Prospective evaluation of haemoglobin oxygen saturation at rest and after exercise in paediatric sickle cell disease patients

A lowering of the haemoglobin oxygen saturation as determined by pulse oximetry is common in patients with sickle cell disease at steady state despite the lack of overt evidence of pulmonary dysfunction or intrinsic lung disease (Rackoff et al, 1993; Homi et al, 1997; Setty et al, 2003; Quinn & Ahmad, 2005). Decreased affinity of haemoglobin S for oxygen (Seakins et al, 1973; Ueda et al, 1979) and increased erythrocyte 2,3-bisphosphoglycerate (Milner, 1974) may partially, but probably not fully, explain decreased oxygen saturation in sickle cell disease given the wide range of saturations in patients. Several groups have reported the association of low with elevated serum lactate dehydrogenase, severity of anaemia and/or reticulocytosis, suggesting a possible aetiological relationship of haemolysis with hypoxemia (Rackoff et al, 1993; Homi et al, 1997; Setty et al, 2003; Quinn & Ahmad, 2005; Kato et al, 2006). It has been proposed that this association might involve haemolysis-associated ventilation-perfusion mismatch (Kato et al, 2007a). A developing paradigm of sickle cell disease manifestations proposes two overlapping but distinctively characteristic subphenotypes (Kato et al, 2007a). In the vasculopathy subphenotype, complications such as stroke, pulmonary hypertension, priapism and leg ulcers predominate and are linked to the degree of haemolysis and associated vascular dysfunction. In the vaso-occlusive subphenotype, markers of increased blood viscosity predict risk for infarctive complications, such as frequent pain crises, acute chest syndrome and avascular necrosis of bone. Steady state haemoglobin oxygen desaturation is a risk factor for overt stroke (Quinn & Sargent, 2008) and for pulmonary hypertension (Pashankar et al, 2008; Liem et al, 2009; Minniti et al, 2009) in sickle cell disease, two of the prominent manifestations of the haemolytic subphenotype. Nocturnal oxygen desaturation is also a risk factor for stroke, silent infarct or seizure (Kirkham et al, 2001). On the other hand, reported associations of lower haemoglobin oxygen saturation with increased episodes of pain (Hargrave et al, 2003) and acute chest syndrome (Rackoff et al, 1993), manifestations of the vaso-occlusive subphenotype, have not been confirmed in other studies (Quinn & Ahmad, 2005; Uong et al, 2006). We recently reported the initial results of an ongoing prospective, multicenter study of the prevalence and risk factors for developing pulmonary hypertension in children with sickle cell disease (PUSH Study) (Minniti et al, 2009). Both haemolysis and oxygen desaturation were independently associated with elevated tricuspid regurgitation velocity in this study. Pulmonary function testing and a six-minute walk were performed as a part of this study and pulse oximetry measurements were made before and after the walk. We hypothesized that lower oxygen saturations at steady state and oxygen desaturation during the six-minute walk may reflect pulmonary ventilation/perfusion mismatch related to the vascular effects of accelerated haemolysis. We investigated the relationship of oxygen saturation with medical history, echocardiographic measurements, pulmonary function testing and laboratory test results in this cohort.