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Ankle sprains PAGE 40

Emerging viral respiratory pathogens 19

CASE REPORT Staphylococcal sepsis in a toddler


REVIEW ARTICLE Ankle sprains


WHAT’S NEW IN … … Men’s Health


PA QUANDARIES Is fast-track ED care ethical?


>>Earn 1 AAPA Category I CME credit with this issue CME Childhood vaccination challenges 22

CME Complex regional pain syndrome


CME Posttest


PUBLISHING STAFF Editor Tanya Gregory, PhD Production editor/Web producer Rick Maffei Manuscript editor Lauren Rich Proofreader James Fraleigh

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Reamer L. Bushardt, PharmD, PA-C, Editor in chief

Chief executive officer, Jennifer L. Dorn

Jim Anderson, PA-C, ATC, University of Washington School of Medicine, Seattle • Diane Bruessow, PA-C, DFAAPA, New York, NY • L. Gail Curtis, MPAS, PA-C, DFAAPA, AAPA Board of Directors • Richard Dehn, MPA, PA-C, DFAAPA, College of Health and Human Services, Northern Arizona University, Flagstaff • Alexandra Godfrey, MS, PA-C, St. Joseph’s Mercy Hospital, Ypsilanti, MI • Wanda C. Gonsalves, MD, Medical University of South Carolina, Charleston • Kristine A. Himmerick, MPAS, PA-C, University of California, Davis, Sacramento • Amy M. Klingler, MS, PA-C, Salmon River Clinic, Stanley, ID • Brian T. Maurer, PA-C, Enfield Pediatric Associates, Enfield, CT • Steve Wilson, PA-C, Peninsula Regional Medical Center, Salisbury, MD • Robert L. Wooten, PA-C, AAPA Board of Directors

Executive publisher, JAAPA, and senior vice president, marketing & communications, AAPA, Howard Glassroth

DEPARTMENT EDITORS Brief Report: Richard Dehn, MPA, PA-C, DFAAPA • Case of the Month: Erich Fogg, PA-C, MMSc • Dermatology Digest: Joe R. Monroe, PA-C, MPAS • Diagnostic Imaging Review: Julie Edmiston, PA-C, RT • Humane Medicine: Brian T. Maurer, PA-C • PA Quandaries: F. J. Gianola, PA; Jim Anderson, PA-C, ATC • Pharmacology Consult: Larissa DeDea, PharmD, BCPS, PA-C • Quick Recertification Series: Dawn Colomb-Lippa, MHS, PA-C; Amy M. Klingler, MS, PA-C • The Surgical Patient: Steve Wilson, PA-C • Topics in Infectious Diseases: Roy A. Borchardt, PA-C, PhD • What’s New: Mark E. Archambault, DHSc, PA-C • When the Patient Asks: Mary L. Hewett, MS, PA-C

AAPA BOARD OF DIRECTORS President, James E. Delaney, PA-C • Immediate past president/ Chair of the Board, Robert L. Wooten, PA-C • President-elect, Lawrence M. Herman, PA-C, MPA, DFAAPA • Vice president/ Speaker of the House, Alan Hull, PA-C • Secretary/Treasurer, Josanne K. Pagel, MPAS, PA-C, KarunaRMT® • First vice speaker of the House, L. Gail Curtis, MPAS, PA-C, DFAAPA • Second vice speaker of the House, David I. Jackson, DHSc, PA-C, DFAAPA • Directors-at-large, Michelle Ona DiBaise, MPAS, PA-C, DFAAPA; Jeffrey Katz, PA-C, DFAAPA; John McGinnity, MS, PA-C; Michael Clyde Doll, MPAS, PA-C, DFAAPA; Melinda A. Moore, PA-C • Student representative, Emilie Thornhill, PA-C

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Table of Contents VO L. 2 5, N O. 10

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12 WEB ARTICLES FOR OCTOBER 13 EDITORIAL Professionalism and the power of words: A meditation Reamer L. Bushardt, PharmD, PA-C

14 PHARMACOLOGY CONSULT Truvada for HIV prophylaxis in heterosexual patients Larissa DeDea, PharmD, BCPS, PA-C

30 CASE REPORT Disseminated staphylococcal disease and sepsis in a 23-month-old child Roma Patel, PA-C

34 CASE REPORT Colonic ulceration in a patient with renal disease and hyperkalemia Johanna L. Chelcun, MHS, PA-C; Robert A. Sable, MD, FACP, FACG, AFAF; Kenneth Friedman, MD


16 DERMATOLOGY DIGEST A very firm, pearly nodule on the face Anya Stassiy, PA-C; Amor Kachemoune, MD, FAAD, FACMS


COMPETENCY RATINGS IN JAAPA Articles in JAAPA address the six competencies that PAs are expected to acquire and maintain throughout their careers. The competencies are defined in “Competencies for the physician assistant profession.” JAAPA. 2005;18(7):16-18.

Shaun Grammer, MS, PA-C In this issue of JAAPA:

19 TOPICS IN INFECTIOUS DISEASES Respiratory tract infections: Emerging viral pathogens Roy A. Borchardt, PA-C, PhD; Kenneth V. I. Rolston, MD


Addressed in the articles on pages

Medical knowledge

14, 16, 19, 22, 30, 34, 40, 46, 55, 59, 67

Interpersonal and communication skills


22 CME ARTICLE Vaccines in childhood: Strategies to address the concerns of parents Patti Ragan, PhD, MPH, PA-C; Diane M. Duffy, MD 6

JAAPA • OCTOBER 2012 • 25(10) •

13, 14, 17, 22, 57, 62

Patient care

14, 16, 17, 19, 22, 30, 34, 40, 46, 55, 57, 59, 62, 67 13, 14, 16, 17, 19, 22, 30, 34, 40, 46, 52, 54, 55, 57, 59, 62, 67

Practice-based learning and improvement

14, 16, 19, 22, 30, 34, 40, 46, 55, 59, 67

Systems-based practice

13, 52, 54, 57, 62

Contents 40 REVIEW ARTICLE Ankle sprains: Treating to prevent the long-term consequences Erik A. Wikstrom, PhD, ATC, FACSM; April M. Wikstrom, PA-C, ATC; Tricia Hubbard-Turner, PhD, ATC, FACSM

46 CME ARTICLE Helping patients meet the challenge of complex regional pain syndrome Christopher Skory, PA, MS; Denise Rizzolo, PA-C, PhD

51 CME POSTTEST 52 BRIEF REPORT Roles and responsibilities of physician assistants practicing in Mohs surgery Samantha Gaffney; Constance Goldgar, MS, PA-C; Mark Hyde, MMS, PA-C

54 BRIEF REPORT Where the Canadian physician assistants are in 2012 Ian W. Jones, MPAS, PA-C, CCPA

55 WHAT’S NEW IN … … MEN’S HEALTH Faster-acting oral drug for ED Reamer L. Bushardt, PharmD, PA-C; Mark E. Archambault, DHSc, PA-C

57 PA QUANDARIES Fast-track areas in the emergency department: Are they ethical? Brett Bergman

Staci Hoops, a student in the Drexel Hahnemann PA program, class of 2012, has won the JAAPA 25th Anniversary Challenge for August. When asked what it will be like to be a PA 25 years from now, she answered as follows:

Patients and health care professionals alike will not only be more aware of the PA profession but will respect, trust, and appreciate our contributions to quality health care delivery and management teams. While the advancement of PAs into specialty care will continue, we will also excel as primary care providers and advocates for public health and public policy. The profession will continue to be exciting and rewarding, with unlimited opportunities! Visit to see the Anniversary Challenge for October and submit your answer. You could win a $100 gift card.

DISCLAIMER: The articles published in JAAPA represent the opinions of the authors and do not reflect the official policy of the American Academy of Physician Assistants, unless this is clearly specified. EDITORIAL MISSION: JAAPA is the peer-reviewed clinical journal of the American Academy of Physician Assistants. Its mission is to support the ongoing education and advancement of PAs by publishing current information and research on clinical, health policy, and professional issues. THIS ISSUE OF JAAPA includes articles that have been reviewed and approved for Category I (Preapproved) CME credit by the American Academy of Physician Assistants for a maximum of 1 hour. Approval is valid for 1 year from the issue date, and participants may complete the selfassessment at any time during that period. Category I CME articles included in JAAPA are planned and developed in accordance with AAPA’s CME Standards for Journal Articles and for Commercial Support of Journal Articles.

59 DIAGNOSTIC IMAGING REVIEW Unexpected consequences of rough play with friends Julie Edmiston, PA-C, RT

62 HUMANE MEDICINE Ebb and flow: Murmurings that are more than sweet nothings Brian T. Maurer, PA-C


JAAPA • OCTOBER 2012 • 25(10) •

JAAPA’S PEER REVIEW PROCESS: Peer review is the process journals use to evaluate a submitted manuscript to determine whether it meets the clinical and scientific standards necessary for publication. JAAPA wants to ensure not only that it meets these standards but also that articles offer information that is both practical enough and important enough to a large enough group of PAs to warrant publication. To this end, the editors send submissions to several reviewers who have expertise in the relevant field. If you are interested in joining JAAPA’s panel of peer reviewers, please send an e-mail to List your areas of expertise in the message, and attach a CV. COVER ILLUSTRATION: Molly Borman-Pullen

THIS MONTH’S ARTICLES Online columns Ask a Librarian! Our experts answer your questions about how to find information and resources in medical libraries.

Like a sandwich without the bread Jim Anderson, PA-C, ATC A 4-dimensional approach to reducing health disparities just might make a difference. The problem with primary care Brian T. Maurer, PA-C Even if we succeed in bolstering the numbers of PAs in primary care, how can we be sure to retain them in these roles?

Inside the AAPA Policy Manual JAAPA’s policy wonk increases your awareness of Academy history and policy and explains their relevance.

Exploring sex and gender Diane Bruessow, PA-C, DFAAPA Medicine is supposed to be evidence-based, yet sex and gender are often referenced in evidence-based contexts using less than evidentiary insight.

Atrial Kick: Cardiothoracic Surgery Perspectives David Bunnell, MSHS, PA-C Advice for a successful cardiothoracic surgery clinical rotation Here’s a list of essentials for PA students interested in a cardiothoracic surgery rotation. Research challenges common practice of stopping ACEIs before CABG A new study suggests that ACE inhibitors may do more good than harm in cardiac surgery patients. It is a small world after all You are a representative of our profession to every patient and to every person you talk to who may consider being a PA.

HIT Blog Jim Anderson, PA-C, ATC Kind and gentle CMS gives us all a bonus year Stage 2 of meaningful use has been postponed. Now the deadline to comply with final rules is 2014.

Health Disparities Blog AAPA Health Disparities Work Group Social determinants? Health disparities? Making it all fit. When the topic of health disparities comes up, most PAs probably don’t think about social determinants of health.

The October Challenge How do you handle it when you and your supervising physician disagree? Go to the JAAPA 25th Anniversary Monthly Challenge on to send us your answer, and you could win a $100 gift card.


JAAPA • OCTOBER 2012 • 25(10) •

EDITORIAL Reamer L. Bushardt, PharmD, PA-C, is professor and chair, Department of Physician Assistant Studies, Wake Forest School of Medicine, Winston-Salem, North Carolina, and the editor in chief of JAAPA.

Professionalism and the power of words: A meditation


ords have the power to uplift and inspire, or to injure and oppress. I am fascinated by the power of words. Life is the ultimate course for studying what people say (or don’t say) and the truth beneath the words (or the silence). Pennebaker discovered that how we use even the simplest of words reveals our social identity and individual psyche.1 As clinicians, our relationships with patients and our ability to connect patterns of symptoms with a diagnosis integrally involve the power of words. This summer brought with it myriad milestones for our country and profession. The Supreme Court’s decision—in words—upheld the Affordable Care Act. If you follow the onslaught of rhetoric flowing from the presidential campaigns, you already know the future of our health system and sustainability of our country’s economic power both hinge on your casting the right vote in November. Pulitzer Prize-winning journalist George Will remarked that “a politician’s words reveal less about what he thinks about his subject than what he thinks about his audience.” In the midst of a transformative, rapidly evolving climate for health care, how do we discern the truth and stay focused on what really matters for our patients and our profession? The end of summer also heralds a milestone for my family. My first-born, 5-year-old Isabella, strapped on her backpack and left for her first day of kindergarten. My wife returned from the panic-provoking school drop-off zone looking pale and defeated. I turned to deep breathing to suppress the protective behaviors that lie beneath the surface of a father’s skin when his little girl is thrust out into the world. How will my inquisitive, thoughtful child fare against those less virtuous? Arming myself against this fear, I sought out research on the matter and discovered that by second grade, children are able to understand that a person will lie out of self-interest. So, I am committed to keeping watch like a hawk for the next 3 years. Ironically, this is a lesson I learned in Mrs. Kelley’s second-grade class. The realization that people can lie or manipulate the truth changes the way we view the world and forever infects us with a propensity for suspicion. As the poet Tennyson said, “words, like nature, half reveal and half conceal the soul within.” Political leaders, health system administrators, and representatives from various health professional organizations are all weighing in on what represents the ideal in health reform. Words describe the most effective models of care, who is the right person to provide the right care at the right time, and how precious health care dollars should be spent to improve care and lower costs. More affirmations will surely follow the

November elections. Who will speak for (or against) the PA profession? Who will simply not speak of us at all? After the Supreme Court decision on the ACA, California Medical Association president Dr. James Hay cautioned that his state may struggle to find enough physicians to provide regular medical care to millions more people in the coming years. When it was suggested that further integration of PAs and NPs might fill these gaps in access to care, Dr. Hay responded that the California Medical Association, which represents 35,000 doctors, supports that—but only if a doctor remains in charge of a patient’s care. “Because we believe,” he added, “that patients want to have their medical care supervised by a physician, even if it’s ultimately delivered by a nurse practitioner or a physician assistant.”2 His words left me bewildered. Words are how we create rapport and forge partnerships. My PA career has created collaborative practice opportunities with more than a dozen family physicians. Each has encouraged me, fostered my professional development, and valued our unique partnership. I never questioned that they were in charge, but none ever felt the need to articulate it. Maybe they felt my being a PA made it clear enough, or perhaps using words to build a collaborative relationship was more important to them than clarifying the power of their position. I hope to learn more about how California leaders are supporting the advancement of the PA profession in their state. I appreciate Dr. Hay’s comments because they encourage me to be mindful of how I speak of other professions during this dynamic period of reform. I am ready to advocate for my own profession. Am I also advocating for other members of our health care teams, including physicians, nurses, and other health professionals? Good clinicians are expert listeners and skilled in building relationships with patients that foster open communication. Experienced clinicians become keen observers who can distinguish the truth amidst what our patients say and do. Exceptional clinicians learn to use words to inspire, comfort, and heal. In a sentinel work on medical professionalism, Swick reminds us that we must subordinate our own interests to the interests of others.3 I might even call those words to live by. JAAPA REFERENCES 1. Pennebaker JW. The Secret Life of Pronouns: What Our Words Say About Us. New York, NY: Bloomsbury Press; August 2011. 2. Rogers J. California officials say bring on health insurance overhaul. June 29, 2012. Accessed September 4, 2012. 3. Swick HM. Toward a normative definition of medical professionalism. Acad Med. 2000;75(6):612-616. • OCTOBER 2012 • 25(10) • JAAPA


PHARMACOLOGY CONSULT Larissa DeDea, PharmD, BCPS, PA-C, is a clinical pharmacist with Northern Arizona Healthcare, Flagstaff, Arizona. In addition to being board certified in pharmacotherapy, she is a graduate of the Yale University PA program.

Truvada for HIV prophylaxis in heterosexual patients


n estimated 50,000 people in the United States become infected with HIV annually. Truvada (a combination tablet containing tenofovir 300 mg plus emtricitabine 200 mg) was recently granted FDA approval for preexposure prophylaxis (PrEP) of HIV infection in carefully selected high-risk patients. PrEP is a relatively new and controversial strategy to prevent HIV transmission in people at highest risk of acquiring the virus. In 2011, the CDC released interim guidelines for HIV PrEP in men who have sex with men. These guidelines were recently updated to include recommendations for heterosexual serodiscordant couples (couples in which one partner is infected with HIV and the other partner is not infected).

›WHO SHOULD RECEIVE PREP? The best candidates for PrEP in the United States are those in a sexual relationship with partners known to have HIV infection. Patients must understand that PrEP is not 100% effective, however, and it should not replace routine safer-sex practices. Rather, PrEP is an adjunct to a comprehensive set of prevention services, including risk reduction counseling and ready access to condoms. Medication adherence is critical, and clinicians should stress that PREP fails if adherence is poor.

›WHAT DOES THE RESEARCH SHOW? Truvada was granted FDA approval for HIV PrEP in heterosexual men and women based on the results of two randomized, double-blind, placebo-controlled trials conducted in Africa. Both trials offered risk reduction counseling to all patients, 14

free male and female condoms, and screening and treatment of sexually transmitted infections (STIs). The first trial that showed benefit of HIV PrEP enrolled more than 4,700 serodiscordant couples.1 The HIVuninfected partner was assigned to Truvada, tenofovir alone, or placebo. At the time of enrollment, national guidelines prevented the HIV-infected partner from receiving antiretroviral therapy. In theory, this would represent a population at high risk of viral transmission because of unsuppressed viral loads. Couples were followed for up to 36 months. During this time, there were 13 infections in the Truvada group (0.82%), 17 in the tenofovir group (1.07%), and 52 in the placebo group (3.28%). This is a relative risk reduction of 75% with Truvada compared with placebo. Notably, of the people assigned to Truvada or tenofovir who became HIV-positive, approximately 70% had undetectable levels of medication in the blood. In the second trial, 1,216 heterosexual men and women were assigned to either Truvada or placebo.2 Although this trial did not specifically enroll serodiscordant couples, it was conducted in Botswana, which has the world’s second highest prevalence of HIV infection. Of the 610 volunteers assigned to the Truvada group, 9 became infected with HIV (1.48%) compared with 24 of 606 people assigned to placebo (3.96%). This translates into a relative risk reduction of greater than 62%. Of the patients in the treatment arm who became infected, approximately half had no detectable medication in the blood. When medication was detectable, levels were often very low. In contrast, of the people who did not acquire infection, more than 80% had detect-

JAAPA • OCTOBER 2012 • 25(10) •

able serum medication, and their average blood level was much higher than in those who became infected. This highlights the importance of adherence.

›PRESCRIBING TRUVADA Based on these trials, the FDA approved Truvada 1 tablet daily for PrEP in persons at high risk of acquiring HIV infection. This is the first drug to be approved for this use. Only persons who are confirmed to be HIV-negative immediately prior to initiating therapy can receive Truvada. Drug-resistant strains have emerged in patients who were HIVpositive and received Truvada for PrEP following undetected acute HIV infection. Therefore, anyone with signs or symptoms of acute HIV infection (fever, lymphadenopathy, rash, myalgias, malaise) should not receive Truvada. PAs should review the CDC guidelines for HIV PrEP for assistance in prescribing and monitoring therapy, particularly with special populations, such as women of childbearing age.3 Key points of these guidelines are summarized in Table 1 (available online). Finally, the cost of PrEP is significant. The drug alone can cost more than $1,000 a month. Risks, benefits, and adherence be discussed with each patient. Providers should know that Truvada is not approved for HIV PrEP in IV drug users. JAAPA REFERENCES 1. Baeten JM, Donnell D, Ndase P, et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med. 2012;367(5):399-410. 2. Thigpen MC, Kebaabetswe PM, Paxton LA, et al. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. N Engl J Med. 2012;367(5):423-434. 3. CDC Fact Sheet. PrEP: A new tool for HIV prevention. Published August 2012. Accessed September 5, 2012.

Dermatology Digest A N YA STASS I Y, PA-C ; A M O R KAC HEM OU NE, M D, FA A D, FAC M S

›CASE FIGURE 1 Facial lesion

A 14-year-old healthy female sought evaluation of a nodule on the left nasolabial fold. The lesion had been present for 7 years, with slight change in size, color, and shape. Examination revealed a pearly, very firm, slightly tender nodule with telangiectasias (Figure 1). The lesion measured 11×10 mm. The patient’s paternal grandfather had had a similar lesion in the same location, but it was never biopsied or excised. No other family members had similar lesions. An attempt to incise the surface of the nodule to check for discharge was unsuccessful.


A very firm, pearly nodule on the face Anya Stassiy practices at Dermatology Associates in Staten Island, NY. Amor Khachemoune is a dermatologist, Mohs surgeon, and dermatopathologist at the Veterans Affairs Medical Center and State University of New York at Downstate, both in Brooklyn, NY. No relationships to disclose.


• • • • •

Basal cell carcinoma Cylindroma Spiradenoma Pilomatricoma Trichoepithelioma

›DISCUSSION The lesion was excised and determined to be a benign spiradenoma. The exact nature of the grandfather’s lesion is unknown, but genetic counseling was not considered because the patient had only one lesion and was otherwise healthy. Spiradenomas are rare tumors, most likely of eccrine origin. They may be painful and most often arise on the anterior upper body. The lesions measure approximately 1.0 cm and do not progress in size. Color varies from gray to purple to pink. Spiradenomas have a small risk of malignant transformation. Excision of the lesion provides definitive diagnosis and treatment. Facial lesions can present a conundrum. They may range from simple and benign to cancerous and rare. Although basal cell carcinoma (BCC) is often described as a pearly papule and may have telangiectasias, the tenderness and lack of prolonged sun exposure made BCC an unlikely diagnosis in our patient. Dermal eccrine cylindromas are benign, nontender tumors that occur

JAAPA • OCTOBER 2012 • 25(10) •

on the head and neck area in persons of middle age. Solitary tumors are usually sporadic and without genetic predisposition, whereas multiple cylindromas may have an autosomal dominant inheritance.1 Advanced involvement of the scalp is termed turban syndrome. Evidence involving four members of two families afflicted by this syndrome led researchers to believe that a tumor suppressor gene is responsible.2 Pilomatricomas are benign tumors of the head and neck. They usually appear before the age of 20 years and manifest as painless, bluish papules; some demonstrate ulcerations. Pilomatricomas are the second most common growths excised in children after epidermoid cysts.3 Trichoepitheliomas are benign, slowgrowing, nonulcerating tumors. Most often seen on the face and scalp, they can also involve the upper body. Lesions may be solitary or multiple and manifest as firm, skin-colored papules measuring 2 to 8 mm. Because there is an autosomal dominant predisposition, the lesions may start to appear in early childhood.4 Biopsy confirms the diagnosis. Brooke-Spiegler syndrome may manifest with all three types of tumors: cylindromas, spiradenomas, and trichoepitheliomas. A defective cylindromatosis gene (CYLD) on chromosome 9 continues to produce new mutations and requires further research.5 JAAPA Joe R. Monroe, PA-C, MPAS, department editor REFERENCES 1. Office of Rare Diseases Research. Dermal eccrine cylindroma. aspx?PageID=4&diseaseID=10345. Accessed September 5, 2012. 2. Biggs PF, Wooster R, Ford D, et al. Familial cylindromatosis (turban tumour syndrome) gene localised to chromosome 16q12—q13: evidence for its role as a tumour suppressor gene. Nat Genet. 1995;11(4):441-443. 3. Lan M-Y, Lan M-C, Ho C-Y, et al. Pilomatricoma of the head and neck: a retrospective review of 179 cases. Arch Otolaryngol Head Neck Surg. 2003;29(12):1327-1330. 4. Prieto VG. Trichoepithelioma. Medscape Reference Web site. Updated January 29, 2010. Accessed September 5, 2012. 5. Scheinfeld NS. Spiradenoma. http://emedicine.medscape. com/article/1062079. Medscape Reference Web site. Updated June 26, 2012. Accessed September 5, 2012.

A Day in the Life Shaun Grammer, MS, PA-C

The author (left) guides students in developing their clinical skills.


wo years ago, I accepted a PA faculty position at Indiana State University in Terre Haute. The change from clinic to classroom was difficult at first, but the excitement and enthusiasm of the students made the transition smooth. I recall my feelings of excitement in PA school and can see similar feelings in the students. While PA educators are paid less than clinicians, the reward of educating future professionals makes every day special to me, and working part-time in a pediatric clinic allows me to maintain my clinical skills. Overall, the students are energizing, and teaching provides me opportunities to become more involved in the profession that I did not have when I was a full-time clinician. Shaun Grammer is an assistant professor in the Physician Assistant Studies Program, Department of Applied Medicine and Rehabilitation, Indiana State University, Terre Haute, Indiana. He has worked as a family practice PA for the past 5 years. No relationships to disclose.

