Monday, January 02, 2006

Lit Bits: January 2, 2006

From the recent medical literature...

1. ED Management of Recent-onset Atrial Fibrillation (AF)

AF is the most common arrhythmia seen in the ED. Traditionally, most patients with acute AF are admitted to exclude a serious cardiac condition, and to monitor for complications.

Several studies demonstrate that acute AF can be managed successfully in the ED with high short term conversion and discharge rates, for example, cf. the Kaiser Sacramento study by Burton JH, et al. Electrical cardioversion of emergency department patients with atrial fibrillation. Ann Emerg Med. 2004;44:20-30. Reports have shown that biphasic defibrillators are more effective and deliver less energy than monophasic defibrillators. These studies were performed in a cardiology outpatient setting, and there are very few data describing biphasic cardioversion of acute AF in the ED.

Fatovich and Haig report the effectiveness and outcome of biphasic cardioversion of acute AF in a tertiary referral ED.

Biphasic cardioversion of acute atrial fibrillation in the emergency department. Emerg Med J 2006;23:51-53.

Introduction: There is a trend towards accelerated management of acute atrial fibrillation (AF) in the emergency department (ED). We report our experience with biphasic cardioversion of acute AF.

Methods: This was a prospective, descriptive study at a tertiary hospital ED over a 6 month period. Acute AF was defined as symptoms that had been present for <48 hours. Patients who received biphasic cardioversion for acute AF in the ED were enrolled. Data collected included: patient demographics, past medical history, details of biphasic cardioversion, outcome, complications, disposition, and length of stay.

Results: There were 34 attempts at cardioversion in 33 patients. The mean (SD) age was 56 (16) years and 21 patients (64%) were men. Biphasic cardioversion was successful in 31 attempts (91%). In 24 attempts (71%), 100 J was selected as the initial energy level. This was successful in 21 attempts (88%). There were three minor complications related to sedation. The mean (SD) length of stay was 5.6 (2.8) hours in the ED and 15 (25) hours in the hospital. The three patients who failed to revert were older (mean age 64 years), had underlying cardiovascular disease, and spent longer in hospital (50 v 12 hours, p = 0.01). Telephone follow up was conducted with 32 patients (97%) at 3 months. Recurrence of AF occurred in 7 patients (22%). Most patients (31, 97%) were satisfied with the biphasic cardioversion.

Conclusions: Biphasic cardioversion of acute AF is effective. The majority of patients can be managed as outpatients, and there is very high patient satisfaction with this approach. An initial shock energy level of 100 J is usually effective

There are no current recommendations on the initial energy level used in biphasic cardioversion. We usually found 100 J to be effective and recommend that as the starting level.

Recently, there have been several clinical trials demonstrating that rate control is not inferior to rhythm control in AF. These studies examined patients with significant cardiovascular comorbidities and the patients were older (70 years), had persistent or permanent AF, and were minimally symptomatic. In our study, the patients were younger (56 years), healthier, had acute AF, and were highly symptomatic.

2. ED Pt Acutely Agitated? Which drug is best?

Droperidol (Inapsine)? Midazolam (Versed)? Or some new antipsychotic (ziprasidone)?

“Agitated patients commonly present to the ED and present a unique problem for the health care provider. The etiology is typically unclear and complicates the evaluation and expeditious management of the patient. In general, the goal of the emergency physician is to manage the patients' agitation, assess for the presence of any acute medical or traumatic conditions, and subsequently arrange appropriate disposition.

“Acute undifferentiated agitation (AUA) may be the result of trauma, acute psychiatric or medical disorders, or intoxication from alcohol or illicit substances. The etiology of acute agitation and altered mental status is infrequently studied in the ED setting. As a result of excessive agitation, both the patient and the health care providers are placed at risk of injury.

“The decision to use physical and chemical restraints is often difficult, because complications can occur with the use of either modality. Several sudden deaths have been reported in the physically restrained, agitated patient. High-potency antipsychotics and benzodiazepines have been the traditional "chemical restraint" for agitation management. Both classes of medications have been shown to be effective in the ED setting but have the potential for undesirable side effects. Benzodiazepines, such as lorazepam and midazolam, have potential central nervous system and cardiovascular depressant effects. These include significant sedation, respiratory depression requiring airway management, and hypotension. The potential adverse affects of antipsychotics such as droperidol include hypotension, seizures, dystonia, akathisia, and dysrhythmia (QT prolongation and torsades de pointes). Little has been published on the use of the newer parenteral atypical antipsychotics, such as ziprasidone, in the ED management of AUA” (from Martel et al below).

