Christopher F. Barnett

Severity of pulmonary hypertension during vaso‐occlusive pain crisis and exercise in patients with sickle cell disease

Pulmonary hypertension is associated with sudden death and is a risk factor for mortality in adult patients with sickle cell disease. The high mortality despite only mild‐to‐moderate increases in pulmonary vascular resistance remains an unresolved paradox. Accordingly, little is known about the cardiovascular effects of stressors, such as vaso‐occlusive pain crisis (VOC) and exercise, which may acutely increase pulmonary pressures and impair right heart function. We therefore evaluated pulmonary artery pressures by echocardiogram in 25 patients with sickle cell disease in steady‐state and during VOC, and by right heart catheterisation with exercise in a second cohort of 21 patients to determine whether pulmonary hypertension worsens during acute cardiopulmonary stress. TRV increased during VOC (P < 0·001), and the increased pulmonary pressures during VOC were associated with decreases in haemoglobin levels (P < 0·001), and increases in lactate dehydrogenase (P < 0·001) and plasma haemoglobin levels (P = 0·03). During exercise stress performed during cardiac catheterisation, mean pulmonary artery pressures (P < 0·001) and pulmonary vascular resistance increased (P < 0·001) in all subjects. These data suggest that acute elevations in pulmonary pressures during VOC or exercise may contribute to morbidity and mortality in patients with sickle cell disease.

Treatment of Sarcoidosis-Associated Pulmonary Hypertension: A Two-Center Experience

BACKGROUND Pulmonary hypertension (PH) is a common complication of sarcoidosis that is associated with increased mortality. The pathogenesis of PH in sarcoidosis is uncertain, and the role of pulmonary arterial hypertension (PAH)-specific therapies remains to be determined. METHODS We conducted a retrospective study of patients with sarcoidosis and PH at two referral centers. New York Heart Association (NYHA) functional class, exercise capacity, hemodynamic data, pulmonary function tests, and survival were collected and analyzed. RESULTS Twenty-two sarcoidosis patients treated with PAH-specific therapies were identified. After a median of 11 months of follow-up, NYHA class was improved in nine subjects. Mean 6-min walk distance (n = 18) increased by 59 m (p = 0.032). Patients with a higher FVC experienced a greater increment in exercise capacity. Among 12 patients with follow-up hemodynamic data, mean pulmonary artery pressure was reduced from 48.5 +/- 4.3 to 39.4 +/- 2.8 mm Hg (p = 0.008). The 1- and 3-year transplant-free survival rates were 90% and 74%, respectively. CONCLUSIONS PAH-specific therapy may improve functional class, exercise capacity, and hemodynamics in PH associated with sarcoidosis. Prospective, controlled trials of PAH therapies for sarcoidosis are warranted to verify this apparent benefit. Mortality among the study population was high, highlighting the need for urgent evaluation at a lung transplant center.

Pulmonary Hypertension: An Increasingly Recognized Complication of Hereditary Hemolytic Anemias and HIV Infection

Modern health care has greatly increased longevity for patients with congenital hemolytic anemias (such as sickle cell disease and thalassemia) and human immunodeficiency virus (HIV) infection. It is estimated that 10% of patients with hemoglobinopathies and 0.5% of patients with HIV infection develop moderate to severe pulmonary hypertension. Pulmonary hypertension is a relentlessly progressive disease leading to right heart failure and death. Worldwide, there are an estimated 30 million patients with sickle cell disease or thalassemia and 40 million patients with HIV disease. Considering the prevalence of pulmonary vascular disease in these populations, sickle cell disease and HIV disease may be the most common causes of pulmonary hypertension worldwide. In this review, the available data on epidemiology, hemodynamics, mechanisms, and therapeutic strategies for these diseases are summarized. Because therapy is likely to reduce morbidity and prolong survival, efforts to screen, diagnose, and treat these patients represent a global health opportunity.

