Abstract
OBJECTIVE:
To evaluate the incidence of injury-associated anemia and functional iron deficiency after operative fracture care.
METHODS.
Design: Prospective cohort study.
Setting: Level 1, academic trauma center.
Patient Selection Criteria: All patients with operative fracture who presented between April 2022 and August 2023 were screened.
Outcome Measure and Comparisons: Laboratory tests for anemia were performed on postoperative day 1 including complete blood count, serum iron, total iron binding capacity, percent transferrin saturation, transferrin, and ferritin levels. Values were enumerated to capture the previously unknown incidence of injury-associated anemia.
RESULTS:
In total, 844 patients were screened after operative fracture management [mean: 52 years (SD 22), 58% men]. Injury-associated anemia was present in 94.7% (median hemoglobin: 10.0 [IQR: 8.5–11.1]) of the 844 eligible patients; 72.5% of patients with anemia did not reach transfusion requirements (hgb <7.0). Only 33% (270/800) received an ICD-10 diagnosis code for anemia during the hospital admission. Functional iron deficiency was present in 80.9% of eligible patients, while 94.5% demonstrated derangements in body iron stores. Ferritin levels were measured at levels less than 50 ng/mL in 89.8% of patients overall and 96.9% in patients with all other iron studies low. Patients with fractures in multiple extremities demonstrated 52% higher odds of elevated ferritin levels than patients with isolated fractures after controlling for transfusions and sex (adjusted OR 1.52, 95% CI, 1.06–2.17, P = 0.02).
CONCLUSIONS:
The incidence of injury-associated anemia and functional iron deficiency was common after operative orthopaedic trauma. Ferritin was more likely to be normal or high even when all other iron values were low, indicating that iron may become sequestered and unavailable for replenishing blood cell volume. Improving documentation of perioperative anemia after trauma and directing future research to counteract both anemia and functional iron deficiency may benefit most patients with orthopaedic trauma.
Keywords: anemia, iron deficiency, fracture
INTRODUCTION
Acute blood loss in orthopaedic trauma combined with perioperative blood loss during operative fracture care has widespread consequences for patients sustaining operative orthopaedic injuries. The resulting persistent anemia combined with the postinjury inflammatory state is best referred to as “injury-associated anemia.”1–4 Injury-associated anemia begins with the loss of circulating red blood cell volume from an injury, but additionally considers the fallout: a persistent anemic state, paired with prolonged but not permanent inflammation,2,5 lasting months after injury and initial resuscitation.3,4,6–9 This distinct clinical entity exists between “acute blood loss anemia” that best describes isolated hemorrhage,10 and “anemia of chronic disease” that describes a permanent disease state that is not alleviated by therapy or time. “Injury-associated anemia” is instead an all-encompassing diagnosis focusing on the consequences of blood loss related to trauma and inflammation.2,3
The consequences of injury-associated anemia are broad with well-defined underlying pathophysiology but limited research in the clinical setting. Acute blood loss, trauma, fractures, and surgery incite a clinical scenario of increased systemic inflammatory response and increased erythropoiesis requirement. These factors mechanistically contribute to functional iron deficiency whereby there is a relative insufficiency of iron available to meet the increased demand despite normal iron stores in bone marrow macrophages.7–9,11,12 Studies suggest inflammatory responses play a negative role in erythropoiesis.6 Anemia is associated with fatigue, impaired physical performance, decreased exercise capacity, and mood disturbances such as depression and anxiety that negatively affect quality of life13–16 and physical recovery in patients with orthopaedic trauma.14,17 Iron deficiency without clinical anemia has been shown to also have negative consequences, including chronic fatigue.9 Because the historic allogenic blood transfusion threshold was lowered from 10 to 7 g/dL, fewer patients experienced transfusion reactions but more patients began recovery in a profound anemic state.18–20 Despite the significant impact of anemia, there has been little literature describing the incidence and magnitude of persistent, injury-associated anemia in the orthopaedic trauma population.
