Wednesday, February 14, 2007

Lit Bits: February 14, 2007

From the recent medical literature…

1. Myth: Parenteral ketorolac provides more effective analgesia than oral ibuprofen

Arora S, Herbert M, et al (from UCLA). Can J Emerg Med 2007;9:30-2

Acute pain is an extremely common presenting symptom to the emergency department (ED), making it imperative that emergency physicians provide adequate, safe and cost-effective analgesia. Nonsteroidal anti-inflammatory drugs (NSAIDs) are often first-line treatments for moderate to severe pain. Physicians can choose between intramuscular (IM) or intravenous (IV) ketorolac and an oral NSAID. The mechanism of action (reversible inhibition of prostaglandin synthesis at the level of cyclooxygenase) is identical irrespective of the route the medication is given.1 Despite the similar pharmacodynamics, many physicians believe that parenteral ketorolac is more efficacious, despite a greater cost and a more invasive route of administration. To investigate this myth (i.e., that parenteral ketorolac provides greater analgesic effect than an oral NSAID), we conducted a review of the literature, with specific focus on ibuprofen as the prototypical — and least expensive — oral NSAID.

For the missing middle portion of this evidence-based article, see the link below.

The higher cost of ketorolac, the pain and difficulty associated with its administration, the risk of extravasation, and the exposure of practitioners to possible needle-stick injuries, all argue that there is no use for IM or IV ketorolac over oral ibuprofen in the ED for routine analgesia, unless oral administration of ibuprofen is unfeasible or contraindicated. Only in specific acute pain syndromes associated with nausea and vomiting, like renal colic, may its use be warranted. The belief that IM/IV medications are perceived as being stronger than oral medications and therefore result in a more powerful placebo effect has also been shown to be false. With the exception of 1 study in post-op patients with a significantly flawed study design, the evidence overwhelmingly shows that inexpensive and relatively safe oral ibuprofen has equal efficacy to the more expensive and potentially dangerous IM or IV ketorolac.

The full-text (free!) can be found here:

2. Lancet Focuses on Stroke

Stroke is the focus of several studies in the Jan 27th issue of the Lancet.

A. MRI beats CT for acute CVA. One study found MRI better than CT for detecting acute stroke in a sample of 356 patients who underwent both procedures. MRI had an accuracy of 89%, compared with CT's 54%. (Both were equally effective in detecting acute intracranial hemorrhage.) The authors write that MRI "should be the preferred test for accurate diagnosis of patients with suspected acute stroke."

B. tPA in “routine clinical practice.” In a second study, designed to evaluate the effectiveness of alteplase in routine clinical practice, European investigators followed up on some 6500 patients who had received the drug in almost 300 treatment centers. They report that alteplase -- which must be used within 3 hours -- has a safety profile at least as good as that seen in randomized trials and that "thrombolysis should now be considered a part of routine care."

C. Risk-stratifying our TIA patients. The third study helps clinicians predict which TIA patients are at risk for short-term stroke.

Unified Score Improves Prediction of Stroke After TIA

January 30, 2007 — Researchers of the California and ABCD risk scores have collaborated on a new unified score, dubbed ABCD2, that appears to improve the prediction of stroke risk after a previous transient ischemic attack (TIA) over either score alone.

Their findings, a collaboration between researchers at the Radcliffe Infirmary, Oxford in the United Kingdom; the University of California, San Francisco; and Kaiser Permanente Northern California in Oakland, are published in the January 27 issue of The Lancet.

"The purpose here was rather than to have competing scores out there, to work together with our colleagues across the Atlantic to come up with the best possible score," S. Claiborne Johnston, MD, of the University of California, San Francisco, and Kaiser Permanente Northern California told Medscape. In particular, he noted, they wanted, "a score that would tell treating physicians what the 2-day stroke risk is, when the decision to admit or to treat a TIA as an emergency is particularly relevant."

Currently, patients with a TIA are treated differently between hospitals in various medical settings, Dr. Johnston said. "For instance, some hospitals admit the majority of patients with TIA, as high as 80% or more; others admit very few patients — fewer than 20% or 10% — and in the UK, really none."

The ABCD2 score is meant to help clinicians make more rational decisions about who to admit and who requires other urgent interventions or evaluations to prevent a stroke in patients with TIA, Dr. Johnston said. The unified score draws together elements of the California score, previously published but not ultimately validated by Dr. Johnston's group (Johnston SC, et al. JAMA. 2000;284:2901-2906), and of the ABCD score, published and validated in their own population by Peter Rothwell, MD, and colleagues at Oxford (Rothwell PM, et al. Lancet. 2005;366:29-36).

"We combined our various cohorts into one large study, developed a new rule that really combines the prior 2 rules and then validated that on 4 independent cohorts and came up with ABCD2," Dr. Johnston said.

The 2 existing scores predicted the risk for stroke similarly in the 4 validation cohorts, totaling 2893 patients, for stroke risk at 2, 7, and 90 days with c statistics ranging from 0.60 to 0.81, the authors note. However, the combined score was more accurate than either of these in the groups where the tools had been derived, some 1916 patients.

