Lit Bits: February 22, 2006

From the recent medical literature...

1. AHA Issues New Guidelines for Emergency Cardiovascular Care

News Author: Laurie Barclay, MD. Dec. 1, 2005 — The American Heart Association (AHA) has published new guidelines for cardiopulmonary resuscitation (CPR) and emergency cardiovascular care (ECC) in the Nov. 28 Rapid Access issue of Circulation . The guidelines are available at: http://www.americanheart.org/presenter.jhtml?identifier=3035517.

In revising the 2000 guidelines, the AHA has attempted to simplify existing guidelines and apply newly available evidence reviewed at the 2005 International Consensus Conference on CPR and ECC Science With Treatment Recommendations, hosted by the AHA and held in Dallas, Texas, from Jan. 23 - 30.

"The most important determinant of survival from sudden cardiac arrest [SCA] is the presence of a trained rescuer who is ready, willing, able, and equipped to act," the guidelines note. "Any improvements resulting from advanced life support therapies are less substantial than the increases in survival rate reported from successful deployment of lay rescuer CPR and automated external defibrillation (AED) programs in the community."

The objective of these revised recommendations is to improve survival from SCA and acute, life-threatening cardiopulmonary problems. Compared with previous guidelines, the 2005 guidelines are based on the most extensive evidence review of CPR yet published; they were developed using a new structured and transparent process for ongoing disclosure and management of potential conflicts of interest, and they have been streamlined to reduce the amount of information that rescuers need to learn and remember and to clarify the most important skills that rescuers need to perform.

The evidence evaluation process underlying these guidelines relied on the International Liaison Committee on Resuscitation (ILCOR), which was formed to systematically review resuscitation science and develop an evidence-based consensus to guide resuscitation practice worldwide. The 6 task forces of ILCOR include basic life support, advanced life support, acute coronary syndromes, pediatric life support, neonatal life support, and an interdisciplinary task force to address overlapping topics. The AHA added 2 more task forces on stroke and first aid.

Based on available evidence, the AHA classified its recommendations as class I (high-level prospective studies support the action or therapy, and the risk substantially outweighs the potential for harm); class IIa (the weight of evidence supports the action or therapy, and the therapy is considered acceptable and useful); and class IIb (the evidence documents only short-term benefits from the therapy, or positive results were documented with lower levels of evidence).

"The 12 AHA CPR and ECC algorithms contained in these guidelines highlight essential assessments and interventions recommended to treat cardiac arrest or a life-threatening condition," the authors write. "These algorithms have been developed using a template with specific box shapes and colors. Memorizing the box colors and shapes is not recommended, nor is it necessary for use of the algorithms."

The most significant changes in the guidelines attempt to simplify CPR instruction, to increase the number of chest compressions delivered per minute, and to reduce interruptions in chest compressions during CPR. Some of the most significant new recommendations are as follows:

The lay rescuer no longer needs to assess signs of circulation before beginning chest compressions but should instead be taught to deliver 2 rescue breaths to the unresponsive victim who is not breathing and to then begin chest compressions immediately.

Instructions for rescue breaths are simplified: all breaths, whether delivered mouth-to-mouth, mouth-to-mask, bag-mask, or bag-to–advanced airway, should be given over 1 second with sufficient volume to achieve visible chest rise.

The lay rescuer no longer needs to be trained in rescue breathing without chest compressions.

A single (universal) compression-to-ventilation ratio of 30:2 is recommended for single rescuers of victims of all ages, except for newborn infants. This recommendation should simplify teaching and provide longer periods of uninterrupted chest compressions.

For application of pediatric basic life support guidelines for healthcare providers, the definition of "pediatric victim" is modified to preadolescent (prepubescent) victim. However, there is no change to the lay rescuer application of child CPR guidelines (1 to 8 years).

The importance of chest compressions is emphasized. Rescuers will be taught to "push hard, push fast" (at 100 compressions per minute), to allow complete chest recoil, and to minimize interruptions in chest compressions.

For unwitnessed arrest, Emergency Medical Services providers may consider provision of about 5 cycles (or about 2 minutes) of CPR before defibrillation, particularly when the interval from the call to the Emergency Medical Services dispatcher to response at the scene is more than 4 to 5 minutes.

During treatment of pulseless arrest, about 5 cycles (or about 2 minutes) of CPR should be provided between rhythm checks. Instead of checking the rhythm or a pulse immediately after shock delivery, rescuers should immediately resume CPR, beginning with chest compressions, and they should check the rhythm after 5 cycles (or about 2 minutes) of CPR.

All rescue efforts, including insertion of an advanced airway, administration of medications, and reassessment of the patient should be performed in a manner that minimizes interruption of chest compressions. Pulse checks should be limited during the treatment of pulseless arrest.

For treatment of ventricular fibrillation or pulseless ventricular tachycardia, there should be only 1 shock, instead of 3 stacked shocks, followed immediately by CPR (beginning with chest compressions). This change is based on the high first-shock success rate of new defibrillators and the knowledge that if the first shock fails, intervening chest compressions may improve oxygen and glucose delivery to the myocardium, making the subsequent shock more likely to result in defibrillation.

For resuscitation of the newborn infant, there is greater emphasis on the importance of ventilation and less emphasis on the importance of using high concentrations of oxygen.

The guidelines reaffirm that intravenous administration of fibrinolytics (tPA) can improve outcome in patients with acute ischemic stroke who meet the National Institute of Neurological Disorders and Stroke eligibility criteria. This should be done by physicians following a clearly defined protocol, as part of a knowledgeable team, and at an institution committed to stroke care.

The guidelines include new first aid recommendations. "The recommendations in the 2005 AHA Guidelines for CPR and ECC confirm the safety and effectiveness of many approaches, acknowledge that other approaches may not be optimal, and recommend new treatments that have undergone evidence evaluation," the authors write. "These new recommendations do not imply that care involving the use of earlier guidelines is unsafe. In addition, it is important to note that these guidelines will not apply to all rescuers and all victims in all situations."

Future directions recommended by the guideline authors include improvement of lay rescuer education and continuous quality improvement of resuscitation programs.

In an accompanying editorial, Mary Fran Hazinski, RN, MSN, and colleagues note that there was unanimous support for ensuring that rescuers deliver high-quality CPR, even though high-level evidence is insufficient to support many recommendations.

"Although researchers continue to try to identify therapies that may improve short-term outcomes, the goal of resuscitation research remains the identification of interventions that improve neurologically intact survival to hospital discharge following cardiac arrest," the editorialists write. "A striking finding of the 2005 Consensus Conference was the contrast of data that showed the critical role of early, high-quality CPR in increasing rates of survival from cardiac arrest with data that showed that few victims of cardiac arrest receive CPR, and even fewer receive high-quality CPR."

The editorial summarizes several key changes in resuscitation skills and sequences recommended by the new guidelines, often based on consensus opinion and bolstered by laboratory, clinical, and educational research and outcome data rather than by level 1 evidence.

"Simply put: rescuers should push hard, push fast, allow full chest recoil, minimize interruptions in compressions, and defibrillate promptly when appropriate," the editorialists conclude. "In the final analysis, the most important determinant of survival from sudden cardiac arrest is the presence of a rescuer who is trained, willing, able, and equipped to act in an emergency. Our greatest challenge and highest priority is the training of lay rescuers and healthcare providers in simple, high-quality CPR skills that can be easily taught, remembered, and implemented to save lives."

Circulation. Posted online Nov. 28, 2005.

2. Minority of Stroke Patients Receive TPA, Often Due to Treatment Delay

NEW YORK (Reuters Health) Feb 13 - In a study of more than 2000 patients with nonhemorrhagic strokes, just 2.1% received tissue plasminogen activator (tPA), an agent known to improve stroke morbidity and mortality, according to a report in the February 14th issue of Neurology.

In many cases, tPA was not given simply because the patient did not arrive at the hospital within 3 hours of stroke onset, the recommended therapeutic window, Dr. Mathew J. Reeves, from Michigan State University in East Lansing, and colleagues note.

The findings are based on a study of 2566 stroke admissions recorded in Michigan from May to November 2002. Of these, 330 were considered eligible for tPA therapy and 2236 were not. Reasons for not being eligible for tPA therapy included evidence of hemorrhage in 21% of cases, unknown stroke onset time in 35%, onset to arrival time >3 hours in 38%, and a physician-documented contraindication in 6%.

Among the patients considered eligible for tPA, only 13% actually received it, the report shows. Factors predictive of receiving the drug included male gender, use of emergency medical services, and rapid presentation. As a result, out of 2097 patients with nonhemorrhagic strokes, only 43 patients (2.1%) received tPA, the authors note.

"People need to learn the warning signs of stroke and call 911 immediately if they think someone might be having a stroke," Dr. Reeves said in a statement. "It's very important to be able to tell the medical staff when the symptoms started," he added. "It could mean the difference between receiving treatment and not receiving treatment."

Neurology 2006;66:306-312.

3. Intimate Kissing May Be a Risk Factor for Meningococcal Meningitis

WebMD News Author: Laurie Barclay, MD. Feb. 14, 2006 — Intimate kissing is a risk factor for meningococcal meningitis in adolescents, according to the results of a prospective, population-based study reported in the February 10 Online First issue of the BMJ.

"Adolescence is a period of biopsychosocial maturation during which the adoption of potentially risky behaviors may produce a distinct risk profile," write Joanna Tully, MD, from the University of London, United Kingdom, and colleagues. "Studies have found living in college dormitories, patronage of campus bars, and active smoking to be risk factors. Other factors relevant to teenagers may include infection with Epstein-Barr virus, behaviors such as deep kissing, and substance misuse."

From January 1999 to June 2000, 144 adolescents, age 15 to 19 years, with meningococcal disease were recruited at hospital admission in 6 regions representing 65% of the population of England, and 144 controls recruited from the general practitioner were matched to the cases for age and sex. Blood samples and prenasal and throat swabs were taken from case patients at admission and from cases and control patients at the time of the confidential interview regarding potential risk factors.

