Wednesday, February 28, 2007

Lit Bits: February 28, 2007

From the recent medical literature...

1. Multislice CT Angiography Offers Effective Evaluation of Chest Pain in ED

from Heartwire — a professional news service of WebMD. February 21, 2007 — For patients presenting to emergency departments with chest pain, multislice computed tomography angiography (CTA) using a 64-slice scanner can definitively establish or rule out coronary disease, a randomized trial suggests.

"The problem with the traditional stress-test approach is that it's time-consuming, expensive, and it's not always definitive," James Goldstein, MD, of the William Beaumont Hospital in Royal Oak, Michigan, explained to heartwire. "We showed that CTA was extremely accurate and helpful in deciding, in the vast majority of patients, whether their chest pain was potentially attributable to blockages in the arteries. And in terms of efficiency we demonstrated that multislice CTA reduced the time it took to make a diagnosis by about 75% and also reduced cost."

Goldstein and colleagues report the results of their study online in the February 20 Rapid Access issue of the Journal of the American College of Cardiology. The article will also appear in the February 27 print issue of the journal.

Time and Money
For their study, Goldstein and colleagues randomized 197 patients presenting to the emergency department with chest pain to either multislice CTA or standard of care (diagnostic algorithms based on serial electrocardiograms, cardiac enzyme tests, and nuclear stress testing). In the CTA group, patients with few or no signs of coronary disease were discharged, and those with stenoses higher than 70% were sent for cardiac catheterization.

In all, 75% of patients were either discharged or sent on for cardiac catheterization based on the CTA results; the remainder — those with intermediate lesions or those in whom the scans could not be interpreted — were sent for stress testing, according to the study protocol. Compared with patients treated according to the standard of care, diagnostic times were significantly shorter and cheaper in the multislice CTA group. During 6 months of follow-up, the number of patients deemed "normal" during their initial visits who returned to the hospital for reevaluation was numerically higher in the standard-of-care group, although this difference was not statistically significant. There were no safety issues between groups.

A "significant limitation" of the CTA strategy is that it does not offer information on cardiac function — the rest/stress imaging protocol used in the standard-of-care algorithm, in contrast, might help minimize catheterizations and unnecessary revascularization procedures, the authors note.

Radiation and Noncardiac Causes
In an accompanying editorial, Pim J. de Feyter, MD, and Niels van Pelt, MD, of the University Hospital Rotterdam, the Netherlands, point to 2 other problems with the use of multislice CTA. One is radiation exposure: the editorialists note that the effective radiation dose for a nonpulsing 64-slice scanner is between 9.6 and 21.4 mSv and is reduced to 4.8 to 14 mSv if electrocardiogram pulsing is used. In comparison, technetium nuclear testing entails 10.6 to 12 mSv, whereas traditional coronary angiography entails 4 to 6 mSv. For a patient exposed first to a CTA test that proves inconclusive, followed by a stress test that might indicate a need for invasive coronary angiography, the effective radiation dose would be at least double and possibly triple that of a patient referred directly for a nuclear stress test.

They also point out that patients presenting with chest pain in the emergency department should be checked for other potentially fatal causes, including aortic dissections and pulmonary emboli. "This would require a CT-scan protocol with a large field of view allowing global evaluation of thoracic structures, but that would compromise the evaluation of the coronary arteries and might lead to misinterpretation of coronary lesions."

To heartwire, Goldstein agreed that effective radiation dose could be high if nuclear stress testing is used after an inconclusive CTA — one solution would be to use a stress echocardiogram instead to verify indeterminate results, he said. Goldstein also agreed with de Feyter and van Pelt on the need to evaluate noncardiac structures and suggested that this is another one of the attractive features of cardiac computed tomography. But most attractive, he emphasized, is the increased efficiency in the larger proportion of patients with no previous history of coronary heart disease found to have a normal electrocardiogram and normal cardiac enzyme tests.

"We see at least 15 patients like that every day in our emergency room and they're undergoing these laborious tests," Goldstein said, noting that results from the various tests can sometimes take several days. "Then, if they have recurrent chest pain two weeks later we go through the whole rigmarole again.... Whereas if a patient comes in now, at 4:15 PM, I can send them to the CT scanner and we'll have the diagnosis by 5:00 PM and if the heart looks fine they'll be out having dinner that night."

J Am Coll Cardiol. 2007;49:863-871.

2. ED Co-Pay Decreases Visits

The largest-ever study on the effects of health care co-payment costs on emergency department visits has revealed that requiring patients to pay for a portion of the cost can reduce the number of visits. The study also finds that this decrease does not negatively affect health.

The population-based experiment followed over two million commercially insured (with Kaiser Permanente–Northern California, a prepaid integrated delivery system) and 250,000 Medicare insured patients.

"The results of this study are encouraging in that these modest co-payments appeared to reduce health care use, and therefore overall costs, without harming patients," says Dr. John Hsu, lead author of the study.

While emergency visit rates decrease substantially as the co-payment increases, the findings show no increase in the rate of unfavorable clinical events (hospitalization, intensive care admission) and no increase in deaths.

