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Monday, April 30, 2007

International Diabetes Federation (IDF): Consensus statement on Type 2 diabetes prevention

International Diabetes Federation (IDF): Consensus statement on Type 2 diabetes prevention

The International Diabetes Federation (IDF) has issued a consensus statement on the prevention of type 2 diabetes in both the developed and the developing world. The consensus statement advises that prevention of Type 2 diabetes is based on controlling modifiable risk factors and can be divided into two target groups:

  • People at high risk of developing Type 2 diabetes
  • The entire population
In planning national measures for the prevention of Type 2 diabetes, it is recommended that both groups should be targeted simultaneously with lifestyle modification the primary goal through a stepwise approach. For identifying people at high risk, the IDF recommends the use of opportunistic screening by health-care personnel including those working in general practice, nurses and pharmacists.

The IDF recommends that lifestyle modification should be the first choice to prevent or delay diabetes. With respect to drugs, the following is recommended (directly from source):
  • The IDF recommends that when lifestyle intervention alone has not achieved the desired weight loss, and/or improved glucose tolerance goals, as set by the health-care provider, metformin in the dose of 250–850 mg b.i.d. (depending on tolerance) should be considered as a diabetes prevention strategy (particularly in those aged less than 60 years with a BMI > 30 kg/m2 (greater than 27 kg/m2 in certain ethnic populations) and a FPG > 6.1 mmol/l or 110 mg/dl who do not have any contraindications).
  • Acarbose is also worthy of consideration for those who can tolerate it.
  • PPAR gamma agonists such as rosiglitazone have shown promising results, but concerns must remain about side-effects including weight gain and congestive heart failure as well as durability, and so we do not recommend them for routine use at present.
  • A further option for the obese might be orlistat.
  • Similarly, newer agents such as rimonabant show some promise, but long-term safety and specific diabetes preventive efficacy data are lacking and are not currently recommended for diabetes prevention in those at increased risk. The IDF working group awaits with interest the results of ongoing studies into newer therapies.

The announcement from the IDF is here; and the Consensus has been published in Diabetic Medicine 2007: 24; 451-63 (link to abstract, full text available free at time of posting)

Waking up from the DREAM of preventing diabetes with drugs

Waking up from the DREAM of preventing diabetes with drugs

The authors of this “Analysis” article discuss the research investigating whether drugs can reduce an individual’s risk of developing diabetes. In particular, they note that the recent DREAM trial found rosiglitazone decreased the risk of diabetes in people at risk and this has led to the promotion of rosiglitazone for the prevention of diabetes. However, they argue that strategies such as this “will bring harms and additional costs while the benefits for patients remain questionable.”

The following topics are discussed in the article:

  • Preventing diabetes
  • Effectiveness of drugs
  • Use of a composite end point
  • Are patients better off taking pills to prevent diabetes?
  • Downsides of taking pills to prevent diabetes
  • Benefits of diabetes prevention with glitazones
The authors conclude, “Because of the risk of harming people with no or minimal symptoms, the threshold for use of drugs in otherwise healthy people must be set high. To get the required data for rosiglitazone requires large and long randomised controlled trials measuring its effect on outcomes important to patients and use of healthcare resources. Clinical use of glitazones to prevent diabetes is, at present, impossible to justify because of unproved benefit on patient important outcomes or lasting effect on serum glucose, increased burden of disease labelling, serious adverse effects, increased economic burden, and the availability of effective and less costly lifestyle measures”.

The main summary points (taken directly from the article) are provided below:
  • Lifestyle changes and certain drugs are effective in preventing the diagnosis of diabetes
  • No trial has shown that prevention with drugs improves outcomes important to patients
  • Lifestyle changes are equally effective, much safer, and cheaper
  • Clinical use of glitazones for prevention cannot be justified

Br Med J 2007; 334: 882-4 (link to extract);
BBC News report (
Anti-diabetes pills 'unjustified')

Chromium supplements don't seem to have any benefit in type 2 diabetes

Chromium supplements don't seem to have any benefit in type 2 diabetes

A controlled trial found no benefits from adding chromium, in the form of chromium yeast, to standard therapy in patients with type 2 diabetes. Chromium is known to be an important trace mineral with a role in glucose metabolism, and as a result it is widely touted as supplement with potential benefits for people with diabetes. Previous controlled trials have been equivocal, and systematic results have concluded that the effects of chromium on diabetic control are inconclusive. One form of chromium that was widely used, chromium picolinate, has been banned due to concerns over its toxicity: this study aimed to determine whether an alternative form, chromium-enriched brewers yeast, had any benefits. Patients enrolled were from one area in the Netherlands and had type 2 diabetes moderately-well controlled on oral hypoglycaemic agents. They were randomised to treatment with a supplement containing chromium yeast equivalent to 400micrograms daily or placebo; study duration was six months, and the primary outcome was change in levels of haemoglobin A1c (HbA1c).

A total of 57 patients was randomised, of whom one did not complete the study. In the remainder, there was no difference between the active and placebo groups in the primary outcome, or in any of the secondary outcomes measured. One patient in each group reported adverse effects: nausea with chromium yeast and 'non-specific stomach problems' with the placebo. The authors conclude that chromium supplementation using chromium yeast had no effect on glycaemic control in their population of moderately well controlled Western patients with type 2 diabetes. They note that patients were not selected on the basis of chromium deficiency, as there is currently no consensus on what this might be; they also note that treatment duration was only six months. On the basis of current evidence, however, they suggest that there is no reason to recommend chromium therapy in Western patients treated with oral hypoglycaemic agents or insulin.

Diabetes Care 2007; 30: 1092-6 (link to abstract)

Review: Assessment and management of severe asthma in adults in hospital

Review: Assessment and management of severe asthma in adults in hospital

The fifth instalment of a series of review articles on acute asthma exacerbations has been published in Thorax. This review covers the assessment and management of severe asthma in adults in hospital, under the following headings:

  • History
  • Clinical examination
  • Assessment (lung function tests, oxygen assessment and other tests)
  • Management (oxygen, NIPPV, inhaled bronchodilators, intravenous bronchodilators, systemic corticosteroids, inhaled corticosteroids)
  • Response to treatment
  • ICU transfer
  • Ward admission
  • Discharge arrangements
  • Assessment sheets and treatment protocols
The authors note the following key points:
  • The management of asthma in the emergency department can be improved through the use of simple assessment and treatment protocols.
  • Assessment of asthma severity should be based primarily on the measurement of FEV1, expressed as the percentage of normal predicted values.
  • For most patients, initial treatment with high-flow oxygen, nebulised beta-agonists and oral corticosteroids is sufficient.
  • Currently available evidence does not support the routine use of intravenous theophylline or intravenous beta-agonist treatment in acute asthma; magnesium is the preferred intravenous bronchodilator in life-threatening asthma.
  • Patients with any feature of a severe attack persisting after initial treatment should be admitted; patient circumstances should also be considered.
  • For patients who are discharged, long-term management should be reviewed and medical follow-up arranged.

