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Diagnostic blood loss from phlebotomy and hospital acquired anemia in patients with severe burns
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ScienceDirect journal homepage: www.elsevier.com/locate/burns
Diagnostic blood loss from phlebotomy and hospital acquired anemia in patients with severe burns Ren-qi Yao a,b,1 , Guo-sheng Wu a,1 , Long Xu a,1 , Bing Ma a, Jia Lin c , Lei Shi c , He-shan Tang d, Yong-ming Yao b, * , Zhao-fan Xia a, ** a
Department of Burn Surgery, Changhai Hospital, Navy Medical University, Shanghai 200433, People’s Republic of China b Trauma Research Center, Fourth Medical Center of the Chinese PLA General Hospital, Beijing 100048, People’s Republic of China c Department of Laboratory Diagnosis, Changhai Hospital, Navy Medical University, Shanghai 200433, People’s Republic of China d Department of Blood Transfusion, Changhai Hospital, Navy Medical University, Shanghai, People’s Republic of China
article info
abstract
Article history:
Purpose: The study was performed to estimate the diagnostic blood loss (DBL) volume during
Accepted 29 August 2019
hospitalization and investigate its relationship with the development of moderate to severe
Available online xxx
hospital acquired anemia (HAA) and increased number of red blood cell (RBC) transfusion following extensive burns.
Keywords: Diagnostic blood loss Hospital acquired anemia Severe burns Transfusion
Materials and methods: This was a retrospective study of adult burned patients with total body surface area (TBSA) burn larger than 40%, who were admitted to burn center of Changhai hospital between January 2005 and December 2017. Results: We included a final number of 157 patients in the present study. Moderate to severe HAA within the fourth week postburn was developed in 46 of 121 patients who stayed over 28-day hospitalization. Patients with moderate to severe HAA had both significantly higher total DBL volume [245 (IQR: 183.75, 325.25) mL vs 168 (119, 163) mL ; P = 0.001] and DBL volume per day [10.22 (IQR: 8.57, 12.38) mL vs 6.63 (5.22, 10.42) mL/day; P = 0.005]. Logistic regression analysis revealed that both DBL volume per day and TBSA burn were independent risk factors for the development of moderate to severe HAA. Conclusions: Severely burned patients appear to be prone to develop HAA during hospitalization. The DBL volume contribute to the occurrence of moderate to severe HAA, which might be a modifiable target for preventing HAA. © 2019 Elsevier Ltd and ISBI. All rights reserved.
* Corresponding author at: Trauma Research Center, Fourth Medical Center of the Chinese PLA General Hospital, 51 Fucheng Road, Haidian District, Beijing 100048, People’s Republic of China. ** Corresponding author at: Department of Burn Surgery, Changhai Hospital, Navy Medical University, 168 Changhai Road, Yangpu District, Shanghai 200433, People’s Republic of China. E-mail addresses: [email protected] (Y.-m. Yao), [email protected] (Z.-f. Xia). 1 These authors contributed equally to this manuscript. https://doi.org/10.1016/j.burns.2019.08.020 0305-4179/© 2019 Elsevier Ltd and ISBI. All rights reserved.
Please cite this article in press as: R.- Yao, et al., Diagnostic blood loss from phlebotomy and hospital acquired anemia in patients with severe burns, Burns (2019), https://doi.org/10.1016/j.burns.2019.08.020
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1.
Introduction
Hospital acquired anemia (HAA) refers to the condition, in which patients are not anemic at admission, but develop anemia during hospitalization [1,2]. Similar to other types of anemia, HAA has been demonstrated to directly link to the worsening prognosis and even death in critically ill patients [3,4]. Previous study indicated that anemia of critical illness mostly occurred in the second and fourth weeks after admission to intensive care unit (ICU) [5 7]. Multiple factors may contribute to the reduction of hemoglobin (Hb) level, which can be divided into two categories: one can be attributed to various pathophysiological states, including inflammation, chronic renal disease, and heart failure; the other one is related to iatrogenic factors. Indeed, it was reported that the diagnostic blood loss (DBL) volume from phlebotomy was highly associated with drops of Hb and hematocrit levels in patients admitted to internal medicine department and adult/ pediatric ICU [8 10]. Moreover, Salisbury and his colleagues showed that blood loss from greater use of phlebotomy in acute myocardial infarction patients was an independent risk factor of developing HAA [11]. Notably, those iatrogenic events, especially the DBL volume from phlebotomy can be feasible target for minimizing HAA. Through implementing some measurements, either by restricting phlebotomy frequency or by using pediatric tubes, can we limit DBL volume and further reduce the incidence of HAA [12 16]? Due to the prolonged hemodynamic perturbation and initial injury, severely burned patients with burn size more than 40% total body surface area (TBSA) are more likely to develop anemia compared to other critically ill patients [17,18]. Those patients are at great risk of developing acute or chronic coagulopathy during their hospitalization, which is also demonstrated to play a role in HAA. Meanwhile, the duration of their hospitalizations are much longer, usually weeks to months, which result in the increased numbers of operations, bedside procedures (placement of central venous catheters or arterial catheters and wound care) and DBL due to phlebotomy (blood collected from central venous and arterial lines) and repetitive laboratory testing. Of note, some regularly used antibiotics, including piperacillin, cefotetan, and ceftriaxone, also inhibit bone marrow’s ability to produce red blood cell (RBC). Given that, as a particular population of critically ill patients, patients with major burns require higher volume of RBC transfusion and closer surveillance for prevention of HAA. Since there is no literature report concerning the relationship between the DBL volume and the development of HAA in severely burned patients so far, we seek to identify whether the DBL volume is independently associated with HAA and increased RBC transfusion simultaneously.
2.
Materials and methods
2.1.
Design and patient population
The current work was a single-center retrospective study conducted at burn center of Changhai hospital in Shanghai,
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China. Changhai hospital was a tertiary care hospital and its burn center was one of the best institutions specialized in treating burns among mainland China. This study was complied with the Declaration of Helsinki and was approved by the committee on the ethics of medicine, Changhai hospital in September 30, 2018. Adult patients (aged >18 years) admitted to this center from January 1, 2005, to December 31, 2017, with burn size 40% TBSA, were potentially eligible for this study. We excluded patients who (1) died within 10 days postburn; (2) were transferred to our hospital over 72 h after injury; (3) had incomplete medical data record.
2.2.
Data extraction
The electronic patient record system and Changhai 360 online databank recorded medical data of all eligible patients, including patients’ demographic characteristics, etiology of burn, TBSA burn, depth of burn, inhalation injury, comorbidities, ICU and hospital length of stay (LOS). Moreover, detailed information of laboratory tests, medications, number of operations, and the units of RBC transfusion were also collected. The date and type of every diagnostic blood test were documented in the Changhai 360 online databank. Results of laboratory tests were needed, including Hb level at admission (within 48 h) and within the fourth week after admission, which could be obtained from the electronic patient record system. The counts and types of blood tubes used for diagnostic tests during entire hospitalization had been listed and were required for the estimation of total DBL volume. The estimation was based on several conservative hypotheses as the following: (1) no extra blood loss during the implementation of each phlebotomy event; (2) the volume of each blood draw was close to the assigned volume of particular type of blood tube accordingly; (3) all required tests could be proceeded effectively by using minimal blood volume. In addition, we considered the DBL volume per day of hospitalization as a latent risk factor of HAA, which was calculated by dividing total DBL volume by hospitalization length. The hospitalization length was defined as the number of days between the first and last phlebotomy events. Based on the protocol of diagnostic blood test in Changhai hospital, blood routine tubes were assigned a volume of 2 mL, hepatology laboratory tubes of 4 mL, serum chemistries laboratory tubes of 4 mL, coagulation tubes of 3 mL, arterial blood gas tubes of 1 mL, and blood cultures of 6 mL. For other diagnostic blood tests, we assigned a volume of 4 mL for each tube.
2.3.
Definitions
Patients were defined as developing HAA at week 4 if they were not anemic at admission while their nadir Hb level within the fourth week reduction below the diagnostic criterion of anemia. To this end, we applied Chinese definition of anemia as the following: Hb level lower than 120 g/dL for adult male, lower than 110 g/dL for non-pregnant adult female, and lower than 100 g/dL for pregnant female patients. Patients with Hb level lower than 90 g/dL were diagnosed of having moderate to severe anemia. In consideration of clinical and prognostic
Please cite this article in press as: R.- Yao, et al., Diagnostic blood loss from phlebotomy and hospital acquired anemia in patients with severe burns, Burns (2019), https://doi.org/10.1016/j.burns.2019.08.020
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significance, HAA during the fourth week of hospitalization was applied as the primary outcome of the current study. Coagulopathy was defined as abnormalities on coagulation assays which referred to the prothrombin time (PT) > 16.3 s or activated partial thromboplastin time (APTT) > 45 s or an international normalized ratio (INR) > 1.5. Additionally, the secondary outcome was the units of RBC transfusion. Of note, our center applied restrictive transfusion strategy, in which the transfusion threshold was 7 g/dL.
