Research Article
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The Intraoperative Use of Hypochlorous Acid in Infected Hip Arthroplasty Revision Surgery

Year 2023, Volume: 25 Issue: 2, 189 - 194, 30.08.2023
https://doi.org/10.18678/dtfd.1314747

Abstract

Aim: Arthroplasty infections are serious and difficult to treat complications. Hypochlorous acid (HOCl) is an oxidant produced endogenously in the body as a physiological part of the inflammatory process, with the aim of eliminating pathogens activated by neutrophils. The aim of this study was to evaluate the positive and negative effects on clinical results of HOCl used as an irrigation solution during surgical treatment.
Material and Methods: The study included 37 patients who underwent single- or two-stage revision surgery at the University of Health Sciences Şişli Hamidiye Etfal Training and Research Hospital Orthopedics and Traumatology Clinic between January 2017 and December 2021. Treatment was applied according to our standard protocol of irrigation with 450 cc HOCl following implant removal and an additional 50 cc HOCl to the subcutaneous tissue after closing the fascia. The patients were evaluated during follow-up in respect of infections.
Results: While single-stage revision surgery applied to 20 patients, two-stage revision surgery applied to 17 patients. 17 (45.9%) of the patients were male and 20 (54.1%) were female with a mean age of 72.8±11.1 years. The mean follow-up period was 25.8±14.1 months. Revision surgery was performed on one patient in each of the single and two-stage surgery groups. A success rate of 94.6% (n=37) was obtained when all patients were evaluated.
Conclusion: The HOCl solution can be considered to make a positive contribution to the eradication of infections in revision hip arthroplasty and can be an effective and safe alternative to other irrigation solutions.