Thorax 2007; 62: 447-58 (link to abstract)

Wednesday, April 25, 2007

Anti-secretory agents - especially PPI - and nitrates reduce NSAID-associated GI bleeding

Anti-secretory agents - especially PPI - and nitrates reduce NSAID-associated GI bleeding

A large epidemiological study suggests that anti-secretory drugs reduce the risk of gastro-intestinal bleeding in patients taking NSAID, as do nitrates, however proton-pump inhibitors (PPI are much the most effective. The authors note that gastro-intestinal bleeding is a major risk with NSAID therapy, a problem for which various strategies are suggested. Use of COX-2 selective agents has been recommended, however drug withdrawals and reported cardiovascular problems with this group has reduced their popularity. Misoprostol has proven benefit, but is poorly tolerated by many people. Anti-secretory agents are widely used, but the evidence for their protective effects is weaker, and some experimental work suggests that organic nitrates may have clinically useful benefit.

This study was carried out to determine which agents were effective in reducing the risk of upper GI peptic ulcer bleeds associated with nonselective NSAIDs, aspirin and other antiplatelet agents, and anticoagulants. It was a case-control study, with prospective case determination and retrospective data collection, carried out during 2001 to 2004 and using data collected from Spanish hospital associated with a gastroenterology network. Cases were adults hospitalised with confirmed upper GI peptic ulcer bleeding: each case was matched with two controls by age, hospital and admission month, admitted or seen in outpatients for any condition not related to NSAID use, any GI bleeding, and cardiovascular or joint diseases. Cases and controls were classified as having a history of ulcer, dyspepsia, or neither. Current relevant drug use included NSAID, aspirin or other antiplatelet drugs, anticoagulants, PPI, histamine-2 receptor antagonists, and any nitrate.

A total of 2,777 patients were matched with 5,532 controls. Unsurprisingly, use of NSAID (including aspirin) was associated with increased risk of peptic ulcer bleeding, as was use of antiplatelet agents and anticoagulants. PPI, histamine-2 blockers, and nitrates all reduced the risk of peptic ulcer bleeding, with relative risks compare to non-use of 0.33, 0.65, and 0.52 respectively. Use of PPI was associated with greatest risk reductions for NSAID and antiplatelet drugs, however no agent reduced the risk with oral anticoagulants. There was no difference between omeprazole and other PPI.

Based on their analysis, the authors conclude that all three drug groups - PPI, histamine-2 blockers, and nitrates - reduce the risk of peptic ulcer bleeding in patients taking NSAID and antiplatelet drugs. PPI, however, gave the most marked and consistent reduction in risk. None of the drugs studied reduce the risk associated with oral anticoagulants.

Am J Gastroenterol 2007;102:507-15 (link to abstract); from Reuters Health for 25th April 2007, via Medscape (free registration required)

Tuesday, April 24, 2007

Follow-up, and continuity of care important in ensuring medication adherence

Follow-up, and continuity of care important in ensuring medication adherence

Patients who stop taking statins are more likely to re-start if they have good follow-up and they see the same doctor who originally prescribed for them, according to a study published today. The authors note that adherence to prescribed statins is relatively poor, with many patients stopping them within a year of initiation. They therefore attempted to determine some of the factors that result in patients re-starting treatment using a case-crossover study design.

Data on new users of a statin were obtained from healthcare databases in British Columbia, Canada, Medication dispensing for these individuals was then followed to determine those who became non-adherent, defined as 90 days from finishing one supply to having a new one dispensed. These individuals were then followed to determine what factors prompted re-starting statin use.

Between January 1997 and June 2004, a total of 253,951 patients were started on a statin. After exclusions (mainly those started on cerivastatin), there were 239,911 studied. Of these, over half had (129,167, 53.8%) had a period of non-adherence that lasted for at least 90 days. About half of these (48%) restarted within a year of stopping, and 60% within two years. The factor most strongly associated with re-starting was, perhaps not surprisingly, incident MI - the odds ratio for re-starting after MI was 12.2 (95% CI, 8.9-16.9) - although the number of actual events was small. Numerically, the most frequent factor was visiting any doctor (OR, 2.9; 95% CI, 2.8-3.0), and visiting the doctor who started the statin was the second-strongest factor (OR 6.1; 95% CI, 5.9-6.3). Having a cholesterol test and hospital admission for any other cardiovascular condition were also factors.

The authors conclude that patients frequently interrupt statin use, with long periods of non-adherence. The most important factor in re-starting use is visiting the doctor who originally started the therapy, especially when the visit is combined with a cholesterol test. The message therefore, is that regular follow-up and continuity of care are major factors likely to improve long-term adherence to statins.

Arch Intern Med 2007; 167: 847-52 (link to abstract)

Monday, April 23, 2007

Dietary sodium reduction seems to reduce cardiovascular events long term

Dietary sodium reduction seems to reduce cardiovascular events long term

According to the findings of this long term follow up study, sodium reduction, previously shown to lower blood pressure, may also reduce long term risk of cardiovascular events. The study followed up participants in two randomised lifestyle intervention trials - the trials of hypertension prevention I (TOHP I) and II (TOHP II) - for subsequent cardiovascular outcomes. The original trials found small but significant direct effects of sodium reduction on reducing blood pressure in adults with high normal blood pressure. TOHP I involved 10 clinic sites between 1987-90 and TOHP II involved 9 sites between 1990-5.

In this study, the authors determined the long term effects, over a period of 10-15 years, of sodium reduction on cardiovascular disease and mortality. Data was collected on all events occurring since the end of the original trials. A co-ordinating centre conducted the follow-up centrally by mail and phone. Questionnaires (seeking detailed information on cardiovascular and other health outcomes) were posted in January 2000, followed by phone calls as needed. Additional questionnaires were sent to responders at two year intervals through early 2005. The primary outcome measure used in the study was cardiovascular disease, a composite of myocardial infarction, stroke, coronary artery bypass graft (CABG), percutaneous transluminal coronary angioplasty (PTCA), or death with a cardiovascular cause. In the original studies, 744 participants in TOHP I and 2382 in TOHP II were randomised to a sodium reduction intervention or control.

The results found:

  • Follow-up information on cardiovascular outcomes or death was obtained for 2415 participants (77%).
  • 200 participants reported a cardiovascular event. Risk of a cardiovascular event was 25% lower among those in the intervention group (relative risk 0.75, 95% confidence interval 0.57 to 0.99, P=0.04), adjusted for trial, clinic, age, race, and sex
  • The risk was 30% lower after further adjustment for baseline sodium excretion and weight (0.70, 0.53 to 0.94), with similar results in each trial.
  • In secondary analyses, it was found 67 of the total 3126 participants died; 35 in the intervention groups and 42 in the comparison groups. After adjustment for baseline characteristics, including weight and sodium excretion, there was a 20% lower mortality among those in the sodium reduction intervention (0.80, 0.51 to 1.26, P=0.34 – not significant).
The authors note limitations of their study, including the lack of direct measurement of blood pressure, weight, and sodium intake during follow-up. They also note the less than complete rate of follow up, although add that the rates were high (77% for morbidity and 100% for mortality).

[Editor's note: to add perspective, the relative reduction in cardiovascular events is similar to that associated with statins - but with no significant adverse effects. Applied across the whole population, the absolute risk reduction would be small, nevertheless because of the numbers involved the reduction in cardiovascular events would be large. A modelling paper published last October looked at this issue and gives an indication of the potential differences between interventions in populations and interventions in at-risk individuals.]

