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1 파라쿼트중독환자에서 deferoxamine 의치료효과 인제대학교의과대학내과학교실 1, 울산대학교의과대학내과학교실 2, 울산대학교의과대학서울아산병원호흡기내과 3 허진원 1, 제갈양진 2, 홍상범 3, 오연목 3, 심태선 3, 임채만 3, 이상도 3, 김우성 3, 김동순 3, 김원동 3, 고윤석 3 Efficacy of deferoxamine on paraquat poisoning Jin Won Huh, M.D. 1, Yangjin Jegal, M.D. 2, Sang-Bum Hong, M.D. 3, Yeon Mok Oh, M.D. 3, Tae Sun Shim, M.D. 3, Chae-Man Lim, M.D. 3, Sang Do Lee, M.D. 3, Woo Sung Kim, M.D. 3, Dong Soon Kim, M.D. 3, Won Dong Kim, M.D. 3, Younsuck Koh, M.D. 3. Department of Internal Medicine Inje University 1, Department of Internal Medicine University of Ulsan 2, Division of Pulmonary and Critical Care Medicine, Asan Medical Center University of Ulsan College of Medicine 3, Seoul, Korea Background: Paraquat is known to induce oxidant injury that results in multiorgan failure and lung fibrosis. Iron has been considered to play a key role in paraquat-induced oxidant lung injury. This study examined the effect of deferoxamine, an iron-chelating agent, in the treatment of paraquat poisoning. Methods: From September, 2001 to April, 2005, 28 patients with paraquat poisoning who were admitted at a medical intensive care unit of a University-affiliated hospital, were enrolled in this study. Sixteen patients were treated according to the paraquat poisoning treatment guidelines and 12 received an intravenous infusion of deferoxamine in addition to the treatment guidelines. Results: There were no differences between the two groups in terms of age, gender, severity of paraquat poisoning, and the time elapsed from ingestion to presentation at hospital. There was no difference in overall mortality between the two groups but the incidence of respiratory failure in the deferoxamine group was higher than in the conventional group(4/7 versus 0/9, p=0.019). Conclusion: Deferoxamine seems to have no clinical benefit compared with the conventional treatment. (Tuberc Respir Dis 2007; 62: ) Key words: Paraquat, Deferoxamine, Mortality. 서 우리나라에서최근의파라쿼트중독은자살을목적으로한경우가대부분으로매년사망률은대개 40-50% 정도로추정되고있다 1. 급성파라쿼트중독은심한전신성조직파괴와동반된쇽으로 시간내에사망하거나, 수일내에신장, 간장, 심장, 중추신경계, 부신, 골격근, 비장등을손상시키는다발성장기부전으로사망한다. 파라쿼트는복용후 시간이내에폐부종, 폐출혈, 울혈이발생하고이후폐섬유증으로진행된다. 론 Address for correspondence: Younsuck Koh, M.D. Division of Pulmonary & Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine Pungnap Dong, Songpa Ku, Seoul, , Korea Phone: Fax: yskoh@amc.seoul.kr Received: Oct Accepted: Jan 년초반에는위세척과흡수된파라쿼트의배설을촉진시키기위해생리식염수와만니톨을이용한강제이뇨, 혈액투석및폐섬유화를완화시킬목적으로스테로이드등을사용하였으나환자의생존율을개선시키지는못하였다 2-5. 하지만파라쿼트에의한폐손상을차단하기위해항산화제와면역억제요법이효과가있다는몇몇보고가있은후 N-acetylcysteine, cyclophosphamide, dexamethasone 등이이들환자에게사용되고있으며중독정도에따라생존율이 30-70% 까지다양하게보고되고있다 파라쿼트중독의주요기전이철이나구리와같은자유금속이온 (free metal ions) 을매개로하여과산화물이온 (superoxide ion) 과같은자유산소유리기 (free radical) 의생성으로인한세포손상임이알려지면서철킬레이트제제 (iron chelating agent) 인 deferoxamine이치료효과가있을것으로추정되었다. 동물실험에서 deferoxamine 을파라쿼트중독전이나직후에주입시생존율의증가를보였으나사람을대상으로는증례보고 113

