In non-COVID-19 acute hypoxaemic respiratory failure, the entity of dyspnoea has been associated with severity of hypoxaemia, and represents a factor predicting noninvasive ventilation (NIV) failure, the need for endotracheal intubation and mortality [1].
Short abstract
In #COVID19 patients, presence of moderate-to-severe dyspnoea is a marker of disease severity correlated to clinical outcomes https://bit.ly/3Bp2G1b
To the Editor:
In non-COVID-19 acute hypoxaemic respiratory failure, the entity of dyspnoea has been associated with severity of hypoxaemia, and represents a factor predicting noninvasive ventilation (NIV) failure, the need for endotracheal intubation and mortality [1].
In COVID-19 respiratory failure, the concept of “silent hypoxaemia” has been described: this is a condition of hypoxaemia without concomitant dyspnoea and/or signs of respiratory distress [2].
Whether in COVID-19 patients dyspnoea is related to outcome is unknown. We performed a post hoc analysis of a multicentre randomised trial (www.clinicaltrials.gov identifier number NCT04502576) that compared helmet NIV and high-flow nasal oxygen, aiming to assess the prevalence of dyspnoea in COVID-19 patients admitted to the intensive care unit (ICU) and to determine whether this may be related to study outcomes [3].
109 patients admitted to four ICUs and receiving noninvasive respiratory support due to COVID-19 acute hypoxaemic respiratory failure (arterial oxygen tension (PaO2)/inspiratory oxygen fraction (FIO2) ratio ≤200) were analysed. The full protocol and study procedures are described elsewhere [3].
On ICU admission, all patients were asked to rate the subjective sensation of dyspnoea from 0 to 10, with 10 representing the worst symptom, through a visual analogue scale (VAS) [4–6]. Dyspnoea was re-evaluated at 1, 6, 12, 24 and 48 h after the initiation of the assigned treatment, which was either high-flow nasal oxygen or helmet NIV. Patients with VAS dyspnoea ≥4 were considered to have moderate-to-severe dyspnoea, while patients with VAS dyspnoea <4 were considered to have mild or no dyspnoea, as previously suggested [1].
The number of days free of advanced respiratory support (including high-flow nasal oxygen, NIV and invasive ventilation) within 28 days after enrolment; the proportion of patients who required endotracheal intubation within 28 days from study enrolment; the number of days free of invasive mechanical ventilation at day 28 and 60; 28-day, 60-day, in-ICU and in-hospital mortality; and ICU and hospital length of stay were the analysed outcomes.
Data are expressed as number of events (percentage) or median (interquartile range). Ordinal quantitative variables were compared with the Mann–Whitney U-test. Comparisons between groups regarding qualitative variables was performed with the Fisher's exact or the Chi-square test, as appropriate. Correlation was assessed with Pearson's correlation. Multivariate analyses adjusting for covariates were conducted through linear or logistic regression models. Kaplan–Meier curves are displayed for results concerning intubation rate. Intergroup differences in quantitative variables distribution in the initial 48 h of treatment were assessed with ANOVA. All results with two-sided p-values ≤0.05 were considered statistically significant. A post hoc calculation of power was computed for the days free of respiratory support at 28 days, adjusting for the covariates, resulting in a power of 0.70. Statistical analysis was performed with IBM SPSS Statistics 26 and GraphPad Prism 7.
In the whole population (109 patients, median age 65 years (interquartile range (IQR) 55–70 years); 21 (19%) women), median (IQR) PaO2/FIO2 on ICU admission was 102 (82–125) mmHg, median respiratory rate was 28 (24–32) breaths per min and median VAS dyspnoea was 4 (1–7). 52 (48%) had moderate-to-severe dyspnoea while 57 (52%) had mild or no dyspnoea.
