|
|
| |||||||||||||||||||||||||||||||||||||||
Background Because of their susceptibility to pneumococcal sepsis, children with sickle cell disease and fever are usually hospitalized for antibiotic therapy. Outpatient treatment may be a safe and less expensive alternative for selected patients.
Methods After evaluation in the emergency room, children ranging from 6 months to 12 years of age who had sickle hemoglobinopathies and temperatures exceeding 38.5 °C were randomly assigned to treatment as either inpatients or outpatients. We excluded from randomization children at higher risk of sepsis (as defined by specific criteria, including temperature above 40 °C, white-cell count below 5000 per cubic millimeter or above 30,000 per cubic millimeter, and the presence of pulmonary infiltrates) or with complications of sickle cell disease (such as a hemoglobin level below 5 g per deciliter, dehydration, or severe pain); these children were treated as inpatients. All patients received an initial intravenous dose of ceftriaxone (50 mg per kilogram of body weight). Those treated as outpatients returned 24 hours later for a second dose of ceftriaxone, whereas the inpatients were treated as directed by their physicians.
Results None of the 86 patients (with a total of 98 febrile episodes) in the randomized groups had sepsis, as compared with 6 of the 70 patients (7 of 86 episodes) excluded because of higher risk (P = 0.004). Among the 44 children (50 episodes) assigned to outpatient treatment, there were 11 hospitalizations (22 percent of episodes) within two weeks after treatment (95 percent confidence interval, 12 to 36 percent), whereas after inpatient care only a single patient (2 percent of episodes) was rehospitalized. When the randomized groups were compared, outpatient treatment saved a mean of $1,195 per febrile episode. The median hospital stay was 3 days (range, 1 to 6) for the children randomly assigned to inpatient care and 4 days (range, 1 to 18) for the higher-risk children treated as inpatients (P<0.001).
Conclusions With the use of conservative eligibility criteria, at least half the febrile episodes in children with sickle cell disease can be treated safely on an outpatient basis, with substantial reductions in cost.
With the availability of newer antibiotics that provide effective coverage against S. pneumoniae and have prolonged serum half-lives, outpatient therapy has been suggested for selected patients with sickle cell disease whose main symptom is fever3,4. There are encouraging data from small series and retrospective studies to support this approach, but evidence of safety and efficacy from controlled, prospective studies is not available. Selection criteria are needed to exclude not only patients at an unusually high risk of septicemia but also those who are likely to require hospitalization for other illnesses related to their hemoglobinopathies.
We conducted a prospective, randomized comparison of outpatient therapy and routine inpatient management, with both approaches based on intravenous ceftriaxone, in febrile patients followed in a sickle cell disease program. A pilot study showed that the pharmacokinetic values of ceftriaxone in this group of patients did not differ from normal values. We used risk-based eligibility criteria to exclude children at risk for bacteremia.
Methods
Patient Population
The patients were drawn from a population of 450 children with sickle hemoglobinopathies followed in the Mid-South Sickle Cell Disease Program. Most patients were given their diagnoses by screening soon after birth and have been followed from infancy. All parents complete a comprehensive educational program emphasizing that febrile episodes need immediate attention and that penicillin prophylaxis must be administered consistently5. The children receive penicillin prophylactically until the age of five years, after which eligible patients are randomly assigned to continue penicillin treatment or to receive placebo as part of a national study of prophylactic penicillin. The decision regarding continued penicillin prophylaxis for ineligible patients is made by the parents after the risks and benefits have been discussed. Pneumococcal vaccine is given at the age of two years; all children receive Haemophilus influenzae type b vaccine. All patients are seen in the clinic or contacted by telephone at least every six months.
Eligibility Criteria
Children with homozygous sickle cell disease, hemoglobin SC disease, or hemoglobin S-beta-thalassemia were evaluated for inclusion in the study if they were 6 months to 12 years of age and presented to LeBonheur Children's Medical Center with temperatures in excess of 38.5 °C. The study, which was approved by the appropriate institutional review boards, remained open from October 1, 1990, to March 30, 1992.
