key: cord-0850487-215ec3ff authors: Deng, L.; Lei, S.; Jiang, F.; Lubarsky, D. A.; Zhang, L.; Liu, D.; Han, C.; Zhou, D.; Wang, Z.; Sun, X.; Zhang, Y.; Cheung, C. W.; Wang, S.; Xia, Z.-y.; Applegate, R. L.; Liu, H.; Tang, J.; Xia, Z. title: The Outcome Impact of Early vs Late HFNC Oxygen Therapy in Elderly Patients with COVID-19 and ARDS date: 2020-05-26 journal: nan DOI: 10.1101/2020.05.23.20111450 sha: 0608558a2d8f1c76f6dfc9efd11fee7a75255d32 doc_id: 850487 cord_uid: 215ec3ff Coronavirus disease-2019 (COVID-19) has rapidly spread worldwide. High-flow nasal cannula therapy (HFNC) is a major oxygen supporting therapy for severely ill patients, but information regarding the timing of HFNC application is scarce, especially in elderly patients. We retrospectively analyzed the clinical data of 110 elderly patients ([≥]65 years) who received HFNC from Renmin Hospital of Wuhan University, People's Hospital of Xiantao City and Chinese Medicine Hospital of Shishou City in Hubei Province, China, and from Affiliated Hospital of Guangdong Medical University, People's Hospital of Yangjiang City, People's Hospital of Maoming City in Guangdong Province, China. Of the 110 patients, the median age was 71 years (IQR, 68-78) and 59.1% was male. Thirty-eight patients received HFNC when 200 mmHg < PO2/FiO2 [≤] 300 mmHg (early HFNC group), and 72 patients received HFNC treatment when 100 mmHg < PaO2/FiO2 [≤] 200 mmHg (late HFNC group). Compared with the late HFNC group, patients in the early HFNC group had a lower likelihood of developing severe ARDS, longer time from illness onset to severe ARDS and shorter duration of viral shedding after illness onset, as well as shorter lengths of ICU and hospital stay. Twenty-four patients died during hospitalization, of whom 22 deaths (30.6%) were in the late HFNC group and 2(5.3%) in the early HFNC group. It is concluded that the prognosis was better in severely ill elderly patients with COVID-19 receiving early compared to late HFNC. This suggests HFNC could be considered early in this disease process. Coronavirus disease-2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first reported in December 2019 in Wuhan, Hubei, China, but has rapidly spread worldwide. [1] Since initial detection of the virus, more than 2,626,000 cases of COVID- 19 have been confirmed worldwide, with more than 181,000 deaths as of April 24, 2020. COVID-19 is more likely to affect elderly patients with comorbidities, and can result in severe or fatal respiratory diseases such as acute respiratory distress syndrome (ARDS). [2] Initial reports from China [3] , Italy [4] and the United States [5] suggested high mortality for elderly and critically ill patients with COVID-19. No specific therapeutic agents or vaccines for COVID -19 are available, although several antiviral medications such as remdesivir and favipiravir are under investigation. [6 , 7] Patients with severe illness may develop dyspnea and hypoxemia within one week after the onset of COVID-19 and may quickly progress to ARDS, [2] a major cause of death in patients with COVID-19. [8] Thus, respiratory support and intensive care management are vital to saving lives. Reports showed that both conventional oxygen therapy and non-invasive ventilation (NIV), such as NIPPV (non-invasive positive pressure ventilation), are commonly used in COVID-19 patients to improve oxygenation and reduce the possibility of intubation. [9 , 10] However, the risk of airborne transmission with NIPPV is a major concern, while that for high flow nasal cannula therapy (HFNC) is judged minimal. [11] A guideline for the management of critically ill adults with COVID-19 published in JAMA March 26, 2020 recommended the use of HFNC relative to NIPPV in the circumstance of acute hypoxemic respiratory failure despite conventional oxygen therapy. [11] However, evidence is lacking regarding optimal timing to apply HFNC. In this study, we report the clinical characteristics of elderly (≥65 years) patients with COVID-19 who developed ARDS on or shortly after admission and compared outcomes of patients who started HFNC at different stages of ARDS. . CC-BY-NC-ND 4.0 International license It is made available under a 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 May 26, 2020. China. All elderly patients who were diagnosed with severe COVID-19 according to WHO interim guidance, and those who were treated with HFNC between January 14, 2020 (when the first patients were admitted in these hospitals) and March 5, 2020 , were included in the present study. Due to the lack of understanding of this new disease, the timing of HFNC treatment was uncertain. In this retrospective