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In this review, we aimed to comprehensively summarize current literature on pathophysiology, relevance, diagnosis and treatment of fluid accumulation in patients with sepsis/septic shock. Fluid accumulation syndrome (FAS) is defined as fluid accumulation (any degree, expressed as percentage from baseline body weight) with new onset organ-failure. Over the years, many studies have described the negative impact of FAS on clinically relevant outcomes. While the relationship between FAS and ICU outcomes is well described, uncertainty exists regarding its diagnosis, monitoring and treatment. A stepwise approach is suggested to prevent and treat FAS in patients with septic shock, including minimizing fluid intake (e.g., by limiting intravenous fluid administration and employing de-escalation whenever possible), limiting sodium and chloride administration, and maximizing fluid output (e.g., with diuretics, or renal replacement therapy). Current literature implies the need for a multi-tier, multi-modal approach to de-resuscitation, combining a restrictive fluid management regime with a standardized early active de-resuscitation, maintenance fluid reduction (avoiding fluid creep) and potentially using physical measures such as compression stockings.Trial registration: Not applicable.

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BACKGROUND: Fluid overload is associated with increased mortality in intensive care unit (ICU) patients. The GODIF trial aims to assess the benefits and harms of fluid removal with furosemide versus placebo in stable adult patients with moderate to severe fluid overload in the ICU. This article describes the detailed statistical analysis plan for the primary results of the second version of the GODIF trial. METHODS: The GODIF trial is an international, multi-centre, randomised, stratified, blinded, parallel-group, pragmatic clinical trial, allocating 1000 adult ICU patients with moderate to severe fluid overload 1:1 to furosemide versus placebo. The primary outcome is days alive and out of hospital within 90 days post-randomisation. With a power of 90% and an alpha level of 5%, we may reject or detect an improvement of 8%. The primary analyses of all outcomes will be performed in the intention-to-treat population. For the primary outcome, the Kryger Jensen and Lange method will be used to compare the two treatment groups adjusted for stratification variables supplemented with sensitivity analyses in the per-protocol population and with further adjustments for prognostic variables. Secondary outcomes will be analysed with multiple linear regressions, logistic regressions or the Kryger Jensen and Lange method as suitable with adjustment for stratification variables. CONCLUSION: The GODIF trial data will increase the certainty about the effects of fluid removal using furosemide in adult ICU patients with fluid overload. TRIAL REGISTRATIONS: EudraCT identifier: 2019-004292-40 and ClinicalTrials.org: NCT04180397.

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Goals of volume management are to accurately assess intravascular and extravascular volume and predict response to volume administration, vasopressor support or volume removal. Data are reviewed that support the following: (i) Dynamic parameters reliably guide volume administration and may improve clinical outcomes compared with static parameters, but some are invasive or only validated with mechanical ventilation without spontaneous breathing. (ii) Ultrasound visualization of inferior vena cava (IVC) diameter variations with respiration reliably assesses intravascular volume and predicts volume responsiveness. (iii) Although physiology of IVC respiratory variations differs with mechanical ventilation and spontaneous breathing, the IVC collapsibility index (CI) and distensibility index are interconvertible. (iv) Prediction of volume responsiveness by IVC CI is comparable for mechanical ventilation and spontaneous breathing patients. (v) Respiratory variations of subclavian/proximal axillary and internal jugular veins by ultrasound are alternative sites, with comparable reliability. (vi) Data support clinical applicability of IVC CI to predict hypotension with anesthesia, guide ultrafiltration goals, predict dry weight, predict intra-dialytic hypotension and assess acute decompensated heart failure. (vii) IVC ultrasound may complement ultrasound of heart and lungs, and abdominal organs for venous congestion, for assessing and managing volume overload and deresuscitation, renal failure and shock. (viii) IVC ultrasound has limitations including inadequate visualization. Ultrasound data should always be interpreted in clinical context. Additional studies are required to further assess and validate the role of bedside ultrasonography in clinical care.

