A Contemporary Analysis of Phlebotomy and Iatrogenic Anemia Development throughout Hospitalization in Critically Ill Adults

Abstract

BACKGROUND:

Anemia is common in critically ill patients and may be exacerbated through phlebotomy-associated iatrogenic blood loss. Differences in phlebotomy practice across patient demographic characteristics, clinical features, and practice environments are unclear. This investigation provides a comprehensive description of contemporary phlebotomy practices for critically ill adults.

METHODS:

This is an observational cohort study of adults ≥18 years requiring intensive care unit (ICU) admission between 01/01/2019 – 12/31/2019 at a large academic medical center. Descriptive statistics were utilized to summarize all phlebotomy episodes throughout hospitalization, with each phlebotomy episode defined by unique peripheral venous, central venous or arterial accesses for laboratory draws, exclusive of finger-sticks. Secondarily, financial costs of phlebotomy and the relationships between phlebotomy practices, hemoglobin concentrations, and red blood cell (RBC) transfusions were evaluated.

RESULTS:

6194 patients were included; 59% male with a median (interquartile range) age of 66 (54, 76) years and median ICU and hospital durations of 2.1 (1.4, 3.9) and 7.1 (4.3, 11.8) days, respectively. The median number of unique laboratory draws was 41 (18, 88) throughout hospitalization with median volume of 232 (121, 442) milliliters (ml), corresponding to 5.2 (2.6, 8.8) draws and 29 (19, 43) ml per day. Waste (i.e. discard) volume was responsible for 10.8% of total phlebotomy volume. Surgical patients had a higher number of phlebotomy episodes and greater total phlebotomy volumes compared to non-surgical patients. Phlebotomy practices differed across ICU types, with the greatest frequency of laboratory draws in the cardiac surgical ICU and the greatest daily phlebotomy volume in the medical ICU. Across hospitalization, ICU environments had the greatest frequency and volumes of laboratory draws, with the least intensive phlebotomy practice observed in the general hospital wards. Patients in the highest quartile of cumulative blood drawn experienced the longest hospitalizations, lowest nadir hemoglobin concentrations, and greatest red blood cell transfusion utilization. Differences in phlebotomy practice were limited across patient age, gender, and race. Hemoglobin concentrations declined during hospitalization congruent with intensity of phlebotomy practice. Each 100 ml of phlebotomy volume during hospitalization was associated with a 1.15 (95% CI 1.14, 1.17; p<0.001) multiplicative increase in RBC units transfused in adjusted analyses. Estimated annual phlebotomy costs exceeded $15 million, or approximately $2,500 per patient admission.

CONCLUSION:

Phlebotomy continues to be a major source of blood loss in hospitalized patients with critical illness, and more intensive phlebotomy practices are associated with lower hemoglobin concentrations and greater transfusion utilization.

INTRODUCTION:

Anemia has an exceedingly high prevalence in critically ill patients, and the pathophysiologic effects of anemia may be augmented in this population.^1,2 Critically ill patients with anemia have worse outcomes than their non-anemic counterparts, including increased length of stay, higher transfusion requirements, and increased mortality.^1–7 Further, anemia experienced during critical illness may have lasting impacts beyond discharge.^8,9 Anemia during critical illness is often related to multiple processes, including bleeding, acute and chronic inflammatory states, and nutritional deficiencies, amongst other causes. Additionally, iatrogenic blood loss secondary to diagnostic phlebotomy has been recognized as a key contributor to anemia development during hospitalization, which may be particularly problematic in the critically ill who are simultaneously at the highest risk for anemia and frequent laboratory testing. Indeed, the burden of anemia in critical illness may be magnified by phlebotomy practices, which are often considered an essential component of high-quality care provision.^2,10

Fortunately, techniques utilizing reduced blood draw volumes, pediatric collection tubes, closed-system sampling lines, and educational initiatives may reduce phlebotomy volumes without compromising diagnostic accuracy.^4,10–16 However, anemia experienced during critical illness and the potential contributions of phlebotomy practice to anemia remain largely overlooked in contemporary clinical practice, which may explain why the uptake of interventions designed to minimize the burden of phlebotomy has been slow and incomplete in adult intensive care practices. Additionally, significant knowledge gaps remain regarding contemporary phlebotomy practice, including differences in phlebotomy across patient demographic and clinical features, practice environments (i.e., intensive care unit [ICU] types and other hospital locations), and duration of hospitalization.

