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A pilot study of outpatient management of febrile neutropenic children with cancer at low risk of bacteremia
CLINICAL AND LABORATORY OBSERVATIONS
A pilot study of outpatient management of febrile neutropenic children with cancer at low risk of bacteremia Mahmoud M. Mustafa, MD, Victor M. Aquino, MD, Alberto Pappo, MD,a Isabelle Tkaczewski, RN, and George R. Buchanan, MD From the Department of Pediatrics, The University of Texas Southwestern Medical Center and the Center for Cancer and Blood Disorders, Children's Medical Center of Dallas, Dallas, Texas
Febrile neutropenic children with cancer were eligible for outpatient management with intravenous ceftriaxone therapy if they displayed selected low-risk criteria. Nineteen children were enrolled. All patients had sterile blood cultures, and only one of them was hospitalized because of persistent fever. This pilot study suggests that selected children with febrile neutropenia might be successfully managed without hospitalization. (J Pediatr 1996; 128:847-9) It has recently been demonstrated that febrile neutropenic patients do not represent a homogeneous group. 1 Features that help define patients at lower risk of bacteremia during hospitalization include the presence of some degree of bone marrow recovery,2' 3 short duration of fever, 2-4 and underlying disease in remission, e' 3, 5 It has been demonstrated that selected febrile neutropenic patients can be safely discharged before complete resolution of neutropenia. 2s This experience has suggested that similar criteria might be applied at the onset of fever to select a group of relatively lower-risk neutropenic patients in whom hospitalization might be avoided altogether. Therefore we conducted a pilot study of outpatient management of patients with febrile neutropenia meeting selected low-risk criteria. METHODS
All children and adolescents with cancer who were receiving intermittent pulse cytotoxic chemotherapy be-
Supported by National Institutes of Health T32 training grant No. CA09640, the Children's Cancer Fund of Dallas, and A Weekend to Wipe Out Cancer. Submitted for publication July 24, 1995; accepted Feb. 6, 1996. Reprint requests: George R. Buchanan, MD, Department of Pediatrics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75235-9063. aCurrently at St. Jude Children's Research Hospital, Memphis, Tenn. Copyright © 1996 by Mosby-Year Book, Inc. 0022-3476/96/$5.00 + 0 9/22/72554
tween January 1992 and September 1994 were eligible for enrollment. The study was approved by the institutional review board of the University of Texas Southwestern Medical Center at Dallas, and written informed consent was obtained. At the time of febrile neutropenia the child was carefully evaluated, and a complete blood cell count with differential leukocyte count and blood cultures were obtained. Chest x-ray film and urine culture were obtained only when clinically indicated. Children were eligible for outpatient management if they did not have serious concurrent comorbidity other than fever and neutropenia and if they met the following lower-risk ANC
Absoluteneutrophil count
[
criteria: age greater than 12 months, leukemia in complete remission or solid tumor in complete or partial remission, 10 days having elapsed since the initiation of the last course of cytotoxic chemotherapy, and either an absolute neutrophil count between 100 and 500/ram 3 or, if the ANC was less than 100/mm 3, a platelet count greater than 75,000/ram 3. The child was also required to have reliable parents, a telephone in the home, adequate transportation, agreement to daily follow-up, and residence within 100 miles of our institution. Patients with severe mucositis, abdominal or perirectal tenderness, or other indications for hospitalization (e.g., inability to take oral fluids, symptomatic anemia, hemorrhage caused by thrombocytopenia) were not eligible for the study.
847
848
Mustafa et al.
The Journal of Pediatrics June 1996
T a b l e I. Characteristics of 19 low-risk febrile neutropenic children with cancer treated as outpatients Mean age (Y0 Sex Male Female Underlying diagnosis Leukemia/lymphoma Solid tumor Central line Yes No Concomitant-G-CSF therapy
7.5 (range, 2-15) 12 (63%) 7 13 (68%) 6 17 (89%) 2 2 (11%)
G-CSF, Granulocytecolony-stimulatingfactor.