■ 8:00 AM

I arrive on campus to teach my first class. Today, the subject is thyroid disorders. We begin the class with a case study I developed last night. The 30 first-year PA students listen carefully as I describe the case of a 30-year-old female with symptoms suggestive of hypothyroidism. I chose this case because hypothyroidism is a common problem that they will see in practice. The students are actively participating by asking history and physical (H&P) questions and trying to put the case together. Once I have sparked their interest, I begin the formal lecture. I have found this to be an effective method to begin class; holding students’ attention at 8 AM is often difficult. Getting them to engage actively allows me to keep their attention for the entire lecture, and it reviews and refines their H&P skills. I present the anatomy, pathophysiology, signs and symptoms, and laboratory studies associated with hypothyroidism, and then we discuss various treatment options. At the end of the lecture, we return to the case and decide the proper treatment for this particular patient. I also emphasize the importance of patient education and proper follow-up care. I found a case-based learning format effective when I was in PA school, so I have incorporated it into my teaching style. ■ 9:00 AM

The topic for my next class is personality disorders. Again I have decided to stay away from the traditional lecture format. Yesterday, I secretly chose five students to act out narcissistic, histrionic, paranoid, antisocial, and dependent personality disorders during my lecture. As I begin speaking, each of the five students interacts and interrupts me, appropriate to the personality disorder he or she is portraying. The rest of the class seems confused at first, but as the lecture continues, I can see that most of the students are beginning to understand what is going on. Once the lecture is complete, I reveal what has been happening, and we all have a good laugh. All the students agree that they will never forget these personality disorders. ■ 10:00 AM

The 10 students in my physical diagnosis laboratory break into their small groups. Today’s topic is the heart and lungs. I demonstrate proper technique for examination of the heart and lungs, including inspection, percussion, palpation, and auscultation. At first, the students have trouble distinguishing the various heart sounds. As I walk around the room, I begin to assist individual groups. I correct technique and explain what they should be hearing. I answer questions and explain why various techniques are used and when they should be performed. After a few minutes of practice, we gather again as a large group and listen to recordings of heart and lung sounds. We discuss what is normal and what is abnormal. When the students break back into their small groups to listen to the sounds again, I see recognition in several faces. I enjoy seeing the satisfaction on students’ faces as they begin to understand what they are doing. Labs are one of my favorite parts of the day because I have the opportunity to spend one-on-one time with the • OCTOBER 2012 • 25(10) • JAAPA


A Day in the Life: Shaun Grammer, MS, PA-C

“Deciding to become an educator was one of the best choices I’ve ever made.” students. During physical diagnosis lab, I am able to assist students in improving their skills in the areas where they need the most help. ■ 11:00 AM

This class involves clinic simulation. I divide the 10 students in my lab into pairs. Half the students enter the mock examination rooms and read a patient case. They are going to become patients, while the remaining students become the clinicians. As I enter the control room to observe the proceedings, the “clinicians” enter the exam rooms and begin their assessment. I listen to them as they interview the “patients.” I can see tremendous improvement in all of the students, compared with the previous semester. The hard work of the faculty seems to be paying off. When the clinicians have completed their assessments, they present their findings to me as if I were their preceptor. I notice the nervousness in their voices and remember my experiences as a student. To reassure them, I explain that being nervous is normal, but they need to speak confidently since they know the material. Building student confidence is important. I ask the clinicians what they think is going on with the patients; each clinician gives me one or two diagnoses. I encourage their responses but ask for a more extensive differential. As the student clinicians struggle, I provide verbal clues to help them remember previous lectures. A major obstacle for students to overcome is developing a thorough differential diagnosis. Students become confident in a single diagnosis and forget to think about all the other possibilities. Once we agree on the differential, we discuss the plan. I am teaching the students to recall and apply what they have learned in the classroom setting. Overall, I think participation in the simulations will allow them to enter clinical rotations with more refined physical examination skills; improved ability to generate a differential diagnosis; and, most important, confidence. ■ 1:00 PM

The time has come to head to my clinical job. Changing jobs mid-day is difficult, as the educator’s mind-set can be different than the clinician’s mind-set. However, the change 18

JAAPA • OCTOBER 2012 • 25(10) •

does provide a nice variety to the day. While I love teaching, I also enjoy working in the clinic and would not want to give that up. In addition, continuing to practice as a PA is important for maintaining the skills necessary to be a successful educator. ■ 4:50 PM

My fifth patient is a 9-year-old girl who presents with urinary incontinence that has persisted for 2 years. She has already been seen several times by the local urologist. Her workup has been entirely normal, but the problem continues. Questioning reveals a history of pilonidal sinus and strawberry hemangioma over the spine as an infant. I schedule an MRI for a possible tethered cord. I recall seeing a similar patient during my pediatric rotation as a student. Developing a similar case may make an interesting presentation for my students. While they may not be able to make the correct diagnosis because this condition is so rare, going through the investigative process will teach them the importance of conducting a thorough H&P, maintaining a broad differential diagnosis, and distinguishing normal findings from abnormal findings. ■ 5:10 PM

My next patient presents with right lower-quadrant abdominal pain. She reports an acute onset with guarding, so I schedule a CT to rule out appendicitis. I discuss the case with my supervising physician because he will be following this patient once the clinic closes. A drawback to working in the clinic only 6 hours per week is that I am unable to follow my patients in the hospital. As a full-time clinician, I was able to maintain contact with my patients from beginning to end. Even though I am not able to follow this patient, I think about her for the rest of the clinic. My supervising physician calls me at the end of the day to let me know that the patient did indeed have appendicitis and was going to the OR. ■ 9:00 PM

An educator’s day is never over! After spending some time with my family, I begin to prepare for tomorrow’s classes and respond to student e-mails. I review several resources as I create my presentation, find pictures, and think over my instructional strategy. I write test questions covering the material before finally heading off to bed. When I reflect, I really am happy that I made the transition to PA education. My days are full of variety, and opportunities to become active in the profession are greater than when I was doing full-time clinical work. The students always keep me on my toes with regard to clinical knowledge; I have to prepare well because I know they are going to ask a lot of good questions. Deciding to become an educator was one of the best career choices I have ever made. JAAPA

Topics in Infectious Diseases ROY A . BO RC H A R DT, PA-C , PhD; KENNET H V. I . ROLSTON, M D


Emerging viral pathogens


iral respiratory infections are the most common cause of symptomatic disease and account for more lost workdays than any other infection. Respiratory viruses have an established role in the pathogenesis of upper respiratory tract infections (URTIs), such as the common cold, but are gaining recognition as significant pathogens contributing to lower respiratory tract infections (LRTIs), including bronchitis, bronchiolitis, and pneumonia. Viral pneumonia is a significant cause of community-acquired pneumonia (CAP), responsible for an estimated 18% to 28% of cases. Viral pneumonia typically manifests with fever, cough, dyspnea, sputum production, and pleuritic chest pain.1 In patients older than 65 years, these respiratory symptoms and fever may be lacking; nonspecific symptoms, such as anorexia, dizziness, altered mental status, or frequent falls, may be the only presenting clue to a viral pneumonia.2 Viral infections of the lower respiratory tract are capable of producing severe disease and triggering an inflammatory response that can cause acute lung injury, including diffuse alveolar hemorrhage and acute respiratory distress syndrome (ARDS). While viral pneumonia alone can be fatal, it is often associated with development of secondary bacterial infection. The most common bacterial pathogens in those cases are Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae.1 Those at greatest risk for severe viral respiratory disease are very young children and the elderly, the immunocompromised, residents of long-term care facilities, and persons with chronic cardiopulmonary conditions.2

›IMPROVED IDENTIFICATION The discovery of the influenza A virus in 1933 heralded a new era of understanding and identification of respiratory viral pathogens. Several other respiratory viruses were identified through 1965, including coxsackievirus, echovirus, adenovirus, respiratory syncytial virus (RSV), rhinovirus, parainfluenza virus, and coronavirus. The development of polymerase chain reaction (PCR) techniques in the 1990s gave rise to new tools with which to investigate respiratory viruses. In 1997, these new molecular techniques were employed during the H5N1 avian influenza virus epidemic, and since then, they have resulted in the identification of several previously undetected respiratory viruses.3

›NEWLY DISCOVERED VIRUSES Human metapneumovirus (hMPV)

First isolated in 2001 from symptomatic children with LRTIs in the Netherlands, hMPV typically affects children younger than 5 years; immunocompromised patients;

residents of long-term care facilities; and adults with underlying respiratory conditions, such as chronic obstructive pulmonary disease (COPD). In children, infection manifests as a bronchiolitis.4 Influenzalike symptoms with cough, nasal congestion, rhinorrhea, dyspnea, hoarseness, and wheezing are common manifestations of hMPV infection in adults.1 Elderly patients are more likely to present with lower respiratory manifestations of dyspnea and wheezing.2 Infection with hMPV is usually self-limiting, although pneumonia and death have been noted in immunocompromised patients with hematologic malignancies who have undergone human stem cell transplantation.1 The prevalence of hMPV is less than 2% in the elderly, whether symptomatic or asymptomatic, but increases to 7% in residents of longterm care facilities. In outbreaks at such facilities, hMPV may infect up to 72% of the residents, with 31% of patients having radiographically confirmed pneumonia and a subsequent death rate approaching 50%.2 Although hMPV has only recently been identified, retrospective analysis of sera has determined that this virus has been in circulation for at least 50 years. The treatment for hMPV is currently supportive care.4 Human rhinovirus group C (HRVC)

TAKE-HOME POINTS ■ New molecular techniques and detec-

tion methodologies have identified several new human respiratory viruses in the past decade. ■ The clinical role of these newly identified viruses has yet to be clearly established, but they appear to be capable of causing a variety of respiratory illnesses, including severe lower respiratory tract infections that may be fatal. ■ Treatments of respiratory infections related to these new viruses also have not been clearly established and, therefore, are limited to symptom management and supportive care.

Rhinovirus is the most common respiratory pathogen isolated from humans, regardless of age. It causes the common cold and is the most common viral trigger of asthma exacerbations in all agegroups and of COPD exacerbations in adults. Two genetically distinct groups of rhinovirus, groups A and B, were The authors work in the Department of Infectious Diseases, Infection Control and Employee Health, University of Texas M.D. Anderson Cancer Center, Houston. Roy Borchardt is a physician assistant and the department editor, and Ken Rolston is a professor of medicine. No relationships to disclose. • OCTOBER 2012 • 25(10) • JAAPA


Topics in Infectious Diseases previously established. More recently, rhinovirus group C has been identified, but taxonomic ratification as a separate species is pending. Identified in 2003, HRVC has been circulating for at least 10 years and may be associated with a higher morbidity than that of groups A and B. HRVC may account for half of all rhinovirus-associated hospitalizations in children. In addition to the common cold, HRVC causes symptoms observed in pharyngitis, croup, acute otitis media, bronchiolitis, and pneumonia. Half of all virus-positive fluid samples from the middle ear of children with otitis media are attributed to HRVC. Serotyping studies to date suggest that more than 100 rhinovirus strains may exist, many of which circulate year-round and remain detectable in subsequent years; however, their respective contribution to human respiratory diseases has yet to be clearly understood. There are no effective vaccines against HRVC or any of the rhinoviruses, so treatment is supportive care.5 Coronaviruses (CoV) Responsible for 15% of adult common colds, coronaviruses cause epidemics every 2 to 3 years. CoV infections typically manifest with mild URTI, but there have been cases of severe LRTIs. The CoV family includes severe acute respiratory syndrome coronavirus (SARS-CoV), identified in 2003, and the human coronaviruses HCoVNL63 and HCoV-HKU1, which were identified in 2005-2006 from patients with respiratory symptoms. Between 2002 and 2003, SARS-CoV was responsible for more than 8,000 infections and caused 774 confirmed deaths; additional cases were prevented by extraordinary worldwide containment efforts. Initially, SARS-CoV infection manifests with fever, chills, rigors, myalgia, malaise, headache, and a nonproductive cough. Rhinorrhea and sore throat may occur but are uncommon. Dyspnea with rapid progression of pulmonary infiltrates and respiratory failure necessitating mechanical ventilation usually occurs later in the course of illness. Death typically occurs from respiratory failure or a sepsislike syndrome with multiorgan failure.

Samples from patients with CAP that were positive for HCoV-HKU-1 were isolated predominantly from elderly patients with underlying cardiopulmonary disease. There are no approved antiviral medications to treat CoV infections; hence, treatment is centered on symptom control and supportive care.5 Human polyomaviruses Between 2007 and 2011, seven new human polyomaviruses were identified, two of which may be linked to respiratory illness: polyomavirus WUPyV and polyomavirus KIPyV. These two viruses were named after the institutions where they were first identified: polyomavirus WUPyV at Washington University and polyomavirus KIPyV at the Karolinska Institute, respectively. The role these polyomaviruses play in respiratory infection is still unclear; however, their prevalence in respiratory samples ranges between 0.4% and 7% in symptomatic patients. Most patients with WUPyVor KIPyV-detectable DNA respiratory samples and concurrent respiratory symptoms appear to be young children. Seroprevalence rates ranging from 50% to 80% in healthy adults and children suggest that exposure and primary infection occur during childhood. Because they are newly identified respiratory viruses, little is known about WUPyV and KIPyV, and treatment is therefore centered on management of symptoms.3 Human parechoviruses (HPeV)

Isolation 50 years ago led to identification of the first two genotypes of HPeV, formerly called echovirus 22 and 23. Since then, the genotypes have been extended to 16, of which 6 circulate worldwide. HPeV infections are common in all age-groups, but symptomatic infections are observed primarily in neonates and children younger than 3 years. In a retrospective study, 20 of 28 children had bronchiolitis, pneumonia, or both. One death attributed to HPeV was reported in a child with acute lymphoblastic leukemia who received consolidative chemotherapy. Current treatment is limited to supportive care.6

20 JAAPA • OCTOBER 2012 • 25(10) •

Bocavirus From a molecular standpoint, the bocavirus most closely resembles bovine parvovirus and canine minute virus, thus giving rise to the name human bocavirus. First identified from nasopharyngeal samples, bocavirus is most commonly seen in young children between the ages of 6 and 48 months. The virus has been isolated from the upper and lower respiratory tracts of such children with acute asthma and pneumonia. As with the other newly identified respiratory viruses, distribution is worldwide, and treatment is symptomatic control and supportive care.7

›NOVEL INFLUENZA VIRUSES The variant influenza A (H3N2v) virus was identified recently in 29 cases reported since July 12, 2011; 16 of those cases occurred between July 12 and August 3, 2012, in three states, with all infected persons having had prior contact with swine. Since 2007, when novel influenza viruses became a nationally notifiable condition, fewer than 6 cases of influenza originating from animals have been reported annually. There were 14 cases of novel influenza viruses in 2011; most followed contact with swine, but some were transmitted from human to human. This influenza variant contains a matrix gene from influenza A (H1N1) pdm09 virus that increases transmission between humans. Early treatment with oral oseltamivir or inhaled zanamivir is recommended for patients with confirmed or suspected infection.8 JAAPA REFERENCES 1. Radigan KA, Wunderink RG. Epidemic viral pneumonia and other emerging pathogens. Clin Chest Med. 2011;32(3):451-467. 2. Jartti L, Langen H, Söderlund-Venermo M, et al. New respiratory viruses and the elderly. Open Respir Med J. 2011;5:61-69. 3. Jartti T, Jartti L, Ruuskanen O, Söderlund-Venermo M. New respiratory viral infections. Curr Opin Pulm Med. 2012;18(3):271-278. 4. Feuillet F, Lina B, Rosa-Calatrava M, Boivin G. Ten years of human metapneumovirus research. J Clin Virol. 2012;53(2):97-105. 5. Greenberg SB. Update on rhinovirus and coronavirus infections. Semin Respir Crit Care Med. 2011:32(4):433-446. 6. Ren L, Xiang Z, Guo L, Wang J. Viral infections of the lower respiratory tract. Curr Infect Dis Rep. 2012;14(3):284-291. 7. Jartti T, Hedman K, Jartti L, et al. Human bocavirus—the first 5 years. Rev Med Virol. 2012;22(1):46-64. 8. Centers for Disease Control and Prevention Health Advisory. Increase in influenza A H3N2v virus infections in three U.S. states. Published August 3, 2012. Accessed September 1, 2012.


EARN CATEGORY I CME CREDIT by reading this article and the article beginning on page 46 and successfully completing the posttest on page 51. Successful completion is defined as a cumulative score of at least 70% correct. This material has been reviewed and is approved for 1 hour of clinical Category I (Preapproved) CME credit by the AAPA. The term of approval is for 1 year from the publication date of October 2012.


Describe the impact of vaccines in preventing childhood diseases Explain the importance of maintaining high immunization levels to prevent outbreaks Identify beliefs and factors associated with nonvaccination Incorporate strategies in clinical practice to enhance childhood immunization

Vaccines in childhood: Strategies to address the concerns of parents The decline in vaccine-preventable diseases—a consequence of successful immunization campaigns—may have convinced some parents that these diseases are no longer a threat.

Patti Ragan, PhD, MPH, PA-C; Diane M. Duffy, MD

22 JAAPA • OCTOBER 2012 • 25(10) •



he success of vaccine programs has considerably improved the health of children in the United States. Access to vaccines and high rates of immunization have resulted in a substantial decline in vaccine-preventable diseases, particularly in higher-income countries.1 While infectious diseases accounted for most premature death in the United States in the early 20th century, a greater proportion of morbidity and mortality is now attributed to chronic disease. Vaccinations have eliminated smallpox worldwide, and in the United States, naturally occurring polio has not been seen since 1979. Diphtheria, tetanus, and invasive Haemophilus influenzae infection are rare today compared with the prevaccine era.2 Since the varicella vaccine was introduced in 1995, the incidence of chickenpox and the number of chickenpox-related hospitalizations and deaths have declined significantly.3 In 2005, the elimination of rubella virus in the United States marked another major milestone in the battle against childhood diseases.4 According to Jagessar and colleagues, “The record of vaccination stands as one of the most successful and cost-effective public health tools for preventing serious disability and death.”5 Ironically, the success of vaccines has promoted the perception that susceptibility to and morbidity and mortality from vaccine-preventable diseases are no longer a concern. Many parents, as well as health care providers who administer the vaccines, have never experienced the toll taken by measles and polio just a few decades ago (Figure 1). Fear of disease has become fear of vaccines and an increase in the number of parents refusing immunization for their children, primarily through nonmedical exemptions of children from

FIGURE 1. Child with leg deformity due to polio

required school vaccinations.6 As a result, there is evidence of resurgence of some vaccine-preventable diseases, such as measles and pertussis, especially in areas where vaccination coverage is low or where enclaves of unimmunized persons exist.1,3,6,7 The variance in state policies and ease of obtaining exemptions,6 along with the lack of a fully operational population-based immunization registry,8 presents challenges to increasing and sustaining vaccination coverage. VACCINATION STRATEGIES

Vaccination programs rely on herd immunity to ensure optimal protection of a community from communicable disease transmission.9 The more people that are vaccinated, the fewer susceptible individuals will be exposed and the less likely person-to-person transmission will occur or be sustained. The level of herd immunity required varies with disease virulence and transmissibility as well as vaccine efficacy. While vaccinating 95% of a population is considered optimal, measles outbreaks can occur at thresholds where less than 10% of the population is susceptible,10 suggesting coverage must be high and sustained to prevent breakthrough with highly transmissible disease. Herd immunity protects children who are too young to be immunized, persons who are not fully immunized or did not have a sufficient immunologic response, and those who cannot be immunized because of medical contraindications. However, persons who are unvaccinated and undervaccinated remain at risk for contracting vaccine-preventable disease, placing both individuals and communities at risk.6 The goal to increase immunization levels and reduce preventable infectious disease continues to be a priority in the 2020 Healthy People objectives.8 CURRENT VACCINATION COVERAGE LEVELS

High vaccination coverage is critical to reduce the burden of vaccine-preventable disease and to prevent resurgence of disease that has been contained or eliminated.11 The protection of young children, who are often at greatest risk, is of paramount importance. Immunization coverage in the United States has reached its highest levels in recent years. Results of the 2010 National Immunization Survey show that compared with 2009, vaccine coverage increased or remained stable among children aged 19 to 35 months. Immunization

against poliovirus; measles, mumps, and rubella; hepatitis B; and varicella continue to be at or above the recommended national health objective target of 90% for their respective vaccines.12 The percentage of children who received no vaccinations was less than 1%. Nevertheless, geographic pockets of susceptibility or individual susceptibility as a result of immunization refusal, partial immunization, or delays in receiving immunizations can result in breakthrough disease and outbreaks. Geographic clustering of exemptions from school vaccination programs are not well understood but have been shown to increase the risk of vaccine-preventable disease when it occurs.6 PUBLIC POLICY VERSUS PUBLIC FEAR AND TRUST

Public perception of vaccine safety and efficacy is influenced by scientific evidence; economic considerations; history; and psychological, sociocultural, and political factors.13 Mistrust of government policies and conflicting views generate debate and, at times, backlash. In the midst of the uncertainty, policies mandating vaccination have increasingly received scrutiny. Not surprisingly, opposition to

“Among the common reasons given for refusing a vaccine were concerns about a possible link between thimerosal and autism.” mandatory vaccination policies has been around for almost as long as vaccines.14 In recent years, the antivaccine movement has clamored to discourage parents from immunizing their children.13 Celebrity-endorsed emotional stories about children purported to be harmed by vaccines also have encouraged parents to question the wisdom of vaccinating their children. Rapid dissemination of information through social media can also help fuel speculation and validation of unscientific views. Fears about sterility related to oral polio and tetanus vaccinations have been linked to reduced vaccine acceptance and disruption in vaccine programs.13 In 2001, thimerosal, a mercury-containing preservative, was

KEY POINTS ■ Some vaccine-preventable diseases, such as measles and pertussis, are experiencing a resurgence, especially in areas where vaccina-

tion coverage is low or where enclaves of unimmunized persons exist. ■ PAs should explain to parents that current vaccines contain fewer antigens than in the past and are thoroughly tested by the FDA

before being licensed for use by the public. ■ PAs should also ensure that the immunization experience as stress-free as possible. ■ A follow-up phone call may be an opportunity to discern if the missed visit was the result of vaccine concerns and, if so, to initiate

further discussion. ■ When parents refuse immunizations, the discussion should be documented and parents should sign a refusal (declination) waiver. • OCTOBER 2012 • 25(10) • JAAPA


CME Childhood immunizations removed or reduced in childhood vaccines as a preventive measure. Over the next decade, this action fueled concern among parents who were convinced that their child’s autism was caused by mercury-containing vaccines and further undermined their faith in the vaccine infrastructure,15 despite numerous studies finding no link between thimerosal exposure and autism.16 The now-discredited study published in The Lancet by Wakefield and colleagues in 1998 suggesting a causal link between the measles, mumps, rubella (MMR) vaccine and autism was the harbinger for a decline in MMR vaccine coverage in the United Kingdom13 and the resurgence of endemic measles by 2008.17 Although the study was retracted in February 2010 after conclusive evidence showed that the data had been manipulated and misrepresented, MMR vaccine coverage has not yet rebounded to prior levels. Despite a 2000 declaration that it had entered the postelimination era of measles, the United States has also experienced an upsurge in measles cases. During 2011, the United States had 222 confirmed measles cases and 17 measles outbreaks.18 Most cases have been associated with importation from areas where measles is endemic or where outbreaks were occurring, and they can usually be traced to unvaccinated US travelers going abroad, unvaccinated visitors, and people linked to the cases. Increased refusal of vaccinations, creating pockets of susceptibility, contributes to the problem.7 BELIEFS AND FACTORS ASSOCIATED WITH NONVACCINATION

As the number of vaccines has risen, concerns about childhood immunizations have increased. Religious beliefs, health

SEE THE ONLINE VERSION OF THIS ARTICLE TO LINK TO American Academy of Pediatrics: Documenting Parental Refusal to Have Their Children Vaccinated RefusaltoVaccinate.pdf American Academy of Pediatrics Immunization: Resources for Vaccine Conversations communicating.html CDC: If You Choose Not to Vaccinate Your Child, Understand the Risks and Responsibilities not-vacc-risks-bw-office.pdf Complete Advisory Committee on Immunization Practices immunization schedules and footnotes 0-6yrs-schedule-pr.pdf 7-18yrs-schedule-pr.pdf catchup-schedule-pr.pdf

24 JAAPA • OCTOBER 2012 • 25(10) •

beliefs, socioeconomic status, educational status, personal experience, and relationship with the provider may all play a role in parents’ decisions to immunize their children. A survey conducted by the American Academy of Pediatrics (AAP) found that 74% of pediatricians reported having at least one vaccine refusal during the prior year and 2% of families refused all vaccines.19 The most common reasons given for refusing a vaccine were concerns that included a possible link between thimerosal and autism (74%), other concerns about vaccine safety or side effects (73%), the belief that immunizations are unnecessary (63%), and discomfort to the child receiving multiple shots at one time (42%). Thirty-two percent of parents who initially refused vaccines changed their minds after educational efforts. In a study among Connecticut pediatricians, 74% reported an increase in the number of parental vaccine concerns and refusals in the past 10 years.20 Suburban and rural physicians were more likely than urban physicians to report more parental vaccine concerns, vaccine delay, or refusal. Wealthier, better-educated parents had more concerns about vaccines and refused them more often than other parents. A study examining the differences between undervaccinated and unvaccinated children found that they were uniquely different.21 Undervaccinated children were more likely to be black; have a younger, unmarried mother who did not have a college degree; and live in a central city household with four or more children near the poverty level, suggesting access and socioeconomic factors may account for missed vaccinations. Unvaccinated children were disproportionately white and tended to have a mother who was married and college-educated and to live in a household with an annual income exceeding $75,000; they were even more likely to be living in a household with four or more children. Parents with unvaccinated children were more likely to report that doctors do not influence their decision to vaccinate their children. The declining incidence of vaccine-preventable disease that has resulted from successful immunization campaigns may lead parents to believe that disease is no longer a threat and therefore exposure and susceptibility to contracting disease are low. This view, coupled with the belief that the safety and efficacy of vaccines are low, has been associated with refusal to vaccinate. In a study using data from the 2009 National Immunization Survey and the framework of the Health Belief Model, Smith and colleagues found that 60.2% of parents with children aged 24 to 35 months neither delayed nor refused vaccines, 25.8% delayed vaccines, 8.2% refused vaccines, and 5.8% both delayed and refused vaccines.22 Compared with parents who neither delayed nor refused vaccines, parents who delayed and refused were significantly less likely to believe that vaccines were necessary, that their child was at greater risk of getting a disease if not vaccinated, and that vaccines are safe. Children of parents who delayed and refused had significantly lower coverage for all 10 childhood vaccines. Factors associated with the immunization visit may also impact attitudes toward vaccines. Parents who had negative

experiences, such as a child’s crying or other indications of distress; perceived attitudes of indifference on the part of providers or staff; or a prolonged waiting time are more likely to have underimmunized children.23 State childhood immunization policies and laws also may influence parents’ decisions to vaccinate. States that permit personal and philosophical exemptions to school immunization requirements and easy exemption processes are associated with higher and increasing rates of nonmedical exemptions to vaccines and higher rates of disease.6 STRATEGIES TO ENHANCE VACCINATION

Understanding parents’ concerns about childhood immunizations provides an opportunity for having the conversation about the crucial role of vaccination in preventing disease. Health care providers continue to be a primary source of information about immunization and are in the best position to address parental concerns about childhood vaccinations.24 Clinicians who explain the benefits of immunization and address the risks play a key role in overcoming parental concerns. Endorsing immunization for the benefit of the child as well as the greater community may be the first step to opening up a conversation. Parents are likely to have concerns and questions about childhood vaccines. Anticipating these and providing patient education materials and resources in advance of the visit may be helpful. This can serve as a reminder that an immunization visit is coming up. The appointment visit is an opportunity to review February 2012 immunization and catch-up schedules recommended by the Advisory Committee for Immunization Practices (ACIP).25 While the discussion may be tailored to the specific needs of the visit, current guidelines recommend that for optimal health protection, children and adolescents aged 0 through 18 years receive immunizations for 16 vaccine-preventable diseases. Table 1 is a summary of ACIP recommendations. In order to provide continuity of care, the ACIP provides three schedules, including one for children aged 4 months to 18 years who have missed an immunization, that are intended to be used in conjunction with each other rather than as stand-alone entities. Combination vaccines may be used to minimize the number of injections. Use of alternative immunization schedules, which can include vaccine delays or omissions26 and result in undervaccination, should be discouraged.27 Health care providers should solicit questions and listen respectfully to specific concerns parents have about vaccines. Discussing individual vaccines, along with providing honest, evidence-based information about safety, harms, benefits, efficacy, and uncertainty, allows parents to receive accurate information and understand the importance of vaccine protection in the face of risk uncertainty. Using risk ratios to compare the risk of a vaccine-associated adverse event versus the risk of morbidity and mortality associated with the disease can help parents better understand the risk of disease in an unvaccinated child. As appropriate, providers may want to share an experience they have had with an

TABLE 1. Recommended immunizations for persons aged 0 through 18 years—United States, 201225 For persons aged 0 through 6 yearsa Diphtheria, tetanus, pertussis Haemophilus influenzae type b Hepatitis A Hepatitis B Inactivated poliovirus Influenza Measles, mumps, rubella Meningococcal Pneumococcal Rotavirus Varicella For persons aged 7 through 18 yearsb Hepatitis A Hepatitis B Human papillomavirus Inactivated poliovirus Influenza Measles, mumps, rubella Meningococcal Pneumococcal Tetanus, diphtheria, pertussis Varicella a

