Characterizing the Racial Discrepancy in Hypoxemia Detection in VV-ECMO: An ELSO Registry Analysis

doi:10.21203/rs.3.rs-3617237/v1

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Characterizing the Racial Discrepancy in Hypoxemia Detection in VV-ECMO: An ELSO Registry Analysis

https://doi.org/10.21203/rs.3.rs-3617237/v1

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Importance: Skin pigmentation influences peripheral oxygen saturation (SpO₂) measured by pulse oximetry compared to the arterial saturation of oxygen (SaO₂) measured via arterial blood gas analysis. However, data on SpO₂-SaO₂ discrepancy are limited in venovenous-extracorporeal membrane oxygenation (VV-ECMO) patients.

Objective: To determine whether there is racial/ethnical discrepancy between SpO₂ and SaO₂ in patients receiving VV-ECMO. We hypothesized VV-ECMO cannulation, in addition to race/ethnicity, accentuates the SpO₂-SaO₂ discrepancy due to significant hemolysis.

Design: Retrospective cohort study of the Extracorporeal Life Support Organization Registry from 1/2018-5/2023.

Setting: International, multicenter registry study including over 500 ECMO centers.

Participants: Adults (≥ 18 years) supported with VV-ECMO with concurrently measured SpO₂ and SaO₂ measurements.

Exposure: Race/ethnicity and ECMO cannulation.

Main outcomes and measures: Occult hypoxemia (SaO₂ ≤ 88% with SpO₂ ≥ 92%) was our primary outcome. Multivariable logistic regressions were performed to examine whether race/ethnicity was associated with occult hypoxemia in pre-ECMO and on-ECMO SpO₂-SaO₂ calculations. Covariates included age, sex, temporary mechanical circulatory support, pre-vasopressors, and pre-inotropes for pre-ECMO analysis, plus single-lumen versus double-lumen cannulation, hemolysis, hyperbilirubinemia, ECMO pump flow rate, and on-ECMO 24h lactate for on-ECMO analysis.

Results: Of 13,171 VV-ECMO patients (median age = 48.6 years, 66% male), there were 7,772 (59%) White, 2,114 (16%) Hispanic, 1,777 (14%) Black, and 1,508 (11%) Asian patients. The frequency of on-ECMO occult hypoxemia was 2.0% (N = 233). Occult hypoxemia was more common in Black and Hispanic versus White patients (3.1% versus 1.7%, P < 0.001 and 2.5% versus 1.7%, P = 0.025, respectively).

In multivariable logistic regression, Black patients were at higher risk of pre-ECMO occult hypoxemia versus White patients (adjusted odds ratio [aOR] = 1.55, 95% confidence interval [CI] = 1.18–2.02, P = 0.001). For on-ECMO occult hypoxemia, Black patients (aOR = 1.79, 95%CI = 1.16–2.75, P = 0.008) and Hispanic patients (aOR = 1.71, 95%CI = 1.15–2.55, P = 0.008) had higher risk versus White patients. Furthermore, higher pump flow rate (aOR = 1.29, 95%CI = 1.08–1.55, P = 0.005) and higher on-ECMO 24h lactate (aOR = 1.06, 95%CI = 1.03–1.10, P < 0.001) significantly increased the risk of on-ECMO occult hypoxemia.

Conclusions and Relevance: Hispanic and Black VV-ECMO patients experienced occult hypoxemia more than White patients. SaO₂ should be carefully monitored during ECMO support for Black and Hispanic patients especially for those with high pump flow and lactate values at risk for occult hypoxemia.

Cardiothoracic Surgery

Critical Care & Emergency Medicine

pulse oximetry

arterial blood gas

venovenous extracorporeal membrane oxygenation

racial/ethnical disparities

hypoxemia

Question: Do race/ethnicity and VV-ECMO cannulation influence the discrepancy between oxygen saturation measured by SpO₂ versus SaO₂?

Findings: In a retrospective cohort study of 13,171 VV-ECMO patients from the Extracorporeal Life Support Organization Registry (1/2018-5/2023), Black and Hispanic patients experienced on-ECMO occult hypoxemia more frequently than White patients. The adjusted frequency of occult hypoxemia was greater in on-ECMO versus pre-ECMO SpO₂-SaO₂ measurements; high pump flow rates and lactate values increased the risk of on-ECMO occult hypoxemia.

Meaning: SaO₂ should be carefully monitored during ECMO support for Black and Hispanic patients especially for those with high pump flow and serum lactate.

