Anemia and Patient Blood Management in Hip and Knee Surgery: A Systematic Review of the Literature

A Medline search (PubMed, U.S. National Library of Medicine of the National Institutes of Health) was performed on May 7, 2009. For consistent information retrieval, the following basic search strings based on medical subject headings (MeSH) terminology used in the controlled vocabulary of the U.S. National Library of Medicine for indexing articles were used: “Arthroplasty, Replacement, Hip” OR “Hip Prosthesis” OR “Hip Fractures” and “Arthroplasty, Replacement, Knee” OR “Knee Prosthesis.” The epidemiologic characteristics of anemia and the associations of anemia with clinical outcomes were obtained by restricting the search results to (“Anemia” NOT “Anemia, Sickle cell”). In addition, search results on selected patient blood management interventions were obtained by combining the basic search strings with the following MeSH terms: “Erythropoietin, Recombinant,”“Ferric Compounds,” and “Ferrous Compounds.” For the latter, search results were restricted to randomized controlled trials, cohort studies, meta-analyses, practice guidelines, and reviews in humans.

Preoperative was defined as any characteristic or measure reported before surgery. Postoperative was used for the time interval between surgery and discharge. The following epidemiologic parameters of interest were predefined: prevalence of pre- and postoperative anemia, prevalence of iron-deficiency anemia and anemia of inflammation, pre- and postoperative hemoglobin levels, blood volume loss, blood transfusion rate, and number of blood units transfused. For the study of associations with anemia, the following clinical outcomes were predefined: physical function, infections, LOS, mortality, and quality of life (QoL). The selected patient blood management interventions were analyzed with regard to their effects on pre- and postoperative hemoglobin levels, ABT rate, and the predefined clinical outcomes that are found associated with perioperative anemia listed earlier.

As shown in figure 1, the search retrieved 361 publications, all of which were screened for appropriateness based on abstracts. Two hundred thirty-eight publications were excluded from the analysis for the following reasons: other surgical procedures (57), case reports or letters (48), miscellaneous anesthesiological measures (43), use of aprotinin or tranexamic acid (25), interventions in coagulation (18), immunologic interventions (17), publications in foreign language with English abstract only (14), no abstract (9), sickle-cell anemia or, thalassemia or aplasia (7). Of the remaining 123 publications, 65 reporting results in less than 100 patients were used to fill possible evidence gaps. Fifty-eight publications reported results in 100 patients or more and underwent full-text review. Of these, nine were excluded for the following reasons: no numerical data on predefined outcomes (6) and reanalysis of already published data (3).

Statistical analysis was purely descriptive based on results as reported. When appropriate, weighted means (arithmetical means adjusted for different study and group sizes) and corresponding standard deviations were calculated. An initially planned formal meta-analysis of the published results was precluded by inconsistencies in variable reporting.

Forty-nine publications matching with the selection criteria and reporting results in the predefined areas were included in the final analysis.

Nineteen prospective and retrospective cross-sectional cohort studies reporting the epidemiologic characteristics of anemia in patients undergoing elective total hip or knee arthroplasty (THA/TKA, 13 studies including 29,068 patients) or hip fracture surgery (6 studies, 6,366 patients) were identified. Patients undergoing elective hip or knee arthroplasty were generally younger than patients hospitalized for surgical repair of hip fracture (weighted mean ±SD): 68.5 ± 3.2 and 79.1 ± 1.8 yr old, respectively. Only 10 publications reported the criteria used for the diagnosis of anemia. These varied across publications ranging from stringent (hemoglobin level less than 10 g/dl)16to liberal (hemoglobin level less than 13 g/dl for both women and men)17thresholds. In addition, the definition was gender-specific in some studies,18–22but not in others,16,17,23–25it was based on the hematocrit level less than 30%25instead of a hemoglobin threshold.