References

  • Tande AJ, Patel R. Prosthetic joint infection. Clin Microbiol Rev. 2014;27(2):302-45.
  • Odum SM, Fehring TK, Lombardi AV, Zmistowski BM, Brown NM, Luna JT, et al. Irrigation and debridement for periprosthetic infections: does the organism matter? J Arthroplasty. 2011;26(6):114-8.
  • Sukeik M, Haddad FS. Periprosthetic joint infections after total hip replacement: an algorithmic approach. SICOT J. 2019;5:5.
  • Ruder JA, Springer BD. Treatment of periprosthetic joint infection using antimicrobials: dilute povidone-iodine lavage. J Bone Jt Infect. 2017;2(1):10-4.
  • van Meurs SJ, Gawlitta D, Heemstra KA, Poolman RW, Vogely HC, Kruyt MC. Selection of an optimal antiseptic solution for intraoperative irrigation: an in vitro study. J Bone Joint Surg Am. 2014;96(4):285-91.
  • Siddiqi A, Abdo ZE, Rossman SR, Kelly MA, Piuzzi NS, Higuera CA, et al. What is the optimal irrigation solution in the management of periprosthetic hip and knee joint infections? J Arthroplasty. 2021;36(10):3570-83.
  • Sakarya S, Gunay N, Karakulak M, Ozturk B, Ertugrul B. Hypochlorous Acid: an ideal wound care agent with powerful microbicidal, antibiofilm, and wound healing potency. Wounds. 2014;26(12):342-50.
  • Kramer A, Dissemond J, Kim S, Willy C, Mayer D, Papke R, et al. Consensus on Wound Antisepsis: Update 2018. Skin Pharmacol Physiol. 2018;31(1):28-58.
  • Day A, Alkhalil A, Carney BC, Hoffman HN, Moffatt LT, Shupp JW. Disruption of biofilms and neutralization of bacteria using hypochlorous acid solution: an in vivo and in vitro evaluation. Adv Skin Wound Care. 2017;30(12):543-51.
  • Wang L, Bassiri M, Najafi R, Najafi K, Yang J, Khosrovi B, et al. Hypochlorous acid as a potential wound care agent: part I. Stabilized hypochlorous acid: a component of the inorganic armamentarium of innate immunity. J Burns Wounds. 2007;6:e5.
  • Clayman E, Beauchamp Z, Troy J. Salvage of infected orthopedic hardware with intraoperative and postoperative hypochlorous acid instillations. Eplasty. 2023;23:e1.
  • Wongkietkachorn A, Surakunprapha P, Wittayapairoch J, Wongkietkachorn N, Wongkietkachorn S. The use of hypochlorous acid lavage to treat infected cavity wounds. Plast Reconstr Surg Glob Open. 2020;8(1):e2604.
  • Bongiovanni CM. Effects of hypochlorous acid solutions on venous leg ulcers (VLU): experience with 1249 VLUs in 897 patients. J Am Coll Clin Wound Spec. 2016;6(3):32-7.
  • Severing AL, Rembe JD, Koester V, Stuermer EK. Safety and efficacy profiles of different commercial sodium hypochlorite/hypochlorous acid solutions (NaClO/HClO): antimicrobial efficacy, cytotoxic impact and physicochemical parameters in vitro. J Antimicrob Chemother. 2019;74(2):365-72.
  • Armstrong DG, Bohn G, Glat P, Kavros SJ, Kirsner R, Snyder R, et al. Expert recommendations for the use of hypochlorous solution: science and clinical application. Ostomy Wound Manage. 2015;61(5):S2-19.
  • Parvizi J, Zmistowski B, Berbari EF, Bauer TW, Springer BD, Della Valle CJ, et al. New definition for periprosthetic joint infection: from the Workgroup of the Musculoskeletal Infection Society. Clin Orthop Relat Res. 2011;469(11):2992-4.
  • Donlan RM, Costerton JW. Biofilms: survival mechanisms of clinically relevant microorganisms. Clin Microbiol Rev. 2002;15(2):167-93.
  • Caid M, Valk J, Danoff J. Irrigation solutions in total joint arthroplasty. Spartan Med Res J. 2022;7(2):37502.
  • Hart A, Hernandez NM, Abdel MP, Mabry TM, Hanssen AD, Perry KI. Povidone-iodine wound lavage to prevent infection after revision total hip and knee arthroplasty: an analysis of 2,884 cases. J Bone Joint Surg Am. 2019;101(13):1151-9.
  • Riesgo AM, Park BK, Herrero CP, Yu S, Schwarzkopf R, Iorio R. Vancomycin povidone-iodine protocol improves survivorship of periprosthetic joint infection treated with irrigation and debridement. J Arthroplasty. 2018;33(3):847-50.
  • Byren I, Bejon P, Atkins BL, Angus B, Masters S, McLardy-Smith P, et al. One hundred and twelve infected arthroplasties treated with 'DAIR' (debridement, antibiotics and implant retention): antibiotic duration and outcome. J Antimicrob Chemother. 2009;63(6):1264-71.
  • Kataoka M, Tsumura H, Kaku N, Torisu T. Toxic effects of povidone-iodine on synovial cell and articular cartilage. Clin Rheumatol. 2006;25(5):632-8.
  • von Keudell A, Canseco JA, Gomoll AH. Deleterious effects of diluted povidone-iodine on articular cartilage. J Arthroplasty. 2013;28(6):918-21.
  • Sipahi H, Reis R, Dinc O, Kavaz T, Dimoglo A, Aydın A. In vitro biocompatibility study approaches to evaluate the safety profile of electrolyzed water for skin and eye. Hum Exp Toxicol. 2019;38(11):1314-26.
  • Adam LC, Fabian I, Suzuki K, Gordon G. Hypochlorous acid decomposition in the pH 5-8 region. Inorg Chem. 1992;31(17): 3534-41.
  • Kunutsor SK, Whitehouse MR, Blom AW, Beswick AD; INFORM Team. Re-infection outcomes following one- and two-stage surgical revision of infected hip prosthesis: a systematic review and meta-analysis. PLoS One. 2015;10(9):e0139166.
  • Winkler H, Stoiber A, Kaudela K, Winter F, Menschik F. One stage uncemented revision of infected total hip replacement using cancellous allograft bone impregnated with antibiotics. J Bone Joint Surg Br. 2008;90(12):1580-4.
  • Rudelli S, Uip D, Honda E, Lima AL. One-stage revision of infected total hip arthroplasty with bone graft. J Arthroplasty. 2008;23(8):1165-77.
  • Yoo JJ, Kwon YS, Koo KH, Yoon KS, Kim YM, Kim HJ. One-stage cementless revision arthroplasty for infected hip replacements. Int Orthop. 2009;33(5):1195-201.
  • Klouche S, Leonard P, Zeller V, Lhotellier L, Graff W, Leclerc P, et al. Infected total hip arthroplasty revision: one - or two-stage procedure? Orthop Traumatol Surg Res. 2012;98(2):144-50.
  • Choi HR, Kwon YM, Freiberg AA, Malchau H. Comparison of one-stage revision with antibiotic cement versus two-stage revision results for infected total hip arthroplasty. J Arthroplasty. 2013;28(8):66-70.
  • Hansen E, Tetreault M, Zmistowski B, Della Valle CJ, Parvizi J, Haddad FS, et al. Outcome of one-stage cementless exchange for acute postoperative periprosthetic hip infection. Clin Orthop Relat Res. 2013;471(10):3214-22.
  • Zeller V, Lhotellier L, Marmor S, Leclerc P, Krain A, Graff W, et al. One-stage exchange arthroplasty for chronic periprosthetic hip infection: results of a large prospective cohort study. J Bone Joint Surg Am. 2014;96(1):e1.
  • Masri BA, Panagiotopoulos KP, Greidanus NV, Garbuz DS, Duncan CP. Cementless two-stage exchange arthroplasty for infection after total hip arthroplasty. J Arthroplasty. 2007;22(1):72-8.
  • Biring GS, Kostamo T, Garbuz DS, Masri BA, Duncan CP. Two-stage revision arthroplasty of the hip for infection using an interim articulated Prostalac hip spacer: a 10- to 15-year follow-up study. J Bone Joint Surg Br. 2009;91(11):1431-7.
  • Oussedik SI, Dodd MB, Haddad FS. Outcomes of revision total hip replacement for infection after grading according to a standard protocol. J Bone Joint Surg Br. 2010;92(9):1222-6.
  • Engesæter LB, Dale H, Schrama JC, Hallan G, Lie SA. Surgical procedures in the treatment of 784 infected THAs reported to the Norwegian Arthroplasty Register. Acta Orthop. 2011;82(5):530-7.
  • Ibrahim MS, Raja S, Khan MA, Haddad FS. A multidisciplinary team approach to two-stage revision for the infected hip replacement : A minimum five-year follow-up study. Bone Joint J. 2014;96-B(10):1312-8.
  • Chen SY, Hu CC, Chen CC, Chang YH, Hsieh PH. Two-stage revision arthroplasty for periprosthetic hip infection: mean follow-up of ten years. Biomed Res Int. 2015;2015:345475.

