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Background Optimal fluid management in critically ill patients varies across different phases of care. This study examined the feasibility of adding a restrictive fluid strategy with early de-escalation to standard care for patients with circulatory shock. Methods We performed a single-center, feasibility, randomized controlled trial, involving patients with shock who required fluid resuscitation and were admitted in the medical intensive care unit. After initial fluid resuscitation, patients were randomly assigned (1:1) to either a restrictive fluid strategy or usual care. The restrictive group targeted a near-zero fluid balance over 3 days by limiting fluid intake and using diuretics or mechanical fluid removal when needed. The primary outcome was cumulative fluid balance at day 3. The secondary outcomes were the lengths of stay in the intensive care unit and the hospital, the mechanical ventilation duration, acute kidney injury, renal replacement therapy, and mortality. Results We enrolled 100 patients, assigning 50 to the restrictive strategy and 50 to usual care. By day 3, the restrictive group showed a lower cumulative fluid balance than usual care (‒2353 mL vs. 793 mL, p  < 0.001). This trend continued to day 7 (‒3032 mL vs. 1125 mL, p  < 0.001). The restrictive group also had shorter stays in the intensive care unit and the hospital (7 vs. 10 days, p  = 0.006; 16 vs. 22 days, p  = 0.02). There were no statistically significant differences in hospital or 30-day mortality rates between the groups (18% vs. 38%, p  = 0.05; 12% vs. 30%, p  = 0.05, respectively). Similarly, no significant differences were observed in the incidence of acute kidney injury or the use of renal replacement therapy. Conclusions A restrictive fluid strategy with early de-escalation and de-resuscitation is feasible and may reduce fluid accumulation and showed a signal for reduced hospital stay without increasing adverse events in critically ill patients following acute fluid resuscitation. Trial registration TCTR20220719002 (The trial has been reviewed and approved by TCTR committee on July 16th, 2022). Key messages A restrictive fluid strategy that employs a protocol-based intervention to achieve a target fluid balance after initial resuscitation in patients with sepsis appears feasible, does not increase harm, and may improve outcomes.

Purpose To determine the effects of the sodium content of maintenance fluid therapy on cumulative fluid balance and electrolyte disorders. Methods We performed a randomized controlled trial of adults undergoing major thoracic surgery, randomly assigned (1:1) to receive maintenance fluids containing 154 mmol/L (Na154) or 54 mmol/L (Na54) of sodium from the start of surgery until their discharge from the ICU, the occurrence of a serious adverse event or the third postoperative day at the latest. Investigators, caregivers and patients were blinded to the treatment. Primary outcome was cumulative fluid balance. Electrolyte disturbances were assessed as secondary endpoints, different adverse events and physiological markers as safety and exploratory endpoints. Findings We randomly assigned 70 patients; primary outcome data were available for 33 and 34 patients in the Na54 and Na154 treatment arms, respectively. Estimated cumulative fluid balance at 72 h was 1369 mL (95% CI 601–2137) more positive in the Na154 arm ( p  < 0.001), despite comparable non-study fluid sources. Hyponatremia < 135 mmol/L was encountered in four patients (11.8%) under Na54 compared to none under Na154 ( p  = 0.04), but there was no significantly more hyponatremia < 130 mmol/L (1 versus 0; p  = 0.31). There was more hyperchloremia > 109 mmol/L under Na154 (24/35 patients, 68.6%) than under Na54 (4/34 patients, 11.8%) ( p  < 0.001). The treating clinicians discontinued the study due to clinical or radiographic fluid overload in six patients receiving Na154 compared to one patient under Na54 (excess risk 14.2%; 95% CI − 0.2–30.4%, p  = 0.05). Conclusions In adult surgical patients, sodium-rich maintenance solutions were associated with a more positive cumulative fluid balance and hyperchloremia; hypotonic fluids were associated with mild and asymptomatic hyponatremia.

