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. 2022 Nov 14;17(11):e0277641. doi: 10.1371/journal.pone.0277641

Risk factors for mechanical ventilation and ECMO in COVID-19 patients admitted to the ICU: A multicenter retrospective observational study

Ryo Takada 1, Tomonori Takazawa 1,*, Yoshihiko Takahashi 2, Kenji Fujizuka 2, Kazuki Akieda 3, Shigeru Saito 4
Editor: Gulali Aktas5
PMCID: PMC9662741  PMID: 36374929

Abstract

Background

The primary purpose of this study was to investigate risk factors associated with the need for mechanical ventilation (MV) and extracorporeal membrane oxygenation (ECMO) in COVID-19 patients admitted to the intensive care unit (ICU).

Methods

We retrospectively enrolled 66 consecutive COVID-19 patients admitted to the ICUs of three Japanese institutions from February 2020 to January 2021. We performed logistic regression analyses to identify risk factors associated with subsequent MV and ECMO requirements. Further, multivariate analyses were performed following adjustment for Acute Physiology and Chronic Health Evaluation (APACHE) II scores.

Results

At ICU admission, the risk factors for subsequent MV identified were: higher age (Odds Ratio (OR) 1.04, 95% Confidence Interval (CI) 1.00–1.08, P = 0.03), higher values of APACHE II score (OR 1.20, 95% CI 1.08–1.33, P < 0.001), Sequential Organ Failure Assessment score (OR 1.53, 95% CI 1.18–1.97, P < 0.001), lactate dehydrogenase (LDH) (OR 1.01, 95% CI 1.00–1.02, p<0.001) and C-reactive protein (OR 1.09, 95% CI 1.00–1.19, P = 0.04), and lower values of lymphocytes (OR 1.00, 95% CI 1.00–1.00, P = 0.02) and antithrombin (OR 0.95, 95% CI 0.91–0.95, P < 0.01). Patients who subsequently required ECMO showed lower values of estimated glomerular filtration rate (OR 0.98, 95% CI 0.96–1.00, P = 0.04) and antithrombin (OR 0.94, 95% CI 0.88–1.00, P = 0.03) at ICU admission. Multivariate analysis showed that higher body mass index (OR 1.19, 95% CI 1.00–1.40, P = 0.04) and higher levels of LDH (OR 1.01, 95% CI 1.01–1.02, P < 0.01) were independent risk factors for the need for MV. Lower level of antithrombin (OR 0.94, 95% CI 0.88–1.00, P = 0.03) was a risk factor for the need for ECMO.

Conclusion

We showed that low antithrombin level at ICU admission might be a risk factor for subsequent ECMO requirements, in addition to other previously reported factors.

Introduction

Currently, as of September 2022, although the number of severe cases has diminished as compared to the time of the delta and earlier variants, the global COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still ongoing. A small number of patients still become critically ill and require mechanical ventilation (MV), and some of them require temporary lung rest with extracorporeal circulation. As during the delta and earlier waves, a potential future increase in the number of severe cases would likely again lead to a shortage of intensive care unit (ICU) beds and various medical resources, such as mechanical ventilators, extracorporeal circulators, and skilled medical staff [1].

Since the early stages of the pandemic, many retrospective studies have been published on patient risk factors predicting COVID-19 mortality. For example, Sequential Organ Failure Assessment (SOFA) score [2, 3], advanced age [2–8], low lymphocyte count [5, 8, 9], and high lactate dehydrogenase (LDH) [5, 8] and d-dimer [2] levels have been repeatedly identified as risk factors for severe disease and death.

The course of COVID-19 in individual patients is variable, and there are several cases of hypoxemia requiring MV within a few days of symptom onset. Patients who require MV or extracorporeal membrane oxygenation (ECMO) tend to have a prolonged treatment period, resulting in a worse prognosis and increased consumption of medical resources [10–12]. Although many studies have been published to predict the mortality of severe COVID-19 patients, few have investigated the association between patient risk factors at ICU admission and the subsequent requirements of MV or ECMO. Prediction of COVID-19 patients subsequently requiring MV or ECMO might help prevent the disease’s deterioration through early intervention. This study aimed to explore patient risk factors that are likely to predispose them to the need for MV and ECMO by analyzing the data of COVID-19 patients admitted to the ICU.

Methods

Study design

We conducted a retrospective observational study of severe COVID-19 patients. The study included all consecutive patients admitted to the ICUs of three hospitals in Gunma Prefecture, Japan: Gunma University Hospital, Japanese Red Cross Maebashi Hospital, and Subaru Health Insurance Society Ota Memorial Hospital. These hospitals treat severe COVID-19 patients and are equipped with mechanical ventilators and ECMO devices. The case enrollment period was from February 9, 2020, to January 31, 2021, before the alpha strain epidemic in Japan. The patients were followed up for at least three months after admission to the ICU. The diagnosis of COVID-19 was made by a polymerase chain reaction (PCR) test or a quantitative antigen test. Eligibility criteria were patients who received intensive care for COVID-19 at any of the three hospitals participating in the study within the study period. Exclusion criteria were patients who were deemed unsuitable for study inclusion by the physician for ethical reasons, and patients who did not wish to be included in the study after reading the disclosure notice. The decision to introduce MV and ECMO was at the discretion of the attending physicians. Although we have no standardized protocol for the introduction of MV and ECMO, published standard guidelines were used as references [13, 14].

