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September 2000
Volume 64 |
Number 9
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| ASA – Leadership
in Medicine: The National Halothane Study |
R. Dennis Bastron,
M.D.
I lecture to third-year medical students at Texas A&M College
of Medicine about leadership in medicine using examples from ASA
as case studies. One example I like to use is the National Halothane
Study. This study, headed by John Bunker, M.D., was the largest,
most expensive study ever performed on the subject. I have discovered
that many of my younger colleagues are not familiar with this
landmark study, so I am happy to briefly review it.
During the 1950s and 1960s, E. M. Papper, M.D., chair of anesthesiology
at Columbia University, convinced the National Institutes of Health
that the high mortality rate in anesthesia was a public health
threat that deserved attention in the form of financial support
of anesthesia-related research and training of faculty. Dr. Papper
later became the chair of the Committee on Anesthesia of the National
Academy of Sciences-National Research Council.
Halothane was first synthesized in 1951 by Charles W. Suckling
in a systematic effort to develop a potent, nonflammable inhalation
agent. By 1956, James Raventos had worked out the pharmacology
of halothane; that same year, it was first used clinically in
England by Michael Johnstone, M.D., and then in the United States
by C. Ronald Stephen, M.D., and his associates at Duke University.
Dr. Stephen reported preliminary results of halothane anesthesia
in 145 patients at the 1956 ASA Annual Meeting in Kansas City,
Missouri. Halothane was released for clinical use in the United
States in 1958 and rapidly became the most commonly used general
anesthetic because it is easy to administer, well tolerated by
patients and loved by surgeons for its nonflammability.
The first reported death from acute yellow atrophy following
halothane was in 1958. Dr. Bunker recalls that in 1960 or early
1961, he was asked by Charles Blumenfeld, M.D., a pathologist
in Sacramento, California, about two patients who died with massive
liver necrosis following relatively minor surgery under halothane
anesthesia. Several cases had been reported from Dr. Papper's
institution, and he was under pressure from some of his medical
and surgical colleagues to stop using halothane (Papper personal
communication, April 20, 2000). After 12 new cases of fatal liver
necrosis, Ayerst Laboratories, the manufacturers of halothane
in the United States, issued a drug warning. Dr. Papper felt that
the Committee on Anesthesia was the best vehicle for a study to
determine the safety of the anesthetic agent. He then established
a subcommittee on the National Halothane Study chaired by Dr.
Bunker.
Dr. Bunker wrote, "What may not have been described by
any of the reports are the extraordinary circumstances surrounding
the study's initiation. The possibility of halothane-induced harm
was raised shortly after the thalidomide tragedy, and the risk
of iatrogenic injury had become a matter of grave public health
concern. The drug warning issued by Ayerst was clearly in response
to a Food and Drug Administration (FDA) directive, and I have
long believed, though without evidence in writing, that the FDA
was poised to withdraw halothane from the market. That it did
not do so can be attributed to the establishment of the halothane
study" (personal communication, April 11, 2000).
The Subcommittee on the National Halothane Study included Leroy
D. Vandam, M.D., editor of Anesthesiology and one of the most
respected scientific editors in the country, along with prominent
statisticians, hepatologists and pathologists. The subcommittee
resembled a "who’s who" of those special disciplines.
A randomized, prospective, multi-institutional study was considered
but eliminated after several more reports of deaths following
halothane. For a variety of reasons, the subcommittee decided
to do a retrospective study of 1 million cases done over the four-year
period after the release of halothane for clinical use.
One of the statisticians, Frederick Mosteller, M.D., had been
involved in anesthesia studies with Henry K. Beecher, M.D., at
Harvard University. Big computers had just been developed and
the statisticians were anxious to try them out on such a massive
study. New statistical techniques and approaches were required
and were subsequently developed. Pathologists were excited by
the prospect of huge numbers of samples to study but were not
thrilled about being blinded to the anesthetic used "since
they only make diagnoses with the entire clinical record available
to them" (Bunker personal communication). Fifty-four medical
centers volunteered to participate in the study, but 16 dropped
out when the requirements were made clear. Three more dropped
out after the pilot protocol was tested, so 35 institutions collected
data for the four-year period. However, one institution did not
meet the criteria set by the committee and the final report was
based on 865,000 patients from 34 institutions. (One of the "perks"
when I was an anesthesiology resident at the University of Iowa
in the mid 1960s was to have Leo DeBacker, M.D., hand me a pile
of charts to abstract for the study.)
The results of this massive study were quite interesting. The
incidence of fatal liver necrosis was 1:10,000. Most of the cases
were explained by the patients’ clinical course rather than the
anesthetic. Only nine cases were unexplained. The overall mortality
following halothane was better than average. A sample size of
just under 1 million was simply not big enough to conclude that
halothane did or did not cause massive liver necrosis. Another
interesting, and as yet unresolved, finding was the variation
in surgical mortality among hospitals that was not entirely explained
by the nature of the patients and operations. (Those interested
in more detail should read the report, "The National Halothane
Study," published by the National Institutes of Health, Bethesda,
1969, or see "Summary of the National Halothane Study"
JAMA. 1966; 197:775-788.)
Four decades later, we know that "halothane hepatitis"
is a real but rare entity. Statistical methods developed for the
study are now in common use. Differences in rates of medical and
surgical complications and mortality still exist between institutions
and are not understood. Anesthesiology continues to lead the way
in patient care and safety thanks to the early leadership of Drs.
Papper, Bunker and Vandam.
Incidentally, one of the advantages of entering the specialty
in the 1960s is that I have had the privilege and honor to meet
many of the giants of anesthesiology. Anyone who is interested
in meeting the pioneers who made our specialty what it is may
attend the Anesthesia History Association dinner at the ASA Annual
Meeting. You may meet C. Ronald Stephen, M.D., Leroy D. Vandam,
M.D., E.M. Papper, M.D., and many other leaders of years past.
Acknowledgements:
I am indebted to W.K. Hamilton, M.D., E.M. Papper, M.D., Arthur
S. Keats, M.D., Leroy D. Vandam, M.D., and John P. Bunker, M.D.,
for their help with this article.
R. Dennis Bastron, M.D., is Professor of
Anesthesiology, Texas A&M Health Science Center, Temple, Texas.
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