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Prepublished online as a Blood First Edition Paper on September 12, 2002; DOI 10.1182/blood-2002-05-1392.
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Blood, 1 February 2003, Vol. 101, No. 3, pp. 846-848
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Brief report
Nocturnal oxygen saturation and painful sickle cell crises
in children
Darren R. Hargrave,
Angie Wade,
Jane P. M. Evans,
Deborah K. M. Hewes, and
Fenella J. Kirkham
From the Department of Paediatric Epidemiology and
Biostatistics and from the Neurosciences Unit, Institute of Child
Health; Great Ormond Street Hospital; and Department of Haematology,
University College Hospital; all of London, United Kingdom; and
Paediatric Oncology Unit, The Royal Marsden Hospital, Sutton,
United Kingdom.
 |
Abstract |
The pathogenesis of acute painful crisis in children with sickle
cell disease is poorly understood; suggested risk factors include
sickle cell type, severity of anemia, fetal hemoglobin concentration,
and hypoxemia from upper airway obstruction. In a cohort study of 95 patients the relationship between clinical, laboratory, and sleep study
data and frequency of painful crisis was investigated. Both univariate
and multiple regression modeling showed that low nocturnal oxygen
saturation was highly significantly associated with a higher rate of
painful crisis in childhood (P < .0001). Screening and
treatment for hypoxemia may reduce the frequency of this and other
complications of the disease.
(Blood. 2003;101:846-848)
© 2003 by The American Society of Hematology.
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Introduction |
Painful crisis is the most common event in children
with sickle cell disease (SCD), but the pathogenesis remains poorly
understood. Acutely, precipitating factors may include cold,
dehydration, infection, and hypoxia, and there are epidemiologic data
suggesting that genotype, early dactylitis, leucocytosis, hemoglobin,
and hemoglobin F are risk factors for frequent
pain.1-4
There is increasing evidence that pulse oximetry measurements in sickle
cell disease reflect arterial oxygen saturation.5 Nocturnal desaturation, measured using pulse oximetry, is common in
SCD, possibly secondary to upper airway obstruction
(UAO).6-10 We have previously published the results of a
cohort study investigating the relationship between nocturnal hypoxemia
and central nervous morbidity9; we present here the effect
on pain as a secondary end point.
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Study design |
The cohort of 95 patients attending the sickle cell clinic at
the Queen Elizabeth Children's Hospital in London was studied from
January 1, 1991, to April 30, 2000. The hospital ethics committee approved the study, and written informed consent was obtained. Painful
crises requiring hospital treatment (emergency department and/or
admission) were recorded. A pain rate (hospital days for pain per years
of follow-up) was calculated for the whole follow-up period or until
death (2 patients) or the initiation of regular transfusion (14 patients) or hydroxyurea (1 patient). Data were recorded on risk
factors previously reported in the literature,3,4 including dactylitis in the first year of life, mean hemoglobin (early
Hb) and white blood cell count (early WBC) from the second year,
baseline hemoglobin and hematocrit (Hb, Hct, at sleep study), fetal
hemoglobin levels (HbF, only homozygous sickle cell disease [HbSS]),
and timing of adenotonsillectomy if performed.
A pulse oximeter (Ohmeda Biox 3700, Hatfield, United Kingdom)
was used to record oxygen saturation (SaO2)
continuously during sleep, and the data were analyzed blind to the pain
data. Sixty-three sleep studies took place in the patients' home; the
remainder took place in the Sleep Laboratory at Great Ormond Street
Hospital. Studies lasted from 4.3 to 8.2 hours (median, 7.5 hours).
Movement artifact was excluded manually. We examined the data for mean and minimum SaO2 and percentage of sleep spent
at SaO2 less than 90% and less than 80%. We
also classified the sleep studies as with or without significant
transient or prolonged dips (more than 4% from baseline) in
oxygenation associated with acute pulse rate rises, suggestive of
obstructive sleep apnea.
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Results and discussion |
The mean follow-up period from the time of the sleep study was 4.6 years (SD, 2.85 years). The mean pain rate was 2.94 days (SD, 3.8 days)
per year; 9 of the 95 patients had no pain episodes recorded. There
were 2 sickle-related deaths, and 6 patients had a stroke. Chest
syndrome was recorded in 12 patients, with a range of episodes per
individual of 0 to 8 events. Table 1
shows the baseline characteristics and univariate analysis of the
relationship between the risk factors and the average number of pain
days per year in the study cohort. Lower baseline Hct and Hb were
significantly associated with increased pain rate, as was HbSS
genotype. There were significant associations between a decreased pain
rate and higher mean SaO2 (average fall, 0.75 [95% confidence interval (CI), 0.58, 0.92] per unit increase
in SaO2), higher minimum
SaO2, and decreased percentage of sleep study
with SaO2 less than 80% or less than 90%.
There were no significant associations with the other variables.
