OBJECTIVES. The objectives of this study were (1) to determine the prevalence and risk factors of elevated pulmonary artery pressures in children with homozygous SS or Sβ° thalassemia using Doppler echocardiography and (2) to determine a correlation between abnormal transcranial Doppler examinations and elevated pulmonary artery pressures.
METHODS. Screening echocardiograms were prospectively performed during an annual comprehensive clinic visit on children who were older than 6 years and had homozygous SS or Sβ° thalassemia. Detailed history, examination, and laboratory tests were done, and transcranial Doppler examinations were obtained in children 2 to 14 years of age. Pulmonary hypertension was defined as pulmonary artery systolic pressure of at least 30 mmHg corresponding to a peak tricuspid regurgitant jet velocity of ≥2.5 m/second. Mild pulmonary hypertension was defined as tricuspid regurgitant jet velocity ≥2.5 to 2.9 m/second. Moderate pulmonary hypertension was defined as tricuspid regurgitant jet velocity ≥3 m/second. Patients with pulmonary stenosis or right outflow obstruction were excluded. Characteristics were compared between patients with mild, moderate, and no pulmonary hypertension using 1-way analysis of variance for continuous variable and Fisher's exact test for categorical variables.
RESULTS. Of the 75 patients who had homozygous SS/Sβ° thalassemia and were older than 6 years, echocardiograms were obtained for 62 (82.6%). Thirty percent (19 of 62) of patients had elevated tricuspid regurgitant jet velocity ≥2.5 m/second. One third of these patients had tricuspid regurgitant jet velocity ≥3 m/second. All patients with elevated tricuspid regurgitant jet velocity had SS disease. A high reticulocyte count, low oxygen saturation, and a high platelet count were significantly associated with elevated pulmonary artery pressures. There was no difference in age, gender, history of acute chest syndrome, hydroxyurea therapy, chronic blood transfusion, stroke, hemoglobin, and bilirubin between patients with and without elevated pulmonary artery pressures. A total of 47% patients with elevated tricuspid regurgitant jet velocity and 57% without elevated tricuspid regurgitant jet velocity had screening transcranial Doppler examinations. Transcranial Doppler examinations were normal for all patients.
CONCLUSIONS. High pulmonary artery pressures do occur in children with sickle cell disease. Screening by echocardiography can lead to early detection and intervention that may potentially reverse this disease process. There was no correlation between elevated pulmonary artery pressures and abnormal transcranial Doppler examination in our study.
Pulmonary hypertension (PHT) is a widely recognized complication of hereditary hemolytic anemias including sickle cell disease,1–10 thalassemia,11–13 hereditary spherocytosis,14 and paroxysmal nocturnal hemoglobinuria.15 It occurs in 32% of adults with sickle cell disease and is associated with an increased risk for mortality.6
There are limited data on the prevalence of PHT in children with sickle cell disease. Recent studies have found the prevalence of PHT in children to be between 16% and 26.2%.16–18; however, these studies were retrospective and limited by the fact that only a small subset of eligible patients had undergone echocardiography, thereby introducing sample bias. Because PHT is a serious complication associated with the potential for morbidity and mortality, we designed this study to determine prospectively the prevalence of elevated pulmonary artery pressures in children who were older than 6 years and had homozygous SS or Sβ° thalassemia.
The definitive diagnosis of PHT is made by the direct measurement of pulmonary artery pressure and vascular resistance at the time of cardiac catheterization; however, this is an invasive test and is not suitable for screening. Measurement of tricuspid regurgitant jet velocity (TRV) by Doppler echocardiography can be used to estimate peak right ventricular systolic pressure with the use of the modified Bernoulli equation.6 In the absence of structural obstruction to pulmonary blood flow, the right ventricular systolic pressure is equal to pulmonary artery systolic pressure. Estimates of pulmonary artery systolic pressure by Doppler echocardiography correlate well with those obtained by cardiac catheterization19,20; therefore, Doppler echocardiography can be used to identify patients with PHT noninvasively. The specific aims of this study were to (1) determine the prevalence of elevated pulmonary artery pressures in children who were ≥6 years of age and had homozygous SS or Sβ° thalassemia using echocardiography, (2) identify risk factors that are associated with the development of elevated pulmonary artery pressures, and (3) determine whether there is a correlation between abnormal transcranial Doppler (TCD) examinations and elevated pulmonary artery pressures.