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BACKGROUND: Fluid therapy is a common intervention in critically ill patients. It is increasingly recognised that deresuscitation is an essential part of fluid therapy and delayed deresuscitation is associated with longer invasive ventilation and length of intensive care unit (ICU) stay. However, optimal timing and rate of deresuscitation remain unclear. Lung ultrasound (LUS) may be used to identify fluid overload. We hypothesise that daily LUS-guided deresuscitation is superior to deresuscitation without LUS in critically ill patients expected to undergo invasive ventilation for more than 24 h in terms of ventilator free-days and being alive at day 28. METHODS: The "effect of lung ultrasound-guided fluid deresuscitation on duration of ventilation in intensive care unit patients" (CONFIDENCE) is a national, multicentre, open-label, randomised controlled trial (RCT) in adult critically ill patients that are expected to be invasively ventilated for at least 24 h. Patients with conditions that preclude a negative fluid balance or LUS examination are excluded. CONFIDENCE will operate in 10 ICUs in the Netherlands and enrol 1000 patients. After hemodynamic stabilisation, patients assigned to the intervention will receive daily LUS with fluid balance recommendations. Subjects in the control arm are deresuscitated at the physician's discretion without the use of LUS. The primary endpoint is the number of ventilator-free days and being alive at day 28. Secondary endpoints include the duration of invasive ventilation; 28-day mortality; 90-day mortality; ICU, in hospital and total length of stay; cumulative fluid balance on days 1-7 after randomisation and on days 1-7 after start of LUS examination; mean serum lactate on days 1-7; the incidence of reintubations, chest drain placement, atrial fibrillation, kidney injury (KDIGO stadium ≥ 2) and hypernatremia; the use of invasive hemodynamic monitoring, and chest-X-ray; and quality of life at day 28. DISCUSSION: The CONFIDENCE trial is the first RCT comparing the effect of LUS-guided deresuscitation to routine care in invasively ventilated ICU patients. If proven effective, LUS-guided deresuscitation could improve outcomes in some of the most vulnerable and resource-intensive patients in a manner that is non-invasive, easy to perform, and well-implementable. TRIAL REGISTRATION: ClinicalTrials.gov NCT05188092. Registered since January 12, 2022.

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STUDY OBJECTIVE: Although fluid resuscitation is recommended by the Society of Critical Care Medicine Surviving Sepsis Campaign Guidelines, risks of volume overload persist.The objective of this systematic review is to assess the effects of a restrictive fluid resuscitation approach in the septic patient both during and after the initial resuscitation period (30 ml/kg). DESIGN: A systematic review and meta-analysis with trial sequential analysis (TSA) of randomized controlled trials was conducted. Two blinded reviewers independently assessed and included studies that evaluated adult patients with sepsis involving a comparator group with an effective restrictive fluid resuscitation approach. The primary outcome was mortality. Secondary outcomes included rates of acute kidney injury (AKI), renal replacement therapy (RRT), ventilator days, intensive care unit (ICU) and hospital length of stay (LOS), duration of vasopressor therapy, and limb (or digital) ischemia. SETTING: PubMed and Medline databases were queried for the search. PATIENTS: A total of eight trials in 2375 patients were included. INTERVENTION: Effective restrictive fluid resuscitation compared with standard of care. MEASUREMENTS AND MAIN RESULTS: The risk of bias was high in six studies and low in two studies, and all studies implemented fluid restriction after a 30-ml/kg infusion of fluids. Fluid restriction did not significantly reduce mortality in all studies compared to usual care (37% vs. 40% with usual care; risk ratio [RR] 0.90, 95% confidence interval [CI] 0.76-1.06, p = 0.23, I2  = 24%) or by TSA findings. There were no significant differences in rates of AKI or RRT (5 studies), LOS in ICU (4 studies) or hospital (3 studies), duration of vasopressor therapy (6 studies), or incidence of limb or digital ischemia (3 studies). However, fluid restriction significantly reduced ventilator days as evaluated in seven studies (mean difference - 1.25 days, 95% CI -1.92 to -0.58 days, p = 0.0003, I2  = 90%). CONCLUSION: This study demonstrated that a restrictive resuscitation strategy in sepsis resulted in no difference in mortality but may reduce ventilator days. Larger randomized trials are required to determine the optimal management of fluids in patients with sepsis.

