December 2011 Clinical Advisor

THE CLINICAL ADVISOR • DECEMBER 2011

A F O RU M F O R P H Y S I C I A N A S S I S TA N T S

NEWSLINE

■ Adolescent diabetes care ■ HPV vaccination for boys ■ Yoga eases low back pain ADVISOR FORUM

■ Effectiveness of sinus CT ■ Auscultation techniques ■ Pedal cracking LEGAL ADVISOR

Inadequate patient history has predictable consequences

✶ FREE CME COURSES!

■ Dermatology Clinic

DEPIGMENTATION NEAR A MOLE PAGE 107

VOLUME 14, NUMBER 12

■ Dermatologic Look-Alikes

YELLOW FACIAL PROCESSES PAGE 131 Expanded job listings! www.ClinicalAdvisor.com/Jobs

| D E C E M B E R 2 011 | www.ClinicalAdvisor.com

TREATING AND PREVENTING

MRSA INFECTION Up to 80% of people are colonized with Staphylococcus aureus (yellow).

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Editor Joe Kopcha, editor@clinicaladvisor.com Managing editor Marina Galanakis Senior editor Delicia Yard Web editor Nicole Blazek Contributing editors Bruce D. Askey, MSN, CRNP; Philip R. Cohen, MD; Peter F. Cohn, MD; JoAnn Deasy, PA-C, MPH; Melody French, PhD, PA, FNP; Virginia H. Joslin, PA-C, MPH; Norma M. Keller, MD; Debra August King, PhD, PA; Ann W. Latner, JD; Cheryl F. MacDonald, MSN, MPH, CRNP; Malka G. Messner, RPA-C, MPAS; Daniel R. Mishell Jr, MD; Claire B. O’Connell, MPH, PA-C; Patrick G. O’Connor, MD, MPH; Michael E. Ryan, DO; Sherril Sego, FNP, DNP; Lisa Stern, APRN; Karen T. Vujevich, RN-C, MSN, CRNP; Julee B. Waldrop, MS, PNP; Reuben W. Zimmerman, PA-C; Michael E. Zychowicz, RN, MS, NP-C Group art director, Haymarket Medical Jennifer Dvoretz Assistant art director Natasha Marcano-Dillon Production director Leslie Carsman Circulation manager Paul Silver Assistant circulation manager Monica Bond Audience development director John Crewe National accounts manager Alison McCauley, 646.638.6098 alison.mccauley@haymarketmedical.com Group publisher Thomas P. Hennessy, 646.638.6085 tom.hennessy@haymarketmedia.com Editorial director Tanya Gregory Vice president, medical magazines and digital products Jim Burke CEO, Haymarket Media Inc. Lee Maniscalco

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WIND DOWN WITH A LAUGH

Persons appearing in photographs in “Newsline,” “The Legal Advisor,” and “Clinical Challenge” are not the actual individuals mentioned in the articles.They appear for illustrative purposes only.

“There goes Claudius in his new All-Terrain-Vehicle.”

2 THE CLINICAL ADVISOR • DECEMBER 2011 • www.clinicaladvisor.com

© Roy Delgado

The Clinical Advisor® (USPS 017-546, ISSN 1524-7317), Volume 14, Number 12, is published 12 times a year, monthly, for $75.00 per year in the United States; $85.00 in Canada; $110.00 for all other foreign, in U.S. dollars, by Haymarket Media, Inc., 114 West 26th Street, 4th Floor, New York, NY 10001. Single copy: $20 U.S.; $30 foreign. www.ClinicalAdvisor.com. To order or update your paid subscription, call 800.436.9269. Periodicals postage rate paid at New York, NY, and additional mailing offices. POSTMASTER: Send all address changes to:The Clinical Advisor, c/o DMDData Inc., 2340 River Road, Des Plaines, IL 60018. Call 800.430.5450 to change your address or make other subscription inquiries. Requests for subscriptions from outside the United States must be accompanied by payment.

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Copyright © 2011.

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CONTENTS DECEMBER 2011

NEWS AND COMMENT 22

53

Alternative therapy for gestational diabetes Insulin is the only agent recommended to lower glucose levels in pregnant women, but the sulfonylurea glyburide may provide another option.

67

CME/CE Urinary incontinence in the older female population Despite what clinicians and patients think, accurate evaluation and targeted interventions can relieve symptoms and improve quality of life.

78

Antivirals used as an adjuct to flu vaccine In individuals with confirmed or suspected influenza and a high risk of complications, the CDC recommends treatment with one of two agents.

86

Alleviating depression resistant to treatment Anywhere from 10% to 30% of patients taking a single antidepressant face obstacles to successful treatment, including undiagnosed illness.

Newsline ■ Prepare youths to take over

diabetes care ■ Drospirenone-containing oral

contraceptives linked to higher VTE ■ New recommendations may cut SIDS rate ■ Lung cancer screening may detect COPD ■ Boys on track for HPV vaccination, too ■ Hormones, insomnia, and cardiovascular risk ■ Supplements may cause harm in older women ■ Last of the CFC inhalers exits this month ■ Yoga a good remedy for low back pain ■ Less frequent mammograms mean fewer false-positives 35

Drug Update ■ Once-daily combination pill for HIV infection ■ Fentanyl nasal spray manages cancer pain

Helping adolescents take over diabetes care 22

Lowering glucose in gestational diabetes 53

Continues on page 8 146 Commentary

FEATURES 43

Updated information on MRSA infections The number of hospital-acquired MRSA infections is down, but community-acquired MRSA infections continue to rise.

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Poisoning leads to neurologic damage 111

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CONTENTS DEPARTMENTS 103 Stat Consult The most recent information on diagnosing and treating celiac disease.

125 Legal Advisor After a routine procedure, serious complications—including pain and lack of sensation—combine with lack of follow-up and result in a lawsuit.

107 CME/CE Dermatology Clinic ■ A feverish man with a history of atopy presented with a rapidly spreading rash that began on his upper lip.

131 CME/CE Dermatologic Look-Alikes Two yellow processes on the face of one woman—one on top of her eyelid and the other on her cheek

■ Several years after its fi rst appearance, a painless and nonpruritic mole on a young man developed a depigmented halo.

137 CME/CE Posttest Punched-out lesions on the cheeks and lip 107

111 Clinical Challenge ■ A father is rushed to the emergency department after drinking three beers and ingest ing rat poison.

142 Evidence-Based Medicine ■ Fluid bolus increases mortality in children with severe febrile illness and impaired perfusion in lowresource settings ■ Intensive-dose statins increase risk of diabetes but lower cardiovascular risk compared with moderate-dose statins

■ After a trip and fall, a man develops pain, ecchymosis, and swelling in the hand on which he landed.

124 Derm Dx Read the clinical descriptions, view the images, and then make your diagnosis at ClinicalAdvisor.com.

138 Alternative Meds Update Boasting a very high concentration of vitamin C, rose hips are valued for their antioxidative properties.

Genital irritation ends in malpractice 125

Continues on page 12

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While there are many diabetes complications,

PAINFUL DPN IS ONE THEY CAN’T IGNORE Help manage your patients’ painful Diabetic Peripheral Neuropathy with LYRICA

ONLY LYRICA IS RECOMMENDED AS LEVEL A by AAN evidence-based guideline for the treatment of painful diabetic neuropathy (PDN)1 “If clinically appropriate, pregabalin should be offered for the treatment of PDN (Level A).”1 The medical organizations that developed this guideline (the AAN, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation) recognize that specific care decisions are the prerogative of the patient and physician caring for the patient, based on all of the circumstances involved.

For full guideline, visit www.aan.com/guidelines.

Level A=Established as effective, based on at least 2 Class I studies.

Class I level evidence includes a randomized, controlled clinical trial of the intervention of interest with masked or objective outcome assessment, in a representative population, and other specified criteria.

AAN=American Academy of Neurology.

LYRICA is indicated for the management of neuropathic pain associated with Diabetic Peripheral Neuropathy, management of Postherpetic Neuralgia, as adjunctive therapy for adult patients with Partial Onset Seizures, and management of Fibromyalgia.

PBP01859D/407532-01

02-08531_D_R1_LYR_DPN_Asize_JA.indd 1

© 2011 Pfizer Inc.

Selected safety information: LYRICA is contraindicated in patients with known hypersensitivity to pregabalin or any of its other components. There have been postmarketing reports of hypersensitivity in patients shortly after initiation of treatment with LYRICA. Adverse reactions included skin redness, blisters, hives, rash, dyspnea, and wheezing. Discontinue LYRICA immediately in patients with these symptoms.

There have been postmarketing reports of angioedema in patients during initial and chronic treatment with LYRICA. Specific symptoms included swelling of the face, mouth (tongue, lips, and gums), and neck (throat and larynx). There were reports of lifethreatening angioedema with respiratory compromise requiring emergency treatment. Discontinue LYRICA immediately in patients with these symptoms.

Antiepileptic drugs (AEDs) including LYRICA increase the risk of suicidal thoughts or behavior in patients taking AEDs for any indication. Monitor patients treated with any AED for any indication for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses showed clinical trial patients taking an AED had approximately twice the risk of suicidal thoughts or behavior than placebotreated patients, and estimated the incidence rate of suicidal behavior or ideation was approximately one patient for every 530 patients treated with an AED. The most common adverse reactions across all LYRICA All rights reserved.

clinical trials are dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, constipation, euphoric mood, balance disorder, increased appetite, and thinking abnormal (primarily difficulty with concentration/attention).

Inform patients taking LYRICA that dizziness and somnolence may impair their ability to perform potentially hazardous tasks such as driving or operating complex machinery until they have sufficient experience with LYRICA to determine its effect on cognitive and motor function.

Higher frequency of weight gain and edema was observed in patients taking both LYRICA and thiazolidinedione antidiabetic drugs. Exercise caution when coadministering these drugs. Patients who are taking other drugs associated with angioedema such as angiotensin-converting enzyme inhibitors (ACE inhibitors) may be at increased risk of developing angioedema. Exercise caution when using LYRICA in patients who have had a previous episode of angioedema.

For Full Prescribing Information and Medication Guide, please visit www.LyricaHCP.com.

Please see the Brief Summary of Prescribing Information on adjacent pages.

Reference: 1. Bril V, England JD, Franklin GM, et al. Evidence-based guideline: treatment of painful diabetic neuropathy. Report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology. 2011;76:1758-1765.

September 2011

10/20/11 5:44 PM

CONTENTS ■ Preoperative echocardiography does

not appear to improve survival in patients having elective noncardiac surgery ■ Prophylactic azithromycin reduces COPD exacerbations in high-risk patients ■ Addition of intracranial arterial stenting to aggressive medical management increases stroke in high-risk patients

■ Bad auscultation techniques ■ Decreasing fear of rapid

hyperglycemia ■ Low testosterone in young,

healthy men ■ Pedal cracking ■ Differences in thyroid tests ■ Rude awakenings via migraine

Rose hips are used as an anti-inflammatory 138

98

ADVISOR FORUM 94

Consultations ■ Maturity onset diabetes of the young ■ Chest CT before leaving the ED to prevent pulmonary embolism ■ How is microalbumin:creatinine ratio interpreted?

■ Effectiveness of a sinus CT ■ Choosing the best inflammation marker

99 How effective is ECG before surgery? 142

Clinical Pearls ■ A visual hypertension warning ■ Preventing diarrhea after esophageal reconstruction ■ Timely reminder to keep stretching ■ Spray toward the ears to avoid bloody noses ■ Size up, not down, when choosing a catheter for men ■ A recipe for regularity Your Comments ■ Abstinence is free, healthy,

and effective

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Xarelto reduces heart-attack mortality Adding the oral anticoagulant rivaroxaban (Xarelto, Janssen) to standard therapy after myocardial infarction (MI) or unstable angina significantly reduced the risk for cardiovascular mortality.

Diabetes lifestyle tips Lifestyle decisions are just as important as medications in managing diabetes, so be prepared to offer patients with diabetes practical tips as part of their treatment plans. Such tips include maintaining a lowglycemic diet and completing 30 minutes of daily exercise.

FDA approves first cord-blood product Hemacord, a cord-blood product containing hematopoeitic progenitor cells, offers potentially lifesaving treatment options for patients with certain blood cancers or inherited metabolic or immune-system disorders.

Chemotherapy-felated skin toxicities As cancer diagnoses increase worldwide, chemotherapy-related skin toxicities are also on the rise. Clinicians and patients alike should be prepared to recognize these disorders, which include folliculitis, paronychia, trichomegaly, and hyperpigmentation.

Excess neurons associated with autism Children with autism had 67% more neurons in the prefrontal cortex, providing the first evidence that other brain cells may not be involved in the developmental disorder.

The Waiting Room Official Blog of The Clinical Advisor ClinicalAdvisor.com/Blog Robyn Carlisle, MSN, CNM, WHNP Helping patients cope with pregnancy loss Health-care providers may unknowingly come off as too callous after an expectant mother experiences a miscarriage.

Derm Dx Interact with your peers by viewing the images and offering your diagnosis and comments.

ClinicalAdvisor.com/DermDx Anogenital ulcerations in a female with HIV/AIDS A woman, aged 23 years, presented to the ED with extremely painful genital ulcers that would heal and reappear.

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Leigh Montejo, MSN, FNP-BC Establishing patient treatment contracts for managing chronic pain Pain is the one concern that more often than not prompts people to see a health-care provider, so addressing these complaints adequately can significantly influence the relationship you have with your patients.

Julee B. Waldrop, DNP, PNP, FNP Discussing differences in primary- and acute-care nurse practitioners Both primary-care and acute-care nurse practitioners must ensure that they are working within their respective scopes of practice to avoid the legal ramifications of misrepresenting themselves.

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www.clinicaladvisor.com • THE CLINICAL ADVISOR • DECEMBER 2011 15

CME CE

PROGRAM OUTLINE DECEMBER 2011

0.5 CREDITS

Page 67 FEATURE Urinary incontinence in the older female population Linda J. Keilman, DNP, GNP-BC ■ LEARNING OBJECTIVES: • Name the type of urinary incontinence (UI) associated with detrusor overactivity.

• Know which drug may cause chronic cough, making its use a risk factor associated with UI. • Describe the preferred method for determining postvoid residual urine volume.

• Identify the lifestyle intervention used in the treatment of overflow incontinence.

0.5 CREDITS

Page 107 DERMATOLOGY CLINIC Case #1: Vesicular eruption coupled with fever William S. Gillen and Julia R. Nunley, MD

Case #2: Depigmented area surrounding a mole Kerri Robbins, MD ■ LEARNING OBJECTIVES: • To increase awareness of dermatologic conditions, their diagnosis, and up-to-date treatment.

Page 131 DERMATOLOGIC LOOK-ALIKES Yellow processes on the face Noah Scheinfeld, MD, JD ■ LEARNING OBJECTIVE: • To improve the clinician’s ability to distinguish and properly treat dermatologic conditions with similar presentations.

Page 137 POSTTEST

This program has been reviewed and is approved for a maximum of 1 hour of AAPA Category I CME credit by the Physician Assistant Review Panel. Approval is valid for one year from the issue date of December 2011. Participants may submit the self-assessment at any time during that period. This program was planned in accordance with AAPA’s CME Standards for Enduring Material Programs and for Commercial Support of Enduring Material Programs.

The Nurse Practitioner Associates for Continuing Education (NPACE) is an approved provider of continuing education by the Massachusetts Association of Registered Nurses, Inc. (MARN), an accredited approver by the American Nurses Credentialing Center’s Commission on Accreditation (ANCC). NPACE designates this educational activity for a maximum of 1 contact hour of credit. Participants should only claim credit commensurate with the extent of their participation in the activity.

16 THE CLINICAL ADVISOR • DECEMBER 2011 • www.ClinicalAdvisor.com

Newsline

Boys are also advised to get the HPV vaccine page 26

Drospirenone contraceptives raise clot risk page 25

D E C E M B E R 2 0 11

Yoga is beneficial for those with low back pain page 28

© CMSP

Prepare youths to take over diabetes care

Preparation should start one year before the transition to adult care.

should be redirected to the teen rather than focused exclusively on the parents or guardian.

Pediatric providers should supply transitioning patients as well as the future adult-care clinician with written summaries of care issues and medication lists and refer these patients to adultcare practitioners with experience in intensive management.

The adolescent should also be informed about the differences in approaches between pediatriccare and adult-care providers.

Ongoing visits should occur every three months for insulin users and every three to six months for patients with type 2 diabetes not taking insulin. Both pediatric-care and adult-care providers should ensure that their patients with diabetes also receive ongoing primary and preventive health services.

Past year mental health treatment among adults These numbers exclude treatment for alcohol or drug abuse.

Respondents could report more than one type of treatment.

Source: 2009 Substance Abuse and Mental Health Services Administration National Survey on Drug Use and Health

20 Percent of adults

ADOLESCENTS with type 1 or type 2 diabetes need assistance to move from supervised pediatric care to adult care, in which they are responsible for managing their own health. However, this can also be a challenging assignment for clinicians, prompting a fi rst-ever position statement on the topic from the American Diabetes Association (ADA).

With representation from numerous organizations, the ADA position statement advises pediatric health-care providers to begin preparing adolescents at least one year prior to the transition, with the help of the patient’s family (Diabetes Care.

2011;34:2477-2485; available at care.diabetesjournals.org/ c o n t e n t / 3 4 /11 / 2 4 7 7. f u l l .pdf+html, accessed November 15, 2011). However, the authors acknowledge several “substantial challenges” involved in this

process, including but not limited to: (1) the dearth of empirical evidence on the best approaches to the transition process; (2) fundamental differences in health-care delivery between providers of pediatric health care and adult health care; (3) lack of well-defined criteria for determination of transition readiness; and (4) deficiencies in training of health-care professionals in care delivery for emerging adults with diabetes.

The ADA describes several steps clinicians can take to ease the transition. For example, providers should encourage a gradual shift of diabetes-care responsibilities from the parent or guardian to the patient. This would entail having the young people start monitoring glucose levels and diabetes supplies, self-administering insulin, and scheduling health-care appointments. Diabetes education

Female

17.1

16 12

Male

14.7 9.2 7.6

8

8.2 4.3

4

0.9 0

Any type of treatment/ counseling

22 THE CLINICAL ADVISOR • DECEMBER 2011 • www.ClinicalAdvisor.com

Prescription medication

Outpatient

0.8

Inpatient

Newsline

TOP PHOTO: © BIOPHOTO ASSOCIATES / PHOTO RESEARCHERS, INC. ; BOTTOM PHOTO: © ISTOCKPHOTO.COM / YUKO HIRAO

Drospirenone OC linked to higher VTE THE FDA is reviewing the potential increased risk of blood clots in women who use oral contraceptives (OC) containing the progestin drospirenone.

After informing the public in May that it was assessing new information regarding this matter and confirming its concern four months later, the FDA released the fi nal report of a study that evaluated the risk of blood clots in users of several different hormonal contraceptives (available at www .fda.gov/Drugs/DrugSafet y /ucm 277346.htm; accessed November 15, 2011). The report concluded that the results “add to the small body of literature” showing (1) the norelgestromin/ ethinyl estradiol (NGMN) transdermal patch is associated with a higher risk of venous thromboembolism (VTE) relative to standard combined hormonal

contraceptives (CHCs) and (2) the drospirenone/ethinyl estradiol (DRSP) tablet is associated with increased risk of VTE relative to standard low-dose CHC pills.

DRSP was associated with higher risk of arterial thrombotic events in new users aged 35 to 55 years.

Separately, a Danish report also found that women using OCs containing one of the newer types of progestogen—drospirenone, desogestrel, or gestodene—have double the risk of VTE than do women on pills containing levonorgestrel, an older progestogen (BMJ. 2011;343:d6423; available at www.ncbi.nlm.nih. gov/pmc/articles/PMC3202015/, accessed November 15, 2011).

Finally, an analysis of 329,995 users of OCs in Israel led by Naomi Gronich, MD, uncovered an elevated risk of venous thrombotic events (deep vein thrombosis and

A blood clot (red) blocks the lumen of a vein in the calf muscle.

pulmonary embolism), but not arterial thrombotic events (transient ischemic attack and cerebrovascular accident), for drospirenone compared with second- and third-generation OCs (CMAJ. 2011; published online ahead of print, available at www.cmaj .ca/content/early/2011/11/07 /cmaj.110463.full.pdf+html, accessed November 15, 2011).

New recommendations may cut SIDS rate TO ADDRESS an increase in sleep-related deaths among infants, the American Academy of Pediatrics (AAP) has updated its policy on how to prevent sudden infant death syndrome (SIDS), adding three important measures to the existing recommendations.

The major decrease in the incidence of SIDS that followed the AAP’s 1992 recommendation that babies be placed on their backs to sleep has plateaued in recent years, notes the organization’s SIDS task force in its new policy statement

Nursing is associated with a reduced risk of SIDS.

and technical report (Pediatrics.

2011;128:1030-1039; available at pediatrics.aappublications.org/ content/128/5/1030.long, accessed November 15, 2011). Other causes of sudden unexpected infant death that occur during sleep, including suffocation, asphyxia, entrapment, and ill-defined or unspecified causes have increased in incidence, particularly since the AAP’s last statement on SIDS in 2005.

The AAP document highlights three added recommendations that can be shared with new parents:

• Breastfeeding is recommended and is associated with a reduced risk of SIDS. • Infants should receive all recommended vaccinations; evidence suggests that immunization reduces the risk of SIDS by 50%.

• Bumper pads should not be used in cribs. There is currently no evidence that these products prevent injuries, and they create a potential risk of suffocation, strangulation, or entrapment.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2011 25

Newsline AMONG MEN who are current and former heavy smokers, low-dose computed tomography (LDCT) scans—inspiratory and expiratory—obtained for lung screening can identify persons who have chronic obstructive pulmonary disease (COPD), researchers report.

With smoking being a major risk factor for both cancer and COPD, CT-based lung-cancer screening may provide an opportunity to detect additional individuals with COPD at an early stage. In a study of 1,140 men undergoing lung-cancer screening, 437 (38%) had COPD according to lungfunction testing. A diagnostic model based on an individual’s CT findings, BMI, pack-years, and smoking status identified 274 participants as having COPD,

with 85 false-positives. These 274 men comprised 54% of all participants with mild obstruction, 73% of all those with moderate obstruction, and 100% of all those with severe obstruction.

This translated to a sensitivity of 63% and a specificity of 88% for CT detection of COPD ( JAMA. 2011;306:1775-1781).

In other COPD news, low vitamin D levels are unrelated to acute exacerbations of the disease, according to an American Journal of Respiratory and Critical Care Medicine report from Ken M. Kunisaki, MD, and colleagues (published online ahead of print on November 10, 2011).

Although low blood levels of 25-hydroxyvitamin D have been linked with a higher risk of respiratory infections in general

Pulmonary emphysema (shown) is often linked to smoking.

populations and a higher risk of lung-disease exacerbations in people with asthma, the investigators learned from their oneyear study of 973 patients that baseline levels of this vitamin are not predictive of subsequent acute exacerbations of COPD in patients with severe disease.

Boys on track for HPV vaccination, too NEARLY 5.5 years after the CDC Advisory Committee on Immunization Practices (ACIP) recommended vaccinating 11- to 12-year-old girls against human papillomavirus (HPV), as well as all women through age 26 years who hadn’t already received the vaccine, boys are now receiving the same recommendation.

The ACIP recommends routine quadrivalent HPV vaccination for boys aged 11 or 12 years, and for others up to age 21 years who hadn’t already received the vaccine.

Vaccination for boys and girls could begin as young as age 9 years.

Approximately 20 million Americans were infected with HPV by the time the new ACIP recommendation was announced.

The virus is associated with cancers of the cervix, vulva, vagina, penis, and anus, and with head and neck cancer. By mid-September 2011, nearly 40 million doses of the vaccine Gardasil have been distributed in the United States.

After reviewing vaccine effectiveness and cost-effectiveness, disease trends, safety, and practical implementation issues for providers and parents, the ACIP delivered its recommendations to the CDC.

26 THE CLINICAL ADVISOR • DECEMBER 2011 • www.ClinicalAdvisor.com

Once these have been written up and approved by the CDC, they will be published in Morbidity and Mortality Weekly Report.

Separately, Professor Attila T. Lorincz, PhD, and colleagues reported in The Lancet that vaginal self-sampling for HPV testing demonstrated a relatively low but acceptable positive predictive value in a large trial of women of low socioeconomic status in underserved areas of Mexico. The investigators concluded that vaginal self-sampling could increase HPV screening rates in other populations as well.

TOP PHOTO: © BSIP / PHOTO RESEARCHERS, INC.; BOTTOM PHOTO: © ISTOCKPHOTO.COM / ALEXANDER RATHS

Lung cancer screening may detect COPD

Supplements may cause harm Hormones, ALTHOUGH THE consumption of dietary supplements has increased considerably over the past decade, most of these products do not reduce total mortality in older women, and many appear to be associated with increased mortality risk (Arch Intern Med. 2011;171:1625-1633).

The use of vitamin and mineral supplements in relation to total mortality was assessed based on data from 38,772 older participants (mean age 61.6 years at baseline in 1986) in the Iowa Women’s Health Study. Supplement use was selfreported in 1986, 1997, and 2004.

Consumption rose substantially throughout that that time frame, with 62.7% of women taking at least one supplement daily in 1986, compared with 75.1% in 1997 and 85.1% in 2004.

A total of 15,594 deaths (40.2%) occurred by December 31, 2008 (mean follow-up 19 years). The

In older women, most supplements did not reduce mortality.

investigators calculated that most supplements did not reduce mortality in this population, and that the use of multivitamins, vitamin B6, folic acid, iron, magnesium, zinc, and copper were associated with increased risk of total mortality when compared with corresponding nonuse. The association was strongest with supplemental iron. The use of calcium supplements, however, was associated with reduced mortality risk.

The findings for both the iron and the calcium supplements were replicated in separate, short-term analyses with follow-up occurring at four, six, and 10 years.

The results provide little justification for the general and widespread use of dietary supplements, according to the authors, who recommend that these products be used with strong medically based cause, such as symptomatic nutrient deficiency disease.

© ISTOCKPHOTO.COM / RADU RAZVAN

Last of the CFC inhalers exits this month Primatene Mist—the only over the counter asthma inhaler sold in the United States— will no longer be available after December 31, 2011. The product’s disappearance is part of a phase-out of epinephrine inhalers containing chlorofluorocarbons (CFCs), an ozone-depleting substance.

The FDA initiated public discussion about the use of CFCs for epinephrine inhalers in January 2006 and finalized the phase-out date in November 2008.

A number of manufacturers have already changed their inhalers to replace CFCs with

the propellant hydrofluoroalkane (HFA).

Albuterol HFA inhalers—as well as all other inhalers—will be available for purchase only with a prescription beginning on January 1, 2012.

Patients can continue using the last of their Primatene Mist supplies beyond December 31 unless it has expired, but clinicians should help them transition to other treatment options best suited to the person’s needs. If another inhaler is used, be sure the patient is using the device correctly and is obtaining the proper dose.

insomnia, and CV risk ALTHOUGH LOW serum testosterone is associated with increased adiposity, an adverse metabolic risk profi le, and atherosclerosis, few studies have shown a protective link between endogenous testosterone and cardiovascular (CV) events, according to investigators ( J Am Coll Cardiol. 2011;58:16741681). The researchers analyzed baseline levels of testosterone in 2,416 men, aged 69 to 81 years.

During a median 5-year followup, 485 CV events occurred. Men in the highest quartile of testosterone (>550 ng/dL) had a lower risk of CV events compared with men in the three lower quartiles.

A different team conducted another prospective study, this one to clarify the relationship between insomnia symptoms and acute MI (Circulation. 2011;124:20732081). The investigators followed 52,610 men and women for a first acute MI; 2,368 incident acute MIs occurred during 11.4 years of follow-up.

Compared with subjects who rarely had trouble sleeping: • Persons who had trouble falling asleep daily were 45% more likely to have a heart attack.

• Persons who had problems staying asleep almost every night were 30% more likely to have a heart attack.

• Persons who felt unrefreshed in the morning more than once a week were 27% more likely to have a heart attack.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2011 27

Newsline TWO LARGE studies have underscored the benefits of yoga for people suffering from low back pain.

In one project, 313 adults in the United Kingdom with chronic or recurrent low back pain received an education booklet, after which 156 were randomized to a 12-class, three-month yoga program; the remaining participants were deemed the usual-care group.

Participation in the yoga program led to greater improvements in back function than did usual care (Ann Intern Med. 2011;155:569578; available at www.annals. org/content/155/9/569.long, accessed November 15, 2011): Compared with the usual-care group, the adjusted mean RolandMorris Disability Questionnaire score was 2.17 points lower in the yoga group at three months; 1.48

points lower at six months, and 1.57 points lower at 12 months.

The two groups had similar scores on back pain and general health at all three points. The yoga participants had higher pain self-efficacy scores at three and six months, but not at 12 months.

Adverse events—mostly increased pain—were reported by 12 of the 156 yoga patients and two of the 157 usual-care members.

In a similar randomized trial, this one taking place in the United States, 228 adults with chronic low back pain were also randomized to 12 weekly classes of yoga, conventional stretching exercises, or a self-care book.

Karen J. Sherman, PhD, MPH, and colleagues affirmed in Archives of Internal Medicine that after adjustment for baseline values, 12-week

© ISTOCKPHOTO.COM / BLEND IMAGES

Yoga a good remedy for low back pain

Yoga improves function and reduces symptoms due to low back pain.

outcomes for the yoga group were superior to those for the self-care group in terms of improving function and reducing symptoms due to chronic low back pain, and remained so at the 26-week mark.

However, yoga was not superior to conventional stretching exercises at any time point.

Less frequent mammograms mean fewer false-positives After undergoing 10 years of annual mammography screening, more than half of women will receive at least one falsepositive recall and 7% to 9% will receive a false-positive biopsy recommendation, according to a recent analysis (Ann Intern Med. 2011;155:481-492).

The study looked at data from 169,456 U.S. women who had their first screening mammograms at age 40 to 59 years, between 1994 and 2006; and 4,492 women diagnosed with invasive breast cancer between 1996 and 2006. Over 10 years, 61.3% of women who started annual screening mammography at age 40 years could expect to be called back for additional normal imaging, compared with 41.6% of women who began biennial screening at age 40 years. In addition, 7% of women in the annual-screening group could expect to be advised to get a breast biopsy that would not ultimately lead to a diagnosis of breast cancer, compared with 4.8% of women screened biennially. Estimates were similar when screening began at age 50 years.

Although these results support the recommendation that biennial mammography will reduce a woman’s probability of obtaining a false-positive reading, the two-year screening interval appeared to be associated with a small absolute increase in the probability of late-stage cancer diagnosis.

Adding to the screening-mammography controversy is another recent finding indicating that the probability a woman with screen-detected breast cancer has avoided a breast cancer death because of screening mammography is now likely to be well below 10%.

“Most women with screen-detected breast cancer have not had their life saved by screening,” concluded H. Gilbert Welch, MD, MPH, and Brittney A. Frankel in Archives of Internal Medicine (available archinte.ama-assn.org/cgi/content/ full/archinternmed.2011.476v1, accessed November 15, 2011).

“They are instead either diagnosed early (with no effect on their mortality) or overdiagnosed.” ■

28 THE CLINICAL ADVISOR • DECEMBER 2011 • www.ClinicalAdvisor.com

DrugUpdate New drug information from the publishers of MPR

Once-daily combo pill for HIV infection Product: Complera Company: Gilead Sciences Pharmacologic class:

Nucleoside analogue reverse transcriptase inhibitors + non-nucleoside reverse transcriptase inhibitor.

Active ingredients: Emtricitabine 200 mg, tenofovir disoproxil fumarate 300 mg, rilpivirine 25 mg; tabs.

Indication: HIV-1 infection.

Pharmacology: Complera is a fixed-dose combination of the antiviral drugs emtricitabine, rilpivirine, and tenofovir disoproxil fumarate.

Clinical trials: The efficacy of rilpivirine is based on the analyses of 48-week data from two trials (ECHO and THRIVE) in antiretroviral treatment– naïve adults. In ECHO, the background regimen (BR) was tenofovir DF + emtricitabine. In THRIVE, the BR consisted of one of the following: tenofovir DF + emtricitabine or zidovudine + lamivudine

or abacavir + lamivudine.

Subjects were randomized to receive either rilpivirine 25 mg once daily or efavirenz 600 mg once daily in addition to a BR. Based on the pooled data from both trials at 48 weeks, the proportion of subjects with <50 HIV-1 RNA copies/ mL receiving rilpivirine/ tenofovir DF/emtricitabine (N=550) compared with subjects receiving efavirenz/tenofovir DF/ emtricitabine (N=546) was 83% and 81%, respectively. The mean CD4+ cell count increase from baseline was 193 cells/mm3

Complera is for adults who have not yet taken any other HIV medications.

for rilpivirine-treated subjects and 182 cells/mm3 for efavirenz-treated subjects.

Adults: Take with a meal. One tablet once daily. Renal impairment (creatinine clearance [CrCl] <50 mL/min): not recommended.

Children: <18 years: not recommended.

Contraindications: Concomitant carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole, systemic dexamethasone (more than single dose), St. John’s wort.

Warnings/Precautions: Suspend if lactic acidosis or hepatotoxicity occurs.

Women, obesity, prolonged nucleoside exposure, other risk factors for hepatic dysfunction: increased risk of toxicity. Not for treating chronic hepatitis B; test for hepatitis B virus (HBV) before starting therapy and monitor patients coinfected with HIV-1 and HBV during and for several months after stopping treatment (discontinuing therapy may exacerbate HBV infection).

Renal impairment: monitor

Pharma Pharmacologic class: Opioid Active ingredient: Fentanyl 100 µg, 400 µg; per 100 µL nasal spray.

Indication: Breakthrough pain in opioid-tolerant patients who are already receiving and tolerant to continuous opioid therapy for underlying persistent cancer pain.

Pharmacology: Like other pure opioid agonists, fentanyl acts on the mu-receptors in the central nervous system (CNS) to produce analgesia and CNS depression.

Clinical trials: The efficacy of Lazanda was evaluated in a clinical trial in opioidtolerant adult patients experiencing breakthrough cancer pain. The trial included an open-label titration phase in which a dose was identified that provided adequate analgesia with tolerable side effects, within the range of 100 to 800 µg. In the double-blind,

Continued pg. 36

Continued pg. 36

Fentanyl nasal spray manages cancer pain Product: Lazanda Company: Archimedes

For more products, visit www.eMPR.com

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2011 35

Evolving anticoagulation in patients with NVAF, including those at increased stroke risk...

HELP INTERCEPT STROKE RISK

...combining proven protection, a demonstrated safety profile, and convenient once-daily dosing XARELTO® (rivaroxaban) is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF).

There are limited data on the relative effectiveness of XARELTO® and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is well controlled.

IMPORTANT SAFETY INFORMATION WARNING A. DISCONTINUING XARELTO® IN PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATION Discontinuing XARELTO® places patients at an increased risk of thrombotic events. An increased rate of stroke was observed following XARELTO® discontinuation in clinical trials in atrial fibrillation patients. If anticoagulation with XARELTO® must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant.

Please see additional Important Safety Information and brief summary of Prescribing Information, including Boxed WARNINGS, on following pages.

Once-daily XARELTO® delivers...

Proven protection Effective reduction in risk of stroke and non-CNS systemic embolism* Results achieved in NVAF patients with multiple comorbidities reflecting increased risk of stroke

A demonstrated safety profile Comparable major bleed rates† versus warfarin: rivaroxaban 3.6, warfarin 3.5 per 100 patient-years In bleeding categories of great concern, such as bleeding into a critical organ‡ and fatal bleeding, fewer events were observed with XARELTO®§ In the categories of transfusions and gastrointestinal bleed, more events were observed with XARELTO®§

Convenient once-daily dosing and administration Oral 20-mg fixed dose taken once daily with the evening meal (15 mg for patients with CrCl 15 mL/min to 50 mL/min) No routine monitoring of INR or other coagulation parameters is required1 If a dose of XARELTO® is not taken at the scheduled time, administer the dose as soon as possible on the same day

E vent rates per 100 patient-years, rivaroxaban versus warfarin: critical-organ bleeding 0.8 versus 1.2; fatal bleeding 0.2 versus 0.5; bleeding resulting in transfusion of ≥2 units of whole blood or packed red blood cells 1.7 versus 1.3; gastrointestinal bleeding 2.0 versus 1.2.

§

IMPORTANT SAFETY INFORMATION (cont’d) Warning (cont’d) B. SPINAL/EPIDURAL HEMATOMA Epidural or spinal hematomas have occurred in patients treated with XARELTO® who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: Use of indwelling epidural catheters Concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants, see Drug Interactions A history of traumatic or repeated epidural or spinal punctures A history of spinal deformity or spinal surgery Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary.

Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis.

CONTRAINDICATIONS Active pathological bleeding and severe hypersensitivity reaction to XARELTO®.

WARNINGS AND PRECAUTIONS Increased Risk of Stroke After Discontinuation in Nonvalvular Atrial Fibrillation: Discontinuing XARELTO®, in the absence of adequate alternative

anticoagulation, increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from XARELTO® to warfarin in clinical trials in atrial fibrillation patients. If XARELTO® must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant.

Risk of Bleeding: XARELTO® increases the risk of bleeding and can cause serious or fatal bleeding. In deciding whether to prescribe XARELTO® to patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding.

Promptly evaluate any signs or symptoms of blood loss. Discontinue XARELTO® in patients with active pathological hemorrhage.

• A specific antidote for rivaroxaban is not available.

Because of high plasma protein binding, rivaroxaban is not expected to be dialyzable. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving rivaroxaban. There is neither scientific rationale for benefit nor experience with systemic hemostatics (desmopressin and aprotinin) in individuals receiving rivaroxaban. Use of procoagulant reversal agents such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC), or recombinant factor VIIa (rFVIIa) may be considered, but has not been evaluated in clinical trials.

• Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, and NSAIDs.

Please see additional Important Safety Information and brief summary of Prescribing Information, including Boxed WARNINGS, on following pages.