T a b l e II. Results of outpatient management of 19 low-risk febrile neutropenic children with cancer Absolute neutrophil count at study entry (/mm3) Absolute phagocyte count? at study entry (/mm3) Platelet count at study entry (xl03/mm3) Number of days since first day of last course of chemotherapy Days in study Days febrile on study Children with focal infections Pneumonia Mucositis Otitis media Celhilitis Doses of ceftriax0ne 1 Dose 2 Doses 3 Doses Admission for intravenous antibiotic therapy Sterile blood cultures
189 -+ 37 (0-442)* 575 _+69 (38-1080)* 141 _+25 (25-461)* 13.0 _+0.4 (10-17)* 3.2 (range, 2-5) 1.6 (range, 1-4) 5/19 (26%) 1 '2 1 1 8 patients 10 patients 1 patients 1/19 episodes 19/19 episodes
*Mean _+SE (range). "~Absolutephagocyte count: total leukocytes/mm3 x (% segmentednentrophils + % band forms + % monocytes).
After study entry, an intravenous dose of ceftriaxone (80 mg/kg; maximum dose, 2.0 gin) was administered. The patient was observed for 30 minutes and discharged. The child returned to the outpatient unit and his condition was evaluated daily. Each day that the child remained febrile, additional blood samples were obtained for culture, and ceftriaxone was administered. Daily follow-up evaluations and blood cell counts were obtained until the child had sterile blood cultures and either attained an ANC of 500/ram 3 or was afebrile for 48 hours or more, after which telephone follow-up and every-other-day complete blood cell counts were obtained until recovery of the ANC to greater than
500/mm 3. Orally administered antibiotics were prescribed as needed to treat a focal infection. If the child worsened clinically in any way or if blood culture results were positive, the patient was immediately hospitalized for intravenous antibiotic therapy. A charge analysis was performed to compare charges between patients in the study and those who were eligible but hospitalized nevertheless.
RESULTS Of 60 eligible patients, 19 were enrolled in this pilot study; their characteristics are summarized in Table I. There was a slight predominance of children with hematologic malignancies (13/19, 68%). The most common reason for a patient to be hospitalized despite meeting the low-risk criteria was having been seen late at night in the emergency department and/or the on-call physician's having overlooked considering the patient for inclusion in the study. The results of this approach are summarized in Table II. Patients were febrile for an average of 1.6 days and remained in the study for an average of 4 days. Study subject's received an average of 1.6 doses of ceftriaxone. Five patients (26%) had a primary focus of infection at the onset of fever. All 19 of the children had sterile blood cultures. Eighteen patients (95%; 95% confidence interval, 85% to 100%) were successfully managed entirely in the outpatient setting. One child required hospitalization for intravenous antibiotic therapy because of persistent fever, cough, and chills that developed 48 hours after enrollment. The patient r e m a i n e d hospitalized for 2 days. All cultures were sterile, and the child was discharged after an uneventful hospital course. An economic analysis comparing the 19 low-risk febrile neutropenic children managed as outpatients with those 41 managed in the hospital was performed. None of the children who were hospitalized had positive blood culture results. The mean number of days of hospitalization was 3.6 _+ 0.3, which was not significantly different from the number of days of study enrollment for the outpatient group (t7 -- 0.69, Student t test). The mean total charge for those managed as outpatients was $831 - $64; for those treated as inpatients, it was $6465 _ $1090 (p <0.001, Student t test). The cost of outpatient management was 12% that of inpatient therapy, and the average savings for each patient's parents and thirdparty payers was approximately $5600 per episode.
DISCUSSION This pilot study demonstrates that febrile neutropenic children who meet certain low-risk criteria might be safely managed as outpatients using dally intravenous ceftriaxone therapy. Outpatient antibiotic therapy for febrile neutropenia can provide many theoretical benefits beside cost savings,
The Journal of Pediatrics Volume 128, Number 6
such as decreased exposure to nosocomial pathogens as well as improved quality of life. 9, 10 Parents and children enrolled in the study uniformly expressed satisfaction with this approach. In this trial, only one third of the children who were eligible were actually enrolled. Most patients not included in the study were initially seen during the evening hours or on weekends, and the on-call oncologist failed to enroll the patient, whereas neutropenic children whose fever developed during regular clinic hours were more likely to be included. We do not believe that this induced a selection bias, because the children who met the low-risk criteria but were treated in the hospital received antibiotics for the same number of days as the children who remained in the outpatient study (p = 0.69) and had sterile cultures and uncomplicated hospitalizations. A review of our institution's experience during a recent 12-month period showed that approximately 20% of all episodes of fever during a period of neutropenia occurred in cancer patients with the low-risk features described, and these patients would therefore be expected to have negative blood culture results and to be candidates for outpatient management. This study suggests that some febrile neutropenic children who are at relatively low risk of bacteremia might be successfully treated a s outpatients. These results should be viewed as preliminary because of the small number of patients enrolled and the single-arm design of the study, so this Outpatient management approach cannot be recommended as the standard of care at the present time. Further research aimed at identifying low-risk febrile neu~ropenic patients and providing less costly and more "user friendly" care to them deserves the continued attention of clinical investigators.
