the complete blood count and reticulocyte count–are they necessary in the evaluation of acute...

CBC and Reticulocyte Count in Sickle-cell Crisis, b p e z el al. 751

The Complete Blood Count and Reticulocyte Count- Are They Necessary in the Evaluation of Acute Vasoocclusive Sic kle-cell Crisis? Bernard L. b p e z , MD, Sharon K. Griswold. MD. Anke Navek, MD, Linda Urbanski, MD

I ABSTRACT

Objective: To assess the usefulness of the complete blood count (CBC) and the reticulocyte count in the evaluation of adult patients with acute vasoocclusive sickle-cell crisis (SCC) presenting to the ED.

Methods: A 2-part study was performed. Part 1 was a retrospective chart review of patients with a sole ED diagnosis of acute SCC. Part 2 was a prospective evaluation of consecutive patients presenting in SCC. In both parts of the study, patients with coexisting acute disease were excluded. The remaining patients were divided into 2 groups: admitted and released. The mean values for white blood cell (WBC) count, hemoglobin (Hb) level, and reticulocyte count were compared. In Part 2. the change (A) from the patient's baseline in WBC count, Hb level, and reticulocyte count also was determined. Data were analyzed by 2-tailed Student's t-test.

Results: Part 1: There was no difference between the admitted (n = 33) and the released (n = 86) groups in mean WBC count (p = 0.10), Hb level (p = 0.25), or reticulocyte count (p = 0.08). Part 2: There was no difference between the admitted (n = 44) and the released ( n = 160) groups i n mean Hb level (p = 0.88). reticulocyte count (p = 0.47). AHb level (p = 0.88). and Areticulocyte count (p = 0.76). There was a difference in mean WBC counts (15.8 5 4.9 X 109/L admitted vs 12.8 2 4.9 X 109L released, p = 0.003) and AWBC counts (5.1 2 4.6 X 109/L admitted vs 1.8 2 4.6 X 109/L released, p < 0.002).

Conclusion: Determination of the Hb level and the reticulocyte count do not appear useful in the evaluation of acute SCC in the ED. Admission decisions appear associated with elevations in the WBC count. Further study is required to determine the true value of the WBC count in such decisions.

Key words: sickle-cell anemia; laboratory test; decision making; complete blood count; CBC; reticulocyte count; emergency department.

Acad. Emerg. Med. 1996; 3:75 1-757.

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From the Jefferson Medical College, Philadelphia. PA. Division of EmLrgency Medicine.

Received: July I2. 1995; revision received: October 11. 1995; ac- cepted: OcCober 16. 1995; updated: November I . 1995.

Prior presentation: SAEM annual meeting, San Antonio. TX, May 1995.

Address for correspondence and reprinis: Bernard L Lopet UD. Di- vision of Emergency Medicine, Thomas Jefferson Universiry Hospital. 1020 Walnut Street. Philadelphia, PA 19107. Fax: 215-923-6225; e-mail: [email protected]

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I Sickle-cell anemia (SCA) is a disease that affects approximately I in 625 black Americans.' The most com- mon ED presentation is acute, painful vasoocclusive sickle-cell crisis (SCC). I n the adult SCA population, approximately 95-99% of all SCA-related ED visits are for SCC.'" The standard treatment of these patients is analgesia and hydrati~n.~ In addition, the emergency physician (EP) must evaluate these patients for more serious complications such as infection, severe anemia. and aplastic ~ r i s i s . ~ Diagnostic studies such as a com-

752 ACADEMIC EMERGENCY MEDICINE AUG 1996 VOL 3/NO 8

I TABLE 1 Admission Guidelines for Sickle-cell Anemia Pa- tients ............................................................................

1. Persistent severe pain after standard therapy 2. Decrease in hemoglobin 220 g/L of baseline 3. Fever >38.3”C (>lOl°F) 4. White blood cell count 1.5 times baseline 5 . Priapism 6. Neurologic signs and symptoms 7. Joint swelling 8. Evidence of infection or other serious medical problem

plete blood count (CBC) and reticulocyte as well as urinalysis and radiography,’ are commonly done.

