October 2011 Clinical Advisor by The Clinical Advisor

THE CLINICAL ADVISOR • OCTOBER 2011

A F O RU M F O R N U R S E P R AC T I T I O N E R S

NEWSLINE

■ New weight-loss tool ■ Blood-clot risk calculator ■ Emerging infections ADVISOR FORUM

■ Recurrent biliary colic ■ GI upset in a teenager ■ Vaginal-ring insertion

✶ FREE CE COURSES! ■ Dyspnea with comorbid

HEART FAILURE AND COPD PAGE 59

■ Dermatology Clinic

A CHILD’S FACIAL RASH SPREADS PAGE 105

VOLUME 14, NUMBER 10

■ Dermatologic Look-Alikes

NEW BACK AND NECK PAPULES PAGE 133 Expanded job listings! www.ClinicalAdvisor.com/Jobs

| O C TO B E R 2 011 | www.ClinicalAdvisor.com

DISEASES & TUMORS OF THE

SALIVARY GLAND A sialolith (white) is a stonelike concretion of calcium formed in the salivary duct.

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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. The Clinical Advisor® (USPS 017-546, ISSN 1524-7371), Volume 14, Number 9, 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. All rights reserved. Reproduction in whole or in part without permission is prohibited. Copyright © 2011.

Now you can see our cartoons online, too. Treat yourself to a smile or chuckle and view our cartoon slideshows at ClinicalAdvisor.com/ cartoons

“The pills go down easy. It’s the price that’s hard to swallow.”

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • OCTOBER 2011 3

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

CONTENTS OCTOBER 2011

NEWS AND COMMENT 15

Newsline ■ CDC: Spread the word on flu vaccination ■ Infant rotavirus vaccine shields others, too ■ Pain relievers may increase bleeding ■ Infertility and celiac disease ■ New NIH weight-loss tool ■ Abnormal liver tests pose death risk for elderly ■ Cervical screening over-recommended ■ Risk calculator computes blood-clot odds ■ HbA1c sharpens predicted CVD risk ■ Esophageal cancer with GERD ■ Suicidal patients often seen in primary care ■ CDC warns of emerging infections ■ Women are overscreened and undertreated for osteoporosis Drug Update HIV therapy ■ Blood thinner for treatment of ACS

FEATURES

CME/CE Dyspnea with comorbid

heart failure and COPD In patients with pulmonary congestion, integrating heart failure and COPD guidelines presents a unique challenge. 71

When to screen for prostate cancer Men should make an informed decision with their clinician as to whether to be tested for prostate cancer.

New-onset diabetes in children and teens Clinicians must be able to differentiate between type 1 and type 2 diabetes in this patient population.

DEPARTMENTS

Continues on page 8

Tumors and diseases of the salivary glands These conditions can be categorized as inflammatory and infectious swellings, traumatic disorders, or benign and malignant tumors.

MAKING CONTACT

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

145 Commentary

An algorithm for managing breast pain A practical strategy is presented for the clinical management of this common but unsettling experience.

Flu vaccination among health professionals 15

Options for managing breast pain 47

■ New option for those starting

Dyspnea with heart failure and COPD 59

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CONTENTS DEPARTMENTS, cont’d

they failed to remove a BP cuff that she claimed was hurting her arm.

105 CME/CE Dermatology Clinic ■ A boy developed a red-brown facial rash six months after birth that soon spread to his ears, neck, and trunk.

133 CME/CE Dermatologic Look-Alikes Two cases of newly developed moles— one an asymmetrical papule, the other a lesion with a greasy appearance.

■ A woman with gestational diabetes and hypertension gave birth to a girl with an indurated plaque on her back.

111 Clinical Challenge ■ After falling duing a run, a woman fractured her humerus. Imaging studies revealed a large osteolytic lesion of the humeral head, neck, and shaft.

137 CME/CE Posttest

Seasonal influenza in children 125

■ Bacterial meningitis is a concern

141 Evidence-Based Medicine ■ For HIV-infected adults with positive tuberculin skin test, TB prophylaxis with isoniazid for 36 months appears more effective than for six months ■ Exemestane may reduce risk of invasive breast cancer in at-risk postmenopausal women ■ Vitamin D3 decreases all-cause mortality in elderly women with vitamin D insufficiency

when a man develops fever, headache, and a rash following a pneumococcal vaccination. 125 Stat Consult Find out the most recent information on diagnosis, testing, and treatment of influenza in children. 128 Legal Advisor A notoriously difficult patient charged a pair of clinicians with battery after

138 Alternative Meds Update Noted for its nutrient content, royal jelly is used as a treatment for hypertension, hyperlipidemia, inflammation, and possibly male infertility.

Assault with a deadly BP cuff? 128

Continues on page 10

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O C TO B E R 2 011 | www.ClinicalAdvisor.com

NEWSLINE

■ New weight-loss tool ■ Blood-clot risk calculator ■ Emerging infections ADVISOR FORUM

■ Recurrent biliary colic ■ GI upset in a teenager ■ Vaginal-ring insertion

✶ FREE CE/CME COURSES! ■ Dyspnea with comorbid

HEART FAILURE AND COPD PAGE 59

■ Dermatology Clinic

A CHILD’S FACIAL RASH SPREADS PAGE 105

■ Dermatologic Look-Alikes

NEW BACK AND NECK PAPULES PAGE 133 Expanded job listings! www.ClinicalAdvisor.com/Jobs

DISEASES & TUMORS OF THE

SALIVARY GLAND A sialolith (white) is a stonelike concretion of calcium formed in the salivary duct.

CONTENTS DEPARTMENTS, cont’d

■ Treatment of chronic

esophageal reflux Evidence-Based Medicine (cont’d) ■ Benefit of corticosteroids uncertain in adults hospitalized with pneumonia ■ Addition of androgen-deprivation therapy to radiation therapy may improve survival in patients with intermediate-risk localized prostate cancer

■ High-dose beta blockers in a

patient with pulmonary disease ■ Cardioprotection in a complex

patient ■ Was this rash related to

terbinafine? Royal jelly is rich in antioxidants 138

Clinical Pearls ■ Simple pounds-to-kilograms conversion ■ Dietary-restriction tool is money in the bank ■ Tricky vaginal-ring insertion ■ Tartrate or succinate? ■ Precision counts when applying medication to the scalp

Your Comments ■ Who is “too stupid”now? ■ Provide older patients with a list of current medications

ADVISOR FORUM 82

Consultations ■ Treating atrial fibrillation

during pregnancy ■ Depression treatment in an over-

weight recent ex-smoker ■ Reflux rebound after stopping

PPI therapy ■ Recurrent bouts of biliary colic ■ GI upset in a teenager

Cholecystectomy for biliary colic? 84

Visit us on the Web No appointment necessary We are constantly updating our Web site to provide enhanced presentation of the award-winning content readers of The Clinical Advisor have come to expect. • More news • More interactivity • More features • More resources • Plus the opportunity to sign up for weekly newsletters and earn FREE CME/CE credits each month. To see all this and much more, visit ClinicalAdvisor.com.

EXCLUSIVE TO THE WEB THIS MONTH AT

ClinicalAdvisor.com/web-only Web Exclusives

Slideshows

ClinicalAdvisor.com/WebExclusives

ClinicalAdvisor.com/Slideshows

IUDs protect against cervical cancer Women who reported using an intrauterine device (IUD) for contraception had almost half the risk of developing cervical cancer compared with those who had not, study findings indicate.

Measles, mumps, and rubella Waning vaccination coverage in some U.S. communities continues to put vulnerable populations at risk for these acute viral infections. Would you recognize if a child had one of these diseases?

Non-aspirin NSAIDs linked to kidney cancer Although aspirin and other NSAIDs are thought to protect against some types of cancer, new data suggests that non-aspirin NSAIDs may increase the risk for renal cell carcinoma.

Diabetes Resource Center ClinicalAdvisor.com/DiabetesResourceCenter Diabetes and obesity: A co-epidemic? Increases in type 2 diabetes parallel increases in obesity prevalence, epidemiological data from the past 20 years indicate.

Risk for new infections with TNF-alpha blockers reported The FDA is updating boxed warnings on all tumor necrosis factor-alpha-inhibiting drugs to reflect risk for infection with the bacteria Legionella and Listeria.

Prescribing diabetes medications Before prescribing drugs to control diabetes, clinicians should consider potential adverse events and drug interactions.

The Waiting Room Official Blog of The Clinical Advisor ClinicalAdvisor.com/Blog

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

Julee B. Waldrop, DNP, PNP, FNP Flu vaccine facts to persuade reluctant parents Influenza-related hospitalizations fell 34% after recommendations to vaccinate children aged 2 to 4 years were adopted.

ClinicalAdvisor.com/DermDx

Robyn Carlisle, MSN, CNM, WHNP

Hypopigmented macules on a woman’s back An otherwise healthy 33-year-old woman presented for a routine annual full-body skin exam. She was concerned about a white area on her mid-upper back.

MAKING CONTACT

Coping with oppositional patients Providers can spend hours dealing with insurance companies and pharmacists. It’s time we ask difficult patients to meet us halfway. Leigh Montejo, MSN, FNP-BC The white coat as a metaphor for the clinician-patient relationship Many health-profession programs have a white-coat ceremony for students on successful completion. A family nurse practitioner blogs about what the white coat means to her.

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www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • OCTOBER 2011 13

CME CE

PROGRAM OUTLINE OCTOBER 2011

0.5 CREDITS

Page 59 FEATURE Dyspnea with comorbid heart failure and COPD Maija Bamford, ANP, and Matthew R. Paulus, ANP-BC ■ LEARNING OBJECTIVES: • Identify which physical finding has the highest suggested value for affirming heart failure (HF). • List the findings that strongly suggest a pulmonary cause of dyspnea. • Discover the most specific lab test to establish fluid overload associated with HF. • Identify the cornerstone of pharmacologic therapy for HF.

0.5 CREDITS

Page 105 DERMATOLOGY CLINIC Case 1: Macules spread to the ears, neck, and trunk Kerri Robbins, MD

Case 2: Hardened plaque on a neonate’s back Maya Fetter, MD, and Julia R. Nunley, MD ■ LEARNING OBJECTIVES: • To increase awareness of dermatologic conditions, their diagnosis, and up-to-date treatment.

Page 133 DERMATOLOGIC LOOK-ALIKES Newly developed brown papules Kerri Robbins, MD ■ 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 October 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.

14 THE CLINICAL ADVISOR • OCTOBER 2011 • www.ClinicalAdvisor.com

Newsline

Treating celiac disease may help with infertility page 19

O C T O B E R 2 0 11

Online calculator predicts future VTE risk page 22

Inappropriate screening for osteoporosis page 24

CDC: Spread the word on flu vaccination

THE CDC wants to increase inf luenza vaccination among health-care personnel, after a survey of 1,931 such individuals indicated that only 63.5% got shots for the 2010-2011 season. “Influenza vaccination coverage among [health-care personnel] is important for patient safety, and health-care administrators should make vaccination readily accessible to all [health-care personnel] as an important part of any comprehensive infectioncontrol program,” stated agency representatives in a press release. Survey respondents who reported being subject to an employer requirement for flu vaccination reported near-universal coverage. Providers were also more likely to be vaccinated when the service was offered onsite and free of charge on multiple days. Clinicians also should help increase flu vaccination among

Increasing flu-vaccination among pregnant women is advised.

pregnant women, according to the CDC. A survey showed that only 49% of pregnant women were vaccinated during the 20102011 season, but that those who were offered flu vaccination by a provider were five times more likely to be vaccinated than were others. However, four of 10 women surveyed did not receive such an offer. Inf luenza vaccine strains for the 2011-2012 season remain unchanged from those of 20102011, but the CDC is recommending annual vaccination even for those who were vaccinated in the previous season, according to the agency’s Advisory Committee on Immunization Practices (ACIP). As was the case in 2010, all persons aged 6 months and older should undergo annual immunization against the flu (MMWR. 2011;60:1128-1132; available at

www.cdc.gov/mmwr/preview/ mmwrhtml/mm6033a3.htm, accessed September 15, 2011). However, since the vaccine strains are unchanged this season, children aged 6 months through 8 years who received at least one dose of the 2010-2011 seasonal vaccine will require only one dose of the 2011-2012 vaccine. The ACIP also now recommends that people with egg allergy receive the flu shot, especially if they only have had mild eggallergic reactions such as hives. (This recommendation does not apply to the nasal spray influenza vaccine.) These individuals should receive live attenuated influenza vaccine, administered by a provider familiar with the potential manifestations of egg allergy. The recipient should be observed for at least 30 minutes following the administration of each vaccine dose.

Physicians working with at least one NP, PA, or midwife Compared with other specialties, primarycare physicians were more likely to employ NPs, PAs, or midwives.

60 50

55.4% 49.1%

45.9% 40.8%

40 30 20 10

Source: CDC/NCHS, National Ambulatory Medical Care Survey, 2009

0 Total

Primary

Surgical

Medical

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • OCTOBER 2011 15

When it comes to invasive pneumococcal disease (IPD)

Even at her age, 1 risk still lies ahead

FOR CHILDREN 15 MONTHS TO 5 YEARS OF AGE FULLY VACCINATED WITH 4 DOSES OF PCV7…

HELP BRIDGE THE GAP TODAY WITH 1 CATCH-UP DOSE OF PREVNAR 13® One catch-up dose of Prevnar 13® helps cover children against 6 additional serotypes that can cause invasive pneumococcal disease, including increasingly drug-resistant serotype 19A2-6

A RE CIP CO * a MM nd EN AAP † DE D 5,6

• The immune responses induced by this Prevnar 13® schedule may result in lower antibody concentrations for the 6 additional serotypes (types 1, 3, 5, 6A, 7F, and 19A), compared to antibody concentrations following 4 doses of Prevnar 13®2

*Advisory Committee on Immunization Practices. † American Academy of Pediatrics.

Prevnar 13® does not provide 100% protection against vaccine serotypes or protect against nonvaccine serotypes.

INDICATION FOR PREVNAR 13® • Prevnar 13® is a vaccine approved for use in children 6 weeks through 5 years of age (prior to the 6th birthday) • Prevnar 13® is indicated for active immunization for the prevention of invasive disease caused by Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F IMPORTANT SAFETY INFORMATION FOR PREVNAR 13® • Severe allergic reaction (eg, anaphylaxis) to any component of Prevnar 13®, Prevnar ® (Pneumococcal 7-valent Conjugate Vaccine [Diphtheria CRM197 Protein]), or any diphtheria toxoid–containing vaccine is a contraindication to the use of Prevnar 13® • Prevnar 13® does not provide 100% protection against vaccine serotypes or protect against nonvaccine serotypes • Immunocompromised children or children with impaired immune responsiveness due to the use of immunosuppressive therapy may have reduced antibody response to active immunization PREVNAR and PREVNAR 13 are registered trademarks of Wyeth LLC.

• Apnea following intramuscular vaccination has been observed in some infants born prematurely. Decisions about when to administer an intramuscular vaccine, including Prevnar 13®, to infants born prematurely should be based on consideration of the individual infant’s medical status and the potential benefits and possible risks of vaccination • The most commonly reported serious adverse events were bronchiolitis (0.9%, 1.1%), gastroenteritis (0.9%, 0.9%), and pneumonia (0.9%, 0.5%) for Prevnar 13® and Prevnar®, respectively • The most commonly reported solicited adverse reactions (≥20%) in US clinical trials with Prevnar 13® were redness, swelling and tenderness at the injection site, fever, decreased appetite, irritability, increased sleep, and decreased sleep Please see Brief Summary of Prescribing Information on reverse side. For more information about Prevnar 13®, please visit www.prevnar13hcp.com or call 1-800-666-7248. References: 1. Centers for Disease Control and Prevention. Invasive pneumococcal disease before licensure of 13-valent pneumococcal conjugate vaccine—United States, 2007. MMWR. 2010;59:253-257. 2. Prevnar 13® (Pneumococcal 13-valent Conjugate Vaccine [Diphtheria CRM197 Protein]) Prescribing Information, Wyeth Pharmaceuticals Inc. 3. Moore MR, Gertz RE Jr, Woodbury RL, et al. Population snapshot of emergent Streptococcus pneumoniae serotype 19A in the United States, 2005. J Infect Dis. 2008;197:1016-1027. 4. Pilishvili T, Lexau C, Farley MM, et al; for the Active Bacterial Core Surveillance/Emerging Infections Program Network. Sustained reductions in invasive pneumococcal disease in the era of conjugate vaccine. J Infect Dis. 2010;201:32-41. 5. Centers for Disease Control and Prevention. Licensure of a 13-valent pneumococcal conjugate vaccine (PCV13) and recommendations for use among children—Advisory Committee on Immunization Practices (ACIP), 2010. MMWR. 2010;59:258-261. 6. American Academy of Pediatrics. Committee on Infectious Diseases. Policy statement — recommendations for the prevention of Streptococcus pneumoniae infections in infants and children: use of 13-valent pneumococcal conjugate vaccine (PCV13) and pneumococcal polysaccharide vaccine (PPSV23). Pediatrics. 2010;126(1):186-190. doi:10.1542/peds.2010-1280.

Manufactured by Wyeth Pharmaceuticals Inc.

Marketed by Pfizer Inc.

PSP292745-01

August 2011

FOR CHILDREN 15 MONTHS TO 5 YEARS OF AGE FULLY VACCINATED WITH 4 DOSES OF PCV7…

A RE CIP CO * a MM nd EN AAP † DE D 5,6

*Advisory Committee on Immunization Practices. † American Academy of Pediatrics.

Prevnar 13® does not provide 100% protection against vaccine serotypes or protect against nonvaccine serotypes.

Manufactured by Wyeth Pharmaceuticals Inc.

Marketed by Pfizer Inc.

PSP292745-01

August 2011

BRIEF SUMMARY: These highlights do not include all the information needed to use Prevnar 13® safely and effectively. Before prescribing, please consult the full Prescribing Information for Prevnar 13®. INDICATIONS AND USAGE: Prevnar 13® is a vaccine approved for use in children 6 weeks through 5 years of age (prior to the 6th birthday). Prevnar 13® is indicated for active immunization for the prevention of invasive disease caused by Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F. Prevnar 13® is also indicated for the prevention of otitis media caused by Streptococcus pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F. No otitis media efficacy data are available for serotypes 1, 3, 5, 6A, 7F, and 19A. DOSAGE AND ADMINISTRATION: For intramuscular injection only. Do not inject intravenously, intradermally, or subcutaneously. Vaccine Schedule for Infants and Toddlers – Prevnar 13® is to be administered as a 4-dose series at 2, 4, 6, and 12-15 months of age. Vaccine Schedule for Unvaccinated Children ≥7 Months of Age – For children who are beyond the age of the routine infant schedule and have not received Prevnar® (Pneumococcal 7-valent Conjugate Vaccine [Diphtheria CRM197 Protein]) or Prevnar 13®, Prevnar 13® is to be administered as a 3-dose series beginning at 7-11 months of age; a 2-dose series beginning at 12-23 months of age; and as a single dose at 24 months through 5 years of age (prior to the 6th birthday). The immune responses induced by this catch-up schedule may result in lower antibody concentrations for some serotypes, compared to antibody concentrations following 4 doses of Prevnar 13® (given at 2, 4, 6, and 12-15 months). In children 24 months through 5 years of age, the catch-up schedule may result in lower antibody concentrations for some serotypes, compared to antibody concentrations following 3 doses of Prevnar 13® (given at 2, 4, and 6 months). Prevnar 13® Vaccine Schedule for Children Previously Vaccinated With Prevnar® (Streptococcus pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F) – Children who have received 1 or more doses of Prevnar® may complete the immunization series with Prevnar 13®. Children 15 months through 5 years of age who are considered completely immunized with Prevnar® may receive 1 dose of Prevnar 13® to elicit immune responses to the 6 additional serotypes. This catch-up (supplemental) dose of Prevnar 13® should be administered with an interval of at least 8 weeks after the final dose of Prevnar®. The immune responses induced by this Prevnar 13® schedule may result in lower antibody concentrations for the 6 additional serotypes (types 1, 3, 5, 6A, 7F, and 19A) compared to antibody concentrations following 4 doses of Prevnar 13® (given at 2, 4, 6, and 12-15 months). DOSAGE FORMS AND STRENGTHS: Prevnar 13® is a suspension for intramuscular injection available in 0.5-mL single-dose pre-filled syringes. CONTRAINDICATIONS: Severe allergic reaction (eg, anaphylaxis) to any component of Prevnar 13®, Prevnar®, or any diphtheria toxoid-containing vaccine. WARNINGS AND PRECAUTIONS: Management of Allergic Reactions or Other Adverse Reactions – Before administration of any dose, all precautions should be taken to prevent allergic or any other adverse reactions. This includes a review of the patient’s immunization history for possible sensitivity to the vaccine or similar vaccines and for previous vaccination-related adverse reactions in order to determine the existence of any contraindication to immunization with Prevnar 13® and to allow an assessment of risks and benefits. Epinephrine and other appropriate agents used for the control of immediate allergic reactions must be immediately available should an acute anaphylactic reaction occur following the administration of the vaccine. Limitations of Vaccine Effectiveness – Prevnar 13® may not protect all individuals receiving the vaccine. Prevnar 13® will not protect against Streptococcus pneumoniae serotypes that are not in the vaccine or serotypes unrelated to those in the vaccine. It will also not protect against other microorganisms. This vaccine does not treat active infection. Protection against otitis media is expected to be substantially lower than protection against invasive disease. In addition, because otitis media is caused by many organisms other than the 7 serotypes of Streptococcus pneumoniae included in the indication, protection against all causes of otitis media is expected to be lower than for pneumococcal otitis media caused by these 7 vaccine serotypes. The duration of protection from immunization is not known. Altered Immunocompetence – Data on the safety and effectiveness of Prevnar 13® when administered to children in specific groups at higher risk for invasive pneumococcal disease (eg, children with congenital or acquired splenic dysfunction, HIV infection, malignancy, or nephrotic syndrome) are not available. Children in these groups may have reduced antibody response to active immunization due to impaired immune responsiveness. Vaccination in high-risk groups should be considered on an individual basis. The use of pneumococcal conjugate vaccine does not replace the use of 23-valent pneumococcal polysaccharide vaccine (PPV23) in children ≥24 months of age with sickle cell disease, asplenia, HIV infection, chronic illness, or who are otherwise immunocompromised. Premature Infants – Apnea following intramuscular vaccination has been observed in some infants born prematurely. Decisions about when to administer an intramuscular vaccine, including Prevnar 13®, to infants born prematurely should be based on consideration of the individual infant’s medical status and the potential benefits and possible risks of vaccination.

ADVERSE REACTIONS: Because clinical trials are conducted under widely varying conditions, adverse-reaction rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trials of another vaccine and may not reflect the rates observed in practice. As with any vaccine, there is the possibility that broad use of Prevnar 13® could reveal adverse reactions not observed in clinical trials. Serious Adverse Events in All Infant and Toddler Clinical Studies – Serious adverse events were collected throughout the study period for all 13 clinical trials. This reporting period is longer than the 30-day post-vaccination period used in some vaccine trials. The longer reporting may have resulted in serious adverse events being reported in a higher percentage of subjects than for other vaccines. Serious adverse events reported following vaccination in infants and toddlers occurred in 8.2% among Prevnar 13® recipients and 7.2% among Prevnar® recipients. The most commonly reported serious adverse events were in the “Infections and infestations” system organ class, including bronchiolitis (0.9%, 1.1%), gastroenteritis (0.9%, 0.9%), and pneumonia (0.9%, 0.5%) for Prevnar 13® and Prevnar®, respectively. There were 3 (0.063%) deaths among Prevnar 13® recipients and 1 (0.036%) death in Prevnar® recipients, all as a result of Sudden Infant Death Syndrome (SIDS). These SIDS rates are consistent with published age specific background rates of SIDS from the year 2000. There was 1 hypotonic-hyporesponsive episode adverse reaction reported (0.015%). Solicited Adverse Reactions in the 3 US Infant and Toddler Studies – The most commonly reported solicited adverse reactions (≥20%) in US clinical trials with Prevnar 13® were redness, swelling and tenderness at the injection site, fever, decreased appetite, irritability, increased sleep, and decreased sleep. Unsolicited Adverse Reactions in the 3 US Infant and Toddler Safety Studies – The following were determined to be adverse drug reactions based on experience with Prevnar 13® in clinical trials: Reactions occurring in greater than 1% of infants and toddlers: diarrhea, vomiting, and rash. Reactions occurring in less than 1% of infants and toddlers: crying, hypersensitivity reaction (including face edema, dyspnea, and bronchospasm), seizures (including febrile seizures), and urticaria or urticaria-like rash. DRUG INTERACTIONS: Concomitant Immunizations – In clinical trials, Prevnar 13® was administered concomitantly with the following US licensed vaccines: Pediarix [Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Hepatitis B (Recombinant), and Inactivated Poliovirus Vaccine Combined] (DTaP-HBV-IPV) and ActHIB [Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate)] (PRP-T) for the first 3 doses and with PedvaxHIB [Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate)] (PRP-OMP), M-M-R II [Measles, Mumps, Rubella Virus Vaccine Live] (MMR), and Varivax [Varicella Virus Vaccine Live], or ProQuad [Measles, Mumps, Rubella, and Varicella Virus Vaccine Live] (MMRV) and VAQTA [Hepatitis A vaccine, Inactivated] (HepA) for dose 4. When Prevnar 13® is administered at the same time as another injectable vaccine(s), the vaccines should always be administered with different syringes and given at different injection sites. Do not mix Prevnar 13® with other vaccines/products in the same syringe. Immunosuppressive Therapies – Children with impaired immune responsiveness due to the use of immunosuppressive therapy (including irradiation, corticosteroids, antimetabolites, alkylating agents, and cytotoxic agents) may not respond optimally to active immunization. USE IN SPECIFIC POPULATIONS: Pregnancy Pregnancy Category C – Animal reproduction studies have not been conducted with Prevnar 13®. It is also not known whether Prevnar 13® can cause fetal harm when administered to a pregnant woman or whether it can affect reproductive capacity. Pediatric Use – Safety and effectiveness of Prevnar 13® in children below the age of 6 weeks or on or after the 6th birthday have not been established. Prevnar 13® is not approved for use in children in these age groups. Immune responses elicited by Prevnar 13® among infants born prematurely have not been specifically studied. Geriatric Use – The safety and effectiveness of Prevnar 13® in geriatric populations have not been established. Prevnar 13® is not to be used as a substitute for 23-valent pneumococcal polysaccharide vaccine (PPV23) in geriatric populations. OVERDOSAGE: Overdose with Prevnar 13® is unlikely due to its presentation as a pre-filled syringe. However, there have been reports of overdose with Prevnar 13® defined as subsequent doses administered closer than recommended to the previous dose. In general, adverse events reported with overdose are consistent with those which have been reported with doses given in the recommended schedules of Prevnar 13®. NONCLINICAL TOXICOLOGY: Carcinogenesis, Mutagenesis, Impairment of Fertility – Prevnar 13® has not been evaluated for any carcinogenic or mutagenic potential, or impairment of fertility. HOW SUPPLIED/STORAGE AND HANDLING: Pre-filled syringe, 1 dose (10 per package) – NDC 0005-1971-02. Store refrigerated at +2ºC to +8ºC (36ºF to 46ºF). The tip cap and rubber plunger of the pre-filled syringe do not contain latex. Do not freeze. Discard if the vaccine has been frozen. This product’s label may have been updated. For current package insert and further product information, please visit www.wyethhcp.com or call our medical communications department toll-free at 1-800-934-5556. Manufactured by

Wyeth Pharmaceuticals Inc A subsidiary of Pfizer Inc, Philadelphia, PA 19101

U.S. Govt. License No. 3 LAB-0469-3.0 Rev 04/11 CPT Code 90670

PSP292745-02

Newsline VACCINATION of U.S. infants against rotavirus appears to provide indirect protection to older children and adults, according to a recent analysis ( J Infect Dis. 2011;204:980-986). In 2006, the CDC recommended routine vaccination against rotavirus, a major cause of severe diarrhea in infants and young children. By January 2008, approximately 57% of children younger than age 1 year and 17% of 1-year-olds were vaccinated. An analysis of nationally representative data from 2000-2008 shows that rates of all-cause diarrhea hospitalizations among children younger than age 5 years during the 2008 rotavirus season declined by 46%. Significant reductions were also seen in the 5-14-year and 15-24-year age

groups, particularly in March—the historic peak rotavirus month in the prevaccine era—and particularly among 24-year-olds, who were not eligible for the vaccine. These findings suggest that rotavirus vaccination has also reduced transmission of wild virus, thereby providing indirect protection. Vaccines in general were the subject of another recent report, this one issued by the Institute of Medicine (IOM). On reviewing more than 1,000 research articles, a committee of experts found no links between autism and some serious conditions that have raised concerns, including type 1 diabetes and autism. Convincing evidence was found showing 14 health outcomes—including seizures, inflammation of the brain, and fainting—that can be caused

Infant rotavirus vaccine shields others, too

Electron micrograph shows intact rotavirus particles (blue).

by certain vaccines, although these outcomes occur rarely. Indicative but less clear data were found on associations between specific vaccines and four other effects, such as allergic reactions and temporary joint pain. The report, Adverse Effects of Vaccines: Evidence and Causality, is available at www.iom.edu/ Reports.aspx (accessed September 15, 2011).

