To study the effect of hydroxyurea on transcranial Doppler in patients with sickle cell anemia

Background: The estimated rate of prevalence of SCD in the population of Chhattisgarh is about 10 to 15% of which about 1 to 1.27% are likely to be sufferers and the rest carriers. The frequency of stroke in SCD is estimated as at0.61 per 100 patients per year. TCD is a valuable screening test in many clinical conditions such as SCD, to identify the patients at risk of stroke. An abnormally high blood speed is an indicator of a narrowed cerebral blood vessel and/or increased blood volume and a warning marker of high risk for stroke [1-8]. Methods: This was a prospective comparative cross-sectional observational hospital hospital-based study, conducted over a period of 17 months (JulyJULY 2016 to NovemberNOVEMBER 2017) in the Department Of Pediatrics and Radiodiagnosis, Dr R.B.R.A.M.H, Raipur (C.G.).Children between 2 to 14years diagnosed as SCD SS who were receiving long term (>6months) HU (hydroxyurea) treatment (cases) – HU group, and those who had never received this treatment (control) – HU naïve group, were enrolled. Results: The total number of children enrolled in the presentour study was 120, out of which 40 were cases and 80 were controls. The mean blood flow velocity of cases was significantly lower than controls. Among cases and controls maximum mean blood flow velocity was found in Left MCA followed by Right MCA. In addition to this, it was also found that there was no significant interhemispheric difference in both groups. (p p-value more than 0.05).There was werenNo significant associations between blood flow of Right and Left Side of MCA, ACA and& ophthalmic arteries among cases. Conclusion: The Mean mean blood flow velocity in the HU group and HU naïve group was within the normal range (<170cm/sec), as per STOP criteria. The mean blood flow velocity in patients who were on the HU group was found to be significantly lower than the HU naïve group.


Introduction
Sickle Cell disorders are a group of inherited genetic disorders and a major public health problem in Chhattisgarh. These disorders can be transmitted from one generation to the next through the Mendelian recessive type of inheritance.
The public health implications of sickle cell disorders are significant. This impact on human health may be assessed against the yardsticks of infant mortality, under-five mortality, and maternal mortality. However, complete curative therapy for Sickle Cell Disorders is not available in any systems of Medicine. Symptomatic and supportive treatment is the only mainstay. [1][2][3][4][5][6][7][8]. Stroke is a serious complication of sickle cell disease. The majority of strokes are ischemic events caused by stenosis of large cerebral arteries.' Stroke generally occurs without warning and cause significant long termlong-term neurologic sequelae in at least 50% of cases.Chronic transfusion therapy for children who suffer strokesuffer stroke decreases the recurrent stroke rate from 90 % to less than 10 %. [1][2][3][4][5][6][7][8].
TCD is a valuable screening test in many clinical conditions such as SCD, to identify the patients at risk of stroke. An abnormally high blood speed is an indicator of a narrowed cerebral blood vessel and/or increased blood volume and a warning marker of high risk for stroke. Regular blood transfusion and treatment with Hydroxyurea can significantly reduce the incidence of stroke in children with SCD who are found to be at high All the transcranial Doppler examinations were performed in quiet and wakeful patients by the same professional who had been trained to performtranscranial Doppler using the machine Make and& Model Make:-Toshiba, Model: AplioMX, Model SSA-780A with a Toshiba Phased Array Transducer, (Model-PST 30BT 3 MHz), and following the criteria of the STOP (Stroke Prevention Trial in Sickle Cell Anaemia) study." From this examination, the time-averaged maximum mean velocities weredetermined every 2 mm along the following arteries: bilateral anterior cerebral, middle cerebral arteries, bilateral ophthalmic arteries and basilar artery using appropriate windows-trans trans-temporal (MCA, ACA).Trans orbital (ophthalmic artery),sub occipital (basilar artery).
TCD was done in a total of 120 children with SCD, comprising of 40 in HU group and 80 in HU naïve group. It was done in the same condition of temperature and posture (supine) for both the groups. Before transcranial Doppler was done, enough time was given to them until their pulse rate and blood pressure would reach a stable condition. The surrounding environment was quietly calm and this provided the possibility of detecting low amplitude signals with high frequency.
TCD studies has have been performed in steady-state STEATY STATE defined as crises free period extending from at least 3 weeks since last clinical event and 3 months or more since last blood transfusion, before the start of new clinical events.
The highest value from the right or left middle cerebral arteries, anterior cerebral artery, ophthalmic arteries, and basilar artery was taken as the time -average-averaged maximum mean velocity for each patient and was used in the data analysis. When the time-averaged maximum mean velocity result was conditional or abnormal, the examinations were repeated until two consecutive abnormal results were obtained.
As per STOP study [12,13] velocities were classified as below [12,13]. Normal -< 170 cm/sec Conditional -170--199 cm/sec High or abnormal -> 200 cm/sec Data was compiled in MS excel and checked for its completeness and correctness then it was analyzed by suitable statistical test (chichi-square test and t t-tTest was were applied ) and P P-value < 0.05 was conditional as statisticalstatistically significant.