Arterial blood gas (ABG) analysis is the gold-standard method to measure arterial oxygen saturation (SaO₂) as it directly measures the partial pressure of oxygen in arterial blood.¹ Pulse oximetry is a standard non-invasive continuous method of monitoring peripheral oxygen saturation (SpO₂) via measurement of hemoglobin saturation through spectroscopy. Darker skin pigmentation may worsen occult hypoxemia (previously defined as SaO₂ ≤ 88% despite SpO₂ ≥ 92%²) as was seen in a cohort of 10,001 intensive care unit (ICU) patients where Black patients experienced occult hypoxemia 3-fold more than White patients.³ In a study of respiratory failure patients 6 hours before extracorporeal membrane oxygenation (ECMO) cannulation, the frequency of pre-ECMO occult hypoxemia in Black patients was higher than in White patients.² However, this study analyzed only pre-ECMO oxygen saturation values and did not account for clinically-relevant covariates such as hemolysis or presence of vasopressor usage.

In addition to skin pigmentation bias, SpO₂ is also unable to distinguish between oxygen bound to hemoglobin (oxyhemoglobin), carbon monoxide bound to hemoglobin (carboxyhemoglobin) or oxidized hemoglobin (methemoglobin or sulfhemoglobinemia), which can further cause inaccurate pulse oximetry readings.^4–6 This is particularly important in ECMO patients, where accurate oxygenation measurements are critical and their complex physiology⁷ can further influence the accuracy of these measurements. Specifically, high ECMO pump flow rate and larger cannula size⁸ can cause hemolysis due to mechanical shearing of red blood cells,^9–11 leading to formation of carboxyhemoglobin and thus causing inaccurate SpO₂ measurements. This phenomenon was observed in a cohort of 40 venovenous (VV)-ECMO patients; however, this study is limited by small sample size and did not account for ECMO-relevant covariates or race/ethnicity in their analyses.¹²

We sought to address these previous limitations using concurrently measured SpO₂ and SaO₂ data points within a multicenter, international cohort of ECMO patients, to examine for discrepancy by race/ethnicity. In addition, we hypothesized that ECMO-induced hemolysis would worsen occult hypoxemia in VV-ECMO patients. Finally, as the single-lumen cannula may require greater resistance of perfusion and overall pump flow to maintain adequate perfusion, we also hypothesized that single versus double-lumen cannulation strategies may impact the SpO₂-SaO₂ discrepancy.

Study design and population

This study was approved by the Johns Hopkins Hospital Institutional Review Board with a waiver of informed consent, as this was a retrospective observational study (IRB00216321). The Extracorporeal Life Support Organization (ELSO) registry is an international multicenter registry from over 500 ECMO centers globally¹³. The registry collects demographic information, pre-ECMO comorbidities, pre-ECMO and on-ECMO laboratory and hemodynamic information, on-ECMO complications, and outcomes.¹⁴ Comorbidity information was recorded using International Classification of Diseases, 10th Revision (ICD-10) codes.

We included patients who were 1) 18 years of age or older; 2) supported with VV-ECMO; and 3) had data on race/ethnicity. We excluded repeat ECMO runs within individual patients to reduce bias, patients without data on hypoxemia at either time points, and patients with extreme outlier values for the difference between SpO₂ and SaO₂. Multiple imputation was not used as most variables did not meet appropriate criteria.

Data collection

The ELSO registry collects ABG and hemodynamic information prior to and after ECMO cannulation (i.e., “pre-ECMO” and “on-ECMO”, respectively). Pre-ECMO ABGs were drawn no later than 6 hours prior to ECMO cannulation, and pre-ECMO ventilator settings were recorded within 6 hours of ECMO cannulation. If multiple ABGs existed within a specific duration, the pre-ECMO ABG that was closest to the start of ECMO cannulation was chosen. On-ECMO ABGs were drawn after ECMO cannulation began, no later than 30 hours after cannulation. If multiple ABGs existed, the on-ECMO ABG closest to 24 hours after the start of cannulation was selected. On-ECMO hemodynamics were collected closest to 24 hours after ECMO cannulation, though they could be collected at 18–30 hours. SpO₂ and SaO₂ data were abstracted by a trained ELSO data manager/abstracter from each center and were pulled simultaneously.

Definitions

SpO₂ was defined as the noninvasive pulse oximeter measured oxyhemoglobin saturation while SaO₂ was the percent arterial blood oxyhemoglobin saturation from ABG. Pre-ECMO ventilator type settings included conventional ventilation, high-frequency oscillatory ventilation, other high frequency ventilation (high frequency jet ventilation or percussive ventilation), other non-specified ventilations, and no ventilation. Pre-ECMO mechanical circulatory support included intra-aortic balloon pump, Impella®, and left ventricular assist device. Pre-ECMO vasopressor infusions included dopamine, epinephrine, norepinephrine, phenylephrine, and vasopressin. Pre-ECMO inotrope infusions included dobutamine, enoximone, levosimendan, milrinone, nicardipine, nitroglycerin, nitroprusside, and tolazoline. Infusions were treated as a binary covariate (i.e., the presence or absence of the infusion). Pre-ECMO vasopressor and inotrope infusions were employed for at least 6 hours within 24 hours of the start of ECMO cannulation. By definition, single-lumen cannulation involves placement in two vascular access sites and double-lumen cannulation involves placement of a cannula in single vascular access site.