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PURPOSE: To evaluate the impact of active fluid de-resuscitation on mortality in critically ill patients with septic shock. METHODS: A systematic search was performed on PubMed, EmBase, and the Cochrane Library databases. Trials investigating active fluid de-resuscitation and reporting data on mortality in patients with septic shock were eligible. The primary objective was the impact of active de-resuscitation in patients with septic shock on short-term mortality. Secondary outcomes were whether de-resuscitation lead to a fluid separation, and the impact of de-resuscitation on patient-centred outcomes. RESULTS: Thirteen trials (8,030 patients) were included in the systematic review, whereof 5 randomised-controlled trials (RCTs) were included in the meta-analysis. None of the RCTs showed a reduction in mortality with active de-resuscitation measures (relative risk (RR) 1.12 [95%-CI 0.84 - 1.48]). Fluid separation was achieved by two RCTs. Evidence from non-randomised trials suggests a mortality benefit with de-resuscitation strategies and indicates a trend towards a more negative fluid balance. Patient-centred outcomes were not influenced in the RCTs, and only one non-randomised trial revealed an impact on the duration of mechanical ventilation and renal replacement requirement (RRT). CONCLUSION: We found no evidence for superiority of active fluid de-resuscitation compared to usual care regarding mortality, fluid balance or patient-centred outcomes in patients with septic shock. Current evidence is limited by the lack of high-quality RCTs in patients with septic shock, the small sample sizes and the heterogeneity of the applied de-resuscitation techniques. In addition, validity of the majority of RCTs is compromised by their inability to achieve fluid separation.

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Bioelectrical impedance analysis (BIA) is a promising tool to evaluate the body composition of critically-ill patients. The present study aimed to assess its value as a fluid management monitoring tool during standardized deresuscitation strategy. A historical cohort of critically-ill adult patients with fluid overload and continuous renal replacement therapy was used to explore both relationship and agreement between changes in cumulative fluid balance and BIA-derived hydration variables within the 5 days following initiation of deresuscitation strategy using net ultrafiltration. Correlations were described using Spearman's rank correlation coefficient, and agreement using Bland-Altman analysis for repeated measurements. Sixty-one couples of fluid shift measurements from 30 patients were analyzed. The deresuscitation strategy induced a negative mean (± SD) cumulative fluid balance (- 4.2 ± 3.8 L) and a significant decrease in extra- and intracellular water (P < 0.001). Decreases in extra- and intracellular water were independent of weight variations inputted in the BIA device. Total body water (rho = 0.63), extracellular water (rho = 0.68), and intracellular water (rho = 0.67) were significantly correlated with cumulative fluid balance (all P values < 0.001). The limits of agreement did not allow interchangeability for a delta of 2L between cumulative fluid balance and BIA-derived hydration variables (P > 0.05). BIA hydration-derived variables are significantly correlated with cumulative fluid balance but the large limits of agreements exclude interchangeability of the measures.

