The Effect of Orthostatic Hypotension Detected Pre-Operatively on Post-Operative Outcome.

BACKGROUND: Exacerbation of or new onset orthostatic hypotension in perioperative patients can occur. There is complex underlying pathophysiology with further derailment likely caused by acute cardiovascular changes associated with surgery. The implications for post-operative recovery are unclear, particularly in frail and older patients. We retrospectively explored patient notes for evidence of post-operative orthostatic intolerance in relation to pre-operative orthostatic hypotension. METHODS: Supine and 1-minute and 3-minute standing blood pressure measures obtained from adult patients before mainly general, orthopedic or uro/gynecology surgery were compared to post-operative outcome, specifically, evidence in patient notes about falls, feeling dizzy/unsteady and/or fearful to stand. Orthostatic hypotension was defined as a 20 mmHg or more and/or 10 mmHg or more fall in systolic and diastolic blood pressure, respectively, within ~3 minutes of standing after lying supine for an electrocardiogram. RESULTS: Whilst all patients included had a 1-minute standing blood pressure assessment (N = 170), 3-minute assessment was performed less commonly (N = 113). Nevertheless, one-quarter (23.5%; N = 40) of 170 patients had pre-operative orthostatic hypotension. This was not clearly explained by cardiac or neurological disease or by common medications, but did occur more frequently in older patients and in those aged 65 years or more with higher clinical frailty scale scores. The COVID-19 pandemic reduced the number of patients progressing to surgery within the planned study timescale (N = 143/170; 84.1%). Nevertheless, patients with orthostatic hypotension stayed longer in hospital post-operatively and were more likely to have an episode of fall, unsteadiness and/or dizziness documented (un-prompted) in their notes. CONCLUSIONS: These data provide further impetus for research into modifiable perioperative risk factors associated with orthostatic hypotension. These risks are not confined to those with a pre-existing dysautonomia diagnosis.

A prospective five-year cohort study of undiagnosed sleep apnea in patients undergoing coronary artery bypass graft surgery.

BACKGROUND: We aimed to study prospectively the nature and effect of sleep apnea-hypopnea syndrome (SAHS) in patients undergoing coronary artery bypass graft (CABG) surgery over five years of follow-up. METHODS: Patients undergoing CABG surgery (N.=145) were assessed longitudinally (baseline, 1 year, and 5 years post-surgery) using the 'STOP-BANG' screen of sleep apnea risk. Additionally, all patients had a preoperative multiple-channel sleep-study, providing acceptable data for an obstructive and central apnea, and desaturation index in 97 patients. RESULTS: Preoperatively, over half (63%) of patients obtained an apnea-hypopnea index score (combining apnea types) in the moderate-severe range for SAHS, and STOP-BANG threshold score (>3/8) was reached by most (95%) patients. Despite some improvement in 'STOP symptoms' at 1-year follow-up, most patients (98%) remained at risk of SAHS at 5 years post-surgery. There was an underlying and chronic relationship between STOP-BANG score and cardiac symptoms at both baseline and 5-year follow-up. Additionally, SAHS variables were associated with greater incidence of acute postoperative events, and generally with increased length of stay on the intensive care unit. CONCLUSIONS: We confirm that SAHS is common in CABG-surgery patients, presenting additional clinical challenges and cost implications. The underlying pathophysiology is complex, including upper airway obstruction and cardiorespiratory changes of heart failure. In patients presenting for CABG-surgery, we show chronic susceptibility to SAHS, likely associated with traditional risk factors e.g. obesity but perhaps also with gradual decline in heart function itself. Superimposed on this, there is potential for exacerbated risk of morbidity at the time of CABG surgery itself.

Hearing loss mediates executive function impairment in sleep-disordered breathing.