On-ECMO complications included ECMO mechanical circuit failure, renal replacement therapy, hemolysis, hyperbilirubinemia, cardiac arrhythmia, and gastrointestinal hemorrhage. Definitions for each are provided in the eMethods.

Race/ethnicity was coded per patient as one of: Asian, Black, Hispanic, Middle Eastern or North African, Native American, Native Pacific Islander, Multiple, Other, Unknown, and White. We restricted our primary analysis to Asian, Black, Hispanic, and White patients. White patients were chosen as the reference comparator based on previous literature showing the first pulse oximeters were calibrated to this race/ethnicity.^15,16

Outcomes

Occult hypoxemia was defined as SaO₂ ≤ 88% with a time-matched SpO₂ ≥ 92%.² The primary outcomes were the occult hypoxemia (binary variable) and SpO₂-SaO₂ discrepancy (continuous variable), which were compared between different races/ethnicities. We also assessed the accuracy and precision for SpO₂ to predict SaO₂.

Statistical Analysis

Continuous variables were assessed for normality with the Kolmogorov-Smirnov test, and all were determined to be not normally distributed. Therefore, these variables are denoted as median with interquartile range (IQR). Categorical variables are represented as frequency with percentages. The Kruskal-Wallis, Wilcoxon rank-sum, and Pearson chi-square tests were utilized to compare continuous and categorical variables, respectively. SpO₂-SaO₂ differences were compared with Kruskal-Wallis and Wilcoxon rank-sum tests. A P value < 0.05 was considered statistically significant (eMethods contain more details).

Bland-Altman analyses were used to assess agreement between SpO₂ and the gold standard, SaO₂, by calculating the difference between SpO₂ and SaO₂, the mean of SpO₂ and SaO₂, the estimated bias (median difference) and limits of agreement (median and 95% limits of agreement at 2.5th and 97.5th percentiles) using a nonparametric method to estimate the limits given the non-normality of the differences between SpO₂ and SaO₂.^17,18 The one-sample Wilcoxon signed-rank test was used to compare the median difference between SpO₂ and SaO₂ (estimated bias) for Asian, Black, and Hispanic patient groups as compared to the median value for White patients (hypothetical value set at 0). Boxplots were performed to visually assess the SpO₂-SaO₂ discrepancy while scatterplots were used to visually assess the correlation between SpO₂ and SaO₂. Spearman correlations were conducted for pre-ECMO and on-ECMO SpO₂ and SaO₂ by race/ethnicity.

Multivariable logistic regressions were performed to examine whether race/ethnicity was associated with occult hypoxemia in pre-ECMO and on-ECMO measurements. One pre-ECMO SpO₂-SaO₂ pair and a corresponding on-ECMO SpO₂-SaO₂ pair was measured from the same patient for adequate comparison. We selected covariates a priori that were hypothesized to be associated with the SpO₂-SaO₂ discrepancy based on clinical judgement and prior data. Covariates in both the pre-ECMO and on-ECMO models included age, sex, presence of pre-ECMO temporary mechanical circulatory support (tMCS), and presence of pre-ECMO vasopressor and inotrope infusions. The on-ECMO model also included hemolysis, hyperbilirubinemia, cannulation strategy (single- versus double-lumen), ECMO pump flow rate, and on-ECMO serum lactate value. Adjusted odds ratios (OR) are presented with 95% confidence intervals (CIs).

As a sensitivity analysis, multivariable linear regression was used to assess the on-ECMO SpO₂-SaO₂ discrepancy as a continuous variable by race/ethnicity. The model included covariates selected a priori based on clinical judgement and prior data: age, sex, cannulation strategy, hemolysis, on-ECMO lactate, pre-ECMO tMCS, ECMO duration, pre-ECMO inotrope infusions, and pre-ECMO ventilation strategy.

Receiver-operating characteristic curve (ROC) analyses were performed to determine the accuracy of on-ECMO SpO₂ in predicting SaO₂. Based on previous literature,^19–22 the following on-ECMO SaO₂ thresholds were tested: 88%, 92%, and 95%. All SpO₂ values were tested to detect the specific SaO₂ threshold at or below its value. Area under the receiver-operating characteristic curve (AUC), sensitivity, and specificity were calculated. In addition, the AUC for each SaO₂ threshold was compared by race/ethnicity groups. All statistical analyses were performed using R Studio (R 4.1.2, www.r-project.org) or IBM SPSS Statistics for Windows, Version 28.0 (IBM Corp, Armonk, NY).