Multiple linear regression was used to quantify the association between
overnight SaO2 measurements and pain, both
before and after adjustment for potential confounding variables. Of the
5 overnight measurements, mean saturation was most strongly associated
with average pain. After accounting for variability in mean saturation,
only minimum saturation remained of borderline significance
(P = .051) when modeling the variation in pain rates. After adjustment for genotype (SC, SS, S thal), dactylitis
before 1 year of age, baseline Hb, HbF, early Hb, and WBC, mean
saturation remained significantly associated with pain rate
(P < .000 05). The presence of dips was additionally
significant within this model (P = .007). An increase of
one unit in mean SaO2 was associated with an
average fall of 0.83 (95% CI, 0.58, 1.07) in the number of days of
pain per year (P < .000 05). The presence of dips was associated with 2.97 (95% CI, 0.85, 5.10) more days of pain on average
per year. The results were similar when adjusted for hematocrit in the
79 patients for whom it was available.
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Table 1.
Linear regression analysis of clinical, laboratory, and
sleep study variables against pain rate (number of pain days per years
of follow-up)
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For patients who underwent adenotonsillectomy (n = 28; 30%), there
was a decrease in the number of days in pain from the year before to
the year after surgery (3.75 vs 2.64, a difference of  1.11 [95% CI,
2.68, 0.46] days per year), which did not reach statistical
significance (P = .16, paired t test). Nine of
27 patients who underwent adenotonsillectomy had sleep study data collected postoperatively as well as preoperatively because of persistent symptoms, at a median time postoperatively of 4.5 years (range, 0.5-7 years). Six still had significant dips in
SaO2 as defined above, and mean saturation fell
from an average of 94.8% to 92.9% (difference, 1.9% [95% CI,
5.9%, 2.0%], P = .29). Interestingly, if the results
are split into patients undergoing adenotonsillectomy for obstructive
sleep apnea (OSA; n = 11) or for repeated infections (n = 17), the
OSA patients do not show any correlation with frequency of painful
episodes, but there was an association for those for whom the
indication was recurrent infection (P = .02).
In our study, low nocturnal oxygen saturation appears to be highly
significantly associated with frequent painful vasoocclusive crisis in
SCD, perhaps because it is one of the factors involved in precipitating
hypoxic-ischemic pathology in bone marrow. Interestingly, lower
hemoglobin was associated with more frequent painful crises in these
children, in contrast to the previous literature but in line with our
finding that low oxygen saturation is associated with
anemia.11 It is possible that the paradoxical association of higher hemoglobin/hematocrit3 and oxygen
saturation4 seen in adults with frequent painful crisis is
not manifest in early childhood, perhaps because it depends on the
degree of adaptive acclimatization to chronic hypoxemia; future
longitudinal studies may elucidate this. Increased viscosity as
measured by hematocrit was significantly associated with an increased
pain rate.
Our data require confirmation in other populations, because there are
sources of bias. This is a hospital-based rather than a birth cohort,
which may explain the high proportion of children with at least one
painful episode requiring hospital attendance. We did not attempt to
measure the experience of pain at home, which has considerable
methodologic difficulties. At the time of the study, most families in
the local community used Queen Elizabeth Hospital for primary care, but
with changes in the configuration of health services children are now
more likely to be managed at home, and there are now validated methods
of assessing pain outside the hospital. We did not have the resources
to undertake rigorous reproducibility testing of our home sleep
studies. Because the mean saturation is a better predictor of frequent
pain than frequent dips, it may be possible to screen the population
using a short period of daytime pulse oximetry, and we are at present investigating the reproducibility of clinic measurements and the correlation with overnight saturation monitoring.
Although UAO is relatively common in the sickle population it may not
be the major cause of nocturnal hypoxemia, and in this study
adenotonsillectomy did not significantly reduce the number of painful
crises. Indeed, the main effect of adenotonsillectomy was seen in
patients where the indication for operation was recurrent tonsillitis,
suggesting that it is the absence of infection that may be the benefit
and that this is the real risk factor in this group.12
Hypoxemia may persist around the clock,9 perhaps secondary
to mechanisms other than UAO and chronic anemia. The size of the airway
may be determined in early life, perhaps explaining why
adenotonsillectomy does not always improve the oxygen
saturation.13 Nocturnal hypoxemia might precipitate
vasoocclusion in the lung as well as the bone marrow, with progressive
parenchymal lung injury and poor gas exchange14; the
investigation of this type of vicious cycle would require a
longitudinal study with repeated lung function testing. However, it has
long been postulated that hypoxia is a physiologic precipitating factor
in the formation of the sickled cell, and it is the basis for avoidance
of hypoxic environments, for example, in anesthesia and high-altitude
travel.15 The possibility that appropriate management of
chronic hypoxemia reduces the incidence of stroke, acute painful
crises, and death in children with SCD will be examined in the planned
controlled trial, funded by the Stroke Association, of
overnight oxygen supplementation.
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Footnotes |
Submitted May 30, 2002; accepted August 26, 2002.
Prepublished online
as Blood First Edition Paper, September 12, 2002; DOI
10.1182/blood-2002-05-1392.
Supported by the Wellcome Trust (F.J.K.) and Action Research. The work
was undertaken at Queen Elizabeth Hospital for Children, London, which
received some of its funding from the National Health Service Executive.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
Reprints: Darren R. Hargrave, Paediatric Oncology
Unit, The Royal Marsden Hospital, Sutton, Surrey, SM2 5PT, United
Kingdom; e-mail:
darren.hargrave{at}rmh.nthames.nhs.uk.
| |
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Top
Abstract
Introduction