Beneficial Effect of Intravenous Dexamethasone in Children With Mild to Moderately Severe Acute Chest Syndrome Complicating Sickle Cell Disease

ACUTE CHEST SYNDROME (ACS) is one of the most frequent complications requiring hospitalization and a leading cause of death in children with sickle cell disease (SCD).1-4 ACS is an acute illness characterized by fever, cough, chest pain, dyspnea, and new pulmonary infiltrates.3-6 Significant hypoxemia may occur, and the hemoglobin concentration often falls below steady state values, which necessitates blood transfusions.5,7,8 Pulmonary fibrosis and cor pulmonale may result from repetitive episodes.9-12 

Despite its substantial morbidity and mortality, relatively little is known about the etiology and pathophysiology of ACS. Some cases of ACS are clearly due to infection.5,13,14 Additional factors that may precipitate ACS include hypoventilation after opioid analgesics, splinting due to rib infarction, and excessive intravenous hydration.4,15 More recently, fat embolism has been implicated in some cases.16,17 Although multiple factors may cause ACS, pulmonary sequestration and/or sickling with resultant pulmonary infarction probably play a key role.1,4,5,8 

Historically, the management of ACS has included oxygen, intravenous fluids, antibiotics, and blood transfusions.2,4,5,7,18-20The role of transfusion therapy (including exchange transfusion) is unclear.21 Specific therapy that decreases the severity and/or duration of ACS has not been identified. We have previously demonstrated that high-dose intravenous methylprednisolone shortens the duration of hospitalization and reduces opioid requirements in children with painful events.22 This effect may have resulted from the inhibitory effects of glucocorticoids on the inflammatory response that accompanies tissue ischemia/infarction. We hypothesized that because the pathophysiology of ACS and vaso-occlusive crisis is similar, corticosteroids might also reduce the severity of ACS. Therefore, we undertook a randomized, double-blind placebo-controlled study to assess the efficacy of intravenous dexamethasone in children with mild or moderately severe ACS.

Patients between 1 and 21 years of age with sickle cell anemia, sickle hemoglobin-C disease, and sickle β⁰-thalassemia who were followed in the sickle cell program of Children’s Medical Center of Dallas were eligible if they had mild or moderately severe ACS (see definitions below). Children with severe ACS (see definitions below) were excluded because we deemed it appropriate to study the therapeutic role and possible adverse effects of dexamethasone first in patients without life-threatening illness. However, patients who were enrolled with mild or moderately severe ACS but developed severe ACS during the study continued to receive study drug and remained evaluable. Other exclusion criteria were exacerbation of reactive airways disease, strong suspicion of bacterial infection, or any condition that might preclude the use of glucocorticoids, such as diabetes mellitus, hypertension, gastrointestinal bleeding, etc. The many patients who developed ACS while hospitalized for another reason (eg, surgical procedure, vaso-occlusive pain crisis, fever, or respiratory distress without a pulmonary infiltrate on the initial chest radiograph) were also excluded. Patients with mild or moderately severe ACS and concomitant vaso-occlusive crisis at the time of admission were not excluded.

The study protocol was approved by the Institutional Review Board of The University of Texas Southwestern Medical Center at Dallas. Written informed consent was obtained from the parents or guardians.

ACS is defined as the presence of a new pulmonary infiltrate (confirmed by a pediatric radiologist) and two or more of the following: fever, tachypnea, dyspnea, retractions, nasal flaring, grunting, or chest pain.4-6 

This is defined as some respiratory distress present (age adjusted tachypnea, dyspnea, nasal flaring, retractions, and/or grunting), but normal mental status and no extensive pulmonary infiltrates (complete lung involvement) or marked arterial hypoxemia (transcutaneous oxygen saturation <85% despite supplemental oxygen).

Severe ACS is defined as lethargy, marked respiratory distress, extensive bilateral pulmonary infiltrates (or complete lung involvement unilaterally) and marked arterial hypoxemia.

Clinical deterioration is defined as an increase in oxygen requirement and respiratory rate 12 hours or more after the administration of the first dose of the study drug.

Score 0, no respiratory distress; 1, age-adjusted tachypnea; 2, age-adjusted tachypnea and retractions.10 

Opioid therapy consists of intravenous morphine and/or oral acetaminophen with codeine.