Weighted mean (±SD) hemoglobin levels decreased from 13.6 ± 0.4 (preoperative) to 10.6 ± 0.8 g/dl (postoperative) in THA/TKA patients and from 12.5 ± 0.2 to 8.2 ± 2.1 g/dl in hip fracture patients. According to the definitions of anemia retained by the different authors, preoperative and postoperative anemia was present in 24 ± 9% and 51% (single record) of the THA/TKA patients and in 44 ± 9% and 87 ± 10% of the hip fracture patients, respectively. The weighted mean volume of blood loss was 1,004 ± 302 ml in patients undergoing THA/TKA and was not reported for hip fracture patients. ABT rates were similar in both patient groups: 45 ± 25% (range, 10–69%) and 44 ± 15% (range, 34–69%) for THA/TKA and hip fracture patients, respectively. They were similar in patients undergoing hip and knee replacement and in patients undergoing primary and revision arthroplasty.17,26–28The lowest transfusion rate was achieved in the study with the most stringent transfusion trigger (hemoglobin level < 8 g/dl or clinical symptoms of anemia). The weighted mean number of blood units transfused per transfused patient was 2.6 ± 0.6 (range, 2.2–3.8 units) and was similar in THA/TKA and hip fracture patients, although the latter single report did not mention whether this figure applied to included patients or to transfused patients. Detailed findings by study are shown in table 1. Results from studies reporting characteristics of interest in patients after THA or TKA did not usually provide sufficient granularity for comparative analysis between these two procedures, with the exception of ABT rates. The weighted average ABT rates and ranges were 46% (10–92%) and 44% (9–84%) for THA and TKA, respectively.

Only three studies attempted to differentiate between anemia of inflammation and iron-deficiency anemia.21,22,24Consolidated results are shown in table 2. Of note, the study by Saleh et al .21included a high proportion of elderly patients with rheumatoid arthritis, which was proposed by the authors as a possible explanation for the high proportion of normocytic normochromic anemia in their patient population.

Seven studies reported the association of anemia with one or more prespecified clinical outcomes, wherein six of these studies were performed in patients undergoing hip fracture repair,16,18–20,23,29one in patients undergoing elective THA,10and none in patients with TKA. Detailed results are shown in table 3.

Functional mobility in the early postoperative phase after a hip fracture surgery was impaired by early postoperative (first 3 days postsurgery) anemia (hemoglobin less than 10 g/dl) in a prospective study with 487 consecutive hip fracture patients treated according to a multimodal rehabilitation program. In this study, anemia was significantly associated with an impaired ability to walk on each of the first 3 days after surgery and was identified as an independent risk factor for not being able to walk on the third postoperative day in an adjusted multiple regression analysis (odds ratio 0.41, P = 0.002).16These observations confirmed earlier findings of a retrospective cohort study with 5,793 patients who underwent surgical hip repair, in which lower postoperative hemoglobin level was independently associated with shorter walking distance at time of hospital discharge (P < 0.001).29 

In contrast, three studies reported the absence of an association between anemia and poorer physical functioning. Halm et al .23found a significant association between the Functional Independence Motor score and hemoglobin level at admission (P = 0.04). However, this significance disappeared after adjustment for prefracture patient characteristics (such as mobility, age, and degree of independence), clinical status at admission (RAND comorbidity index30and Acute Physiology and Chronic Health Evaluation score31), discharge status, and blood transfusions. In a retrospective analysis of prospectively collected data of 844 community-dwelling patients who had undergone hip (neck or trochanter) fracture surgical repair, those with postoperative anemia (hemoglobin level less than 12.0 g/dl in women and 13.0 g/dl in men) or with anemia at discharge were more likely to experience a decline in instrumental activities of daily living compared with those without anemia, although this difference did not reach statistical significance. Hemoglobin values were available for 714 patients of which 643 (90%) were anemic at discharge and 312 (44%) were anemic at discharge but not at admission.18Finally, in a prospective study with 395 hip fracture patients, the difference in recovery of ambulatory activity and of basic and instrumental activities of daily living status at 3, 6, or 12 months after surgical intervention did not reach statistical significance, although it was numerically in favor of patients without anemia.20 

In a prospective analysis of 225 patients undergoing elective THA of which 15% were anemic on admission, preoperative anemia compared with no anemia was associated with an increased incidence of postoperative urinary tract infections (28 vs.  14%, P = 0.039) and numerically more frequent respiratory tract infections.22In parallel, the postoperative ABT rate in the anemic group was 71.0% compared with 10.5% in the nonanemic group.22 

Anemia on admission20,23and postoperative anemia16,22were both associated with a significantly increased LOS of the same order of magnitude in all four prospective cohort studies reporting this clinical outcome. In anemic patients compared with nonanemic patients, mean LOS was 18 versus  11 days (P < 0.001),2213 versus  8 days (P < 0.001),16and 16 versus  8 days (P < 0.01).23Finally, Gruson et al .20reported without quantifying their findings that anemia at hospital admission was significantly associated with an increased hospital LOS (P < 0.01).