Hsu J, et al. Cost-Sharing for Emergency Care and Unfavorable Clinical Events: Findings from the Safety and Financial Ramifications of ED Copayments Study. Health Services Research 2006;41:1801–1820.


3. Simple Clinical Predictors May Obviate Urgent Endoscopy in Selected Patients With Nonvariceal UGI Bleeding

Romagnuolo R, et al. for the Registry for Upper GI Bleeding and Endoscopy Investigator Group. Arch Intern Med. 2007;167:265-270.

Background: The validated Blatchford risk score (BRS) predicts outcomes in patients with nonvariceal upper gastrointestinal tract bleeding, before endoscopy; completion of the Rockall score requires endoscopy. The aims of this study were to predict whether the modified BRS (mBRS) can predict (1) endoscopic high-risk stigmata (HRS) and (2) rebleeding and mortality.

Methods: Clinical and demographic characteristics on 1869 patients from 6 Canadian provinces were prospectively entered into the Registry for Upper GI Bleeding and Endoscopy database, recording 30-day rebleeding and mortality. The Rockall score and mBRS (hemoglobin level, hemodynamic instability, and presence of melena, liver disease, or cardiac failure; urea and syncope were not recorded) were calculated. Logistic regression was used to assess the association between an mBRS of 1 or less with HRS and with rebleeding and mortality.

Results: The mean (SD) age of the patients was 66 (17) years, with 62% men and a mean of 2.5 comorbidities. Of the 1860 patients with 30-day rebleeding data, 334 (18.0%) rebled; 5.3% died. The mBRS was 0 in 3% and 1 or less in 9.8% of patients; HRS were seen in 31.0% of patients. An mBRS of 1 or less was associated with lower rebleeding (5% vs 19%; P less than .001) and mortality (0.5% vs 5.8%; P=.003), and was significant in multivariate analysis for rebleeding (odds ratio, 0.24; 95% confidence interval, 0.12-0.48) and mortality (odds ratio, 0.12; 95% confidence interval, 0.02-0.90). The HRS were less frequent when the mBRS was 1 or less (16.9% vs 32.7%; odds ratio, 0.4; 95% confidence interval, 0.3-0.6). Patients with a low mBRS with HRS had a low rebleeding rate (3.3%) and a lower apparent benefit from endoscopic therapy.

Conclusions: A modified Blatchford risk score of 1 or less identifies approximately 10% of patients with gastrointestinal tract bleeding with a low likelihood of having HRS and a low risk of adverse outcomes. A prospective randomized study is required to examine whether this subgroup of patients presenting after hours could be discharged safely from emergency departments with arrangements for (urgent) outpatient endoscopy.

4. Empirical Ophthalmic Antibiotics indicated for Pediatric Conjunctivitis

Patel PB, et al. Clinical Features of Bacterial Conjunctivitis in Children. Acad Emerg Med 2007; 14:1-5.

INTRO: Conjunctivitis is a common cause of pediatric primary care visits and is a common ophthalmologic complaint in the pediatric emergency department (ED). Conjunctivitis can be extremely contagious. It is feared that it may be easily spread in day care centers and school classrooms, leading to absences and lost time from work for parents.

The most common causes of conjunctivitis are bacterial and viral infections. In the primary care setting, treatment is based solely on the clinical examination. A 1981 study showed that in the pediatric population, approximately 54% of cases of acute infectious conjunctivitis are caused by a bacterial pathogen.1 However, physicians prescribe antibiotics nearly 80%–95% of the time. Ocular antibiotics, therefore, are considered to be frequently overprescribed, and concerns for increased cost of health care, antibiotic resistance, and adverse reactions are often raised. The objective of our study was to describe the point prevalence and clinical features associated with bacterial conjunctivitis in children and to determine if and when empirical topical antimicrobial therapy for conjunctivitis is indicated.

DISCUSSION (excerpt): Conjunctivitis is a common pediatric diagnosis made in both the primary care and ED settings. Its prevalence is significant to the general population, because it is a leading cause of day care and school absences. Even though most cases of bacterial conjunctivitis are self-limited, it can take up to three weeks for the infection to clear. Treatment of acute conjunctivitis helps to shorten the clinical course, reduces spread of the contagion and discomfort, and allows the patient to resume activities earlier. The etiology is difficult to delineate on clinical grounds alone, and there is much pressure on physicians to prescribe antibiotics due to the social impact the diagnosis holds. Thus, physicians are faced with the dilemma of potentially overprescribing antibiotics in an era of increasing bacterial resistance and increased awareness of cost.

Pediatric and emergency medicine literature lacks clinical diagnostic indicators to assist practitioners in making a more informative decision about the need for ocular antibiotics because results from a culture of the conjunctiva may be delayed by several days. Most cases of acute infectious conjunctivitis are self-limited, and 64% resolve in two to five days. Untreated, acute bacterial conjunctivitis is clinically cured within three to five days in 28% of cases, and by eight to ten days there is a 72% clinical cure rate. There is bacteriologic cure of 19% and 31% of the same untreated groups. If treated with antibiotics, these numbers improve to 62% clinical cure at three to five days and 91% at eight to ten days, with bacteriologic cure of 71% and 79%, respectively. Recent studies have shown that topical antibiotics impact microbiologic remission by six to ten days. Thus, there is support for treating bacterial conjunctivitis because it leads to more rapid and improved rates of clinical remission.

