Fluid balance in critically ill children with acute lung injury.
ABSTRACT: In the Fluid and Catheter Treatment Trial (NCT00281268), adults with acute lung injury randomized to a conservative vs. liberal fluid management protocol had increased days alive and free of mechanical ventilator support (ventilator-free days). Recruiting sufficient children with acute lung injury into a pediatric trial is challenging. A Bayesian statistical approach relies on the adult trial for the a priori effect estimate, requiring fewer patients. Preparing for a Bayesian pediatric trial mirroring the Fluid and Catheter Treatment Trial, we aimed to: 1) identify an inverse association between fluid balance and ventilator-free days; and 2) determine if fluid balance over time is more similar to adults in the Fluid and Catheter Treatment Trial liberal or conservative arms.Multicentered retrospective cohort study.Five pediatric intensive care units.Mechanically ventilated children (age?1 month to <18 yrs) with acute lung injury admitted in 2007-2010.None.Fluid intake, output, and net fluid balance were collected on days 1-7 in 168 children with acute lung injury (median age 3 yrs, median PaO2/FIO2 138) and weight-adjusted (mL/kg). Using multivariable linear regression to adjust for age, gender, race, admission day illness severity, PaO2/FIO2, and vasopressor use, increasing cumulative fluid balance (mL/kg) on day 3 was associated with fewer ventilator-free days (p=.02). Adjusted for weight, daily fluid balance on days 1-3 and cumulative fluid balance on days 1-7 were higher in these children compared to adults in the Fluid and Catheter Treatment Trial conservative arm (p<.001, each day) and was similar to adults in the liberal arm.Increasing fluid balance on day 3 in children with acute lung injury at these centers is independently associated with fewer ventilator-free days. Our findings and the similarity of fluid balance patterns in our cohort to adults in the Fluid and Catheter Treatment Trial liberal arm demonstrate the need to determine whether a conservative fluid management strategy improves clinical outcomes in children with acute lung injury and support a Bayesian trial mirroring the Fluid and Catheter Treatment Trial.
Project description:In the Fluid and Catheter Treatment Trial (FACTT) of the National Institutes of Health Acute Respiratory Distress Syndrome Network, a conservative fluid protocol (FACTT Conservative) resulted in a lower cumulative fluid balance and better outcomes than a liberal fluid protocol (FACTT Liberal). Subsequent Acute Respiratory Distress Syndrome Network studies used a simplified conservative fluid protocol (FACTT Lite). The objective of this study was to compare the performance of FACTT Lite, FACTT Conservative, and FACTT Liberal protocols.Retrospective comparison of FACTT Lite, FACTT Conservative, and FACTT Liberal. Primary outcome was cumulative fluid balance over 7 days. Secondary outcomes were 60-day adjusted mortality and ventilator-free days through day 28. Safety outcomes were prevalence of acute kidney injury and new shock.ICUs of Acute Respiratory Distress Syndrome Network participating hospitals.Five hundred three subjects managed with FACTT Conservative, 497 subjects managed with FACTT Liberal, and 1,124 subjects managed with FACTT Lite.Fluid management by protocol.Cumulative fluid balance was 1,918 ± 323 mL in FACTT Lite, -136 ± 491 mL in FACTT Conservative, and 6,992 ± 502 mL in FACTT Liberal (p < 0.001). Mortality was not different between groups (24% in FACTT Lite, 25% in FACTT Conservative and Liberal, p = 0.84). Ventilator-free days in FACTT Lite (14.9 ± 0.3) were equivalent to FACTT Conservative (14.6 ± 0.5) (p = 0.61) and greater than in FACTT Liberal (12.1 ± 0.5, p < 0.001 vs Lite). Acute kidney injury prevalence was 58% in FACTT Lite and 57% in FACTT Conservative (p = 0.72). Prevalence of new shock in FACTT Lite (9%) was lower than in FACTT Conservative (13%) (p = 0.007 vs Lite) and similar to FACTT Liberal (11%) (p = 0.18 vs Lite).FACTT Lite had a greater cumulative fluid balance than FACTT Conservative but had equivalent clinical and safety outcomes. FACTT Lite is an alternative to FACTT Conservative for fluid management in Acute Respiratory Distress Syndrome.
