Normal saline versus a balanced crystalloid for goal-directed perioperative fluid therapy in major abdominal surgery: a double-blind randomised controlled study

British Journal of Anaesthesia 2018;120(2):274-283

Presented by: Dr I Rees

Background

  • Normal saline 0.9% amongst most commonly used crystalloid for fluid therapy
  • However normal saline not ‘normal’
    • Sodium and chloride concentrations 154mmol/l
    • Risk of hyperchloraemic metabolic acidosis and reduced anion gap
    • Linked to increased risk of renal dysfunction, transfusion and mortality in patients undergoing abdominal surgery
  • Balanced crystalloids contain metabolisable anions (lactate or acetate)
    • Maintain electrolyte stability
    • Less associated with metabolic acidosis
    • Metabolised to bicarbonate
  • Recent study in same centre demonstrated patients undergoing cadaveric renal transplantation required significantly less catecholamine support if receiving balanced crystalloid, compared to the group receiving normal saline
  • Authors hypothesised that patients undergoing major surgery might require less vasopressor support if they received a balanced crystalloid, as opposed to normal saline perioperatively

Design & Setting

  • Single-centre (Department of Anaesthesiology of the Medical University of Vienna, Austria)
  • Prospective double-blinded randomised controlled study of patients undergoing elective major abdominal surgery
  • Patients and anaesthetists blinded
  • Ethics approved
  • Sample size calculated (based on previous transplantation study) – 120 patients per group (240 total) to give α 5% and 80% power

Subjects

Inclusion criteria:

  1. Adult, non-pregnant patients
  2. Undergoing elective major abdominal surgery (any general, gynaecological or urological procedure requiring laparotomy)

Exclusion criteria:

  1. LV ejection fraction <30%
  2. Renal dysfunction (GFR <30ml/min) and severe liver disease
  3. Chronic inflammatory diseases requiring long-term steroids
  4. Pre-operative sepsis or critical care patients
  5. Contraindications to oesophageal doppler
  6. Intraoperative epidural analgesia

Intervention

  • Patients randomised on day of surgery to receive either normal saline or a chloride-reduced acetate-buffered balanced crystalloid (Elomel Isoton)
  • No pre-operative fluid infusion
  • Blinded fluids given to anaesthetist before induction of anaesthesia
  • Standardised anaesthetic:
    • Standardised induction (propofol 2-3mg/kg, rocuronium 0.6mg/kg and fentanyl 2-3mcg/kg)
    • Standard monitoring including arterial line and CVP + depth of anaesthesia monitoring (Narcotrend), train-of-four ulnar montoring and oesophageal doppler (CardioQ)
    • Sevoflurane administration according to Narcotrend; FiO2and fentanyl boluses according to clinical requirement; Rocuronium to maintain one or two twitches on TOF
    • Ventilation to maintain end-tidal CO2 near 35mmHg (~4.6kPa) – tidal volume 8-10ml/kg (LBW), peak pressure <30mmHg (~40cmH2O) and PEEP of 5mmHg (~7cmH2O) or higher according to patient need.
    • Temperature >36oC using forced air warmer and hourly arterial blood gases
    • Fluid maintenance 2ml/kg/hr (IBW as per Robinson’s formula) increased to 5ml/kg/hr on exposure of viscera
  • Target MAP according to pre-operative blood pressure the day before surgery:
Pre-operative Blood Pressure (mmHg) Intraoperative Target MAP (mmHg)
Hypotensive SBP <120 60
Normotensive SBP 120-139 / DBP 80-89 70
Hypertensive SBP >140 / DBP >90 80
  • If MAP fell, standardised protocol followed:
    • SV responsiveness assessed using 250ml fluid challenge
    • If >10% increase in SV but MAP still below desired value, further 250ml boluses until SV increase <10% or target MAP achieved
    • If target MAP still not achieved and SV ‘unresponsive’, phenylephrine 0.1-0.2mcg bolus given (maximum 0.8mcg/hr)
    • If still insufficient, noradrenaline infusion started at 0.01-0.02 mcg/kg/min and titrated to desired MAP by increments of 0.05-0.1mcg/kg
    • If SV fell by >10% of the value following the last fluid challenge, a further 250ml was given
    • Noradrenaline titrated down or stopped if fluid challenges sufficient in maintaining MAP
  • Exit criteria: pH below 7.2, bicarbonate below 14mmol/l, base excess below -10mmol/l or response to catecholamines insufficient – fluid changed to balanced crystalloid and study was terminated.

Outcomes

Primary:

  1. Need for vasopressors

Secondary:

  1. Total dose of catecholamines
  2. Total perioperative fluid
  3. Unplanned intensive care admissions

Results

  • Terminated early for safety reasons (hyperchloraemic metabolic acidosis) after discussion with study safety board and local authority
  • Only 60 of the total planned 240 were studied (30 in each group)
  • More patients required vasopressors in the normal saline group than the balanced crystalloid (97% vs67% respectively,p=0.033)
  • Median weight and duration-adjusted dose of norepinephrine were 0.11(0.00-0.45)mcg/kg/min in the normal saline group compared with 0.00mcg/kg/min in the balanced crystalloid group (p=0.003)
  • No difference between groups in total perioperative fluid and unplanned intensive care admissions
  • Cox regression showed need for vasopressors related to high volume of administered fluid, normal saline resuscitation and lower MAP

Conclusions

  • Study suggests that patients undergoing major abdominal surgery with normal saline fluid therapy have a significantly larger vasopressor requirement than those receiving a more physiological crystalloid.
  • Hyperchloraemia with or without acidosis may be a direct trigger for unfavourable cardiovascular effects – leads to increased nitric oxide, as seen in rats

Strengths

  • Focused question asked
  • Hypothesis based on previous study
  • Prospective double-blinded RCT
  • Patient groups comparable
  • Appropriate inclusion and exclusion criteria
  • Extremely standardised protocol
  • Appropriate statistical analysis i.e. Mann-Whitney U Test for quantitative, non-parametric analysis of 2 unpaired groups

Weaknesses

  • Terminated due to patient safety
  • Underpowered (67%) for primary outcome due to low numbers – power 90% for secondary outcomes
  • Single-centre
  • Protocol resulted in large amounts of intraoperative fluid infusion (median 3427ml of normal saline and 3144 of the balanced crystalloid)
  • No mention of blood products
  • No epidural or intrathecal block
  • Is it an important clinical question?

Implications/Potential for impact

  • Is our practice likely to change following this study?
  • Inference that normal saline may cause detrimental cardiovascular effects due to hyperchloraemic acidosis (leading to increased nitric oxide, as seen in rats) is interesting
  • Vast majority of anaesthetists likely to use a balanced crystalloid e.g Hartmann’s solution, rather than normal saline for elective adult surgery (save for a few circumstances e.g. liver failure etc) as it is more ‘physiological’ – why cause further stress during the stress response?

Following this underpowered study that put patients in harm’s way, I will do as the authors suggest i.e. exactly what I’ve been doing this entire time.