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. Author manuscript; available in PMC: 2021 Sep 1.
Published in final edited form as: Anesth Analg. 2020 Sep;131(3):901–908. doi: 10.1213/ANE.0000000000004807

Blood Utilization and Clinical Outcomes in ECMO Patients

Caroline X Qin 1, Lekha V Yesantharao 2, Kevin R Merkel 3, Dheeraj K Goswami 4, Alejandro V Garcia 5, Glen J Whitman 6, Steven M Frank 7, Melania M Bembea 8
PMCID: PMC7853404  NIHMSID: NIHMS1638194  PMID: 32304461

Abstract

Background:

Patients requiring extracorporeal membrane oxygenation (ECMO) support are critically ill, and have substantial transfusion requirements, which convey both risks and benefits. A retrospective analysis was conducted to assess the association between blood component administration and adverse outcomes in adult, pediatric, and neonatal ECMO patients.

Methods:

We evaluated 217 ECMO patients at a single center hospitalized between January 2009 to June 2016. Three cohorts (88 adult, 57 pediatric, and 72 neonatal patients), were included for assessment of patient characteristics, blood utilization, and clinical outcomes. Univariable and multivariable analyses to were used to assess the association between transfusions and clinical outcomes (primary outcome – mortality, and secondary outcomes – morbid events). The analysis included the main exposure of interest (total number of blood component units transfused), and potential confounding variables – age group cohort, case mix index, sex, ECMO mode and duration, and primary ECMO indication.

Results:

After adjustment for confounders, with each additional blood component unit transfused there was an estimated increase in odds for mortality by 1% (OR 1.01, 95% CI 1.00-1.02, P=0.013), and an increase in odds for thrombotic events by 1% (OR 1.01, 95% CI 1.00-1.02, P=0.007). Mortality was higher in the adult (57 of 88; 64.8%) and pediatric (37 of 57; 64.9%) compared to the neonatal cohort (19 of 72; 26.4%) (P<0.0001). Median total blood components transfused per day followed a similar pattern for the adult (2.3 units; IQR 0.8-7.0), pediatric (2.9 units; IQR 1.1-10), and neonatal (1.0 units; IQR 0.7-1.6) cohorts; (P<0.0001). Over the entire hospitalization, the total median blood components transfused was highest in the neonatal (41 units; IQR 24-94) and pediatric (41 units; IQR 17-113), compared to the adult cohort (30 units; IQR 9-58); (P=0.007). There was no significant interaction between total units transfused over the hospital stay and age cohort for mortality (P=0.35).

Conclusions:

Given the association between transfusion and adverse outcomes, effective blood management strategies may be beneficial in ECMO patients.

INTRODUCTION

Extracorporeal membrane oxygenation (ECMO) is a mode of life support employed as an advanced medical therapy for patients with severe respiratory and/or cardiac failure. ECMO use has progressed remarkably in recent years, with an estimated 12,644 cases at 420 centers internationally in 2018.1 This increase has been coupled with a dramatic growth in the number of hospitals offering ECMO, especially for adult patients.2

Despite its widespread use, ECMO remains a somewhat controversial therapy associated with high morbidity and mortality. Two early randomized controlled trials failed to show benefit in adults being treated for acute respiratory failure;3,4 however, successful application of ECMO in the 2009 influenza A (H1N1) pandemic5 and the CESAR randomized controlled trial published the same year6 have contributed to its growth. Depending on the type of ECMO support utilized and underlying comorbidities, reported overall ECMO mortality ranges from 27-58% for neonatal, 41-58% for pediatric, and 41-71% for adult patients.1

Extracorporeal support demands a considerable amount of resources, including blood products. The additional risk, cost, and adverse outcomes associated with blood transfusions in the general patient population7-9 have raised concerns over blood utilization and appropriate transfusion protocols for ECMO patients. The small number of studies examining these variables specifically in ECMO patients have reported that blood utilization varies widely depending on institution, clinical indication for ECMO, and age group examined.10-14

