Interferon Beta-1b and Lopinavir-Ritonavir for Middle East Respiratory Syndrome.

BACKGROUND: Whether combined treatment with recombinant interferon beta-1b and lopinavir-ritonavir reduces mortality among patients hospitalized with Middle East respiratory syndrome (MERS) is unclear. METHODS: We conducted a randomized, adaptive, double-blind, placebo-controlled trial that enrolled patients at nine sites in Saudi Arabia. Hospitalized adults with laboratory-confirmed MERS were randomly assigned to receive recombinant interferon beta-1b plus lopinavir-ritonavir (intervention) or placebo for 14 days. The primary outcome was 90-day all-cause mortality, with a one-sided P-value threshold of 0.025. Prespecified subgroup analyses and safety analyses were conducted. Because of the pandemic of coronavirus disease 2019, the data and safety monitoring board requested an unplanned interim analysis and subsequently recommended the termination of enrollment and the reporting of the results. RESULTS: A total of 95 patients were enrolled; 43 patients were assigned to the intervention group and 52 to the placebo group. A total of 12 patients (28%) in the intervention group and 23 (44%) in the placebo group died by day 90. The analysis of the primary outcome, with accounting for the adaptive design, yielded a risk difference of -19 percentage points (upper boundary of the 97.5% confidence interval [CI], -3; one-sided P = 0.024). In a prespecified subgroup analysis, treatment within 7 days after symptom onset led to lower 90-day mortality than use of placebo (relative risk, 0.19; 95% CI, 0.05 to 0.75), whereas later treatment did not. Serious adverse events occurred in 4 patients (9%) in the intervention group and in 10 (19%) in the placebo group. CONCLUSIONS: A combination of recombinant interferon beta-1b and lopinavir-ritonavir led to lower mortality than placebo among patients who had been hospitalized with laboratory-confirmed MERS. The effect was greatest when treatment was started within 7 days after symptom onset. (Funded by the King Abdullah International Medical Research Center; MIRACLE ClinicalTrials.gov number, NCT02845843.).

Corticosteroid Therapy for Critically Ill Patients with Middle East Respiratory Syndrome.

RATIONALE: Corticosteroid therapy is commonly used among critically ill patients with Middle East Respiratory Syndrome (MERS), but its impact on outcomes is uncertain. Analyses of observational studies often do not account for patients' clinical condition at the time of corticosteroid therapy initiation. OBJECTIVES: To investigate the association of corticosteroid therapy on mortality and on MERS coronavirus RNA clearance in critically ill patients with MERS. METHODS: ICU patients with MERs were included from 14 Saudi Arabian centers between September 2012 and October 2015. We performed marginal structural modeling to account for baseline and time-varying confounders. MEASUREMENTS AND MAIN RESULTS: Of 309 patients, 151 received corticosteroids. Corticosteroids were initiated at a median of 3.0 days (quartile 1 [Q1]-Q3, 1.0-7.0) from ICU admission. Patients who received corticosteroids were more likely to receive invasive ventilation (141 of 151 [93.4%] vs. 121 of 158 [76.6%]; P < 0.0001) and had higher 90-day crude mortality (112 of 151 [74.2%] vs. 91 of 158 [57.6%]; P = 0.002). Using marginal structural modeling, corticosteroid therapy was not significantly associated with 90-day mortality (adjusted odds ratio, 0.75; 95% confidence interval, 0.52-1.07; P = 0.12) but was associated with delay in MERS coronavirus RNA clearance (adjusted hazard ratio, 0.35; 95% CI, 0.17-0.72; P = 0.005). CONCLUSIONS: Corticosteroid therapy in patients with MERS was not associated with a difference in mortality after adjustment for time-varying confounders but was associated with delayed MERS coronavirus RNA clearance. These findings highlight the challenges and importance of adjusting for baseline and time-varying confounders when estimating clinical effects of treatments using observational studies.

Psychometric properties of the Arabic version of the confusion assessment method for the intensive care unit (CAM-ICU).

