Statistical analysis plan for the replacing protein via enteral nutrition in a stepwise approach in critically ill patients (REPLENISH) randomized clinical trial.

BACKGROUND: The optimal amount and timing of protein intake in critically ill patients are unknown. REPLENISH (Replacing Protein via Enteral Nutrition in a Stepwise Approach in Critically Ill Patients) trial evaluates whether supplemental enteral protein added to standard enteral nutrition to achieve a high amount of enteral protein given from ICU day five until ICU discharge or ICU day 90 as compared to no supplemental enteral protein to achieve a moderate amount of enteral protein would reduce all-cause 90-day mortality in adult critically ill mechanically ventilated patients. METHODS: In this multicenter randomized trial, critically ill patients will be randomized to receive supplemental enteral protein (1.2 g/kg/day) added to standard enteral nutrition to achieve a high amount of enteral protein (range of 2-2.4 g/kg/day) or no supplemental enteral protein to achieve a moderate amount of enteral protein (0.8-1.2 g/kg/day). The primary outcome is 90-day all-cause mortality; other outcomes include functional and health-related quality-of-life assessments at 90 days. The study sample size of 2502 patients will have 80% power to detect a 5% absolute risk reduction in 90-day mortality from 30 to 25%. Consistent with international guidelines, this statistical analysis plan specifies the methods for evaluating primary and secondary outcomes and subgroups. Applying this statistical analysis plan to the REPLENISH trial will facilitate unbiased analyses of clinical data. CONCLUSION: Ethics approval was obtained from the institutional review board, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia (RC19/414/R). Approvals were also obtained from the institutional review boards of each participating institution. Our findings will be disseminated in an international peer-reviewed journal and presented at relevant conferences and meetings. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04475666 . Registered on July 17, 2020.

Prevalence of Adverse Pregnancy Outcomes in Women With and Without Gestational Diabetes Mellitus in Al-Baha Region, Saudi Arabia.

BACKGROUND: Gestational diabetes mellitus (GDM) is a condition characterized by glucose intolerance that develops during pregnancy. It is associated with adverse maternal and fetal outcomes and has long-term health implications for both the mother and the child. This study aimed to estimate the prevalence of adverse pregnancy outcomes in women with and without GDM in the Al-Baha region, Saudi Arabia. METHODS: A cross-sectional study was conducted in the Al-Baha region from April 2023 to November 2023. The study included mothers residing in the Al-Baha region who were willing to participate and had access to a social media account. A simple random sampling technique was used, and the estimated sample size was 422. A self-administered electronic questionnaire was used to collect data on socio-demographic and lifestyle factors, as well as the pregnancy outcomes of diabetic and non-diabetic mothers. Descriptive and inferential statistical analyses were performed using IBM SPSS Statistics for Windows, Version 28.0 (Released 2012; IBM Corp., Armonk, New York, United States). RESULTS: We included 422 women in the study with the majority of participants in the age group of 36-40 years(15.4%, n=74). Most participants (66.6%, n=321) had attained a university degree, and a significant proportion resided in Al-Baha City (52.3%, n=252). Maternal outcomes indicated a significant association between GDM and the development of eclampsia (OR = 8.296, 95%CI: 4.353-15.810, p < 0.001), as well as an increased risk of thyroid diseases (OR = 2.723, 95%CI: 1.428-5.193, p = 0.002). Fetal outcomes revealed a significant association between GDM and respiratory distress/lack of oxygen in newborns (OR = 2.032, 95%CI: 1.085-3.805, p = 0.024), and infants of GDM patients had a higher risk of hypoglycemia (OR = 8.099, 95%CI: 3.350-19.581, p < 0.001). CONCLUSION: We found that GDM increased the risk of complications such as eclampsia, thyroid problems, and postpartum hemorrhage. GDM was also associated with shorter pregnancy durations, higher cesarean section rates, and an increased risk of developing type 2 diabetes post pregnancy. The study emphasized the importance of comprehensive GDM therapy and monitoring.

Replacing protein via enteral nutrition in a stepwise approach in critically ill patients: the REPLENISH randomized clinical trial protocol.