A recent review by the Pediatric Critical Care Transfusion and Anemia Expertise Initiative panel concluded that there is insufficient evidence to recommend laboratory-based transfusion thresholds in pediatric ECMO patients.15 While recent Extracorporeal Life Support Organization (ELSO) guidelines refrain from recommending specific hemoglobin transfusion thresholds in patients supported on ECMO,16 several investigations support lower hemoglobin thresholds in critically ill patients.10,17-20 Evidence from multiple studies suggest that a greater number of transfusions in ECMO patients is associated with higher mortality,11,12,21-25 while other investigators have found no such association.26

In an effort to better understand transfusion-associated risks in these critically ill patients, we conducted a retrospective study using a single-institution, hospital-wide transfusion database to assess blood utilization and clinical outcomes in adult, pediatric, and neonatal ECMO patients. The primary objective was to examine the relationship between transfusions and adverse outcomes (morbidity and mortality).

METHODS

Patient Identification

After receiving Institutional Review Board approval with a waiver for informed consent, we conducted a retrospective cohort study using a patient blood management database that included patients who were hospitalized between January 2009 and June 2016. The study population included all identified patients who received ECMO support in the database (n=217) and was divided into three cohorts according to the ELSO age group definitions: neonatal (age ≤ 28 days), pediatric (age 28 days to < 18 years), and adult (age ≥ 18 years).27

Database Information

The patient database, which has been previously described,28 provided basic patient demographic information, in-hospital mortality, and the weighted Medicare severity diagnosis-related group (MSDRGWt) or “case mix index (CMI)”. CMI is used to indicate disease severity and the complexity of operative procedures and has also been shown to correlate with both transfusion requirements29 and clinical outcomes.30 CMI data were missing for 2 neonatal patients. All relevant transfusion and hemoglobin data were obtained through a blood management intelligence portal (IMPACT Online, Haemonetics, Inc., Braintree, MA) that links the institutional electronic medical record with the blood bank information system. Data on red blood cells (RBC), plasma, platelets (PLT), and cryoprecipitate (CRYO) utilization throughout the entire hospital stay were obtained. The majority of plasma was “FP24” (frozen within 24 hours of donation). A unit of PLTs was defined as an apheresis single donor unit (~300 mL). A unit of CRYO was defined as a 5-donor equivalent pool (~120 mL). Partial blood component units that were aliquoted for multiple transfusions in smaller patients were counted as a whole unit, since we report the number of units purchased from our blood supplier required to support each individual patient’s need. The first, lowest (nadir) and last hemoglobin concentrations over the entire hospitalization were collected. The nadir hemoglobin was used to define the pre-transfusion hemoglobin threshold, and the last measured hemoglobin concentration before discharge (or death) was used to define the post-transfusion hemoglobin as we have previously described.31 Hemoglobin data were missing for 3 adult patients.

An institutional administrative pediatric ECMO database was queried for pediatric and neonatal patients to provide data for ECMO mode (venoarterial or venovenous) and duration. Patient chart review from the institutional electronic health record was done to obtain the corresponding information for the adult patients. ECMO mode was missing for total of 30 patients (12 adult, 11 pediatric, and 7 neonatal), and ECMO duration was missing for 25 patients (10 adult, 10 pediatric, 5 neonatal). There were 5 patients who underwent ECMO mode conversion during their hospital stay, and they were not included in the analysis.

Data Analysis and Clinical Outcomes

Adult, pediatric, and neonatal patients were compared. The primary clinical outcome assessed was in-hospital mortality. Secondary outcomes included: 1) composite morbidity and individual incidence of morbid events, and 2) blood utilization. Composite morbidity was defined as the occurrence of any of the following hospital-acquired morbid events: thrombotic events (deep venous thrombosis, pulmonary embolus, or disseminated intravascular coagulation), ischemic events (myocardial infarction, transient ischemic attack, or cerebrovascular injury), infection (Clostridioides difficile, sepsis, surgical site infection, or drug-resistant infection), new onset renal insufficiency, and new onset respiratory insufficiency. These hospital-acquired morbid events were defined by the International Classification of Diseases, Ninth Revision, or International Classification of Diseases, Tenth Revision, codes, as we have previously described.9 Conditions that were flagged as present on admission were excluded from the hospital-acquired morbid events.