Revizyon Yapılan Enfekte Kalça Artroplastilerinde İntraoperatif Hipokloröz Asit Kullanımı

Year 2023, Volume: 25 Issue: 2, 189 - 194, 30.08.2023
https://doi.org/10.18678/dtfd.1314747

Abstract

Amaç: Artroplasti enfeksiyonları ciddi ve tedavisi güç olan komplikasyonlardır. Hipokloröz asit (hypochlorous acid, HOCl), patojenleri ortadan kaldırmak amacıyla, nötrofiller tarafından aktive edilen inflamatuar sürecin fizyolojik kısmının bir parçası olarak vücutta endojen olarak üretilen bir oksidandır. Bu çalışmanın amacı, cerrahi tedavi sırasında irrigasyon solüsyonu olarak kullanılan HOCl'nin klinik sonuçlar üzerindeki olumlu ve olumsuz etkilerini değerlendirmektir.
Gereç ve Yöntemler: Çalışmaya Ocak 2017 ve Aralık 2021 tarihleri arasında Sağlık Bilimleri Üniversitesi Şişli Hamidiye Etfal Eğitim ve Araştırma Hastanesi Ortopedi ve Travmatoloji kliniğinde tek veya iki aşamalı kalça revizyon cerrahisi geçiren 37 hasta dahil edildi. Tedavi tüm implantlar çıkarıldıktan sonra standart protokolümüze göre 450 cc HOCl ile irrigasyon ve fasya kapatıldıktan sonra subkutan dokuya ek 50 cc HOCl uygulandı. Hastalar takip sırasında enfeksiyonlar açısından değerlendirildi.
Bulgular: 20 hastaya tek aşamalı revizyon cerrahisi uygulanırken, 17 hastaya ise iki aşamalı revizyon cerrahisi uygulandı. Hastaların 17'si (%45,9) erkek ve 20'si (%54,1) kadın olup ortalama yaşları 72,8±11,1 yıl idi. Ortalama takip süresi 25,8±14,1 ay idi. Tek ve iki aşamalı cerrahi uygulanan gruplardan ikisinde de birer hastaya revizyon cerrahisi uygulandı. Hastaların tamamı değerlendirildiğinde %94,6'lık (n=37) bir başarı oranı elde edildi.
Sonuç: HOCl solüsyonunun revizyon kalça artroplastilerinde enfeksiyonların eradikasyonu açısından olumlu katkılarının olduğu ve diğer irrigasyon solüsyonlarına alternatif olarak etkin ve güvenli bir yıkama solüsyonu olabileceğini öngörmekteyiz.

