Identification of the enzyme responsible for oxidative halothane metabolism: implications for prevention of halothane hepatitis
Summary Background Fulminant hepatic necrosis ("halothane hepatitis") is an unusual and often fatal complication of halothane anaesthesia. It is mediated by immune sensitisation in susceptible individuals to trifluoroacetylated liver protein neoantigens, formed by oxidative halothane metab...
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| Veröffentlicht in: | The Lancet (British edition) 1996-05, Vol.347 (9012), p.1367-1371 |
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| creator | Kharasch, E.D. Hankins, D. Mautz, D. Kharasch, E.D. Thummel, K.E. |
| description | Summary
Background Fulminant hepatic necrosis ("halothane hepatitis") is an unusual and often fatal complication of halothane anaesthesia. It is mediated by immune sensitisation in susceptible individuals to trifluoroacetylated liver protein neoantigens, formed by oxidative halothane metabolism. The seminal event in halothane hepatitis is hepatic metabolism, yet the enzyme responsible for oxidative halothane metabolism and trifluoroacetylated neoantigen formation remains unidentified. This investigation tested the hypothesis that cytochrome P450 2E1 (CYP2E1) is responsible for human halothane metabolism in vivo.
Methods 20 elective surgical patients received either disulfiram (500 mg orally, n=10) or nothing (controls, n=10) the night before surgery. Disulfiram, converted in vivo to an effective inhibitor of P450 2E1, was used as a metabolic probe for P450 2E1. All patients received standard halothane anaesthesia (1·0% end-tidal, 3 h). Blood halothane and plasma and urine trifluoroacetic acid, bromide, and fluoride concentrations were measured for up to 96 h postoperatively.
Findings Total halothane dose, measured by cumulative end-tidal (3·8 SE 0·1 minimum alveolar concentration hours) and blood halothane concentrations, was similar in the two groups. Plasma concentrations and urinary excretion of trifluoroacetic acid and bromide, indicative of oxidative and total (oxidative and reductive) halothane metabolism, respectively, were significantly diminished in disulfiram-treated patients. In control and disulfiram-treated patients cumulative 96 h postoperative trifluoroacetic acid excretion was 12 900 (SE 1700) and 2010 (440) μmol, respectively (p |
| doi_str_mv | 10.1016/S0140-6736(96)91011-9 |
| format | Article |
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Background Fulminant hepatic necrosis ("halothane hepatitis") is an unusual and often fatal complication of halothane anaesthesia. It is mediated by immune sensitisation in susceptible individuals to trifluoroacetylated liver protein neoantigens, formed by oxidative halothane metabolism. The seminal event in halothane hepatitis is hepatic metabolism, yet the enzyme responsible for oxidative halothane metabolism and trifluoroacetylated neoantigen formation remains unidentified. This investigation tested the hypothesis that cytochrome P450 2E1 (CYP2E1) is responsible for human halothane metabolism in vivo.
Methods 20 elective surgical patients received either disulfiram (500 mg orally, n=10) or nothing (controls, n=10) the night before surgery. Disulfiram, converted in vivo to an effective inhibitor of P450 2E1, was used as a metabolic probe for P450 2E1. All patients received standard halothane anaesthesia (1·0% end-tidal, 3 h). Blood halothane and plasma and urine trifluoroacetic acid, bromide, and fluoride concentrations were measured for up to 96 h postoperatively.
Findings Total halothane dose, measured by cumulative end-tidal (3·8 SE 0·1 minimum alveolar concentration hours) and blood halothane concentrations, was similar in the two groups. Plasma concentrations and urinary excretion of trifluoroacetic acid and bromide, indicative of oxidative and total (oxidative and reductive) halothane metabolism, respectively, were significantly diminished in disulfiram-treated patients. In control and disulfiram-treated patients cumulative 96 h postoperative trifluoroacetic acid excretion was 12 900 (SE 1700) and 2010 (440) μmol, respectively (p<0·001) while that of bromide was 1720 (290) and 160 (70) μmol (p<0·001).
