CI 1.8-19.1), and two patients had objectively confirmed VTEs that occurred during clinical follow-up of at least 3 months (two of 86 patients; 2.3%; 95% CI 0-5.5). None of the patients had a fatal PE during follow-up. CONCLUSIONS: A normal multidetector CTPA result alone may not safely exclude PE in patients with a high clinical pretest probability.

Prognostic significance of tricuspid annular displacement in normotensive patients with acute symptomatic pulmonary embolism.

BACKGROUND: Tricuspid annular plane systolic excursion (TAPSE) is an emerging prognostic indicator in patients with acute symptomatic pulmonary embolism (PE). METHODS AND RESULTS: We prospectively examined 782 normotensive patients with PE who underwent echocardiography in a multicenter study. As compared with patients with a TAPSE of > 1.6 cm, those with a TAPSE of ≤ 1.6 cm had increased systolic pulmonary artery pressure (53.7 ± 16.7 mmHg vs. 40.0 ± 15.5 mmHg, P < 0.001), right ventricle (RV) end-diastolic diameter (3.5 ± 0.8 cm vs. 3.0 ± 0.6 cm, P < 0.001), and RV to left ventricle end-diastolic diameter ratio (1.0 ± 0.3 vs. 0.8 ± 0.2, P < 0.001), and a higher prevalence of RV free wall hypokinesis (68% vs. 11%, P < 0.001). Patients with a TAPSE of ≤ 1.6 cm at the time of PE diagnosis were significantly more likely to die from any cause (hazard ratio [HR] 2.3; 95% confidence interval [CI] 1.2-4.7; P = 0.02) and from PE (HR 4.4; 95% CI 1.3-15.3; P = 0.02) during follow-up. In an external validation cohort of 1326 patients with acute PE enrolled in the international multicenter Registro Informatizado de la Enfermedad TromboEmbólica, a TAPSE of ≤ 1.6 cm remained a significant predictor of all-cause mortality (HR 2.1; 95% CI 1.3-3.2; P = 0.001) and PE-specific mortality (HR 2.5; 95% CI 1.2-5.2; P = 0.01). CONCLUSIONS: In normotensive patients with PE, TAPSE reflects right ventricular function. For these patients, TAPSE is independently predictive of survival.

D-dimer as a predictor of venous thromboembolism in acutely ill, hospitalized patients: a subanalysis of the randomized controlled MAGELLAN trial.

BACKGROUND: D-dimer concentrations have not been evaluated extensively as a predictor of increased venous thromboembolism (VTE) risk in acutely ill, hospitalized medical patients. OBJECTIVES: To analyze the relationships between D-dimer concentration, VTE and bleeding in the MAGELLAN trial (NCT00571649). PATIENTS/METHODS: This was a multicenter, randomized, controlled trial. Patients aged ≥ 40 years, hospitalized for acute medical illnesses with risk factors for VTE received subcutaneous enoxaparin 40 mg once daily for 10 ± 4 days then placebo up to day 35, or oral rivaroxaban 10 mg once daily for 35 ± 4 days. Patients (n = 7581) were grouped by baseline D-dimer ≤ 2 × or > 2 × the upper limit of normal. VTE and major plus non-major clinically relevant bleeding were recorded at day 10, day 35, and between days 11 and 35. RESULTS: The frequency of VTE was 3.5-fold greater in patients with high D-dimer concentrations. Multivariate analysis showed that D-dimer was an independent predictor of the risk of VTE (odds ratio 2.29 [95% confidence interval 1.75-2.98]), and had a similar association to established risk factors for VTE, for example cancer and advanced age. In the high D-dimer group, rivaroxaban was non-inferior to enoxaparin at day 10 and, unlike the low D-dimer group, superior to placebo at day 35 (P < 0.001) and days 11-35 (P < 0.001). In both groups, bleeding outcomes favored enoxaparin/placebo. CONCLUSIONS: Elevated baseline D-dimer concentrations may identify acutely ill, hospitalized medical patients at high risk of VTE for whom extended anticoagulant prophylaxis may provide greater benefit than for those with low D-dimer concentrations.

Delivery of intravenous treprostinil at low infusion rates using a miniaturized infusion pump in patients with pulmonary arterial hypertension.

