The Oncologist, Vol. 12, No. 8, 1019-1026, August 2007; doi:10.1634/theoncologist.12-8-1019
© 2007 AlphaMed Press
Symptom Management and Supportive Care |
Cancer-Associated Neutropenic Fever: Clinical Outcome and Economic Costs of Emergency Department Care
D. Mark Courtneya,
Amer Z. Aldeena,
Stephen M. Gormana,
Jonathan A. Handlera,
Steven M. Trifiliob,
Jorge P. Paradac,
Paul R. Yarnolda,
Charles L. Bennettd,e
aDepartment of Emergency Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA;
bDepartment of Pharmacy, Northwestern Memorial Hospital, Chicago, Illinois, USA;
cStritch School of Medicine, Loyola University, Chicago, Illinois, USA;
dJesse Brown VA Medical Center/Mid-West Center for Health Services and Policy Research, Chicago, Illinois, USA;
eDivision of Hematology/Oncology and the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, USA
Key Words. Febrile neutropenia • Neutropenic fever • Emergency department • Cancer-induced neutropenia
Correspondence: Charles L. Bennett, M.D., Ph.D., VA Lakeside Medical Center, Division of General Internal Medicine, Department of Medicine, 400 E. Ontario Street, Suite 205, Chicago, Illinois 60611, USA. Telephone: 312-469-4410; Fax: 312-640-2496; e-mail: cbenne{at}northwestern.edu
Received March 21, 2007;
accepted for publication June 22, 2007.
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ABSTRACT
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Purpose. Febrile neutropenia (FN) is a common, costly, and potentially fatal complication in oncology. While FN in the inpatient setting has been extensively studied, only one study has evaluated emergency department (ED) care for FN cancer patients. That study found that 96% of patients survived the complication. We evaluated clinical and economic outcomes for cancer patients with chemotherapy-associated FN treated in an ED.
Methods. ED records for consecutive oncology patients with FN were reviewed for information on death, intensive care unit (ICU) use, blood cultures, and costs.
Results. Forty-eight patients (n = 57 visits) were evaluated. Six patients died from FN (12%) and four received ICU care within 2 weeks and survived (8%). Blood cultures were positive for 37% of the ED visits. The median ED time was 3.3 hours. In 91% of visits, i.v. antibiotics were administered in the ED, ordered at a median of 1.7 hours from triage (interquartile range [IQR], 1.2–2.8 hours). All patients with death or ICU in 2 weeks and all but one patient with positive blood cultures received antibiotics. The median per patient ED costs were $1,455 (IQR, $1,300–$1,579)—42.4% for hospital/nursing, 23.5% for radiology, 20.8% for physician services, 10.9% for diagnostic tests, and 2.4% for antibiotics.
Conclusions. Cancer patients with FN in this sample presenting to the ED frequently had no identified source of infection. One third of the patients had positive ED blood cultures and one fifth died or required ICU care within 2 weeks. Costs of ED care were similar to the cost of a single day of inpatient care.
Disclosure of potential conflicts of interest is found at the end of this article.
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INTRODUCTION
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Patients with febrile neutropenia (FN) typically have a temperature 
100.4°F and an absolute neutrophil count (ANC) <500–1,000 cells/ml and are known to be at elevated risk for serious bacterial infection. In 1966, a direct relationship between the degree of granulocytopenia and infectious complication was first identified [1]. Despite efforts to risk-stratify oncology patients with neutropenic fever at select tertiary care medical centers [2–4], the majority of cancer patients with FN who present to an emergency department (ED) receive inpatient care for close monitoring, evaluation for identification of a source of infection, and empiric antibiotics. These patients may appear relatively stable in the ED but subsequently experience clinical deterioration after several hours or days.
ED care is of increasing importance, with continuing concerns over high health care costs and the potential for less expensive management in the home or ambulatory care setting for some cancer patients with FN. While the patient is in the ED, critical decisions are made, such as potential discharge to home or, more likely, admission to a regular medical bed or an intensive care unit (ICU). The ED is also the location where volume replacement if needed is given and the diagnostic workup and antibiotic therapy plan is initiated. While clinicians view these patients as being at high risk for morbidity and mortality, patients often experience delays in time to being seen by a physician and time to antibiotic and fluid administration, and may wait several hours in the ED before an inpatient bed is available.
