Page 1


2 0 1 1



2 4 ,


1 2


w w w. j a a p a . c o m



PHARMACOLOGY CONSULT Treating extravasation injuries


REVIEW ARTICLE Managing interactions between supplements and drugs


PA QUANDARIES The impact of errors on clinicians


DIAGNOSTIC IMAGING REVIEW A potentially fatal infection




>>Earn 1 AAPA Category I CME credit with this issue CME Childhood obesity, part 1


CME Childhood obesity, part 2


CME Posttest


Childhood obesity PAGE 58

PUBLISHING STAFF Editor Tanya Gregory, PhD Production editor/Web producer Rick Maffei Web editor Traci Dantoni Manuscript editor Lauren Rich Copyeditor Ruth Hammer

Vice president and publisher Dominic Barone Editorial director Tanya Gregory, PhD Publishing director Mark Bugni Vice president, medical magazines Jim Burke, RPh CEO, Haymarket Media Inc Lee Maniscalco

Editorial coordinator Candy Iemma Group art director, Haymarket Medical Jennifer Dvoretz Assistant art director Natasha Marcano-Dillon Assistant circulation manager Monica Bond Group circulation manager Paul Silver VP, audience development and operations John Crewe Production manager Kathleen Millea

Sales office Haymarket Media Inc, 114 West 26th Street, 4th Floor, New York, NY 10001; Phone: (646) 638-6000; Fax: (646) 638-6117 Editorial office Haymarket Media Inc, 25 Philips Parkway, Suite 105, Montvale, NJ 07645; Phone: (201) 799-4821; Fax: (201) 391-0880 Classified sales office Russell Johns Associates, LLC Phone: (877) 394-1388; Fax: (727) 445-9380; Reprints Wright’s Reprints (877) 652-5295 Permissions



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

Brief Report: Richard W. Dehn, MPA, PA-C • Critically Appraised Topic: Mark E. Archambault, DHSc, PA-C • 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 • Genomics in PA Practice: Michael Rackover, PA-C, MS; Constance Goldgar, MS, PA-C • PA Quandaries: F. J. Gianola, PA; Jim Anderson, PA-C, ATC • Quick Recertification Series: Dawn Colomb-Lippa, MHS, PA-C; Amy Mercantini Klingler, MS, PA-C • The Surgical Patient: Steve Wilson, PA-C • When the Patient Asks: Mary L. Hewett, MS, PA-C

Jim Anderson, PA-C, ATC, University of Washington Medicine— IT Services, Seattle, WA • Diane Bruessow, RPA-C, New York, NY • Dawn Colomb-Lippa, MHS, PA-C, Quinnipiac University, Hamden, CT • L. Gail Curtis, MPAS, PA-C, DFAAPA, AAPA Board of Directors • Richard W. Dehn, MPA, PA-C, College of Health and Human Services, Northern Arizona University, Flagstaff • Alexandra Godfrey, PA-C, St. Joseph’s Mercy Hospital, Ypsilanti, MI • Wanda Gonsalves, MD, Medical University of South Carolina, Charleston • Zachary Hartsell, MPAS, PA-C, Mayo Clinic Hospital, Phoenix, AZ • Kristine A. Himmerick, MPAS, PA-C, University of California, Davis, Sacramento • Patrick E. Killeen, MS, PA-C, AAPA Board of Directors • Amy Mercantini 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

AMERICAN ACADEMY OF PHYSICIAN ASSISTANTS Executive vice president/CEO, Jennifer L. Dorn Chief operating officer, Sabrina Smith, DHA Executive publisher, JAAPA, and senior vice president, marketing & communications, AAPA, Howard Glassroth

AAPA BOARD OF DIRECTORS President, Robert L. Wooten, PA-C • President-elect, James E. Delaney, PA-C • Immediate past president, Patrick E. Killeen, MS, PA-C • Vice president/Speaker, House of Delegates, Alan Hull, PA-C • Secretary/Treasurer, Bruce C. Fichandler, PA • Directors at large, Michelle Ona DiBaise, MPAS, PA-C; Michael Clyde Doll, MPAS, PA-C, DFAAPA; Lawrence M. Herman, MPA, RPA-C, DFAAPA; Jeffrey Katz, PA-C; John McGinnity, MS, PA-C • First vice speaker, HOD, L. Gail Curtis, MPAS, PA-C, DFAAPA • Second vice speaker, HOD, David I. Jackson, PA-C • Student representative, Peggy Walsh, PA-C American Academy of Physician Assistants 2318 Mill Road, Suite 1300 Alexandria, VA 22314

(703) 836-2272;

JAAPA/Journal of the American Academy of Physician Assistants (ISSN 1547-1896) (Canadian GST No. R-124213133RT001, Publications Mail Agreement No. 40017597. Printed in the USA) is published monthly (12 issues per volume, one volume per year) by Haymarket Media Inc, 114 W 26th St, 4th Fl, New York, NY 10001. Volume 24, Number 12, December 2011. One-year subscription rates: $75 in the United States and Possessions; $85 for Canada; $110 all other foreign. Single copies (prepaid only): $20 in the United States; $30 all other countries. To order or update your paid subscription, call 800-436-9269 or visit Periodicals postage rate paid at New York, NY 10001 and additional mailing offices. © 2011 American Academy of Physician Assistants and Haymarket Media Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including by photocopy, recording, or information storage and retrieval system, without permission in writing from the publisher. POSTMASTER: Send address changes to Journal of the American Academy of Physician Assistants, 2318 Mill Road, Suite 1300, Alexandria, VA 22314; (703) 836-2272.




Table of Contents VO L. 2 4, N O. 12


w w w. j a a p a . c o m

12 WEB ARTICLES FOR DECEMBER 14 EDITORIAL A parent’s death: Helping a child after devastating trauma Reamer L. Bushardt, PharmD, PA-C; Lloyd “Chip” Taylor, PhD

17 PHARMACOLOGY CONSULT How should extravasation injuries be treated? Larissa DeDea, PharmD, BCPS, PA-C

41 CASE REPORT Immune thrombocytopenic purpura develops in a 67-year-old female Mackenzie L. Pennington, MS, PA-C; Alison C. Essary, MHPE, PA-C

44 REVIEW ARTICLE Interactions between supplements and drugs: Deciphering the evidence John Laird, ND CONTENTS CONTINUED ON PAGE 8

18 DERMATOLOGY DIGEST Nodules that developed months after treatment Khalid Al Aboud, MD; Daifullah Al Aboud, MD

23 A DAY IN THE LIFE Kaatje van der Gaarden, PA-C

30 CME ARTICLE Childhood obesity: Understanding the causes, beginning the discussion Katie J. Perpich, PA-C; Rachel Russ, PA-C; Denise Rizzolo, PA-C, PhD; Mona Sedrak, PA-C, PhD 6

JAAPA • DECEMBER 2011 • 24(12) •

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. In this issue of JAAPA:


Addressed in the articles on pages

Medical knowledge

17, 18, 23, 30, 41, 44, 58, 65, 74, 79, 83

Interpersonal and communication skills

14, 23, 30, 44, 58, 71, 79

Patient care

14, 17, 18, 23, 30, 41, 44, 58, 65, 71, 74, 79, 83


14, 17, 18, 23, 30, 41, 44, 50, 58, 65, 71, 74, 79, 83

Practice-based learning and improvement

17, 18, 30, 41, 44, 58, 65, 71, 74, 83

Systems-based practice

23, 50, 71

Contents 50 RESEARCH REPORT The physician assistant workforce in Indiana: Preparing to meet future health care needs Jennifer Snyder, MPAS, PA-C, DFAAPA; Jennifer Zorn, MS, PA-C; Tom Gjerde, PhD; Jennifer Burkhart, PA-C; Lori Rosebrock, PA-C

Take the JAAPA 25th Anniversary Challenge! 2012 is JAAPA’s 25th anniversary year, and we invite you to help us celebrate … all year long! Each month we’ll pose a different challenge, and each month we’ll pick the best response. The winner will receive a $100 gift card. Visit for more details of our 25th anniversary celebration!

58 CME ARTICLE Childhood obesity: Complications, prevention strategies, treatment Georgina A. Robinson, PA-C; Megan Geier; Denise Rizzolo, PA-C, PhD; Mona Sedrak, PA-C; PhD

CORRECTION In the case section of the October 2011 Diagnostic Imaging Review, we mislabeled Figure 2. It is an MRI, not magnetic resonance angiography. The online versions of the article have been corrected.

64 CME POSTTEST 65 WHAT’S NEW IN … … LUNG CANCER Screening, staging, targeted therapies Michele Taffaro-Neskey, PA-C

71 PA QUANDARIES After the error, then what? The emotional impact of errors on clinicians Jim Anderson, PA-C, ATC

74 DIAGNOSTIC IMAGING REVIEW Atypical manifestations of a potentially fatal infection Jamie P. Fairgrieve; Urvi R. Shah, MD; Joseph M. Candelario, FNP-BC

79 HUMANE MEDICINE An unlikely afternoon hero: When being there is good enough Brian T. Maurer, PA-C


JAAPA • DECEMBER 2011 • 24(12) •

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.

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: Michele Graham

THIS MONTH’S ARTICLES Online-only articles

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

Online Case Report Rhinocerebral mucormycosis: A rare fungal infection linked to diabetes Sarah Asman, MPA, PA-C; Mehrdad M. Behnia, MD, FACP, FCCP Critically Appraised Topic Is rifaximin an effective treatment option for irritable bowel syndrome? Rachel E. Smith, BSN; Wilson Crone, MD, PhD POEMs • Surgery effective for spinal stenosis unresponsive to conservative treatment • Risk of serious maternal morbidity with multiple cesarean deliveries • High-dose saw palmetto no better than placebo for BPH symptoms • Benefits and harms of atypical antipsychotics for off-label use • Adenoidectomy does not decrease URIs in children • Dabigatran cost-effective for AF prophylaxis in select patients Interpreting ECGs James F. Ginter, MPAS, PA-C; Patrick J. Loftis, PA-C, MPAS, RN

Answering the call: Joining the fight for oral health Wanda C. Gonsalves, MD Did you know that among young children, the most common chronic illness isn’t diabetes or even asthma? It is early childhood caries (ECC)—chronic tooth decay. And it doesn’t just edge out those other diseases for the number one position. ECC affects more than five times as many children as asthma. Reading “The Help”: What I remember, and what I learned Reamer L. Bushardt, PharmD, PA-C As I reflect on the lives of these women and consider how they shaped my view of the world, I feel like they already knew the secret to dismantling racism. Despite the adversity each faced, they demonstrated enormous respect for the people around them, were kind and loving, celebrated the little joys of life, and left the judging to a higher power.

E-mail the Editor Send letters and comments to


JAAPA • DECEMBER 2011 • 24(12) •

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

HIT Blog Jim Anderson, PA-C, ATC A glimpse of the future through a blogger’s eyes For practicing PAs, seeing someone go through what for all of us was a very rich, stressful, and even emotional experience can bring back a flood of memories.

Health Disparities Blog AAPA Health Disparities Work Group AIDS: We’ve come a long way, but in some ways we’ve barely made a dent This December 1st marks the 23rd World AIDS Day. How far have we yet to go?

Resources Visit Drug Information under our TOOLS & LINKS tab on the JAAPA Web site to find various online resources that can help you prescribe effective medications for patients and help your patients take their medications correctly.

EDITORIAL Reamer L. Bushardt, PharmD, PA-C (left), is the editor in chief of JAAPA. Lloyd “Chip” Taylor, PhD (right), is an associate professor of psychology at The Citadel, Charleston, South Carolina.

A parent’s death: Helping a child after devastating trauma


was about to begin a collaborative practice with a very talented physician when he died in a tragic accident. He left behind many grateful patients and heartbroken colleagues. He also left behind 5-year-old twins whose lives are forever changed. I have hugged my own children a little tighter since his death, and I think about his son and daughter often. As a PA, do you feel prepared to help young children after such devastating trauma? I asked one of my favorite colleagues, Dr. Lloyd “Chip” Taylor, a talented clinical psychologist with expertise in caring for children and families in similar situations, for his advice. Here is what he shared. The death of a parent is one of the most difficult events a child might face. It prematurely exposes the child to the unpredictability of life and the tenuous nature of daily existence. As recently as two generations ago, death and dying were common enough that children experienced them routinely.1 This exposure reduced the impact and normalized the grieving process. Death is much less common now, however, and as a result it is more traumatic to children and adults alike. We are especially not accustomed to the death of a parent of young children. When working with a child who has lost a parent, PAs must consider developmental factors that influence how the child responds to the event.2 Toddlers cannot understand death and dying, and while they may cry and demonstrate affective deregulation, these expressions of emotion are likely the result of watching adults’ grief and mirroring those behaviors.1 Changes in the routines and structure of the home will affect how well the child adjusts to the loss of a parent. The most important thing PAs can do is to emphasize the importance of consistency among chaos. Consistency in interactions and routines provides the child with a sense of stability, and caregivers should be encouraged to recognize this. If order is not maintained, children will evidence adjustment difficulties—not directly as a result of the loss but due to the environmental changes resulting from that loss. Caregivers also must recognize the impact of their own mourning on their ability to parent consistently. If grieving makes it difficult for the remaining parent or caregiver to engage with the child, others should be encouraged to step in. Consistency across routines and environments is essential, especially for younger children. Preschool children view death as a temporary, reversible condition. They have experienced times when loved ones have gone away, only to later return.1 These prior experiences provide evidence to support the child’s notion that mom or dad will return from death. The finality of death and the chronicity of subsequent mental health concerns are 14

JAAPA • DECEMBER 2011 • 24(12) •

not components of the preschool child’s cognitive schemas. The child may ask when the dead loved one will return and also may engage in behaviors, such as preparing for the dead parent’s return, which look odd but make perfect sense from a developmental perspective. Children will respond emotionally to the loss of a parent, frequently crying or becoming disruptive. Symptoms of depression routinely manifest as disruptive behavior in children. Externalizing behaviors such as outbursts and aggression are common manifestations of depression among children and are likely to be the result of the child sensing that something is wrong in the environment. These behaviors are not necessarily permanent and frequently will resolve as the child’s world adjusts to the loss. Changes in routines can also lead to anxiety and depression in children. Understanding the source of these behaviors will be helpful as you work with parents and children dealing with loss. This is a time to be cautious with diagnosis and to view behaviors in light of the ongoing changes the child is experiencing rather than as manifestation of a behavioral disorder. The grieving process is repeated across every successive developmental hurdle.1 As the child becomes a young adult, the permanency of death and the ongoing “losses” will take on new meaning in light of the social demands facing that child. The death of a parent is not an event but a process a child goes through uniquely, and repeatedly, at each stage of development. PAs are intimately involved with the best and worst moments in our patients’ lives. They trust us to have answers when they do not or when hope is lost. If I have learned anything from my professional interactions with children suffering from mental illness and loss, it is that the atypical is typical. As Chip describes, we can demystify these symptoms or behaviors and help a remaining parent or caregiver understand why they are occurring. PAs are ideally situated to intervene in situations of parental loss. We can do much to help these children, such as providing practical strategies that help create environments that support healing and normal development. If you have not done so already, I encourage you to develop a relationship with a licensed counselor or psychologist in your own community when a team approach makes sense. JAAPA REFERENCES 1. Willis C. The grieving process in children: strategies for understanding, educating, and reconciling children’s perceptions of death. Early Childhood Education Journal. 2002;29(4):221-226. 2. Costa L, Holliday D. Helping children cope with the death of a parent. Elementary School Guidance and Counseling. 1994;28(3):206-213.

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.