Ethics approval and informed consent

The ethics committee of each participating hospital (Gunma University Hospital: HS2020-197, Japanese Red Cross Maebashi Hospital: 2021–6, and Subaru Health Insurance Society Ota Memorial Hospital: OR20048) approved this study, and it was performed according to the guidelines of the Declaration of Helsinki. Since the ethics committees of the participating institutions waived the need for obtaining verbal or written consent from the patients participating in this study, patient informed consent was obtained in the form of the option to opt-out on the institutions’ websites.

Variables

The primary endpoint of this study was the impact of patient factors at ICU admission on subsequent MV and ECMO requirements. Possible patient risk factors at admission that might have affected the outcomes, including patient characteristics, preexisting diseases and blood test results, were collected and analyzed. The APACHE II score [15] and SOFA score [16], which are indices of patient severity, were calculated based on data at ICU admission. The preexisting diseases and blood tests for analysis were selected based on similar previous studies.

We also collected data on medications, renal replacement therapy and airway management during ICU admission that might have affected patient outcomes, although they were not likely to be directly related to the primary endpoints.

Statistical methods

We performed logistic regression analysis to compare the two patient groups, those who required MV and those who did not, and odds ratios (ORs) and 95% confidence intervals were calculated. Similar comparisons were performed between the MV-only group and ECMO group. Kruskal-Wallis ANOVA with the post-hoc Bonferroni test was used to compare patient outcomes between groups. P-values were two-tailed, and those less than 0.05 were considered statistically significant. All statistical analyses were performed with R software (The R Foundation for Statistical Computing, Vienna, Austria).

Results

Sixty-six consecutive COVID-19 patients admitted to the ICUs of the three hospitals during the study period were included. No patients were excluded from the study. Forty-two of the 66 patients (67%) were treated with MV, and 20 (30.3%) required ECMO. Seven patients died while in the hospital. Table 1 shows baseline patient characteristics at the time of ICU admission.

Table 1. Patient baseline characteristics at the time of intensive care unit admission.

All (n = 66)
Demographics
Age, years 67 (53–71)
Sex, male 47 (71.2%)
Body mass index, kg/m2 26.1 (23.4–29.0)
Race
Asian 56 (84.8%)
Latino 10 (15.2%)
Scoring at ICU admission
APACHE II 15 (9–21)
SOFA 4 (2–7)
Hospital
Gunma University Hospital 24 (36%)
Japanese Red Cross Maebashi Hospital 23 (35%)
Subaru Health Insurance Society Ota Memorial Hospital 19 (29%)
Comorbidities
Cancer 3 (4.6%)
Diabetes mellitus 29 (43.9%)
Obesity 12 (18.2%)
Hypertension 37 (56.1%)
Chronic heart failure 4 (6.1%)
Angina/previous myocardial infarction 7 (10.6%)
Chronic kidney disease 13 (19.7%)
Dialysis 7 (10.6%)
Laboratory data at admission
White blood cells, ×109/mL 7650 (4950–9925)
Lymphocytes, ×106/mL 680 (480–960)
Platelet count, ×103/mL 174.0 (125.3–228.8)
Lactate dehydrogenase, U/L 347 (270–466)
Creatine kinase, U/L 86 (49–170)
Aspartate transaminase, U/L 37 (28–54)
Alanine transaminase, U/L 27 (17–40)
Total bilirubin, mg/dL 0.6 (0.4–0.8)
Blood urea nitrogen, mg/dL 18 (13–32)
Serum creatinine, mg/dL 0.79 (0.62–1.27)
eGFR, mL/min/m2 70.0(42.0–88.6)
C-reactive protein, mg/dL 7.52 (3.83–13.46)
PT-INR 1.04 (0.99–1.11)
APTT, sec 33.5 (30.2–38.2)
Fibrinogen, mg/dL 546 (452–616)
Antithrombin activity †, % 82.5 (75.1–96.0)
D-dimer, μg/mL 1.5 (1.0–2.4)
Heparin usage before admission 5 (7.5%)
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Data are presented as the median (interquartile range) or number (%). APACHE II, Acute Physiology and Chronic Health Evaluation II score; SOFA, Sequential Organ Failure Assessment score; COPD, chronic obstructive pulmonary disease; eGFR, estimated glomerular filtration rate; PT-INR, the international normalized ratio of prothrombin time; APTT, activated partial thromboplastin time. Obesity was defined as a body mass index of over 30 kg/m2. † Four patients in the no-mechanical ventilation group lacked data on antithrombin activity.

The covariates associated with the need for MV were as follows: higher age (OR 1.04, 95% CI 1.00–1.08, P = 0.03) and higher levels of APACHE II score (OR 1.20, 95% CI 1.08–1.33, P < 0.001), SOFA score (OR 1.53, 95% CI 1.18–1.97, P < 0.001), C-reactive protein (OR 1.09, 95% CI 1.00–1.19, P = 0.04) and LDH (OR 1.01, 95% CI 1.00–1.02, P < 0.001), and lower levels of antithrombin (OR 0.95, 95% CI 0.91–0.98, P = 0.005) at the time of ICU admission (Table 2). The covariates associated with the need for ECMO were lower levels of antithrombin (OR 0.94, 95% CI 0.88–1.00, P = 0.03) and estimated glomerular filtration rate (eGFR) (OR 0.98, 95% CI 0.96–1.00, P = 0.04) at the time of ICU admission (Table 3). In addition, we used multivariate logistic regression models adjusted for APACHE II score, because the severity of illness at the time of ICU admission was likely to have been different among the patient groups. After adjustment for APACHE II scores, patients who required MV had higher BMI (OR 1.19, 95% CI 1.00–1.40, P = 0.04) and higher levels of LDH (OR 1.01, 95% CI 1.01–1.02, P < 0.01), while those who received ECMO had lower levels of antithrombin (OR 0.94, 95% CI 0.88–1.00, P = 0.03) at ICU admission (Tables 2 and 3).

