By Drayton Hammond, PharmD, MBA, BCPS, BCCCP

Clinical Pharmacy Specialist, Adult Critical Care, Rush University Medical Center, Chicago

Dr. Hammond reports no financial relationships relevant to this field of study.

SYNOPSIS: Compared to saline, balanced crystalloids reduced in-hospital mortality and major adverse kidney events within 30 days in critically ill patients with sepsis or septic shock.

SOURCE: Brown RM, Wang L, Coston TD, et al; SMART Investigators and the Pragmatic Critical Care Research Group. Balanced crystalloids versus saline in sepsis: A secondary analysis of the SMART Trial. Am J Respir Crit Care Med 2019 Aug. 27 [Epub ahead of print].

Fluid resuscitation for critically ill adults with sepsis or septic shock is necessary to combat significant vasodilation and distributive shock. The current Surviving Sepsis Campaign guidelines have a strong recommendation based on low quality of evidence for initial volume resuscitation with intravenous crystalloid fluids.1 However, there is no preferential recommendation for balanced crystalloid (e.g., lactated Ringers, Plasma-Lyte) vs. 0.9% sodium chloride (saline). Significant attention was given to the SMART trial after its publication in 2018, which suggested that critically ill patients resuscitated with balanced crystalloids experienced fewer major adverse kidney events within 30 days of hospital admission (MAKE30, defined as the incidence of the composite outcome of death, new renal replacement therapy [RRT], or persistent renal dysfunction).2 In a pre-specified subgroup analysis, patients with sepsis were found to have lower odds of MAKE30 (odds ratio [OR] 0.80; 95% confidence interval [CI], 0.67-0.94) than those without sepsis (OR 0.96; 95% CI, 0.86-1.07), although this difference was not significant following a test for interaction (P = 0.06).

The SMART investigators conducted a pre-specified secondary analysis of critically ill adults with sepsis or septic shock who received care in the medical intensive care unit at Vanderbilt University Medical Center enrolled in SMART.3 All patients in the saline group received 0.9% sodium chloride, whereas patients in the balanced group received lactated Ringers (91%) or Plasma-Lyte (9%). Of the 1,641 included patients (balanced group n = 824; saline group n = 817), 34.1% were in shock at ICU admission. Minimal amounts of non-study crystalloids were provided in the 24 hours prior to ICU admission (approximately 300 mL) and prior to hospital discharge or 30 days (approximately 600-1,400 mL). The incidence of 30-day mortality was greater for patients in the saline group (26.3% vs. 31.2%, adjusted OR 0.74; 95% CI, 0.59-0.93). This finding was maintained following multiple sensitivity analyses, including care being provided in other ICUs and culture-positive sepsis. MAKE30 also occurred less frequently among patients in the balanced group (35.4% vs. 40.1%; adjusted OR 0.78; 95% CI, 0.63-0.97), with no difference in new RRT (7.4% vs. 10.3%; adjusted OR 0.71; 95% CI, 0.48-1.04) but fewer patients progressing to stage II or greater acute kidney injury (AKI) (27.4% vs. 31.9%; adjusted OR 0.79; 95% CI, 0.63-1.00). Patients in the balanced crystalloids group had a greater amount of ventilator-free, vasopressor-free, and RRT-free days than patients in the saline group. Vasopressor requirements and serum lactate concentrations were lower following ICU admission in the balanced crystalloids group.

COMMENTARY

Following publication of the SMART trial, systematic reviews and meta-analyses were performed to evaluate the impact of balanced crystalloids on outcomes in critically ill adults and relevant subgroups of critical illness, including sepsis and septic shock.2,4,5 From a pathophysiology perspective, the benefits from balanced crystalloids appear evident, as they may improve resolution of metabolic acidosis and AKI that frequently develop or worsen during sepsis and septic shock.6 These meta-analyses suggested trends toward improved in-hospital mortality with balanced crystalloids in sepsis, which now have been confirmed by this subgroup analysis of the SMART trial.

These improved outcomes with balanced crystalloids may be achievable with relatively small volumes of intravenous fluids, as most patients received an average of 4 L of intravenous fluids during the study period. While the exact mechanisms of benefit and harm require further investigation, improved end-organ function evidenced by greater time without vasopressor, mechanical ventilator, and RRT support in the balanced crystalloids group suggests multiple mechanisms are involved. Based on the point estimates, narrow confidence intervals, and robustness of the findings to multiple sensitivity analyses, clinicians may be assured that using balanced crystalloids as resuscitative fluids in critically ill patients with sepsis or septic shock improves their likelihood of better outcomes.

REFERENCES

  1. Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: International guidelines for management of sepsis and septic shock: 2016. Intensive Care Med 2017;43:304-377.
  2. Semler MW, Self WH, Wanderer JP, et al. Balanced crystalloids versus saline in critically ill adults. N Engl J Med 2018;378:829-839.
  3. Brown RM, Wang L, Coston TD, et al; SMART Investigators and the Pragmatic Critical Care Research Group. Balanced crystalloids versus saline in sepsis: A secondary analysis of the SMART trial. Am J Respir Crit Care Med 2019 Aug 27. doi: 10.1164/rccm.201903-0557OC. [Epub ahead of print].
  4. Xue M, Zhang X, Liu F, et al. Effects of chloride content of intravenous crystalloid solutions in critically ill adult patients: A meta-analysis with trial sequential analysis of randomized trials. Ann Intensive Care 2019;9:30.
  5. Hammond DA, Lam SW, Rech MA, et al. Balanced crystalloids versus saline in critically ill adults: A systematic review and meta-analysis. Ann Pharmacother 2019 Jul 31:1060028019866420. doi:10.1177/1060028019866420. [Epub ahead of print].
  6. Chowdhury AH, Cox EF, Francis ST, Lobo DN. A randomized, controlled, double-blind crossover study on the effects of 2-L infusions of 0.9% saline and Plasma-Lyte® 148 on renal blood glow velocity and renal cortical tissue perfusion in healthy volunteers. Ann Surg 2012;256:18-24.