Demographics and most relevant study results are displayed in table 1. VAS dyspnoea on ICU admission was not related to respiratory rate (r=0.16, p=0.09), PaO2/FIO2 (r= −0.14, p=0.15), arterial carbon dioxide tension (PaCO2) (r<0.1, p=0.97) or PaO2 (r=0.07, p=0.50).
TABLE 1.
Characteristics at inclusion and study outcomes, according to study group
| Moderate-to-severe dyspnoea (n=52) | Mild or no dyspnoea (n=57) | Adjusted mean difference (95% CI) | OR (95% CI) | p-value | |
| Demographics | |||||
| Age, years | 61 (53–70) | 65 (58–71) | 0.15 | ||
| Female sex | 9 (17) | 12 (21) | 0.64 | ||
| Male sex | 43 (83) | 45 (79) | 0.64 | ||
| Body mass index, kg·m−2 | 28 (26–30) | 27 (25–30) | 0.37 | ||
| Respiratory rate at enrolment, breaths per min | 28 (24–33) | 27 (23–30) | 0.13 | ||
| Device-related discomfort at enrolment# | 2 (0–5) | 0 (0–0) | <0.001 | ||
| Arterial blood gases at enrolment | |||||
| PaO2/FIO2 ratio, mmHg | 97 (82–117) | 110 (83–132) | 0.12 | ||
| PaO2, mmHg | 60 (54–74) | 66 (55–75) | 0.71 | ||
| pH | 7.46 (7.45–7.49) | 7.46 (7.45–7.48) | 0.95 | ||
| PaCO2, mmHg | 34 (31–37) | 34 (32–37) | 0.50 | ||
| Allocated treatment¶ | |||||
| Helmet noninvasive ventilation | 27 (52) | 27 (47) | 0.70 | ||
| High-flow oxygen | 25 (48) | 30 (53) | 0.70 | ||
| Outcomes | |||||
| Respiratory support+-free days at 28 days | 12 (0–23) | 21 (4–25) | −5 (−8– −1) | 0.008 | |
| Intubation within 28 days from enrolment | 27 (52) | 17 (30) | 3.8 (1.5–9.9) | 0.006 | |
| Invasive ventilation-free days at 28 days | 20 (4–28) | 28 (16–28) | −5 (−9– −1) | 0.02 | |
| Invasive ventilation free days at 60 days | 52 (11–60) | 60 (48–60) | −9 (−17– −1) | 0.03 | |
| 28-day mortality | 10 (19) | 8 (14) | 1.8 (0.6–5) | 0.29 | |
| 60-day mortality | 14 (27) | 11 (19) | 2 (0.8–5.5) | 0.16 | |
| Intensive care unit mortality | 15 (29) | 10 (17) | 2.8 (1–7.7) | 0.05 | |
| Hospital mortality§ | 16 (31) | 11 (19) | 2.6 (1–7) | 0.05 | |
| Length of stay in the intensive care unit, days | 12 (6–29) | 7 (4–12) | 6 (0–6) | 0.05 | |
| Length of stay in the hospital, days | 24 (16–41) | 18 (12–29) | 8 (0–15) | 0.04 |
Data are presented as median (interquartile range) or n (%), unless otherwise stated. There were no missing data among the two groups. Mean difference and odds ratio were adjusted for Simplified Acute Physiology Score II, allocated treatment (high-flow nasal oxygen or helmet noninvasive ventilation) and arterial oxygen tension (PaO2)/inspiratory oxygen fraction (FIO2) ratio on intensive care unit admission. For non-normal quantitative variables, comparison between groups was performed with Mann–Whitney test. Comparison between groups for qualitative variables were performed with the Chi-squared test or the Fisher's exact test, as appropriate in agreement with tests assumptions. All the calculations were unadjusted. PaCO2: arterial carbon dioxide tension. #: discomfort was assessed through visual analogue scales adapted for intensive care unit patients, ranging from 0 to 10; ¶: advanced respiratory support interface used in the first 48 h; +: invasive or noninvasive mechanical ventilation, high-flow nasal oxygen; §: one patient was discharged from hospital but died upon readmission.