The main difference between the California and ABCD scores was that the California score included diabetes but not hypertension as a cofactor while the Oxford score included hypertension but not diabetes, Dr. Johnston noted. The new tool includes both diabetes and hypertension and is based on points summed from 5 clinical factors: age older than 60 years (1 point), blood pressure of 140/90 mm Hg or higher (1 point), clinical features including unilateral weakness (2 points), speech impairment without weakness (1 point), duration of 60 minutes or higher (2 points) or 10 to 59 minutes (1 point), and diabetes (1 point).

"It's a more comprehensive score than either of the prior ones, and so not surprisingly, it works better," he said.

The ABCD2 score validated well, was more accurate than either of the previous scores in the 2 groups where they had been derived, and generally performed better in the 4 validation cohorts. In the 4799 patients with complete data in the combined validation groups, the 2-day risk for stroke was 1.0% with a score of 0 to 3 seen in 1012 patients or 21% who were deemed low risk, 4.1% with a score of 4 or 5 in 2169 or 45% considered at moderate risk, and 8.1% with a score of 6 or 7 in 1628 patients or 34% who were deemed at high risk.

Unified Score
The hope with the score is to set 1 clinical standard that can then be used consistently for guidelines and teaching purposes, Dr. Johnston said. This has been an issue for other prognostic scores, he noted. "For instance there are several that predict risk of stroke in patients with atrial fibrillation, and that's not helpful to anyone," he said. "That shouldn't happen here, because we have now a score that has been embraced by the 2 groups that have done the most work in this, and in all our studies now include over 4,000 patients so it should hold up."

Recent guidelines from the National Stroke Association anticipate this new rule based on a previous presentation of these data at a scientific meeting, he noted, but future guidelines will hopefully be able to be more explicit about the role of aggressive interventions and hospitalization in patients at different levels of the score.

"Dealing in Futures"
In an accompanying comment, Walter N. Kernan, MD, of Yale University School of Medicine in New Haven, Connecticut, writes that "patients who present soon after a TIA should be evaluated for short-term stroke risk and the ABCD2 system is currently the best available method."

However, Dr. Kernan raised a couple of points about the tool that otherwise, he writes, "holds up well to scrutiny." First, the diagnosis of TIA was not made according to a uniform definition, such as that proposed by the TIA Working Group. "Diagnostic standardization helps to assure that a clinical prediction instrument is applied to populations for which it has been developed (and in which it would be expected to work best)."

Second, he notes, the tool was tested in the same population areas where the systems from which it was derived were developed. "Additional testing will ascertain whether it successfully stratifies risk beyond San Francisco and Oxfordshire and in the hands of different users."

ABCD2 reminds us that an effective clinician "deals in futures," Dr. Kernan states. The "great virtue" of the system as an aid to prognosis is "its simplicity and easy applicability," he concludes. "We should consider it now for communication and triage, but recognize that prognosis is dynamic and can be affected by clinical data and treatment. The day after initial evaluation, the ABCD2 score might be old news, but the patient could have a brighter future."

As Dr. Kernan anticipates in his editorial, Dr. Johnston responded that the ABCD2 group sees the lack of a strict definition for TIA, but rather relying on the clinician's diagnosis in the field as a strength, not a weakness, that increases the generalizability of the score. As for the populations in which the prediction tool was tested, while technically it is true that it was tested in the same populations where it was derived, the populations are vastly different from each other.

"The score works well in a system in Oxford where almost everybody's white and it's fairly affluent, and no one gets admitted to the hospital, and in a system in California where patients are getting admitted to the hospital, where only 50% are white and the rest are all different races, and where a broader spectrum of socioeconomic status is represented," Dr. Johnston pointed out.

S Claiborne Johnston, et al. Validation and refinement of scores to predict very early stroke risk after transient ischaemic attack. Lancet. 2007;369:251-252, 283-292.

3. The Role of Cardiac Risk Factor Burden in Diagnosing ACS in the ED Setting

Han JH, et al. Ann Emerg Med 2007; 49:145-152.e1.

Clinicians commonly assume that the more cardiac risk factors a patient has (cardiac risk factor burden), the higher the risk of acute coronary syndromes in those with suspected acute coronary syndromes. In the emergency department (ED) setting, Jayes et al observed that individual risk factors were not useful for diagnosing acute coronary syndromes but did not study the role of cardiac risk factor burden on clinical decision-making. As a result, the role of cardiac risk factor burden in the ED setting remains unclear. Recently, the Framingham Heart Study found that patients with 2 or more cardiac risk factors had a substantially higher lifetime risk for cardiovascular disease, but this was a population-based longitudinal study, limiting this study’s generalizability to the ED population. Additionally, associations between cardiac risk factors and acute coronary syndromes are not uniform across the entire population. Different cardiac risk factors are associated with acute coronary syndromes in men and women. However, the effect modification of age on the relationship between cardiac risk factor burden and acute coronary syndromes is not well studied.

Editor’s Summary
What question this study addressed: Whether cardiac risk factors as defined for the general population are useful in identifying acute coronary syndrome in patients undergoing ED evaluation for acute coronary syndrome.

