Longitudinal ventilatory ratio monitoring for COVID-19: its potential in predicting severity and assessing treatment response,Critical Care

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Longitudinal ventilatory ratio monitoring for COVID-19: its potential in predicting severity and assessing treatment response
Critical Care ( IF 8.8 ) Pub Date : 2021-10-20 , DOI: 10.1186/s13054-021-03768-2
Natsuko Kaku _{1,

2} , Yu Nakagama ₁ , Michinori Shirano ₃ , Sari Shinomiya ₂ , Kazuhiro Shimazu ₂ , Katsuaki Yamazaki ₄ , Yoshito Maehata ₂ , Ryo Morita ₃ , Yuko Nitahara ₁ , Hiromasa Yamamoto ₅ , Yasumitsu Mizobata ₅ , Yasutoshi Kido ₁

Affiliation

To the Editor:

We read with great interest the recent research article, published in Critical Care: “Longitudinal changes in compliance, oxygenation and ventilatory ratio in COVID-19 versus non-COVID-19 pulmonary acute respiratory distress syndrome”, by Beloncle and collaborators [1]. We agree with their conclusion that increase in ventilatory ratio (VR) during the first week of illness is characteristic to COVID-19 ARDS and reflects its uniqueness in pathophysiology. In addition, we herein wish to propose that VR in COVID-19 ARDS may serve as a potential bedside marker reflecting clinical severity and that its longitudinal monitoring may harbor prognostic value.

In our 28-day observational study including 39 patients with critically ill COVID-19 [2], longitudinal increase in VR values were associated with failure in discontinuing respiratory support (Fig. 1). Upon predicting failure, a VR threshold of 1.56 achieved the highest predictivity with a sensitivity of 0.667 and a specificity of 0.762 on day 5 of respiratory support. Of 21 patients with a VR value lower than 1.56 on day 5, 17 had successfully extubated within 28 days from respiratory support, suggesting that longitudinal VR monitoring could predict better outcome in COVID-19. Similar findings were obtained in another research applying VR changes from day 0 to 3 of respiratory support as a prognostic indicator [3]. Although statistically insignificant, Beloncle and collaborators have also shown an apparent trend towards better prognosis for a lower VR (Table S3; mortality in “VR < 2” versus “VR ≥ 2” were 15.5% versus 30%). It would be of great interest to validate our observations in their cohort as well, by assessing longitudinally the prognostic value of VR, if sufficient data were provided. The wide variety of VR values observed along the chronological course of COVID-19 ARDS, shown in Fig. 1D, may indicate the variable responses following therapeutic interventions. The expanding but yet investigatory list of therapeutics against COVID-19 warrants a deeper description of the therapeutic interventions received within the cohort.

Elevation in VR, a surrogate marker of the increasing dead space fraction, is attributed to the progressive exudative damage affecting the alveoli, as well as the development of micro-embolism in the pulmonary circulation [4, 5], both known histopathological determinants of COVID-19 clinical severity. In addition to the here proposed prognostic value of VR monitoring in predicting natural history of COVID-19, future interest resides in whether longitudinal evaluation of VR may further reflect clinical response to treatment.

François Beloncle,
Antoine Studer,
Valérie Seegers,
Jean-Christophe Richard,
Christophe Desprez,
Nicolas Fage,
Hamid Merdji,
Bertrand Pavlovsky,
Julie Helms,
Sibylle Cunat,
Satar Mortaza,
Julien Demiselle,
Laurent Brochard,
AlainAlain Mercat &
Ferhat Meziani

Dear editor,

We thank Drs Natsuko Kaku et al. for their interest in our study “Longitudinal changes in compliance, oxygenation and ventilatory ratio in COVID-19 versus non-COVID-19 pulmonary acute respiratory distress syndrome” that was recently published in Critical Care [1]. We also thank them for their valuable comment, in which they point out that an increase in Ventilatory Ratio (VR), a surrogate marker of an increase in dead space fraction [6], may allow to predict a poor outcome in patients with COVID-19 associated acute respiratory distress syndrome (ARDS).

We found in our cohort of 135 patients with COVID-19 associated ARDS that VR at day 1, day 3 and day 7 after intubation was higher in non-survivors than in survivors at day 28 (2.1 [1.7–2.4] vs 1.7 [1.5–2.0], p = 0.006; 2.4 [2.1–2.8] vs 1.9 [1.6–2.2], p = 0.003 and 3.2 [2.3–3.9] vs 2.3 [1.8–2.7], p = 0.001, respectively). Discrepancies between the two cohorts might be related to different time course evolutions which may be due to potential differences in non-invasive oxygenation strategies before intubation.