2.4.
Statistical analysis
All data analyses were performed by using the IBM SPSS Statistics 22 software. Descriptive analysis was applied to summarize baseline characteristics of all included patients. We compared the proportion of patients who became anemic at admission and at week 4 by using paired chi-square test (McNemar test). In order to evaluate if the DBL volume was the independent risk factor associated with the development of moderate to severe HAA at week 4, we used both univariate and multivariate logistic regression. Patients with at least 28 days hospital-LOS were included in the model and the DBL volume was re-calculated based on 28 days of hospitalization. Other confounders were considered as variates in accordance with previously published literature and clinical practice, which included demographics (age, gender), severity and depth of burn injury (TBSA burn, TBSA burn full thickness), the DBL volume per day, inhalation injury status, interventions (number of operations, tracheostomy), and the presence of coagulopathy. Variables with significance on univariate analysis at P < 0.1 was subsequently adjusted in them multivariable model by using enter method. Variates of significance level of P < 0.05 were preserved, while other variates were removed after performing multivariate regression. Similarly, we carried out univariate and multivariate linear regression to assess the correlation between the DBL volume and the amount of RBC transfusion among all survivors. Other than variates included in logistic regression, we also added two potential confounders into liner regression, which were ICU and hospital-LOS. Of note, the significance level of linear regression was in line with aforementioned level of logistic regression.
3.
Results
3.1. Patient characteristics and development of moderate to severe HAA A total number of 320 patients with TBSA burn 40% were admitted to the burn center of Changhai hospital during our pre-defined observational period. By screening medical history of those patients, we excluded 140 patients because they moved to our center over 72 h after initial injury. Among the remaining 180 patients, 15 patients were excluded for staying less than 10 days in hospital postburn and there left 165 patients, from whom 8 patients were not incorporated into the patient cohort due to incomplete data. Therefore, a population of 157 patients was enrolled in the current study. The detailed process of enrollment was shown in Fig. 1.
Fig. 1 – Screening and enrollment.
The baseline characteristics of all 157 patients were presented in Table 1. Of those, the mean age was 41.2 1.2 years. Majority of patients (70.1%) were male, while 47 enrolled patients were female (29.9%). The median total burn size of included patients was 64 [inter-quartile range (IQR): 45, 83.5]% TBSA. Besides, the full thickness burn size was 26 (IQR: 8, 49.3)% TBSA. Among diverse factors causing burns, flame (82.2%) was the top-ranking reason for admission, 8 patients were scalded (5.1%), and chemical (1.3%) as well as electrical (1.3%) mechanisms were responsible for burn injury of 3 patients each. Upon admission, 111 patients (70.7%) were diagnosed of having disparate status of inhalation injury, from whom 39 patients (24.8%) were complicated by mild inhalation injury, while 43 (27.4%) and 29 (18.5%) patients were verified to have moderate and severe inhalation injury, respectively. Thirty-one patients (19.7%) developed coagulopathy in acute phase, while 33 patients had coagulopathy at late stage. There were 15 patients (9.6%) who died during hospitalization. The median number of operations performed on patients was 4 (IQR: 2, 8) times. The hospital-LOS and ICU-LOS of all incorporated patients were 48 (IQR: 30.5, 81) days and 31 (IQR: 16, 48) days, respectively. After removing patients whose LOS were less than 4 weeks, we further compared baseline characteristics of patients between who developed moderate to severe HAA and who did not in Table 2. Among 121 eligible patients who stayed in
Please cite this article in press as: R.- Yao, et al., Diagnostic blood loss from phlebotomy and hospital acquired anemia in patients with severe burns, Burns (2019), https://doi.org/10.1016/j.burns.2019.08.020
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Table 1 – Baseline characteristics and diagnostic blood loss of enrolled patients. Characteristic
Total (n = 157)
Age (yrs), mean (SD) Male, n (%) TBSA burn total%, median (IQR) TBSA burn full thickness %, median (IQR) Inhalation injury, n (%) Mild Moderate Severe Etiology, n (%) Flame Scald Chemical Electrical Others Hemoglobin level (g/L) at admission, mean (SD) Total DBL volumea (mL), median (IQR) DBL volume per daya (mL/day), median (IQR) DBL volume (mL) according to test typea, median (IQR) Blood routine Arterial blood gas Serum chemistries Coagulation laboratory Hepatology laboratory Blood culture Others Patients who developed HAA during week 4, n (%) Patients who became anemic during admission, n (%) Patients who became anemic during week 4, n (%) Patients who became moderate to severe anemic during week 4, n (%) Mortality, n (%) Hospital length of stay (days), median (IQR) ICU length of stay (days), median (IQR) No. of operations, median (IQR) Coagulopathyb , n (%) Acute Late RBC transfusion volume (units), median (IQR)
41.2 (1.2) 110 (70.1) 64 (45, 83.5) 26 (8, 49.3) 39 (24.8) 43 (27.4) 29 (18.5) 129 (82.2) 8 (5.1) 3 (1.9) 3 (1.9) 14 (8.9) 152.0 (3.0) 272 (150.5, 440.5) 6.8 (4.7, 10.0) 44 (27, 69) 8 (2, 16.5) 92 (52, 140) 9 (3, 15) 12 (4, 54) 4.8 (0, 24) 48 (16, 128) 46 (29.3) 23 (14.6) 111 (70.7) 49 (31.2) 15 (9.6) 48 (30.5, 81) 31 (16, 48) 4 (2, 8) 31 (19.7) 33 (21.0) 17 (3, 35)
Abbreviations: SD, standard deviation; TBSA, total body surface area; IQR, inter-quartile range; ICU, intensive care unit; DBL, diagnostic blood loss; HAA, hospital acquired anemia; RBC, red blood cell. a The DBL volume was calculated based on 90-day hospitalization. b The diagnosis of coagulopathy was based on laboratory abnormalities such as prothrombin time (PT) > 16.3 s or activated partial thromboplastin time (APTT) > 45 s or an international normalized ratio (INR) > 1.5, which represented our local laboratory’s definition of coagulopathy.
hospital over 28 days, moderate to severe HAA was occurred in 46 patients. Patients with moderate to severe HAA had significantly higher TBSA burn [80 (IQR: 70, 87)% vs 60 (45, 75)%; P < 0.001] and full thickness burn size [39 (IQR: 18, 65)% vs 20.5 (10, 38.25)%; P = 0.045] when compared to patients who did not. The median hemoglobin level during admission was higher in HAA group which was of statistical significance [160.8 3.87 g/L vs 148.2 4.2 g/L; P = 0.008].
3.2.
Changes in Hb levels within hospitalization
At the time of admission, mean Hb level was 152.0 3.0 and minority of patients became anemic (14.6%). Nevertheless, most of inpatients (70.7%) suffered varying degree of anemia within week 4, 49 patients (31.2%) even had moderate to severe anemia. The proportion of patients who became anemic was significantly increased from admission to week 4 (P < 0.0001), which was indicated by performing McNemar chi-square test.
3.3.