Blood utilization was assessed by the number of units transfused per patient and whether or not a patient required transfusion (percentage transfused). The four major blood components (RBC, plasma, PLT, and CRYO) were analyzed separately and combined as total blood component units transfused.

Data and Statistical Analysis

All data were processed and analyzed with JMP, v. 12.1.0 (SAS Institute, Cary, NC). Continuous variables are presented as mean ± standard deviation (SD) or median with interquartile range (IQR), as appropriate. ANOVA and Kruskall Wallis tests were used to compare continuous variables among the three cohorts, as appropriate. Categorical variables were analyzed as proportions and assessed by Chi-squared and Fisher’s Exact tests, as appropriate.

Multivariable logistic regression was performed to evaluate the association of blood utilization with adverse outcomes. The independent variable entered into the multivariable model included the primary exposure of interest (total blood component units transfused throughout the in-hospital stay), and potential confounders: age cohort, CMI, sex (M/F), cardiac failure as an indication for ECMO (Y/N), respiratory disease as an indication for ECMO (Y/N), ECMO mode [venoarterial (VA)/venovenous (VV)], and ECMO duration. An interaction term was included in the multivariable model to determine if the association between total units transfused and mortality differed among age cohorts. Results of the logistic regression analyses are presented as odds ratios (ORs) with 95% confidence intervals (CIs).

Statistical significance was defined as P<0.05 (two-tailed). For secondary outcomes (the five hospital-acquired morbid events), Bonferroni adjustment for multiple comparisons was used to control for type I error (P<0.01 defined significance).

RESULTS

Patient Characteristics

In the 8-year period reviewed, there were a total of 217 patients with 88 adult, 57 pediatric, and 72 neonatal patients. Median age for adult patients was 53 years, for pediatric patients 1 year, and for neonatal patients 0 days. Proportions of male sex in the adult, pediatric, and neonatal groups were similar (54.6%, 54.4%, and 65.3%, respectively, P=0.32). There were no significant differences between the three cohorts in ECMO mode (P=0.43). A majority of patients in the adult (86.8%), pediatric (84.8%), and neonatal (92.3%) groups underwent VA ECMO. Neonatal patients had the longest (median 6 days) and adults had the shortest (median 3 days) ECMO duration (P<0.0001). When only survivors were included, these same differences persisted.

Proportion of the following comorbidities were significantly different in the adult, pediatric, and neonatal cohorts: cardiac failure, diabetes mellitus, hypertension, obesity, pulmonary comorbidities, and coagulopathy. Adult patients, compared to pediatric or neonatal patients, had the highest incidence of all these comorbidities except for coagulopathy, for which pediatric patients had the highest incidence (Table 1).

Table 1.