BACKGROUND: Protein intake is recommended in critically ill patients to mitigate the negative effects of critical illness-induced catabolism and muscle wasting. However, the optimal dose of enteral protein remains unknown. We hypothesize that supplemental enteral protein (1.2 g/kg/day) added to standard enteral nutrition formula to achieve high amount of enteral protein (range 2-2.4 g/kg/day) given from ICU day 5 until ICU discharge or ICU day 90 as compared to no supplemental enteral protein to achieve moderate amount enteral protein (0.8-1.2 g/kg/day) would reduce all-cause 90-day mortality in adult critically ill mechanically ventilated patients. METHODS: The REPLENISH (Replacing Protein Via Enteral Nutrition in a Stepwise Approach in Critically Ill Patients) trial is an open-label, multicenter randomized clinical trial. Patients will be randomized to the supplemental protein group or the control group. Patients in both groups will receive the primary enteral formula as per the treating team, which includes a maximum protein 1.2 g/kg/day. The supplemental protein group will receive, in addition, supplemental protein at 1.2 g/kg/day starting the fifth ICU day. The control group will receive the primary formula without supplemental protein. The primary outcome is 90-day all-cause mortality. Other outcomes include functional and quality of life assessments at 90 days. The trial will enroll 2502 patients. DISCUSSION: The study has been initiated in September 2021. Interim analysis is planned at one third and two thirds of the target sample size. The study is expected to be completed by the end of 2025. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04475666 . Registered on July 17, 2020.

Tocilizumab Outcomes in Critically Ill COVID-19 Patients Admitted to the ICU and the Role of Non-Tocilizumab COVID-19-Specific Medical Therapeutics.

BACKGROUND: Tocilizumab is a monoclonal antibody proposed to manage cytokine release syndrome (CRS) associated with severe COVID-19. Previously published reports have shown that tocilizumab may improve the clinical outcomes of critically ill patients admitted to the ICU. However, no precise data about the role of other medical therapeutics concurrently used for COVID-19 on this outcome have been published. OBJECTIVES: We aimed to compare the overall outcome of critically ill COVID-19 patients admitted to the ICU who received tocilizumab with the outcome of matched patients who did not receive tocilizumab while controlling for other confounders, including medical therapeutics for critically ill patients admitted to ICUs. METHODS: A prospective, observational, multicenter cohort study was conducted among critically ill COVID-19 patients admitted to the ICU of 14 hospitals in Saudi Arabia between 1 March 2020, and October 31, 2020. Propensity-score matching was utilized to compare patients who received tocilizumab to patients who did not. In addition, the log-rank test was used to compare the 28 day hospital survival of patients who received tocilizumab with those who did not. Then, a multivariate logistic regression analysis of the matched groups was performed to evaluate the impact of the remaining concurrent medical therapeutics that could not be excluded via matching 28 day hospital survival rates. The primary outcome measure was patients' overall 28 day hospital survival, and the secondary outcomes were ICU length of stay and ICU survival to hospital discharge. RESULTS: A total of 1470 unmatched patients were included, of whom 426 received tocilizumab. The total number of propensity-matched patients was 1278. Overall, 28 day hospital survival revealed a significant difference between the unmatched non-tocilizumab group (586; 56.1%) and the tocilizumab group (269; 63.1%) (p-value = 0.016), and this difference increased even more in the propensity-matched analysis between the non-tocilizumab group (466.7; 54.6%) and the tocilizumab group (269; 63.1%) (p-value = 0.005). The matching model successfully matched the two groups' common medical therapeutics used to treat COVID-19. Two medical therapeutics remained significantly different, favoring the tocilizumab group. A multivariate logistic regression was performed for the 28 day hospital survival in the propensity-matched patients. It showed that neither steroids (OR: 1.07 (95% CI: 0.75-1.53)) (p = 0.697) nor favipiravir (OR: 1.08 (95% CI: 0.61-1.9)) (p = 0.799) remained as a predictor for an increase in 28 day survival. CONCLUSION: The tocilizumab treatment in critically ill COVID-19 patients admitted to the ICU improved the overall 28 day hospital survival, which might not be influenced by the concurrent use of other COVID-19 medical therapeutics, although further research is needed to confirm this.

Impact of a national collaborative project to improve the care of mechanically ventilated patients.

This prospective quasi-experimental study from the NASAM (National Approach to Standardize and Improve Mechanical Ventilation) collaborative assessed the impact of evidence-based practices including subglottic suctioning, daily assessment for spontaneous awakening trial (SAT), spontaneous breathing trial (SBT), head of bed elevation, and avoidance of neuromuscular blockers unless otherwise indicated. The study outcomes included VAE (primary) and intensive care unit (ICU) mortality. Changes in daily care process measures and outcomes were evaluated using repeated measures mixed modeling. The results were reported as incident rate ratio (IRR) for each additional month with 95% confidence interval (CI). A comprehensive program that included education on evidence-based practices for optimal care of mechanically ventilated patients with real-time benchmarking of daily care process measures to drive improvement in forty-two ICUs from 26 hospitals in Saudi Arabia (>27,000 days of observation). Compliance with subglottic suctioning, SAT and SBT increased monthly during the project by 3.5%, 2.1% and 1.9%, respectively (IRR 1.035, 95%CI 1.007-1.064, p = 0.0148; 1.021, 95% CI 1.010-1.032, p = 0.0003; and 1.019, 95%CI 1.009-1.029, p = 0.0001, respectively). The use of neuromuscular blockers decreased monthly by 2.5% (IRR 0.975, 95%CI 0.953-0.998, p = 0.0341). The compliance with head of bed elevation was high at baseline and did not change over time. Based on data for 83153 ventilator days, VAE rate was 15.2/1000 ventilator day (95%CI 12.6-18.1) at baseline and did not change during the project (IRR 1.019, 95%CI 0.985-1.053, p = 0.2812). Based on data for 8523 patients; the mortality was 30.4% (95%CI 27.4-33.6) at baseline, and decreased monthly during the project by 1.6% (IRR 0.984, 95%CI 0.973-0.996, p = 0.0067). A national quality improvement collaborative was associated with improvements in daily care processes. These changes were associated with a reduction in mortality but not VAEs. Registration The study is registered in clinicaltrials.gov (NCT03790150).