The goal of this investigation is to provide a comprehensive descriptive analysis of contemporary phlebotomy practices for adult critically ill patients hospitalized in a large tertiary-care medical center. Specifically, our primary aim is to assess phlebotomy practices with granular detail across key patient demographic and clinical features and across unique practice environments as patients transition through the hospital. Secondarily, we estimate hospital costs associated with phlebotomy practices and assess the relationships between phlebotomy practices, hemoglobin concentrations, and red blood cell (RBC) transfusion volumes, which may provide the foundation for future research and quality improvement efforts to optimize phlebotomy practice.

METHODS:

This is a retrospective observational cohort study approved by the local Institutional Review Board (IRB). All participants had previously granted permission to use their medical records for research (consistent with Minnesota Statute 144.295); thus, the requirement for written informed consent was waived by the IRB. The study was designed and conducted in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology guidelines.¹⁷

The study cohort included all adult patients (age ≥ 18 years) with ICU admission from 01/01/2019 – 12/31/2019. Admissions to any of the institutional ICUs (Cardiac Medical, Cardiovascular Surgical and Transplant, Medical, Medical/Surgical/Transplant, Multispeciality [i.e. thoracic surgery, vascular surgery, medical], Neuroscience, and Trauma ICU) at our large tertiary care facility with 2 free-standing hospital campuses were included. Patients were excluded due to the following reasons: age < 18 years, admission < 24 hours, previous inclusion in the study during a prior hospitalization with ICU admission, or absent research authorization.

The primary variables of interest were the frequency and volume of blood phlebotomized in critically ill patients evaluated throughout their hospital admission, including used volume (i.e. the volume sent to the laboratory for analysis), waste volume (i.e. the volume discarded during blood sampling), and total volume (i.e. used plus waste volume) expressed in milliliters (ml). These volumes were ascertained through our laboratory electronic recording system with verification by phlebotomists and laboratory personnel (Supplemental Table 1). Waste volumes (i.e. the protocol-based volume discarded while accessing an existing intravenous or arterial catheter) at the study institution were defined as the following: 1) no waste volume for arterial line draws, as this blood is generally returned to patients; 2) 5 ml of waste volume for draws from pre-existing venous catheters for most laboratory tests with the exception of 10 ml of waste volume prior to any phlebotomy episode requiring coagulation testing; and 3) no waste volume for fresh sticks. The used volume was defined as the volume collected in the appropriate vial and transferred to the laboratory for analysis and not the actual volume used by the laboratory for the diagnostic assay(s). Phlebotomy episodes were assessed throughout the entirety of hospitalization, including prior to, during ICU admission and during transitions into other care environments including post-ICU hospitalization care. Of note, it is common practice for multiple laboratory samples to be analyzed from a single collection tube or for multiple tubes to be collected in a single phlebotomy episode or “draw”. For clarity, each phlebotomy episode was defined by unique peripheral venous, central venous or arterial accesses for laboratory draws, exclusive of finger-sticks (i.e. point of care glucose monitoring). As an example, a central venous access that resulted in the filling of 3 tubes of blood for laboratory testing was counted as a single phlebotomy episode and would only have a single waste volume associated with it. Indications (i.e. laboratory tests) were recorded for all phlebotomy episodes. In addition to phlebotomy data, we also collected all hemoglobin concentration measurements and allogeneic RBC transfusions throughout hospitalization up until time of hospital discharge.

To estimate costs associated with contemporary phlebotomy practices, Centers for Medicare and Medicaid Services (CMS) 2021 reimbursement data were extracted for the 50 most commonly ordered laboratory tests by linking Current Procedural Terminology (CPT) codes to laboratory tests (Supplemental Table 2), with estimates of laboratory direct costs then made by multiplying the CMS reimbursement rate by the number of unique tests. CMS does not provide direct cost data; however, CMS reimbursement rates were utilized as an estimation of costs. Since arterial and venous blood gases typically contain multiple CPT codes (linked to individual result components of these studies), CMS reimbursement rates would likely overestimate laboratory direct costs; hence, a flat estimated direct cost of $12.50 was utilized for each blood gas. For the remaining less-commonly ordered laboratory tests, the median reimbursement rate obtained from the top 50 tests (i.e. $8.17) was utilized to estimate the direct cost of each test. Conservative and liberal estimates for these remaining tests were also provided using 1^st (i.e. $4.76) and 3^rd quartile (i.e. $12.47) data from the 50 most common tests. In addition to the estimated direct costs of each laboratory test, there are also costs associated with the performance of each venipuncture or arterial/venous access that are not captured in CMS reimbursement but are nevertheless relevant when assessing resources allocated to phlebotomy in hospitalized patients. Based upon benchmarked data at the study institution and other similar medical centers, a conservative estimate of $12 was utilized per unique phlebotomy episode, as defined previously. Hence, the total venipuncture costs were estimated by multiplying this number by the total number of unique phlebotomy episodes per patient.

