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Phase II Randomized Double Blind Trial of Methylprednisolone and N-acetylcysteine in Hepatic Resections.

Phase 2
18 Years
70 Years
Open (Enrolling)
Ischemic Reperfusion Injury, Insufficiency; Hepatic, Postoperative, Liver Tumour

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Trial Information

Phase II Randomized Double Blind Trial of Methylprednisolone and N-acetylcysteine in Hepatic Resections.

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).

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

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver), Primary Purpose: Treatment

Outcome Measure:

A decrease of 100 UI/L of AST and ALT compared with placebo.

Outcome 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.

Outcome 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

Safety Issue:


Principal Investigator

Guido Torzilli, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Facoltà di Medicina e Chirurgia dell'Università degli Studi di Milano


Italy: The Italian Medicines Agency

Study ID:

CE ICH 178-12



Start Date:

November 2012

Completion Date:

December 2014

Related Keywords:

  • Ischemic Reperfusion Injury
  • Insufficiency; Hepatic, Postoperative
  • Liver Tumour
  • N-Acetylcysteine
  • Methylprednisolone
  • Liver ischemia reperfusion injury
  • Pringle manoeuvre
  • Hepatic resection
  • Liver Neoplasms
  • Reperfusion Injury
  • Hepatic Insufficiency