References

  • Tande AJ, Patel R. Prosthetic joint infection. Clin Microbiol Rev. 2014;27(2):302-45.
  • Odum SM, Fehring TK, Lombardi AV, Zmistowski BM, Brown NM, Luna JT, et al. Irrigation and debridement for periprosthetic infections: does the organism matter? J Arthroplasty. 2011;26(6):114-8.
  • Sukeik M, Haddad FS. Periprosthetic joint infections after total hip replacement: an algorithmic approach. SICOT J. 2019;5:5.
  • Ruder JA, Springer BD. Treatment of periprosthetic joint infection using antimicrobials: dilute povidone-iodine lavage. J Bone Jt Infect. 2017;2(1):10-4.
  • van Meurs SJ, Gawlitta D, Heemstra KA, Poolman RW, Vogely HC, Kruyt MC. Selection of an optimal antiseptic solution for intraoperative irrigation: an in vitro study. J Bone Joint Surg Am. 2014;96(4):285-91.
  • Siddiqi A, Abdo ZE, Rossman SR, Kelly MA, Piuzzi NS, Higuera CA, et al. What is the optimal irrigation solution in the management of periprosthetic hip and knee joint infections? J Arthroplasty. 2021;36(10):3570-83.
  • Sakarya S, Gunay N, Karakulak M, Ozturk B, Ertugrul B. Hypochlorous Acid: an ideal wound care agent with powerful microbicidal, antibiofilm, and wound healing potency. Wounds. 2014;26(12):342-50.
  • Kramer A, Dissemond J, Kim S, Willy C, Mayer D, Papke R, et al. Consensus on Wound Antisepsis: Update 2018. Skin Pharmacol Physiol. 2018;31(1):28-58.
  • Day A, Alkhalil A, Carney BC, Hoffman HN, Moffatt LT, Shupp JW. Disruption of biofilms and neutralization of bacteria using hypochlorous acid solution: an in vivo and in vitro evaluation. Adv Skin Wound Care. 2017;30(12):543-51.
  • Wang L, Bassiri M, Najafi R, Najafi K, Yang J, Khosrovi B, et al. Hypochlorous acid as a potential wound care agent: part I. Stabilized hypochlorous acid: a component of the inorganic armamentarium of innate immunity. J Burns Wounds. 2007;6:e5.
  • Clayman E, Beauchamp Z, Troy J. Salvage of infected orthopedic hardware with intraoperative and postoperative hypochlorous acid instillations. Eplasty. 2023;23:e1.
  • Wongkietkachorn A, Surakunprapha P, Wittayapairoch J, Wongkietkachorn N, Wongkietkachorn S. The use of hypochlorous acid lavage to treat infected cavity wounds. Plast Reconstr Surg Glob Open. 2020;8(1):e2604.
  • Bongiovanni CM. Effects of hypochlorous acid solutions on venous leg ulcers (VLU): experience with 1249 VLUs in 897 patients. J Am Coll Clin Wound Spec. 2016;6(3):32-7.
  • Severing AL, Rembe JD, Koester V, Stuermer EK. Safety and efficacy profiles of different commercial sodium hypochlorite/hypochlorous acid solutions (NaClO/HClO): antimicrobial efficacy, cytotoxic impact and physicochemical parameters in vitro. J Antimicrob Chemother. 2019;74(2):365-72.
  • Armstrong DG, Bohn G, Glat P, Kavros SJ, Kirsner R, Snyder R, et al. Expert recommendations for the use of hypochlorous solution: science and clinical application. Ostomy Wound Manage. 2015;61(5):S2-19.
  • Parvizi J, Zmistowski B, Berbari EF, Bauer TW, Springer BD, Della Valle CJ, et al. New definition for periprosthetic joint infection: from the Workgroup of the Musculoskeletal Infection Society. Clin Orthop Relat Res. 2011;469(11):2992-4.
  • Donlan RM, Costerton JW. Biofilms: survival mechanisms of clinically relevant microorganisms. Clin Microbiol Rev. 2002;15(2):167-93.
  • Caid M, Valk J, Danoff J. Irrigation solutions in total joint arthroplasty. Spartan Med Res J. 2022;7(2):37502.
  • Hart A, Hernandez NM, Abdel MP, Mabry TM, Hanssen AD, Perry KI. Povidone-iodine wound lavage to prevent infection after revision total hip and knee arthroplasty: an analysis of 2,884 cases. J Bone Joint Surg Am. 2019;101(13):1151-9.
  • Riesgo AM, Park BK, Herrero CP, Yu S, Schwarzkopf R, Iorio R. Vancomycin povidone-iodine protocol improves survivorship of periprosthetic joint infection treated with irrigation and debridement. J Arthroplasty. 2018;33(3):847-50.