PURPOSE: Treprostinil is approved for the treatment of pulmonary arterial hypertension (PAH) via continuous intravenous (IV) infusion. Treprostinil's anti-platelet aggregation characteristics and stability at room temperature may allow for low infusion rates (0.1-0.2 mL/hr) using a miniaturized infusion pump. METHODS: A 12-week, multi-center, open-label study in 12 adult PAH patients, evaluated the feasibility and safety of low-flow IV treprostinil administration via the 407C miniaturized pump. Patients receiving IV treprostinil at a stable dose were transitioned from their current CADD-Legacy pump to the 407C and were assessed for adverse events including catheter occlusions, pump alarms, and efficacy (six minute walk distance (6MWD), Borg Dyspnea Score (BDS), NYHA functional class, and PAH signs/symptoms). All patients were also maintained on therapeutic doses of warfarin, heparin or low molecular weight heparin throughout the study. RESULTS: Baseline mean (+/-SD) 6MWD was 477 +/- 76 m (n = 9) with mean BDS of 2.1 +/- 1.2 (n = 9). Week 12 mean 6MWD and BDS were 500 +/- 92 m and 2.3 +/- 1.7, respectively (n = 9). Four patients discontinued the study prematurely (3 AEs and 1 consent withdrawn). Adverse events included headache, flushing, and nausea. Pump complications occurred in 5 of 12 patients, and although no catheter occlusions occurred in any patient during the 12-week study, further study is needed regarding pump complications. CONCLUSION: This study demonstrates that treprostinil can be administered intravenously at infusion rates as low as 0.1 mL/hr for 12 weeks without catheter occlusions. Further studies are warranted because the potential for adverse events is of some concern.

The 6-min walk test (6MW) as an efficacy endpoint in pulmonary arterial hypertension clinical trials: demonstration of a ceiling effect.

BACKGROUND: PAH trials traditionally use 6MW as the primary endpoint. Concerns regarding a "ceiling effect" masking efficacy have led to exclusion of patients with milder disease from most trials (BL 6MW>450 m). STRIDE I evaluated the selective endothelin A receptor antagonist, sitaxsentan (SITAX), in a 12-week randomized, double-blind, trial (178 patients) employing placebo (PBO), 100 mg or 300 mg SITAX orally once daily in PAH and included patients with NYHA class II, congenital heart disease and a BL 6MW>450 m, groups often excluded from previous trials. METHODS: We analyzed 6MW effects For All Pts (intention-to treat) and those meeting Traditional enrollment criteria, defined as patients with NYHA class III or IV and 6MW< or =450 m at BL with idiopathic PAH or PAH related to connective tissue disease. The 100 mg and 300 mg SITAX arms are pooled based on similar treatment effects on 6MW. CONCLUSION: Existence of a "ceiling effect" is supported by these data. The magnitude of the treatment effect and statistical power when using 6MW as the endpoint. Comparisons between PAH trials that do not adjust for the effects of differing enrollment criteria require caution.

Prophylaxis strategies for patients with acute venous thromboembolism.

Pulmonary embolism is one of the most common causes of unexpected death in hospitalized patients and one of the top diseases leading to medical malpractice lawsuits. In order to effectively prevent venous thromboembolism (VTE), physicians must assess patients' risk factors and stratify their risk accordingly. Studies show general medical patients are most likely to suffer from deep vein thrombosis. Research also indicates that once-daily prophylaxis of such patients with 40 mg of the low-molecular-weight heparin (LMWH) enoxaparin is at least as effective or more effective as prophylaxis with unfractionated heparin, and may be preferable in some populations. It is now being recommended that hospitals develop formal strategies that address the prevention of thromboembolic complications and that general medical patients at risk of VTE receive unfractionated heparin or LMWH.

Prognostic value of serum carcinoembryonic antigen levels in patients who undergo lung transplantation.

BACKGROUND: Potential candidates for lung transplantation undergo a rigorous evaluation before transplant. Serum carcinoembryonic antigen (CEA) levels are used as a screening tool for occult malignancy in many lung transplant centers. We reviewed the pre-transplant CEA levels in lung transplant recipients in our institution to determine their prognostic significance. MATERIALS AND METHODS: We performed a retrospective database review of the first 200 patients that had undergone lung or heart-lung transplant at our institution (dates were 1/20/92-7/25/98). Data extracted included CEA levels (in ng/ml) at the time of lung transplant evaluation, demographic data, and survival. Patients had one of the following diagnoses: alpha-1-anti-trypsin deficiency, cystic fibrosis, chronic obstructive pulmonary disease, Eisenmenger's syndrome, idiopathic pulmonary fibrosis, primary pulmonary hypertension, sarcoidosis, or other. RESULTS: After excluding re-transplants, CEA results were available for 174 of 193 (90.2%) patients. CEA levels were elevated in 85 patients (48.9%) with a mean value of 3.15 +/- 2.55 (normal < 2.5). Solid organ cancers developed in 6 patients, at a median follow-up of 27.5 months after transplant. Their mean pre-transplant CEA level was similar to the rest of the group (3.52 +/- 2.05). Pre-transplant CEA levels did not predict post-transplant survival. Patients with idiopathic pulmonary fibrosis had the highest pre-transplant CEA levels, whereas patients with primary pulmonary hypertension and Eisenmenger's syndrome had the lowest (5.36 +/- 4.59, 0.83 +/- 0.56, and 1.43 +/- 0.81, respectively; p = 0.0001). CONCLUSIONS: CEA levels are high in patients with end-stage lung disease, especially IPF. Their levels appear to be a marker of the underlying disease and do not predict the post-transplant survival or development of malignancy.

Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study.

BACKGROUND: Endothelin 1, a powerful endogenous vasoconstrictor and mitogen, might be a cause of pulmonary hypertension. We describe the efficacy and safety of bosentan, a dual endothelin-receptor antagonist that can be taken orally, in patients with severe pulmonary hypertension. METHODS: In this double-blind, placebo-controlled study, 32 patients with pulmonary hypertension (primary or associated with scleroderma) were randomly assigned to bosentan (62.5mg taken twice daily for 4 weeks then 125 mg twice daily) or placebo for a minimum of 12 weeks. The primary endpoint was change in exercise capacity. Secondary endpoints included changes in cardiopulmonary haemodynamics, Borg dyspnoea index, WHO functional class, and withdrawal due to clinical worsening. Analysis was by intention to treat. FINDINGS: In patients given bosentan, the distance walked in 6 min improved by 70 m at 12 weeks compared with baseline, whereas it worsened by 6 m in those on placebo (difference 76 m [95% CI 12-139], p=0.021). The improvement was maintained for at least 20 weeks. The cardiac index was 1.0 L min(-1) m(-2) (95% CI 0.6-1.4, p<0.0001) greater in patients given bosentan than in those given placebo. Pulmonary vascular resistance decreased by 223 dyn s cm(-)(5) with bosentan, but increased by 191 dyn s cm(-5) with placebo (difference -415 [-608 to -221], p=0.0002). Patients given bosentan had a reduced Borg dyspnoea index and an improved WHO functional class. All three withdrawals from clinical worsening were in the placebo group (p=0.033). The number and nature of adverse events did not differ between the two groups. INTERPRETATION: Bosentan increases exercise capacity and improves haemodynamics in patients with pulmonary hypertension, suggesting that endothelin has an important role in pulmonary hypertension.

Safety of aerosolized amphotericin B lipid complex in lung transplant recipients.

BACKGROUND: Fungal infections remain an important cause of morbidity and mortality in lung transplant recipients. Aerosolized amphotericin B lipid complex (ABLC) may be more efficacious than conventional amphotericin B in the prevention of fungal infections in animal models, but experience with aerosolized ABLC in humans is lacking. METHODS: We conducted a prospective, noncomparative study designed to evaluate safety of aerosolized ABLC in lung or heart-lung transplant recipients. RESULTS: A total of 381 treatments were administered to 51 patients. Complete spirometry records were available for 335 treatments (69 in intubated patients, 266 in extubated patients). ABLC was subjectively well tolerated in 98% of patients. Pulmonary mechanics worsened by 20% or more posttreatment in less than 5% of all treatments. There were no significant adverse events related to study medication in any patient, and 1-year survival for all enrolled patients was 78%. CONCLUSION: Administration of nebulized ABLC is safe in the short-term and well-tolerated in lung transplant recipients. Additional prospective, randomized studies are needed to determine the efficacy of aerosolized ABLC alone or in conjunction with systemic therapies in the prevention of fungal infections in lung transplant recipients.

Infectious complications of lung transplantation.

Lung transplantation is associated with a high incidence of infection which directly impacts the morbidity and mortality associated with the procedure. In addition, these infections may also have immunologic consequences that play a role in the evolution of lung injury syndromes, resulting in earlier loss of graft than otherwise would be expected to occur. Although bacteria are responsible for the majority of infections following lung transplantation, fungal infections are associated with the highest mortality. This paper is an overview of the major infectious complications encountered in the lung transplant population. The epidemiology, prophylaxis, and treatment of infections following lung transplantation are critical areas for continued research.

Results of a randomized, prospective, multicenter trial of mycophenolate mofetil versus azathioprine in the prevention of acute lung allograft rejection.

BACKGROUND: Although the use of mycophenolate mofetil (MMF) has reduced the incidence of acute rejection in heart and kidney allograft recipients, its role in lung transplantation remains controversial. Therefore, we conducted a randomized, prospective, open-label, multicenter study in lung transplant recipients to determine whether MMF decreases episodes of acute allograft rejection when compared with azathioprine (AZA). METHODS: Between March of 1997 and January of 1999, 81 consecutive lung transplant recipients from two centers were prospectively randomized to receive cyclosporine, corticosteroids, and either 2 mg/kg per day of AZA or 1 g twice daily of MMF. The primary study endpoint was biopsy-proven acute allograft rejection over the first 6 months posttransplant. Secondary endpoints included clinical rejection, cytomegalovirus (CMV) infection, adverse events, and survival. Surveillance bronchoscopies were performed at 1, 3, and 6 months, or if clinically indicated. Pathologists interpreting the biopsy results were blinded to the randomization. Results were analyzed according to intention-to-treat. Between group comparisons of means and proportions were made by using two sample t tests and Fisher's exact tests, respectively. Six-month survival was calculated by the Kaplan-Meier method and compared by the log rank test. RESULTS: Thirty-eight patients were prospectively randomized to receive AZA, and 43 MMF. The incidence of biopsy proven grade II or greater acute allograft rejection at 6 months was 58% in the AZA group and 63% in the MMF group (P=0.82). The 6-month survival rates in the MMF and AZA groups were 86% and 82%, respectively (P=0.57). Rates of CMV infection and adverse events were not significantly different between the two groups. CONCLUSIONS: Acute rejection rates and overall survival at 6 months are similar in lung transplant recipients treated with either MMF- or AZA-based immunosuppression.

