Moira C. Dick

The comprehensive care of sickle cell disease

Abstract: Millions of people across the world have sickle cell disease (SCD). Although the true prevalence of SCD in Europe is not certain, London (UK) alone had an estimated 9000 people with the disorder in 1997. People affected by SCD are best managed by a multidisciplinary team of professionals who deliver comprehensive care: a model of healthcare based on interaction of medical and non‐medical services with the affected persons. The components of comprehensive care include patient/parent information, genetic counselling, social services, prevention of infections, dietary advice and supplementation, psychotherapy, renal and other specialist medical care, maternal and child health, orthopaedic and general surgery, pain control, physiotherapy, dental and eye care, drug dependency services and specialist sickle cell nursing. The traditional role of haematologists remains to co‐ordinate overall management and liase with other specialities as necessary. Co‐operation from the affected persons is indispensable to the delivery of comprehensive care. Working in partnership with the hospital or community health service administration and voluntary agencies enhances the success of the multidisciplinary team. Holistic care improves the quality of life of people affected by SCD, and reduces the number as well as length of hospital admissions. Disease‐related morbidity is reduced by early detection and treatment of chronic complications. Comprehensive care promotes awareness of SCD among affected persons who are encouraged to take greater control of their own lives, and achieves better patient management than the solo efforts of any single group of professionals. This cost‐effective model of care is an option for taking haemoglobinopathy services forward in the new millennium.

Windy weather and low humidity are associated with an increased number of hospital admissions for acute pain and sickle cell disease in an urban environment with a maritime temperate climate

Sickle cell disease (SCD) is characterised by intermittent episodes of acute severe pain, related to vaso‐occlusion. Environmental factors are thought to play an important role, and studies in tropical countries have suggested that cold and rainy seasons are associated with increased episodes of acute pain. We have studied retrospectively the number of admissions with acute pain and SCD to Kings College Hospital, London, together with daily meteorological records collected locally. Data from 1400 d and 1047 separate admissions were analysed. Increased admissions were significantly associated with increased wind speed and low humidity, but showed no relationship to temperature, rainfall or barometric pressure. The strongest effect was for (maximum wind speed)/humidity, with 464 admissions on days in the lowest two quartiles of this parameter and 582 in the highest quartiles. The effect of high wind and low humidity is likely to be related to skin cooling.

Coping and health service utilisation in a UK study of paediatric sickle cell pain.

Aims: To assess sickle cell pain and coping in children and to examine the relation between these factors and the utilisation of health services. Methods: Cross sectional study involving 67 children with sickle cell disease attending three London hospitals. Interviews and questionnaires involved measures of pain, health service utilisation, and coping responses (measured with the Coping Strategies Questionnaire (CSQ), revised for children with sickle cell disease). Medical data on complications, haemoglobin (Hb) levels, and foetal haemoglobin (HbF) percentage were also collected. Results: Pain accounted for about 24% of hospital service use, independent of age, sex, number of with sickle cell disease complications, and Hb levels. However, 42% of patients had not utilised hospital services in the past 12 months. Three higher order factors emerged from analysis of the CSQ (active coping, affective coping, passive adherence coping). Pain severity was predicted by passive adherence coping, while utilisation of hospital services was predicted by active coping. Conclusions: Sickle cell disease in children involves severe recurrent pain leading to hospitalisation in some cases. Psychological coping patterns are relevant to both pain experience, and the use of acute hospital services. It is likely that children would benefit from community based interventions that incorporate both medical and psychological assessments.

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

Sleep related breathing disorders and especially low nocturnal oxygen saturation may favor complications of sickle cell disease (SCD) In this phase I trial, autoadjusting continuous positive airway pressure (CPAP) was shown to be a feasible and safe therapy for SCD children. Sleep breathing disorders were improved, and there was evidence of a trend towards reduction of diurnal pain. Low nocturnal oxygen saturation (SpO2) 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 SpO2 ≥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 SpO2 (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.

Serum lactate dehydrogenase activity as a biomarker in children with sickle cell disease

Serum lactate dehydrogenase (LDH) levels were studied in children with HbSS and HbSC in a single institution, and their relationship to cerebral vasculopathy as assessed by transcranial Doppler scanning (TCD). All children with HbSS (n = 97) and HbSC (n = 18) who underwent a TCD scan in 2006 were studied. LDH levels were higher in HbSS patients than HbSC (581 IU/l vs. 305 IU/l, P < 0·001). In children with HbSS, LDH correlated significantly with haemoglobin, reticulocytes, aspartate transaminase and creatinine. LDH also correlated positively and significantly with TCD measurements in the middle and anterior cerebral artery circulations in the children with HbSS.

A Simple Index Using Age, Hemoglobin, and Aspartate Transaminase Predicts Increased Intracerebral Blood Velocity as Measured by Transcranial Doppler Scanning in Children With Sickle Cell Anemia

OBJECTIVE. Increased intracerebral blood velocity measured by transcranial Doppler scanning identifies children with sickle cell anemia who are at increased risk of stroke. We have tried to develop an index based on routine clinical measurements that also predicts increased intracerebral blood flow. METHOD. Routinely collected clinical and laboratory data were correlated with transcranial Doppler measurements on children with sickle cell anemia seen in a single institution in 2006. The index produced was validated on a second independent data set from children with sickle cell anemia. RESULTS. The time-averaged mean of the maximum velocity in centimeters per second in the middle cerebral artery circulation correlated significantly with age, hemoglobin, lactate dehydrogenase, and aspartate transaminase levels, white blood cell count, and creatinine level. On multiple regression, hemoglobin and aspartate transaminase levels maintained their significance, whereas age had borderline significance, and an index was developed linked to a time-averaged mean of the maximum velocity of 220 − (8 × hemoglobin) − (1.4 × age) + (0.4 × aspartate transaminase). This detected a time-averaged mean of the maximum velocity of >170 cm/second with 100% sensitivity and 58% specificity. The index was validated on the second data set and again showed 100% sensitivity with 73% specificity. CONCLUSION. This simple index has the potential to identify children who are at higher risk of cerebrovascular disease to allow them to be prioritized for transcranial Doppler scanning and other intracerebral imaging.

The associations between air quality and the number of hospital admissions for acute pain and sickle-cell disease in an urban environment.

The clinical severity of sickle‐cell disease (SCD) is dependent on genetic and environmental variables. Environmental factors have been poorly studied. We have investigated possible links between air pollution and acute pain in SCD. We retrospectively studied the numbers of daily admissions with acute sickle‐cell pain to Kings College Hospital, London, in relation to local daily air quality measurements. We analysed 1047 admissions over 1400 d (1st January 1998–31st October 2001). Time series analysis was performed using the cross‐correlation function (CCF). CCF showed a significant association between increased numbers of admissions and low levels of nitric oxide (NO), low levels of carbon monoxide (CO) and high levels of ozone (O3). There was no association with sulphur dioxide (SO2), nitrogen dioxide or PM10 (dust). The significant results were further examined using quartile analysis. This confirmed that high levels of O3 and low levels of CO were associated with increased numbers of hospital admissions. Low NO levels were also associated with increased admissions but did not reach statistical significance on quartile analysis. Our study suggests air quality has a significant effect on acute pain in SCD and that patients should be counselled accordingly. The potential beneficial effect of CO and NO is intriguing and requires further investigation.

Transcranial Doppler scanning and the assessment of stroke risk in children with haemoglobin sickle cell disease

Objective : To assess the role of transcranial Doppler (TCD) scanning in assessing the risk of stroke in children with haemoglobin SC (HbSC) disease. TCD scanning has an established role in primary stroke prevention in sickle cell anaemia but its value in HbSC is unknown. Design : A retrospective audit of routinely performed TCD scans and routinely collected clinical data. Setting : A paediatric sickle cell clinic in a teaching hospital in south London, UK. Patients : 46 children with HbSC disease who have undergone routinely performed TCD scans and steady-state blood tests. Main outcome measures: The time-averaged mean of the maximum velocity (TAMMV) in the middle cerebral artery circulation correlated with clinical and laboratory data. Results: The mean TAMMV was 94 cm/s, with a 98th centile of 128 cm/s. This is significantly less than the published ranges for HbSS, with a mean reading of 129 cm/s. One child had a stroke at the age of 5 years, when her TAMMV was measured at 146 cm/s. Conclusions: Further studies are needed to assess stroke risk in HbSC disease, but we suggest that TCD measurements are potentially useful in this condition, and that readings greater than 128 cm/s are abnormally high and warrant further investigation.

Portacaths are safe for long-term regular blood transfusion in children with sickle cell anaemia

Peripheral venous access in children with sickle cell anaemia (SCA) requiring regular blood transfusions can become difficult over time. Previous reports have suggested the use of totally implantable venous access devices, Portacaths (PAC) in this patient group are associated with unacceptable high rates of complications. We present our experience in seven children with SCA over a 9-year period. Seven devices were placed for a total of 9754 PAC days during the study period. The median age at insertion was 6.3 years (range 3–15 years). The rate of PAC associated infection was 0.2 per 1000 PAC days. There were no episodes of thrombosis. The median length of time in situ during the study period was 3.7 years (range 1.3–7.5 years). Our experience highlights the safe and reliable use of PAC in children with SCA requiring regular blood transfusions when venous access has become a major problem.

The measurement of urinary hydroxyurea in sickle cell anaemia

Hydroxyurea is increasingly used in the treatment of sickle cell disease (SCD) although there is little evidence on how best to monitor treatment and compliance. It is also not known why 10–50% patients do not benefit from the drug and whether some of this resistance is because of pharmacokinetic factors. We have developed an assay using mass spectrometry (MS) to measure urinary concentrations of hydroxyurea. We have used this assay to study 12 children and six adults with SCD taking hydroxyurea and found that urinary hydroxyurea was present for at least 12 h following tablet ingestion. Thirty‐five urine samples were analysed that were expected to contain hydroxyurea, based on the reported timing of the last dose and hydroxyurea was detected in 29 (83%) of these. There were also marked differences in urinary hydroxyurea concentrations, suggesting pharmacokinetic variability may explain some of the differences in response to hydroxyurea. Urine samples were also analysed by MS for penicillin metabolites and 43 of the 57 (75%) contained phenoxyacetate, suggesting the ingestion of penicillin within the last 12 h. These assays are potentially useful to study hydroxyurea metabolism further, develop optimal dosing regimes and monitor compliance with treatment.