Interpretation The substantial attenuation of trifluoroacetic acid production by disulfiram after halothane anaesthesia suggests that P450 2E1 is a predominant enzyme responsible for human oxidative halothane metabolism. Inhibition of P450 2E1 by a single preoperative oral disulfiram dose greatly diminished production of the halothane metabolite responsible for the neoantigen formation that initiates halothane hepatitis. Single-dose disulfiram may provide effective prophylaxis against halothane hepatitis.</description><identifier>ISSN: 0140-6736</identifier><identifier>EISSN: 1474-547X</identifier><identifier>DOI: 10.1016/S0140-6736(96)91011-9</identifier><identifier>PMID: 8637342</identifier><identifier>CODEN: LANCAO</identifier><language>eng</language><publisher>London: Elsevier Ltd</publisher><subject>Acid production ; Acids ; Adult ; Alanine Transaminase - blood ; Alveoli ; Anesthesia ; Attenuation ; Biological and medical sciences ; Blood ; Blood levels ; Cytochrome P-450 CYP2E1 ; Cytochrome P-450 Enzyme Inhibitors ; Cytochrome P-450 Enzyme System - metabolism ; Cytochrome P450 ; Cytochromes P450 ; Disulfiram ; Disulfiram - pharmacology ; Disulfiram - therapeutic use ; Drug toxicity and drugs side effects treatment ; Enzymes ; Excretion ; Fluorides ; Halothane ; Halothane - adverse effects ; Halothane - metabolism ; Hepatic Encephalopathy - chemically induced ; Hepatic Encephalopathy - enzymology ; Hepatic Encephalopathy - prevention & control ; Hepatitis ; Human behavior ; Humans ; In vivo methods and tests ; Liver ; Male ; Medical sciences ; Metabolism ; Metabolites ; Necrosis ; Neoantigens ; Oxidative metabolism ; Oxidoreductases, N-Demethylating - antagonists & inhibitors ; Oxidoreductases, N-Demethylating - metabolism ; Patients ; Pharmacology. Drug treatments ; Preoperative Care ; Prophylaxis ; Protein turnover ; Proteins ; Surgery ; Toxicity: digestive system ; Trifluoroacetic acid ; Trifluoroacetic Acid - blood ; Trifluoroacetic Acid - urine ; Urine</subject><ispartof>The Lancet (British edition), 1996-05, Vol.347 (9012), p.1367-1371</ispartof><rights>1996</rights><rights>1996 INIST-CNRS</rights><rights>Copyright Elsevier Limited May 18, 1996</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c611t-a5dbc38060d6b22d78abc402cf59ef4966681f88fab48d538276db3ad69db2043</citedby><cites>FETCH-LOGICAL-c611t-a5dbc38060d6b22d78abc402cf59ef4966681f88fab48d538276db3ad69db2043</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.proquest.com/docview/2155866812?pq-origsite=primo$$EHTML$$P50$$Gproquest$$H</linktohtml><link.rule.ids>314,780,784,3548,27922,27923,45993,64383,64387,72239</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=3080566$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/8637342$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kharasch, E.D.</creatorcontrib><creatorcontrib>Hankins, D.</creatorcontrib><creatorcontrib>Mautz, D.</creatorcontrib><creatorcontrib>Kharasch, E.D.</creatorcontrib><creatorcontrib>Thummel, K.E.</creatorcontrib><title>Identification of the enzyme responsible for oxidative halothane metabolism: implications for prevention of halothane hepatitis</title><title>The Lancet (British edition)</title><addtitle>Lancet</addtitle><description>Summary
Background Fulminant hepatic necrosis ("halothane hepatitis") is an unusual and often fatal complication of halothane anaesthesia. It is mediated by immune sensitisation in susceptible individuals to trifluoroacetylated liver protein neoantigens, formed by oxidative halothane metabolism. The seminal event in halothane hepatitis is hepatic metabolism, yet the enzyme responsible for oxidative halothane metabolism and trifluoroacetylated neoantigen formation remains unidentified. This investigation tested the hypothesis that cytochrome P450 2E1 (CYP2E1) is responsible for human halothane metabolism in vivo.
Methods 20 elective surgical patients received either disulfiram (500 mg orally, n=10) or nothing (controls, n=10) the night before surgery. Disulfiram, converted in vivo to an effective inhibitor of P450 2E1, was used as a metabolic probe for P450 2E1. All patients received standard halothane anaesthesia (1·0% end-tidal, 3 h). Blood halothane and plasma and urine trifluoroacetic acid, bromide, and fluoride concentrations were measured for up to 96 h postoperatively.
