National Halothane Study: a Study of the Possible Association Between Halothane Anesthesia and Postoperative Hepatic Necrosis; Report. Edited by John P. Bunker [and Others] (1969)

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THE NATIONAL HALOTHANE STUDY If A STUDY OF THE POSSIBLE ASSOCIATION BETWEEN HALOTHANE ANESTHESIA AND POSTOPERATIVE HEPATIC NECROSIS Report of The Subcommittee on the National Halothane Study, of the Committee on Anesthesia, Division of Medical Sciences, National Academy of Sciences-National Research Council Washington, D.C. Edited by John P. Bunker, M.D., William H. Forrest, Jr., M.D. Frederick Mosteller, Ph.D., and Leroy D. Vandam, M.D. Supported by Department of Health, Education, and Welfare Public Health Service, National Institute of General Medical Sciences Contract PH43-63-65 NAS-MAE APR 251969 National Institutes of Health National Institute of General Medical Sciences Bethesda, Md. 1969 For sale by the Superintendent of Documents, U.S. Government Printing Office, Washington, D.C. 20402 - Price S3.75 (paper cover)

MEMBERS OF SUBCOMMITTEE John P. Bunker, M.D., Chairman Charles G. Child III, M.D. Charles S. Davidson, M.D. Edward A. Gall, M.D. Gerald Klatskin, M.D. Leonard Laster, M.D. Lincoln E. Moses, Ph. D. Edward A. Gall, M.D., Chairman Archie H. Baggenstoss, M.D. I. Nathan Dubin, M.D. Yvonne M.M. Bishop, Ph. D. Byron W. Brown, Ph. D. W. Morven Gentleman, Ph. D. John P. Gilbert, Ph. D. Lincoln E. Moses, Ph. D. Frederick Mosteller, Ph. D. Shih-hsun Ngai, M.D. Leroy D. Vandam, M.D. Staff: William H. Forrest, Jr., M.D. Sam F. Seeley, M.D. John P. Gilbert, Ph. D. PANEL OF PATHOLOGISTS Paul R. Glunz, M.D. Hans Popper, M.D. Hans F. Smetana, M.D. PANEL OF STATISTICIANS Frederick Mosteller, Ph. D. John W. Tukey, Ph. D. Staff: Jerry Halpern, M.S. Lawrence G. Tesler, A.M. CONSULTANTS AND ASSOCIATES Clinical Pharmacology: J. Weldon Bellville, M.D. Clinical Analyses: Bernard M. Babior, M.D. William E. Dozier, M.D. Pathology: Charles W. Blumenfeld, M.D. Beatrice W. Ishak, M.D. Kamal K. Ishak, M.D. Toxicology: Ellis N. Cohen, M.D. Project Officers, National Institute of General Medical Sciences: Ruth K. Beecroft, M.D. Carl R. Brewer, Ph. D. Louis P. Hellman, M.A. Staff, Division of Medical Sciences, National Academy of Sciences- National Research Council Gilbert W. Beebe, Ph. D. R. Keith Cannan, Ph. D. Sam F. Seeley, M.D.

PARTICIPATING INSTITUTIONS USAF Hospital, Andrews AFB, Washington, D.C., Lt. Col. Robert J. McCann, USAF (MC) USAF Hospital, Lackland AFB, Texas, Col. Arthur B. Tarrow, USAF (MC), and Maj. Richard C. Wolff, USAF (MC) Albany Medical College, Albany, N.Y., Charles H. Landmesser, M.D., and S.A. Akdikmen, M.D. Albert Einstein College of Medicine, New York, Howard L. Zauder, M.D., Louis R. Orkin, M.D., and Andrew Fellini, M.D. University of California Medical Center, Los Angeles, Leonard F. Walts, M.D., and David Cohen, M.D. University of California Medical Center, San Francisco, Walter L. Way, M.D., and Stuart C. Cullen, M.D. Columbia Presbyterian Medical Center, New York, Shih-Hsun Ngai, M.D., and Daniel Pino, M.D. Duke University School of Medicine, Durham, N.C., William C. North, M.D., and Charles R. Stephen, M.D. George Washington University School of Medicine, Washington, D.C., Charles S. Coakley, M.D. Harbor General Hospital, Torrance, Calif., Paul H. Lorhan, M.D. University of Iowa College of Medicine, Iowa City, William K. Hamilton, M.D., and Leo J. DeBacker, Jr., M.D. Jefferson Medical College, Philadelphia, Louis J. Hampton, M.D. Hospital for Joint Diseases, New York, Albert M. Betcher, M.D. University of Kentucky College of Medicine, Lexington, Peter P. Bosomworth, M.D. King County Hospital, Seattle, John J. Bonica, M.D., Lydia J. Deveny, M.D., and John M. Hansen, M.D. Massachusetts General Hospital, Boston, Donald P. Todd, M.D. Mayo Clinic, Rochester, Minn., Richard A. Theye, M.D. University of Miami School of Medicine, Jackson Memorial Hospital, Miami, Fla., Frank Moya, M.D., and Jerome H. Modell, M.D. University of Michigan Medical School, Ann Arbor, Robert B. Sweet, M.D. University of Minnesota Medical School, Minneapolis, Frederick H. Van Bergen, M.D., and Joseph J. Buckley, M.D. National Institutes of Health Clinical Center, Bethesda, Md., D. H. Morrow, M.D., and William M. Dixon, M.D. New York Hospital-Cornell University Medical College, New York, Joseph F. Artusio, Jr., M.D. Ohio State University College of Medicine, Columbus, William Hamelberg, M.D. iii

