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Screening for Stroke in Sickle Cell Anemia: Comparison of Transcranial Doppler Imaging and Nonimaging US Techniques¹

¹ From the Department of Radiology, Children’s Health Care of Atlanta at Scottish Rite, 1001 Johnson Ferry Rd NE, Atlanta, GA 30342. Received February 27, 2001; revision requested April 2; final revision received September 14; accepted September 20. Funding for purchase of Nicolet Companion EME Transcranial Doppler machine was provided by the Children’s Health Care of Atlanta Foundation. Address correspondence to A.S.N. (e-mail: ariane.neish@choa.org).

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To determine whether criteria for screening patients with sickle cell anemia for stroke established with a nonimaging transcranial Doppler ultrasonographic (US) technique are applicable to studies performed with a transcranial Doppler US imaging technique.

MATERIALS AND METHODS: One hundred sixty-eight examinations in 66 children were performed for sickle cell stroke screening. Children were examined with nonimaging and imaging transcranial Doppler US techniques on the same day, for a total of 84 paired examinations. The time-averaged maximum mean velocity (V_mean) and resistive index (RI) were calculated in the middle cerebral arteries, bifurcations of the distal internal carotid arteries, distal internal carotid arteries, anterior cerebral arteries, posterior cerebral arteries, and basilar arteries. The maximum systolic velocity (V_max) was evaluated in the distal internal carotid arteries and middle cerebral arteries. V_mean, V_max, and RI measurements were subjected to repeated-measures multivariate analysis of covariance, and the Pearson product moment correlation was used for middle cerebral artery velocity, age, and hemoglobin.

RESULTS: V_mean measurements obtained with nonimaging and imaging techniques varied substantially for the bifurcation of the distal internal carotid artery, the posterior cerebral artery, and the basilar artery. Substantial differences were found in RIs for every vessel. Examination time was shorter with the nonimaging technique.

CONCLUSION: V_mean measurements in the middle cerebral artery, distal internal carotid artery, and anterior cerebral artery did not vary substantially between nonimaging and imaging transcranial Doppler US. RI data did not yield comparable measurements.

© RSNA, 2002

Index terms: Brain, infarction, 17.78, 10.651 • Brain, US, 17.12989, 17.12983 • Sickle cell disease (SS, SC), 17.651, 10.651 • Ultrasound (US), comparative studies, 17.12989, 17.12983 • Ultrasound (US), Doppler studies, 17.12989, 17.12983

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Eleven percent of children with sickle cell disease will have a stroke by 20 years of age (1–3). Cerebral infarction is associated with occlusive vasculopathy that most often affects the distal internal carotid arteries and the proximal middle cerebral arteries (4,5). Transcranial Doppler ultrasonography (US) has been used to detect arterial stenoses. Insonation of stenotic vessels yields high systolic blood flow velocities (6–8). The Stroke Prevention Trial in Sickle Cell Anemia (STOP) demonstrated that transcranial Doppler US screening could be used to help identify a subset of children with sickle cell anemia who are at higher risk for stroke (3). The multicenter trial included 3,929 transcranial Doppler US examinations in 1,934 children. Children who were identified at US to be at higher risk were randomly assigned to receive either prophylactic transfusions or standard care. The National Heart, Lung, and Blood Institute (NHLBI) terminated the study early because of the compelling success of the trial. This initial work showed that transcranial Doppler US screening can help identify a subset of children with sickle cell disease who are at high risk for stroke and that prophylactic transfusion therapy can prevent stroke.

Transcranial Doppler US examinations are now considered standard in the care of children with sickle cell anemia (3,8). US examinations in the STOP trial were performed with a nonimaging pulsed Doppler technique that generated a waveform. A slightly different technique, transcranial Doppler imaging, uses a duplex technique to simultaneously generate a gray-scale and color image, as well as a Doppler waveform. Radiologists are more familiar with this imaging technique, and the necessary imaging equipment is widely available in most radiology departments. The purpose of this study was to determine whether criteria established with the nonimaging transcranial Doppler US technique are applicable to studies performed with the transcranial Doppler US imaging technique.

