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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, and 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 30–25%. 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 King Abdullah International Medical Research Center, 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 Identifier: NCT04475666. Registered on July 17, 2020 https://clinicaltrials.gov/ct2/show/NCT04475666

Background The COVID-19 pandemic has strained ICUs worldwide. To learn from our experience, we described the critical care response to the outbreak. Methods This is a case study of the response of the Intensive Care Department (75-bed capacity) at a tertiary-care hospital to COVID-19 pandemic, which resulted in a high number of critically ill patients. Results Between March 1 and July 31, 2020, 822 patients were admitted to the adult non-cardiac ICUs with suspected (72%)/confirmed (38%) COVID-19. At the peak of the surge, 125 critically ill patients with COVID-19 were managed on single day. To accommodate these numbers, the bed capacity of 4 ICUs was increased internally from 58 to 71 beds (+40%) by cohorting 2 patients/room in selected rooms; forty additional ICUs beds were created in 2 general wards; one cardiac ICU was converted to managed non-COVID-19 general ICU patients and one ward was used as a stepdown for COVID-19 patients. To manage respiratory failure, 53 new ICU ventilators, 90 helmets for non-invasive ventilation and 47 high-flow nasal cannula machines were added to the existing capacity. Dedicated medical teams cared for the COVID-19 patients to prevent cross-contamination. The nurse-to-patient and RT-to-patient ratio remained mostly 1:1 and 1:6, respectively. One-hundred-ten ward nurses were up-skilled to care for COVID-19 and other ICU patients using tiered staffing model. Daily executive rounds were conducted to identify patients for transfer and at least 10 beds were made available for new COVID-19 admissions/day. The consumption of PPE increased multiple fold compared with the period preceding the pandemic. Regular family visits were not allowed and families were updated daily by videoconferencing and phone calls. Conclusions Our ICU response to the COVID-19 pandemic required almost doubling ICU bed capacity and changing multiple aspects of ICU workflow to be able to care for high numbers of affected patients.

Summary 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.

We examined the association between surveillance for deep vein thrombosis (DVT) among medical-surgical critically ill patients by twice-weekly ultrasonography and 90-day all-cause mortality. This was a pre-planned sub-study of the Pneumatic Compression for Preventing Venous Thromboembolism (PREVENT) trial (Clinicaltrials.gov: NCT02040103) that compared addition of intermittent pneumatic compression (IPC) to pharmacologic prophylaxis versus pharmacologic prophylaxis alone. The surveillance group included enrolled patients in the trial, while the non-surveillance group included eligible non-enrolled patients. Using logistic regression and Cox proportional hazards models, we examined the association of surveillance with the primary outcome of 90-day mortality. Secondary outcomes were DVT and pulmonary embolism (PE). The surveillance group consisted of 1682 patients and the non-surveillance group included 383 patients. Using Cox proportional hazards model with bootstrapping, surveillance was associated with a decrease in 90-day mortality (adjusted HR 0.75; 95% CI 0.57, 0.98). Surveillance was associated with earlier diagnosis of DVT [(median 4 days (IQR 2, 10) vs. 20 days (IQR 16, 22)] and PE [median 4 days (IQR 2.5, 5) vs. 7.5 days (IQR 6.1, 28.9)]. There was an increase in diagnosis of DVT (adjusted HR 5.49; 95% CI 2.92, 13.02) with no change in frequency in diagnosis of PE (adjusted HR 0.56; 95% CI 0.19, 1.91). Twice-weekly surveillance ultrasonography was associated with an increase in DVT detection, reduction in diagnostic testing for non-lower limb DVT and PE, earlier diagnosis of DVT and PE, and lower 90-day mortality. The PREVENT trial is registered at ClinicalTrials.gov, ID: NCT02040103. Registered on 3 November 2013; Current controlled trials, ID: ISRCTN44653506. Registered on 30 October 2013.