While the CBC and reticulocyte count are routinely ordered for evaluating SCC, their usefulness is questionable. These tests are frequently suggested in various texts and journals6-’ as part of the routine evaluation of adult SCA patients presenting in crisis, yet there is very little scientific evidence to support this. A MEDLINE search (key words: emergency medical services, sickle cell anemia, complete blood count, reticulocyte count; English language only) of the emergency medicine (EM) literature of the past 30 years reveals no specific study regarding the use of these 2 tests in the ED management of SCC. The current study seeks to evaluate the usefulness of the CBC and reticulocyte count for aiding disposition of the SCC patient. We hypothesized that there would be no difference in the CBC parameters or reticulocyte counts of adult SCA patients presenting to the ED with uncomplicated, acute vasoocclusive crisis, whether they were admitted or released from the ED.

I METHODS

Study Design

We conducted a 2-part study. Part 1 was a retrospective chart review and Part 2 was a prospective obser- vational inception cohort study. Both parts evaluated the association of the CBC and reticulocyte count with the admission decision for SCA patients presenting to the ED with a chief complaint of typical, acute SCC. The study was approved by the Institutional Review Board of Thomas Jefferson University.

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Setting and Population

The study was conducted at an urban university ED with an accredited, 3-year EM residency program. The ED is a designated regional SCA center for Philadelphia, PA, with an ED census of 52,000 visits per year. The ED receives approximately 1,700 adult visits per year related to SCA, representing an SCA patient population base of 150. In 1994, all SCA patients who visited the ED had a primary chief complaint of typical acute SCC.

The Thomas Jefferson University Hospital ED is staffed 24 hours a day by board-certified attending EPs, second- and third-year EM residents, and first-year resident housestaff from EM, internal medicine, and family medicine. All patients are evaluated either primarily by the attending EP or by EM housestaff. All evaluations conducted primarily by EM housestaff are done so under the direct supervision of the attending EP. SCA patients who, in the opinion of the attending EP, are stable for release home are released without the need for consul- tation with other housestaff or medical staff. SCA patients thought to require admission are evaluated by an internal medicine resident. This resident then discusses the case with the patient’s attending physician. All data, including laboratory results, are available to the housestaff as well as to the attending medical staff. At our institution, the vast majority of SCC patients are admitted for in-hospital pain control based on the subjective finding of inadequate pain relief in the ED. A set of written guidelines (which are not absolute reyuire- ments) is available to assist with patient disposition (Ta- ble 1).

In both parts of the study, all patients aged 2 18 years with a chief complaint of typical SCC pain were eligible for the study. “Typical” crisis pain was defined by the patient as pain consistent in duration, severity, quality, and distribution with prior episodes of SCC. All patients had hemoglobin (Hb) sickle-cell disease as documented by prior outpatient, noncrisis Hb electrophoresis by our department of hematology. Exclusion criteria were: age e l 8 years, leaving prior to completion of the workup, absence of laboratory testing, non- “typical” pain, or evidence of acute, coexisting illness. “Acute, coexisting illness” was defined as an infectious or traumatic illness of <7 days’ duration according to history, along with any of the following abnormal vital signs on presentation: fever 238.3”C (>101”F), tachycardia >120 beatdmin, tachypnea >30 breathdmin, and/or systolic blood pres- sure <lo0 mm Hg.

Experimental Protocol and Measurements

Part 1 was a retrospective chart review of all SCA patients who presented during the month of March 1994 with a sole ED diagnosis of acute SCC. Charts were reviewed for the results of the CBC and reticulocyte count (all study patients had both the CBC and reticulocyte count measured when any blood testing was done) as well as for history and physical examination data. To assess for subsequent patient complications, a review of ED charts for the month of April 1994 was conducted to search for cases of aplastic anemia, severe anemia, or severe infection that necessitated admission. In addition, the primary care physicians for the patients who presented in the study month were contacted to inquire

CBC and Reticulocyte Count in Sickle-cell Crisis, Lopez et al. 753

about subsequent complications during both March and April 1994.