Diagnostic blood loss
The median volume of DBL from phlebotomy events within 90 hospitalization days and the DBL volume per day were shown in Table 1. Phlebotomy volume drawn for different type of diagnostic tests was documented individually. Among all enrolled patients, the median volume of total DBL was 272 (IQR: 150.5, 440.5) mL, and the DBL volume per 24 h was 6.8 (IQR: 4.7, 10) mL. Notably, phlebotomy volume drawn for serum chemistries test was account for largest portion of DBL, whose median was 92 (IQR: 52, 140) mL. The median volume of blood loss from blood routine test and arterial blood gas test were 44 (IQR: 27, 69) mL and 8 (IQR: 2, 16.5) mL, respectively. The median volume of coagulation laboratory test was 9 (IQR: 3, 15) mL. By estimating for each day during hospitalization, we observed that the total DBL volume was highest on the first 2 hospital days and dropped subsequently. The detailed time course of the DBL volume
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Table 2 – Baseline characteristics in accordance with moderate to severe HAA status during the fourth week postburn. Moderate to severe HAA
Characteristic
Age (years), mean (SD) Male, n (%) TBSA burn total%, median (IQR) TBSA burn full thickness %, median (IQR) Inhalation injury, n (%) Mild Moderate Severe Etiology, n (%) Flame Scald Chemical Electrical Others Hemoglobin level (g/L) at admission, mean (SD) Mortality, n (%) Hospital length of stay (days), median (IQR) ICU length of stay (days), median (IQR) No. of operations, median (IQR) Coagulopathya , n (%) Acute Late RBC transfusion volume (units), median (IQR)
P value
Yes (n = 46)
No (n = 75)
39.2 (1.87) 28 (60.9) 80 (70, 87) 39 (18, 65) 31 (67.4) 10 (21.7) 13 (28.3) 8 (17.4)
39.0 (1.44) 57 (76.0) 60 (45, 75) 20.5 (10.0, 38.25) 55 (73.3) 21 (28) 21 (28) 13 (17.3)
0.934 0.362 <0.001 0.045 0.484 0.444 0.975 0.993
35 (76.1) 2 (4.3) 2 (4.3) 0 (0) 1 (2.2) 160.8 (3.87) 2 (4.3) 58.5 (40, 100.5) 42.5 (30.5, 59) 3 (2, 4)
61 (81.3) 5 (6.7) 1 (1.3) 2 (2.7) 2 (2.7) 148.2 (4.20) 2 (2.7) 59 (44, 96) 37 (22, 50) 4 (2, 4)
0.489 0.596 0.301 0.525 0.866 0.008 0.95 0.715 0.215 0.689
9 (19.6) 11 (23.9) 21 (8.5, 55)
12 (16) 16 (21.3) 18 (4, 33)
0.615 0.741 0.073
Abbreviations: SD, standard deviation; TBSA, total body surface area; IQR, inter-quartile range; ICU, intensive care unit; DBL, diagnostic blood loss; HAA, hospital acquired anemia; RBC, red blood cell. a The diagnosis of coagulopathy was based on laboratory abnormalities such as prothrombin time (PT) > 16.3 s or activated partial thromboplastin time (APTT) > 45 s or an international normalized ratio (INR) > 1.5, which represented our local laboratory’s definition of coagulopathy.
from phlebotomy per day during 90 hospitalization days was shown in Fig. 2. As shown in Table 3, patients who developed moderate to severe HAA during the fourth week postburn had both significantly higher total DBL volume [245 (IQR: 183.75, 325.25) mL vs 168 (119, 163) mL ; P = 0.001] and DBL volume per day [10.22 (IQR: 8.57, 12.38) mL vs 6.63 (5.22, 10.42) mL/day ; P = 0.005]. Of note, the median DBL volume of patients with moderate to severe HAA was nearly 80 mL higher than that of patients without HAA. Meanwhile, the DBL volume from phlebotomy events per day among patients with moderate to severe HAA was approximately two times of those who without HAA.
3.4.
Predictors of moderate to severe HAA during week 4
Among 157 enrolled patients, 121 patients stayed in hospital longer than 28 days, which were eligible for entering the logistic regression model. The detailed outcomes of univariate as well as multivariate analyses were summarized in Table 4. Potential risk factors of the development of moderate to severe HAA on univariate analysis were the DBL volume per day within 28-day hospitalization, total DBL volume before within 28-day hospitalization, TBSA burn, and TBSA burn full thickness. After performing multivariate analysis by using enter method, we identified that patients with large burn size had higher possibility of developing moderate to severe HAA during the fourth week from admission (OR = 1.04; 95% CI 1.01 1.08; P = 0.02). Total DBL volume failed to be independently associated with the occurrence of HAA, whereas the DBL
volume from phlebotomy per day remained a high significance in predicting moderate to severe HAA during week 4 after adjusting for other variates which were significant in univariate analysis (OR = 1.49; 95% CI 1.09 2.05; P = 0.01). In addition, TBSA burn was demonstrated to be independently associated with increased incidence rate of HAA. As shown in Fig. 3, nonsurvival patients lost relatively more blood from diagnostic blood tests compared to survival patients during 4 hospitalization weeks, suggesting the DBL volume was directly associated with worsening prognosis or even early death.
3.5.
Predictors of RBC transfusion in survivors
Next, we tried to determine whether DBL would affect RBC transfusion. One hundred and forty-two patients survived before discharging form hospital. Predictors of RBC transfusion volume in survivors were presented in Table 5. Univariate regression analysis identified several potentially significant factors, including total DBL volume of 90-day hospitalization (coefficient = 0.08), TBSA burn (coefficient = 0.80), TBSA burn full thickness (coefficient = 0.79), inhalation injury status (coefficient = 6.82), tracheostomy (coefficient = 24.12), number of operations (coefficient = 4.17), ICU-LOS (coefficient = 0.73), and hospital-LOS (coefficient = 0.13). Nevertheless, by adjusting those factors in the multivariate regression model, TBSA burn full thickness (coefficient = 0.38), number of operations (coefficient = 2.06), ICU-LOS (coefficient = 0.38), and hospitalLOS (coefficient = 0.09) were manifested to be the independent risk factors of elevated volume of RBC transfusion. In contrast, total DBL volume of 90 hospitalization days and TBSA
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Fig. 2 – Mean volume of blood lost due to phlebotomy per day (mL). The box plot showed the time course of the DBL volume from phlebotomy per day during 90 hospitalization days. The total DBL volume was highest on the first 2 hospital days and dropped subsequently. Table 3 – Diagnostic blood loss among patients with or without moderate to severe HAA. Moderate to severe HAA
Characteristic
Total DBL volumea (mL), median (IQR) DBL volume per daya (mL/day), median (IQR) DBL volume (mL) according to test typea , median (IQR) Blood routine Arterial blood gas Serum chemistries Coagulation laboratory Hepatology laboratory Blood culture Others a
P value
Yes (n = 46)
No (n = 75)
245 (183.75, 325.25) 10.22 (8.57, 12.38)
168 (119, 263) 6.63 (5.22, 10.42)
0.001 0.005
46 (32, 58.5) 11.5 (5, 19) 88 (71, 118) 9 (5.25, 15) 20 (4, 61) 12 (0, 36) 26 (12, 56)
36 (24, 46) 8 (2, 14) 76 (48, 92) 6 (3, 9) 12 (4, 44) 0 (0, 24) 16 (8, 28)
0.003 0.134 0.004 0.028 0.272 0.858 0.025
Abbreviations: DBL, diagnostic blood loss; IQR, inter-quartile range. The DBL volume was calculated based on 4-week hospitalization.
burn no longer had impact on the units of RBC transfusion when adjusted for other variates. The concerning of multicollinearity was testified as well, which was proved to be nonsignificant.
4.
Discussion
4.1.
Major findings
Several studies reported correlation between the blood loss from diagnostic tests and the development of HAA in disparate
patient cohort [8,11,19]. However, no literature is available with regard to this issue in severely burned patients. Thus, to our knowledge, the current work is the first to directly evaluate connections between the DBL volume and incidence of HAA in patients following extensive burns. As reported, we observed that merely a fraction of patients developed anemia at the time of admission, while many of them became anemic during the fourth week of hospitalization, indicating a prevalence of HAA in severely burned patients. We found that patients with moderate to severe HAA during the fourth week postburn had remarkably higher DBL volume due to phlebotomy events compared to patients
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Table 4 – Predictors of moderate to severe hospital acquired anemia during week 4 postburn. Univariate analyses
Variable
a
DBL per day DBL totala Age Male TBSA burn III TBSA burn Inhalation injury Tracheostomy No. of operations Coagulopathy
a
OR
95%CI
1.16 1.00 1.00 0.68 1.04 1.01 0.95 1.60 0.95 0.90
1.05, 1.28 1.00, 1.01 0.97, 1.03 0.29, 1.57 1.02, 1.06 1.00, 1.03 0.67, 1.36 0.72, 3.55 0.73, 1.23 0.43, 1.88
Multivariate analyses P value
OR
95%CI
P value
0.002 0.01 0.93 0.36 0.001 0.05 0.79 0.25 0.69 0.77
1.49 0.99
1.09, 2.05 0.98,1.00
0.01 0.06
1.04 1.00
1.01, 1.08 0.98, 1.02
0.02 0.62
Abbreviations: DBL, diagnostic blood loss; TBSA, total body surface area. Bold numbers were statistically significant (P < 0.05). The inclusion criteria was 0.1 and the exclusion criteria was 0.1. The DBL volume was calculated based on 4-week hospitalization.
Fig. 3 – The DBL volume per day between survival and non-survival patients. The line graph displayed the mean DBL volume from phlebotomy events each day between survival and non-survival patients during 28 hospitalization days. Survival patients had higher DBL volume per day compared to patients who died.
who did not develop moderate to severe HAA. Indeed, our study revealed that the DBL volume from phlebotomy per day could be a predictor of the occurrence of moderate to severe HAA during week 4, suggesting the DBL volume per day appeared to be an independent risk factor of moderate to severe HAA. Meanwhile, patients with large burn size were more likely developed moderate to severe HAA. In addition, we had identified that number of operations, TBSA burn full thickness, ICU-LOS, and hospital-LOS were independently associated with the increased volume of blood transfusion.
4.2.
