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When do we screen and treat pediatric sickle cell patients for pulmonary hypertension?

Sickle cell disease centers are increasingly using echocardiograms to screen adolescents for pulmonary hypertension.

Issue: July 1, 2006

ByAndrew D. Campbell

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End-organ damage is the sequelae of ongoing systemic vasculopathy seen in sickle cell disease. Fortunately, recent clinical and translational studies are improving our understanding of how sickle cell disease affects various bodily organs.

Johnson et al reviewed mortality data in 1,056 patients with sickle cell disease and found that chronic lung disease (with pulmonary hypertension), renal disease and stroke were the leading causes of death. Screening for the early onset of chronic-end organ damage and early treatment could decrease the morbidity and mortality of sickle cell disease.

Transcranial Doppler screening (measuring the velocities of the middle cerebral [MCA] or intracranial internal carotid arteries [ICA] in the brain) in children has been crucial in identifying patients with sickle cell disease who are at risk for developing a stroke. Patients with transcranial Doppler velocities greater than 200 cm/s in the ICA or MCA have a 10% per year risk of developing a stroke. Prophylactic blood transfusions to keep the percentages of hemoglobin S (Hgb S) less than 30% to 40% have decreased the stroke rate by 90%.

Pulmonary artery vasculopathy

Recently, there has been increasing concern over vasculopathy involving the pulmonary arteries of patients with sickle cell disease resulting in secondary pulmonary hypertension. In the most well-known study to date, Gladwin et al found that 32% of adult patients with sickle cell disease had pulmonary hypertension based on tricuspid regurgitant jet velocity greater than 2.5 cm/s.

What’s more concerning is that the 18-month mortality rate was approximately 20% in patients with sickle cell disease, patients who also had pulmonary hypertension. An earlier study by Sutton and Castro revealed a 40% mortality rate at two years. The risk factors for developing pulmonary hypertension were:

• history of cardiovascular or renal complications,
• systemic hypertension,
• elevated LDH,
• history of priapism,
• elevated alkaline phosphatase and
• low transferrin levels.

Surprisingly, fetal hemoglobin levels or markers of inflammation were not associated with the development of pulmonary hypertension, defined as a mean pulmonary artery pressure greater than 25 mm Hg at rest or greater than 30 mm Hg with exercise. An echocardiogram can estimate the pulmonary artery systolic pressure by measuring the regurgitant blood across the tricus- pid valve (tricuspid regurgitant jet velocity) using the modified Bernoulli’s equation (4x[tricuspid regurgitant jet velocity]²).

Nitric oxide metabolism

Gladwin et al showed that there is dysregulated nitric oxide (NO) metabolism in patients with sickle cell disease who have pulmonary hypertension. The pathophysiology of pulmonary hypertension in patients with sickle cell underlies an ongoing systemic vasculopathy and accelerated hemolysis.

Other studies by Gladwin and colleagues have shown that cell-free hemoglobin released under high rates of hemolysis resulted in NO scavenging. In addition to limited NO availability, patients with sickle cell disease have elevated endothelin (ET-1), a potent pulmonary artery vasoconstrictor; elevated arginase, which destroys arginine, the substrate for NO; elevated platelet activation; and elevated thrombin generation. This is supported clinically by studies showing that elevated LDH is associated independently with tricuspid regurgitant jet velocity greater than 2.5 m/s.

Furthermore, up to 50% of adults with pulmonary hypertension have chronic thromboembolic disease. Gladwin described this pulmonary vasculopathy in patients with pulmonary hypertension as hemolysis-associated endothelial dysfunction. Other chronic hemolytic conditions, such as hereditary spherocytosis and Â-thalassemia have reported cases of secondary pulmonary hypertension. As more patients with sickle cell disease enter the second and third decades of life, there is growing concern that children may develop pulmonary artery vasculopathy and may be at risk for developing pulmonary hypertension as adults.