Part 2 was a l-month (December 1994) prospective validation of the retrospective study. Both a CBC and a reticulocyte count were obtained when laboratory testing was done. Other studies were ordered at the discretion of the treating physician. As in Part 1, the patient’s primary care physician was contacted to inquire about subsequent complications both during the study period and over the following month.

The CBC (WBC count and Hb determination) was measured using an automated Coulter Hematology An- alyzer (Model STKS, Coulter Co., Miami, FL). The daily variation of the analyzer is 0.34 for the WBC count (2 SD) and 0.36 for the Hb determination (2 SD). The reticulocyte count was measured manually via methyl- ene blue stain. The daily variation for the latter was 0.5% (2 SD). There was no change in the laboratory tech- niques between the 2 parts of the study.

Data Analysis

In both parts of the study, the patients were divided into 2 groups for comparison: those admitted to the hospital vs those released from the ED. We divided patients into these 2 groups to determine whether the CBC a n d or reticulocyte count values were associated with admission for acute vasoocclusive crisis. During both parts, we compared the mean WBC counts, Hb values, and reticulocyte counts.

In Part 2, in addition to the above measurements, we calculated the change in the WBC count, hemoglobin value, and reticulocyte count from the patient’s mean baseline measurements. Baseline measurements were determined by prior outpatient laboratory testing by our department of hematology. We used an average af data from 3 outpatient well visits to establish baseline values. The patient’s values were updated every 6 months, or sooner as needed. The mean changes from baseline were compared between groups.

Interval data were analyzed with an u n p a i d , two- tailed 1-test, with significance set at p = 0.05. A prestudy power analysis revealed that 30 patients were required in each group to detect a 20-g/L difference in Hb levels with the p error set at 0.1 and Q error set at 0.05, Using the same Q and p error values, 35 patients would be needed in each group to detect a 2% change in the reticulocyte count and 40 patients would be needed in each group to detect a 3.0 X I O 9 L change in the WBC count.

I RESULTS

Part 1 (Retrospective) Two hundred consecutive SCC visits were reviewed.

Of these visits, 8 1 were excluded (in 25 visits the patient

I TABLE 2 Mean (+SD) Hemoglobin (Hb) Level. Reticulocyte Count. and White Blood Cell (WBC) Count for Pan 1 (Retro- spectivc Portion) of the Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . , . ,

Admitted Released (n = 33) (11 = 86) p-value

Hb level (gL) 84 ? 19 92 -+ 19 0.10 Rcticulocyte count (5%) 9.2 -C 1.9 13.9 2 8.8 0.25 WBC count (cells X 17.0 ? 10.0 13.2 t 4.2 0.08

1 0 9 ~ )

was found to have at least 1 identifiable abnormal vital sign as defined in the exclusion criteria, as well as a history of an acute illness or traumatic event of<7 days prior to the ED visit; in 56 visits the patient did not have laboratory testing), leaving 119 ED visits fQr review. The 119 visits represented 53 patients; there were 37 men and 16 women with an overal1 mean age of 29 -t 5 years. There was no significant difference in the mean WBC counts, hemoglobin levels, or reticulocyte counts between the admitted (n = 33) and the released groups (n = 86) (Table 2). The 86 visits ending in ED release represented 31 patients. giving a revisit rate of 2.8 visits per patient. Of these 31 patients, 1 I were subsequently admitted to our hospital within 1 month of an ED visit.

There was no subsequent episode of severe anemia, aplastic crisis, or significant infection necessitating admission in the month following the ED visit of the 119 visits analyzed. Similarly, no admission for these factors occurred in the month following the ED visit for the 56 visits excluded due t9 the absence of laboratory testing. This chart review finding was verified by contact with the patient’s primary care physician. Primary care physician information revealed 21 documented SCC visits to other hospital EDs during the study or following month, None of these ED visits required hospital admission.