The median (IQR) days free of respiratory support within 28 days after randomisation were 12 (0–23) in the moderate-to-severe dyspnoea group and 21 (4–25) in the mild or no dyspnoea group (p=0.01, after adjustment for PaO2/FIO2 at enrolment, Simplified Acute Physiology Score (SAPS) II and use of helmet NIV or high-flow oxygen).
44 patients required endotracheal intubation within 28 days of enrolment. The rate of endotracheal intubation was higher in patients with moderate-to-severe dyspnoea than those with mild or no dyspnoea (52% versus 30%), with an odds ratio of 3.8 (95% CI 1.5–9.9) (p=0.006, adjusted for PaO2/FIO2 at enrolment, SAPS II score and use of helmet NIV or high-flow oxygen).
After 1 h of respiratory support, only patients that had moderate-to-severe dyspnoea on arrival showed significant improvement in VAS dyspnoea (median (IQR) VAS dyspnoea at enrolment versus after 1 h of the allocated treatment: 6.5 (5–7) versus 4 (2–5) respectively; mean difference 2.3 (95% CI 1.6–3), p<0.001), while patients with mild or no dyspnoea at arrival showed no changes in VAS dyspnoea (p=0.80). Nevertheless, despite the use of the allocated interface, patients that, on enrolment, showed higher VAS dyspnoea remained, overall, most dyspnoeic over time (mean±sd 3.6±2.4 versus 1.5±1.7 respectively; mean difference 2.1 (95% CI 1.7–2.5), one-way ANOVA p<0.001).
Conversely, over the initial 48 h of treatment, patients who subsequently required endotracheal intubation had higher mean VAS dyspnoea than the those who avoided intubation through the noninvasive treatment (3.4±2.6 versus 2.1±2.1 respectively; mean difference 1 (95% CI 1–2), p<0.001).
Patients with moderate-to-severe dyspnoea had fewer days free of invasive ventilation at days 28 and 60, longer ICU and hospital lengths of stay, and higher in-ICU and in-hospital mortality. There was no significant difference in 28- and 60-day mortality (table 1).
In this post hoc analysis of a randomised clinical trial conducted in COVID-19 patients admitted to the ICU with moderate-to-severe hypoxaemic respiratory failure and receiving a trial of noninvasive respiratory support, 52 patients (48%) showed moderate-to-severe dyspnoea on ICU admission. Conversely, 57 patients (52%) had moderate-to-severe oxygenation impairment with mild or no dyspnoea, possibly representing silent hypoxaemia.
Reporting moderate-to-severe dyspnoea on ICU admission was independently associated with increased need for endotracheal intubation, fewer respiratory support-free days, fewer invasive mechanical ventilation-free days at day 28 and 60, longer ICU and hospital length of stay, and higher in-ICU and in-hospital mortality.
The perception of dyspnoea is mediated by many physiological factors, including PaO2 and PaCO2. Increases in respiratory drive and dyspnoea appear only when PaO2 falls below 60–70 mmHg and PaCO2 is >39 mmHg [2, 7, 8]; however, PaO2 is usually maintained by clinicians >60 mmHg for safety reasons and PaCO2 is commonly <39 mmHg due to higher sensitivity of the respiratory centre to carbon dioxide stimulus in patients with acute respiratory failure [8]. Indeed, only five patients exhibited PaO2 <60 mmHg and/or PaCO2 >39 mmHg, and among them, only two were not showing signs of dyspnoea.
In our cohort, patients that showed high-to-moderate dyspnoea on enrolment had a higher risk of endotracheal intubation and higher in-ICU mortality, confirming that the self-reported sensation of dyspnoea is not related to hypoxaemia or hypercapnia per se, but rather to the entity of pulmonary damage and to the severity of illness.
