Saline Nasal Irrigation for Upper Respiratory Conditions

Saline nasal irrigation is an adjunctive therapy for upper respiratory conditions that bathes the nasal cavity with spray or liquid saline. Nasal irrigation with liquid saline is used to manage symptoms associated with chronic rhino-sinusitis. Less conclusive evidence supports the use of spray and liquid saline nasal irrigation to manage symptoms of mild to moderate allergic rhinitis and acute upper respiratory tract infections. Consensus guidelines recommend saline nasal irrigation as a treatment for a variety of other conditions, including rhinitis of pregnancy and acute rhinosinusitis. Saline nasal irrigation appears safe, with no reported serious adverse events. Minor adverse effects can be avoided with technique modification and salinity adjustment.

Upper respiratory conditions, such as acute and chronic rhinosinusitis, viral upper respiratory tract infection (URTI), and allergic rhinitis, are common disorders that negatively affect patients' quality of life. Saline nasal irrigation is an adjunctive therapy for upper respiratory conditions, likely originating in the ayurvedic medical tradition.1 Its use, including indications, solutions, and administration devices, was first described in medical literature in the early 20th century.2 Saline nasal irrigation is an effective management strategy for many sinonasal conditions.3 In a survey of 330 family physicians, 87 percent reported recommending it to their patients for one or more conditions.4

Nasal irrigation is performed by instilling saline into one nostril and allowing it to drain out of the other nostril, bathing the nasal cavity. Saline nasal irrigation can be performed with low positive pressure from a spray or squirt bottle, or with gravity-based pressure using a vessel with a nasal spout, such as a neti pot. Both are available over the counter.

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to https://www.aafp.org/afpsort.xml.

The exact mechanism of action of saline nasal irrigation is unknown. One possibility is that the breakdown of the protective function of the nasal mucosa plays a role in upper respiratory conditions. Saline nasal irrigation may improve nasal mucosa function through several physiologic effects, including direct cleansing56; removal of inflammatory mediators78; and improved mucociliary function, as suggested by increased ciliary beat frequency.910

Chronic rhinosinusitis (i.e., persisting for longer than 12 weeks) is the most common indication for saline nasal irrigation.4 Based on positive clinical and functional outcomes, a Cochrane review concluded that saline nasal irrigation is an appropriate adjunctive therapy for the symptoms of chronic rhinosinusitis.11 The strongest study in the review reported that patients with chronic sinus symptoms who used 2 percent liquid saline daily in addition to routine care had a 64 percent improvement in overall symptom severity compared with patients who used routine care alone.12 Patients also showed significant improvement in disease-specific quality of life at six months12 and at 18 months.13 These results were not reported for spray saline.14 Patients who used liquid saline also reported significantly decreased use of antibiotics and medication-based, non-saline nasal sprays.12

Two studies evaluated the effect of liquid saline on chronic rhinosinusitis in the context of workplace airborne irritants.1516 After performing daily nasal irrigation with liquid saline, woodworkers (n = 45) exposed to varying levels of wood dust demonstrated significantly improved sinus symptoms, mucociliary clearance, and expiratory nasal flow.15 A similar study of volunteer woodworkers also reported positive findings.16

Liquid and spray saline nasal irrigation have been evaluated for the treatment and prevention of viral URTI. A Cochrane review is in progress.17 Two studies assessing treatment reported conflicting results.1819 The studies used different outcome measures, which limits comparability. In a three-arm randomized controlled trial (RCT), 143 adults with viral URTI received hypertonic spray saline, normal saline, or no treatment.18 The treatments did not have a measurable effect on the duration or severity of nasal symptoms compared with the control group. However, in an RCT of 200 adults with viral URTI, patients treated with micronized saline spray had improved rhinometric resistance, nasal volume, mucociliary transit time, and symptom severity scores compared with patients using liquid saline.19 Compliance rates were not reported, making it difficult to compare micronized saline with liquid saline nasal irrigation.

An RCT of 60 adults evaluated the effectiveness of daily spray saline irrigation as preventive therapy for viral URTI.20 Patients performing preventive saline nasal irrigation reported significantly fewer infections, shorter symptom duration, and fewer days with nasal symptoms compared with those who did not perform preventive nasal irrigation.

Effects of daily saline irrigation were evaluated in a two-phase RCT of 390 children with URTI.21 The children were randomized into two groups. The first group received routine care and performed isotonic saline nasal irrigation with liquid or fine spray. The second group received routine care, but did not perform nasal irrigation. The trial consisted of a three-week treatment phase, followed by a nine-week prevention phase. In both phases, the patients performing nasal irrigation reported significantly better outcomes on nasal secretion, obstruction, and medication use assessments.

Saline nasal irrigation has been reported to benefit patients with allergic rhinitis. One study assessed the effects of small molecule spray (mist), large molecule spray, and liquid saline nasal irrigation on the concentration of inflammatory mediators in nasal secretions in patients with seasonal allergic rhinitis.8 The liquid and large molecule spray forms of saline significantly reduced the levels of histamine and leukotrienes. A small RCT evaluated children with laboratory-confirmed, pollen-triggered rhinitis and found that antihistamine medication plus liquid saline nasal irrigation significantly reduced allergy symptom severity and antihistamine medication use, compared with antihistamines alone.22 In another study, patients with a history of allergic rhinitis reported improvement of allergy symptoms when using liquid saline nasal irrigation.23

In consensus guidelines, saline nasal irrigation is considered safe and possibly effective for mild to moderate rhinitis of pregnancy and acute rhinosinusitis,24 although no clinical trials have assessed the treatment for these indications. A recent survey of family physicians who prescribe saline nasal irrigation showed that 17 percent have recommended it for rhinitis of pregnancy and 67 percent have recommended it for acute rhinosinusitis.4 Saline nasal irrigation has also been recommended for postoperative care of patients undergoing endoscopic sinus surgery,25 for sinonasal sarcoidosis,26 and for Wegener granulomatosis,27 although there is little evidence to support these uses.

Saline nasal irrigation appears safe, with no studies reporting serious adverse events. Minor adverse effects are common, including a sense of discomfort and nervousness during the first use.23 Fewer than 10 percent of patients using saline nasal irrigation reported adverse effects, such as self-limited ear fullness, stinging of the nasal mucosa, and epistaxis (rare).121428 Adverse effects were ameliorated with technique modification and salinity adjustment,23 and did not cause patients to discontinue nasal irrigation.1214 Similar adverse effects occurred with spray and liquid saline.14

Contraindications for saline nasal irrigation include incompletely healed facial trauma, because of the potential to leak saline into unwanted tissue planes or spaces; and neurologic or musculoskeletal problems, such as significant intention tremor, that increase the risk of aspiration.

