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ADVERSE DRUG REACTIONS MAY CAUSE OVER 100,000 DEATHS AMONG HOSPITALIZEDPATIENTS EACH YEAR

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Science News Update

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 available releases.


THIS WEEK'S CONTENTS

JAMA REPORTS

ARCHIVES REPORT


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 U.S.

CHICAGO—Adverse 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 diabetes.

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 clinical issue."
(JAMA. 1998;279:1200-1205)

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 institutions."

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."
(JAMA. 1998;279:1216-1217)

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MEDICATION EFFECTIVE IN TREATING ASTHMA IN CHILDREN
Leukotriene blocker offers therapeutic benefit with few adverse effects

CHICAGO—The 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."
(JAMA. 1998;279:1181-1186)

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 children

CHICAGO—Poor 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 pharmaceutical products."
(JAMA. 1998: 279:1175-1180)

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

CHICAGO—Medical 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 or discrimination.

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 percent).

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 week.
  • 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 (excellent).
  • 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."
(JAMA. 1998;279:1194-1199)

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Archives Briefs

·         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."
(Arch 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 AMBULATORY PATIENTS
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.
(Arch Intern Med. 1998;158:705-712)

·         GENETICS AND LIFESTYLE PLAY KEY ROLE IN PEPTIC ULCER DISEASE
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.
(Arch 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.
(Arch Surg. 1998;133:426-431)

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