Citation for published version (APA): Nijboer, J. M. M. (2009). New insights in outcome after major trauma Groningen: s.n.

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1 University of Groningen New insights in outcome after major trauma Nijboer, Johanna Maria Margaretha IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2009 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Nijboer, J. M. M. (2009). New insights in outcome after major trauma Groningen: s.n. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date:

2 RETICULOCYTE COUNTS AND THEIR RELATION TO HEMOGLOBIN LEVELS IN TRAUMA PATIENTS 8 Marie-Louise Otterman Johanna M.M. Nijboer Iwan C.C. van der Horst Matijs van Meurs Hendrik-Jan ten Duis Maarten W.N. Nijsten J Trauma. 2009;67(1):121-4.

3 ABSTRACT Background Increased production of red blood cells (RBCs) should be reflected by increased reticulocyte counts (RC). With the introduction of modern fully automated measurements of RC, the recovery of hemoglobin (Hb) after blood loss might be assessed earlier. We investigated the temporal relation of Hb and RC in trauma patients. Methods Over a 10-month period, all patients with trauma admitted to our University Medical Center were analyzed. Both Hb (reference values: males, g/dl; females, g/dl) and RC (8 26 promille) were determined with a Sysmex XE-2100 analyzer. RBC transfusions were administered in otherwise healthy patients below an Hb threshold of 6.9 g/dl. Hb and RC were analyzed for a maximum of 30 days post-trauma and related in multivariate analysis to age, sex, and co-morbidity. 96 Results Two hundred and forty-one patients (age 52 ± 21 years) were studied. In 28 patients (12%), one or more RBCs were administered with a mean of 2.2 RBCs (range, 1 4). Hb decreased to 10.9 g/dl ± 2.1 g/dl on day 3. RC rose from 16 ± 11 at admission to 38 ± 21 promille on day 13 (p < ). Nadir Hb values and maximum RC values were inversely related according to univariate analysis (Pearson R = -0.62, p < 0.001). In multivariate analysis, Hb remained the only significant determinant of RC (R = 0.64, p < 0.001). Conclusions Hb and RC are clearly related in trauma patients. Measuring RC may be helpful in predicting the rise of Hb after acute blood loss.

4 INTRODUCTION Trauma-related blood loss is a major cause of anemia. The return of hemoglobin (Hb) to normal levels is affected by several factors, such as age, underlying diseases, and persisting inflammation. Increased production of red blood cells (RBCs) is reflected by increased reticulocyte counts (RC). Within a few days after acute blood loss, the RC will increase, later followed by a slower and less pronounced rise of Hb 1. For many years, determining RC was not trivial because the reticulocytes had to be counted manually 2. The procedure was time-intensive and often less accurate because of the interobserver variability between the analysts 3. With the introduction of advanced analyzers, measurement of the RC has become easier, cheaper, and more reliable 4. Although the additional information provided by the RC might be useful in predicting the recovery of Hb, the value of the modern RC measurement in assessing recovery of Hb after blood loss has not been investigated. We assessed the impact of decreased Hb on RC in trauma patients by evaluating time-dependent changes in Hb and RC, the relation between Hb and RC, and their relation with other factors. PATIENTS AND METHODS In a retrospective descriptive study covering a 10-month period, all patients admitted to the adult traumatology ward of the University Medical Center Groningen were analyzed. The reason of admission was (any kind of) diagnosis related to acute trauma. Previous admission to the intensive care unit (ICU) before transfer to the traumatology ward was separately recorded. Patients admitted for other pathology than trauma were excluded. As recovery of Hb to normal levels can be adversely affected by underlying diseases, we categorized the following co-morbidities: coronary artery disease, atrial fibrillation, diabetes mellitus, chronic renal failure, chronic obstructive pulmonary disease, central nervous disease, liver disease including alcohol abuse, cancer, inflammatory bowel disease, arthritis, transplantation, and hematological disease. Patients were classified according to admission type: urgent with an operation, urgent without an operation, not urgent with an operation, and not urgent without an operation. Outcome and discharge destination were recorded. Chapter 8 Reticulocytes and hemoglobin 97 When a routine Hb measurement (reference values: males, g/dl; females, g/dl) was considered necessary by the treating physicians, a RC was also performed in the same sample. Both Hb and RC (8 26 promille in both males and females) were determined in 3 ml ethylenediamine tetra-acetic acid-anticoagulated vacuum blood tubes in the central laboratory with a Sysmex XE-2100 analyzer. As the production of reticulocytes was not expected to change very rapidly, no more than

