Advertisement

Journal of Gastroenterology

, Volume 49, Issue 3, pp 388–399 | Cite as

Pharmacologic prophylaxis of post-endoscopic retrograde cholangiopancreatography pancreatitis: protease inhibitors and NSAIDs in a meta-analysis

  • Hiroki Yuhara
  • Masami Ogawa
  • Yoshiaki Kawaguchi
  • Muneki Igarashi
  • Tooru Shimosegawa
  • Tetsuya Mine
Review

Abstract

Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis is the most frequent complication of ERCP. Several meta-analyses have examined the effects of protease inhibitors (gabexate mesilate, ulinastatin, and nafamostat mesilate) and non-steroidal anti-inflammatory drugs (NSAIDs) on post-ERCP pancreatitis, but the results have been confusing. Since the previous meta-analysis, several new studies have been published on this topic. To provide an updated quantitative assessment of the effectiveness of protease inhibitors and NSAIDs in preventing post-ERCP pancreatitis, we conducted a meta-analysis of randomized trials for patients at risk of post-ERCP pancreatitis. Twenty-six articles were included in this meta-analysis. Nafamostat mesilate (summary RR = 0.41; 95 %CI 0.28–0.59; n = 4 studies) and NSAIDs (summary RR = 0.58; 95 %CI = 0.44–0.76; n = 7 studies) were associated with decreased risk of post-ERCP pancreatitis in the high-quality studies. However, gabexate mesilate (summary RR = 0.64; 95 %CI = 0.36–1.13; n = 6 studies) and ulinastatin (summary RR = 0.65; 95 %CI = 0.33–1.30; n = 2 studies) were not associated with decreased risk of post-ERCP pancreatitis in the high-quality studies. This is the first meta-analysis to compare the effects of three protease inhibitors. Solid evidence supports the use of nafamostat mesilate and NSAIDs for preventing post-ERCP pancreatitis.

Keywords

Post-ERCP pancreatitis Protease inhibitor Gabexate mesilate Ulinastatin Nafamostat mesilate NSAIDs 

Notes

Acknowledgments

We wish to thank the Research Committee of Intractable Pancreatic Diseases (Principal Investigator: Dr. Tooru Shimosegawa) provided by the Ministry of Health, Labour, and Welfare of Japan.

Conflict of interest

The authors have no potential conflicts of interest to declare.