	MATERIALS AND METHODS

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We performed side-by-side comparisons of nonimaging and imaging transcranial Doppler US techniques in a prospective manner. Children who were inpatients or who had fever, pain crisis, or pneumonia were not examined until they returned to their baseline level of health. Children undergoing transfusion therapy and those who had had a previous stroke were excluded from this trial. All children who were screened between August 1999 and December 2000 were enrolled consecutively in this study and were examined with both nonimaging and imaging transcranial Doppler US on the same day. One hundred sixty-eight examinations were performed in 66 children and adolescents (30 male and 36 female patients), all of whom met our inclusion criteria. Eighteen children came for screening twice during this period, and each visit was considered a unique case. The unit of analysis was a pair of velocity readings, not an individual child. The mean age in this cohort was 9.3 years ± 3.7 (SD) (range, 3.8–19.5 years). Fifty-two of the 66 children (79%) were homozygous for sickle cell disease, and 14 children (21%) had either sickle cell hemoglobin C disease (n = 11, 17%) or sickle cell ß thalassemia (n = 3, 4%). The mean hemoglobin and hematocrit at entry were 8.8 ± 1.4 g/dL (88 ± 14 g/L) and 25.7% ± 4.5 (0.257 ± 0.045), respectively. No children were lost to follow-up. Children were not permitted to sleep during the examinations and were not sedated. The Clinical Research Oversight Committee and Institutional Review Board at Children’s Health Care of Atlanta approved the study. A parent or legal guardian provided written informed consent before his or her child was enrolled.

The children underwent two complete transcranial Doppler US examinations, one performed with a nonimaging technique and a 2-MHz probe (Nicolet Companion EME; Nicolet Vascular, Madison, Wis), and one performed with an imaging technique. Transcranial Doppler US imaging examinations were performed with one of two machines. Forty-two children were examined with an Acuson machine (Sequoia; Acuson, Mountain View, Calif) with a 2–3-MHz multifrequency probe (3V2C) used at 2 MHz, and 42 were examined with a GE machine (GE Logics 700 Expert Series 99; GE Medical Systems, Milwaukee, Wis) with a 2–4-MHz multifrequency probe (227s) used at 2 MHz. The examinations were performed by one of three sonographers (including A.J.S.) under the supervision of one of two pediatric radiologists (A.S.N, D.E.B.); all five had participated in transcranial Doppler US training courses. Nonimaging and imaging examinations were performed on the same day by the same examiner. The duration of both the nonimaging and the imaging examinations were recorded. Sonographers alternated the order in which the examinations were performed.

Imaging Protocol
Doppler tracings were obtained of the middle cerebral artery, the bifurcation of the distal internal carotid artery, the distal internal carotid artery, the anterior cerebral artery, the posterior cerebral artery, and the basilar artery. No angle correction was used in order to mimic nonimaging technique. Angle-adjusted velocity measurements tend to be elevated compared with velocity measurements that are taken assuming a 0° angle of insonation. A concerted effort was made to search along each vessel to find the highest velocity and to optimize imaging parameters. Gain settings were maximized to document peak systolic velocities and a well-defined spectral envelope. The middle cerebral artery was insonated at 2-mm increments with a 6-mm gate. A minimum of five tracings of this artery were generated, and at least two tracings were obtained from all other vessels. The highest maximum systolic velocity (V_max) and the time-averaged mean maximum velocity (V_mean) obtained in each artery were recorded. V_mean is the time-averaged mean maximum velocity across the entire envelope of one cardiac cycle.

The resistive index (RI) was calculated (as V_max - EDV/V_max), where EDV is end-diastolic velocity, for every tracing. RI calculations were based on electronic measurements of V_max and end-diastolic velocity for all nonimaging examinations. RI calculations were based on manual identification of V_max and end-diastolic velocity for the imaging examinations performed with the GE Logics 700. RI calculations were based on electronic identification of V_max and end-diastolic velocity for the imaging examinations performed with the Acuson Sequoia.

Velocity measurements recorded for imaging examinations performed with the GE Logics 700 were based on manual measurements for all vessels. The peak velocity envelope was traced over one cardiac cycle manually; the V_mean was automatically calculated by means of this manual envelope tracing. Peak systolic and peak diastolic velocities were also assigned manually to calculated RIs. Velocity measurements recorded for imaging examinations performed with the Acuson Sequoia were based on electronic measurements unless the signal-to-noise ratio was suboptimal, necessitating manual tracing. This occurred infrequently, but low signal-to-noise spectra were obtained more often when vessel velocities were high or when the transtemporal window was small. The Doppler spectrum in each nonimaging examination was analyzed both electronically and manually. Manual readings were assigned at the midpoint between peak systolic velocity and end-diastolic velocity (9). These manual readings were obtained for the middle cerebral artery and for the distal internal carotid artery to duplicate the method used in the STOP trial. Electronic measurements were used for all other vessels.