Interpretations
Intriguingly, we found that patients with larger TBSA burn were inclined to develop HAA in the present observation. Such
phenomenon could attribute to the hemoconcentration status that severely burned patients possessed. Initial phase of severe burns is always accompanied with a great amount of fluid exudation, which subsequently leads to highly concentrated blood. Given that, patients with large burn size clearly lose more blood cells per mL from diagnostic blood tests when compared to patients in normal Hb level. Although, total DBL volume and DBL volume per day within 4 weeks were found to be of statistical significance on univariate analysis, only DBL volume per day was independently associated with the occurrence of HAA after the performance of multivariate analysis. We assumed this discrepancy might be mainly due to the disparate LOS among all enrolled patients, which could be an important confounding factor. Obviously, patients with longer LOS were inclined to have more laboratory tests and
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Table 5 – Predictors of RBC transfusion in all survivors. Univariate analyses
Variable Coefficient a
DBL total Age Male TBSA burn III TBSA burn Inhalation injury Tracheostomy Hb during admission No. of operations ICU length of stay Hospital length of stay Coagulopathy (acute) (late)
a
0.08 0.07 7.95 0.80 0.79 6.82 24.12 0.04 4.17 0.73 0.13 10.59 8.57
Multivariate analyses
SE
P value
0.009 0.21 5.73 0.12 0.08 2.40 4.81 0.08 0.50 0.07 0.04 6.47 6.17
<0.001 0.73 0.17 <0.001 <0.001 0.005 <0.001 0.59 <0.001 <0.001 0.001 0.10 0.17
Coefficient
SE
P value
0.02
0.01
0.12
0.003 0.38 1.52 3.19
0.13 0.11 2.30 4.86
0.98 0.001 0.51 0.51
2.06 0.38 0.09
0.65 0.12 0.03
0.002 0.002 0.006
Abbreviations: SE, standard error; DBL, diagnostic blood loss; TBSA, total body surface area; ICU, intensive care unit. Bold numbers were statistically significant (P < 0.05). The inclusion criteria was 0.1 and the exclusion criteria was 0.1. The DBL volume was calculated based on 90-day hospitalization.
DBL volume than others. Given that, by removing the potential influence of LOS, DBL volume per day seems to be independently correlated to the development of HAA. In this study, we identified that full thickness TBSA burn and number of operations were significantly associated with increased number of RBC transfusion. Notably, patients who had frequently undergone operations, such as escharectomy and grafting, resulted in massive surgical blood loss, implying an increased demand of blood transfusion than others. However, total DBL volume during hospitalization were significant on univariate analysis, while lost the significance in adjusted multivariate regression model. We do not have a conclusive interpretation towards this finding, it is possible that phlebotomy events might be overlapped with operative events.
4.3.
Relation to previous works
Previous studies focused on relevant topic have consistently reported the marked correlation between blood loss from diagnostic tests and Hb alteration. Thavendiranathan and his colleagues noticed a decrease of 0.07 g/L in Hb level for every 1 mL DBL volume [8]. This study was conducted in the cohort of general internal medicine inpatients, while a recently published work identified DBL as a strong predictor of the Hb alteration in patients with myasthenia gravis (MG) exacerbation [19]. Both aforementioned single-institution investigations failed to testify the direct link between phlebotomy event and the occurrence of HAA, which obviously lacked profound clinical implication. The study conducted by Salisbury was the first to directly assess the association between DBL and HAA among patients with acute myocardial infarction [11]. By classifying patients into two groups, they found the mean blood loss from phlebotomy was almost 100 mL higher during hospitalization among patients who developed moderate to severe HAA compared with those without HAA. Particularly, large DBL was relatively common in patients with moderate to severe HAA. The multicenter research with large sample size initially documented DBL as an independent risk factor of the
development of HAA [11]. In agreement with those findings, our results revealed the trend that severely burned patients with frequent blood tests per day were more inclined to become anemic during hospitalization.
4.4.
Clinical implications
HAA is a critical issue which is demonstrated to directly link to prolonged hospital-LOS and increased mortality [20]. Salisbury and his colleagues noted a positive correlation between inhospital mortality and severity of HAA, especially among those who developed moderate to severe HAA [21]. Likewise, recent studies showed that severe HAA was obviously related to adverse post-discharge outcomes for medical inpatients [1]. Accumulating evidences have implicated the detrimental role of HAA in the pathogenesis of poor prognosis. In the current study, we identified that blood loss from diagnostic tests could be a modifiable yet rationale target for preventing HAA. Of note, only a minimal volume of blood is needed to run the test with the same accuracy, indicating the use of pediatric tubes might be a promising strategy [11,22]. Indeed, it was found a remarkable decline of the DBL volume from phlebotomy by using pediatric-size tubes [11]. Similarly, physicians were reported to constantly neglect the routine check of blood order for inpatients, resulting in patients undergoing more tests than necessary. Therefore, the frequency of diagnostic blood test should be reduced as well, which can be accomplished by rigorous observation of patients’ status in clinical practice. Additionally, informing both physicians and nurses the latent risk of over ordering diagnostic test is a feasible way in all institutions [8,23]. Although blood transfusion serves as the primary intervention in the treatment of HAA, it simultaneously brings about many adverse effects, such as infection, anaphylactic and hemolytic transfusion reactions, transfusion related acute lung injury, and transfusion associated circulatory overload [24]. Consistent with our prior work, we found that the number of operations was an independent risk factor of increased units of RBC transfusion, suggesting that surgical blood loss was
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responsible for the consecutive requirement of blood transfusion [17]. If we measured the relative impact of variables which was of statistical significance by adjusted regression coefficient, number of operations had highest impact among other risk factors, with every time of operation, approximately 2 more units of blood were transfused. Accordingly, it suggests that blood conservation sampling devices can be used to reduce operation-associated blood loss, which can significantly decrease the occurrence of HAA and requirements of RBC transfusion [25,26]. Furthermore, a more restrictive threshold of transfusion for critically ill patients can be beneficial. We assume that the outcome of this study might apply to border population other than severely burned patients. Critically ill patients share some common features and more susceptible to phlebotomy events. Therefore, randomized clinical trial (RCT) or prospective cohorts are required to uncover the causal relationship between excessive DBL and development of HAA. It may reveal a new approach to prevent the occurrence of HAA and improve clinical prognosis by minimizing unnecessary diagnostic blood tests.
4.5.
Limitations
Several limitations should be taken into consideration when interpreting our findings. Firstly, given the retrospective nature and single-center design of the current study, it is challenging to draw the conclusion that blood loss from overordered diagnostic tests directly leads to HAA. The possibility of a reverse causal-relationship that HAA drives diagnostic tests should be taken into account as well. However, our data showed a subsequent decline of the DBL volume per day after the initial peak of phlebotomy event, which partially excluded this hypothesis. As such, prospective cohort studies or multicenter RCTs are needed to testify this causal relationship in the future studies. Secondly, the sample size of this work was relatively small. Without performing selective enrollment, we incorporated all patients who had matched the pre-assigned inclusion criteria during the study period from 2005 to 2017. That being said, the data of included patients was superior in quality, and was sufficient for the establishment of our regression model. Thirdly, the estimated DBL volume used in the present observation was based on several consumptions, including no blood waste in the process of phlebotomy performance, and each blood draw being close to the preassigned volume of a particular type of blood tube. Thus, the estimation was conservative, which was stand for the lowest volume of DBL possible in clinical practice. Clearly, our findings were unlikely to exaggerate the impact of the DBL volume on the development of HAA. Fourthly, pathophysiological status, especially increased microvascular permeability postburn might alter and exaggerate the Hb level at admission. Disparate transfer time and timing of blood draw unable us to standardize Hb level after initial burn injury. Given that, we applied Hb level within 48 h after admission to avoid the effect came from increased microvascular permeability as much as possible. Finally, other confounders, such as the use of medications, underlying diseases, and intricate complications were not regarded as variates, which might have potential effect in altering red cell homeostasis. We believed this effect was trivial and will not reverse our results.
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Other factors, including postburn proinflammatory state, bone marrow dysfunction and nutritional deficiencies were unable to measure in retrospective design, which required further attention in prospective studies.
5.
Conclusions
In conclusion, we find that HAA appears to be of frequent occurrence among patients with severe burn injury. It has been demonstrated that the DBL volume from phlebotomy events is an independent risk factor of the development of HAA. The current study highlights the clinical significance of optimizing both quantity and frequency of diagnostic blood tests in the prevention of HAA in the setting of major burns. The direct correlation between DBL and poor prognosis among these particular populations requires further exploration.
Funding sources This work was supported by grants from the National Natural Science Foundation of China (Nos. 81801937, 81842025), the Key Project of Military Medical Innovation Program (No. 18CXZ026), and the Shanghai Sailing Program (No. 18YFC1422900).
