key: cord-0959526-6wtqoyl7
authors: Yaqoob, Hamid; Greenberg, Daniel; Hwang, Frank; Lee, Curtis; Vernik, David; Manglani, Ravi; Wang, Zhen; Murad, M. Hassan; Chandy, Dipak; Epelbaum, Oleg
title: Comparison of pulse‐dose and high‐dose corticosteroids with no corticosteroid treatment for COVID‐19 pneumonia in the intensive care unit
date: 2021-09-28
journal: J Med Virol
DOI: 10.1002/jmv.27351
sha: 5bd04c78fdb842876eebab2c5d93dd51dc1533a3
doc_id: 959526
cord_uid: 6wtqoyl7

Corticosteroid dosing in the range of 0.5–2 mg/kg/day of methylprednisolone equivalents has become a standard part of the management of intensive care unit (ICU) patients with COVID‐19 pneumonia based on positive results of randomized trials and a meta‐analysis. Alongside such conventional dosing, administration of 1 gm of methylprednisolone daily (pulse dosing) has also been reported in the literature with claims of favorable outcomes. Comparisons between such disparate approaches to corticosteroids for Coronavirus disease 2019 (COVID‐19) pneumonia are lacking. In this retrospective study of patients admitted to the ICU with COVID‐19 pneumonia, we compared patients treated with 0.5–2 mg/kg/day in methylprednisolone equivalents (high‐dose corticosteroids) and patients treated with 1 gm of methylprednisolone (pulse‐dose corticosteroids) to those who did not receive any corticosteroids. The endpoints of interest were hospital mortality, ICU‐free days at Day 28, and complications potentially attributable to corticosteroids. Pulse‐dose corticosteroid therapy was associated with a significant increase in ICU‐free days at Day 28 compared to no receipt: adjusted relative risk (aRR): 1.45 (95% confidence interval [CI]: 1.05–2.02; p = 0.03) and compared with high‐dose corticosteroid administration (p = 0.003). Nonetheless, receipt of high‐dose corticosteroids—but not of pulse‐dose corticosteroids—significantly reduced the odds of hospital mortality compared to no receipt: adjusted Odds ratio (aOR) 0.31 (95% CI: 0.12–0.77; p = 0.01). High‐dose corticosteroids reduced mortality compared to pulse‐dose corticosteroids (p = 0.04). Pulse‐dose corticosteroids—but not high‐dose corticosteroids—significantly increased the odds of acute kidney injury requiring renal replacement therapy compared to no receipt: aOR 3.53 (95% CI: 1.27–9.82; p = 0.02). The odds of this complication were also significantly higher in the pulse‐dose group when compared to the high‐dose group (p = 0.05 for the comparison). In this single‐center study, pulse‐dose corticosteroid therapy for COVID‐19 pneumonia in the ICU was associated with an increase in ICU‐free days but failed to impact hospital mortality, perhaps because of its association with development of severe renal failure. In line with existing trial data, the effect of high‐dose corticosteroids on mortality was favorable.

Following skepticism in the early phase of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic, corticosteroids were ultimately adopted as the standard of care for critically ill patients with coronavirus disease 2019 (COVID- 19) pneumonia after survival benefit was demonstrated by the RECOVERY randomized controlled trial (RCT) 1 and then recapitulated by a prospective meta-analysis. 2 On this basis, guideline recommendations for the critical care of COVID-19 pneumonia 3 now advocate for corticosteroid use according to the dosage studied in the RECOVERY RCT: dexamethasone 6 mg daily, which translates to 32 mg of methylprednisolone or 40 mg of prednisone. Of the currently available major RCTs, the highest studied corticosteroid dose has been 20 mg of dexamethasone daily, 4 corresponding to 107 mg of methylprednisolone and 133 mg of prednisone. Thus, the dosing regimens used in major RCTs of corticosteroids in critical pneumonia are in the approximate range of 0.5-2 mg/kg/day in methylprednisolone equivalents assuming an average-sized man weighing 70 kg and an average-sized woman weighing 50 kg. Unlike for SARS, 5 no comparison exists for SARS-CoV-2 between any such high-dose corticosteroid regimen and pulse administration of corticosteroids (i.e., ≥250 mg of methylprednisolone/day). When a pulse methylprednisolone course of 250 mg daily for 3 days in hospitalized patients with COVID-19 pneumonia was prospectively compared to conventional management without corticosteroids, a mortality benefit was observed. 6 As corticosteroid regimens such as dexamethasone 6 mg daily from RECOVERY have seen widespread adoption as the standard of care for COVID-19 pneumonia, comparisons of different approaches to corticosteroid administration may be possible only through turning back to the early phase of the pandemic. In the present study, we analyzed our institutional experience from the first wave of the pandemic to compare outcomes and adverse events of three distinct corticosteroid strategies in critical COVID-19 pneumonia: pulse-dose, high-dose, and no administration.

