Association of carboxyhemoglobin and methemoglobin levels with hemolysis during extracorporeal membrane oxygenation

Abstract

Introduction:

Hemolysis, characterized by increased carboxyhemoglobin (COHb) and methemoglobin (MetHb) levels, is a complication of extracorporeal membrane oxygenation (ECMO).

Methods:

This prospective single-center study aimed to investigate the correlation between COHb and MetHb levels and hemolysis during ECMO. This study included 32 patients requiring ECMO for circulatory or respiratory failure. Plasma-free hemoglobin (pfHb), COHb, and MetHb levels were measured simultaneously within 6 h of ECMO induction, daily during ECMO, within 6 h after decannulation, and 2 days after decannulation unless death occurred before. Patients were classified into hemolysis and non-hemolysis groups based on whether the maximum pfHb level during ECMO was ⩾50 mg/dL.

Results:

No significant difference in maximum COHb levels during ECMO (COHb_ECMO) was observed between the hemolysis and non-hemolysis groups (2.15% [interquartile range (IQR) = 1.83, 2.60] vs 1.65% [IQR = 1.40, 2.10], p = 0.159). However, maximum MetHb levels during ECMO (MetHb_ECMO) were significantly higher in the hemolysis group (1.35% [IQR = 1.12, 1.78] vs 1.10% [IQR = 0.90, 1.37], p = 0.045). The Spearman’s correlation coefficients for COHb_ECMO and MetHb_ECMO were 0.39 (95% confidence interval [CI] = 0.456–0.649) and 0.66 (95% CI = 0.404–0.820), respectively.

Conclusion:

Elevated MetHb levels in patients undergoing ECMO may be associated with hemolysis.

Keywords

ECMO hemolysis plasma free hemoglobin carboxyhemoglobin methemoglobin

Introduction

Hemolysis is a complication of mechanical support strategies, including extracorporeal membrane oxygenation (ECMO) and cardiopulmonary bypass (CPB). Hemolysis during mechanical support is associated with adverse clinical outcomes, such as acute kidney injury (AKI).^1
–3 One cause of AKI during mechanical support is the release of plasma-free hemoglobin (pfHb) from red blood cells (RBCs) following hemolysis. pfHb is typically excreted in the plasma by forming a complex with haptoglobin; however, when haptoglobin is depleted due to rapid hemolysis, pfHb remains and leaks heme, causing AKI. Consequently, measuring pfHb levels is considered the gold standard for monitoring intravascular hemolysis, as recommended by the Extracorporeal Life Support Organization.⁴

Despite its utility, pfHb measurement requires special equipment and is not covered by medical insurance in some countries. Therefore, although pfHb measurement is ideal for the diagnosis of hemolysis, it is not always practical.

Certain blood gas analyzers provide information on carboxyhemoglobin (COHb) and methemoglobin (MetHb). COHb has been suggested as a potential hemolysis biomarker,^5
–9 and MetHb has been reported to be associated with hemolysis during pediatric CPB.¹⁰ Utilizing point-of-care devices, such as blood gas analyzers, for the early detection of hemolysis during ECMO may be of great clinical value because these devices are widely available and provide rapid results in intensive care units (ICU). However, evidence regarding the association between COHb, particularly MetHb, and hemolysis during ECMO remains insufficient. To date, no prospective studies have simultaneously measured pfHb, COHb, and MetHb levels or investigated their association with hemolysis during ECMO.

This study aimed to investigate whether COHb and MetHb levels, as well as pfHb, increase during ECMO; compare pfHb, COHb, and MetHb levels between patients with and without hemolysis during ECMO; and assess the predictive ability of COHb and MetHb as biomarkers for hemolysis. We hypothesized that COHb and MetHb levels would increase with hemolysis and serve as hemolysis biomarkers during ECMO.

Methods

Study design and ethical oversight

This prospective single-center study was conducted from February 2022 to May 2023. Before initiation, this study was registered with the University Hospital Medical Information Network Individual Case Data Repository (registration number: UMIN000046369) and was approved by the Institutional Review Board of Okayama University Hospital, Okayama, Japan (approval number: 2112-020). The study was conducted in accordance with the principles of the Declaration of Helsinki and adhered to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement. Written informed consent was obtained from each patient or their legal representative during the ECMO.

