<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01726465</url>
  </required_header>
  <id_info>
    <org_study_id>CE ICH 178-12</org_study_id>
    <nct_id>NCT01726465</nct_id>
  </id_info>
  <brief_title>Methylprednisolone N Acetylcysteine in Hepatic Resections</brief_title>
  <acronym>MENHIR</acronym>
  <official_title>Phase II Randomized Double Blind Trial of Methylprednisolone and N-acetylcysteine in Hepatic Resections.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Istituto Clinico Humanitas</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Istituto Clinico Humanitas</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a prospective double-blind randomized phase II clinical trial, with two groups of&#xD;
      intervention (one with administration of N-acetylcysteine and the other with administration&#xD;
      of methylprednisolone), and one group of placebo. The purpose of this study is to investigate&#xD;
      the role of N-acetylcysteine and Methylprednisolone in the modulation of warm ischemia of the&#xD;
      liver during hepatic resection. In fact to avoid massive blood loss in liver surgery,&#xD;
      continuous or intermittent vascular clamping of the hepatic hilum ('Pringle maneuver') is&#xD;
      generally used with good results. However, as a consequence, ischemia and subsequent&#xD;
      reperfusion result in complex metabolic, immunological, and microvascular changes, which&#xD;
      together might contribute to hepatocellular damage and dysfunction. This phenomenon, known as&#xD;
      ischemia-reperfusion (IR) injury of the liver, is a complex multi-path process leading to the&#xD;
      activation of some inflammatory pathways. Any patient candidate to liver resection will be&#xD;
      enrolled in the study based on the aforementioned criteria. The primary objective of the&#xD;
      study is to assess the real efficacy of Methylprednisolone and N-acetylcysteine in reducing&#xD;
      the secondary damage from ischemia reperfusion injury in liver resection and in reducing&#xD;
      inflammatory response. Secondary objective of the study is whether the reduction of&#xD;
      ischemia-reperfusion injury results in: lower incidence of postoperative liver failure,&#xD;
      improvement of postoperative liver function, and reduction of blood components transfusions.&#xD;
      The randomization will be done the day before the operation. The drugs will be prepared in a&#xD;
      blind fashion by the hospital pharmacy. The hospital pharmacy will provide to each patient a&#xD;
      drip to make bolus of about an hour before the start of the liver resection and a syringe&#xD;
      pump for an infusion of approximately 6 hours. If the patient is enrolled and randomized in&#xD;
      the placebo arm, he/she will receive 250 ml of glucose 5% plus the infusion of 100 ml of&#xD;
      glucose 5% If the patient is randomized in the Methylprednisolone arm, he/she will receive a&#xD;
      dose of 500 mg in 250 ml of glucose 5% plus 100 mg of glucose 5%. If the patient is&#xD;
      randomized in the N-acetylcysteine arm, he/she will receive a dose of 150 mg/kg in 250 ml of&#xD;
      glucose 5% plus N-acetylcysteine 50 mg/kg in 100 ml glucose 5%. Systematic sampling of liver&#xD;
      function tests will be done the day before the operation, at the end of the operation, as&#xD;
      well as in postoperative day 1, 3, 5 and 7.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Elective liver resection is performed mainly for benign and malignant liver tumors. The&#xD;
      malignant tumors may arise primarily within the liver (hepatocellular carcinoma and&#xD;
      cholangiocarcinoma) or represent metastases from malignancies of other organs. During hepatic&#xD;
      resection, the risk of severe intraoperative bleeding represents a major risk. To avoid&#xD;
      massive blood loss, continuous or intermittent vascular clamping of the hepatic artery and&#xD;
      portal vein ('Pringle maneuver') is an efficient method to reduce hemorrhage. However, as a&#xD;
      consequence, ischemia and subsequent reperfusion result in complex metabolic, immunological,&#xD;
      and microvascular changes, which together might contribute to hepatocellular damage and&#xD;
      dysfunction. This phenomenon, known as ischemia-reperfusion (IR) injury of the liver, is a&#xD;
