Restrictive versus Liberal Fluid Therapy for Major Abdominal Surgery (RELIEF)

 New England Journal of Medicine. DOI: 10.1056/NEJMoa1801601.

 Presented by: Dr Helen Ivatt Clinical Fellow Anaesthetics

 Background

Traditional intravenous fluid regimes have been shown to deliver up to 7 litres fluid on the day of surgery resulting in significant tissue oedema and weight gain.  In 2003 Brandstrup et al demonstrated a halving of the complication rate with a near zero fluid balance compared with a judicious fluid regime1. Several other small studies demonstrated a similar effect 2-4.  Fluid restriction in major abdominal surgery is supported by recent consensus statements, and the enhanced recovery after surgery (ERAS) pathway which is widely adopted as a standard of care during major abdominal surgery also takes this approach5.  However, the evidence is not comprehensive or conclusive therefore the RELIEF trial was designed to compare outcomes using a restrictive v’s liberal fluid regime in high risk patients undergoing major abdominal surgery.

 Design & Setting

RELIEF is a large, multicentre, randomised, international, single blind, pragmatic trial, with patients randomly assigned to either restrictive or liberal fluid groups, stratified by site and by planned high dependency unit (HDU) or intensive care unit (ICU) admission.

The study ran from May 2013 – Sept 2016 in 47 centres across seven countries and included 3000 participants.

 Subjects

Inclusion criteria

Adults undergoing elective major abdominal surgery that included a skin incision with an expected duration of at least 2 hours and an expected hospital stay of at least 3 days who were at increased risk of complications defined by at least one of the following:

  • ≥70 years
  • Coronary artery disease
  • Heart failure
  • Diabetes (On oral hypoglycaemics +/- Insulin)
  • Preoperative serum creatinine >200μmol/L
  • BMI >35kg/m2
  • Preoperative serum albumin <30g/l
  • Anaerobic threshold <12ml/kg/min

Or two or more of the following:

  • ASA 3 or 4
  • Chronic respiratory disease
  • BMI 35kg/m2
  • Anaerobic threshold 12 – 14 mL/kg/min
  • Aortic or peripheral vascular disease
  • Preoperative Hb <100g/L
  • Preoperative serum creatinine 150-199 μmol/L

Exclusion criteria

  • Time-critical surgery
  • ASA 5
  • Chronic renal failure requiring dialysis
  • Pulmonary or cardiac surgery
  • Liver resection
  • Minor or intermediate surgery (e.g. lap cholecystectomy, TURP, inguinal hernia repair.)

Randomisation

Patients were randomly assigned in a 1:1 ratio using a web based service.  Permuted blocks stratified by both site and planned post op area of care (ICU, HDU or Ward) were used to ensure that prognostic factors and patient characteristics were balanced between groups.

Power calculation

Sample size calculation was based on the groups own data and other published studies.  A type I error of 0.05 was set along with an expected disability free survival at 1yr of 65% and a hazard ratio of >1.25.  This estimated that 1300 patients would be required in each group to provide 90% power thus a target recruitment of 2800 patients was set to make up for losses.

As the event rate was significantly less than expected (14.6% rather than an expected 35%) the sample size was increased to 3000 to provide 80% power.

Intervention

Participants were assigned to either Liberal or Restrictive fluid groups:

Liberal fluid group

  • 10ml/kg bolus of crystalloid at the start of surgery.
  • 8ml/kg/hr crystalloid until the end of surgery (reduced if clinically indicated after 4hrs)
  • Bolus colloid/blood was used intraoperatively to replace blood loss (mL for mL)
  • Maintenance 1.5ml/kg/hr for at least 24 hrs (reduced or increased according to hypovolaemia, fluid overload etc).
  • Treat hypotension with a fluid bolus in the first instance

Weight >100kg both bolus and maintenance limited to that for a 100kg patient.

Restrictive (‘zero balance’) intravenous fluid group

  • ≤5 mL/kg bolus of crystalloid at the beginning of surgery
  • 5 mL/kg/hr was to be administered until the end of surgery
  • Bolus colloid/blood was used intraoperatively to replace blood loss (mL for mL)
  • Maintenance 0.8mL/kg/hr until cessation of fluid within 24 hours (Reduced or increased according to hypovolaemia, fluid overload etc)
  • Treat hypotension with vasoconstrictor in the first instance.

Outcomes

Primary endpoint

Disability free survival at 1yr after surgery (Measured by the WHODAS score).