Part 2 (Prospective)

A total of 277 SCC visits to the ED occurred during the study period. There were 270 visits in which the patient did not have evidence of acute, coexisting disease as chosen for exclusion criteria. There were 9 instances in which the patient left the ED without or during treatment. Another 57 visits were excluded due to omission of laboratory testing (13 patients admitted, 44 released). Hence. a total of 204 visits. representing 64 patients (39 men, 25 women; mean overall age 30 2 4 years) were analyzed. Of these visits, 44 ended in hospital admission and 160 ended in release from the ED. The I60 visits ending in ED release represented 42 patients, for a revisit rate of 3.8 visits per patient. Of these 42 patients, 16 were subsequently admitted (all for uncomplicated SCC) within 1 month of an ED release.


* 2

L

information revealed that there were 18 documented SCC visits to other EDs after a visit to our ED during the same 2-month period. All 18 patients who visited other EDs had a sole diagnosis of SCC, and all were released from the ED.

There was a total of 57 admissions to our hospital (13 without laboratory testing, 44 with testing) for SCC during the study period; of these, 23 were admissions occurring <1 week after a previous ED visit. All 57 patients had a sole.diagnosis of SCC on discharge from the hospital.

0 I I

A R

Disposition

I FIGURE 1. White blood cell (WBC) count in Part 2 of the study. Hinges represent interquartile distance; solid horizontal line represents median: dotted line represents mean. * Represents outliers. Disposi- tion: A = admitted; R = released.

There was a significant difference in mean WBC counts (Fig. 1, Table 2) and mean changes in WBC from baseline (Table 3) between the groups, with the admitted group having higher values. None of the patients in the study were being treated with steroids for a preexisting condition.

There was no difference in mean Hb level and reticulocyte count between the initially admitted and the released groups (Figs. 2 and 3; Table 3). In addition, there was no difference between the groups in the change from baseline Hb level or change from baseline reticulocyte count (Table 3).

The hospital discharge summaries of the admitted patients with ED laboratory studies were examined. All 44 admitted patients had a primary diagnosis of SCC. One of the 44 admitted patients had a secondary diagnosis of urinary tract infection (determined by rtrine culture). This patient had no fever or symptoms throughout the hospital course.

Of the 57 excluded patients who did not have laboratory evaluation, and of the 7 patients who were excluded by other injuryJillness criteria, none had, or de- veloped, significant anemia, aplastic crisis, or significant illness necessitating hospital admission in the months of December 1994 and January 1995. As before, follow-up was determined by chart review and contact with the patient’s primary care physician. Primary care physician

I DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

The routine management of SCC is primarily that of pain management. Additionally, the EP should search for a precipitating cause for the SCC (e.g., infection, stress, dehydration, pulmonary infarction, hypoxia, or alcohol intoxication).”.” The history and physical examination, along with various diagnostic studies, are used in this evaluation.

The determination of the CBC and reticulocyte count is commonly suggested as part of the routine ED management of adult SCC.’-’ While these tests are commonly recommended in textbooks and journal articles, there is little scientific evidence to support this practice. Sanders et a1.l’ stated that “A CBC with reticulocyte count . . . will not only help to evaluate for infection, but . . . can also aid in detecting aplastic crisis ...... Hamilton and Braen’ state that “All patients should have a complete blood cell count, and present blood levels should be compared with those of previous visits.” Statements such as these, though logical, are not refer- enced to supportive studies. Our MEDLINE search of the literature over the past 30 years revealed only 1 study specifically addressing the issue of the usefulness of the CBC and reticulocyte count in acute adult SCC; there

I TABLE 3 Mean (?SD) Hemoglobin (Hb) Level, Reticulocyte Count, White Blood Cell (WBC) Count, and Change in These Variables (from Baseline) for Part 2 (Prospective Portion) of the Study ............................................................................