Patients with an appropriate indication should be considered for a trial of saline nasal irrigation. Optimal salinity is unknown, although 0.9 to 3 percent saline solutions have been used most often. Optimal pH and temperature are also unknown, but are likely patient-specific.23 In the United States, lukewarm tap water appears safe for saline preparation; sterile water or premixed solution is recommended if potability is in doubt.

Saline nasal irrigation techniques are easily taught in primary care settings. Patients have identified effective education methods (e.g., coached practice, patient handouts) as key to successful initiation and maintenance.23 Free evidence-based bilingual resources (e.g., a recipe for saline solution, instructions for irrigation, troubleshooting tips, links to audio and video teaching media) are available from the University of Wisconsin School of Medicine and Public Health at http://www.fammed.wisc.edu/research/past-projects/nasal-irrigation.

This therapy rinses your nasal cavity, the area behind your nose, with salt water (saline). You can do it at home to help with your sinus problems, such as a stuffy or runny nose.

You can use a nasal cup, also known as a neti pot, and nasal saline salt packs. You can get these at many pharmacies. To use a nasal cup, follow three steps:

1. Mix the solution. Follow the directions on the salt package to make salt water using lukewarm water. Put 4 fl oz (100 mL) of the solution in the nasal cup.
2. Position the nasal cup. Lean over the sink so you are looking down into the basin. Turn your head slightly to one side, and gently put the spout of the nasal cup into your upper nostril so that it forms a comfortable seal. Do not press the spout against the middle part (septum) of your nose.
3. Pour the solution. Tip the nasal cup so that the solution pours into your upper nostril. Make sure to breathe through your mouth. The solution will soon drain out of your other nostril (see drawings). When the cup is empty, breathe out through both nostrils to clear out extra salt water and mucus. Gently blow your nose into a tissue. Then, repeat the process in the other nostril.

A variety of squirt and spray bottles are also available for nasal irrigation.

Start with one irrigation per day while you have symptoms. If you feel better, you may want to do it twice a day as part of your regular routine. Some patients use it to prevent sinus problems even when they don't have symptoms.

It is normal for drops of water to occasionally drain from your nose for up to 30 minutes after irrigation. You may want to carry tissues with you. If your nose stings or burns, try using half as much salt next time. You may also want to try a different water temperature. Do not use very hot or very cold water. You can also try nasal irrigation while you are in the shower.

Always rinse out the extra salt water and wash the nasal cup with soap and water after using it. Most nasal cups are dishwasher safe. When you want to use the cup again, mix a fresh salt water solution.

Nephrotic syndrome may be caused by primary (idiopathic) renal disease or by a variety of secondary causes. Patients present with marked edema, proteinuria, hypoalbuminemia, and often hyperlipidemia. In adults, diabetes mellitus is the most common secondary cause, and focal segmental glomerulosclerosis and membranous nephropathy are the most common primary causes. Venous thromboembolism is a possible complication; acute renal failure and serious bacterial infection are also possible, but much less common. There are no established guidelines on the diagnostic workup or management of nephrotic syndrome. Imaging studies are generally not needed, and blood tests should be used selectively to diagnose specific disorders rather than for a broad or unguided workup. Renal biopsy may be useful in some cases to confirm an underlying disease or to identify idiopathic disease that is more likely to respond to corticosteroids. Treatment of most patients should include fluid and sodium restriction, oral or intravenous diuretics, and angiotensin-converting enzyme inhibitors. Some adults with nephrotic syndrome may benefit from corticosteroid treatment, although research data are limited. Intravenous albumin, prophylactic antibiotics, and prophylactic anticoagulation are not currently recommended.

In nephrotic syndrome, a variety of disorders cause proteinuria, often resulting in marked edema and hypoalbuminemia. Hyperlipidemia is a common associated finding. Family physicians may encounter persons with nephrotic syndrome from primary (idiopathic) renal disease or a number of secondary causes, and should initiate appropriate diagnostic workup and medical management pending specialist consultation.

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to https://www.aafp.org/afpsort.xml.

Most cases of nephrotic syndrome appear to be caused by primary kidney disease. Table 1 summarizes the recognized histologic patterns and features of primary nephrotic syndrome.1 Membranous nephropathy and focal segmental glomerulosclerosis (FSGS) each account for about one third of cases of primary nephrotic syndrome; however, FSGS is the most common cause of idiopathic nephrotic syndrome in adults.2 Minimal change disease and (less commonly) immunoglobulin A (IgA) nephropathy cause approximately 25 percent of cases of idiopathic nephrotic syndrome.2 Other conditions, such as membranoproliferative glomerulonephritis, are less common. FSGS accounts for approximately 3.3 percent of new cases of end-stage renal disease.2 A large number of secondary causes of nephrotic syndrome have been identified (Table 2), 3 with diabetes mellitus being the most common.

Information from reference 1.

note:Causes are in approximate order of most to least common. HIV = human immunodeficiency virus.

The underlying pathophysiology of nephrotic syndrome is not completely clear.4 Although the more intuitive “underfill” mechanism of edema from reduced oncotic pressure caused by marked proteinuria may be the primary mechanism in children with acute nephrotic syndrome, edema in adults may be caused by a more complex mechanism. Massive proteinuria causes renal tubulointerstitial inflammation, with resulting increased sodium retention that overwhelms the physiologic mechanisms for removing edema.5 Patients may have an “overfilled” or expanded plasma volume in addition to expanded interstitial fluid volume. This may be clinically important if over-rapid diuresis leads to acute renal failure from reduced glomerular blood flow, despite persistent edema.

Progressive lower extremity edema, weight gain, and fatigue are typical presenting symptoms of nephrotic syndrome. In advanced disease, patients may develop periorbital or genital edema, ascites, or pleural or pericardial effusion. Persons who present with new edema or ascites, without typical dyspnea of congestive heart failure or stigmata of cirrhosis, should be assessed for nephrotic syndrome.

Nephrotic-range proteinuria is typically defined as greater than 3 to 3.5 g of protein in a 24-hour urine collection; however, not all persons with this range of proteinuria have nephrotic syndrome. Although a urine dipstick proteinuria value of 3+ is a useful semiquantitative means of identifying nephrotic-range proteinuria, given the logistic difficulties of collecting a 24-hour urine sample, the random urine protein/creatinine ratio is a more convenient quantitative measure. The numeric spot urine protein/creatinine ratio, in mg/mg, accurately estimates protein excretion in g per day per 1.73 m2 of body surface area, so a ratio of 3 to 3.5 represents nephrotic-range proteinuria.6 Low serum albumin levels (less than 2.5 g per dL [25 g per L]) and severe hyperlipidemia are also typical features of nephrotic syndrome. In one study of persons with nephrotic syndrome, 53 percent had a total cholesterol level greater than 300 mg per dL (7.77 mmol per L) and 25 percent had a total cholesterol level greater than 400 mg per dL (10.36 mmol per L).7