Below are two recent studies on this topic. The first was a randomized comparison of midazolam and droperidol; the second threw in a third comparator.

A. Randomized Clinical Trial Comparing Intravenous Midazolam and Droperidol for Sedation of the Acutely Agitated Patient in the Emergency Department. Knott JC, Taylor DM, Castle DJ. Ann Emerg Med. 2006; 47:61-67
Study objective
We compare intravenous midazolam and droperidol for the onset of sedation of acutely agitated patients in the emergency department (ED).

This was a double-blind, randomized, clinical trial set in the ED of a university teaching hospital. Subjects were adults, acutely agitated because of mental illness, intoxication, or both, who received midazolam or droperidol, 5 mg intravenously, every 5 minutes until sedated. We analyzed time to sedation using survival analysis, median times to sedation, and proportions sedated at 5 and 10 minutes.

Seventy-four patients received midazolam; 79 patients, droperidol. Survival analysis showed no difference in time to sedation (hazard ratio 0.86; 95% confidence interval [CI] 0.61 to 1.23), P=.42. Median time to sedation was 6.5 minutes for midazolam (median dose 5 mg) and 8 minutes for droperidol (median dose 10 mg), P=.075 (effect size 1.5 minutes; 95% CI 0 to 4 minutes). At 5 minutes, 33 of 74 (44.6%) patients from the midazolam group were adequately sedated compared with 13 of 79 (16.5%) patients from the droperidol group, a difference of 28.1% (95% CI 12.9% to 43.4%; P<.001). By 10 minutes, 41 of 74 (55.4%) from the midazolam group were sedated compared to 42 of 79 (53.2%) from droperidol, a difference of 2.2% (95% CI −14.9% to 19.3%; P=.91). Eleven adverse events occurred in the midazolam group and 10 in the droperidol group. Three patients required active airway management (3 patients with assisted ventilation and 1 patient intubated); all received midazolam.

There is no difference in onset of adequate sedation of agitated patients using midazolam or droperidol. Patients sedated with midazolam may have an increased need for active airway management.

B. Management of Acute Undifferentiated Agitation in the Emergency Department: A Randomized Double-Blind Trial of Droperidol, Ziprasidone, and Midazolam. Martel M, et al. Acad Emerg Med. 2005 12: 1167-1172

Our objective was to compare the efficacy of sedation of droperidol, ziprasidone, and midazolam for the treatment of AUA in ED patients. Additionally, we evaluated the need for rescue sedation, rates of respiratory depression, and other clinically significant complications.

Methods: A prospective, randomized, double-blind trial of agitated ED patients requiring emergent sedation was performed. Patients were randomized to receive droperidol 5 mg, ziprasidone 20 mg, or midazolam 5 mg intramuscularly. Interval measurements were made at 0, 15, 30, 45, 60, and 120 minutes and included Altered Mental Status Scale (AMS) scores, oxygen saturations, and end-tidal carbon dioxide levels.

Results: A total of 144 patients were enrolled; 50 patients received droperidol, 46 received ziprasidone, and 48 received midazolam. Adequate sedation (mean AMS score <0) was achieved at 15 minutes in patients receiving midazolam (mean AMS score, –0.81) and 30 minutes for patients receiving droperidol (mean AMS score, –1.3) and ziprasidone (mean AMS score, –0.74). Rescue medication for sedation was necessary in 38 of 144 patients (droperidol, 5 of 50; ziprasidone, 9 of 46; midazolam, 24 of 48; p < 0.05). No cardiac dysrhythmias were identified in any treatment group. Respiratory depression that clinically required treatment with supplemental oxygen occurred in 21 of 144 patients (droperidol, 4 of 50; ziprasidone, 7 of 46; midazolam, 10 of 48; p = 0.20). No patients required endotracheal intubation.

Conclusions: Acutely agitated ED patients sedated with droperidol or ziprasidone required rescue medications to achieve adequate sedation less frequently than those sedated with midazolam. The onset of adequate sedation is delayed with ziprasidone, relative to the other agents.
Discussion (excerpt): Droperidol, ziprasidone, and midazolam are commonly used medications in the ED for agitation of any etiology. The medication dosages used were determined based on our clinical experience in addition to previous studies. The recommended dosing of ziprasidone ranges from 10 to 20 mg. Ziprasidone 20 mg was used based on research by Daniel et al. and discussion with Pfizer representatives. To our knowledge, there are no available data on the equivalence of dosing for droperidol, midazolam, and ziprasidone.

