The Press Association, 3/23/07:
A man hoping to cheer up an ailing relative at Wilcox Memorial Hospital in Hawaii had not considered one of the visiting rules: No horses allowed.
Man and horse entered the hospital and took the lift to the third floor, where they were met and stopped by security guards.
The visitor’s good intentions were further dashed when his relative was brought out to see the animal and declared: “That’s not my horse.”
Purpose of review: This review highlights a growing literature regarding the safety of long-acting β-2 agonists as add-on therapy to inhaled corticosteroids.
Recent findings: Two studies have demonstrated a mortality increase with use of long-acting β-2 agonists in asthmatic patients. They were not well controlled and thus raise the question of whether this mortality increase was the result of using long-acting β-2 agonists as monotherapy or whether there is some rare susceptibility to an untoward effect of this class of medicine.
Summary: When inhaled corticosteroids and long-acting β-2 agonists are used in combination, prospective studies demonstrate improvement in asthma control and exacerbation rate. Two studies showed an increase in asthma mortality with long-acting β-2 agonists, but they allowed β-2 agonists to be used as monotherapy and did not address the safety of their appropriate use in conjunction with inhaled corticosteroids. Although the majority of asthmatic patients appear to benefit from the use of long-acting β-2 agonists, a small subclass may be prone to deleterious effect. It is uncertained whether this is some rare susceptibility to these drugs, or, more likely, that this is the consequence of monotherapy with long-acting β-2 agonists controlling the signs and symptoms while masking inflammation.
Safety concerns regarding the use of long-acting β-2 agonists (LABAs) have been voiced since soon after their availability. In a letter to the editor of the New England Journal of Medicine, Finkelstein described two elderly asthmatic patients who died while ‘clutching their inhalers’.[1] These fears have been reinvigorated following the publication of the recent Salmeterol Multicenter Asthma Research Trial (SMART) study,[2**] the meta-analysis by Salpeter and colleagues,[3] as well as the New England Journal of Medicine opinion piece by Martinez.[4]
Why is it then that the most recent asthma guidelines recommend LABAs as add-on therapy in patients not adequately controlled on inhaled corticosteroids (ICSs) alone?[5-7] Such recommendations are made because of the robust literature that has demonstrated that this class of medicine is of added benefit to patients not adequately controlled on ICSs alone.[8] Here we will review the literature that addresses the safety of LABA use in the care of asthma.
Currently two LABAs are available: salmeterol and formoterol. Both demonstrate bronchodilation exceeding 12 h in most patients while formoterol has a rapid onset of action similar to albuterol. Although studies have demonstrated that, over time, there appears to be subsensitization or reduction in effect of protection in both exercise-induced asthma as well as methacholine reactivity, there appears to be no such loss in the beneficial effect on measures of asthma control when used with a concomitant ICS.[9-11] This includes improvement in symptom scores, lung function and requirement for rescue bronchodilators. Many studies and several meta-analyses have demonstrated that in patients not controlled with ICS alone the addition of a LABA is more effective than increasing the dose of ICS in improving asthma control and reducing asthma exacerbations.[12-14] Likewise the addition of a LABA to an ICS is steroid-sparing, in that despite ICS dose reduction, no significant decrement in asthma control (symptom scores, lung function or rescue β-agonist requirement) or exacerbation rate is seen whereas reduction to the same dose of ICS used as monotherapy results in loss of asthma control.[15] The efficacy with regard to LABA anti-inflammatory effect will be discussed in greater detail in this issue of Current Opinion of Pulmonary Medicine in an article by Dr Prenner (see pp. 57-63 in this issue).
When LABAs are used as monotherapy as well as when added to ICS, there are inconsistent findings with regard to potential LABA anti-inflammatory effect. In examining the potential anti-inflammatory effects of LABA as monotherapy, Wallin and colleagues[16] examined the effects of therapy with formoterol, budesonide or placebo on bronchial mucosa inflammation in 64 subjects with mild asthma by comparing bronchial biopsies following 8 weeks of therapy to baseline specimens. They found that in subjects with more severe airway inflammation (defined as an eosinophil count of ≥10/mm2 at baseline), both budesonide and formoterol resulted in a significant reduction in mast cell and eosinophil numbers compared with pretreatment values. Maneechotesutwan and colleagues[17] examined, in a double-blind, randomized, crossover study, the effects of 4 weeks of treatment with formoterol, 24 μg twice daily, compared with placebo on sputum neutrophil numbers and interleukin (IL)-8 levels in 15 steroid-naïve nonsmoking patients with mild persistent asthma. The use of formoterol significantly reduced sputum IL-8 levels and neutrophil numbers compared with the placebo. There was a significant correlation between the reduction in sputum IL-8 levels and the number of neutrophils, indicating that formoterol may reduce neutrophils by attenuating IL-8 production. This may be of benefit in preventing asthma exacerbations in a subgroup of asthmatics with an upregulation of neutrophils. On the other hand, Roberts and colleagues[18] demonstrated a lack of anti-inflammatory effect when salmeterol was used as monotherapy. They performed a double-blind study in asthmatic subjects, randomizing them to 6 weeks of treatment with either salmeterol 50 mg twice daily (n = 14) or placebo (n = 12), examining bronchoscopy with lavage and biopsy at baseline and following 6 weeks of treatment. Although the salmeterol group demonstrated improved clinical indices of asthma control there were no changes in biopsy or lavage indices of inflammation. The authors concluded that regular treatment with salmeterol improves clinical indices of asthma, but has no effect on the underlying inflammatory process, and go on to say that these findings strengthen guideline recommendations that long-acting β-2 agonists should not be prescribed as the sole anti-asthma medication.
When considering the potential anti-inflammatory effect of LABA co-administered with ICS, several studies provide input. An early study in-vitro study by Eickelberg et al.[19] provided very encouraging results regarding the potential for LABA to upregulate the anti-inflammatory effects of ICS via a ligand-independent activation of the glucocorticoid receptor. In a clinical study by Koopmans and colleagues,[20] patients with allergic asthma were randomized to receive fluticasone twice daily with or without co-administration of salmeterol for 1 year in a double-blind, parallel-group design. Of no surprise is the fact that adding the LABA to ICS improved peak expiratory flows (PEFs), symptom scores, rescue medication usage and bronchial hyperresponsiveness. Although there was no sustained effect on sputum cell differential and cytokine concentrations the addition of the LABA significantly reduced sputum ratios of α2-macroglobulin to albumin, indicating that the co-administration of the LABA with the ICS significantly improved size selectivity of plasma-protein permeation across the respiratory membrane.
Overbeek and colleagues[21] performed a double-blind parallel-group trial in 40 asthma patients with FEV1 of 50-90% of predicted with a positive methacholine challenge who had used no ICSs in the prior 4 weeks. They randomized these subjects to 8 weeks of treatment with 100 μg of budesonide twice daily plus placebo or 100 μg of budesonide twice daily plus 12 μg of formoterol.[21] The dose of budesonide was then increased to 400 μg twice daily for a further 8 weeks in both treatment groups. When comparing bronchial biopsy specimens between groups, there was no added anti-inflammatory benefit with the addition of the LABA, with either concomitant lower or higher doses of budesonide.
Lastly, in a study by Jarjour et al.[22] asthmatic subjects unstable on fluticasone propionate 100 μg twice daily, but stable on fluticasone propionate 250 μg twice daily, were randomized to either fluticasone/salmeterol combination 100/50 μg or to continue on fluticasone propionate 250 μg twice daily. Bronchial biopsies and bronchoalveolar lavage were obtained at randomization and after 24 weeks of treatment and compared with 75 matched pairs of biopsies. There were no significant differences in eosinophils [median numbers of eosinophils per square millimeter of submucosa were: fluticasone propionate 1.18 compared with 0 and fluticasone/salmeterol combination 0.86 compared with 0.99, respectively (P = 0.297)], there were modest decreases in mast cells in both groups, and no significant differences in neutrophils, total T-cell numbers or subsets. Bronchoalveolar lavage samples were available for 76 subjects and demonstrated no difference in numbers of eosinophils, macrophages, lymphocytes or neutrophils or concentrations of granulocyte macrophage colony-stimulating factor, IL-8 or eosinophilic cationic protein. The study therefore provides direct evidence that reduction of ICS when performed in conjunction with introduction of a LABA is safe and does not lead to a worsening of airway inflammation.