We found that in ED patients with suspected acute coronary syndromes, the greater the number of cardiac risk factors identified, the greater the odds of acute coronary syndromes being present, but the relationship between cardiac risk factor burden and acute coronary syndromes was significantly modified by age. In this retrospective analysis of a clinical registry with 10,806 eligible ED patients with suspected acute coronary syndrome, cardiac risk factor burden was moderately predictive of acute coronary syndrome in those younger than 40 years but was not helpful in older patients. For patients older than 65 years, cardiac risk factor burden was less useful for the prediction of acute coronary syndromes. These findings reflect that older age is a powerful risk for acute coronary syndromes in and of itself.

How this might change clinical practice: These data suggest that clinicians should not use cardiac risk factor burden to define the probability of acute coronary syndrome in ED patients who are older than 40 years and are being evaluated for this condition.


4. Pay for Performance Shows Modest Benefit on Quality Measures

An experimental Centers for Medicare and Medicaid Services pay-for-performance hospital plan modestly improved compliance with several quality measures in a controlled study released early online by the New England Journal of Medicine.

Researchers compared compliance with quality measures for heart failure, acute MI, and pneumonia at hospitals with and without pay for performance. Bonuses for good performance were 1% to 2%, and the program similarly levied small penalties for poor performance.

After adjustment for several factors, pay for performance was associated with a roughly 2.5% to 4.0% improvement in compliance compared with the control hospitals over the 2-year study period. The improvement was significantly greater in hospitals with a weak baseline performance.

Both the authors and an editorialist note several limitations of this study. The editorialist concludes that the CMS will gain "from recognizing that pay for performance is ... likely to have only modest incremental value."

NEJM abstract (free):

5. Thrombolysis (Tissue Plasminogen Activator-tPA) in Stroke: A Medical-Legal Perspective

Here is a note from Steven C. Gabaeff, M.D., President CalAAEM. He writes: “Here is an article from the Legal Medicine Perspectives, November/December 2006 Vol. 15, No. 6. This is a publication of the American College of Legal Medicine, an excellent organization of which I am a member. I encourage others to consider joining at This article describes the legal issues currently surrounding the use or non-use of thrombolytics in the ED setting. It creates quite a conundrum.”

Only the Intro and one selected paragraph are appended below. The remainder of the article can be found here:


This issue’s Colleagues’ Corner examines the medical-legal quagmire that exists when physicians are faced with the decision to use thrombolytics in the treatment of acute strokes. This article is an edited version of the recently published article in Stroke on the subject by Michael I. Weintraub, MD, FACP, FAAN. As. Dr. Weintraub makes clear despite the success of the 1995 National Institutes of Neurological Disorders and Stroke (NINDS) study using IV recombinant tissue plasminogen activator (tPA) within 3 hours in acute stroke and its subsequent FDA approval, there has been a reluctance to use tPA because of safety and efficacy issues with high incidence of intracerebral hemorrhage, and protocol violations. This article and the cases will illustrate the increased number of malpractice lawsuits generated by the controversy over the “standard of care” and educate clinicians regarding several specific issues surrounding tPA and how to avoid the legal pitfalls.

Overall, his extensive review has led Dr. Weintraub to conclude that neurologists, emergency room physicians and hospitals are at increased liability risk if they use or do not use tPA. Detailed documentation, informed consent or timely transfer should reduce threat of legal action. This article is likely to generate opinions pro and con. Accordingly, the editors of LMP encourage the Fellows and Members of the ACLM on file their concurring and dissenting opinions on LEGALMEDNET so that we may all benefit from our collective knowledge.

Elements of a Malpractice Claim

Currently, there is a marked increase in the number of lawsuits regarding stroke and tPA. PHYSICIANS RECIPROCAL INSURERS. DOCUMENTATION OF MEDICALREASONING/ JUDGEMENT. ALERT: 2006; 1. Physicians are currently being sued if they treat or do not treat with tPA. This topic is somewhat complex but usually revolves around several issues relating to documentation, informed consent, etc. Inherent in this is the fact that there are protocol deviations noted with absence of National Institutes of Health Stroke Scale (NIHSS) in 84%, and a recent retrospective analysis study revealed that one major protocol deviation in 67% and 97% had combined major and minor protocol deviations. When protocol deviations arise, there is increased mortality and morbidity.

6. Infectious Diseases Society Seeks Mandatory Flu Shots for Healthcare Workers

The Infectious Diseases Society of America is recommending that the government increase its efforts to encourage healthcare workers to receive annual influenza vaccinations.

In a statement released Thursday, the society said the U.S. should strengthen policies to include mandatory annual vaccinations while allowing healthcare workers to decline only if they specify in writing that they have religious or philosophical objections or medical contraindications. It also recommended that:

-- Influenza vaccine coverage rates be a quality measure for hospitals and individual practices;

-- Annual flu shots be given onsite to all healthcare workers with patient contact at hospitals, clinics, and other facilities;

-- The vaccinations be paid for by employers or by the employees' health insurance.

ISDA Statement:

7. Is Informed Consent Required in the ED for the Administration of IV Contrast?

Iverson K. Ann Emerg Med 2007;49:231-233.

An excerpt from the essay:

We know that a wide variation exists in the practice of obtaining informed consent before the administration of intravenous contrast, and the need to obtain such consent remains controversial. Information about the risks of intravenous contrast material is not common knowledge among the general population, and most patients want some information before contrast injection; about half view such information as essential. Yet in many hospitals and physician groups, obtaining such consent is not routine: physicians associated with larger hospitals (greater than 250 beds); larger physician groups (greater than 10 physicians), no matter what their specialty; and university hospitals use written informed consent less often than those in smaller groups, those associated with smaller hospitals, or those in private practice. In university settings, radiology technologists are most likely to inform patients about nonemergency computed tomography (CT) and the possible risks, whereas ordering physicians are most likely to inform patients about a CT scan’s purpose.