      complex multi-path process leading to the activation of inflammatory pathways, in which&#xD;
      cellular injury results from events occurring during both the ischemic and reperfusion&#xD;
      phases. The key mechanism of tissue injury is the intense and excessive inflammatory response&#xD;
      to reperfusion. Although initially considered a condition mediated by innate immune&#xD;
      responses, IR injury also triggers adaptive immunity, such as activated Kupffer cells that&#xD;
      express cytokines and chemokines thereby leading to further neutrophils activation and&#xD;
      recruitment. Neutrophils inflict tissue damage on the liver through the generation of some&#xD;
      reactive oxygen-species (ROS) and of some proteolytic enzymes. Various methods and many&#xD;
      pharmacological agents have been attempted to decrease the IR injury associated with&#xD;
      prolonged duration of vascular occlusion, no one is a standard of care in protocols for liver&#xD;
      resection. After a tough review of the literature we considered the most promising data on&#xD;
      two drugs: N-acetylcysteine (NAC) and Methylprednisolone (MET). NAC seems more active in&#xD;
      ischemic phase and in the early reperfusion period. In fact when blood flow is interrupted&#xD;
      cellular adenosine triphosphate (ATP) is depleted and there is a buildup of adenosine&#xD;
      monophosphate, which is catabolized to hypoxanthine that is oxidized to xanthine by the&#xD;
      enzyme xanthine oxidase, generating ROS in the process. Glutathione (GSH), that is an&#xD;
      antioxidant present in the liver, offers protection against oxygen free radicals. During&#xD;
      hypoxia, GSH stores are consumed, which predisposes to oxidative injury. N-acetylcysteine&#xD;
      (NAC) serves as a precursor to GSH and can replenish intracellular GSH stores, it directly&#xD;
      scavenge hydrogen peroxide. It has also been shown to impair the chemo taxis and generation&#xD;
      of oxygen radicals by human phagocytic cells through an anti-inflammatory action, inhibit&#xD;
      cytokine-mediated induction of nitric oxide synthase in human hepatocytes in vitro and have&#xD;
      probably an anti-inflammatory mechanism of hepatoprotection against oxidative injury from&#xD;
      nitric oxide (NO). So there is a substantial body of experimental work evaluating the role of&#xD;
      NAC in liver I/R injury, but these studies are small in terms of patients, and more&#xD;
      importantly they utilize a widely disparate range of protocols of administration. Yet, there&#xD;
      is only one small study describing the outcome of a randomized controlled trial in patients&#xD;
      undergoing liver resection. Thus, we decide, after the 'a priori' sample power calculation,&#xD;
      to investigate the effect of NAC in patients submitted to hepatic resection systematically&#xD;
      performed with the 'Pringle maneuver' using the same loading dose and subsequent infusion of&#xD;
      some Randomized Clinical Trial in liver transplantation. Together with NAC we decide to&#xD;
      investigate the effects of MET, which is a glucocorticoid steroid that acts as an&#xD;
      anti-inflammatory agent, reducing inflammatory markers and apoptotic cell count in&#xD;
      experimental liver IR injury. To our knowledge, there are only three published studies that&#xD;
      evaluated the role of MET in liver resection, but only one of those was associated to a&#xD;
      significant decrease of transaminase enzymes (AST and ALT). The basic hypothesis is that the&#xD;
      protective effects of Methylprednisolone may become more apparent as the extent of liver&#xD;
      resection and/or the duration of vascular occlusion increases. Therefore, the investigators&#xD;
      designed a randomized controlled trial with adequate sample size with the aim to recognize in&#xD;
      the intervention groups, one with NAC and one with MET, a statistically significant reduction&#xD;
      of ALT and AST (100U/L) compared with the placebo group. No stratifications are planned. Two&#xD;
      comparisons are planned Experimental (MET+NAC) vs. Standard and MET vs. NAC. A randomization&#xD;
      ratio MET:NAC:STD=1:1:1 is planned; for the Experimental (EXP) Vs Standard (STD) comparison&#xD;