However, in line with the results reported by Drs. Natsuko Kaku et al., we found in patients with COVID-19 that the increase in VR from day 1 to day 7 tended to be higher in the non-survivors than in the survivors at day 28 (0.8 [0.3–1.8] vs 0.5 [0.1–0.9], p = 0.053). This tendency was not observed in the control patients with non-COVID-19 pulmonary ARDS. High VR are known to be associated with poor outcomes in patients with non-COVID-19 ARDS [6, 7]. Even if it has to be confirmed in larger cohorts, the potential specific prognostic value of the changes in VR over time in COVID-19 associated ARDS may be consistent with the distinct evolution of clinical features observed in this population during the first week of mechanical ventilation. As highlighted in our paper, this particular evolution may be in part due to different ventilatory strategies (in particular of positive end-expiratory pressure (PEEP) titration). We agree with Drs. Natsuko Kaku et al. that whether VR changes may help the clinicians to assess the efficacy of some therapeutics as PEEP levels or prone positioning is an interesting question which remains to be addressed.

The datasets analyzed in our study are available at https://www.medrxiv.org/content/10.1101/2021.07.20.21260754v1.supplementary-material.

COVID-19:: Coronavirus disease of 2019
ARDS:: Acute respiratory distress syndrome
VR:: Ventilatory ratio
ROC:: Receiver operating characteristic

1.
Beloncle F, Studer A, Seegers V, Richard J-C, Desprez C, Fage N, et al. Longitudinal changes in compliance, oxygenation and ventilatory ratio in COVID-19 versus non-COVID-19 pulmonary acute respiratory distress syndrome. Crit Care. 2021;25(1):248.
Article Google Scholar
2.
Kaku N, Nakagama Y, Shirano M, Shinomiya S, Shimazu K, Yamazaki K, et al. Increase in ventilatory ratio indicates progressive alveolar damage and suggests poor prognosis in severe COVID-19: a single-center retrospective observational study. medRxiv. 2021. https://doi.org/10.1101/2021.07.20.21260754.
3.
the PRoVENT-COVID Study Group, Morales-Quinteros L, Neto AS, Artigas A, Blanch L, Botta M, et al. Dead space estimates may not be independently associated with 28-day mortality in COVID-19 ARDS. Crit Care. 2021;25(1):171.
Article Google Scholar
4.
Bösmüller H, Matter M, Fend F, Tzankov A. The pulmonary pathology of COVID-19. Virchows Arch. 2021;478(1):137–50.
Article Google Scholar
5.
Menter T, Haslbauer JD, Nienhold R, Savic S, Hopfer H, Deigendesch N, et al. Postmortem examination of COVID-19 patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings in lungs and other organs suggesting vascular dysfunction. Histopathology. 2020;77(2):198–209.
Article Google Scholar
6.
Sinha P, Calfee CS, Beitler JR, Soni N, Ho K, Matthay MA, et al. Physiologic Analysis and Clinical Performance of the Ventilatory Ratio in Acute Respiratory Distress Syndrome. Am J Respir Crit Care Med. 2019;199:333–41.
Article Google Scholar
7.
Morales-Quinteros L, Schultz MJ, Bringué J, Calfee CS, Camprubí M, Cremer OL, et al. Estimated dead space fraction and the ventilatory ratio are associated with mortality in early ARDS. Ann Intensive Care. 2019;9:128.
Article Google Scholar

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I am grateful to FORTE science communications for the manuscript revision. I would like to thank the members of Osaka City General Hospital, where the main results of this paper were obtained, especially Dr. T. Nishida and Dr. T. Shigemoto. I would also like to take this opportunity to thank Dr. T. Akamine, Dr. E. Kataoka-Nakamatsu, Dr. R. Uchida, and Dr. Y. Morimoto for their kind supports.

This work was funded by Japan Agency for Medical Research and Development (AMED) under Grant number JP20wm0125003 (YK), JP20he1122001 (YK), JP20nk0101627 (YK), and JP20jk0110021 (YN). This work was also supported by JSPS KAKENHI Grans Number JP21441824 (NK). We also receive the COVID-19 Private Fund (to the Shinya Yamanaka laboratory, CiRA, Kyoto University). We received support from Osaka City University's "Special Reserves" fund for COVID-19.