PurposeAfter cardiac surgery, fluid bolus therapy (FBT) with 20% human albumin may facilitate less fluid and vasopressor administration than FBT with crystalloids. We aimed to determine whether, after cardiac surgery, FBT with 20% albumin reduces the duration of vasopressor therapy compared with crystalloid FBT.MethodsWe conducted a multicentre, parallel-group, open-label, randomised clinical trial in six intensive care units (ICUs) involving cardiac surgery patients deemed to require FBT. We randomised 240 patients to receive up to 400 mL of 20% albumin/day as FBT, followed by 4% albumin for any subsequent FBT on that day, or to crystalloid FBT for at least the first 1000 mL, with use of crystalloid or 4% albumin FBT thereafter. The primary outcome was the cumulative duration of vasopressor therapy. Secondary outcomes included fluid balance.ResultsOf 480 randomised patients, 466 provided consent and contributed to the primary outcome (mean age 65 years; median EuroSCORE II 1.4). The cumulative median duration of vasopressor therapy was 7 (interquartile range [IQR] 0–19.6) hours with 20% albumin and 10.8 (IQR 0–22.8) hours with crystalloids (difference − 3.8 h, 95% confidence interval [CI] − 8 to 0.4; P = 0.08). Day one fluid balance was less with 20% albumin FBT (mean difference − 701 mL, 95% CI − 872 to − 530).ConclusionsIn patients after cardiac surgery, when compared to a crystalloid-based FBT, 20% albumin FBT was associated with a reduced positive fluid balance but did not significantly reduce the duration of vasopressor therapy.

Background In septic shock, the classic fluid resuscitation strategy can lead to a potentially harmful positive fluid balance. This multicenter, randomized, single-blind, parallel, controlled pilot study assessed the effectiveness of a restrictive fluid strategy aiming to limit daily volume. Methods Patients 18–85 years’ old admitted to the ICU department of three French hospitals were eligible for inclusion if they had septic shock and were in the first 24 h of vasopressor infusion. Exclusion criteria were acute kidney injury requiring renal replacement therapy, end stage chronic kidney disease, and severe malnutrition. Patients were electronically randomized 1:1 to either an optimized fluid restriction (reducing fluid intake as much as possible in terms of maintenance fluids and fluids for drug dilution during the first 7 days) or standard fluid strategy. The primary outcome was cumulative fluid balance (ml/kg) in the first 5 days. Patients and statisticians were blinded to group arm, but not clinicians. Results Between September 2021 and February 2023, 1201 patients were screened and 50 included, with two in the control group withdrawing, thus 48 patients were analyzed (24 in each group). In the first 5 days, the optimized restrictive strategy and control groups received 89.7 (IQR 35; 128.9) and 114.3 (IQR 78.8; 168.5) ml/kg of fluid, respectively (mean difference: 35.9 ml/kg [0.0; 71.8], p  = 0.0506). After 5 days, the median cumulative fluid balance was 6.9 (IQR − 13.7; 52.1) and 35.0 (IQR − 7.9; 40.2) ml/kg in the optimized restrictive strategy and control groups, respectively (absolute difference 13.2 [95%CI − 15.2; 41.6], p  = 0.42). After 28 days, mortality and the numbers of days alive without life support were similar between groups. The main adverse events were severe hypernatremia in 1 and 2 patients in the fluid restriction strategy and control groups, respectively, and acute kidney injury KDIGO 3 in 4 and 7 patients in the fluid restriction strategy and control groups, respectively. Conclusions In ICU patients with septic shock, an optimized restrictive fluid strategy targeting hidden fluid intakes did not reduce the overall fluid balance at day 5. Trial registration ClinicalTrials.gov identifier NCT04947904, registered on 1 July 2021. Graphical Abstract

