Methylprednisolone N Acetylcysteine in Hepatic Resections (MENHIR)

This study has been terminated.
(The first phase was completed)
Sponsor:
Information provided by (Responsible Party):
Istituto Clinico Humanitas
ClinicalTrials.gov Identifier:
NCT01726465
First received: November 7, 2012
Last updated: November 9, 2013
Last verified: November 2013
  Purpose

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.


Condition Intervention Phase
Ischemic Reperfusion Injury
Insufficiency; Hepatic, Postoperative
Liver Tumour
Drug: Methylprednisolone
Drug: N-acetylcysteine
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver)
Primary Purpose: Treatment
Official Title: Phase II Randomized Double Blind Trial of Methylprednisolone and N-acetylcysteine in Hepatic Resections.

Resource links provided by NLM:


Further study details as provided by Istituto Clinico Humanitas:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
    This secondary endpoint want to assess difference in total bilirubin expression between the intervention groups and the placebo group.

  • 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 ] [ Designated as safety issue: No ]
    This secondary endpoint want to assess difference in blood transfusion between the intervention groups and the placebo group.


Enrollment: 50
Study Start Date: November 2012
Study Completion Date: November 2013
Primary Completion Date: October 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: N-acetylcysteine
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.
Drug: N-acetylcysteine
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.
Other Name: N-acetyl cysteine
Experimental: Methylprednisolone
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).
Drug: Methylprednisolone
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.
Other Name: methylprednisolone sodium succinate
Placebo Comparator: Placebo
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).

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  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Any sex, any race, any ethnicity
  • Age > 18
  • Primary and secondary liver tumors
  • Normal renal function
  • Anticipated Pringle's length > 30 minutes

Exclusion Criteria:

  • Renal failure of any grade
  • ASA 4
  • Associate major surgery
  • Intraoperative bleeding > 1500 ml
  • Allergy to N-acetylcysteine or Methylprednisolone
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01726465

Locations
Italy
Istituto Clinico Humanitas IRCCS
Rozzano, Milano, Italy, 20089
Sponsors and Collaborators
Istituto Clinico Humanitas
Investigators
Principal Investigator: Guido Torzilli, PhD Facoltà di Medicina e Chirurgia dell'Università degli Studi di Milano
Principal Investigator: Giovanni Bordone, PhD Facoltà di Medicina e Chirurgia dell'Università degli Studi di Milano
  More Information

No publications provided

Responsible Party: Istituto Clinico Humanitas
ClinicalTrials.gov Identifier: NCT01726465     History of Changes
Other Study ID Numbers: CE ICH 178-12
Study First Received: November 7, 2012
Last Updated: November 9, 2013
Health Authority: Italy: The Italian Medicines Agency

Keywords provided by Istituto Clinico Humanitas:
N-Acetylcysteine
Methylprednisolone
Liver ischemia reperfusion injury
Pringle manoeuvre
Hepatic resection

Additional relevant MeSH terms:
Hepatic Insufficiency
Reperfusion Injury
Cardiovascular Diseases
Digestive System Diseases
Liver Diseases
Pathologic Processes
Postoperative Complications
Vascular Diseases
Acetylcysteine
Methylprednisolone
Methylprednisolone acetate
Methylprednisolone Hemisuccinate
N-monoacetylcystine
Prednisolone
Prednisolone acetate
Prednisolone hemisuccinate
Prednisolone phosphate
Anti-Infective Agents
Anti-Inflammatory Agents
Antidotes
Antiemetics
Antineoplastic Agents
Antineoplastic Agents, Hormonal
Antioxidants
Antiviral Agents
Autonomic Agents
Central Nervous System Agents
Expectorants
Free Radical Scavengers
Gastrointestinal Agents

ClinicalTrials.gov processed this record on October 21, 2014