After the decision was made to admit the patient to the hospital and the consent form was signed, the patient was randomly assigned in a double-blind fashion to receive dexamethasone or placebo. The hospital pharmacist dispensed either dexamethasone or normal saline placebo according to a computer-generated list of random assignments. The pharmacist was the only unblinded study participant, but had no direct involvement in patient care.

Patients randomized to the study drug received dexamethasone, 0.3 mg per kg of body weight intravenously in 20 mL of normal saline on admission and 12, 24, and 36 hours after the first dose. Patients randomized to placebo received an equivalent volume of normal saline on the same schedule. The dexamethasone and saline solution had an identical appearance. All syringes were labeled “steroid study drug.” The drug was infused over 30 minutes.

Each patient received identical monitoring and supportive care, which included intravenous cefuroxime (50 mg per kg per day administered every 8 hours), oral erythromycin (40 mg per kg per day in three divided doses), intravenous fluids (5% dextrose with 0.45 saline) at maintenance rate, and supplemental oxygen by mask or nasal cannula to maintain oxygen saturation greater than 90%. Patients were placed on transcutaneous oxygen saturation monitors. Opioid agents, morphine intravenously or acetaminophen with codeine orally, were administered as needed. Simple and/or exchange red blood cell transfusions were ordered at the discretion of the attending physician based on the patient’s clinical condition and laboratory parameters. Patients were discharged on erythromycin (40 mg per kg per day) to complete a 7-day course. A follow-up clinic appointment including a chest radiograph was scheduled for all patients 7 days after discharge from the hospital.

Clinical severity at diagnosis was determined or categorized as described above.10 Physical examination, including weight determination, was performed at least daily. During the hospitalization, vital signs every 4 hours and continuous oxygen saturation measurement were recorded. Patients were discharged at the discretion of the attending physician when respiratory distress (ie, tachypnea, dyspnea, use of respiratory accessory muscles, nasal flaring), fever, chest pain, and oxygen requirement had resolved. Completion of the four doses of study drug was not required for patient discharge.

Admission baseline studies included a chest radiograph, complete blood cell count, reticulocyte count, blood culture, and percutaneous oxygen saturation determination. During hospitalization, daily laboratory monitoring included a chest radiograph, complete blood cell count, and reticulocyte count. Complete blood count was determined on a Coultermax (Coulter, Hialeah, FL). Reticulocyte count was performed by the new methylene blue stain technique. Oxygen saturation measurement was determined using a Nelcor pulse oximeter (Nelcor Inc, Hayward, CA). Hemoglobin concentration and percutaneous oxygen saturation measured during hospitalization were compared with the patient’s steady state values. Chest radiograph results at discharge and during follow-up were compared with those obtained on admission.

A retrospective chart review of 30 patients with ACS who met inclusion criteria was used to determine the sample size required. The primary outcome measurement was length of hospital stay (in hours). Based on an observed standard deviation equal to 28 hours, 21 subjects per treatment group would be required to detect an overall difference of 24 hours with a power equal to 80% and a two-sided test of significance at the .05 level.

Descriptive summary statistics include frequencies and percents for categorical variables and mean, median, range, and standard deviation for numerical values. The .05 level was selected for significance tests.

Comparison of baseline and outcome variables was made using χ² contingency table analysis (with Yates correction) or Fisher’s exact test for categorical variables. Student’st-test for independent samples was used for comparison of numerical outcomes. The relationship of age, sex, number of previous episodes of ACS, presence of pain, and treatment assigned (dexamethasone or placebo) to length of hospital stay was assessed using stepwise multiple linear regression analysis. Exploratory subgroup analyses were made to provide direction for further research. Collected data were stored in Paradox for Windows; statistical analyses were performed using the SAS statistical package (SAS/STAT Guide for Personal Computers, Version 6.04; SAS Institute Inc, Cary, NC, 1987). Except when otherwise specified, the statistical analyses were based on the number of episodes and not on the number of patients. All times recorded begin with the administration of the first dose of study medication, that is, the time when the nurse executed the physician’s order and not when the order had been written.