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Introduction: Fluid overload in patients in the intensive care unit (ICU) is associated with higher mortality. There are few randomized controlled trials to guide physicians in treating patients with fluid overload in the ICU, and no guidelines exist. We aimed to elucidate how ICU physicians from Nordic countries define, assess, and treat fluid overload in the ICU. Materials and methods: We developed an online questionnaire with 18 questions. The questions were pre-tested and revised by specialists in intensive care medicine. Through a network of national coordinators. The survey was distributed to a wide range of Nordic ICU physicians. The distribution started on January 5th, 2022 and ended on May 6th, 2022. Results: We received a total of 1,066 responses from Denmark, Norway, Finland, Sweden, and Iceland. When assessing fluid status, respondents applied clinical parameters such as clinical examination findings, cumulative fluid balance, body weight, and urine output more frequently than cardiac/lung ultrasound, radiological appearances, and cardiac output monitoring. A large proportion of the respondents agreed that a 5% increase or more in body weight from baseline supported the diagnosis of fluid overload. The preferred de-resuscitation strategy was diuretics (91%), followed by minimization of maintenance (76%) and resuscitation fluids (71%). The majority declared that despite mild hypotension, mild hypernatremia, and ongoing vasopressor, they would not withhold treatment of fluid overload and would continue diuretics. The respondents were divided when it came to treating fluid overload with loop diuretics in patients receiving noradrenaline. Around 1% would not administer noradrenaline and diuretics simultaneously and 35% did not have a fixed upper limit for the dosage. The remaining respondents 63% reported different upper limits of noradrenaline infusion (0.05-0.50 mcg/kg/min) when administering loop diuretics. Conclusion: Self-reported practices among Nordic ICU physicians when assessing, diagnosing, and treating fluid overload reveals variability in the practice. A 5% increase in body weight was considered a minimum to support the diagnosis of fluid overload. Clinical examination findings were preferred for assessing, diagnosing and treating fluid overload, and diuretics were the preferred treatment modality.

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Background and Objectives: Albumin binding of the loop diuretic furosemide forms the basis for its transport to the kidney and subsequent tubular secretion, which is a prerequisite for its therapeutic effects. Accordingly, high albumin concentrations should result in higher efficacy of furosemide. However, study results on the combination of furosemide in conjunction with albumin, and on the efficacy of furosemide in hypoalbuminemia, did not confirm this hypothesis. The aim of this study was to determine the efficacy of furosemide not only in relation to albumin concentration, but also taking albumin function into account. Materials and Methods: In a prospective and non-interventional clinical observational trial, blood and urine samples from 50 intensive care patients receiving continuous intravenous furosemide therapy were evaluated. Albumin binding capacity (ABiC) determination allowed conclusions to be drawn about the binding site-specific loading state of albumin, by quantifying the unbound fraction of the fluorescent marker dansylsarcosine. In addition, assessment of the total concentration of furosemide in plasma and urine, as well as the concentration of free furosemide fraction in plasma, was performed by HPLC−MS. The efficacy of furosemide was evaluated by the ratio of urine excretion to fluid intake. Results: In patients with an ABiC ≥ 60% free furosemide fraction was significantly lower compared to patients with a lower ABiC (p < 0.001), urinary furosemide concentration was higher (p = 0.136), and a significantly higher proportion of infused furosemide was excreted renally (p = 0.010). ABiC was positively correlated (r = 0.908, p = 0.017) with increase in the urine excretion to fluid input ratio after initiation of furosemide therapy. Conclusions: ABiC could serve as a marker for individual response to furosemide and could be used to generate patient-specific therapeutic regimens. In view of the relatively low number of patients in this study, the relationship between furosemide efficacy and albumin function should be investigated in larger studies in the future.

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BACKGROUND: Active fluid removal has been suggested to improve prognosis following the resolution of acute circulatory failure. We have implemented a routine care protocol to guide fluid removal during continuous renal replacement therapy (CRRT). We designed a before-after pilot study to evaluate the impact of this deresuscitation strategy on the fluid balance. METHODS: Consecutive ICU patients suffering from fluid overload and undergoing CRRT for acute kidney injury underwent a perfusion-based deresuscitation protocol combining a restrictive intake, net ultrafiltration (UFnet) of 2 mL/kg/h, and monitoring of perfusion (early dry group, N = 42) and were compared to a historical group managed according to usual practices (control group, N = 45). The primary outcome was the cumulative fluid balance at day 5 or at discharge. RESULTS: Adjusted cumulative fluid balance was significantly lower in the early dry group (median [IQR]: -7784 [-11,833 to -2933] mL) compared to the control group (-3492 [-9935 to -1736] mL; p = 0.04). The difference was mainly driven by a greater daily UFnet (31 [22-46] mL/kg/day vs. 24 [15-32] mL/kg/day; p = 0.01). There was no significant difference between both groups regarding hemodynamic tolerance. CONCLUSION: Our perfusion-based deresuscitation protocol achieved a greater negative cumulative fluid balance compared to standard practices and was hemodynamically well tolerated.