  • Byren I, Bejon P, Atkins BL, Angus B, Masters S, McLardy-Smith P, et al. One hundred and twelve infected arthroplasties treated with 'DAIR' (debridement, antibiotics and implant retention): antibiotic duration and outcome. J Antimicrob Chemother. 2009;63(6):1264-71.
  • Kataoka M, Tsumura H, Kaku N, Torisu T. Toxic effects of povidone-iodine on synovial cell and articular cartilage. Clin Rheumatol. 2006;25(5):632-8.
  • von Keudell A, Canseco JA, Gomoll AH. Deleterious effects of diluted povidone-iodine on articular cartilage. J Arthroplasty. 2013;28(6):918-21.
  • Sipahi H, Reis R, Dinc O, Kavaz T, Dimoglo A, Aydın A. In vitro biocompatibility study approaches to evaluate the safety profile of electrolyzed water for skin and eye. Hum Exp Toxicol. 2019;38(11):1314-26.
  • Adam LC, Fabian I, Suzuki K, Gordon G. Hypochlorous acid decomposition in the pH 5-8 region. Inorg Chem. 1992;31(17): 3534-41.
  • Kunutsor SK, Whitehouse MR, Blom AW, Beswick AD; INFORM Team. Re-infection outcomes following one- and two-stage surgical revision of infected hip prosthesis: a systematic review and meta-analysis. PLoS One. 2015;10(9):e0139166.
  • Winkler H, Stoiber A, Kaudela K, Winter F, Menschik F. One stage uncemented revision of infected total hip replacement using cancellous allograft bone impregnated with antibiotics. J Bone Joint Surg Br. 2008;90(12):1580-4.
  • Rudelli S, Uip D, Honda E, Lima AL. One-stage revision of infected total hip arthroplasty with bone graft. J Arthroplasty. 2008;23(8):1165-77.
  • Yoo JJ, Kwon YS, Koo KH, Yoon KS, Kim YM, Kim HJ. One-stage cementless revision arthroplasty for infected hip replacements. Int Orthop. 2009;33(5):1195-201.
  • Klouche S, Leonard P, Zeller V, Lhotellier L, Graff W, Leclerc P, et al. Infected total hip arthroplasty revision: one - or two-stage procedure? Orthop Traumatol Surg Res. 2012;98(2):144-50.
  • Choi HR, Kwon YM, Freiberg AA, Malchau H. Comparison of one-stage revision with antibiotic cement versus two-stage revision results for infected total hip arthroplasty. J Arthroplasty. 2013;28(8):66-70.
  • Hansen E, Tetreault M, Zmistowski B, Della Valle CJ, Parvizi J, Haddad FS, et al. Outcome of one-stage cementless exchange for acute postoperative periprosthetic hip infection. Clin Orthop Relat Res. 2013;471(10):3214-22.
  • Zeller V, Lhotellier L, Marmor S, Leclerc P, Krain A, Graff W, et al. One-stage exchange arthroplasty for chronic periprosthetic hip infection: results of a large prospective cohort study. J Bone Joint Surg Am. 2014;96(1):e1.
  • Masri BA, Panagiotopoulos KP, Greidanus NV, Garbuz DS, Duncan CP. Cementless two-stage exchange arthroplasty for infection after total hip arthroplasty. J Arthroplasty. 2007;22(1):72-8.
  • Biring GS, Kostamo T, Garbuz DS, Masri BA, Duncan CP. Two-stage revision arthroplasty of the hip for infection using an interim articulated Prostalac hip spacer: a 10- to 15-year follow-up study. J Bone Joint Surg Br. 2009;91(11):1431-7.
  • Oussedik SI, Dodd MB, Haddad FS. Outcomes of revision total hip replacement for infection after grading according to a standard protocol. J Bone Joint Surg Br. 2010;92(9):1222-6.
  • Engesæter LB, Dale H, Schrama JC, Hallan G, Lie SA. Surgical procedures in the treatment of 784 infected THAs reported to the Norwegian Arthroplasty Register. Acta Orthop. 2011;82(5):530-7.
  • Ibrahim MS, Raja S, Khan MA, Haddad FS. A multidisciplinary team approach to two-stage revision for the infected hip replacement : A minimum five-year follow-up study. Bone Joint J. 2014;96-B(10):1312-8.
  • Chen SY, Hu CC, Chen CC, Chang YH, Hsieh PH. Two-stage revision arthroplasty for periprosthetic hip infection: mean follow-up of ten years. Biomed Res Int. 2015;2015:345475.
There are 39 citations in total.