Br Med J, published early online 20 April 2007; doi:10.1136/bmj.39147.604896.55 (link to abstract)

Delivering Diabetes care in Africa

Delivering diabetes care in Africa

Diabetes is a difficult disease to treat even with the best drugs and support, and in most parts of Africa the problems are enormous. Even regular supplies of insulin are often difficult to maintain. The range of tablets is limited, and self-monitoring equipment absent. Specialist doctors are few, as are nurse educators, chiropodists, and dieticians. Glycosylated haemoglobin (HbAlc) – ‘the gold standard’ test for overall glycaemic control – is usually too difficult and expensive to provide, and specialist services for complications are well beyond health budget capabilities, (e.g. laser photocoagulation, dialysis, and

Unsurprisingly, most people with diabetes in the African continent rely on rudimentary services from local doctors or nurses, or, if they are fortunate, may be able to access a Diabetic Clinic - usually only available at major teaching centres. Even at these hospitals, the services offered are severely hampered by the shortages described above.

There have, however, been recent attempts to improve Diabetes care delivery in some parts of Africa by a variety of partnership projects, eg. The London-based Tropical Health and Education Trust (THET) has been supporting devolved care of diabetes, and other non-communicable diseases, in the Gondar area of Ethiopia. In South Africa, the Liverpool School of Tropical Medicine has been linking with Hlabisa Hospital in Kwazulu Natal to promote nurse-led protocol-based diabetes care at both central and primary health clinic (PHC) levels.

In a recent issue of the British Medical Journal, Kaushik Ramaiya reports on a larger and more ambitious diabetes care delivery system from Tanzania. External support has been provided mostly by Novo Nordisk’s World Partnership Programme, but the Tanzanian Ministry of Health has also given help. Diabetes clinics have been established in all major hospitals in the country, as well as on the offshore islands of Zanzibar and Pemba. The Tanzanian Diabetes Association has also played a major part in the reorganisation, including the establishment of healthcare worker training programmes.

Ramaiya points out that current predictions suggest that within the next 20 v-ears non-communicable disease mortality will exceed infective deaths. The setting up of appropriate and efficient diabetes care delivery systems now will help to combat this growing problem.

Ref:
African Health: Medicine Review – Delivering Diabetes care in
Africa. Medical Education Resource Africa MERA, May 2005, p.25.
Ramaiya K. Tanzania and Diabetes – a model for developing countries?
British Med J 2005; 330: 679.

Thursday, April 19, 2007

Asthma (3)

Asthma - Epidemiology

Asthma is usually diagnosed in childhood. The risk factors for asthma include:

  • a personal or family history of asthma or atopy;
  • triggers (see Asthma Pathophysiology);
  • premature birth or low birth weight;
  • viral respiratory infection in early childhood;
  • maternal smoking;
  • being male, for asthma in prepubertal children; and
  • being female, for persistence of asthma into adulthood.

There is a reduced occurrence of asthma in people who were breast-fed as babies. Current research suggests that the prevalence of childhood asthma has been increasing. According to the Centers for Disease Control and Prevention 's National Health Interview Surveys, some 9% of US children below 18 years of age had asthma in 2001, compared with just 3.6% in 1980. The World Health Organization (WHO) reports that some 8% of the Swiss population suffers from asthma today, compared with just 2% some 25–30 years ago. Although asthma is more common in affluent countries, it is by no means a problem restricted to the affluent; the WHO estimate that there are between 15 and 20 million asthmatics in India. In the U.S., urban residents, Hispanics, and African Americans are affected more than the population as a whole. Globally, asthma is responsible for around 180,000 deaths annually.

On the island Tristan da Cunha , 50% of the population are asthmatics due to heredity transmission of a mutation in the gen CC16.

Socioeconomic factors

The incidence of asthma is higher among low-income populations, which in the western world are disproportionately minority, and more likely to live near industrial areas. Additionally, asthma has been strongly associated with the presence of cockroaches in living quarters, which is more likely in such neighbourhoods.

The quality of asthma treatment varies along racial lines, likely because many low-income people cannot afford health insurance and because there is still a correlation between class and race. For example, black Americans are less likely to receive outpatient treatment for asthma despite having a higher prevalence of the disease. They are much more likely to have emergency room visits or hospitalization for asthma, and are three times as likely to die from an asthma attack compared to whites. The prevalence of "severe persistent" asthma is also greater in low-income communities compared with communities with better access to treatment.

Asthma and athletics

Asthma appears to be more prevalent in athletes than in the general population. One survey of participants in the 1996 Summer Olympic Games showed that 15% had been diagnosed with asthma, and that 10% were on asthma medication. These statistics have been questioned on at least two bases. Persons with mild asthma may be more likely to be diagnosed with the condition than others because even subtle symptoms may interfere with their performance and lead to pursuit of a diagnosis. It has also been suggested that some professional athletes who do not suffer from asthma claim to do so in order to obtain special permits to use certain performance-enhancing drugs.

There appears to be a relatively high incidence of asthma in sports such as cycling, mountain biking, and long-distance running , and a relatively lower incidence in weightlifting and diving. It is unclear how much of these disparities are from the effects of training in the sport, and from self-selection of sports that may appear to minimize the triggering of asthma.

In addition, there exists a variant of asthma called exercise-induced asthma that shares many features with allergic asthma. It may occur either independently, or concurrent with the latter. Exercise studies may be helpful in diagnosing and assessing this condition.

Thank you.

Asthma (2)

Asthma

Asthma is a disease of the respiratory system in which the airways constrict, become inflamed, and are lined with excessive amounts of mucus, often in response to one or more "triggers," such as exposure to an environmental stimulant (or allergen ), cold air, exercise , or emotional stress. In children, the most common triggers are viral illnesses such as those that cause the common cold. This airway narrowing causes symptoms such as wheezing, shortness of breath , chest tightness, and coughing, which respond to bronchodilators. Between episodes, most patients feel fine.

Asthma - Diagnosis

In most cases, a physician can diagnose asthma on the basis of typical findings in a patient's clinical history and examination. Asthma is strongly suspected if a patient suffers from eczema or other allergic conditions—suggesting a general atopic constitution —or has a family history of asthma. While measurement of airway function is possible for adults, most new cases are diagnosed in children who are unable to perform such tests. Diagnosis in children is based on a careful compilation and analysis of the patient's medical history and subsequent improvement with an inhaled bronchodilator medication. In adults, diagnosis can be made with a peak flow meter (which tests airway restriction), looking at both the diurnal variation and any reversibility following inhaled bronchodilator medication .

Testing peak flow at rest (or baseline) and after exercise can be helpful, especially in young asthmatics who may experience only exercise-induced asthma. If the diagnosis is in doubt, a more formal lung function test may be conducted. Once a diagnosis of asthma is made, a patient can use peak flow meter testing to monitor the severity of the disease.

Differential diagnosis

Before diagnosing someone as asthmatic, alternative possibilities should be considered. A physician taking a history should check whether the patient is using any known bronchoconstrictors (substances that cause narrowing of the airways, e.g., certain anti-inflammatory agents or beta-blockers).