Only one study has evaluated ED care of cancer patients with FN [5]. In that study of 55 episodes of cancer-associated FN treated in the ED at the Hospital of the University of Pennsylvania, all of the patients received antibiotics in the ED, and 53 patients survived the FN episode. Costs and resource utilization were not measured. In this study, we evaluated clinical and economic outcomes for ED care of cancer patients with FN.
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METHODS
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Study Design
We conducted a retrospective consecutive review of oncology patients seen over a 22-month period in the ED at Northwestern Memorial Hospital from November 2001 to October 2003. Patient privacy was safeguarded throughout the study. As a retrospective chart medical record review, this study involved minimal risk and human subject protection was approved by the Institutional Review Board at Northwestern University Feinberg School of Medicine. Northwestern Memorial Hospital is an urban, adult, university academic center with over 70,000 patients seen annually in the ED. The adjoining Robert H. Lurie Comprehensive Cancer Center is a National Cancer Institute–designated comprehensive cancer center and member of the National Comprehensive Cancer Network that provides care to a large population of cancer patients. Patient ED visits were identified by International Classification of Diseases (ICD)-9 code search for "agranulocytosis"(288.0) or "aplastic anemia including pancytopenia" (284.8) as a diagnosis from either the ED discharge or hospital discharge billing data. Medical records were evaluated to confirm that the patients met all of the following inclusion criteria: fever 100.4°F in the ED or measured in the 24 hours preceding the ED visit, ANC 
500 cells/ml as measured in the ED, no do not resuscitate order, and age 18 years.
Data Collection
Data were abstracted in a standardized fashion using a predefined data collection instrument that included patient demographic information, presumed reason for neutropenia, type of malignancy, recent chemotherapy, outpatient antimicrobial use, and specific comorbid illness. Clinical data while the patients were in the ED included: vital sign data, laboratory and radiological data, and therapies instituted in the ED. Severity of illness was evaluated using two validated FN risk-stratification systems—the Talcott risk group [2] and the Multinational Association of Supportive Care in Cancer (MASCC) score [3].
Blood cultures drawn in the ED were classified as positive if microbial carbon dioxide production was detected by the BactecTM automated method of continuous blood culturing monitoring (BD: Diagnostic Systems, Sparks, MD) per existing laboratory protocol. These samples were cultured and considered positive if pathologic organisms were detected and subsequently treated. Urine cultures were considered to be positive if >50,000 colony-forming units of pathologic organisms per milliliter were detected and subsequently treated with ongoing antibiotics.
The financial cost of ED neutropenic fever care was estimated and described as the aggregate costs of all hospital/nursing care, physician care, radiology testing, laboratory testing, and antibiotics while in the ED (Table 1). These data were abstracted for each patient visit by reviewing complete hard copy and electronic medical records to determine what tests, labs, and antibiotics were used in each visit. Costs of these items were determined from individual itemized costs as determined by our hospital pricing catalog and are reported in 2005 U.S. dollars.
The primary clinical outcome of interest was the proportion of patients with severe neutropenia and fever who expired or required ICU care in the 2 weeks subsequent to the ED presentation. Secondary outcome included the proportion of patients with ED blood cultures that were positive for pathologic organisms. Outcome determination was confirmed by manual review of electronic and nonelectronic medical records. At our study site, all patients admitted to the ICU have an ICU note in the electronic medical record and all patients who expired in the hospital have a death note in the electronic medical record. Billing data were also reviewed to determine discharge status and discharge date. All patients who were discharged from inpatient care prior to 2 weeks underwent detailed medical record reviews to verify clinical status at 2 weeks after ED visit, or social security death index search to identify any deaths after ED presentation.
Analysis
Data analysis was done using StatsDirect© 2004 version 2.3.7 (Cheshire, UK). Continuous parametric data were analyzed using Student's t-test; nonparametric data were analyzed with the Mann-Whitney U test. Exact 95% confidence intervals (CIs) were calculated using the Clopper-Pearson method to describe proportions. Data describing patient demographics, cancer type, and the primary outcome of death or ICU care within 2 weeks are reported per unique patient in Table 2A. Data describing ED care, antibiotics, blood culture outcome, and costs are reported per patient visit (Table 2B).