ImportanceHelmet noninvasive ventilation has been used in patients with COVID-19 with the premise that helmet interface is more effective than mask interface in delivering prolonged treatments with high positive airway pressure, but data about its effectiveness are limited.ObjectiveTo evaluate whether helmet noninvasive ventilation compared with usual respiratory support reduces mortality in patients with acute hypoxemic respiratory failure due to COVID-19 pneumonia.Design, Setting, and ParticipantsThis was a multicenter, pragmatic, randomized clinical trial that was conducted in 8 sites in Saudi Arabia and Kuwait between February 8, 2021, and November 16, 2021. Adult patients with acute hypoxemic respiratory failure (n = 320) due to suspected or confirmed COVID-19 were included. The final follow-up date for the primary outcome was December 14, 2021.InterventionsPatients were randomized to receive helmet noninvasive ventilation (n = 159) or usual respiratory support (n = 161), which included mask noninvasive ventilation, high-flow nasal oxygen, and standard oxygen.Main Outcomes and MeasuresThe primary outcome was 28-day all-cause mortality. There were 12 prespecified secondary outcomes, including endotracheal intubation, barotrauma, skin pressure injury, and serious adverse events.ResultsAmong 322 patients who were randomized, 320 were included in the primary analysis, all of whom completed the trial. Median age was 58 years, and 187 were men (58.4%). Within 28 days, 43 of 159 patients (27.0%) died in the helmet noninvasive ventilation group compared with 42 of 161 (26.1%) in the usual respiratory support group (risk difference, 1.0% [95% CI, −8.7% to 10.6%]; relative risk, 1.04 [95% CI, 0.72-1.49]; P = .85). Within 28 days, 75 of 159 patients (47.2%) required endotracheal intubation in the helmet noninvasive ventilation group compared with 81 of 161 (50.3%) in the usual respiratory support group (risk difference, −3.1% [95% CI, −14.1% to 7.8%]; relative risk, 0.94 [95% CI, 0.75-1.17]). There were no significant differences between the 2 groups in any of the prespecified secondary end points. Barotrauma occurred in 30 of 159 patients (18.9%) in the helmet noninvasive ventilation group and 25 of 161 (15.5%) in the usual respiratory support group. Skin pressure injury occurred in 5 of 159 patients (3.1%) in the helmet noninvasive ventilation group and 10 of 161 (6.2%) in the usual respiratory support group. There were 2 serious adverse events in the helmet noninvasive ventilation group and 1 in the usual respiratory support group.Conclusions and RelevanceResults of this study suggest that helmet noninvasive ventilation did not significantly reduce 28-day mortality compared with usual respiratory support among patients with acute hypoxemic respiratory failure due to COVID-19 pneumonia. However, interpretation of the findings is limited by imprecision in the effect estimate, which does not exclude potentially clinically important benefit or harm.Trial RegistrationClinicalTrials.gov Identifier: NCT04477668

The objective of this study is to examine the IgG antibody response in critically ill patients with the Middle East respiratory syndrome (MERS) and to examine the association of early antibody response with mortality and viral clearance. We collected blood samples from 40 consecutive real-time reverse transcription-polymerase chain reaction (rRT-PCR) confirmed critically ill MERS patients on ICU days 1, 3, 7, 14 and 28. MERS-CoV antibodies were detected by enzyme-linked immunosorbent assay (ELISA), using wells coated with MERS-CoV S1 antigen. Patients were admitted to ICU after a median (Q1, Q3) of 9 (4, 13) days from onset of symptoms with an admission Sequential Organ Failure Assessment (SOFA) score of 11 (6.5, 12). Among the study cohort, 38 patients (95%) received invasive ventilation, 35 (88%) vasopressors, 21 (53%) renal replacement therapy and 17 (43%) corticosteroids. Median (Q1,Q3) ELISA optical density (OD) ratio significantly increased with time (p

Objectives In this study, we evaluated the inflammatory response in patients with severe acute respiratory infection due to the Middle East respiratory syndrome and non-Middle East respiratory syndrome and assessed the presence of distinct inflammatory subphenotypes using latent class analysis. Design Prospective cohort study. Setting A tertiary care ICU in Riyadh, Saudi Arabia. Patients Consecutive critically ill patients with laboratory-confirmed Middle East respiratory syndrome severe acute respiratory infection and non-Middle East respiratory syndrome severe acute respiratory infection. Intervention None. Measurements and main results We measured cytokines on days 1, 3, 7, and 14 of ICU stay. We included 116 patients (40 with Middle East respiratory syndrome severe acute respiratory infection and 76 with non-Middle East respiratory syndrome severe acute respiratory infection). On ICU day 1, both patients with Middle East respiratory syndrome severe acute respiratory infection and non-Middle East respiratory syndrome severe acute respiratory infection had higher levels of interleukin-3, interleukin-4, interleukin-6, interleukin-8, interleukin-17A, eotaxin, and epidermal growth factor compared with healthy controls. There were no differences in cytokines over time between patients with Middle East respiratory syndrome severe acute respiratory infection and non-Middle East respiratory syndrome severe acute respiratory infection. Using day 1 cytokine levels, latent class analysis categorized patients into two subphenotypes: subphenotype 1 (n = 74 [64%]) and subphenotype 2 (n = 42 [36%]); the latter had significantly higher levels of interleukin-1β, interleukin-1ra, interleukin-2, interleukin-6, interleukin-7, interleukin-8, interleukin-10, interleukin-12p70, interleukin-15, interleukin-17A, inducible protein-10, monocyte chemoattractant protein-1, macrophage inflammatory protein-1α, macrophage inflammatory protein-1β, tumor necrosis factor-α, granulocyte-macrophage colony-stimulating factor, granulocyte-colony stimulating factor, interferon-α, and interferon-γ. Although baseline characteristics were not different between the two subphenotypes, patients in the subphenotype 2 had higher ICU mortality compared with the subphenotype 1 (18/42 [43%] vs 17/74 [23%]; p = 0.03). Conclusions One third of critically ill patients with Middle East respiratory syndrome severe acute respiratory infection and non-Middle East respiratory syndrome severe acute respiratory infection demonstrated a subphenotype characterized by increased proinflammatory cytokines, consistent with cytokine storm. Further research is needed to examine whether immunomodulators have differential effects based on inflammatory subphenotypes.