Chronic obstructive pulmonary disease , which closely resembles asthma, is correlated with more exposure to cigarette smoke, an older patient, less symptom reversibility after bronchodilator administration (as measured by spirometry ), and decreased likelihood of family history of atopy.

Pulmonary aspiration , whether direct due to dysphagia (swallowing disorder) or indirect (due to acid reflux), can show similar symptoms to asthma. However, with aspiration, fevers might also indicate aspiration pneumonia . Direct aspiration (dysphagia) can be diagnosed by performing a Modified Barium Swallow test and treated with feeding therapy by a qualified speech therapist . If the aspiration is indirect (from acid reflux) then treatment directed at this is indicated.

Only a minority of asthma sufferers have an identifiable allergy trigger. The majority of these triggers can often be identified from the history; for instance, asthmatics with hay fever or pollen allergy will have seasonal symptoms, those with allergies to pets may experience an abatement of symptoms when away from home, and those with occupational asthma may improve during leave from work. Occasionally, allergy tests are warranted and, if positive, may help in identifying avoidable symptom triggers.

After pulmonary function has been measured, radiological tests, such as a chest X-ray or CT scan , may be required to exclude the possibility of other lung diseases. In some people, asthma may be triggered by gastroesophageal reflux disease , which can be treated with suitable antacids . Very occasionally, specialized tests after inhalation of methacholine - or, even less commonly, histamine — may be performed.

Asthma is categorized by the NIH Heart Lung and Blood Institute as falling into one of four categories: mild intermittent, mild persistent, moderate persistent and severe persistent. The diagnosis of "severe persistent asthma" occurs when symptoms are continual with frequent exacerbations and frequent nighttime symptoms, result in limited physical activity and when lung function as measured by PEV or FEV1 tests is less than 60% predicted with PEF variability greater than 30%.


Asthma - Pathophysiology

Bronchoconstriction

During an asthma episode, inflamed airways react to environmental triggers such as smoke, dust, or pollen. The airways narrow and produce excess mucus , making it difficult to breathe.

In essence, asthma is the result of an abnormal immune response in the bronchial airways. The airways of asthmatics are " hypersensitive " to certain triggers, also known as stimuli. In response to exposure to these triggers, the bronchi (large airways) contract into spasm (an "asthma attack"). Inflammation soon follows, leading to a further narrowing of the airways and excessive mucus production, which leads to coughing and other breathing difficulties.

There are seven categories of stimuli:

  • allergens , typically inhaled, which include waste from common household insects, such as the house dust mite and cockroach , grass pollen , mould spores and pet epithelial cells;
  • medications , including aspirin and ß-adrenergic antagonists (beta blockers);
  • air pollution , such as ozone , nitrogen dioxide , and sulfur dioxide , which is thought to be one of the major reasons for the high prevalence of asthma in urban areas;
  • various industrial compounds and other chemicals, notably sulfites; chlorinated swimming pools generate chloramines —monochloramine (NH 2 Cl), dichloramine (NHCl 2) and trichloramine (NCl 3)—in the air around them, which are known to induce asthma.
  • early childhood infections, especially viral respiratory infections. However, persons of any age can have asthma triggered by colds and other respiratory infections even though their normal stimuli might be from another category (e.g. pollen) and absent at the time of infection.
  • exercise, the effects of which differ somewhat from those of the other triggers; and
  • emotional stress, which is poorly understood as a trigger.

Bronchial inflammation

The mechanisms behind allergic asthma—i.e., asthma resulting from an immune response to inhaled allergens —are the best understood of the causal factors. In both asthmatics and non-asthmatics, inhaled allergens that find their way to the inner airways are ingested by a type of cell known as antigen presenting cells, or APCs. APCs then "present" pieces of the allergen to other immune system cells. In most people, these other immune cells ( T H 0 cells ) "check" and usually ignore the allergen molecules. In asthmatics, however, these cells transform into a different type of cell (T H 2), for reasons that are not well understood. The resultant T H 2 cells activate an important arm of the immune system, known as the humoral immune system . The humoral immune system produces antibodies against the inhaled allergen. Later, when an asthmatic inhales the same allergen, these antibodies "recognize" it and activate a humoral response . Inflammation results: chemicals are produced that cause the airways to constrict and release more mucus, and the cell-mediated arm of the immune system is activated. The inflammatory response is responsible for the clinical manifestations of an asthma attack. The following section describes this complex series of events in more detail.

Pathogenesis

The fundamental problem in asthma appears to be immunological : young children in the early stages of asthma show signs of excessive inflammation in their airways. Epidemiological findings give clues as to the pathogenesis : the incidence of asthma seems to be increasing worldwide, and asthma is now very much more common in affluent countries.

In 1968 Andor Szentivanyi first described The Beta Adrenergic Theory of Asthma; in which blockage of the Beta-2 receptors of pulmonary smooth muscle cells causes asthma. Szentivanyi's Beta Adrenergic Theory is a citation classic [10] and has been cited more times than any other article in the history of the Journal of Allergy.

In 1995 Szentivanyi and colleagues demonstrated that IgE blocks Beta2 receptors. Since overproduction of IgE is central to all atopic diseases, this was a watershed moment in the world of Allergy.

The Beta-Adrenergic Theory has been cited in the scholarship of such noted investigtors as Richard Lockey (former President of The American Academy of Allergy, Asthma, and Immunology), Charles Reed (Chief of Allergy at Mayo Medical School), and Craig Venter (Human Genome Project).

One theory of pathogenesis is that asthma is a disease of hygiene. In nature, babies are exposed to bacteria and other antigens soon after birth, "switching on" the T H 1 lymphocyte cells of the immune system that deal with bacterial infection. If this stimulus is insufficient—as it may be in modern, clean environments—then T H 2 cells predominate, and asthma and other allergic diseases may develop. This " hygiene hypothesis " may explain the increase in asthma in affluent populations. The T H 2 lymphocytes and eosinophil cells that protect us against parasites and other infectious agents are the same cells responsible for the allergic reaction. In the developed world, these parasites are now rarely encountered, but the immune response remains and is wrongly triggered in some individuals by certain allergens.

Another theory is based on the correlation of air pollution and the incidence of asthma. Although it is well known that substantial exposures to certain industrial chemicals can cause acute asthmatic episodes, it has not been proven that air pollution is responsible for the development of asthma. In Western Europe , most atmospheric pollutants have fallen significantly over the last 40 years, while the prevalence of asthma has risen.

Finally, it has been postulated that some forms of asthma may be related to infection, in particular by Chlamydia pneumoniae . This issue remains controversial, as the relationship is not borne out by meta-analysis of the research. The correlation seems to be not with the onset, but rather with accelerated loss of lung function in adults with new onset of non-atopic asthma. One possible explanation is that some asthmatics may have altered immune response that facilitates long-term chlamydia pneumonia infection.] The response to targeting with macrolide antibiotics has been investigated, but the temporary benefit reported in some studies may reflect just their anti-inflammatory activities rather than their antimicrobic action.