5 three RC measurements were performed per week in the case of more frequent Hb measurements. All Hb and RC values until discharge with a maximum of 30 days after admission to the traumatology ward were recorded. We chose this arbitrary limit because the median duration of hospital admission of trauma patients was two weeks, and the known time of maximal reticulocytosis usually falls within the first three weeks. To minimize bias of patients with frequent Hb or RC measurements compared with patients with infrequent measurements in the analysis of time-dependent changes the Hb and RC, values for individual patients were linearly interpolated to daily values before further analysis. The maximal period that was interpolated in this manner was four days. The relation between Hb and RC was analyzed in univariate linear regression analysis. In multivariate linear regression analysis, RC was related to Hb, age, sex, the presence of co-morbidity, and previous ICU-stay. 98 RBC transfusions were administered according to widely accepted restrictive transfusion guidelines 5 with a threshold of 6.9 g/dl in previously healthy patients and higher thresholds in patients who, for example, had active coronary artery disease. All RBCs administered during the first 30 days were recorded and related to the Hb level at time of the transfusion. Results are presented as mean ± SD unless otherwise specified. Statistical tests were performed on noninterpolated and interpolated values and only considered significant when this was the case for both. Means were compared with Students t test. Statistical analyses were performed using the SPSS version 15.0 for Windows. RESULTS In total, 241 patients with a mean age of 52 ± 21 years were studied. The general characteristics of these patients are shown in Table 1. Thirty (12%) patients were treated at the ICU for a mean of 12 ± 15 days before transfer to the traumatology ward. Mean length of stay at the traumatology department was 15 ± 15 days (range, 1 110). A majority of patients (59%) were admitted for urgent surgery, and in total 75% of the patients underwent an operation. In nearly half of the patients (44%, N = 107), important co-morbidity was present (Table 2). A total of 1,053 Hb and 635 RC values were analyzed. The lowest Hb value was 5.8 g/ dl and the highest RC was 121 promille. Hb decreased from a mean of 12.2 ± 2.4 g/dl (males, 12.6 ± 2.6 g/dl; females, 11.8 ± 2.1 g/dl) at admission to 10.9 ± 2.1 g/dl on day 3, with a slower decrease afterward (Figure 1A). The RC value was 16 ± 11 promille at admission, which is within the normal range. RC rose to 28 ± 18 promille on day 6 (p = 0.007) and to 38 ± 21 promille on day 13 (p = ; Figure 1B). The mean max RC was 25 ± 19 promille (range, promille). The highest RC of 121 promille was measured in a 19-year-old female without significant co-morbidity. RC values did not

6 Table 1. Baseline demographic and clinical characteristics Number of included patients 241 N (%) Gender (male) 144 (60) Age (years, mean ± SD) 52 ± 21 Relevant co-morbidity 107 (44) Operation performed 181 (75) Way of admission After urgent operation 141 (59) Urgent without operation 56 (23) For non-urgent operation 40 (17) Non-urgent without operation 4 (2) Patients who received RBC 28 (12) Location before admission to ward Emergency department 132 (55) Via intensive care 30 (12) Other 79 (33) Hospital mortality 2 (1) Chapter 8 Reticulocytes and hemoglobin 99 Figure 1. Time course of mean ± SD Hb (A) and RC (B). After the development of anemia (Hb < 12.1 g/dl and < 14.0 g/dl, respectively, in women and men), reticulocytosis (> 26 promille) developed after 6 days.

7 Table 2. Presence of co-morbidity in the 241 patients studied N (%) Coronary artery disease 36 (15) Diabetes mellitus 29 (12) Liver disease 24 (10) Atrial fibrillation 25 (10) Chronic obstructive pulmonary disease 18 (7) Haematological disease 13 (5) Chronic renal failure 7 (3) Central nervous disease 7 (3) Inflammatory bowel disease, arthritis 6 (3) Cancer 6 (3) Transplant 3 (1) differ between males and females. Seventy-eight (32%) patients developed a RC above the normal range. 100 In 28 patients (12%), one or more RBCs were administered. These patients received a mean of 2.2 RBCs (range, 1 4) during the 30-day study period. The mean Hb at time of transfusion was 8.1 ± 1.3 g/dl (range, ). The majority of these 28 patients (93%) received the RBCs peri-operatively, mainly after urgent admission and surgery. Of the patients who received RBCs, ten had a history of pre-existing cardiac disease and another patient had chronic renal failure. The mean Hb at the time of transfusion for these 11 patients was 8.9 ± 1.8 g/dl (range, g/dl). The mean threshold Hb for transfusion in the other 17 patients was 7.4 ± 1.3 g/dl (range, g/dl). None of the patients received erythropoietin. Hb values and maximum RC values were inversely related in univariate analysis (Pearson R = -0.62, p < 0.001, Figure 2). Likewise, multivariate linear regression analysis with maximal RC as dependent variable and the following independent variables: type of admission, minimal Hb, age, sex, the presence of co-morbidity, RBC transfusion, and previous admission on the ICU showed that only Hb was a significant independent determinant for RC (Pearson R = 0.64).