Statistical Analyses:

Patient baseline demographics and clinical characteristics are provided with median (interquartile range [IQR]) for continuous data and number (percentage) for categorical data. The total volume of phlebotomized blood was divided into quartiles, and pre-specified patient demographic and clinical features were described across these groups. Per day calculations were based on the absolute number of draws or volume drawn each day, regardless of the proportion of time that a patient was hospitalized on a given day. Mean number of individual laboratory tests obtained per patient per admission and per hospital day are also reported for surgical and non-surgical admissions. Although the primary nature of this analysis was descriptive, we also explored differences in phlebotomy across patient demographic, clinical, laboratory, and transfusion characteristics with Chi-square tests for categorical variables and Wilcoxon rank sum tests and Kruskal-Wallis tests for continuous variables. As an additional exploratory analysis, the relationship between total phlebotomy volume and total RBC units was assessed with unadjusted and adjusted Negative Binomial regression models. The multivariable model was adjusted for pre-specified covariates of age, gender, admission hemoglobin concentration, admission APACHE score, surgical vs. medical admission status, and hospital length of stay. For all analyses, p-values < 0.05 were used to signify statistical significance without correction for multiple testing given the exploratory nature of non-descriptive analyses. All analyses were performed in SAS Studio 3.8 (SAS Institute Inc, Cary, North Carolina) and RStudio (RStudio Team 2021, Boston, Massachusetts).

RESULTS:

A total of 6194 patients were hospitalized with a qualifying ICU admission during the study period (Supplemental Figure 1). Of these, 59% were male with a median (IQR) age of 66 (54, 76) years and APACHE III score of 73 (52, 97; Table 1). Median ICU and hospital lengths of stay were 2.1 (1.4, 3.9) and 7.1 (4.3, 11.8) days, respectively. Hospital lengths of stay were greater in surgical (8.2 [5.3, 13.8] days) than medical admissions (5.9 [3.4, 10.0] days; p<0.001). Most patients were admitted to the Medical ICU (26%) followed by Cardiovascular Surgical and Transplant ICU (19%). Surgical admissions accounted for 50.8% of all admissions. The most common laboratory tests (mean tests per patient per admission) were blood glucose (28.8), basic metabolic panel (22.1), arterial blood gas (11.5), and complete blood count (10.8 without differential, 9.2 with differential; Supplemental Table 1), with mean tests per patient per day for non-surgical and surgical admissions displayed in Supplemental Table 3.

Table 1:

Patient demographic and clinical characteristics

Variable	Overall (N=6194)
Age	66 (54, 76)
Sex
Female	2566 (41%)
Male	3628 (59%)
Race, N=6156
American Indian	34 (1%)
Asian	112 (2%)
Black or African American	88 (1%)
Other	189 (4%)
Unknown	136 (2%)
White	5597 (91%)
Admission type
Surgical	3145 (50.7%)
Medical	3049 (49.3%)
Admission ICU
Cardiac ICU	747 (12%)
Cardiovascular Surgical and Transplant ICU	1158 (19%)
Medical ICU	1592 (26%)
Medical/Surgical/Transplant ICU	679 (11%)
Multispecialty ICU	757 (12%)
Neuroscience ICU	833 (13%)
Pediatric ICU	10 (0%)
Surgical/Trauma ICU	418 (7%)
Admission Hemoglobin, N=5941	11.8 (9.9, 13.4)
Charlson Score	4 (2, 7)
ICU Admission APACHE-III Score, N=6183	73 (52, 97)
Comorbidities
Myocardial Infarction	772 (12%)
Congestive Heart Failure	1177 (19%)
Stroke/Cerebrovascular accident	744 (12%)
COPD	860 (14%)
Diabetes	1423 (23%)
Complicated Diabetes	628 (10%)
CKD/Mod-Severe Kidney Disease	1333 (22%)
Cancer	1336 (22%)
ICU length of stay	2.1 (1.4, 3.9)
Hospital length of stay	7.1 (4.3, 11.8)
Hospital mortality	471 (8%)

Data presented as median (IQR) for continuous variables and n (%) for categorical variables.