Present asthma guidelines universally recommend that LABAs should only be used as add-on therapy to ICSs.[5,6] This recommendation comes from multiple studies that have demonstrated that when LABAs are used as monotherapy they reduce neither airway inflammation nor exacerbations. The ineffectiveness of LABA monotherapy is best exemplified by the Salmeterol or Corticosteroids (SOCS) trial.[23] This study examined a group of subjects whose asthma had been brought under control by treatment with inhaled triamcinalone. Subjects were randomized to receive salmeterol or placebo, or to continue on triamcinalone for 16 weeks. Although both salmeterol and triamcinalone resulted in improved morning PEF, rescue β-agonist use, symptom scores and quality-of-life measures compared to placebo, the LABA group demonstrated an increase in markers of inflammation and exacerbation rates similar to the placebo group. In the accompanying Salmeterol ± Inhaled Corticosteroids (SLIC) trial[24] the investigators highlighted the steroid-sparing effect of adding a LABA by examining those subjects whose asthma had not been fully controlled by inhaled triamcinalone and demonstrated the ability of the LABA to reduce the dose of ICS in over 90% of the subjects by 50% without an increase in exacerbation rate.[24] Lastly, in a study by McIvor et al.,[25] 13 subjects requiring a median dose of 2700 μg of ICS underwent an ICS taper protocol with concomitant salmeterol or placebo, until exacerbation of asthma occurred. PEF rate and symptoms were measured daily and sputum eosinophils, methacholine reactivity, eosinophilic cationic protein and spirometry weekly. At the time of exacerbation, the LABA arm was using a median dose of ICS of 277 μg as compared to 612 μg of ICS in the placebo group. This reduction in ICS came at a cost of an increase in sputum eosinophils (19.3%) in the LABA group, when compared with the placebo group (9.3%; P = 0.006) at time of exacerbation. It should be noted however, that at the time of exacerbation in the group receiving the LABA, almost half (6/13) of the subjects were on no ICS at all. The results of this study are profoundly different from the study by Jarjour and colleagues.[22] Taken together, these results reinforce that LABAs should never be used as monotherapy in asthma, whereas, when added to ICS, they allow tapering of the ICS dose without an increase in the exacerbation rate or a rise in markers of inflammation.
The FACET trial confirmed the utility of the combination of a LABA with an ICS.[26] This was a year-long, double-blind, placebo-controlled study examining the exacerbation rate in 852 adult asthmatics, comparing a year of low-dose ICS (100 μg budesonide twice daily) with or without concomitant formoterol, with high-dose ICS (400 μg budesonide twice daily) with or without concomitant LABA. The authors found that the addition of a LABA reduced the exacerbation rate, in both the high- and low-dose ICS groups. When analyzing the characteristics of those subjects suffering from an exacerbation, Tattersfield and colleagues[27] found that there was no decrement in indices of loss of control (i.e. increased albuterol use or nocturnal awakening) or prolongation of the exacerbation when it did occur.
The first large-scale study demonstrating a potential deleterious signal associated with the use of a LABA was the Serevent Nationwide Surveillance Study.[28] In this study over 25 000 asthmatic subjects continued their prior asthma therapy and used, in addition, either albuterol (four times daily) or salmeterol (twice daily) for a period of 16 weeks. Although asthma exacerbations as a whole were decreased in the salmeterol group, a small, nonsignificant increase in asthma-related deaths (12 out of 16 787 salmeterol subjects compared with two of 8393 albuterol subjects; P = 0.105) was seen. Several potential concerns with this study should be noted. They include the fact that 31% of subjects randomized to both the arms of the study were on no ICS at baseline and there were no measures of adherence to ICS performed during the study.
In the prospective SMART trial, Nelson and colleagues[2**] assessed the impact on mortality associated with the use of this class of medicine. This study was designed to assess the safety of added salmeterol in approximately 60 000 subjects with a history of asthma who had no prior exposure to a LABA. Unlike most clinical research studies, the monitoring employed in this study was quite cursory since it was designed to be a ‘real-world study’. Investigators obtained only minimal baseline demographics which included age, race and what, if any, controller medicines were used. There was no monitoring of symptoms or pulmonary function and no measure of compliance with controller medicine(s). Intervention included the subject being provided with 7 months of study medicine (salmeterol or placebo) and a monthly telephone call to determine whether the subject was still taking the study medication, had made any other changes in asthma medication and had experienced a life-threatening asthma episode. Enrollment in this study was terminated following a planned interim analysis that demonstrated an increase in mortality, especially in the African American subjects. As detailed in the discussion section of this paper a potential explanation for the increase in mortality was the use of a LABA as monotherapy in a population less than half of whom were using ICSs at baseline and who were recruited by mass advertising and hence with no established relationship with the study sites, once again reinforcing the concern that a LABA should not be used without an accompanying ICS.
In a meta-analysis of the LABA data, Salpeter and associates[3] performed a search of databases through 2005 to assess the risk for severe, life-threatening, or fatal asthma exacerbations associated with the use of LABA. They limited their search to placebo-controlled trials that lasted at least 3 months and evaluated LABA use in patients with asthma. The results reported for fatal and near-fatal asthma attacks largely repeated the previously published data from the SMART study. Pooled results from 12 trials involving about 5091 subjects found that LABAs increased exacerbations requiring hospitalization (odds ratio, 2.6; 95% confidence interval, 1.6-4.3). In the discussion section of the paper the authors highlight the rise in asthma mortality since 1960 and intimate that LABAs may in part be responsible for this rise. There are many flaws associated with this supposition, as outlined in a letter by Nelson and Dorinsky,[29] principally the fact that asthma mortality has been steadily declining in the USA since the introduction of LABAs. A paper from the Canadian Asthma Guidelines Group pointed out the more serious deficiency of the paper by Salpeter et al.; that is, that most of the studies analyzed did not require concomitant use of ICSs. The Canadian group noted two Cochrane meta-analyses examining the use of LABAs with steroids compared with steroids alone, both of which showed a statistically nonsignificant reduction in hospitalization for asthma with the combination compared to the ICS alone.[30] The database regarding the risk of hospitalization with LABA was expanded by the presentation of two posters at the 2007 meeting of the American Thoracic Society. A meta-analysis of 63 double-blind, placebo-controlled studies that included an ICS arm and a salmeterol-plus-ICS arm with a total of 20 591 subjects demonstrated that the combination resulted in a risk of hospitalization for asthma of 0.94 (0.57-1.3) compared with ICS alone.[31] A meta-analysis of a subset of 24 of these studies with 7549 subjects reported asthma exacerbations requiring oral corticosteroids in 4.9% of those on the combination compared with 8.3% on ICS alone (P < 0.0001). A meta-analysis was also reported regarding 18 double-blind, placebo-controlled studies with 6988 subjects receiving either ICS alone or ICS plus formoterol.[32] The risk of hospitalization for asthma was only 0.59 (0.38-0.92) for those on the combination compared with those on ICS alone.
Although in both the Surveillance study and SMART study a signal of fatal exacerbations of asthma was seen in the salmeterol group, in each case we are left to grapple with the question of whether this was solely the result of inappropriate use of a LABA without concomitant use of an ICS or a potential deleterious effect of the LABA in a subgroup of asthmatic patients. In trying to better understand what patients may be at greater risk, researchers have begun to investigate specific phenotypes or genotypes. In the post-hoc analysis of the SMART trial, African Americans were at greater risk of suffering a fatal or near-fatal outcome when compared with whites.[2**] Since genetic polymorphisms of the β-adrenergic receptor are more common in African Americans than in the white population, this suggests to some that genetic variation in the β-adrenergic receptor may explain the results in SMART.
