Balanced Multielectrolyte Solution versus Saline in Critically Ill Adults.

BACKGROUND: Whether the use of balanced multielectrolyte solution (BMES) in preference to 0.9% sodium chloride solution (saline) in critically ill patients reduces the risk of acute kidney injury or death is uncertain. METHODS: In a double-blind, randomized, controlled trial, we assigned critically ill patients to receive BMES (Plasma-Lyte 148) or saline as fluid therapy in the intensive care unit (ICU) for 90 days. The primary outcome was death from any cause within 90 days after randomization. Secondary outcomes were receipt of new renal-replacement therapy and the maximum increase in the creatinine level during ICU stay. RESULTS: A total of 5037 patients were recruited from 53 ICUs in Australia and New Zealand - 2515 patients were assigned to the BMES group and 2522 to the saline group. Death within 90 days after randomization occurred in 530 of 2433 patients (21.8%) in the BMES group and in 530 of 2413 patients (22.0%) in the saline group, for a difference of -0.15 percentage points (95% confidence interval [CI], -3.60 to 3.30; P = 0.90). New renal-replacement therapy was initiated in 306 of 2403 patients (12.7%) in the BMES group and in 310 of 2394 patients (12.9%) in the saline group, for a difference of -0.20 percentage points (95% CI, -2.96 to 2.56). The mean (±SD) maximum increase in serum creatinine level was 0.41±1.06 mg per deciliter (36.6±94.0 µmol per liter) in the BMES group and 0.41±1.02 mg per deciliter (36.1±90.0 µmol per liter) in the saline group, for a difference of 0.01 mg per deciliter (95% CI, -0.05 to 0.06) (0.5 µmol per liter [95% CI, -4.7 to 5.7]). The number of adverse and serious adverse events did not differ meaningfully between the groups. CONCLUSIONS: We found no evidence that the risk of death or acute kidney injury among critically ill adults in the ICU was lower with the use of BMES than with saline. (Funded by the National Health and Medical Research Council of Australia and the Health Research Council of New Zealand; PLUS ClinicalTrials.gov number, NCT02721654.).

Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest.

BACKGROUND: Targeted temperature management is recommended for patients after cardiac arrest, but the supporting evidence is of low certainty. METHODS: In an open-label trial with blinded assessment of outcomes, we randomly assigned 1900 adults with coma who had had an out-of-hospital cardiac arrest of presumed cardiac or unknown cause to undergo targeted hypothermia at 33°C, followed by controlled rewarming, or targeted normothermia with early treatment of fever (body temperature, ≥37.8°C). The primary outcome was death from any cause at 6 months. Secondary outcomes included functional outcome at 6 months as assessed with the modified Rankin scale. Prespecified subgroups were defined according to sex, age, initial cardiac rhythm, time to return of spontaneous circulation, and presence or absence of shock on admission. Prespecified adverse events were pneumonia, sepsis, bleeding, arrhythmia resulting in hemodynamic compromise, and skin complications related to the temperature management device. RESULTS: A total of 1850 patients were evaluated for the primary outcome. At 6 months, 465 of 925 patients (50%) in the hypothermia group had died, as compared with 446 of 925 (48%) in the normothermia group (relative risk with hypothermia, 1.04; 95% confidence interval [CI], 0.94 to 1.14; P = 0.37). Of the 1747 patients in whom the functional outcome was assessed, 488 of 881 (55%) in the hypothermia group had moderately severe disability or worse (modified Rankin scale score ≥4), as compared with 479 of 866 (55%) in the normothermia group (relative risk with hypothermia, 1.00; 95% CI, 0.92 to 1.09). Outcomes were consistent in the prespecified subgroups. Arrhythmia resulting in hemodynamic compromise was more common in the hypothermia group than in the normothermia group (24% vs. 17%, P<0.001). The incidence of other adverse events did not differ significantly between the two groups. CONCLUSIONS: In patients with coma after out-of-hospital cardiac arrest, targeted hypothermia did not lead to a lower incidence of death by 6 months than targeted normothermia. (Funded by the Swedish Research Council and others; TTM2 ClinicalTrials.gov number, NCT02908308.).

Selective Extraction of Thorium(IV) from Uranium and Rare Earth Elements Using Tetraphenylethane-1,2-diylbis(phosphoramidate).