The question remains: Should all emergency physicians be required to obtain informed consent before their patients have studies with intravenous contrast or any other specific procedure? The answer depends, as noted above, on applicable law and local customary practice. However, so that variation in obtaining formal written informed consent does not exist within an institution, or at least within the ED, each department (following any institutional guidelines) should develop brief lists of frequently performed procedures that require written informed consent. If possible, separate consent forms for common procedures that list substantive risks should be available to help clinicians provide all necessary information.

Once the decision is made to obtain formal informed consent, the individual responsible for the procedure, usually the physician, should provide the information, answer questions, and obtain the consent, although others may help complete the documentation. When necessary, a trained translator should be available to ensure accurate information transmission.

The key points about formal written informed consent in the ED are that differences in local custom, hospital policies, and state law lead to a wide variability in which procedures require written informed consent and who obtains it. Yet, since patients often don’t know information about procedures that we consider common knowledge, obtaining patient cooperation and consent for procedures, whether or not one obtains formal written informed consent, is a vital part of practicing elegant emergency medicine. Basing an ED requirement for informed consent on the relative risk of procedures is fraught with hazards because scant data are available. Therefore, the best practice continues to be emphasizing excellent physician-patient communication.

Full-text (requires subscription):

8. New Guidelines for Thromboembolism Issued

There are new guidelines for venous thromboembolism. Issued jointly by the American College of Physicians and the American Academy of Family Physicians, the guidelines include the following recommendations:

-- Use validated prediction rules (such as the Wells prediction rules) to estimate pretest probabilities of disease.

-- In patients with low pretest probabilities, use a D-dimer test to rule out deep-venous thrombosis and pulmonary embolism.

-- Use ultrasound to investigate those with intermediate to high pretest probabilities of deep-venous thrombosis in lower extremities.

-- In suspected pulmonary embolism, patients with intermediate or high pretest probabilities of disease require imaging studies.

-- Use low-molecular-weight heparin for the initial inpatient treatment of deep venous thrombosis (either unfractionated or low-molecular-weight forms may be used for pulmonary embolism).

-- Outpatient treatment of deep venous thrombosis (and possibly pulmonary embolism) with low-molecular-weight heparin is safe for selected patients.

-- Either unfractionated heparin or LMWH is appropriate for the initial treatment of pulmonary embolism.

-- Use compression stockings within a month of diagnosis and continue for at least a year.

AIM Guidelines (free):

9. Hyperglycemic Crises in Adult Patients With Diabetes: A consensus statement from the American Diabetes Association (ADA)

Kitabchi AE, et al. Diabetes Care 2006;29:2739-2748.

In December 2006 the ADA released their latest guidelines. The full-text (free): can be found here: Below is just a small sampling.

Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are the two most serious acute metabolic complications of diabetes. Most patients with DKA have autoimmune type 1 diabetes; however, patients with type 2 diabetes are also at risk during the catabolic stress of acute illness such as trauma, surgery, or infection. Table 1 outlines the diagnostic criteria and electrolyte and fluid deficits for both disorders. The mortality rate in patients with DKA is less than 5% in experienced centers, whereas the mortality rate of patients with HHS still remains high at 11%. Death in these conditions is rarely due to the metabolic complications of hyperglycemia or ketoacidosis but rather relates to the underlying precipitating illness. The prognosis of both conditions is substantially worsened at the extremes of age and in the presence of coma and hypotension. [DRV: note the terminology—hyperosmolar “state” is in, “coma” is out, like the passé terms “near-drowning” and “MVA”]

This consensus statement will outline precipitating factors and recommendations for the diagnosis, treatment, and prevention of DKA and HHS in adult subjects. It is based on a previous technical review and more recently published peer-reviewed articles since 2001, which should be consulted for further information.

-- DKA diagnostic criteria: serum glucose over 250 mg/dl, arterial pH below 7.3, serum bicarbonate less than 18 mEq/l, and moderate ketonuria or ketonemia.

-- HHS diagnostic criteria: serum glucose greater than 600 mg/dl, arterial pH above 7.3, serum bicarbonate greater than 15 mEq/l, and minimal ketonuria and ketonemia.

-- The two most common precipitating factors in the development of DKA or HHS are inadequate or inappropriate insulin therapy or infection.

-- During the past decade, an increasing number of DKA cases without precipitating cause have been reported in children, adolescents, and adult subjects with type 2 diabetes.

-- Not all patients with ketoacidosis have DKA.

-- Unless the episode of DKA is uncomplicated and mild/moderate, regular insulin by continuous intravenous infusion is the treatment of choice. In adult patients, once hypokalemia (K+ less than 3.3) is excluded, an intravenous bolus of regular insulin at 0.1 unit/kg, followed by a continuous infusion of regular insulin at a dose of 0.1 unit/kg should be administered.

