The Use of OTC Medications in Older Adults

Miranda Wilhelm, PharmD
Clinical Assistant Professor
Department of Pharmacy Practice
Southern Illinois University Edwardsville
School of Pharmacy, Edwardsville, Illinois

J. Mark Ruscin, PharmD, BCPS
Professor
Department of Pharmacy Practice
Southern Illinois University Edwardsville
School of Pharmacy, Edwardsville, Illinois

6/18/2009
US Pharm. 2009;34(6):44-47.

With the introduction of the Beers Criteria, there has been a virtual explosion of literature regarding the inappropriate use of medications in older adults. The Beers Criteria focus on prescription medications, with only a few OTC medications being addressed (diphenhydramine, mineral oil, cimetidine).¹ However, this provides little guidance for practitioners when making recommendations with respect to appropriate medications, particularly among many available OTC products.

Older adults generally have more medical problems and use more medications, both prescription and OTC, when compared to younger adults. Many older adult patients self-treat using OTC medications. Older adults account for about 13% of the United States population and purchase 40% of all OTCs consumed.² Pharmacists, as one of the most accessible health care providers, have an opportunity to assist these patients when making decisions in the OTC aisle. As the baby boomers age, there will be even more opportunities for pharmacists to assist older adults with making appropriate OTC medication choices. To do this successfully, it is essential for pharmacists to be able to evaluate and assess patient symptoms. One quick and effective method for determining the needs of patients and to see if they are candidates for self-care is the QuEST/SCHOLAR process.^3,4 QuEST is a mnemonic for assessing and counseling the patient (TABLE 1). SCHOLAR is a mnemonic to assist with symptom assessment (TABLE 2). The purpose of this article is to provide the practicing pharmacist with a review of various OTC options, for some of the more common medical problems or disease states, that are generally safe for older adults.

Allergy

Allergic rhinitis has an estimated prevalence of between 9% and 40% in the U.S. adult population.⁵ It can be seasonal if occurring only during certain parts of the year, or perennial if symptoms occur year round. Mild-to-moderate symptoms are most often treated with antihistamines and decongestants. Cromolyn sodium is an intranasal mast cell stabilizer that prevents the release of histamine and other mediators of allergic rhinitis. The nasal spray is approved for the treatment and prevention of seasonal and perennial allergic rhinitis symptoms such as sneezing and runny, stuffy, and itchy noses. As a topical nasal spray, it exhibits a local effect with minimal systemic absorption. The most common adverse effects relate to the local action and include sneezing and nasal stinging and burning. Since it exerts only a local effect, no drug interactions are reported. No dosage adjustments are needed for renal or hepatic impairment. The minimal adverse effects and no drug interactions therefore make cromolyn sodium a good choice for treating allergic rhinitis in older adults.

Ketotifen is an ocular antihistamine, mast cell stabilizer, and eosinophil inhibitor that prevents the release of histamine and other mediators of allergic conjunctivitis. The ophthalmic solution is approved for the prevention of ocular itching due to allergic conjunctivitis. Previously available only by prescription, ketotifen is now available OTC. Most of the OTC eye drops contain an antihistamine and a decongestant to treat the itching and redness associated with allergic conjunctivitis. Ocular decongestants have the same problem of rebound congestion as the nasal decongestants. As a result, patients should be counseled not to use the products longer than 3 to 5 days consecutively. Ketotifen is not a decongestant and therefore does not have the rebound congestion problem. As a topical ophthalmic solution, it exhibits a local effect with minimal systemic absorption. The most common adverse effects include conjunctiva congestion, headache, and rhinitis. No systemic drug interactions have been reported with ketotifen since it has only a local effect. No dosage adjustments are needed for renal or hepatic impairment. The lack of rebound congestion and lack of reported drug interactions make ketotifen a good choice for treating allergic conjunctivitis in older adults.

Loratadine is a second-generation oral antihistamine. It is approved for the relief of seasonal and perennial allergic rhinitis symptoms, such as sneezing, itching, and rhinorrhea. As a large protein-bound lipophobic molecule with charged side chains, it does not cross the blood-brain barrier easily. This is what accounts for the lack of sedating effects. Unlike the sedating, first-generation antihistamines, loratadine does not activate alpha-adrenergic receptors or block cholinergic receptors. Therefore, it does not produce substantial anticholinergic adverse effects such as dry mouth, dry eye, urinary retention, and constipation, which are commonly seen with the sedating antihistamines. Older adults are also more susceptible to the cognitive side effects associated with antihistamines having anticholinergic effects. The lack of sedating and anticholinergic effects makes loratadine one of the better choices for treating allergic rhinitis in older adults.

Patients with more severe symptoms or with symptoms that do not resolve with a trial of OTC medications should be referred to their primary care provider (PCP). Patients should also be referred to their PCP if sinusitis is suspected.

The Common Cold

The common cold, which is caused by rhinoviruses or coronoviruses, cannot be cured with any available drug therapies at this time. As a result, recommended treatments are primarily symptomatic. The most common symptoms include sore throat, runny nose, congestion, sneezing, coughing, muscle aches, and fatigue. Although there is an abundance of OTC products available to treat cold symptoms, most products contain combinations of antihistamines, decongestants, expectorants, and cough suppressants. Many of these medications may not be appropriate for patients who have other medical problems (hypertension, diabetes) or take other medications.

Oxymetazoline is an alpha-adrenergic receptor agonist available as a nasal spray. It causes vasoconstriction of the mucous membranes resulting in decreased nasal mucosa edema. This promotes drainage and improves breathing. The nasal spray is approved for relief of stuffy nose symptoms associated with the common cold, sinusitis, hay fever, and nonseasonal, seasonal, and perennial allergic rhinitis. When administered intranasally, it exhibits a local effect with minimal systemic absorption. Unlike oral decongestants that can increase blood pressure, the topical decongestants do not have this effect; therefore, patients who are taking blood pressure-lowering medication would not need to worry about oxymetazoline raising their blood pressure. The most common adverse effects relate to the local action and include nasal stinging and burning, dryness, and sneezing. The use of oxymetazoline can result in rebound nasal congestion, so patients should be counseled not to use the product longer than 3 to 5 days consecutively. It has only a local effect, so little to no drug interactions are suspected. No dosage adjustments are needed for renal or hepatic impairment. Minimal adverse effects and no drug interactions make oxymetazoline a good choice for the short-term treatment of nasal congestion symptoms associated with the common cold in older adults.

In older adults, viral infections can increase the risk of developing secondary bacterial infections, such as bronchitis, pneumonia, or sinusitis. If one of these is suspected, patients should be referred to their PCP.

Osteoarthritis

Osteoarthritis affects nearly 50 million adults in the U.S., and the prevalence increases substantially with age.⁶ Pain due to osteoarthritis is one of the most common medical complaints among older adults.⁷ Limitations in physical activity and physical functioning are strongly associated with pain symptoms in osteoarthritis. Acetaminophen is a centrally acting analgesic. It is approved for the treatment of mild pain, fever, osteoarthritis, and migraine headaches. It is also approved for the temporary relief of headache, myalgia, back pain, dental pain, dysmenorrhea, arthralgia, or minor aches and pain associated with the common cold or influenza. Acetaminophen is the drug of choice for osteoarthritis when there is little to no inflammation involved. The American College of Rheumatology recommends acetaminophen as the first-line treatment option for osteoarthritis of the hip and knee.⁸ Compared to the alternative OTC pain relievers, nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen has a more favorable adverse-effect profile. Older adults are at increased risk for the renal dysfunction, gastrointestinal irritation and bleeding, and exacerbations of hypertension that NSAIDs can cause. Acetaminophen's adverse effects are mainly seen at high doses used long-term or when the medication is used inappropriately (overdose). Acetaminophen should be used with caution in patients with hepatic impairment or history of alcohol use/abuse. It is the drug of choice for pain relief in patients with renal impairment, but dosage titration based on clinical effect is encouraged. When used as directed in doses not exceeding 4 g per day, acetaminophen is a safe and effective pain reliever for older adults. Despite its relative safety, some older patients may not get adequate analgesic effects from acetaminophen because of age-related changes in gastric motility, disease-related changes such as diabetic gastroparesis, or anticholinergic drug effects. Acetaminophen is primarily absorbed in the small intestine, and delayed presentation of the drug to the site of absorption may lead to inadequate analgesic effects.

Although not a pharmacologic agent, continuous low-level heat wrap therapy products are available in the OTC pain relief aisle. Low-level heat wrap therapy is approved for the treatment of arthritis and muscle pain. Low-level heat helps to relax sore and tight muscles, increasing flexibility and range of motion.⁹ With one application, the wraps provide heat for 8 to 12 hours. On the other hand, topical treatments such as counterirritants require application three to four times daily to maintain pain relief. Counterirritants, available as creams and ointments, can be messy, greasy, and are generally not acceptable to patients for long-term use. The heat wraps contain no medication, so there are no drug interactions and no dosage adjustments are required for renal or hepatic impairment. Neither heat nor occlusive dressings should be used in combination with other topical analgesics. Using the combination can increase the risk of systemic side effects. Low-level heat wraps provide a safe and effective alternative to OTC pain relief medications as well as an adjunct to oral therapy for older adults.

Heartburn

Heartburn and gastroesophageal reflux are very common symptoms in adults in the U.S., with an estimated 10% to 20% of adults having reflux symptoms on a weekly basis.¹⁰ Repeated exposure of the esophagus to refluxed stomach contents can lead to inflammation and erosions. However, for many patients, lifestyle changes and use of OTC acid-blocking medications can control symptoms and prevent complications of esophagitis.¹¹ Famotidine and nizatidine, as histamine₂-receptor antagonists, decrease gastric acid by blocking the effect of histamine on gastric cell receptors. They are approved for the prevention and treatment of mild-to-moderate, infrequent heartburn associated with acid indigestion or sour stomach. One dose taken 1 hour prior to anticipated heartburn or at the onset of heartburn can provide relief for up to 12 hours. This is useful for patients who experience heartburn at night. Histamine₂-receptor antagonists in general have a low incidence of adverse effects. Famotidine and nizatidine are not metabolized by the CYP450 system and, therefore, lack the drug interactions commonly seen with cimetidine. Ranitidine is metabolized by the CYP450 system, but to a lesser extent than cimetidine, so drug interactions are possible but are not seen clinically with OTC doses. The main drug interactions reported with famotidine and nizatidine are related to their acid-lowering effects. Medications that require an acidic environment to be absorbed, such as ketoconazole and itraconazole, will have reduced bioavailability. Dosage adjustments are needed for patients with renal impairment but not with hepatic impairment. The limited adverse effects and minimal drug interactions associated with famotidine and nizatidine make these two histamine₂-receptor antagonists, with dosage adjustments as needed, a good choice for patients with heartburn.

Omeprazole, as a proton pump inhibitor, decreases gastric acid by inhibiting acid secretion. It is approved for the treatment of frequent heartburn in patients experiencing symptoms 2 or more days per week. Omeprazole is not indicated for immediate relief of infrequent heartburn, and it may take up to 4 days for the full benefit to be seen. Omeprazole is taken once daily 30 minutes prior to the morning meal for 14 days and can be repeated after 4 months if symptoms return, or as directed by a physician. If heartburn symptoms persist or return before the 4-month time period, the patient should be instructed to consult with a physician. Omeprazole has a low incidence of adverse effects. No dosage adjustments are required for renal impairment, but dosage reductions are recommended for patients with severe hepatic impairment. One caution for pharmacists and something that patients should be aware of relates to drug interactions. Omeprazole has the same interaction as the histamine₂-receptor antagonists with regard to lower bioavailability of medications that require an acidic environment. Also, omeprazole is an inhibitor of the CYP450 system and therefore will interact with other medications metabolized by this system.