Admitted Released (n = 44) (n = 160) p-value

Hb level (a) 87 2 20 88 2 18 0.8800 Reticulocyte 10.4 2 6.7 11.2 -t 6.7 0.4700

count (%)

(cells x io9k) WBC count 15.8 2 4.9 12.8 2 4.9 0.0003

AHb level (a) 7.0 2 2.1 -0.7 ? 1.1 0.8800 AReticulocyte 0.39 t 0.94 0.07 t 0.52 0.7600

AWBC count 5.1 -C 4.6 1.8 2 4.6 0.0020 count (9%)

(cells x 109m

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_I *

T

A R

Disposition

I FIGURE 2. Hemoglobin i n Part 2 of the study. Hinges represent interquartile distance; solid horizontal line represents median; dotted line represents mean. * Represents outliers. Disposition: A = admitted; R = released.

was no study in the EM literature. Haddy et al.13 found that the Hb level and reticulocyte count tended to be lower in adult patients with acute crisis and infection. but that there was sufficient variability to preclude making conclusions regarding their usefulness. Given the lack of scientific support for these studies despite their historical use, further study evaluating the usefulness of these routine tests is needed. Since these tests are frequently ordered in acute SCC, the proper and judicious use of these tests would likely translate into significant savings in terms of reduced patient suffering (from mul- tiple venipunctures) and reduced personnelhesource ex- penditure.

Our results support the concept that the CBC and the reticulocyte count overall contribute little to the admission decision of a patient with a complaint of acute vasoocclusive SCC. In both the retrospective and the prospective parts of the study, there was no significant difference in mean Hb level and reticulocyte count between the admitted and the released groups. In addition, there was no difference in the change in Hb level and reticulocyte count from the patient’s baseline mea- surement.

A benefit to this finding is the potential for significant dollar savings. At our institution, a patient is charged $24 for a CBC with differential and $28 for a reticulocyte count. Elimination of the 2 tests would result in a

* * *

4 *

A R

Disposition

I FIGURE 3. Reticulocyte count in Part 2 of the study. Hinges represent interquartile distance; solid horizontal line represents median; dotted line represents mean. * Represents outliers. Disposition: A = admitted: R = released.

$52 saving per patient visit. In the most extreme ex- ample, if both of these tests were eliminated in the prospective study sample of 204 patients, a total of $10,608 in patient charges would have been saved during the 1- month study period. Depending on the frequency of SCC ED visits, this could translate into significant health care savings. This is certainly important in this age of limited health care dollars. However, in any discussion of cost- benefit analysis, one must consider the consequences of missing severe or aplastic anemia. Though severe anemia and aplastic crisis in the adult SCC patient are extremely rareI4 and the likelihood of a missed diagnosis without significant clues in the history and physical examination is small, the consequences are potentially large in terms of morbidity and mortality (as well as potential litigation costs).

One interesting finding was the higher WBC count and change from baseline WBC count in the admitted group during the prospective portion of the study. Fur- ther review of both the ED and the inpatient hospital records revealed no difference in the presence of significant infection or final discharge diagnosis. Several pos- sible explanations exist. First, infection is a potentially significant precipitating cause of vasoocclusive Although none of the admitted patients in Part 2 of the study had overt signs of infection, the possibility of a subclinical infection causing an elevated WBC count re-


mains. Second, elevated WBC counts have been associated with various bodily stressors.*,I6 The higher WBC values in the admitted group may reflect a higher stress level secondary to pain (i.e., the admitted patients have more pain) or enhanced bone marrow activity. Third, the physicians caring for these patients were not blinded to the laboratory results. At our institution, a WBC count 1.5 times the patient’s baseline is one guideline used for admission [this number was determined arbitrarily by a consensus decision by our department of hematology based on prior (though unpublished) experience at our institution]. Hence, the elevated mean WBC count in the admitted group may simply reflect application of the admission criterion. Interestingly, in Part 2 of the study, for 53 of the 160 visits involving ED release, the patient had a WBC count > 1.5 times his or her baseline; additionally, 23 of the 44 admitted patients had ~ 1 . 5 times their baseline WBC counts, indicating that the elevated WBC count was not an absolute criterion for disposition.