-- ED Management? Prospective and randomized studies have reported on the efficacy and cost effectiveness of subcutaneous rapid-acting insulin analogs in the management of patients with uncomplicated DKA. Patients treated with subcutaneous rapid-acting insulin received an initial injection of 0.2 units/kg followed by 0.1 unit/kg every hour or an initial dose of 0.3 units/kg followed by 0.2 units/kg every 2 h until blood glucose was less than 250 mg/dl, then the insulin dose was decreased by half to 0.05 or 0.1 unit/kg, respectively, and administered every 1 or 2 h until resolution of DKA. There were no differences in length of hospital stay, total amount of insulin administration until resolution of hyperglycemia or ketoacidosis, or number of hypoglycemic events among treatment groups. In addition, the use of insulin analogs allowed treatment of DKA in general wards or in the emergency department, avoiding admission to an intensive care unit. By avoiding intensive care admissions, these investigators reported a reduction of 30% in the cost of hospitalization

-- Check the K before you start the insulin. Rarely, DKA patients may present with significant hypokalemia. In such cases, potassium replacement should begin with fluid therapy, and insulin treatment should be delayed until potassium concentration is restored to greater than 3.3 mEq/l to avoid arrhythmias or cardiac arrest and respiratory muscle weakness.

-- Bicarbonate use in DKA remains controversial. At a pH greater than 7.0, administration of insulin blocks lipolysis and resolves ketoacidosis without any added bicarbonate. However, the administration of bicarbonate may be associated with several deleterious effects including an increased risk of hypokalemia, decreased tissue oxygen uptake, and cerebral edema

-- The routine use of phosphate in the treatment of DKA or HHS has resulted in no clinical benefit to the patient.

10. Early Detection of Cerebral Edema during Treatment of Pediatric DKA

Muir AB, et al. Diabetes Care 2004; 27:1541-1546.

Most children with diabetic ketoacidosis (DKA) exhibit abnormal neurological function. Therefore, evidence-based guidance for discerning the patients who require lifesaving intervention is needed. Cerebral dysfunction in DKA is usually a manifestation of metabolic derangement, but cerebral edema (CE) arises in 1% of episodes and is a complication that frequently causes irreversible brain damage and death. Neurological collapse from CE is typically described as having sudden onset and progressing rapidly, with recovery depending on prompt reduction of intracranial pressure. The object of this study was to delineate the signs and symptoms of neurological compromise that predict progression to severe CE in children with DKA.

CE occurs rarely in patients older than age 20 years, despite the presence of asymptomatic CE in most adults and children with DKA. This age dependence may point to developmental changes in cerebral metabolism as critical elements in the pathogenesis of CE. For example, children’s brains are reported to have higher fuel and oxygen requirements than those of adults. Hypoxia is further implicated because the brains of patients with DKA may extract blood oxygen less efficiently than healthy individuals and the reported association of symptomatic CE with low partial pressures of carbon dioxide in arterial blood may reflect harmful cerebral vasoconstriction. Exuberant rehydration with hypotonic fluid and bicarbonate administration may aggravate the CE; however, the evidence that CE is primarily iatrogenic is not compelling. In the absence of an understanding of the pathogenesis of CE and its prevention, emphasis must be on early recognition of the disease to permit quick intervention, with the hope of reducing morbidity and mortality.

OBJECTIVE—Children who develop cerebral edema (CE) during diabetic ketoacidosis (DKA) exhibit definable signs and symptoms of neurological collapse early enough to allow intervention to prevent brain damage. Our objective was to develop a model for early detection of CE in children with DKA.

RESEARCH DESIGN AND METHODS—A training sample of 26 occurrences of DKA complicated by severe CE and 69 episodes of uncomplicated DKA was reviewed. Signs of neurological disease were incorporated into a bedside evaluation protocol that was applied to an independent test sample of 17 patients previously reported to have developed symptomatic CE during treatment for DKA. Head computed tomograms and their reports were reviewed.

RESULTS—The protocol allowed 92% sensitivity and 96% specificity for the recognition of CE sufficiently early for intervention. The diagnostic criteria were fulfilled in two temporal patterns, defining early- and late-onset CE. Although initial computed tomograms were often normal, the findings also included diffuse CE and focal brain injury, the latter only in patients with an early onset of abnormal neurological signs.

CONCLUSIONS—CE may occur in the absence of acute changes on head computed tomograms. Early detection of CE at the bedside using an evidence-based protocol permits intervention in time to prevent permanent brain damage.

What were the signs? Consult the full-text (free):

11. TV Drug Ads Play on Emotions, U.S. Study Says

By Susan Heavey. WASHINGTON (Reuters) Jan 30 - Television drug advertisements rely heavily on emotional appeals rather than comprehensive disease information to attract consumers' attention, according to one of the first studies to analyze such commercials.

The study, published in the Annals of Family Medicine Monday, investigated dozens of TV drug ads for some of the nation's top-selling drugs at those times when most viewers tune in.

Researchers analyzed the ads based on how they portrayed the medication and disease, emotions and lifestyles changes. They found companies used various tactics to appeal to viewers with limited facts that could oversimplify their decisions. "The benefits of prescription drugs are rarely that black and white," lead author Dominick Frosch, an assistant professor of medicine at the University of California in Los Angeles, told Reuters.