Of the 144 case-control pairs, 74 (51%) were male; median age was 17.6; and 114 cases (79%) were confirmed microbiologically. Significant independent risk factors for meningococcal disease were history of preceding illness (matched odds ratio [OR], 2.9; 95% confidence interval [CI], 1.4 - 5.9), intimate kissing with multiple partners (OR, 3.7; 95% CI, 1.7 - 8.1), being a university student (OR, 3.4; 95% CI, 1.2 - 10), and preterm birth (OR, 3.7; 95% CI, 1.0 - 13.5). Protective factors were religious observance (OR, 0.09; 95% CI, 0.02 - 0.6) and meningococcal vaccination (OR, 0.12; 95% CI, 0.04 - 0.4).

Study limitations were the biases common to case-control studies, including selection and recall biases and confounding; and exclusion of the few cases that died.

"Activities and events increasing risk for meningococcal disease in adolescence are different from in childhood," the authors write. "Altering personal behaviors could moderate the risk. However, the development of further effective meningococcal vaccines remains a key public health priority."

4. Anticholinergic Use in Elderly May Lead to Diagnosis of Mild Cognitive Impairment

WebMD. News Author: Laurie Barclay, MD. Feb. 3, 2006 — Many elderly patients using anticholinergic drugs are at increased risk of being diagnosed as mildly cognitively impaired, although they are not at increased risk for dementia, according to the results of a longitudinal cohort study reported in the February 1 Online First issue of the BMJ.

"Not only do doctors commonly fail to associate cognitive dysfunction in elderly people with anticholinergic agents, they also underestimate anticholinergic toxicity, prescribing such drugs at high to excessive doses," write Marie L. Ancelin, MD, from the Inserm, in Montpellier, France, and colleagues. "Moreover, an increasing number of such compounds are available without prescription, so there is a high risk of unregulated toxicity."

The investigators enrolled 372 people aged 60 years or older without dementia at recruitment, drawing from 63 randomly selected general practices in the Montpellier region of southern France. Primary endpoints were anticholinergic burden from drug use, cognitive examination, and neurologic assessment.

During the year before cognitive assessment, 9.2% of subjects continuously used anticholinergic drugs. Compared with nonusers, they had poorer performance on tests of reaction time, attention, delayed nonverbal memory, narrative recall, visuospatial construction, and language tasks, even after adjustment for confounding variables. The 2 groups had no differences on tests of reasoning, immediate and delayed recall of word lists, and implicit memory.

Mild cognitive impairment was diagnosed in 80% of the continuous users and in 35% of nonusers, and anticholinergic drug use was a strong predictor of mild cognitive impairment (odds ratio [OR], 5.12; P = .001). However, follow-up after 8 years revealed no difference between users and nonusers in risk of developing dementia.

"Elderly people taking anticholinergic drugs had significant deficits in cognitive functioning and were highly likely to be classified as mildly cognitively impaired, although not at increased risk for dementia," the authors write. "Doctors should assess current use of anticholinergic drugs in elderly people with mild cognitive impairment before considering administration of acetylcholinesterase inhibitors."

The French Social Security, the Fondation de France, the Direction Générale de la Santé, and the Region Languedoc Roussillon supported this study. The authors have disclosed no relevant financial relationships.

BMJ. Posted online February 1, 2006.

5. Neuroprotective Agent Improves Outcome After Ischemic Stroke

By Martha Kerr. NEW YORK (Reuters Health) Feb 09 - The first neuroprotective agent to show positive results in a phase 3 trial significantly reduces disability after ischemic stroke, according to results of the Stroke-Acute Ischemic NXY Treatment (SAINT I) trial published in the February 9, 2006 issue of The New England Journal of Medicine.

The trial involved 1,699 patients with acute ischemic stroke randomly assigned to receive either a 72-hour infusion of NXY-059 (AstraZeneca, Wilmington, DE) or placebo within six hours of the onset of ischemic stroke. The primary endpoint was disability at 90 days as measured by the Rankin scale, with 0 meaning no residual disability and 5 indicating bedbound and requiring constant care.

Dr. James Grotta, of the University of Texas at Houston, and his fellow SAINT I investigators report that disability was significantly reduced in the treatment arm at 90 days. The odds ratio for improvement was 1.20 across all categories of the Rankin scale.

However, mortality and rates of serious and non-serious adverse events were similar in both arms of the study. Active treatment did not result in improvements in neurological function compared with placebo. The subset of patients who also received alteplase had a lower incidence of intracranial hemorrhage.

"Neuroprotective drugs don't do anything to the artery with regards to recanalization or increased flow," Dr. Grotta told Reuters Health. "The mechanism of action is to correct imbalances at the cellular level that result from the blockage." The drug soaks up free radicals.

Dr. Grotta said that SAINT II, involving 3,200 patients, is ongoing to confirm the SAINT I results. Results of SAINT II are expected in 2007. "If the results are positive, then we can expect FDA approval," Dr. Grotta remarked.

Editorialist Dr. Gregory del Zoppa cautions that while promising, the results with NXY-059 might not yield a significant benefit in the bigger picture of ischemic stroke. He writes "effective strategies for ischemic stroke may need to provide protection to the entire neurovascular unit," rather than reducing neuronal cell damage alone.

N Engl J Med 2006;354:588-600.

6. Antipyretic Treatment in Young Children With Fever: Acetaminophen, Ibuprofen, or Both Alternating in a Randomized, Double-blind Study

E. Michael Sarrell, MD; Eliahu Wielunsky, MD; Herman Avner Cohen, MD
Arch Pediatr Adolesc Med. 2006;160:197-202.

Objective To compare the antipyretic benefit of acetaminophen or ibuprofen monotherapy with an alternating regimen of both drugs in young children aged 6 to 36 months.

Design Randomized, double-blind, parallel-group trial.

Setting Three primary pediatric community ambulatory centers in central Israel.

Participants A total of 464 children aged 6 to 36 months with fever.

Intervention Infants were assigned to receive either acetaminophen (12.5 mg/kg per dose every 6 hours) (n = 154) or ibuprofen (5 mg/kg per dose every 8 hours) (n = 155) or to receive alternating acetaminophen and ibuprofen (every 4 hours) (n = 155) for 3 days after a loading dose.

Main Outcome Measures Temperature, stress score, amount of antipyretic received, total days that the infant or caregiver was absent from day care or work, respectively, at the 3-day time point, recurrence of fever, and number of emergency department visits.

Results The group given the alternating regimen was characterized by a lower mean temperature, more rapid reduction of fever, receiving less antipyretic medication, less stress, and less absenteeism from day care as compared with the other groups; all of the differences were statistically significant (P<.001). None of the regimens were associated with a significantly higher number of emergency department visits (P = .65) or serious long-term complications (P = .66). The drug used for initial loading had no effect on outcome in any of the groups.

Conclusions An alternating treatment regimen of acetaminophen (12.5 mg/kg per dose) and ibuprofen (5 mg/kg per dose) every 4 hours for 3 days, regardless of the initial loading medication, is more effective than monotherapy in lowering fever in infants and children.

7. Simple Test Picks Best Candidates for Implantable Cardioverter-Defibrillator Prophylaxis

NEW YORK (Reuters Health) Feb 07 - Microvolt T-wave alternans (MTWA) testing, which evaluates the heart's electrical activity during exercise, may help identify patients who would benefit most from implantable cardioverter-defibrillator (ICD) prophylaxis, US researchers report.

"Until now, it's been difficult to determine which patients need prophylactic ICDs and which are unlikely to be helped by them, but this noninvasive and inexpensive office-based test can identify up to a third of candidates for the devices who are not likely to benefit from them," study co-author, Dr. J. Thomas Bigger, from Columbia University Medical Center in New York, said in a statement.

The new findings, which appear in the Journal of the American College of Cardiology for January 17, are based on a study of 549 patients at 11 centers in the US who were considered possible candidates for ICD prophylaxis. All of the subjects had ejection fractions no greater than 40%, no history of sustained ventricular arrhythmias, and did not currently have atrial fibrillation, unstable coronary artery disease, or severe heart failure.

The average ejection fraction was 25% and ischemic heart disease was identified in 49% of patients, the report indicates. Sixty-six percent of subjects had an abnormal MTWA test, the authors note. The 2-year actuarial rate of death or non-fatal sustained ventricular arrhythmia was 15.0% in the abnormal MTWA group and 2.5% in the normal group, yielding a hazard ratio of 6.5.

The results suggest that a normal MTWA test is useful in identifying patients who would not benefit from ICD prophylaxis. Indeed, the 2-year survival rate for patients with a normal test was high - 97.5%. The findings also indicate that MTWA testing is useful regardless of the cause of left ventricular dysfunction.

"Because the positive and negative accuracy of MTWA were similar in patients with ischemic heart disease and in those with (non-ischemic) cardiomyopathy, clinicians can feel comfortable using MTWA to select patients for ICD prophylaxis without concern for the etiology of left ventricular dysfunction," the authors emphasize.

J Am Coll Cardiol 2006;47:456-463.

8. Magnesium Sulfate Underused in Treatment of Acute Asthma

By Will Boggs, MD. NEW YORK (Reuters Health) Feb 07 - Magnesium sulfate has been shown to be effective in treating patients with severe acute asthma but few such patients receive it as part of their treatment, according to a report in the January Journal of Allergy and Clinical Immunology.

"[Magnesium sulfate is] cheap, safe at this dose, and complements the other evidence-based treatments for acute asthma (systemic corticosteroids, inhaled beta-agonists and anticholinergics)," Dr. Brian H. Rowe from University of Alberta, Edmonton, Canada told Reuters Health.

Dr. Rowe and the Multicenter Airway Research Collaboration (MARC) investigators evaluated the prevalence of use of magnesium sulfate among a group of North American emergency department providers and sought to determine whether magnesium sulfate use adhered to current evidence according to asthma severity and response to initial therapy.

Out of 9,475 emergency department patients with acute asthma, only 240 (2.5%) received magnesium sulfate, the authors report. Patients admitted to the hospital were 10 times more likely than nonadmitted patients to receive magnesium sulfate therapy.

Most survey respondents (92%), however, indicated that their emergency departments had magnesium sulfate and used it for acute asthma. Nearly two thirds of the respondents had personally prescribed it in the preceding six months. In contrast, only 39% of intensive care units that responded to the survey used magnesium sulfate for acute asthma. The main factors influencing magnesium sulfate use were asthma severity and failure of the patient to respond to initial beta-agonists, the researchers note.

"The emergency department data suggest that emergency physicians rarely use the agent in clinical practice," the investigators write. "However, when they do, it appears the use is appropriate."

