Darren B. Taichman

Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): a randomised controlled trial.

BACKGROUND Approaches to removal of sedation and mechanical ventilation for critically ill patients vary widely. Our aim was to assess a protocol that paired spontaneous awakening trials (SATs)-ie, daily interruption of sedatives-with spontaneous breathing trials (SBTs). METHODS In four tertiary-care hospitals, we randomly assigned 336 mechanically ventilated patients in intensive care to management with a daily SAT followed by an SBT (intervention group; n=168) or with sedation per usual care plus a daily SBT (control group; n=168). The primary endpoint was time breathing without assistance. Data were analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00097630. FINDINGS One patient in the intervention group did not begin their assigned treatment protocol because of withdrawal of consent and thus was excluded from analyses and lost to follow-up. Seven patients in the control group discontinued their assigned protocol, and two of these patients were lost to follow-up. Patients in the intervention group spent more days breathing without assistance during the 28-day study period than did those in the control group (14.7 days vs 11.6 days; mean difference 3.1 days, 95% CI 0.7 to 5.6; p=0.02) and were discharged from intensive care (median time in intensive care 9.1 days vs 12.9 days; p=0.01) and the hospital earlier (median time in the hospital 14.9 days vs 19.2 days; p=0.04). More patients in the intervention group self-extubated than in the control group (16 patients vs six patients; 6.0% difference, 95% CI 0.6% to 11.8%; p=0.03), but the number of patients who required reintubation after self-extubation was similar (five patients vs three patients; 1.2% difference, 95% CI -5.2% to 2.5%; p=0.47), as were total reintubation rates (13.8%vs 12.5%; 1.3% difference, 95% CI -8.6% to 6.1%; p=0.73). At any instant during the year after enrolment, patients in the intervention group were less likely to die than were patients in the control group (HR 0.68, 95% CI 0.50 to 0.92; p=0.01). For every seven patients treated with the intervention, one life was saved (number needed to treat was 7.4, 95% CI 4.2 to 35.5). INTERPRETATION Our results suggest that a wake up and breathe protocol that pairs daily spontaneous awakening trials (ie, interruption of sedatives) with daily spontaneous breathing trials results in better outcomes for mechanically ventilated patients in intensive care than current standard approaches and should become routine practice.

Validation of 6-Minute Walk Distance as a Surrogate End Point in Pulmonary Arterial Hypertension Trials

Background— Nearly all available treatments for pulmonary arterial hypertension have been approved based on change in 6-minute walk distance (&Dgr;6MWD) as a clinically important end point, but its validity as a surrogate end point has never been shown. We aimed to validate the difference in &Dgr;6MWD against the probability of a clinical event in pulmonary arterial hypertension trials. Methods and Results— First, to determine whether &Dgr;6MWD between baseline and 12 weeks mediated the relationship between treatment assignment and development of clinical events, we conducted a pooled analysis of patient-level data from the 10 randomized placebo-controlled trials previously submitted to the US Food and Drug Administration (n=2404 patients). Second, to identify a threshold effect for the &Dgr;6MWD that indicated a statistically significant reduction in clinical events, we conducted a meta-regression among 21 drug/dose-level combinations. &Dgr;6MWD accounted for 22.1% (95% confidence interval, 12.1%– 31.1%) of the treatment effect (P<0.001). The meta-analysis showed an average difference in &Dgr;6MWD of 22.4 m (95% confidence interval, 17.4–27.5 m), favoring active treatment over placebo. Active treatment decreased the probability of a clinical event (summary odds ratio, 0.44; 95% confidence interval, 0.33–0.57). The meta-regression revealed a significant threshold effect of 41.8 m. Conclusions— Our results suggest that &Dgr;6MWD does not explain a large proportion of the treatment effect, has only modest validity as a surrogate end point for clinical events, and may not be a sufficient surrogate end point. Further research is necessary to determine whether the threshold value of 41.8 m is valid for long-term outcomes or whether it differs among trials using background therapy or lacking placebo controls entirely.

Clinical risk factors for portopulmonary hypertension.

