Current Fluid Management Practice in Critically Ill Adults on Continuous Renal Replacement Therapy: A Binational, Observational Study.

INTRODUCTION: In critically ill patients undergoing continuous renal replacement therapy (CRRT), a positive fluid balance (FB) is associated with adverse outcomes. However, current FB management practices in CRRT patients are poorly understood. We aimed to study FB and its components in British and Australian CRRT patients to inform future trials. METHODS: We obtained detailed electronic health record data on all fluid-related variables during CRRT and hourly FB for the first 7 days of treatment. RESULTS: We studied 1,616 patients from three tertiary intensive care units (ICUs) in two countries. After the start of CRRT, the mean cumulative FB became negative at 31 h and remained negative over 7 days to a mean nadir of -4.1 L (95% confidence interval (CI) of -4.6 to -3.5). The net ultrafiltration (NUF) rate was the dominant fluid variable (-67.7 mL/h; standard deviation (SD): 75.7); however, residual urine output (-34.7 mL/h; SD: 54.5), crystalloid administration (48.1 mL/h; SD: 44.6), and nutritional input (36.4 mL/h; SD: 29.7) significantly contributed to FB. Patients with a positive FB after 72 h of CRRT were more severely ill, required high-dose vasopressors, and had high lactate concentrations (5.0 mmol/L; interquartile range: 2.3-10.5). A positive FB was independently associated with increased hospital mortality (odds ratio: 1.70; 95% CI; p = 0.004). CONCLUSION: In the study ICUs, most CRRT patients achieved a predominantly NUF-dependent negative FB. Patients with a positive FB at 72 h had greater illness severity and haemodynamic instability. Achieving equipoise for conducting trials that target a negative early FB in such patients may be difficult.

Sepsis-associated acute kidney injury in patients with chronic kidney disease: Patient characteristics, prevalence, timing, trajectory, treatment and associated outcomes.

AIM: The features and outcomes of sepsis-associated acute kidney injury (SA-AKI) may be affected by chronic kidney disease (CKD). Accordingly, we aimed to compare SA-AKI in patients with or without CKD. METHODS: Retrospective cohort study in 12 intensive care units (ICU). We studied the prevalence, patient characteristics, timing, trajectory, treatment and outcomes of SA-AKI with and without CKD. RESULTS: Of 84 240 admissions, 7255 (8.6%) involved patients with CKD. SA-AKI was more common in patients with CKD (21% vs 14%; p < .001). CKD patients were older (70 vs. 60 years; p < .001), had a higher median Charlson co-morbidity index (5 vs. 3; p < .001) and acute physiology and chronic health evaluation (APACHE) III score (78 vs. 60; p < .001) and were more likely to receive renal replacement therapy (RRT) (25% vs. 17%; p < .001). They had less complete return to baseline function at ICU discharge (48% vs. 60%; p < .001), higher major adverse kidney events at day 30 (MAKE-30) (38% vs. 27%; p < .001), and higher hospital and 90-day mortality (21% vs. 13%; p < .001, and 27% vs. 16%; p < .001, respectively). After adjustment for patient characteristics and severity of illness, however, CKD was not an independent risk factor for increased 90-day mortality (OR 0.88; 95% CI 0.76-1.02; p = .08) or MAKE-30 (OR 0.98; 95% CI 0.80-1.09; p = .4). CONCLUSION: SA-AKI is more common in patients with CKD. Such patients are older, more co-morbid, have higher disease severity, receive different ICU therapies and have different trajectories of renal recovery and greater unadjusted mortality. However, after adjustment day-90 mortality and MAKE-30 risk were not increased by CKD.

Manifestations and Management of Trimethoprim/Sulfamethoxazole-Resistant Nocardia otitidiscaviarum Infection.

Nocardia can cause systemic infections with varying manifestations. Resistance patterns vary by species. We describe N. otitidiscavarium infection with pulmonary and cutaneous manifestations in a man in the United States. He received multidrug treatment that included trimethoprim/sulfamethoxazole but died. Our case highlights the need to treat with combination therapy until drug susceptibilities are known.

Sodium Bicarbonate for Metabolic Acidosis in the ICU: Results of a Pilot Randomized Double-Blind Clinical Trial.