Background: Early detection of acute kidney dysfunction (AKD) in cirrhotic patients is crucial. Urinary neutrophil gelatinase-associated lipocalin (uNGAL) has been identified as an early marker of AKD. The aim of the study was to evaluate serial uNGAL as a marker and predictor of AKD in liver cirrhosis patients. Methods: Serial uNGAL and serum creatinine (sCr) levels were measured daily during the first 6 days of admission. Furthermore, sCr levels and the estimated glomerular filtration rate (eGFR) were measured after 3 - 6 weeks. The uNGAL levels in patients with and without abnormal sCr were compared. Results: Fifty-seven consecutive cirrhotic patients were enrolled in the study. Eight of 14 patients (57%) who developed abnormal uNGAL level also had abnormal sCr level (odds ratio (OR) = 3.4, 95% CI: 0.99 - 12.03, P = 0.05). After 6 weeks, 41% of patients exhibited an abnormal uNGAL level and abnormal sCr (OR = 6.7, 95% CI: 1.55 - 28.85, P = 0.01). Area under the curve (AUROC) and the best cut-off point for highest NGAL in 6 days were 0.64 and 72.55 ng/mL, respectively. Conclusions: There is a modest association between highest uNGAL in the first 6 days of admission and sCr at week 6 in all participants. This may indicate that in cirrhotic patients, uNGAL level during the first 6 days of admission has a potential predictability for the development of high sCr and low eGFR 6 weeks later. The AUROC of 0.64 quantifies the overall ability of uNGAL to discriminate between those individuals who will have a raised sCr levels and those who will not. J Clin Med Res. 2018;10(5):419-428 doi: https://doi.org/10.14740/jocmr3366w

This study aimed to investigate the influence of using written interaction through Skype to facilitate learning English Language, It focused on using Skype as a social networking program to act as communication tool for individuals. This study combined the quantitative and qualitative methods to achieve research purposes. Quantitative data was established by using questionnaire. It designed to evaluate the student responses towards the class activity. Qualitative data attempted to analyze the conversations between students through screenshots. Thirty Korean nonnative speakers, both male and female, from Kangwon National University were randomly assigned into five groups, six students for each group. Participants attended two Skype chat sessions per week. It continued for two weeks. Every Skype chat activity spent about twenty minutes. The results of this study illustrated that Learners showed the tendency of using fragmented syntactic structures. They were able to use some of the discourse markers. In addition, a Skype Chat supported participants to recover common grammatical errors. According to SPSS analysis, there were a lot of effective aspects of using Skype for learning English. Some of them were: space of convenience and increasing the motivation between students by using the online technologies.

Rationale: The optimal nutritional strategy for critically ill adults at high nutritional risk is unclear.Objectives: To examine the effect of permissive underfeeding with full protein intake compared with standard feeding on 90-day mortality in patients with different baseline nutritional risk.Methods: This is a post hoc analysis of the PermiT (Permissive Underfeeding versus Target Enteral Feeding in Adult Critically Ill Patients) trial.Measurements and Main Results: Nutritional risk was categorized by the modified Nutrition Risk in Critically Ill score, with high nutritional risk defined as a score of 5–9 and low nutritional risk as a score of 0–4. Additional analyses were performed by categorizing patients by body mass index, prealbumin, transferrin, phosphate, urinary urea nitrogen, and nitrogen balance. Based on the Nutrition Risk in Critically Ill score, 378 of 894 (42.3%) patients were categorized as high nutritional risk and 516 of 894 (57.7%) as low nutritional risk. There was no association betw...