Study population

Of 30,407 VV-ECMO patients, we included 13,171 patients for our study after applying the inclusion and exclusion criteria (Fig. 1). Of 13,171 VV-ECMO patients (median age = 48.6 years, 66% male), 7,772 (59%) were White, 2,114 (16%) were Hispanic, 1,777 (14%) were Black, and 1,508 (11%) were Asian (Table 1). Of 9,851 patients with valid COVID-19 data, 59% (N = 5,830) had a diagnosis of SARS CoV-2 and COVID-19. The median ECMO duration was 11.4 days (IQR = 5.7–22.9). Of patients with complete cannulation information (N = 12,966), 9,833 (76%) received single-lumen VV-ECMO versus 3,133 (24%) received double-lumen VV-ECMO. Asian patients were more likely to have single-lumen-cannulation strategy (N = 1,279, 88%) whereas Black patients were less likely to have single-lumen cannulation (N = 1,206, 69%) compared to other races/ethnicities.

Table 1

Baseline characteristics and clinical variables of VV-ECMO patients stratified by race/ethnicity.
	Total (N = 13,171)	Asian (n = 1,508, 11%)	Black (n = 1,777, 14%)	Hispanic (n = 2,114, 16%)	White (n = 7,772, 59%)
Demographics
Age (years)	48.6 (37.0-58.3)	49.8 (38.7–60.7)	44.3 (32.4–55.0)	44.9 (35.4–54.5)	50.2 (38.3–59.5)
Male	8,675 (66)	1,029 (68)	1,021 (58)	1,519 (72)	5,106 (66)
Body Mass Index, kg/m²	30.7 (26.0-36.4)	25.6 (22.9–29.7)	32.5 (26.5–38.7)	31.1 (27.1–36.2)	31.1 (26.5–36.9)
Year ECLS
2018	1,626 (12)	217 (14)	197 (11)	120 (6)	1,092 (14)
2019	2,096 (16)	296 (20)	250 (14)	198 (9)	1,352 (17)
2020	3,756 (29)	472 (31)	537 (30)	881 (42)	1,866 (24)
2021	3,909 (30)	377 (25)	514 (29)	683 (32)	2,335 (30)
2022	1,576 (12)	137 (9)	250 (14)	206 (10)	983 (13)
2023	208 (2)	9 (1)	29 (2)	26 (1)	144 (2)
Past medical history
Diabetes	1,372 (10)	96 (6)	242 (14)	316 (15)	718 (9)
Hypertension	1,873 (14)	112 (7)	331 (19)	285 (13)	1,145 (15)
Atrial fibrillation	845 (6)	36 (2)	108 (6)	94 (4)	607 (8)
Cardiomyopathy	177 (1)	10 (1)	40 (2)	27 (1%)	100 (1)
COPD	478 (4)	20 (1)	46 (3)	21 (1)	391 (5)
COVID-19 status (N = 9,851)	5,830 (59)	621 (59)	722 (53)	1,433 (79)	3,054 (54)
Pre-ECMO support
tMCS	310 (2)	23 (2)	71 (4)	17 (1)	199 (3)
Vasopressor Infusions	8,119 (62)	992 (66)	1,059 (60)	1,194 (57)	4,874 (63)
Inotrope Infusions	870 (7)	82 (5)	144 (8)	113 (5)	531 (7)
Pre-ECMO mean blood pressure (mm Hg)	77 (69–88)	78 (69–90)	78 (69–90)	80 (71–89)	76 (68–87)
Pre-ECMO ABG
pH	7.28 (7.19–7.36)	7.28 (7.19–7.36)	7.27 (7.17–7.35)	7.29 (7.20–7.37)	7.28 (7.18–7.36)
HCO₃- (mEq/L)	26.6 (22.1–31.4)	25.0 (21.0-29.6)	26 (22.1–30.2)	28.0 (24.0–34.0)	26.6 (22.0-31.2)
PaO₂	67 (56–84)	65 (56–80)	68 (53–87)	68 (57–84)	68 (56–84)
PaCO₂	59 (48–74)	58 (46–74)	59 (47–74)	60 (49–75)	59 (48–73)
Lactate (mmol/L)	1.8 (1.2-3.0)	1.9 (1.2–3.2)	1.8 (1.2–3.4)	1.6 (1.2–2.4)	1.7 (1.2-3.0)
SpO₂	91 (85–95)	90 (84–94)	91 (84–96)	91 (86–95)	91 (86–95)
SaO₂	91 (85–95)	90 (84–94)	90 (83–95)	91 (85–95)	91 (85–95)
On-ECMO mean blood pressure (mm Hg)	76 (70–85)	79 (71–88)	77 (71–86)	77 (70–85)	75 (69–83)
On-ECMO pulse pressure (mm Hg)	55 (46–66)	52 (43–63)	55 (45–68)	56 (47–67)	56 (46–67)
On-ECMO ABG
pH	7.40 (7.36–7.44)	7.40 (7.36–7.46)	7.40 (7.36–7.44)	7.41 (7.37–7.45)	7.40 (7.36–7.44)
HCO₃- (mEq/L)	27 (24–31)	26 (23–29)	26 (23–29)	28 (24–32)	27 (24–31)
PaO₂	78 (66–100)	83 (68–107)	80 (67–109)	75 (63–94)	78 (66–98)
PaCO₂	44 (38–50)	42 (36–48)	43 (38–48)	44 (39–51)	44 (39–50)
Lactate (mmol/L)	1.5 (1.1–2.2)	1.6 (1.2–2.4)	1.5 (1.1–2.2)	1.4 (1.1-2.0)	1.5 (1.0-2.2)
SpO₂	96 (93–98)	97 (94–99)	97 (93–99)	95 (92–98)	96 (93–98)
SaO₂	95 (92–98)	96 (93–98)	96 (93–98)	95 (91–97)	95 (93–97)
Pump Flow (4 hours)	4.10 (3.60–4.65)	3.95 (3.40–4.36)	4.15 (3.65–4.70)	4.13 (3.68–4.70)	4.15 (3.60–4.70)
Pump Flow (24 hours)	4.14 (3.60–4.72)	3.95 (3.40–4.42)	4.12 (3.60–4.72)	4.20 (3.70–4.79)	4.20 (3.65–4.80)
Cannulation Strategy (N = 12,966)
Single-Lumen (Two Sites)	9,833 (76)	1,279 (88)	1,206 (69)	1,572 (75)	5,776 (75)
Double-Lumen (One Site)	3,133 (24)	169 (12)	545 (31)	525 (25)	1,894 (25)
Days on ECMO support	11.4 (5.7–22.9)	11.3 (5.8–23.2)	10.1 (5.3–21.2)	15.8 (7.6–30.2)	10.7 (5.3–21.0)
ECMO complications
ECMO circuit mechanical failure	1,224 (9)	138 (9)	156 (9)	237 (11)	693 (9)
Renal replacement therapy	3,419 (26)	368 (24)	483 (27)	490 (23)	2,078 (27)
Hemolysis	659 (5)	44 (3)	80 (5)	155 (7)	380 (5)
Hyperbilirubinemia	534 (4)	56 (4)	69 (4)	114 (5)	295 (4)
Cardiac arrhythmia	1,202 (9)	93 (6)	156 (9)	165 (8)	788 (10)
Gastrointestinal hemorrhage	790 (6)	92 (6)	112 (6)	156 (7)	430 (6)