METHODS: This was a prospective study in a children's hospital ED. Conjunctival swabs for bacterial culture were obtained from patients aged 1 month to 18 years presenting with red or pink eye and/or the diagnosis of conjunctivitis.

RESULTS: A total of 111 patients were enrolled over one year. Patients had a mean (±SD) age of 33.2 (±37.5) months, and 55% were male. Eighty-seven patients (78%) had positive bacterial cultures. Nontypeable Haemophilus influenzae accounted for 82% (71/87), Streptococcus pneumoniae for 16% (14/87), and Staphylococcus aureus for 2.2% (2/87). Five clinical variables were significantly associated with a positive bacterial culture. Regression analysis revealed that the combination of a history of gluey or sticky eyelids and the physical finding of mucoid or purulent discharge had a posttest probability of 96% (95% CI = 90% to 99%). Subjective scoring by physicians for a positive culture was 50.6%.

CONCLUSIONS: Conjunctivitis in children is predominantly bacterial, with nontypeable H. influenzae being the most common organism. A history of gluey or sticky eyelids and physical findings of mucoid or purulent discharge are highly predictive of bacterial infection. Based on the above data, empirical ophthalmic antibiotic therapy may be appropriate in children presenting with conjunctivitis.

5. The Effect of Low-Complexity Patients on ED Waiting Times

Schull MJ, et al. Ann Emerg Med 2007;49: 257-264.e1.

Study objective
The extent to which patients presenting to emergency departments (EDs) with minor conditions contribute to delays and crowding is controversial. To test this question, we study the effect of low-complexity ED patients on the waiting times of other patients.

We obtained administrative records on all ED visits to Ontario hospitals from April 2002 to March 2003. For each ED, we determined the association between the number of new low-complexity patients (defined as ambulatory arrival, low-acuity triage level, and discharged) presenting in each 8-hour interval and the mean ED length of stay and time to first physician contact for medium- and high-complexity patients. Covariates were the number of new high- and medium-complexity patients, mean patient age, sex distribution, hospital teaching status, work shift, weekday/weekend, and total patient-hours. Autoregression modeling was used given correlation in the data.

One thousand ninety-five consecutive 8-hour intervals at 110 EDs were analyzed; 4.1 million patient visits occurred, 50.8% of patients were women, and mean age was 38.4 years. Low-, medium-, and high-complexity patients represented 50.9%, 37.1%, and 12% of all patients, respectively. Mean (median) ED length of stay was 6.3 (4.7), 3.9 (2.8), and 2.2 (1.6) hours for high-, medium-, and low-complexity patients, respectively, and mean (median) time to first physician contact was 1.1 (0.7), 1.3 (0.9), and 1.1 (0.8) hours. In adjusted analyses, every 10 low-complexity patients arriving per 8 hours was associated with a 5.4-minute (95% confidence interval [CI] 4.2 to 6.0 minutes) increase in mean length of stay and a 2.1-minute (95% CI 1.8 to 2.4 minutes) increase in mean time to first physician contact for medium- and high-complexity patients. Results were similar regardless of ED volume and teaching status.

Low-complexity ED patients are associated with a negligible increase in ED length of stay and time to first physician contact for other ED patients. Reducing the number of low-complexity ED patients is unlikely to reduce waiting times for other patients or lessen crowding.

6. Algorithm More Accurately Predicts Cardiovascular Risk in Women

Researchers have developed an improved algorithm for predicting 10-year cardiovascular risk in women, according to a report in a recent issue of JAMA.

The Reynolds Risk Score algorithm was created using data from nearly 25,000 healthy women, aged 45 or older, who were monitored for cardiovascular events over a median of about 10 years. Researchers derived the algorithm using data from two-thirds of the cohort, then validated it in the remainder. The algorithm incorporates two variables not used by the current ATP-III algorithm: family history of premature coronary heart disease and C-reactive protein.

An editorial calls the study an "important contribution" and observes: "Overall, approximately 20% of women will have different lipid treatment goals based on the Reynolds model than recommended by the ATP-III guidelines."

Ridker PM, et al. JAMA. 2007;297:611-619.

JAMA abstract:

Reynolds Risk Score:

7. FDA Notes Cases of Intussusception After New Rotavirus Vaccine

The FDA issued a public health notice yesterday regarding 28 cases of intussusception that have occurred over the past year following receipt of live, oral, pentavalent rotavirus vaccine (RotaTeq).

Whether any of these cases is related to the vaccine is unknown. Premarketing studies did not identify an increased risk; however, an earlier rotavirus vaccine was withdrawn because of concerns about higher rates of intussusception. The manufacturer and the CDC are conducting further studies to assess the risk.

