Transfusion management during extracorporeal membrane oxygenation for extended indications: a narrative review

Introduction

Establishing a transfusion threshold can be a challenge in critically ill patients undergoing extracorporeal membrane oxygenation (ECMO) support. Extracorporeal Life Support Organization (ELSO) recommends maintaining Hb levels to achieve an optimal oxygen delivery (for most ECMO centres this level is between 7–12 g/dL) (1) but these data are not yet supported by solid scientific evidence. There are several reasons why clinicians may decide to transfuse a patient with ECMO support: to counteract the haemodilution resulting from circuit priming, to improve oxygen delivery, to restore the haemostatic balance and to compensate for blood losses due to hemolysis and, frequently, for haemorrhagic complications. For each of these scenarios, it is unsurprising that patients on ECMO support have a higher transfusion requirement (2).

What complicates the determination of the transfusion threshold is the variability of blood component requirements for different clinical conditions. For example, both adult and paediatric venovenous (VV) ECMO patients with respiratory failure are shown to be less need of transfusions than venoarterial (VA) ECMO patients mainly because of hemolysis and haemorrhagic complications which often occur during VA ECMO configuration. The longer ECMO circuit and duration performed in adult patients compared to paediatric patients can partially explain why the former has greater transfusion requirements (3).

However, modern ECMO circuits are shorter, more biocompatible and heparin-coated, and have smaller oxygenators resulting in less haemolysis and ultimately a lower haemorrhagic risk. The shorter circuit and less haemodilution by priming with crystalloid (<1 L) ultimately means a lower transfusion requirement for all patients (4).

New ECMO indications

Upcoming technological advances are boosting the implementation of ECMO in several forms of cardiorespiratory support. The major indications for ECMO support are both hypoxemic and hypercapnic respiratory failure (5) and cardiac/circulatory failure [including refractory cardiogenic shock (6,7) and cardiac arrest (8)]. Along with these “conventional” indications, the positive outcomes, have resulted in a recent resurgent interest also for other clinical conditions (Table 1) (9,10).

As stated above, evidence-based transfusion thresholds for haemocomponents during ECMO support do not exist in the literature. One reason for this is that blood transfusions are associated with adverse events, such as volume overload, transfusion-associated acute lung injury (11), immunomodulation, human leukocyte antigen (HLA) sensitization, red blood cell (RBC) antigen sensitization, and transfusion-transmitted infection. As a result, it is necessary to perform a careful risk-benefit analysis (12) before deciding on transfusion. Studies report that stored RBCs have a lower concentration of 2,3-diphosphoglycerate (2,3-DPG) and adenosine triphosphate (ATP) leading to a reduced O₂-binding capacity. In addition, during storage, RBCs are prone to increased membrane stiffness and osmotic fragility, and once transfused, they might activate the inflammation system resulting in an increased risk of thrombosis (13). ECMO blood flow is an important determinant of oxygen delivery to the tissues, and RBC transfusion is found to increase oxygen content, resulting in augmented delivery even at lower ECMO blood flow rates (14).

Aim of the review

This review aims to examine the different transfusion strategies present in the literature, focusing on the circumstances in which liberal protocols are adopted, with a particular interest in emerging indications. We present the following article in accordance with the Narrative Review reporting checklist (available at https://aob.amegroups.com/article/view/10.21037/aob-21-81/rc).

Methods

We conducted our search on the electronic database PubMed. The search was limited for articles in English languages and published from 1999 to 2022. Keywords used for the search were: “extracorporeal membrane oxygenation”, “blood transfusion”, “blood transfusion triggers (or thresholds)”, “extended (or broadened) indications for ECMO”, “ECMO for special circumstances”. Of the 30 results, we counted only ten articles (shown in Table 2) in which authors established laboratory parameters as transfusion triggers.

Discussion: conventional vs. unconventional uses of ECMO

Conventional indications: liberal vs. restrictive transfusion strategy

There are several retrospective studies showing the safety of the restrictive strategy (14). Despite the conventional haemoglobin threshold to define restrictive strategy being 7 g/dL, in ECMO the current practice is to consider the restrictive strategy with a higher threshold (15). There is a meta-analysis that demonstrates that the higher the haemoglobin transfusion threshold the higher the mortality rate (16). A recently published multicentre, prospective, cohort study including 604 adult patients on VV-ECMO for ARDS enrolled between 1 December 2021 and 22 February 2022, identified 7 g/dL as the only PRBC transfusion threshold associated with lower mortality rate (17).

In a retrospective study (18), including 402 patients treated with VV ECMO between 2011 and 2017, different strategies were compared. In 2014, after switching from a liberal to a restrictive transfusion protocol (with a haemoglobin transfusion threshold below 8 g/dL), investigators described the outcomes, complications related to transfusions and costs of patients treated with a liberal vs. restrictive strategy. Mortality rates were comparable between the two groups and to those of the ELSO registry. When a restrictive transfusion strategy was used, the average number of units transfused fell by 0.2 RBC units per ECMO day. This could result in significant cost-sparing effect and prevent unnecessary use of blood products. Moreover, with restrictive transfusion, there was a decrease in the extracorporeal blood flow of 0.5 L/min. However, non-survivors on VV ECMO had higher RBC transfusion requirements following a shift in transfusion practice.