The objective of this study was to evaluate leptin, ghrelin, and leptin/ghrelin ratio in critically ill patients and association of leptin/ghrelin ratio with outcomes. This is a sub-study of the PermiT trial (ISRCTN68144998). A subset of 72 patients who were expected to stay &gt, 14 days in the Intensive care unit were enrolled. Blood samples were collected on days 1, 3, 5, 7, and 14. Samples were analyzed for leptin and active ghrelin in addition to other hormones. Baseline leptin/ghrelin ratio was calculated, and patients were stratified into low and high leptin/ghrelin ratio based on the median value of 236. There was a considerable variation in baseline leptin level: Median 5.22 ng/mL (Q1, Q3: 1.26, 17.60). Ghrelin level was generally low: 10.61 pg/mL (Q1, Q3: 8.62, 25.36). Patients with high leptin/ghrelin ratio compared to patients with low leptin/ghrelin ratio were older, had higher body mass index and more likely to be diabetic. There were no differences in leptin/ghrelin ratio between patients who received permissive underfeeding and standard feeding. Multivariable logistic regression analysis showed that age and body mass index were significant independent predictors of high leptin&ndash, ghrelin ratio. Leptin&ndash, ghrelin ratio was not associated with 90-day mortality or other outcomes. Age and body mass index are predictors of high leptin/ghrelin ratio. Leptin/ghrelin ratio is not affected by permissive underfeeding and is not associated with mortality

Background The objective of this study was to evaluate the effect of ribavirin and recombinant interferon (RBV/rIFN) therapy on the outcomes of critically ill patients with Middle East respiratory syndrome (MERS), accounting for time-varying confounders. Methods This is a retrospective cohort study of critically ill patients with laboratory-confirmed MERS from 14 hospitals in Saudi Arabia diagnosed between September 2012 and January 2018. We evaluated the association of RBV/rIFN with 90-day mortality and MERS coronavirus (MERS-CoV) RNA clearance using marginal structural modeling to account for baseline and time-varying confounders. Results Of 349 MERS patients, 144 (41.3%) patients received RBV/rIFN (RBV and/or rIFN-α2a, rIFN-α2b, or rIFN-β1a; none received rIFN-β1b). RBV/rIFN was initiated at a median of 2 days (Q1, Q3: 1, 3 days) from intensive care unit admission. Crude 90-day mortality was higher in patients with RBV/rIFN compared to no RBV/rIFN (106/144 [73.6%] vs 126/205 [61.5%]; P = .02]. After adjusting for baseline and time-varying confounders using a marginal structural model, RBV/rIFN was not associated with changes in 90-day mortality (adjusted odds ratio, 1.03 [95% confidence interval {CI}, .73–1.44]; P = .87) or with more rapid MERS-CoV RNA clearance (adjusted hazard ratio, 0.65 [95% CI, .30–1.44]; P = .29). Conclusions In this observational study, RBV/rIFN (RBV and/or rIFN-α2a, rIFN-α2b, or rIFN-β1a) therapy was commonly used in critically ill MERS patients but was not associated with reduction in 90-day mortality or in faster MERS-CoV RNA clearance., In this observational study accounting for baseline and time-varying confounders, ribavirin and recombinant interferon (rIFN-α2a, rIFN-α2b, or rIFN-β1a) therapy was not associated with reduction in 90-day mortality or in faster MERS-CoV RNA clearance.

Objectives: The objectives of this study were to evaluate the clinical and nutritional correlates of high free fatty acids (FFAs) level in critically ill patients and the association with outcomes, and to study the effect of short-term caloric restriction (permissive underfeeding) on FFAs level during critical illness. Patients/Method: In this pre-planned sub-study of the PermiT (Permissive Underfeeding vs. Target Enteral Feeding in Adult Critically Ill Patients) trial, we included critically ill patients who were expected to stay for &ge, 14 days in the intensive care unit. We measured FFAs level on day 1, 3, 5, 7, and 14 of enrollment. Of 70 enrolled patients, 23 (32.8%) patients had high FFAs level (baseline FFAs level &gt, 0.45 mmol/L in females and &gt, 0.6 mmol/L in males). Results: Patients with high FFAs level were significantly older and more likely to be females and diabetics and they had lower ratio of partial pressure of oxygen to the fraction of inspired oxygen, higher creatinine, and higher total cholesterol levels than those with normal FFAs level. During the study period, patients with high FFAs level had higher blood glucose and required more insulin. On multivariable logistic regression analysis, the predictors of high baseline FFAs level were diabetes (adjusted odds ratio (aOR): 5.36, 95% confidence interval (CI): 1.56, 18.43, p = 0.008) and baseline cholesterol level (aOR, 4.29, 95% CI: 11.64, 11.19, p = 0.003). Serial levels of FFAs did not differ with time between permissive underfeeding and standard feeding groups. FFAs level was not associated with 90-day mortality (aOR: 0.49, 95% CI: 0.09, 2.60, p = 0.40). Conclusion: We conclude that high FFAs level in critically ill patients is associated with features of metabolic syndrome and is not affected by short-term permissive underfeeding.