Possible complications of nephrotic syndrome include venous thromboembolism caused by loss of clotting factors in the urine, infection caused by urinary loss of immunoglobulins, and acute renal failure. Thromboembolism has long been recognized as a complication of nephrotic syndrome.8 In a large retrospective review, the relative risk of deep venous thrombosis (DVT) in patients with nephrotic syndrome was 1.7 compared with those without nephrotic syndrome, with an annual incidence of DVT of 1.5 percent9; the risk seems highest in the first six months after diagnosis.10 The relative risk of pulmonary embolism was 1.4 and was especially high in persons 18 to 39 years of age (relative risk = 6.8). Renal venous thrombosis is a possible complication of nephrotic syndrome, but was uncommon in this case series. Membranous nephropathy and serum albumin levels less than 2.0 to 2.5 g per dL (20 to 25 g per L) seem to confer an increased risk of DVT. Arterial thrombotic complications can occur, but are rare.9

Infection is also a possible complication of nephrotic syndrome; however, this risk appears primarily in children and in persons who have relapses of nephrotic syndrome or who require longer-term corticosteroid therapy.11 Invasive bacterial infections, especially cellulitis, peritonitis, and sepsis, are the most common infections attributable to nephrotic syndrome. The mechanisms of infection are unclear, but may relate to the degree of edema, loss of serum IgG with overall proteinuria,1 effects of corticosteroid therapy, reduced complement or T cell function, or impaired phagocytic function.3 The risk of serious bacterial infection attributable to nephrotic syndrome in adults in the United States is unclear, but seems low.

Acute renal failure is a rare, spontaneous complication of nephrotic syndrome. Although older persons, children, and those with more profound edema and proteinuria are at highest risk, there are many possible causes or contributing factors to acute renal failure in this setting. Excessive diuresis, therapeutic drug complications, sepsis, renal venous thrombosis, renal interstitial edema, and marked hypotension may cause or contribute to acute renal failure.12

Typical clinical and laboratory features of nephrotic syndrome are sufficient to establish the diagnosis of nephrotic syndrome. The diagnostic evaluation focuses on identification of an underlying cause and on the role of renal biopsy. However, there are no published practice guidelines available about the diagnostic evaluation of persons with nephrotic syndrome.3

Initial investigation should include history, physical examination, and a serum chemistry panel. Given the large number of potential causes of nephrotic syndrome and the relatively nonspecific aspect of therapy, the diagnostic evaluation should be guided by clinical suspicion for specific disorders, rather than a broad or unguided approach to ruling out multiple illnesses. Table 3 lists selected diagnostic studies for some common secondary causes of nephrotic syndrome, as well as baseline evaluations that should be obtained in all persons with nephrotic syndrome.

HIV = human immunodeficiency virus.

Imaging studies are generally not helpful in assessing persons with nephrotic syndrome. Renal ultrasonography may identify renal venous thrombosis if suggestive features, such as flank pain, hematuria, or acute renal failure, are present.

Renal biopsy is often recommended in persons with nephrotic syndrome to establish the pathologic subtype of the disease, to assess disease activity, or to confirm the diagnosis of diseases, such as amyloidosis or systemic lupus erythematosus. There are, however, no clear guidelines on when renal biopsy is indicated or whether it is needed in all persons with nephrotic syndrome. For example, in diabetic nephropathy, the leading cause of secondary nephrotic syndrome, renal biopsy may not be necessary if the patient has enlarged kidneys, a bland urinary sediment without cellular casts, or other evidence of microvascular disease, such as proliferative retinopathy or peripheral neuropathy. Although renal biopsy is often recommended to assess the likelihood that nephrotic syndrome will respond to corticosteroid treatment, there are no biopsy findings that accurately predict corticosteroid responsiveness. No recent studies have elucidated the true benefit of renal biopsy in guiding management; the best available evidence is from a prospective study in which the results of renal biopsy changed management in 24 of 28 persons with nephrotic syndrome, primarily through the addition of corticosteroid treatment, although the actual patient benefit is unknown.13 In most cases, family physicians should consult specialists in renal medicine about the need for renal biopsy in individual patients.

There are no clinical guidelines and few high-quality studies on the management of nephrotic syndrome in adults. Recommendations are based primarily on early case series, other observational studies, and expert opinion.3

Creating a negative sodium balance will help reduce edema, presumably as the underlying illness is treated or as renal inflammation slowly resolves. Patients should limit their sodium intake to 3 g per day, and may need to restrict fluid intake (to less than approximately 1.5 L per day).

Diuretics are the mainstay of medical management; however, there is no evidence to guide drug selection or dosage. Based on expert opinion, diuresis should aim for a target weight loss of 1 to 2 lb (0.5 to 1 kg) per day3 to avoid acute renal failure or electrolyte disorders. Loop diuretics, such as furosemide (Lasix) or bumetanide, are most commonly used. Large doses (e.g., 80 to 120 mg of furosemide) are often required,14 and these drugs typically must be given intravenously because of the poor absorption of oral drugs caused by intestinal edema.3 Low serum albumin levels also limit diuretic effectiveness and necessitate higher doses. Thiazide diuretics, potassium-sparing diuretics, or metolazone (Zaroxolyn) may be useful as adjunctive or synergistic diuretics.14

Angiotensin-converting enzyme (ACE) inhibitors have been shown to reduce proteinuria and reduce the risk of progression to renal disease in persons with nephrotic syndrome.1516 One study found no improvement in response when corticosteroid treatment was added to treatment with ACE inhibitors.17 The recommended dosage is unclear, and enalapril (Vasotec) dosages from 2.5 to 20 mg per day were used. Most persons with nephrotic syndrome should be started on ACE inhibitor treatment to reduce proteinuria, regardless of blood pressure.

Intravenous albumin has been proposed to aid diuresis, because edema may be caused by hypoalbuminemia and resulting oncotic pressures. However, there is no evidence to indicate benefit from treatment with albumin,18 and adverse effects, such as hypertension or pulmonary edema, as well as high cost, limit its use.

Treatment with corticosteroids remains controversial in the management of nephrotic syndrome in adults. It has no proven benefit, but is recommended in some persons who do not respond to conservative treatment.1920 Treatment of children with nephrotic syndrome is different, and it is more clearly established that children respond well to corticosteroid treatment.21 Classically, minimal change disease responds better to corticosteroids than FSGS; however, this difference is found primarily in children with nephrotic syndrome. One older study found that corticosteroid treatment improved proteinuria and renal function in persons with minimal change disease, but not membranous nephropathy or proliferative glomerulonephritis.22 Another small older study found that persons with less severe glomerular changes responded well to corticosteroids.23 One case series in black persons with FSGS found no benefit from corticosteroid treatment.19 Two Cochrane reviews on the treatment of nephrotic syndrome in adults found no benefit for mortality or need for dialysis with corticosteroid therapy for membranous nephropathy or minimal change disease, but found a weak benefit for disease remission and proteinuria in persons with membranous nephropathy.2024 However, the findings for minimal change disease were based on only one randomized trial, and the role of corticosteroid treatment remains unclear. Many experts recommend the use of corticosteroids, particularly for persons with minimal change disease1; however, adverse effects from corticosteroids often lead to discontinuation.