The patients were children from the sickle cell program at Yale New Haven Children's Hospital, which follows children with sickle cell disease in southern Connecticut. Patients are seen for a comprehensive visit at least annually, during which a detailed history and physical examination are performed and annual screening laboratory tests are done as recommended by the American Academy of Pediatrics.21 Laboratory studies include complete blood count, reticulocyte count, lactate dehydrogenase (LDH) level, total and direct bilirubin levels, serum urea nitrogen level, and creatinine level. Oxyhemoglobin saturation by pulse oximetry was measured during the clinic visit, and for children with oxyhemoglobin saturation <94%, it was repeated at subsequent visits for confirmation. Patients who had homozygous SS or Sβ° thalassemia and were between the ages of 2 and 14 years had a transcranial Doppler examination for stroke screening. Beginning in October 2005, screening echocardiogram was performed as part of the annual comprehensive evaluation on children who are older than 6 years and have homozygous SS or Sβ° thalassemia. Echocardiograms were performed on an outpatient basis in the Pediatric Echocardiography Laboratory, when patients were in steady state, at least 2 weeks after admission for vaso-occlusive crises.
For this study, all patients who had a screening echocardiogram were included. Patients with pulmonary stenosis or other structural obstruction to pulmonary blood flow were excluded. Medical charts were reviewed for clinical and laboratory data and results of imaging studies. The study was approved by the institutional review board for human investigation of Yale University.
Two-dimensional Doppler echocardiography was performed for all patients using the Acuson Sequoia Ultrasound System (Siemens Medical Solutions, Malvern, PA) or the Philips IE33 ultrasound system (Philips Medical Systems, Bothell, WA). Appropriate transthoracic transducer selection was made at the time of the evaluation. Cardiac measurements were performed according to the guidelines of American Society of Echocardiography. TRV was measured by pulsed-wave and continuous-wave Doppler echocardiography where applicable. Multiple views (apical 4-chamber, parasternal short axis, parasternal long axis) were obtained to record optimal tricuspid Doppler flow signals, and a minimum of 5 sequential signals were recorded. The right ventricular to right atrial systolic pressure gradient was calculated using the modified Bernoulli equation (4 × V2). Pulmonary artery systolic pressure was quantified by adding the Bernoulli-derived right ventricular systolic peak pressure to the estimated mean right atrial pressure (5 mmHg). Pulmonary artery diastolic pressure was estimated by measurement of the end diastolic velocity of the pulmonary insufficiency jet by similar Doppler techniques. Pulmonary hypertension was defined as a peak TRV of at least 2.5 m/second equating to a pulmonary artery pressure of at least 30 mmHg. Mild PHT was defined as peak TRV of 2.5 to 2.9 m/second, corresponding to pulmonary artery systolic pressure of 30 to 39 mmHg. Moderate PHT was defined as a peak TRV ≥3 m/second. Patients with no measurable TRV or TRV <2.5 m/second were considered to have normal pulmonary artery pressures, and these patients constituted the no PHT group.
Clinical characteristics were compared between patients with no PHT, mild PHT, and moderate PHT. Data analysis was performed using 1-way analysis of variance to compare continuous variables. Comparison for categorical variables was made using the Fisher's exact test. P < .05 was considered statistically significant.
A total of 169 children with sickle cell disease were followed at Yale New Haven Children's Hospital Sickle Cell Center. The mean age was 9.4 years (range: 0.32–20.41 years; Table 1). A total of 104 children had homozygous SS disease or Sβ° thalassemia; 75 children were older than 6 years and eligible for the study. Echocardiograms were obtained for 62 (82.6%) patients.