Guthrie Clinic Ltd., Robert Packer Hospital, Sayre, Pa., Edward A. Talmage, M.D. Peter Bent Brigham Hospital, Harvard Medical School, Boston, Leroy D. Vandam, M.D. Providence Hospital, Seattle, Lucien E. Morris, M.D. Royal Victoria Hospital, Montreal, A. B. Noble, M.D., and C. A. Sheridan, M.D. St. Luke's-Texas Children's Episcopal Hospital, Houston, James D. Carter, M.D., and Arthur S. Keats, M.D. Sutter Hospitals, Sacramento, Calif., William H. Forrest, Jr., M.D., and Charles M. Blumenfeld, M.D. Temple University School of Medicine, Philadelphia, Thomas C. Deas, M.D., and LeRoy W. Krumperman, M.D. Veterans Administration Hospital, Houston, Walter H. Mannheimer, M.D., and Arthur S. Keats, M.D. University of Washington School of Medicine, Seattle, John J. Bonica, M.D., Richard J. Ward, M.D., and Felix G. Freund, M.D. Washington University School of Medicine, Barnes Hospital, St. Louis, Robert B. Dodd, M.D. White Memorial Medical Center, Los Angeles, Forrest E. Leffingwell, M.D., and Howard T. Morse, Jr., M.D. Yale University School of Medicine, New Haven, Conn., Robert L. Willenkin, M.D., and Nicholas M. Greene, M.D.

FOREWORD The National Halothane Study is a statistical and pathologic investigation of the possible association between halothane anesthesia and postoperative hepatic necrosis, and an examination of the effect of general anesthetic agents, including halothane, on postoperative mortality. The data collected constitute, in addition, a great body of information on hepatic pathology and on over-all mortality in surgical patients. The design of the Study may serve as a useful guide for the clinical pharmacologist or other investigator who wishes to study rare untoward events in medicine. And the statistical techniques devised especially for the Study are immediately and widely applicable to projects, both experimental and observational, in which allowance must be made for multiple interacting variables. The text of this report ranges from general clinical discussion to highly technical statistical detail. The presentation is organized to allow the reader easy access to those parts in which he may have special interest. For those who wish to go directly to a summary of findings, separate, relatively detailed summaries and conclusions are presented for the study of hepatic necrosis (Chapter III - 5) and for the study of death rates (Chapter IV - 8). The Subcommittee's recommendations, which it is hoped will be of special interest to the medical profession, are presented at the conclusion of the report (Part VI). A task of this magnitude could not have been accomplished without the extraordinary dedication of the very large group of participants. For some the Study represented a response to the need to solve an urgent problem in the practice of anesthesia; for others it was necessary to define the importance of the problem as a public health issue. For many the Study offered opportunities for new and experimental approaches to the collection, analysis, and interpretation of epidemiologic data. And for all it was an irresistible challenge. Our special thanks are extended to R. Keith Cannan, Chairman of the Division of Medical Sciences, National Academy of Sciences-National Research Council, for his continued support and encouragement; to E. M. Papper, Chairman of the Committee on Anesthesia of the Division of Medical Sciences, and Carl R. Brewer, Project Officer of the National Institute of General Medical Sciences for the National Halothane Study, who recognized the need for the Study and were largely responsible for its activation; to Sam F. Seeley, for the wisdom and efficiency with which he provided administrative assistance; and to William H. Forrest, Jr., who, with ingenuity, skill, and perseverance, coordinated collection and analysis of the vast amount of data necessary for successful completion of the Study. Preparation and distribution of approximately 3000 tissue slides to members of the Pathology Panel were supervised by Major General Joe M. Blumberg, Director, Armed Forces Institute of Pathology; Paul R. Glunz and Kamal G. Ishak, of the Hepatic Branch; and Lee Luna and Walter McAllister, of the Histopathology Laboratory. Procurement and processing of basic data were coordinated by the staff of the Sutter Research Foundation: Dana J. Bach, Edna J. Collins, Beth Ann Hapgood, Velma J. Holmes, and Mary J. Wallace. The great task of data management, including coding, editing, and error checking, was supervised by William H. Forrest, Jr., working in close collaboration with the principal investigators at the several institu- tions. To make the data available in a form suitable for high-speed computation, John P. Gilbert supervised the preparation and introduction of the data onto magnetic tape and wrote programs for the initial analyses. Dr. Forrest also managed the data for the study of hepatic necrosis, and he and Dr. Gilbert aided with the statistical analysis. The main program of computing was carried out at the Stanford Computation Center, and additional computing was done at the Harvard Computing Center. In those institutions, Lawrence G. Tesler, Kerstin Bengtsson, Alberta Bryan, Michael L. Goodman, and William S. Mosteller assisted in the preparation of computer programs. Cleo Youtz assisted in mathematical analysis and in editing the final manuscript of Part IV.