A COMBINATION of ibuprofen and acetaminophen can relieve chronic knee pain—including that caused by osteoarthritis—but at the cost of increased side effects, mainly GI bleeding. Investigators conducted a randomized, double-blind trial to explore short-term (10-day) and long-term (13-week) benefits and side effects of four regimens, each taken t.i.d.: (1) ibuprofen 400 mg; (2) acetaminophen 1,000 mg; (3) one fixed-dose combination tablet of ibuprofen 200 mg and acetaminophen 500 mg; and (4) two fixed-dose combination

tablets of ibuprofen 400 mg and acetaminophen 1,000 mg. Of the 892 participants, 63% had radiographic knee osteoarthritis and 85% fulfilled American College of Rheumatology criteria for osteoarthritis. At day 10 of the study, the two-combination-tablet regimen proved to be superior to acetaminophen for pain relief. At 13 weeks, significantly more participants taking one or two combination tablets rated their treatment as excellent/good compared with those taking acetaminophen. By 13 weeks, hemoglobin levels fell by at least 1 g/dL in some

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

participants in all groups. The reduction occurred in twice as many participants taking two combination tablets compared with persons on monotherapy. “Ibuprofen/[acetaminophen] combination analgesia, at nonprescription doses, confers modest short-term benefits for knee pain/osteoarthritis,” the authors concluded (Ann Rheum Dis. 2011;70:1534-1541). “In this population, [aceta minophen] 3 g/day may cause similar degrees of blood loss as ibuprofen 1,200 mg/day, and the combination of the two appears to be additive.”

Pain relievers may increase bleeding

Newsline

WOMEN with unexplained infertility are at heightened risk for having undiagnosed celiac disease (CD), which may be a modifiable and treatable risk factor, recent research suggests. To determine whether an increased prevalence of undiagnosed CD might exist among a population of infertile women, investigators conducted a prospective cohort study at a U.S. infertilit y clinic. Serologic screening uncovered CD in four of 188 subjects, translating to an overall prevalence in this population of 2.1%. Although this rate was not significantly higher than the expected 1.3%, undiagnosed CD was significantly more prevalent in the subset of 51 women presenting with unexplained infertility: Three (5.9%) of these women had previously undiagnosed CD ( J Reprod Med. 2011;56:199-203). All four women found to have CD underwent nutrition counseling to help them change over to a gluten-free diet. All four became pregnant within a year of diagnosis. “Diagnosing CD in an infertile woman would be particularly beneficial if the low-cost (and low-risk) therapy of pursuing a gluten-free diet could improve chances for conception,” commented lead study author Janet Choi, MD, in a statement describing her group’s findings.

New NIH weight-loss tool A NEW ONLINE simulation instrument can be used to predict how body weight will change and how long a person is likely to take to reach weight goals based on a starting weight and estimated physical activity. Developed by researchers at the National Institutes of Health, the body-weight simulator (available at bwsimulator.niddk.nih.gov, and intended for general research use only) demonstrates how diet and exercise can alter metabolism over time, leading to changes of weight and body fat. As reported in The Lancet (2011;378:826-827), the tool shows that body-weight response to a change of energy intake is slow, with half-times of about one year.

The tool shows a slow response to a change of energy intake.

The computer simulations directly challenge the commonly held belief among many that consuming 3,500 fewer calories or burning them off through exercise will always result in one pound of weight loss. The model indicates that this assumption overestimates weight loss, because it fails to account for how metabolism changes. As the simulations show, these metabolic changes can significantly differ among people. The body-weight simulator also shows how long an individual would have to follow a single permanent change of diet or exercise—such as cutting 10 calories per day from the diet—to meet a weight-loss target.

Abnormal liver tests pose death risk for elderly Liver tests are common, but the occurrence and consequences of abnormal results have been unclear. Now, a research team has determined that one in six people aged 75 years and older is likely to have at least one abnormal liver test, and those who have two or more are twice as likely to die from cancer and 17 times more likely to die from liver disease. Using a random sampling of 13,276 patients registered with 53 general practices, the investigators compared patients who had abnormal liver tests with patients in the same age group who had normal results during an average follow-up period of just over seven years. The liver tests included those for abnormal levels of aspartate transaminase (AST), alkaline phosphatase (ALP), and bilirubin.

A total of 2,175 subjects (16.1%) had at least one abnormal test. In addition, 1.5% of patients had two abnormal tests, and 0.07% had three abnormal tests. The prevalence of a single abnormal liver test was 3.3% for AST, 9.2% for ALP, and 5.4% for bilirubin. Abnormal AST was also associated with a sevenfold increased risk of death from liver disease. However, only 1.8% of patients with an abnormal AST died from liver disease during follow-up. Abnormal ALP carried a nearly sixfold increased risk of death from liver disease, and raised the risk of death from heart disease by 34%, cancer by 61%, and respiratory disease by 58%. Only 1% of patients with an abnormal ALP died from liver disease during follow-up (Aliment Pharmacol Ther. 2011;34:324-334).

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • OCTOBER 2011 19

NIH

Infertility and celiac disease

Newsline PRIMARY-CARE providers continue to recommend annual cervical cancer screening, despite recommendations that suggest three-year intervals for such testing. American Cancer Society and American College of Obstetricians and Gynecologists guidelines recommend that women aged 30 years and older undergo an HPV co-test—a Pap test and a human papillomavirus (HPV) test—and, if results are normal, waiting three years before being tested again. However, when Katherine B. Roland, MPH, and colleagues surveyed 376 private office-based providers and 216 from hospitals and outpatient facilities, they found that less than 15% made the three-year recommendation, and recommended annual screening instead (American Journal of Obstetrics

& Gynecology; published online ahead of print). In related news, results of the large ATHENA study suggest that the HPV test should become the primary screening tool to rule out cervical cancer. Combining HPV testing and cytology provided little benefit over HPV testing alone (Lancet Oncol. 2011;12:880-890). Among subjects who underwent

Pap smear shows epithelial squamous cells infected with HPV.

colposcopy, many more existing high-grade precancers were detected in those undergoing HPV testing than in those undergoing cytology. A different project showed that contrary to popular belief, intrauterine devices (IUDs) might protect against cervical cancer. Although IUDs were not shown to affect the risk of HPV infection, Xavier Castellsagué, MD, and colleagues found that women with a history of IUD use had almost half the risk of developing cervical cancer than did those who had never used this method of birth control. The reduced risk was seen in the first year of use, with the protective effect remaining significant even after 10 years of use (The Lancet Oncology; published online ahead of print).

Risk calculator computes blood-clot odds A NEW risk-prediction model designed for primary-care use can help identify asymptomatic patients at high risk of venous thromboembolism (VTE). T he QT h rombo si s Web Calculator (available at qthrombosis.org/) employs algorithms based on simple clinical variables. Users are asked to provide the patient’s age, gender, height, and weight; such clinical information as smoking status, presence of varicose veins, and presence of such conditions as cancer, heart failure, or chronic kidney disease; and information on current

A history of superficial VTE led to an increased risk of DVT and PE.

medication use. The tool then calculates VTE risk for one to five years. The developers validated the risk-prediction algorithm in 564 general practices in England and Wales, studying data from more than 3.5 million patients aged 25 to 84 years. First-time cases of VTE—either deep-venous thrombosis (DVT) or pulmonary embolism (PE)—were identified from a patient’s medical records or death certificate (BMJ. 2011;343:d4656; available www.bmj.com/content/343/bmj.d4656.long, accessed September 15, 2011).

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

The QThrombosis risk calculator is not suitable for persons with a history of venous thrombosis, with symptoms suggestive of venous thrombosis, or with a family history of thrombosis; for pregnant women; or for persons taking anticoagulants. In another other large VTE research project, Suzanne C. Cannegieter, MD, PhD, and colleagues found that people with a history of clinical superficial venous thrombosis had a 6.3-fold increased risk of DVT and a 3.9fold risk of PE (Blood; published online ahead of print).

TOP PHOTO: © SPL / CUSTOM MEDICAL STOCK PHOTO; BOTTOM PHOTO: © SPL / CUSTOM MEDICAL STOCK PHOTO

Cervical screening over-recommended

INCLUDING measurements of hemoglobin (Hb) A1c improved 10-year-risk prediction for cardiovascular disease (CVD) in persons with diabetes diabetes compared with simply classifying as a cardiovascular risk equivalent. Nina P. Paynter, PhD, and colleagues followed participants from the Women’s Health Study for a median 10.2 years and men from the Physicians’ Health Study II for a median 11.8 years. Models for CVD risk were generated using the traditional CVD risk factors, with the addition of a term for HbA1c levels for the 685 women and 563 men with diabetes at baseline. During follow-up, 125 cardiovascular events occurred among the women who began the study with diabetes, and 170 events among the men. For both genders, including HbA1c in the riskmodeling improved prediction of CVD compared with classification of all diabetes participants as high-risk. This was especially pronounced among women. “Presence of diabetes alone did not confer a 10-year risk of CVD higher than 20%, and measurement of HbA1c level in diabetic subjects improved risk prediction compared with classification as cardiovascular risk equivalent,” noted the authors in their report, published online ahead of print by Archives of Internal Medicine.

Esophageal cancer with GERD ALTHOUGH screening for esophageal adenocarcinoma has focused on identifying Barrett’s esophagus in persons with severe, long-standing symptoms of gastroesophageal ref lux disease (GERD), a recent study has shown that medically treated patients with mild or absent GERD symptoms have significantly higher odds of developing this form of cancer. “This finding may explain the failure of the current screening paradigm in which the threshold for primary endoscopic examination is based on symptom severity,” noted the investigators (Arch Surg. 2011;146:851-858). As explained in a statement announcing the results, many people who develop adenocarcinoma—a common form of esophageal cancer—are unaware that they have Barrett’s esophagus, which is

Mild GERD symptoms raise the odds of esophageal cancer.

characterized by a change in the cells lining the esophagus, often due to repeated exposure to stomach acids. Barrett’s esophagus can develop into esophageal cancer. In a study of 769 GERD patients presenting for their fi rst upper endoscopy, Barrett’s esophagus or adenocarcinoma was discovered in 15.9%. Those who were adequately managing their GERD symptoms with proton-pump inhibitors (PPIs) were 61% more likely to have Barrett’s esophagus or adenocarcinoma if they reported no severe GERD symptoms, compared with PPI users who reported severe symptoms. Results showed that even patients without severe GERD symptoms may benefit from Barrett’s esophagus screening, so that the condition can be identified before it becomes cancerous.

Suicidal patients often seen in primary care Primary-care clinicians write more prescriptions for antidepressants and see patients more frequently in the month before the person commits suicide than do mental health clinicians, according to a report in Mayo Clinic Proceedings (2011;86:792-800). While acknowledging that treatment of depression in primary care is improving, investigators contend that opportunities remain in addressing suicide-related treatment variables. “Management of suicide risk includes understanding the difference between risk factors and warning signs, developing a suicide risk assessment, and practically managing suicidal crises,” they state.

The authors offer recommendations for managing suicide risk in primary-care patients, such as identifying and treating alcohol-use disorders and anxiety symptoms, both of which are comorbid conditions in suicidal patients. Collaborative-care models for the treatment of depression have the potential to improve outcomes for patients and reduce suicide risk. Separately, Valerie Callanan and colleagues reported online in the journal Sex Roles that firearms are the preferred method of suicide among both men and women, and that those experiencing stressful life events are far more likely to employ an especially lethal method of suicide.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • OCTOBER 2011 23

HbA1c sharpens predicted CVD risk

Newsline FUNGAL INFECTIONS, invasive Haemophilus influenza, and legionellosis are all on the rise in the United States, according to the CDC. Older adults in the midwestern and western parts of the country appear to be at highest risk for histoplasmosis, coccidioidomycosis, and blastomycosis. Histoplasmosis was the most common endemic mycosis identified. Histoplasmosis and blastomycosis incidence were highest in the Midwest, and coccidioidomycosis incidence rate was highest in the West. COPD was the most common underlying disease for each endemic mycosis. “[Clinicians] in these areas should consider fungal infections in older patients with respiratory disease,” advised the CDC (Emerg Infect Dis. 2011;17:1664-1669).

The same journal issue included a study on invasive disease caused by H. influenzae among Utah adults during 1998-2008 (pp. 1645-1650). Although a vaccine has made H. influenzae type b (HiB) almost nonexistent in children, the incidence of invasive H. influenzae appears to be increasing among Utah adults, particularly those aged 65 years and older. This increase is mostly due to the rising incidence of nontypeable H. influenzae and H. influenzae type f. The case-fatality rate was 22%. Finally, the CDC announced that the number of U.S. legionellosis cases increased by 217% from 2000 (1,110 cases reported) to 2009 (3,522 cases reported) (MMWR. 2011;60;1083-1086; available at www.cdc.gov/mmwr/ preview/mmwrhtml/mm6032a3. htm, accessed September 15, 2011). The most common forms

CDC warns of emerging infections

H. influenzae (yellow) lives in the upper respiratory tract.

of legionellosis are Legionnaires disease and Pontiac fever. The FDA now requires all tumor necrosis factor-alpha blockers to carry updated Boxed Warnings that include the risk of infection from Legionella as well as Listeria (available at www.fda.gov/Drugs/ DrugSafety/ucm270849.htm, accessed September 15, 2011).

Women are overscreened, undertreated for osteoporosis A large number of women are not beeing properly screened or treated for osteoporosis, warn researchers. In a cohort of 615 postmenopausal women who underwent dual-energy x-ray absorptiometry screening, nearly half (41.3%) did not meet The North American Menopause Society (NAMS) criteria for bone-density testing. In addition, 25.5% of the women in the cohort were not taking calcium, 31.1% were not taking vitamin D, and 59.8% were not exercising for at least 30 minutes per week. Using the NAMS 2006 Osteoporosis Position Statement for screening and therapeutic guidelines, investigators Peter F. Schnatz, DO, and associates found that among the 102 women with any of the approved indications for treatment, 15.7% were not taking calcium; 18.6% were not taking vitamin D; 52.7% were not exercising at least two hours per week; and 35.3% were not receiving therapy. Yet of the 467 women with no

indication for treatment, 17.8% were receiving bisphosphonate, raloxifene (Evista), or calcitonin therapy. “Inappropriate screening may also lead to improper management of osteoporosis and its associated complications,” noted the investigators in their online report for Menopause. Although there have been conflicting findings as to whether using oral bisphosphonates heightens a person’s risk of developing esophageal cancer, the FDA has issued a statement expressing the belief that the benefits of these drugs continue to outweigh their potential risks for people with osteoporosis (www.fda.gov/Drugs/DrugSafety/ucm263320.htm, accessed September 15, 2011). The FDA’s review is ongoing, and the agency has not concluded that patients taking oral bisphosphonates do in fact have an increased risk of esophageal cancer. However, the agency noted, “esophageal cancer is rare, especially in women.” ■

24 THE CLINICAL ADVISOR • OCTOBER 2011 • www.ClinicalAdvisor.com

DrugUpdate New drug information from the publishers of MPR

New option for those starting HIV therapy Product: Edurant Company: Janssen Pharmacologic class:

Non-nucleoside reverse transcriptase inhibitor (NNRTI) Active ingredient: Rilpivirine 25 mg; tablets. Indication: HIV-1 infection in antiretroviral treatment-naïve adult patients, in combination with other antiretroviral agents. Pharmacology: Rilpivirine is a diarylpyrimidine NNRTI of HIV-1 and inhibits HIV-1 replication by noncompetitive inhibition of HIV-1 reverse transcriptase. Clinical trials: The efficacy of rilpivirine is based on the analyses of 48-week data from two Phase 3 trials TMC278-C209 and TMC278-C215 and from a 96-week (with extension to 192 weeks) Phase 2b trial in antiretroviral treatment-naïve adults. Antiretroviral treatmentnaïve HIV-1 infected subjects enrolled in the Phase 3 trials had a plasma HIV-1 RNA ≥5,000 copies/mL and were screened for susceptibility to nucleos(t)ide reverse transcriptase inhibitors (N[t]RTIs) and for absence of

specific NNRTI resistanceassociated mutations (RAMs). In TMC278-C209, the background regimen (BR) was tenofovir disoproxil fumarate + emtricitabine. In TMC278-C215, the BR consisted of one of the following: tenofovir disoproxil fumarate + emtricitabine or zidovudine + lamivudine or abacavir + lamivudine. Based on the pooled data from both trials at 48 weeks, the proportion of subjects with <50 HIV-1 RNA copies/mL receiving rilpivirine 25 mg (N=686) compared with subjects receiving efavirenz (N=682) was 83% and 80%, respectively. The mean

Rilpivirine helps blocks an enzyme necessary for HIV replication.

CD4+ cell count increase from baseline was 192 cells/mm3 for rilpivirine-treated subjects and 176 cells/mm3 for efavirenztreated subjects. Study TMC278-C204 enrolled 368 HIV-1-infected treatment-naïve adult subjects who had a plasma HIV-1 RNA ≥5,000 copies/mL, previously received two or fewer weeks of treatment with an N(t)RTI or protease inhibitor, had no prior use of NNRTIs, and were screened for susceptibility to N(t)RTI and for absence of specific NNRTI RAMs. At 96 weeks, the proportion of subjects with <50 HIV-1 RNA copies/mL receiving rilpivirine 25 mg (N=93) compared with subjects receiving efavirenz (N=89) was 76% and 71%, respectively. The mean increase from baseline in CD4+ counts was 146 ⳯ 106 cells/mm3 in subjects receiving rilpivirine 25 mg and 160 x 106 cells/mm3 in subjects receiving efavirenz. At 192 weeks, 63% of subjects who originally received 25 mg once daily achieved HIV RNA <50 copies/mL compared to 61% of subjects in the control group. Adults: Take with a meal. 25 mg once daily. Children: Not recommended. Contraindications: Concomitant carbamazepine,

P2Y12 platelet inhibitor (cyclopentyltriazolopyrimidine) Active ingredient: Ticagrelor 90 mg; tablets. Indication: To reduce the rate of thrombotic cardiovascular (CV) events in patients with acute coronary syndrome (ACS) (unstable angina or non-ST-elevation MI or ST-elevation MI). Pharmacology: Ticagrelor is a platelet activation and aggregation inhibitor mediated by the P2Y12 class of adenosine diphosphate (ADP) receptors. Ticagrelor and its major metabolite reversibly interact with the platelet P2Y12 ADP-receptor to prevent signal transduction and platelet activation. Both ticagrelor and its active metabolite are approximately equipotent. Clinical trials: In a randomized, double-blind study, the use of ticagrelor was compared with a regimen of clopidogrel, both given in combination with aspirin and other standard therapy in patients with acute coronary syndromes. Patients were

Continued pg. 30

For more products, visit www.eMPR.com

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

Blood thinner for treatment of ACS Product: Brilinta Company: AstraZeneca Pharmacologic class:

DrugUpdate Edurant from pg. 28

oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole, dexamethasone (more than single dose), St. John’s wort. Warnings/Precautions: May prolong QTc interval with

Brilinta from pg. 28

treated for at least six months and for up to 12 months. The primary endpoint was the composite of first occurrence of cardiovascular death, nonfatal MI (excluding silent MI), or nonfatal stroke. The components were assessed as secondary endpoints. At study completion, ticagrelor had been shown to significantly reduce the rate of a combined endpoint of cardiovascular death, MI, or stroke compared with clopidogrel (9.8% vs. 11.7%, respectively, hazard ratio [HR] 0.84). The difference between treatments on the composite resulted from effects on CV death (HR 0.79) and MI (HR 0.84); each was statistically significant when considered as a secondary endpoint and there was no difference on strokes. There was also a decrease in all-cause mortality. Among 11,298 patients with percutaneous coronary intervention (PCI) receiving any stent during this study, there was

supratherapeutic doses. Severe renal or hepatic impairment. Pregnancy (Cat. B). Nursing mothers: not recommended. Interactions: Concomitant NNRTIs: not recommended. Potentiated by CYP3A inhibitors. Antagonized by CYP3A inducers (see Contraindications). May antagonize azole antifungals

(monitor for breakthrough fungal 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) rilpivirine; drugs that increase gastric pH may result in decreased plasma concentrations. Caution with

drugs with a known risk for torsades de pointes. Adverse reactions: Depression, insomnia, headache, rash; fat redistribution, immune reconstitution syndrome. How supplied: Tabs—30

a lower risk of stent thrombosis (1.3% for adjudicated “definite”) than with clopidogrel (1.9%). Adults: Initiate loading dose: 180 mg once, then continue with 90 mg twice daily. After the initial loading dose of aspirin (usually 325 mg), take ticagrelor with maintenance dose of aspirin 75-100 mg daily. ACS patients: may start ticagrelor after receiving a loading dose of clopidogrel. Children: Not established. Contraindications: History

of intracranial hemorrhage. Active pathological bleeding (e.g., peptic ulcer, intracranial hemorrhage). Severe hepatic impairment. Warnings/Precautions: Do not start in patients planned to undergo urgent coronary artery bypass graft (CABG). When possible, discontinue at least five days before any surgery. Suspect bleeding in hypotensive patients who have recently undergone coronary angiography, PCI, CABG, or other surgery. Older age, history of bleeding disorders, undergoing percutaneous invasive procedures, concomitant anticoagulants, fibrinolytics, higher doses of aspirin, and chronic nonsteroidal anti-inflammatory drug use: increased risk of bleeding. Avoid interruption of treatment; if temporarily discontinued, restart as soon as possible. Premature discontinuation increases risk for CV events (e.g., MI, stent thrombosis, death). Effectiveness reduced with aspirin maintenance dose

>100 mg; avoid. Moderate hepatic impairment. Pregnancy (Cat. C). Nursing mothers: not recommended. Interactions: Concomitant strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir, telithromycin,) or potent CYP3A inducers (e.g., rifampin, dexamethasone, phenytoin, carbamazepine, phenobarbital): not recommended. Potentiates simvastatin, lovastatin; avoid doses >40 mg/day. Monitor digoxin during ticagrelor initiation and dose adjustments. Adverse reactions: Bleeding (may be fatal), dyspnea, headache, cough, dizziness, GI upset, atrial fibrillation, hyperor hypotension, back pain, fatigue, chest pain. How supplied: Tabs—60, 180

Ticagrelor reduces cardiovascular death and heart attack in patients with ACS.

For more products, visit www.eMPR.com

30 THE CLINICAL ADVISOR • OCTOBER 2011 • www.ClinicalAdvisor.com

For more information, call 800.526.7736 or visit www.Edurant-info.com.

For more information, call 800.236.9933 or visit www.Brilinta.com. ■

FEATURE: STEPHANIE WEISS, DDS, MD

Tumors and diseases of the salivary glands When diagnosing, consider the location and duration of the lesion, the patient’s age, underlying systemic disorders, and clinical appearance.

A siaolith (white) can block the salivary gland and cause painful inflammation.

rimary-care providers (PCPs) see a wide variety of tumors and diseases that originate in the salivary glands. The three major salivary glands are the parotid, the submandibular, and the sublingual. Hundreds of additional minor salivary glands within the mouth can also develop pathology. Theare many different causes of salivary gland pathology can be classified broadly as inflammatory and infectious swellings, traumatic disorders, and benign and malignant tumors of the salivary gland. In addition, systemic disorders can involve the salivary glands. Each of these entities has a unique clinical presentation, and proper identification is critical to providing the correct and most efficient course of treatment. Inflammatory and infectious swellings

Inflammatory and infectious swellings present acutely and are often painful enlargements of the salivary glands. Sialoliths and granulomatous diseases are inflammatory conditions that cause enlargement and pain but do not have an infectious etiology. Typically found in the submandibular gland, sialolithiasis is the most common cause of salivary gland enlargement. It results from the formation of a stone within salivary ducts. It is thought that the long path of the submandibular duct and its thicker mucoid secretions may be responsible for the increased frequency of sialoliths in this location. Radiographic examination will usually show an opaque mass in the duct if the stone is well calcified. The stone blocks 32 THE CLINICAL ADVISOR • OCTOBER 2011 • www.ClinicalAdvisor.com

TUMORS AND DISEASES OF THE SALIVARY GLANDS

The backup of salivary flow predisposes the gland to secondary bacterial infection, causing fever, redness, and purulent discharge. salivary flow out of the gland, causing pain and swelling, especially before or during mealtime. If the stone is located near the duct orifice, the clinician typically will be able to feel a hard mass beneath the oral mucosa. Small sialoliths can sometimes be removed by gentle massage, sialogogues, moist heat, or increased fluid intake. The treatment of larger inaccessible stones involves the complete removal of the stones, usually by cannulation and dilation of the duct. Although the stone is not infectious, the backup of salivary flow predisposes the gland to secondary bacterial infection, causing fever, redness, and purulent discharge. This is why treatment includes antibiotics. Occasionally, more aggressive treatment—including complete gland removal—is needed if the stone does not resolve or continues to recur. Examples of infectious causes of salivary gland enlargement include mumps, parotitis, and HIV lymphadenitis. Acute suppurative parotitis presents with painful parotid swelling, fever, redness, and purulent discharge from Stensen’s duct. Parotitis is attributable to a retrograde infection of the gland, usually bacterial in nature. This condition is typically seen in immunocompromised patients or subsequent to receiving a general anesthetic during a surgical procedure, especially abdominal surgery. Parotitis is thought to arise when a patient is given atropine intraoperatively after having had nothing to eat or drink, which decreases salivary flow and makes it easier for the bacteria to invade the gland. The most common pathogens associated with acute bacterial parotitis are Staphylococcus aureus and anaerobic bacteria. Samples for culture and sensitivity testing can be obtained by milking the gland to obtain the purulent material. Therapy includes maintenance of hydration and administration of parenteral antimicrobial therapy. Once an abscess has formed, surgical drainage is required. Swellings and cysts of the salivary glands may also be associated with HIV infection and such granulomatous diseases as sarcoidosis and tuberculosis. For example, patients with HIV may demonstrate bilateral lymphoepithelial cysts. Chronic nonspecific sialadenitis is a lower grade salivary inflammation that usually involves one or both parotid glands. The etiology is not definitively known; it is most likely multifactorial and includes decreased salivation, stasis, and an ascending retrograde duct infection. Sialadenitis is also thought to be caused by obstruction of one of the salivary ducts from either a stone or external radiation. The patient will complain of pain and such symptoms as fever

and malaise. Fortunately, the swelling is self-limiting and typically resolves with anti-staphylococcal antibiotic therapy and increased fluid intake. Refractory cases are treated with surgical resection after failure of antimicrobial therapy. Mumps, an acute infectious inflammation of the parotid gland, is an acute contagious viral infection typically seen in childhood. True mumps is caused by the mumps paramyxovirus, but a similar clinical disease can also be seen with coxsackievirus A and echovirus. Mumps typically causes bilateral inflammation of the parotid glands (parotitis), but it can occur unilaterally. Fever, headache, painful testicular swelling (orchitis), and a rash may occur as well. The symptoms are generally not severe in children. This disease is self-limiting, so such palliative treatment as analgesics, antipyretics, and fluid intake is appropriate. Isolation from other nonimmune individuals will prevent further spread. Although serious, sterility from orchitis is a rare complication of mumps. Noninfectious infl ammatory disorders can also cause enlargement of the salivary glands. These include the systemic diseases sarcoidosis and Sjögren’s syndrome. Sarcoidosis can cause swelling of the parotid gland and sometimes facialnerve palsy. Heerfordt’s uveoparotitis is a manifestation of sarcoidosis that occurs when the lacrimal gland, uveal tract, and parotid gland are involved. An autoimmune disease caused by anti-SS-A and anti-SS-B antibodies, Sjögren’s syndrome presents as xerostomia, dry eyes, and bilateral swelling of the major salivary glands. Sjögren’s syndrome is often associated with such other autoimmune diseases as rheumatoid arthritis. Traumatic disorders

The most common traumatic salivary disorder encountered by PCPs is a mucocele. Other disorders include a ranula (Figure 1) and a salivary duct cyst. A mucocele, also known as a mucous extravasation phenomenon or a mucous retention cyst, is not a true cyst because it lacks an epithelial lining. It is a submucosal cystic swelling of a gland-bearing area commonly found in children and young adults. It is thought to arise following the rupture of a salivary gland duct. Mucoceles typically present on the lower lip as a domeshaped and fluctuant mucosal swelling. Some mucoceles may be only 1 to 2 mm in diameter, but most measure between 5 and 10 mm. Mucoceles are painless swellings and are frequently recurrent. Treatment involves excision

34 THE CLINICAL ADVISOR • OCTOBER 2011 • www.ClinicalAdvisor.com

TUMORS AND DISEASES OF THE SALIVARY GLANDS

of the mucocele with associated minor salivary glands to decrease the chance for recurrence. Occasionally, mucoceles will rupture spontaneously and heal without surgical treatment. The history of trauma followed by the lesion appearing and, at times, increasing and decreasing in size is characteristic of a mucocele. A ranula is a swelling found on the floor of the mouth. It is caused by mucous extravasations brought on by trauma to the sublingual gland. A ranula usually presents lateral to the midline and may elevate the tongue. Ranulae are usually unilateral and produce a translucent blue swelling. Treatment involves unroofi ng the lesion (marsupialization) and/or complete excision. “Plunging” or cervical ranulae dissect through the mylohyoid muscle to produce neck swelling. Like mucoceles, these lesions are filled with mucin and will be fluctuant to palpation and easily moveable. Ranulae are not painful unless recently traumatized. A salivary duct cyst is a true cyst with an epithelial lining. These cysts are most commonly found in adults and are often slowly enlarging, painless swellings affecting a single gland. They may be caused by a ductal obstruction, but the source of the obstruction is not always apparent. Salivary duct cysts clinically resemble mucoceles but are usually found in the upper lip. They are treated with conservative surgical excision. For cysts seen in the major glands, partial or total removal of the gland may be necessary.