Patients who have frequent symptoms or symptoms that do not respond to OTC medications or who experience what is termed alarmsymptoms (continual pain, chest pain, dysphagia, odynophagia, weight loss, or choking) should be referred to their PCP.¹¹

Constipation

Constipation is a common problem among older adults, and many patients choose to initiate self-treatment. Although it is often considered a fairly benign issue, constipation not appropriately addressed can lead to bowel obstruction and hospitalization. Constipation is defined on the basis of stool frequency, stool consistency, and difficulty passing stools.^12,13 In the U.S., insufficient dietary fiber is a frequent underlying issue for many patients with constipation. Commonly used medications are also associated with constipation, including opiate analgesics, anticholinergics, and calcium or iron products. General nondrug approaches to improving constipation include dietary fiber (at least 10 g daily of crude fiber), adequate fluid intake, and exercise. Fruits, vegetables, and cereals are among the best foods to increase dietary fiber intake. There are numerous OTC medications to treat constipation, but not all are appropriate in all situations. For patients who have symptoms of obstruction (nausea, vomiting, abdominal pain or distention) or fecal impaction, OTC treatments should not be recommended, and these patients should be referred to their PCP for evaluation or disimpaction prior to the use of oral laxative agents.

Bulk-forming laxatives, including psyllium and methylcellulose, can be used to supplement dietary fiber if patients do not have adequate intake of dietary fiber. Bulk-forming laxatives are generally safe since they are not systemically absorbed. However, these agents must be taken with adequate fluid to prevent intestinal obstruction. Bulk-forming agents can be useful for ongoing treatment and for preventing chronic constipation. These agents are not optimal for patients who have acute constipation, as they can take several days to produce the desired effect. Some patients may experience abdominal distention and flatus with increases in dietary fiber, but these symptoms typically decline over time.

Emollient laxatives, such as docusate sodium, are not exceptionally effective for treating constipation but may be useful in situations where straining during defecation should be avoided, such as with hemorrhoids or following rectal surgery or a myocardial infarction.

Polyethylene glycol 3350 is an osmotic laxative that is generally safe to use for older patients with constipation. It does not cause electrolyte disturbances, as can be seen with other saline-type osmotic laxatives, including magnesium citrate or sodium phosphate. As a result, polyethylene glycol-containing products are safer for patients with significant renal dysfunction or with congestive heart failure. The laxative works by osmotic action and retention of fluid in the gastrointestinal tract, which leads to softening of the stool. Unlike some of the saline-type osmotic laxatives, which work quickly (hours), polyethylene glycol takes slightly longer to produce the desired effect (1 to a few days).

Acute constipation can be relieved with the use of glycerin suppositories. Glycerin is considered very safe, and the onset of action is usually less than 30 minutes. Occasionally, patients may experience mild rectal irritation.

Insomnia

Complaints regarding sleep increase dramatically with advancing age. Aging is associated with changes in sleep architecture, including decreased sleep efficiency, total sleep time, and restful sleep stages.¹⁴ Numerous factors can also impact sleep, such as pain, urinary symptoms associated with benign prostatic hyperplasia or overactive bladder, restless legs syndrome, sleep apnea, issues with sleep hygiene, or side effects of medications. It is very important to look for underlying causes of sleep problems before initiating medications to treat sleep symptoms. Improving sleep hygiene and healthy sleep habits (limit napping, avoid late-day exercise, avoid late-day caffeine and fluid intake, etc.) are also important to consider prior to initiating medications for sleep.¹⁵

Many OTC sleep products contain sedating antihistamines, such as diphenhydramine. These products are generally not recommended for older adults because of the anticholinergic side effects. The food supplement melatonin has been advocated for sleep in older adults, since aging has been associated with a decrease in this natural hormone secreted by the pineal gland.¹⁶ Supplementation with melatonin in older adults with low levels of melatonin does improve sleep efficiency.¹⁷ There have been several studies of melatonin in elderly patients with insomnia, but most have been small and the melatonin products have been varied, including both controlled-release and immediate-release products in dosages ranging from 0.5 mg to 6 mg dosed at bedtime.^18,19 One study also showed improvements in sundowning symptoms in patients with dementia and agitated nighttime behaviors.¹⁹ Melatonin is considered fairly safe, and reported side effects have been minimal in the available published studies.

Urinalysis: A Guide for Pharmacists

Kirandeep Panesar,
BPharm (Hons), MRPharmS, RPh, CPh
Freelance Medical Writer
Orlando, Florida,
Consultant Pharmacist
Acacia Pharmacy,
Nairobi, Kenya

FACULTY DISCLOSURE STATEMENTS:

Kirandeep Panesar has no actual or potential conflict of interest in relation to this activity.

U.S. Pharmacist does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.

The evolving role of pharmacists as providers of health and health care information encompasses both in-pharmacy clinical testing and the provision of counseling on tests carried out in the more traditional laboratory setting. Clinical laboratory tests can be used to confirm or support a diagnosis, assess the severity of a disease (e.g., MRI for tumor size), monitor the response to treatment, monitor appropriate drug dosing, and help prevent toxic side effects and interactions.¹ To facilitate the role of pharmacists in health promotion, a basic knowledge of clinical testing is useful for both institutional and retail pharmacists. This will assist pharmacists when counseling patients on preparing for laboratory procedures and receiving test results; adjusting drug therapy based on test results; providing in-pharmacy testing to promote patient health; and liaising with other health professionals to optimize patient therapy.

Urine testing provides a broad spectrum of information to health care providers and offers a noninvasive and therefore pain-free option to diagnostic testing for a number of conditions. Urinalysis has been used in diagnostic medicine for thousands of years, dating as far back as ancient Egypt, where there are descriptions of polyuria. “In the 7th century AD, Protosharis suggested that it was important to look at the color of urine and by 1674 Thomas Willis, a professor at Oxford University, recorded that the urine of his patients with diabetes tasted sweet.”² However, it is only with the introduction of the microscope in the 19th century that there have been major advances in this field. Dipstick testing, the application of modern chemical and microscopic techniques to constituent analysis, automation, and, most recently, monoclonal antibody and recombinant gene technology, have enhanced and improved urine examination.³

Today, urinalysis is a popular test in medical diagnosis and is frequently ordered with hospital admissions and regular checkups since it is relatively simple, inexpensive, and pain free. It may specifically be ordered in patients complaining of lower back pain, abdominal pain, and problems with urination or in pregnancy. Most importantly, testing urine samples may reveal disease conditions that would otherwise go unnoticed. For example, it has been shown that rising thyroid-stimulating hormone levels may be due to a rare condition called nephrotic syndrome and not to poor compliance with thyroxine therapy. This condition can be suspected with dipstick urinalysis and confirmed with biochemical testing and a renal biopsy.⁴

The test itself can be broken down into three components: visual examination (macroscopic analysis), dip-and-read tests, and microscopic analysis. There are a large number of dip-and-read tests now available for OTC purchase, and pharmacists will often be asked to provide instructions on the use of these kits. Additionally, pharmacists may be required to counsel patients on collecting urine samples, interpreting test results, and adjusting drug therapy based on these results.

COLLECTING URINE FOR TESTING

Obtaining a good urine sample is a tricky procedure, since the patient provides a majority of the samples. Consequently, patients need to be clear on how and when to collect the sample. Clean-catch of midstream urine collection is suitable for most test procedures. Some tests may require timed urine collection such as the 24-hour urine collection. In hospitals, urine samples from inpatients are frequently collected by catheterization. Recently, the accuracy of the 24-hour sample, a time-consuming and inconvenient procedure, has been questioned for testing proteinuria. Accordingly, the National Kidney Foundation recommends the use of spot urine samples that correct for creatinine concentration over the 24-hour sample.⁵

Patients who are required to collect their own samples should ideally be provided with a container specifically designed for urine collection, free of any chemicals that may affect the test results. When testing babies, the parent or caregiver should be given a urine collection bag. Specific advice for patients collecting urine is given in TABLE 1.

Table 1

Collecting Urine: Advice for Your Patients

For clean-catch or midstream urine collection

Use a container provided specifically for urine collection Wash your hands before collecting the sample Remove the lid of the collection container and place it with the inner surface up, making sure you do not touch the inside of the lid or the container Clean the area around the genitals using a medicated swab or towelette - Males should pull their foreskin back, if present, and clean the tip of the penis - Females should open the folds of the labia (vagina) and clean from the front to the back Urinate into the toilet or urinal for a few seconds, then pause Continue urinating into the collection container until enough urine has been collected Finish urinating into the toilet or urinal, if necessary Carefully replace the lid and return the container for testing If the sample is not being tested immediately, store it in a refrigerator Always wear gloves if helping another patient to collect urine

For 24-hour urine collection

Ensure that the specimen container is kept refrigerated at all times Start the urine test by urinating directly into the toilet. Do not collect this sample, but make a note of the time and date on the storage container For the next 24 hours, urinate into the collection container and transfer the urine into the storage container If you need to use more than one container during the 24-hour period, fill one container first before you start filling the next one At the end of the 24-hour period, urinate and transfer this sample into the storage container. Make a note of the time and date for the end of this period on your container Keep the sample refrigerated and return it to the testing center as soon as possible

Urine samples should be tested immediately after collection to prevent false results. If immediate testing is not possible, the sample should be refrigerated and allowed to return to room temperature before testing. Samples that are stored incorrectly may give inaccurate results owing to reduced clarity because of crystallization of solutes; increased alkalinity (pH) due to the loss of CO₂; loss of ketone bodies and bilirubin (if present); dissolution of cells and casts; and overgrowth of contaminating microorganisms.

VISUAL EXAMINATION (MACROSCOPIC ANALYSIS)

Normal urine is a clear, pale yellow-colored fluid that has a slight odor of urea and is slightly acidic; any changes in the color, clarity, and smell of a urine sample can signal potential problems that may require further investigation. Dehydration results in an increase in the concentration of urochrome, the chemical that gives urine its distinct color, causing a darkening of the urine to an orange hue. Often, changes in urine color are a result of certain foods or drugs, and pharmacists should essentially rule out this possibility (TABLE 2). Blue urine is distinctive of the rare, inherited metabolic disorder termed the blue diaper syndrome. It is caused by incomplete breakdown and intestinal absorption of tryptophan in children.

Table 2
Factors That Can Change the Color of Urine
Color of Urine	Foods	Drugs	Diseases
Cloudy	Diet high in purine-rich foods	NA	Kidney stones, excessive cellular material, proteinuria, UTI accompanied by a foul odor
Orange	Vitamin C, carrots, carrot juice	Rifampin, warfarin, phenazopyridine	Dehydration due to increased concentration of urochrome
Red or pink	Beets, blackberries, rhubarb	Levodopa, chlorpromazine, thioridazine, propofol, rifampin	Hematuria
Blue or green	Asparagus	Amitriptyline, indomethacin, cimetidine, promethazine, triamterene	Blue diaper syndrome, pseudomonal UTI
Dark brown	Fava beans, rhubarb, aloe	Chloroquine, primaquine, metronidazole, nitrofurantoin, methocarbamol, senna, vitamin B complex	Liver disorders such as hepatitis, jaundice, and cirrhosis accompanied by yellow skin and pale stools; myoglobin; renal disorders that affect the kidney’s ability to excrete fluid and waste materials
Black	NA	Ferrous salts	NA
NA: not applicable; UTI: urinary tract infection.

The odor of urine may also provide some direction toward a diagnosis. Patients who have diabetes mellitus pass sweet, fruity-smelling urine caused by the excretion of acetone, and after prolonged bladder retention, alkaline fermentation causes an ammoniacal odor.⁶ The urine of anorexic patients often smells like pear drops, and patients with urinary tract infections (UTIs) often pass urine with a pungent smell. Gastrointestinal-bladder fistulas in which feces may be deposited in the bladder commonly result in urine with a fecal odor; the formation of sulfur compounds in cystine decomposition disorders causes urine to have a sulfuric smell.⁶

DIP-AND-READ TESTING
How to Use the Test Strips

Dipsticks are very simple and convenient to use, but results can be easily misinterpreted since they are semi-quantitative. Semiquantitative analysis reports results as a range within which the actual result may lie, using a color chart or other qualitative reading. Reagent strips can be used to test pH, urine specific gravity (USG), UTIs, proteins, glucose, ketone bodies, bilirubin, and urobilinogen, and to confirm pregnancy and the presence of certain drugs (TABLE 3). However, the reliability of this method of testing is still controversial since the results may be highly inaccurate.

