Skip to main content

Advertisement

Log in

Pharmacological Modulation of Ischemic-Reperfusion Injury during Pringle Maneuver in Hepatic Surgery. A Prospective Randomized Pilot Study

  • Original Scientific Report
  • Published:
World Journal of Surgery Aims and scope Submit manuscript

Abstract

Background

The Pringle maneuver, which is performed during liver surgery to reduce blood loss, may result in liver ischemia/reperfusion injury resulting in metabolic, immunological, and microvascular changes, which may lead to hepatocellular damage. The aim of this study was the investigation of the effects of N-acetylcysteine (NAC) and methylprednisolone (MET) in the modulation of liver warm ischemia during hepatic resection.

Methods

Forty-eight patients were enrolled in a pilot double-blind, randomized clinical trial. The patients received either NAC, MET, or placebo. The primary endpoint was the reduction in postoperative alanine aminotransferase and bilirubin. The secondary endpoint was the difference in morbidity and mortality.

Results

All the 48 patients had liver resection with no mortality. Morbidity was observed in 8 (16 %) patients equally distributed among the groups. There was a significant favorable recovery of liver function tests in patients treated with NAC or MET compared with the placebo when the Pringle maneuver exceeded 70 min.

Conclusions

The administration of NAC or MET prior to the Pringle maneuver during hepatic resection is associated with lower postoperative aberration in liver function tests compared with placebo when the Pringle maneuver exceeded 70 min. Larger studies are required to validate our findings and to investigate the specific role of NAC and MET in liver surgery.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Jamieson GG, Corbel L, Campion JP et al (1992) Major liver resection without a blood transfusion: is it a realistic objective? Surgery 112:32–36

    CAS  PubMed  Google Scholar 

  2. Kooby DA, Stockman J, Ben-Porat L et al (2003) Influence of transfusions on perioperative and long-term outcome in patients following hepatic resection for colorectal metastases. Ann Surg 237:860–870

    PubMed  PubMed Central  Google Scholar 

  3. Makuuchi M, Takayama T, Gunvén P et al (1989) Restrictive versus liberal blood transfusion policy for hepatectomies in cirrhotic patients. World J Surg 13:644–648. doi:10.1007/bf01658893

    Article  CAS  PubMed  Google Scholar 

  4. Torzilli G, Makuuchi M, Inoue K et al (1999) No-mortality liver resection for hepatocellular carcinoma in cirrhotic and noncirrhotic patients: is there a way? A prospective analysis of our approach. Arch Surg 134:984–992

    Article  CAS  PubMed  Google Scholar 

  5. Yamamoto J, Kosuge T, Takayama T et al (1994) Perioperative blood transfusion promotes recurrence of hepatocellular carcinoma after hepatectomy. Surgery 115:303–309

    CAS  PubMed  Google Scholar 

  6. Pringle JH (1908) Notes on the arrest of hepatic hemorrhage due to trauma. Ann Surg 48:541–549

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Imamura H, Kokudo N, Sugawara Y et al (2004) Pringle’s maneuver and selective inflow occlusion in living donor liver hepatectomy. Liver Transpl 10:771–778

    Article  PubMed  Google Scholar 

  8. Torzilli G, Procopio F, Donadon M et al (2012) Safety of intermittent Pringle maneuver cumulative time exceeding 120 minutes in liver resection: a further step in favor of the “radical but conservative” policy. Ann Surg 255:270–280

    Article  PubMed  Google Scholar 

  9. Glanemann M, Vollmar B, Nussler AK et al (2003) Ischemic preconditioning protects from hepatic ischemia/reperfusion-injury by preservation of microcirculation and mitochondrial redox-state. J Hepatol 38:59–66

    Article  CAS  PubMed  Google Scholar 

  10. Jaeschke H (2003) Molecular mechanisms of hepatic ischemia-reperfusion injury and preconditioning. Am J Physiol Gastrointest Liver Physiol 284:G15–G26

    Article  CAS  PubMed  Google Scholar 

  11. Serracino-Inglott F, Habib NA, Mathie RT (2001) Hepatic ischemia-reperfusion injury. Am J Surg 181:160–166

    Article  CAS  PubMed  Google Scholar 

  12. Kupiec-Weglinski JW, Busuttil RW (2005) Ischemia and reperfusion injury in liver transplantation. Transpl Proc 37:1653–1656

    Article  CAS  Google Scholar 

  13. Ilmakunnas M, Tukiainen EM, Rouhiainen A et al (2008) High mobility group box 1 protein as a marker of hepatocellular injury in human liver transplantation. Liver Transpl 14:1517–1525