FIGURE 1. A ranula is a painless cyst on the floor of the mouth caused by trauma to the sublingual gland.

PCPs should also be knowledgeable about the clinical presentation and treatment of necrotizing sialometaplasia (NSM). This benign disease presents as an ulcerated or craterlike lesion, usually on the posterior palate and seen twice as frequently in men. These lesions may be bilateral in up to one-third of all cases. NSM is believed to be caused by local ischemia, which produces an infarction of salivary acini most often attributable to trauma. Lesions are often observed after local anesthetic injection, use of ill-fitting dentures, cocaine abuse, and trauma during intubation. Due to its clinical presentation, NSM may be confused for squamous cell carcinoma (SCC). To rule out malignancy, perform an incisional biopsy if the etiology is not clear. Ask the patient about recent trauma to the area to avoid unnecessary invasive treatment. Unlike SCC, NSM is self-limiting and usually resolves within six to eight weeks. Benign and malignant tumors

Tumors will also cause enlargement of the salivary glands. Salivary tumors are uncommon and represent 2%-4% of head and neck neoplasms. The major salivary glands (i.e., parotid, submandibular, sublingual) are affected 80%-85% of the time. Approximately 64% to 80% of all salivary gland tumors occur in the parotid gland. Fewer then 10% occur in the submandibular gland and fewer then 1% in the sublingual gland. However, tumors observed in the sublingual gland have a high rate of malignancy. About 10% to 20% of salivary tumors occur in the minor salivary glands. The palate is the most common site, accounting for at least 55% of the cases seen. Most tumors of the parotid gland—90% of which are pleomorphic adenomas (PAs) (Figure 2)—are benign. The most common salivary gland tumor found intraorally, PAs usually develop between age 30 and 50 years (younger than most other salivary gland tumors) and occur more often in women. Clinically, PAs typically appear as slow-growing, dome-shaped, painless, and nonulcerated masses, most often located in the tail of the parotid gland. In the palate—the most common site of development in minor salivary glands—PAs are usually found lateral to the midline. Facial nerve paralysis in association with PAs almost never occurs, even with extremely large tumors. During biopsy, take the specimen from the center of the lesion so that normal tissue doesn’t get seeded with the tumor. The treatment of choice is a wide surgical excision with lobectomy for the parotid gland and excision beyond the capsule for intraoral tumors. PAs found in the submandibular gland are typically treated by total removal of the gland. PAs have a five-year recurrence rate

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • OCTOBER 2011 39

TUMORS AND DISEASES OF THE SALIVARY GLANDS

Monomorphic adenomas refer to a group of rare tumors of the salivary gland that include basal cell adenomas and canalicular adenomas.

of 5% to 10%. A carcinoma can arise in a pre-existing PA 2% to 11% of the time. This carcinoma usually occurs in a long-standing PA, with ulceration and rapid growth as the common presenting signs. PA with multiple recurrences is also more susceptible to malignant transformation. Comprising 5% to 10% of all parotid tumors, Warthin tumor (papillary cystadenoma lymphomatosum) is the second most common benign salivary gland tumor. These soft, painless, slow-growing, and compressible masses are often seen near the angle of the mandible. Many sources state that men aged 50 to 70 years are most commonly affected, but other literature supports an equal gender predilection. Approximately 10% of Warthin tumors can present bilaterally. These masses have a strong association with individuals who smoke. These benign tumors are treated by conservative surgical excision, with a recurrence rate of 5% to 12%. Monomorphic adenomas refer to a group of rare tumors of the salivary gland that include basal cell adenomas and canalicular adenomas. Basal cell adenomas are observed predominantly in the parotid gland and present as slowgrowing and movable masses. Found most commonly in middle-aged and older adults, these painless tumors have a male predilection. Canalicular adenomas are found almost

FIGURE 2. Although mostly harmless, pleomorphic adenomas can grow to large proportions, hindering jaw function.

exclusively in the minor salivary glands and present as slowgrowing, well-circumscribed, firm, painless, and unfixed nodules. Masses may be fluctuant and bluish in color and have a predilection for the upper lip. Most monomorphic adenomas display nonaggressive behavior and are adequately treated with surgical excision, with rare recurrence reported. Benign lymphoepithelial lesions (BLELs) most often develop as component of Sjögren’s syndrome. These lesions present as firm and diffuse swellings of the affected gland, usually without pain. Women aged 50 years and older are most commonly afflicted. BLELs have a good prognosis after surgical removal, but individuals who have these lesions are at much greater risk for lymphoma. Mucoepidermoid carcinoma (MEC) is the second most common salivary gland tumor, and the most common malignant epithelial salivary gland tumor. Seen between the first and seventh decades of life, MEC is divided into low-, medium-, and high-grade tumors based on histological and clinical characteristics. MEC occurs most often in the parotid gland, where it presents as an asymptomatic swelling. This tumor is more common in women and is found most frequently on the palate intraorally. Low-grade tumors will have a similar presentation to PA. High-grade tumors may grow rapidly and cause considerable pain and/or facial nerve palsy. Treatment of lower-grade tumors involves wide surgical excision, with a survival rate of 90% to 100%. High-grade tumors need to be treated like carcinomas and have a five-year survival rate of 50%. Adenoid cystic carcinoma (ACC) is the second most common salivary malignancy overall. It has a female predilection and usually is seen in the fifth or sixth decade of life. About 50% of these lesions are found in the minor salivary glands. When seen intraorally, the palate is the most common site. ACC is the most common malignant salivary gland tumor in the submandibular gland. These tumors may ulcerate or cause a constant dull ache due to infiltration around the nerves. Treatment involves wide surgical excision, although radiation appears to be beneficial. Because of its relentless infi ltration and invasion and its tendency to spread along perineural space, this high-grade malignancy is prone to recurrences and metastasis. Long-term follow-up is required. Five-year survival rate is approximately 70% to 80%, with the 20-year survival rate dropping to about 13%. Acinic cell adenocarcinoma represents 17% of malignant salivary gland tumors. These tumors are found in a broad age

40 THE CLINICAL ADVISOR • OCTOBER 2011 • www.ClinicalAdvisor.com

biopsied for definitive histopathologic diagnosis to rule out a malignant cause. ■ Dr. Weiss is an oral and maxillofacial surgery resident at Kings County Hospital Center, Brooklyn, N.Y. Read on ■

Cysts of the salivary glands. In: Shear M, Speight PM. Cysts of the Oral and

Maxillofacial Regions. 4th ed. Oxford: Blackwell Publishing, Ltd.; 2007:171-180. ■

Ellis GL, Auclair PL. Atlas of Tumor Pathology; Tumors of the Salivary Glands.

Third Series, Fascicle 17. Washington, D.C.: Armed Forces Institute of Pathology; 1996:173-185. ■

Salivary gland pathology. In: Neville BW, Damm DD, Allen CM, Bouquot

J. Oral and Maxillofacial Pathology, 3rd ed. St. Louis, Mo.: Saunders/Elsevier; 2009:453-506. ■

Dardick I. Color Atlas/Text of Salivary Gland Tumor Pathology. Philadelphia,

Pa.: Lippincott Williams & Wilkins; 1996. ■

Medscape. Salivary gland tumors, major, benign. Available at emedicine.

medscape.com/article/194357-overview. ■

Tumors of the salivary gland. In: Shafer W, Hine M, Levy B. Shafer’s

Textbook of Oral Pathology. 6th ed. St. Louis, Mo.: Saunders/Elsevier; 2009:219-253. ■

Fonseca RJ. Oral and Maxillofacial Surgery: Surgical Pathology. Philadelphia,

Pa.: W.B. Saunders; 2000. All electronic documents accessed September 15, 2011.

group that ranges from the second to the seventh decades. Acinic cell adenocarcinoma is a low-grade malignancy with a good prognosis. Approximately 85% of tumors occur in the parotid gland. Acinic cell adenocarcinoma typically presents as a solitary and unfixed mass that may appear bluish. Up to 3% of cases appear bilaterally. More than one in three patients with this tumor present with pain. Polymorphous low-grade adenocarcinoma (PLGA) is a malignant salivary gland tumor that occurs almost exclusively in the minor salivary glands. About 60% of these cases occur on the hard or soft palate. This tumor presents as a slow-growing mass, occasionally accompanied by bleeding or discomfort. PLGA is considered a low-grade malignancy that rarely metastasizes. Perineural invasion is a frequent occurrence. Treatment consists of wide surgical excision that sometimes includes resection of underlying bone. Death due to this tumor is considered rare. The PCP also may encounter salivary tumorlike conditions. Sialadenosis is an unusual noninflammatory disorder presenting with asymptomatic enlargement of the salivary glands. Most cases involve slowly developing and painless swellings of the parotid glands. This condition is frequently associated with an underlying systemic problem that may be endocrine, nutritional, or neurogenic in nature. The best known of such conditions include diabetes, malnutrition, alcoholism, and bulimia. It is thought that these conditions produce a dysregulation of the autonomic innervation of the salivary acini, resulting in the enlargement. Treatment involves attempting to control the underlying systemic condition. Surgery may be used to correct the problem if cosmetic issues occur. Furthermore, low-dose radiation to a salivary gland can also cause an acute and tender swelling within 24 hours. Summary

Tumors and diseases of the salivary gland origin should be recognized by the PCP and treated accordingly. Clues to the diagnosis include location and duration of the lesion, age of the patient, associated symptoms, underlying systemic disorders, and clinical appearance. Long-standing, slow growing enlargements are typical of more benign pathology. Acute and rapidly enlarging conditions are usually infectious or inflammatory in nature. Malignant conditions often present with such other constitutional symptoms as weight loss, malaise, facial paralysis, and paresthesia. A thorough history and clinical exam will often help in differentiating these conditions. Any condition that is believed to be infectious or inflammatory that does not resolve should be

“It’s fancy-schmantzy. I just wanted fancy.”

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • OCTOBER 2011 41

FEATURE: GLENDA BELL FLYNN, FNP-C, AOCNP, AND CATHERINE TIPTON, MSN, FNP-BC

An algorithm for managing breast pain Breast pain can be a frightening experience, but the primary-care provider can often allay the patient’s fears and capably manage the condition.

A breast cyst (center) can arise from the blockage of a duct in glandular tissue.

reast pain is one of the most common problems for which women consult primary-care providers, gynecologists, and breast specialists. Women often think that breast pain indicates cancer, causing them significant anxiety. In reality, the prevalence of women presenting with mastalgia who actually have breast cancer is 1.2%-6.7%.1 In our breast-specialty practice, an estimated one-third of the women referred have breast pain. Unfortunately, options for evidence-based practice for the management of breast pain are sparse in the literature.2 To better serve this patient population, we have created a comprehensive algorithm to guide clinicians in the management of breast pain (Figure 1). This algorithm is based on research, personal practice, and anecdotal literature. Since the etiology of breast pain is multifactorial, an understanding of breast anatomy and physiology (Figure 2) is essential to the management of mastalgia. The breasts are paired mammary glands located on the anterior chest wall, superficial to the pectoralis major and serratus anterior muscles. The female breast is composed of glandular and fibrous tissue and subcutaneous and retromammary fat. The glandular tissue of each breast is arranged into 15 to 20 lobes that radiate around the nipple. Each lobe is composed of 20 to 40 lobules. A lactiferous duct drains milk from each lobe to the surface of the nipple. Vascular supply to the breast is provided primarily through branches of the internal mammary artery and the lateral thoracic artery. These branches supply blood to the deeper tissues of

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • OCTOBER 2011 47

MANAGING BREAST PAIN

Breast pain Workup consider mammogram, focused ultrasound, pain chart

Significant finding

No significant finding

Tissue diagnosis

Reassurance

Prolonged pain and/or pain that interferes with activity

Pain cyclical in nature

Pain cyclical in nature No

Yes

Pain localized No

Yes

Debilitating symptoms

Strategies Danazol (Danocrine) "ROMOCRIPTINE #YCLOSET 0ARLODEL

Strategies s ,IDOCAINE ,IDODERM TOPICAL .3!)$ s 'ABAPENTIN .EURONTIN PREGABALIN ,YRICA FOR NEUROPATHIC PAIN s 6ENLAFAXINE %FFEXOR s !MITRIPTYLINE %LAVIL s !CUPUNCTURE s #OGNITIVE BEHAVIORAL THERAPY s 2EFERRAL TO PAIN CLINIC

Strategies

Yes Pharmacologic s #ONSIDER LOW DOSE oral contraception or decrease estrogen s .3!)$S ORAL OR TOPICAL s &ISH OIL OIL OF EVENING primrose s -ULTIVITAMINS s 2EVIEW OF ALL medications

Non-pharmacologic s (EAT COLD s "RA MEASUREMENT s %XERCISE s 7EIGHT LOSS s 3TRESS REDUCTION s 3LEEP s #HECK VITAMIN $ AND 43( LEVELS

Danazol 200-400 mg (need barrier contraception) Response Yes

No 3WITCH TO BROMOCRIPTINE

$AY $OSE MG AT BEDTIME $AY $OSE MG AT BEDTIME $AY $OSE MG IN !$AY ONWARD $OSE MG B I D

Treat 2-4 months Reduce by half each month TO MG THEN DISCONTINUE

Response Yes

No Response

Treat 2-4 months

*Not frequently used due to side effects

s 4RICYCLIC ANTIDEPRESSANTS (e.g., amitriptyline) s 6ENLAFAXINE MAY BE USED IN CONJUNCTION WITH TAMOXIFEN s 'ABAPENTIN s $ANAZOL s !CUPUNCTURE s #OGNITIVE THERAPY

Yes Treat 2-4 months

FIGURE 1. Algorithm for managing breast pain

48 THE CLINICAL ADVISOR â&#x20AC;¢ OCTOBER 2011 â&#x20AC;¢ www.ClinicalAdvisor.com

Switch to: s 4AMOXIFEN MG DAY n success rates for cyclic mastalgia NOT APPROVED BY &$! s ,EUPROLIDE ,UPRON $EPOT

MANAGING BREAST PAIN

the breast and nipple. The intercostal arteries help supply the superficial tissues. Subcutaneous and retromammary fat surrounds the glandular tissue and constitutes most of the bulk of the breast.3 Stimulation of breast tissue by hormone fluctuations during the menstrual cycle may cause breast pain. Hormonal changes associated with ovulation can stimulate the proliferation of glandular breast tissue, resulting in breast swelling during the luteal phase of the menstrual cycle. For most women, this causes minor discomfort. Typically, breast pain is categorized as cyclical, noncyclical, or musculoskeletal (Table 1). Cyclical mastalgia is more severe and persistent.4 Women with cyclical mastalgia have higher mean luteal levels of luteinizing hormone and follicle-stimulating hormone,5.6 but research has not found a consistent abnormality of estradiol levels in these women.7,8 Breast pain can also arise from the myofacia. Evaluation of breast pain starts with a comprehensive health history. This history should include the type of pain, relationship to menses, duration, location, impact on activities of daily living, factors that aggravate and alleviate the pain, and any other medical problems and comorbidities. Check the patient’s current medications carefully, including any

FIGURE 2. The lactiferous duct (pink) drains milk from each lobe of the mammary glands (purple) to the surface of the nipple.

POLL POSITION Nearly 70% of your peers would recommend lifestyle changes for breast pain that does not resolve on its own, according to the results of our online poll.

n=342

Topical NSAIDs

Prescription medication

Lifestyle changes

69%

Alternative medicine

11%

Other

10%

For more polls, visit www.ClinicalAdvisor/polls

use of alternative therapies and/or herbal remedies. Physical examination should include a thorough evaluation, taking into consideration any medical conditions that might contribute to breast pain. A complete breast examination begins with the patient in a seated position. Look for symmetry, skin changes (i.e., dimpling, retraction, or lesions), architectural distortion, and changes in upper-extremity mobility. The breast examination provides a good opportunity to check underneath the breasts for yeast infections and skin nodules as well. Palpation is usually performed with the patient in a supine position. Start with gentle palpation or a sweeping technique before moving on to deeper palpation using a vertical stripping method. Be sure to check the underlying ribs and costal cartilage.9 Additional information regarding breast examination is available at the American Cancer Society website (www.cancer.org). Using the fi ndings from the health history and breast examination, the practitioner is now guided by the algorithm to manage breast pain. In the absence of a discrete mass and in younger women, mammography is not routinely used in clinical evaluation. Ultrasound is also unlikely to provide useful information. Clinicians in our practice, however, use focused ultrasound at the area of point tenderness to check for an incidental finding that may be causing the mastalgia (e.g., a cyst) and to reassure the patient. MRI is not ordered to evaluate breast pain. Of course, any palpable breast lump requires triple assessment (clinical breast exam, diagnostic study, and biopsy for pathology). If clinical breast examination and diagnostic studies fail to identify an abnormal lesion, various treatment options for

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

TABLE 1: 1: Characteristics of breast pain by type Cyclical

Noncyclical

Musculoskeletal

Age of onset

30s

30s-40s

Any age

Location

Bilateral, upperouter quadrant

Unilateral, one area

Usually unilateral near the breastbone

Area

Spread out

One spot

Different parts of the breast

Description of pain

Dull, aching

Sharp, stabbing

Burning, aching

Menstrual status

Premenopausal

Pre- or postmenopausal

Any age

Hormone therapy

Responds well

Minimal response

No response

Ibuprofen/ aspirin

Some help

Very helpful

Adapted from Provenzano DA, Levin M. Chronic pain syndromes: how to break the cycle, part 1. Consultant. 2008;4:297-298.

breast pain can be employed. The initial approach begins with reassurance of the patient. When breast cancer has been ruled out, reassurance alone has been shown to result in resolution of the symptom in 86% of women with mild pain and in 52% of women with severe pain.10 Other recommendations include alteration of dietary factors, such as advising the patient to reduce caffeine, salt, and saturated fat intake. Broad lifestyle recommendations can also improve comfort and overall quality of life.11-14 The algorithm also addresses pharmacologic approaches designed to treat debilitating and nondebilitating breast pain.15-22 A short course of a scheduled oral nonsteroidal anti-infl ammatory medication can be used to improve breast comfort. Anecdotally, addition of daily omega-3 has shown beneficial anti-inflammatory effects. Fish oil (1,000 to 1,200 mg daily) is an easily accessible and cost-effective option. An old study suggests that oil of evening primrose can significantly diminish cyclic breast pain,23 but four additional studies have found no evidence of benefit.24-27 Furthermore, this treatment requires frequent dosing and is prohibitively expensive. The associated side effects of the

PEER PERSPECTIVES

various pharmacologic approaches to the management of breast pain make them a less appealing option for patient and clinician alike. Extra-mammary pain falls in the category of myofacial or musculoskeletal pain (Table 1). Such referred pain is typically treated by managing the underlying cause. Treatment strategies can include referral to a pain-management specialist for steroid injections, topical analgesic application, and oral therapies.28 Because the etiology of breast pain is multifactorial, the clinical management must be fluid in nature. Many of the management strategies suggested take time to work. We routinely have women return for re-evaluation in three to six months. Additional research investigating causation of breast pain and new techniques for breast-pain management is warranted. ■ Ms. Bell Flynn and Ms. Tipton are family nurse practitioners at Baystate Surgical Oncology’s Comprehensive Breast Center in Springfield, Mass. References 1. Smith RL, Pruthi S, Fitzpatrick LA. Evaluation and management of breast pain. Mayo Clin Proc. 2004;79:353-372. Available at www.mayoclinicproceedings.com/content/79/3/353.long. 2. Harris JR, Lippman ME, Morrow M, Osborne CK, eds. Diseases of the Breast. 4th ed. Philadelphia, Pa.: Lippincott Williams and Wilkins; 2010:52-57. 3. Seidel HM, Ball JW, Dains JE, Benedict GW. Mosby’s Guide to Physical Examination. 5th ed. Philadelphia, Pa.: Mosby; 2003:496. 4. Hughes LE, Mansel RE, Webster DJ. Aberrations of normal development and involution (ANDI): a new perspective on pathogenesis and nomenclature of benign breast disorders. Lancet. 1987;2:1316-1319. 5. Ecochard R, Marret H, Rabilloud M, et al. Gonadotropin level abnormalities in women with cyclic mastalgia. Eur J Obstet Gynecol Reprod Biol. 2001;94:92-96. 6. Jørgensen J, Watt-Boolsen S. Cyclical mastalgia and breast pathology. Acta Chir Scand. 1985;151:319-321. 7. Watt-Boolsen S, Andersen AN, Blichert-Toft M. Serum prolactin and oestradiol levels in women with cyclical mastalgia. Horm Metab Res. 1981;13:700-702. Continues on page 54

“If the pain is cyclical/monthly in nature, eliminate caffeine and chocolate from the diet—particularly coinciding with day 14 through menses onset—and monitor for lessening of the discomfort. I also often recommend evening primrose oil 500 mg b.i.d. concurrently with dietary modifications.” — Lois Purvis, PA-C, Lahaina, Hawaii (via ClinicalAdvisor.com)

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

MANAGING BREAST PAIN

21. Mansel R, Goyal A, Nestour EL, et al. A phase II trial of Afimoxifene

CLINICAL SLIDESHOW

(4-hydroxytamoxifen gel) for cyclical mastalgia in premenopausal women. Breast Cancer Res Treat. 2007;106:389-397. 22. Mansel RE, Goyal A, Preece P, et al. European randomized, multicenter

For additional information on the evaluation of breast pain, view the slideshow at ClinicalAdvisor.com/MastalgiaSlideshow.

study of goserelin (Zoladex) in the management of mastalgia. Am J Obstet Gynecol. 2004;191:1942-1949. 23. Preece PE, Hanslip JI, Gilbert L, et al. Evening primrose oil for mastalgia. In: Horrobin D., ed. Clinical Uses of Essential Fatty Acids. Montreal: Eden Press; 1982:147-154. 24. Budeiri D, Li Wan Po A, Dornan JC. Is evening primrose oil of value in the

8. Walsh PV, McDicken IW, Bulbrook RD, et al. Serum oestradiol-17 beta

treatment of premenstrual syndrome? Control Clin Trials. 1996;17:60-68.

and prolactin concentrations during the luteal phase in women with

25. Collins A, Cerin A, Coleman G, Landgren BM. Essential fatty acids in

benign breast disease. Eur J Cancer Clin Oncol. 1984;20:1345-1351.

the treatment of premenstrual syndrome. Obstet Gynecol. 1993;81:93-98.

9. Auerbach RD. A Guide to Breast Health Care. Trumbull, Conn.: Budlong

26. Khoo SK, Munro C, Battistutta D. Evening primrose oil and treatment

Press, 2006:25.

of premenstrual syndrome. Med J Aust. 1990;153:189-192.

10. Barros AC, Mottola J, Ruiz CA, et al. Reassurance in the treatment of

27. Blommers J, de Lange-De Klerk ES, Kuik DJ, et al. Evening primrose oil

mastalgia. Breast J. 1999;5:162-165.

and fish oil for severe chronic mastalgia: a randomized, double-blind, con-

11. Ernster VL, Goodson WH 3rd, Hunt TK, et al. Vitamin E and benign

trolled trial. Am J Obstet Gynecol. 2002;187:1389-1394.

breast “disease”: a double-blind, randomized clinical trial. Surgery.

28. Colak T, Ipek T, Kanik A, et al. Efficacy of topical nonsteroidal antiinflam-

1985;97:490-494.

matory drugs in mastalgia treatment. J Am Coll Surg. 2003;196:525-530.

12. Colin C, Gaspard U, Lambotte R. Relationship of mastodynia with its endocrine environment and treatment in a double blind trial with

All electronic documents accessed September 15, 2011.

lynestrenol. Arch Gynakol. 1978;225:7-13. 13. Gunston KD. Premenstrual syndrome in Cape Town. Part II. A doubleblind placebo-controlled study of the efficacy of mefenamic acid. S Afr Med © The New Yorker Collection 2011 from cartoonbank.com. All Rights Reserved.

J. 1986;70:159-160. 14. Ernster VL, Mason L, Goodson WH 3rd, et al. Effects of caffeine-free diet on benign breast disease: a randomized trial. Surgery. 1982;91:263-267. 15. Mansel RE, Wisbey JR, Hughes LE. Controlled trial of the antigonadotropin danazol in painful nodular benign breast disease. Lancet. 1982;1:928-930. 16. Döberl A, Tobiassen T, Rasmussen T. Treatment of recurrent cyclical mastodynia in patients with fibrocystic breast disease. A double-blind placebo-controlled study—the Hjørring project. Acta Obstet Gynecol Scand Suppl. 1984;123:177-184. 17. Mansel RE, Dogliotti L. European multicentre trial of bromocriptine in cyclical mastalgia. Lancet. 1990;335:190-193. 18. Fentiman IS, Caleffi M, Brame K, et al. Double-blind controlled trial of tamoxifen therapy for mastalgia. Lancet. 1986;1:287-288. 19. Messinis IE, Lolis D. Treatment of premenstrual mastalgia with tamoxifen. Acta Obstet Gynecol Scand. 1988;67:307-309. 20. Kontostolis E, Stefanidis K, Navrozoglou I, Lolis D. Comparison of tamoxifen with danazol for treatment of cyclical mastalgia. Gynecol Endocrinol. 1997;11:393-397.

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CME CE FEATURE

■ LEARNING OBJECTIVES : • Identify which physical finding has the highest suggested value for affirming heart failure (HF). • List the findings that strongly suggest a pulmonary cause of dyspnea. • Discover the most specific lab test to establish fluid overload associated with HF. • Identify the cornerstone of pharmacologic therapy for HF. ■ COMPLETE THE POSTTEST: Page 137 ■ ADDITIONAL CME/CE: Pages 105, 133

MAIJA BAMFORD, ANP, AND MATTHEW R. PAULUS, ANP-BC

Dyspnea with comorbid heart failure and COPD There are guidelines for the management of each as a separate condition, but how do you evaluate and treat them when they appear together?