Table 3
Select Dip-and-Read Test Strips
Brand	Test
Clinistix	Glucose
Hemastix	Blood
Ketostix	Ketones
Bayer Multistix 10 SG	Bilirubin, blood, glucose, ketones, leukocytes, nitrite, pH, protein, urine specific gravity, urobilinogen
Uristix	Glucose and protein
Uristix 4	Glucose, protein, nitrite, leukocytes
Clearblue, EPT, First Response	hCG hormone (pregnancy)
hCG: human chorionic gonadotropin.

When using a dipstick, the urine specimen should be collected in a sample bottle. Then the test area of the strip should be completely immersed in the urine sample and removed immediately. Shake off any excess urine by gently tapping the strip against the side of the specimen container. The strip should be left to react for the prescribed time. Finally, compare the color of the test area to the chart provided.⁷

Storage of Test Strips

Test strips should be stored at a constant temperature between 15°C and 30°C in a tightly closed container. The provided desiccant should not be removed from the container. Bayer Multistix 10 SG test strips exposed to the air for prolonged times have been shown to give false-positive results for glucose and false-negative results for microscopic hematuria (TABLE 4).⁸ Furthermore, Gallagher et al found that out of nine reagents tested in the Chemstrip-9 dipstick (leukocyte esterase [LE], pH, protein, glucose, ketones, urobilinogen, bilirubin, blood, and nitrites), only the nitrite portion of the exposed dipsticks showed a rapid cumulative loss of specificity over time.⁹ All other tests demonstrated reproducible results after exposure to room temperature and humidity for 1 to 15 days.⁹ Therefore, even though manufacturers indicate that the strips should be stored in a tightly closed container and the desiccant should not be removed, all reactants may not lose their activity if exposed to air or humidity. However, it is a good practice to follow the label guidelines, and patients should be similarly advised. Discard any strips past their expiration date or any unused strips after 6 months of first opening.

Table 4
Factors That Can Change the Color of Urine
Dipstick Test	False-Positive	False-Negative
pH	Acidic urine: ingestion of proteins and acidic foods Alkaline urine: urine stored at room temperature, diet high in citrate, antiepileptic drugs, aged urine specimen	NA
USG	Dextran solutions, proteinuria	Alkaline urine
Leukocyte esterase	Contamination	Elevated USG, glycosuria, ketonuria, proteinuria, ascorbic acid, certain antibiotics (tetracycline, cephalexin, gentamicin, nitrofurantoin)
Nitrites	Contamination, exposure of dipstick to air, phenazopyridine	Elevated USG and urobilinogen level, nitrate reductase-negative bacteria, pH <6.0,>
Proteins	Alkaline or concentrated urine, phenazopyridine, ranitidine (Zantac)	Acidic or dilute urine
Glucose	Ketones, levodopa, exposure of dipstick to air	Elevated USG, uric acid, vitamin C
Ketones	Acidic urine, elevated USG, mesna, phenolphthalein, some drug metabolites (e.g., levodopa)	Delay in examination of urine
Blood	Dehydration, exercise, menstrual blood	Captopril, elevated USG, pH <5.1,>
Bilirubin	Phenazopyridine	Chlorpromazine, selenium
Urobilinogen	Elevated nitrate levels, phenazopyridine	NA
NA: not applicable; USG: urine specific gravity. Source: References 9-11.

Uses of Dip-and-Read Testing

Urinary Tract Infections: UTIs are characterized by an increase in the enzyme LE, nitrite, and protein levels. LE is a component of white blood cells that is normally found with bacteria, and nitrite levels rise in urinary infections since the pathogens reduce urine nitrate to nitrite.¹² Most dipsticks test for at least two of these chemicals depending on the brand used.

Numerous studies, meta-analyses, and reviews have been conducted to determine the accuracy of dip-stick testing for UTIs and compare the reliability of reagent strips to culture assays, but there remains a discrepancy over the results. Yuen et al reviewed the use of leukocyte esterase dipstick testing in children and concluded that it should not be used as a replacement for microscopic examination.¹³ Conversely, a recent meta-analysis showed that a true negative can be concluded if both nitrites and leukocyte esterase test negative with a dipstick test.¹⁴ Moreover, Gorelick and Shaw demonstrated that the results of a dipstick analysis for both nitrite and leukocyte esterase are comparable to those of a Gram stain test and “superior to a microscopic analysis for pyuria.”¹⁵

However, in patients with a high risk of contracting a UTI, it has been shown that a negative urine dip-stick test does not rule out the possibility of an infection.¹⁶ More specifically in the long-term care setting, high rates of false-negative results for LE and nitrite with dipstick tests have been demonstrated.¹² With an aim to overcoming this discrepancy, Mariani et al have proposed a protocol to determine which results of screening urine specimens that are positive on a dip-stick culture would be confirmed by a properly performed microscopic urinalysis.¹⁷

In an attempt to contain costs and save time by eliminating the urine culture step, the use of immunochromatography strips using antibodies to detect infectious agents has been examined.¹⁸ Even though immunochromatography has been found to be useful in urinalysis, this form of testing is yet to be fully developed. The newer dipslides offer a convenient way to perform a culture assay. They consist of a sterile paddle that is coated with agar on both sides, ready to use in a clear plastic tube.

Urinary pH: Health care professionals may use the urinary pH to select drug therapy for UTIs. The effectiveness of some antibiotics used to treat UTIs is affected by the urinary pH. Methenamine, for example, works only in an acidic environment, whereas streptomycin and neomycin work better in an alkaline environment.⁷ Urinary pH may also be used to reduce the risk of kidney stones. Uric acid and calcium oxalate stones form well in acidic urine, whereas alkaline urine is optimal for the formation of calcium carbonate and calcium phosphate stones.

Desai and Assimos indicated that determining uri-nary pH is an important part of the initial evaluation of certain patients with nephrolithiasis.¹⁹ Urinary pH manipulation therapy may be used to treat patients with cystine and uric acid stones, which results in the dissolution of uric acid stones. Monitoring the pH of patients receiving therapy for hypocitraturia is necessary to ensure that the pH does not go above 7.0, since overalkalinization can cause the formation of calcium phosphate stones.

Urinary pH is normally acidic, ranging from 4.5 to 8.0, but it is not as well regulated as blood pH due the absence of buffers in the urine. An elevated (alkaline) pH may be the result of:

• Aged urine specimen; the loss of CO₂ causes increased alkalinity.
• Systemic alkalosis; this can be further confirmed by testing serum pH, which is a better indicator.
• Urine left at room temperature; Cook et al demonstrated that urine stored at room temperature has a pH of >9.0 and that the pH of samples stored below -20°C was relatively stable.²⁰
• Infection; bacteria break down urea to ammonia that combines with hydrogen ions and raises pH.
• Certain medications (e.g., antiepileptics that have been shown to cause an increased tendency to form alkaline urine as the number of coadministered antiepileptics increases).²¹
• Diet high in citrate.
• Magnesium-ammonium phosphate crystals.

Acidic urine may be the result of ingestion of proteins or acidic foods. Urinary pH can also be used to detect renal tubular acidosis. In this condition, the patient is unable to acidify urine to a pH of less than 5.5 following the administration of an acid load and an overnight fast.

Therefore, it is important for pharmacists to emphasize that urine that is not tested immediately should be stored in a refrigerator and to encourage patients to take the sample to the clinic as soon as possible for testing. Home urinary pH is increasingly being recommended by urologists for patients with uric acid and calcium phosphate stones, as well as for patients on medication therapy for hypocitraturia. The study conducted by Desai and Assimos found that Chemstrip and litmus paper are more accurate than Multistix in determining urinary pH.¹⁹ When recommending a suitable dipstick for a patient, pharmacists need to keep in mind that the litmus paper is significantly cheaper than the Chemstrip and is an adequate test for patients who are attempting to maintain therapeutic urinary pH levels.

Handheld urinary pH monitors are becoming available on the market, but their accuracy and cost-effectiveness have yet to be tested. These monitors will probably prove useful in busy clinical settings or for patients who need to monitor urinary pH for the long-term.

Hematuria: Hematuria is generally defined as the presence of three or more red blood cells per high-power field (HPF).⁶ Hematuria causes pink or red urine and can be due to a number of factors ranging from strenuous exercise and UTIs to more severe conditions such as kidney or bladder cancers. Rarely, it is due to an inherited disorder known as porphyria, in which heme precursors are excreted in the urine. Exposure of the urine to sunlight in patients with porphyria will result in dark reddish urine that may slowly change to a brown color.

Hematuria is detected by the peroxidase activity of erythrocytes; however, hemoglobin and myoglobin can also catalyze this reaction, giving false-positive results.⁶ Additionally, dipstick testing is highly sensitive and may pick up levels as low as one to two red blood cells per HPF.²² Further microscopic evaluation is recommended to confirm the findings of a dipstick test.

Urine Specific Gravity: USG is a measure of the amount of substances dissolved in the urine and is expressed in grams/mL. It indicates the kidneys’ ability to concentrate urine and the patient’s dehydration status, with normal values between 1.001 and 1.305. Decreased USG is observed in diabetes insipidus and overhydration. USG less than 1.02 for over 12 hours is indicative of generalized renal impairment, nephrogenic diabetes insipidus, and symptoms of inappropriate antidiuretic hormone. End-stage renal disease is characterized by specific gravity values between 1.007 and 1.010.

On the other hand, dehydration, contaminated urine, diarrhea, and heart failure will result in a higher reading for USG. Increased USG is also noted in patients who have been given low molecular weight dextrans or IV radiographic dyes for radiographic studies.

Protein: The glomerular capillary wall filters low molecular weight proteins that are then reabsorbed and metabolized by the proximal tubule cells. The normal value for protein levels in the urine varies from 0 to 30 mg/dL; the proteins consist of albumin, serum globulins, and proteins secreted by the nephron. Sustained protein-uria from 10 to 20 mg/dL may be a symptom of renal damage and requires further investigation. Most dip-stick tests detect protein by production if color with bromphenol blue is sensitive to albumin, but these tests may not detect low levels of gamma-globulin and Bence-Jones protein. If a positive result is obtained for proteins in the urine, further investigation should be performed to confirm the diagnosis.²³ Other causes of proteinuria include excessive exercise, exposure to cold, postural changes, pregnancy, febrile illness, UTIs, and diabetes mellitus.

Options for a differential diagnosis include a 24-hour urinary protein excretion (TABLE 5), spot urinary protein-creatinine ratio, precipitation tests, and microscopy. It has been shown that ranitidine (Zantac) can cause a false-positive test for proteinuria with Multistix. The manufacturers of Zantac therefore recommend testing proteinuria with sulfosalicylic acid. This is a more sensitive precipitation test that can detect albumin, globulins, and Bence-Jones protein at low concentrations.

Table 5
Extent of Renal Damage as Indicated by Amount of Protein in Urine
Protein Reading	Extent of Renal Damage
<1.0 g/24 h 1.0-3.5 g/24 h >3.5 g/24 h	Mild Moderate Severe nephrosis

Glucose: Urine testing for glucose is useful for patients who find blood glucose monitoring difficult. Glucose levels should read below 130 mg/24 hours; higher values are often observed in diabetes mellitus, pregnancy, sepsis, tubular damage, Cushing’s syndrome, and liver and pancreatic disease. Most dipsticks employ the glucose oxidase reaction, are specific to glucose, and do not detect reducing sugars. To overcome this, patients may be tested further using the Clinitest that is based on Benedict’s copper reduction test.

Ketones: Ketone bodies are the breakdown product of fat, and their presence in urine (positive dipstick test) may be seen in patients with poorly managed diabetes mellitus, in anorexic patients, or in those who are dieting (e.g., with the Atkins diet). Dipstick tests or test tablets detect acetic acid through a reaction with sodium nitroprusside.

