Perioperative Medicine
The Future of Anesthesiology
Anemia & Transfusion
Definition
Anaemia is a condition in which there is a reduced number of red blood cells or the haemoglobin concentration within the red blood cells is lower than normal.
Haemoglobin is needed to carry oxygen and if you have too few or abnormal red blood cells, or not enough haemoglobin, there will be a decreased capacity of the blood to carry oxygen to the body’s tissues. This results in symptoms such as fatigue, weakness, dizziness and shortness of breath, among others.
The optimal haemoglobin concentration needed to meet physiologic needs varies by age, sex, elevation of residence, smoking habits, and pregnancy status.
The most common causes of anaemia include nutritional deficiencies, particularly iron deficiency though deficiencies in folate, vitamins B12 and A are also important causes; haemoglobinopathies; and infectious diseases, such as malaria, tuberculosis, HIV and parasitic infections.
​
Anaemia is a serious global public health problem that particularly affects young children and pregnant women. WHO estimates that 42% of children less than 5 years of age and 40% of pregnant women worldwide are anaemic.
Kei T, Mistry N, Curley G, et al. Efficacy and safety of erythropoietin and iron therapy to reduce red blood cell transfusion in surgical patients: a systematic review and meta-analysis. Efficacité et innocuité d’un traitement d’érythropoïétine et de fer pour réduire la transfusion de culots sanguins chez les patients chirurgicaux: une revue systématique et méta-analyse. Can J Anaesth. 2019;66(6):716-731. doi:10.1007/s12630-019-01351-6
Bottom line: This 2019 Toronto-based meta-analysis reviewed the evidence of the efficacy and safety of erythropoietin stimulating agent (ESA) therapy plus iron vs. iron therapy alone in reducing red blood cell transfusions in 4,719 surgical patients across 25 different studies. Their findings suggest that there is evidence that ESA + iron therapy is superior to iron alone in reducing RBC transfusions without increasing the risk of serious adverse events.
Major points:
1. ESA + iron therapy vs iron therapy alone reduced the risk (RR=0.67) of requiring a blood transfusion. There was no differences when ESA was added to oral vs IV iron. While cardiac and orthopedic surgical patients did see a benefit with ESA, colorectal patients did not. This was postulated to be because colorectal surgery patients predominantly have iron deficiency anemias whereas cardiac/ortho patients likely have anemia of chronic inflammation. Population bias could not be excluded given a number of smaller studies missing on the side of increased transfusion on the funnel plot.
2. ESA + iron therapy increased pre-op Hb by 8.28 g/L more vs iron therapy alone. The RBC units transfused was decreased by 0.51 units when ESA therapy was added. Post-op Hb concentration was 9.01 g/L higher when ESA therapy was added.
3. Adding ESA therapy did not increase risk of mortality, stroke, MI, renal dysfunction or PE. Low dose ESA (<80,000 IU) did not increase risk of DVT, however, there was a trend towards increasing incidence of DVT with higher ESA doses. Despite evidence for more clinically important thrombotic events with higher-dose ESA therapy, most surgical patients however, would only receive the low-dose ESA pre-operatively.
Muñoz M, Acheson AG, Auerbach M, et al. International consensus statement on the peri-operative management of anaemia and iron deficiency. Anaesthesia. 2017;72(2):233-247. doi:10.1111/anae.13773
Bottom line: This 2017 international consensus statement suggests that anemia should be investigated as early as possible in all surgical procedures with >500mL expected blood loss, and, if non-urgent, these procedures should be delayed to facilitate adequate diagnosis and management of anemia and iron deficiency. Target Hb should be 130 g/L for both sexes. Oral iron should be the first-line agent, but IV iron is safe to use in refractory patients, intolerant patients and when surgery is imminent (<4 weeks).
Major points:
1. The prevalence of iron deficiency (with or without anemia) is estimated at around 34% of non-cardiac surgical patients. In critically ill patients, it is associated with increased duration of SIRS and prolonged ICU LOS. Ferritin < 30 mcg/L is the most sensitive (92%) and specific (98%) for diagnosing absolute iron deficiency. Treating iron deficiency even without anemia has benefits – boosting recovery from post-op anemia. Although in these cases, a GI cause of absolute iron deficiency should be sought.