Patient Characteristics

Adults (n=88) Pediatrics (n=57) Neonates (n=72) P-value
Age, median (IQR) 53 (36-64) yrs 1 (0-7) yrs 0 (0-2) days <0.0001
Male Sex, n (%) 48 (54.6) 31 (54.4) 47 (65.3) 0.32
ECMO Mode (VA), n (%) 66 (86.8) 39 (84.8) 60 (92.3) 0.43
ECMO Duration, days, median (IQR) 3 (1-5) 4 (1-9) 6 (3-14) <0.0001
ECMO Duration in survivors, days, median (IQR) 2 (2-5) 4 (2-8) 5 (3-10) 0.003
CMI, median (IQR) 17.99 (17.64-18.12) 17.74 (17.66-18.12) 18.12 (17.66-18.27) 0.29
Comorbidities* n (%)
 Cardiac Failure 47 (53.4) 11 (19.3) 10 (13.9) <0.0001
 Diabetes Mellitus 23 (26.1) 0 (0.0) 0 (0.0) <0.0001
 Hypertension 39 (44.3) 7 (12.3) 2 (2.8) <0.0001
 Obesity 18 (20.5) 0 (0.0) 0 (0.0) <0.0001
 Pulmonary 12 (13.6) 6 (10.5) 1 (1.4) 0.011
 Coagulopathy 20 (22.7) 22 (38.6) 4 (5.6) <0.0001
 Tumor 0 (0.0) 0 (0.0) 1 (1.4) 0.59
 Mets 1 (1.1) 0 (0.0) 0 (0.0) 1.00
 Liver 3 (3.4) 1 (1.8) 3 (4.2) 0.89
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ECMO – Extracorporeal membrane oxygenation, VA – venoarterial, CMI – Medicare severity diagnosis-related group (MSDRGWt) or “case mix index,” Mets – metastatic cancer.

*

By international classification of diseases (ICD)-9 prior to October 2015 and ICD-10 afterwards.

CMI data were missing for 2 neonates.

Blood Product Utilization

Over the entire hospitalization, the total blood component units transfused differed significantly among the three cohorts. Neonatal and pediatric patients had the highest blood product utilization with a median number of 41; IQR 24-94, and 41; IQR 17-113 units, respectively, compared to 30; IQR 9-58 units for adults (P=0.0068) (Table 2). Median total blood component units transfused per day was higher in the adult (2.3; IQR 0.8-7.0) and pediatric (2.9; IQR 1.1-10) compared to the neonatal (1.0; IQR 0.7-1.6) cohort (P<0.0001). Neonatal patients had the highest mean hemoglobin concentrations pre- and post-transfusion, followed by pediatric patients, while adult patients had the lowest (Table 2).

Table 2.

Blood Utilization and Hemoglobin Concentrations

Adults (n=88) Pediatrics (n=57) Neonates (n=72) P-value
Blood Usage (units), median (IQR)
 RBC 16 (7-40) 20 (8-50) 24 (11-46) 0.10
 Plasma 5 (0-15) 9 (3-26) 7 (4-13) 0.092
 PLT 2 (0-10) 11 (3-29) 12 (6-29) <0.0001
 CRYO 0 (0-1) 1 (0-2) 1 (0-2) 0.0005
 Total Blood Components 30 (9-58) 41 (17-113) 41 (24-94) 0.0068
Total Blood Components (units/day), median (IQR) 2.3 (0.8-7.0) 2.9 (1.1-10) 1.0 (0.7-1.6) <0.0001
% Transfused, n (%)
 RBC 86 (97.7) 54 (94.7) 72 (100.0) 0.14
 Plasma 64 (72.7) 52 (91.2) 71 (98.6) <0.0001
 PLT 62 (70.5) 54 (94.7) 72 (100.0) <0.0001
 CRYO 22 (25.0) 31 (54.4) 38 (52.8) 0.0002
Hemoglobin (g/dL), mean ± SD
 First 12.4 ± 2.8 11.9 ± 2.8 15.0 ± 2.6 <0.0001
 Lowest (Nadir) 7.4 ± 2.0 8.1 ± 2.0 8.4 ± 1.6 0.0020
 Last 9.9 ± 2.3 11.1 ± 2.3 11.7 ± 2.4 <0.0001
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RBC – red blood cells, PLT – platelets, CRYO – cryoprecipitate, Total blood units of component transfused – combined RBC, plasma, PLT, CRYO.

All data include the entire duration of the hospitalization. Hemoglobin data were missing for 3 adults.