Portopulmonary hypertension affects up to 6% of patients with advanced liver disease, but the predictors and biologic mechanism for the development of this complication are unknown. We sought to determine the clinical risk factors for portopulmonary hypertension in patients with advanced liver disease. We performed a multicenter case‐control study nested within a prospective cohort of patients with portal hypertension recruited from tertiary care centers. Cases had a mean pulmonary artery pressure > 25 mm Hg, pulmonary vascular resistance > 240 dynes · second · cm−5, and pulmonary capillary wedge pressure ≤ 15 mm Hg. Controls had a right ventricular systolic pressure < 40 mm Hg (if estimable) and normal right‐sided cardiac morphology by transthoracic echocardiography. The study sample included 34 cases and 141 controls. Female sex was associated with a higher risk of portopulmonary hypertension than male sex (adjusted odds ratio = 2.90, 95% confidence interval 1.20‐7.01, P = 0.018). Autoimmune hepatitis was associated with an increased risk (adjusted odds ratio = 4.02, 95% confidence interval 1.14‐14.23, P = 0.031), and hepatitis C infection was associated with a decreased risk (adjusted odds ratio = 0.24, 95% confidence interval 0.09‐0.65, P = 0.005) of portopulmonary hypertension. The severity of liver disease was not related to the risk of portopulmonary hypertension. Conclusion: Female sex and autoimmune hepatitis were associated with an increased risk of portopulmonary hypertension, whereas hepatitis C infection was associated with a decreased risk in patients with advanced liver disease. Hormonal and immunologic factors may therefore be integral to the development of portopulmonary hypertension. (HEPATOLOGY 2008.)

Pharmacologic Therapy for Pulmonary Arterial Hypertension in Adults: CHEST Guideline and Expert Panel Report

OBJECTIVE Choices of pharmacologic therapies for pulmonary arterial hypertension (PAH) are ideally guided by high-level evidence. The objective of this guideline is to provide clinicians advice regarding pharmacologic therapy for adult patients with PAH as informed by available evidence. METHODS This guideline was based on systematic reviews of English language evidence published between 1990 and November 2013, identified using the MEDLINE and Cochrane Library databases. The strength of available evidence was graded using the Grades of Recommendations, Assessment, Development, and Evaluation methodology. Guideline recommendations, or consensus statements when available evidence was insufficient to support recommendations, were developed using a modified Delphi technique to achieve consensus. RESULTS Available evidence is limited in its ability to support high-level recommendations. Therefore, we drafted consensus statements to address many clinical questions regarding pharmacotherapy for patients with PAH. A total of 79 recommendations or consensus statements were adopted and graded. CONCLUSIONS Clinical decisions regarding pharmacotherapy for PAH should be guided by high-level recommendations when sufficient evidence is available. Absent higher level evidence, consensus statements based upon available information must be used. Further studies are needed to address the gaps in available knowledge regarding optimal pharmacotherapy for PAH.

Genetic Risk Factors for Portopulmonary Hypertension in Patients with Advanced Liver Disease

RATIONALE Portopulmonary hypertension (PPHTN) occurs in 6% of liver transplant candidates. The pathogenesis of this complication of portal hypertension is poorly understood. OBJECTIVES To identify genetic risk factors for PPHTN in patients with advanced liver disease. METHODS We performed a multicenter case-control study of patients with portal hypertension. Cases had a mean pulmonary artery pressure >25 mm Hg, pulmonary vascular resistance >240 dynes.s(-1).cm(-5), and pulmonary capillary wedge pressure < or =15 mm Hg. Controls had a right ventricular systolic pressure < 40 mm Hg (if estimated) and normal right-sided cardiac morphology by transthoracic echocardiography. We genotyped 1,079 common single nucleotide polymorphisms (SNPs) in 93 candidate genes in each patient. MEASUREMENTS AND MAIN RESULTS The study sample included 31 cases and 104 controls. Twenty-nine SNPs in 15 candidate genes were associated with the risk of PPHTN (P < 0.05). Multiple SNPs in the genes coding for estrogen receptor 1, aromatase, phosphodiesterase 5, angiopoietin 1, and calcium binding protein A4 were associated with the risk of PPHTN. The biological relevance of one of the aromatase SNPs was supported by an association with plasma estradiol levels. CONCLUSIONS Genetic variation in estrogen signaling and cell growth regulators is associated with the risk of PPHTN. These biologic pathways may elucidate the mechanism for the development of PPHTN in certain patients with severe liver disease.