BACKGROUND: Sleep-disordered breathing (SDB) is often co-morbid with conductive hearing loss in early childhood due to a shared aetiology of adenotonsillar hypertrophy. Hearing loss is independently associated with impairment of executive function and behavioural difficulties. We hypothesised that these impairments in children with SDB may be mediated through hearing loss. METHODS: Fifty-eight children including 37 snorers awaiting adenotonsillectomy and 21 healthy non-snoring controls, aged 3-5 years, were assessed with pure tone audiometry, Strengths and Difficulties (SDQ), Behaviour Rating of Executive Function (BRIEF-P), and Childhood Middle Ear Disease and Hearing questionnaires. Polysomnography in snoring children generated an obstructive apnoea/hypopnea index (OAHI). Two regression models examined the effect of SDB and the mediating impact of hearing loss on BRIEF and SDQ. RESULTS: Snoring children had significantly poorer hearing, greater past exposure to hearing loss, and higher total SDQ and BRIEF-P scores than non-snoring controls. The first regression model, including all children, demonstrated that the impact of snoring on BRIEF_P, but not SDQ, was entirely mediated by a history of hearing loss exposure but not same-day audiometry. The second model examined snoring children only, categorising the group into 12 with obstructive sleep apnoea (OSA) (OAHI ≥ 5) and 25 without OSA. OSA had a direct effect on SDQ scores, but this was not mediated by a history of hearing loss. CONCLUSION: In early childhood, conductive hearing loss mediates the relationship between SDB, irrespective of severity, and parent report of executive function but not behaviour. Treatment of hearing loss in pre-school SDB might improve executive function.

Precursors of executive function in infants with sickle cell anemia.

Executive dysfunction occurs in sickle cell anemia, but there are few early data. Infants with sickle cell anemia (n = 14) and controls (n = 14) performed the "A-not-B" and Object Retrieval search tasks, measuring precursors of executive function at 9 and 12 months. Significant group differences were not found. However, for the A-not-B task, 7 of 11 sickle cell anemia infants scored in the lower 2 performance categories at 9 months, but only 1 at 12 months (P = .024); controls obtained scores at 12 months that were statistically comparable to the scores they had already obtained at 9 months. On the Object Retrieval task, 9- and 12-month controls showed comparable scores, whereas infants with sickle cell anemia continued to improve (P = .027); at 9 months, those with lower hemoglobin oxygen saturation passed fewer trials (R s = 0.670, P = .024) and took longer to obtain the toy (R s = -0.664, P = .013). Subtle delays in acquiring developmental skills may underlie abnormal executive function in childhood.

A meta-analysis of cognitive outcome following coronary artery bypass graft surgery.

Coronary artery bypass graft (CABG) surgery is an established treatment for complex coronary artery disease. There is a widely held belief that cognitive decline presents post-operatively. A consensus statement of core neuropsychological tests was published in 1995 with the intention of guiding investigation into this issue. We conducted a meta-analysis evaluating the evidence for cognitive decline post-CABG surgery. Twenty-eight published studies, accumulating data from up to 2043 patients undergoing CABG surgery, were included. Results were examined at 'very early' (<2 weeks), 'early' (3 months) and 'late' (6-12 months) time periods post-operatively. Two of the four tests suggested an initial very early decrease in psychomotor speed that was not present at subsequent testing. Rather, the omnibus data indicated subtle improvement in function relative to pre-operative baseline testing. Our findings suggest improvement in cognitive function in the first year following CABG surgery. This is contrary to the more negative interpretation of results of some individual publications included in our review, which may reflect poor outcomes in a few patients and/or methodological issues.

Changing patterns of neuropsychological functioning in children living at high altitude above and below 4000 m: a report from the Bolivian Children Living at Altitude (BoCLA) study.

The brain is highly sensitive to environmental hypoxia. Little is known, however, about the neuropsychological effects of high altitude residence in the developing brain. We recently described only minor changes in processing speed in native Bolivian children and adolescents living at approximately 3700 m. However, evidence for loss of cerebral autoregulation above this altitude (4000 m) suggests a potential threshold of hypoxia severity over which neuropsychological functioning may be compromised. We conducted physiological and neuropsychological assessments in 62 Bolivian children and adolescents living at La Paz (∼3700 m) and El Alto (∼4100 m) in order to address this issue. Groups were equivalent in terms of age, gender, social class, schooling, parental education and genetic admixture. Apart from percentage of hemoglobin saturated with oxygen in arterial blood (%SpO(2)), participants did not differ in their basal cardiac and cerebrovascular performance as explored by heart rate, mean arterial pressure, end-tidal carbon dioxide, and cerebral blood flow velocity at the basilar, anterior, middle and posterior cerebral arteries. A comprehensive neuropsychological assessment was administered, including tests of executive functions, attention, memory and psychomotor performance. Participants living at extreme altitude showed lower levels of performance in all executive tests (Cohen effect size = -0.91), whereas all other domains remained unaffected by altitude of residence. These results are compatible with earlier physiological evidence of a transitional zone for cerebral autoregulation at an altitude of 4000 m. We now show that above this threshold, the developing brain is apparently increasingly vulnerable to neuropsychological deficit.

Neurophysiological evidence for cognitive and brain functional adaptation in adolescents living at high altitude.