Tetraphenylethane-1,2-diylbis(phosphoramidate) in conjugation with a room temperature ionic liquid in chloroform medium is reported for the first time in the liquid-liquid extraction of thorium (Th). The extracted Th(IV) is collected as a white solid in the organic medium, thereby facilitating its easy separation. A high distribution ratio (D) of (12.4 ± 0.1) × 103 in 2-8 mol L-1 acidity range and high decontamination factors (α) of Th(IV) from uranium, lanthanides, and a number of transition elements makes this extraction process versatile and selective. A number of experimental investigations in synergism with extended X-ray absorption fine structure (EXAFS) spectroscopy and density functional theory (DFT) studies are interpreted to confirm the structure of the chelated complex. A 1:2 metal/ligand complex in which the two oxygen and two nitrogen atoms of each bis(phosphoramidate) molecule satisfying the eight coordination sites of Th(IV) is found to be formed. The extracted white solid thorium complex is easily converted to ThO2 after washing and heating at 1300 °C under O2 atmosphere. This work is expected to find direct application in the thorium fuel cycle, especially in the mining process of thorium from its ores and in the separation of fissile 233U from fertile 232Th in irradiated fuel.

Oxygen targets and 6-month outcome after out of hospital cardiac arrest: a pre-planned sub-analysis of the targeted hypothermia versus targeted normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trial.

BACKGROUND: Optimal oxygen targets in patients resuscitated after cardiac arrest are uncertain. The primary aim of this study was to describe the values of partial pressure of oxygen values (PaO2) and the episodes of hypoxemia and hyperoxemia occurring within the first 72 h of mechanical ventilation in out of hospital cardiac arrest (OHCA) patients. The secondary aim was to evaluate the association of PaO2 with patients' outcome. METHODS: Preplanned secondary analysis of the targeted hypothermia versus targeted normothermia after OHCA (TTM2) trial. Arterial blood gases values were collected from randomization every 4 h for the first 32 h, and then, every 8 h until day 3. Hypoxemia was defined as PaO2 < 60 mmHg and severe hyperoxemia as PaO2 > 300 mmHg. Mortality and poor neurological outcome (defined according to modified Rankin scale) were collected at 6 months. RESULTS: 1418 patients were included in the analysis. The mean age was 64 ± 14 years, and 292 patients (20.6%) were female. 24.9% of patients had at least one episode of hypoxemia, and 7.6% of patients had at least one episode of severe hyperoxemia. Both hypoxemia and hyperoxemia were independently associated with 6-month mortality, but not with poor neurological outcome. The best cutoff point associated with 6-month mortality for hypoxemia was 69 mmHg (Risk Ratio, RR = 1.009, 95% CI 0.93-1.09), and for hyperoxemia was 195 mmHg (RR = 1.006, 95% CI 0.95-1.06). The time exposure, i.e., the area under the curve (PaO2-AUC), for hyperoxemia was significantly associated with mortality (p = 0.003). CONCLUSIONS: In OHCA patients, both hypoxemia and hyperoxemia are associated with 6-months mortality, with an effect mediated by the timing exposure to high values of oxygen. Precise titration of oxygen levels should be considered in this group of patients. TRIAL REGISTRATION: clinicaltrials.gov NCT02908308 , Registered September 20, 2016.

Speed of cooling after cardiac arrest in relation to the intervention effect: a sub-study from the TTM2-trial.

BACKGROUND: Targeted temperature management (TTM) is recommended following cardiac arrest; however, time to target temperature varies in clinical practice. We hypothesised the effects of a target temperature of 33 °C when compared to normothermia would differ based on average time to hypothermia and those patients achieving hypothermia fastest would have more favorable outcomes. METHODS: In this post-hoc analysis of the TTM-2 trial, patients after out of hospital cardiac arrest were randomized to targeted hypothermia (33 °C), followed by controlled re-warming, or normothermia with early treatment of fever (body temperature, ≥ 37.8 °C). The average temperature at 4 h (240 min) after return of spontaneous circulation (ROSC) was calculated for participating sites. Primary outcome was death from any cause at 6 months. Secondary outcome was poor functional outcome at 6 months (score of 4-6 on modified Rankin scale). RESULTS: A total of 1592 participants were evaluated for the primary outcome. We found no evidence of heterogeneity of intervention effect based on the average time to target temperature on mortality (p = 0.17). Of patients allocated to hypothermia at the fastest sites, 71 of 145 (49%) had died compared to 68 of 148 (46%) of the normothermia group (relative risk with hypothermia, 1.07; 95% confidence interval 0.84-1.36). Poor functional outcome was reported in 74/144 (51%) patients in the hypothermia group, and 75/147 (51%) patients in the normothermia group (relative risk with hypothermia 1.01 (95% CI 0.80-1.26). CONCLUSIONS: Using a hospital's average time to hypothermia did not significantly alter the effect of TTM of 33 °C compared to normothermia and early treatment of fever.

Protocol for an individual patient data meta-analysis on blood pressure targets after cardiac arrest.