Most respondents (72%) agreed or strongly agreed that magnesium sulfate is beneficial in the treatment of severe acute asthma, the report indicates, but respondents generally disagreed with the idea that magnesium sulfate should be used in all patients presenting to the emergency department with asthma.

"The survey results suggest that the penetration of the findings from recent trials and systematic reviews has been relatively successful for emergency physicians in both the United States and Canada," the investigators explain. "However, the effectiveness of this agent appears to be less accepted in the ICU settings of the same hospitals."

"[This] suggests that widespread dissemination of the effect of magnesium sulfate has yet to reach all who treat severe asthma exacerbations," the authors conclude.

"Our goal is to avoid intubation if at all possible, and this evidence suggests that intravenous magnesium sulfate may improve outcomes for this patient group," Dr. Rowe said. "In patients who are unresponsive to beta-agonists, present with severe airway obstruction, and/or those with status asthmaticus, treatment with intravenous magnesium sulfate should be a high priority."

"It's already used in the emergency department and ICU for a variety of other problems, so it is already available," Dr. Rowe added.

J Allergy Clin Immunol 2006;117:53-58.

9. Stroke thrombolysis safe at community hospitals

February 9, 2006. By Clementine Wallace. NEW YORK (Reuters Health) - In treating patients with acute ischemic stoke, community hospitals use thrombolytic therapy as safely as do academic medical centers, researchers report in the February issue of Stroke. So far, most prospective trials evaluating the safety and efficacy of thrombolysis have been conducted at university hospitals, say the investigators. Little is known about the safety and efficacy of this procedure in the US community.

"So," co-author Christian Schumacher of Columbia University, New York told Reuters Health, "we wanted to take a look at what's going on."

To do so, Dr. Schumacher and colleagues examined cases reported in a discharge database for the years 1999 to 2002 and covering a sample of all non-federal hospitals. In all, of 248,964 patients admitted through the emergency room with acute ischemic stroke, 2,594 were treated with thrombolysis. This cohort had a higher in-hospital mortality rate than non-thrombolysis patients (11.4% versus to 6.8%). As Dr. Schumacher pointed out, "this was not a surprise since it is those patients with more severe cases of stroke who usually receive thrombolysis."

The rate of intracerebral hemorrhage was 4.4% for the thrombolysis group versus 0.4% for non-thrombolysis patients. "Those findings are also in the range of those obtained in previous prospective trials," said Dr. Schumacher, and relative to academic centers, "show that thrombolysis is applied in the community with the same safety."

Nevertheless, he concluded that "our results can only be preliminary since we had to use a discharge database. A prospective stroke registry that will be similar to the National Cancer Registry is currently in the pilot phase so, in the future, we will have better data to work from."

Stroke 2006;37:440-445.

10. Human Botulism Immunoglobulin May Be Safe, Effective for Infant Botulism

Medscape from WebMD. News Author: Laurie Barclay, MD. Feb. 1, 2006 — Human Botulism Immune Globulin Intravenous (BIG-IV) is safe and effective for infant botulism, according to the results of a randomized trial and open-label study reported in the February 2 issue of The New England Journal of Medicine.

"The equine botulism antitoxin used for adult patients has not been used to treat patients with infant botulism in the United States, because of its serious side effects when given to adults (including serum sickness and anaphylaxis), its short half-life (5 to 7 days), and its potential for lifelong sensitization to equine proteins," write Stephen S. Arnon, MD, from the California Department of Health Services in Richmond, and colleagues. "For these reasons, we created BIG-IV, a human-derived botulism antitoxin that neutralizes botulinum toxin.

In a 5-year, double-blind trial, 122 infants with suspected (and subsequently laboratory-confirmed) infant botulism were randomized to receive BIG-IV or placebo within 3 days after hospital admission. Of these 122 cases, 75 were caused by type A Clostridium botulinum toxin, and 47 by type B toxin. The primary efficacy outcome measure in this trial was the mean length of hospital stay. The investigators subsequently performed a 6-year nationwide, open-label study of 382 laboratory-confirmed cases of infant botulism treated within 18 days after hospitalization.

In the randomized trial, infants treated with BIG-IV compared with the control group had a reduction in the mean length of the hospital stay from 5.7 weeks to 2.6 weeks (P < .001). BIG-IV treatment was also associated with a reduction in mean duration of intensive care by 3.2 weeks (P < .001), in mean duration of mechanical ventilation by 2.6 weeks (P = .01), in mean duration of tube or intravenous feeding by 6.4 weeks (P < .001), and in mean hospital charges per patient by $88,600 (in 2004 US dollars; P < .001). There were no serious adverse events ascribed to BIG-IV treatment, although some patients experienced a transient, blush-like erythematous rash.

In the open-label study, infants treated with BIG-IV within 7 days of admission had a mean length of hospital stay of 2.2 weeks. Early treatment with BIG-IV shortened the mean length of stay significantly more than did later treatment.

"Prompt treatment of infant botulism type A or type B with BIG-IV was safe and effective in shortening the length and cost of the hospital stay and the severity of illness," the authors write. "Keen clinical awareness may be needed to recognize this rare disease, since infant botulism was suspected at admission in only half the infants enrolled in the randomized trial.... Treatment should be given as soon as possible after hospital admission and should not be delayed for confirmatory testing of feces or enema."

The Food and Drug Administration (FDA) Office of Orphan Products Development and the California Department of Health Services supported this study and 2 of its authors.

An accompanying FDA perspective by M.E. Haffner, MD, director of the Office of Orphan Products Development, discusses drug development outcomes related to the Orphan Drug Act passed in 1982.

"By most measures, ... the Orphan Drug Act has been successful in enabling patients with rare diseases to receive treatments that would otherwise never have been developed," Dr. Haffner writes. "The Orphan Drug Act has had not only domestic but also global benefits for patients with serious and rare diseases — benefits that will only expand as genomic medicine fuels more rapid progress in alleviating the effects of devastating diseases."

N Engl J Med. 2006;354:445-447, 462-471

11. Correlation of initial ED pulse oximetry values in asthma severity classes (steps) with the risk of hospitalization

Rodney B. Boychuk, et al. Amer J Emerg Med 2006;24:48-52.

Abstract
Background
The oxygen saturation (OSAT) of wheezing children presenting to an emergency department has been shown to be a predictor for hospitalization. The purpose of this study is to determine if hospitalization predictive power can be increased by further stratifying this by the step severity categories (based on chronic symptoms).

Methods
Data were collected prospectively at 6 centers over a 22-month period on 1219 pediatric patients. Asthma step severity categorization was determined by chronic symptom history. Presenting ED OSAT values, extensive clinical histories (obtained in the ED and during several telephone follow-up calls by study personnel), treatments, and disposition were recorded for each study subject.

Results
The overall hospitalization rate was 15%. Hospitalization rates in severity step categories 1, 2, 3, and 4 were 13%, 16%, 13%, and 22% (P = .008), respectively. Hospitalization rates by presenting OSATs were 98% or higher (6%), 95% to 97% (12%), 93% to 94% (28%), 90% to 92% (45%), 85% to 89% (65%), and 80% to 84% (100%). From 95% to 100% OSAT values, hospitalization rates are similar between the severity groups.

In the 93% to 94% OSAT group, the hospitalization rate is 43% in step category 4 patients, compared with 27%, 24%, and 13% for step categories 1, 2, and 3, respectively, but this difference was not statistically significant. At presenting OSAT values of 90% and below, the hospitalization rates are higher but did not differ significantly between the severity step groups. No recognizable trend was present to suggest that the hospitalization predictive value is increased by adding the step severity categories.

Conclusions
The presenting OSAT is the dominant initial predictor of hospitalization. The step severity categories do not appear to provide substantial additional predictive value for hospitalization.

12. Study Finds Little Benefit From Low-Fat Diets ...

By Jennifer Couzin. ScienceNOW Daily News. 7 February 2006

A massive study of nearly 49,000 older women examining links between low-fat diets and health found that the diets don't seem to stave off cancer and heart disease--but confusion remained about how to interpret the results. Women had trouble sticking to the diets, and the study may not have been long enough to gauge diet's effects on slow-growing cancers.

The 8-year diet study is the second of three from the Women's Health Initiative (WHI), an effort launched in the early 1990s because few women were being included in clinical trials. It sought to examine whether a low-fat diet could help prevent breast cancer, colorectal cancer, and cardiovascular disease. The first WHI study found that hormone replacement therapy raised the risk of breast cancer and heart disease, prompting a stampede away from the drugs. The third examines the effects of calcium and vitamin D on bone health and will be published next week.

The diet study, published in the 8 February Journal of the American Medical Association, included 40 medical centers around the United States. More than 19,000 women went on a diet low in fat and high in fruits, vegetables, and grains. Some 29,000 others acted as a comparison group. WHI researchers hoped that the dieters could slash their fat intake to 20% of calories, while the comparison group would hover around 40%. But, as is common in nutrition studies, participants had trouble sticking to the diet. After 6 years, dieters were consuming 30% of their calories from fat, compared with 38% in the control group.

After 8 years, there was no difference in colorectal cancer or cardiovascular disease rates; today it's thought that the type of fat consumed plays a more powerful role in heart disease and stroke than the quantity. Dieters did suffer 9% fewer cases of breast cancer, but that result was not statistically significant, meaning it could have occurred by chance.

That frustrates researchers. "We have a very sobering situation," says Harvard University epidemiologist Walter Willett. While praising the dedication of WHI investigators, he notes that "this was the biggest and most expensive [diet] study ever done," and it arrived at "a very crude result." In addition to adherence, the study might have been limited by its length, because diet's effect on cancer may take more than 8 years to surface, says Willett.

It's also not clear whether the older age of the women had an effect; researchers don't know whether intervening earlier in life to prevent cancer works better than intervening later. Still, some consider the breast cancer finding meaningful. "I don't think it can be dismissed," says Lynn Rosenberg of Boston University School of Public Health. A low-fat diet is currently being tested against breast cancer in younger women in Canada.

JAMA 2006;629-666,693-694.

13. FDA Safety Changes: Imodium

Web MD News Author: Yael Waknine. Feb. 1, 2006 — The U.S. Food and Drug Administration (FDA) has approved safety labeling revisions to advise of contraindications and drug interactions associated with use of loperamide capsules, and the risk for hypersensitivity reactions and decreased renal function in patients receiving sirolimus therapy.

