key: cord-0754929-r3xdcj90
authors: Isaka, Yuri; Hirasawa, Yasutaka; Terada, Jiro; Shionoya, Yu; Takeshita, Yuichiro; Kinouchi, Toru; Koshikawa, Ken; Tajima, Hiroshi; Kinoshita, Taku; Tada, Yuji; Tatsumi, Koichiro; Tsushima, Kenji
title: Preliminary study regarding the predicted body weight-based dexamethasone therapy in patients with COVID-19 pneumonia
date: 2021-12-17
journal: Pulm Pharmacol Ther
DOI: 10.1016/j.pupt.2021.102108
sha: e8372258162e2a974088355284b5be69dd80f322
doc_id: 754929
cord_uid: r3xdcj90

BACKGROUND: The RECOVERY clinical trial reported that 6 mg of dexamethasone once daily for up to 10 days reduces the 28-day mortality in patients with coronavirus disease 2019 (COVID-19) receiving respiratory support. In our clinical setting, a fixed dose of dexamethasone has prompted the question of whether inflammatory modulation effects sufficiently reduce lung injury. Therefore, preliminary verification on the possibility of predicted body weight (PBW)-based dexamethasone therapy was conducted in patients with COVID-19 pneumonia. METHODS: This single-center retrospective study was conducted in a Japanese University Hospital to compare the treatment strategies/management in different periods. Consecutive patients (n = 90) with COVID-19 pneumonia requiring oxygen therapy and were treated with dexamethasone between June 2020 and May 2021 were analyzed. Initially, 60 patients administered a fixed dexamethasone dose of 6.6 mg/day were defined as the conventional group, and then, 30 patients were changed to PBW-based therapy. The 30-day discharged alive rate and duration of oxygen therapy were analyzed using the Kaplan–Meier method and compared using the log-rank test. The multivariable Cox regression was used to evaluate the effects of PBW-based dexamethasone therapy on high-flow nasal cannula (HFNC), noninvasive ventilation (NIV), or mechanical ventilation (MV). RESULTS: In the PBW-based group, 9, 13, and 8 patients were administered 6.6, 9.9, and 13.2 mg/day of dexamethasone, respectively. Additional respiratory support including HFNC, NIV, or MV was significantly less frequently used in the PBW-based group (P = 0.0046), with significantly greater cumulative incidence of being discharged alive and shorter oxygen demand within 30 days (92 vs. 89%, log-rank P = 0.0094, 90 vs. 92%, log-rank P = 0.0002, respectively). Patients treated with PBW-based therapy significantly decreased the use of additional respiratory support after adjusting for baseline imbalances (adjusted odds ratio, 0.224; 95% confidence interval, 0.062–0.813, P = 0.023). Infection occurred in 13 (21%) and 2 (7%) patients in the conventional and PBW-based groups, respectively (P = 0.082). CONCLUSIONS: In patients with COVID-19 pneumonia requiring oxygen therapy, PBW-based dexamethasone therapy may potentially shorten the length of hospital stay and duration of oxygen therapy and risk of using HFNC, NPPV, or MV without increasing serious adverse events or 30-day mortality.

or underweight cannot affect its results [10, 11] . Because individuals with obesity were reported to be more 1 at risk for COVID-19 pneumonia and higher hospitalization, intensive care unit admission, and mortality 2 rates, obese patients have more opportunities to be treated by dexamethasone [12] . When considering the 3 dexamethasone dosage to treat COVID-19 pneumonia, the therapeutic dose based on the actual bodyweight 4 may be higher for obese patients, since this dosage could be susceptible to infection or hyperglycemia. In 5 contrast, the dexamethasone dosage would not sufficiently prevent hyperinflammation in underweight 6 patients. PBW-based dexamethasone therapy, which is not dependent on the actual body weight but height 7 and sex, has beneficial potential for COVID-19 therapy. 8 Herein, a retrospective cohort study was conducted to investigate the efficacy and safety of based dexamethasone therapy in patients with COVID-19 pneumonia who needed oxygen therapy through 10 comparison with the conventional group. 11 12 

All study procedures involving human participants were approved by the Human Ethics 15

Committee of the International University of Health and Welfare (no. 20-Nr-101). This study was designed 16 and conducted following the ethical principles of the 1964 Helsinki Declaration and subsequent amendments. 17 The requirement for informed consent was waived by the ethics committee because this retrospective 18 analysis was limited to the preexisting data collected as the standard of care by respiratory physicians. Data 1 anonymization was followed, and privacy issues were protected. 2 3 

This single-center retrospective study that compares treatment strategy/management in certain 5 different periods included consecutive patients with COVID-19 pneumonia who needed oxygen therapy and 6 were treated with dexamethasone between June 2020 and May 2021 at the International University of Health 7 and Welfare Narita Hospital in Japan. COVID-19 was diagnosed through the detection of SARS-CoV-2 by 8 polymerase chain reaction from a nasopharyngeal swab specimen, and pneumonia was defined as having 9 pulmonary infiltrate on chest computed tomography. 10 11 