Between October 1992 and July 1995, 131 episodes of ACS were diagnosed in our center. Fifty-seven episodes occurred in patients already hospitalized with another disease complication (usually pain crisis). Two additional patients had severe ACS at presentation and received an immediate exchange transfusion. The 72 remaining episodes fulfilled the study eligibility criteria. Twenty episodes of ACS occurred in patients who were not enrolled because parents or guardians were not present or declined to participate. When these 20 episodes were analyzed separately, the clinical, laboratory, and demographic measures at diagnosis were similar to the study population. In addition, the length of hospitalization and overall hospital course were similar to the study patients who received placebo (Table1).

Fifty-two of these episodes of ACS were included in the study. Of the 52 episodes in which randomization occurred, 9 were not fully evaluable for the following reasons: parents withdrew consent (n = 3), no infiltrate was present on chest radiograph at admission on retrospective review by the pediatric radiologist (n = 4), or intravenous methylprednisolone had been administered for expiratory wheezing (n = 2). Thus, 43 episodes of ACS were evaluable for analysis in 38 children (29 males and 9 females; 34 with sickle cell anemia, 3 with sickle hemoglobin C disease, and 1 with sickle-β⁰thalassemia) aged 1.4 to 15 years (median, 6.7 years) (Table 2).

Twenty-two episodes were randomized to dexamethasone and 21 to placebo. Four patients who were enrolled on two or more occasions were males with homozygous SCD. One patient who was enrolled three times received dexamethasone once and placebo twice. Three other patients were enrolled twice; two were randomized to placebo during one episode and to dexamethasone the other, and the third child received placebo on both occasions. Polyvalent pneumococcal vaccine had been administered to all patients over age 2 years at some time before their hospitalization. Nine patients (3 of 22 in the dexamethasone group and 6 of 21 in the placebo group; P = .28) were not receiving prophylactic penicillin when they developed ACS, either because they were participating on the National Institutes of Health-sponsored Prophylactic Penicillin Study Group II (PROPS II) trial and were assigned to placebo23 or because they were over 5 years old and were not receiving penicillin prophylaxis according to institutional policy.

There were no statistically significant differences between the two groups (dexamethasone v placebo) in any measured demographic, clinical, or laboratory characteristic. The degree of respiratory distress on admission, assessed by the previously described scoring system,10 was not significantly different between the two groups (Table 2).

The length of hospitalization, determined from the time of administration of the first dose of study drug to the time of hospital discharge, was significantly shorter in the dexamethasone-treated group (47 v 80 hours; P = .006; Table 3). None of the study patients remained hospitalized for any other reason (eg, pain, psychosocial problems, etc) after the respiratory distress had resolved. Four of the nine patients whose episodes of ACS were not fully evaluable for reasons other than having received methylprednisolone for wheezing received at least 2 doses of study drug. When these episodes were included in the analysis (totaling 47 episodes), the difference in the mean hospital stay continued to be statistically significant, favoring the dexamethasone group (45 v 77 hours; P = .005).

To further assess the efficacy of dexamethasone, the length of the second hospital admission of the patient who was readmitted with exacerbation of ACS 72 hours after discharge (patient 6, Table 4) was added to the initial hospital admission as if it were a single prolonged admission. The difference in duration of hospitalization in the two groups remained significant (53v 80 hours; P = .033). However, when a similar analysis was performed considering all six patients readmitted within 72 hours after discharge due to exacerbation of ACS or development of vaso-occlusive events (patients 1 to 6, Table 4), the difference in duration of hospitalization in the two groups was no longer significant (66 v 80; P = .31).

Eight (8 of 22) patients in the placebo group, but none (0 of 21) in the dexamethasone group (P < .001) experienced clinical deterioration (see definition above) of their respiratory status (Table3). Two patients in the placebo group required endotracheal intubation with mechanical ventilation and double-volume exchange transfusions. Both recovered.

All 43 patients had a history of fever before admission, and 36 children (84%) were documented to be febrile (> 38.5°C) on presentation (including 19 in the dexamethasone group; Table 2). After administration of the first dose of dexamethasone, all patients except one became afebrile within 4 hours and remained so during the remainder of the hospital admission. In comparison, 14 of the 17 children who received placebo had persistent fever (intermittent or persistent fever over 38.5°C after the administration of the first dose of placebo or dexamethasone) for a median of 36 hours (mean, 52 hours; range, 13 to 120 hours; Table 3). The difference in the percentage of patients with persistent fever was highly significant (P < .001). One patient, randomized to placebo, had a positive blood culture (obtained at admission) due to Staphylococcus aureus. His chest radiograph at presentation showed infiltrates in the right middle and lower lobes. Because the patient did not appear seriously ill, became afebrile during the second hospital day, and had two negative repeat blood cultures, no modification was made in antibiotic coverage. He had no complications during the hospital course. During his follow-up clinic visit, he remained asymptomatic, and a chest radiograph showed improvement of the pulmonary infiltrates.

