BaSICS

12 August 2021 George Walker Intensive Care Medicine Leave a comment

The BaSICS (Balanced Solution versus Saline in Intensive Care Study) Randomized Clinical Trial

(Fluid Type) Zampieri FG; JAMA 2021; doi:10.1001/jama.2021.11684

(Fluid Rate) Zampieri FG; JAMA 2021; doi:10.1001/jama.2021.11444

Clinical Questions

In adult intensive care patients does the use of a balanced crystalloid compared to 0.9% saline reduce 90-day all-cause mortality?
In adult intensive care patients needing administration of resuscitation fluids, does the slow infusion compared to a fast infusion of a fluid boluses reduce 90-day all-cause mortality?

Background

Almost all patients in ICU receive intravenous fluids
The SPLIT and SMART trials compare Plasma-Lyte and 0.9% saline
- The SPLIT trial, with a median of 2000ml administered in each arm, showed no difference in 90 day AKI
- The SMART trial, with a median of 1000ml administered in each arm, showed a significant greater 30 day occurrence of Major Adverse Kidney Events (a composite of death, new RRT or persistent renal dysfunction)
The use of rapid fluid boluses, a very common intervention in unwell patients, has been hypothesised to result in unfavourable cardiovascular physiological outcomes, such as reduced arterial elastance
- The FEAST trial showed that in African children with hypotension the use of saline or albumin boluses resulted in an increased risk of 48-hour mortality
- The FENICE study looking at fluid bolus administration in over 2000 ICU patients found that the practice was very variable (with regards to volume, rate, end-points)

Design

Factorial 2 x 2 randomised study
- Randomised in 1:1:1:1 ratio to each fluid (balanced solution – Plasma-Lyte and 0.9% sodium chloride) and each rate of administration (333ml/hr and 999ml/hr)
Randomisation via online software in random permutated blocks of 12 patients
Those involved in patient care were blinded to fluid type but not to the rate of administration
Fluid supplied in identical 500ml bags labelled with a letter (A – F)
Data and protocol adherence checked on days 1,2,3 and 7
Follow up phone call at day 90 to assess vital status and need for RRT
Power Calculations:
- Planned sample size 11,000
- Based on 35% 90d mortality rate in control (0.9% sodium chloride or rapid infusion)
- 89% power to detect a hazard ratio of 0.9 or less for 90d mortality with an alpha level of 0.05
- Absence of interaction between fluid type and speed was assumed
Pre-specified secondary, tertiary outcomes and subgroups
Ideally, prospective informed consent sought but deferred consent allowed
Appropriate ethical approval gained

Setting

75 ICUs in Brazil
Data collected from 29th May 2017 – 2nd March 2020

Population

Inclusion:
- Admitted to ICU with a need for fluid resuscitation (defined by 1 sign of hypoperfusion + 1 sign of fluid responsiveness)
- Not expected to be discharged the day after admission
- At least 1 risk factor for AKI (Age > 65 years, hypotension, sepsis, mechanical ventilation, oliguria, raised serum creatinine level, cirrhosis or acute liver failure)
Exclusion:
- < 18 years
- RRT, or expectation to require RRT, within 6 hours
- Severe electrolyte disturbance (Na⁺<120 or >160, K⁺>5.5)
- Death expected within next 24 hours
- Suspected or confirmed brain death
- Receipt of palliative care treatment only
- Prior enrolment
11,052 patients randomised
- 486 subsequently refused consent, 46 duplicate randomisations, 25 lost to follow up at 90d
  - 5,290 randomised to receive 0.9% sodium chloride
    - 0.9% sodium chloride at rapid infusion rate: 2,641
    - 0.9% sodium chloride at slower infusion rate: 2,649
  - 5,230 randomised to receive balanced solution
    - Balanced solution at rapid infusion rate: 2,603
    - Balanced solution at slower infusion rate: 2,627
Comparing baseline characteristics of intervention vs. control group
- Baseline characteristics similar across all groups

Intervention

Two interventions were assessed:
- The use of a balanced crystalloid (Plasma-Lyte)
- Giving a slower rate infusion (333ml/hr) if fluid boluses were required

Control

Two controls were assessed:
- The use of 0.9% Sodium Chloride
- Giving a rapid rate infusion (999ml/hr) if fluid boluses were required

Management common to both groups

Fluid that patient randomised to was used for entire ICU stay (up to 90 days)
Guidelines provided for when a fluid challenge is required, and when to commence RRT
Used for resuscitation, maintenance and drug dilution if possible
- If fluid is indicated:
  - Maintenance – given study fluid patient randomised
  - Fluid bolus – given study fluid at the rate patient randomised
  - Other fluid (bicarbonate, albumin, blood etc) – allowed
Volumes and frequency of administration at discretion of treating clinicians
In some scenarios (e.g. severe hypernatraemia), study fluid not allowed so can use alternate fluid
- Use of study fluid was to resume as soon as contraindication resolved