Examination results were interpreted as normal if all V_mean values were less than 170 cm/sec and if no V_max was over 170 cm/sec in any artery (3,10,11). Examination results were interpreted as conditional if the V_mean was greater than or equal to 170 cm/sec but was less than 200 cm/sec in any vessel, if the V_mean in the posterior cerebral artery was greater than that in the middle cerebral artery, if any RI was less than 30, and/or if the V_max in the middle cerebral artery or the internal carotid artery was greater than or equal to 200 cm/sec. Examination results were interpreted as abnormal if the V_mean in the middle cerebral artery, the bifurcation of the distal internal carotid artery, or the distal internal carotid artery was greater than or equal to 200 cm/sec. Children with these results were referred for a repeat examination. The referring hematologists offered children with two abnormal examination results transfusion therapy.

Statistical Analysis
All data were initially entered into an Excel database (Microsoft, Redmond, Wash) and then imported into SYSTAT 10 (SPSS Science, Chicago, Ill) for all statistical analyses. A repeated-measures multivariate analysis of covariance was performed with V_mean measurements in the middle cerebral artery, the bifurcation of the distal internal carotid artery, the distal internal carotid artery, the anterior cerebral artery, the posterior cerebral artery, and the basilar artery and V_max measurements in the middle cerebral artery, the distal internal carotid artery, and the basilar artery as the dependent variables and sex, age, and examination type (ie, nonimaging or imaging) as the independent variables. The paired nonimaging and imaging examination results were treated as repeated measures to appropriately account for any within-patient variability. The model statistically controlled for the effects of age and sex by treating them as covariates.

A second similar repeated-measures multivariate analysis of covariance model was used with the RIs (calculated in the same vessels indicated above) as the dependent variables to compare the RIs obtained with the nonimaging technique and those obtained with the imaging technique. The ² test was used to evaluate the differences in the final classifications of examination results (ie, as normal, conditional, or abnormal) between the nonimaging and the imaging techniques. A Pearson product moment correlation was used to help evaluate the relationship between velocity in the middle cerebral artery and age and the relationship between velocity in the middle cerebral artery and hemoglobin values.

	RESULTS

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Adequate tracings were acquired in every vessel during most examinations (Table 1). The first group of patients was examined with the GE machine during the imaging examination. A number of tracings acquired in the bifurcation of the distal internal carotid artery were mislabeled as having been acquired in the middle cerebral artery; these tracings were discarded from the study.

Statistical analyses were performed that compared the velocity and RI measurements obtained with each technique (Tables 2, 3; Figs 1, 2).

View larger version (27K): [in this window] [in a new window] [Download PPT slide]   Figure 1. Bar graph shows comparison of velocity readings in centimeters per second obtained at nonimaging transcranial Doppler US with a Nicolet machine (black bars) and those obtained at transcranial Doppler US imaging with GE or Acuson machines (white bars). No significant differences in velocity measurements were found in the middle cerebral artery (MCA), distal internal carotid artery (ICA), or anterior cerebral artery (ACA). However, significant differences were identified in velocity readings in the bifurcation of the distal internal carotid artery (BIF), in the posterior cerebral artery (PCA), and in the basilar artery (BA). The values reported represent means of velocities of the data reported in Table 1.

View larger version (26K): [in this window] [in a new window] [Download PPT slide]   Figure 2. Bar graph shows comparison of RIs obtained at nonimaging transcranial Doppler US with a Nicolet machine (black bars) and those obtained at transcranial Doppler US imaging with GE or Acuson machines (white bars). The values reported represent means of RIs calculated from the data reported in Table 1. The graph depicts significant differences in RI measurements for every vessel. ACA = anterior cerebral artery, BA = basilar artery, BIF = bifurcation of the distal internal carotid artery, ICA = internal carotid artery, MCA = middle cerebral artery, PCA = posterior cerebral artery.

In the 65 patients in whom hemoglobin and hematocrit values were available, hemoglobin values correlated significantly and negatively with Nicolet (r = -0.49, P < .001), GE (r = -0.4, P < .001) and Acuson (r = -0.52, P < .001) readings of middle cerebral artery velocity. Hematocrit values were not significantly correlated with velocity readings from any of the three machines. Chronologic age also correlated negatively with middle cerebral artery velocity readings: Nicolet (r = -0.41, P < .02), GE (r = -0.43, P < .01), and Acuson (r = -0.38, P < .001).