OBJECTIVES: To identify the best population, design of the intervention, and to assess between-group biochemical separation, in preparation for a future phase III trial. DESIGN: Investigator-initiated, parallel-group, pilot randomized double-blind trial. SETTING: Eight ICUs in Australia, New Zealand, and Japan, with participants recruited from April 2021 to August 2022. PATIENTS: Thirty patients greater than or equal to 18 years, within 48 hours of admission to the ICU, receiving a vasopressor, and with metabolic acidosis (pH < 7.30, base excess [BE] < -4 mEq/L, and Pa co2 < 45 mm Hg). INTERVENTIONS: Sodium bicarbonate or placebo (5% dextrose). MEASUREMENTS AND MAIN RESULT: The primary feasibility aim was to assess eligibility, recruitment rate, protocol compliance, and acid-base group separation. The primary clinical outcome was the number of hours alive and free of vasopressors on day 7. The recruitment rate and the enrollment-to-screening ratio were 1.9 patients per month and 0.13 patients, respectively. Time until BE correction (median difference, -45.86 [95% CI, -63.11 to -28.61] hr; p < 0.001) and pH correction (median difference, -10.69 [95% CI, -19.16 to -2.22] hr; p = 0.020) were shorter in the sodium bicarbonate group, and mean bicarbonate levels in the first 24 hours were higher (median difference, 6.50 [95% CI, 4.18 to 8.82] mmol/L; p < 0.001). Seven days after randomization, patients in the sodium bicarbonate and placebo group had a median of 132.2 (85.6-139.1) and 97.1 (69.3-132.4) hours alive and free of vasopressor, respectively (median difference, 35.07 [95% CI, -9.14 to 79.28]; p = 0.131). Recurrence of metabolic acidosis in the first 7 days of follow-up was lower in the sodium bicarbonate group (3 [20.0%] vs. 15 [100.0%]; p < 0.001). No adverse events were reported. CONCLUSIONS: The findings confirm the feasibility of a larger phase III sodium bicarbonate trial; eligibility criteria may require modification to facilitate recruitment.

90-day Case-Fatality in Critically ill Patients with Chronic Liver Disease Influenced by Presence of Portal Hypertension, Results from a Multicentre Retrospective Cohort Study.

BACKGROUND: Critical illness in patients with chronic liver disease (CLD) is increasing in occurrence, and by virtue of its adverse effect on prognosis, its presence may influence the decision to offer admission to intensive care units (ICU). Our objective was to examine the determinants and outcome of patients with CLD admitted to ICU. METHODS: A retrospective cohort of patients admitted to four adult ICUs in Queensland, Australia from 2017 to 2019. Patients with mild or moderate-severe CLD were defined by the absence and presence of portal hypertension, respectively, and were was determined using granular ICU and state-wide administrative databases. The primary outcome was 90-day all cause case-fatality. RESULTS: We included 3836 patients in the analysis, of which, 60 (2%) had mild liver disease and 132 (3%) had moderate-severe liver disease . Patients with CLD had higher incidence of other co-morbidities with the median adjusted-Charlson co-morbidity index (CCI) was 1 (interquartile range; IQR 0-3) for no CLD, 2 (IQR 1.5-4) for mild CLD, and 3 (IQR 2-5) for moderate-severe CLD. Case-fatality rates at 90 days was 17% for no CLD, 25% for mild CLD, and 41% for moderate-severe CLD. Among those with mild and moderate-severe CLD, an increased co-morbidity burden as measured by an adjusted CCI score of low (0-3), medium (4-5), high (6-7) and very high (>7) resulted in increasing case-fatality rates of 24-40%, 11-28.5%, 33-62%, and 50% respectively. Moderate-severe CLD, but not mild CLD, was independently associated with increased case-fatality at 90 days (Odds Ratio 1.58; 95% confidence interval 1.01-2.48; p = 0.004) after adjusting for medical co-morbidities and severity of illness using logistic regression analysis. CONCLUSIONS: Although patients with moderate-severe CLD have an increased risk for 90-day case-fatality, patients with mild CLD are not at higher risk for death following ICU admission.

Impact of Continuous Renal Replacement Therapy Initiation on Urine Output and Fluid Balance: A Multicenter Study.