Saline (0.9% sodium chloride), the fluid most commonly used to treat diabetic ketoacidosis (DKA), can cause hyperchloremic metabolic acidosis. Balanced crystalloids, an alternative class of fluids for volume expansion, do not cause acidosis and, therefore, may lead to faster resolution of DKA than saline. To compare the clinical effects of balanced crystalloids with the clinical effects of saline for the acute treatment of adults with DKA. This study was a subgroup analysis of adults with DKA in 2 previously reported companion trials-Saline Against Lactated Ringer's or Plasma-Lyte in the Emergency Department (SALT-ED) and the Isotonic Solutions and Major Adverse Renal Events Trial (SMART). These trials, conducted between January 2016 and March 2017 in an academic medical center in the US, were pragmatic, multiple-crossover, cluster, randomized clinical trials comparing balanced crystalloids vs saline in emergency department (ED) and intensive care unit (ICU) patients. This study included adults who presented to the ED with DKA, defined as a clinical diagnosis of DKA, plasma glucose greater than 250 mg/dL, plasma bicarbonate less than or equal to 18 mmol/L, and anion gap greater than 10 mmol/L. Data analysis was performed from January to April 2020. Balanced crystalloids (clinician's choice of Ringer lactate solution or Plasma-Lyte A solution) vs saline for fluid administration in the ED and ICU according to the same cluster-randomized multiple-crossover schedule. The primary outcome was time between ED presentation and DKA resolution, as defined by American Diabetes Association criteria. The secondary outcome was time between initiation and discontinuation of continuous insulin infusion. Among 172 adults included in this secondary analysis of cluster trials, 94 were assigned to balanced crystalloids and 78 to saline. The median (interquartile range [IQR]) age was 29 (24-45) years, and 90 (52.3%) were women. The median (IQR) volume of isotonic fluid administered in the ED and ICU was 4478 (3000-6372) mL. Cumulative incidence analysis revealed shorter time to DKA resolution in the balanced crystalloids group (median time to resolution: 13.0 hours; IQR: 9.5-18.8 hours) than the saline group (median: 16.9 hours; IQR: 11.9-34.5 hours) (adjusted hazard ratio [aHR] = 1.68; 95% CI, 1.18-2.38; P = .004). Cumulative incidence analysis also revealed shorter time to insulin infusion discontinuation in the balanced crystalloids group (median: 9.8 hours; IQR: 5.1-17.0 hours) than the saline group (median: 13.4 hours; IQR: 11.0-17.9 hours) (aHR = 1.45; 95% CI, 1.03-2.03; P = .03). In this secondary analysis of 2 cluster randomized clinical trials, compared with saline, treatment with balanced crystalloids resulted in more rapid resolution of DKA, suggesting that balanced crystalloids may be preferred over saline for acute management of adults with DKA. ClinicalTrials.gov Identifiers: NCT02614040; NCT02444988.

Evaluate the utility of a joint model when analysing a patient-reported endpoint as part of a randomized controlled trial (RCT) in which censoring occurs when patients die during follow-up. The present study comprises two parts as follows: first we reanalyzed data from a previously published RCT comparing two fluid regimens in the first 24 hours of major abdomino-pelvic surgery ('Restrictive versus Liberal Fluid Therapy for Major Abdominal Surgery [RELIEF]' trial). In this trial, patient-reported disability was measured at multiple timepoints before and after surgery. Next, we conducted a simulation study to jointly emulate patient-reported disability and survival, similar to the RELIEF trial, under nine treatment-outcome scenarios. In both parts, we compared a joint model analysis to a linear mixed-effect model combined with one of the several traditional methods of handling longitudinal missingness as follows: available data analysis, complete case analysis, last observation carried forward, and worst-case assumption. In part one, the joint model revealed no between-group differences in patient-reported disability at 1, 3, 6, and 12 months after surgery. The worst-case approach consistently resulted in the largest deviation from the joint model estimates, although in this particular setting none of the approaches materially changed the study's conclusions. In part two, the simulations revealed that across all treatment-outcome scenarios, the joint model expectedly produced unbiased estimates of patient-reported disability. Similarly, employing an approach based on all available data (ie, relying on the maximum likelihood estimator for handling missingness) yielded disability estimates close to the simulated values, albeit with slight bias across some scenarios. The last observation carried forward approach that mirrored the joint model's estimates except when the treatment had a nonnull effect on patient-reported disability. The worst-case analysis resulted in high bias, which was particularly evident when the treatment had a large effect on survival. The complete case analysis resulted in high bias across all scenarios. In randomized trials that employ a patient-reported outcome as one of their endpoints, a joint model can address bias arising from informative missingness related to death. Methods for handling missingness based on all available data appear to be a reasonable alternative to joint models, with only slight bias across some simulated scenarios. ‘Patient-centered research’ focuses on outcomes that are prioritized by patients. This approach often involves asking patients to complete questionnaires about their health experiences. However, if a patient does not finish a study, dealing with their missing answers can pose significant challenges. Joint models are a recent statistical method that may help address this issue. In this study, we used joint models in a real-world clinical trial, and in a series of simulated trials, to determine how well they handle missing questionnaire data from patients. We found that joint models offer significant benefits over most traditional methods used to analyze clinical trials.