Existing literature on perioperative anemia within the orthopaedic trauma realm is focused on geriatric hip fractures, which can give us some reference point but is not generalizable to all patients with fracture. Preoperative anemia has been observed as up to 50% in this population21,22 and up to 87% postoperatively.22 However, fragility fractures resulting from low-energy mechanisms are a different entity entirely from high-energy traumatic injuries that disproportionally affect patients in the first 5 decades of life; traumatic injury is the leading cause of death less than the age of 45 years.23,24 Therefore, hip fracture data are of limited generalizability to the larger patients population with orthopaedic trauma but suggests that patients involved in higher energy trauma are at even greater risk of injury-associated anemia.
The aim of this study was to quantify the incidence of perioperative anemia and iron derangements in patients with orthopaedic trauma after operative fracture care. The authors performed a prospective screening cohort, investigating postoperative laboratory tests to identify the incidence of patients who would leave the hospital and begin recovery in an anemic state. This was a foundational first step before consideration of interventions in this specific population, and would produce critical information on the scope of injury-associated anemia. The authors hypothesized that anemia is widespread and traumatic injury induces derangements in body iron stores consistent with functional iron deficiency, which may contribute to impaired anemia resolution in the acute postoperative period after orthopaedic fracture care.
METHODS
All patients admitted to Oregon Health & Science University (OHSU), a level 1 academic trauma center, after traumatic injury requiring operative fracture management were prospectively evaluated in this observational study between April 2022 and August 2023. The study was approved by the institutional review board at OHSU and is reported using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.25 This work is intended to capture the state of patients with orthopaedic trauma immediately after fracture surgery to report on the incidence of patients initiating recovery in an anemic state.
Patient demographics, injury and surgical details, and blood product transfusions from admission to postoperative day 1 (POD1) were included in analysis. Given the wide variety in the length of stay of these patients, subsequent laboratory tests were not reviewed for uniformity, using POD1 as the window of observation. Injuries were classified by location (shoulder, humerus/elbow, forearm/wrist, hand, pelvis/acetabulum, femur/knee, leg/ankle, foot) or as orthopaedic polytraumas defined by fractures in more than 1 extremity. Postoperative complete blood count (CBC) and iron studies comprising serum iron, total iron binding capacity (TIBC), percentage transferrin saturation (TSAT), transferrin, and ferritin levels were recorded. CBC and iron studies were collected on POD1 per department protocol instituted April 2022. Institutional reference ranges were used to interpret laboratory values as low, normal, or high with anemia defined as hemoglobin <13.5 g/dL in men and <12 g/dL in women. This study was observational in nature and therefore did not alter patient care. In particular, this research carried no influence on clinical decisions involving fluid resuscitation nor blood transfusion. The blood transfusion threshold at the authors’ institution is based on hemoglobin laboratories: <7.0 g/dL or clinically significant blood loss at the discretion of the primary clinician. Functional iron deficiency was defined as serum ferritin ≥30 ng/mL and a TSAT <20%, while absolute iron deficiency was defined as a serum ferritin <30 ng/mL regardless of TSAT.26 Hospital encounter records for all patients were assessed for association of an anemia diagnosis code (ICD10 D50—D64.9) assigned by any clinician during the encounter. All patients with laboratory studies collected were included for review, including those in whom values could not be calculated by the laboratory. Only patients without complete blood count or iron studies collected were excluded from review.
Statistical Analysis
Descriptive statistics were used to summarize demographic data, injury characteristics, and laboratory values. Means and SDs were used for continuous variables and frequencies with proportions for categorical variables. Pearson chi-squared tests were used to compare categorical variables. Multivariable logistic regression models estimated the association between multiple fractures and elevated ferritin level as well as functional iron deficiency when controlling for transfusions and sex. Transfusion was selected for its confounding relationship between more severe injury and direct effect on circulating blood levels. Sex is known to be associated with circulating blood volume, injury severity, and ferritin levels and consequently was controlled for. All statistical analyses were performed using R version 4.2.2 (Vienna, Austria) and the packages gtsummary and ggplot2.27
RESULTS
A total of 961 patients received orthopaedic fracture care during the study period. Of them, 844 patients were included for review; 117 patients did not have a complete blood count or iron panel collected on POD1 for analysis and were, therefore, excluded. Table 1 details patient, injury, and transfusion characteristics. Owing to rare laboratory processing errors, 2 platelet counts, 12 TSAT, and 1 transferrin value were unable to be calculated; the remainder of these patients’ laboratories were included.