The most extensively studied genetic polymorphism in therapeutic asthma response involves the β-2 adrenergic receptor. The β-2 receptor belongs to the G-protein-coupled receptor superfamily, which contains 413 amino acids and was cloned in 1987.[33] Since then, several single nucleotide polymorphisms have been identified, resulting in amino acid substitutions at the 16th, 27th and 164th codons. These have been reviewed in detail elsewhere.[34] The most common homozygous genotype at the 16th amino acid position of the β-2 receptor is Gly-Gly; however, in approximately one-sixth of the North American population, Arg-Arg is found. The Arg-16 genotype appears to carry significant potential clinical consequences. In a study by Martinez et al.[35] 269 children who were β-2-naïve and participating in a longitudinal asthma study had their bronchodilator response measured following the acute administration of albuterol. A positive response was considered as a rise in FEV1 of greater than 15.3%. When compared with homozygotes for Gly-16, homozygotes for Arg-16 were 5.3 times more likely to have a positive response. On the other hand, when examining the chronic administration of short-acting β-agonists a very different picture is seen. Israel et al.[36] examined the genotypes in a group of 190 asthmatic patients who had participated in a trial examining the effects of regular compared with albuterol as needed for 16 weeks. When they retrospectively analyzed the response based upon genotype of the β-adrenergic receptor they found a small decline in morning PEF in patients homozygous for Arg-16 who used albuterol regularly. This effect, however, was magnified during a 4-week run-out period, during which all subjects returned to using albuterol as needed. By the end of the study, subjects who were homozygous for Arg-16 who had regularly used albuterol had a morning PEF of 30.5 ± 12.1 l/min lower (P = 0.012) than subjects with a similar β-adrenergic receptor genotype who had used albuterol on an as-needed basis. At the same time, there was no such decline in peak flows with regular use of albuterol in patients who were homozygous for Gly-16.
When the same group prospectively studied the response to chronic administration (16 weeks) of albuterol stratified by genotype, they demonstrated that while the Arg-16 group suffered a small reduction the Gly-16 group demonstrated a rise in peak flows.[37] The resultant difference was
24 l/min (P = 0.0003). Similar genotype-specific attributable effects were seen in FEV1, symptom control and use of supplemental reliever medicine.
Taylor and colleagues[38] performed a retrospective analysis of the relationship between β-2 receptor genotype and clinical outcomes in a placebo-controlled, crossover trial examining the use of regularly scheduled albuterol or salmeterol each administered for 24 weeks in a group of 115 mild to moderate asthmatics. Once again, chronic use of albuterol in the Arg-16 subjects was associated with lower morning peak flows and increased rates of exacerbations (P = 0.005); however, the opposite trends were observed with chronic administration of salmeterol, with morning PEFs tending to be higher and exacerbations less common than with placebo.
These findings indicated that the β-receptor genotype effect was limited to short-acting β-agonists only. However, a recent publication by Weschsler et al.[39] indicated that the response to LABAs might also be affected by a patient’s genetic make-up. In their study, a retrospective re-evaluation of the SOCS and SLIC trials, data were analyzed based upon genetic polymorphism. When these studies were re-analyzed stratified to genotype, both the SOCS and SLIC trials demonstrated with the use of salmeterol a significant fall in PEF rate in the Arg-16 group, while a rise was seen in the Gly-16 group (P = 0.005 and 0.048 respectively). It should be noted that decline in lung function was delayed in the SLIC study when compared with the SOCS trial. This may be a manifestation of the concomitant use of an ICS protecting from the deleterious effect of the LABA in this genotype.
These data, although interesting, are at variance not only with the data of Taylor et al.[38] but also other reports mentioned below. Furthermore, the Weschsler report is based on a very small sample size. The group randomized to LABA alone in the SOCS trial with the Arg-16 β-adrenergic receptor genotype was only five and in the SLIC re-analysis there were only eight subjects with the Arg-16 β-adrenergic genotype. In a recent retrospective analysis of the Advair clinical trials, Bleecker and colleagues[40] failed to demonstrate any decline in pulmonary function or deleterious effects on other aspects of asthma control over a 12-week period, in a larger group of Arg-16 subjects (n = 29). One limitation of this study is that the duration of observations was only 12 weeks, while the decline in pulmonary function in the SLIC trial occurred only toward the end of their 16-week studies. The same limitation applies to response by genotype data reported at the American Thoracic Society for formoterol, which also failed to show any difference in the response to this LABA by β-receptor genotype.[41] These studies have, however, resulted in two ongoing prospective studies employing larger numbers of subjects stratified by genotype of the β-adrenergic receptor. One, entitled the LARGE (Long Acting Beta Response by Genotype) study, is being conducted by the National Institutes of Health-funded Asthma Clinical Research Network, while a similar study by GlaxoSmithKline has just been completed and data should soon be available.
In conclusion, LABA should only be used in combination with ICSs in patients not adequately controlled on low-dose ICS alone. When used in combination with ICSs, prospective studies demonstrate improvement in both asthma control and exacerbation rate. In two large studies, an increase in asthma mortality was seen when LABAs were used. However, these studies allowed LABAs to be used as monotherapy and thus do not address the safety of LABAs used appropriately, in conjunction with ICSs. Although the majority of asthmatic patients appear to benefit from the use of LABAs, a small subclass may be prone to deleterious effect. From the data available it cannot be ascertained for certain whether this is some rare susceptibility to an untoward effect of these drugs, or, more likely, that this is the consequence of monotherapy with LABAs controlling the signs and symptoms while masking inflammation in patients who may lack adequate access to medical care.
John Oppenheimer, MD, UMDNJ-New Jersey Medical School, Pulmonary and Allergy Association, 1 Springfield Ave, Summit, NJ 07901, USA Fax: 1 973 540 0472; e-mail: Nallopp@pol.net
Papers of particular interest, published within the annual period of review, have been highlighted as:
* of special interest
** of outstanding interest
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MedScape, 3/21/08: The American College of Obstetricians and Gynecologists (ACOG) has issued a practice bulletin to address the diagnosis, treatment, and prevention of uncomplicated acute bacterial cystitis and acute bacterial pyelonephritis in nonpregnant women. The new recommendations are published in the March issue of Obstetrics and Gynecology.”An estimated 11% of U.S. women report at least one physician-diagnosed urinary tract infection (UTI) per year, and the lifetime probability that a woman will have a UTI is 60%,” write Jeanne Sheffield, MD, and colleagues from the ACOG Committee on Practice Bulletins. “Despite the frequency of UTIs, there is confusion about diagnostic strategies, and changes in antimicrobial resistance among uropathogens require alterations in traditional treatment regimens. The purpose of this bulletin is to address the diagnosis, treatment, and prevention of uncomplicated acute bacterial cystitis and acute bacterial pyelonephritis in nonpregnant women.”
These guidelines do not address management of complicated UTIs (eg, those occurring in patients with diabetes mellitus, abnormal anatomy, previous urologic surgery, a history of kidney stones, an indwelling urinary catheter, spinal cord injury, immunocompromise, or pregnancy).
Acute bacterial cystitis usually presents with dysuria, urinary frequency and urgency, sometimes with suprapubic pain or pressure, and rarely with hematuria or fever. The symptoms of acute urethritis from Neisseria gonorrhoeae or Chlamydia trachomatis infection, or genital herpes simplex virus type 1 and herpes simplex virus type 2, may be similar, and these conditions should be ruled out.
Upper UTI or acute pyelonephritis often presents with fever, chills, flank pain, and varying degrees of dysuria, urgency, and frequency.
Specific practice recommendations and their accompanying level of scientific evidence are as follows:
A proposed performance measure is the percentage of women diagnosed with acute pyelonephritis who receive antimicrobial treatment for 14 days.
For uncomplicated acute bacterial cystitis, recommended treatment regimens are as follows:
“A 3-day antimicrobial regimen is now the recommended treatment for uncomplicated acute bacterial cystitis in women, with bacterial eradication rates consistently higher than 90%,” the authors of the recommendations write. “Use of trimethoprim–sulfamethoxazole for 3 days is considered the preferred therapy, with a 94% bacterial eradication rate. However, in areas where resistance to this antimicrobial agent exceeds 15-20%, another one of the listed regimens should be chosen.”