Details

Primary Language English
Subjects Orthopaedics
Journal Section Research Article
Authors

Muharrem Kanar 0000-0003-1035-9183

Necmi Cam 0000-0001-7101-3106

Enver İpek 0000-0001-6205-1207

Hacı Mustafa Özdemir 0000-0001-6189-3605

Early Pub Date August 17, 2023
Publication Date August 30, 2023
Submission Date June 17, 2023
Published in Issue Year 2023 Volume: 25 Issue: 2

Cite

APA Kanar, M., Cam, N., İpek, E., Özdemir, H. M. (2023). The Intraoperative Use of Hypochlorous Acid in Infected Hip Arthroplasty Revision Surgery. Duzce Medical Journal, 25(2), 189-194. https://doi.org/10.18678/dtfd.1314747
AMA Kanar M, Cam N, İpek E, Özdemir HM. The Intraoperative Use of Hypochlorous Acid in Infected Hip Arthroplasty Revision Surgery. Duzce Med J. August 2023;25(2):189-194. doi:10.18678/dtfd.1314747
Chicago Kanar, Muharrem, Necmi Cam, Enver İpek, and Hacı Mustafa Özdemir. “The Intraoperative Use of Hypochlorous Acid in Infected Hip Arthroplasty Revision Surgery”. Duzce Medical Journal 25, no. 2 (August 2023): 189-94. https://doi.org/10.18678/dtfd.1314747.
EndNote Kanar M, Cam N, İpek E, Özdemir HM (August 1, 2023) The Intraoperative Use of Hypochlorous Acid in Infected Hip Arthroplasty Revision Surgery. Duzce Medical Journal 25 2 189–194.
IEEE M. Kanar, N. Cam, E. İpek, and H. M. Özdemir, “The Intraoperative Use of Hypochlorous Acid in Infected Hip Arthroplasty Revision Surgery”, Duzce Med J, vol. 25, no. 2, pp. 189–194, 2023, doi: 10.18678/dtfd.1314747.
ISNAD Kanar, Muharrem et al. “The Intraoperative Use of Hypochlorous Acid in Infected Hip Arthroplasty Revision Surgery”. Duzce Medical Journal 25/2 (August 2023), 189-194. https://doi.org/10.18678/dtfd.1314747.
JAMA Kanar M, Cam N, İpek E, Özdemir HM. The Intraoperative Use of Hypochlorous Acid in Infected Hip Arthroplasty Revision Surgery. Duzce Med J. 2023;25:189–194.
MLA Kanar, Muharrem et al. “The Intraoperative Use of Hypochlorous Acid in Infected Hip Arthroplasty Revision Surgery”. Duzce Medical Journal, vol. 25, no. 2, 2023, pp. 189-94, doi:10.18678/dtfd.1314747.
Vancouver Kanar M, Cam N, İpek E, Özdemir HM. The Intraoperative Use of Hypochlorous Acid in Infected Hip Arthroplasty Revision Surgery. Duzce Med J. 2023;25(2):189-94.