There was no significant difference in the transcutaneous oxygen saturation or supplemental oxygen requirement between the two groups at the time of admission (Table 2; P = .96 and .60, respectively). However, after randomization, the mean duration of oxygen therapy was significantly less in patients receiving dexamethasone (30 v 61 hours; P = .004; Table 3).

The mean duration of opioid therapy was significantly less in the dexamethasone-treated group (16.8 v 76.8 hours; P < .001; Table 3). Also, the mean number of opioid doses administered was significantly less in the dexamethasone-treated patients (2.5 v20 doses; P < .001; Table 3). Patients receiving placebo were more likely to require modifications (eg, changing the route of opioid administration from oral to intravenous or from intermittent intravenous to a continuous infusion and/or increasing the dose) of the analgesic therapy (five events v one event;P = .08).

A total of 12 blood transfusions were administered during 10 episodes of ACS. Two transfusions were administered during two different dexamethasone-treated episodes of ACS, whereas 10 transfusions, including two exchange transfusions, were given during eight episodes of placebo-treated patients (P = .013; Table 3). Clinical deterioration and a decline in hemoglobin concentration were the indication for 8 of the 10 transfusions in the placebo-treated group. The two dexamethasone-treated patients received a transfusion for a decline in hemoglobin concentration (from 8.7 g/dL to 5.3 g/dL and from 7.0 g/dL to 5.7 g/dL, respectively). Their clinical course was otherwise stable.

Comparison of steady state hemoglobin concentration and transcutaneous oxygen saturation levels with nadir values observed during the episode of ACS indicated that dexamethasone therapy did not prevent a significant decline in these measurements (P = .07 andP = .79, respectively).

Comparison of chest radiograph findings on admission and discharge disclosed no apparent impact of dexamethasone therapy on short-term progression or resolution of the pulmonary infiltrates. Five patients in the dexamethasone group and nine in the placebo group had a partial or complete resolution of their infiltrate by the time of discharge. Ten patients in the dexamethasone group and seven in the placebo group had no change in their pulmonary infiltrates, while four patients in the dexamethasone group and three patients in the placebo group had extension of the pulmonary infiltrates noted on admission. Five patients (two in the placebo-treated group) did not have a repeat chest radiograph at the time of discharge.

All enrolled patients were evaluated for readmission to the hospital for 3 weeks after discharge. Seven patients (six of whom had received dexamethasone; Table 3; P = .095) were readmitted, each within 72 hours after initial discharge. Nevertheless, only one patient was readmitted with ACS (P = 1.00). The seven patients who were readmitted exhibited no apparent demographic, clinical, and/or laboratory characteristics that differed from the rest of the study population (Table 4).

The dexamethasone-treated patient readmitted because of a cerebrovascular accident (patient 2; Table 4) was a 6-year-old boy who developed left hemiparesis and headache 36 hours after discharge. During the previous admission, he had no dexamethasone-related complications (such as hypertension) known to contribute to stroke. However, he had received a blood transfusion because of a decline in hemoglobin concentration (from 7.0 to 5.7 g/dL). His posttransfusion hemoglobin concentration was 9.5 g/dL. On readmission, magnetic resonance imaging showed a cerebral infarct in the right middle cerebral artery distribution. Magnetic resonance angiography imaging and transcranial Doppler studies showed extensive large vessel disease. The patient experienced a near complete neurological recovery and remains on a chronic transfusion program without further sequelae.

No specific complications related to the use of dexamethasone (such as hypertension, psychosis, symptomatic osteonecrosis, gastrointestinal bleeding, hyperglycemia, or opportunistic infection) were observed during the study period or on follow-up in any of the 38 patients. All blood pressure values were within the age-related normal range for pediatric patients. A specific comparison of individual blood pressure measurements in each dexamethasone- or placebo-treated patient was not undertaken.