Abbreviations: ICU = intensive care unit, APACHE = acute physiologic assessment and chronic health evaluation, COPD = chronic obstructive pulmonary disease, CKD = chronic kidney disease

Throughout hospitalization, the median number of unique phlebotomy episodes per patient was 41 (18, 88), with a median cumulative volume of 231.9 (120.5, 441.9) ml (Table 2). Patients experienced 5.2 (2.6, 8.8) phlebotomy episodes per day with a median total daily volume of 29.2 (18.8, 43.0) ml (Table 2). Compared to non-surgical patients, surgical patients experienced greater total number of laboratory draws (56 [22, 115] vs. 32 [15, 64]; p<0.001), greater number of daily draws (5.8 [2.6, 10.0] vs. 4.6 [2.6, 7.8]; p<0.001), and greater total phlebotomy volumes (251.2 [126.7, 497.9] ml vs. 215.1 [114.2, 392.9] ml; p<0.001) but lower total volume drawn per day (27.7 [17.8, 39.5] ml vs. 31.0 [19.7, 46.8] ml; p<0.001). Median waste volume throughout hospitalization was 25.0 (5.0, 65.0) ml, representing 10.8% of all phlebotomized volume, and was greatest in surgical patients.

Table 2:

Phlebotomy details throughout hospitalization by surgical vs. non-surgical status

	Overall (n=6194)	Surgical (n=3145)	Non-surgical (n=3049)	p-value
Total lab draws (entire LOS)	41 (18, 88)	56 (22, 115)	32 (15, 64)	<0.001
Total lab draws (per day)	5.2 (2.6, 8.8)	5.8 (2.6, 10.0)	4.6 (2.6, 7.8)	<0.001
Total used volume of blood drawn (entire LOS)	199.9 (104.3, 380.2)	211.4 (106.6, 420.8)	191.5 (101.5, 346.0)	<0.001
Total used volume of blood drawn (per day)	24.9 (16.3, 36.7)	23.2 (14.8, 32.7)	27.2 (17.6, 40.8)	<0.001
Total waste volume of blood drawn (entire LOS)	25.0 (5.0, 65.0)	35.0 (10.0, 80.0)	15.0 (0, 50.0)	<0.001
Total waste volume of blood drawn (per day)	3.2 (0.7, 6.8)	4.0 (1.7, 7.2)	2.2 (0, 6.3)	<0.001
Total volume of blood drawn (entire LOS)	231.9 (120.5, 441.9)	251.2 (126.7, 497.9)	215.1 (114.2, 392.9)	<0.001
Total volume of blood drawn (per day)	29.2 (18.8, 43.0)	27.7 (17.8, 39.5)	31.0 (19.7, 46.8)	<0.001

Data presented as median (IQR) for continuous variables

Abbreviations: LOS = length of stay

The daily median volume and frequency of blood drawn varied by physical location in the hospital, with the greatest volumes and frequency in the ICU (35.6 [19.5, 55.7] ml/day and 6.0 [2.7, 11.7] draws/day, respectively) and the lowest on the general hospital floor (11.1 [7.5, 17.4] ml/day and 1.9 [1.0, 3.5] draws/day, respectively; Figure 1, Supplemental Table 4). Detailed phlebotomy characteristics for each ICU environment are available in Supplemental Table 5, with the greatest median volume of blood drawn per day in the Medical ICU (47.1 [28.0, 69.0] ml) and the lowest volume of blood drawn per day in the Neuroscience ICU (8.8 [2.7, 22.9] ml).

Figure 1:

Phlebotomy based on physical location. A) Volume of blood drawn per day; B) Number of blood draws per day

Abbreviations: ED = emergency department, OR = operating room, ICU = intensive care unit, PCU = progressive care unit, floor = general hospital ward

Patient characteristics differed by total blood volume drawn throughout hospitalization (Table 3). The median total phlebotomy volume drawn throughout hospitalization was 720.2 (544.7, 1093.5) ml for those in the upper quartile compared to 60.9 (29.5, 90.7) ml in the lowest quartile. Among patients in the upper quartile, 58.3% were non-surgical compared to 47.2% in the lowest quartile (overall p<0.001). Patients in the highest quartile of blood drawn had the greatest severity of illness (i.e. APACHE III score 92 (69, 118) vs. 55 (42, 70) in the lowest quartile; overall p<0.001) and longest hospital durations (16.0 (10.8, 24.9) days vs. 3.5 (2.3, 5.3) days, respectively; overall p<0.001). Differences in phlebotomy by patient age, race, and sex (Supplemental Table 6) were limited in nature.