TABLE 1.
Patient Characteristics
| Characteristic | N = 844 |
|---|---|
| Age (y), mean (SD) | 52 (22) |
| Male, n (%) | 490 (58) |
| Fracture category, n (%) | |
| Shoulder | 7 (0.8) |
| Humerus/elbow | 30 (3.6) |
| Forearm/wrist | 32 (3.8) |
| Hand | 1 (0.1) |
| Pelvis/acetabulum | 91 (11) |
| Femur/knee | 290 (34) |
| Leg/ankle | 175 (21) |
| Foot | 13 (1.5) |
| Polytrauma | 205 (24) |
| Gustilo-Anderson, n (%) | |
| Closed | 622 (74) |
| Type I open | 48 (5.7) |
| Type II open | 82 (9.7) |
| Type III open | 92 (11) |
| Timing of transfusions, n (%) | |
| No transfusions | 623 (74) |
| Between trauma through postoperative day 1 | 197 (23) |
| Postoperative day 1 only | 24 (2.8) |
| Received transfusion, n (%) | 221 (26) |
| Lower extremity fracture, n (%) | 556 (66) |
| Pelvis and acetabulum fractures, n (%) | 91 (11) |
| Pelvis, acetabulum, femur, and tibia fractures, n (%) | 761 (90) |
In total, 94.7% (799/844) of patients met criteria for postoperative anemia (hemoglobin <13.5 g/dL in men and <12 g/dL in women), of which 24.4% (195/800) required transfusion of blood products between presentation to the hospital and the day of surgery. An additional 24 patients received a transfusion on POD1 (Table 2). One patient received blood product transfusion and subsequently was found to have a hemoglobin within normal range on POD1 laboratory analysis. Therefore, 72.5% (580/800) of patients with anemia did not reach the transfusion threshold. Only 33% (270/800) received an anemia diagnosis code associated with their hospital encounter despite meeting diagnostic criteria of anemia.
TABLE 2.
Institutional Laboratory Reference Ranges, Median Laboratory Values, and Laboratory Value Category Frequency Between Patients Who Did Not Require Blood Product Transfusion (NT) and Those Who Did Require Transfusion (T) Between Admission and Postoperative Day 1
| Hemoglobin | Hematocrit | Platelet Count | Serum Iron | Total Iron Binding Capacity | Transferrin Saturation | Transferrin | Ferritin | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Reference Range (unit) | M 13.5–17.5 F 12.0–16.0 (g/dL) | M 41.0–53.0 F 36.0–46.0 (%) | 150–400 (K/mm3) | M 50–170 F 30–160 (μg/dL) |
240–450 (μg/dL) | 20–50 (%) | 200–400 (mg/dL) | 51–200 (ng/mL) | ||||||||
| NT n = 623 | T n = 221 | NT n = 623 | T n = 221 | NT n = 622* | T n = 220* | NT n = 623 | T n = 221 | NT n = 623 | T n = 221 | NT n 617* | T n = 215* | NT n = 623 | T n = 220* | NT n = 623 | T n = 221 | |
| Median (IQR) | 10.5 (9.3, 11.6) | 8.3 (7.5, 9.2) | 31.3 (27.8, 34.3) | 24.9 (22.5, 27.4) | 196 (155, 243) | 152 (111, 220) | 28 (20, 41) | 25 (17, 38) | 263 (231, 299) | 216 (186, 253) | 11 (8, 16) | 12 (8, 18) | 188 (165, 214) | 154 (133, 181) | 137 (83, 224) | 223 (115, 462) |
| Low (%) | 93.1 | 99.5 | 95.0 | 99.5 | 20.7 | 48.2 | 73.2 | 74.7 | 32.1 | 68.3 | 88.2 | 79.5 | 62.1 | 87.7 | 11.4 | 6.8 |
| Normal (%) | 6.9 | 0.5 | 5.0 | 0.5 | 76.7 | 47.3 | 26.6 | 24.4 | 67.7 | 31.7 | 11.5 | 16.7 | 37.9 | 12.3 | 58.1 | 40.7 |
| High (%) | 0.0 | 0.0 | 0.0 | 0.0 | 2.6 | 4.5 | 0.2 | 0.9 | 0.2 | 0.0 | 0.3 | 3.7 | 0.0 | 0.0 | 30.5 | 52.5 |
| P | <0.001 | <0.001 | <0.0001 | 0.23 | <0.0001 | <0.001 | <0.0001 | <0.0001 | ||||||||
IQR, interquartile range; 2 platelet, 12 transferrin saturation, and 1 transferrin values were unable to be calculated by the laboratory.