"Choosing the wrong prescription drug can cause serious health problems and it can also be very costly to the larger society," he added. While such strategies are frequently used for other consumer products, they raise questions when it comes to pharmaceuticals, Frosch and other researchers wrote.

"Our findings suggest the need to reconsider the distinction between selling soap or other consumer products and selling prescription drugs," they said.

In their review, researchers analyzed 38 commercials that aired over the course of four weeks of prime-time television in mid-2004. They coded ads for common themes such as humor or product information, then rated how often each was used. While all the ads met regulations, they often made vague claims, the researchers said. About one-quarter offered details on the cause of a disease or who was at risk.

They also found that nearly all ads relied on characters who seemed happy after taking a drug or otherwise showed positive emotions. Some mentioned changing habits in addition to medication, but none offered such change as an alternative. Print drug ads have been analyzed before, but this study is one of the first aimed at televised versions and comes as Congress prepares to consider allowing drugmakers to pay U.S. regulators to have their commercials screened before airing.

Prescription drug ads have raised concerns since the Food and Drug Administration loosened restrictions on them in 1997. Since then critics have charged both TV and print ads are misleading and encourage consumers to seek drugs they don't need. Companies and other supporters have said they can educate consumers about possible treatments.

Industry lobbying group the Pharmaceutical Researchers and Manufacturers of America (PhRMA) released voluntary guidelines in 2005 to address the concerns, but some say they fall short. PhRMA criticized the study for using ads that aired before its guidelines were implemented. Early indications show "that advertisements airing since the Principles took effect have tended to be more educational and informative," said the group's senior vice president, Ken Johnson.

Still, Frosch said the guidelines don't offer specifics and avoid the issue of emotional appeals. "I don't think prescription drug advertising needs to be banned, but it does need to be more responsible," he told Reuters. This spring Frosch will launch a related study on consumers' reaction to TV drug ads, with results expected next year.

12. New Treatment for Diabetes type 2: DPP-4 Inhibitors

In October 2006, the U.S. Food and Drug Administration (FDA) approved Januvia as monotherapy and as add-on therapy to either of two other types of oral diabetes medications, metformin or thiazolidinediones (TZDs), to improve glucose control in patients with type 2 diabetes when diet and exercise are not enough. The recommended dose of Januvia is 100 mg once daily. Januvia should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings.

Januvia (Sitagliptin Phosphate) is an oral, once-daily, selective DPP-4 inhibitor. DPP-4 inhibitors work by enhancing a natural body process that lowers blood sugar, the incretin system. When blood sugar is elevated, incretins work in two ways to help the body regulate high blood sugar levels: they trigger the pancreas to increase the release of insulin and signal the liver to reduce its production of glucose. DPP-4 inhibitors enhance the body's own ability to control blood sugar levels by increasing the active levels of these incretin hormones in the body, helping to decrease blood sugar levels in patients with type 2 diabetes.

In clinical trials, Januvia demonstrated an overall incidence of side effects comparable to placebo. The most common side effects reported with Januvia (more than 5 percent and higher than placebo) were stuffy or runny nose and sore throat, upper respiratory infection, and headache. The incidence of selected gastrointestinal adverse reactions in patients treated with Januvia was as follows: abdominal pain (2.3 percent; placebo, 2.1 percent), nausea (1.4 percent; placebo, 0.6 percent) and diarrhea (3.0 percent; placebo, 2.3 percent).

13. Myth: Interpretation of a single ammonia level in patients with chronic liver disease can confirm or rule out hepatic encephalopathy

Arora S, et al. Can J Emerg Med 2006;8:433-5.

Although the exact pathophysiology of hepatic encephalopathy (HE) is not fully understood, for more than a century ammonia has been thought to play a critical role. However, the interpretation and utility of ammonia levels in patients with chronic liver disease (CLD) presenting with HE has been a long-standing source of confusion. It is a common belief in the emergency department and on the wards that a single elevated ammonia level in a patient with CLD can confirm the diagnosis of HE, and a normal level essentially rules it out. This confusion stems from the fact that early studies showed a correlation between degree of encephalopathy and the ammonia level, but numerous subsequent studies have shown that severely encephalopathic patients often have normal ammonia levels.

The degree of the correlation between ammonia levels and the severity of hepatic encephalopathy continues to be controversial. What is evident from the literature is that a single normal ammonia level does not rule out HE in a patient with CLD, and serial levels may not correlate with the evolving clinical picture. An ammonia level is merely a data point among the constellation of variables that may contribute to the development of HE and, for now, the final diagnosis remains a clinical one. Reliance on ammonia levels to make the diagnosis of HE is inappropriate and perhaps dangerous if it results in failure to seek other causes of altered mentation in ED patients with CLD.


14. Atypical Clinical Features of Pediatric Appendicitis

Becker T, et al. Acad Emerg Med 2007; 14, 124-129.

INTRO: In classic descriptions of appendicitis, the first symptom is periumbilical pain, followed by nausea, right lower quadrant pain, and later, vomiting with fever. This sequence of events is noted in only 50% of adults, and it is even less common in children. The classic symptoms are often not present in children, making the diagnosis difficult and sometimes leading to missed diagnoses with significant morbidity and mortality, as well as professional liability. In addition to making the correct diagnosis, it is imperative to make the diagnosis in a timely manner. Delay in diagnosis ultimately leads to an increase in the perforation rate, with associated complications. Recently, the medical literature has emphasized the use of advanced radiologic imaging (computed tomography [CT] or ultrasound [US]) to aid in the diagnosis of appendicitis, especially in cases in which examination findings or history are atypical. These interventions can lead to delays in care as well as unnecessary radiation exposure. Often, patients with atypical findings are not candidates for immediate triage to the operating room. It would be helpful to know the frequency of atypical findings and which, if any, are strong negative predictors.