FIGURE 1. Hyperinflation of the lungs (note how small the heart is in comparison) points to a pulmonary cause of dyspnea.

white man aged 55 years presents to a primar y-care clinic complaining of increased dyspnea on exertion over the past three months. Before the onset of dyspnea, he was able to walk 50 yards before having to rest and catch his breath. He currently cannot walk more than 50 feet without resting. The man is a frequent patient with a history of chronic obstructive pulmonary disease (COPD)—most likely attributable to a 72-pack-year history of cigarette use—and heart failure (HF) secondary to prolonged undiagnosed hypertension. According to the Global Initiative for Chronic Obstructive Pulmonary Diseases guidelines, the patient has stage II (moderate) COPD.1 This man also has stage III HF, based on the New York Heart Association (NYHA) functional classification system (Table 1).2 He is compliant with his medications, which include a cardioselective beta blocker, an ACE inhibitor, a diuretic for HF, and a combination shortacting beta-agonist and anticholinergic/long-acting beta-agonist for COPD. The patient’s last pulmonary

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The interventions used to treat heart failure have little positive effect—and potential adverse effects—on the pulmonary system. function test (PFT) was three years ago and showed a forced expiratory volume in one second (FEV1) of 45% of normal and a ratio of FEV1 to forced vital capacity (FVC) of 51%. His most recent ejection fraction (EF), obtained one year ago and measured by means of coronary CT angiography, was 21%. All acute pulmonary and cardiac differential diagnoses, including MI and pulmonary embolism, have been ruled out based on history of present illness or physical-exam findings. The overlapping signs and symptoms of comorbid heart and lung diseases make it difficult to determine the cause of dyspnea in this patient and present a number challenges for the primary-care practitioner (PCP). Although not every patient who presents with dyspnea will have coexisting heart and lung diseases, it is estimated that between 20% and 30% of patients who have HF have comorbid COPD.3 While there are long-established guidelines for the management of COPD1 and HF4 as separate conditions, there are no guidelines and few clinical recommendations for the management of these disease processes when they appear concurrently. This article outlines the principles and considerations of managing progressive dyspnea in an adult with coexisting COPD and HF from a primary-care perspective. Delineating dyspnea

Because multiple pathologic processes likely contribute to progressive dyspnea in patients with coexisting heart and

lung diseases, it is unlikely that a single causative agent can be established. The challenge becomes determining the extent to which the patient’s existing pathologic processes are contributing to his or her progressive dyspnea once obvious differential diagnoses have been ruled out. Establishing the likely causes of a patient’s dyspnea is crucial to effective management because the interventions used to treat HF have little positive effect—and potential adverse effects—on the pulmonary system. The converse is also true with interventions used to treat pulmonary causes of dyspnea. An example of this is the use of beta blockers for HF and beta-agonists for COPD. The mechanism of dyspnea in HF

The isolated cardiac differential diagnoses, including HF, are all disease processes that lead to the heart failing as a pump.5 In such cases, the dyspnea is not caused by inadequate oxygenation but by inadequate distribution. This inadequate distribution can manifest itself as pulmonary edema (as seen in left-sided HF) or peripheral edema, ascites, and jugular venous distension (as seen in right-sided HF). Similarly, a weakened pump compromises systemic perfusion, and although the blood may be adequately oxygenated, there is inadequate circulation to meet the body’s metabolic needs. The mechanism of dyspnea in COPD

TABLE 1. 1.The stages of heart failure Class

Patient symptoms

I (mild)

No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, or dyspnea.

II (mild)

Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in fatigue, palpitation, or dyspnea.

III (moderate)

Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes fatigue, palpitation, or dyspnea.

IV (severe)

Unable to carry out any physical activity without discomfort; symptoms of cardiac insufficiency at rest; if any physical activity is undertaken, discomfort is increased

Adapted from the Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels. Vessels. 9th ed. Boston, Mass: Little, Brown & Co; 1994:253-256.

The isolated pulmonary disorders, which include COPD, are similar to the cardiac disorders in that they all share a common mechanism. With the isolated pulmonary disorders, ventilation deficit is the common cause of dyspnea. Patients who have COPD are usually classified as having either emphysema or chronic bronchitis. This is somewhat misleading because most patients have both conditions, one of which is predominant.5 In COPD, emphysema is caused by inadequate ventilation attributable to poor lung compliance, whereas chronic bronchitis is caused by obstruction due to secretions. Objective physical findings consistent with HF

The underlying pathology of HF contributes to inadequate fluid distribution and subsequent fluid overload. Patients experiencing fluid overload often present with increased BP, pulmonary rales, an S3 gallop, ascites, and lower-extremity edema. The PCP may be able to elicit

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The absence of orthopnea strongly suggests a pulmonary cause of dyspnea in patients with existing COPD and heart failure. jugular venous distension ( JVD) and hepatojugular reflex (HJR).6 Of these physical findings, the presence of an S3 gallop had the highest suggestive value for affirming HF. The presence of pulmonary rales, any cardiac murmur, JVD, HJR, and lower-extremity edema were also highly suggestive of HF.7 Objective physical findings consistent with COPD

The physical-exam findings in COPD reflect mechanical processes that impair gas exchange. Wheezes and rhonchi are often present on auscultation, and percussion tends to reveal hyperresonance. The presence of wheezes helps rule in pulmonary causes and rule out cardiac causes of dyspnea.7 Because of physical changes in the patient’s thorax, inadequate chest excursion and barrel-chest deformity are commonly found. In patients with acute exacerbations following physical exertion, tripod positioning and pursed-lip breathing are frequently seen in an attempt to provide the best position for full lung expansion and to keep terminal airways open. Individuals who are chronic-bronchitisdominant will often have a cough that produces copious amounts of sputum. Patients who are emphysema-dominant will have a dry cough and a flushed appearance related to polycythemia.5

(PEEP) through pursed-lip breathing. When asked to describe their dyspnea, COPD patients use such phrases as, “I can’t take a deep enough breath,” or “It takes more effort to breathe.”8 This may be related to the structural pathology of COPD and the fact that increasing the work of breathing often helps to reduce signs and symptoms by aiding in the expansion of the thoracic cavity, which allows for greater fi lling of the lungs; providing a greater PEEP, which resists full collapse of the alveoli; and raising the respiratory, which provides more oxygenated air available for gas exchange. The absence of orthopnea strongly suggests a pulmonary cause of dyspnea in patients with coexisting COPD and HF.7 Laboratory tests used to determe the cause of dyspnea

To rule out acute coronary syndrome as a causative agent in HF, testing for such cardiac biomarkers as troponin and creatinine kinase is advised in patients complaining of dyspnea. Similarly, a complete blood count (CBC) helps rule out anemic causes of dyspnea. A renal panel will determine whether the kidneys are contributing to the patient’s fluid

Subjective findings consistent with HF

Individuals who experience dyspnea related to HF will often get some relief in an upright position. In the supine position, there is an increase in venous return from the lower extremities. This increased volume cannot to be managed effectively by the failing pump, leading to pulmonary congestion.3 Patients often complain of having to sleep on multiple pillows due to orthopnea and report difficulty breathing at night (paroxysmal nocturnal dyspnea). Those with dyspnea caused by HF will describe their breathing difficulty as “air hunger” or “suffocation.”8 This response is likely related to inadequate perfusion and distribution caused by pump failure.8 Subjective findings consistent with COPD

Positioning for COPD patients is relevant but for different reasons than those of HF patients. Individuals with COPD prefer to sit upright because of the mechanics of breathing. These patients will assume positions that allow for maximal lung expansion and create positive end-expiratory pressure

FIGURE 2. The presence of Kerley B lines (arrows) on x-ray is one indication of a cardiac cause of dyspnea.

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Increased pulmonary vasculature, interstitial infiltrates confirmed by Kerley B lines, and pleural effusions indicate a cardiac cause of dyspnea. overload. If malnutrition and cachexia are suspected—as is often the case in advanced COPD—liver function tests (LFTs), including serum albumin, are advisable. Serum electrolytes, including magnesium, calcium, and D-dimer, are helpful in discerning noncardiac causes of dyspnea. Arterial blood gases are not widely used in the primary-care setting and have been omitted from this discussion. The natriuretic peptides, specifically brain natriuretic peptide (BNP), are the most specific and applicable laboratory tests available to establish fluid overload associated with HF.9 BNP is secreted by cardiac cells in the ventricles in response to stretch-receptor stimuli. When fluid volumes increase, the ventricles stretch and, in turn, secrete BNP. The BNP then provides feedback to the renin-aldosterone system in an attempt to regulate this fluid imbalance. The use of BNP in determining fluid overload in patients with dyspnea has become well established over the past several years. Citing several studies that supported the use of BNP in patients with dyspnea and TABLE 2. 2. Signs and symptoms of dyspnea Indicative of COPD

Indicative of heart failure

Wheezes

Peripheral edema

Rhonchi

Ascites

Hyperresonance to percussion

Jugular venous distension

Inadequate chest excursion

Increased BP

Barrel chest

Rales

Tripod positioning

S3 gallop

Cough with copious amounts of sputum

Murmur

Dry cough and a flushed appearance

Lower-extremity edema

Absence of orthopnea

Orthopnea

Pursed-lip breathing

Paroxysmal nocturnal dyspnea

Prefer to sit upright

Elevated troponin, creatinine kinase, brain natriuretic peptide

Such statements as, “Cannot take a deep enough breath,” or “It takes more effort to breathe,” used to describe symptoms

Such statements as, “Air hunger,” or “a feeling of suffocation,” used to describe symptoms

Radiography shows hyperinflation, decreased pulmonary vasculature, bullae, thickened bronchial markings, and an enlarged right heart.

Radiography shows increased pulmonary vasculature and interstitial infiltrates confirmed by Kerley B lines.

with comorbid heart and lung disease, Le Jemtel et al. suggested that BNP >500 pg/mL is indicative of overt congestive HF in a patient with established COPD.10 Likewise, a BNP <100 pg/mL provided evidence against HF as a contributing cause of dyspnea in patients with COPD.10 A BNP level should be drawn in any patient with progressive dyspnea who has established comorbid heart and lung diseases. This provides useful information regarding fluid status and can greatly assist the PCP in delineating cardiac causes of dyspnea. Imaging studies of the dyspneic patient

The importance of chest radiographs in the diagnosis of a dyspneic individual cannot be overstated. These x-rays provide a great deal of information that assists the PCP in sorting out the origin of a dyspneic episode. The presence of lobar infi ltrates, hyperinflation, decreased pulmonary vasculature, bullae, thickened bronchial markings, and an enlarged right heart are indicative of pulmonary abnormalities that may be contributing to a patient’s dyspnea (Figure 1). In contrast, increased pulmonary vasculature, interstitial infi ltrates confirmed by Kerley B lines, and pleural effusions indicate a cardiac cause of dyspnea (Figure 2). Of these findings, the presence of interstitial infi ltrates is the most suggestive of HF. The presence of interstitial infiltrates also helps to rule out pulmonary causes of dyspnea.7 ECG will determine the presence of dysrhythmia, conduction abnormalities, ischemia, or infarct. Although ECG cannot indicate the mechanical status of the heart, it can alert the practitioner to any new abnormalities, especially when compared with past ECGs. In the primary-care setting, echocardiograms are referred out. Echocardiograms help establish a baseline EF, determine chamber size, distinguish the type of HF, and point to disease progression, but their utility in determining acute exacerbations is limited.7 PFTs are similar to echocardiograms in that they can be used to establish a baseline and determine disease progression. For more acute exacerbations, however, their use is limited. PFTs also require referral and are not necessary on a routine basis. Coronary CT angiograms, nuclear stress tests, cardiac catherizations, and V/Q scans can be used in the initial workup of a patient who is suspected of having comorbid COPD and HF. However, these tests are not recommended in acute exacerbations of dyspnea in patients well-known to a primary-care practice.

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Table 2 summarizes the most common signs and symptoms of dsypnea. COPD treatment guidelines

According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD), the goals of treatment for COPD are relief of symptoms, prevention of disease progression, improvement of exercise tolerance, prevention and treatment of complications and exacerbations, and reduction of mortality.1 To date, no pharmacologic therapies have been shown to slow the progression of COPD symptoms. Aggressive patient education and nonpharmacologic support is the cornerstone of treatment.1 The pharmacologic management of COPD is determined by the GOLD classifications, which are based on PFT parameters; medication recommendations are made within each classification. Five stages of COPD are recognized:1 Stage 0 (at risk). Characterized by the presence of cough, sputum, and breathlessness without airflow obstruction. Stage I (mild). Characterized by mild airflow limitation (FEV1/FVC <0.70; FEV1 ≥80% predicted). Stage II (moderate). Characterized by worsening airf low limitation (FEV1/FVC <0.70; FEV1 50% to 80% predicted). Stage III (severe). Characterized by further worsening of airflow limitation (FEV1/FVC <0.70; FEV1 30% to 50% predicted). Stage IV (very severe). Characterized by severe airflow limitation (FEV1/FVC <0.70; FEV1 <30% predicted or <50% predicted plus the presence of chronic respiratory failure). Patient assessment is driven by symptom severity— especially breathlessness and reduced exercise capacity—as well as by the development of complications. Management decisions are often based on symptomatic response (bronchodilator treatment) rather than changes in spirometry, which is a poor predictor. Nevertheless, spirometry is a necessary requirement for the diagnosis of COPD and is a useful indicator of disease progression.11 Bronchodilators with beta2-agonists, anticholonergics, and methylxanthines are central to the management of COPD

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and are used singly or in combination. Regular treatment with long-acting bronchodilators has proven to be more effective and convenient than that with short-acting bronchodilators. The addition of inhaled glucocorticosteroids is appropriate for symptomatic COPD with FEV1 <50% and repeated exacerbations. However, chronic treatment with glucocorticosteroids should be avoided due to an unfavorable benefit-to-risk ratio.1 A yearly influenza vaccine reduces serious illness and death in COPD patients by nearly 50%. Pneumococcal polysaccharide vaccine is also recommended for COPD patients aged 65 years and older or those younger than age 65 years with an FEV1 <40% predicted.1 Long-term oxygen therapy is indicated for patients with chronic respiratory failure and has been shown to increase survival rates. The primary goal is to increase the baseline PaO2 to at least 60 mm Hg at rest and SaO2 to at least 90%.1 Nonpharmacologic considerations include reduction or elimination of exposure to tobacco smoke, occupational dust and chemicals, and air pollutants. For patients with COPD, health education is essential to effective treatment, as it plays a vital role in smoking cessation, medication compliance, and the ability to cope with illness.1 Pharmacologic and nonpharmacologic HF treatment

The cornerstones of pharmacologic therapy for HF are ACE inhibitors and beta blockers. Unless contraindicated, an ACE inhibitor should be started in all patients with symptomatic HF and left-ventricle EF (LVEF) <40%. Beta blockers should be used in all patients with symptomatic HF and LVEF <40%. Both treatment modalities will improve ventricular function and patient well-being, reduce hospitalizations, and increase survival rates.3 Angiotensin II receptor blockers (ARBs) are recommended as an alternative for those who cannot tolerate ACE inhibitors (LVEF <40%, NYHA class III-IV). Another indication for use of an ARB is persistent symptoms despite treatment with an ACE inhibitor and beta blocker. Consider aldosterone antagonists for all patients with EF <35%, NYHA class III-IV with moderate-to-severe symptoms, and after optimal dose of beta blocker and ACE inhibitor or ARB. Used in combination, hydralazine and isosorbide dinitrate are an alternative when an ACE inhibitor or ARB is not tolerated. They can be used as an add-on therapy to an ACE inhibitor if an ARB or aldosterone antagonist is not tolerated. The evidence for such use is strongest in African-Americans.

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The presence of pulmonary congestion is best established through objective and subjective exam findings, laboratory data, and imaging. Diuretics are recommended in HF patients with clinical signs and symptoms of pulmonary congestion. Since diuretics can activate the renin-angiotensin-aldosterone system in patients with mild symptoms of HF, they should be used in combination with an ACE inhibitor or ARB. Loop diuretics are recommended for moderate or severe HF. A thiazide diuretic may be used in combination with loop diuretics for resistant edema. Digoxin may be necessary in patients with HF and atrial fibrillation and may be used to slow a rapid ventricular rate. In patients with AF and LVEF <40%, digoxin should be used to control heart rate in addition to or prior to a beta blocker. Nonpharmacologic recommendations for treatment of HF include revascularization, valvular surgery, cardiac resynchronization therapy, pacemaker and/or implantable cardioverter defibrillator (ICD), left ventricular assist devices, or heart transplantation. TABLE 3. 3. Clinical findings and treatment plan Chief complaint

Progressive dyspnea

Subjective findings

• Was able to walk 50 yards, now cannot walk 50 feet • Three-pillow orthopnea • Paroxysmal nocturnal dyspnea

Objective findings

• Vital signs: normal • BP: 150/90 mm Hg (right arm); 146/98 (left arm) • Rales noted bilaterally • Positive hepatojugular reflex • No gallop, murmur, or jugular venous distension • No lower-extremity edema

Assessment

• Progressive dyspnea • Hypertension

Plan

• Chest radiography • Complete blood count, renal panel, electrolytes, liver function tests, brain natriuretic peptide, and D-dimer ordered • Pulmonology consult for pulmonary function tests • Hydralazine (Apresoline) 10 mg t.i.d. • Interventional cardiology consult for bi-ventricular pacemaker/implantable cardioverter defibrillator device. • Follow up in two weeks • Mixed cardiac/pulmonary rehabilitation consult for exercise plan

Influenza vaccine and pneumococcal vaccine are also important considerations. Vigilance in terms of anemia, cachexia, and gout are recommended as well. Integrating HF and COPD guidelines in clinical practice

The detection and treatment of pulmonary congestion is the highest priority for patients with combined HF and COPD. The presence of pulmonary congestion is best established through a combination of objective and subjective exam findings, laboratory data, and imaging. Specifically, BNP >500 ng/mL, orthopnea, S3 gallop, rales, and interstitial pulmonary infi ltrates on chest x-ray are suggestive of fluid overload. Agents with documented effects on morbidity and mortality such as ACE inhibitors, beta blockers, and ARBs should be continued in patients with comorbid COPD and HF. The majority of patients with HF and COPD can safely tolerate beta blockers, especially when initiated at a low dose and gradually titrated up. Mild deterioration of pulmonary function and symptoms should not lead to prompt discontinuation of beta blockers. If symptoms worsen, a reduction of the dosage or withdrawal may be necessary. Selective beta blockers are preferred to nonselective beta blockers in patients with coexisting COPD and HF. Similarly, inhaled beta-agonists should be administered in accordance with the established guidelines in patients with COPD in the presence of HF.3 Adjustments in medication should be based on assessment findings, laboratory tests, imaging, and whether a patient is at maximum levels of established pharmacologic therapy. For patients who are on maximum therapeutic doses of medications, the addition of hydralazine and isosorbide dinitrate is considered prudent. Similarly, adjustments to diuretic therapy may be beneficial by means of up-titration or changing from a thiazide-type diuretic to a loop diuretic. These recommendations are not as firmly established as the existing guidelines for the management of the diseases as they occur separately. The management of patients with coexisting COPD and HF should include input from pulmonology and cardiology. Case study outcome

Table 3 summarizes of the exam findings and treatment plan of the patient described at the beginning of this article. Because pulmonary function testing had not been performed for several years, a referral to a pulmonologist

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was recommended. Likewise, a referral to an interventional cardiologist was made to discuss combination bi-ventricular pacemaker/ICD placement. Combined cardiac and pulmonary rehabilitation was also recommended. Hydralazine was added to his existing medications in an attempt to confront hypertension and decreased EF. A chest x-ray, ECG, CBC, electrolytes, BNP, LFTs, and a renal panel were obtained. Follow-up in two weeks was advised to evaluate the effectiveness of the interventions.

developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation. 2009;119:e391-e479. Available at circ.ahajournals.org/content/119/14/e391.long. 5. Gonzales R, Nadler PL. Common symptoms. In: McPhee SJ, Papadakis MA, eds. Current Medical Diagnosis & Treatment. 49th ed. New York, N.Y.: McGraw-Hill; 2010:22-30. 6. Ferri FF. Ferri’s Clinical Advisor. Philadelphia, Pa.: Elsevier Mosby:439. 7. Wang CS, FitzGerald JM, Schulzer M, et al. Does this dyspneic patient in the emergency department have congestive heart failure? JAMA. 2005;294:1944-1956.

Conclusions

8. Simon PM, Schwartzstein RM, Weiss JW, et al. Distinguishable types

Medical specialties have traditionally separated HF and COPD into distinct components, even when they coexist in the same patient. This compartmentalization of disease processes makes it difficult for PCPs to manage individuals who have these diseases comorbidly, because the varying disciplines often have differing opinions on the management of the patient. This forces the PCP to become the mediator for appropriate management of these patients. The lack of guidance on these comorbid disease processes further complicates matters for PCPs and points to the need for further interdisciplinary dialogue and research. ■

of dyspnea in patients with shortness of breath. Am Rev Respir Dis. 1990;142:1009-1014. 9. Chernecky CC, Berger BJ. Laboratory Tests and Diagnostic Procedures. 5th ed. St. Louis, Mo.: Saunders Elsevier; 2008:808. 10. Le Jemtel TH, Padeletti M, Jelic S. Diagnostic and therapeutic challenges in patients with coexistent chronic obstructive pulmonary disease and chronic heart failure. J Am Coll Cardiol. 2007;49:171-180. 11. Gross NJ. The GOLD standard for chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2001;163:1047-1048. Available at ajrccm. atsjournals.org/cgi/content/full/163/5/1047. All electronic documents accessed September 15, 2011.

Ms. Bamford is a registered nurse at Ohio State’s Ross Heart Hospital in Columbus. Mr. Paulus is a Federal Nurse Practitioner Fellow in Columbus. The authors have no relationships to disclose regarding the content of this article. References 1. Rabe KF, Hurd S, Anzueto A, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: © The New Yorker Collection 2011 from cartoonbank.com. All Rights Reserved.

GOLD executive summary. Am J Respir Crit Care Med. 2007;176:532-555. Available at ajrccm.atsjournals.org/cgi/content/full/176/6/532. 2. The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels. 9th ed. Boston, Mass: Little, Brown & Co; 1994:253-256. 3. Dickstein K, Cohen-Solal A, Filippatos G, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). Eur Heart J. 2008;29:2388-2442. Available at eurheartj.oxfordjournals.org/content/29/19/2388.long. 4. Hunt SA, Abraham WT, Chin MH, et al. 2009 focused update incorporated into the ACC/AHA 2005 guidelines for the diagnosis and management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines:

“What say you buzz me in tonight, honey?”

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • OCTOBER 2011 65

FEATURE: CARL SHERMAN

When to screen for prostate cancer In an update of its 2001 guidelines, the American Cancer Society stresses the importance of sharing the screening decision with the patient.

creening for prostate cancer—a prostatespecific antigen (PSA) blood test and a digital rectal examination (DRE)—is part of the yearly checkup ritual for many men. But is prostate screening necessary or even desirable? This unanswered question dominates the American Cancer Society’s (ACS) most recent update of its Guideline for the Early Detection of Prostate Cancer.1 The authors of the guideline do not outright recommend screening for any male patient. Rather, they clarify and elaborate in detail the shared, informed decision-making process that should determine whether or not screening takes place. “In the case of colorectal and breast cancer, screening is much more likely to be helpful than harmful, so we recommend that patients have it done. With prostate cancer, we don’t have that level of certainty,” explains Durado Brooks, MD, director of Prostate and Colorectal Cancer in the Cancer Control Department of ACS. “The decision of whether to be screened is part of the discussion, not which test to use.” The slow-growing nature of most prostate cancers, the risk that standard treatments pose to quality of life, and the lack of unequivocal evidence that screening for cancer actual reduces mortality underlie that position, Dr. Brooks says.

Colored MRI shows cancer (red) of the prostate gland (brown, center).

Who needs counseling, and when?

One unambiguous recommendation is that men whose age and health status give them a life expectancy of less than 10 years should www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • OCTOBER 2011 71

PROSTATE SCREENING

Treatments commonly used today may lead to urinary, bowel, sexual, and other health problems, which in some cases are severe and permanent. not be screened. It serves no positive purpose,” points out Dr. Brooks. Even in clinical trials that found mortality reductions with screening, it took seven to eight years for the benefit to emerge. For most men, discussions about whether to screen should begin at age 50 years. Individuals at higher risk—black men and those with a father or brother diagnosed with prostate cancer before age 65 years—should start five years earlier. Men who have multiple family members diagnosed before age 65 years are at appreciably higher risk and should consider screening from age 40 years, the ACS guideline authors recommend. Simply initiating such discussions may take effort. “Most men are used to going to the doctor and being told they have to have some test done. They are not accustomed to the idea that they themselves are to make the decision,” Dr. Brooks cautions. For the man who defers to professional judgment, the clinician should factor in what he or she knows about the patient’s values and feelings about risk, sickness, and health care, along with specific needs or health issues that may alter the risk/benefit equation. The discussion

The 2001 version of the ACS guideline also recommended shared decision-making; the update emphasizes it more strongly and describes the process in greater detail. The clinician’s role, according to the guideline, should be “helping men to make this decision by assuring that they have adequate information and by helping them to clarify their values relevant to the decision.” Although the level of detail provided should be tailored to the patient’s individual needs and capacities, the guideline specifies core elements of information, which should include the following: • Prostate cancer is an important health concern. • Screening with PSA alone or with PSA and DRE detects cancer at an earlier stage than otherwise possible.

• Screening may reduce the risk of dying from prostate cancer, but the evidence is conflicting, and there is no expert consensus on the value of screening. • PSA and DRE tests may produce false-positive or falsenegative results, which can result in unnecessary anxiety and additional testing, or missed cancer. • Abnormal PSA or DRE results commonly require prostate biopsy, which can be painful, may lead to complications, and sometimes miss significant cancer. • If cancer is detected, it is currently impossible to predict which men will likely benefit from treatment, and who will have died from unrelated causes whether or not they were treated. • Treatments commonly used today may lead to urinary, bowel, sexual, and other health problems, which in some cases are severe and permanent. • Not all men whose prostate cancer is detected require immediate treatment. For some, “active surveillance” with periodic blood tests, biopsy, or other testing may safely determine when, if ever, treatment is necessary. The process of clarifying values helps men look at pros and cons of screening in light of what is important to them, how they feel about risk and uncertainty, and their attitude toward health care. This discussion might include reasons why men decide for or against screening and hypothetical scenarios to illustrate them. Like most guidelines, the ACS document includes a review of the evidence behind its recommendations. Here, summaries of studies on the risks and benefits of screening, harms associated with early detection, and the effects of various treatments also provide material for a more informed discussion. Printed, Web-based, or CD-based material may be effective adjunctive tools to help patients make informed decisions. Such decision aids, if made available for men to review in advance, may foster more efficient discussions within the time constraints of a primary-care practice, notes Dr. Brooks. The ACS guideline includes a list of decision aids issued by reputable organizations and available online. Most of these are also available on the ACS website.2

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Screening

The ACS guideline updates recommendations for men who choose to be screened. The principal PSA thresholds are unchanged: When blood levels exceed 4.0 ng/mL, further

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The authors suggest that the screening interval may be extended from one to two years for men whose PSA is lower than 2.5 ng/mL. Community-based screening

Although community programs may provide a useful opportunity to those who otherwise would not have access to screening, these initiatives too often lack the resources for proper risk assessment and informed decision making or the means to assure appropriate counseling and follow-up care when results are positive. In their absence, the ACS discourages men from participating in such programs. More generally, screening by a primary-care provider is a better choice than even well-conducted community programs, according to the ACS guideline authors. ■ Mr. Sherman is a freelance medical writer in New York City. References 1. Wolf AM, Wender RC, Etzioni RB, et al. American Cancer Society guideline for the early detection of prostate cancer: update 2010. CA Cancer J Clin. 2010;60:70-98. 2. American Cancer Society. Information for health-care professionals. Available at www.cancer.org/Healthy/ InformationforHealthCareProfessionals/index. All electronic documents accessed September 15, 2011.

evaluation, perhaps including biopsy, “remains a reasonable approach.” Between 2.5 ng/mL and 4.0 ng/mL, such evaluation should be considered, based on an assessment of the man’s risk that takes into account such factors as age, race, family history, abnormal DRE, and results on previous biopsies. As before, the guideline does not recommend biopsy based on PSA velocity alone independent of the PSA score. In a change from previous recommendations, the authors suggest that the screening interval may be extended from one to two years for men whose PSA is <2.5 ng/mL. Based on data from various studies, this approach would not add appreciably to mortality and would reduce unnecessary biopsies along with unnecessary testing. Once considered a routine part of screening, DRE is now optional, to be considered on an individual basis (e.g., when PSA falls between 2.5 ng/mL and 4.0 ng/mL). Even with “optimal performance,” studies have found that DRE appears to increase cancer detection by relatively little. “It is clear that cultural issues make DRE problematic for some men,” Dr. Brooks says, and this might deter those who would otherwise opt for screening. “It seems an unreasonable, unnecessary barrier.”