    Article  PubMed  Google Scholar 

  14. Abu-Amara M, Gurusamy K, Hori S et al (2010) Systematic review of randomized controlled trials of pharmacological interventions to reduce ischaemia-reperfusion injury in elective liver resection with vascular occlusion. HPB (Oxford) 12:4–14

    Article  Google Scholar 

  15. Hayashi Y, Takayama T, Yamazaki S et al (2011) Validation of perioperative steroids administration in liver resection: a randomized controlled trial. Ann Surg 253:50–55

    Article  PubMed  Google Scholar 

  16. Jegatheeswaran S, Siriwardena AK (2011) Experimental and clinical evidence for modification of hepatic ischaemia-reperfusion injury by N-acetylcysteine during major liver surgery. HPB (Oxford) 13:71–78

    Article  Google Scholar 

  17. McKay A, Cassidy D, Sutherland F et al (2008) Clinical results of N-acetylcysteine after major hepatic surgery: a review. J Hepatobiliary Pancreat Surg 15:473–478

    Article  PubMed  Google Scholar 

  18. Muratore A, Ribero D, Ferrero A et al (2003) Prospective randomized study of steroids in the prevention of ischaemic injury during hepatic resection with pedicle clamping. Br J Surg 90:17–22

    Article  CAS  PubMed  Google Scholar 

  19. Yamashita Y, Shimada M, Hamatsu T et al (2001) Effects of preoperative steroid administration on surgical stress in hepatic resection: prospective randomized trial. Arch Surg 136:328–333

    Article  CAS  PubMed  Google Scholar 

  20. Saidi RF, Chang J, Verb S et al (2007) The effect of methylprednisolone on warm ischemia-reperfusion injury in the liver. Am J Surg 193:345–347

    Article  CAS  PubMed  Google Scholar 

  21. Belghiti J, Clavien P, Gadzijev E et al (2000) The Brisbane 2000 terminology of liver anatomy and resections. HPB (Oxford) 2:333–339

    Google Scholar 

  22. Dindo D, Demartines N, Clavien PA (2004) Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 240:205–213

    Article  PubMed  PubMed Central  Google Scholar 

  23. Schulz KF, Altman DG, Moher D (2010) CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. BMJ 340:c332

    Article  PubMed  PubMed Central  Google Scholar 

  24. Torzilli G, Procopio F, Costa G (2014) Resection guidance. In: Ultrasound-guided liver surgery: an atlas. Springer, New York, NY, pp 117–168

  25. Donadon M, Costa G, Gatti A et al (2014) Thoracoabdominal approach in liver surgery: how, when, and why. Updates Surg 66:121–125

    Article  PubMed  Google Scholar 

  26. Torzilli G, Procopio F, Costa G (2014) Planning of the surgical strategy. In: Ultrasound-guided liver surgery: an atlas. Springer, New York, NY, pp 75–116

  27. Gurusamy KS, Pamecha V, Sharma D et al (2009) Techniques for liver parenchymal transection in liver resection. Cochrane Database Syst Rev 1:Cd006880

    PubMed  Google Scholar 

  28. Lesurtel M, Selzner M, Petrowsky H et al (2005) How should transection of the liver be performed?: a prospective randomized study in 100 consecutive patients: comparing four different transection strategies. Ann Surg 242:814–823

    Article  PubMed  PubMed Central  Google Scholar 

  29. Takayama T, Makuuchi M, Kubota K et al (2001) Randomized comparison of ultrasonic vs clamp transection of the liver. Arch Surg 136:922–928

    Article  CAS  PubMed  Google Scholar 

  30. Torzilli G, Makuuchi M, Inoue K (2002) The vascular control in liver resection: revisitation of a controversial issue. Hepatogastroenterology 49:28–31

    PubMed  Google Scholar 

  31. Donadon M, Costa G, Cimino M et al (2015) Diagnosis and management of bile leaks after hepatectomy: results of a prospective analysis of 475 hepatectomies. World J Surg 39:237–243. doi:10.1007/s00268-015-3143-0

    Article  PubMed  Google Scholar 

  32. Pulitanò C, Aldrighetti L, Arru M et al (2007) Prospective randomized study of the benefits of preoperative corticosteroid administration on hepatic ischemia-reperfusion injury and cytokine response in patients undergoing hepatic resection. HPB 9:183–189

    Article  PubMed  PubMed Central  Google Scholar 

  33. Sugimoto T, Sozu T, Hamasaki T (2012) A convenient formula for sample size calculations in clinical trials with multiple co-primary continuous endpoints. Pharm Stat 11:118–128

    Article  PubMed  Google Scholar 

  34. Man K, Fan ST, Ng IO et al (1997) Prospective evaluation of Pringle maneuver in hepatectomy for liver tumors by a randomized study. Ann Surg 226:704–713

