Patients being treated for sepsis, a serious infection that can lower blood pressure, are often treated with fluids through an IV. Previous studies have shown that a positive fluid balance, or more fluids taken in than out, may be connected to problems with kidney and lung function. The BALANCE pilot trial enrolled 30 patients; 15 patients received fluid in a conservative and restrictive manner, and 15 patients were given the typical fluid care. Results showed that the conservative fluid approach did not decrease fluid balance for patients with sepsis.  These findings suggest that future research on fluid treatment for sepsis will need to find ways to achieve bigger differences in the amount of fluid being received between the approaches being examined.

Rationale: The feasibility and clinical outcomes of conservative fluid management after sepsis resuscitation remain unknown.

Objectives: To evaluate the effect of a conservative fluid management protocol on fluid balance and intensive care unit (ICU)-free days among patients with sepsis.

Methods: In a single-center phase II/III randomized trial, we enrolled adults with suspected infection, ≥2 systemic inflammatory response syndrome criteria, and either shock (mean arterial pressure <60 mm Hg or vasopressors) or respiratory insufficiency (mechanical ventilation or oxygen saturation <97% and fraction of inspired oxygen ≥0.3). Patients were randomized 1:1 to usual care or a conservative fluid management protocol. The protocol restricted intravenous fluid administration during shock to treatment of oliguria or increasing vasopressor requirement. In the absence of shock, loop diuretic infusion targeted equal fluid input and output each study day. The primary outcomes were mean daily fluid balance (phase II) and ICU-free days (phase III).

Results: At the completion of phase II (n = 30), the difference in mean daily fluid balance between groups (-398 mL) was less than the prespecified threshold (-500 mL) and the trial was stopped. Patients in the conservative fluid management (n = 15) and usual care (n = 15) groups experienced similar cumulative fluid input (8450 mL vs 7049 mL; P = .90) of which only 14% was intravenous crystalloid or colloid. Loop diuretic infusion occurred more frequently in the conservative fluid management group (40% vs 0%; P = .02), and cumulative fluid output was 10 645 mL in the conservative fluid management group compared to 6286 mL in the usual care group (P = .39). Hemodynamic, respiratory, and renal function did not differ between the groups.

Conclusions: In this phase II trial, a conservative fluid management protocol did not decrease mean daily fluid balance by more than 500 mL among patients with sepsis.

Registration: Clinicaltrials.gov; NCT02159079.

Keywords: acute kidney injury; intravenous fluid; sepsis.

Conflict of interest statement

CONFLICTS OF INTEREST

All authors completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors declared no potential conflicts of interest with the current work. W.H.S. reported serving on advisory boards for Venaxis, Inc., Ferring Pharmaceuticals, and Cempra Pharmaceuticals, and as a consultant for Abbott Point-of-Care. T.W.R. reported serving on an advisory board for Avisa Pharma, LLC and as the Director of Medical Affairs for Cumberland Pharmaceuticals, Inc.

Manuscript Title: “Conservative Fluid Management After Sepsis Resuscitation: A Pilot Randomized Trial.”

Journal: Journal of Intensive Care Medicine

PMID: 30630380

Importance: Hypotension is common during tracheal intubation of critically ill adults and increases the risk of cardiac arrest and death. Whether administering an intravenous fluid bolus to critically ill adults undergoing tracheal intubation prevents severe hypotension, cardiac arrest, or death remains uncertain.

Objective: To determine the effect of fluid bolus administration on the incidence of severe hypotension, cardiac arrest, and death.

Design, setting, and participants: This randomized clinical trial enrolled 1067 critically ill adults undergoing tracheal intubation with sedation and positive pressure ventilation at 11 intensive care units in the US between February 1, 2019, and May 24, 2021. The date of final follow-up was June 21, 2021.

Interventions: Patients were randomly assigned to receive either a 500-mL intravenous fluid bolus (n = 538) or no fluid bolus (n = 527).

Main outcomes and measures: The primary outcome was cardiovascular collapse (defined as new or increased receipt of vasopressors or a systolic blood pressure <65 mm Hg between induction of anesthesia and 2 minutes after tracheal intubation, or cardiac arrest or death between induction of anesthesia and 1 hour after tracheal intubation). The secondary outcome was the incidence of death prior to day 28, which was censored at hospital discharge.