The patients were classified according to risk. Those considered to be at standard risk underwent randomization. Patients were excluded from randomization and assigned to the higher-risk group if they had any of the following features: a seriously ill appearance (moderate or severe impairment as measured by the McCarthy scale,6 which is used to evaluate serious illness in febrile children), hypotension (systolic blood pressure of <70 mm Hg at 1 year of age or <70 mm Hg + 2 x the age in years for older children), poor perfusion (capillary-refill time, >4 seconds), a temperature above 40.0 °C, a corrected white-cell count above 30,000 per cubic millimeter or below 5000 per cubic millimeter, a platelet count below 100,000 per cubic millimeter, or a history of pneumococcal sepsis. Also assigned to the higher-risk group were children with signs or symptoms associated with complications of sickle cell disease likely to necessitate hospitalization -- severe pain, dehydration (poor skin turgor, dry mucous membranes, history of poor fluid intake, or decreased output of urine), infiltration of a segment or a larger portion of the lung, and a hemoglobin level below 5.0 g per deciliter -- and those allergic to penicillin or cephalosporins.
Study Design and Procedures
All patients were given intravenous ceftriaxone (Rocephin) in a dose of 50 mg per kilogram of body weight shortly after presentation to the emergency room, and laboratory tests (see below) were ordered promptly. The patients were examined and observed until the results of blood tests were known. All children eligible for randomization were reexamined by one of the investigators, who explained the study and obtained informed consent from the parents or guardians. The first 10 patients who met the eligibility criteria participated in a separate pilot study of feasibility and pharmacokinetics. Subsequently, eligible patients were randomly assigned to inpatient or outpatient treatment with the use of sequentially numbered sealed envelopes. The patients were reevaluated for randomization if they presented with fever a second time during the 18-month study period; all subsequent episodes were excluded from the study.
The probability of treatment assignment was based on an adaptive randomization plan. If the treatment assignment was balanced, a patient had a 50 percent chance of being randomly assigned to either treatment; if the treatment balance differed by one patient, the next patient had an 85 percent chance of assignment to the underrepresented group; and if the treatment balance differed by two patients, the next patient was assigned to the underrepresented group. The study was designed to accrue 50 episodes of fever in each randomized group, providing at least an 80 percent probability of detecting differences of 
0.5 SD (alpha = 0.05 by one-sided tests).
Parents whose child was assigned to outpatient management were instructed to return for a follow-up visit one day (20 to 30 hours) after the child's discharge from the emergency room or clinic, or at any sign of problems. On the second visit, another dose of intravenous ceftriaxone (50 mg per kilogram) was given, a complete blood count was obtained, and bilirubin levels were measured. Oral antibiotics were prescribed only for children with an identified focus of infection. The children randomly assigned to the inpatient group and those assigned to the higher-risk group were treated according to the plan of the attending hematologist, which typically involved at least one additional dose of ceftriaxone.
Laboratory and Pharmacokinetic Studies
The following were performed on admission to the emergency room and as indicated thereafter: a complete blood count; urinalysis; measurements of total and direct bilirubin; chest roentgenography; and cultures of blood (two), throat swabs, and urine. The complete blood count and bilirubin measurements were repeated at 24 hours. All laboratory analyses were performed at LeBonheur Children's Medical Center.
Patients enrolled in the preliminary study of ceftriaxone pharmacokinetics received the initial dose of intravenous ceftriaxone of 50 mg per kilogram and were admitted for measurement of serum levels at 2, 4, 8, and 24 hours. Ceftriaxone levels were measured in the Infectious Diseases Laboratory at St. Jude Children's Research Hospital by a bioassay with Escherichia coli (American Type Culture Collection 25922). Serum levels of ceftriaxone were calculated by comparing the zones of inhibition produced in agar plates with a standard curve of known ceftriaxone concentrations7,8. These data were also collected for the first four patients randomly assigned to inpatient therapy. A one-compartment model was fit to each patient's data, and the volume of distribution and the first-order elimination-rate constant were estimated with the maximum-likelihood method. Each observation was weighted on the basis of an estimate of the variance determined from the model. Clearance was calculated from the estimates of the volume of distribution and the elimination rate.
