Wednesday, February 22, 2006

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:

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.

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).

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.

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.

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