How should extravasation injuries be treated?


xtravasation is the unintentional leakage of medications from the vein into the perivascular space and should be treated as a medical emergency. Although most cases of extravasation will not cause significant injury, severe tissue necrosis can occur. The risk of a serious extravasation injury depends on drug characteristics, including osmolarity, pH, cytotoxicity, and vasoactivity. (Vasoconstrictors, such as norepinephrine, have a higher potential for causing injury than vasodilators). Drugs that tend to result in an inflammatory reaction at the site of administration are considered irritants. Clinical signs include erythema, warmth, swelling, induration, and tenderness. Symptoms are of short duration, with no long-term sequelae. Drugs that have the potential to cause skin necrosis, ulceration, gangrene, and complications that may lead to limb amputation are referred to as vesicants. If possible, vesicants should be administered through a central venous catheter to reduce the risk of a severe extravasation injury. Any patient receiving IV medication is at risk of extravasation. The first symptom is often stinging or burning at the site of administration. Patients who are unable to communicate pain (pediatric population, non-English speakers) are at higher risk of having their extravasation go unnoticed. Agitation and delirium are also risk factors because interference with the catheter may lead to decannulation. Finally, patients with fragile skin or veins (neonates and geriatric patients) are also at higher risk of extravasation. If a patient complains about burning during an IV infusion, the etiology

should be promptly investigated. Extravasation should be suspected in the following situations: • Erythema, swelling, or leakage is observed at the injection site. • An IV infusion does not flow freely or the rate is reduced. • Resistance is felt during administration of IV push medications. • No blood return occurs with aspiration. Notably, blood return does not exclude extravasation, and ruling out infiltration because of blood return has been implicated in a number of serious extravasation injuries. Although no guidelines apply to the management of all drug extravasations, some general recommendations do exist. If extravasation occurs, the injection should be stopped immediately and the IV tubing disconnected. Avoid applying pressure to the site, and do not flush the line. Leave the original catheter in place, and attempt to aspirate as much of the infiltrated drug as possible. Additional measures include application of topical corticosteroids (hydrocortisone 1%), a thermal compress, and elevation of the affected limb. Thermal compresses should be applied only after determining if the extravasated drug requires a hot or a cool compress. Applying a compress that is the wrong temperature can exacerbate the injury. Further management depends upon the particular drug extravasated. Extravasation of chemotherapy agents deserves special acknowledgment because these drugs are cytotoxic by nature and many are known vesicants. Additionally, some antineoplastic agents have antidotes that may be used if extravasation occurs. Most

hospitals and health care centers that administer chemotherapy have protocols or extravasation kits available to provide rapid assistance to the clinician in the event of drug infiltration. No single agent is used to treat extravasation of noncytotoxic medications. Early identification and intervention at the first sign of infiltration is probably the most critical step. If the decision is made to use an antidote, it should be administered as soon as possible. Phentolamine (Oraverse, Regitine, generic) may be given in cases of vasopressor extravasation (dopamine, norepinephrine [Levophed, generics], epinephrine). Hyaluronidase (Amphadase, Vitrase) has been used off label for vesicant drug extravasation, but it should not be used for infiltration of vasopressors. Knowing when these agents are indicated is crucial. Hospital protocols may prove useful. Finally, if extravasation occurs, the site should be monitored every 2 hours for 24 hours, every 8 hours for 72 hours, and then daily for erythema, blanching, necrosis, swelling, drainage, pain, and temperature. The affected extremity should be elevated for 24 to 48 hours and assessed every 8 hours for sensation, movement, and pulses. If there is any deterioration of the affected area (continued pain, necrosis, ulceration, suspected compartment syndrome), surgery should be consulted immediately. Some protocols recommend early surgical consult if a known vesicant is extravasated, but this practice is controversial. JAAPA

TO ASK OUR CONSULTANT a drug-related question, please e-mail • DECEMBER 2011 • 24(12) • JAAPA


Dermatology Digest K H A LI D A L A BOU D, M D; DA I FU LLA H A L A BOU D, M D

›CASE FIGURE 1 Papules at the edges of healed leishmaniasis lesions

Nodules that developed months after treatment Khalid Al Aboud is a consultant dermatologist at King Faisal Hospital, Makkah, Saudi Arabia. Daifullah Al Aboud is an assistant professor in the dermatology department, Taif University, Taif, Saudi Arabia. The authors have indicated no relationships to disclose relating to the content of this article.


Two otherwise healthy Saudi sisters, aged 15 and 13 years, presented with multiple ulcerating skin nodules on the face. The sisters had recently visited a village near Aleppo, Syria, an area known to be endemic for cutaneous leishmaniasis (CL). In both patients, smears from the lesional borders revealed histiocytes filled with microorganisms containing identifiable kinetoplasts. After CL was confirmed, the sisters were treated successfully with a combination of IM sodium stibogluconate (Penostam) and cryotherapy for 10 days. Eight months later, both girls developed skin-colored papules at the peripheries of their leishmaniasis scars (Figure 1). A punch biopsy confirmed that these papules were caused by leishmaniasis.

›THE MOST LIKELY DIAGNOSIS IS • Sporotrichoid CL • Diffuse CL • Leishmaniasis recidivans • Post–kala-azar dermal leishmaniasis (PKADL) ›DISCUSSION Leishmaniasis is a sandfly-borne infection caused by a protozoan parasite of the Leishmania species. Infection may be restricted to the skin in cutaneous (Old World) leishmaniasis, limited to the mucous membranes in mucosal or mucocutaneous leishmaniasis (MCL), or spread throughout the reticuloendothelial system in visceral leishmaniasis (VL), or kala-azar. Leishmaniasis in its various forms is present on all continents except Australia and Antarctica. The United States has seen an increasing number of cases because of the number of Americans, both military and civilian, traveling to endemic countries. Since 1980, more than 25 nonmilitary cases of CL have been identified in persons living in Texas, suggesting that

JAAPA • DECEMBER 2011 • 24(12) •

the disease may be endemic in that region. Nevertheless, almost all cases of leishmaniasis in the United States are thought to have been imported from elsewhere. Rare clinical variants of cutaneous leishmaniasis include sporotrichoid CL, diffuse CL, leishmaniasis recidivans, and post–kala-azar dermal leishmaniasis. Other dermatoses that should be considered in the differential diagnosis of cutaneous leishmaniasis include cutaneous sarcoidosis, cutaneous tuberculosis, and basal cell carcinoma. Diagnosis In countries where cutaneous leishmaniasis is endemic, diagnosis is often made on clinical grounds only. Suspicion for leishmaniasis should be raised in any patient who has returned from an endemic area and presents with a characteristic persistent, scaly, erythematous, or ulcerated plaque on an exposed site. The diagnosis is confirmed by a skin biopsy from the lesion edge or with a skin scraping from the ulcer base demonstrating the presence of amastigotes in the macrophages. Given our patients’ recent history of CL and the appearance of their new lesions, the diagnosis was leishmaniasis recidivans. Treatment Local treatment modalities for cutaneous leishmaniasis include topical paromomycin, cryotherapy, controlled heat, carbon dioxide laser therapy, or intralesional meglumine antimoniate. If lesions of CL are left untreated, complications, such as secondary bacterial infection spreading to contiguous mucous membranes or significant disfigurement, are possible. Leishmaniasis recidivans is known to be resistant to treatment. Our patients’ disease responded to daily IM injections of sodium stibogluconate 20 mg/kg/day (maximum dose, 800 mg daily) for 20 days. JAAPA Joe Monroe, PA-C, MPAS, department editor

A Day in the Life Kaatje van der Gaarden, PA-C

■ 8:15 AM

I live on site in the accommodation provided by the hospital, so my commute takes about 2 minutes. As always, I start the day with an American-size mug of Earl Grey tea with milk. I report directly to one of the consultants (supervising physicians), each of whom is responsible for half of the 30 patients. I am lucky to work with Hajeena, an excellent junior doctor (resident). Although we share the same duties, I sometimes have additional responsibilities, such as the Outpatient Clinic and writing discharge reports. Patients are mainly spread out over two wards: rehabilitation in the Spinal Injury Unit (SIU) and prevention and care of bed sores in the Angus McKinnon Unit (AMU). Duties center around admitting a newly diagnosed paraplegic or tetraplegic patient; neurologic assessments; and managing a broad range of medical issues, such as pneumonias and UTIs. ■ 8:30 AM

The author at the entrance of the Royal National Orthopaedic Hospital


he Royal National Orthopaedic Hospital is located just outside London, England. When in November 2009 I came across an opportunity to work at its nationally acclaimed Spinal Cord Injury Centre, I immediately applied. Once known as “The Cure of Crippled Children Centre,” the hospital is spread across buildings constructed in the 1920s. Americans also erected Nissen huts in the early 1940s. Made from corrugated steel, the prefabricated huts, which are similar to Quonset huts, are used as patient wards. The hospital is due for a much-needed renovation, starting next year.

Kaatje van der Gaarden practiced rehabilitation medicine at the Spinal Cord Injury Centre, Royal National Orthopaedic Hospital, Stanmore, England, when this article was written. She currently works for the gastroenterology inpatient service at Presbyterian Hospital in Albuquerque, New Mexico. Of note, she has an incomplete spinal cord injury. The author has indicated no relationships to disclose relating to the content of this article.

Rebecca, the ward sister (senior nurse), and I discuss Mr. L outside his room. Mr. L is 60 years old and has tetraplegia, ankylosing spondylitis, schizophrenia, and dysphagia. He receives humidified oxygen through a tracheotomy, as he is incapable of swallowing even saliva. Several neurologists, the speech-language therapist, gastroenterologist, and anesthesiologist have evaluated Mr. L without finding the etiology of the dysphagia. CT and video swallowing studies show a lack of coordination and immobile pharyngeal muscles. One possibility is postsurgical complications arising from an anterior approach to spinal fixation. Mr. L needs constant suctioning and has severe hematuria. ■ 9:15 AM

I need to monitor Mr. L’s hemoglobin. Nurses do not take blood samples or start IVs on this ward, so after “bleeding” the patient, I fill out the requisition form and put the blood tubes in the attached plastic bag. The bag is then sent to the in-house pathology laboratory. Urine samples and nonroutine laboratory tests, such as thyroid, folate, and B12 determinations, are sent by taxis to a nearby hospital. Because the system is elaborate and samples do go missing, I call to ensure that samples for blood cultures or other urgent requests have arrived. After documenting tests in Mr. L’s paper medical record (there is no electronic record), I continue with the daily ward round. ■ 9:45 AM

Ms. T has C5 tetraplegia after a truck hit her in a parking lot. She remembers her accident clearly and felt her neck break. Ms. T is in week 11 of her rehabilitation and has developed neuropathic pain, which arises in 80% of spinal injury patients. Neuropathic pain is debilitating in itself, with only one-third of patients responding to medications. Ms. T and I decide to try her on pregabalin 75 mg at night. I write the medication on the chart and hand it over to the junior doctor or consultant, who cosigns. PAs do not have prescription rights in the United Kingdom. I find this difficult, as the wards are very spread out, and some days I feel as if I am constantly hunting down my colleagues for signatures. Continued on page 29 • DECEMBER 2011 • 24(12) • JAAPA


A Day in the Life: Kaatje van der Gaarden, PA-C

“Each day, I realize that practicing in the UK is akin to the early days of our profession.” ■ 10:30 AM

After completing the documentation for patients at SIU, I’m off to AMU, the ward specializing in tissue viability, or pressure sore management. Unfortunately, pressure sores in spinal injury patients can take up to a year to heal. I take my down coat and brace myself for the cold since only makeshift hallways connect the wards. I go down the steep slope shivering and arrive at a warm AMU. Sunita, an experienced ward sister, requests a new drug chart for Mr. S. Every patient has a paper chart that has to be rewritten about once every month when it is full (which requires cosignatures). I also check on Mr. S, who has no new complaints. He was admitted with a grade 4 pressure sore and osteomyelitis. While in hospital, he spilled hot coffee over his right lower leg and required a skin graft for the burn. Both the donor site on his right thigh and the burn wound are healing quite nicely. ■ 11:30 AM

I check the inpatient lab results. Mr. L’s hemoglobin is 7.9%. The consultant, Dr. Gawronski, advises holding off on blood transfusion and repeating blood tests in 48 hours. I reply to internal e-mails and call a surgical specialty registrar. Most of our patients wear a body brace after neurosurgery, and the surgical team determines when the brace can be safely removed. I ask the specialty registrar to see Mr. P, who is anxious to have his cervicothoraciclumbosacral body brace removed. ■ 12:00 PM

Tomorrow morning is the weekly consultant ward round, so I follow up on pending radiology and laboratory results. Dr. Gawronski, a nurse, and I will evaluate the progress of each patient, look at pressure sores, prescribe, and overall manage care. This ward round is followed by a multidisciplinary team meeting that includes the consultants, psychiatrist, social worker, nurse, psychologist, rehabilitation assistants, physiotherapists, and occupational therapists. ■ 1:00 PM

I receive a beep regarding an admission for rehabilitation. Ms. C is a kind, elderly Indian woman who is recovering from spinal fixation for a lumbar fracture. The American Spinal Injury

Association has developed an examination to determine the level of the spinal injury. The examination is used worldwide as the most important diagnostic and prognostic indicator. Ms. C has an L5 incomplete spinal injury. I document the results of her physical examination and a cognitive screen and take a psychosocial history. Typically, a spinal injury patient will arrive from other hospitals after stabilization, undergo neurosurgery and spine decompression here, and then go through a rehabilitation process that can take 8 weeks for incomplete paraplegia and up to 6 months for complete tetraplegia. After teaching Ms. C about bladder and bowel management, including intermittent catheterization, I head back out in the cold and take another hallway to reach the Outpatient Clinic, where I spend the next part of my day. ■ 2:00 PM

Once a week, I see patients in the Outpatient Clinic. These patients have done their rehabilitation here and are seen for a yearly checkup. Because spinal injury patients are at a higher risk of cardiovascular disease and osteoporosis, this may include ordering dual-energy x-ray absorptiometry (DEXA), routine labs, and lipid determinations or providing health counseling. I review the two scheduled patients and check pending lab results. ■ 3:30 PM

Mr W comes in with his wife; both have paraplegia. Mr. W is 38 years old and has been bothered by abdominal pain for the past 6 months. The stomach pain exacerbates his spasms and neuropathic pain. He denies any first-degree family history of colon cancer, prior irritable bowel symptoms, rectal bleeding, change in bowel habits, fever, or weight loss. An abdominal examination detects normal bowel sounds and left lower-quadrant tenderness. I fill out laboratory requests and once again regret that occult blood testing is not available in the hospital. On the recommendation of Dr. Gawronski, I order a CT scan and dictate a referral letter to the gastroenterologist. There is an online system for ordering and checking radiology results. Mr. W’s blood will be drawn today, and I will follow up with a phone call or letter. I am beeped by the SIU that one of the patients has pyrexia. After checking with the consultant, I head to the ward immediately. ■ 5:15 PM

I download the audio file and e-mail it to Dr. Gawronski’s administrative assistant. She will transcribe the files the next day. Secretarial and administrative assistants are called PAs in the UK, and I hope this does not affect the implementation of physician assistants here. I bid Hajeena good night and head out. It’s been another intense yet fulfilling day, and I look forward to swimming in the staff pool. Not a day goes by without my realizing that practicing in the UK is akin to the early days of our profession. It is a testimony to how much has been accomplished by PAs in the United States. JAAPA • DECEMBER 2011 • 24(12) • JAAPA



EARN CATEGORY I CME CREDIT by reading this article and the article beginning on page 58 and successfully completing the posttest on page 64. 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 December 2011.


Discuss the historical aspects of childhood obesity Review the epidemiology of childhood obesity Recognize common causes of childhood obesity Discuss diagnostic and screening tests for childhood obesity

Childhood obesity: Understanding the causes, beginning the discussion Obesity in childhood is influenced by social and familial factors as well as the child’s genetics and activity level. Understanding the problem is only the first step in combating it.

Katie J. Perpich, PA-C; Rachel Russ, PA-C; Denise Rizzolo, PA-C, PhD; Mona Sedrak, PA-C, PhD

30 JAAPA • DECEMBER 2011 • 24(12) •

© / Chris Fertnig


n February 2010, Michelle Obama announced the “Let’s Move” initiative. The goal of this comprehensive program is to eliminate childhood obesity.1 Her goal may seem ambitious, but achieving it is necessary. Childhood obesity has become a growing problem among US children.2 Currently, an estimated 16.9% of them between 2 and 19 years old are obese or above the 95th percentile according to the body mass index (BMI)for-age growth charts; 11.9% of US children in the 2- to 19-year-old age-group are at or above the 97th percentile.3 In addition, the number of overweight and obese children has increased in almost all countries worldwide.4 Genetic factors, lack of physical activity, and increased consumption of fast food are all possible explanations for childhood obesity.5 Research suggests that families are eating out much more today than they did in the late 1970s.5 One study reported that between 1970 and the mid- to late-1990s, the number of meals eaten away from home by children in the United States nearly doubled.5 Not only is there a convenience factor to less healthy food choices, but the cost of healthy foods seems to be increasing.5 The prices of fruits and vegetables increased by 118% between 1985 and 2000, while the prices of foods high in fats and oils increased by 35%.6 These statistics suggest that foods with added sugars and fats may be the only affordable dietary option for those with limited family incomes.6 Eating a diet that is rich in fat and sugar and limited in fruits and vegetables can lead to childhood obesity and subsequently to adverse consequences, such as issues of self-esteem, insulin resistance, and chronic health concerns, including cardiovascular problems.7

Because of this growing epidemic, physician assistants must maintain an awareness of childhood obesity and be able to recognize children who are obese, overweight, or at risk of becoming obese. This article, the first of two in the current issue of JAAPA, focuses on the etiology, pathophysiology, diagnosis, treatment, complications, and prevention of childhood obesity. DEFINING CHILDHOOD OBESITY

Obesity is a disease in which a person is at increased risk of unfavorable health outcomes as a result of excess body fat.8 Many methods have been utilized to classify a person as overweight or obese. These methods include measuring waist circumference, calculating BMI, and assessing skinfold tests. Various organizations have advocated different methods of classifying childhood obesity. For example, according to the CDC, the best tool for monitoring weight in children is the BMI,9 which is first calculated based on the child’s weight and height, then plotted according to age and gender.9,10 Table 1 presents the equations used to calculate BMI and the corresponding weight category status by percentiles. The World Health Organization (WHO) does not state a preference for one method over another, noting that measuring obesity is challenging because there is no standard definition worldwide. Thus, WHO has developed several charts and tables for clinicians to use to assess a child’s weight status.11 These include weight-for-age, weight-for-height, BMI-for-age, and triceps skinfold-forage, among others.11 The American Academy of Pediatrics (AAP) uses the same guidelines for BMI-for-age as the CDC to define childhood obesity and states that for children older than 2 years, BMI is an acceptable measure to assess obesity.10 BMI has high specificity and is moderately sensitive, which means that using BMI alone will underestimate obesity in some children.8 Both waist circumference and triceps skinfold determinations have been used in addition to BMI to define obesity. However, neither waist circumference nor skinfold determinations have a set cutoff point, so they cannot be used alone to determine whether a child is overweight or obese.8 While BMI may not be perfect, it is the most acceptable gross screening measure for overweight children.9