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RESULTS
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Characteristics of Patients
A total of 763 patient charts with the relevant ICD-9 codes were reviewed. Of these, 618 were excluded because of a lack of confirmed neutropenia in the ED, 72 were excluded for lack of observed fever in the ED, 13 were excluded for incomplete data, and three were nonmalignancy patients and were excluded. A total of 48 unique patients and 57 episodes met the inclusion criteria and are included in the study. Seven patients had two ED visits and one patient had three ED visits. The mean patient age was 58.3 years and 52% were male (Table 2A). Malignancies included acute myelogenous leukemia (n = 16) and solid tumors (n = 11). Overall, 85% of the patients had indwelling venous catheters, 75% were undergoing chemotherapy, and 67% were on prophylactic antimicrobial medications at home prior to presentation. The mean ANC was 98 cells/ml.
Clinical Course in the ED
Patients were in the ED a median of 3.3 hours (interquartile range [IQR], 2.3–4.0 hours). At the time of ED evaluation, the pulse was >120 per minute for 30% and the systolic blood pressure was <100 mmHg for 25% of the FN episodes. Blood cultures were obtained in the ED for all of the visits, urine cultures were obtained in 61.4% of the visits (per lab protocol, only when a urinalysis sample was suggestive of a urinary tract infection was a urine culture performed), sputum cultures were obtained in 12.2%, a chest radiograph was obtained for 91.2%, and ED i.v. antibiotics were given for 91.2%. Radiology examinations included chest radiographs (n = 45), chest computed tomography (CT) scan (n = 5), abdominal CT scan (n = 5), neck CT scan (n = 1), and central nervous system CT scan (n = 7). A single antibiotic was used for 22 FN episodes, two antibiotics for 23 FN episodes, and three antibiotics were used for seven FN episodes. The most common antibiotic prescribed was cefepime. The median time from patient triage to antibiotic order was 1.7 hours (IQR, 1.2–2.8 hours). Overall, none of the episodes were treated with mechanical ventilation in the ED and no patient expired in the ED. All patients were admitted to the hospital with 3 of 57 (5.3%) of the episodes being admitted directly from the ED to the ICU.
Clinical Outcomes
Blood cultures identified bacterial growth in 36.7% of the FN episodes (Table 3). Pseudomonas spp., Escherichia coli, Streptococcus spp., Staphylococcus aureus, and Klebsiella spp. were the most common bacteria identified in the cultures. Urine cultures identified bacterial growth for five episodes, primarily Gram-negative organisms (Klebsiella spp., E. coli, Enterococcus spp.). Of the 21 FN episodes associated with positive blood cultures, all but one episode was treated with empiric antibiotics in the ED. All patient episodes that resulted in death or ICU care in the 2 weeks subsequent to their ED presentation received empiric antibiotics in the ED. There were no significant differences in the mean time to ED antibiotic order when comparing by blood culture results or when comparing by 2-week death/ICU care (data not shown).
Overall, evaluating only the most recent FN episode for each patient, 12.5% of the patients died from FN, 8.3% survived the FN episode but required ICU care, and 20.8% met the predefined criteria for death or ICU care within 2 weeks. Of the six patients who died from FN, three had systolic blood pressures in the ED <100 mmHg, four had tachycardia >100, and five had platelet counts <50,000 cells/ml (Table 4). All six were categorized as Talcott risk group II (the highest risk group possible for outpatients) and four were high risk (<21) by the MASCC scoring system. The median MASCC scores were significantly lower (poorer) for patients who died from FN (19 versus 22; 95% CI for difference, –6 to –1). Univariate factors measured in the ED significantly associated with death/ICU care included a higher maximum heart rate in the ED (mean, 129 versus 108 beats per minute [bpm]; 95% CI for difference, +6 to +35 bpm) and a lower platelet count (median, 10.5 versus 30.5 x 1,000 cells/ml; 95% CI for difference, 2–45 x 1,000 cells/ml), while factors not significantly associated with this outcome included presence of indwelling venous catheters, outpatient antibiotic use prior to ED visit, degree of neutropenia, and subsequent identification of a positive blood culture.