2. Pre-op iron deficiency anemia can be treated with <60mg daily oral iron, or 80-100 mg on alternating days. If ineffective, patient dose not tolerate, or surgery is within 4 weeks, a one-time 1000-1500mg IV iron dose over 1hr is sufficient for most surgical patients. Hb responds within 5 days in 50% of patients.
3. Uncorrected pre-operative anemia is a risk factor for poor outcome, but there is little evidence that reversing the condition improves outcomes. There is evidence for reducing transfusions and a possible reduction in LOS. For treating benign diseases (as opposed to cancer), most guidelines recommend delaying 4 weeks to allow for treatment.
4. Post-operative anemia has an incidence 90% after major surgery. Oral iron is not recommended during this period (poor absorption, side-effects). Post-operatively, IV iron has shown safety, efficacy and cost-effectiveness compared to the alternative: RBC transfusions.
Munting KE, Klein AA. Optimisation of pre-operative anaemia in patients before elective major surgery - why, who, when and how?. Anaesthesia. 2019;74 Suppl 1:49-57. doi:10.1111/anae.14466
Bottom line: Pre-operative anemia is a common condition in the surgical population with an incidence of ~39.1% according to one study. Major surgical patients with anemia are at increased risk of morbidity, mortality and receiving RBC transfusions. While large RCTs are currently underway to assess whether managing pre-op anemia reduces morbidity and mortality, for now it appears reasonable to identify anemia and manage anemia in specifically in patients preparing for major surgery (>500mL of blood loss expected).
Major points:
1. Studies have shown that 39.1% of major surgery patients have pre-op anemia and this is associated with increasing morbidity, mortality, prolonged LOS, and more ICU admits, as well as increasing incidence of AKI and infection. The Hb cut-off should be 130 g/L for both sexes, the point below a further decrease in Hb has been shown to have a linear association with worse outcomes.
2. In oncological patients, RBC transfusions has negative impact on tumor recurrence and survival but there are no studies on clinical outcome after Hb treatment. Orthopedic patients have a higher expected blood loss, are undergoing mostly elective procedures which can be postponed and studies have shown that treating anemia pre-op increases Hb and reduces transfusions. Lower Hb levels in cardiac surgery patients is associated with increased risk of mortality and transfusion. RBC transfusion is independently associated with worse outcomes. Research is underway whether treating the anemia improves outcomes. Obstetrical patients usually have a hemodilutional anemia as well as a iron deficiency anemia. The latter of which is associated with increased maternal and fetal morbidity.
3. The surgeon or primary care provider should test a point-of-care Hb concentration at least 2 weeks pre-op (ideally 4 weeks) to allow for postponement of elective surgeries to diagnose and treat pre-op anemia. If anemia is found on point-of-care testing, a full CBC, serum ferritin, transferrin saturation, Vit B12, folate, CRP and serum creatinine should be ordered to further delineate the cause.
4. Iron deficiency anemia is the most common type of anemia worldwide and usually results from nutritional deficiencies or chronic inflammatory states. There are three possible mechanisms of iron deficiency. Absolute iron deficiency (ferritin < 30 mcg/L) points to severely decreased iron stores. Functional iron deficiency results from insufficient mobilization of iron despite adequate stores. Finally, iron sequestration, which is most common in inflammatory conditions leading to anemia of chronic disease, is caused by upregulation of hepcidin, poor intestinal absorption and sequestration of iron in the liver and by macrophages.
5. When iron deficiency anemia is identified, treatment with iron raises Hb concentration, lowers transfusion rates and improves quality of life. When surgery is > 6 weeks away, 40-60mg daily or 80-100mg q2 days iron should be given orally with 4-week follow-up. If oral iron is ineffective/poorly tolerated at 4 weeks, surgery is less than 4 weeks away, or functional iron deficiency exists, IV iron should be given – which has shown safety and efficacy. EPO should only be used in patients who refuse RBC transfusions (Jehovah’s Witnesses) or when the appropriate blood type is not available.
Mazer CD, Whitlock RP, Fergusson DA, et al. Restrictive or Liberal Red-Cell Transfusion for Cardiac Surgery. N Engl J Med. 2017;377(22):2133-2144. doi:10.1056/NEJMoa1711818
Bottom line: This 2017 multicenter, randomized, controlled trial of 4860 adults across 19 countries undergoing cardiac surgery requiring cardiopulmonary by-pass (who had a mod-high risk of death) showed noninferiority with respect to a composite of mortality and major morbidity (non-fatal MI, stroke, renal failure requiring dialysis) when using a restrictive (75g/L threshold) vs a liberal (95 g/L intra-op and ICU post-op, 85 g/L non-ICU post-op threshold) perioperative transfusion strategy while significantly reducing the amount of RBCs transfused.
