Effect of Hydroxyurea Therapy on Resting Energy Expenditure in Children With Sickle Cell Disease

Abstract Pulmonary hypertension develops in most forms of hereditary and chronic hemolytic anemia, including sickle cell disease, thalassemia, hereditary spherocytosis, and paroxysmal nocturnal hemoglobinuria, suggesting that there is a clinical syndrome of hemolysis-associated pulmonary hypertension. Retrospective studies from tertiary care referral centers suggest a prevalence of pulmonary hypertension in adults with sickle cell disease ranging from 20 to 40%. Despite the fact the elevations in pulmonary artery pressures are slight, morbidity and mortality are high. In adult sickle cell anemia patients, pulmonary hypertension is emerging as a major risk factor for death. We performed Doppler echocardiographic assessments of pulmonary-artery systolic pressure in 80 consecutive patients (20 men and 60 women; mean [±SD] age, 30 ± 10.8 years) between 1/20/2006 and 1/20/2008. The genotype on the basis of hematologic and hemoglobin characteristics was hemoglobin SS in all patients. Pulmonary hypertension was prospectively defined as a tricuspid regurgitant Jet velocity (TFJV) of at least 2.5 m per second. Patients were followed for a mean of 18 months (6–24 months), and data were censored at the time of death or loss to follow-up. Doppler-defined pulmonary hypertension occurred in 37.5 percent of patients (30/80). Multiple logistic-regression analysis, with the use of the dichotomous variable of a tricuspid regurgitant jet velocity of less than 2.5 m per second or 2.5 m per second or more, identified age, female sex, deferasirox therapy, left ventricular mass index, pulmonary artery systolic pressure, reticulocytes, white-cell count, platelet count, lactate dehydrogenase (a marker of hemolysis), blood urea nitrogen, creatinine, uric acid and self-reported history of cardiovascular complication, billiary stones, retinopathy and acute chest syndrome, as significant independent correlates of pulmonary hypertension. The hemoglobin level, fetal hemoglobin level, hydroxyurea therapy and serum ferritin level were unrelated to pulmonary hypertension. Hazard rate for death according to the TFJV of at least 2.5 m per second, as compared with a velocity of less than 2.5 m per second, was associated with an increased risk of death (0.00 versus 2.54; P=0.998). Mortality rate in 24 months was 6.7% (2/30) for patients with TRJ velocity ≥ 2.5 m/sec versus 0.0% (0/50) for patients without pulmonary hypertension. Pulmonary hypertension, diagnosed by Doppler echocardiography, is common in adults with sickle cell disease. It appears to be a complication of chronic hemolysis, is resistant to hydroxyurea therapy, and confers a high risk of death. Large trials evaluating the effects of treatment for pulmonary hypertension in the sickle cell anemia population are indicated.

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Elevated Cerebral Metabolic Oxygen Consumption in Sickle Cell Disease

Blood ◽

10.1182/blood.v124.21.2706.2706 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2706-2706 ◽

Cited By ~ 3

Author(s):

Adam M Bush ◽

Matthew Borzage ◽

Soyoung Choi ◽

Thomas Coates ◽

John C Wood

Keyword(s):

