Patient blood management in the ICU: A narrative review of the literature : European Journal of Anaesthesiology and Intensive Care

Secondary Logo

Journal Logo

REVIEW ARTICLE

Patient blood management in the ICU

A narrative review of the literature

Neef, Vanessa; Blum, Lea; Hof, Lotta; Choorapoikayil, Suma; Kieserling, Kira; Meybohm, Patrick; Steinbicker, Andrea U.; Zacharowski, Kai; Piekarski, Florian

Author Information
European Journal of Anaesthesiology and Intensive Care 1(2):p e002, April 2022. | DOI: 10.1097/EA9.0000000000000002
  • Open

Abstract

KEY POINTS

  • A restrictive transfusion strategy – considering individual compensation mechanisms – should be applied in a guideline-compliant approach.
  • The administration of intravenous iron and erythropoiesis-stimulating agents can be useful alternatives to RBC administration for non-emergency cases in iron deficiency anaemia but not for immediate oxygen support supply.
  • Reduction of iatrogenic blood loss and measures for haemostasis and coagulopathy are of great importance for ICU patients.

Introduction

Anaemia is defined by the WHO as a condition in which the number of red blood cell (RBC) concentrates or the haemoglobin (Hb) concentration is reduced or insufficient to meet the body's physiologic needs. In adults, anaemia is defined as Hb less than 13 g dl-1 in men and less than 12 g dl-1 in women.1 Overall, anaemia leads to a reduced quality of life, increased fatigue, impaired physical recovery as well as increased mortality after surgery.2–4 Major factors contributing to anaemia during the ICU stay are surgery, inflammation, occult bleeding and iatrogenic blood loss.

The cause of anaemia is multifactorial. Up to 50% of all anaemias are caused by iron deficiency.5 The second most common form of anaemia results from inflammatory, acute or chronic diseases, hence named anaemia of chronic disease (ACD) or anaemia of inflammation.6 For hospitalised patients, anaemia is aggravated by bleeding, blood sampling, decreased erythropoiesis, inflammation, malnutrition, vitamin deficiency, erythropoietin deficiency and many more causes.7 More than 60% of patients are anaemic at admission to the ICU and the prevalence increases up to 80% at the time of discharge from the ICU.2–4 The major cause of anaemia in ICU patients might differ during their stay. Patients admitted due to surgery or trauma usually present with iron deficiency anaemia (IDA) due to blood loss. This might be influenced by major surgery, which induces the iron regulatory hormone hepcidin and inflammatory processes, so that anaemia of chronic disease develops. Inflammation of any cause also contributes to anaemia of inflammation. In addition, continuous blood loss due to blood sampling often plays a major role. As inflammation is mostly cured prior to discharge, IDA dominates at discharge.

In general, infections influence the standard laboratory variables, leading to a diagnosis of anaemia. This review therefore discusses the possible role of the iron regulatory hormone hepcidin as a supportive measure to diagnose anaemia in ICU patients.

Historically, allogeneic RBC transfusions have been the primary means of increasing Hb concentrations and treating anaemia. A meta-analysis by Zhang et al.8 provided evidence that a more restrictive transfusion strategy in adult ICU patients can lead to a reduction in hospital mortality.

Patient blood management (PBM) is a multimodal and multidisciplinary programme to detect and treat anaemia, reduce blood loss and apply rational, evidence-based blood transfusion guidelines (Fig. 1).9 PBM programmes to achieve such targets have been successfully implemented in many hospitals around the world.10 In Germany, the implementation was first initiated at four University hospitals11 and then spread out to many other University and non-University hospitals.

F1
FIGURE 1:
Patient blood management measures in intensive care patients.

This review presents the current research of therapeutic treatment options for anaemia in the ICU and emphasises measures to reduce blood loss.

Therapeutic strategies: red blood cell, intravenous iron or erythropoietin?

In the ICU, management of anaemia is critical to maintain life. Overall, three major therapeutic options exist: RBC transfusion, intravenous iron substitution and erythropoietin supplementation.

Red blood cell transfusion

Obviously, a RBC transfusion is a treatment that increases Hb and thereby oxygen supply instantly. Indications include acute or chronic bleeding, volume deficiency or emergency situations with massive transfusion scenarios.12–14 However, RBCs are associated with a variety of complications, such as transfusion reactions. The most frequent serious transfusion reaction is transfusion-associated circulatory overload (TACO), which occurs in about 1% of transfusion procedures. Other major side effects are transfusion-related acute lung injury (TRALI) and anaphylactic reactions, which occur in 0.08 and 0.02% of cases, respectively. Minor reactions such as febrile non-haemolytic and allergic reactions occur more frequently with an incidence of 0.62 and 0.29% of blood transfusions, respectively.15

Transfusion triggers and thresholds

As the ICU patient cohort is heterogeneous, individual consideration is necessary in each case to decide upon RBC transfusions. Table 1 provides an overview of randomised controlled trials (RCTs) and meta-analyses comparing different Hb thresholds in different cohorts. Several studies showed that a restrictive transfusion threshold for critically ill patients does not increase mortality and length of hospital stay.8,16–21 The PBM Consensus Conference recommended an RBC transfusion threshold (Hb < 7 g dl-1) for critically ill but stable patients.22 A meta-analysis by Zang et al.8 also assessed this threshold of 7 g dl-1 as well tolerated in stable critically ill adults.