IMPORTANT SAFETY INFORMATION (cont’d) • Concomitant use of drugs that are combined P-gp and CYP3A4 inhibitors (eg, ketoconazole and ritonavir) increases rivaroxaban exposure and may increase bleeding risk.

Spinal/Epidural Anesthesia or Puncture: When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma, which can result in long-term or permanent paralysis.

An epidural catheter should not be removed earlier than 18 hours after the last administration of XARELTO®. The next XARELTO® dose is not to be administered earlier than 6 hours after the removal of the catheter. Delay the administration of XARELTO® for 24 hours if traumatic puncture occurs.

Risk of Pregnancy-Related Hemorrhage: Use with caution in pregnant women and only if the potential benefit justifies the potential risk to the mother and fetus. The anticoagulant effect of XARELTO® cannot be monitored with standard laboratory testing and is not readily reversed. Promptly evaluate any signs or symptoms suggesting blood loss (eg, a drop in

hemoglobin and/or hematocrit, hypotension, or fetal distress). Pregnancy Category C Severe Hypersensitivity Reactions: There were postmarketing cases of anaphylaxis in patients treated with XARELTO® to reduce the risk of deep vein thrombosis (DVT). Patients who have a history of a severe hypersensitivity reaction to XARELTO® should not receive XARELTO®.

DRUG INTERACTIONS Drugs That Inhibit CYP3A4 Enzymes and Drug Transport Systems: Avoid concomitant administration of XARELTO® with combined P-gp and strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, lopinavir/ ritonavir, ritonavir, indinavir/ritonavir, and conivaptan), which cause significant increases in rivaroxaban exposure that may increase bleeding risk.

Drugs That Induce CYP3A4 Enzymes and Drug Transport Systems: Avoid concomitant use of XARELTO® with drugs that are combined P-gp and strong CYP3A4 inducers (eg, carbamazepine, phenytoin, rifampin, St. John’s wort) due to decreases in rivaroxaban exposure that may decrease efficacy.

CNS = central nervous system; CrCl = creatinine clearance; INR = international normalized ratio.

*A randomized, phase 3, multicenter, active-controlled, double-blind, double-dummy,

event-driven study in more than 14,000 patients with NVAF. Patients received XARELTO® 20 mg once daily (15 mg once daily in patients with CrCl 30 mL/min-50 mL/min) or dose-adjusted warfarin titrated to an INR range of 2.0-3.0.1 † Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL, transfusion of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. Hemorrhagic strokes were counted as both bleeding and efficacy events. Major bleeding rates excluding strokes were 3.3 for XARELTO® and 2.9 for warfarin per 100 patient-years. ‡ The majority of critical-organ bleeding events were intracranial, and also included intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, or retroperitoneal.

Learn more at www.XARELTOhcp.com

Once-daily XARELTO® delivers...

Proven protection Effective reduction in risk of stroke and non-CNS systemic embolism* Results achieved in NVAF patients with multiple comorbidities reflecting increased risk of stroke

A demonstrated safety profile Comparable major bleed rates† versus warfarin: rivaroxaban 3.6, warfarin 3.5 per 100 patient-years In bleeding categories of great concern, such as bleeding into a critical organ‡ and fatal bleeding, fewer events were observed with XARELTO®§ In the categories of transfusions and gastrointestinal bleed, more events were observed with XARELTO®§

Convenient once-daily dosing and administration Oral 20-mg fixed dose taken once daily with the evening meal (15 mg for patients with CrCl 15 mL/min to 50 mL/min) No routine monitoring of INR or other coagulation parameters is required1 If a dose of XARELTO® is not taken at the scheduled time, administer the dose as soon as possible on the same day

E vent rates per 100 patient-years, rivaroxaban versus warfarin: critical-organ bleeding 0.8 versus 1.2; fatal bleeding 0.2 versus 0.5; bleeding resulting in transfusion of ≥2 units of whole blood or packed red blood cells 1.7 versus 1.3; gastrointestinal bleeding 2.0 versus 1.2.

§

IMPORTANT SAFETY INFORMATION (cont’d) Warning (cont’d) B. SPINAL/EPIDURAL HEMATOMA Epidural or spinal hematomas have occurred in patients treated with XARELTO® who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: Use of indwelling epidural catheters Concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants, see Drug Interactions A history of traumatic or repeated epidural or spinal punctures A history of spinal deformity or spinal surgery Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary.

Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis.

CONTRAINDICATIONS Active pathological bleeding and severe hypersensitivity reaction to XARELTO®.

WARNINGS AND PRECAUTIONS Increased Risk of Stroke After Discontinuation in Nonvalvular Atrial Fibrillation: Discontinuing XARELTO®, in the absence of adequate alternative

anticoagulation, increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from XARELTO® to warfarin in clinical trials in atrial fibrillation patients. If XARELTO® must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant.

Risk of Bleeding: XARELTO® increases the risk of bleeding and can cause serious or fatal bleeding. In deciding whether to prescribe XARELTO® to patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding.

Promptly evaluate any signs or symptoms of blood loss. Discontinue XARELTO® in patients with active pathological hemorrhage.

• A specific antidote for rivaroxaban is not available.

Because of high plasma protein binding, rivaroxaban is not expected to be dialyzable. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving rivaroxaban. There is neither scientific rationale for benefit nor experience with systemic hemostatics (desmopressin and aprotinin) in individuals receiving rivaroxaban. Use of procoagulant reversal agents such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC), or recombinant factor VIIa (rFVIIa) may be considered, but has not been evaluated in clinical trials.

• Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, and NSAIDs.

Please see additional Important Safety Information and brief summary of Prescribing Information, including Boxed WARNINGS, on following pages.

IMPORTANT SAFETY INFORMATION (cont’d) • Concomitant use of drugs that are combined P-gp and CYP3A4 inhibitors (eg, ketoconazole and ritonavir) increases rivaroxaban exposure and may increase bleeding risk.

Spinal/Epidural Anesthesia or Puncture: When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma, which can result in long-term or permanent paralysis.

An epidural catheter should not be removed earlier than 18 hours after the last administration of XARELTO®. The next XARELTO® dose is not to be administered earlier than 6 hours after the removal of the catheter. Delay the administration of XARELTO® for 24 hours if traumatic puncture occurs.

Risk of Pregnancy-Related Hemorrhage: Use with caution in pregnant women and only if the potential benefit justifies the potential risk to the mother and fetus. The anticoagulant effect of XARELTO® cannot be monitored with standard laboratory testing and is not readily reversed. Promptly evaluate any signs or symptoms suggesting blood loss (eg, a drop in

hemoglobin and/or hematocrit, hypotension, or fetal distress). Pregnancy Category C Severe Hypersensitivity Reactions: There were postmarketing cases of anaphylaxis in patients treated with XARELTO® to reduce the risk of deep vein thrombosis (DVT). Patients who have a history of a severe hypersensitivity reaction to XARELTO® should not receive XARELTO®.

DRUG INTERACTIONS Drugs That Inhibit CYP3A4 Enzymes and Drug Transport Systems: Avoid concomitant administration of XARELTO® with combined P-gp and strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, lopinavir/ ritonavir, ritonavir, indinavir/ritonavir, and conivaptan), which cause significant increases in rivaroxaban exposure that may increase bleeding risk.

Drugs That Induce CYP3A4 Enzymes and Drug Transport Systems: Avoid concomitant use of XARELTO® with drugs that are combined P-gp and strong CYP3A4 inducers (eg, carbamazepine, phenytoin, rifampin, St. John’s wort) due to decreases in rivaroxaban exposure that may decrease efficacy.

CNS = central nervous system; CrCl = creatinine clearance; INR = international normalized ratio.

*A randomized, phase 3, multicenter, active-controlled, double-blind, double-dummy,

event-driven study in more than 14,000 patients with NVAF. Patients received XARELTO® 20 mg once daily (15 mg once daily in patients with CrCl 30 mL/min-50 mL/min) or dose-adjusted warfarin titrated to an INR range of 2.0-3.0.1 † Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL, transfusion of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. Hemorrhagic strokes were counted as both bleeding and efficacy events. Major bleeding rates excluding strokes were 3.3 for XARELTO® and 2.9 for warfarin per 100 patient-years. ‡ The majority of critical-organ bleeding events were intracranial, and also included intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, or retroperitoneal.

Learn more at www.XARELTOhcp.com

IMPORTANT SAFETY INFORMATION (cont’d) NSAIDs/Aspirin: NSAIDs/aspirin are known to increase bleeding; therefore, bleeding risk may be increased when these drugs are used concomitantly with XARELTO®. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs. Clopidogrel: Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with clopidogrel.

Drug-Disease Interactions With Drugs That Inhibit CYP3A4 Enzymes and Drug Transport Systems: Use in patients with CrCl 15 mL/min to 50 mL/min who are receiving concomitant combined P-gp and weak or moderate CYP3A4 inhibitors only if the potential benefit justifies the potential risk.

USE IN SPECIFIC POPULATIONS Nursing Mothers: It is not known if rivaroxaban is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from rivaroxaban, a decision should be made whether to discontinue nursing or discontinue XARELTO®, taking into account the importance of the drug to the mother.

Geriatric Use: In clinical trials the efficacy of XARELTO® in the elderly (65 years or older) was similar to that seen in patients younger than 65 years. Both thrombotic and bleeding event rates were higher in these older patients, but the risk-benefit profile was favorable in all age groups.

Renal Impairment • Patients with renal impairment taking P-gp and weak to moderate CYP3A4 inhibitors may have significant increases in exposure, which may increase bleeding risk.

• For patients with CrCl 15 mL/min to 50 mL/min, the recommended dose of XARELTO® is 15 mg once daily with the evening meal. Avoid use in patients with CrCl <15 mL/min. Periodically assess renal function as clinically indicated (ie, more frequently in

situations in which renal function may decline) and adjust therapy accordingly. Discontinue XARELTO® in patients who develop acute renal failure while on XARELTO®.

Hepatic Impairment: No clinical data are available for patients with severe hepatic impairment. Avoid the use of XARELTO® in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy.

OVERDOSAGE Overdose of XARELTO® may lead to hemorrhage.

A specific antidote for rivaroxaban is not available.

Rivaroxaban systemic exposure is not further increased at single doses >50 mg due to limited absorption.

Discontinue XARELTO® and initiate appropriate therapy if bleeding complications associated with overdosage occur. The use of activated charcoal to reduce absorption in case of XARELTO® overdose may be considered. Due to the high plasma protein binding, rivaroxaban is not expected to be dialyzable.

ADVERSE REACTIONS IN CLINICAL STUDIES Hemorrhage: The most common adverse reactions with XARELTO® were bleeding complications.

The most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 4.3% for XARELTO® versus 3.1% for warfarin. The incidence of discontinuations for nonbleeding adverse events was similar in both treatment groups. In XARELTO®- versus warfarintreated patients, respectively, major bleeding events were 5.6% versus 5.4%.

Other Clinical Trial Experience: In an investigational study of acute medically ill patients being treated with XARELTO® 10-mg tablets, cases of pulmonary hemorrhage and pulmonary hemorrhage with bronchiectasis were observed.

Please see brief summary of Prescribing Information, including Boxed WARNINGS, on following pages.

Learn more at www.XARELTOhcp.com

Reference: 1. Patel MR, Mahaffey KW, Garg J, et al; and the ROCKET AF Steering Committee, for the ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-891.

XARELTO® is licensed from Bayer HealthCare AG, 51368 Leverkusen, Germany. © Janssen Pharmaceuticals, Inc. 2011 November 2011 02X11227

Janssen Pharmaceuticals, Inc.

Brief Summary of Prescribing Information for XARELTO® (rivaroxaban) XARELTO® (rivaroxaban) tablets, for oral use See package insert for full Prescribing Information WARNINGS: (A) DISCONTINUING XARELTO IN PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATION INCREASES RISK OF STROKE, (B) SPINAL/EPIDURAL HEMATOMA A. DISCONTINUING XARELTO IN PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATION Discontinuing XARELTO places patients at an increased risk of thrombotic events. An increased rate of stroke was observed following XARELTO discontinuation in clinical trials in atrial fibrillation patients. If anticoagulation with XARELTO must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant [see Dosage and Administration (2.1) in full Prescribing Information, Warnings and Precautions, and Clinical Studies (14.1) in full Prescribing Information].

B. SPINAL/EPIDURAL HEMATOMA Epidural or spinal hematomas have occurred in patients treated with XARELTO who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: • use of indwelling epidural catheters • concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants • a history of traumatic or repeated epidural or spinal punctures • a history of spinal deformity or spinal surgery [see Warnings and Precautions and Adverse Reactions].

Monitor patients frequently for signs and symptoms of neurological impairment.

If neurological compromise is noted, urgent treatment is necessary [see Warnings and Precautions].

Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis [see Warnings and Precautions].

INDICATIONS AND USAGE Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation: XARELTO (rivaroxaban) is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

There are limited data on the relative effectiveness of XARELTO and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is wellcontrolled [see Clinical Studies (14.1) in full Prescribing Information].

CONTRAINDICATIONS XARELTO is contraindicated in patients with: • active pathological bleeding [see Warnings and Precautions] • severe hypersensitivity reaction to XARELTO [see Warnings and Precautions] WARNINGS AND PRECAUTIONS Increased Risk of Stroke after Discontinuation in Nonvalvular Atrial Fibrillation: Discontinuing XARELTO in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from XARELTO to warfarin in clinical trials in atrial fibrillation patients. If XARELTO must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant [see Dosage and Administration (2.1) and Clinical Studies (14.1) in full Prescribing Information].

Risk of Bleeding: XARELTO increases the risk of bleeding and can cause serious or fatal bleeding. In deciding whether to prescribe XARELTO to patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding.

Promptly evaluate any signs or symptoms of blood loss. Discontinue XARELTO in patients with active pathological hemorrhage.

A specific antidote for rivaroxaban is not available. Because of high plasma protein binding, rivaroxaban is not expected to be dialyzable [see Clinical Pharmacology (12.3) in full Prescribing Information]. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving rivaroxaban. There is neither scientific rationale for benefit nor experience with systemic hemostatics (desmopressin and aprotinin) in individuals receiving rivaroxaban. Use of procoagulant reversal agents such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC), or recombinant factor VIIa (rFVIIa) may be considered, but has not been evaluated in clinical trials.

Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, and non-steroidal anti-inflammatory drugs (NSAIDs) [see Drug Interactions].

Concomitant use of drugs that are combined P-gp and CYP3A4 inhibitors (e.g. ketoconazole and ritonavir) increases rivaroxaban exposure and may increase bleeding risk [see Drug Interactions].

Spinal/Epidural Anesthesia or Puncture: When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis [see Boxed Warning].

An epidural catheter should not be removed earlier than 18 hours after the last administration of XARELTO. The next XARELTO dose is not to be administered earlier than 6 hours after the removal of the catheter. If traumatic puncture occurs, the administration of XARELTO is to be delayed for 24 hours.

Risk of Pregnancy Related Hemorrhage: XARELTO should be used with caution in pregnant women and only if the potential benefit justifies the potential risk to the mother and fetus. XARELTO dosing in pregnancy has not been studied.

The anticoagulant effect of XARELTO cannot be monitored with standard laboratory testing nor readily reversed. Promptly evaluate any signs or symptoms suggesting blood loss (e.g., a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress).

XARELTO® (rivaroxaban) tablets Severe Hypersensitivity Reactions: There were postmarketing cases of anaphylaxis in patients treated with XARELTO to reduce the risk of DVT. Patients who have a history of a severe hypersensitivity reaction to XARELTO should not receive XARELTO [see Adverse Reactions].

ADVERSE REACTIONS Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

During clinical development for the approved indications, 11598 patients were exposed to XARELTO. These included 7111 patients who received XARELTO 15 mg or 20 mg orally once daily for a mean of 19 months (5558 for 12 months and 2512 for 24 months) to reduce the risk of stroke and systemic embolism in nonvalvular atrial fibrillation (ROCKET AF) and 4487 patients who received XARELTO 10 mg orally once daily for prophylaxis of DVT following hip or knee replacement surgery (RECORD 1-3).

Hemorrhage: The most common adverse reactions with XARELTO were bleeding complications [see Warnings and Precautions].

Nonvalvular Atrial Fibrillation: In the ROCKET AF trial, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 4.3% for XARELTO vs. 3.1% for warfarin. The incidence of discontinuations for non-bleeding adverse events was similar in both treatment groups.

Table 1 shows the number of patients experiencing various types of bleeding events in the ROCKET AF study.

Table 1: Bleeding Events in ROCKET AF* Parameter

XARELTO N = 7111 n (%) 395 (5.6) 91 (1.3)

Event Rate (per 100 Pt-yrs) 3.6 0.8

Warfarin N = 7125 n (%) 386 (5.4) 133 (1.9)

Event Rate (per 100 Pt-yrs) 3.5 1.2

Major bleeding† Bleeding into a critical organ‡ Fatal bleeding 27 (0.4) 0.2 55 (0.8) 0.5 Bleeding resulting in 183 (2.6) 1.7 149 (2.1) 1.3 transfusion of ≥ 2 units of whole blood or packed red blood cells Gastrointestinal bleeding 221 (3.1) 2.0 140 (2.0) 1.2 * For all sub-types of major bleeding, single events may be represented in more than one row, and individual patients may have more than one event. † Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥ 2 g/dL, transfusion of ≥ 2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. Hemorrhagic strokes are counted as both bleeding and efficacy events. Major bleeding rates excluding strokes are 3.3 per 100 Pt-yrs for XARELTO vs. 2.9 per 100 Pt-yrs for warfarin. ‡ The majority of the events were intracranial, and also included intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome, or retroperitoneal.

Postmarketing Experience: The following adverse reactions have been identified during post-approval use of rivaroxaban. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and lymphatic system disorders: agranulocytosis Gastrointestinal disorders: retroperitoneal hemorrhage Hepatobiliary disorders: jaundice, cholestasis, cytolytic hepatitis Immune system disorders: hypersensitivity, anaphylactic reaction, anaphylactic shock Nervous system disorders: cerebral hemorrhage, subdural hematoma, epidural hematoma, hemiparesis Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome DRUG INTERACTIONS Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the P-gp and ATP-binding cassette G2 (ABCG2) transporters. Inhibitors and inducers of these CYP450 enzymes or transporters (e.g., P-gp) may result in changes in rivaroxaban exposure.

Drugs that Inhibit Cytochrome P450 3A4 Enzymes and Drug Transport Systems: In drug interaction studies evaluating the concomitant use with drugs that are combined P-gp and CYP3A4 inhibitors, increases in rivaroxaban exposure and pharmacodynamic effects (i.e., factor Xa inhibition and PT prolongation) were observed.

Significant increases in rivaroxaban exposure may increase bleeding risk.

• Ketoconazole (combined P-gp and strong CYP3A4 inhibitor): Steady-state rivaroxaban AUC and Cmax increased by 160% and 70%, respectively. Similar increases in pharmacodynamic effects were also observed.

• Ritonavir (combined P-gp and strong CYP3A4 inhibitor): Single-dose rivaroxaban AUC and Cmax increased by 150% and 60%, respectively. Similar increases in pharmacodynamic effects were also observed.

• Clarithromycin (combined P-gp and strong CYP3A4 inhibitor): Single-dose rivaroxaban AUC and Cmax increased by 50% and 40%, respectively. The smaller increases in exposure observed for clarithromycin compared to ketoconazole or ritonavir may be due to the relative difference in P-gp inhibition.

• Erythromycin (combined P-gp and moderate CYP3A4 inhibitor): Both the single-dose rivaroxaban AUC and Cmax increased by 30%.

• Fluconazole (moderate CYP3A4 inhibitor): Single-dose rivaroxaban AUC and Cmax increased by 40% and 30%, respectively.

Avoid concomitant administration of XARELTO with combined P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir/ ritonavir, and conivaptan), which cause significant increases in rivaroxaban exposure that may increase bleeding risk.

IMPORTANT SAFETY INFORMATION (cont’d) NSAIDs/Aspirin: NSAIDs/aspirin are known to increase bleeding; therefore, bleeding risk may be increased when these drugs are used concomitantly with XARELTO®. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs. Clopidogrel: Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with clopidogrel.

Drug-Disease Interactions With Drugs That Inhibit CYP3A4 Enzymes and Drug Transport Systems: Use in patients with CrCl 15 mL/min to 50 mL/min who are receiving concomitant combined P-gp and weak or moderate CYP3A4 inhibitors only if the potential benefit justifies the potential risk.

USE IN SPECIFIC POPULATIONS Nursing Mothers: It is not known if rivaroxaban is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from rivaroxaban, a decision should be made whether to discontinue nursing or discontinue XARELTO®, taking into account the importance of the drug to the mother.

Geriatric Use: In clinical trials the efficacy of XARELTO® in the elderly (65 years or older) was similar to that seen in patients younger than 65 years. Both thrombotic and bleeding event rates were higher in these older patients, but the risk-benefit profile was favorable in all age groups.

Renal Impairment • Patients with renal impairment taking P-gp and weak to moderate CYP3A4 inhibitors may have significant increases in exposure, which may increase bleeding risk.

• For patients with CrCl 15 mL/min to 50 mL/min, the recommended dose of XARELTO® is 15 mg once daily with the evening meal. Avoid use in patients with CrCl <15 mL/min. Periodically assess renal function as clinically indicated (ie, more frequently in

situations in which renal function may decline) and adjust therapy accordingly. Discontinue XARELTO® in patients who develop acute renal failure while on XARELTO®.

Hepatic Impairment: No clinical data are available for patients with severe hepatic impairment. Avoid the use of XARELTO® in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy.

OVERDOSAGE Overdose of XARELTO® may lead to hemorrhage.

A specific antidote for rivaroxaban is not available.

Rivaroxaban systemic exposure is not further increased at single doses >50 mg due to limited absorption.

Discontinue XARELTO® and initiate appropriate therapy if bleeding complications associated with overdosage occur. The use of activated charcoal to reduce absorption in case of XARELTO® overdose may be considered. Due to the high plasma protein binding, rivaroxaban is not expected to be dialyzable.

ADVERSE REACTIONS IN CLINICAL STUDIES Hemorrhage: The most common adverse reactions with XARELTO® were bleeding complications.

The most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 4.3% for XARELTO® versus 3.1% for warfarin. The incidence of discontinuations for nonbleeding adverse events was similar in both treatment groups. In XARELTO®- versus warfarintreated patients, respectively, major bleeding events were 5.6% versus 5.4%.

Other Clinical Trial Experience: In an investigational study of acute medically ill patients being treated with XARELTO® 10-mg tablets, cases of pulmonary hemorrhage and pulmonary hemorrhage with bronchiectasis were observed.

Please see brief summary of Prescribing Information, including Boxed WARNINGS, on following pages.

Learn more at www.XARELTOhcp.com

Reference: 1. Patel MR, Mahaffey KW, Garg J, et al; and the ROCKET AF Steering Committee, for the ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-891.

XARELTO® is licensed from Bayer HealthCare AG, 51368 Leverkusen, Germany. © Janssen Pharmaceuticals, Inc. 2011 November 2011 02X11227

Janssen Pharmaceuticals, Inc.

Brief Summary of Prescribing Information for XARELTO® (rivaroxaban) XARELTO® (rivaroxaban) tablets, for oral use See package insert for full Prescribing Information WARNINGS: (A) DISCONTINUING XARELTO IN PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATION INCREASES RISK OF STROKE, (B) SPINAL/EPIDURAL HEMATOMA A. DISCONTINUING XARELTO IN PATIENTS WITH NONVALVULAR ATRIAL FIBRILLATION Discontinuing XARELTO places patients at an increased risk of thrombotic events. An increased rate of stroke was observed following XARELTO discontinuation in clinical trials in atrial fibrillation patients. If anticoagulation with XARELTO must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant [see Dosage and Administration (2.1) in full Prescribing Information, Warnings and Precautions, and Clinical Studies (14.1) in full Prescribing Information].

B. SPINAL/EPIDURAL HEMATOMA Epidural or spinal hematomas have occurred in patients treated with XARELTO who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: • use of indwelling epidural catheters • concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants • a history of traumatic or repeated epidural or spinal punctures • a history of spinal deformity or spinal surgery [see Warnings and Precautions and Adverse Reactions].

Monitor patients frequently for signs and symptoms of neurological impairment.

If neurological compromise is noted, urgent treatment is necessary [see Warnings and Precautions].

Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis [see Warnings and Precautions].

INDICATIONS AND USAGE Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation: XARELTO (rivaroxaban) is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

There are limited data on the relative effectiveness of XARELTO and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is wellcontrolled [see Clinical Studies (14.1) in full Prescribing Information].

CONTRAINDICATIONS XARELTO is contraindicated in patients with: • active pathological bleeding [see Warnings and Precautions] • severe hypersensitivity reaction to XARELTO [see Warnings and Precautions] WARNINGS AND PRECAUTIONS Increased Risk of Stroke after Discontinuation in Nonvalvular Atrial Fibrillation: Discontinuing XARELTO in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from XARELTO to warfarin in clinical trials in atrial fibrillation patients. If XARELTO must be discontinued for a reason other than pathological bleeding, consider administering another anticoagulant [see Dosage and Administration (2.1) and Clinical Studies (14.1) in full Prescribing Information].

Risk of Bleeding: XARELTO increases the risk of bleeding and can cause serious or fatal bleeding. In deciding whether to prescribe XARELTO to patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding.

Promptly evaluate any signs or symptoms of blood loss. Discontinue XARELTO in patients with active pathological hemorrhage.

A specific antidote for rivaroxaban is not available. Because of high plasma protein binding, rivaroxaban is not expected to be dialyzable [see Clinical Pharmacology (12.3) in full Prescribing Information]. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving rivaroxaban. There is neither scientific rationale for benefit nor experience with systemic hemostatics (desmopressin and aprotinin) in individuals receiving rivaroxaban. Use of procoagulant reversal agents such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC), or recombinant factor VIIa (rFVIIa) may be considered, but has not been evaluated in clinical trials.

Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, and non-steroidal anti-inflammatory drugs (NSAIDs) [see Drug Interactions].

Concomitant use of drugs that are combined P-gp and CYP3A4 inhibitors (e.g. ketoconazole and ritonavir) increases rivaroxaban exposure and may increase bleeding risk [see Drug Interactions].

Spinal/Epidural Anesthesia or Puncture: When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis [see Boxed Warning].

An epidural catheter should not be removed earlier than 18 hours after the last administration of XARELTO. The next XARELTO dose is not to be administered earlier than 6 hours after the removal of the catheter. If traumatic puncture occurs, the administration of XARELTO is to be delayed for 24 hours.

Risk of Pregnancy Related Hemorrhage: XARELTO should be used with caution in pregnant women and only if the potential benefit justifies the potential risk to the mother and fetus. XARELTO dosing in pregnancy has not been studied.

The anticoagulant effect of XARELTO cannot be monitored with standard laboratory testing nor readily reversed. Promptly evaluate any signs or symptoms suggesting blood loss (e.g., a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress).

XARELTO® (rivaroxaban) tablets Severe Hypersensitivity Reactions: There were postmarketing cases of anaphylaxis in patients treated with XARELTO to reduce the risk of DVT. Patients who have a history of a severe hypersensitivity reaction to XARELTO should not receive XARELTO [see Adverse Reactions].

ADVERSE REACTIONS Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

During clinical development for the approved indications, 11598 patients were exposed to XARELTO. These included 7111 patients who received XARELTO 15 mg or 20 mg orally once daily for a mean of 19 months (5558 for 12 months and 2512 for 24 months) to reduce the risk of stroke and systemic embolism in nonvalvular atrial fibrillation (ROCKET AF) and 4487 patients who received XARELTO 10 mg orally once daily for prophylaxis of DVT following hip or knee replacement surgery (RECORD 1-3).

Hemorrhage: The most common adverse reactions with XARELTO were bleeding complications [see Warnings and Precautions].

Nonvalvular Atrial Fibrillation: In the ROCKET AF trial, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 4.3% for XARELTO vs. 3.1% for warfarin. The incidence of discontinuations for non-bleeding adverse events was similar in both treatment groups.

Table 1 shows the number of patients experiencing various types of bleeding events in the ROCKET AF study.

Table 1: Bleeding Events in ROCKET AF* Parameter

XARELTO N = 7111 n (%) 395 (5.6) 91 (1.3)

Event Rate (per 100 Pt-yrs) 3.6 0.8

Warfarin N = 7125 n (%) 386 (5.4) 133 (1.9)

Event Rate (per 100 Pt-yrs) 3.5 1.2

Major bleeding† Bleeding into a critical organ‡ Fatal bleeding 27 (0.4) 0.2 55 (0.8) 0.5 Bleeding resulting in 183 (2.6) 1.7 149 (2.1) 1.3 transfusion of ≥ 2 units of whole blood or packed red blood cells Gastrointestinal bleeding 221 (3.1) 2.0 140 (2.0) 1.2 * For all sub-types of major bleeding, single events may be represented in more than one row, and individual patients may have more than one event. † Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥ 2 g/dL, transfusion of ≥ 2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. Hemorrhagic strokes are counted as both bleeding and efficacy events. Major bleeding rates excluding strokes are 3.3 per 100 Pt-yrs for XARELTO vs. 2.9 per 100 Pt-yrs for warfarin. ‡ The majority of the events were intracranial, and also included intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome, or retroperitoneal.

Postmarketing Experience: The following adverse reactions have been identified during post-approval use of rivaroxaban. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and lymphatic system disorders: agranulocytosis Gastrointestinal disorders: retroperitoneal hemorrhage Hepatobiliary disorders: jaundice, cholestasis, cytolytic hepatitis Immune system disorders: hypersensitivity, anaphylactic reaction, anaphylactic shock Nervous system disorders: cerebral hemorrhage, subdural hematoma, epidural hematoma, hemiparesis Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome DRUG INTERACTIONS Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the P-gp and ATP-binding cassette G2 (ABCG2) transporters. Inhibitors and inducers of these CYP450 enzymes or transporters (e.g., P-gp) may result in changes in rivaroxaban exposure.

Drugs that Inhibit Cytochrome P450 3A4 Enzymes and Drug Transport Systems: In drug interaction studies evaluating the concomitant use with drugs that are combined P-gp and CYP3A4 inhibitors, increases in rivaroxaban exposure and pharmacodynamic effects (i.e., factor Xa inhibition and PT prolongation) were observed.

Significant increases in rivaroxaban exposure may increase bleeding risk.

• Ketoconazole (combined P-gp and strong CYP3A4 inhibitor): Steady-state rivaroxaban AUC and Cmax increased by 160% and 70%, respectively. Similar increases in pharmacodynamic effects were also observed.

• Ritonavir (combined P-gp and strong CYP3A4 inhibitor): Single-dose rivaroxaban AUC and Cmax increased by 150% and 60%, respectively. Similar increases in pharmacodynamic effects were also observed.

• Clarithromycin (combined P-gp and strong CYP3A4 inhibitor): Single-dose rivaroxaban AUC and Cmax increased by 50% and 40%, respectively. The smaller increases in exposure observed for clarithromycin compared to ketoconazole or ritonavir may be due to the relative difference in P-gp inhibition.

• Erythromycin (combined P-gp and moderate CYP3A4 inhibitor): Both the single-dose rivaroxaban AUC and Cmax increased by 30%.

• Fluconazole (moderate CYP3A4 inhibitor): Single-dose rivaroxaban AUC and Cmax increased by 40% and 30%, respectively.

Avoid concomitant administration of XARELTO with combined P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir/ ritonavir, and conivaptan), which cause significant increases in rivaroxaban exposure that may increase bleeding risk.

XARELTO® (rivaroxaban) tablets

XARELTO® (rivaroxaban) tablets

Drugs that Induce Cytochrome P450 3A4 Enzymes and Drug Transport Systems: In a drug interaction study, co-administration of XARELTO (20 mg single dose with food) with a drug that is a combined P-gp and strong CYP3A4 inducer (rifampicin titrated up to 600 mg once daily) led to an approximate decrease of 50% and 22% in AUC and Cmax, respectively. Similar decreases in pharmacodynamic effects were also observed. These decreases in exposure to rivaroxaban may decrease efficacy.

Avoid concomitant use of XARELTO with drugs that are combined P-gp and strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St. John’s wort).

Anticoagulants: In a drug interaction study, single doses of enoxaparin (40 mg subcutaneous) and XARELTO (10 mg) given concomitantly resulted in an additive effect on anti-factor Xa activity. Enoxaparin did not affect the pharmacokinetics of rivaroxaban. In another study, single doses of warfarin (15 mg) and XARELTO (5 mg) resulted in an additive effect on factor Xa inhibition and PT. Warfarin did not affect the pharmacokinetics of rivaroxaban.

NSAIDs/Aspirin: In ROCKET AF, concomitant aspirin use (almost exclusively at a dose of 100 mg or less) during the double-blind phase was identified as an independent risk factor for major bleeding. NSAIDs are known to increase bleeding, and bleeding risk may be increased when NSAIDs are used concomitantly with XARELTO. In a singledose drug interaction study there were no pharmacokinetic or pharmacodynamic interactions observed after concomitant administration of naproxen or aspirin (acetylsalicylic acid) with XARELTO. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs [see Warnings and Precautions].

Clopidogrel: In two drug interaction studies where clopidogrel (300 mg loading dose followed by 75 mg daily maintenance dose) and XARELTO (15 mg single dose) were co-administered in healthy subjects, an increase in bleeding time to 45 minutes was observed in approximately 45% and 30% of subjects in these studies, respectively. The change in bleeding time was approximately twice the maximum increase seen with either drug alone. There was no change in the pharmacokinetics of either drug.

Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with clopidogrel [see Warnings and Precautions].

Drug-Disease Interactions with Drugs that Inhibit Cytochrome P450 3A4 Enzymes and Drug Transport Systems: Based on simulated pharmacokinetic data, patients with renal impairment receiving full dose XARELTO in combination with drugs classified as combined P-gp and weak or moderate CYP3A4 inhibitors (e.g., amiodarone, diltiazem, verapamil, quinidine, ranolazine, dronedarone, felodipine, erythromycin, and azithromycin) may have significant increases in exposure compared with patients with normal renal function and no inhibitor use, since both pathways of rivaroxaban elimination are affected.

While increases in rivaroxaban exposure can be expected under such conditions, results from an analysis in the ROCKET AF trial, which allowed concomitant use with combined P-gp and weak or moderate CYP3A4 inhibitors (e.g., amiodarone, diltiazem, verapamil, chloramphenicol, cimetidine, and erythromycin), did not show an increase in bleeding in patients with CrCl 30 to <50 mL/min [Hazard Ratio (95% CI): 1.05 (0.77, 1.42)]. XARELTO should be used in patients with CrCL 15 to 50 mL/min who are receiving concomitant combined P-gp and weak or moderate CYP3A4 inhibitors only if the potential benefit justifies the potential risk [see Use in Specific Populations].

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category C: There are no adequate or well-controlled studies of XARELTO in pregnant women, and dosing for pregnant women has not been established. Use XARELTO with caution in pregnant patients because of the potential for pregnancy related hemorrhage and/or emergent delivery with an anticoagulant that is not readily reversible. The anticoagulant effect of XARELTO cannot be reliably monitored with standard laboratory testing. Animal reproduction studies showed no increased risk of structural malformations, but increased post-implantation pregnancy loss occurred in rabbits. XARELTO should be used during pregnancy only if the potential benefit justifies the potential risk to mother and fetus [see Warnings and Precautions].

Rivaroxaban crosses the placenta in animals. Animal reproduction studies have shown pronounced maternal hemorrhagic complications in rats and an increased incidence of post-implantation pregnancy loss in rabbits. Rivaroxaban increased fetal toxicity (increased resorptions, decreased number of live fetuses, and decreased fetal body weight) when pregnant rabbits were given oral doses of ≥10 mg/kg rivaroxaban during the period of organogenesis. This dose corresponds to about 4 times the human exposure of unbound drug, based on AUC comparisons at the highest recommended human dose of 20 mg/day. Fetal body weights decreased when pregnant rats were given oral doses of 120 mg/kg. This dose corresponds to about 14 times the human exposure of unbound drug.

Labor and Delivery: Safety and effectiveness of XARELTO during labor and delivery have not been studied in clinical trials. However, in animal studies maternal bleeding and maternal and fetal death occurred at the rivaroxaban dose of 40 mg/kg (about 6 times maximum human exposure of the unbound drug at the human dose of 20 mg/day).

Nursing Mothers: It is not known if rivaroxaban is excreted in human milk.

Rivaroxaban and/or its metabolites were excreted into the milk of rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from rivaroxaban, a decision should be made whether to discontinue nursing or discontinue XARELTO, taking into account the importance of the drug to the mother.

Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

Geriatric Use: Of the total number of patients in the RECORD 1-3 clinical studies evaluating XARELTO, about 54% were 65 years and over, while about 15% were >75 years. In ROCKET AF, approximately 77% were 65 years and over and about 38% were >75 years. In clinical trials the efficacy of XARELTO in the elderly (65 years or older) was similar to that seen in patients younger than 65 years. Both thrombotic and bleeding event rates were higher in these older patients, but the risk-benefit profile was favorable in all age groups [see Clinical Pharmacology (12.3) and Clinical Studies (14) in full Prescribing Information].

Females of Reproductive Potential: Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician.

Renal Impairment: The safety and pharmacokinetics of single-dose XARELTO (10 mg) were evaluated in a study in healthy subjects [CrCl ≥80 mL/min (n=8)] and in subjects with varying degrees of renal impairment (see Table 2). Compared to healthy subjects with normal creatinine clearance, rivaroxaban exposure increased in subjects with renal impairment. Increases in pharmacodynamic effects were also observed.

Table 2: Percent Increase of Rivaroxaban PK and PD Parameters from Normal in Subjects with Renal Insufficiency from a Dedicated Renal Impairment Study Renal Impairment Class [CrCl (mL/min)] Parameter Mild Moderate Severe [50 to 79] [30 to 49] [15 to 29] N=8 N=8 N=8 Exposure AUC 44 52 64 28 12 26 (% increase relative to normal) Cmax FXa Inhibition AUC 50 86 100 9 10 12 (% increase relative to normal) Emax PT Prolongation AUC 33 116 144 4 17 20 (% increase relative to normal) Emax PT = Prothrombin time; FXa = Coagulation factor Xa; AUC = Area under the concentration or effect curve; Cmax = maximum concentration; Emax = maximum effect; and CrCl = creatinine clearance Patients with renal impairment taking P-gp and weak to moderate CYP3A4 inhibitors may have significant increases in exposure which may increase bleeding risk [see Drug Interactions].