Over half a million children die each year of diarrheal illness, although nearly all deaths could be prevented with oral rehydration salts (ORS). The literature on ORS documents both impressive health benefits and persistent underuse. At the same time, little is known about why ORS is underused and what can be done to increase use. We hypothesized that price and inconvenience are important barriers to ORS use and tested whether eliminating financial and access constraints increases ORS coverage. In July of 2016, we recruited 118 community health workers (CHWs; representing 10,384 households) in Central and Eastern Uganda to participate in the study. Study villages were predominantly peri-urban, and most caretakers had no more than primary school education. In March of 2017, we randomized CHWs to one of four methods of ORS distribution: (1) free delivery of ORS prior to illness (free and convenient); (2) home sales of ORS prior to illness (convenient only); (3) free ORS upon retrieval using voucher (free only); and (4) status quo CHW distribution, where ORS is sold and not delivered (control). CHWs offered zinc supplements in addition to ORS in all treatment arms (free in groups 1 and 3 and for sale in group 2), following international treatment guidelines. We used household surveys to measure ORS (primary outcome) and ORS + zinc use 4 weeks after the interventions began (between April and May 2017). We assessed impact using an intention-to-treat (ITT) framework. During follow-up, we identified 2,363 child cases of diarrhea within 4 weeks of the survey (584 in free and convenient [25.6% of households], 527 in convenient only [26.1% of households], 648 in free only [26.8% of households], and 597 in control [28.5% of households]). The share of cases treated with ORS was 77% (448/584) in the free and convenient group, 64% (340/527) in the convenient only group, 74% (447/648) in the free only group, and 56% (335/597) in the control group. After adjusting for potential confounders, instructing CHWs to provide free and convenient distribution increased ORS coverage by 19 percentage points relative to the control group (95% CI 13-26; P < 0.001), 12 percentage points relative to convenient only (95% CI 6-18; P < 0.001), and 2 percentage points (not significant) relative to free only (95% CI -4 to 8; P = 0.38). Effect sizes were similar, but more pronounced, for the use of both ORS and zinc. Limitations include short follow-up period, self-reported outcomes, and limited generalizability. Most caretakers of children with diarrhea in low-income countries seek care in the private sector where they are required to pay for ORS. However, our results suggest that price is an important barrier to ORS use and that switching to free distribution by CHWs substantially increases ORS coverage. Switching to free distribution is low-cost, easily scalable, and could substantially reduce child mortality. Convenience was not important in this context. Trial registry number AEARCTR-0001288.

Perioperative hemodynamic optimisation improves postoperative outcome for patients undergoing high-risk surgery (HRS). In this prospective randomized multicentre study we studied the effects of an individualized, goal-directed fluid management based on continuous stroke volume variation (SVV) and stroke volume (SV) monitoring on postoperative outcomes. 64 patients undergoing HRS were randomized either to a control group (CON, n = 32) or a goal-directed group (GDT, n = 32). In GDT, SVV and SV were continuously monitored (FloTrac/Vigileo) and patients were brought to and maintained on the plateau of the Frank-Starling curve (SVV <10 % and SV increase <10 % in response to fluid loading). Organ dysfunction was assessed using the SOFA score and resource utilization using the TISS score. Patients were followed up to 28 days for postoperative complications. Main outcome measures were the number of complications (infectious, cardiac, respiratory, renal, hematologic and abdominal post-operative complications), maximum SOFA score and cumulative TISS score during ICU stay, duration of mechanical ventilation, length of ICU stay, and time until fit for discharge. 12 patients had to be excluded from final analysis (6 in each group). During surgery, GDT received more colloids than CON (1,589 vs. 927 ml, P  < 0.05) and SVV decreased in GDT (from 9.0 to 8.0 %, P  < 0.05) but not in CON. The number of postoperative wound infections was lower in GDT (0 vs. 7, P  < 0.01). Although not statistically significant, the proportion of patients with at least one complication (46 vs. 62 %), the number of postoperative complications per patient (0.65 vs. 1.40), the maximum sofa score (5.9 vs. 7.2), and the cumulative TISS score (69 vs. 83) tended to be lower. This multicentre study shows that fluid management based on a SVV and SV optimisation protocol is feasible and decreases postoperative wound infections. Our findings also suggest that a goal-directed strategy might decrease postoperative organ dysfunction.

