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.

Incidence, diagnosis, management and outcome of acute mesenteric ischaemia: a prospective, multicentre observational study (AMESI Study).

BACKGROUND: The aim of this multicentre prospective observational study was to identify the incidence, patient characteristics, diagnostic pathway, management and outcome of acute mesenteric ischaemia (AMI). METHODS: All adult patients with clinical suspicion of AMI admitted or transferred to 32 participating hospitals from 06.06.2022 to 05.04.2023 were included. Participants who were subsequently shown not to have AMI or had localized intestinal gangrene due to strangulating bowel obstruction had only baseline and outcome data collected. RESULTS: AMI occurred in 0.038% of adult admissions in participating acute care hospitals worldwide. From a total of 705 included patients, 418 patients had confirmed AMI. In 69% AMI was the primary reason for admission, while in 31% AMI occurred after having been admitted with another diagnosis. Median time from onset of symptoms to hospital admission in patients admitted due to AMI was 24 h (interquartile range 9-48h) and time from admission to diagnosis was 6h (1-12 h). Occlusive arterial AMI was diagnosed in 231 (55.3%), venous in 73 (17.5%), non-occlusive (NOMI) in 55 (13.2%), other type in 11 (2.6%) and the subtype could not be classified in 48 (11.5%) patients. Surgery was the initial management in 242 (58%) patients, of which 59 (24.4%) underwent revascularization. Endovascular revascularization alone was carried out in 54 (13%), conservative treatment in 76 (18%) and palliative care in 46 (11%) patients. From patients with occlusive arterial AMI, revascularization was undertaken in 104 (45%), with 40 (38%) of them in one site admitting selected patients. Overall in-hospital and 90-day mortality of AMI was 49% and 53.3%, respectively, and among subtypes was lowest for venous AMI (13.7% and 16.4%) and highest for NOMI (72.7% and 74.5%). There was a high variability between participating sites for most variables studied. CONCLUSIONS: The overall incidence of AMI and AMI subtypes varies worldwide, and case ascertainment is challenging. Pre-hospital delay in presentation was greater than delays after arriving at hospital. Surgery without revascularization was the most common management approach. Nearly half of the patients with AMI died during their index hospitalization. Together, these findings suggest a need for greater awareness of AMI, and better guidance in diagnosis and management. TRIAL REGISTRATION: NCT05218863 (registered 19.01.2022).

Variation in Severity-Adjusted Resource use and Outcome for Neurosurgical Emergencies in the Intensive Care Unit.

BACKGROUND: The correlation between the standardized resource use ratio (SRUR) and standardized hospital mortality ratio (SMR) for neurosurgical emergencies is not known. We studied SRUR and SMR and the factors affecting these in patients with traumatic brain injury (TBI), nontraumatic intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH). METHODS: We extracted data of patients treated in six university hospitals in three countries (2015-2017). Resource use was measured as SRUR based on purchasing power parity-adjusted direct costs and either intensive care unit (ICU) length of stay (costSRURlength of stay) or daily Therapeutic Intervention Scoring System scores (costSRURTherapeutic Intervention Scoring System). Five a priori defined variables reflecting differences in structure and organization between the ICUs were used as explanatory variables in bivariable models, separately for the included neurosurgical diseases. RESULTS: Out of 28,363 emergency patients treated in six ICUs, 6,162 patients (22%) were admitted with a neurosurgical emergency (41% nontraumatic ICH, 23% SAH, 13% multitrauma TBI, and 23% isolated TBI). The mean costs for neurosurgical admissions were higher than for nonneurosurgical admissions, and the neurosurgical admissions corresponded to 23.6-26.0% of all direct costs related to ICU emergency admissions. A higher physician-to-bed ratio was associated with lower SMRs in the nonneurosurgical admissions but not in the neurosurgical admissions. In patients with nontraumatic ICH, lower costSRURs were associated with higher SMRs. In the bivariable models, independent organization of an ICU was associated with lower costSRURs in patients with nontraumatic ICH and isolated/multitrauma TBI but with higher SMRs in patients with nontraumatic ICH. A higher physician-to-bed ratio was associated with higher costSRURs for patients with SAH. Larger units had higher SMRs for patients with nontraumatic ICH and isolated TBI. None of the ICU-related factors were associated with costSRURs in nonneurosurgical emergency admissions. CONCLUSIONS: Neurosurgical emergencies constitute a major proportion of all emergency ICU admissions. A lower SRUR was associated with higher SMR in patients with nontraumatic ICH but not for the other diagnoses. Different organizational and structural factors seemed to affect resource use for the neurosurgical patients compared with nonneurosurgical patients. This emphasizes the importance of case-mix adjustment when benchmarking resource use and outcomes.

