Ventilation and gas exchange during exercise in sickle cell anemia

Adults with sickle cell anemia (SCA) have restrictive lung impairment, increased alveolar dead space, and hypoxemia. These factors, together with increased anaerobic metabolism, are thought to cause exercise hyperventilation. To assess the role of each of these in children, 34 patients with SCA and 16 control subjects performed pulmonary function and exercise tests. Twenty-eight patients with SCA had spirometric values and lung volumes, and all but two patients with SCA had arterial saturation greater than 91% during exercise. Despite a low VO2max (30.07 +/- 6.55 ml/min/kg), the ventilatory anaerobic threshold (VAT) in the patients occurred at a similar %VO2max as in the control subjects (69 +/- 9% versus 63 +/- 12%). The slope of the delta VE/delta VCO2 relationship for sub-VAT work was steeper in the patients (29.4 +/- 6.5 versus 24.7 +/- 5.2, p = 0.01), and the ventilatory equivalent for CO2 (VE/VCO2) in steady-state exercise was greater in the patients than in the control subjects (33.2 +/- 3.5 versus 30.8 +/- 3.5, p = 0.03). End-tidal PCO2 did not differ (38.3 +/- 3.0 versus 39.2 +/- 3.1), indicating equivalent alveolar ventilation. The patients had a higher dead space:tidal volume ratio (VD/VT) than did the control subjects (0.204 +/- 0.033 versus 0.173 +/- 0.024, p = 0.0005). The PaCO2 was significantly lower in those with lower Hb, but there was no difference in pH. In conclusion, children with SCA have an increased exercise ventilatory response caused in part by increased physiologic dead space, and in part by their low Hb. The greater dead space may be the result of sickle cells impairing capillary perfusion to ventilated alveoli.     

Cardiopulmonary responses to exercise in women with sickle cell anemia

Multiple factors contribute to exercise intolerance in patients with sickle cell anemia, but little information exists regarding the safety of maximal cardiopulmonary exercise testing (CPET) or the mechanisms of exercise limitation in these patients. The purpose of the present study was to examine these issues. Seventeen adult women with sickle cell anemia underwent symptom-limited maximal CPET using cycle ergometry and ramp protocols; blood gases and lactate concentrations were measured every 2 minutes. All patients completed CPET without complications. No patient demonstrated a mechanical ventilatory limitation to exercise or had evidence of myocardial ischemia. However, we observed three pathophysiologic patterns of response to exercise in these patients. Eleven patients had low peak VO2, low anaerobic threshold (AT), gas exchange abnormalities, and high ventilatory reserve; this pattern is consistent with exercise limitation due to pulmonary vascular disease in this patient subgroup. Three patients had low peak VO2, low AT, no gas exchange abnormalities, and a high heart rate reserve, a pattern consistent with peripheral vascular disease and/or a myopathy. The remaining three patients had low peak VO2, low AT, no gas exchange abnormalities, and a low heart rate reserve; this pattern of exercise limitation is best explained by anemia.     

Effect of zinc on hyperammonemia in sickle cell anemia subjects

An increase in plasma ammonia level in human volunteers on restricted zinc intake, and in zinc-deficient rats, has recently been reported. Inasmuch as zinc deficiency has been observed in sickle cell anemia patients, we measured plasma ammonia levels in such subjects. In this report we document hyperammonemia in sickle cell anemia patients that was corrected with zinc therapy.     

Chronic intrahepatic cholestasis in sickle cell disease requiring exchange transfusion.

A 15 year old boy with sickle cell disease developed intrahepatic cholestasis. A course of exchange transfusion successfully corrected the extreme hyperbilirubinaemia over one year. Upon stopping the exchange transfusion programme the hyperbilirubinaemia relapsed but transfusion was effective when reinstituted.     