Dexamethasone was administered to patients with COVID-19 pneumonia with peripheral capillary 13 oxygen saturation (SpO₂) of ≤93% at room temperature at sea level or who needed oxygen therapy. Its 14 administration had been approved before the study by the Ministry of Health, Labour, and Welfare in Japan. 15 Injectable dexamethasone including 4.4 mg as dexamethasone sodium phosphate was also approved at 3. April and May 2021, the therapeutic protocol was modified by the pulmonary department, and the dose was 5 changed based on PBW [15] . For clinical implication, the PBW-based dose group was divided into four: 6 males with ≥170 cm height (>66 kg at PBW) were administered 13.2 mg/day dexamethasone; males with 7 <170 cm height were administered 9.9 mg/day; females with ≥150 cm height were administered 9.9 mg/day; 8 and female with <150 cm height (<43 kg at PBW) were administered 6.6 mg/day. Dexamethasone was 9 intravenously administered once daily for up to 10 days or until hospital discharge in both groups. 10 11 

Remdesivir was also administered to patients with COVID-19 pneumonia with SpO₂ of ≤93% at 13 room temperature at sea level or who needed oxygen therapy. The study was conducted after the approval 14 of the Ministry of Health, Labour and Welfare in Japan. Off-label use of tocilizumab was approved by the 15 Human Ethics Committee of International University of Health and Welfare Narita Hospital, and written 16 informed consent was obtained. Tocilizumab was also used in some patients (shown in Table 1 ). During the 17 study period (from April 23), baricitinib was approved for COVID-19 pneumonia by the Ministry of Health, 18 Labour, and Welfare in Japan. Patients treated with baricitinib were not included in this study population. 1 2 2.5 Data collection 3

The following information was collected from medical records: age, sex, BMI, comorbidities, 4 laboratory data on the day of starting dexamethasone or latest data before the initiation, previous treatment, 5 the dose and timing of dexamethasone therapy, and clinical outcomes. The clinical outcome included the 6 following adverse events: hyperglycemia or infection, re-administration of corticosteroids, need for 7 additional respiratory support including high-flow nasal cannula therapy (HFNC), noninvasive ventilation 8 (NIV) and mechanical ventilation (MV), 30-day mortality, length of hospital stay, and duration of oxygen 9 therapy. 10 11

Data are expressed as median and interquartile ranges. Baseline characteristics were analyzed 13 using Fisher's exact test or Mann-Whitney U test. The analysis included a Cox regression to test significant 14 effects on the hazard of using HFNC, NIV, or MV. This approach was selected to adjust for baseline 15 imbalances in variables, such as sex, age, BMI, and diabetes mellitus (DM), based on previous reports [16-16 18 ]. Cumulative incidence of discharged alive rate and oxygen-free rate within 30 days were analyzed using 17 the Kaplan-Meier method and compared by the log-rank test. Two-tailed P-values of <0.05 were considered 18 significant. All analyses were performed using the JMP pro 13.2.0 (SAS Institute Inc. Cary, NC, USA). 1 2

During the study period, 96 hospitalized patients who needed oxygen therapy due to COVID-19 4 pneumonia were administered dexamethasone. Three patients treated with oral dexamethasone in each 5 group were excluded, and 90 patients administered intravenous dexamethasone were analyzed. Of these, 60 6 patients were administered dexamethasone at a fixed dose of 6.6 mg in the conventional-dose group, and 30 7 patients were at a dose defined based on PBW (Figure 1) . Table 1 . The number of male patients in the PBW-6 based dose group was significantly smaller than those in the conventional-dose group (85 vs. 63%, P = 0.03). 7 Three patients in PBW-based group were administered insulin therapy (10 vs. 0%, P = 0.035). Twenty-three 8 patients (40%) needed additional insulin therapy in the conventional-dose group and 13 (45%) in the PBW-9 based dose group (P = 0.65). Diabetic ketoacidosis or hyperosmolar hyperglycemic state was not reported 10 in both groups; however, infection occurred in 13 (21%) patients, namely, bacterial pneumonia (n = 11), 11 urinary tract infection (n = 1), and catheter-related bloodstream infection (n = 1), in the conventional group 12 and 2 patients (7%) had pneumonia (n = 1) and soft-tissue infection (n = 1) in PBW-based group (P = 0.082). 13

In the PBW-based dose group, 9, 13, and 8 patients were administered 6.6, 9.9, and 13.2 mg/day 14 of dexamethasone, respectively. Remdesivir was not administered due to its short supply in 20 patients. 15

Twenty-five patients (28%) were included in several clinical trials as pretreatment (e.g., favipiravir); 16 however, these trials were terminated due to worsened respiratory condition, and dexamethasone therapy 17 was initiated for meeting the criteria. 1 frequently in the PBW-based group (P = 0.0046). The length of hospital stay and duration of oxygen therapy 2 were significantly shorter in the PBW-based group (14 vs. 11 days, P = 0.023, 11 vs. 6 days, P < 0.0001, 3 respectively). alive from the hospital and shorter oxygen demand within 30 days (92 vs. 89%, log-rank P = 0.0094, 90 vs. 1 92%, log-rank P = 0.0002, respectively) (Figures 2 and 3) . 