Loperamide (Imodium) Contraindicated in Infants Younger Than 2 Years
On October 21, the FDA approved safety labeling revisions for loperamide HCl capsules (Imodium, made by McNeil Consumer and Specialty Pharmaceuticals) to advise of contraindications and drug interactions associated with their use.

Loperamide capsules should not be used in patients with a known sensitivity to the active ingredient or any of the excipients, including cornstarch, talc, magnesium stearate, and FD&C Yellow No. 6. Loperamide also is contraindicated for use in patients with abdominal pain in the absence of diarrhea and in infants younger than 24 months.

In addition, loperamide should not be used as the primary therapy in patients with acute dysentery; acute ulcerative colitis; bacterial enterocolitis caused by invasive organisms, including Salmonella, Shigella, and Campylobacter; or pseudomembranous colitis associated with use of broad-spectrum antibiotics.

In general, loperamide should not be used when peristalsis inhibition is to be avoided because of the risk for significant sequelae, such as ileus, megacolon, and toxic megacolon. Treatment should be discontinued promptly in patients who develop constipation, abdominal distention, or ileus.

Loperamide should be used with caution in patients with hepatic impairment because of reduced first-pass metabolism. Patients with reduced hepatic function should be monitored closely for signs of central nervous system toxicity while receiving loperamide.

The FDA also advised that recommended doses of loperamide (2 mg up to 16 mg daily) be used with caution in patients receiving quinidine or ritonavir because of the risk for enhanced central effects.

Because loperamide is a P-glycoprotein substrate, plasma levels can be significantly increased with concurrent use of P-glycoprotein inhibitors, such as quinidine or ritonavir. In pharmacokinetic studies, loperamide plasma levels from a single 16-mg dose were increased 2- to 3-fold by concomitant administration of a single 600-mg dose of quinidine or ritonavir.

Concurrent use of loperamide may also decrease the therapeutic effect of saquinavir. In studies, concomitant administration of 16-mg loperamide and 600-mg saquinavir increased saquinavir exposure by 54%. The FDA recommends close monitoring of saquinavir therapeutic efficacy in patients receiving both drugs.

Loperamide is indicated for the control and symptomatic relief of acute nonspecific diarrhea and of chronic diarrhea associated with inflammatory bowel disease. It is also indicated for reducing the volume of discharge from iliostomies. Because treatment of diarrhea is symptomatic, only specific therapies should be used to target its underlying etiology when appropriate.

14. Drug Therapy Before PCI Not Useful, Possibly Harmful

NEW YORK (Reuters Health) Feb 13 - As a treatment for ST-elevation MI (STEMI), coronary-opening drug therapy before percutaneous coronary intervention (PCI) -- so-called "facilitated" PCI -- does not improve outcomes and may actually be harmful, according to the results of two studies in the February 14th online issue of The Lancet.

Dr. Ellen C. Keeley, from the University of Texas Southwestern Medical Center in Dallas, and colleagues conducted a review of 17 randomized trials that involved 2237 patients treated with facilitated PCI and 2267 treated with primary PCI. Although facilitated PCI resulted in greater initial coronary flow than did primary PCI, the final flow outcomes were similar, the report indicates.

Treatment with the facilitated approach was associated with significantly higher rates of death, non-fatal reinfarction, urgent target vessel revascularization, and major bleeding. The rates of any of these outcomes, with either approach, did not exceed 7%.

Further analysis indicated that the elevated adverse event rate seen with the facilitated approach was mainly confined to thrombolytic-based regimens. Moreover, use of thrombolytic-based regimens was also tied to elevated hemorrhagic and total stroke rates. With either approach, the rate of these outcomes did not exceed 1.1%. Given these findings, the authors recommend against the use of thrombolytic-based regimens for facilitated PCI and note that other facilitated regimens should not be used outside of a randomized trial setting.

In the second study, Dr. Frans Van de Werf, from Gasthuisberg University Hospital in Leuven, Belgium, and colleagues assessed the outcomes of 1667 patients who were randomized to receive tenecteplase-facilitated or primary PCI for acute STEMI.

The authors note that they had planned to include 4000 patients in the study, but that the safety monitoring board stopped the trial early due to a higher rate of in-hospital death in the tenecteplase group: 6% vs. 3% (p = 0.0105). Moreover, the rate of the primary endpoint, a composite of death, heart failure, or shock within 90 days, was 19% in the facilitated group, significantly higher than the 13% rate in the primary PCI group.

In-hospital strokes and ischemic cardiac complications were also more common in the tenecteplase group, the report indicates. The facilitated approach with tenecteplase was associated with more major adverse events than primary PCI and therefore cannot be recommended, Dr. Van de Werf's team concludes.

Although it is still possible that certain subgroups of patients might benefit from facilitated PCI, "there is currently no justification to pretreat any patient in whom primary angioplasty is intended with thrombolytic therapy or glycoprotein IIb/IIIa inhibitors, or both, irrespective of the time since onset of symptoms or delays expected to catheterization," Dr. Gregg W. Stone, from Columbia University in New York, and Dr. Bernard J. Gersh, from the Mayo Clinic in Rochester, Minnesota, comment in a related editorial.

Lancet 2006.

15. Inhaled Insulin: Exubera Approved Despite Initial Lung Function Concerns

Laurie Barclay, MD. Feb. 9, 2006 — Despite initial concerns regarding lung function, the US Food and Drug Administration (FDA) approved Pfizer's inhaled insulin Exubera for adult patients with type 1 and type 2 diabetes. The approval came on January 27, one day after approval of this drug in the European Union. This inhaled powder form of recombinant human insulin is the first new insulin delivery option introduced since the discovery of insulin in the 1920s. Trial data suggest that use of Exubera is associated with initial but nonprogressive declines in pulmonary function, with efficacy comparable to that of regular insulin and with the advantage of patient preference.

"The pulmonary safety of Exubera was a major focus of the FDA in the development and subsequent review of Exubera," FDA public affairs specialist Christine S. Parker told Medscape. "In patients without overt lung diseases, such as asthma or chronic obstructive pulmonary disease (COPD), and without concurrent smoking, a small decline in 2 common lung function parameters — FEV1 and DLCO — was seen very soon after starting the drug. However, this decline did not worsen over time from the extensive database available to FDA and seems to revert to baseline levels if the drug is stopped."

In nonsmokers without pulmonary disease at baseline, there were no severe decreases in lung function attributed to Exubera, and high-resolution chest computed tomography revealed no evidence of notable lung changes. Completed phase 2 and 3 studies that followed patients for up to 4 years indicate that the differences over time in pulmonary function changes between patients treated with Exubera and control patients are small, nonprogressive, clinically insignificant, and reverse after discontinuation of Exubera therapy.

"There was some evidence that in people who stopped Exubera,...the decline in lung function was at least partially reversible, but it was not a large enough group to be able to draw a firm conclusion about that," Jay S. Skyler, MD, MACP, a professor of endocrinology, diabetes, and metabolism, and associate director of the Diabetes Research Institute at the University of Miami Miller School of Medicine in Florida, told Medscape. "The pulmonologists describe it as an acute response to exposure, a form of acute injury response that you get on initial exposure but that does not show any further evidence of decline over 2 to 4 years. What we don't yet have any idea about is what happens over 5 to 10 years."

However, few patients with progressive diabetes may actually be taking Exubera for 5 years or more, explained Dr. Skyler, who is also chairman of the National Institute of Diabetes and Digestive and Kidney Diseases' Type 1 Diabetes TrialNet. He was also a lead investigator on a study of Exubera in patients with type 1 diabetes. Most of these patients would require insulin injections after 5 years, either alone or with inhaled insulin, and most would be accustomed to self-injection and find less of an advantage to the inhaled formulation than would initial insulin users.

"The FDA, preceded by its advisory committee, found that Exubera is safe in patients with normal lung function," Ms. Parker said. "More data are needed to make a final determination on the safety in individuals with asthma or COPD and therefore the drug is not recommended, although not contraindicated, for use in those populations at this time."

Although Pfizer did not extensively study smokers, these patients have a 2 – to 5-fold higher exposure to inhaled insulin than do non-smokers, and exposure can fluctuate with changes in smoking habits. "Smoking is a contraindication to Exubera, even if the patient quit within 6 months, as is use in patients with unstable or poorly controlled lung disease," Ms. Parker says.

Recommended precautions are that patients be screened with pulmonary function tests, such as FEV1, before starting Exubera, after 6 months of treatment, and yearly thereafter. If there is a persistent, significant decrease in FEV1, Exubera should be discontinued. In clinical trials, other drug-related adverse effects included cough, shortness of breath, sore throat, and dry mouth. To help ensure that Exubera is used correctly, pharmacists dispensing the drug are required to distribute a medication guide containing FDA-approved information written especially for patients.

To further evaluate pulmonary safety with extended use, Pfizer has agreed to conduct a large safety study of 5000 patients over 5 years; to complete and report ongoing studies of inhaled insulin use in patients with asthma and COPD; and to provide 5- and 7-year safety information from ongoing studies in patients with type 1 and type 2 diabetes. Pfizer will also annually evaluate and report the extent to which Exubera is being prescribed for and used by smokers, to assess whether patient and physician labeling are effectively preventing such use.

Other precautions in the drug labeling are similar to those provided for other insulin products, including hypoglycemia necessitating blood glucose monitoring. Because of insufficient data on safety and efficacy, Exubera is not recommended for use in children at this time.

Dr. Skyler noted that Exubera is associated with formation of more insulin antibodies than are injectable formulations, but that "the levels are trivial compared to what we used to see with the impure insulins. In the clinical trials, there have been no demonstrated effects with Exubera of antibodies either impairing the action of insulin, or unexpected insulin release causing hypoglycemia, or any allergic reaction."

Exubera safety and efficacy have been evaluated in clinical trials enrolling a total of approximately 2500 adult patients with type 1 and type 2 diabetes. However, Dr. Skyler said that most of these trials have compared preprandial Exubera with regular insulin, whereas most experts would prefer to use a rapid-acting insulin analogue in this situation.

"In none of the studies to date in which Exubera was compared to insulin have they been able to achieve the target blood glucoses that we desire to and can achieve when meticulously using insulin analogues and insulin pumps," Dr. Skyler pointed out. "It remains an open question whether or not you can achieve optimal control with Exubera — it just hasn't been demonstrated in the trials to date."