BACKGROUND: It is recommended that critically ill patients undergo routine delirium monitoring with a valid and reliable tool such as the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). However, the validity and reliability of the Arabic version of the CAM-ICU has not been investigated. Here, we test the validity and reliability of the Arabic CAM-ICU. METHODS: We conducted a psychometric study at ICUs in a tertiary-care hospital in Saudi Arabia. We recruited consecutive adult Arabic-speaking patients, who had stayed in the ICU for at least 24 hours, and had a Richmond Agitation-Sedation Scale (RASS) score ≥ - 2 at examination. Two well-trained examiners (ICU nurse and intensivist) independently assessed delirium in eligible patients with the Arabic CAM-ICU. Evaluations by the two examiners were compared with psychiatrist blind clinical assessment of delirium according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Subgroup analyses were conducted for age, invasive mechanical ventilation, and gender. RESULTS: We included 108 patients (mean age: 62.6 ± 17.6; male: 51.9%), of whom 37% were on invasive mechanical ventilation. Delirium was diagnosed in 63% of enrolled patients as per the psychiatrist clinical assessment. The Arabic CAM-ICU sensitivity was 74% (95% confidence interval [CI] = 0.63-0.84) and 56% (95%CI = 0.44-0.68) for the ICU nurse and intensivist, respectively. Specificity was 98% (95%CI = 0.93-1.0) and 92% (95%CI = 0.84-1.0), respectively. Sensitivity was greater for mechanically-ventilated patients, women, and those aged ≥65 years. Specificity was greater for those aged < 65 years, non-mechanically-ventilated patients and men. The median duration to complete the Arabic CAM-ICU was 2 min (interquartile range, 2-3) and 4.5 min (IQR, 3-5) for the ICU nurse and intensivist, respectively. Inter-rater reliability (kappa) was 0.66. CONCLUSIONS: The Arabic CAM-ICU demonstrated acceptable reliability and validity to assess delirium in Arabic-speaking ICU patients.

Computerized physician order entry of a sedation protocol is not associated with improved sedation practice or outcomes in critically ill patients.

BACKGROUND: Computerized Physician Order Entry (CPOE) analgesia-sedation protocols may improve sedation practice and patients' outcomes. We aimed to evaluate the impact of the introduction of CPOE protocol. METHODS: This was a prospective, observational cohort study of adult patients receiving mechanical ventilation, requiring intravenous infusion of analgesics and/or sedatives, and expected to stay in the intensive care unit (ICU) ≥24 h. As a quality improvement project, the study had three phases: phase 1, no protocol, July 1st to September 30th, 2010; phase 2, post implementation of CPOE protocol, October 1st to December 31st, 2010; and phase 3, revised (age, kidney and liver function adjusted) CPOE protocol, August 1st to October 31st, 2011. Multivariate analyses were performed to determine the independent predictors of mortality. RESULTS: Two hundred seventy nine patients were included (no protocol = 91, CPOE protocol = 97, revised CPOE protocol = 91). Implementation of CPOE protocol was associated with increase of the average daily dose of fentanyl (3720 ± 3286 vs. 2647 ± 2212 mcg/day; p = 0.009) and decrease of hospital length of stay (40 ± 37 vs. 63 ± 85 days, p = 0.02). The revised CPOE protocol was associated with, compared to the CPOE protocol, a decrease of the average daily dose of fentanyl (2208 ± 2115 vs. 3720 ± 3286 mcg/day, p = 0.0002) and lorazepam (0 ± 0 vs. 0.06 ± 0.26 mg/day, p = 0.04), sedation-related complications during ICU stay (3.3 % vs. 29.9 %, p <0.0001), and ICU mortality (18 % vs. 39 %, p = 0.001). The impact of the revised CPOE protocol was more evident on patients aged >70 years or with severe kidney or liver impairment. Both the original CPOE protocol and the revised CPOE protocol were not independent predictors of ICU (adjusted odds ratio [aOR] = 1.85, confidence interval [CI] = 0.90-3.78; p = 0.09; aOR = 0.70, CI = 0.32-1.53, p = 0.37; respectively) or hospital mortality (aOR = 1.12, CI = 0.57-2.21, p = 0.74; aOR = 0.80, CI = 0.40-1.59, p = 0.52; respectively). CONCLUSIONS: The implementation of a CPOE analgesia-sedation protocol was not associated with improved sedation practices or patients' outcome but with unpredicted increases of an analgesic dose. However, the revised CPOE protocol (age, kidney and liver function adjusted) was associated with improved sedation practices. This study highlights the importance of carefully evaluating the impact of changes in practice to detect unanticipated outcomes.

Embracing Paradigmatic Diversity in Nursing: The Stadium Model in Nursing.

Arguably, the quest for a central, unifying paradigm in nursing has distracted from moving disciplinary knowledge forward in an accessible, meaningful manner. In this discursive philosophical article, we uphold that multiparadigmatic research teams and diverse approaches inform effective nursing praxis. We provide an overview of our worldviews (dialectical pluralism, critical realism, humanism, and pragmatism) and their philosophical assumptions and describe how they are commensurate with nursing. We present the Stadium Model in Nursing as a metaphor to illustrate how various worldviews function like different sections of a stadium to offer diverse, yet important vantages of our nursing phenomena of interest.