Functional iron deficiency was evident in 80.9% (683/844) of patients, while 3.3% (28/844) met criteria for absolute iron deficiency. In total, 30.1% (254/844) of patients demonstrated abnormal low values in all 4 measures of iron body stores (iron, TIBC, TSAT, and transferrin values). In contrast, ferritin level was measured at levels less than 50 ng/mL in 89.8% (758/844) of patients overall and in 96.9% (246/254) of patients with all other iron studies low. Most patients with an elevated ferritin based on institutional norms (>200 ng/mL) were classified as pelvis/acetabulum, lower extremity, or orthopaedic polytraumas (286/306; 93.5%). In total, 50.2% (103/205) of patients categorized as orthopaedic polytraumas demonstrated an elevated ferritin (Table 3). Patients with fractures in >1 extremity exhibited a 52% higher odds of elevated ferritin level than patients with isolated fractures after controlling for transfusions and sex (adjusted OR 1.52, 95% CI, 1.06–2.17, P = 0.02); though patients with multiple extremity fractures demonstrated no increased odds of functional iron deficiency over trauma patients with isolated extremity fractures (adjusted OR 1.14, 95% CI, 0.72–1.83, P = 0.6).
TABLE 3.
Laboratory Results by Fracture Region
| Characteristic | Overall N = 844 |
Shoulder N = 7 |
Humerus/Elbow, N = 30 |
Forearm/Wrist, N = 32 |
Hand N = 1 |
Pelvis/Acetabulum, N = 91 |
Femur/Knee N = 290 |
Leg/Ankle N = 175 |
Foot N = 13 |
Polytrauma N = 205 |
|---|---|---|---|---|---|---|---|---|---|---|
| Hemoglobin | ||||||||||
| Mean (SD) | 9.96 (1.79) | 10.50 (1.84) | 10.55 (2.17) | 11.07 (1.53) | 12.60 (NA) | 9.91 (1.87) | 9.81 (1.62) | 10.80 (1.61) | 10.02 (1.58) | 9.16 (1.70) |
| Range | 5.50, 16.20 | 7.40, 12.20 | 6.70, 16.20 | 8.10, 13.90 | 12.60, 12.60 | 6.30, 14.70 | 5.50, 14.50 | 6.00, 14.40 | 7.60, 12.60 | 5.60, 14.50 |
| Low | 799 (95%) | 6 (86%) | 27 (90%) | 27 (84%) | 1 (100%) | 86 (95%) | 283 (98%) | 160 (91%) | 13 (100%) | 196 (96%) |
| Normal | 44 (5.2%) | 1 (14%) | 3 (10%) | 5 (16%) | 0 (0%) | 5 (5.5%) | 7 (2.4%) | 15 (8.6%) | 0 (0%) | 8 (3.9%) |
| Hematocrit | ||||||||||
| Mean (SD) | 29.7 (5.2) | 30.8 (6.0) | 31.2 (6.1) | 32.9 (4.5) | 37.8 (NA) | 29.5 (5.4) | 29.4 (4.6) | 32.2 (4.7) | 30.0 (3.7) | 27.1 (5.0) |
| Range | 15.6, 46.3 | 21.5, 37.4 | 20.8, 46.3 | 24.1, 41.1 | 37.8, 37.8 | 18.4, 42.2 | 15.6, 41.8 | 17.6, 42.4 | 23.5, 35.4 | 17.2, 43.3 |
| Low | 811 (96%) | 7 (100%) | 27 (90%) | 27 (84%) | 1 (100%) | 88 (97%) | 284 (98%) | 165 (94%) | 13 (100%) | 199 (98%) |
| Normal | 32 (3.8%) | 0 (0%) | 3 (10%) | 5 (16%) | 0 (0%) | 3 (3.3%) | 6 (2.1%) | 10 (5.7%) | 0 (0%) | 5 (2.5%) |