In the October 18, 2005, issue of the Annals of Internal Medicine, Julio Rosenstock, MD, from the Dallas Diabetes and Endocrine Center in Texas, and colleagues reported on a 12-week trial of 309 patients with type 2 diabetes, no clinically significant respiratory disease, and hemoglobin A1c level of 8% to 11% who were receiving dual oral therapy with an insulin secretagogue and sensitizer. Inhaled insulin improved overall glycemic control and hemoglobin A1c level when added to or substituted for dual oral agent therapy. Hypoglycemia, mild weight gain, mild cough, and insulin antibodies were more common in patients receiving inhaled insulin, but pulmonary function was similar among all groups.

Dr. Skyler and colleagues performed a trial in 328 patients with type 1 diabetes who were receiving twice-daily subcutaneous basal injections of neutral protamine Hagedorn (NPH) insulin and were randomized to receive also either premeal Exubera or subcutaneous regular insulin. After 6 months of treatment, glycemic control was comparable in both groups, with decreases in mean hemoglobin A1c of 0.3% with Exubera and and 0.1% with subcutaneous insulin. Although 2-hour postprandial declines in glucose were similar in between the groups, fasting plasma glucose levels declined more in the patients using Exubera. The study was published in the July 2005 issue of Diabetes Care.

"Exubera is an effective insulin and in head-to-head trials with short-acting insulins, appears as effective," Ms. Parker said. "Inhaled insulin from Exubera has an onset comparable to the fast-acting insulin analogues, such as Apidra, and a duration of action similar to regular insulin. It is therefore an option to use as a mealtime insulin, similar to the way the short-acting insulins are used."

Pharmacodynamic studies reveal that Exubera reaches peak insulin concentration more quickly than injected regular insulin, with peak insulin levels achieved at 49 minutes (range, 30 - 90 minutes) for Exubera compared with 105 minutes (range, 60 - 240 minutes) for regular insulin. In patients with type 1 diabetes, inhaled insulin may be added to longer-acting insulins as a replacement for short-acting insulin taken with meals. In patients with type 2 diabetes, inhaled insulin may be used alone, along with oral hypoglycemic agents or with longer-acting insulins.

"How broadly Exubera will be used is a matter of conjecture," Ms. Parker said. "It is worth noting that this product will not replace all insulin injections for patients with type 1 diabetes and in some patients with type 2 diabetes. This is because most all type 1 patients and a proportion of type 2 patients will still need long-acting insulins for basal control of blood sugars."

Compliance and patient satisfaction studies done during the clinical trials showed that patients were quite satisfied with the inhaled formulation and that quality-of-life indices improved. However, Dr. Skyler noted that patients who are motivated to participate in a clinical trial may be subject to bias favoring satisfaction with their assigned regimen.

"There's certainly a lot of pent-up enthusiasm and desire for an inhaled insulin," Dr. Skyler said, noting overwhelming local response to recent media coverage. "We've never had such a response to anything we've done — even the first islet transplants."

Although no cost-effectiveness studies have been done, and the cost per prescription has not yet been made known to the investigators, Dr. Skyler said he believes that reduction of diabetic complications in greater numbers of people could translate into healthcare savings.

"Exubera could be very helpful on a population basis to reduce the glucose burden in the country, and the complications of glycosemia, by improving overall diabetes management in people with type 2 diabetes who are otherwise reluctant to go onto insulin when they need it, and who are not having adequate glucose control, " Dr. Skyler said. "Since there is no unique advantage other than inducing some patients to use insulin earlier, the potential for widespread use of Exubera is going to be contingent on the value that payors place on it, at what price it is marketed, and what people are actually willing to pay."

Dr. Skyler is a consultant for Pfizer on Exubera and chaired the company's Global Advisory Committee. He is also a consultant regarding inhaled insulins for Mankind, Novo Nordisk, and KOS, and he is a consultant for Eli Lilly on matters unrelated to inhaled insulins.

Reviewed by Gary D. Vogin, MD

Lit Bits: February 4, 2006

From the recent medical literature...

1. Administration of steroids in acute exacerbations of COPD

Shweta Gidwani, Clinical Effectiveness Fellow and Craig Ferguson, Clinical Research Fellow. Manchester Royal Infirmary . Emerg Med J 2006; 23:142-143.

A short cut review was carried out to establish whether post discharge steroids are beneficial in acute exacerbations of COPD. 237 papers were found using the reported search, of which one presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of this best paper are tabulated. It is concluded that post-discharge steroids are beneficial in the short term.

Clinical scenario
A 55 year old man, known to have COPD, attends the Emergency Department complaining of being more short of breath than usual and having a productive cough. You treat him with continuous nebulised bronchodilator therapy, oral steroids and antibiotics. He starts to improve and, on reassessing him clinically after reviewing his chest x-ray and blood tests you decide to discharge him with community follow up. You wonder whether he should continue on a short course of steroids in addition to his antibiotics.

Three part question
In [patients with an acute exacerbation of COPD] are [steroids prior to discharge better than no steroids] at [improving outcome and hastening recovery]?

Search strategy (details not included)
COCHRANE LIBRARY Issue 4 2005
Ovid MEDLINE 1966-November 2005
Embase 1980–2005 Week 47

Outcome
237 papers found of which one was a recently updated well done systematic review found

Comments
Treatment of patients with acute exacerbations of COPD with corticosteroids is a common practice. The evidence shows that this significantly improves lung function and breathlessness up to the first 72 hours. It also reduces the treatment failure within the first 30 days. However, these effects appear to be short lived and there is no effect on mortality. Also there is an increased incidence of adverse effects related to steroids. However, the studies were not designed to look at long term mortality outcomes and this seems reasonable as the intervention was a short course of steroids and hence the effects were observed for a maximum period of 30 days.

CLINICAL BOTTOM LINE: The use of steroids has clear benefit in the acute management of the patient but with added risk of adverse drug effects and with no clear long term benefit in improvement in lung function or increased life expectancy

2. Model identifies low-risk patients with pulmonary embolism, so low-risk that outpt management is considered safe

January 25, 2006

NEW YORK (Reuters Health) - A simple rule based on 10 demographic, history, and clinical factors predicts 30-day risk of mortality among patients with pulmonary embolism (PE) and identifies those who could be safely treated as outpatients, investigators report in the Archives of Internal Medicine for January 23.

Authors of two other papers in the Archives observe that bedside testing, including testing for D-dimer, can identify some patients at low risk of PE who don't require imaging studies.

Although evidence is growing that outpatient treatment is safe for selected patients with nonmassive PE, there are no explicit clinical criteria to accurately identify those who are at low risk of adverse outcomes, Dr. Drahomir Aujesky, from Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland, and colleagues note in their report (this abstract follows the news report below).

They identified patients with PE treated between 2000 and 2002 whose data were registered in the Pennsylvania Health Care Cost Containment Council database. They derived a prediction rule using classification tree analysis, with 30-day mortality as the outcome and demographic and clinical variables as predictors.

The final 10 predictors were age 70 or older, a history of five comorbid diseases (cancer, heart failure, chronic lung disease, chronic renal disease, and cerebrovascular disease), and the presence of four clinical abnormalities (pulse rate 110 beats/minute or higher, systolic blood pressure < 100 mm Hg, altered mental status, and arterial oxygen saturation < 90%). In the 10,354-patient derivation sample, overall 30-day mortality was 9.2%. Among the 21.6% of subjects deemed to be at low risk based on the model, 30-day mortality was 0.6%.

In the investigators' internal validation sample, which included 5177 patients, overall 30-day mortality was 9.5%. It was 1.5% among the 21.6% found to be at low risk, based on the prediction rule. They externally validated their sample using 221 patients treated at three hospitals in Switzerland and France. The overall mortality was 2.7%. Among the 33.9% estimated to be at low risk, none died within 30 days of the initial examination.

Dr. Aujesky's team calculates that the prediction rule has a sensitivity of 97% to 100% and negative predictive value of 98% to 100% for predicting 30-day mortality. They estimate that up to $91 million per year could be saved in the US if 20% of patients with low-risk PE were treated as outpatients. However, they recommend that their prediction rule be validated in a prospective study.

For the second study, Dr. Marc A. Rodger, from the University of Ottawa in Ontario, Canada, and his associates randomly assigned patients suspected of having PE to an initial ventilation-perfusion (V/Q) scan or to BIOPED (bedside investigation of pulmonary embolism diagnosis) that evaluated clinical variables, a D-dimer test, and alveolar dead-space fraction. Variables included in the BIOPED analysis were clinical signs or symptoms of DVT, alternate diagnosis less likely than PE, heart rate > 100 beat/min, previous DVT or PE, major surgery or immobilization within 4 weeks, active malignant neoplasm and hemoptysis.

There were 199 subjects in the BIOPED group and 200 in the V/Q scan group. During follow, 2.4% of patients not taking anticoagulant agents in the BIOPED group and 3.0% in the V/Q scan group had a venous thromboembolism event during 3-month follow-up.

The BIOPED technique eliminated the need for diagnostic imaging in 34% of patients with suspected PE, the authors report.

In the third paper, Dr. Gregoire Le Gal, from Brest University Hospital in France and his colleagues note that D-dimer testing still has a place when evaluating patients for PE who have had a previous venous thromboembolism (VTE). However, the proportion of negative results will be lower in such patients.

The researchers analyzed data from two prospective studies that included 1721 consecutive patients with suspected PE. Previous VTE was documented in 308.
The D-dimer level was less than 500 'g/L in 32.7% of those without history of VTE and in 15.9% of those with a previous VTE. Among those in whom PE was ruled out by a negative D-dimer test result and who did not receive anticoagulant agents, there were no VTEs during the next 3 months in those with or without a previous VTE.

"The combination of a low pretest probability and a negative D-dimer test result should obviate the need for further testing," Dr. Lisa K. Moores, from Walter Reed Army Medical center in Washington, DC, states in a related editorial.

However, she notes that in patients with comorbidities, elderly patients, and those with a history of VTE, "an alveolar dead-space measurement could be used in combination with pretest probability to guide the selection of patients who require further diagnostic testing."

Arch Intern Med 2006;166:147-148,169-187.

ABSTRACT for A Prediction Rule to Identify Low-Risk Patients With Pulmonary Embolism. Drahomir Aujesky, MD, and others including Michael J. Fine, MD, MSc (one of the docs behind the pneumonia clinical prediction rules we use at Kaiser). Arch Intern Med. 2006;166:169-175.