Oxygen Consumption ◽

White Matter ◽

Sickle Cell Disease ◽

Energy Expenditure ◽

Metabolic Rate ◽

Grey Matter ◽

Brain Volume ◽

Resting Energy Expenditure ◽

Cell Disease ◽

T2 Relaxation

Abstract Introduction Stroke occurs when cerebral blood flow (CBF) is inadequate to the metabolic needs of the brain. In sickle cell disease (SCD) stroke is common, however accurate quantification of basal cerebral oxygen consumption (CMRO2) has not been performed. Early PET studies suggested CMRO2 was decreased in SCD patients, but these studies lacked data regarding brain volume and gray-white matter fractions; lower CMRO2 may simply have reflected brain loss from prior stroke. In contrast, NIRS and global resting energy expenditure studies have demonstrated elevated peripheral metabolic rate in SCD patients at baseline, with further increases during painful crisis. In those studies, oxygen consumption was correlated with markers of inflammation, particularly white blood cell count, consistent with metabolic consequences of neutrophil activation. Characterizing CMRO2 in SCD provides insight into better prevention and management of stroke in the SCD population. Accordingly, we measured CBF and cerebral venous saturation (SvO2) via a recently developed magnetic resonance imaging (MRI) technique: T2 Relaxation Under Spin Tagging (TRUST). Using the Fick Principle, this allowed for quantification of oxygen extraction fraction (OEF) and the first quantitative measurements of CMRO2in SCD patients. Methods All patients were recruited with informed consent or assent and this study was approved by the CHLA IRB. Exclusion criteria included pregnancy, previous stroke, acute chest or pain crisis hospitalization within one month. Fifteen patients with SCD and 12 healthy ethnicity matched controls (CTL) were studied. Arterial oxygen saturation (SaO2) was measured via peripheral pulse oximetery. TRUST was used to measured T2 relaxation of blood within the sagittal sinus; T2 relaxation was converted to SvO2 using established calibration curves. OEF represented the difference of SaO2 andSvO2 .Phase Contrast (PC) of the carotid and vertebral arteries was used to measure global CBF. CMRO2 was calculated as the product of CBF and OEF. High resolution, 3D, T1 weighted images were used for grey-white segmentation and brain volume calculations using BrainSuiteñ software. Relative grey matter CMRO2 and white matterCMRO2 were estimated by assuming that (gm) CMRO2 was three-fold higher than (wm) CRMRO2. Complete blood count, cell free hemoglobin, LDH, and hemoglobin electrophoresis were measured at the study visit. Results Table 1 summarizes the results. To compensate for their chronic anemia, SCD patients had 67% greater CBF than control subjects, producing a normal SvO2 and OEF. Oxygen delivery also trended higher than for controls leading to higher total CMRO2 in the SCD patients. CMRO2 increases remained significant even after correction for differences in grey and white matter volumes. We found no correlation between WBC and CMRO2when tested by population. Discussion Our study demonstrates elevated cerebral metabolism in SCD, mirroring increases in global resting energy expenditure and peripheral metabolic rate described by other groups. The etiology of the increased CMRO2 is unknown but could reflect neuroinflammation or energy demands from chronic injury/repair. Regardless, our observation at least partially explains the increase of CBF beyond predicted by anemia alone. By excluding patients with overt stroke and by correcting for differences in brain volume and composition, our results are the first CMRO2 measurements in SCD that are unconfounded by brain volume loss. Given the age differences between our study and control populations, we cannot exclude developmental differences in CMRO2 among patients and controls. However, in general, CMRO2 increases with age, which would tend to lessen rather than increase the CMRO2 differences seen in our study. Table 1 Controls SCD p Age (years) 37.2 + 2.8 20.3 + 2.6 <0.05 Sex 9 F, 3 M 9 F, 6 M ns Hemoglobin (g/dl) 13.5 + 1.2 9.6 + 1.1 <0.05 WBC (103/uL) 6.1 + 2.2 11.0 + 4.2 <0.05 Sa O2 (%) 95.7 + 1.5 94.1 + 4.1 ns Sv O2 (%) 65.6 + 6.7 63.6 + 8.4 ns OEF 30.0 + 7.1 32.3 + 7.4 ns CBF (ml/100g/min) 70.0 + 4.6 116.8 + 19.1 <0.05 Cerebral O2 delivery (umol O2/100g/min) 193.0 + 44.9 239.0 + 35.7 ns Grey Matter Mass (ml) 499.6 + 72.0 528.4 + 58.1 ns White Matter Mass (ml) 444.6 + 58.2 422.9 + 59.5 ns CMRO2 (umol O2/100g/min) 193.1 + 44.9 239.0 + 35.7 <0.05 (gm)CMRO2 250.7 + 58.7 292.7 + 39.7 <0.05 (wm) CMRO2 175.5 + 41.1 204.9 + 27.8 <0.05 Disclosures Coates: Novartis: Honoraria, Speakers Bureau; Apo Pharma: Consultancy, Honoraria; Acceleron: Consultancy, Honoraria; SHire: Consultancy, Honoraria.