Table 1 - Randomised controlled trials and meta-analyses on transfusion threshold for critically ill patients
Reference Study design Study population/ Sample size Restrictive threshold Liberal threshold Primary outcomes/results
General ICU Hebert et al. 57 RCT ICU patients (n = 838) 7 g dl-1 10 g dl-1 No difference in overall 30-day mortality (18.7% restrictive versus 23.3% liberal; P = 0.11)
Walsh et al. 58 RCT ICU patients (n = 100) 7 to 9 g dl-1 9 to 11 g dl-1 Mortality at 180 days post randomisation trended towards higher rates in the liberal group (55%) than in the restrictive group (37%); relative risk was 0.68 (95% CI, 0.44 to 1.05; P = 0.073).
Carson et al. 59 Cochrane Review ICU patients (nine RCTs, n = 3529) 7 to 7.5 g dl-1 8 to 9 g dl-1 No clear effect on mortality of a restrictive compared with a liberal transfusion strategy (RR 1.06, 95% CI 0.85 to 1.32)
Yao et al. 21 Meta-analysis ICU patients (eight RCTs, n = 3415) 7 g dl-1 9 to 10 g dl-1 No significant difference in short-term mortality [OR: 0.90 (0.67 to 1.21) P = 0.48], length of hospital stay [SMD: -0.11 (-0.30 to 0.07), P = 0.24], length of ICU stay [SMD: -0.03 (-0.14 to 0.08), P = 0.54] or ischemic events [OR: 0.80 (0.43 to 1.48), P = 0.48]
Zang et al. 8 Meta-analysis ICU Patients (seven RCTs n = 7363) 7 g dl-1 9 g dl-1 No significant difference in ICU mortality [RR 0.82, (0.62 to 1.08) P = 0.15)], 28/30-day mortality [RR 0.98 (0.84 to 1.13), P = 0.74], 60-day mortality [RR 1.01, (0.87 to 1.16) P = 0.91], 90-day mortality [RR 1.02, (0.92 to 1.14) P = 0.69], 120-day mortality (RR 1.29 (0.67 to 2.47) P = 0.44], and 180-day mortality [RR 0.91, (0.75 to 1.12) P = 0.38]
Sepsis/Septic shock Holst et al. 16 RCT Septic shock (n = 998) 7 g dl-1 9 g dl-1 No significant difference in 90-day mortality [RR 0.94; (0.78–1.09) P = 0.44]
Bergamin et al. 60 RCT Adult cancer patients with septic shock (n = 300) < 7 g dl-1 < 9 g dl-1 Mortality rate (D 28) in the liberal group was 45% [67 patients) versus 56% (84 patients) in the restrictive group (hazard ratio, 0.74; 95% CI, 0.53 to 1.04; P = 0.08]
Cardiac surgery Mazer et al. 61 RCT Cardiac surgery (n = 5243) 7.5 g dl-1 9.5 g dl-1 Mortality was 3.0% in the restrictive-threshold group and 3.6% in the liberal-threshold group (odds ratio, 0.85; 95% CI, 0.62 to 1.16).
Murphy et al. 62 RCT Cardiac surgery (n = 2003) 7.5 g dl-1 9 g dl-1
Zeroual et al. 23 RCT n = 100 9 g dl-1, ScvO2 ≤65% 9 g dl-1 Less RBC transfusion in patients with restrictive transfusion threshold adjusted with Scvo2 [P < 0.001 odds ratio, 0.031 (0 to 0.153)]
Kashani et al. 17 Meta-analysis Patients after cardiac surgery (10 RCTs, n = 9101) 7 to 8 g dl-1, HCT 20 to 25% 8 to 10 g dl-1, HCT 25 to 32% No significant difference in mortality [RR 1.08 (0.76 to 1.54) I 2 = 33%]
Kheiri et al. 18 Systematic review and meta-analysis Patients after cardiac surgery (nine RCTs, n = 9005) 7 to 8 g dl-1 HCT <24 to 25% 8 to 9.5 g dl-1 HCT <28 to 32% No significant difference in mortality [RR 1.03 (0.74 to 1.45) P = 0.86], infections (RR 1.09 [0.94 to 1.26) P = 0.26], stroke [RR 0.998 (0.72 to 1.35) P = 0.91], myocardial infarction RR 1.0 (0.8 to 1.24) P = 0.99)
Cardiovascular disease Docherty et al. 19 Meta-analysis Cardiovascular disease in a noncardiac surgery setting (11 RCTs, n = 3033) 7 g dl-1 9 g dl-1 No significant difference in 30d mortality: RR: 1.15 (0.88–1.50, P = 0.50), with little heterogeneity (I 2 = 14%). The risk of acute coronary syndrome in liberal transfusion was increased (nine trials; RR 1.78 (1.18 to 2.70), P = 0.01, I 2 = 0%).
Acute coronary syndrome Ducrocq et al. 63 RCT Patients with acute myocardial infarction and anaemia (n = 666) 8 g dl-1 10 g dl-1 Risk for major adverse cardiovascular events (MACE) composite of all-cause death, stroke, recurrent myocardial infarction or emergency revascularisation prompted by ischemia. RR MACE restrictive versus liberal: 0.79 (0.00 to 1.19).
Gastrointestinal bleeding Odutayo et al. 20 Systematic review and meta-analysis Five RCTs, n = 1965 <7 to 8 g dl-1 <9 to 10 g dl-1 Restrictive transfusion was associated with lower risk of all-cause mortality [RR: 0.65 (0.44 to 0.97) P = 0.03] and rebleeding overall [RR 0.58 (0.40 to 0.84, P = 0.004]. No significant difference in risk of ischaemic events.
Neurosurgery/Neurology Robertson et al. 64 RCT Association between liberal transfusion threshold and progressive haemorrhagic injury (PHI) in patients with traumatic brain injury (n = 200) 7 g dl-1 10 g dl-1 Adjusted risk of severe PHI was 2.3 times higher for patients with a liberal transfusion threshold (95% confidence interval 1.1 to 4.7; P = 0.02)
Transfusion Strategies in Acute Brain Injured Patients) (TRAIN) RCT Traumatic brain injury, subarachnoid haemorrhage or intracranial haemorrhage 7 g dl-1 9 g dl-1 Ongoing study (primary outcome: neurological Outcome defined by the extended Glasgow Outcome Scale (eGOS))ClinicalTrials.gov Identifier: NCT02968654
Burns Palmieri et al. 65 RCT 20% or more total body surface area burn patients (n = 345) 7 to 8 g dl-1 10 to 11 g dl-1 No significant difference in blood stream infection incidence, organ dysfunction, ventilator days, time to wound healing and 30-day mortality.
Elderly Meybohm et al. 66 RCT 2470 elderly (≥70 years) patients undergoing intermediate- or high-risk noncardiac surgery. 7.5 to 9 g dl-1 9 to 10.5 g dl-1 Ongoing RCT