      the allocation ratio is therefore 2:1. In order to verify the superiority of EXP (MET+NAC) it&#xD;
      was assumed that with the standard treatment the mean value of ALT was 800 units with a&#xD;
      standard deviation (SD) of 100, as reported in literature. the investigators decided to&#xD;
      consider of interest a reduction of 100 for the experimental treatments leading to consider a&#xD;
      value of 700 as desirable. Considering α value of 0.025 (one-sided) and a power of 90%, a&#xD;
      total of 48 evaluable patients are required (16 in each arm). If the test results in a&#xD;
      statistical significant advantage for EXP arms (MET+NAC), the study will continue the accrual&#xD;
      for MET and NAC only, with the aim of comparing MET vs. NAC, considering a difference of&#xD;
      interest of 50 units, with α value of 0.05 (two-sided) and a power of 80%. Further 94 Pts&#xD;
      need to be enrolled for a total of 126 evaluable patients available for the comparison of MET&#xD;
      vs. NAC. The total sample size will be 142 (63 treated with MET, 63 treated with NAC and 16&#xD;
      treated with standard therapy).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    The first phase was completed&#xD;
  </why_stopped>
  <start_date>November 2012</start_date>
  <completion_date type="Actual">November 2013</completion_date>
  <primary_completion_date type="Actual">October 2013</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Care Provider)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>A decrease of 100 UI/L of AST and ALT compared with placebo.</measure>
    <time_frame>Systematic sampling of liver function tests the day before the operation, at the end of the operation, as well as in postoperative day 1, 3, 5 and 7</time_frame>
    <description>The primary endpoint of the study is the modulation of the IR injury made by NAC and/or MET in patients undergoing liver surgery. For this purpose a decrease of 100 UI/L of AST and ALT is expected compared with placebo.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Difference in total bilirubin expression.</measure>
    <time_frame>Systematic sampling of liver function tests the day before the operation, at the end of the operation, as well as in postoperative day 1, 3, 5 and 7</time_frame>
    <description>This secondary endpoint want to assess difference in total bilirubin expression between the intervention groups and the placebo group.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Difference in blood transfusions.</measure>
    <time_frame>Systematic sampling of liver function tests the day before the operation, at the end of the operation, as well as in postoperative day 1, 3, 5 and 7</time_frame>
    <description>This secondary endpoint want to assess difference in blood transfusion between the intervention groups and the placebo group.</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">50</enrollment>
  <condition>Ischemic Reperfusion Injury</condition>
  <condition>Insufficiency; Hepatic, Postoperative</condition>
  <condition>Liver Tumour</condition>
  <arm_group>
    <arm_group_label>N-acetylcysteine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients were randomized to this arm will receive a bolus of N-acetylcysteine in an hour of 150 mg/kg after the beginning of the operation. After the bolus will start a 6-hour infusion of 50mg/kg/h of N-acetylcysteine.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Methylprednisolone</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients were randomized to this arm will receive a bolus of methylprednisolone in an hour of 500 mg after the beginning of the operation. After the bolus will start a 6-hour infusion of placebo (Ringer's acetate).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Patients were randomized to this arm will receive placebo (Ringer's acetate) in an hour after the beginning of the operation. After the bolus will start a 6-hour infusion of placebo (Ringer's acetate).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Methylprednisolone</intervention_name>
