key: cord-0271938-lx3wibvo
authors: Kaku, N.; Nakagama, Y.; Shirano, M.; Shinomiya, S.; Shimazu, K.; Yamazaki, K.; Maehata, Y.; Morita, R.; Nitahara, Y.; Yamamoto, H.; Mizobata, Y.; Kido, Y.
title: Increase in ventilatory ratio indicates progressive alveolar damage and suggests poor prognosis in severe COVID-19: A single-center retrospective observational study.
date: 2021-07-22
journal: nan
DOI: 10.1101/2021.07.20.21260754
sha: fdc89515c71c270e4d5cfe7169f974e9e41f1300
doc_id: 271938
cord_uid: lx3wibvo

Background: The symptoms of severe COVID-19 are complex and wide-ranging even in intensive care unit (ICU) patients, who may successfully discontinue respiratory support in a short period or conversely require prolonged respiratory support. Damage in the lungs of COVID-19 patients is characterized pathologically as diffuse alveolar damage, the degree of which correlates with the severity of the disease. We hypothesized that the ventilatory ratio (VR), a surrogate parameter for the dead space fraction, might stratify the severity of COVID-19 and predict the successful discontinuation of respiratory support. Methods: Forty COVID-19 patients in our ICU were enrolled in this study. Respiratory variables were collected from 2 hours (day 0) after the initiation of respiratory support. We monitored the longitudinal values of VR and other respiratory parameters for 28 days. Patients successfully discontinued from respiratory support by day 28 of ICU stay were defined as the successfully discontinued group, while those who died or failed to discontinue were defined as the failed to discontinue group. VR and other respiratory parameters were compared between these groups. Results: Except for advanced age, prolonged ventilation period, and higher mortality in the failed to discontinue group, there were no significant differences between the groups in terms of any other background or respiratory parameter at 2 hours (day 0) after initiation of respiratory support. Longitudinal VR monitoring revealed significantly higher VR values in the failed to discontinue group than the successfully discontinued group on day 4 of respiratory support. Upon predicting the failure to discontinue respiratory support, the area under the receiver operating characteristic curve of VR values on day 4 of respiratory support was 0.748. A threshold of 1.56 achieved the highest predictive performance with a sensitivity of 0.667 and a specificity of 0.762. This threshold enabled the prediction of the successfully discontinued outcome at 0.810 of the negative predictive value. Conclusions: Elevated VR values on day 4 of respiratory support were predictive of successful discontinuation of respiratory support in patients with severe COVID-19. Longitudinal VR values after initiation of respiratory support can be used as a practical index to stratify severe COVID-19.

the failed to discontinue group than the successfully discontinued group on day 4 of 48 respiratory support. Upon predicting the failure to discontinue respiratory support, the area 49 under the receiver operating characteristic curve of VR values on day 4 of respiratory support 50 was 0.748. A threshold of 1.56 achieved the highest predictive performance with a sensitivity 51 of 0.667 and a specificity of 0.762. This threshold enabled the prediction of the successfully 52 discontinued outcome at 0.810 of the negative predictive value. 53

Conclusions: Elevated VR values on day 4 of respiratory support were predictive of successful 54 All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 22, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 4 discontinuation of respiratory support in patients with severe values after initiation of respiratory support can be used as a practical index to stratify severe 56 Keywords: severe COVID-19, SARS-CoV-2, ARDS, ventilatory ratio, dead space, alveolar 58 damage 59

Background 60 COVID-19, an infectious disease caused by severe acute respiratory syndrome coronavirus 2 61 , that emerged at the end of 2019, has a broad spectrum of manifestations from 62 asymptomatic to critical illness. Even in the case of critically ill patients who are admitted to 63 intensive care units (ICUs), some improve after only a few days of respiratory support, 64

whereas others require prolonged respiratory support resulting in poor prognosis. 65 Similar to other lethal human coronaviruses such as SARS-CoV and MERS-CoV, the SARS-66