Project description:Conservative fluid management increases ventilator-free days without influencing overall mortality in acute respiratory distress syndrome. Plasma concentrations of B-type natriuretic peptide (a marker of ventricular filling) or aldosterone (a marker of effective circulating volume) may identify patients for whom fluid management impacts survival.This was a retrospective analysis of the Fluid and Catheter Treatment Trial (FACTT), a randomized trial comparing conservative with liberal fluid management in acute respiratory distress syndrome. Using plasma collected at study enrollment, we measured B-type natriuretic peptide and aldosterone by immunoassay. Multivariable analyses examined the interaction between B-type natriuretic peptide or aldosterone concentration and fluid strategy with regard to 60-day in-hospital mortality.Among 625 patients with adequate plasma, median B-type natriuretic peptide concentration was 825 pg/mL (interquartile range, 144-1,574 pg/mL), and median aldosterone was 2.49 ng/dL (interquartile range, 1.1-4.3 ng/dL). B-type natriuretic peptide did not predict overall mortality, correlate with fluid balance, or modify the effect of conservative vs liberal fluid management on outcomes. In contrast, among patients with lower aldosterone concentrations, conservative fluid management increased ventilator-free days (17.1 ± 9.8 vs 12.5 ± 10.3, P < .001) and decreased mortality (19% vs 30%, P = .03) (P value for interaction = .01).In acute respiratory distress syndrome, B-type natriuretic peptide does not modify the effect of fluid management on outcomes. Lower initial aldosterone appears to identify patients for whom conservative fluid management may improve mortality.
Project description:Diabetes mellitus results in an attenuated inflammatory response, reduces pulmonary microvascular permeability, and may decrease the risk of developing acute respiratory distress syndrome (ARDS). Studies have shown that patients with ARDS are better managed by a conservative as compared to liberal fluid management strategy. However, it is not known if the same fluid management principles hold true for patients with comorbid diabetes mellitus and ARDS.As diabetes mellitus results in reduced pulmonary microvascular permeability and an attenuated inflammatory response, we hypothesize that in the setting of ARDS, diabetic patients will be able to tolerate a positive fluid balance better than patients without diabetes.The Fluid and Catheter Treatment Trial (FACTT) randomized patients with ARDS to conservative versus liberal fluid management strategies. In a secondary analysis of this trial, we calculated the interaction of diabetic status and differing fluid strategies on outcomes. Propensity score subclassification matching was used to control for the differing baseline characteristics between patients with and without diabetes.Nine hundred fifty-six patients were analyzed. In a propensity score matched analysis, the difference in the effect of a conservative as compared to liberal fluid management strategy on ventilator free days was 2.23 days (95% CI: -0.97 to 5.43 days) in diabetic patients, and 2.37 days (95% CI: -0.21 to 4.95 days) in non-diabetic patients. The difference in the effect of a conservative as compared to liberal fluid management on 60 day mortality was 2% (95% CI: -11.8% to 15.8%) in diabetic patients, and -7.9% (95% CI: -21.7% to 5.9%) in non-diabetic patients.When comparing a conservative fluid management strategy to a liberal fluid management strategy, diabetic patients with ARDS did not have a statistically significant difference in outcomes than non-diabetic patients.
