A double-blind clinical trial to compare the efficacy and safety of a multiple amino acid-based ORS with the standard WHO-ORS in the management of non-cholera acute watery diarrhea in infants and young children: "VS002A" trial protocol.

BACKGROUND: Diarrhea is the second deadliest disease for under-five children globally and the situation is more serious in developing countries. Oral rehydration solution (ORS) is being used as a standard treatment for acute watery diarrhea for a long time. Our objective is to compare the efficacy of amino acid-based ORS "VS002A" compared to standard glucose-based WHO-ORS in infants and young children suffering from acute non-cholera watery diarrhea. METHODS: It is a randomized, double-blind, two-cell clinical trial at Dhaka Hospital of icddr,b. A total of 312 male children aged 6-36 months old with acute non-bloody watery diarrhea are included in this study. Intervention arm participants get amino acid-based ORS (VS002A) and the control arm gets standard glucose-based WHO-ORS. The primary efficacy endpoint is the duration of diarrhea in the hospital. DISCUSSION: Oral rehydration therapy (ORT) with the present ORS formulation has certain limitations - it does not reduce the volume, frequency, or duration of diarrhea. Additionally, the failure of present standard ORS to significantly reduce stool output likely contributes to the relatively limited use of ORS by mothers as they do not feel that ORS is helping their child recover from the episode of diarrhea. Certain neutral amino acids (e.g., glycine, L-alanine, L-glutamine) can enhance the absorption of sodium ions and water from the gut. By using this concept, a shelf-stable, sugar-free amino acid-based hydration medicinal food named 'VS002A' that effectively rehydrates, and improves the barrier function of the bowel following infections targeting the gastrointestinal tract has been developed. If the trial shows significant benefits of VS002A use, this may provide evidence to support consideration of the use of VS002A in the present WHO diarrhea management guidelines. Conversely, if there is no evidence of benefit, these results will reaffirm the current guidelines. TRIAL REGISTRATION: ClinicalTrials.gov NCT04677296 . Registered on December 21, 2020.

Balanced Crystalloids Versus Saline in Critically Ill Adults: A Systematic Review and Meta-analysis.

Background: The optimal resuscitative fluid remains controversial. Objective: To assess the association between crystalloid fluid and outcomes in critically ill adults. Methods: Cumulative Index to Nursing and Allied Health Literature, Scopus, PubMed, and Cochrane Central Register for Controlled Trials were searched from inception through July 2019. Cohort studies and randomized trials of critically ill adults provided predominantly nonperioperative fluid resuscitation with balanced crystalloids or 0.9% sodium chloride (saline) were included. Results: Thirteen studies (n = 30 950) were included. Balanced crystalloids demonstrated lower hospital or 28-/30-day mortality (risk ratio [RR] = 0.86; 95% CI = 0.75-0.99; I2 = 82%) overall, in observational studies (RR = 0.64; 95% CI = 0.41-0.99; I2 = 63%), and approached significance in randomized trials (RR = 0.94; 95% CI = 0.88-1.02; I2 = 0%). New acute kidney injury occurred less frequently with balanced crystalloids (RR = 0.91; 95% CI = 0.85-0.98; I2 = 0%), though progression to renal replacement therapy was similar (RR = 0.91; 95% CI = 0.79-1.04; I2 = 38%). In the sepsis cohort, odds of hospital or 28-/30-day mortality were similar, but the odds of major adverse kidney events occurring in the first 30 days were less with balanced crystalloids than saline (OR = 0.78; 95% CI = 0.66-0.91; I2 = 42%). Conclusion and Relevance: Resuscitation with balanced crystalloids demonstrated lower hospital or 28-/30-day mortality compared with saline in critically ill adults but not specifically those with sepsis. Balanced crystalloids should be provided preferentially to saline in most critically ill adult patients.

Efficacy of an Oral Rehydration Solution Enriched with Lactobacillus reuteri DSM 17938 and Zinc in the Management of Acute Diarrhoea in Infants: A Randomized, Double-Blind, Placebo-Controlled Trial.