Efficacy testing will be challenging because of the small pool of donors with sufficiently high antibody titers., We explored the feasibility of collecting convalescent plasma for passive immunotherapy of Middle East respiratory syndrome coronavirus (MERS-CoV) infection by using ELISA to screen serum samples from 443 potential plasma donors: 196 patients with suspected or laboratory-confirmed MERS-CoV infection, 230 healthcare workers, and 17 household contacts exposed to MERS-CoV. ELISA-reactive samples were further tested by indirect fluorescent antibody and microneutralization assays. Of the 443 tested samples, 12 (2.7%) had a reactive ELISA result, and 9 of the 12 had reactive indirect fluorescent antibody and microneutralization assay titers. Undertaking clinical trials of convalescent plasma for passive immunotherapy of MERS-CoV infection may be feasible, but such trials would be challenging because of the small pool of potential donors with sufficiently high antibody titers. Alternative strategies to identify convalescent plasma donors with adequate antibody titers should be explored, including the sampling of serum from patients with more severe disease and sampling at earlier points during illness.

BackgroundDuring critical illness in humans, the effects of caloric restriction on the inflammatory response are not well understood. The aim of this study is to examine the associations of caloric restriction, inflammatory response profiles and outcomes in critically ill patients.MethodsThis is a sub-study of the PermiT trial (Permissive Underfeeding or Standard Enteral Feeding in Critically Ill Adults Trial- ISRCTN68144998). Serum samples were collected on study days 1, 3, 5, 7 and 14 and analyzed for a panel of 29 cytokines. We used principal component analysis to convert possibly correlated variables (cytokine levels) into a limited number of linearly uncorrelated variables (principal components). We constructed repeated measures mixed linear models to assess whether permissive underfeeding compared to standard feeding was associated with difference cytokine levels over time.ResultsA total of 72 critically ill patients were enrolled in this study (permissive underfeeding n = 36 and standard feeding n = 36). Principal component analysis identified 6 components that were responsible for 78% of the total variance. When adjusted to principal components, permissive underfeeding was not associated with 90-day mortality (adjusted odds ratio 1.75, 95% confidence interval 0.44, 6.95, p = 0.43) or with incident renal replacement therapy. The cytokines did not differ with time between permissive underfeeding and standard feeding groups.ConclusionsThe association of permissive underfeeding compared to standard feeding with mortality was not influenced by the inflammatory profile. Permissive underfeeding compared to standard feeding was not associated with differences in the serum levels of cytokines in critically ill patients.

The effect of short-term caloric restriction on gene expression in critically ill patients has not been studied. In this sub-study of the PermiT trial (Permissive Underfeeding or Standard Enteral Feeding in Critically Ill Adults Trial- ISRCTN68144998), we examined gene expression patterns in peripheral white blood cells (buffy coat) associated with moderate caloric restriction (permissive underfeeding) in critically ill patients compared to standard feeding. Blood samples collected on study day 1 and 14 were subjected to total RNA extraction and gene expression using microarray analysis. We enrolled 50 patients, 25 in each group. Among 1751 tested genes, 332 genes in 12 pathways were found to be significantly upregulated or downregulated between study day 1 and 14 (global p value for the pathway ≤ 0.05). Using the heatmap, the differential expression of genes from day 1 to 14 in the permissive underfeeding group was compared to the standard feeding group. We further compared gene expression signal intensity in permissive underfeeding compared standard feeding by constructing univariate and multivariate linear regression models on individual patient data. We found differential expression of several genes with permissive underfeeding, most notably those related to metabolism, autophagy and other cellular functions, indicating that moderate differences in caloric intake trigger different cellular pathways.

Abstract The MIRACLE trial (MERS-CoV Infection tReated with A Combination of Lopinavir/ritonavir and intErferon-β1b) investigates the efficacy of a combination therapy of lopinavir/ritonavir and recombinant interferon-β1b 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.