Clinical Outcomes

Clinical outcomes comparing adult, pediatric, and neonatal patients are shown in Table 3. All three cohorts significantly differed from each other by length of stay (LOS). Adult patients had the shortest LOS while neonatal patients had the longest LOS. The LOS of neonatal patients was almost 4 times longer than that for adult patients and 2.5 times longer than that for pediatric patients. These differences were less profound when only survivors were included, however still statistically significant.

Table 3.

Clinical Outcomes

Adults (n=88) Pediatrics (n=57) Neonates (n=72) P-value
LOS, days, median (IQR) 10 (3-32) 14 (2-47) 37 (25-67) <0.0001
LOS in survivors, median (IQR) 27 (16-51) 27 (15-65) 40 (26-72) 0.02
Mortality, n (%) 57 (64.8) 37 (64.9) 19 (26.4) <0.0001
Composite morbidity (any event), n (%) 66 (75.0) 35 (61.4) 55 (76.4) 0.12
 Thrombotic 30 (34.1) 26 (45.6) 14 (19.4) 0.0061
 Infection 28 (31.8) 18 (31.6) 47 (65.3) <0.0001
 Ischemic 28 (31.8) 7 (12.3) 6 (8.3) 0.0003
 Respiratory 11 (12.5) 1 (1.8) 0 (0.0) 0.0004
 Renal 5 (5.7) 0 (0.0) 1 (1.4) 0.12
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LOS – Length of stay.

ECMO mode data were missing for 12 adults, 11 pediatrics, and 7 neonates. ECMO duration data were missing for 10 adults, 10 pediatrics, and 5 neonates.

Thrombotic events included deep venous thrombosis, pulmonary embolus, or disseminated intravascular coagulation. Ischemic events included myocardial infarction, transient ischemic attack, or cerebrovascular injury, infections included Clostridioides difficile, sepsis, surgical site infection, or drug-resistant infection.

Mortality was similar for adult (64.8%) and pediatric (64.9%) patients but substantially lower for neonatal patients (26.4%) (P<0.0001) (Table 3). Composite morbidity (any hospital acquired morbid event) was high (adult 75.0%, pediatric 61.4%, and neonatal 76.4%) for all three patient cohorts and did not differ significantly among the three groups (P=0.12). When morbid events were assessed independently, adult patients had the highest rates of ischemic and respiratory events, adult and pediatric patients had higher rates of thrombotic events compared to neonates, and neonatal patients had the highest rate of infectious events. The incidence of renal morbidity was similar between adult, pediatric, and neonatal patients.

In univariable analysis (Table 4), adult and pediatric patients had increased mortality compared to neonatal patients. Pulmonary comorbidity and total number of blood component units transfused were also significantly associated with mortality. The multivariable model included an interaction term for total blood component units transfused and age group cohort, with mortality as the primary outcome. The interaction term was not statistically significant (P=0.35), so the final model was run without the interaction term. In this model (Table 4) there was increased mortality in the adult (OR 8.65; 95% CI 3.56-22.50; P<0.0001) and pediatric (OR 3.89; 95% CI 1.58-9.97; P=0.003) patients compared to neonatal patients. Total blood component units transfused during the hospital stay was independently associated with mortality (OR 1.01; 95% CI 1.00-1.02; P=0.013). VA (vs. VV) ECMO mode was also independently associated with mortality (OR 3.57; 95% CI 1.15-12.34; P=0.027).

Table 4.

Univariable and Multivariable Associations between Clinical Variables and Mortality