study, of 110 HFNC-treated patients, 38 received HFNC treatment when 200 mmHg < PO 2 /FiO 2 ≤ 300 mmHg (early HFNC group), while 72 were first treated with conventional oxygen therapies (e.g., low flow nasal catheter ventilation) and then HFNC when 100 mmHg < PO 2 /FiO 2 ≤ 200 mmHg (late HFNC group). HFNC was started from low levels and gradually titrated to 60 L/min for patients without obvious complaint of chest distress or shortness of breath. However, for patients who were short of breath (e.g., respiratory rate >30/min) the flow rates were commenced at 60 L/min. The goal of oxygen therapy was to maintain the oxygen saturation (SpO 2 ) at 93%-96%, which is in keeping with the recent guideline recommendation of a reasonable SpO2 range of 92-96% for patients receiving oxygen . [12] This study was reviewed and approved by the Medical Ethical Committee of participating institutes (PJ2020-005), and the informed consent was waived by the Medical Ethical Committee. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 26, 2020. . https://doi.org/10.1101/2020.05.23.20111450 doi: medRxiv preprint Patients' medical records were reviewed and epidemiological, clinical, laboratory, and radiological characteristics and treatment and outcomes data were obtained with data collection forms. Two research investigators (LD and SL) independently reviewed the data collection forms to verify accuracy. We collected data on age, sex, exposure history, comorbidities (e.g., hypertension, diabetes, malignancy, cardiovascular disease, cerebrovascular disease, chronic pulmonary disease, chronic kidney disease), chest CT images, signs and symptoms (e.g., fever, fatigue, dry cough, dyspnea), time of first symptom to dyspnea, ARDS and ICU admission, vital signs (heart rate, respiratory rate, blood pressure) and laboratory values (e.g., white blood cell count, neutrophil count, lymphocyte count, procalcitonin concentration, arterial blood gas analysis, fraction of inspired oxygen (FiO 2 ), partial pressure of arterial oxygen (PaO 2 ), and lactate concentration) on hospital admission and disease progression, treatments (e.g., oxygen support, antiviral therapy, antibiotic therapy, glucocorticoids, immunoglobulin), complications (e.g., septic shock, ARDS, secondary infection), and discharge/death. The numbers of patients requiring mechanical ventilation, the numbers of patients requiring FiO 2 = 100%, > 80% and > 60% for more than 72 hours continuously, length of ICU stay, and length of stay (LOS) were also collected. The primary outcome was in-hospital mortality. Secondary outcomes included incidence of severe ARDS, the numbers of ICU admission and patients requiring mechanical ventilation. The ICU admission standard is patients require invasive mechanical ventilation, or have shock or other organ failure that need ICU monitoring and treatment. [13 , 14] ARDS was defined as acute . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) Continuous variables were presented as mean with standard deviation (SD) when normally distributed and compared by independent sample t test, or expressed as median with interquartile range (IQR) if non-normally distributed and compared by Mann-Whitney U test. Categorical variables were expressed as n (%) and compared by Pearson's chi-square or Fisher's exact test between early HFNC and late HFNC groups. A two-sided α of less than 0.05 was considered statistically significant. All statistical analyses were performed with the SPSS (version 25) software. A total of 638 elderly patients (≥ 65 years) with confirmed SARS-CoV-2 infection were admitted to participating hospitals during the defined study time period. Of these, 502 patients who did not receive HFNC treatment were excluded, as were 19 patients due to missing key information in their medical records, and 7 patients who had cardiac arrest within 24 hours after admission. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 26, 2020. Table 1 ). The most common abnormal laboratory findings were lymphocytopenia, increased C-reactive protein, and decreased CD3, CD4 and CD8 counts on hospital admission (Table 1 ). The overall median SPO 2 was 95% (IQR 93-98%) on admission, and the median ratio of PaO 2 /FiO 2 was 238 mmHg (IQR 221-277). There were no significant differences in admission SPO 2 or PaO 2 /FiO 2 between early and late HFNC groups. Both SpO 2 and PaO 2 /FiO 2 ratio at initiation of HFNC were higher and the time from admission to HFNC treatment was shorter in the early HFNC group (Table 1) . All patients showed bilateral lung involvement on chest CT scan at admission, including consolidation, ground-glass opacity, interstitial