Nonvalvular Atrial Fibrillation: In the ROCKET AF trial, patients with CrCl 30 to 50 mL/min were administered XARELTO 15 mg once daily resulting in serum concentrations of rivaroxaban and clinical outcomes similar to those in patients with better renal function administered XARELTO 20 mg once daily. Patients with CrCl 15 to 30 mL/min were not studied, but administration of XARELTO 15 mg once daily is also expected to result in serum concentrations of rivaroxaban similar to those in patients with normal renal function [see Dosage and Administration (2.1) in full Prescribing Information].

Hepatic Impairment: The safety and pharmacokinetics of single-dose XARELTO (10 mg) were evaluated in a study in healthy subjects (n=16) and subjects with varying degrees of hepatic impairment (see Table 3). No patients with severe hepatic impairment (Child-Pugh C) were studied. Compared to healthy subjects with normal liver function, significant increases in rivaroxaban exposure were observed in subjects with moderate hepatic impairment (Child-Pugh B). Increases in pharmacodynamic effects were also observed.

Table 3: Percent Increase of Rivaroxaban PK and PD Parameters from Normal in Subjects with Hepatic Insufficiency from a Dedicated Hepatic Impairment Study Hepatic Impairment Class (Child-Pugh Class) Parameter Mild Moderate (Child-Pugh A) (Child-Pugh B) N=8 N=8 Exposure AUC 15 127 0 27 (% increase relative to normal) Cmax FXa Inhibition AUC 8 159 0 24 (% increase relative to normal) Emax PT Prolongation AUC 6 114 2 41 (% increase relative to normal) Emax PT = Prothrombin time; FXa = Coagulation factor Xa; AUC = Area under the concentration or effect curve; Cmax = maximum concentration; Emax = maximum effect Avoid the use of XARELTO in patients with moderate (Child-Pugh B) and severe (ChildPugh C) hepatic impairment or with any hepatic disease associated with coagulopathy [see Dosage and Administration (2.3) in full Prescribing Information and Warnings and Precautions].

OVERDOSAGE Overdose of XARELTO may lead to hemorrhage. A specific antidote for rivaroxaban is not available. Rivaroxaban systemic exposure is not further increased at single doses >50 mg due to limited absorption. Discontinue XARELTO and initiate appropriate therapy if bleeding complications associated with overdosage occur. The use of activated charcoal to reduce absorption in case of XARELTO overdose may be considered. Due to the high plasma protein binding, rivaroxaban is not expected to be dialyzable [see Warnings and Precautions and Clinical Pharmacology (12.3) in full Prescribing Information].

Active Ingredient Made in Germany Finished Product Manufactured by: Janssen Ortho, LLC Gurabo, PR 00778

Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560

© Janssen Pharmaceuticals, Inc. 2011 10185201 02X11309BBA

Licensed from: Bayer HealthCare AG 51368 Leverkusen, Germany

DrugUpdate Complera from pg. 35

CrCl and serum phosphorus.

May prolong QTc interval with supratherapeutic doses.

History or risk of fractures or osteopenia: monitor bone mineral density; consider vitamin D and calcium supplementation. Pregnancy (Cat. B). Nursing mothers: not recommended.

Interactions: Avoid concomitant drugs that contain emtricitabine, tenofovir, rilpivirine, lamivudine,

Lazanda from pg. 35

placebo-controlled portion of the study, patients who were titrated to an adequate dose were randomized to a blinded sequence of 10 treatments, with seven being the identified dose of Lazanda and three being placebo. The mean sum of the pain-intensity difference at 30 minutes was statistically significantly higher for Lazanda than for placebo.

Adults: ≥18years: Initially one 100 µg spray in one nostril; if adequate analgesia obtained within 30 minutes, treat subsequent episodes with this dose. If adequate analgesia not achieved, dose-escalate in a stepwise manner over consecutive episodes until adequate analgesia achieved; wait at least two hours before using for the next episode. Titration

or adefovir dipivoxil.

Emtricitabine/tenofovir: Monitor drugs that reduce renal function or compete for renal tubular secretion (e.g., adefovir dipivoxil, cidofovir, acyclovir, valacyclovir, ganciclovir, valganciclovir). Avoid concomitant or recent use of nephrotoxic agents. Rilpivirine: Potentiated by CYP3A inhibitors. Antagonized

by CYP3A inducers (see Contraindications). May

antagonize azole antifungals (monitor for breakthrough infections), methadone (monitor). Separate antacids (by at least two hours before or at least four hours after) and H2-receptor antagonists (by at least 12 hours before or four hours after); drugs that increase gastric pH may result in decreased plasma concentrations. Caution with drugs with a known risk for torsades de pointes.

steps: 100 µg using 1 ⫻ 100 µg spray; 200 µg using 2 ⫻ 100 µg spray (1 in each nostril); 400 µg using 1 ⫻ 400 µg; 800 µg using 2 ⫻ 400 µg (one in each nostril); maximum 800 µg. Maintenance: once an appropriate dose has been established, use that dose for subsequent breakthrough episodes. Limit to <4 doses per day. May use rescue medication if there is inadequate pain relief after 30 minutes of Lazanda dosing or if a separate episode occurs before the next dose of Lazanda is permitted.

Contraindications: Opioid-nontolerant patients. Acute or postoperative pain (including headache/migraine, dental pain, or emergency department).

Warnings/Precautions: Do not substitute with other fentanyl products; not

equivalent to other fentanyl products on a µg-to-µg basis. Respiratory disorders or depression. Head injury.

Increased intracranial pressure. Bradyarrhythmias.

Impaired pulmonary, cardio, renal, or hepatic function. Elderly. Debilitated.

Pregnancy (Cat. C). Labor & delivery, nursing mothers: not recommended.

Interactions: Not recommended within 14 days of monoamine oxidase inhibitors. Potentiates CNS depression with alcohol, other CNS depressants (e.g., phenothiazines, skeletal muscle relaxants, antihistamines, hypnotics).

Potentiated by CYP3A4 inhibitors (e.g., macrolides, azole antifungals, aprepitant, protease inhibitors, nefazodone, verapamil, diltiazem). Antagonized

For more products, visit www.eMPR.com

36 THE CLINICAL ADVISOR • DECEMBER 2011 • www.ClinicalAdvisor.com

Adverse reactions:

Insomnia, headache, GI upset, fatigue, dizziness, depression, abnormal dreams, rash; fat redistribution, immune reconstitution syndrome, lactic acidosis, severe hepatomegaly with steatosis (may be fatal).

How supplied: Tabs—30 For more information, call 800.445.3235 or visit www.Complera.com.

by CYP3A4 inducers (e.g., barbiturates, efavirenz, modafinil, nevirapine, anticonvulsants, pioglitazone, troglitazone, rifabutin, rifampin, St John’s wort).

Efficacy may be lowered with concomitant vasoconstrictive nasal agents used to treat allergic rhinitis.

Adverse reactions: GI upset, constipation, dizziness, pyrexia.

Notes: Available by restricted distribution program. Call 855.841.4234 or visit www.LazandaREMS. com to enroll. Caution patients and caregivers in proper handling and disposal; may be fatal to children.

How supplied: Nasal spray (8 sprays/bottle)—1 For more information, call 866.435.6775 or visit www.Lazanda.com. ■

FEATURE: JOE GILBOY, PA-C

Updated information on MRSA infections The number of hospital-acquired MRSA infections is down; however, community-acquired MRSA infections continue to rise.

© JAMES CAVALLINI / PHOTO RESEARCHERS, INC.

Staphylococcus aureus (yellow) is a bacterium found in the skin and mucous membranes.

M

any people mistake the fi rst signs of methicillin-resistant Staphylococcus aureus (MRSA) infection for a spider bite. In fact, what appears as a small, red pimple could be the start of a potentially serious infection with a staphylococcus that is impervious to many antibiotics and poses an increasing threat in the community setting.

Scientists fi rst discovered S. aureus in the 1880s.1 Traditionally, the bacterium has caused skin and tissue infections, but it can also cause food poisoning and, in more serious cases, bacterial pneumonia or septicemia.

In the late 1940s, S. aureus began a dangerous evolution when it became resistant to penicillin.

With their primary weapon against the organism taken out of commission, clinicians began using methicillin, a relative of penicillin, to treat S. aureus infections. But in 1961, scientists got some bad news with the discovery of S. aureus strains that had become resistant to beta-lactams, including amoxicillin and methicillin, giving MRSA its name.1 History

The fi rst infection involving MRSA in the United States was diagnosed in 1968, and the organism has continued to evolve ever since.

Beginning in 2002, there have been a handful of cases documented in which the bacterium was also found to be resistant to one of the last available drugs being used to treat it— vancomycin (Vancocin).

Continues on page 44

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2011 43

MRSA INFECTIONS

The most common route to infection with methicillin-resistant Staphylococcus aureus remains transmission through direct skin-to-skin contact.

Despite that ominous development, there has recently been encouraging news from the CDC that hospital-acquired MRSA (HA-MRSA) infections are decreasing.2 Invasive HA-MRSA infections dropped by 28% between 2005 and 2008. Unfortunately, the same is not true of communityacquired MRSA (CA-MRSA) cases, which have risen rapidly in the past 10 years.2 Because MRSA is circulating widely in the general population, primary-care clinicians must be prepared to recognize it, treat it effectively, and take steps to reduce its transmission.

Community-acquired MRSA

Historically, most cases of MRSA infection occurred in the hospital setting, but in 1982, cases began cropping up in community settings among individuals who had not been hospitalized. The first domestic cluster involved a group of IV-drug users in Detroit. A second cluster of drug users was infected in 1992, and the prevalence of CA-MRSA began to increase in the community at large in the mid-1990s.

Most CA-MRSA cases have originated in prisons, day-care centers, and athletic or military facilities. But MRSA is not limited to those sites. It has also been found in other locations, including Washington State beaches and marine water.

CA-MRSA typically causes skin and soft-tissue infections (Figure 1), often in young and otherwise healthy patients.

These infections are typically easier to treat than HA-MRSA infections, but some patients with CA-MRSA develop such serious conditions as necrotizing pneumonia, disseminated invasive osteomyelitis, septic arthritis, or endocarditis.3 While the majority of CA-MRSA cases are more easily treated than HA-MRSA cases, the bacterium responsible for CA-MRSA is actually more virulent than its hospital counterpart. Three different S. aureus strains typically cause community infection, which often involves a variety of toxins including leukocyte toxins, exfoliative toxins, and exotoxins, making the causative organisms highly virulent pathogens.

Risk factors for CA-MRSA infections

MRSA colonization is a risk factor for infection, although the link between colonization and infection needs further investigation. The organism is sometimes found on the skin or carried inside the nose of healthy individuals. According to the CDC, an estimated 25% to 30% of people carry colonies of staphylococci in their noses, but less than 2% are colonized with MRSA.2 Most health-care professionals who

are colonized with MRSA spontaneously clear the organism from their systems without ever developing an infection.

Other risk factors for infection include • Close skin-to-skin contact with other individuals • Cuts or abrasions on the skin • Contact with contaminated items or surfaces • Living in crowded conditions • Poor hygiene.4 People who come into contact with farm animals may also be at greater risk for infection. Pigs, cattle, and poultry are increasingly being found with a new clone of MRSA, CC398. And farm animals are not the only ones becoming infected. Rates of MRSA are also up among household pets, such as dogs and cats.

While people can contract MRSA infections from many different sources, the most common route to infection remains transmission through direct skin-to-skin contact.

Clinicians should remember that when it comes to MRSA, essentially everyone is at risk.

Clinical presentation of CA-MRSA

Most patients with CA-MRSA will present with a skin or soft-tissue infection. Clinicians should assume that any spider bite, large pimple, or boil is MRSA until they have evidence to the contrary.

Treating MRSA

The first step in treating MRSA infections is to incise and drain the area. This may be sufficient to treat abscesses <5 cm in diameter. The clinician should send a sample of the material collected for culture and sensitivity. Once the incision and drainage is complete, antibiotic treatment should be considered.

IV antibiotics. A number of IV antibiotics can effectively treat MRSA infections, including the following: • First-line therapy: vancomycin. Appropriate dosage is 30 mg/kg, but the dose should not exceed 2 g in any 24-hour period. It is important to administer vancomycin

WHAT DO YOU THINK? Add your comments to this article —or any article — by going to www.ClinicalAdvisor.com.You will also see what your colleagues are saying.

44 THE CLINICAL ADVISOR • DECEMBER 2011 • www.ClinicalAdvisor.com

© SCOTT CAMAZINE / PHOTO RESEARCHERS, INC.

slowly over 90 minutes to prevent “red man syndrome,” a hypersensitivity reaction linked to rapid administration of the antibiotic.5 • Second-line therapy: daptomycin (Cubicin). Proper dosage is 4 to 6 mg/kg administered via IV piggyback every 24 hours. This drug has been shown to be safe, although it can occasionally cause elevations in creatine kinase levels.

• Third-line therapy: linezolid (Zyvoz). Dosage is 600 mg every 12 hours. Linezolid is a monoamine oxidase inhibitor that offers 100% bioavailability. Zyvox is very expensive, although the oral formulation has shown a cost savings for outpatient treatment.6 The usefulness of linezolid is limited by its cost and toxicity as well as the potential for the organism to develop resistance to the drug. Possible side effects related to treatment include thrombocytopenia, peripheral and optic neuropathy, and lactic acidosis in patients receiving prolonged therapy.

• Fourth-line therapy: tigecycline (Tygacil). Dosage is 100 mg IV once, then 50 mg IV every 12 hours. This drug has a broader spectrum of antimicrobial activity.

• Fifth-line therapy: quinupristin/dalfopristin (Synercid).

In addition to the antibiotics listed above, a number of emerging therapies may be useful for the treatment of MRSA, including dalbavancin, telavancin (Vibativ, Theravance), and ceftobiprole.

Oral antibiotics. Some antibiotics available in oral formulations are treatment options for MRSA: • First-line therapy: trimethoprim-sulfamethoxazole (TMPSMX; Bactrim DS, Septra DS. Sulfamethoprim-DS). This agent has been shown to be 95% effective.

• Second-line therapy: clindamycin (Cleocin). Keep in mind that the organism may develop resistance to this drug, particularly if it is resistant to erythromycin. Also remember that patients exposed to clindamycin are at risk for infection with Clostridium difficile.

• Third-line therapy: tetracycline or doxycycline/minocycline (Dynacin, Minocin). This agent is administered for 21 days.

• Fourth-line therapy: linezolid.

Rifampin (Rifadin) may also be used. It is typically effective in combination with other drugs. Because rifampin achieves high concentrations in mucosal surfaces, its inclusion in a regimen to treat MRSA is theoretically beneficial.

Drugs to be avoided. Erythromycin (Ery-tab, PCE) and cephalexin (Keflex) are ineffective against MRSA, and ciprofloxacin (Cipro) and levofloxacin (Levaquin) are to be avoided because rates of MRSA infection are increased in hospitalized patients treated with quinolones. Bacitracin

FIGURE 1. MRSA skin infections (shown here) typically start as small red bumps but can quickly turn into painful abscesses.

and neomycin, two common ingredients in OTC antibacterial ointments, are not recommended for the treatment of MRSA, although a recent study indicates that they may be effective against a specific clone of MRSA.7 Empiric MRSA coverage is not necessary for children who have uncomplicated skin infections. Researchers found no difference in outcome between children randomly assigned to receive cephalexin, an antibiotic without MRSA activity, or clindamycin. The children received cephalexin 40 mg/ kg/day in three divided doses or clindamycin 20 mg/kg/ day also in three divided doses for seven days.8 Decolonization

While the CDC does not routinely recommend decolonization,9 this treatment may be advisable in certain circumstances. For example: (1) patients who are immunocompromised (e.g., those with leukemia, another cancer, or HIV) and might develop particularly life-threatening infections; and (2) patients who live in close quarters with others, such as in mental institutions, prisons, or military barracks.

Decolonization can be accomplished by washing with chlorhexidine (Hibiclens, Exidine, CIDA-STAT).

Hexachlorophene (Phisohex) can also be used, but only in combination with mupirocin (Bactroban), not by itself.

Mupirocin ointment placed in the nostrils twice daily for seven days will also result in decolonization.

Mupirocin nasal ointment plus bleach baths (one tablespoon of bleach in one quart of water) will achieve long-term S. aureus decolonization of the skin. Some strains of MRSA

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2011 45

MRSA INFECTIONS

Masks and eye protection prevent body fluids or blood from spraying into mucous membranes of the eyes, nose, and mouth during procedures. are resistant to mupirocin (mupA gene found on USA300 MRSA clones).

New nondrug therapies are also being considered for their potential to combat MRSA. These include lemongrass essential oil, which research has shown to be effective in completely inhibiting all MRSA colony growth.10 Tea tree oil also has been shown to be effective. There is clinical evidence that topical preparations may be more effective than conventional antibiotics in preventing transmission of CA-MRSA.11 Another substance being considered to combat MRSA is French clay. The clay has been found to kill several types of bacteria, and researchers recently discovered that specific minerals in the clay are toxic to MRSA.12 Treating complications

Not all patients with MRSA cellulitis will respond to initial treatment, and clinicians must recognize when patients need more aggressive treatment or hospitalization. Patients who meet at least two of the following criteria may need hospital treatment: • Fever >100.4°F • WBC count >13,000/µL • Bands >10% • Hand cellulitis • Facial cellulitis • Immunocompromise • Older than age 70 years • Failing outpatient treatment Another warning sign is the presence of cellulitis with no drainable pus. This raises concern of group A streptococcal infection. In this instance, clinicians should keep in mind that TMP-SMX and doxycycline, both of which are effective against MRSA, are less effective against group A AT A GLANCE ●

Methicillin-resistant Staphylococcus aureus (MRSA) colonization is a risk factor for infection.

●

Clinicians should assume that any spider bite, large pimple, or boil is MRSA until they have evidence to the contrary.

●

The first step in treating MRSA infections is to incise and drain the area.

●

Standard precautions taken by the clinician will help reduce the risk of spreading MRSA to others.

streptococcus. Therefore, treatment should also include amoxicillin, ampicillin, or penicillin. Use of clindamycin should also be considered in these cases because it may be effective against both MRSA and group A streptococcus.

The typical regimen for treating a co-infection should include vancomycin and clindamycin.

Preventing transmission

When treating patients with MRSA infections, health-care workers should take care to reduce the risk of spreading the organism to others. Standard precautions will help accomplish this goal.

Clinicians must be certain to wash their hands before and after examining patients, and they should wear gloves anytime they might come into contact with blood, body fluids, secretions, or contaminated items. The gloves should be removed immediately after use to prevent transfer of microorganisms. Health-care workers who do not remove gloves quickly could contaminate environmental surfaces or spread the organism to other patients. For example, if a clinician examines a patient and then touches a drawer, chart, or doorknob without removing his or her gloves, those surfaces may become contaminated, and the organism may be spread. MRSA can live on some surfaces for hours or even days.

Clinicians should wash their hands after each examination whether they wore gloves or not.

In addition to gloves, other personal protective equipment should be used to prevent the spread of MRSA. Practitioners should wear masks and eye protection to prevent body fluids and blood from spraying into mucous membranes of the provider’s eyes, nose, and mouth during procedures or patient-care activities. Clinicians should also wear a disposable gown, both to protect their skin and to prevent their clothing from becoming contaminated during patient care.

Any patient-care equipment that has been soiled with blood, body fluids, secretions, or excretions must be handled properly to avoid transferring microorganisms to other patients and environments. The same is true for linens.

Additionally, rooms used by patients with MRSA must undergo terminal cleaning.

A new disinfecting tool may be on the horizon, however.

Aerosolized hydrogen peroxide has been shown to neutralize MRSA on environmental surfaces.13 Studies have demonstrated that the hydrogen peroxide is nearly 100% effective

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2011 51

MRSA INFECTIONS

Managing MRSA requires a comprehensive approach that includes prevention, timely treatment, and efforts to reduce transmission. and that its disinfecting effect lasts for weeks. Aerosolized hydrogen peroxide is also cost-effective, making it a promising new infection-control measure.

8. Chen AE, Carroll KC, Diener-West M, et al. Randomized controlled trial of cephalexin versus clindamycin for uncomplicated pediatric skin infections. Pediatrics. 2011;127:e573-e580.

9. Centers for Disease Control and Prevention. Management of Multidrug

Alternate strategies

Resistant Organisms in Healthcare Settings, 2006. Available at: www.cdc.

In addition to environmental cleaning, clinicians may want to explore other methods for reducing MRSA transmission, including: • Aggressively screening health-care workers for MRSA colonization • Performing active-surveillance cultures for MRSA in at-risk patients and putting those who test positive on contact precautions.

Ultimately, managing MRSA requires a comprehensive approach that includes prevention, timely treatment, and efforts to reduce transmission. The more informed clinicians are about how to undertake each of these steps, the more likely that the number of CA-MRSA cases will decline in the future. ■

gov/hicpac/mdro/mdro_4.html.

Mr. Gilboy is a staff member in the emergency department at Hoag Hospital, Newport Beach, Calif., and an educational consultant to the physician assistant programs at Stanford University, Palo Alto, Calif.; San Joaquin Valley College, Visalia, Calif.; Loma Linda University, Loma Linda, Calif.; and Touro University, Henderson, Nev.

All electronic documents accessed November 15, 2011.

10. Chao S, Young G, Oberg C, Nakaoka K. Inhibition of methicillinresistant Staphylococcus aureus (MRSA) by essential oils. Flav Frag J. 2008;23:444-449.

11. Dryden MS, Dailly S, Crouch M. A randomized, controlled trial of tea tree topical preparations versus a standard topical regimen for the clearance of MRSA colonization. J Hosp Infect. 2004;56:283-286.

12. French clay can kill MRSA and “flesh-eating” bacteria. ScienceDaily.

Science News. October 25, 2007. Available at www.sciencedaily.com/ releases/2007/10/071025120514.htm.

13. Dryden M, Parnaby R, Dailly S, et al. Hydrogen peroxide vapour decontamination in the control of a polyclonal meticillin-resistant Staphylococcus aureus outbreak on a surgical ward. J Hosp Infect.

2008;68:190-192.

References © The New Yorker Collection 2011 from cartoonbank.com. All Rights Reserved.

1. National Institute of Allergy and Infectious Diseases. Methicillin-resistant Staphylococcus aureus. Available at www.niaid.nih.gov/topics /antimicrobialResistance/Examples/mrsa/Pages/history.aspx.

2. Centers for Disease Control and Prevention. MRSA statistics. Available at www.cdc.gov/mrsa/statistics/index.html.

3. State of Rhode Island Department of Health. CA-MRSA. Available at www.health.ri.gov/disease/communicable/providers_mrsa060705.php.

4. Centers for Disease Control and Prevention. People at Risk of Acquiring MRSA Infections. Available at www.cdc.gov/mrsa/riskfactors/index.html.

5. Sivagnanam S, Deleu D. Red man syndrome. Crit Care. 2003;7:119-120.

Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC270616/.

6. Oral Zyvox shows cost savings for outpatient treatment of skin, other infections vs. vancomycin. Medical News Today. October 8, 2005. Available at www.medicalnewstoday.com/releases/31736.php.

7. Suzuki M, Kazuhiro Y, Nagao MI, et al. Antimicrobial ointments and methicillin-resistant Staphylococcus aureus USA300. Emerg Infect Dis. 2011;17:1917-1920. Available at wwwnc.cdc.gov/eid/article/17/10/pdfs /10-1365.pdf.

“You knew I was a columnist when you married me.”

52 THE CLINICAL ADVISOR • DECEMBER 2011 • www.ClinicalAdvisor.com

FEATURE: MARY PITTMAN, PA-C, AND JUDITH STALLINGS, MHE, PA-C

Alternative therapy for gestational diabetes Insulin is the only agent recommended to lower glucose levels in pregnant women, but a second-generation sulfonylurea may provide another option.

© VISUALS UNLIMITED, INC.

G

estational diabetes mellitus (GDM) is a common medical complication of pregnancy and a growing problem worldwide. The condition is defined as glucose intolerance (of variable degree) with onset or first recognition in pregnancy.1 It is estimated that GDM affects about 200,000 (5%) of the more than 4 million births annually1 and is associated with higher rates of such adverse neonatal outcomes as macrosomia, neonatal hypoglycemia, shoulder dystocia, and brachial plexus injuries.2 In addition, infants who are born with extreme macrosomia may be predisposed to developing glucose intolerance or GDM as adults.2 Glyburide (Diabeta, Glycron, Glynase, Micronase) is a second-generation sulfonylurea used in the treatment of diabetes mellitus. It lowers blood glucose levels by stimulating the excretion of endogenous insulin from beta cells in the pancreas.3 At this time, oral hypoglycemic agents have not been approved for the treatment of GDM, and insulin continues to be the only recommended agent to lower glucose levels in pregnant women.4 However, acceptance of the use of glyburide in management of GDM has been growing. The question that must be answered is, is glyburide a clinically effective alternative to insulin therapy in GDM?

Tight glycemic control is essential for the well-being of the mother and neonate.

Etiology

GDM most commonly occurs early in the third trimester of pregnancy as a result of metabolic changes.5 Critical anabolic hormones responsible

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2011 53

GESTATIONAL DIABETES

for fetal growth and development increase dramatically in the final 20 weeks of gestation. These hormones mobilize the woman’s nutritional resources—primarily glucose—making them available to the fetus. This increase in glucose mobilization occurs along with a decrease in insulin sensitivity from human placental lactogen, a placental hormone with strong anti-insulin and lipolytic effects.6 Peripheral insulin sensitivity during the third trimester decreases to 50% of that seen in the first trimester, and despite higher insulin levels, basal hepatic glucose output is 30% higher.6 Glucose intolerance is the result of the combination of late-pregnancy hormones and a chronic form of insulin resistance that was present before but exacerbated by pregnancy. It is thought that pregnancy unmasks the onset of beta-cell dysfunction that was present before conception.7 Screening

Fasting and preprandial glucose values are lower during pregnancy in both diabetic and nondiabetic women. Euglycemia is considered to be 60-70 mg/dL while fasting and <120 mg/ dL two hours after meals.5 Keep in mind that 50% of women present with glucosuria at some point during pregnancy as a result of increased glomerular filtration rate and glucose load presented to the kidneys.8 Because such other symptoms as increased urination and thirst may also be normal findings in pregnancy, the diagnosis of GDM may be overlooked without careful screening.4 The diabetes risk assessment should be performed at the first prenatal visit. Women who are considered at high risk have one or more of the following: severe obesity, a strong family history of type 2 diabetes, impaired glucose metabolism, polycystic ovary syndrome, or a history of GDM or delivery of large-for-gestational-age (LGA) infant.7 Diagnosis

Patients are diagnosed by means of the glucose challenge test, a two-step approach using an initial screening measuring plasma or serum glucose one hour after a 50-g oral glucose load. If the plasma glucose is >140 mg/dL (7.8 mmol/L), an oral glucose tolerance test (OGTT) should be performed. The OGTT is administered over the course of three hours with

PEER PERSPECTIVES

TABLE 1. Diagnosis of gestational diabetes with a 100-g or 75-g glucose load 100-g glucose load Fasting

95 mg/dL

5.3 mmol/L

One-hour

180 mg/dL

10.0 mmol/L

Two-hour

155 mg/dL

8.6 mmol/L

Three-hour

140 mg/dL

7.8 mmol/L

Fasting

95 mg/dL

5.3 mmol/L

One-hour

180 mg/dL

10.0 mmol/L

Two-hour

155 mg/dL

8.6 mmol/L

75-g glucose load

either a 100- or 75-g load of glucose.5 GDM is confirmed if two or more of the findings listed in Table 1 are present in venous plasma after an overnight fast (8-14 hours).5 Management

The American College of Obstetricians and Gynecologists and the American Diabetes Association (ADA) have each developed guidelines for the management of GDM that emphasize the importance of glucose control to minimize the risk of complications. Individualized nutrition therapy along with daily self-monitoring of glucose is the cornerstone of treatment. When dietary management fails to achieve glycemic control, both guidelines recommend that maternal hyperglycemia be managed medically. The ADA currently advocates the use of insulin in this circumstance.1 After the diagnosis of GDM has been made, the American Diabetes Association recommends the following glucose goals:5 • ≤95 mg/dL (5.3 mmol/L) and either: • One-hour postprandial ≤140mg/dL (7.8 mmol/L) or • Two-hour postprandial ≤120mg/dL (6.7 mmol/L) Glyburide in pregnancy

Previous experience with first-generation sulfonylurea drugs in pregnancy, such as tolbutamide (Orinase, Tol-Tab) and chlorpropamide (Diabinese, Insulase), was not encouraging.

These drugs readily crossed the placenta, resulting in the

“With regard to cutaneous manifestations of diabetes (see ClinicalAdvisor.com/DiabetesSlideshow), some diabetic patients also report transient pruritus with postprandial blood glucose elevation that occurs mostly on the anterior lower legs and dorsal forearms.”

Nadia Dobraya, FNP, Portland, Ore. (via ClinicalAdvisor.com)

54 THE CLINICAL ADVISOR • DECEMBER 2011 • www.ClinicalAdvisor.com

GESTATIONAL DIABETES

potential to cause neonatal hypoglycemia and fetal abnormalities. Hypoglycemia in the neonate leads to fetal hyperinsulinemia, which is associated with many of the complications that occur in GDM (e.g., macrosomia, hypoxia, and death).9 For this reason, several authoritative bodies advise against giving sulfonylurea drugs in pregnancy.

One study measured the transport of the second-generation sulfonylurea, glyburide, across the human placenta in vitro.

The results showed that glyburide did not cross the placenta in significant amounts.10 This information sparked new interest in the use of glyburide in pregnancy.

In 2000, the first randomized controlled trial was performed to test the hypothesis that glyburide might be an alternative to insulin therapy in women with GDM. Of the 404 women in the study, 201 were assigned to receive glyburide, and 203 were assigned to receive insulin. The degree of glycemic control and the perinatal outcomes were essentially the same for both groups.11 There were no significant differences in mean maternal glucose concentrations, percentage of LGA infants, macrosomia, neonatal intensive care unit (NICU) admission, or fetal anomalies. More important, glyburide was not detected in the cord serum of any infant.11 The results of this study suggest that glyburide may be considered as a clinical equivalent to insulin therapy.

There have been few to no new randomized controlled trials conducted since this initial discovery, but a number of retrospective studies have been performed. No consistent evidence of an increase in adverse maternal or neonatal outcomes when compared with insulin therapy has been shown.12 In addition, there was no significant difference in birth weights, percentage of LGA infants, neonatal hypoglycemia, NICU admissions, or pre-eclampsia.12 However, the failure to achieve glycemic goals with glyburide was approximately 20% higher in most clinical populations. Women who did not achieve target glycemic goals with the maximum dose of 20 mg/day were switched to insulin therapy. There were no significant differences in maternal or neonatal outcomes in women who were switched to insulin therapy. The most common predictor of treatment failure was pretreatment fasting glucose value >115mg/dL.12 Although this data may demonstrate glyburide’s clinical equivocacy with insulin in the treatment of GDM, there

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were notable limitations in the previous studies, including small sample sizes, differences in study design, a lack of power analysis or effect size estimations for outcome measures, and varying definitions of hypoglycemia and other measures.1 These factors may have accounted for the lack of detectable differences in treatment outcomes.

Conclusion

Proper treatment of GDM with tight glycemic control is essential for maternal and neonatal well-being. Current evidence does not exclude the use of glyburide as an alternative to insulin therapy, and because of the limited data, there is room for speculation. However, larger randomized controlled trials need to be performed before the use of glyburide in the treatment of GDM can be justified. If providers choose to implement this type of therapy, patients need to be informed of the current research and clearly understand the potential risks and benefits. ■ Ms. Pittman is a physician assistant at Carl R. Darnall Army Medical Center in Fort Hood, Tex. Ms. Stallings is an assistant professor and clinical medicine coordinator of the obstetrics and gynecology section in the physician assistant program at Georgia Health Sciences University in Augusta.

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GESTATIONAL DIABETES

CLINICAL SLIDESHOW For more information on the cutaneous manifestations of diabetes, view the clinical slideshow at ClinicalAdvisor.com/DiabetesSlideshow.

References 1. Nicholson W, Bolen S, Witkop CT, et al. Benefi ts and risks of oral diabetes agents compared with insulin in women with gestational diabetes: a systematic review. Obstet Gynecol. 2009;113:193-205.

2. American Diabetes Association. Standards of medical care in diabe-

“Anyone following me on Twitter already knows what I did this past summer.”

tes—2010. Diabetes Care. 2010;33 Suppl 1:S11-S61. Available at care.diabetesjournals.org/content/33/Supplement_1/S11.full.

3. PubMed Health. Glyburide. AHFS consumer medication information.

Available at www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000833/.

4. American Diabetes Association. Gestational diabetes mellitus. Diabetes Care. 2004;27 Suppl 1:S88-S90. Available at care.diabetesjournals.org/ content/27/suppl_1/s88.long.

5. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2010;33 Suppl 1:S62-S69. Available at care.diabetesjournals.org/content/33/Supplement_1/S62.long.

6. Hicks P. Gestational diabetes in primary care. Medscape Womens Health.

2000;5:2.

7. Metzger BE, Gabbe SG, Persson B, et al. International association of diaclassification of hyperglycemia in pregnancy. Diabetes Care. 2010;33:676682. Available at care.diabetesjournals.org/content/33/3/676.long.

8. Alto WA. No need for glycosuria/proteinuria screen in pregnant

“Enough medical mumbo jumbo, just give it to me straight, Doc—will I ever be able to play piano again?”

women. J Fam Pract. 2005;54:978-983. Available at www.jfponline.com/ Pages.asp?AID=2812.

9. Greene MF. Oral hypoglycemic drugs for gestational diabetes. N Engl J Med. 2000;343:1178-1179.

10. Elliott BD, Langer O, Schenker S, Johnson RF. Insignificant transfer of glyburide occurs across the human placenta. Am J Obstet Gynecol.

1991;165(4 Pt 1):807-812.

11. Langer O, Conway DL, Berkus MD, et al. A comparison of glyburide and insulin in women with gestational diabetes mellitus. N Engl J Med. 2000;343:1134-1138.

12. Moore TR. Glyburide for the treatment of gestational diabetes.

A critical appraisal. Diabetes Care. 2007;30 Suppl 2:S209-S213.

Available at care.diabetesjournals.org/content/30/Supplement_2 /S209.long.

All electronic documents accessed November 15, 2011.

58 THE CLINICAL ADVISOR • DECEMBER 2011 • www.ClinicalAdvisor.com

“Momma? Is Rick Perry real?”

© The New Yorker Collection 2011 from cartoonbank.com. All Rights Reserved.

betes and pregnancy study groups recommendations on the diagnosis and

Writers’ Guidelines The Clinical Advisor welcomes submissions from its readers. Writing for us is an opportunity to share your knowledge and experience with your colleagues — and to collect a fee in the bargain! We pay an honorarium for every submission we accept.

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66 THE CLINICAL ADVISOR • DECEMBER 2011 • www.ClinicalAdvisor.com

CME CE GERIATRICS

■ LEARNING OBJECTIVES : • Name the type of urinary incontinence (UI) associated with detrusor overactivity.

• Know which drug may cause chronic cough, making its use a risk factor associated with UI. • Describe the preferred method for determining postvoid residual urine volume.

• Identify the lifestyle intervention used in the treatment of overflow incontinence.

■ COMPLETE THE POSTTEST: Page 137 ■ ADDITIONAL CME/CE: Pages 107, 131

LINDA J. KEILMAN, DNP, GNP-BC

Urinary incontinence in the older female population Despite what clinicians and patients think, accurate evaluation and targeted interventions can relieve symptoms and improve quality of life.

© STEVE OH, M.S. / PHOTOTAKE

Urine leakage can be caused by weakened pelvic-floor muscles.

U

rinary incontinence (UI), the involuntary loss of urine in any amount, is very common in older adults. Unfortunately, some believe UI is a normal part of the aging process. While the prevalence of UI does increase with age, the condition is neither normal nor inevitable.1 With accurate evaluation and targeted interventions, UI and its associated symptoms can be relieved.

Many older adults do not mention urine leakage at health-care appointments, and most clinicians do not ask about unintentional leakage or offer assessment and intervention. With the number of older adults increasing, clinicians can expect to see more people with UI in their practice settings.

This article presents an overview of UI in the older woman and offers ways to assess and implement conservative management interventions.