2 JW Huh et al: Efficacy of deferoxamine treatment for paraquat poisoning 만있었다 이에본연구는파라쿼트중독환자의초기시점에서투여한 deferoxamine의치료효과를알아보고자시행되었다. 대상및방법 1. 대상환자의선택 2001년 10월부터 2005년 4월까지 37명의환자가사고나자살목적으로파라쿼트를섭취하여한대학병원내과계중환자실로입원하였고이들중섭취후 24 시간내에도착하여연구에동의한 28명이대상환자가되었다. 파라쿼트중독은환자가마신병을확인하였거나혈액에서파라쿼트의농도측정이나소변이 sodium dithionite test에양성인경우에만진단하였다. 대상환자들은무작위표를이용하여 deferoxamine 사용군 12명, 비사용군 16명으로분류되었다. 2. 치료프로토콜 모든환자들은동일한프로토콜 (Table 1) 에따라서치료가시행되었다. 간단히설명하면초기위세척시행후위장관에서의파라쿼트의흡수를막기위해활성탄 (active charcoal) 이나 Fuller s earth를투여하였으며파라쿼트중독후 24시간내에내원한경우혈관류 (hemoperfusion) 를시행하였다. 초기이뇨후에폐손상을억제하기위해 cyclophosphamide, dexamethasone, N-acetylcysteine 을투여하였다. Deferoxamine의사용은환자나보호자에게동의서를받은후첫 24시간에걸쳐100 mg/kg를정주하였다 11. 본연구는서울아산병원윤리위원회의승인후에시행되었다. 3. 대상환자들의임상자료획득입원당시의대상환자들의혈색소. 동맥혈가스, 간기능, 신기능을측정하였고가장악화시의간기능, 신기능을측정하였다. 그외에중증도 (APACHE II score), 중환자실재원일수, 병원재원일수, 사망여부를측정하였다. 4. 장기부전의정의장기부전의정의는 Brussels 표를이용하여평가하였다 (Appendix 1). Brussels 표에서는장기부전을 moderate, severe, extreme으로분류하였지만여기서는하나의카테고리로묶어서분석하였다. 5. 통계값분석모든데이터의분석은 SPSS version 11.0 (Chicago, IL) 을이용하였고모든통계값은중앙값 ( 최소값, 최대값 ) 으로표기하였다. 두군사이의통계값비교는연속변수는 Mann-Whitney test, categorical data는 Fisher's exact test를이용하였다. p value Table 1. AMC paraquat intoxication treatment protocol Diuresis Decontamination Protection of lung injury Mechanism 8 hr 2 wks 1 month 0.9 % NaCl Gastric lavage Activated charcoal Pd : prednisolone, NO : nitric oxide, PFR * : PaO 2/FiO 2 Initial hydration 200 cc/hr (urine output 50 cc/hr) 5-10 L Initial: 1g/kg, Repeat dose: 0.5g/kg Hypooxygenation Target : SaO % Cyclophophamide 15 mg/kg pulse therapy for 2 days Dexamethasone (I.V P.O) 10 mg q 12 h Pd 60 mg/d N-acetylcysteine 150 mg/kg/d NO inhalation If PFR *

3 Tuberculosis and Respiratory Diseases Vol. 62. No.2, Feb Table 2. Initial clinical characteristics of patients at admission depending on deferoxamine therapy Deferoxamine group (n=12) Conventional group (n=16) P-value Sex, M/F (n) 9/3 10/ Age, yrs 44.5 (22-67) 51.5 (17-83) Alcohol intake 7/12 (58.3%) 4/16 (25.0%) Intentional ingestion 11/12 (91.7%) 11/16 (68.8%) Time elapsed from ingestion to arrival at hospital, hr 4.0 (1-20) 6.5 ( ) Estimated average amount ingested, gm 12.3 ( ) 6.1 ( ) Hospital stay, day 3 (0-29) 2.5 (1-11) Hypoxia 6/12 (50%) 3/16 (16.8%) MOF, n 3 (0-4) 1 (0-5) APACHE II score 9.5 (2-20) 9.0 (0-34) Mortality 9/12 (75%) 7/16 (43.8%) MOF : multiple organ falune Table 3. Laboratory data of patients at the initial and the worst time. Deferoxamine group (n=12) Conventional group (n=16) P-value ABGA at admission (on room air) ph 7.37 ( ) 7.41 ( ) PaCO 2, mm Hg 33.7 ( ) 22.1 ( ) PaO 2, mm Hg 87.9 ( ) 106 ( ) HCO 3 mm Eq/L 17.8 ( ) 11.2 (11-23) Laboratory data Initial AST, IU/L 37 (29-49) 30 (28-182) ALT, IU/L 26 (15-34) 19 (19-71) BUN, mg/dl 18 (9-37) 22 (13-23) Creatinine, mg/dl 1.3 ( ) 1.1 ( ) Peak Worst AST, IU/L 147 (48-884) 49 (31-227) ALT, IU/L 150 ( ) 139 ( ) BUN, mg/dl 63.5 (23-77) 48 (43-57) Creatinine, mg/dl 5.1 ( ) 3.4 ( ) <0.05을의미있는차이로간주하였다. 