Most literature surrounding childhood appendicitis extrapolates the presenting signs and symptoms from adult patients. Presenting symptoms and signs will vary by age and the ability to achieve a reliable, but often limited, examination. In one small case series, approximately one third of children with appendicitis have atypical findings.

The objectives of this investigation were to determine the frequency of atypical clinical features among pediatric patients with appendicitis and to investigate which atypical features are the strongest negative predictors for appendicitis.

BACKGROUND: The diagnosis of appendicitis remains challenging in children. Delays in diagnosis, or misdiagnosis, have important medical and legal implications. The typical, or classic, presentation of pediatric appendicitis has been modeled after adult disease; however, many children present atypically with subtle findings or unusual signs.

OBJECTIVES: To determine the frequency of atypical clinical features among pediatric patients with appendicitis and to investigate which atypical features are the strongest negative predictors for appendicitis among patients being evaluated for appendicitis.

METHODS: Children and adolescents with suspected appendicitis were enrolled over 20 consecutive months. Pediatric emergency physicians completed standardized data collection forms on eligible patients. Final diagnosis was determined by pathology or follow-up telephone call. Typical and atypical findings were defined strictly a priori.

RESULTS: Seven hundred fifty-five patients were enrolled. The median age was 11.9 years (interquartile range [IQR]: 8.5, 14.9 yr); 36% of patients were diagnosed with appendicitis. Among patients with appendicitis, the most common atypical features included absence of pyrexia (83%), absence of Rovsing's sign (68%), normal or increased bowel sounds (64%), absence of rebound pain (52%), lack of migration of pain (50%), lack of guarding (47%), abrupt onset of pain (45%), lack of anorexia (40%), absence of maximal pain in the right lower quadrant (32%), and absence of percussive tenderness (31%). Forty-four percent of patients with proven appendicitis had six or more atypical characteristics. The median number of atypical features for patients with proven appendicitis was five (IQR: 4.0, 7.0). The greatest negative predictors, on the basis of likelihood ratios, were as follows: white blood cell count (WBC) of less than 10,000 per cubic millimeter (likelihood ratios [LR], 0.18), absolute neutrophil count (ANC) of less than 7,500 per cubic millimeter (LR, 0.35), lack of percussive tenderness (LR, 0.50), lack of guarding (LR, 0.63), and no nausea or emesis (LR, 0.65).

CONCLUSIONS: Appendicitis in pediatric patients is difficult to diagnose because children present with a wide variety of atypical clinical features. Forty-four percent of patients with appendicitis presented with six or more atypical features. Two atypical features are the strongest negative predictors of appendicitis in children: WBC of less than 10,000 per cubic millimeter and an ANC of less than 7,500 per cubic millimeter.

15. FDA Warns on Potentially Lethal Side Effects of Topical Anesthetics

The FDA is warning consumers that improper use of topical anesthetics can cause serious side effects, including irregular heart beat, seizures, difficulty breathing, and death. The products, available over the counter or by prescription, contain agents such as lidocaine, tetracaine, benzocaine, or prilocaine. Compounded versions that combine agents or use high concentrations of the drugs are often used after cosmetic procedures and have been linked with two deaths.

Two women in their 20s died after applying large amounts of compounded topical anesthetic cream to their legs and then wrapping them in plastic. Such wrapping, along with applying the products to a large area, keeping the products on too long, heating the skin, or applying to irritated skin may increase the risk.

FDA Advisory:

16. Wanna lose weight? FDA Approves OTC Orlistat

The FDA approved an over-the-counter version of the weight loss drug Xenical (orlistat) on Wednesday. The lipase inhibitor will be sold under the name Alli as a 60 mg capsule -- a lower dose than the prescription version of the drug.

Alli is meant to be used by adults with a BMI of 27 or more, in conjunction with a reduced-calorie diet and exercise plan. Users can take up to three capsules a day, one with each fat-containing meal, and should take a multivitamin at bedtime, as the drug can block the absorption of some vitamins.

The most common side effects are diarrhea and other changes in bowel habits, which can be reduced by eating a low-fat diet. The drug is contraindicated in transplant recipients. Patients on anticoagulants or who are being treated for diabetes or thyroid disease should only use the product under physician supervision.

Here’s the manufacturer’s spin:

17. As Asthma Inhalers Are Phased Out, Shortages Expected; Physicians Must Prepare Patients for Switch to Ozone-Friendly Inhalers

Physicians should be aware that asthma rescue medications are in short supply as prescription drug manufacturers begin phasing out metered-dose inhalers containing ozone-depleting chlorofluorocarbons (CFCs). The FDA in 2005 ordered drugmakers to stop making inhalers with CFC propellants by the end of 2008.

