COVID-19 is alternatively designated as severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) and is sometimes referred to as 2019-nCoV which is considered as a fast-spreading viral infection belonging to the Coronavirus family that is hitting the world as a new pandemic causing significant morbidities and mortalities after the first case was identified in Wuhan, China in 2019. COVID-19. [1-2]. It primarily affects the parenchymal lung tissues and specifically injuries alveolar architecture which resulting in diffuse alveolar distortion and exaggerated pro-inflammatory cells infiltration accompanied with disseminated microvascular thrombosis. [3-4]. Although most COVID-19 cases are uncomplicated with severity degree ranging from mild to moderate, up to approximately 12% of admitted hospitalized severe COVID-19 infected patients progresses into more advanced critical situation necessitating invasive mechanical ventilation due to primarily Acute Respiratory Distress Syndrome (ARDS) which clinically manifested by the low partial pressure of oxygen (PaO2) in relative to the fractional oxygen input (Fi02) [5-9].

Clinically, ARDS can be described as a multifactorial-based distressing syndrome emerging from imbalancing between pro-inflammatory/anti-inflammatory mediators with a markedly elevated number of proinflammatory   cytokines    and   chemokines which ultimately results in dysregulated hyperactive diffuse-severe systemic inflammation associated cytokine storm leading to acute hypoxemic respiratory failure dependent mechanical ventilation (MV) with high mortality (40–60%). [10] It is known that the hyper-inflammatory associated cytokine storm accompanied with other subsequential storms, including primarily the hyper-oxidative radical storm and hyper-coagulopathy thrombotic storm are the primary culprits for the mechanically ventilated critically ill COVID-19 infected patient’s mortality [11].

Although the mild COVID-19 infection cases can be managed at home with symptomatic treatment and the moderate COVID-19 infection cases are primarily managed at the hospital with various treatment modalities along with oxygen supplementation, the severe COVID-19 infected cases are usually managed on critical care units. [12-13] While there is no approved specific anti-COVID-19 drug and there are extrapolated and new emerging data regarding corticosteroids (Cs) positive clinical impacts in management mechanically ventilated critically ill patients with moderate-severe ARDS, Cs like dexamethasone and methylprednisolone are commonly used now as part of first-line drug management in these high-risk COVID-19 infected cohort via their powerful rebalancing efficacy for the distorted imbalance between hyper-inflammatory and anti-inflammatory mediators [14-15]. 

Although the clinical efficacy of Cs on COVID-19 related complications on critically ill patients remains controversial and unknown,  there has been continuously emerging data signify the interesting pulmonary damage attenuation effects via primarily there’s dual anti-inflammatory and anti-fibrotic effects, and restoring some of the downregulated glucocorticosteroid receptors. [16-17]. Based on those emerging pieces of evidence, systemic administration of Dexamethasone or Methylprednisolone, the most two commonly used systemic corticosteroids, has been proposed as a cytokine storm controller and an alternative salvage treatment tool to early avoid the SARS-CoV-2-associated mortality in these mechanically ventilated critically ill patients. [18-19] Though there are no adequate shreds of evidence to elucidate whether higher dose regimens of Cs may have superior positive clinical impacts over the standard dose regimens, this debatable point is the primary aim of our study, and accordingly we postulated that higher dose regimens of Dexamethasone (DEX HD Cohort] and Methylprednisolone [MET HD Cohort) could have a significantly higher positive clinical impact compared with standard-dose regimens of Dexamethasone [DEX SD Cohort] and Methylprednisolone (MET SD Cohort). 