A vulnerable group of patients are those with cardiovascular diseases, as they display a special risk profile and often present with ischemic complications. The recent meta-analysis by Zang et al.8 also showed no significant difference in mortality between restrictive and liberal transfusion thresholds in critically ill patients after cardiac surgery (Table 1). A RCT by Zeroual et al.23 examined the effect of measurement of central venous oxygen saturation on the indication to transfuse RBCs. The data indicate a significantly lower RBC consumption in patients who received RBCs at ScvO2 below 65%.23

Physicians should decide on RBC transfusion based on transfusion triggers, symptoms caused by anaemia and the lack of oxygen carrier (resulting in a mismatch of oxygen demand and consumption), including tachycardia, hypotension, dyspnoea, ST-segment elevation or decrease, new cardiac arrhythmias, new-onset regional wall motion abnormality (RWMA) and signs of increased oxygen consumption [mixed venous oxygen saturation (SvO2) <50%, ScvO2 <65 to 70%, lactic acidosis type A].24

Intravenous iron substitution

The second therapeutic option to treat anaemia is with intravenous iron substitution. In IDA, the most common form of anaemia in the general population, the substrate to build RBCs in the bone marrow, is missing.25 On the ICU, IDA is rare.26 In a study by Peters et al.,26 anaemia prevalence was, at 86%, very high in a cohort of cardiac surgical patients. However, only about 10 to 20% presented with IDA. In contrast, the majority of patients on the ICU present with anaemia of inflammation, also termed ‘anaemia of chronic disease’. This form of anaemia, which is the most common type of anaemia in ICU patients, is characterised by an induction of hepcidin. Hepcidin, the iron regulatory protein, is synthesised by multiple stimuli such as cytokines, activation of the bone morphogenetic pathway and iron.25 In contrast, hepcidin synthesis is inhibited by erythropoietic demand, hypoxia and hormonal stimulation such as oestrogens.25 Iron is one component of RBC transfusion, so that RBC transfusion increases free iron concentrations and serum hepcidin concentrations. In addition, prolonged surgery causes an induction of hepcidin. The latter then binds to ferroportin, the known iron export channel expressed in enterocytes, hepatocytes and macrophages. As a consequence, iron absorption from the diet and iron release from iron storage cells is inhibited; thus anaemia of inflammation develops.7,25 Peters et al.26 investigated the option to treat ICU patients directly upon 24 h after arrival on the ICU with intravenous iron. Only 18% of patients presented with IDA. Patients with IDA treated with 500 mg of iron carboxymaltose were compared with nontreated IDA patients. IVI treatment with iron carboxymaltose associated with a median Hb increase of +0.4 g dl-1 (IQR -0.9 to 1.2) versus -0.1 g dl-1 (IQR: -0.5 to 0.7) in the control group after 7 days.26 Khalafallah et al.27 showed in a prospective, open-label, randomised, controlled study of patients at two centres (a general hospital and a private healthcare centre) in Tasmania, Australia, that Hb concentrations increased in ICU patients with IDA undergoing elective surgery after 4 weeks by 0.7 g dl-1 after a single dose of intravenous 1000 mg ferric carboxymaltose in comparison with standard care. Compared with weekly blood loss, this effect seems low, but undeniable. A multicentre, randomised controlled trial pilot study was performed in which anaemic patients were treated with or without 1000 mg iron carboxymaltose upon discharge from the ICU.28 Patients treated with intravenous iron had higher Hb concentrations after 28 and 90 days, while the re-admission rate to the hospital was lower. We would now expect a large RCT following this pilot RCT.