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Belghiti J, Noun R, Malafosse R et al (1999) Continuous versus intermittent portal triad clamping for liver resection: a controlled study. Ann Surg 229:369–375

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Elias D, Desruennes E, Lasser P (1991) Prolonged intermittent clamping of the portal triad during hepatectomy. Br J Surg 78:42–44

    Article  CAS  PubMed  Google Scholar 

  37. Makuuchi M, Mori T, Gunven P et al (1987) Safety of hemihepatic vascular occlusion during resection of the liver. Surg Gynecol Obstet 164:155–158

    CAS  PubMed  Google Scholar 

  38. Kosuge T, Yamamoto J, Takayama T et al (1994) An isolated, complete resection of the caudate lobe, including the paracaval portion, for hepatocellular carcinoma. Arch Surg 129:280–284

    Article  CAS  PubMed  Google Scholar 

  39. Wu CC, Hwang CR, Liu TL et al (1996) Effects and limitations of prolonged ischaemia for hepatic resection of the cirrhotic liver. Br J Surg 83:121–124

    Article  CAS  PubMed  Google Scholar 

  40. Sakamoto Y, Makuuchi M, Takayama T et al (1999) Pringle’s maneuver lasting 322 min. Hepatogastroenterology 46:457–458

    CAS  PubMed  Google Scholar 

  41. Ishizaki Y, Yoshimoto J, Miwa K et al (2006) Safety of prolonged intermittent Pringle maneuver during hepatic resection. Arch Surg 141:649–653

    Article  PubMed  Google Scholar 

  42. Procopio F, Torzilli G (2012) Forty-nine colorectal cancer liver metastases in one-stage hepatectomy with cumulative Pringle time lasting 348 min. Updates Surg 64:241–243

    Article  PubMed  Google Scholar 

  43. Ferrero A, Russolillo N, Vigano L et al (2010) Does Pringle maneuver affect survival in patients with colorectal liver metastases? World J Surg 34:2418–2425. doi:10.1007/s00268-010-0682-2

    Article  PubMed  Google Scholar 

  44. Giuliante F, Ardito F, Pulitano C et al (2010) Does hepatic pedicle clamping affect disease-free survival following liver resection for colorectal metastases? Ann Surg 252:1020–1026

    Article  PubMed  Google Scholar 

  45. Imamura H, Seyama Y, Kokudo N et al (2003) One thousand fifty-six hepatectomies without mortality in 8 years. Arch Surg 138:1198–1206

    Article  PubMed  Google Scholar 

  46. Sugiyama Y, Ishizaki Y, Imamura H et al (2010) Effects of intermittent Pringle’s manoeuvre on cirrhotic compared with normal liver. Br J Surg 97:1062–1069

    Article  CAS  PubMed  Google Scholar 

  47. Capussotti L, Muratore A, Ferrero A et al (2006) Randomized clinical trial of liver resection with and without hepatic pedicle clamping. Br J Surg 93:685–689

    Article  CAS  PubMed  Google Scholar 

  48. Hammond CL, Lee TK, Ballatori N (2001) Novel roles for glutathione in gene expression, cell death, and membrane transport of organic solutes. J Hepatol 34:946–954

    Article  CAS  PubMed  Google Scholar 

  49. McCord JM (1985) Oxygen-derived free radicals in postischemic tissue injury. N Engl J Med 312:159–163

    Article  CAS  PubMed  Google Scholar 

  50. Aruoma OI, Halliwell B, Hoey BM et al (1989) The antioxidant action of N-acetylcysteine: its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid. Free Radic Biol Med 6:593–597

    Article  CAS  PubMed  Google Scholar 

  51. Zafarullah M, Li WQ, Sylvester J et al (2003) Molecular mechanisms of N-acetylcysteine actions. Cell Mol Life Sci 60:6–20

    Article  CAS  PubMed  Google Scholar 

  52. Kharazmi A, Nielsen H, Schiotz PO (1988) N-acetylcysteine inhibits human neutrophil and monocyte chemotaxis and oxidative metabolism. Int J Immunopharmacol 10:39–46

    Article  CAS  PubMed  Google Scholar 

  53. Majano PL, Medina J, Zubia I et al (2004) N-Acetyl-cysteine modulates inducible nitric oxide synthase gene expression in human hepatocytes. J Hepatol 40:632–637

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Guido Torzilli.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Donadon, M., Molinari, A.F., Corazzi, F. et al. Pharmacological Modulation of Ischemic-Reperfusion Injury during Pringle Maneuver in Hepatic Surgery. A Prospective Randomized Pilot Study. World J Surg 40, 2202–2212 (2016). https://doi.org/10.1007/s00268-016-3506-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00268-016-3506-1

Keywords

Navigation