Influence of fluid accumulation on major adverse kidney events in critically ill patients - an observational cohort study.

BACKGROUND: Fluid accumulation (FA) is known to be associated with acute kidney injury (AKI) during intensive care unit (ICU) stay but data on mid-term renal outcome is scarce. The aim of this study was to investigate the association between FA at ICU day 3 and major adverse kidney events in the first 30 days after ICU admission (MAKE30). METHODS: Retrospective, single-center cohort study including adult ICU patients with sufficient data to compute FA and MAKE30. We defined FA as a positive cumulative fluid balance greater than 5% of bodyweight. The association between FA and MAKE30, including its sub-components, as well as the serum creatinine trajectories during ICU stay were examined. In addition, we performed a sensitivity analysis for the stage of AKI and the presence of chronic kidney disease (CKD). RESULTS: Out of 13,326 included patients, 1,100 (8.3%) met the FA definition. FA at ICU day 3 was significantly associated with MAKE30 (adjusted odds ratio [aOR] 1.96; 95% confidence interval [CI] 1.67-2.30; p < 0.001) and all sub-components: need for renal replacement therapy (aOR 3.83; 95%CI 3.02-4.84), persistent renal dysfunction (aOR 1.72; 95%CI 1.40-2.12), and 30-day mortality (aOR 1.70; 95%CI 1.38-2.09), p all < 0.001. The sensitivity analysis showed an association of FA with MAKE30 independent from a pre-existing CKD, but exclusively in patients with AKI stage 3. Furthermore, FA was independently associated with the creatinine trajectory over the whole observation period. CONCLUSIONS: Fluid accumulation is significantly associated with MAKE30 in critically ill patients. This association is independent from pre-existing CKD and strongest in patients with AKI stage 3.

Protocolised early de-resuscitation in septic shock (REDUCE): protocol for a randomised controlled multicentre feasibility trial.

BACKGROUND: Fluid overload is associated with excess mortality in septic shock. Current approaches to reduce fluid overload include restrictive administration of fluid or active removal of accumulated fluid. However, evidence on active fluid removal is scarce. The aim of this study is to assess the efficacy and feasibility of an early de-resuscitation protocol in patients with septic shock. METHODS: All patients admitted to the intensive care unit (ICU) with a septic shock are screened, and eligible patients will be randomised in a 1:1 ratio to intervention or standard of care. INTERVENTION: Fluid management will be performed according to the REDUCE protocol, where resuscitation fluid will be restricted to patients showing signs of poor tissue perfusion. After the lactate has peaked, the patient is deemed stable and assessed for active de-resuscitation (signs of fluid overload). The primary objective of this study is the proportion of patients with a negative cumulative fluid balance at day 3 after ICU. Secondary objectives are cumulative fluid balances throughout the ICU stay, number of patients with fluid overload, feasibility and safety outcomes and patient-centred outcomes. The primary outcome will be assessed by a logistic regression model adjusting for the stratification variables (trial site and chronic renal failure) in the intention-to-treat population. ETHICS AND DISSEMINATION: The study was approved by the respective ethical committees (No 2020-02197). The results of the REDUCE trial will be published in an international peer-reviewed medical journal regardless of the results. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, NCT04931485.

Choice of creep or maintenance fluid type and their impact on total daily ICU sodium burden in critically ill patients: A systematic review and meta-analysis.

PURPOSE: Maintenance and hidden/creep fluids are a major source of fluid and sodium intake in intensive care unit (ICU) patients. Recent research indicates that low versus high sodium content maintenance fluids could decrease fluid and sodium burden. We conducted a systematic review (SR) with meta-analysis to summarize the impact of maintenance fluid choice on total daily sodium in ICU patients. MATERIALS AND METHODS: Systematic literature search in Pubmed, Embase, the Cochrane Library and the. CLINICAL TRIALS REGISTRY: Only controlled clinical trials were included. EXCLUSION CRITERIA: trials on resuscitation fluids, performed in the emergency department only and in pediatric patients. Primary objective was the reduction in mean total sodium intake with low versus high sodium content maintenance/creep fluids. RESULTS: Five studies (1105 patients) were included. Heterogeneity was high.Risk of bias was moderate. Mean daily sodium reduction was 117 mmol (95%Confidence Interval [CI] -174; -59; p < 0.001) with low versus high sodium content maintenance/creep fluids. Incidence of hyperchloremia was lower (OR 0.26; 95%CI 0.1; 0.64) with low sodium. There were no differences in the incidences of hyper-/hyponatremia and fluid balances. CONCLUSION: Using low sodium content maintenance/creep fluids substantially reduces daily sodium burden in adult ICU patients. Significant knowledge/research gaps exist regarding relevance and safety. TRIAL REGISTRATION: PROSPERO 2022 CRD42022300577 (February 2022).