Approved by the Advisory Committee on Immunization Practices, the American Academy of Pediatrics and the American Academy of Family Physicians. The complete schedule and footnotes can be found at child/0-6yrs-schedule-pr.pdf.

b Approved by the Advisory Committee on Immunization Practices, the American Academy of Pediatrics, and the American Academy of Family Physicians. The complete schedule and footnotes can be found at downloads/child/7-18yrs-schedule-pr.pdf.

unimmunized child in their practice who became ill with a vaccine-preventable disease. From a safety standpoint, make certain parents understand that current vaccines contain fewer antigens than in the past and are thoroughly tested by the FDA before being licensed for use by the public. Monitoring of side effects through the Vaccine Adverse Event Reporting System (VAERS) shows that most adverse reactions reported tend to be mild.28 The visit at which immunization occurs also is a good time to dispel the myth that having the natural disease is “better” than a vaccination and to explain that while no vaccine is 100% efficacious, disease that occurs in fully immunized persons is typically milder and follows an indolent course.29 Intentionally exposing unimmunized children to infected children (such as attending chickenpox and H1N1 influenza parties) poses the risk that a child will contract severe disease and serious complications.27 In the event of local community and school outbreaks, clinicians should provide recommendations to parents to help protect their children, including vaccination when appropriate. Continued on page 26 • OCTOBER 2012 • 25(10) • JAAPA


CME Childhood immunizations Steps should be taken to optimize the vaccination experience by making it as stress-free as possible.30 Providers and staff should encourage parents to bring a favorite toy or blanket or to distract children by talking to them, maintaining eye contact, or asking them to “blow bubbles.” Praising children after the injection can reassure them that everything is okay. For parents who are especially concerned during the immunization visit, a follow-up phone call a day or two later can be helpful to reassure them as well. For missed immunization appointments, a reminder postcard or follow-up phone call may be necessary to reschedule the visit. The phone call may also be an opportunity to discern if the missed visit was the result of vaccine concerns and, if so, to initiate further discussion. Visits for other health concerns can be a time to make sure vaccinations are up to date as well. At times, providers will be faced with parents who refuse some or all vaccines for their children. This can leave providers concerned, frustrated, and uncertain as to whether they can continue to provide care for the family. In a study of pediatricians’ attitudes toward parents who refuse vaccination for their children, reasons for dismissing a family included a breakdown in trust, fear of litigation, and lack of a common commitment to standard medical care for children.31 Unimmunized children who become sick may place other children in the waiting room at risk. One recent study in Connecticut noted that 30% of physician respondents had dismissed families because of a refusal to vaccinate.20 The CDC and AAP Committee on Bioethics recommend against dismissing families who refuse immunization.2 Instead, providers should document their discussions and have parents sign a refusal (declination) waiver for opting out of childhood vaccinations. One such form is available from the AAP. Having the form in the child’s chart will provide a reminder to revisit the vaccination discussion in subsequent visits. The CDC provides a fact sheet entitled “If you choose not to vaccinate your child: Understand the risks and responsibilities” that can be distributed to parents who choose not to vaccinate. Discharging a family from care on the basis of immunization refusal should be a last resort, since it may drive families to seek care at practices more tolerant of their decision not to vaccinate20 or to place them at risk of not receiving regular medical care. CONCLUSION

The decline in vaccine preventable diseases represents one of the greatest achievements in public health. As the number of vaccines has grown, concern over vaccine safety and efficacy has also increased. In recent years, more parents are opting out of vaccinating their children, resulting in greater numbers of unvaccinated and undervaccinated children who are at risk for serious disease, morbidity, and mortality. Helping parents understand the benefits of childhood immunization and placing vaccine risk in appropriate context are fundamental to overcoming parental concerns and ensuring a highly vaccinated population. JAAPA 26 JAAPA • OCTOBER 2012 • 25(10) •

The authors are members of the PA program faculty at Elon University, Elon, North Carolina. Patti Ragan is an associate professor, and Diane Duffy is director of clinical education. No relationships to disclose. REFERENCES 1. Omer SB, Salmon DA, Orenstein WA. Vaccine refusal, mandatory immunization, and the risks of vaccine-preventable disease. N Engl J Med. 2009;360(19):1981-1988. 2. Diekema DS, American Academy of Pediatrics Committee on Bioethics. Responding to parental refusals of immunization of children. Pediatrics. 2005;115(5):1428-1431. 3. Grose C. Varicella vaccination of children in the United States: assessment after the first decade 1995-2005. J Clin Virol. 2005;33(2):89-95. 4. Centers for Disease Control and Prevention. Elimination of rubella and congenital rubella syndrome—United States, 1969-2004. MMWR Morb Mortal Wkly Rep. 2005;54(11):279-282. 5. Jagessar N, Lazarus JV, Laurent E, et al. Immunization: mind the gap. Vaccine. 2008;26(52): 6736-6737. 6. Omer SB, Pan WK, Halsey NA, et al. Nonmedical exemptions to school immunization requirements: secular trends and association of state policies with pertussis incidence. JAMA. 2006;296(14):1757-1763. 7. Ostroff SM. Measles: going, going, but not gone. J Infect Dis. 2011;203(11):1507-1509. 8. Immunization and infectious diseases. Healthy People 2020 Web site. http://www.healthypeople. gov/2020/topicsobjectives2020/overview.aspx?topicid=23. Last updated May 1, 2012. Accessed September 19, 2012. 9. Shim E, Grefenstette JJ, Albert SM, et al. A game dynamic model for vaccine skeptics and vaccine believers: measles as an example. J Theor Biol. 2012;295:194-203. 10. Gay NJ. The theory of measles elimination: implications for the design of elimination strategies. J Infect Dis. 2004;189(suppl 1):s27-s35. 11. Centers for Disease Control and Prevention. Ten great public health achievements—United States, 2001-2010. MMWR Morb Mortal Wkly Rep. 2011;60(19):619-623. 12. Centers for Disease Control and Prevention. National and state vaccination coverage among children aged 19-35 months—United States, 2010. MMWR Morb Mortal Wkly Rep. 2011;60(34):1157-1163. 13. Larson HJ, Cooper LZ, Eskola J, et al. Addressing the vaccine confidence gap. Lancet. 2011; 378(9790):526-535. 14. Smith PJ, Wood D, Darden PM. Highlights of historical events leading to national surveillance of vaccination coverage in the United States. Public Health Rep. 2011;126(suppl 2):3-12. 15. Offit PA. Thimerosal and vaccines—a cautionary tale. N Engl J Med. 2007;357(13):1278-1279. 16. Price CS, Thompson WW, Goodson B, et al. Prenatal and infant exposure to thimerosal from vaccines and immunoglobulins and risk of autism. Pediatrics. 2010;126(4):656-664. 17. Editorial team. Measles once again endemic in the United Kingdom. Eurosurveillance Web site. Accessed September 19, 2012. 18. Centers for Disease Control and Prevention. Measles—United States, 2011. MMWR Morb Mortal Wkly Rep. 2012;61(15):253-257. 19. American Academy of Pediatrics (AAP). Periodic Survey #66: Pediatricians’ attitudes and practices surrounding the delivery of immunizations (part 2)—Communication and documentation of vaccine risks and benefits. AAP Web site. en-us/professional-resources/Research/Pages/PS66_Executive_Summary_ PediatriciansAttitudesandPracticesSurroundingtheDeliveryofImmunizationsPart2.aspx. Accessed September 19, 2012. 20. Leib S, Liberatos P, Edwards K. Pediatricians’ experience with and response to parental vaccine safety concerns and vaccine refusals: a survey of Connecticut pediatricians. Public Health Rep. 2011;126(suppl 2):13-23. 21. Smith PJ, Chu SY, Barker LE. Children who have received no vaccines: who are they and where do they live? Pediatrics. 2004;114(1):187-195. 22. Smith PJ, Humiston SG, Marcuse EK, et al. Parental delay or refusal of vaccine doses, childhood vaccination coverage at 24 months of age, and the Health Belief Model. Public Health Rep. 2011;126(suppl 2):135-146. 23. Stockwell MS, Irigoyen M, Martinez RA, Findley S. How parents’ negative experiences at immunization visits affect child immunization status in a community in New York City. Public Health Rep. 2011;126(suppl 2):24-32. 24. Gust DA, Darling N, Kennedy A, Schwartz B. Parents with doubts about vaccines: which vaccines and reasons why. Pediatrics. 2008;122(4):718-725. 25. Committee on Infectious Diseases. Recommended childhood and adolescent immunization schedules—United States, 2012. Pediatrics. 2012;129(2):385-386. 26. Dempsey AF, Schaffer S, Singer D, et al. Alternative vaccination schedule preferences among parents of young children. Pediatrics. 2011;128(5):848-856. 27. Offit PA, Moser CA. The problem with Dr Bob’s alternative vaccine schedule. Pediatrics. 2009; 123(1):e164-e169. 28. Healy CM, Pickering LK. How to communicate with vaccine-hesitant parents. Pediatrics. 2011; 127(suppl 1):S127-S133. 29. Gould PL, Leung J, Scott C, et al. An outbreak of varicella in elementary school children with two-dose varicella vaccine recipients—Arkansas, 2006. Pediatr Infect Dis J. 2009;28(8):678-681. 30. Schuchat A. Overcoming vaccine concerns and refusals. Centers for Disease Control and Prevention Expert Commentary. Published June 6, 2011. Accessed September 19, 2012. 31. Flanagan-Klygis EA, Sharp L, Frader JE. Dismissing the family who refuses vaccines: a study of pediatrician attitudes. Arch Pediatr Adolesc Med. 2005;159(10):929-934.


Disseminated staphylococcal disease and sepsis in a 23-month-old child Unilateral leg pain and inability to bear weight combined with fever and decreased urinary output were the first signs of a life-threatening infection in a toddler.

Roma Patel, PA-C CASE

A 23-month-old male was brought to the pediatric emergency department with a 3-day history of fever, decreased urinary output, and right hip pain that was causing him to limp. The medical history was significant for bilateral placement of pressure-equalizing tubes 3 weeks prior to presentation. A course of unknown antibiotics was completed at that time. There was no history of known trauma. The patient’s immunizations were current. His mother reported a strong family history of multiple skin abscesses that were susceptible to clindamycin. The family home was used as a day-care center for multiple children. Physical evaluation The patient was an ill-appearing male in no acute distress. He was febrile (temperature, 101°F), tachycardic (heart rate as rapid as 120 beats per minute), and normotensive. The patient was unable to bear weight on the right leg, and he had pain with palpation and range of motion assessment of the right hip. Muscle strength was limited by pain. No rash, murmur, or skin abscess was noted. The remainder of the examination was unremarkable. Initial diagnostic studies Results of admission laboratory studies were significant for an elevated C-reactive protein level (3.2 mg/L) and a normal WBC count. Blood samples were obtained for culture. An orthopedic specialist, who was consulted on initial presentation, recommended MRI of the right hip. Treatment plan The clinical impression was osteomyelitis. The patient was admitted to the general pediatric floor, and blood was drawn for culture. Empiric therapy with clindamycin was started. MRI with contrast revealed changes in the right hip consistent with osteomyelitis. The patient underwent aspiration of the hip and open arthrotomy within 16 hours of admission. The initial blood culture was positive for Staphylococcus aureus within 24 hours of admission, a finding that prompted consultation with a specialist in infectious diseases, who recommended the addition of nafcillin and gentamicin to the clindamycin.

30 JAAPA • OCTOBER 2012 • 25(10) •

Within 30 hours of admission, the patient developed acute severe respiratory distress, with oxygen saturations of 80% requiring supplemental oxygen. A chest radiograph demonstrated acute respiratory distress syndrome (Figure 1). New, generalized pustular lesions were visible on the patient’s skin. Laboratory studies revealed neutropenia with a WBC count of 2,830/µL, thrombocytopenia (platelet count, 52×103/µL), and elevations in partial thromboplastin time and prothrombin time. Elevated gamma-glutamyltransferase and conjugated bilirubin levels (66 U/L and 1.2 mg/dL, respectively) indicated liver dysfunction, and a bicarbonate level of 17 mEq/L indicated metabolic acidosis. BUN and creatinine were normal for age. Results of culture and sensitivity testing of the aspirate from the hip were positive for

FIGURE 1. A chest radiograph taken on admission showed evidence of acute respiratory distress syndrome.

CASE REPORT | Staphylococcal disease

FIGURE 2. Right pleural effusion and a large right pneumothorax were visible after 6 days in the ICU.

FIGURE 2. A pigtail catheter was inserted to alleviate the right pneumothorax.

methicillin-susceptible S aureus (MSSA) that is resistant to clindamycin. The patient was transferred immediately to the pediatric ICU, intubated, and placed on mechanical ventilation for hypoxemic respiratory failure. He required aggressive volume resuscitation, multiple blood products, and inotropic medications. In light of the drug resistance observed on C&S and the worsening clinical picture, clindamycin was discontinued and vancomycin was added to optimize antimicrobial coverage. Over the course of the next 6 days in the PICU, the child experienced worsening respiratory failure requiring high-frequency oscillator ventilation, and he developed liver failure and renal insufficiency. He suffered multiple complications, including a right pleural effusion and a large right pneumothorax (Figure 2) requiring thoracostomy decompression with a pigtail catheter (Figure 3). A repeat aspiration of the right hip performed at the patient’s bedside produced a copious amount of purulent material, and he was taken to the OR for a second open debridement. Serial daily blood cultures continued to be positive for a total of 7 days. Based on the patient’s worsening clinical illness, continuing positive results on blood cultures, and findings suspicious of

septic pulmonary emboli (PE) on radiography, MRI of the brain, spine, chest, abdomen, pelvis, and upper and lower extremities was done to evaluate for multifocal disease. Findings on MRI were consistent with septic PE; multifocal pyomyositis; osteomyelitis of the right ischium, right distal radius, and bilateral tibias; multiple small abscesses in bilateral kidneys; and a right iliac deep venous thrombosis (DVT). A hematology consult was requested. The diagnosis was disseminated staphylococcal disease (DSD). The patient did not require further debridement of the additional infectious foci found on MRI. Management consisted of IV antimicrobials and supportive care. The right iliac DVT was treated with low molecular weight heparin. The patient’s blood cultures remained positive until day 7 of appropriate antibiotic therapy. He was weaned off supportive care, including mechanical ventilation, and inotropes over the following 2 weeks. After a 2-month hospital stay, he was discharged to an inpatient rehabilitation facility. DISCUSSION

Disseminated staphylococcal disease is defined as a triad of DVT, septic PE, and acute osteomyelitis. Diagnostic criteria

TEACHING POINTS ■ Staphylococcus aureus is the most common cause of osteomyelitis and septic arthritis in children, accounting for 40% to 80% of cases. ■ Any child presenting to a primary care clinic with symptoms suspicious for osteomyelitis or septic arthritis should be referred to the

nearest emergency center with pediatric expertise for management. ■ Patients with sepsis should be identified and treated quickly with fluid resuscitation; broad-spectrum empiric antibiotics; and, if needed,

inotropic medications to improve outcomes in addition to appropriate surgical debridement. ■ Patients with DSD should be cared for in an ICU. Early involvement of specialty services, such as orthopedics and infectious diseases,

will optimize patient outcomes. ■ With the increased incidence of community-acquired drug-resistant S aureus, a detailed history, including prior history of abscesses, is

the key to early identification and treatment with the appropriate and most up-to-date recommended treatment regimen.

32 JAAPA • OCTOBER 2012 • 25(10) •

include infection at two or more anatomic sites. The most common sites are the lungs, bones, and joints.1 Our patient had evidence of staphylococcal disease in the lungs, bones, muscles, joints, kidneys, and skin. He also developed a right iliac DVT and septic PE. S aureus is the most common pathogen involved in osteomyelitis and septic arthritis in children, accounting for 40% to 80% of cases.1 Children with osteomyelitis and septic arthritis are at high risk of developing disseminated staphylococcal disease, which occurs primarily between the ages of 5 and 15 years.1 The mortality rate ranges from 13% to 27%.1 Morbidity and mortality associated with DSD are often the result of a heightened coagulopathic state leading to DVT. S aureus organisms have been found to release alpha endotoxin, which acts on the cell membrane and may cause aggregation of platelets and smooth muscle spasms that increase clot risk and lead to DVT.1 S aureus also releases a coagulase that interacts specifically with fibrinogen to cause platelet clotting. In disseminated staphylococcal disease, the femoral veins are most commonly affected, and the DVT is usually adjacent to the site of the osteomyelitis or pyomyositis.2 Because of its potential to cause multiple organ dysfunction and a number of other life-threatening complications, DSD should be considered in all pediatric patients who present with fever and joint or bone pain with evidence of systemic inflammatory response (SIRS).


With the epidemic spread of drug-resistant S aureus strains in the community, DSD is becoming a significant risk in the pediatric population. Therefore, obtaining a detailed history in children who present with bone or joint pain and fever is the first defense against DSD. The gold standard of management for DSD includes starting broad-spectrum antimicrobial therapy with an antistaphylococcal penicillin (nafcillin) and vancomycin.3 In patients with DSD, daily monitoring of blood cultures, coagulation studies, and imaging to identify possible DVTs should be strongly considered. Early consultation with infectious diseases and orthopedics specialists may be vital to caring for a critically ill patient with staphylococcal sepsis. JAAPA Roma Patel practiced pediatric critical care medicine at Texas Children’s Hospital, Baylor College of Medicine, in Houston when this article was written. She currently practices neuromuscular medicine at Stanford Hospital and Clinics in Stanford, California. No relationships to disclose. REFERENCES 1. Gorenstein A, Gross E, Houri S, et al. The pivotal role of deep vein thrombophlebitis in the development of acute disseminated staphylococcal disease in children. Pediatrics. 2000;106(6):E87. 2. Gonzalez BE, Teruya J, Mahoney DH Jr, et al. Venous thrombosis associated with staphylococcal osteomyelitis in children. Pediatrics. 2006;117(5):1673-1679. 3. American Academy of Pediatrics. Staphylococcal infections. In: Pickering LK, ed. Red Book: 2012 Report of the Committee on Infectious Diseases. 29th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2012. American Academy of Pediatrics.

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Colonic ulceration in a patient with renal disease and hyperkalemia A drug commonly used to treat hyperkalemia has the potential to damage the GI mucosa, especially in surgical patients or patients with end-stage renal disease.

Johanna L. Chelcun, MHS, PA-C; Robert A. Sable, MD, FACP, FACG, AFAF; Kenneth Friedman, MD CASE

A 51-year-old male presented to the emergency department (ED) with pain and swelling of his right thigh. Approximately 2 weeks prior to presentation, the patient had fallen from a chair onto his buttocks while visiting his native country, the Dominican Republic. For the past week, he had been experiencing worsening pain and swelling of the right medial and posterior thigh. He described the pain as a constant “stabbing” sensation and rated it a 6 on a scale of 1 to 10. The patient reported that the pain was associated with fever and chills. He denied chest pain, shortness of breath, abdominal pain, nausea, and vomiting. History The patient’s medical history included endstage renal disease (ESRD) requiring hemodialysis, coronary artery disease (CAD), type 2 diabetes mellitus, hypertension, and asthma. He also had a documented history of atrial flutter, for which he had undergone successful cardioversion the previous year. Current medications included aspirin, clopidogrel bisulfate, minoxidil, lisinopril, metoprolol, hydralazine, atorvastatin, insulin glargine, albuterol and ipratropium inhalers, and weekly darbepoetin alfa injections at hemodialysis. Warfarin was discontinued by his cardiologist 3 days prior to presentation because of gingival bleeding. The patient had no known allergies, and he denied any toxic habits. Evaluation In the ED, the patient was alert and oriented and did not appear acutely distressed. Vital signs were as follows: BP, 152/68 mm Hg; heart rate, 73 beats per minute; respiration rate, 18 breaths per minute; maximum temperature, 101.2°F orally; and oxygen saturation, 100% on room air. Physical examination revealed clear lungs and regular heart rate and rhythm. The patient had an arteriovenous fistula with a palpable thrill in the left upper extremity and an edematous right thigh, which was warm and tender to palpation. Range of motion was limited in the right leg secondary to pain. Peripheral pulses were 2+ bilaterally. No neurologic abnormalities were appreciated.

34 JAAPA • OCTOBER 2012 • 25(10) •

CBC revealed a WBC count of 28,500/µL with 83% neutrophils; hemoglobin, 8.7 g/dL; hematocrit, 25.5%; and platelet count, 553×103/µL. Additional laboratory results were significant for elevated potassium of 6.7 mEq/L; glucose, 190 mg/dL; creatine kinase (CK), 152 U/L; international normalized ratio (INR), 2.6, and D-dimer, 2.10 µg/mL. Results of duplex ultrasonography of the lower extremities were negative for deep venous thrombosis (DVT). ECG demonstrated a heart rate of 72 beats per minute, sinus rhythm, and peaked T waves. In the ED, the patient received a “hyperkalemia cocktail,” which included calcium gluconate, insulin, glucose,



FIGURE 1. On colonoscopy, a large ulcer was found at the ileocecal valve (A and B).

CASE REPORT | Colonic ulceration the ileocecal valve (Figure 1). Multiple biopsy samples were taken from the area. The endoscopic differential diagnosis for ulcer included NSAID use, carcinoma, cytomegalovirus (CMV) infection, ischemia, and inflammatory bowel disease (IBD). Upper endoscopy was not performed because the colonoscopic findings were thought to explain the GI bleeding. Biopsy results were reported as reactive colonic mucosa with ulceration and prominent acute inflammatory exudate containing basophilic crystals consistent with SPS use (Figure 2). The diagnosis was determined to be drugassociated colitis secondary to SPS administration. The patient’s medication history and anticoagulation status likely contributed to the degree of blood loss from the ulceration. DISCUSSION FIGURE 2. Basophilic crystals were consistent with sodium polystyrene sulfonate (hematoxylin-eosin, original magnification 40×).

and a 30-g oral dose of sodium polystyrene sulfonate (SPS). The decision was made to admit the patient for further workup of a possible leg abscess versus a hematoma and to treat and monitor the hyperkalemia. Blood cultures were drawn prior to administration of empiric IV antibiotics, and morphine and acetaminophen were given for pain and fever. The renal service was consulted for dialysis, and a repeat basic metabolic panel was ordered. Hospital course The patient was admitted to the medicine service, and IV antibiotics were continued. A noncontrast CT revealed a large heterogeneous mass measuring approximately 14×7×9 cm in the medial right thigh, extending to the midthigh. Because the patient had an elevated WBC count and had been febrile, infection was suspected. CT-guided drainage of the right thigh lesion yielded 150 mL of purulent fluid, and a pigtail catheter was placed for continued drainage. A fluid sample grew methicillin-sensitive Staphylococcus aureus (MSSA), and antibiotics were tailored accordingly. Postprocedural CT showed a decreased amount of fluid collection. Results of blood cultures were negative, and with dialysis, the patient’s serum potassium level decreased to 4.8 mEq/L. The platelet count increased to 619×103/µL and peaked at 911×103/µL. Decreases in hemoglobin and hematocrit to 6.7 g/dL and 21%, respectively, indicated worsening anemia, and the patient was transfused with packed RBCs. Because of the anemia and a history of “dark” stools while in the hospital, the patient underwent colonoscopy on hospital day 11. A large ulcer surrounded by erythema was found at

Sodium polystyrene sulfonate is a commonly prescribed drug indicated for the treatment of hyperkalemia. However, SPS administration has been associated with colonic necrosis, more commonly in surgical patients or those with ESRD. Current literature suggests that SPS-associated colonic necrosis is a rare adverse event. Gerstman and colleagues estimated the incidence of intestinal necrosis associated with SPS in postoperative patients to be 1.8%,1 and Rashid and Hamilton described only 15 cases of SPS crystals in all surgical pathology reports between 1984 and 1995 at a large university hospital.2 All patients in the latter study had renal insufficiency of varying degrees, and more than half were dialysis-dependent. While case studies have traditionally described lower GI damage after SPS enemas, upper GI tract injury after oral administration of the drug has also been described.3 The mechanism by which oral SPS lowers serum potassium begins in the stomach, where sodium cations are exchanged for hydrogen ions. Hydrogen is then exchanged for potassium during transit through the intestinal tract, and the excess potassium is evacuated with the stool.3,4 Because SPS can cause constipation or even impaction, it is routinely administered as a suspension in hypertonic sorbitol (an osmotic laxative). This sorbitol additive is thought to be the cause of GI tract injury, leading to mucosal erosion, ulceration, and bowel ischemia or necrosis. In patients with acute or chronic renal failure (CRF), the risk of bowel ischemia may be increased due to abnormal renin levels, angiotensin secretion, and vasoconstriction.2 Although the specific mechanism of mucosal damage is unknown, cases of colonic perforation and patient death have been reported.3,5 In a case series that identified 11 patients with intestinal necrosis secondary to

TEACHING POINTS ■ Sodium polystyrene sulfonate (SPS) administration has been associated with colonic necrosis, more commonly in surgical patients or

those with ESRD. ■ Sorbitol that is added to SPS to prevent constipation and impaction may lead to necrosis of the intestinal mucosa. ■ During in vitro clot formation, platelets release potassium into serum; therefore, an increased platelet count can lead to more potassium

leakage and resulting pseudohyperkalemia. • OCTOBER 2012 • 25(10) • JAAPA


CASE REPORT | Colonic ulceration SPS administration at one institution between 1998 and 2007, McGowan and colleagues found the mortality rate to be 36%.5 Symptoms of GI injury after SPS administration are nonspecific and include bleeding (hematemesis, melena), nausea, vomiting, dysphagia, abdominal pain, and chest pain. In one study, GI bleeding was the most common reason for further endoscopic investigation.3 Endoscopic findings range from erythema and mild inflammation to erosions, masses, or bowel perforation. Mucosal injury can occur in any portion of the GI tract, from the esophagus to the rectum.2,3,5 SPS-induced bowel injury requires confirmation of crystals on microscopy, which distinguishes it from other causes of ischemic colitis. SPS crystals are typically polygonal in shape, basophilic, and nonpolarizing and have a mosaic pattern. The histologic pattern of mucosal injury can have a range of features. Focal ulceration with acute inflammation and a fibro-inflammatory exudate can predominate in less severe cases. In more severe cases, the inflammation can extend through the bowel wall, causing transmural necrosis with perforation. SPS crystals are often seen along the surface of the injured colonic epithelium or within inflammatory exudates associated with the lesion.2,5 Patient-specific factors appear to play a role in SPS-induced GI tract injury. In addition to renal insufficiency, predisposing factors include immunosuppression and mechanical obstructions (eg, tumors).3 Constipation, postoperative bowel ileus, or opiate use can slow elimination of the drug and increase the risk of mucosal damage. Intestinal injury with histologic confirmation of SPS crystals has been reported up to 11 days after administration of the drug.5 Treatment includes supportive care; avoidance of the offending agent; and surgical intervention if necessary in severe cases, with some patients requiring bowel resection or colectomy.2,5 The onset of SPS action ranges from hours to days, making it a less-than-ideal choice for rapid treatment of hyperkalemia. In patients with ESRD, a wiser approach may be to avoid SPS and perform hemodialysis to decrease potassium levels. In all patients with hyperkalemia, risk factors for GI tract injury (eg, bowel motility, uremia, postoperative condition) should be considered prior to treatment with SPS.6 When evaluating patients with elevated potassium levels, consideration should be given to all potential causes, including pseudohyperkalemia. While our patient’s potassium was most likely elevated because of his CRF, his thrombocytosis may have also contributed to the fluctuations in his potassium level. During in vitro clot formation, platelets release potassium into serum; therefore, an increased platelet count can lead to more potassium leakage and a resulting pseudohyperkalemia.7,8 The rise in potassium levels is not proportional to the level of thrombocytosis.7 Patient outcome Although the patient’s potassium levels fluctuated between 4 and 7 mEq/L throughout admission, SPS administration was avoided and our patient continued to receive hemodialysis. After the patient was closely observed on IV antibiotics, the drainage catheter was removed from his right thigh, and WBC and platelet counts 38 JAAPA • OCTOBER 2012 • 25(10) •

decreased. Hemoglobin and hematocrit levels remained stable. No further blood transfusions or surgical intervention were required for the patient’s ileocecal ulceration. He was discharged home, with follow-up appointments scheduled. CONCLUSION

