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Methods
Study design
This study is related to the Saudi Critical Care Pharmacy Research (SCAPE) platform which conducted several observational studies to evaluate the safety and effectiveness of several treatments in critically ill patients. A multi-center with a retrospective cohort design of adult patients who were critically ill patients and admitted to Intensive Care Units (ICUs) with COVID-19 between March 1, 2020, and July 31, 2021, at three centers in the Kingdom of Saudi Arabia (KSA). Following patient screening based on the eligibility criteria, eligible patients were categorized into two sub-cohorts based on the timing to reach the protein target of 0.8 mg/kg/day at day three of feeding initiation (0.8 mg/kg/day vs. 0.8 mg/kg/day). Patients in the control sub-cohort were critically ill with COVID-19 and did not reach a target of protein 0.8 mg/kg/day on day three of feeding initiation. Severe acute respiratory syndrome coronavirus 2 (SARSCoV2) was confirmed using either Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) nasopharyngeal or throat swabs. All patients were followed until discharged or died during their in-hospital stay.
Study setting
The study was carried out at three medical centers in different geographic distributions within KSA. The principal center was King Abdulaziz Medical City (KAMC), a tertiary care institution in Riyadh; other centers included were King Abdullah bin Abdulaziz University Hospital (Riyadh) and Royal Commission Hospital (Jubail). Study sites were chosen based on their willingness to participate, electronic records availability, and geographic dispersion.
Study participants
Critically ill adult patients (aged 18 years) with confirmed SARSCoV2 admitted to the ICUs at three study centers were assessed for eligibility. Patients were excluded if they did not receive mechanical ventilation (MV) within 24 hours of admission, received oral feeding, or total parenteral nutrition (TPN). Additionally, patients who were designated as “Do-Not-Resuscitate,” died within the first 24 hours of ICU admission or had an ICU length of stay (LOS) one day were excluded from our cohort (Figure 1).
Data collection
Variables and data were collected using the Research Electronic Data Capture (REDCap) platform hosted by the KAIMRC that included demographic data, comorbidities, laboratory, vital signs, baseline severity details of data collected could be found in the supplemental file 1.
Outcomes
The primary endpoint was AKI during ICU stay. The secondary endpoints were gastric residual volume, and re-feeding syndrome at day three of EN initiation. Additional secondary endpoints include complications during ICU stay such as liver injury and new onset atrial fibrillation, length of stay (ICU and hospital), MV duration, mortality (Outcomes definition Supplementary file 1).
Statistical analysis
Propensity score matching procedure was used to match patients who received Favipiravir (active group) to patients who did not (control group) using 1:1 ratio (Proc PS match). These PS scores were generated through propensity score analysis after considering all relevant covariates, which included the patient’s APACHE II score, baseline AKI status, MV status, inotropes/vasopressors use, baseline albumin, ferritin, INR, platelets count and the early use of Dexamethasone within 24 hours of ICU admission. A greedy nearest-neighbor matching method was used, which eventually produced the smallest within-pair difference among all available pairs with treated patients. Patients were matched only if the difference in the logits of the propensity scores for pairs of patients from the two groups was less than or equal to 0.1 times the pooled estimate of the standard deviation.
Multivariable Cox proportional hazards regression analyses were performed for the 30-day and in-hospital mortality. The proportionality assumption was assessed before fitting the cox model. Visual assessment was performed to assess the assumption by plotting a log(-log) plot and testing the correlation of scaled Schoenfeld residuals with rank-ordered time. Multivariable logistic and negative binomial regression analysis were used as appropriate for the other outcomes considered in this study. Regression analysis was performed by considering the PS score as one of the covariates in the model. The Hosmer-Lemeshow goodness-of-fit test was used to evaluate model fit. The hazard ratio (HR), odds ratios (OR), or estimates with 95% confidence intervals (CI) were reported as appropriate. No imputation was made for missing data, as the cohort of patients in our study was not derived from random selection. We considered a P-value of < 0.05 statistically significant. The SAS software was used for all statistical analyses (SAS Version 9.4, SAS Institute Inc. Cary, NC, USA).