lesions, and exudative lesions (figure 1). Patients who received early HFNC had a lower likelihood of developing severe pneumonia, manifested as more than 50% increase in pneumonitis foci on chest CT scan during disease progression ( Table 2 ). All patients received antiviral medications (lopinavir or ritonavir), and 66 (60%) patients also received antibiotics. Thirty-eight (34.5%) patients required prone ventilation, 24 (21.8%) received non-invasive ventilation, and 42 (38.2%) patients required invasive mechanical . CC-BY-NC-ND 4.0 International license It is made available under a 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 May 26, 2020. . https://doi.org/10.1101/2020.05.23.20111450 doi: medRxiv preprint ventilation, of whom 7 received extracorporeal membrane oxygenation as rescue therapy. were less likely to have secondary infection or severe ARDS, and less likely to receive prone position ventilation and invasive mechanical ventilation than the patients who receive late HFNC. Major laboratory markers and SOFA score were tracked from hospital admission (figure 2). Lymphocyte count was higher in patients who received early HFNC during hospitalization. Lactate dehydrogenase level did not differ between these two groups on day 3 after admission, but continued to increase in the late HFNC group and was significantly higher on day 9 after admission and onwards. Both the levels of D-dimer and C-reactive protein were significantly lower throughout the clinical course in patients who received early HFNC. Lactate concentration and SOFA score were similar between groups on day 3 after admission. Patients who received early HFNC showed lower lactate concentration on day 15 and lower SOFA score on day 9 after admission and onwards (figure 2). Of the 110 patients who received HFNC, 40 (36.4%) patients required more than 60% FiO 2 , 23 (22.7%) patients required FiO 2 more than 80%, and 4 (3.6%) patients required 100% FiO 2 (table 1). All 22 patients in the late HFNC group who died during hospitalization received FiO 2 > 60% for more than 72 hours continuously (table 3). The numbers of patients who required higher than 60% FiO 2 and those who required more than 80% FiO 2 were smaller in the early HFNC group. FiO 2 and PO 2 /FiO 2 were tracked during hospitalization. As shown in figure 3, baseline FiO 2 and PaO 2 /FiO 2 were similar between the two groups. The patients in the early HFNC group . CC-BY-NC-ND 4.0 International license It is made available under a 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 May 26, 2020. . https://doi.org/10.1101/2020.05.23.20111450 doi: medRxiv preprint showed higher ratio of PaO 2 /FiO 2 on day 3 after admission, and required lower FiO 2 on day 6 after admission and onwards. The median time from illness onset to ICU admission was 11 days (IQR [8] [9] [10] [11] [12] [13] [14] , and 12 days (IQR 11-15) to severe ARDS. The length of ICU stay was 17 days (IQR 12-22), LOS was 27 days (IQR 16-32), and duration of viral shedding after illness onset was 16 days (IQR 13-21). Patients who received early HFNC were less likely to admit to ICU, less likely to stay in ICU longer than 7 days, had less chance to develop severe ARDS and had longer time from COVID-19 onset to severe ARDS (if any). Duration of viral shedding after illness onset and length of ICU and hospital stay were shorter in the early HFNC group. A total of 86 (78.2%) patients had been discharged, and 24 (21.8%) patients had died. The mortality in late HFNC group was higher than that in early HFNC (22 [30. 6%] vs. 2 [5.3%]) as shown in Table 2 and Figure 3C . This report, presents the outcomes of 110 severely ill elderly COVID-19 patients who received oxygen therapy with HFNC. Mortality was lower (5.3%) in 38 patients who received HNFC treatment at the mild ARDS stage, compared to 30.6% in 72 patients in whom HNFC treatment was started at the moderate ARDS stage. The mortality rate in this study was lower than that reported from a multi-national study regarding the mortality for patients with ARDS, which was 34.9% and 40.3% respectively for those with mild or moderate ARDS. [17] An early report from China [3] and a recent report from the United States [5] reported 61.5% and 50% mortalities respectively for critically ill patients with COVID-19, while the mortality for critically ill patients aged 60 years or older was as high as 70.3%. [3] HFNC, as an innovative and effective modality for oxygen therapy, delivers titratable oxygen . CC-BY-NC-ND 4.0 International license It is made available under a 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 May 26, 2020. . 