Abbreviations: ECMO, extracorporeal oxygenation membrane; tMCS, temporary mechanical circulatory support; VV, venovenous.

Occult Hypoxemia

Overall, on-ECMO occult hypoxemia was observed in 2.0% of patients (233 of 11,709). On-ECMO occult hypoxemia was more common in Black (3.1% vs 1.7%, P < 0.001) and Hispanic (2.5% vs 1.7%, P = 0.025) patients versus White patients. The proportion of on-ECMO occult hypoxemia was similar between Asian and White patients (1.6%% vs 1.7%, P = 0.787).

In a multivariable logistic regression, Black patients were at higher risk of pre-ECMO occult hypoxemia versus White patients (aOR = 1.55, 95%CI = 1.18–2.02, P = 0.001; Fig. 2A, eTable 1). No other race/ethnicity group differences were found.

For on-ECMO occult hypoxemia, multivariable logistic regression analysis found that Black patients (aOR = 1.79, P = 0.008) and Hispanic patients (aOR = 1.71, P = 0.008) had greater risk versus White patients (Table 2, Fig. 2B). Other significant risk factors included pump flow rate at 24 hours on ECMO (aOR = 1.29, P = 0.005) and on-ECMO lactate (aOR = 1.06, P < 0.001; Table 2).

Table 2

Factors associated with on-ECMO occult hypoxemia frequencies in multivariable logistic regression analysis.
	OR	95% CI	P value
Age	0.99	0.98-1.00	0.069
Female sex	1.30	0.91–1.84	0.147
Race/ethnicity
White	Reference
Black	1.79	1.16–2.75	0.008
Asian	1.28	0.78–2.09	0.332
Hispanic	1.71	1.15–2.55	0.008
Pre-ECMO support
Pre-ECMO tMCS	0.22	0.03–1.65	0.142
Pre-ECMO inotrope infusions	1.44	0.80–2.59	0.228
Pre-ECMO vasopressor infusions	1.04	0.75–1.43	0.830
ECMO physiology
Double-lumen cannula (one-site)	0.97	0.66–1.42	0.874
Hemolysis	1.68	0.98–2.88	0.060
Hyperbilirubinemia	1.31	0.70–2.43	0.402
Pump flow at 24 hours on-ECMO	1.29	1.08–1.55	0.005
On-ECMO lactate	1.06	1.03–1.10	< 0.001
Abbreviations: CI, confidence interval; ECMO, extracorporeal membrane oxygenation; OR, odds ratio; tMCS, temporary mechanical circulatory support.
Pre-ECMO tMCS consisted of intra-aortic balloon pump, Impella, and left ventricular assist devices. Pre-ECMO inotropic infusions consisted of dobutamine, enoximone, levosimendan, milrinone, nicardipine, nitroglycerin, nitroprusside, tolazoline. Pre-ECMO vasopressor infusions included dopamine, epinephrine, norepinephrine, phenylephrine, and vasopressin. Hemolysis was defined as a peak plasma hemoglobin of at least 50 mg/dL occurring at least once during the ECMO run and sustained for at least 2 consecutive days. Hyperbilirubinemia was defined as a total bilirubin > 10 mg/dL, conjugated bilirubin > 3 mg/dL, or need for extracorporeal purification for elevated bilirubin.