Twenty-four patients (12 in each group) returned for a follow-up outpatient clinic visit 7 days after discharge. All patients were free of symptoms. There were no statistically significant differences between the two groups when the results of follow-up chest radiographs were compared with the findings at discharge. Specifically, 10 patients in the dexamethasone group and nine in the placebo group had partial or complete resolution of pulmonary infiltrates between discharge and the follow-up visit. One patient in each group had no change, while one patient in the dexamethasone group and two patients in the placebo group had extension of previous pulmonary infiltrates. The distribution of results in the two groups is similar (P = .40).

Stepwise multiple regression analysis explored the relationship of age, gender, number of previous ACS episodes, presence or absence of concomitant pain, and type of treatment to the length of hospitalization. In order of importance, three variables entered the prediction equation: type of treatment, number of previous episodes, and gender. The multiple regression was significant at the P = .002 level with a multiple R = .565.

Results of this analysis indicated that irrespective of treatment group, the males tended to have a shorter hospitalization than did females, and those children with no previous ACS episodes tended to have a shorter hospital stay than those with one or more prior events. Patients’ age and the presence of concomitant pain played no role in predicting response to dexamethasone as measured by length of hospital stay.

The treatment of ACS has included hospitalization, supplemental oxygen, intravenous and/or oral antibiotics, analgesics, and simple or exchange transfusion.2,18-21 However, no single therapeutic approach has previously been shown to be effective in ACS when tested by a randomized controlled trial. Although aggressive blood transfusion support has been widely used and is seemingly beneficial, there is no consensus on its indications or method of administration.21 

To our knowledge, the use of glucocorticoids in patients with SCD and ACS has not been previously reported. However, steroids have been used to treat acute vaso-occlusive crises.22,24 Griffin et al22 studied the role of methylprednisolone (15 mg/kg) in patients with SCD and pain. Duration of analgesic therapy and hospital stay were significantly reduced in the steroid-treated group. However, an excess number of patients randomized to methylprednisolone were readmitted due to recurrence of pain. Concerns about administering such high doses of methylprednisolone and the possible “rebound” effect suggested the use of a lower dose of a longer acting glucocorticoid (eg, dexamethasone) in the current study. The dexamethasone dose and schedule used here was comparable to that previously used in infants and children with bacterial meningitis and croup.25,26 

In this double-blind placebo-controlled trial, which assessed the efficacy of dexamethasone in children with mild to moderately severe ACS, treatment with dexamethasone reduced the length of hospitalization by about 40%. In our patients, adjuvant dexamethasone therapy appears to have prevented clinical deterioration and reduced the need for blood transfusion to treat the worsening anemia that often characterizes ACS.4,5,7 Furthermore, dexamethasone therapy had a highly favorable impact on the duration of fever, oxygen requirement, and need for opioid analgesia.

Numerous observers have suggested that recurrent and severe episodes of ACS may result in permanent lung disease.9-12,17,27,28 Therefore, by shortening the duration of symptomatic ACS and reducing the accompanying inflammatory process, dexamethasone therapy may diminish or prevent irreversible injury to the pulmonary parenchyma.

Although the number of children in each subgroup was too small to provide definitive conclusions, in a stepwise multiple regression analysis, males and patients with fewer prior ACS episodes appeared to have a particularly favorable response to dexamethasone. Lung damage caused by previous episodes of ACS might have adversely influenced the response to dexamethasone. Additionally, young males have been shown to have a smaller peripheral airway diameter than females29,30so might therefore have benefitted more from the antiinflammatory properties of glucocorticoids.

The specific mechanisms by which dexamethasone may be beneficial during ACS are unclear. Because many of the signs and symptoms of painful vaso-occlusive crisis (and perhaps of intrapulmonary sickling as well) resemble those seen in states of inflammation, the salutary effects of dexamethasone noted here may have resulted from inhibition of the inflammatory response that accompanies tissue ischemia/infarction. Cytokines (eg, interleukins, tumor necrosis factor, prostaglandins, etc) released during infection and episodes of ischemia have been shown to play a pivotal role in inflammatory reactions within the lung.31 Glucocorticoids inhibit the production of cytokines and alter arachidonic acid metabolism.32-34The clinical significance of these antiinflammatory pharmacologic properties have been well demonstrated in bacterial meningitis.25 This mechanism may also explain the dramatic effect of dexamethasone on the resolution of fever in our patients.