Table 2. Factors correlating with the need for mechanical ventilation in COVID-19 patients.

No mechanical ventilation (n = 24) Mechanical ventilation (n = 42) Odds ratio (95% CI) P-value Adjusted odds ratio (95% CI) P-value
Age, years 60 (46–71) 69 (55–71) 1.04 (1.00–1.08) 0.03 NA
Sex, male 17 (68.0%) 31 (73.8%) 1.41 (0.43–4.20) 0.54 1.59 (0.44–5.73) 0.48
Body mass index, kg/m2 25.4 (22.8–29.5) 26.4 (23.5–28.9) 1.04 (0.93–1.17) 0.49 1.19 (1.00–1.40) 0.04
APACHE II score 8 (7–12) 18 (13–25) 1.20 (1.08–1.33) <0.001 NA
SOFA score 3 (2–4) 6 (3–9) 1.53 (1.18–1.97) <0.001 NA
Cancer 1 (4.0%) 2 (4.8%) 1.15 (0.10–13.40) 0.91 1.01 (0.01–16.70) 0.99
Diabetes mellitus 9 (36.0%) 20 (47.6%) 1.52 (0.54–4.22) 0.43 1.05 (0.32–3.49) 0.93
Obesity 6 (24.0%) 6 (14.3%) 0.50 (0.14–1.77) 0.28 0.81 (0.18–3.56) 0.78
Hypertension 11 (44.0%) 27 (64.3%) 2.52 (0.90–7.05) 0.08 1.95 (0.59–6.46) 0.27
Chronic heart failure 2 (8.0%) 2 (4.8%) 0.55 (0.07–4.18) 0.56 0.20 (0.02–2.16) 0.18
Angina/previous MI 4 (16.0%) 3 (7.1%) 0.39 (0.08–1.89) 0.24 0.16 (0.02–1.09) 0.06
Chronic kidney disease 6 (24.0%) 7 (16.7%) 0.60 (0.18–2.05) 0.42 0.34 (0.08–1.56) 0.17
Dialysis 3 (12.0%) 4 (9.5%) 0.74 (0.15–3.61) 0.71 0.18 (0.02–1.28) 0.09
White blood cells, ×109/mL 6600 (4700–8800) 8300 (6810–10248) 1.00 (1.00–1.00) 0.19 NA
Lymphocytes, ×106/mL 1331 (744–2145) 630 (430–898) 1.00 (1.00–1.00) 0.02 1.00 (1.00–1.00) 0.12
Platelet count, ×103/mL 175.0 (132.0–247.0) 166.0 (125.8–211.3) 1.00 (1.00–1.00) 0.34 1.00 (1.00–1.00) 0.41
Lactate dehydrogenase, U/L 272 (224–339) 397 (329–514) 1.01 (1.00–1.02) <0.001 1.01 (1.00–1.02) <0.01
Creatine kinase, U/L 53 (40–170) 100 (61–212) 1.00 (1.00–1.01) 0.18 1.00 (1.00–1.01) 0.22
Aspartate transaminase, U/L 35 (26–44) 39 (29–60) 1.02 (1.00–1.05) 0.12 1.02(0.99–1.06) 0.18
Alanine transaminase, U/L 33 (16–41) 27 (17–39) 1.00 (0.98–1.02) 0.99 1.01(0.98–1.03) 0.63
Total bilirubin, mg/dL 0.55 (0.46–0.7) 0.61 (0.41–0.9) 3.07 (0.59–16.00) 0.18 3.10 (0.45–21.20) 0.25
Blood urea nitrogen, mg/dL 15 (11–22) 20 (15–33) 1.02 (0.99–1.00) 0.21 1.00 (0.97–1.03) 0.83
Serum creatinine, mg/dL 0.77 (0.64–0.93) 0.84 (0.62–1.39) 1.05 (0.90–1.23) 0.53 NA
eGFR, mL/min/m2 80.9 (61.2–91.2) 69.4 (40.2–84.0) 0.99 (0.978–1.01) 0.25 NA
C-reactive protein, mg/dL 4.64 (2.14–11.2) 9.65 (6.5–14.68) 1.09 (1.00–1.19) 0.04 1.10 (0.99–1.22) 0.08
PT-INR 1.01 (0.95–1.11) 1.04 (1.0–1.1) 9.02 (0.08–1040.0) 0.36 2.92 (0.03–273.00) 0.64
APTT, sec 33.8 (30.1–36.9) 33.4 (30.4–38.7) 1.00 (0.95–1.06) 0.88 1.02 (0.96–1.09) 0.50
Fibrinogen, mg/dL 551 (452–616) 54 7(453–629) 1.00 (1.00–1.00) 0.89 1.00 (1.00–1.01) 0.76
Antithrombin activity, % 92.6 (83.0–101.8) 77.8 (74.2–88.8) 0.95 (0.91–0.98) < 0.01 0.97 (0.93–1.01) 0.13
D-dimer, μg/mL 1.3 (0.8–1.6) 1.7 (1.1–2.7) 1.01 (0.96–1.05) 0.78 1.0 2(0.97–1.06) 0.51
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Multivariate analyses were performed after adjusting for disease severity at ICU admission based on APACHE II scores. Data are presented as the median (interquartile range) or number (%). NA, not applicable; APACHE II, Acute Physiology and Chronic Health Evaluation II score; SOFA, Sequential Organ Failure Assessment score; MI, myocardial infarction; eGFR, estimated glomerular filtration rate; PT-INR, the international normalized ratio of prothrombin time; APTT, activated partial thromboplastin time.