Diagnostic accuracy of biomarkers to detect acute mesenteric ischaemia in adult patients: a systematic review and meta-analysis.

BACKGROUND: Acute mesenteric ischaemia (AMI) is a disease with different pathophysiological mechanisms, leading to a life-threatening condition that is difficult to diagnose based solely on clinical signs. Despite widely acknowledged need for biomarkers in diagnosis of AMI, a broad systematic review on all studied biomarkers in different types of AMI is currently lacking. The aim of this study was to estimate the diagnostic accuracy of all potential biomarkers of AMI studied in humans. METHODS: A systematic literature search in PubMed, The Cochrane Library, Web of Science and Scopus was conducted in December 2022. Studies assessing potential biomarkers of AMI in (at least 10) adult patients and reporting their diagnostic accuracy were included. Meta-analyses of biomarkers' sensitivity, specificity, and positive and negative likelihood ratios were conducted. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed, and the study quality was assessed with the QUADAS-2 tool. RESULTS: Seventy-five studies including a total of 9914 patients assessed 18 different biomarkers in serum/plasma and one in urine (each reported in at least two studies), which were included in meta-analyses. None of the biomarkers reached a conclusive level for accurate prediction. The best predictive value overall (all studies with any type and stage of AMI pooled) was observed for Ischaemia-modified albumin (2 studies, sensitivity 94.7 and specificity 90.5), interleukin-6 (n = 4, 96.3 and 82.6), procalcitonin (n = 6, 80.1 and 86.7), and intestinal fatty acid-binding protein (I-FABP) measured in serum (n = 16, 73.9 and 90.5) or in urine (n = 4, 87.9 and 78.9). In assessment of transmural mesenteric ischaemia, urinary I-FABP (n = 2, 92.3 and 85.2) and D-dimer (n = 3, 87.6 and 83.6) showed moderate predictive value. Overall risk of bias was high, mainly because of selected study populations and unclear timings of the biomarker measurements after onset of symptoms. Combinations of biomarkers were rarely studied, not allowing meta-analyses. CONCLUSIONS: None of the studied biomarkers had sufficient sensitivity and specificity to diagnose AMI, although some biomarkers showed moderate predictive accuracy. Future studies should focus on timing of measurements of biomarkers, distinguishing between early stage and transmural necrosis, and between different types of AMI. Additionally, studies on combinations of biomarkers are warranted. PROSPERO registration: CRD42022379341.

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.

Acute abdominal pain at referral emergency departments: an analysis of performance of three time-dependent quality indicators.

BACKGROUND: Abdominal pain is one of the most frequent causes for emergency department (ED) visits. The quality of care and outcomes are determined by time-dependent interventions with barriers to implementation at crowded EDs. OBJECTIVES: The study aimed to analyze three prominent quality indicators (QI) including pain assessment (QI1), analgesia in patients reporting severe pain (QI2), and ED length of stay (LOS) (QI3) in adult patients requiring immediate or urgent care due to acute abdominal pain. We aimed to characterize current practice regarding pain management, and we hypothesized that extended ED LOS (≥ 360 min) is associated with poor outcomes in this cohort of ED referrals. METHODS: This is a retrospective cohort study enrolling all patients with acute abdominal pain as the main cause of ED presentation, triage category red, orange, or yellow, and age ≥ 30 years during two months period. Univariate and multivariable analyses were deployed to determine independent risk factors for QIs performance. For QI1 and QI2, compliance with the QIs were analyzed, while 30-day mortality was set as primary outcome for QI3. RESULTS: Overall, 965 patients were analyzed including 501 (52%) males with a mean age of 61.8 years. Seventeen percent (167/965) of the patients had immediate or very urgent triage category. Age ≥ 65 years, and red and orange triage categories were risk factors for non-compliance with pain assessment. Seventy four per cent of patients with severe pain (numeric rating scale ≥ 7) received analgesia during the ED visit, in median within 64 min (IQR 35-105 min). Age ≥ 65 years and need for surgical consultation were risk factors for prolonged ED stay. After adjustment to age, gender and triage category, ED LOS ≥ 360 min proved to be independent risk factor for 30-day mortality (HR 1.89, 95% CI 1.71-3.40, p = 0.034). CONCLUSION: Our investigation identified that non-compliance with pain assessment, analgesia and ED length of stay among patients presenting with abdominal pain to ED results in poor quality of care and detrimental outcomes. Our data support enhanced quality-assessment initiatives for this subset of ED patients.