SpO₂-SaO₂ Discrepancy

Figure 3 depicts boxplots of the on-ECMO SpO₂-SaO₂ difference for each race/ethnicity. The overall on-ECMO estimated bias for the entire cohort was 1.0 (median difference between SpO₂ and SaO₂) with 95% limits of agreement at -6.0 and 7.0 (2.5th and 97.5th percentiles). In Bland-Altman plots, the limits of agreement for Asian, Black, and Hispanic patients were wider as compared to White patients (eFigure 1). In addition, the median difference of the SpO₂-SaO₂ difference for Asian, Black, and Hispanic patients was significantly higher than the hypothetical value set at the median for White patients. The overall Spearman correlation coefficient comparing on-ECMO SpO₂ with SaO₂ was moderate (r_s=0.69, P < 0.001). The Spearman correlation coefficients comparing on-ECMO SpO₂ with SaO₂ were relatively comparable in magnitude across the race/ethnicity groups, and all were significant (P < 0.001): Asian patients (r_s=0.69), Black patients (r_s=0.67), Hispanic patients (r_s=0.72), and White patients (r_s=0.68), but Fisher r-to-z transformation did find a significant difference in r_s between White and Hispanic patients (z=-2.84, P = 0.005).

Sensitivity Analysis for SpO₂-SaO₂ discrepancy

A multivariable linear regression was performed to corroborate the results of the primary logistic regression analysis for on-ECMO occult hypoxemia, using the continuous variable of the difference between on-ECMO SpO₂ and SaO₂. After adjusting for the covariate set (F = 3.3, P < 0.001), the addition of race/ethnicity to the model was associated with a significant r² change (0.01, P < 0.001). Each race/ethnicity group was found to have greater on-ECMO discrepancies as a continuous variable as compared with White patients after adjustment for the covariates (eTable 2). The double-lumen cannula was also found to have greater on-ECMO discrepancies as a continuous variable as compared to single-lumen cannula.

On-ECMO Receiver-operating characteristic curve analyses

At an 88% SaO₂ threshold, SpO₂ predicted hypoxemia with an AUC of 0.89 (95%CI = 0.88–0.90), at a 92% threshold, SpO₂ predicted hypoxemia with an AUC of 0.87 (95%CI = 0.86–0.88), and at a 95% threshold, SpO₂ predicted hypoxemia with an AUC of 0.83 (95%CI = 0.83–0.84; eFigure 2), sensitivity of 0%, and specificity of 100%. There were no significant race/ethnicity group differences in AUC for SpO₂ at an 88% SaO₂ threshold between White patients (AUC = 0.90) and Asian (AUC = 0.88), Black (AUC = 0.89), and Hispanic (AUC = 0.88) patients. At a 92% SaO₂ threshold, the AUC was smaller for Black patients (AUC = 0.85) versus White patients (AUC = 0.88, P = 0.037), but not for Asian (AUC = 0.86) or Hispanic (AUC = 0.86) patients versus White patients. No significant race/ethnicity group differences in AUC for SpO₂ at an 95% SaO₂ threshold were found between White patients (AUC = 0.83) and Asian (AUC = 0.84), Black (AUC = 0.83), and Hispanic (AUC = 0.85) patients.

Exploratory Analysis: Single-lumen versus Double-lumen

There was no difference in the incidence of on-ECMO occult hypoxemia for single-lumen versus dual-lumen cannulation (2% vs 2%, P = 0.527). However, the correlation between on-ECMO SpO₂ and SaO₂ was weaker for single-lumen (r_s=0.68, P < 0.001) versus double-lumen (r_s=0.72, P < 0.001) using Fisher r-to-z transformation to compare r_s values (z=-3.45, P < 0.001).In patients with confirmed hemolysis, there was no difference in the incidence of on-ECMO occult hypoxemia for single-lumen versus double-lumen cannulation (6% vs 4%, P = 0.463). The correlation between on-ECMO SpO₂ and SaO₂ was weaker for single-lumen (r_s=0.67, P < 0.001) versus double-lumen (r_s=0.83, P < 0.001) using Fisher r-to-z transformation to compare r_s values (z= -4.28, P < 0.001).