Sodium polystyrene sulfonate, a drug commonly used to lower serum potassium levels, can be associated with such adverse effects as GI mucosal damage, ulceration, and necrosis. The mechanism of action is unknown, although the mucosal damage appears to be caused by the sorbitol that is administered with SPS to prevent constipation and impaction. Patients may develop GI ulceration up to 11 days after oral or rectal SPS administration, with symptoms including dysphagia, chest or abdominal pain, and GI bleeding. Endoscopic and histopathologic findings confirm the diagnosis of SPS-induced mucosal injury. Treatment includes avoidance of the drug and supportive therapy or surgical intervention for necrosis or perforation. In January 2011, the FDA instituted a labeling change for Kayexalate, outlining the risks of colonic necrosis with use of the drug. The FDA now cautions prescribers that concomitant use of sorbitol with Kayexalate may result in fatal cases of intestinal necrosis and is therefore not recommended.9 The possibility of damage to the GI mucosa should be considered prior to administration of sodium polystyrene sulfonate preparations, especially in patients with ESRD or those who have had recent surgery. In patients at risk for this rare adverse drug effect, alternative methods for lowering serum potassium levels should be considered. JAAPA Acknowledgment: The authors wish to thank Peter Sandor, RRT, MHS, PA-C, for his review of this report and his input. Johanna Chelcun is a hospital-based PA and a clinical assistant professor at the Quinnipiac University PA program in Hamden, Connecticut. Robert Sable is an attending physician specializing in gastroenterology at Montefiore Medical Center, Bronx, New York, and a clinical assistant professor of medicine at the Albert Einstein College of Medicine, also in the Bronx. Kenneth Friedman is a resident physician with the Department of Pathology at Montefiore Medical Center. No relationships to disclose. REFERENCES 1. Gerstman BB, Kirkman R, Platt R. Intestinal necrosis associated with postoperative orally administered sodium polystyrene sulfonate in sorbitol. Am J Kidney Dis. 1992;20(2):159-161. 2. Rashid A, Hamilton SR. Necrosis of the gastrointestinal tract in uremic patients as a result of sodium polystyrene sulfonate (Kayexalate) in sorbitol: an underrecognized condition. Am J Surg Pathol. 1997;21(1):60-69. 3. Abraham SC, Bhagavan BS, Lee LA, et al. Upper gastrointestinal tract injury in patients receiving Kayexalate (sodium polystyrene sulfonate) in sorbitol. Am J Surg Pathol. 2001;25(5):637-644. 4. Scherr L, Ogden DA, Mead AW, et al. Management of hyperkalemia with a cation-exchange resin. N Engl J Med. 1961;264(3):115-119. 5. McGowan CE, Saha S, Chu G, et al. Intestinal necrosis due to sodium polystyrene sulfonate (Kayexalate) in sorbitol. South Med J. 2009;102(5):493-497. 6. Roy-Chaudhury P, Meisels IS, Freedman S, et al. Combined gastric and ileocecal toxicity (serpiginous ulcers) after oral Kayexalate in sorbitol therapy. Am J Kidney Dis. 1997;30(1):120-122. 7. Sevastos N, Theodossiades G, Efstathiou S, et al. Pseudohyperkalemia in serum: the phenomenon and its clinical magnitude. J Lab Clin Med. 2006;147(3):139-144. 8. Stankovic AK, Smith S. Elevated serum potassium values: the role of preanalytic variables. Am J Clin Pathol. 2004;121(suppl 1):S105-S112. 9. Food and Drug Administration. Safety labeling changes approved by FDA Center for Drug Evaluation and Research (CDER). January 2011. ucm186845.htm. Published January 2011. Updated February 17, 2011. Accessed September 1, 2012.


Ankle sprains: Treating to prevent the long-term consequences Ankle sprains are often believed—quite wrongly—to be inconsequential. As a result, more than half of people who sprain an ankle do not seek medical treatment.

Erik A. Wikstrom, PhD, ATC, FACSM; April M. Wikstrom, PA-C, ATC; Tricia Hubbard-Turner, PhD, ATC, FACSM


ateral ankle sprains (LAS) are the most common musculoskeletal injuries.1 They occur during all types of physical activity and often cause sequelae that plague patients for the remainder of their lives. Indeed, an estimated 23,000 LAS occur each day in the United States alone.2 Additionally, LAS account for 1.6 million office visits and 11,000 hospitalizations a year.3 Despite the frequency of LAS, the injury is often erroneously considered to be inconsequential, and about 55% of affected persons do not seek treatment from a health care professional as a result.4 Thus, the true incidence of injury may be much greater than is reported. Even more concerning are the roughly 30% of people who suffer a first-time ankle sprain and subsequently develop residual symptoms.5 This means that at least one of every three people who sprains an ankle will go on to suffer residual symptoms indefinitely, but the number of such patients has been reported to be as high as 75%.6 The development of these residual symptoms has been termed chronic ankle instability (CAI). This condition is characterized by pain, mechanical adaptations, neuromuscular adaptations, episodes of giving way, recurrent sprains, permanently decreased physical activity, and decreased quality of life.7-9 CAI also leads to articular degeneration of the talus and an increased risk of posttraumatic ankle osteoarthritis (OA).10 Given the high incidence of CAI and potential for the development of ankle OA, early effective management of LAS essential. This article reviews the pathophysiology, assessment guidelines, and evidence regarding two common treatment techniques: immobilization/external support and balance exercises.

the ATFL occurs in 66% of LAS, while ATFL and CFL ruptures occur concurrently in another 20%11; the PTFL is not commonly injured. The subtalar ligaments can also be injured.12 Injury to the subtalar joint is generally thought to occur in combination with injury to the lateral ankle ligaments, but little empiric evidence supports this assumption. Damage to the ligamentous stabilizers following LAS allows an associated increase in hypermobility (motion occurring between the bones of the ankle/foot complex). This hypermobility is believed to launch a cascade of events that ultimately leads to CAI and posttraumatic ankle OA.13 Based on the current literature, ligament healing takes more than 6 weeks to occur.14,15 Joint laxity 6 months post injury has been documented14 and may be due to inappropriate

Tibia Fibula Anterior Tibiofibular Ligament

Posterior Tibiofibular Ligament

Anterior Talofibular Ligament

Posterior Talofibular Ligament

Forceful ankle plantar flexion and inversion is the most common mechanism of a lateral ankle sprain and often leads to tearing of the lateral ligaments (Figure 1). The anterior talofibular ligament (ATFL) is first ligament injured.11 Damage to the calcaneofibular ligament (CFL) and finally to the posterior talofibular ligament (PTFL) almost always occurs only after the ATFL is injured.11 Isolated injury to 40 JAAPA • OCTOBER 2012 • 25(10) •

Calcaneofibular Ligament


FIGURE 1. Lateral ligaments of the ankle

© Molly Borman-Pullen


treatment and rehabilitation. Thus, all health care providers need to be able to accurately diagnose LAS and prescribe effective treatment. ACUTE INVERSION INJURIES

The differential diagnosis for any self-reported acute traumatic incident involving forced inversion includes, at a minimum, LAS, distal fibular fracture, and fracture to the base of the fifth metatarsal. Peroneal strains, impingement of the medial joint capsule, osteochondral fractures of the talus, and fractures of the medial malleolus can occur concurrently with LAS. Patients with acute LAS will usually report pain on the lateral aspect of the ankle, typically at the malleolus and sinus tarsi. Hearing a “pop” or reporting a tearing sensation is also possible, but neither is an indicator of injury severity.16 Inspection of the area will typically reveal swelling and discoloration around the lateral joint capsule that may or may not spread to the dorsum of the foot and into the sinus tarsi area. Discoloration can occur up to 24 to 48 hours after injury.17 Because interobserver agreement for the visual inspection of discoloration and swelling is poor to fair,18,19 these signs should not be used solely as indicators of injury presence or severity. If quantifying the magnitude of swelling is of interest, we recommend the figure-8 technique, which uses a simple flexible tape measure and has excellent reliability20 (Figure 2). Evaluation Palpation often elicits pain along the involved ligaments and particularly the sinus tarsi area, which is directly over the ATFL. The reliability of eliciting ATFL tenderness has been found to be moderate,18 but examiners should be aware that pain is often diffuse during the initial examination, becoming more localized to the ATFL 5 days post injury.21 The elicitation of pain over the CFL has been shown to be a better indicator of ligament rupture (72%) than tenderness over the ATFL (58%) in confirmed cases.22 Further, the interobserver reliability of eliciting CFL pain is fair for patients with known ligament sprains.18 Palpation of the medial structures, especially the deltoid ligaments and medial malleolus, should be part of the initial examination despite the lateral nature of the injury. During severe LAS, the medial wall of the talus can strike the distal medial malleolus, resulting in bone bruises and/or fractures. Severe LAS can also result in a posteromedial impingement,

FIGURE 2. Figure-8 technique to measure ankle joint swelling after a lateral ankle sprain

in which the posterior fibers of the deltoid ligament are pinched between the talus and medial malleolus. Symptoms on the medial side of the ankle are not typically prominent during the evaluation; they should be considered a sign of significant trauma17 and be referred to an orthopedic specialist. Assessment of joint and muscle function is also an important component of the LAS evaluation. Range of motion (ROM) will typically be decreased in all planes because of pain and swelling. Additionally, active plantar flexion and inversion will result in pain over the lateral ligaments because the ATFL and CFL are being stretched. Passive inversion will elicit lateral pain for the same reason. Medial pain during ROM assessment is indicative of posteromedial impingement and a sign of significant trauma. Testing Two ligamentous stress tests are performed during the evaluation for lateral ankle sprain: the anterior drawer test (Figure 3) and the talar tilt test (Figure 4). In general, ligamentous stress testing is best performed between 4 and 7 days after injury, when acute pain and swelling have diminished and the patient is able to relax.21,23 The anterior drawer test evaluates ATFL integrity and should be performed as the patient is seated over the edge of the table with knees flexed to prevent false-negative

KEY POINTS ■ At least one of every three people who sprains an ankle will go on to suffer residual symptoms indefinitely. ■ Chronic ankle instability (CAI) is characterized by pain, mechanical adaptations, neuromuscular adaptations, episodes of giving way,

recurrent sprains, and decreased physical activity and quality of life. ■ Ligament healing takes more than 6 weeks to occur. Joint laxity has been documented 6 months after injury and may be due to

inappropriate treatment and rehabilitation. ■ Too much early activity with insufficient protection may not allow adequate time for ligament healing. If joint stability is not reestablished,

a vicious cycle of neuromuscular deficits and further instability may develop. ■ Balance training improves postural control and reduces the risk of recurrent lateral ankle sprain. • OCTOBER 2012 • 25(10) • JAAPA


REVIEW ARTICLE | Ankle sprains

FIGURE 3. Hand placement and direction of hand motion for the anterior drawer test

FIGURE 4. Hand placement and hand motion for the talar tilt test

results from gastrocnemius tightness.24 To perform the anterior drawer test, use one hand to stabilize the lower leg while making sure not to occlude the talar dome. The other hand will cup the calcaneus while supporting the foot in a slightly plantar-flexed position (approximately 10° to 20°).17 Once positioned, the provider will draw the calcaneus forward while providing a stabilizing force to the tibia (Figure 3). Increased anterior translation of the talus relative to the contralateral side represents a positive result, which is often associated with a soft end feel, pain, and apprehension. The talar tilt test should also be performed with the patient seated and with one hand stabilizing the lower leg while the other hand grasps the calcaneus and talus.17 Grasping the calcaneus and talus as a single unit is important to limit unwanted subtalar motion,17 which makes interpretation of the results more difficult. The foot is maintained in about 10° of dorsiflexion to better isolate and put tension on the CFL before applying an inversion stress by rolling the calcaneus medially25 (Figure 4). A positive result is indicated by excessive tilting or gapping (greater than 10°) of the talus relative to the uninjured contralateral limb.17 Radiography To determine if radiographs are needed, the Ottawa Ankle Rules19 should be applied. Ankle radiographs should be ordered for patients who (1) are unable to complete 4 weight-bearing steps immediately after the injury and at the time of evaluation and (2) experience bone tenderness at the posterior edge or inferior tip of either the lateral or medial malleolus.19 Radiographs of the midfoot should be ordered for patients who meet both of those criteria and who have bone tenderness at the base of the fifth metatarsal, cuboid, or navicular bones.19 The Ottawa Ankle Rules have a pooled negative likelihood ratio of 0.08 for the ankle and 0.08 for the midfoot.26 These low negative likelihood ratios indicate that when the previously described criteria are not met, the probability of a foot/ankle joint complex fracture is extremely low.


42 JAAPA • OCTOBER 2012 • 25(10) •

Multiple grading scales have been reported, making comparison of diagnostic evidence and intervention effectiveness difficult to determine. Each scale is unique, and each has limitations (Table 1). In short, grading ankle sprains remains largely subjective, and agreement among independent observers varies. MANAGEMENT STRATEGIES

Management of acute lateral ankle sprain typically involves rest, ice, compression, elevation (RICE) and functional rehabilitation (early mobilization with support).27 RICE is prescribed to reduce secondary injury, limit neural inhibition, and promote proper alignment of new collagen fibers. In more severe cases, LAS are treated with crutches and RICE and typically immobilized for a few days, after which the patient is instructed to perform specific exercises designed to help restore ROM (eg, ankle pumps and circles) and strength (eg, resistance bands, heel raises).27 To date, numerous investigations have assessed the efficacy of various rehabilitation techniques in improving clinical outcomes after LAS,28,29 but these studies have focused mostly on short-term outcomes such as pain, ROM, and return to work/activity. Immobilization/external support As with any acute musculoskeletal injury, managing pain, controlling inflammation, and protecting the joint are crucial. With an LAS, the lateral ligaments of the ankle have been damaged (depending on the severity of the injury) and need to be protected to promote healing.30 Although early movement of the ankle joint is encouraged, too much early activity with insufficient protection may not allow adequate time for ligament healing. If joint stability is not reestablished, a vicious cycle of neuromuscular deficits and further instability may develop and lead to CAI. Research has demonstrated that results of anterior drawer tests were still positive in 3% to 31% of subjects 6 months after injury.31 Further, Hubbard

REVIEW ARTICLE | Ankle sprains TABLE 1. Ankle sprain grading systems Type of scale

Grade 1

Grade 2

Grade 3


Clinical severity40

Mild: little swelling and tenderness; minimal or no loss of function; no mechanical instability

Moderate: moderate pain, swelling, and tenderness; some joint motion is lost; instability is present (mild to moderate)

Severe: significant swelling, hemorrhaging, and tenderness; loss of function with significant increases in joint instability and reductions in joint motion

Does not consider patient-to-patient variability in sign and symptom presentation


ATFL only



Evidence of each ligament’s involvement is absent unless treated surgically


Microscopic injury without stretching of a ligament

Macroscopic stretching, but the ligament remains intact

Complete rupture

Focused on a single ligament and ignores the potential of multiple ligament involvement

Key: ATFL, anterior talofibular ligament; CFL, calcaneofibular ligament (CFL); PTFL, posterior talofibular ligament (PTFL).

and Cordova reported that ankle laxity did not significantly decrease during the 8 weeks following an acute LAS.32 Based on the current literature, immediate care and management of LAS should encourage protection of the ankle through immobilization and/or external support. To determine the best type of immobilization/support, Beynnon and colleagues28 compared an elastic wrap (common standard of care in the United States), an Air-Stirrup ankle brace, Air-Stirrup ankle brace with an elastic wrap, and a fiberglass walking cast. Treating grade 1 and grade 2 ankle sprains with an Air-Stirrup brace combined with an elastic wrap allowed patients to return to preinjury function more quickly than treatment with other immobilizers/supports.28 For grade 3 sprains, there were no differences between the Air-Stirrup brace and the fiberglass walking cast. More recently, three different mechanical supports (Aircast brace [DJO Incorporated, Vista, CA], Bledsoe boot [Medical Technology Inc, Grand Prairie, TX], and a 10-day belowknee cast) were compared with the current standard of care in the United Kingdom (double-layer tubular compression bandage) for treating grade 3 LAS.29 The authors reported that a short period of immobilization in a below-knee cast resulted in the fastest recovery, while an Aircast ankle brace also led to faster recovery times than the standard of care.29 The results suggest that in order to provide protection and prevent long-term instability after less severe LAS (grade 1 and grade 2), an air-stirrup brace combined with elastic wrap appears to restore function best. Elastic or tubular wraps alone are not recommended, even for minor grade 1 sprains because research suggests that they do not provide adequate protection to allow restoration of function relative to other immobilizers and/or external supports. In more severe cases (grade 3), preliminary evidence suggests that a below-knee cast may best enable return to normal function, but more research is needed. 44 JAAPA • OCTOBER 2012 • 25(10) •

Future research also needs to focus on the length of time the various immobilization/support techniques should be used. Based on our knowledge of the healing process, we recommend that immobilization and/or external support devices (eg, an air-stirrup brace) be worn through the inflammatory and repair phases of healing (approximately 3 weeks post injury, depending on injury severity) to ensure proper ligament healing. Balance exercises In addition to ligament laxity, balance deficits are considered among the worst consequences of an LAS and have been reported regardless of sprain severity. Recent evidence has demonstrated that postural control is impaired in both the involved limb33 and the uninvolved limb34 of patients with LAS relative to an uninjured control group within 6 weeks of a sprain. Further, impaired postural control is associated with an increased risk of recurrent ankle injury.35 Balance training improves postural control after an acute LAS and in those with CAI33 and reduces the risk of recurrent LAS.36,37 A wide variety of exercises (eg, single-limb stance) appear to be effective at improving balance, but the exact prescription (duration, intensity, etc) needed to bring about balance improvements and reduce recurrent injury risk remains unknown. Generally speaking, the longer a balance training program is implemented, the greater the preventive effects.38 Therefore, the recommendation is to integrate balance training programs into activities of daily living and/or physical activity to promote long-term (greater than 1 year) training. REFERRAL CONSIDERATIONS

Unless they are severe, most LAS do not require referral to an orthopedic specialist, particularly upon the initial evaluation. Instead, patients should be prescribed an immobilizer or external support based on sprain severity and hypothesized adherence to the prescribed support and therapy. If a

formal referral for therapy is not given, the provider should, at a minimum, teach patients how to perform a series of “at home” exercises to improve ROM, strength, and balance. Patients should be asked to return for a mandatory follow-up to quantify the resolution of symptoms and assess adherence to prescribed treatments. Anecdotally, we have observed that adherence often depends on the importance assigned to the prescriptions by the provider. The follow-up visit will also allow the provider to make a better decision about orthopedic referral and/or the need for formal referral for therapy. To assist the provider, patients can complete an ankle-specific self-assessed disability questionnaire (eg, the Foot and Ankle Ability Measure [FAAM]) upon the initial visit and follow-up.39 Such questionnaires require less than 5 minutes to administer and are an excellent way to quantify the resolution of symptoms and the impact of the injury on quality of life. JAAPA Erik Wikstrom is an assistant professor of kinesiology at the University of North Carolina at Charlotte. April Wikstrom practices orthopedics at OrthoCarolina, also in Charlotte. Tricia Hubbard-Turner is an associate professor of kinesiology at the University of North Carolina at Charlotte. No relationships to disclose. REFERENCES 1. Hootman JM, Dick R, Agel J. Epidemiology of collegiate injuries for 15 sports: summary and recommendations for injury prevention initiatives. J Athl Train. 2007;42(2):311-319. 2. Kannus P, Renström PA. Treatment for acute tears of the lateral ligaments of the ankle. Operation, cast, or early controlled mobilization. J Bone Joint Surg Am. 1991;73(2):305-312. 3. Praemer A, Furner S, Rice DP. Musculoskeletal Conditions in the United States. Rosemont, IL: American Academy of Orthopaedic Surgeons; 1999: chap 6. 4. McKay GD, Goldie PA, Payne WR, Oakes BW. Ankle injuries in basketball: injury rate and risk factors. Br J Sports Med. 2001;35(2):103-108. 5. Peters JW, Trevino SG, Renstrom PA. Chronic lateral ankle instability. Foot Ankle. 1991;12(3):182-191. 6. Anandacoomarasamy A, Barnsley L. Long term outcomes of inversion ankle injuries. Br J Sports Med. 2005;39(3):e14. 7. Arnold BL, Wright CJ, Ross SE. Functional ankle instability and health-related quality of life. J Athl Train. 2011;46(6):634-641. 8. Verhagen RA, de Keizer G, van Dijk CN. Long-term follow-up of inversion trauma of the ankle. Arch Orthop Trauma Surg. 1995;114(2):92-96. 9. Hertel J. Sensorimotor deficits with ankle sprains and chronic ankle instability. Clin Sports Med. 2008;27(3):353-370, vii. 10. Hintermann B, Boss A, Schäfer D. Arthroscopic findings in patients with chronic ankle instability. Am J Sports Med. 2002;30(3):402-409. 11. Broström L. Sprained ankles. I. Anatomic lesions in recent sprains. Acta Chir Scand. 1964;128:483-495. 12. Rubin G, Witten M. The subtalar joint and the symptom of turning over on the ankle. A new method of evaluation utilizing tomography. Am J Orthop. 1962;4:16-19. 13. McKeon PO, Hubbard TJ, Wikstrom EA. Consequences of ankle inversion trauma: a novel recognition and treatment paradigm. In: Zaslav KR, ed. An International Perspective on Topics in Sports Medicine and Sports Injury. Rijeka, Croatia: InTech; 2012.

14. Broström L. Sprained ankles. V. Treatment and prognosis in recent ligament ruptures. Acta Chir Scand. 1966;132(5):537-550. 15. Eiff MP, Smith AT, Smith GE. Early mobilization versus immobilization in the treatment of lateral ankle sprains. Am J Sports Med. 1994;22(1):83-88. 16. Nilsson S. Sprains of the lateral ankle ligaments, part II: epidemiological and clinical study with special reference to different forms of conservative treatment. J Oslo City Hosp. 1983;33(2-3):13-36. 17. Lynch SA. Assessment of the injured ankle in the athlete. J Athl Train. 2002;37(4):406-412. 18. Stiell IG, McKnight RD, Greenberg GH, et al. Interobserver agreement in the examination of acute ankle injury patients. Am J Emerg Med. 1992;10(1):14-17. 19. Stiell IG, Greenberg GH, McKnight RD, et al. A study to develop clinical decision rules for the use of radiography in acute ankle injuries. Ann Emerg Med. 1992;21(4):384-390. 20. Petersen EJ, Irish SM, Lyons CL, et al. Reliability of water volumetry and the figure of eight method on subjects with ankle joint swelling. J Orthop Sports Phys Ther. 1999;29(10):609-615. 21. van Dijk CN, Lim LS, Bossuyt PM, Marti RK. Physical examination is sufficient for the diagnosis of sprained ankles. J Bone Joint Surg Br. 1996;78(6):958-962. 22. Funder V, Jørgensen J, Andersen A, et al. Ruptures of the lateral ligaments of the ankle. Clinical diagnosis. Acta Orthop Scand. 1982;53(6):997-1000. 23. van Dijk CN, Mol BW, Lim LS, et al. Diagnosis of ligament rupture of the ankle joint. Physical examination, arthrography, stress radiography and sonography compared in 160 patients after inversion trauma. Acta Orthop Scand. 1996;67(6):566-570. 24. Tohyama H, Yasuda K, Ohkoshi Y, et al. Anterior drawer test for acute anterior talofibular ligament injuries of the ankle. How much load should be applied during the test? Am J Sports Med. 2003;31(2):226-232. 25. Bahr R, Pena F, Shine J, et al. Mechanics of the anterior drawer and talar tilt tests. A cadaveric study of lateral ligament injuries of the ankle. Acta Orthop Scand. 1997;68(5):435-441. 26. Bachmann LM, Kolb E, Koller MT, et al. Accuracy of Ottawa ankle rules to exclude fractures of the ankle and mid-foot: systematic review. BMJ. 2003;326(7386):417-423. 27. Mattacola CG, Dwyer MK. Rehabilitation of the ankle after acute sprain or chronic instability. J Athl Train. 2002;37(4):413-429. 28. Beynnon BD, Renström PA, Haugh L, et al. A prospective, randomized clinical investigation of the treatment of first-time ankle sprains. Am J Sports Med. 2006;34(9):1401-1412. 29. Lamb SE, Marsh JL, Hutton JL, et al. Mechanical supports for acute, severe ankle sprain: a pragmatic, multicentre, randomised controlled trial. Lancet. 2009;373(9663):575-581. 30. Hubbard TJ, Wikstrom EA. Ankle sprain: pathophysiology, predisposing factors, and management strategies. Open Access Journal of Sports Medicine Web site. articles.php?article_id=4869. Accessed September 1, 2012. 31. Cetti R, Christensen SE, Corfitzen MT. Ruptured fibular ankle ligament: plaster or Pliton brace? Br J Sports Med. 1984;18(2):104-109. 32. Hubbard TJ, Cordova M. Mechanical instability after an acute lateral ankle sprain. Arch Phys Med Rehabil. 2009;90(7):1142-1146. 33. Wikstrom EA, Naik S, Lodha N, Cauraugh JH. Balance capabilities after lateral ankle trauma and intervention: a meta-analysis. Med Sci Sports Exerc. 2009;41(6):1287-1295. 34. Wikstrom EA, Naik S, Lodha N, Cauraugh JH. Bilateral balance impairments after lateral ankle trauma: a systematic review and meta-analysis. Gait Posture. 2010;31(4):407-414. 35. Wang HK, Chen CH, Shiang TY, et al. Risk-factor analysis of high school basketball-player ankle injuries: a prospective controlled cohort study evaluating postural sway, ankle strength, and flexibility. Arch Phys Med Rehabil. 2006;87(6):821-825. 36. Emery CA, Rose MS, McAllister J, Meeuwisse WH. A prevention strategy to reduce the incidence of injury in high school basketball: a cluster randomized controlled trial. Clin J Sport Med. 2007;17(1):17-24. 37. McHugh MP, Tyler TF, Mirabella MR, et al. The effectiveness of a balance training intervention in reducing the incidence of noncontact ankle sprains in high school football players. Am J Sports Med. 2007;35(8):1289-1294. 38. Bahr R, Lian O, Bahr IA. A twofold reduction in the incidence of acute ankle sprains in volleyball after the introduction of an injury prevention program: a prospective cohort study. Scand J Med Sci Sports. 1997;7(3):172-177. 39. Eechaute C, Vaes P, Van Aerschot L, Asman S, Duquet W. The clinimetric qualities of patientassessed instruments for measuring chronic ankle instability: a systematic review. BMC Musculoskelet Disord. 2007;8:6. 40. Balduini FC, Tetzlaff J. Historical perspectives on injuries of the ligaments of the ankle. Clin Sports Med. 1982;1(1):3-12.