Asthma and Sleep Apnea

It is recognized with increasing frequency, that patients who have both obstructive sleep apnea (OSA) and bronchial asthma, often improve tremendously when the sleep apnea is diagnosed and treated. Individuals who have OSA have repetitive episodes of upper airway closure during sleep. Upper airway clossure results in low arterial oxygen levels and CO 2 retention, both of which stimulate the respiratory center. The patient makes increasingly stronger efforts to breathe, which only worsens the upper airway collapse ("like sucking a thick milkshake through a straw"). When the patient starts arousing and the pharyngeal muscles recover their tone, the airway suddenly opens up, airflow is suddenly restored (manifested as a loud "heroic" gasping breath), during which contents of the oropharynx may be aspirated. If gastro-esophageal reflux disease is present, the patient may have repetitive episodes of acid aspiration, which results in airway inflammation and "irritant-induced" asthma.

Treatment, Epidemiology.

To be continued . . .


Asthma

Asthma

Asthma is a disease of the respiratory system in which the airways constrict, become inflamed, and are lined with excessive amounts of mucus, often in response to one or more "triggers," such as exposure to an environmental stimulant (or allergen ), cold air, exercise , or emotional stress. In children, the most common triggers are viral illnesses such as those that cause the common cold. This airway narrowing causes symptoms such as wheezing, shortness of breath , chest tightness, and coughing, which respond to bronchodilators. Between episodes, most patients feel fine.

Asthma

The Asthma disorder is a chronic or recurring inflammatory condition in which the airways develop increased responsiveness to various stimuli, characterized by bronchial hyper-responsiveness, inflammation, increased mucus production, and intermittent airway obstruction. The symptoms of asthma, which can range from mild to life threatening, can usually be controlled with a combination of drugs and lifestyle changes.

Public attention in the developed world has recently focused on asthma because of its rapidly increasing prevalence, affecting up to one in four urban children. Susceptibility to asthma can be explained in part by genetic factors, but no clear pattern of inheritance has been found. Asthma is a complex disease that is influenced by multiple genetic, developmental, and environmental factors, which interact to produce the overall condition.


Asthma - Symptoms

In some individuals, asthma is characterized by chronic respiratory impairment. In others it is an intermittent illness marked by episodic symptoms that may result from a number of triggering events, including upper respiratory infection, airborne allergens, and exercise.

An acute exacerbation of asthma is referred to as an asthma attack. The clinical hallmarks of an attack are shortness of breath ( dyspnea ) and wheezing. Although the latter is "often regarded as the sine qua non of asthma," some victims present primarily with coughing, and in the late stages of an attack, air motion may be so impaired that no wheezing may be heard. When present the cough may sometimes produce clear sputum. The onset may be sudden, with a sense of constriction in the chest, breathing becomes difficult, and wheezing occurs (primarily upon expiration, but can be in both respiratory phases).

Signs of an asthmatic episode are wheezing, rapid breathing ( tachypnea ), prolonged expiration, a rapid heart rate ( tachycardia ), rhonchous lung sounds ( audible through a stethoscope ), and over-inflation of the chest. During a serious asthma attack, the accessory muscles of respiration (sternocleidomastoid and scalene muscles of the neck) may be used, shown as in-drawing of tissues between the ribs and above the sternum and clavicles , and the presence of a paradoxical pulse (a pulse that is weaker during inhalation and stronger during exhalation). During very severe attacks, an asthma sufferer can turn blue from lack of oxygen, and can experience chest pain or even loss of consciousness. Severe asthma attacks may lead to respiratory arrest and death. Despite the severity of symptoms during an asthmatic episode, between attacks an asthmatic may show few signs of the disease.


Diagnosis, Pathophysiology, Treatment, Epidemiology.

To be continued. . .



Omeprazole before endoscopy beneficial in patients with gastrointestinal bleeding

Omeprazole before endoscopy beneficial in patients with gastrointestinal bleeding

A study published in the New England Journal of Medicine has evaluated the effect of pre-emptive infusion of omeprazole before endoscopy on the need for endoscopic therapy.

Over a 17-month period, consecutive patients admitted with upper GI bleeding were stabilised and then randomised to omeprazole 80-mg IV bolus followed by 8mg/hour infusion (n= 319) or matching placebo (n= 319) before endoscopy the next morning.

The following findings were reported:

  • Need for endoscopic treatment was lower in the omeprazole compared with placebo group (60 of 314 patients included in analysis [19.1%] vs. 90 of 317 patients [28.4%], p = 0.007).
  • There were no significant differences between the omeprazole and placebo group in:
  • mean amount of blood transfused (1.54 and 1.88 units)
  • number of patients who had recurrent bleeding (11 and 8),
  • number who underwent emergency surgery (3 and 4),
  • number who died within 30 days (8 and 7)
  • Hospital stay was < p =" 0.005).">
  • On endoscopy, fewer patients on omeprazole had actively bleeding ulcers (12 of 187, vs. 28 of 190 in the placebo group; p = 0.01) and more omeprazole-treated patients had ulcers with clean bases (120 vs. 90, p = 0.001).
The study concluded “infusion of high-dose omeprazole before endoscopy accelerated the resolution of signs of bleeding in ulcers and reduced the need for endoscopic therapy.”

N Engl J Med 2007; 356: 1631-40 (link to abstract)

HRT and the incidence of ovarian and breast cancer

HRT and the incidence of ovarian and breast cancer

Two major epidemiological studies published today look at the possible increased risk of ovarian and breast cancers associated with hormone replacement therapy (HRT). They have, inevitably, generated significant media interest.

A study published early online by the Lancet found that current use of HRT for prolonged periods is associated with a 20% increase in risk of ovarian cancer. The authors used data from the Million Women Study, a large prospective cohort study of UK women aged 50 and over that is investigating a range of factors that affect women's health. Data collected at recruitment includes whether the woman is using HRT, confirmed by subsequent questionnaire three years later if possible. Each participant is followed-up for death, emigration, or cancer registration, so that relevant events are reported to the study investigators.

This analysis aimed to determine whether use of HRT affected risk of ovarian cancer; it involved women from the cohort who were post-menopausal, had no history of cancer or bilateral oophorectomy, and for whom data on use of HRT was available. They were followed for averages of 5.3 years for incident ovarian cancer and 6.9 years for death. Primary outcome of the analysis was relative risk for ovarian cancer, adjusted for a range of relevant factors.

A total of 1.3 million women were recruited into the Million Women Study cohort. Of these, 948, 576 were included in the analysis. When they last reported data to the study, 50% reported current or past use of HRT - 30% were current users and 20% past users: the two groups were fairly similar with only past use of oral contraceptives and hysterectomy being major differences between them (both higher in HRT users). Mean duration of use was 7.7 years.

There were 2,273 ovarian cancers in total and 1,591 deaths from ovarian cancer. Women who were current users of HRT had a statistically significant increase in risk both of ovarian cancer (relative risk 1.20, 95% CI 1.09 to 1.32; p=0.0002) and death from ovarian cancer (RR 1.23, 95% CI 1.09 to 1.32; p=0.0002). Risk increased with duration of use, however past users were not at significantly increased risk. Crude incidence rate in the study population as a whole was 2.2 per 1,000 women; in never-users it was 2.2 per 1,000, and in users 2.6 per 1000 (rates for death from ovarian cancer 1.3, 1.3, and 1.6 per 1,000 respectively). From these figures, assuming that the differences are due to HRT the authors calculate that over a five year period there would be about one extra case of ovarian cancer for every 2,500 users (and one extra death per 3,300 users).