A single-center, observational, retrospective study was conducted on all mechanically ventilated critically I'll COVID-19 infected patients that were admitted into the intensive care units (ICUs) of our Royal Medical Services (RMS) institutions, Jordan between April 2020 and Dec 2020. Owing to our study’s retrospective design, a signed consent form was waived. This study was approved by our institutional ethical review board (IRB). All eligible mechanically ventilated critically ill COVID-19 infected patients for this study, were admitted from other COVID-19 isolation wards and all had moderate-severe ARDS as explained numerically by persistent average Pa02 / FiO2 <200 and radiologically confirmed. Analytical variables were firstly evaluated for normality of distribution by using Kolmogorov-Smirnov Test. Normally distributed continuous variables were expressed as Mean±SD by using One-Way ANOVA Test while non-parametric categorical/ordinal variables were expressed as either Number (Percentages) by Chi Square Test or as Median (IQR) by using the Kruskal–Wallis Test by Ranks, respectively. 

All demographical, co-morbidities, biochemical, clinical, radiological, and pharmacological data were extracted from the institutional electronic system (Hakeem). Comparative variables were compared across four mechanically ventilated critically ill COVID-19 infected patients allocated cohorts (DEX SD Cohort (6 mg IV once daily), MET SD Cohort (20 mg IV twice daily), DEX HD Cohort (6 mg IV twice daily), and MET HD Cohort (40 mg IV twice daily)). Statistical analyses were performed using IBM SPSS ver. 25 (IBM Corp., Armonk, NY, USA) and P-values≤0.05 were considered statistically significant. The primary outcome of our study was to compare the major clinical impacts of admission days (ICU and overall hospital) and mortalities (early, late, and overall 28-day ICU mortality) across two investigated Cs dose regimens (SD vs HD) between two proposed Cs drugs (DEX vs MET). Other secondary endpoints were also investigated in our study, including but not excluded from, the comparison of the most commonly used validated mortality prognosticators between the four tested cohorts.

From three hundred and seventy-four (N = 374) adult and elderly admitted mechanically ventilated critically ill COVID-19 infected patients in our COVID-19 isolation ICU department at Queen Alia Military Hospital, Royal Medical Services, Amman, Jordan between May 2020 and Dec 2020, two hundred and forty-three (N = 243) were finally included in this study with sixty (N = 60), fifty (N = 50), twelve (N = 12), twenty-four (N = 24), and thirteen (N  =  13) cases were excluded from the study due to either not developing moderate-severe ARDS (persistent Pa02: FiO2<200 and radiologically confirmed), not receiving Dexamethasone or Methylprednisolone as the steroid of choice, not receiving steroidal agents at all, incompleted recruited baseline data, or incompleted recruited follow-up data, respectively. One hundred and twenty-one (N  =  121, 49.8%) of the eligible COVID-19 infected patients have received the standard doses of Dexamethasone (N  =  61, 25.1%) and Methylprednisolone (N = 60, 24.7%) which are equivalent to 6 mg IV once daily and 20 mg IV twice daily, respectively. In contrast, one hundred and twenty-two (N = 122, 50.2%) of the eligible whole tested cohort were received the higher doses of Dexamethasone (N = 63, 25.9%) and Methylprednisolone (N = 59, 24.3%) which are equivalent to 6 mg IV twice daily and 40 mg IV twice daily, respectively. 

Table 1: Mechanically Ventilated Critically Ill COVID-19 Infected Patients’ Comparative Variables and Analyzed Outcome Data between Group I (DEX SD Cohort), Group II (MET SD Cohort), Group III (DEX HD Cohort), and Group IV (MET HD Cohort)