There is increasing evidence that fat embolism resulting from bone marrow infarction may play a cardinal role in the pathophysiology of ACS.16,17,35 Although we did not investigate our patients for fat embolism, it is of interest that glucocorticoids are often used in the prevention of pulmonary fat embolism after orthopedic trauma.36,37 The precise mechanisms for the damaging effects of pulmonary fat embolism in ACS are not well understood. In a recent study, Styles et al38 reported a 140-fold increase in levels of plasma phospholipase A₂ in patients with SCD and ACS compared with controls. Phospholipase A₂ and free fatty acids are known to cause bronchoconstriction and increase pulmonary vascular permeability, mucus secretion, and leukocyte chemotaxis.39-43 Dexamethasone is a potent inhibitor of phospholipase A₂,39,44,45 so perhaps its beneficial effects in ACS are mediated by blocking the liberation of free fatty acids and preventing their damaging effects on the lungs.

There were no significant differences in the clinical course or duration of hospital stay between our placebo-treated group and patients who were eligible, but not enrolled (Table 1). However, the average hospital stay in placebo-treated patients was shorter than in most previous reports of ACS.4,5,8,17 There are several explanations for this observation. First, patients with severe ACS were excluded from the study. Such patients usually require exchange transfusion, intensive care, and prolonged hospitalization. Second, most reported series of ACS include patients admitted initially with ACS, as well as those who develop ACS while hospitalized for other reasons. Our cohort of study patients included only those with ACS diagnosed on admission. Not surprisingly, such patients have shorter hospitalizations than those whose ACS develops while already hospitalized.4 Third, it has been reported that older patients with multiple prior events of ACS have longer hospitalizations.3,7,46 Thus, the younger age (mean, 6.7 years) and fewer prior episodes of ACS (median, 2 previous events) may explain the relatively brief hospital stay of the placebo-treated group.

Although no complications of dexamethasone therapy were observed in our patients, caution must be exercised when using glucocorticoids in patients with sickle cell anemia, as such individuals are predisposed to develop avascular necrosis of the hip and shoulder. However, when extremely high glucocorticoid doses are used for prolonged periods in children without SCD, avascular necrosis has rarely been reported.46,47 

Patient 2 (Table 4) had a stroke within 48 hours after discharge. During his hospital admission, he received a simple packed red blood cell transfusion. Strokes have been described after simple or exchange transfusion resulting in a posttransfusion hemoglobin concentration over 12 g/dL.48,49 However, this was not the case in our patient. Furthermore, ACS appears to be an independent significant risk factor for stroke in patients with sickle cell anemia.50 Although our patient had neither hypertension nor other obvious complications of corticosteroids, we cannot definitively exclude the possibility that dexamethasone might have played a role in this event.

Although the readmission rate among dexamethasone-treated patients was not significantly higher (P = .095) than placebo-treated patients, individuals randomized to dexamethasone therapy were more likely to be readmitted with sickle cell-related complications. When all vaso-occlusive-related hospital readmissions were taken into consideration, the hospital stay length between the two groups became insignificant. Yet, dexamethasone therapy still played a key role in improving the overall well-being of the patients by preventing clinical deterioration, decreasing the need for oxygen therapy, red blood cell transfusions, opioid therapy, and the resolution of fever. There is no clear explanation for this phenomenon. It can be hypothesized that because the time between the reappearance of their symptoms and the last dose of study drug is similar to the plasma half-life of dexamethasone (24 hours), the exacerbation of the symptoms might have represented a “rebound” effect. In addition, there are three case reports of glucocorticoids precipitating vaso-occlusive crises and or bone marrow fat necrosis. However, the relationship between the development of the event and the administration of glucocorticoid appears to be only temporal, not causal.16,51 To our knowledge, there is no physiologic or pharmacologic explanation for this phenomenon.

Dexamethasone is the first therapeutic intervention shown to benefit children with ACS in a randomized, double-blind placebo-controlled trial. ACS in children differs appreciably in its clinical features from the disease in adults.3 Because the study did not include older adolescents and/or adults, severely affected patients, or patients who developed ACS while in the hospital for another reason, further study of dexamethasone is warranted in patients with ACS and SCD.

We are grateful for the invaluable assistance of Isabelle Tkaczewski, RN, for assisting with the data acquisition and analysis and to the hematology-oncology fellows, pediatric residents, and nurse practitioners at Children’s Medical Center of Dallas who cared for these patients.