Study population

Patients of any age, including children, who required ECMO management owing to circulatory or respiratory failure during the study period were assessed for eligibility. Patients undergoing a second and subsequent ECMO procedure during the study period were excluded. As this was a prospective observational study, haptoglobin and nitric oxide (NO) therapies were administered at the discretion of the clinical physician.

Data collection

Data collection included demographic variables (age, sex, height, weight, and body surface area) and laboratory test results, before, during, and after ECMO. Laboratory data included hemoglobin, hematocrit, total bilirubin, lactate dehydrogenase, and creatinine. pfHb, COHb, and MetHb levels were measured simultaneously within 6 h after ECMO induction, daily during ECMO, within 6 h after decannulation, and 2 days after decannulation unless death occurred before. The pfHb levels at ECMO induction, maximum pfHb level during ECMO, and maximum pfHb level following ECMO weaning were defined as pfHb_day0, pfHb_ECMO, and pfHb_post, respectively. The COHb level at ECMO induction (COHb_day0), MetHb level at ECMO induction (MetHb_day0), maximum COHb level during ECMO (COHb_ECMO), maximum MetHb level during ECMO (MetHb_ECMO), maximum COHb level after ECMO weaning-off (COHb_post), and maximum MetHb level after ECMO weaning-off (MetHb_post) were similarly defined. Blood gas samples were collected using standard heparinized blood gas syringes, while measurements were performed using a blood gas analyzer (ABL 800, 13B2X00079000003, Radiometer Co., Copenhagen, Denmark). The analyzer measured whole-blood samples at 37°C. pfHb was measured using a Hemocue^® plasma/low hemoglobin system (Hemocue, Lake Forest, CA). Approximately 2 ml of blood from the blood gas sample was centrifuged at 3000 rpm for 3 min and a small amount of the supernatant fluid was administered into a Hemocue^® cartridge.

Management for ECMO

The ECMO prime comprised an acetate Ringer’s solution. RBCs were also primed to achieve the expected Hct level of >30% in the priming solution. Heparin was administered to maintain the activated clotting time or the activated partial thromboplastin time at approximately 1.5 times the upper limit of the normal range.

For adults, we used a Capiox EBS^® (TERUMO Inc., Tokyo, Japan) or SOLAS^® (SENKO Inc., Tokyo, Japan) centrifugal pump; in children, the Gyro^® (Medtronic Inc., Dublin, Ireland), Rotaflow^® (Getinge Inc., Dubai, UAE), or Biocube^® (NIPRO Inc., Osaka, Japan). Aortic cannulation in adults was performed with a 16–20 Fr cannula OptiSite^® (Edwards Lifesciences Inc., Roussin, Marseille) or DLP malleable^® (Medtronic Inc., Dublin, Ireland), depending on target flow and patient size. In children, we used an 8–12 Fr cannula Stokert A272^® (LivaNova Inc., London, UK), Bio-Medicus^® (Medtronic Inc., Dublin, Ireland), or DLP malleable^® (Medtronic Inc., Dublin, Ireland). Venous cannulation in adults was performed using either a 17–28 Fr cannula OptiSite^® (Edwards Lifesiences Inc., Roussin, Marseille), Capiox percutaneous catheter^® (TERUMO Inc., Tokyo, Japan), HLS cannulae^® (Getinge Inc., Dubai, UAE), PCKCV^® (SENKO Inc., Tokyo, Japan), or DLP malleable^® (Medtronic Inc., Dublin, Ireland), depending on the target flow and patient size. Conversely, in children, an 8–18 Fr cannula Stokert A272^® (LivaNova Inc., London, UK), Bio-Medicus^® (Medtronic Inc., Dublin, Ireland), or DLP malleable^® (Medtronic Inc., Dublin, Ireland) were used. The target flow was 150–180 mL/kg/min for neonates/infants, 150 mL/kg/min for pediatric patients weighing ⩽10 kg or 2.4 L/min/m² for patients weighing ⩾10 kg, and 2.4 L/m²/min for adults. The target mean arterial pressure to maintain adequate organ perfusion was 30–40 mmHg for neonates and infants, 40–50 mmHg for pediatric patients, and 60–80 mmHg for adult patients. The sweep gas oxygen fraction (FsO₂) in the circuit was controlled to achieve a partial pressure of arterial oxygen between 150 and 300 mmHg.