For women with frequent recurrences of lower UTI, continuous prophylaxis has been shown to decrease the risk for recurrence by 95%. Suitable prophylactic regimens include once-daily treatment with nitrofurantoin, norfloxacin, ciprofloxacin, trimethoprim, trimethoprim–sulfamethoxazole, or another agent listed in this article. The need for continued therapy can be re-evaluated after 6 to 12 months.
Although acute pyelonephritis traditionally has been treated with hospitalization and parenteral antibiotics, cost-savings measures have prompted a recent shift to outpatient management, whenever feasible.
“Imaging of the urinary tract rarely is required in women — it is not cost-effective nor does it provide useful information in the setting of uncomplicated lower or upper UTIs,” the authors conclude. “Women with infections that do not respond to appropriate antimicrobial therapy or in whom the clinical status worsens require further evaluation. Renal ultrasonography is the best noninvasive method to evaluate renal collecting system obstruction, [and] an intravenous pyelography also may be useful in this situation.”
Obstet Gynecol. 2008;111:785-794.
Upon completion of this activity, participants will be able to:
In the United States, there is a tremendous burden from UTIs on both the clinical and financial aspects of healthcare. Of the more than 62 million adults aged 20 years and older who have reported at least 1 episode of a UTI or cystitis, more than 50 million (81%) were women. In 2000, the cost to the healthcare system for evaluation and treatment of UTI was estimated at $3.5 billion.
More than one half of women will have at least 1 UTI during her lifetime, and 3% to 5% of all women will have multiple recurrences. ACOG has issued a practice bulletin to address the diagnosis, treatment, and prevention of uncomplicated acute bacterial cystitis and acute bacterial pyelonephritis in nonpregnant women, hoping to resolve the existing confusion about diagnostic strategies and changes in antimicrobial resistance among uropathogens.
Postings #716, 718, 719, 723, 724, 725, 727, 728.
Today is World TB Day. Take someone out to lunch and cough on them.
Here’s some more information about PRES. You remember Pres. I posted info about it yesterday. It’s posterior reversible encephalopathy syndrome. It sounds like you won’t make the diagnosis in the ER. You just treat symptomatically. Control the hypertension and the seizures and get a CT scan. The radiologist will make the diagnosis. Anyway, it’s good to know the term so that you are conversant about it when you talk to the radiologist and the neurologist. Ah, I can see it now: Hospital CEO: “We have to cancel the ER group’s contract.” Hospital Board: “Why?” CEO: “They’re too expensive.” Board: “You can’t do that. They’re the only ones who know about PRES.”
http://omniphysicians.com/2008/03/23/a-deeper-look-into-pres/
April and May are biggest months for suicide, according to ACEP. Why? No one knows. Ah, springtime! When the robins sing, the flowers bloom, and cyanotic, distorted bodies are hanging from tree limbs.
http://omniphysicians.com/2008/03/24/aprilmay-suicide-months/
An average day in the hospital. The wheelchair bomber had a detonator, but no bomb (discovered later). He was shot, but not killed. He died in surgery. Wouldn’t it be ironic if his estate sued for malpractice? Anyway, it underscores the fact that hospitals and especially ERs are a lightning rod for kooks, crackpots, and the deranged. And that’s only the medical staff.
http://omniphysicians.com/2008/03/24/have-wheelchair-will-bomb/
Given the current heparin crisis, this report cites experts who are developing synthetic heparin. This idea is years away and will be quite expensive.
http://omniphysicians.com/2008/03/24/is-this-the-time-for-synthetic-heparin/
There is concern that insurance companies will want to restrict advanced imaging techniques in order to save the patient from cancer. How noble! Will this concept invade the ER practice of medicine? It may be only a matter of time.
http://omniphysicians.com/2008/03/24/will-insurance-companies-dictate-medical-imaging-in-the-er/
This one hospital has banned cell phones because people, using them, have been taking unauthorized photos of patients. I post this because I’m always wary when people use their cell phones while I’m examining patients because I don’t know if they are photographing me or recording me. Be careful.
http://omniphysicians.com/2008/03/24/is-he-photographing-me/
EMS in San Diego is armed with protocols and equipment that have reduced the time to take a STEMI patient to cath lab from over 125 minutes to 62 minutes. It would be down to 40 minutes if they didn’t make a stop at Time Horton’s for a donut and a cappucino.
http://omniphysicians.com/2008/03/24/san-diego-speeds-up-stemi-protocols/
Here is a news article that further exposes the travails associated with working the night shift. Increases in heart disease, miscarriages, and cancer.
http://omniphysicians.com/2008/03/24/night-shift-why-we-beat-our-dogs/
HealthCare Security weekly, 3/24/08: A man in a wheelchair, who went into a Boulder, CO hospital and claimed he had a bomb, died after police shot him in the chest.
The man had threatened to blow himself up after going into the lobby by the glass doors to the emergency department at the Boulder Community Hospital on March 17 and calling police. The 32-year-old man told police he had a detonator device hooked up to an oxygen tank he had with him, reported 9 News in Denver.
Police negotiated with the man for several hours. Authorities moved patients to the east end of the hospital where they considered them safe, and placed the 200-bed hospital into lockdown, the TV station reported. When the man tried to leave the lobby area and enter the hospital, police hit him with several rounds of less-than-lethal ammunition, which did not stop him.
A member of a SWAT team then fired from a sniper rifle and hit the man once in the chest, the TV station reported. The man underwent surgery at the hospital but died later that night. Police removed a device and were able to detonate it safety. Investigators determine it did not contain explosives.
A psychiatric hospital within the University of California Los Angeles (UCLA) health system has banned all cell phones and notebook computers after a patient posted photos of other patients on a Web page, the Los Angeles Times reported March 18.
.
The patients at Resnick Neuropsychiatric Hospital at UCLA reportedly gave their consent to be photographed, a hospital spokesperson told the Times. However, hospital officials were worried about the possibility of photos being taken without consent and showing up online, particularly considering the mental conditions of some psychiatric patients.Rather than examine every cell phone or computer for the presence of a camera, hospital officials decided to prohibit these items outright.
WebMD, 3/21/08: March 21, 2008 — The FDA today announced its approval of the use of Prilosec in children as young as 1 year old.
The FDA yesterday approved Prilosec delayed-release oral suspension (liquid) for the short-term treatment of gastroesophageal reflux disease (GERD) and the healing of erosive esophagitis (erosions in the lining of the esophagus) in children aged 1-2.
Prilosec, made by AstraZeneca, was previously approved for use in children aged 2 to 16.
Last month, the FDA approved another GERD drug, Nexium, for use in children aged 1-11. Nexium, which is also made by AstraZeneca, was already approved for use in kids aged 12-17.
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LA Times, 3/24/08: AT 6 a.m., the hospital’s bright hallway lights flicker on, signaling the start of a new day. Doctors in crisp business clothes appear on their early-morning rounds, and the clang of breakfast carts will soon echo through the unit.
For registered nurse Liberty Bunag, however, it’s finally time to go home and sleep. She began her shift 12 hours ago with an extra-large coffee and since has consumed a liter of caffeinated soda, more coffee and lots of rice, her personal energy food. Sometimes she and the other nurses on the orthopedic ward of White Memorial Medical Center in Los Angeles practice foreign languages to stay alert, squelching the yawns and drowsiness — the body’s way of protesting this nocturnal activity.
In a 24/7 world, such fatigue passes for normal. Twenty percent of American workers are night-shift workers, and the number is growing by about 3% per year, according to the Bureau of Labor Statistics. While the rest of society sleeps, police officers, security guards, truck drivers, office cleaning crews, hotel desk clerks, nurses, pilots and many others keep patients alive, streets safe and packages moving. But at a price.
