BigPAK-2 – preventive care strategy to reduce acute kidney injury after major surgery

Intensive Care Medicine, Peri-operative Medicine Leave a comment

A preventive care strategy to reduce moderate or severe acute kidney injury after major surgery (BigpAK-2); a multinational, randomised clinical trial

Zarbock. The Lancet 2025. doi: 10.1016/S0140-6736(25)01717-9

Clinical Question

  • In patients at high risk of AKI undergoing major surgery, does a preventative care strategy based on KDIGO guidelines, compared to standard care lead to a reduction in moderate/severe AKI within 72h post-surgery?

Background

  • AKI is a common complication of major surgery, associated with increased morbidity and risk of CKD
  • Guideline recommended preventative strategies are not routinely implemented
  • The KDIGO guidelines recommend implementing specific supportive measures to reduce haemodynamic changes, nephrotoxic exposures and inflammation
  • Smaller preliminary studies have suggested implementation of the KDIGO guidelines can reduce incidence of AKI

Design

  • Multicentre RCT
  • Investigator initiated, open-label
  • Adaptive design – Interim analysis of data at pre-specified point for sample size recalculation to ensure power greater than 80%
  • Population enrichment with urinary biomarker screening
    • Biomarkers TIMP-2 and IGFBP7 used to identify patients at high risk for moderate or severe AKI
    • Urinary TIMP-2 x IGFBP7 of < 0.3 (ng/ml)^2/1000 has NPV of 96.3% for moderate/severe AKI
    • Important given low rates of post-op AKI in general population (6.7% general surgery and 24.2% in cardiac surgery)
  • Randomisation: 1:1 into intervention or control via a web-based system with use of computer-generated, permuted block sequences
    • Stratification: According to site
  • Blinding: Participants and staff unblinded given nature of intervention but outcome assessors blinded to treatment groups
  • Telephone follow up at 30- and 90-days
  • Amendments: 
    • Extension of period of biomarker measurement for 0-4h post-op to 4-18h
    • Inclusion of up to 500 cardiac surgical patients
  • Primary outcome: Proportion of patients who developed moderate or severe AKI (KDIGO stage 2-3) within 72h of major surgery: 
    • Serum creatinine > 2.0 times baseline (pre-operative measurement as baseline) and/or urine output <0.5ml/kg/h for >12 hours
  • Power Calculation and analysis:
    • Based on hypothesised event rates of 20% in the control group and 14% in intervention (based on BigpAK trial)
    • Adaptive plan with an interim analysis for sample size recalculation to ensure power of 80%
    • Intention-to-treat and per-protocol analyses
    • Additional sensitivity analyses for each modular component of KDIGO preventative strategy

Setting

  • 34 hospitals across Europe (France, Belgium, Germany, Italy, Netherlands, Spain, UK)
  • Nov 2020 -> Jun 2024