BACKGROUND: Hypotension is common after cardiac arrest (CA), and current guidelines recommend using vasopressors to target mean arterial blood pressure (MAP) higher than 65 mmHg. Pilot trials have compared higher and lower MAP targets. We will review the evidence on whether higher MAP improves outcome after cardiac arrest. METHODS: This systematic review and meta-analysis will be conducted based on a systematic search of relevant major medical databases from their inception onwards, including MEDLINE, Embase and the Cochrane Central Register of Controlled Trials (CENTRAL), as well as clinical trial registries. We will identify randomised controlled trials published in the English language that compare targeting a MAP higher than 65-70 mmHg in CA patients using vasopressors, inotropes and intravenous fluids. The data extraction will be performed separately by two authors (a third author will be involved in case of disagreement), followed by a bias assessment with the Cochrane Risk of Bias tool using an eight-step procedure for assessing if thresholds for clinical significance are crossed. The outcomes will be all-cause mortality, functional long-term outcomes and serious adverse events. We will contact the authors of the identified trials to request individual anonymised patient data to enable individual patient data meta-analysis, aggregate data meta-analyses, trial sequential analyses and multivariable regression, controlling for baseline characteristics. The certainty of the evidence will be assessed by the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system. We will register this systematic review with Prospero and aim to redo it when larger trials are published in the near future. CONCLUSIONS: This protocol defines the performance of a systematic review on whether a higher MAP after cardiac arrest improves patient outcome. Repeating this systematic review including more data likely will allow for more certainty regarding the effect of the intervention and possible sub-groups differences.

The cuff leak test in critically ill patients: An international survey of intensivists.

BACKGROUND: The cuff leak test (CLT) is used to assess laryngeal edema prior to extubation. There is limited evidence for its diagnostic accuracy and conflicting guidelines surrounding its use in critically ill patients who do not have risk factors for laryngeal edema. The primary study aim was to describe intensivists' beliefs, attitudes, and practice regarding the use of the CLT. METHODS: A 13-item survey was developed, pilot-tested, and subjected to clinical sensibility testing. The survey was distributed electronically through MetaClinician®. Descriptive statistics and multivariable regression analysis were performed to examine associations between participant demographics and survey responses. RESULTS: 1184 practicing intensivists from 17 countries in North and South America, Europe, Oceania, and Asia participated. The majority (59%) of respondents reported rarely or never perform the CLT prior to extubating patients not at high risk of laryngeal edema, which correlated with 54% of respondents reporting they believed a failed CLT did not predict reintubation. Intensivists from the Middle East were 2.4 times more likely to request a CLT compared to those from North America. Intensivists with base training in medicine or emergency medicine were more likely to request a CLT prior to extubation compared to those with base training in anesthesiology. CONCLUSION: Use of the CLT prior to extubating patients not at high risk of laryngeal edema in the intensive care unit is highly variable. Practice appears to be influenced by country of practice and base specialty training.

Effects of empagliflozin on proinflammatory cytokines and other coronary risk factors in patients with type 2 diabetes mellitus: A single-arm real-world observation.

OBJECTIVE: This single-arm real-world observation aims to examine the effects of empagliflozin (EMPA) on coronary risk factors among subjects with known diabetes. MATERIALS AND METHODS: Records of 63 subjects with type 2 diabetes mellitus, receiving EMPA were drawn for this study. Of 63 patients with diabetes, 6 were excluded, and the remaining 57 received EMPA (25 mg/day) for 24 weeks. Clinical data, dietary intakes, and physical activity were assessed by validated questionnaires. RESULTS: Treatment with EMPA was associated with significant decline in fasting and 2-hour post-prandial blood glucose and Hb1c indicating that this agent has potential antidiabetic effects. Pro-inflammatory cytokines; C-reactive protein, TNF-α, and interleukin-6 showed significant reduction after treatment with EMPA, compared to baseline levels. Apart from these changes, parameters of oxidative stress, thiobarbituric acid reactive substances, malondialdehyde, and diene conjugates as well as uric acid, showed a significant decline with an increase in antioxidant vitamins A, E, and C and beta-carotene as well as nitrite. There was a significant decline in serum uric acid, systolic and diastolic blood pressures, and angiotensin-converting enzyme (ACE), with a non-significant reduction in body weight and body mass index as well as in waist circumference of modest significance, after intervention of 12 weeks compared to baseline levels. Total cholesterol, VLDL cholesterol and triglycerides showed non-significant decline compared to baseline levels. CONCLUSION: It is possible that EMPA administration can cause a significant decline in pro-inflammatory cytokines along with blood glucose, Hb1c, oxidative stress, uric acid, blood pressures, and ACE with an increase in antioxidant vitamins and nitrite. Randomized, controlled intervention trials would be necessary to confirm our findings.

Relative Hypotension and Adverse Kidney-related Outcomes among Critically Ill Patients with Shock. A Multicenter, Prospective Cohort Study.