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BACKGROUND: Fluid overload is a risk factor for mortality in intensive care unit (ICU) patients. Administration of loop diuretics is the predominant treatment of fluid overload, but evidence for its benefit is very uncertain when assessed in a systematic review of randomised clinical trials. The GODIF trial will assess the benefits and harms of goal directed fluid removal with furosemide versus placebo in ICU patients with fluid overload. METHODS: An investigator-initiated, international, randomised, stratified, blinded, parallel-group trial allocating 1000 adult ICU patients with fluid overload to infusion of furosemide versus placebo. The goal is to achieve a neutral fluid balance. The primary outcome is days alive and out of hospital 90 days after randomisation. Secondary outcomes are all-cause mortality at day 90 and 1-year after randomisation; days alive at day 90 without life support; number of participants with one or more serious adverse events or reactions; health-related quality of life and cognitive function at 1-year follow-up. A sample size of 1000 participants is required to detect an improvement of 8% in days alive and out of hospital 90 days after randomisation with a power of 90% and a risk of type 1 error of 5%. The conclusion of the trial will be based on the point estimate and 95% confidence interval; dichotomisation will not be used. CLINICALTRIALS: gov identifier: NCT04180397. PERSPECTIVE: The GODIF trial will provide important evidence of possible benefits and harms of fluid removal with furosemide in adult ICU patients with fluid overload.

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PURPOSE: Fluid overload is common in critical illness and is associated with mortality. This study investigated the feasibility of a randomised trial comparing conservative fluid administration and deresuscitation (active removal of accumulated fluid using diuretics or ultrafiltration) with usual care in critical illness. METHODS: Open-label, parallel-group, allocation-concealed randomised clinical feasibility trial. Mechanically ventilated adult patients expected to require critical care beyond the next calendar day were enrolled between 24 and 48 h following admission to the intensive care unit (ICU). Patients were randomised to either a 2-stage fluid strategy comprising conservative fluid administration and, if fluid overload was present, active deresuscitation, or usual care. The primary endpoint was fluid balance in the 24 h up to the start of study day 3. Secondary endpoints included cumulative fluid balance, mortality, and duration of mechanical ventilation. RESULTS: One hundred and eighty patients were randomised. After withdrawal of 1 patient, 89 patients assigned to the intervention were compared with 90 patients assigned to the usual care group. The mean plus standard deviation (SD) 24-h fluid balance up to study day 3 was lower in the intervention group (- 840 ± 1746 mL) than the usual care group (+ 130 ± 1401 mL; P < 0.01). Cumulative fluid balance was lower in the intervention group at days 3 and 5. Overall, clinical outcomes did not differ significantly between the two groups, although the point estimate for 30-day mortality favoured the usual care group [intervention arm: 19 of 90 (21.6%) versus usual care: 14 of 89 (15.6%), P = 0.32]. Baseline imbalances between groups and lack of statistical power limit interpretation of clinical outcomes. CONCLUSIONS: A strategy of conservative fluid administration and active deresuscitation is feasible, reduces fluid balance compared with usual care, and may cause benefit or harm. In view of wide variations in contemporary clinical practice, large, adequately powered trials investigating the clinical effectiveness of conservative fluid strategies in critically ill patients are warranted.

