key: cord-0863305-6znw9zcz
authors: Baron, D. M.; Franchini, M.; Goobie, S. M.; Javidroozi, M.; Klein, A. A.; Lasocki, S.; Liumbruno, G. M.; Muñoz, M.; Shander, A.; Spahn, D. R.; Zacharowski, K.; Meybohm, P.
title: Patient blood management during the COVID–19 pandemic: a narrative review
date: 2020-05-06
journal: Anaesthesia
DOI: 10.1111/anae.15095
sha: 09ea585a48301ff089231f69c00e949ed5502c6f
doc_id: 863305
cord_uid: 6znw9zcz

As COVID–19 disease escalates globally, optimising patient outcome during this catastrophic healthcare crisis is the number one priority. The principles of patient blood management are fundamental strategies to improve patient outcomes and should be given high priority in this crisis situation. The aim of this expert review is to provide clinicians and healthcare authorities with information regarding how to apply established principles of patient blood management during the COVID–19 pandemic. In particular, this review considers the impact of the COVID–19 pandemic on blood supply and specifies important aspects of donor management. We discuss how preventative and control measures implemented during the COVID–19 crisis could affect the prevalence of anaemia, and highlight issues regarding the diagnosis and treatment of anaemia in patients requiring elective or emergency surgery. In addition, we review aspects related to patient blood management of critically ill patients with known or suspected COVID–19, and discuss important alterations of the coagulation system in patients hospitalised due to COVID–19. Finally, we address special considerations pertaining to supply‐demand and cost‐benefit issues of patient blood management during the COVID–19 pandemic.

In December 2019, the first reports of patients with coronavirus disease 2019 (COVID-19) emerged, a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1] . Over the course of a few months, COVID-19 has spread globally, with more than 2.8 million confirmed cases at the time of writing [2] . This prompted the World Health Organization (WHO) to declare the COVID-19 outbreak a pandemic [3] . During times of crisis, clinicians are constantly being pushed to their limits. As numbers of patients with COVID-19 are continuing to increase, new scientific findings need to be integrated into routine clinical practice. However, established evidence-based medical concepts should still be followed when treating patients.

Patient blood management is a multimodal, multidisciplinary approach based on timely application of a bundle of evidence-based medical and surgical concepts aimed at improving the outcome of patients at risk [4] . The three pillars of patient blood management encompass measures to optimise the patient's red cell mass, reduce peri-operative blood loss and enhance anaemia tolerance [5] . In addition, patient blood management implementation results in reduced transfusion rates and lower healthcare costs [6, 7] . These aspects are crucial for national medical systems during times when resources and funding are limited. The aim of this expert review is to provide clinicians and healthcare authorities with information on how to apply the principles of patient blood management during the COVID-19 pandemic.

This article is a focused expert review. The authors used 

In most countries around the world, COVID-19 has generated an unprecedented healthcare and socioeconomic emergency. As a consequence of social restrictions made by governments to fight the spread of COVID-19, the number of blood donations has significantly decreased during the last few weeks. In addition, although to our knowledge there has been no scientifically documented evidence yet of the transmission of COVID-19 infection through transfusion of blood components, the current outbreak has produced a heated debate regarding the safety of blood donations in endemic countries [8] . 

The Italian National Blood Centre (Centro Nazionale Sangue, CNS), the Health Ministry's technical and scientific advisory body on matters related to blood and blood products, has issued a number of measures aimed at maintaining high standards of blood donation and blood safety in Italy, one of the countries with a higher incidence of COVID-19-related casualties worldwide [10] :

1 Strengthen surveillance measures of individuals in contact with subjects with documented COVID-19; 2 Defer blood donations from donors returning from any national or international territory with a travel health notice for 14 days, donors who have possibly been 

In major elective surgery, patients can be exposed to the effects of pre-operative anaemia, blood loss and red cell transfusion, all of which adversely influence postoperative outcome [11, 12] . In patients undergoing major surgical procedures, it is recommended that pre-operative anaemia be defined by haemoglobin < 130 g.l À1 , irrespective of sex [13, 14] . Using this definition, in a large cohort of major elective procedures, the overall prevalence of pre-operative anaemia was 36%. Over 70% of anaemic patients presented with absolute or functional iron deficiency, resulting in ironrestricted erythropoiesis [15] . In addition, pre-operative iron deficiency in patients undergoing cardiac surgery is associated with a three-fold increased 90-day mortality [16] .

Non-anaemic haematinic deficiencies are also prevalent and may hamper pre-operative haemoglobin optimisation and/or recovery from postoperative anaemia [5, 15] . As for non-elective procedures, up to 75% of patients undergoing hip fracture repair surgery presented with haemoglobin < 130 g.l À1 on admission [17] .