During the stay in the ICU, inflammation is treated and the acute phase reaction decreases. Hepcidin serum concentrations also decrease, and IDA develops. Whether hepcidin is a predictor of iron deficiency at discharge from the ICU was assessed in a prospective, multicentre trial study performed in 28 ICUs.29 The investigators followed survivors up to 1 year after ICU discharge and measured all-cause mortality and poor quality of life as the primary end-points. At discharge, 1161 patients had blood drawn in which serum hepcidin was determined. Hepcidin concentration indicated iron deficiency at release from the ICU in 37% of patients and was an independent predictor of 1-year mortality and poor physical recovery.29

In the following randomised trial, hepcidin-guided treatment was investigated after discharge from the ICU.30 In total, 399 patients were randomised at anticipated discharge from the ICU and divided into an intervention and control group. Absolute iron deficiency was defined as a hepcidin concentration less than 20 μg l-1 and functional iron deficiency as a hepcidin level from 20 μg l-1 to less than 41 μg l-1. In the intervention group, intravenous iron was given if hepcidin concentration was less than 20 μg l-1, and iron and erythropoietin were substituted if serum hepcidin concentration was between 20 and 41 μg l-1 or less. The analyses indicate that the hepcidin-guided treatment resulted in a significant reduction of 90-day mortality and an improvement of 1-year survival rate.30

These studies show and collectively suggest that IDA develops during ICU stay. Therefore, treatment with intravenous iron directly on admission to the ICU is considered critical due to hepcidin induction and dysregulation of the hepcidin/ferroportin circuitry. Consequently, patients should be treated at least until discharge from the ICU to improve survival and quality of life.

The other ‘iron markers’ transferrin and ferritin are only of limited significance in critically ill patients due to their function as acute-phase proteins. Cut-off values for ferritin concentrations in patients with chronic inflammatory conditions are controversial. A consensus statement provided guidance on the cut-off concentrations to start intravenous iron therapy in chronic diseases (such as heart failure, renal insufficiency, chronic inflammatory bowel syndrome or rheumatoid arthritis and cancer), and suggested that threshold ferritin and transferrin saturation should be increased below 300 ng ml-1 and below 20%, respectively.31 In addition, ferritin and iron also contribute to serum hepcidin induction, so that serum hepcidin concentrations might be valuable diagnostic markers in the future to guide anaemia treatment in ICU patients.32 However, hepcidin has not yet been established as a routine test.

Erythropoietin

Erythropoietin (EPO) is another compound that increases RBC synthesis. EPO promotes terminal differentiation of progenitor cells into erythrocytes in the bone marrow. Several stimuli including reduced oxygen availability due to anaemia, hypotension or hypoxaemia induce EPO production. EPO is mainly produced in the kidney and in small amounts in the liver; EPO deficiency is expected in chronic kidney disease and frequently used in haemodialysis patients. Inflammatory mediators such as interleukin-1 (IL-1) and tumour necrosis factor (TNF), which are expressed in critically ill patients, can inhibit EPO production.33

But which role does EPO play in anaemia treatment in ICU patients? One systematic review and one meta-analysis investigated pre-operative erythropoietin substitution in critically ill patients.34,35 EPO administration was associated with survival benefits in critically ill patients. This analysis by Litton et al.34 showed that in-hospital mortality was lower in the EPO group (12.6%) than in the comparison group (15.4%) [relative risk (RR) 0.82, 95% CI 0.71 to 0.94, P = 0.006, I2 = 0.0%]. The RR of SAEs and thromboembolic events for the EPO and comparison groups were found similar. Data from animal models suggest that the beneficial effects of EPO therapy in critical illness may be mediated by anti-inflammatory and anti-apoptotic effects that target a common pathway of severe systemic inflammation that occurs in a variety of critically ill patients.36

The National Institute for Health and Care Excellence in the UK-(NICE) recommends intravenous iron substitution in patients with chronic kidney disease patients with IDA. Therapy with EPO should not be started in the presence of absolute iron deficiency without also managing iron deficiency. The application of EPO should be carried out under a risk-benefit assessment and under constant control of the effects.37

Nevertheless, treatment should be guided individually, as the risk of thromboembolic events associated with EPO is still under investigation. In addition, a novel biosimilar for EPO-stimulating agent has received approval in the USA.38

Treatment of other causes of anaemia

Rare causes of anaemia include vitamin A, C, B12 or folic acid deficiency as well as genetic inherited causes for anaemia. Vitamin B12 and folic acid are essential for normal erythrocyte growth. Deficiency can contribute to impaired erythropoiesis in critically ill patients. Rodriguez et al.36 demonstrated vitamin B12 deficiency and folic acid deficiency at 2% each in ICU patients. In a randomised trial investigating the effect of vitamin C on pathological parameters and survival of critically ill patients infected with SARS-CoV2 coronavirus disease in 2019, there was no effect on Hb concentration after daily administration of 500 mg of vitamin C for 14 days.39

These therapeutic strategies in the case of a deficiency should be approached individually, as they are seldom.