Table 3:

Patient characteristics by total volume of blood drawn quartiles

	Lower 25%	25% - Median	Median - 75%	Upper 75%	p-value
Age	63.2 (48.9, 74.9)	67.6 (55.6, 76.9)	67.5 (55.6, 76.7)	64.6 (54.6, 73.1)	<0.001
Sex					0.003
Female	669 (43.2)	680 (44.0)	590 (38.1)	627 (40.5)
Male	881 (56.8)	867 (56.0)	959 (61.9)	921 (59.5)
Race					0.469
American Indian	11 (0.7)	5 (0.3)	6 (0.4)	12 (0.8)
Asian	30 (1.9)	22 (1.4)	26 (1.7)	34 (2.2)
Black or African American	25 (1.6)	16 (1.0)	20 (1.3)	27 (1.8)
Other	51 (3.3)	45 (2.9)	48 (3.1)	45 (2.9)
Unknown	36 (2.3)	29 (1.9)	30 (2.0)	41 (2.7)
White	1393 (90.1)	1421 (92.4)	1410 (91.6)	1373 (89.6)
Surgical status					<0.001
Surgical	819 (52.8)	815 (52.7)	770 (49.7)	645 (41.7)
Non-surgical	731 (47.2)	732 (47.3)	779 (50.3)	903 (58.3)
Charlson score	3 (1, 6)	4 (2, 7)	4 (2, 7)	4 (2, 7)	<0.001
1st ICU Admission APACHE 3 Score	54.5 (42.0, 70.0)	71.0 (54.0, 90.0)	81.0 (60.0, 102.5)	92.0 (69.0, 118.0)	<0.001
Hospital LOS	3.5 (2.3, 5.3)	5.5 (4.2, 7.3)	8.2 (6.2, 11.1)	16.0 (10.8, 24.9)	<0.001
ICU LOS	1.4 (1.1, 1.9)	1.8 (1.2, 2.6)	2.5 (1.7, 3.8)	5.2 (3.0, 8.9)	<0.001
Hospital mortality	37 (2.4)	62 (4.0)	130 (8.4)	242 (15.6)
Total phlebotomy volume	60.9 (29.5, 90.7)	173.5 (146.1, 200.0)	314.3 (268.0, 368.4)	720.2 (544.7, 1093.5)	<0.001
Total phlebotomy volume per day	12.8 (6.5, 19.3)	26.6 (20.7, 34.4)	34.8 (26.7, 45.0)	46.6 (35.3, 63.5)	<0.001
Admit Hemoglobin	12.6 (10.9, 14.0)	11.9 (10.4, 13.6)	11.7 (9.8, 13.4)	10.7 (9.0, 12.8)	<0.001
Minimum Hemoglobin during hospital stay	11.4 (9.7, 13.0)	9.7 (8.2, 11.2)	8.4 (7.4, 10.3)	7.3 (6.7, 8.4)	<0.001
RBC transfusion during hospitalization	146 (9.4)	373 (24.1)	622 (40.2)	1051 (67.9)	<0.001
RBC units during hospital stay (all patients)	0 (0, 0)	0 (0, 0)	0 (0, 2.0)	2.0 (0, 6.0)	<0.001
RBC units during hospital stay (transfused patients)	2 (1, 3)	2 (1, 4)	2 (1, 4)	4 (2, 8)	<0.001

Data presented as median (IQR) for continuous variables and n (%) for categorical variables.