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PEDIATRICS REVIEW•

LESLIE K. SCOTT PHD, PNP-BC, CDE

New-onset diabetes in children and teens Type 2 diabetes in this population is increasing, but type1 diabetes is more prevalent. The ability to differentiate between these conditions is crucial.

he prevalence of childhood obesity in the United States continues to rise. Clinicians are also seeing more children with clinical features of type 2 diabetes mellitus (T2DM) present at diagnosis.1 As a result, it is becoming more difficult to differentiate between type 1 diabetes mellitus (T1DM) and T2DM in this patient population. Although the incidence of T2DM in children is increasing, this condition remains relatively rare, with a reported incidence of 8.4 per 100,000 non-Hispanic white youths.2 As the more prevalent condition (affecting 1 in 300 children),3 T1DM must be ruled out. Making the appropriate diagnosis is critical given the differences in treatment regimens, educational approaches, and dietary counseling strategies. To illustrate, consider the following case study.

PUNCHSTOCK

Case study

Use current glucose level to determine management of a child with diabetes.

Adam, an 11-year-old non-Hispanic white male, was referred to the pediatric diabetes clinic for evaluation and management of newonset T2DM. He presented to his primary-care provider (PCP) five days earlier with complaints of upper-respiratory infection/allergy symptom exacerbation and fatigue with weight loss (11 lbs. over the previous three months). Adam’s mother casually mentioned a recent history of polydipsia, polyuria, and nocturia. A fingerstick blood glucose level obtained in the office measured >300 mg/dL. The PCP then ordered further studies (Table 1). Continues on page 77

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

NEW-ONSET DIABETES IN CHILDREN

TABLE 1. 1. Initial laboratory studies Laboratory study

Result

Normal range

Hemoglobin (Hb) A1c

11.6%

4.3%-5.7%

Serum glucose (non-fasting)

628 mg/dL

<140 mg/dL

C-peptide

1.5 ng/mL

1.1 ng/mL-4.4ng/mL

Adam was started on metformin (Fortamet, Glucophage, Glumetza, Riomet) 500 mg daily and twice-daily blood glucose monitoring. He was then referred to the pediatric diabetes clinic for further evaluation, dietary instruction, and diabetes self-management training. A complete history and physical examination were obtained at the diabetes clinic. No known drug allergies were noted. Since the initiation of metformin six days earlier, Adam’s home glucose values measured >200 mg/dL throughout the day. Ketone monitoring was not ordered. The family implemented a diet eliminating concentrated sweets. The patient’s father had recently been diagnosed with T2DM. No endocrine or autoimmune disorders were reported in other family members. A review of systems was notable for continued fatigue, polyuria, polydipsia, and polyphagia. On physical exam, Adam was alert, interactive, and in no apparent distress. Height was 160 cm, weight 70 kg, BMI

27.3, BP 107/56 mm Hg, and heart rate 76 beats per minute. Skin was warm and dry with no rash or stria. Mild acanthosis nigricans (AN) was noted on the posterior neck. Laboratory studies obtained by pediatric endocrinology are listed in Table 2. Adam’s HbA1c and glucose levels were elevated. He showed no clinical symptoms or laboratory analyses suggesting diabetic ketoacidosis (DKA). However, based on these laboratory findings and the presence of classic clinical symptoms, he clearly had diabetes. Due to an extremely elevated HbA1c, intensive insulin therapy was initiated during his initial clinic visit, pending further laboratory analysis. Because of Adam’s age, family history, and clinical presentation, it is important to determine whether he had T1DM or T2DM. Given such physical findings as high BMI and mild AN, along with his positive family history of T2DM, the patient was started on metformin. While the presence of mild AN suggests insulin resistance and hyperinsulinemia, Adam’s C-peptide level was not elevated. The AN was more likely related to his high BMI.4 Laboratory findings did not show acidosis, which would support the possibility of T2DM. Although Adam’s C-peptide level fell within the normal range, given his degree of hyperglycemia, a normal C-peptide may actually have demonstrated insulin deficiency—a characteristic of T1DM. Two of the diabetes

TABLE 2. 2. Laboratory studies obtained by pediatric endocrinology Laboratory studies

Result

Normal value

Clinical indication/assessment

Fasting plasma glucose

245 mg/dL

<100 mg/dL

Assess glucose metabolism-pancreatic function

CO2

26 mmol/L

20-31 mmol/L

Assess acid-base balance

Anion gap

8 mmol/L

5-11mmol/L

Assess for metabolic acidosis

Thyroid-stimulating hormone

3.19 mIU/L

0.5-4.5 mIU/L

Assess thyroid function

Serum creatinine

.57 mg/dl

0.5-1.0 mg/dl

Assess renal function

HbA1c

11.8%

4.3%-5.7%

Assess blood-glucose control

Total cholesterol

153 mg/dL

<170 mg/dL

Assess risk of heart disease

HDL

33 mg/dL

>59 mg/dL

LDL

84 mg/dL

<100 mg/dL

Triglycerides

180 mg/dL

<150 mg/dL

Assess lipid/metabolic process

C-peptide

1.0 ng/mL

0.8-3.5 ng/mL

Assess endogenous insulin production

Glutamic acid decarboxylase antibody

4.04 U/mL

0.0-1.45 U/mL

Assess autoimmune response

Insulinoma associated-2 antibody

10.5 U/mL

<0.76 U/mL

Assess autoimmune response

Insulin antibody

<0.4 U/mL

Assess autoimmune response

Serum ketone

Negative

Assess for metabolic acidosis

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NEW-ONSET DIABETES IN CHILDREN

The positivity of antibodies decreases over time in patients with type 1 diabetes, so there is no need to measure antibodies years after onset. autoantibody studies (glutamic acid decarboxylase [GAD] and insulinoma associated [IA]-2) were positive, demonstrating pancreatic autoimmunity, which is also suggestive of T1DM.1 Finally, Adam’s insulin autoantibody was negative, but since he was insulin (exogenous)-naïve, this was not unexpected.5 Considering his history and laboratory assessment, Adam was diagnosed with T1DM. Type 1 diabetes mellitus

Accounting for only 5%-10% of all diabetes cases,1 T1DM is caused by the immune-mediated destruction of the pancreatic beta-cells, resulting in an absolute deficiency of insulin secretion. Such environmental triggers as particular viruses can instigate the immune-mediated response, which leads to T1DM in genetically predisposed individuals.6 Treatment includes insulin administration to replace/supplement the insufficiency of secreted insulin. Type 2 diabetes mellitus

Accounting for 90%-95% of all diabetes cases,1 T2DM is caused by a complex combination of metabolic disorders arising from such defects as cellular insulin resistance, increased hepatic glucose production, and relative decreased pancreatic insulin secretion. There is a known strong genetic predisposition for T2DM among family members.6 Treatment strategies for T2DM are based on the individual’s ability to achieve glycemic goals. The American Academy of Clinical Endocrinologists’ (AACE) diabetes-management guidelines are based on HbA1c levels and clinical symptoms (Table 3).7 Typically, an insulin sensitizer (e.g., metformin) coupled with lifestyle changes is the fi rst line of treatment for T2DM. However, the use of metformin has only been able to lead to a 1% -2% reduction in HbA1c levels.7 According to the AACE guidelines, insulin should be initiated for HbA1c levels >10% to control hyperglycemia and reverse glucose toxicity.7 Insulin treatment may be modified as glucose toxicity resolves and clinical condition improves. In light of Adam’s extremely elevated HbA1c level, insulin should have been considered. When considering initiating pharmacologic therapy for the management of T2DM, keep in mind that most oral agents used in adults are not approved for use in children. All pharmacologic interventions should be monitored closely and adjusted as necessary to ensure adequate effect of treatment.

Diabetes autoantibodies

In cases of T1DM, one or more of the diabetes autoantibodies will be present in 95% of those affected at the time of initial diagnosis.5 With T2DM, the autoantibodies are typically absent. Four autoantibodies demonstrate the beta-cell autoimmunity of T1DM: While the islet cell autoantibody is positive in 70% to 80% new-onset cases of T1DM,8 it is not specific to the beta-cell. The GAD autoantibody, detected in 80% of newonset T1DM cases, is specific to the beta-cell protein5 and is the most commonly detected autoantibody. Protein tyrosine phosphatase-like protein (IA-2) autoantibodies are antigen-specific islet autoantibodies and are frequently detected in children with T1DM (about 60% at diagnosis).5,8 Insulin autoantibodies are present in 50% of children with T1DM at the time of diagnosis. Insulin autoantibodies cannot distinguish between endogenous and exogenous insulin and are a poor test for those on insulin therapy. In fact, individuals who have received exogenous insulin therapy for more than two to three weeks may have positive insulin autoantibodies on analysis.6 Autoantibodies may even be present in individuals without diabetes. Presence of autoantibodies in the absence of diabetes does not guarantee the development of T1DM. The risk of T1DM is directly proportional to the number and titer of autoantibodies present.9 The presence of GAD autoantibody and IA-2 autoantibody predicts beta–cell failure, thus demonstrating T1DM.8 The positivity of autoantibodies decreases over time in T1DM, so there is no need to measure autoantibodies years after onset. Continues on page 80

TABLE 3 3.. Management of type 2 diabetes in children HbA1c level

Pharmacologic therapy

6%-7%

Monotherapy (metformin)

7%-8%

Metformin + secretagogue or insulin analog

8%-10%

Aggressive use of combination therapies to improve fasting and postprandial glucose levels (will likely need to initiate insulin therapy)

>10%

Initiate intensive insulin therapy

Adapted from Rodbard HW, Blonde L, Braithwaite SS, et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus. Endocr Pract. Pract. 2007;13 Suppl 1:1-68. Available at aace.metapress.com/ content/300404/. Accessed September 15, 2011.

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NEW-ONSET DIABETES IN CHILDREN

TABLE 4. Laboratory differentiation of type 1 and type 2 diabetes Laboratory studies

References 1. National Diabetes Education Program. Overview of diabetes in children and adolescents. Available at http://ndep.nih.gov/media/Youth_FactSheet.pdf.

Type 1 diabetes

Type 2 diabetes

2. National Institute of Diabetes and Digestive and Kidney Diseases. National diabetes statistics, 2011. Available at diabetes.niddk.nih.gov/dm/

Ketones

Positive (may be negative, Negative (may be depending the degree of positive if the child is insulin insufficiency) fasting or ill)

pubs/statistics/. 3. Bell RA, Mayer-Davis EJ, Beyer JW, et al. Diabetes in non-Hispanic white youth: prevalence, incidence, and clinical characteristics: the SEARCH for

CO2

Normal (may be low if acidosis/DKA is present)

Normal

C-peptide

Low to normal

Typically elevated

GAD autoantibody

Positive

Negative

IA-2 autoantibody

Positive

Negative

Insulin autoantibody

Positive (may be negative if the child is insulin naïve)

Negative (may be positive if exogenous insulin is initiated)

Diabetes in Youth Study. Diabetes Care. 2009;32:S102-S111. Available at care.diabetesjournals.org/content/32/Supplement_2/S102.long. 4. Rai VM, Balachandran C. Generalized acanthosis nigricans in childhood. Dermatol Online J. 2006;12:14. 5. Johns Hopkins Medicine. Autoantibodies in type 1 diabetes. Available at www.hopkins-diabetesguide.org/clinical_tests/immunology/autoantibodies/. 6. Centre for Genetics Education. Diabetes types 1 and 2 and inherited predisposition. Available at www.genetics.edu.au/pdf/factsheets/fs57.pdf. 7. Rodbard HW, Blonde L, Braithwaite SS, et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus. Endocr Pract. 2007;13 Suppl 1:1-68.

Putting it all together

Available at aace.metapress.com/content/300404/.

In the clinical setting, how can one differentiate between the onset of T1DM and T2DM in children? Laboratory studies can be helpful (Table 4). Keep in mind that autoantibody results can take up to two weeks. Clinical presentation, current glucose level, presence of ketones, and HbA1c level can help the clinician determine how best to proceed with the initial stabilization and medical management of a child with diabetes. In Adam’s case, clinical presentation warranted the initiation of insulin based on the AACE management guidelines.7 His extremely elevated HbA1c level demonstrated a degree of glucose toxicity. Two to three months of insulin was recommended to combat glucose toxicity and to allow time for laboratory evaluation to determine proper diagnosis (T1DM vs. T2DM). Of course, pharmacologic intervention should be considered in addition to glucose/ketone monitoring strategies, dietary intervention/instruction, and management of daily activities in individuals with either T1DM or T2DM. Children with suspected T2DM and HbA1c <10% can be managed less aggressively according to their clinical presentation and initial laboratory analyses. However, if laboratory analyses demonstrate the presence of diabetes autoantibodies, insulin should be initiated to prevent DKA, which can result from a delay in treatment. ■

8. American Association of Clinical Chemistry. Diabetes-related autoantibod9. Borg H, Gottsäter A, Fernlund P, Sundkvist G. A 12-year prospective study of the relationship between islet antibodies and beta-cell function at and after the diagnosis in patients with adult-onset diabetes. Diabetes. 2002;51:1754-1762. Available at diabetes.diabetesjournals.org/content/51/6/1754.long. All electronic documents accessed September 15, 2011.

Dr. Scott is an assistant professor and pediatric BSN-DNP coordinator at the University of Kentucky College of Nursing in Lexington.

ies. Available at labtestsonline.org/understanding/analytes/diabetes-auto/.

“I’m an elephant podiatrist. What do you do?”

80 THE CLINICAL ADVISOR • OCTOBER 2011 • www.ClinicalAdvisor.com

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 O C TO B E R 2 0 1 1

Consultations GI upset in a teenager . . . . . . . . . . . .84 Treatment of chronic esophageal reflux . . . . . . . . . . . . . . .84 High-dose beta blockers in a patient with pulmonary disease . . .86 Cardioprotection in a complex patient . . . . . . . . . . . . . . . .86 Was this rash related to terbinafine? . . .86

Clinical Pearls Simple pounds-to-kilograms conversion. . . . . . . . . . . . . . . . . . . .90 Dietary-restriction tool is money in the bank. . . . . . . . . . . . . .90 Tricky vaginal-ring insertion . . . . . . .90 Tartrate or succinate? . . . . . . . . . . . . .90 And more . . . . . . . . . . . . . . . . . . . . .90

Your Comments Who is “too stupid” now? . . . . . . . . .92 Provide older patients with a list of current medications . . . . . . . . . . .92

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.

CONSULTATIONS TREATING ATRIAL FIBRILLATION DURING PREGNANCY How often should follow-up ECG be done on a pregnant patient with atrial fibrillation (AF) that resolves with medication that is then discontinued?—CONNIE KELLY, FNP, Franklin, N.Y. The first factor to consider in such a patient is whether the echo indicates a normal left atrium. If so, think about a 14-day cardiac monitor for asymptomatic AF. Pregnancy is a hypercoagulation time frame, and stroke prevention may need to be considered. The Zio Patch is a minimal invasive cardiac rhythm monitor. Consult an electrophysiologist when treating AF during pregnancy. Monitor rhythm during labor, as AF decreases cardiac output, which can affect the unborn child. If abnormalities are detected in the echo, consult an electrophysiologist.—Maria Kidner, DNP, FNP-C (156-1)

DEPRESSION TREATMENT IN AN OVERWEIGHT RECENT EX-SMOKER Which antidepressant would you recommend for a woman aged 47 years who presents with depressed mood, low energy, decreased motivation, and hypersomnia? The patient is overweight, has elevated liver enzymes and a

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

Peter F. Cohn, MD, is chief of

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.

cardiology and professor of medicine at State University of New York at Stony Brook.

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

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

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.

history for binge drinking, and recently stopped smoking using varenicline (Chantix). She is also being evaluated for possible multiple sclerosis.—AMY A. PAYSON, EdD, APRN, CNS-BC, PMHNP-BC, Trumball, Conn. This patient is presenting with classic symptoms of depression and would likely respond well to bupropion (Wellbutrin). This drug is indicated for the treatment of depression and seasonal affective disorder. Bupropion is also used to decrease cravings and helps people to stop smoking. In the brain, bupropion blocks noradrenergic reuptake and dopaminergic reuptake. Dopamine, a neurotransmitter, is involved with feelings of enjoyment and pleasure and increases motivation. A person who is dopamine-defi cient will often complain of depression, fatigue, and decreased motivation. Bupropion is contraindicated in patients with a history of seizure disorder, bulimia, and anorexia nervosa. For patients with hepatic cirrhosis or renal impairment, consideration should be given for reduced dosing. Patients with chronic medical problems are at risk for depression and should be treated appropriately.—Eileen F. Campbell, MSN, CRNP (156-2)

REFLUX REBOUND AFTER STOPPING PPI THERAPY What is the likelihood of acid-reflux rebound in a patient stopping a proton-pump inhibitor (PPI) (pantoprazole [Protonix]) after taking for one month or more? Breakthrough rebound is common, so how can it be controlled in a patient who does not want to continue using a PPI?—MAUREEN IRWIN, PA, Taylor, Mich.

asymptomatic), placed them on a daily PPI for eight weeks, and then stopped the PPI. Greater than 40% of participants experienced rebound acid hypersecretion syndrome (RAHS) symptoms of varying degrees of severity (Gastroenterology, 2009;137:80-87). Treatment for RAHS is necessary but should not become long-term whenever possible. I have successfully weaned a number of patients off PPIs with a gradual wean supplemented by OTC antacids. In addition to avoidance of known triggers, I encourage gradually increasing the time between PPI doses, treating symptoms episodically, and a bland diet.—Rebecca H. Bryan, APRN, CNP (156-3)

RECURRENT BOUTS OF BILIARY COLIC For five years, my patient has been experiencing several episodes a year of what appears to be biliary colic—severe epigastric and right-upper-quadrant abdominal pain that begins shortly after eating, is associated with nausea and vomiting, and lasts about four hours. Two abdominal ultrasounds were normal, as were a complete blood count, liver function tests, and lipase and amylase levels. An upper GI series was negative. The gastroenterologist ordered a cholecystokinin-hepato-iminodiacetic acid (CCK-HIDA) scan. The biliary ejection fraction was 3%, and the patient experienced nausea after injection of the CCK. Both the gastroenterologist and a surgeon have recommended cholecystectomy. Please explain the CCK-HIDA scan. Would you advise surgery for this patient?—DANIEL FEDERMAN, MD, Newtown, Conn.

Patients are increasingly becoming aware of the detriments of prolonged PPI use, which include osteoporosis and vitamin deficiencies. A recent study took 120 reflux-free participants (clean endoscopy,

When a patient has chronic acalculous gallbladder dysfunction (CAGD), a traditional HIDA scan may be inconclusive, since no stones are present to lead to frank cystic duct obstruction. In these cases, use of CCK, a powerful stimulant for gallbladder contraction, can be helpful. In the CCK-HIDA scan, or “gallbladder ejection

Susan Kashaf, MD, MPH, is assistant

Sherril Sego, FNP-C, DNP, is a

Daniel G.Tobin, MD, is assistant

Julee B.Waldrop, DNP, is associate

Jeffrey Weinberg, MD, is director of

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.

professor at the University of Central Florida (UCF), Orlando, and practices pediatrics at the UCF Health Center.

clinical research, Department of Dermatology, St. Luke’s-Roosevelt Hospital Center, New York City.

professor of medicine, Yale University School of Medicine, New Haven, Conn.

Maria Kidner, DNP, FNP-C, is

a nurse practitioner with Cheyenne Cardiology Associates in Cheyenne, Wyo.

Debra August King, PhD, PA, is senior

physician assistant, New YorkPresbyterian Hospital, New York City.

Claire Babcock O’Connell, MPH, PA-C, is an

associate professor, University of Medicine and Dentistry of New Jersey, PA program, Piscataway.

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testing she had (blood test or biopsy) and the exact results. Does she have a family history of celiac disease? Did she try a strict gluten–free diet as a trial? Third, determine exactly what labs she had done. What stool studies were done? What was the parasite that she tested positive for? Did she have stool tests for possible osmotic diarrhea? Did she have multiple biopsies from her EGD and colonoscopy? Finally, find out whether she had a breath test for small-bowel bacterial overgrowth, which can be associated with irritable bowel syndrome. It would be helpful to know if she had a small-bowel series or capsule endoscopy as well.—Sharon DudleyBrown, PhD, FNP-BC, co-director, gastroenterology & hepatology, nurse practitioner fellowship program, Johns Hopkins University Schools of Medicine & Nursing, Baltimore (156-5) Gallstones (center) may obstruct the flow of bile to the intestines.

fraction test,” gallbladder function is determined by measurement of the percent decrease in gallbladder radioactivity over a specified period after infusion of CCK. Normal gallbladder ejection fractions range from 35%-75%, and numerous studies have suggested that for patients with values <35%, cholecystectomy can be highly effective for symptom relief. I therefore understand why the gastroenterologist and surgeon have recommended cholecystectomy. A study has brought the utility of this test into question (Am J Gastroenterol. 2003;98:2605-2611), however, and I would advise you to read this excellent review before making a final decision.—Daniel G. Tobin, MD (156-4)

GI UPSET IN A TEENAGER A woman aged 19 years has a three-year histor y of recurrent chronic abdominal pain and diarrhea. Esophagogastroduodenoscopy (EGD), colonoscopy, complement fixation, celiac, sonogram, gynecologic workup, and routine labs have all been negative. A lactose-free diet resulted in slight improvement. She was treated empirically after a positive stool culture for a parasite that may or may not cause symptoms, which seemed to help for a while. What steps should be taken next?—TINA CLARK, CRNP, Owings Mills, Md. First, assess whether her symptoms fit the Rome III criteria for functional GI disorders, specifically irritable bowel syndrome (IBS) (available at www.romecriteria.org/assets/pdf/19_RomeIII_ apA_885-898.pdf, accessed September 15, 2011). Does she have symptom-free days? Are there any abnormalities on physical exam (e.g., weight loss)? Are there any red flags in her history (e.g., nighttime symptoms)? Second, find out what type of celiac

TREATMENT OF CHRONIC ESOPHAGEAL REFLUX What treatment options are available for chronic esophageal reflux? Is surgery ever preferable to long-term treatment with a proton-pump inhibitor (PPI)?—KANDACE McCARVER, PA-C, Clermont, Fla. Treatment of chronic reflux begins with lifestyle modifi cations. Patients should be encouraged to eat small, frequent meals, and lying down should be avoided for at least two hours after eating. Overweight and obesity should be confronted, as these conditions increase the risk of reflux. Cigarette smoking and alcohol should be avoided. Patients should avoid any foods that trigger their particular reflux symptoms; common trigger foods include tomato products, hot/spicy foods, fatty or fried foods, chocolate, and mint. Anatacids provide symptomatic relief, but long-term use results in rebound heartburn symptoms, diarrhea, or constipation. Longer-term control can be sought through administration of H2 receptor blockers (e.g., cimetidine [Tagamet), ranitidine [Zantac]) or PPIs (e.g., omeprazole [Prilosec], lansoprazole [Prevacid]). Although both types of medications result in reduced acid production and resolution of symptoms, PPIs are more likely to promote healing. Prokinetic agents (metoclopramide [Reglan], cisapride [Propulsid]) promote gastric emptying, thereby reducing risk of reflux, and also tighten the gastroesophageal sphincter. Medication types can be combined for greater efficacy. Reserve such surgical procedures as fundoplication, endoluminal gastroplication, and electrocautery for severely symptomatic individuals who fail lifestyle and medication management. There is also anecdotal evidence supporting such alternative treatments as herbal remedies (e.g., licorice, slippery elm, chamomile), relaxation therapy, and acupuncture.—Claire Babcock O’Connell, MPH, PA-C (156-6)

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Continues on page 86

Advisor Forum

Patients with COPD often die of cardiovascular causes, as impaired lung function has been shown to be an independent risk factor for coronary events and cardiac arrhythmias. Beta blockers have been proven effective in the management of patients with cardiovascular disease yet have been underused in patients with COPD due to a concern for acute bronchospasm. Evidence from various clinical trials and meta-analyses indicates that such cardioselective beta blockers as metoprolol have benefits that outweigh the risks and should not be withheld from patients with COPD. Although the recommendation is to start patients at a low dose of a beta blocker and titrate up as needed while assessing lung function, there are studies that show doses of 200 mg of metoprolol had no clinically significant effect on respiratory function (Respir Med. 2003;97:1094-1101).—Eileen F. Campbell, MSN, CRNP (156-7)

CARDIOPROTECTION IN A COMPLEX PATIENT What is the best choice for cardioprotection in a woman aged 75 years with episodic symptomatic angina, MI one year earlier, and a sensitivity to nitroglycerin patches (i.e., skin erythema, burning, and itching) and spray (i.e., acute syncope)? She also has allergy or adverse reaction to aspirin, ACE inhibitor, clopidogrel (Plavix), and telmisartan (Micardis). The patient has a low resting heart rate (58 beats/minute) and is on a maximum-tolerated dose of beta blocker.—BARBARA FOX, FNP, Victoria, B.C. This is a complex situation. First, clarify her exact adverse reaction to ACE inhibitors and angiotensin II receptor blockers (ARBs). In the event of true histamine or angioedema, do not try any other drugs in this class. If it was dizziness, feeling poorly, or the patient just didn’t like them, try another ACE inhibitor or ARB or aliskiren (Tekturna). The choices for this patient’s angina are ranolazine (Renexa), which affects the sodium channel gates, or isosorbide mononitrate (Imdur, Ismo, Isotrate, Monoket) as a long-acting nitroglycerin (start low [30 mg], since there was syncope). When multiple allergies prevent you from implementing all the guideline medications, remember that quality of life and education are the priorities. Explain why certain medications are being tried and what the expected outcomes are. Always ask about diet, exercise,

and smoking. In cardiology, 80% of complications are preventable through lifestyle management. The choice of beta blocker depends on the ejection fraction. If >40%, nebivolol (Bystolic) would be a great choice because of its effect on the nitric oxide pathway. If <40%, metoprolol succinate (Toprol) and carvedilol (Coreg) are the only choices. If the patient is diabetic, carvedilol and nebivolol are the only options.—Maria Kidner, DNP, FNP-C (156-8)

WAS THIS RASH RELATED TO TERBINAFINE? A man with onychogryphosis had been taking terbinafine (Lamisil) daily for about seven weeks without any side effects. During a trip to the Caribbean, the weather was rainy and overcast. He swam in rather stirred-up seas for a couple of days and was in the sun off and on. After a few days, he developed a fine pruritic rash over the exposed areas of his body (upper trunk, limbs), but not on his face. He thought this might be a little “sun poisoning” or a reaction to microplankton in the sea, although he wasn’t aware of having been stung. Despite his efforts to avoid the sun as much as possible, the rash continued. Eventually, he developed flulike symptoms (headache, fever, muscle soreness, and diarrhea). After a week in the Caribbean, he returned to Ohio, where he had no further sun exposure. Nevertheless, the rash persisted and increased; he also developed a few small pustules. Except for the itching, he felt well. Worried about the worsening rash, he stopped the terbinafine and applied an OTC topical © The New Yorker Collection 2011 from cartoonbank.com. All Rights Reserved.

HIGH-DOSE BETA BLOCKERS IN A PATIENT WITH PULMONARY DISEASE Is it safe for a patient with chronic obstructive pulmonary disease (COPD) to be on high doses (e.g., 100 mg b.i.d.) of metoprolol (Toprol XL)?—CARMEN BOOTH, ARNPBC, Hahira, Ga.

“You’re thinking of Zeus—he throws the lightning bolts.”

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

Advisor Forum

divide by two. For example, if a child weighs 46 lb, subtract 4 (the first digit) from 46 (the child’s weight in pounds). This gives you 42. Divide by two to get 21 kg. It works every time! This is faster and easier than trying to divide by 2.2 quickly in your head or having to look all over for a calculator.—DEBRA MALLORY, RN, PhD, NP-BC, Terre Haute, Ind. (156-10)

Onychogryphosis results in gross thickening of the toenails.

steroid. His family physician gave him a steroid injection. The rash cleared a few days later. Could the rash have been a delayed reaction to terbinafine that was aggravated by sun exposure? Can the patient ever take terbinafine again? How can he get rid of the onychogryphosis, which is still pretty severe?—PATRICIA E. WONGSAM, MD, Lewis Center, Ohio The rash is not one commonly seen with terbinafine, although any drug can cause any rash at any time. Taken together, the signs and symptoms sound like a viral exanthem or photodermatitis. It might be useful to rechallenge the patient with terbinafine. If he has severe onychogryphosis, debridement by a podiatrist—whether or not you restart the terbinafine—would certainly help. If you do not want to restart the terbinafine, oral itraconazole would be another option.—Jeffrey M. Weinberg, MD (156-9)

CLINICAL PEARLS Congratulations to the winners of our first clinical pearls contest. The five readers below will each receive a $100 American Express Gift Cheque. The previous five winners appeared in the September 2011 issue. If you have a pearl you would like to share with your peers, send it to editor@ClinicalAdvisor.com.