Results
The total number of children enrolled in the presentour study was 120, out of which 40 were cases and 80 were controls. Among 120 child patients, there were 83 male children and 37 female children i.e. 69.2% males and 30.8% females. Age variations in the series were from 2 years to 14 years, out of which the majority of the patient were in the age group of 6 to 10 years. A majority of the subjects were vaccinated (94.2%). 92.5% among cases and 95% among controls were completely vaccinated with routine vaccines which was werefound to be non-significant. In this study Hemoglobin concentration of the majority of the subjects were was5-10gm. Maximum controls (80.0%) had hemoglobin concentration in 5-10 gm% range but with none had hemoglobin concentration in > 10gm% range. Hb status was significantly higher in cases than in the control group. Also, it was found that, in the presentour study, the most common reason for the previous admission was a vasoocclusive crisis (case 52.5% and controls 47.5% ) followed by the hemolytic crisis (cases27.5% and controls 35%) and blood transfusion (cases 12.5% and controls 11.2%).
Pediatric Review: International Journal of Pediatric Research Available online at: www.medresearch.in 138|P a g e In both cases and controls, the mean velocity was in the normal range (< 170 cm/sec) in all patients. Table 1 shows the distribution of the mean velocity of intracranial vessels in case and controls. The mean blood flow velocity of cases was significantly lower than controls(p<0.05). Among cases and controls maximum mean blood flow velocity was found in Left MCA followed by Right MCA. Table 2 shows the comparisons of mean velocities of intracranial vessels between cases and controls. In addition to this, it was also found that there was no significant interhemispheric difference in both groups. (p pvalue more than 0.05).There was wereno significant associations between blood flow of Right and Left Side of MCA, ACA,and ophthalmic arteries among cases. Table 3 shows the interhemispheric difference in mean velocity in cases and controls.

Discussion
In this cross sectionalcross-sectional hospital-based study, the currentwe observed that the Mean blood flow velocity of the HU group was lower than the HU naïve group. (P Pvalue is less than 0.05),but none of the study subjects (SCA SS) had TCD flow velocity in conditional or high high-risk range as per STOP criteria.
The finding of distribution of the mean velocity of intracranial vessels in the presentour study differed with the data from a similar study conducted by The Stroke Prevention Trial in Sickle Cell Anaemia (STOP) which reported prevalence of abnormal TCD in 6.72% of the studied patients (130/1934). AlsoAlso, Robert Adams, et al 1992 found abnormal velocity (170cm/sec) in 23 out of 190 patients SCD SS (12%) [14].Ariane S., et al, 2002 found the mean velocity in the MCA and ACA was 123.7 cm/sec and 99.43 cm/sec respectively [15].Another observation made from this study was that the Mean blood flow velocity of the HU group was significantly lower than the HU naïve group. The maximum Mean blood flow Pediatric Review: International Journal of Pediatric Research Available online at: www.medresearch.in 139|P a g e velocity was found in Left MCA followed by Right MCA in both the groups. This was supported by the study of Zimmerman SA, et al which also indicated that hydroxyurea can significantly decrease elevated TCD flow velocities, often into the normal range [16]. They suggested a multicenter trial is warranted to determine the efficacy of hydroxyurea for the management of increased TCD values, and ultimately for primary stroke prevention in children with SCA.
In addition, it was also found that there was no significant interhemispheric difference in both groups. (p-value more than 0.05). No significant association was found between the blood flow of Rt. and Lt. Side of MCA, ACA and ophthalmic arteries among HU group and HU naïve group. This was in consonance with the data from the study conducted by Jesper Bay Hansen et al [17],Mikolaj A. Pawlak, et al [18], Mohammad Ali et al [19] which also showed no significant interhemispheric differences in mean velocity in both the groups.
MohammadAliMolavi, MohammadRezaAliz, KamyarMolavi, et al conducted a study and found that in cases who have been treated with hydroxyurea blood flow velocity was less in comparison to those who did not take it which was same as other researches [19].
Melo, et al (In Sergipe), 2005 gathered data on 34 patients with sickle cell anaemia, aged less than 18 years, and compared them with 80 controls. Among the results from the patients, none of them (0,0%) presented abnormal time-averaged maximum mean velocity and four (11.7%) presented conditional results [18]. 18 Park, et al (In São Paulo), 2006 evaluated 77 patients with sickle cell disease, aged between 2 and 16 years.
They found two patients (2.6%) with abnormal timeaveraged maximum mean velocity and li (14.3%) with conditional results [19]. Valadi N, et al, 2006 found adults with SCD had a higher mean time time-averaged maximum mean velocity (110.9± +/-25.7 cm/s) compared with healthy controls (71.1±+/-12.0 cm/s), and the difference is approximately proportional to their anaemia [20]. No cases with velocities >/=200 cm/sec were found in this sample. Another observation made from this study was that Mean blood flow velocity of HU group was significantly lower than HU naïve group.
The maximum Mean blood flow velocity was found in Left MCA followed by Right MCA in both the groups. This was supported by the study of Zimmerman SA, et al (2007) 14 which also indicated that hydroxyurea can significantly decrease elevated TCD flow velocities, often into the normal range. They suggested a multicenter trial is warranted to determine the efficacy of hydroxyurea for the management of increased TCD values, and ultimately for primary stroke prevention in children with SCA. MohammadAliMolavi, MohammadRezaAliz, KamyarMolavi, et al(2012) conducted a study and found that, in cases who has been treated with hydroxyurea blood flow velocity was less in compare to those who did not take it which was same as other researches.17 In addition , we also found that there was no significant inter hemispheric difference in both the groups.

Conclusion
The current study concluded that We conclude that;the 1. Mean blood flow velocity in the HU group and HU naïve group was within the normal range (<170cm/sec), as per STOP criteria. 2. In the currentour study mean blood flow velocity in patients who were inthe HU group was found to be significantly lower than the HU naïve group. HoweverHowever, none of the patients under the study groups had TCD flow velocity in the high high-risk range as per stop criteria.
Hence long term followfollows up studies are needed to conclusively access the effect of hydroxyurea therapy on TCD flow velocity inpatient of SCA SS.

What does theis study adds to the existing knowledge?
Long term followfollows up studies are needed to conclusively access the effect of hydroxyurea therapy on TCD flow velocity inpatient of SCA SS. The patients on hydroxyurea therapy had significantly lower TCD flow velocities as compared to those who did not.