Droperidol has been used extensively in our ED for more than a decade. It continues to be a mainstay of treatment in a variety of acute medical conditions. The safe and efficacious use of droperidol has been established in ED patients. Similarly, we have found increased complications and resource utilization associated with the use of midazolam in out-of-hospital patients with AUA as compared with droperidol. Ziprasidone is a novel, atypical antipsychotic approved for the treatment of schizophrenia. To the best of our knowledge, the use of ziprasidone in the ED and for undifferentiated agitation has not been previously studied. This study was subsequently performed in an effort to prospectively evaluate our out-of-hospital findings and compare a novel method of agitation management.

Overall, each studied medication was successful at managing acute agitation, although with ziprasidone there were more agitated patients at 15 minutes than with either droperidol or midazolam. Deeper sedation was seen in these patients treated with ziprasidone when assessed between 60 and 120 minutes. The duration of agitation control with midazolam appeared shorter than with either droperidol or ziprasidone. There were an increased number of agitated patients in the midazolam group at 45 minutes. A significant number of these patients required subsequent rescue sedation. The shorter duration of effective sedation and the need for repeated injections may limit the utility of midazolam in the ED setting. However, the rapid onset of action of midazolam may be more appropriate for the out-of-hospital setting, despite its shorter duration of sedation. In contrast to the previous retrospective study of out-of-hospital midazolam use, midazolam does not appear to be associated with increased resource utilization or intensive care unit admission in this prospective study.

3. Chest Pain in the ED. Who can go home?

Are there some clinical prediction rules to help determine which chest pain patients are safe to send home, along the lines of the NEXUS or Ottawa? Yes, indeed, conclude these Canadian researchers. Their introduction and abstract follow.

A Clinical Prediction Rule for Early Discharge of Patients With Chest Pain. Christenson J, Innes G, McKnight D, et al. Ann Emerg Med. 2006;47:1-10

Approximately 15% to 25% of patients who present to EDs with undifferentiated chest pain prove to have acute coronary syndrome within 30 days. US data suggest that 2.1% of patients with acute myocardial infarction and 2.3% of patients with unstable angina are initially misdiagnosed, whereas a recent Canadian study identified 11 of 241 (4.6%) missed cases of acute myocardial infarction and 10 of 157 (6.4%) cases of missed unstable angina. Chest pain units reduce the rate of missed myocardial infarction but do so in part by including very-low-risk patients in extensive rule-out myocardial infarction protocols.

Many investigators have developed chest pain risk stratification tools. Goldman et al developed a clinical/ECG algorithm that identified patients with less than 7% risk of acute myocardial infarction. Limkakeng et al subsequently found that 4.9% of patients who had low-risk Goldman criteria and a negative initial troponin I assay result experienced death, acute myocardial infarction, or revascularization within 30 days. Pozen et al developed a 7-item predictive equation that reduced coronary care unit admissions but not inappropriate discharges. Selker et al modified this to create the acute cardiac ischemia time-insensitive predictive instrument (ACI-TIPI), which defined low risk as less than 10% chance of acute coronary syndrome. The Erlanger protocol is an intense 2-hour assessment that includes serial ECGs and creatine kinase-MB (CK-MB) and troponin measurements, but it does not define a subset of patients who can forgo nuclear stress testing.

The American Heart Association/Agency for Health Care Policy and Research guidelines suggest early discharge only for patients with “evidence” of an alternate diagnosis. Unfortunately, few patients clearly fall into this category. Our own study of patients with chest pain at Vancouver hospitals identified that 5.4% of patients with acute coronary syndrome were discharged from the ED without a diagnosis or planned investigations and only 30% of those without acute coronary syndrome were discharged less than three hours after ED admission.

Clinical prediction rules are decision-making tools for clinicians that contain elements of the medical history, physical examination, and simple diagnostic tests. An objective clinical prediction rule to identify very-low-risk patients with chest pain who can be safely discharged without prolonged ED observation, expensive rule-out protocols, or provocative testing is needed. Such a rule would help reduce emergency crowding, minimize patient inconvenience, and improve cost-effectiveness of acute coronary syndrome diagnostic testing.

Goals of This Investigation
Our specific objective was to develop a clinical prediction rule that would improve on current practice by identifying patients with chest pain who are safe for discharge after 2 hours of ED evaluation. The rule will miss fewer than 2% of acute coronary syndrome patients and allow discharge within 2 to 3 hours of at least 30% of patients without acute coronary syndrome.