Urobilinogen and Bilirubin: Urobilinogen and bilirubin are only detected in the urine in liver dysfunction and indicate further evaluation. The Chemstrip-9 test uses diazonium dyes that turn red with urobilinogen and bilirubin. Kupka et al demonstrated that urine bilirubin and urobilinogen assays may offer a cost-effective way of predicting liver function abnormalities.²⁴

Pregnancy Testing: Initial pregnancy tests can be performed on urine samples and later confirmed with a blood test. The levels of human chorionic gonadotropin (hCG) hormone double almost every 2.2 days during the first trimester of pregnancy, and these levels can be detected in the patient’s urine. Detectable levels start at 5 mIU/mL during the first week of gestation and rise to 100,000 mIU/mL at 2 to 3 months.²

Pregnancy test kits use monoclonal and polyclonal anti-hCG antibodies placed sequentially to detect the presence of hCG via a color change. The test area of the test strip is held under a stream of urine and then allowed to sit for about 1 minute. The specimen migrates from the test area by capillary action to a pad containing monoclonal anti-hCG antibody. If hCG is present, it forms a complex with the antibody, which then moves further to the test line. The test line is spotted with polyclonal hCG antibody, which binds the complex and causes a color change if hCG is detected. Some kits come with a control test line that will change color whether or not hCG is detected; this helps the patients ensure that they have performed the test correctly.

Sometimes, the levels of hCG are too low to be detected and patients may get a false-negative result. It is therefore important to advise the patient that she may need to perform a second test if she is testing very early on in the pregnancy. Some manufacturers provide two kits in the package so that patients may repeat the test a couple of weeks later if needed. Additionally, patients should test the first-morning midstream urine, when the levels of hCG are the highest. Patients taking diuretics and promethazine may also obtain a false-negative, whereas patients on anticonvulsants, anti-Parkinson drugs, hypnotics, and tranquilizers may get a false-positive result as well. Other causes of false-positive results are very rare but may indicate trophoblastic disease.

MICROSCOPIC ANALYSIS

Microscopic analysis reveals cells, pathogens, and contaminants visible under a HPF, and casts that can be viewed under a low-power field (LPF). The reference range for leukocytes, erythrocytes, and epithelial cells is 0 to 4/HPF. Normally urine does not contain any erythrocytes, as they are too large to pass through the renal tubules. Any red blood cells in the urine indicate hematuria and are a sign of a potential abnormality. White blood cells and transitional epithelial cells are visible in normal urine and only signal a problem if their concentrations increase. On the other hand, renal tubular cells are present in very low amounts and have normally disintegrated by the time the urine is voided. Intact renal tubular cells are an indication of renal tubular disease.

The presence of bacteria and yeasts in normal urine should be further analyzed using a culture. They may be a normal part of the microbial flora (e.g., bacteria), contaminants (e.g., yeast), or a sign of an infection.

Hyaline casts are formed from mucoprotein in the distal convoluted tubule and the collecting duct in the absence of cells. High numbers (>1/LPF) may suggest proteinuria, but such casts are normally present in lower numbers in the urine of most patients. Cellular casts contain leukocytes, erythrocytes or renal tubular cells, and sticky protein, and their presence is a symptom of renal inflammation, hematuria, or severe renal disease, respectively. When renal tubular cellular casts remain in the nephron for some time before being flushed out, they become granular casts, and then finally waxy casts. The granular and waxy casts are an indication of increasing renal damage.

The urine of healthy patients will commonly contain crystals of calcium oxalate and triple phosphate; their concentration is dependent on the urinary pH. However, the presence of cystine, tyrosine, and leucine crystals is abnormal and needs to be investigated.

In many cases, analyzing a urine sample microscopically is fairly challenging, and it may be difficult to identify and count the components even with a trained eye. This said, microscopic analysis is an indispensable part of urinalysis that can confirm a number of diagnoses made with dipstick testing.

CONCLUSION

Pharmacists play a vital role in guiding patients through the vast amount of information available today. Since urinalysis is an essential tool in clinical testing, it is important for modern pharmacists to have a working knowledge of these analytical procedures. Opportunities for counseling exist during the recommendation for OTC tests, interpretation of test results, referral of patients for further investigation, and adjustment of patients’ drug therapy.

pressure ulcer

Goldina Ikezuagu Erowele, PharmD
Clinical Pharmacy Specialist
Formulary Management & Pharmacoeconomics Services
Harris County Hospital District
Houston, Texas

Ruth Ebiasah, PharmD, MS
Clinical Pharmacy Specialist,
Palliative Care & Oncology
Holy Cross Hospital
Silver Spring, Maryland

In 2007, the National Pressure Ulcer Advisory Panel (NPUAP) redefined pressure ulcer as a localized injury to the skin and/or underlying tissue, usually over a bony prominence, as a result of pressure alone or in combination with shear or friction.¹ The earliest documentation of pressure ulcers was made by Hippocrates in 400 BC. Paget, in his clinical lectures on bedsores in 1873, said that pressure ulcers sometimes erupt from beneath intact skin. Pressure ulcers are a significant clinical, quality-of-life, economic, regulatory, and legal problem for providers and patients alike.² Pressure sores are a serious and common occurrence in older people, and they will continue to be a major health care concern as the population ages.

PREVALENCE

The prevalence of pressure ulcers has been described extensively in various health care settings, including long-term care facilities, acute- and critical-care settings, and general surgical settings. In the United States, prevalence is estimated to be 1.3 million to 3 million.³ Ranges in prevalence rates vary widely depending on the health care setting. According to the NPUAP, rates range from 10% to 18% in general acute care, 2.3% to 28% in long-term care, and 0% to 29% in home care.⁴ Other reported data have indicated rates of 3% to 14% in hospital settings.⁵

Pressure ulcers are a major cause of morbidity and mortality in older people and are the most common care problem among nursing home residents, with prevalence estimated at 2.6% to 24%.^1,6 In one longitudinal study, 17% of patients admitted to nursing homes had pressure sores at the time of admission.⁷ Among patients who did not have a pressure ulcer at admission, the risk of developing one after admission was 13% in the first year postadmission and 21% by the second year.^2,5 Additionally, it has been reported that the risk of developing a pressure ulcer following surgery is five times greater in patients older than 70 years of age than in those younger than 60 years.⁸

RISK FACTORS

The development of pressure ulcers is directly associated with the tissue's tolerance to pressure, as well as the intensity and duration of this pressure.⁹ Risk factors for the development of pressure ulcers are classified as intrinsic or extrinsic (TABLE 1).^8-10

Intrinsic Factors

Intrinsic factors are those that internally influence the integrity of the skin. These factors include, but are not limited to, the following:

Immobility: All bed-bound patients are at risk for developing pressure ulcers. Limited activity, an immobilized body part, or total inability to move or ambulate is a central, underlying risk factor for the development of pressure ulcers.

Advanced Age: Patients older than 75 years appear to be at greatest risk, possibly due to age-related changes in the skin.¹¹ Skin undergoes physical, structural, physiologic, and immunologic changes with increasing age. These changes may cause decreased barrier function, increased susceptibility to shearing forces, and decreased vascularity.

Impaired Sensory Perception: Conditions resulting in loss of sensation, pain perception, or level of consciousness (e.g., Parkinson's disease, Alzheimer's disease, diabetes mellitus, stroke, spinal-cord injury) may reduce mobility and cause loss of motor control, resulting in abnormal shear forces and friction on skin.⁹ Additionally, medications that impair sensory perception or level of consciousness (e.g., sedative-hypnotics, narcotic analgesics) can contribute to the development of pressure ulcers.

Poor Nutritional Status: Poor dietary intake and dehydration may contribute to the development of hypoalbuminemia, anemia, or vitamin or mineral deficiency (e.g., vitamin C, zinc), leading to impaired wound healing.⁹

Comorbidities: Any disease that results in diminished or altered tissue perfusion (e.g., ischemic heart disease, peripheral vascular disease, renal insufficiency, or hypotension) can contribute to the development of pressure ulcers.

Incontinence: Fecal or urinary incontinence can result in prolonged moisture and bacterial contamination. This promotes the breakdown of skin and facilitates the development of pressure sores. Moisture from incontinence may increase the risk of pressure ulcer fivefold.⁸

Extrinsic Factors

Extrinsic factors are related to the degree of external forces that are applied to the skin surrounding the potential wound site.⁹ These include pressure, frictional force, and shearing force.

Pressure: Pressure, the most important extrinsic factor, is created when the external surface against the skin and a person's skeleton compress soft tissue sufficiently to halt circulation.^8,9,12 The normal capillary filling pressure is 20 mmHg to 30 mmHg; the pressure required to compress capillaries and interrupt circulation is generally considered to be 32 mmHg.¹⁰ A patient lying on a hospital mattress can generate a pressure of 45 mmHg to 75 mmHg over such bony prominences as the sacrum, greater trochanters, and heels, where pressure ulcers commonly form.⁸ If this pressure is sustained for more than 2 hours and exceeds capillary filling pressure within the deep tissue, a pressure sore may result.⁸

Frictional Force: Frictional forces act to pull on the skin while the weight of the body moves in the opposite direction. This may occur when a patient is repositioned in bed or transferred from bed to a wheelchair.

Shearing Force: Shearing forces are exerted when gravity causes the body to slide while in a fixed position, as when a patient is positioned with the head of the bed in a raised position, generally at greater than a 30° angle.^8,9

SCREENING

Since numerous risk factors exist for pressure ulcer, prediction-assessment tools are widely used to stratify patients' risk. There is insufficient evidence for one scale being superior to others. Currently, the Braden and Norton scales are the most widely used prediction tools for pressure ulcer.^13,14 The Braden Scale, developed to foster early identification, comprises six sub-scales that rate sensory perception, skin moisture, activity, mobility, friction and shear, and nutritional status. The Braden Scale is performed upon admission, at least quarterly in long-term care facilities, after a major change in clinical status, or after return from the hospital. When the Braden Scale score is 16 or less, prevention protocols should be implemented. The Norton Scale rates physical and mental activity, mobility, and incontinence on a scale of 1 to 4. A score of 14 or less means that the patient is at risk.

PATHOPHYSIOLOGY

The skin consists of three major layers: the epidermis (outermost layer), the dermis (connective tissue containing nerves, blood vessels, and lymphatics), and the subcutaneous layer (containing adipose tissue).⁹ Skin repair and regeneration are a natural bodily process involving several complex steps. These steps, which may overlap, are categorized as the inflammatory phase, the proliferative phase, and the remodeling phase.

Following hemostasis at the site of injury, the beginning of the inflammatory phase is marked by initiation of an inflammatory response and attraction of neutrophils to the area by degranulating platelets. Transforming growth factor (TGF) beta, tumor necrosis factor (TNF) alpha, and fibroblast cells are released from the damaged blood vessels, and these attract inflammatory cells to the wound site.¹⁵ Responding neutrophils and macrophages synthesize additional growth and inflammatory factors and continue the breakdown and cleansing process.

The proliferative phase is characterized by the creation of an extracellular matrix and basement membrane degradation, in addition to the formation of new vasculature. This phase may last for up to 4 weeks in a clean, uncontaminated wound.⁹

After the third week, the remodeling phase begins; this phase can last for years after the initial injury. The tissue undergoes extensive remodeling as collagen and elastin are added and degraded by fibroblasts. The wound tissue's maximal tensile strength (approximately 80% of the tensile strength of the original tissue) is achieved by the 12th week, and the process of healing is complete.⁹

The aggravating event in pressure sores is purported to be an unrelieved external force—such as a mattress, wheelchair pad, or bed rail—or traumatic forces that may be present, including frictional and shearing forces. These forces cause circulatory interruption, resulting in ischemia and subsequent inflammation and tissue anoxia. Tissue anoxia leads to cell death, necrosis, and ulceration.