    <description>Methylprednisolone is a glucocorticoid, which is an adrenocortical steroid. The chemical name for methylprednisolone is pregna-1,4-diene-3,20-dione, 11,17,21-trihydroxy-6-methyl-, (6α,11β)-and the molecular weight is 374.48. It is an analog of naturally occurring glucocorticoid (hydrocortisone and cortisone), which also have salt-retaining properties, are used as replacement therapy in adrenocortical deficiency states. Methylprednisolone is used for their potent anti-inflammatory effects in disorders of many organ systems, it modify the body's immune responses to diverse stimuli. The usual dosage of medication varies in relation to pathology for which is prescribed: normally varies from about 40-60 mg per day up to very high doses of 30 mg/kg bolus as used in spinal cord injury.</description>
    <arm_group_label>Methylprednisolone</arm_group_label>
    <other_name>methylprednisolone sodium succinate</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>N-acetylcysteine</intervention_name>
    <description>Acetylcysteine is the N-acetyl derivative of the naturally occurring amino acid, L-cysteine. Chemically, it is N-acetyl-L-cysteine. The compound is a white crystalline powder which melts at 104°-110°C and has a very slight odor. Acetylcysteine may form cysteine, disulfides, and conjugates in vivo (N, N'-diacetylcysteine, N-acetylcysteine- cysteine, N-acetylcysteine-glutathione, N-acetylcysteine-protein, etc). No metabolites were identified. Acetylcysteine likely protects the liver by maintaining or restoring the glutathione levels, or by acting as an alternate substrate for conjugation with, and thus detoxification of, the reactive metabolite.</description>
    <arm_group_label>N-acetylcysteine</arm_group_label>
    <other_name>N-acetyl cysteine</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Any sex, any race, any ethnicity&#xD;
&#xD;
          -  Age &gt; 18&#xD;
&#xD;
          -  Primary and secondary liver tumors&#xD;
&#xD;
          -  Normal renal function&#xD;
&#xD;
          -  Anticipated Pringle's length &gt; 30 minutes&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Renal failure of any grade&#xD;
&#xD;
          -  ASA 4&#xD;
&#xD;
          -  Associate major surgery&#xD;
&#xD;
          -  Intraoperative bleeding &gt; 1500 ml&#xD;
&#xD;
          -  Allergy to N-acetylcysteine or Methylprednisolone&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Guido Torzilli, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Facoltà di Medicina e Chirurgia dell'Università degli Studi di Milano</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Giovanni Bordone, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Facoltà di Medicina e Chirurgia dell'Università degli Studi di Milano</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Istituto Clinico Humanitas IRCCS</name>
      <address>
        <city>Rozzano</city>
        <state>Milano</state>
        <zip>20089</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <verification_date>November 2013</verification_date>
  <study_first_submitted>November 7, 2012</study_first_submitted>
  <study_first_submitted_qc>November 9, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 15, 2012</study_first_posted>
  <last_update_submitted>November 9, 2013</last_update_submitted>
  <last_update_submitted_qc>November 9, 2013</last_update_submitted_qc>
  <last_update_posted type="Estimate">November 13, 2013</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>N-Acetylcysteine</keyword>
  <keyword>Methylprednisolone</keyword>
  <keyword>Liver ischemia reperfusion injury</keyword>
  <keyword>Pringle manoeuvre</keyword>
  <keyword>Hepatic resection</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Liver Failure</mesh_term>
    <mesh_term>Hepatic Insufficiency</mesh_term>
    <mesh_term>Reperfusion Injury</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Acetylcysteine</mesh_term>
    <mesh_term>Methylprednisolone</mesh_term>
    <mesh_term>Methylprednisolone Acetate</mesh_term>
    <mesh_term>Methylprednisolone Hemisuccinate</mesh_term>
    <mesh_term>Prednisolone</mesh_term>
    <mesh_term>Prednisolone acetate</mesh_term>
    <mesh_term>Prednisolone hemisuccinate</mesh_term>
    <mesh_term>Prednisolone phosphate</mesh_term>
    <mesh_term>N-monoacetylcystine</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01726465
org study id: CE ICH 178-12
nct id: NCT01726465
lead sponsor: 
has dmc: No
This is a prospective double-blind randomized phase II clinical trial, with two groups of