Rationale: There are no prospective observational studies exploring the relationship between relative hypotension and adverse kidney-related outcomes among critically ill patients with shock.Objectives: To investigate the magnitude of relative hypotension during vasopressor support among critically ill patients with shock and to determine whether such relative hypotension is associated with new significant acute kidney injury (AKI) or major adverse kidney events (MAKE) within 14 days of vasopressor initiation.Methods: At seven multidisciplinary ICUs, 302 patients, aged ≥40 years and requiring ≥4 hours of vasopressor support for nonhemorrhagic shock, were prospectively enrolled. We assessed the time-weighted average of the mean perfusion pressure (MPP) deficit (i.e., the percentage difference between patients' preillness basal MPP and achieved MPP) during vasopressor support and the percentage of time points with an MPP deficit > 20% as key exposure variables. New significant AKI was defined as an AKI-stage increase of two or more (Kidney Disease: Improving Global Outcome creatinine-based criteria).Measurements and Main Results: The median MPP deficit was 19% (interquartile range, 13-25), and 54% (interquartile range, 19-82) of time points were spent with an MPP deficit > 20%. Seventy-three (24%) patients developed new significant AKI; 86 (29%) patients developed MAKE. For every percentage increase in the time-weighted average MPP deficit, multivariable-adjusted odds of developing new significant AKI and MAKE increased by 5.6% (95% confidence interval, 2.2-9.1; P = 0.001) and 5.9% (95% confidence interval, 2.2-9.8; P = 0.002), respectively. Likewise, for every one-unit increase in the percentage of time points with an MPP deficit > 20%, multivariable-adjusted odds of developing new significant AKI and MAKE increased by 1.2% (0.3-2.2; P = 0.008) and 1.4% (0.4-2.4; P = 0.004), respectively.Conclusions: Vasopressor-treated patients with shock are often exposed to a significant degree and duration of relative hypotension, which is associated with new-onset, adverse kidney-related outcomes.Study registered with Australian New Zealand Clinical Trial Registry (ACTRN 12613001368729).

Plasma Cortisol, Aldosterone, and Ascorbic Acid Concentrations in Patients with Septic Shock Do Not Predict Treatment Effect of Hydrocortisone on Mortality. A Nested Cohort Study.

Rationale: Whether biomarkers can identify subgroups of patients with septic shock with differential treatment responses to hydrocortisone is unknown.Objectives: To determine if there is heterogeneity in effect for hydrocortisone on mortality, shock resolution, and other clinical outcomes based on baseline cortisol, aldosterone, and ascorbic acid concentrations.Methods: From May 2014 to April 2017, we obtained serum samples from 529 patients with septic shock from 22 ICUs in Australia and New Zealand.Measurements and Main Results: There were no significant interactions between the association with 90-day mortality and treatment with either hydrocortisone or placebo for total cortisol (odds ratio [OR], 1.09; 95% confidence interval [CI], 1.02-1.16 vs. OR, 1.07; 95% CI, 1.00-1.13; P = 0.70), free cortisol (OR, 1.20; 95% CI, 1.04-1.38 vs. OR, 1.16; 95% CI, 1.02-1.32; P = 0.75), aldosterone (OR, 1.01; 95% CI, 0.97-1.05 vs. OR, 1.01; 95% CI, 0.98-1.04; P = 0.99), or ascorbic acid (OR, 1.11; 95% CI, 0.89-1.39 vs. OR, 1.05; 95% CI, 0.91-1.22; P = 0.70), respectively. Similar results were observed for the association with shock resolution. Elevated free cortisol was significantly associated with 90-day mortality (OR, 1.13; 95% CI, 1.00-1.27; P = 0.04), but total cortisol, aldosterone, and ascorbic acid were not.Conclusions: In patients with septic shock, there was no heterogeneity in effect of adjunctive hydrocortisone on mortality, shock resolution, or other clinical outcomes based on cortisol, aldosterone, and ascorbic acid concentrations. Plasma aldosterone and ascorbic acid concentrations are not associated with outcome.

An international comparison of the cost of fluid resuscitation therapies.

OBJECTIVE: Fluid resuscitation is a ubiquitous intervention in the management of patients treated in the intensive care unit, which has implications for intensive care unit resourcing and budgets. Our objective was to calculate the relative cost of resuscitation fluids in several countries to inform future economic evaluations. METHODS: We collected site-level data regarding the availability and cost of fluids as part of an international survey. We normalised costs to net present values using purchasing power parities and published inflation figures. Costs were also adjusted for equi-effective dosing based on intravascular volume expansion effectiveness and expressed as US dollars (USD) per 100 mL crystalloid equivalent. RESULTS: A total of 187 sites had access to cost data. Between countries, there was an approximate six fold variation in the cost of crystalloids and colloids overall. The average cost for crystalloids overall was less than 1 USD per 100 mL. In contrast, colloid fluids had higher average costs (59 USD per 100 mL). After adjusting for equi-effective dosing, saline was ∼27 times less costly than albumin (saline: 0.6 USD per 100 mL crystalloid equivalent; albumin 4-5%: 16.4 USD; albumin 20-25%: 15.8 USD) and ∼4 times less costly than hydroxyethyl starch solution (saline: 0.6 USD; hydroxyethyl starch solution: 2.5 USD). Buffered salt solutions, such as compound sodium acetate solutions (e.g., Plasmalyte®), had the highest average cost of crystalloid fluids, costing between 3 and 4 USD per 100 mL. CONCLUSION: The cost of fluid varies substantially between fluid types and between countries, although normal (0.9%) saline is consistently less costly than colloid preparations and some buffered salt solutions. These data can be used to inform future economic evaluations of fluid preparations.