The efficacy of oral rehydration solution (ORS) enriched with Lactobacillus reuteri DSM 17938 and zinc in infants with acute gastroenteritis, is poorly defined. The aim of this double-blind, randomized, placebo-controlled study, was to assess the efficacy of an ORS enriched with Lactobacillus reuteri DSM 17938 and zinc (ORS⁺Lr&Z) in well-nourished, non-hospitalized infants with acute diarrhoea. Fifty one infants with acute diarrhoea were randomly assigned to receive either ORS⁺Lr&Z (28 infants, mean ± SD age 1.7 ± 0.7 years, 21 males), or standard ORS (ORS-Lr&Z; 23 infants, mean ± SD age 1.8 ± 0.7 years, 16 males). Stools volume and consistency were recorded pre- and posttreatment using the Amsterdam Infant Stool Scale and were compared between the two groups, as well as lost work/day care days, drug administration and need for hospitalization. Both groups showed reduction in the severity of diarrhoea on day two (p < 0.001) while, all outcomes showed a trend to be better in the ORS⁺Lr&Z group, without reaching statistical significance, probably due to the relatively small number of patients. No adverse effects were recorded. In conclusion, both ORS were effective in managing acute diarrhoea in well-nourished, non-hospitalized infants. ORS enriched with L. reuteri DSM 17938 and zinc was well tolerated with no adverse effects.

Restrictive versus Liberal Fluid Therapy for Major Abdominal Surgery.

BACKGROUND: Guidelines to promote the early recovery of patients undergoing major surgery recommend a restrictive intravenous-fluid strategy for abdominal surgery. However, the supporting evidence is limited, and there is concern about impaired organ perfusion. METHODS: In a pragmatic, international trial, we randomly assigned 3000 patients who had an increased risk of complications while undergoing major abdominal surgery to receive a restrictive or liberal intravenous-fluid regimen during and up to 24 hours after surgery. The primary outcome was disability-free survival at 1 year. Key secondary outcomes were acute kidney injury at 30 days, renal-replacement therapy at 90 days, and a composite of septic complications, surgical-site infection, or death. RESULTS: During and up to 24 hours after surgery, 1490 patients in the restrictive fluid group had a median intravenous-fluid intake of 3.7 liters (interquartile range, 2.9 to 4.9), as compared with 6.1 liters (interquartile range, 5.0 to 7.4) in 1493 patients in the liberal fluid group (P<0.001). The rate of disability-free survival at 1 year was 81.9% in the restrictive fluid group and 82.3% in the liberal fluid group (hazard ratio for death or disability, 1.05; 95% confidence interval, 0.88 to 1.24; P=0.61). The rate of acute kidney injury was 8.6% in the restrictive fluid group and 5.0% in the liberal fluid group (P<0.001). The rate of septic complications or death was 21.8% in the restrictive fluid group and 19.8% in the liberal fluid group (P=0.19); rates of surgical-site infection (16.5% vs. 13.6%, P=0.02) and renal-replacement therapy (0.9% vs. 0.3%, P=0.048) were higher in the restrictive fluid group, but the between-group difference was not significant after adjustment for multiple testing. CONCLUSIONS: Among patients at increased risk for complications during major abdominal surgery, a restrictive fluid regimen was not associated with a higher rate of disability-free survival than a liberal fluid regimen and was associated with a higher rate of acute kidney injury. (Funded by the Australian National Health and Medical Research Council and others; RELIEF ClinicalTrials.gov number, NCT01424150 .).

Insidious Harm of Medication Diluents as a Contributor to Cumulative Volume and Hyperchloremia: A Prospective, Open-Label, Sequential Period Pilot Study.