Affiliations

Department of Parasitology, Research Center for Infectious Disease Sciences, Graduate School of Medicine, Osaka City University, 1-4-3 Asahimachi, Abeno-ku, Osaka, 545-8585, Japan
Natsuko Kaku, Yu Nakagama, Yuko Nitahara & Yasutoshi Kido
Department of Traumatology and Critical Care Medicine, Graduate School of Medicine, Osaka City University, 1-4-3 Asahimachi, Abeno-ku, Osaka, 545-8585, Japan
Hiromasa Yamamoto & Yasumitsu Mizobata
Department of Infectious Diseases, Osaka City General Hospital, Osaka City Hospital Organization, 2-13-22 Miyakojima-hondori Miyakojima-ku, Osaka, 534-0021, Japan
Michinori Shirano & Ryo Morita
Department of Anesthesia and Intensive Care Medicine, Osaka City General Hospital, Osaka City Hospital Organization, 2-13-22 Miyakojima-hondori Miyakojima-ku, Osaka, 534-0021, Japan
Natsuko Kaku, Sari Shinomiya, Kazuhiro Shimazu & Yoshito Maehata
Department of Anesthesiology, National Cerebral and Cardiovascular Center Hospital, 6-1 Kishibe-Shimmachi, Suita, Osaka, 564-8565, Japan
Katsuaki Yamazaki

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Yasutoshi KidoView author publications
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Contributions

NK, MS, and YK designed the concept of the study. NK, SS, KY, KS, YM, and RM conducted the study and performed the data acquisition. NK, YN, YN, and YK assessed the quality of the study and performed the analysis and interpretation. NK, YN, and YK wrote the manuscript, and the other authors made substantial revisions and edits. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Yasutoshi Kido.

Ethics approval and consent to participate

This study was conducted under the approval of the Institutional Review Board of Osaka City University (#2020-003) and the Clinical Research Ethics Committee of the Osaka Municipal Hospital Organization (#2005020), Osaka, Japan. All necessary patient consent has been obtained and the appropriate institutional form has been archived.

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Not applicable.

Competing interests

Not applicable.

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Kaku, N., Nakagama, Y., Shirano, M. et al. Longitudinal ventilatory ratio monitoring for COVID-19: its potential in predicting severity and assessing treatment response. Crit Care 25, 366 (2021). https://doi.org/10.1186/s13054-021-03768-2

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Received: 13 August 2021
Accepted: 18 August 2021
Published: 20 October 2021
DOI: https://doi.org/10.1186/s13054-021-03768-2

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中文翻译：

COVID-19 的纵向通气比监测：其在预测严重程度和评估治疗反应方面的潜力

致编辑：

我们非常感兴趣地阅读了 Beloncle 及其合作者最近发表在重症监护上的研究文章：“COVID-19 与非 COVID-19 肺急性呼吸窘迫综合征的顺应性、氧合和通气比的纵向变化”[1]。我们同意他们的结论，即疾病第一周通气比 (VR) 的增加是 COVID-19 ARDS 的特征，反映了其在病理生理学上的独特性。此外，我们在此希望提出 COVID-19 ARDS 中的 VR 可作为反映临床严重程度的潜在床边标志物，并且其纵向监测可能具有预后价值。

在我们为期 28 天的观察性研究中，包括 39 名 COVID-19 危重患者 [2]，VR 值的纵向增加与停止呼吸支持失败有关（图 1）。在预测失败时，1.56 的 VR 阈值在呼吸支持的第 5 天实现了最高的预测性，灵敏度为 0.667，特异性为 0.762。在第 5 天 VR 值低于 1.56 的 21 名患者中，17 名在呼吸支持后 28 天内成功拔管，这表明纵向 VR 监测可以预测 COVID-19 的更好结果。在另一项研究中获得了类似的发现，该研究将呼吸支持第 0 天到第 3 天的 VR 变化作为预后指标 [3]。虽然在统计上不显着，Beloncle 和合作者也显示出较低 VR 预后更好的明显趋势（表 S3；“VR < 2”与“VR ≥ 2”的死亡率分别为 15.5% 和 30%）。如果提供了足够的数据，通过纵向评估 VR 的预后价值来验证我们在他们的队列中的观察结果也将非常有趣。如图 1D 所示，在 COVID-19 ARDS 的时间顺序过程中观察到的各种 VR 值可能表明治疗干预后的不同反应。针对 COVID-19 的治疗方法不断扩大但仍在调查中，需要对队列中接受的治疗干预措施进行更深入的描述。如果提供了足够的数据，则通过纵向评估 VR 的预后价值。如图 1D 所示，在 COVID-19 ARDS 的时间顺序过程中观察到的各种 VR 值可能表明治疗干预后的不同反应。针对 COVID-19 的治疗方法不断扩大但仍在调查中，需要对队列中接受的治疗干预措施进行更深入的描述。如果提供了足够的数据，则通过纵向评估 VR 的预后价值。如图 1D 所示，在 COVID-19 ARDS 的时间顺序过程中观察到的各种 VR 值可能表明治疗干预后的不同反应。针对 COVID-19 的治疗方法不断扩大但仍在调查中，需要对队列中接受的治疗干预措施进行更深入的描述。