Frailty, delirium and hospital mortality of older adults admitted to intensive care: the Delirium (Deli) in ICU study.

BACKGROUND: Clinical frailty among older adults admitted to intensive care has been proposed as an important determinant of patient outcomes. Among this group of patients, an acute episode of delirium is also common, but its relationship to frailty and increased risk of mortality has not been extensively explored. Therefore, the aim of this study was to explore the relationship between clinical frailty, delirium and hospital mortality of older adults admitted to intensive care. METHODS: This study is part of a Delirium in Intensive Care (Deli) Study. During the initial 6-month baseline period, clinical frailty status on admission to intensive care, among adults aged 50 years or more; acute episodes of delirium; and the outcomes of intensive care and hospital stay were explored. RESULTS: During the 6-month baseline period, 997 patients, aged 50 years or more, were included in this study. The average age was 71 years (IQR, 63-79); 55% were male (n = 537). Among these patients, 39.2% (95% CI 36.1-42.3%, n = 396) had a Clinical Frailty Score (CFS) of 5 or more, and 13.0% (n = 127) had at least one acute episode of delirium. Frail patients were at greater risk of an episode of delirium (17% versus 10%, adjusted rate ratio (adjRR) = 1.71, 95% confidence interval (CI) 1.20-2.43, p = 0.003), had a longer hospital stay (2.6 days, 95% CI 1-7 days, p = 0.009) and had a higher risk of hospital mortality (19% versus 7%, adjRR = 2.54, 95% CI 1.72-3.75, p < 0.001), when compared to non-frail patients. Patients who were frail and experienced an acute episode of delirium in the intensive care had a 35% rate of hospital mortality versus 10% among non-frail patients who also experienced delirium in the ICU. CONCLUSION: Frailty and delirium significantly increase the risk of hospital mortality. Therefore, it is important to identify patients who are frail and institute measures to reduce the risk of adverse events in the ICU such as delirium and, importantly, to discuss these issues in an open and empathetic way with the patient and their families.

Interventions to reduce body temperature to 35 °C to 37 °C in adults and children with traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) is a major cause of death and disability, with an estimated 5.5 million people experiencing severe TBI worldwide every year. Observational clinical studies of people with TBI suggest an association between raised body temperature and unfavourable outcome, although this relationship is inconsistent. Additionally, preclinical models suggest that reducing temperature to 35 °C to 37.5 °C improves biochemical and histopathological outcomes compared to reducing temperature to a lower threshold of 33 °C to 35 °C. It is unknown whether reducing body temperature to 35 °C to 37.5 °C in people admitted to hospital with TBI is beneficial, has no effect, or causes harm. This is an update of a review last published in 2014. OBJECTIVES: To assess the effects of pharmacological interventions or physical interventions given with the intention of reducing body temperature to 35 °C to 37.5 °C in adults and children admitted to hospital after TBI. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Web of Science, and PubMed on 28 November 2019. We searched clinical trials registers, grey literature and references lists of reviews, and we carried out forward citation searches of included studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) with participants of any age admitted to hospital following TBI. We included interventions that aimed to reduce body temperature to 35 °C to 37.5 °C: these included pharmacological interventions (such as paracetamol, or non-steroidal anti-inflammatory drugs), or physical interventions (such as surface cooling devices, bedside fans, or cooled intravenous fluids). Eligible comparators were placebo or usual care. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion, extracted data, and assessed risks of bias. We assessed the certainty of the evidence with GRADE. MAIN RESULTS: We included one RCT with 41 participants. This study recruited adult participants admitted to two intensive care units in Australia, and evaluated a pharmacological intervention. Researchers gave participants 1 g paracetamol or a placebo intravenously at four-hourly intervals for 72 hours. We could not be certain whether intravenous paracetamol influenced mortality at 28 days (risk ratio 2.86, 95% confidence interval 0.32 to 25.24). We judged the evidence for this outcome to be very low certainty, meaning we have very little confidence in this effect estimate, and the true result may be substantially different to this effect. We downgraded the certainty for imprecision (because the evidence was from a single study with very few participants), and study limitations (because we noted a high risk of selective reporting bias). This study was otherwise at low risk of bias. The included study did not report the primary outcome for this review, which was the number of people with a poor outcome at the end of follow-up (defined as death or dependency, as measured on a scale such as the Glasgow Outcome Score), or any of our secondary outcomes, which included the number of people with further intracranial haemorrhage, extracranial haemorrhage, abnormal intracranial pressure, or pneumonia or other serious infections. The only other completed trial that we found was of a physical intervention that compared advanced fever control (using a surface cooling device) versus conventional fever control in 12 participants. The trial was published as an abstract only, with insufficient details to allow inclusion, so we have added this to the 'studies awaiting classification' section, pending further information from the study authors or publication of the full study report. We identified four ongoing studies that will contribute evidence to future updates of the review if they measure relevant outcomes and, in studies with a mixed population, report data separately for participants with TBI. AUTHORS' CONCLUSIONS: One small study contributed very low-certainty evidence for mortality to this review. The uncertainty is largely driven by limited research into reduction of body temperature to 35 °C to 37.5 °C in people with TBI. Further research that evaluates pharmacological or physical interventions, or both, may increase certainty in this field. We propose that future updates of the review, and ongoing and future research in this field, incorporate outcomes that are important to the people receiving the interventions, including side effects of any pharmacological agent (e.g. nausea or vomiting), and discomfort caused by physical therapies.