SEE THE ONLINE VERSION OF THIS ARTICLE TO LINK TO CDC table for calculated body mass index values for selected heights and weights for ages 2 to 20 years bmi/00binaries/bmi-tables.pdf CDC BMI-for-age percentiles American Academy of Pediatrics pediatric weight management medical summary MedicalSummary_20091015.pdf


From 1976 to 1980, the prevalence of US children between 2 and 19 years old with a BMI above the 99th percentile was 0.8%.2 In 1999 to 2004, the prevalence of BMI above the 99th percentile for the same age-group was 3.8%, an increase of more than 300%.2 From the 1970s through the 1990s, the number of children classified as either overweight or obese doubled or tripled in many countries.4 North America and Europe exhibit the highest prevalence of overweight children, while areas of Southeast Asia and sub-Saharan Africa have the lowest prevalence.4 As countries have become more industrialized, eg, Brazil, Chile, Mexico, and Egypt, they have seen an increase in overweight school-age children.4 Numerous factors influence the rising trend of obesity, as noted by the CDC and other researchers. Age, race, gender, and socioeconomic status are some of the most significant epidemiologic factors. Age The highest rate of obesity lies between the ages of 10 and 11 years; 21.89% of children within this age range are classified as obese. In the 12- to 14-year-old age range, 14.43% of children are considered obese. Finally, between the ages of 15 and 17 years, 10.72% of adolescents were found to be obese.12 Ethnicity and socioeconomic status Increased prevalence of obesity is also linked to ethnicity and socioeconomic status.12 One study found a greater than threefold increase

KEY POINTS ■ BMI has high specificity and is moderately sensitive, so using BMI alone will underestimate obesity in some children. Waist circumfer-

ence and triceps skinfold determinations have also been used to define obesity, but neither can be used alone to determine whether a child is overweight or obese. ■ Socioeconomic status is one of the most significant epidemiologic factors in childhood obesity. Compared with children of middle class or affluent households, children of households at or below the poverty level have an 83% increased risk of becoming obese. ■ One theory holds that spending more time in sedentary pursuits increases the risk of becoming obese. Physical activity can promote a healthy lifestyle and decrease the risk of obesity among children. ■ One way to open the discussion of overweight or obesity is to have a BMI chart on hand. When the BMI places a child in the overweight or obese category (BMI in the 85th percentile or higher), the clinician can show the child and/or parent the objective information about the specific BMI. • DECEMBER 2011 • 24(12) • JAAPA


CME Childhood obesity, part 1 TABLE 1. Weight status categories and the corresponding percentiles24 Category Underweight Healthy weight Overweight Obese

Percentile <5th 5th to <85th 85th to <95th ≥95th

Note: Use the following formulas to calculate BMI: Weight in pounds ÷ height in inches ÷ height in inches × 703 = BMI Weight in kilograms ÷ height in meters ÷ height in meters = BMI

in risk of obesity in poor black children compared with wealthy white children.12 Native Americans/American Indians and Alaskan natives were found to have the highest rate of obesity in 2008 (21.2%), with Hispanics ranking second at 18.5%.9 The CDC also found that in 2008, Colorado and Hawaii were the only states where the number of low-income preschool-age children considered to be obese was 10% or less.9 Indian Tribal Organizations were the only groups with rates higher than 20% (Table 2). Household income and risk of childhood obesity are inversely proportional. As household income increases, the risk of childhood obesity decreases.13 Household income is a major contributing factor to poverty status among households containing multiple children. Compared with children of middle class or affluent households, children of households at or below the poverty level have an increased risk (83%) of becoming obese.12 Neighborhood social

“A diet consisting of low-fat dairy products, vegetables, fruits, and legumes decreases the probability of becoming obese.” capital, an index of parents’ perceptions of social support (eg, cohesion, trust, reciprocity) where they live, is also associated with childhood obesity rates. Children residing in neighborhoods with high social capital have a decreased probability of obesity compared with the probability of obesity for children residing in neighborhoods with low social capital.12 Gender In children 12 years and younger, gender discrepancy in the prevalence of childhood obesity is minimal. However, in children 12 to 17 years, gender differences become more apparent. In one study, males 12 years and older were more likely than their female counterparts to become overweight.13 This is believed to be the result of increased concern with body self-image among females in comparison to their male counterparts. Another study found that African American female children and Mexican 32 JAAPA • DECEMBER 2011 • 24(12) •

TABLE 2. Prevalence of obesity among low-income preschool-age children in 20089 Ethnic group

Percent prevalence



Black, non-Hispanic


White, non-Hispanic




American Indian/Alaskan native


American male children between 5 and 18 years maintain the highest prevalence of obesity; the reasons for this are unknown.14 CAUSES OF CHILDHOOD OBESITY

Etiologic factors contributing to the prevalence and development of childhood obesity are numerous and varied. Many times, there is more than one contributing cause, compounding the problem. Activity level Physical activity increases body metabolism, burns calories, improves cardiovascular health, and decreases the amount of body fat that is stored. One theory holds that children who engage in little to no physical activity are at increased risk of becoming obese.12 A sedentary lifestyle reflects greater amounts of time spent in such activities as television viewing, video game playing, and computer use. Having electronic equipment or a television in the bedroom increases sedentary lifestyle habits.15 For example, children who have a television or electronic equipment in the bedroom have higher BMIs than children who do not.15 Additionally, increased television viewing and video game use, specifically for 3 or more hours per day, is positively correlated with increased risk of obesity among children.12,16 Exercise and other physical activity, such as participation in sports, can promote healthy behaviors and decrease the risk of obesity among children. However, obese children are less likely to participate in sports or extracurricular activities at school, thus increasing the risk for remaining at their current body weight.15 Participating in physical activity—for example, sports, dance classes, or other recreational activities—promotes a healthy weight in children.15 Environment Factors in a child’s environment that contribute to the rising trend in childhood obesity include but are not limited to parental education level, location of residence, and characteristics of residence. In their 2008 study, Singh and colleagues showed that parental educational level is inversely proportional to childhood obesity.12 Children with parents who have 12 or fewer years of education have a 50% higher risk of obesity than children with collegeeducated parents. Children residing in urban or metropolitan areas have an increased risk of obesity attributable to decreased space for outdoor activities, higher crime rates,

fewer markets selling fresh produce, and increased presence of fast-food establishments.14 Nutrition Food consumption among children and adolescents is a multifaceted topic that includes the types of food consumed, the location of dining, the preparation of the food, and the eating habits of other members of the household. Nutritional status of children and adolescents is often dictated by their household guardian. Children who reside in a household in which the guardian displays unhealthy eating habits and consumes increased amount of fats and oil have a higher risk of becoming obese than children residing in a household surrounded by healthy eating habits.13 A diet consisting of low-fat dairy products, vegetables, fruits, and legumes decreases the probability of becoming obese, whereas a diet composed of increased amounts of fats, oils, soft drinks, and sodium increases the probability of becoming obese.13 Children who eat regular meals at home are less likely to be obese than children whose family frequently dines out at restaurants or fast-food chains.13 Likewise, children who reside in a household in which the guardian prepares meals using prepackaged or canned food items are more likely to become obese than children who reside in a household in which the guardian prepares meals using fresh produce and protein sources.13 Media and marketing Current technological breakthroughs support the increased use of media devices, such as televisions, iPods, video game devices, and interactive portable devices. Because of these electronic advancements, children are being exposed to a constant flow of advertisements—on average, one food advertisement every 5 minutes.17 Food advertisements target younger children because they are impressionable and cannot comprehend the persuasiveness of the message. Such advertisements use toys, cartoon characters, video games, and professional athletes to sell the food, beverage, or candy product.17 Most food advertisements targeted at children campaign for sugary sweet treats, fast food, and other unhealthy alternatives. Each year, $3 billion is spent by the fast-food industry for advertisement and marketing TABLE 3. Causes of childhood obesity8,19 Diseases

Genetic disorders


•Brain damage and CNS disorders —Post chemotherapy —Surgery —Trauma

•Bardet-Biedl syndrome

•Antidepressants: monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, tricyclics

•Cushing syndrome •Growth hormone deficiency •Hypothyroidism, pseudohypoparathyroidism

•Cohen syndrome •Prader-LabhartWilli syndrome

•Atypical antipsychotics •Risperidone

campaigns directed toward children.18 This increases the likelihood that children will engage in unhealthy eating habits.18 Childhood diseases Childhood obesity can be attributed to endocrine disorders, such as hypothyroidism, pseudohypoparathyroidism, growth hormone deficiency, and Cushing syndrome. Brain injury and CNS disorders resulting from trauma or surgery or following chemotherapy can also lead to obesity in children (Table 3).8 Genetics While genetic abnormalities are extremely rare and should be the last diagnoses considered when evaluating an obese child, they are worth mentioning. Genetic abnormalities that can lead to childhood obesity result from

“Any child whose BMI is in the 95th percentile or higher requires liver function testing, as well as insulin and lipid profiles.” a mutation or polymorphism of numerous receptors, hormones, and enzymes. Signaling molecules, such as leptin, adiponectin, visfatin, and resistin that are present in adipose tissue, can be associated with the development of childhood obesity (Table 3).19 HISTORY AND PHYSICAL EXAMINATION

Begin the evaluation of a child by obtaining a family history. Current recommendations call for children with a family history of dyslipidemia, cardiovascular disease, hypertension, diabetes, and obesity to be screened with a fasting lipid profile when they are between 2 and 10 years of age.20 Information regarding the child’s physical activity should be part of the history as well. Determine how much television viewing, computer-related activity, and exercise the child does daily. This information can be recorded and followed using an obesity worksheet provided by The American Academy of Pediatrics (also available in Spanish). After a thorough history is completed, a physical examination should follow. Weight and height should be recorded for all children at every visit regardless of age and the BMI then calculated.21 The BMI scale can be used for both adults and children; however, children have different result parameters and classifications. Children with a moderately elevated BMI, such as those who fall into the “overweight” category, can be further assessed for obesity using skinfold thickness and waist circumference measurements.22 The age at which to start BMI assessment is a highly debatable subject. Both the CDC and the AAP agree that BMI calculations should begin at age 2 years and continue annually. BMI can then be plotted over time on a growth curve to track any changes over time. A complete physical examination of the child found to be overweight or obese includes an assessment of adiposity • DECEMBER 2011 • 24(12) • JAAPA


CME Childhood obesity, part 1 distribution, syndromic features, and vital signs. A funduscopic examination will detect blurring of the optic disk margins, which could indicate pseudotumor cerebri. Also, examination of the neck to detect thyromegaly as well as assessment of the cardiovascular system, pulmonary system, and abdomen should be completed. Clinicians should examine the skin for signs of acanthosis nigricans, hirsutism, and striae. Finally, the patient’s sexual maturity should be assessed to document pubertal status and psychological health. Children deemed to be at increased risk of metabolic syndrome should begin oral glucose tolerance testing at age 10 years.23 Any child whose BMI is in the 95th percentile or higher requires liver function testing, a fasting glucose determination, and insulin and lipid profiles.23 Comorbidities worthy of consideration in overweight and obese children include hypertension, sleep apnea, and orthopedic problems.23

sity. The potential causes of childhood obesity are many. Diseases, genetic abnormalities, activity level and nutritional status of the child, and mass media and marketing can all lead to obesity in children. Screening tests, such as BMI, as well as other diagnostic tests and a detailed history and physical examination can be used to evaluate the weight and health of a child. The second article on childhood obesity discusses the physical and psychological consequences of childhood obesity as well as management and preventive strategies for this growing epidemic. JAAPA


REFERENCES 1. Hall M, Hellmich M. Michelle Obama aims to end child obesity in a generation. USA Today. http:// February 9, 2010; Health & Behavior. Accessed November 7, 2011. 2. Skelton JA, Cook SR, Auinger P, et al. Prevalence and trends of severe obesity among US children and adolescents. Acad Pediatr. 2009;9(5):322-329. 3. Ogden CL, Carroll MD, Curtin LR, et al. Prevalence of high body mass index in US children and adolescents, 2007-2008. JAMA. 2010;303(3):242-249. 4. Wang Y, Lobstein T. Worldwide trends in childhood overweight and obesity. Int J Pediatr Obes. 2006;1(1):11-25. 5. Ebbeling CB, Pawlak DB, Ludwig DS. Childhood obesity: public-health crisis, common sense cure. Lancet. 2002;360(9331):473-482. 6. Drewnowski A. Obesity and the food environment: dietary energy density and diet costs. Am J Prev Med. 2004;27(3 suppl):154-162. 7. Ludwig DS. Childhood obesity—the shape of things to come. N Engl J Med. 2007;357(23): 2325-2327. 8. Reilly JJ. Descriptive epidemiology and health consequences of childhood obesity. Best Pract Res Clin Endocrinol Metab. 2005;19(3):327–341. 9. Centers for Disease Control and Prevention. Obesity prevalence among low-income, preschoolaged children—United States, 1998-2008. mm5828a1.htm. Reviewed July 23, 2009. Accessed November 7, 2011. 10. American Academy of Pediatrics. About childhood obesity. html. Accessed November 7, 2011. 11. World Health Organization. Obesity and overweight. factsheets/fs311/en/. Updated March 2011. Accessed November 7, 2011. 12. Singh G, Kogan M, Dyck P, Siahpush M. Racial/ethnic, socioeconomic, and behavioral determinants of childhood and adolescent obesity in the United States: analyzing independent joint associations. Ann Epidemiol. 2008;18(9):682-695. 13. Boumtje PI, Huang CL, Lee J-Y, Lin B-H. Dietary habits, demographics, and the development of overweight and obesity among children in the United States. Food Policy. 2005;30(2):115-128. 14. Wieting J. Cause and effect in childhood obesity: solutions for a national epidemic. J Am Osteopath Assoc. 2008;108(10):545-552. 15. Rosenberg DE, Sallis JF, Kerr J, et al. Brief scales to assess physical activity and sedentary equipment in the home. Int J Behav Nutr Phys Act. 2010;7:10 16. Schwimmer JB, Burwinkle TM, Varni JW. Health-related quality of life of severely obese children and adolescents. JAMA. 2003;289(14):1813-1819. 17. Kunkel D. Children and television advertising. In: Singer DG, Singer JL, eds. The Handbook of Children and the Media. Thousand Oaks, CA: Sage Publications; 2001:375-394. 18. Schlosser E. Fast Food Nation: The Dark Side of the All-American Meal. Boston, MA: Houghton Mifflin Co; 2001. 19. Kiess W, Blüher S, Kapellen T, et al. Physiology of obesity in childhood and adolescence. Curr Paediatrics. 2006;16(2):123-131. 20. Daniels SR, Greer FR; Committee on Nutrition. Lipid screening and cardiovascular health in childhood. Pediatrics. 2008;122(1):198-208. 21. Nihiser AJ, Lee SM, Wechsler H, et al. Body mass index measurement in schools. J Sch Health. 2007;77(10):651-671. 22. Freedman DS, Sherry B. The validity of BMI as an indicator of body fatness and risk among children. Pediatrics. 2009;124(suppl 1):S23-S34. 23. Speiser PW, Rudolf MC, Anhalt H, et al. Consensus statement: childhood obesity. J Clin Endocrinol Metab. 2005;90(3):1871-1887. 24. Centers for Disease Control and Prevention. About BMI for Children and Teens. http://www.cdc. gov/healthyweight/assessing/bmi/childrens_bmi/about_childrens_bmi.html. Updated September 13, 2011. Accessed November 7, 2011.

Discussing obesity with a child, a teenager, or even the parent can be difficult. Children rarely present with an initial chief complaint relating to weight. Many times, the clinician will have to raise the issue of weight with the child or parent dur-

“Cultural awareness and ethnic meal preparations should be taken into consideration when reviewing the eating habits of the family.” ing a well-child visit, sports physical examination, or other health assessment. Whether or not the child or, in some cases, the parent should be in the room during the conversation is determined on a case-by-case basis, taking into consideration the relationship between the clinician, child, and the child’s family, as well as the child’s age and emotional maturity. One way to open the discussion is to have a BMI chart on hand. Copies can be obtained from the CDC Web site. When the BMI places a child in the overweight or obese category (BMI in the 85th percentile or higher), the clinician can show the child and/or parent the objective information about the risks associated with that BMI. Following the BMI evaluation, a discussion of the child’s as well as the family’s eating habits should begin. Detailed questions regarding meal preparation, snacks, and fast foods are in order. Cultural awareness and ethnic meal preparations should also be taken into consideration when reviewing the eating habits of the child and other family members. CONCLUSION

Obesity increases the risk of health problems resulting from excess body fat.8 Epidemiologic factors such as age, race, gender, and socioeconomic status are influential components affecting the increasing rates of childhood obe34 JAAPA • DECEMBER 2011 • 24(12) •

Katie Perpich and Rachel Russ recently graduated from the Seton Hall University PA program in South Orange, New Jersey. Denise Rizzolo is an associate professor in the Seton Hall PA program and works at the Care Station in Springfield, New Jersey. Mona Sedrak is an associate professor and program director of the Seton Hall PA program. The authors have indicated no relationships to disclose relating to the content of this article.