VR 升高是死腔分数增加的替代标志物，归因于影响肺泡的渐进性渗出性损伤以及肺循环中微栓塞的发展 [4, 5]，这两种都是已知的 COVID 组织病理学决定因素-19 临床严重程度。除了这里提出的 VR 监测在预测 COVID-19 自然病程方面的预后价值之外，未来的兴趣在于 VR 的纵向评估是否可以进一步反映对治疗的临床反应。

弗朗索瓦·贝隆克勒
安托万·斯图德
瓦莱丽·西格斯，
让-克里斯托夫·理查德，
克里斯托夫·德斯普雷兹
尼古拉斯·法奇
哈米德·梅尔吉
伯特兰·巴甫洛夫斯基
朱莉·赫尔姆斯
西比尔·库纳特，
萨塔尔·莫尔塔萨
朱利安·德米塞尔
洛朗·布罗查德
阿兰·阿兰·梅尔卡特 &
费哈特·梅齐亚尼

亲爱的编辑，

我们感谢 Natsuko Kaku 博士等人。因为他们对我们最近发表在重症监护 [1] 上的研究“COVID-19 与非 COVID-19 肺急性呼吸窘迫综合征的顺应性、氧合和通气比的纵向变化”感兴趣。我们也感谢他们的宝贵意见，他们指出通气比 (VR) 的增加（死腔分数增加的替代标志物 [6]）可能有助于预测 COVID- 19 相关的急性呼吸窘迫综合征 (ARDS)。

我们在 135 名 COVID-19 相关 ARDS 患者的队列中发现，在插管后第 1、3 和 7 天，非幸存者的 VR 高于第 28 天的幸存者（2.1 [1.7–2.4] vs 1.7 [1.5]） –2.0]，p = 0.006；2.4 [2.1–2.8] vs 1.9 [1.6–2.2]，p = 0.003 和 3.2 [2.3–3.9] vs 2.3 [1.8–2.7]，p = 0.001，分别）。两个队列之间的差异可能与不同的时间进程演变有关，这可能是由于插管前无创氧合策略的潜在差异。

然而，根据 Drs 报告的结果。Natsuko Kaku 等人，我们在 COVID-19 患者中发现，从第 1 天到第 7 天，非幸存者的 VR 增加往往高于第 28 天的幸存者（0.8 [0.3–1.8] vs 0.5 [0.1–0.9], p = 0.053）。在非 COVID-19 肺 ARDS 对照患者中未观察到这种趋势。众所周知，高 VR 与非 COVID-19 ARDS 患者的不良预后相关 [6, 7]。即使必须在更大的队列中证实，在 COVID-19 相关 ARDS 中 VR 随时间变化的潜在特异性预后价值可能与机械通气第一周期间在该人群中观察到的临床特征的明显演变一致. 正如我们在论文中强调的那样，这种特殊的演变可能部分是由于不同的通气策略（特别是呼气末正压 (PEEP) 滴定）。我们同意博士。Natsuko Kaku 等。

我们研究中分析的数据集可在 https://www.medrxiv.org/content/10.1101/2021.07.20.21260754v1.supplementary-material 获得。