Associations between elevated high-sensitive cardiac troponin t and outcomes in patients with acute abdominal pain.

PURPOSE: The purpose of this study was to determine outcomes in patients presenting to emergency department (ED) with acute abdominal pain and suspected occult myocardial injury [OMI (high-sensitive cardiac troponin T, hs-cTnT level > 14 ng/L)] without clinical signs of myocardial ischaemia. We hypothesized that OMI is a common entity associated with poor outcomes. METHODS: After institutional research ethics committee approval, a retrospective review was performed on patients subjected to extended use of hs-cTnT measurements during two months period in patients admitted to ED with a chief complaint of abdominal pain, aged 30 years or older and triaged to red, orange, or yellow categories. Primary outcomes were 30-day, six-month, and one-year mortality, respectively. Adjusted mortality rates were compared using the Cox proportional hazard regression model. RESULTS: Overall, 1000 consecutive patients were screened. A total of 375 patients were subjected to hs-cTnT measurement and 156 of them (41.6%) experienced OMI. None of the patients had acute myocardial infarction diagnosed in the ED. Patients with OMI had a significantly higher 30-day, six-month and one-year mortality compared to the normal hs-cTnT level group [12.8% (20/156) vs. 3.7% (8/219), p = 0.001, 34.0% (53/156) vs. 6.9% (15/219), p < 0.001 and 39.1% (61/156) vs. 9.1 (20/219), p < 0.001, respectively]. OMI was an independent risk factor for mortality at every time point analyzed. CONCLUSION: Our investigation noted OMI in older patients with co-morbidities and in higher triage category presenting with abdominal pain to ED, respectively. OMI is an independent risk factor for poor outcomes that warrants appropriate screening and management strategy. Our results support the use of hs-cTnT as a prognostication tool in this subgroup of ED patients.

Incidence and outcomes of acute mesenteric ischaemia: a systematic review and meta-analysis.

OBJECTIVE: To estimate the incidence of acute mesenteric ischaemia (AMI), proportions of its different forms and short-term and long-term mortality. DESIGN: Systematic review and meta-analysis. DATA SOURCES: MEDLINE (Ovid), Web of Science, Scopus and Cochrane Library were searched until 26 July 2022. ELIGIBILITY CRITERIA: Studies reporting data on the incidence and outcomes of AMI in adult populations. DATA EXTRACTION AND SYNTHESIS: Data extraction and quality assessment with modified Newcastle-Ottawa scale were performed using predeveloped standard forms. The outcomes were the incidence of AMI and its different forms in the general population and in patients admitted to hospital, and the mortality of AMI in its different forms. RESULTS: From 3064 records, 335 full texts were reviewed and 163 included in the quantitative analysis. The mean incidence of AMI was 6.2 (95% CI 1.9 to 12.9) per 100 000 person years. On average 5.0 (95% CI 3.3 to 7.1) of 10 000 hospital admissions were due to AMI. Occlusive arterial AMI was the most common form constituting 68.6% (95% CI 63.7 to 73.2) of all AMI cases, with similar proportions of embolism and thrombosis.Overall short-term mortality (in-hospital or within 30 days) of AMI was 59.6% (95% CI 55.5 to 63.6), being 68.7% (95% CI 60.8 to 74.9) in patients treated before the year 2000 and 55.0% (95% CI 45.5 to 64.1) in patients treated from 2000 onwards (p<0.05). The mid/long-term mortality of AMI was 68.2% (95% CI 60.7 to 74.9). Mortality due to mesenteric venous thrombosis was 24.6% (95% CI 17.0 to 32.9) and of non-occlusive mesenteric ischaemia 58.4% (95% CI 48.6 to 67.7). The short-term mortality of revascularised occlusive arterial AMI was 33.9% (95% CI 30.7 to 37.4). CONCLUSIONS: In adult patients, AMI is a rarely diagnosed condition with high mortality, although with improvement of treatment results over the last decades. Two thirds of AMI cases are of occlusive arterial origin with potential for better survival if revascularised. PROSPERO REGISTRATION NUMBER: CRD42021247148.