References

  1. 1.
    McCune WS, Shorb PE, Moscovitz H. Endoscopic cannulation of the ampulla of Vater: a preliminary report. Ann Surg. 1968;167:752–6.PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Mazen JM, Yoon EJ, Saadi A, et al. Trends in the utilization of endoscopic retrograde cholangiopancreatography (ERCP) in the United States. Am J Gastroenterol. 2007;102(5):966–75.CrossRefGoogle Scholar
  3. 3.
    Freeman ML, Guda NM. Prevention of post-ERCP pancreatitis: a comprehensive review. Gastrointest Endosc. 2004;59:845–64.PubMedCrossRefGoogle Scholar
  4. 4.
    Rabenstein T, Hahn EG. Post-ERCP pancreatitis: new momentum. Endoscopy. 2002;34:325–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Dumonceau JM, Andriulli A, Deviere J, European Society of Gastrointestinal Endoscopy. European Society of Gastrointestinal Endoscopy (ESGE) Guideline: prophylaxis of post-ERCP pancreatitis. Endoscopy. 2010;42:503–15.PubMedCrossRefGoogle Scholar
  6. 6.
    Prat F, Amaris J, Ducot B. Nifedipine for prevention of post-ERCP pancreatitis: a prospective, double-blind randomized study. Gastrointest Endosc. 2002;56:202–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Sand J, Nordback I. Prospective randomized trial of the effect of nifedipine on pancreatic irritation after endoscopic retrograde cholangiopancreatography. Digestion. 1993;54:105–11.PubMedCrossRefGoogle Scholar
  8. 8.
    Schwartz JJ, Lew RJ, Ahmad NA. The effect of lidocaine sprayed on the major duodenal papilla on the frequency of post-ERCP pancreatitis. Gastrointest Endosc. 2004;59:179–84.PubMedCrossRefGoogle Scholar
  9. 9.
    Xu LH, Qian JB, Gu LG. Prevention of postendoscopic retrograde cholangiopancreatography pancreatitis by epinephrine sprayed on the papilla. J Gastroenterol Hepatol. 2011;26:1139–44.PubMedCrossRefGoogle Scholar
  10. 10.
    Andriulli A, Leandro G, Federici T. Prophylactic administration of somatostatin or gabexate does not prevent pancreatitis after ERCP: an updated meta-analysis. Gastrointest Endosc. 2007;65:624–32.PubMedCrossRefGoogle Scholar
  11. 11.
    Bai Y, Gao J, Zou DW, Li ZS. Prophylactic octreotide administration does not prevent postendoscopic retrograde cholangiopancreatography pancreatitis: a meta-analysis of randomized controlled trials. Pancreas. 2008;37:241–6.PubMedCrossRefGoogle Scholar
  12. 12.
    Omata F, Deshpande G, Tokuda Y, Takahashi O, Ohde S, Carr-Locke DL, Jacobs JL, Mine T, Fukui T. Meta-analysis: somatostatin or its long-acting analogue, octreotide, for prophylaxis against post-ERCP pancreatitis. J Gastroenterol. 2010;45(8):885–95.PubMedCrossRefGoogle Scholar
  13. 13.
    Bai Y, Gao J, Shi X. Prophylactic corticosteroids do not prevent post-ERCP pancreatitis: a meta-analysis of randomized controlled trials. Pancreatology. 2008;8:504–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Zheng M, Chen Y, Bai J. Meta-analysis of prophylactic allopurinol use in postendoscopic retrograde cholangiopancreatography pancreatitis. Pancreas. 2008;37:247–53.PubMedCrossRefGoogle Scholar
  15. 15.
    Katsinelos P, Kountouras J, Paroutoglou G. Intravenous N-acetylcysteine does not prevent post-ERCP pancreatitis. Gastrointest Endosc. 2005;62:105–11.PubMedCrossRefGoogle Scholar
  16. 16.
    Rabenstein T, Fischer B, Wiessner V. Low-molecular-weight heparin does not prevent acute post-ERCP pancreatitis. Gastrointest Endosc. 2004;59:606–13.PubMedCrossRefGoogle Scholar
  17. 17.
    Oh HC, Cheon YK, Cho YD, Do JH. Use of udenafil is not associated with a reduction in post-ERCP pancreatitis: results of a randomized, placebo-controlled, multicenter trial. Gastrointest Endosc. 2011;74:556–62.PubMedCrossRefGoogle Scholar