생존곡선은 Kaplan Meier method 를이용하였고 log-rank test를이용하여두값을비교하였다. 결과 1. 대상군들의특징연구에포함된 28명의환자중 16명은기존의프로 토콜대로치료하였고 12명이 deferoxamine 을첫 24 시간동안추가로사용하였다. 두군간의성별, 나이의차이는없었고 deferoxamine 군에서자살목적으로술과같이파라쿼트를섭취한경향이높았다 (Table 2). 파라쿼트섭취후병원에도착하여응급치료를받기까지시간은평균 6시간이었고, deferoxamine군에서내원당시장기부전의개수나재원일수가긴경향을보였으며특히저산소증이 deferoxamine 군에서심한경향을보였다 (P=0.09). 입원 3일째 deferoxamine 115

4 JW Huh et al: Efficacy of deferoxamine treatment for paraquat poisoning Table 4. Clinical characteristics of nonsurvivors between the two groups Deferoxamine group (n=9) Conventional group (n=7) P-value Sex, M/F (n) 7/2 4/ Age, yrs 45 (22-67) 56 (34-83) Alcohol intake 6/9 (66.7%) 1/7 (14.3%) Intentional ingestion 8/9 (88.9%) 7/7 (100%) Time elapsed from ingestion to arrival at hospital, hr 4.0 (1-17) 7.0 ( ) Estimated average amount ingested, gm 12.3 ( ) 24.5 ( ) Hypoxia 6/9 (66.7%) 2/7 (28.6%) Ventilator support 8/9 (88.9%) 3/7 (42.9%) MOF, n 4.0 (2-4) 2 (1-5) APACHE II score 11.0 (3-20) 18.0 (12-34) Mortality within 48 hours 5/9 (55.6%) 7/7 (100%) MOF : multiple organ failune 군중 2명에서대기중동맥혈산소분압 (PaO 2 ) 이 60 mmhg 이하의저산소증이관찰되었다. 두군모두섭취후 3-4일경에간기능과신기능의상승이가장높았고 deferoxamine군에서가장악화시의 creatinine과 alanine transferase (ALT) 가높은경향을보였다. 2. Deferoxamine 의치료효과전체환자 28명중 12명이생존하여전체사망률은 57.1% 이었고이중 48 시간이내에쇽과대사성산증으로사망한환자가 12명으로사망환자의대부분 (75%) 을차지하였다. Deferoxamine 치료군의경우 9 명 (75%) 이사망하였고이중 5명이 48시간이내쇽으로사망하였고 4명이호흡부전과동반된다발성장기부전으로사망하였다. 대조군의경우 7명 (43.8%) 이사망하였고이들모두 48시간내에대사성산증과쇽으로사망하였다. 두군간의사망률은통계학적으로유의한차이는보이지않았지만 48시간이후의사망은 deferoxamine 군에서만관찰되었다 (57.1% vs. 0%, p=0.019). 사망군만비교시 deferoxamine 군에서알코올과같이섭취한빈도가높았고 (P=0.03), 중증도는낮았지만저산소증으로인한기계환기의빈도는높았다 (Table 4). 고찰본연구는파라쿼트의중독시폐손상의주된기전으로알려진자유산소기의생성을억제하는철킬레이트제제인 deferoxamine의치료효과를보고자시행되었다. 대상환자군의수가적고환자간의파라쿼트섭취량이나치료시작시간의차이는있었으나 deferoxamine의치료시생존율의호전을보이지는않았다. 파라쿼트중독시섭취농도가가장중요한사망결정인자로 20% 그라목손을 ml (3-4 gm) 이상만섭취해도폐섬유화를유발할수있고과량섭취시쇽과급성호흡부전으로사망한다 16. 그외에도구토여부, 초기치료, 전반적인환자의상태, 치료법등이예후에영향을미칠수있다 17. 또한장기적인예후평가에고해상전산단층촬영 (HRCT) 을이용한추적검사를통한폐손상의양상과범위의변화가중요한역할을한다 18. 몇몇연구에서파라쿼트중독후폐섬유화의치료에고용량의 cyclophosphamide와 dexamethasone이효과적이다는보고후 6-9 현재는항산화제, 면역억제제등이치료의기본을이루고있으나 19 그치료법이정립되지않았다. 파라쿼트에의해유발되는산화스트레스에철이나구리같은자유금속이온 (free metal 116

5 Tuberculosis and Respiratory Diseases Vol. 62. No.2, Feb ions) 들이중요한역할을하는것으로알려지면서효과적인철킬레이트제제인 deferoxamine이파라쿼트중독의치료제로서의가능성이주목을받고있다. 동물실험에서파라쿼트중독전, 직후에 deferoxamine 주입시생존율의증가를보였고, 철을주입후생존기간이짧다는것이보고되었다 20. 사람의경우는중증파라쿼트중독시 deferoxamine이치료에효과적이었다는증례보고가있었다 11. 하지만고용량의 deferoxamine 을장기간사용시오히려산화스트레스가증가된상태에서세포독성이증가되고 21 철중독에 deferoxamine 사용시호흡부전을유발한다는보고도있다 22,23. 본연구에서는이전의증례보고에서사용된저용량의 deferoxamine (100 mg/kg 처음 24 h) 을사용했으나생존율의차이는없었고오히려호흡부전의빈도가증가하는경향을보였다. 