Type I interferon autoantibodies in hospitalized patients with Middle East respiratory syndrome and association with outcomes and treatment effect of interferon beta-1b in MIRACLE clinical trial.

Background: Type I interferons (IFNs) are essential antiviral cytokines induced upon respiratory exposure to coronaviruses. Defects in type I IFN signaling can result in severe disease upon exposure to respiratory viral infection and are associated with worse clinical outcomes. Neutralizing autoantibodies (auto-Abs) to type I IFNs were reported as a risk factor for life-threatening COVID-19, but their presence has not been evaluated in patients with severe Middle East respiratory syndrome (MERS). Methods: We evaluated the prevalence of type I IFN auto-Abs in a cohort of hospitalized patients with MERS who were enrolled in a placebo-controlled clinical trial for treatment with IFN-ß1b and lopinavir-ritonavir (MIRACLE trial). Samples were tested for type I IFN auto-Abs using a multiplex particle-based assay. Results: Among the 62 enrolled patients, 15 (24.2%) were positive for immunoglobulin G auto-Abs for at least one subtype of type I IFNs. Auto-Abs positive patients were not different from auto-Abs negative patients in age, sex, or comorbidities. However, the majority (93.3%) of patients who were auto-Abs positive were critically ill and admitted to the ICU at the time of enrollment compared to 66% in the auto-Abs negative patients. The effect of treatment with IFN-ß1b and lopinavir-ritonavir did not significantly differ between the two groups. Conclusion: This study demonstrates the presence of type I IFN auto-Abs in hospitalized patients with MERS.

Heterogeneity of treatment effect of interferon-ß1b and lopinavir-ritonavir in patients with Middle East respiratory syndrome by cytokine levels.

Animal and human data indicate variable effects of interferons in treating coronavirus infections according to inflammatory status and timing of therapy. In this sub-study of the MIRACLE trial (MERS-CoV Infection Treated with a Combination of Lopinavir-Ritonavir and Interferon ß-1b), we evaluated the heterogeneity of treatment effect of interferon-ß1b and lopinavir-ritonavir versus placebo among hospitalized patients with MERS on 90-day mortality, according to cytokine levels and timing of therapy. We measured plasma levels of 17 cytokines at enrollment and tested the treatment effect on 90-day mortality according to cytokine levels (higher versus lower levels using the upper tertile (67%) as a cutoff point) and time to treatment (≤ 7 days versus > 7 days of symptom onset) using interaction tests. Among 70 included patients, 32 received interferon-ß1b and lopinavir-ritonavir and 38 received placebo. Interferon-ß1b and lopinavir-ritonavir reduced mortality in patients with lower IL-2, IL-8 and IL-13 plasma concentrations but not in patients with higher levels (p-value for interaction = 0.09, 0.07, and 0.05, respectively) and with early but not late therapy (p = 0.002). There was no statistically significant heterogeneity of treatment effect according to other cytokine levels. Further work is needed to evaluate whether the assessment of inflammatory status can help in identifying patients with MERS who may benefit from interferon-ß1b and lopinavir-ritonavir. Trial registration: This is a sub-study of the MIRACLE trial (ClinicalTrials.gov number, NCT02845843).

Treatment of Middle East respiratory syndrome with a combination of lopinavir/ritonavir and interferon-ß1b (MIRACLE trial): statistical analysis plan for a recursive two-stage group sequential randomized controlled trial.

The MIRACLE trial (MERS-CoV Infection tReated with A Combination of Lopinavir/ritonavir and intErferon-ß1b) investigates the efficacy of a combination therapy of lopinavir/ritonavir and recombinant interferon-ß1b provided with standard supportive care, compared to placebo provided with standard supportive care, in hospitalized patients with laboratory-confirmed MERS. The MIRACLE trial is designed as a recursive, two-stage, group sequential, multicenter, placebo-controlled, double-blind randomized controlled trial. The aim of this article is to describe the statistical analysis plan for the MIRACLE trial. The primary outcome is 90-day mortality. The primary analysis will follow the intention-to-treat principle. The MIRACLE trial is the first randomized controlled trial for MERS treatment. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02845843. Registered on 27 July 2016.

Knowledge of and attitudes toward clinical trials in Saudi Arabia: a cross-sectional study.