Enteral nutrition and dynamics of citrulline and intestinal fatty acid-binding protein in adult ICU patients.

BACKGROUND AND AIMS: Plasma citrulline and intestinal fatty acid binding protein (I-FABP) are biomarkers reflecting enterocyte function and intestinal mucosal injury. The aim was to describe daily dynamics of citrulline and I-FABP concentrations in association with enteral nutrition (EN) in adult ICU patients. We hypothesized that success or failure of EN is reflected by differences in citrulline and I-FABP levels at admission, as well as in daily dynamics over the first week. METHODS: The present study was a planned sub-study of the iSOFA study (ClinicalTrials.gov Identifier: NCT02613000). With delayed informed consent we included adult (18 years or older) patients admitted for unlimited care to 5 ICUs in Europe. Citrulline and I-FABP were assessed and nutritional data recorded daily during the first week of the patients' ICU stay. RESULTS: The study included 224 patients with 693 plasma samples analyzed for citrulline and 695 for I-FABP. The median ICU stay was 2 (IQR 1-4) days and 35 patients (15.6 %) stayed in the ICU for ≥ 7 days. The majority of patients (184/224; 82.1 %) received EN or oral nutrition (ON) during their ICU stay, in 164 patients (73.2 %) nutrition was started within 48 h of admission (early enteral or oral nutrition, EEN/ON). Median biomarker concentrations on admission were: citrulline 24.5 (IQR 18.1-31.7) µmol/L and I-FABP 2763 (1326-4805) pg/mL. Reference range for citrulline was 17-46 µmol/L and for I-FABP 377-2049 pg/mL. Patients with EEN/ON demonstrated an increase in citrulline concentrations over the first week in ICU unlike those not receiving EEN/ON (P = 0.049 for the mean log-citrulline values over time between groups) as well as higher average citrulline concentrations. Success of EEN/ON (80 % of caloric target achieved by day 4) was associated with citrulline values increasing from day 4, whereas a slight decrease was observed with unsuccessful EEN/ON. However, these dynamics over time were not statistically significantly different (P = 0.654). Patients with EEN/ON unexpectedly had I-FABP values higher than those without (average values for all days P = 0.004). Median I-FABP values on day 3 were higher with successful EEN/ON (646 (IQR 313-1116) vs 278 (IQR 190-701) pg/mL, P = 0.022). CONCLUSIONS: EEN/ON was associated with higher values and different dynamics of citrulline over the first week in ICU. No clear difference of measured biomarkers was seen when patients were compared according to success of EEN/ON. Our study does not allow suggesting certain thresholds of citrulline nor I-FABP that could be used for bedside decision-making with regard to EN. This study was a planned sub-study of the iSOFA study (ClinicalTrials.gov Identifier: NCT02613000).

Development of the Gastrointestinal Dysfunction Score (GIDS) for critically ill patients - A prospective multicenter observational study (iSOFA study).