Original ResearchPulmonary HypertensionTreatment of Sarcoidosis-Associated Pulmonary Hypertension: A Two-Center Experience

BACKGROUND Pulmonary hypertension (PH) is a common complication of sarcoidosis that is associated with increased mortality. The pathogenesis of PH in sarcoidosis is uncertain, and the role of pulmonary arterial hypertension (PAH)-specific therapies remains to be determined. METHODS We conducted a retrospective study of patients with sarcoidosis and PH at two referral centers. New York Heart Association (NYHA) functional class, exercise capacity, hemodynamic data, pulmonary function tests, and survival were collected and analyzed. RESULTS Twenty-two sarcoidosis patients treated with PAH-specific therapies were identified. After a median of 11 months of follow-up, NYHA class was improved in nine subjects. Mean 6-min walk distance (n = 18) increased by 59 m (p = 0.032). Patients with a higher FVC experienced a greater increment in exercise capacity. Among 12 patients with follow-up hemodynamic data, mean pulmonary artery pressure was reduced from 48.5 +/- 4.3 to 39.4 +/- 2.8 mm Hg (p = 0.008). The 1- and 3-year transplant-free survival rates were 90% and 74%, respectively. CONCLUSIONS PAH-specific therapy may improve functional class, exercise capacity, and hemodynamics in PH associated with sarcoidosis. Prospective, controlled trials of PAH therapies for sarcoidosis are warranted to verify this apparent benefit. Mortality among the study population was high, highlighting the need for urgent evaluation at a lung transplant center.

Sodium nitrite promotes regional blood flow in patients with sickle cell disease: a phase I/II study

In addition to vaso‐occlusion by sickled erythrocytes, the pathophysiology of sickle cell disease (SCD) is compounded by the diminished bioavailability of nitric oxide (NO), associated with vasoconstriction, endothelial activation and cell adhesion. We tested the ability of sodium nitrite, which can be converted to NO by deoxyhaemoglobin at acid pH and low oxygen tension, to improve blood flow in patients with SCD. In a phase I/II clinical trial, sodium nitroprusside, NG‐monomethyl‐L‐arginine, and sodium nitrite were infused sequentially into the brachial artery in 14 patients at steady state. In a dose‐dependent manner, sodium nitrite infusion rates of 0·4, 4 and 40 μmol/min into the brachial artery augmented mean venous plasma nitrite concentrations (P < 0·0001) and stimulated forearm blood flow up to 77 ± 11% above baseline (P < 0·0001), measured by venous occlusion strain gauge plethysmography. This nitrite response was blunted significantly compared to controls without SCD, as previously seen with other NO donors. Sodium nitrite infusions were well tolerated without hypotension, clinically significant methaemoglobinaemia or other untoward events. The unique pharmacological properties of nitrite as a hypoxia‐potentiated vasodilator and cytoprotective agent in the setting of ischaemia‐reperfusion injury make this anion a plausible NO donor for future clinical trials in SCD.

Hemodynamic Predictors of Mortality in Adults with Sickle Cell Disease

BACKGROUND Pulmonary hypertension (PH) in adults with sickle cell disease (SCD) is associated with early mortality, but no prior studies have evaluated quantitative relationships of mortality to physiological measures of pre- and postcapillary PH. OBJECTIVES To identify risk factors associated with mortality and to estimate the expected survival in a cohort of patients with SCD with PH documented by right heart catheterization. METHODS Nine-year follow-up data (median, 4.7 yr) from the National Institutes of Health SCD PH screening study are reported. A total of 529 adults with SCD were screened by echocardiography between 2001 and 2010 with no exclusion criteria. Hemodynamic data were collected from 84 patients. PH was defined as mean pulmonary artery pressure (PAP) ≥ 25 mm Hg. Survival rates were estimated by the Kaplan-Meier method, and mortality risk factors were analyzed by the Cox proportional hazards regression. MEASUREMENTS AND MAIN RESULTS Specific hemodynamic variables were independently related to mortality: mean PAP (hazard ratio [HR], 1.61; 95% confidence interval [CI], 1.05-2.45 per 10 mm Hg increase; P = 0.027), diastolic PAP (HR, 1.83; 95% CI, 1.09-3.08 per 10 mm Hg increase; P = 0.022), diastolic PAP - pulmonary capillary wedge pressure (HR, 2.19; 95% CI, 1.23-3.89 per 10 mm Hg increase; P = 0.008), transpulmonary gradient (HR, 1.78; 95% CI, 1.14-2.79 per 10 mm Hg increase; P = 0.011), and pulmonary vascular resistance (HR, 1.44; 95% CI, 1.09-1.89 per Wood unit increase; P = 0.009) as risk factors for mortality. CONCLUSIONS Mortality in adults with SCD and PH is proportional to the physiological severity of precapillary PH, demonstrating its prognostic and clinical relevance despite anemia-induced high cardiac output and less severely elevated pulmonary vascular resistance.

