High Volume Veno-venous Hemofiltration Versus Standard Care for Post-cardiac Surgery Shock
Condition: Shock
MeSH terms: Shock
Study type: Interventional

Summary: 
      This study seeks to determine if early continuous High Volume Veno-venous Hemofiltration
      (HVHF) reduces 30-day all cause mortality in post-cardiac surgery patients developing shock
      requiring high doses catecholamines.
    

Detailed description: 
      Study Title - Early continuous high volume veno-venous hemofiltration vs. standard care for
      post-cardiac surgery shock requiring high dose catecholamines. An open label randomized
      multicenter controlled trial. The HEROICS Study: HEmofiltration to Rescue severe shOck
      followIng Cardiac Surgery.

      Clinical Phase - III Study Rationale - Systemic inflammatory response syndrome associated
      with cardiac surgery under cardiopulmonary bypass (CPB) shares many pathophysiologic features
      of septic shock and post-resuscitation syndrome. Since high volume hemofiltration has been
      shown to markedly improve hemodynamic profile and survival in these situations, there is a
      strong rationale for testing, with an adequately powered randomized controlled trial, this
      purification technique in patients developing post-cardiac surgery shock requiring high doses
      catecholamine.

      Trial Design -

      The proposed study will compare high volume hemofiltration (80 ml/kg/h or a maximum of 8L/h)
      for 48 hours following heart surgery to standard treatment, where extra-renal replacement
      therapy (CVVHDF mode, total effluent <35 ml/kg/h) will be initiated only if the following
      criteria are met:

        -  Serum creatinine > 350 micromol/L or increase x3.0 from pre-operative value OR

        -  Diuresis < 0.3 ml/kg/h for 24 hours despite adequate fluid resuscitation OR

        -  Or serum urea > 36 mmol/l OR

        -  Or life threatening hyperkalemia. In the experimental arm, hemofiltration will be
           stopped after 48h if diuresis >1500 ml without diuretics and if IV infusion of
           catecholamines is less than 0.1 microg/kg/min of epinephrine, 0.2 microg/kg/min of
           norepinephrine or the sum of epinephrine + norepinephrine/2 is less than 0.1
           microg/kg/min. In other cases, hemodiafiltration (CVVHDF) will be initiated until the
           above objectives are reached, with equal flow rate of dialysate and reinfusion fluid,
           the sum of which being 35 ml/kg/h (or a maximum of 3500 ml/h).

      Subject Participation - 90 days

      Rationale for Number of Subjects - The study will follow a sequential analytical plan with
      stopping rules based on the triangular test. The expected mortality of the control group is
      expected to be 25% and the expected absolute mortality reduction with the experimental
      treatment of 12%. For 80% power and a 5% α-risk, the study characteristics, calculated with
      the triangular test, are as follows: a maximum of 540 subjects to be included and a 90%
      probability of stopping the study before 330 subjects have been included. With an inclusion
      rate of 120-150 patients per year, the maximum duration of the study is 2 years and 3 months
      and the probability of stopping the study before 18 months is 90%.

      Approximate duration of Study - 27 months

      Study Objective(s) Primary - The primary study outcome is death from all causes at 30 days
      after randomisation.

      Secondary

        1. Mortality 60 and 90 days following study enrollment

        2. ICU and Hospital mortality

        3. Mortality adjusted on the type of surgery and patient severity at randomization

        4. Duration of catecholamine infusion and number of catecholamine-free days at 30 days
           following study enrollment

        5. Duration of renal replacement therapy and number of renal replacement therapy -free days
           at 30 days following study enrollment

        6. Recovery of renal failure and dialysis independent survival

        7. Duration of mechanical ventilation and number of mechanical ventilation -free days at 30
           days following study enrollment

        8. SOFA score on days 1, 2 ,3 ,4 ,7 ,15 , and 30 following study enrollment

        9. Reduction in markers of overt coagulation and inflammation at days 2, 4 and 7 following
           study enrollment

       10. ICU and Hospital length of stay

       11. Mortality analysis according to subgroups of patients (type of surgery, severity at
           randomization, renal function at randomization)

      Approximate Number of Subjects - 330

      Approximate Number of Study Centres - 8 centres distributed in France will participate in the
      study.

      Treatment Administration - Each participant will be randomised to receive high volume
      hemofiltration (CVVH, 80 ml/kg/h or a maximum of 8L/h) for 48 hours following heart surgery
      or standard treatment, where extra-renal replacement therapy (CVVHDF mode, total effluent <35
      ml/kg/h) will be initiated only if criteria for renal failure are met.

      Safety Evaluation - Safety for individual patients will be assessed on an ongoing basis by
      physical examination, including vital signs, outputs from dialysis machine records,
      laboratory assessments, and monitoring of adverse events. Overall study safety will be
      ensured by an Independent Data Safety Monitoring Committee, independent from all Trial
      investigators, which will perform ongoing review of predefined safety parameters and study
      conduct.

      Efficacy Evaluation - Overall survival at 30 days post randomisation

      Statistical Analysis - The first analysis is scheduled after the inclusion of 60 subjects.
      Thereafter, stopping rules are scheduled to be sequentially applied, based on the triangular
      test. This will allow us to stop the trial as soon as there are sufficient evidence that one
      of the 2 treatment strategies are more dangerous or that there was no longer a chance of
      demonstrating the postulated treatment difference of 12%, while controlling the risks of type
      I and II errors. Sequential analyses will be conducted every 20 patients. The baseline and
      outcome variables will be compared using Students t test, Chi squared and the Mann-Whitney U
      test as appropriate. Kaplan-Meier survival curves for the 30 days following randomization
      will be compared with a log-rank test., with survival being calculated from the date of
      randomization.
    

Intervention name(s): high volume hemofiltration; standard care
Intervention type(s): Procedure; Procedure
Intervention description(s): (80 ml/kg/h or a maximum of 8L/h) for 48 hours following heart surgery. Hemofiltration will be stopped after 48h if diuresis >1500 ml without diuretics and if IV infusion of catecholamines is less than 0.1 microg/kg/min of epinephrine, 0.2 microg/kg/min of norepinephrine or the sum of epinephrine + nor epinephrine/2 is less than 0.1 microg/kg/min. In other cases, hemodiafiltration (CVVHDF) will be initiated until the above objectives are reached, with equal flow rate of dialysate and reinfusion fluid, the sum of which being <35 ml/kg/h (or a maximum of 3500 ml/h).; extra-renal replacement therapy (CVVHDF mode, total effluent <35 ml/kg/h or a maximum of 3500 ml/h) will be initiated only if the following criteria are met:
Serum creatinine > 350 micromol/L or increase x3.0 from pre-operative value OR
Diuresis < 0.3 ml/kg/h for 24 hours despite adequate fluid resuscitation OR
Or serum urea > 36 mmol/l OR
Or life threatening hyperkalemia
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Cardiac surgery; Shock; Continuous Veno-Venous Haemofiltration; Continuous Renal Replacement Therapy; Renal Insufficiency; Acute