RELIEF: More Fluids mean Less AKI?

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N Engl J Med. 2018 Jun 14;378(24):2263-2274. doi: 10.1056/NEJMoa1801601. Epub 2018 May 9.

Restrictive versus Liberal Fluid Therapy for Major Abdominal Surgery.

Myles PSBellomo RCorcoran TForbes APeyton PStory DChristophi CLeslie KMcGuinness SParke RSerpell JChan MTVPainter TMcCluskey SMinto GWallace SAustralian and New Zealand College of Anaesthetists Clinical Trials Network and the Australian and New Zealand Intensive Care Society Clinical Trials Group.

PMID: 29742967 Full Text at NEJM

Published protocol in BMJ Open

Related editorial from Birgitte Brandstrup

Introduction

A least 310 million patients undergo major abdominal surgery per year. Traditionally, this involves a flood of intravenous fluids, with a view to compensating for peri-operative fluid shifts, correction of volume deficiency from preoperative fasting, to maintain urine output, and to enhance perfusion. The optimum regimen for intravenous fluid administration remains unclear and can prove challenging in the peri-operative period. NephJC recently covered trials addressing the type of fluids here but this week we are addressing the quantity of fluids. Excessive intravenous fluids is associated with weight gain, tissue oedema, arrhythmia and pulmonary oedema. On the flip side, fluid restriction may increase the risk of hypoperfusion and end organ damage. The traditional approach errored on the side of excess fluid administration -- with 3-6 kg post-operative weight gains being common. A trial in 2003 of 172 patients undergoing colorectal surgery demonstrated that post-operative complications (including deaths) were less common with the restrictive fluid strategy -- mostly driven by decreased wound and pulmonary complications.

Postoperative complications were reduced from 51% to 33% with a restrictive strategy. NNT 4 for any complication, NNT 7 for major complications. Adding to the validity, they found a dose dependent relationship between complications and weight gain. Same with complications and fluid balance (P<0.001 for trend).

Based on this and other trials and a meta-analysis, the surgical consensus guidelines moved towards a restrictive fluid strategy. Even outside the post-operative scenario, intensive care medicine practice has shifted towards a restrictive fluid startegy, based on shorter ventilatory requirement and ICU length of stay.

However, the aforementioned meta-analysis on the merits of a restrictive fluid strategy in the post-operative period had significant heterogeneity. A subsequent meta-analysis suggested varying definitions made firm conclusions about the superiority of a restrictive strategy somewhat tenuous. With a view to unravelling the optimum approach, Myles et al undertook an international, randomised, controlled, and assessor-blinded trial. They compared a restrictive intravenous-fluid strategy with a relatively liberal fluid strategy during the peri-operative period in 3,000 patients across 47 centres (mean patient number per site 64) in 7 countries (Australia contributing over half the sample, followed by Canada, UK, Hong Kong, US, and New Zealand) across a three-year period.

The Study

Methods

Inclusion criteria

The study population was adults undergoing elective major abdominal surgery (including skin incision, operative duration > 2 hours, expected hospital stay of 3+ days) who were deemed to be at an increased risk of complications as defined as

  • At least 1 of the following:
    • Age greater or equal to 70 years
    • ischaemic heart disease
    • renal impairment (creatinine > 2.2 mg/dL (200 micromol/L)
    • morbid obesity (BMI greater than or equal to 35kg/m2)
    • preoperative serum albumin <30g/L
    • anaerobic threshold (if done) < 12mL/kg/min
  • or at least 2 of the following:
    • ASA 3 or 4, chronic respiratory disease
    • obesity (BMI 30-35)
    • aortic or peripheral vascular disease
    • preoperative Hb < 100g/L
    • pre-operative serum creatinine 150-199 micromol/L
    • anaerobic threshold (if done) 12-14 mL/kg/min

Exclusion criteria

Patients were excluded if they were undergoing urgent or time-critical surgery, liver resection, or less extensive surgery or if they had end stage kidney disease requiring dialysis.

Intervention

  From Myles et al,  BMJ Open 2016

From Myles et al, BMJ Open 2016

relief2.png

Beyond the immediate post-operative period, for patients in the restrictive arm, even on the floor, a handout was provided to encourage vasopressor use and/or colloid boluses if hypotension occured - whereas in the liberal group, IV fluids could be administered as needed. 

Blinding

Most medical and nursing staff caring for patients were not blinded and had knowledge of the group assignments. All research staff members responsible for the primary outcome assessment remained blinded and unaware of the group assignments.

Outcomes and Analysis

The primary outcome was disability free survival up to 1 year after surgery

Disability was defined as persistent impairment in health status lasting > 6 months  as measured by a score of at least 24 points on the WHO Disability Assessment Schedule (WHODAS) questionnaire, which reflects a disability level of at least 25%.