Exploratory Analysis: COVID-19 vs non-COVID-19

In those with COVID-19 (N = 5,830, 59%), the incidence of pre-ECMO occult hypoxemia did not differ for patients with and without COVID-19 (4% vs 4% P = 0.993), but the incidence of on-ECMO occult hypoxemia was significantly greater for patients with COVID-19 (2.4% vs 1.5%, P = 0.003).

In this retrospective observational analysis of the international multicenter ELSO Registry, we found that the frequency of unadjusted and adjusted occult hypoxemia in VV-ECMO patients was higher in Black and Hispanic patients versus White patients. After adjusting for clinically relevant risk factors, we found that ECMO support exacerbated occult hypoxemia (compared to pre-ECMO). This finding suggests that, in addition to race/ethnicity, being supported by VV-ECMO may lead to more inaccurate pulse oximetry measurements likely mediated by greater ECMO pump flow and corresponding associated hemolysis.

Pre-ECMO vs On-ECMO Occult Hypoxemia

While a previous ELSO Registry study using solely pre-ECMO SpO₂ and SaO₂ measurements found a similar frequency of occult hypoxemia in Hispanic patients compared to White patients,² we found a higher frequency of occult hypoxemia in Hispanic versus White patients in “on-ECMO” SpO₂ and SaO₂ values. This finding suggests the SpO₂-SaO₂ discrepancy is worse during the time that patients were supported with ECMO. Besides one single-center study analyzing this discrepancy in 57 VV-ECMO patients,²² which found the unadjusted frequency of occult hypoxemia to be greater in Black versus White patients but not in Hispanic or Asian versus White patients, no other literature exists pertaining to this discrepancy directly for patients supported on ECMO.

Undetected hypoxemia during cannulation is important as ECMO patients are already at high-risk for many complications such as acute brain injury from inadequate oxygen delivery, which increases mortality.^23,24 Occult hypoxemia may increase in-hospital mortality due to increased risk of organ dysfunction,^25,26 lung injury,²⁷ and worse neurocognition.²⁸ Accordingly, monitoring for occult hypoxemia in patients with such risk factors (Black and Hispanic race/ethnicity, high pump-flow and lactate) in ECMO is extremely important.

Additionally, compared to this pre-ECMO ELSO study, our study has several strengths including 1) having a larger sample size (N = 13,171 versus N = 1,562), 2) the use of methodically rigorous statistical methods such as the Kolmogorov-Smirnov test to assess for non-normality and nonparametric analyses when comparing the SpO₂-SaO₂ discrepancy, and 3) the adjustment of more clinically-relevant and ECMO-specific covariates versus only adjusting for measured SpO₂ and sex as was done in this prior study.

Cannulation strategy, ECMO pump flow rate, and hemolysis

In contrast to previous data,⁷ we found no differences in the SpO₂-SaO₂ discrepancy between patients with single-lumen versus double-lumen, perhaps because the rates of hemolysis in our population were similar (5.5% versus 5.4%) which may be the primary driver of increased SpO₂-SaO₂ discrepancy via carbon monoxide production increasing carboxyhemoglobin. However, we still observed the correlation between SpO₂ versus SaO₂ was weaker in single-lumen versus double-lumen, with and without confirmed hemolysis. However, relative to single-lumen, the double-lumen cannula enhanced the SpO₂-SaO₂ discrepancy in our multivariable linear regression analysis. Overall, further research is warranted to investigate the association between cannulation strategy and the SpO₂-SaO₂ discrepancy.

Although “ELSO-defined” hemolysis during ECMO was not independently associated with occult hypoxemia, higher ECMO pump flow rates were associated with higher occurrence of occult hypoxemia. This finding may indicate varying degree of hemolysis is occurring with high ECMO pump flow rates.^7,8,29 Due to shear mechanical stress that is produced by high pump flow rates in combination with large cannula sizes⁸ throughout the ECMO circuit and oxygenator, ECMO-associated hemolysis can occur.³⁰ Furthermore, intravascular hemolysis, which has been reported to occur in 18% of ECMO-supported patients, can increase plasma hemoglobin.³¹ This hemoglobin can then scavenge endothelial-derived nitric oxide, which causes oxidative stress and triggers inflammatory signaling pathways that can potentially worsen the discrepancy as well.^29,32

Limitations

In line with previous studies,^2,3,33,34 race/ethnicity was used as a substitute for skin tone as clinicians do not obtain this information, which likely does not completely reflect the heterogeneity of skin pigmentation found within races/ethnicities. The ELSO registry is an international consortium of over 500 ECMO centers; therefore, heterogeneity in data collection and the patient cohort inherently exists. However, this diversity in sampling may be offset by the large sample size of our study. Frequency of occult hypoxemia was relatively low in our cohort; however, it was measured at a single timepoint during ECMO cannulation and may not reflect the SpO₂-SaO₂ discrepancy throughout the entire ECMO run, as observed in previous studies.^7,22 Additionally, prospective observational studies are needed to assess causation effects.