      intervention (one with administration of N-acetylcysteine and the other with administration
      of methylprednisolone), and one group of placebo. The purpose of this study is to investigate
      the role of N-acetylcysteine and Methylprednisolone in the modulation of warm ischemia of the
      liver during hepatic resection. In fact to avoid massive blood loss in liver surgery,
      continuous or intermittent vascular clamping of the hepatic hilum ('Pringle maneuver') is
      generally used with good results. However, as a consequence, ischemia and subsequent
      reperfusion result in complex metabolic, immunological, and microvascular changes, which
      together might contribute to hepatocellular damage and dysfunction. This phenomenon, known as
      ischemia-reperfusion (IR) injury of the liver, is a complex multi-path process leading to the
      activation of some inflammatory pathways. Any patient candidate to liver resection will be
      enrolled in the study based on the aforementioned criteria. The primary objective of the
      study is to assess the real efficacy of Methylprednisolone and N-acetylcysteine in reducing
      the secondary damage from ischemia reperfusion injury in liver resection and in reducing
      inflammatory response. Secondary objective of the study is whether the reduction of
      ischemia-reperfusion injury results in: lower incidence of postoperative liver failure,
      improvement of postoperative liver function, and reduction of blood components transfusions.
      The randomization will be done the day before the operation. The drugs will be prepared in a
      blind fashion by the hospital pharmacy. The hospital pharmacy will provide to each patient a
      drip to make bolus of about an hour before the start of the liver resection and a syringe
      pump for an infusion of approximately 6 hours. If the patient is enrolled and randomized in
      the placebo arm, he/she will receive 250 ml of glucose 5% plus the infusion of 100 ml of
      glucose 5% If the patient is randomized in the Methylprednisolone arm, he/she will receive a
      dose of 500 mg in 250 ml of glucose 5% plus 100 mg of glucose 5%. If the patient is
      randomized in the N-acetylcysteine arm, he/she will receive a dose of 150 mg/kg in 250 ml of
      glucose 5% plus N-acetylcysteine 50 mg/kg in 100 ml glucose 5%. Systematic sampling of liver
      function tests will be done the day before the operation, at the end of the operation, as
      well as in postoperative day 1, 3, 5 and 7.
Elective liver resection is performed mainly for benign and malignant liver tumors. The
      malignant tumors may arise primarily within the liver (hepatocellular carcinoma and
      cholangiocarcinoma) or represent metastases from malignancies of other organs. During hepatic
      resection, the risk of severe intraoperative bleeding represents a major risk. To avoid
      massive blood loss, continuous or intermittent vascular clamping of the hepatic artery and
      portal vein ('Pringle maneuver') is an efficient method to reduce hemorrhage. However, as a
      consequence, ischemia and subsequent reperfusion result in complex metabolic, immunological,
      and microvascular changes, which together might contribute to hepatocellular damage and
      dysfunction. This phenomenon, known as ischemia-reperfusion (IR) injury of the liver, is a
      complex multi-path process leading to the activation of inflammatory pathways, in which
      cellular injury results from events occurring during both the ischemic and reperfusion
      phases. The key mechanism of tissue injury is the intense and excessive inflammatory response
      to reperfusion. Although initially considered a condition mediated by innate immune
      responses, IR injury also triggers adaptive immunity, such as activated Kupffer cells that
      express cytokines and chemokines thereby leading to further neutrophils activation and
      recruitment. Neutrophils inflict tissue damage on the liver through the generation of some
      reactive oxygen-species (ROS) and of some proteolytic enzymes. Various methods and many
      pharmacological agents have been attempted to decrease the IR injury associated with