These workers — and people with more conventionally sleep-deprived lifestyles — are known to be at higher risk for accidents, sleep disorders and psychological stress due to daytime demands, such as family and other obligations, that interfere with sleeping. Now scientific evidence suggests their disrupted circadian rhythms may also cause a kind of biological revolt, raising their likelihood of obesity, cancer, reproductive health problems, mental illness and gastrointestinal disorders.
The evidence for an increased cancer risk is so compelling that, in December, the International Agency for Research on Cancer, a unit of the World Health Organization, declared that shift work is “probably carcinogenic to humans.”
Researchers are beginning to understand why. Among the most significant — and startling — reasons: As much as 15% of human genes function on a schedule, with highly regulated, oscillating patterns of activity.
These clocklike genes are common features of most cells and can be found in every major organ in the body. They, in turn, affect the schedule of scores of biological functions, from metabolism to cell division to cognitive processes.
“Less than 10 years ago, it was thought that sleep was for the brain and not for the rest of the body, so lack of sleep would make you tired, moody and more likely to have accidents,” says sleep researcher Eve Van Cauter, a professor of medicine at the University of Chicago. “But sleep deprivation may be bad for the body too, representing a risk for a variety of abnormal conditions.”
Evolution supports that theory. Life on Earth began with single-cell organisms that depended on sunlight for converting energy to food. “Life has been adapting to a light-dark cycle since the beginning of the planet,” says Paolo Sassone-Corsi, chairman of the department of pharmacology at UC Irvine.
But modern humans wrongly think they can override their natural sleep patterns with impunity, says Dr. Charles Czeisler, director of the division of sleep medicine at Harvard Medical School. “It’s a myth that we alone, among all animals, have the power to sleep when we want,” he says.
Disrupted rhythms
Dennis Corrigan sometimes questions his decision to switch to a night shift 12 years ago.
By working nights, the UPS truck driver from West Covina, age 52, avoids the physical demands of the day shift, when lifting boxes is part of the job, plus the worst of L.A. traffic. The 10:45 p.m.-to-11 a.m. shift also allowed him to attend all of his son’s high-school football games.
But Corrigan now sleeps only about six hours a day. He has put on weight and gets less exercise than before the switch and was diagnosed with diabetes five years ago.
“The rough part is, when I come home, I’m hungry,” he says. “I eat a heavy meal before going off to bed. You’re not supposed to do that. It’s a worry.”
His circadian rhythms may be to blame. Those rhythms determine when certain body processes take place. For example, melatonin, the hormone that aids sleep, is released at night; the hormone cortisol is low at night and pours out in the morning, jump-starting the body’s daytime functions. But in night workers, melatonin continues to peak at night — even though they’re awake — and cortisol levels continue to peak in the early morning hours, even when night-shift workers are eager to get some sleep.
Those disrupted circadian rhythms are why night-shift workers sleep less and with poorer quality, Van Cauter says: They try to sleep when their bodies want to be awake.
Chronic sleep deprivation may carry some of the same risks as disrupted circadian rhythms, she says. Today, Americans average about one hour less of sleep per night than they did 30 years ago.
Bunag feels the effect of night-shift work on her days off. If she tries to sleep at night, she often wakes around 3 a.m. and is alert until dawn, when she falls back to sleep, often for 10 hours. On work days, she sleeps about six hours during the day but still awakens tired.
“My problem is not while working but on my days off,” she says. “I feel unproductive because all I do is sleep all day, and I’m up the whole night when nothing much can get done.”
She finds herself less willing to socialize these days and worries that her irritability may border on depression. She also wonders about the long-term health consequences of her schedule. “I want to be able to sleep normally at night when the body does all of its detoxifying, cleansing, repairing and recharging. But I haven’t figured out what’s going to work for me.”
Her concerns are well-founded.
* Night-shift workers have a 40% to 50% increased risk of heart disease compared with day workers, various studies have found.
* People who get five hours of sleep, common among night-shift workers, are 50% more likely to be obese than normal sleepers, Columbia University researchers have found. Several dozen other studies have tied sleep loss to weight gain as well.
* Women night-shift workers have higher rates of miscarriage, pre-term birth and low birth-weight babies.
* Night-shift workers show increased rates of breast (by 50%) and colon (by 35%) cancer in numerous, independent studies. And animal studies have shown that exposure to dim light during the night-time can substantially increase tumor development.
“It’s been known for years that there is an increased risk of a variety of medical conditions in the population of shift workers,” says Dr. Diane Boivin, associate professor of psychiatry and director of the Centre for Study and Treatment of Circadian Rhythms at Douglas Mental Health University Institute in Montreal. “What is difficult to parcel out is the exact contribution of this circadian misalignment and sleep deprivation. We think it’s major, but it’s very difficult to be sure.”
Genes that keep time
Science is inching closer to understanding how a lack of sleep — or sleep at the wrong time — can wreak biological havoc. In the last few years, researchers have made surprising discoveries about the body’s sophisticated time-keeping.
Scientists once assumed the body’s sole “clock” was nestled in a place in the brain called the suprachiasmatic nucleus, or SCN. Light — particularly sunlight — is the primary synchronizer for circadian rhythms. When we open our eyes each morning, light reaches photoreceptors in the retina and creates signals that travel to the SCN to jump-start the body’s hormones, neurotransmitters, temperature and metabolism for the new day.
But that’s not the body’s only timepiece. Circadian time-keeping genes can be found in organs all over the body. These peripheral clocks control the activity of many cellular processes and biological functions, and their presence may explain why sleep dysfunction seems to have such a broad effect on overall health. Light sets the circadian clocks in the SCN, but scientists still aren’t sure what compels the body’s peripheral clocks to work in unison. After all, the liver and the digestive tract don’t have direct access to sunlight.
“The SCN is like a musical conductor and the peripheral clocks are the instruments that need to play their music with peak activity at certain times of the day to get good harmony across the body,” Boivin says. “They must be in sync.”
The SCN somehow “talks” to these peripheral clocks by using hormones or other messengers, Van Cauter says.
For example, among its many functions, the nighttime release of hormone melatonin is thought to inhibit tumor growth. Melatonin production usually peaks in the middle of the night. But it stops being secreted when light reaches the eye in the morning — or when a light is switched on during the night.
This disruption could influence the genes involved in tumor development, Sassone-Corsi says, and provide a possible explanation for why cancer rates appear higher in shift workers.
How food can play a part
Food intake can also affect body clocks — and vice versa. The movement of glucose and nutrients through the bloodstream to organs affects appetite, digestion and metabolism. Travelers frequently encounter stomach and digestive difficulties when crossing time zones, for example, because food intake is in conflict with the time-keeping molecules in the body’s digestive system.
“When you’re a shift worker and displace your sleep, you also displace your feeding schedule,” Van Cauter says. The liver, pancreas and digestive system are not expecting food at the time that they’re getting it.
Sleep schedules that buck the body’s natural circadian rhythms can disrupt insulin production and other hormones that are important to weight control, Van Cauter says. In a series of studies, she found that sleep-deprived adults produce more ghrelin, a hormone that promotes hunger, and less leptin, a hormone that suppresses appetite. Thus, the brains of tired people are sending out compelling messages to eat — especially foods that are starchy, sweet and high-carb.
Accordingly, people who sleep less may have more trouble keeping their blood sugar stable. In one of Van Cauter’s studies, healthy young men were restricted to four hours of sleep per night for six consecutive nights and were found to have blood test results for insulin sensitivity so abnormal they almost matched those of diabetics.
Other research is exploring effects of sleep and shift work on neurotransmitters called orexins. These brain chemicals have unique, dual roles, making sure humans are alert when hungry to maximize food-seeking behavior.
After a big meal, fast-rising glucose levels in the body switch off orexin neurons, often making people feel sleepy — possibly an evolutionary response signaling humans to conserve energy after eating. “There is wiring in our brains that links feeding and being awake,” Van Cauter says.