Background A simple prognostic model could help identify patients with pulmonary embolism who are at low risk of death and are candidates for outpatient treatment.

Methods We randomly allocated 15 531 retrospectively identified inpatients who had a discharge diagnosis of pulmonary embolism from 186 Pennsylvania hospitals to derivation (67%) and internal validation (33%) samples. We derived our rule to predict 30-day mortality using classification tree analysis and patient data routinely available at initial examination as potential predictor variables. We used data from a European prospective study to externally validate the rule among 221 inpatients with pulmonary embolism. We determined mortality and nonfatal adverse medical outcomes across derivation and validation samples.

Results Our final model consisted of 10 patient factors (age 70 years; history of cancer, heart failure, chronic lung disease, chronic renal disease, and cerebrovascular disease; and clinical variables of pulse rate 110 beats/min, systolic blood pressure <100 mm Hg, altered mental status, and arterial oxygen saturation <90%). Patients with none of these factors were defined as low risk. The 30-day mortality rates for low-risk patients were 0.6%, 1.5%, and 0% in the derivation, internal validation, and external validation samples, respectively. The rates of nonfatal adverse medical outcomes were less than 1% among low-risk patients across all study samples.

Conclusions This simple prediction rule accurately identifies patients with pulmonary embolism who are at low risk of short-term mortality and other adverse medical outcomes. Prospective validation of this rule is important before its implementation as a decision aid for outpatient treatment.

3. American Heart Association Does Not Recommend Isoflavone Supplements

Jan. 25, 2006 —The American Heart Association (AHA) nutrition committee found a lack of benefit from soy and therefore does not recommend isoflavone supplements in food or pills, according to a report in the January 17 Rapid Access issue of Circulation.

"Soy protein and isoflavones (phytoestrogens) have gained considerable attention for their potential role in improving risk factors for cardiovascular disease," write Frank M. Sacks, MD, and colleagues from the AHA Nutrition Committee. "This scientific advisory assesses the more recent work published on soy protein and its component isoflavones."

In most of 22 randomized trials reviewed, isolated soy protein with isoflavones, as compared with milk or other proteins, decreased low-density lipoprotein (LDL) cholesterol concentrations by an average amount of about only 3%. This reduction was small relative to the large amount of soy protein tested in these studies, which was about 50 g, or half the usual total daily protein intake. There were no significant effects on high-density lipoprotein (HDL) cholesterol, triglycerides, lipoprotein(a), or blood pressure.

In 19 studies of soy isoflavones, there was no effect on LDL cholesterol or on other lipid risk factors. The panel also noted no demonstrated benefit on vasomotor symptoms of menopause, and mixed results in terms of slowing postmenopausal bone loss. Similarly, the efficacy and safety of soy isoflavones for prevention or treatment of cancer of the breast, endometrium, and prostate are undetermined, and evidence from clinical trials is limited but suggests a possible adverse effect.

"For this reason, use of isoflavone supplements in food or pills is not recommended," the authors write. "Thus, earlier research indicating that soy protein has clinically important favorable effects as compared with other proteins has not been confirmed. In contrast, many soy products should be beneficial to cardiovascular and overall health because of their high content of polyunsaturated fats, fiber, vitamins, and minerals and low content of saturated fat."

Circulation. Posted online January 17, 2006.

4. Myocardial Injury and Long-term Mortality Following Moderate to Severe Carbon Monoxide Poisoning.

Christopher R. Henry, BS; et al. JAMA. 2006;295:398-402.

Context Carbon monoxide (CO) poisoning is a common cause of toxicological morbidity and mortality. Myocardial injury is a frequent consequence of moderate to severe CO poisoning. While the in-hospital mortality for these patients is low, the long-term outcome of myocardial injury in this setting is unknown.

Objective To determine the association between myocardial injury and long-term mortality in patients following moderate to severe CO poisoning.

Design, Setting, and Participants Prospective cohort study of 230 consecutive adult patients treated for moderate to severe CO poisoning with hyperbaric oxygen and admitted to the Hennepin County Medical Center, a regional center for treatment of CO poisoning, between January 1, 1994, and January 1, 2002. Follow-up was through November 11, 2005.

Main Outcome Measure All-cause mortality.

Results Myocardial injury (cardiac troponin I level 0.7 ng/mL or creatine kinase-MB level 5.0 ng/mL and/or diagnostic electrocardiogram changes) occurred in 85 (37%) of 230 patients. At a median follow-up of 7.6 years (range: in-hospital only to 11.8 years), there were 54 deaths (24%). Twelve of those deaths (5%) occurred in the hospital as a result of a combination of burn injury and anoxic brain injury (n = 8) or cardiac arrest and anoxic brain injury (n = 4). Among the 85 patients who sustained myocardial injury from CO poisoning, 32 (38%) eventually died compared with 22 (15%) of 145 patients who did not sustain myocardial injury (adjusted hazard ratio, 2.1; 95% confidence interval, 1.2-3.7; P = .009).

Conclusion Myocardial injury occurs frequently in patients hospitalized for moderate to severe CO poisoning and is a significant predictor of mortality.

5. Chronic Stress at Work Raises Risk for Metabolic Syndrome

Does this apply to us??

NEW YORK (Reuters Health) Jan 19 - People with high job stress over a protracted period of time have double the risk of developing the metabolic syndrome, British investigators report. This relationship may help explain the reported link between stressors of everyday life and heart disease.

Dr. Tarani Chandola and colleagues at University College London evaluated data from the prospective Whitehall II study, which recruited 10,308 participants ages 35 to 55 from 20 civil service departments between 1985 and 1988.

Surveys regarding job demands, job control, lack of social support at work, and health behaviors were completed at baseline and in 1989, 1991-1993, and 1997-1999. There were 7034 subjects remaining at the final evaluation.

Subjects underwent clinical examinations to determine the prevalence of metabolic syndrome, defined by the presence of three or more risk factors (abdominal obesity, hypertriglyceridemia, low high density lipoprotein cholesterol, hypertension, and hyperglycemia).

As reported in BMJ Online First, published on January 19, work stress was defined as being in the lowest third of work social support, with high job demands and low job control.

Compared with subjects who never reported work stress, those who reported work stress three or more times over the 14-year study period had double the risk of metabolic syndrome.

The authors observed a dose-response relationship. After adjusting for age, employment grade, health behaviors and excluding patients who were obese at baseline, the odds ratio for those reporting high work stress only one time was 1.11, rising to 1.47 for those reporting high job stress at two time points. The odds ratio was 2.29 for those with high job stress three or more times (p = 0.01 for trend).

Dr. Chandola's group also observed a social gradient, in which those in the lowest employment grades had more than double the risk of developing metabolic syndrome than those in the highest grades. After adjusting for work stress and health behaviors, the social gradient was no longer significant.

The mechanism underlying the relationship between work stress and metabolic syndrome remains unknown. The authors posit that the effects of stress on the autonomic nervous system, neuroendocrine activity, biological resilience, and adrenocortical function may be involved.

BMJ Online First 2006.

6. First Complex Seizure? How Many of These have Intracranial Pathology that requires Emergency Neurosurgical or Medical Intervention?

Teng D, et al.Risk of Intracranial Pathologic Conditions Requiring Emergency Intervention After a First Complex Febrile Seizure Episode Among Children. Pediatrics 2006; 117: 304-308.

OBJECTIVE. To determine the likelihood of intracranial pathologic conditions requiring emergency neurosurgical or medical intervention among children without meningitis who presented to the pediatric emergency department after a first complex febrile seizure.

METHODS. We performed a retrospective review of prospectively collected data for children in neurologically normal condition who presented to a single pediatric emergency department after a first complex febrile seizure (focal, multiple, or prolonged). The complex febrile seizure classification was determined independently by 2 epileptologists. The presence of intracranial pathologic conditions was determined through review of neuroimaging results, telephone interviews, or medical record review.

RESULTS. Data for 71 children with first complex febrile seizures were analyzed. Fifty-one (72%) had a single complex feature (20 focal, 22 multiple, and 9 prolonged), and 20 (28%) had multiple complex features. None of the 71 patients (1-sided 95% confidence interval: 4%) had intracranial pathologic conditions that required emergency neurosurgical or medical intervention.

CONCLUSIONS. For children with first complex febrile seizures, the risk of intracranial pathologic conditions that require emergency neurosurgical or medical intervention is low, which suggests that routine emergency neuroimaging for this population is unnecessary.

7. Nasal Steroids for Acute Rhinosinusitis

Because the common cold often includes both nasal and sinus symptoms, the term "rhinosinusitis" has become popular. Inflammation contributes to rhinosinusitis symptoms, and the effect of antibiotics on mild sinusitis is controversial. Therefore, researchers performed a double-blind, randomized trial in which 981 patients with acute, uncomplicated rhinosinusitis received the nasal corticosteroid mometasone furoate (Nasonex; 200 µg, either once or twice daily, for 15 days), oral amoxicillin (500 mg thrice daily for 10 days), or placebo. The study was sponsored by the maker of mometasone.

All patients had been symptomatic for 7 to 28 days with combinations of nasal congestion, nasal drainage, sinus headache, and facial pain or pressure. Patients with high fever and severe unilateral facial pain were excluded. Compared with results in the placebo group, improvement in symptoms during the 15-day treatment course was significantly greater in both mometasone groups, but not in the amoxicillin group. Improvement was greater with twice-daily than with once-daily mometasone. However, the benefit of mometasone was modest: For example, mean symptom scores (about 8.3 at baseline on a 15-point scale) declined by about 3.7 points with placebo and 4.5 points with twice-daily mometasone.

Comment: In essence, these results suggest that when common cold symptoms linger for more than a week without high fever or severe unilateral facial pain, a nasal steroid is more beneficial than amoxicillin. Wider prescribing of nasal steroids for this purpose presumably would reduce antibiotic use. However, nasal mometasone is rather expensive; it would be interesting to see whether it works better than topical and oral decongestants in these patients.

— Allan S. Brett, MD. Published in Journal Watch January 10, 2006. Source: Meltzer EO et al. Treating acute rhinosinusitis: Comparing efficacy and safety of mometasone furoate nasal spray, amoxicillin, and placebo. J Allergy Clin Immunol 2005 Dec; 116:1289-95.