Preoperative20,23and postoperative16anemia were both associated with a significantly increased mortality in all three prospective studies that investigated this association. In anemic patients compared with nonanemic patients, 30-day postoperative mortality after hip fracture repair was 13 versus  6% (P < 0.05),16the adjusted odds ratio for death within 60 days after discharge was 1.5 (P < 0.05),23and the overall odds ratios for death at 6 and 12 months after discharge were 2.9 (P = 0.02) and 2.6 (P = 0.01), respectively.20Interestingly, in the latter study, patients with severe anemia (hemoglobin < 10 g/dl) were five times more likely to die within 6 and 12 months after discharge (P ≤ 0.01) than patients with mild anemia (defined as hemoglobin level from 10 to 11.9 g/dl for women and to 12.9 g/dl for men).20Only one retrospective study found no association between anemia and mortality.18 

None of the selected studies reported the effects of anemia on QoL in patients undergoing hip or knee surgery. Among studies including fewer than 100 patients, one found a positive correlation between hemoglobin levels at discharge and change in QoL scores during 2 months after primary hip arthroplasty (N = 87),32whereas another one (n = 30) found no evidence of such an association during 56 days after surgery.33 

Detailed findings on clinical outcomes are shown in table 4. Two cohort studies reported the effects of preoperative treatment with oral iron before primary TKA34and intravenous iron given 4 days or less before surgical hip fracture repair.35Iron therapy was shown to reduce the need for ABT.34,35Iron therapy also significantly reduced the postoperative infection rate.35Although mean LOS and 30-day mortality were numerically reduced with iron therapy, the difference did not reach statistical significance.

Another study exploring the effects of iron in orthopedic surgery patients was not included in the table because of its peculiar design.36In a prospective series of 322 patients undergoing THA, those identified as anemic (hemoglobin < 12 g/dl) were provided oral iron therapy while on the waiting list (n = 26). The ABT rate was 3% in the nonanemic group versus  23% in the anemic group treated with oral iron (P < 0.05). Within the latter, the transfusion rate was 9% in those who responded to iron therapy and increased their preoperative hemoglobin level more than 12 g/dl (n = 11) versus  33% in those who did not (P < 0.05). The mean LOS was significantly (P < 0.05) higher in nonresponder anemic patients (8.6 days) than in anemic responders (6.1 day) and in nonanemic patients (6.6 days).36 

Eight studies reported the effects of rHuEPO in patients undergoing major orthopedic surgery.37–44With the exception of two studies using a placebo as comparator,43,44all other used an active control group (CS, PAD, and/or iron therapy). rHuEPO was given in combination with oral or intravenous iron in all studies. The weighted mean hemoglobin levels in gram per deciliter at first consultation, pre- and postsurgery were 12.7 ± 0.6 g/dl, 14.3 ± 0.3 g/dl, and 11.4 ± 0.1 g/dl in the rHuEPO-based treatment groups and 12.7 ± 0.6, 12.4 ± 0.4, and 9.7 ± 0.1 g/dl in the control groups, respectively.37,38,41,43,44rHuEPO-based treatments consistently reduced the need for ABT, the effect being more pronounced when more liberal transfusion triggers were used. The clinical outcomes of postoperative infections, LOS, and 30-day mortality were generally not significantly different between rHuEPO-based regimens and the active control groups. However, none of the studies was adequately designed or powered for these outcomes.

Two studies reported physical function endpoints (data not shown). Keating et al .38showed that the mean overall change in a previously validated vigor score (similar to a combined activities of daily living and QoL score)45was significantly greater with an rHuEPO-based treatment than with PAD after adjusting for baseline hemoglobin, gender, age, weight, height, and baseline scores (P = 0.001). However, changes in handgrip strength were not significantly different between groups.38Weber et al .41found that time to ambulation (3.3 ± 2.7 days) and time to discharge (10.8 ± 5.5 days) did not differ significantly when a rHuEPO-based treatment was compared with usual care in patients undergoing major orthopedic surgery. However, these parameters were significantly higher in transfused than in nontransfused patients (3.8 vs.  3.1 day, P = 0.004 and 12.9 vs.  10.2 days, P < 0.001, respectively) in both the rHuEPO and the control group.41 