Thus, eating at midnight and sleeping at noon could lay the groundwork for the obesity, diabetes and heart disease seen more commonly in night workers. Moreover, as people age, they spend less time each night in phases of deep sleep. Van Cauter’s research team is investigating whether this poorer-quality sleep may contribute to a variety of ailments in old age.
Preventing the damage
For people such as Bunag and Corrigan — and for society as a whole — night-shift work is a reality. “Our entire transportation infrastructure would break down if those trucks decided to use the roads during the day,” Harvard’s Czeisler says.
That’s why, ultimately, scientists want to prevent the damage from shift work or insufficient sleep.
It’s not easy, however, to tease apart the biological effect of disrupted circadian rhythms from other factors that may influence night-shift workers’ health, such as poor diets, stress and lack of exercise. Many diseases, such as cancer and heart disease, are also influenced by risk factors that have nothing to do with occupation.
Moreover, individuals differ in how they cope with circadian rhythm disruption. As many as 10% adapt well, but 15% to 20% simply can’t tolerate staying awake all night, according to Czeisler. The remainder cope, but with difficulty.
Sleep researchers have devised compensation tactics, such as the use of bright lights and melatonin supplements, to help night-shift workers remain alert on the job and sleep better after the shift. But the research on the body’s molecular clocks may lead the way to better therapies, Sassone-Corsi says.
Identifying the molecular clocks that affect cell division, for example, may point the way to treatments to prevent cancer.
In a paper published in December in the journal Nature, Sassone-Corsi found that a single amino acid activates the genes that regulate circadian rhythms. This chemical switch could perhaps be manipulated by a medication of some sort to restore circadian rhythms that have gone awry.
“If we can explain how these molecules work, we can get targets” for potential therapies, he says. “We cannot beat the system, but we can work on it.”
For now, however, researchers and sleep doctors alike implore people to show a little respect for slumber.
“People think of sleep as a waste of time,” Sassone-Corsi says. “But it’s essential. A correct sleep-wake cycle is as important to health as any other thing in our lives.”
HealthDay, 3/24/08: SUNDAY, March 23 (HealthDay News) — While many people view spring as a time of renewal and hope, the greatest number of suicides in the United States occur each year in April and May, notes the American College of Emergency Physicians.
It’s not clear why suicide rates spike in the spring, said ACEP President Dr. Linda L. Lawrence. But “we do know that suicide is the 11th leading cause of death for all ages in the United States, with one suicide occurring every 16 minutes or about 11 suicides per 100,000 people,” she said in a prepared statement.
“Moreover, suicide is the second leading cause of death among 25- to 34-year-olds and the third leading cause of death among 15- to 24-year-olds. Men take their own lives nearly four times more often than women, with men ages 75 and older having the highest rate of suicide, although over a lifetime, women attempt suicide two to three times as often as men,” Lawrence said.
For every successful suicide attempt, there are 25 failed attempts that often leave people seriously injured and in need of medical care. More than 90 percent of all suicides are linked with a mood disorder or other psychiatric illnesses, which can be treated through behavioral therapy and medication, Lawrence said.
“So we want to build greater public awareness and understanding of suicide in order to prevent these needless deaths and injuries from occurring,” she said.
As part of that effort, the ACEP wants to educate people about the warning signs of suicidal behavior, which include:
If a person is threatening to commit suicide, take it seriously, remain calm and take the following steps, ACEP advises:
AP, 3/23/08: Insurance companies are taking a harder look at advanced medical scans like CT scans, citing spiraling costs and safety concerns. And some doctors agree there’s emerging evidence that these scans are being over-prescribed.”Costs are soaring in this area, quality concerns are mounting and safety concerns are mounting,” said Karen Ignagni, chief executive officer of the trade group America’s Health Insurance Plan.
Health insurers are requiring more pre-authorizations before patients can receive these scans, and setting other restrictions including mandating that the imaging equipment and medical staff operating it be credentialed in advance.
Insurers fear some patients are being exposed to dangerous radiation levels from having repeated CT and PET scans, which use many times the radiation of a regular chest X-ray. Sometimes scans are repeated because the first ones were not done properly, using outdated equipment or by poorly trained technicians.
Doctors, too, are concerned about patients getting excessive radiation exposure when they receive scans that aren’t needed or are ordered as “defensive medicine” to protect against possible lawsuits. There also is concern that a small number of unscrupulous doctors without adequate expertise are referring patients for tests in their own offices or imaging facilities in which they have a financial interest.
“There is a definite concern that in-office imaging could lead to scanning for dollars,” said Dr. Robert Hendel, a heart specialist who sits on American College of Cardiology panels focused on quality and appropriateness of imaging.
But doctor experts say the bigger problem with medical imaging tests is the insurance red tape needed to get them.
“Is this a preauthorization process or are these (insurance) companies practicing medicine?” asks Dr. Arl Van Moore, board chairman at the American College of Radiology, the specialists in medical imaging.
Moore cited another reason for increasing costs: Doctors sometimes order a diagnostic test that doesn’t need preauthorization — even if it provides less-helpful information than the one they prefer — then seek approval for a more advanced test if the first one shows it’s needed.
Worse yet, sometimes patients end up getting a riskier, more invasive test than what they really need, said Hendel. For example, cardiologists wanting to assess blood flow and blockages inside a patient’s heart arteries would prefer a nuclear cardiology test. With that, a small amount of a radioactive substance is injected in the blood and tracked using a camera.
Some doctors will instead order a cardiac catheterization, which doesn’t require advance authorization, Hendel said. But that involves threading a catheter through a blood vessel up into the patient’s heart — and carries a 10-times higher risk of complications such as a heart attack or stroke, he said.
The two doctor specialist groups are fighting improper use of scans by supporting accreditation of the machines and doctors using them and by publicizing criteria for quality and appropriateness of various imaging tests.
“There is substantial evidence that these types of techniques, when used appropriately — and I want to emphasize the word ‘appropriately’ — can keep the lid on expenses and improve outcomes,” such as by catching cardiac problems early enough to prevent a heart attack, Hendel said.
Patients who are inconvenienced tend to blame the doctor and office staff, Hendel noted.
“They (patients) show up expecting a test to be performed. We’ve booked a slot,” and then discover the problem, Hendel said. “We have no choice but to reschedule. Are they upset? Yes!”
He said use of strategies to hold down imaging costs was fairly limited until last year, when it really ramped up, triggering the growth of a new industry of insurance consultants called radiology benefit managers.
A recent study by the Center for Studying Health System Change, which is funded by the Robert Wood Johnson Foundation of Plainsboro, N.J., the nation’s biggest health care charity, also found that limitations on use of MRIs, CT scans, PET scans and nuclear cardiology imaging became widespread last year. The report was based on visits and interviews in 2007 with officials of health plans, hospitals, doctors’ practices, major employers and others in 12 metropolitan areas.
The report noted use of CT scans in the U.S. nearly doubled between 2000 and 2005, from 12 scans per 100 people to 22 per 100. That’s partly because improved technology has made the imaging machines, which can cost $1 million to $2 million each, useful for diagnosing more problems.
“The hospitals and physicians purchase it, and then there’s a strong incentive to use the equipment,” said Ignani, the insurance trade group CEO, adding that manufacturers aggressively market the machines.
Revenues from the tests, which can run $500 to $1,000 or more apiece, can be tempting to financially struggling hospitals and doctors squeezed by shrinking reimbursements from government health programs and commercial insurers. At least one medical education firm is pitching a training conference titled: “Practice Expansion for Primary Care Physicians: How to Grow Your Income by Adding In-Office Imaging!”
The insurer restrictions seem to be working: After one health plan that was seeing 20 percent annual jumps in advanced imaging use began requiring preauthorization, its growth rate plunged. Yet the insurer said only 1.5 percent of requests were being denied, indicating doctors were ordering fewer tests, according to the report.
“Most health plans believe it’s been successful,” said Ann Tynan, the study’s lead author.
Insurers are looking at ways to put similar restrictions on other high-cost areas, and some already are doing so for stomach-reduction surgery and very expensive medications, she said.
Doctors see some hopeful signs, though, after passionate arguments by physician groups reversed changes they were fighting.