Family physicians should discuss with patients and consulting nephrologists whether treatment with corticosteroids is advisable, weighing the uncertain benefits and possibility of adverse effects. Alkylating agents (e.g., cyclophosphamide [Cytoxan]) also have weak evidence for improving disease remission and reducing proteinuria, but may be considered for persons with severe or resistant disease who do not respond to corticosteroids.

A Cochrane review is underway to investigate the benefits and harms of lipid-lowering agents in nephrotic syndrome.25 Some evidence suggests an increased risk of atherogenesis or myocardial infarction in persons with nephrotic syndrome, possibly related to increased lipid levels.25 However, the role of treatment for increased lipids is unknown and, at present, the decision to start lipid-lowering therapy in persons with nephrotic syndrome should be made on the same basis as in other patients.

There are no data from prospective clinical trials about treatment and prevention of infection in adults with nephrotic syndrome. Given the uncertain risks of infection in adults with nephrotic syndrome in the United States, there are currently no indications for antibiotics or other interventions to prevent infection in this population. Persons who are appropriate candidates should receive pneumococcal vaccination.

There are currently no recommendations for prophylactic anticoagulation to prevent thromboembolic events in persons with nephrotic syndrome who have not had previous thrombotic events, and clinical practice varies. A Cochrane review is in process.26 Physicians should remain alert for signs or symptoms suggesting thromboembolism and, if it is diagnosed, these events should be treated as in other patients. Persons who are otherwise at high risk of thromboembolism (e.g., based on previous events, known coagulopathy) should be considered for prophylactic anticoagulation while they have active nephrotic syndrome.

Nephrotic (nef-RAH-tik) syndrome (NS) is when your kidneys don't filter out toxic substances and waste from your blood.

Your legs can swell over a few weeks or months, which may also make you gain weight. You may feel tired, and you can have large amounts of protein in your urine. Some people get fluid around the lungs, but they usually don't get short of breath.

NS is usually caused by inflammation in your kidneys that does not have a definite cause. It may also run in families. In some people, NS is caused by another disease, most often diabetes. Some medicines, such as anti-inflammatory drugs, can also cause it.

Your doctor will measure the amount of protein in your urine and blood to see if the swelling in your legs is from NS or something else. He or she may do blood tests for diabetes, lupus, infections, or other causes. Your doctor may also look at a small piece of your kidney under a microscope (this is called a biopsy).

You will probably need to be treated in the hospital for at least a few days. You may need to eat less salt. Your doctor may also give you diuretics (also called water pills). Some blood pressure medicines can reduce swelling, and steroid medicines can reduce the inflammation in your kidneys. Some people with NS are more likely to get blood clots, so your doctor may also prescribe blood-thinning medicines.

The swelling usually gets better after taking diuretics or other medicines. But you may have swelling for years and may need to keep taking medicine every day. It is important for you to keep seeing your doctor to make sure that your kidneys are not being damaged.

The U.S. Preventive Services Task Force (USPSTF) recommends screening for type 2 diabetes mellitus in asymptomatic adults with sustained blood pressure (treated or untreated) greater than 135/80 mm Hg ( Online Table A). B recommendation.

The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for type 2 diabetes in asymptomatic adults with blood pressure of 135/80 mm Hg or lower ( Online Table A). I statement.

Importance. The prevalence of type 2 diabetes in the United States is increasing. About 9 percent of U.S. adults currently have this disorder. Diabetes is a leading cause of blindness, renal disease, and amputation, and leads to increased mortality, primarily from cardiovascular events.

Detection. The USPSTF found convincing evidence that available screening tests accurately detect type 2 diabetes during an early, asymptomatic phase.

Benefits of detection and early treatment. In adults with sustained blood pressure greater than 135/80 mm Hg: The USPSTF found adequate evidence that lowering blood pressure below conventional target values in adults who have hypertension and diabetes reduces the incidence of cardiovascular events and cardiovascular mortality.

In adults with blood pressure 135/80 mm Hg or lower: The USPSTF found convincing evidence that intensive glycemic control in persons with clinically detected (as opposed to screening-detected) diabetes can reduce progression of microvascular disease. However, the benefits of tight glycemic control on microvascular clinical outcomes, such as severe visual impairment or end-stage renal disease, take years to become apparent. There is inadequate evidence that early diabetes control as a result of screening provides an incremental benefit for microvascular clinical outcomes compared with initiating treatment after clinical diagnosis.

There is inadequate evidence that tight glycemic control significantly reduces macro-vascular complications, such as myocardial infarction and stroke.

Harms of detection and early treatment. The USPSTF found adequate evidence that the short-term harms of screening for diabetes, such as anxiety, are small. However, the longer-term effects of labeling a large proportion of U.S. adults as abnormal are unknown.

USPSTF assessment. The USPSTF concludes that for adults with sustained blood pressure greater than 135/80 mm Hg, there is moderate certainty that the net benefit of screening for diabetes is substantial.

The USPSTF concludes that for adults with blood pressure 135/80 mm Hg or lower, evidence of the value of screening for diabetes is lacking, and the balance of benefits and harms cannot be determined.

• Patient population. This recommendation concerns adults without symptoms of diabetes or evidence of possible diabetes complications. Symptoms of diabetes include polyuria, polydipsia, and polyphagia. Possible diabetes complications include nonhealing ulcers or infections, and established vascular disease (e.g., coronary artery disease, stroke, peripheral artery disease). Persons with these symptoms or conditions should be tested for diabetes.
• Suggestions for practice (I statement). In persons with blood pressure of 135/80 mm Hg or lower, screening may be considered on an individual basis if knowledge of diabetes status would help inform decisions about coronary heart disease (CHD) prevention strategies. These include assessment of CHD risk and subsequent consideration of lipid-lowering agents or aspirin.

For example, consider a patient for whom lipid-lowering treatment would be recommended if his or her 10-year CHD risk was 20 percent or greater (see risk assessment). If the patient's calculated risk was 17 percent without diabetes and greater than 20 percent with diabetes, then screening for diabetes would be useful in determining treatment. However, if the patient's calculated risk was 10 percent without diabetes and 15 percent with diabetes, then the screening test result would have no effect on the decision whether to use lipid-lowering treatment.