Effect of Stress Ulcer Prophylaxis With Proton Pump Inhibitors vs Histamine-2 Receptor Blockers on In-Hospital Mortality Among ICU Patients Receiving Invasive Mechanical Ventilation: The PEPTIC Randomized Clinical Trial.

Importance: Proton pump inhibitors (PPIs) or histamine-2 receptor blockers (H2RBs) are often prescribed for patients as stress ulcer prophylaxis drugs in the intensive care unit (ICU). The comparative effect of these drugs on mortality is unknown. Objective: To compare in-hospital mortality rates using PPIs vs H2RBs for stress ulcer prophylaxis. Design, Setting, and Participants: Cluster crossover randomized clinical trial conducted at 50 ICUs in 5 countries between August 2016 and January 2019. Patients requiring invasive mechanical ventilation within 24 hours of ICU admission were followed up for 90 days at the hospital. Interventions: Two stress ulcer prophylaxis strategies were compared (preferential use with PPIs vs preferential use with H2RBs). Each ICU used each strategy sequentially for 6 months in random order; 25 ICUs were randomized to the sequence with use of PPIs and then use of H2RBs and 25 ICUs were randomized to the sequence with use of H2RBs and then use of PPIs (13 436 patients randomized by site to PPIs and 13 392 randomized by site to H2RBs). Main Outcomes and Measures: The primary outcome was all-cause mortality within 90 days during index hospitalization. Secondary outcomes were clinically important upper gastrointestinal bleeding, Clostridioides difficile infection, and ICU and hospital lengths of stay. Results: Among 26 982 patients who were randomized, 154 opted out, and 26 828 were analyzed (mean [SD] age, 58 [17.0] years; 9691 [36.1%] were women). There were 26 771 patients (99.2%) included in the mortality analysis; 2459 of 13 415 patients (18.3%) in the PPI group died at the hospital by day 90 and 2333 of 13 356 patients (17.5%) in the H2RB group died at the hospital by day 90 (risk ratio, 1.05 [95% CI, 1.00 to 1.10]; absolute risk difference, 0.93 percentage points [95% CI, -0.01 to 1.88] percentage points; P = .054). An estimated 4.1% of patients randomized by ICU site to PPIs actually received H2RBs and an estimated 20.1% of patients randomized by ICU site to H2RBs actually received PPIs. Clinically important upper gastrointestinal bleeding occurred in 1.3% of the PPI group and 1.8% of the H2RB group (risk ratio, 0.73 [95% CI, 0.57 to 0.92]; absolute risk difference, -0.51 percentage points [95% CI, -0.90 to -0.12 percentage points]; P = .009). Rates of Clostridioides difficile infection and ICU and hospital lengths of stay were not significantly different by treatment group. One adverse event (an allergic reaction) was reported in 1 patient in the PPI group. Conclusions and Relevance: Among ICU patients requiring mechanical ventilation, a strategy of stress ulcer prophylaxis with use of proton pump inhibitors vs histamine-2 receptor blockers resulted in hospital mortality rates of 18.3% vs 17.5%, respectively, a difference that did not reach the significance threshold. However, study interpretation may be limited by crossover in the use of the assigned medication. Trial Registration: anzctr.org.au Identifier: ACTRN12616000481471.

Targeted hypothermia versus targeted Normothermia after out-of-hospital cardiac arrest (TTM2): A randomized clinical trial-Rationale and design.