Table 3. Factors correlating with the need for ECMO in COVID-19 patients.

Mechanical ventilation-only (n = 22) ECMO (n = 20) Odds ratio (95% CI) P-value Adjusted odds ratio (95% CI) P-value
Age 69 (60–70) 67 (53–72) 0.97 (0.92–1.03) 0.35 NA
Sex, Male 14 (63.6%) 17 (85.0%) 3.24 (0.72–14.60) 0.13 3.56 (0.76–16.80) 0.11
Body mass index, kg/m2 25.6 (23.0–28.4) 26.5 (24.4–29.4) 1.04 (0.90–1.21) 0.60 1.05 (0.90–1.22) 0.57
APACHE II score 16 (13–24) 20 (13–25) 1.01 (0.95–1.09) 0.69 NA
SOFA score 5 (3–8) 7 (4–9) 1.12 (0.94–1.33) 0.22 NA
Cancer 1 (4.6%) 1 (5.0%) 1.11 (0.07–18.90) 0.95 1.05 (0.06–18.40) 0.97
Diabetes mellitus 11 (50.0%) 9 (45.0%) 0.82 (0.24–2.76) 0.75 0.82 (0.24–2.75) 0.74
Obesity 3 (13.6%) 3 (15.0%) 1.12 (0.20–6.30) 0.90 1.19 (0.21–6.87) 0.85
Hypertension 15 (68.2%) 12 (60.0%) 0.70 (0.20–2.49) 0.58 0.72 (0.20–2.57) 0.61
Chronic heart failure 1 (4.6%) 1 (5.0%) 1.11 (0.07–18.90) 0.95 1.11 (0.07–19.00) 0.94
Angina/previous MI 2 (9.1%) 1 (5.0%) 0.53 (0.04–6.29) 0.61 0.54 (0.05–6.50) 0.63
Chronic kidney disease 3 (13.6%) 4 (20.0%) 1.58 (0.31–8.15) 0.58 1.56 (0.30–8.07) 0.60
Dialysis 2 (9.1%) 2 (10.0%) 1.11 (0.11–8.73) 0.92 1.06 (0.13–8.50) 0.95
White blood cells, ×109/mL 8300 (5145–10248) 8175 (7200–9925) 1.00 (1.00–1.00) 0.52 NA
Lymphocytes, ×106/mL 707 (430–905) 595 (442–893) 1.00 (1.00–1.00) 0.68 1.00 (1.00–1.00) 0.75
Platelet count, ×103/mL 161.0 (114.5–205.0) 182.5 (131.3–221.3) 1.00 (1.00–1.00) 0.61 1.00 (1.00–1.00) 0.58
Lactate dehydrogenase, U/L 438 (323–523) 378 (333–479) 1.00 (1.00–1.00) 0.99 1.00 (1.00–1.00) 0.96
Creatine kinase, U/L 96 (67–121) 141 (54–233) 1.00 (1.00.-1.00) 0.65 1.00 (1.00–1.00) 0.60
Aspartate transaminase, U/L 38 (28–51) 46 (31–65) 1.01 (0.99–1.03) 0.44 1.01 (0.99–1.03) 0.45
Alanine transaminase, U/L 25 (17–38) 29 (19–42) 1.01 (0.991.04) 0.31 1.01 (0.99–1.04) 0.30
Total bilirubin, mg/dL 0.6 (0.4–0.7) 0.79 (0.48–1.0) 5.31 (0.79–35.60) 0.09 5.46 (0.81–36.90) 0.08
Blood urea nitrogen, mg/dL 18.0 (12.3–32.0) 20 (18–34) 1.00 (0.98–1.03) 0.51 1.01 (0.98–1.04) 0.48
Serum creatinine, mg/dL 0.67 (0.53–0.91) 1.12 (0.85–1.67) 1.04 (0.90–1.22) 0.58 NA
eGFR, mL/min/m2 83.2 (63.8–88.6) 50.1 (34.8–68.7) 0.98 (0.96–1.00) 0.04 NA
C-reactive protein, mg/dL 8.58 (6.5–12.65) 11.92 (6.52–16.33) 1.07 (0.98–1.18) 0.15 1.07 (0.97–1.18) 0.16
PT-INR 1.02 (0.99–1.06) 1.08 (1.02–1.11) 6.40 (0.08–529.00) 0.41 6.47 (0.07–566.00) 0.41
APTT, sec 33.5 (27.9–37.7) 33.0 (30.9–40.5) 1.07 (0.98–1.16) 0.13 1.07 (0.99–1.17) 0.11
Fibrinogen, mg/dL 561 (477–614) 484 (437–644) 1.00 (1.00–1.010 0.79 1.00 (1.00–1.01) 0.78
Antithrombin activity, % 83.2 (76.2–90.0) 75.7 (70.1–79.6) 0.94 (0.88–1.00) 0.03 0.94 (0.88–1.00) 0.03
D-dimer, μg/mL 1.7 (1.3–2.7) 1.6 (0.9–2.5) 1.00 (0.95–1.06) 0.97 1.00 (0.95–1.06) 0.92
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Multivariate analyses were performed after adjusting for disease severity at ICU admission based on APACHE II scores. Data are presented as the median (interquartile range) or number (%). NA, not applicable; APACHE II, Acute Physiology and Chronic Health Evaluation II score; SOFA, Sequential Organ Failure Assessment score; MI, myocardial infarction; eGFR, estimated glomerular filtration rate; PT-INR, the international normalized ratio of prothrombin time; APTT, activated partial thromboplastin time.