Detailed findings are shown in table 5. Eleven studies reporting the effects of CS compared with standard drain without retransfusion of autologous blood and including 100 patients or more who underwent knee or hip arthroplasty were identified.46–56Of these, only three included THA patients.46,48,49CS measures consisting of retransfusion of washed or nonwashed shed blood generally reduced the need for ABT, independent of the study site-specific transfusion trigger. Reported reductions in infection rates were not significant. Mean LOS was numerically lower in patients after CS and reached statistical significance in two studies.52,57Time to ambulation was reduced after CS compared with standard drain in two studies: 6.0 versus  7.0 days (P < 0.01)53and 4.6 versus  5.1 day (P = 0.395),46respectively. Thirty-day mortality was not reported in any study.

Interestingly, del Trujillo et al .46noted that although the overall differences in postoperative infection rates, time to ambulation, and mean LOS were not statistically significant with CS compared with standard drain, they were in patients having received an ABT compared with those who had not: postoperative infection rate, 12.1 versus  2.6%, P = 0.046; time to ambulation, 4.4 versus  5.7 days, P = 0.013; and mean LOS, 9.6 versus  13.5 days, P = 0.001.46 

Four cohort studies,58–61including 100 patients or more, reported the effects of PAD on the ABT rate. PAD was compared with either usual care with no PAD58,59,61or with PAD restricted to 2 units of blood.60In studies comparing PAD with no PAD, ABT rates were reduced from 40 to 3%,5952 to 18%,58and 91 to 9%61corresponding to a weighted average reduction (±SD) from 73% (±27) to 8% (±8). PAD of 4 units of blood was not significantly superior to PAD of 2 units.60The effects of PAD on the other predefined clinical outcomes were not reported in any study.

Wong et al .62evaluated the effectiveness of a blood conservation algorithm aiming at reducing the need for ABT (patient and physician education, use of iron or rHuEPO or PAD in accordance with predefined preoperative hemoglobin level categorized) in patients undergoing THA in 30 hospitals randomly assigned to implement the algorithm or to continue with usual care. Transfusion triggers were set at hemoglobin less than 7 g/dl or hemoglobin between 7 and 10 g/dl and symptoms. The allogeneic transfusion rate was substantially reduced in hospitals randomized to the blood conservation algorithm compared with usual care (16.5% vs.  26.1%, P = 0.02) with no difference in the use of autologous blood. Mean LOS was numerically but not significantly lower in hospitals randomized to the blood conservation algorithm (5.8 vs.  6.3 days).

Eindhoven et al .63performed a cohort study to compare the implementation of conservative blood transfusion triggers (6–8-10 g/dl Flexinorm) in one hospital with continued usual care (hemoglobin less than 10 g/dl or hematocrit less than 30%) in another. The allogeneic transfusion rate over 12 months was 14 and 40% (P < 0.0001), respectively. No data on clinical outcomes were reported.

Intraoperative hemodilution may be a measure of interest for patient blood management in patients undergoing elective hip surgery. Our search retrieved eight studies, all randomized controlled trials, reporting results of acute normovolemic hemodilution.64–71As the largest study enrolled 49 patients,68they were excluded from detailed analysis. Briefly, in these studies, the primary endpoint of interest generally was the ABT rate. Three studies showed a significantly lower ABT rate with hemodilution,65,67,70the remainder showed no significant difference versus  controls.

A systematic literature search identified preoperative anemia and even more so postoperative anemia after intraoperative blood loss as highly prevalent in patients undergoing major elective orthopedic surgery (THA/TKA) and surgical repair of hip fractures. In these patients, anemia was associated with significant adverse clinical outcomes, such as increased allogeneic transfusion rates, decreased physical functioning, increased infection rates, increased LOS, and increased mortality. In randomized controlled trials and cohort studies, patient blood management interventions based on preoperative iron or erythropoietin therapy and postoperative retransfusion of salvaged cells generally allowed a statistically significant and clinically relevant reduction of ABTs.