Population

  • Inclusion:
    • Adults
    • Major surgery (>2h long, expected ICU/HDU admission post)
    • ICU/HDU admission
    • IDC and CVC
    • At least one risk factor for AKI:
      • >= 75 years old
      • Ongoing post-op vasopressor and/or mechanical ventilation requirement
      • Pre-existing CKD stage 3 (eGFR 30-59)
      • Intraoperative radiocontrast agents
    • Urinary biomarkers present
      • TIMP-2xIGFBP7 conc of >0.3/1000 (ng/ml)^2
      • Within 4-18 hours post-surgery
  • Exclusion:
    • Pre-existing advanced CKD stage 4-5 (eGFR < 30)
    • Renal transplant within past 12 months
    • RRT within the past 90 days
    • Pre-existing anuria, AKI or indications for RRT
    • Known glomerulonephritis, interstitial nephritis or vasculitis
    • Urinary biomarkers not present
  • Participant numbers: 7873 screened -> 1176 included -> 587 intervention, 589 control
    • Of those screened but not enrolled (6693) – 4021 no additional AKI risk factor, 1446 had TIMP-2 x IGFBP7 < 0.3, 747 no ICU admission, 575 CKD 4/5, 263 logistical reasons / no biomarker kits available
  • Comparing baseline characteristics of intervention vs. control group
    • Age: 72 vs 71
    • Male: 66.2% vs 66.7%
    • Pre-op creatinine (mg/dl): 0.90 vs 0.91
    • Medications:
      • ACEi: 27.2 vs 25.2%
      • ARB: 24.2% vs 24.4%
    • CKD stage 
      • 3a: 15.5% vs 12.4%
      • 3b: 7.6% vs 8.1%
    • Diabetes:
      • Insulin Dependent: 7.1 vs 8.2%
      • Non Insulin Dependent: 18.3 vs 15.6%
    • ASA score > 2: 78.5% vs 77.7%
    • Median APACHE II: 14 vs 15
    • Median baseline TIMP-2 x IGFBP7: 0.65 vs 0.66
    • Surgery
      • Emergency: 10.8% vs 8.8%
      • General Surgery: 33.5% vs 35.5%
      • Cardiac: 34.0% vs 31.6%
      • Vascular: 15.0% vs 15.9%
    • Intra-operative management
      • Crystalloid Fluid administration (ml): 2243 vs 2366
      • Total fluid balance (ml): 1920 vs 1998
      • Vasopressors (median cumulative dose to ICU admission)
        • Noradrenaline (microg): 1720 vs 1590
        • Adrenaline (microg):  491 vs 592
        • Vasopressin (IU): 9.8 vs 4.8
        • Dobutamine (mg): 27.7 vs 28.2

Intervention

  • Preventative KDIGO-recommended care
  • Expectation of adherence to all study interventions unless deemed inappropriate by treating clinician
  • These consisted of:
    • Haemodynamic optimisation for at least 12h post-randomisation
      • Passive leg raise manoeuvre 3-hourly to assess fluid-responsiveness
        • If positive (CO incr by > 10%) then for 0.5-1L crystalloid bolus
      • Targeting MAP > 65 mmHg
        • Use of vasopressors to achieve this if necessary
    • Advanced haemodynamic monitoring targeting CI > 2.5 ml/min/m^2
      • Methods: transpulmonary thermodilution, pulse contour analysis, PAC, TTE/TOE (at discretion of treating clinician) 
      • Use of dobutamine/epinephrine if necessary
    • Withholding nephrotoxic medications
      • ACEi and ARBs withheld at least 48h post-op
      • Other potential nephrotoxics withheld for 72h if possible 
    • Tight BSL control (5.5-8.3 mmol/L) – Insulin infusion if required

Control

  • Standard care as per institution

Management common to both groups

  • Each site received training in the KDIGO recommended interventions in a site-specific initiation visit
  • Pre and intraoperative care standard care as per institution