| Platelet | ||||||||||
| Mean (SD) | 201 (87) | 179 (56) | 220 (75) | 211 (51) | 152 (NA) | 191 (78) | 204 (82) | 214 (69) | 210 (81) | 188 (112) |
| Range | 25, 829 | 103, 275 | 53, 400 | 113, 311 | 152, 152 | 59, 568 | 57, 657 | 40, 415 | 73, 351 | 25, 829 |
| Low | 233 (28%) | 2 (29%) | 5 (17%) | 5 (16%) | 0 (0%) | 31 (34%) | 69 (24%) | 26 (15%) | 4 (31%) | 91 (45%) |
| Normal | 581 (69%) | 5 (71%) | 25 (83%) | 27 (84%) | 1 (100%) | 58 (64%) | 212 (73%) | 144 (83%) | 9 (69%) | 100 (49%) |
| High | 26 (3.1%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 2 (2.2%) | 9 (3.1%) | 3 (1.7%) | 0 (0%) | 12 (5.9%) |
| Iron | ||||||||||
| Mean (SD) | 33 (25) | 40 (18) | 42 (22) | 36 (19) | 42 (NA) | 32 (20) | 31 (29) | 38 (21) | 28 (11) | 30 (24) |
| Range | 0, 368 | 20, 67 | 12, 84 | 0, 88 | 42, 42 | 0, 154 | 0, 368 | 10, 131 | 16, 55 | 0, 203 |
| Low | 621 (74%) | 4 (57%) | 18 (60%) | 23 (72%) | 1 (100%) | 71 (78%) | 227 (78%) | 109 (62%) | 10 (77%) | 158 (77%) |
| Normal | 220 (26%) | 3 (43%) | 12 (40%) | 9 (28%) | 0 (0%) | 20 (22%) | 61 (21%) | 66 (38%) | 3 (23%) | 46 (22%) |
| High | 3 (0.4%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 2 (0.7%) | 0 (0%) | 0 (0%) | 1 (0.5%) |
| TIBC | ||||||||||
| Mean (SD) | 255 (58) | 252 (51) | 257 (72) | 277 (52) | 246 (NA) | 248 (58) | 252 (57) | 278 (54) | 295 (82) | 235 (50) |
| Range | 13, 463 | 157, 304 | 13, 405 | 189, 385 | 246, 246 | 24, 421 | 69, 463 | 105, 420 | 157, 434 | 132, 419 |
| Low | 351 (42%) | 2 (29%) | 12 (40%) | 9 (28%) | 0 (0%) | 44 (48%) | 122 (42%) | 43 (25%) | 4 (31%) | 115 (56%) |
| Normal | 492 (58%) | 5 (71%) | 18 (60%) | 23 (72%) | 1 (100%) | 47 (52%) | 167 (58%) | 132 (75%) | 9 (69%) | 90 (44%) |
| %Sat | ||||||||||
| Mean (SD) | 14 (9) | 16 (6) | 16 (8) | 14 (7) | 17 (NA) | 14 (9) | 13 (9) | 14 (7) | 10 (6) | 14 (12) |
| Range | 3, 87 | 9, 24 | 3, 35 | 5, 31 | 17, 17 | 4, 65 | 3, 79 | 4, 46 | 5, 25 | 3, 87 |
| Low | 706 (86%) | 4 (57%) | 21 (70%) | 24 (80%) | 1 (100%) | 74 (85%) | 259 (92%) | 146 (84%) | 12 (92%) | 165 (84%) |
| Normal | 106 (13%) | 3 (43%) | 9 (30%) | 6 (20%) | 0 (0%) | 11 (13%) | 20 (7.1%) | 28 (16%) | 1 (7.7%) | 28 (14%) |
| High | 9 (1.1%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 2 (2.3%) | 3 (1.1%) | 0 (0%) | 0 (0%) | 4 (2.0%) |
| Transferrin | ||||||||||
| Mean (SD) | 182 (40) | 180 (37) | 188 (40) | 198 (37) | 176 (NA) | 180 (38) | 180 (39) | 199 (38) | 206 (64) | 167 (35) |
| Range | 75, 310 | 112, 217 | 119, 289 | 135, 275 | 176, 176 | 108, 301 | 75, 304 | 75, 300 | 111, 310 | 94, 261 |