Findings Total halothane dose, measured by cumulative end-tidal (3·8 SE 0·1 minimum alveolar concentration hours) and blood halothane concentrations, was similar in the two groups. Plasma concentrations and urinary excretion of trifluoroacetic acid and bromide, indicative of oxidative and total (oxidative and reductive) halothane metabolism, respectively, were significantly diminished in disulfiram-treated patients. In control and disulfiram-treated patients cumulative 96 h postoperative trifluoroacetic acid excretion was 12 900 (SE 1700) and 2010 (440) μmol, respectively (p<0·001) while that of bromide was 1720 (290) and 160 (70) μmol (p<0·001).
Interpretation The substantial attenuation of trifluoroacetic acid production by disulfiram after halothane anaesthesia suggests that P450 2E1 is a predominant enzyme responsible for human oxidative halothane metabolism. Inhibition of P450 2E1 by a single preoperative oral disulfiram dose greatly diminished production of the halothane metabolite responsible for the neoantigen formation that initiates halothane hepatitis. Single-dose disulfiram may provide effective prophylaxis against halothane hepatitis.</description><subject>Acid production</subject><subject>Acids</subject><subject>Adult</subject><subject>Alanine Transaminase - blood</subject><subject>Alveoli</subject><subject>Anesthesia</subject><subject>Attenuation</subject><subject>Biological and medical sciences</subject><subject>Blood</subject><subject>Blood levels</subject><subject>Cytochrome P-450 CYP2E1</subject><subject>Cytochrome P-450 Enzyme Inhibitors</subject><subject>Cytochrome P-450 Enzyme System - metabolism</subject><subject>Cytochrome P450</subject><subject>Cytochromes P450</subject><subject>Disulfiram</subject><subject>Disulfiram - pharmacology</subject><subject>Disulfiram - therapeutic use</subject><subject>Drug toxicity and drugs side effects treatment</subject><subject>Enzymes</subject><subject>Excretion</subject><subject>Fluorides</subject><subject>Halothane</subject><subject>Halothane - adverse effects</subject><subject>Halothane - metabolism</subject><subject>Hepatic Encephalopathy - chemically induced</subject><subject>Hepatic Encephalopathy - enzymology</subject><subject>Hepatic Encephalopathy - prevention & control</subject><subject>Hepatitis</subject><subject>Human behavior</subject><subject>Humans</subject><subject>In vivo methods and tests</subject><subject>Liver</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Metabolism</subject><subject>Metabolites</subject><subject>Necrosis</subject><subject>Neoantigens</subject><subject>Oxidative metabolism</subject><subject>Oxidoreductases, N-Demethylating - antagonists & inhibitors</subject><subject>Oxidoreductases, N-Demethylating - metabolism</subject><subject>Patients</subject><subject>Pharmacology. Drug treatments</subject><subject>Preoperative Care</subject><subject>Prophylaxis</subject><subject>Protein turnover</subject><subject>Proteins</subject><subject>Surgery</subject><subject>Toxicity: digestive system</subject><subject>Trifluoroacetic acid</subject><subject>Trifluoroacetic Acid - blood</subject><subject>Trifluoroacetic Acid - urine</subject><subject>Urine</subject><issn>0140-6736</issn><issn>1474-547X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1996</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqFkE1rFTEUhoMo9bb6EwoDuqiL0WQmyWTciBQ_CgUXKrgL-TjhpsxMxiT30nbTv26md7guC4FAzvO-JzwInRP8nmDCP_zEhOKady2_6Pm7vryRun-GNoR2tGa0-_McbY7IS3Sa0g3GmHLMTtCJ4G3X0maDHq4sTNk7b1T2YaqCq_IWKpju70aoIqQ5TMnrASoXYhVuvS3cHqqtGkLeqgmqEbLSYfBp_Fj5cR7WpvQYmCPsl_5D8__QFuZCZZ9eoRdODQler_cZ-v31y6_L7_X1j29Xl5-va8MJybViVptWYI4t101jO6G0obgxjvXgaM85F8QJ4ZSmwrJWNB23ulWW91Y3mLZn6M2hd47h7w5SljdhF6eyUjaEMbHkm0KxA2ViSCmCk3P0o4p3kmC5WJeP1uWiVPblLNZlX3Lna_tOj2CPqVVzmb9d5yoZNbioJuPTEWuxwIzzgn06YFBM7D1EmYyHyYD1EUyWNvgnPvIPM52hVw</recordid><startdate>19960518</startdate><enddate>19960518</enddate><creator>Kharasch, E.D.</creator><creator>Hankins, D.</creator><creator>Mautz, D.</creator><creator>Kharasch, E.D.</creator><creator>Thummel, K.E.</creator><general>Elsevier Ltd</general><general>Lancet</general><general>Elsevier Limited</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>0TT</scope><scope>0TZ</scope><scope>0U~</scope><scope>3V.