OBJECTIVES: Although the potential dangers of hyperchloremia from resuscitation fluids continue to emerge, no study to date has considered the contribution of medication diluents to cumulative volume and hyperchloremia. This study compares saline versus dextrose 5% in water as the primary medication diluent and the occurrence of hyperchloremia in critically ill patients. DESIGN: Prospective, open-label, sequential period pilot study. SETTING: Medical ICU of a large academic medical center. PATIENTS: Adult patients admitted to the medical ICU were eligible for inclusion. Patients who were admitted for less than 48 hours, less than 18 years old, pregnant, incarcerated, or who had brain injury were excluded. INTERVENTIONS: Saline as the primary medication diluent for 2 months followed by dextrose 5% in water as the primary medication diluent for 2 months. MEASUREMENTS AND MAIN RESULTS: A total of 426 patients were included, 216 in the saline group and 210 in the dextrose 5% in water group. Medication diluents accounted for 63% of the total IV volume over the observation period. In the saline group, 17.9% developed hyperchloremia compared with 10.5% in the dextrose 5% in water group (p = 0.037), which was statistically significant in multivariable analysis (odds ratio, 0.50; 95% CI, 0.26-0.94; p = 0.031). In the saline group, 34.2% developed acute kidney injury versus 24.5% in the dextrose 5% in water group (p = 0.035); however, this was not statistically significant when adjusting for baseline covariates. No other significant differences in dysnatremias, insulin requirements, glucose control, ICU length of stay, or ICU mortality were observed. CONCLUSIONS: This study identified that medication diluents contribute substantially to the total IV volume received by critically ill patients. Saline as the primary medication diluent compared with dextrose 5% in water is associated with hyperchloremia, a possible risk factor for acute kidney injury.

Maintenance fluid therapy and fluid creep impose more significant fluid, sodium, and chloride burdens than resuscitation fluids in critically ill patients: a retrospective study in a tertiary mixed ICU population.

PURPOSE: Research on intravenous fluid therapy and its side effects, volume, sodium, and chloride overload, has focused almost exclusively on the resuscitation setting. We aimed to quantify all fluid sources in the ICU and assess fluid creep, the hidden and unintentional volume administered as a vehicle for medication or electrolytes. METHODS: We precisely recorded the volume, sodium, and chloride burdens imposed by every fluid source administered to 14,654 patients during the cumulative 103,098 days they resided in our 45-bed tertiary ICU and simulated the impact of important strategic fluid choices on patients' chloride burdens. In septic patients, we assessed the impact of the different fluid sources on cumulative fluid balance, an established marker of morbidity. RESULTS: Maintenance and replacement fluids accounted for 24.7% of the mean daily total fluid volume, thereby far exceeding resuscitation fluids (6.5%) and were the most important sources of sodium and chloride. Fluid creep represented a striking 32.6% of the mean daily total fluid volume [median 645 mL (IQR 308-1039 mL)]. Chloride levels can be more effectively reduced by adopting a hypotonic maintenance strategy [a daily difference in chloride burden of 30.8 mmol (95% CI 30.5-31.1)] than a balanced resuscitation strategy [daily difference 3.0 mmol (95% CI 2.9-3.1)]. In septic patients, non-resuscitation fluids had a larger absolute impact on cumulative fluid balance than did resuscitation fluids. CONCLUSIONS: Inadvertent daily volume, sodium, and chloride loading should be avoided when prescribing maintenance fluids in view of the vast amounts of fluid creep. This is especially important when adopting an isotonic maintenance strategy.

Effects of Intraoperative Fluid Management on Postoperative Outcomes: A Hospital Registry Study.