Beginning in 2008, only hydrofluoroalkane (HFA) propellants may be used in metered-dose inhalers. Several manufacturers have already slowed or halted production of CFC inhalers in preparation for the switch to HFA products. This shortage is expected to become more pronounced in coming months, as Schering-Plough, through its Warrick Pharmaceutical Division, announced it would stop production of CFC inhalers this spring.

Because of the shortage, patients with nonspecific prescriptions may unknowingly be switched to alternative HFA agents. Even though HFA propellant formulations are not generically interchangeable with their CFC counterparts, there have been some reports of substitutions being made without physician approval. Accordingly, physicians writing prescriptions for bronchodilators should be sure to indicate specifically which medication they are prescribing.

Physicians should also be aware that HFA propellants may “feel different” to patients accustomed to CFC inhalers. Physicians and pharmacists should educate patients about what to expect when making the switch to avoid potential overuse, product waste, or patient dissatisfaction.

Medi-Cal has added HFA agents to its list of covered drugs and will only cover CFC inhalers with prior authorization. Many health plans, however, still do not cover HFA inhalers without prior authorization.

18. Clinical prediction rule to distinguish PID from acute appendicitis in women of childbearing age

Morishita K, et al. Amer J Emerg Med 2007;25:152-157.

We aimed to develop a clinical prediction rule to distinguish pelvic inflammatory disease (PID) from acute appendicitis in women of childbearing age.

We reviewed medical records over a 4-year period of female patients of childbearing age who had presented with abdominal pain at an urban emergency department and had either appendicitis (n = 109) or PID (n = 72). A prediction rule was developed by use of recursive partitioning based on significant factors for the discrimination.

The significant factors to favor PID over appendicitis were (1) no migration of pain (odds ratio [OR], 4.2; 95% confidence interval [CI], 1.5-11.5), (2) bilateral abdominal tenderness (OR, 16.7; 95% CI, 5.3-50.0), and (3) absence of nausea and vomiting (OR, 8.4; 95% CI, 2.8-24.8). The prediction rule could rule out appendicitis from PID with sensitivity of 99% (95% CI, 94-100%) when classified as a low-risk group by the following factors: (1) no migration of pain, (2) bilateral abdominal tenderness, and (3) no nausea and vomiting.

We developed a prediction rule for childbearing-aged women presenting with acute abdominal pain to distinguish acute appendicitis from PID based on 3 simple, clinical features: migration of pain, bilateral abdominal tenderness, and nausea and vomiting. Prospective validation is needed in other settings.

19. Acute Stroke Management: News from the American Stroke Association International Stroke Conference 2007

A. No Benefit of Glucose-Lowering on Stroke Morbidity, Mortality

February 12, 2007 (San Francisco) — Aggressive lowering of blood glucose levels following acute stroke does not improve patient outcomes, a new study suggests.

Here at the American Stroke Association International Stroke Conference 2007, researchers presented the results of the UK Glucose Insulin in Stroke Trial (GIST-UK), the first-ever randomized clinical trial to compare intensive glucose modulation following acute stroke with conventional care.

The study found no evidence to support acute management of raised blood glucose following stroke. Furthermore, an IV infusion of glucose/potassium/insulin (GKI) had a significant impact on blood pressure lowering that may be potentially harmful.

"The bottom line is that in the majority of patients there is no need to intensively reduce blood glucose levels. For stroke patients with extreme glucose elevation, treatment may be worthwhile. But in the absence of this, there is absolutely no demonstrable benefit of glucose-lowering treatment with respect to outcome in stroke patients," principal investigator Dr. Christopher Gray, MD, from the Newcastle University School of Clinical Medical Sciences, in the United Kingdom, told Medscape.

Full story:

B. Intra-Arterial Thrombolysis Prompts "Lazarus" Phenomenon

February 12, 2007 (San Francisco) — A new study shows almost 25% of patients with acute ischemic stroke experience significant and immediate improvement following intra-arterial (IA) thrombolytic therapy.

Presented here at the American Stroke Association International Stroke Conference 2007, investigators from the Ohio State University College of Medicine, in Columbus, looked at factors influencing the so-called "Lazarus phenomenon" (LP), in which ischemic stroke patients experience a decrease in National Institutes of Health Stroke Scale (NIHSS) score by at least 50% within 24 hours following treatment.

Investigators found the most significant predictors of LP were shorter time to IA thrombolytic treatment, good pial collateral formation, and reperfusion flow of greater than 50%.

"Some people experience a dramatic improvement [with IA] and some people don't, and we're trying to figure out the reasons for this. Based on these results, it is clear time is a major factor and every minute counts," the study's principal investigator, Dr. Gregory A. Christoforidis, told Medscape.


20. FDA Warns on Look-Alike Heparin Vials

The FDA and Baxter International warned of potentially dangerous medication errors involving two heparin products with similar labels. Three infants died when they were given the higher dose Heparin Sodium Injection 10,000 units/mL instead of the lower dose HEP-LOCK U/P 10 units/mL. Both products use blue as the primary background color on their labels, though in different shades.

Baxter is looking for ways to vary the packaging to prevent future errors. In the meantime, it suggests that healthcare workers check their inventory to ensure no mix-up has occurred; notify staff of the problem; be sure not to rely solely on package color to identify a product; and always read the label and verify that the correct dose and product are being used.

Manufacturer’s letter: