Sandra O'Driscoll

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.

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.

Combined blood transfusion and hydroxycarbamide in children with sickle cell anaemia

Cerebrovascular disease is the main cause of chronic morbidity in children with sickle cell anaemia (SCA), with 11% suffering overt stroke by 20 years of age (Ohene-Frempong, et al 1998), and recurrent stroke occurring in more than 70% without intervention. Primary stroke prevention, using transcranial Doppler (TCD) assessment and blood transfusion, reduces the incidence of ischaemic stroke by 90%, and the incidence of recurrent stroke can be reduced to 10–15% by regular blood transfusions (Adams 2000). Hydroxycarbamide (HC) may also be beneficial in cerebrovascular disease, reducing TCD velocities and the risk of stroke recurrence (Ware et al, 2004). Most children with SCA and cerebrovascular disease are treated with regular blood transfusions, but deterioration still occurs in up to 50% (Bernaudin et al, 2011). Children with advanced cerebrovascular disease are at highest risk of progressive vasculopathy (Dobson et al, 2002; Brousse et al, 2009). We have audited the combined use of HC and regular blood transfusion in seven children with progressive vasculopathy despite optimal transfusion therapy, to assess potential toxicities, laboratory changes and clinical benefits. This retrospective audit was conducted in two hospitals caring for about 1000 children with SCA; approximately 50 receive regular blood transfusions for cerebrovascular disease, and about 180 are on HC. Seven children with SCA were receiving both HC and blood transfusions. All were started on blood transfusion because of cerebrovascular problems, and HC subsequently added. Progressive cerebrovascular disease was evident in all children and none had a human leucocyte antigen-matched sibling donor. Complete information on the use of HC in this setting was given to the families. Results were averaged from three steady-state readings on regular transfusions before HC was started, and from three steady-state readings after at least four months of both HC and transfusions. TCD velocities were recorded on regular transfusions and at least four months after HC was added. All patients were homozygous for the b mutation and had been on combined treatment a total of 27 patient years (Table I). All seven patients remained clinically stable on combined treatment, with no overt strokes; one patient (E) continued to have transient ischaemic attacks when HC was started, although these eventually stopped, without any deterioration on magnetic resonance imaging (MRI) or magnetic resonance angiography (MRA). Six of the seven children showed stabilization of their cerebrovascular disease, with no further brain infarction on MRI and no increase in vasculopathy on MRA, although three also had revascularization surgery. One child (D) developed worsening vasculopathy and moyamoya, but no further brain infarcts. Five children had evaluable TCDs before and after starting HC and velocities fell in three (Table II). The pretransfusion haemoglobin increased in all seven children after starting HC, with a corresponding fall in HbS. HbF levels were only available for four children, and these increased in all cases after HC. The total white cell count fell in six of the seven patients. No patients suffered significant side effects that required interruption of treatment. One patient (G) stopped HC after 16 months due to lack of efficacy, with no significant decrease in TCD velocities. This audit shows that it is possible to combine transfusion and HC safely, although there is a potential risk of side effects from both. It is encouraging that none of our patients suffered further strokes, despite their severe cerebrovascular disease. In particular, four patients had a history of overt stroke with moyamoya and progressive vasculopathy, and following the introduction of HC there was no further worsening of the vasculopathy on MRA, and no new overt strokes or silent strokes on MRI. This compares favourably with other retrospective studies: Scothorn et al (2002) found that, with transfusion alone, up to 45% of patients had further overt or silent cerebral infarction at five years and Dobson et al (2002) showed that the presence of moyamoya was associated with a 41% risk of recurrent cerebrovascular events. In our study, three children underwent revascularization surgery before starting HC, which may also have contributed to the good outcome. Overall, in this study, only one patient (D) showed signs of progressive cerebrovascular disease, with development of worsening arterial stenosis and moyamoya, although clinically they also remained stable. The scope for HC to cause beneficial changes to erythroid parameters is greatly reduced by the presence of 70–80% transfused erythrocytes. Regular transfusions also decrease erythropoietic drive and reduce HbF production relative to adult haemoglobins (Rees et al, 1999). Nevertheless, the addition of HC was associated with a significant increase in pretransfusion haemoglobin, with a decrease in HbS and increase in HbF. It is likely that progressive vasculopathy despite transfusion results from the continued adverse effects of the residual sickle cells, and significantly altering their phenotype in this way with HC could limit further vascular damage. It is also encouraging that the white cell count fell in six of the seven patients, with high white cell counts Correspondence

Changing pattern of hospital admissions of children with sickle cell disease over the last 50 years.

A study published in 1981 examined the causes of hospital admission for a cohort of children with sickle cell disease (SCD). Since that time, the incidence and prevalence of SCD has increased markedly in the UK, and there have been many changes in the management of this disease. We undertook a study examining the causes of hospital admission of children with SCD to the same hospital as the previous study, over the 2-year period from 2008 to 2009. We found that the numbers of children being cared for by our hospital had dramatically increased over the last 50 years, but rates of hospital admission had significantly fallen (41 hospital admissions per 100 patient-years, compared with 111.3 admissions per 100 patient-years in the original study). This fall in admission rates is accounted for by 2 major components: acute painful episodes (15.7 admissions per 100 patient-years compared with 39.3 in the previous study) and admission for elective blood transfusion (0.2 admissions per 100 patient-years compared with 26.7 in the previous study). It is interesting to note that, 541 elective transfusions were carried out during the study period, but in a day-care setting rather than requiring overnight admission. This study illustrates the changes in management of SCD over the past 30 years, and reflects the overall trend common to most hospital specialties of increasing community and ambulatory care.

Outcome of children with sickle cell disease admitted to intensive care - a single institution experience.

We retrospectively audited children with sickle cell disease (SCD) admitted to paediatric intensive care (PICU) at King’s College Hospital between January 2000 and December 2008. Forty‐six children with SCD were admitted, on 49 separate occasions. Ages ranged from 4 months to 15 years (median 7·6 years). Three children died in PICU, however two presented to hospital in cardiorespiratory arrest; overall mortality was 6%. The most common reason for admission was acute chest syndrome (43%). 88% of admissions required blood transfusion, of which 74% had exchange blood transfusions. The mortality among children with SCD admitted to PICU is low.

Outcome of children with sickle cell disease admitted to intensive care

We retrospectively audited children with sickle cell disease (SCD) admitted to paediatric intensive care (PICU) at King’s College Hospital between January 2000 and December 2008. Forty‐six children with SCD were admitted, on 49 separate occasions. Ages ranged from 4 months to 15 years (median 7·6 years). Three children died in PICU, however two presented to hospital in cardiorespiratory arrest; overall mortality was 6%. The most common reason for admission was acute chest syndrome (43%). 88% of admissions required blood transfusion, of which 74% had exchange blood transfusions. The mortality among children with SCD admitted to PICU is low.