The authors conclude that women who use HRT are at greater risk of ovarian cancer and of death due to it. The risk increases with duration of use: mean duration of use in the study population was 7.7 years and this was associated with a 20% increase in risk. It is related to current use, not past use, and falls back to baseline level soon after use is stopped. An accompanying Comment discusses the paper and its implications; the author discusses some potential mechanisms for the effect, and notes the difference between pre-menopausal use of the same hormones as oral contraceptives, which is protective, and the data on HRT. He notes that although the absolute increase in risk is small, the large number of women who used HRT until recently meant that the toll in terms of cancers and mortality was significant.

The second paper reports that the rate of breast cancer in the US fell appreciably in 2003 compared to the rate in 2002; while a number of explanations are possible, the decrease seems to be related to reporting of results from the Women's Health Initiative in 2002 that was followed by a decrease in HRT use among post-menopausal women in the US.
The authors use data from a program (SEER) run by the US National Cancer Institute: this collects data from nine cancer registries reporting on 9% of the total US population. Data from the registries were adjusted for reporting delays and standardised to the US female population in 2000. Annual incidence rates were plotted and compared to determine trends.

The results show a sharp fall in incidence of 6.7% in 2003 compared to 2002; the incidence stabilised in 2004 with little further decrease. Analysis showed that the decrease actually started in mid-2002 and had begun to level off by mid-2003, and comparison between 2001 and 2004 showed an overall decrease of 8.6% (95% CI 6.8 to 10.4%). The decrease was age-specific and occurred only in women aged over 50; there was no significant change in incidence in younger women. It was also primarily in oestrogen-receptor positive tumours. Examination of trends since 1975 showed a steady increase in women aged over 50 from the late 1970's onwards, with rates rising by about 0.5% per year during most of the 1990's. Rates in women under 50 were substantially the same over the whole of this period.

The authors discuss a number of possible reasons for the changed incidence, but conclude that reductions in HRT use are the most likely. There is evidence that stopping HRT may cause clinically occult oestrogen-receptor positive breast cancers to stop growing or even regress soon after withdrawal, and evidence of studies involving hormonal manipulation therapies (e.g. tamoxifen) supports this. HRT prescriptions in the US declined sharply during 2002 and 2003 and stabilised at a lower level in 2004, from around 60 million to 21 million prescriptions per year.

The MHRA has issued a statement on the two papers. The new evidence is being reviewed by experts, but is unlikely to result in major changes in current advice: this is that HRT is effective for short-term relief of menopausal symptoms but should be used in the lowest effective dose and the minimum duration.

Ovarian cancer study: Lancet, published early online 19 April 2007; DOI:10.1016/S0140-6736(07)60534-0 (link to abstract) and Lancet, published early online 19 April 2007; DOI:10.1016/S0140-6736(07)60535-2 (Comment; link to full text, may be available to subscribers only);
breast cancer study: New Engl J Med 2007; 356: 1670-4 (link to abstract, full text available free at time of posting)
The MHRA statement is available here
BBC News report;
there is full information on the Million Women Study on its website

Moderate-dose methylprednisolone effective for severe adult respiratory distress syndrome?

Moderate-dose methylprednisolone effective for severe adult respiratory distress syndrome?

According to the results of a randomised controlled trial (RCT) reported in the journal ‘Chest’, the use of early, moderate-dose, prolonged methylprednisolone therapy successfully down-regulates systemic inflammation, reduces organ dysfunction and improves outcome of patients with severe adult respiratory distress syndrome (ARDS).
The trial involved 91 patients in the ICUs of five hospitals in the US, who had severe early ARDS (within the first 72 hours); 66% had sepsis. Participants were randomised to receive methylprednisolone infusion (n=63) or placebo (n=28) for up to 28 days. Methylprednisolone was administered as a loading dose of 1 mg/kg followed by an infusion of 1 mg/kg/d from day 1 to day 14, 0.5 mg/kg/d from day 15 to day 21, 0.25 mg/kg/d from day 22 to day 25, and 0.125 mg/kg/d from day 26 to day 28. If the patient was extubated between days 1 and 14, the patient was advanced to day 15 of drug therapy and tapered according to schedule. Once enteral intake was resumed, the methylprednisolone was converted to a single oral dose. The study’s primary endpoint was a 1-point reduction in lung injury score (LIS) or successful extubation by day 7, and the results were analysed according to the intention-to-treat principle.

The main results were as follows:

  • At Day 7, 69.8% of those receiving active treatment achieved a 1-point reduction in LIS compared to 35.7% in the placebo group (p = 0.002)
  • At Day 7, 53.9% of those receiving active treatment were breathing without assistance versus 25.0% of the placebo group (p = 0.01).
  • Active treatment was also associated with improvements in various secondary endpoints including a reduction in the duration of mechanical ventilation (5 days versus 9.5 days; p = 0.002), ICU stay (7 days versus 14.5 days; p = 0.007), ICU mortality (20.6% versus 42.9%; p = 0.03) and a reduced rate of infections (p = 0.0002).
The authors conclude that “the findings of this study provide evidence that glucocorticoid treatment-induced down-regulation of systemic inflammation in ARDS is associated with a significant improvement in pulmonary and extrapulmonary organ dysfunction and a reduction in duration of mechanical ventilation and ICU length of stay. ….A larger trial is necessary to confirm the mortality findings of this study. In a future trial, we recommend adding stratification by shock at study entry, and strict implementation and monitoring of a ventilator and weaning protocol”.

Chest 2007;131:954-963 (link to abstract)

Impact of oral anti-hyperglycaemic therapy on all-cause mortality in diabetics

Impact of oral anti-hyperglycaemic therapy on all-cause mortality in diabetics

The authors of this retrospective study note that several observational studies have produced conflicting results on the effect of different classes of oral anti-hyperglycaemics on all-cause mortality. It has also been difficult to draw conclusions due to ‘confounding by indication’, whereby patients with more severe disease are exposed to more aggressive therapy and are more likely to suffer from an adverse outcome.

In the present study, researchers studied data from a cohort of patients with diabetes from the Veterans Health Administration (VHA). They sought to evaluate the impact of several classes of oral anti-hyperglycaemics relative to sulfonylurea monotherapy on overall mortality, adjusting for a number of confounding factors in an attempt to limit any confounding by indication.

All users of oral anti-hyperglycaemic therapy were identified (n=39,721) and classified into the following cohorts

  • sulfonylurea monotherapy (S)
  • metformin monotherapy (M)
  • metformin + sulfonylurea (MS)
  • TZD use alone or in combination with other oral agents (TZD; all users were pooled together as there were few deaths in the various sub-groups)
  • no drug therapy
The authors found no difference between all-cause mortality between the S cohort and any of the other treatment cohorts. The adjusted odds ratios (each group compared to S) were 0.87 (95% CI 0.68- 1.10) for M, 0.92 (0.82-1.05) for MS, and 1.04 (0.75-1.46) for TZD.