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
The NHLBI recommends that children with homozygous sickle cell anemia who are between the ages of 2 and 16 years be screened for stroke risk with a transcranial Doppler US examination (10). This recommendation was based on results from the STOP trial, which used a nonimaging transcranial Doppler US technique. There has been a marked increase in demand for transcranial Doppler US imaging examinations as pediatric hematologists attempt to comply with the recommendations set forth by the NHLBI. Nonimaging machines are not readily available in radiology departments, and the nonimaging transcranial Doppler US technique is unfamiliar to most radiologists and sonographers. Radiologists in some centers are using their readily available imaging machines to perform these stroke screening examinations in order to meet the requests of their colleagues in hematology.

In addition to the availability of equipment, an advantage of the imaging technique is that it permits the visualization of intracranial anatomy. This shortens training time for sonographers and allows for confident identification of tortuous and anomalous vessels. A disadvantage of the transcranial Doppler US imaging technique is that the image may distract the examiner from the audible Doppler signal characteristics that often help identify the segment of vessel with the highest-pitched signal and highest resultant mean flow velocity. However, the principal disadvantage of the imaging technique is the relative lack of data that correlate transcranial Doppler US imaging velocity readings with those obtained with the nonimaging transcranial Doppler US technique.

The advantage of the nonimaging technique is the large number of nonimaging transcranial Doppler US studies acquired in the STOP trial that correlate with outcome. Transcranial Doppler US velocity readings are the current standard by which hematologists make case-management decisions. The equipment is inexpensive and portable. The transducer is smaller, allowing for easier manipulation, which is particularly advantageous for children with a limited transtemporal window. A large amount of quantitative data are collected during a nonimaging transcranial Doppler US examination. The nonimaging equipment allows the examiner to automatically record velocity readings, depths of insonation, and RIs in tables that may be stored electronically or printed out on summary sheets, thus simplifying data management for clinical and research purposes. In our study, the average nonimaging examination was faster than the average imaging examination (29 minutes vs 43 minutes). Disadvantages of the nonimaging transcranial Doppler US technique include the inability to visualize vessels, increased learning time, and lack of machine availability in most radiology departments.

Authors of previous studies on transcranial Doppler US imaging have suggested that results may vary slightly between nonimaging and imaging techniques (9,11–13). Bulas et al (9) compared nonimaging and imaging velocity readings in 22 children obtained with an EME TC 2000 machine (Nicolet Vascular) and an HDI 5000 machine (ATL, Bothell, Wash), respectively. That trial demonstrated that V_mean values obtained with the transcranial Doppler US imaging system were approximately 10% lower than those obtained with the nonimaging transcranial Doppler US system (9). Velocity readings were most concordant in the middle cerebral artery and in the distal internal carotid artery. Velocity readings were most discordant in the basilar artery, the anterior cerebral artery, and the bifurcation of the distal internal carotid artery. Jones et al (11) obtained similar results in a two-phase study that compared transcranial Doppler US imaging and nonimaging transcranial Doppler US results in children with sickle cell anemia. In the second phase of this study, the authors compared nonimaging and imaging middle cerebral artery velocity readings obtained in 15 children with the TC 2000 (Nicolet Vascular) and Aspen (Acuson) machines, respectively. Middle cerebral artery velocity readings were 10%–11% lower with the transcranial Doppler US imaging technique than with the nonimaging transcranial Doppler US technique (11).

Fujioka et al (12) compared nonimaging and imaging peak systolic flow velocities in 30 subjects obtained with a Transpect machine (Medasonics, Fremont, Calif) and a Sonos 1000 machine (Hewlett-Packard, Andover, Mass), respectively. That trial demonstrated that V_max values within cerebral arteries were 0%–10% lower when measured with transcranial Doppler US imaging than when measured with nonimaging transcranial Doppler US (12). The velocity readings that were most concordant in the trial were found in the basilar artery and the middle cerebral artery. Velocity readings that were most discordant were found in the anterior cerebral artery and the posterior cerebral artery. The trial also demonstrated that V_max values were comparable between nonimaging and imaging transcranial Doppler US with and without angle correction. The angle of insonation was shown to be between 0° and 30° in 72% of arteries.

Rosendahl et al (13) compared nonimaging and imaging V_mean and V_max values in 25 subjects. Only middle cerebral artery readings were reported. Velocity readings varied by less than 10% when no angle correction was used for the imaging examination (13). Velocity readings varied more substantially (<20%) with angle correction. This trial demonstrated that 46% of the middle cerebral arteries imaged with transcranial Doppler US imaging required angles greater than 35° for angle-corrected measurements.