The FDA said that it issued the notice "to remind people that intussusception is a potential complication of RotaTeq" and to encourage reporting of any further cases of intussusception that may have occurred to the Vaccine Adverse Event Reporting System.

FDA Public Health Notice:

8. Pitfalls in the Diagnosis of Cerebellar Infarction

BACKGROUND: Cerebellar infarction is an important cause of acute neurologic disease and accounts for 2%–3% of the 600,000 ischemic stroke cases annually in the United States. Delayed or missed diagnosis of cerebellar infarction may result in serious morbidity and mortality due to hydrocephalus, mass effect, and brain stem compression. Misdiagnosis also delays detecting the underlying cause of brain ischemia such as cardiac disorders and vascular occlusive lesions within the intracranial and extracranial circulation, leaving patients at continued risk for further strokes. There are only scattered case reports about misdiagnosis of cerebellar strokes and no information about the causes and consequences of failure to recognize this condition. To identify sources of preventable medical errors, we analyzed 15 cases of cerebellar infarcts that were initially misdiagnosed in the emergency department (ED). We report the clinical features, diagnostic tests, and outcome of these cases.

OBJECTIVES: To identify sources of preventable medical errors, the authors obtained pilot data on cerebellar ischemic strokes that were initially misdiagnosed in the emergency department.

METHODS: Fifteen cases of misdiagnosed cerebellar infarctions were collected, all seen, or reviewed by the authors during a five-year period. For each patient, they report the presenting symptoms, the findings on neurologic examination performed in the emergency department, specific areas of the examination not performed or documented, diagnostic testing, the follow-up course after misdiagnosis, and outcome. The different types of errors leading to misdiagnosis are categorized.

RESULTS: Half of the patients were younger than 50 years and presented with headache and dizziness. All patients had either incomplete or poorly documented neurologic examinations. Almost all patients had a computed tomographic scan of the head interpreted as normal, and most of these patients underwent subsequent magnetic resonance imaging showing cerebellar infarction. The initial incorrect diagnoses included migraine, toxic encephalopathy, gastritis, meningitis, myocardial infarction, and polyneuropathy. The overall mortality in this patient cohort was 40%. Among the survivors, about 50% had disabling deficits. Pitfalls leading to misdiagnosis involved the clinical evaluation, diagnostic testing, and establishing a diagnosis and disposition.

CONCLUSIONS: This study demonstrates how the diagnosis of cerebellar infarction can be missed or delayed in patients presenting to the emergency department.

Savitz SI, et al. Acad Emerg Med 2007;14:63-68.

9. Kawasaki Disease's Cardiovascular Effects Not Ameliorated by Corticosteroid Pulse

Patients with Kawasaki disease did not benefit from the addition of a pulsed dose of corticosteroid to standard therapy, researchers report in the Feb 15 issue of the New England Journal of Medicine.

Some 200 children with the disease were randomized to receive either a pulsed intravenous dose of methylprednisolone given over 2 to 3 hours or placebo infusion. All patients also received standard therapy with immune globulin and aspirin.

At weeks 1 and 5 after randomization, measurements of the patients' coronary arteries -- the primary outcome of the study -- showed no differences between groups. Corticosteroid-treated children had slightly shorter initial hospital stays and a lower median erythrocyte sedimentation rate at week 1.

The author of an accompanying perspective writes that "the failure of corticosteroids to benefit these patients underscores the difference between Kawasaki disease and other chronic vasculitides, for which corticosteroids are the foundation of most treatment strategies."

By the way, just what are the symptoms of Kawasaki disease?

Here’s a review (written with parents in mind): The first phase, which can last for up to 2 weeks, usually involves a persistent fever that is higher than 104 F, and lasts for at least 5 days. Other typical symptoms include: severe redness in the eyes; a rash on the child's stomach, chest, and genitals; red, dry, cracked lips; swollen tongue with a white coating and big red bumps; sore, irritated throat; swollen palms of the hands and soles of the feet with a purple-red color; swollen lymph nodes. During the second phase of the illness, which usually begins within two weeks of when the fever first begins, the skin on the child's hands and feet may begin to peel in large pieces. The child may also experience joint pain, diarrhea, vomiting, or abdominal pain.

10. Combination Therapy for COPD Offers No Survival Benefit

Combination therapy with a long-acting beta-agonist plus a corticosteroid offers some benefits for COPD patients, but not survival benefits, according to a study in the Feb 22 issue of the New England Journal of Medicine.

In the international, industry-supported TORCH trial, researchers randomized more than 6000 COPD patients to receive either inhaled salmeterol and fluticasone propionate, each drug alone, or placebo. At 3 years, rates of all-cause mortality (the primary outcome) were 12.6% with combination therapy, 13.5% with salmeterol, 16.0% with fluticasone, and 15.2% with placebo. The mortality difference between the combination-therapy and placebo groups fell just short of statistical significance (P=0.052). However, combination therapy was associated with significant improvements in health status, lung function, and the frequency of COPD exacerbations. Patients taking fluticasone, alone or in combination, had an increased rate of pneumonia.