INTRODUCTION: The effect of continuous renal replacement therapy (CRRT) on renal function is poorly understood. However, the initiation of CRRT may induce oliguria. We aimed to investigate the impact of CRRT commencement on urine output (UO). METHODS: This was a retrospective cohort study in two intensive care units. We included all patients who underwent CRRT and collected data on hourly UO and fluid balance before and after CRRT commencement. We performed an interrupted time series analysis using segmented regression to assess the relationship between CRRT commencement and UO. RESULTS: We studied 1,057 patients. Median age was 60.7 years (interquartile range [IQR], 48.3-70.6), and the median APACHE III was 95 (IQR, 76-115). Median time to CRRT was 17 h (IQR, 5-49). With start of CRRT, the absolute difference in mean hourly UO and mean hourly fluid balance was -27.0 mL/h (95% CI: -32.1 to -21.8; p value < 0.01) and - 129.3 mL/h (95% CI: -169.2 to -133.3), respectively. When controlling for pre-CRRT temporal trends and patient characteristics, there was a rapid post-initiation decrease in UO (-0.12 mL/kg/h; 95% CI: -0.17 to -0.08; p value < 0.01) and fluid balance (-78.1 mL/h; 95% CI: -87.9 to -68.3; p value < 0.01), which was sustained over the first 24 h of CRRT. Change in UO and fluid balance were only weakly correlated (r -0.29; 95% CI: -0.35 to -0.23; p value < 0.01). CONCLUSION: Commencement of CRRT was associated with a significant decrease in UO that could not be explained by extracorporeal fluid removal.

Peripheral blood metabolite profiles associated with new onset atrial fibrillation.

BACKGROUND: Peripheral blood metabolite profiles have yielded mechanistic insights into various cardiovascular disease states. We hypothesized that peripheral blood metabolite profiles would be associated with new onset atrial fibrillation (AF). METHODS AND RESULTS: The study population comprised 1892 patients without AF at baseline, who, as part the MURDOCK Cardiovascular Disease Study molecular profiling cohort (n = 2023), had previously had determination of levels of 69 metabolites from frozen, fasting plasma specimens obtained during coronary angiography. We used Cox proportional hazards models to examine the association of 13 uncorrelated metabolite factors created from these data using principal components analysis (PCA) with new occurrences of AF during a median follow up of 2.8 (0.1-4.9) years. A total of 233 patients developed new AF (12.3%) during follow up. Patients with new onset AF were older (median 67 vs. 60 years); more often white (82 vs. 71%) and male (68 vs. 60%), and had more comorbidities than those who did not develop AF. After adjustment, PCA factor 1 (medium chain acylcarnitines; hazard ratio [HR]: 1.11 [1.01-1.22]), factor 2 (short chain dicarboxylacylcarnitines; HR: 1.21 [1.09-1.34]) and factor 5 (long chain acylcarnitines; HR: 1.19 [1.06-1.34]) were associated with new onset AF. CONCLUSION: Metabolite profiles were associated with new onset AF among patients referred for coronary angiography. Validation of these observations in broader patient populations may provide better mechanistic insight into the development of AF, and may provide new opportunities for prevention and treatment.

Derivation and validation of a risk score for predicting mortality among inpatients following rapid response team activation.

PURPOSE OF THE STUDY: Despite mature rapid response systems (RRS) for clinical deterioration, individuals activating RRS have poor outcomes, with up to one in four dying in hospital. We aimed to derive and validate a risk prediction tool for estimating risk of 28-day mortality among hospitalised patients following rapid response team (RRT) activation. STUDY DESIGN: Analysis of prospectively collected data on 1151 consecutive RRT activations involving 800 inpatients at a tertiary adult hospital. Patient characteristics, RRT triggers and actions, and mortality were ascertained from medical records and death registries. A multivariable risk prediction regression model, derived from 600 randomly selected patients, was validated in the remaining 200 patients. Main outcome was accuracy of weighted risk score (measured by area under receiver operator curve (AUC)) and performance characteristics for various cut-off scores. RESULTS: At 28 days, 150 (18.8%) patients had died. Increasing age, emergency admission, chronic liver disease, chronic kidney disease, malignancy, after-hours RRT activation, increasing National Early Warning Score, major/intense RRT intervention and multiple RRT activations were predictors of mortality. The risk score (0-105) in derivation and validation cohorts had AUCs 0.86 (95% CI 0.82 to 0.89) and 0.82 (95% CI 0.75 to 0.90), respectively. In the validation cohort, cut-off score of 32.5 or higher maximised sensitivity: 81.6% (95% CI 68.4% to 92.1%), specificity: 56.2% (95% CI 49.4% to 63.6%), positive likelihood ratio (LR): 1.9 (95% CI 1.5 to 2.3) and negative LR: 0.3 (95% CI 0.2 to 0.6). CONCLUSION: A validated risk score predicted risk of post-RRT death with more than 80% accuracy, helping to identify patients for whom targeted rescue care may improve survival.