BACKGROUND: Less than 500 participants have been included in randomized trials comparing hypothermia with regular care for out-of-hospital cardiac arrest patients, and many of these trials were small and at a high risk of bias. Consequently, the accrued data on this potentially beneficial intervention resembles that of a drug following small phase II trials. A large confirmatory trial is therefore warranted. METHODS: The TTM2-trial is an international, multicenter, parallel group, investigator-initiated, randomized, superiority trial in which a target temperature of 33°C after cardiac arrest will be compared with a strategy to maintain normothermia and early treatment of fever (≥37.8°C). Participants will be randomized within 3 hours of return of spontaneous circulation with the intervention period lasting 40 hours in both groups. Sedation will be mandatory for all patients throughout the intervention period. The clinical team involved with direct patient care will not be blinded to allocation group due to the inherent difficulty in blinding the intervention. Prognosticators, outcome-assessors, the steering group, the trial coordinating team, and trial statistician will be blinded. The primary outcome will be all-cause mortality at 180 days after randomization. We estimate a 55% mortality in the control group. To detect an absolute risk reduction of 7.5% with an alpha of 0.05 and 90% power, 1900 participants will be enrolled. The main secondary neurological outcome will be poor functional outcome (modified Rankin Scale 4-6) at 180 days after arrest. DISCUSSION: The TTM2-trial will compare hypothermia to 33°C with normothermia and early treatment of fever (≥37.8°C) after out-of-hospital cardiac arrest.

Red blood cell transfusion in critically ill patients with traumatic brain injury: an international survey of physicians' attitudes.

INTRODUCTION: Restrictive transfusion strategies have been advocated in critically ill patients. Nevertheless, considerable uncertainty exists regarding optimal transfusion thresholds in traumatic brain injury (TBI) patients because the injured brain is susceptible to hypoxemic damage. We aimed to identify the determinants of red blood cell (RBC) transfusion and the perceived optimal transfusion thresholds in adult patients with moderate-to-severe TBI. METHODS: We conducted an electronic, self-administered survey targeting critical care specialists and neurosurgeons from Canada, Australia, and the United Kingdom caring for TBI patients. The questionnaire was initially developed by a panel of experts using a structured process (domains/items generation and reduction). The questionnaire was validated for clinical sensibility, reliability, and content. RESULTS: The response rate was 28.7% (218/760). When presented with the hypothetical scenario of a young adult TBI patient, a wide range of transfusion practices was observed, with 47 (95% confidence interval [CI], 41 to 54)% favouring RBC transfusion at a hemoglobin level of ≤ 70 g·L-1 in the acute phase of care, while 73 (95% CI, 67 to 79)% would use this trigger in the plateau phase of care. Multiple trauma, neuro-monitoring data, hemorrhagic shock, and planned surgery were the main factors that influenced the need for transfusion. The lack of clinical evidence and guidelines was responsible for uncertainty regarding RBC transfusion strategies in this patient population. CONCLUSION: In our survey about critically ill TBI patients, transfusion practice was found to be mainly influenced by the acuity of care, patient characteristics, and neuro-monitoring. Clinical equipoise regarding optimal transfusion strategy is believed to be mainly attributed to the lack of clear clinical evidence and guidelines. Appropriate randomized-controlled trials are required to determine the optimal transfusion strategies in TBI patients.

Colorimetric and visual determination of ultratrace uranium concentrations based on the aggregation of amidoxime functionalized gold nanoparticles.

The authors describe the synthesis and characterization of 3-mercaptopropionylamidoxime functionalized gold nanoparticles (AuNPs) for visual detection of uranium (U) by cloud point extraction. The method is capable of quantifying U at the concentration limits set by the World Health Organization in drinking water i.e., 30.0 ng mL-1. The method is based on the gradual color change from red to blue that occurs as a result of the interaction between uranyl ion and the modified AuNPs leading to particle aggregation. Such analyte-triggered aggregation results in AuNP's peak absorbance quenching as well as red shift in the wavelength range of 520 to 543 nm. The colorimetric response at 520 nm is linear in the 2-100 ng mL-1 U concentration range, and the limit of detection is 0.3 ng mL-1. No interferences by other ions are found, and the relative standard deviation is ≤4% (for n = 5). The method is validated by analyzing a certified reference material (NIST SRM 1640a; natural water), and also applied to the quantification of U in four (spiked) water samples. Graphical abstract Schematic presentation of cloud point extraction (CPE) assisted coloirmetric and visual detection of uranium (U). In CPE of gold nanoparticles (AuNPs) the color of surfactant rich phase (SRP) turns red in absence of U(VI) and blue in presence of U(VI).

Exploring titanium(IV) chemical proximity to iron(III) to elucidate a function for Ti(IV) in the human body.