BACKGROUND & AIMS: To develop a five grade score (0-4 points) for the assessment of gastrointestinal (GI) dysfunction in adult critically ill patients. METHODS: This prospective multicenter observational study enrolled consecutive adult patients admitted to 11 intensive care units in nine countries. At all sites, daily clinical data with emphasis on GI clinical symptoms were collected and intra-abdominal pressure measured. In five out of 11 sites, the biomarkers citrulline and intestinal fatty acid-binding protein (I-FABP) were measured additionally. Cox models with time-dependent scores were used to analyze associations with 28- and 90-day mortality. The models were estimated with stratification for study center. RESULTS: We included 540 patients (224 with biomarker measurements) with median age of 65 years (range 18-94), the Simplified Acute Physiology Score II score of 38 (interquartile range 26-53) points, and Sequential Organ Failure Assessment (SOFA) score of 6 (interquartile range 3-9) points at admission. Median ICU length of stay was 3 (interquartile range 1-6) days and 90-day mortality 18.9%. A new five grade Gastrointestinal Dysfunction Score (GIDS) was developed based on the rationale of the previously developed Acute GI Injury (AGI) grading. Citrulline and I-FABP did not prove their potential for scoring of GI dysfunction in critically ill. GIDS was independently associated with 28- and 90-day mortality when added to SOFA total score (HR 1.40; 95%CI 1.07-1.84 and HR 1.40; 95%CI 1.02-1.79, respectively) or to a model containing all SOFA subscores (HR 1.48; 95%CI 1.13-1.92 and HR 1.47; 95%CI 1.15-1.87, respectively), improving predictive power of SOFA score in all analyses. CONCLUSIONS: The newly developed GIDS is additive to SOFA score in prediction of 28- and 90-day mortality. The clinical usefulness of this score should be validated prospectively. TRIAL REGISTRATION: NCT02613000, retrospectively registered 24 November 2015.

Deepening of sedation with propofol has limited effect on intra-abdominal pressure - An interventional study in mechanically ventilated adult patients with intra-abdominal hypertension.

PURPOSE: To evaluate the effect of deepening of sedation on intra-abdominal pressure (IAP). METHODS: 37 adult mechanically ventilated ICU patients with intra-abdominal hypertension received a bolus dose and subsequent infusion of propofol (bolus: 1 mg/kg, infusion: 3 mg/kg/h). IAP, mean arterial pressure (MAP), abdominal perfusion pressure (APP), depth of sedation according to Richmond Agitation-Sedation Scale (RASS), respiratory parameters, and vasopressor dose were assessed after bolus and at 15, 30 and 60 min of infusion of propofol. RESULTS: Median IAP at baseline was 15 (13-16) mm Hg. During the intervention, median IAP decreased by 1 mm Hg at all time points. In 24% of patients IAP decreased by ≥3 mm Hg. Compared to baseline, MAP and APP were reduced at all time points. Deepening of sedation per RASS was achieved in 70% of patients at all time points. No changes in respiratory tidal volumes nor plateau pressures were observed. Vasopressor therapy with noradrenaline was started or increased in 43% of patients, whereas the increase in patients already receiving noradrenaline prior to the intervention was not significant. CONCLUSIONS: Deepening of sedation with propofol results in a small decrease in IAP and greater simultaneous decrease in MAP and APP, requiring increased vasopressor support in some cases.

Intra-abdominal hypertension and abdominal compartment syndrome in the critically ill liver cirrhotic patient-prevalence and clinical outcomes. A multicentric retrospective cohort study in intensive care.

BACKGROUND: Liver cirrhosis and ascites are risk factors for intra-abdominal hypertension (IAH) and abdominal compartment syndrome (ACS); however, data is scarce. We aimed to determine the prevalence of IAH/ACS in a population of critically ill cirrhotic patients with acute medical illness in intensive care and to assess for risk factors and clinical outcomes. METHODS: This was a multicentric retrospective cohort study including two general ICUs and pooled data from a multicentric study between January 2009 and October 2019. RESULTS: A total of 9,345 patients were screened, and 95 were included in the analysis. Mean age was 56.7±1.3 years, and 79% were male. Liver cirrhosis etiology included alcohol in 45.3% and alcohol plus hepatitis C virus in 9.5%. Precipitating events included infection in 26% and bleeding in 21% of cases. Mean severity score MELD and SAPS II were 26.2±9.9 and 48.5±15.3, respectively, at ICU admission. The prevalence of IAH and ACS was respectively 82.1% and 23.2% with a mean value of maximum IAP of 16.0±5.7 mmHg and IAH grades: absent 17.9%, I 26.3%, II 33.7%, III 17.9%, and IV 4.2%. Independent risk factors for IAH were alcoholic cirrhosis (p = 0.01), West-Haven score (p = 0.01), and PaO2/FiO2 ratio (p = 0.02); as well as infection (p = 0.048) for ACS. Overall, 28-day mortality was 52.6% associated with higher IAP and ACS, and independent risk factors were MELD (p = 0.001), white blood cell count (p = 0.03), PaO2/FiO2 ratio (p = 0.03), and lactate concentration (p = 0.04) at ICU admission. CONCLUSIONS: This study demonstrates a very high prevalence of IAH/ACS in the critically ill cirrhotic patient in intensive care. Increased IAP and ACS were associated with severity of disease and adverse outcomes and independent risk factors for IAH were alcoholic cirrhosis, hepatic encephalopathy and PO2/FiO2 ratio, as well as infection for ACS. Early diagnosis, prevention, and treatment of IAH/ACS might improve outcome in critically ill cirrhotic patients.