OBJECTIVE: Evaluate the dose-response relationship between intraoperative fluid administration and postoperative outcomes in a large cohort of surgical patients. BACKGROUND: Healthy humans may live in a state of fluid responsiveness without the need for fluid supplementation. Goal-directed protocols driven by such measures are limited in their ability to define the optimal fluid state during surgery. METHODS: This analysis of data on file included 92,094 adult patients undergoing noncardiac surgery with endotracheal intubation between 2007 and 2014 at an academic tertiary care hospital and two affiliated community hospitals. The primary exposure variable was total intraoperative volume of crystalloid and colloid administered. The primary outcome was 30-day survival. Secondary outcomes were respiratory complications within three postoperative days (pulmonary edema, reintubation, pneumonia, or respiratory failure) and acute kidney injury. Exploratory outcomes were postoperative length of stay and total cost of care. Our models were adjusted for patient-, procedure-, and anesthesia-related factors. RESULTS: A U-shaped association was observed between the volume of fluid administered intraoperatively and 30-day mortality, costs, and postoperative length of stay. Liberal fluid volumes (highest quintile of fluid administration practice) were significantly associated with respiratory complications whereas both liberal and restrictive (lowest quintile) volumes were significantly associated with acute kidney injury. Moderately restrictive volumes (second quintile) were consistently associated with optimal postoperative outcomes and were characterized by volumes approximately 40% less than traditional textbook estimates: infusion rates of approximately 6-7 mL/kg/hr or 1 L of fluid for a 3-hour case. CONCLUSIONS: Intraoperative fluid dosing at the liberal and restrictive margins of observed practice is associated with increased morbidity, mortality, cost, and length of stay.

Comparison of Postoperative Pain and Residual Gas Between Restrictive and Liberal Fluid Therapy in Patients Undergoing Laparoscopic Cholecystectomy.

BACKGROUND: Different fluid regimens are used in the clinical management of perioperative fluid therapy, but there still is the argument about which fluid regimen is better for patients. This study was mainly designed to compare different fluid regimens on postoperative pain and residual gas in patients undergoing laparoscopic cholecystectomy. METHODS: A total of 100 patients were equally randomized to receive restrictive fluid infusion (n=50) with lactated Ringer (LR) solution 5 mL/kg/h or liberal fluid infusion (n=50), with 30 mL/kg/h lactated Ringer solution. Postoperative pain was evaluated at 1, 6, and 24 hours after surgery using a visual analog scale (VAS). Postoperative subdiaphragmatic residual gas was monitored by x-ray at 24 hours after surgery. RESULTS: Patients in the restrictive group had significantly higher VAS pain scores at 6 hours after surgery than those in the liberal group (P=0.009). The incidence of subdiaphragmatic residual gas in the restrictive group was higher than in the liberal group (P=0.045). Patients who had residual gas had higher VAS pain scores than those with no residual gas in the restrictive group at 6 hours after surgery (P=0.02). CONCLUSIONS: Patients undergoing laparoscopic cholecystectomy with restrictive fluid therapy may suffer more severe postoperative pain than those receiving liberal fluid therapy. It suggests that the higher incidence of subdiaphragmatic residual gas may have occurred with restrictive fluid therapy.

The impact of phosphate-balanced crystalloid infusion on acid-base homeostasis (PALANCE study): study protocol for a randomized controlled trial.

BACKGROUND: This study aims to investigate the effects of a modified, balanced crystalloid including phosphate in a perioperative setting in order to maintain a stable electrolyte and acid-base homeostasis in the patient. METHODS/DESIGN: This is a single-centre, open-label, randomized controlled trial involving two parallel groups of female patients comparing a perioperative infusion regime with sodium glycerophosphate and Jonosteril® (treatment group) or Jonosteril® (comparator) alone. The primary endpoint is to maintain a stable concentration of weak acids [A-] according to the Stewart approach of acid-base balance. Secondary endpoints are measurement of serum phosphate levels, other acid-base parameters such as the strong ion difference (SID), the onset and severity of postoperative nausea and vomiting (PONV), electrolyte levels and their excretion in the urine, monitoring of renal function and glycocalyx components, haemodynamics, amounts of catecholamines and other vasopressors used and the safety of the infusion regime. DISCUSSION: Perioperative fluid replacement with the use of currently available crystalloid preparations still fail to maintain a stable acid-base balance and experts agree that common balanced solutions are still not ideal. This study aims to investigate the effectivity and safety of a new crystalloid solution by adding sodium glycerophosphate to a standardized crystalloid preparation in order to maintain a balanced perioperative acid-base homeostasis. TRIAL REGISTRATION: EudraCT number 201002422520 . Registered on 30 November 2010.