STAGES OF PRESSURE ULCER

Clinical assessment of pressure ulcer should be initiated by determining whether a patient is at risk and performing an examination for early signs of pressure-sore formation at the anatomical sites where such sores are most commonly encountered.⁸ Pressure ulcers usually occur on the lower part of the body, predominantly the sacral region and heels. Other sites include the elbows, ankles, trochanters, ischia, knees, scapulas, shoulders, and occiput.⁹

Pressure ulcers are staged according to one of four categories. In February 2007, the NPUAP redefined these categories and added stages for deep-tissue injury and unstageable pressure ulcers.¹

Suspected Deep-Tissue Injury: This is a maroon or purplish localized area of discolored, intact skin or a blood-filled blister that is caused by damage of the underlying soft tissue by pressure or shear. The affected region may be preceded by tissue that is painful, firm, mushy, boggy, warm, or cool compared with the adjacent tissue. It may be hard to detect deep-tissue injury in patients with dark skin. Evolution may involve a thin blister over a dark wound bed. The wound may evolve further and become covered in thin eschar. Even with optimal treatment, evolution may be rapid and expose additional layers of tissue.

Stage I: This stage consists of intact skin with nonblanchable redness of a localized region, usually over a bony prominence. Dark skin may not have visible blanching, but its color may differ from the surrounding area. The area may be painful, firm, soft, warm, or cool compared with the adjacent tissue. It may be difficult to detect this stage in patients with darkly pigmented skin. This stage may be a heralding sign of risk.

Stage II: This stage involves partial-thickness tissue loss and presents as a shallow, open ulcer with a reddish-pink wound bed without slough. This stage of ulcer may also present as an intact or open/ruptured serum-filled blister. It may present as a shiny or dry shallow ulcer without slough or bruising (bruising signifies suspected deep-tissue injury). This stage should not be used to describe skin tears, tape burns, perineal dermatitis, excoriation, or maceration.

Stage III: This stage is characterized by full-thickness tissue loss. Subcutaneous fat may be visible, but bone, muscle, and tendon are not exposed. Slough may be present, but the depth of tissue loss is not obscured. Undermining and tunneling may be involved. The depth of an ulcer of this stage varies by anatomical location: Since the ear, the bridge of the nose, the occiput, and the malleolus do not have subcutaneous tissue, stage III ulcers in these locations can be shallow; areas of significant adiposity, in contrast, can develop ulcers of this stage that are quite deep. Bone and tendon are not visible or directly palpable.

Stage IV: Stage IV comprises full-thickness tissue loss with exposed bone, muscle, or tendon. Slough or eschar may be found on some areas of the wound bed. Undermining and tunneling often are involved. The depth of an ulcer of this stage varies by anatomical location, as described in stage III above. Stage IV ulcers can extend into the muscle or supporting structures (e.g., tendon, fascia, or joint capsule), rendering osteomyelitis a possibility. Exposed bone and tendon are visible or directly palpable.

Unstageable: Unstageable pressure sores involve full-thickness tissue loss, and the base of the ulcer is covered by slough (yellow, tan, brown, green, or gray), eschar (brown, tan, or black), or both, in the wound bed. Until enough of the slough or eschar is removed to expose the base of the wound, the true depth and stage of the ulcer cannot be determined. Stable (dry, intact, and adherent, with no erythema or fluctuance) eschar on the heels should not be removed.

THERAPEUTIC TREATMENT OPTIONS

Nonpharmacologic treatments include reduction of tissue pressure, frequent repositioning, and the use of surfaces that are protective and supportive.¹⁶ Frequent repositioning (and selection of proper position) is extremely important. Bed-bound patients should be turned a minimum of every 2 hours, and they should be elevated as minimally as possible to avoid the shear forces on tissues that result from sliding down the bed. Lifting devices or bed linen should be used to reposition patients, rather than pulling or pushing the patient (which causes friction and shear forces). Patients placed in chairs should be repositioned every hour, and they should be encouraged to change position on their own every 30 minutes. Protective padding includes pillows or foam wedges that can placed between the knees, ankles, and heels when patients are lying on their sides; pillows, foam, and heel protectors can be used when patients are supine. Support surfaces under bed-bound patients can be changed to reduce pressure.

A change from standard mattresses is necessary when patients are unable to reposition themselves and periodic repositioning care is unavailable. Special mattresses are indicated for patients with stage I ulcers who develop hyperemia on static surfaces and for patients with stage III or IV ulcers. Air-fluidized or high-air-loss mattresses contain silicone-coated beads that liquefy when air is pumped through the bed. Advantages include cooling and reduction of moisture on surfaces. These mattresses are indicated for patients with nonhealing stage III and IV sores or numerous truncal ulcers.

PHARMACOLOGIC TREATMENT OPTIONS

The yearly cost of preventing and treating pressure ulcers is astronomically high, proving the dictum of preventive therapy being beneficial not only for the patient, but also for the economics of the health care system.¹⁷ Conservative treatment of pressure sores includes appropriate wound care, debridement of necrotic tissue, optimization of nutrition, release of pressure, and minimization of muscle spasticity in order to provide the patient with the best opportunity to heal by secondary intention. Stage I and II pressure sores are treated conservatively. Some patients with stage III and IV pressure ulcers must be treated conservatively because of coexisting medical problems.¹⁸

Therapeutic measures for a pressure sore should be appropriate to its stage and should be consistent with the patient's therapeutic goals. Many therapeutic interventions follow the same principles as preventive interventions. In one study, independent predictors of healing included pressure ulcer size, older age, and receiving rehabilitation services.¹⁹ Both immobility and incontinence were associated with poor healing of pressure ulcer.

Wound Care

Wound fluids may contain tissue growth factors that facilitate re-epithelialization. Thus, healing of pressure ulcers is promoted by dressings that maintain a moist wound environment while keeping the surrounding intact skin dry.²⁰ The goal is to keep the ulcer bed moist to retain tissue growth factors while allowing some evaporation and inflow of oxygen to keep surrounding skin dry, facilitate autolytic debridement, and establish a barrier to infection.^9,12,18 A moist wound environment is achieved by loosely packing the wound with saline-moistened gauze that is not allowed to dry (occlusive dressings are equally effective and reduce the nursing time required for wound care). Several types of dressings are available commercially; there are no clear recommendations for use of one type of dressing versus another, but individual circumstances may favor one form of dressing over another.²¹

Transparent films provide an effective barrier for retaining moisture; they are good secondary dressings when combined with another product for full-thickness wounds, and they may be used alone for partial-thickness wounds. Hydrocolloids generally are effective for retaining moisture and are useful for promoting autolytic debridement; they come in a variety of sizes and shapes for use on different parts of the body. A comparison study of transparent absorbent acrylic dressings and hydrocolloid dressings in the management of stage II and shallow stage III pressure sores demonstrated that the transparent film dressing improved the ability to assess the ulcer as well as patient comfort, although time to wound closure was nearly identical between the two groups.²²

Hydrogels, which are designed to maintain a moist wound bed, and can be used for deep wounds with little exudate. Both alginates and foams are highly absorptive and are useful for wounds with significant exudate.^9,23 A study of 110 elderly (mean age 83.5 years) patients in a geriatric hospital ward with stage III or IV pressure ulcers found that sequential use of a calcium alginate dressing for 4 weeks followed by a hydrocolloid dressing for 4 weeks was preferable to a hydrocolloid dressing alone for 8 weeks (control condition). In this study, the mean absolute surface area reduction (SAR) was significantly larger in the sequential-treatment group than in the group that had just the hydrocolloid dressing (7.6 cm² vs. 3.1 cm² at week 8). Similarly, at week 8, significantly more patients in the sequential-therapy group had a 40% SAR (75% vs. 59% for controls).²⁴ Iodine-solution wet gauze comes in a variety of forms and provides broad-spectrum antimicrobial coverage in the setting of a moist wound environment.¹⁸ Further information about the various dressings used to treat pressure ulcers is given in TABLE 2.^9,10,15-17

Nutrition

Poor nutritional status or dehydration can weaken the skin and make a person more vulnerable to developing pressure ulcers. Nutritional screening must be a part of the evaluation of any patient with pressure sores. Dietary consultation is recommended for patients who are malnourished, and an evaluation of swallowing ability should be considered.

Nutritional interventions to prevent or treat pressure ulcers include providing additional nutrition and dietary supplements and encouraging adequate dietary intake by the patient. High-calorie foods and supplements should be used to prevent malnutrition.^12,18 If oral dietary intake is impractical, enteral or parenteral feeding—if compatible with the patient's wishes—should be considered to achieve a positive nitrogen balance (≈30-35 calories/kg/day and 1.25 g-1.5 g protein/kg/day). Zinc supplementation supports wound healing, and replacement at a dose of 50 mg tid may be useful. Supplemental vitamin C (1 g/day) may be administered if intake is insufficient and deficiency is present, although data supporting its effectiveness in accelerating healing have been inconsistent.²⁵ A 2003 Cochrane review of four trials found that although there is some evidence that nutritional interventions may be able to reduce the occurrence of pressure ulcers, more evidence is needed to identify effective dietary interventions.²⁶

Topical Growth Factors

Growth factors have been found in vivo and in vitro to show promise for tissue repair.²⁷ Several growth factors, including TGF, epidermal growth factor, platelet-derived growth factor, fibroblast growth factor, interleukin-1 and interleukin-2, and TNF, have been shown to mediate the healing process in acute wounds.²⁸

To date, no growth factor has received FDA-approved labeling for such use. Topical recombinant human BB platelet-derived growth factor (rPDGF-BB) has been found to stimulate the migration of neutrophils, macrophages, and fibroblasts into wounds; hasten the accumulation of glycosaminoglycans and fibronectin; and enhance collagen production.²⁹ The commercially available rPDGFBB becaplermin has been the most extensively studied for wound healing in humans.

One trial enrolled 124 patients with stage III or IV pressure ulcers who were randomized to receive 100 mcg/g becaplermin gel once daily alternating with placebo gel every 12 hours (n = 31); 300 mcg/g becaplermin gel once daily alternating with placebo gel every 12 hours (n = 32); 100 mcg/g becaplermin gel twice daily (n = 30); or placebo (n = 31).³⁰ Complete healing was significantly more frequent with 100 mcg/g or 300 mcg/g becaplermin once daily than with placebo (P = .005 and P = .008, respectively). A difference was not observed between the becaplermin 100 mcg/g twice-daily group and the placebo group. No sores in placebo recipients healed completely, compared with 3% in patients given becaplermin 100 mcg/g twice daily, 19% in the 300-mcg/g once-daily group, and 23% in the 100 mcg/g once-daily group. Interpretation of the results, however, may be confounded by the negative dose-response effect, a substantially lower rate of healing than observed for other standard treatments, and failure of any ulcers to heal in placebo recipients. Adverse effects were similar in all treatment groups and included skin ulceration, urinary-tract infection, rash, erythema, and fever.

In June 2008, the FDA issued a follow-up "Dear Healthcare Professional" letter regarding an earlier safety review of becaplermin. In March 2008, the FDA had announced that it had received information from a retrospective study and was investigating the possibility of an increased risk of cancer or mortality from cancer in patients with diabetes who used becaplermin, compared to patients who did not use becaplermin. The FDA completed its review of this study and noted an increased risk of mortality from cancer in patients who used three or more tubes of becaplermin gel. As a result, the becaplermin prescribing information was updated to include a new black box warning regarding this finding. It is important to note that while the study showed an increase in mortality from cancer, the number of mortalities was small, there was no overall increase in the incidence of cancer, and the observed malignancies were remote from the ulcer treatment site. The FDA recommends the use of becaplermin only when the potential benefits outweigh the risks.³¹

Pain Control

Primary treatment of pain is treatment of the pressure sore itself. Options for treatment should include nonsteroidal anti-inflammatories (such as naproxen or ibuprofen) or acetaminophen, which are used for mild-to-moderate pain. Opioids may be necessary during dressing changes and debridement. In cognitively impaired patients, changes in vital signs can be used as an indication of pain. Opioids should be avoided when possible because sedation promotes immobility.

THE PHARMACIST'S ROLE

The cornerstones of therapy for pressure ulcers remain elimination of the source of the pressure or friction and appropriate wound care. Prevention is imperative, because once a pressure ulcer forms, prolonged hospitalization and expensive therapy are distinct possibilities. The pharmacist's role in the prevention of pressure ulcers includes educating patients about the contributing factors and monitoring patient progress to ensure successful healing of the sore when therapies are initiated. Patient education about the proper use of prescribed discharge medications and preventive steps necessary to ensure that the ulcer will not occur again is quite important for reducing the health care burden of pressure ulcers on society.