Conflicts of interest The authors have declared that no conflicts of interest exist.
Authors’ contributions ZFX and YMY co-conceived the study. RQY, GSW, LX, BM, JL, LS, and HST participated in material collection. RQY, GSW, and LX wrote and edited the manuscript. RQY undertook the statistical analyses. All authors read and approved the final manuscript.
Acknowledgment Not applicable. REFERENCES
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ScienceDirect journal homepage: www.elsevier.com/locate/burns
Diagnostic blood loss from phlebotomy and hospital acquired anemia in patients with severe burns Ren-qi Yao a,b,1 , Guo-sheng Wu a,1 , Long Xu a,1 , Bing Ma a, Jia Lin c , Lei Shi c , He-shan Tang d, Yong-ming Yao b, * , Zhao-fan Xia a, ** a
Department of Burn Surgery, Changhai Hospital, Navy Medical University, Shanghai 200433, People’s Republic of China b Trauma Research Center, Fourth Medical Center of the Chinese PLA General Hospital, Beijing 100048, People’s Republic of China c Department of Laboratory Diagnosis, Changhai Hospital, Navy Medical University, Shanghai 200433, People’s Republic of China d Department of Blood Transfusion, Changhai Hospital, Navy Medical University, Shanghai, People’s Republic of China
article info
abstract
Article history:
Purpose: The study was performed to estimate the diagnostic blood loss (DBL) volume during
Accepted 29 August 2019
hospitalization and investigate its relationship with the development of moderate to severe
Available online xxx
hospital acquired anemia (HAA) and increased number of red blood cell (RBC) transfusion following extensive burns.
Keywords: Diagnostic blood loss Hospital acquired anemia Severe burns Transfusion
Materials and methods: This was a retrospective study of adult burned patients with total body surface area (TBSA) burn larger than 40%, who were admitted to burn center of Changhai hospital between January 2005 and December 2017. Results: We included a final number of 157 patients in the present study. Moderate to severe HAA within the fourth week postburn was developed in 46 of 121 patients who stayed over 28-day hospitalization. Patients with moderate to severe HAA had both significantly higher total DBL volume [245 (IQR: 183.75, 325.25) mL vs 168 (119, 163) mL ; P = 0.001] and DBL volume per day [10.22 (IQR: 8.57, 12.38) mL vs 6.63 (5.22, 10.42) mL/day; P = 0.005]. Logistic regression analysis revealed that both DBL volume per day and TBSA burn were independent risk factors for the development of moderate to severe HAA. Conclusions: Severely burned patients appear to be prone to develop HAA during hospitalization. The DBL volume contribute to the occurrence of moderate to severe HAA, which might be a modifiable target for preventing HAA. © 2019 Elsevier Ltd and ISBI. All rights reserved.
* Corresponding author at: Trauma Research Center, Fourth Medical Center of the Chinese PLA General Hospital, 51 Fucheng Road, Haidian District, Beijing 100048, People’s Republic of China. ** Corresponding author at: Department of Burn Surgery, Changhai Hospital, Navy Medical University, 168 Changhai Road, Yangpu District, Shanghai 200433, People’s Republic of China. E-mail addresses: [email protected] (Y.-m. Yao), [email protected] (Z.-f. Xia). 1 These authors contributed equally to this manuscript. https://doi.org/10.1016/j.burns.2019.08.020 0305-4179/© 2019 Elsevier Ltd and ISBI. All rights reserved.
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1.
Introduction
Hospital acquired anemia (HAA) refers to the condition, in which patients are not anemic at admission, but develop anemia during hospitalization [1,2]. Similar to other types of anemia, HAA has been demonstrated to directly link to the worsening prognosis and even death in critically ill patients [3,4]. Previous study indicated that anemia of critical illness mostly occurred in the second and fourth weeks after admission to intensive care unit (ICU) [5 7]. Multiple factors may contribute to the reduction of hemoglobin (Hb) level, which can be divided into two categories: one can be attributed to various pathophysiological states, including inflammation, chronic renal disease, and heart failure; the other one is related to iatrogenic factors. Indeed, it was reported that the diagnostic blood loss (DBL) volume from phlebotomy was highly associated with drops of Hb and hematocrit levels in patients admitted to internal medicine department and adult/ pediatric ICU [8 10]. Moreover, Salisbury and his colleagues showed that blood loss from greater use of phlebotomy in acute myocardial infarction patients was an independent risk factor of developing HAA [11]. Notably, those iatrogenic events, especially the DBL volume from phlebotomy can be feasible target for minimizing HAA. Through implementing some measurements, either by restricting phlebotomy frequency or by using pediatric tubes, can we limit DBL volume and further reduce the incidence of HAA [12 16]? Due to the prolonged hemodynamic perturbation and initial injury, severely burned patients with burn size more than 40% total body surface area (TBSA) are more likely to develop anemia compared to other critically ill patients [17,18]. Those patients are at great risk of developing acute or chronic coagulopathy during their hospitalization, which is also demonstrated to play a role in HAA. Meanwhile, the duration of their hospitalizations are much longer, usually weeks to months, which result in the increased numbers of operations, bedside procedures (placement of central venous catheters or arterial catheters and wound care) and DBL due to phlebotomy (blood collected from central venous and arterial lines) and repetitive laboratory testing. Of note, some regularly used antibiotics, including piperacillin, cefotetan, and ceftriaxone, also inhibit bone marrow’s ability to produce red blood cell (RBC). Given that, as a particular population of critically ill patients, patients with major burns require higher volume of RBC transfusion and closer surveillance for prevention of HAA. Since there is no literature report concerning the relationship between the DBL volume and the development of HAA in severely burned patients so far, we seek to identify whether the DBL volume is independently associated with HAA and increased RBC transfusion simultaneously.
2.
Materials and methods
2.1.
Design and patient population
The current work was a single-center retrospective study conducted at burn center of Changhai hospital in Shanghai,
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China. Changhai hospital was a tertiary care hospital and its burn center was one of the best institutions specialized in treating burns among mainland China. This study was complied with the Declaration of Helsinki and was approved by the committee on the ethics of medicine, Changhai hospital in September 30, 2018. Adult patients (aged >18 years) admitted to this center from January 1, 2005, to December 31, 2017, with burn size 40% TBSA, were potentially eligible for this study. We excluded patients who (1) died within 10 days postburn; (2) were transferred to our hospital over 72 h after injury; (3) had incomplete medical data record.
2.2.
Data extraction
The electronic patient record system and Changhai 360 online databank recorded medical data of all eligible patients, including patients’ demographic characteristics, etiology of burn, TBSA burn, depth of burn, inhalation injury, comorbidities, ICU and hospital length of stay (LOS). Moreover, detailed information of laboratory tests, medications, number of operations, and the units of RBC transfusion were also collected. The date and type of every diagnostic blood test were documented in the Changhai 360 online databank. Results of laboratory tests were needed, including Hb level at admission (within 48 h) and within the fourth week after admission, which could be obtained from the electronic patient record system. The counts and types of blood tubes used for diagnostic tests during entire hospitalization had been listed and were required for the estimation of total DBL volume. The estimation was based on several conservative hypotheses as the following: (1) no extra blood loss during the implementation of each phlebotomy event; (2) the volume of each blood draw was close to the assigned volume of particular type of blood tube accordingly; (3) all required tests could be proceeded effectively by using minimal blood volume. In addition, we considered the DBL volume per day of hospitalization as a latent risk factor of HAA, which was calculated by dividing total DBL volume by hospitalization length. The hospitalization length was defined as the number of days between the first and last phlebotomy events. Based on the protocol of diagnostic blood test in Changhai hospital, blood routine tubes were assigned a volume of 2 mL, hepatology laboratory tubes of 4 mL, serum chemistries laboratory tubes of 4 mL, coagulation tubes of 3 mL, arterial blood gas tubes of 1 mL, and blood cultures of 6 mL. For other diagnostic blood tests, we assigned a volume of 4 mL for each tube.
2.3.
Definitions
Patients were defined as developing HAA at week 4 if they were not anemic at admission while their nadir Hb level within the fourth week reduction below the diagnostic criterion of anemia. To this end, we applied Chinese definition of anemia as the following: Hb level lower than 120 g/dL for adult male, lower than 110 g/dL for non-pregnant adult female, and lower than 100 g/dL for pregnant female patients. Patients with Hb level lower than 90 g/dL were diagnosed of having moderate to severe anemia. In consideration of clinical and prognostic
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significance, HAA during the fourth week of hospitalization was applied as the primary outcome of the current study. Coagulopathy was defined as abnormalities on coagulation assays which referred to the prothrombin time (PT) > 16.3 s or activated partial thromboplastin time (APTT) > 45 s or an international normalized ratio (INR) > 1.5. Additionally, the secondary outcome was the units of RBC transfusion. Of note, our center applied restrictive transfusion strategy, in which the transfusion threshold was 7 g/dL.