Outcomes

The primary outcome was whether COHb and MetHb levels increased in the hemolysis group, in the same way that pfHb levels increase when hemolysis occurs during ECMO. The secondary outcome was to investigate whether COHb and MetHb levels during ECMO correlated with pfHb levels.

Statistical analysis

Sample size calculations were not performed as this was a preliminary study. The number of patients requiring ECMO at our hospital during the study period was expected to be 40, and because 80% of these patients were expected to consent to participate in the study, the expected number of study participants was set at 32. Hemolysis was diagnosed when the maximum pfHb level was ⩾50 mg/dL at any time during ECMO.⁴

Data are presented as n (percentages), median (interquartile range [IQR] = 25% quartile, 75% quartile), or mean (standard deviation). The Wilcoxon rank-sum test (two groups) was used for group-wise comparisons of continuous variables. Fisher’s exact test or chi-square test was performed for categorical variables. Receiver operating characteristic (ROC) curves were generated to assess the predictive performance of the COHb and MetHb levels during ECMO. The area under the ROC curve was calculated to identify the best predictor of hemolysis among these parameters. Spearman’s correlation coefficients were applied to determine the correlation between pfHb, COHb, and MetHb levels during ECMO.

All statistical comparisons were two-sided, and statistical significance was set at p < 0.05. All statistical analyses were performed using R 3.6.0 (R Foundation for Statistical Computing, Vienna, Austria).

Results

Participants

A total of 34 patients on ECMO were considered eligible for the study. After excluding two patients who received ECMO for a second or subsequent time within the study period, 32 patients were enrolled in this study. The patient characteristics are presented in Table 1. The ICU at our hospital is mainly used by post-operative patients, and relatively few severe internal medicine patients are admitted. Therefore, the majority of ECMO breakdowns are Veno-Arterial ECMO. Hemolysis during ECMO occurred in 14 patients (43.8%). No significant differences in age, sex, or weight were observed between patients with and without hemolysis. During ECMO, MetHb, but not COHb, was significantly higher in patients with hemolysis than in those without hemolysis (1.35% [1.12, 1.78] vs 1.10% [0.90, 1.37], p = 0.045). Haptoglobin was administered in only one case, 35 days after the diagnosis of hemolysis. iNO use was not significantly different depending on the presence of hemolysis; iNO was applied in four cases; in two of the three cases in the hemolysis group, it was administered after the diagnosis of hemolysis. In patients who had been administered iNO, it was up to a maximum of 20 ppm.

Table 1.

Comparison of clinical characteristics between patients with and without hemolysis.

Variable	All (n = 32)	Hemolysis (n = 14)	Non-hemolysis (n = 18)	p-value
Age, years [IQR]	36.50 [0.00, 55.25]	41.00 [18.5, 54.00]	12.50 [0.00, 55.75]	0.591
Male, n (%)	15 (46.9)	6 (42.9)	9 (50)	0.964
Weight, kg [IQR]	47.35 [8.95, 68.88]	59.45 [28.27, 69.02]	26.25 [5.71, 64.58]	0.305
T-Bil before ECMO, mg/dL [IQR]	0.72 [0.59, 1.61	0.73 [0.62, 2.72]	0.72 [0.59, 0.94]	0.414
LDH before ECMO, U/L [IQR]	374 [268, 516]	435 [260, 591]	350 [276, 490]	0.436
ECMO related data
Veno-Arterial ECMO, n (%)	30 (93.8)	12 (85.7)	18 (100)	0.358
Central ECMO, n (%)	14 (43.8)	7 (50)	7 (38.9)	0.788
Post operation, n (%)	14 (43.8)	6 (42.9)	8 (44.4)	1.000
iNO, n (%)	4 (12.9)	3 (23.1)	1 (5.6)	0.372
Circuit exchange, n (%)	10 (31.2)	7 (50.0)	3 (16.7)	0.102
Blood transfusion, n (%)	28 (87.5)	12 (85.7)	16 (88.9)	1.000
Circuit max FsO₂, % [IQR]	60 [50, 80]	78 [60, 88]	55 [50, 60]	0.031*
max PaO₂, mmHg [IQR]	316.5 [250.5, 411.5]	316.0 [247.0, 449.8]	319.5 [256.5, 380.0]	0.595
max rotations, rpm [IQR]	2033 [1738, 2335]	2107 [1954, 2380]	1951 [1685, 2285]	0.287
PFH_day0, mg/dL [IQR]	10 [0, 50]	60 [10, 90]	0 [0, 10]	0.001*
PFH_ECMO, mg/dL [IQR]	40 [10, 70]	80 [60, 230]	10 [0, 30]	<0.001*
PFH_post, mg/dL [IQR]	0 [0, 30]	30 [0, 80]	0 [0, 10]	0.079
COHb_day0, % [IQR]	1.40 [1.00, 1.65]	1.10 [0.80, 1.50]	1.50 [1.20, 1.67]	0.132
COHb_ECMO, % [IQR]	1.95 [1.48, 2.35]	2.15 [1.83, 2.60]	1.65 [1.40, 2.10]	0.159
COHb_post, % [IQR]	1.50 [1.30, 1.80]	1.70 [1.40, 2.10]	1.30 [1.20, 1.80]	0.032*
MetHb_day0, % [IQR]	0.90 [0.70, 1.10]	1.00 [0.70, 1.70]	0.85 [0.72, 1.00]	0.267
MetHb_ECMO, % [IQR]	1.20 [0.98, 1.50]	1.35 [1.12, 1.78]	1.10 [0.90, 1.37]	0.045*
MetHb_post, % [IQR]	1.10 [0.80, 1.30]	1.05 [0.88, 1.33]	1.10 [0.80, 1.20]	0.672