Contemporary Options for the Management of Scars

Yvette C. Terrie , BSPharm, RPh
Jeffrey R. Marcus , MD, FAAP, FACS

By definition, a scar is the end result of the normal healing process. For many individuals, the effects of scarring are nonproblematic. Injuries that only involve the epithelium are not likely to cause significant scarring, but injuries that involve the dermis and deeper tissues have greater potential to leave a visible scar.¹ Scarring occurs along a continuum of expression both across and within populations. Normal scars can be faintly perceptible in some cases and prominent in others. We know that variation in normal scarring is associated with such factors as skin color, skin quality, age, and ethnicity. Scarring is a normal process, but several specific types of scars are abnormal and result from aberrant wound healing. Some individuals or populations may be more susceptible to developing such types of abnormal scarring.

Annually, an estimated 100 million individuals will develop some type of scar. Approximately 55 million will develop problematic scars as the result of elective surgeries, and 25 million will develop scars from operations after trauma or disease.² In addition, 11 million keloid scars and 4 million scars from burns exist, of which 70% occur in children.^2,3 The latter abnormal scars are often described as painful, disfiguring, embarrassing, and even functionally disabling.⁴ Patients may experience pruritus, psychological stress, and loss of motion from contracture.^4,5

Over the past 2 decades, researchers have gained significant insight with regard to the prevention, treatment, and management of scarring. An accurate assessment of the scar is a crucial step prior to initiating possible treatment and management.^2,5 Factors that need to be considered prior to electing to treat a scar include²:

1. Is the scar getting worse or showing signs of improvement?
2. The anatomical location of the scar.
3. Symptoms that the patient presents.
4. Presence and/or severity of functional impairment. (Does the scar affect mobility of joints?)
5. Stigma of the scar. (Evaluate the impact of the scar on the patient's quality of life.)
6. Likelihood of improvement with treatment.

Whereas the severity of a scar can be estimated subjectively, accurate representation (for the purpose of investigation) must be based on objective methodology. Objective assessment provides quantitative data and is a key element in the critical evaluation of treatment efficacy. Many objective tools are available for scar assessment. One example is the Vancouver Scar Scale.

The Vancouver scale is a clinical assessment tool that rates and scores scars according to pigmentation, vascularity, height/elevation, and pliability.^2,6,7 From this assessment, a score is obtained; the lower the score, the better the scar.² The scores can then be compared over periods of time and across potential treatment modalities.^2,6,7 Table 1⁸ shows the Vancouver Scar Scale. In this evolving field, it is important for health care professionals to keep abreast of treatment options and the clinical evidence that support their use. This continuing education article will review the stages of wound healing, the types of abnormal scars, and the treatment options currently available.

Table 1

Pathophysiology of Wound Healing and Scar Formation

For the purposes of this discussion, "injury" refers to any loss of skin continuity whether intentional (surgical) or unintentional (traumatic). The healing process is typically divided into 3 stages that begin immediately after an injury and continue for a period lasting weeks to months to years.^1,9,10 The stages of the healing process include inflammation, proliferation, and maturation (matrix remodeling).^1,9,10 The scar is the discernible end result of this process.^1,9,10

Inflammatory Phase
Although the exact role of the inflammatory response in the progression of scar formation is still not entirely clear, it is evident that early inflammation sets the stage for the production of scar tissue and may contribute to the end result.¹⁰ It appears that the development of the scar is programmed during and by certain parts of the inflammatory process.¹⁰

During the inflammatory phase, which lasts 3 to 4 days, the body responds to injury by preparing the wound for subsequent tissue replacement. This consists of 2 primary processes: hemostasis and inflammation.⁹ Hemostasis is initiated immediately as the first major function of the platelets.^1,11 In response to the initial injury, vasoconstriction in combination with clot formation and platelet aggregation occur.¹¹ The aggregation of platelets results in the formation of the primary platelet plug.¹¹ Aggregation and attachment to exposed collagen surfaces activates the platelets.¹²

Once aggregated, the platelets degranulate and release mediators that assist in the development of the fibrin clot, together with growth factors and chemoattractants.¹¹ The platelets are critical to the initial phase of healing, because they release cytokines such as platelet-derived growth factor, insulinlike growth factor-1, epidermal growth factor (EGF), and transforming growth factor-beta (TGF-beta) into the wound bed.^9,11 Neutrophils and macrophages travel into the wound and secrete additional growth factors, such as transforming growth factor-alpha (TGF-alpha), heparin-binding epidermal growth factor (HB-EGF), and basic fibroblast growth factor, which further the progression of the inflammatory process.¹¹

After hemostasis is achieved, the active inflammatory process is initiated by chemotactic factors that draw neutrophils into the wound. Under normal circumstances, neutrophils phagocytize debris and bacteria in the wound within 24 to 48 hours.⁹ Platelets also release mediators such as bradykinin, histamine, and prostaglandins into the wound area, thus initiating vasodilation among the surrounding vessels. This process then increases blood flow to the area, allowing further inflammatory and mediator cells to reach the site. As a result, the wound appears erythematous and edematous.^9,12 The final stage of the inflammatory phase is the epithelial migration into the wound.^3,9

Proliferative Phase
During the proliferative phase, the wound is filled with new connective tissue and covered with new epithelium. This phase involves the formation of granulation tissue, which is a collection of fibroblasts and newly synthesized collagen, new capillaries, and inflammatory cells.⁹ Granulation tissue begins forming approximately 3 to 5 days following injury and overlaps with the preceding inflammatory phase.¹² The synthesis of collagen by fibroblasts is directed by cytokines produced by stimulated macrophages.⁹ As granulation tissue is being processed, epithelial cells, which started to migrate during the inflammatory process, resurface the damage of the wound.⁹ The process of epithelialization then signals a down-regulation in proliferation. The final step in the proliferative phase includes the process of wound contraction and involves the mobilization and pulling together of the edges of the wound.⁹

Maturation Phase
The maturation phase, also known as the matrix remodeling phase, is the longest phase and begins at about 3 weeks after an injury.^9,10,12 During this phase, the wound is completely closed by connective tissue and resurfaced by epithelial cells. This phase can continue for as long as 2 years after an injury, depending on the extent of the injury.⁹ This phase involves an ongoing process of the synthesis of collagen with hightensile strength collagen.⁹ Peak tensile strength of a wound occurs approximately 60 days after an injury occurs.¹² The end product is the formation of a scar that has an estimated 70% to 80% of the original strength of the skin that it replaced.^9,12

Factors That Affect Wound Healing

Various factors can interfere with the wound-healing process, affecting any of the 3 phases.³ Multiple factors have been identified as contributing to impaired wound healing. Examples of these factors include advanced age, malnutrition, and impaired tissue perfusion and oxygenation. Oxygen availability is critical to the healing and is limited by smoking, diabetes, anemia, hypotension, peripheral vascular disease, and congestive heart failure.⁹ Radiation is a specific example of impaired perfusion due to microvascular fibrosis. Other examples of factors negatively affecting healing include infection, immunosuppressives, chemotherapy, steroids, and inadequate wound care.^1,9,13,14

Scarring

Scarring is part of the skin's natural wound-healing process and is a sign that a wound is healing. For the formation of a normal scar, the maturation phase involves gradual fading and flattening of the scar tissue which, on average, takes about 12 to 18 months, but can take up to 2 years.^1,9 Scarring follows local skin trauma through injury, disease, or surgery, inflammatory disorders (eg, acne vulgaris, mumps/measles/chickenpox infections), or lacerations/piercings (eg, cuts, bites, tattoos, vaccinations, surgery).⁵ Normal scars initially appear pink or red and raised, but then flatten and fade to varying degrees. Abnormal scars are thought to be caused by disturbances in the wound-healing process. During the maturation phase, the manifestation of abnormal scarring becomes apparent.¹⁵

As mentioned previously, many factors can affect the severity of scarring. These factors can be divided into 4 main elements: injury factors, patient factors, technical factors, and care factors.

Injury factors include the depth, orientation, contamination, mechanism, and extent of the injury. Tissue loss, crush injuries, and irregular tears of the skin are particularly problematic. Surgical incisions, on the other hand, are highly controlled. The injury itself is a significant determinant of longterm scar outcome. Patient factors were discussed earlier and relate to the individual's inherent ability to heal well and the potential predisposition to exuberant scar formation. It is worth mentioning that age plays a significant factor among all populations. During 2 periods of development, the process of healing typically results in less conspicuous scars. These are at 2 extremes—the very young and the elderly. Privileged healing does seem to occur during infancy and extends, perhaps to a lesser degree, for several years. By puberty, the qualities of the skin lend themselves to a more proinflammatory state. This exaggeration of the inflammatory and proliferative phase often results in unsightly and/or abnormal scars during this time. With increasing age, the qualities of the skin continue to change, as does the scar response. In later years, the skin becomes thinner and less elastic. The process of wound healing is less exuberant, and scarring during this period is again diminished.

Injury factors and patient factors cannot be willfully changed; therefore, a significant aspect of determining outcome is out of the control of the caregiver. The final 2 factors, however, can be influenced significantly, and these are the subject of interventions designed to optimize scar formation. Technical factors relate to the surgeon's ability to manage and repair the injury in the most optimal manner. Care factors relate to the manner in which an injury or wound are treated after surgical or nonsurgical treatment. Most types of scar treatments are directed at this aspect of the scar process.

Types of Abnormal Scars

Several types of abnormal scars exist, including keloids, hypertrophic scars, atrophic scars, widened scars, and contractures that can be differentiated by various characteristics (Table 2).

Table 2

Keloid and Hypertrophic Scars
The exact etiology of keloid and hypertrophic scar development remains unclear. Several theories suggest, however, that abnormalities in cell migration, proliferation, inflammation, and the synthesis and secretion of extracellular matrix proteins, cytokines, and remodeling can contribute to keloid and hypertrophic scar formation.¹²

Keloids
In the United States, keloids affect an estimated 15% of the population and are more prevalent among certain ethnic groups, such as African Americans, Asian Americans, Latin Americans, and other darker-pigmented ethnicities.¹⁶ Some studies suggest that keloids are related to an inherited metabolic alteration in collagen.¹⁶ Although keloids can occur at any age, they are rarely found in newborns or among the elderly and tend to have their greatest occurrence rate among individuals between 10 and 30 years of age.^1,5,17 Cosman et al reported that the average age of patients at the time of receiving initial treatment was 25.8 years, and the average age of onset was 22.3 years in women and 22.6 years in men.¹⁸ Furthermore, research has demonstrated that, because keloids typically have accelerated growth during both puberty and pregnancy and, in general, resolve upon menopause, both androgens and estrogen have been considered contributing factors to keloid formation.⁵ Other hormones that may be connected to the formation of keloids include thyroid hormone alterations and melanocyte-stimulating hormones.⁵

Keloids are defined clinically by 2 factors: first, the growth of the keloid extends beyond the boundaries of the initial wound/injury. Second, keloids are typically symptomatic over a prolonged course, described as painful and pruritic.¹⁹ Genetic predisposition coupled with some form of trauma or injury to the skin may play a pivotal role in the development of keloids.^5,17 Examples of skin injuries that may precipitate formation of keloid scars include surgery, ear piercing, abscess, abrasions, lacerations, tattoos, insect bites, burns, vaccinations, and any process that may cause inflammation of the skin, such as acne, chickenpox, or folliculitis.¹⁷ Butler et al states that the formation of keloids is a response to inflammation that is caused by keloidderived fibroblasts, which involve an abnormal secretion of proinflammatory mediators and an abnormal response to other inflammatory signals.¹⁶

Keloids occur more frequently on the shoulders, chest, earlobes, upper arms, upper back, and cheeks, although the reason for this occurrence is unknown.^20-22 Some theories postulate that these areas have increased susceptibility to formation of keloid scars since they are subject to elevated levels of muscle and skin tension.^23,24 The areas of the head and neck that are typically safe from keloid formation include the eyelids and the mucous membranes.²⁴