We used other vendors, namely Acuson and GE. Also, both nonimaging and imaging examinations were performed by the same sonographer and radiologist team. The advantage of this method is that it removed the variable of individual technical skill, although it is possible that an individual may be more proficient with a particular machine. A potential disadvantage is that the examiners were not blinded to the results from the paired examination. This could have influenced the attention paid to a particular vessel.

In our study, velocity readings were most variable in the posterior cerebral artery and in the bifurcation of the distal internal carotid artery, followed by the basilar artery. These findings are similar to those of the trials conducted by Bulas et al (9) and Fujioka et al (12). The V_mean values in each of these vessels were slightly higher at nonimaging US than at imaging US, as was also demonstrated in the Bulas et al and Fujioka et al trials. However, in our trial, V_max differences yielded slightly higher readings at imaging US than at nonimaging US.

In our study, the differences in velocity measurements fell close enough to cutoff points to result in a different classification of risk (normal, abnormal, conditional) for 14 patients. Two of the 16 discrepant cases were classified as normal at imaging examinations, but nonimaging readings for these cases were considered inadequate due to difficulties in obtaining adequate Doppler spectra. In these cases, hematologists used the imaging examination to make management decisions. At our institution, we have subsequently adopted the practice of examining children with both techniques when their results approach the abnormal velocity threshold.

Discrepant readings between techniques and vendors suggest multiple factors. The nonimaging transcranial Doppler US technique assumes an angle of insonation between 0° and 30°. Data from the trial conducted by Fujioka et al (12) suggest that 21% of arterial segments demonstrate angles between 31° and 40°, and 7% demonstrate angles greater than 40°. Angles of insonation were between 31° and 40° most often in the posterior cerebral artery (33%) and middle cerebral artery (22%). Errors introduced by lack of angle correction would result in underestimation of velocity readings.

The transcranial Doppler US imaging examiner is guided by the gray-scale and color Doppler image of the arteries and may be less attentive to the audible Doppler signal. The nonimaging transcranial Doppler US examiner is guided by the audible Doppler signal, which is most useful in identifying a stenotic segment because the highest-pitched signal (Doppler shift) corresponds to the highest velocity. This may account for a tendency to underestimate velocity readings with the transcranial Doppler US imaging technique. The imaging transducers for both machines used in this study are slightly larger than the nonimaging transducer, and this may have resulted in less optimal positioning through the transtemporal window.

Variations in velocity measurements may also be introduced by the method used to interpret the Doppler spectrum. Electronic measurements could not be obtained with the GE Logics 700 system if the signal demonstrated suboptimal signal-to-noise ratio. For this reason, a manual envelope of peak velocities was traced for every spectrum and the V_mean was electronically calculated based on the manual envelope. Electronic measurements were obtained with the Acuson Sequoia unless poor signal-to-noise ratios necessitated manual readings. Velocity measurements obtained with the nonimaging technique were interpreted manually to reproduce the methods used in the STOP trial (3).

Velocity measurements vary with physiologic factors such as hematocrit, temperature, and PCO₂ (14). Children in this study underwent both nonimaging and imaging examinations on the same day and were kept awake in order to control for these variables.

The percentage of children whose results were classified as conditional (21%) in our series was higher than that reported by Adams et al (15) for their series (9%). This was anticipated, because 29 (44%) of the 66 children included in this trial had been previously screened with a transcranial Doppler US imaging technique. The low proportion with abnormal results in this cohort is typical of a prescreened population, because children whose results were previously classified as abnormal entered transfusion programs and did not qualify for entry into this study. The high proportion with conditional results in this cohort is also typical of a prescreened population, because children whose results were previously classified as conditional were referred for more frequent examinations. In addition, while criteria for abnormal results were identical to those used in the STOP trial, additional criteria were used for results to meet conditional status, as defined by Seibert et al (8). We refer children with conditional results for closer interval follow-up examinations.

The mean age of our cohort was slightly higher (9.3 years in our series; 8.8 years in the series studied by Adams et al [15]). The mean hemoglobin and hematocrit values were higher in our cohort (hemoglobin, 8.8 g/dL [88 g/L]; hematocrit, 25.7% [0.257]) compared with the Adams et al cohort (hemoglobin, 7.8 g/dL [78 g/L]; hematocrit, 23.3% [0.233]). Although the differences in cohort characteristics were small, the older age and higher hemoglobin values in our cohort would each tend to yield lower velocity readings.