Reduction of iatrogenic blood loss

Critically ill patients are at a high risk to develop hospital-acquired anaemia (HAA), which is associated with prolonged hospital stay, increased risk for complications and mortality.40,41 One of the main causes for HAA is iatrogenic blood loss due to phlebotomy. A systematic review by Helmer et al.42 revealed differences in phlebotomised blood volumes between ICUs. In a general ICU, Jackson Chornenki et al.43 estimated a daily iatrogenic blood loss of 25 (14–43) ml accumulating to 213 (133 to 382) ml throughout the ICU stay [5 (3 to 10) days].43 For 24 critically ill COVID-19 patients, Beverina et al.44 calculated a phlebotomy volume of 719 (424 to 1342) ml throughout a length of stay of 29 (20–43) days. In healthy individuals, about 50 ml of blood are newly produced per day, which, however, is potentially impaired in critically ill patients. Subsequently, it is not surprising that 45 to 50% of the ICU patients require at least one blood transfusion.41,43–45

Especially in ICU patients, frequent laboratory diagnostic tests are vital. However, blood collection unadjusted towards the patients’ needs results in unnecessarily drawn and subsequently discarded blood. One of the main factors contributing to the large phlebotomy volumes is discarded blood arising in the blood withdrawal procedure.41 Several measures exist to prevent iatrogenic blood loss, such as switching to small-volume blood collection tubes, closed-loop systems, point-of-care diagnostic tests or continuous intravascular sensors.46–48 Consequently, it is important to raise awareness for the harm of iatrogenic blood loss in ICU patients and frequently train personnel in their diagnostic decisions.

Measures for haemostasis and coagulopathy

Severe bleeding is common in ICU patients. Coagulopathies may be caused by anticoagulation medications, hyperfibrinolysis, haemodilution due to major surgery or hypothermia due to trauma. In ongoing major bleeding episodes, it is therefore crucial to understand the underlying causes in order to provide effective treatment. Overall, it is of high relevance to maintain physiological conditions to support haemostasis. Physiological conditions include a body temperature more than 35°C, a physiological pH more than 7.2 and ionised calcium more than 1.0 mmol l-1.49 In case hyperfibrinolysis is the cause of major bleeding, administration of tranexamic acid (TXA) is recommended. TXA does not only reduce bleeding in patients undergoing elective surgery, but also has been especially recommended in trauma patients. Early treatment (≤1 h since injury) significantly reduces the risk of death due to bleeding compared with placebo (P < 0.001).50,51 For some time now, uncertainty has existed about a potential association between TXA and increased thromboembolic events. Taeuber et al.52 performed a meta-analysis of 216 studies and 125 550 patients, which revealed that intravenous TXA, irrespective of dosing, is not associated with an increased risk of thromboembolic events. In addition, point-of-care diagnostic tests (e.g., rotational thromboelastometry) are a helpful method for differentiated decision making in coagulation management. This method allows a goal-directed therapy with specific haemostatic drugs (e.g. fibrinogen), coagulation factor concentrates, prothrombin complex concentrate and blood products (e.g. platelets).53 A study by Weber et al.54 in cardiac surgery patients demonstrated that the use of POC testing significantly reduces the median RBC transfusion rate compared with conventional coagulation analyses [3 (2;6) versus 5 (4;9) units (25th and 75th percentile), P < 0.001].

Cell salvage in ICU patients

Cell salvage collects blood by aspiration of the operative field to produce autologous RBC for re-transfusion. Thus, cell salvage aims to reduce the need for allogeneic RBC transfusion and may therefore decrease the risk associated with the use of allogeneic blood products.55 Bleeding after cardiac surgery is a well known serious complication increasing the rate of requirement of allogeneic blood transfusion. In these cases, blood may be collected by cell salvage and re-infused into the patient. Despite the fact that cell salvage is mainly an intra-operative measure, it may be used especially in cardiac surgery patients with postoperative major bleeding in the ICU. A Cochrane review of 29 trials on postoperative cell salvage used in cardiac and orthopaedic surgery revealed a reduction of allogeneic RBCs by 41% (RR 0.59; 95% CI 0.48 to 0.73).56

Conclusion

PBM measures must be established in intensive care to ensure blood conservation and a guideline-adherent transfusion strategy. Measures such as point of care diagnostic tests and the use of cell salvage can help reduce blood loss in the ICU. Research is still needed on transfusion thresholds, but there is evidence that a restrictive strategy is not disadvantageous for the patient. The use of intravenous iron and erythropoietin can be part of an individualised and patient-centred therapy. Measurement of serum hepcidin concentration may introduce a new method to improve diagnosis and treatment of anaemia in the ICU.

Acknowledgements relating to this article

Assistance with the article: none.