Portopulmonary Hypertension: A Report From the US-Based REVEAL Registry

BACKGROUND We evaluated survival and hospitalization rates in patients with group 1 portopulmonary hypertension (PoPH) in the Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL Registry). METHODS The REVEAL Registry is a multicenter, observational, US-based study evaluating demographics and management of patients with pulmonary arterial hypertension (PAH). Outcomes were examined using Kaplan-Meier time-to-event estimates and compared with patients with idiopathic PAH (IPAH) or familial PAH (FPAH). RESULTS One hundred seventy-four patients with PoPH were enrolled in the REVEAL Registry (IPAH/FPAH; n = 1,478) from March 2006 to December 2009. Mean age was 53 ± 10 years, 52% were female, 32% were newly diagnosed, and 6% were New York Heart Association/World Health Organization functional class IV. Outcome parameters were worse for PoPH vs IPAH/FPAH, respectively: 2-year survival from enrollment (67% vs 85%, P < .001), 5-year survival from time of diagnosis (40% vs 64%, P < .001), and 2-year freedom from all-cause hospitalization (49% vs 59%, P = .019). However, despite worse outcomes, hemodynamic parameters at diagnosis were better for PoPH vs IPAH/FPAH, respectively: mean pulmonary artery pressure (49 mm Hg vs 53 mm Hg, P < .001), mean right atrial pressure (9 mm Hg vs 10 mm Hg, P = .005), pulmonary vascular resistance (8 Wood units vs 12 Wood units, P < .001), and cardiac output (5 L/min vs 4 L/min, P < .001). Compared with patients with IPAH/FPAH, patients with PoPH were less likely to be on a PAH-specific therapy at enrollment (P < .001), suggesting potential delays in therapy for patients with PoPH. CONCLUSIONS Patients with PoPH had significantly poorer survival and all-cause hospitalization rates compared with patients with IPAH/FPAH, despite having better hemodynamics at diagnosis. Further studies should investigate such outcomes and differences in treatment patterns. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT00370214; URL: www.clinicaltrials.gov.

Hemodynamics and survival of patients with portopulmonary hypertension.

It is not known whether patients with pulmonary arterial hypertension associated with portal hypertension (portopulmonary hypertension (PPHTN) have different disease characteristics from those of patients with other forms of pulmonary arterial hypertension. We performed a retrospective cohort study of patients with PPHTN and patients with pulmonary arterial hypertension that was idiopathic, familial, or associated with anorexigen use (IPAH) to determine whether hemodynamics or survival were different between these groups. We included consecutive patients who underwent initial pulmonary artery catheterization and vasodilator testing at our center between January 1997 and May 2001 and who were followed until January 2004. Patients with PPHTN (N = 13) had a higher cardiac index and lower pulmonary vascular resistance than patients with IPAH (N = 33) (P ≤ 0.001). Right atrial pressure and pulmonary artery pressure were similar between the groups. Patients with PPHTN had a higher risk of death in multivariate analysis (hazard ratio: [HR] = 2.8, 95% CI 1.04‐7.4; P = 0.04). These findings were not affected by adjustment for differences in laboratory values, hemodynamics, or therapy. In conclusion, patients with PPHTN have a higher risk of death than that of patients with IPAH, despite having a higher cardiac index and lower pulmonary vascular resistance. Future studies of the specific mechanisms of and therapy for pulmonary arterial hypertension should focus on the distinctions between the different forms of this disease. (Liver Transpl 2005;11:1107–1111.)

Delay in recognition of pulmonary arterial hypertension: factors identified from the REVEAL Registry.