Table 4 shows the durations of ICU and hospital stays and clinical outcomes in the study subjects. The duration of ICU stay differed between all groups, being longer in the ECMO, MV-only and No MV groups in descending order. The duration of hospital stay was significantly longer in the MV-only and ECMO groups than in the No MV group. However, there was no significant difference between the MV-only and ECMO groups. The percentage of patients discharged home was higher in the No MV group, MV-only group and ECMO group, in that order. The percentage of patients discharged to another acute care hospital was highest in the ECMO group, and the percentage of patients discharged to a long-term care center was highest in the MV-only group. There were no deaths in the No MV group, although four and three patients, respectively, in the MV-only and ECMO groups, died in the ICU or ward.

Table 4. Patient outcomes.

All (n = 66) No mechanical ventilation (n = 24) Mechanical ventilation-only (n = 22) ECMO (n = 20)
Duration of ICU stay * 11.0 (5.0–31.5) 4.0 (2.8–5.3) 14.0 (10.3–29.0) 36.0 (21.0–46.0)
Duration of hospital stay † 21.0 (15.5–41.0) 16.0 (13.0–20.3) 30.0 (20.0–41.5) 52.0 (32.0–75.0)
Discharged to home 37 (56.1%) 20 (83.3%) 11 (50.0%) 6 (30.0%)
Discharged to another acute hospital 10 (16.7%) 2 (8.3%) 1 (4.5%) 7 (35.0%)
Discharged to long-term care center 9 (13.6%) 2 (8.3%) 5 (22.7%) 2 (10.0%)
Still hospitalized 3 (4.5%) 0 1 (4.5%) 2 (10.0%)
Death 7 (10.6%) 0 4 (18.2%) 3 (15.0%)
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Data are presented as the median (interquartile range) or number (%). We used Kruskal-Wallis ANOVA with post-hoc Bonferroni test to compare the durations of ICU and hospital stays. Since the dead were excluded from the ICU and hospital stay duration analysis, the number of patients in the mechanical ventilation-only and ECMO groups was 18 and 17, respectively. * P value was less than 0.05 among all groups. † P value was less than 0.05 except between the mechanical ventilation-only and ECMO groups.

Details about the medications, renal replacement therapy and airway management after ICU admission in each group are shown in S1 Table. A complete dataset of individual data used for analysis is presented in S2 Table.

Discussion

This study retrospectively investigated risk factors for the need for subsequent MV and ECMO in COVID-19 patients admitted to the ICU. The following items at ICU admission were identified as risk factors for subsequent MV: advanced age, higher APACHE II and SOFA scores, higher C-reactive protein levels, lower lymphocyte count, higher LDH levels, and lower antithrombin levels. Higher LDH levels and BMI were independent risk factors for the need for MV after adjusting for APACHE II score. Further, lower eGFR and lower antithrombin levels were associated with subsequent ECMO requirements. Lower antithrombin levels remained an independent risk factor for ECMO after adjustment for APACHE II score.

Previous studies showed the following risk factors for MV in COVID-19 patients: acute respiratory distress syndrome [8], lower antithrombin levels [17], hypercoagulative state on viscoelastic tests [18], disseminated intravascular coagulopathy (DIC) [19], lower ratio of oxygen saturation (ROX) index [10, 20, 21], older age [22], male sex [22], higher C-reactive protein [23] and LDH [21] levels, lower serum creatinine levels [21], and higher D-dimer levels [24]. Our study results were consistent with these studies.

We demonstrated that higher LDH levels are an independent risk factor for the need for MV. Many earlier studies have shown the association between high LDH levels and COVID-19 severity [2, 8, 25]. Moreover, one other study also showed a correlation between high LDH levels and the need for MV in COVID-19 patients [21], which is consistent with our findings. After adjusting for APACHE II scores, BMI was also identified as an independent risk factor for MV in this study. BMI has also been previously reported as a risk factor for in-hospital mortality and morbidity in patients with COVID-19 [26–28], which is consistent with the results of this study.