Interventions Received in both groups

  • Taken from Table S6 and S8

Outcome

  • Primary outcome:
  • Intervention 14.4% (84/587) vs Control 22.3% (131/589)
    • OR 0.57 (95% CI 0.40 – 0.79) p=0.0002
    • No difference in any subgroups (Sex, CKD 0-2 vs 3), Surgical type, biomarker measurement timing (< 9, > 9 hr)
  • Secondary outcomes:
  • Less in KDIGO-recommended care group
    • Stage 2 AKI (23.5% vs 38.8%, Absolute Difference -15.3%; 95% CI -23.7 to -6.9%)
  • Greater in KDIGO-recommended care group
    • Stage 1 AKI (60.6% vs 45.4%, Absolute Difference 15.2%; 95% CI 6.1 to 24.2 %)
    • Full KDIGO adherence
      • Intervention 46.9% vs Control 5.0%, OR 11.58 (7.16 – 18.73)
  • No difference:
    • AKI (any stage) within 72h
      • Intervention 36.5% vs Control 40.8%, OR 0.78 (95% CI 0.6 – 1.01)
    • Stage 3 AKI:
      • 16.0 vs 15.8%
    • Persistent (>48H) moderate or severe AKI
      • 39.0% vs 44.5%
    • Change in biomarker values 12h post initial measurement
    • RRT up to day 90
      • 5.1% vs 5.9%
    • 90 day mortality
      • 7.0% vs 7.0%
    • ICU or hospital length of stay
    • Days without vasopressor support (to day 3)
    • Days without mechanical ventilation (to day 3)
    • MAKE 90
      • 11.0% vs 10.6%, OR 1.026 (0.692 – 1.522)
    • Adverse events
  • Multivariable analysis
    • Association of individual components of KDIGO guidelines with reduction in odds of primary outcome (exploratory only):
      • Avoidance of hypotension (MAP < 65): OR 0.19 (95% CI 0.07 – 0.53), (p=0.001)
      • Discontinuation of ACEi/ARBs: OR 0.36 (0.19 – 0.70), (p=0.002)
      • All other components had 95% CI crossing 1

Authors’ Conclusions

  • Compared with usual care, in major surgery patients at high risk for AKI, a KDIGO-recommended preventive care strategy significantly decreased the occurrence of moderate or severe AKI within 72 h of surgery

Strengths

  • Multicentre RCT across multiple countries
  • Study groups well balanced with similar baseline characteristics
  • Adaptive design ensured adequate power
  • Bias was minimised with computer-generated randomisation and blinding of primary outcome assessors
  • Inclusion of multiple surgical specialties increases generalisability
  • Clinically relevant primary endpoint
  • Primary endpoint demonstrated on ITT, PP and AT analyses
  • Minimal loss to follow up with 99.66% of participants included in primary endpoint
  • All pre-specified primary and secondary endpoints reported

Weaknesses

  • Unblinded participants and clinicians, however, primary endpoint is objective
  • Poor protocol adherence in intervention group and some crossover from control group
    • < 50% in intervention group received full preventative strategy – increased to 62% without hyperglycaemia management component
    • Around 10% in control group had functional haemodynamic monitoring and regular PLR
  • Intervention was a cluster of cares with education delivered to staff at each site prior to study, however, randomisation was performed at patient level
    • This may account for some unmeasured crossover between groups if staff are implementing both strategies for different patients; however one would expect this to bias towards the null
  • The control arm consisted of standard care, with potential heterogeneity of practice across multiple centres and countries
  • Cardiac surgical patients are at significantly higher risk of post-op AKI when compared to general surgical patients (24.2% vs 6.7%)
  • Exclusion of biomarker negative patients and patients with Stage 4-5 CKD limits generalisability and effect size likely much smaller in general population that a clinician would see on a day to day basis
  • Unclear which component(s) of the bundle had greatest effect
    • On exploratory analysis avoidance of ARB/ACEi and hypotension seem key
    • Despite monitoring it appears that the actual differences in haemodynamic interventions are minimal (increased use of dobutamine and a median difference of around +200mls fluid within 12 hours)
    • Potential that it is an ancillary effect of regular clinician review and examination of patients that has occurred in the implementation of this bundle
  • Whilst rates of Stage 2/3 AKI reduced it, no change in any AKI (largely as increased rates of Stage 1 AKI in intervention group). This is important if Stage 1 AKI has clinically important longer term effects

The Bottom Line

  • This RCT demonstrated that adherence to the KDIGO guidelines is associated with a reduction in the rate of moderate to severe AKI in the first 72h following major surgery. However, it did not demonstrate a difference when compared to standard care with longer term, patient orientated outcomes 
  • It appears AKI risk can be reduced from high-quality supportive care with frequent patient assessment

External Links

Metadata

Summary author: Patrick MacNamara
Summary date: 12th March 2026
Peer-review editor: George Walker

Picture by: Pexels

 

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