Abbreviations: ICU = intensive care unit, APACHE = acute physiologic assessment and chronic health evaluation, LOS = length of stay, RBC = red blood cell

Admission hemoglobin and minimum hemoglobin concentrations during hospitalization were inversely associated with total volume of blood drawn (Table 3). Overall, hemoglobin concentrations declined during hospitalization in congruence with the intensity of phlebotomy practice, with the most significant decreases in hemoglobin observed in the first three days of admission (Figure 2). Daily volumes of phlebotomized blood were greatest in the first days of admission and generally leveled off by hospital day 4. The frequency and volume of blood draws were inversely related to nadir hemoglobin concentrations, such that patients with lower daily hemoglobin concentrations experienced greater frequency and volume of blood drawn (Figure 3). Patients in the highest quartile of phlebotomy had the highest rates of RBC transfusion (67.9% vs. 9.4% for the lowest quartile; p<0.001) and received greater RBC volumes when transfused (4 [2, 8] units vs. 2 [1, 3] units, respectively; p<0.001). Total phlebotomy volume during hospitalization was associated with RBC administration (multiplicative increase in RBC units per 100 ml of phlebotomy volume: 1.21, 95% CI [1.19, 1.23], p<0.001), with this association persisting after multivariable adjustment (multiplicative increase: 1.15, 95% CI [1.14, 1.17], p<0.001; Supplemental Table 7).

Figure 2:

Temporal relationship of total and daily volume of blood drawn during hospital days 1–10. A) Cumulative median blood volume drawn in mL and daily nadir hemoglobin; B) Daily median volume of blood drawn per day

Figure 3:

Frequency and volume of blood draws with respect to nadir hemoglobin. A) Number of daily blood draws; B) Total volume per day of blood drawn

The estimated direct costs for laboratory testing were $9,975,442.15 ($1,610.50 per patient), with conservative and liberal estimates of $9,400,038.75 and $10,701,024.15. Further, there were 469,612 unique phlebotomy episodes for the entire cohort, corresponding to estimated venipuncture/access costs of $5,635,344 ($909.80 per patient). Together, costs associated with laboratory testing totaled $15,610,786.20 ($2,520.31 per patient).

DISCUSSION:

The main finding of this investigation is that critically ill patients continue to experience substantial phlebotomy-mediated blood loss in contemporary practice, including median volumes of nearly 40 ml per day during intensive care and approximately 30 ml per day throughout the entirety of hospitalization. Surgical patients experienced more frequent blood draws and a 17% higher total phlebotomized volume during hospitalization when compared to their non-surgical counterparts, though non-surgical patients experienced modestly higher daily phlebotomy losses after accounting for longer hospital durations in surgical patients. There were large disparities in phlebotomy practices across ICU environments, with patients in the medical ICU experiencing the most volume of blood drawn per day at nearly 50 ml, patients in the cardiac surgical ICU experiencing the most frequent blood draws at more than 15 per day, and patients in the neuroscience ICU experiencing the fewest lab draws and lowest phlebotomized volumes, including only 1 draw per day and less than 10 ml in total daily volume, respectively. These disparities may reflect differences in patient features (e.g., acuity of illness, disease pathology), provider practice preferences (e.g., training background), or clinical workflows (e.g., postoperative or medical admission care pathways), and future research and/or quality improvement efforts are necessary to identify opportunities to improve phlebotomy practices across various adult critical care practices.

Importantly, there were inverse relationships between phlebotomized volumes and hemoglobin concentrations such that higher phlebotomy volumes were associated with greater decreases in hemoglobin concentrations, findings which were most pronounced through day 3 of hospitalization. Further, patients with lower hemoglobin concentrations on any given hospital day experienced greater phlebotomy volumes and a greater number of blood draws, highlighting an “anemia-phlebotomy paradox”, wherein patients with severe anemia at greatest risk for harm from further iatrogenic blood loss experience disproportionately more phlebotomy. Indeed, greater phlebotomy volumes were associated with increased RBC transfusion utilization in adjusted analyses, suggesting that minimization of iatrogenic phlebotomy-mediated blood loss may potentially translate to reductions in transfusion requirements.

This contemporary analysis builds upon prior investigations, showing limited-to-no change in the intensity of phlebotomy practice during critical illness over 30 years.¹⁸ Critically ill patients continue to have higher totals of phlebotomized blood than patients on the general ward.⁶ Additionally, this study provides novel insights on phlebotomy practices throughout multiple other practice environments, including operating rooms (OR), the emergency department (ED), and progressive care units (PCU, i.e. ICU “step-downs”), though it should be recognized that phlebotomy practices in these environments are limited to those patients who also had an ICU admission. Daily phlebotomy volumes in the OR and ED were quite high at approximately 25 ml per day, while volumes in the PCU were only modestly higher than those in the general hospital ward at approximately 10 ml per day. As the OR and ED represent high-acuity environments, higher phlebotomy volumes are consistent with the concept of congruence between phlebotomy intensity and acute illness severity. It should be emphasized however that the ICU stay remains the period of greatest patient risk for phlebotomy in terms of both frequency and volumes.