Univariable OR (95% CI) P-value Multivariable OR (95% CI) P-value
 Adult vs Pediatric 0.99 (0.49-1.99) 0.99 2.23 (0.91-5.55) 0.078
 Pediatric vs Neonates 5.16 (2.46-11.21) <0.0001 3.89 (1.58-9.97) 0.003
 Adults vs Neonates 5.13 (2.63-10.34) <0.0001 8.65 (3.56-22.50) <0.0001
 CMI (per 1 unit change) 1.19 (0.98-1.54) 0.11 1.05 (0.82-1.45) 0.71
 Sex (M vs F) 0.60 (0.35-1.04) 0.068 0.76 (0.39-1.47) 0.41
 Cardiac Failure 1.62 (0.91-2.93) 0.10 0.65 (0.29-1.46) 0.30
 Pulmonary Disease 2.80 (1.03-8.93) 0.044 1.67 (0.46-7.28) 0.44
 ECMO Mode (VA vs VV) 1.95 (0.79-5.12) 0.15 3.57 (1.15-12.34) 0.027
 ECMO Duration (per day) 1.02 (0.99-1.06) 0.23 1.01 (0.96-1.07) 0.71
 Total Blood Products (per unit transfused) 1.01 (1.00-1.01) 0.0035 1.01 (1.00-1.02) 0.013
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CMI – Medicare severity diagnosis-related group (MSDRGWt) or “case mix index,” ECMO – Extracorporeal membrane oxygenation, VA – venoarterial, VV – venovenous, Total added blood products – combined number of RBC, Plasma, PLT, CRYO units.

ECMO mode data were missing for 12 adults, 11 pediatrics, and 7 neonates. ECMO duration data were missing for 10 adults, 10 pediatrics, and 5 neonates. Total blood products – total units of all blood components transfused over the entire hospital stay.

When the interaction term (Total blood products*Adult, Pediatric, Neonatal cohort) was added to the model it was not significantly associated with mortality (P=0.35) so the reported model above is without the interaction term.

The multivariable analyses testing whether the total number of blood component units transfused was independently associated with individual morbid events (thrombotic, infectious, ischemic, respiratory, and renal) are shown in Table 5. Each analysis was adjusted for the following potential confounders: age group (adult vs pediatric vs neonatal), CMI, sex, cardiac failure, respiratory disease, ECMO mode (VA/VV), and ECMO duration. Total blood component units transfused was independently associated with thrombotic events (OR 1.01; 95% CI 1.00-1.02; P=0.007), even after correction for multiple comparisons, however the association with renal morbidity (OR 1.03; 95% CI 1.00-1.06; P=0.04) was not significant after Bonferroni adjustment for multiple comparisons.

Table 5.

Association between Blood Transfusion and Adverse Outcomes by Multivariable Analyses

n (%) Odds Ratio 95% CI P-value
Mortality 113 (52.1) 1.01 1.00-1.02 0.013
Morbid events
 Thrombotic 70 (32.3) 1.01 1.00-1.02 0.007
 Infection 41 (18.9) 1.00 0.99-1.01 0.38
 Ischemic 41 (18.9) 1.00 1.00-1.01 0.89
 Respiratory 12 (5.5) 0.99 0.98-1.01 0.68
 Renal 6 (2.8) 1.03 1.00-1.06 0.04
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Odds ratios represent the incremental change for each additional unit of any blood component transfused over the entire hospital stay.

ECMO mode data were missing for 12 adults, 11 pediatrics, and 7 neonates. ECMO duration data were missing for 10 adults, 10 pediatrics, and 5 neonates. Independent variables included in the multivariable models for potential confounder adjustment were: age group (adults vs. pediatrics vs neonates), case mix index, sex (M/F), cardiac failure (Y/N), respiratory disease (Y/N), ECMO mode [venoarterial (VA)/venovenous (VV)], and ECMO duration. For the five morbid events, a Bonferroni adjustment was used for multiple comparisons so P<0.01 defined significance.