가능한원인들로는첫째, 환자군의분류당시 deferoxamine 치료군에서대상환자수가적어통계학적유의성은없었으나자살목적으로인한파라쿼트를섭취한경우가많아섭취량도대조군에비해평균 2배이었다. 또한알코올의동반섭취정도, 초기장기부전의수가많아비록환자를무작위표에따라분류하였으나 deferoxamine군환자들의중증도가더높았을가능성이크다. 이는입원시점에서저산소증의발생빈도가 deferoxamine군이 50%, 대조군이 16.8% 인점에서도반영이되었다. 둘째, 투여한 deferoxamine이폐실질내에충분히분포하지않았거나용량이적어 chelator로써의역할을충분히하지못했을가능성도있다. 또한파라쿼트와 deferoxamine의상호작용에의해자유라디칼에의한다장기손상을더진행시켰을가능성도추정할수있다. Deferoxamine 과유사한친수성환원제인아스코르빈산의경우에도파라쿼트의독성을증가시킬수있어파라쿼트중독환자에서는사용이추천되지않는것을 고려시생체내에서이런환원제와파라쿼트와의작용을예측하기힘들다. 이상의결과로서중증도에따른무작위분류가정확히되지않았다는제한점에도불구하고파라쿼트중독시본연구에서적용된용량과기간의 deferoxamine 은치료효과가없을것으로추정되었다. 요 연구배경 : 파라쿼트중독은다발성장기부전과폐섬유화를유발하여높은사망률을초래한다. 폐섬유화의약화를위해여러종류의면역억제제가사용되었으나그치료효과는다양하다. 철은파라쿼트로유발된산화스트레스에의한폐손상에중요한역할은한다. 본연구는파라쿼트중독의치료시철킬레이트제제인 deferoxamine의효과를보고자시행되었다. 방법 : 2001년 10월부터 2005년 4월까지파라쿼트중독으로내과계중환자실에입원한 37명중 28명이본연구에포함되었다. 환자들은서울아산병원의파라쿼트치료프로토콜에따라서치료되었다. 이중 12 명이추가로 deferoxamine 투여군으로무작위분류되었다. 결과 : 두군간의성별, 나이, 파라쿼트중독의정도, 섭취후병원까지의도착시간등은유의한차이를보이지않았다. 파라쿼트섭취후간기능과신기능의변화도유의한차이를보이지않았다. 전체사망률은두군간의차이는없었으나 deferoxamine 투여군에서대조군과비교시호흡부전의빈도가높았다 (4/7 versus 0/9, p=0.019). 결론 : 파라쿼트중독시본연구에서적용된용량과기간의 deferoxamine (100mg/kg during 24 h) 은치료효과가없을것으로사료된다. 약 참고문헌 1. Hwang KY, Lee EY, Hong SY. Paraquat intoxication in Korea. Arch Environ Health 2002;57: Suzuki K, Takasu N, Okabe T, Ishimatsu S, Ueda A, Tanaka S, et al. Effect of aggressive haemoperfusion on the clinical course of patients with paraquat poisoning. Hum Exp Toxicol 1993;12: Koo JR, Kim JC, Yoon JW, Kim GH, Jeon RW, Kim HJ, et al. Failure of continuous venovenous hemofiltration to prevent death in paraquat poisoning. Am J Kidney Dis 2002;39: Fock KM. Clinical features and prognosis of paraquat poisoning: a review of 27 cases. Singapore Med J 1987;28:

6 JW Huh et al: Efficacy of deferoxamine treatment for paraquat poisoning 5. Suzuki K, Takasu N, Arita S, Maenosono A, Ishimatsu S, Nishina M, et al. A new method for predicting the outcome and survival period in paraquat poisoning. Hum Toxicol 1989;8: Addo E, Ramdial S, Poon-King T. High dosage cyclophosphamide and dexamethasone treatment of paraquat poisoning with 75% survival. West Indian Med J 1984;33: Addo E, Poon-King T. Leucocyte suppression in treatment of 72 patients with paraquat poisoning. Lancet 1986;1: Perriens JH, Benimadho S, Kiauw IL, Wisse J, Chee H. High-dose cyclophosphamide and dexamethasone in paraquat poisoning: a prospective study. Hum Exp Toxicol 1992;11: Lin JL, Wei MC, Liu YC. Pulse therapy with cyclophosphamide and methylprednisolone in patients with moderate to severe paraquat poisoning: a preliminary report. Thorax 1996;51: Lin JL, Leu ML, Liu YC, Chen GH. A prospective clinical trial of pulse therapy with glucocorticoid and cyclophosphamide in moderate to severe paraquatpoisoned patients. Am J Respir Crit Care Med 1999;159: Lheureux P, Leduc D, Vanbinst