Low Nocturnal Hemoglobin Oxygen Saturation Does Not Predict Pain or Acute Chest Syndrome Episodes in Children with Sickle Cell Anemia

Background: Previous evidence has shown that low mean nocturnal oxyhemoglobin saturation is significantly associated with a higher number of pain days per year Hargrave et al. (Blood. 2003; 101(3)846-8). We tested the primary hypothesis that sleep disordered breathing, described by low mean nocturnal oxygen saturation (SpO₂), is associated with increased rates of severe vaso-occlusive pain and acute chest syndrome (ACS). Our secondary hypothesis investigated the association between high obstructive apnea hypopnea index (OAHI; the number of obstructive apneas and hypopneas with >3% SpO₂desaturations or arousals per hour of sleep) with increased incidence of severe pain requiring hospitalization and ACS episodes.

Study design: A prospective cohort study of children and adolescents from the Sleep and Asthma Cohort (SAC) was assembled. Children with sickle cell anemia (SCA), defined as HgbSS or Hb Sβ°, were enrolled from 4 to 18 years of age at three clinical centers, Washington University School of Medicine in St. Louis, Missouri; Case Western Reserve University in Cleveland, Ohio; and University College London in London, UK (which recruited from three London hospitals). At each site, SAC study-certified technicians performed full 12 channel in-laboratory research polysomnography (PSG) including continuous measurements of nocturnal oxygen saturation using standardized protocols according to American Academy of Sleep Medicine guidelines for data acquisition and scoring. All PSGs were read centrally at Vanderbilt University School of Medicine. Negative binomial regression was used to test the association between nocturnal SpO₂ and the incidence rate of severe pain requiring hospitalization and ACS episodes. Covariates in the primary models for pain and ACS included: age at polysomnography, sex, hemoglobin, white blood cell count (WBC), OAHI, and mean nocturnal SpO₂. All covariates meeting a significance criteria of p<0.20 were subsequently included in the final model for pain or ACS. Pain rate was defined as number of vaso-occlusive pain events that required hospitalization per year. ACS event was defined as an episode of acute respiratory distress associated with a new radiodensity on chest roentgenogram and at least one of the following: temperature greater than 38° Celsius, increased respiratory effort, decreased oxygen saturation, or increased respiratory rate documented in the medical record. A diagnosis of pneumonia was considered an ACS episode. If a pain event occurred with an ACS episode, the participant was counted as having an ACS event.

Results: A total of 252 participants with SCA underwent polysomnography and after quality control, 243 were included; of these 223 had values for pain and ACS after polysomnography; missing data were due to lack of follow-up. Of the 223 participants, 18 on hydroxyurea therapy at the time of PSG and one with missing hydroxyurea status were excluded in primary analyses as hydroxyurea treatment is known to significantly influence pain incidence. The final sample included 204 participants, median age 10.4 years (interquartile range 7.3). Participants were followed for median 5.0 years (interquartile range 1.8 after PSG). After adjusting for age, sex, WBC, and hemoglobin, higher nocturnal SpO₂ was associated with increased incidence of pain, which is in the opposite direction of our hypothesis (incidence rate ratio 1.11, 95% CI 1.06-1.17, p<0.001). Mean nocturnal SpO₂ was not associated with ACS (incidence rate ratio 1.02, CI 0.96-1.09, p=0.500). In separate models, adjusting for age, sex, WBC, and hemoglobin, OAHI was not associated with future pain using either the log OAHI (IRR 0.99, CI 0.88-1.10, p=0.805) or with OAHI ≥2 (IRR 0.87, CI 0.55-1.41, p=0.569). After adjustment for covariates, OAHI was not associated with ACS using either the log OAHI (IRR 1.06, CI 0.92-1.21, p=0.450) or with OAHI ≥2 (IRR 0.86, CI 0.53-1.39, p=0.541). In an attempt to replicate the Hargrave analysis (Blood. 2003; 101(3)846-8), we investigated whether pain days per year was associated with nocturnal SpO₂. Nocturnal SpO₂was associated with pain days per year, but in the opposite direction of our hypothesis (IRR 1.12, 95% CI 1.05-1.20, p= 0.001).

Conclusion: In an unselected group of children with SCA, low mean nocturnal SpO₂ and elevated OAHI are not associated with clinically relevant increased incidence rates of vaso-occlusive pain or ACS.