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EARN CATEGORY I CME CREDIT by reading this article and the article beginning on page 22 and successfully completing the posttest on page 51. Successful completion is defined as a cumulative score of at least 70% correct. This material has been reviewed and is approved for 1 hour of clinical Category I (Preapproved) CME credit by the AAPA. The term of approval is for 1 year from the publication date of October 2012.


Define and classify complex regional pain syndrome (CRPS) Discuss the pathophysiologic insults linked to CRPS Formulate a diagnostic approach for CRPS that incorporates recent disease criteria Describe current and emerging treatment strategies for CRPS

Helping patients meet the challenge of complex regional pain syndrome No conclusive test rules out or confirms the presence of CRPS, but greater awareness of the signs and symptoms of this disorder could result in earlier diagnosis and treatment.

Christopher Skory, PA, MS; Denise Rizzolo, PA-C, PhD


omplex regional pain syndrome (CRPS) is a debilitating neuropathic disease that affects not only the body but also the patient’s social life. In addition to agonizing pain and crippling body changes, patients experience depression, isolation from family, loss of friends, increased divorce rates, emergency department visits, and narcotic use. CRPS can be difficult to diagnosis. There is no cure, no conclusive test to rule out or confirm its presence, and no universal guidelines for therapy. The medical literature suggests that better patient outcomes stem from earlier diagnosis and treatment,1 but unless a patient is evaluated in a specialty pain clinic, CRPS is often not recognized or appropriately diagnosed.2 Clinicians who are familiar with the signs and symptoms of CRPS can provide more responsive therapies that lessen patients’ suffering. Complex regional pain syndrome arises in an extremity following acute tissue trauma.3-5 Patients usually experience an intense burning pain that may be out of proportion to the initiating trauma and persists beyond the expected healing time.6 The pain may be accompanied by hyperalgesia and/or allodynia.6 Hyperalgesia is a heightened sensitivity to a normally painful stimulus. For example, a pinch that would cause a brief sensation of mild pain in a healthy person could result in prolonged, debilitating, and agonizing pain in a patient with CRPS. Allodynia is pain experienced from a stimulus that is not usually painful. A slight breeze brushing along the arm can be perceived by the CRPS patient as intense burning. What distinguishes complex regional pain syndrome from other 46 JAAPA • OCTOBER 2012 • 25(10) •

© CMSP / National Medical Slide Bank


Bone scintigram showing algodystrophy of the right hand

neuropathic pain disorders are significant autonomic features that include changes to localized skin color and temperature, presence of edema, and an increase or decrease of hidrosis in the affected area.6 Changes in the growth pattern of nails, hair, and skin are also apparent.6 Changes in motor function can include decreased active range of motion (ROM), loss of strength, and tremor.6 Two types In 1993, the International Association for the Study of Pain (IASP) proposed the name complex regional pain syndrome as a descriptive and general term for those syndromes that consist of pain accompanied by vasomotor (blood vessel function) and sudomotor (sweat function) changes.7 The IASP divides CRPS into two subtypes. In CRPS type 1, formerly known as reflex sympathetic dystrophy, there is no evidence of nerve trauma or lesion, while in CRPS type 2, formerly known as causalgia, nerve trauma or lesion is apparent. If either type is relieved after administration of a sympathetic block, it can be classified as type 1 or 2 with sympathetically maintained pain (SMP). If the sympathetic block does not alleviate the pain, the condition can be referred to as type 1 or 2 with sympathetically independent pain (SIP). This article focuses on CRPS type 1, but except for the presence or absence of a nerve lesion, there is not much to distinguish one form from the other. Both types share most of the known pathophysiology and the same treatments. Warm and cold CRPS If examination detects differences in skin temperature between the affected limb and the unaffected (contralateral) limb, then a subclassification can be made. Increased temperature of the affected area is called warm CRPS, which is believed to be an acute form of CRPS. Decreased skin temperature in the affected limb is termed cold CRPS, which is believed to be an indication of the chronic form of CRPS.8 Most CRPS cases are classified as warm (acute) and believed to develop later into cold (chronic) CRPS.8 Thirty percent of patients present with decreased temperature at onset of disease (primarily cold CRPS) that usually persists throughout the course of the disease.8.9 BACKGROUND Prevalence Although CRPS type 1 is frequently seen in clin-

ical settings, data on its occurrence in the general population are lacking and the available reports seem to be inconsistent.3 In 2003, Sandroni and colleagues found the incidence of CRPS to be 5.46 new cases per 100,000 person-years.3,4

Later, in 2007, de Mos and colleagues reported the incidence of CRPS to be 26.2 new cases per 100,000 person-years, a statistic that is generally accepted as more accurate.3,5 Both studies agree that the prevalence is higher in females and that the most common age of onset is about 50 to 70 years, although any age-group is susceptible.3-5 Etiology The most common precipitating factors are traumatic physical injuries, such as a sprain or fracture to a limb.4,5 CRPS may also be precipitated iatrogenically following certain procedures, including amputations, excisions, or injections into nerves. In 5% to 10% of cases, no precipitating event can be found.6,10 No single hypothesis has accounted for all features of CRPS type 1 or 2, and the many hypotheses that do exist often disagree. Although the pathophysiology of CRPS is complex and remains unclear, studies have suggested that peripheral and CNS deregulation is the primary etiology.11 Pathophysiology of the peripheral nervous system

When CRPS involves the peripheral nervous system, the initial tissue trauma is thought to induce peripheral sensitization. This tissue trauma causes primary afferent fibers to release pronociceptive neuropeptides. These peptides promote firing in the presence of nociceptive stimuli, increase background firing, and lower the firing threshold for thermal and mechanical stimuli,12,13 all of which may be responsible for hyperalgesia and allodynia.12 Furthermore, these neuropeptides, such as calcitonin gene-related peptide (CGRP), substance P, and bradykinin, contribute to vasodilation of blood vessels, which leads to increased temperature, erythema, hyperhidrosis, and hair growth.14,15 Studies also suggest that patients with CRPS have higher levels of pro-inflammatory cytokines and lower levels of anti-inflammatory cytokines, a combination that contributes to inflammation.16-20 Pathophysiology of the CNS Studies suggest that CRPS patients exhibit differences in processing thermal, noxious, and tactile stimuli within the somatosensory system and that patients with unilateral CRPS show changes even within the bilateral sympathetic system.11 These changes may extend to the somatomotor system as well.11 Additionally, bilateral reductions in sympathetic nervous system (SNS) function can predict CRPS occurrence.21 Similar to peripheral sensitization, CNS sensitization can result from the persistent presence of noxious input due to tissue trauma. This increases the excitability of nociceptive neurons within the spinal cord

KEY POINTS ■ Complex regional pain syndrome (CRPS) follows acute tissue trauma usually as an intense burning pain that may be out of proportion

to the initiating trauma and persists beyond the expected healing time. ■ In CRPS type 1, there is no evidence of nerve trauma or lesion, while in CRPS type 2, nerve trauma or lesion is apparent. ■ The goal of treatment is to minimize pain, autonomic abnormalities, and trophic changes and to increase motor functions and improve

quality of life. This is best achieved with a multidisciplinary collaboration among providers of primary care, pain management, and neurologic, physical, and psychological therapies. • OCTOBER 2012 • 25(10) • JAAPA


CME Complex regional pain syndrome and the resulting release of neuropeptides. These include bradykinin, substance P, and glutamine, which interact at N-methyl-D-aspartic acid receptors in the spine to contribute to hyperalgesia and allodynia.22,23 CNS involvement is also expressed in the movement disorders and body perception disturbances found in some CRPS patients.24,25 Other possible contributing factors Catecholamines, genetics, and psychological input may also be implicated in the development of CRPS. Patients have an exaggerated response to catecholamines due to increased upregulation and reduced sympathetic outflow.26,27 Affected limbs have been shown to have lower levels of norepinephrine than unaffected limbs.28 A genetic link has been established between CRPS and human leukocyte antigen (HLA)-related alleles.29 Also, polymorphism of the tumor necrosis factoralpha (TNF-␣) promoter gene has been associated with acute CRPS.30 Psychological factors may be significant. Anxiety may have an effect on predicting acute CRPS after knee arthroplasty,31 and emotional arousal may impact pain in CRPS differently than in other chronic pain conditions.32,33 Peripheral versus CNS involvement Research indicates that processes in peripheral sensitization may contribute to the exaggerated state of inflammation associated with the acute form of complex regional pain syndrome (warm CRPS).8 Although this view has been gaining more acceptance, there is no conclusive evidence to date that peripheral mechanisms are a definitive cause of warm CRPS. Chronic CRPS (cold CRPS) lacks this exaggerated inflammation and may be more closely associated with CNS dysfunction than with peripheral dysfunction.8 Support for this association includes the higher frequency of dystonia in chronic CRPS and the observation that compared with patients who have acute CRPS, those with chronic CRPS more often report histories of other pain disorders.8 Evidence for cold CRPS as a result of CNS dysfunction is also not conclusive. One hypothesis suggests that cold CRPS may be caused by changes in sympathetic outflow or vascular disturbances.34,35 The lack of clear evidence, research, and/or consensus on the pathophysiology of CRPS, makes accurate diagnosis difficult and opens the possibility of misdiagnosis. DIAGNOSIS

The IASP has established diagnostic criteria for both CRPS type 1 and 2. Under the IASP criteria, the patient must present with pain following a noxious event, such as a sprain or a fracture.7 The pain may be localized to the

SEE THE ONLINE VERSION OF THIS ARTICLE TO LINK TO Reflex Sympathetic Dystrophy Syndrome Association: Local support group index American RSDHope

48 JAAPA • OCTOBER 2012 • 25(10) •

area of the event, but it is greater than what is expected for the course of the inciting event and it continues beyond the expected healing time.7 If the patient describes symptoms of edema or changes in skin color, temperature, or sweating or the clinician finds signs of edema or changes in skin color, temperature, or sweating locally, and no other medical conditions can account for these findings, then a diagnosis of CRPS is probable.7 Although, the IASP criteria provide standardization for CRPS and continue to be accepted, they are based on a consensus with low specificity, which leads to their inconsistent utilization in the literature.36-38 An attempt to update the criteria and increase their specificity10 prompted a closed workshop in Budapest, Hungary, in 2003. Under the proposed Budapest modified criteria, patients must present with pain that is disproportionate to the inciting event (as in the IASP criteria), but they must also report one or more symptoms in at least three of four categories: (1) sensory, (2) vasomotor, (3) sudomotor/edema, and (4) motor/trophic changes.39 The clinician most also find at least one sign in two or more of the four categories.39 The IASP diagnosis criteria are very sensitive for diagnosis of CRPS (sensitivity is equal to 0.98), which can be beneficial for early recognition and treatment.39 Overdiagnosis using the IASP criteria can be a concern, however, with their specificity of 0.36.3,10 The Budapest modifications proposed to reduce overdiagnosis by increasing the number of symptoms and signs needed for diagnosis and thereby increasing specificity to 0.69.10,39 Many conditions share similar signs and symptoms with CRPS and must be excluded before a diagnosis can be made: • Inflammation, such as from bursitis, erysipelas, rheumatologic conditions, seronegative arthritis • Injuries, such as tennis elbow • Myofascial pain from disuse, fibromyalgia, overuse, or repetitive strain • Other neuropathic pain diseases, such as motor neuron disease, nerve entrapment, peripheral polyneuropathy, plexopathy, postcerebrovascular accident deafferentation pain, postherpetic neuralgia, or radiculopathy • Psychiatric disorders, such as Munchausen syndrome or somatoform pain • Vascular diseases, such as acrocyanosis, atherosclerosis, erythromelalgia, Raynaud disease, or thrombosis.40 TREATMENT

The goal of treatment is to minimize pain, autonomic abnormalities, and trophic changes and to increase motor functions and improve quality of life. This is best achieved with a multidisciplinary collaboration among providers of primary care, pain management, and neurologic, physical, and psychological therapies. Once the diagnosis of CRPS type 1 is confirmed, first-line treatment is active mobilization physical therapy,41 beginning early in the disease process. The patient also receives graded motor imagery treatment,42,43 which uses lateral

TABLE 1. Symptom-based pharmacologic treatment of CRPS40 Symptom/disorder




Pain/sensory disorder

Analgesics/antidepressants/ antiepileptics

Vasomotor disorder


Motor disorder

Muscle relaxants/antispasmodics

reconstruction, motor imagery, and mirror therapy that targets synapses in the brain. These therapies are administered in conjunction with pharmacologic pain management tailored to address symptoms. Examples of symptombased pharmacology are listed in Table 1. If there is no improvement or symptoms have been experienced over an extended period of time, psychological approaches, such as cognitive behavior therapy (CBT), may be warranted.40 Additionally, if pain persists after appropriate physical and pharmacologic therapies, interventions such as percutaneous sympathetic blocks, surgical sympathectomy, and spinal cord stimulation can be considered.40 Disparities in pain management Lack of adequate pain management continues for racial minorities, women, and persons with histories of substance abuse in our health care system.44 Using pain management guidelines is the best approach for combatting these disparities.44 In disorders lacking clear or established guidelines, such as CRPS, these problems are more difficult to address. The practitioner must be conscious of the lack of equal care often provided to these groups and be especially vigilant when addressing these added concerns. The IAPS promotes the idea of “pain as a fifth vital sign,” meaning that pain should be measured and treated as seriously as abnormalities in vital signs.44 Additionally, taking a few extra minutes to make certain patients feel their concerns have been fully addressed and that pain control is effective can be beneficial. THE DUTCH TREATMENT TASK FORCE

In an effort to develop evidence-based treatment guidelines for CRPS type 1, a multidisciplinary task force was convened to perform a meta-analysis of the literature from 1980 to 2005.45 The recommendations are currently approved by all Dutch professional associations involved in CRPS type 1 treatment.45 Since the United States currently does not have any recommended guidelines, clinicians may choose to follow the guidelines of the Dutch task force, which stresses that further research is needed.45 The Dutch guidelines recommend that, with the exception of strong opioids, clinicians treating patients with CRPS type 1 use the World Health Organization (WHO) analgesic ladder for pain.45 For neuropathic pain, anticonvulsants such as gabapentin and tricyclic antidepressants (TCAs) may be considered.46,47 The free radical scavengers dimethylsulfoxide (DMSO) cream or N-acetylcysteine may be used for inflammatory symptoms.48 Vasodilatory medications may be

considered to promote blood flow; if the subsequent increase in blood flow is insufficient, then percutaneous sympathetic blockade may be used.45 The task force also advises use of standardized physiotherapy to decrease functional limitations.45 Under preventive treatments, the use of vitamin C to prevent CRPS type 1 post wrist fracture is recommended.49,50 To reduce iatrogenic occurrences of CRPS type 1, limitation of operating time, adequate perioperative analgesia, limited use of tourniquets, and use of regional anesthetic techniques are recommended.45 CONCLUSION

A clear understanding of the symptoms, pathophysiology, diagnosis, and treatment strategies of CRPS type 1 remains elusive. What is known is that CRPS type 1 is a clinically diagnosed chronic condition in which patients may experience debilitating pain and physiologic and psychological changes. A multidisciplinary regimen involving pain management, physical therapies, and psychological therapies is warranted. Early diagnosis and treatment by informed and up-to-date health care professionals provides patients with the best possible outcomes. JAAPA Christopher Skory recently completed his master’s degree at Pace University, New York, New York. Denise Rizzolo is a clinical assistant professor in the Pace University PA program and an associate professor in the Seton Hall University PA program in South Orange, New Jersey. No relationships to disclose. REFERENCES 1. Lee J, Nandi P. Early aggressive treatment improves prognosis in complex regional pain syndrome. Practitioner. 2011;255(1736):3, 23-26. 2. Quisel A, Gill JM, Witherell P. Complex regional pain syndrome underdiagnosed. J Fam Pract. 2005;54(6):524-532. 3. Bruehl S, Chung OY. How common is complex regional pain syndrome-Type I? Pain. 2007;129(1-2):1-2. 4. Sandroni P, Benrud-Larson LM, McClelland RL, Low PA. Complex regional pain syndrome type I: incidence and prevalence in Olmsted county, a population-based study. Pain. 2003;103(1-2):199-207. 5. de Mos M, de Bruijn AG, Huygen FJ, et al. The incidence of complex regional pain syndrome: a population-based study. Pain. 2007;129(1-2):12-20. 6. Veldman PH, Reynen HM, Arntz IE, Goris RJ. Signs and symptoms of reflex sympathetic dystrophy: prospective study of 829 patients. Lancet. 1993;342(8878):1012-1016. 7. Stanton-Hicks M, Jänig W, Hassenbusch S, et al. Reflex sympathetic dystrophy: changing concepts and taxonomy. Pain. 1995;63(1):127-133. 8. Eberle T, Doganci B, Krämer HH, et al. Warm and cold complex regional pain syndromes: differences beyond skin temperature? Neurology. 2009;72(6):505-512. 9. Bruehl S, Harden RN, Galer BS, et al. Complex regional pain syndrome: are there distinct subtypes and sequential stages of the syndrome? Pain. 2002;95(1-2):119-124. 10. Harden RN, Bruehl S, Stanton-Hicks M, Wilson PR. Proposed new diagnostic criteria for complex regional pain syndrome. Pain Med. 2007;8(4):326-331. 11. Jänig W, Baron R. Complex regional pain syndrome is a disease of the central nervous system. Clin Auton Res. 2002;12(3):150-164. 12. Cheng JK, Ji RR. Intracellular signaling in primary sensory neurons and persistent pain. Neurochem Res. 2008;33(10):1970-1978. 13. Couture R, Harrisson M, Vianna RM, Cloutier F. Kinin receptors in pain and inflammation. Eur J Pharmacol. 2001;429(1-3):161-176. 14. Birklein F, Schmelz M. Neuropeptides, neurogenic inflammation and complex regional pain syndrome (CRPS). Neurosci Lett. 2008;437(3):199-202. 15. Schlereth T, Dittmar JO, Seewald B, Birklein F. Peripheral amplification of sweating—a role for calcitonin gene-related peptide. J Physiol. 2006;576(3):823-832. 16. Alexander GM, van Rijn MA, van Hilten JJ, et al. Changes in cerebrospinal fluid levels of proinflammatory cytokines in CRPS. Pain. 2005;116(3):213-219. 17. Maihöfner C, Handwerker HO, Neundörfer B, Birklein F. Mechanical hyperalgesia in complex regional pain syndrome: a role for TNF-alpha? Neurology. 2005;65(2):311-313. 18. Uçeyler N, Eberle T, Rolke R, et al. Differential expression patterns of cytokines in complex regional pain syndrome. Pain. 2007;132(1-2):195-205. 19. Wesseldijk F, Huygen FJ, Heijmans-Antonissen C, et al. Six years follow-up of the levels of TNF-alpha and IL-6 in patients with complex regional pain syndrome type 1. Mediators Inflamm. 2008;2008:469439. • OCTOBER 2012 • 25(10) • JAAPA


CME Complex regional pain syndrome 20. Wesseldijk F, Huygen FJ, Heijmans-Antonissen C, et al. Tumor necrosis factor-alpha and interleukin-6 are not correlated with the characteristics of Complex Regional Pain Syndrome type 1 in 66 patients. Eur J Pain. 2008;12(6):716-721. 21. Schürmann M, Gradl G, Zaspel J, et al. Peripheral sympathetic function as a predictor of complex regional pain syndrome type I (CRPS I) in patients with radial fracture. Auton Neurosci. 2000; 86(1-2):127-134. 22. Ji RR, Woolf CJ. Neuronal plasticity and signal transduction in nociceptive neurons: implications for the initiation and maintenance of pathological pain. Neurobiol Dis. 2001;8(1):1-10. 23. Wang H, Kohno T, Amaya F, et al. Bradykinin produces pain hypersensitivity by potentiating spinal cord glutamatergic synaptic transmission. J Neurosci. 2005;25(35):7986-7992. 24. van Rijn MA, Marinus J, Putter H, van Hilten JJ. Onset and progression of dystonia in complex regional pain syndrome. Pain. 2007;130(3):287-293. 25. Frettlöh J, Hüppe M, Maier C. Severity and specificity of neglect-like symptoms in patients with complex regional pain syndrome (CRPS) compared to chronic limb pain of other origins. Pain. 2006;124(1-2):184-189. 26. Wasner G, Schattschneider J, Heckmann K, et al. Vascular abnormalities in reflex sympathetic dystrophy (CRPS I): mechanisms and diagnostic value. Brain. 2001;124(pt 3):587-599. 27. Wasner G, Heckmann K, Maier C, Baron R. Vascular abnormalities in acute reflex sympathetic dystrophy (CRPS I): complete inhibition of sympathetic nerve activity with recovery. Arch Neurol. 1999;56(5):613-620. 28. Harden RN, Duc TA, Williams TR, et al. Norepinephrine and epinephrine levels in affected versus unaffected limbs in sympathetically maintained pain. Clin J Pain. 1994;10(4):324-330. 29. de Rooij AM, Florencia Gosso M, Haasnoot GW, et al. HLA-B62 and HLA-DQ8 are associated with Complex Regional Pain Syndrome with fixed dystonia. Pain. 2009;145(1-2):82-85. 30. Vaneker M, van der Laan L, Allebes WA, Goris JA. Genetic factors associated with complex regional pain syndrome I: HLA DRB and TNF␣ promoter gene polymorphism. Disabil Med. 2002;2(3):68-74. 31. Harden RN, Bruehl S, Stanos S, et al. Prospective examination of pain-related and psychological predictors of CRPS-like phenomena following total knee arthroplasty: a preliminary study. Pain. 2003;106(3):393-400. 32. Bruehl S, Chung OY, Burns JW. Differential effects of expressive anger regulation on chronic pain intensity in CRPS and non-CRPS limb pain patients. Pain. 2003;104(3):647-654. 33. Bruehl S, Husfeldt B, Lubenow T, et al. Psychological differences between reflex sympathetic dystrophy and non-RSD chronic pain patients. Pain. 1996;67(1):107-114. 34. Baron R, Schattschneider J, Binder A, et al. Relation between sympathetic vasoconstrictor activity and pain and hyperalgesia in complex regional pain syndromes: a case-control study. Lancet. 2002;359(9318):1655-1660.

35. Groeneweg JG, Huygen FJ, Heijmans-Antonissen C, et al. Increased endothelin-1 and diminished nitric oxide levels in blister fluids of patients with intermediate cold type complex regional pain syndrome type 1. BMC Musculoskelet Disord. 2006;7:91. 36. Reinders MF, Geertzen JH, Dijkstra PU. Complex regional pain syndrome type I: use of the International Association for the Study of Pain diagnostic criteria defined in 1994. Clin J Pain. 2002;18(4):207-215. 37. Harden RN, Bruehl S, Galer BS, et al. Complex regional pain syndrome: are the IASP diagnostic criteria valid and sufficiently comprehensive? Pain. 1999;83(2):211-219. 38. Bruehl S, Harden RN, Galer BS, et al. External validation of IASP diagnostic criteria for complex regional pain syndrome and proposed research diagnostic criteria. Pain. 1999;81(1-2):147-154. 39. Harden RN, Bruehl SP. Diagnosis of complex regional pain syndrome: signs, symptoms, and new empirically derived diagnostic criteria. Clin J Pain. 2006;22(5):415-419. 40. van Eijs F, Stanton-Hicks M, Van Zundert J, et al. Evidence-based interventional pain medicine according to clinical diagnoses. 16. Complex regional pain syndrome. Pain Pract. 2011;11(1):70-87. 41. Oerlemans HM, Oostendorp RA, de Boo T, Goris RJ. Pain and reduced mobility in complex regional pain syndrome I: outcome of a prospective randomised controlled clinical trial of adjuvant physical therapy versus occupational therapy. Pain. 1999;83(1):77-83. 42. Moseley GL. Graded motor imagery is effective for long-standing complex regional pain syndrome: a randomised controlled trial. Pain. 2004;108(1-2):192-198. 43. Daly AE, Bialocerkowski AE. Does evidence support physiotherapy management of adult Complex Regional Pain Syndrome Type One? A systematic review. Eur J Pain. 2009;13(4):339-353. 44. Paulson MR, Dekker AH, Aguilar-Gaxiola S. Eliminating disparities in pain management. J Am Osteopath Assoc. 2007;107(9 suppl 5):ES17-20. 45. Perez RS, Zollinger PE, Dijkstra PU, et al. Evidence-based guidelines for complex regional pain syndrome type 1. BMC Neurology. 2010;10:20. 46. Serpell MG. Gabapentin in neuropathic pain syndromes: a randomised, double-blind, placebocontrolled trial. Pain. 2002;99(3):557-566. 47. van de Vusse AC, Stomp-van Berg SG, Kessels AH, Weber WE. Randomised controlled trial of gabapentin in Complex Regional Pain Syndrome type 1 [ISRCTN84121379]. BMC Neurol. 2004;4:13. 48. Perez RS, Zuurmond WW, Bezemer PD, et al. The treatment of complex regional pain syndrome type I with free radical scavengers: a randomized controlled study. Pain. 2003;102(3):297-307. 49. Zollinger PE, Tuinebreijer WE, Kreis RW, Breederveld RS. Effect of vitamin C on frequency of reflex sympathetic dystrophy in wrist fractures: a randomised trial. Lancet. 1999;354(9195):2025-2028. 50. Zollinger PE, Tuinebreijer WE, Breederveld RS, Kreis RW. Can vitamin C prevent complex regional pain syndrome in patients with wrist fractures? A randomized, controlled, multicenter doseresponse study. J Bone Joint Surg Am. 2007;89(7):1424-1431.

Traumatic Brain Injury

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All posttests must be completed and submitted online. AAPA members should complete and submit posttests on the AAPA Web site by going to and searching for keyword JAAPA post-tests. All others may complete and submit posttests online at no charge at To obtain 1 hour of AAPA Category I CME credit, PAs must receive a score of 70% or better on each test taken.