• Risk assessment. Blood pressure is an important predictor of complications of cardiovascular disease (CVD), including CHD and stroke, in persons with type 2 diabetes. Blood pressure measurement should be the first step in applying this recommendation. The examination of global CHD and stroke risk allows the physician to determine how aggressive treatment for CVD risk factors needs to be. In making this assessment, physicians should use any of several validated CHD risk assessment calculators, such as the one based on Framingham Heart Study data (http://hp2010.nhlbihin.net/atpiii/calculator.asp).
• Screening tests. Three tests have been used to screen for diabetes: fasting plasma glucose, two-hour postload plasma glucose, and A1C testing. Each has advantages and disadvantages. The American Diabetes Association (ADA) has recommended the fasting plasma glucose test for screening because it is easier and faster to perform, more convenient and acceptable to patients, and less expensive than other screening tests. The fasting plasma glucose test has more reproducible results than the two-hour postload plasma glucose test; less intra-individual variation; and similar predictive value for development of microvascular complications of diabetes. The ADA defines diabetes as a fasting plasma glucose level of 126 mg per dL (6.99 mmol per L) or greater, and recommends confirmation with a repeat screening test on a separate day, especially in persons with borderline results.
• Treatment of persons with sustained blood pressure of 135/80 mm Hg or greater. Blood pressure targets should be lower for persons who have type 2 diabetes than for those who do not. Lower blood pressure targets for persons with diabetes and high blood pressure reduce CVD events compared with higher targets. Attention to other risk factors for CVD, such as physical inactivity, lipid levels, diet, and obesity, is also important to decrease risk of CHD and to improve glucose control.
• Screening intervals. The optimal screening interval is not known. The ADA recommends a three-year interval on the basis of expert opinion.
• Other approaches to prevention. There is no evidence of benefit in health outcomes from screening for impaired glucose tolerance or impaired fasting glucose. However, intensive programs of lifestyle modification (e.g., diet, exercise, behavior) reduce the incidence of diabetes. Regardless of whether the physician and patient decide to screen for diabetes, all patients should eat a healthful diet, be active, and maintain a healthy weight. These behaviors have other benefits in addition to preventing or forestalling type 2 diabetes. The USPSTF recommends intensive interventions for persons who are obese who desire to lose weight. Population-based approaches to increasing physical activity and reducing obesity, as recommended by the Task Force on Community Preventive Services, should be supported.
• Useful resources. Evidence and USPSTF recommendations regarding blood pressure, diet, physical activity, and obesity are available at http://www.uspreventiveservicestaskforce.org/recommendations.htm. The reviews and recommendations for the Task Force on Community Preventive Services are available at http://www.thecommunityguide.org.

KENNETH W. LIN, MD, Medical Officer, U.S. Preventive Services Task Force Program, Agency for Healthcare Research and Quality

A 50-year-old woman with a history of hyperlipidemia visits your office for a physical examination. Her blood pressure is 140/82 mm Hg, and her body mass index is 30 kg per m2. She reports no symptoms of polydipsia, polyphagia, or polyuria. Her blood pressure has been less than 130/80 mm Hg at previous visits.

1. Based on recommendations from the U.S. Preventive Services Task Force (USPSTF), which one of the following actions regarding screening and prevention of type 2 diabetes mellitus is appropriate for this patient?

A. Obtain a fasting plasma glucose level because of her history of hyperlipidemia.

B. Obtain a fasting plasma glucose level because of her elevated blood pressure at this office visit.

C. Obtain an A1C measurement because of her elevated blood pressure at this visit.

D. Obtain a random blood glucose level because of her history of hyperlipidemia.

E. Repeat blood pressure measurement at a subsequent visit.

2. Which of the following statements about early identification and treatment of type 2 diabetes and their effects on long-term complications is/are correct?

A. Aggressive blood pressure control in persons with type 2 diabetes reduces total cardiovascular events by 50 percent.

B. Tight glycemic control before clinical detection of type 2 diabetes reduces total cardiovascular events by 30 percent.

C. Implementation of foot care programs before clinical detection of type 2 diabetes decreases patients' risk of lower-limb amputation.

D. Tight glycemic and blood pressure control in persons with type 2 diabetes decreases development and progression of albuminuria, but it is unclear whether initiating control earlier has an important impact on chronic renal failure.

1. The correct answer is E. The USPSTF recommends screening for type 2 diabetes in asymptomatic persons with sustained elevated blood pressure greater than or equal to 135/80 mm Hg. A single elevated measurement does not constitute hypertension.

Recent randomized controlled studies have demonstrated that aggressive control of blood pressure in patients with diabetes significantly decreases cardiovascular events. Treatment of isolated systolic hypertension in persons older than 60 years with diabetes also decreases cardiovascular events.

The USPSTF no longer recommends routine screening for type 2 diabetes in normotensive adults with hyperlipidemia.

The American Diabetes Association recommends screening for type 2 diabetes with fasting plasma glucose measurement. There are no widely accepted criteria for using A1C or random blood sugar levels as screening tests for type 2 diabetes.

2. The correct answers are A and D. Blood pressure control in patients with diabetes reduces cardiovascular events by 50 percent. In addition, treatment of isolated systolic hypertension among persons older than 60 years with diabetes reduces cardiovascular events by 34 to 69 percent.

There is inadequate evidence that tight glycemic control reduces macrovascular complications, such as myocardial infarction (MI) and stroke. No randomized, controlled trial has demonstrated a statistically significant reduction in total cardiovascular events from tight glycemic control. In the U.K. Prospective Diabetes Study, patients assigned to tight glycemic control had non-significantly lower rates of MI and sudden death. However, there were no reductions in strokes, heart failure, angina, or all-cause mortality compared with patients receiving conventional management after 10 years of follow-up.

Although evidence shows a decrease in development of and progression to albuminuria in patients with diabetes who have tight glycemic and blood pressure control and who use angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, it cannot be determined whether initiating these treatments earlier as a result of screening would have an important impact on chronic renal failure.

Early initiation of foot care programs, tight glycemic control, and blood pressure control in the preclinical phase does not appear to affect the long-term outcome of lower-limb amputation.

1. U.S. Preventive Services Task Force. Screening for type 2 diabetes mellitus in adults: U.S. Preventive Services Task Force recommendation statement [published correction appears in Ann Intern Med. 2008;149(2):147]. Ann Intern Med. 2008;148(11):846-854.

A healthy-appearing 23-year-old woman with no notable medical history presented with a headache, neck stiffness, and visual changes that have persisted for 10 days. The patient reported double vision, blurred vision, and transient visual changes when opening her eyes; however, she had normal visual acuity. She also reported paresthesia in her left arm and hand. She denied having fevers, myalgias, or incontinence. She was afebrile at presentation. Examination revealed tachycardia (heart rate of 110 beats per minute), a body mass index of 35 kg per m2, and nuchal rigidity. Her pupils were equal in size, round, and reactive to light and accommodation. Her vision was 20/20 in both eyes. Funduscopic examination was performed (see accompanying figure).

Based on the patient's history and physical examination, which one of the following is the most likely diagnosis?