Fluid overload and mortality in critically ill patients with severe heart failure and cardiogenic shock-An observational cohort study.

Objective: Patients with heart failure (HF) and cardiogenic shock are especially prone to the negative effects of fluid overload (FO); however, fluid resuscitation in respective patients is sometimes necessary resulting in FO. We aimed to study the association of FO at ICU discharge with 30-day mortality in patients admitted to the ICU due to severe heart failure and/or cardiogenic shock. Methods: Retrospective, single-center cohort study. Patients with admission diagnoses of severe HF and/or cardiogenic shock were eligible. The following exclusion criteria were applied: (I) patients younger than 16 years, (II) patients admitted to our intermediate care unit, and (III) patients with incomplete data to determine FO at ICU discharge. We used a cumulative weight-adjusted definition of fluid balance and defined more than 5% as FO. The data were analyzed by univariate and adjusted univariate logistic regression. Results: We included 2,158 patients in our analysis. 185 patients (8.6%) were fluid overloaded at ICU discharge. The mean FO in the FO group was 7.2% [interquartile range (IQR) 5.8-10%]. In patients with FO at ICU discharge, 30-day mortality was 22.7% compared to 11.7% in non-FO patients (p < 0.001). In adjusted univariate logistic regression, we did not observe any association of FO at discharge with 30-day mortality [odds ratio (OR) 1.48; 95% confidence interval (CI) 0.81-2.71, p = 0.2]. No association between FO and 30-day mortality was found in the subgroups with HF only or cardiogenic shock (all p > 0.05). Baseline lactate (adjusted OR 1.27; 95% CI 1.13-1.42; p < 0.001) and cardiac surgery at admission (adjusted OR 1.94; 95% CI 1.0-3.76; p = 0.05) were the main associated factors with FO at ICU discharge. Conclusion: In patients admitted to the ICU due to severe HF and/or cardiogenic shock, FO at ICU discharge seems not to be associated with 30-day mortality.

Dysphagia Post-Extubation Affects Long-Term Mortality in Mixed Adult ICU Patients-Data From a Large Prospective Observational Study With Systematic Dysphagia Screening.

Data on long-term effects of post-extubation dysphagia is lacking. We investigate mid- and long-term clinical outcomes in a large sample of ICU patients with systematic dysphagia screening. DESIGN: Outcome analysis with a follow-up of 6 years or death (whichever occurred earlier) of ICU patients from a prospective observational trial (Dysphagia in Mechanically Ventilated ICU Patients study) with systematic dysphagia screening. SETTING: ICU of a tertiary care academic center. PATIENTS: Nine-hundred thirty-three mixed medical-surgical ICU patients (median age, 66 yr; interquartile range [IQR], 54-74, Acute Physiology and Chronic Health Evaluation II score 19 [IQR, 14-24], 71% male). INTERVENTIONS: ICU patients were followed up for a mean follow-up period of 1,731 ± 772 days (4.7 ± 2.1 yr). Primary outcome measures were 180-day and 360-day all-cause mortality in ICU patients with versus without dysphagia. MEASUREMENTS AND MAIN RESULTS: Two-hundred seventy-three patients died (29.3%) during the observational interval (n = 76 lost to follow-up). In dysphagia screening positive versus negative ICU patients, mortality at 180 days was 16% versus 5.8% (excess mortality 10.2%), whereas mortality at 360 days was 25% versus 9.1% (excess mortality 15.9%). Adjustment for confounders in a Cox model revealed a significant association of dysphagia with all-cause mortality in a time-dependent manner. The risk of death in ICU patients with versus without post-extubation dysphagia declined from about 2.5 times higher to about equal risk for both groups over the first year (i.e. 1.03 yr) post-ICU admission (at 360 d: hazard ratio [HR], 1.03; 95% CI, 0.42-3.70). The mean mortality HR for the first year post-ICU admission was HR 2.09 (95% CI, 1.34-3.24; p = 0.0009). CONCLUSIONS: Long-term follow-up of a large cohort of medical-surgical adult ICU patients systematically screened for dysphagia showed that dysphagia is associated with increased hazards for death for up to 1 year after ICU admission. Our data underline effects of post-extubation dysphagia on long-term clinical outcomes in affected critically ill patients.

Methods of Assessing Frailty in the Critically Ill: A Systematic Review of the Current Literature.