In another study (19), 415 transfused acute respiratory distress syndrome (ARDS) patients were divided into two main groups: 128 with a 10 g/dL transfusion threshold and 240 patients at 8 g/dL (47 patients were excluded for incomplete data sets) The latter group was analyzed with 1:1 propensity score matching; 99 patients were placed on ECMO and 70 were not. During the first 28 days from ARDS onset, authors found that patients in the lower-threshold group were more difficult to wean from mechanical ventilation than higher-threshold group patients, while among patients who underwent ECMO support, those in the higher-threshold group had comparable rates of ECMO weaning than the lower-threshold group.

Unconventional indications

ECMO and transplantation

Today, patients with respiratory and cardiac failure for end-stage disease can benefit from ECMO support as a bridge treatment for transplantation (20,21). However, we found few studies in which transfusion triggers were clearly defined.

VV ECMO, acting as a valid substitute for maximal ventilatory support, can avoid ventilatory-induced lung injury and deep sedation and ultimately attenuate cardiorespiratory, musculoskeletal, and metabolic deconditioning. One study (22) investigated patients listed for lung transplantation who developed acute respiratory failure and compared the outcomes between those who received ECMO support as bridging treatment (15 patients) to those who did not (10 patients). In this study, the main triggers to PRBC transfusion were: active bleeding, hypoxemia, and haematocrit below 25%. Among the ECMO group, 9 patients survived to hospital discharge. Of these patients, seven were transplanted. The amount of RBCs transfused was significantly higher in non-survivors (3.3 vs. 18.5 U, P=0.003).

Similarly, VA ECMO is a fundamental mechanical circulatory support for patients with heart failure awaiting heart transplantation. In a retrospective single-centre observational study (23) that included 64 children undergoing mechanical circulatory support for at least 2 days, over a period of approximately 12 years (January 1990 to July 2002), the authors compared outcomes of interest among those on ECMO support (34 patients) and those who were on a pulsatile flow (paracorporal and pneumatically driven) mechanical support device called Berlin heart (30 patients). Of the 64 children with terminal heart disease, nearly half (31 patients) were on the list for heart transplantation: 23 received Berlin heart support and 9 received ECMO as a bridge to transplant treatment. The local transfusion protocol was to transfuse PRBC, fresh frozen plasma, and platelets when haemoglobin was below 9 g/dL, fibrinogen was below 180 mg/dL, and platelets were below 70,000/mm³. In general, children on ECMO support had a significantly higher daily transfusion requirement (mL/kg bw/day) of RBCs (60.32±17.18 vs. 17.18±2.2, P<0.001), fresh frozen plasma (46.96±21.01 vs. 8.50±3.98, P<0.001) and platelets (24.63±6.26 vs. 4.32±0.98, P<0.001) than those on Berlin heart support. These results suggest that the decision-making process to transfuse the patients should take into account not only the levels of haemoglobin but also the circuit management and the ECMO configuration.

Regarding ECMO support during liver transplantation, applying a restrictive strategy to transfusion is imperative due to the higher risk of bleeding. We are aware of a case report (24) in which VA ECMO was used as a rescue option in the case of portopulmonary hypertension recognized intraoperatively. The authors emphasize the temporary nature of this support because of the well-known higher risk of bleeding and infection typically observed in patients who undergo liver transplantation.

ECMO and sepsis

ECMO has also shown benefits as a rescue treatment in patients with sepsis-related respiratory failure. Since the lung is the most common source of sepsis (25), successful treatment of respiratory failure can reduce the mortality rate in patients with sepsis. However, choosing the right timing and transfusion threshold in the septic patient can be a challenge due to the increased oxygen consumption typically observed in this cluster of patients. In a large multicentre observational study (26), data from 3,195 patients with severe sepsis or septic shock admitted to 42 ICUs from 40 institutions across Japan were retrospectively analyzed. Among patients diagnosed with severe respiratory failure, those who received ECMO support (n=40) were matched with those who did not (n=150), and the outcomes were compared between the two groups. The transfusion strategy in ECMO patients complied with ELSO’s recommendations to maintain haemoglobin levels between 12 and 14 g/dL. Although there was no statistically significant difference in mortality between the two groups, the ECMO group received significantly more transfusions of RBCs {6 [0–14] vs. 0 [0–4], P=0.000}, fresh frozen plasma {0 [0–4] vs. 0 [0–10], P=0.019} and platelets {10 [0–30] vs. 0 [0–15], P=0.001} than the control group.