Although many cohort studies investigated the characteristics and outcomes of severe COVID-19 patients, few studies have investigated differences in COVID-19 patients with and without ECMO. A previous prospective study that validated a urinalysis-based prediction model of COVID-19 showed that abnormal urinalysis results on admission correlated with mortality, MV or ECMO requirements [29]. Since chronic kidney disease and pre-existing hemodialysis treatment were reported as risk factors for severe COVID-19 [30], it is plausible that lower eGFR is associated with the need for ECMO in COVID-19 patients.

We found that antithrombin levels were significantly lower in the more severe COVID-19 patients group. Although the correlation between outcomes and antithrombin levels in COVID-19 patients has been reported in several previous studies, those results were controversial. Several studies showed that lower antithrombin levels were associated with higher mortality in patients with COVID-19 [17, 29, 31]. Conversely, several reports suggested that antithrombin levels were not associated with severity or mortality in COVID-19 patients [4, 32]. These discrepancies might have been due to the background of the patients studied. Although previous studies recruited COVID-19 patients in various disease stages, our study only included patients admitted to the ICU. Although the results of our study do not reveal the mechanism by which antithrombin levels decrease in severe cases, the following possible mechanisms should be considered. Antithrombin might be consumed by hypercoagulation due to higher inflammation and vascular endothelial damage in severe cases [19, 33, 34]. Alternatively, increased vascular permeability caused by inflammation in severe cases might result in leakage of antithrombin out of blood vessels [35]. In terms of treatment, the administration of antithrombin concentrates has reduced the mortality rate of patients with severe septic DIC [36, 37]. Although the pathophysiology of DIC associated with COVID-19 differs from that of septic DIC [38, 39], antithrombin supplementation might also improve outcomes in severe COVID-19 patients with DIC [40]. Further investigation is needed to determine the potential therapeutic application of antithrombin in the future.

This study has several limitations. First, this was a retrospective observational study with a limited sample size. Second, since this study enrolled patients with COVID-19 who developed the disease before January 31, 2021, the current risk factors for the subsequent need of MV and ECMO might differ from our findings because the currently prevalent SARS-CoV-2 strains, including BA.5 variants, are different from those at the time the study was conducted. Third, since we could not follow patients who were discharged to another acute hospital or long-care center, their precise outcomes were unclear. Fourth, there were no standard methods or protocols defining the specific criteria or indications for MV and ECMO support; hence, decision-making for the introduction of MV and ECMO differed by hospital and physician. Fifth, we collected laboratory data only once, at the time of ICU admission, and changes in these variables over time were not included in the analyses.

Early recognition of COVID-19 patients with a high risk of exacerbation allows physicians to make adequate clinical decisions, including the need for hospitalization, strict monitoring and medication. Identification of high-risk patients will improve their outcomes, and would enable more appropriate distribution of medical resources.

Conclusions

We showed that low antithrombin level at ICU admission might be a risk factor for subsequent ECMO requirements, in addition to other previously reported factors.

Supporting information

S1 Table. Medications, renal replacement therapy and airway management during ICU admission.

Data are presented as the median (interquartile range) or number (%). Other medications included hydroxychloroquine, favipiravir and lopinavir-ritonavir. The total number of patients receiving renal replacement therapy indicates the number of patients who underwent hemodialysis and/or continuous hemodiafiltration. † Mechanical ventilation-only vs. ECMO group, P < 0.01, Mann-Whitney U test. Patients who died were excluded from the analysis. ‡ Two patients in the ECMO group who were intubated before ICU admission were excluded from the analysis. HD, hemodialysis; CHDF, continuous hemodiafiltration; NA, not applicable.

(DOCX)

Click here for additional data file. (17.1KB, docx)
S2 Table. Complete dataset of all the study subjects that was used for analysis.

In the table, presence of the factor in the individual was indicated as ‘1’, while absence of the factor was indicated as ‘0’. Please see the regular tables for units. Obesity was defined as body mass index of over 30 kg/m2. BMI, body mass index; APACHE II, Acute Physiology and Chronic Health Evaluation II score; SOFA, Sequential Organ Failure Assessment score; CHF, chronic heart failure; OMI, old myocardial infarction; CRF, chronic renal failure; WBC, white blood cells; LDH, lactate dehydrogenase; CK, creatinine kinase; AST, aspartate aminotransferase; ALT; alanine aminotransferase; BUN, blood urea nitrogen; eGFR, estimated glomerular filtration rate; CRP; C-reactive protein; PT-INR, international normalized ratio of prothrombin time; APTT, activated partial thromboplastin time; AT; antithrombin activity; MV, mechanical ventilation; HD, hemodialysis; CHDF; continuous hemodiafiltration; GUH, Gunma University Hospital; JRCMH; Japanese Red Cross Maebashi Hospital; OMH, Ota Memorial Hospital; ND, no data; NA, not applicable.

(XLSX)

Click here for additional data file. (28.3KB, xlsx)

Abbreviations

ARDS

Acute respiratory distress syndrome

ANOVA

Analysis of variance

APACHE II score

Acute physiology and chronic health evaluation II score

CI

Confidence interval

COVID-19

Coronavirus disease 2019

DIC

Disseminated intravascular coagulopathy

ECMO

Extra-corporeal membrane oxygenation

eGFR

estimated glomerular filtration rate

ICU

Intensive care unit

OR

Odds ratio

SARS-CoV-2

severe acute respiratory syndrome coronavirus 2

SOFA score

Sequential organ failure assessment score

Data Availability

All relevant data are within the paper and its Supporting Information files.