2.4.
Statistical analysis
All data analyses were performed by using the IBM SPSS Statistics 22 software. Descriptive analysis was applied to summarize baseline characteristics of all included patients. We compared the proportion of patients who became anemic at admission and at week 4 by using paired chi-square test (McNemar test). In order to evaluate if the DBL volume was the independent risk factor associated with the development of moderate to severe HAA at week 4, we used both univariate and multivariate logistic regression. Patients with at least 28 days hospital-LOS were included in the model and the DBL volume was re-calculated based on 28 days of hospitalization. Other confounders were considered as variates in accordance with previously published literature and clinical practice, which included demographics (age, gender), severity and depth of burn injury (TBSA burn, TBSA burn full thickness), the DBL volume per day, inhalation injury status, interventions (number of operations, tracheostomy), and the presence of coagulopathy. Variables with significance on univariate analysis at P < 0.1 was subsequently adjusted in them multivariable model by using enter method. Variates of significance level of P < 0.05 were preserved, while other variates were removed after performing multivariate regression. Similarly, we carried out univariate and multivariate linear regression to assess the correlation between the DBL volume and the amount of RBC transfusion among all survivors. Other than variates included in logistic regression, we also added two potential confounders into liner regression, which were ICU and hospital-LOS. Of note, the significance level of linear regression was in line with aforementioned level of logistic regression.
3.
Results
3.1. Patient characteristics and development of moderate to severe HAA A total number of 320 patients with TBSA burn 40% were admitted to the burn center of Changhai hospital during our pre-defined observational period. By screening medical history of those patients, we excluded 140 patients because they moved to our center over 72 h after initial injury. Among the remaining 180 patients, 15 patients were excluded for staying less than 10 days in hospital postburn and there left 165 patients, from whom 8 patients were not incorporated into the patient cohort due to incomplete data. Therefore, a population of 157 patients was enrolled in the current study. The detailed process of enrollment was shown in Fig. 1.
Fig. 1 – Screening and enrollment.
The baseline characteristics of all 157 patients were presented in Table 1. Of those, the mean age was 41.2 1.2 years. Majority of patients (70.1%) were male, while 47 enrolled patients were female (29.9%). The median total burn size of included patients was 64 [inter-quartile range (IQR): 45, 83.5]% TBSA. Besides, the full thickness burn size was 26 (IQR: 8, 49.3)% TBSA. Among diverse factors causing burns, flame (82.2%) was the top-ranking reason for admission, 8 patients were scalded (5.1%), and chemical (1.3%) as well as electrical (1.3%) mechanisms were responsible for burn injury of 3 patients each. Upon admission, 111 patients (70.7%) were diagnosed of having disparate status of inhalation injury, from whom 39 patients (24.8%) were complicated by mild inhalation injury, while 43 (27.4%) and 29 (18.5%) patients were verified to have moderate and severe inhalation injury, respectively. Thirty-one patients (19.7%) developed coagulopathy in acute phase, while 33 patients had coagulopathy at late stage. There were 15 patients (9.6%) who died during hospitalization. The median number of operations performed on patients was 4 (IQR: 2, 8) times. The hospital-LOS and ICU-LOS of all incorporated patients were 48 (IQR: 30.5, 81) days and 31 (IQR: 16, 48) days, respectively. After removing patients whose LOS were less than 4 weeks, we further compared baseline characteristics of patients between who developed moderate to severe HAA and who did not in Table 2. Among 121 eligible patients who stayed in
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Table 1 – Baseline characteristics and diagnostic blood loss of enrolled patients. Characteristic
Total (n = 157)
Age (yrs), mean (SD) Male, n (%) TBSA burn total%, median (IQR) TBSA burn full thickness %, median (IQR) Inhalation injury, n (%) Mild Moderate Severe Etiology, n (%) Flame Scald Chemical Electrical Others Hemoglobin level (g/L) at admission, mean (SD) Total DBL volumea (mL), median (IQR) DBL volume per daya (mL/day), median (IQR) DBL volume (mL) according to test typea, median (IQR) Blood routine Arterial blood gas Serum chemistries Coagulation laboratory Hepatology laboratory Blood culture Others Patients who developed HAA during week 4, n (%) Patients who became anemic during admission, n (%) Patients who became anemic during week 4, n (%) Patients who became moderate to severe anemic during week 4, n (%) Mortality, n (%) Hospital length of stay (days), median (IQR) ICU length of stay (days), median (IQR) No. of operations, median (IQR) Coagulopathyb , n (%) Acute Late RBC transfusion volume (units), median (IQR)
41.2 (1.2) 110 (70.1) 64 (45, 83.5) 26 (8, 49.3) 39 (24.8) 43 (27.4) 29 (18.5) 129 (82.2) 8 (5.1) 3 (1.9) 3 (1.9) 14 (8.9) 152.0 (3.0) 272 (150.5, 440.5) 6.8 (4.7, 10.0) 44 (27, 69) 8 (2, 16.5) 92 (52, 140) 9 (3, 15) 12 (4, 54) 4.8 (0, 24) 48 (16, 128) 46 (29.3) 23 (14.6) 111 (70.7) 49 (31.2) 15 (9.6) 48 (30.5, 81) 31 (16, 48) 4 (2, 8) 31 (19.7) 33 (21.0) 17 (3, 35)
Abbreviations: SD, standard deviation; TBSA, total body surface area; IQR, inter-quartile range; ICU, intensive care unit; DBL, diagnostic blood loss; HAA, hospital acquired anemia; RBC, red blood cell. a The DBL volume was calculated based on 90-day hospitalization. b The diagnosis of coagulopathy was based on laboratory abnormalities such as prothrombin time (PT) > 16.3 s or activated partial thromboplastin time (APTT) > 45 s or an international normalized ratio (INR) > 1.5, which represented our local laboratory’s definition of coagulopathy.
hospital over 28 days, moderate to severe HAA was occurred in 46 patients. Patients with moderate to severe HAA had significantly higher TBSA burn [80 (IQR: 70, 87)% vs 60 (45, 75)%; P < 0.001] and full thickness burn size [39 (IQR: 18, 65)% vs 20.5 (10, 38.25)%; P = 0.045] when compared to patients who did not. The median hemoglobin level during admission was higher in HAA group which was of statistical significance [160.8 3.87 g/L vs 148.2 4.2 g/L; P = 0.008].
3.2.
Changes in Hb levels within hospitalization
At the time of admission, mean Hb level was 152.0 3.0 and minority of patients became anemic (14.6%). Nevertheless, most of inpatients (70.7%) suffered varying degree of anemia within week 4, 49 patients (31.2%) even had moderate to severe anemia. The proportion of patients who became anemic was significantly increased from admission to week 4 (P < 0.0001), which was indicated by performing McNemar chi-square test.
3.3.
Diagnostic blood loss
The median volume of DBL from phlebotomy events within 90 hospitalization days and the DBL volume per day were shown in Table 1. Phlebotomy volume drawn for different type of diagnostic tests was documented individually. Among all enrolled patients, the median volume of total DBL was 272 (IQR: 150.5, 440.5) mL, and the DBL volume per 24 h was 6.8 (IQR: 4.7, 10) mL. Notably, phlebotomy volume drawn for serum chemistries test was account for largest portion of DBL, whose median was 92 (IQR: 52, 140) mL. The median volume of blood loss from blood routine test and arterial blood gas test were 44 (IQR: 27, 69) mL and 8 (IQR: 2, 16.5) mL, respectively. The median volume of coagulation laboratory test was 9 (IQR: 3, 15) mL. By estimating for each day during hospitalization, we observed that the total DBL volume was highest on the first 2 hospital days and dropped subsequently. The detailed time course of the DBL volume
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Table 2 – Baseline characteristics in accordance with moderate to severe HAA status during the fourth week postburn. Moderate to severe HAA
Characteristic
Age (years), mean (SD) Male, n (%) TBSA burn total%, median (IQR) TBSA burn full thickness %, median (IQR) Inhalation injury, n (%) Mild Moderate Severe Etiology, n (%) Flame Scald Chemical Electrical Others Hemoglobin level (g/L) at admission, mean (SD) Mortality, n (%) Hospital length of stay (days), median (IQR) ICU length of stay (days), median (IQR) No. of operations, median (IQR) Coagulopathya , n (%) Acute Late RBC transfusion volume (units), median (IQR)
P value
Yes (n = 46)
No (n = 75)
39.2 (1.87) 28 (60.9) 80 (70, 87) 39 (18, 65) 31 (67.4) 10 (21.7) 13 (28.3) 8 (17.4)
39.0 (1.44) 57 (76.0) 60 (45, 75) 20.5 (10.0, 38.25) 55 (73.3) 21 (28) 21 (28) 13 (17.3)
0.934 0.362 <0.001 0.045 0.484 0.444 0.975 0.993
35 (76.1) 2 (4.3) 2 (4.3) 0 (0) 1 (2.2) 160.8 (3.87) 2 (4.3) 58.5 (40, 100.5) 42.5 (30.5, 59) 3 (2, 4)
61 (81.3) 5 (6.7) 1 (1.3) 2 (2.7) 2 (2.7) 148.2 (4.20) 2 (2.7) 59 (44, 96) 37 (22, 50) 4 (2, 4)
0.489 0.596 0.301 0.525 0.866 0.008 0.95 0.715 0.215 0.689
9 (19.6) 11 (23.9) 21 (8.5, 55)
12 (16) 16 (21.3) 18 (4, 33)
0.615 0.741 0.073
Abbreviations: SD, standard deviation; TBSA, total body surface area; IQR, inter-quartile range; ICU, intensive care unit; DBL, diagnostic blood loss; HAA, hospital acquired anemia; RBC, red blood cell. a The diagnosis of coagulopathy was based on laboratory abnormalities such as prothrombin time (PT) > 16.3 s or activated partial thromboplastin time (APTT) > 45 s or an international normalized ratio (INR) > 1.5, which represented our local laboratory’s definition of coagulopathy.