The parametric comparative variables are presented as Mean±SD and are analyzed by using ANOVA Test. The non-parametric comparative variables are presented as either Number (Percentage) by using Chi Square Test or as Median (Range) by using Kruscal-Wallis Test.Group I (DEX SD Cohort): Mechanically ventilated critically ill COVID-19 infected patients who’s Cytokine Storm were primarily managed by the standard dose (SD) of Dexamethasone (DEX) which is equivalent to 6 mg IV once daily. Group II (MET SD Cohort): Mechanically ventilated critically ill COVID-19 infected patients who’s Cytokine Storm were primarily managed by the standard dose (SD) of Methylprednisolone (MET) which is equivalent to 20 mg IV twice daily. Group III (DEX HD Cohort): Mechanically ventilated critically ill COVID-19 infected patients who’s Cytokine Storm were primarily managed by the higher dose (HD) of Dexamethasone (DEX) which is equivalent to 6 mg IV twice daily. Group IV (MET SD Cohort): Mechanically ventilated critically ill COVID-19 infected patients who’s Cytokine Storm were primarily managed by the standard dose (HD) of Methylprednisolone (MET) which is equivalent to 40 mg IV twice daily. FiO2: Fraction of Inspired oxygen. PaO2: Partial Pressure of Oxygen. PaCO2: Partial Pressure of Carbon Dioxide. PD: Protein density. ARDS: Acute respiratory distress syndrome. GCS: Glasgow coma scale. Tavg: The average of core body temperature. T var: The variation of core body temperature. LOS: Length of stay day(s). SD: Standard dose. HD: Higher dose. DEX: Dexamethasone. MET: Methylprednisolone. Cs: Corticosteroid

Table 2: Mechanically Ventilated Critically Ill COVID-19 Infected Patients’ Comparative Variables and Analyzed Outcome Data between Group I (DEX SD Cohort), Group II (MET SD Cohort), Group III (DEX HD Cohort), and Group IV (MET HD Cohort)

The parametric comparative variables are presented as Mean±SD and are analyzed by using ANOVA Test. The non-parametric comparative variables are presented as either Number (Percentage) by using Chi Square Test or as Median (Range) by using Kruscal-Wallis Test. Group I (DEX SD Cohort): Mechanically ventilated critically ill COVID-19 infected patients who’s Cytokine Storm were primarily managed by the standard dose (SD) of Dexamethasone (DEX) which is equivalent to 6 mg IV once daily. Group II (MET SD Cohort): Mechanically ventilated critically ill COVID-19 infected patients who’s Cytokine Storm were primarily managed by the standard dose (SD) of Methylprednisolone (MET) which is equivalent to 20 mg IV twice daily. Group III (DEX HD Cohort): Mechanically ventilated critically ill COVID-19 infected patients who’s Cytokine Storm were primarily managed by the higher dose (HD) of Dexamethasone (DEX) which is equivalent to 6 mg IV twice daily. Group IV (MET SD Cohort): Mechanically ventilated critically ill COVID-19 infected patients who’s Cytokine Storm were primarily managed by the standard dose (HD) of Methylprednisolone (MET) which is equivalent to 40 mg IV twice daily. Yrs: Years. CRP: C-reactive protein.  CRP: ALB: C-reactive protein to albumin ratio. ALB: Albumin level. ARDS: Acute respiratory distress syndrome. H.ALB: Human Albumin 20%. NE: Norepinephrine. S: Significant (P-Value <0.05). NS: Non-significant (P-Value >0.05). SCr: Serum creatinine.BUN: Blood urea nitrogen.N: Number of study’s hospitalized patients. LDH: Lactate dehydrogenase. SI: Shock index. FER: Ferritin level. SD: Standard dose. HD: Higher dose. DEX: Dexamethasone. MET: Methylprednisolone. CrCl: Creatinine clearance. UO: Urine output.

The average age of our whole study cohort was 59.80±10.74 years, and the DEX Cohorts (DEX SD Cohort and DEX HD Cohort) were insignificantly older than the MET Cohorts (MET SD Cohort and MET HD Cohort) with Mean±SD of 61.55±12.18 years and 60.65±9.45 years versus 56.78±8.65 years and 59.8±11.76 years, respectively, p>0.05). Significantly, males were distributed in the study in M: F ratio of approximately 2.42: 1 [162 (66.67%) versus 67 (27.57%), respectively, p<0.05) in which 53 (86.89%), 35 (58.33%), 37 (58.73%), and 37 (62.71%) of the mechanically ventilated critically ill COVID-19 infected men were allocated into Group I (DEX SD Cohort),  Group II (MET SD Cohort), Group III [DEX HD Cohort], and Group IV (MET HD Cohort) compared to 8 (13.11%), 25 (41.67%), 26 (41.27%), and 22 (37.29%) of the mechanically ventilated critically ill COVID-19 infected women, respectively.