OBJECTIVE: Neurophysiological methods were used to study the effects of high altitude living on brain functions in a subgroup of participants of the Bolivian Children Living at Altitude (BoCLA) project. METHODS: Electroencephalogram (EEG), event-related potentials (ERP) and cerebral blood flow velocity (CBFV) were recorded in two groups of adolescents (aged 13-16 years), living either at sea-level or high altitude (~3700m). RESULTS: Neuropsychological testing revealed no deficits in the high altitude group, despite significantly reduced blood oxygen saturation. In agreement, ERPs elicited by oddball target detection and choice reaction time tasks were not different between groups. In contrast, resting state EEG showed reductions in delta and beta frequency amplitudes in adolescents living at high altitude. The EEG attenuations were correlated with lower CBFV, and the EEG group differences diminished during task performance. CONCLUSIONS: No indication was found for negative sequelae of chronic hypoxia in adolescents born and living at an altitude of ~3700m, rather evidence for successful neurophysiological adaptation was found under such conditions. SIGNIFICANCE: Dynamic regulation of metabolic demand is one adaptive mechanism that preserves cognitive development at high altitude.

Effects of aging on habituation to novelty: an ERP study.

Age-related effects on novelty processing have been reported and are linked with changes in frontal lobe functioning. Auditory novelty processing and habituation of the novelty P3 event-related potential were investigated in younger and older adults. Novelty processing, as indexed by novelty P3 amplitude, was similar between the groups. We found the expected decrease in novelty P3 amplitude at frontal regions in younger adults with repetition of novel stimuli. In contrast, older adults displayed no evidence of habituation, rather an increase in novelty P3 amplitude at frontal sites was found when novel stimuli were repeated. We extend current understanding of novelty processing in normal aging by comparing this habituation related-hyperfrontality with intellectual functioning.

Development of aptitude at altitude.

Millions of people currently live at altitudes in excess of 2500 metres, where oxygen supply is limited, but very little is known about the development of brain and behavioural function under such hypoxic conditions. We describe the physiological, cognitive and behavioural profile of a large cohort of infants (6-12 months), children (6-10 years) and adolescents (13-16 years) who were born and are living at three altitude locations in Bolivia ( approximately 500 m, approximately 2500 m and approximately 3700 m). Level of haemoglobin oxygen saturation and end-tidal carbon dioxide were significantly lower in all age groups living above 2500 metres, confirming the presence of hypoxia and hypocapnia, but without any detectable detriment to health. Infant measures of neurodevelopment and behaviour yielded comparable results across altitude groups. Neuropsychological assessment in children and adolescent groups indicated a minor reduction in psychomotor speed with increasing altitude, with no effect of age. This may result from slowing of underlying brain activity in parallel with reduced cerebral metabolism and blood flow, evidenced here by reduced cerebral blood flow velocity, particularly in the basilar artery, in children and adolescents. The proportion of European, Native American and African genetic admixture was comparable across altitude groups, suggesting that adaptation to high altitude in these children occurred in response to chronic hypoxic exposure irrespective of ethnic origin. Thus, psychomotor slowing is proposed to be an adaptive rather than a deficient trait, perhaps enabling accuracy of mental activity in hypoxic conditions.

Auditory and visual novelty processing in normally-developing Kenyan children.

OBJECTIVE: The aim of this study was to describe the normative development of the electrophysiological response to auditory and visual novelty in children living in rural Kenya. METHODS: We examined event-related potentials (ERPs) elicited by novel auditory and visual stimuli in 178 normally-developing children aged 4-12 years (86 boys, mean 6.7 years, SD 1.8 years and 92 girls, mean 6.6 years, SD 1.5 years) who were living in rural Kenya. RESULTS: The latency of early components (auditory P1 and visual N170) decreased with age and their amplitudes also tended to decrease with age. The changes in longer-latency components (Auditory N2, P3a and visual Nc, P3a) were more modality-specific; the N2 amplitude to novel stimuli decreased with age and the auditory P3a increased in both latency and amplitude with age. The Nc amplitude decreased with age while visual P3a amplitude tended to increase, though not linearly. CONCLUSIONS: The changes in the timing and magnitude of early-latency ERPs likely reflect brain maturational processes. The age-related changes to auditory stimuli generally occurred later than those to visual stimuli suggesting that visual processing matures faster than auditory processing. SIGNIFICANCE: ERPs may be used to assess children's cognitive development in rural areas of Africa.

Auto-adjusting positive airway pressure in children with sickle cell anemia: results of a phase I randomized controlled trial.

Low nocturnal oxygen saturation (SpO(2)) is implicated in complications of Sickle Cell Anemia (SCA). Twenty-four children with SCA were randomized to receive overnight auto-adjusting continuous positive airway pressure (auto-CPAP) with supplemental oxygen, if required, to maintain SpO(2) >or=94% or as controls. We assessed adherence, safety, sleep parameters, cognition and pain. Twelve participants randomized to auto-CPAP (3 with oxygen) showed improvement in Apnea/Hypopnea Index (p<0.001), average desaturation events >3%/hour (p=0.02), mean nocturnal SpO(2) (p=0.02) and cognition. Primary efficacy endpoint (Processing Speed Index) showed no group differences (p=0.67), but a second measure of processing speed and attention (Cancellation) improved in those receiving treatment (p=0.01). No bone marrow suppression, rebound pain or serious adverse event resulting from auto-CPAP use was observed. Six weeks of auto-CPAP therapy is feasible and safe in children with SCA, significantly improving sleep-related breathing disorders and at least one aspect of cognition.

Cerebral blood flow velocity and cognition in children before and after adenotonsillectomy.

OBJECTIVE: The goal was to determine whether amelioration of sleep-disordered breathing through adenotonsillectomy would reduce middle cerebral artery velocity in parallel with improvements in cognition and behavior. METHODS: For 19 children (mean age: 6 years) with mild sleep-disordered breathing, and 14 healthy, ethnically similar and age-similar, control subjects, parents repeated the Pediatric Sleep Questionnaire an average of 12 months after adenotonsillectomy. Children with sleep-disordered breathing underwent repeated overnight measurement of mean oxyhemoglobin saturation. Neurobehavioral tests that yielded significant group differences preoperatively were readministered. Middle cerebral artery velocity measurements were repeated with blinding to sleep study and neuropsychological results, and mixed-design analyses of variance were performed. RESULTS: The median Pediatric Sleep Questionnaire score significantly improved postoperatively, and there was a significant increase in mean overnight oxyhemoglobin saturation. The middle cerebral artery velocity decreased in the sleep-disordered breathing group postoperatively, whereas control subjects showed a slight increase. A preoperative group difference was reduced by the postoperative assessment, which suggests normalization of middle cerebral artery velocity in those with sleep-disordered breathing. The increase in mean overnight oxyhemoglobin saturation postoperatively was associated with a reduction in middle cerebral artery velocity in a subgroup of children. A preoperative group difference in processing speed was reduced postoperatively. Similarly, a trend for a preoperative group difference in visual attention was reduced postoperatively. Executive function remained significantly worse for the children with sleep-disordered breathing, compared with control subjects, although mean postoperative scores were lower than preoperative scores. CONCLUSIONS: Otherwise-healthy young children with apparently mild sleep-disordered breathing have potentially reversible cerebral hemodynamic and neurobehavioral changes.

To sleep, perchance to enrich learning?

There is evidence that sleep enhances memory and learning. Childhood is a critical period for neurodevelopment, and minor but persistent disruption of sleep may have long-term implications for cognitive performance. Sleep is critical for health and is undervalued both in our 24 h society and in paediatric clinical practice. Paediatricians need to understand the neurodevelopmental consequences of poor quality sleep in children.

Brain response to unexpected novel noises in children with low and high trait anxiety.

The behavioral inhibition system [Gray, J. A. The neuropsychology of anxiety: An enquiry into the functions of the septo-hippocampal system. Oxford: Oxford University Press, 1982] proposes that anxiety is associated with the processing of novel stimuli. We aimed to explore this relationship by recording auditory event-related potentials associated with unexpected novel noises in typically developing children. Children aged 10-14 years with low (n = 12) and high (n = 11) self-report trait anxiety were assessed using a novelty oddball task. The N1 associated with novel stimuli, specifically the "N1c" component maximal at temporal lobe sites, was of significantly longer latency (p = .014) and greater amplitude (p = .004) in the high compared with the low anxious group. This group difference was supported by linear correlations between N1c amplitude and trait anxiety scores. There was no effect of anxiety on the later novelty P3. These data suggest a subtle moderating role of trait anxiety on brain response to novelty, and further research with clinically anxious children is indicated.

Increased cerebral blood flow velocity in children with mild sleep-disordered breathing: a possible association with abnormal neuropsychological function.