from phlebotomy per day during 90 hospitalization days was shown in Fig. 2. As shown in Table 3, patients who developed moderate to severe HAA during the fourth week postburn had both significantly higher total DBL volume [245 (IQR: 183.75, 325.25) mL vs 168 (119, 163) mL ; P = 0.001] and DBL volume per day [10.22 (IQR: 8.57, 12.38) mL vs 6.63 (5.22, 10.42) mL/day ; P = 0.005]. Of note, the median DBL volume of patients with moderate to severe HAA was nearly 80 mL higher than that of patients without HAA. Meanwhile, the DBL volume from phlebotomy events per day among patients with moderate to severe HAA was approximately two times of those who without HAA.
3.4.
Predictors of moderate to severe HAA during week 4
Among 157 enrolled patients, 121 patients stayed in hospital longer than 28 days, which were eligible for entering the logistic regression model. The detailed outcomes of univariate as well as multivariate analyses were summarized in Table 4. Potential risk factors of the development of moderate to severe HAA on univariate analysis were the DBL volume per day within 28-day hospitalization, total DBL volume before within 28-day hospitalization, TBSA burn, and TBSA burn full thickness. After performing multivariate analysis by using enter method, we identified that patients with large burn size had higher possibility of developing moderate to severe HAA during the fourth week from admission (OR = 1.04; 95% CI 1.01 1.08; P = 0.02). Total DBL volume failed to be independently associated with the occurrence of HAA, whereas the DBL
volume from phlebotomy per day remained a high significance in predicting moderate to severe HAA during week 4 after adjusting for other variates which were significant in univariate analysis (OR = 1.49; 95% CI 1.09 2.05; P = 0.01). In addition, TBSA burn was demonstrated to be independently associated with increased incidence rate of HAA. As shown in Fig. 3, nonsurvival patients lost relatively more blood from diagnostic blood tests compared to survival patients during 4 hospitalization weeks, suggesting the DBL volume was directly associated with worsening prognosis or even early death.
3.5.
Predictors of RBC transfusion in survivors
Next, we tried to determine whether DBL would affect RBC transfusion. One hundred and forty-two patients survived before discharging form hospital. Predictors of RBC transfusion volume in survivors were presented in Table 5. Univariate regression analysis identified several potentially significant factors, including total DBL volume of 90-day hospitalization (coefficient = 0.08), TBSA burn (coefficient = 0.80), TBSA burn full thickness (coefficient = 0.79), inhalation injury status (coefficient = 6.82), tracheostomy (coefficient = 24.12), number of operations (coefficient = 4.17), ICU-LOS (coefficient = 0.73), and hospital-LOS (coefficient = 0.13). Nevertheless, by adjusting those factors in the multivariate regression model, TBSA burn full thickness (coefficient = 0.38), number of operations (coefficient = 2.06), ICU-LOS (coefficient = 0.38), and hospitalLOS (coefficient = 0.09) were manifested to be the independent risk factors of elevated volume of RBC transfusion. In contrast, total DBL volume of 90 hospitalization days and TBSA
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Fig. 2 – Mean volume of blood lost due to phlebotomy per day (mL). The box plot showed the time course of the DBL volume from phlebotomy per day during 90 hospitalization days. The total DBL volume was highest on the first 2 hospital days and dropped subsequently. Table 3 – Diagnostic blood loss among patients with or without moderate to severe HAA. Moderate to severe HAA
Characteristic
Total DBL volumea (mL), median (IQR) DBL volume per daya (mL/day), median (IQR) DBL volume (mL) according to test typea , median (IQR) Blood routine Arterial blood gas Serum chemistries Coagulation laboratory Hepatology laboratory Blood culture Others a
P value
Yes (n = 46)
No (n = 75)
245 (183.75, 325.25) 10.22 (8.57, 12.38)
168 (119, 263) 6.63 (5.22, 10.42)
0.001 0.005
46 (32, 58.5) 11.5 (5, 19) 88 (71, 118) 9 (5.25, 15) 20 (4, 61) 12 (0, 36) 26 (12, 56)
36 (24, 46) 8 (2, 14) 76 (48, 92) 6 (3, 9) 12 (4, 44) 0 (0, 24) 16 (8, 28)
0.003 0.134 0.004 0.028 0.272 0.858 0.025
Abbreviations: DBL, diagnostic blood loss; IQR, inter-quartile range. The DBL volume was calculated based on 4-week hospitalization.
burn no longer had impact on the units of RBC transfusion when adjusted for other variates. The concerning of multicollinearity was testified as well, which was proved to be nonsignificant.
4.
Discussion
4.1.
Major findings
Several studies reported correlation between the blood loss from diagnostic tests and the development of HAA in disparate
patient cohort [8,11,19]. However, no literature is available with regard to this issue in severely burned patients. Thus, to our knowledge, the current work is the first to directly evaluate connections between the DBL volume and incidence of HAA in patients following extensive burns. As reported, we observed that merely a fraction of patients developed anemia at the time of admission, while many of them became anemic during the fourth week of hospitalization, indicating a prevalence of HAA in severely burned patients. We found that patients with moderate to severe HAA during the fourth week postburn had remarkably higher DBL volume due to phlebotomy events compared to patients
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Table 4 – Predictors of moderate to severe hospital acquired anemia during week 4 postburn. Univariate analyses
Variable
a
DBL per day DBL totala Age Male TBSA burn III TBSA burn Inhalation injury Tracheostomy No. of operations Coagulopathy
a
OR
95%CI
1.16 1.00 1.00 0.68 1.04 1.01 0.95 1.60 0.95 0.90
1.05, 1.28 1.00, 1.01 0.97, 1.03 0.29, 1.57 1.02, 1.06 1.00, 1.03 0.67, 1.36 0.72, 3.55 0.73, 1.23 0.43, 1.88
Multivariate analyses P value
OR
95%CI
P value
0.002 0.01 0.93 0.36 0.001 0.05 0.79 0.25 0.69 0.77
1.49 0.99
1.09, 2.05 0.98,1.00
0.01 0.06
1.04 1.00
1.01, 1.08 0.98, 1.02
0.02 0.62
Abbreviations: DBL, diagnostic blood loss; TBSA, total body surface area. Bold numbers were statistically significant (P < 0.05). The inclusion criteria was 0.1 and the exclusion criteria was 0.1. The DBL volume was calculated based on 4-week hospitalization.
Fig. 3 – The DBL volume per day between survival and non-survival patients. The line graph displayed the mean DBL volume from phlebotomy events each day between survival and non-survival patients during 28 hospitalization days. Survival patients had higher DBL volume per day compared to patients who died.
who did not develop moderate to severe HAA. Indeed, our study revealed that the DBL volume from phlebotomy per day could be a predictor of the occurrence of moderate to severe HAA during week 4, suggesting the DBL volume per day appeared to be an independent risk factor of moderate to severe HAA. Meanwhile, patients with large burn size were more likely developed moderate to severe HAA. In addition, we had identified that number of operations, TBSA burn full thickness, ICU-LOS, and hospital-LOS were independently associated with the increased volume of blood transfusion.
4.2.