1 0 up to 60 liters/minutes with heating and humidification to produce a low-level positive endexpiratory pressure and to achieve FiO 2 as high as 95-100%. [9] HFNC has been shown to reduce the risk of requiring more advanced ventilation and relieve dyspnea better than conventional oxygen therapy and has been suggested as a first-line therapy even before making a clear diagnosis for dyspnea. [10] In our study, 10.5% patients in the early HFNC group converted to invasive mechanic ventilation, which is in contrast to the 52.7% in the late HFNC group ( Table 2 ). These findings can be compared to other published reports. A cohort study in 17 COVID-19 patients indicated starting HFNC when PaO 2 /FiO 2 >200 reduced the need of mechanical ventilation, although the impact on mortality was not reported. [18] Starting HFNC or invasive mechanical ventilation at a relatively late stage of disease severity such as moderate to severe ARDS may prompt the physician to apply high FiO 2 . Critically ill patients with COVID-19 in the Seattle region [5] had reported 50% mortality at the time of data cut off with several patients continuing to receive mechanical ventilation in the ICU. In the study, [5] the initial median FiO 2 on day 1 of mechanical ventilation was 90% (IQR 70-100%), and the FiO 2 decreased to 60% (IQR 50-70%) on day 3 but no further information was provided about FiO 2 afterwards. It is possible that the FiO 2 had to be readjusted to higher levels due to the subsequent difficulty in reaching targeted PaO 2 and/or PaO 2 /FiO 2 . High oxygen mediated oxidative lung damage [19] may further exacerbate oxygenation, which may paradoxically push for the need of higher FiO 2 . In addition, oxidative stress during respiratory viral infection may also exacerbate a "cytokine storm". [20] In the late HFNC group, the required FiO 2 increase over time we found (Figure 3) was coincident with progressive increases of D-dimer and C-reactive protein (Figure 2) , indicators of inflammation that could be related to a relatively higher mortality rate in the late HFNC group. . CC-BY-NC-ND 4.0 International license It is made available under a 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 May 26, 2020. . https://doi.org/10.1101/2020.05.23.20111450 doi: medRxiv preprint 1 Evidence shows that liberal oxygen therapy increases mortality without improving other outcomes and that supplemental oxygen might become unfavorable above a SpO 2 range of 94-96%. [21] A multicenter study of critically ill patients with the Middle East Respiratory Syndrome (MERS) related to MERS-CoV infection showed that non-survivors received significantly higher FiO2 than survivors on ICU day 1. [22] Thus, despite the generally accepted normal range of PaO 2 80 -100 mmHg breathing room air at sea level in healthy young adults, we took into consideration the relatively lower reference values for PaO 2 in the elderly compared to young adults as well as gender differences. [23 , 24] Previous studies showed that in elders over 70 years old the normal PaO 2 for men was 77 mmHg (SD. 9.1; and lower limit of normal at 62mmHg), while PaO 2 for women was 73.5 mmHg (SD. 8.4; lower limit of normal at 59.6mmHg), [23] and normal reference values reduce with age. [24] In practice, we estimated the acceptable normal values of PaO 2 using the formula: normal PaO 2 at sea level (in mmHg) = 100 minus the number of years over ago 40, as proposed. [25] For SpO 2 , we recommended 93% for men and 92% for women as the lower limit of normal.We also recommended SpO 2 95% or 96% as the highest target value, which is generally in keeping with the recommendation by Chinese CDC and the recently published guideline recommending of no higher than 96%. [26] However, accuracy of SpO 2 readings may be affected by factors such as low perfusion and the use of vasodilator, [27] so target values of SpO 2 were set at the discretion of treating physician, and arterial blood gas analysis was used to adjust treatments (e.g., FiO 2 and/or flow rate). In our study, FiO 2 values were maintained significantly lower in the early HFNC group ( Figure 2 ). Post-hoc subgroup analysis in the late HFNC group revealed that FiO 2 of survivors was significantly lower than that of the non-survivors (table 3) , and initial targeted SpO 2 was also relatively higher in the non-survivor subgroup (data not shown). In the current study, all the . CC-BY-NC-ND 4.0 International license It is made available under a 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 May 26, 2020. . https://doi.org/10.1101/2020.05.23.20111450 doi: medRxiv preprint baseline characteristics and laboratory values were comparable between early and late HFNC