  18. 18.
    Sherman S, Cheng C-L, Costamagna G. Efficacy of recombinant human interleukin-10 in prevention of postendoscopic retrograde cholangiopancreatography pancreatitis in subjects with increased risk. Pancreas. 2009;38:267–74.PubMedCrossRefGoogle Scholar
  19. 19.
    George S, Kulkarni AA, Stevens G. Role of osmolality of contrast media in the development of post-ERCP pancreatitis: a meta-analysis. Dig Dis Sci. 2004;49:503–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Kishida S, Takeyama Y, Ueda T, et al. Clinical effects of ulinastatin on severe acute pancreatitis. Shokakika. 1994;19:424–32.Google Scholar
  21. 21.
    Chen SY, Wang JY. Ulinastatin in the treatment of acute pancreatitis: a multicenter clinical trial. Chin J Dig. 2002;3:70–4.Google Scholar
  22. 22.
    Hara A, Arai J, Matsukawa H, et al. Combination therapy of continuous arterial infusion of nafamostat mesilate and arterial injection of human urinary trypsin inhibitor (ulinastatin) for severe acute pancreatitis. Ther Res. 2002;23:1265–75.Google Scholar
  23. 23.
    Cavallini G, Tittobello A, Frulloni L, The Gabexate in Digestive Endoscopy-Italian Group, et al. Gabexate for the prevention of pancreatic damage related to endoscopic retrograde cholangiopancreatography. N Engl J Med. 1996;335:919–23.PubMedCrossRefGoogle Scholar
  24. 24.
    Masci E, Cavallini G, Mariani A, The Gabexate in Digestive Endoscopy-Italian Group II, et al. Comparison of two dosing regimens of gabexate in the prophylaxis of post-ERCP pancreatitis. Am J Gastroenterol. 2003;98:2182–6.PubMedCrossRefGoogle Scholar
  25. 25.
    Sugiura Y, Nakajima K, Kawase H, et al. Evaluation of a large dose intravenous administration of ulinastatin. Jpn J Acute Med. 1988;12:1153–6.Google Scholar
  26. 26.
    Ohara H, Goto K, Noguchi Y, et al. The usefulness of ulinastatin for post-ERCP pancreatitis and hyperpancreatoenzymemia-comparative examination between one-shot injection and drip infusion of ulinastatin. Gastroenterology (Tokyo). 1990;12:361–8.Google Scholar
  27. 27.
    Yoo KS, Huh KR, Kim YJ. Nafamostat mesilate for prevention of postendoscopic retrograde cholangiopancreatography pancreatitis: a prospective, randomized, double-blind, controlled trial. Pancreas. 2011;40:181–6.PubMedCrossRefGoogle Scholar
  28. 28.
    Seta T, Noguchi Y. Protease inhibitors for preventing complications associated with ERCP: an updated metaanalysis. Gastrointest Endosc. 2011;73:700–6.PubMedCrossRefGoogle Scholar
  29. 29.
    Dumonceau JM, Andriulli A, Deviere J, et al. European Society of Gastrointestinal Endoscopy (ESGE) Guideline: prophylaxis of post-ERCP pancreatitis. Endoscopy. 2010;42:503.PubMedCrossRefGoogle Scholar
  30. 30.
    ASGE Standards of Practice Committee, Anderson MA, Fisher L, Jain R. Complications of ERCP. Gastrointest Endosc. 2012;75(3):467–73.PubMedCrossRefGoogle Scholar
  31. 31.
  32. 32.
    Gross V, Leser HG, Heinisch A, et al. Inflammatory mediators and cytokines—new aspects of the pathophysiology and assessment of severity of acute pancreatitis? Hepatogastroenterology. 1993;40:522–30.PubMedGoogle Scholar
  33. 33.
    Mäkelä A, Kuusi T, Schröder T. Inhibition of serum phospholipase-A2 in acute pancreatitis by pharmacologic agents in vitro. Scand J Clin Lab Invest. 1997;57:401–8.PubMedCrossRefGoogle Scholar
  34. 34.