Economic Cost of ED Care
The median FN episode cost was $1,455 (IQR, $1,300–$1,579). Hospital and nursing costs accounted for 42.4% of the total ED cost (median per patient visit, $712; IQR, $590–$753) and included costs for the ED bed, venipuncture, i.v. administration of fluids and medications, nursing level of care costs, and other items listed in Table 1. Radiology costs accounted for 23.5% of the ED costs (median per patient visit, $119; IQR, $119–$119). Seven episodes were evaluated with a CT of the brain, 5 episodes were evaluated with a CT scan of the abdomen and pelvis, and five episodes were evaluated with chest CT. The primary radiology cost was for standard chest radiography performed in 52 patients. ED physician service costs accounted for 20.8% of the total median costs (median per patient visit, $418; IQR, $267–$418). Laboratory costs accounted for 10.9% of the ED costs (median per patient visit, $190; IQR, $166–$190) primarily for CBC, basic metabolic package blood analysis, and urine and blood cultures. Fifty-four episodes were treated with 91 unique i.v. administrations of antibiotics in the ED, representing 2.4% of overall costs of ED care (median per patient visit, $42; IQR, $36–$51).
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DISCUSSION
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Fever in the neutropenic cancer patient is considered a medical emergency. In our study of cancer patients with chemotherapy-associated FN who received care in an ED, 12% died from FN in the hospital within 2 weeks of their ED presentation, and 8% survived, but required ICU care. In interpreting our findings, several factors should be considered.
First, outcomes of ED care for cancer patients with FN differed between the one prior review of ED care from the University of Pennsylvania (hereafter, the Penn study) and this report (Table 5) [5]. Rates of bacteremia and death in our FN population were 37% and 12.5%, versus only 14.5% and 3.8%, respectively, in the Penn study. Of note, mean ANCs in our study were fourfold less than in the Penn study and we included patients with an ANC 500 cells/ml whereas their cutoff was 1,000. Following ED care, the mean duration of inpatient hospitalization was 12 days in our cohort versus 6 days in the Penn study. Taken together, these results suggest that the two cohorts differed in baseline severity of illness. Also, patients in our report were much less likely to have a source of infection identified in the ED. Only one of the five patients with positive ED urine cultures had a urinalysis that was abnormal. Only three patients had abnormalities on ED chest radiography interpreted as a definite or possible infiltrate, and only one subject had pulmonary consolidation on CT imaging consistent with pneumonia. Taken together, this indicates that, in our study, only 9% of subject visits (5 of 57) had an ED-identified possible infection source. This contrasts with the Penn study, in which a source was identified in the ED in 38% of visits (21 of 55). An additional difference is that our study reports a median MASCC score and finds this to be significantly associated with the outcome of death in 2 weeks, whereas the Penn study does not provide risk stratification data.
Second, the intensity of care in the ED was high. The median time to antibiotic administration was 145 minutes in this study and 170 minutes in the Penn study. The 2003 Infectious Disease Society of America Clinical Guidelines on the Treatment of Community-Acquired Pneumonia in Adults recommends initiation of antibiotics within 4 hours, a threshold generally achieved in both studies [6]. Although there are no specific guideline recommendations for time to antibiotic administration for FN patients, it would seem reasonable that a shorter time from presentation to administration for patients with suppressed immune systems would be reasonable and prudent.
Third, no prior study has reported on costs of ED care for cancer patients with FN. We found a median ED cost of $1,455, an amount that is similar to the estimated cost of a single inpatient day for cancer patients with FN [7, 8]. These ED costs have not been explicitly incorporated into previously reported cost-minimization models for the use of colony-stimulating factors that estimate cost neutrality at a 15%–20% rate of FN [8]. Our findings suggest that the threshold for cost-effective prophylactic initiation of colony-stimulating factors could be lower, if some care is provided at an ED. The importance of performing cost-effectiveness studies as part of clinical trials or from computer-generated models has been emphasized [9], as well as the importance of accurately including all direct costs when considering economic factors affecting treatment thresholds. Recent American Society of Clinical Oncology recommendations for the use of white blood cell growth factors noted that recommendations were made primarily on clinical grounds alone, but noted that further research into the cost implications of these agents is needed [10]. This study indicates that ED care may be an important contributor to total direct costs and should be considered in future cost-effectiveness studies and practice guidelines/recommendations.