The answer is C: idiopathic intracranial hypertension. The accompanying figure shows widening and blurring of the optic disc margin with compensatory reduction of cup diameter, which is consistent with papilledema. Idiopathic intracranial hypertension, or pseudotumor cerebri, is a syndrome of increased intracranial pressure without a space-occupying lesion. Patients typically present with headache, visual changes, tinnitus, and paresthesia. Brain imaging should be performed initially to rule out a space-occupying lesion and to ensure normal ventricular size. It is then safe to perform a lumbar puncture to demonstrate an elevated opening pressure (greater than 25 cm of water) in the lateral decubitus position.1 When performing a lumbar puncture, it is appropriate to send cerebrospinal fluid for cytology and culture, although specific tests for herpes simplex virus, viral, and Lyme infections are necessary only if the presentation suggests these diagnoses.

Although idiopathic intracranial hypertension is rare, with an incidence of one in 100,000 persons per year, it is 20 times more common in women 20 to 44 years of age who are more than 20 percent above their ideal body weight.2 The syndrome is very rare in persons older than 45 years.

Headache with nuchal rigidity suggests meningeal inflammation, even without a fever. However, papilledema occurs in less than 5 percent of acute bacterial meningitis cases and is very rare with aseptic meningitis.3

Although a complicated migraine headache may be associated with neurologic findings, it does not lead to papilledema.

Multiple sclerosis is more common in young women and can cause a variety of neurologic symptoms, including visual complications from optic neuritis. Optic neuritis causes a papillitis that is difficult to distinguish from papilledema, but papillitis leads to decreased visual acuity.4

A brain tumor must be considered as a cause of papilledema before performing the lumbar puncture. However, in a young woman who is obese with no known cancer history, the probability of a brain tumor is less than that of idiopathic intracranial hypertension.5

What is the best way to diagnose lumbar spinal stenosis in patients with leg pain or numbness?

Lumbar spinal stenosis is an important cause of pain and disability, and surgery is beneficial for appropriately selected patients.12 Therefore, it is important for primary care physicians to distinguish patients with spinal stenosis from those with musculoskeletal low back pain, peripheral vascular disease, or spinal disk disease.

Individual signs and symptoms suggestive of lumbar spinal stenosis include older age at onset, longer duration of symptoms, symptoms that worsen with walking or standing, numbness of the lower legs with activity, symptoms that improve with bending forward, and symptoms that worsen with bending backward. The findings that most strongly suggest lumbar spinal stenosis are symptoms that improve with bending forward, urinary disturbance, and intermittent claudication.

Table 1 includes accuracy data for individual signs and symptoms.3 These data are derived from the best study to date of the clinical diagnosis of lumbar spinal stenosis.3 The study included patients presenting to an orthopedic surgeon with a primary complaint of pain or numbness in the legs. All patients had plain radiography and magnetic resonance imaging (MRI) of the lumbar spine, as well as a standardized history and physical examination. The reference standard was diagnosis of lumbar spinal stenosis by the referring orthopedic surgeon and the study coordinator; a consensus panel established the final diagnosis when the surgeon and coordinator disagreed (this occurred with 243 patients). Of the 468 patients in the study, 222 patients received a final diagnosis of spinal stenosis. This percentage is higher than in a typical primary care population, suggesting that their prediction tools may overestimate the risk of spinal stenosis.

note: Data from patients with pain or numbness requiring referral to an orthopedic surgeon. LR– = negative likelihood ratio; LR+ = positive likelihood ratio. Information from reference 3.

The authors of the study developed several clinical prediction tools based on this data set. First, the authors created an integer-based scoring system using 10 history and physical examination findings.3 This tool has good accuracy, with a likelihood ratio of 3.3 for a positive test result and 0.1 for a negative test result. However, it has not been prospectively validated. A second rule (Table 2), which does not include physical examination findings, was developed using 80 percent of the data set and validated using the remaining 20 percent.4 Finally, the researchers created a self-administered, 10-item patient survey (Figure 1) to identify patients with lumbar spinal stenosis and then distinguish between those with radicular lumbar spinal stenosis and those with cauda equina syndrome.5

note: Decision rule uses patient-reported symptoms. *— Data are combined from the group of patients used to derive this decision rule and the group used to validate it. The two groups had similar results. Adapted with permission from Sugioka T, Hayashino Y, Konno S, Kikuchi S, Fukuhara S. Predictive value of self-reported patient information for the identification of lumbar spinal stenosis. Fam Pract. 2008;25(4):242.

Self-administered, self-reported questionnaire for patients with symptoms of spinal stenosis.

A recent systematic review evaluated the accuracy of diagnostic tests for lumbar spinal stenosis.6 Fifteen studies of imaging for the diagnosis of the condition were identified. Although most of the studies were of poor quality and the accuracy of the tests varied considerably between studies, the authors of the review concluded that myelography, computed tomography, and MRI appear to have similar accuracy. Evidence from two studies showed that three-dimensional magnetic resonance myelography may be somewhat more sensitive than other tests, but it is more expensive.6

It is important for physicians to consider cauda equina syndrome in the differential diagnosis of back pain and numbness. Any patient with signs or symptoms of possible cauda equina syndrome (e.g., saddle anesthesia, bowel or bladder symptoms) should receive emergent referral to a neurosurgeon.

A 64-year-old man presents with leg pain that has gradually worsened since its onset eight months ago. The pain worsens when he walks or stands up, improves when he bends forward, and does not change when he bends backward. He denies having urinary incontinence. What is the patient's risk of lumbar spinal stenosis?

Answer: Using the clinical decision rule in Table 24 the patient receives a score of 8 points (two points for age, one for time of onset, two for improved pain with bending forward, two for worsening pain with standing, and one for worsening pain with walking [claudication]). This puts him in the highest risk category for lumbar spinal stenosis (75 percent probability). After ruling out peripheral vascular disease by confirming that his ankle brachial indices are normal, you order an MRI to confirm lumbar spinal stenosis.

1. Weinstein JN, Tosteson TD, Lurie JD, et al.; for the SPORT Investigators. Surgical versus nonsurgical therapy for lumbar spinal stenosis. N Engl J Med. 2008;358(8):794-810.

MELISSA MAGUIRE, James Cook University Hospital, Middlesbrough, United Kingdom

SRIDHARAN RAMARATNAM, Apollo Hospitals, Chennai (Madras), India

Author disclosure: Anthony Marson has been paid by Johnson & Johnson, Janssen-Cilag, Sanofi Aventis, and UCB for speaking at meetings, and by Glaxo Wellcome and UCB for attending conferences. Sridharan Ramaratnam has received hospitality from Sun Pharmaceutical (India), Novartis (India), and Sanofi Aventis for attending conferences; is involved in ongoing clinical trials for UCB, Pfizer, and Johnson & Johnson; and is an author of systematic reviews referenced in this review.

About 3 percent of persons are diagnosed with epilepsy during their lifetime, but about 70 percent of persons with epilepsy eventually go into remission.