Results: Among 1067 patients randomized, 1065 (99.8%) completed the trial and were included in the primary analysis (median age, 62 years [IQR, 51-70 years]; 42.1% were women). Cardiovascular collapse occurred in 113 patients (21.0%) in the fluid bolus group and in 96 patients (18.2%) in the no fluid bolus group (absolute difference, 2.8% [95% CI, -2.2% to 7.7%]; P = .25). New or increased receipt of vasopressors occurred in 20.6% of patients in the fluid bolus group compared with 17.6% of patients in the no fluid bolus group, a systolic blood pressure of less than 65 mm Hg occurred in 3.9% vs 4.2%, respectively, cardiac arrest occurred in 1.7% vs 1.5%, and death occurred in 0.7% vs 0.6%. Death prior to day 28 (censored at hospital discharge) occurred in 218 patients (40.5%) in the fluid bolus group compared with 223 patients (42.3%) in the no fluid bolus group (absolute difference, -1.8% [95% CI, -7.9% to 4.3%]; P = .55).

Conclusions and relevance: Among critically ill adults undergoing tracheal intubation, administration of an intravenous fluid bolus compared with no fluid bolus did not significantly decrease the incidence of cardiovascular collapse.

Manuscript Title: “Effect of Fluid Bolus Administration on Cardiovascular Collapse Among Critically Ill Patients Undergoing Tracheal Intubation: A Randomized Clinical Trial”

Patients in the intensive care unit frequently receive IV fluid.  For more than 100 years, two basic types of IV fluid have been available: saline (which contains more chloride than human blood) and balanced crystalloids (which contains about the same amount of chloride as human blood).  No large trials had previously evaluated which fluid resulted in the best outcomes for patients.  Among almost 16,000 patients in 5 intensive care units, the SMART trial found that using balanced crystalloids instead of saline decreased the risk of death, dialysis, or lasting kidney problems.  These findings suggest that most hospitalized patients without a specific reason for receiving saline should be treated with balanced crystalloids when an IV fluid is needed.

Background: Both balanced crystalloids and saline are used for intravenous fluid administration in critically ill adults, but it is not known which results in better clinical outcomes.

Methods: In a pragmatic, cluster-randomized, multiple-crossover trial conducted in five intensive care units at an academic center, we assigned 15,802 adults to receive saline (0.9% sodium chloride) or balanced crystalloids (lactated Ringer’s solution or Plasma-Lyte A) according to the randomization of the unit to which they were admitted. The primary outcome was a major adverse kidney event within 30 days – a composite of death from any cause, new renal-replacement therapy, or persistent renal dysfunction (defined as an elevation of the creatinine level to ≥200% of baseline) – all censored at hospital discharge or 30 days, whichever occurred first.

Results: Among the 7942 patients in the balanced-crystalloids group, 1139 (14.3%) had a major adverse kidney event, as compared with 1211 of 7860 patients (15.4%) in the saline group (marginal odds ratio, 0.91; 95% confidence interval [CI], 0.84 to 0.99; conditional odds ratio, 0.90; 95% CI, 0.82 to 0.99; P=0.04). In-hospital mortality at 30 days was 10.3% in the balanced-crystalloids group and 11.1% in the saline group (P=0.06). The incidence of new renal-replacement therapy was 2.5% and 2.9%, respectively (P=0.08), and the incidence of persistent renal dysfunction was 6.4% and 6.6%, respectively (P=0.60).

Conclusions: Among critically ill adults, the use of balanced crystalloids for intravenous fluid administration resulted in a lower rate of the composite outcome of death from any cause, new renal-replacement therapy, or persistent renal dysfunction than the use of saline. (Funded by the Vanderbilt Institute for Clinical and Translational Research and others; SMART-MED and SMART-SURG ClinicalTrials.gov numbers, NCT02444988 and NCT02547779 .).

Manuscript Title: “Balanced Crystalloids versus Saline in Critically Ill Adults.”

Journal: New England Journal of Medicine

PMID: 29485925

Patients in the emergency department are frequently given fluids through an IV as a treatment for a wide variety of injuries and medical complications. Historically, the most common fluid given to patients had been saline.  Saline contains a higher concentration of chloride than that of human blood, which could have negative effects on patients’ kidneys and blood vessels. Another type of fluid, called “balanced crystalloids”, has a chloride concentration more similar to that of human blood.  Whether using balanced crystalloids would result in better outcomes than using saline had been unknown.  Among approximately 13,000 patients receiving fluid in an emergency department prior to admission to the hospital, the  SALT-ED trial found using balanced crystalloids rather than saline did not increase the number of days alive outside the hospital but did decrease patients chances of dying, receiving dialysis, or having lasting kidney problems.  These findings suggest that balanced crystalloids should be used rather than saline for most patients receiving IV fluid in an emergency department.

Background: Comparative clinical effects of balanced crystalloids and saline are uncertain, particularly in noncritically ill patients cared for outside an intensive care unit (ICU).