The authors note that the duration of retrospective data was a limitation of the study, and suggest that ‘future work should assess whether long-term exposure to oral anti-hyperglycaemic medications have the potential to reduce all-cause or cause-specific mortality.’

Tuesday, April 10, 2007

DRUGS in LACTATION; Breastfeeding mothers and medicines - general guidance

DRUGS in LACTATION

UK Drugs in Lactation Advisory Service

A joint service provided by the West Midlands and Trent Drug Information Services

Anti-asthma agents | Anti-coagulants | Anti-convulsants | Anti-depressants
Anti-diarrhoeals | Anti-histamines | Anti-hypertensives | Corticosteroids
Laxatives | Non-steroidal Anti-inflammatories | Vitamins

Breastfeeding mothers and medicines - general guidance

The following principles should be followed when prescribing for breastfeeding mothers :

  • Avoid unnecessary drug use and limit use of over-the-counter (OTC) products

  • Breastfeeding mothers should seek advice on the suitability of OTC products

  • Assess the benefit/risk ratio for both mother and infant

  • Avoid use of drugs known to cause serious toxicity in adults or children

  • Drugs licensed for use in infants do not generally pose a hazard

  • Neonates (and particularly premature infants) are at greater risk from exposure to drugs via breast milk, because of immature excretory functions and the consequent risk of drug accumulation

  • Choose a regimen and route of administration which presents the minimum amount of drug to the infant

  • It is best to avoid long-acting preparations, especially those of drugs likely to cause serious side effects (e.g. antipsychotic agents), as it is difficult to time feeds to avoid significant amounts of drug in breast milk

  • Multiple drug regimens may pose an increased risk especially when adverse effects such as drowsiness are additive

  • Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms

  • Avoid new drugs if a therapeutically equivalent alternative that has been more widely used is available. A robust assessment of the balance of benefit to risk requires data both on the drug's passage into breast milk and its effects in infants: there is rarely enough information available for new drugs to allow such an assessment to be made. If a drug with limited data is deemed to be clinically necessary or for any further information, contact the UK Drugs in Lactation Advisory Service for further advice - click here for contact details.

Tuesday, April 3, 2007

Metformin and Glimepiride: Safe and Effective short-term in paediatric type 2 diabetes

Metformin and Glimepiride: Safe and Effective short-term in paediatric type 2 diabetes

Metformin and Glimepiride have similar efficacy and safety over six months in children with type 2 diabetes, according to a controlled trial.

The authors of the study comment that the incidence of type 2 diabetes in children is increasing rapidly, and that as the course of the condition may be more aggressive in this patient group early control is important. There is therefore a need for data on the safety and efficacy of oral hypoglycaemic agents in children.

Metformin is licensed in the US for this age group, however there are no sulphonylureas so licensed; this study aimed to compare the safety and efficacy of the two drugs in a paediatric population. It involved children with type 2 diabetes who were not adequately controlled on their existing treatment. After two weeks stabilisation, participants were grouped by age (<12> 12 years) and randomised to either metformin or glimepiride for the 24 weeks study period (12 weeks titration, 12 weeks maintenance). Primary outcome was mean change in haemoglobin A1c (A1C) from baseline to week 24.

A total of 285 children were randomised, with a mean age of 13.8 (range 8 to 17) at randomisation; they were significantly obese, with a mean BMI of about 31.7kg/m2. Of these, 284 received at least one dose of study drug and were evaluated for safety: 283 took at least one dose and had at least one A1C measurement to allow assessment of efficacy, thus becoming the intention to treat population.

Significant reduction of A1C:
Both drug groups (Metformin and Glimepiride) had a significant reduction of A1C from baseline by week 24: for glimepiride the reduction was 0.54% and for METFORMIN 0.71% (both differences statistically significant from baseline). Values taken at week 12 were similar. One patient in each group had a severe hypoglycaemic episode; adverse event rates in the two groups were similar, and adverse event rates considered possibly due to the drug were 7.7% in the glimepiride group and 13.4% in the metformin group.

Weight gain with Glimepiride:
Patients in the glimepiride group gained body weight (increase in BMI 0.26 kg/m2) whereas those in the Metformin group lost weight (decrease in BMI 0.33 kg/m2).

Comparative effectiveness:
The authors conclude that glimepiride was as effective as metformin in controlling A1C levels and similarly tolerated, although it was associated with a greater degree of weight gain.

[Editor's comment: six months is a relatively short-term study of a therapy for type 2 diabetes. While glimepiride does control blood glucose over this period, the increase in weight in what was already an obese population would raise some concern.]

Diabetes Care 2007; 30: 790-4 (link to abstract)

Garlic maybe not so useful in Hypercholesterolemia after all?

Garlic maybe not so useful in Hypercholesterolemia after all?

A study published in the Archives of Internal Medicine has investigated the effect of raw garlic and two garlic supplements on cholesterol concentrations in adults with moderate hypercholesterolaemia.
The trial involved 192 adults with low-density lipoprotein cholesterol (LDL-C) concentrations of 3.36-4.91 mmol/L who were randomised to receive one of the following: raw garlic, powdered garlic supplement, aged garlic extract supplement, or placebo (the garlic supplement doses were equivalent to 1 average-sized garlic clove). The products were consumed 6 days a week for 6 months. The primary outcome measure was of LDL-C concentrations at 6 months.

The researchers reported that the 6-month mean (SD) changes in LDL-C concentrations were +0.01 [0.50] mmol/L for raw garlic, +0.08 [0.44] mmol/L for the powdered supplement, +0.005 [0.46] mmol/L for the extract supplement and –0.10 [0.43] mmol/L for placebo (all p = not significant). Additionally, there were no statistically significant effects on high-density lipoprotein cholesterol, triglyceride levels, or total cholesterol–high-density lipoprotein cholesterol ratio.

The researchers concluded that none of the forms of garlic used in this study provided a statistically or clinically significant effect on LDL-C or other plasma lipid concentrations in adults with moderate hypercholesterolemia.

In a related editorial, the author comments that although the researchers of the study demonstrate that raw garlic and 2 popularly used supplements do not reduce LDL-C more than 0.26 mmol/L when used for 6 months vs. placebo for 6 months, the results do not demonstrate that garlic has no usefulness in the prevention of cardiovascular disease.

Effect of raw garlic vs commercial garlic supplements on plasma lipid concentrations in adults with moderate hypercholesterolemia: a randomized clinical trial. Arch Intern Med 2007; 167: 346-53 (link to abstract); Arch Intern Med 2007; 167: 325-6 (editorial, link to extract)
BBC News report

Ibuprofen vs Paracetamol or Codeine for acute pain in children

Ibuprofen vs Paracetamol or Codeine for acute pain in children

A double-blind study published in Pediatrics has investigated the efficacy of single dose paracetamol, codeine and ibuprofen for children presenting with pain from acute musculoskeletal injuries.

Outcome data was presented for 300 patients aged 6 to 17 years who had suffered pain from a musculoskeletal injury (to extremities, neck, and back) that occurred in the preceding 48 hours before presentation in the emergency department. Patients were randomised to receive either 15 mg/kg paracetamol (n=100), 10 mg/kg ibuprofen (n=100), or 1 mg/kg codeine (n=100). The primary outcome was change in pain from baseline to 60 minutes after treatment with study medication as measured by using a visual analogue scale.