COHb, carboxyhemoglobin; ECMO, extracorporeal membrane oxygenation; IQR, interquartile range; LDH, lactate dehydrogenase; MetHb, methemoglobin; PFH, plasma free hemoglobin; T-bil, total bilirubin

Statistical significance: p < 0.05.

pfHb during ECMO

Supplemental Figures 1a and 1b display the daily pfHb measurements during ECMO in all patients and in patients with and without hemolysis, respectively. pfHb_day0 in the hemolysis group was significantly higher than that on day 1 (60 mg/dL [10, 90] vs 20 mg/dL [0, 30], p = 0.02). The pfHb in the hemolysis group appeared to increase with each passing day. In contrast, pfHb in the non-hemolysis group remained low from pfHb_day0 and was constant with little increase over time.

COHb and MetHb during ECMO

Figure 1(a) and (b) illustrate the daily measurements of COHb during ECMO in all patients and in patients with and without hemolysis, respectively. COHb levels in the hemolysis group at day 1 (1.85% [1.10, 2.08], p = 0.005), day 2 (1.50% [1.23, 1.88], p = 0.006), day 3 (1.80% [1.30, 2.23], p = 0.025), and day 4 (2.00% [1.35, 2.05], p = 0.025) were significantly increased compared to COHb_day0 (1.10% [0.80, 1.50]). In contrast, COHb levels in the non-hemolysis group did not significantly increase from COHb_day0.

Figure 2(a) and (b) present the daily MetHb measurements during ECMO in all patients with and without hemolysis, respectively. MetHb levels in patients with hemolysis showed no significant increase. In the non-hemolysis group, MetHb levels on day 1 were significantly higher than MetHb_day0 (0.95% [0.83, 1.00] vs 0.85% [0.73, 1.00], p = 0.025).

Predictive performance of COHb and MetHb for hemolysis during ECMO

An unadjusted ROC curve analysis was performed to predict hemolysis (Supplemental Figure 2). The area under the ROC curve of COHb_ECMO in all patients was 0.647 (95% confidence interval [CI]: 0.441–0.853, cutoff value = 1.75%), whereas that of MetHb_ECMO was 0.708 (95% CI = 0.519–0.898, cutoff value = 1.55%). The correlation coefficients between pfHb, COHb, and MetHb levels were calculated. The Spearman’s correlation coefficients for COHb_ECMO was 0.39 (p < 0.001) and for MetHb_ECMO was 0.66 (p < 0.001) (Figure 3(a) and (b), respectively). From the above results, although COHb and MetHb levels did not consistently increase due to hemolysis during ECMO, MetHb demonstrated a strong correlation with pfHb levels.