SIMPLE POUNDS-TO-KILOGRAMS CONVERSION I often need to convert pounds to kilograms when calculating pediatric doses. To do so, subtract the first digit of the patient’s weight from the total number of pounds and

DIETARY-RESTRICTION TOOL IS MONEY IN THE BANK Individuals on fluid or sodium restriction should think of their daily allowance as the balance in a checkbook. For example, start out with 50 oz and subtract each time you drink some fluid. Or start with 2,000 mg and subtract the sodium content of your food. The patient will always know how much is left. Remind them not to overdraw the account. Just think of the penalties!—TERESE PRENTICE, NP, Skillman, N.J. (156-11)

TRICKY VAGINAL-RING INSERTION Some patients have difficulty inserting a contraceptive vaginal ring. Have these women take the cotton out of a tampon, fold the vaginal ring into the applicator (leaving an inch or so exposed), and insert. This takes the fear out of properly placing vaginal contraceptives.—BELINDA ISLEY, CRNP, Birmingham, Ala. (156-12)

TARTRATE OR SUCCINATE? Many providers confuse metoprolol tartrate (Lopressor) and metoprolol succinate (Toprol XL). Here is an easy way to keep them straight: Tartrate with a T is Twice a day or more, and succinate with an S is usually a Single dose daily.—DORI LAWSON, CRNP, FNP-BC, Reading, Pa. (156-13)

PRECISION COUNTS WHEN APPLYING MEDICATION TO THE SCALP A dental syringe—like the type used to irrigate after tooth extraction—is very helpful when applying solutions to the scalp. The very fine tip allows you to apply slowly, keeping the medication on the scalp instead of saturating the hair. This also allows more pinpoint application and decreases the amount of steroid exposure.—LINDA KENISON, RN-C, San Diego (156-14)

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Continues on page 92

Advisor Forum YOUR COMMENTS 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.

WHO IS “TOO STUPID” NOW? Ms. Carlisle’s post (“Expanding nurse practitioner roles benefits patients,” posted August 11, 2011) mentioned a colleague who overheard a physician tell a patient that nurse practitioners are “too stupid to get into medical school” and do not offer quality care. I did, in fact, get into med school many years ago and chose to stay in nursing. I am a family nurse practitioner and love my work. Maybe it is time for NPs to level some financial sanctions against physician groups that exclude us. We should resolve to boycott any conferences taught only by physicians. Until advance practice nurses are included, we stay home. That’s a start.—DEBORAH SAMPSON, FNP, Hancock, N.H. (156-15)

That physician’s ignorance is a shame, but he or she is the exception. I have worked as an NP in various settings since 1995, and the vast majority of physicians I have had the pleasure of collaborating with valued my experience and expertise. We enjoyed a great relationship, and they always complimented my performance. After all, would a stupid person have been able to diagnose abdominal aortic aneurysm, pulmonary embolism, appendicitis, and brainstem herniation?—EVELYN TORRES, NP, New York City (156-16)

“Let me check my card file for a joke about your condition.”

This comment was written in response to an entry in our monthly dermatology quiz, Derm Dx. To view this case and others like it, visit www.ClinicalAdvisor.com/DermDx.

PROVIDE OLDER PATIENTS WITH A LIST OF CURRENT MEDICATIONS It disturbs me that the patient described does not at least have a medications list in his wallet (“Elderly man with blue-gray pigmentation,” see page 102). I provide such a list to all of my older patients and revise it at every visit. In addition to listing current medications, I include allergies as well. This keeps these patients out of all sorts of trouble when they see specialists or have to visit the emergency department.—MARSHA DELAVAN, PA-C, Hollywood, S.C. (156-17) ■

“Water...water...and maybe just a tiny piece of pie.”

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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. We’ll be glad to work with you to develop your ideas into compelling articles. As for length, that depends on which kind of article you submit. CLINICAL FEATURES update our readers with the latest information about conditions seen in everyday practice. Running no more than 2,500 words, features can be written either as regular narratives or as a series of questions and answers. Topics should be selected with the busy primary-care clinician in mind; specialists should review specialty topics from the primary-care point of view. If at all possible, articles should be accompanied by clinical photos, for which we pay extra. Charts, tables, and algorithms are also encouraged. References are optional; if you opt not to use any, please provide a recommended reading list of books, articles, and websites. In addition, include your curriculum vitae, which should list all current titles and affi liations. CLINICAL CHALLENGE is our popular department comprising histories of difficult cases. Each case is presented as a step-by-step, chronological account, revealing the author’s thought processes along the way. It is divided into sections in this order: the patient presentation; the patient history; the twists and turns eventually leading to a diagnosis; the treatment and outcome; and a discussion of the lessons learned or of the condition in general. We pay extra for any photographs or images that we use. The length should be about 1,500 words. Please include your title, affi liations, and curriculum vitae. DERMATOLOGY CLINIC is a department that presents photos of actual cases and asks readers to identify the condition. Each case opens with one or two color photos and a brief description of the patient and/or his or her presentation, without giving away the diagnosis. This is followed by a 750- to 1,000-word summary that includes a fuller description of the ailment, how the correct diagnosis was achieved, a general review of the condition along with a differential diagnosis, and a description of the patient’s treatment and outcome. Topics must be approved by the editor prior to submission. COMMENTARY is our guest editorial page. It gives you the opportunity to sound off on an issue of importance to your colleagues nationwide. Support your views with as many facts, statistics, studies, and personal anecdotes as possible. A typical Commentary runs about 600 words in length. To discuss your editorial ideas, contact us by phone at 646.638.6077; by e-mail to editor@ClinicalAdvisor.com; or by mail to: The Clinical Advisor, 114 West 26th Street, 4th Floor, New York, NY 10001.

100 THE CLINICAL ADVISOR • OCTOBER 2011 • www.ClinicalAdvisor.com

Derm Dx Test your clinical acumen with our monthly quizzes

Elderly man with blue-gray pigmentation An 87-year-old man presented to the dermatology clinic concerned about a gradual darkening of his bilateral lower extremities. What is your diagnosis?

• • • • •

Minocycline-induced hyperpigmentation Lead poisoning Ecchymoses Exogenous ochronosis Post-inf lammatory hyperpigmentation

Mildly pruritic pink papules on a patient’s forehead An otherwise healthy 47-year-old man with type 2 diabetes presented complaining of multiple mildly pruritic pink bumps on his forehead. What is your diagnosis?

• • • •

Granuloma faciale Lymphocytoma cutis Angiolymphoid hyperplasia with eosinophilia Sarcoidosis

To post your answer, obtain more clues, or view similar cases, visit www.ClinicalAdvisor.com/DermDx. Learn more about diagnosing and treating these conditions, and see how you compare with your peers.

Clues are available for these other Derm Dx cases as well:

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Hypopigmented macules on a woman’s back

Child with diffuse pinpoint papules

Visit ClinicalAdvisor.com

Expand your practice In addition to the award-winning news and features found every month in our print edition, ClinicalAdvisor.com is an invaluable resource that now offers: • Free on-line CME/CE • Job advice and salary information • Medical slideshows • Derm Dx

• PLUS the opportunity to sign up for weekly newsletters and submit clinical questions and pearls to our popular Advisor Forum

To see all this and much more, visit 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 59. 133

CASE #1

Macules spread to the ears, neck, and trunk KERRI ROBBINS, MD

The mother of a boy aged 3 years brought her child to the dermatology clinic because she was concerned about a rash that had developed approximately six months after birth. The rash started on his face but soon spread to his ears, neck, and trunk. The lesions had been stable, but the mother is concerned for her son’s health and worried about the cosmetic appearance of the rash as he gets older. No pruritus was reported, and no previous treatments were described. Physical examination reveals multiple red-brown macules and papules on the face, ears, neck, and trunk. What is your diagnosis? Turn to page 106

CASE #2

Hardened plaque on a neonate’s back MAYA FETTER, MD, AND JULIA R. NUNLEY, MD

A full-term, healthy female infant was born to a woman aged 24 years. It was the mother’s fi rst pregnancy and was complicated by gestational diabetes and borderline hypertension. APGAR scores were 8 and 9, despite the presence of meconium staining at birth. Two weeks after discharge, the infant was brought to the pediatrician because the mother was worried about a rash on the girl’s back. Examination revealed an irregular, lobulated, indurated 7 ⳯ 9 cm plaque across the infant’s back; a smaller lesion was noted below the left axilla. The anterior trunk, extremities and face were spared. What is your diagnosis? Turn to page 107 www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • OCTOBER 2011 105

CME CE

CASE #1

Dermatology Clinic

Benign cephalic histiocytosis

In 1971, Gianotti described a condition as, “Infantile histiocytosis with intracytoplasmic wormlike bodies.”1 This description arose from such findings as the commashaped structures by ultrastructural studies (electron microscopy).1 It was later clear that many histiocyte disorders had similar ultrastructural findings, and the condition was renamed benign cephalic histiocytosis. The histiocytoses are a group of proliferative disorders with a common progenitor cell in the bone marrow. The three histiocytes of cutaneous importance are the Langerhans cell, the mononuclear cell/macrophage, and the dermal dendrocyte. The dysfunction of these cells leads to various disorders that are grouped into either Langerhans cell histiocytosis or non-Langerhans cell histiocytosis. Benign cephalic histiocytosis is a member of the non-Langerhans cell histiocytosis. Only 40 cases of benign cephalic histiocytosis have been documented to date.1 The disorder usually involves the head and neck, with an average age of onset of 15 months to 3 years. Approximatly 45% of the cases occur in children younger than age 6 months.2 There has been one report of an adult case in which the patient had T-cell lymphoma and the lesions were thought to be very similar to those found in benign cephalic histiocytosis. Overall, the disease is not gender-specific.1,2

Papules usually are first noticed on the face; they also may be on the ears and neck later in the course of the disease. The cause of benign cephalic histiocytosis is not yet known. Researchers have started to pinpoint the pathogenesis using the given similarities in histopathology, immunohistochemical profi le, and ultrastructural appearance to those of juvenile xanthogranuloma (JXG) and generalized eruptive histiocytoma. Some authors and researchers suspect benign cephalic histiocytosis to be a variant of the former disorders. A research study compared cases of generalized

eruptive histiocytosis, benign cephalic histiocytosis, and JXG histopathologically.1,3 The conditions were so similar that investigators recommended they be classified as a single disease with a spectrum of clinical features.4 Clinically, benign cephalic histiocytosis is characterized by red to red-brown macules and papules that range from 2 to 5 mm in diameter. The papules usually are first noticed on the face; they also may be found on the ears and neck later in the course of the disease.5 On occasion, papules may be seen on trunk, arms, and thighs. This is uncommon and is only appreciated when benign cephalic histiocytosis reaches advanced stages. The lesions may coalesce together in a reticular pattern.6 As time progresses, the papules will flatten and become hyperpigmented. The papules and macules will resolve spontaneously, but this may take months to years for some patients. The lesions are asymptomatic, and the course of the disease can be marked by exacerbations. There is usually no mucosal membrane or systemic involvement. However, there has been one reported case of a young woman with benign cephalic histiocytosis who also developed diabetes insipidus.7 If unsure, a biopsy can definitively diagnose the patient. Benign cephalic histiocytosis has three histologic patterns: a lichenoid pattern, a diffuse pattern, and a papillary dermal pattern.1,8 In the lichenoid pattern, occasional lymphocytes are seen along with small regular histiocytes located perivascularly and within the superficial dermis. In the diffuse pattern, histiocytes are found throughout the dermis. These histiocytes are usually round and regular, with minimal cytoplasm and no pleomorphic features. In contrast, pleomorphic histiocytes with abundant eosinophilic cytoplasm, hyperchromatic and sometimes indented nuclei, and large nucleoli are a characteristic feature of the papillary dermal pattern.1 This is the most common pattern, and the infi ltrate is often well-defined and closely approximated to the epidermis. Touton giant cells are absent in this all three patterns. Electron microscopy studies may reveal classic cells with intracytoplasmic comma-shaped or wormlike bodies. However, such bodies are also found in many other disorders, such as Langerhans cell histiocytosis, JXG, generalized eruptive histiocytoma, and Rosai-Dorfman disease.1,9 JXG is by far the most difficult disorder to differentiate from benign cephalic histiocytosis. Found mostly in children, JXG is a benign, asymptomatic, and self-healing disorder. In comparison with benign cephalic histiocytosis, the lesions of JXG tend to be larger and are often classified as nodules rather than macules and papules. Also, lesions of JXG are

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Lesions will heal spontaneously, leaving behind flat or atrophic hyperpigmented scars that will fade away over time. often found as either one or several individual nodules or are widespread and numerous. Benign cephalic histiocytosis is generally a self-limited disorder without any complications, and treatment is not necessary. The individual lesions will heal spontaneously, leaving behind flat or atrophic hyperpigmented scars. Over time, these too will fade away. Nevertheless, follow-up is recommended since exacerbations of the disease and diabetes insipidus have been known to occur.5,7 The parent and patient in this case were given extensive education and anticipatory guidance regarding the benign nature of this disorder. At the last follow-up appointment, some of the lesions had resolved, and the patient’s course had not been complicated by any exacerbations or the development of diabetes insipidus. 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. JL Bolognia, JL Jorizzo, RP Rapini, eds. Dermatology, 2nd ed., St. Louis, Mo.: Elsevier-Mosby; 2008:1400-1401. 2. Jih DM, Salcedo SL, Jaworsky C. Benign cephalic histiocytosis: a case report and review. J Am Acad Dermatol. 2002;47:908-913. 3. Zelger BG, Zelger B, Steiner H, Mikuz G. Solitary giant xanthogranuloma and benign cephalic histiocytosis—variants of juvenile xanthogranuloma. Br J Dermatol. 1995;133:598-604. 4. Gianotti F, Alessi E, Caputo R. Benign cephalic histiocytosis: a distinct entity or a part of a wide spectrum of histiocytic proliferative disorders of children? Am J Dermatopathol. 1993;15:315-319. 5. Paller AS, Mancini AJ. Hurwitz Clinical Pediatric Dermatology, 3rd ed. Philadelphia, Pa.: Elsevier Saunders; 2006:251-252. 6. Peña-Penabad C, Unamuno P, Garcia-Silva J, et al. Benign cephalic histiocytosis: case report and literature review. Pediatr Dermatol. 1994;11:164-167. 7. Weston WL, Travers SH, Mierau GW, et al. Benign cephalic histiocytosis with diabetes insipidus. Pediatr Dermatol. 2000;17:296-298. 8. DE Elder, R Elenitsas, BL Johnson, GF Murphy, X Xu, eds. Lever’s Histopathology of the Skin. 10th ed., Philadelphia, Pa.: Lippincott Williams & Wilkins; 2009:677-678. 9. RP Rapini. Practical Dermatopathology. Philadelphia, Pa.: Elsevier-Mosby; 2005:111.

CASE #2

Subcutaneous fat necrosis

A skin biopsy showed patchy fat necrosis surrounded by a granulomatous process consisting of histiocytes and multinucleated giant cells; needle-shaped clefts were present within the histiocytes and giant cells.1 These findings were consistent with the diagnosis of subcutaneous fat necrosis of the newborn (SFN). Laboratory studies were consequently ordered and serially followed. Primarily seen in otherwise healthy full- or post-term infants, SFN is an uncommon, idiopathic, self-limited, inflammatory panniculitis. Although many infants with SFN are products of uncomplicated pregnancies via straightforward vaginal or cesarean deliveries, others have been subjected to stress or trauma related to labor and delivery. Associated conditions include perinatal asphyxia, hypothermia, meconium aspiration syndrome, cord accidents, hypothermia, hypoglycemia, newborn failure to thrive, and such maternal complications as diabetes and pre-eclampsia.1-3 The onset of SFN is early, typically within the first few days to weeks of life, but it may be as late as two months.3 Commonly affected areas include the cheeks, buttocks, back, arms, and thighs; there is a predilection to form over bony prominences. The anterior trunk is characteristically spared.2,3 Over time, affected areas progressively develop one or more localized, firm, smooth, and well-circumscribed areas of induration. Lesions may be small nodules or large plaques, and some are lobulated. The degree of overlying erythema is variable. Although typically painless, some lesions may cause the infant to cry when handled. Lesions typically self-involute within several weeks to months without any sequelae. However, some become fluctuant as the fat necroses and liquefies, while other lesions calcify. Fluctuant lesions may be aspirated to decompress the area and promote resolution.1 Mild cutaneous atrophy may occur as a short-term consequence of SFN. Although the pathogenesis of SFN is not well understood, it is hypothesized that an obstetric trauma or perinatal stress or hypothermia results in injury to the immature pannus, triggering fat necrosis. Some investigators have suggested that neonatal fat has a higher melting point than adult fat, affording it a greater propensity to solidify and crystallize under stress.2 The incidence of SFN is unknown. There

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CME CE

Dermatology Clinic

is no apparent predilection for a specific ethnic or racial group, gender, or geographic region.1 Early histologic fi ndings include perivascular infl ammation and endothelial swelling. Later, fat necrosis with granulomatous changes consisting of histiocytes and multinucleated giant cells can be seen. The needle-shaped clefts and refractile crystals within the podocytes, histiocytes, and giant cells are thought to be attributable to triglycerides.1-3 Later in the disease, fibrosis develops as the lesions resolve; calcium deposition may be seen. Although SFN is usually a banal, self-resolving process, rare complications—some of which are life-threatening— may occur, and patients should be monitored. Hypercalcemia occurs during the resolution phase of this condition and is probably the most serious of the complications, which also include thrombocytopenia, hypoglycemia, hypertriglyceridemia, and infection. Significant hypercalcemia may result in infant lethargy, irritability, hypotonia, polyuria, polydipsia, failure to thrive, seizures, and cardiac arrest if not recognized and treated appropriately. Infants should be monitored with laboratory studies weekly or biweekly until the fat necrosis resolves. The time to resolution is typically one to six months.1-3 The pathogenesis of SFN-associated hypercalcemia is merely postulated. Staining of skin biopsy specimens has identified the presence of 25-hydroxyvitamin D3 1␣-hydroxylase within the granulomatous infi ltrate. Investigators propose that the granulomatous process of SFN is responsible for excess production of 1,25-dihydroxycholecalciferol in a fashion analogous to such other granulomatous disease as sarcoidosis. Excessive vitamin D subsequently increases absorption of calcium, resulting in hypercalcemia.1-3 If hypercalcemia occurs, intervention is needed. Treatment includes hydration; judicial use of loop diuretics; and a lowcalcium, low-vitamin-D diet. Corticosteroids, calcitonin, or bisphosponates may be of some benefit. The differential diagnoses of SFN include sclerema neonatorum (SN), lipogranulomatosis, deep-tissue infection, and nodular panniculitis. The well-being of most infants with SNF—along with the histologic findings—readily distinguish it from these other conditions. SN is probably the

most confusing early on, since it also occurs in the first few months of life. However, SN is more common in preterm infants than in term infants.4 Although both conditions affect the adipose tissue, skin findings are somewhat different. Unlike SFN, the skin lesions in SN are diffuse and consist of waxlike hardening of the subcutaneous tissue. The skin

Infants should be monitored with laboratory studies weekly or biweekly until the fat necrosis resolves. of infants with SN is bound to the underlying muscle and bone, whereas lesions of SFN are freely mobile. Because of the self-limited, benign nature of SFN, most patients may be managed with supportive therapy and periodic monitoring. If lesions become fluctuant they may be aspirated to prevent rupture. In this patient, initial monitoring demonstrated a slight thrombocytopenia that quickly resolved without sequelae. Calcium levels, monitored weekly, were always within the normal reference range. The lesions on the infant’s back resolved, leaving a slight irregularity that could be found only on deep palpation. At her 12-month well-baby visit, only mild atrophic changes could be detected. ■ Dr. Fetter is an intern in internal medicine at Carolinas Medical Center in Charlotte, N.C. Dr. Nunley is professor of dermatology at Medical College of Virginia Hospitals, Virginia Commonwealth University, in Richmond. Neither author has any relationship to disclose relating to the content of this article. References 1. Burden AD, Krafchik BR. Subcutaneous fat necrosis of the newborn: a review of 11 cases. Pediatr Dermatol. 1999;16:384-387. 2. Tran JT, Sheth AP. Complications of subcutaneous fat necrosis of the newborn: a case report and review of the literature. Pediatr Dermatol. 2003;20:257-261. 3. UpToDate. Skin nodules in newborns and infants. Available at www. uptodate.com/contents/skin-nodules-in-newborns-and-infants. 4. Aucharaz KS, Baker EL, Millman GC, Ball RJ. Neonatal subcutaneous

MORE DERMATOLOGY ON THE WEB

fat necrosis with characteristic rash and hypercalcaemia. Arch Dis Child

Test your diagnostic skills. Our FREE archive of Dermatology Clinic and Dermatologic Look-Alikes is now available online at www.ClinicalAdvisor.com.

Fetal Neonatal Ed. 2007;92:F304. Available at www.ncbi.nlm.nih.gov/pmc/ articles/PMC2675437/. All electronic documents accessed September 15, 2011.

108 THE CLINICAL ADVISOR • OCTOBER 2011 • www.ClinicalAdvisor.com

Clinical Challenge A running accident leads to the discovery of a humeral lesion JEFFREY L. SPIVEY, MPAS, PA-C

A woman fractured her upper arm in a fall while exercising. A large osteolytic growth was discovered on x-ray.

Ms. E is a healthy, 19-yearold wh ite woman who injured her right shoulder after falling while running. At the emergency department, she was told that she had a proximal humerus fracture. Her arm was placed in a standard sling, and she was instructed to make an appointment with an orthopedic surgeon in the next few weeks. She deferred orthopedic evaluation for six weeks while she prepared to move to another state. New x-rays taken by her primary-care clinician revealed a minimally displaced proximal humerus fracture with a large osteolytic lesion of the humeral head, neck, and proximal shaft (Figures 1 and 2). The patient underwent a CT scan that day and was referred to the orthopedic department for further evaluation.

CASE #1

1. BACKGROUND

FIGURE 1. Minimally displaced fracture through the anatomical neck of the humerus

Ms. E reported no major illnesses or medical problems prior to this injury. No family history of cancer was noted. She had multiple surgeries as a child for right-hand pre-axial polydactyly. Ms. E was recently married to an active-duty soldier and reported no illicit drug or alcohol use. Prescribed medications included acetaminophen and hydrocodone (Vicodin) 5/500 as needed for pain, zolpidem (Ambien) for sleep, and oral contraceptives.

2. REVIEW OF SYSTEMS

FIGURE 2. Extensive osteolysis of the humeral head and neck

The patient reported no fever, chills, night sweats, unexplained weight loss, fatigue, or malaise. She stated her overall health was “great until this.” She reported no headaches, visual disturbances, sore throat, or sinus problems. No recent history of any swollen glands or neck pain was noted. Ms. E had no cardiac history, no swelling of the right upper extremity, and no coldness or pallor of the right upper extremity. She had no cough and no dyspnea at rest or with exertion. No nausea, vomiting, diarrhea, rectal bleeding, or change in stool habits was

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Clinical Challenge reported. Ms. E was in a monogamous relationship with no prior sexual encounters. There was no history of vaginal discharge, itching, or lesions. She reported no prior injuries to the affected shoulder. Ms. E currently had shoulder pain with active range of motion, with no pain at rest or distal to the shoulder. She had no history of transient or migratory arthralgias. While no numbness, tingling, or weakness in the right upper extremity was reported, Ms. E did note atrophy of the right shoulder musculature.

proximal humerus on gross examination, appearing apex anterior translation. Motion testing of the shoulder showed moderate limitation in forward flexion, abduction, and external rotation. There was full range of motion of the elbow, forearm, wrist, and hand with symmetrical grip strength. Mild atrophy consistent with disuse was noted. There was no tenderness to palpation of the acromioclavicular joint or proximal humerus. Ms. E had no loss of sensation to light touch throughout the right upper extremity.

3. PHYSICAL EXAMINATION

4. DIFFERENTIAL DIAGNOSIS

The patient was well-developed, well-nourished, non-illappearing, and in no obvious distress. Her head was normocephalic with no signs of trauma. The neck showed no goiter or palpable lymph nodes. She had a quiet respiratory effort with no use of accessory muscles, wheezing, or cough. Examination of the right upper arm showed no pallor or coldness to touch and a radial pulse of 2+. Ms. E had a subtle deformity of the

There were several concerning and compelling diagnoses requiring prompt workup in this case. Metastatic bone neoplasm—including breast cancer, renal cancer, thyroid cancer, lymphoma, and lung cancer—was a possibility. With Ms. E’s excellent health history and young age, this diagnosis was less likely than a primary malignant bone neoplasm, such as osteosarcoma or Ewing’s sarcoma. Nonmalignant bone neoplasm—including giant cell tumor (GCT), nonossifying fibroma, enchondroma, and fibrous dysplasia—are also seen in this area. While nonmalignant, these can cause disfiguring pathologic fractures and permanent destruction of the bone and/or surrounding joint. Lastly, an infectious process such as pyogenic osteomyelitis should also be considered. The immediate concern in this case was primary malignant bone neoplasm, followed by an aggressive nonmalignant bone neoplasm.

5. TREATMENT

FIGURE 3. T2 coronal MRI shows high-intensity heterogeneous signal changes.

Ms. E was referred to a local orthopedic-tumor specialist. After reviewing her x-ray and CT scan, he obtained her consent for in-office core needle biopsy under local anesthesia. The specimen was obtained without complications and submitted for histopathologic analysis. A chest x-ray and an MRI of the upper extremity was ordered. The chest x-ray showed two solitary pulmonary nodules (<4 mm) with indeterminate features but low suspicion for metastatic or primary disease. MRI showed a locally aggressive, destructive lesion involving the entire humeral head, neck, and proximal shaft, with no extension into the glenoid fossa (Figure 3). Presumptive diagnosis of GCT was made by the radiologist and confirmed by the histopathologic tissue exam. Ms. E underwent standard curettage of the lesion with cement augmentation and open reduction internal fi xation the following week (Figures 4 and 5).

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Continues on page 114

Clinical Challenge 6. DISCUSSION

TABLE 1. 1. GCT staging Stage I

Benign latent

No local aggressive activity

Stage II

Benign active

Alteration of the cortical bone structure

Stage III

Locally aggressive

Lytic lesion with destruction of the medullary and cortical bone; can penetrate the cortex and invade surrounding soft tissues

GCT is a common benign but locally aggressive lesion of unknown etiology. It occurs more often in men between the third and fi fth decades. The tumor is an expansile, lytic lesion on the epiphysis and metaphysis of the involved bone. GCT can erode and penetrate the subchondral bone, articular cartilage, and supporting ligaments near the joint. The epiphysis of the distal femur, proximal tibia, and distal radius are the most common locations of GCT. Other sites include the fibula, sacrum, proximal humerus, distal tibia, and ilium near the sacroiliac joint and sacrum. Table 1 lists the staging for GCT. The prognosis for GCT is varied. A GCT with malignant cells will behave as a malignant tumor and has potential for metastasis. Unfortunately, even benign-appearing lesions can metastasize, with 5% of patients having pulmonary metastasis. If the tumor is benign, then it is assumed that the pulmonary lesions are benign.

7. OUTCOME

FIGURE 4. Open reduction internal fixation (ORIF)/cement grafting (internal rotation view)

Ms. E did very well with her postoperative rehabilitation. At her six-month visit, she had regained 80% range of motion in her shoulder. There was little to no pain with her activities of daily living. A CT scan of the chest done at six months postoperatively showed no changes in the two pulmonary nodules and no evidence of metastatic disease.

8. CONCLUSION In a young and healthy patient who has a relatively lowimpact mechanism of injury, a fracture of a long bone is something that warrants close follow-up and should raise the clinician’s index of suspicion for a pathologic fracture. X-rays may or may not show the findings seen in this patient. While many bone tumors are benign in histopathology, they are commonly destructive to the local area and can invade other local structures if they penetrate the cortex of the bone. ■ Mr. Spivey is a physician assistant in the orthopedic clinic of the Carl R. Darnall Army Medical Center in Fort Hood, Tex. Read on ■

Wheeless’ Textbook of Orthopaedics. Giant cell tumor of bone.

Available at www.wheelessonline.com/ortho/giant_cell_tumor_of_bone.

FIGURE 5. ORIF/cement grafting (anteroposterior view)

Accessed September 15, 2011.