DISCUSSION

The results demonstrate an association between the amount of blood transfused and both mortality and thrombotic events, even after adjustment for potential confounders. These findings suggest that transfusion is associated with an incremental risk of adverse outcomes, and that blood should be transfused judiciously in ECMO patients. Our finding of no significant interaction between age cohort and transfusion requirements in association with mortality suggests that that no particular age cohort was more susceptible to transfusion-associated adverse outcomes. In addition, neonatal ECMO patients had higher survival rates relative to pediatric or adult ECMO patients, a finding that has been previously described.1,32

Previous studies have examined blood utilization and mortality in critically ill ECMO patients. Similar to our study, higher rates of transfusion were associated with higher mortality, though percentage values differed.11,12,21-25 A retrospective study by Smith et al.12 found that each RBC transfusion volume of 10 mL/kg/day was associated with a 24% increase in the odds of in-hospital mortality in pediatric non-cardiac ECMO patients. Another study by Muszynski et al.11 showed a 9% increase in the odds of in-hospital mortality for pediatric patients per 10 mL/kg/day RBC transfusion volume. Additionally, Mazzeffi et al.24 reported a 3% increase in mortality per unit of RBC transfused in adult ECMO patients.

ECMO is known to be associated with high transfusion requirements due to common complications including hemorrhage (e.g., surgical site and cannula insertion site bleeding) and impaired coagulation related to platelet dysfunction and a consumptive coagulopathy.33 Due to the lack of standardization, there is substantial variation in institutional protocols for anticoagulation and blood product administration management.34 Reported blood utilization during ECMO varies widely and has rapidly evolved with improvements in anticoagulation and transfusion practice. In the 1990s, one retrospective study reported mean blood utilization of 2 units RBCs, 300 mL plasma, 8 units platelets for neonatal patients,13 and another reported 41 units RBCs, 9 units plasma, 108 units platelets, and 2 units CRYO for adult patients.14 A blood conservation intervention in adults supported on ECMO for acute respiratory distress syndrome resulted in even lower transfusion requirements (equivalent to 0.11 units/ECMO day) when a pre-transfusion hemoglobin threshold of 7 g/dL was instituted, without an increase in mortality or organ dysfunction.10

Previous studies have reported high transfusion requirements for adult ECMO but also a minimal impact of neonatal ECMO transfusion needs on hospital transfusion services.13,14 In our study, neonatal and pediatric patients received significantly more total blood component units than adult patients. Our results also demonstrated that neonatal and pediatric patients were transfused more liberally with regard to hemoglobin thresholds compared to adult patients. This difference could account for some of the higher product usage by neonatal and pediatric patients. During the study period, our institutional protocol for neonatal and pediatric ECMO included a hematocrit of less than 40% and 35%, respectively. In addition, neonatal patients in our study had significantly longer ECMO support duration and hospital LOS compared to both adult and pediatric patients. These differences persisted when only survivors were included – although the differences were smaller. It is reasonable to assume that patients who remain in the hospital and on ECMO longer are more likely to receive higher amounts of blood products and those with short length of stay, perhaps from early death, are likely to have lower blood utilization.

In addition to analyzing the association between transfusion requirements and mortality, we also found that increased transfusion requirement was associated with a greater risk of thrombotic events. Our results are consistent with published literature supporting the high risk of transfusion-related morbidity. Specifically, thrombotic events associated with transfusion have been reported and are believed to occur at a higher, dose-dependent frequency compared to other morbidities, such as ischemic events.9,35,36 Stored RBCs are known to be prothrombotic due to decreased cell membrane deformability, and increased endothelial adherence.37,38 Furthermore, the implementation of patient blood management programs to reduce unnecessary transfusions have resulted in lower morbidity, including thrombotic events.39,40

This study has several limitations. First, it is retrospective and observational in nature, and we could not reliably adjust for all potential confounding variables (including the indications for ECMO), and this residual confounding may have important implications for observed exposure-outcome relationships. The findings of this study support associations and not causation. The sample size is relatively small, especially in light of the three groups we compared. Because this is a single institution study, the external validity of the results may be limited. Furthermore, the primary outcome reported was in-hospital mortality. We did not investigate long-term, post-discharge mortality, or long-term disability. Due to sample size limitations, we were unable to robustly assess for 1) differences in exposure-outcome relationships across age groups, and 2) the contributions of individual blood component therapies on clinical outcomes. Finally, a potential limitation is the use of ICD-9 and ICD-10 codes to assess secondary outcomes. Based on the nuances of coding charts, this method may not be as reliable as prospectively collected event rates for morbidity, however it is less prone to investigator bias. Furthermore, the timing of these hospital-acquired morbidities relative to the transfusions cannot be established. To minimize this limitation, we did, however, exclude morbidity that was present on admission, which is a required data element at our institution.