Scope of the problem

UI is very common among older women. 2,3 Prevalence increases with age, with one-third of women older than age 65 years experiencing some www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2011 67

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TABLE 1. Overview of female age-related changes and their potential impact Changes

Potential impact

Decrease in bladder elasticity and capacity

Increased frequency in voiding

Decrease in strength of detrusor muscle

Incomplete emptying of the bladder; straining to void

Loss of muscle tone

Impaired voluntary control of the external sphincter muscle; reduced urinary stream; incomplete emptying; continuous dribbling; urinary retention; overflow voiding; pooling of urine leading to increased risk for UTI

Decrease in size of the urinary bladder (capacity)

Increased frequency of voiding urge

Spontaneous contractions of detrusor muscle or increase in muscle hyperactivity

Urge symptoms; contraction of the bladder before it is full

Laxity of detrusor muscle

Large, atonic bladder leading to insufficient intravesicular pressure to initiate urination

Urethral shortening and thinning of the lining

Sphincter tightness diminishes, resulting in leakage

Decrease in kidney mass and weight

Decreased surface area available for filtration; dose adjustment required for medications excreted through the kidneys

Decrease in number of functional nephrons

Less sensitive to effects of antidiuretic hormones, resulting in less sodium and water reabsorption and greater potassium loss, leading to production of less concentrated urine

Decrease in renal blood flow

Drugs excreted through the kidney require dose adjustment; altered glomerular filtration rate (GFR); creatinine clearance formula requires adjustment

Kidneys less efficient at concentrating urine

Increase in urine volume

Decrease in estrogen production

Decline of the supportive tissues around the bladder and urethra; weakened pelvic floor muscles

Atrophy of the external urinary sphincter

Relaxation of the pelvic floor

Reduction in hormonal response (vasopressin) with an impaired ability to conserve sodium

Increased risk for dehydration

Alterations in diurnal and nocturnal production of urine related to circadian sleep-awake pattern

Nocturia episodes increase; greater risk of falls

Changes in antidiuretic, atrial natriuretic, and renin-aldosterone hormones

Nocturia

Atrophic vaginitis and urethritis

Reduced urethral mucosal seal; irritation; more prone to UTIs

Decrease in overall bone mass; curving and compression of the spinal column; degenerative changes in joints

Decreased hand dexterity leading to inability to manipulate belts, suspenders, zippers, and buttons on clothing; increased pain on ambulation; slower movement

Decrease in muscle mass and strength

Falls or fear of falling; slowed or unsteady gait

Decrease in pupil size, visual acuity, ability to accommodate

Decreased ability to adjust to changes in lighting; poor eyesight

Adapted from Keilman LJ. Urinary incontinence: basic evaluation and management in the primary care office. Prim Care. 2005;32:699-722.23

degree of UI and 12% reporting daily urine leakage.4 UI is less prevalent in men until they reach the ninth decade of life.5 Among women older than age 80 years living in the community, 57% have some form of UI.6 UI in women is a costly health concern in the United States.

In 2004, estimated expenses were already in the billions of dollars, and they are continually rising, causing decreased quality of life (QOL) and excessive burden on older adults and the health-care system.7,8

UI can lead to loss of independence, depression, falls, dermatologic conditions (including rash and breakdown), urinary tract infections (UTIs), and placement in a care facility.9 In some studies, UI has been reported as a leading cause of institutionalization, possibly as a result of the stress experienced by caregivers of individuals who develop UI.5,10 The most profound effect of UI, however, may be on QOL. While clinicians working with older adults may recognize that maintaining function and independence is important,

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the connection between UI and QOL is not always obvious.

Active older adults who develop UI or experience worsening UI symptoms often give up some aspect of their lives, including community involvement, hobbies, lifelong interests, and travel. Older women with UI also report a decreased desire for sexual intimacy because of concerns about urine leakage. Withdrawal from these important life events and experiences may eventually lead to social isolation, low selfesteem, spiritual distress, hopelessness, depression, functional decline, falls, fractures, and loss of independence.

Etiology

UI in older adults can be caused by a number of factors, not all of which are related to the genitourinary (GU) system.

Problems associated with urine leakage manifest differently in older women than in younger women. These differences are related to physiologic changes in the aging GU tract, an accumulation of lifestyle choices or habits, the presence of comorbid conditions, functional impairments, and the use of multiple medications.5,11 More studies are emerging that report race and ethnic differences in female GU anatomy and function, leading to potential increases in the incidence of UI and differences in treatment outcomes.12 Stated simply, UI occurs when there is dysfunction in the storage capability and/or the emptying mechanism of the lower urinary tract (LUT). Age-related changes may also predispose the older woman to UI. These changes are gradual, progressive, and unique for each individual, and they occur in the GU tract as well as other body systems Clinicians must be knowledgeable about these changes and able to recognize them during assessment and evaluation.

A summary of some of the female age-related changes and their potential impact are presented in Table 1.

Clinicians also need to consider the risk factors for development of UI. The more risk factors an older woman has, the more likely she is to develop UI. But the more risk factors that can be successfully identified and addressed, the greater the potential for alleviating the urine leakage. Some of the most common risk factors are listed in Table 2. The clinician and the older woman need to work together to identify and address as many risk factors as possible and increase the likelihood of arriving at an accurate diagnosis and developing an effective treatment plan with measurable outcomes.

Classification of urinary incontinence

The types of UI are identified primarily by the symptoms associated with the leakage. The main priority is to recognize that the patient has urine leakage, regardless of whether

a definitive diagnosis of UI is initially established. Following recognition that a problem exists, a more complete evaluation should be carried out to determine the underlying cause and an appropriate management plan. An accurate diagnosis and quickly implemented management plan can help to eliminate potentially harmful physical, emotional, and negative spiritual effects and the impact of UI on the older woman. A thorough evaluation also allows the clinician to classify the UI according to one of the standard categories: stress, urge, mixed, overflow, or functional.

A history of urine leakage (generally small amounts) during periods of increased abdominal pressure (laughing, sneezing, coughing, lifting, high-impact physical activity) suggests a diagnosis of stress UI (SUI). SUI is related to urethralsphincter changes that result in impaired support and/or closure, as well as pelvic-floor weakness. SUI is generally more common in younger women than in older women.

Sudden overwhelming feelings of urgency or the inability to prevent urine leakage before arriving at the bathroom is generally considered urge UI (UUI). UUI occurs most commonly in women over the age 65 years and is associated with detrusor overactivity (DO) or uninhibited bladder contractions. With aging, there is thought to be some impairment in central nervous system activity along with DO. The neuronal control of the LUT is complex, and disruption of the pathways can lead to UI.13 Mixed UI (MUI) is a combination of symptoms related to both urge and stress UI. In most cases, MUI can be identified while gathering the patient history. Generally, a cluster of symptoms will occur more frequently with each individual patient. MUI is the second most common type of UI in older women.

Although less common in older adults, a history of continual dampness or frequent dribbling, with or without a sensation of fullness, may indicate a diagnosis of overflow UI. The loss of urine in this manner is associated with bladder distension related to inefficient bladder emptying or outflow obstruction.13,14 Functional UI (FUI) has more to do with issues outside the GU tract, as many individuals presenting with this type of leakage have intact voiding systems. No clear-cut symptoms identify UI as functional, other than the older womanâ&#x20AC;&#x2122;s selfreport of specific difficulties, which may include inability to reach the bathroom independently, limited access, or lack of caregiver assistance. After other types of incontinence are ruled out, FUI becomes a diagnosis of exclusion given cognitive and functional status. Individuals presenting with these symptoms generally have positive outcomes if the cause

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TABLE 2. Common risk factors associated with UI in older females Risk factor

Specifics

Age

•Age-related changes in anatomy and physiology •Number of comorbid conditions •Multiple medications •Possibility of functional and cognitive decline

Gender

•Twice as many women affected as men (until the ninth decade of life) •Pregnancy-related factors •Childbirth •Menopause •Normal female anatomy

Smoking (current or history of)

•Nicotine is a bladder irritant •Chronic cough places stress on urinary sphincter

Increased BMI and waist circumference

•Being overweight or obese increases pressure on bladder and GU muscles and ligaments

Presence of specific chronic conditions

•Diabetes •Hypertension •Kidney disease •Arthritis •Chronic obstructive pulmonary disease

•Heart failure •Neurologic disorders •Depression •Sleep disorders

Medication

•Alpha-adrenergic blockers and agonists •Diuretics •Anticholinergic agents •Opiate-based narcotics •Antihistamines

•Calcium channel blockers •Sedatives/hypnotics •ACE inhibitors (causing chronic cough) •OTC preparations containing caffeine or alcohol

Surgical history

•Abdominal •Gynecologic •Urinary •Rectal

Ingestion of bladder irritants

•Alcohol •Caffeine (coffee, tea, cola, dark chocolate) •Carbonated beverages •Acidic foods and juices

Amount of daily fluid intake

•Too much can lead to bladder overfill and nocturia •Too little can lead to bladder irritation and pooling of concentrated urine, resulting in UTIs

Impaired functional status and mobility

•Requires some assistance or total assistance in activities of daily living and/or instrumental activities of daily living •History of falls, with or without injury •Arthritis •Gait (speed), balance, leg strength •Lack of caregiver assistance

Decreased cognition or delirium

•Unable to express need to toilet •Unable to remember where toilet facilities are even if able to recognize need to urinate

Alteration in bowel habits

•Chronic constipation •Fecal impaction •Fecal incontinence

Pain

•Chronic, acute, undertreated •Too severe for the patient to move or walk

Environmental barriers

•Proximity of bed to bathroom facilities •Pathway obstruction •Low lighting

High-impact physical activity

•Sudden pressure on the abdomen can lead to opening of the sphincter and release of urine (exercise-induced stress urinary incontinence)

70 THE CLINICAL ADVISOR • DECEMBER 2011 • www.ClinicalAdvisor.com

•Dairy products (yogurt, cheese, sour cream) •Tomato-based products •Artificial sweeteners, sugar, corn syrup •Spicy foods

is identified and altered. FUI can be associated with transient or potentially reversible causes of UI. Potential barriers to diagnosis

The literature is filled with explanations of why UI continues to be underdiagnosed and undertreated. Older women have attributes or issues that contribute to the problem, such as considering the topic to be taboo, being powerless over the condition, or believing that UI is inevitable with aging or not a serious medical condition requiring treatment.15,16 Lack of knowledge, inaccurate information, and misperceptions on the part of the patient can delay appropriate diagnosis and treatment of UI. Individuals who are actively engaged in the control of their health experience have been found to have a better QOL.17,18 An improved QOL leads to a happier and healthier woman. Clinicians can empower women to gain control over their UI. Clinicians have been generally reluctant to incorporate evidence-based UI guidelines into their practice.19 The literature indicates that older women are not asked about urine leakage, and fewer than 50% of women experiencing leakage report the problem to their provider.20 The current education of health-care providers is insufficient to improve detection and treatment of UI.20,21 UI is a complicated disorder, and many clinicians feel they do not have the time to acquire the subjective and objective data needed to make a diagnosis or develop a treatment plan.

Evaluation

The most important aspect of evaluating and managing UI is to initiate a dialogue by asking, “Do you ever leak urine or have difficulty getting to the toilet in time?” Every older woman should be asked this question routinely. If the answer is yes, an evaluation should follow. A thorough and age-appropriate history is the single best tool for gathering accurate information about urine leakage. The amount and frequency of the incontinence should not be the determining factor in proceeding with a thorough assessment. If urine leakage is discovered—in any amount—evaluation is warranted.

The purpose of a systematic evaluation is to identify potentially reversible or transient causes of UI, recognize individual patient risk factors, and determine the actual or potential effect of UI on QOL and functional status. A consistent approach to evaluation will enable the clinician to develop a set of interventions that target the risk factors and causes for each older woman. All these data need not be collected

in one patient visit, and printed materials can be sent to the patient to complete at home prior to an office visit.

Transient UI (TUI) usually refers to leakage or other symptoms of relatively new onset and is often based on factors outside the GU tract. TUI may be temporary or reversible, acute or chronic (persistent). Some of the potential causes of TUI are listed in Table 3. Determining and treating underlying issues, including depression and cognitive impairment, may lead to resolution of the leakage.

History. A focused, holistic history related to urine leakage should be obtained. Initially, the history can be brief and targeted to identify UI type.22 In many instances, the type of UI can be diagnosed through history alone. At a second patient visit, a detailed review of the patient’s medical (including obstetrical) and surgical history to identify pre-existing or comorbid conditions can be accomplished.

A review of systems should identify sensory, mobility, or functional problems, as well as cognitive or emotional disorders, and can elicit clues to a change in functional status, weight, eating habits, or fluid intake.23 Asking the woman how urine leakage has impacted QOL is imperative.

During the focused history, the woman should be questioned about usual bladder habits; frequency; urgency; hesitancy; leakage with coughing, sneezing, laughing, bending, lifting, or physical activity; difficulty starting and maintaining the urine stream; a feeling of bladder fullness that persists after urination; and straining to complete the voiding process. Asking about UTI history, GU tract procedures, and any history of catheterization is crucial. Nighttime voiding pattern, sleep and rest patterns, usual activity pattern, bowel habits, dysuria, and pain on urination are also important aspects of the history-gathering process. Duration and severity of all symptoms should be assessed. Asking about prior UI interventions and outcomes is informative as well.

A basic social history—generally related to lifestyle choices and culture—is also very important. Topics that need to be covered include smoking/tobacco history, alcohol use, hobbies, leisure or recreational interests, exercise pattern, and any illicit drug use. Gathering data on level of education, occupation, and sexual history can also provide cues for treatment and for establishing patient goals.

If possible, the patient should be asked to complete a 24-hour dietary recall or similar nutrition/fluid diary and bring the document to the next visit. This information helps the clinician to understand dietary habits, favorite foods and drink, and alcohol consumption. Reviewing the data with the patient helps to ensure a better understanding of eating

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TABLE 3. Causes of transient or potentially reversible urinary incontinence (DIAPPERS) D

Delirium, dementia; other confusional states

I

Infections: urinary (symptomatic), respiratory, skin

A

•Atrophic vaginitis, urethritis •Alcohol ingestion •Acute illness

P

Psychological causes: depression, grief/loss, spiritual distress, hopelessness, behavioral disturbances

P

Pharmacologic agents (including side effects): diuretics, sedatives/ hypnotics, anticholinergics, alpha-adrenergic blockers, alphaadrenergic agonists, calcium channel blockers, antidepressants, antipsychotics, narcotic analgesics, antiparkinson medications, some ACE inhibitors

E

•Endocrine disorders, metabolic disorders (hypercalcemia, hyperglycemia) •Excess urine output •Excessive fluid intake •Edema (pedal)

R

Restricted mobility: physical restraints, musculoskeletal disorders or fractures, inappropriate or no assistive devices, environmental barriers, lack of caregiver assistance

S

Stool impaction, chronic constipation, fecal incontinence

and drinking patterns and consumption of potential bladder irritants. In addition, since many older women engage in socialization at mealtime, this is a logical point at which to ask about social support, relationships, and use of available community resources.

Questions about living arrangements and the environment should also be posed. Lighting, steps, rugs and floor coverings, location and number of bathrooms, and distance to the bathroom may be important. Understanding the living environment helps the clinician make positive suggestions that may enable the patient to maintain independence with relatively modest environmental changes versus recommending a different living situation.

A urinary symptom/voiding diary or bladder log can provide patient-reported information that may be helpful to the clinician. The data obtained from this material are considered some of the most important components of the evaluation process. A diary/journal completed by the patient at home can be the focal point of the office visit and serve as the framework for collecting the previously described historical information. When reviewing the diary, look for patterns and associations. How frequent are the symptoms? Is there any regularity to them? What activity was occurring at the time of leakage? Does consumption of a particular food or beverage seem to be associated with urge or incontinence

or both? Even frail older women living independently are capable of keeping an accurate diary for three days (these do not have to be consecutive days). Diaries need to be configured with a larger font, follow the health-literacy guidelines, and allow enough space for the individual to make notes. The form should also include space to record the number of times that undergarments, clothes, or absorbent products needed to be changed. A section for bowel movements can also be helpful in diagnosing constipation. Finally, the diary can be used as a monitoring tool to determine the effectiveness of interventions. Free forms are available on the Internet.

Older adults are often taking multiple medications, and a complete review should be performed at least yearly. Asking patients to bring in all the medications they have at home is a common approach used to gain perspective on past and current health issues. This technique has been called the “brown bag test.”24 The review should include not only prescription medications but all OTC drugs, home remedies, and supplemental or alternative herbal therapies as well as a report of caffeine and alcohol intake. During a medication review, the clinician often discovers the potential reason for the patient’s UI. Any suspicious medication should be decreased or carefully discontinued, if possible. For the patient who requires a particular class of drugs, consider substituting within the class with a medication that has a different side-effect profi le.

Last, talking with the older woman about her goals and expectations of treatment is crucial to the therapeutic patientprovider relationship as well as the patient’s QOL. Are the goals and expectations realistic? Is the time frame reasonable?

Is a support system in place? Will treatment be affordable for the patient? Will the treatment plan fit with the patient’s lifestyle? Is the patient able to understand and comprehend treatment plans? Is she motivated? While these questions may seem logical, they are often not considered by the clinician, and sometimes patients have unrealistic expectations.

Acquiring this specific information helps in the clinical decision-making process.

Physical examination. The physical examination must be approached carefully, taking into consideration the age, overall health status, and history of the individual, and the clinical setting.15 The physical exam helps clarify possible causes of transient UI, detect underlying conditions and causes associated with persistent UI, evaluate comorbid conditions, and determine functional ability. What the examination includes is different for each woman and is dependent on the data collected during history-taking and review of the completed patient forms. General appearance,

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cognitive status, skin integrity, and cardiopulmonary status are important indicators of overall patient health. In addition, look for lower-extremity edema, palpate peripheral pulses, and check for venous insufficiency.

Functional status—especially mobility—is one of the keys to controlling UI. The first part of a mobility assessment can begin with observation of the patient as she is escorted to the examination room. Observe whether an assistive device is being used (and if it is being used correctly); whether the patient requires support from the wall, handrail, or another person; and whether she requires a rest period. Watch her gait pattern and balance. Notice the type of shoe she is wearing and ask whether this is her usual footgear. In the examination room, pay attention to how the patient gets on and off the examination table and up and down from a chair; for example, does she need assistance or use the arms of the chair? When entering the room, extend your hand for a handshake, as this can provide information about the patient’s vision, strength, dexterity, and gross coordination. These are all integral aspects of the toileting experience and manipulation of clothing.

The neurologic examination should include a measure of cognition. Lower-extremity and perineal sensation and anal and bulbocavernosus reflexes should be assessed if the patient can tolerate the examination. The abdominal assessment should include checking for diastasis recti, masses, hernias, ascites, and organomegaly, all of which can influence intraabdominal pressure and urinary-tract function.

In some older women, the gynecologic examination needs to be approached in a conservative manner, keeping it as minimally invasive as possible. Consider performing a digital examination rather than a speculum examination.25 Assess for perineal dermatitis, pelvic-organ prolapse, pelvicfloor muscle tone, and presence of anatomic abnormalities.

Document any atrophy, vaginal stenosis, or scar tissue.

The ability of the older woman to tolerate a rectal examination should also be considered. If the clinician decides to perform this assessment, explanations about what is being done and why can make the examination tolerable for the patient and allow the clinician to gain valuable information.

The rectal examination should include looking for skin irritation, perianal lesions, masses, and hemorrhoids and checking sphincter tone and perianal sensation. If stool is present in the anal canal, test for occult blood.

Diagnostic studies. Diagnostic tests should be conducted only if knowing the results will clarify the diagnosis, guide treatment decisions, or change treatment interventions.26 Whether to send a urine specimen for laboratory analysis is controversial. Some authors believe urinalysis (UA) by

dipstick testing is useful in ruling out bladder infection and in detecting the presence of glucose, protein, and hemoglobin.27 If findings are negative, the specimen does not need to be sent to the laboratory for further analysis. If dipstick findings are positive, the specimen should be sent for microscopy and culture and sensitivity.

In 2010, the International Scientific Committee on Incontinence strongly recommended UA as a diagnostic measure but indicated that testing could range from dipstick to urine microscopy and culture when indicated.28 Thus, the decision about which diagnostic tests should be done lies within the clinician’s judgment but should include consideration of costs and usefulness of the information obtained.

In older women with suspected voiding dysfunction, prevoid, portable, noninvasive ultrasonography should be performed with the bladder full. This test provides an estimate of bladder capacity. The postvoid residual urine volume (PVR) is performed within five minutes of an intentional void.

When determining PVR, bladder ultrasound is preferable to in-out catheterization because of the latter’s potential for trauma and infection. A PVR ≤50 mL is considered normal, while a PVR of 50 to 100 mL is suggestive of weakness or possible obstruction; a PVR >100 mL is considered abnormal, and a PVR >200 mL may indicate the need for referral.29 Recently, obtaining PVR has been found to be of little help unless the patient has recurrent UTIs, neurologic disorders, or pelvic-organ prolapse beyond the introitus.22 Since bladder ultrasound may not be available in many practice settings, PVR should not be considered an essential component of an initial UI workup.

Treatment and management interventions

Each older adult’s life experience is unique, as is each person’s experience with UI. Effective treatment requires a multifaceted approach that focuses on the level of patient understanding and the impact of UI on QOL and function.

Lifestyle interventions. Behavior modification, lifestyle changes, and environmental interventions are first-line treatments for UI, with the goals of improving QOL, maintaining function, and enhancing self-esteem. A specific UI diagnosis is not necessary before beginning treatment with noninvasive interventions that are simple, inexpensive, and measurable.

Basic interventions and explanations for the common types of UI are presented in Table 4. All behavioral interventions require active participation and motivation on the part of the person living with UI. Interventions should be individualized and mutually agreed upon with the older adult.

Continues on page 74

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TABLE 4. Basic behavior and lifestyle interventions for treatment of UI Type of UI

Intervention

Stress

•Pelvic floor muscle exercises (PFMEs), or Kegel exercises •Timed (or scheduled) voiding—toileting on a fixed schedule that is consistent; every two hours while awake is typical •Habit training—patient utilizes the toilet at a set time interval based on findings from voiding diary; generally start at 30 minutes before leakage occurs; intervals can be adjusted based on the individual’s voiding pattern; goal is to gradually increase the intervals between voiding without leakage

Urge

•PFMEs •Timed voiding •Habit training •Urge inhibition—resisting or inhibiting the urge to urinate through education; stopping current activity; relaxation and distraction techniques, including thinking about something other than urinating; counting backward from 100 by 7s; “quick flicks,” or squeezing and releasing pelvic floor muscles quickly; delaying urge for only 10-20 minutes and then continuing to the bathroom •Bladder training—starting with a short voiding interval (usually every hour) and gradually increasing (usually in two- to three-hour intervals) time between toileting, with the goal of staying dry and suppressing the urge •Fluid management

Mixed

•Directed at whichever type of UI seems to be predominant

Overflow

•Double-voiding technique—attempting to void twice during one trip to the bathroom; may void and then sit for two to 10 minutes, and then try revoiding; if stable, may stand up, press abdomen up toward chin, sit down, and try to void again •Crede maneuver—using one or both hands, press firmly on the abdomen over the bladder during voiding to facilitate emptying

Functional

•Appropriate assistive mobility devices should be nearby at all times •Environment alterations to allow easier access to toilet (increase lighting, remove clutter) •Elderly-friendly furniture can be used for ease of maneuverability (arms on chairs, firm cushion seats) •Adjustments can be made to toilet facility (raised seat, grab bars) •Patient can consider adaptable clothing (elastic, snaps, Velcro) •Prompted voiding (or routine toileting)—older adults living alone can set an alarm or kitchen timer to remind them to use the toilet facility; caregiver reminds or asks the patient to use the toilet on a regular schedule, generally every two hours during waking hours •Check for possible underlying depression or cognitive impairment, and treat the condition •Advise patient to use alternative toiletry device (female urinal, bedpan, bedside commode) •Advise patient to have vision checked on a regular basis

Risk factors that can be modified—such as weight, smoking, alcohol consumption, physical activity, ingestion of bladder irritants, and fluid intake—as well as normalizing bowel patterns should be addressed with appropriate patients.

Education is a crucial component in the management of UI and should be accomplished with all patients regardless of UI diagnosis. Education dispels myths, helps with compliance issues, and empowers the older woman in optimal care of her health.

Pelvic-floor muscle exercises (PFMEs), or Kegel exercises, provide the foundation for an effective UI management program. While many women will report they are familiar with PFMEs, patients often explain that they practice while urinating on the toilet and starting/stopping the urine stream.

This method actually disrupts voiding patterns, weakens pelvic muscles, and can lead to retention and UTIs. Women can use this method initially to identify the specific muscle group involved, but they should not engage in this method routinely. The correct method to perform the exercises must

be explained; written instructions should be given as well.

Having the patient do several exercises while in the office will confirm that she is executing them correctly.

An effective approach to teaching PFMEs is to ask the patient to imagine trying to hold back the passage of flatus by squeezing the muscles in the pelvic region. If the patient is comfortable doing so, another method is to have her insert a finger into the vagina and squeeze the surrounding muscles. Relaxing the muscle helps the patient recognize the sensation she should feel when accurately performing PFMEs independently. Patients should pull up the muscle as if they were trying to touch their chin. Exercises should be done following urination and can be accomplished in any position. Patients should be told not to lift their buttocks, tighten the abdomen or thigh muscles, move their legs, strain down, or hold their breath. In the beginning, the activity should be held for a slow count of 5 or 10, depending on the functional status and frailty of the patient. The patient should then relax for twice as long, or a count of 10 (20 if initially

74 THE CLINICAL ADVISOR • DECEMBER 2011 • www.ClinicalAdvisor.com

held for 10), to be sure the muscle has returned to baseline and there are no fasciculations. PFMEs should be carried out in a series of three to five repetitions at least three times a day. Patients should be instructed to do the exercises every day. To begin, the older adult should associate performing PFMEs while engaged in a daily activity, such as eating, grooming, or taking medication, which helps promote adherence to the treatment regimen. Inform the patient that a change in severity of urine leakage may take four to 12 weeks to achieve. PFMEs have been reported to provide an 81% reduction in urine leakage episodes.30 Emphasize the need for persistence with the exercises, which should become part of the woman’s daily routine. Positive benefits gained from performing PFMEs will be lost if the exercises are stopped, as the muscles will atrophy.31 A variety of devices are available to help patients with SUI, but numerous studies report poor adherence.32 Keep in mind the patient’s manual dexterity, visual acuity, and willingness to actually touch herself and insert the devices.

Decisions on whether to utilize any of these devices should be individualized and mutually determined.

There are a plethora of absorbent products on the market.

Know what is available and what is appropriate for each patient.

While decreasing urine leakage is the expected outcome, it may still be necessary for the older adult to wear some type of disposable product to engage in social activities and decrease the possibility of urine odor, thus maintaining or improving QOL. The type of pads or protective garments recommended should be individualized based on UI diagnosis, volume of incontinence, and cost.33 The use of such products should not foster dependence or take away from other desirable treatment.34 Older adults should be discouraged from using plastic-lined, tight-fitting products at night because of the potential for skin breakdown and infection related to the warm and moist environment created by the use of various products and urine.

Pharmacotherapy. Medications are a major cause of UI and urinary retention in the elderly. Many frequently prescribed medications can cause urinary symptoms, including frequency and urge. Keep in mind that if a patient is receiving a sedative, hypnotic, or analgesic, “any drug that dulls the brain, dulls the bladder, because your brain tells you when you have to void.”35 Pharmacotherapy may be useful to augment behavioral and lifestyle treatment and management interventions.

Most traditional anticholinergic therapies are limited in their effectiveness. For the treatment of SUI, anticholinergics are inappropriate and ineffective.36 Medications for UUI

should not be used until other treatment interventions and modalities have failed over a sufficient period of time. Drugs can be particularly helpful for women who have prominent urge symptoms, no cardiac problems or cognitive deficits, and can tolerate and address the side effects of dry mouth, blurry vision, or constipation. If possible, halt or decrease dosages of current medications that may be contributing to UI before adding a drug to treat it.37 The well-known mantra for geriatric pharmacology, “start low and go slow,” should be invoked when prescribing drug therapy for UI. At times, the patient is so distraught about UI that she is unable to engage in behavioral interventions at the outset of the treatment process. Appropriate drug therapy may help her gain some control over her symptoms and become more motivated to work on behavioral or lifestyle interventions.

Behavioral therapies, lifestyle changes, and environmental enhancement are the interventions of choice.

Referral. For most patients, UI can be handled effectively in the office setting. Interventions described in this article can be appropriately implemented and monitored by knowledgeable office-based clinicians. Circumstances for which referral should be considered include: • Failure to respond to treatment over time • Worsening symptoms • Appearance of new symptoms • Microscopic hematuria in the absence of infection • Anatomical abnormalities or severe prolapse • History of prior urologic corrective surgery followed by urine leakage • Inability to determine a diagnosis after working with the patient for a reasonable length of time • Positive neurologic findings in the absence of a current diagnosis • A PVR (if completed) >200 mL on two occasions.

Maintaining positive relationships with providers in the community who have expertise in UI is imperative.

Continues on page 76

AT A GLANCE ●

Prevalence of urinary incontinence (UI) increases with age, partcularly among women.

●

UI occurs when there is dysfunction in the storage capacity and/or emptying mechanism of the lower urinary tract.

●

Initiate a dialogue by asking, “Do you ever leak urine or have difficulty getting to the toilet in time?”

●

Behavior modification, lifestyle changes, and environmental interventions are first-line treatments for UI.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2011 75

CME CE

URINARY INCONTINENCE

2. Kang Y. Knowledge and attitudes about urinary incontinence among

WHAT DO YOU THINK?

community-dwelling Korean American women. J Wound Ostomy

Add your comments to this article —or any article — by going to www.ClinicalAdvisor.com.You will also see what your colleagues are saying.

Continence Nurs. 2009;36:194-199.

3. Melville JL, Wagner LE, Fan MY, et al. Women’s perceptions about the etiology of urinary incontinence. J Womens Health (Larchmt).

2008;17:1093-1098. Available at www.ncbi.nlm.nih.gov/pmc/articles/ PMC2944440/.

Continence surgery is indicated whenever conservative treatment fails or the patient wants definitive treatment.27 Surgery is the fi nal management option for individuals with UI. Palliative measures can be used for those patients whose UI is not curable.38

4. Kincade JE, Dougherty MC, Carlson JR, et al. Factors related to urinary incontinence in community-dwelling women. Urol Nurs. 2007;27:307-317.

5. Kuchel GA, DuBeau CE. Urinary incontinence in the elderly. In: The American Society of Nephrology, Online Geriatric Nephrology Curriculum.

Available at www.asn-online.org/education_and_meetings/geriatrics/ OnlineGeriatricsCurriculum.pdf.

Conclusion

6. Talley KM, Wyman JF, Shamliyan TA. State of the science: conservative

Perhaps the single most important action that clinicians can take is to ask every older woman about UI and then to follow with the basic approaches to evaluation and management.

Age-appropriate, evidence-based UI guidelines need to be part of the office practice. UI should be approached from an interdisciplinary perspective in which a variety of healthcare team members are able to gather information from the patient and provide individualized education in a holistic manner. Evidence exists that older adults demonstrate significant improvement in UI symptoms when education, counseling, support, and encouragement in behavior management and lifestyle interventions are provided.

Continued UI research is warranted, especially research that includes older adults who reside in the community.

Information obtained from voiding diaries is used extensively, yet reliability and validity of any specific instrument have not been tested with older adults. Hopelessness and spiritual distress, as precursors to health decline, and impact on QOL need to be studied more extensively in older adults with UI. Research should aim at developing better outcome measures to assess the effectiveness of basic interventions for UI. UI is an aging problem and the people of the world are aging, thus making UI a global health concern that will not be going away soon. ■

interventions for urinary incontinence in frail community-dwelling older adults. Nurs Outlook. 2011;59:215-220.

7. Hu TW, Wagner TH, Bentkover JD, et al. Costs of urinary incontinence and overactive bladder in the United States: a comparative study. Urology.

2004;63:461-465.

8. Carson CC. The cost of urologic care in America: $11 billion and growing. Contemp Urology. 2007;19:6.

9. McCarthy G, McCormack B, Coffey A, et al. Incontinence: prevalence, management, staff knowledge and professional practice environment in rehabilitation units. Int J Older People Nurs. 2009;4:3-11.

10. Kinchen KS, Burgio K, Diokno AC, et al. Factors associated with women’s decisions to seek treatment for urinary incontinence. J Womens Health (Larchmt). 2003;12:687-698.

11. Gomelsky A. Urinary incontinence in the elderly female. Ann Long-Term Care; Clinical Care and Aging. 2009;17:41-45. Available at www.annalsoflongtermcare.com/content/urinary-incontinence-in-the-elderly-female.

12. Townsend MK, Curhan GC, Resnick NM, Grodstein F. Rates of remission, improvement, and progression of urinary incontinence in Asian, black, and white women. Am J Nurs. 2011;111:26-33.

13. Mangera A, Patel AK, Chapple CR. Pathophysiology of urinary incontinence. Surgery. 2011;29:249-253.

14. Frank C, Szlanta A. Office management of urinary incontinence among older patients. Can Fam Physician. 2010;56:1115-1120. Available at www. cfp.ca/content/56/11/1115.full.pdf+html.

15. Hägglund D, Ahlström G. The meaning of women’s experience of

Dr. Keilman is an assistant professor and a gerontologic nurse practitioner at Michigan State University College of Nursing in East Lansing. The author has no relationships to disclose regarding the content of this article.

living with long-term urinary incontinence is powerlessness. J Clin Nurs.

2007;16:1946-1954.

16. Hägglund D, Walker-Engström ML, Larsson G, Leppert J. Reasons why women with long-term urinary incontinence do not seek professional help: a cross-sectional population-based cohort study. Int Urogynecol J Pelvic

References

Floor Dysfunct. 2003;14:296-304.

1. Botlero R, Davis SR, Urquhart DM, Bell RJ. Incidence and resolution

17. Shaw C. A review of the psychosocial predictors of help-seeking

rates of different types of urinary incontinence in women: findings from a

behaviour and impact on quality of life in people with urinary incontinence.

cohort study. J Urol. 2011;185:1331-1337.

J Clin Nurs. 2001;10:15-24.

76 THE CLINICAL ADVISOR • DECEMBER 2011 • www.ClinicalAdvisor.com

18. Lambert SD, Loiselle CG. Health information seeking behavior. Qual

pelvic organ prolapse, and fecal incontinence. Neurourol Urodyn. 2010:

Health Res. 2007;17:1006-1019.

29:213-240.

19. Karlowicz KA. Evaluation of the Urinary Incontinence Scales to

29. Weiss BD. Selecting medications for the treatment of urinary incon-

measure change after experiential learning: a pilot study. Urol Nurs.

tinence. Am Fam Physician. 2005;71:315-322. Available at www.aafp.org/

2009;29:40-46.

afp/2005/0115/p315.html.

20. Keilman LJ, Dunn KS. Knowledge, attitudes, and perceptions of

30. Burgio KL, Locher LJ, Goode PS, et al. Behavioral vs drug treatment

advanced practice nurses regarding urinary incontinence in older adult

for urge urinary incontinence in older women: a randomized controlled

women. Res Theory Nurs Pract. 2010;24:260-279.

trial. JAMA. 1998;280:1995-2000. Available at jama.ama-assn.org/con-

21. Landefeld CS, Bowers BJ, Feld AD, et al. National Institutes of Health

tent/280/23/1995.full.pdf+html.

state-of-the-science conference statement: prevention of fecal and urinary

31. Josephson KL, Ginsberg DA. Key considerations when treating the

incontinence in adults. Ann Intern Med. 2008;148:449-458. Available at

older patient with symptoms of urinary frequency and urgency. Ann Long-

www.annals.org/content/148/6/449.full.pdf+html.

Term Care. 2004;12:25-32.

22. Goode PS, Burgio KL, Richter HE, Markland AD. Incontinence in older

32. Sampselle CM. Behavioral interventions in young and middle-age

women. JAMA. 2010;303:2172-2181.

women. Am J Nurs. 2003; 103:9-19.

23. Keilman LJ. Urinary incontinence: basic evaluation and management in

33. Imam KA. The role of the primary care physician in the management

the primary care office. Prim Care. 2005;32:699-722.

of bladder dysfunction. Rev Urol. 2004;(6 suppl 1):S38-S44. Available at

24. Freml JM, Farris KB, Fang G, Currie J. Iowa priority’s brown bag medi-

www.ncbi.nlm.nih.gov/pmc/articles/PMC1472846/.

cation reviews: a comparison of pharmacy students and pharmacists. Am J

34. Lekan-Rutledge D, Doughty D, Moore KN, Wooldridge L. Promoting

Pharm Educ. 2004;68:article 50.

social continence: products and devices in the management of urinary

25. Lekan-Rutledge D. Urinary incontinence strategies for frail elderly

incontinence. Urol Nurs. 2003;23:416-428,458.

women. Urol Nurs. 2004;24:281-283, 287-301.

35. Newman DK, Harms D. Addressing the unmet needs of patients with

26. Ouslander JG, Dutcher JA. Overactive bladder: assessment and

overactive bladder. CE-Today for Nurse Practitioners. 2004;3/5:7-17.

nonpharmacological interventions. Consult Pharm. 2003;18(Suppl B):

36. Weiss BD. Selecting medications for the treatment of urinary incon-

13-20.

tinence. Am Fam Physician. 2005;71:315-322. Available at www.aafp.org/

27. Thakar R, Addison R, Sultan A. Management of urinary incontinence

afp/2005/0115/p315.html.

in the older female patient. Clin Geriatr. 2005;13:44-54. Available at www.

37. DuBeau CE. The continuum of urinary incontinence in an aging popula-

clinicalgeriatrics.com/articles/Management-Urinary-Incontinence-Older-

tion. Geriatrics. 2002;57(Suppl 1):S12-S17.

Female-Patient.

38. Engberg S, Kincade J, Thompson D. Future directions for incontinence

28. Abrams P, Andersson KE, Birder L, et al. Fourth International

research with frail elders. Nurs Res. 2004;53(6 Suppl):S22-S29.

Consultation on Incontinence Recommendations of the International All electronic documents accessed November 15, 2011. © The New Yorker Collection 2011 from cartoonbank.com. All Rights Reserved.

Scientific Committee: evaluation and treatment of urinary incontinence,

“Beats me—I’ve never dealt with a sovereign debt crisis before.” www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2011 77

FEATURE: CARL SHERMAN

Antivirals used as an adjunct to flu vaccine In individuals with confirmed or suspected influenza and a high risk of complications, the CDC recommends treatment with one of two agents.

A

substantial proportion of people with influenza should be treated with antiviral medications, according to 2011 recommendations from the Advisory Committee on Immunization Practices (ACIP) of the CDC.1 The drugs should be administered as promptly as possible after symptoms appear. “The earlier the treatment, the bigger the benefit,” said Timothy M. Uyeki, MD, medical epidemiologist in the influenza division of the CDC and an author of the recommendations.

While annual vaccination continues to be the primary goal of the CDC, “Since the vaccine is not 100% effective, we need to encourage individuals, particularly those at higher risk for complications of influenza, to seek medical care for acute respiratory illness right away,” explained Dr. Uyeki.

© BURGER / PHANIE / PHOTO RESEARCHERS, INC.

Who needs treatment?