BACKGROUND Pulmonary arterial hypertension (PAH) is a progressive and fatal disorder. Despite the emergence of effective therapy, PAH is commonly at an advanced stage when recognized. Factors associated with a prolonged symptomatic period before the recognition of PAH have not been fully evaluated. METHODS The Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL Registry) enrolled 2,967 US adult patients with PAH from March 2006 to September 2007. Patients were considered to have delayed disease recognition if > 2 years elapsed between symptom onset and the patient receiving a PAH diagnosis, starting on PAH-specific therapy, or receiving a diagnosis by right-sided heart catheterization. RESULTS In 21.1% of patients, symptoms were experienced for > 2 years before PAH was recognized. Patients with onset of PAH symptoms before age 36 years showed the highest likelihood of delayed disease recognition (OR, 3.07; 95% CI, 2.03-4.66). History of obstructive airways disease (OR, 1.93; 95% CI, 1.5-2.47) and sleep apnea (OR, 1.72; 95% CI, 1.33-2.22) were independently associated with delayed PAH recognition. Six-minute walk distance < 250 m (OR, 1.91; 95% CI, 1.16-3.13), right atrial pressure < 10 mm Hg (OR, 1.77; 95% CI, 1.26-2.48), and pulmonary vascular resistance < 10 Wood units (OR, 1.28; 95% CI, 1.02-1.60) were also associated with delayed disease recognition, but sex, race/ethnicity, and geographic region showed no association. CONCLUSIONS One in five patients in the REVEAL Registry who were diagnosed with PAH reported symptoms for > 2 years before their disease was recognized. Younger individuals and patients with histories of common respiratory disorders were most likely to experience delayed PAH recognition. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT00370214; URL: www.clinicaltrials.gov.

Loss of PECAM-1 Function Impairs Alveolarization

The final stage of lung development in humans and rodents occurs principally after birth and involves the partitioning of the large primary saccules into smaller air spaces by the inward protrusion of septae derived from the walls of the saccules. Several observations in animal models implicate angiogenesis as critical to this process of alveolarization, but all anti-angiogenic treatments examined to date have resulted in endothelial cell (EC) death. We therefore targeted the function of platelet endothelial cell adhesion molecule, (PECAM-1), an EC surface molecule that promotes EC migration and has been implicated in in vivo angiogenesis. Administration of an anti-PECAM-1 antibody that inhibits EC migration, but not proliferation or survival in vitro, disrupted normal alveolar septation in neonatal rat pups without reducing EC content. Three-dimensional reconstruction of lungs showed that pups treated with a blocking PECAM-1 antibody had remodeling of more proximal branches resulting in large tubular airways. Subsequent studies in PECAM-1-null mice confirmed that the absence of PECAM-1 impaired murine alveolarization, without affecting EC content, proliferation, or survival. Further, cell migration was reduced in lung endothelial cells isolated from these mice. These data suggest that the loss of PECAM-1 function compromises postnatal lung development and provide evidence that inhibition of EC function, in contrast to a loss of viable EC, inhibits alveolarization.

Health-related Quality of Life and Patient-reported Outcomes in Pulmonary Arterial Hypertension

Advances in our understanding of the basic pathophysiology of pulmonary arterial hypertension (PAH) has led to an expanding number of therapeutic options. The ultimate goals of therapy are to lengthen survival while improving symptoms and quality of life. A wealth of research in other conditions has established health-related quality of life (HRQoL) to be an important clinical endpoint. Until recently, however, little was known about HRQoL in PAH, and how best to measure it. Over the past few years, several studies have begun contributing to this growing area of research. Instruments used to assess HRQoL have varied between studies. The extent to which these instruments are valid in PAH depend on their specific measurement properties. In this article, we provide an overview of the different types of patient-reported outcomes (PROs) used in PAH, focusing in particular on the measurement of HRQoL. In the process, we review the current literature on HRQoL in PAH, summarize the available data from randomized controlled trials, and discuss the implications of these findings on future research. Despite significant progress, the study of HRQoL in PAH remains a nascent field relative to other conditions. As the use of PROs continues to increase, additional work will be needed to begin standardizing the reporting and interpretation of such outcomes in future clinical trials.