Statistical Analysis
The primary variables of interest were the duration of hospitalization for randomized and higher-risk patients, the frequency of hospitalization during the two-week period after randomization, the number of episodes of documented bacteremia in randomized as compared with higher-risk patients, and the costs of care for the episodes in randomized patients. Two patients with white-cell counts below 5000 per cubic millimeter were mistakenly included in the randomization procedure; both were assigned to inpatient therapy. Data for these two patients have been dropped from the randomized inpatient group and included in the higher-risk group. Comparisons between groups were performed with Fisher's exact test or Wilcoxon's rank-sum test, as appropriate.
Results
A total of 233 febrile episodes in 197 children with sickle cell disease were evaluated during the study period. The first 10 patients participated only in the pilot pharmacokinetic study. Eighty-six patients with a total of 98 episodes met the criteria for randomization; 44 patients (50 episodes) were randomly assigned to the outpatient group, and 42 patients (48 episodes) to the inpatient group. Seventy patients with a total of 86 episodes were excluded from randomization and assigned to the higher-risk inpatient group. The remaining 31 patients (39 episodes) declined to participate, were unable to make a return visit, or were not identified and were therefore not included in the study.
The measurement of serum ceftriaxone concentrations in the pilot study (14 patients; mean of 3.9 samples per patient) revealed a mean clearance of 0.036 liter per hour per kilogram (range, 0.021 to 0.057), a mean terminal half-life of 5.6 hours (range, 4.1 to 7.0), and a volume of distribution of 0.29 liter per kilogram (range, 0.14 to 0.53). Serum concentrations ranged from 96 to 268 mg per liter 2 hours after the administration of ceftriaxone and from 2.7 to 17.5 mg per liter at 24 hours. There were no significant differences between these values and published normal values9 (Figure 1). There was no increase in bilirubin levels 24 hours after the administration of ceftriaxone: initial and 24-hour median levels were 1.5 mg per deciliter, suggesting that one dose of ceftriaxone did not result in substantial sludging of bile.
|
|
|
|
|
Discussion
In this prospective study we found that outpatient therapy with an initial dose of intravenous ceftriaxone of 50 mg per kilogram and a second dose within 20 to 30 hours is appropriate management for febrile children with sickle cell disease -- provided that patients with higher-risk features are excluded. We were initially concerned that the pharmacokinetics of ceftriaxone might be altered in children with sickle cell disease because of their increased glomerular filtration rate,10 and that biliary disease might be exacerbated as a result of the biliary secretion associated with ceftriaxone11. Our pharmacokinetic study of ceftriaxone in 14 febrile children did not identify any significant differences as compared with published findings in normal children9. The concentration at 24 hours was approximately 100-fold higher than the usual minimal inhibitory concentration for S. pneumoniae. We were also reassured by the absence of change in the median bilirubin level 24 hours after the administration of ceftriaxone, which suggested that bile sludging does not occur after a single intravenous dose of 50 mg per kilogram.
Another goal of this study was to identify criteria that would exclude patients with a higher risk of sepsis or with complications of sickle cell disease likely to necessitate hospitalization. We were largely successful in meeting this goal. The six children in whom bacterial sepsis subsequently developed were all excluded from randomization to outpatient therapy by our eligibility criteria. Furthermore, patients considered to be at higher risk had a significantly longer median hospital stay than those randomly assigned to inpatient therapy. Finally, only 11 patients (11 of 50 episodes) assigned to outpatient therapy were hospitalized -- most for reasons unrelated to sickle cell disease -- within two weeks of randomization.