Once initiated, a full course of antiviral medication is usually indicated.

The CDC statement recommends antiviral treatment for people with confirmed or suspected influenza who are at high risk of complications.

Within this category are persons aged 65 years and older and younger than age 5 years, and those with a wide variety of chronic conditions: chronic pulmonary disease, including asthma; cardiovascular disease (except hypertension); renal and hepatic conditions; diabetes and other metabolic disorders; and neurologic and neurodevelopmental disorders, including stroke and mental retardation.

Patients who are immunocompromised by disease such as HIV infection or by medication should also be treated.

Continues on page 83

78 THE CLINICAL ADVISOR • DECEMBER 2011 • www.ClinicalAdvisor.com

ANTIVIRALS FOR INFLUENZA

Drug choice and timing

Of the four antiviral agents approved for influenza in the United States, two are recommended: oseltamivir (Tamiflu) and zanamivir ( Relenza), which are active against both A and B viruses. The others, amantadine (Symadien, Symmetrel) and rimantadine (Flumadine), are not advised because they are ineffective against influenza B viruses, and resistance to them among influenza A strains is widespread.

Oseltamivir is taken orally and indicated for patients of virtually any age without restrictions. Zanamivir, which is inhaled as a powder, is approved for treatment of adults and children aged 7 years and older but contraindicated in individuals with underlying respiratory disease, including asthma and COPD. Resistance to oseltamivir was problematic during the 2009 H1N1 pandemic but is now uncommon—more than 99% of influenza A and B viruses tested after September 2009 have been oseltamivir-susceptible—and resistance to zanamivir is rarer still.

AT A GLANCE ●

Antiviral treatment is advised for persons aged 65 years and older as well as those younger than age 5 years.

●

In high-risk patients, antivirals should not be withheld because of a history of influenza vaccination.

●

Antivirals might best be prescribed empirically, based on symptoms and patterns of infection.

●

Initiate chemoprophylaxis within 48 hours of the most recent exposure and continue for no more than 10 days.

The influenza A virus (orange) is the most virulent human pathogen of the three influenza types (A, B, and C).

Nevertheless, clinicians should monitor emerging antiviral resistance patterns (weekly CDC updates are available at www. cdc.gov/flu/weekly/fluactivitysurv.htm, accessed November 15, 2011), and adjust prescribing practices accordingly.

Antiviral therapy for high-risk individuals and those with severe disease should be initiated as soon as possible. Ideally, this will be within 48 hours of the onset of symptoms, “but observational data suggests that treatment will have some benefit [if started later], up to five days,” Dr. Uyeki said.

Diagnostic tests for influenza have a limited role in treatment decisions. In the outpatient context, rapid influenza diagnostic tests are most feasible, but poor to moderate sensitivity (20%70%) results in many false-negatives, particularly during outbreaks. Immunofluorescence and viral culture tests are more accurate but take longer. “We don’t want doctors to delay antiviral treatment waiting for test results,” warned Dr. Uyeki.

From a practical perspective, antivirals might best be prescribed empirically, based on symptoms and patterns of infection. Once initiated, a full course of treatment— generally five days, possibly longer for severely ill or immunocompromised patients—is usually indicated, unless an alternative diagnosis can be confirmed.

Treating children

The FDA has approved oseltamivir for children aged 1 year and older. But because younger infants are at higher risk of complications and hospitalization, and death rates are highest for those younger than age 6 months, the CDC recommends treatment with the drug down to birth.

The authors noted that the Emergency Use Authorization (EUA) issued by the FDA in response to the 2009 H1N1 influenza pandemic allowed for treatment (and chemoprophylaxis) of infants younger than age 1 year. The dosages recommended in the ACIP statement are based on the EUA directive.

Continues on page 84

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2011 83

© EYE OF SCIENCE / PHOTO RESEARCHERS, INC.

Antiviral therapy also should be offered to women who become ill while pregnant and up to two weeks postpartum and to persons who are morbidly obese (BMI >40), American Indians and Alaskan natives, and patients younger than age 19 years who are receiving long-term aspirin therapy.

The authors also stress the importance of antiviral treatment for patients who have been hospitalized with apparent or confirmed influenza or whose disease is severe, progressive, or complicated (e.g., by viral pneumonia, concomitant bacterial pneumonia or upper-respiratory disease, or exacerbation of comorbid medical conditions).

According to the ACIP recommendations, antiviral treatment for high-risk patients or those with severe disease should not be withheld because of a history of influenza vaccination.

Although high-risk and seriously ill patients are a priority, clinicians may consider antivirals for other previously healthy individuals with symptoms that suggest influenza.

ANTIVIRALS FOR INFLUENZA

WHAT DO YOU THINK? Add your comments to this article —or any article — by going to www.ClinicalAdvisor.com.You will also see what your colleagues are saying.

Chemoprophylaxis

“I couldn’t find a nail file, like you asked, so I brought you some nail polish and lip gloss instead.”

“Try to forget him.

He’s focussed on one thing, and it’s not you and it never will be you.”

Mr. Sherman is a freelance medical writer in New York City.

References 1. Fiore AE, Fry A, Shay D, et al. Antiviral agents for the treatment and chemoprophylaxis of influenza – recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2011;60:1-24. Available at www.cdc.gov/mmwr/preview/mmwrhtml/rr6001a1.htm.

2. Centers for Disease Control and Prevention. 2001–2012 Influenza antiviral medications: Summary for clinicians. Available at www.cdc.gov/flu /professionals/antivirals/summary-clinicians.htm.

All electronic documents accessed November 15, 2011.

“But if I’m not a senior collateral analyst for a high-volume, global marketing corporation ... who am I?”

84 THE CLINICAL ADVISOR • DECEMBER 2011 • www.ClinicalAdvisor.com

© The New Yorker Collection 2011 from cartoonbank.com. All Rights Reserved.

The CDC advises clinicians to consider oseltamivir or zanamivir to prevent influenza in people who are at high risk of influenza complications, have had close contact with family members or others with the disease, and have not been vaccinated against the strains prevalent at the time of exposure (or had been vaccinated less than two weeks before).

Unvaccinated health-care workers who have been similarly exposed may be considered for chemoprophylaxis as well.

Other candidates include individuals who may not respond adequately to the vaccine because of immunodeficiency or drug-related immunosuppression and those in whom vaccination is otherwise contraindicated.

Depending on the patient’s risk of complications, the availability of antiviral agents, and the nature of contact, close monitoring for early signs and symptoms of influenza and prompt treatment may be a superior alternative.

Chemoprophylaxis should be initiated within 48 hours of the most recent exposure and continued for no more than 10 days after that exposure, the CDC advises.

The recommendations also allow for pre-exposure chemoprophylaxis. But since this requires medication for the duration of influenza activity in the community, which might promote the development of antiviral-resistant strains, it should only be considered for individuals at extremely high risk of complications who cannot be protected by vaccination or other measures.

A more concise, updated version of the ACIP recommendations is also available.2 ■

FEATURE: CHASE B. SPELL, PA-C, AND LAURA M. GUNDER, DHSC, MHE, PA-C

Alleviating depression resistant to treatment Anywhere from 10% to 30% of individuals taking a single antidepressant face obstacles to successful treatment, including undiagnosed illness.

T

© ANDREA MORINI / GETTY IMAGES

reatment-resistant depression (TRD) is defined as the failure to achieve remission of symptoms after continuous therapy for six to 12 weeks with an adequate dose of a single antidepressant.1 Individuals receiving antidepressant monotherapy may be partially or totally resistant to treatment in up to 30% of cases.2

Treatment-resistant depression will likely require behavioral therapy.

86 THE CLINICAL ADVISOR • DECEMBER 2011 • www.ClinicalAdvisor.com

Q: What is the etiology of TRD? A: About 15% of the population will experience some form of depression throughout their life span. Approximately 6% to 8% of outpatients satisfy most of the depression criteria. Depression is almost twice as common in women as in men, and the incidence increases with age in both sexes. The cause of TRD is unknown.

The causes of depression are usually related to a neuroendocrine abnormality. The signs and symptoms of depression that these abnormalities stem from include increased secretion of cortisol and corticotropin-releasing hormone, increased adrenal size, decreased inhibitory response of glucocorticoids to dexamethasone, and a blunted response to thyroid-stimulating hormone. TRD has also developed as a result of inappropriate management of patients with clinical depression.

These causes are usually iatrogenic and include inadequate dose of antidepressant medication, inadequate duration of treatment, and inadequate evaluation of response to medications.

The misuse of antidepressant medications has directly led to the increase in TRD. Most cases of depression begin in the earlyadult stage of life. The number of past episodes

of depression is a good indicator of risk of recurrence.

About 50% to 60% of patients with one episode are likely to have at least one or two recurrences in their lifetime. 3 Q: What findings in the history and physical examination can be used to diagnose TRD? A: Be alert for any signs and symptoms of depression that are refractory to treatment, such as sadness, indifference, apathy, irritation, changes in sleep patterns or appetite, weight loss or weight gain, motor agitation, loss of interest in pleasurable activities, impaired concentration and decision making, feelings of shame or guilt, and thoughts of death or dying. On physical exam, the patient could present with a flat affect, looking at the floor to avoid eye contact. A depressed patient may speak in a monotone or cry when answering questions. A loss of concentration may alter the patient’s comprehension of the questions asked by the clinician. If previous records are available, a change in BP could be noted. Aigns of dementia that may be present are considered pseudodementia, because depression is usually the cause. The Hamilton Depression Rating Scale (HAM-D) is a valuable clinical tool used to evaluate the progress of the disease. 3,4 Grading the patient’s responses to a questionnaire designed to measure the severity of depressive symptoms, the scale classifies depression as normal (0-7), mild (8-13), moderate (1418), severe (19-22), and very severe (>23).

Q: What tests are available to diagnose TRD? A: In one study, an electroencephalogram monitor showed cordance of the frontal lobe in patients resistant to treatment with a selective serotonin reuptake inhibitor (SSRI).5 Decreases in prefrontal cordance differentiated treatment responders from nonresponders as well. These fi ndings suggest that cordance biomarkers may be helpful in diagnosing TRD.

(Paxil, Pexeva) is unlikely to respond to further treatment.7 After an adequate trial of antidepressant therapy has been identified, referral to a mental-health specialist is recommended. The specialist will reassess to make sure the depression was not caused by an undiagnosed illness or prescribed medications. Other diagnoses that must be ruled out before initiating treatment for TRD include somatoform disorder, personality disorders, bipolar disorder, anxiety disorders, anorexia nervosa, multiple sclerosis, Parkinson disease, alcohol or drug abuse, hypothyroidism, and bereavement.

Q: What treatment options are available for TRD? A: Most clinicians will begin with a stepwise increase in treatment. Start with one antidepressant medication, and maximize the therapeutic dose and duration. Then reassess the patient to see if the signs and symptom have been alleviated. If not, another antidepressant agent may be added from another class. If combination drug therapy fails to alleviate the depression, electroconvulsive therapy is an option.

TRD is a medical condition that will likely require behavioral therapy to improve the signs and symptoms. A therapist identifies unhealthy behavior and helps implement new behaviors designed to treat TRD. Once a patient has successfully been treated and the signs and symptoms of TRD have abated, he or she should be kept on maintenance therapy for approximately two years to prevent relapse of depressive symptoms. Pharmacotherapy options for the treatment of depression include SSRIs, serotonin and norepinephrine reuptake inhibitors, norepinephrine and dopamine reuptake inhibitors, atypical antidepressants, tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors. An SSRI is typically considered the first-line therapy. SSRIs have fewer side effects than do other medications. Given the number of medications available to treat depression, patients need to be evaluated individually to ensure the maximal pharmacotherapeutic effect.6

Q: What is the standard workup for TRD?

A: Once a patient presents with depression that appears to be refractory, it is important to determine if an adequate trial of antidepressant medication (typically four to six weeks) was used.6 If any improvement was seen, the dosage can be increased and treatment continued for an additional four to six weeks. Anywhere from eight to 10 weeks will give the clinician a clear picture of the effectiveness of the medication, and another treatment may be applied.

One study found that a depressed individual who had not improved by the third week of treatment with paroxetine

Q: What is the prognosis for people with TRD? A: Once deemed effective, the treatment plan should be continued and reassessed periodically for patient

WHAT DO YOU THINK? Add your comments to this article —or any article — by going to www.ClinicalAdvisor.com.You will also see what your colleagues are saying.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2011 87

TREATMENT-RESISTANT DEPRESSION

Expect a poorer clinical outcome if the signs and symptoms of depression can only be controlled with the use of multiple antidepressants. compliance and improvement. Expect a poorer clinical outcome if the signs and symptoms of depression can only be controlled with the use of multiple antidepressants. Absence of early improvement is highly predictive of overall response failure.8 One study noted that longer unsuccessful treatment leads to a worse long-term prognosis.9 Other research, found disappointing long-term therapeutic results in patients with depression and raised the possibility that impaired sleep—especially insomnia— is at least partly responsible.10 Impaired sleep has led to increased morbidity and mortality in TRD. These studies illustrate the need for more research on the topic of TRD. The general prognosis is not good once a depressed person becomes resistant to treatment.

Patients must be constantly reassessed in long-term treatment for the recurrence of symptoms or the onset of new symptoms. To assure compliance and maximize treatment, reassess the medication side-effect profi le in patients with TRD.10

Sometimes a full remission of symptoms is not possible even with the best therapy, which can be frustrating for the patient and provider alike. Additional research will lead to a better understanding of the etiology of TRD, and patients will see much improved therapies in the future. ■ Mr. Spell is a physician assistant at Georgia Sports Medicine and Orthopedic Clinic in Tifton. Dr. Gunder is assistant professor and director of research and faculty development at Georgia Health Sciences University in Augusta.

References 1. Fava M. Diagnosis and definition of treatment-resistant depression. Biol Psychiatry. 2003;53:649-659.

2. Cadieux RJ. Practical management of treatment-resistant depression.

Am Fam Physician. 1998;58:2059-2062. Available at www.aafp.org /afp/1998/1201/p2059.html.

3. Kasper DL, Braunwald E, Fauci AS, et al., eds. Harrison’s Principles of Internal Medicine. 17th ed. New York, N.Y.: The McGraw-Hill Companies; 2008:2716-2718.

Q: What preventive measures can be used to stop the incidence of TRD? A: A study compared the effects of treatment with fluoxetine (Prozac) plus cognitive behavior therapy (CBT) with those of fluoxetine alone. Estimated probabilities of relapse at 36 weeks were 37% in the fluoxetine group and 15% in the fluoxetine-plus-CBT group.11 Although more studies must be done to confi rm the results, this suggests that CBT is effective in preventing relapse in patients being treated for depression. In other words, psychotherapy might be a way to achieve greater efficacy of antidepressants and might be a promising strategy to prevent relapse and the development of TRD.11

4. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry.

1960;23:56-62. Available at www.ncbi.nlm.nih.gov/pmc/articles/ PMC495331/.

5. Cook IA, Leuchter AF, Morgan ML, et al. Changes in prefrontal activity characterize clinical response in SSRI nonresponders: a pilot study. J Psychiatr Res. 2005;39:461-466.

6. Nemeroff CB. Augmentation strategies in patients with refractory depression. Depress Anxiety. 1996-1997;4:169-181.

7. Feighner JP, Boyer WF. Paroxetine in the treatment of depression: a comparison with imipramine and placebo. J Clin Psychiatry. 1992;53:44-47.

8. Fekadu A, Wooderson SC, Markopoulo K, et al. What happens to patients with treatment-resistant depression? A systematic review of medium to long term outcome studies. J Affect Disord. 2009;116:4-11.

9. Papakostas GI, Petersen T, Pava J, et al. Hopelessness and suicidal ide-

Q: What are the barriers to achieving successful remission of TRD? A: Part of the difficulty of treating TRD is that the cause of this condition is not fully understood. An individual’s misunderstanding of how his or her treatment plan works is one of the main reasons for failure. Most patients do not realize that medication must continue even if symptoms improve. Once the medications are out of the person’s system, a relapse can occur. The person then returns to the clinic for more medications, more treatments plans have failed, and the likelihood of TRD increases.

ation in outpatients with treatment-resistant depression: prevalence and impact on treatment outcome. J Nerv Ment Dis. 2003;191:444-449.

10. Mendlewicz J. Sleep disturbances: core symptoms of major depressive disorder rather than associated or comorbid disorders. World J Biol Psychiatry. 2009;10:269-275.

11. Kennard BD, Emslie GJ, Mayes TL, et al. Cognitive-behavioral therapy to prevent relapse in pediatric responders to pharmacotherapy for major depressive disorder. J Am Acad Child Adolesc Psychiatry. 2008;47:1395-1404.

Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC2826176/.

All electronic documents accessed November 15, 2011.

92 THE CLINICAL ADVISOR • DECEMBER 2011 • www.ClinicalAdvisor.com

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Advisor Forum These are letters from practitioners around the country who want to share their clinical problems and successes, observations, and pearls with their colleagues. Responding consultants are identified below. We invite you to participate.

Inside the Forum DECEMBER 2011

Consultations Choosing the best inflammation marker . . . . . . . . . . . . . . . . . . . . . .96 Bad auscultation techniques . . . . . . . .96 Decreasing fear of rapid hyperglycemia . . . . . . . . . . . . .96 Low testosterone in young and healthy men . . . . . . . . . . . . . . . . . .97 Pedal cracking . . . . . . . . . . . . . . . . . .97 And more . . . . . . . . . . . . . . . . . . . . .98

Clinical Pearls A visual hypertension warning . . . . . .98 Preventing diarrhea after esophageal reconstruction. . . . . . . . .98 Timely reminder to keep stretching . .99 Spray toward the ears to avoid a bloody nose . . . . . . . . . . . . . . . . .99 And more . . . . . . . . . . . . . . . . . . . . .99

Your Comments

Send us your letters with questions and comments to: Advisor Forum, The Clinical Advisor, 114 West 26th Street, 4th Floor, New York, NY 10001.

You may also fax (646) 638-6117, or contact us by e-mail at letters@ clinicaladvisor.com.

If you are writing in response to a published letter, please indicate so by including the number in parentheses at the end of each item. Letters are edited for length and clarity. The Clinical Advisor’s policy is to print the author’s name with the letter.

No anonymous contributions will be accepted.

Abstinence is free, healthy, and effective . . . . . . . . . . . . . . . . . .99

CONSULTATIONS MATURITY ONSET DIABETES OF THE YOUNG What is maturity onset diabetes of the young (MODY)? How does it differ from types 1 and 2 diabetes?—CAROLINE LUKE, FNP, New York City MODY is an inherited form of diabetes primarily caused by defects in beta-cell function and secretion; approximately 2% of all individuals with diabetes have MODY. The condition is commonly misdiagnosed as either type 1 or type 2 diabetes. The nomenclature of MODY is being replaced by the more accurate name of “genetic defects in beta-cell function.”

There are actually eight different autosomal-dominant genetic mutations associated with MODY, so these patients present clinically with a strong family history of diabetes. Mutations in glucokinase, hepatocyte nuclear factor-4-alpha, hepatocyte nuclear factor-1-alpha, insulin promoter factor-1, and neurogenic differentiation factor-1 can all adversely affect various beta-cell functions. The most common mutations seen in adults are glucokinase (formerly known as MODY-2) and hepatocyte nuclear factor-4-alpha (formerly known as MODY-3). Glucokinase is sometimes thought of as the glucose sensor for the beta cell, and mutations in glucokinase usually result in a slightly higher glucose threshold for insulin secretion in the beta cell.

Clinically, this is manifested by mild, stable fasting hyperglycemia, and mild elevations in the hemoglogin A1c. Interestingly, MODY-2

OUR CONSULTANTS

Bruce D. Askey, MSN, CRNP, is

Rebecca H. Bryan, APRN, CNP, is a

Eileen Campbell, MSN, CRNP,

Philip R. Cohen, MD, is clinical

a clinician in the Department of Hepatology/ Gastroenterology at the Guthrie Clinic in Sayre, Pa.

lecturer in the Family Health NP Program, University of Pennsylvania School of Nursing, Philadelphia.

is associate program director, Family Health NP Program, University of Pennsylvania School of Nursing, Philadelphia

associate professor of dermatology, University of Texas Medical Center, Houston.

Deborah L. Cross, MPH, CRNP, ANPBC, is associate

program director, gerontology NP program, University of Pennsylvania School of Nursing, Philadelphia

94 THE CLINICAL ADVISOR • DECEMBER 2011 • www.ClinicalAdvisor.com

JoAnn Deasy, PA-C, MPH,

Virginia H. Joslin, PA-C, MPH, is

a primary-care clinician, teaches in the PA program at Pace UniversityLenox Hill Hospital, New York City.

assistant professor and PA Program division director at Emory University School of Medicine in Atlanta.

Maria Kidner, DNP, FNP-C, is

a nurse practitioner with Cheyenne Cardiology Associates in Cheyenne, Wyo.

does not typically improve with insulin or oral diabetes therapies.

Characteristics of MODY-3 include decreased insulin secretion, but these patients are quite sensitive to sulfonylurea drugs when used to correct hyperglycemia.

In differentiating patients with MODY from type 1 and type 2 diabetes, remember that individuals with MODY are not insulinresistant (unlike those with type 2 diabetes) and usually have some beta-cell secretory capacity (unlike those with type 1 diabetes). While genetic testing is available for MODY, it is quite expensive (N Engl J Med. 2001;345:971-980).—Kathy Pereira, MSN, FNP-BC, assistant professor, co-coordinator, family nurse practitioner program, Duke University School of Nursing, Durham, N.C. (158-1)

Rivaroxaban is currently approved for DVT prophylaxis, whereas dabigatran is for thromboembolism and stroke prevention.—Maria Kidner, DNP, FNP-C (158-2)

CHEST CT BEFORE LEAVING THE ED TO PREVENT PULMONARY EMBOLISM In the emergency department (ED), it has become common practice to treat deep venous thrombosis (DVT) “below the knee” with enoxaparin (Lovenox) injection prior to discharge, followed by warfarin (Coumadin) at home. Since up to 50% may have associated pulmonary embolism (PE) (not all of them symptomatic), should it also be common practice to do a chest CT on all of these patients prior to discharge from the ED? Given the radiation exposure associated with CT, would it be preferable to admit these patients for observation and treatment?—DAWN RIESETT, PA-C, Frederick, Md.

The microalbumin:creatinine ratio is an abbreviated form of a 24-hour urine assay for microalbumin. A simultaneous sampling of serum creatinine and spot urine microalbumin will yield the result.

Although there is no definitive reference range (age, gender, and lab methodology all play a part), the accepted levels are as follows: Normal: 0-30 µg/mg creatinine; microalbuminuria: 30-300 µg/ mg creatinine; clinical albuminuria: >300 µg/mg creatinine. Any patient whose ratio is >30 µg should undergo an initial evaluation by a nephrologist.—Sherril Sego, FNP-C, DNP (158-3)

In the ED setting for DVT, a negative d-dimer rules out a PE. If the d-dimer is elevated, consider a chest CT with PE protocol, or VQ scan. However, home treatment with subcutaneous enoxaparin 1 mg/kg SQ b.i.d. while warfarin becomes therapeutic is appropriate. Consider cost, radiation exposure, and risk of PE. The newest anticoagulants are dabigatran (Pradaxa) and rivaroxaban (Xarelto).

Debra August King, PhD, PA,

Samuel J. Mann, MD is associate

Daniel R. Mishell Jr, MD, is chairman

is senior physician assistant, New York-Presbyterian Hospital, New York City.

professor of clinical medicine, Weill Medical College of Cornell University, New York City

of the Department of Obstetrics and Gynecology, University of Southern California, Los Angeles.

Claire Babcock O’Connell, MPH, PA-C, is an

associate professor, University of Medicine and Dentistry of New Jersey, PA program, Piscataway.

HOW IS MICROALBUMIN:CREATININE RATIO INTERPRETED? Instead of simply checking microalbumin levels of our diabetic and hypertensive patients, we have begun to do spot urinalysis for a microalbumin:creatinine ratio. I am not sure how to interpret elevated results. When is it appropriate to refer to a renal specialist?—LINDA SZOCIK, FNP, St. Francis, Wis.

EFFECTIVENESS OF A SINUS CT How reliable is a CT scan of the sinuses in a patient who does not respond to an initial extended course of antimicrobial treatment for sinusitis?—LISA GORDON, PA-C, New Port Richey, Fla. There is no need for imaging in a case of acute sinusitis. CT scanning is considered the imaging procedure of choice for subacute (lasting one to three months) or chronic (lasting longer than

Christopher Ruser, MD, is

Sherril Sego, FNP-C, DNP, is a

Daniel G.Tobin, MD, is assistant

Jeffrey Weinberg, MD, is director of

assistant professor of medicine, Yale University School of Medicine, New Haven, Conn.

primary-care nurse practitioner at the Department of Veterans Affairs Medical Center in Kansas City, Mo.

professor of medicine, Yale University School of Medicine, New Haven, Conn.

clinical research, Department of Dermatology, St. Luke’s-Roosevelt Hospital Center, New York City.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2011 95

© JAMES CAVALLINI / PHOTO RESEARCHERS, INC.

Advisor Forum

Sinus MRI shows inflammation of the mucous membrane (pink).

three months) sinusitis, especially if surgery is being considered.

Inadequate drainage is believed to be the cause of sinusitis. Removal of the obstruction is the goal of surgical interventions. Functional endoscopic sinus surgery (FESS) has revolutionized the treatment of sinusitis. CT scanning can provide excellent imaging of the anatomy and pathologic patterns of the sinuses prior to surgery.

Plain radiography, taken with the patient standing erect, may show fluid levels in acute sinusitis; mucosal thickening and retention cysts may be seen in chronic sinusitis.

The superiority of CT scanning using cuts of 2-3 mm has severely limited the role of plain radiography in assessing sinus disease.

However, up to 40% of asymptomatic adults will show abnormalities of their sinuses on CT; diagnosis should be made in conjunction with history, physical exam, and endoscopic findings. MRI is preferred in cases of complicated sinus disease because it provides excellent imaging of soft tissue but not of bone. MRI is indicated in patients with intracranial complications, an extension of infection, or suspected superior sagittal venous thrombosis.—Claire Babcock O’Connell, MPH, PA-C (158-4)

CHOOSING THE BEST INFLAMMATION MARKER Which serologic measure of inflammation is the most costeffective and reliable when monitoring inflammatory disease?

What should be done if there is a discrepancy in a patient’s C-reactive protein (CRP) level and erythrocyte sedimentation rate (ESR), i.e., high ESR/low CRP or low ESR/high CRP?—RICH GREMILLION, MD, Sandy, Utah

Both ESR and CRP can be useful measures of active inflammation, but in many ways, CRP is a more useful test. CRP is made exclusively in the liver and can rise and fall within hours of an acute inflammatory stimulus. In contrast, ESR is more reflective of the concentration of fibrinogen and various noninflammatory immunoglobulins that have half-lives of days to weeks, resulting in a significant lag time in the rise and fall of the ESR. This difference in specificity and rapidity of response often accounts for an apparent discrepancy between the ESR and CRP. There are conditions in which the ESR remains the more useful test. For example, ESR can be elevated in various paraproteinemias, which often don’t provoke an acute inflammatory response, and in systemic lupus erythematosus and progressive systemic sclerosis. In both conditions, there is typically only a trivial increase in CRP, but the ESR may be very high. The reason for this discrepancy is unclear, but it indicates the two tests are complementary and should be used selectively based on the clinical scenario.—Daniel G. Tobin, MD (158-5)

BAD AUSCULTATION TECHNIQUES I was taught that good contact between the chest and stethoscope is essential for accurate auscultation—even to the point of wetting the chest in some particularly hirsute men. These days, I see clinicians listening through garments, i.e., undershirts, even shirts or dresses. Is this practice to be condoned or condemned?—RUDI KIRSCHNER, MD, Phoenix Performing auscultation through garments violates the basic acoustic properties of the stethoscope at the very least and should be condemned.

By failing to undress patients, we also run the risk of missing equally important visual diagnostic clues. This question draws attention to only one of many physical exam techniques that have deteriorated in direct contrast to the purported “progress” of modern, technologydriven medicine.—Christopher Ruser, MD (158-6)

DECREASING FEAR OF RAPID HYPERGLYCEMIA When trying to lower hemoglobin (Hb)A1c levels to <6.5, I find that diabetic patients experience frequent rapid hyperglycemia. Many of these patients become afraid to socialize because they are concerned that they won’t recognize the drop in blood sugar until it is too late. This confusion and fear decreases quality of life. What does the American Diabetes Association consider realistic parameters for HbA1c?—EMILY B. GRASER, FNP-BC, Lafayette, La.

96 THE CLINICAL ADVISOR • DECEMBER 2011 • www.ClinicalAdvisor.com

LOW TESTOSTERONE IN YOUNG AND HEALTHY MEN I treat a number of young, muscular, active men with low free and total testosterone (100-225 ng/dL) who complain of fatigue. These men work out regularly and deny any supplement use—oral or injectable. They are otherwise healthy. In all cases, follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, and thyroid-stimulating hormone levels are normal. Why is their testosterone so low?—STEVEN T. MARGOLIS, MD, Troy, Mich.

Low testosterone is the hallmark of hypogonadism. Hypogonadism results from dysfunction anywhere along the hypothalamic-pituitarytestis axis and is referred to as primary when the defect is at the level of the testes, secondary when abnormal pituitary function results in inadequate gonadotropic stimulation of the testes, and tertiary when the defect is at the level of the hypothalamus. Through a complex feedback loop, primary hypogonadism should result in elevated levels of LH and FSH. Similarly, tertiary hypogonadism leads to low levels of LH and FSH. If the LH and FSH are truly normal, both primary and tertiary hypogonadism are very unlikely. In contrast, secondary hypogonadism can frequently manifest with low testosterone levels and “inappropriately normal” LH and FSH levels.

You have already ruled out hyperprolactinemia and thyroid disease,

but if you think the onset was postpubertal (normal testes size), consider hemochromatosis, pituitary macroadenomas, and medication effect as well. Despite your patients’ insistence that they don’t use supplements, I would not rule out the possibility of occult use of anabolic steroids, especially in otherwise healthy, muscular young men. If workup remains unrevealing, consider enlisting the help of an endocrinologist.—Daniel G. Tobin, MD (158-8)

PEDAL CRACKING For the past three years in the early spring, a woman aged 25 years woman has experienced cutaneous cracking on both feet. Her feet are raw, and there is some bleeding.

Itching that starts before the cracks appear becomes pain that impedes walking. In addition, vesicles on the index fi nger as well as on the sole and heel have appeared prior to each episode of cracking. Two days of silver sulfadiazine (Silvadene) with dressings helped. The patient has just started a decreasing course of prednisone (60 mg daily for seven days, then 40 mg for two days, etc.). She washes her feet three to four times a day. Another physician previously diagnosed eczema, but I am also considering dyshidrosis.—GENNARO M. POLVERINO, MD, Monroeville, Pa. Dyshidrosis, a form of eczema, is certainly a possibility. However, I would recommend patch testing to rule out an allergic contact dermatitis and a KOH preparation to rule out a dermatophyte infection.

© The New Yorker Collection 2011 from cartoonbank.com. All Rights Reserved.

According to its 2011 Clinical Practice Recommendations, the American Diabetes Association recommends an HbA1C goal of <7.0, so this patient is certainly at goal for diabetes (Diabetes Care. 2011;34:11S-61S; available at care.diabetesjournals.org/ content/34/5/e53.long, accessed November 15, 2011). The key, however, is not to get the patient to goal with insulin therapy, but to get him or her to goal while avoiding significant hypoglycemia.

Hypoglycemia is the biggest dose-limiting factor for insulin therapy and a major safety risk for patients on insulin. As a patient gets closer to normal glucose readings on insulin therapy, the more likely it is that he or she will flirt with hypoglycemia more often. It also sounds like this patient might have hypoglycemic unawareness (loss of the autonomic nervous system symptoms of hypoglycemia) until the sugars are dangerously low. When this happens, reset the goal sugars to a higher range so symptoms of hypoglycemia can re-emerge.

Frequent hypoglycemia can significantly decrease quality of life, and clinicians can help by dropping insulin doses to avoid hypoglycemia.

This may mean settling for a slightly higher HbA1c, such as 7.2, but results in much improved safety for the patient.—Kathy Pereira, MSN, FNP-BC, assistant professor, co-coordinator, family nurse practitioner program, Duke University School of Nursing, Durham, N.C. (158-7)

“Maybe you can talk him down.”

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2011 97

Advisor Forum RUDE AWAKENINGS VIA MIGRAINE Several of my patients complain of being awakened by migraines in the early morning hours. Prophylactic medications are not warranted because of the infrequency of events (once every couple of months). Since the headache is full-blown when the patient becomes aware of it, abortive medications have been ineffective. How should these patients be managed?—JAN TIVEL, ARNP, FNP, Mount Vernon, Wash.

© ISM / PHOTOTAKE

Keep a careful record of the events preceding the headache. Did the patient drink alcohol the night before or get too much or not enough sleep? What foods were eaten the day before? Infrequent earlymorning migraine is likely due to a trigger. Regarding treatment, abortive medications are often still the best solution but may need to be repeated after 30-60 minutes for maximum effect.—Sherril Sego, FNP-C, DNP (158-11) Dyshidrosis is caused by excessive sweat production on the soles.

If the diagnosis is dyshidrosis, I would recommend topical steroids and moisturization. Irritant avoidance and decreased exposure to water would also be beneficial. If these steps are not successful, topical phototherapy would be an option to consider.—Jeffrey Weinberg, MD (158-9)

CLINICAL PEARLS

DIFFERENCES IN THYROID TESTS When screening for thyroid disease, why is a thyroxine (T4) test usually ordered along with a thyroid-stimulating hormone (TSH) test? Isn’t the TSH alone sufficient?—MELISSA PFITZER, PA-C, Southport, N.C.

A VISUAL HYPERTENSION WARNING After capturing an elevated BP reading, place the stethoscope tube over the patient’s antecubital area and explain, “Your vein under the skin here is approximately this big, and the blood is moving too fast. When it moves through tiny tubes like the veins in your kidneys, eyes, and brain, the blood is moving even faster and could blow out the tubing.” The conversation then moves to adherence to antihypertensive medication.—VALERIE ARMSTRONG, NP, Jacksonville, Fla. (158-12)

If elevated TSH levels are found, the next step is measurement of total T4 and binding proteins. Thyroxine is highly protein-bound, but the levels of binding proteins can vary in disease states. Free T4 assays measure unbound hormone, but these levels can be unreliable in severe illness. Free-thyroid hormone levels can be estimated by calculating the percentage of available thyroid-hormone binding sites or by measuring the concentration of thyroid-binding globulin.

Sustained rising TSH levels characterize primary hypothyroidism.

Early in the disease, as the TSH rises, T4 is converted to triiodothyronine (T3) more readily than usual to maintain T3 levels. Thus, early hypothyroid patients have an elevated TSH, normal to low T4, and normal T3. Elevated TSH with normal free hormone (T4 ) likely indicates mild or subclinical disease. For a thorough review of thyroid laboratory values, visit emedicine.medscape.com/ article/122393-workup (accessed November 15, 2011).—Claire Babcock O’Connell, MPH, PA-C (158-10)

PREVENTING DIARRHEA AFTER ESOPHAGEAL RECONSTRUCTION I work in a thoracic surgery program that includes patients who have recently undergone esophageal reconstruction.

Occasionally, these patients will experience post-vagotomy syndrome, which causes frequent bouts of liquid diarrhea, especially after eating. Despite changes in diet, the diarrhea may persist. These patients often respond to OTC loperamide (Imodium) in pill or liquid form. The instructions are followed as per the medication insert with one exception – the loperamide is taken 20 minutes before eating, beginning with breakfast, and not after the bowel movement. This slows the transit time down prior to eating and allows the patient to decrease the number of bowel movements and enjoy the meal.—KIM QUINN, CRNP, Baltimore (158-13)

98 THE CLINICAL ADVISOR • DECEMBER 2011 • www.ClinicalAdvisor.com

SPRAY TOWARD THE EARS TO AVOID A BLOODY NOSE When prescribing a steroid nasal spray, instruct the patient to angle the applicator toward the ipsilateral ear once inserted into the nose. This will prevent the medication from being sprayed onto the highly vascular nasal septum and prevent the annoying side effect of a bloody nose that occasionally accompanies the use of these medications.—MELISSA DONAIS, RN, FNP-BC, Andover, Mass. (158-15)

SIZE UP, NOT DOWN, WHEN CHOOSING A CATHETER FOR A MAN When a male patient is in need of a catheter, “Bigger is better for boys.” For example, if a patient has known benign prostatic hyperplasia and you try an 18F catheter without luck, go a size or two bigger rather than smaller. The larger catheter is stiffer and can pass through the prostatic urethra more easily.—CHARLENE KREIENSIECK, PA-C, Laconia, N.H. (158-16)

ABSTINENCE IS FREE, HEALTHY, AND EFFECTIVE When discussing sex with adolescents, you can be honest and still promote abstinence as an option (“Preventing teen pregnancy: Emphasize honesty over abstinence,” posted October 12, 2011). Ask broad general questions before moving on to specifics and exploring for more details, depending on the nature of the patient’s concerns. No judgments should ever be passed, of course, but keep in mind that one in five teens has a sexually transmitted infection, and pregnancy does happen when you engage in sexual intercourse. I tend to listen, provide the likely scenario of certain actions, assess the teen’s thought process, and then give a gentle reminder that abstinence is the easiest way to prevent disease spread and pregnancy. It is a free and healthy option with no side effects. That is honesty.—MARK ANDERSON, Springfield, Mich.

My objective was to emphasize the importance of talking to teens and young adults before they become sexually active and promoting abstinence for all the reasons Mr. Anderson lists. But abstinenceonly education has not been proven effective. We do adolescents a disservice by not educating them honestly about contraception and counseling them on “side effects” of sexual activity beyond pregnancy and disease. Most teens know that pregnancy can be prevented, but they have no idea of the impact that sexual activity can have on their future.—Robyn Carlisle, MSN, CNM, WHNP (158-18) ■

A RECIPE FOR REGULARITY This is a recipe to prevent constipation. Combine 16 oz of unsweetened applesauce, one cup of ground flaxseeds, four cups of all-bran cereal, and 16 oz of prune juice with pulp.