The Medicare program is trying to find ways to hold down its spending on imaging services after the annual cost jumped from $6 billion in 2000 to $12 billion in 2005. It had proposed no longer paying for cardiac CT scans unless patients were enrolled in a study of their effectiveness. In mid-March, it said it would continue to cover the scans.
And Horizon Blue Cross Blue Shield of New Jersey, the state’s biggest insurer, recently halted a plan to require preauthorization for relatively inexpensive EKGs, or echocardiograms, even though it is starting to require advance approval for expensive cardiac imaging.
Reuters (3/22) reported that the Food and Drug Administration (FDA) has “recommended updating the prescribing instructions for a Baxter International anesthesia drug,” Suprane (desflurane), “after three reports of cardiac arrest in children,” according to agency documents. The drug’s label “already carries warnings about other cardiac problems including heart attacks, irregular heart beats, and unstable blood pressure.”
NY Times, 3/24/08:
Those precautions had mixed results, and an estimated 675,000 Americans died during that outbreak, according to the Centers for Disease Control and Prevention in Atlanta.
Today, New Jersey, Connecticut and New York are much more prepared than they were 90 years ago in the event that an influenza outbreak turns into a pandemic. But five years after an avian flu outbreak in Asia made pandemic flu planning a priority, some experts are concerned that states have not been equally vigilant about preparing, and as attention and federal financing begin to decrease, they fear that preparedness efforts will slacken.
“There is a worry that there was a lot more attention to the issue two or three years ago,” said Richard Hamburg, government relations director for Trust for America’s Health, a Washington-based nonprofit health watchdog. “The fact is that it’s still spreading. There are still cases throughout the world. Preparedness is not a one-shot deal. You don’t know if this will hit this year, next year, five years, 10 years from now.”
Federal officials are tracking the flu worldwide, but it is up to cities and states to prepare their own public health plans. So in 2002, when fears of a new pandemic began to escalate, the federal government agreed to send the states billions of dollars to prepare for a pandemic. The health and human services secretary, Michael O. Leavitt, warned states in 2005 that if they expected the federal government to bail them out when a pandemic hit, they would be “tragically wrong.”
Trust for America’s Health released a report late last year examining how states were preparing for public health emergencies. The report graded the states on their efforts to protect against a pandemic. Over half of the states received a score of 5 or less for their health emergency preparedness capabilities, with 10 being the highest score.
In this region, Connecticut received a score of 8; the state lost points for failing to buy enough antivirals and failing to use a disease surveillance system that is compatible with the federal system to track the progress of an outbreak as it moves across the country. New York scored a 9 — for failing to increase public health financing as quickly as inflation, though state officials said financing has since risen — and New Jersey received a 10.
Pandemics occur when the flu virus mutates into a more deadly form and begins to spread easily from person to person. Health officials are worried about pandemic flu now because they fear the avian flu that has spread to Asia and Europe could mutate into a more deadly and transmissible form.
During the 1918 flu pandemic, which killed about 50 million worldwide, the federal government did not ask states to report their flu tallies until weeks or months after the disease had begun to spread. This time around, the government has been tracking the flu for years.
And in 1918, scientists were unable to make an effective vaccine; in an outbreak today, a vaccine could most likely be created within six months.
Connecticut, New Jersey and New York expect to use two basic methods to keep the flu under control before the vaccine is ready: antiviral drugs and a kind of mass crowd control. The federal government has bought 50 million courses of antiviral drugs that federal officials said could limit the severity of flu infections and possibly serve to protect uninfected people from the disease.
The Department of Health and Human Services has urged states to buy antivirals through a discount program that offers a federal subsidy, cutting the cost of a course of drugs (enough for one person) to $20 from $80, said Dr. William F. Raub, science adviser to Secretary Leavitt. The eventual goal is to have enough antiviral medication to cover at least one-fourth of the population.
In the region, the states have taken different approaches to stockpiling antivirals. Connecticut decided not to buy its full share of antivirals, though it has bought about 11,000 courses with federal money and sent a letter to the federal government indicating it wants to buy 8,465 more. Even after including the 520,000 courses in the federal stockpile designated for Connecticut, the state would still have only enough antivirals for about one-sixth of its population.
William Gerrish, a spokesman for the Connecticut Department of Public Health, said state officials haven’t put as much emphasis or money into antivirals as other states because they have “limited utility and limited shelf life.”
Indeed, federal officials are uncertain just how effective antivirals would be in the event of a pandemic and whether they could serve some prophylactic purpose. And because antivirals currently have a five-year shelf life, states are spending millions of dollars on medicine they may have to throw away in the next few years. But other state officials said they weren’t willing to take chances.
“If you had a novel strain causing a pandemic that was responsive to antivirals and your state had no stockpile, I could predict that the public would be pretty upset,” said Dr. Eddy Bresnitz, the state epidemiologist in New Jersey, which has bought 850,000 of the 900,000 courses available under the federal cost-sharing program. He acknowledged, however, that if the antivirals expire, “that’s a lot of dollars flushed down the drain.”
Similarly, New York has gone so far as to buy supplies of antiviral medications that were initially designated for other states that decided not to buy them.
The bulk of the planning, however, has focused on other methods to keep people from getting sick during a pandemic, ranging from surveillance to shutting down public gatherings and schools to quarantining people who are exposed to the flu and isolating those who have it.
The states have held drills for public health and safety workers to determine what to do when the flu hits, and they have developed increasingly sophisticated reporting systems that make doctors pick up the telephone immediately after seeing signs of certain diseases.
New Jersey has been particularly diligent: the state compiles analyses of school absenteeism and flu diagnoses each week and links to its pandemic flu plans from the top of its Web site. The challenge, state officials say, is keeping their plans current and local officials up to date on flu preparedness.
Meanwhile, state officials said they have received less money for outreach to local communities that they have done in the past. Congress turned down the president’s request for $870 million in this year’s budget for flu preparedness, and state officials said they expected future grants to be much more competitive.
“It means the system is a little bit thinner,” said Dr. Gus Birkhead, New York’s deputy commissioner for public health.
NBC News, 3/22/08: (3/22, story 12, 2:25, Holt) reported, “Public hospitals like San Francisco General make up two percent of America’s hospitals,” yet they “take care of 25 percent of patients with little or no medical coverage.” However, they are “disappearing at an alarming rate, down almost 22 percent since 1990.” According to Larry Gage, of the National Association of general hospitals, these closures are due to “a combination of budget cuts at almost every level of government, increased numbers of uninsured, [and] increased demand on the emergency” department “and the trauma systems.”
San Diego Union Tribune, 3/22/08: Patients with the most lethal type of heart attack are receiving lifesaving care in half the time as before 2007 under a cardiac-response system launched early last year, county officials said yesterday.
EDUARDO CONTRERAS / Union-Tribune
Dr. David Spiegel explained a procedure yesterday to patient Eleanor Kendall at Tri-City Medical Center in Oceanside. Kendall underwent angioplasty and stent placement.
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Now, paramedic ambulances carry special equipment that allows them to diagnose these heart attacks in the field. The paramedics then call any of 13 designated hospitals’ heart attack teams to let them know a patient will soon arrive so they can be prepared, said Dr. Bruce Haynes, medical director of the county’s Emergency Medical Services.In the years before the Cardiac System of Care was created, patients would arrive at the emergency room and have to wait 125 to 140 minutes before they could go into a cardiac catheterization lab and have their artery blockages cleared, Haynes said.
That time was reduced to 62 minutes during the first year of the program, which was launched in January 2007. “Medical research shows this saves lives and is truly a great benefit,” Haynes said.
He said 330 patients benefited from the new system in 2007.
Haynes, hospital cardiologists, paramedics and county officials held a news conference yesterday to announce its success. County officials said they don’t know how many deaths the program prevented or how many patients had less damage to their heart muscle because blood flow was restored faster.
But county Supervisor Greg Cox said he is sure the system has made a lifesaving impact. “Today, heart attack victims have a much better chance to survive and recover,” he said.