As described previously, the utilization of pediatric tubes and “micro-draw” techniques have been shown to provide similar accuracy to traditional phlebotomy draws, while removing a substantially smaller volume of blood.¹⁹ Unfortunately, there has not been widespread adoption of these practices in adult populations, which may be related to several perceived barriers to implementation, including: 1) concern for increased risk of clotting with small sample volumes or concern for insufficient sample quantities, which may result in increased rates of re-draw, even though available evidence does not support higher re-draw rates²⁰, 2) lack of availability of microtainer tubes due to supply chain issues, especially coagulation tubes, and 3) higher labor costs associated with manual processing and aliquoting requirements for some microtainer samples compared to traditional samples that can be processed in an automated core lab. Quality improvement efforts will be necessary to address these barriers with sustainable solutions that work within local practice environments.

Beyond differences in phlebotomy by physical practice location, the current analysis also revealed higher phlebotomy frequency and volumes in surgical compared to non-surgical patients, which may represent longer hospitalizations and higher phlebotomy intensity in response to acute surgical blood loss and resuscitation. However, non-surgical patients experienced modestly higher daily phlebotomy volumes and were disproportionately represented in the upper quartile of total phlebotomy volume, which suggests that daily phlebotomy intensity throughout hospitalization is generally highest in those with non-surgical critical illness. Although the precise drivers of differences in phlebotomy intensity between admission types are unclear and likely related to various patient, provider, and practice factors, it is notable that blood cultures, which utilize 10 ml of blood per bottle, were obtained more frequently in non-surgical patients (i.e., mean 0.4 vs. 0.2 cultures obtained per patient per day for non-surgical and surgical admissions, respectively), which may explain some of this discrepancy.

It is critical to consider phlebotomy-induced blood losses in relation to the body’s erythropoietic potential. Assuming an RBC life span of 120 days, just under 1% of RBCs are turned over daily. Hence, if you assume a typical adult blood volume of 5000 ml of which 2000 ml is comprised of RBCs (i.e. hematocrit 40%), then the body has a basal replacement rate of approximately 15 ml of RBC losses daily. Adding 40 ml of daily phlebotomy loss during critical illness (i.e. approximately 15 ml RBCs assuming normal hematocrit), the body must double erythropoiesis to maintain RBC mass. While this may be possible over the short-term in healthy patients with preserved iron stores and optimal nutritional status, this is unlikely to be sustainable in patients with critical illness characterized by inflammation, infection, nutritional deficiencies, ongoing iron depletion via repeated episodes of acute blood loss, and a host of other erythropoietic challenges. As a real-world correlate, average menstrual blood loss in healthy women of reproductive age is 30–40 ml distributed over a 4–5 day menstrual cycle, with approximately 10–20% of otherwise healthy women being anemic.^21,22 The prevalence of anemia in those with heavy menstrual bleeding (i.e. >80 ml blood loss per cycle or bleeding lasting longer than 7 days)²³, the equivalent of phlebotomy-mediated blood loss experienced over an ICU stay of just 2 days, is 2–3 fold-higher^22,24, highlighting the dangers of repeated phlebotomy losses during hospitalization. Further, studies in healthy blood donors reveal that it takes 40–60 days in the presence of iron supplementation for hemoglobin concentrations to fully recover after a 500 ml whole blood donation (i.e. 200 ml RBCs),²⁵ corresponding to recovery of approximately 3–5 ml of lost RBCs daily, a number which is greatly outweighed by the intensity of phlebotomy practice described here. Importantly, patients with hemoglobin concentrations of 7 g/dL or less in this study experienced the greatest burden of phlebotomy in terms of frequency and daily volumes, which likely reflects, in part, the fact that patients with lower hemoglobin concentrations may be more acutely ill and thus receive more intensive laboratory testing. However, patients with this severity of anemia are likely already operating at their maximum erythropoietic potential and are least likely to tolerate additional RBC losses. Hence, these patients are precisely those most likely to benefit from rigorous blood conservation strategies despite being phlebotomized the most. While several techniques and system-based approaches to minimize phlebotomy losses have been proposed,^{4,10,11,19,26} clearly more work is necessary, particularly with regards to implementation in high acuity practice environments.