INTRODUCTION: As new treatments have become established, more frail pre-ICU patients are being admitted to intensive care units (ICUs); this is creating new challenges to provide adequate care and to ensure that resources are allocated in an ethical and economical manner. This systematic review evaluates the current standard for assessing frailty on the ICU, including methods of assessment, time point of measurements, and cut-offs. METHODS: A systematic search was conducted on MEDLINE, Clinical Trials, Cochrane Library, and Embase. Randomized and non-randomized controlled studies were included that evaluated diagnostic tools and ICU outcomes for frailty. Exclusion criteria were the following: studies without baseline assessment of frailty on ICU admission, studies in paediatric patients or pregnant women, and studies that targeted very narrow populations of ICU patients. Eligible articles were included until January 31, 2021. Methodological quality was assessed using the Newcastle-Ottawa Scale. No meta-analysis was performed, due to heterogeneity. RESULTS: N = 57 articles (253,376 patients) were included using 19 different methods to assess frailty or a surrogate. Frailty on ICU admission was most frequently detected using the Clinical Frailty Scale (CFS) (n = 35, 60.3%), the Frailty Index (n = 5, 8.6%), and Fried's frailty phenotype (n = 6, 10.3%). N = 22 (37.9%) studies assessed functional status. Cut-offs, time points, and manner of baseline assessment of frailty on ICU admission varied widely. Frailty on ICU admission was associated with short- and long-term mortality, functional and cognitive impairment, increased health care dependency, and impaired quality of life post-ICU discharge. CONCLUSIONS: Frailty assessment on the ICU is heterogeneous with respect to methods, cut-offs, and time points. The CFS may best reflect frailty in the ICU. Frailty assessments should be harmonized and performed routinely in the critically ill.

Correction: (TIMP2) x (IGFBP7) as early renal biomarker for the prediction of acute kidney injury in aortic surgery (TIGER). A single center observational study.

[This corrects the article DOI: 10.1371/journal.pone.0244658.].

(TIMP2) x (IGFBP7) as early renal biomarker for the prediction of acute kidney injury in aortic surgery (TIGER). A single center observational study.

OBJECTIVE: Postoperative acute kidney injury (po-AKI) is frequently observed after major vascular surgery and impacts on mortality rates. Early identification of po-AKI patients using the novel urinary biomarkers insulin-like growth factor-binding-protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2) might help in early identification of individuals at risk of AKI and enable timely introduction of preventative or therapeutic interventions with the aim of reducing the incidence of po-AKI. We investigated whether biomarker-based monitoring would allow for early detection of po-AKI in patients undergoing abdominal aortic interventions. METHODS: In an investigator-initiated prospective single-center observational study in a tertiary care academic center, adult patients with emergency/ elective abdominal aortic repair were included. Patients were tested for concentrations of urinary (TIMP-2) x (IGFBP7) at baseline, after surgical interventions (PO), and in the mornings of the first postoperative day (POD1). The primary endpoint was a difference in urinary (TIMP-2) x (IGFBP7) levels at POD1 in patients with/ without po-AKI (all KDIGO stages, po-AKI until seven days after surgery). Secondary endpoints included sensitivity/ specificity analyses of previously proposed cut-off levels and clinical outcome measures (e.g. need for renal replacement therapy). RESULTS: 93 patients (n = 71 open surgery) were included. Po-AKI was observed in 33% (31/93) of patients. Urinary (TIMP-2) x (IGFBP7) levels at POD1 did not differ between patients with/ without AKI (median 0.39, interquartile range [IQR] 0.13-1.05 and median 0.23, IQR 0.14-0.53, p = .11, respectively) and PO (median 0.2, IQR 0.08-0.42, 0.18, IQR 0.09-0.46; p = .79). Higher median (TIMP-2) x (IGFBP7) levels were noted in KDIGO stage 3 pAKI patients at POD1 (3.75, IQR 1.97-6.92; p = .003). Previously proposed cutoff levels (0.3, 2) showed moderate sensitivity/ specificity (0.58/0.58 and 0.16/0.98, respectively). CONCLUSION: In a prospective monocentric observational study in patients after abdominal aortic repair, early assessment of urinary (TIMP-2) x (IGFBP7) did not appear to have adequate sensitivity/ specificity to identify patients that later developed postoperative AKI. CLINICALTRIALS.GOV: NCT03469765, registered March 19, 2018.

Hypertonic saline for fluid resuscitation in ICU patients post-cardiac surgery (HERACLES): a double-blind randomized controlled clinical trial.