1. A recent survey found that compared with 2009, vaccine coverage in 2010 increased or remained stable among children aged a. 5 to 11 months b. 12 to 18 months c. 19 to 35 months d. 36 to 48 months

7. Allodynia is defined as a. Pain that is experienced from a stimulus that is not usually painful b. Heightened sensitivity to a normally painful stimulus c. Diminished sensitivity to any type of noxious stimulation d. Absence of pain in response to stimulation

2. A now discredited 1998 study by Wakefield and colleagues suggested a causal link between autism and the a. MMR vaccine b. Varicella vaccine c. DTaP vaccine d. HepB vaccine

8. A subclassification for complex regional pain syndrome (CRPS) can be made if a. The pain has lasted longer than 3 months without a pain-free interval b. Skin temperature is different between the affected and the unaffected limb c. OTC analgesics are no longer able to provide adequate pain control d. There is a bilateral decrease in the active range of motion

3. In an American Academy of Pediatrics survey, the most common reason for refusing a vaccine was a. Discomfort to the child receiving multiple shots at one time b. Possible link between thimerosal and autism c. Belief that immunizations are unnecessary d. Concerns about vaccine safety and side effects 4. According to a 2004 study, undervaccinated children are more likely to a. Have a college-educated father b. Have an older, married mother c. Be black d. Have an annual household income greater than $75,000 5. Which parental experience is more likely to result in underimmunized children? a. Crying or other indications of distress in the child b. Perceived attitudes of indifference on the part of providers or staff c. Prolonged waiting time d. All of the above 6. When advising parents about childhood vaccination, providers should explain that a. Most adverse reactions are mild (injection site inflammation) b. Alternative immunization schedules can be used c. Risk ratios can be difficult to understand d. Having the natural disease is “better” than a vaccination

9. The most common precipitating factor of CRPS is a. Infection b. Emotional stress c. Traumatic physical injury d. Surgery 10. The release of neuropeptides in CRPS results in a. Increased temperature b. Erythema c. Hyperhidrosis d. All of the above 11. The first-line treatment for CRPS is a. Active mobilization physical therapy b. Cognitive behavior therapy c. NSAIDs d. Opioid analgesics 12. What class of medications may be considered in the treatment of neuropathic pain? a. Vasodilators b. Tricyclic antidepressants c. Antispasmodics d. Muscle relaxants • OCTOBER 2012 • 25(10) • JAAPA



Roles and responsibilities of physician assistants practicing in Mohs surgery ABSTRACT An estimated 30% of members of the American College of Mohs Surgery (ACMS) are using physician assistants (PAs).1 In Mohs surgery, the surgeon and the pathologist are the same person,2 so understanding which tasks are being delegated to PAs working in Mohs surgery is important. Our survey explores the number of PAs working with Mohs surgeons and the tasks delegated to PAs in this specialty.


ohs surgeons undergo extensive training to develop the specialized skills of a dermatologist, dermatopathologist, and reconstructive surgeon. This training raises questions about which portions of the procedure can be delegated to other providers while maintaining patient safety and efficacy.2 In this study, we expand on a recent survey that queried Mohs surgeons on their use of PAs by surveying the PAs themselves on their roles in the procedure. Methods After permission was obtained from the Institutional Review Board at the University of Utah, 832 offices of 875 ACMS fellows were contacted by phone to determine whether they employed a PA. Employed PAs who could be identified were invited by fax or e-mail to participate in an electronic survey. The initial data point was the number of PAs employed by fellowship-trained Mohs surgeons. The survey then focused on tasks delegated to PAs in Mohs surgery. Results Of 832 offices contacted, 218 (26%) employed PAs; 85 offices (10%) employed more than one PA. A total of 307 PAs were employed, Samantha Gaffney is a PA student at the University of Colorado in Denver. Constance Goldgar is associate program director of the University of Utah PA program in Salt Lake City. Mark Hyde practices with the melanoma and cutaneous oncology team at the Huntsman Cancer Institute at the University of Utah. No relationships to disclose.

with a PA-to-physician ratio of 0.35. Contact information was obtained for 265 PAs, 57 of whom responded to the survey (21.5%). Of these 57 PAs, 33 (61%) reported currently participating in some aspect of the Mohs surgery process. The other 39% worked with fellowship-trained Mohs surgeons but were only seeing general dermatology patients. (All respondents reported seeing general dermatology patients.) Table 1 shows a breakdown of the activities performed by PAs in the process of Mohs surgery. Of the 33 PAs participating in Mohs surgery, 12 (36%) reported referring 1 to 5 tumors per week for Mohs surgery. Another 12 referred 6 to 10 tumors per week, and 7 PAs (21%) referred 11 to 15 tumors per week. Combining all groups, these PAs refer an average of 6 to 10 tumors per week to Mohs surgery. Discussion These results validate the previous study reporting that 30% of fellowship-trained Mohs surgeons use PAs in aspects of Mohs surgery as well as to see general dermatology patients.1 Tasks most frequently delegated to PAs are presurgical consults and postsurgery follow-ups. PAs are also involved with reconstruction after Mohs surgery. They are rarely involved in parts of the process that are unique to Mohs surgery, such as excising Mohs stages and interpreting pathology. Based on data from the 2007 practice profile survey by the American

52 JAAPA • OCTOBER 2012 • 25(10) •

Academy of Dermatology (AAD), 23% of respondents used PAs in their dermatology practices.3 This number is only expected to grow, and 36% of dermatologists were expected to employ PAs or nurse practitioners (NPs) by 2010.4 Respondents to the 2007 AAD survey who spent most of their time on cosmetic or surgical procedures reported that their PAs and/ or NPs spent 72% of their time seeing medical dermatology patients.4 Clearly, PAs are being used throughout dermatology practices to expand services and keep up with patient demand. In a survey by the Society of Dermatology Physician Assistants, 94% of respondents reported that new patients were on their daily schedules.5 When practices consider hiring a PA, profitability must be considered; however, determining the profitability of a PA who is assisting in the Mohs process and seeing general dermatology patients is difficult. According to a recent evaluation of the multiple procedure reduction (MPR) rule, the average cost of Mohs micrographic surgery on the arm is $848 ($1,131 minus 25% to correct for MPR) and $947 on the face ($1,263 minus 25% to correct for MPR).6 If we multiply reimbursement numbers by our average number of referrals from a PA each week (6-10), we find that the average PA might generate $5,000 to $9,000 in surgery referrals each week, not including reimbursements for reconstructive processes. Conclusion These data provide information about the number of PAs working in Mohs surgery and about how they can most efficiently be used. JAAPA Richard Dehn, MPA, PA-C, DFAAPA, department editor

To view the references and table, please see the online version of this article at

Brief Report I A N W. JO NES, M PAS, PA-C , CC PA

Where the Canadian physician assistants are in 2012 ABSTRACT Canada’s physician assistant (PA) profession remains relatively unknown to the majority of Canadians, and the distribution of the approximately 300 Canadian PAs is uncertain. This report presents March 2012 findings from the 2011 Canadian PA survey, including the number of PAs employed and where they work.


lthough Canada’s PA profession is growing, it remains unknown to the majority of Canadians, and its distribution across Canada is uncertain. Not every member of the profession is a member of the national professional organization. Furthermore, lack of regulation in some jurisdictions means that not all physician assistants are formally identified as such. The 217 respondents to the electronic survey of 20111 represented an estimated 70% of 310 known physician assistants in Canada at that time. We investigated whether the Canadian National PA survey tool used was representative of the number of physician assistants employed in Canada; where those physician assistants were; and what those physician assistants were doing. METHODS

The methods used to determine actual PA numbers in March 2012 involved using phone calls and e-mails to survey employers and, where available, the regulatory agencies across Canada. In Canada, physician assistants are newly regulated health professionals in the two provinces of Manitoba (since 1999) and New Brunswick (2009), with demonstration projects in Ontario (ongoing since 2007).2 Manitoba continues to use clinical Ian Jones is the program director of the University of Manitoba Physician Assistant Education Program. No relationships to disclose.

assistants in physician extender roles to address the shortage of physician assistants. Alberta currently uses a voluntary registry through their College of Physicians and Surgeons. Physician assistants are found in industries such as the Northern Territories diamond mines, Northern Ontario mines, Alberta oil fields, or working as unregulated PAs for private physicians across Canada. RESULTS

Between July 2004 and January 2012, there were 248 graduates of Canadian Physician Assistant education programs that used a 2-year curriculum (24-26 months in duration).3 From 1984 to 2004, the Canadian Forces used a series of courses over 15 years that culminated in an intensive 6-month capstone program for PA education. How many total physician assistants have entered from the older Canadian Forces pathway or from United States PA programs into Canadian medical practice is unknown. At present, there is no separate stream for international medical graduates (IMGs) who are directed to university PA education programs to become eligible for certification. LIMITATIONS

Determining the exact number of PAs in Canada is difficult because the profession is unregulated in several jurisdictions, with no mandatory government licensing record kept or required. Although we can determine

54 JAAPA • OCTOBER 2012 • 25(10) •

the number of graduates of Canadian programs since 2004, the influx of American-educated physician assistants and those Canadian graduates who chose not to belong to professional associations have resulted in an incomplete tracking and lost souls. CONCLUSIONS

Our findings suggest that as of March 2012, there are 143 Canadian Forces physician assistants and 163 civilian employed physician assistants, for a minimum of 306 working PAs in Canada (with 322 Canadian certified physician assistants). These findings suggest that some 16 to 20 PAs are unemployed, retired, or employed outside the main government agencies. The disparity between certified and employed is related to the Canadian certification and maintenance of certification process, which is a voluntary professional standard and as yet not required for practice outside Alberta and New Brunswick. The profession is still young in Canada and is establishing solid roots. The number of physician assistants graduating from training programs, combined with the demand for PAs from industry and civilian practice, suggests that the profession will continue to thrive. JAAPA Richard Dehn, MPA, PA-C, DFAAPA, department editor REFERENCES 1. Jones IW. 2011 Canadian national physician assistant survey results. Presentation to the Canadian Association of Physician Assistants. 2011 CAPA Annual Conference. Montreal, Quebec, Canada, October 27, 2011. 2. Jones IW, Hooker RS. Physician assistants in Canada: update on health policy initiatives. Can Fam Physician. March 2011;57:e83-e88. 3. Jones IW. Canadian Association of Physician Assistants 2011 President’s Annual Report to the Membership. October 27, 2011.

To view the table and figures, please see the online version of this article at



Faster-acting oral drug for ED


n April 2012, the FDA approved avanafil (Stendra), the latest orally administered phosphodiesterase 5 (PDE5) inhibitor for the treatment of erectile dysfunction (ED).1 Goals for the advancement of this class of medications include faster time to onset, longer half-life, and improved safety profiles.2,3 Avanafil is a potent selective PDE5 inhibitor with the primary advantage of more rapid pharmacokinetic properties compared with other PDE5 inhibitors.3

›PHARMACOKINETICS Avanafil’s pharmacokinetic properties include a more rapid time to maximum concentration (Tmax) but also a shorter half-life (t1/2) when compared with sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra, Staxyn) (Table 1, available online). The pharmacokinetic properties support selecting avanafil for patients who desire a shorter time to onset of action, although the observed time of onset appears similar across all agents. All four PDE5 inhibitors undergo hepatic biotransformation via two key cytochrome P-450 isoenzymes (CYP3A4, CYP2C9). Avanafil is excreted as metabolites predominantly in feces and to a lesser degree in urine. When avanafil is administered to patients with mild or moderate renal or hepatic impairment, only minimal changes in plasma concentration are noted. No data are available to guide dosing for patients with severe renal or hepatic impairment. Avanafil is highly protein-bound. The drug’s extensive hepatic metabolism and protein binding require caution to avoid deleterious drug-drug interactions. Strong CYP34 inhibitors (ie, ketoconazole [Nizoral, generics], ritonavir [Norvir]) and moderate CYP3A4 inhibitors (ie, erythromycin) increase plasma concentrations of avanafil; therefore, coadministration should be considered carefully. Reamer Bushardt is professor and chair, Department of Physician Assistant Studies, Wake Forest School of Medicine, Winston-Salem, North Carolina, and the editor in chief of JAAPA. Mark Archambault is associate professor and chair, Department of Physician Assistant Studies, Elon University, Elon, North Carolina, and the department editor for What’s New. No relationships to disclose.

›SAFETY In three placebo-controlled clinical trials lasting 3 months, common adverse effects associated with avanafil use included headache, flushing, nasal congestion, nasopharyngitis, and back pain. Headache and nasopharyngitis were common at 100-and 200-mg doses versus a 50-mg dose. Adverse-effect data are available for one open-label long-term extension study (treatment duration of 1 year) of two of the trials. Less than 3% of patients in the trials discontinued use of drug because of adverse reactions.4 The rates for the most common adverse reactions associated with long-term asneeded use of avanafil are headache (5.6%), flushing (3.5%), nasopharyngitis (3.4%), and nasal congestion (2.1%). Adverse effects are very similar among sildenafil, vardenafil, and tadalafil and are generally attributed to peripheral vasodilation, including facial flushing, nasal congestion, rhinitis, epistaxis, headache, and dyspepsia. These are similar to patient experiences with avanafil. A few differences in adverse effects are noted among agents. Cyanopsia is most common with sildenafil. Low back pain appears to be more common with tadalafil and avanafil. In vitro research suggests these drug-specific differences may be related to varying levels of selectivity for inhibition of PDE enzyme types.5,6 Yet to be seen is whether in vitro enzyme selectivity of avanafil will lead to population-wide improvements in safety as compared with other PDE5 inhibitors. All PDE5 inhibitors are contraindicated with nitrates because of risk for severe hypotension. PDE5 inhibitors can be used cautiously with alpha-blockers. Select patients who have been well-maintained on an alpha-blocker, separate PDE5 inhibitor dosing from the alpha-blocker by at least 4 hours, and attempt to limit avanafil dosing to 50 mg per day. Potential serious adverse events linked to PDE5 inhibitors include angina, optic neuropathy, sudden hearing loss, and priapism. PDE5 inhibitors should be used with caution in patients at risk of acute coronary syndrome, vision loss (ie, nonarteritic anterior ischemic optic neuropathy), or priapism (ie, those with leukemia and multiple myeloma).2

›EFFICACY Participants in the clinical trials of avanafil took as-needed doses of 50 mg, 100 mg, and 200 mg approximately 30 minutes prior to initiation of sexual activity.4 Compared with placebo, avanafil demonstrated significant improvement for men with ED (mean duration, 6 years) across three primary outcome measures, including the erectile function domain of the International Index of Erectile Function (IIEF) and two questions from the Sexual Encounter Profile (SEP). The IIEF questionnaire was administered at baseline and at 4-week intervals. The IIEF has a 30-point total score, and • OCTOBER 2012 • 25(10) • JAAPA


What’s New in … ›DOSAGE AND ADMINISTRATION TAKE-HOME POINTS ■ The usual starting daily dose of avanafil is 100 mg as needed

approximately 30 minutes before sexual activity but may be decreased to 50 mg or increased to 200 mg based on tolerability or efficacy. Always use the lowest effective dose. ■ Avanafil is contraindicated in patients using nitrates and should be used cautiously in patients who are also receiving an alpha-blocker or other agent associated with hypotension. ■ Common adverse events associated with avanafil are headache, flushing, nasal congestion, nasopharyngitis, and back pain. Potential serious adverse events linked to PDE5 inhibitors include angina, optic neuropathy, sudden hearing loss, and priapism. PDE5 inhibitors should be used with caution in patients at risk of acute coronary syndrome, vision loss, or priapism. ■ The primary benefit of avanafil over other agents is its rapid onset of action. Patient preference and cost should also be considered.

higher scores reflect better erectile function. Trial I evaluated avanafil use in a general population, and trial II evaluated use in men with diabetes mellitus. The results are summarized in Table 2 and Table 3 (available online).

›COMPARATIVE EFFICACY No head-to-head comparisons of avanafil against other commercially available PDE5 inhibitors or other ED treatments could be identified that evaluated patient-oriented outcomes. Comparisons between drugs have also been difficult to accomplish because of inconsistencies within trial designs (ie, vardenafil and tadalafil trials have excluded subjects who did not respond to sildenafil, and several studies used mathematical models to compensate for patient variability, which complicates comparison). A 2009 systematic review and meta-analysis evaluated 130 placebo-controlled, randomized clinical trials of less than 12 weeks’ duration with sildenafil, vardenafil, and tadalafil (n = approximately 35,000; range, 12 to 4,262).7 Results show that all PDE5 inhibitors consistently improve erectile functioning compared with placebo: 73% to 88% of drug-treated patients experienced improved erectile function versus 26% to 32% with placebo. Subgroup analysis of men treated with sildenafil versus placebo reveals that younger patients experience successful intercourse more often than older patients (ie, 60% versus 23% among men younger than 65 years [P <.05]; 46% versus 14% among men older than 65 years [P <.05]). Sildenafil, vardenafil, and tadalafil are generally considered to have comparable efficacy based on data comparing each agent to placebo, meta-analysis, and several direct-comparison trials. Direct comparisons among these three agents have revealed small but not statistically or clinically significant differences.5 The efficacy of avanafil appears to be comparable to that of sildenafil, vardenafil, and tadalafil. 56 JAAPA • OCTOBER 2012 • 25(10) •

Most men begin avanafil with a starting dose of 100 mg taken about 30 minutes before sexual activity as needed, not to exceed one dose a day. The dose may be decreased to 50 mg or increased to 200 mg based on tolerability or efficacy, and the lowest effective dose should be prescribed. Avanafil may be taken with or without food. If coadministration with a moderate CYP34 inhibitor is desired, the avanafil dose should not exceed 50 mg/day. A few trials have evaluated avanafil use with alcohol, but alcohol intake should be minimized because of a risk for hypotension. No dosage adjustments are necessary based upon age. Avanafil should be avoided in patients with severe renal or hepatic impairment.

›FACTORS INFLUENCING DRUG SELECTION The primary therapeutic differences among available agents are speed of onset and duration of action. A few other distinctions may also guide prescribing. Avanafil offers the most rapid onset of action. A once-daily version of tadalafil may be advantageous for spontaneous sexual activity. A portable packet containing orally disintegrating tablets (ODTs) of vardenafil is available (efficacy of ODTs is shown in Table 4, available online). If one PDE5 inhibitor does not work or is not tolerated, another may be considered.

›THE FUTURE OF PDE5 INHIBITORS New research is advancing our knowledge of the association between ED and cardiovascular disease (CVD) as well as of new uses for PDE5 inhibitors in patients with CVD. Sildenafil is approved for the treatment of idiopathic pulmonary artery hypertension. PDE5 inhibitors may be a therapeutic option for patients who cannot tolerate standard therapy for heart failure or who remain symptomatic with standard therapy.8 The evolving understanding of PDE5 inhibition in the management of CVD may lead to use of PDE5 inhibitors in select patients with specific cardiovascular diagnoses. JAAPA REFERENCES 1. FDA News Release: FDA approves Stendra for erectile dysfunction. NewsEvents/Newsroom/PressAnnouncements/ucm302140.htm. Released April 27, 2012. Accessed September 4, 2012. 2. Hatzimouratidis K, Hatzichristou DG. Looking to the future for erectile dysfunction therapies. Drugs. 2008;68(2):231-250. 3. McNamara ER, Donatucci CF. Newer phosphodiesterase inhibitors: comparison with established agents. Urol Clin North Am. 2011;38(2):155-163. 4. Stendra [package insert]. Mountain View, CA: Vivus, Inc; April 2012. assets/pdf/STENDRA-avanafil-tablets-full-PI.pdf Accessed September 4, 2012. 5. Lee M. Focus on phosphodiesterase inhibitors for the treatment of erectile dysfunction in older men. Clin Ther. 2011;33(11):1590-1608. 6. Montague DK, Jarow JP, Broderick GA, et al. The management of erectile dysfunction: An update. American Urological Association Web site. Published 2005. Updated 2006. Accessed September 4, 2012. 7. Tsertsvadze A, Fink HA, Yazdi F, et al. Oral phosphodiesterase-5 inhibitors and hormonal treatments for erectile dysfunction: a systematic review and meta-analysis. Ann Intern Med. 2009;151(9):650-661. 8. Cvelich RG, Roberts SC, Brown JN. Phosphodiesterase type 5 inhibitors as adjunctive therapy in the management of systolic heart failure. Ann Pharmacother. 2011 Dec;45(12):1551-1558.


Fast-track areas in the emergency department: Are they ethical? ›HYPOTHETICAL CASE


A 46-year-old female comes into an emergency department (ED) that, like many other emergency facilities, is often affected by overcrowding. In an attempt to compensate for the increased demand for services, the ED has created a fast-track area (FTA). The PA on duty in the FTA sees the patients who are considered “nonurgent” based on diagnostic group, probability of discharge, acuity by triage criteria, and acuity of care. The woman presents with fever (temperature, 101°F), chills, and abdominal pain. The triage nurse decides that the patient is nonurgent and places her in the FTA queue. The administration has explained that the role of the PA is to expedite care in order for more patients to be seen in the ED. The PA examines the patient and suspects that she is mildly dehydrated from her fever. However, the PA is unsure whether to start IV fluids, which might be indicated if the patient were being seen in the normal track of the ED. The PA also wants to order diagnostic tests, including CBC, blood culture, CT of the abdomen, and urinalysis. Starting IV fluids and running tests will require more time and resources. The patient is uninsured, and the PA is concerned that this lack of insurance might have been a contributing factor in the decision to place her in the FTA.

Overcrowding in EDs has become an increasingly emerging theme in modern medicine and the focus of a broad scope of hospital policies to address the issue. With increased utilization of PAs, many EDs have created FTAs to assess patients who are deemed nonurgent. As FTAs become more common in the United States, the need for providers to have a solid foundation in the ethics of delivering necessary health care is growing. Equally important is that hospital administrators and policy makers establish a system of health delivery that is ethical for all patient populations. The principles of autonomy, nonmaleficence, beneficence, and justice provide an ethical framework to address these issues. Autonomy is the basis for informed consent, and the question that first needs addressing is, do patients have the right to choose their provider (eg, choosing to be seen by an MD/ DO versus a PA)? According to one study, four out of five patients expect to be seen by a physician regardless of acuity or potential for cost saving.1 However, this preference may be

›ETHICAL QUANDARY Are fast-track areas ethically permissible? If so, what ethical principles ought to guide setting priorities for treating patients? Brett Bergman is a graduate student in the PA program at Loma Linda University, Loma Linda, California. No relationships to disclose.

CONTACT US Do you have an ethical quandary? This department addresses the realworld ethics concerns and problems of PAs. These might include problems in practice that may be inconspicuous, problems related to systems of care, problems related to the process of care, and preventive ethics. Please e-mail your ethics question to We will consider it for discussion in a future installment of PA Quandaries

largely based on prejudice or a lack of understanding rather than empiric evidence of a difference in the quality of care.2 Respect for patient autonomy does not require providing all services requested but only that competent patients have the right to decide among reasonable medical options.3 To be in line with the principle of autonomy and informed consent, (1) the care provided in an FTA should be comparable and equivalent to that provided by physicians in the ED, and (2) all patients should be explicitly told that a PA is seeing them. Nonmaleficence requires that PAs not create an unnecessary harm and that we follow the standard of care. Studies have shown that FTAs have reduced rates of patients who left without being seen (LWBS) and have decreased length of stay (LOS) and overall wait time.4,5 Furthermore, this is accomplished without differences in mortality and unscheduled revisits.4,5 The emergency care system has been shown to be oriented toward the efficient care of high-acuity patients but less effective for lowacuity patients, even though a vast majority of ED visits involve lowacuity patients.6 This adds perspective to how PAs may be useful in an attempt to deliver higher quality care to low-acuity patients. The validity of measuring quality of care is highly debated, with one study concluding that mortality is a good measure for patients with acute illnesses who are not supposed to die but is ineffective when used to measure persons with chronic disease.7 To be in line with notions of nonmaleficence, (1) FTAs should improve the efficiency of the entire ED as a whole and should allow more patients to be • OCTOBER 2012 • 25(10) • JAAPA


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PA QUANDARIES “Fast-track areas present a unique situation in which injustice to patients may result from attempts to fix an overwhelmed ED.” seen by the appropriate level of providers while (2) not lowering the standard of care to the group of patients assigned to the FTA. Beneficence requires that PAs promote good and act in the best interest of the patient. Research has shown that financial pressures adversely affect short-term health outcomes.8 In one study in a pediatric ED with an FTA, patients from the ED were more likely to be admitted to the hospital and be given IV fluids. Moreover, patients from the ED had a longer mean length of time from triage to discharge than patients from the FTA.9 Within the two groups, however, patients in the FTA had a higher mean temperature, which is an important diagnostic indication for treatment.9 This study also investigated patient satisfaction and outcomes with follow-up and found no differences in patient outcomes or rate of unscheduled visits.9 One limitation of this study, as the researchers themselves admit, is that nonurgent cases often self-resolve, which is consistent with the presumed minor nature of their illnesses.9 Furthermore, patients may not be able to perceive harm if they are unaware of the option or benefits of having IV fluids, and thus the lack of IV fluids likely would not influence their responses on satisfaction surveys. The study by Saunders found that urinalyses, procedures, radiographs, and blood tests had increasing impact on the time required to treat the patient.6 This further demonstrates the conflict of having expedient care as the goal, while thorough testing increases the length of the visit. To be in line with beneficence, FTA policies (1) should not restrict the use

of laboratory testing when it would otherwise be indicated and (2) should not restrict the use of IV fluids or other medical interventions when they could benefit the patient. Justice requires that PAs ensure equality of care to all patients. Studies have shown that triage assessments by experienced personnel are inconsistent, thus challenging the reliability of current ED triage practices.10 Furthermore, other studies have indicated that even when using the same criteria, health professionals frequently disagree about the urgency of care in ED patients, which has important implications when considering FTAs, where patients needing more urgent care are placed in a pool with patients whose needs are less urgent.11 The argument can be made that being seen by a provider, even if only briefly by a PA, is better than not being seen by a provider at all. Moreover, FTAs allow more patients to have access to health care, as they reduce the wait times of the privileged (insured) as well as the wait times of the unprivileged (uninsured) in an apparent equal manner. One study found that two-thirds of patients placed in the FTA were classified as self-pay or as having no insurance.12 To be in line with the principles of justice, (1) all patients of a certain triage category ought to have equal chances of being placed in the regular ED, and (2) nonmedical criteria, such as ability to pay, should not influence being placed in the FTA. These criteria ensure that all eligible patients share equally the benefits and burdens of FTAs.