Financial support and sponsorship: this review was supported by internal institutional research funds from the Department of Anaesthesiology, Intensive Care and Pain Therapy, University Hospital Frankfurt, Goethe University, Frankfurt, Germany.

Conflicts of interest: VN, LB, LH, SC and KK have no conflicts of interest. PM received honoraria for scientific lectures from CSL Behring GmbH and ViforPharma GmbH, and is supported by the German Research Foundation (Deutsche Forschungsgemeinschaft) grant ME3559/3-1 to perform a multicentre, prospective trial on RBC transfusion triggers. AUS is supported by the German Research Foundation (Deutsche Forschungsgemeinschaft) grant STE 1895/9-1, STE 1895/10-1 and a research grant from Pharmacosmos, Denmark, to perform a single-centre, prospective trial on pre-operative anaemia treatment. KZ and his department received support from B. Braun Melsungen, CSL Behring, Fresenius Kabi and Vifor Pharma for the implementation of Frankfurt‘s Patient Blood Management programme and received honoraria for scientific lectures from CSL Behring, implatcast GmbH, med Update GmbH, Pharmacosmos, GE Healthcare and Vifor Pharma and received honoraria for participation in advisory board meetings for Haemonetics and Vifor. He is the Principal Investigator of the EU-Horizon 2020 project ENVISION (Intelligent plug-and-play digital tool for real-time surveillance of COVID-19 patients and smart decision-making in Intensive Care Units) and Horizon Europe 2021 project COVend (Biomarker and AI-supported FX06 therapy to prevent progression from mild and moderate to severe stages of COVID-19). FP received honoraria from Pharmacosmos for scientific lectures.

Presentation: none.