The primary outcome of this study (An overall 28-day ICU mortality) was detected in one hundred and thirty-six (N = 136) of the COVID-19 infected patients with an overall incidence of 55.97% during an average of 13.40±4.79 days and 19.67±6.81 days of the ICU and hospital stay days, respectively, in which it was significantly lowest in the DEX HD Cohort (27 (42.86%)) followed by MET HD Cohort (33 (55.93%)), MET SD Cohort (37 (61.67%)), and lastly by DEX SD Cohort (39 (63.93%)). Also in our study, we further subdivided the overall 28-day ICU mortality into two phases, The Early Phase (≤14 days) and the Late Phase (>14 days), for which the incidence of mortality of our eligible studied mechanically ventilated critically ill COVID-19 infected patients was significantly lower in the Early Phase compared to the Late Phase (60 (24.69%) vs 76 (31.28%), respectively, p<0.05).

Hemodynamically, the shock index (SI) is significantly lower in the MET Cohorts [MET HD Cohort and MET SD Cohort] compared with DEX Cohorts [DEX HD Cohort and DEX SD Cohort] with Mean±SD of (1.12±0.03 bpm/mmHg and 1.22±0.04 bpm/mmHg) vs (1.29±0.17 bpm/mmHg and 1.31±0.23 bpm/mmHg) even though there was a statistically insignificant difference regarding Norepinephrine (NE) rate across the aforementioned cohorts (9.01±1.67 mcg/min and 9.94±1.89 mcg/min)  vs (9.27±1.68 mcg/min and 9.55±2.49 mcg/min), respectively. Biochemically, the diagnostic and prognostic biochemical indicators of c-reactive protein (CRP), ferritin (FER), lactate dehydrogenase (LDH), and D-Dimer had significant;y distributed values in order that matched the overall 28-day ICU mortality in which the DEX HD Cohort had the lowest significant values and the DEX SD Cohort had the highest significant values (88.38±34.38 mg/dl, 465.8±154.1 ng/ml, 234.6±34.2 IU/ml, and 0.58±0.21 mg/l, respectively, p<0.05) vs (156.55±51.88 mg/dl, 1009.9±465.9 ng/ml, 414.2±67.1 IU/l, and 0.87±0.33 mg/l, respectively, p<0.05). Also, the derivative diagnostic and prognostic ratios of CRP: ALB and FER: ALB were significantly ordered in the same aforementioned manner, DEX HD Cohort (31.92±19.06 and 176.3±76.6) < MET HD Cohort 53.76±27.09 and 293.2±107.6) <MET SD Cohort (58.71±24.91 and 346.1±112.9) <DEX SD Cohort (61.47±21.11 and 396.3±175.9), respectively, p<0.05.

Though there were insignificant differences across the four tested Group I-IV regarding average core body temperature (Tavg), (37.91±3.31 °C, 37.34±2.66 °C, 37.51±0.45 °C, and 37.40±1.53 °C, respectively, p>0.05), the daily core body temperature variation was significantly lowest in Group III (4.9%±0.7%] followed by Group IV (5.6%±2.5%), Group II (6.7%±2.4%), and lastly Group I (9.5%±2.1%). Across our tested Group I-IV, There were insignificant differences regarding the Glasgow Coma Scale (GSC), Child-Pugh Score, anthropometric body weight (BW), estimated creatinine clearance (CrCl), and the analgosedative of morphine infusion rate with an overall Median (Range) or Mean±SD of  (12 (12-13), 6 (6-8), 73.91±10.33 kg, 72.8±23.5 ml/min, and 2.46±1.74 mg/hr, respectively, p>0.05). The Mechanically ventilated critically ill COVID-19 infected patients’ comparative variables and analyzed outcome data between DEX SD Cohort (Group I), MET SD Cohort (Group II), DEX HD Cohort (Group III), and MET HD Cohort (Group IV) are fully summarized in Tables 1-2.