Intra-abdominal hypertension and hypoxic respiratory failure together predict adverse outcome - A sub-analysis of a prospective cohort.

PURPOSE: To assess whether the combination of intra-abdominal hypertension (IAH, intra-abdominal pressure ≥ 12 mmHg) and hypoxic respiratory failure (HRF, PaO2/FiO2 ratio < 300 mmHg) in patients receiving invasive ventilation is an independent risk factor for 90- and 28-day mortality as well as ICU- and ventilation-free days. METHODS: Mechanically ventilated patients who had blood gas analyses performed and intra-abdominal pressure measured, were included from a prospective cohort. Subgroups were defined by the absence (Group 1) or the presence of either IAH (Group 2) or HRF (Group 3) or both (Group 4). Mixed-effects regression analysis was performed. RESULTS: Ninety-day mortality increased from 16% (Group 1, n = 50) to 30% (Group 2, n = 20) and 27% (Group 3, n = 100) to 49% (Group 4, n = 142), log-rank test p < 0.001. The combination of IAH and HRF was associated with increased 90- and 28-day mortality as well as with fewer ICU- and ventilation-free days. The association with 90-day mortality was no longer present after adjustment for independent variables. However, the association with 28-day mortality, ICU- and ventilation-free days persisted after adjusting for independent variables. CONCLUSIONS: In our sub-analysis, the combination of IAH and HRF was not independently associated with 90-day mortality but independently increased the odds of 28-day mortality, and reduced the number of ICU- and ventilation-free days.

Monitoring and parenteral administration of micronutrients, phosphate and magnesium in critically ill patients: The VITA-TRACE survey.

BACKGROUND & AIMS: Despite the presumed importance of preventing and treating micronutrient and mineral deficiencies, it is still not clear how to optimize measurement and administration in critically ill patients. In order to design future comparative trials aimed at optimizing micronutrient and mineral management, an important first step is to gain insight in the current practice of micronutrient, phosphate and magnesium monitoring and administration. METHODS: Within the metabolism-endocrinology-nutrition (MEN) section of the European Society of Intensive Care Medicine (ESICM), the micronutrient working group designed a survey addressing current practice in parenteral micronutrient and mineral administration and monitoring. Invitations were sent by the ESICM research department to all ESICM members and past members. RESULTS: Three hundred thirty-four respondents completed the survey, predominantly consisting of physicians (321 [96.1%]) and participants working in Europe (262 [78.4%]). Eighty-one (24.3%) respondents reported to monitor micronutrient deficiencies through clinical signs and/or laboratory abnormalities, and 148 (44.3%) reportedly measure blood micronutrient concentrations on a routine basis. Two hundred ninety-two (87.4%) participants provided specific data on parenteral micronutrient supplementation, of whom 150 (51.4%) reported early administration of combined multivitamin and trace element preparations at least in selected patients. Among specific parenteral micronutrient preparations, thiamine (146 [50.0%]) was reported to be the most frequently administered micronutrient, followed by vitamin B complex (104 [35.6%]) and folic acid (86 [29.5%]). One hundred twenty (35.9%) and 113 (33.8%) participants reported to perform daily measurements of phosphate and magnesium, respectively, whereas 173 (59.2%) and 185 (63.4%) reported to routinely supplement these minerals parenterally. CONCLUSION: The survey revealed a wide variation in current practices of micronutrient, phosphate and magnesium measurement and parenteral administration, suggesting a risk of insufficient prevention, diagnosis and treatment of deficiencies. These results provide the context for future comparative studies, and identify areas for knowledge translation and recommendations.