groups. There is evidence to show that airborne transmission with HFNC is minimal [11 , 28] and that risk of hospital-acquired infection did not increase with the use of HFNC provided there is good mask fitting. [29] However, the safety of HFNV in these patients is controversial given SARS-CoV-2 virus is highly contagious. [30] Because of risks, all staff in ward or ICU care settings are strongly recommended/required to wear a disposable surgical cap, medical protective mask (N95), disposable medical protective uniform and disposable gloves with full-face respiratory protective devices when performing procedures like tracheal intubation. [31] In conclusion, the application of HFNC in elderly patients (≥ 65 years) with COVID-19, especially when used with conservative oxygen delivery, may prove to be a promising treatment modality for critically ill patients with acute ARDS in general, and of critically ill elderly COVID-19 patients in particular, although larger scale prospective studies are needed to confirm its effectiveness. Our current study provides evidence that application of HFNC earlier during the mild stage of ARDS may be associated with reduced need for mechanic ventilation and mortality in critically ill elderly patients with COVID-19 pneumonia. The fact that early application of HFNC was associated with shorter time duration of SARS-CoV-2 viral shedding may be of significance in reducing transmission. • High-flow nasal cannula therapy (HFNC) is a major oxygen supporting therapy for severely ill patients, and is recommended for use in COVID-19 patients. However, study is lacking regarding the optimal timing of high-flow nasal cannula (HFNC) application among critically ill . CC-BY-NC-ND 4.0 International license It is made available under a 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 May 26, 2020. All authors declare no competing interests. . CC-BY-NC-ND 4.0 International license It is made available under a 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 May 26, 2020. . https://doi.org/10.1101/2020.05. 23.20111450 doi: medRxiv preprint With the permission of the corresponding authors, the participant data without names and identifiers can be provided, but not the study protocol and statistical analysis plan. The data will be available for others to request after publication of study findings. The research team will provide an email address for communication once the data can be made public. The corresponding authors have the right to decide whether or not to share the data based on research objectives and plan provided. The authors' work was supported by the grants from National Natural Science Foundation of China (NSFC 813000674, 81670770, 81970247). We acknowledge all health-care workers involved in the diagnosis and treatment of patients in Wuhan. We thank the patients and their families for providing requested data and information. . CC-BY-NC-ND 4.0 International license It is made available under a 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 May 26, 2020. . https://doi.org/10.1101/2020.05.23.20111450 doi: medRxiv preprint . CC-BY-NC-ND 4.0 International license It is made available under a 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 May 26, 2020. . CC-BY-NC-ND 4.0 International license It is made available under a 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 May 26, 2020. . CC-BY-NC-ND 4.0 International license It is made available under a 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 May 26, 2020. . https://doi.org/10.1101/2020.05.23.20111450 doi: medRxiv preprint . CC-BY-NC-ND 4.0 International license It is made available under a 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 May 26, 2020. . https://doi.org/10.1101/2020.05.23.20111450 doi: medRxiv preprint 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 May 26, 2020. P < 0.05 was considered statistically significant. . CC-BY-NC-ND 4.0 International license It is made available under a 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 May 26, 2020. P < 0.05 was considered statistically significant. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 26, 2020. . https://doi.org/10.1101/2020.05.23.20111450 doi: medRxiv preprint . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted May 26, 2020. Data are median (IQR), n (%), or n/N (%). FiO 2 =fraction of inspired oxygen. HFNC=high flow nasal cannula. PaO 2 =partial pressure of oxygen. a P values indicate differences between Non-survivors and Survivors. P < 0.05 was considered statistically significant. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 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