The savings associated with outpatient management are considerable. Our review of emergency room, laboratory, and hospitalization charges indicated a mean saving of $1,195 per febrile episode, including the costs of all hospitalizations within two weeks of outpatient treatment. We believe that the frequency of such hospitalizations, and the associated costs, will decrease as both physicians and families become more comfortable with managing fever on an outpatient basis, and our current management reflects changes in this direction.
Our choice of the intravenous route for ceftriaxone was based on two factors: our standard emergency room practice, which includes the placement of an intravenous catheter, and the painfulness of intramuscular injections of ceftriaxone. Because the pharmacokinetics of ceftriaxone are similar after intramuscular or intravenous injections, the intramuscular route should be effective if there are problems with intravenous access.
While our study was in progress, Rogers and coworkers published the results of a retrospective study of outpatient therapy for febrile episodes using a single dose of ceftriaxone followed by an oral antibiotic for at least three days4. This approach, if proved safe in a prospective trial with monitoring of compliance, would be more convenient and cost effective than the protocol described here. We are currently conducting such a study.
Unlike Rogers et al.,4 we included children with hemoglobin SC disease. Although these patients are at lower risk of pneumococcal sepsis than those with homozygous sickle cell disease, their risk is increased as compared with that for the general population, and they have intermittent asplenia12,13. It has been our practice to hospitalize such patients for parenteral antibiotic therapy when they present with fever -- a policy supported by the fact that two of six episodes of pneumococcal bacteremia during the study period occurred in patients with this form of hemoglobinopathy.
The criteria we used to select candidates for outpatient therapy are simple to apply, requiring information readily available in most emergency rooms. According to these criteria, slightly more than half the children in our sickle cell disease program would be eligible for outpatient care. We are using these criteria in our current study of compliance with outpatient oral antibiotic therapy.
The results of the present study, combined with data from other centers,4,14 indicate that outpatient therapy for selected febrile children with sickle cell disease is a medically sound alternative to hospitalization. This approach is well received by parents and patients and is highly cost effective.
Supported in part by a grant (RR 00211) from the U.S. Public Health Service General Clinical Research Center, grants (CA 23944 and CA 21765) from the National Cancer Institute, and the American Lebanese Syrian Associated Charities.
We are indebted to Christy Wright and John Gilbert for helpful comments; to Tracey Gibbs and Roche Pharmaceuticals for supplying ceftriaxone; to Derek Richardson for help with assays; to Donald Baker, Pharm.D., for pharmacokinetic analysis; and to the pediatric house staff, hematology-oncology fellows, and emergency room staff of LeBonheur Children's Medical Center for their cooperation with this study.
Source Information
From the Departments of Hematology-Oncology (J.A.W., S.H., S.W.D., J.M.E., W.C.W.), Infectious Diseases (P.M.F.), Pharmaceutical Sciences (J.H.R.), and Biostatistics (D.L.F.), St. Jude Children's Research Hospital; LeBonheur Children's Medical Center (R.S.); and the Department of Pediatrics, University of Tennessee College of Medicine (J.A.W., P.J.C., W.C.W.) -- all in Memphis.
Address reprint requests to Dr. Wilimas at the Department of Hematology-Oncology, St. Jude Children's Research Hospital, P.O. Box 318, Memphis, TN 38101.
References
| |||||||||||||||||||||||||||||||||||||||
Related Letters:
Outpatient Treatment of Febrile Children with Sickle Cell Disease
Ros S. P., Sarnaik S. A., Wilimas J., Wang W.
Extract |
Full Text
N Engl J Med 1994;
330:219-220, Jan 20, 1994.
Correspondence
This article has been cited by other articles:
HOME | SUBSCRIBE | SEARCH | CURRENT ISSUE | PAST ISSUES | COLLECTIONS | PRIVACY | HELP | beta.nejm.org Comments and questions? Please contact us. The New England Journal of Medicine is owned, published, and copyrighted © 2008 Massachusetts Medical Society. All rights reserved. |
Previous