Major points:
1. Less patients in the restrictive transfusion group required RBC transfusions (52.3%) compared to the liberal group (72.6%). Similarly, the restrictive group received a median of 2 units of blood during their stay compared to the median 3 units received by the liberal group.
2. There was no statistically significant difference in the primary outcome(composite of mortality, non-fatal MI, stroke or new-onset renal failure requiring dialysis) between the two groups (11.4% restrictive vs 12.5% in liberal). Similarly, there was no statistically significant difference in any of the individual components of the composite between the two groups. Mortality was 3.0% and 3.6% in the restrictive and liberal groups respectively.
3. In the subgroup analysis, there was a lower risk of the primary outcome in patients older than 75 who received the restrictive transfusion strategy.
4. There was no statistically significant difference in any of the secondary outcomes between the two groups, including: ICU LOS, hospital LOS, duration of mechanical ventilation, prolonged state of low cardiac output, infections, AKI, seizures, delirium or encephalopathy.
Mueller MM, Van Remoortel H, Meybohm P, et al. Patient Blood Management: Recommendations From the 2018 Frankfurt Consensus Conference. JAMA. 2019;321(10):983-997. doi:10.1001/jama.2019.0554
Bottom line: This 2018 consensus meeting involved 188 experts from 10 clinical disciplines and 33 different countries underwent a rigorous review of 145 studies to provide 10 clinical recommendations. The quality of evidence for these clinical recommendations was generally moderate to very low and as such only 3 of the 10 recommendations were strong (the rest were conditional): (1) anemia should be detected and managed early in the course before major elective surgery, (2) a Hb transfusion threshold of <70g/L should be used in hemodynamically stable critically ill patients and; (3) a Hb transfusion threshold of 75 g/L should be used in patients undergoing cardiac surgery.
Major points:
1. The group was able to provide conditional recommendations that iron supplementation should be given to elective surgery patients with iron deficiency anemia. Also, that ESA should not be routinely used pre-op for anemic elective surgery patients and that only a short-acting ESA in addition to iron supplementation may be considered for patients with Hb < 130 and undergoing major orthopedic surgeries.
2. A conditional recommendation was made that hip fracture patients with cardiovascular risk factors be transfused below a threshold of 80 g/L. Similarly, stable acute GI bleed patients should have a transfusion threshold of 70-80 g/L – another conditional recommendation.
3. In order to improve appropriate RBC utilization, patient blood management (PBM) programs should be implemented and ideally have computerized decision support systems embedded within them. Studies have shown less blood products transfused and decreased LOS with no differences in morbidity/mortality when PBM programs are implemented. These were conditional recommendations given the paucity of high-quality prospective trials available.
​
4. A transfusion threshold of 70 g/L should be used for hemodynamically stable critically ill patients. A slightly higher threshold of 75 g/L is recommended in patients undergoing cardiac surgery.
Poeran J, Chan JJ, Zubizarreta N, Mazumdar M, Galatz LM, Moucha CS. Safety of Tranexamic Acid in Hip and Knee Arthroplasty in High-risk Patients. Anesthesiology. 2021 Jul 1;135(1):57-68. doi: 10.1097/ALN.0000000000003772. PMID: 33857300.
Bottom line: In this multi-centre, retrospective study of 765, 011 total hip and knee arthroplasties in high-risk patients, tranexamic acid (TXA) reduced the blood transfusion rate by 10% without increasing the rates of venous thromboembolism, myocardial infarction, seizures, ischemic stroke or transient ischemic attack. This is one of the first large-scale studies to examine the use of TXA specifically in high-risk patients, who have historically been excluded from clinical trials despite representing a significant proportion of joint arthroplasty patients.
Major points:
1. High risk patients were defined as patients with history of DVT, PE, MI, seizures, ischemic stroke; renal disease; or atrial fibrillation, and split into three separate groups for analysis. Across all three groups, the use of TXA did not increase the odds of having any of VTE, MI, new-onset seizures, ischemic stroke or TIA (odds ratio 0.49 [CI 0.49-1.59], 0.89 [CI 0.58-1.67], 0.93 [CI 0.54-1.61]). TXA was used in 52.9% of cases.