One of the first patients to benefit from the cardiac system was Ron Rosenbaum of San Marcos, who experienced pain in his arm a year ago and went to a Carlsbad fire station to get checked out.
The station hooked him up to an electrocardiogram machine and immediately determined he was having a type of heart attack called ST-segment elevation myocardial infarction, or STEMI. He was promptly transported to a hospital where heart specialists awaited.
“It was no time at all before I was in the cath lab . . . and had two stents put in,” Rosenbaum said. “I didn’t realize then, but I do now, how lucky I was with this system. If they didn’t have their specialized team there . . . . I might not be lucky enough to be standing here.”
One reason for delays in the old system is that paramedics would routinely take symptomatic patients to the nearest hospital, regardless of whether it had a cath lab team ready to go, seven days a week, 24 hours a day. Paramedics didn’t know which patients were having a true heart attack.
“We used to fly blind, without knowing the true condition of the patient,” said Paul Maxwell, a county paramedic.
The improvement brings the county to a speed – called a door-to-balloon time – that is even faster than the national target of 90 minutes. Hospitals across the country have been dramatically reducing their times as well. Two years ago, the national goal was 120 minutes.
Part of the success of the new system is that every ambulance with a paramedic in the county now carries a 12-lead electrocardiogram machine, county officials said. These devices can identify STEMI heart attacks.
In a STEMI, the artery is completely occluded, causing heart muscle downstream to die rapidly, said Dr. Paul Phillips, a cardiologist at Scripps Mercy Hospital in Hillcrest and one of the first to advocate the new system.
STEMIs are also called “tombstones” in part because of the heart waves’ appearance on a printout. About one in every three heart attacks is classified as a STEMI.
The blockages almost always occur in the left ventricle, and they’re far more likely to cause death more quickly than most other kinds of heart attacks.
Each year, about 400,000 people in the nation suffer a STEMI, according to the American Heart Association. Many of them die without reaching the hospital.
Non-STEMI heart attacks are less urgent because they are usually caused by clots or blockages that haven’t blocked blood flow entirely.
“You could say that other kinds of heart attacks, your kitchen sink is draining slowly, but it’s still draining. But with a STEMI, there’s no flow at all,” said Ori Ben-Yehuda, director of the Coronary Care Unit at UCSD Medical Center in Hillcrest.
The most effective way to treat a STEMI is prompt catheterization. Of the nearly 5,000 acute-care hospitals in the United States, less than half have catheterization labs and only 1,200 have equipment and specialized teams ready to do such procedures.
In San Diego County, paramedics don’t automatically route non-STEMI patients to one of the 13 hospitals participating in the cardiac-response program.
Non-STEMI heart attacks are tougher to identify. Their symptoms can resemble those of indigestion, anxiety or other problems. That’s why health experts say that people who suspect they’re having a heart attack should call 911 instead of going to the hospital themselves.
The countywide cardiac-response system was made possible in large part because of a $536,000 gift to the city of San Diego from La Jolla stock adviser Jack White, who suffered a STEMI heart attack in 2004. When paramedics arrived at his home, they couldn’t diagnose him because they lacked the 12-lead equipment, he recalled.
“They told me the city hadn’t been able to fund them to buy it, and how important it was to get this equipment because every second after a heart attack, a little more muscle is destroyed,” White said in a 2006 interview. “So I asked them how much money it would take.”
Ambulance companies, hospitals and fire departments have provided most of the remaining financial support.
Hospital officials around the county are delighted with the system.
“There’s no question that the quality of care given to people having heart attacks in this county has improved,” said Dr. Jerrold Glassman, a cardiologist and chief of staff at Scripps Mercy Hospital in Hillcrest.
Palomar Pomerado Health pioneered the STEMI-response concept in San Diego County in November 2003. Its ambulances were the first to have the 12-lead electrocardiogram machines.
Before November 2003, the average door-to-balloon time for patients using the 911 system was 136 minutes. Today, the time is 72 minutes, said Andy Hoang, a spokesman for Palomar Pomerado Health.
“That’s a huge difference,” Hoang said.
Chicago Tribune, 3/22/08: The pursuit of a synthetic version of heparin, free of animal materials and made with stricter quality controls, is gaining more attention as awareness grows that the blood thinner can be sourced from an unregulated supply chain that starts with hog lots in rural China.
The U.S. Food and Drug Administration this week disclosed that low-cost animal cartilage made its way into Baxter International Inc.’s heparin, raising fears conventional quality-control procedures do not adequately protect American consumers. Baxter’s product, recalled in the U.S. last month, has been linked to hundreds of potentially dangerous allergic reactions and at least four deaths. On Friday, the FDA said another American heparin-maker, B. Braun Medical Inc., recalled, as a precaution, more than 20 lots made by the same Chinese plant that supplied Baxter.
“The reason we are pushing for the synthetic is that you can completely control the production process,” said Jian Liu, associate professor of medicinal chemistry and natural products at the University of North Carolina School of Pharmacy, who is developing a synthetic heparin that is years from the U.S. market. “For the time being, we are stuck with the pig stuff. It has served us well for 50 years, but it was only a matter of time until something like this happened. It is too easy for the heparin extraction process to be contaminated if strict controls are not maintained.”
The synthetic process purifies the drug and its ingredients every step of the way in laboratories, in contrast to the need for scrutiny of village workshops and farms in China that are now under investigation by U.S. and Chinese health officials.
The FDA on Wednesday said as much as 50 percent of Baxter’s heparin tested from suspect lots recalled showed that the raw ingredient used to make the drug contained oversulfated chondroitin sulfate, an unapproved dietary supplement taken orally to treat joint pain.
Synthetic heparin has its own drawbacks, however. It is complex to make and development costs could push the price up between five and 40 times the $1 per-vial cost of the decades-old heparin, researchers and analysts said.
“It’s been inexpensive to derive heparin from animal sources so that there has been little incentive to consider a synthetic version of this particular heparin,” said FDA spokeswoman Karen Riley.
Indeed, Wisconsin-based Scientific Protein Laboratories four years ago opened a manufacturing plant in Changzhou, China, to keep its heparin costs low. Scientific Protein, which supplied active ingredients used to make heparin for both Baxter and B. Braun, made the move to China after supplies of pigs were inadequate in the U.S. and Canada.
Currently, there is no FDA-approved synthetically derived heparin with the broad indications awarded Baxter’s heparin, which is used for dialysis and before heart surgery. The synthetics that are available are approved for specific uses, the FDA and researchers said.
The push for synthetic heparin also comes as some industry experts wonder whether there could one day be supply issues with pigs just like there were concerns decades ago from international health officials about shortages of cow and pig pancreases that had been used for decades to make insulin.
Such concerns in the 1980s forced insulin-makers like Eli Lilly & Co. to begin to move to synthetic versions as the world’s diabetes epidemic began to take off. In 2005, the Indianapolis-based drug giant produced its last insulin derived from pigs. “If we did not think of better ways to produce it, we could be facing a potential problem because the diabetes epidemic was starting,” Lilly spokesman Scott MacGregor said.
Synthetics are being pursued in other areas. This spring, biotech company Discovery Laboratories Inc. of Warrington, Pa., expects to win FDA approval to market a synthetic lung treatment, Surfaxin, for respiratory diseases in premature babies. It hopes to compete with North Chicago-based Abbott Laboratories‘ cow-derived product known as Survanta.
Proponents of synthetics claim they’re safer. “Animal-derived products carry the risk of developing an immune response,” said Thomas Miller, senior vice president of commercial operations for Discovery.
Analysts said Surfaxin, once it’s approved by the FDA, could be $200 to $400 a vial more expensive than Abbott’s product, and Discovery will have to convince insurance companies the expense is worth it. But Miller believes doctors and hospitals will find it as a long-overdue alternative.
“If it was my child, this would be my choice,” Miller said. “I don’t think cost would be at the top of my mind in my decision analysis.”
Abbott, however, said “there is no evidence that synthetic sources are inherently safer or more efficacious than naturally derived ones.”
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