Comparison of RI values obtained with nonimaging and imaging techniques demonstrated significant differences for every vessel examined with both of the transcranial Doppler US imaging systems used in our study. The discordance in RI calculations between nonimaging and imaging techniques was seen when both manual and electronic methods were used to identify V_max and end-diastolic velocity. The discrepancies may result from difficulties in identifying peak diastolic flow with less than optimal signal-to-noise spectra. This information was acquired because an RI value less than 30 in any vessel has previously been identified as an indicator of increased risk for stroke in children with sickle cell disease (8). However, this was not one of the standard criteria used in the STOP trial to make decisions regarding transfusion therapy. Given the variability of RI values between nonimaging and imaging transcranial Doppler US techniques, this measurement may be less useful.

In conclusion, velocity measurements in the middle cerebral artery, the distal internal carotid artery, and the anterior cerebral artery obtained at nonimaging transcranial Doppler US and at transcranial Doppler US imaging were not significantly different in our study. These results validate the use of STOP criteria to interpret transcranial Doppler US imaging examinations when the imaging examinations are performed with the equipment, software, and techniques specified in this study. These authors recommend that operators performing transcranial Doppler US studies with imaging equipment compare their measurements with those obtained at nonimaging transcranial Doppler US, the current diagnostic standard.

V_mean measurements were substantially lower in the basilar artery, in the bifurcation of the distal internal carotid artery, and in the posterior cerebral artery at transcranial Doppler US imaging compared with those obtained at nonimaging transcranial Doppler US. Risk may be underestimated if decisions are based on velocities measured in these vessels. RIs obtained with nonimaging and imaging techniques were substantially different in this series, but these differences did not result in changes in patient care. In addition, the STOP trial did not compare RI values with patient outcome. RI values have been advocated by one author (8) as potentially useful secondary criteria for clarifying conditional scans and stratifying patients who might benefit from magnetic resonance (MR) imaging or MR angiography. However, hematologists adhering to the STOP protocol do not use RI values to make decisions regarding prophylactic transfusion therapy. Given the lack of reproducibility and the lack of prospective data comparing RI values with patient outcome, the RI calculation may be of limited value. At our institution, we advocate the nonimaging US technique for initial screening because of its superior sound quality, ease of data management, shorter examination time, and smaller transducer. We supplement nonimaging transcranial Doppler US with transcranial Doppler US imaging in any case in which the initial nonimaging examination was technically inadequate or yielded conditional or abnormal results.

	FOOTNOTES

 
Abbreviations: NHLBI = National Heart, Lung, and Blood Institute, RI = resistive index, STOP = Stroke Prevention Trial in Sickle Cell Anemia, V_max = maximum systolic velocity, V_mean = time-averaged mean maximum velocity

Author contributions: Guarantors of integrity of entire study, A.S.N., D.E.B.; study concepts, A.S.N., D.E.B.; study design, A.S.N.; literature research, A.S.N.; clinical studies, A.J.S., A.S.N., D.E.B.; data acquisition, A.J.S., A.S.N., D.E.B.; data analysis/interpretation, A.S.N., D.E.B., C.A.S., R.K.M.; statistical analysis, R.K.M., C.A.S.; manuscript preparation, A.S.N., D.E.B., R.K.M., C.A.S.; manuscript definition of intellectual content, A.S.N., D.E.B.; manuscript editing and revision/review, A.S.N., D.E.B., R.K.M., C.A.S.; manuscript final version approval, A.S.N., D.E.B., R.K.M.

	REFERENCES

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 

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3. Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by transfusions in children with sickle-cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med 1998; 339:5-11.
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5. Gerald B, Sebes JI, Langston JW. Cerebral infarction secondary to sickle cell disease: arteriographic findings. AJR Am J Roentgenol 1980; 134:1209-1212.
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9. Bulas DI, Jones A, Seibert JJ, Driscoll C, O’Donnell R, Adams RJ. Transcranial Doppler (TCD) screening for stroke prevention in sickle cell anemia: pitfalls in technique variation. Pediatr Radiol 2000; 30:733-738.
10. Adams RJ, McKie VC, Brambilla DJ, et al. Stroke prevention trial in sickle cell anemia. Control Clin Trials 1998; 19:110-129.
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12. Fujioka KA, Gates DT, Spencer MP. A comparison of transcranial color Doppler imaging and standard static pulsed wave Doppler in the assessment of intracranial hemodynamics. J Vasc Tech 1998; 18:29-35.
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