Mustafa et al.
849
We are grateful to our program's hematology-oncology fellows and nurses for their assistance with the conduct of this study. REFERENCES
1. Buchanan GR. Approach to treatment of febrile cancer patients with low-risk neutropenia. Hematol Oncol Clin North Am 1993;7:937-60. 2. Griffin TC, Buchanan GR. Hematologic predictors of bone marrow recovery in neutropenic patients hospitalized for fever: implications for discontinuation of antibiotics and early hospital discharge. J Pediatr 1992;121:29-33. 3. Mullen CA, Buchanan GR. Early discharge of children with cancer treated for fever and neutropenia: identification and management of the low-risk patient. J Clin Oncol 1990;8:19982004. 4. Talcott JA, Finberg R, Meyer FH, et al. The medical course of cancer patients with fever and neutropenia: clinical identification of a low-risk subgroup at presentation. Arch Intern Med 1988;148:2561-8. 5. Bash RO, Katz JA, Cash JV, et al. Safety and cost-effectiveness of early hospital discharge of lower-risk children with cancer admitted for fever and neutropenia. Cancer 1994;74:18996. 6. Kaplan AH, Weber DJ, Daves L, et al. Short courses of antibiotics in selected febrile neutropenic patients. Am J Med Sci 1991;302:353-4. 7. Jones GR, Konsler GK, Dunaway RP, et al. Risk factors for recurrent fever after the discontinuation of empiric antibiotic therapy for fever and neutropenia in pediatric patients with a malignancy or hematologic condition. J Pediatr 1994;124: 702-9. 8. Tomiak AT, Yan JC, Huan HD, et al. Duration of intravenous antibiotics for patients with neutropenic fever. Ann Oncol 1994;5:441-5. 9. Eisenberg JM, Kitz DS. Savings from outpatient antibiotic therapy -for osteomyelitis. JAMA 1986;255:1584-8. 10. Smego RA, Gainer RB. Home intravenous antimicrobial therapy provided by a community hospital and a university hospital. Am J Hosp Pharm 1989;42:2185-9.
A pilot study of outpatient management of febrile neutropenic children with cancer at low risk of bacteremia Mahmoud M. Mustafa, MD, Victor M. Aquino, MD, Alberto Pappo, MD,a Isabelle Tkaczewski, RN, and George R. Buchanan, MD From the Department of Pediatrics, The University of Texas Southwestern Medical Center and the Center for Cancer and Blood Disorders, Children's Medical Center of Dallas, Dallas, Texas
Febrile neutropenic children with cancer were eligible for outpatient management with intravenous ceftriaxone therapy if they displayed selected low-risk criteria. Nineteen children were enrolled. All patients had sterile blood cultures, and only one of them was hospitalized because of persistent fever. This pilot study suggests that selected children with febrile neutropenia might be successfully managed without hospitalization. (J Pediatr 1996; 128:847-9) It has recently been demonstrated that febrile neutropenic patients do not represent a homogeneous group. 1 Features that help define patients at lower risk of bacteremia during hospitalization include the presence of some degree of bone marrow recovery,2' 3 short duration of fever, 2-4 and underlying disease in remission, e' 3, 5 It has been demonstrated that selected febrile neutropenic patients can be safely discharged before complete resolution of neutropenia. 2s This experience has suggested that similar criteria might be applied at the onset of fever to select a group of relatively lower-risk neutropenic patients in whom hospitalization might be avoided altogether. Therefore we conducted a pilot study of outpatient management of patients with febrile neutropenia meeting selected low-risk criteria. METHODS
All children and adolescents with cancer who were receiving intermittent pulse cytotoxic chemotherapy be-
Supported by National Institutes of Health T32 training grant No. CA09640, the Children's Cancer Fund of Dallas, and A Weekend to Wipe Out Cancer. Submitted for publication July 24, 1995; accepted Feb. 6, 1996. Reprint requests: George R. Buchanan, MD, Department of Pediatrics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75235-9063. aCurrently at St. Jude Children's Research Hospital, Memphis, Tenn. Copyright © 1996 by Mosby-Year Book, Inc. 0022-3476/96/$5.00 + 0 9/22/72554
tween January 1992 and September 1994 were eligible for enrollment. The study was approved by the institutional review board of the University of Texas Southwestern Medical Center at Dallas, and written informed consent was obtained. At the time of febrile neutropenia the child was carefully evaluated, and a complete blood cell count with differential leukocyte count and blood cultures were obtained. Chest x-ray film and urine culture were obtained only when clinically indicated. Children were eligible for outpatient management if they did not have serious concurrent comorbidity other than fever and neutropenia and if they met the following lower-risk ANC
Absoluteneutrophil count
[
criteria: age greater than 12 months, leukemia in complete remission or solid tumor in complete or partial remission, 10 days having elapsed since the initiation of the last course of cytotoxic chemotherapy, and either an absolute neutrophil count between 100 and 500/ram 3 or, if the ANC was less than 100/mm 3, a platelet count greater than 75,000/ram 3. The child was also required to have reliable parents, a telephone in the home, adequate transportation, agreement to daily follow-up, and residence within 100 miles of our institution. Patients with severe mucositis, abdominal or perirectal tenderness, or other indications for hospitalization (e.g., inability to take oral fluids, symptomatic anemia, hemorrhage caused by thrombocytopenia) were not eligible for the study.