Funding Statement

The authors received no specific funding for this work.

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Decision Letter 0

Gulali Aktas

27 Sep 2022

PONE-D-22-26070Risk factors for mechanical ventilation and ECMO in COVID-19 patients admitted to ICU: A multi-center retrospective observation studyPLOS ONE

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Additional Editor Comments :

Dear Dr. Takazawa

Manuscript ID PONE-D-22-26070 entitled "Risk factors for mechanical ventilation and ECMO in COVID-19 patients admitted to ICU: A multi-center retrospective observation study" which you submitted to the PLOS ONE, has been reviewed. The comments of the reviewer(s) are included at the bottom of this letter.

The reviewer(s) have suggest some minor revisions to your manuscript. Therefore, I invite you to respond to the reviewer(s)' comments and revise your manuscript.

Comments of Reviewer 1

Manuscript is a clear, concise, and well-written with relevant introduction. Conclusion in abstract should be written more clearly and precisely. In Methodology explain terms PACHE II score, SOFA score, and how did you calculate them.

Some values in Table 1 and others are express as numbers and percentages, please write n(%) for that variables. If it is possible, please divide Table 2 and Table 3 into two or more tables.

Comments of Reviewer 2

The manuscript PONE-D-22-26070 is a well prepared original article about risk factors of intensive care either with ECMO or mechanical ventilation in Covid-19 patients. I congratulate authors for such a good work. My comments about the sections of the manuscript are as following:

Title is relevant as keywords after abstract which is an adequate summary of the study.

Rationale and aims are clearly mentioned in introduction

Methods and the study design expressed perfectly. Statistical analyses are correct and adequate for the study design.

Presentation of the results is clear. Tables improved the readiness. However, unit of all variables must be stated in the tables. I advise n,% for categorical variables.

Discussion is fair enough. Yet, I suggest discussing the role of inflammatory burden on necessity of ECMO or mechanical ventilation. Studies in literature reported higher inflammatory markers in serious Covid-19 cases compared to the patients with mild or moderate disease (Hematology 2021;26(1):529-542. DOI: 10.1080/16078454.2021.1950898). Discuss.

Conclusions must be clarified. The statement 'This study revealed several risk factors on ICU admission that are related to the 261 need for subsequent MV or ECMO in COVID-19 patients admitted to the ICU.' is not the best conclusion that could be drawn from the study.

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Reviewers' comments:

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Comments to the Author

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Reviewer #1: Yes

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

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Reviewer #1: Yes

Reviewer #2: Yes

**********

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Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Manuscript is a clear, concise, and well-written with relevant introduction. Conclusion in abstract should be written more clearly and precisely. In Methodology explain terms PACHE II score, SOFA score, and how did you calculate them.

Some values in Table 1 and others are express as numbers and percentages, please write n(%) for that variables. If it is possible, please divide Table 2 and Table 3 into two or more tables.

Reviewer #2: The manuscript PONE-D-22-26070 is a well prepared original article about risk factors of intensive care either with ECMO or mechanical ventilation in Covid-19 patients. I congratulate authors for such a good work. My comments about the sections of the manuscript are as following:

Title is relevant as keywords after abstract which is an adequate summary of the study.

Rationale and aims are clearly mentioned in introduction

Methods and the study design expressed perfectly. Statistical analyses are correct and adequate for the study design.

Presentation of the results is clear. Tables improved the readiness. However, unit of all variables must be stated in the tables. I advise n,% for categorical variables.

Discussion is fair enough. Yet, I suggest discussing the role of inflammatory burden on necessity of ECMO or mechanical ventilation. Studies in literature reported higher inflammatory markers in serious Covid-19 cases compared to the patients with mild or moderate disease (Hematology 2021;26(1):529-542. DOI: 10.1080/16078454.2021.1950898). Discuss.

Conclusions must be clarified. The statement 'This study revealed several risk factors on ICU admission that are related to the 261 need for subsequent MV or ECMO in COVID-19 patients admitted to the ICU.' is not the best conclusion that could be drawn from the study.

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Reviewer #1: No

Reviewer #2: Yes: Ozge Kurtkulagi

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PLoS One. 2022 Nov 14;17(11):e0277641. doi: 10.1371/journal.pone.0277641.r002

Author response to Decision Letter 0

19 Oct 2022

Comments of Reviewer 1

Manuscript is a clear, concise, and well-written with relevant introduction.

Conclusion in abstract should be written more clearly and precisely.

Reply: We have modified the conclusion in the abstract according to your suggestion.

In Methodology explain terms APACHE II score, SOFA score, and how did you calculate them.

Reply: We have added a description of APACHE II and SOFA scores in the Methods section Further, we have cited references for where more information on these scores can be obtained.

Some values in Table 1 and others are express as numbers and percentages, please write n(%) for that variables.

Reply: We have changed the display of the variables in Table 1, as recommended.

If it is possible, please divide Table 2 and Table 3 into two or more tables.

Reply: Tables 2 and 3 are certainly large, but we would like to present the findings at a glance. Hence, we would prefer to retain the table in its current form, if there are no space constraints according to the journal requirements.

Comments of Reviewer 2

The manuscript PONE-D-22-26070 is a well prepared original article about risk factors of intensive care either with ECMO or mechanical ventilation in Covid-19 patients. I congratulate authors for such a good work. My comments about the sections of the manuscript are as following:

Title is relevant as keywords after abstract which is an adequate summary of the study.