Summary Background The effect of moderate caloric enteral intake in critically ill patients with hypercapnic acute respiratory failure (HCARF) is unclear. We studied the impact of permissive underfeeding (PUF) compared with standard feeding (SF) on various HCARF outcomes. Materials and methods The PermiT trial randomized 894 patients to either PUF (40–60% caloric requirement) or SF (70–100% requirement) with similar protein intake and found no difference in mortality, mechanical ventilation (MV) duration and ventilator-free days. In this post-hoc study, we restricted analysis to mechanically-ventilated patients with HCARF (PaCO2 >45 mmHg on the first two study days) and assessed the impact of trial interventions and fat-to-carbohydrate ratio on outcomes. Results One-hundred-twenty patients had HCARF (59 PUF and 61 SF, age 53.7 ± 17.8 years, body mass index 31.1 ± 11.2 kg/m2, Acute Physiology and Chronic Health Evaluation II score 21.7 ± 7.1 and day-1 PaCO2 61 ± 16 mmHg). Caloric intake was 815 ± 270 kcal/day in PUF group and 1289 ± 407 kcal/day in SF group. The two groups had similar PaCO2 levels during ICU stay. The 90-day mortality (33.9% versus 35.6%, p = 0.85), MV duration (10.7 ± 6.8 versus 11.1 ± 8.1 days, p = 0.56) and ventilator-free days (52.9 ± 38.6 versus 51.2 ± 38.0 days, p = 0.80) were also similar in PUF and SF groups, respectively. Ventilator-free days and 90-day mortality were similar when the fat-to-carbohydrate ratio was Conclusions In patients with HCARF, SF and PUF were associated with similar PaCO2, MV duration, ventilator-free days and mortality. Fat-to-carbohydrate ratio was not associated with mortality or ventilator-free days. Trial registration ISRCTN Registry: ISRCTN68144998.

SPIRIT 2013 Checklist. (PDF 238 kb)

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-β1b (IFN-β1b) 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-β1b 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. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2427-0) contains supplementary material, which is available to authorized users.

Online supplement. (DOCX 63 kb)

SPIRIT 2013 Checklist: recommended items to address in a clinical trial protocol and related documents*. (DOC 120 kb)

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 24 h. 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.

Rationale Corticosteroid therapy is commonly used among critically ill patients with the 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 MERS ICU patients were included from 14 Saudi Arabian centers between September 2012 and October 2015. We carried out 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 Q1, 3: 1.0, 7.0) from ICU admission. Patients who received corticosteroids were more likely to receive invasive ventilation (141/151 [93.4%] vs. 121/158 [76.6%], p≤0.0001) and had higher 90-day crude mortality (112/151 [74.2%] vs. 91/158 [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% CI 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.

Objectives:To describe patient characteristics, clinical manifestations, disease course including viral replication patterns, and outcomes of critically ill patients with severe acute respiratory infection from the Middle East respiratory syndrome and to compare these features with patients with severe acute respiratory infection due to other etiologies. Design:Retrospective cohort study. Setting:Patients admitted to ICUs in 14 Saudi Arabian hospitals. Patients:Critically ill patients with laboratory-confirmed Middle East respiratory syndrome severe acute respiratory infection (n= 330) admitted between September 2012 and October 2015 were compared to consecutive critically ill patients with community-acquired severe acute respiratory infection of non–Middle East respiratory syndrome etiology (non–Middle East respiratory syndrome severe acute respiratory infection) (n= 222). Interventions:None. Measurements and Main Results:Although Middle East respiratory syndrome severe acute respiratory infection patients were younger than those with non–Middle East respiratory syndrome severe acute respiratory infection (median [quartile 1, quartile 3] 58 yr [44, 69] vs 70 [52, 78];p< 0.001), clinical presentations and comorbidities overlapped substantially. Patients with Middle East respiratory syndrome severe acute respiratory infection had more severe hypoxemic respiratory failure (PaO2/FIO2: 106 [66, 160] vs 176 [104, 252];p< 0.001) and more frequent nonrespiratory organ failure (nonrespiratory Sequential Organ Failure Assessment score: 6 [4, 9] vs 5 [3, 7];p= 0.002), thus required more frequently invasive mechanical ventilation (85.2% vs 73.0%;p< 0.001), oxygen rescue therapies (extracorporeal membrane oxygenation 5.8% vs 0.9%;p= 0.003), vasopressor support (79.4% vs 55.0%;p< 0.001), and renal replacement therapy (48.8% vs 22.1%;p< 0.001). After adjustment for potential confounding factors, Middle East respiratory syndrome was independently associated with death compared to non–Middle East respiratory syndrome severe acute respiratory infection (adjusted odds ratio, 5.87; 95% CI, 4.02–8.56;p< 0.001). Conclusions:Substantial overlap exists in the clinical presentation and comorbidities among patients with Middle East respiratory syndrome severe acute respiratory infection from other etiologies; therefore, a high index of suspicion combined with diagnostic testing is essential component of severe acute respiratory infection investigation for at-risk patients. The lack of distinguishing clinical features, the need to rely on real-time reverse transcription polymerase chain reaction from respiratory samples, variability in viral shedding duration, lack of effective therapy, and high mortality represent substantial clinical challenges and help guide ongoing clinical research efforts.