Machine learning decision tree algorithm role for predicting mortality in critically ill adult COVID-19 patients admitted to the ICU.

BACKGROUND: Coronavirus disease-19 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is currently a major cause of intensive care unit (ICU) admissions globally. The role of machine learning in the ICU is evolving but currently limited to diagnostic and prognostic values. A decision tree (DT) algorithm is a simple and intuitive machine learning method that provides sequential nonlinear analysis of variables. It is simple and might be a valuable tool for bedside physicians during COVID-19 to predict ICU outcomes and help in critical decision-making like end-of-life decisions and bed allocation in the event of limited ICU bed capacities. Herein, we utilized a machine learning DT algorithm to describe the association of a predefined set of variables and 28-day ICU outcome in adult COVID-19 patients admitted to the ICU. We highlight the value of utilizing a machine learning DT algorithm in the ICU at the time of a COVID-19 pandemic. METHODS: This was a prospective and multicenter cohort study involving 14 hospitals in Saudi Arabia. We included critically ill COVID-19 patients admitted to the ICU between March 1, 2020, and October 31, 2020. The predictors of 28-day ICU mortality were identified using two predictive models: conventional logistic regression and DT analyses. RESULTS: There were 1468 critically ill COVID-19 patients included in the study. The 28-day ICU mortality was 540 (36.8 %), and the 90-day mortality was 600 (40.9 %). The DT algorithm identified five variables that were integrated into the algorithm to predict 28-day ICU outcomes: need for intubation, need for vasopressors, age, gender, and PaO2/FiO2 ratio. CONCLUSION: DT is a simple tool that might be utilized in the ICU to identify critically ill COVID-19 patients who are at high risk of 28-day ICU mortality. However, further studies and external validation are still required.

Predictors of survival from Acinetobacter in Saudi Arabian intensive care units: A prospective, one-year, six-city, ten-center cohort study.

BACKGROUND: Antibiotic-resistant Acinetobacter baumannii is a continuously-emerging worldwide health crisis, with mortality rates approaching 50% in intensive care unit (ICU) patients. The objective of this study was to evaluate regional, patient-related, and organism-related predictors of survival among critically-ill patients with confirmed Acinetobacter infection. METHODS: This prospective cohort study was conducted within ten ICUs across six geographically- and climatologically-distinct cities across Saudi Arabia over 13 months. RESULTS: Of 169 patients with confirmed Acinetobacter infection enrolled in the study, 80 (47.6%) died. Survivors were statistically younger, predominantly male, more likely to be admitted for trauma, less likely to have hypertension, diabetes, or have undergone hemodialysis, and more likely to have been treated with antibiotics prior to having a positive culture for Acinetobacter, but less likely to have received an aminoglycoside. Survivors also had lower baseline APACHE II and SOFA scores and were infected with stains of Acinetobacter that had less meropenem- or colistin-resistance. Multivariate analysis identified the following independent predictors of survival: younger age, lower ICU-day#1 APACHE-II and ICU-day#3 SOFA scores, being admitted for trauma, and having no history of hemodialysis. CONCLUSIONS: Patient-related factors outweigh regional and hospital-related factors as predictors of survival among critically-ill patients with Acinetobacter infection.

Incidence, outcomes, and predictors of Acinetobacter infection in Saudi Arabian critical care units.