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Overlapping Onset and Sequential Progression of Vasculopathy in Multiple Organs in Sickle Cell Disease

Blood ◽

10.1182/blood.v128.22.3660.3660 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3660-3660

Author(s):

Shruti Chaturvedi ◽

Djamila Ghafuri ◽

Adetola A. Kassim ◽

Michael DeBaun

Keyword(s):

Pulmonary Hypertension ◽

Magnetic Resonance ◽

Sickle Cell Disease ◽

Mortality Rate ◽

Sickle Cell ◽

Conflicts Of Interest ◽

Age Of Onset ◽

Cell Disease ◽

Multiple Organs ◽

Hydroxyurea Therapy

Abstract Background: Sickle cell disease (SCD) is associated with vasculopathy in multiple vital organs, which ultimately leads to complications such as stroke, proliferative retinopathy, chronic kidney disease and pulmonary hypertension. Existing studies focus on single organ specific vasculopathy without an emphasis on shared mechanisms and simultaneous progression of vasculopathy in multiple organs. We conducted this retrospective cohort study to determine the onset and progression, as well as sequence of involvement of vasculopathy in the central nervous system (CNS), eye, kidney and lungs of adults with SCD. Methods: Our institutional practice is to perform annual magnetic resonance imaging with magnetic resonance angiography (MRI/MRA, for CNS vasculopathy and silent cerebral infarcts), echocardiography (for tricuspidregurgitant jet velocity > 2.5 m/sec, a surrogate of pulmonary hypertension), retinal examination, and measurement of urinaryalbumin:creatinine ratio, and serum creatinine in all adults with SCD. All patients were followed until death or last clinical encounter. Data were summarized as counts and proportions. Multivariable logistic regression was used to identify associations of number of organs affected with mortality. Results: We identified 280 adults with SCD followed for a median period of 66 months (interquartile range [IQR] 15.7 to 112 months). Median age was 31.1 (IQR 25.4 to 39.7) years and 49.6% were female. Over half (51.8%) were on hydroxyurea therapy. The prevalence of vasculopathy in different organs was: CNS, 37.8%; retinopathy 26.1%, proteinuria, 20.7% (nephropathy 5.71%); and pulmonary hypertension, 15.36%. There was no evidence of vasculopathy in 103 (36.8%) individuals. Of the remaining 177 (63.2%) adults, vasculopathy was present in one, two, three and all four end organs in100, 55, 18, and 4 individuals respectively. Median age of onset was earliest for CNS vasculopathy [25.42 (IQR 19.31, 38.85)] years followed by retinopathy [28.41 (IQR 23.04, 35.79)] years, proteinuria [31.25 (IQR 25.6, 46.0)] years, and pulmonary hypertension [33.08 (IQR 23.83, 47.17)] years (Figure 1). Mortality rate was 1.69 per 100 patient-years. Patients with vasculopathy affecting 3 or 4 organs had a significantly higher mortality rate than those with 0-2 organs affected by vasculopathy [odds ratio 5.50 (95%CI 4.49-20.35), p=0.007], adjusted for phenotype, age, sex, hydroxyurea therapy, and smoking status. Conclusion: Vasculopathy in SCD occurs in multiple organs simultaneously, with a predisposition to affectthe CNS first. These data strongly support that multiple vasculopathy is common, and when present in at least three organs, is associated with earlier mortality. Disclosures No relevant conflicts of interest to declare.

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