Week of April 15, 1998
American Medical Association Science News Updates are made available to
the public after 3 p.m. Central time (U.S.) on the first four Tuesdays of
each month. We keep some back issues on this issue and have a list of
THIS WEEK'S CONTENTS
ADVERSE DRUG REACTIONS MAY CAUSE OVER 100,000 DEATHS AMONG HOSPITALIZED
PATIENTS EACH YEAR
Study suggests adverse drug reactions are among the top causes of death in
CHICAGOAdverse drug reactions (ADRs) in U.S. hospitals may be responsible
for more than 100,000 deaths nationwide each year, making it one of the
leading causes of death, according to an article in the April 14 issue of The
Journal of American Medical Association (JAMA).
Bruce H. Pomeranz, M.D., Ph.D., and colleagues from the University of
Toronto, analyzed 39 studies of ADRs in the United States to estimate the
incidence of serious and fatal adverse drug reactions in hospital patients.
To obtain overall incidence rates of ADRs in hospitalized patients, the
researchers combined the incidence of ADRs in the hospital and the incidence
of ADRs causing admission to the hospital.
The authors estimated that 2,216,000 hospital patients experienced a
serious ADR and 106,000 deaths were caused by ADRs in the United States. This
could account for 4.6 percent of all causes of recorded death in 1994, making
these reactions between the fourth and sixth leading cause of death.
The World Health Organization defines ADRs as any noxious, unintended and
undesired effect of a drug, which occurs at doses used in humans for
prophylaxis [prevention], diagnosis or therapy. The authors define a serious
ADR as one requiring hospitalization prolonging hospitalization, or one that
is permanently disabling or results in death.
The researchers found no significant correlation between ADR incidence and
year the studies were conducted. They write: "This result seems
surprising since great changes have occurred over the last four decades in
U.S. hospitals that should have affected the incidence of ADRs. Perhaps,
while length of hospital stay is decreasing, the number of drugs per day may
be rising to compensate. Therefore, while the actual incidence of ADRs has
not changed over the last 32 years, the pattern of their occurrence has,
undoubtedly changed," the authors write.
The authors determined that ADRs are one of the leading causes of death by
using the highest and lowest possible estimates. Using the higher estimate
placed ADRs as the fourth leading cause of death, behind heart disease
(743,460 deaths), cancer (529,904 deaths) and stroke (150,108 deaths). Using
the lower estimate placed ADRs as the sixth leading cause of death behind
those previously mentioned, as well as pulmonary disease (101,077 deaths) and
accidents (90,523 deaths). ADRs would then rank ahead of pneumonia and
The authors conclude: "While our results must be viewed with some
circumspection because of the heterogeneity among the studies and small
biases in the sample, these data suggest that ADRs represent an important
Editorial: How Worried Should We Be?
In an accompanying editorial in the April 15 JAMA, David W. Bates,
M.D., M.Sc., of Partners Healthcare Systems, and Brigham and Women's
Hospital, Boston, Mass., cautions that there are several concerns about the
way the study was done, although the authors adhered to the generally
accepted criteria for meta-analyses. "First, an inherent limitation of
meta-analysis is that combining the results of small, heterogeneous studies
does not necessarily bring one closer to truth, particularly if the processes
used to identify and to validate the presence of the events were
heterogeneous. Second, the hospitals studied are probably not representative
of hospitals at large. Such studies are more likely to be conducted in
academic, tertiary care hospitals; these hospitals have sicker patients, and
these patients have more ADRs. Another issue is whether the sites of care
sampled within the institutions were representative of the
Dr. Bates adds: "Nonetheless, these data are important, and even if
the true incidence of ADRs is somewhat lower than that reported ... it is
still high, and much higher than generally recognized."
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MEDICATION EFFECTIVE IN TREATING ASTHMA IN CHILDREN
Leukotriene blocker offers therapeutic benefit with few adverse effects
CHICAGOThe orally administered drug montelukast, taken once a day, is
effective therapy for 6- to 14-year-old children with chronic asthma,
according to an article in the April 15 issue of The Journal of the
American Medical Association (JAMA).