Outcomes

Fluid Type: Sodium Chloride vs. Balanced Solutions

Primary outcome: No significant difference in 90-day mortality
- 1381 of 5230 patients (26.4%) assigned to a balanced solution died vs 1439 of 5290 patients (27.2%) assigned to saline solution (adjusted HR, 0.97 [95% CI, 0.90-1.05]; P = .47)
Secondary outcomes: SOFA score at day 7 was significantly different for the balanced solution group
- median difference, 0.27 [95% CI, 0.08-0.45]), mostly due to a higher neurological SOFA score (>2) at day 7 (32.1% vs 26.0% for the saline solution group; odds ratio, 1.40 [95% CI, 1.18-1.66])
- There was no statistical difference in the other 17 secondary outcomes including incidence of AKI with need for RRT within 90 days per 1000 patient days
Sub-group analyses: statistically significant interaction between presence of traumatic brain injury, fluid type, and 90-day mortality
- 31.3% for the balanced solution group vs 21.1% for the saline solution group [HR, 1.48; 95% CI, 1.03-2.12]
- 26.2% vs 27.5% for patients without a traumatic brain injury

Fluid Rate: Rapid vs. Slow administration of fluid challenges

Primary outcome: No significant difference in 90-day mortality
- In the slower infusion group, 1406 of 5276 patients (26.6%) had died by day 90 compared with 1414 of 5244 patients (27.0%) in the control group
  - HR 1.03 [95% CI 0.96 – 1.11], p = 0.46
Secondary outcomes: differences in Day 3 cardiovascular, respiratory and coagulation SOFA scores significant. By Day 7 no differences in SOFA scores significant.
- Day 3 cardiovascular SOFA scores lower in slower group, 32.5 vs. 35.3
  - OR 0.89 [95% CI 0.80 – 0.98]
- Day 3 respiratory SOFA score lower in slower group, 6.2 vs. 7.5
  - OR 0.81 [95% CI 0.68 – 0.97]
- Day 3 coagulation SOFA score higher in slower group, 4.7 vs. 3.9
  - OR 1.31 [95% CI 1.05 – 1.64]

Authors’ Conclusions

Among patients in intensive care:
- The use of a balanced crystalloid compared to 0.9% sodium chloride did not reduce 90-day mortality
- The use of slower infusion rates when a fluid bolus is required compared to a faster rate of infusion did not reduce 90-day mortality

Strengths

An extremely large, multi-centre trial designed to answer an important clinical question given the frequency of fluid use in ICU
Excellent internal validity
- Good randomisation strategy. This strategy was tested at end when principal investigators were asked if they could guess which fluid each letter corresponded too
  - 6/66 who replied, correctly guessed the association between all letters and fluid type (this was compatible with hypothesis that the answers guess were random)
- Appropriate blinding for fluid type (not blinded for rate)
- Minimal loss to follow-up: 0.2% (25/11052)
- Balanced baseline characteristics
- Pre-printed statistical analysis plan
Sensible secondary outcomes and pre-specified subgroups
- The authors rightly identify these being as hypothesis generating only
To complete, process and write up such a large and methodologically rigorous RCT whilst in the midst of Brazil’s COVID-19 situation is impressive

Weaknesses

Not analysed as intention to treat
- Given that majority (~87%) of those who did not receive treatment as randomised was due to withdrawal of consent, this is unlikely to be clinically relevant
Mortality lower than anticipated in power calculations (~27% vs. 35%)
- May reduce power of study to detect important differences
Mostly lower acuity ICU patients (median APACHE II score 12 and SOFA 4) with nearly 50% elective surgical and 40% of patients not hypotensive
Median volumes of trial fluid administered were low (mean <1 L/day) making a difference in outcomes potentially less likely to be detected
- 24 hours study fluid: 1.5L in each group
- 72 hours total study fluid: 2.9L in each group
- 72 hours total fluid (study and non study fluid): 4.1L (SD 2.9L)
The administration of non-study fluids could confound results:
- 68% of all patients received fluid prior to randomisation (~32% in the 0.9% sodium chloride received >1L balanced fluid and ~18% in the balanced group received >1L 0.9% sodium chloride).
- Following randomisation ~30% of the total fluid received by day 3 was non-study crystalloid (eTable 2, Supplement 3)
- Additionally, dextrose, albumin and synthetic colloids were also transfused
Chloride load hypothesised to be reason for increased mortality and organ failure. Whilst mean serum chloride levels were higher in 0.9% sodium chloride group at 48 hour (108 mEq/L vs. ~105.5 mEq/L), this was only 2 mEq/L above the upper limit of normal range which is not a meaningful clinical important difference
The slower infusion rate was defined arbitrarily at 333 mL/hr. The authors provide explanation that as this is less than 25% percentile in the Fluid Challenges in Intensive Care (FENICE) cohort study (500 mL/h) it still represented a value that was considered as a bolus (and not maintenance) by clinicians
No data collected on reason for administration of fluid bolus or immediate haemodynamic effects

The Bottom Line

On the basis of this trial, the use of 0.9% sodium chloride in ICU appears safe
Given some of the limitations above, and conflicting data from other trials, I will continue to use balanced crystalloid for those patients who are acutely unwell with an unplanned ICU admission
- Although the secondary outcomes are hypothesis generating, it would seem reasonable to use 0.9% saline in TBI patients
The need for (rapidly administered) fluid boluses for intensive care patients should be evaluated on an individual patient basis, rather than be a reflexive action given lack of benefit and potential harm shown
The PLUS trial will continue to inform practice

External Links

Metadata

Summary author: George Walker @hgmwalker89
Summary date: 11th August 2021
Peer-review editor: Steve Mathieu @stevemathieu75

Picture by: iStock

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