In a case series (27), the outcomes of six adult patients with respiratory failure and a mean SOFA score of 9.6 who underwent VV ECMO between 30 March 2001 and 30 April 2001 were retrospectively analyzed. Only two patients required transfusion of fresh frozen plasma. Fibrinogen was maintained between 1.4 and 6 g/dL and no patient required cryoprecipitate. Platelets were transfused to maintain platelet counts above 65,000. To maintain haemoglobin levels above 14 g/dL, the average daily requirement for RBCs was 11.8 units. All patients survived. Moreover, when sepsis accompanies other conditions in which ECMO is indicated (for example, pulmonary hypertension) (28) it is evident that the average platelet transfusion requirement increases. This can also be explained by the fact that the patients with sepsis had significantly longer runs of ECMO than the other groups.

ECMO and pulmonary hypertension

Another extended indication for ECMO support is pulmonary hypertension. In a multicentre historical cohort study (28) of 234 infants needed ECMO support, the cut-off for platelet administration was between 110,000/mm³ (centre A) and 100,000/mm³ (centres B and C). For patients with pulmonary hypertension, the mean daily platelet transfusion requirement was 1.4±0.6 units with a mean duration of ECMO therapy of 6.9±4.2 days.

ECMO and trauma

In the last case-series cited, two of the six patients had trauma-related respiratory failure. Indeed, ECMO support is increasingly better performing also in trauma-related cardiorespiratory failure. In another case series (29), 24 polytrauma patients with respiratory failure unresponsive to conventional ventilation therapy were treated with ECMO. Triggers to transfuse RBCs, fresh frozen plasma, and platelets show further variability: haematocrit >40–45%, fibrinogen >200 mg/dL, platelets >100,000/mm³ (>150,000 if active bleeding was ongoing). The most frequent complication was bleeding (75%) and the survival rate was 63%.

In a retrospective study (30), mortality among 81 patients receiving ECMO via subgroup analyses of trauma and non-trauma patients was analyzed. During the study period, significantly increased mortality in the group with a haematocrit greater than 31% [relative risk (RR): 1.73 with a 95% CI: 1.134–2.639] was identified. The targeted values of the restrictive protocol were haemoglobin 8–9.5 g/dL, fibrinogen >250 mg/dL and platelet count >50,000/mm³. The more blood products transfused, the higher the mortality rate observed both in the overall population and in the trauma group (26).

A further multicentre retrospective cohort study (31) evaluated records of adult trauma patients between 16 and 55 years of age treated for acute hypoxemic respiratory failure between January 2001 and December 2009. The authors reported that in many instances transfusions were given to maintain haemoglobin above 10 g/dL and platelet counts above 75,000/mm³ (27).

ECMO and pregnancy

ECMO support was successfully adopted also in pregnant (32,33) despite the well-known higher risks of haemolysis. In one case series (34), blood transfusions were given to four pregnant patients on ECMO support for respiratory failure to maintain hematocrit above 28%. In another case series, the authors defined a transfusion threshold of 7 g/dL of haemoglobin in seven pregnant patients on VA ECMO support for cardiogenic shock, unless there was evidence of dysoxia despite optimization of circuit support (35).

As shown in Table 3, we collected ten articles in which was explicated clear transfusion triggers. All are observational studies (mainly case series and retrospective studies). The main population investigated was adults but two studies investigated their endpoints among paediatric patients and two among pregnant patients. The most frequent ECMO configuration was VV; only two studies investigate their endpoints in VA ECMO support populations and two studies reported the VV to VA configuration changing. Most of these studies considered laboratory levels of haemoglobin as PRBC transfusion trigger but in three studies the clinical decision to transfuse PRBC was based on the haematocrit percentage threshold. Among the studies considered, only the case series of Desai respect the criteria of restrictive transfusion strategy (haemoglobin threshold of 7 g/dL).

Summary

Though it is currently possible to explore haemoglobin thresholds for transfusion in “conventional” indications for ECMO support, like ARDS due to bacterial or viral pneumonia (36), there is still too much heterogeneity among studies considering the recently advanced indications for ECMO. The main issues are the cases when the patient has a very high risk of bleeding like in trauma or perioperative periods, or the case of high risk of fluid shift like in burn injuries. Haemoglobin and vascular mass are fundamental to achieving adequate blood flow during ECMO support for reaching higher oxygen delivery, and the administration of PRBC should always be balanced with the patient’s needs, O₂ availability and blood flow determined by the clinical situation.

The analysis of several studies with specific indications confirmed the high heterogeneity but the tendency of reducing the transfusions is evident. Moreover, the important step-up for research would compare the different strategies for transfusions in homogenous groups according to indications for ECMO and configuration. Before starting new trials on this topic, broader observational studies, unbiased due to long enrolment periods, should be attempted to understand the current evolving practice and to propose changes to improve management, costs, and outcomes.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Blood for the series “Blood Transfusion Practice in ECMO Patients”. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://aob.amegroups.com/article/view/10.21037/aob-21-81/rc

Peer Review File: Available at https://aob.amegroups.com/article/view/10.21037/aob-21-81/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aob.amegroups.com/article/view/10.21037/aob-21-81/coif). The series “Blood Transfusion Practice in ECMO Patients” was commissioned by the editorial office without any funding or sponsorship. GM served as the unpaid Guest Editor of the series. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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