Beyond the negative physiological effects of repeated iatrogenic blood loss, there are also substantial financial implications of intensive phlebotomy practices. Total phlebotomy-associated costs over the study year were estimated at more than $15.5 million, including nearly $10 million in direct laboratory costs and more than $5.5 million in costs associated with the actual venipuncture process. As such, reducing the frequency of phlebotomy episodes would readily translate into real institutional cost-savings by simply reducing costs of laboratory testing. For example, a 10% reduction in phlebotomy (i.e. 10% fewer tests and phlebotomy draws) would result in more than $1.5 million in annual institutional cost-savings. Further, elimination of just one phlebotomy episode per patient per day (i.e. 7 tests per patient over a 7-day hospitalization) would result in nearly $1 million in annual phlebotomy-associated cost savings. Additional financial benefit could also be observed through potential downstream consequences of less intensive phlebotomy practices, including reductions in RBC transfusions and minimization of low-value diagnostic testing directed towards aberrant laboratory values. It is therefore critically important to not overlook the clinical nor the financial impact of phlebotomy practices.

Other notable findings of this investigation include the presence of persistent daily phlebotomy despite the resolution of ICU-level cares. Beyond hospital day 4, patients on average continue to lose approximately 15 mL of blood through phlebotomy daily for the remainder of the hospitalization. While some of these laboratory tests are indeed likely to be important for patient care, this finding emphasizes the common occurrence of daily lab orders and should prompt clinicians to reflect on the necessity of laboratory tests after acute stabilization. Additionally, this study assessed differences in phlebotomy intensity across patient demographic characteristics. While statistically significant differences were observed in phlebotomy volumes by age and sex, these were limited and unlikely to be of clinical significance. Hospital duration, acuity of illness, and practice environments clearly seem to be the principal drivers of phlebotomy intensity.

There are several important limitations of this investigation. First, data was collected retrospectively with assignment of volumes (used and waste) based upon phlebotomy and laboratory standard operating procedures. It is possible that some phlebotomy volumes could have been over- or underestimated. For example, we assumed that all waste volume from arterial lines was returned to the patient, when this may not uniformly be true. Waste volumes from central venous catheters were not recorded but were estimated in accordance with institutional protocols. Additionally, we did not assess for the presence of low-volume blood draws, as these are not recorded in our electronic system, but are estimated to occur in less than 5% of patients. Second, the findings presented here are descriptive in nature. Presented relationships between phlebotomy, hemoglobin concentrations, and RBC transfusions do not imply causality. Third, given the retrospective nature, we were unable to identify the appropriateness or actionability of laboratory assessments nor were we able to distinguish standing laboratory orders from orders designed to answer a specific clinical question. Future studies will be necessary to better define these relationships. Fourth, this is a single center study, thus the results may not be generalizable to other healthcare institutions. Fifth, laboratory direct costs were based on estimates from CMS reimbursement data, which invariably do not capture all costs associated with phlebotomy practice. Finally, we did not describe several factors which may contribute to phlebotomy losses, such as the presence or absence of invasive arterial and central venous catheters, though this information has been reported previously.⁶

In summary, phlebotomy-induced blood losses remain a significant concern in adult patients requiring hospitalization for critical illness. This emphasizes the importance of implementation of comprehensive patient blood management (PBM) strategies to optimize hemoglobin concentrations, maintain hemostasis, and conserve a patient’s own blood throughout hospitalization. The intensity of phlebotomy practices remains largely unchanged despite more than 30 years of evidence highlighting phlebotomy’s contribution to anemia development. Further optimization of phlebotomy practices in hospitalized patients is needed to minimize potential adverse effects of iatrogenic anemia.

Key Points:

Question:

What is the current state of phlebotomy practice in hospitalized critically ill adults?

Findings:

Patients generally lose approximately 30 ml of blood per day via phlebotomy over the course of hospitalization, and patients with the greatest intensity of phlebotomy experience the lowest nadir hemoglobin concentrations and highest red blood cell utilization.

Meaning:

Iatrogenic anemia from phlebotomy continues to be a major source of blood loss in critically ill patients with paradoxically greater phlebotomy losses in patients with severe anemia who are at greatest risk from further red cell losses.

Glossary:

ICU

intensive care unit

RBC

red blood cell

IQR

interquartile range

OR

operating room

ED

emergency department

PCU

progressive care unit

PBM

patient blood management