Pulmonary Hypertension as a Risk Factor for Death in Patients with Sickle Cell Disease
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《新英格兰医药杂志》
To the Editor: We commend Gladwin et al. (Feb. 26 issue)1 on their large prospective study of pulmonary hypertension in the population of patients with sickle cell disease. The pathogenesis of pulmonary hypertension in sickle cell disease remains unclear and is probably multifactorial. In general, elevated pulmonary-artery pressures occur most commonly because of left-sided heart disease, a well-described complication of sickle cell disease.2 Consequently, pulmonary hypertension has been defined as a mean pulmonary-artery pressure of 25 mm Hg at rest and a pulmonary-capillary wedge pressure of less than 15 mm Hg.3 The 18 patients who underwent catheterization had a mean (±SE) pulmonary-artery pressure of 34.5±2.7 mm Hg and a mean pulmonary-capillary wedge pressure of 17.2±1.2 mm Hg; their mean pulmonary vascular resistance was normal (148±26.2 dyn·sec·cm–5), suggesting that isolated pulmonary vascular disease was absent in some patients. Although neither systolic nor diastolic left ventricular dysfunction was apparent on echocardiography, the elevated mean pulmonary-capillary wedge pressure suggests that some of the patients had left ventricular disease. It is unknown whether pulmonary hypertension with concomitant left ventricular disease is associated with a different mortality rate than pulmonary hypertension alone. This study emphasizes the importance of further investigation of the pathogenesis of pulmonary hypertension related to sickle cell disease and possible treatment strategies.
Elizabeth S. Klings, M.D.
Harrison W. Farber, M.D.
Boston University School of Medicine
Boston, MA 02118
eklings@lung.bumc.bu.edu
References
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.
Covitz W, Espeland M, Gallagher D, Hellenbrand W, Leff S, Talner N. The heart in sickle cell anemia: the Cooperative Study of Sickle Cell Disease (CSSCD). Chest 1995;108:1214-1219.
Rubin LJ. Primary pulmonary hypertension. N Engl J Med 1997;336:111-117.
To the Editor: Gladwin et al. suggest that pulmonary hypertension, diagnosed by Doppler echocardiography, is linked to death in patients with sickle cell disease. However, we believe that their study had several shortcomings. First, it is unclear how the 18 patients (9.2 percent of the study population) who underwent cardiac catheterization were selected for that procedure. Assuming they were a representative subgroup, the cohort had only moderate pulmonary hypertension and a minimal increase in pulmonary vascular resistance (mean, 148±26.2 dyn·sec·cm–5). Since right ventricular failure is the usual cause of death in patients with pulmonary hypertension,1 it is surprising that a more comprehensive evaluation of right cardiac function is not mentioned. Right atrial pressure, a predictor of death in patients with pulmonary hypertension,1 is not reported. Although echocardiography revealed an increase in right atrial size, evidence of other known predictors of mortality in pulmonary hypertension (e.g., an increase in the right ventricular diastolic eccentricity index and the presence of pericardial effusion)2 is not provided. For these reasons, we believe that there is insufficient evidence to conclude that pulmonary hypertension confers an increased risk of death in patients with sickle cell disease.
Paul M. Hassoun, M.D.
Jerry A. Krishnan, M.D.
Johns Hopkins Hospital
Baltimore, MD 21224
phassoun@jhmi.edu
References
D'Alonzo GE, Bars RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension: results from a national prospective registry. Ann Intern Med 1991;115:343-349.
Raymond RJ, Hinderliter AL, Willis PW, et al. Echocardiographic predictors of adverse outcomes in primary pulmonary hypertension. J Am Coll Cardiol 2002;39:1214-1219.