With the exception of trauma, exact etiologic factors responsible for keloid formation have not been fully understood.²⁵ Keloids are frequently associated with negative wound-healing factors, such as infection, excessive tension, foreign bodies, and repetitive trauma; however, keloids may form in simple clean wounds.²⁵

Many patients with keloids are affected both physically and psychologically and express a significant negative impact on their quality of life.²¹ In the results from one study, Lee et al evaluated 28 patients with keloids and reported that more than 80% of the patients reported keloid-associated pruritus, and an estimated 50% reported pain.²⁶

Hypertrophic Scars
Hypertrophic scars are more common than keloids. Hypertrophic scars may occur in persons of any age or at any site, and they tend to spontaneously regress. In addition, hypertrophic scars are more likely to respond to treatment.⁵ Hypertrophic scars typically develop within 8 weeks of skin injury, such as a burn wound infection. In general, their normal course includes a rapid growth stage for up to 6 months that can then be followed by regression during the next 12 to 18 months.²⁷

Differentiating Between Keloid and Hypertrophic Scars
Both keloid and hypertrophic scars are characterized by an accumulation of excess collagen and are not always easy to differentiate from one another.^16,21 It is important for health care professionals to distinguish between the 2 types of scars, because inappropriate therapy may cause formation of larger scars.³ Crucial differences between these 2 types of abnormal scars include histologic morphology, cellular response to growth factors, and scar appearance.²⁸

Keloids tend to grow beyond the borders of the original wound, invading the surrounding areas of the skin, and they typically do not resolve spontaneously. Hypertrophic scars stay within the boundaries of the original wound and tend to regress spontaneously.^1,5,13,25 In addition, hypertrophic scars are typically visible soon after an injury to tissue and are often related to a contracture across a joint surface, whereas keloids may develop as late as 12 months after an injury.^1,5,24 Hypertrophic scars appear as red, raised, nodular lesions occurring in areas of thick skin, and they may cause pruritus or pain. Keloid scars appear puckered and nodular and are reddish-purple in color and exhibit a prolonged, proliferative phase resulting in the appearance of thick hyalinized collagen bundles similar to those produced by hypertrophic scars.^17,27 Upon palpitation, keloids appear to be firmer when compared with hypertrophic scars and can also be painful and itchy.^1,28

Atrophic Scars
Atrophic scars are flat and depressed below the dermal area. They are generally small in size with an indented or inverted center.^2,3,16,29,30 They are most commonly the result of collagen destruction during the course of an inflammatory skin disease, such as from the result of acne vulgaris, varicella, and immunization sites.^3,28 Initially, atrophic scars appear erythematous and become increasingly fibrotic and hypopigmented as time progresses.³⁰

Widened Scars
Widened scars are described as stretched scars that normally occur in sites of higher tension.^1,5 The response to tension perpendicular to the wound edges is a widened scar regardless of whether there is separation or disruption of the wound.^1,5 Widened scars can occur at any age and have no predisposition to ethnicity, sex, or familial history. The arms, legs, and abdomen are the most common areas of the body that may form a widened scar.⁵ In addition, sun tanning can contribute to scar widening through attenuation of the tissues.⁵

Widened scars initially appear as a pale red color-typically flat, soft, symptomless scars often seen after knee or shoulder surgery, for example.^1,2,5 The stretch marks that often appear during or after pregnancy are a type of widened scar in which there is trauma/injury to the dermis and subcutaneous tissues but the epidermis is unbreached.⁵ Moreover, mature widened scars have no elevation, thickening, or nodularity, which distinguishes them from hypertrophic scars.²

Scars with Contractures
A contracture scar is characterized as a permanent shortening of a scar that can be disfiguring and disabling, because they can limit an individual's movement.² A contracture scar typically occurs when the wound occurs across a joint or when a large area of the dermal area has been damaged, such as when an individual experiences a severe burn.^1,2 Scar contracture is thought to be mediated by myofibroblasts, which are also thought to play a role in other similar disorders of tissue healing.

Treatment

If a scar causes functional or cosmetic concerns, then treatment may be warranted. The treatment of scarring can be categorized into 2 categories: invasive or noninvasive modalities.^1,7 Although advances have been made with regard to the nature of wound healing and scar formation and the modulation of these processes, a consensus in the literature regarding optimal treatment has not been reached.^1,10 The efficacy of many existing treatments is difficult to assess due to the lack of well-controlled clinical trials.^1,10 There remains a need for more in-depth clinical studies, particularly with regard to nonsurgical therapies in double-blind, placebo-controlled, multicenter, randomized trials with objective, evaluative measures.¹⁰

Invasive treatment options include intralesional corticosteroid injections (eg, triamcinolone), surgical excision, injection of interferons and other chemotherapeutic agents, radiotherapy, laser resurfacing, dermabrasion, cryotherapy, and chemical peels. Noninvasive treatment options include silicone gel sheets, silicone gel ointments/ creams, topical vitamin E, topical onion extract (and compounds derived from allivum), pressure/tissue compression, and topical retinoids. The main problem with most nonsurgical treatments is that little or no evidence of efficacy exists.¹ Many of these treatments are supported only by anecdotal or insufficient clinical data.^1,7 Several modalities are discussed below. Based on a 2002 publication, International Clinical Recommendations on Scar Management by Mustoe et al, however, evidence supports only 2 interventions: silicone gel sheets and intralesional corticosteroid injections.^1,7 These guidelines recommend that silicone gel sheeting should be the first line of treatment in the management of scars, particularly in the prevention of keloids and hypertrophic scars.⁷ In addition, it was recommended that silicone gel sheet therapy be considered as first-line prophylaxis following surgical excision.²¹

Noninvasive Treatment Options

Silicone Gel Sheeting and Silicone Gel Ointment
The use of silicone gel sheeting to prevent and treat hypertrophic and keloid scarring is still relatively new; it began in 1981 with the treatment of burn scars.^10,31 The therapeutic efficacy of silicone gel has been well-documented in the literature.^7,10 Studies show that early intervention with silicone gel appears to be ideal but that older scars have also showed improvement from treatment. When used appropriately, improvements in scar thickness, color, and texture have been noted.^17,32

Topical silicone gel sheeting and silicone gel ointments have been used with the intent to reduce the size, induration, erythema, and pruritus of preexisting hypertrophic scars and possibly prevent the formation of new scars.²⁷ Silicone is characterized as a soft, semi-occlusive scar cover composed of a cross-linked polydimethylsiloxone polymer that has extensibility comparable with the skin.²⁷

Although the exact mechanism of action of silicone gel is not fully known, several theories exist. Many researchers agree that silicone gel sheets act at the stratum corneum, which reduces evaporation and restores homeostasis.^10,27,33 Silicone gel sheeting has an evaporative water loss almost half that of skin.²⁷ In addition, many researchers postulate that silicone acts by creating a hydrated, occluded environment that reduces activity of the capillaries, thus decreasing fibroblast-induced collagen deposition and scar hypertrophy.^25,34 Studies also have shown that silicone gel sheets do not change the pressure, temperature, or oxygen tension at the site of the wound.²⁵ Results from at least 8 randomized controlled clinical trials and a meta study of 27 trials showed that silicone gel sheeting is a safe and effective treatment option for both hypertrophic and keloid scars.⁷

In a 2008 publication, Tandara and Mustoe tested the hypothesis that the use of silicone sheeting in vivo has a beneficial effect on scarring by reducing keratinocyte stimulation, with a resulting decrease in dermal thickness.³⁵ In the study, sheets of silicone adhesive gel were applied to scars in a rabbit ear model of hypertrophic scarring 14 days postwounding for a total of 16 days. Results from the study reported that the scar evaluation index was greatly decreased after silicone gel sheet application when compared with the untreated scars.³⁵ Total occlusion decreased scar hypertrophy by 80%, compared with semi-occlusion. The epidermal thickness index of untreated scars was increased by more than 100%, compared with uninjured skin. Furthermore, silicone gel treatment significantly reduced epidermal thickness by more than 30%. The findings showed that 2 weeks of silicone gel application at a very early onset of scarring decreased both dermal and epidermal thickness, which appears to be due to a reduction in keratinocyte stimulation.³⁵ The study also concluded that oxygen could be ruled out as a mechanism of action of silicone occlusive treatment. The hydration of the keratinocytes seems to be the key stimulus.³⁵

Silicone gel sheets should never be applied to open wounds and should be applied as soon as the skin shows signs of complete epithelialization and/or after surgical sutures have been removed, if applicable.³ The sheets should be worn for a minimum of 12 hours daily and may require use for as long as 6 months. The sheet can be removed for normal skin washing, and the product can be washed and reused. Many gel sheets will last for 14 to 28 days.¹ Silicone gel sheeting is an easy and pain-free therapeutic option for many individuals, especially children. From a practical standpoint, one difficulty with the use of silicone sheeting is the application to contoured/irregular body surfaces or surfaces that are difficult to conceal, like the face.

Silicone gel is gaining popularity, because it can be applied to a smaller area such as the face.⁵ Silicone gel has demonstrated significant reduction in scar volume when used over time. Additionally, some studies have shown an 80% to 100% overall improvement in hypertrophic scar formation.⁵ Chan et al evaluated the use of silicone gel in the prevention of hypertrophic scar development in median sternotomy wounds. The study concluded that the use of silicone gel in the prevention of hypertrophic scar development in sternotomy wounds was effective.³³ No incidence of adverse effects was reported, and patient compliance was satisfactory.³³ The topical use of silicone gel appears to improve the color, appearance, texture, and thickness of hypertrophic and keloid scars and decreases the incidence of itching.³ It has been shown to soften and reduce hypertrophic scars much more rapidly without interfering with pressure, temperature, or oxygen tension.³ Silicone gel is typically applied 1 to 2 times per day. It is colorless and odorless; it dries on the surface of the skin and is imperceptible. For these reasons, it is a particularly attractive and very welltolerated option for children.

Topical Vitamin E
Topical vitamin E (tocopherol) is classified as a lipid-soluble antioxidant.²⁷ To date, the effects of vitamin E on wound healing and improving the cosmetic effects of burns and other dermal injuries are due to anecdotal claims, with little scientific evidence to support them.^1,27 In a study conducted by Jenkins et al, the effects of vitamin E with regard to reducing scarring after reconstructive surgery were evaluated.^34,36 The study found no significant variances between the control group and the treatment group, and an estimated 20% of the study subjects reported a local reaction to vitamin E such as dermatitis.³⁶

Baumann and Spencer investigated the effect of vitamin E on the cosmetic appearance of scars. The results of the study demonstrated no benefit to the cosmetic appearance of scars after the use of topical vitamin E after surgery.³⁷ In addition, the study found that topical vitamin E might actually be harmful to the appearance of scars, because 33% of the study participants developed contact dermatitis.³⁷ Thus, the study concluded that the use of topical vitamin E should be dissuaded.³⁷

Onion Extract (Allivum Derivatives)
Allium cepa or onion extract is found in several nonprescription products marketed for scar treatment. Due to its simple use, widespread availability, botanical ingredients, and reasonable cost, many patients may elect to use scar treatment products containing this ingredient. Theories suggest that onion extract appears to exhibit antiinflammatory, bacteriostatic, and collagen down-regulatory properties and improves collagen organization in a rabbit ear model. Despite the popularity of this ingredient, a lack of clinical evidence exists regarding the beneficial effects of improving hypertrophic scars, however.²⁷

Jackson and Shelton evaluated the efficacy of topical onion extract gel on both the appearance and symptomatology of postsurgical scars, and the results were compared with those of a topical emollient ointment.³⁸ The study concluded that a significant decrease in erythema was visible in the scars of those using the topical emollient ointment and that the onion extract gel was ineffective in decreasing scar erythema.³⁸

Chung et al compared the effectiveness of onion extract gel and a petrolatum- based emollient with regard to improving the appearance and symptoms of new surgical scars.³⁹ The study concluded that although participants tolerated both treatments without incidence of allergic reactions, no significant differences were noted in the appearance of the scars when comparing both products.³⁹