Discussion

Hemolysis during mechanical support is associated with adverse clinical outcomes, such as AKI.^1
–3 Hemolysis-induced pfHb causes capillary damage and platelet aggregation,¹¹ potentially resulting in the development of serious complications such as renal dysfunction and multiple organ failure. Additionally, it has been associated with mortality.¹² Thus, it is essential to quickly identify hemolysis in patients during ECMO, which is a serious condition. Herein, we investigated the association between COHb, MetHb, and hemolysis in 32 patients who required ECMO due to circulatory or respiratory failure. First, we found that a significant difference in the maximum value during ECMO by hemolysis was observed in pfHb and MetHb levels. However, only COHb levels showed a significant increase during ECMO. Finally, although our results did not indicate that COHb and MetHb levels during ECMO consistently increase due to hemolysis, the correlation coefficient between MetHb and pfHb levels was high.

Carbon monoxide (CO) is endogenously produced, and hemoglobin released by hemolysis can be degraded by heme oxygenase into iron, biliverdin, and carbon monoxide, which form COHb.¹³ MetHb is another state of hemoglobin that results from the oxidized ferric form (Fe³⁺) instead of the usual reduced ferrous form (Fe²⁺). During hemolysis, hemoglobin is released into the circulation as oxyhemoglobin, which is expected to be oxidized to MetHb.¹⁴ Recent retrospective studies have indicated that COHb levels during ECMO are increased in both adult and pediatric patients with hemolysis and may be a biomarker for hemolysis^{8,15,16,17,18}; however, no reports on MetHb and hemolysis during ECMO have been published. To the best of our knowledge, this is the first prospective study to examine the potential use of COHb and MetHb as markers of hemolysis during ECMO by simultaneously measuring pfHb. In the hemolysis group, COHb levels increased significantly from day 0 after ECMO initiation and showed an increasing trend during ECMO, whereas MetHb levels did not increase significantly during ECMO. However, with respect to COHb_ECMO, there were no significant differences in hemolysis and the Spearman’s correlation coefficient was low for pfHb levels. These results differ slightly from those of previous retrospective studies for several reasons. First, the sample size was too small to determine statistical significance. Second, Chawla et al. reported that the distribution of COHb differs between children and adults.¹⁹ Finally, the increase in COHb levels during ECMO may be due to factors other than hemolysis. COHb levels increase in critically ill patients as heme oxygenase-1 levels increase with oxidative stress.^20,21 In a prior prospective study on adult cardiac patients undergoing CPB, Schober et al. reported that cardiac surgery with CPB was associated with increased CO production due to oxidative stress.²² Therefore, the possibility that the increase in COHb levels in this study was not only due to hemolysis but also due to oxidative stress during ECMO cannot be ruled out.

Herein, we observed a significant difference in MetHb_ECMO between patients with and without hemolysis, the AUC for the prediction of hemolysis in MetHb was slightly higher than that in COHb, and the Spearman’s correlation coefficient was high for pfHb levels. In a retrospective study of 191 pediatric patients who underwent CPB, we reported an association between MetHb levels during CPB and hemolysis.⁹ We observed that MetHb levels were significantly higher during CPB than before CPB initiation or after weaning off CPB. Additionally, MetHb levels showed an upward trend with an extended CPB duration. These MetHb trends were similar to the pfHb trends observed during CPB in a prior study.²³ These trends during CPB differ from those observed during ECMO. One possible explanation for this could be the difference in the half-life of MetHb and the duration of CPB and ECMO. The half-life of MetHb is 55 min.²⁴ In the case of CPB with short-term management, it is easy to detect an increase in MetHb levels because changes can be detected at short intervals. However, in the case of ECMO, which is performed for a long period, blood samples are collected daily, making it difficult to monitor MetHb trends.

With regard to iNO use, no significant difference was found in the presence or absence of hemolysis. Of the three cases in the hemolysis group, one was administered iNO prior to the diagnosis of hemolysis, whereas two received iNO following the diagnosis of hemolysis. In the patient who was administered iNO before hemolysis diagnosis, iNO administration might have affected MetHb levels, but the effect is unknown due to the small number of cases.

Initial PFH was significantly higher in the hemolysis group (Supplemental Figure 1). High pump speed when ECMO is initiated is a risk factor for AKI in adult patients receiving ECMO.²⁵ As for the mechanism of hemolysis, pfHb increases initially, leading to a later corresponding increase in COHb and MetHb; thus, at the start of ECMO, only pfHb levels are high, with no difference in COHb or MetHb levels at this point. This phenomenon may have also occurred in this study, although we cannot definitively confirm this; future research should investigate this aspect.