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Severe headache, fever, and arm rash after vaccination EUGENE WONG, MD, JONATHAN RIEBER, MD, AND GABRIELLE FLAMM

Given the patient’s symptoms, lumbar puncture was required to rule out a diagnosis of meningitis.

were visible on Gram stain. A stress echocardiogram revealed no clinical, electrocardiographic, or echocardiographic evidence of ischemia. On his third day at the hospital, the patient had no fever, but a 20 ⳯ 10 cm area of erythema was seen on the left arm at the site of the vaccination. No antibiotics were given, as the patient was improving with regard to temperature, and the reaction was likely an immune response to pneumococcal vaccine and not bacterial in origin. Mr. B’s severe headache in the occipital area was worse when standing or sitting and improved when lying down. No photophobia, chills, neck pain, confusion, or visual changes were noted. The headache did not resolve with IV hydration, bed rest, liberal fluid intake, oral analgesics, and IV caffeine. An epidural blood patch placed on the fourth day of Mr. B’s hospital stay completely resolved his headache. The patient remained afebrile, with roughly 90% of the erythema resolved, and he was discharged home the next day. A report was fi led online through the U. S. Department of Health and Human Services’ Vaccine Adverse Event Reporting System (vaers.hhs.gov/index).

1. DISCUSSION

FIGURE 1. Localized redness was noted at the site of the patient’s pneumococcal vaccination.

Mr. B, aged 46 years, had a medical history significant for hypertension. He presented to the hospital with a three-day history of intermittent left-sided chest pain following cocaine use. Vitals on presentation showed temperature 98.4˚F, BP 146/78 mm Hg, heart rate 106 beats per minute, and respiratory rate 12 breaths per minute. Physical examination was unremarkable. As part of an admission order protocol, Mr. B received an influenza vaccine in the right deltoid and a pneumococcal vaccine (Pneumovax) in the left deltoid. On his second day in the hospital, Mr. B had a temperature of 104˚F with sinus tachycardia to 140 beats per minute and was treated with acetaminophen (Tylenol). Localized redness was noted on the left upper arm at the site of injection (Figure 1). The patient also complained of a headache located in the frontal region. Cerebrospinal fluid (CSF) analysis following lumbar puncture showed WBC 9/µL with 92% lymphocytes. No organisms or polymorphonuclear WBCs

CASE #2

Approximately 1.2 million cases of bacterial meningitis occur annually worldwide, resulting in 135,000 deaths. Bacterial meningitis can be difficult to diagnose. Patients may present with the classic triad of fever, nuchal rigidity, and a change in mental status, but in a study of 696 cases of community-acquired bacterial meningitis, only 44% exhibited all three findings.1 The clinical history is generally not useful in diagnosing meningitis. The onset is often subacute with a preceding upper-respiratory-tract infection. Clinical history lacks specificity for diagnosing meningitis, with one prospective trial showing specificity of 15% for a nonpulsatile headache, 50% for a generalized headache, and 60% for nausea and vomiting.2 The definitive diagnosis depends on the results of examination of the CSF. Gram stain of the CSF reveals the causative agent in 70% to 80% of cases and is positive in 80% to 90% of patients with bacterial meningitis.3 The physical exam can provide clues to the diagnosis, including nuchal rigidity, change in mental status, Kernig’s sign, and Brudzinski’s sign. Nuchal rigidity refers to flexion of the neck (either active or passive) with inability to touch the chin to the chest. If full range of motion is present, nuchal rigidity is absent. Continues on page 120

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Clinical Challenge pneumococcal pneumonia. However, only 32.8% of U.S. adults aged 18 to 64 years at high risk have received the vaccine as of 2007. Of those aged 65 years and older, only 65.6% have been vaccinated.7 The CDC’s Advisory Committee on Immunization Practices recommends routine vaccination for the following groups:8 1. All immunocompetent patients aged 65 years and older 2. Individuals aged 2 to 64 years with certain high-risk condition(s) — Chronic cardiovascular disease (heart failure and cardiomyopathies) — Chronic pulmonary disease (including chronic obstructive pulmonary disease and emphysema) — Diabetes mellitus — Alcoholism — Chronic liver disease (including cirrhosis) — CSF leaks — Functional or anatomic asplenia (including sickle-cell disease and splenectomy) — Immunocompromising conditions (including HIV infection, leukemia, lymphoma, Hodgkin’s disease, multiple myeloma, generalized malignancy, chronic renal failure, nephritic syndrome; patients receiving immunosuppressive chemotherapy, including corticosteroids; and patients who have received an organ or bone marrow transplant). Continues on page 122

Signs of meningeal irritation can be assessed by the appearance of Kernig’s and Brudzinski’s signs. Kernig’s sign refers to extension of the knee eliciting pain in the lower back or posterior thigh when the patient is lying supine and the hip is flexed at 90˚. Patients may also show opisthotonus spasm of the whole body that causes the legs and head to be bent back and the body bowed backward. Kernig’s sign may indicate subarachnoid hemorrhage or meningitis. Brudzinski’s sign is present when passive neck flexion in a supine patient results in involuntary flexion of the knees and hips. A separate sign—the contralateral reflex—is present if passive flexion of one hip and knee causes flexion of the contralateral leg. None of the physical examination findings are sensitive, however. In a study of 297 patients with suspected meningitis, the sensitivity of Kernig’s sign, Brudzinski’s sign, and nuchal rigidity was 5%, 5 %, and 30%, respectively.4 The specificity was 95% for Kernig’s and Brudzinski’s signs, and 68% for nuchal rigidity.4 Jolt accentuation of headache is one of the most sensitive maneuvers used in the diagnosis of meningitis. A positive test consists of the headache worsening when the patient turns the head horizontally at two to three rotations per second. In a study of 34 patients, jolt accentuation had a sensitivity of 97% and a specificity of 60%.5 Meningitis should always be considered in the differential diagnosis of a patient with an unexplained change in mental status. Clinical findings often do not help in establishing the diagnosis. In Mr. B’s case, lumbar puncture was necessary to establish or refute the diagnosis of meningitis, given the findings of fever, headache, and rash. Rash is most frequently seen in meningitis caused by Neisseria meningitidis. It was thought that an inflammatory reaction to Pneumovax caused Mr. B’s fever, headache, left upper-extremity erythema/swelling, and lymphocyte-predominant leukocytosis. The adverse drug event resulted in injury and a longer length of stay in the hospital. It is arguable whether the vaccine should have been administered to this patient. National hospital expenses to treat patients who suffer adverse drug events during hospitalization are estimated to be between $1.56 and $5.6 billion annually.6 The most common adverse experiences reported with Pneumovax were local reaction at injection site, soreness, erythema, warmth, swelling, induration, and fever up to 102˚F. Studies involving the pneumococcal vaccine have not demonstrated effectiveness in preventing communityacquired pneumonia, but most show the vaccine is effective in preventing invasive pneumococcal disease. Current guidelines recommend the vaccine for those at high risk of

Neisseria meningitidis (red) bacteria are typically seen in pairs.

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Clinical Challenge 2. Attia J, Hatala R, Cook DJ, Wong JG. The rational clinical examination.

WHAT DO YOU THINK?

Does this adult patient have acute meningitis? JAMA. 1999;282:175-181.

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

3. WM Scheld, RJ Whitley, and CM Marra, eds. Infections of the Central Nervous System, 3rd ed. Philadelphia, Pa.: Lippincott Williams & Wilkins; 2004:393. 4. Thomas KE, Hasbun R, Jekel J, Quagliarello VJ. The diagnostic accuracy of Kernig’s sign, Brudzinski’s sign, and nuchal rigidity in adults with sus-

3. Adults aged 19 to 64 years who smoke cigarettes or have asthma 4. Persons aged 2 to 64 years with cochlear implants It is important to discuss the benefits and risks of the vaccine with patients before proceeding and to vaccinate as many high-risk patients as possible. ■

pected meningitis. Clin Infect Dis. 2002;35:46-52. Available at cid.oxfordjournals.org/content/35/1/46.long. 5. Uchihara T, Tsukagoshi H. Jolt accentuation of headache: the most sensitive sign of CSF pleocytosis. Headache. 1991;31:167-171. 6. Bates DW, Spell N, Cullen DJ, et al. The costs of adverse drug events in hospitalized patients. JAMA 1997;277:307-311. 7. Centers for Disease Control and Prevention. Vaccination coverage

Dr. Wong is attending physician, internal medicine at New York Presbyterian –The Allen Hospital, in New York City. Dr. Rieber is attending physician in a private gastroenterology practice in New York City. Ms. Flamm is a student at Carleton College, Northfield, Minn.

among U.S. adults. Available at www.cdc.gov/vaccines/stats-surv/nis/ downloads/nis-adult-summer-2007.pdf. 8. Centers for Disease Control and Prevention (CDC); Advisory Committee on Immunization Practices. Updated recommendations for prevention of invasive pneumococcal disease among adults using the 23-valent pneumococcal polysaccharide vaccine (PPSV23). MMWR Morb

References

Mortal Wkly Rep. 2010;59:1102-1106. Available at www.cdc.gov/mmwr/

1. van de Beek D, de Gans J, Spanjaard L, et al. Clinical features and prognos-

preview/mmwrhtml/mm5934a3.htm.

tic factors in adults with bacterial meningitis. N Engl J Med. 2004;351:1849All electronic documents accessed September 15, 2011.

1859. Available at www.nejm.org/doi/full/10.1056/NEJMoa040845.

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Stat Consult

A quick review of common conditions, using the best global evidence

Description

• Respiratory infection caused by influenza A or influenza B virus

Influenza in children BY ALAN EHRLICH, MD, AND ERNEST KUCHAR, MD, PHD

Dr. Ehrlich is a family physician and Deputy Editor for DynaMed, (www. ebscohost.com/dynamed), a database of comprehensive updated summaries covering more than 3,200 clinical topics. Dr. Kuchar is an assistant professor of pediatrics and infectious disease at Wroclaw Medical University in Poland and a reviewer for DynaMed.

ICD-9 codes • 487.0 influenza with pneumonia • 487.1 inf luenza with other respiratory manifestations • 487.8 influenza with other manifestations • 488 influenza due to certain identified influenza viruses — 488.0 influenza due to identified avian influenza virus — 488.1 influenza due to identified novel H1N1 influenza virus • V04.81 need for prophylactic vaccination and inoculation, influenza Epidemiology

• Annual epidemics of seasonal influenza typically occur during late fall through early spring. — Typical incubation period is one to four days (mean two days). — Children may be infectious for >10 days (from six days before the onset to 10 days after). — Influenza can survive on dry inanimate surfaces for one to two days.

Complications

Influenza A viruses (yellow) are enveloped with a segmented genome .

• Illness may be more serious in children younger than age 2 years, especially age 6 months and younger, and in children with chronic immunosuppression or with respiratory or neurologic conditions. • Common complications include — Pneumonia — Otitis media — Tracheobronchitis — Acute sinusitis — Exacerbations of chronic pulmonary or cardiac disease • Febrile seizure Continues on page 126

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Stat Consult History

• Pattern of illness may vary from mild respiratory illness to prostration with nonspecific signs and symptoms. • Initial presentation may be abrupt onset of fever (temperature 37.7-40˚C [100-104˚F]) and dry cough. • Symptoms that are often more common or more severe with influenza than with the common cold include — Fever — Myalgia — Arthralgia — Anorexia — Headache — Dry cough — Malaise — Fatigue — Weakness • Symptoms that are often less common with influenza (more common with common cold) include — Nasal congestion — Sneezing — Sore throat Physical examination

• Fever is common. • Other findings may include — Conjunctival injection — Nonexudative pharyngitis — Rhonchi or scattered rales Diagnosis

• Accuracy of clinical diagnosis based on symptoms alone may be limited due to overlap with symptoms of respiratory illnesses. • Once influenza activity has been documented in community or geographic area, clinical diagnosis of influenza (without testing) is acceptable, especially during periods of peak influenza activity. • Influenza testing is recommended for patients with clinical signs and symptoms compatible with influenza for whom test results will change clinical care or change clinical practice for other patients. — Rapid antigen testing ■ Office-based tests can detect influenza viruses within 15 minutes. ■ No rapid influenza diagnostic test identifies any A subtypes. ■ Nasopharyngeal and nasal specimens have higher yields than throat-swab specimens for rapid detection.

Lower nasal swabs are accurate compared with nasopharyngeal swabs for identifying influenza and respiratory syncytial virus in children. ■ Negative results on rapid influenza diagnostic tests do not exclude influenza if suggestive clinical presentation due to limited (<70%) sensitivity and negative predictive value — Reverse transcriptase-polymerase chain reaction is reported to be the most sensitive and specific test for influenza and is recommended as the test of choice by Infectious Diseases Society of America. • Other tests to consider — Chest x-ray if signs or symptoms of pneumonia — WBC may be normal or decreased, and elevated WBC may be sign of secondary bacterial infection. ■

Treatment

• Antiviral medication — Include neuraminidase inhibitors (oseltamivir [Tamiflu], zanamivir [Relenza]) and adamantines (amantadine [Symmetrel], rimantadine [Flumadine]) — Oseltamivir or zanamivir are the drugs of choice based on circulating viruses and antiviral resistance patterns. — Neuraminidase inhibitors may reduce illness duration and hasten return to normal activity. — Antiviral treatment recommended as soon as possible for children with confirmed or suspected influenza who ■ Have severe, complicated or progressive illness ■ Require hospitalization ■ Are at higher risk for influenza complications — Antiviral treatment may also be considered for any outpatient with confirmed or suspected influenza if treatment can be started within 48 hours of illness onset. — Dosing in children (treatment duration five days) ■ Oseltamivir 75 mg orally twice daily for adolescents; dose varies with weight for children aged 1 to 12 years and with age for infants younger than age 1 year (usually 2 mg/kg up to a total of 75 mg b.i.d.) ■ Zanamivir 10 mg (two inhalations) b.i.d. in children aged 7 years and older; not recommended in patients with airways disease — Cautions and adverse effects of antivirals ■ For all antivirals, avoid use two days before and two weeks after live influenza virus vaccine. ■ GI effects, headache, dizziness reported ■ Neuraminidase inhibitors have been associated with neuropsychiatric symptoms including self-injury and delirium.

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Zanamivir is associated with upper respiratory adverse effects. ■ Amantadine has a high rate of adverse CNS effects, including possible increased seizure activity. • Antipyretics may reduce fever and provide analgesia, but avoid aspirin due to association with Reye’s syndrome. • Consider prophylaxis of high-risk close contacts. • Exclusion from school for at least 24 hours after last fever appropriate for most situations, but in health-care settings and places with significant numbers of high-risk individuals, exclusion for one week is advised. ■

Prevention

Antiviral prophylaxis

• Drug of choice for antiviral chemoprophylaxis is either oseltamivir or zanamivir — Zanamivir 10 mg (two 5-mg inhalations) once daily in adults and in children aged 5 years and older — Oseltamivir 75 mg orally once daily in adults and children aged 13 years and older, with weight-based dosing for children younger than age 13 years (usually 2 mg/kg up to a total dose of 75 mg) • Postexposure chemoprophylaxis — Only used when antivirals can be started within 48 hours of exposure — Treat for up to 10 days after last known exposure to close contact known to have influenza. • For pre-exposure prophylaxis — Duration is based on duration of community influenza activity. — Treatment regimens up to 28 days for zanamivir and up to 42 days for oseltamivir have been welltolerated. ■

• Vaccination — Annual influenza vaccination is recommended for all persons aged 6 months and older. — Vaccination efforts should begin as soon as vaccines are available and continue through influenza season. — Trivalent inactivated seasonal influenza vaccine can be used for any person older than age 6 months without contraindications (hypersensitivity to egg or vaccine component). — Live, attenuated influenza vaccine can be used for healthy, nonpregnant children aged 2-21 years.

— Children younger than age 9 years receiving immunization for first time require two doses one month apart.

“Performance art eludes me.” www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • OCTOBER 2011 127

LEGAL ADVISOR CASE

Painful BP cuff leads to arm injury Can a clinician be sued for battery if a patient objects to a medical treatment, even after giving consent?

ANN W. LATNER, JD

Ms. G worked as a nurse at an outpatient surgical facility. In this role, she had the opportunity to work with numerous physicians. One of her favorites was Dr. K, an ophthalmologist. Unlike some of the other doctors, Dr. K was friendly and dealt with Ms. G as a colleague, treating surgical procedures as teaching opportunities. Ms. G appreciated this, and found working with Dr. K interesting and informative. One day, Ms. G’s supervisor told her that Dr. K had requested that she assist during surgery. The patient, Mrs. M, was having a small mass on her eyelid removed. Prior to the procedure, Dr. K took Ms. G aside to speak with her. “It’s a very routine procedure,” said Dr. K, “but I wanted to warn you that the patient can be a bit prickly. She seems to be very suspicious and a bit of a complainer. I’ve been treating her for years, but she sought five second opinions before agreeing to this. I never had a patient who asked so many questions. I just want you to be aware.” Ms. G told the physician that she understood. The clinicians then went into the patient’s room

After the third inflation, the cuff was removed, and the rest of the procedure took place without BP monitoring.

128 THE CLINICAL ADVISOR • OCTOBER 2011 • www.ClinicalAdvisor.com

and began preparing for the procedure. Mrs. M had signed all the consent forms and was introduced to Ms. G. The procedure went well, and the mass was successfully removed from Mrs. M’s eyelid. However, the patient began reciting a litany of complaints almost as soon as surgery began. She loudly complained about the temperature of the room (too cold), the anesthetic injection (too painful), and the temperature of the ECG pads (also too cold). And when Ms. G started to inflate the automatic BP cuff, the patient began shrieking. “Ouch!” Mrs. M yelled. “That hurts! Take it off!” At that point, the cuff defl ated but began inflating a minute later. Mrs. M continued to complain about the pain, demanding that Ms. G remove the cuff immediately. Ms. G looked at 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.

LEGAL ADVISOR Dr. K, who shrugged. Ms. G left the cuff in place, but after the third inflation—and the third outburst from Mrs. M—the physician nodded at Ms. G and she removed the cuff. The rest of the procedure took place without BP monitoring. After Mrs. M went home, the two clinicians shook their heads and made a few comments to each other, assuming they had seen (and heard) the last of the patient for a while.

With battery—defined as unlawful touching or touching once consent has been withdrawn—injury is not relevant. Following the operation, Mrs. M went to another surgeon who performed a pronator teres release and discovered damage to her right arm. The blood vessels in her arm had hemorrhaged, and blood had collected around her median nerve, causing severe and permanent injury. Mrs. M retained a plaintiff ’s attorney and fi led a malpractice lawsuit against Dr. K, Ms. G, and the surgical facility. When Ms. G was notified of the suit, she was shocked. She immediately placed a call to Dr. K. “I can’t believe it,” said the physician. “The BP cuff was above the elbow, and the alleged damage was below. How could she prove that the cuff was responsible?” Both clinicians consulted defense attorneys and both were given the same advice—the plaintiff ’s case was weak, and they should go to trial if necessary. The case progressed through depositions and discovery. At trial, Mrs. M testified that when the automatic BP cuff inflated, she suffered terrible pain and began sweating and trembling. She testified that she told the clinicians in no uncertain terms to “take it off,” yet they allowed the cuff to inflate two more times before removing it. A physician brought in by the plaintiff ’s attorney testified as to the severity of Mrs. M’s arm injury but stopped short of saying that the BP cuff had caused it. The defense introduced its own physician, who testified that a BP cuff could not possibly be the source of the patient’s injury. Before the jurors began deliberating, the plaintiff’s attorney asked the judge to provide instructions as to what would be necessary to find the defendants liable for the tort of battery. The judge refused, and the jurors deliberated as to whether the clinicians had been negligent in their treatment of Mrs. M. Ms. G and Dr. K were found not liable.

The clinicians’ relief was short-lived. Mrs. M appealed the decision to the state court. Her attorney claimed that the trial court had erred in not giving the jurors the opportunity to decide whether the clinicians had committed battery by not removing the BP cuff when Mrs. M complained. The judges on the appeals court agreed with the trial court and dismissed the case. Mrs. M was still not deterred and appealed the case to the State Supreme Court. The State Supreme Court came up with a two-pronged test to determine whether practitioners can be found liable for battery. First, the patient must use language or act in a way that makes it clear that consent for the procedure, treatment, or examination has been revoked. Second, it must be medically feasible for the practitioner to stop the treatment or examination without it being detrimental or dangerous to the patient. Using these criteria, the court determined that Mrs. M had clearly revoked her consent to part of the procedure and that the clinicians were feasibly able to stop. The court ruled that Ms. G and Dr. K could be sued for battery, and the case was sent back for a new trial. Legal background

With regard to charges of battery—defined as unlawful touching or touching once consent has been withdrawn—it does not matter whether Mrs. M suffered injuries. Injuries are not relevant, as they are in negligence. While this case has yet to be retried, the clinicians may be found liable under this scenario. The case will probably hinge on how swiftly Ms. G and Dr. K responded to Mrs. M’s complaints about the BP cuff and whether they removed it as soon as it became clear than Mrs. M was no longer consenting to its use. Protecting yourself

There may have been nothing that the clinicians could have done to prevent this lawsuit, but acting faster might have helped. Ms. G could have removed the BP cuff after the first or second inflation once Mrs. M complained. Waiting until after the third inflation provided more ammunition for the claim that the patient’s revocation of consent had been ignored. Battery can apply to examinations as well as surgery. It is essential to keep an open dialogue with the patient about what is being done. Ask the patient frequently if he or she is comfortable with what is going on. ■ Ms. Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.

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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 59, 105

Newly developed brown papules KERRI ROBBINS, MD

CASE #1

CASE #2

Seven months ago, a man aged 45 years noticed a new mole on his back. Since that time, it had continued to grow and was occasionally associated with pruritus and bleeding. No family history of nonmelanoma or melanoma skin cancers was reported. Medical history was significant for six blistering sunburns as a child. He worked outside in construction and did not use daily sun protection. On physical exam, a 7-mm brown papule with asymmetry, irregular borders, and striking color variation was noted on the lower back.

A man aged 47 years presented to the dermatology clinic with a six-month history of a brown “mole” growing on his posterior neck. The lesion was associated with occasional pruritus. On physical examination, a 6-mm brown-black stuck-on papule with a greasy appearance was noted on the posterior neck. Medical history was significant for two episodes of blistering sunburns as a child. He has no personal or family history of nonmelanoma skin cancer or malignant melanoma and uses daily sun protection.

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CME CE

CASE #1

Dermatologic Look-Alikes

Melanoma

Melanoma is a malignant tumor developed from melanocytes. It is the most frequently seen cancer in young adults. Up to 20% of people who develop this cancer will ultimately die from it due to metastatic disease.1 The annual incidence rate of melanoma has been rising steadily by 3% to 7% per year. It is the most rapid rise out of all known malignancies.2 For this reason alone, melanoma has become a significant public health issue. Although only discovered in the late 1780s, melanoma has killed people for thousands of years. In the 1960s, there were discoveries of melanoma in Peruvian mummies dating back 2,400 years. An English surgeon named John Hunter fi rst discovered melanoma. At the time, he had written the condition off as a cancerous fungus because he was unsure of the etiology. In 1802, a French physician named Rene Laennec was the first to name the skin anomaly as melanoma. Samuel Cooper was the first physician to do research on the progression of the cancer and concluded that the longer the cancer went untreated, the more strongly it was associated with higher mortality. In 1840, Cooper concluded that there was no cure for the cancer beyond a certain period. This still holds true today. However, new early-detection techniques and skin screenings by dermatologists have continued to lower the mortality rate. There are many risk factors for developing melanoma, including predisposing genetic factors (e.g., skin color and type), family history, immunosuppression, the presence of large congential nevi (>20 cm), an increased number of common nevi, the presence of atypical or dysplastic nevi, ephelides (freckles) and UV radiation.3 UV radiation is particularly dangerous for children, but attention needs to be given to adults as well. Abnormal clone of melanocytes may be activated by exposure to sunlight. Major pathways that have been implicated in nevogenesis and malignant transformation include the Rb pathway (CKDN2A, CDK4), the p53 pathway (p53, p14ARF, the PI3K/AKT pathway, and most important, the RAS/MAPK pathway [NRAS, BRAF]).2 Approximately 20%-30% of melanomas have activating NRAS mutations, and 55%-60% have BRAF mutations.2 The major gene locus prone to familial clustering of melanoma is the CDKN2A gene, which encodes the

proteins p16 and p14ARF. These same mutations are also responsible for an increase in pancreatic cancer.4 The four main subtypes of primary melanoma are superficial spreading melanoma, nodular melanoma, acral lentiginous melanoma, and lentigo maligna melanoma. Superficial spreading melanoma is the most common of the four types, accounting for 60% -70% of cutaneous melanomas.5 Approximately half of these melanomas develop in a pre-existing nevus.2 Growth is usually slow and horizontal but progresses into a fast vertical growth. During this period, it is common to see a papule or nodule. This type of melanoma is most commonly seen on the trunk of men and the legs of women. Nodular melanomas account for 15% -30% of cutaneous melanomas. This melanoma is thought to arise de novo and is most frequently found on the trunk, head, and neck. Nodular melanomas appear as a dark-blue papule before entering the fast-growth phase, which is geared toward vertical growth. This type seems to occur more frequently in men and is associated with a poorer prognosis. Acral lentiginous melanoma accounts for 5% -10% of all cutaneous melanomas and is most commonly found on the palms, soles, or nail apparatus. The incidence is similar across all racial and ethnic groups; however, it represents a disproportionate percentage of melanomas diagnosed in individuals with darker complexions. Lesions are brown and black macules with asymmetrical borders and irregular pigmenation. Lesions on the nail apparatus tend to have a width >3 mm and/or irregular pigmentation. Lentigo maligna melanoma accounts for the last 5% -15% of cutaneous melanoma. These lesions typically arise on a background of severely sun-damaged skin and are most commonly seen on the face. They appear as a large patch with irregular borders and color variation.2 As the lesions progress, they may develop a nodular component. Other variants include amelanotic melanoma, nevoid melanoma, malignant blue nevus, desmoplastic melanoma, clear-cell sarcoma, animal-type melanoma, ocular melanoma, and mucosal melanoma. Superficially, the epidermis is variable in appearance, with ulceration predicating the worse prognosis. Melanocyte

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.

134 THE CLINICAL ADVISOR â&#x20AC;˘ MONTH 2011 â&#x20AC;˘ www.ClinicalAdvisor.com

Early detection is the most important factor in combating melanoma. Examine suspicious lesions every six months. proliferation is often asymmetrical and poorly defi ned. Atypical melanocytes with differing amounts of cytologic atypia, pleomorphism, hyperchromatism, increased mitoses, and prominent nucleoli may be seen arising at the dermal junction and invading into the dermis. Deeper melanocytes are often just as large and atypical as the superficial ones, demonstrating poor maturation. Pagetoid spread may also be seen in the epidermis. Lymphocytes are most commonly seen in a lichenoid pattern throughout the dermis and less commonly in perivascular or sparse distribution. Vascular fibrous tissue in the papillary dermis signifies regression. For challenging cases, melanocytes may be stained with S100 protein, HMB-45, and Mart-1.6 The depth of invasion into the dermis is the primary prognostic indicator. Early detection is the single most important factor in combating melanoma. The risk factors in children and adults are parallel. Skin exams and monitoring of suspicious lesions should occur every six months.Clinicians should take photographs to document any changes to suspicious nevi. Keep in mind the ABCDEs (Asymmetry, Border irregularity, Color variation, Diameter, Evolution) when evaluating a suspicious nevus. Patients can also be taught this mnemonic to monitor lesions at home. There are many other melanocytic and nonmelanocytic simulators of melanoma. Some melanocytic simulators include acral nevi, halo nevi, congenital nevi, blue nevi, atypical nevi, spitz nevi, and longitudinal melanonychia. Nonmelanocytic simulators include seborrheic keratosis, pigmented basal cell carcinoma, pigmented actinic keratosis, dermatofibroma, subungual hematoma, black heel (hemorrhage in stratum corneum due to trauma), and tinea nigra. Complete surgical excision of the tumor with margins based on Breslow’s tumor thickness is the treatment of choice. For in situ melanoma, taking 0.5-cm margins is recommended. For tumors <2 mm in thickness, 1.0-cm margins are necessary. For tumors thicker than 2.0 mm, 2.0-cm margins are generally recommended.3 Lymph nodes should be surgically removed and histologically evaluated if you suspect they are compromised. Tracing techniques allow the lymph node to be “sampled” to determine whether it needs to be surgically removed. Treatments of melanoma

that has reached advanced stages include radiotherapy, chemotherapy, and immunotherapy. Immunotherapy is controversial as to the effectiveness of treatment. Thanks to early detection, 83% of melanomas are diagnosed at a localized stage (Stage I and Stage II). These tumors have a five-year survival rate of 97% with appropriate treatment. Regional involvement at the time of diagnosis (stage III) has a five-year survival rate of 60%. Patients who have distant metastases (stage IV) at the time of diagnosis have a five-year survival rate of only 16%. Patients with family history of melanoma or known genetic predisposing factors need to undergo a visual inspection of the skin on a regular basis to detect suspicious lesions. On biopsy, this patient’s lesion was diagnosed as a superficial spreading malignant melanoma with a Breslow depth of 0.7 mm. The patient was treated with wide local excision with 1.0-cm margins. Complete excision was confirmed on pathology, and he is followed every three months for full-body skin exams.