Prevalence of Elevated Pulmonary Artery Pressures
Echocardiograms showed a dilated left ventricle, with left ventricular end diastolic volume >95th percentile for age in 45 (72.5%) patients. Left ventricular wall thickness and ejection fraction were normal for all patients. Thirty percent (19 of 62) of the patients with sickle cell disease had a peak TRV ≥2.5 m/second, corresponding to pulmonary artery systolic pressures ≥30 mmHg. One third of these patients had TRV of ≥3 m/second. The characteristics of these patients are outlined in Table 2. The prevalence of high pulmonary artery pressures did not vary with age (P = .55; Fig 1). The TRV was <2.5 m/second for 38 patients, and 5 patients had no measurable TRV, indicating normal pulmonary artery pressures. These 43 patients comprised the no PHT group.
Risk Factors for Elevated Pulmonary Artery Pressures
Table 3 compares the demographic and clinical data of patients with and without elevated pulmonary artery pressures. All patients with elevated pulmonary artery pressures had homozygous sickle cell disease. There was no difference for age or gender between the affected and unaffected group. Patients with elevated pulmonary artery pressures had significantly higher reticulocyte count compared with unaffected patients (P = .01), although there was no difference in other parameters of hemolysis, including degree of anemia, bilirubin level, and LDH level. Low oxygen saturation documented at an outpatient clinic visit was significantly associated with elevated pulmonary artery pressures (P = .01). Patients with PHT had significantly higher platelet counts compared with the unaffected group (P = .03).
Stroke/Abnormal TCD Examinations and PHT
Eight (12.9%) of 62 patients had had a previous stroke or abnormal TCD examinations. Of these, 7 patients were receiving chronic transfusion, and 1 patient was receiving hydroxyurea. Echocardiograms did not reveal any evidence of PHT in these patients.
Of the 54 patients without previous stroke or abnormal TCD examination, screening TCD examinations were performed for 29 patients either at the time of echocardiography or within 6 months. A total of 47% of patients with elevated pulmonary artery pressures and 57% of patients without elevated pulmonary artery pressures had screening TCD examinations. TCD examinations were normal for all patients. Two patients had conditional velocities on initial examination (1 patient with high TRV and 1 patient with normal TRV) that were normal on repeat examinations. Both patients had normal cranial MRI/magnetic resonance angiography examination. There was no correlation between the presence of elevated pulmonary artery pressures and abnormal screening TCD examination.
This is the first prospective study in which screening echocardiograms were performed on >80% of all eligible children to determine the prevalence of elevated pulmonary artery pressures in children with sickle cell disease. The overall prevalence of elevated pulmonary artery pressure was 30%, which is similar to the prevalence reported for adults6,7 and in previous retrospective pediatric studies.16,17 Suell et al16 reviewed echocardiograms of 80 adolescents (12 to 22.8 years of age) and reported a 26% prevalence of PHT. Of the 21 patients with elevated TRV, only 9 echocardiograms were done as outpatients. Echocardiograms that are done during an acute illness may overestimate the prevalence of elevated pulmonary artery pressures. Ambrusko et al17 reviewed outpatient echocardiograms of 44 adolescent patients and reported a prevalence of PHT of 26.2%. Qureshi et al18 did a case-control comparison of echocardiograms of patients with sickle cell disease and healthy control subjects and reported a 16% prevalence of PHT; however these studies were retrospective, and only a subset of the eligible patients were included.
On evaluation of risk factors for elevated pulmonary artery pressures, we found no correlation between age and elevated TRVs. A similar observation was made by Qureshi et al.18 In their study, the youngest child with elevated TRV was 9 years old. Our youngest patient was 6.81 years, and the mean age of our patients was 13.3 years.