References

1. World Health Organization Haemoglobin concentrations for the diagnosis of anaemia and assessment of severity. 2011; Switz World Heal Organ, Geneva:1-6.
2. Docherty AB, Turgeon AF, Walsh TS. Best practice in critical care: anaemia in acute and critical illness. Transfus Med 2018; 28:181–189.
3. Walsh TS, Saleh EE, Lee RJ, McClelland DB. The prevalence and characteristics of anaemia at discharge home after intensive care. Intensive Care Med 2006; 32:1206–1213.
4. van der Laan S, Billah T, Chi C, et al. Anaemia among intensive care unit survivors and association with days alive and at home: an observational study. Anaesthesia 2021; 76:1352–1357.
5. Pasricha SR, Tye-Din J, Muckenthaler MU, Swinkels DW. Iron deficiency. Lancet 2021; 397:233–248.
6. Ganz T. Anemia of Inflammation. N Engl J Med 2019; 381:1148–1157.
7. Peters F, Ellermann I, Steinbicker AU. Intravenous iron for treatment of anemia in the 3 perisurgical phases: a review and analysis of the current literature. Anesth Analg 2018; 126:1268–1282.
8. Zhang W, Zheng Y, Yu K, Gu J. Liberal transfusion versus restrictive transfusion and outcomes in critically ill adults: a meta-analysis. Transfus Med Hemother 2021; 48:60–68.
9. Meybohm P, Richards T, Isbister J, et al. Patient blood management bundles to facilitate implementation. Transfus Med Rev 2017; 31:62–71.
10. Althoff FC, Neb H, Herrmann E, et al. Multimodal patient blood management program based on a three-pillar strategy: a systematic review and meta-analysis. Ann Surg 2019; 269:794–804.
11. Meybohm P, Herrmann E, Steinbicker AU, et al. Patient blood management is associated with a substantial reduction of red blood cell utilization and safe for patient's outcome: a prospective, multicenter cohort study with a noninferiority design. Ann Surg 2016; 264:203–211.
12. Vincent JL, Baron JF, Reinhart K, et al. Anemia and blood transfusion in critically ill patients. JAMA 2002; 288:1499–1507.
13. Walsh TS, Lee RJ, Maciver CR, et al. Anemia during and at discharge from intensive care: the impact of restrictive blood transfusion practice. Intensive Care Med 2006; 32:100–109.
14. Vincent JL, Jaschinski U, Wittebole X, et al. Worldwide audit of blood transfusion practice in critically ill patients. Crit Care 2018; 22:102.
15. Hendrickson JE, Roubinian NH, Chowdhury D, et al. Incidence of transfusion reactions: a multicenter study utilizing systematic active surveillance and expert adjudication. Transfusion 2016; 56:2587–2596.
16. Holst LB, Haase N, Wetterslev J, et al. Lower versus higher hemoglobin threshold for transfusion in septic shock. N Engl J Med 2014; 371:1381–1391.
17. Kashani HH, Lodewyks C, Kavosh MS, et al. The effect of restrictive versus liberal transfusion strategies on longer-term outcomes after cardiac surgery: a systematic review and meta-analysis with trial sequential analysis. Can J Anaesth 2020; 67:577–587.
18. Kheiri B, Abdalla A, Osman M, et al. Restrictive versus liberal red blood cell transfusion for cardiac surgery: a systematic review and meta-analysis of randomized controlled trials. J Thromb Thrombolysis 2019; 47:179–185.
19. Docherty AB, O’Donnell R, Brunskill S, et al. Effect of restrictive versus liberal transfusion strategies on outcomes in patients with cardiovascular disease in a noncardiac surgery setting: systematic review and meta-analysis. BMJ 2016; 352:i1351.
20. Odutayo A, Desborough MJ, Trivella M, et al. Restrictive versus liberal blood transfusion for gastrointestinal bleeding: a systematic review and meta-analysis of randomised controlled trials. Lancet Gastroenterol Hepatol 2017; 2:354–360.
21. Yao RQ, Ren C, Zhang ZC, et al. Is haemoglobin below 7.0 g/dL an optimal trigger for allogenic red blood cell transfusion in patients admitted to intensive care units? A meta-analysis and systematic review. BMJ Open 2020; 10:e030854.
22. Mueller MM, Van Remoortel H, Meybohm P, et al. Patient blood management: recommendations from the 2018 Frankfurt Consensus Conference. JAMA 2019; 321:983–997.
23. Zeroual N, Blin C, Saour M, et al. Restrictive transfusion strategy after cardiac surgery. Anesthesiology 2021; 134:370–380.
24. Vallet B, Adamczyk S, Barreau O, Lebuffe G. Physiologic transfusion triggers. Best Pract Res Clin Anaesthesiol 2007; 21:173–181.
25. Steinbicker AU, Muckenthaler MU. Out of balance: systemic iron homeostasis in iron-related disorders. Nutrients 2013; 5:3034–3061.
26. Peters F, Eveslage M, Gallitz I, et al. Post-operative iron carboxymaltose may have an effect on haemoglobin levels in cardiothoracic surgical patients on the ICU: an observational pilot study about anaemia treatment with intravenous iron. Transfus Med Hemother 2018; 45:42–46.
27. Khalafallah AA, Yan C, Al-Badri R, et al. Intravenous ferric carboxymaltose versus standard care in the management of postoperative anaemia: a prospective, open-label, randomised controlled trial. Lancet Haematol 2016; 3:e415–e425.
28. Shah A, Chester-Jones M, Dutton SJ, et al. Intravenous iron to treat anaemia following critical care: a multicentre feasibility randomised trial. Br J Anaesth 2022; 128:272–282.
29. Lasocki S, Lefebvre T, Mayeur C, et al. Iron deficiency diagnosed using hepcidin on critical care discharge is an independent risk factor for death and poor quality of life at one year: an observational prospective study on 1161 patients. Crit Care 2018; 22:314.
30. Lasocki S, Asfar P, Jaber S, et al. Impact of treating iron deficiency, diagnosed according to hepcidin quantification, on outcomes after a prolonged ICU stay compared to standard care: a multicenter, randomized, single-blinded trial. Crit Care 2021; 25:62.
31. Cappellini MD, Comin-Colet J, de Francisco A, et al. Iron deficiency across chronic inflammatory conditions: international expert opinion on definition, diagnosis, and management. Am J Hematol 2017; 92:1068–1078.
32. Shah A, Wray K, James T, et al. Serum hepcidin potentially identifies iron deficiency in survivors of critical illness at the time of hospital discharge. Br J Haematol 2019; 184:279–281.
33. Jelkmann WE, Fandrey J, Frede S, Pagel H. Inhibition of erythropoietin production by cytokines. Implications for the anemia involved in inflammatory states. Ann N Y Acad Sci 1994; 718:300–309. discussion 9-11.
34. Litton E, Latham P, Inman J, et al. Safety and efficacy of erythropoiesis-stimulating agents in critically ill patients admitted to the intensive care unit: a systematic review and meta-analysis. Intensive Care Med 2019; 45:1190–1199.