CoV-2 virus enters host cells, harnessing its spike protein to angiotensin-converting enzyme 67 2 (ACE2) receptor on the surface of the host cell (1). ACE2 is highly expressed in lung alveolar 68 cells and bronchial epithelium, where the virus enters initially and proliferates (2). Therefore, 69 the principal pathological manifestation of COVID-19 is considered to be alveolar damage, 70 and the severity may depend on the progress of diffuse alveolar damage (DAD) (3,4) which 71 is a typical feature of acute respiratory distress syndrome (ARDS) (5). However, the lack of 72 All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 22, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 5 appropriate indices for real-time monitoring of DAD is currently limiting stratification of 73 patients who are critically ill with DAD reduces effective gas exchange between alveolar epithelial cells and the pulmonary 75 capillaries, thus increasing the functional dead space. Dead space fraction (VD/VT) is the most 76 crucial factor dictating respiratory adequacy. Several studies have demonstrated the 77 importance of VD/VT in ARDS patients, in terms of both prognostication and disease 78 progression (6). Despite its effectiveness, VD/VT is seldom measured in usual ICU practice 79 because of the complexity of calculation and the associated equipment costs (6). 80

Ventilatory ratio (VR) is a simple bedside index that has recently been proposed as a surrogate 81 parameter for VD/VT (6,7). It is easily calculated using minute ventilation and arterial partial 82 pressure of carbon dioxide (PaCO2), as follows (8): 83 [minute ventilation (mL) × PaCO2 (mmHg)]/predicted body weight × 100 × 37.5. 84

Sinha et al. have reported high VR as an independent predictor of mortality in two distinct 85 ARDS randomized controlled trials (9,10), and have confirmed a significant correlation 86 between VR and VD/VT in ARDS (8). 87 Therefore, we monitored longitudinal VR in patients with severe COVID-19 who required 88 respiratory support in our ICU with the aim of determining whether VR could stratify the 89 severity of COVID-19 and predicting successfully discontinued prognosis. 90 All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. This is a retrospective, single-center, observational study that enrolled patients with severe 93 COVID-19 admitted into our ICU from February 29 to November 20, 2020. To identify the 94 relationship between patient characteristics and prolonged respiratory support, the patients 95 were stratified into two groups based on respiratory support dependency for the observed 28 96 days because the failure to discontinue respiratory support during the initial 28 days is known 97 to have a strong correlation with mortality (11). In the observation period, patients who could 98 not discontinue respiratory support were included to the failed to discontinue group and 99 patients who could successfully discontinue respiratory support were included to the 100 successfully discontinued group. 101

Data from patients' electronic medical records were collected and reviewed by physicians 103 trained in critical care. The inclusion criteria were age ≧18 years; SARS-CoV-2 infection 104 confirmed by PCR or antigen test; and ICU admission for respiratory support, defined as the 105 use of invasive mechanical ventilation. Of 45 eligible patients, 5 who were not ventilated at 106 our hospital were excluded, and a total of 40 patients were included in the study. 107

The recorded data included patients demographics (age, gender, body mass index (BMI), 108 All rights reserved. No reuse allowed without permission.

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The copyright holder for this preprint this version posted July 22, 2021. ; https://doi.org/10.1101/2021.07.20.21260754 doi: medRxiv preprint comorbidities), disease course (days from onset to O2 requirement, days from onset to 109 respiratory support, days of respiratory support, ICU mortality), laboratory and ventilatory 110 parameters (minute ventilation (MV), tidal volume (TV), set PEEP, plateau pressure (Pplat), 111 static lung compliance (Cstat), PaCO2, PaCO2/FiO2 (P/F) ratio, and VR). A complete data 112 set was obtained 2 hours (day 0) after the patients was placed on respiratory support. VR and 113

Cstat were calculated as follows: 114

All analyses were performed with GraphPad Prism 9.1.1 (GraphPad Software, Inc., San Diego, 119 CA). Variables were compared between the groups using Mann-Whitney test for continuous 120 variables and Chi-square test for binary data. To assess differences in longitudinal VR and its 121 factors between the groups, VR values after starting respiratory support were plotted and 122 analyzed by Mann-Whitney test. To validate whether the increased VR can become a 123 prognostic index for successfully discontinued from respiratory support in severe COVID-19, 124 we performed receiver operating characteristic (ROC) curves analysis of VR values on days 125 0-4 after respiratory support. All time points to events were defined from 2 hours (day 0) after 126 All rights reserved. No reuse allowed without permission.