Cardiac output and oxygen delivery during exercise in sickle cell anemia

Desaturation in patients with sickle cell anemia (SCA) can lead to intravascular sickling and vascular occlusion. The increased metabolic demands of exercise tend to increase oxygen extraction, giving rise to a fall in saturation in the capillary bed that may predispose to sickling. This could be minimized with an increase in cardiac output. The aims of this study were to assess the role of increased stroke volume (SV) in augmenting cardiac output (Q) and to estimate the role of enlarged arteriovenous O2 content difference in maintaining O2 transport in children with SCA. A group of 30 children with SCA (Hb 65 to 133 g/L) and 16 healthy controls of the same racial group and of similar height and weight performed incremental and steady-state exercise at 50% Wmax. Cardiac output (Q) was measured by the indirect (CO2) Fick method during steady state. The slope of delta HR/delta VO2 during incremental exercise was higher in SCA subjects compared with controls (4.01 +/- 1.73 versus 2.80 +/- 0.61 bpm per ml/min/kg VO2, p = 0.001). Q for VO2 was abnormally high in patients, particularly older ones with lower Hb levels. HR (% predicted) was higher in patients than in controls (106 +/- 11 versus 92 +/- 8% predicted, p less than 0.0001), as was SV (113 +/- 16 versus 98 +/- 14% predicted, p = 0.002). Multiple linear regression of Q % predicted and SV % predicted on Hb and age showed a positive correlation with age and a negative correlation with Hb (r = 0.84 for Q and r = 0.76 for SV).(ABSTRACT TRUNCATED AT 250 WORDS)     

A prophylactic transfusion program for children with sickle cell anemia complicated by CNS infarction

CNS infarction is a devastating complication in sickle cell anemia. Episodes are frequently repetitive and often result in permanent neurologic abnormalities. In an attempt to prevent such recurences a periodic transfusion program was begun at the Children's Hospital of Michigan in 1969. Twenty-one children currently on the program receive buffy-coat poor transfusions on an out-patient basis every 3 weeks. Of 15 who have been on the program for periods of from 9 months to 5 ¾ years, none have had progression of neurologic abnormalities, and several have had definite improvement in neurologic function. One child who was not brought in regularly had recurrent CNS infarction. The only recognized complication has been one instance of serum hepatitis. While such a transfusion of neurologic abnormalities resulting from recurrent CNS infarction in sickle cell anemia.     

Excess HLA antigens after transfusion of sickle cell patient with AIDS

A woman with sickle cell-hemoglobin C disease developed the acquired immunodeficiency syndrome (AIDS), possibly as the result of blood transfusions administered 4 years earlier. Three months after subsequent transfusions, she had excess HLA-A and DR antigens (triplets) on her circulating lymphocytes. Three of her first-degree relatives were HLA-typed, and none had excess antigens. Family studies also indicated that the patient had at least one HLA-A antigen that was probably not inherited. These findings suggest the possibility that transient hemopoietic engraftment can occur in transfused sickle cell patients with AIDS.     

Cardiovascular adaptations to transfusion/chelation therapy of homozygote sickle cell anemia

The effect of transfusion/chelation therapy on the cardiovascular adaptations to chronic anemia in pediatric and young adult patients with homozygous sickle cell disease is uncertain. This study compares left ventricular (LV) function indexes and thoracoabdominal aortic systolic and diastolic blood flow in nontransfused and transfused patients with homozygous sickle cell disease. The study population consisted of 29 nontransfused patients with homozygous sickle cell disease, ages 0.4 to 20.9 years (group 1) and 11 chronically transfused/chelated patients, ages 4.0 to 21.8 years (group 2). The mean total hemoglobin concentration in group 2 was 28% greater than that in group 1. The mean duration of transfusion/chelation therapy in group 2 was 3.7 years. The percent of predicted LV end-diastolic and end-systolic dimensions were significantly greater than the respective controls in both groups. There was no significant difference in percent of predicted LV end-diastolic dimension (group 1, 120 +/- 12%; group 2, 120 +/- 12%) or percent of predicted LV end-systolic dimension (group 1, 120 +/- 12%; group 2, 117 +/- 8) between the groups. The percent of LV shortening fraction was similar in study groups and control subjects. Aortic systolic blood flow (cc/min/m2) for group 1 (2,426 +/- 841) and 2 (2,374 +/- 1.004) were significantly greater than corresponding control values (1,683 +/- 442, 1,736 +/- 430, respectively). Aortic diastolic blood flow was significantly greater than corresponding control values for both group 1 (699 +/- 313 vs 488 +/- 212) and group 2 (1,080 +/- 607 vs 588 +/- 219).(ABSTRACT TRUNCATED AT 250 WORDS)     