After a first seizure, antiepileptic drugs may delay or prevent subsequent seizures, but they can cause adverse effects, and their long-term benefit is unknown. Antiepileptic drug treatment after a single seizure does not reduce the risk of drug-resistant epilepsy in the long term.

Carbamazepine, phenobarbital, phenytoin, lamotrigine, sodium valproate, and topiramate are widely considered effective in controlling seizures in newly diagnosed partial or generalized (tonic-clonic) epilepsy, but we found no randomized controlled trials comparing the drugs with placebo. A placebo-controlled trial would now be considered unethical.

• Systematic reviews found no reliable evidence on which to base a choice among anti-epileptic drugs.
• Adding second-line drugs to usual treatment reduces seizure frequency in persons with drug-resistant partial epilepsy, but increases adverse effects such as dizziness and somnolence. We do not know if any one antiepileptic drug is more likely to reduce seizures compared with others.

In persons who have been seizure-free for at least two years while on treatment, almost 60 percent of those who withdraw from antiepileptic treatment remain seizure-free, compared with almost 80 percent of persons who continue treatment.

Educational programs may reduce seizure frequency and improve psychosocial functioning in persons with epilepsy, but we do not know whether other behavioral or psychological treatments are beneficial.

There is consensus that temporal lobectomy or amygdalohippocampectomy can improve seizure control and quality of life in persons with drug-resistant temporal lobe epilepsy, but the procedures can cause neurologic adverse effects.

High-level vagus nerve stimulation may reduce seizure frequency in persons with drug-resistant partial seizures, but it may cause hoarseness and dyspnea, and long-term effects are unknown. We do not know whether different stimulation cycles more effectively reduce seizure frequency or increase the proportion of responders.

We do not know whether hemispherectomy improves seizure control in persons with drug-resistant epilepsy.

Caution: Vigabatrin, which may be used as second-line treatment, causes concentric visual field abnormalities, which are probably irreversible in about 40 percent of persons.

• — Categorization based on consensus.

Epilepsy is a group of disorders rather than a single disorder. Seizures can be classified as partial or focal (categorized as simple partial, complex partial, and secondary generalized tonic-clonic seizures) or as generalized (categorized as generalized tonic-clonic, absence, myoclonic, tonic, and atonic seizures). Temporal lobe epilepsy is a form of partial or focal epilepsy. Persons are considered to have epilepsy if they have had two or more unprovoked seizures.

Epilepsy is common, with an estimated prevalence in resource-rich countries of five to 10 out of 1,000 persons, and an annual incidence of 50 out of 100,000 persons. About 3 percent of persons will be diagnosed with epilepsy at some time in their lives.

Epilepsy is a symptom rather than a disease, and it may be caused by various disorders involving the brain. The causes and risk factors include birth or neonatal injuries, congenital or metabolic disorders, head injuries, tumors, infections of the brain or meninges, genetic defects, degenerative disease of the brain, cerebrovascular disease, and demyelinating disease. Epilepsy can be classified by cause. Idiopathic generalized epilepsies (e.g., juvenile myoclonic epilepsy, childhood absence epilepsy) are largely genetic. Symptomatic epilepsies result from a known cerebral abnormality. For example, temporal lobe epilepsy may result from a congenital defect, mesial temporal sclerosis, or a tumor. Cryptogenic epilepsies are those that cannot be classified as idiopathic or symptomatic.

About 60 percent of untreated persons have no further seizures during the two years after their first seizure. Prognosis is good for most persons with epilepsy. About 70 percent go into remission, defined as being seizure-free for five years on or off treatment. This leaves 20 to 30 percent who develop chronic epilepsy, which is often treated with multiple antiepileptic drugs.

editor's note: Esclicarbazepine, losigamone, and retigabine are not available in the United States.

Background: The role of vitamin D in reducing fractures has been questioned by several recent trials, including a 2007 meta-analysis that found no benefit. However, epidemiologic data support a positive association between 25-hydroxyvitamin D levels and fracture reduction. This disparity might be explained if fracture reduction occurred only at higher levels of vitamin D intake, because previous reviews did not stratify results based on vitamin D dosage. Bischoff-Ferrari and colleagues performed a meta-analysis of oral vitamin D supplementation in preventing nonvertebral and hip fractures in adults older than 65 years.

The Study: The study evaluated 12 double-blind trials, including 42,279 participants with a mean age of 78 years. Only randomized controlled trials with at least one year of follow-up were reviewed. Studies were excluded if they included patients with organ transplantation or stroke, or who were receiving corticosteroid therapy. The primary outcome was the relative risk of a nonvertebral or hip fracture in persons receiving supplemental vitamin D with or without calcium supplementation, compared with those receiving placebo. Studies were screened for result heterogeneity, which could mask notable changes if the results were nonselectively pooled. In these cases, the data were stratified according to vitamin D dosage (less than or equal to 400 IU per day or greater than 400 IU per day) and achieved 25-hydroxyvitamin D level.

Results: No benefit of vitamin D supplementation was found in general, but a dose-response effect occurred when results were stratified by dosage. Patients receiving less than 400 IU per day of vitamin D continued to show no reduction in fractures compared with placebo. However, patients receiving more than 400 IU per day of vitamin D (482 to 770 IU per day) were less likely to have a nonvertebral or hip fracture (relative risk = 0.80 and 0.82, respectively; numbers needed to treat = 93 and 168, respectively). Calcium supplementation in addition to high-dose vitamin D intake was not associated with further decrease in nonvertebral fracture risk.

Conclusion: High-dose supplemental vitamin D (482 to 770 IU per day) can reduce risk of nonvertebral fractures by at least 20 percent, and hip fractures by at least 18 percent. Lower vitamin D intake does not appear to confer any protective benefit.

Reference(s)

1. Bischoff-Ferrari HA, et al. Prevention of nonvertebral fractures with oral vitamin D and dose dependency: a meta-analysis of randomized controlled trials. Arch Intern Med. March 23, 2009;169(6):551-561.

Background: Caffeine is consumed in coffee, tea, soft drinks, and chocolate, and is the most commonly ingested chemical during pregnancy. Data on its effect on pregnancy outcomes are mixed; consuming more than 300 mg of caffeine daily seems to be associated with fetal growth restriction and spontaneous miscarriage, but the evidence for adverse effects with smaller amounts is inconclusive. Previous studies may be confounded by significant variations in mothers' rates of caffeine metabolism and incomplete measurement of caffeine consumption. Konje and colleagues measured comprehensive caffeine intake, estimated variations in caffeine metabolism, and reported pregnancy outcomes to establish a safe upper limit of caffeine consumption.

The Study: The authors of this prospective observational study recruited 2,635 low-risk patients from two large teaching hospitals in the United Kingdom between 2003 and 2006. Women were identified in the first trimester through pregnancy screening notes, and were invited to participate. Those who agreed were interviewed between eight and 12 weeks' gestation to assess demographic information, including age, parity, maternal height and weight, socioeconomic status, and gestational age. Women with medical conditions, including human immunodeficiency virus or hepatitis B infection, or psychiatric disorders were excluded.