In this single-center retrospective-observational study which was conducted in the COVID-19 isolation critical care unit at Queen Alia Military Hospital, Jordan between May 2020 and Nov 2020, four proposed corticosteroidal dose regimens were evaluated across four mechanically ventilated critically ill COVID-19 infected patients allocated cohorts (DEX SD Cohort (6 mg IV once daily), MET SD Cohort (20 mg IV twice daily), DEX HD Cohort (6 mg IV twice daily), and MET HD Cohort (40 mg IV twice daily)). To the best of our knowledge, at least in our middle-east regions, the uniqueness of this study is primarily involved in the direct comparison of two investigated Cs (Dexamethasone vs Methylprednisolone) among two proposed dose regimens (Standard dose regimen vs higher dose regimen) in moderate-moderate ARDS affected mechanically ventilated critically ill COVID-19 infected patients regarding major clinical outcomes of admission days (ICU and overall hospital) and mortality (early, late, and 28-day overall mortality) and major valid mortality prognosticators.

In this emerging debatable issue during the corresponding outbreaks of COVID-19, therapeutic immuno-suppressive/ immuno-modulator drugs were initially proposed based on many strong knowledgeable-based rationales and theories. One of these immuno-controller drugs that are extensively and consequently being studied, including corticosteroids (Cs), especially Dexamethasone and Methylprednisolone. [20-22] Since the global outbreak of COVID-19 infection, Cs had been extensively used in advanced COVID-19 infectious cases management, specifically the ARDS affected mechanically ventilated critically ill patients with evidence of cytokine storm associated pulmonary V-Q mismatching. [23-24].

The rationales for the immuno-suppressive role of Cs in the management of COVID-19 eliciting immuno-mediated acute lung injury (ALI) are primarily based on postmortem histopathology observations. [25-27] In addition to the reported postmortem case series and afterward retrospectively or prospectively, non-randomized, and observational studies, the significant positive impacts that were investigated in the UK randomized, controlled, and open-label studies, positioned Cs therapy as the most and first evidence-based highly cost-effective therapeutic modality that most likely benefit COVID-19 infected patients with a higher severity index (SI) with expected positive clinical outcomes, including but not excluded to, improving ventilation free days (VFDs), reducing ICU and overall hospital LOS, lowering the probability of immuno-mediated associated multi-organs failure (MOF), facilitating the post-ICU recovery phase, minimizing the burden of COVID-19 associated complications, lowering the risk of early, late, and overall mortality. [28-30]

Despite the aforementioned positive outcomes expected from using Cs in moderate-severe cases, there is still uncertainty about whether a higher dose regimen (HD) of Dexamethasone or Methylprednisolone could provide a greater benefit, especially in the moderate-severe ARDS affected mechanically ventilated critically ill COVID-19, infected patients. In Villar et al. clinical trial, 277 moderate-severe ARDS affected hospitalized COVID-19 infected patients intervened with either low dose (<10 mg/day) of Dexamethasone IV [equivalent to the DEX SD that was used in our study], moderate dose (<20 mg/day) of Dexamethasone IV (equivalent to the DEX HD that was used in our study), or standard care without Cs management. The aforementioned study revealed that a low-moderate dose of Dexamethasone IV for an average Cs course time of 10 days had sizable significant positive outcomes regarding VFDs and overall ICU mortality rate. [31-32] Similarly, Our study demonstrated a mortality Cs benefits in the tested moderate-severe ARDS affected mechanically ventilated critically ill COVID-19 infected patients for the two investigated Cs (Dexamethasone and Methylprednisolone) at the two investigated dose strength (Standard dose and higher dose) over an insignificant average Cs course time of 9.33±2.87 days for which it was significantly lowest in the DEX HD Cohort (27 (42.86%)) followed by MET HD Cohort (33 (55.93%)), MET SD Cohort (37 (61.67%)), and lastly by DEX SD Cohort (39 (63.93%)). However, results for the Cs role in COVID-19 infection are inconclusive in most studies due to fact that the Cs may delay the clearance of SARS-CoV-2 and even be harmful to the treated patients if they are early used among hospitalized COVID-19 infected patients. [33-34]