Mix everything together, and store in the refrigerator. The mixture will last about one month. I recommend using four tablespoons daily. Believe it or not, it’s a tasty addition to oatmeal, smoothies, and vanilla yogurt.—PRISCILLA MERRILL, FNP-BC, Newmarket, N.H. (158-17)

YOUR COMMENTS Editor’s note: These comments were written in response to a post in The Waiting Room, our collection of expert blogs. To read more, visit the website at www.ClinicalAdvisor.com/blog. www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2011 99

© The New Yorker Collection 2011 from cartoonbank.com. All Rights Reserved.

TIMELY REMINDER TO KEEP STRETCHING Getting patients to perform stretching exercises for minor rehabilitation was a problem until I came up with the 30-3030-30 plan. This routine involved stretching for 30 seconds every 30 minutes, 30 times a day, for 30 days. I tell the patient to think of it as a reminder to stretch every time the clock is on the hour or half-hour.—TERRENCE MOREHOUSE, PA-C, Schertz, Tex. (158-14)

Stat Consult

A quick review of common conditions, using the best global evidence

Description

Celiac disease

• Malabsorption syndrome related to immune reaction to gluten in diet. Also referred to as celiac sprue or gluten intolerance.

ICD-9 codes

• 579.0 celiac disease Epidemiology

BY BRIAN RANDALL, MD

Dr. Randall is a clinical editor for DynaMed (www.ebscohost.com/ dynamed), a database of comprehensive updated summaries covering more than 3,200 clinical topics, and Assistant Clinical Professor of Family Medicine at Tufts University School of Medicine.

Photomicrograph showing complete atrophy of the duodenal villi.

• Celiac disease may be more common than recognized.

• Almost 1% of the Western population is estimated to have celiac disease.

• Peak incidence occurs in adults who are aged 40-50 years.

• Celiac disease is more common in women than in men (3.33:1) Causes

• Thought to be attributable to — Genetics — Toxic effect of gluten/gliadin (gliadin is a glycoprotein component of gluten) — Immune reaction (antibody to gluten/ gliadin) Pathogenesis

• Gluten is found in most food products that contain wheat, barley, and rye, so it is widely prevalent in typical diets.

• Effects on intestinal mucosa — Villi become blunted or flat — Crypts hypertrophy — Increased numbers of intraepithelial lymphocytes, plasma cells, and lymphocytes in lamina propria Risk factors

© ISM / PHOTOTAKE

• Family history of celiac disease • Diabetes mellitus type 1 Complications

• Collagenous sprue • Intestinal ulcers or strictures Continues on page 104

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2011 103

Stat Consult • Nutritional complications — Malabsorption — Vitamin D deficiency — Osteomalacia/rickets ■ Short stature ■ Iron-resistant anemia • Delayed puberty • Low bone mineral density and bone mineral content • Malignancy (e.g. gastrointestinal cancer, non-Hogkin lymphoma) Associated conditions

• Dermatologic conditions (e.g. dermatitis herpetiformis, xerosis, keratosis pilaris) • Immunologic conditions — Immunoglobulin (Ig)A deficiency — Common variable immunodeficiency • Rheumatologic conditions — Sjögren syndrome — Rheumatoid arthritis • Gastrointestinal conditions — Esophagitis — Microscopic colitis and irritable bowel syndrome — Association between celiac disease and primary biliary cirrhosis is controversial.

• Endocrine conditions — Thyroid disease in children — Osteoporosis — Diabetes mellitus type 1 • Neurologic disorders (e.g. hypotonia, developmental delay, learning disorders, headache, attention-deficit hyperactivity disorder) • Down syndrome • IgA nephropathy • Social phobia and depression History

• • • • •

Chronic diarrhea Foul-smelling stools (pale, bulky, frothy, floating) Abdominal bloating and pain Vomiting and weight loss Weakness, fatigue

Physical Exam

• In infants — Growth retardation — Failure to thrive — Irritability

• In children — Short stature — Delayed puberty • Most patients are thin • Dermatologic findings such as xerosis or keratosis pilaris • Abdominal distention may occur Making the diagnosis

• A presumptive diagnosis is based on a combination of clinical presentation and positive serology (tissue transglutaminase or antiendomysial antibody tests).

• Distal duodenal biopsy is needed to confirm diagnosis.

• All initial serology testing and biopsies should be performed before starting gluten restriction.

Rule out

• Infection — Rotavirus gastroenteritis — Giardiasis • Immunologic conditions — Allergic enterocolitis (milk protein allergy, soy allergy, rice allergy) — Breast milk intolerance — Collagenous colitis • Malabsorption — Lactose intolerance — Tropical sprue — Pancreatic insufficiency — Crohn’s disease • Microscopic colitis • Lymphoma Testing to consider

• Serologic testing — IgA tissue transglutaminase antibody (tTG) — IgA antiendomysial antibody (EMA) • If antibody testing is positive, confirm with distal duodenal biopsy.

— Positive findings on biopsy include: ■ Villous atrophy ■ Flattening of mucosa ■ Lymphocytes and plasma cells in lamina propria ■ Increased mitoses in crypts • If negative IgA tTG or IgA EMA and celiac disease is still suspected — Serum IgA level (if selective IgA deficiency, immunoglobulin G [Ig]G, tTG or IgG EMA can be used)

104 THE CLINICAL ADVISOR • DECEMBER 2011 • www.ClinicalAdvisor.com

Continues on page 106

Stat Consult — HLA genetic testing (absence of DQ2 or DQ8 alleles rules out celiac disease) — Upper intestinal endoscopy and distal duodenal biopsy if otherwise warranted • Testing for nutritional deficiencies (hemoglobin, iron, folate, calcium, vitamin D) • Radiographic studies are not necessary for celiac disease, but may be used to rule out other diagnoses.

Treatment overview

Additional considerations

• Refer patient to experienced dietitian • Refer patient to support group • In patients with newly diagnosed celiac disease who also have anxiety and depression, adding psychological support when starting a gluten-free diet is associated with lower rates of depression after six months.

• Gluten-free camp attendance reported to improve quality of life in children with celiac disease Follow-up

• Monitor patients for improved symptoms in response to a gluten-free diet (expected after six to 12 months) • Monitor dietary compliance • Check bone mineral density to assess for osteoporosis. ■

© The New Yorker Collection 2011 from cartoonbank.com. All Rights Reserved.

• Lifelong gluten-free diet recommended — Avoid all foods containing wheat, rye, and barley gluten — Avoid all foods containing oats and lactose initially — Avoid beers, lagers, ales, and stouts — Other foods that may include gluten include dextrins, malt, and caramel coloring.

— Beware of gluten in medications, and in food additives, emulsifiers, and stabilizers.

— Wheat flour may be used in many prepared foods including canned products, salad dressings, and ice creams.

— Use only rice, corn, maize, buckwheat, potato, soybean, or tapioca flours, meals, or starches.

— Look for foods with the gluten-free symbol.

— Try wheat starch with gluten removed, oats, and lactose after diagnosis is established.

• The amount of gluten that causes symptoms varies among patients with celiac disease.

• Strict adherence to a gluten-free diet for more than five years may reduce risk for non-Hodgkin lymphoma.

• Oats in diet appear safe in controlled trials, but some patients may have oat intolerance and commercial oats are often contaminated with gluten.

• Treat nutritional deficiencies with special attention to iron, folate, and vitamin B12.

• Addition of budesonide to a gluten-free diet may improve symptoms in patients with celiac disease with malabsorption • Limited evidence for immunosuppression therapy (e.g. azathioprine, infl iximab, cyclosporine) for refractory celiac disease

“We laugh, but it’s a mirthless laugh.”

106 THE CLINICAL ADVISOR • DECEMBER 2011 • www.ClinicalAdvisor.com

Test your clinical acumen with our monthly quiz

CME Dermatology Clinic CE

■ LEARNING OBJECTIVES: To increase awareness of dermatologic conditions, their diagnosis, and up-to-date treatment.

■ COMPLETE THE POSTTEST: Page 137

■ ADDITIONAL CME/CE: Pages 67, 131

CASE #1

Vesicular eruption coupled with fever WILLIAM S. GILLEN AND JULIA R. NUNLEY, MD

A man aged 42 years presented with complaints of a tender, rapidly spreading rash that began on his upper lip two days earlier. Except for allergic rhinitis, childhood asthma, and moderately severe atopic dermatitis, he was in good health. His dermatologist had discussed starting systemic immunotherapy because the man was currently using a topical steroid as well as a topical immune modulator daily on his face to control his eczema. The patient appeared ill with a fever of 102.1°F. Examination revealed erythema with discrete punched-out erosions on his cheeks and upper lip. Submandibular and anterior cervical lymphadenopathy was present.

What is your diagnosis? Turn to page 108

CASE #2

Depigmented area surrounding a mole KERRI ROBBINS, MD

A man aged 26 years presented to the dermatology clinic for a general skin examination. He was specifically concerned about a mole that had been present for a number of years. The mole had recently developed a depigmented halo. No pain or pruritus was reported. The man had not had any trauma to the area. Physical examination revealed a 5-mm melanocytic nevus with regular borders and no color variegation. This nevus was surrounded by a 3-mm depigmented halo. A similar nevus was appreciated on the man’s right lower back.

What is your diagnosis? Turn to page 109 www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2011 107

CME CE

CASE #1

Dermatology Clinic

Eczema herpeticum

The patient’s history of atopy, requiring daily topical immunosuppressant therapy, along with the characteristic punched-out eroded lesions developing rapidly in association with fever and lymphadenopathy, should raise the concern for the diagnosis of eczema herpeticum, a potentially serious complication of herpes simplex virus (HSV) infection. More common in children with severe atopic dermatitis,1 this infection can occasionally be seen in adults.

In children, eczema herpeticum typically presents with the primary HSV-1 infection; a history of a recent cold sore from a parent or care provider can often be obtained.2 In adults, the associated HSV infection may be either primary or recurrent. Although HSV-1 is the more common culprit, cases have been attributed to HSV-2 as well. Prompt diagnosis is important because of the potential for serious complications: Although the condition may be mild and transient, it may also be associated with keratoconjunctivitis, which can result in blindness, and viremia with meningitis/ encephalitis, which may be fatal, especially in infants.2 The classic presentation of eczema herpeticum is that of a child with a history of eczema previously well controlled, who is brought in because of an unusually severe flare that is unresponsive to topical corticosteroids. If a history of a recent episode of herpes labialis in a parent or daycare worker can be obtained, the diagnosis is fairly straightforward.2 A child with uncomplicated atopic dermatitis tends to be moderately fussy, but those with eczema herpeticum are systemically ill with high fever and adenopathy.2 Clinically, grouped lesions, papules, or vesicles typically found on an erythematous base eventually umbilicate and evolve into pustules over several days.2 Some lesions may coalesce to form characteristic hemorrhagic ulcers with scalloped borders. The face is the most commonly affected area, but any skin surface with significant eczema is at risk of involvement; the infection may spread to intact skin as well.

The rapidity of disease progression is partially attributed to the impaired epidermal barrier function associated with the pathogenesis of atopic dermatitis, as well as immunologic impairment from topical or systemic immunosuppressive agents.3 Viremia with systemic spread of infection to various organ systems can cause great morbidity and may be fatal.2

Any suspicion of ocular involvement requires prompt evaluation by an ophthalmologist to ameliorate risk of blindness.

Recurrence of eczema herpeticum is uncommon and generally less severe, especially in children, where it is usually associated with the primary HSV infection.

The diagnosis of eczema herpeticum is mainly clinical and requires a high index of suspicion; however, clinicians should attempt to confirm the diagnosis with laboratory tests. Of the many options available, none is perfect.4 Viral culture has been considered the gold standard for confirmation, but timing of the culture and strict requirements for handling the sample impact the test’s sensitivity. A Tzanck smear demonstrating multinucleated giant cells on microscopy may be useful for rapid diagnosis early on. Obtain samples

Grouped lesions, papules, or vesicles found on an erythematous base will umbilicate and evolve into pustules over several days. from the base of a freshly uncovered vesicle; this test is less reliable after lesions have evolved to pustules or ulcers. Direct fluorescent antibody staining and polymerase chain reaction may also be used to confirm diagnosis, but the sensitivity and specificity for these tests have not been well studied, and they are not readily available in all clinical settings.2,4 A comparable pathologic and morphologic pattern can develop in individuals with pre-existing skin diseases other than eczema that make them similarly susceptible to HSV infection. The term Kaposi’s varicelliform eruption is used to encompass all of these HSV-infected conditions.5 Mycosis fungoides, ichthyosis vulgaris, pemphigus, other primary blistering disorders, and severe burns can each predispose a person to develop this type of herpetic infection.5 Kaposi’s varicelliform eruption is especially difficult to discern in burn lesions since such lesions typically form crusts as well.

Burn lesions should be monitored for peripheral vesiculation, which raises the suspicion for HSV. Given its association with a higher mortality rate, bacterial superinfection is also of great concern in cases of eczema herpeticum or Kaposi’s varicelliform eruption.6 A large percentage of patients with moderate-to-severe atopic dermatitis are chronically colonized with pathogenic strains of Staphylococcus aureus.3 Other pathogens associated with super infection include Streptococcus and Pseudomonas species.6 Secondary impetiginization of eczema herpeticum—manifesting with

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a characteristic honey-colored crust—in a patient who is no longer febrile should not be interpreted as a systemic infection or significant cellulitis. Use skin and blood cultures to guide antibiotic treatment in patients with eczema herpeticum suspected of having a superinfection.2 Treat adult patients with an appropriate antiviral agent administered either orally or intravenously for at least one week. Discuss suppressive antiviral therapy, especially in an individual who has frequent HSV outbreaks or is on systemic immune suppression.3 In the pediatric population, eczema herpeticum is considered a true emergency.2,3 Hospital admission with at least 24 to 48 hours of IV antiviral therapy is necessary, followed by continuous oral antiviral treatment at a therapeutic dose for at least one week and a three- to six-month course of suppressive therapy. 2,3 Further questioning of this patient established a history of recurrent herpes labialis; the diagnosis of HSV-1 was confimed with a culture. He was treated with valacyclovir (Valtrex) 1 gm b.i.d. for 10 days plus topical mupirocin (Bactroban, Centany) applied t.i.d. The man’s systemic symptoms resolved quickly, and the lesions healed over the ensuing weeks. He has experienced no recurrence while maintaining suppressive antiviral therapy. ■ Mr. Gillen is a fourth-year medical student at Medical College of Virginia Hospitals, Virginia Commonwealth University, in Richmond, where Dr. Nunley is a professor of dermatology. Neither author has any relationship to disclose relating to the content of this article.

References 1 Shiohara T, Sato Y, Takahashi R, et al. Increased susceptibility to cutaneous viral infections in atopic dermatitis: the roles of regulatory T cells and innate immune defects. Curr Probl Dermatol. 2011;41:125-135.

2. Mackley CL, Adams DR, Anderson B, Miller JJ. Eczema herpeticum: a dermatologic emergency. Dermatol Nurs. 2002;14:307-310, 323.

3. Kress DW. Pediatric dermatology emergencies. Curr Opin Pediatr.

2011;23:403-406.

4. Cohen PR. Tests for detecting herpes simplex virus and varicella-zoster virus infections. Dermatol Clin. 1994;12:51-68.

5. Nath AK, Sori T, Thappa DM. A case series of Kaposi’s varicelliform eruption in dermatology in-patients in a tertiary-care centre. Indian J Dermatol. 2011;56:110-115. Available at www.ncbi.nlm.nih.gov/pmc/ articles/PMC3088919/.

6. Brook I. Secondary bacterial infections complicating skin lesions.

J Med Microbiol 2002;51:808-812. Available at jmm.sgmjournals.org /content/51/10/808.long.

All electronic documents accessed November 15, 2011.

CASE #2

Halo nevus

Halo nevi have been around for centuries, but it was not until 1916 that the condition entered the medical field. The lesion was originally described as “leukoderma acquisita centrifugum.” It has been reported that less than 1% of individuals younger than age 20 years have halo nevi.1 The median age of onset is 15 years; however, there have been cases of patients as old as age 42 years. Halo nevi affect all races and sexes equally. Individuals with halo nevi tend to have an overall increased number of melanocyctic nevi. Approximately 20% of patients with halo nevi will also have vitiligo.1 The path for nevus cell destruction is not well known, but both cellular and humoral immunologic factors have been examined. There are two main theories regarding the basis for the development of the halo of depigmentation in halo nevi. The first—and most widely accepted—posits that a physical, chemical, or other event causes a nonspecific change to a nevomelanocyte.2 The body then directly mounts a cell-mediated and/or humoral response to this change. An autoimmune pathogenesis, such as that seen with vitiligo, has also been theorized.2 The second theory suggests that an immunologic response is mounted against an antigenically altered nevus, which shows tumor progression (dysplasia).2 The response is the same as that seen with tumorigenesis.

Copeman et al were the first to show that the human body has antibodies against melanoma cells.2 Individuals with conventional nevi do not have these antibodies; however, people with primary melanoma who have not developed metastases do. On examination of lymphocytes taken from individuals with halo nevi and melanoma, cytotoxicity was shown toward melanoma cells.3 It is not known whether these observations are important in the pathogenesis of halo nevi or whether they are a secondary effect that stems from the underlying pathogenesis. The central nevus in halo nevi is associated with an infiltrate of scattered macrophages, lymphocytes, and CD4 (helper) and CD8 (cytotoxic) T-cells.

The peripheral white halo has little infiltrate, and the pathogenesis for its formation is not well known. The destruction of melanocytes in the depigmented zone is secondary to the diffusion of an unknown cytotoxic factor.4 A halo nevus is unique in its appearance. Centrally, it has a melanocytic nevus that may be flat or raised and dark-brown

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CME CE

Dermatology Clinic

to pink in color. The nevus may be anywhere from 3 to 6 mm in diameter with consistent and well-defi ned borders.5 The color will also be homogenous across the nevus.

Occasionally, the nevus will have scale or crusting on the surface. Just prior to the development of the halo, the area surrounding the nevus may become erythematous. The halo is appreciated as a well-circumscribed, depigmented area that typically measures a few millimeters in diameter. Its borders are usually symmetric, but may also be in the shape of an oval.6 Use a Wood’s lamp or dermoscope if a more thorough clinical examination of the halo is needed.

Persons with halo nevi should have a fullbody skin exam to evaluate for vitiligo and evidence of dysplastic nevi or melanoma.

Halo nevi may be found anywhere on the body, but most are concentrated on the upper back.2 Individuals with one halo nevus should be carefully examined for more, as anywhere from 25% to 50% will have additional lesions.2 A biopsy of a halo nevus in an early stage will show a dense inflammatory infi ltrate penetrating nests of nevus cells in the upper dermis and at the epidermal-dermal junction.7 This correlates clinically with the central nevus.

The halo will reveal a noticeable reduction of melanin and will have little to no inflammation. In the later stages of the lesion, nevus cells are decreased and will be absent in some instances.

All melanocytic proliferations associated with halos are in the differential diagnosis, including blue nevi, Spitz nevi, primary melanoma, atypical melanocytic nevi, and congenital nevi. Other non-melanocytic lesions that are associated with halos—such as dermatofibromas, flat warts, basal cell carcinoma, lichen planus, psoriasis, and seborrheic keratoses—must also be considered in the differential diagnosis.8 Halo nevi have been erroneously confused with melanoma and have been the source of anxiety for clinicians and patients. To differentiate the two, observe the halo.

In a halo nevus, the depigmented area is symmetrical and has regular borders. With melanoma, the halo is often asymmetrical with irregular borders. However, this is frequently not enough to diagnose the disease properly. The next step is to examine the central nevi. If the nevus is irregular in color, has notched borders, or is larger than a centimeter, melanoma should be suspected.9

Treatment of halo nevi is not necessary. However, persons with halo nevi should have a full-body skin examination to evaluate for vitiligo and any evidence of dysplastic nevi or melanoma.2 Encourage the patient to proactively monitor the lesion and record any changes within the nevus.

If irregularity, bleeding, itching and/or pain develop, the patient should seek a health-care provider to make sure the lesion is not developing into a cutaneous melanoma.9 Halo nevi are asymptomatic and benign in nature. Because they are benign, their prognosis is considered excellent.2 The central nevus may involute over time; if it does not, it is very important to monitor the nevus, as it may start to change. Evolution of the nevus would indicate the possibility of cutaneous melanoma, and the lesion should be removed as soon as possible. The halo often becomes repigmented, but this process may take months to years. Inflammation may occur with crusting in the depigmented zone. Multiple halo nevi may be a sign of an ocular or cutanous melanoma elsewhere on the body, especially in adults.5 All patients are instructed to have regular skin exams.

A full-body skin exam was performed on this patient, and no suspicious nevi were identified. No further treatment was necessary, and regular skin exams were encouraged. ■ Dr. Robbins is a resident in the Department of Dermatology at Baylor College of Medicine in Houston. The author has no relationships to disclose relating to the content of this article.

References 1. Herd RM, Hunter JA. Familial halo naevi. Clin Exp Dermatol. 1998;23:68-69.

2. Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology, 2nd ed., St. Louis, Mo.: Elsevier-Mosby; 2008:1725-1726.

3. Zeff RA, Freitag A, Grin CM, Grant-Kels JM. The immune response in halo nevi. J Am Acad Dermatol. 1997;37:620-624.

4. Patrizi A, Neri I, Sabattini E, et al. Unusual inflammatory and hyperkeratotic halo naevus in children. Br J Dermatol. 2005;152:357-360.

5. Paller AS, Mancini AJ. Hurwitz Clinical Pediatric Dermatology. 3rd ed.

Philadelphia, Pa.: Elsevier Saunders; 2006:215.

6. Habif, TP. Skin Disease: Diagnosis and Treatment. 2nd ed. St. Louis, Mo: Mosby/Elsevier; 2005. Page 465.

7. Elder DE, Elenitsas R, Johnson BL, et al, eds. Lever’s Histopathology of the Skin. 10th ed., Philadelphia, Pa.: Lippincott Williams & Wilkins; 2009:730732.

8. Rapini RP. Practical Dermatopathology. Philadelphia, Pa.: Elsevier Mosby; 2005:266.

9. Fitzpatrick TB, Johnson RA, Wolff K, Suurmond R, eds. Color Atlas and Synopsis of Clinical Dermatology, 5th ed. New York, N.Y.: McGraw-Hill; 2005:170-171.

110 THE CLINICAL ADVISOR • DECEMBER 2011 • www.ClinicalAdvisor.com

Clinical Challenge Respiratory distress and pronounced muscular weakness signal trouble EUGENE WONG, MD, JEFFREY REYES, PA, AND JONATHAN RIEBER, MD

A father is rushed to the emergency department after ingestion of a foreign, powderlike substance.

Mr. S was brought to the emergency department (ED) by ambulance after a presumed suicide attempt.

Earlier in the day, he had an argument with his 13-year-old daughter, who was threatening to hurt herself after being bullied at school.

When questioned in the ED, Mr. S admitted to drinking three 12-oz cans of beer and ingesting four packets of a substance known to be rat poison just prior to arrival. During preliminary examination, Mr. S complained of shortness of breath, dizziness, and excess secretions in his mouth. He displayed fecal and urinary incontinence, and muscular spasms in his abdomen and both legs.

CASE #1

1. HISTORY The patient denied any prior psychiatric history, other drug use, or active suicidal ideation. He also claimed to have no history of chest pain, alcohol withdrawal, or seizures. Medical history was significant for alcohol use (a minimum of two 6-packs of beer every weekend). Mr. S was hospitalized for pancreatitis in 2002 and a subsequent cholecystectomy.

© ISTOCKPHOTO.COM / CATHERINE YEULET

2. EXAMINATION

Patient with suspected poisoning is treated immediately by emergency staff, as signs of toxicity are already present.

Vital signs in the ED were as follows: temperature 36.7, BP 125/93, heart rate 56, respiratory rate of 16 beats per minute, and oxygen saturation was 87% on room air. Head exam was notable for pinpoint pupils; there was noticeable hypersalivation. Lungs were clear. Heart sounds were normal. Abdomen was mildly distended and tender to palpation in epigastrium. Extremities were warm and without edema. Calf muscle fasciculations were noted bilaterally.

3. LABORATORY RESULTS ECG showed sinus rhythm at a rate of 68 with no ischemic changes. QTc was 433 msec.

Continues on page 112

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Clinical Challenge WBC was 14,800/uL with hemoglobin 16.6 g/dL. International normalized ratio was 0.91. Liver panel showed aspartate transaminase 33 units/L, alanine aminotransferase 84 units/L, and alkaline phosphatase 80 units/L. Urine toxicology screen was notable for amphetamines. Alcohol level was 23 mg/dL. Chest x-ray was unremarkable.

Taking a detailed history and recognition of the physical symptoms of cholinergic crisis are most important in diagnosis, as toxicology screens will be of little utility.1 Many chemical agents have a characteristic petroleum or garlic-like odor. The clinical features of cholinergic excess— best remembered by the mnemonic SLUDGE (Salivation, Lacrimation, Urination, Defecation, Gastrointestinal Distress, Emesis) or DUMBELS (Diarrhea, Urination, Miosis, Bradycardia, Emesis, Lacrimation, Salivation)— should raise the question of organophosphate poisoning.1 Children present differently from adults, with the most common manifestations being seizures (in 22% -25%), and mental status changes including lethargy and coma (in 54% -96%) one study noted.2 Every attempt should be made to identify the toxic agent.

When diagnosing, laboratory tests are generally not helpful. RBC acetylcholinesterase and plasma pseudocholinesterase levels will be depressed, if these tests are available.

Therefore, it is important to administer treatment prior to laboratory confi rmation of toxicity. Chest radiographs may reveal pulmonary edema. Sinus tachycardia is the most common finding seen on ECG, although sinus bradycardia with PR prolongation can develop secondary to increased parasympathetic activation.

5. TREATMENT The case was immediately discussed with the New York City Poison Control Center. Recommendation was to administer IV atropine intermittently until secretions improved. Mr. S was given a total of 14 mg atropine and 1 g IV pralidoxime (2-PAM), which resulted in rapid improvement in secretions and respirations. No activated charcoal was given.

The patient was admitted to intensive care.

After admission, the patient was seen by psychiatry and inpatient psychiatric treatment was recommended. Mr. S did not require any additional atropine or 2-PAM. Severe organophosphosphate and carbamate poisoning is a medical emergency. Treatment for such patients includes

© MEHAU KULYK / PHOTO RESEARCHERS, INC.

4. DIAGNOSIS

A colored MRI scan of the brain showing the neurologic damage (enlarged fluid-filled ventricles [at center] and clefts) that can occur from prolonged exposure to organophosphates

airway management, including oxygen and intubation in patients with excessive secretions.3 Succinylcholine should not be used when performing rapid sequence intubation as it is metabolized by acetylcholinesterase, leading to prolonged neuromuscular blockade/paralysis.3 In addition, continuous cardiac monitoring and pulse oximetry should be employed.3 Hypotension, if it occurs, can be managed with fluid resuscitation—either normal saline or lactate ringer’s solution.

Specific antidotes such as a muscarinic antagonist (usually atropine) and 2-PAM should be used. In cholinergic excess, atropine competes with acetylcholine, and should be administered until signs and symptoms are resolved.

Atropine can be given usually in doses of 2 mg to 5 mg at a time with no ceiling; it should be uptitrated until respiratory secretions are eliminated and there is adequate oxygenation, and this means up to hundreds of milligrams can be given over the next several days.

Since it works on the nicotinic receptors that atropine does not bind to, 2-PAM is used. Typically, we administer about 2 g for the average adult over 30 minutes in addition to atropine to provide antidotal effects. The clinical response to 2-PAM is quite variable and not well understood.

Health-care providers should utilize personal protective equipment such as neoprene gloves and gowns. Hydrocarbons

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can penetrate nonpolar substances such as latex and vinyl.

Discarding patient clothes and cleansing the patient with soap and water is typically recommended.

Gastric lavage is not performed, as this is only helpful if it can be completed within one hour after ingestion and only after other measures such as atropine and 2-PAM are given.3 For clinicians, this window of opportunity is narrow, and also involves risk of aspiration. Activated charcoal (again, after initial resuscitation and treatment with atropine and 2-PAM) can be given, but this too is only shown to be useful within the first hour after ingestion, with questionable effectiveness thereafter.The standard dose is 1 g/kg (maximum dose 50 g). However, the risk is high for aspiration and would not be indicated if the patient is not awake enough or not intubated.

Remember that emergent consultation with the U.S. Poison Control Network can and should be obtained. The national number, 800.222.1222, will automatically reroute all calls to a local poison-control center.

6. DISCUSSION Organophosphate compounds have been widely used in domestic and industrial settings for the past 50 years.

Organophosphates are commonly used in insecticides, such as the widely available, commercial “RAID” insecticides.

Organophosphate use has decreased in the last 10 to 20 years, in part due to the development of carbamate insecticides such as “Tres Pasitos.”

Organophosphate poisoning is the most prominent cause of death from acute poisoning worldwide with an estimated 300,000 deaths occurring globally, particularly in rural Asia.4 In developed countries such as the United States, by comparison, more then 8,000 patients sought medical attention in 2008 for organophosphate poisoning and fewer than 15 died.1 Organophosphates are nerve agents developed in the 1940’s, which became widely known when the Japanese religious cult, Aum Shinrikyo, carried out a sarin gas attack in 1995 in the Tokyo subway system. That incident killed 13 people, severely injuring 50 others, and caused temporary vision problems for nearly a thousand people in the vicinity.

Organophosphate agents bind to and disable acetylcholinesterase, the enzyme responsible for breaking down acetylcholine.3 Specifically, they phosphorylate the serine hydroxyl group of acetylcholinesterase. This results in a buildup of acetylcholine leading to recognizable symptoms (SLUDGE or DUMBELS). Recognizing these signs

of cholinergic excess is important in diagnosis. Also seen are nicotinic effects such as muscular fasciculations from acetylcholine stimulation at the neuromuscular junctions, and respiratory depression. Central nervous system effects can include anxiety, confusion, tremors, seizures, coma, and ataxia, as there are nicotinic and muscarinic receptors in the brain. Death generally results from acute respiratory failure, but can also result from cardiovascular collapse due to an unclear mechanism.

The mechanism of carbamate compounds is identical to that of organophosphate agents except that carbamate compounds are transient cholinesterase inhibitors, which spontaneously hydrolyze from the cholinesterase enzymatic site within 48 hours. Cases involving carbamate toxicity tend to have shorter duration, but similar mortality rate.

Intermediate syndrome affects 10% to 40 % of individuals poisoned by organophosphates within 24 to 96 hours after exposure. It is characterized by acute respiratory failure and by muscle weakness primarily in the facial, neck, and proximal limb muscles. Decreased deep tendon reflexes and cranial nerve palsies are typically noted.

Organophosphate-induced delayed polyneuropathy can occur two to three weeks after exposure to certain agents, such as chlorpyrifos. Distal muscle weakness with relative sparing of the neck muscles, cranial nerves, and proximal muscle groups is noted, and recovery may take up to one year. Transient, painful stocking glove paresthesias followed by a symmetrical motor polyneuropathy (flaccid weakness of the lower extremities that ascends to include the upper extremities) can manifest as well. Carbamate compounds are rarely associated with this entity.

“Tres Pasitos,” the brand name of the substance Mr. S ingested, is an illegally imported and highly-toxic rodenticide. It is produced and sold legally only in the Dominican Republic and in Mexico. “Tres Pasitos” literally translated signifies the three little steps that a rat can take before death after ingestion.

The main ingredient in this poison is aldicarb, a potent carbamate insecticide that causes fulminant cholinergic crisis. Aldicarb causes reversible carbamylation of the acetylcholinesterase enzyme.The poison consists of brown grains

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www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2011 113

Clinical Challenge and is typically sold in unlabeled plastic bags. It can easily be mistaken for food. An alert from the New York City Department of Health and Mental Hygiene publicized that there were 15 reported cases of human poisoning by Tres Pasitos in 2006.5 The alert also noted one in three households in New York City used pesticides that may be hazardous to human health.

7. SUMMARY Organophosphate and carbamate poisoning is a worldwide health problem. In the developed world, such poisoning is usually the result of accidental ingestion or suicide attempts. This case has relevance for emergency clinicians as carbamates and organophosphates are still used as insecticides and emergency clinicians working in rural areas may have to evaluate and manage patients with these types of poisoning.

Recognizing and diagnosing toxicity is clinically essential for patient survival. The case presented here illustrates the need to recognize signs and symptoms of cholinergic excess, which may involve the autonomic nervous system, neuromuscular junction, and central nervous system. If there are strong indications or suspicion of acute poisoning, the patient should be treated immediately.

Acute toxicity is a medical emergency. All symptomatic patients should receive oxygen, atropine, 2-PAM, and benzodiazepine. Further research is needed to demonstrate how these therapies should be best administered. ■

When a patient falls, the pain indicates dislocation LEAH FAVRET, MSN, CNP

Tenderness over the hypothenar eminence, swelling, and limited flexion also suggest fracture.

Dr. Wong is an attending physician in internal medicine at New York-Presbyterian-The Allen Hospital. Mr. Reyes is a physician assistant at New York-Presbyterian-The Allen Hospital. Dr. Rieber is a gastroenterologist in private practice in New York City.

References 1. Senanayake N, Karalliedde, L. Neurotoxic effects of organophosporus

FIGURE 1. Radiograph showing a lateral view of the right hand

insecticides. An intermediate syndrome. N Engl J Med. 1987;316:761-763.

2. Zweinter RJ, Ginsburg CM. Organophosphate and carbamate poisoning in infants and children. Pediatrics. 1988;81:121-126.

3. Eddleston M, Buckley NA, Eyer P, Dawson AH. Management of acute organophosphorus pesticide poisioning. Lancet. 2008;371:597-607.

4. Abou-Donia MB. Organophosphorus ester-induced chronic neurotoxicity. Arch Environ Health. 2003;58:484-497.

5. The City of New York Department of Health and Mental Hygiene. 2006 Alert #38: Poisonings associated with the use of an illegal pesticide Tres

After sustaining a fall the previous evening, Mr. A, a man aged 29 years, presented to the emergency department (ED). He reported that he tripped over his child’s toy and that his right hand broke his fall; he landed on a clenched fist. On presentation, Mr. A described pain in the right hand, and there was significant ecchymosis, and swelling. The patient reported no other injuries as a result of the fall.

CASE #2

Pasitos, in New York City. November 1, 2006.

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Continues on page 119

Clinical Challenge 1. HISTORY Mr. A did not report any personal or family medical history.

He did report a nicotine habit, having smoked one pack of cigarettes per day for 12 years, but denied any alcohol or drug use. He also reported that he does not take any daily prescription or OTC medication.

2. EXAMINATION Mr. A had significant edema on the dorsum and palmar surfaces of his right hand, mostly over the carpals and proximal metacarpals. There was ecchymosis noted over the palm, thenar, and hypothenar eminences. The patient had limited range of motion in his metacarpophalangeal joints due to pain. There was also very limited right-wrist flexion and extension due to pain and sw elling. Mr. A was most tender over the hypothenar eminence. The right radial pulse was +2 and regular. Capillary refi ll of the right fi ngers was brisk. Mr. A had good sensation of all righthand fi ngers, dorsum, and palm of the hand. He denied any numbness or tingling.

3. DIFFERENTIAL DIAGNOSIS

FIGURE 2. Thin-cut CT scan showing an acute comminuted fracture of the hamate with displacements of the fragments

There are several diagnoses to consider with this injury and physical presentation: (1) metacarpal head, neck, or shaft fractures; (2) carpal fractures; (3) joint dislocation; (4) hand contusion; (5) tendon, ligament, or muscle injury; (6) cellulitis; or (7) deep tissue infection. Given this particular history, infection is unlikely. However, if the fall resulted in an open wound, infection is possible. The physical exam in this case did not show any evidence of open injury, erythema, warmth, or fluctuance, so infection was ruled out. Metacarpal and carpal fracture, and joint dislocations should be suspected with this mechanism of injury and physical presentation. Plain radiographs should be obtained to evaluate for this. Fractures of the fifth metacarpal neck, usually referred to as a Boxer’s fracture, are a very common injury with punch or axial force injuries.1 If hand and wrist x-rays are negative for bone or joint injury or contusion, then tendon, ligament, or muscle injuries should be considered.

4. RADIOGRAPHIC FINDINGS Initially, x-rays of the right wrist and hand (taken while the patient was in the ED) were read as negative for any acute

fracture, bone, joint, or soft tissue abnormality (Figure 1).

Still, the ED physician suspected a fracture, due to the amount of swelling and ecchymosis present in Mr. A’s hand. A CT scan was obtained to rule out any occult fracture or bone/joint injury. The scan showed evidence of an acute, comminuted, coronal fracture of the hamate with displacement of the fragments of about 5 mm (Figure 2).

The hand surgeon consulted also noted dislocation of the right fourth and fi fth carpometacarpal (CMC) joints.

5. DIAGNOSIS AND TREATMENT Mr. A was diagnosed with right fourth and fifth CMC dislocations with fracture of the hamate. The patient was placed in a plaster volar splint in the ED and instructed to follow up in the hand trauma clinic in two days time.

Repeat x-rays obtained at the follow-up visit demonstrated no further dislocation or displacement of the fracture.

Treatment options were discussed with the patient and surgical fi xation was scheduled. Mr. A underwent open reduction and internal fi xation of his hamate fracture and CMC dislocations (Figure 3). Fracture fi xation was

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2011 119

Clinical Challenge obtained using two lag screws, and the CMC dislocations were reduced using three Kirschner wires.