Fourth, given the large number of patients who present to EDs and the high potential morbidity and mortality, our findings, in conjunction with the results from the Penn study, suggest that a systematic approach to ED evaluation and treatment is needed. Relative to other high-visibility, high-mortality disease processes seen in the ED, FN is not considered as much of a medical emergency as trauma or chest pain from the standpoint of potential clinical deterioration. Cardiac and stroke teams have been implemented to rapidly evaluate, confirm, and treat acute myocardial infarction and stroke. EDs and cardiology groups are evaluated closely for meeting accepted door-to-reperfusion times. Trauma patients are cared for immediately under the concept that a "golden hour" exists during which time recognition and treatment of shock or hemorrhage is critical. It may be that a more protocolized approach to cancer patients who arrive at triage with chemotherapy-associated FN is needed. Elements of a protocol targeted to known or likely chemotherapy-related neutropenia would include: immediate blood culture, urine culture, chemistry, and CBC drawn at triage even before physician availability, noninvasive hemodynamic monitoring, and FN-specific nursing triage protocols to avoid an excessive potentially dangerous nonmonitored time in the ED waiting room. Such guidelines may be helpful in setting ED benchmark standards for laboratory turnaround times, antibiotic availability and delivery times, and goal-directed care targeted toward identifying early sepsis and optimizing timely pathogen detection. This would facilitate prospective tracking of important clinical and economic outcomes as well.
Our study has several limitations. Selection bias is possible because of the retrospective single-center study design. Patients with FN who were not included in the ICD-9 search or who had missing data may have been different from the patients described herein. However, there is no reason to suspect that they would be more or less likely to experience death in 2 weeks or bacteremia, or to contribute more or less to the estimation of costs relative to included patients. Also, some costs were not included in our economic analysis. Overall, we conservatively estimated costs, and if inaccuracy exists based on the chart abstraction method of cost estimation, it is likely to underestimate the true overall costs. While our study does not provide information on the total population of FN patients at our center, even the lower limit of the 95% CI suggests that, at a minimum, the true 2-week mortality rate in this sample is likely to be at least 5%, and the rate of bacteremia is likely at least 24%. Another limitation is uncertainty over the actual cause of death in these patients. While it is possible that acute infectious processes directly caused death in these patients, myocardial infarction, pulmonary embolism, drug-related reactions, and advanced malignancy may have contributed to some of the deaths. Additionally, even in patients with death likely resulting from infection, it is unclear whether death within 2 weeks was a result of the primary infectious process, or whether a more deadly nosocomial pathogen was contracted in the inpatient setting.
We acknowledge these limitations and indicate that this report does not intend to suggest that the experience in our ED is generalizable to all EDs. However, as this represents only the second study describing the care of these patients in the ED, and as more and more patients with chemotherapy are managed as outpatients with the possibility of fever during weekends, evening hours, and in situations when oncologists may not be able to see them, their care is important to examine and work toward optimization. These preliminary data suggest an opportunity for improvement and the importance of future work.
We conclude that the clinical outcomes of this sample of ED patients with cancer chemotherapy–associated FN are substantial, and poorer than those included in the prior study on this subject. Most of the patients in this sample did not have a focus identified while in the ED, and the 37% rate of bacteremia was high. Also, the cost for this ED care approximates that of a single inpatient day ($1,455) and should be considered in future cost-effectiveness studies that involve potential ED care.
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DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
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The authors indicate no potential conflicts of interest.
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ACKNOWLEDGMENTS
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This work was presented as an abstract at the Midwest Regional Society for Academic Emergency Medicine Meeting, Milwaukee, Wisconsin, September 2004. D.M.C. has received support from grant K23HL077404-02 from the National Heart Lung and Blood Institute.
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REFERENCES
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Abstract
Introduction