Although there were insignificant differences across the Group I-IV in analgosedative requirements of Morphine and the vasopressor requirements of Norepinephrine (2.37±1.68 mg/hr and 9.55±2.49 mcg/min vs 2.26±1.85 mg/hr and 9.94±1.89 mcg/min vs 2.60±1.71 mg/hr and 9.27±1.68 mcg/min vs 2.69±1.74 mg/hr and 9.01±1.67 mcg/min, retrospectively, p>0.05), the septic shock (SI) which were significantly lower in HD Group I vs SD Group II (12.12±2.91 mcg/min vs 14.23±3.00 mcg/min, respectively, p<0.05), the shock index (SI), a bedside hemodynamic stability assessment indicator that numerically defines as heart rate (HR) over systolic blood pressure (SBP) with a normal range of 0.5 to 0.7 in healthy adults, is significantly lowest in the MET Cohorts (MET HD Cohort (1.12±0.03 bpm/mmHg) and MET SD Cohort (1.22±0.04 bpm/mmHg)) compared with DEX Cohorts (DEX HD Cohort (1.29±0.17 bpm/mmHg) and DEX SD Cohort (1.31±0.23 bpm/mmHg)), respectively, p<0.05. The significantly lower SI in MET Cohorts compared with DEX Cohorts is most likely due to higher mineralocorticoid activity for Methylprednisolone (1/2 Cortisol at equivalent dose) compared with Dexamethasone (No mineralocorticoid activity). [25]

Generally, the COVID-19 associated complications and mortality result from complex and interrelated pathology mechanistics of uncontrolled dysfunctional hyperimmunity reaction, hyperinflammatory associated cytokine storm, exaggerated positive acute phase reactants of c-reactive protein (CRP) and Ferritin (FER) levels, hyper-oxidative stress associated radical storm, and hypercoagulopathy associated thrombotic storm [36-37]. Many studies investigated the validities, utilities, performances, sensitivities, specificities, accuracies, positive and negative predictive values, and the youden’s indices for numerous proposed biochemical indicators as an early diagnosticator or prognosticator or both for COVID-19 infection.  The most commonly used prognosticators in COVID-19 infected critically ill patients either mechanically ventilated or non-intubated, including but not excluded to, CRP, FER, ratios of CRP and FER to albumin levels (CRP: ALB and FER: ALB, respectively), D-Dimer, and lactate dehydrogenase (LDH). [33-34] In this study, we demonstrated a significantly lower Mean±SD of CRP, FER, LDH, D-Dimer, CRP: ALB, and FER: ALB prognosticators in HD Cohorts compared with SD Cohorts as thoroughly described in the result section.

In conclusion, higher dose regimens of either Dexamethasone (12 mg/day) or Methylprednisolone (80 mg/day) in moderate-severe affected ARDS mechanically ventilated critically ill COVID-19 infected patients have a significantly higher positive clinical impact, including but not excluded to, admission days and mortalities compared with lower dose regimens of either Dexamethasone (6 mg/day) or Methylprednisolone (40 mg/day). Individually, Methylprednisolone 40 mg/day has superior positive clinical impacts over Dexamethasone 6 mg/day at the lower Cs level while at the higher Cs level, Dexamethasone 12 mg/day has superior positive clinical impacts over Methylprednisonole 80 mg/day. The retrospective, observational, and single center design of our study may limit the value of its conclusions. Despite these limitations, our conclusions may have an added value to the current excessively evolving controversial pieces of evidence regarding the clear role of higher versus lower dose regimens of various Cs in moderate-severe ARDS-affected COVID-19 management, especially in the mechanically ventilated critically ill cohorts.

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