Preoperative Use of Oral Beta-Adrenergic Blocking Agents and the Incidence of New-Onset Atrial Fibrillation After Cardiac Surgery. A Systematic Review and Meta-Analysis.

BACKGROUND: Current epidemiological data suggests that postoperative atrial fibrillation or atrial flutter (POAF) causes significant morbidity and mortality after cardiac surgery. The literature for prophylactic management of POAF is limited, resulting in the lack of clear guidelines on management recommendations. AIM: To examine the efficacy of prophylactic rate control agents in reducing the incidence of new-onset POAF in patients undergoing elective cardiac surgery. METHODS: Cochrane Central Register of Controlled Trials (CENTRAL), Embase, and Medline were systematically searched for blinded randomised controlled studies (RCT) evaluating adults with no history of atrial fibrillation randomised to a pharmacological agent (either beta blocker, calcium channel blocker or digoxin), compared to placebo. Utilising Cochrane guidance, three reviewers screened, extracted and the quality of the evidence was assessed. We used a random effects meta-analysis to compare a rate-control agent with placebo. RESULTS: Five RCTs (688 subjects, mean age 61±8.9, 69% male) were included. Beta blocker administration prior to elective cardiac surgery significantly reduced the incidence of POAF (OR 0.43, 95%Cl [0.30-0.61], I2=0%) without significant impact on ischaemic stroke (OR 0.49, 95%Cl [0.10-2.44], I2=0%), non-fatal myocardial infarction (OR 0.76, 95%Cl [0.08-7.44], I2=0%), overall mortality (OR 0.83, 95%Cl [0.19-3.66], I2=0%), or length of stay (mean -0.96days 95%Cl [-1.49 to -0.42], I2=0%). An increased rate of bradycardic episodes was observed (OR 3.53, 95%Cl [1.22-10.23], I2=0%). CONCLUSIONS: This review suggests that selective administration of prophylactic oral beta blockers prior to elective cardiac surgery is safe and may reduce the incidence of POAF.

The interaction of net ultrafiltration rate with urine output and fluid balance after continuous renal replacement therapy initiation: A multi-Centre study.

PURPOSE: During continuous renal replacement therapy (CRRT), a high net ultrafiltration rate (NUF) may worsen the decrease in urine output (UO) associated with starting CRRT. However, fluid balance (FB) may modulate this association. We aimed to examine the relationship between NUF, UO and FB at the start of CRRT. METHODS: A retrospective cohort study of 1030 CRRT-treated patients admitted to two tertiary ICUs. RESULTS: Median age was 60 years (IQR, 48-70), median APACHE III was 94 (IQR, 76-114) and median NUF rate was 0.7 mL/kg/h. In the 24 h after CRRT started, the mean hourly UO decreased from 25.5 mL to 11.9 mL (P < 0.001). Moreover, after adjusting for multiple confounders on multivariable analysis, a higher NUF was not significantly associated with a lower UO (-1.5 mL/kg for every 1 mL/kg/h increase in NUF; 95% CI -3.1 to 0.04; p = 0.064). In addition, pre-CRRT FB did not modulate the above relationship between higher NUF and lower UO. CONCLUSION: A higher NUF rate was not significantly associated with a greater immediate and sustained reduction in UO after CRRT commencement. FB before CRRT was also not associated with a greater reduction in UO. These findings do not provide evidence for an effect of NUF on renal function.