PURPOSE: Recent evidence questions a liberal approach to fluid resuscitation in intensive care unit (ICU) patients. Here, we assess whether use of hypertonic saline applied as single infusion at ICU admission after cardiac surgery can reduce cumulative perioperative fluid volume. METHODS: Prospective randomized double-blind single-center clinical trial investigates effects of a single infusion of hypertonic saline (HS) versus normal saline (comparator). Primary endpoint was the cumulative amount of fluid administered in patients in the hypertonic saline versus the 0.9% saline groups (during ICU stay). Upon ICU admission, patients received a single infusion of 5 ml/kg body weight of 7.3% NaCl (or 0.9% NaCl) over 60 min. Patients undergoing cardiac surgery for elective valvular and/or coronary heart disease were included. Patients with advanced organ dysfunction, infection, and/or patients on chronic steroid medication were excluded. RESULTS: A total of 101 patients were randomized to receive the study intervention (HS n = 53, NS n = 48). Cumulative fluid intake on the ICU (primary endpoint) did not differ between the HS and the NS groups [median 3193 ml (IQR 2052-4333 ml) vs. 3345 ml (IQR 2332-5043 ml)]. Postoperative urinary output until ICU discharge was increased in HS-treated patients [median 2250 ml (IQR 1640-2690 ml) vs. 1545 ml (IQR 1087-1976 ml)], and ICU fluid balance was lower in the HS group when compared to the NS group [296 ml (IQR - 441 to 1412 ml) vs. 1137 ml (IQR 322-2660 ml)]. CONCLUSION: In a monocentric prospective double-blind randomized clinical trial, we observed that hypertonic saline did not reduce the total fluid volume administered on the ICU in critically ill cardiac surgery patients. Hypertonic saline infusion was associated with timely increase in urinary output. Variations in electrolyte and acid-base homeostasis were transient, but substantial in all patients.

Hypertonic saline for fluid resuscitation after cardiac surgery (HERACLES): study protocol for a preliminary randomised controlled clinical trial.

BACKGROUND: Intraoperative and postoperative management of cardiac surgery patients is complex, involving the application of differential vasopressors and volume therapy. It has been shown that a positive fluid balance has a major impact on postoperative outcome. Today, the advantages and disadvantages of buffered crystalloid solutes are a topic of controversy, with no consensus being reached so far. The use of hypertonic saline (HS) has shown promising results with respect to lower total fluid balance and postoperative weight gain in critically ill patients in preliminary studies. However, collection of more data on HS in critically ill patients seems warranted. This preliminary study aims to investigate whether fluid resuscitation using HS in patients following cardiac surgery results in less total fluid volume being administered. METHODS: In a prospective double-blind randomised controlled clinical trial, we aim to recruit 96 patients undergoing elective cardiac surgery for ischaemic and/or valvular heart disease. After postoperative admission to the intensive care unit (ICU), patients will be randomly assigned to receive 5 ml/kg ideal body weight HS (7.3% NaCl) or normal saline (NS, 0.9% NaCl) infused within 60 min. Blood and urine samples will be collected preoperatively and postoperatively up to day 6 to assess changes in renal, cardiac, inflammatory, acid-base, and electrolyte parameters. Additionally, we will perform renal ultrasonography studies to assess renal blood flow before, during, and after infusion, and we will measure total body water using preoperative and postoperative body composition analysis (bioimpedance). Patients will be followed up for 90 days. DISCUSSION: The key objective of this study is to assess the cumulative amount of fluid administered in the intervention (HS) group versus control (NS) group during the ICU stay. In this preliminary, prospective, randomised controlled clinical trial we will test the hypothesis that use of HS results in less total fluids infused and less postoperative weight gain when compared to the standard of intensive care in cardiac surgery patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03280745 . Registered on 12 September 2017.

Mannitol for the Prevention of Peri-Operative Acute Kidney Injury: A Systematic Review.

OBJECTIVE/BACKGROUND: Post-operative acute kidney injury (AKI) is a frequent peri-operative complication that negatively affects morbidity and mortality. Mannitol is frequently used peri-operatively for renal protection, although evidence for its use is ambiguous. A systematic review was conducted to clarify whether there is evidence supporting peri-operative mannitol administration for the prevention of post-operative AKI. METHODS: A systematic literature search was performed in MEDLINE/Pubmed, Embase, the Cochrane Library, Clinical Trials registry, and the Cochrane Central Register of Controlled Trials (CENTRAL). Eligibility criteria were (i) population (studies involving adult patients undergoing surgery or a related intervention); (ii) intervention (intravenous mannitol administered in either the pre- or intra-operative period with comparison to controls); and (iii) predefined outcomes (post-operative AKI or respective renal end points/surrogates). RESULTS: In total, 1,538 articles published between January 1990 and October 2018 were identified. After checking for eligibility, 22 studies, including 17 prospective and/or randomised controlled trials and five retrospective studies, were included. The investigations involved various fields of surgery, such as aortic surgery, cardiac surgery with cardiopulmonary bypass, and urological procedures, including partial nephrectomy. Significant heterogeneity, limited sample size, and mostly short follow up periods were noted. CONCLUSION: Given the available evidence, the peri-operative use of mannitol to prevent AKI cannot be considered an evidence based intervention in cardiac surgery, partial nephrectomy, and/or other major surgery. Further research is required with a focus on patients at high risk of post-operative AKI.