There is continued controversy regarding the benefits of goal-directed fluid therapy, with earlier studies showing marked improvement in morbidity and length-of-stay that have not been replicated more recently. The aim of this study was to compare patient outcomes in elective colorectal surgery patients having goal-directed versus restrictive fluid therapy. Inclusion criteria included suitability for an Enhanced Recovery After Surgery care pathway and patients with an American Society of Anesthesiologists Physical Status score of 1 to 3. Patients were intraoperatively randomised to either restrictive or Doppler-guided goal-directed fluid therapy. The primary outcome was length-of-stay; secondary outcomes included complication rate, change in haemodynamic variables and fluid volumes. One hundred patients, 50 in each group, were included in the analysis. Compared to restrictive therapy, goal-directed therapy resulted in a greater volume of intraoperative fluid, 2115 (interquartile range 1350 to 2560) ml versus 1500 (1200 to 2000) ml, P=0.008, and was associated with an increase in Doppler-derived stroke volume index from beginning to end of surgery, 43.7 (16.3) to 54.2 (21.1) ml/m 2 , P <0.001, in the latter group. Length-of-stay was similar, P=0.421. The number of patients with any complication (minor or major) was similar; 60% (30) versus 52% (26), P=0.42, or major complications, 1 (2%) versus 4 (8%), P=0.36, respectively. The increased perioperative fluid volumes and increased stroke volumes at the end of surgery in patients receiving goal-directed therapy did not translate to a significant difference in length-of-stay and we did not observe a difference in the number of patients experiencing minor or major complications.

Background Previous study drew different conclusions on significant differences between saline and balanced crystalloid solution infused in critical illness but both showed a statistical difference in the sepsis subgroup. Thus, we will specifically focus on septic patients in this study to compare the effects of saline and balanced solution. We hypothesize that effects of saline on renal outcomes are related to the underline acute kidney injury (AKI) severity and total volumes of infusion. Methods/design The investigators designed a pragmatic, multi-center parallel controlled trial recruiting 312 patients who are diagnosed with sepsis/septic shock in the intensive care unit (ICU) and will be assigned with either acetate Ringer’s solution or saline in the corresponding month. Patients with an end-stage renal disease (ESRD) or who need renal replacement therapy (RRT) prior to or at the time of enrolment are excluded. Enrolled patients will be regarded as with mild, moderate, or severe sepsis on the basis of the severity of their illness and will be divided into subgroups according to their initial renal function and various intravenous infusion volumes when being analyzed. The primary outcome is major adverse kidney events within 28 days (MAKE28), including the composite of in-hospital death, receipt of new renal replacement therapy, or persistent renal dysfunction. Secondary outcomes include 28-day mortality, internal environment disturbance, incidence and duration of vasoactive drug treatment, duration of mechanical ventilation, duration of RRT, and ICU and hospital length of stay. Results and conclusions To our knowledge, this study will be the first to focus on septic patients and provide credible and evident data on the comparison of outcome between acetate Ringer’s solution and saline for intravenous infusion in adult septic patients on the basis of baseline renal function and infusion volumes taken into consideration. Trial registration ClinicalTrials.gov NCT03685214 . Registered on August 15, 2018