​
2. Blood transfusion rates were significantly reduced across the entire study group (5.5% vs. 15.2%, odds ratio 0.31), including across each group of high-risk patients.
3. Hospital length of stay and cost of hospitalization were both decreased in high-risk patients who received TXA. This was speculated by the authors to potentially stem from selective avoidance of TXA in specific high-risk patients, a clinical decision which was not supported by the data in this study.
4. Although an off-label use, there is significant evidence in favour of TXA administration to reduce rate of blood transfusion in the general joint arthroplasty population. This study supports the use of TXA in high-risk patients specifically as a blood conservation strategy that does not appear to be associated with increased risk of potential TXA-related complications.
Kaufner L, von Heymann C, Henkelmann A, Pace NL, Weibel S, Kranke P, Meerpohl JJ, Gill R. Erythropoietin plus iron versus control treatment including placebo or iron for preoperative anaemic adults undergoing non-cardiac surgery. Cochrane Database Syst Rev. 2020 Aug 13;8(8):CD012451. doi: 10.1002/14651858.CD012451.pub2. PMID: 32790892; PMCID: PMC8095002.
Bottom line: This 2020 Cochrane review looked at the evidence of preoperative recombinant human erythropoietin (rHuEPO) with iron supplementation at reducing allogenic transfusion in anemic patients undergoing non-cardiac surgery. Compared to standard of care with or without iron supplementation, rHuEPO with iron reduces the need for RBC transfusions, and at higher doses, may increase pre-op Hb levels.
Major points:
1. 12 trials with 1880 mild-moderately anemic patients for orthopedic, gastrointestinal and gynecological surgery were studied. Study arm included rHuEPO + iron, control included placebo or standard of care with or without iron. Duration and timing of rHuEPO therapy varied per study (once daily x 5-10 days or once-twice/week x 4 weeks). Two studies were multiarmed trials with a high and low dose regimen:Low: 150-300IU/kg TBW & High: 500-600IU/kg TBW.
​
2. Moderate quality of evidence showing preop rHuEPO + iron therapy vs. control reduced the risk (RR = 0.55) of requiring allogenic RBC transfusion intra-op and up to 5 days post-op.
3. No difference in number of allogenic RBC units transfused between rHuEPO + iron and control groups. This may be due to the administration of complete units of RBC rather than the exact volume of RBCS each individual needed.
​
4. High dose rHuEPO + iron therapy increased pre-op Hb levels (MD 18.7g/L) compared to control. Low dose therapy did not show a difference between groups. However, there is insufficient data to conclude that low dose is less efficient to the high dose regimen.
​
5. No difference in risk in adverse events (renal dysfunction, heart failure, cardiac arrest, atrial fibrillation, venous thromboembolism, systemic infection, wound infections and hematomas, allergic reaction, H/A, fever, constipation), risk of mortality at 30 days, or hospital length of stay, between rHuEPO + iron and control groups.
​
6. Applicability of results is limited as the cause of anemia was not analysed preoperatively. If the cause of anemia is known, specific pre-operative targeted therapy may be beneficial in optimizing anemic patients.
Carson JL, Brooks MM, Hébert PC, Goodman SG, Bertolet M, Glynn SA, Chaitman BR, Simon T, Lopes RD, Goldsweig AM, DeFilippis AP, Abbott JD, Potter BJ, Carrier FM, Rao SV, Cooper HA, Ghafghazi S, Fergusson DA, Kostis WJ, Noveck H, Kim S, Tessalee M, Ducrocq G, de Barros E Silva PGM, Triulzi DJ, Alsweiler C, Menegus MA, Neary JD, Uhl L, Strom JB, Fordyce CB, Ferrari E, Silvain J, Wood FO, Daneault B, Polonsky TS, Senaratne M, Puymirat E, Bouleti C, Lattuca B, White HD, Kelsey SF, Steg PG, Alexander JH; MINT Investigators. Restrictive or Liberal Transfusion Strategy in Myocardial Infarction and Anemia. N Engl J Med. 2023 Dec 28;389(26):2446-2456. doi: 10.1056/NEJMoa2307983. Epub 2023 Nov 11. PMID: 37952133.