›CONCLUSION FTAs present a unique situation in which injustice may be easily perpetuated by attempts to fix an overwhelmed ED. As long as safeguards are in place, the use of PAs in conjunction with FTAs is ethically permissible. Such safeguards include integrating some of the ethical conclusions of this paper into hospital policies (ie, not restricting treatment guidelines in FTAs and not using ability to pay as a criterion when triaging). Additional research still needs to be done by reviewing charts of previous patients to ensure that every patient placed in the FTA received all appropriate and indicated medical care. JAAPA F.J. Gianola, PA, and Jim Anderson, PA-C, ATC, department editors REFERENCES 1. Larkin GL, Hooker RS. Patient willingness to be seen by physician assistants, nurse practitioners, and residents in the emergency department: does the presumption of assent have an empirical basis? Am J Bioeth. 2010;10(8):1-10. 2. Antommaria AH, Melini J. Is it reasonable to refuse to be seen by a nurse practitioner in the emergency department? Am J Bioeth. 2010;10(8):15-17. 3. Jecker NS. The ethics of substituting physician assistants, nurse practitioners, and residents for attending physicians. Am J Bioeth. 2010;10(8):11-13. 4. Sanchez M, Smally AJ, Grant RJ, Jacobs LM. Effects of a fasttrack area on emergency department performance. J Emerg Med. 2006;31(1):117-120. 5. Ducharme J, Alder RJ, Pelletier C, et al. The impact on patient flow after the integration of nurse practitioners and physician assistants in 6 Ontario emergency departments. CJEM. 2009;11(5):455-461. 6. Saunders CE. Time study of patient movement through the emergency department: sources of delay in relation to patient acuity. Ann Emerg Med. 1987;16(11):1244-1248. 7. Holloway RG, Quill TE. Mortality as a measure of quality: implications for palliative and end-of-life care. JAMA. 2007;298(7):802-804. 8. Shen Y-C. The effect of financial pressure on the quality of care in hospitals. J Health Econ. 2003;22(2):243-269. 9. Hampers LC, Cha S, Gutglass DJ, et al. Fast track and the pediatric emergency department: resource utilization and patient outcomes. Acad Emerg Med. 1999;6(11):1153-1159. 10. Wuerz R, Fernandes CM, Alarcon J. Inconsistency of emergency department triage. Emergency Department Operations Research Working Group. Ann Emerg Med. 1998;32(4):431-435. 11. Gill JM, Reese CL 4th, Diamond JJ. Disagreement among health care professionals about the urgent care needs of emergency department patients. Ann Emerg Med. 1996;28(5):474-479. 12. Nash K, Zachariah B, Nitschmann J, Psencik B. Evaluation of the fast track unit of a university emergency department. J Emerg Nurs. 2007;33(1):14-20.

Tell us what you think! Go to to comment on this article. 58 JAAPA • OCTOBER 2012 • 25(10) •

Diagnostic Imaging Review J U LI E EDM I STON, PA-C , RT

FIGURE 1 Posteroanterior chest film

Unexpected consequences of rough play with friends ›CASE A 7-year-old male presented to his pediatrician with a cough after possible aspiration of a foreign body. The patient had been chewing on the tab from a canned soda while “horsing around” with friends, and before he knew it, he had swallowed the tab. On evaluation, the patient had a nonproductive cough. He was afebrile and did not appear in acute distress. On auscultation of the chest, breath sounds on the right side were decreased compared with the left, and occasional wheezing could be heard on the right. Imaging began with erect posteroanterior and lateral chest films. On the initial chest radiographs, no foreign body was visible, but there was asymmetry between the lung markings on

the right side compared with the left and the right side appeared hyperlucent. The following day, an inspiration and expiration chest radiograph was obtained (Figure 1). What did the radiograph show?

›DISCUSSION The radiograph demonstrated significantly decreased lung markings on the right side compared with the left and a small foreign body in the right mainstem bronchus. CT confirmed the presence of a foreign body in the right mainstem bronchus and decreased lung markings on the right side compared with the left, findings consistent with obstructive emphysema (Figure 2). Foreign body aspiration can occur in people of all ages and can be a

life-threatening emergency. An aspirated foreign body can become lodged in the larynx, trachea, or bronchi. Children aged 3 years and younger are the most likely to have a foreign body aspiration compared with other age-groups.1 This is secondary to many factors. In children aged 3 years and younger, the molar teeth are not well-developed, and therefore food is not chewed well. In addition, toddlers are constantly in motion and like to explore their environment by putting things in their mouth. Older children who are watching a younger sibling may not pay attention to what the younger child is placing in his or her mouth.2 In adults, aspiration may occur in those who are intoxicated or sedated secondary to alcohol, drugs or medications; patients suffering from neurologic or psychiatric disorders; and in wearers of dental appliances.3 Aspirated foreign bodies are predominantly organic, such as food. Commonly aspirated food items include nuts; small fruit, such as raisins, grapes, or blueberries; seeds; and poorly chopped or improperly chewed meats, such as hot dogs and sausages. Small smooth and/ or round items are more likely to lodge in the trachea and cause asphyxiation. Dried foods can absorb water over time and cause progressive obstruction.1 Inorganic substances that may be aspirated include pins, beads, toy parts, balloons, coins, or pen caps. Presenting symptoms of an aspirated foreign body can include cough, choking, difficulty breathing, wheezing, stridor, or gagging leading to cyanosis, stupor, excessive sputum production, unresolved pulmonary infection, or suffocation. If the event is unwitnessed, diagnosis can become more complicated. Foreign body aspiration can be Julie Edmiston practices in radiology in Hammond, Louisiana, and is the department editor for Diagnostic Imaging Review. No relationships to disclose. • OCTOBER 2012 • 25(10) • JAAPA


Diagnostic Imaging Review

foreign body in right bronchus right and left mainstream bronchi

FIGURE 2. CT demonstrated a foreign body in the right mainstem bronchus and decreased lung markings on the right side compared with the left.

easily mistaken for another disease process, such as upper respiratory tract infection, asthma, pneumonia, or croup.4 Findings on physical examination may include decreased or abnormal breath sounds, cough, stridor, wheezing, or cyanosis. Chest radiographs are commonly obtained. When evaluating a chest radiograph, look for asymmetry between the two lungs. However, if the foreign body is in the trachea or involves both mainstem bronchi, the lungs may appear symmetric. Sometimes the foreign body is radiopaque and visible; however, most foreign bodies are radiolucent. Secondary signs of an aspirated foreign body can include obstructive emphysema, atelectasis, or lobar pneumonia on the affected side. In obstructive emphysema, the affected lung will have fewer vascular markings and appear hyperinflated compared with

the contralateral side. There may also be mediastinal shift away from the affected side. If atelectasis is present, there may be mediastinal shift toward the affected side. Notably, up to 20% of patients with an aspirated foreign body have a negative history and normal radiographs.2 The foreign body can also become lodged in the neck region. Chest radiographs do not typically include this entire area, and therefore, soft-tissue neck radiographs may be necessary. If foreign body aspiration is still suspected despite negative radiographs, the patient should undergo bronchoscopy.5 Sometimes decubitus views of the chest or inspiration/expiration views are helpful. On inspiration/ expiration views, the affected side will remain hyperexpanded on both views as a result of air trapping. On normal decubitus views, the mediastinum shifts downward toward the dependent

side, but if there is air trapping from a foreign body in the bronchus, the mediastinum will not shift downward. While CT can be helpful in locating an aspirated foreign body and is more sensitive than radiographs, it is not always utilized because of concerns about radiation exposure and cost. Moreover, bronchoscopy is safe, and the foreign body can typically be removed at the same time the bronchoscopy is performed. Management of an aspirated foreign body depends on the patient’s symptoms and the location of the impaction. If the foreign body is in the subglottic or laryngeal region and the patient is in distress, urgent tracheostomy or bronchoscopy may be necessary. In nonurgent situations, most foreign bodies can safely be removed with bronchoscopy. Complications from delayed diagnosis can include lung abscess, bronchial stenosis, bronchiectasis, recurrent pneumonia, pneumothorax, or pneumomediastinum.2 If the foreign body is removed within 24 hours, the complication rate is low. In addition to being alert to the symptoms of an aspirated foreign body, PAs must also maintain a high index of suspicion if a patient returns with recurrent respiratory tract infections. JAAPA REFERENCES 1. Bye MR. Pediatric airway foreign body. Medscape Reference Web site. Updated July 22, 2011. Accessed September 4, 2012. 2. Fong E. Foreign body aspiration. University of Hawaii John A. Burns School of Medicine Web site. http://www.hawaii. edu/medicine/pediatrics/pedtext/s08c06.html. March 2002. Accessed September 4, 2012. 3. Warshawsky ME. Foreign body aspiration. Medscape Reference Web site. article/298940-overview. Updated June 6, 2012. Accessed September 4, 2012. 4. Hilliard T, Sim R, Saunders M, et al. Delayed diagnosis of foreign body aspiration in children. Emergency Medicine Journal Web site. Published January 2003. Accessed September 4, 2012. 5. Lederman HM. Airway foreign body imaging. Medscape Reference Web site. article/405994-overview. Updated May 25, 2011. Accessed September 4, 2012.

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HUMANE MEDICINE Brian T. Maurer, PA-C, practices pediatrics at Enfield Pediatric Associates, Enfield, Connecticut. He is the author of Patients Are a Virtue and a member of the JAAPA editorial board. Visit the author at

Ebb and flow: Murmurings that are more than sweet nothings Aquí en la isla / el mar / y cuánto mar / se sale de si mismo / a cada rato, / dice que si, que no, / que no, que no, que no. — Pablo Neruda, “Ode to the Sea”


his family is new to the practice. The parents bucked recent trends and chose to migrate from the Deep South to New England, following the Atlantic flyway to a job in the northeast. At summer’s end, the mother has brought her 5-year-old twin girls to the office for school entrance physical exams. She tells me that her daughters have been the picture of health—no prior hospitalizations, surgeries, injuries, or allergies. A brief review of the medical records she hands me testifies to this fact. Besides, who could survey two identical blonde-haired, blue-eyed cuties sporting peaches-and-cream complexions and entertain even a remote thought of illness? Before proceeding with their physical examinations, I spend some time playfully engaging my new charges with several ice-breaking questions. “How old are you?” “Does your birthday come on the same day every year?” “Does it snow sandflakes in Florida?” One of the girls is bubbly, full of giggles; the other decidedly more reserved. I start in with the first girl and work down her body, examining eyes, ears, nose, throat, neck, chest, and abdomen in turn. Bubbly Giggles turns out to be ticklish as well; it’s a bit of a challenge to complete the abdominal exam— “What did you eat for a snack: a giggle cookie?”—but in the end, we make it through in good stead. I help her descend from the exam table. “Next!” I say, beckoning her sister to climb up. “Now it’s your turn.” Reticently, the child complies. I tone down the level of my voice, speaking to her in whispers. She, in turn, whispers back. I place my stethoscope on her chest and listen for the familiar lub-dub sounds of the cardiac cycle. Instead of clearcut first and second sounds I am greeted with the churning whoosh of sea waves falling and receding on the beach. Lulled by the ebb and flow of this sea inside, I listen at length to her chest and back; I listen while she leans forward and again when she lies down. The words of Pablo Neruda’s “Ode to the Sea” run through my head: Here, surrounding the island, / there’s sea, / but what sea: / it’s always / overflowing, / says yes then no, / then no again, and no, / says yes in blue, / in sea spray, raging, / says no and no again.

62 JAAPA • OCTOBER 2012 • 25(10) •

Out of the corner of my eye, I can see the mother smiling at her daughter. I, in turn, must now work to keep the smile from fading from my own lips. At the conclusion of the exam, I pop the stethoscope out of my ears and address the mother. “Did anyone ever mention before that your daughter has a heart murmur?” I ask. “Yes, the pediatrician in Florida noted it several times. He reassured me that it was an innocent murmur—something of no consequence.” An innocent murmur, something of no consequence. I could imagine how he must have listened to the same set of sounds that I myself have just heard; how easily he could have chosen merely to make a note of them, thinking to listen again at a subsequent well-child visit, ultimately convincing himself of their innocence—only the ebb and flow of the sea inside. Yet this sea that I have heard is not the musical two-tongued carol-singing sea of Dylan Thomas, no; this is Neruda’s sea that can’t be still, that stammers “My name is Sea!” as it slaps repeatedly against the rocks, murmuring passionately as it strives to capture the listener’s attention. “Many children have a slight heart murmur detected on physical exam at one time or another,” I explain. “Most of these innocent murmurs are just the sound of blood rushing through the heart. In your daughter’s case, the sound seems to be more continuous than I would expect.” “Isn’t that because her heart keeps pumping the blood?” “It’s possible, but I think we might consider having a pediatric cardiologist listen to her heart—just to be sure.” “Well, if you really think we should....” Now the smile fades from the mother’s lips as well. “It can’t hurt. My staff will make the necessary arrangements.” It is always difficult to hand a new patient a disturbing diagnosis, or even to suggest that there might be something amiss, particularly in the light of past reassurances from an unknown colleague. Nobody bats a thousand; we all make mistakes. Sometimes we work hard to convince ourselves that what we have witnessed does not portend a pathologic diagnosis. The longer we wait, the harder it becomes to broach the subject; yet broach it we must. The cardiac evaluation demonstrates a PDA, a persistently patent congenital vessel bridging the gap between the child’s pulmonary artery and her aorta. After surgical correction, she once again assumes her usual state of good health: blonde hair, blue eyes, peaches-and cream complexion outside; and now a two-tongued carol-singing sea within. JAAPA

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While there are many diabetes complications,

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

ONLY LYRICA IS RECOMMENDED AS LEVEL A by AAN evidence-based guideline for the treatment of painful diabetic neuropathy (PDN)1 “If clinically appropriate, pregabalin should be offered for the treatment of PDN (Level A).”1 The medical organizations that developed this guideline (the AAN, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation) recognize that specific care decisions are the prerogative of the patient and physician caring for the patient, based on all of the circumstances involved. For full guideline, visit Level A=Established as effective, based on at least 2 Class I studies. Class I level evidence includes a randomized, controlled clinical trial of the intervention of interest with masked or objective outcome assessment, in a representative population, and other specified criteria. AAN=American Academy of Neurology. LYRICA is indicated for the management of neuropathic pain associated with Diabetic Peripheral Neuropathy, management of Postherpetic Neuralgia, as adjunctive therapy for adult patients with Partial Onset Seizures, and management of Fibromyalgia. PBP485919-01

© 2012 Pfizer Inc.

Selected safety information: LYRICA is contraindicated in patients with known hypersensitivity to pregabalin or any of its other components. There have been postmarketing reports of hypersensitivity in patients shortly after initiation of treatment with LYRICA. Adverse reactions included skin redness, blisters, hives, rash, dyspnea, and wheezing. Discontinue LYRICA immediately in patients with these symptoms. There have been postmarketing reports of angioedema in patients during initial and chronic treatment with LYRICA. Specific symptoms included swelling of the face, mouth (tongue, lips, and gums), and neck (throat and larynx). There were reports of lifethreatening angioedema with respiratory compromise requiring emergency treatment. Discontinue LYRICA immediately in patients with these symptoms. Antiepileptic drugs (AEDs) including LYRICA increase the risk of suicidal thoughts or behavior in patients taking AEDs for any indication. Monitor patients treated with any AED for any indication for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses showed clinical trial patients taking an AED had approximately twice the risk of suicidal thoughts or behavior than placebotreated patients, and estimated the incidence rate of suicidal behavior or ideation was approximately one patient for every 530 patients treated with an AED. The most common adverse reactions across all LYRICA All rights reserved.

clinical trials are dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, constipation, euphoric mood, balance disorder, increased appetite, and thinking abnormal (primarily difficulty with concentration/attention). Inform patients taking LYRICA that dizziness and somnolence may impair their ability to perform potentially hazardous tasks such as driving or operating complex machinery until they have sufficient experience with LYRICA to determine its effect on cognitive and motor function. Higher frequency of weight gain and edema was observed in patients taking both LYRICA and thiazolidinedione antidiabetic drugs. Exercise caution when coadministering these drugs. Patients who are taking other drugs associated with angioedema such as angiotensin-converting enzyme inhibitors (ACE inhibitors) may be at increased risk of developing angioedema. Exercise caution when using LYRICA in patients who have had a previous episode of angioedema. Click here for Full Prescribing Information and Medication Guide. Please see the Brief Summary of Prescribing Information on adjacent pages. Reference: 1. Bril V, England JD, Franklin GM, et al. Evidence-based guideline: treatment of painful diabetic neuropathy. Report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology. 2011;76:1758-1765.

September 2012

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LYRICA® (pregabalin) CAPSULES BRIEF SUMMARY: For full prescribing information, see package insert. INDICATION AND USAGE LYRICA is indicated for: • Management of neuropathic pain associated with diabetic peripheral neuropathy DOSAGE AND ADMINISTRATION LYRICA is given orally with or without food. When discontinuing LYRICA, taper gradually over a minimum of 1 week. Neuropathic Pain Associated with Diabetic Peripheral Neuropathy: • Administer in 3 divided doses per day • Begin dosing at 150 mg/day • May be increased to a maximum of 300 mg/day within 1 week • Dose should be adjusted for patients with reduced renal function Patients with Renal Impairment In view of dose-dependent adverse reactions and since LYRICA is eliminated primarily by renal excretion, adjust the dose in patients with reduced renal function. Base the dose adjustment in patients with renal impairment on creatinine clearance (CLcr), as indicated in Table 1. To use this dosing table, an estimate of the patient’s CLcr in mL/min is needed. CLcr in mL/min may be estimated from serum creatinine (mg/dL) determination using the Cockcroft and Gault equation: [140 - age (years)] x weight (kg) CLCr =

(x 0.85 for female patients) 72 x serum creatinine (mg/dL)

Next, refer to the Dosage and Administration section to determine the recommended total daily dose based on indication, for a patient with normal renal function (CLcr ≥60 mL/min). Then refer to Table 1 to determine the corresponding renal adjusted dose. (For example: A patient initiating LYRICA therapy for postherpetic neuralgia with normal renal function (CLcr ≥60 mL/min), receives a total daily dose of 150 mg/day pregabalin. Therefore, a renal impaired patient with a CLcr of 50 mL/min would receive a total daily dose of 75 mg/day pregabalin administered in two or three divided doses.) For patients undergoing hemodialysis, adjust the pregabalin daily dose based on renal function. In addition to the daily dose adjustment, administer a supplemental dose immediately following every 4-hour hemodialysis treatment (see Table 1). Table 1. Pregabalin Dosage Adjustment Based on Renal Function Creatinine Clearance Total Pregabalin Daily Dose (CLcr) (mL/min) (mg/day)*

Dose Regimen

























Supplementary dosage following hemodialysis (mg)† Patients on the 25 mg QD regimen: take one supplemental dose of 25 mg or 50 mg Patients on the 25–50 mg QD regimen: take one supplemental dose of 50 mg or 75 mg Patients on the 50–75 mg QD regimen: take one supplemental dose of 75 mg or 100 mg Patients on the 75 mg QD regimen: take one supplemental dose of 100 mg or 150 mg TID = Three divided doses; BID = Two divided doses; QD = Single daily dose. *Total daily dose (mg/day) should be divided as indicated by dose regimen to provide mg/dose. †Supplementary dose is a single additional dose. CONTRAINDICATIONS LYRICA is contraindicated in patients with known hypersensitivity to pregabalin or any of its components. Angioedema and hypersensitivity reactions have occurred in patients receiving pregabalin therapy. WARNINGS AND PRECAUTIONS Angioedema There have been postmarketing reports of angioedema in patients during initial and chronic treatment with LYRICA. Specific symptoms included swelling of the face, mouth (tongue, lips, and gums), and neck (throat and larynx). There were reports of life-threatening angioedema with respiratory compromise requiring emergency treatment. Discontinue LYRICA immediately in patients with these symptoms. Exercise caution when prescribing LYRICA to patients who have had a previous episode of angioedema. In addition, patients who are taking other drugs associated with angioedema (e.g., angiotensin converting enzyme inhibitors [ACE-inhibitors]) may be at increased risk of developing angioedema. Hypersensitivity There have been postmarketing reports of hypersensitivity in patients shortly after initiation of treatment with LYRICA. Adverse reactions included skin redness, blisters, hives, rash, dyspnea, and wheezing. Discontinue LYRICA immediately in patients with these symptoms. Withdrawal of Antiepileptic Drugs (AEDs) As with all AEDs, withdraw LYRICA gradually to minimize the potential of increased seizure frequency in patients with seizure disorders. If LYRICA is discontinued, taper the drug gradually over a minimum of 1 week. Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including LYRICA, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Monitor patients treated with any AED for any indication for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebocontrolled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI: 1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebotreated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 2 shows absolute and relative risk by indication for all evaluated AEDs. Table 2. Risk by indication for antiepileptic drugs in the pooled analysis Indication Placebo Patients Drug Patients Relative Risk: Risk Difference: with Events Per with Events Per Incidence of Events Additional Drug Patients 1000 Patients 1000 Patients in Drug Patients/Incidence with Events Per in Placebo Patients 1000 Patients Epilepsy Psychiatric Other Total

1.0 5.7 1.0 2.4

3.4 8.5 1.8 4.3

3.5 1.5 1.9 1.8

2.4 2.9 0.9 1.9

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing LYRICA or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Inform patients, their caregivers, and families that LYRICA and other AEDs increase the risk of suicidal thoughts and behavior and advise them of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Report

behaviors of concern immediately to healthcare providers. Peripheral Edema LYRICA treatment may cause peripheral edema. In short-term trials of patients without clinically significant heart or peripheral vascular disease, there was no apparent association between peripheral edema and cardiovascular complications such as hypertension or congestive heart failure. Peripheral edema was not associated with laboratory changes suggestive of deterioration in renal or hepatic function. In controlled clinical trials the incidence of peripheral edema was 6% in the LYRICA group compared with 2% in the placebo group. In controlled clinical trials, 0.5% of LYRICA patients and 0.2% placebo patients withdrew due to peripheral edema. Higher frequencies of weight gain and peripheral edema were observed in patients taking both LYRICA and a thiazolidinedione antidiabetic agent compared to patients taking either drug alone. The majority of patients using thiazolidinedione antidiabetic agents in the overall safety database were participants in studies of pain associated with diabetic peripheral neuropathy. In this population, peripheral edema was reported in 3% (2/60) of patients who were using thiazolidinedione antidiabetic agents only, 8% (69/859) of patients who were treated with LYRICA only, and 19% (23/120) of patients who were on both LYRICA and thiazolidinedione antidiabetic agents. Similarly, weight gain was reported in 0% (0/60) of patients on thiazolidinediones only; 4% (35/859) of patients on LYRICA only; and 7.5% (9/120) of patients on both drugs. As the thiazolidinedione class of antidiabetic drugs can cause weight gain and/or fluid retention, possibly exacerbating or leading to heart failure, exercise caution when coadministering LYRICA and these agents. Because there are limited data on congestive heart failure patients with New York Heart Association (NYHA) Class III or IV cardiac status, exercise caution when using LYRICA in these patients. Dizziness and Somnolence LYRICA may cause dizziness and somnolence. Inform patients that LYRICA-related dizziness and somnolence may impair their ability to perform tasks such as driving or operating machinery. In the LYRICA controlled trials, dizziness was experienced by 30% of LYRICA-treated patients compared to 8% of placebo-treated patients; somnolence was experienced by 23% of LYRICA-treated patients compared to 8% of placebo-treated patients. Dizziness and somnolence generally began shortly after the initiation of LYRICA therapy and occurred more frequently at higher doses. Dizziness and somnolence were the adverse reactions most frequently leading to withdrawal (4% each) from controlled studies. In LYRICA-treated patients reporting these adverse reactions in short-term, controlled studies, dizziness persisted until the last dose in 30% and somnolence persisted until the last dose in 42% of patients. Weight Gain LYRICA treatment may cause weight gain. In LYRICA controlled clinical trials of up to 14 weeks, a gain of 7% or more over baseline weight was observed in 9% of LYRICA-treated patients and 2% of placebo-treated patients. Few patients treated with LYRICA (0.3%) withdrew from controlled trials due to weight gain. LYRICA associated weight gain was related to dose and duration of exposure, but did not appear to be associated with baseline BMI, gender, or age. Weight gain was not limited to patients with edema [see Warnings and Precautions, Peripheral Edema]. Although weight gain was not associated with clinically important changes in blood pressure in short-term controlled studies, the longterm cardiovascular effects of LYRICA-associated weight gain are unknown. Among diabetic patients, LYRICA-treated patients gained an average of 1.6 kg (range: -16 to 16 kg), compared to an average 0.3 kg (range: -10 to 9 kg) weight gain in placebo patients. In a cohort of 333 diabetic patients who received LYRICA for at least 2 years, the average weight gain was 5.2 kg. While the effects of LYRICA-associated weight gain on glycemic control have not been systematically assessed, in controlled and longer-term open label clinical trials with diabetic patients, LYRICA treatment did not appear to be associated with loss of glycemic control (as measured by HbA1C). Abrupt or Rapid Discontinuation Following abrupt or rapid discontinuation of LYRICA, some patients reported symptoms including insomnia, nausea, headache, anxiety, hyperhidrosis, and diarrhea. Taper LYRICA gradually over a minimum of 1 week rather than discontinuing the drug abruptly. Tumorigenic Potential In standard preclinical in vivo lifetime carcinogenicity studies of LYRICA, an unexpectedly high incidence of hemangiosarcoma was identified in two different strains of mice [see Nonclinical Toxicology, Carcinogenesis, Mutagenesis, Impairment of Fertility]. The clinical significance of this finding is unknown. Clinical experience during LYRICA’s premarketing development provides no direct means to assess its potential for inducing tumors in humans. In clinical studies across various patient populations, comprising 6396 patient-years of exposure in patients >12 years of age, new or worsening-preexisting tumors were reported in 57 patients. Without knowledge of the background incidence and recurrence in similar populations not treated with LYRICA, it is impossible to know whether the incidence seen in these cohorts is or is not affected by treatment. Ophthalmological Effects In controlled studies, a higher proportion of patients treated with LYRICA reported blurred vision (7%) than did patients treated with placebo (2%), which resolved in a majority of cases with continued dosing. Less than 1% of patients discontinued LYRICA treatment due to vision-related events (primarily blurred vision). Prospectively planned ophthalmologic testing, including visual acuity testing, formal visual field testing and dilated funduscopic examination, was performed in over 3600 patients. In these patients, visual acuity was reduced in 7% of patients treated with LYRICA, and 5% of placebo-treated patients. Visual field changes were detected in 13% of LYRICA-treated, and 12% of placebo-treated patients. Funduscopic changes were observed in 2% of LYRICA-treated and 2% of placebo-treated patients. Although the clinical significance of the ophthalmologic findings is unknown, inform patients to notify their physician if changes in vision occur. If visual disturbance persists, consider further assessment. Consider more frequent assessment for patients who are already routinely monitored for ocular conditions. Creatine Kinase Elevations LYRICA treatment was associated with creatine kinase elevations. Mean changes in creatine kinase from baseline to the maximum value were 60 U/L for LYRICA-treated patients and 28 U/L for the placebo patients. In all controlled trials across multiple patient populations, 1.5% of patients on LYRICA and 0.7% of placebo patients had a value of creatine kinase at least three times the upper limit of normal. Three LYRICA-treated subjects had events reported as rhabdomyolysis in premarketing clinical trials. The relationship between these myopathy events and LYRICA is not completely understood because the cases had documented factors that may have caused or contributed to these events. Instruct patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if these muscle symptoms are accompanied by malaise or fever. Discontinue treatment with LYRICA if myopathy is diagnosed or suspected or if markedly elevated creatine kinase levels occur. Decreased Platelet Count LYRICA treatment was associated with a decrease in platelet count. LYRICA-treated subjects experienced a mean maximal decrease in platelet count of 20 x 10 3/µL, compared to 11 x 10 3/µL in placebo patients. In the overall database of controlled trials, 2% of placebo patients and 3% of LYRICA patients experienced a potentially clinically significant decrease in platelets, defined as 20% below baseline value and <150 x 10 3/µL. A single LYRICA treated subject developed severe thrombocytopenia with a platelet count less than 20 x 103/µL. In randomized controlled trials, LYRICA was not associated with an increase in bleeding-related adverse reactions. PR Interval Prolongation LYRICA treatment was associated with PR interval prolongation. In analyses of clinical trial ECG data, the mean PR interval increase was 3–6 msec at LYRICA doses ≥300 mg/day. This mean change difference was not associated with an increased risk of PR increase ≥25% from baseline, an increased percentage of subjects with on-treatment PR >200 msec, or an increased risk of adverse reactions of second or third degree AV block. Subgroup analyses did not identify an increased risk of PR prolongation in patients with baseline PR prolongation or in patients taking other PR prolonging medications. However, these analyses cannot be considered definitive because of the limited number of patients in these categories. ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In all controlled and uncontrolled trials across various patient populations during the premarketing development of LYRICA, more than 10,000 patients have received LYRICA. Approximately 5000 patients were treated for 6 months or more, over 3100 patients were treated for 1 year or longer, and over 1400 patients were treated for at least 2 years. Adverse Reactions Most Commonly Leading to Discontinuation in All Premarketing Controlled Clinical Studies In premarketing controlled trials of all populations combined, 14% of patients treated with LYRICA and 7% of patients treated with placebo discontinued prematurely due to adverse reactions. In the LYRICA treatment group, the adverse reactions most frequently leading to discontinuation were dizziness (4%) and somnolence (4%). In the placebo group, 1% of patients withdrew due to dizziness and <1% withdrew due to somnolence. Other adverse reactions that led to discontinuation from controlled trials more frequently in the LYRICA group compared to the placebo group were ataxia, confusion, asthenia, thinking abnormal, blurred vision, incoordination, and peripheral edema (1% each). Most Common Adverse Reactions in All Premarketing Controlled Clinical Studies In premarketing controlled trials of all patient populations combined, dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, and “thinking abnormal” (primarily difficulty with concentration/attention) were more commonly reported by subjects treated with LYRICA than by subjects treated with placebo (≥5% and twice the rate of that seen in placebo). Controlled Studies with Neuropathic Pain Associated with Diabetic Peripheral Neuropathy Adverse Reactions Leading to Discontinuation In clinical trials in patients with neuropathic pain associated with diabetic peripheral neuropathy, 9% of patients treated with LYRICA and 4% of patients treated with placebo discontinued prematurely due to adverse reactions. In the LYRICA treatment group, the most common reasons for discontinuation due to adverse reactions were dizziness (3%) and somnolence (2%). In comparison, <1% of placebo patients withdrew due to dizziness and somnolence. Other reasons for discontinuation from the trials, occurring with greater frequency in the LYRICA group than in the placebo group, were asthenia, confusion, and peripheral edema. Each of these events led to withdrawal in approximately 1% of patients. Most Common Adverse Reactions Table 3 lists all adverse reactions, regardless of causality, occurring in ≥1% of patients with neuropathic pain associated with diabetic neuropathy in the combined LYRICA group for which the incidence was greater in this combined LYRICA group than in the placebo group. A majority of pregabalin-treated patients in clinical studies had adverse reactions with a maximum intensity of “mild” or “moderate”.