      prolonged duration of vascular occlusion, no one is a standard of care in protocols for liver
      resection. After a tough review of the literature we considered the most promising data on
      two drugs: N-acetylcysteine (NAC) and Methylprednisolone (MET). NAC seems more active in
      ischemic phase and in the early reperfusion period. In fact when blood flow is interrupted
      cellular adenosine triphosphate (ATP) is depleted and there is a buildup of adenosine
      monophosphate, which is catabolized to hypoxanthine that is oxidized to xanthine by the
      enzyme xanthine oxidase, generating ROS in the process. Glutathione (GSH), that is an
      antioxidant present in the liver, offers protection against oxygen free radicals. During
      hypoxia, GSH stores are consumed, which predisposes to oxidative injury. N-acetylcysteine
      (NAC) serves as a precursor to GSH and can replenish intracellular GSH stores, it directly
      scavenge hydrogen peroxide. It has also been shown to impair the chemo taxis and generation
      of oxygen radicals by human phagocytic cells through an anti-inflammatory action, inhibit
      cytokine-mediated induction of nitric oxide synthase in human hepatocytes in vitro and have
      probably an anti-inflammatory mechanism of hepatoprotection against oxidative injury from
      nitric oxide (NO). So there is a substantial body of experimental work evaluating the role of
      NAC in liver I/R injury, but these studies are small in terms of patients, and more
      importantly they utilize a widely disparate range of protocols of administration. Yet, there
      is only one small study describing the outcome of a randomized controlled trial in patients
      undergoing liver resection. Thus, we decide, after the 'a priori' sample power calculation,
      to investigate the effect of NAC in patients submitted to hepatic resection systematically
      performed with the 'Pringle maneuver' using the same loading dose and subsequent infusion of
      some Randomized Clinical Trial in liver transplantation. Together with NAC we decide to
      investigate the effects of MET, which is a glucocorticoid steroid that acts as an
      anti-inflammatory agent, reducing inflammatory markers and apoptotic cell count in
      experimental liver IR injury. To our knowledge, there are only three published studies that
      evaluated the role of MET in liver resection, but only one of those was associated to a
      significant decrease of transaminase enzymes (AST and ALT). The basic hypothesis is that the
      protective effects of Methylprednisolone may become more apparent as the extent of liver
      resection and/or the duration of vascular occlusion increases. Therefore, the investigators
      designed a randomized controlled trial with adequate sample size with the aim to recognize in
      the intervention groups, one with NAC and one with MET, a statistically significant reduction
      of ALT and AST (100U/L) compared with the placebo group. No stratifications are planned. Two
      comparisons are planned Experimental (MET+NAC) vs. Standard and MET vs. NAC. A randomization
      ratio MET:NAC:STD=1:1:1 is planned; for the Experimental (EXP) Vs Standard (STD) comparison
      the allocation ratio is therefore 2:1. In order to verify the superiority of EXP (MET+NAC) it
      was assumed that with the standard treatment the mean value of ALT was 800 units with a
      standard deviation (SD) of 100, as reported in literature. the investigators decided to
      consider of interest a reduction of 100 for the experimental treatments leading to consider a
      value of 700 as desirable. Considering α value of 0.025 (one-sided) and a power of 90%, a
      total of 48 evaluable patients are required (16 in each arm). If the test results in a
      statistical significant advantage for EXP arms (MET+NAC), the study will continue the accrual
      for MET and NAC only, with the aim of comparing MET vs. NAC, considering a difference of
      interest of 50 units, with α value of 0.05 (two-sided) and a power of 80%. Further 94 Pts
      need to be enrolled for a total of 126 evaluable patients available for the comparison of MET
      vs. NAC. The total sample size will be 142 (63 treated with MET, 63 treated with NAC and 16
      treated with standard therapy).