Black and Hispanic VV-ECMO patients are at higher risk for occult hypoxemia and overestimated true oxygen saturation measurements compared to White patients. Patients who were supported with ECMO had an increased risk of the SpO₂-SaO₂ discrepancy compared to the pre-ECMO SpO₂-SaO₂ discrepancy, which was greater in non-White patients. As occult hypoxemia and SpO₂-SaO₂ discrepancy may worsen in patients with ECMO support, clinicians should carefully monitor ABGs during ECMO support for those with such risk factors.

ABG	arterial blood gas
aOR	adjusted odds ratio
AUC	area under the receiver-operating characteristic curve
CI	confidence interval
COVID-19	Coronavirus Disease 19
ECMO	extracorporeal membrane oxygenation
ELSO	Extracorporeal Life Support Organization
IQR	interquartile range
PaO₂	partial pressure of oxygen
ROC	receiver-operating characteristic
SaO₂	oxygen saturation measured by arterial blood gas
SpO₂	oxygen saturation measured by pulse oximetry
SD	standard deviation
tMCS	temporary mechanical circulatory support
VV-ECMO	venovenous ECMO

Acknowledgements: We would like to acknowledge Dr. Theodore J. Iwashyna for his guidance regarding this study.

Disclosures: The authors have nothing to disclose

Conflict of Interest and Sources of Funding: Dr. Tonna is supported by a Career Development Award from the National Institutes of Health/National Heart, Lung, And Blood Institute (K23 HL141596). Dr. Tonna is the Chair of the Registry Committee of the Extracorporeal Life Support Organization (ELSO). Dr. Brodie receives research support from and consults for LivaNova. He has been on the medical advisory boards for Abiomed, Xenios, Medtronic, Inspira and Cellenkos. He is the President-elect of the Extracorporeal Life Support Organization (ELSO) and the Chair of the Executive Committee of the International ECMO Network (ECMONet), and he writes for UpToDate. Dr. Lorusso is a consultant for Medtronic, LivaNova, Getinge and ASbiomed, and Member of the Medical Advisory Board of Eurosets and Xenios. He is the ELSO Research Committee Chair, and Honorary Secretary of EuroELSO. The authors do not have any additional conflicts of interest to declare. SPK is supported by NHLBI (5K08HL14332). SMC is supported by NHLBI (1K23HL157610).

IRB Approval: This study was approved by the Johns Hopkins Hospital Institutional Review Board (IRB00216321) on 10/22/2019. The study title is “Retrospective Analysis of Outcomes of Patients on Extracorporeal Membrane Oxygenation”. All procedures were followed in accordance with the ethical standards of the responsible committee on human experimentation (institutional or regional) and with the Helsinki Declaration of 1975.

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Characterizing the Racial Discrepancy in Hypoxemia Detection in VV-ECMO: An ELSO Registry Analysis

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Version 1

Abstract

Figures

Key Points

Introduction

Methods

Study design and population

Data collection

Definitions

Outcomes

Statistical Analysis

Results

Study population

Occult Hypoxemia

SpO₂-SaO₂ Discrepancy

Sensitivity Analysis for SpO₂-SaO₂ discrepancy

On-ECMO Receiver-operating characteristic curve analyses

Exploratory Analysis: Single-lumen versus Double-lumen

Exploratory Analysis: COVID-19 vs non-COVID-19

Discussion

Pre-ECMO vs On-ECMO Occult Hypoxemia

Cannulation strategy, ECMO pump flow rate, and hemolysis

Limitations

Conclusions

Abbreviations

Declarations

References

Supplementary Files

Status:

Version 1

Characterizing the Racial Discrepancy in Hypoxemia Detection in VV-ECMO: An ELSO Registry Analysis

Status:

Version 1

Abstract

Figures

Key Points

Introduction

Methods

Study design and population

Data collection

Definitions

Outcomes

Statistical Analysis

Results

Study population

Occult Hypoxemia

SpO2-SaO2 Discrepancy

Sensitivity Analysis for SpO2-SaO2 discrepancy

On-ECMO Receiver-operating characteristic curve analyses

Exploratory Analysis: Single-lumen versus Double-lumen

Exploratory Analysis: COVID-19 vs non-COVID-19

Discussion

Pre-ECMO vs On-ECMO Occult Hypoxemia

Cannulation strategy, ECMO pump flow rate, and hemolysis

Limitations

Conclusions

Abbreviations

Declarations

References

Supplementary Files

Status:

Version 1

SpO₂-SaO₂ Discrepancy

Sensitivity Analysis for SpO₂-SaO₂ discrepancy