6. DISCUSSION The hamate is a carpal bone that has two components: the body and the hook. It articulates with the triquetrum proximally and the fourth and fi fth metacarpals distally.2 Hamate fractures consist of about 2% of all carpal fractures.1 Of the two types of hamate fractures, the most common are fractures of the hook. Because of the hook’s prominence on the palmar side of the hand, it is often fractured as a result of a direct blow during sports that involve holding a racket or a bat. The second, and much less common, type is a fracture through the body of the hamate. 3 The fractures of the body of the hamate have been further divided into four major categories: proximal pole fractures, medial tuberostiy fractures, sagittal oblique fractures, and dorsal coronal fractures.1 Coronal fractures usually occur from a punch injury or from axial forces being applied through the metacarpals.1, 3 Dislocation or subluxation of the CMC joint may also be associated with this fracture type.2

Coronal fractures of the hamate are frequently missed on plain radiographs because the hamate-metacarpal joint is not easily seen. There can also be overlap of the carpals and metacarpals in anteroposterior and lateral views.2 CT scan should be considered in cases where there is swelling, ecchymosis, or continued hand and/or wrist pain with negative x-rays.4 Delays in the diagnosis and treatment of these types of fractures can lead to poor outcomes, including nonunion, residual subluxation of the CMC joints, pain, arthritis, loss of grip strength, and decreased range of motion in the wrist.1,5 Non-displaced fractures of the body of the hamate can be treated conservatively with splinting/casting and immobilization.1 Open reduction and internal fi xation is usually the best treatment option for displaced fractures of the hamate body. This includes fracture fi xation with compression screws or an H-plate, as well as joint stabilization using Kirschner wires if necessary.1 In the primary-care setting, if a patient presents with a painful and swollen hand, diagnoses to consider would be fracture; dislocation; hand contusion; ligament; tendon, or muscle injury; cellulitis; or deep tissue infection.

A thorough history is needed to determine the mechanism of injur y and to determine whether or not an open injur y occurred. This includes puncture wounds, animal/insect bites, lacerations, or abrasions.

Prompt hand-surgery referral is appropriate for any suspected fractures, dislocations, tendon or ligamentous injury, or hand infection to ensure proper management and to prevent complications. ■ Ms. Favret works as a nurse practitioner with the hand and orthopedic trauma service at Riverside Methodist Hospital in Columbus, Ohio.

References 1. Wolfe SW, Hotchkiss RN, Pederson WC, Kozin SH. Green’s Operative Hand Surgery. 6th ed. Philadelphia, Pa.: Elsevier;2011:686-689.

2. Ebraheim NA, Skie MC, Savolaine ER, Jackson TW. Coronal fracture of the body of the hamate. J Trauma. 1995;38:169-174.

3. Bucholz RW, Court-Brown CM, Heckman JD, Tornet P. Rockwood and Green’s Fractures in Adults. 7th ed. Philadelphia, Pa.: Lippincott Williams & Wilkins;2010:807-808.

4. Gella S, Borse V, Rutten E. Coronal fractures of the hamate: are they rare or rarely spotted? J Hand Surg Eur Vol. 2007;32:721-722.

FIGURE 3. X-ray showing fracture fixation with insertion of two lag screws across the fracture to provide compression

5. Wharton DM, Casaletto JA, Choa R, Brown DJ. Outcome following coronal fractures of the hamate. J Hand Surg Eur Vol. 2010;35:146-149.

120 THE CLINICAL ADVISOR • DECEMBER 2011 • www.ClinicalAdvisor.com

Derm Dx

EXCLUSIVE TO THE WEB

INTERACT WITH YOUR PEERS by viewing the images and offering your diagnosis and comments. To post your answer, obtain more clues, or view similar cases, visit ClinicalAdvisor.com/DermDx. Learn more about diagnosing and treating these conditions, and see how you compare with your fellow colleagues.

A rash response to southern exposure A 28-year-old Hispanic man presented with a 10-month history of a pruritic rash on his right flank. One to two weeks prior to noticing the lesion, he had spent five days in Arizona. According to the patient, the lesion had doubled in size in one month. He had no history of similar rashes or lesions and was otherwise healthy.

WHAT IS YOUR DIAGNOSIS?

• • • •

Histoplasmosis Keloids Squamous cell carcinoma Coccidioidomycosis

● See the full case at ClinicalAdvisor.com/DermDx1211A

Black discoloration of the hands A 75-year-old man develops black discoloration on his palms after peeling apples for pies with a carbon knife and a stainless steel peeler.

WHAT IS YOUR DIAGNOSIS?

• • • •

Riehl’s melanosis Acanthosis nigricans Post-inflammatory hyperpigmentation Black dermographism

● See the full case at ClinicalAdvisor.com/DermDx1211B

Have you missed any recent Derm Dx cases? Go to ClinicalAdvisor.com/DermDx for a complete archive of past quizzes as well as additional images of last month’s other cases.

Anogenital ulcerations in a female with HIV/AIDS

124 THE CLINICAL ADVISOR • DECEMBER 2011 • www.ClinicalAdvisor.com

Multiple spreading skin lesions in a Vietnam War veteran

LEGAL ADVISOR CASE

© ISTOCKPHOTO.COM / ABEL MITJA VARELA

A detailed history is crucial Postsurgical complications from a routine procedure and lack of follow-up land a clinician in court.

BY ANN W. LATNER, JD

Dr. T, age 41 years, was a urologist in a small Midwestern community who had opened his solo practice two years earlier. With no shortage of patients, he felt positive about his professional prospects and his future. His family was young—the twin boys were aged 9 years and in fourth grade—and Dr. T and his wife were enjoying the best part of life. He could never have imagined that an encounter with one patient would change all that.

It all started very routinely, when a new patient came in for a consult. Mr. K was a terrificlooking 53-year-old man who was referred to Dr. T by his general practitioner. Mr. K was the epitome of fitness; he was trim and appeared to be the picture of health. Mr. K, too, had a relatively young family—a wife and four teenage daughters. As a new patient, Mr. K was asked to fill out standard medical-information forms and to provide his insurance information upfront.

Once in the examination room, Dr. T introduced himself, skimmed the documents, and asked his new patient what brought him here.

Mr. K told the urologist that he was itchy and

Patients do not always divulge all the facts of their medical history during examination.

How do you get them to fill in the gaps?

uncomfortable in his private area. In the course of evaluation, Dr. T surveyed a penile lesion that the patient said he’d had for months and it just would not heal. When asked, Mr. K reported having periodic irritations and occasional lesions in his genital area. Dr. T recommended circumcision, and scheduled Mr. K for the procedure the following week.

The surgery was successfully performed in Dr. T’s office under local anesthesia. As the procedure was routine, Dr. T anticipated a positive outcome and he told Mr. K that the lesion would clear up gradually, and that in the future he would be free of these wounds.

However, serious complications soon developed. Over the next three months, Mr. K returned to Dr. T’s office on several occasions complaining of a host of issues: general pain and pain upon urination, an unusual protrusion on Cases presented are based on actual occurrences.

Names of participants and details have been changed.

Cases are informational only; no specific legal advice is intended. Persons pictured are not the actual individuals mentioned in the article.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2011 125

LEGAL ADVISOR the shaft, other urination difficulties, and a reported lack of sensation. The patient was distraught.

With Dr. T providing no definitive answers, Mr. K abruptly switched physicians.

Mr. K’s new urologist, Dr. G, reviewed his history and listened to his complaints. Dr. G then immediately ordered a urinalysis. The workup revealed that Mr. K was diabetic and that his insulin levels were not in check. When Dr. G asked Mr. K if he was aware that he had diabetes, the patient answered, “Yes.” “Do you take any medication to manage your diabetes?”

Dr. G asked.

“No, Doctor. I just try, for the most part, to eat healthy and exercise,” Mr. K replied.

“Did you tell your previous doctor that you were diabetic?” the physician queried.

“He never asked me,” Mr. K said.

“And did Dr. T do a urinalysis before your circumcision?”

Dr. G followed up.

“No, he didn’t,” replied Mr. K. “Should he have?”

Dr. G then explained that uncontrolled diabetes was probably responsible for his poor recovery from surgery. Diabetic patients, Dr. G informed, typically experience impaired wound healing and are at increased risk for infection. This probably explains the urinary tract infection that ensued postprocedure and was the cause of the genital discomfort.

Armed with this information, Mr. K sought the advice of counsel. He hired a crackerjack attorney who filed suit against Dr. T, alleging negligence for failing to order a urinalysis prior to surgery. In addition, Dr. T was brought up on charges that he failed to properly treat the patient postoperatively.

At trial, an expert witness for the plaintiff testified that, in his opinion, Dr. T should have performed a urinalysis prior to performing circumcision. “Uncontrolled diabetes in surgical patients is fraught with many, many complications— including fungal infections,” the expert stated. In failing to check for diabetes, a common ailment in this country, Dr. T did not give the appropriate standard of care to Mr. K. Doing so might have averted many of Mr. K’s postoperative difficulties.

After the expert testimony, Mr. K was called to the stand to relate the pain and discomfort he had suffered. He related, candidly, that he and his wife were still unable to engage in marital relations, and that he was experiencing urinary difficulties to this day.

Mr. K’s attorney then asked him about the medical form he fi lled out at first visit to Dr. T’s office.

“Did you put down that you have diabetes when you filled out the form?” the attorney asked.

“No, I did not,” stated Mr. K. “May I ask why?” counsel continued.

“Because nowhere on the form did it ask if I had diabetes,” said Mr. K. “I never saw the word ‘diabetes’ on there.”

Dr. T’s attorney hit this hard during cross-examination.

After grilling Mr. K about the fact that he had diabetes and chose to manage it conservatively, the lawyer broached

Diabetic patients typically experience impaired wound healing and are at increased risk for infection. the question of why Mr. K did not explicitly state that he was diabetic when asked to do so on the medical history form.

“The information form you received—and filled out—in Dr. T’s office that morning asked explicitly if you had any medical conditions, didn’t it?” the lawyer asked.

“Yes,” Mr. K said sheepishly.

“And it asked you to write down what, if any, those medical conditions were. There was—and correct me if I’m wrong— a set of blank lines underneath the question for writing in responses, wasn’t there?” the defense continued.

“I guess so,” Mr. K admitted.

“Did you believe that diabetes didn’t fall in that category— that it wasn’t a medical condition?”

“I guess I expected it would ask specifically about things like that,” Mr. K added.

After a set of impassioned closing arguments by both attorneys, the jury retired to deliberate. While the plaintiff ’s attorney emphasized the pain and discomfort his client suffered and was still suffering, the defense pointed to Mr. K’s failure to disclose a vital piece of information pre-surgery.

A mere six hours later the jury returned. They found Dr. T to be 54% at fault for Mr. K’s injuries, and Mr. K 46% responsible for his situation. Damages were set at $2 million, but Mr. K received only $1.08 million.

Legal background

The jury was instructed to weigh all aspects of the evidence before coming to a verdict. Since it was clear that the actions of both parties contributed to Mr. K’s postsurgical

126 THE CLINICAL ADVISOR • DECEMBER 2011 • www.ClinicalAdvisor.com

DEXILANT MAY BE COADMINISTERED WITH PLAVIX (CLOPIDOGREL BISULFATE) DEXILANT had no clinically important impact on the antiplatelet activity of Plavix in healthy volunteers • DEXILANT 60 mg had no clinically important effect on Plavix active metabolite pharmacodynamics, as measured by Inhibition of Platelet Aggregation (IPA) and inhibition of Platelet Reactivity Index (PRI) based on co-primary endpoints of the study1 • DEXILANT minimally reduced the mean AUC of the Plavix active metabolite by 9%2 • No dose adjustment of Plavix is necessary when administered with an approved dose of DEXILANT2 % decrease in IPA* with Plavix and PPI coadministration (day 9)1

DATA PRESENTED AT ACC IN 2011

% decrease in inhibition of PRI with Plavix and PPI coadministration (day 9)1

0.2% 4.7% 22.5% DEXILANT 60 mg (n=40) Positive control (omeprazole 80 mg; n=40)

35.2%

Results from a Phase 1, open-label, multiple-dose, 2-period crossover study (n=160) of CYP2C19 extensive metabolizers receiving once-daily administration of Plavix 75 mg alone or concomitantly with 1 of 4 PPI agents. Co-primary endpoints were the measurement of PRI and Mean Platelet Aggregation (MPA) of Plavix + PPI vs Plavix alone. *ADP 5μM.

Conclusions of comparative efficacy cannot be drawn from this information.

The clinical relevance of these data has not been established.

Indications for DEXILANT • Healing all grades of erosive esophagitis (EE) for up to 8 weeks • Maintaining healing of EE and relief of heartburn for up to 6 months • Treating heartburn associated with symptomatic non-erosive gastroesophageal reflux disease (GERD) for 4 weeks

Please see accompanying brief summary for DEXILANT. References: 1. Data on file, Takeda Pharmaceuticals North America, Inc. 2. DEXILANT (dexlansoprazole) package insert, Takeda Pharmaceuticals America, Inc. DEXILANT and DEXILANT (with design) are trademarks of Takeda Pharmaceuticals North America, Inc., registered in the U.S. Patent and Trademark Office and used under license by Takeda Pharmaceuticals America, Inc. Plavix is a registered trademark of sanofi-aventis Corp.

©2011 Takeda Pharmaceuticals North America, Inc. LPD-01954 11/11 Printed in U.S.A.

141862_a01 Takeda 11/14/11

Important Safety Information • DEXILANT is contraindicated in patients with known hypersensitivity to any component of the formulation. Hypersensitivity and anaphylaxis have been reported with DEXILANT use.

• Symptomatic response with DEXILANT does not preclude the presence of gastric malignancy.

• Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.

• Hypomagnesemia has been reported rarely with prolonged treatment with PPIs. • Most commonly reported adverse reactions were diarrhea (4.8%), abdominal pain (4.0%), nausea (2.9%), upper respiratory tract infection (1.9%), vomiting (1.6%), and flatulence (1.6%).

• Do not co-administer atazanavir with DEXILANT because atazanavir systemic concentrations may be substantially decreased. DEXILANT may interfere with absorption of drugs for which gastric pH is important for bioavailability (e.g., ampicillin esters, digoxin, iron salts, ketoconazole).

Patients taking concomitant warfarin may require monitoring for increases in international normalized ratio (INR) and prothrombin time.

Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Concomitant tacrolimus use may increase tacrolimus whole blood concentrations.

CONTRAINDICATIONS DEXILANT is contraindicated in patients with known hypersensitivity to any component of the formulation. Hypersensitivity and anaphylaxis have been reported with DEXILANT use [see Adverse Reactions].

WARNINGS AND PRECAUTIONS Gastric Malignancy Symptomatic response with DEXILANT does not preclude the presence of gastric malignancy.

Bone Fracture Several published observational studies suggest that proton pump inhibitor (PPI) therapy may be associated with an increased risk for osteoporosisrelated fractures of the hip, wrist or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines [see Adverse Reactions].

Hypomagnesemia Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI. For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically [see Adverse Reactions].

ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of DEXILANT was evaluated in 4548 patients in controlled and uncontrolled clinical studies, including 863 patients treated for at least 6 months and 203 patients treated for one year. Patients ranged in age from 18 to 90 years (median age 48 years), with 54% female, 85% Caucasian, 8% Black, 4% Asian, and 3% other races. Six randomized controlled clinical trials were conducted for the treatment of EE, maintenance of healed EE, and symptomatic GERD, which included 896 patients on placebo, 455 patients on DEXILANT 30 mg, 2218 patients on DEXILANT 60 mg, and 1363 patients on lansoprazole 30 mg once daily.

Most Commonly Reported Adverse Reactions The most common adverse reactions (≥2%) that occurred at a higher incidence for DEXILANT than placebo in the controlled studies are presented in Table 2.

Table 2: Incidence of Adverse Reactions in Controlled Studies Placebo DEXILANT DEXILANT DEXILANT Lansoprazole 30 mg 60 mg Total 30 mg (N=896) (N=455) (N=2218) (N=2621) (N=1363) % % Adverse Reaction % % % Diarrhea 2.9 5.1 4.7 4.8 3.2 Abdominal Pain 3.5 3.5 4.0 4.0 2.6 Nausea 2.6 3.3 2.8 2.9 1.8 Upper Respiratory 0.8 2.9 1.7 1.9 0.8 Tract Infection Vomiting 0.8 2.2 1.4 1.6 1.1 Flatulence 0.6 2.6 1.4 1.6 1.2 Adverse Reactions Resulting in Discontinuation In controlled clinical studies, the most common adverse reaction leading to discontinuation from DEXILANT therapy was diarrhea (0.7%).

Other Adverse Reactions Other adverse reactions that were reported in controlled studies at an incidence of less than 2% are listed below by body system: Blood and Lymphatic System Disorders: anemia, lymphadenopathy; Cardiac Disorders: angina, arrhythmia, bradycardia, chest pain, edema, myocardial

infarction, palpitation, tachycardia; Ear and Labyrinth Disorders: ear pain, tinnitus, vertigo; Endocrine Disorders: goiter; Eye Disorders: eye irritation, eye swelling; Gastrointestinal Disorders: abdominal discomfort, abdominal tenderness, abnormal feces, anal discomfort, Barrett’s esophagus, bezoar, bowel sounds abnormal, breath odor, colitis microscopic, colonic polyp, constipation, dry mouth, duodenitis, dyspepsia, dysphagia, enteritis, eructation, esophagitis, gastric polyp, gastritis, gastroenteritis, gastrointestinal disorders, gastrointestinal hypermotility disorders, GERD, GI ulcers and perforation, hematemesis, hematochezia, hemorrhoids, impaired gastric emptying, irritable bowel syndrome, mucus stools, oral mucosal blistering, painful defecation, proctitis, paresthesia oral, rectal hemorrhage, retching; General Disorders and Administration Site Conditions: adverse drug reaction, asthenia, chest pain, chills, feeling abnormal, inflammation, mucosal inflammation, nodule, pain, pyrexia; Hepatobiliary Disorders: biliary colic, cholelithiasis, hepatomegaly; Immune System Disorders: hypersensitivity; Infections and Infestations: candida infections, influenza, nasopharyngitis, oral herpes, pharyngitis, sinusitis, viral infection, vulvovaginal infection; Injury, Poisoning and Procedural Complications: falls, fractures, joint sprains, overdose, procedural pain, sunburn; Laboratory Investigations: ALP increased, ALT increased, AST increased, bilirubin decreased/increased, blood creatinine increased, blood gastrin increased, blood glucose increased, blood potassium increased, liver function test abnormal, platelet count decreased, total protein increased, weight increase; Metabolism and Nutrition Disorders: appetite changes, hypercalcemia, hypokalemia; Musculoskeletal and Connective Tissue Disorders: arthralgia, arthritis, muscle cramps, musculoskeletal pain, myalgia; Nervous System Disorders: altered taste, convulsion, dizziness, headaches, migraine, memory impairment, paresthesia, psychomotor hyperactivity, tremor, trigeminal neuralgia; Psychiatric Disorders: abnormal dreams, anxiety, depression, insomnia, libido changes; Renal and Urinary Disorders: dysuria, micturition urgency; Reproductive System and Breast Disorders: dysmenorrhea, dyspareunia, menorrhagia, menstrual disorder; Respiratory, Thoracic and Mediastinal Disorders: aspiration, asthma, bronchitis, cough, dyspnoea, hiccups, hyperventilation, respiratory tract congestion, sore throat; Skin and Subcutaneous Tissue Disorders: acne, dermatitis, erythema, pruritis, rash, skin lesion, urticaria; Vascular Disorders: deep vein thrombosis, hot flush, hypertension Additional adverse reactions that were reported in a long-term uncontrolled study and were considered related to DEXILANT by the treating physician included: anaphylaxis, auditory hallucination, B-cell lymphoma, bursitis, central obesity, cholecystitis acute, dehydration, diabetes mellitus, dysphonia, epistaxis, folliculitis, gout, herpes zoster, hyperlipidemia, hypothyroidism, increased neutrophils, MCHC decrease, neutropenia, rectal tenesmus, restless legs syndrome, somnolence, tonsillitis.

Other adverse reactions not observed with DEXILANT, but occurring with the racemate lansoprazole can be found in the lansoprazole prescribing information, ADVERSE REACTIONS section.

Postmarketing Experience The following adverse reactions have been identified during post-approval of DEXILANT. As these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System Disorders: autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura Ear and Labyrinth Disorders: deafness Eye Disorders: blurred vision Gastrointestinal Disorders: oral edema, pancreatitis General Disorders and Administration Site Conditions: facial edema Hepatobiliary Disorders: drug-induced hepatitis Immune System Disorders: anaphylactic shock (requiring emergency intervention), exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis (some fatal) Metabolism and Nutrition Disorders: hypomagnesemia, hyponatremia Musculoskeletal System Disorders: bone fracture Nervous System Disorders: cerebrovascular accident, transient ischemic attack Renal and Urinary Disorders: acute renal failure Respiratory, Thoracic and Mediastinal Disorders: pharyngeal edema, throat tightness Skin and Subcutaneous Tissue Disorders: generalized rash, leucocytoclastic vasculitis DRUG INTERACTIONS Drugs with pH-Dependent Absorption Pharmacokinetics DEXILANT causes inhibition of gastric acid secretion. DEXILANT is likely to substantially decrease the systemic concentrations of the HIV protease inhibitor atazanavir, which is dependent upon the presence of gastric acid for absorption, and may result in a loss of therapeutic effect of atazanavir and the development of HIV resistance. Therefore, DEXILANT should not be co-administered with atazanavir.

141862_b02 Takeda 11/17/11

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION DEXILANT (dexlansoprazole) delayed-release capsules for oral use INDICATIONS AND USAGE DEXILANT is indicated for: • the healing of all grades of erosive esophagitis (EE) for up to 8 weeks • maintaining healing of EE and relief of heartburn for up to 6 months • the treatment of heartburn associated with symptomatic non-erosive gastroesophageal reflux disease (GERD) for 4 weeks.

CLINICAL PHARMACOLOGY Pharmacodynamics Serum Gastrin Effects The effect of DEXILANT on serum gastrin concentrations was evaluated in approximately 3460 patients in clinical trials up to 8 weeks and in 1023 patients for up to 6 to 12 months. The mean fasting gastrin concentrations increased from baseline during treatment with DEXILANT 30 mg and 60 mg doses.

In patients treated for more than 6 months, mean serum gastrin levels increased during approximately the first 3 months of treatment and were stable for the remainder of treatment. Mean serum gastrin levels returned to pre-treatment levels within one month of discontinuation of treatment.

Enterochromaffin-Like Cell (ECL) Effects There were no reports of ECL cell hyperplasia in gastric biopsy specimens obtained from 653 patients treated with DEXILANT 30 mg, 60 mg or 90 mg for up to 12 months.

During lifetime exposure of rats dosed daily with up to 150 mg per kg per day of lansoprazole, marked hypergastrinemia was observed followed by ECL cell proliferation and formation of carcinoid tumors, especially in female rats [see Nonclinical Toxicology].

Effect on Cardiac Repolarization A study was conducted to assess the potential of DEXILANT to prolong the QT/QTc interval in healthy adult subjects. DEXILANT doses of 90 mg or 300 mg did not delay cardiac repolarization compared to placebo. The positive control (moxifloxacin) produced statistically significantly greater mean maximum and time-averaged QT/QTc intervals compared to placebo.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic potential of dexlansoprazole was assessed using lansoprazole studies. In two 24-month carcinogenicity studies, SpragueDawley rats were treated orally with lansoprazole at doses of 5 to 150 mg per kg per day, about 1 to 40 times the exposure on a body surface (mg/m2) basis of a 50 kg person of average height [1.46 m2 body surface area (BSA)] given the recommended human dose of lansoprazole 30 mg per day.

Lansoprazole produced dose-related gastric ECL cell hyperplasia and ECL cell carcinoids in both male and female rats [see Clinical Pharmacology].

In rats, lansoprazole also increased the incidence of intestinal metaplasia of the gastric epithelium in both sexes. In male rats, lansoprazole produced a dose-related increase of testicular interstitial cell adenomas. The incidence of these adenomas in rats receiving doses of 15 to 150 mg per kg per day (4 to 40 times the recommended human lansoprazole dose based on BSA) exceeded the low background incidence (range = 1.4 to 10%) for this strain of rat.

In a 24-month carcinogenicity study, CD-1 mice were treated orally with lansoprazole doses of 15 to 600 mg per kg per day, 2 to 80 times the recommended human lansoprazole dose based on BSA. Lansoprazole produced a dose-related increased incidence of gastric ECL cell hyperplasia.

It also produced an increased incidence of liver tumors (hepatocellular adenoma plus carcinoma). The tumor incidences in male mice treated with 300 and 600 mg lansoprazole per kg per day (40 to 80 times the recommended human lansoprazole dose based on BSA) and female mice treated with 150 to 600 mg lansoprazole per kg per day (20 to 80 times the recommended human lansoprazole dose based on BSA) exceeded the ranges of background incidences in historical controls for this strain of mice.

Lansoprazole treatment produced adenoma of rete testis in male mice receiving 75 to 600 mg per kg per day (10 to 80 times the recommended human lansoprazole dose based on BSA).

A 26-week p53 (+/-) transgenic mouse carcinogenicity study of lansoprazole was not positive.

Lansoprazole was positive in the Ames test and the in vitro human lymphocyte chromosomal aberration assay. Lansoprazole was not genotoxic in the ex vivo rat hepatocyte unscheduled DNA synthesis (UDS) test, the in vivo mouse micronucleus test or the rat bone marrow cell chromosomal aberration test.

Dexlansoprazole was positive in the Ames test and in the in vitro chromosome aberration test using Chinese hamster lung cells. Dexlansoprazole was negative in the in vivo mouse micronucleus test.

The potential effects of dexlansoprazole on fertility and reproductive performance were assessed using lansoprazole studies. Lansoprazole at oral doses up to 150 mg per kg per day (40 times the recommended human lansoprazole dose based on BSA) was found to have no effect on fertility and reproductive performance of male and female rats.

PATIENT COUNSELING INFORMATION To ensure the safe and effective use of DEXILANT, this information and instructions provided in the FDA-approved Patient Information Leaflet should be discussed with the patient.

Inform the patient to watch for signs of an allergic reaction as these could be serious and may require that DEXILANT be discontinued.

141862_c01 Takeda 11/14/11

DEXILANT may interfere with the absorption of other drugs where gastric pH is an important determinant of oral bioavailability (e.g., ampicillin esters, digoxin, iron salts, ketoconazole).

Warfarin Co-administration of DEXILANT 90 mg and warfarin 25 mg did not affect the pharmacokinetics of warfarin or INR [see Clinical Pharmacology].

However, there have been reports of increased INR and prothrombin time in patients receiving PPIs and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.

Patients treated with DEXILANT and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time.

Tacrolimus Concomitant administration of dexlansoprazole and tacrolimus may increase whole blood levels of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.

Clopidogrel Concomitant administration of dexlansoprazole and clopidogrel in healthy subjects had no clinically important effect on exposure to the active metabolite of clopidogrel-induced platelet inhibition. No dose adjustment of clopidogrel is necessary when administered with an approved dose of DEXILANT. USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects Pregnancy Category B. There are no adequate and well-controlled studies with dexlansoprazole in pregnant women. There were no adverse fetal effects in animal reproduction studies of dexlansoprazole in rabbits. Because animal reproduction studies are not always predictive of human response, DEXILANT should be used during pregnancy only if clearly needed.

A reproduction study conducted in rabbits at oral dexlansoprazole doses up to approximately 9 times the maximum recommended human dexlansoprazole dose (60 mg per day) revealed no evidence of impaired fertility or harm to the fetus due to dexlansoprazole. In addition, reproduction studies performed in pregnant rats with oral lansoprazole at doses up to 40 times the recommended human lansoprazole dose and in pregnant rabbits at oral lansoprazole doses up to 16 times the recommended human lansoprazole dose revealed no evidence of impaired fertility or harm to the fetus due to lansoprazole [see Nonclinical Toxicology].

Nursing Mothers It is not known whether dexlansoprazole is excreted in human milk.

However, lansoprazole and its metabolites are present in rat milk following the administration of lansoprazole. As many drugs are excreted in human milk, and because of the potential for tumorigenicity shown for lansoprazole in rat carcinogenicity studies [see Nonclinical Toxicology], a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use Safety and effectiveness of DEXILANT in pediatric patients (less than 18 years of age) have not been established.

Geriatric Use In clinical studies of DEXILANT, 11% of patients were aged 65 years and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified significant differences in responses between geriatric and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Renal Impairment No dosage adjustment of DEXILANT is necessary in patients with renal impairment. The pharmacokinetics of dexlansoprazole in patients with renal impairment are not expected to be altered since dexlansoprazole is extensively metabolized in the liver to inactive metabolites, and no parent drug is recovered in the urine following an oral dose of dexlansoprazole.

Hepatic Impairment No dosage adjustment for DEXILANT is necessary for patients with mild hepatic impairment (Child-Pugh Class A). DEXILANT 30 mg should be considered for patients with moderate hepatic impairment (Child-Pugh Class B). No studies have been conducted in patients with severe hepatic impairment (Child-Pugh Class C).

OVERDOSAGE There have been no reports of significant overdose of DEXILANT. Multiple doses of DEXILANT 120 mg and a single dose of DEXILANT 300 mg did not result in death or other severe adverse events. However, serious adverse events of hypertension have been reported in association with twice daily doses of DEXILANT 60 mg. Non-serious adverse reactions observed with twice daily doses of DEXILANT 60 mg include hot flashes, contusion, oropharyngeal pain, and weight loss. Dexlansoprazole is not expected to be removed from the circulation by hemodialysis. If an overdose occurs, treatment should be symptomatic and supportive.

Advise the patient to immediately report and seek care for any cardiovascular or neurological symptoms including palpitations, dizziness, seizures, and tetany as these may be signs of hypomagnesemia [see Warnings and Precautions].

Advise the patient to tell their health care provider if they take atazanavir, tacrolimus, warfarin and drugs that are affected by gastric pH changes [see Drug Interactions].

Advise the patient to follow the dosing instructions in the Patient Information Leaflet and inform the patient that: • DEXILANT is available as a delayed release capsule.

• DEXILANT may be taken without regard to food.

• DEXILANT should be swallowed whole.

• Alternatively, DEXILANT capsules can be administered as follows: – Open capsule; – Sprinkle intact granules on one tablespoon of applesauce; – Swallow immediately. Granules should not be chewed.

– Do not store for later use.

Distributed by Takeda Pharmaceuticals America, Inc. Deerfield, IL 60015 DEXILANT is a trademark of Takeda Pharmaceuticals North America, Inc. and used under license by Takeda Pharmaceuticals America, Inc. Trademark registered with the U.S. Patent and Trademark office.

All other trademark names are the property of their respective owners. ©2009, 2011 Takeda Pharmaceuticals America, Inc. DEX006 R15_BS Revised: October 2011 L-LPD-1011-2

LEGAL ADVISOR complications, the verdict was split to reflect “comparative negligence” between the two parties.

Comparative negligence is a rule of law used in applicable cases to determine responsibility and damages based on the degree of negligence of every party directly involved. In a situation where each party has some degree of negligence, the responsibility to the other person(s) is reduced by the others’ degree of negligence. In this case, Mr. K was found to be 46% responsible for neglecting to inform Dr. T that he was, in fact, diabetic. His total award is therefore reduced by 46%. Dr. T was found to be 54% comparatively negligent for failing to ascertain (prior to surgery) that Mr. K had diabetes. Thus, Dr. T was responsible for paying 54% of the $2 million award.

Not all states utilize the principle of comparative negligence—and those that do vary in their interpretation of the precept. “Pure” comparative negligence, which was employed

The patient’s failure to disclose a vital piece of information pre-surgery was recognized as fault on his part. in this case, works from the principle that no matter what percentage of fault is attributed to the plaintiff, he or she will collect the remainder of the reward.

“Modified” or “limited” comparative negligence allows for the plaintiff to collect a portion of the reward only if he or she is responsible for less than a certain percent of the blame. This percentage varies from state to state.

Protecting yourself

The fact that the jury found Mr. K to be 46% at fault indicates that jurors expect patients to know that they should alert their clinicians about serious health conditions, such as diabetes. It is understandable that Mr. K was angry and upset by the surgical complications, and that he would want to seek monetary recompense, but clearly he was at fault here too.

Dr. T’s mistake, besides not having a more detailed intake form, was his failure to take a thorough history. He should have spent more time discussing Mr. K’s medical history.

Asking more questions up front might have prompted Mr. K to divulge that he had been diagnosed with diabetes. ■ Ms. Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.

CME CE

Dermatologic Look-Alikes ■ LEARNING OBJECTIVE: To improve the clinician’s ability to distinguish and properly treat dermatologic conditions with similar presentations.

■ COMPLETE THE POSTTEST: Page 137

■ ADDITIONAL CME/CE: Pages 67, 107

Yellow processes on the face NOAH SCHEINFELD, MD, JD

CASE #1

CASE #2

A woman aged 50 years with no significant medical history presented with a yellow plaque on top of her left eyelid. Blood chemistry and lipid tests administered by the woman’s primary-care clinician showed that she was in good health, and she had no systemic complaints.

The yellow plaque and papule did not itch, burn, or hurt. A biopsy of the plaque revealed foam histiocytes in the dermis.

At the same visit, the woman from Case #1 also presented to the dermatology clinic with a yellow papule on her left cheek. A biopsy of the lesion revealed large aggregates of sebaceous glands. No similar lesions on other areas with sebaceous glands (e.g., the chest, breasts, or genitals) were noted. At the end of the visit, the papule was removed with low-voltage electro desiccation and curettage.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2011 131

CME CE

CASE #1

Dermatologic Look-Alikes

Xanthelasma palpebrarum

Xanthelasma (or xanthelasma palpebrarum) is a yellow plaque that occurs on the eyelids. The word is derived from the Greek terms xanthos (yellow) combined with the elasma (beaten metal plate).

The yellow color is a visual manifestation of esterif ied cholesterol in the middle and superficial layers of the dermis (and more rarely in the subcutaneous fat) that has been swallowed by macrophages.

The upper eyelid is more affected than the lower eyelid, and the inner canthus of the eye is more affected than the lateral canthus. The term xanthoma refers to fatty deposits that are histologically the same as xanthelasma but occur off the eyelid. However, a variant system of nosology suggests that xanthelasma may instead be referred to as a xanthoma when becoming larger and nodular, manifesting in tumorous dimension. Xanthelasma is not uncommon and is much more prevalent than xanthoma.

Xanthelasma is usually yellow in color but can appear white, particularly if the epidermis is removed. On palpation, the lesion can be soft or hard. Frequently, xanthelasmas are symmetrical, involving upper and lower and right and left eyelids. Xanthelasmas have a tendency to progress, coalesce, and become permanent. It is thought that xanthelasma occurs on the eyelid because that structure is mechanically stressed and the surrounding is usually in rapid positional flux.

Once formed, xanthelasma typically remains static or increases in size; the lesions rarely disappear spontaneously.

More common in women,1 xanthelasma can manifest at any age. The lesions seem to occur in all groups, and may be more frequent in people of Asian origin and those from the Mediterranean region.1 The mechanism that starts macrophage accumulation, cholesterol uptake, and foam-cell formation in a normolipemic patient following an infl ammatory skin disorder remains undefi ned. It is thought that increased plasma lipid peroxidation (coming from oxidized LDL) could initiate accumulation of cholesterol in macrophages and the transformation to foam cells.

Xanthelasmata are cosmetically unacceptable to most patients. Some note that the lesions obscure vision, but the pupil, sclera, or eyelid are not affected directly.

Some types and cases of xanthoma suggest coincident lipid metabolism disorders (e.g. hyperlipidemia or high blood fats). Half of xanthelasmata are associated with elevated plasma lipid levels.1 Thus, xanthoma can be linked to heart disease, circulatory disease (i.e., atheromatous disease, high lipids), and, occasionally, pancreatitis (acute pancreatitis during hyperlipoproteinemic crisis, aggravation of insulin resistance, and decompensation of type 2 diabetes mellitus). Xanthelasma most likely manifest in patients with type II and type IV hyperlipidemia.1 A study of almost 13,000 people found that individuals with xanthelasma are 12% more likely to suffer from heart disease and more likely to have a heart attack or die within 10 years.2 Treating these conditions can aid in the resolution of the xanthomas.

Xanthelasma presents a wide differential diagnosis that includes: (1) xanthogranulomatous inflammation of the orbit with a prominent population of immunoglobulin (Ig) G4-positive plasma cells, which might be a novel variant of IgG4 sclerosing disease of the orbit; (2) diffuse plane xanthomas are characterized by the presence of yellowish plaques on the eyelids, neck, upper trunk, buttocks, and flexural folds; histology shows foamy histiocytes in the dermis; approximately half of diffuse plane xanthomas are associated with lymphoproliferative disorders; (3) atypical lymphoid hyperplasia; (4) necrobiotic xanthogranuloma; (5) sebaceous hyperplasia; (6) sebaceous carcinoma; and (7) Erdheim-Chester disease.

Treatment of xanthomas is surgical rather than medical.

A variety of options exist for the removal of xanthelasma palpebrarum, including surgical excision, argon and carbon dioxide laser ablation, chemical peeling, electrodesiccation and curettage, and cryotherapy.3 Surgery can involve simple excision, as scarring tends to blend in with the surrounding eyelid wrinkles. Techniques can entail blepharoplasty with extension of the excision and incision parameters. Smaller bulging xanthelasmata may be “uncapped” and excised with a flap that can be replaced and sutured. Another method uses a surgical microscope to undermine between the xanthelasma and the orbicularis oculi with a #11 scalpel blade, raise the

MORE DERMATOLOGY ON THE WEB Test your diagnostic skills. Our FREE archive of Dermatology Clinic and Dermatologic Look-Alikes is now available online at www.ClinicalAdvisor.com/Derm.

132 THE CLINICAL ADVISOR • DECEMBER 2011 • www.ClinicalAdvisor.com

fl ap, carefully remove the xanthelasma bit by b it with microscissors from the reverse side, and then suture the flap with 7-0 nylon.4 There are surgical risks, however. Full-thickness and lower-lid lesions are more complex to remove than thinner upper-lid xanthelasma. Side effects include risk of eyelid retraction and ectropion. An individual who has repeated excision and blepharoplasty should be warned of lagophthalmos secondary to the medial position and absence of medial dermatochalasis. Scar tissue will complicate subsequent surgeries. Xanthelasma can infi ltrate into surgical scars, again complicating repeat surgeries.