It is tempting, given our findings, to suggest that one eliminate the Hb determination and reticulocyte count and simply obtain the WBC count alone. However, this would be difficult for 2 reasons. First are the inherent limitations of the study (discussed below). Second, in screening for aplastic anemia, it has been suggested that at least 2 of 3 (WBC count, Hb determination, and reticulocyte count) tests must be abnormally low to make the diagnosis.” Obviously, one risks missing the diagnosis if only the WBC count is used.

I LIMITATIONS AND FUTURE QUESTIONS

Our study had several limitations. First, and most important, there was no episode of either aplastic anemia or severe anemia necessitating blood transfusion. Ideally, we would have found a number of these presentations so that we could determine whether there were any clinical characteristics related to their presentations that would have guided the ordering of the tests. However, given the seriousness of aplastic anemia, it is unlikely to be seen in the ED without significant findings such as fever, tachycardia, tachypnea, or hypotension, or other signs of significant infection.”

Second, and related to the first limitation, our sample size is relatively small considering the extremely low incidence of aplastic crisis and severe anemia. By con- servative estimate, we would need a sample size of 12,000 patients to include 1 case of aplastic crisis given the extremely low incidence of severe anemia and aplastic crisis in the adult SCA patient. It is conservatively estimated that the incidence is about 0.001 of the SCA p~pula t ion’~ and, in actuality, may be even lower. Future study should characterize patients with significant ane-

mia or aplastic crisis. While this may be difficult to achieve with a prospective study, a multicenter retrospective study might provide sufficient information related to clinical presentation to address whether severe anemia or aplastic crisis in the adult SCA patient can appear occult other than the findings on hematologic studies.

Third, the physicians caring for the patients were not blinded to the results of the CBC and reticulocyte count. This may have biased assignment of patients into inpatient and outpatient groups. Certainly, the established guideline of an elevated WBC count 1.5 times baseline for admission may bias the results found here. The physicians caring for these patients are knowledgeable about the increased risk of infection in this population. Even with no clinical evidence of infection, an elevated WBC count may have influenced admission decisions. Addi- tionally, disposition was based primarily on the subjective assessments of both the patients and the treating physicians, as the SCC patients who did not show any objective signs of an acute, coexisting disease were admitted or released from the ED in an essentially subjective manner. No effort was made to standardize admission or release criteria. Guidelines are in place in our ED to assist with the disposition in questionable cases, but anecdotally these guidelines are rarely used by either the ED physicians or the admitting internal medicine resident. Future study regarding the CBC and reticulocyte count should use a standardized admissionhelease criteria. Such a study might focus on our study exclusion criteria and their relationship with the CBC and reticulocyte count. In addition, a study in which the physician is blinded to the result of the blood tests would be more useful to the clinician, since, at least in theory, some of the biases noted above would be removed.

Fourth, the populations in the 2 parts of the study were different. In Part 1. 25 of the 200 visits were excluded by the presence of acute, coexisting illness, whereas in Part 2, only 7 of 277 visits were excluded based on coexistent disease. This may imply a more ill population in Part 1 when compared with Part 2. This finding also may be related to seasonal differences. Al- ternatively, the difference may be due to the differences in retrospective and prospective study designs. A larger, prospective study over a longer period would be desir- able to verify our findings.

Finally, the potential of loss of follow-up is significant. Neither we nor the patient’s primary care physician had a fail-safe mechanism to objectively determine whether the patient sought care at another institution after being evaluated in our ED. ED visits to other insti- tutions are essentially self-reported to the primary care physician. A significant illness may therefore have been missed. Future studies should rigorously address follow- up care.

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CONCLUSIONS

There is no difference in hemoglobin level and reticulocyte count between admitted and released sickle-cell crisis patients in the ED. During the prospective portion of the study, the WBC count was slightly higher in the admitted than in the released patients. These findings suggest that the hemoglobin level and the reticulocyte count may not be useful in the evaluation of acute vasoocclusive sickle-cell crisis. Further investigation is needed to determine the usefulness of the WBC count.

The authors thank Lucia Webster. RN, for her assistance with the data collection. They also thank Mark Zwanger, MD, and Alison Mc- Donald, MD, for their help in the preparation of the manuscript.

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