Rationale and aims are clearly mentioned in introduction

Methods and the study design expressed perfectly. Statistical analyses are correct and adequate for the study design.

Presentation of the results is clear. Tables improved the readiness. However, unit of all variables must be stated in the tables. I advise n,% for categorical variables.

Reply: We have mentioned the units of the variables in Table 1, as recommended.

Discussion is fair enough. Yet, I suggest discussing the role of inflammatory burden on necessity of ECMO or mechanical ventilation. Studies in literature reported higher inflammatory markers in serious Covid-19 cases compared to the patients with mild or moderate disease (Hematology 2021;26(1):529-542. DOI: 10.1080/16078454.2021.1950898).

Reply: Thank you for presenting this important article. The article emphasizes a decrease in lymphocytes as an indicator of COVID-19 severity, especially when compared to neutrophils and platelets. We have cited this article as Reference 9.

Conclusions must be clarified. The statement 'This study revealed several risk factors on ICU admission that are related to the 261 need for subsequent MV or ECMO in COVID-19 patients admitted to the ICU.' is not the best conclusion that could be drawn from the study.

Reply: We have modified the conclusion according to your suggestion.

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Reply: We have made revisions to ensure that the manuscript matches the style of PLOS ONE.

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Reply: We have added the following sentence as additional details regarding participant consent: Since the ethics committees of the participating institutions waived the need for obtaining verbal or written consent from the patients participating in this study, patient informed consent was obtained in the form of the option to opt-out on the institutions’ websites.

The current study did not include minors.

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We will update your Data Availability statement to reflect the information you provide in your cover letter.

Reply: In this revision, we provide the minimal underlying dataset of the study as Supplementary Table S2. The table contains anonymized patient data.

4. Please amend either the title on the online submission form (via Edit Submission) or the title in the manuscript so that they are identical.

Reply: We confirmed that the title on the online submission form (via Edit Submission) and the title in the manuscript are identical.

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Reply: We have removed the ethics statement apart from that in the methods section.

6. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Reply: We have confirmed that the reference list is complete and correct. The references we have cited do not include retracted articles.

Attachment

Submitted filename: Response to Reviewers 101922ver2.docx

Click here for additional data file. (22.1KB, docx)

Decision Letter 1

Gulali Aktas

2 Nov 2022

Risk factors for mechanical ventilation and ECMO in COVID-19 patients admitted to the ICU: A multicenter retrospective observational study

PONE-D-22-26070R1

Dear Dr. Takazawa,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Gulali Aktas

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Authors were very responsive to the reviewers' comments. The manuscript is improved significantly. Therefore it is acceptable for publication.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

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4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #2: All review suggestions were followed b y the authors. Well done. There is nothing more that require further revision. I recommend publication.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

**********

Acceptance letter

Gulali Aktas

4 Nov 2022

PONE-D-22-26070R1

Risk factors for mechanical ventilation and ECMO in COVID-19 patients admitted to the ICU: A multicenter retrospective observational study

Dear Dr. Takazawa:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Professor Gulali Aktas

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Table. Medications, renal replacement therapy and airway management during ICU admission.

    Data are presented as the median (interquartile range) or number (%). Other medications included hydroxychloroquine, favipiravir and lopinavir-ritonavir. The total number of patients receiving renal replacement therapy indicates the number of patients who underwent hemodialysis and/or continuous hemodiafiltration. † Mechanical ventilation-only vs. ECMO group, P < 0.01, Mann-Whitney U test. Patients who died were excluded from the analysis. ‡ Two patients in the ECMO group who were intubated before ICU admission were excluded from the analysis. HD, hemodialysis; CHDF, continuous hemodiafiltration; NA, not applicable.

    (DOCX)

    Click here for additional data file. (17.1KB, docx)
    S2 Table. Complete dataset of all the study subjects that was used for analysis.

    In the table, presence of the factor in the individual was indicated as ‘1’, while absence of the factor was indicated as ‘0’. Please see the regular tables for units. Obesity was defined as body mass index of over 30 kg/m2. BMI, body mass index; APACHE II, Acute Physiology and Chronic Health Evaluation II score; SOFA, Sequential Organ Failure Assessment score; CHF, chronic heart failure; OMI, old myocardial infarction; CRF, chronic renal failure; WBC, white blood cells; LDH, lactate dehydrogenase; CK, creatinine kinase; AST, aspartate aminotransferase; ALT; alanine aminotransferase; BUN, blood urea nitrogen; eGFR, estimated glomerular filtration rate; CRP; C-reactive protein; PT-INR, international normalized ratio of prothrombin time; APTT, activated partial thromboplastin time; AT; antithrombin activity; MV, mechanical ventilation; HD, hemodialysis; CHDF; continuous hemodiafiltration; GUH, Gunma University Hospital; JRCMH; Japanese Red Cross Maebashi Hospital; OMH, Ota Memorial Hospital; ND, no data; NA, not applicable.

    (XLSX)

    Click here for additional data file. (28.3KB, xlsx)
    Attachment

    Submitted filename: Response to Reviewers 101922ver2.docx

    Click here for additional data file. (22.1KB, docx)

    Data Availability Statement

    All relevant data are within the paper and its Supporting Information files.

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