Bottom line: This was a prospective randomized trial of a restrictive (transfusion to target Hb 70-80 g/L) vs liberal (transfusion to target Hb 100 g/L) transfusion strategy in 3504 adult patients with STEMI or NSTEMI and anemia (Hb <100 g/L). The investigators found that a liberal strategy was non-superior to a restrictive strategy with respect to 30-day all-cause death and recurrent MI.
Major points:
1. The primary outcomes, death and recurrent MI, were numerically but not significantly increased in the restrictive group. Some of the secondary outcomes (which were not multiplicity-adjusted) appeared to favour a liberal strategy, and the overall safety of the liberal strategy was notable. Conversely, from a blood conservation standpoint, there was a large difference in the number of units of RBCs transfused in the liberal group without a clear clinical benefit.
2. The most obvious disadvantage of a liberal strategy in this patient population, the potential for volume overload, was cited as a potential reason for imperfect adherence to the liberal group’s transfusion threshold (which was 86.3%). Accordingly, the risk of volume overload from a liberal strategy is potentially underestimated in this trial.
3. The main numerical benefit for a liberal strategy was in the type 1 MI group (95% CI for risk ratio 1.04–1.67), whereas there appeared to be less benefit in the type 2 MI group (95% CI for risk ratio 0.85–1.29). Type 2 MI is common in the perioperative setting, and this study does not support a higher transfusion target in that patient population.
​
Devereaux PJ, Marcucci M, Painter TW, Conen D, Lomivorotov V, Sessler DI, Chan MTV, Borges FK, Martínez-Zapata MJ, Wang CY, Xavier D, Ofori SN, Wang MK, Efremov S, Landoni G, Kleinlugtenbelt YV, Szczeklik W, Schmartz D, Garg AX, Short TG, Wittmann M, Meyhoff CS, Amir M, Torres D, Patel A, Duceppe E, Ruetzler K, Parlow JL, Tandon V, Fleischmann E, Polanczyk CA, Lamy A, Astrakov SV, Rao M, Wu WKK, Bhatt K, de Nadal M, Likhvantsev VV, Paniagua P, Aguado HJ, Whitlock RP, McGillion MH, Prystajecky M, Vincent J, Eikelboom J, Copland I, Balasubramanian K, Turan A, Bangdiwala SI, Stillo D, Gross PL, Cafaro T, Alfonsi P, Roshanov PS, Belley-Côté EP, Spence J, Richards T, VanHelder T, McIntyre W, Guyatt G, Yusuf S, Leslie K; POISE-3 Investigators. Tranexamic Acid in Patients Undergoing Noncardiac Surgery. N Engl J Med. 2022 May 26;386(21):1986-1997. doi: 10.1056/NEJMoa2201171. Epub 2022 Apr 2. PMID: 35363452.
Bottom Line:
In patients with increased bleeding and cardiovascular risk undergoing inpatient noncardiac surgery, perioperative use of tranexamic acid significantly reduced the composite incidence of life-threatening bleeding, major bleeding, and bleeding into a critical organ at 30 days. This finding was consistent across patients undergoing all noncardiac surgery and both orthopedic and nonorthopedic noncardiac surgery in subgroup analysis.
Major Points:
1. Patients studied were 45 years of age or older undergoing inpatient noncardiac surgery at increased risk of bleeding or cardiovascular complications (identified as known atherosclerotic disease, major surgery, age of ≥70 years, and/or a serum creatinine level of >175 μmol/L). Exclusion criteria included cardiac surgery, intracranial neurosurgery, surgery where tranexamic acid administration was already planned, and patients with an eGFR <30 mL/min and/or were on dialysis.
​
2. Tranexamic acid administration was NOT found to be noninferior to placebo with regards to the composite safety outcome of myocardial infarction or isolated ischemic troponin elevation, nonhemorrhagic stroke, peripheral arterial thrombosis, and symptomatic proximal venous thromboembolism.
3. Tranexamic acid doses of 2g/day were evaluated in the study protocol and seizures were uncommon with a hazard ratio of 3.35; 95% CI, 0.92 to 12.20.
4. It is important to identify patients who may be at risk of increased perioperative bleeding and cardiovascular complications. Consider using a risk calculator, such as the Bleeding Independently associated with Mortality after noncardiac Surgery (BIMS) calculator, for perioperative bleeding risk evaluation, planning, and management.
​