An editorialist writes that although the combination therapy results are difficult to interpret, "monotherapy with corticosteroids should not be advocated for patients with COPD," while "monotherapy with a long-acting bronchodilator appears to be safe."

NEJM abstract:

11. Thrombolysis for Pulmonary Embolus: How Good Is It?

THE ROLE OF THROMBOLYTIC therapy in acute pulmonary embolism has long been debated. Compared with heparin sodium alone, the addition of thrombolytic therapy improves hemodynamic and scintigraphic outcomes within 24 hours of administration, but these benefits diminish over time. For patients with pulmonary embolism and arterial hypotension, thrombolysis is considered to be the standard of care because prognosis in this group is so poor without thrombolytic therapy that the potential benefits are thought to far outweigh the risks. The controversy centers on treatment of hemodynamically stable patients with pulmonary embolism, especially those with right ventricular dysfunction. Right ventricular dysfunction is thought to be a sign of possible impending hemodynamic instability. It is present in 40% to 50% of patients with pulmonary embolism who are hemodynamically stable at the time of presentation, and right heart failure is a common cause of death in these patients. Patients with submassive pulmonary embolism and right ventricular dysfunction have mortality rates that are 2 times higher than those with normal right ventricular function.

Proponents of thrombolytic therapy argue that its potential benefits justify the greater cost and the increased risk of intracerebral hemorrhage and other major bleeding complications in hemodynamically stable patients with right ventricular dysfunction. A recent randomized controlled trial 14 in this population demonstrated that primary thrombolysis with alteplase and heparin was more effective than treatment with heparin alone in preventing the combined end point of death or the requirement for treatment escalation, including the need for catecholamine infusion, mechanical ventilation, or secondary thrombolysis. However, mortality rates were lower than expected and similar in both treatment groups. The authors concluded that their results supported the use of primary thrombolysis based on the less-frequent requirement for treatment escalation in the intervention group.

Methods: We performed a cost-effectiveness analysis to compare health effects and costs of treatment with alteplase plus heparin sodium vs heparin alone in hemodynamically stable patients with pulmonary embolism and right ventricular dysfunction by developing a Markov model and using data from clinical trials and administrative sources.

Results: Based on data from a recent randomized trial, we assumed that the risk of clinical deterioration requiring treatment escalation was almost 3 times higher in patients who received heparin alone (23.2% vs 7.6%) but that the risk of death was equal in the 2 cohorts (2.7%). Based on registry data, we assumed that the risk of intracranial hemorrhage was approximately 3 times higher in patients who received alteplase plus heparin (1.2% vs 0.4%). Under these and other assumptions, thrombolysis resulted in marginally higher total lifetime health care costs ($43 900 vs $43 300) and was slightly less effective (10.52 vs 10.57 quality-adjusted life-years) than treatment with heparin alone. Thrombolysis was more effective and cost less than $50 000 per quality-adjusted life-year gained when we assumed that the baseline risk of death in the heparin group was 3 times the base-case value (8.1%) and that alteplase reduced the relative risk of death by at least 10%.

Conclusions: Available data do not support the routine use of thrombolysis to treat patients with submassive pulmonary embolism. However, thrombolysis may prove to be cost-effective in selected subgroups of hemodynamically stable patients in whom the risk of death is higher.

Perlroth DJ, et al. Arch Intern Med. 2007;167:74-80.

12. AHA Prevention Guidelines for Women Recommend Aspirin for All

Updated American Heart Association guidelines for prevention of cardiovascular disease in women say routine low-dose aspirin should be considered for women of all ages to prevent strokes.

The guidelines, last revised in 2004, were released online Feb 19th by Circulation. For women under age 65 who are healthy or at moderate risk, they suggest aspirin (81 mg daily or 100 mg every other day), as long as the benefit of preventing an ischemic stroke appears to outweigh the risk for gastrointestinal bleeding and hemorrhagic stroke. They offer the same advice for women over 65 to prevent both MI and stroke if their blood pressure is controlled.

Other changes include the following:

-- Physicians should consider other factors besides the Framingham global risk score -- such as medical, lifestyle, and family histories -- when making decisions about women's preventive therapy.

-- The guidelines no longer recommend hormone replacement therapy, antioxidant supplements, or folic acid to prevent cardiovascular disease.

-- Women who need to lose or keep off weight should get a minimum of 60 to 90 minutes of moderate-intensity physical activity on most days.

AHA Guideline in Circulation:

13. Concerns Raised Over Studies supporting Mannitol for Head Injury

Excerpt from the BMJ article: Each year, worldwide, many thousands of people are treated in emergency departments for head injuries. Mannitol is an osmotic diuretic that is believed to reduce intracranial pressure after head injury and may improve patient outcome. Between 2001 and 2004, a Brazilian neurosurgeon Julio Cruz and colleagues published three clinical trials comparing high dose and conventional dose mannitol in the treatment of head injury. No other trials had examined this question.