Results
The current study included 466 critically ill patients with COVID-19, out of 1451 patients who were screened. Based on protein advancement at day 3 of feeding initiation, 353 patients (75.8 %) received protein of less than or equal 0.8 gm/kg/day (Control); while 116 patients were above 0.8 gm/kg/day. After cardinality matching with a 2:1 ratio, the control group included 192 compared with 96 patients in the active group. The median protein at starting day was 19.4 grams per kg (11.70, 28.40) with a median target calorie 1620.0 (1512.00, 1700.00).
Demographics and Clinical Characteristics
Most of the patients in our cohort were male (60.3%) with a mean age of 63.5 15.26 and a median BMI of 30.6 (26.43, 36.09). The most prevalent underlying comorbidities were hypertension (59.9%), diabetes mellitus (59.2%), dyslipidemia (26.6%), and chronic kidney disease (13.7%). Before PS matching, there were notable differences in baseline characteristics such as mechanical ventilation within 24 hours of ICU admission, platelet count, and C-reactive protein (CRP) levels, which were all significantly higher in the control group (Table 1). In terms of total calories (kcal/day), at the first day, the group administered more than 0.8 g/kg/day had a higher risk of refeeding syndrome on day 2.
On the other hand, before PS matching, the active group had higher mean age and received more nephrotoxic medications and had higher gastric residuals at the start of nutrition. After using Cardinlity PS matching, most of these differences became comparable between the two groups, except for patients who received more than or equal to 0.8 g/kg/day had a higher BMI, and a higher risk of refeeding syndrome on day 2 of starting nutrition (Table 1).
AKI and other complications during ICU stay
The crude analysis revealed that the incidence of acute kidney injury (AKI) was lower in patients who received protein more than 0.8 g/kg/day compared with the control group at day three of feeding initiation (37.5 % versus 47.9; p-value=0.09). However, it did not reach statistical significance at logistic regression (OR 0.63; CI: 0.37, 1.06; P = 0.08). However, in terms of serum creatinine were comparable between the groups before and after matching (92 % versus 92.5 %; p-value=0.95) and (96.5 % versus 96.0 %; p-value=0.94). (Table 2)
Patients who received more than 0.8 g/kg/day had a lower incidence of atrial fibrillation compared to the control group in the crude analysis (11.5% vs. 22.9%; p = 0.01) as well as in the regression analysis (OR: 0.233; 95% CI: (0.118, 0.462); P = 0.02) (refer to Table 3). Other outcomes during ICU stay, such as liver injury, aspiration, and refeeding syndrome risk, did not significantly differ between the two groups (Table 3).
30-day and In-hospital Mortality
The study found no significant differences in either 30-day mortality (49% vs. 59.2%; P = 0.15) or in-hospital mortality (55.6% vs. 64.6%; P = 0.17) in the crude analysis. Moreover, the multivariable Cox proportional hazards regression analyses did not show a statistical significance between the two groups in 30-day and in-hospital mortality (HR: 1.33, 95%CI: (0.91, 1.96), P = 0.14 and HR: 1.21, 95%CI: (0.85, 1.72), P = 0.29, respectively) (Table 2).
MV duration and LOS
Patients who received protein at day three above 0.8 g/kg/day had a non-significant longer duration of mechanical ventilation (MV) in crude analysis (20.5 vs. 18.4 days; p-value = 0.32) as well in the linear regression analysis (beta coefficient: -0.16, 95% CI: [-0.04, 0.37], P = 0.12). Additionally, the ICU and hospital length of stays (LOS) were lower between the two groups; however, it failed to reach the statistical significance (beta coefficient: -0.06, 95% CI: [-0.23, 0.11]; P = 0.51 and beta coefficient: -0.04, 95% CI: [-0.23, 0.16], P = 0.73, respectively) (Table 2).