Background The optimal amount of protein intake in critically ill patients is uncertain. Objective In this post hoc analysis of the PermiT (Permissive Underfeeding vs. Target Enteral Feeding in Adult Critically Ill Patients) trial, we tested the hypothesis that higher total protein intake was associated with lower 90-d mortality and improved protein biomarkers in critically ill patients. Design In this post hoc analysis of the PermiT trial, we included patients who received enteral feeding for ≥3 consecutive days. Using the median protein intake of the cohort as a cutoff, patients were categorized into 2 groups: a higher-protein group (>0.80 g · kg-1 · d-1) and a lower-protein group (≤0.80 g · kg-1 · d-1). We developed a propensity score for receiving higher protein. Primary outcome was 90-d mortality. We also compared serial values of prealbumin, transferrin, 24-h urinary nitrogen, and 24-h nitrogen balance on days 1, 7, and 14. Results Among the 729 patients included in this analysis, the average protein intake was 0.8 ± 0.3 g · kg-1 · d-1 [1.0 ± 0.2 g · kg-1 · d-1 in the higher-protein group (n = 365) and 0.6 ± 0.2 g · kg-1 · d-1 in the lower-protein group (n = 364); P

Since September 2012, 170 confirmed infections with Middle East respiratory syndrome coronavirus (MERS-CoV) have been reported to the World Health Organization, including 72 deaths. Data on critically ill patients with MERS-CoV infection are limited.To describe the critical illness associated with MERS-CoV.Case series.3 intensive care units (ICUs) at 2 tertiary care hospitals in Saudi Arabia.12 patients with confirmed or probable MERS-CoV infection.Presenting symptoms, comorbid conditions, pulmonary and extrapulmonary manifestations, measures of severity of illness and organ failure, ICU course, and outcome are described, as are the results of surveillance of health care workers (HCWs) and patients with potential exposure.Between December 2012 and August 2013, 114 patients were tested for suspected MERS-CoV; of these, 11 ICU patients (10%) met the definition of confirmed or probable cases. Three of these patients were part of a health care-associated cluster that also included 3 HCWs. One HCW became critically ill and was the 12th patient in this case series. Median Acute Physiology and Chronic Health Evaluation II score was 28 (range, 16 to 36). All 12 patients had underlying comorbid conditions and presented with acute severe hypoxemic respiratory failure. Most patients (92%) had extrapulmonary manifestations, including shock, acute kidney injury, and thrombocytopenia. Five (42%) were alive at day 90. Of the 520 exposed HCWs, only 4 (1%) were positive.The sample size was small.MERS-CoV causes severe acute hypoxemic respiratory failure and considerable extrapulmonary organ dysfunction and is associated with high mortality. Community-acquired and health care-associated MERS-CoV infection occurs in patients with chronic comorbid conditions. The health care-associated cluster suggests that human-to-human transmission does occur with unprotected exposure.None.

Purpose: This study examined the effect of permissive underfeeding compared to target feeding and intensive insulin therapy (IIT) compared to conventional insulin therapy (CIT) on the inflammatory mediators monocyte chemoattractant protein 1 (MCP-1), soluble intercellular adhesion molecule 1 (sICAM-1), and tissue factor (TF) in critically ill patients. Methodology: This was a substudy of a 2 &times, 2 factorial design randomized controlled trial in which intensive care unit (ICU) patients were randomized into permissive underfeeding compared to target feeding groups and into IIT compared to CIT groups (ISRCTN96294863). In this substudy, we included 91 patients with almost equal numbers across randomization groups. Blood samples were collected at baseline and at days 3, 5, and 7 of an ICU stay. Linear mixed models were used to assess the differences in MCP-1, sICAM-1, and TF across randomization groups over time. Results: Baseline characteristics were balanced across randomization groups. Daily caloric intake was significantly higher in the target feeding than in the permissive underfeeding groups (P-value &lt, 0.01), and the daily insulin dose was significantly higher in the IIT than in the CIT groups (P-value &lt, 0.01). MCP-1, sICAM-1, and TF did not show any significant difference between the randomization groups, while there was a time effect for MCP-1. Baseline sequential organ failure assessment (SOFA) score and platelets had a significant effect on sICAM-1 (P-value &lt, 0.01). For TF, there was a significant association with age (P-value &lt, 0.01). Conclusions: Although it has been previously demonstrated that insulin inhibits MCP-1, sICAM-1 in critically ill patients, and TF in non-critically ill patients, our study demonstrated that IIT in critically ill patients did not affect these inflammatory mediators. Similarly, caloric intake had a negligible effect on the inflammatory mediators studied.