847
848
Mustafa et al.
The Journal of Pediatrics June 1996
T a b l e I. Characteristics of 19 low-risk febrile neutropenic children with cancer treated as outpatients Mean age (Y0 Sex Male Female Underlying diagnosis Leukemia/lymphoma Solid tumor Central line Yes No Concomitant-G-CSF therapy
7.5 (range, 2-15) 12 (63%) 7 13 (68%) 6 17 (89%) 2 2 (11%)
G-CSF, Granulocytecolony-stimulatingfactor.
T a b l e II. Results of outpatient management of 19 low-risk febrile neutropenic children with cancer Absolute neutrophil count at study entry (/mm3) Absolute phagocyte count? at study entry (/mm3) Platelet count at study entry (xl03/mm3) Number of days since first day of last course of chemotherapy Days in study Days febrile on study Children with focal infections Pneumonia Mucositis Otitis media Celhilitis Doses of ceftriax0ne 1 Dose 2 Doses 3 Doses Admission for intravenous antibiotic therapy Sterile blood cultures
189 -+ 37 (0-442)* 575 _+69 (38-1080)* 141 _+25 (25-461)* 13.0 _+0.4 (10-17)* 3.2 (range, 2-5) 1.6 (range, 1-4) 5/19 (26%) 1 '2 1 1 8 patients 10 patients 1 patients 1/19 episodes 19/19 episodes
*Mean _+SE (range). "~Absolutephagocyte count: total leukocytes/mm3 x (% segmentednentrophils + % band forms + % monocytes).
After study entry, an intravenous dose of ceftriaxone (80 mg/kg; maximum dose, 2.0 gin) was administered. The patient was observed for 30 minutes and discharged. The child returned to the outpatient unit and his condition was evaluated daily. Each day that the child remained febrile, additional blood samples were obtained for culture, and ceftriaxone was administered. Daily follow-up evaluations and blood cell counts were obtained until the child had sterile blood cultures and either attained an ANC of 500/ram 3 or was afebrile for 48 hours or more, after which telephone follow-up and every-other-day complete blood cell counts were obtained until recovery of the ANC to greater than
500/mm 3. Orally administered antibiotics were prescribed as needed to treat a focal infection. If the child worsened clinically in any way or if blood culture results were positive, the patient was immediately hospitalized for intravenous antibiotic therapy. A charge analysis was performed to compare charges between patients in the study and those who were eligible but hospitalized nevertheless.
RESULTS Of 60 eligible patients, 19 were enrolled in this pilot study; their characteristics are summarized in Table I. There was a slight predominance of children with hematologic malignancies (13/19, 68%). The most common reason for a patient to be hospitalized despite meeting the low-risk criteria was having been seen late at night in the emergency department and/or the on-call physician's having overlooked considering the patient for inclusion in the study. The results of this approach are summarized in Table II. Patients were febrile for an average of 1.6 days and remained in the study for an average of 4 days. Study subject's received an average of 1.6 doses of ceftriaxone. Five patients (26%) had a primary focus of infection at the onset of fever. All 19 of the children had sterile blood cultures. Eighteen patients (95%; 95% confidence interval, 85% to 100%) were successfully managed entirely in the outpatient setting. One child required hospitalization for intravenous antibiotic therapy because of persistent fever, cough, and chills that developed 48 hours after enrollment. The patient r e m a i n e d hospitalized for 2 days. All cultures were sterile, and the child was discharged after an uneventful hospital course. An economic analysis comparing the 19 low-risk febrile neutropenic children managed as outpatients with those 41 managed in the hospital was performed. None of the children who were hospitalized had positive blood culture results. The mean number of days of hospitalization was 3.6 _+ 0.3, which was not significantly different from the number of days of study enrollment for the outpatient group (t7 -- 0.69, Student t test). The mean total charge for those managed as outpatients was $831 - $64; for those treated as inpatients, it was $6465 _ $1090 (p <0.001, Student t test). The cost of outpatient management was 12% that of inpatient therapy, and the average savings for each patient's parents and thirdparty payers was approximately $5600 per episode.