    Dumonceau JM, Rigaux J, Kahaleh M, Gomez CM, Vandermeeren A, Devière J. Prophylaxis of post-ERCP pancreatitis: a practice survey. Gastrointest Endosc. 2010;71(6):934–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Zheng M, Chen Y, Yang X, et al. Gabexate in the prophylaxis of post-ERCP pancreatitis: a meta-analysis of randomized controlled trials. BMC Gastroenterol. 2007;7:6.PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Chen S, Shi H, Zou X, Luo H. Role of ulinastatin in preventing post-endoscopic retrograde cholangiopancreatography pancreatitis: the Emperor’s New Clothes or Aladdin’s Magic Lamp? Pancreas. 2010;39(8):1231–7.PubMedCrossRefGoogle Scholar
  37. 37.
    Elmunzer BJ, Waljee AK, Elta GH, Taylor JR, Fehmi SM, Higgins PD. A meta-analysis of rectal NSAIDs in the prevention of post-ERCP pancreatitis. Gut. 2008;57(9):1262–7.PubMedCrossRefGoogle Scholar
  38. 38.
    Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17:1–12.PubMedCrossRefGoogle Scholar
  39. 39.
    Greenland S. Meta-analysis. In: Rothman K, Greenland S, editors. Modern Epidemiology. 2nd ed. Philadelphia: Lippincott Raven; 1998. p. 643–73.Google Scholar
  40. 40.
    DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–88.PubMedCrossRefGoogle Scholar
  41. 41.
    Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539–58.PubMedCrossRefGoogle Scholar
  42. 42.
    Egger M, DaveySmith G, Schneider M, et al. Bias in meta-analysis detected by a simple, graphical test. Br Med J. 1997;315:629–34.CrossRefGoogle Scholar
  43. 43.
    Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50:1088–101.PubMedCrossRefGoogle Scholar
  44. 44.
    Cavallini G, Tittobello A, Frulloni L. Gabexate for the prevention of pancreatic damage related to endoscopic retrograde cholangiopancreatography. Gabexate in digestive endoscopy–Italian Group. N Engl J Med. 1996;335(13):919–23.PubMedCrossRefGoogle Scholar
  45. 45.
    Andriulli A, Clemente R, Solmi L. Gabexate or somatostatin administration before ERCP in patients at high risk for post-ERCP pancreatitis: a multicenter, placebo-controlled, randomized clinical trial. Gastrointest Endosc. 2002;56(4):488–95.PubMedCrossRefGoogle Scholar
  46. 46.
    Yokohata K, Maeyama R, Nagata M, et al. Gastoenterol Endoscopy. 2003;45(Suppl 1):567.Google Scholar
  47. 47.
    Andriulli A, Solmi L, Loperfido S. Prophylaxis of ERCP-related pancreatitis: a randomized, controlled trial of somatostatin and gabexate mesylate. Clin Gastroenterol Hepatol. 2004;2(8):713–8.PubMedCrossRefGoogle Scholar
  48. 48.
    Xiong GS, Wu SM, Zhang XW. Clinical trial of gabexate in the prophylaxis of post-endoscopic retrograde cholangiopancreatography pancreatitis. Braz J Med Biol Res. 2006;39(1):85–90 Epub 2005 Dec 15.PubMedCrossRefGoogle Scholar
  49. 49.
    Manes G, Ardizzone S, Lombardi G, Uomo G, Pieramico O, Porro GB. Efficacy of postprocedure administration of gabexate mesylate in the prevention of post-ERCP pancreatitis: a randomized, controlled, multicenter study. Gastrointest Endosc. 2007;65(7):982–7.PubMedCrossRefGoogle Scholar
  50. 50.
    Yoo YW, Cha SW, Kim A. The use of gabexate mesylate and ulinastatin for the prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis. Gut Liver. 2012;6(2):256–61.PubMedCentralPubMedCrossRefGoogle Scholar
  51. 51.
    Tsujino T, Komatsu Y, Isayama H. Ulinastatin for pancreatitis after endoscopic retrograde cholangiopancreatography: a randomized, controlled trial. Clin Gastroenterol Hepatol. 2005;3(4):376–83.PubMedCrossRefGoogle Scholar
  52. 52.
    Gong P, Wang ZY, Tai PJ, et al. Prevention and treatment for post ERCP pancreatitis. J Hepatobiliary Surg. 2004;12:101–3.Google Scholar
  53. 53.
    Song AL, Yin LN, Kou ZM. Preventive effects of ulinastatin on post ERCP hyperamylasemia and acute pancreatitis. J Lanzhou Univ (Med Sci). 2005;31:24–5.Google Scholar