The results showed that high dose mannitol greatly reduced death and disability six months after the head injury. A Cochrane systematic review that included these trials concluded: "high dose mannitol seems to be preferable to conventional dose mannitol in the acute management of comatose patients with severe head injury." However, one of the trials was accompanied by an editorial that questioned the reliability and validity of the results, calling for further multicentre studies. A subsequent investigation by the Cochrane Collaboration was unable to confirm that the studies took place.

Doubts over the data
In May 2006, Dr Jorge Mejia, the Colombian national coordinator of the CRASH-2 (clinical randomisation of an antifibrinolytic in significant haemorrhage; trial, wrote to IR (who is editor of the Cochrane Injuries Group) after attending a meeting of the Latin American Brain Injury Consortium in Brazil. He was concerned about the inclusion of the Cruz trials in the Cochrane review:

"During the discussion some Brazilian physicians expressed some surprise with the inclusion of Julio Cruz' paper in the meta-analysis (Cruz 2004; J Neurosurgery, 100:376) ... Cruz had no patients at his arrival to Brasil, back from USA where he had developed his research career."

Dr Mejia was clearly shocked by this revelation: "I do not know what to do, but I feel betrayed. I guess that someone should contact the others authors and ask them. I feel that I can not stay passive, but I have no evidence."

Dr Cruz, the lead author, had killed himself in 2005. However, the reports had coauthors from Italy and Japan, and we contacted them for further information…

NEW YORK (Reuters Health) Feb 22 - Using high-dose mannitol to treat head injuries may not be a sound strategy as the three main studies supporting this practice may not have even taken place, according to a report in British Medical Journal for February 24.

Between 2001 and 2004, a research group led by Brazilian neurosurgeon Dr. Julio Cruz published three trials showing that high-dose mannitol is preferable to the conventional dose in treating head injury. In particular, a reduction in death and disability was noted at 6 months by using high- rather than standard-dose mannitol.

However, concerns over the data began to surface. In an editorial accompanying one of the studies, the validity and reliability of the findings were called into question, largely because the research was conducted "at only one institution." A later investigation by the Cochrane Collaboration was unable to verify that any of the studies had actually occurred.

In the present report, appearing in the British Medical Journal for February 24, Dr. Ian Roberts, coordinating editor of the Cochrane Injuries Group, and colleagues describe the numerous unsuccessful efforts they took to verify the data from Cruz's studies.

One major problem in confirming the data was that Dr. Cruz committed suicide in 2005. Another problem was that Dr. Roberts' team could not determine where the patients included in the studies had come from. The Federal University of Sao Paulo, which was listed as Dr. Cruz's affiliation on the papers, later told the investigators that it had never employed Dr. Cruz.

Dr. Roberts' team contacted the living co-authors in an effort to retract the reports. These authors declined to seek retraction and supported Dr. Cruz, commenting that "he would never have been able to do something false."

After considerable efforts to confirm the data, Dr. Roberts and colleagues conclude, "We are left with serious doubt about important studies but with no way of determining with confidence whether the results are fabricated or real. The main author is dead. There is no institution to investigate. The implications for patients are serious."

BMJ 2007;334:392-394.

14. Can aggressively lowering BP in hypertensive patients with CAD be dangerous?

Messerli FH, et al. Ann Intern Med 2006;144:884–93.

Extensive literature exists regarding control of hypertension in patients with coronary artery disease (CAD). However, debate continues with respect to the effects of excessive lowering of the diastolic blood pressure. This study is a secondary analysis of a large cohort of patients from the International Verapamil-Trandolapril Study (INVEST), in which the authors examined the data to determine if low diastolic blood pressure is associated with increased morbidity and mortality in patients with CAD and hypertension.

In this study, 22,576 patients were included. Data from averaged systolic and diastolic pressures was pooled into 10 mm Hg subsets. The primary outcome was defined as the first occurrence of all-cause death, nonfatal myocardial infarction (MI), or nonfatal stroke. The rates of these outcomes were distributed along the systolic and diastolic blood pressure strata, and the relationship was determined to be a J-shaped pattern. The J-curve for diastolic pressure was more pronounced, and the findings led the authors to conclude that diastolic pressures below 70 mm Hg increased the risk for primary outcome events, particularly death from all causes and from MI, both fatal and nonfatal.

Comment: These data suggest that patients with hypertension and CAD are at increased risk for complications (defined by mortality, MI, or stroke) when their diastolic pressures were lowered below 70 to 80 mm Hg.

15. MRI Contrast Agents Linked to Skin Disorder in Renal Disease Patients

The CDC this month warned physicians to avoid using gadolinium-containing MRI contrast agents when possible in patients with advanced renal failure because of the risk for a serious skin disease.

In an article in MMWR, gadolinium agents were linked to nephrogenic fibrosing dermopathy (NFD), which can cause thickening and hardening of the skin. Researchers conducted a matched case-control study that included 19 cases from a St. Louis hospital. In multivariate analysis, patients with renal disease who developed NFD were nearly nine times as likely to have been exposed to gadolinium contrast agents in the previous year as those who did not develop the skin condition. Patients receiving peritoneal dialysis appeared to be at greater risk than those receiving hemodialysis.