How a positive fluid balance develops in acute kidney injury: A binational, observational study.

PURPOSE: A positive fluid balance (FB) is associated with harm in intensive care unit (ICU) patients with acute kidney injury (AKI). We aimed to understand how a positive balance develops in such patients. METHODS: Multinational, retrospective cohort study of critically ill patients with AKI not requiring renal replacement therapy. RESULTS: AKI occurred at a median of two days after admission in 7894 (17.3%) patients. Cumulative FB became progressively positive, peaking on day three despite only 848 (10.7%) patients receiving fluid resuscitation in the ICU. In those three days, persistent crystalloid use (median:60.0 mL/h; IQR 28.9-89.2), nutritional intake (median:18.2 mL/h; IQR 0.0-45.9) and limited urine output (UO) (median:70.8 mL/h; IQR 49.0-96.7) contributed to a positive FB. Although UO increased each day, it failed to match input, with only 797 (10.1%) patients receiving diuretics in ICU. After adjustment, a positive FB four days after AKI diagnosis was associated with an increased risk of hospital mortality (OR 1.12;95% confidence intervals 1.05-1.19;p-value <0.001). CONCLUSION: Among ICU patients with AKI, cumulative FB increased after diagnosis and was associated with an increased risk of mortality. Continued crystalloid administration, increased nutritional intake, limited UO, and minimal use of diuretics all contributed to positive FB. KEY POINTS: Question How does a positive fluid balance develop in critically ill patients with acute kidney injury? Findings Cumulative FB increased after AKI diagnosis and was secondary to persistent crystalloid fluid administration, increasing nutritional fluid intake, and insufficient urine output. Despite the absence of resuscitation fluid and an increasing cumulative FB, there was persistently low diuretics use, ongoing crystalloid use, and a progressive escalation of nutritional fluid therapy. Meaning Current management results in fluid accumulation after diagnosis of AKI, as a result of ongoing crystalloid administration, increasing nutritional fluid, limited urine output and minimal diuretic use.

Point-of-care creatinine vs. central laboratory creatinine in the critically ill.

Objective: Frequent measurement of creatinine by point-of-care testing (POCT) may facilitate the earlier detection of acute kidney injury (AKI) in critically ill patients. However, no robust data exist to confirm its equivalence to central laboratory testing. We aimed to conduct a multicenter study to compare POCT with central laboratory creatinine (CrC) measurement. Design: Retrospective observational study, using hospital electronic medical records. Obtained paired point-of-care creatinine (CrP) from arterial blood gas machines and CrC. Setting: Four intensive care units in Queensland, Australia. Participants: Critically ill patients, where greater than 50% of POCT contained creatinine. Main outcome measures: Mean difference, bias, and limits of agreement between two methods, and biochemical confounders. Results: We studied 79,767 paired measurements in 19,118 patients, with a median Acute Physiology and Chronic Health Evaluation 3 score of 51. The mean CrC was 115.5 µmol/L (standard deviation: 100.2) compared to a CrP mean of 115 µmol/L (standard deviation: 100.7) (Pearson coefficient of 0.99). The mean difference between CrP and CrC was 0.49 µmol/L with 95% limits of agreement of -27 µmol/L and +28 µmol/L. Several biochemical variables were independently associated with the difference between tests (e.g., pH, potassium, lactate, glucose, and bilirubin), but their impact was small. Conclusion: In critically ill patients, measurement of creatinine by POCT yields clinically equivalent values to those obtained by central laboratory measurement and can be easily used for more frequent monitoring of kidney function in such patients. These findings open the door to the use of POCT for the earlier detection of acute kidney injury in critically ill patients.

Pilot Study of a Mobile Phone Chatbot for Medication Adherence and Toxicity Management Among Patients With GI Cancers on Capecitabine.