  54. 54.
    Chen XT, Fei ZY, Shen YF, et al. Clinical observation on ulinastatin for the prevention of post-ERCP pancreatitis. Shandong Med J. 2005;45:44–5.Google Scholar
  55. 55.
    Yoo JW, Ryu JK, Lee SH. Preventive effects of ulinastatin on post-endoscopic retrograde cholangiopancreatography pancreatitis in high-risk patients: a prospective, randomized, placebo-controlled trial. Pancreas. 2008;37(4):366–70.PubMedCrossRefGoogle Scholar
  56. 56.
    Choi CW, Kang DH, Kim GH. Nafamostat mesylate in the prevention of post-ERCP pancreatitis and risk factors for post-ERCP pancreatitis. Gastrointest Endosc. 2009;69(4):e11–8.PubMedCrossRefGoogle Scholar
  57. 57.
    Yamashita Y, Ito K, Noda H, et al. Gastoenterol Endosc. 2010;52(Suppl 1):1048.Google Scholar
  58. 58.
    Park KT, Kang DH, Choi CW. Is high-dose nafamostat mesilate effective for the prevention of post-ERCP pancreatitis, especially in high-risk patients? Pancreas. 2011;40(8):1215–9.PubMedCrossRefGoogle Scholar
  59. 59.
    Yoo KS, Huh KR, Kim YJ. Nafamostat mesilate for prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis: a prospective, randomized, double-blind, controlled trial. Pancreas. 2011;40(2):181–6.PubMedCrossRefGoogle Scholar
  60. 60.
    Ohuchida J, Ashiyoshi M, Chijiiwa K. Gastoenterol Endosc. 2011;53(Suppl 2):2445.Google Scholar
  61. 61.
    Murray B, Carter R, Imrie C. Diclofenac reduces the incidence of acute pancreatitis after endoscopic retrograde cholangiopancreatography. Gastroenterology. 2003;124(7):1786–91.PubMedCrossRefGoogle Scholar
  62. 62.
    Sotoudehmanesh R, Khatibian M, Kolahdoozan S. Indomethacin may reduce the incidence and severity of acute pancreatitis after ERCP. Am J Gastroenterol. 2007;102(5):978–83.PubMedCrossRefGoogle Scholar
  63. 63.
    MontañoLoza A, RodríguezLomelí X, GarcíaCorrea JE. Effect of the administration of rectal indomethacin on amylase serum levels after endoscopic retrograde cholangiopancreatography, and its impact on the development of secondary pancreatitis episodes. Rev Esp Enferm Dig. 2007;99(6):330–6.Google Scholar
  64. 64.
    Khoshbaten M, Khorram H, Madad L. Role of diclofenac in reducing post-endoscopic retrograde cholangiopancreatography pancreatitis. J Gastroenterol Hepatol. 2008;23(7 Pt 2):e11–6.PubMedCrossRefGoogle Scholar
  65. 65.
    Cheon YK, Cho KB, Watkins JL. Efficacy of diclofenac in the prevention of post-ERCP pancreatitis in predominantly high-risk patients: a randomized double-blind prospective trial. Gastrointest Endosc. 2007;66(6):1126–32.PubMedCrossRefGoogle Scholar
  66. 66.
    Senol A, Saritas U, Demirkan H. Efficacy of intramuscular diclofenac and fluid replacement in prevention of post-ERCP pancreatitis. World J Gastroenterol. 2009;15(32):3999–4004.PubMedCentralPubMedCrossRefGoogle Scholar
  67. 67.
    Bhatia V, Ahuja V, Acharya SK. A randomized controlled trial of valdecoxib and glyceryl trinitrate for the prevention of post-ERCP pancreatitis. J Clin Gastroenterol. 2011;45(2):170–6.PubMedCrossRefGoogle Scholar
  68. 68.
    Elmunzer BJ, Scheiman JM, Lehman GA, U.S. Cooperative for Outcomes Research in Endoscopy (USCORE). A randomized trial of rectal indomethacin to prevent post-ERCP pancreatitis. N Engl J Med. 2012;366(15):1414–22.PubMedCentralPubMedCrossRefGoogle Scholar
  69. 69.
    Otsuka T, Kawazoe S, Nakashita S. Low-dose rectal diclofenac for prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis: a randomized controlled trial. J Gastroenterol. 2012;47(8):912–7.PubMedCrossRefGoogle Scholar
  70. 70.