The pathogenesis of PHT in sickle cell disease is likely multifactorial. Proposed mechanisms include hemolysis-induced endothelial dysfunction, chronic hypoxemia, chronic thromboembolism, asplenia, parenchymal and intravascular sequestration of sickled erythrocytes, and iron overload. In our study, we found that a high reticulocyte count, hypoxia, and elevated platelet count were significantly associated with elevated pulmonary artery pressures. The role of hemolysis in the development of PHT in adult patients with sickle cell disease has been described by several authors.22–25 Hemolysis releases free plasma hemoglobin, which scavenges nitric oxide and catalyzes the formation of reactive oxygen and nitrogen species, which leads to acute and chronic pulmonary vasoconstriction. It also releases erythrocyte arginase, an enzyme that converts l-arginine to ornithine, thereby decreasing synthesis of nitric oxide. In our study, a high reticulocyte count was significantly associated with elevated pulmonary artery pressures; however, other parameters of hemolysis, including degree of anemia and bilirubin and LDH levels, were not different between the groups. The hemoglobin showed a downward trend with increasing TRV but was not statistically significant, probably because of the small numbers. Similar to our study, other authors did not find a significant association between markers of hemolysis and elevated pulmonary artery pressures.7,16
Hypoxemia was significantly associated with elevated pulmonary artery pressures in our cohort. The mechanism of hypoxemia in sickle cell disease may result from the degree of anemia, intrinsic lung disease, or upper airway obstruction secondary to obstructive sleep apnea.26–29 Setty et al30 found an increase in adhesion (LTB4) and markers of white cell (L-selectin), platelet (P-selectin), and endothelial activation (vascular cellular adhesion molecule 1) in hypoxemic patients with sickle cell disease. Nocturnal hypoxemia has been significantly associated with a higher rate of painful crises31 and central nervous system events.32 It therefore is likely that in addition to hemolysis, hypoxemia plays a significant role in the pathogenesis of PHT, by the enhanced release of proadhesive ligands from activated circulating cells.
Functional asplenia may also contribute to the development of PHT in patients with sickle cell disease. Splenectomy has been reported to be a risk factor for PHT in patients with thalassemia33 and hereditary spherocytosis.14 It is speculated that loss of splenic function increases the circulation of platelet-derived mediators, and senescent and abnormal erythrocytes in the circulation trigger platelet activation, promoting pulmonary microthrombosis and red cell adhesion to the endothelium.22
Recently Kato et al34 described 6 patients who had PHT and developed cerebrovascular disease and suggested a clinical association between the 2 conditions in patients with sickle cell disease. PHT and stroke share some common risk factors,35 including low steady-state hemoglobin, higher systolic pressures, and hypoxia. We compared the results of TCD examinations done for stroke screening with echocardiography results of patients with sickle cell disease and did not find an association between abnormal screening TCD examinations and presence of PHT. This may be because of the smaller sample size and the limited number of patients who had simultaneous TCD examinations. Screening echocardiograms and TCD examinations were done at 1 time point, and additional follow-up of this cohort may reveal an evolving process. To our knowledge, this is the first study to examine this association.
PHT is a serious complication in adults with sickle cell disease and is significantly associated with mortality. Our study shows that this complication has its origins in childhood. Early detection of elevated pulmonary artery pressures in childhood and appropriate intervention with optimization of antihemolytic therapy and treatment of associated conditions such as hypoxia and obstructive sleep apnea may prevent progression of this complication and thereby reduce morbidity and mortality associated with PHT. In addition, novel pharmacologic therapies for the treatment of PHT, such as sildanefil and other vasodilators, may have therapeutic benefit in this patient population. We therefore recommend that screening transthoracic echocardiography be incorporated into the routine annual evaluation for children with sickle cell disease.
- Accepted August 27, 2007.
- Address correspondence to Farzana D. Pashankar MD, Department of Pediatrics, Yale University School of Medicine, LMP 2073, 333 Cedar St, PO Box 208064, New Haven, CT 06520-8064. E-mail:
The authors have indicated they have no financial relationships relevant to this article to disclose.
What's Known on This Subject
Retrospective data on prevalence of high pulmonary artery pressures in children.
What This Study Adds
This is the first prospective study on prevalence and risk factors of elevated pulmonary artery pressures in children.
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