PURPOSE: Capecitabine is an oral chemotherapy used to treat many gastrointestinal cancers. Its complex dosing and narrow therapeutic index make medication adherence and toxicity management crucial for quality care. METHODS: We conducted a pilot study of PENNY-GI, a mobile phone text messaging-based chatbot that leverages algorithmic surveys and natural language processing to promote medication adherence and toxicity management among patients with gastrointestinal cancers on capecitabine. Eligibility initially included all capecitabine-containing regimens but was subsequently restricted to capecitabine monotherapy because of challenges in integrating PENNY-GI with radiation and intravenous chemotherapy schedules. We used design thinking principles and real-time data on safety, accuracy, and usefulness to make iterative refinements to PENNY-GI with the goal of minimizing the proportion of text messaging exchanges with incorrect medication or symptom management recommendations. All patients were invited to participate in structured exit interviews to provide feedback on PENNY-GI. RESULTS: We enrolled 40 patients (median age 64.5 years, 52.5% male, 62.5% White, 55.0% with colorectal cancer, 50.0% on capecitabine monotherapy). We identified 284 of 3,895 (7.3%) medication-related and 13 of 527 (2.5%) symptom-related text messaging exchanges with incorrect recommendations. In exit interviews with 24 patients, participants reported finding the medication reminders reliable and user-friendly, but the symptom management tool was too simplistic to be helpful. CONCLUSION: Although PENNY-GI provided accurate recommendations in >90% of text messaging exchanges, we identified multiple limitations with respect to the intervention's generalizability, usefulness, and scalability. Lessons from this pilot study should inform future efforts to develop and implement digital health interventions in oncology.

Associations between Late Lactate Clearance and Clinical Outcomes in Adults with Hyperlactataemia in the Setting of Diabetic Ketoacidosis.

Objective: This study aimed to determine the associations between lactate clearance in hyperlactataemic patients with diabetic ketoacidosis (DKA) and intensive care unit (ICU), hospital length of stay (LOS), and case-fatality. Methods: A retrospective, multicentre, cohort study of adult patients admitted to ICU with hyperlactataemia and a primary diagnosis of DKA from twelve sites in Queensland, Australia was conducted utilising pre-existing datasets that were linked for research purposes. The patients were divided into early and late lactate clearance groups; the early lactate clearance group included patients whose lactate returned to <2.0 mmol/L within 12 h, and the remainder were classified as late lactate clearance group. Results: The final dataset included 511 patients, 427 in the early lactate clearance group and 84 in the late lactate clearance group. Late lactate clearance was associated with increasing ICU LOS (ß = +15.82, 95% CI +0.05 to +31.59, p < 0.049), increasing hospital LOS (ß = +7.24, 95% CI +0.11 to 14.37, p = 0.048) and increasing Acute Physiology and Chronic Health Evaluation(APACHE) III score (ICU LOS outcome variable ß = +1.05, 95% CI +0.88 to +1.22, p < 0.001; hospital LOS outcome variable ß = +3.40, 95% CI +2.22 to 4.57, p < 0.001). Hospital case-fatality was not significantly different (2.2% in the early clearance group vs. 1.7% in the late clearance group, p = 0.496). Conclusions: In hyperlactataemic patients with DKA, late lactate clearance was associated with a statistically significant increase in both ICU and hospital LOS, though the clinical significance in both is minor.

Epidemiology of hypophosphatemia in critical illness: A multicentre, retrospective cohort study.

INTRODUCTION: Hypophosphatemia is common in critically ill patients. We have described the epidemiology of hypophosphatemia in patients admitted to the Intensive Care Units. METHODS: A multicentre, retrospective cohort study of 12 ICUs in Queensland, Australia from January 1st, 2015, to December 31st, 2021. Exclusions included readmissions, renal replacement therapy, end-stage renal disease, and palliative intent admissions and transfers from other ICUs. Patients were classified into four groups based on the severity of the first episode of low serum phosphate (PO4): "None" (PO4: ≥0.81 mmol/L, "Mild" (PO4: ≥0.50 & <0.81 mmol/L) "Moderate" (PO4: ≥0.30 & <0.50 mmol/L) and "Severe" (PO4: <0.30 mmol/L). A mixed-effect logistic regression model, including hospital as a random effect, was developed to examine factors associated with 90-day case fatality. RESULTS: Of the 89,776 patients admitted, 68,699 patients were included in this study, with 23,485 (34.2%) having hypophosphatemia with onset mostly on Day 2 of ICU admission and correcting to normal 3 days after hypophosphatemia was identified. There was substantial variation among participating ICUs in phosphate replacement; the threshold, and the route by which it was replaced. Day-90 case fatality increased with severity of hypophosphatemia (None: 3974 (8.8%), Mild: 2306 (11%), Moderate: 377 (14%); Severe: 108 (21%) (p < 0.001)). Multivariable regression analysis showed that compared to those without hypophosphatemia, patients with moderate (odds ratio (OR) 1.24; 95% confidence intervals (CI) 1.07-1.44; p = 0.004) or severe (OR 1.49; 95% CI 1.13-1.97; p = 0.005) hypophosphatemia had increased risk of 90-day case fatality. CONCLUSION: Hypophosphatemia was common, and mostly occurred on day 2 with early correction of serum phosphate. Phosphate replacement practices were variable among ICUs. Moderate and severe hypophosphatemia was associated with increased 90-day case fatality.