Immune thrombocytopenic purpura develops in a 67-year-old female After a careful diagnostic workup and a process of elimination, the patient’s attempt to treat her leg cramps was revealed to be the most probable cause of her hemorrhagic lesions.


A 67-year-old female presented to the emergency department (ED) with a 12-hour history of oral petechiae and a single episode of epistaxis. In addition, she reported pruritus of the scalp and ears and episodes of melena and hematuria for 2 days preceding her arrival. She denied any current pain, although she reported two episodes of severe headache 1 week prior. She denied associated syncope, paresthesias, visual changes, or weakness. There had been no history of arthralgias, myalgias, or rashes. The patient reported recent travel to a rural region in the United States, but she had not noticed any ticks and/or bites. Review of systems was negative for fever, weight loss, nausea, vomiting, or diarrhea. Prescription medications included conjugated estrogens, levothyroxine, oxybutynin, and alendronate. In addition, the patient revealed periodic use of OTC nutritional supplements, including Ginkgo biloba, vitamin E, and red yeast rice. Two weeks before this illness, the patient had had leg cramps for which she had taken two quinine tablets of unknown quantity. The medical history included hysterectomy secondary to cervical dysplasia, hemithyroidectomy, and bilateral mastectomy for fibroadenoma disease. Her mother and father had died secondary to multiple myeloma and prostate cancer, respectively. Her sister also died secondary to metastatic disease of unknown origin. There was no known family history of leukemia or platelet disorders. The patient had a 40-pack-year smoking history. She denied alcohol use. Physical examination The patient was a well-nourished female in no acute distress, who was afebrile and normotensive. A 2-cm submucosal hemorrhagic lesion on the palate was noted, as well as multiple buccal petechiae and excoriations on the scalp. Diffuse petechiae were observed over the patient’s legs, arms, and trunk. Multiple ecchymoses ranging from 1 to 5 cm in diameter were visible on the forearms and thighs. The abdomen was nontender

and soft with no hepatosplenomegaly. No edema was observed in the extremities. There was no evidence of cervical or femoral lymphadenopathy. Cranial nerves were grossly intact. No focal neurologic deficits were noted. Laboratory studies Initial laboratory results revealed a platelet count of 6×103/µL (reference range, 150-400×103/ µL) with hemoglobin of 14.9 g/dL (reference range, 12.015.0 g/dL) and a hematocrit of 42.9% (35-45%), respectively. WBC count was 9×103/µL (3.2-9.8×103/µL). Results of a complete metabolic panel (CMP) were significant for a nonfasting glucose level of 156 mg/dL (reference range,

© Mediscan

Mackenzie L. Pennington, MS, PA-C; Alison C. Essary, MHPE, PA-C

Immune thrombocytopenic purpura (ITP) • DECEMBER 2011 • 24(12) • JAAPA


CASE REPORT | Immune thrombocytopenic purpura less than 110 mg/dL). AST, ALT, total protein, albumin, and alkaline phosphatase levels were normal. Prothrombin time (PT), international normalized ratio (INR), and activated partial thromboplastin time (aPTT) were unremarkable. ESR was not elevated. Serum protein electrophoresis was normal. Hospital course The patient was admitted to the hospital and underwent further laboratory and diagnostic testing. Fibrinogen, lactate dehydrogenase (LDH), haptoglobin, and serial PT/aPTT determinations were normal. HIV and hepatitis C virus (HCV) assay findings were negative. Results of a direct Coombs test were negative. Abdominal ultrasound found no sign of hepatosplenomegaly.

“Although platelet immunologic assays have been studied, they are not sensitive or specific enough to use as diagnostic parameters.” The diagnosis was immune thrombocytopenic purpura (ITP). The patient was treated aggressively with corticosteroids, platelet transfusion, IV immunoglobulin G (IVIG), and anti-Rho immunoglobulin. Within a few days, the platelet count had increased to 68×103/µL and all signs of hemorrhage ceased. There was no recurrence of headache or pruritus. The patient was discharged to outpatient therapy for continued monitoring of platelet levels. Although the majority of ITP cases are believed to be idiopathic, a small percentage have identifiable etiologies. Given the temporal relationship between this patient’s quinine dosing and development of ITP symptoms, she was advised to discontinue quinine permanently in the event that it was the causative variable. DISCUSSION

The annual incidence of ITP is less than 4 cases per 100,000 population.1,2 Prevalence rates vary between studies but increase with age. The risk of fatal hemorrhage in patients older than 60 years is 13%, compared to 0.4% in patients younger than 40 years.3 Thus, careful monitoring of platelet levels and response to therapy is critical in the older population.

The primary pathologic feature of ITP includes autoantibodies to platelets.4 Clearance of antibody-coated platelets occurs in the spleen via phagocytosis. The autoantibody production is B- and T-cell mediated, and derangements may occur centrally (ie, in the bone marrow) or in peripherally circulating lymphocytes. Centrally located disturbances in lymphocytic cells may be less responsive to immunotherapy.4 In 80% of cases, ITP occurs as a primary disorder; in the remaining cases, it is secondary to identifiable etiologic factors. Known secondary causes promote aberrations at different stages of the lymphocytic life cycle. For example, systemic lupus erythematosus (SLE), Evans syndrome, and lymphoproliferative disorders alter lymphocytes at the level of bone marrow synthesis. Chronic lymphocytic leukemia and organ transplant status affect lymphocyte differentiation. In the peripheral blood, destruction of platelets as a result of viral illness and vaccination reaction occurs via cross-reaction of antiviral antibodies and platelet antigens.4 Diagnosis of ITP A thorough history should include a review of the constitutional and neurologic systems. History of blood transfusion, persistent anemia, rheumatologic disease, risk factors for HCV and HIV, and use of drugs that may induce ITP should be elicited. A small percentage of patients have a family history of thrombotic disorders. The presence of deep muscle bleeding, retroperitoneal bleeding, or hemarthroses increase suspicion for a coagulation factor deficiency since bleeding with ITP is typically mucocutaneous. Hyperpyrexia, lymphadenopathy, and splenomegaly suggest infectious, rheumatologic, or malignant etiologies.5 Laboratory evaluation should include a CBC, peripheral blood smear, direct antiglobulin test (DAT; direct Coombs test), coagulant studies, HIV and hepatitis assays, and antinuclear antibody determination.5 The literature suggests bone marrow biopsy for adults older than 60 years, as thrombocytopenia may be a sign of myelodysplasia. Platelet immunologic assays have been studied but are not sensitive or specific enough to use as diagnostic parameters.5 This may be the result of unidentified surface antigens that are implicated in the disease or platelet loss through undefined mechanisms.4 The characteristic laboratory abnormality is thrombocytopenia. Results of the remaining hematologic studies fall within normal limits. Thus, ITP fundamentally remains a diagnosis of exclusion.

TEACHING POINTS ■ ITP is a diagnosis of exclusion. Laboratory abnormalities other than the platelet count widen the differential diagnosis. ■ Although most ITP cases are believed to be idiopathic, a small percentage of cases have identifiable etiologies. In this patient, quinine

was thought to be the catalyst for disease development. ■ The natural history of ITP in adults is characterized by refractory or relapsing disease. ■ Repeated use of IVIG or anti-Rho in chronic ITP may allow patients to avoid splenectomy.

42 JAAPA • DECEMBER 2011 • 24(12) •

Management and prognosis of ITP While ITP is most often transient in children, it can be refractory or relapsing in adults. Less than 10% of patients have chronic disease, limiting the amount of available data on appropriate management.6 In patients with platelet counts greater than 30×103/µL and no active bleeding, treatment is not usually necessary unless surgical or dental procedures are required. Management: Acute stage In new-onset ITP, glucocorticoids, IVIG, platelet transfusion, and anti-Rho immunoglobulin should be considered first-line therapies.2,6 Glucocorticoids (ie, prednisolone) alone are effective for new-onset ITP in two-thirds of patients, but only about 20% of those patients can expect long-term remission. IVIG is indicated as adjunct therapy for severe bleeding in acute ITP but also does not offer a durable recovery. Platelet transfusion should be considered if GI bleeding is a presenting symptom. A combination of corticosteroids, IVIG, and platelet transfusion therapy is preferred for patients with life-threatening bleeding.2,6 Anti-Rho immunoglobulin may also be used in new-onset ITP for rhesus-D-positive patients who have not had a splenectomy.2 Anti-Rho increases platelet levels in most patients

ITP following splenectomy have an accessory spleen, which can be identified through radioisotope imaging and should be surgically removed. Immunosuppressants, such as cyclophosphamide (Cytoxan, generics), may be used with caution in patients with severe refractory ITP because these agents can induce secondary malignancies.2 Future directions There is some speculation that the pathophysiology of ITP includes the decreased production of platelets. Romiplostim (Nplate) and eltrombopag (Promacta) show promise in their ability to increase platelet counts, particularly in patients with refractory ITP.7 Phase 4 clinical trials are ongoing for the evaluation of rituximab (Rituxan), an immunomodulator that acts as an antibody to B cells. Preliminary studies suggest that rituximab may induce remission in patients with early-stage ITP.4,8 Other studies have shown improvement in platelet counts following eradication of Helicobacter pylori, likely as a result of hampering cross-reactivity between H pylori antibodies and platelet antigens. In addition, ongoing trials will evaluate the use of peripheral blood stem cell transplantation in the treatment of autoimmune diseases, including ITP.4 CONCLUSION

“The prudent course is to advise adult patients with ITP that the disease may relapse and require additional treatment.” within 24 hours and provides several weeks of stability in about 50% of patients. A direct Coombs test must be completed prior to initiation of therapy because anti-Rho immunoglobulin can precipitate hemolytic anemia. Management: Chronic stage When relapse occurs, longterm corticosteroids may be employed to maintain platelet levels. Because of the risks associated with chronic steroid use, splenectomy may provide a viable treatment alternative. Splenectomy is curative in two-thirds of patients; in those for whom it is not curative, splenectomy provides partial improvement in platelet count. Repeat IVIG or anti-Rho therapies are additional options that may prevent the need for splenectomy.2 Management: Refractory stage ITP that has been refractory to treatment in the acute and chronic stages, including splenectomy, is referred to as chronic refractory ITP. Options for patients with refractory ITP may include high-dose steroids, evaluation for an accessory spleen, and/or immunosuppressant therapy.2,6 High-dose corticosteroids (eg, dexamethasone or highdose parenteral methylprednisolone) may be used on a short-term basis. Risk factors associated with steroid use include osteoporosis, myopathy, hyperglycemia, and avascular necrosis. Twenty percent of patients with refractory

Careful acquisition of patient history and appropriate evaluation of laboratory results narrow the diagnosis to immune thrombocytopenia purpura in the patient presenting with mucocutaneous hemorrhage. Consultation with a hematology/oncology specialist provides confirmation of the diagnosis and further guidance for therapy. The prudent course is to advise adult patients with ITP that the disease may relapse and require additional treatment. Many therapeutic approaches are available in the management of ITP. Future drug therapies may decrease the need for splenectomy as well as the incidence of chronic and refractory ITP. JAAPA Mackenzie Pennington practices primary and urgent care in Southern California. Alison Essary is an associate professor and associate director of the PA Program at Midwestern University in Glendale, Arizona. The authors have indicated no relationships to disclose relating to the content of this article. REFERENCES 1. Abrahamson PE, Hall SA, Feudjo-Tepie M, et al. The incidence of idiopathic thrombocytopenic purpura among adults: a population-based study and literature review. Eur J Haematol. 2009; 83(2):83-89. 2. Stasi R, Evangelista ML, Stipa E, et al. Idiopathic thrombocytopenic purpura: current concepts in pathophysiology and management. Thromb Haemost. 2008;99(1):4-13. 3. Cohen YC, Djulbegovic B, Shamai-Lubovitz O, Mozes B. The bleeding risk and natural history of idiopathic thrombocytopenic purpura in patients with persistent low platelet counts. Arch Intern Med. 2000;160(11):1630-1638. 4. Cines DB, Bussel JB, Liebman HA, Luning Prak ET. The ITP syndrome: pathogenic and clinical diversity. Blood. 2009;113(26):6511-6521. 5. Psaila B, Bussel JB. Immune thrombocytopenic purpura. Hematol Oncol Clin North Am. 2007; 21(4):743-759. 6. Provan D, Newland A. Fifty years of idiopathic thrombocytopenia purpura (ITP): management of refractory ITP in adults. Br J Haematol. 2002;118(4):933-944. 7. Nurden AT, Viallard JF, Nurden P. New-generation drugs that stimulate platelet production in chronic immune thrombocytopenic purpura. Lancet. 2009;373(9764):1562-1569. 8. Godeau B, Porcher R, Fain O, et al. Rituximab efficacy and safety in adult splenectomy candidates with chronic immune thrombocytopenia purpura: results of a prospective multicenter phase 2 study. Blood. 2008;112(4):999-1004. • DECEMBER 2011 • 24(12) • JAAPA



Interactions between supplements and drugs: Deciphering the evidence Make sure you know what dietary supplements your patient uses because the potential for interaction with a medication you prescribe is significant.

John Laird, ND


s defined by the Dietary Supplement Health Education Act of 1994, a dietary supplement is any of the following: vitamin, mineral, herb or botanical, amino acid, enzyme, organ tissues, glandular substance, metabolites, or other “dietary ingredient” (eg, essential fatty acid, lycopene, probiotic).1 Dietary supplements do not include homeopathic remedies, which are regulated separately by the FDA. Dietary supplements are commonly used by adults in the United States. According to the 2007 National Health Interview Survey (NHIS), 17.7% of adults had taken a nonvitamin, nonmineral product in the previous 12 months.2

The 2002 NHIS found that 19% of adults had used an herbal product in the prior 12 months.3 A survey of patients attending six specialty clinics at the Mayo Clinic found that an average of 39.6% used dietary supplements; usage ranged from 32% in the physical medicine clinic to 51% in the fibromyalgia clinic.4 The number of older adults who take a dietary supplement concurrently with a prescription medication is significant. Interviews of 3,005 community-dwelling adults aged 57 to 85 years in the National Social Life, Health and Aging Project (NSHAP) revealed that 52% took at least one dietary supplement concurrently with a prescription medication.5 An analysis of 3,070 ambulatory adults aged 75 years and older who were enrolled in the Ginkgo Evaluation of Memory Study found that 74% used at least one dietary supplement concurrently with one or more prescription medications.6 The rate of disclosure of dietary supplement use to conventional health care providers is low. Sixty-nine percent of adults who took a dietary supplement concurrently with a prescription medication in the previous 12 months did not inform their conventional health care professional of such use.7 Considering the ubiquity of dietary supplement use and the lack of disclosure by patients, the potential for significant interactions between dietary supplements and prescription medications is an important issue for clinicians to consider with each patient encounter. REPORTS OF DIETARY SUPPLEMENT-DRUG INTERACTIONS

© / Amanda Rohde

The number of reported dietary supplement-drug interactions is low. A chart review of 804 outpatients attending six clinics associated with the Santa Clara Valley Medical Center in California found that 6% had taken a supplement and a drug that had the potential for an adverse interaction; 1% had an observed adverse interaction that was rated as mild in severity.8 When the analysis was limited to those patients who used herbs rather than any other type of supplement, the observed adverse interaction rate was 7%.8 A 1-year prospective surveillance study conducted at the San Francisco division of the California Poison Control System determined that 2% of calls related to dietary supplements were likely attributable to dietary supplement-drug interactions.9 In the previously described Mayo Clinic survey, 29% 44 JAAPA • DECEMBER 2011 • 24(12) •

of potential dietary supplement-drug interactions (N = 369) were identified as clinically significant; 68% of those involved garlic, ginkgo, kava, St. John’s wort, or valerian.4 Although the number of potential interactions is high, the number of observed interactions is relatively low. This difference is likely the result of underreporting or a lack of awareness. It may also indicate that theoretical interactions do not always manifest clinically. Adverse dietary supplement-drug interactions are reported in several ways: (1) as case reports, (2) as surveillance data that are part of a clinical trial, (3) as in vitro and in vivo experimental data, and (4) as a clinical trial in healthy subjects. The interactions are also described in terms of pharmacodynamic and pharmacokinetic processes. Because dietary supplement-drug interactions are reported in so many ways, health care professionals may find themselves faced with conflicting information. Of significant concern to clinicians is the interaction between medications that prolong bleeding time, either directly or as an adverse effect, and dietary supplements that potentiate or inhibit such medications. Reports of the effects of garlic and ginkgo on bleeding time are examples of the contradictory information that clinicians encounter in daily practice. Garlic, the third highest-selling herbal supplement in 2008, is noted to have antiplatelet, antithrombotic, and fibrinolytic activity.10,11 A 51-year-old male who consumed 1,200 mg of aged garlic per day and no other drugs developed a kidney hematoma after undergoing extracorporeal shock wave lithotripsy (ESWL).12 Ginkgo, the fifth highest-selling herbal supplement in 2008, inhibits platelet activating factor (PAF).10,13 Spontaneous bleeding and a prolonged bleeding time of greater than 15 minutes were reported in a 73-year-old male who consumed 75 mg/ day of a standardized extract of ginkgo. The bleeding and prolonged bleeding time resolved with discontinuation of the supplement.14 Given the mechanisms of action of garlic and ginkgo, the prolonged bleeding and hemorrhage seen in these patients were likely a result of their consuming those supplements. EVIDENCE FROM PHARMACODYNAMIC STUDIES