Study objective
Current risk stratification tools do not identify very-low-risk patients who can be safely discharged without prolonged emergency department (ED) observation, expensive rule-out protocols, or provocative testing. We seek to develop a clinical prediction rule applicable within 2 hours of ED arrival that would miss fewer than 2% of acute coronary syndrome patients and allow discharge within 2 to 3 hours for at least 30% of patients without acute coronary syndrome.

This prospective, cohort study enrolled consenting eligible subjects at least 25 years old at a single site. At 30 days, investigators assigned a diagnosis of acute coronary syndrome or no acute coronary syndrome according to predefined explicit definitions. A recursive partitioning model included risk factors, pain characteristics, physical and ECG findings, and cardiac marker results.

Of 769 patients studied, 77 (10.0%) had acute myocardial infarction and 88 (11.4%) definite unstable angina. We derived a clinical prediction rule that was 98.8% sensitive and 32.5% specific. Patients have very low risk of acute coronary syndrome if they have a normal initial ECG, no previous ischemic chest pain, and age younger than 40 years. In addition, patients at least 40 years old and with a normal ECG result, no previous ischemic chest pain, and low-risk pain characteristics have very low risk if they have an initial creatine kinase-MB (CK-MB) less than 3.0 μg/L or an initial CK-MB greater than or equal to 3.0 μg/L but no ECG or serum-marker increase at 2 hours.

The Vancouver Chest Pain Rule for early discharge defines a group of patients who can be safely discharged after a brief evaluation in the ED. Prospective validation is needed.

4. Parents’ Views of Shared Decision Making in Otitis Media Management

It has been shown of late that acute otitis media in well children over the age of 2 may not require antibiotic intervention. This allows then for variations of acceptable management. These investigators sought to determine the impact on parent satisfaction of allowing them an active role in the choice of management. What do you think? Does shared decision making increase parent satisfaction?

Many clinicians advocate shared decision making (SDM) between physicians and patients. To examine parents’ preferences for SDM, investigators randomly assigned 466 parents at two family practices in Baltimore to receive a survey that presented one of three clinical vignettes.

All vignettes described a 2.5-year-old child with acute otitis media (AOM) and a physician who informed parents that AOM is not contagious, that some children get better without antibiotics, and that three treatment options are available: immediate 10-day prescription for antibiotics; acetaminophen first, followed by a call back to the doctor if the child does not improve in 2 to 3 days; or a prescription for an antibiotic, to be used only if the child is not better in 2 to 3 days. The vignette ended in one of three ways: the physician suggested that the child receive antibiotics (paternalistic vignette); the physician indicated that treatment is the parents’ choice (SDM vignette); or the physician recommended treatment with acetaminophen first and provided an antibiotic prescription to use if needed (acetaminophen-SDM vignette).

Parents who were presented with either of the two SDM vignettes reported more satisfaction with the child’s care than parents who were presented with the paternalistic vignette (93% and 84% for SDM and acetaminophen–SDM groups, respectively, vs. 76%), and they were significantly less likely to want antibiotics immediately (7% and 7% vs. 26%, respectively).

Comment: AOM is an excellent diagnosis in which to incorporate shared decision making because the need for treatment is uncertain, the diagnosis can be difficult to make, and complications are rare. The benefits are substantial: greater parental satisfaction and probably less antibiotic use.

— Howard Bauchner, MD. Published in Journal Watch December 16, 2005. Source: Merenstein D et al. An assessment of the shared-decision model in parents of children with acute otitis media. Pediatrics. 2005 Dec; 116:1267-75.

5. Prevalence of peptic ulcers high during low-dose aspirin use

[Low-dose aspirin. So many of our patients are on it. How big a contributor is it to the development of peptic ulcers? --DRV]

December 13, 2005. NEW YORK (Reuters Health) - The prevalence of gastroduodenal ulcers is about 10% among patients taking low-dose aspirin for vascular protection, and these ulcers often cause no symptoms, investigators report.

Although aspirin is associated with ulcers, it is unclear whether patients taking aspirin get ulcers more often, or if they are just more likely to bleed from ulcers caused by other factors due to aspirin's antiplatelet effects, Dr. Neville D. Yeomans and colleagues note in their paper, published in the November issue of Alimentary Pharmacology and Therapeutics.

To answer this question, Dr. Yeomans, a gastroenterologist at the University of Western Sydney in Australia, and his team performed endoscopic assessments on 187 patients who had been taking aspirin at doses of 75 to 325 mg daily for at least a month. The investigators found the point prevalence of ulcers measuring at least 3mm in diameter was 10.7%. "Only 20% had dyspeptic symptoms, not significantly different from patients without ulcer," the team reports.