Hosnuter et al evaluated the therapeutic activity of onion extract gel on both hypertrophic and keloid scars with an emphasis on elevation, redness, hardness, itching, and pain.⁴⁰ The study involved 60 patients divided into 3 groups. Group 1 was treated solely with onion extract gel; group 2 was treated with only silicone gel; and group 3 was treated with a combination of both onion extract gel and silicone gel sheet. After 6 months, the onion gel was more effective with regard to scar color, whereas the silicone gel sheet was superior in reducing the height of the scar. The most effective results were observed in group 3, where both onion extract gel and silicone gel sheeting were used.⁴⁰

In 2008, Draelos evaluated the ability of onion extract gel to improve the appearance of scars following excision.⁴¹ The study involved 60 participants who had symmetrical seborrheic keratoses of at least 8 mm in diameter on the right and left upper chest. The lesions were removed, and the surgical sites were allowed to heal for 2 to 3 weeks.⁴¹ During that time, the subjects were divided into 2 groups with each receiving either topical treatment of onion gel or no treatment at all. Results from the study concluded that the use of topical onion extract gel improved scar softness, redness, texture, and overall appearance at the excision site when assessed by the blinded investigator at study weeks 4, 6, and 10.⁴¹

Topical Retinoids
The use of topical retinoic acid has been successful in the treatment of keloids and hypertrophic scars. Panabiere- Castaings reported both a decrease in size and weight of lesions after a trial period of 12 weeks.⁴² The daily topical application of retinoic acid to both intractable hypertrophic and keloid scars has been shown to cause scar softening as well as decrease the size of scarring and the incidence of pruritus.⁵

It is important to note, however, that although rare, it is possible for topical retinoids to be absorbed systemically and cause adverse effects such as hypervitaminosis and teratogenicity.²⁷ Therefore, topical retinoid use should be limited or avoided, especially among certain patient populations (ie, pregnant women or those concurrently using oral vitamin supplements).²⁷ Furthermore, insufficient data exist regarding the effectiveness of topical retinoids on treating hypertrophic scarring.²⁷

Pressure/Tissue Compression
Since the 1970s, pressure therapy has been considered the preferred conservative treatment for the management of scars and the standard therapy for the treatment of hypertrophic scarring after a burn injury.^7,29 It can also be used for treatment of keloid scars.^3,7

A successful response rate ranging from 90% to 100% has been reported among patients treated with pressure therapy after keloid excisions, especially in those patients with ear lobe keloids.²⁴ The amount of pressure delivered should be between 24 and 30 mm Hg to avoid decreased peripheral blood circulation.²⁴

Pressure treatment is believed to accelerate wound maturation by several mechanisms, namely, a thinning of the dermis, decrease in edema, and a reduction of blood flow and oxygen.²⁷ Pressure therapy is particularly successful when applied while the scar is active; it loses some degree of efficacy after 6 months of treatment.^7,27

Typically, the materials used in pressure therapy are custom-made from an elastic material that contains a high spandex content. To prevent a decrease in the elasticity of the materials, they should be changed every 6 to 8 weeks.²⁷ To be effective, pressure must be applied continuously, and the garments are to be worn for approximately 1 year until the scar heals.^3,27

Various factors may be considered drawbacks of using pressure therapy, including its limited use in anatomic depressions, flexures, or areas of high movement, and the need to be worn at all times. The patient also may experience discomfort, and there is the possibility of occasional skin ulceration from uneven pressure distribution.²⁷ Many of these drawbacks can contribute to a decrease in patient compliance, with reports of noncompliance ranging from 8.5% to 59%.²⁷

Imiquimod Cream
Imiquimod 5% cream, which is classified as a topical immune response modifier, is FDA-approved for treating genital warts, basal cell carcinoma, and actinic keratoses. Imiquimod has been used in an attempt to reduce keloid recurrences after excision. Because of the success of imiquimod 5% cream in lowering keloid recurrences after operation, its role in the prevention of hypertrophic scars is currently under evaluation.²⁷ Imiquimod has been shown to improve hypertrophic scar quality after operation in a preliminary small, randomized, prospective clinical trial, but further clinical studies with a larger sample size and longer follow- up are needed to ascertain the role of imiquimod 5% cream in hypertrophic scar therapy.²⁷

Invasive Treatment Options

Corticosteroid Injections
Intralesional corticosteroid injections have been widely used to treat keloid and hypertrophic scars since the 1960s.¹⁰ Despite their use over a long period, however, the primary mechanism of action is still unknown.⁷ It is believed that steroids suppress the inflammatory phase of wound healing, decrease collagen production by the fibroblast, and decrease fibroblast proliferation.²⁴ Intralesional corticosteroid injections are considered the first line of therapy for the treatment of keloid scars and the second line of therapy for hypertrophic scars that have not responded to other treatments.^3,7 The most commonly used corticosteroid for scar treatment is triamcinolone.¹⁰ Multiple studies have shown 50% to 100% efficacy of intralesional injection of triamcinolone as a monotherapeutic agent in reducing scars.^7,10

Typically, the treatment of intralesional corticosteroids involves dosages that range from 10 to 100 mg administered every 3 to 6 weeks for several months.¹⁰ Length of administration depends on how well the scar responds to therapy. Because no standard of therapy exists, the patient's length of therapy is geared to the patient's response.³

Although the use of corticosteroids has been proven to be effective in decreasing scar formation, their use is associated with various adverse effects that occur in as many as 63% of patients. Adverse effects around the injection site include hypopigmentation, particularly in patients with darker pigmentation, dermal atrophy, telangiectasia (superficial blood vessels), widening of the scar, and delayed wound healing.^3,7 Intralesional corticosteroid injections also are associated with significant injection pain.^3,7

Other Invasive Therapies
Examples of other invasive therapies used for the treatment and management of scarring include surgical excision, radiotherapy, cryotherapy, laser therapy, chemical peels, and interferon injections. Whereas surgical excision may be beneficial and provide an immediate improvement in appearance, surgical excision of keloids alone is not always favorable, because the recurrence rate of scars can range from 45% to 93%.^21,24

The use of adjuvant therapies such as postexcisional steroid injections should be considered.²¹ Furthermore, data exist suggesting that preoperative steroid injection in combination with postoperative steroid injection offers a substantial reduction in recurrence associated with keloid excision. In addition, data exist suggesting the potential benefits of using topical mitomycin C as an adjunct to surgical excision; however, these are also small studies with short-term follow-up.²¹

Radiation can be used as monotherapy or in combination with surgical excision in order to prevent recurrence.⁴³ Success with monotherapy has not been acceptable, with recurrence rates reaching 100%. Some success has been shown with large doses of monotherapy; however, this may lead to malignant transformation 15 to 30 years later. Thus, large-dose monotherapy is no longer recommended.⁴³

Cryotherapy has been used for smaller hypertrophic scars, severe atrophic scars, and some keloids. The proposed mechanism of action is cell damage, resultant necrosis, leading to decreased scar bulk.²¹ Its use is restricted due to the occurrence of considerable pain and sometimes prolonged healing following treatment. Because multiple treatments are often required, the risk for hypopigmentation in darker-skinned patients is a significant obstacle.²¹

Atrophic scars have shown improvement with chemical peels, cutaneous laser resurfacing, dermabrasion, punch excisions, and the use of soft tissue biologic fillers.²

Emerging Therapies

Recently, several pharmacologic agents have been investigated as emerging and promising treatments for keloid scars. Although only a few clinical studies have been conducted, monotherapy with intralesional 5-fluorouracil (FU) or bleomycin tattooing have reported moderate to significant flattening of keloid scars in 88% of patients treated with 5-FU and in 92% treated with bleomycin.¹⁶ In addition, no recurrences in those scars that initially responded to these treatments were reported.¹⁶

The mechanism by which 5-FU reduces scarring has not been fully elucidated, but it has been shown that 5-FU inhibits fibroblast proliferation by blocking DNA synthesis and transcription through competitive inhibition of thymidylate synthesis.¹⁰

Adverse effects commonly associated with the use of 5-FU with up to 1 year of follow-up include transient hyperpigmentation (100%), tissue sloughing (21.4%-30%), transient burning sensation (7.1%), or pain (100%) at the injection site. No studies to date have reported systemic complications in patients treated with 5-FU for scar reduction. Long-term follow-up studies show no adverse effects.¹⁰

Bleomycin

Various studies have shown that intradermal injections of bleomycin, which is classified as a polypeptide antibiotic with well-known antitumor, antibacterial, or antiviral activity, have resulted in noticeable improvement in both keloid and hypertrophic scars.¹⁰ The exact mechanism by which bleomycin reduces scarring is not fully understood, but studies have shown that bleomycin inhibits collagen synthesis in dermal fibroblasts through decreased stimulation by TGF-beta1.¹⁰

Adverse effects commonly associated with its use include hyperpigmentation (75%) and dermal atrophy in the skin surrounding treated scars (10%-30%).¹⁰ To date, no systemic toxicity has been reported with low doses of bleomycin when used to treat hypertrophic scars. Future investigations will provide more information about the mechanism by which this drug acts and the effectiveness of this agent with regard to scars.¹⁰

Scar Prevention

Ideally, preventing abnormal scarring is better than treating it. The 2 aspects of the scar process that can be controlled are the technical aspects of wound repair and the postoperative management. From a surgical standpoint, the tissues of a laceration or incision should be handled delicately and be approximated meticulously. Initial dressings should be appropriately protective. Healing incisions on the trunk and extremities are often treated with a semi-occlusive dressing for up to 14 days. For facial incisions, dressings are used less frequently. Meticulous cleaning by patients and families is the single most important factor in control of the patient to affect wound healing and scarring. During the first 3 weeks following injury/repair, the focus should be on maintaining a clean incision.

For open wounds, achieving rapid epithelialization by providing a moist healing environment with ointment and semi-occlusive dressing is appropriate.^9,22 When epithelialization is prolonged past a time frame of 10 to 14 days, the likelihood of hypertrophic scarring increases dramatically.²² In burn injuries, early intervention is indicated, such as through the use of silicone and pressure garments after epithelialization has been complete.³

Just as many treatment approaches exist, many options potentially exist for prevention. For routine postoperative care of incision sites in visible locations, such as the face, the author favors an initial period (2-3 weeks) during which attention is focused on maintaining a clean surgical site. This is followed by 6 to 8 weeks of treatment using topical silicone gel. In the event of hypertrophic scar formation, silicone gel or sheets would be continued, and corticosteroid injection would be considered.

A combination of therapies to improve scar appearance probably holds the best possibility for successful treatment of both normal and abnormal scars. Future studies should continue to focus on evaluating the efficacy of various agents and exploring the potential role of emerging and novel agents for scar reduction.¹⁰

As more treatments and strategies for preventing scarring emerge, one of the best tools health care professionals can give patients is a thorough knowledge of the importance of immediate and proper wound care management, which can play a vital role in preventing or reducing the incidence of scarring. Again, the attention to maintaining a clean surgical/repair site cannot be overemphasized. Regarding counseling, patients with a history of keloid scars or familial history of keloids should be advised to avoid getting body piercings or tattoos, and they also should be discouraged from getting elective procedures at highrisk sites such as the upper arms, chest, or ears.^17,21

Because pharmacists are likely to encounter patients seeking counsel regarding wound care and the various scar treatments currently on the market, it is imperative for pharmacists to advise patients not to rely on the use of anecdotal information found on the Internet and to use products with well-demonstrated clinical efficacy. For the effective management of wounds and scars, it is essential for patients to be informed about the proper protocol regarding treatment and management. It is important for pharmacists to make patients aware of the availability of effective, noninvasive scar products—Table 3^27,44-51 lists topical scar products currently available-and encourage those patients with signs of abnormal scarring to seek the advice of their primary health care provider for proper treatment and to prevent further progression. Examples of when to seek medical attention include wounds that appear to enlarge, that are accompanied by discomfort or pain, show any signs of infection, or restrict movement of a joint.^1,9,10

Table 3