8. Warfarin Reversal: Another Door-to-Drug Time Goal

Intracerebral hemorrhage (ICH) accounts for roughly 10% of strokes and 1% of all deaths in the U.S. Patients taking warfarin have a sixfold increased risk for ICH and are likely to have ongoing bleeding. Reversal of anticoagulation is first-line therapy in such cases. To assess the timing and outcomes of therapy with vitamin K and fresh frozen plasma (FFP), these authors retrospectively reviewed all cases of nontraumatic warfarin-associated ICH that presented to a single emergency department from 1998 to 2004.

After exclusions for incomplete records, initial international normalized ratio (INR) 1.4, and do-not-resuscitate orders, 69 of 160 cases were included in the analysis. At 24 hours, 57 patients (83%) had adequate reversal (defined as INR 1.4). In multivariate analyses adjusting for disease severity, researchers found that shorter times to FFP administration and to vitamin K administration each were independently associated with the likelihood of successful reversal (odds ratio, 0.8 for both agents). Neither success of anticoagulation reversal nor dose of FFP or vitamin K affected clinical outcomes at 90 days.

Comment: These authors document delays in reversal of anticoagulation and a correlation between such delays and inadequate reversal at 24 hours. Although there is no direct evidence that reversal saves lives, reversal is certainly desirable in the context of intracranial or other serious hemorrhage.

Why the delays? FFP takes time to obtain, thaw, and hang. With vitamin K, concern about anaphylactoid reactions might result in delays. Although intravenous vitamin K is associated with rare anaphylactoid reactions, such concerns do not have a place in the treatment of life-threatening warfarin-associated hemorrhages. Only 27 deaths from vitamin K anaphylactoid reaction have ever been reported in the English-language literature. (See J Thromb Thrombolysis 2001; 11:175-83). If vitamin K cannot be given intravenously, it should be given orally.

— Daniel J. Pallin, MD, MPH. Published in Journal Watch Emergency Medicine January 17, 2006. Source: Goldstein JN et al. Timing of fresh frozen plasma administration and rapid correction of coagulopathy in warfarin-related intracerebral hemorrhage. Stroke 2006 Jan; 37:151-5.

9. Exercise Is Associated with Reduced Risk for Incident Dementia among Persons 65 Years of Age and Older

This could be useful for us!

The authors followed 1740 persons who did not have cognitive impairment at baseline. During a mean follow-up of 6.2 years, 158 participants developed dementia; the incidence rate was 13.0 per 1000 person-years for those who exercised 3 or more times per week at baseline and 19.7 per 1000 person-years for those who exercised less frequently. The results were similar in the 107 participants who developed Alzheimer disease.

However, the existing evidence does not prove that regular exercise is associated with a lower dementia risk.

Larson and colleagues provide important evidence that more physical exercise is associated with lower rates of dementia, adding significantly to several other recent studies on the association between physical activity and dementia risk. We now need randomized trials to examine the effect of physical activity on cognitive function measures, and we need researchers to include clinical dementia end points in ongoing trials of lifestyle modification.

Eric B. Larson, et al. Ann Intern Med 2006; 144:73-81

10. Early Symptoms May Allow Earlier Diagnosis of Meningococcus in Children

Web MD. News Author: Laurie Barclay, MD

Jan. 13, 2006 — Early symptoms may allow earlier diagnosis of meningococcus in children, according to the results of a study reported in the January 11 Early Online Publication issue of The Lancet.

"Recognizing early symptoms of sepsis could increase the proportion of children identified by primary-care physicians and shorten the time to hospital admission," lead author Matthew Thompson, MD, from the University of Oxford in the United Kingdom, said in a news release. "The framework within which meningococcal disease is diagnosed should be changed to emphasize identification of these early symptoms by parents and clinicians."

The investigators analyzed questionnaires completed by parents and primary-care records for the course of illness before hospitalization in 448 children, aged 16 years or younger, with meningococcal disease. Of the 448 cases, 103 (23%) were fatal, and microbiological techniques confirmed the diagnosis in 373 cases. The remaining cases were diagnosed on the basis of purpuric rash and either meningitis or evidence of septicemic shock.

The timeframe for clinical diagnosis was narrow because most children had only nonspecific symptoms in the first 4 to 6 hours but were moribund by 24 hours. Only 165 children (51%) were hospitalized after the first consultation, and median time to hospitalization was 19 hours. Early symptoms of sepsis, including leg pains, cold hands and feet, and abnormal skin color, occurred in 72% of children at a median time of 8 hours. Classic features of hemorrhagic rash, meningism, and impaired consciousness developed late, with a median onset of 13 to 22 hours.

"We have identified three important clinical features — leg pain, cold hands and feet, and abnormal skin color — that are signs of early meningococcal disease in children and adolescents," the authors write. "Classic clinical features of meningococcal disease appear late in the illness."

Study limitations include retrospective data collection and associated recall bias and lack of data for children with other illnesses to compare symptom frequency.

"Encouraging recognition of sepsis symptoms (and perhaps measurement of vital signs) in primary care could reduce the proportion of cases missed at first consultation from a half to a quarter," the authors conclude. "However, achieving earlier diagnosis for the final 25% needs increased awareness of the early symptoms of sepsis and a change in help-seeking behavior by parents as well as clinicians."

The Meningitis Research Foundation and the Medical Research Council supported this study. The authors have disclosed no relevant financial relationships.

In an accompanying comment, Cristiana M. Nascimento-Carvalho, MD, and Otávio A. Moreno-Carvalho, MD, from the University of Bahia in Salvador, Brazil, note that early diagnosis can be challenging because the initial, nonspecific symptoms are similar to those of many common, self-limiting viral illnesses. The editorialists recommend a study to determine positive and negative predictive values of leg pain, cold extremities, and abnormal skin color for the diagnosis of meningococcal disease.

"Until this information is available, doctors should be encouraged to schedule clinical review within 4 - 6 hours if early meningococcal disease cannot be ruled out at the first contact," Drs. Nascimento-Carvalho and Moreno-Carvalho write. "To wait for the late signs of meningitis, such as neck stiffness, photophobia, and bulging fontanelle, is a glaring mistake if meningococcal disease is to be promptly diagnosed, because those signs usually arise as late as 12 - 15 h after onset of illness.... The recognition of early signs of meningococcal disease could reduce subsequent mortality."

ABSTRACT from the Lancet, Posted online January 11, 2006.

Background
Meningococcal disease is a rapidly progressive childhood infection of global importance. To our knowledge, no systematic quantitative research exists into the occurrence of symptoms before admission to hospital.

Methods
Data were obtained from questionnaires answered by parents and from primary-care records for the course of illness before admission to hospital in 448 children (103 fatal, 345 non-fatal), aged 16 years or younger, with meningococcal disease. In 373 cases, diagnosis was confirmed with microbiological techniques. The rest of the children were included because they had a purpuric rash, and either meningitis or evidence of septicaemic shock. Results were standardised to UK case-fatality rates.

Findings
The time-window for clinical diagnosis was narrow. Most children had only non-specific symptoms in the first 4–6 h, but were close to death by 24 h. Only 165 (51%) children were sent to hospital after the first consultation. The classic features of haemorrhagic rash, meningism, and impaired consciousness developed late (median onset 13–22 h). By contrast, 72% of children had early symptoms of sepsis (leg pains, cold hands and feet, abnormal skin colour) that first developed at a median time of 8 h, much earlier than the median time to hospital admission of 19 h.

Interpretation
Classic clinical features of meningococcal disease appear late in the illness. Recognising early symptoms of sepsis could increase the proportion of children identified by primary-care clinicians and shorten the time to hospital admission. The framework within which meningococcal disease is diagnosed should be changed to emphasise identification of these early symptoms by parents and clinicians.

11. Chest radiographs negative for one in five acute heart failure patients

January 13, 2006. By Anne Harding. NEW YORK (Reuters Health) - Nearly one in five patients admitted to an emergency department with decompensated heart failure will have negative chest radiography results, a new analysis of registry data suggests.

The findings are consistent with past research suggesting that the test will find no signs of congestion in a substantial proportion of acute heart failure patients, Dr. Sean P. Collins of the University of Cincinnati, Ohio, told Reuters Health.

"The chest X-ray is still really an invaluable tool in the emergency physician's workup of heart failure," he said. But physicians who suspect heart failure in a patient should not conclude it isn't there if a chest radiograph is negative, he added.

Dr. Collins and his colleagues reviewed data from the Acute Decompensated Heart Failure National Registry (ADHERE). Among the 85,376 patients for whom chest radiographs and an admitting diagnosis were available, 15,937, or 18.7%, had no signs of congestion on chest radiography. There was no difference in the percentage of negative chest radiography based on race or sex.
Patients with negative chest X-rays were more likely to have been admitted to the hospital with a diagnosis other than heart failure than those with positive chest radiography (23.3% vs. 13.0%, respectively).

"Clinicians should consider the prevalence of chest radiography that lacks signs of congestion when evaluating patients for possible acute decompensated heart failure," Dr. Collins and his team conclude in the January issue of the Annals of Emergency Medicine.

In an editorial accompanying the study, Dr. Richelle J. Cooper of the UCLA Emergency Medicine Center points out the limitations of the ADHERE data, including the inability to confirm a patient's discharge diagnosis and the biased nature of the sample.

"Until there is better research to suggest differently, I will continue to order a simple chest radiograph and not feel angst that I am missing clinically important cases of heart failure because the radiograph is 'negative,'" she concludes.

Ann Emerg Med 2006;47:13-21.

12. Clinical Cases Make Blog a Popular Resource

WebMD. Posted 01/04/2006. Nicholas Genes, MD, PhD

When people first learn about medical blogs, they assume that these sites are simply online diaries written by healthcare professionals. And it's true that many are. But medical blogs come in all shapes and sizes, a testament to the diversity and inventiveness of their writers. Many blogs feature educational content, and some are exclusively educational, such as the Clinical Cases and Images Blog, managed by Dr. Ves Dimov.

Dr. Dimov started this blog as an outgrowth of a learning tool, also called "Clinical Cases and Images," which he developed with residents at Case Western Reserve University in Cleveland, Ohio. Now a hospitalist at the Cleveland Clinic, Dr. Dimov has continued adding to the site, making it a tremendous resource for physicians and students around the world. Featuring step-by-step guides to line placement, x-ray interpretation, and more, the site fills a gap in medical textbooks and everyday practice. His work has received praise from numerous sources, including the British Medical Journal.