Barbara Knorr, M.D., of Merck Research Laboratories in Rahway, N.J., and
colleagues studied 336 children at 47 outpatient centers in the United States
and Canada to determine the effectiveness of montelukast on 6- to 14-year-
old children. Montelukast is one of a new class of asthma medications known
as leukotriene inhibitors, which block leukotrienes that are produced and
released from inflammatory cells. The inhibitors cause narrowing of the
airways in the lungs, mucous secretion and increased vascular permeability.
Other studies have found that compounds which block leukotrienes can improve
asthma control for adults and adolescents.
The children in this study had a history of intermittent or persistent
asthma symptoms. Each had a forced expiratory volume in one second (FEV1)
between 50 percent to 85 percent. All the children used short-acting inhaled
beta-agonists, as needed, to treat their asthma. After a two-week placebo
run-in period, 201 children received montelukast in a five-milligram chewable
tablet, taken at bedtime. The other 135 children were given a placebo.
Asthma is the most common chronic illness of childhood, affecting
approximately ten percent of children. Each year, approximately 2.2 million
doctor visits are make by children seeking treatment for asthma.
The researchers found that montelukast significantly improved FEV1.
Several secondary outcomes also improved. They write: "Patients treated
with either as-needed beta-agonist alone or inhaled corticosteroids had
significant improvement in their asthma control when they received
montelukast. ... Though the magnitude of the changes observed appeared
modest, they were consistent with those reported in other pediatric trials
using currently available therapies."
The researchers found that treatment effects usually occurred within one
day after the first dose of montelukast. They write: "Montelukast not
only demonstrated a rapid onset of action, but its treatment effects were
maintained consistently over time. There was no evidence of tolerance in this
or a prior adult study, suggesting that montelukast continues to be effective
in the long-term treatment of asthma."
Among other findings of the study:
Montelukast demonstrated a significant improvement in
daily as-needed beta-agonist use, and in the percentage of days and percentage
of patients with asthma exacerbation.
- The effects of
montelukast were similar across age, sex, race and other subgroups.
- Patients receiving
montelukast reported significant improvements in the physical and
emotional aspects of their lives.
The most common adverse experiences were headache, asthma, and upper
respiratory tract infection. Eleven patients were discontinued from the study
because of adverse effects.
The researchers conclude: "Overall, the results of this study suggest
that montelukast would be a well-tolerated and effective therapeutic option
to current asthma therapies in 6- to 14-year-old patients."
Note: This research was funded by Merck & Co., Inc.
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CHILDREN POISONED BY LAX DRUG MANUFACTURING PRACTICES
Contaminated acetaminophen syrup associated with the deaths of 88 Haitian
CHICAGOPoor quality control measures in the manufacture of a children's
medicine were responsible for its contamination and the subsequent death of
88 Haitian children, according to an article in the April 15 issue of The
Journal of the American Medical Association (JAMA).
Katherine L. O'Brien, M.D., M.P.H., from the Centers for Disease Control
and Prevention in Atlanta, Ga., and colleagues investigated the deaths of 88
children caused by sudden kidney failure that occurred in Haiti between
October 1995 and July 1996.
The researchers identified were 109 children with acute renal failure, of
whom 88 died. Further investigation found that glycerin imported to Haiti
from China through Europe was used in locally manufactured acetaminophen
syrup and was found to be contaminated with diethylene glycol (DEG), a toxic
chemical with industrial uses including antifreeze, plasticizer and solvent.
The researchers believe that between 45 and 75 additional cases of DEG
toxicity were averted by an intervention. Immediately following the discovery
of the source of the toxin, notification went out through radio, television,
newspapers and other sources.
The researchers write: "This outbreak highlights the challenges in
developing countries where there may not be adequate regulation, enforcement,
or strict implementation of current good manufacturing practice regulations
in the pharmaceutical sector. Not only should strict quality control procedures
be required in all countries where pharmaceutical products are manufactured,
but these procedures must be consistently and fully applied, otherwise an
outbreak such as this could occur even in countries where quality control
procedures are usually strictly applied."