These figures could be expected to increase during the COVID-19 pandemic due to changes in diet and lifestyle, aggravated by a reduced purchasing power and decreased incomes. Possible consequences include: a reduced consumption of fresh food, including fruit and vegetables (vitamin C, folic acid), dairy products (vitamin D), fish and meat (iron, vitamin B6, vitamin B12); and a lack of sunlight exposure and muscle atrophy resulting from curfew restrictions and social distancing. Consequently, proliferation of red cell progenitors, iron homeostasis and haemoglobin synthesis, as well as overall physical and mental performance, could be affected [18, 19] . Depending on their general health condition and the duration of the COVID-19 pandemic, the elderly are likely to be the most affected [20] . Most importantly, this population has the greatest comorbidity load and represents the largest proportion of hospitalised medical and surgical patients.

During the COVID-19 pandemic, elective medical activity is markedly reduced and elective surgery is frequently postponed, with priority given to urgent and emergency surgery. Pre-operative anaemia clinics, which function to screen, diagnose, and treat iron deficiency and other causes of anaemia are mostly closed and appointments cancelled. anxiety; low mood/depression; aching and restless legs; alopecia, brittle/ridged fingernails; and pica (appetite for non-nutritive substances). Patients with these symptoms should be expedited to iron therapy. Iron deficiency anaemia may worsen over time, so early treatment is favoured. Intravenous (i.v.) iron administration is preferred, either via anaemia clinics or through general practitioners as it yields rapid results. However, as administering i.v. iron might not be feasible during the pandemic, oral iron may be the treatment of choice to correct iron deficiency and treat anaemia when non-urgent surgery is delayed and waiting periods are prolonged. Alternate-day treatment with oral iron is recommended, rather than daily doses, to improve uptake and compliance [21] . Newer oral iron formulations with enhanced absorption and gastro-intestinal tolerability, such as sucrosomial iron, should be considered [22] . This line of action is also practicable in individuals who cannot leave their home due to quarantine measures. Once surgery is rescheduled, diagnostic testing for haemoglobin, ferritin, C-reactive protein (CRP), and transferrin saturation should be undertaken during pre-operative assessment.

Diagnosis and treatment of anaemia in patients admitted for emergency surgery As stated above, the incidence and severity of anaemia is likely to increase during the pandemic due to changes in diet and lifestyle. Thus, we may experience a greater proportion of patients admitted for urgent or emergency surgery being anaemic. Low ferritin (< 30 ng.ml À1 ) is often used as an indicator of very low iron stores and iron deficiency. However, ferritin is increased during acute phase inflammation as may be seen with viral infections such as COVID-19. Consequently, the use of ferritin to diagnose iron deficiency may be problematic in patients with COVID-19 disease, who may have normal or high ferritin levels despite very low iron stores [23] . Hence, we recommend concurrent measurement of CRP and transferrin saturations. Transferrin saturation < 20% strongly suggests iron deficiency, especially when ferritin is < 100 ng.l À1 [13] . Increased CRP (> 4 mg.l À1 ) indicates that ferritin measurement alone is unreliable due to acute inflammation or viraemia. The bone marrow response to i.v. iron starts early after infusion, with a peak haemoglobin concentration within the following 4-6 weeks [24] . If urgent surgery is necessary in patients with iron deficiency anaemia, i.v. iron should be favoured over oral iron [13] . The benefit of short-term treatment with i.v. iron has been demonstrated in patients undergoing orthopaedic [25] and cancer surgery [26] [27] [28] . In addition, administering highdose i.v. iron pre-operatively, even on the day of surgery, could help prevent postoperative anaemia [29] . This approach is also feasible in iron-deficient COVID-19 patients admitted for urgent procedures. In patients with more profound anaemia, an ultra-short-term treatment course (1-2 days before surgery) of erythropoietin and i.v.

iron may be more effective. A regimen of 40,000 IU epoetin alpha and 1000 mg i.v. iron, together with 1 mg subcutaneous vitamin B12 and 5 mg oral folic acid, has been shown to reduce blood transfusion in cardiac surgery patients [30] . The beneficial effects of very short-term treatment with i.v. iron and epoetin alpha have also been observed in elective and non-elective orthopaedic surgery [25] . Intravenous iron is also effective for treating postoperative anaemia, and should be considered, even in cancer patients who are undergoing surgery during the COVID-19 crisis [26, 31, 32] .