The authors reply: In response to Drs. Klings and Farber, we wish to emphasize that patients with sickle cell disease normally have a cardiac output of 10 to 12 liters per minute and a pulmonary vascular resistance of 58 dyn·sec·cm–5.1 This hyperdynamic state compensates for critical anemia associated with steady-state hemoglobin levels of approximately 7 to 8 g per deciliter. With the development of pulmonary arteriopathy, the pulmonary vascular resistance nearly triples, to a mean value of 148.5 dyn·sec·cm–5 (range, 65.0 to 440.0); this value, though still within the "normal" range, is decidedly abnormal for patients with severe anemia. High filling pressures (i.e., pulmonary-capillary wedge pressures) are typical of patients with anemia, and we observed no correlation between pulmonary-artery pressure and cardiac output. Although measures of diastolic and systolic dysfunction did not contribute to mortality in a proportional-hazards regression analysis, the small number of deaths does not allow us to rule out some association.
Drs. Hassoun and Krishnan suggest that there is insufficient evidence to link pulmonary hypertension with death in patients with sickle cell disease. The mean right atrial pressure in the patients who underwent catheterization was 12.27±1.5 (range, 5.0 to 27.0), and few had evidence of right ventricular failure. Although we caution that this disease, which requires a steady-state cardiac output of 10 liters per minute in the face of critical anemia, is clearly different from primary pulmonary hypertension, we appreciate their caveat.
We do not yet know whether elevated tricuspid regurgitant jet velocity is a marker or cause of death. Pulmonary-artery pressures certainly rise during episodic vaso-occlusive crises characterized by oxyhemoglobin desaturation, intensification of hemolysis, nitric oxide consumption, and endothelin-1 expression,2,3,4 suggesting that acute-on-chronic pulmonary hypertension in the setting of severe anemia may result in hemodynamic collapse. In fact, since our article was published, two additional patients, both in the cohort with pulmonary hypertension, have died; both deaths were sudden. Alternatively, an elevation in pulmonary-artery pressures may be a sensitive marker of systemic vasculopathy and organ dysfunction (with concomitant cardiac microinfarction and iron overload), which together lead to an increased proclivity for dysrhythmia and sudden death. Therefore, therapy for these patients requires the intensification of proven treatments (hydroxyurea, oxygen, warfarin, iron chelation, and transfusion) as appropriate and then consideration of pulmonary vasodilators and remodeling agents.
Mark T. Gladwin, M.D.
Vandana Sachdev, M.D.
Frederick P. Ognibene, M.D.
National Institutes of Health
Bethesda, MD 20892-1662
mgladwin@nih.gov
References
Castro OL, Hoque M, Brown BD. Pulmonary hypertension in sickle cell disease: cardiac catheterization results and survival. Blood 2002;101:1257-1261.
Naumann HN, Diggs LW, Barreras L, Williams BJ. Plasma hemoglobin and hemoglobin fractions in sickle cell crisis. Am J Clin Pathol 1971;56:137-147.
Hammerman SI, Kourembanas S, Conca TJ, Tucci M, Brauer M, Farber HW. Endothelin-1 production during the acute chest syndrome in sickle cell disease. Am J Respir Crit Care Med 1997;156:280-285.
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.
Elizabeth S. Klings, M.D.
Harrison W. Farber, M.D.
Boston University School of Medicine
Boston, MA 02118
eklings@lung.bumc.bu.edu
References
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.
Covitz W, Espeland M, Gallagher D, Hellenbrand W, Leff S, Talner N. The heart in sickle cell anemia: the Cooperative Study of Sickle Cell Disease (CSSCD). Chest 1995;108:1214-1219.
Rubin LJ. Primary pulmonary hypertension. N Engl J Med 1997;336:111-117.
To the Editor: Gladwin et al. suggest that pulmonary hypertension, diagnosed by Doppler echocardiography, is linked to death in patients with sickle cell disease. However, we believe that their study had several shortcomings. First, it is unclear how the 18 patients (9.2 percent of the study population) who underwent cardiac catheterization were selected for that procedure. Assuming they were a representative subgroup, the cohort had only moderate pulmonary hypertension and a minimal increase in pulmonary vascular resistance (mean, 148±26.2 dyn·sec·cm–5). Since right ventricular failure is the usual cause of death in patients with pulmonary hypertension,1 it is surprising that a more comprehensive evaluation of right cardiac function is not mentioned. Right atrial pressure, a predictor of death in patients with pulmonary hypertension,1 is not reported. Although echocardiography revealed an increase in right atrial size, evidence of other known predictors of mortality in pulmonary hypertension (e.g., an increase in the right ventricular diastolic eccentricity index and the presence of pericardial effusion)2 is not provided. For these reasons, we believe that there is insufficient evidence to conclude that pulmonary hypertension confers an increased risk of death in patients with sickle cell disease.