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The copyright holder for this preprint this version posted July 22, 2021. ; https://doi.org/10.1101/2021.07.20.21260754 doi: medRxiv preprint 8 initiation of invasive respiratory support. Missing data were not imputed. Days of respiratory 127 support of patients who prolonged respiratory support longer than the observation period 128 were deemed 28. Descriptive variables were expressed as the percentage or median and 129 interquartile range (IQR), as appropriate. All tests were two-sided, and a p-value < 0.05 was 130 considered statistically significant. 131

Among 45 patients admitted to our ICU between 29 Feb and 20 Nov 2020, 40 patients who 133 met the inclusion criteria were enrolled in this study and followed for at least 28 days. The 134 patient demographics, disease course, laboratory and respiratory parameters are listed in 135 Table 1 . Time from symptom onset to initiation of oxygen therapy was 7 days (IQR: 6 9 136 days) and that to initiation of respiratory support was 8 days (IQR: 7 10 days). Extraordinary 137 short interval of 1 day from oxygen therapy to respiratory support indicates a rapid worsening 138 of hypoxemia in COVID-19. The duration of respiratory support was 11 days (IQR: 5 18 139 days), and the overall mortality rate in ICU was 25.0%. Days of respiratory support were 19 140 vs 7 days and ICU mortality was 71.4% vs 0.0% in the failed to discontinue and successfully 141 discontinued groups, respectively (significant difference, both p-value < 0.001).

Age was significantly greater in the failed to discontinue group than the successfully 143 discontinued group (median, 75 vs 67 years respectively, p-value = 0.027). There was a 144 All rights reserved. No reuse allowed without permission.

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The copyright holder for this preprint this version posted July 22, 2021. ; https://doi.org/10.1101/2021.07.20.21260754 doi: medRxiv preprint predominance of males (34/40, 85.0%). Median BMI was 25 kg/m 2 (IQR, 22 29 kg/m 2 ). 145

The incidence of the comorbidities of diabetes (18/40, 45.0%) and hypertension (21/40, 146 52.5%) in all patients in the study were higher than the prevalence in Japanese men (13.8% 147 and 23.0%, respectively adjusted by age)(12). 148

The median values of respiratory parameters at 2 hours ( severity. VR was 1.5 (IQR, 1.3 2.0), higher than the value of 1. The normal value of VR is 156 around 1, but increases with worsening ventilation mechanics, excess CO2 production, or both 157 (7). There was no significant difference in any of these respiratory parameters between the 158 two groups. 159 Figure 1 shows the longitudinal VR values from 2 hours (day 0) of respiratory support to day 160 6. VR was stable until around day 2 after initiation of respiratory support in both groups. In 161 the failed to discontinue group, VR increased on day 3. VR was significantly higher in the 162 All rights reserved. No reuse allowed without permission.

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The copyright holder for this preprint this version posted July 22, 2021. ; https://doi.org/10. 1101 /2021 failed to discontinue group than in the successfully discontinued group on day 4 after 163 respiratory support (p-value = 0.027) (Figure 1a) . Throughout the observation period there 164 was no apparent trend in the change in PaCO2 or MV, which are both used to calculate VR 165 (Figure 1b, c) . 166 This study monitored longitudinal VR in patients with severe COVID-19 who required 177 respiratory support in our ICU with aim of determining whether VR could stratify the severity 178 of COVID-19 and predicting successfully discontinued prognosis. The main findings were 179 that VR on day 4 after initiation of respiratory support was higher than in the failed to 180 All rights reserved. No reuse allowed without permission.

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The copyright holder for this preprint this version posted July 22, 2021. ; https://doi.org/10.1101/2021.07.20.21260754 doi: medRxiv preprint discontinue group than the successfully discontinued group, and that a threshold of VR < 1.56 181 was predictive of successful discontinuation with a predictive value of 0.810. 182

Pulmonary pathology of COVID-19 can be subdivided into four main morphological stages: 183

[1] early stage (day 0 1) with edema, incipient epithelial damage, and capillaritis, (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 22, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 within 9 15 days after symptom onset, and patients with moderate/severe symptoms 199 exhibited more robust responses than those with mild disease. Higher frequencies of secreting T cells at around day 15 from symptom onset were present in mild, but not in 201 moderate/severe COVID-19 patients (18). Considering interval from symptom onset to 202 respiratory support averaged to 8 days, the time point of the VR increase on day 4 after 203 respiratory support in the failed to discontinue group coincided with the immunological 204 turning point at around days 10 15 from symptom onset. The increased VR on day 4 after 205 respiratory support might reflect the immunological dynamics in patients with severe 206 The ROC curve of VR on day 4 after initiation of respiratory support was predictive of 208 successful discontinuation from respiratory support with a high predictive value in this cohort. 209 Therefore, VR values may indicate the effectiveness of current treatment. Moreover, the 210 stratification of severe COVID-19 according to VR may enable consideration of the 211 appropriate therapy on an individual basis, such as the decision whether to continue with 212 aggressive COVID-19-specific therapies. VR has a potential to be a candidate predictor for 213

improving predictive abilities of current risk prediction models for ICU patients with . 215

In contrast to the present study, some previous reports (21-23) that have used VR to assess 216 All rights reserved. No reuse allowed without permission.