OBJECTIVE: Sleep-disordered breathing describes a spectrum of upper airway obstruction in sleep from simple primary snoring, estimated to affect 10% of preschool children, to the syndrome of obstructive sleep apnea. Emerging evidence has challenged previous assumptions that primary snoring is benign. A recent report identified reduced attention and higher levels of social problems and anxiety/depressive symptoms in snoring children compared with controls. Uncertainty persists regarding clinical thresholds for medical or surgical intervention in sleep-disordered breathing, underlining the need to better understand the pathophysiology of this condition. Adults with sleep-disordered breathing have an increased risk of cerebrovascular disease independent of atherosclerotic risk factors. There has been little focus on cerebrovascular function in children with sleep-disordered breathing, although this would seem an important line of investigation, because studies have identified abnormalities of the systemic vasculature. Raised cerebral blood flow velocities on transcranial Doppler, compatible with raised blood flow and/or vascular narrowing, are associated with neuropsychological deficits in children with sickle cell disease, a condition in which sleep-disordered breathing is common. We hypothesized that there would be cerebral blood flow velocity differences in sleep-disordered breathing children without sickle cell disease that might contribute to the association with neuropsychological deficits. DESIGN: Thirty-one snoring children aged 3 to 7 years were recruited from adenotonsillectomy waiting lists, and 17 control children were identified through a local Sunday school or as siblings of cases. Children with craniofacial abnormalities, neuromuscular disorders, moderate or severe learning disabilities, chronic respiratory/cardiac conditions, or allergic rhinitis were excluded. Severity of sleep-disordered breathing in snoring children was categorized by attended polysomnography. Weight, height, and head circumference were measured in all of the children. BMI and occipitofrontal circumference z scores were computed. Resting systolic and diastolic blood pressure were obtained. Both sleep-disordered breathing children and the age- and BMI-similar controls were assessed using the Behavior Rating Inventory of Executive Function (BRIEF), Neuropsychological Test Battery for Children (NEPSY) visual attention and visuomotor integration, and IQ assessment (Wechsler Preschool and Primary Scale of Intelligence Version III). Transcranial Doppler was performed using a TL2-64b 2-MHz pulsed Doppler device between 2 pm and 7 pm in all of the patients and the majority of controls while awake. Time-averaged mean of the maximal cerebral blood flow velocities was measured in the left and right middle cerebral artery and the higher used for analysis. RESULTS: Twenty-one snoring children had an apnea/hypopnea index <5, consistent with mild sleep-disordered breathing below the conventional threshold for surgical intervention. Compared with 17 nonsnoring controls, these children had significantly raised middle cerebral artery blood flow velocities. There was no correlation between cerebral blood flow velocities and BMI or systolic or diastolic blood pressure indices. Exploratory analyses did not reveal any significant associations with apnea/hypopnea index, apnea index, hypopnea index, mean pulse oxygen saturation, lowest pulse oxygen saturation, accumulated time at pulse oxygen saturation <90%, or respiratory arousals when examined in separate bivariate correlations or in aggregate when entered simultaneously. Similarly, there was no significant association between cerebral blood flow velocities and parental estimation of child's exposure to sleep-disordered breathing. However, it is important to note that whereas the sleep-disordered breathing group did not exhibit significant hypoxia at the time of study, it was unclear to what extent this may have been a feature of their sleep-disordered breathing in the past. IQ measures were in the average range and comparable between groups. Measures of processing speed and visual attention were significantly lower in sleep-disordered breathing children compared with controls, although within the average range. There were similar group differences in parental-reported executive function behavior. Although there were no direct correlations, adjusting for cerebral blood flow velocities eliminated significant group differences between processing speed and visual attention and decreased the significance of differences in Behavior Rating Inventory of Executive Function scores, suggesting that cerebral hemodynamic factors contribute to the relationship between mild sleep-disordered breathing and these outcome measures. CONCLUSIONS: Cerebral blood flow velocities measured by noninvasive transcranial Doppler provide evidence for increased cerebral blood flow and/or vascular narrowing in childhood sleep-disordered breathing; the relationship with neuropsychological deficits requires further exploration. A number of physiologic changes might alter cerebral blood flow and/or vessel diameter and, therefore, affect cerebral blood flow velocities. We were able to explore potential confounding influences of obesity and hypertension, neither of which explained our findings. Second, although cerebral blood flow velocities increase with increasing partial pressure of carbon dioxide and hypoxia, it is unlikely that the observed differences could be accounted for by arterial blood gas tensions, because all of the children in the study were healthy, with no cardiorespiratory disease, other than sleep-disordered breathing in the snoring group. Although arterial partial pressure of oxygen and partial pressure of carbon dioxide were not monitored during cerebral blood flow velocity measurement, assessment was undertaken during the afternoon/early evening when the child was awake, and all of the sleep-disordered breathing children had normal resting oxyhemoglobin saturation at the outset of their subsequent sleep studies that day. Finally, there is an inverse linear relationship between cerebral blood flow and hematocrit in adults, and it is known that iron-deficient erythropoiesis is associated with chronic infection, such as recurrent tonsillitis, a clinical feature of many of the snoring children in the study. Preoperative full blood counts were not performed routinely in these children, and, therefore, it was not possible to exclude anemia as a cause of increased cerebral blood flow velocity in the sleep-disordered breathing group. However, hemoglobin levels were obtained in 4 children, 2 of whom had borderline low levels (10.9 and 10.2 g/dL). Although there was no apparent relationship with cerebral blood flow velocity in these children (cerebral blood flow velocity values of 131 and 130 cm/second compared with 130 and 137 cm/second in the 2 children with normal hemoglobin levels), this requires verification. It is of particular interest that our data suggest a relationship among snoring, increased cerebral blood flow velocities and indices of cognition (processing speed and visual attention) and perhaps behavioral (Behavior Rating Inventory of Executive Function) function. This finding is preliminary: a causal relationship is not established, and the physiologic mechanisms underlying such a relationship are not clear. Prospective studies that quantify cumulative exposure to the physiologic consequences of sleep-disordered breathing, such as hypoxia, would be informative.