DISCUSSION This pilot study demonstrates that febrile neutropenic children who meet certain low-risk criteria might be safely managed as outpatients using dally intravenous ceftriaxone therapy. Outpatient antibiotic therapy for febrile neutropenia can provide many theoretical benefits beside cost savings,
The Journal of Pediatrics Volume 128, Number 6
such as decreased exposure to nosocomial pathogens as well as improved quality of life. 9, 10 Parents and children enrolled in the study uniformly expressed satisfaction with this approach. In this trial, only one third of the children who were eligible were actually enrolled. Most patients not included in the study were initially seen during the evening hours or on weekends, and the on-call oncologist failed to enroll the patient, whereas neutropenic children whose fever developed during regular clinic hours were more likely to be included. We do not believe that this induced a selection bias, because the children who met the low-risk criteria but were treated in the hospital received antibiotics for the same number of days as the children who remained in the outpatient study (p = 0.69) and had sterile cultures and uncomplicated hospitalizations. A review of our institution's experience during a recent 12-month period showed that approximately 20% of all episodes of fever during a period of neutropenia occurred in cancer patients with the low-risk features described, and these patients would therefore be expected to have negative blood culture results and to be candidates for outpatient management. This study suggests that some febrile neutropenic children who are at relatively low risk of bacteremia might be successfully treated a s outpatients. These results should be viewed as preliminary because of the small number of patients enrolled and the single-arm design of the study, so this Outpatient management approach cannot be recommended as the standard of care at the present time. Further research aimed at identifying low-risk febrile neu~ropenic patients and providing less costly and more "user friendly" care to them deserves the continued attention of clinical investigators.
Mustafa et al.
849
We are grateful to our program's hematology-oncology fellows and nurses for their assistance with the conduct of this study. REFERENCES
1. Buchanan GR. Approach to treatment of febrile cancer patients with low-risk neutropenia. Hematol Oncol Clin North Am 1993;7:937-60. 2. Griffin TC, Buchanan GR. Hematologic predictors of bone marrow recovery in neutropenic patients hospitalized for fever: implications for discontinuation of antibiotics and early hospital discharge. J Pediatr 1992;121:29-33. 3. Mullen CA, Buchanan GR. Early discharge of children with cancer treated for fever and neutropenia: identification and management of the low-risk patient. J Clin Oncol 1990;8:19982004. 4. Talcott JA, Finberg R, Meyer FH, et al. The medical course of cancer patients with fever and neutropenia: clinical identification of a low-risk subgroup at presentation. Arch Intern Med 1988;148:2561-8. 5. Bash RO, Katz JA, Cash JV, et al. Safety and cost-effectiveness of early hospital discharge of lower-risk children with cancer admitted for fever and neutropenia. Cancer 1994;74:18996. 6. Kaplan AH, Weber DJ, Daves L, et al. Short courses of antibiotics in selected febrile neutropenic patients. Am J Med Sci 1991;302:353-4. 7. Jones GR, Konsler GK, Dunaway RP, et al. Risk factors for recurrent fever after the discontinuation of empiric antibiotic therapy for fever and neutropenia in pediatric patients with a malignancy or hematologic condition. J Pediatr 1994;124: 702-9. 8. Tomiak AT, Yan JC, Huan HD, et al. Duration of intravenous antibiotics for patients with neutropenic fever. Ann Oncol 1994;5:441-5. 9. Eisenberg JM, Kitz DS. Savings from outpatient antibiotic therapy -for osteomyelitis. JAMA 1986;255:1584-8. 10. Smego RA, Gainer RB. Home intravenous antimicrobial therapy provided by a community hospital and a university hospital. Am J Hosp Pharm 1989;42:2185-9.