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The copyright holder for this preprint this version posted July 22, 2021. ; https://doi.org/10.1101/2021.07.20.21260754 doi: medRxiv preprint 13 the clinical condition of patients with COVID-19 have concluded that VR is a minimally useful 217

indicator. The reason for the discrepancy in results may be that these previous studies 218 calculated VR only once, on the day that respiratory support was initiated. As demonstrated 219 in the present study, a significant difference in VR values between the failed to discontinue 220 and successfully discontinued groups was apparent on day 4 after initiation of respiratory 221 support, and the difference was a predictor of successfully discontinued prognosis. VR being 222 an easily calculated bedside friendly parameter, frequent assessment and longitudinal 223 monitoring is feasible and potentially useful in understanding the severity status of This study has some limitations. The most appropriate VR value to be used as the threshold 226 requires further evaluation. This study only used data up to day 6 of respiratory support. Data 227

were not available after day 7 because a large number of patients were withdrawn from 228 respiratory support at the time. Finally, we cannot rule out the possibility of selection bias 229 because we included only a small number of patients collected at a single institution. 230

Increased VR values on day 4 after initiation of respiratory support is predictive of successful 232 discontinuation in patients with severe COVID-19. Day 4 after respiratory support coincides 233 with the time point of the exudative DAD stage in pulmonary pathology, and the turning point 234 All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 22, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 PaO2: the partial pressure of oxygen 252 All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Availability of data and materials 270 All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. of respiratory support. The prognostic ability of VR on the individual day was evaluated by 305 ROC curve analysis. A failed to discontinue outcome was analyzed as positive. The area under 306 All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted July 22, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 the ROC curve (AUC) maximized on day 4 after initiation of respiratory support at 0.748, 307 which indicates moderate accuracy. The standard error was 0.091, 95% confidential interval 308 was 0.570 to 0.927, and the p-value was 0.019 (Table 2 ). The cut-off value for a maximum 309 diagnostic performance with a sensitivity of 0.667 and a specificity of 0.762 was VR > 1.56. 310

Supplement Table 1 . Detailed information of demographic data, disease course, and 311 respiratory variables. 312 Supplement Table 2 . Raw data of ventilatory ratio from 2 hours (day 0) to day 6 after initiation 313 of respiratory support. 314 Supplement Table 3 . Raw data of PaCO2 from 2 hours (day 0) to day 6 after initiation of 315 respiratory support. 316 Supplement Table 4 . Raw data of minute ventilation from 2 hours (day 0) to day 6 after 317 initiation of respiratory support. 318

SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically 321

COVID-323 19 pulmonary pathology: a multi-institutional autopsy cohort from Italy

Pulmonary pathology of ARDS in COVID-19: A pathological 326 review for clinicians. Respiratory Medicine

* ICU mortality -no (%)

The datasets used and analyzed during the current study are available in Microsoft Excel files 271 titled 'Supplement Table 1 We received support from Osaka City University's "Special Reserves" fund for Authors' contributions 282 N Kaku, M Shirano, and Y Kido designed the concept of the study. N Kaku, S Shinomiya, K 283Yamazaki, K Shimazu, and Y Maehata, and R Morita performed the data acquisition. N Kaku, 284 Y Nakagama, Y Nitahara, and Y Kido assessed the quality of the study and performed the 285 analysis and interpretation. N Kaku, Y Nakagama, and Y Kido wrote the manuscript, and the 286 other authors made substantial revisions and edits. All authors read and approved the final 287 manuscript. 288 All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint this version posted July 22, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint this version posted July 22, 2021. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint this version posted July 22, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 Figure 1. Dynamics of ventilatory ratio, PaCO2, and minute ventilation from 2 hours (day 0) to day 6 after initiation of respiratory support. All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Figure 2 ) on each day after initiation of respiratory support are described. An asterisk indicates statistically significance. ROC receiver operating characteristics, CI confidential interval All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint this version posted July 22, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021