Hypophosphatemia in critically ill adults and children - A systematic review.

BACKGROUND & AIMS: Phosphate is the main intracellular anion essential for numerous biological processes. Symptoms of hypophosphatemia are non-specific, yet potentially life-threatening. This systematic review process was initiated to gain a global insight into hypophosphatemia, associated morbidity and treatments. METHODS: A systematic review was conducted (PROSPERO CRD42020163191). Nine clinically relevant questions were generated, seven for adult and two for pediatric critically ill patients, and prevalence of hypophosphatemia was assessed in both groups. We identified trials through systematic searches of Medline, EMBASE, Scopus, Cochrane Central Register of Controlled Trials, CINAHL, and Web of Science. Quality assessment was performed using the Cochrane risk of bias tool for randomized controlled trials and the Newcastle-Ottawa Scale for observational studies. RESULTS: For all research questions, we identified 2727 titles in total, assessed 399 full texts, and retained 82 full texts for evidence synthesis, with 20 of them identified for several research questions. Only 3 randomized controlled trials were identified with two of them published only in abstract form, as well as 28 prospective and 31 retrospective studies, and 20 case reports. Relevant risk of bias regarding selection and comparability was identified for most of the studies. No meta-analysis could be performed. The prevalence of hypophosphatemia varied substantially in critically ill adults and children, but no study assessed consecutive admissions to intensive care. In both critically ill adults and children, several studies report that hypophosphatemia is associated with worse outcome (prolonged length of stay and the need for respiratory support, and higher mortality). However, there was insufficient evidence regarding the optimal threshold upon which hypophosphatemia becomes critical and requires treatment. We found no studies regarding the optimal frequency of phosphate measurements, and regarding the time window to correct hypophosphatemia. In adults, nutrient restriction on top of phosphate repletion in patients with refeeding syndrome may improve survival, although evidence is weak. CONCLUSIONS: Evidence on the definition, outcome and treatment of clinically relevant hypophosphatemia in critically ill adults and children is scarce and does not allow answering clinically relevant questions. High quality clinical research is crucial for the development of respective guidelines.

Remote ischaemic preconditioning influences the levels of acylcarnitines in vascular surgery: a randomised clinical trial.

BACKGROUND: Vascular surgery patients have reduced tissues` blood supply, which may lead to mitochondrial dysfunction and accumulation of acylcarnitines (ACs). It has been suggested that remote ischaemic preconditioning (RIPC) has its organ protective effect via promoting mitochondrial function. The aim of this study was to evaluate the effect of RIPC on the profile of ACs in the vascular surgery patients. METHODS: This is a randomised, sham-controlled, double-blinded, single-centre study. Patients undergoing open surgical repair of abdominal aortic aneurysm, surgical lower limb revascularisation surgery or carotid endarterectomy were recruited non-consecutively. The RIPC protocol consisting of 4 cycles of 5 min of ischaemia, followed by 5 min of reperfusion, was applied. A blood pressure cuff was used for RIPC or a sham procedure. Blood was collected preoperatively and approximately 24 h postoperatively. The profile of ACs was analysed using the AbsoluteIDQp180 kit (Biocrates Life Sciences AG, Innsbruck, Austria). RESULTS: Ninety-eight patients were recruited and randomised into the study groups and 45 patients from the RIPC group and 47 patients from the sham group were included in final analysis. There was a statistically significant difference between the groups regarding the changes in C3-OH (p = 0.023)-there was a decrease (- 0.007 µmol/L, ± 0.020 µmol/L, p = 0.0233) in the RIPC group and increase (0.002 µmol/L, ± 0.015 µmol/L, p = 0.481) in the sham group. Additionally, a decrease from baseline to 24 h after surgery (p < 0.05) was detected both in the sham and the RIPC group in the levels of following ACs: C2, C8, C10, C10:1, C12, C12:1, C14:1, C14:2, C16, C16:1, C18, C18:1, C18:2. In the sham group, there was an increase (p < 0.05) in the levels of C0 (carnitine) and a decrease in the level of C18:1-OH. In the RIPC group, a decrease (p < 0.05) was noted in the levels of C3-OH, C3-DC (C4-OH), C6:1, C9, C10:2. CONCLUSIONS: It can be concluded that RIPC may have an effect on the levels of ACs and might therefore have protective effects on mitochondria in the vascular surgery patients. Further larger studies conducted on homogenous populations are needed to make more definite conclusions about the effect of RIPC on the metabolism of ACs. TRIAL REGISTRATION: ClinicalTrials.gov database, NCT02689414. Registered 24 February 2016-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02689414.