| Low | 580 (69%) | 4 (57%) | 18 (60%) | 14 (44%) | 1 (100%) | 64 (70%) | 211 (73%) | 90 (51%) | 6 (46%) | 172 (84%) |
| Normal | 263 (31%) | 3 (43%) | 12 (40%) | 18 (56%) | 0 (0%) | 27 (30%) | 78 (27%) | 85 (49%) | 7 (54%) | 33 (16%) |
| Ferritin | ||||||||||
| Mean (SD) | 240 (336) | 146 (72) | 201 (140) | 153 (107) | 266 (NA) | 277 (234) | 221 (374) | 153 (132) | 207 (286) | 349 (444) |
| Range | 6, 4105 | 75, 258 | 44, 537 | 27, 501 | 266, 266 | 9, 1170 | 9, 4105 | 9, 957 | 12, 1073 | 6, 3759 |
| Low | 86 (10%) | 0 (0%) | 2 (6.7%) | 4 (12%) | 0 (0%) | 7 (7.7%) | 30 (10%) | 33 (19%) | 3 (23%) | 7 (3.4%) |
| Normal | 452 (54%) | 5 (71%) | 19 (63%) | 20 (62%) | 0 (0%) | 38 (42%) | 172 (59%) | 97 (55%) | 6 (46%) | 95 (46%) |
| High | 306 (36%) | 2 (29%) | 9 (30%) | 8 (25%) | 1 (100%) | 46 (51%) | 88 (30%) | 45 (26%) | 4 (31%) | 103 (50%) |
| Function iron deficiency | 683 (83%) | 4 (57%) | 21 (70%) | 23 (77%) | 1 (100%) | 73 (82%) | 251 (89%) | 137 (79%) | 10 (77%) | 163 (83%) |
| Absolute iron deficiency | 28 (3.3%) | 0 (0%) | 0 (0%) | 1 (3.1%) | 0 (0%) | 3 (3.3%) | 9 (3.1%) | 11 (6.3%) | 2 (15%) | 2 (1.0%) |
| Iron body store derangement | 808 (96%) | 6 (86%) | 25 (83%) | 30 (94%) | 1 (100%) | 90 (99%) | 280 (97%) | 160 (91%) | 13 (100%) | 203 (99%) |
| High ferritin, low iron stores | 138 (16%) | 1 (14%) | 4 (13%) | 0 (0%) | 0 (0%) | 23 (26%) | 45 (16%) | 12 (6.9%) | 3 (23%) | 50 (25%) |
| Transfusion | 221 (26%) | 1 (14%) | 7 (23%) | 6 (19%) | 0 (0%) | 26 (29%) | 57 (20%) | 11 (6.3%) | 2 (15%) | 111 (54%) |
No patient had high hgb, hct, or transferrin; 1 patient in femur/knee region had high TIBC.
Figure 1 depicts the laboratory results for patients who required blood transfusion compared with those who did not. Platelet count, TIBC, and transferrin were lower on average in patients who required transfusion, whereas ferritin was more commonly elevated (Fig. 2, Table 2). More patients (85%, 521/623), who did not require a blood transfusion, met criteria for functional iron deficiency compared with 78% (162/221) of those receiving blood transfusions (P = 0.04). However, ferritin was high (>200 ng/mL), while all body iron stores were low in 28% (60/221) of patients who received a blood transfusion, more than twice as often as the group without transfusions (13%, 78/623, P < 0.001). Only 4.3% (36/844) of patients demonstrated normal iron, TIBC, TSAT, and transferrin values. In total, 95.7% overall and 94.5% of patients who did not require transfusion demonstrated some degree of body iron store derangement from institutional reference ranges (Table 2).