35. French CJ, Glassford NJ, Gantner D, et al. Erythropoiesis-stimulating agents in critically ill trauma patients: a systematic review and meta-analysis. Ann Surg 2017; 265:54–62.
36. Nairz M, Sonnweber T, Schroll A, et al. The pleiotropic effects of erythropoietin in infection and inflammation. Microbes Infect 2012; 14:238–246.
37. National Institute for Healthcare Excellence. Chronic kidney disease: assessment and management NICE guideline [NG203]. 2021. Available at: https://www.nice.org.uk/guidance/ng203, Published: 25 August 2021 Last updated: 24 November 2021
38. Anand S, Al-Mondhiry J, Fischer K, Glaspy J. Epoetin alfa-epbx: a new entrant into a crowded market. a historical review of the role of erythropoietin stimulating agents and the development of the first epoetin biosimilar in the United States. Expert Rev Clin Pharmacol 2021; 14:1–8.
39. Majidi N, Rabbani F, Gholami S, et al. The effect of vitamin C on pathological parameters and survival duration of critically ill coronavirus disease 2019 patients: a randomized clinical trial. Front Immunol 2021; 12:717816.
40. Shander A, Corwin HL. A narrative review on hospital-acquired anemia: keeping blood where it belongs. Transfus Med Rev 2020; 34:195–199.
41. Bodley T, Chan M, Levi O, et al. Patient harm associated with serial phlebotomy and blood waste in the intensive care unit: A retrospective cohort study. PLoS One 2021; 16:e0243782.
42. Helmer P, Hottenrott S, Steinisch A, et al. Avoidable blood loss in critical care and patient blood management: scoping review of diagnostic blood loss. J Clin Med 2022; 11:320.
43. Jackson Chornenki NL, James TE, Barty R, et al. Blood loss from laboratory testing, anemia, and red blood cell transfusion in the intensive care unit: a retrospective study. Transfusion 2020; 60:256–261.
44. Beverina I, Borotto E, Novelli C, et al. Iatrogenic anaemia and transfusion thresholds in ICU patients with COVID-19 disease at a tertiary care hospital. Transfus Apher Sci 2021; 60:103068.
45. Koch CG, Reineks EZ, Tang AS, et al. Contemporary bloodletting in cardiac surgical care. Ann Thorac Surg 2015; 99:779–784.
46. Adam EH, Zacharowski K, Hintereder G, et al. Validation of a new small-volume sodium citrate collection tube for coagulation testing in critically ill patients with coagulopathy. Clin Lab 2018; 64:1083–1089.
47. Siegal DM, Manning N, Jackson Chornenki NL, et al. Devices to reduce the volume of blood taken for laboratory testing in ICU patients: a systematic review. J Intensive Care Med 2020; 35:1074–1079.
48. Crane BC, Barwell NP, Gopal P, et al. The development of a continuous intravascular glucose monitoring sensor. J Diabetes Sci Technol 2015; 9:751–761.
49. Lier H, Krep H, Schroeder S, Stuber F. Preconditions of hemostasis in trauma: a review. The influence of acidosis, hypocalcemia, anemia, and hypothermia on functional hemostasis in trauma. J Trauma 2008; 65:951–960.
50. Roberts I, Shakur H, Coats T, et al. The CRASH-2 trial: a randomised controlled trial and economic evaluation of the effects of tranexamic acid on death, vascular occlusive events and transfusion requirement in bleeding trauma patients. Health Technol Assess 2013; 17:1–79.
51. CRASH-3 trial collaborators Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial. Lancet 2019; 394:1713–1723.
52. Taeuber I, Weibel S, Herrmann E, et al. Association of intravenous tranexamic acid with thromboembolic events and mortality: a systematic review, meta-analysis, and meta-regression. JAMA Surg 2021; 156:e210884.
53. Lier H, Vorweg M, Hanke A, Gorlinger K. Thromboelastometry guided therapy of severe bleeding. Essener Runde algorithm. Hamostaseologie 2013; 33:51–61.
54. Weber CF, Gorlinger K, Meininger D, et al. Point-of-care testing: a prospective, randomized clinical trial of efficacy in coagulopathic cardiac surgery patients. Anesthesiology 2012; 117:531–547.
55. Pinto MA, Chedid MF, Sekine L, et al. Intraoperative cell salvage with autologous transfusion in liver transplantation. World J Gastrointest Surg 2019; 11:11–18.
56. Carless PA, Henry DA, Moxey AJ, et al. Cell salvage for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev 2010; CD001888.
57. Hebert 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; 340:409–417.
58. Walsh TS, Boyd JA, Watson D, et al. Restrictive versus liberal transfusion strategies for older mechanically ventilated critically ill patients: a randomized pilot trial. Crit Care Med 2013; 41:2354–2363.
59. Carson JL, Stanworth SJ, Dennis JA, et al. Transfusion thresholds for guiding red blood cell transfusion. Cochrane Database Syst Rev 2021; 12:CD002042.
60. Bergamin FS, Almeida JP, Landoni G, et al. Liberal versus restrictive transfusion strategy in critically ill oncologic patients: the transfusion requirements in critically Ill oncologic patients randomized controlled trial. Crit Care Med 2017; 45:766–773.
61. Mazer CD, Whitlock RP, Fergusson DA, et al. Restrictive or liberal red-cell transfusion for cardiac surgery. N Engl J Med 2017; 377:2133–2144.
62. Murphy GJ, Pike K, Rogers CA, et al. Liberal or restrictive transfusion after cardiac surgery. N Engl J Med 2015; 372:997–1008.
63. Ducrocq G, Gonzalez-Juanatey JR, Puymirat E, et al. Effect of a restrictive vs liberal blood transfusion strategy on major cardiovascular events among patients with acute myocardial infarction and anemia: the REALITY randomized clinical trial. JAMA 2021; 325:552–560.
64. Robertson CS, Hannay HJ, Yamal JM, et al. Effect of erythropoietin and transfusion threshold on neurological recovery after traumatic brain injury: a randomized clinical trial. JAMA 2014; 312:36–47.
65. Palmieri TL, Holmes JHt, Arnoldo B, et al. Transfusion requirement in burn care evaluation (TRIBE): a multicenter randomized prospective trial of blood transfusion in major burn injury. Ann Surg 2017; 266:595–602.
66. Meybohm P, Lindau S, Treskatsch S, et al. Liberal transfusion strategy to prevent mortality and anaemia-associated, ischaemic events in elderly non-cardiac surgical patients - the study design of the LIBERAL-Trial. Trials 2019; 20:101.

Vanessa Neef, Lea Blum, Kai Zacharowski and Florian Piekarski contributed equally to this work.

Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Society of Anaesthesiology and Intensive Care.