The secondary outcomes were acute kidney injury, a composite of 30-day mortality or major septic complications (sepsis, surgical site infection, anastomotic leak), serum lactate level, peak CRP, duration of ICU and hospital stay, blood transfusion, unplanned admission to the ICU and quality of recovery.

With an expected probability of 1-year disability-free survival of 65% and a type I error of 0.05, the authors calculated that 2650 patients (with 850 events of death or disability) were required to provide a power of 90% to detect a hazard ratio of 0.80 using the log-rank test. In June 2016, the steering committee observed a smaller than expected event rate, and increased sample size to 3,000. Despite that, they overall observed 533 events (rather than 850) thus ending up with 80% power to detect a hazard ratio of 0.78. 

Kaplan–Meier method was used to calculate the probability of the primary outcome. Hazard ratios for the time until the occurrence of disability or death between the two groups were estimated with the use of a Cox proportional-hazards model.  

Funding Source

The trial was funded by the Australian National Health and Medical Research Council and others; ClinicalTrials.gov registration number, NCT01424150.

Results

5,223 patients met the inclusion criteria after screening: 3,000 patients were randomised: 1,501 patients to restrictive regimen, 1,499 to the liberal fluid regimen. Mean patient age was 46, 44% underwent colorectal surgery, 64% underwent cancer surgery. About 7% had moderate or severe renal disease at baseline. 

There was a clear separation of the amount of fluid administered:

  • During surgery (median volumes 1,677 vs 3,000 ml)
  • Post op day 1 (1,556 vs 2,600 ml)
  • Cumulative volume 24 hours post-op (3,671 vs 6,146 ml)

The primary outcome was negative. There was no difference in disability-free survival 1-year after surgery (HR of 1.05, 95% CI 0.88 - 1.24).

The secondary outcomes were likewise unremarkable with the exception of AKI:

  • AKI (doubling of serum creatinine or GFR decrease by at least 50%) at 30 days occurred more commonly in the restrictive fluid group (7.6% vs 5%, p<0.001)
  • Renal replacement therapy was performed in 13 patients and 4 patients respectively (HR 3.27, p = 0.048).
  • Septic complications or death up to 30 days after surgery occurred in 323 patients in the restrictive fluid group (21.7%) and 295 patients in the liberal fluid group (19.8%; p=0.19)
  • There were 31 deaths in the restrictive fluid group vs 18 in the liberal (p = 0.06) at 90 days, though at 12 months this was almost the same at 95 and 96 respectively. 
  • Surgical site infection occurred in 245 patients (16.5%) in the restrictive fluid group vs 202 patients (13.6%) in the liberal fluid group; anastomotic leaks also were slightly more common in the restrictive group (3.3 vs 2.4%) - however both changes were not statistically significant after adjustment for multiple comparisons.
  • Pulmonary edema was lower in the restrictive arm, but not significantly so (p = 0.10)
  Table 3 from Myles et al, NEJM 2018

Table 3 from Myles et al, NEJM 2018

In the subgroup analysis (figure 2) the effect of restrictive fluid therapy on the risk of disability-free survival was consistent across subgroups, including planned use of a goal-directed device (P=0.37), with the exception of sex and country, including a significant between-group difference among residents of New Zealand (Figure 2, below).     

  Figure 2 from Myles et al, NEJM 2018

Figure 2 from Myles et al, NEJM 2018

Discussion

Strengths:

This study represented an important research question which was evaluated through a large, multicentre international study which was conducted appropriately for the research question. This study provides additional prospective data to the question of the amount of fluid to give patients peri- and post-operatively. Blinding of the outcome assessors reduces the possibility of assessment bias. The risk of AKI in the restrictive fluid group was highly significant and was reflected in increased rates of oliguria and use of renal replacement therapy.

Weaknesses:

Clinicians obviously cannot administer IV fluids in a blinded fashion which may potentially introduce bias (but what kind of bias would result in a difference in AKI?). The primary outcome was negative - could this secondary outcome be a chance finding? The study had a lower event rate than the study designers antcipated. Even after expanding the trial size, they were unable to get the number of events originally anticipated. So the study was under-powered compared to the original trial design.

What do we learn from this trial? How will it change our clinical practice?

A “modestly liberal” fluid regimen of CSL seems to be the optimum strategy for patients at increased risk for complications while undergoing elective major abdominal surgery, although this is tenuous to define.  What we need is a fluid regimen which exceeds the zero fluid balance, is adjusted for patients in whom an ERAS protocol is used and one in which oliguria and hypotension are recognised and treated appropriately with IV fluids.

Summary by Laura Slattery

NSMC Intern, Class of 2018