8 Figure 2. Relation between minimal Hb and maximal RC in 241 patients. Males are denoted by squares and females by filled circles. Note that males have a normal Hb range of 14.0 to 17.1 g/ dl and females of 12.1 to 15.9 g/dl. DISCUSSION Our results show that in agreement with the expected physiologic response to acute anemia there is a strong relationship between minimal Hb and maximum RC in trauma patients. This relation was observed irrespective of co-morbidity, age, or sex. As direct precursors of erythrocytes, reticulocytes are detectable in the circulation in numbers that amount to a few percent of the total number of erythrocytes (8 26 per 1,000). When an otherwise healthy person develops anemia after blood loss a decrease in tissue oxygenation will result in enhanced erythropoietin expression that will stimulate the bone marrow to increase production of RBCs. Evolved progenitors enter the bloodstream as reticulocytes. After a few days, these reticulocytes evolve into erythrocytes. In acute anemia, the transit time from proerythroblast to the emergence of the reticulocyte into the circulation can be as short as one to two days, compared with the usual approximately five days 1,2. This is underscored by the rise of the RC we observed (Figure 1B). Because of the low threshold and the few transfusions in our cohort, Figure 1A shows the natural course of Hb and RC. In our patients, mean RC was above the normal range after six days and stayed elevated for remainder of the observation period. Also as expected, patients with anemia displayed stronger increases in RC, with levels up to four times the normal upper range. Figure 2 shows this inverse relation between Hb and RC, with the most pronounced increase in RC occurring in patients with the lowest Hb. Chapter 8 Reticulocytes and hemoglobin 101

9 102 Very few of our patients had RC that were below normal range. This implies that our patients were generally healthy or had chronic diseases that do not suppress the marrow. Figure 2 does suggest that some patients had an inappropriately low RC in relation with their low Hb. However, these patients did not differ in relevant co-morbidity or sex from the group with a physiologic response to anemia. This may be related to bone marrow dysfunction that is seen in trauma patients or patients with burns. Erythropoietin production after trauma is well preserved, but the bone marrow may fail to respond to erythropoietin 6,7. As erythropoietin levels may be appropriate while the marrow s response is inappropriate, determining the RC may be more useful than measuring erythropoeitin to forecast the recovery of Hb. The role of the RC has only been investigated in a few studies on trauma patients. In a study that assessed the effectiveness of the administration of erythropoeitin, only a peak in RC was observed at day 22, paralleling the increase in Hb, but the time course of RC was not otherwise specified 8. Whether a particular patient needs to be transfused can be a difficult decision and depends on many factors. The main clinical value of RC might lie in supporting transfusion decisions. Currently, in our traumatology ward this decision is based on the restrictive transfusion guidelines with a threshold of 6.9 g/dl. A major reason to adhere to restrictive transfusion guidelines is the favorable effect on outcome 5,9,10. It may be hypothesized that in patients with an Hb near the transfusion threshold but with a strongly elevated RC a transfusion might be (temporally) withheld to await the spontaneous rise in Hb. Future prospective research will have to determine whether RC can actually play such a role. Our study has a number of relevant limitations. The design was retrospective because no specific interventions were intended in this observational study. Measurement of erythropoietin levels could have been of interest, although as pointed out above, current evidence suggests that RC would display a stronger relationship with erythropoiesis than erythropoietin. Likewise, we did not qualify systemic inflammation in patients (e.g., with C-reactive protein), as inflammation depresses erythropoiesis. Unfortunately, C-reactive protein was not available. In summary, a strong relationship between Hb and reticulocytes in trauma patients may make measurement of reticulocytes clinically useful in predicting the recovery of Hb levels.

10 REFERENCES 1. Guyton AC, Hall JE. Red blood cells, anemia, and polycythemia. In: Guyton AC, Hall JE, eds. Textbook of Medical Physiology. Philadelphia, PA: W.B. Saunders Company; 2000: Castle WB. The conquest of pernicious anemia. In: Wintrobe MM, ed. Blood Pure and Eloquent. New York, NY: McGraw-Hill Education; Peebles DA, Hochberg A, Clarke TD, et al. Analysis of manual reticulocyte counting. Am J Clin Pathol. 1981;76: Peng L, Yang H, Jiang H, Su J, Peng Z. Automated reticulocyte counting using the Sysmex RAM-1. Clin Lab Haematol. 2001;23: Hébert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med. 1999;340: Livingston DH, Anjaria D, Wu J, et al. Bone marrow failure following severe injury in humans. Ann Surg. 2003;238: Deitch EA, Sittig KM. A serial study of the erythropoietic response to thermal injury. Ann Surg. 1993;217: Corwin HL, Gettinger A, Fabian TC, et al. Efficacy and safety of epoetin alfa in critically ill patients. N Engl J Med. 2007;357: Silverboard H, Aisiku I, Martin GS, Adams M, Rozycki G, Moss M. The role of acute blood transfusion in the development of acute respiratory distress syndrome in patients with severe trauma. J Trauma. 2005;59: Yepes D, Gil B. Anemia management program reduces transfusion volumes, incidence of ventilator-associated pneumonia, and cost in trauma patients. J Trauma. 2007;62:1065. Chapter 8 Reticulocytes and hemoglobin 103

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