Caffeine intake was estimated with a previously validated caffeine assessment questionnaire, which recorded habitual caffeine intake before and during the pregnancy. The amounts and brand names of caffeinated foods, beverages, and medications were tallied for three time periods: four weeks before pregnancy until the first interview at eight to 12 weeks', 13 to 28 weeks', and 29 to 40 weeks' gestation. Possible confounders to caffeine metabolism rates, including smoking, alcohol use, and nausea, were also assessed. Participants' baseline caffeine metabolism rate and smoking status were measured using salivary cotinine (for nicotine exposure) and salivary caffeine levels at one and five hours after a caffeine challenge.

Pregnancy outcomes included fetal growth restriction defined as birth weight less than the 10th centile (using a customized growth chart that accounted for the women's demographic data), late miscarriage, preterm delivery, gestational hypertension and preeclampsia, and stillbirth. Birth outcomes were obtained from the electronic maternity database.

Results: Caffeine intake was reported as milligrams per day and was averaged for each trimester and over the full pregnancy. Participants consumed an average of 159 mg per day during pregnancy. Pre-pregnancy consumption averaged 238 mg per day, which decreased to 139 mg per day by week 12, and remained fairly stable until the third trimester, when it gradually increased to 153 mg per day. In this study, approximately 62 percent of the caffeine came from tea; 14 percent from coffee; and 22 percent from colas, chocolate, and other soft drinks. Other beverages contributed less than 4 percent of the total caffeine consumed.

The prevalence of fetal growth restriction was 13 percent in this population and rose with increasing caffeine consumption. Women who consumed less than 50 mg per day by the end of the first trimester had babies weighing on average 161 g (5.75 oz) more than those of women who maintained a caffeine consumption of more than 300 mg per day throughout the pregnancy. Similarly, women who consumed more than 200 mg per day had babies who weighed 60 to 70 g (2.15 to 2.50 oz) less than those of women with minimal caffeine intake. This relationship persisted across all trimesters. When measured as a continuous variable, the risk of fetal growth restriction increased sharply from baseline up to 30 mg of daily caffeine consumption, and continued to increase in an almost linear fashion. At no point did the estimated risk stop increasing as caffeine intake increased.

Conclusion: Caffeine intake is directly correlated with small but notable fetal growth restriction. Although a safe threshold cannot be determined, maternal caffeine intake of less than 100 mg per day minimizes the risk of fetal growth restriction.

editor's note: This study provides additional support for limiting caffeine during pregnancy beyond current recommendations; the American College of Obstetricians and Gynecologists suggests a maximum of 300 mg per day, and the U.K. government's Food Standards Agency recommends no more than 200 mg per day. In an accompanying editorial, Olsen and Bech highlight the complexities of measuring caffeine intake and caffeine's potential fetotoxic effects.1 Several earlier studies used coffee use as a prime measure of caffeine intake, whereas this study carefully included caffeine from all sources, and found tea to provide the majority of caffeine. Additionally, the authors measured each participant's individual caffeine metabolism and found some evidence that those with faster caffeine metabolism were at higher risk of fetal growth restriction, suggesting that a metabolite may prove more harmful than caffeine itself. Further study is needed to clarify this relationship. Finally, the amount of growth restriction needs to be put into perspective with other risks; with the highest caffeine intake (more than 300 mg per day), birth-weight reduction is about 140 g (5 oz). In an otherwise healthy infant, this amount may not have clinical significance. However, if added to growth restriction from maternal smoking and alcohol use, the difference may affect infant mortality and morbidity. Consequently, the editorial tempers the study's recommendation: although it may be helpful to reduce maternal caffeine intake, it is not advantageous to do so by replacing caffeinated beverages with those containing alcohol or high amounts of sugar.—a.c.f.

Reference(s)

1. CARE Study Group. Maternal caffeine intake during pregnancy and risk of fetal growth restriction: a large prospective observational study. BMJ. November 3, 2008;337:a2332.

Background: Recent concern about rosiglitazone (Avandia) started with a 2007 meta-analysis associating its use with higher rates of myocardial infarction (MI) and congestive heart failure (CHF). There is some concern about whether pioglitazone (Actos)—as a related drug—might also pose similar risks. One study reported a lower incidence of a combined end point of MI, stroke, and cardiovascular mortality with pioglitazone, but did not examine these outcomes individually. Head-to-head comparisons of these two drugs have been rare, and have generally not addressed long-term clinical outcomes. Winkelmayer and colleagues compared cardiovascular outcomes and mortality rates between patients starting rosiglitazone and pioglitazone.

The Study: The authors conducted a population-based cohort study of U.S. Medicare beneficiaries older than 65 years. They reviewed medical claims data over a seven-year period, using National Drug Code numbers to identify patients who were started on rosiglitazone or pioglitazone, as well as comorbidities, cardiac procedures, and hospitalizations. The primary end point was all-cause mortality, with secondary end points of MI, stroke, and hospitalization for CHF.

Results: Of the 28,361 eligible patients, 50.3 percent were started on pioglitazone and 49.7 percent on rosiglitazone. Baseline traits were similar between the groups, although the rosiglitazone group had slightly more diagnoses of coronary artery disease and CHF at baseline. Rosiglitazone users had a 15 percent greater mortality rate compared with pioglitazone users, but whether this was specifically of cardiovascular origin could not be determined. Rosiglitazone users also had a 13 percent greater risk of hospitalization for CHF compared with pioglitazone users. Risks of MI or stroke were comparable using either medication.

Conclusion: The authors conclude that patients started on rosiglitazone have higher rates of all-cause mortality and hospitalization for CHF than those using pioglitazone. The risks of MI or stroke are comparable for the two drugs. This study confirms the safety concerns of rosiglitazone relative to pioglitazone, although pioglitazone has also been shown to increase risk of CHF.

editor's note: Although this study shows that pioglitazone may be ‘safer’ than rosiglitazone, this is a relative distinction only; both drugs are linked with higher rates of CHF.1 For this reason, the American Diabetes Association (ADA) has advised caution with the use of either agent, especially with class III or IV heart failure. New guidelines from the ADA and the European Association for the Study of Diabetes recommend a “back-to-basics” approach for treating diabetes. Lifestyle modification and metformin (Glucophage) should be used initially, followed by insulin, sulfonylureas, or both if further control is needed. Thiazolidinediones and other drug classes should be reserved for cases in which the initial treatments are unsuccessful in achieving target glycemic goals.2—k.t.m.

Reference(s)

1. Winkelmayer WC, et al. Comparison of cardiovascular outcomes in elderly patients with diabetes who initiated rosiglitazone vs pioglitazone therapy. Arch Intern Med. November 24, 2008;168(21):2368-2375.