The manuscript was prepared largely at Stanford and at Harvard, with the assistance of the following staffs: Stanford Department of Anesthesia: Adena Goodart, Lee Amideo, and Jacqueline Hardy; Stanford Department of Statistics: Ginnie Currey and Margaret Cline; Harvard Department of Statistics: Monica Anvoner, Linda Falcone, Lynn Holtz, Nancy Larson, Holly Lasewicz, Louise Rothman, and Patricia Scott; Harvard Department of Anesthesia: Helen T. Gallahue; and Bell Telephone Laboratories: Elizabeth L. La Jeunesse. Our thanks are extended to Princeton University, particularly in connection with research sponsored by the Army Research Office (Durham), and Bell Telephone Laboratories for the participation of W. Morven Gentleman and of John W. Tukey; to the Center for Advanced Study in the Behavioral Sciences at Stanford California, and to the University of North Carolina at Chapel Hill, especially through the National Institute of Mental Health's grant MH-10006 to the Psychometric Laboratory, and to the Harvard Computing Center for the services of John P. Gilbert; to Harvard University and the National Science Foundation for facilitating, through grant GS-341, the participation of Frederick Mosteller and Cleo Youtz; to the Harvard School of Public Health for facilitating, through biostatistics training grant 6893-2, the participation of Yvonne M. M. Bishop; and to the Stanford Department of Statistics for facilitating, through biostatistics training grant GM-00025, the participation of Jerry Halpern. Among our statistical colleagues, Raj Bahadur, James R. Boen, K. A. Brownlee, W. G. Cochran, Arthur P. Dempster, Leo A. Goodman, William Kruskal, Paul Meier, Rupert G. Miller, Jr., Charles Stein, and David L. Wallace have been generous with their advice. John P. Bunker Chairman Subcommittee on the National Halothane Study VI