When they repeated endoscopy after 3 months among the 113 patients with no ulcers at baseline, they observed that 7.1% had developed an ulcer during the interim, which translates to an annual ulcer incidence of 28%. Age 70 and older or the presence of H. pylori infection raised the risk of an ulcer by about 3-fold, the authors report. However, smoking, higher aspirin doses, previous ulcer history and gender did not significantly affect risk.

"Aspirin can be of great benefit to those at high risk of heart attack or stroke," Dr. Yeomans says in a University press release, "but the risks as well as the benefits need to be carefully weighed before embarking on its long-term use in people who are at only low cardiovascular risk."

Aliment Pharmacol Ther. 2005;22:795-801.

6. Possible Renal Colic? Do we really need a CT?

[Maybe. But for the diagnostic work-up these docs suggest that in many cases just a bedside US and a UA may be sufficient. --DRV]

Gaspari RJ, et al. Emergency Ultrasound and Urinalysis in the Evaluation of Flank Pain. Acad Emerg Med. 2005; 12: 1180-1184.

Objectives: To determine the sensitivity and specificity of limited emergency ultrasonography of the kidney in diagnosing renal colic.

Methods: This was a prospective observational trial from December 2001 to December 2003 at a suburban emergency department. Patients who presented with flank pain suspicious for renal colic were enrolled. Exclusion criteria included fever, trauma, known current kidney stone, unstable vital signs, and inability to provide consent. All patients underwent sequential emergency ultrasonography and computed tomography of the kidneys and bladder. Data were analyzed using chi-square analysis. The primary outcome was the sensitivity and specificity of ultrasonography. Results were also stratified for presence of hematuria.

Results: Fifty-eight of the 104 patients enrolled in the study were diagnosed with renal colic. The overall sensitivity and specificity of bedside ultrasonography for the detection of hydronephrosis were 86.8 (95% confidence interval [CI] = 78.8 to 92.3) and 82.4 (95% CI = 74.1 to 88.1), respectively. In patients with hematuria, hydronephrosis by emergency ultrasonography demonstrated a sensitivity and specificity of 87.8 (95% CI = 80.3 to 92.5) and 84.8 (95% CI = 73.7 to 91.9), respectively. In 55 of the cases, the initial computed tomograph was read by a resident and later re-read by an attending physician. Using the reading of the attending physician as the criterion standard resulted in a sensitivity and specificity of 83.3 (95% CI = 73.2 to 88.0) and 92.0 (95% CI = 79.9 to 97.6), respectively.

Conclusions: Emergency ultrasonography of the kidneys shows very good sensitivity and specificity for diagnosing renal colic in patients with flank pain and hematuria.

7. Glucosamine and chondroitin. Do they really work?

Too often these OTC dietary supplements remain untested. Fortunately, in this case, the NIH undertook a $14 million RCT to test the effects of glucosamine and chondroitin for treatment of knee osteoarthritis (the GAIT study). This was the largest placebo controlled, double blind, clinical trial ever conducted to test the effectiveness of these agents. All 1,258 patients who completed the study were over the age of 40 with knee pain and randomly assigned placebo; glucosamine 1500 mg; chondroitin 1200mg; glucosamine/chondroitin at above mentioned doses; or celecoxib (Celebrex) 200 mg daily for 6 months. The abstract, presented in November at the American College of Rheumatology’s Scientific Meeting in San Diego, concluded that 79% of patients with moderate-to-severe osteoarthritis pain who received a combination of glucosamine and chondroitin experienced pain relief as compared to 69% who took celecoxib and 54% who were given a placebo.

From Prescriber’s Letter: “People are asking about glucosamine and chondroitin for osteoarthritis now that NIH's big GAIT study is making news. But the study merely adds to the debate. Proponents are using this study to say that glucosamine and chondroitin are effective for osteoarthritis of the knee. Opponents say these supplements are a waste of time and money. The two camps are citing different conclusions from the same study. Opponents point out that most patients in the GAIT study showed NO improvement in knee pain...proponents are saying that a small group with moderate to severe pain did get SOME improvement.