They conclude: "It is likely that disasters such as these will
continue to occur until strict quality control procedures are used
consistently by all pharmaceutical manufacturers and until countries around
the world adopt and enforce regulations that ensure the safety of
Editorial: The Haitian Diethylene Glycol Poisoning Tragedy
In an accompanying editorial, Alan D. Woolf, M.D., M.P.H., of Children's
Hospital in Boston, Mass., writes: "It is significant that the outbreak
of DEG poisoning reported by O'Brien et al occurred in an impoverished
developing country. In the global accounting of richer developed vs. poorer
developing countries, inadequate regulation and surveillance of the safety of
medications seems an extraordinarily regressive tax."
Similar epidemics, in which medication was contaminated with DEG, have
been reported in Argentina, Bangladesh, Spain, Nigeria, and South Africa. The
first reported DEG contamination occurred in the United States more than 60
years ago when 72 percent solution of DEG was mistakenly used to dissolve
sulfanilamide, resulting in more than 105 deaths. This prompted the U.S.
Congress to enact the 1938 Federal Food, Drug and Cosmetic Act, legislation
that thereafter closely regulated the formulation and safety of medicinal
products, according to Dr. Woolf.
Dr. Woolf concludes: "Improved surveillance and early detection of
DEG in adulterated medications using inexpensive methods applicable in the
field, as suggested by O'Brien et al, may be additional strategies
implemented in a successful global approach. The Haitian epidemic replays all
the past folly involved with DEG contamination. There are no new public
health lessons from the Haitian tragedy."
(JAMA. 1998; 279:1215-1216)
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MEDICAL RESIDENTS REPORT MISTREATMENT DURING INTERNSHIP
Satisfaction with internship enhanced by positive learning experiences
CHICAGOMedical residents say they experienced perceived mistreatment,
discrimination, sexual harassment and other problems during their internship,
according to an article in the April 15 issue of The Journal of the
American Medical Association (JAMA).
Steven R. Daugherty, Ph.D., of the Rush Primary Care Institute and Rush
Medical College in Chicago, Ill., and colleagues surveyed a total of 1,277
second-year residents listed in the American Medical Association's medical
research and information database. Residents were asked about their first
year of residency, with questions focusing on general satisfaction, on-call
and sleep schedules, incidents of perceived mistreatment or abuse,
observations of unethical behavior by others, and experiences with harassment
Overall, 1,185 residents (93 percent) reported experiencing at least one
incident of perceived mistreatment. The researchers write: "Of the specific
types reported, the highest percentage was recorded for public humiliation or
belittlement. Attending faculty and residents at a higher level were
mentioned most often as the source of the mistreatment."
When asked about perceived mistreatment that occurred on three or more
occasions, 53 percent of residents reported that they were belittled or
humiliated by senior residents, while 21 percent reported someone else taking
credit for their work. Being given "tasks for punishment," "being
slapped, pushed, kicked or hit," and having someone 'threatening your
reputation or career" were reported as occurring on three or more
occasions by more than ten percent of the residents.
Thirty percent of the residents reported experiencing at least one episode
of what they considered discrimination or sexual harassment, while 63 percent
of female residents reported such incidents: For women, such harassment or
discrimination was most commonly reported as sexual slurs or comments (35.8
percent), followed by favoritism (23.7 percent), sexual advances (16.4
percent), denied opportunities (15.9 percent) and poor evaluations (13.1
Among other findings of the survey:
45 percent of residents reported observing someone
falsifying medical records.
- About 70 percent of
respondents reported observing what they considered to be mistreatment
of patients by other residents.
- 70 percent of
residents reported observing a colleague working in an impaired
condition. Lack of sleep was the leading cause (56.9 percent).
- Residents reported
they spent an average of 56.9 hours a week on call at the hospital.
About 25 percent of residents said they were on call over 80 hours a
- 10 percent of
residents indicated sleep deprivation was an almost daily occurrence.
- Overall, residents
reported a moderate level of satisfaction with their internship, with an
average rating of 4.56 (good) on a scale of one (poor) to seven
- Residents reported the
highest contribution to their learning came from other residents, with special
patients ranked second.