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BACKGROUND: Fluid overload is associated with poor outcomes. Clinicians might be reluctant to initiate diuretic therapy for patients with recent vasopressor use. We estimated the effect on 30-day mortality of withholding or delaying diuretics after vasopressor use in patients with probable fluid overload. METHODS: This was a retrospective cohort study of adults admitted to ICUs of an academic medical centre between 2008 and 2012. Using a database of time-stamped patient records, we followed individuals from the time they first required vasopressor support and had >5 L cumulative positive fluid balance (plus additional inclusion/exclusion criteria). We compared mortality under usual care (the mix of care actually delivered in the cohort) and treatment strategies restricting diuretic initiation during and for various durations after vasopressor use. We adjusted for baseline and time-varying confounding via inverse probability weighting. RESULTS: The study included 1501 patients, and the observed 30-day mortality rate was 11%. After adjusting for observed confounders, withholding diuretics for at least 24 h after stopping most recent vasopressor use was estimated to increase 30-day mortality rate by 2.2% (95% confidence interval [CI], 0.9-3.6%) compared with usual care. Data were consistent with moderate harm or slight benefit from withholding diuretic initiation only during concomitant vasopressor use; the estimated mortality rate increased by 0.5% (95% CI, -0.2% to 1.1%). CONCLUSIONS: Withholding diuretic initiation after vasopressor use in patients with high cumulative positive balance (>5 L) was estimated to increase 30-day mortality. These findings are hypothesis generating and should be tested in a clinical trial.

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Critically ill patients are often presumed to be in a state of "constant dehydration" or in need of fluid, thereby justifying a continuous infusion with some form of intravenous (IV) fluid, despite their clinical data suggesting otherwise. Overzealous fluid administration and subsequent fluid accumulation and overload are associated with poorer outcomes. Fluids are drugs, and their use should be tailored to meet the patient's individualized needs; fluids should never be given as routine maintenance unless indicated. Before prescribing any fluids, the physician should consider the patient's characteristics and the nature of the illness, and assess the risks and benefits of fluid therapy. Decisions regarding fluid therapy present a daily challenge in many hospital departments: emergency rooms, regular wards, operating rooms, and intensive care units. Traditional fluid prescription is full of paradigms and unnecessary routines as well as malpractice in the form of choosing the wrong solutions for maintenance or not meeting daily requirements. Prescribing maintenance fluids for patients on oral intake will lead to fluid creep and fluid overload. Fluid overload, defined as a 10% increase in cumulative fluid balance from baseline weight, is an independent predictor for morbidity and mortality, and thus hospital cost. In the last decade, increasing evidence has emerged supporting a restrictive fluid approach. In this manuscript, we aim to provide a pragmatic description of novel concepts related to the use of IV fluids in critically ill patients, with emphasis on the different indications and common clinical scenarios. We also discuss active deresuscitation, or the timely cessation of fluid administration, with the intention of achieving a zero cumulative fluid balance.

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Background: The relation between deresuscitative fluid management after the resuscitation phase and clinical outcome in patients with abdominal sepsis is not completely clear. The aim of this study was to assess the contribution of deresuscitative management to death and organ dysfunction in abdominal sepsis. Methods: Consecutive patients with abdominal sepsis requiring fluid resuscitation were included in this study. According to the fluid management given in the later stage of resuscitation, a conservative group and a deresuscitative fluid management group were compared. The primary outcome was in-hospital death, whereas secondary outcomes were categorized as organ dysfunction and other adverse events. Results: A total of 138 patients were enrolled in this study. Conservative fluid management was given to 47.8% of patients, whereas deresuscitative fluid management occurred in 52.2%. The deresuscitative strategy was associated with a markedly lower prevalence of new-onset acute kidney injury and a decrease in the duration of continuous renal replacement therapy (CRRT). There was a greater risk of needing new-onset intubation and the mechanical ventilation duration in the conservative group than in the deresuscitative group. However, the deresuscitative group did not differ from the conservative group with respect to open abdomen and intra-abdominal hypertension or new-onset abdominal compartment syndrome. The conservative treatment was associated with prolonged stays as well as a higher in-hospital mortality rate. A multivariable logistic regression model showed that deresuscitative fluid management imparts a protective effect against in-hospital death (odds ratio 4.343; 95% confidence interva1 1.466-12.866; p = 0.008), whereas septic shock, source control failure, and CRRT duration were associated with a higher mortality rate. Conclusions: Fluid balance achieved using deresuscitative treatment is correlated with better outcomes in patients with abdominal sepsis, indicating that this treatment may be useful as a therapeutic strategy.