“The study design also leaves other issues unresolved. For example, the NIH used glucosamine HYDROCHLORIDE 500 mg TID. But most studies showing benefit used glucosamine SULFATE 1500 mg DAILY. The different salts or dosing regimens MIGHT make a difference. There's also still no answer on whether combining glucosamine and chondroitin works any better than either one alone. For now, tell people that these supplements are worth a try. Adverse effects are mild...patients may have some GI distress. Suggest starting with glucosamine ALONE...preferably glucosamine SULFATE if available. The combo with chondroitin is okay to try. Tell patients it can take up to 8 weeks to see an improvement... but if it doesn't help by then, to stop it and save their money.

8. Sedative Use in Older People Causes More Harm than Benefit

Physicians often prescribe sedative hypnotics to older people with insomnia, but the risks and benefits are not well defined. In this meta-analysis published in the BMJ, investigators identified 24 randomized, controlled trials of pharmacologic treatment in 2411 people with insomnia. All treatments were given for at least five consecutive nights, and the mean age in each study population was at least 60. A total of 830 participants received a benzodiazepine, 609 zaleplon (Sonata), 468 placebo, 384 zolpidem (Ambien), 106 zopiclone (Lunesta), and 14 diphenhydramine.

Based on four studies, 13 people would need to be treated with sedatives for one to have an improvement in sleep quality. Although sleep-quality scores were significantly better with sedatives than with placebo, the effect size was very small (a 0.1 improvement on a 7-point scale). Compared with placebo, sedatives added an average of 25 minutes to sleep time and reduced the average number of awakenings by 0.63.

Based on 16 studies, the number needed to harm was 6. Common adverse effects of sedatives included drowsiness or fatigue, headache, nightmares, and nausea or gastrointestinal disturbances. Compared with placebo, sedatives were significantly associated with more adverse effects on cognition and with greater impairment in performing tasks the morning after treatment.

Comment: The average benefit of sedatives in this analysis was statistically significant but not clinically meaningful, and adverse effects were twice as likely to occur as beneficial effects. Older patients should be informed of these data when considering the use of sedatives to improve sleep. At the time of publication, the full text of the original article was available free of charge.

— Keith I. Marton, MD. Published in Journal Watch December 27, 2005. Source: Glass J et al. Sedative hypnotics in older people with insomnia: Meta-analysis of risks and benefits. BMJ 2005 Nov 19; 331:1169-73.

9. Cardiac Risk Factors….Don’t Forget to Ask about Siblings.

Sibling Cardiovascular Disease as a Risk Factor for Cardiovascular Disease in Middle-aged Adults. Joanne M. Murabito, MD, et al. JAMA. 2005;294:3117-3123.

Context While parental cardiovascular disease (CVD) doubles the risk for CVD in offspring, the extent of increased risk associated with sibling CVD is unclear.
Objective To determine, using validated events, whether sibling CVD predicts outcome in middle-aged adults independent of other risk factors.

Design, Setting, and Participants The Framingham Offspring Study, an inception cohort of the Framingham Heart Study, a prospective population-based cohort study initiated in 1948 with the offspring cohort initiated in 1971. Participants (n = 2475) were members of the offspring cohort aged 30 years or older, free of CVD, and with at least 1 sibling in the study; all were followed up for 8 years.

Main Outcome Measures Association of sibling CVD with 8-year personal risk for CVD using pooled logistic regression. A secondary analysis restricted to offspring with both parents in the study assessed the joint impact of parental and sibling CVD occurrence.

Results Among 973 person-examinations in the sibling CVD group (mean age, 57 years) and 4506 person-examinations in the no sibling CVD group (mean age, 47 years), 329 CVD events occurred during follow-up. Baseline risk factors were more prevalent in the sibling CVD group compared with the no sibling CVD group. Sibling CVD was associated with a significantly increased risk for incident CVD (age- and sex-adjusted odds ratio [OR], 1.55; 95% confidence interval [CI], 1.19-2.03). Adjustment for risk factors did not substantially attenuate the risk (adjusted OR, 1.45; 95% CI, 1.10-1.91). In the analysis restricted to persons with both parents in the study, in models adjusting for both sibling and parental CVD, the multivariable-adjusted OR for sibling CVD (1.99; 95% CI, 1.32-3.00) exceeded that for parental CVD (1.45; 95% CI, 1.02-2.05).

Conclusion Using validated events, sibling CVD conferred increased risk of future CVD events above and beyond established risk factors and parental CVD in middle-aged adults.

10. Antithrombotic Drugs Often Misdosed in Non-ST-Segment Elevation ACS

By Anthony J. Brown, MD. NEW YORK (Reuters Health) Dec 28 - In a study of nearly 400 US hospitals, 42% of patients with a non-ST-segment elevation acute coronary syndrome (ACS) received a dose of an antithrombotic agent that fell outside the recommended range. The report also confirms that the more excessive the dose, the greater the bleeding risk.