In contrast to the case reports, an in vivo PFA-100 assay of platelet function in 10 healthy adults found that consump-

SEE THE ONLINE VERSION OF THIS ARTICLE TO LINK TO Natural Medicines Comprehensive Database http://naturaldatabase.therapeuticresearch. com/home.aspx?tab=3 Natural Standard Herb and Supplement database FDA form 3900 to report an adverse dietary supplement-drug interaction ucm085568.htm

tion of GNC brand garlic or ginkgo herbal product for 2 weeks had no effect on platelet function.15 Another study, a randomized, double-blind, placebo-controlled trial, looked at the use of Ginkgo biloba (EGb 761) at a dose of 300 mg/ day combined with aspirin at 325 mg/day for 4 weeks in 60 adults with peripheral arterial disease. Results showed that compared with the use of aspirin alone, ginkgo had no additive effect on platelet function.16 PHARMACOKINETICS OF SELECTED HERBS

Pharmacokinetic studies may offer insight into the differences observed between case report and clinical trial findings. Hepatic and intestinal metabolism of drugs occurs via the microsomal cytochrome P-450 (CYP450) enzyme system. The percentage of clinical drugs metabolized by these enzymes is 50% by CYP3A4, 25% by CYP2D6, 15% by CYP2C9, and 10% by CYP2C19.17 Examples of drugs metabolized by these enzymes include • Statins, macrolide antibiotics, and dihydropyridine calcium channel blockers via CYP3A4 • Selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants (TCAs) via CYP2D6 • S-warfarin, NSAIDs, and angiotensin-receptor blockers (ARBs) via CYP2C9 • Proton pump inhibitors and benzodiazepines via CYP2C19.17 In vitro studies have identified herbs that induce or inhibit the specific CYP450 enzymes, thus potentially decreasing or increasing serum levels of drugs that are metabolized

KEY POINTS ■ Dietary supplements are commonly used by US adults, but many adults who took a dietary supplement concurrently with a prescription

medication did not inform their health care professional of such use. ■ Although the number of potential interactions is high, the number of observed interactions is relatively low. This is likely because of

underreporting and a lack of awareness. It may also indicate that theoretical interactions do not always manifest clinically. ■ Of significant concern to clinicians is the interaction between medications that prolong bleeding time, either directly or as an adverse

effect, and dietary supplements that potentiate or inhibit such medications. ■ When prescribing medications to a patient who has reported use of dietary supplements, access a peer-reviewed electronic database

to check for dietary supplement-drug interactions. • DECEMBER 2011 • 24(12) • JAAPA


REVIEW ARTICLE | Supplement-drug interactions TABLE 1. In vitro effects of herbal products on CYP450 microsomal enzymes18-20,22,23,42 CYP2C9 Herb









Echinacea Garlic










Yes Yes




Yes Yes



St. John’s wort




Valerian a








Ginsenosides F1, Rh1.

TABLE 2. Human in vivo effects of herbal products on CYP450 microsomal enzymes11,23,24,26,27,29,30-35,43 CYP2C9 Herb







Echinacea Garlic











Induce No














St. John’s wort



via the same pathways. St. John’s wort and ginkgo induced CYP2C19 at low concentrations but inhibited the enzyme at high concentrations during in vitro studies in cultured human hepatocytes.18 In vitro studies have found St. John’s wort to both induce and inhibit CYP3A4.19,20 What accounts for the discrepancy in results for the same herb? As compared with in vitro studies of prescriptiondrug effects on CYP450 enzymes, in vitro studies of herbalproduct effects have several significant limitations. Because the pharmacokinetics, such as bioavailability and first-pass metabolism of herbal products, are not well-characterized, predicting which real-life hepatic concentration of herbal product to use in the in vitro trials is difficult. There is also a lack of standardization of herbal products between manufacturers, and the resultant variability in herbal formulations adds to the difficulty of determining herbal pharmacokinetics.21 Therefore, in vitro studies of herbal-product effects on the CYP450 enzymes may yield variable results, as evidenced in the trials of ginkgo, St. John’s wort, and valerian noted in Table 1.18-20 46 JAAPA • DECEMBER 2011 • 24(12) •

Yes No








Yes Minimal effect


There is also a difference between in vitro and human in vivo results of pharmacokinetic effects on CYP450 enzymes as seen in a comparison of Table 1 and Table 2. For example, in vitro ginkgo and garlic each inhibit CYP2C9 but have no in vivo effect.22-24 Utilizing in vitro results for garlic and ginkgo would lead one to predict a potentiating effect on warfarin therapy, whereas in vivo results would indicate no interaction. However, garlic did not alter the pharmacokinetics of warfarin when coadministered in an open-label randomized crossover trial involving 12 healthy males, and ginkgo did not alter the pharmacokinetics of warfarin in 24 healthy subjects.24,25 In vitro garlic and ginkgo interactions with CYP2C9 also predict a potentiating effect on ibuprofen, indomethacin, and piroxicam and thus increased risk for hemorrhage, but in vivo results predict no interaction.17 Additionally, in vitro results for ginkgo predict an antagonistic effect on clopidogrel, which is metabolized to its active form via CYP3A4, whereas in vivo results predict no interaction.17,26 Echinacea has in vitro inhibitory effects on CYP2D6 and CYP3A4 but

REVIEW ARTICLE | Supplement-drug interactions TABLE 3. Clinically significant dietary supplement-drug interactions from human in vivo trials17,31-33,36, 44,45 Dietary supplement

Effect on drug


Decreases saquinavir


Decreases omeprazole

Ginseng (American)

Decreases warfarin


Increases (theoretical) antiarrhythmics, antiemetics, beta-blockers, neuroleptics, opioids, SSRIs, TCAs, macrolide antibiotics, statins, taxanes, cyclosporine, and other CYP3A4 substrates

St. John’s wort

Decreases benzodiazepines, cyclosporine, digoxin, ethinyl estradiol, fexofenadine, imatinib, indinavir, methadone, nifedipine, omeprazole, statins, TCAs, verapamil, warfarin

Key: SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant.

no in vivo effects on those enzymes.19,20,27 A review of drugechinacea interactions estimates that the risk of an adverse event is less than 1 in 100,000.28 Which herb-drug interactions are especially relevant in clinical practice? Significant in vivo effects on CYP enzymes from human clinical trials are (1) induction of CYP2C9, CYP2C19, and CYP3A4 by St. John’s wort,26,29,30 (2) inhibition of CYP2D6 and CYP3A4 by goldenseal,31,32 and (3) variable induction of CYP2C19 by ginkgo.33 The clinical significance of these findings is that • St. John’s wort should not be combined with most prescription medications • Goldenseal will theoretically cause an increase in the serum levels of drugs metabolized by CYP2D6, such as antidepressants and atypical antipsychotics, and by CYP3A4, such as statins and macrolide antibiotics17 • Ginkgo has been found to decrease the serum levels of omeprazole but not voriconazole or diazepam.33-35 In addition, garlic decreases saquinavir serum levels in healthy volunteers despite results seen in human in vivo trials that are negative for effects on CYP3A436 (Table 3). Two reputable Internet resources that describe the pharmacokinetics of dietary supplement-drug interactions are the Natural Medicines Comprehensive Database, available by subscription, and the Natural Standard Herb & Supplement database.37 POTENTIAL ROLE OF PHARMACOGENETICS

How does one account for case reports of adverse dietary supplement-drug interactions given the conflicting data from in vitro and in vivo pharmacodynamic and phar48 JAAPA • DECEMBER 2011 • 24(12) •

macokinetic research? Leaving aside the confounders of incomplete data on dosage, duration, dietary supplement formulation variability, and interactions with concomitant prescription medications, one can speculate about the role of pharmacogenetics. Patients with the variant CYP2C9*2 and CYP2C9*3 alleles are known to have reduced warfarin metabolism, resulting in an elevated international normalized ratio (INR).38 Glucosamine has been reported to increase the INR when taken concurrently with warfarin and would probably further exacerbate the risk for hemorrhage in those with variant CYP2C9 alleles.39 There are 72 different alleles of the CYP2D6 gene, and their effect on metabolism subdivides people into ultra, extensive, intermediate, or poor metabolizers.17 For example, the CYP2D6*4 allele occurs with a frequency of 20% to 25% and accounts for most (70%) of the poor metabolizers in Caucasians. CYP2D6*17 is more commonly found in Africans and accounts for most of the poor and intermediate metabolizers in this population.17 The clinical significance of the allelic variation is demonstrated by the projected decrease in metabolism of SSRIs and TCAs by poor metabolizers, which would result in higher plasma drug concentrations and a potentially higher incidence of adverse effects. The clinical significance of a dietary supplement-drug interaction in a poor metabolizer is exemplified by the ingestion of the herb goldenseal, which is an inhibitor of CYP2D6. In this scenario, the individual would likely develop an even more elevated SSRI or TCA plasma level and possibly be at greater risk for adverse effects, such as sexual dysfunction and orthostatic hypotension, respectively. The information on dietary supplement-drug interactions is highly variable even when referencing reputable databases.37 Case reports alert clinicians to a potential interaction but often lack complete data to draw a definitive conclusion. In vitro studies identify mechanisms of action for the interaction, but the results are confounded by incomplete knowledge of the supplement, especially herbal pharmacokinetics. Clinical trials of dietary supplement-drug interactions in healthy subjects based on known pharmacokinetics provide the most complete data but also have limitations when translating to patients with significant disease. Further research in pharmacogenetics will permit individualized analysis of dietary supplement-drug interactions. CONCLUSION

What are the best strategies for a physician assistant to incorporate in the management of a patient who is taking dietary supplements? 1. Ask the patient to bring all dietary supplements to the office visit. 2. Access a peer-reviewed electronic database of dietary supplement-drug interactions, such as the Natural Medicines Comprehensive Database, during the consultation. 3. Recommend discontinuation of the dietary supplement in any of the following circumstances: Interaction is

“When a dietary supplement-drug interaction is suspected, consider the etiology to better understand the potential effects in patients.” rated as “major” in the database; documentation of an adverse interaction is based on human in vivo trials; the patient’s symptoms match those occurring from interactions classified as “minor” or “moderate” in the database; or the patient is scheduled for surgery in 2 weeks (except for a low-dose multivitamin/mineral agent).40 4. Report adverse dietary supplement events to the FDA by phone at (800) FDA-1088 or online.41 5. Document potential minor and moderate interactions and provide pertinent patient education. 6. Recommend that patients select dietary supplements produced with Good Manufacturing Practices (GMP) verified by the United States Pharmacopeia (USP), National Sanitation Foundation (NSF), Natural Products Association (NPA), or Consumer Labs ( When a dietary supplement-drug interaction is suspected, be sure to consider the etiology based on the pharmacodynamic, pharmacokinetic, and pharmacogenetic properties in order to better understand the potential effects in patients. JAAPA John Laird is an associate professor in the PA program at Chatham University, Pittsburgh, Pennsylvania, and a naturopathic counselor at the Center for Integrative Medicine, University of Pittsburgh Medical Center-Shadyside Hospital. The author has indicated no relationships to disclose relating to the content of this article. REFERENCES 1. Overview of dietary supplements. FDA Web site. ConsumerInformation/ucm110417.htm. Updated November 9, 2009. Accessed Novmber 17, 2011. 2. Barnes PM, Bloom B, Nahin RL. Complementary and Alternative Medicine Use Among Adults and Children: United States, 2007. National health statistics reports; no 12. Hyattsville, MD: National Center for Health Statistics; 2008. 3. Gardiner P, Graham R, Legedza AT, et al. Factors associated with herbal therapy use by adults in the United States. Altern Ther Health Med. 2007;13(2):22-29. 4. Sood A, Sood R, Brinker FJ, et al. Potential for interactions between dietary supplements and prescription medications. Am J Med. 2008;121(3):207-211. 5. Qato DM, Alexander GC, Conti RM, et al. Use of prescription and over-the-counter medications and dietary supplements among older adults in the United States. JAMA. 2008;300(24): 2867-2878. 6. Nahin RL, Pecha M, Welmerink DB, et al. Concomitant use of prescription drugs and dietary supplements in ambulatory elderly people. J Am Geriatr Soc. 2009;57(7):1197-1205. 7. Gardiner P, Graham RE, Legedza AT, et al. Factors associated with dietary supplement use among prescription medication users. Arch Intern Med. 2006;166(18):1968-1974. 8. Bush TM, Rayburn KS, Holloway SW, et al. Adverse interactions between herbal and dietary substances and prescription medications: a clinical survey. Altern Ther Health Med. 2007; 13(2):30-35. 9. Haller CA, Kearney T, Bent S, et al. Dietary supplement adverse events: report of a one-year poison center surveillance project. J Med Toxicol. 2008;4(2):84-92. 10. Cavaliere C, Rea P, Lynch ME, et al. Herbal supplement sales experience slight increase in 2008. HerbalGram. 2009;82:58-61. 11. Borelli F, Capasso R, Izzo AA. Garlic (Allium sativum L.): adverse effects and drug interactions in humans. Mol Nutr Food Res. 2007;51(11):1386-1397. 12. Gravas S, Tzortzis V, Rountas C, et al. Extracorporeal shock-wave lithotripsy and garlic consumption: a lesson to learn. Urol Res. 2010;38(1):61-63.

13. Norred CL, Brinker F. Potential coagulation effects of preoperative complementary and alternative medicines. Altern Ther Health Med. 2001;7(6):58-67. 14. Bent S, Goldberg H, Padula A, Avins AL. Spontaneous bleeding associated with Ginkgo biloba: a case report and systematic review of the literature. J Gen Intern Med. 2005;20(7):657-661. 15. Beckart BW, Concannon MJ, Henry SL, et al. The effect of herbal medicines on platelet function: an in vivo experiment and review of the literature. Plast Reconstr Surg. 2007;120(7):2044-2050. 16. Gardner CD, Zehnder JL, Rigby AJ, et al. Effect of Ginkgo biloba (EGb 761) and aspirin on platelet aggregation and platelet function analysis among older adults at risk of cardiovascular disease: a randomized clinical trial. Blood Coagul Fibrinolysis. 2007;18(8):787-793. 17. Zhou SF, Liu JP, Chowbay B. Polymorphism of human cytochrome P450 enzymes and its clinical impact. Drug Metab Rev. 2009;41(2):289-295. 18. Hellum BH, Hu Z, Nilsen OG. Trade herbal products and induction of CYP2C19 and CYP2E1 in cultured human hepatocytes. Basic Clin Pharmacol Toxicol. 2009;105(1):58-63. 19. Hellum BH, Hu Z, Nilsen OG. The induction of CYP1A2, CYP2D6 and CYP3A4 by six trade herbal products in cultured primary human hepatocytes. Basic Clin Pharmacol Toxicol. 2007;100(1):23-30. 20. Hellum BH, Nilsen OG. In vitro inhibition of CYP3A4 metabolism and P-glycoprotein-mediated transport by trade herbal products. Basic Clin Pharmacol Toxicol. 2008;102(5):466-475. 21. Markowitz JS, von Moltke LL, Donovan JL. Predicting interactions between conventional medications and botanical products on the basis of in vitro investigations. Mol Nutr Food Res. 2008;52(7):747-754. 22. Foster BC, Foster MS, Vandenhoek S, et al. An in vitro evaluation of human cytochrome P450 3A4 and P-glycoprotein inhibition by garlic. J Pharm Pharm Sci. 2001;4(2):176-184. 23. Mohutsky MA, Anderson GD, Miller JW, Elmer GW. Ginkgo biloba: evaluation of CYP2C9 drug interactions in vitro and in vivo. Am J Ther. 2006;13(1):24-31. 24. Abdul MMI, Jiang X, Williams KM, et al. Pharmacodynamic interaction of warfarin with cranberry but not with garlic in healthy subjects. Br J Pharmacol. 2008;154(8):1691-1700. 25. Jiang X, Blair EY, McLachlan AJ. Investigation of the effects of herbal medicines on warfarin response in healthy subjects: a population pharmacokinetic-pharmacodynamic modeling approach. J Clin Pharmacol. 2006;46(11):1370-1378. 26. Gurley BJ, Gardner SF, Hubbard MA, et al. Cytochrome P450 phenotypic ratios for predicting herb-drug interactions in humans. Clin Pharmacol Ther. 2002;72(3):276-287. 27. Gurley BJ, Gardner SF, Hubbard MA, et al. In vivo assessment of botanical supplementation on human cytochrome P450 phenotypes: Citrus aurantium, Echinacea purpurea, milk thistle, and saw palmetto. Clin Pharmacol Ther. 2004;76(5):428-440. 28. Freeman C, Spelman K. A critical evaluation of drug interactions with Echinacea spp. Mol Nutr Food Res. 2008;52(7):789-798. 29. Xu H, Williams KM, Liauw WS, et al. Effects of St. John’s wort and CYP2C9 genotype on the pharmacokinetics and pharmacodynamics of gliclazide. Br J Pharmacol. 2008;153(7):1579-1586. 30. Wang LS, Zhu B, Abd El-Aty AM, et al. The influence of St. John’s wort on CYP2C19 activity with respect to genotype. J Clin Pharmacol. 2004;44(6):577-581. 31. Gurley BJ, Swain A, Hubbard MA, et al. Clinical assessment of CYP2D6-mediated herb-drug interactions in humans: effects of milk thistle, black cohosh, goldenseal, kava kava, St. John’s wort, and Echinacea. Mol Nutr Food Res. 2008;52(7):755-763. 32. Gurley BJ, Gardner SF, Hubbard MA, et al. In vivo effects of goldenseal, kava kava, black cohosh, and valerian on human cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 phenotypes. Clin Pharmacol Ther. 2005;77(5):415-426. 33. Yin OQ, Tomlinson B, Waye MM, et al. Pharmacogenetics and herb-drug interactions: experience with Ginkgo biloba and omeprazole. Pharmacogenetics. 2004;14(12):841-850. 34. Lei HP, Wang G, Wang LS, et al. Lack of effect of Ginkgo biloba on voriconazole pharmacokinetics in Chinese volunteers identified as CYP2C19 poor and extensive metabolizers. Ann Pharmacother. 2009;43(4):726-731. 35. Zuo XC, Zhang BK, Jia SJ, et al. Effects of Ginkgo biloba extracts on diazepam metabolism: a pharmacokinetic study in healthy Chinese male subjects. Eur J Clin Pharmacol. 2010;66(5): 503-509. 36. Piscitelli SC, Burstein AH, Welden N, et al. The effect of garlic supplements on the pharmacokinetics of saquinavir. Clin Infect Dis. 2002;34(2):234-238. 37. Faubert G, Lebel D, Bussières JF. A pilot study to compare natural health product-drug interactions in two databases in Canada. Pharm World Sci. 2010;32(2):179-186. 38. Glurich I, Burmester JK, Caldwell MD. Understanding the pharmacogenetic approach to warfarin dosing. Heart Fail Rev. 2010;15(3):239-248. 39. Knudsen JF, Sokol GH. Potential glucosamine-warfarin interaction resulting in increased international normalized ratio: case report and review of the literature and MedWatch database. Pharmacotherapy. 2008;28(4):540-548. 40. Ang-Lee MK, Moss J, Yuan CS. Herbal medicines and perioperative care. JAMA. 2001;286(2): 208-216. 41. Reporting by health professionals. FDA Web site. HowToReport/ucm085568.htm. Accessed November 9, 2011. 42. Etheridge AS, Black SR, Patel PR, et al. An in vitro evaluation of cytochrome P450 inhibition and P-glycoprotein interaction with goldenseal, Ginkgo biloba, grape seed, milk thistle, and ginseng extracts and their constituents. Planta Med. 2007;73(8):731-741. 43. Donovan JL, DeVane CL, Chavin KD, et al. Multiple night-time doses of valerian (Valeriana officinalis) had minimal effects on CYP3A4 activity and no effect on CYP2D6 activity in healthy volunteers. Drug Metab Dispos. 2004;32(12):1333-1336. 44. Yuan CS, Wei G, Dey L, et al. Brief communication: American ginseng reduces warfarin’s effect in healthy patients. Ann Intern Med. 2004;141(1):23-27. 45. Izzo AA, Ernst E. Interactions between herbal medicines and prescribed drugs: an updated systematic review. Drugs. 2009;69(13):1777-1798. • DECEMBER 2011 • 24(12) • JAAPA