In the prospective and retrospective cohort studies included in the present review, preoperative anemia was prevalent in approximately 25% of the patients undergoing elective THA/TKA and 50% of the patients undergoing surgical hip fracture repair. This is consistent with the observation that hip fracture patients were 10 yr older than THA/TKA patients on average and with the increasing incidence of anemia with age.72However, the definition of anemia used for assessing its prevalence was often not reported or deviated from the definition of World Health Organization (hemoglobin level less than 13 g/dl in men and less than 12 g/dl in women),73possibly reflecting the ongoing debate about the validity of these values, especially in an elderly population.74Independent of the authors' beliefs with regard to the appropriate definition of anemia, postoperative hemoglobin levels were consistently much lower than before surgery (on average 3.0 g/dl after THA/TKA and 4.3 g/dl after surgical hip fracture repair) and the prevalence of anemia further increased consistently after surgery, reaching 51% after THA/TKA and 87% after hip fracture repair.

In patients with iron deficiency, anemia develops once iron stores are depleted. Iron loss due to surgical bleeding will exaggerate a possibly preexisting iron deficiency and may aggravate postoperative anemia. The marked postoperative increase in the prevalence of anemia after major orthopedic surgery suggests that preoperative iron store depletion may be widespread in this patient population. Although preoperative iron therapy contributes to increase in preoperative hemoglobin levels and thereby to decrease in the risk of postoperative anemia requiring ABT,34,35postoperative iron administration aims at correcting anemia by supporting erythropoiesis and at replenishing the iron stores. However, this has not yet been studied clinically so far. By assuming that circulating erythrocytes contain 1,800 mg of iron in 5,000 ml of blood,75the loss of 1,000 ml of blood during major hip or knee surgery corresponds to a net loss of 360 mg of hemoglobin-bound iron. Patients perioperatively administered 360 mg of elemental iron will therefore be discharged with iron stores at the level they were before surgery, thus possibly with persisting iron deficiency.

Transfusion triggers varied across studies and were inconsistently reported. Accordingly, the ABT rates ranged from 10 to 89%. However, the average ABT rates and the average number of blood units transfused were similar after THA, TKA, and hip fracture repair (44–45% and 2.3–2.6 units, respectively), indicating possible differences in the perception of the severity of postoperative anemia between these two patient groups, that is, lower postoperative hemoglobin levels seemingly being more acceptable in elderly than in younger patients. At the time of writing this manuscript, the publication of the results of the recently completed FOCUS outcome trial was still pending. The FOCUS trial was designed to compare an aggressive erythrocyte transfusion strategy (transfusions to maintain hemoglobin levels at or more than 10 g/dl through hospital discharge or up to 30 days after randomization) with a more conservative strategy (transfusions withheld until the patient develops symptoms from anemia and permitted if hemoglobin level falls less than 8 g/dl) in patients with cardiovascular disease who had undergone surgical repair for a hip fracture with the following outcome measures: time to ambulation (primary endpoint); myocardial infarction or death, postoperative complications, survival, nursing home placement, and function (secondary endpoints).76The only randomized controlled clinical endpoint trial that assessed the effects of ABT in anemic adult patients was performed in the critically ill.77In this study, a restrictive strategy of transfusion (ABT if hemoglobin less than 7.0 g/dl and hemoglobin level maintained at 7.0–9.0 g/dl) compared with a liberal strategy (ABT if hemoglobin less than 10.0 g/dl and hemoglobin level maintained at 10.0–12.0 g/dl) lead to a numerically lower 30-day mortality rate in the overall population of critically ill patients, which reached statistical significance in patients who were less acutely ill and among patients younger than 55 years of age.77Supported by the recently reviewed results from retrospective and prospective studies and by many pathophysiologic observations of deleterious effects of storage on red blood cells,78,79this array of consistent and accumulating evidence strongly suggests that ABT are a risk factor for poorer clinical outcomes and triggered a growingly acknowledged need for patient blood management interventions aiming at minimizing the need for ABT.13,80 

Preoperative anemia is a major risk factor for adverse outcome in major surgery.5,9,10,81,82Preoperative anemia is also one of the most important risk factor for perioperative blood transfusions.2,5,17,83The question thus arises as to whether preoperative anemia or perioperative ABT is responsible for the observed adverse outcome. Despite its complexity, this has been investigated in cardiac and general surgery.5,9,10,81,82With various multivariate statistics and propensity score matching in some studies, the authors unanimously found that preoperative anemia and perioperative ABT were both independent risk factors for postoperative mortality, ischemia, and infections.5,9,10,81,82Unfortunately, no such big observational studies exist in orthopedic surgery. However, the probability of such fundamental associations being different in orthopedic surgery should be considered as reasonably low. Therefore, treatment modalities aimed at reducing preoperative anemia and perioperative erythrocyte transfusion seem justified already today, although only the final proof that such measures will indeed improve outcome is pending the results of future randomized controlled trials.