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Table 3. Treatment-emergent adverse reaction incidence in controlled trials in neuropathic pain associated with Diabetic Peripheral Neuropathy (events in at least 1% of all LYRICA-treated patients and at least numerically more in all LYRICA than in the placebo group) 75 mg/d 150 mg/d 300 mg/d 600 mg/d All PGB* Placebo Body System [N=77] [N=212] [N=321] [N=369] [N=979] [N=459] - Preferred term % % % % % % Body as a whole Asthenia 4 2 4 7 5 2 Accidental injury 5 2 2 6 4 3 Back pain 0 2 1 2 2 0 Chest pain 4 1 1 2 2 1 Face edema 0 1 1 2 1 0 Digestive system Dry mouth 3 2 5 7 5 1 Constipation 0 2 4 6 4 2 Flatulence 3 0 2 3 2 1 Metabolic and nutritional disorders Peripheral edema 4 6 9 12 9 2 Weight gain 0 4 4 6 4 0 Edema 0 2 4 2 2 0 Hypoglycemia 1 3 2 1 2 1 Nervous system Dizziness 8 9 23 29 21 5 Somnolence 4 6 13 16 12 3 Neuropathy 9 2 2 5 4 3 Ataxia 6 1 2 4 3 1 Vertigo 1 2 2 4 3 1 Confusion 0 1 2 3 2 1 Euphoria 0 0 3 2 2 0 Incoordination 1 0 2 2 2 0 Thinking abnormal† 1 0 1 3 2 0 Tremor 1 1 1 2 1 0 Abnormal gait 1 0 1 3 1 0 Amnesia 3 1 0 2 1 0 Nervousness 0 1 1 1 1 0 Respiratory system Dyspnea 3 0 2 2 2 1 Special senses Blurry vision‡ 3 1 3 6 4 2 Abnormal vision 1 0 1 1 1 0 *PGB: pregabalin † Thinking abnormal primarily consists of events related to difficulty with concentration/attention but also includes events related to cognition and language problems and slowed thinking. ‡ Investigator term; summary level term is amblyopia. Other Adverse Reactions Observed During the Clinical Studies of LYRICA Following is a list of treatment-emergent adverse reactions reported by patients treated with LYRICA during all clinical trials. The listing does not include those events already listed in the previous tables or elsewhere in labeling, those events for which a drug cause was remote, those events which were so general as to be uninformative, and those events reported only once which did not have a substantial probability of being acutely life-threatening. Events are categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse reactions are those occurring on one or more occasions in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients. Events of major clinical importance are described in the Warnings and Precautions section. Body as a Whole – Frequent: Abdominal pain, Allergic reaction, Fever; Infrequent: Abscess, Cellulitis, Chills, Malaise, Neck rigidity, Overdose, Pelvic pain, Photosensitivity reaction; Rare: Anaphylactoid reaction, Ascites, Granuloma, Hangover effect, Intentional Injury, Retroperitoneal Fibrosis, Shock. Cardiovascular System – Infrequent: Deep thrombophlebitis, Heart failure, Hypotension, Postural hypotension, Retinal vascular disorder, Syncope; Rare: ST Depressed, Ventricular Fibrillation. Digestive System – Frequent: Gastroenteritis, Increased appetite; Infrequent: Cholecystitis, Cholelithiasis, Colitis, Dysphagia, Esophagitis, Gastritis, Gastrointestinal hemorrhage, Melena, Mouth ulceration, Pancreatitis, Rectal hemorrhage, Tongue edema; Rare: Aphthous stomatitis, Esophageal Ulcer, Periodontal abscess. Hemic and Lymphatic System – Frequent: Ecchymosis; Infrequent: Anemia, Eosinophilia, Hypochromic anemia, Leukocytosis, Leukopenia, Lymphadenopathy, Thrombocytopenia; Rare: Myelofibrosis, Polycythemia, Prothrombin decreased, Purpura, Thrombocythemia. Metabolic and Nutritional Disorders – Rare: Glucose Tolerance Decreased, Urate Crystalluria. Musculoskeletal System – Frequent: Arthralgia, Leg cramps, Myalgia, Myasthenia; Infrequent: Arthrosis; Rare: Chondrodystrophy, Generalized Spasm. Nervous System – Frequent: Anxiety, Depersonalization, Hypertonia, Hypesthesia, Libido decreased, Nystagmus, Paresthesia, Sedation, Stupor, Twitching; Infrequent: Abnormal dreams, Agitation, Apathy, Aphasia, Circumoral paresthesia, Dysarthria, Hallucinations, Hostility, Hyperalgesia, Hyperesthesia, Hyperkinesia, Hypokinesia, Hypotonia, Libido increased, Myoclonus, Neuralgia; Rare: Addiction, Cerebellar syndrome, Cogwheel rigidity, Coma, Delirium, Delusions, Dysautonomia, Dyskinesia, Dystonia, Encephalopathy, Extrapyramidal syndrome, Guillain-Barré syndrome, Hypalgesia, Intracranial hypertension, Manic reaction, Paranoid reaction, Peripheral neuritis, Personality disorder, Psychotic depression, Schizophrenic reaction, Sleep disorder, Torticollis, Trismus. Respiratory System – Rare: Apnea, Atelectasis, Bronchiolitis, Hiccup, Laryngismus, Lung edema, Lung fibrosis, Yawn. Skin and Appendages – Frequent: Pruritus; Infrequent: Alopecia, Dry skin, Eczema, Hirsutism, Skin ulcer, Urticaria, Vesiculobullous rash; Rare: Angioedema, Exfoliative dermatitis, Lichenoid dermatitis, Melanosis, Nail Disorder, Petechial rash, Purpuric rash, Pustular rash, Skin atrophy, Skin necrosis, Skin nodule, Stevens-Johnson syndrome, Subcutaneous nodule. Special senses – Frequent: Conjunctivitis, Diplopia, Otitis media, Tinnitus; Infrequent: Abnormality of accommodation, Blepharitis, Dry eyes, Eye hemorrhage, Hyperacusis, Photophobia, Retinal edema, Taste loss, Taste perversion; Rare: Anisocoria, Blindness, Corneal ulcer, Exophthalmos, Extraocular palsy, Iritis, Keratitis, Keratoconjunctivitis, Miosis, Mydriasis, Night blindness, Ophthalmoplegia, Optic atrophy, Papilledema, Parosmia, Ptosis, Uveitis. Urogenital System – Frequent: Anorgasmia, Impotence, Urinary frequency, Urinary incontinence; Infrequent: Abnormal ejaculation, Albuminuria, Amenorrhea, Dysmenorrhea, Dysuria, Hematuria, Kidney calculus, Leukorrhea, Menorrhagia, Metrorrhagia, Nephritis, Oliguria, Urinary retention, Urine abnormality; Rare: Acute kidney failure, Balanitis, Bladder Neoplasm, Cervicitis, Dyspareunia, Epididymitis, Female lactation, Glomerulitis, Ovarian disorder, Pyelonephritis. Comparison of Gender and Race The overall adverse event profile of pregabalin was similar between women and men. There are insufficient data to support a statement regarding the distribution of adverse experience reports by race. Post-marketing Experience The following adverse reactions have been identified during postapproval use of LYRICA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Nervous System Disorders – Headache. Gastrointestinal Disorders – Nausea, Diarrhea. Reproductive System and Breast Disorders – Gynecomastia, Breast Enlargement. In addition, there are post-marketing reports of events related to reduced lower gastrointestinal tract function (e.g., intestinal obstruction, paralytic ileus, constipation) when LYRICA was co-administered with medications that have the potential to produce constipation, such as opioid analgesics. There are also post-marketing reports of respiratory failure and coma in patients taking pregabalin and other CNS depressant medications. DRUG INTERACTIONS Since LYRICA is predominantly excreted unchanged in the urine, undergoes negligible metabolism in humans (<2% of a dose recovered in urine as metabolites), and does not bind to plasma proteins, its pharmacokinetics are unlikely to be affected by other agents through metabolic interactions or protein binding displacement. In vitro and in vivo studies showed that LYRICA is unlikely to be involved in significant pharmacokinetic drug interactions. Specifically, there are no pharmacokinetic interactions between pregabalin and the following antiepileptic drugs: carbamazepine, valproic acid, lamotrigine, phenytoin, phenobarbital, and topiramate. Important pharmacokinetic interactions would also not be expected to occur between LYRICA and commonly used antiepileptic drugs. Pharmacodynamics Multiple oral doses of LYRICA were co-administered with oxycodone, lorazepam, or ethanol. Although no pharmacokinetic interactions were seen, additive effects on cognitive and gross motor functioning were seen when LYRICA was co-administered with these drugs. No clinically important effects on respiration were seen. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C. Increased incidences of fetal structural abnormalities and other manifestations of developmental toxicity, including lethality, growth retardation, and nervous and reproductive system functional impairment, were observed in the offspring of rats and rabbits given pregabalin during pregnancy, at doses that produced plasma pregabalin exposures (AUC) ≥5 times human exposure at the maximum recommended dose (MRD) of 600 mg/day. When pregnant rats were given pregabalin (500, 1250, or 2500 mg/kg) orally throughout the period of organogenesis, incidences of specific skull alterations attributed to abnormally advanced ossification (premature fusion of the jugal and nasal sutures) were increased at ≥1250 mg/kg, and incidences of skeletal

variations and retarded ossification were increased at all doses. Fetal body weights were decreased at the highest dose. The low dose in this study was associated with a plasma exposure (AUC) approximately 17 times human exposure at the MRD of 600 mg/day. A no-effect dose for rat embryo-fetal developmental toxicity was not established. When pregnant rabbits were given LYRICA (250, 500, or 1250 mg/kg) orally throughout the period of organogenesis, decreased fetal body weight and increased incidences of skeletal malformations, visceral variations, and retarded ossification were observed at the highest dose. The no-effect dose for developmental toxicity in rabbits (500 mg/kg) was associated with a plasma exposure approximately 16 times human exposure at the MRD. In a study in which female rats were dosed with LYRICA (50, 100, 250, 1250, or 2500 mg/kg) throughout gestation and lactation, offspring growth was reduced at ≥100 mg/kg and offspring survival was decreased at ≥250 mg/kg. The effect on offspring survival was pronounced at doses ≥1250 mg/kg, with 100% mortality in high-dose litters. When offspring were tested as adults, neurobehavioral abnormalities (decreased auditory startle responding) were observed at ≥250 mg/kg and reproductive impairment (decreased fertility and litter size) was seen at 1250 mg/kg. The no-effect dose for pre- and postnatal developmental toxicity in rats (50 mg/kg) produced a plasma exposure approximately 2 times human exposure at the MRD. There are no adequate and well-controlled studies in pregnant women. Use LYRICA during pregnancy only if the potential benefit justifies the potential risk to the fetus. To provide information regarding the effects of in utero exposure to LYRICA, physicians are advised to recommend that pregnant patients taking LYRICA enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website Labor and Delivery The effects of LYRICA on labor and delivery in pregnant women are unknown. In the prenatal-postnatal study in rats, pregabalin prolonged gestation and induced dystocia at exposures ≥50 times the mean human exposure (AUC (0–24) of 123 µg•hr/mL) at the maximum recommended clinical dose of 600 mg/day. Nursing Mothers It is not known if pregabalin is excreted in human milk; it is, however, present in the milk of rats. Because many drugs are excreted in human milk, and because of the potential for tumorigenicity shown for pregabalin in animal studies, decide whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and efficacy of pregabalin in pediatric patients have not been established. In studies in which pregabalin (50 to 500 mg/kg) was orally administered to young rats from early in the postnatal period (Postnatal Day 7) through sexual maturity, neurobehavioral abnormalities (deficits in learning and memory, altered locomotor activity, decreased auditory startle responding and habituation) and reproductive impairment (delayed sexual maturation and decreased fertility in males and females) were observed at doses ≥50 mg/kg. The neurobehavioral changes of acoustic startle persisted at ≥250 mg/kg and locomotor activity and water maze performance at ≥500 mg/kg in animals tested after cessation of dosing and, thus, were considered to represent long-term effects. The low effect dose for developmental neurotoxicity and reproductive impairment in juvenile rats (50 mg/kg) was associated with a plasma pregabalin exposure (AUC) approximately equal to human exposure at the maximum recommended dose of 600 mg/day. A no-effect dose was not established. Geriatric Use In controlled clinical studies of LYRICA in neuropathic pain associated with diabetic peripheral neuropathy, 246 patients were 65 to 74 years of age, and 73 patients were 75 years of age or older. In controlled clinical studies of LYRICA in neuropathic pain associated with postherpetic neuralgia, 282 patients were 65 to 74 years of age, and 379 patients were 75 years of age or older. No overall differences in safety and efficacy were observed between these patients and younger patients. In controlled clinical studies of LYRICA in fibromyalgia, 106 patients were 65 years of age or older. Although the adverse reaction profile was similar between the two age groups, the following neurological adverse reactions were more frequent in patients 65 years of age or older: dizziness, vision blurred, balance disorder, tremor, confusional state, coordination abnormal, and lethargy. LYRICA is known to be substantially excreted by the kidney, and the risk of toxic reactions to LYRICA may be greater in patients with impaired renal function. Because LYRICA is eliminated primarily by renal excretion, adjust the dose for elderly patients with renal impairment. DRUG ABUSE AND DEPENDENCE Controlled Substance LYRICA is a Schedule V controlled substance. LYRICA is not known to be active at receptor sites associated with drugs of abuse. As with any CNS active drug, carefully evaluate patients for history of drug abuse and observe them for signs of LYRICA misuse or abuse (e.g., development of tolerance, dose escalation, drug-seeking behavior). Abuse In a study of recreational users (N=15) of sedative/hypnotic drugs, including alcohol, LYRICA (450 mg, single dose) received subjective ratings of “good drug effect,” “high” and “liking” to a degree that was similar to diazepam (30 mg, single dose). In controlled clinical studies in over 5500 patients, 4% of LYRICA-treated patients and 1% of placebo-treated patients overall reported euphoria as an adverse reaction, though in some patient populations studied, this reporting rate was higher and ranged from 1 to 12%. Dependence In clinical studies, following abrupt or rapid discontinuation of LYRICA, some patients reported symptoms including insomnia, nausea, headache or diarrhea [see Warnings and Precautions, Abrupt or Rapid Discontinuation], consistent with physical dependence. In the postmarketing experience, in addition to these reported symptoms there have also been reported cases of anxiety and hyperhidrosis. OVERDOSAGE Signs, Symptoms and Laboratory Findings of Acute Overdosage in Humans There is limited experience with overdose of LYRICA. The highest reported accidental overdose of LYRICA during the clinical development program was 8000 mg, and there were no notable clinical consequences. Treatment or Management of Overdose There is no specific antidote for overdose with LYRICA. If indicated, elimination of unabsorbed drug may be attempted by emesis or gastric lavage; observe usual precautions to maintain the airway. General supportive care of the patient is indicated including monitoring of vital signs and observation of the clinical status of the patient. Contact a Certified Poison Control Center for up-to-date information on the management of overdose with LYRICA. Although hemodialysis has not been performed in the few known cases of overdose, it may be indicated by the patient’s clinical state or in patients with significant renal impairment. Standard hemodialysis procedures result in significant clearance of pregabalin (approximately 50% in 4 hours). NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis A dose-dependent increase in the incidence of malignant vascular tumors (hemangiosarcomas) was observed in two strains of mice (B6C3F1 and CD-1) given pregabalin (200, 1000, or 5000 mg/kg) in the diet for two years. Plasma pregabalin exposure (AUC) in mice receiving the lowest dose that increased hemangiosarcomas was approximately equal to the human exposure at the maximum recommended dose (MRD) of 600 mg/day. A no-effect dose for induction of hemangiosarcomas in mice was not established. No evidence of carcinogenicity was seen in two studies in Wistar rats following dietary administration of pregabalin for two years at doses (50, 150, or 450 mg/kg in males and 100, 300, or 900 mg/kg in females) that were associated with plasma exposures in males and females up to approximately 14 and 24 times, respectively, human exposure at the MRD. Mutagenesis Pregabalin was not mutagenic in bacteria or in mammalian cells in vitro, was not clastogenic in mammalian systems in vitro and in vivo, and did not induce unscheduled DNA synthesis in mouse or rat hepatocytes. Impairment of Fertility In fertility studies in which male rats were orally administered pregabalin (50 to 2500 mg/kg) prior to and during mating with untreated females, a number of adverse reproductive and developmental effects were observed. These included decreased sperm counts and sperm motility, increased sperm abnormalities, reduced fertility, increased preimplantation embryo loss, decreased litter size, decreased fetal body weights, and an increased incidence of fetal abnormalities. Effects on sperm and fertility parameters were reversible in studies of this duration (3–4 months). The no-effect dose for male reproductive toxicity in these studies (100 mg/kg) was associated with a plasma pregabalin exposure (AUC) approximately 3 times human exposure at the maximum recommended dose (MRD) of 600 mg/day. In addition, adverse reactions on reproductive organ (testes, epididymides) histopathology were observed in male rats exposed to pregabalin (500 to 1250 mg/kg) in general toxicology studies of four weeks or greater duration. The no-effect dose for male reproductive organ histopathology in rats (250 mg/kg) was associated with a plasma exposure approximately 8 times human exposure at the MRD. In a fertility study in which female rats were given pregabalin (500, 1250, or 2500 mg/kg) orally prior to and during mating and early gestation, disrupted estrous cyclicity and an increased number of days to mating were seen at all doses, and embryolethality occurred at the highest dose. The low dose in this study produced a plasma exposure approximately 9 times that in humans receiving the MRD. A no-effect dose for female reproductive toxicity in rats was not established. Human Data In a double-blind, placebo-controlled clinical trial to assess the effect of pregabalin on sperm motility, 30 healthy male subjects were exposed to pregabalin at a dose of 600 mg/day. After 3 months of treatment (one complete sperm cycle), the difference between placebo- and pregabalin-treated subjects in mean percent sperm with normal motility was <4% and neither group had a mean change from baseline of more than 2%. Effects on other male reproductive parameters in humans have not been adequately studied. Animal Toxicology and/or Pharmacology Dermatopathy Skin lesions ranging from erythema to necrosis were seen in repeateddose toxicology studies in both rats and monkeys. The etiology of these skin lesions is unknown. At the maximum recommended human dose (MRD) of 600 mg/day, there is a 2-fold safety margin for the dermatological lesions. The more severe dermatopathies involving necrosis were associated with pregabalin exposures (as expressed by plasma AUCs) of approximately 3 to 8 times those achieved in humans given the MRD. No increase in incidence of skin lesions was observed in clinical studies. Ocular Lesions Ocular lesions (characterized by retinal atrophy [including loss of photoreceptor cells] and/or corneal inflammation/mineralization) were observed in two lifetime carcinogenicity studies in Wistar rats. These findings were observed at plasma pregabalin exposures (AUC) ≥2 times those achieved in humans given the maximum recommended dose of 600 mg/day. A no-effect dose for ocular lesions was not established. Similar lesions were not observed in lifetime carcinogenicity studies in two strains of mice or in monkeys treated for 1 year. LAB-0294-22.0 June 2012 This brief summary is based on LYRICA Prescribing Information LAB-0294-22.0, revised June 2012.

© 2012 Pfizer Inc.

All rights reserved.

September 2012

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Case of the Month FIGURE 1 Lumbar spine

›CASE A 17-year-old male presented with low back pain that had been present for months but intensified after he started participating in spring football. Because the practice field was being renovated, practices had been moved to the dirt parking lot. The teenager also worked part-time on his family’s farm. He thought the back pain had started while he was lifting weights. Initially, his pain was worse with movement and improved with rest, but at presentation, his back hurt all the time. He had no radiating symptoms or leg weakness, and he did not report any incontinence or perineal numbness. At first, he had taken ibuprofen occasionally, but by the time he came to our clinic, he was taking the medication daily. Ten days earlier, the patient’s primary care provider had ordered a radiograph of his lower back that was reported as negative. The patient was told he had a lumbar muscle strain and advised to rest for 1 week. He was given a prescription for muscle relaxers to take if the back pain worsened and advised to use a heating pad. His mother stated that the muscle relaxers made her son too sleepy, and he had stopped taking them after the second day. The patient reported no significant medical or surgical history. He denied using tobacco products, alcohol, or drugs. He had no allergies.

Thomas V. Gocke III, MS, ATC, PA-C, DFAAPA

Vital signs were stable. The patient was able to stand and walk without difficulty, although he was hunched over when standing. He had some palpable lumbar muscle tenderness but no flank pain. He was able to walk heel-to-toe and do a half-squat, with some difficulty. In addition, he was able to forward flex with his fingers touching his knees, but he was unable to fully extend his spine to the neutral position. The patient reported increased back pain and some left lateral thigh and groin pain with extension. Range of motion in his hips was excellent. Results of an abdominal examination were unremarkable. A straight leg raise test produced no radicular symptoms but elicited increased localized transverse lumbar pain. A femoral nerve stretch test was positive for pain in his groin. The patient had very tight hamstring, quadriceps, and hip flexor muscles in both legs. Lowerextremity pulses, sensation, and reflexes were normal. A radiograph of his lumbar spine was obtained (Figure 1).

›WHAT IS YOUR DIAGNOSIS? • Chronic musculoskeletal lumbar muscle strain • Herniated far lateral lumbar disk (L3-4 disk) • Stress fracture lumbar spine • Vertebral body compression fracture

›DISCUSSION On radiography, a sclerotic area on the pars intra-articularis of the L2 vertebral body (Figure 1, arrow) was determined to be a stress fracture caused by the patient’s repetitive and overall marked increase in activity. Noncontrast MRI confirmed the diagnosis. The patient’s poor flexibility contributed to his back pain and to increased pain when he tried to stand erect with a symptomatic lumbar stress fracture. The pain on the femoral nerve stress test was referred pain from pulling of the iliopsoas muscle on the L2 transverse process. Although the patient did have muscle strain symptoms, his historical informa-

tion, pain with lumbar extension, and duration of symptoms raised suspicion for stress fracture. Moreover, exercise or work on hard surfaces, such as the dirt parking lot, can inhibit the body’s ability to absorb stresses and contribute to stress reactions in bone. No clinical evidence indicated herniated lumbar disk. The patient was advised to refrain from all physical activity for 6 weeks. He was prescribed a muscle relaxer to take at bedtime for muscle spasm and hydrocodone for pain, both as needed, and advised to stop taking NSAIDs, which are reported to inhibit or delay bone healing. Whether he required immobilization in a thoracolumbar stabilizing orthosis (TLSO) was discussed. The TLSO brace can immobilize the lumbar spine and aid in fracture healing. However, based on history, physical findings, and imaging studies, the fracture was thought to be stable and therefore not requiring external structural support. The patient was sent to physical therapy to start a flexibility program. A follow-up examination and radiograph at 6 weeks showed healing of the L2 stress fracture. By 12 weeks, he was pain-free and had noticeably improved flexibility. The patient was released to return to running activities and resume weight lifting at the 16-week mark. He was scheduled to have a follow-up examination and radiographs prior to the start of fall football. Lumbar pain can have causes other than muscle strain. This patient’s history, duration of symptoms, and constant pain is a classic presentation for overuse injury. All PAs treating young healthy patients with back pain must include stress fracture in their differential diagnosis. JAAPA Thomas Gocke practices in orthopedic surgery at Campbell Clinic, Memphis, Tennesee, and is president and founder of Orthopaedic Educational Services Inc, Germantown, Tennessee. No relationships to disclose. Erich Fogg, PA-C, MMSc, department editor • OCTOBER 2012 • 25(10) • JAAPA


JAAPA October 2012  

JAAPA is the peer-reviewed clinical journal of the American Academy of Physician Assistants (AAPA)

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