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Despite evidence highlighting harms of fluid overload, minimal guidance exists on counteraction via utilization of diuretics in the de-resuscitation phase. While diuretics have been shown to decrease net volume and improve clinical outcomes in the critically ill, a lack of standardization surrounding selection of diuretic regimen or monitoring of de-resuscitation exists. Current monitoring parameters of de-resuscitation often rely on clinical signs of fluid overload, end organ recovery and other biochemical surrogate markers which are often deemed unreliable. The majority of evidence suggests that achieving a net-negative fluid balance within 72 h after shock resolution may be of benefit; however, approaches to such goal are uncertain. Loop diuretics are a widely available type of diuretic for removal of volume in patients with sufficient kidney function, with the potential for adjunct diuretics in special circumstances. At present, administration of diuretics within the broad critically ill population fails to find uniformity and often efficacy. Given the lack of randomized controlled trials in this susceptible population, we aim to provide a thorough therapeutic understanding of diuretic pharmacotherapy which is necessary in order to achieve desired goal of fluid balance and improve overall outcomes.

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Accumulation of a positive fluid balance is common in critically ill patients, and is associated with adverse outcomes, including mortality. However, there are few randomised clinical trials to guide clinicians as to the most appropriate fluid strategy following initial resuscitation and on the use of deresuscitation (removal of accumulated fluid using diuretics and/or renal replacement therapy). To inform the design of randomised trials, we surveyed critical care physicians with regard to perceptions of fluid overload in critical care, self-reported practice, acceptability of a variety of approaches to deresuscitation, appropriate safety parameters, and overall acceptability of a randomised trial of deresuscitation. Of 524 critical care specialists completing the survey, the majority practiced in mixed medical/surgical intensive care units in the United Kingdom. Most (309 of 363 respondents, 85%) believed fluid overload to be a modifiable source of morbidity; there was strong support (395 of 457, 86%) for a randomised trial of deresuscitation in critical illness. Marked practice variability was evident among respondents. In a given clinical scenario, self-reported practice ranged from the administration of fluid (N = 59, 14%) to the administration of a diuretic (N = 285, 67%). The majority (95%) considered it appropriate to administer diuretics for fluid overload in the setting of noradrenaline infusion and to continue to administer diuretics despite mild dysnatraemias, hypotension, metabolic alkalosis, and hypokalaemia. The majority of critical care physicians view fluid overload as a common and modifiable source of morbidity; deresuscitation is widely practiced, and there is widespread support for randomised trials of deresuscitation in critical illness.

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This comprehensive review comparatively evaluates the safety and benefits of parenteral fluids used in resuscitation with a focus on sepsis. It also provides a random-effects meta-analysis of studies comparing restrictive resuscitation and usual care in sepsis with the primary outcome of mortality. In the septic patient, fluid therapy remains a complex interplay between fluid compartments in the body, the integrity of the endothelial barrier, and the inflammatory tone of the patient. Recent data have emerged describing the pharmacokinetics of fluid resuscitation that can be affected by the factors just listed, as well as mean arterial pressure, rate of infusion, volume of fluid infusate, nature of the fluid, and drug interactions. Fluid overload in sepsis has been associated with vasodilation, kidney injury, and increased mortality. Restrictive resuscitation after the initial septic insult is an emerging practice. Our search strategy of Medline databases revealed six randomized studies with 706 patients that examined restrictive resuscitation in sepsis. Results of this meta-analysis demonstrated no differences in mortality with restrictive resuscitation compared with usual care (30.6% vs 37.8%; risk ratio 0.83, 95% confidence interval 0.66-1.05, respectively) but was limited by the small number of studies and larger quantities of pre-randomization fluids. Another approach to address fluid overload is active (diuresis) de-resuscitation strategies that may shorten the need for mechanical ventilation and intensive care unit length of stay. Data suggest that colloids may confer mortality benefit over saline in the most severely ill septic patients. Compared with isotonic saline, balanced resuscitation fluids are associated with a lower incidence of acute kidney injury and mortality. The benefits of balanced resuscitation fluids are most evident when higher volumes of fluids are used for sepsis. Clinicians should consider these pharmacotherapeutic factors when selecting a fluid, its quantity, and rate of infusion.

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