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Care Provider)
measure: A decrease of 100 UI/L of AST and ALT compared with placebo.
time frame: Systematic sampling of liver function tests the day before the operation, at the end of the operation, as well as in postoperative day 1, 3, 5 and 7
description: The primary endpoint of the study is the modulation of the IR injury made by NAC and/or MET in patients undergoing liver surgery. For this purpose a decrease of 100 UI/L of AST and ALT is expected compared with placebo.
measure: Difference in total bilirubin expression.
time frame: Systematic sampling of liver function tests the day before the operation, at the end of the operation, as well as in postoperative day 1, 3, 5 and 7
description: This secondary endpoint want to assess difference in total bilirubin expression between the intervention groups and the placebo group.
measure: Difference in blood transfusions.
time frame: Systematic sampling of liver function tests the day before the operation, at the end of the operation, as well as in postoperative day 1, 3, 5 and 7
description: This secondary endpoint want to assess difference in blood transfusion between the intervention groups and the placebo group.
arm group label: N-acetylcysteine
arm group type: Experimental
description: Patients were randomized to this arm will receive a bolus of N-acetylcysteine in an hour of 150 mg/kg after the beginning of the operation. After the bolus will start a 6-hour infusion of 50mg/kg/h of N-acetylcysteine.
arm group label: Methylprednisolone
arm group type: Experimental
description: Patients were randomized to this arm will receive a bolus of methylprednisolone in an hour of 500 mg after the beginning of the operation. After the bolus will start a 6-hour infusion of placebo (Ringer's acetate).
arm group label: Placebo
arm group type: Placebo Comparator
description: Patients were randomized to this arm will receive placebo (Ringer's acetate) in an hour after the beginning of the operation. After the bolus will start a 6-hour infusion of placebo (Ringer's acetate).
intervention type: Drug
intervention name: Methylprednisolone
description: Methylprednisolone is a glucocorticoid, which is an adrenocortical steroid. The chemical name for methylprednisolone is pregna-1,4-diene-3,20-dione, 11,17,21-trihydroxy-6-methyl-, (6α,11β)-and the molecular weight is 374.48. It is an analog of naturally occurring glucocorticoid (hydrocortisone and cortisone), which also have salt-retaining properties, are used as replacement therapy in adrenocortical deficiency states. Methylprednisolone is used for their potent anti-inflammatory effects in disorders of many organ systems, it modify the body's immune responses to diverse stimuli. The usual dosage of medication varies in relation to pathology for which is prescribed: normally varies from about 40-60 mg per day up to very high doses of 30 mg/kg bolus as used in spinal cord injury.
arm group label: Methylprednisolone
other name: methylprednisolone sodium succinate
intervention type: Drug
intervention name: N-acetylcysteine
description: Acetylcysteine is the N-acetyl derivative of the naturally occurring amino acid, L-cysteine. Chemically, it is N-acetyl-L-cysteine. The compound is a white crystalline powder which melts at 104°-110°C and has a very slight odor. Acetylcysteine may form cysteine, disulfides, and conjugates in vivo (N, N'-diacetylcysteine, N-acetylcysteine- cysteine, N-acetylcysteine-glutathione, N-acetylcysteine-protein, etc). No metabolites were identified. Acetylcysteine likely protects the liver by maintaining or restoring the glutathione levels, or by acting as an alternate substrate for conjugation with, and thus detoxification of, the reactive metabolite.
arm group label: N-acetylcysteine
other name: N-acetyl cysteine
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Guido Torzilli, PhD
role: Principal Investigator
affiliation: Facoltà di Medicina e Chirurgia dell'Università degli Studi di Milano
last name: Giovanni Bordone, PhD
role: Principal Investigator
affiliation: Facoltà di Medicina e Chirurgia dell'Università degli Studi di Milano
facility: 
country: Italy
responsible party type: Sponsor
mesh term: Liver Failure
mesh term: Hepatic Insufficiency
mesh term: Reperfusion Injury
mesh term: Acetylcysteine
mesh term: Methylprednisolone
mesh term: Methylprednisolone Acetate
mesh term: Methylprednisolone Hemisuccinate
mesh term: Prednisolone
mesh term: Prednisolone acetate
mesh term: Prednisolone hemisuccinate
mesh term: Prednisolone phosphate
mesh term: N-monoacetylcystine