FIGURE 1.
Laboratory results compared with reference ranges stratified based on transfusion requirement.
FIGURE 2.
Laboratory value category frequency (low, normal, high) in patients who did not require blood product transfusion compared with those who did require transfusion between admission and postoperative day 1.
DISCUSSION
The incidence of injury-associated anemia and functional iron deficiency in the study cohort was 94.7% and 80.9%, respectively, as identified on POD1 laboratory analysis. Most significantly, approximately three-quarters of patients with anemia did not reach transfusion requirements and, therefore, went untreated, while nearly all (94.5%) patients sustained derangement in their iron laboratory panel.
The authors found injury-associated anemia to be nearly universal among patients with orthopaedic trauma on POD1 in the level 1 trauma population. In addition, injury-associated anemia was found to be persistent after allogenic blood transfusion. The incidence of anemia is higher in this study (94%) than previously reported (87%) in the geriatric hip fracture population as hypothesized given the proposed mechanism of injury-associated anemia. Compared with previous studies on perioperative anemia in the geriatric fracture population, this study’s population sustained fractures from a higher mechanism of injury on average. Studies suggest that inflammatory responses play a negative role in erythropoiesis and that the degree of catecholamine and cytokine release is directly associated with increasing injury severity.1 In elderly murine fracture models, anemia in the perioperative period has been found to persist for months.28 Likewise, in a smaller longitudinal study, 97% of severely traumatized patients with long bone fractures were anemic at 2 weeks and anemia persisted in 30% of these patients at 6 months.4 Early diagnosis is the first step toward measures that may improve outcomes during recovery and reduce the risk of persistent anemia.
A substantial number of patients (81%) after orthopaedic trauma were found to have functional iron deficiency. Although postoperative anemia is commonly recognized, functional iron deficiency is not routinely monitored or treated during recovery. In this study population, ferritin was more likely to be normal or high overall even in the setting of all other iron values being low. The observed elevation of ferritin in the perioperative period is consistent with the role of ferritin as an acute phase reactant.1,26 The finding of elevated ferritin with otherwise altered iron indices suggests that iron becomes sequestered and unavailable for use in replenishing blood cell volume in the setting of orthopaedic trauma, as reflective of a state of functional iron deficiency. In this population, functional iron deficiency was 25 times more common than absolute iron deficiency (where the etiology is inadequate iron). In addition, transferrin (a key component of iron metabolism and marker of iron transport capabilities) and TIBC (a measure of the body’s potential to attach iron)29 were found to be low in 69% and 42% of patients, respectively. This highlights that iron homeostasis is likely compromised, possibly because of the inflammatory state induced by trauma. These patterns are notably different than those observed in chronic iron deficiency (ie, due to poor diet), where iron, TSAT, and ferritin are low, leaving TIBC to be elevated and transferrin rises to compensate.1 One prospective observational study found that plasma norepinephrine, interluekin-6 (IL-6), tumor necrosis factor-alpha, and hepcidin were increased with ISS in a population of both blunt trauma and patients with elective hip arthroplasty.30 Specific to orthopaedic trauma, a recent study found that synovial fluid concentrations of IL-6 (among other proinflammatory cytokines and matrix metallopeptidases) are similarly correlated with increasing CT-quantified fracture energy.31 As the direct relationship between markers of innate immune system activation and ISS would suggest, the magnitude of ferritin elevation and suggested functional iron deficiency seem to be exacerbated in patients with multiple orthopaedic injuries in this observational study.