Paul M. Hassoun, M.D.
Jerry A. Krishnan, M.D.
Johns Hopkins Hospital
Baltimore, MD 21224
phassoun@jhmi.edu
References
D'Alonzo GE, Bars RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension: results from a national prospective registry. Ann Intern Med 1991;115:343-349.
Raymond RJ, Hinderliter AL, Willis PW, et al. Echocardiographic predictors of adverse outcomes in primary pulmonary hypertension. J Am Coll Cardiol 2002;39:1214-1219.
The authors reply: In response to Drs. Klings and Farber, we wish to emphasize that patients with sickle cell disease normally have a cardiac output of 10 to 12 liters per minute and a pulmonary vascular resistance of 58 dyn·sec·cm–5.1 This hyperdynamic state compensates for critical anemia associated with steady-state hemoglobin levels of approximately 7 to 8 g per deciliter. With the development of pulmonary arteriopathy, the pulmonary vascular resistance nearly triples, to a mean value of 148.5 dyn·sec·cm–5 (range, 65.0 to 440.0); this value, though still within the "normal" range, is decidedly abnormal for patients with severe anemia. High filling pressures (i.e., pulmonary-capillary wedge pressures) are typical of patients with anemia, and we observed no correlation between pulmonary-artery pressure and cardiac output. Although measures of diastolic and systolic dysfunction did not contribute to mortality in a proportional-hazards regression analysis, the small number of deaths does not allow us to rule out some association.
Drs. Hassoun and Krishnan suggest that there is insufficient evidence to link pulmonary hypertension with death in patients with sickle cell disease. The mean right atrial pressure in the patients who underwent catheterization was 12.27±1.5 (range, 5.0 to 27.0), and few had evidence of right ventricular failure. Although we caution that this disease, which requires a steady-state cardiac output of 10 liters per minute in the face of critical anemia, is clearly different from primary pulmonary hypertension, we appreciate their caveat.
We do not yet know whether elevated tricuspid regurgitant jet velocity is a marker or cause of death. Pulmonary-artery pressures certainly rise during episodic vaso-occlusive crises characterized by oxyhemoglobin desaturation, intensification of hemolysis, nitric oxide consumption, and endothelin-1 expression,2,3,4 suggesting that acute-on-chronic pulmonary hypertension in the setting of severe anemia may result in hemodynamic collapse. In fact, since our article was published, two additional patients, both in the cohort with pulmonary hypertension, have died; both deaths were sudden. Alternatively, an elevation in pulmonary-artery pressures may be a sensitive marker of systemic vasculopathy and organ dysfunction (with concomitant cardiac microinfarction and iron overload), which together lead to an increased proclivity for dysrhythmia and sudden death. Therefore, therapy for these patients requires the intensification of proven treatments (hydroxyurea, oxygen, warfarin, iron chelation, and transfusion) as appropriate and then consideration of pulmonary vasodilators and remodeling agents.
Mark T. Gladwin, M.D.
Vandana Sachdev, M.D.
Frederick P. Ognibene, M.D.
National Institutes of Health
Bethesda, MD 20892-1662
mgladwin@nih.gov
References
Castro OL, Hoque M, Brown BD. Pulmonary hypertension in sickle cell disease: cardiac catheterization results and survival. Blood 2002;101:1257-1261.
Naumann HN, Diggs LW, Barreras L, Williams BJ. Plasma hemoglobin and hemoglobin fractions in sickle cell crisis. Am J Clin Pathol 1971;56:137-147.
Hammerman SI, Kourembanas S, Conca TJ, Tucci M, Brauer M, Farber HW. Endothelin-1 production during the acute chest syndrome in sickle cell disease. Am J Respir Crit Care Med 1997;156:280-285.
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.