Impact of frontal white matter lesions on performance monitoring: ERP evidence for cortical disconnection.

We examined the impact of discrete white matter lesions in the frontal lobes on event-related potential (ERP) correlates of performance monitoring. We tested the hypothesis that abnormal performance monitoring may result from injury to white matter without evidence of injury to grey matter in the frontal lobes. It was predicted that such lesions may result in disconnection of the lateral and medial frontal cortices. The close interaction of these two areas has been implicated in performance monitoring. Two fast-choice response tasks were administered to patients with MRI-confirmed frontal white matter lesions due to sickle cell disease (SCD) vasculopathy (n = 11; age = 11-23 years; 6 unilateral left lesions and 5 bilateral lesions) and two control groups: SCD patients without brain lesions and non-sickle cell sibling controls (n = 11 each). Stimulus-locked ERP components N2 and P3 were not significantly affected by presence of lesions. The difference between response-locked components to correct trials (correct-response negativity--CRN) and erroneous trials (error-related negativity--ERN) was diminished in patients with unilateral and bilateral frontal white matter lesions. This finding was due to a significantly attenuated ERN amplitude in lesion patients compared with both sibling and non-lesion control groups. These ERP findings were not due to performance differences between groups and hence reflect a compromised neural substrate underlying performance monitoring. The latter may also contribute to the deficits in executive function tasks observed in these patients. As disruption to ERP markers of error processing was found in the absence of lesions to the lateral or medial frontal cortex, we conclude that a functional connection between these areas facilitates performance monitoring, possibly implemented via tracts traversing the deep frontal white matter.

Physiological correlates of intellectual function in children with sickle cell disease: hypoxaemia, hyperaemia and brain infarction.

Lowered intelligence relative to controls is evident by mid-childhood in children with sickle cell disease. There is consensus that brain infarct contributes to this deficit, but the subtle lowering of IQ in children with normal MRI scans might be accounted for by chronic systemic complications leading to insufficient oxygen delivery to the brain. We investigated the relationship between daytime oxyhaemoglobin saturation (SpO2), cerebral blood flow velocity (CBFV) and intellectual function (IQ) using path-analysis in 30 adolescents with sickle cell disease (mean age 17.4 years, SD 4.2). Initial analyses revealed that the association between SpO2 and Full Scale IQ (FSIQ) was fully mediated by increased CBFV, whereby SpO2 was negatively correlated with CBFV and CBFV was negatively correlated with FSIQ, i.e. decreases in oxygen saturation are associated with increases in velocity, and increased velocity is associated with lowered IQ scores. The mediated relationship suggests that lowered IQ may be a function of abnormal oxygen delivery to the brain. Further analyses showed that the association between CBFV and IQ was significant for verbal but not for performance IQ. The pathophysiology characteristic of SCD can interfere with brain function and constrain intellectual development, even in the absence of an infarct. This supports the hypothesis that lowered intellectual function is partly explained by chronic hypoxia, and has wider implications for our understanding of SCD pathophysiology.