Induction of fetal hemoglobin production in subjects with sickle cell anemia by oral sodium phenylbutyrate

Intravenous arginine butyrate has been shown to increase fetal hemoglobin (HbF) in sickle cell and thalassemia patients. Recently, we observed that sodium 4-phenylbutyrate, a drug administered orally to treat urea cycle disorders, increases HbF production in nonanemic children and adults. We treated six subjects with sickle cell disease over a period of 14 to 179 days. All subjects received their initial therapy of 9 to 13 g/m2/day as 0.5-g tablets of sodium 4-phenylbutyrate as inpatients. All subjects showed a rapid increase in the percentage of F-reticulocytes (pretreatment, 1% to 20%; posttreatment, 10% to 44%). Four subjects were treated only 11 to 25 days as inpatients. Two of these four subjects failed to respond to the outpatient component because of their inability to maintain an intake of 30 to 40 tablets per day. One subject (C) developed a rash at day 10 and discontinued treatment at day 14. Another subject (B) was transfused for a painful crisis on day 25. Subject A, treated for 179 days, has an increased percentage of F cells, from 54% to 77%, and increased HbF levels, from 10.6% to 18%. Subject F, treated for 154 days, has an increased percentage of F cells, from 59% to 73%, and an increased percentage of HbF, from 10.4% to 16%. All subjects showed some increase in weight. Subject A developed mild transient ankle edema. Myelotoxicity was not seen in any treated patient. Oral administration of sodium 4- phenylbutyrate rapidly increases F-cell production in sickle cell disease.     

Stroke risk in siblings with sickle cell anemia

Cerebrovascular disease is a common cause of morbidity in sickle cell anemia (HbSS): approximately 10% of patients have a clinical stroke before 20 years of age, and another 22% have silent infarction on magnetic resonance imaging. The phenotypic variation among patients with HbSS suggests a role for modifier genes and/or environmental influences. To assess the familial component of clinical stroke in HbSS, we estimated the prevalence of clinical stroke among all patients and among HbSS sibling pairs at 9 pediatric centers. The sample included 3425 patients with sickle cell disease who were younger than 21 years, including 2353 patients with HbSS. The stroke prevalence was 4.9% for all genotypes; 7.1% for patients with HbSS; 1.1% for patients with HbSbeta(o) thalassemia; 0.6% for patients with Sbeta(+) thalassemia; and 0% for patients with HbSC. In 207 sibships, more than 1 child had HbSS. There were 42 sibships in which at least 1 sibling had a stroke, and in 10 of the 42, 2 siblings had a stroke. A permutation test indicated that the number of families in which 2 children had strokes was larger than the number expected if strokes were randomly distributed among children in sibships (P =.0012). There was no difference in stroke prevalence based on sex, nor was the mean age at stroke presentation significantly different between singletons and sibships with stroke. We conclude that there is a familial predisposition to stroke in HbSS. Attempts to identify genetic modifiers should be initiated with family-based studies.     

Serum autoantibodies in patients with sickle cell anemia

The prevalence of serum autoantibodies was determined in 50 black adult patients with sickle cell anemia, and in 33 age- and sex-matched healthy black individuals. Twenty-seven of the patients (54%) had at least one type of autoantibody, in contrast to only four (18.2%) of the control subjects (P less than .01). Antismooth muscle, antiskeletal muscle and antinuclear antibodies were the most frequently seen autoantibodies. There was no correlation between the presence of autoantibodies and history of hepatitis, number of blood transfusions or concurrent drug therapy. Sickle cell anemia is associated with the induction of autoimmune phenomena.