The physician assistant workforce in Indiana: Preparing to meet future health care needs Jennifer Snyder, MPAS, PA-C, DFAAPA; Jennifer Zorn, MS, PA-C; Tom Gjerde, PhD; Jennifer Burkhart, PA-C; Lori Rosebrock, PA-C

ABSTRACT Objective: This study identifies baseline demographic and descriptive statistics for physician assistants (PAs) in Indiana from 1978 to 2010.

Methods: Data were obtained from Indiana Professional Licensing Agency applications, the Indiana State Department of Health, and PA educational programs. Descriptive statistics were used to characterize the PA workforce as well as their supervising physicians.

Results: Most PAs working in Indiana were born and educated outside the state. Of those educated in Indiana, 77% obtained an initial license in Indiana; as of May 2010, 62% were still licensed in the state. In the past 8 years, Indiana had a 97% increase in active licensed PAs. Only 24% of PAs work in primary care; 92% work in metropolitan areas. For 40 years, PAs have increasingly worked in areas that are


stablishing teams of physicians and nonphysician clinicians will help meet the needs of primary care patients covered by recently proposed changes in health care policy.1 In Indiana, physician assistants (PAs) have been in clinical practice since 1974.2 However, Indiana did not pass authorizing legislation until 1977.3 Current Indiana law requires that PAs graduate from an educational program recognized by the Accreditation Review Commission on the Education of Physician Assistants, that they pass a national certification examination, and that they apply to the Indiana Professional Licensing Agency (IPLA) for licensure to practice in the state. A second application must be submitted to the IPLA to obtain prescriptive privileges and a Controlled Substance Registration (CSR) when the applicant has met the following requirements: completed at least 30 contact hours in pharmacology from an approved educational program and worked as a PA for more than 1,800 hours. In Indiana, PAs must complete 100 hours of continuing medical education every 2 years, renew state licensure with the IPLA every 2 years, and take a national recertifying examination every 6 years to maintain state licensure. A physician may supervise a maximum of two PAs at any one time.4 Since 1974, three accredited institutions have graduated PAs in Indiana. The first program, which was offered by Indiana 50 JAAPA • DECEMBER 2011 • 24(12) •

medically underserved or experiencing a shortage of health professionals. However, the overall numbers of PAs working in those areas remain low.

Conclusions: More PAs in Indiana are practicing in medical specialties than in primary care. As health care policy and regulatory changes evolve, future studies will be needed to understand the impact on the health care workforce of Indiana PAs. This study will serve as a baseline for those studies.

When this article was written, the authors were affiliated with Butler University in Indianapolis, Indiana. Currently, Jennifer Snyder is an associate professor and Jennifer Zorn is an assistant professor in the Butler University College of Pharmacy and Health Sciences PA program, Indianapolis, Indiana. Tom Gjerde is assistant dean, Clark H. Byrum School of Business, Marian University, Indianapolis. Jennifer Burkhart is practicing family medicine and Lori Rosebrock is practicing emergency medicine, both in Indianapolis. The authors have indicated no relationships to disclose relating to the content of this article.

University (Fort Wayne), granted a certificate at completion of the curriculum, but the program closed in 1977. According to the Director of Medical Student Records, Indiana University School of Medicine (IUSOM), in Indianapolis, that program graduated 70 students (Dennis Deal, e-mail communication, May 26, 2010). While several Indiana universities are planning to start PA programs, two educational programs are currently in operation and have transitioned from a bachelor’s degree to a Master of Physician Assistant Studies degree: Butler University (Indianapolis) graduated 289 students with bachelor’s degrees (1996-2007) and 80 students with master’s degrees (2008-2009), and the Department of Physician Assistant Studies at the University of St. Francis (Fort Wayne; formerly Lutheran College) reports graduating 38 students with bachelor’s degrees (1997-2003) and 123 students with master’s degrees (2004-2009) (Dawn LaBarbera, PhD, PA-C, e-mail communication, May 12, 2010). The availability of primary care providers in Indiana is based on geographic, demographic, and socioeconomic factors and varies widely.5,6 Primary care is defined as family/ general medicine, general internal medicine, general pediatrics, geriatrics, and obstetrics and gynecology.7 While 40% of physicians who graduate from the Indiana University School of Medicine (IUSOM), in Indianapolis, choose a primary

PA workforce | RESEARCH REPORT FIGURE 1. Initially licensed female and male PAs in Indiana from 1978 to April 2010 by specialty

FIGURE 2. Percent change in initial license specialty by decade in Indiana


=Xd`cpD\[`Z`e\ >\e\iXc@D <d\i^\eZpD\[`Z`e\ >\e\iXcG\[`Xki`Zj >\e\iXcJli^\ip @D1:Xi[`fcf^p Fk_\i@DJlYj G\[`Xki`ZjJlYj Jli^1Fik_fg\[`Zj Jli^:M&:Xi[`fk_fiXZ`Z Jli^1E\lifcf^`ZXc Fk_\iJli^`ZXcJlYj FY&>pe FZZlgXk`feXcD\[`Z`e\ ;\idXkfcf^p Fk_\i $)'

>\e\iXc@D <d\i^\eZpD\[`Z`e\ >\e\iXcG\[`Xki`Zj >\e\iXcJli^\ip @D1:Xi[`fcf^p Fk_\i@DJlYj G\[`Xki`ZJlYj Jli^1Fik_fg\[`Zj Jli^:M&:Xi[`fk_fiXZ`Z Jli^1E\lifcf^`ZXc


Fk_\iJli^`ZXcJlYj FY&>pe


FZZlgXk`feXcD\[`Z`e\ ;\idXkfcf^p Fk_\i '






care specialty, one-half of graduates leave the state to practice medicine. Because the allopathic IUSOM is currently the only medical school in the state, a subcommittee of the Indiana University Health Reform Study Group concluded that the total number of practicing primary physicians in the state of Indiana by the year 2020 will be little impacted by increasing class size at IUSOM.5 In early 2010, plans were announced to develop an osteopathic medical school at Marian University in Indianapolis.8,9 This program is anticipating admission to its first class in August 2013. Similar to their physician counterparts, PAs across the country have been lured from primary to specialty and subspecialty care over the past 40 years.10 The impact of specialty care on the Indiana PA workforce is unknown. This study quantifies the number of Indiana PAs in primary care versus specialty care. The US Department of Health and Human Services defines health professional shortage areas (HPSAs) as “having a shortage of primary medical care, dental, or mental health providers”11 and medically underserved areas

.'jkf/'j /'jkf0'j 0'jkf''j








(MUAs) as areas that have high poverty rate, elderly population, infant mortality rate, or shortage of primary care providers.12 Fifty-six of the 92 counties (61%) in Indiana have been designated by the federal government in whole or in part as MUAs, and 39 (42%) were designated primary care HPSAs.12 The number of Indiana PAs who work in MUA/ HPSA areas is investigated in this study. The Bureau of Labor Statistics forecasts a 27% increase in the number of practicing PAs between 2006 and 2016, making the profession one of the fastest-growing occupations in the United States.13 The actual growth rate may be higher in Indiana than it is nationally given the fact that in July 2007, Indiana became the last state to authorize PA prescriptive privileges.14,15 This is particularly important considering that within 3 years of receiving prescriptive privileges in Texas, the number of PAs practicing in rural health clinics in that state tripled in a single year.16 The rapid increase in the number of PAs in the United States and the change in prescriptive law in Indiana highlight

TABLE 1. Distribution of PAs nationally and in Indiana, both initial applications and with an active license as of April 2010 Metro >1M


Nonmetro, adjacent to metro area

250K - 1M



2.5K - 20K

Nonmetro, not adjacent to metro area




2.5K - 20K

























































Indiana 2010c




















National physician assistant census report 2009, Research and Technology Services, American Academy of Physician Assistants All PAs granted an initial license by the Indiana Professional Licensing Agency. N=1,140; missing urban center code information for 89 licensed PAs c Physician assistants with active Indiana license through April 2010. N=770; n=436 b • DECEMBER 2011 • 24(12) • JAAPA


RESEARCH REPORT | PA workforce the importance of developing a set of baseline demographic and descriptive statistics associated with the profession. In addition, this study evaluates the number of Indiana PAs in primary care versus specialty care and the number of Indiana PAs who work in HPSAs and/or MUAs. The study also identifies the number of PAs with CSRs since being granted prescriptive authority. The beneficiaries of such a study include policy makers, employers, and educators, who will ultimately shoulder the responsibility of crafting future policy as the PA profession in Indiana evolves.

FIGURE 3. PAs licensed in Indiana by county


Blue: Number of PAs active in 2010 Red: Number of PAs issued an initial license, 1978 to April 2010

TABLE 2. Indiana PAs in primary and specialty care working in HPSAs and MUAs by initial license application, 1978 to 2010

Primary care



Percent (%)



















Specialty care



Key: HPSA, health professional shortage area; MUA, medically underserved area.

54 JAAPA • DECEMBER 2011 • 24(12) •

A database was developed through public domain documents obtained from initial applications to the IPLA from 1978 to May 2010, CSR applications, and Indiana State Department of Health renewal survey data. The information obtained included education, specialty, physician characteristics, prescribing privileges, and practice locations. Other practice information was verified through the National Commission on Certification of Physician Assistants (Johns Creek, Georgia), the American Academy of Physician Assistants (Alexandria, Virginia), Indiana University (Fort Wayne, Indiana), Butler University (Indianapolis, Indiana), and the University of St. Francis (Fort Wayne, Indiana). For the purpose of this study, primary care was defined as family practice, general internal medicine, general pediatrics, obstetrics and gynecology, and internal medicinepediatrics. Descriptive statistics and frequency counts were performed by Statistical Analysis Software (SAS), version 9.2. Approval was obtained from the Butler University Institutional Review Board. RESULTS Indiana PA demographics, 1978 to 2010 Through 2010,

1,140 PA licenses have been granted in Indiana. In 2010, the number of PAs with an active Indiana license was 770; 5 Indiana licenses were considered to be inactive. The median year of birth for all applicants was 1974, and the median year of graduation from a PA program was 2002. Figure 1 reveals that the ratio of practicing male-to-female PAs in Indiana fluctuated during the study period. In the past 10 years, gender ratios have remained steady as a higher percentage of women in a given year are applying to practice as PAs. Of the active licensed PAs in 2010, 505 (66%) were female and 265 (34%) were male. The percentage of Indiana PAs who renewed their license in 2008 and were working in primary care was 24%, whereas nationally, this figure was 37%.7 In Indiana, the largest percentage of PAs was working in an emergency medicine specialty (19%). This was followed closely by family medicine (18%), orthopedic surgery (17%), and other internal medicine subspecialties (17%). Female PAs have chosen to enter emergency and family medicine at higher ratios relative to female PAs in all other specialties, while male PAs have chosen to enter family medicine and orthopedic surgery at higher ratios (Figure 1).

In the past three decades, PA initial license applications were characterized by large shifts to medical specialties (Figure 2). The number of PAs in family medicine was relatively stable until the 2000s, but a particularly large shift occurred during the most recent decade. In that same time frame, the number of PAs increased overall and proportionally and PAs began to choose other medical specialties more often than primary care. As of 2010, 92% of practicing Indiana PAs worked in a metropolitan area; nationally, this same rate was 85% (Table 1).17 In Indiana, PAs currently work (in order of decreasing numbers), in Marion (n = 212), Allen (n = 107), Lake (n = 46), Hamilton (n = 39), Vanderburgh (n = 25), Hendricks (n = 22), and Monroe (n = 21) counties. Seventeen counties have never had a PA work within their borders; the remaining counties currently have fewer than 20 PAs (Figure 3). While the trend of initial license applications has continued to increase over time, the percentage of initial applications in both primary and specialty care in HPSAand/or MUA-designated locations remains low (Table 2). Supervising physician demographics Since 1978, 793 license applications have been filed with the IPLA to serve as a supervising physician. Of those physicians, 58% were educated outside Indiana. Ninety-four percent of physician supervisors attended an allopathic medical school; the remaining 6.0% were trained in an osteopathic school. Ninety-one percent of physician

TABLE 3. States of birth and education of PAs with an initial license in Indiana, 1978-2010 Born




Outside Indiana

Initial license (%) 24.0

Outside Indiana




Outside Indiana


supervisors have been male. Female and male physicians waited a median of 13 and 18 years, respectively, following graduation from medical school before choosing to supervise a PA. PA education in Indiana More PAs working in Indiana in 2010 were born and educated outside the state than were born and educated in Indiana (Table 3). Since 1978, the number of PAs who applied for a license to practice in Indiana has increasingly been educated there (Figure 4). Of Indiana-educated PAs, 77% applied for an initial license, and 62% were still active in Indiana in 2010. The percentage of graduates who obtained an initial license in Indiana was Indiana University (Fort Wayne), 67%; Butler University, 71%; and University of St. Francis, 94%. Of the PAs who practiced with an active license in 2010, 479 (62%) obtained a controlled substance registration. The rate of CSRs varied between educational programs (Table 4). Only

February 8-12, 2012 • Buena Vista Palace Resort & Spa • Lake Buena Vista, Florida HOTEL RESERVATIONS: 866-397-6516 • ROOM RATE: $169 (plus tax) single/double Great CME, our popular PA Professional Track, and hands-on workshops including Suture, ACLS, and BLS recertification. Plus, FAPA is recognized by the Board of Certification, Inc. to offer continuing education for certified athletic trainers.

ONLINE REGISTRATION IS NOW OPEN! Take advantage of early bird registration rates and register by January 6, 2012. Visit to register online and view the preliminary program!