Methods: We conducted a single-center, pragmatic, multiple-crossover trial comparing balanced crystalloids (lactated Ringer’s solution or Plasma-Lyte A) with saline among adults who were treated with intravenous crystalloids in the emergency department and were subsequently hospitalized outside an ICU. The type of crystalloid that was administered in the emergency department was assigned to each patient on the basis of calendar month, with the entire emergency department crossing over between balanced crystalloids and saline monthly during the 16-month trial. The primary outcome was hospital-free days (days alive after discharge before day 28). Secondary outcomes included major adverse kidney events within 30 days – a composite of death from any cause, new renal-replacement therapy, or persistent renal dysfunction (defined as an elevation of the creatinine level to ≥200% of baseline) – all censored at hospital discharge or 30 days, whichever occurred first.

Results: A total of 13,347 patients were enrolled, with a median crystalloid volume administered in the emergency department of 1079 ml and 88.3% of the patients exclusively receiving the assigned crystalloid. The number of hospital-free days did not differ between the balanced-crystalloids and saline groups (median, 25 days in each group; adjusted odds ratio with balanced crystalloids, 0.98; 95% confidence interval [CI], 0.92 to 1.04; P=0.41). Balanced crystalloids resulted in a lower incidence of major adverse kidney events within 30 days than saline (4.7% vs. 5.6%; adjusted odds ratio, 0.82; 95% CI, 0.70 to 0.95; P=0.01).

Conclusions: Among noncritically ill adults treated with intravenous fluids in the emergency department, there was no difference in hospital-free days between treatment with balanced crystalloids and treatment with saline. (Funded by the Vanderbilt Institute for Clinical and Translational Research and others; SALT-ED ClinicalTrials.gov number, NCT02614040 .).

Conflict of interest statement

Dr. Self reports receiving advisory board fees from Venaxis, Cempra Pharmaceuticals, Ferring Pharmaceuticals, and Biotest, consulting fees from Abbott Point of Care, and travel support from Gilead Sciences; and Dr. Rice, receiving consulting fees from Cumberland Pharmaceuticals and Avisa Pharma. No other potential conflict of interest relevant to this article was reported.

Manuscript Title: “Balanced Crystalloids versus Saline in Noncritically Ill Adults.”

Journal: New England Journal of Medicine

PMID: 29485926

Patients in the intensive care unit frequently receive IV fluid.  Two basic types of IV fluid exist: saline (which contains more chloride than human blood) and balanced crystalloids (which contains about the same amount of chloride as human blood).  No large trials had previously evaluated which fluid resulted in the best outcomes for patients.  In preparation for a large trial examining this question, the SALT pilot trial aimed to determine whether software tools in the hospital’s electronic health record would produce balanced study groups and divide study participants to either receive balanced crystalloids or saline in a separate and equal way. Results of the study showed that this approach can produce well-balanced study groups and separate the receipt of saline or balanced crystalloids in an effective way.  These findings suggest that electronic health records may be used to efficiently conduct trials comparing treatments commonly used in clinical care.

Rationale: Saline is the intravenous fluid most commonly administered to critically ill adults, but it may be associated with acute kidney injury and death. Whether use of balanced crystalloids rather than saline affects patient outcomes remains unknown.

Objectives: To pilot a cluster-randomized, multiple-crossover trial using software tools within the electronic health record to compare saline to balanced crystalloids.

Methods: This was a cluster-randomized, multiple-crossover trial among 974 adults admitted to a tertiary medical intensive care unit from February 3, 2015 to May 31, 2015. The intravenous crystalloid used in the unit alternated monthly between saline (0.9% sodium chloride) and balanced crystalloids (lactated Ringer’s solution or Plasma-Lyte A). Enrollment, fluid delivery, and data collection were performed using software tools within the electronic health record. The primary outcome was the difference between study groups in the proportion of isotonic crystalloid administered that was saline. The secondary outcome was major adverse kidney events within 30 days (MAKE30), a composite of death, dialysis, or persistent renal dysfunction.

Measurements and main results: Patients assigned to saline (n = 454) and balanced crystalloids (n = 520) were similar at baseline and received similar volumes of crystalloid by 30 days (median [interquartile range]: 1,424 ml [500-3,377] vs. 1,617 ml [500-3,628]; P = 0.40). Saline made up a larger proportion of the isotonic crystalloid given in the saline group than in the balanced crystalloid group (91% vs. 21%; P < 0.001). MAKE30 did not differ between groups (24.7% vs. 24.6%; P = 0.98).

Conclusions: An electronic health record-embedded, cluster-randomized, multiple-crossover trial comparing saline with balanced crystalloids can produce well-balanced study groups and separation in crystalloid receipt. Clinical trial registered with www.clinicaltrials.gov (NCT 02345486).

Trial registration: ClinicalTrials.gov NCT02345486.

Keywords: acute kidney injury; critical illness; crystalloid; intravenous fluid; saline.

Manuscript Title: “Balanced Crystalloids versus Saline in the Intensive Care Unit. The SALT Randomized Trial.”

Journal: American Journal of Respiratory and Critical Care Medicine

PMID: 27749094