R, Askenasi R. Survival in a case of massive paraquat ingestion. Chest 1995;107: Hershko C, Weatherall DJ. Iron-chelating therapy. Crit Rev Clin Lab Sci 1988;26: van Asbeck BS, Hillen FC, Boonen HC, de Jong Y, Dormans JA, van der Wal NA, et al. Continuous intravenous infusion of deferoxamine reduces mortality by paraquat in vitamin E-deficient rats. Am Rev Respir Dis 1989;139: van der Wal NA, van Oirschot JF, van Dijk A, Verhoef J, van Asbeck BS. Mechanism of protection of alveolar type II cells against paraquat-induced cytotoxicity by deferoxamine. Biochem Pharmacol 1990;39: van der Wal NA, Smith LL, van Oirschot JF, van Asbeck BS. Effect of iron chelators on paraquat toxicity in rats and alveolar type II cells. Am Rev Respir Dis 1992;145: Proudfoot AT, Stewart MS, Levitt T, Widdop B. Paraquat poisoning: significance of plasma-paraquat concentrations. Lancet 1979;2: Tsatsakis AM, Perakis K, Koumantakis E. Experience with acute paraquat poisoning in Crete. Vet Hum Toxicol 1996;38: Huh JW, Hong SB, Lim CM, Do KH, Lee JS, Koh Y. Sequential radiologic and functional pulmonary changes in patients with paraquat intoxication. Int J Occup Environ Health 2006;12: Hong SY, Yang DH, Hwang KY. Associations between laboratory parameters and outcome of paraquat poisoning. Toxicol Lett 2000;118: Kohen R, Chevion M. Paraquat toxicity is enhanced by iron and reduced by desferrioxamine in laboratory mice. Biochem Pharmacol 1985;34: Poot M, Rabinovitch PS, Hoehn H. Free radical mediated cytotoxicity of desferrioxamine. Free Radic Res Commun 1989;6: Osheroff MR, Schaich KM, Drew RT, Borg DC. Failure of desferrioxamine to modify the toxicity of paraquat in rats. J Free Radic Biol Med 1985;1: Tenenbein M, Kowalski S, Sienko A, Bowden DH, Adamson IY. Pulmonary toxic effects of continuous desferrioxamine administration in acute iron poisoning. Lancet 1992;339: Buettner GR, Jurkiewicz BA. Catalytic metals, ascorbate and free radicals: combinations to avoid. Radiat Res 1996;145: Carr A, Frei B. Does vitamin C act as a pro-oxidant under physiological conditions? FASEB J 1999;13: Kang SA, Jang YJ, Park H. In vivo dual effects of vitamin C on paraquat-induced lung damage: dependence on released metals from the damaged tissue. Free Radic Res 1998;28: Appendix 1. Brussels table of organ dysfunction Cardiovascular (systolic BP, mm Hg) Clinically Significant Organ Dysfunction Organs Moderate Severe Extreme 90 Not fluid response 90 ph ph 7.2 Pulmonary (PaO 2/FiO 2) CNS (Glasgow Coma Score) Coagulation (platelets, thousands/mm 3 ) Renal (creatinine, mg/dl) Hepatic (bilirubin, mg/dl)

012임수진

012임수진 Received : 2012. 11. 27 Reviewed : 2012. 12. 10 Accepted : 2012. 12. 12 A Clinical Study on Effect of Electro-acupuncture Treatment for Low Back Pain and Radicular Pain in Patients Diagnosed with Lumbar