Secondary endpoints

  • All-cause mortality at 90 days, and survival up to 12 months after surgery.
  • Composite and individual incidence of sepsis, surgical site infection, anastomotic leak and pneumonia.
  • AKI
  • Pulmonary oedema
  • Duration of mechanical ventilation
  • Day 3 CRP
  • Lactate within 24hrs of surgery
  • Blood transfusion following surgery
  • Unplanned admission to HDU/ICU within 30 days of surgery.
  • Total HDU/ICU stay.
  • Total hospital stay up to day 30.
  • Quality of recovery on days 1, 3 and 30.

 Results

2983 out of 3000 met criteria for a modified intention to treat population (patients had to be both randomised and undergo induction of GA). There were no significant baseline differences and the loss to follow up was small at 3.3% (82 patients).

In the first 24 hrs there was a significant difference in median fluid infusion (3.7L v’s 6.1L P<0.001).

There was no significant difference between groups for the primary endpoint of disability free survival. Subgroup analysis also failed to find a difference.

Acute kidney injury occurred in 124 (8.6%) patients in the restrictive group and 72 (5%) patients in the liberal group (p<0.001).

The need for renal replacement therapy and the incidence of surgical site infection was significantly greater in the restricted group but significance was lost after adjustment for multiple comparisons.

No significant difference was found with any of the other secondary outcomes.

 Conclusions

The authors conclude that in patients at increased risk for complications while undergoing major abdominal surgery, a restrictive fluid regimen was not associated with a higher rate of disability-free survival than a liberal fluid regimen 1 year after surgery. However, the restrictive regimen was associated with a higher rate of acute kidney injury.

 Strengths

  • Large multicentre, multinational randomised design.
  • Modified intention to treat approach.
  • Primary outcome of disability free survival may be seen as more meaningful endpoint than the traditional outcomes of morbidity and mortality.
  • Correction for multiple testing carried out.

 Weaknesses

  • Clinicians could not be blinded to volume administration, which could have lead to bias in outcome recording however research staff responsible for the primary outcome were blinded to allocated treatment.
  • The surgeries performed were heterogenous which risks a cancelling out of effect, and a lack of generalizability.
  • Fluid administered after the first 24hrs was not recorded.
  • The event rate was lower than previously documented in the literature meaning that the study was less well powered than previously thought and increases the chance of a type II error.
  • The ERAS protocol was not adhered to in a large number of patients though this was not significantly different between groups

 Implications

The findings of this fairly robust study do not support the previously accepted notion that fluid restriction is better that judicious IV infusion.  There are a number of reasons why this may be the case; previous papers have reported greater infusion volumes on the day of surgery (up to 7L intraoperatively), and much greater weight gains than demonstrated in the current paper (4-6kg cf 0.3-1.6kg).  Some of the reason for this weight gain will be fluid volume related but it may also be related to the fact that surgical techniques are minimally invasive and so reduces the metabolic stress that leads to fluid retention.

Therefore we could conclude that with modern surgical techniques and fluid regimes, modest fluid administration that exceeds a zero balance is no longer associated with harm to the patient and may reduce the incidence of AKI. The paper should, however, not be used to support excessive IV administration.

Potential for impact

This is a well designed large multicentre study which is the first of it’s kind.  It is applicable to our high risk patients and though it has limitations it rejects the current trend for fluid restriction and advocates a more modest approach to fluid administration in the 24hrs post surgery.

 References

  1. Brandstrup B, Tønnesen H,Beier-Holgersen R, et al. Effects of intravenous fluid restriction on postoperative complications: comparison of two perioperative fluid regimens: a randomized assessor-blinded multicenter trial. Ann Surg 2003;238:641-648.
  2. de Aguilar-Nascimento JE, Diniz BN, do Carmo AV, Silveira EA, Silva RM. Clinical benefits after the implementation of a protocol of restricted perioperative intravenous crystalloid fluids in major abdominal operations. World J Surg 2009;33:925-930.
  3. Lobo DN, Bostock KA, Neal KR, Perkins AC, Rowlands BJ, Allison SP. Effect of salt and water balance on recovery of gastrointestinal function after elective colonic resection: a randomised controlled trial. Lancet 2002;359:1812-1818.
  4. McArdle GT, McAuley DF, McKinley A, Blair P, Hoper M, Harkin DW. Preliminary results of a prospective randomized trial of restrictive versus standard fluid regime in elective open abdominal aortic aneurysm repair. Ann Surg 2009;250:28-34.
  5. Gustafsson UO, Scott MJ, Schwenk W, et al. Guidelines for perioperative care in elective colonic surgery: Enhanced Recovery After Surgery (ERAS) Society recommendations. Clin Nutr 2012;31:783-800.