MMWR article:

16. A Randomized Controlled Trial Comparing Intranasal Fentanyl to IV Morphine for Managing Acute Pain in Children in the ED

Borland M, et al. Ann Emerg Med 2007;49:335-340.

In the pediatric emergency department (ED), rapid, effective, and painless delivery of analgesia is desired. As a consequence, it is routine in many facilities to give intravenous (IV) morphine to children presenting to the ED in moderate to severe pain. However, the insertion of an IV cannula can, at times, require special skills, is time and staff dependent, and is painful and anxiety provoking for some children. Alternative methods of providing safe and effective analgesia include the intranasal route for the administration of opiates such as fentanyl and diamorphine. A study in a tertiary pediatric ED illustrated the safety and efficacy of intranasal fentanyl in a pediatric population. Two other ED studies have compared an intranasal opiate with intramuscular morphine as their criterion standard.

There has not been a study comparing an intranasal opiate with a drug with a similar onset of action. Intramuscular morphine would be expected to take up to 30 minutes to achieve adequate analgesia, whereas intranasal formulations take 5 to 10 minutes. In addition, if it were possible to provide adequate analgesia without IV access, then the administration of
analgesia would be hastened, which would equate to greater patient comfort and satisfaction.

Study objective
We compare the efficacy of intranasal fentanyl versus intravenous morphine in a pediatric population presenting to an emergency department (ED) with acute long-bone fractures.

We conducted a prospective, randomized, double-blind, placebo-controlled, clinical trial in a tertiary pediatric ED between September 2001 and January 2005. A convenience sample of children aged 7 to 15 years with clinically deformed closed long-bone fractures was included to receive either active intravenous morphine (10 mg/mL) and intranasal placebo or active intranasal concentrated fentanyl (150 µg/mL) and intravenous placebo. Exclusion criteria were narcotic analgesia within 4 hours of arrival, significant head injury, allergy to opiates, nasal blockage, or inability to perform pain scoring. Pain scores were rated by using a 100-mm visual analog scale at 0, 5, 10, 20, and 30 minutes. Routine clinical observations and adverse events were recorded.

Sixty-seven children were enrolled (mean age 10.9 years [SD 2.4]). Fractures were radius or ulna 53 (79.1%), humerus 9 (13.4%), tibia or fibula 4 (6.0%), and femur 1 (1.5%). Thirty-four children received intravenous (IV) morphine and 33 received intranasal fentanyl. Statistically significant differences in visual analog scale scores were not observed between the 2 treatment arms either preanalgesia or at 5, 10, 20, or 30 minutes postanalgesia (P=.333). At 10 minutes, the difference in mean visual analog scale between the morphine and fentanyl groups was -5 mm (95% confidence interval -16 to 7 mm). Reductions in combined pain scores occurred at 5 minutes (20 mm; P=.000), 10 minutes (4 mm; P=.012), and 20 minutes (8 mm; P=.000) postanalgesia. The mean total INF dose was 1.7 µg/kg, and the mean total IV morphine dose was 0.11 mg/kg. There were no serious adverse events.

Intranasal fentanyl delivered as 150 µg/mL at a dose of 1.7 µg/kg was shown to be an effective analgesic in children aged 7 to 15 years presenting to an ED with an acute fracture when compared to intravenous morphine at 0.1 mg/kg.

17. Prehypertension Is “On the Map” of Cardiovascular Risk Factors

DALLAS, TX -- February 20, 2007 -- According to researchers studying postmenopausal women in the Women's Health Initiative, prehypertension exists in about 40% of postmenopausal women and it is associated with a 58% higher risk of cardiovascular death, regardless of ethnicity, compared to normal blood pressure.

Using the most recent definitions for hypertension, normal blood pressure is systolic pressure (the top number in a blood pressure reading) less than 120 mm Hg and diastolic (bottom number) less than 80 mm Hg; prehypertension is systolic pressure of 120-139 or diastolic 80-89 mm Hg; and hypertension is systolic pressure of 140 mm Hg or higher, or diastolic pressure of 90 mm Hg or higher or currently taking antihypertensive medication.

"Is the cardiovascular risk with blood pressures slightly above 120/80 mm Hg clinically important enough to justify the label of prehypertension?" asked the study authors. "The increased cardiovascular risk with prehypertension is certainly smaller than the risk associated with having diabetes (158% higher risk), but is greater than that associated with smoking (34% higher). Since smoking is pretty much unchallenged as a cardiovascular risk factor, perhaps prehypertension should be afforded the same acceptance."

Researchers studied 60,785 postmenopausal women in the Women's Health Initiative during a 7.7-year follow-up. At the start of the study, 26% had normal blood pressure, 39% had prehypertension and 35% had hypertension. Prehypertension rates among women of different ethnic groups were 39.5% for whites, 32.1 for blacks, 42.6 for Hispanics, 38.7 for American Indians and 40.3% for Asians.

Women with higher blood pressures were more likely to be older, have higher body mass index, diabetes or high cholesterol. Smoking was more common among women with normal blood pressure (10%). The 10-year incidence of cardiovascular events was 3.63% for women with normal blood pressure, 7.11% for women with prehypertension; and 14.16% for women with high blood pressure.