</scope><scope>7QL</scope><scope>7QP</scope><scope>7RV</scope><scope>7TK</scope><scope>7U7</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88C</scope><scope>88E</scope><scope>88G</scope><scope>88I</scope><scope>8AF</scope><scope>8AO</scope><scope>8C1</scope><scope>8C2</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AN0</scope><scope>ASE</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BEC</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FPQ</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K6X</scope><scope>K9-</scope><scope>K9.</scope><scope>KB0</scope><scope>KB~</scope><scope>LK8</scope><scope>M0R</scope><scope>M0S</scope><scope>M0T</scope><scope>M1P</scope><scope>M2M</scope><scope>M2O</scope><scope>M2P</scope><scope>M7N</scope><scope>M7P</scope><scope>MBDVC</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PSYQQ</scope><scope>Q9U</scope><scope>S0X</scope></search><sort><creationdate>19960518</creationdate><title>Identification of the enzyme responsible for oxidative halothane metabolism: implications for prevention of halothane hepatitis</title><author>Kharasch, E.D. ; Hankins, D. ; Mautz, D. ; Kharasch, E.D. ; Thummel, K.E.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c611t-a5dbc38060d6b22d78abc402cf59ef4966681f88fab48d538276db3ad69db2043</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1996</creationdate><topic>Acid production</topic><topic>Acids</topic><topic>Adult</topic><topic>Alanine Transaminase - blood</topic><topic>Alveoli</topic><topic>Anesthesia</topic><topic>Attenuation</topic><topic>Biological and medical sciences</topic><topic>Blood</topic><topic>Blood levels</topic><topic>Cytochrome P-450 CYP2E1</topic><topic>Cytochrome P-450 Enzyme Inhibitors</topic><topic>Cytochrome P-450 Enzyme System - metabolism</topic><topic>Cytochrome P450</topic><topic>Cytochromes P450</topic><topic>Disulfiram</topic><topic>Disulfiram - pharmacology</topic><topic>Disulfiram - therapeutic use</topic><topic>Drug toxicity and drugs side effects treatment</topic><topic>Enzymes</topic><topic>Excretion</topic><topic>Fluorides</topic><topic>Halothane</topic><topic>Halothane - adverse effects</topic><topic>Halothane - metabolism</topic><topic>Hepatic Encephalopathy - chemically induced</topic><topic>Hepatic Encephalopathy - enzymology</topic><topic>Hepatic Encephalopathy - prevention & control</topic><topic>Hepatitis</topic><topic>Human behavior</topic><topic>Humans</topic><topic>In vivo methods and tests</topic><topic>Liver</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Metabolism</topic><topic>Metabolites</topic><topic>Necrosis</topic><topic>Neoantigens</topic><topic>Oxidative metabolism</topic><topic>Oxidoreductases, N-Demethylating - antagonists & inhibitors</topic><topic>Oxidoreductases, N-Demethylating - metabolism</topic><topic>Patients</topic><topic>Pharmacology. 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E.D.</au><au>Hankins, D.</au><au>Mautz, D.</au><au>Kharasch, E.D.</au><au>Thummel, K.E.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification of the enzyme responsible for oxidative halothane metabolism: implications for prevention of halothane hepatitis</atitle><jtitle>The Lancet (British edition)</jtitle><addtitle>Lancet</addtitle><date>1996-05-18</date><risdate>1996</risdate><volume>347</volume><issue>9012</issue><spage>1367</spage><epage>1371</epage><pages>1367-1371</pages><issn>0140-6736</issn><eissn>1474-547X</eissn><coden>LANCAO</coden><abstract>Summary
Background Fulminant hepatic necrosis ("halothane hepatitis") is an unusual and often fatal complication of halothane anaesthesia. It is mediated by immune sensitisation in susceptible individuals to trifluoroacetylated liver protein neoantigens, formed by oxidative halothane metabolism. The seminal event in halothane hepatitis is hepatic metabolism, yet the enzyme responsible for oxidative halothane metabolism and trifluoroacetylated neoantigen formation remains unidentified. This investigation tested the hypothesis that cytochrome P450 2E1 (CYP2E1) is responsible for human halothane metabolism in vivo.