The researchers reported that:

  • Patients in the ibuprofen group had a significantly greater improvement in pain score (mean decrease: 24 mm) than those in the codeine group (mean decrease: 11 mm; p<0.001) p="0.001" p="0.98).
  • At 60 minutes more patients in the ibuprofen group achieved adequate analgesia (as defined by a visual analogue scale <30mm)>vs. codeine (p=0.85); paracetamol vs. ibuprofen (p=0.026); codeine versus ibuprofen (p=0.006) .
  • There was no significant difference between patients in the codeine and acetaminophen groups in the change in pain score at any time period or in the number of patients achieving adequate analgesia.

The researchers concluded that for the treatment of acute traumatic musculoskeletal injuries, ibuprofen provides the best analgesia among the 3 study medications.

Pediatrics. 2007 Mar;119 (3):460-7
Link to abstract

Ibuprofen best option for acute pain in children with musculoskeletal injuries?

Ibuprofen best option for acute pain in children with musculoskeletal injuries?

A double-blind study published in Pediatrics has investigated the efficacy of single dose paracetamol, codeine and ibuprofen for children presenting with pain from acute musculoskeletal injuries.

Outcome data was presented for 300 patients aged 6 to 17 years who had suffered pain from a musculoskeletal injury (to extremities, neck, and back) that occurred in the preceding 48 hours before presentation in the emergency department.

Patients were randomised to receive either 15 mg/kg paracetamol (n=100), 10 mg/kg ibuprofen (n=100), or 1 mg/kg codeine (n=100).

The primary outcome was change in pain from baseline to 60 minutes after treatment with study medication as measured by using a visual analogue scale.

The researchers reported that:

  • Patients in the ibuprofen group had a significantly greater improvement in pain score (mean decrease: 24 mm) than those in the codeine group (mean decrease: 11 mm; p<0.001) p="0.001)" p="0.98).
  • At 60 minutes more patients in the ibuprofen group achieved adequate analgesia (as defined by a visual analogue scale <30mm) p="0.85);" p="0.026);" p="0.006).">
  • There was no significant difference between patients in the codeine and acetaminophen groups in the change in pain score at any time period or in the number of patients achieving adequate analgesia.
The researchers concluded that for the treatment of acute traumatic musculoskeletal injuries, ibuprofen provides the best analgesia among the three study medications.

Pediatrics 2007; 119: 460-7 (link to abstract)

Clinical update - Post-Operative Pain

Clinical update - Post-Operative Pain

This article in the Lancet gives a brief and didactic overview of pain control in the postoperative (post-op) period. The authors note that poorly controlled and persistent pain after surgery does occur, and can result in a chronic pain state. It may also slow healing and increase the risk of complications.

They discuss appropriate methods of pain control following minor, intermediate, and major surgery.

After minor surgery, oral analgesia is normally sufficient, and they suggest paracetamol, NSAID, oxycodone, or tramadol as suitable agents.

Patients undergoing more extensive surgery may require parenteral analgesia, and more potent drugs including opioids, and they discuss the moat appropriate use of these.

They suggest that improved postoperative pain control can be helped by the use of simple multimodal regimens, and present a series of steps that could be used.

Lancet 2007; 369: 810-2 (link to full text, available to subscribers only).

Review: Asthma in pregnancy

Review: Asthma in pregnancy

This is the first in a series of occasional articles in the BMJ about how to manage a pre-existing medical condition during pregnancy. The article begins with a case scenario and addresses the following topics:

  • How common is asthma in pregnancy?
  • Does pregnancy affect asthma?
  • Does asthma affect pregnancy?
  • Management of asthma in pregnancy
  • Does asthma affect labour and delivery?
  • Does asthma affect postpartum period and breast feeding?
In terms of treatment, the article notes that it is safer to use asthma drugs in pregnancy than to leave asthma uncontrolled, as adverse perinatal outcomes are associated with uncontrolled asthma and reduced expiratory flow. Inhaled corticosteroids, theophylline, and short acting beta 2 agonists do not increase the risk of foetal congenital malformations, pre-eclampsia, preterm delivery, or low birth weight. The dose or regimen of asthma medications do not usually need to be changed in pregnancy.

Oral corticosteroids in the first trimester are associated with an increased risk of foetal cleft lip or palate. However, the increased incidence is small compared with the benefits of using such treatment and they should continue to be used in severe asthma and life threatening situations. Oral corticosteroids are also associated with preterm delivery and pre-eclampsia. Of note, 90% of prednisone is inactivated by the placenta, which limits foetal exposure and the risk of foetal withdrawal. Inhaled corticosteroids are safe in pregnancy, and they are not associated with foetal malformations or perinatal morbidity. Most studies in pregnancy have used budesonide, but the corticosteroid that was used successfully before pregnancy should be continued into childbirth.

Cromolyn sodium and short acting beta 2 agonists are safe to use during pregnancy. There are few data on long acting beta 2 agonists; salmeterol and formoterol have not been found to cause malformations, preterm delivery, or low birth weight in the limited number of women using them in prospective studies. Data on the safety of leukotriene modifiers in pregnancy are scarce therefore it seems reasonable to replace them with an inhaled corticosteroid at the start of pregnancy or with a long acting beta 2 agonist (if this is used as an "add on" therapy). Theophylline has been reported to be safe in human pregnancy at recommended doses; levels should be monitored because drug metabolism changes in pregnancy.

BMJ 2007; 334: 582-5 (link to extract)

Preventing Type-2 Diabetes in At-Risk People (ARP)

Preventing type 2 diabetes in at risk people - the evidence from trials

An editorial in the Annals of Internal Medicine discusses recent trials that studied four potential drug interventions to delay the onset of type 2 diabetes in people at risk.

The drugs studied are rosiglitazone, metformin, ramipril, and acarbose.

Metformin and Acarbose were shown to reduce the onset of diabetes in trials published in 2002 and the recently published DREAM trial found that rosiglitazone also seemed to do so but ramipril did not. This editorial primarily discusses DREAM.

The authors briefly describe the study, and noted that it showed rosiglitazone to be effective in reducing progression to diabetes while ramipril was not. They are concerned, however, over the adverse effect profile of rosiglitazone, with an increased incidence of peripheral oedema, weight gain, and heart failure.

Overall, they emphasized that lifestyle changes remain the first line for prevention of diabetes, as those that work also have many other health benefits. Where patients cannot adopt or maintain such changes, drug treatment may be considered: in this situation, the chosen drug must be safe, as it will be taken long term by many people who will not actually benefit. It must also be more cost-effective than delaying treatment until diabetes develops.

On these criteria, rosiglitazone fails and other medications must be considered. Acarbose is associated with a high incidence of withdrawal due to adverse effects, therefore the authors suggest that METFORMIN is the best option, being effective, generally well tolerated, and relatively low cost.

They warn, however, that the long term benefits and cost-effectiveness of this approach are unproven, and thus more trials are needed.

Ann Intern Med 2007; 146: 461-3 (link to full text, may be available only to subscribers)
There is a NeLM InFocus review of DREAM