Check it out: http://clinicalcases.blogspot.com/

13. The Minimally Symptomatic Hernia: "If It's Not Broken, Don't Fix It"

Watchful Waiting vs Repair of Inguinal Hernia in Minimally Symptomatic Men
A Randomized Clinical Trial. Fitzgibbons RJ, et al. JAMA. 2006;295:285-292. And editorial: 328-329.

January 18, 2006. By Anthony J. Brown, MD. NEW YORK (Reuters Health) - Men who experience few or no symptoms from an inguinal hernia do not require immediate surgery, instead they can be safely followed and treated if symptoms worsen, new research shows. If adopted by the greater surgical community, this approach could markedly reduce the number of hernia repairs performed.

Out of fear that incarceration and other problems may occur, "surgeons are generally taught that all hernias should be repaired at diagnosis," lead author Dr. Robert J. Fitzgibbons, from Creighton University in Omaha, Nebraska told Reuters Health. "Our study questioned this conventional wisdom and found that a watchful waiting approach can be safely applied to men with minimal symptoms. I suspect that 50% of patients with hernias could keep them for the rest of their lives and never have a problem."

One of the key findings "was that there didn't appear to be any penalty for waiting to perform surgery," Dr. Fitzgibbons said. "The concern had been that waiting could lead to worse hernias that are more difficult to repair and associated with greater complications. But in our study, the complication rate for patients having initial surgery and those having delayed surgery was exactly the same."

The study, which is reported in The Journal of the American Medical Association for January 18, involved 720 men with minimally symptomatic inguinal hernias who were randomized to receive immediate surgery or watchful waiting. With the latter approach, subjects were seen at 6 months and then annually to determine if hernia symptoms worsened, an indication for surgery.

At 2-year follow-up, the rate of pain limiting activities in each group was not significantly different, hovering around 3.5%. Likewise, both groups experienced a similar improvement in the physical component score of the Short Form-36 survey.

Twenty-three percent of patients assigned to watchful waiting crossed over to the surgery group, typically due to an increase in hernia-related pain. As noted, these patients were not at heightened risk for surgical complications compared with men who had their hernias repaired immediately.

One patient in the watchful waiting group developed acute hernia incarceration without strangulation within 2 years of enrollment in the study. In addition, another patient in the group had acute incarceration with bowel obstruction at 4 years. Thus, the hernia accident rate was 0.0018 events per patient-year.

Dr. Fitzgibbons believes the new findings will lead many surgeons to "discuss nonoperative options with their hernia patients." He said that for medicolegal reasons, surgeons may have been reluctant to adopt a watchful waiting approach in the past. "But now there is good scientific evidence that it's a reasonable strategy and that takes the medicolegal burden away."

"If the results of this study are reproduced in other populations and for other types of hernia, then the era of preventive hernia repair should go the way of prophylactic tonsillectomy, cholecystectomy, and appendectomy," Dr. David R. Flum, from the University of Washington in Seattle, comments in a related editorial.

14. Aspirin Prevents Cardiovascular Disease in Healthy Adults

By Karla Gale. NEW YORK (Reuters Health) Jan 17 - Low-dose aspirin is effective in preventing cardiovascular events, even among men and women without preexisting cardiovascular disease (CVD), results of a meta-analysis show. However, aspirin also increases the risk of major bleeding, so clinicians must weigh the drug's relative risks and benefits before prescribing it as primary prophylaxis.

"Everyone accepts that aspirin works as secondary prevention," senior author Dr. David L. Brown told Reuters Health. "For primary prevention, especially for women, there is a paucity of data. But despite that lack of data, the American Heart Association and other organizations have been recommending the use of aspirin for primary prevention in women at high risk."

Dr. Brown, a physician at the State University of New York in Stony Brook, and his associates therefore conducted a meta-analysis of prospective, randomized controlled trials of aspirin therapy in patients without cardiovascular disease published between 1966 and 2005. According to their report in the Journal of the American Medical Association for January 18th, they identified six trials that enrolled 51,342 women and 44,114 men. Weighted mean duration of follow-up was 6.4 years, and aspirin doses ranged from 100 mg every other day to 500 mg daily.

Among women, aspirin prophylaxis reduced the odds of a cardiovascular event by 12% (p = 0.03). It did not significantly alter the risk of MI or hemorrhagic stroke, but it did reduce the risk of ischemic stroke by 24% (p = 0.008). Among men, aspirin reduced the risk of major cardiovascular events by 14% (p = 0.01), and of MI by 32% (p = 0.001). While it had no effect on the risk of ischemic stroke among men, it did increase their risk of hemorrhagic stroke by 69% (p = 0.03).

Both genders taking aspirin had a 70% increased risk of major bleeding. The drug appeared to have no effect on cardiovascular or all-cause mortality among men or women.

Dr. Brown's group points out that the study populations were at very low risk. They estimated that the number needed to treat to prevent one cardiovascular event over a mean of 6.4 years was 333 women and 270 men. "While the overall numbers are less in a lower risk population that has not yet had an event, the benefit in terms of reduction of risk is of a similar order of magnitude as it is in the secondary prevention studies," Dr. Brown said. "In my own practice, I recommend one baby aspirin per day for patients who have no obvious increased risk of bleeding and who have one or more risk factors for CVD."

He noted that "instruments used to calculate risk, primarily the Framingham risk calculator, calculate risk of MI, which is great for men because aspirin reduces the risk of MI in men. However, it does not make a lot of sense to use a calculator of risk for MI in women when aspirin does not appear to prevent MI in women, but prevents stroke."

"So a future area of research is to come up with a risk calculator for stroke in women to make the discussion with them about taking aspirin or not more quantitative."

JAMA 2006;295:306-313.

What is your risk for cardiovascular events? Use the calculator: http://hin.nhlbi.nih.gov/atpiii/calculator.asp?usertype=prof

According to the American Heart Association, “Consider 75–160 mg aspirin per day for people at higher risk, especially those with a 10-year CHD risk of 10 percent or greater.” http://www.americanheart.org/presenter.jhtml?identifier=4704

15. Which Kids with Blunt Head Trauma Need Imaging?

Oman JA, et al (including Jerry Hoffman) for the NEXUS II Investigators. Performance of a Decision Rule to Predict Need for Computed Tomography Among Children With Blunt Head Trauma. Pediatrics 2006; 117: e238-e246.

OBJECTIVE. To assess the ability of the NEXUS II head trauma decision instrument to identify patients with clinically important intracranial injury (ICI) from among children with blunt head trauma.

METHODS. An analysis was conducted of the pediatric cohort involved in the derivation set of National Emergency X-Radiography Utilization Study II (NEXUS II), a prospective, observational, multicenter study of all patients who had blunt head trauma and underwent cranial computed tomography (CT) imaging at 1 of 21 emergency departments. We determined the test performance characteristics of the 8-variable NEXUS II decision instrument, derived from the entire NEXUS II cohort, in the pediatric cohort (0–18 years of age), as well as in the very young children (<3 years). Clinically important ICI was defined as ICI that required neurosurgical intervention (craniotomy, intracranial pressure monitoring, or mechanical ventilation) or was likely to be associated with significant long-term neurologic impairment.

RESULTS. NEXUS II enrolled 1666 children, 138 (8.3%) of whom had clinically important ICI. The decision instrument correctly identified 136 of the 138 cases and classified 230 as low risk. A total of 309 children were younger than 3 years, among whom 25 had ICI. The decision instrument identified all 25 cases of clinically important ICI in this subgroup.

CONCLUSIONS. The decision instrument derived in the large NEXUS II cohort performed with similarly high sensitivity among the subgroup of children who were included in this study. Clinically important ICI were rare in children who did not exhibit at least 1 of the NEXUS II risk criteria.

16. Another approach to working up the possible PE

Effectiveness of Managing Suspected Pulmonary Embolism Using an Algorithm Combining Clinical Probability, D-Dimer Testing, and Computed Tomography
Writing Group for the Christopher Study Investigators.* JAMA. 2006;295:172-179.

Context Previous studies have evaluated the safety of relatively complex combinations of clinical decision rules and diagnostic tests in patients with suspected pulmonary embolism.

Objective To assess the clinical effectiveness of a simplified algorithm using a dichotomized clinical decision rule, D-dimer testing, and computed tomography (CT) in patients with suspected pulmonary embolism.

Design, Setting, and Patients Prospective cohort study of consecutive patients with clinically suspected acute pulmonary embolism, conducted in 12 centers in the Netherlands from November 2002 through December 2004. The study population of 3306 patients included 82% outpatients and 57% women.

Interventions Patients were categorized as "pulmonary embolism unlikely" or "pulmonary embolism likely" using a dichotomized version of the Wells clinical decision rule. Patients classified as unlikely had D-dimer testing, and pulmonary embolism was considered excluded if the D-dimer test result was normal. All other patients underwent CT, and pulmonary embolism was considered present or excluded based on the results. Anticoagulants were withheld from patients classified as excluded, and all patients were followed up for 3 months.

Main Outcome Measure Symptomatic or fatal venous thromboembolism (VTE) during 3-month follow-up.

Results Pulmonary embolism was classified as unlikely in 2206 patients (66.7%). The combination of pulmonary embolism unlikely and a normal D-dimer test result occurred in 1057 patients (32.0%), of whom 1028 were not treated with anticoagulants; subsequent nonfatal VTE occurred in 5 patients (0.5% [95% confidence interval {CI}, 0.2%-1.1%]). Computed tomography showed pulmonary embolism in 674 patients (20.4%). Computed tomography excluded pulmonary embolism in 1505 patients, of whom 1436 patients were not treated with anticoagulants; in these patients the 3-month incidence of VTE was 1.3% (95% CI, 0.7%-2.0%). Pulmonary embolism was considered a possible cause of death in 7 patients after a negative CT scan (0.5% [95% CI, 0.2%-1.0%]). The algorithm was completed and allowed a management decision in 97.9% of patients.

Conclusions A diagnostic management strategy using a simple clinical decision rule, D-dimer testing, and CT is effective in the evaluation and management of patients with clinically suspected pulmonary embolism. Its use is associated with low risk for subsequent fatal and nonfatal VTE.