CASE #2

Seborrheic keratosis

Seborrheic keratoses (SKs) are the most common benign tumor in older individuals. It is very uncommon to see the tumor occur before age 30 years. SKs have a variety of clinical appearances and develop from the proliferation of epidermal cells. SKs are most commonly found on the hair-bearing skin of the extremities, face, neck, and back, and are never seen on the mucosa, palms, or soles.5 Statistics show that the tumor is more common among whites. There is no difference in frequency between men and women. Research has found an apparent familial predisposition with a postulated autosomal dominant inheritance with incomplete penetrance. There has been a positive correlation between tumors and sun exposure. This has been established by the increased prevalence in patients residing in tropical climates. The origin of SKs recently has been established as a neoplastic process as opposed to a hyperplastic process as previously thought. This discovery was based on a study that analyzed androgen receptor polymorphisms

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CME CE

Dermatologic Look-Alikes

and demonstrated a clonal origin.7 If the patient is showing signs of irritation, it has been postulated to be caused by apoptosis in areas of squamous differentiation.8 The size of SKs varies considerably. Typical lesions measure 1 to 3 cm but have known to grow as large as 5 cm.

Inflamed or irritated seborrheic keratoses may present with a perivascular, diffuse, or lichenoid lymphocytic infiltrate. The color of the tumor can also range from skin-colored to tan, brown, and black. SKs are typically oval, slightly elevated, and oily or greasy to the touch. White, brown or black pin-sized keratotic areas known as pseudohorned cysts may be found within the tumor. These cysts look as if they are stuck on the skin, and this feature may be helpful when trying to distinguish SKs from such other pigmented lesions as melanoma. Ruptured cysts or trauma to the area can cause inflammation. The area may then become tender, crusted, pustular, and/or erythematous.9 There are at least six histologic subtypes of SKs. The most common subtype is acanthotic SK, which clinically presents as a smooth, dome-shaped papule. The most striking feature of acanthotic SK is the greatly thickened epidermis, typically containing a preponderance of basaloid cells. However, hyperkeratosis, papillomatosis, and an increased number of invaginated horn pseudocysts may all be seen histologically. The base of the epidermis is often linear and sharply demarcated. The reticulated or adenoid types of SKs are histologically seen as delicate strands of epithelium that are interlaced and extend outward from the epidermis. Inflamed or irritated SKs may present with a perivascular, diffuse, or lichenoid lymphocytic infi ltrate. The irritated type often lacks the sharply demarcated horizontal base that is seen with most other types. The hyperkeratotic type—also known as the serrated, digitated, or papillomatosis type—is characterized by prominent hyperkeratosis and papillomatosis. Acanthosis may also be present with a preponderance of squamous cells. Although most types of SKs are easily identified clinically, other conditions may have a similar appearance. These conditions include actinic keratoses, squamous cell carcinomas, solar lentigines, melanocytic nevi, malignant melanoma, verruca vulgaris, condyloma acuminatum, and acrochordons. Clinical differentiation between macular

SKs and such melanocytic neoplasms as melanoma is sometimes impossible, and histologic examination may aid in the diagnosis. Treatment of asymptomatic SKs is only necessary for cosmetic reasons. Destruction, curettage, or shave excision is often used to remove symptomatic lesions. Cryotherapy is the most commonly used method for destruction. Such other methods as laser vaporization or electrodesiccation may be used as well.1 There have been cases in which spontaneous regression occurs, but this is uncommon and is usually attributable to such conditions as pregnancy, coexisting inflammatory dermatoses, and malignancy. While removing SKs is simple, risks may include bleeding, scarring, infection, and recurrence. Individuals who tend to get this condition may develop more growths in the future. The patient in this case elected to have the lesion destroyed by cryotherapy because of the occasional pruritus. ■ 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. Hall BJ, Hall JC. Sauer’s Manual of Skin Disease. 10th ed., Philadelphia, Pa.: Lippincott Williams & Wilkins; 2010:280-284, 313-315. 2. Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology, 2nd ed., St. Louis, Mo.: Elsevier-Mosby; 2008:1661-1664, 1745-1769. 3. Paller AS, Mancini AJ. Hurwitz Clinical Pediatric Dermatology. 3rd ed. Philadelphia, Pa.: Elsevier Saunders; 2006:212-214. 4. Piepkorn M. Melanoma genetics: an update with focus on the CDKN2A(p16)/ARF tumor suppressors. J Am Acad Dermatol. 2000;42:705-722. 5. Fitzpatrick TB, Johnson RA, Wolff K, Suurmond R, eds. Color Atlas and Synopsis of Clinical Dermatology, 5th ed. New York, N.Y.: McGraw-Hill; 2005:204-205, 294-335. 6. Rapini RP. Practical Dermatopathology. Philadelphia, Pa.: Elsevier-Mosby; 2005:273-279, 234-236. 7. Nakamura H, Hirota S, Adachi S, et al. Clonal nature of seborrheic keratosis demonstrated by using the polymorphism of the human androgen receptor locus as a marker. J Invest Dermatol. 2001;116:506-510. Available at www.nature.com/jid/journal/v116/n4/full/5601025a.html. 8. Pesce C, Scalora S. Apoptosis in the areas of squamous differentiation of irritated seborrheic keratosis. J Cutan Pathol. 2000;27:121-123. 9. Winkelmann RK. Superficial spreading (and disappearing) seborrheic keratosis. Cutis. 1999;63:235-237. All electronic documents accessed September 15, 2011.

136 THE CLINICAL ADVISOR • OCTOBER 2011 • www.ClinicalAdvisor.com

POSTTEST Expiration date: October 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 www.myCME.com.You must receive a score of 70% or better on each test taken to obtain credit.

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Feature

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Dermatologic Look-Alikes

page 59

page 105

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Dyspnea with heart failure and COPD

Case #1: Benign cephalic histiocytosis

Case #1: Melanoma

1. Which physical finding has the highest suggested value for affirming heart failure (HF)? a. Ascites b. Pulmonary rales c. Lower-extremity edema d. S3 gallop

1. Benign cephalic histiocytosis usually involves the a. Head and neck b. Trunk c. Upper extremities d. Thighs

2. The absence of which finding strongly suggests a pulmonary cause of dyspnea in patients with coexisting COPD and HF? a. Feeling of suffocation b. Pursed-lip breathing c. Orthopnea d. Tripod positioning 3. What is the most specific and applicable laboratory test available to establish fluid overload associated with HF? a. Brain natriuretic peptide b. Liver function tests with serum albumin c. Cardiac enzymes d. D-dimer 4. What is a cornerstone of pharmacologic therapy for HF? a. Thiazide diuretics b. Digoxin c. Aldosterone antagonists d. ACE inhibitors

TO TAKE THE POSTTEST please go to ClinicalAdvisor.com/CMEFeatureOct2011

2. How is benign cephalic histiocytosis treated? a. Radiation therapy b. Surgical excision c. UVB light therapy d. No treatment necessary Case #2: Subcutaneous fat necrosis 3. There is a predilection for subcutaneous fat necrosis to form over a. Intertriginous areas b. Bony prominences c. Antecubital fossa d. Flexor surfaces 4. What serious complication associated with irritability and hypotonia occurs during the resolution phase of this condition? a. Hypercalcemia b. Thrombocytopenia c. Hypoglycemia d. Hypertriglyceridemia

5. What is the primary prognostic indicator of melanoma? a. Degree of border irregularity b. Changes in size c. Whether macular or nodular d. Depth of invasion 6. What is a characteristic feature of acral lentiginous melanoma? a. Dark-blue papule on head or neck b. Horizontal spread of existing nevus c. Brown and black macules with asymmetrical borders and irregular pigmentation d. Large patch with irregular borders and color variation Case #2: Seborrheic keratosis (SK) 7. In contrast to melanoma, SK is never seen on the a. Extremities b. Palms c. Face d. Back 8. What is the most commonly used method for destruction of SK? a. Cryotherapy b. Shave excision c. Laser vaporization d. Electrodessication

TO TAKE THE POSTTEST please go to ClinicalAdvisor.com/DermOct2011

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • OCTOBER 2011 137

CME

POSTTEST Expiration date: October 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 October 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 www.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

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Feature

Dermatology Clinic

Dermatologic Look-Alikes

page 59

page 105

page 133

Dyspnea with heart failure and COPD

Case #1: Benign cephalic histiocytosis

Case #1: Melanoma

1. Which physical finding has the highest suggested value for affirming heart failure (HF)? a. Ascites b. Pulmonary rales c. Lower-extremity edema d. S3 gallop

1. Benign cephalic histiocytosis usually involves the a. Head and neck b. Trunk c. Upper extremities d. Thighs

TO TAKE THE POSTTEST please go to ClinicalAdvisor.com/CMEFeatureOct2011

TO TAKE THE POSTTEST please go to ClinicalAdvisor.com/DermOct2011

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • OCTOBER 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.

Royal jelly

Royal jelly might sound like something served in the courts of kings and queens. That assumption is partly true, but the queen in question is a honeybee. The queen bee is larger and lives longer than the worker bees and is the only member of the colony capable of reproducing. Worker bees devote their lives to nurturing the queen and the royal larvae when she dies. The larvae are fed on a sticky, nutrient-rich substance produced by the worker bees. This substance is royal jelly.

Background

Science

Royal jelly contains a complex mixture of proteins, vitamins, minerals, and carbohydrates. The B vitamins are found in the largest quantity, followed closely by an assortment of 20 different amino acids, calcium, zinc, iron, and manganese.1 A detailed breakdown of the constituents of royal jelly reveals lipids (3%-7%), carbohydrates (10%-12%), proteins (12%-15%), water (60%-70%), and traces of minerals and vitamins.2 Of particular medical interest is the presence of gamma globulin, one of a group of specific proteins studied for their immune-modulating potential and pro-estrogenic compounds.1 Since the beehive has only one queen, the supply of royal jelly is much lower than that of honey. Honey is used as food for the worker bees, of which there are thousands, but royal jelly is reserved for those select few larvae that will be fed to become queens. A large, healthy hive of honeybees will produce about 500 g of royal jelly in a six-month period.2

Due to its rich content of antioxidants, proteins, and other nutrients, royal jelly is reportedly good for whatever ails you. It is specifically recommended for treatment of hypertension, hyperlipidemia, and inflammation, and is being studied for a possible anti-tumor effect as well as a treatment for male infertility.3 In a small trial, patients were assigned to the royal jelly intervention or placebo. Treatment-group participants were given 6 g daily of royal jelly formulation for four weeks. At the end of the trial, the treatment group’s total cholesterol level was reduced 6%, and LDL was reduced more than 9%.4 Egyptian researchers investigated the effect of royal jelly on conception rates among couples with known male asthenozoospermia. In this study, 99 couples known to be affected by the condition were randomized to one of two groups. The women in the treatment group were instructed to use a royal jelly product intravaginally during intercourse, and

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ALTERNATIVE MEDS UPDATE

Safety, interactions Due to the direct correlation of indigenous pollens and bee venom, there have been severe and even fatal incidents of asthmatic exacerbations and anaphylaxis subsequent to use of royal jelly.1 Anyone with even a remote history of atopy should use this product with extreme caution. Because of royal jelly’s weak but notable estrogenic action, women with a history of breast cancer should avoid its use.3 Royal jelly has not been thoroughly studied in women who are pregnant or nursing or in young children, so use by these patients is not recommended.3 Reported side effects include weight gain, facial rash, and GI discomfort.7 The most notable drug interaction is with warfarin (Coumadin). Royal jelly potentiates the action of warfarin, thereby increasing the risk for unintentional bleeding.3

from 100 mg to 200 mg orally once or twice daily.8 Costs vary, but are typically $20 for a 30-day supply.

Summary

A large beehive will produce about 500 g of royal jelly in six months.

Royal jelly potentiates the action of warfarin, thereby increasing the risk for unintentional bleeding.

Although a number of nutritive entities in royal jelly seem exciting for dealing with human illnesses and ailments, the risk of allergic response is serious and unpredictable. Until further human clinical trials verify the utility and safety of this product, clinicians should exercise extreme caution before recommending its use to pateints. ■ References 1. Fetrow CW, Avila JR. Professional’s Handbook of Complementary & Alternative Medicines. Springhouse, Pa.: Springhouse Corp.; 1999:624-625. 2. Suzuki KM, Isohama Y, Maruyama H, et al. Estrogenic activities of fatty acids and a sterol isolated from royal jelly. Evid Based Complement Alternat Med. 2008;5:295302. Available at www.ncbi.nlm.nih.gov/pmc/articles/ PMC2529378/. 3. Memorial Sloan-Kettering Cancer Center. Royal jelly. Available at www.mskcc.org/mskcc/html/92634.cfm. 4. Guo H, Saiga A, Sato M, et al. Royal jelly supplementation improves lipoprotein metabolism in humans. J Nutr Sci Vitaminol (Tokyo). 2007;53:345-348. 5. Abdelhafiz AT, Muhamad JA. Midcycle pericoital intravaginal bee honey and royal jelly for male factor infertility. Int J Gynaecol Obstet. 2008;101:146-149. 6. Hidaka S, Okamoto Y, Uchiyama S, et al. Royal jelly prevents osteoporosis in rats: beneficial effects in ovariectomy model and in bone tissue culture model. Evid Based Complement Alternat Med. 2006;3:339-348. Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC1513150/. 7. Georgiev DB, Metka M, Huber JC, et al. Effects of an herbal medication containing bee products on menopausal symptoms and cardiovascular risk markers: results of a pilot open-uncontrolled trial. MedGenMed. 2004;6:46. Available at www.ncbi.nlm.nih.gov/pmc/articles/ PMC1480585/. 8. University of Michigan Health System. Royal jelly.

Cost, dose, and how supplied

Available at www.uofmhealth.org/health-library/ hn-2906009.

Royal jelly is usually supplied in capsule form, with the recommended daily dose ranging 140 THE CLINICAL ADVISOR • OCTOBER 2011 • www.ClinicalAdvisor.com

All electronic documents accessed September 15, 2011.

the non-treatment couples were treated with standard intrauterine insemination (IUI). At the end of three monitored cycles, the successful conception rate of the treatment group was 8.1% compared with only 2.6% of the IUI couples.5 The researchers are still studying the mechanism of action in this usage beyond the nutrition-dense composition of royal jelly. The growth and development of bone cells is another area of focus for royal jelly research. Scientists monitored tibial bone density in ovariectomized rats for seven weeks until clinical measurements indicated significant loss of bone density. At this point, the treatment group was given a royal jelly supplement and the active control group was given a 17␤-estradiol treatment. At the end of treatment, the active control group had 100% reversal of tibial bone loss, and the royal jelly group showed 85% bone recovery. Enhanced gastric absorption of calcium was found in this and other studies and could account for a synergistic effect on bone maintenance.6

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.

FOR HIV-INFECTED ADULTS WITH POSITIVE TUBERCULIN SKIN TEST, TB PROPHYLAXIS WITH ISONIAZID FOR 36 MONTHS APPEARS MORE EFFECTIVE THAN FOR SIX MONTHS Level 2: Mid-level evidence Recommendations from the World Health Organization (WHO) call for at least six months of isoniazid therapy for TB prevention in adults who are HIV-positive and have either a positive or unknown tuberculin skin test (purified protein derivative [PPD]) (available at whqlibdoc. who.int/publications/2011/9789241500708_ eng.pdf, accessed September 15, 2011). A randomized trial compared isoniazid prophylaxis for 36 months vs. six months in 1,995 HIV-positive patients in Botswana (Lancet. 2011;377:15881598). Following six months of open-label isoniazid treatment, patients received either continued isoniazid or placebo in blinded fashion for an additional 30 months. Patients with CD4 cell count <200 cells/mcL were given antiretroviral therapy. The primary outcome was any incident TB (defi nite, probable, or possible) defined as clinical presentation consistent with TB and response to anti-TB therapy. The sixmonth open-label phase was completed by 83% of patients, and 78% of patients attended at least 80% of their monthly refill visits. Isoniazid prophylaxis for 36 months was associated with significantly reduced incidence rates of TB (0.72 vs. 1.26 per 100 person-years in intention-to-treat analysis, p=0.047). This difference was primarily attributable to the effect of continued prophylaxis in patients with positive PPD at baseline. In subgroup analyses, incidence rates were 0.57 vs. 2.22 per 100 person-years

(p=0.02) for patients with positive PPD, and 0.75 vs. 1.01 (not significant) for patients with negative PPD. There were no significant differences in overall severe adverse events or mortality.

The difference in rates of TB was primarily attributable to the effect of continued prophylaxis in patients with positive PPD at baseline.

EXEMESTANE MAY REDUCE RISK OF INVASIVE BREAST CANCER IN AT-RISK POSTMENOPAUSAL WOMEN Level 2: Mid-level evidence Selective estrogen-receptor modulators (tamoxifen [Nolvadex, Soltamox], raloxifene [Evista]) have been shown to reduce the risk of breast cancer in postmenopausal women, but also have been associated with increased risk of venous thromboembolism and other serious adverse events (Ann Intern Med. 2009;151:703-715). These risks have limited the use of these drugs for chemoprevention. A new trial suggests that the aromatase inhibitor exemestane (Aromasin) may reduce breast-cancer risk without serious adverse effects. A total of 4,560 postmenopausal women (mean age 63 years) were randomized to exemestane 25 mg daily vs. placebo (N Engl J Med. 2011; 364:2381-2391, available at www.nejm.org/ doi/full/10.1056/NEJMoa1103507, accessed September 15, 2011). All women had at least one risk factor for invasive breast cancer, including age ≥60 years, Gail risk score >1.66%, prior atypical ductal or lobular hyperplasia, lobular carcinoma in situ on breast biopsy, or prior ductal carcinoma in situ treated with mastectomy. Continues on page 142

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).

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • OCTOBER 2011 141

Evidence-Based Medicine

Metastatic breast cancer (brown) found in the lymph nodes

Median treatment duration was 10.2 months in the exemestane group and 14.2 months in the placebo group. Study medication was discontinued early for reasons other than the development of breast events in 27% for exemestane and in 21% for placebo. At median follow-up of 35 months, the exemestane group had significantly fewer women with invasive breast cancer (11 women, 0.48%) than did the placebo group (32 women, 1.4%) (NNT 109). Annual incidence rates appeared stable (and lower with exemestane) for the first four years. Data suggested a sharper increase in breast cancer rates in the placebo group from year four to year five (suggesting NNT 27 over five years), but only 159 women were followed to five years. There were no significant differences in rate of ductal carcinoma in situ, new osteoporosis or cardiovascular events, or quality-of-life scores. Rates of minor adverse events including hot flushes, fatigue, sweating, insomnia, diarrhea, nausea, arthritis, and joint and muscle pain were increased in the exemestane group.

VITAMIN D3 DECREASES ALL-CAUSE MORTALITY IN ELDERLY WOMEN WITH VITAMIN D INSUFFICIENCY Level 1: Likely reliable evidence Vitamin D deficiency is associated with increased risk of all-cause and cardiovascular mortality (Arch Intern Med. 2008;168:1340-1349, available at archinte.ama-assn.org/cgi/

content/full/168/12/1340, accessed September 15, 2011). Studies have suggested that vitamin D supplementation may reduce cancer and cardiovascular disease, but evidence for the effects of supplementation on mortality has been inconsistent. A recent Cochrane review evaluated various forms of vitamin D supplements and found that different forms have different effects on mortality (Cochrane Database Syst Rev. 2011;7:CD007470). The review included 50 randomized trials comparing any vitamin D supplement with placebo or no intervention in 94,148 patients. Most of the participants were women younger than age 70 years. The median treatment duration was two years. In an analysis of 32 trials with 74,789 patients, vitamin D3 (cholecalciferol) significantly decreased all-cause mortality (relative risk [RR] 0.94, 95%CI 0.91-0.98), with an NNT of 161, assuming 10% mortality in controls (Level 1: Likely reliable evidence). Subgroup analyses revealed that this risk reduction was driven primarily by patients with insufficient levels of vitamin D. There were no significant differences in mortality associated with other forms of vitamin D, including vitamin D2 (ergocalciferol) (12 trials), alfacalcidol (four trials), or calcitriol (three trials) (Level 2: Mid-level evidence). Alfacalcidol and calcitriol, both active forms of vitamin D, were associated with increased risk of hypercalcemia. Vitamin D3 combined with calcium supplementation was associated with increased risk of renal calcium stone disease.

BENEFIT OF CORTICOSTEROIDS UNCERTAIN IN ADULTS HOSPITALIZED WITH PNEUMONIA Level 2: Mid-level evidence Corticosteroids are sometimes recommended for patients with sepsis, but their efficacy in patients hospitalized with community-acquired pneumonia is unclear. Most trials have been small, and their results have been inconsistent, with some trials showing improvement and others showing worsening in the clinical course of the disease. A recent Cochrane review (with four trials in 235 adults with pneumonia) suggested that hydrocortisone may reduce the need for mechanical ventilation, but found no significant mortality benefit with either hydrocortisone or prednisolone as adjunctive pneumonia treatment (Cochrane Database Syst Rev. 2011;3:CD007720, available at onlinelibrary.wiley. com/o/cochrane/clsysrev/articles/CD007720/frame.html, accessed September 15, 2011). In a trial with 213 hospitalized patients with pneumonia, oral prednisolone was associated with increased treatment failure (defined as escalation in

142 THE CLINICAL ADVISOR • OCTOBER 2011 • www.ClinicalAdvisor.com

Evidence-Based Medicine

ADDITION OF ANDROGEN-DEPRIVATION THERAPY TO RADIATION THERAPY MAY IMPROVE SURVIVAL IN PATIENTS WITH INTERMEDIATE-RISK LOCALIZED PROSTATE CANCER Level 2: Mid-level evidence Previous research has suggested that androgen-deprivation therapy (ADT) improves survival when added to radiotherapy in men with locally advanced (stage T3 or T4) prostate cancer (Cancer. 2009;115:3446-3456) or with prostate cancer with high metastatic risk (Lancet Oncol. 2010;11:1066-1073). The efficacy of ADT plus radiation therapy has now been evaluated in an unblinded trial that involved 2,028 men with less advanced disease (N Engl J Med. 2011;365:107-118, available at www.nejm.org/doi /full/10.1056/NEJMoa1012348, accessed September 15, 2011). Patients with stage T1b, T1c, T2a, or T2b prostate adenocarcinoma and prostate-specific antigen (PSA) ≤20 ng/mL were randomized to radiation therapy plus ADT for four months vs. radiation therapy alone. ADT, started two months before radiation therapy, included flutamide (Eulexin) 250 mg orally t.i.d. plus either goserelin (Zoladex) 3.6 mg subcutaneously monthly or leuprolide (Lupron) 7.5 mg intramuscularly monthly.

Patients were stratified to low-, intermediate-, and highrisk categories based on multiple factors. Men with Gleason score ≤ 6, PSA ≤10 ng/mL, and clinical stage T1 or T2a were classified as low-risk (685 patients). Men with Gleason score 7 or Gleason score ≤6 with PSA 10-20 ng/mL or clinical stage T2b were classified as intermediate-risk. The remainder of patients, who had Gleason scores between 8 and 10, were classified as high-risk (although these patients had less advanced disease than the patients in the previous trials). Median follow-up was 9.1 years. In the intermediate-risk group, addition of ADT was associated with significantly increased 10-year overall survival (61% vs. 54%, p=0.03, NNT 15). Disease-specific mortality at 10 years for this group was 3% vs. 10% (p=0.004, NNT 15) and the 10-year rate of biochemical failure 22% vs. 32% (p <0.001, NNT 10). In the low-risk group, there were no significant differences in either overall survival (67% vs. 64%) or disease-specific mortality (3% vs. 1%). There were also no significant differences in either overall survival (53% vs. 51%) or diseasespecific mortality (12% vs. 14%) in the high-risk group. Hot flushes (55%) and grade 1 hepatic toxic effects (16%) were the most common adverse events in the ADT group prior to radiotherapy. There were no significant differences in acute or late radiation-induced toxic effects. ■

care) at >72 hours after admission (19.2% vs. 9.2%, p=0.04, NNH 10), again with no significant differences in mortality or in seven-day clinical cure rates (Am J Respir Crit Care Med. 2010;181:975-982, available at ajrccm.atsjournals.org/ cgi/content/full/181/9/975, accessed September 15, 2011). Prednisone was associated with a trend toward lower 30-day clinical cure rates (66.3% vs. 77.1%, p=0.08). In the largest trial to date, 304 patients with communityacquired pneumonia were randomized to dexamethasone 5 mg IV vs. placebo once daily for four days (Lancet. 2011;377: 2023-2030). All patients received IV antibiotics within four hours of hospital admission. Dexamethasone was associated with a significant one-day reduction in median hospital stay (6.5 days vs. 7.5 days, p=0.048), but there were no significant differences in in-hospital mortality (5% vs. 5%), 30-day mortality (6% vs. 7%), intensive-care admissions (5% vs. 7%), hospital readmissions (5% vs. 5%), or empyema or pleural effusion (5% vs. 3%). There was a significant increase in the risk of hyperglycemia in the dexamethasone group (44% vs. 23%, p <0.0001, NNH 4). Considering the inconsistent evidence of these trials, the benefits of corticosteroids in adults hospitalized with community-acquired pneumonia remains uncertain.

“I always ask for a pony for my birthday. I find it gives the most bargaining room.”

144 THE CLINICAL ADVISOR • OCTOBER 2011 • www.ClinicalAdvisor.com

COMMENTARY Scott Stegall, PhD, PA-C, is an Army-trained PA and past vice president of the Texas Academy of Physician Assistants. He has practiced in rural health since leaving the military in 1995.

Step up, speak out—for your own sake Over the last 10 or 12 years, my level of political activity has varied widely. I have had long periods of apathy and complete unawareness, and I also have walked the halls of the state capitol and had meetings with legislators regarding bills that would have a significant impact on my profession here in Texas. But most of the time I have been somewhere in between. In any given election of officers in the Texas Academy of Physician Assistants (TAPA), the end of voting takes place at a TAPA conference attended by 500 to 600 members, yet only 200 to 250 bother to take 60 seconds to fi ll out a ballot. It really makes me sad.

Still not convinced that professional association activity is a great way to be politically involved? I don’t blame you.

On the other end of the spectrum is the core of dedicated volunteers who make up the politically informed and active arm of our state professional association and the leadership past and present. They give untold hours of their time to keep up with the shifting landscape that is Texas politics (and respond to it accordingly). Even within this group there is a smaller element that probably does 90% of the heavy lifting. I suspect these observations translate fairly to most of our professions and associations. So, in my casual observation, we here in Texas have about 10 really politically active leaders. What about you? If it sounds like a damning indictment, well… it is. Politics, laws, rules, and regulations are the very core of what drives what clinicians can and can’t do; it determines reimbursement and therefore your salary. To be blissfully unaware is lazy. To be aware and completely uninvolved is just shameful. I am not shilling for everyone to join their professional society. It isn’t for everyone. But if you are uninvolved you don’t get to complain about what they do or don’t do. Rather, you can complain, but why should you be taken seriously? Also, it would be disingenuous to run to your professional society for help when something goes wrong. I might add that you should feel a pang of guilt when you reap the benefit of your association’s work.

Still not convinced that professional association activity is a great way to be politically involved? I don’t blame you. I personally am not a joiner, although I have been a TAPA member for a long time. But you can still stay involved by reading professional journals, newspapers, magazines, and blogs to keep up with the state and federal happenings that affect your profession and health care in your area. Send letters, faxes, and e-mails to legislators who are sponsoring bills that interest you. Then send a copy to your own representatives. You don’t have to go on a rant; just briefly state your opinion and why you have it. List your credentials as well: Not only does that lend an air of professionalism to your comments, it makes the recipient aware that your profession is paying attention. Your opinion does matter—I recently received a call from my U.S. Representative as a follow-up to a short opinion I sent in. (Seeing “U.S. Government” on the caller ID display is a somewhat frightening experience!) Want to step it up a little? Join societies or associations that share your values and concerns. You may even decide to become a committee member or the chair, or run for an officer’s seat. Time, not money, is the most valuable commodity volunteer organizations have. Feel a little twinge of guilt? Then my work here is done. ■

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