Dr. Karen P. Alexander, from Duke University Medical Center in Durham, North Carolina, and colleagues analyzed data from more than 30,000 patients with a non-ST-segment elevation ACS to assess the frequency and correlates of misdosing unfractionated heparin, low-molecular weight heparin, and glycoprotein IIb/IIIa inhibitors. The findings appear in the December 28th issue of the Journal of the American Medical Association.

"There have been studies looking at dosing accuracy of antithrombotic agents in clinical trial populations," Dr. Alexander told Reuters Health. "To my knowledge, our study is the first to look at this in a large, broad 'real world' setting."

As noted, 42% of subjects treated with at least one antithrombotic agent received a dose outside the recommended range. The rates of excess dosing ranged from 13.8% for low-molecular weight heparin to 32.8% for unfractionated heparin. Correlates of misdosing including female gender, older age, renal insufficiency, low body weight, diabetes mellitus, and congestive heart failure, the report indicates.

Receiving an excess dose of an antithrombotic agent increased the risk of major bleeding, mortality, and length of stay. The increased risk of bleeding ranged from 8% to 39% for excessive dosing of unfractionated heparin and low-molecular weight heparin, respectively.

In patients receiving both a heparin agent and a glycoprotein inhibitor, the risk of bleeding was 6.6% if neither agent was given in excess to 22.2% if both were given in excess. Based on their analysis, the researchers estimate that 15% of the bleeding seen in the study population was associated with excess dosing of antithrombotic agents.

While the findings show that misdosing of antithrombotic drugs is a common and concerning problem, Dr. Alexander believes there is a positive message as well. "Patients who do get the correct dosing adjustments have a much lower rate of bleeding than those who don't. This a positive message because it is something we can actually do something about. It confirms that there is a benefit for taking the time to make careful dosage calculations."

JAMA 2005;294:3108-3116.

11. Avian Flu: Is a Pandemic Coming?

Three avian influenza pandemics occurred in the 20th century. The 1957 and 1968 pandemics were caused by avian viruses that recombined with human flu viruses, creating viruses that were both virulent and easily transmissible among humans. In contrast, the 1918 virus was an avian virus that had not swapped genes with a human flu virus. Rather, it had mutated in some other way — still unclear — that allowed it to be transmissible among humans

(Kaiser J. Resurrected influenza virus yields secrets of deadly 1918 pandemic. Science. 2005 Oct 7; 310:28-9.).

Since a 1997 outbreak of bird and human disease caused by a new avian virus (called H5N1) in Hong Kong, people have feared that a new pandemic would emerge. Although the Hong Kong outbreak and several others were stifled by killing hundreds of millions of domestic poultry, the virus did not disappear. Indeed, since 2003, it has adapted to infect migratory birds and has spread to many Asian countries and to Europe. The H5N1 virus is virulent in birds and humans. More than 100 humans who were in close contact with sick birds have become infected with H5N1, and about half of them have died. So the good news is that the current H5N1 virus does not easily infect humans, but the bad news is that it’s lethal when it does (Ungchusak K et al. Probable person-to-person transmission of avian influenza A (H5N1). N Engl J Med. 2005 Jan 27; 352:333-40.).

How bad could a pandemic be? The 1918 virus infected approximately 40% of the human race in a matter of months and had a mortality rate of about 2% to 3%, leading to 20–50 million deaths. In 2005, a team at the CDC reconstructed the 1918 virus, based on its RNA sequence, and tested its virulence in mice. All infected mice died, with their alveoli filled with mucin and blood cells — a pathological picture similar to that seen in humans who died in 1918. The virulence genes of the 1918 virus are similar to those of the current H5N1 virus.
What can be done to prevent an H5N1 pandemic? In vitro, most strains are susceptible to oseltamivir (Tamiflu).

However, a recent case report demonstrates that the virus can rapidly develop resistance to this drug (Le QM et al. Isolation of drug-resistant H5N1 virus. Nature 2005 Oct 20; 437:1108). Experimental vaccines have elicited an antibody response against H5N1, but that fact does not assure clinical efficacy. And, production of either antivirals or vaccine on the scale that would be required to protect the world population would take years.