This study has some limitations. First, there were no age restrictions on patient enrollment. In fact, the age distribution was bimodal, with 9 patients under the age of 1 year (28%) and 18 patients over the age of 18 years (56%). Second, the sample size was too small to consider several confounding factors that may affect hemolysis, such as the type of ECMO circuit, ECMO flow rate, and cannula size. Third, this study investigated the relationship between COHb, MetHb, and hemolysis during ECMO, and did not mention the relationship with AKI, which is one of the patient prognoses. Fourth, some of the cannulas used in ECMO fall under the category of off-label use according to the product information, and this may have affected hemolysis due to issues such as coating. Finally, Neither COHb nor MetHb is calculated as an absolute value, but rather a percentage of total Hb, which varies depending on various factors such as oxygen. However, since these factors can be measured using a blood gas analyzer is very convenient, and we believe that this is meaningful.

In conclusion, although COHb and MetHb levels did not consistently increase due to hemolysis during ECMO, MetHb demonstrated a strong correlation with pfHb levels. These findings suggest that MetHb may serve as a hemolysis screening tool for most, but not all patients; however, further studies are warranted to address its limitations and refine its application.

Supplemental Material

sj-pdf-1-jao-10.1177_03913988251326398 – Supplemental material for Association of carboxyhemoglobin and methemoglobin levels with hemolysis during extracorporeal membrane oxygenation

Supplemental material, sj-pdf-1-jao-10.1177_03913988251326398 for Association of carboxyhemoglobin and methemoglobin levels with hemolysis during extracorporeal membrane oxygenation by Tsubasa Yoshida, Satoshi Kimura, Takanobu Sakura, Tatsuhiko Shimizu, Tomoyuki Kanazawa, Kazuyoshi Shimizu, Tatsuo Iwasaki and Hiroshi Morimatsu in The International Journal of Artificial Organs

Supplemental Material

sj-pdf-2-jao-10.1177_03913988251326398 – Supplemental material for Association of carboxyhemoglobin and methemoglobin levels with hemolysis during extracorporeal membrane oxygenation

Supplemental material, sj-pdf-2-jao-10.1177_03913988251326398 for Association of carboxyhemoglobin and methemoglobin levels with hemolysis during extracorporeal membrane oxygenation by Tsubasa Yoshida, Satoshi Kimura, Takanobu Sakura, Tatsuhiko Shimizu, Tomoyuki Kanazawa, Kazuyoshi Shimizu, Tatsuo Iwasaki and Hiroshi Morimatsu in The International Journal of Artificial Organs

Supplemental Material

sj-pdf-3-jao-10.1177_03913988251326398 – Supplemental material for Association of carboxyhemoglobin and methemoglobin levels with hemolysis during extracorporeal membrane oxygenation

Supplemental material, sj-pdf-3-jao-10.1177_03913988251326398 for Association of carboxyhemoglobin and methemoglobin levels with hemolysis during extracorporeal membrane oxygenation by Tsubasa Yoshida, Satoshi Kimura, Takanobu Sakura, Tatsuhiko Shimizu, Tomoyuki Kanazawa, Kazuyoshi Shimizu, Tatsuo Iwasaki and Hiroshi Morimatsu in The International Journal of Artificial Organs

Footnotes

Acknowledgements

We would like to thank Editage () for English language editing.

Author contributions

Tsubasa Yoshida aided in data curation and formal analysis and wrote the original draft. Satoshi Kimura aided in project administration and provided critical revisions. Takanobu Sakura, Tatsuhiko Shimizu, Kazuyoshi Shimizu, and Tatsuo Iwasaki provided critical revisions. Hiroshi Morimatsu supervised and provided critical revisions. All authors have read and approved the final manuscript.

Data availability

The research data were stored by the corresponding author and were accessible.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Trail registry

This study was registered with the University Hospital Medical Information Network Individual Case Data Repository (registration number: UMIN000046369).

Ethical approval

This study was approved by the Institutional Review Board of Okayama University Hospital, Okayama, Japan (approval number: 2112-020), was conducted from February 2022 to May 2023.

Consent to participate

Written informed consent was obtained from all of the patients or their legal representatives during ECMO.

Consent for publication

Not applicable.

ORCID iD

Tsubasa Yoshida

Supplemental material

Supplemental material for this article is available online.

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