In this historical cohort study for patients with COVID-19 pneumonia who needed oxygen therapy, 11 the PBW-based dexamethasone dose group had significantly lesser use of additional respiratory support and 12 shorter hospital stay and oxygen demand without increasing the mortality or adverse events compared to the 13 conventional dose group. To our knowledge, the utility and safety of dexamethasone therapy with dosing 14 according to PBW in patients with COVID-19 pneumonia have not been investigated. 15 The efficacy of corticosteroid therapy at the dose using mg/kg based on the actual bodyweight was 16 controversial [19]. Indeed, obesity and DM often recognized in overweight patients are the risks of severe 17 COVID-19 according to previous reports, and hyperglycemia and infection are the major concerns related 1 to the administration of corticosteroids [16, 17, 20] . Indeed, not only cytokine storm but also multiple 2 mechanisms including respiratory dysfunction, pro-thrombotic environment, blocked autophagy, and fat 3 deposition due to obesity are contributing to the poor prognosis of obese patients with COVID-19 [12, 21] . 4 From these points of view, corticosteroid dosages estimated based on the actual bodyweight might be higher 5 for patients with higher BMI and leads to poor outcomes. 6 Although the pharmacokinetics of dexamethasone in patients with COVID-19 is unclear or 7 corticosteroid therapy for other viruses such as severe acute respiratory syndrome and Middle East 8 respiratory syndrome was controversial, our study revealed that the maximum dose escalation of 9 dexamethasone to 13.2 mg/day according to PBW might have beneficial therapeutic potential in patients 10 with COVID-19 pneumonia [22] . 11 The present study revealed that PBW-based dose dexamethasone was associated with less frequent use 12 of additional respiratory support and shorter length of hospital stay and oxygen demand. The course of 13 COVID-19 has been divided into three phases, which are early infection, pulmonary phase, and 14 hyperinflammation phase, including ARDS. Hypoxemia requiring oxygen therapy in the pulmonary phase 15 is a result of host hyperinflammatory response after viral response phase in the early infection [23] . Indeed, 16 glucocorticoid agents are well known to be useful in stopping the inflammatory storm, which is contributed 17 to the excessive activation of immune cells in response to viral infection, if used at the appropriate time 18 during the disease course [24, 25] . Therefore, we believe that sufficient but not excessive amount of 1 dexamethasone should be administered in the hypoxic stage demanding oxygen therapy to properly control 2 the initial host inflammation and to prevent proceeding to the next stage with severe respiratory failure and 3 ARDS and that PBW-based dose dexamethasone may be one of the therapeutic options for Using additional respiratory support including HFNC and NIV in patients with COVID-19 could be 5 aerosol-generating medical procedures (AGMP) and have a potential of transmission to healthcare workers. 6 As a treatment principle, patients with COVID-19 undergoing AGMP should be admitted to a negative 7 pressure room or single-patient room [26] . Shorter oxygen demand and hospital stay are required especially 8 during the pandemic to maintain both human and material resources [27] . Therefore, reduction of the risk 9 for additional respiratory support is very useful in a real-world situation. 10 Finally, it should be noted that our study had a small sample size and was limited because of its 11 retrospective design. Our study population was small because, according to Our World in Data, the number 12 of cumulative confirmed COVID-19 cases in Japan (0.8 million) by the end of May 2021 was much smaller 13 than that of the United Kingdom (4.5 million) or the United States (33 million), and the inclusion of more SpO2/FiO2 ratio instead of the PaO2/FiO2 ratio as indicator of respiratory failure because oxygen therapy 1 was recommended for patients with SpO2 ≤ 93% in room air according to the Japanese clinical management 2 guideline for COVID-19. Indeed, most patients were treated in the inpatient ward, not in the intensive care 3 unit, and Japan experienced a state of emergency several times because of small healthcare capacity. 4 Therefore, obtaining data on arterial blood gas for each patient was difficult. Further large-scale studies must 5 be conducted to confirm the findings of the present study because the number of patients enrolled was small, 6 which could affect the results. 7 8 5. Conclusions 9 In patients with COVID-19 pneumonia who require oxygen therapy, PBW-based dexamethasone 10 therapy may shorten the length of hospital stay and duration of oxygen therapy and risk of using additional 11 respiratory support, including HFNC, NPPV, or MV, without increasing serious adverse events or 30-day 12 mortality. However, randomized controlled studies with PBW-based dose dexamethasone are required to 13 confirm its effect. 14 

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The authors would like to thank Enago (www.enago.jp) for the English language review. 18 19 J o u r n a l P r e -p r o o f

 2 Not applicable 3 4 The datasets used and/or analyzed in the present study are available from the corresponding author upon 5 reasonable request. 6 7 The authors declare that they have no competing interests. 8

This research did not receive any specific grant from funding agencies in the public, commercial, or not-10 for-profit sectors. 11 12 YH, YI, JT, and KTa contributed to the study concept and design. YS, YT, YI, KK, TK, HT, TKi, YTa, and 13