In COVID-19-induced moderate-to-severe acute hypoxaemic respiratory failure, the presence of moderate-to-severe dyspnoea has high prevalence, independently of the degree of oxygenation impairment, similarly to non-COVID-19 moderate-to-severe respiratory failure [1].
Presence of moderate-to-severe dyspnoea might be a marker of disease severity correlated to outcomes, possibly configuring a clinical subphenotype of COVID-19 severe respiratory failure. Use of noninvasive support in COVID-19 patients is common [9–12]. While considering a trial of noninvasive respiratory support in COVID-19 patients with moderate-to-severe respiratory failure, the presence of dyspnoea, measured during conventional oxygen therapy, in conjunction with other variables such as respiratory rate and degree of hypoxia, may represent a simple alert tool to identify patients with the highest risk of endotracheal intubation.
Acknowledgements
We are grateful to all intensive care unit physicians, residents, nurses and personnel from the participating centres, whose sacrifice, efforts, devotion to patients and passion have made possible this timely report.
Members of the COVID-ICU Gemelli study group: Gian Marco Anzellotti, Giuseppe Bello, Maria M. Bitondo, Maria Grazia Bocci, Filippo Bongiovanni, Simone Carelli, Laura Cascarano, Giorgio Conti, Paolo De Santis, Antonio M. Dell'Anna, Mariangela Di Muro, Miriana Durante, Giulia Falò, Nicoletta Filetici, Veronica Gennenzi, Antonio Gullì, Gianmarco Lombardi, Alessio Maccaglia, Riccardo Maviglia, Alessandro Mele, Giovanna Mercurio, Teresa Michi, Tony C. Morena, Luca Montini, Jonathan Montomoli, Martina Murdolo, Daniele Natalini, Mariano Alberto Pennisi, Edoardo Piervincenzi, Stefania Postorino, Francesca Pozzana, Martina Savino, Roberta Scarascia, Angela Scavone, Donatella Settanni, Serena Silva, Savino Spadaro, V. Marco Ranieri, Tommaso Tonetti, Joel Vargas, Matteo Velardo, Carlo Alberto Volta and Carmelina Zaccone.
Footnotes
Author contributions: L.S. Menga, D.L. Grieco and M. Antonelli conceived the study. All authors contributed to data acquisition. T. Rosà conducted statistical analysis. L.S. Menga and T. Rosà interpreted the data and wrote the first draft of the manuscript. D.L. Grieco and M. Antonelli critically revised the manuscript. M. Antonelli organised the study as an overall supervisor. All the authors reviewed the final draft of the manuscript and agreed to submit it to ERJ Open Research.
Conflict of interest: L.S. Menga has nothing to disclose.
Conflict of interest: D.L. Grieco reports nonfinancial support from Maquet and Air Liquide, and grants from GE, outside the submitted work.
Conflict of interest: T. Rosà has nothing to disclose.
Conflict of interest: M. Cesarano has nothing to disclose.
Conflict of interest: L. Delle Cese has nothing to disclose.
Conflict of interest: C. Berardi has nothing to disclose.
Conflict of interest: G. Pintaudi has nothing to disclose.
Conflict of interest: E.S. Tanzarella has nothing to disclose.
Conflict of interest: S.L. Cutuli has nothing to disclose.
Conflict of interest: G. De Pascale has nothing to disclose.
Conflict of interest: S.M. Maggiore reports grants from Fisher and Paykel Healthcare, and personal fees from Dreger Medical and GE Healthcare, outside the submitted work.
Conflict of interest: M. Antonelli reports grants from GE and Toray, and personal fees from Maquet, outside the submitted work.
Support statement: The study was funded by a research grant (2017 MSD award) by the Italian Society of Anesthesia, Analgesia and Intensive Care Medicine (SIAARTI). The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Outside of the submitted work, D.L. Grieco is supported by a research grant by the European Society of Intensive Care Medicine. Funding information for this article has been deposited with the Crossref Funder Registry.
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