Use of the Fluid Challenge in Critically Ill Adult Patients: A Systematic Review.

The fluid challenge (FC) aims at identifying patients in whom fluid administration improves hemodynamics. Although the FC has been extensively studied, the implementation and definition of improvement are not standardized. This systematic review of studies published between January 1, 1994 and December 31, 2014 characterizes these key components of the FC for critically ill adult patients, as described in the medical literature in the last 20 years. A literature search was performed using MEDLINE, Embase, and Cochrane. For each study, data were collected on study design, study size, study setting, patient population, and how the FC was administered. Eligibility criteria for FC were (1) the infusion of a definite quantity of fluid, (2) of a specific type, (3) in a fixed time period (expressed as either span or infusion rate), (4) with a defined hemodynamic variable as the target, and (5) for a predetermined threshold. One hundred fifty-seven full-text manuscripts were extracted from 870 potentially relevant studies. The inclusion criteria were met by 71 studies including 3617 patients. Sixty-six studies were from a single center and 45 were prospective observational in format. The most common amount infused was 500 cc, used by 55 (77.5%) studies. The most commonly infused fluids were colloids (62.0%). In 43 (60.5%) studies, the FC was administered between 20 and 30 minutes. A positive response to fluid administration was defined as an increase ≥15% of cardiac index or cardiac output in 44 (62.6%) studies. Static or dynamic physiologic indices were utilized in a minority of studies (16.9%) and safety limits for interrupting the FC are adopted in 4 (5.6%) studies only. This systematic review indicates that the FC most commonly consists in infusing 500 mL of crystalloids or colloids in 20-30 minutes, and considered an increase in cardiac index ≥15% as a positive response. However, definite standards for FC administration and evaluation remain undefined.

Chloride Content of Fluids Used for Large-Volume Resuscitation Is Associated With Reduced Survival.

OBJECTIVE: We sought to investigate if the chloride content of fluids used in resuscitation was associated with short- and long-term outcomes. DESIGN: We identified patients who received large-volume fluid resuscitation, defined as greater than 60 mL/kg over a 24-hour period. Chloride load was determined for each patient based on the chloride ion concentration of the fluids they received during large-volume fluid resuscitation multiplied by the volume of fluids. We compared the development of hyperchloremic acidosis, acute kidney injury, and survival among those with higher and lower chloride loads. SETTING: University Medical Center. PATIENTS: Patients admitted to ICUs from 2000 to 2008. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 4,710 patients receiving large-volume fluid resuscitation, hyperchloremic acidosis was documented in 523 (11%). Crude rates of hyperchloremic acidosis, acute kidney injury, and hospital mortality all increased significantly as chloride load increased (p < 0.001). However, chloride load was no longer associated with hyperchloremic acidosis or acute kidney injury after controlling for total fluids, age, and baseline severity. Conversely, each 100 mEq increase in chloride load was associated with a 5.5% increase in the hazard of death even after controlling for total fluid volume, age, and severity (p = 0.0015) over 1 year. CONCLUSIONS: Chloride load is associated with significant adverse effects on survival out to 1 year even after controlling for total fluid load, age, and baseline severity of illness. However, the relationship between chloride load and development of hyperchloremic acidosis or acute kidney injury is less clear, and further research is needed to elucidate the mechanisms underlying the adverse effects of chloride load on survival.

Initial 12-h operative fluid volume is an independent risk factor for pleural effusion after hepatectomy.

