Impact of CVVHD With Adsorption Capacity Membranes in Septic Acute Kidney Injury
Condition: Sepsis; Septic Shock; Acute Kidney Injury
MeSH terms: Sepsis; Shock, Septic; Acute Kidney Injury; Wounds and Injuries
Study type: Interventional

Summary: 
      Septic patients with acute kidney injury (SA-AKI) requiring continuous renal replacement
      therapies (CRRT) present high mortality due to systemic inflammatory response, cytokine
      liberation, and finally multiorgan dysfunction. Cytokine plasmatic elimination with
      continuous venovenous hemofiltration (CVVH) presents frequent complications, known as
      "dialytrauma", and a high resource cost both technical and human. The study primary end-point
      is to demonstrate a longer filter life with the use of continuous venovenous hemodialysis
      (CVVHD) respect to CVVH, both modalities employing the same adsorption capacity membrane. As
      secondary end-points investigators will try to demonstrate less dialytrauma events of CVVHD
      respect to CVVH. In order to achieve these objectives investigators have designed a proof of
      concept exploratory trial that will include those patients whom present SA-AKI meeting CRRT
      initiation criteria. During the first 72 hours investigators will measure plasmatic
      elimination capacity of main cytokines, and other clinical and prognostic relevant molecules.
      Investigators will also measure hemodynamic, respiratory, and metabolic parameters. Adverse
      effects related to CRRT ("dialytrauma") will also be registrated. Finally, investigators will
      analyze 90 days survival. Demonstration of a minor complication rate (longer filter patency
      with less dialytrauma events) with a similar immunomodulating capacity and with its
      consequent lower cost, should settle the based evidence principles that recommend the use of
      CVVHD asociated to an adsorption capacity membrane in patients with SA-AKI whom need CRRT.
    

Detailed description: 
      Investigators will warrant a correct protocol application. Study data will be reviewed by an
      external monitoring committee from the clinical assay research central unit (UCICEC -
      IDIBELL). Monitors will contrast registered data from the collection data form (CDF) with
      data from patient´s medical record. All patient´s medical records will be indefinitely saved
      in electronical format to be reviewed if necessary.

      Patients who meet inclusion criteria will be randomized for one of both arms with aleatory
      assignation using a randomisation sequential (RndSeq) program for Statistical Package for the
      Social Sciences (SPSS). Adverse events will be reported (in less than 24 hours if severe) to
      the sponsor center to be properly evaluated. If the severe adverse event (SAE) is finally
      evaluated by the study board as related to the intervention arm, urgent notification to
      health authorities must proceed and study should be interrupted until further decision.

      As a pilot study of at least 50 cases is advisable in many circumstances (Sim and Lewis,
      2012), and we wanted to compare two treatment options, we aimed to recruit at least 100
      patients.

      Missing data will try to be avoided by an exhaustive patient´s follow up by study
      investigators. Intention to treat analysis (ITT) will be the main strategy and statistical
      substitution techniques for missing data will be applied when necessary. Per protocol
      analysis will also be done to avoid possible bias. Out-of-range results will be identified
      and processed with adequate statistical techniques.

      Data registry has been created to include all variables with written individual data
      collection forms (DCF). Data will be bedside registered by the study members but final
      software database registration will be done by the statistics outside investigator who has no
      contact with patients situation. Cytokines levels will be introduced in DCF when measured
      (every six months).

      Statistical analysis will be done by the statistics investigator who wont have any role in
      patient´s selection, randomization, or follow up. SPSS v. 18.0 for statistical analysis will
      be used. Variable distribution will be studied and logarithmic transformation will be used on
      those variables that don't present normal distribution, presumably cytokine levels.
      Univariate analysis comparing clinical, demographic, biochemical, metabolic, hemodynamic and
      respiratory baseline variables between both arms (CVVHD-ST150 and CVVH-ST150), will be done
      with two-tailed t test for continuous variables and chi-square test for categorical
      variables. Variables determined several times (T0, T24, T48, T72) will be analysed using a
      one-way repeated measures ANOVA test in order to demonstrate differences between both arms.
      Multivariate analysis will be completed to control those clinically relevant confounding
      variables as well as to discover baseline differences. According to hypothesis and to the
      dependent variable on study investigators will use a survival analysis (to study mortality)
      with a cox regression model, or a hierarchic multiple linear regression model when the
      dependent variable is continuous (for example dialytrauma score). Arm intervention (CVVHD,
      CVVH) will be considered as the main independent variable adding other control independent
      variables.

      As the study is measuring cytokine levels in five different moments (T0, T24, T48, T72), in
      order to maximize statistical power and reduce control variables number, the area under the
      curve (AUC) we´ll be determined for every cytokine and LPS during the first 72 hours. Due to
      this statistical maneuver investigators will obtain a continuous variable that represents
      each cytokine level during the biochemical study period (72 hours). To evaluate if the arm
      intervention improvement in terms of efficacy and safety could be related to cytokine levels
      during the first 72 hours, a mediation complementary analysis will be done considering
      cytokine (represented by AUC) as a mediator between the independent variable (intervention
      arm) and the effect we study.

      Data dictionary. ICU: Intensive Care Unit; AKI: Acute Kidney Injury; CRRT: Continuous Renal
      Replacement Therapies; IL-1β: interleukin 1β; TNF-α: tumor necrosis factor α; IL-6:
      interleukin 6, IL-10: interleukin 10; IL-4: interleukin 4; CVVH: Continuous Venovenous
      Hemofiltration; CVVHD: Continuous Venovenous Hemodialysis; SPSS: Statistical Package for the
      Social Sciences.
    

Intervention name(s): CVVHD; CVVH
Intervention type(s): Other; Other
Intervention description(s): CVVHD will be used during 72 hours with a prescribed dose of 30 ml/Kg/h Prismasol® 4 as dialysate fluid. Blood flow of 200-250 ml/min, to achieve 12 - 15 L/h will be prescribed. Isovolemic CRRT will be encouraged during this 72 hours if volume overload status is not present. After 72 hours, CVVHD will be continued and dialysate dose (ml/kg/h) will be adjusted to achieve creatinine levels between 80-120 umol/L until patient recovers urine output and / or tolerates intermittent hemodialysis.; CVVH will be used during 72 hours with a prescribed dose of 30 ml/Kg/h Prismasol® 4 as reposition fluid. Blood flow of 200-250 ml/min, to achieve 12 - 15 L/h will be prescribed adjusting the adequate percentage of prefilter reinfusion to maintain a theorical filtration fraction between 18-22%. Isovolemic CRRT will be encouraged if volume overload status is not present. After 72 hours, CVVH will be continued and filtration dose (ml/kg/h) will be adjusted to achieve creatinine levels between 80-120 umol/L until patient recovers urine output and / or tolerates intermittent hemodialysis.
Other intervention name(s): Continuous venovenous hemodialysis; Continuous venovenous hemofiltration
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary purpose: Supportive Care
Keywords: Sepsis; Septic shock; Acute renal failure; Acute kidney injury; Continuous renal replacement therapies CRRT