Early reports have described mild anaemia in COVID-19 patients admitted to the ICU [33, 34] . In general, the most common aetiologies for anaemia in the ICU are inflammation and iron deficiency. Just as in surgical patients, iron, vitamin B12, folic acid and erythropoietin can be administered in critically ill patients [35] . Intravenous iron formulations are superior to oral formulations in such patients, as enteral iron uptake is reduced in inflammatory states due to increased expression of hepcidin. Moreover, a recent meta-analysis suggested that therapy with erythropoietin may decrease mortality in critically ill adults, even though results were described as hypothesisgenerating by the authors [36] . In COVID-19 positive critically ill patients, the risk of thrombosis associated with erythropoiesis-stimulating agents has to be individually considered before each administration, and mitigated with anticoagulation. When a shortage of blood supply is anticipated, treatment should be initiated early, before anaemia reaches critical levels. To balance the risks, haemoglobin should be maintained at levels sufficient to enable adequate oxygenation. This process can be achieved with below-normal haemoglobin values in most patients. In addition, patients should be anticoagulated adequately whenever possible, and special consideration given to the possible prothrombotic nature of COVID-19 in critically ill patients [37] . Prevention of anaemia is just as important as treatment of anaemia in critically ill patients.

Anaemia is aggravated by repeated blood tests in nonbleeding critically ill patients, especially those with acute respiratory distress syndrome (ARDS) or sepsis [38] . Blood sampling is increased in severely affected patients due to frequent blood gas analyses, laboratory testing, and blood culture testing. Two simple ways to prevent iatrogenic blood loss are micro-sampling and the use of blood conservation devices to reduce the amount of discarded blood [39] . For each blood test, the lowest possible amount of blood necessary to perform testing should be drawn, and only tests that are essential for clinical decisions should be ordered.

Acute respiratory distress syndrome is common in COVID-19 patients who develop pneumonia [34, 40] .

Transfusion of red cells has been associated with negative clinical effects on the lung, such as transfusion-related acute lung injury or pulmonary hypertension [41] . These side-effects might enhance the severity of ARDS in affected patients [42] . Thus, it is important to carefully consider each indication for transfusion, taking into account individual factors such as age, intravascular volume status of the patient and concomitant diseases.

Before transfusing allogeneic red cells, measures that increase oxygen delivery should be utilised, including improvement of oxygen saturation and cardiac output.

Total erythrocyte mass is not always reflected by haemoglobin values and it is not advisable to merely focus on transfusion thresholds. Whenever possible, a single-unit policy should be followed in order to limit volume transfused and multiple donor exposure, except in patients with active massive bleeding.

Several reports describe coagulation alterations in patients hospitalised with COVID-19 infection [40, [43] [44] [45] . In these reports, prothrombin time and activated partial thromboplastin time were longer in COVID-19-infected vs.

non-infected individuals. In addition, more abnormal coagulation parameters were found in advanced disease states and in non-survivors compared with survivors [40, 44, 45] , together with elevated fibrinogen concentrations [43, 44] . Markedly elevated D-dimers were described as the most prominent characteristic, a finding interpreted as overt disseminated intravascular coagulation (DIC) [44] . Cardiothoracic Anesthesiology [48] , and by the European Guidelines on management of major bleeding and coagulopathy following trauma [49] . Such timely coagulation monitoring allows rapid detection of disturbances in the coagulation system, and to accurately diagnose the abnormality. On this basis, an individualised goal-directed coagulation treatment using coagulation factors according to an algorithm is possible. The success of such treatment algorithms has been shown in cardiac surgery [50] , trauma [51] , and major postpartum haemorrhage [52] . Of particular relevance during the current COVID-19 pandemic is that the use of treatment algorithms can reduce transfusions of red cells, plasma, and platelets as well as admission to ICU, and shorten ventilation time and ICU length of stay [50] [51] [52] . A simple and pragmatic coagulation algorithm is depicted in Fig. 1 . The success of viscoelastic point-of-care based algorithms is largely independent of the use of thrombo-elastographic or thrombo-elastometric techniques [53] . In addition, in a recent study, the latest models of both types of viscoelastic techniques were found to be largely comparable [54] . needs. Patient blood management practices prevent anaemia (a global health problem) and reduce allogeneic blood transfusion, resulting not only in the best allocation of resources and cost savings, but also decreased patient morbidity and mortality [6, 58] . These improved outcomes and the concomitant cost savings are urgently needed as we deal with a pandemic yet to reach its peak, and the ongoing challenges thereafter.

During the COVID-19 pandemic, the most fundamental aspect of patient blood management is the prevention and management of anaemia. While the exact impact of anaemia on the outcomes of COVID-19 patients is not yet fully understood, data show unequivocally that the prognosis of COVID-19 patients with pre-existing and chronic conditions is significantly worse. As such, it is not unreasonable to expect that anaemia will also have a negative impact on the outcomes of COVID-19 patients and widespread prevention and management of anaemia might confer some protection against more severe cases of COVID-19.

As we are facing the biggest global health challenge of our lives, only a major collaborative effort will allow us to achieve a positive outcome. Using a patient-centred approach, proven evidence-based principles should be applied and established expert-consensus good practice concepts continued. Patient blood management is one piece of the puzzle needed to save patients' lives. Every drop of blood saved can be decisive, even more so in the critical situation we are currently facing.

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