Pleural effusion after hepatectomy is associated with significant morbidity and prolonged hospital stays. Several studies have addressed the risk factors for postoperative pleural effusion. However, there are no researches concerning the role of the initial 12-h operative fluid volume. The aim of this study was to evaluate whether the initial 12-h operative fluid volume during liver resection is an independent risk factor for pleural effusion after hepatectomy. In this study, we retrospectively analyzed clinical data of 470 patients consecutively undergoing elective hepatectomy between January 2011 and December 2012. We prospectively collected and retrospectively analyzed baseline and clinical data, including preoperative, intraoperative, and postoperative variables. Univariate and multivariate analyses were carried out to identify whether the initial 12-h operative fluid volume was an independent risk factor for pleural effusion after hepatectomy. The multivariate analysis identified 2 independent risk factors for pleural effusion: operative time [odds ratio (OR)=10.2] and initial 12-h operative fluid volume (OR=1.0003). Threshold effect analyses revealed that the initial 12 h operative fluid volume was positively correlated with the incidence of pleural effusion when the initial 12-h operative fluid volume exceeded 4636 mL. We conclude that the initial 12-h operative fluid volume during liver resection and operative time are independent risk factors for pleural effusion after hepatectomy. Perioperative intravenous fluids should be restricted properly.

A randomized trial of Plasma-Lyte A and 0.9 % sodium chloride in acute pediatric gastroenteritis.

BACKGROUND: Compare the efficacy and safety of Plasma-Lyte A (PLA) versus 0.9 % sodium chloride (NaCl) intravenous (IV) fluid replacement in children with moderate to severe dehydration secondary to acute gastroenteritis (AGE). METHODS: Prospective, randomized, double-blind study conducted at eight pediatric emergency departments (EDs) in the US and Canada (NCT#01234883). The primary outcome measure was serum bicarbonate level at 4 h. Secondary outcomes included safety and tolerability. The hypothesis was that PLA would be superior to 0.9 % NaCl in improvement of 4-h bicarbonate. Patients (n = 100) aged ≥6 months to <11 years with AGE-induced moderate-to-severe dehydration were enrolled. Patients with a baseline bicarbonate level ≤22 mEq/L formed the modified intent to treat (mITT) group. RESULTS: At baseline, the treatment groups were comparable except that the PLA group was older. At hour 4, the PLA group had greater increases in serum bicarbonate from baseline than did the 0.9 % NaCl group (mean ± SD at 4 h: 18 ± 3.74 vs 18.0 ± 3.67; change from baseline of 1.6 and 0.0, respectively; P = .004). Both treatment groups received similar fluid volumes. The PLA group had less abdominal pain and better dehydration scores at hour 2 (both P = .03) but not at hour 4 (P = 0.15 and 0.08, respectively). No patient experienced clinically relevant worsening of laboratory findings or physical examination, and hospital admission rates were similar. One patient in each treatment group developed hyponatremia. Four patients developed hyperkalemia (PLA:1, 0.9 % NaCl:3). CONCLUSION: In comparison with 0.9 % NaCl, PLA for rehydration in children with AGE was well tolerated and led to more rapid improvement in serum bicarbonate and dehydration score. TRIAL REGISTRATION: NCT#01234883 (Registration Date: November 3, 2010).

Influence of different fluid resuscitation techniques on the number of myeloid-derived suppressor cells in rats.

We investigated the influence of different fluid resuscitation techniques on the number of myeloid-derived suppressor cells (MDSCs) in rats. Seventy-two healthy Sprague-Dawley rats were randomly divided into groups that received sham operation (Sham group), hypertonic saline (HRS group), lactated ringer's solution (LRS group), or crystalloid solution (LCRS group). Six rats from each group were sacrificed by cervical dislocation at 12, 24, and 48 h after resuscitation. The spleens were harvested under sterile conditions and spleen cell suspension was prepared. The number of MDSCs was detected using flow cytometry. The number of MDSCs in the Sham group did not differ significantly among the different time points. Compared with the Sham group, the number of MDSCs after the use of the different fluid resuscitation techniques increased to varying extents and the differences among the groups were significant. The number of MDSCs in the HRS group was much lower than that of the LRS and LCRS groups at both 24 and 48 h (P < 0.05). At 12 h, the number of MDSCs in the HRS group was significantly lower than that of the LRS group (P < 0.05). The differences between the HRS and LCRS groups were not statistically significant. Shortly after hemorrhagic shock resuscitation, the immune function of rats was suppressed to a varying extent and was gradually restored over time. Resuscitation with HRS alleviated the immunosuppression at the early stage after shock.