In conclusion, our findings add to the growing body of literature suggesting that transfusion is associated with dose-related increase in adverse outcomes, including mortality and thrombotic events. Future studies are needed to investigate whether effective patient blood management strategies may be beneficial for ECMO patients.

KEY POINTS.

  • Question: What is the relationship between blood utilization and clinical outcomes in adult, pediatric, and neonatal patients supported by extracorporeal membrane oxygenation (ECMO)?

  • Findings: The majority of ECMO patients have high transfusion requirements, and increased blood utilization was associated with both increased mortality and increased thrombotic events.

  • Meaning: Given the substantial blood requirements and transfusion-related adverse outcomes, patient blood management strategies may be beneficial in ECMO patients.

ACKNOWLEDGEMENTS

The authors would like to acknowledge both financial and project management support from The Johns Hopkins Health System Armstrong Institute for Patient Safety and Quality, Baltimore, Maryland.

S.M.F. has served on scientific advisory boards for Baxter, Haemonetics and Medtronic.

M.M.B.’s institution received funding for ECMO-related research from the National Institute of Neurological Disorders and Stroke (R01NS106292) and from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R21HD096389).

GLOSSARY OF TERMS

ANOVA

analysis of variance

CESAR

Conventional ventilatory support vs extracorporeal membrane oxygenation for severe adult respiratory failure

CI

confidence interval

CMI

case mix index

CRYO

cryoprecipitate

ECMO

extracorporeal membrane oxygenation

IQR

interquartile range

LOS

length of stay

MSDRGWt

weighted Medicare severity diagnosis-related group

OR

odds ratio

PLTS

platelets

RBC

red blood cells

SD

standard deviation

VA

venoarterial

VV

venovenous

Footnotes

This manuscript adheres to the applicable Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.

The other authors declare no competing interests.

Contributor Information

Caroline X. Qin, The Johns Hopkins University School of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland.

Lekha V. Yesantharao, Department of Anesthesiology/Critical Care Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland.

Kevin R. Merkel, Department of Anesthesiology/Critical Care Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland.

Dheeraj K. Goswami, Department of Anesthesiology/Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland.

Alejandro V. Garcia, Department of Surgery (Pediatric), Johns Hopkins University, Baltimore, Maryland.

Glen J. Whitman, Department of Surgery, Johns Hopkins University, Baltimore, Maryland.

Steven M. Frank, Department of Anesthesiology/Critical Care Medicine, Faculty, The Armstrong Institute for Patient Safety and Quality, The Johns Hopkins Medical Institutions, Baltimore, Maryland.

Melania M. Bembea, Department of Anesthesiology/Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland.

Contributions

Caroline X. Qin, B.S.: This author helped conceive and design the study, analyze and interpret the data, and write the manuscript.

Lekha V. Yesantharao: This author helped analyze and interpret the data and critically revise the manuscript.

Kevin R. Merkel, B.A.: This author helped analyze and interpret the data and critically revise the manuscript.

Dheeraj K. Goswami, M.D.: This author helped conceive and design the study, analyze and interpret the data, and edit the manuscript.

Alejandro V. Garcia, M.D.: This author helped conceive and design the study, analyze and interpret the data, and edit the manuscript.

Glen J. Whitman, M.D.: This author helped conceive and design the study, analyze and interpret the data, and edit the manuscript.

Steven M. Frank, MD: This author helped conceive and design the study, analyze and interpret the data, and write the manuscript.

Melania M. Bembea, MD, PhD: This author helped conceive and design the study, analyze and interpret the data, and write and edit the manuscript.

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