RESEARCH REPORT | PA workforce FIGURE 4. PAs trained outside Indiana or within Indiana, by application year 1978-2010

Out of IN


St. Francis, Lutheran Butler IU Fort Wayne /'






































Note: PAs trained in Indiana at University of St. Francis, Butler University, or Indiana University (Fort Wayne).

two specialties, orthopedics and neurosurgery, had a greater percentage of PAs that can prescribe compared with those who cannot. DISCUSSION

Most PAs graduating from Indiana schools have continued working in the state. Additionally, Indiana has attracted a large number of PAs who were educated outside the state. These facts contributed to a 97% increase in the number of active licensed PAs in Indiana over the past 8 years. Nationally, 37% of PAs practice in primary care; 24% of Indiana’s PAs do. Further studies regarding cost-effective use of PAs in primary care may be beneficial. Despite nationwide statistics indicating that specialty occupations largely attract males to flexible work schedules compared with females (47.3% vs 24.7%, respectively), more female PAs in Indiana are entering the flexible work schedules offered in emergency medicine.18 Recent increases in the number of PAs entering emergency medicine are concurrent with more women entering the PA workforce. The PA program with the smallest ratio of graduates obtaining a CSR versus those not obtaining a CSR was Indiana University (Fort Wayne). Since graduating in the late 1970s, these PAs have been practicing in Indiana without prescriptive privileges and likely have developed unique practice relationships with their supervising physician to compensate. These 56 JAAPA • DECEMBER 2011 • 24(12) •

PAs may be close to retirement, may not believe it productive or necessary to adjust their practice relationship, or may not wish to take on the malpractice risk associated with prescribing rights. The second lowest ratio of PAs with a CSR versus those without a CSR included PAs trained outside Indiana. Given the impact of prescriptive authority in Texas and the impact on increased utilization of PAs with new prescriptive authority, future studies should monitor the changes over time. The planned opening of an osteopathic medical school in Indiana could have an impact on health care as well as PAs in the state. Future studies should be done to identify trends or changes in physician supervision patterns. CONCLUSION

Because of the rapid increase in the number of PAs, changes in prescriptive laws, and the opening of a number of new programs, identification of baseline statistics for the current workforce in Indiana is important. Even though 61% of Indiana counties are MUAs and 42% are HPSAs, PAs have an overall low rate of working in these areas (14% and 35%, respectively). With prescriptive authority, the numbers of PAs practicing in these areas may increase over time. This study shows that the national percentage of PAs practicing in primary care is 50% higher than the percentage of Indiana PAs practicing in primary care. This

TABLE 4. Number of controlled substance registrations (CSRs) by program


Frequency (n)


Ratio of CSR Yes to CSR No








Butler University







University of St. Francis







Program Indiana University—Fort Wayne

Outside Indiana







analysis will serve future trending studies and help shape workforce development, policy, educational resources, and legislative/regulatory issues regarding the PA profession in the state. Furthermore, health care reform has introduced the possibility that the number of primary care patients will grow at a more rapid rate than the number of primary care physicians. Indiana PA leaders, employers, and educators have an opportunity to identify policies that will direct PAs to primary care before rationing becomes an issue. Further studies will be needed to trend these data. JAAPA REFERENCES 1. Yarnall K, Østbye T, Krause K, et al. Family physicians as team leaders: “Time” to share the care. Last reviewed August 9, 2011. Accessed November 9, 2011. 2. Youtsey J, Bock W. Utilization of the physician’s assistant in Indiana. J Indiana State Med Assoc. 1975;68(7):639-641. 3. Indiana Academy of Physician Assistants. Chronology of Indiana physician assistant legislative and regulatory action. Published August 8, 2008. Accessed November 9, 2011. 4. Indiana Professional Licensing Agency, Indiana Physician Assistant Committee, Indiana Government Center—South. Indiana Physician Assistant Committee: a compilation of the Indiana code and Indiana administrative code. 2009 Edition. pdf. Published July 2009. Accessed November 9, 2011. 5. McKeag DB, Wright ER, Devine T, et al. Report of the Workforce and Workforce Development Subcommittee of the Indiana University Health Reform Study Group. Indianapolis, IN: Indiana Health Care Reform Study Group; October 2007.




6. Allen DI, Zollinger TW. Where Have All of the Doctors Gone? A Focus on Health Workforce Issues. January 24, 2008. Accessed on November 9, 2011. 7. American Academy of Physician Assistants. Primary Care. AAPA Web site. http://saaapa.aapa. org/advocacy-and-practice-resources/practice-resources/specialty-practice/594-primary-care. Accessed November 9, 2011. 8. Indiana Osteopathic Association. Welcome to the Indiana Osteopathic Association. http://www. Accessed November 9, 2011. 9. $30 Million Pledge to Start Indiana’s First College of Osteopathic Medicine - 1/14/2010. http:// Accessed November 9, 2011. 10. Cawley JF, Hooker RS, Leinweber W. Physician assistant specialization and career mobility. Presented at the 2009 Association of American Medical Colleges Workforce Research Conference; April 2009; Washington, DC. 11. US Department of Health and Human Services. Shortage designation: Health professional shortage areas & medically underserved areas/populations. Updated September 11, 2001. Accessed November 9, 2011. 12. Indiana State Department of Health. Reference materials. Accessed November 9, 2011. 13. Dohm A, Shniper L. Occupational employment projections to 2016. Monthly Labor Rev. 2007;130(11):86-125. 14. Indiana General Assembly. Information maintained by the Office of Code Revision Indiana Legislative Services Agency. Accessed November 9, 2011. 15. American Academy of Physician Assistants. Indiana Governor signs legislation allowing physician assistants to prescribe medicines. Published April 27, 2007. Accessed November 9, 2011. 16. Willis JB. Barriers to PA practice in primary care and rural medically underserved areas. JAAPA. 1993;6:418-422. 17. American Academy of Physician Assistants. National Physician Assistant Census Report. Research and Technology Services. AAPA Web site. Common/Files/National_Final_with_Graphics.pdf. Published 2009. Accessed November 9, 2011. 18. Beers T. Flexible schedules and shift work: replacing the ‘9-to-5’ workday? Monthly Labor Rev. 2000;123(6):33-40.

Take the JAAPA 25th Anniversary Challenge! 2012 is JAAPA’s 25th anniversary year, and we invite you to help us celebrate … all year long! Each month we’ll pose a different challenge, and each month we’ll pick the best response. The winner will receive a $100 gift card. The January Challenge: What is the most important medical advance of the past 25 years? Tell us in 100 words or less, and e-mail your answer to no later than January 31, 2012. (Note that you must be a PA to enter.) And don’t forget to visit in January for more details of our 25th anniversary celebration! • DECEMBER 2011 • 24(12) • JAAPA



EARN CATEGORY I CME CREDIT by reading this article and the article beginning on page 30 and successfully completing the posttest on page 64. 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 December 2011.


Discuss the physical consequences that occur as a result of childhood obesity Review the psychological consequences of childhood obesity Discuss preventive strategies for childhood obesity Explain management strategies for childhood obesity

Childhood obesity: Complications, prevention strategies, treatment Obese children are at risk of acquiring a multitude of complications, and comorbidities of obesity may also leave them at risk for cardiovascular disease and stroke in adulthood.

Georgina A. Robinson, PA-C; Megan Geier; Denise Rizzolo, PA-C, PhD; Mona Sedrak, PA-C, PhD


n estimated 16.9% of children 2 to 19 years old in the United States are obese.1 In addition, the number of overweight and obese children has increased in almost all industrialized countries worldwide and in several lower-income countries.2 The epidemic of obesity is linked to a rise in other serious diseases and disorders in children, including insulin resistance, hypertension, cardiovascular disease, hyperlipidemia, and poor self-esteem.3 Given the increasing prevalence of childhood obesity and its related disorders, as well as the growing emphasis on exercise and proper nutrition in the medical literature and the media, clinicians must take an active role in recognizing, preventing, and managing childhood obesity. Approximately 80% of 10- to 15-year-olds who are overweight become obese adults by the age of 25 years.4 Obesity in children has the potential to cause significant physiologic and psychosocial complications that, if not managed in childhood, will lead to negative health consequences in adulthood.3 Physical complications can involve the cardiovascular, endocrine, GI, musculoskeletal, nervous, and respiratory systems. This article discusses the consequences and comorbidities of childhood obesity, treatment strategies, and when referral should be made. Cardiovascular consequences As a result of the increase in childhood obesity leading to adult obesity, the prevalence of coronary heart disease (CHD) is estimated to increase 5% to 16% by 2035, with more than 100,000 cases of CHD 58 JAAPA • DECEMBER 2011 • 24(12) •

© Michele Graham


The consequences of untreated obesity in childhood can lead to diseases of the cardiovascular, pulmonary, GI, musculoskeletal, and endocrine systems in adulthood.

attributed to the predicted increase in obesity.5 Obesity predisposes humans to changes in both cardiac structure and hemodynamics.6 Combined with excessive adiposity, obesity causes increased blood volume and cardiac output and can lead to cardiomyopathy. Two of the most common cardiac comorbidities of childhood obesity are dyslipidemia and hypertension. According to results of the National Health and Nutrition Examination Survey (NHANES) for 1999 to 2006, the prevalence of dyslipidemia in children 12 to 19 years old was 20.3%.7 Typically, in obese children, serum low-density lipoprotein cholesterol (LDL-C) and triglycerides are increased and high-density lipoprotein cholesterol (HDL-C) levels are decreased.8 The proposed mechanism of dyslipidemia in obese children is an increase in free fatty acids produced by visceral adipocytes and hyperinsulinemia that promotes LDL-C and triglyceride synthesis by the liver.8 Fasting lipid profiles should be obtained every 2 years starting at age 10 years in patients whose body mass index (BMI) is in the 85th percentile or higher, regardless of risk factors.6 More information on specific levels and treatment can be found in Table: Comorbidities of childhood obesity and their findings, diagnostic workup, and treatment in the online version of

this article. The mainstay of treatment for dyslipidemia is diet and exercise; however, appropriate referral should be made if conservative measures are not effective.9 Although hypertension is relatively rare in children, obese children have a threefold higher risk of hypertension than nonobese children.10 Contributing factors for hypertension in an obese child include hyperactivity of the sympathetic nervous system, insulin resistance, and abnormalities in vascular structure and function.10 Diagnosis of hypertension in children is based on BP tables that are adjusted for age, gender, and height.10 Hypertension is considered when a child has three systolic or diastolic BP readings above the 95th percentile.10 Treatment of hypertension in children should be aimed at behavioral approaches, such as diet and exercise, followed by medication in more refractory cases.10 While metabolic syndrome is common in obese adults and criteria for diagnosis in adults exist (Table 1), there are currently no criteria to diagnose metabolic syndrome in children.11,12 However, using modified adult criteria, the overall prevalence of metabolic syndrome is 38.7% in

SEE THE ONLINE VERSION OF THIS ARTICLE TO LINK TO NHLBI blood pressure tables for children and adolescents child_tbl.pdf

moderately obese children and 49.7% in severely obese children.11 Treatment consists of addressing dyslipidemia, hypertension, and type 2 diabetes mellitus (T2DM).6 Endocrine complications Because sex hormone-producing enzymes are expressed in adipose tissue, excess central adiposity can lead to high androgen activity or hyperandrogenemia.6 Up to 50% of free testosterone is derived from fat in young women.6 Hyperandrogenemia and abdominal obesity lead to hyperinsulinemia and insulin resistance, which stimulates androgen and estrogen production by the adrenal glands and the ovaries.6 In addition, lower concentrations of sex hormone-binding globulin (SHBG) in obese females lead to further increases in the levels of free testosterone.6 This increase in testosterone can result in menstrual abnormalities, such as amenorrhea, metrorrhagia, and polycystic ovary syndrome, in obese adolescent girls.6 Obese girls who experience hormone imbalance should be referred to a specialist in order to preserve fertility.9 Over the past two decades, the number of children with a diagnosis of type 2 diabetes mellitus, a disease that previously affected only adults, has increased 10-fold.13 Children who develop T2DM are at risk for microvascular and macrovascular changes, including retinopathy, nephropathy, neuropathy, and atherosclerosis, at younger ages than those who develop the disease later in life.6,13 Puberty is associated with increased secretion of growth hormone, which promotes a transient state of insulin resistance. Therefore, puberty increases a child’s risk of progressing from insulin resistance to frank diabetes.13 Children should be screened for T2DM if their calculated BMI is in the 85th percentile or higher for age and gender and they have additional risk factors for T2DM, such as family history or signs of insulin resistance.13 The diagnostic process for type 2 diabetes mellitus in children is the same as that for adults: fasting or random blood glucose

KEY POINTS ■ Unmanaged obesity in children has the potential to cause significant physiologic and psychosocial complications that can lead to

negative health consequences in adulthood. ■ No exact guidelines exist for when to start treatment. Because obesity can have such negative consequences, a wait-and-see approach

is strongly discouraged. ■ Maintaining current body weight while the child continues to grow should be the goal for the large majority of obese children. Only in

children with severe obesity should weight loss be encouraged. ■ Only adolescents who have not lost weight through lifestyle modifications should be considered for medication use and even then only

when the adolescent has other comorbidities and is continuing to adhere to the previously discussed diet and exercise interventions. • DECEMBER 2011 • 24(12) • JAAPA


CME Childhood obesity, part 2 measurements or oral glucose tolerance testing along with a glycosylated hemoglobin (A1C) determination.13 Treatment depends on the severity of the disease and starts with lifestyle modifications and/or metformin when the fasting blood glucose is between 126 and 200 mg/dL.13 Insulin therapy should begin in those children with a fasting glucose level greater than 200 mg/dL.13 Insulin should also be added when control cannot be achieved after 3 to 6 months of metformin therapy.13 As in adults, target glucose levels for children are between 70 and 100 mg/dL, A1C ranges should be below 6.5% or 7%, and renal function tests and a dilated retinal examination are required yearly.13 Ultimately, to reach their therapeutic goal, children with T2DM are best treated by a multispecialty team. GI effects Obesity, metabolic syndrome, and hyperinsulinemia are all risk factors for the development of cholelithiasis. Therefore, gallbladder disease should be part of the differential diagnosis for an obese adolescent with persistent right upper quadrant pain.6 With an incidence of one in every three obese children, nonalcoholic fatty liver disease (NAFLD), or hepatic steatosis, is becoming more common.3,8 Although most cases are benign, the disease may result in increasing fibrosis and can rarely lead to cirrhosis.6 In NAFLD, the hepatic aminotransferase levels are often elevated as much as four- to fivefold, and the alkaline phosphatase level is generally elevated threefold.6 Liver function testing should be ordered every 2 years starting at age 10 years for children with a BMI in the 95th percentile or higher and in those with a BMI in the 85th to 94th percentile who have risk factors.9 Weight reduction leads to improvement in liver function and histologic features.9 Appropriate referral should be made when ALT or AST results are two times normal values on two different occasions.9 Musculoskeletal complications Overweight and obese children are at greater risk of orthopedic complications than are normal weight children.14,15 Moreover, overweight children show a greater prevalence for fractures (hips), musculoskeletal discomfort, impaired mobility, and lowerextremity malalignment.14 Obesity that continues into adulthood can lead to osteoarthritis and articular cartilage breakdown.14 Childhood obesity can also predispose to several specific orthopedic problems, including slipped capital femoral epiphysis (SCFE) and Blount disease. SCFE results when the force of the capital femoral growth plate increases and the femoral head suddenly separates with an epiphyseal cartilage crack or when chronic force gradually causes a slip. The greater force is often caused by increased body mass.15 A slipped capital femoral epiphysis may cause hip or knee pain and decreased range of motion in the affected hip.9 Blount disease, or tibia vara, is a growth disorder of the tibia caused by overgrowth of the medial aspect of the proximal tibia that causes the lower leg to angle inward.3,8 Because overweight and obese children are more likely to have orthopedic complications, including discomfort with mobility, they also may be less likely to engage in physi60 JAAPA â&#x20AC;˘ DECEMBER 2011 â&#x20AC;˘ 24(12) â&#x20AC;˘

TABLE 1. NCEP ATP III criteria for adult metabolic syndrome12 Characteristic




>130/85 mm Hg

>130/85 mm Hg

Fasting plasma glucose

>100 mg/dL

>100 mg/dL


<40 mg/dL

<50 mg/dL


>150 mg/dL

>150 mg/dL

Waist circumference

>102 cm

>88 cm

Key: HDL-C, high-density lipoprotein cholesterol; NCEP ATP III, National Cholesterol Education Program Adult Treatment Panel III.

cal activity, thus perpetuating the accumulation of excess weight.14 Psychological impact In 2000, Strauss found that obese Hispanic and white females showed decreased levels of global self-esteem compared with their nonobese counterparts.16 The researchers also found that decreases in selfesteem in obese children led to increased rates of sadness, loneliness, and nervousness. Further, children with these problems were more likely to smoke and drink alcohol.16 Obese children are also more likely to be socially isolated and have higher rates of eating disorders, such as binge eating, as well as anxiety and depression.3 At an early age, children associate obesity with negative characteristics, such as laziness and lower intelligence levels.6 This perception can lead to discrimination toward obese children, which can have negative effects later in life.17 Females who were overweight during adolescence complete fewer years of school, are less likely to be married, and have lower household incomes than those who were not overweight during adolescence.17 Also, males who were overweight during adolescence are less likely to be married.17 Respiratory complications Over the past two decades, there has been an increase in prevalence of both asthma and obesity.2,18 From 1980 to 1994, the prevalence of asthma increased 75%.18 While the increasing rates were evident among all races, ages, and sexes, there was a substantial increase among children aged 0 to 4 years (160%) and children aged 5 to 14 years (74%).18 No cause-and-effect relationship between asthma and obesity has been clearly established, but the simultaneous increase in both conditions has led researchers to examine whether there is a link. Possible mechanisms for the development of asthma include diet, gastroesophageal reflux, mechanical effects of obesity, atopy, and hormonal influences.6,19 Symptoms of asthma in obese children are the same as in nonobese children. Pulmonary function testing should be performed on children who are suspected of being asthmatic.9 Treatment is the same as for nonobese children; however, guidance should be provided regarding physical activity so as to not limit the amount of exercise the child does.9 Characterized by episodes of apnea and hypoapnea during sleep, obstructive sleep apnea (OSA) is four to six times

more likely to develop in obese children as it is in children of normal weight.20 OSA is an important risk factor, as its presence in adults is associated with the development of hypertension, cardiovascular disease, cerebrovascular disease, and poor quality of life. In addition, obstructive sleep apnea may contribute to pulmonary arterial hypertension.20 Symptoms of daytime sleepiness, snoring, and nocturnal enuresis can all be symptoms of OSA in children.20 The definitive test for OSA is polysomnography. The diagnosis is confirmed when the apnea-hypoapnea index is five or more incidents per hour.9,20 Treatment consists of adenotonsillectomy for patients with tonsillar or adenoid hypertrophy and referral to a pulmonologist if the surgery is not effective in relieving symptoms.9,20 PREVENTING CHILDHOOD OBESITY