Compared to women with normal blood pressure, prehypertensive women of any ethnicity had a 58% higher risk of cardiovascular death: 76% higher risk of heart attack; 93% higher risk of stroke; 36% higher risk for being hospitalized with heart failure; and 66% higher risk for any cardiovascular event. Even after adjusting for age, body mass index, diabetes, high cholesterol and smoking status, prehypertension was independently associated with a higher risk of cardiovascular events.

Hsia J, et al. Circulation. 2007;115:855-860.


18. Frequent Use of Nonnarcotic Analgesics Associated with Hypertension in Men

Near-daily use of nonnarcotic analgesics, including acetaminophen, confers a moderate increase in the risk for developing hypertension, researchers report in the current Archives of Internal Medicine.

The study group comprised some 16,000 men with an average age of 65 and no history of hypertension. They were subjects in the Health Professionals Follow-up Study. Participants reported the frequency of their use of acetaminophen, NSAIDS, and aspirin at baseline; on two questionnaires over the subsequent 4 years they also reported whether they'd been diagnosed with hypertension.

Compared with nonusers, those who took NSAIDS, aspirin, or acetaminophen 6 or 7 days a week had a multivariable relative risk for incident hypertension of 1.38, 1.26, and 1.34, respectively. The authors suggest the acetaminophen link might be mediated through vasodilatory prostaglandins, oxidative stress, and endothelial function.

The authors say their findings echo others' and "suggest that these agents be used with greater caution."

Archives abstract:

19. Board-type Questions

Compared to patients with permanent atrial fibrillation, patients with paroxysmal atrial fibrillation have a risk of stroke that is

A) 50% less
B) 25% less
C) 25% greater
D) 50% greater
E) similar

A 62-year-old white male has a history of coronary artery disease, hypertension, and osteoarthritis. He is on lovastatin (Mevacor) for hypercholesterolemia. You are choosing a medication to treat his hypertension. Which one of the following could increase this patient’s risk of rhabdomyolysis?

A) Carvedilol (Coreg)
B) Quinapril (Accupril)
C) Losartan (Cozaar)
D) Atenolol (Tenormin)
E) Verapamil (Calan, Isoptin)

Answers follow item 20.

20. Ultrasound Guided Hematoma Block: A Novel Use of US in the Traumatized Patient

Crystal C, et al. J Trauma. 2007;62:532-533.

The procedure is best performed with a high-frequency linear probe, such as the 5.0- to 10-MHz transducer used in this instance. The site is prepared in the usual sterile fashion. A generous amount of sterile conducting gel is placed over the suspected fracture site to allow the transducer to be gently placed upon it. We have found that laying the transducer sagittally over the long axis of the bone provides the best images. By placing the fracture site in the center of the image, one can easily place a needle into the hematoma by entering the skin in the middle of the transducer. Similar to ultrasound-guided venous access, the needle often will not be directly visualized.

The hematoma block is an effective and safe means to provide analgesia before the reduction of fractures. Orthopedic surgeons and emergency physicians have long recognized its value in the management of fractures commonly seen in the ED. It has been used in a variety of fracture sites including wrist, forearm, ankle, and femur. It is safe and effective in both adults and children, with the typical injected dose of local anesthetic not resulting in toxic blood levels. Although it is usually a relatively simple procedure to perform, it may at times be difficult. In our experience, some of this difficulty occurs when body habitus or traumatic soft-tissue swelling precludes the accurate palpation of the exact fracture site.

Emergency physicians now recognize the utility of ultrasound in the emergency department. Recently, its use for fracture identification has been suggested. We could find no citations in the literature on its use in assisting with hematoma blocks. We have found that this technique has enhanced our ability to successfully perform this procedure. Our group has used this technique over 30 times, with many of us performing every hematoma block under ultrasound guidance. Our anecdotal experience suggests that although hematoma block is generally a very safe procedure, ultrasound provides a means to make it even safer because the procedure may be performed successfully on the first attempt, without the risk of placing the anesthetic in an incorrect location requiring repeated attempts with the concomitant risk of complications. Although further study is needed, this may be similar to other areas of medicine (e.g., central venous lines) where ultrasound guidance has been proven safer and more efficacious than a “blind” approach.


Answers to board questions

E to both questions

Patients with paroxysmal atrial fibrillation (i.e., self-terminating) and persistent atrial fibrillation (i.e., that lasts more than 7 days or requires elective cardioversion) appear to have a risk of stroke that is similar to that of patients with permanent atrial fibrillation.

Ref: Page RL: Newly diagnosed atrial fibrillation. N Engl J Med 2004;351:2408-2416.

Lovastatin, as well as other statin cholesterol-lowering medications, is primarily metabolized through the cytochrome P-450 system. Medications that inhibit the enzyme CYP 3A4, such as verapamil, increase serum concentrations of selected statins and subsequently increase the risk of rhabdomyolysis.

Ref: Thompson PD, Clarkson P, Karas RH: Statin-associated myopathy. JAMA 2003;289:1681-1690.