The standard of care for perioperative anemia in orthopaedic trauma is packed red blood cell (pRBC) transfusion. Allogenic blood product transfusion for anemia management does not mitigate the systemic inflammatory response. Anemia remains common in critically ill patients in the intensive care unit even after adequate initial resuscitation. As anticipated, patients who received blood products in this study nearly universally remained anemic despite transfusion and more commonly had iron axis deviation with elevated ferritin and low body iron stores. Only 1 patient of 195 who received allogenic blood products in the perioperative period subsequently had a normal hemoglobin on postoperative day 1. Given the negative associations of blood product transfusion (increased mortality, nosocomial infection, postoperative venous thromboembolism, multisystem organ dysfunction, and acute respiratory distress syndrome), a stringent threshold (hemoglobin <7 g/dL) has been widely accepted for the use of blood products.1 Mullis et al32 have recently investigated and advocated for lowering the transfusion threshold further after the initial resuscitation, which would inherently exasperate the incidence and prevalence of postoperative anemia. Although incompletely studied in orthopaedics and trauma literature, anemia has been associated with fatigue, mood disturbances, and decreased physical performance,1 which may all impede a patients’ ability to fully participate in rehabilitation likely for months after surgery. Patients with persistent anemia in the recovery period have also been shown to have higher incidence of infection.4 For these reasons, others have conducted prospective randomized trials evaluating the utility of intravenous iron therapy (IVIT) in both general trauma and the geriatric hip fracture population, reporting mixed results but notably minimal risks.1 These studies have limitations and the results are unlikely to be generalizable to a younger, higher energy orthopaedic trauma population as described in the current study. The current population demonstrated high levels of ferritin that may be driving a larger systemic response than observed within the geriatric fracture population and, therefore, contributing to the functional iron deficiency in the population. An alternative to pRBCs such as IVIT, especially for patients who do not reach the transfusion threshold, would be desirable given the restrictive transfusion threshold and subsequent negative effects from anemia during recovery.
This study is observational and exploratory in nature and not without limitations. Comparison of anemia present preinjury or on initial presentation is not available. In addition, this study cannot mechanistically evaluate the etiology of anemia; the analysis of perioperative blood loss would require more sophisticated modeling of blood loss in different types of traumatic injury and is out of the scope of the aims in this study.20,33 Preinjury use of anticoagulant medication may influence the prevalence of postoperative anemia; in this case, it would be more likely for older patients to be more anemic on average, which was not the case in this study or in the literature. Similarly, collecting biomarkers of immune system activation and direct measures of iron stores to demonstrate functional iron deficiency was not feasible in this clinical observational study of >800 patients. Prior work has established a relationship between trauma, both injury and surgery initiated, and innate immune system activation.30 In addition, anemia resolution over time was not determined within this cohort, because laboratory work was not routinely obtained at follow-up. The limitation of laboratory testing to a standardized POD1 time point likely underestimates the incidence of anemia, because potentially ongoing blood loss would cause some patients to drift into the anemic state. However, given the finding that approximately 95% of patients met criteria for anemia on POD1, it is unlikely that the further inclusion of patients who met criteria for anemia after POD1 would result in clinically meaningful change in conclusions. Orthopaedic polytraumas were used as a marker of increased severity of overall trauma. However, further work is needed to correlate with a standardized marker of severity such as the injury severity score (ISS). There exists a small percentage of patients for whom laboratory values were not obtained because of service line differences at the initiation of the study period between the orthopaedic trauma service and partner services in the hospital who were primarily caring for patients with orthopaedic trauma at that time. This study’s cohort, therefore, was unable to make a small number of potential observations. The strength of this article is in the establishment of the widespread prevalence of functional iron deficiency and injury-associated anemia, persistent after transfusion, in a large, injury-diverse orthopaedic trauma population.
CONCLUSIONS
The occurrence of injury-associated anemia and functional iron deficiency was common after operative orthopaedic trauma. Any treatments that may reduce the incidence of anemia or its disease burden would affect nearly all patients with orthopaedic trauma given the near universal incidence of anemia after operative fracture care. IVIT34 may be a target for future research to address the functional iron deficiency observed in the population while decreasing the transfusion risks and enhancing recovery.
ACKNOWLEDGMENTS
This work was supported by grants awarded by the Medical Research Foundation (OHSU), the Collins Medical Trust, and the Orthopaedic Trauma Association (OTA).
Footnotes
LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.
The authors report no conflict of interest.
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