Restriction of Intravenous Fluid in ICU Patients with Septic Shock

Meyhoff T. NEJM 2022; DOI: 10.1056/NEJMoa2202707

Clinical Question

• In adult patients in ICU with septic shock, does a restrictive approach to fluid therapy compared to a standard care result in fewer deaths at day 90?

Background

• Fluid therapy in the critically unwell has been widely studied across many patient populations
• Higher volumes of fluid in patients with sepsis and septic shock has been associated with harm, although a meta-analysis showed that the quality of evidence was very low
• The ANDROMEDA SHOCK trial demonstrated in those with septic shock, that by 2 hours only ~25% of patients were deemed to still be fluid responsive
• The CLASSIC pilot study showed that a restrictive fluid strategy was feasible and showed significantly less fluid was used in the first 5 ICU days in the restrictive group
  • Mortality at day 90 was an exploratory outcome and this was reduced in the restrictive group, although not significantly

Design

• Stratified, parallel-group, open-label, international, randomised controlled trial
• Randomised 1:1 using a central web based system
  • Block sizes of 6 or 8
  • Stratified according to site and presence/absence of metastatic or haematological malignancy
• Treatment group assignments not masked for clinicians, patients or investigators
  • Those on data safety monitoring committee, statisticians assessing the outcomes, and the management committee writing the abstract draft were blinded
• Received assigned intervention from randomisation until ICU discharge (for a maximum of 90 days)
  • If re-admitted within 90 days then treatment assignment continued
• Data collected from medical records and registries
  • Patients or relatives contacted if further information needed
• Pre-specified subgroups included need for respiratory support, AKI, Lactate > 4 mmol/L, weight > 76kg, > 30mls/kg of fluids administered in 24 hours prior to randomisation
• Power calculation
  • 1554 patients needed to show a 7% absolute reduction in 90 day mortality from a baseline of 45%
  • Type I and II error rates of 5% and 20% respectively
  • Based on pilot study, prior RCTs and systematic reviews
• Registered with clinicaltrials.gov

Setting

• 31 ICUs in Europe
• November 2018 to November 2021

Population

• Inclusion:
  • Age ≥ 18
  • Septic Shock according to Sepsis-3
    • Suspected or confirmed infection, plasma lactate > 2mmol/L and vasopressor requirement
  • 1L of fluid administered in the prior 24 hours
  • Within 12 hours of screening
• Exclusion:
  • Septic shock > 12 hours
  • Life threatening bleeding
  • Burns > 10% TBSA
  • Known Pregnancy
• 2223 screened –> 1554 randomised
  • 770 to restrictive group
  • 784 to standard group
• Comparing baseline characteristics of restrictive vs. standard group
  • Age (yrs): 71 vs 70
  • Male (%): 59.9 vs 58.2
  • Median time from ICU admission to randomisation (hrs): 3 vs 3
  • Median predicted mortality (%): 40 vs 40
  • Source of admission (%)
    • ED: 39.3 vs 38.5
    • Wards: 34.2 vs 38.7
  • Source of infection (%):
    • GI: 36.8 vs 38.3
    • Respiratory: 27.7 vs 26.5
    • Urinary: 15.8 vs 17.1
  • Median highest lactate (mmol/L): 3.8 vs 3.9
  • Median highest dose of noradrenaline (μg/kg/min): 0.25 vs 0.23
  • Median volume of IV fluids in prior 24 hours (L): 3.2 vs 3.0
  • Systemic glucocorticoid use (%): 28.6 vs 29.1
  • Use of respiratory support (NIV, IMV): 52.6 vs 48.6

Intervention

• Restrictive Group
• Fluids could be given for:
  • Severe hypoperfusion:
    • Lactate > 4 mmol/L
    • MAP < 50 mmHg (with or without vasopressors/inotrope)
    • Mottling beyond kneecap
    • Urine Output < 0.1ml/kg (only within first 2 hours post randomisation)
    • If met any of these criteria then 250-500mls bolus of crystalloid could be given followed by re-evaluation
  • Overt losses (e.g. D+V) but only to correct for loss and not more
  • If oral or enteral route contraindicated for water or electrolyte solutions then IV fluids could be given to correct electrolyte derangements and to ensure a 1L/24hrs total intake
    • Fluids with medications and nutrition count as input
    • Fluids for medications should be reduced to lowest possible volume

Control

• Standard Care
  • No upper limit for use of fluids
  • IV fluids should be given based on SSC guidelines in case of circulatory impairment
  • IV fluids should be given to replace observed or expected losses to correct dehydration or electrolyte derangements
  • IV fluids should be given as maintenance in places with protocols that recommend this

Management common to both groups

• Isotonic crystalloids used
  • Albumin only allowed following abdominal paracentesis
• Concomitant interventions for septic shock detailed in trial protocol (appropriate antibiotics, noradrenaline as a vasopressor, source control and RRT for routine indications)
• All other treatment including diuretic use at discretion of treating clinicians

Outcome

• Primary outcome:
• Death by day 90
  • Restrictive 42.3% vs Standard 42.1%
  • Adjusted absolute difference 0.1 (95% CI -4.7 to 4.9), p = 0.96
• Secondary outcomes:
  • No significant difference in:
    • Number of Serious Adverse Events
    • Number of days alive without life support
    • Number of days alive and out of the hospital

Authors’ Conclusions

• In adult ICU patients with septic shock, IV fluid restriction did not result in fewer deaths at 90 days compared to standard IV fluid therapy

Strengths

• Randomised
• Multi-centre trial involving 31 ICUs across 8 European countries increases external validity
• Pre-published statistical analysis plan
• Intention to treat analysis
• Minimal loss to follow up (0.6%)
• Balanced baseline characteristics
• Unwell patient cohort
• Achieved a separation in fluids administered via trial protocol

Weaknesses

• Unblinded
• The most common infection source was GI – this may have necessitated large volumes of replacement fluid if diarrhoea or vomiting were prominent features
• Powered for a 7% reduction in mortality
• Large volumes of fluid given outside of the trial protocol
  • Nearly 3L of fluid given to each group in 24 hours prior to randomisation
  • The total difference in fluids administered by day 5 was only ~2L (8.8L vs 10.8L), with a difference of only ~800mls in the cumulative day 5 fluid balance
  • These similarities between the groups may result if the standard care delivered in ICUs is already a relatively restrictive (e.g. no maintenance) fluid strategy
    •  This potentially biases the results towards the null
• Large numbers of protocol violations (% patients with at least one violation)
  • 21.5% in restrictive group vs 13.0% in standard group
    • In restrictive group 64% of violations were for fluid bolus use without criteria being met
      • Violations resulted in median of 97ml fluid administered/day
    • In standard group 100% of violations were for no IV fluid being given on any single day in ICU
      • This was 13% of all patients in the standard group
  • However, there was no difference in outcome when violations removed in per-protocol analysis

The Bottom Line

• This study did not confirm my pre-existing biases, in that a restrictive fluid strategy was not shown to be superior, with respect to 90 day mortality, to standard fluid management currently being practiced in European ICUs
•  However, the 5 day cumulative fluid balance in the standard group was not much greater than the restrictive group. Therefore care is still required to ensure that every patient in ICU has a vigilant and considered fluid management strategy. This includes the de-escalation or evacuation phase of fluid therapy.

External Links

• article Restriction of Intravenous Fluids in ICU patients with Septic Shock
• further reading editorial

Metadata

Summary author: George Walker @hgmwalker
Summary date: 17th June 2022
Peer-review editor: @davidslessor

Picture by: Pixabay/Pexels