Rapid uptake of adjunctive corticosteroids for critically ill adults with septic shock following publication of ADRENAL trial. A multicenter, retrospective analysis of prescribing practices in Queensland Intensive Care Units.

BACKGROUND: Septic shock is common and associated with significant morbidity and mortality. The ADRENAL trial examined the use of hydrocortisone in patients with septic shock, demonstrating no difference in patient-centred outcomes but a decrease in the time to shock resolution. The change in clinical practice related to the publication of the ADRENAL trial is currently unknown. METHODS: A retrospective cohort study examining the use of hydrocortisone in patients with septic shock was conducted in 12 intensive care units (ICUs). A segmented linear regression was performed to identify a stepwise change in hydrocortisone administration and 90-day mortality associated with the publication of the ADRENAL trial. RESULTS: We included 4,198 patients with a mean age of 58 years (standard deviation, SD17), and the median noradrenaline equivalent score (NEE) was 0.07 µg/kg/min (IQR 0.02 - 0.17). Segmented regression analysis for hydrocortisone administration identified two breakpoints, 3 months before and 6 months after publication, leading to three periods: Pre-publication, Transition and Post-publication. Compared to the pre-publication period, the Transition and Post-publication cohorts had a higher proportion of hydrocortisone administration (28% vs. 34% vs. 43%; p < 0.0001). Furthermore, after adjustment for temporal change, the transition period had a significant change in the slope of the proportion of patients receiving hydrocortisone (-0.1% per month vs. +1.4% per month; p = 0.026), whereas this was not statistically significant during the post-publication period (+0.1% per month, p = 0.66). After adjusting for confounders, the Transition and Post-publication periods were independently associated with an increase in hydrocortisone (OR 1.4, 95% CI 1.14 - 1.77; p = 0.0015 and OR 2.03; 95% CI 1.74 - 2.36; p < 0.001, respectively). Furthermore, after adjusting for confounders, when compared to the Pre-transition period, the use of hydrocortisone was associated with a statistically significant decrease in 90-day mortality (14% vs. 24% absolute difference, aHR for hydrocortisone effect -0.81; 95% CI 0.65 - 0.99; p = 0.044). CONCLUSION: Publication of the ADRENAL trial changed clinical practice in Queensland ICUs with increased prescription of hydrocortisone for patients with septic shock with an associated reduction in mortality.

HiChIP-Based Epigenomic Footprinting Identifies a Promoter Variant of UXS1 That Confers Genetic Susceptibility to Gastroesophageal Cancer.

Genome-wide association studies (GWAS) have identified more than a hundred single nucleotide variants (SNV) associated with the risk of gastroesophageal cancer (GEC). The majority of the identified SNVs map to noncoding regions of the genome. Uncovering the causal SNVs and genes they modulate could help improve GEC prevention and treatment. Herein, we used HiChIP against histone 3 lysine 27 acetylation (H3K27ac) to simultaneously annotate active promoters and enhancers, identify the interactions between them, and detect nucleosome-free regions (NFR) harboring potential causal SNVs in a single assay. The application of H3K27ac HiChIP in GEC relevant models identified 61 potential functional SNVs that reside in NFRs and interact with 49 genes at 17 loci. The approach led to a 67% reduction in the number of SNVs in linkage disequilibrium at these 17 loci, and at 7 loci, a single putative causal SNV was identified. One SNV, rs147518036, located within the promoter of the UDP-glucuronate decarboxylase 1 (UXS1) gene, seemed to underlie the GEC risk association captured by the rs75460256 index SNV. The rs147518036 SNV creates a GABPA DNA recognition motif, resulting in increased promoter activity, and CRISPR-mediated inhibition of the UXS1 promoter reduced the viability of the GEC cells. These findings provide a framework that simplifies the identification of potentially functional regulatory SNVs and target genes underlying risk-associated loci. In addition, the study implicates increased expression of the enzyme UXS1 and activation of its metabolic pathway as a predisposition to gastric cancer, which highlights potential therapeutic avenues to treat this disease. Significance: Epigenomic footprinting using a histone posttranslational modification targeted 3D genomics methodology elucidates functional noncoding sequence variants and their target genes at cancer risk loci.