Project description:In acute respiratory distress syndrome, conservative fluid management increases ventilator-free days without affecting mortality. Response to fluid management may differ based on patients' initial central venous pressure. We hypothesized that initial central venous pressure would modify the effect of fluid management on outcomes.Retrospective analysis of the Fluid and Catheter Treatment Trial, a multicenter randomized trial comparing conservative with liberal fluid management in acute respiratory distress syndrome. We examined the relationship between initial central venous pressure, fluid strategy, and 60-day mortality in univariate and multivariable analysis.Twenty acute care hospitals.Nine hundred thirty-four ventilated acute respiratory distress syndrome patients with a central venous pressure available at enrollment, 609 without baseline shock (for whom fluid balance was managed by the study protocol).None.Among patients without baseline shock, those with initial central venous pressure greater than 8 mm Hg experienced similar mortality with conservative and liberal fluid management (18% vs 18%; p = 0.928), whereas those with central venous pressure of 8 mm Hg or less experienced lower mortality with a conservative strategy (17% vs 36%; p = 0.005). Multivariable analysis demonstrated an interaction between initial central venous pressure and the effect of fluid strategy on mortality (p = 0.031). At higher initial central venous pressures, the difference in treatment between arms was predominantly furosemide administration, which was not associated with mortality (p = 0.122). At lower initial central venous pressures, the difference between arms was predominantly fluid administration, with additional fluid associated with increased mortality (p = 0.013).Conservative fluid management decreases mortality for acute respiratory distress syndrome patients with a low initial central venous pressure. In this population, the administration of IV fluids seems to increase mortality.
Project description:It has been suggested that fluid accumulation may delay recognition of acute kidney injury. We sought to determine the impact of fluid balance on the incidence of nondialysis requiring acute kidney injury in patients with acute lung injury and to describe associated outcomes, including mortality.Analysis of the Fluid and Catheter Treatment Trial, a factorial randomized clinical trial of conservative vs. liberal fluid management and of management guided by a central venous vs. pulmonary artery catheter.Acute Respiratory Distress Syndrome Network hospitals.One thousand patients.None.The incidence of acute kidney injury, defined as an absolute rise in creatinine of ?0.3 mg/dL or a relative change of >50% over 48 hrs, was examined before and after adjustment of serum creatinine for fluid balance. The incidence of acute kidney injury before adjustment for fluid balance was greater in those managed with the conservative fluid protocol (57% vs. 51%, p = .04). After adjustment for fluid balance, the incidence of acute kidney injury was greater in those managed with the liberal fluid protocol (66% vs. 58%, p = .007). Patients who met acute kidney injury criteria after adjustment of creatinine for fluid balance (but not before) had a mortality rate that was significantly greater than those who did not meet acute kidney injury criteria both before and after adjustment for fluid balance (31% vs. 12%, p < .001) and those who had acute kidney injury before but not after adjustment for fluid balance (31% vs. 11%, p = .005). The mortality of those patients meeting acute kidney injury criteria after but not before adjustment for fluid balance was similar to patients with acute kidney injury both before and after adjustment for fluid balance (31% vs. 38%, p = .18).Fluid management influences serum creatinine and therefore the diagnosis of acute kidney injury using creatinine-based definitions. Patients with "unrecognized" acute kidney injury that is identified after adjusting for positive fluid balance have higher mortality rates, and patients who have acute kidney injury before but not after adjusting for fluid balance have lower mortality rates. Future studies of acute kidney injury should consider potential differences in serum creatinine caused by changes in fluid balance and the impact of these differences on diagnosis and prognosis.
Project description:BACKGROUND:Approximately 800 thousand patients require mechanical ventilation in the United States annually with an in-hospital mortality rate of over 30%. The majority of patients requiring mechanical ventilation are over the age of 65 and advanced age is known to increase the severity of ventilator-induced lung injury (VILI) and in-hospital mortality rates. However, the mechanisms which predispose aging ventilator patients to increased mortality rates are not fully understood. Ventilation with conservative fluid management decreases mortality rates in acute respiratory distress patients, but to date there has been no investigation of the effect of conservative fluid management on VILI and ventilator associated mortality rates. We hypothesized that age-associated increases in susceptibility and incidence of pulmonary edema strongly promote age-related increases in ventilator associated mortality. METHODS:2month old and 20month old male C57BL6 mice were mechanically ventilated with either high tidal volume (HVT) or low tidal volume (LVT) for up to 4h with either liberal or conservative fluid support. During ventilation, lung compliance, total lung capacity, and hysteresis curves were quantified. Following ventilation, bronchoalveolar lavage fluid was analyzed for total protein content and inflammatory cell infiltration. Wet to dry ratios were used to directly measure edema in excised lungs. Lung histology was performed to quantify alveolar barrier damage/destruction. Age matched non-ventilated mice were used as controls. RESULTS:At 4h, both advanced age and HVT ventilation significantly increased markers of inflammation and injury, degraded pulmonary mechanics, and decreased survival rates. Conservative fluid support significantly diminished pulmonary edema and improved pulmonary mechanics by 1h in advanced age HVT subjects. In 4h ventilations, conservative fluid support significantly diminished pulmonary edema, improved lung mechanics, and resulted in significantly lower mortality rates in older subjects. CONCLUSION:Our study demonstrates that conservative fluid alone can attenuate the age associated increase in ventilator associated mortality.