Laser ablation is often used to treat xanthelasma. Carbon dioxide5 and argon lasers3 are the most common lasers used. Laser treatment obviates the need for sutures, does not involve bleeding, minimizing issues with hemostasis, and does not involve direct contact with the xanthelasma, allowing for improved visualization, and is a rapid procedure. Scarring and pigment alteration are the chief side effects of laser treatment of xanthelasma.

The 1064-nm Q-switched Nd:YAG laser has also been used to treat xanthelasma.6 This valuable treatment option eliminates lesions rapidly and results in good healing. The absence of any associated skin destruction allows treatment to be repeated when necessary.

Peeling agents are useful for treating xanthelasma when the epidermis of the eye is very thin and the dermis is close to the outside air. Such chlorinated acetic acids as monochloroacetic acid, dichloroacetic acid, and trichloroacetic acid (TCA) precipitate and coagulate proteins and dissolve lipids. These agents have been found to be effective in the removal of xanthelasma.7 Haygood et al deployed ≤0.01 mL of 100% dichloroacetic acid, noting excellent effect and minimal scarring.8 In my experience, 20% -30% TCA is the most widely used type and concentration of acid used in the treatment of this condition.

Electrodesiccation and curettage and cryotherapy can destroy superficial xanthelasmas but may require repeated treatments. Electrodessication and curettage is inexpensive, effective, and does not cause bleeding. While this procedure occasionally leaves some fatty histiocytes behind, it flattens lesions and renders them much more cosmetically acceptable. Cryotherapy may cause scarring and hypopigmentation and is disfavored.

This patient’s yellow plaque and papule were removed with electrodesiccation and curettage. Three days later, the regions had healed, and the patient was happy with the cosmetic results.

CASE #2

Sebaceous hyperplasia

Sebaceous hyperplasia (SH) is the physical manifestation of enlargement of the sebaceous gland to the point where discrete raised yellow aggregations of cells can be visualized. The discrete papules measure 2-3 mm in diameter and have the consistency of flesh, unlike milia or calcinosis cutis, which are hard to the touch. SH most commonly occurs on the face, in particular the forehead and/or cheek. Sebaceous glands are sensitive to androgens, and any hyperplasia is rare in prepubescents. SH is most common in whites and in the middle-aged and elderly.

Focused examination often demonstrates a central hair follicle surrounded by yellowish lobules. Dermoscopy often reveals prominent blood vessels. Although the hyperplastic glands are large, the glands of SH secrete very little sebum. In contrast to normal sebocytes that contain lipids, the hyperplastic sebaceous glands of SH contain small, undifferentiated sebocytes with large nuclei and scant cytoplasmic lipid.

SH has been noted in body areas other than the face, including the areola, chest, mouth, penis, scrotum, and vulva. On the buccal mucosa, SH is referred to as Fordyce spots; SH on the glans penis or clitoris is called Tyson’s glands; SH on the areolae is also known as Montgomery glands, and SH on the eyelids is hyperplasia of the meibomian glands. Intraoral SH has also been noted.

Although the distribution of papules is usually random, SH has been noted in blaschkoid, linear (on the chest and penis), and zosteriform distributions. Bilateral areolar sebaceous hyperplasia in a woman has been noted,9 as has pubertal giant sebaceous hyperplasia over the nose.

Muir-Torre syndrome (MTS) is a genetic disorder characterized by a variety of pathology of the sebaceous gland, including SH as well as sebaceous adenoma, sebaceous epithelioma, or sebaceous carcinoma combined with internal malignancy (usually GI or genitourinary carcinomas). MTS has autosomal dominant pattern of inheritance in 60% of cases with a high degree of penetrance and variable expression.10 The differential for SH includes any process that results in yellowish papules. Specifically, the related condition of juxtaclavicular beaded lines (yellow papules in parallel or rippled distributions on the chest)11 basal cell carcinoma (in particular with sebaceous differentiation), xanthelasma, flat

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2011 133

CME CE

Dermatologic Look-Alikes

warts, epidermodysplasia verruciformis, and epidermal nevus.

In particular, neoplasms of the sebaceous gland (e.g. sebaceous adenoma, seboacanthoma, sebaceous epithelioma, sebaceoma, mantleoma, sebomatricoma, and sebaceous carcinoma) can mimic SH. Preputial ectopic sebaceous glands mimicking molluscum contagiosum12 and giant solitary sebaceous gland hyperplasia clinically simulating epidermoid cyst13 have been reported. Sebaceous trichofolliculoma and trichofolliculoma rare adnexal tumors can resemble SH. Rosacea is closely associated with SH of the discrete type.

Rhinophyma, a key manifestation of rosacea, can be viewed as a variant of SH. Otophyma and blepharophyma, two rarer forms of sebaceous gland hyperplasia-type phymas, can also occur. Histology of the classic type of rhinophyma usually shows the histopathologic features of fully developed

later the area had healed, and the patient was happy with the cosmetic results. ■ Dr. Scheinfeld is an assistant clinical professor of dermatology at Columbia University in New York City, where he has a private practice. The author has no relationships to disclose relating to the content of this article.

References 1. Medscape Reference. Xanthelasma. Available at emedicine.medscape. com/article/1213423-overview.

2. Christoffersen M, Frikke-Schmidt R, Schnohr P, et al. Xanthelasmata, arcus corneae, and ischaemic vascular disease and death in general population: prospective cohort study. BMJ. 2011;343:d5497. Available at www. bmj.com/content/343/bmj.d5497.

3. Basar E, Oguz H, Ozdemir H, et al. Treatment of xanthelasma palpebrarum with argon laser photocoagulation. Argon laser and xanthelasma

Those with limited cases of sebaceous hyperplasia are best treated with lowvoltage electrodesiccation with curettage.

palpebrarum. Int Ophthalmol. 2004;25:9-1.

4. Doi H, Ogawa Y. A new operative method for treatment of xanthelasma or xanthoma palpebrarum: microsurgical inverted peeling. Plast Reconstr Surg. 1998;102:1171-1174.

5. Santaella RM, Ng JD, Wilson DJ. Carbon dioxide laser-induced combustion of extravasated intraocular silicone oil in the eyelid mimicking xan-

rosacea with the presence of prominent SH. Sometimes phymas demonstrate marked dermal thickness, absence of folliculosebaceous structures, sclerotic collagen bundles with large amounts of mucin, and spreading telangiectasia features akin to the elephantiasis caused by chronic lymphedema. Sebaceous gland hyperplasia and senile comedones (Favre-Racouchot syndrome) often manifest in the same patient.

Oztas and colleagues reported on a series of 17 patients with 30 SH lesions, all of which were evaluated dermatoscopically.14 Cumulus sign, crown vessels, and milia-like cysts were detected in 100%, 86.6%, and 53.3% of the lesions, respectively. In 80% of the lesions, a feature with central umbilication surrounded by cumulus sign was observed (the Bonbon toffee sign).

A variety of treatments have been reported for SH, including oral isotretinoin, antiandrogens (in women), electrodesiccation, CO2 laser surgery, cryosurgery, chemical peeling agents (in particular, bichloracetic acid and trichloracetic acid), and shave excision with curettage. Limited cases are best treated with electrodesiccation with curettage. Photodynamic therapy with 5-aminolevulinic acid and a blue light source or intense pulsed-light source has been successful. Premature familial SH has been effectively treated with oral isotretinoin.

This patient’s papules were effectively treated with lowvoltage electrodesiccation with curettage. Three weeks

thelasma. Ophthal Plast Reconstr Surg. 2011;27:e163-e165.

6. Fusade T.Treatment of xanthelasma palpebrarum by 1064-nm Q-switched Nd:YAG laser: a study of 11 cases. Br J Dermatol. 2008;158:84-87.

7. Akhyani M, Daneshpazhooh M, Jafari AK, et al. Koebner phenomenon in xanthelasma after treatment with trichloroacetic acid. Dermatol Online J. 2006;12:12. Available at dermatology.cdlib.org/122/case_presentations/ xanthelasma/toosi.html.

8. Haygood LJ, Bennett JD, Brodell RT. Treatment of xanthelasma palpebrarum with bichloracetic acid. Dermatol Surg. 1998;24:1027-1031.

9. Krisp A, Krause W. Areolar sebaceous hyperplasia. Acta Derm Venereol.

2003;83:61-62.

10. Mercader P. Muir-Torre syndrome. Adv Exp Med Biol. 2010;685:186-195.

11. Finan MC, Apgar JT. Juxta-clavicular beaded lines: a subepidermal proliferation of sebaceous gland elements. J Cutan Pathol. 1991;18:464-468.

12. Piccinno R, Carrel CF, Menni S, Brancaleon W. Preputial ectopic sebaceous glands mimicking molluscum contagiosum. Acta Derm Venereol.

1990;70:344-345.

13. Kudoh K, Hosokawa M, Miyazawa T, Tagami H. Giant solitary sebaceous gland hyperplasia clinically simulating epidermoid cyst. J Cutan Pathol.

1988;15:396-398.

14. Oztas P, Polat M, Oztas M, et al. Bonbon toffee sign: a new dermatoscopic feature for sebaceous hyperplasia. J Eur Acad Dermatol Venereol.

2008;22:1200-1202.

All electronic documents accessed November 15, 2011.

134 THE CLINICAL ADVISOR • DECEMBER 2011 • www.ClinicalAdvisor.com

CE

POSTTEST Expiration date: December 2012

The Nurse Practitioner Associates for Continuing Education (NPACE) is an approved provider of continuing education by the Massachusetts Association of Registered Nurses, Inc. (MARN), an accredited approver by the American Nurses Credentialing Center’s Commission on Accreditation (ANCC).

The Nurse Practitioner Associates for Continuing Education designates this educational activity for a maximum of 1.0 contact hours of credit. Participants should only claim credit commensurate with the extent of their participation in the activity. Posttests must be completed and submitted online. NPs may register at no charge at myCME.com.You must receive a score of 70% or better on each test taken to obtain credit.

CREDITS: 0.5

CREDITS: 0.5

Feature

Dermatology Clinic

Dermatologic Look-Alikes

page 67

page 107

page 131

Urinary incontinence in the older female population

Case #1: Eczema herpeticum

Case #1: Xanthelasma palpebrarum

1. What test can be useful for rapid diagnosis of eczema herpeticum early on? a. Tzanck smear b. KOH preparation c. Wood’s light examination d. Punch biopsy

5. A recent study found that individuals with xanthelasma are 12% more likely to suffer from a. Hypothyroidism b. Pancreatitis c. Metabolic syndrome d. Heart disease

2. What is a characteristic finding of eczema herpeticum? a. Thick plaques with little to no scaling b. Small vesicles in clusters c. Papules and plaques with silvery scales d. Hemorrhagic ulcers with scalloped borders

6. Which therapy for xanthelasma may cause scarring and hypopigmentation? a. Laser ablation b. Chemical peeling agent c. Cryotherapy d. Electrodesiccation

1. Which type of urinary incontinence (UI) is associated with detrusor overactivity? a. Stress UI b. Urge incontinence c. Overflow UI d. Functional UI 2. Owing to its causing chronic cough, which medication is a risk factor associated with UI? a. Angiotensin II receptor blocker b. Calcium channel blockers c. ACE inhibitors d. Beta blockers 3. What is the preferred method of determining postvoid residual urine volume? a. In-out catheterization b. CT scan c. Bladder ultrasound d. X-ray 4. Which lifestyle intervention is used in the treatment of overflow incontinence? a. Pelvic-floor muscle exercises b. Scheduled voiding c. Habit training d. Double-voiding technique

TO TAKE THE POSTTEST please go to ClinicalAdvisor.com/CMEFeatureDec2011

Case #2: Halo nevus 3. Approximately 20% of patients with halo nevi will also have a. Acanthosis nigricans b. Vitiligo c. Melasma d. Tinea versicolor 4. What is the recommended therapy for a halo nevus? a. No treatment necessary b. Cryotherapy c. Surgical excision d. Topical corticosteroids

Case #2: Sebaceous hyperplasia 7. Sebaceous hyperplasia (SH) is referred to as Fordyce spots when located on the a. Areolae b. Buccal mucosa c. Eyelid d. Chest 8. What condition is closely associated with SH? a. Rosacea b. Eczema c. Pityriasis rosea d. Psoriasis

TO TAKE THE POSTTEST please go to ClinicalAdvisor.com/DermDec2011

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2011 137

CME

POSTTEST Expiration date: December 2012

This program has been reviewed and is approved for a maximum of 1 hour of AAPA Category I CME credit by the Physician Assistant Review Panel. Approval is valid for one year from the issue date of December 2011. Participants may submit the self-assessment at any time during that period.

This program was planned in accordance with AAPA’s CME Standards for Enduring Material Programs and for Commercial Support of Enduring Material Programs.

Posttests must be completed and submitted online. PAs may register at no charge at myCME.com. To obtain 1.0 hour of AAPA Category I CME credit, you must receive a score of 70% or better on each test taken.

CREDITS: 0.5

CREDITS: 0.5

Feature

Dermatology Clinic

Dermatologic Look-Alikes

page 67

page 107

page 131

Urinary incontinence in the older female population

Case #1: Eczema herpeticum

Case #1: Xanthelasma palpebrarum

1. What test can be useful for rapid diagnosis of eczema herpeticum early on? a. Tzanck smear b. KOH preparation c. Wood’s light examination d. Punch biopsy

5. A recent study found that individuals with xanthelasma are 12% more likely to suffer from a. Hypothyroidism b. Pancreatitis c. Metabolic syndrome d. Heart disease

2. What is a characteristic finding of eczema herpeticum? a. Thick plaques with little to no scaling b. Small vesicles in clusters c. Papules and plaques with silvery scales d. Hemorrhagic ulcers with scalloped borders

6. Which therapy for xanthelasma may cause scarring and hypopigmentation? a. Laser ablation b. Chemical peeling agent c. Cryotherapy d. Electrodesiccation

1. Which type of urinary incontinence (UI) is associated with detrusor overactivity? a. Stress UI b. Urge incontinence c. Overflow UI d. Functional UI 2. Owing to its causing chronic cough, which medication is a risk factor associated with UI? a. Angiotensin II receptor blocker b. Calcium channel blockers c. ACE inhibitors d. Beta blockers 3. What is the preferred method of determining postvoid residual urine volume? a. In-out catheterization b. CT scan c. Bladder ultrasound d. X-ray 4. Which lifestyle intervention is used in the treatment of overflow incontinence? a. Pelvic-floor muscle exercises b. Scheduled voiding c. Habit training d. Double-voiding technique

TO TAKE THE POSTTEST please go to ClinicalAdvisor.com/CMEFeatureDec2011

Case #2: Halo nevus 3. Approximately 20% of patients with halo nevi will also have a. Acanthosis nigricans b. Vitiligo c. Melasma d. Tinea versicolor 4. What is the recommended therapy for a halo nevus? a. No treatment necessary b. Cryotherapy c. Surgical excision d. Topical corticosteroids

Case #2: Sebaceous hyperplasia 7. Sebaceous hyperplasia (SH) is referred to as Fordyce spots when located on the a. Areolae b. Buccal mucosa c. Eyelid d. Chest 8. What condition is closely associated with SH? a. Rosacea b. Eczema c. Pityriasis rosea d. Psoriasis

TO TAKE THE POSTTEST please go to ClinicalAdvisor.com/DermDec2011

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2011 137

ALTERNATIVE MEDS UPDATE What you should know about the herbs and supplements patients use

By Sherril Sego, FNP-C, DNP. Ms. Sego is a staff clinician at the VA Hospital in Kansas City, Mo., where she practices adult medicine and women’s health. She also teaches at the nursing schools of the University of Missouri and the University of Kansas.

Rose hips

© TED KINSMAN / PHOTO RESEARCHERS, INC.

Despite sounding like an anatomical structure, the term rose hips actually refers to the seed pods of roses. All rose species bear these, but because most rose bushes are trimmed and pruned we rarely see them today. Normally, species of the Rosa canina family will form these small, berry-sized, reddish seed balls after flower petals fall in late summer.1 The seed pods, harvested in the late fall, are prized for their medicinal properties and widely cultivated for their usefulness.1 According to ancient literature, the Chinese, Persians, Romans, and Greeks all used the rose seed pod for a variety of purposes and sometimes called it a “hip” or a “haw.”1

Background Rose hips are particularly high in vitamin C content, and are said to contain 10 to 50 times as much of this nutrient as in a normal orange.1 Historically, the rose was also referred to as the “dog rose” and was so named because ancient lore held that the extract derived from it could cure the bite of a rabid dog.1 The dog rose was extremely popular during World War II.2 The British people were encouraged to gather rose hips to make vitamin C syrup for children to prevent the development of scurvy.2,3 German submarines were sinking most commercial ships carrying imported citrus fruits from the tropics and children were developing nutritional deficiencies as a result.2,3

Science Much of rose hips’ medicinal activity has been credited to its high concentration of vitamin C. Vitamin C is an essential nutrient with specific functions as an enzymatic cofactor

and potent antioxidant. Unprocessed rose hips contain about 1,250 mg/100 g of pure vitamin C.2 In addition, rose hips contain large amounts of polyphenols, which are also known to possess antioxidative properties.2 Rose hips have been studied for their effect on autoimmune diseases such as rheumatoid arthritis. One doubleblinded, randomized controlled trial examined 89 patients with known rheumatoid arthritis. The subjects were given either capsules fi lled with rose hip powder totaling 5 g per day or placebo for six months.4 Outcomes were based on administration of a health-assessment questionnaire administered at baseline and at six months.4 These scores improved in the active-treatment group but declined in the placebo group.4 However, in a meta-analysis of studies on rose hip use, antioxidant and anti-inflammatory actions were verified, but the German Commission E did not recommend their use, largely due to a lack of sufficient data.5

138 THE CLINICAL ADVISOR • DECEMBER 2011 • www.ClinicalAdvisor.com

Continues on page 140

Available at myCME.com/UMDNJ NEW for 2011-2012 To listen on the go, download audio files to your MP3 player or burn them to a CD

PANCE/PANRE

ONLINE REVIEW COURSE All topics on the NCCPA examination blueprint are covered Lectures presented by UMDNJ faculty—more than 27 hours of instruction for 2011-2012 Study at your own pace while earning AAPA Category 1 CME credit Practice examination questions to achieve peak performance on the PANCE/PANRE All presentation materials can be downloaded and printed for off-line review Fee is $79 per module or $289 for the full five-module program

DELIVERED VIA 5 MODULES FOR EASY REVIEW EACH MODULE IS INDIVIDUALLY ACCREDITED | ACCESS AT MYCME.COM/UMDNJ Module 1

Cardiology/EKG Review

Module 2

Pulmonology, Pediatrics, Ophthalmology, Otorhinolaryngology

Module 3

Orthopedics, Neurology, Psychiatry

Module 4

Infectious Disease, Gastroenterology, Dermatology

Module 5

Reproductive System, Endocrinology, Genitourinary System, Hematology

ACCREDITATION INFORMATION This program has been reviewed and is approved for a maximum of 27.25 hours of AAPA Category 1 CME credit by the Physician Assistant Review Panel. Approval is valid for one year from the issue date of October 17, 2011. Participants may submit the self-assessment at any time during that period.

This program was planned in accordance with the AAPA’s CME Standards for Enduring Material Programs and for Commercial Support of Enduring Material Programs. This program has been planned without commercial support.

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ALTERNATIVE MEDS UPDATE

Safety, interactions Since rose hips are a botanical product, allergic reaction is always a possibility and should be monitored for—especially upon fi rst use of the product. For similar reasons, pregnant or lactating women and infants should avoid these products. Interactions and adverse reactions typically are centered on the vitamin C content.

Excess vitamin C can cause gastrointestinal distress and fatigue.9 Rose hips and vitamin C enhance absorption of any iron-containing supplements and, in large doses, can potentiate warfarin.9

2.5 g b.i.d. is recommended.2 Products made from rose hips are relatively inexpensive, ranging from $5 to $20 for a one-month supply, depending on the form.

Summary

Typically rose hips, when used as a supplement, are found in tea blends.

Rose hips have been studied for their effect on autoimmune diseases such as arthritis, and are suspected of having antiinflammatory properties.

Rose hips are a mild, pleasant supplement that are safe for routine use. While efficacy data are not robust, there is evidence supporting the supplement’s use, and it builds in the long term.

Providers may recommend this product as adjunctive therapy for a wide range of conditions or as a routine preventive regimen. ■ References 1. Hanrahan C, Frey R. Rose hip. Gale Encyclopedia of Alternative Medicine. 2nd Edition. Farmington Hills, Michigan:Gale Cengage Learning;2005. Available at www.encyclopedia.com/doc/1G2-3435100673.html.

2. Fetrow C, Avila J. Complementary & Alternative Medicines. Springhouse, PA: Springhouse Corporation; 1999:351-352.

3. Barlow K. Vitamin C from rose-hips. BMJ. 1941;1:797-799.

4. Willich SN, Rossnagal K, Roll S, et al. Rose hip herbal remedy in patients with rheumatoid arthritis: A randomized controlled trial. Phytomedicine. 2010;17:87-93.

5. Chrubasik C, Roufogalis BD, Muller-Ladner U, et al. A systematic review on the Rosa canina effect and efficacy profiles. Phytother Res. 2008;22:725-733.

6. Rein E, Kharazmi A,Winther K. A herbal remedy, Hyben Vital (stand. powder of a subspecies of Rosa canina fruits), reduces pain and improves general wellbeing in patients with osteoarthritis—a double-blind, placebocontrolled, randomised trial. Phytomedicine. 2004;11:383-391.

7. Christensen R, Bartels EM, Altman RD, et al. Does the powder of Rosa canina (rosehip) reduce pain in osteoarthritis patients? A meta-analysis of randomized controlled trials. Osteoarthritis Cartilage. 2008;16:965-972.

8. Daels-Rakotoarison DA, Gressier B, Trotin F, et al.

Effects of Rosa canina fruit extract on neutrophil respira-

Dosage and cost

tory burst. Phytother Res. 2002;16:157-161.

9. Therapeutic Research Faculty. Rose hip. Natural

Rose hips may be found in powder-filled capsules, liquid extract, or as a tea. Typical daily doses in tea form are 2.0-2.5 grams steeped in 150 cc of water several times a day.2 For rheumatoid arthritis, a powder-filled capsule totaling 140 THE CLINICAL ADVISOR • DECEMBER 2011 • www.ClinicalAdvisor.com

Medicines Comprehensive Database. Available at naturaldatabase.therapeuticresearch.com/nd/PrintVersion. aspx?cs-CP&s=ND&id=839.

All electronic documents accessed on November 15, 2011.

© ISTOCKPHOTO.COM / GABOR IZSO

In another meta-analysis of clinical trials examining the efficacy of rose hips in individuals with osteoarthritis, three studies were identified covering 287 patients for a mean duration of three months.6,7 These were randomized, controlled trials evaluating pain reduction from use of rose hip powder-fi lled capsules. Over the three trials, poststudy pain scores were improved in all active control patients by a 2:1 ratio over placebo.6,7 Even though vitamin C seems to be the major reason for rose hips’ activity, basic research has shown that the polyphenolic compounds in rose hips extract also have therapeutic effects.

One study tested the effect of rose hips on polymorphonuclear white blood cells in the respiratory tract. Knowing that reactive airway results in the stimulation of these cells and the subsequent production of oxidative by-products, researchers developed a rose hip extract without the vitamin C. This extract was then tested on the specific respiratory cell lines.8 The results still showed inhibition of oxidative pathways, confirming that vitamin C is not the only antioxidative component of rose hip products.8

Evidence-Based Medicine This department uses the best available scientific findings to offer practice guidance on a wide range of conditions seen in primary care.The author, Alan Ehrlich, MD, is a deputy editor for DynaMed, Ipswich, Mass., and Assistant Clinical Professor in Family Medicine, University of Massachusetts Medical School in Worcester. DynaMed (www.ebscohost.com/dynamed/) is a database that provides evidence-based information on more than 3,200 clinical topics and is updated daily through systematic surveillance covering more than 500 journals.The most important evidence identified is summarized here.

FLUID BOLUS INCREASES MORTALITY IN CHILDREN WITH SEVERE FEBRILE ILLNESS AND IMPAIRED PERFUSION IN LOW-RESOURCE SETTINGS Level 1: Likely reliable evidence Early fluid resuscitation is recommended for hemodynamic support in critically ill children (Crit Care Med. 2008;36:296-327), but there has been little evidence to guide the type, timing, and volume of fluids to use, especially in children who are not severely hypotensive or dehydrated. The FEAST trial evaluated the use of fluid boluses (saline or albumin) in severely ill children in Uganda, Kenya, and Tanzania (N Engl J Med. 2011;364:2483-2495). A total of 3,141 children (57% positive for malaria parasitemia) without severe hypotension (moderate hypotension in 6%, dehydration in 7%) were randomized to one of three fluid bolus strategies for initial fluid resuscitation: 0.9% saline solution 20 mL/kg IV over one hour vs. 5% albumin solution 20 mL/kg IV over one hour vs. no bolus (the initial bolus in the saline and albumin groups was increased to 40 mL/kg after a trial protocol amendment). All children had severe febrile illness, impaired consciousness and/or respiratory distress, and impaired perfusion.

Children were excluded for severe malnutrition, gastroenteritis, noninfectious causes of shock, or contraindication to fluid expansion.

At 48 hours, mortality was increased for both saline (10.5%, p=0.01, NNH 31) and albumin (10.6%, p=0.008, NNH 30) compared with placebo (7.3%). There were no significant differences in the rates of pulmonary edema or increased intracranial pressure. Mortality was also increased in the saline and albumin groups at 4 months (14.6% vs. 15.2% vs. 11.1%, p=0.01),

A large randomized study in Africa evaluated the use of saline and albumin boluses in children with shock and severe, lifethreatening infections.

142 THE CLINICAL ADVISOR â&#x20AC;˘ DECEMBER 2011 â&#x20AC;˘ www.ClinicalAdvisor.com

with an NNH of 30 for saline and 28 for albumin. There were no significant differences between saline and albumin, and subgroup analyses did not find any subgroup demonstrating benefit for fluid bolus. An additional group of 29 severely hypotensive children, for whom it was considered unethical to withhold fluids, were randomized to saline vs. albumin and showed no significant differences in mortality between the two bolus strategies (69% vs. 56%).

This trial has immediate implications for care in low-resource settings but also raises questions about the standard practice of fluid resuscitation in other settings where benefits have yet to be proven.

INTENSIVE-DOSE STATINS INCREASE RISK OF DIABETES BUT LOWER CARDIOVASCULAR RISK COMPARED WITH MODERATE-DOSE STATINS Level 1: Likely reliable evidence Statins are widely used for treating elevated cholesterol for both primary and secondary prevention of coronary artery disease. One concern about their use has been the possibility of increasing the risk of diabetes. Last year, a randomized trial showed that after two months of treatment with atorvastatin (Lipitor), patients had increases in fasting plasma insulin, insulin resistance, and hemoglobin A1c levels ( J Am Coll Cardiol. 2010;55:1209-1216), and a systematic review found an increase in the The quality of the evidence supporting each item is rated from Level 1 (highest) to Level 3 (lowest). Absolute risk reductions are presented as the number needed to treat (NNT) for one patient to benefit. Absolute risk increases are presented as the number needed to harm (NNH).

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risk of new onset of diabetes of 0.4% with statin use (NNH 255) (Lancet. 2010;375:735-742). The increased risk of new-onset of diabetes was confirmed in a subgroup analysis of patients from the SPARCL trial ( J Am Coll Cardiol.

2011;57:1535-1545). This study found new-onset diabetes in 8.71% with atorvastatin 80 mg/day vs. 6.06% with placebo (p <0.05, NNH 38).

Now, a pooled analysis of five lipid-lowering trials using statins (atorvastatin or simvastatin) with 32,752 patients has found an increased risk of diabetes with high-dose therapy compared with moderate-dose therapy ( JAMA. 2011;305: 2556-2564). Diabetes was diagnosed if it was listed as an adverse event, if there were two or more fasting blood glucose levels >125 mg/dL, or if the patient was started on a glucose-lowering medication. The overall rate of newonset diabetes was 8.4%. Comparing intensive-dose statin vs. moderate-dose statin, the rate of diabetes was 8.8% vs.

8% (odds ratio of 1.12, 95% CI 1.04-1.22). By way of comparison, cardiovascular events occurred in 19.1% of patients taking intensive doses and in 21.7% taking moderate doses (odds ratio 0.84, 95% CI 0.75-0.94). Overall, intensive-dose statin use had a number needed to harm (NNH) of 498 per year for the risk of new-onset diabetes and a number needed to treat (NNT) of 155 per year for the benefit of decreased cardiovascular events.

PREOPERATIVE ECHOCARDIOGRAPHY DOES NOT APPEAR TO IMPROVE SURVIVAL IN PATIENTS HAVING ELECTIVE NONCARDIAC SURGERY Level 2: Mid-level evidence An echocardiogram is often performed prior to non cardiac surgery to identify patients at risk of cardiac complications even though the American College of Cardiology recommends against routine perioperative evaluation of left-ventricular function in such patients (Circulation.

2007;116:e418-e499, available at circ.ahajournals.org/ content/116/17/e418.long, accessed November 15, 2011). A recent retrospective cohort study suggests that preoperative echocardiography may provide little benefit (BMJ. 2011;342: d3695, available at www.bmj.com/content/342/bmj.d3695 .long, accessed November 15, 2011). From a cohort of 264,000 patients aged 40 years and older having elective intermediate or high-risk noncardiac surgery, 35,498 patients who had a preoperative resting echocardiogram were matched to an equal number with no echocardiogram. Matching was based on multiple factors including demographics, comorbidities, type of surgery planned, and hospital characteristics.

© WATNEY COLLECTION / PHOTOTAKE

Evidence-Based Medicine

The preoperative echocardiogram may provide little benefit.

The echocardiogram group had significantly increased mortality at 30 days (2% vs. 1.7%, p <0.05, NNH 423) and at one year (7.4% vs. 6.9%, p <0.05, NNH 222). Echocardiography was also associated with increased hospital stay (mean difference 0.31 days). There were no significant differences in surgical site infections, a marker for perioperative risk that is unaffected by echocardiogram (13.2% vs. 12.9%). A subgroup analysis showed no significant difference in one-year mortality in patients who had a preoperative stress test.

PROPHYLACTIC AZITHROMYCIN REDUCES COPD EXACERBATIONS IN HIGH-RISK PATIENTS Level 1: Likely reliable evidence The guideline from the Global Initiative for Chronic Obstructive Lung Disease (GOLD) does not recommend antibiotics for prevention of COPD exacerbations. Citing decades-old data on the lack of efficacy of tetracyclines or penicillin, the guideline states that there is no benefit to the use of continuous antibiotics for prophylaxis (available at www.goldcopd.org/uploads/users/files/GOLDReport_ April112011.pdf, accessed November 15, 2011). However, in more recent research, both moxifloxacin (Respir Res. 2010;11:10, available at respiratory-research.com/content/11/1/10, accessed November 15, 2011) and erythromycin (Am J Respir Crit Care Med. 2008;178:1139-47, available at ajrccm.atsjournals.org/cgi/content/full/178/11/1139,

144 THE CLINICAL ADVISOR • DECEMBER 2011 • www.ClinicalAdvisor.com

ADDITION OF INTRACRANIAL ARTERIAL STENTING TO AGGRESSIVE MEDICAL MANAGEMENT INCREASES STROKE IN HIGH-RISK PATIENTS Level 1: Likely reliable evidence Patients with a transient ischemic attack (TIA) or stroke due to intracranial arterial stenosis are at high risk of a subsequent stroke. Current recommendations from the American Heart Association and the American Stroke Association classify percutaneous transluminal angioplasty with stenting (PTAS) as an investigational intervention with unknown utility for these patients (Stroke. 2011;42:227-276). Nevertheless, PTAS is sometimes used in this clinical setting. Another relatively new but not fully tested approach is aggressive medical management with dual antiplatelet therapy and intensive risk-factor management. The SAMMPRIS trial evaluated the addition of PTAS to aggressive medical management after a TIA or nondisabling stroke attributed to intracranial artery stenosis of 70%-90% (N Engl J Med. 2011; 365:993-1003). A total of 451 patients (mean age 60 years) were randomized within 30 days of ischemic event to PTAS

plus aggressive medical management vs. aggressive medical management alone.

In the PTAS group, patients had the procedure within three business days of randomization. Most patients had clopidogrel 75 mg for at least five days prior to the procedure. Those who did not were given a loading dose of clopidogrel 600 mg at six to 24 hours before surgery. All patients received aggressive medical management, which included aspirin 325 mg and clopidogrel 75 mg daily for 90 days in addition to medical and lifestyle interventions to improve primary and secondary risk factors (including blood pressure, cholesterol levels, diabetes, smoking, weight, and exercise).

The primary endpoint was a composite of ischemic stroke or death within 30 days of enrollment or a revascularization procedure or stroke in the territory of a qualifying artery at any time beyond 30 days. PTAS significantly increased the risk of this outcome (20.5% vs. 11.5, p=0.009, NNH 12).

Within the first 30 days, ischemic stroke or death occurred in 14.7% of the PTAS group vs. 5.8% of controls (p=0.002, NNH 11). PTAS was also associated with increased risk of stroke at any time during follow-up (22.3% vs. 14.1%, p=0.03, NNH 12) and increased risk of major hemorrhages requiring intervention (9.8% vs. 2.2%, p <0.001, NNH 13). There was no significant difference in overall mortality (3.1% vs. 3.1%). After mean follow-up of 11.9 months, enrollment was terminated due to safety concerns and futility analyses indicating there was minimal chance that PTAS would show benefits by the end of the planned two-year follow-up period. ■

© MICHAEL ENGLISH, MD / CMSP

accessed November 15, 2011) have been associated with reduced exacerbation frequency.

Now, a new randomized trial provides strong evidence that azithromycin reduces exacerbations and improves respiratory function in high-risk patients (N Engl J Med. 2011;365:689-698). A total of 1,142 patients (mean age 66 years) with COPD were randomized to azithromycin 250 mg daily vs. placebo for one year. Most of the patients (83%) had been previously treated with systemic corticosteroids for acute exacerbation, and 58% used long-term oxygen. Patients with (or at risk for) prolonged QTc interval were excluded, as were patients with asthma or with hearing impairment at baseline Azithromycin significantly reduced the frequency of exacerbations (1.48 vs. 1.83 per patient-year, p <0.01), and increased the median time to first exacerbation (266 days vs. 174 days, p <0.001). Acute exacerbations occurred in 57% of the azithromycin group and in 68% of controls.

The azithromycin group was also more likely to show clinically significant improvement in respiratory function scores (defined as a four-point or greater decrease on a 100-point scale) (43% vs. 36%, p=0.03, NNT 15). Azithromycin was associated with increased risk of hearing loss (25% vs. 20%, p=0.04, NNH 20). There were no significant differences in hospitalizations for any cause, hospitalizations related to COPD, or intubation rates.

An angiogram of carotid stenosis. Patients with TIA due to intracranial arterial stenosis are at high-risk of subsequent stroke.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • DECEMBER 2011 145

COMMENTARY David Springer is president of NIP Programs, a division of NIP Group (www.nipgroup. com), Woodbridge, N.J., which designs and manages specialty insurance programs.

The case for liability coverage The U.S. Department of Labor estimates that the number of physician assistants will grow 39% by 2018, and CNN Money/payscale.com reports that the number of nurse practitioners will increase by 23% percent by 2016. As these clinical roles come to the forefront of primary care, malpractice claims against physician extenders have risen in both frequency and severity, according to the American Academy of Physician Assistants and the CNA HealthPro Nurse Practitioner Claims Analysis.

Although some clinicians may think that their employer-provided professional liability insurance coverage is sufficient, a personal professional-liability policy can offer protection in several

Clinicians may be concerned that they are more likely to be named in a suit if they carry their own insurance.

ways that an employer plan might not. You may be covered under an employer’s medical malpractice policy as a dependent practitioner, but you’re still at personal risk for negligence attributed to you in a lawsuit and may be held responsible for all or part of a plaintiff ’s award/ settlement.

If you’re concerned that you might have gaps in your professional-liability coverage, exploring the possibility of obtaining this personal policy could be worthwhile.

Many hospitals and medical facilities have a large “self-insured deductible” in their insurance programs. This means that the facility is responsible for paying the first claims dollars of a loss—often $1 million or more. An insurance policy that is structured this way gives a facility extra incentive to settle a claim against it at a lower cost regardless of an employee’s individual culpability or the impact that losses might have on his or her career.

Also keep in mind that when third-party administrators are handling claims involving multiple health-care providers, these insurers might not communicate with you directly, as they do with your employer. The lack of direct contact could leave you in the dark as to how the case is progressing and unsure of how or whether your interests are being represented.

A personal policy enables you to hire your own attorney if needed.

146 THE CLINICAL ADVISOR • DECEMBER 2011 • www.ClinicalAdvisor.com

Clinicians also should be aware that employer coverage rarely includes defense of a license complaint—disciplinary actions that go before state licensing boards. Another factor to consider is that an employer policy may not be portable. Portability would allow coverage to be continued at the same level when you change employers, or if you work in multiple locations (which increases the extent to which you are at risk), or if a claim is made after you have left a particular job.

With a personal professional-liability policy, you can ensure that your defense costs are covered in a license complaint; that you have portable coverage that follows you with a consistent level and format; and that you have direct access to risk-management tools that can help prevent claims before they happen.

Some clinicians harbor concerns that they are more likely to be named in a suit if they carry their own insurance. However, plaintiffs’ attorneys do not know the provider’s insurance status when they name him or her in a suit; that information does not come to light until the discovery phase of the case. An insurance company cannot release information about a provider’s insurance status without his or her written permission.

Although policy costs will vary, the average annual premium for a full-time physician assistant, for example, is approximately $3,000. ■

For advertising information, contact: Russell Johns Associates, LLC 1001 S Myrtle Ave, #7, Clearwater, FL 33756 Phone: 877.394.1388 or 727.443.7667 • Fax: 727.445.9380 • E-mail: ca@russelljohns.com

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