Most authorities believe that an H5N1 human pandemic is likely, although how severe it might be is unknown. If H5N1 recombines with a human flu virus, it could produce less severe disease than if it leaps directly to humans, as the 1918 virus did. Some experts argue that the risk of a pandemic is overblown. They note that the technologies for diagnosis, treatment, and immunization today are vastly superior to the technologies available during the 20th-century pandemics. They take comfort in the facts that H5N1, although now widespread, is not yet spread easily among humans and that all known past pandemics involved H1, H2, and H3 flu viruses, not H5 strains. Time will tell.
— Anthony L. Komaroff, MD; Published in Journal Watch December 30, 2005.

12. Age no bar to thrombolysis for stroke in octogenarians

December 30, 2005; By David Douglas. NEW YORK (Reuters Health) - Although elderly stroke patients have a greater risk of dying following therapy with IV recombinant tissue plasminogen activator (rtPA), age is not an independent predictor of outcome, Swiss researchers report in the December 13th issue of Neurology.

Dr. S. T. Engelter of University Hospital Basel and colleagues came to this conclusion after studying 325 rtPA-treated stroke patients. Of these, 38 were 80 years old or more and the remaining 287, who ranged in age from 14 to 79 years, had a mean age of 63 years.

The rate of intracranial hemorrhage did not differ between the two groups and overall there was a favorable outcome in 29% of the older patients and 37% of the younger patients. At 3 months, 32% of the elderly patients had died compared with 12% of the younger patients. Among patients who survived for 3 months, the rate of favorable outcome was 42% in the older patients and 43% in the younger patients.

"Logistic regression showed that stroke severity, time to thrombolysis, glucose level, and history of coronary heart disease independently predicted outcome, whereas age did not," the researchers report. Commenting on the findings, Dr. J. Claude Hemphill III, co-author of an accompanying editorial told Reuters Health, "IV rtPA should not be withheld from acute stroke patients just because they are very old."

Dr. Hemphill of the University of California, San Francisco, added that "while older patients might have a higher risk of bleeding from rtPA, we know that older patients also are more likely to die and less likely to recover from the stroke itself."

Neurology 2005;65:1795-1798.

13. New pneumonia category associated with health care

Not all community-acquired pneumonia is alike. Patients with pneumonia who were transferred from another health-care facility, had been receiving long-term hemodialysis, or had prior hospitalization within 30 days were classified into the Health-care-associated pneumonia. As this study explains, it might be important to distinguish this subset of pts from run-of-the-mill CAP pts.

December 29, 2005. NEW YORK (Reuters Health) - Health-care-associated pneumonia (HCAP) is associated with more severe disease, higher mortality rates, and higher costs than is community-acquired pneumonia, according to a report in the December issue of Chest.

Recent research suggests that health-care-associated infections have a unique epidemiology and different outcomes from those seen with community-acquired or nosocomial infections, the authors explain.

Dr. Marin H. Kollef From Washington University School of Medicine, St. Louis, and colleagues evaluated their hypothesis that HCAP is a distinct clinical entity by analyzing the records of patients with culture-positive pneumonia registered in a large US database.

Patients with pneumonia who were transferred from another health-care facility, had been receiving long-term hemodialysis, or had prior hospitalization within 30 days were classified into the HCAP group.

The database included 2221 patients with community-acquired pneumonia, 988 patients with HCAP, 835 patients with hospital-acquired pneumonia and 499 patients with ventilator-associated pneumonia. Patients with HCAP were significantly older than patients with community-acquired pneumonia or ventilator-associated pneumonia but comparable in age to those with hospital-acquired pneumonia, the report indicates. Nearly half the patients with HCAP were admitted from skilled nursing facilities.

Infection with Staphylococcus aureus was more common in the HCAP, hospital-acquired pneumonia and ventilator-associated pneumonia groups, the authors report, and the rate of methicillin-resistant S. aureus was significantly higher in HCAP patients than in patients with all other pneumonia types.

Mortality rates were similar with HCAP and hospital-acquired pneumonia, at about 20%, which were significantly higher than that associated with community-acquired pneumonia (10%) and lower than that associated with VAP (29%). Hospital length of stay was the highest for patients with ventilator-associated pneumonia and the lowest for those with community-acquired pneumonia, the researchers note.

Mean total hospital charges for patients with HCAP ($27,647) were higher than those for patients with community-acquired pneumonia ($25,218) but lower than those for patients with hospital-acquired pneumonia ($65,292) or ventilator-associated pneumonia ($150,841).

The findings suggest that "HCAP, traditionally classified into the community-acquired pneumonia category, is clinically more similar to hospital-acquired pneumonia and should be treated as such until culture data become available," the authors conclude.

Chest 2005;128:3854-3862.