新冠肺炎：: 2019年冠状病毒病
ARDS：: 急性呼吸窘迫综合征
虚拟现实：: 换气比
鹏：: 接收器操作特性

1.
Beloncle F、Studer A、Seegers V、Richard JC、Desprez C、Fage N 等。COVID-19 与非 COVID-19 肺急性呼吸窘迫综合征的顺应性、氧合和通气比的纵向变化。暴击护理。2021;25(1):248。
文章谷歌学术
2.
Kaku N, Nakagama Y, Shirano M, Shinomiya S, Shimazu K, Yamazaki K, et al. 通气比率的增加表明进行性肺泡损伤并表明严重 COVID-19 的预后不良：一项单中心回顾性观察研究。medRxiv。2021. https://doi.org/10.1101/2021.07.20.21260754。
3.
PROVENT-COVID 研究组、Morales-Quinteros L、Neto AS、Artigas A、Blanch L、Botta M 等。死腔估计值可能与 COVID-19 ARDS 的 28 天死亡率无关。暴击护理。2021;25(1):171。
文章谷歌学术
4.
Bösmüller H、Matter M、Fend F、Tzankov A. COVID-19 的肺部病理学。Virchows 拱门。2021;478(1):137–50。
文章谷歌学术
5.
Menter T、Haslbauer JD、Nienhold R、Savic S、Hopfer H、Deigendesch N 等。COVID-19 患者的尸检显示弥漫性肺泡损伤，伴有严重的毛细血管充血，肺部和其他器官的杂色发现表明血管功能障碍。组织病理学。2020;77(2):198-209。
文章谷歌学术
6.
Sinha P、Calfee CS、Beitler JR、Soni N、Ho K、Matthay MA 等。急性呼吸窘迫综合征通气比的生理分析和临床表现。Am J Respir Crit Care Med。2019；199：333-41。
文章谷歌学术
7.
Morales-Quinteros L、Schultz MJ、Bringué J、Calfee CS、Camprubí M、Cremer OL 等。估计的死腔分数和通气比与早期 ARDS 的死亡率相关。安重症监护室。2019；9:128。
文章谷歌学术

下载参考

感谢 FORTE 科学传播对手稿的修改。我要感谢大阪市综合医院的成员，他们获得了本文的主要结果，特别是 T. Nishida 博士和 T. Shigemoto 博士。我还要借此机会感谢 T. Akamine 博士、E. Kataoka-Nakamatsu 博士、R. Uchida 博士和 Y. Morimoto 博士的鼎力支持。

这项工作由日本医学研究与发展局 (AMED) 资助，资助号为 JP20wm0125003 (YK)、JP20he1122001 (YK)、JP20nk0101627 (YK) 和 JP20jk0110021 (YN)。这项工作也得到了 JSPS KAKENHI Grans Number JP21441824 (NK) 的支持。我们还收到了 COVID-19 私募基金（到京都大学 CiRA 的 Shinya Yamanaka 实验室）。我们得到了大阪市立大学针对 COVID-19 的“特别储备”基金的支持。

隶属关系

日本大阪市阿倍野区旭町 1-4-3 大阪市立大学研究生院传染病科学研究中心寄生虫学系 545-8585
加久夏子、中釜优、新田原优子、木户康俊
日本大阪市阿倍野区旭町 1-4-3 大阪市立大学研究生院创伤学和重症监护医学系，545-8585，日本
山本博政 & 沟端康光
大阪市综合医院感染科，大阪市立医院组织，2-13-22 Miyakojima-hondori Miyakojima-ku, Osaka, 534-0021, Japan
白野道典 & 森田亮
日本大阪市宫古岛区 2-13-22 Miyakojima-hondori Miyakojima-ku, 534-0021, Japan, 大阪市综合医院麻醉科和重症监护科
Natsuko Kaku、Sari Shinomiya、Kazuhiro Shimazu 和 Yoshito Maehata
麻醉科，国立脑心血管中心医院，6-1 Kishibe-Shimmachi，吹田，大阪，564-8565，日本
山崎胜明

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贡献

NK、MS 和 YK 设计了研究的概念。NK、SS、KY、KS、YM 和 RM 进行了研究并进行了数据采集。NK、YN、YN 和 YK 评估了研究的质量并进行了分析和解释。NK、YN 和 YK 撰写了手稿，其他作者进行了大量修订和编辑。所有作者阅读并认可的终稿。

通讯作者

与木户康俊的通信。

伦理批准和同意参与

本研究是在大阪市立大学机构审查委员会 (#2020-003) 和大阪市立医院组织 (#2005020) 临床研究伦理委员会（日本大阪）的批准下进行的。已获得所有必要的患者同意，并已存档适当的机构表格。

同意发表

不适用。

利益争夺

不适用。

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