CONTENTS Page FOREWORD, by John P. Bunker v PART I - HISTORICAL BASIS OF THE STUDY Chapter 1 - Introduction, by John P. Bunker 1 Chapter 2 - Pharmacology of Halothane, by S.H. Ngai 3 Chapter 3 - Hepatic Effects of Halothane - Review of the Literature, by S.H. Ngai 11 PART II - DESIGN OF THE STUDY Chapter 1 - Approaches to the Study: A Randomized Trial or a Study of Past Data, by William H. Forrest, Jr., Byron W. Brown, Jr., and J. Weldon Bellville 47 Appendix - Protocol for Pilot Prospective Study 50 Chapter 2 - The Protocol for the National Halothane Study (Including a Discussion of the Problems of Data Collection), by William H. Forrest, Jr., J. Weldon Bellville, Byron W. Brown, Jr., and John P. Bunker 60 PART III - REPORT ON HEPATIC NECROSIS Chapter 1 - Over-All Results of the Study of Hepatic Necrosis, by William H. Forrest, Jr 91 Appendix - Summaries of 80 Cases of Massive Hepatic Necrosis 110 Chapter 2 - Report of the Pathology Panel, by Edward A. Gall 151 Chapter 3 - Analysis of Massive Hepatic Necrosis Data, by John P. Gilbert and John P. Bunker . 162 Chapter 4 - The Clinical Syndromes Associated with Postoperative Hepatic Necrosis, by Bernard M. Babior and Charles S. Davidson 169 Chapter 5 - Summary of Study of Hepatic Necrosis: Clinical Implications, by John P. Bunker and Leroy D. Vandam 177 PART IV - THE STUDY OF DEATH RATES Chapter 1 - Introduction to the Study of Death Rates, by Byron W. Brown, Jr., Frederick Mosteller, Lincoln E. Moses, and W. Morven Gentleman 183 Chapter 2 - Comparison of Crude and Standardized Anesthetic Death Rates, by Lincoln E. Moses 189 Appendix 1 - Detailed Definitions of Anesthetic Practices, by William H. Forrest, Jr 232 Appendix 2 - Definitions of Variables, by Lincoln E. Moses 233 Appendix 3 - Estimation of Death Rates, by Frederick Mosteller 234 Appendix 4 - Formulas for Direct and Indirect Standardization used in Chapter IV-2, by Lincoln E. Moses 236 vii

Page Chapter 3 - Smoothed Contingency-Table Analysis, by Yvonne M. M. Bishop and Frederick Mosteller 237 Appendix - Calculating Smoothed Contingency Tables, by Yvonne M. M. Bishop 273 Chapter 4 - The Smear-and-Sweep Analysis, by W. Morven Gentleman, John P. Gilbert, and John W. Tukey 287 Appendix 1 - (Equally Weighted) Jackknifing in Unequal-Sized Blocks 298 Appendix 2 - Standardization in Broad Groups 299 Appendix 3 - Estimation Bias in Smear-and-Sweep 301 Appendix 4 - Pseudo-values of Over-All Death Rate By Agent 303 Appendix 5 - Pseudo-values of Standardized Death Rates for all five Agents with all five Populations on Middle-Death-Rate Operations 304 Appendix 6 - Middle-Death-Rate Operations: Deaths, Estimated Exposed, and Death Rates by Agent for Final Categories 310 Appendix 7 - Approximate Inquiry into Plausible Indirect Effect of Differences in Standardized Death Rates between Institutions 313 Chapter 5 - Analysis by Regression Methods, by Jerry Halpern, Lincoln E. Moses, and Yvonne M. M. Bishop 316 Appendix 1 - Regression Model used in Chapter IV-5, by Jerry Halpern and Lincoln E. Moses 322 Appendix 2 - Remarks on Sweepup Rules, by Lincoln E. Moses 325 Chapter 6 - Analysis for "Pure-Aggregation" Strata, by Lincoln E. Moses, Jerry Halpern, Lawrence G. Tesler, and Yvonne M. M. Bishop 328 Appendix 1 - Examining the Standard Errors, by Lincoln E. Moses 351 Appendix 2 - A Further Inquiry in to Institutional Differences by Means of Superstandardiza- tion (A Regression Adjustment beyond Standardization), by John W. Tukey . 358 Appendix 3 - The Variability of the Difference between Deaths and Standardized Deaths, by Lincoln E. Moses 370 Appendix 4 - Should We Superstandardize Agent Comparisons? - General Considerations and Apparent Conclusions, by W. Morven Gentleman and John W. Tukey .... 372 Appendix 5 - Development of Certain Formulas, by W. Morven Gentleman and John W. Tukey 381 Appendix 6 - Assessment of Various Structural Regression Coefficients, by W. Morven Gentleman and John W. Tukey 387 viii

Page Chapter 7 - Analysis of Middle-Death-Rate Operations using a Shock-Likelihood Index, by John P. Gilbert 392 Chapter 8 - Afterword for the Study of Death Rates, by Lincoln E. Moses and Frederick Mosteller 395 PART V - THE TOXICOLOGY OF DICHLOROHEXAFLUOROBUTENE, by Ellis N. Cohen 411 PART VI - FORMAL RECOMMENDATIONS, by John P. Bunker 417 Ix

PART I. HISTORICAL BASIS OF THE STUDY