Pediatric screening

To manage these patients, we may need to screen adolescents with sickle cell disease for pulmonary hypertension with echocardiograms — the same way we screen adults for stroke risk with transcranial Doppler. In a pulmonary hypertension screening pilot study done at the University of Michigan, Ann Arbor, and Howard University hospitals in Washington for the past three years, 46% of pediatric adolescents, most with pulmonary complications (restrictive or obstructive lung disease, asthma, obstructive sleep apnea, multiple acute chest syndromes) had pulmonary hypertension based on tricuspid regurgitant jet velocity greater than 2.5 cm/s.

Although the true prevalence of pulmonary hypertension is not known, multiple centers, in largely retrospective studies, have shown that 15% to 26% of pediatric patients have developed pulmonary hypertension by adolescence. Prior lung disease, lower hemoglobin, hypoxia and markers of hemolysis (elevated lactate dehydrogenase, bilirubin, reticulocyte count) have been correlated with pulmonary hypertension in pediatric patients in these studies.

Treating pulmonary hypertension

Larger prospective studies are needed to define the prevalence and the risk factors for the development of pulmonary hypertension in children. There are no well-established guidelines for the treatment of pulmonary hypertension in patients with sickle cell disease. However, for patients with moderate to severe pulmonary hypertension (tricuspid regurgitant jet velocity greater than 3.0), treatment should be considered based on a recent study in the British Journal of Hematology by Machado and Gladwin. Treatment should be multimodal and can be directed toward the underlying risk factors. Some of the treatments:

• lowering sickle cell percentage,
• chronic blood transfusions (lower Hgb S percentage less than 30% to 40% decreasing the hemolytic rate and free hemoglobin),
• treatment of systemic hypertension,
• treatment of hypoxia,
• treatment of asthma,
• tonsillectomy and adenoidectomy for obstructive sleep apnea,
• oxygen for chronic nocturnal hypoxia and
• hydroxyurea (to increase fetal hemoglobin and decrease sickling).

Additionally, the use of pulmonary hypertension-directed therapy in sickle cell disease is now being considered after preliminary success at some centers.

Physicians are evaluating the anti-endothelin-1 drug, bosentan (Tracleer, Actelion Pharmaceuticals Ltd.); sildenafil citrate (Viagra, Pfizer) to increase NO; and arginine to increase NO substrate. Some patients with sickle cell disease and pulmonary emboli are candidates for anticoagulants.

Although no set guidelines are available, many sickle cell disease centers are doing screening with echocardiograms for pulmonary hypertension in adolescents. The challenge will be when and how do we treat those with moderate to severe pulmonary hypertension (tricuspid regurgitant jet velocity greater than 3.0). How early is too early to treat in children? Ongoing national studies will address this dilemma in the next few years.

For more information:

• Machado RF, Gladwin MT. Chronic sickle cell lung disease: new insights into the diagnosis, pathogenesis and treatment of pulmonary hypertension. Br J Haematol. 2005;129:449-464.
• Morris CR, Kato GJ, Poljakovic M, et al. Dysregulated arginine metabolism, hemolysis-associated pulmonary hypertension, and mortality in sickle cell disease. JAMA. 2005;294:81-90.
• Powars DR, Chan LS, Hiti A, et al. Outcome of sickle cell anemia: a 4-decade observational study of 1,056 patients. Medicine (Baltimore). 2005;84:363-376.
• Gladwin MT, Sachdev V, Jison ML, et al. Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. N Engl J Med. 2004;350:886-895.
• Reiter CD, Wang X, Tanus-Santos JE, et al. Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease. Nat Med. 2002;8:1383-1389.
• Sutton LL, Castro O, Cross DJ, et al. Pulmonary hypertension in sickle cell disease. Am J Cardiol. 1994;74:626-628.

About the author:

• Andrew D. Campbell, MD, is director of the Comprehensive Pediatric Sickle Cell Program in the division of pediatric hematology/oncology at the University of Michigan Hospitals, Ann Arbor.