Project description:Background: Fluid overload is common in critically ill children and is associated with adverse outcome. Therefore, restricting fluid intake may be beneficial. This study aims to study the feasibility of a randomized controlled trial (RCT) comparing a conservative to a standard, more liberal, strategy of fluid management in mechanically ventilated pediatric patients with acute respiratory tract infection (ARTI). Methods: This is a feasibility study in a single, tertiary referral pediatric intensive care unit (PICU). Twenty-three children receiving mechanical ventilation for ARTI, without ongoing hemodynamic support, admitted to the PICU of the Emma Children's Hospital/Amsterdam UMC between 2016 and 2018 were included. Patients were randomized to a conservative (<70% of normal intake) or standard (>85% of normal intake) fluid strategy, which was kept throughout the period of mechanical ventilation. Results: Primary endpoints were adherence to fluid strategy and safety parameters such as calorie and protein intake. Secondary outcomes were cumulative fluid intake (CFI) and cumulative fluid balance (CFB) on day 3. In the conservative group, in 75% of the mechanical ventilation days patients achieved their target fluid intake. Median [25th-75th percentiles] calorie intake over all mechanical ventilation days was 67.9 [51.5-74.0] kcal/kg/day in the conservative vs. 67.2 [58.0-75.2] kcal/kg/day in the standard group (p = 0.878). Protein intake was 1.6 [1.3-1.8] gr protein/kg in the conservative and 1.5 [1.2-1.7] gr protein/kg in the standard group (p = 0.598). No adverse effects on hemodynamics or electrolyte imbalances were noted. Mean (±SD) CFI on day 3 was 262.3 (±58.9) ml/kg in the conservative group vs. 360.5 (±52.6) ml/kg in the standard fluid group (p < 0.001), which did not result in a lower CFB. Conclusions: A conservative fluid strategy in mechanically ventilated children with ARTI seems feasible, without limiting metabolic needs. However, in our study a conservative fluid strategy surprisingly did not reduce the degree of fluid overload. This study aids the design and sample size calculation of a future larger multicenter RCT, in which we need to redefine the target fluid strategy, possibly by even further fluid restriction and early initiation of active diuresis. Clinical Trial Registration: ClinicalTrials.gov, identifier: NCT02989051.
Project description:The purpose of the study is to evaluate the association between positive end-expiratory pressure (PEEP) and cardiac index in patients with acute respiratory distress syndrome (ARDS).This is a secondary cross-sectional analysis of the multicenter randomized controlled Fluid and Catheter Treatment Trial enrolling adult patients within 48 hours of ARDS onset. Patients randomized to the pulmonary artery catheter arm, who had PEEP and cardiac index measurements performed within a short period of each other during the first 3 days of the FACTT study enrollment, were included in this study. Because FACTT had a 2 × 2 factorial design, half of the patients were in a "liberal fluids" study arm, and the other half were in a "conservative fluids" study arm.The final study population (833 measurements or observations, in 367 patients) was comparable with the original overall FACTT study population. The mean PEEP level used was 8.2 ± 3.4 cm H2O, and the mean cardiac index was 4.2 ± 1.2 L/min per square meter. There was no association between PEEP and cardiac index in patients with ARDS, even when adjusted for Acute Physiology and Chronic Health Evaluation score, age, fluid study arm in FACTT, and sepsis.In patients with ARDS who are managed with liberal or conservative fluid management protocols, PEEP is not associated with lower cardiac index.