Current management of fluid balance in critically ill patients with acute kidney injury: A scoping review.

Objective: The overall objective of this scoping review is to assess the extent of the literature related to the fluid management of critically ill patients with acute kidney injury (AKI). Introduction: AKI is common in critically ill patients where fluid therapy is a mainstay of treatment. An association between fluid balance (FB) and adverse patient-centred outcomes in critically ill patients with AKI regardless of severity has been demonstrated. The evidence for the prospective intervention of FB and its impact on outcomes is unknown. Inclusion criteria: All studies investigating FB in patients with AKI admitted to an intensive care unit were included. Literature not related to FB in the critically ill patient with AKI population was excluded. Methods: We searched MEDLINE, EMBASE, and CINAHL from January 1st, 2012, onwards. We included primary research studies, experimental and observational, recruiting adult participants admitted to an intensive care unit who had an AKI. We extracted data on study and patient characteristics, as well as FB, renal-based outcomes, and patient-centred outcomes. Two reviewers independently screened citations for eligible studies and performed data extraction. Results: Of the 13,767 studies reviewed, 22 met the inclusion criteria. Two studies examined manipulation of fluid input, 18 studies assessed enhancing fluid removal, and two studies applied a restrictive fluid protocol. Sixteen studies examined patients receiving renal replacement therapy, five studies included non-renal replacement therapy patients, and one study included both. Current evidence is broad with varied approaches to managing fluid input and fluid removal. The studies did not demonstrate a consensus approach for any aspect of the fluid management of critically ill patients. There was a limited application of a restrictive fluid protocol with no conclusions possible. Conclusions: The current body of evidence for the management of FB in critically ill patients with AKI is limited in nature. The current quality of evidence is unable to guide current clinical practice. The key outcome of this review is to highlight areas for future research.

Polygenic risk for alcohol consumption and multisite chronic pain: Associations with ad lib drinking behavior.

Interrelations between alcohol use disorder and chronic pain have received increasing empirical attention, and several lines of evidence support the possibility of shared genetic liability. However, research on the genetic contributions to the component processes of these complex and potentially overlapping phenotypes remains scarce. The goal of the present study was to test polygenic risk scores (PRSs) for alcohol consumption and multisite chronic pain as predictors of ad lib drinking behavior during an experimental taste test. PRSs were calculated for 209 pain-free, moderate-to-heavy drinkers (57.9% male; 63.6% White). Among White participants, the alcohol and chronic pain PRSs showed nominally significant (ps < .05) positive associations with the volume of alcohol consumed and peak blood alcohol concentration (BAC), respectively. However, associations did not survive correction for multiple comparisons. When stratifying results by experimental condition (between-subjects design: no-pain vs. pain), the alcohol PRS was significantly and negatively associated with the volume of alcohol poured, consumed, and peak BAC among Black participants randomized to the no-pain condition (all false discovery rate [FDR]p < .05). Conversely, the chronic pain PRS was significantly and positively associated with study outcomes among White participants in both the no-pain (alcohol consumed; FDRp = .037) and pain conditions (peak BAC; FDRp = .017). These findings lend partial support to the assertion that alcohol consumption in the laboratory is reflective of drinking behavior in naturalistic settings. This was also the first study to use a pain-related PRS to predict alcohol outcomes, which may be indicative of shared etiology between base and target traits. (PsycInfo Database Record (c) 2023 APA, all rights reserved).