Objectives. We compared venous thromboembolism (VTE) prophylaxis practices and incidence in critically ill cirrhotic versus noncirrhotic patients and evaluated cirrhosis as a VTE risk factor. Methods. A cohort of 798 critically ill patients followed for the development of clinically detected VTE were categorized according to the diagnosis of cirrhosis. VTE prophylaxis practices and incidence were compared. Results. Seventy-five (9.4%) patients had cirrhosis with significantly higher INR (2.2 ± 0.9 versus 1.3 ± 0.6, P<0.0001), lower platelet counts (115,000 ± 90,000 versus 258,000 ± 155,000/μL, P<0.0001), and higher creatinine compared to noncirrhotic patients. Among cirrhotics, 31 patients received only mechanical prophylaxis, 24 received pharmacologic prophylaxis, and 20 did not have any prophylaxis. Cirrhotic patients were less likely to receive pharmacologic prophylaxis (odds ratio, 0.08; 95% confidence interval (CI), 0.04–0.14). VTE occurred in only two (2.7%) cirrhotic patients compared to 7.6% in noncirrhotic patients (P=0.11). The incidence rate was 2.2 events per 1000 patient-ICU days for cirrhotic patients and 3.6 events per 1000 patient-ICU days for noncirrhotics (incidence rate ratio, 0.61; 95% CI, 0.15–2.52). On multivariate Cox regression analysis, cirrhosis was not associated with VTE risk (hazard ratio, 0.40; 95% CI, 0.10–1.67). Conclusions. In critically ill cirrhotic patients, VTE incidence did not statistically differ from that in noncirrhotic patients.

Additional file 1: Figure S1. Sepsis Response Team Clinical Pathway. Figure S2. Sepsis Response Team Checklist. Table S1. Sepsis Response Team Policy and Procedures.

Background Venous thromboembolism (VTE) remains a common problem in critically ill patients. Pharmacologic prophylaxis is currently the standard of care based on high-level evidence from randomized controlled trials. However, limited evidence exists regarding the effectiveness of intermittent pneumatic compression (IPC) devices. The Pneumatic compREssion for preventing VENous Thromboembolism (PREVENT trial) aims to determine whether the adjunct use of IPC with pharmacologic prophylaxis compared to pharmacologic prophylaxis alone in critically ill patients reduces the risk of VTE. Methods/Design The PREVENT trial is a multicenter randomized controlled trial, which will recruit 2000 critically ill patients from over 20 hospitals in three countries. The primary outcome is the incidence of proximal lower extremity deep vein thrombosis (DVT) within 28 days after randomization. Radiologists interpreting the scans are blinded to intervention allocation, whereas the patients and caregivers are unblinded. The trial has 80 % power to detect a 3 % absolute risk reduction in proximal DVT from 7 to 4 %. Discussion The first patient was enrolled in July 2014. As of May 2015, a total of 650 patients have been enrolled from 13 centers in Saudi Arabia, Canada and Australia. The first interim analysis is anticipated in July 2016. We expect to complete recruitment by 2018. Trial registration Clinicaltrials.gov: NCT02040103 (registered on 3 November 2013). Current controlled trials: ISRCTN44653506 (registered on 30 October 2013).

Background: Nutritional support has been recognized as an essential part of intensive care unit management. However, the appropriate caloric intake for critically ill patients remains ill defined. Objective: We examined the effect of permissive underfeeding compared with that of target feeding and of intensive insulin therapy (IIT) compared with that of conventional insulin therapy (CIT) on the outcomes of critically ill patients. Design: This study had a 2 · 2 factorial, randomized, controlled design. Eligible patients were randomly assigned to permissive underfeeding or target feeding groups (caloric goal: 60‐70% compared with 90‐100% of calculated requirement, respectively) with either IIT or CIT (target blood glucose: 4.4‐6.1 compared with 10‐11.1 mmol/L, respectively). Results: Twenty-eight-day all-cause mortality was 18.3% in the permissive underfeeding group compared with 23.3% in the target feeding group (relative risk: 0.79; 95% CI: 0.48, 1.29; P = 0.34). Hospital mortality was lower in the permissive underfeeding group than in the target group (30.0% compared with 42.5%; relative risk: 0.71; 95% CI: 0.50, 0.99; P = 0.04). No significant differences in outcomes were observed between the IIT and CIT groups. Conclusion: In critically ill patients, permissive underfeeding may be associated with lower mortality rates than target feeding. This trial was registered at controlled-trials.com as ISRCTN96294863. Am J Clin Nutr 2011;93:569‐77.