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Effects of Pentoxifylline on Liver Regeneration: A Double-Blinded, Randomized, Controlled Trial in 101 Patients Undergoing Major Liver Resection

Petrowsky, Henrik MD*; Breitenstein, Stefan MD*; Slankamenac, Ksenija MD*; Vetter, Diana MD*; Lehmann, Kuno MD*; Heinrich, Stefan MD*; DeOliveira, Michelle L. MD*; Jochum, Wolfram MD; Weishaupt, Dominik MD; Frauenfelder, Thomas MD; Graf, Rolf PhD*; Clavien, Pierre-Alain MD, PhD*

Annals of Surgery:
doi: 10.1097/SLA.0b013e3181fcbc5e
Original Articles from the ESA Proceedings
Abstract

Objectives: To evaluate the effects of pentoxifylline (PTX) on liver regeneration in patients undergoing major liver resection.

Background: Recent experimental data suggest that PTX, a tumor necrosis factor (TNF) α inhibitor, enhances liver regeneration and reduces ischemic injury through activation of the interleukin-6 (IL-6) signaling pathway. However, the clinical impact of PTX in patients undergoing major liver surgery is unknown.

Methods: One hundred one consecutive noncirrhotic patients undergoing major liver surgery with inflow occlusion were included in a double-blinded, randomized, controlled trial (RCT) at a single tertiary care center (2006–2009). Fifty-one patients received intravenous administration of PTX starting 12 hours before and ending 72 hours after surgery, whereas 50 control patients received a placebo infusion. Primary endpoint was liver regeneration as assessed by three-dimensional volumetry based on magnetic resonance (MR) tomography at postoperative day 8 compared with preoperative images. Secondary endpoints were transaminases, cytokines, and postoperative complications.

Results: Both groups were comparable regarding demographics, risk score, preoperative laboratory tests, and type and extent of liver resection. Treatment with PTX resulted in significantly better volume regeneration for small remnant livers [remnant liver to body weight (RLBW) ratio ≤ 1.2%], whereas no beneficial effect was observed for RLBW ratio of more than 1.2%. There was a 3.6-fold stronger induction of IL-6 mRNA for the PTX group (P < 0.001). Postoperative alanine aminotransferase (AST) levels were significantly decreased for the PTX group on the second postoperative day (442 vs 585 U/L, P = 0.025). No significant benefit could be identified regarding the number and severity of postoperative complications and median ICU (1 vs 1 day) and hospital stay (10 vs 10 days). However, the PTX group had significantly more drug-related adverse events (23 vs 8, P = 0.007).

Conclusions: This is the first RCT evaluating the effects of PTX on liver regeneration after major liver resection. The study demonstrates beneficial effects of PTX on regeneration of small remnant livers (RLBW ratio ≤ 1.2%) that seems to be mediated by IL-6.

In Brief

Pentoxyfilline (PTX) has been shown to confer positive effects on liver regeneration in a rodent model of small-for-size liver transplantation. Therefore, we conducted a double-blinded randomized controlled trial (RCT) in 101 unselected patients undergoing major liver resection and found beneficial effects of PTX on the regeneration of small remnant livers (RLBW ratio &amp;#x2264;.2%). There is evidence that these effects are mediated by IL-6.

Author Information

*Swiss HPB (Hepato-Pancreato-Biliary) Center, Departments of Surgery, University Hospital Zurich, Zurich, Switzerland. H.P. is now with The Dumont-UCLA Transplant Center, David Geffen School of Medicine at UCLA, Los Angeles, CA.

Swiss HPB (Hepato-Pancreato-Biliary) Center, Departments of Pathology, University Hospital Zurich, Zurich, Switzerland. H.P. is now with The Dumont-UCLA Transplant Center, David Geffen School of Medicine at UCLA, Los Angeles, CA.

Swiss HPB (Hepato-Pancreato-Biliary) Center, Departments of Radiology, University Hospital Zurich, Zurich, Switzerland. H.P. is now with The Dumont-UCLA Transplant Center, David Geffen School of Medicine at UCLA, Los Angeles, CA.

Reprints: Pierre-Alain Clavien, MD, PhD, Department of Surgery, University Hospital Zurich, Raemistrasse 100, CH-8091 Zurich, Switzerland. E-mail: clavien@access.uzh.ch.

H.P., S.B., and K.S. contributed equally as first authors.

This work was supported by grants (CI 876562444) from the Roche Organ Transplantation Research Foundation (ROTRF) to H.P. and P.A.C. and from Swiss National Foundation (3200B0-709906) to P.A.C.

S.H. and M.L.D.O. are the recipients of the Novartis fellowship in hepatopancreatobiliary surgery and liver transplantation. The authors also thank Udo Ungethuem for his excellent technical assistance in performing the cytokine assays.

Abbreviation: ALT, aspartate aminotransferase; ASA, American Society of Anesthesiologists; AST, alanine aminotransferase; AUC, area under the curve; BMI, body mass index; CVP, central venous pressure; GRWR, graft to recipient's weight ratio; ICU, intensive care unit; IL-6, interleukine-6; INR, international normalized ratio; I/R, ischemia/reperfusion; OLT, orthotopic liver transplantation; POD, postoperative day; PTX, pentoxifylline; RCT, randomized controlled trial; RLBW, remnant liver to body weight; RLV, remnant liver volume; RLW, remnant liver weight; SFSS, small-for-size syndrome; TNF, tumor necrosis factor.

© 2010 Lippincott Williams & Wilkins, Inc.