This retrospective, single-center study was performed at Westchester Medical Center (WMC) in Valhalla, New York State, a tertiary university academic center located in the New York City area, which was the first United States COVID-19 epicenter. All patients at least 18 years of age admitted to the intensive care unit (ICU) services at WMC between March 1, 2020, and May 31, 2020, with an International Classification of Diseases, 10th revision (ICD-10) diagnosis code of U07.1 (COVID-19 virus identified) were eligible for inclusion. SARS-CoV-2 infection was established via reverse-transcriptase polymerase chain reaction testing of nasopharyngeal swab specimens. Patients were excluded from consideration for the study if they met any of the following criteria:

(1) Death in the Emergency Department before transfer to the ICU (2) Primary ICU diagnosis other than COVID-19 pneumonia (incidental positivity for SARS-CoV-2) Those remaining after the application of the above initial exclusion criteria were screened for receipt of what for the purposes of this study was deemed "inappropriate" pulse administration of methylprednisolone, which was defined as either:

(A) Receipt of only a single dose of pulse corticosteroids (B) Initiation of pulse corticosteroids >48 h after admission to the ICU During the study period, WMC had no standard protocol (e.g., biomarker-based) for corticosteroid administration at any dose for ICU COVID-19 patients. However, all pulse corticosteroid recipients in the ICU were treated with uniform dosing of 1 gm/day of methylprednisolone but with variable timing and number of doses. The decision of whether to follow the pulse course with a lower-dose "tail" was left to the discretion of the clinical team. All patients who received corticosteroids at less than pulse-dose were treated with high-dose regimens corresponding to 0.5-2 mg/kg/day in methylprednisolone equivalents. The timing and duration of these regimens were likewise variable. Identification and exclusion of recipients of so-called "inappropriate" pulsing were intended to eliminate patients who received a course that was too abbreviated to be meaningful for study purposes (criterion A above) or who were pulsed out of desperation late in their illness with a low likelihood of efficacy (criterion B above).

Patients remaining after the application of the above exclusion criteria formed the study population, which was then divided into three groups according to corticosteroid dosing: no corticosteroids (control), high-dose corticosteroids, and pulse-dose corticosteroids. Relevant demographic, historical, clinical, and COVID-19 treatment characteristics of these patients were extracted from the institutional electronic medical record and tabulated. Chronic disease burden was summarized using the Charlson Comorbidity Index; 6 critical illness severity was measured by the Acute Physiology and Chronic Health Evaluation IV score. 7 (1) Mean ICU-free days at Day 28.

(2) Overall hospital mortality.

The following ICU adverse events were deemed potential complications of corticosteroid therapy and were compared among the three groups as secondary outcomes:

(1) Acute kidney injury (AKI) requiring renal replacement therapy (RRT) (2) exposure to angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) as potential additional confounders was also performed. The difference between pulsedose and high-dose steroid groups was assessed using the Wald test.

A two-tailed p value ≤0.05 was considered statistically significant. Statistical analyses were conducted using Stata version 14.1 (StataCorp LLP).

The flow diagram illustrating how the final study population was obtained is depicted in Figure 1 Table 1 . Considering demographic and historical variables, the groups were significantly different with respect to age, history of CVA, CAD, history of solid organ transplantation, and ever exposure to ACEI or ARB. Considering their ICU course, the groups differed significantly with respect to the fraction of patients who were mechanically ventilated, who received vasopressors, and who underwent tracheostomy. Also different among the groups were median levels of ferritin, LDH, and CRP measured at ICU entry. Rates of receipt of azithromycin, hydroxychloroquine, and convalescent plasma were likewise different among the groups.

Finally, there was a significant difference among the groups in the rate of hospital mortality and the incidence of AKI requiring RRT.

Results of adjusted regression analyses of the outcome measures are presented in Table 2 Results of the multiple logistic regression analysis of ICU complications of interest are shown in Table 3 . The only significant difference in regard to complications was in the odds of developing AKI requiring RRT, which were increased in the pulse-dose corticosteroid group relative to no receipt of corticosteroids: aOR 3.53 (95% CI: 1.27-9.82; p = 0.02). This complication was significantly more likely to have occurred in the pulse-corticosteroid group than in the high-dose corticosteroid group (p = 0.05).

A sensitivity analysis wherein the regression model was expanded to include the additional variables of vasopressor administration and exposure to ACEI/ARB yielded a minimal change in the results for primary or secondary outcomes. It did, of note, lead to a more statistically robust association between pulse-dose corticosteroids and AKI requiring RRT when compared to high-dose corticosteroids: p value for the comparison 0.03 from 0.05. as well as concerns about unchecked viral propagation from the resultant immunosuppression. 10 The scales gradually tipped in the other direction thanks to the realization that SARS-CoV-2 may produce lung damage by igniting a destructive immune response in that organ rather than through direct viral cytopathic effects 11 also been observed empirically that the onset of AKI in COVID-19

tends to follow the evolution of lung disease. 24 

Compared to no receipt of corticosteroids, this study found no survival advantage to pulse corticosteroid dosing at a level of methylprednisolone 1 gm/day while reaffirming the survival benefit of high-dose corticosteroids in critically ill patients with COVID-19

pneumonia. When compared to each other with respect to mortality, high-dose corticosteroids emerged superior to pulse-dose corticosteroids. Pulse-dose corticosteroid use was associated with increased odds of AKI requiring RRT in this study, an intriguing finding that may account for the observed lack of survival benefit from the pulse-dose regimen despite an increase in ICU-free days.

T A B L E 2 Results of multiple logistic regression and zero-inflated Poisson regression for the outcomes of interest 

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Comparison of pulse-dose and high-dose corticosteroids with no corticosteroid treatment for COVID-19 pneumonia in the intensive care unit

The authors declare that there are no conflict of interests. 

The data that support the findings of this study are available from the corresponding author upon reasonable request.

https://orcid.org/0000-0002-1352-8811