Human Immunodeficiency Virus–Associated Pulmonary Arterial Hypertension

Antiretroviral therapy has greatly increased longevity for individuals with human immunodeficiency virus (HIV) infection. About 0.5% of patients with HIV infection develop moderate to severe pulmonary arterial hypertension, which is several thousand times higher than the incidence of idiopathic pulmonary arterial hypertension. As more than 30 million individuals are chronically infected, HIV infection could soon become one of the most common causes of pulmonary arterial hypertension worldwide. Pulmonary arterial hypertension is a relentlessly progressive disease leading to right heart failure and death. In this article the available data on epidemiology, hemodynamics, mechanisms, and therapeutic strategies for HIV-associated pulmonary arterial hypertension are reviewed.

Organization and staffing practices in US cardiac intensive care units: a survey on behalf of the American Heart Association Writing Group on the Evolution of Critical Care Cardiology:

Background: The cardiac intensive care unit (CICU) has evolved into a complex patient-care environment with escalating acuity and increasing utilization of advanced technologies. These changing demographics of care may require greater clinical expertise among physician providers. Despite these changes, little is known about present-day staffing practices in US CICUs. Methods and Results: We conducted a survey of 178 medical directors of ICUs caring for cardiac patients to assess unit structure and physician staffing practices. Data were obtained from 123 CICUs (69% response rate) that were mostly from academic medical centres. A majority of hospitals utilized a dedicated CICU (68%) and approximately half of those hospitals employed a ‘closed’ unit model. In 46% of CICUs, an intensivist consult was available, but not routinely involved in care of critically ill cardiovascular patients, while 11% did not have a board-certified intensivist available for consultation. Most CICU directors (87%) surveyed agreed that a closed ICU structure provided better care than an open ICU and 81% of respondents identified an unmet need for cardiologists with critical care training. Conclusions: We report contemporary structural models and staffing practices in a sample of US ICUs caring for critically ill cardiovascular patients. Although most hospitals surveyed had dedicated CICUs, a minority of CICUs employed a ‘closed’ CICU model and few had routine intensivist staffing. Most CICU directors agree that there is a need for cardiologists with intensivist training and expertise. These survey data reveal potential areas for continued improvement in US CICU organizational structure and physician staffing.

Effects of Commercial Air Travel on Patients With Pulmonary Hypertension

BACKGROUND Limited data are available on the effects of air travel in patients with pulmonary hypertension (PH), despite their risk of physiologic compromise. We sought to quantify the incidence and severity of hypoxemia experienced by people with PH during commercial air travel. METHODS We recruited 34 participants for a prospective observational study during which cabin pressure, oxygen saturation (Sp O 2 ), heart rate, and symptoms were documented serially at multiple predefined time points throughout commercial flights. Oxygen desaturation was defined as SpO2, <85%. RESULTS Median flight duration was 3.6 h (range, 1.0-7.3 h). Mean ± SD cabin pressure at cruising altitude was equivalent to the pressure 1,968 ± 371 m (6,456 ± 1,218 ft) above sea level (ASL)(maximum altitude 5 2,621 m [8,600 ft] ASL). Median change in Sp O 2 from sea level to cruising altitude was 2 4.9% (range, 2.0% to 2 15.8%). Nine subjects (26% [95% CI, 12%-38%]) experienced oxygen desaturation during flight (minimum Sp O 2 5 74%). Thirteen subjects (38%) reported symptoms during flight, of whom five also experienced desaturations. Oxygen desaturation was associated with cabin pressures equivalent to . 1,829 m (6,000 ft) ASL, ambulation, and flight duration(all P values , .05). CONCLUSIONS Hypoxemia is common among people with PH traveling by air, occurring in one in four people studied. Hypoxemia was associated with lower cabin pressures, ambulation during flight, and longer flight duration. Patients with PH who will be traveling on flights of longer duration or who have a history of oxygen use, including nocturnal use only, should be evaluated for supplemental in-flight oxygen.

Doppler Echocardiography Does Not Accurately Estimate Pulmonary Artery Systolic Pressure in HIV-Infected Patients

Doppler echocardiography is used to screen for HIV-related pulmonary arterial hypertension (HRPAH). We studied patients with HIV infection to determine the accuracy of Doppler echocardiography-estimated pulmonary artery systolic pressure (PASP) compared with PASP measured during right heart catheterization. Doppler echocardiography-estimated PASP was inaccurate in 19.7% of cases. Using Doppler echocardiography-estimated PASP, one in three patients with HRPAH was missed. Doppler echocardiography estimates of PASP are not accurate in patients with HIV.