Project description:RATIONALE:Short-term follow-up in the Fluid and Catheter Treatment Trial (FACTT) suggested differential mortality by race with conservative fluid management, but no significant interaction. OBJECTIVE:In a post hoc analysis of FACTT including 1-year follow-up, we sought to estimate long-term mortality by race and test for an interaction between fluids and race. METHODS:We performed a post hoc analysis of FACTT and the Economic Analysis of Pulmonary Artery Catheters (EAPAC) study (which included 655 of the 1,000 FACTT patients with near-complete 1-year follow up). We fit a multistate Markov model to estimate 1-year mortality for all non-Hispanic black and white randomized FACTT subjects. The model estimated the distribution of time from randomization to hospital discharge or hospital death (available on all patients) and estimated the distribution of time from hospital discharge to death using data on patients after hospital discharge for patients in EAPAC. The 1-year mortality was found by combining these estimates. RESULTS:Non-Hispanic black (n?=?217, 25%) or white identified subjects (n?=?641, 75%) were included. There was a significant interaction between race and fluid treatment (P?=?0.012). One-year mortality was lower for black subjects assigned to conservative fluids (38 vs. 54%; mean mortality difference, 16%; 95% confidence interval, 2-30%; P?=?0.027 between conservative and liberal). Conversely, 1-year mortality for white subjects was 35% versus 30% for conservative versus liberal arms (mean mortality difference, -4.8%; 95% confidence interval, -13% to 3%; P?=?0.23). CONCLUSIONS:In our cohort, conservative fluid management may have improved 1-year mortality for non-Hispanic black patients with ARDS. However, we found no long-term benefit of conservative fluid management in white subjects.
Project description:Liberal fluid strategies in critically ill patients are associated with harm, thought to be due to endothelial and glycocalyx injury. As the restrictive versus liberal fluid therapy for major abdominal surgery trial not only failed to report survival benefit with restrictive fluids but was associated with a higher rate of acute kidney injury, we hypothesized that factors other than endothelial and glycocalyx injury were likely to account for these findings. Consequently, we measured injury biomarkers in a cohort of the restrictive versus liberal fluid therapy for major abdominal surgery trial.<h4>Design</h4>The restrictive versus liberal fluid therapy for major abdominal surgery trial was an international, randomized, assessor-blinded trial comparing restrictive with liberal IV fluid regimens that represented traditional care in patients undergoing major abdominal surgery.<h4>Setting and patients</h4>Cohort of restrictive versus liberal fluid therapy for major abdominal surgery bloods was collected at a single major site (161 patients) prior to, day 1 and day 3 after surgery.<h4>Intervention</h4>Bloods were blindly and randomly batch analyzed for plasma markers of endothelial/glycocalyx injury-angiopoietin-1, angiopoietin-2, soluble tyrosine-protein kinase-2 receptor, soluble intracellular adhesion molecule-1, syndecan, and tumor necrosis factor-?. Data were examined as restrictive versus liberal enrollment groups and high versus low (± 5,000?mL) fluid groups. Differences were examined by linear mixed modeling.<h4>Measurement and main results</h4>There were no significant differences in any biomarkers between the restrictive (<i>n</i> = 75) and liberal (<i>n</i> = 86) groups. When examined as low (<i>n</i> = 81) and high (<i>n</i> = 79) fluid groups, plasma angiopoietin-2 (<i>p</i> = 0.009) and soluble intracellular adhesion molecule-1 (<i>p</i> = 0.01) were elevated in the high fluid group. There were no differences in other biomarkers.<h4>Conclusions</h4>Although these results are consistent with previous findings of vascular injury following liberal fluid therapy, they suggest alternative mechanisms underlie the clinical outcomes from restrictive versus liberal fluid therapy for major abdominal surgery study.<h4>Clinicaltrialsgov identifier</h4>NCT01424150.