The categorization of anemia as iron-deficiency anemia and anemia of inflammation or chronic disease was reported in three studies only, with a prevalence of hypochromic microcytic anemia ranging from 23 to 70%. The clinical relevance of such a categorization has been recently underlined by the discovery of hepcidin as the iron gatekeeper.84–86As opposed to patients with pure iron-deficiency anemia, patients with anemia of chronic inflammation have high serum hepcidin levels. By inducing the internalization of ferroportin in enteric cells and macrophages, the presence of high serum levels of hepcidin plays a key role in the development of anemia of chronic inflammation by impairing the absorption of orally administrated iron and by leading to iron sequestration in macrophages.84In contrast, intravenous iron has been recently shown to overcome hepcidin-induced iron-restricted erythropoiesis in iron-replete patients.87The practical relevance of these findings is that patients with anemia of chronic disease should be expected to be nonresponders to oral iron therapy88and may need higher doses of erythropoietin to trigger sustained erythropoiesis.89Conversely, intravenous iron therapy overcomes oral absorption blockade because of inflammation-reduced rHuEPO need and dose, as shown in dialyzed90–92and nondialyzed93–95anemic patients with chronic kidney disease and in anemic cancer patients.96–98 

The present review identified several clinically important outcomes that were significantly associated with anemia in patients undergoing major orthopedic surgery. Systematic reviews have the advantage of being reproducible while preventing study selection bias. Conversely, they are limited by the publication bias itself (negative outcomes being less likely to be reported than significant findings99,100) and by the quality of MeSH term coding. As an example, the multicentric Austrian benchmark study2reporting blood use in elective surgery and included 1,401 patients with primary THA and 1,296 patients with TKA among 3,622 elective surgical procedures was not retrieved by the present search. MeSH term coding (“Surgical Procedures, Elective”) preempted retrieval by a focused indication driven search. However, the variability in ABT rates, number of units transfused, perioperative blood loss volumes, and overall conclusions of this study were consistent with those reported here.

The selected patient blood management interventions (preoperative iron or erythropoietin therapy, CS, and PAD) were generally powered for the primary endpoints of pre- or postoperative hemoglobin levels or postoperative ABT rates. None of the studies was adequately powered for QoL, physical functioning, LOS, or mortality endpoints. Although the numerical trends were in favor of outcome improvement, solid scientific evidence based on statistically significant differences in adequately designed and powered primary endpoint trials is still lacking. The heterogeneity and inconsistencies in data reporting precluded a meaningful meta-analysis of the reported findings. However, published results available to date are sufficient for generating hypotheses and power calculations required for clinical endpoint trials of patient blood management interventions. For future research, a framework for standardized reporting of clinical trial results in the field of anemia and orthopedic surgery should be developed and implemented to ensure comparability of results across studies and to allow for meta-analyses. As already recommended earlier by other authors,1the definition of anemia and transfusion triggers should be unified across studies or results published according to preoperative hemoglobin level strata. Anemia should be categorized as anemia of inflammation or iron-deficiency anemia and results shown accordingly. ABT rates should refer to the number of units transfused per transfused patient, or, alternatively, the total number of patients transfused and the total number of units transfused should be published. A standardized set of clinical endpoints and their minimal variation considered as clinically (or economically) meaningful should be defined. Among such endpoints of interest, the ABT rate, infection rate, LOS, time to ambulation, QoL, as well as 30-day, 6-month, and 12-month mortality deserve appropriate attention. Finally, perioperative patient blood management interventions should be categorized into pre-, per-, and postoperative measures because different effects on outcomes may be expected from the same intervention (e .g ., iron supplementation) performed at a different point in time (e.g. , pre- vs.  postoperative).

Anemia in the orthopedic perioperative setting was frequent and was associated with increased ABT rates and with adverse clinical outcomes. Patient blood management interventions aiming at decreasing the need for ABTs and at improving patient outcomes deserve increased medical attention.

The author thanks Philippe Kress, M.D., Consulting Physician, Kressmed, Glattbrugg, Switzerland, for his contribution to data collection and to reviewing and copyediting the present manuscript.