Gastrointestinal dysfunction in the critically ill: a systematic scoping review and research agenda proposed by the Section of Metabolism, Endocrinology and Nutrition of the European Society of Intensive Care Medicine.

BACKGROUND: Gastrointestinal (GI) dysfunction is frequent in the critically ill but can be overlooked as a result of the lack of standardization of the diagnostic and therapeutic approaches. We aimed to develop a research agenda for GI dysfunction for future research. We systematically reviewed the current knowledge on a broad range of subtopics from a specific viewpoint of GI dysfunction, highlighting the remaining areas of uncertainty and suggesting future studies. METHODS: This systematic scoping review and research agenda was conducted following successive steps: (1) identify clinically important subtopics within the field of GI function which warrant further research; (2) systematically review the literature for each subtopic using PubMed, CENTRAL and Cochrane Database of Systematic Reviews; (3) summarize evidence for each subtopic; (4) identify areas of uncertainty; (5) formulate and refine study proposals that address these subtopics; and (6) prioritize study proposals via sequential voting rounds. RESULTS: Five major themes were identified: (1) monitoring, (2) associations between GI function and outcome, (3) GI function and nutrition, (4) management of GI dysfunction and (5) pathophysiological mechanisms. Searches on 17 subtopics were performed and evidence summarized. Several areas of uncertainty were identified, six of them needing consensus process. Study proposals ranked among the first ten included: prevention and management of diarrhoea; management of upper and lower feeding intolerance, including indications for post-pyloric feeding and opioid antagonists; acute gastrointestinal injury grading as a bedside tool; the role of intra-abdominal hypertension in the development and monitoring of GI dysfunction and in the development of non-occlusive mesenteric ischaemia; and the effect of proton pump inhibitors on the microbiome in critical illness. CONCLUSIONS: Current evidence on GI dysfunction is scarce, partially due to the lack of precise definitions. The use of core sets of monitoring and outcomes are required to improve the consistency of future studies. We propose several areas for consensus process and outline future study projects.

Remote Ischaemic Preconditioning Reduces Kidney Injury Biomarkers in Patients Undergoing Open Surgical Lower Limb Revascularisation: A Randomised Trial.

BACKGROUND AND AIMS: Perioperative kidney injury affects 12.7% of patients undergoing lower limb revascularisation surgery. Remote ischaemic preconditioning (RIPC) is a potentially protective procedure against organ damage and consists of short nonlethal episodes of ischaemia. The main objective of this substudy was to evaluate the effect of RIPC on kidney function, inflammation, and oxidative stress in patients undergoing open surgical lower limb revascularisation. Materials and Methods. This is a subgroup analysis of a randomised, sham-controlled, double-blinded, single-centre study. A RIPC or a sham procedure was performed noninvasively along with preparation for anaesthesia in patients undergoing open surgical lower limb revascularisation. The RIPC protocol consisted of 4 cycles of 5 minutes of ischaemia, with 5 minutes of reperfusion between every episode. Blood was collected for analysis preoperatively, 2, 8, and 24 hours after surgery, and urine was collected preoperatively and 24 hours after surgery. RESULTS: Data of 56 patients were included in the analysis. Serum creatinine, cystatin C, and beta-2 microglobulin increased, and eGFR decreased across all time points significantly more in the sham group than in the RIPC group (p = 0.021, p = 0.021, p = 0.021, p = 0.021, p = 0.021. CONCLUSIONS: Our finding of reduced release of kidney injury biomarkers may indicate the renoprotective effect of RIPC in patients undergoing open surgical lower limb revascularisation. The trial is registered with ClinicalTrials.gov NCT02689414.