Despite its natural abundance and widespread use as food, paint additive, and in bone implants, no specific biological function of titanium is known in the human body. High concentrations of Ti(IV) could result in cellular toxicity, however, the absence of Ti toxicity in the blood of patients with titanium bone implants indicates the presence of one or more biological mechanisms to mitigate toxicity. Similar to Fe(III), Ti(IV) in blood binds to the iron transport protein serum transferrin (sTf), which gives credence to the possibility of its cellular uptake mechanism by transferrin-directed endocytosis. However, once inside the cell, how sTf bound Ti(IV) is released into the cytoplasm, utilized, or stored remain largely unknown. To explain the molecular mechanisms involved in Ti use in cells we have drawn parallels with those for Fe(III). Based on its chemical similarities with Fe(III), we compare the biological coordination chemistry of Fe(III) and Ti(IV) and hypothesize that Ti(IV) can bind to similar intracellular biomolecules. The comparable ligand affinity profiles suggest that at high Ti(IV) concentrations, Ti(IV) could compete with Fe(III) to bind to biomolecules and would inhibit Fe bioavailability. At the typical Ti concentrations in the body, Ti might exist as a labile pool of Ti(IV) in cells, similar to Fe. Ti could exhibit different types of properties that would determine its cellular functions. We predict some of these functions to mimic those of Fe in the cell and others to be specific to Ti. Bone and cellular speciation and localization studies hint toward various intracellular targets of Ti like phosphoproteins, DNA, ribonucleotide reductase, and ferritin. However, to decipher the exact mechanisms of how Ti might mediate these roles, development of innovative and more sensitive methods are required to track this difficult to trace metal in vivo.

Acetaminophen for Fever in Critically Ill Patients with Suspected Infection.

BACKGROUND: Acetaminophen is a common therapy for fever in patients in the intensive care unit (ICU) who have probable infection, but its effects are unknown. METHODS: We randomly assigned 700 ICU patients with fever (body temperature, ≥38°C) and known or suspected infection to receive either 1 g of intravenous acetaminophen or placebo every 6 hours until ICU discharge, resolution of fever, cessation of antimicrobial therapy, or death. The primary outcome was ICU-free days (days alive and free from the need for intensive care) from randomization to day 28. RESULTS: The number of ICU-free days to day 28 did not differ significantly between the acetaminophen group and the placebo group: 23 days (interquartile range, 13 to 25) among patients assigned to acetaminophen and 22 days (interquartile range, 12 to 25) among patients assigned to placebo (Hodges-Lehmann estimate of absolute difference, 0 days; 96.2% confidence interval [CI], 0 to 1; P=0.07). A total of 55 of 345 patients in the acetaminophen group (15.9%) and 57 of 344 patients in the placebo group (16.6%) had died by day 90 (relative risk, 0.96; 95% CI, 0.66 to 1.39; P=0.84). CONCLUSIONS: Early administration of acetaminophen to treat fever due to probable infection did not affect the number of ICU-free days. (Funded by the Health Research Council of New Zealand and others; HEAT Australian New Zealand Clinical Trials Registry number, ACTRN12612000513819.).

Changes in Temperature Management of Cardiac Arrest Patients Following Publication of the Target Temperature Management Trial.

OBJECTIVES: To evaluate knowledge translation after publication of the target temperature management 33°C versus 36°C after out-of-hospital cardiac arrest trial and associated patient outcomes. Our primary hypothesis was that target temperature management at 36°C was rapidly adopted in Australian and New Zealand ICUs. Secondary hypotheses were that temporal reductions in mortality would be seen and would have accelerated after publication of the target temperature management trial. DESIGN: Retrospective cohort study (January 2005 to December 2016). SETTING: The Australian and New Zealand Intensive Care Society Centre for Outcome and Resource Evaluation adult patient database containing greater than 2 million admission episodes from 186 Australian and New Zealand ICUs. PATIENTS: Sixteen-thousand two-hundred fifty-two adults from 140 hospitals admitted to ICU after out-of-hospital cardiac arrest. INTERVENTIONS: The primary exposure of interest was admission before versus after publication of the target temperature management trial. MEASUREMENTS AND MAIN RESULTS: The primary outcome variable to evaluate changes in temperature management was lowest temperature in the first 24 hours in ICU. The primary clinical outcome variable of interest was inhospital mortality. Secondary outcomes included proportion of patients with fever in the first 24 hours in ICU. Mean ± SD lowest temperature in the first 24 hours in ICU in pre- and posttarget temperature management trial patients was 33.80 ± 1.71°C and 34.70 ± 1.39°C, respectively (absolute difference, 0.98°C [99% CI, 0.89-1.06°C]). Inhospital mortality rate decreased by 1.3 (99% CI, -1.8 to -0.9) percentage points per year from January 2005 until December 2013 and increased by 0.6 (99% CI, -1.4 to 2.6) percentage points per year from January 2014 until December 2016 (change in slope 1.9 percentage points per year [99% CI, -0.6 to 4.4]). Fever occurred in 568 (12.8%) of 4,450 pretarget temperature management trial patients and 853 (16.5%) of 5,184 posttarget temperature management trial patients (odds ratio, 1.35 [99% CI, 1.16-1.57]). CONCLUSIONS: The average lowest temperature of postcardiac arrest patients in the first 24 hours in ICU rose after publication of the target temperature management trial. This change was associated with an increased frequency of fever not seen in the target temperature management trial.