OBJECTIVES: Clinical trials (CTs) are considered an important method for developing new treatments and providing access to potentially effective drugs that are still under investigation. Measuring the public's knowledge of and attitudes toward CTs is important for assessing their readiness for and acceptance of human drug testing, which has previously not been assessed in the Kingdom of Saudi Arabia (KSA). The objective of this study is to explore the Saudi public's knowledge of and attitudes toward CTs as well as participation in trials to test new or approved drugs. DESIGN: Cross-sectional. SETTING: The 2016 Al Jenadriyah cultural/heritage festival in Riyadh, KSA. PARTICIPANTS: Participating booths and exhibition halls, as well as festival visitors, were approached to participate in the study. PRIMARY AND SECONDARY OUTCOME MEASURES: Knowledge of and attitudes toward CTs. RESULTS: The final number of participants was 938. The responses were converted to a percentage mean score (out of 100) for each knowledge-related response and attitude. The total mean knowledge score was 56.8±24.8 and the attitude-related score was 61.5±28.0. Although most of the participants supported testing approved or off-label and new drugs on adult and paediatric patients, only a third (30.5%) agreed that new drugs could be tested on healthy volunteers. The results indicated that gender, educational level, income, medical background, age and health insurance were independently associated with the level of knowledge of CTs. In terms of attitudes toward CTs, the factors that were independently associated were gender, educational level and medical background. CONCLUSIONS: The Saudi public has a low level of knowledge and a moderately positive attitude toward CTs. There is a moderate positive correlation between the two factors such that as knowledge of CTs increases, the Saudi public will hold more positive attitudes toward CTs.

Macrolides in critically ill patients with Middle East Respiratory Syndrome.

OBJECTIVES: Macrolides have been reported to be associated with improved outcomes in patients with viral pneumonia related to influenza and other viruses, possibly because of their immune-modulatory effects. Macrolides have frequently been used in patients with Middle East Respiratory Syndrome (MERS). This study investigated the association of macrolides with 90-day mortality and MERS coronavirus (CoV) RNA clearance in critically ill patients with MERS. METHODS: This retrospective analysis of a multicenter cohort database included 14 tertiary-care hospitals in five cities in Saudi Arabia. Multivariate logistic-regression analysis was used to determine the association of macrolide therapy with 90-day mortality, and the Cox-proportional hazard model to determine the association of macrolide therapy with MERS-CoV RNA clearance. RESULTS: Of 349 critically ill MERS patients, 136 (39%) received macrolide therapy. Azithromycin was most commonly used (97/136; 71.3%). Macrolide therapy was commonly started before the patient arrived in the intensive care unit (ICU) (51/136; 37.5%), or on day1 in ICU (53/136; 39%). On admission to ICU, the baseline characteristics of patients who received and did not receive macrolides were similar, including demographic data and sequential organ failure assessment score. However, patients who received macrolides were more likely to be admitted with community-acquired MERS (P=0.02). Macrolide therapy was not independently associated with a significant difference in 90-day mortality (adjusted odds ratio [OR]: 0.84; 95% confidence interval [CI] :0.47-1.51; P=0.56) or MERS-CoV RNA clearance (adjusted HR: 0.88; 95% CI:0.47-1.64; P=0.68). CONCLUSIONS: These findings indicate that macrolide therapy is not associated with a reduction in 90-day mortality or improvement in MERS-CoV RNA clearance.

Effect of sampling procedure on the quality control metrics of cytoscan HD array for studying cytogenetic aspects of colorectal cancer.

OBJECTIVES: The method of colorectal cancer (CRC) tissue sampling would affect its molecular profile and the downstream processing. In this study, we described the impact of CRC tissue sampling procedures on the quality control (QC) metrics of cytoscan HD array. METHODS: We employed a high-resolution cytoscan HD microarray platform to investigate the chromosomal aberrations that could be associated with CRC. We compared the tissue extraction procedures and their impact on the QC parameters from the cytoscan HD array determined by chromosome analysis software (Suite3.1). Median of absolute values of all pairwise differences (MAPD), waviness-standard deviation (Waviness-SD), and single nucleotide polymorphism QC (SNPQC) were the QC parameters that were analyzed. RESULTS: From 67 patients, we collected 843 colorectal tissues. Of these, 65.7% were obtained through endoscopic procedures, and the rest was after surgical resections. The mean transit time between tissue excision and preservation was 26 ± 15.5 and 74.6 ± 24.8 min, respectively. The tissues extracted from the surgical procedure showed mean MAPD of 0.28 ± 0.06 compared to 0.24 ± 0.06, for endoscopy, P = 0.005, degree of waviness-SD of 0.20 ± 0.1 compared to 0.2 ± 0.1, P = 0.64, and SNPQC of 9.6 ± 4.2 compared to 11.1 ± 4.6, P = 0.23. CONCLUSIONS: This report provides objective results that can help in tissue sampling intended to be used for DNA based molecular studies. Tissue collection protocol should be optimized to support microarray-analysis methods. Tissue extraction from endoscopic procedures had faster transit time and relatively better quality metrics outcome than surgical procedures. However, surgical procedures have less refusal rate, higher tissue quantity, and less negative results for malignancy.