BACKGROUND: Acinetobacter is an increasingly-problematic organism, especially in intensive care units (ICUs). In this study, we compared its incidence, outcomes, and predictors spanning eight ICUs in five geographically and climatologically-diverse cities in Saudi Arabia. METHODS: Geographic, climatologic, hospital-related, and patient-related factors were collected prospectively on 3179 patients admitted to eight Saudi ICUs from June 2018 through June 2019. These data then underwent both bivariable and multivariable analysis, the latter vis hierarchical logistic regression to identify predictors of clinically-manifest Acinetobacter infection. RESULTS: Overall incidence of Acinetobacter infection was 3.9% (n = 124). Of these 124 infections, 122 (98.4%) were cultured as A. baumannii. Incidence ranged from 1.0 to 7.9% across the eight ICUs. On bivariable analysis, incident Acinetobacter infection was more common in university and military hospitals, in hospitals with more total beds and ICU isolation rooms, and in 2018 versus 2019, incidence steadily declining over the 13 study months. Mechanically-ventilated patients had ten-fold increased odds of infection. Adjusted (multivariable) analysis revealed the risk of clinically-manifest Acinetobacter infection to increase the longer patients were on mechanical ventilation. Increased risk also existed at certain hospitals over others, especially in university-affiliated and military hospitals, larger hospitals with more isolation rooms, and hospitals with fewer ICU beds. CONCLUSION: In our study of eight ICUs across Saudi Arabia, inter-hospital differences did appear to account for inter-hospital differences in Acinetobacter incidence rates. Patients requiring mechanical ventilation for longer periods of time were particularly at risk.

Replacing protein via enteral nutrition in a stepwise approach in critically ill patients: A pilot randomized controlled trial (REPLENISH pilot trial).

BACKGROUND AND AIMS: The optimal amount of protein intake in critically ill patients is unclear. The objective of this pilot trial is to assess the feasibility of a large randomized controlled trial testing higher versus lower protein intake in critically ill patients. METHODS: In this pilot randomized controlled trial (REPLacing Protein via Enteral Nutrition in a Stepwise ApproacH in critically ill patients: A pilot randomized controlled trial (REPLENISH pilot trial), critically ill patients underwent 2-step screening for eligibility on ICU day 1 and 5. Patients with renal disease were excluded. Eligible patients were randomized into REPLENISH group (target protein 1.8-2.2 g kg/day) and Standard group (target protein 0.8-1.0 g/kg/day) from day 6-14 after ICU admission. Dietitians adjusted caloric and protein intake throughout the study period (Day 1-14) to maintain similar caloric targets of permissive underfeeding (40-60% of estimated energy expenditure) in both study groups. RESULTS: Of 704 patients screened at 3 centers in Saudi Arabia from May 2018 to May 2019, only 63 (8.9%) were eligible and 40 (5.7% of screened) were randomized with an average of 2 patients enrolled in the trial per month. Among eligible patients, the consenting rate was high at 89%. During the intervention period, patients in the REPLENISH group (N = 21) had a modestly higher protein intake (median of 1.30 g/kg/day (Q1 Q3: 1.11, 1.57)) than those in the standard group (median of 0.77 g/kg/day (Q1 Q3: 0.57, 1.00); P = 0.0004). Only 31.4% of patients in the whole cohort had >80% of prescribed protein. The duration of daily interruption of feeding was almost 4 h in both groups. The 90-day mortality for the patient study cohort was 20.5%. Anthropometric and muscle strength measurements were performed in less than 50% of patients. CONCLUSIONS: This pilot trial highlighted several areas for improvement in the study protocol before launching a large randomized controlled trial. The restrictive eligibility criteria, the complex adjustments of protein and energy and some of the outcome measurements were identified as targets for modifications, to improve enrollment and generalizability and to enhance adherence to study interventions and measurements. TRIAL REGISTRATION: CLINICALTRIALS. GOV IDENTIFIER: NCT03480555.

Transplant-related strongyloidiasis in solid organ transplant recipients in Saudi Arabia and the Gulf Cooperation Council countries.

BACKGROUND: Strongyloidiasis is a devastating disease with a mortality rate exceeding 50% in immunocompromised patients. The disease usually results from reactivation of a latent infection in a transplant patient. Alternatively, donor-derived transmission of Strongyloides may occur. METHODS: In this review, we report a case of Strongyloides hyperinfection syndrome in a liver transplant recipient to illustrate the severity of this infection. Following this, PubMed was searched for cases of transplant-related strongyloidiasis in the Gulf Cooperation Council (GCC) countries. Demographic data, the clinical presentation of recipients, and donor information were recorded. Methods of diagnosis, treatment planning, and clinical outcomes were documented. RESULTS: A total of 12 transplant-related strongyloidiasis cases were identified. Seventy-five percent of the patients were from Saudi Arabia. Three cases from Kuwait shared common donors. All donors were deceased and native to an area endemic for Strongyloides. Five of the patients shared common donors, raising the possibility of donor-derived infection. Neither the donors nor the recipients underwent screening tests for Strongyloides. Concomitant bacteremia and/or meningitis was seen in 50% of cases (6/12). Moreover, when documented, sepsis was detected in all of the patients who died (three cases). The mortality rate in this series was high (41.7%). CONCLUSIONS: Since this is a preventable condition, early diagnosis and treatment is essential. The screening and treatment of potential transplant recipients and donors proved to be an effective preventive measure. There is a growing need for further studies and implementation of screening policies in the GCC countries to prevent this fatal infection.