    Fujishiro H, Adachi K, Imaoka T. Ulinastatin shows preventive effect on post-endoscopic retrograde cholangiopancreatography pancreatitis in a multicenter prospective randomized study. J Gastroenterol Hepatol. 2006;21(6):1065–9.PubMedCrossRefGoogle Scholar
  71. 71.
    Ueki T, Otani K, Kawamoto K, Shimizu A. Comparison between ulinastatin and gabexate mesylate for the prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis: a prospective, randomized trial. J Gastroenterol. 2007;42(2):161–7.PubMedCrossRefGoogle Scholar
  72. 72.
    Testoni PA. Pharmacological prevention of post-ERCP pancreatitis: the facts and the fiction. JOP. 2004;5:171–8.PubMedGoogle Scholar
  73. 73.
    Fujii S, Hitomi Y. New synthetic inhibitors of C1r, C1 esterase, thrombin, plasmin, kallikrein and trypsin. Biochim Biophys Acta. 1981;661:342–5.PubMedCrossRefGoogle Scholar
  74. 74.
    Keck T. Site-specific therapeutic effects of protease inhibitors: effect of route of administration in experimental pancreatitis. Pancreatology. 2001;1:656–61.PubMedGoogle Scholar
  75. 75.
    Iwaki M, Ino Y, Motoyoshi A, et al. Pharmacological studies of FUT-175, nafamostat mesilate. V. Effects on the pancreatic enzymes and experimental acute pancreatitis in rats. Jpn J Pharmacol. 1986;41:155–62.PubMedCrossRefGoogle Scholar
  76. 76.
    Messmann H, Vogt W, Holstege A, et al. Post-ERP pancreatitis as a model for cytokine induced acute phase response in acute pancreatitis. Gut. 1997;40:80–5.PubMedCentralPubMedGoogle Scholar
  77. 77.
    Karne S, Gorelick FS. Etiopathogenesis of acute pancreatitis. Surg Clin N Am. 1999;79:699–710.PubMedCrossRefGoogle Scholar
  78. 78.
    Bhatia M, Brady M, Shokuhi S, Christmas S, Neoptolemos JP, Slavin J. Inflammatory mediators in acute pancreatitis. J Pathol. 2000;190:117–25.PubMedCrossRefGoogle Scholar
  79. 79.
    Rabenstein T, Hahn EG. Post-ERCP pancreatitis: new momentum. Endoscopy. 2002;34(4):325–9.PubMedCrossRefGoogle Scholar
  80. 80.
    Gross V, Leser HG, Heinisch A, Schölmerich J. Inflammatory mediators and cytokines: new aspects of the pathophysiology and assessment of severity of acute pancreatitis? Hepatogastroenterology. 1993;40:522–30.PubMedGoogle Scholar
  81. 81.
    Reddy SC, Draganov PV. ERCP wire systems: the long and the short of it. World J Gastroenterol. 2009;15(1):55–60.PubMedCentralPubMedCrossRefGoogle Scholar
  82. 82.
    Lee TH, Park do H, Park JY, Kim EO, Lee YS, Park JH, Lee SH, Chung IK, Kim HS, Park SH, Kim SJ. Can wire-guided cannulation prevent post-ERCP pancreatitis? A prospective randomized trial. Gastrointest Endosc 2009;69(3 Pt 1):444–9.Google Scholar
  83. 83.
    Ito K, Fujita N, Noda Y, Kobayashi G, Obana T, Horaguchi J, Takasawa O, Koshita S, Kanno Y. Pancreatic guidewire placement for achieving selective biliary cannulation during endoscopic retrograde cholangio-pancreatography. World J Gastroenterol. 2008;14(36):5595–600.PubMedCentralPubMedCrossRefGoogle Scholar
  84. 84.
    Kawaguchi Y, Ogawa M, Omata F, Ito H, Shimosegawa T, Mine T. Randomized controlled trial of pancreatic stenting to prevent pancreatitis after endoscopic retrograde cholangiopancreatography. World J Gastroenterol. 2012;18(14):1635–41.PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Japan 2013

Authors and Affiliations

  • Hiroki Yuhara
    • 1
  • Masami Ogawa
    • 1
  • Yoshiaki Kawaguchi
    • 1
  • Muneki Igarashi
    • 1
  • Tooru Shimosegawa
    • 2
  • Tetsuya Mine
    • 1
  1. 1.Department of GastroenterologyTokai University School of MedicineIseharaJapan
  2. 2.Division of GastroenterologyTohoku University Graduate School of MedicineSendaiJapan

Personalised recommendations