Interpretations
Intriguingly, we found that patients with larger TBSA burn were inclined to develop HAA in the present observation. Such
phenomenon could attribute to the hemoconcentration status that severely burned patients possessed. Initial phase of severe burns is always accompanied with a great amount of fluid exudation, which subsequently leads to highly concentrated blood. Given that, patients with large burn size clearly lose more blood cells per mL from diagnostic blood tests when compared to patients in normal Hb level. Although, total DBL volume and DBL volume per day within 4 weeks were found to be of statistical significance on univariate analysis, only DBL volume per day was independently associated with the occurrence of HAA after the performance of multivariate analysis. We assumed this discrepancy might be mainly due to the disparate LOS among all enrolled patients, which could be an important confounding factor. Obviously, patients with longer LOS were inclined to have more laboratory tests and
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Table 5 – Predictors of RBC transfusion in all survivors. Univariate analyses
Variable Coefficient a
DBL total Age Male TBSA burn III TBSA burn Inhalation injury Tracheostomy Hb during admission No. of operations ICU length of stay Hospital length of stay Coagulopathy (acute) (late)
a
0.08 0.07 7.95 0.80 0.79 6.82 24.12 0.04 4.17 0.73 0.13 10.59 8.57
Multivariate analyses
SE
P value
0.009 0.21 5.73 0.12 0.08 2.40 4.81 0.08 0.50 0.07 0.04 6.47 6.17
<0.001 0.73 0.17 <0.001 <0.001 0.005 <0.001 0.59 <0.001 <0.001 0.001 0.10 0.17
Coefficient
SE
P value
0.02
0.01
0.12
0.003 0.38 1.52 3.19
0.13 0.11 2.30 4.86
0.98 0.001 0.51 0.51
2.06 0.38 0.09
0.65 0.12 0.03
0.002 0.002 0.006
Abbreviations: SE, standard error; DBL, diagnostic blood loss; TBSA, total body surface area; ICU, intensive care unit. Bold numbers were statistically significant (P < 0.05). The inclusion criteria was 0.1 and the exclusion criteria was 0.1. The DBL volume was calculated based on 90-day hospitalization.
DBL volume than others. Given that, by removing the potential influence of LOS, DBL volume per day seems to be independently correlated to the development of HAA. In this study, we identified that full thickness TBSA burn and number of operations were significantly associated with increased number of RBC transfusion. Notably, patients who had frequently undergone operations, such as escharectomy and grafting, resulted in massive surgical blood loss, implying an increased demand of blood transfusion than others. However, total DBL volume during hospitalization were significant on univariate analysis, while lost the significance in adjusted multivariate regression model. We do not have a conclusive interpretation towards this finding, it is possible that phlebotomy events might be overlapped with operative events.
4.3.
Relation to previous works
Previous studies focused on relevant topic have consistently reported the marked correlation between blood loss from diagnostic tests and Hb alteration. Thavendiranathan and his colleagues noticed a decrease of 0.07 g/L in Hb level for every 1 mL DBL volume [8]. This study was conducted in the cohort of general internal medicine inpatients, while a recently published work identified DBL as a strong predictor of the Hb alteration in patients with myasthenia gravis (MG) exacerbation [19]. Both aforementioned single-institution investigations failed to testify the direct link between phlebotomy event and the occurrence of HAA, which obviously lacked profound clinical implication. The study conducted by Salisbury was the first to directly assess the association between DBL and HAA among patients with acute myocardial infarction [11]. By classifying patients into two groups, they found the mean blood loss from phlebotomy was almost 100 mL higher during hospitalization among patients who developed moderate to severe HAA compared with those without HAA. Particularly, large DBL was relatively common in patients with moderate to severe HAA. The multicenter research with large sample size initially documented DBL as an independent risk factor of the
development of HAA [11]. In agreement with those findings, our results revealed the trend that severely burned patients with frequent blood tests per day were more inclined to become anemic during hospitalization.
4.4.
Clinical implications
HAA is a critical issue which is demonstrated to directly link to prolonged hospital-LOS and increased mortality [20]. Salisbury and his colleagues noted a positive correlation between inhospital mortality and severity of HAA, especially among those who developed moderate to severe HAA [21]. Likewise, recent studies showed that severe HAA was obviously related to adverse post-discharge outcomes for medical inpatients [1]. Accumulating evidences have implicated the detrimental role of HAA in the pathogenesis of poor prognosis. In the current study, we identified that blood loss from diagnostic tests could be a modifiable yet rationale target for preventing HAA. Of note, only a minimal volume of blood is needed to run the test with the same accuracy, indicating the use of pediatric tubes might be a promising strategy [11,22]. Indeed, it was found a remarkable decline of the DBL volume from phlebotomy by using pediatric-size tubes [11]. Similarly, physicians were reported to constantly neglect the routine check of blood order for inpatients, resulting in patients undergoing more tests than necessary. Therefore, the frequency of diagnostic blood test should be reduced as well, which can be accomplished by rigorous observation of patients’ status in clinical practice. Additionally, informing both physicians and nurses the latent risk of over ordering diagnostic test is a feasible way in all institutions [8,23]. Although blood transfusion serves as the primary intervention in the treatment of HAA, it simultaneously brings about many adverse effects, such as infection, anaphylactic and hemolytic transfusion reactions, transfusion related acute lung injury, and transfusion associated circulatory overload [24]. Consistent with our prior work, we found that the number of operations was an independent risk factor of increased units of RBC transfusion, suggesting that surgical blood loss was
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responsible for the consecutive requirement of blood transfusion [17]. If we measured the relative impact of variables which was of statistical significance by adjusted regression coefficient, number of operations had highest impact among other risk factors, with every time of operation, approximately 2 more units of blood were transfused. Accordingly, it suggests that blood conservation sampling devices can be used to reduce operation-associated blood loss, which can significantly decrease the occurrence of HAA and requirements of RBC transfusion [25,26]. Furthermore, a more restrictive threshold of transfusion for critically ill patients can be beneficial. We assume that the outcome of this study might apply to border population other than severely burned patients. Critically ill patients share some common features and more susceptible to phlebotomy events. Therefore, randomized clinical trial (RCT) or prospective cohorts are required to uncover the causal relationship between excessive DBL and development of HAA. It may reveal a new approach to prevent the occurrence of HAA and improve clinical prognosis by minimizing unnecessary diagnostic blood tests.
4.5.
Limitations
Several limitations should be taken into consideration when interpreting our findings. Firstly, given the retrospective nature and single-center design of the current study, it is challenging to draw the conclusion that blood loss from overordered diagnostic tests directly leads to HAA. The possibility of a reverse causal-relationship that HAA drives diagnostic tests should be taken into account as well. However, our data showed a subsequent decline of the DBL volume per day after the initial peak of phlebotomy event, which partially excluded this hypothesis. As such, prospective cohort studies or multicenter RCTs are needed to testify this causal relationship in the future studies. Secondly, the sample size of this work was relatively small. Without performing selective enrollment, we incorporated all patients who had matched the pre-assigned inclusion criteria during the study period from 2005 to 2017. That being said, the data of included patients was superior in quality, and was sufficient for the establishment of our regression model. Thirdly, the estimated DBL volume used in the present observation was based on several consumptions, including no blood waste in the process of phlebotomy performance, and each blood draw being close to the preassigned volume of a particular type of blood tube. Thus, the estimation was conservative, which was stand for the lowest volume of DBL possible in clinical practice. Clearly, our findings were unlikely to exaggerate the impact of the DBL volume on the development of HAA. Fourthly, pathophysiological status, especially increased microvascular permeability postburn might alter and exaggerate the Hb level at admission. Disparate transfer time and timing of blood draw unable us to standardize Hb level after initial burn injury. Given that, we applied Hb level within 48 h after admission to avoid the effect came from increased microvascular permeability as much as possible. Finally, other confounders, such as the use of medications, underlying diseases, and intricate complications were not regarded as variates, which might have potential effect in altering red cell homeostasis. We believed this effect was trivial and will not reverse our results.
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Other factors, including postburn proinflammatory state, bone marrow dysfunction and nutritional deficiencies were unable to measure in retrospective design, which required further attention in prospective studies.
5.
Conclusions
In conclusion, we find that HAA appears to be of frequent occurrence among patients with severe burn injury. It has been demonstrated that the DBL volume from phlebotomy events is an independent risk factor of the development of HAA. The current study highlights the clinical significance of optimizing both quantity and frequency of diagnostic blood tests in the prevention of HAA in the setting of major burns. The direct correlation between DBL and poor prognosis among these particular populations requires further exploration.
Funding sources This work was supported by grants from the National Natural Science Foundation of China (Nos. 81801937, 81842025), the Key Project of Military Medical Innovation Program (No. 18CXZ026), and the Shanghai Sailing Program (No. 18YFC1422900).
Conflicts of interest The authors have declared that no conflicts of interest exist.
Authors’ contributions ZFX and YMY co-conceived the study. RQY, GSW, LX, BM, JL, LS, and HST participated in material collection. RQY, GSW, and LX wrote and edited the manuscript. RQY undertook the statistical analyses. All authors read and approved the final manuscript.
Acknowledgment Not applicable. REFERENCES
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