Balanced Crystalloids versus Saline in Critically Ill Adults


Self WH, Semler MW, Wanderer JP et al.

The New England Journal of Medicine 2018; 378: 829-839


Aim of Study

To determine the effect of isotonic crystalloid composition on clinical outcomes in critically ill patients.

Hypothesis: “use of balanced crystalloids would result in a lower overall incidence of death, new renal replacement therapy, and persistent renal dysfunction than saline”

Design and Location

Randomised controlled trial. Un-blinded.

Pragmatic, cluster randomised, multiple crossover trial

5 ICU’s in single centre – Vanderbilt Medical Centre, Nashville, Tennessee

June 2015-April 2017


Inclusion criteria:

Adults >18 years old admitted to participating ICUs during trial period

If discharged from hospital eligible to participate again if readmitted

If discharge to a non-ICU ward, enrolled in SALT-ED trial

15802 patients included

  • 7860 saline group
  • 7942 balanced crystalloids group


  • Saline group: 0.9% sodium chloride
  • Balanced crystalloids group: lactated Ringer’s solution or plasma-lyte A (clinician preference)

ICUs randomised to use balanced crystalloids or saline and then switched fluid group at the beginning of each month

Primary Outcome

Major adverse kidney injury event a day 30 (MAKE30)

Composite of:

  • Death from any cause
  • New renal replacement therapy
  • Persistent renal dysfunction (final plasma creatinine value before hospital discharge >200% of baseline in patient not having RRT prior to ICU admission)

Secondary Outcomes

  • In hospital death before ICU discharge or at 30 days or 60 days
  • ICU free days
  • Ventilator free days
  • Vasopressor free days
  • Days alive and free of RRT during the 28 days after enrolment


Sample size adjusted from 8000 to 14000 patients

Intention to treat analysis

Conditional odds ratios and marginal odds ratios presented


Mean volume of isotonic crystalloid administered:

  • Balanced crystalloid group: 1000ml (IQR 0-3210)
  • Saline group: 1020ml (IQR 0-3500)

Primary outcome:

  • 14.3% in balanced crystalloid group vs 15.4% in saline group had a major adverse kidney event (marginal odds ratio 0.91; 95% CI 0.84-0.99; conditional odds ratio, 0.90; 95% CI 0.82-0.99, p=0.04)
  • NNT to avoid one MAKE 30 outcome: 94

Secondary outcome:

  • No significant difference in:
    • ICU free days
    • Ventilatory free days
    • Vasopressor free days
    • Stage 2 AKI developing after enrolment

Subgroup of patients with sepsis:

  • 30 day hospital mortality 25.2% with balanced crystalloids vs 29.4% with saline p=0.02
  • MAKE30 was 33.8% with balanced crystalloids vs 38.9% with saline p=0.01


Author’s conclusion:

“Use of balanced crystalloids rather than saline resulted in an absolute difference of 1.1 percentage points in favour of balance crystalloids in the primary outcome’

Largest benefit appears to be in septic patients

Recognised that effect size was modest, but if extrapolated across 5 million ICU patients worldwide each year the reduction in persistent renal dysfunction, new RRT or death would be substantial.

Stated Limitations from the Study

  • Single centre
  • Non-blinded
  • Composite outcome
  • Decision to initiate RRT can be susceptible to treatment bias
  • Patients could be exposed to both fluids if remained in ITU at the end of a calendar month
  • Small volumes of fluid administered
  • Lactated ringers and plasma-Lyte A analysed together
  • In patients with traumatic brain injury clinicians could choose to give 0.9% sodium chloride if allocated to balance crystalloids therefore cannot use results from this study to guide isotonic crystalloid use in these patients.

Discussion from Journal Club Meeting (Change of Practice)

Very small fluid volumes used in the study, patients and practice not representative of ITU at Kingston

Fluid choice tends to be dictated by fluid available/local trust guidelines but balance crystalloids appear to be favoured

Summary by Dr A Ostler. Journal Club Meeting 20 September 2018.

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