Lung transplantation after long-term mechanical ventilation : results and 1-year follow-up.

BACKGROUND: Long-term mechanical ventilation is considered as a relative or absolute contraindication for lung transplantation by most centers. We report on the results of transplantation in nine patients requiring long-term mechanical ventilation at two lung transplant centers. METHODS: The study group (group 1) consisted of nine patients receiving mechanical ventilation who underwent lung transplantation at either Duke University Medical Center or the University of Florida between 1992 and 1997. Patients in group 1 met the following criteria: they underwent exercise therapy with a physical therapist, and they were without panresistant bacterial airway colonization. The study patients that met these criteria spent at least 13 days receiving mechanical ventilation prior to transplantation. The control population (group 2; n = 65) consisted of all patients who underwent transplantation at either center in the calendar year 1997 who were ventilator independent. The 1-year survival rates in each group were calculated by the Kaplan-Meier method. The number of days required for extubation in each group were compared by the nonparametric Wilcoxon rank sum test. The FEV(1) value at 1 year was reported in each group. RESULTS: The 1-year survival rates were 78% and 83% in group 1 and group 2, respectively. The mean number of days required until extubation were 41 days in group 1 and 9 days in group 2 (p < 0.01). The allograft function was comparable in the two groups at 1 year. CONCLUSIONS: In a select population of ventilator-dependent patients, the 1-year survival rate is comparable to the standard lung transplant population. However, these ventilator-dependent patients require a significantly longer time until extubation than other transplant recipients.

Vena caval filters in pulmonary embolism.

Since the early 1900s, surgical interruption of the inferior vena cava (IVC) has been utilized in the management of venous thromboembolism (VTE). With the advent of newer-generation percutaneous devices in the late 1970s, their use and indications have expanded. The literature to support their efficacy, however, is limited to several case series and a single randomized controlled trial. Despite this, some have advocated the use of IVC filters as primary treatment of VTE in certain patient populations. In addition, there has been a large amount of interest in their use as prophylaxis against pulmonary embolism (PE) in high-risk patients. In the past 10 years, we have also seen the development and initial use of temporary devices, although their role in the management of this disease is even less certain. This article will review the recent literature on efficacy, complications, and indications for the use of IVC filters in the prevention and treatment of PE.

Inhaled nitric oxide selectively dilates pulmonary vasculature in adult patients with pulmonary hypertension, irrespective of etiology.

OBJECTIVES: We sought to compare the responses of patients with pulmonary hypertension from primary and secondary causes (PPH and SPH, respectively) to inhaled nitric oxide (iNO) in the cardiac catheterization laboratory. BACKGROUND: Pulmonary hypertension can lead to right ventricular pressure overload and failure. Although vasodilators are effective as therapy in patients with PPH, less is known about their role in adults with SPH. Inhaled nitric oxide can accurately predict the response to other vasodilators in PPH and could be similarly utilized in SPH. METHODS: Forty-two patients (26 to 77 years old) with pulmonary hypertension during cardiac catheterization received iNO. Demographic and hemodynamic data were collected. Their response to iNO was defined by a decrease of > or =20% in mean pulmonary artery (PA) pressure or pulmonary vascular resistance (PVR). RESULTS: Mean PA pressures and PVR were lower during nitric oxide (NO) inhalation in all patients with pulmonary hypertension. Seventy-eight percent of patients with PPH and 83% of patients with SPH were responders to iNO. A trend was seen toward a greater response with larger doses of NO in patients with SPH. Nitric oxide was a more sensitive predictor of response (79%), compared with inhaled oxygen (64%), and was well tolerated, with no evidence of systemic effects. Elevation in right ventricular end-diastolic pressure appeared to predict poor vasodilatory response to iNO. CONCLUSIONS: Nitric oxide is a safe and effective screening agent for pulmonary vasoreactivity. Regardless of etiology of pulmonary hypertension, pulmonary vasoreactivity is frequently demonstrated with the use of NO. Right ventricular diastolic dysfunction may predict a poor vasodilator response.