Methods 20 elective surgical patients received either disulfiram (500 mg orally, n=10) or nothing (controls, n=10) the night before surgery. Disulfiram, converted in vivo to an effective inhibitor of P450 2E1, was used as a metabolic probe for P450 2E1. All patients received standard halothane anaesthesia (1·0% end-tidal, 3 h). Blood halothane and plasma and urine trifluoroacetic acid, bromide, and fluoride concentrations were measured for up to 96 h postoperatively.
Findings Total halothane dose, measured by cumulative end-tidal (3·8 SE 0·1 minimum alveolar concentration hours) and blood halothane concentrations, was similar in the two groups. Plasma concentrations and urinary excretion of trifluoroacetic acid and bromide, indicative of oxidative and total (oxidative and reductive) halothane metabolism, respectively, were significantly diminished in disulfiram-treated patients. In control and disulfiram-treated patients cumulative 96 h postoperative trifluoroacetic acid excretion was 12 900 (SE 1700) and 2010 (440) μmol, respectively (p<0·001) while that of bromide was 1720 (290) and 160 (70) μmol (p<0·001).
Interpretation The substantial attenuation of trifluoroacetic acid production by disulfiram after halothane anaesthesia suggests that P450 2E1 is a predominant enzyme responsible for human oxidative halothane metabolism. Inhibition of P450 2E1 by a single preoperative oral disulfiram dose greatly diminished production of the halothane metabolite responsible for the neoantigen formation that initiates halothane hepatitis. Single-dose disulfiram may provide effective prophylaxis against halothane hepatitis.</abstract><cop>London</cop><pub>Elsevier Ltd</pub><pmid>8637342</pmid><doi>10.1016/S0140-6736(96)91011-9</doi><tpages>5</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0140-6736 |
| ispartof | The Lancet (British edition), 1996-05, Vol.347 (9012), p.1367-1371 |
| issn | 0140-6736 1474-547X |
| language | eng |
| recordid | cdi_proquest_journals_2155866812 |
| source | MEDLINE; Elsevier ScienceDirect Journals Complete; EBSCOhost Business Source Complete; ProQuest Central UK/Ireland |
| subjects | Acid production Acids Adult Alanine Transaminase - blood Alveoli Anesthesia Attenuation Biological and medical sciences Blood Blood levels Cytochrome P-450 CYP2E1 Cytochrome P-450 Enzyme Inhibitors Cytochrome P-450 Enzyme System - metabolism Cytochrome P450 Cytochromes P450 Disulfiram Disulfiram - pharmacology Disulfiram - therapeutic use Drug toxicity and drugs side effects treatment Enzymes Excretion Fluorides Halothane Halothane - adverse effects Halothane - metabolism Hepatic Encephalopathy - chemically induced Hepatic Encephalopathy - enzymology Hepatic Encephalopathy - prevention & control Hepatitis Human behavior Humans In vivo methods and tests Liver Male Medical sciences Metabolism Metabolites Necrosis Neoantigens Oxidative metabolism Oxidoreductases, N-Demethylating - antagonists & inhibitors Oxidoreductases, N-Demethylating - metabolism Patients Pharmacology. Drug treatments Preoperative Care Prophylaxis Protein turnover Proteins Surgery Toxicity: digestive system Trifluoroacetic acid Trifluoroacetic Acid - blood Trifluoroacetic Acid - urine Urine |
| title | Identification of the enzyme responsible for oxidative halothane metabolism: implications for prevention of halothane hepatitis |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-14T05%3A35%3A52IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Identification%20of%20the%20enzyme%20responsible%20for%20oxidative%20halothane%20metabolism:%20implications%20for%20prevention%20of%20halothane%20hepatitis&rft.jtitle=The%20Lancet%20(British%20edition)&rft.au=Kharasch,%20E.D.&rft.date=1996-05-18&rft.volume=347&rft.issue=9012&rft.spage=1367&rft.epage=1371&rft.pages=1367-1371&rft.issn=0140-6736&rft.eissn=1474-547X&rft.coden=LANCAO&rft_id=info:doi/10.1016/S0140-6736(96)91011-9&rft_dat=%3Cproquest_cross%3E2155866812%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2155866812&rft_id=info:pmid/8637342&rft_els_id=S0140673696910119&rfr_iscdi=true |