The researchers suggest that satisfaction with residency is the result of
the ratio between positive learning and negative work experience: "If
residents feel mistreated during their contact with their superiors, but feel
that they learn from this contact, they may well discount the short-term
negatives of the experience and focus on the long-term benefits of the
education they receive."
The authors recommend a two-pronged approach to residency directors who
wish to improve feelings of satisfaction among residents: "First, they
should strive to increase the learning opportunities for residents. This can
be accomplished by a combination of things: increasing the accessibility of
residents to attending faculty, facilitating contacts among residents, or
providing time for independent reading. Second, residency directors must make
clear the standards of conduct for all professional personnel and intervene
when conduct falls short of these standards. Although the discomforts of residency
cannot be eliminated, a conscious effort at reducing the intern's sense of
being mistreated should enhance residents' satisfaction."
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RISE OF ANTIBIOTIC-RESISTANT BACTERIA WARRANTS
FOCUSED MEDICAL EDUCATION ON URI TREATMENT
Physicians who are high prescribers of antibiotics for children's upper
respiratory tract infections (URI) are more likely than low prescribers to
have the following characteristics: specialists other than pediatricians;
farther removed from medical school training; more encounters with URI patients
and more likely to prescribe a narrow-spectrum antibiotic, according to a
study in the April issue of the AMA's Archives of Pediatrics &
Adolescent Medicine. The researchers analyzed 34,624 URI treatments for
children younger than 18 years to assess the physician characteristics of
high antibiotic prescribers. The researchers write: "More focused
training regarding treatment of URIs may be warranted in residency and
continuing medical education forums. Training must target whether to
prescribe antibiotics and what kind."
Pediatr Adolesc Med. 1998;152:349-352)
Note: Partial support of this study was received from the Department
of Public Health, Commonwealth of Kentucky.
CAUTION URGED IN TREATMENT OF DEPRESSION IN OLDER
Heterocyclic antidepressants and rational psychological therapies are the
most effective treatments for moderate and mild depression in older
ambulatory patients, according to a study in the April 13 issue of the AMA's Archives
of Internal Medicine. The researchers conducted a meta-analysis of the
literature to assess effectiveness of pharmacological and psychological
treatments of depression in older ambulatory patients. They report that only
modest benefits can be expected in older ambulatory patients from the
therapies that are currently available. Selective serotonin reuptake
inhibitors (SSRIs) appear to be as effective as heterocyclic drugs, but that
was based on a single study. For mild depression, psychological treatment
and/or extra attention are recommended. The authors urge caution in use of
heterocyclic drugs and SSRIs with this population.
Intern Med. 1998;158:705-712)
GENETICS AND LIFESTYLE PLAY KEY ROLE IN PEPTIC
Environmental factors shared by families are not as important in development of
peptic ulcer disease as once thought, according to a study in the April 13
issue of the AMA's Archives of Internal Medicine. Ismo R_ih_, M.D.,
from the University of Turku in Finland, and colleagues studied data on
13,888 twin pairs to weigh the roles of genetics vs. the clustered risk
factors shared by families living in the same environment in the development
of peptic ulcer disease. They found that 39 percent of the liability of
peptic ulcer disease was explained by genetic factors and 61 percent by individual
environmental factors such as current smoking and high stress levels for men
and regular use of analgesics for women.
Intern Med. 1998;158:698-704)
LIVING-DONOR KIDNEY TRANSPLANTATION REPORTED TO BE
LOW RISK TO DONOR
Living-donor kidney transplantation has few surgical complications with a 1
percent or less chance of bleeding, wound infection, pneumonia or urinary
tract infection, according to an article in the April issue of the AMA's
Archives of Surgery. The researchers reviewed 201consecutive living-donor
kidney transplantations done at Beth Israel Deaconess Medical Center to
assess surgical complications, length of donor's hospital stay and recipient
outcome. The researchers report that in addition to low morbidity, the
average length of the donor's hospital stay decreased from 6.2 days to 4.0
days during the 10-year study. The medical center also reports increased
kidney donation by non-relatives.
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