Treatment of Middle East Respiratory Syndrome with a combination of lopinavir-ritonavir and interferon-ß1b (MIRACLE trial): study protocol for a randomized controlled trial.

BACKGROUND: It had been more than 5 years since the first case of Middle East Respiratory Syndrome coronavirus infection (MERS-CoV) was recorded, but no specific treatment has been investigated in randomized clinical trials. Results from in vitro and animal studies suggest that a combination of lopinavir/ritonavir and interferon-ß1b (IFN-ß1b) may be effective against MERS-CoV. The aim of this study is to investigate the efficacy of treatment with a combination of lopinavir/ritonavir and recombinant IFN-ß1b provided with standard supportive care, compared to treatment with placebo provided with standard supportive care in patients with laboratory-confirmed MERS requiring hospital admission. METHODS: The protocol is prepared in accordance with the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidelines. Hospitalized adult patients with laboratory-confirmed MERS will be enrolled in this recursive, two-stage, group sequential, multicenter, placebo-controlled, double-blind randomized controlled trial. The trial is initially designed to include 2 two-stage components. The first two-stage component is designed to adjust sample size and determine futility stopping, but not efficacy stopping. The second two-stage component is designed to determine efficacy stopping and possibly readjustment of sample size. The primary outcome is 90-day mortality. DISCUSSION: This will be the first randomized controlled trial of a potential treatment for MERS. The study is sponsored by King Abdullah International Medical Research Center, Riyadh, Saudi Arabia. Enrollment for this study began in November 2016, and has enrolled thirteen patients as of Jan 24-2018. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02845843 . Registered on 27 July 2016.

Profile, outcome and predictors of mortality of abdomino-pelvic trauma patients in a tertiary intensive care unit in Saudi Arabia.

INTRODUCTION: The Kingdom of Saudi Arabia (KSA) is one of countries with the world's highest number of deaths per 100,000 populations from road traffic accidents (RTAs). Numerous trauma victims sustain abdomino-pelvic injuries, which are associated with considerable morbidity and mortality. The purpose of this study was to describe profile, outcomes and predictors of mortality of patients with abdomino-pelvic trauma admitted to the intensive care unit (ICU) in a tertiary care trauma centre in Riyadh, KSA. METHODS: This was a retrospective analysis of prospectively collected ICU database. All consecutive patients older than 14 years with abdomino-pelvic trauma from March 1999 to June 2013 were included. The followings were extracted: demographics, injury severity, mechanism and type of injury, associated injuries, use of vasopressors and mechanical ventilation, and worst laboratory results in the first 24h. The primary outcome was hospital mortality. We compared profile and outcomes between survivors and non-survivors and reported predictors of mortality. RESULTS: Of the 11,374 trauma patients who were admitted to the hospital during the study period, 2120 (18.6%) patients had abdomino-pelvic injuries, out of which 702 (33.1%) patients were admitted to the ICU. The mean age was 30.7 (SD 14.4) years and the majority was male (89.5%). RTA was the most common cause of abdomino-pelvic trauma (70.4%). Pelvis (46.2%), liver (25.8%), and spleen (23.1%) were the most frequently injured organs; and chest (55.6%), head (41.9%), and lower extremities (27.5%) were the most commonly associated injuries. Mechanical ventilation was required in 89.6% with a mean duration of 9.1 (SD 9.2) days and emergency surgery was performed in 45.0% of the patients with prolonged ICU and hospital length of stay (10.8 [SD 10.8], 56.9 [SD 96.7] days; respectively). Of the 702 patients with abdomino-pelvic trauma, 115 (16.4%) patients did not survive. Associated head trauma and retroperitoneal haematoma, higher level of lactic acid on admission and ISS, and advanced age were potential risk factors for hospital mortality. CONCLUSIONS: Abdomino-pelvic injuries are common in trauma patients, affecting mainly young male victims, and are associated with significant morbidity and mortality, and resource utilisation.