Interventions for childhood obesity should be implemented early, with prevention being the primary goal for all children.21 Obesity and the risk factors for its development should be addressed at all well-child visits.22 Even infants can overeat.23 Parents should be educated on healthy eating

“Teaching portion control, with emphasis on fruits, vegetables, and whole grains, is the mainstay of a healthy and balanced diet.” habits for infants and children. In its 2005 statement on childhood obesity, the Obesity Consensus Working Group put forth a number of suggestions for parents and families, health care providers, schools, local communities, and government and regulatory agencies.6 Parents and families The working group suggested breastfeeding infants for at least 3 months and delaying the introduction of solid foods and sweet liquids.6 Pregnant women might reduce the risk of obesity for their unborn child by normalizing their body mass index before they conceive; not smoking; and exercising moderately, if possible.6 Patients with gestational diabetes should maintain strict glucose control.6 Among the preventive steps that families can take are (1) eating meals at a set time and place; (2) not skipping meals, particularly breakfast; (3) turning off the television at mealtime; (4) using small plates and keeping serving dishes on a counter or somewhere else away from the table; (5) avoiding sweet or fatty foods and soft drinks; (6) not allowing televisions in children’s bedrooms; and (7) limiting the time children are allowed to watch television or play video games.6 Health care providers One suggestion is to educate patients and parents about age-appropriate weight for children and the biological and genetic factors that contribute to obesity.6 In addition, working toward having childhood

obesity classified as a disease will promote recognition of the problem and encourage reimbursement for care and a willingness to provide treatment.6 Schools and communities On a broader basis, schools and the local community can help prevent childhood obesity too. Schools can (1) avoid using cookie and candy sales as fundraisers, (2) make sure vending machines contain healthy choices, (3) educate teachers and students about basic nutrition and the benefits of physical activity, and (4) mandate minimum standards for physical education.6 For their part, communities can increase family-friendly play and exercise facilities, discourage the use of elevators and moving walkways, and provide information on preparing healthier meals.6 Industry The food industry could be called upon to provide age-appropriate nutritional labeling for children or use celebrities in advertising to promote regular meals. For its part, the toy industry might produce interactive video games that require children to exercise while they play.6 Government and regulatory agencies Preventive approaches proposed for government and regulatory agencies include limiting food-related advertising to children and allowing tax deductions for the cost of weight loss and exercise programs.6 The working group also called for government support to classify childhood obesity as a disease. TREATMENT

If prevention fails, treatment should be initiated. Lifestyle and behavioral modifications are the focus of treatment for childhood obesity.23 Medication and bariatric surgery can be considered but should be reserved for more severe, refractory cases.23-25 Moreover, treatment should be individualized according to the child’s age, weight, and current health status. No exact guidelines exist for when to start treatment.24 Because obesity can have such negative consequences, a wait-and-see approach is strongly discouraged.24 Lifestyle modification Incorporating diet, exercise, or behavioral modifications and/or the combination of the three comprise first-line treatment for all children.23 Laying a good foundation for a healthy, well-balanced diet combined with adequate physical activity is the goal of prevention along with treatment. Additionally, the aim of treatment is to educate the child on how to continue this lifestyle into adulthood. Maintaining current body weight while the child continues to grow should be the goal for the large majority of obese children. Only in children with severe obesity should weight loss be encouraged.23,24 Continued on page 62

ONLINE EXTRAS AT • Table: Comorbidities of childhood obesity and their findings, diagnostic workup, and treatment • DECEMBER 2011 • 24(12) • JAAPA


CME Childhood obesity, part 2 Diets differ in structure and content, but whatever dietary intervention is used, reducing total caloric intake is the goal.25 Diets range from being low-calorie to low-fat to lowcarbohydrate to low-glycemic-index, with no one diet being more successful than another.26 Teaching portion control, with emphasis on fruits, vegetables, and whole grains, is the mainstay of a healthy well-balanced diet.26 Sweetened beverages, empty-calorie sweets, and overly processed food should be eliminated from the diets of all overweight and obese children.23,27 Exercise is a key component in the treatment of obesity. While exercise alone can reduce weight, a child who stops the activity will regain the weight.25 In addition to weight loss, exercise has improved metabolic risk factors (ie, hypertension, hyperlipidemia, and T2DM).25 Physical exercise has led to lower lipid levels, reduced BP, increased bone mass and density, reduced depression and anxiety, and improved self-esteem.28 For children who are sedentary, exercise should be started slowly and increased gradually. Recommendations call for a child to exercise between 20 and 30 minutes a day in addition to the physical activity

“Obese adolescents who have failed to lose weight through lifestyle modifications should be considered for medication use.” included in the school day.28 “The President’s Challenge” is a good motivational tool used to get kids 6 to 17 years old to be active. The goal of the challenge is for the child to be active for 60 minutes a day for at least 5 days a week for 6 out of 8 weeks.29 Alternatively, the child can wear a pedometer and aim for a goal of 11,000 steps per day for girls and 13,000 steps per day for boys.29 Sedentary lifestyles are becoming more and more common in the American population. The time the child spends in front of a screen (TV or computer) should be limited to less than 1 hour a day.30 Behavioral modification is aimed at changing behaviors that contribute to excess weight. Initiation of new dietary and physical activity behaviors as previously discussed will help the child lose weight.23,28 Education on nutrition should be addressed to the child and parents. A study done by Golan and Crow showed a significant difference in weight loss by children whose parents were involved and participated in the treatment modalities (diet, exercise, and behavioral modification) compared with those children whose parents were not involved.31 Having children complete a food diary allows them to become aware of what they are consuming.23 Studies suggest that eating together as a family at the table promotes healthier eating habits.22,23,26,27 Parents should limit fatty foods in the house and incorporate healthy meals for the whole family. Physical activity logs should also be 62 JAAPA • DECEMBER 2011 • 24(12) •

kept.32 Setting reasonable goals and tracking weekly progress will allow children to become responsible for their own treatment. Verbal praise and tangible rewards (excluding food) will keep the child motivated.28 A recent Cochrane review deduced that no one weightmanagement program has been proven superior to the others; however, a combined behavioral therapy/lifestyle intervention appears to have an advantage over standard, self-care dietary or activity interventions.33 Encouraging all members of the family to get involved and change their everyday lives will benefit not only the obese child, but also the entire family unit.23,27 Each overweight/obese child’s treatment strategy will differ. The clinician should tailor the approach based on the patient’s age, family involvement, socioeconomic status of the family, and current health status of the child.28 Recommendations can be modified for patients who are very young, patients with a low income, and patients who are severely obese with multiple health complications.9 Medications Only adolescents who have failed to lose weight through lifestyle modifications should be considered for medication use and even then only when the adolescent has other comorbidities and is continuing to adhere to the previously discussed diet and exercise interventions.24 A child for whom all other attempts to lose weight have failed should be referred to an obesity treatment center, where specialized health care providers can tailor their treatments.9 The two drugs currently considered for treatment of pediatric obesity are orlistat (Xenical, Alli) and metformin.24 Orlistat is the suggested first-line drug for obesity unresponsive to lifestyle modifications and is FDA approved for patients 12 years and older.24 Orlistat interferes with intestinal fat absorption and has a relatively low side-effect profile, with most patients complaining only of oily stools and flatulence. Metformin is FDA approved for the treatment of T2DM in children 10 years or older.13 Metformin has also stabilized weight or led to small reductions in weight in diabetic and nondiabetic adults.34 National Health and Medical Research Council guidelines state that metformin has a potential role in the treatment of adolescents and should be considered for obese adolescents with significant hyperinsulinemia and a family history of diabetes.34,35 Concurrent use of a multivitamin is suggested because of the effects of metformin on excretion of vitamins B1 and B6.34,35 Long-term studies currently under way will hopefully define the effects of metformin treatment on obesity-related disease risks in this population.9 Bariatric surgery The caloric intake of a person who undergoes bariatric surgery is reduced via restrictive or malabsorptive actions on the GI tract. Roux-en-Y gastric bypass and laparoscopic adjustable gastric banding are the two main procedures.36 Use of bariatric surgery is highly controversial in the youth population. Consideration of bariatric surgery is recommended only for those adolescents who are finished growing and who have severe, high-risk obesity. Children being considered for surgery must be

assessed by a multidisciplinary team and undergo medical, dietary, and psychological evaluations to determine if they are fit for surgery.37 CONCLUSION

Obese children are at risk of acquiring a multitude of complications,3 and comorbidities of obesity may also leave children at risk for cardiovascular disease and stroke in adulthood.6 Promoting healthy habits in young children to prevent childhood obesity and the medical consequences it brings is essential. Diet, exercise, and behavioral modification should serve as first-line therapy for overweight and obese children.23 Medication and surgery are reserved for severe, refractory cases.24,37 Considering that almost 17% of children in the United States are obese, the complications, prevention, and treatment of childhood obesity will remain the subject of research for years to come.1 JAAPA Georgina Robinson and Megan Geier are former students in the Seton Hall University PA program in South Orange, New Jersey. Georgina Robinson is a hospitalist PA at Evangelical Community Hospital in Lewisburg, Pennsylvania. Denise Rizzolo is an associate professor in the Seton Hall PA program and works at the Care Station in Springfield, New Jersey. Mona Sedrak is an associate professor and program director of the Seton Hall PA program. The authors have indicated no relationships to disclose relating to the content of this article. REFERENCES 1. Ogden CL, Carroll MD, Curtin LR, et al. Prevalence of high body mass index in US children and adolescents, 2007-2008. JAMA. 2010;303(3):242-249. 2. Wang Y, Lobstein T. Worldwide trends in childhood overweight and obesity. Int J Pediatr Obes. 2006;1(1):11-25. 3. Ludwig DS. Childhood obesity—the shape of things to come. N Engl J Med. 2007;357(23): 2325-2327. 4. Whitaker RC, Wright JA, Pepe MS, et al. Predicting obesity in young adulthood from childhood and parental obesity. N Engl J Med. 1997;337(13):869-873. 5. Bibbins-Domingo K, Coxson P, Pletcher MJ, et al. Adolescent overweight and future adult coronary heart disease. N Engl J Med. 2007;357(23):2371-2379. 6. Speiser PW, Rudolf MC, Anhalt H, et al. Consensus statement: childhood obesity. J Clin Endocrinol Metab. 2005;90(3):1871-1887. 7. Centers for Disease Control and Prevention. Prevalence of abnormal lipid levels among youths— United States, 1999-2006. MMWR Morb Mortal Wkly Rep. 2010;59(2):29-33. 8. Dietz WH. Health consequences of obesity in youth: childhood predictors of adult disease. Pediatrics. 1998;101(3 pt 2):518-525. 9. Barlow SE; Expert Committee. Expert committee recommendations regarding the prevention, assessment, and treatment of child and adolescent overweight and obesity: summary report. Pediatrics. 2007;120(suppl 4);S164-S192. 10. Sorof J, Daniels S. Obesity hypertension in children: a problem of epidemic proportions. Hypertension. 2002;40:441-447.

11. Weiss R, Dziura J, Burgert TS, et al. Obesity and the metabolic syndrome in children and adolescents. N Engl J Med. 2004;350(23):2362-2374. 12. Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III): Executive Summary. Bethesda, MD: National Heart, Lung, and Blood Institute; 2001. NIH publication no. 01-3670. 13. Hannon TS, Rao G, Arslanian SA. Childhood obesity and type 2 diabetes mellitus. Pediatrics. 2005;116(2):473-480. 14. Taylor ED, Theim KR, Mirch MC, et al. Orthopedic complications of overweight in children and adolescents. Pediatrics. 2006;117(6):2167-2174. 15. Wills M. Orthopedic complications of childhood obesity. Pediatr Phys Ther. 2004;16(4):230-235. 16. Strauss RS. Childhood obesity and self-esteem. Pediatrics. 2000;105(1):e15. 17. Gortmaker SL, Must A, Perrin JM, et al. Social and economic consequences of overweight in adolescence and young adulthood. N Engl J Med. 1993;329(14):1008-1012. 18. Mannino DM, Homa DM, Pertowski CA, et al. Surveillance for asthma—United States, 1960-1995. MMWR Surveill Summ. 1998;47(SS-1):1-28. 19. Flaherman V, Rutherford GW. A meta-analysis of the effect of high weight on asthma. Arch Dis Child. 2006;91(4):334-339. 20. Young T, Peppard PE, Gottlieb DJ. Epidemiology of obstructive sleep apnea: a population health perspective. Am J Respir Crit Care Med. 2002;165(9):1217-1239. 21. Wang G, Dietz WH. Economic burden of obesity in youths aged 6 to 17 years: 1979-1999. Pediatrics. 2002;109(5):e81. 22. Barnerss L, ed. Pediatric Nutrition Handbook. 3d ed. Elk Grove Village, IL: American Academy of Pediatrics; 1993. 23. Moran R. Evaluation and treatment of childhood obesity. Am Fam Physician. 1999;59(4):862-868, 871-873. 24. Uli N, Sundararajan S, Cuttler L. Treatment of childhood obesity. Curr Opin Endocrinol Diabetes Obes. 2008;15(1):37-47. 25. Nemet D, Barkan S, Epstein Y, et al. Short- and long-term beneficial effects of a combined dietary-behavioral-physical activity intervention for the treatment of childhood obesity. Pediatrics. 2005;115;e443-e449. 26. Collins CE, Warren J, Neve M, et al. Measuring effectiveness of dietetic interventions in child obesity: a systematic review of randomized trials. Arch Pediatr Adolesc Med. 2006;160(9):906-922. 27. Let’s Move: America’s Move to Raise a Healthier Generation of Kids. Accessed November 8, 2011. 28. Davis MM, Gance-Cleveland B, Hassink S, et al. Recommendations for prevention of childhood obesity. Pediatrics. 2007:120(suppl 4);S229-S253. 29. The President’s Council on Fitness, Sports, & Nutrition. The President’s Challenge. http://www. Accessed November 17, 2011. 30. Dietz WH Jr, Gortmaker SL. Do we fatten our children at the television set? Obesity and television viewing in children and adolescents. Pediatrics. 1985;75(5):807-812. 31. Golan M, Crow S. Targeting parents exclusively in the treatment of childhood obesity: long-term results. Obes Res. 2004;12(2):357-361. 32. Williams CL, Campanaro LA, Squillace M, Bollella M. Management of childhood obesity in pediatric practice. Ann N Y Acad Sci. 1997;817:225-240. 33. Oude Luttikhuis H, Baur L, Jansen H, et al. Interventions for treating obesity in children. Cochrane Database Syst Rev. 2009;(1):CD001872. 34. DeBusk B. Metformin plus weight loss intervention reduces symptoms of metabolic syndrome in obese children. Published June 20, 2008. Accessed November 8, 2011. 35. Batch J, Baur L. Management and prevention of obesity and its complications in children and adolescents. Med J Aust. 2005;182(3):130-135. 36. Gastrointestinal surgery for severe obesity: National Institutes of Health Consensus Development Conference Statement. Am J Clin Nutr. 1992;55(suppl 2):615S-619S. 37. Apovian CM, Baker C, Ludwig DS, et al. Best practice guidelines in pediatric/adolescent weight loss surgery. Obes Res. 2005;13(2):274-282.

V Visit to read more CME articles online. C Choose CME on the main navigation bar. Ch • DECEMBER 2011 • 24(12) • JAAPA


TABLE: Comorbidities of childhood obesity and their findings, diagnostic workup, and treatment Condition


Diagnostic workup




• Fasting lipid profile every 2 y, starting at age 10 y when BMI is ≥85th percentile regardless of risk factors • Total cholesterol levels ≥200 mg/ dL and LDL-C levels ≥130 mg/dL are considered high • Triglyceride levels ≥110 mg/dL and HDL-C levels ≤40 mg/dL are considered abnormal

• Reduced-fat and reduced-cholesterol diets • Physical activity • If lipid levels do not respond to diet changes, refer to a pediatric cardiologist or lipid specialist


Elevated BP

Systolic or diastolic BP adjusted for age, gender, and height >95th percentile on three or more occasions is considered hypertension.

Behavioral approaches: diet and exercise to induce weight loss; orlistat may be tried in severe cases in patients ≥12 y

Metabolic syndrome

Central adiposity, xanthoma, acanthosis nigricans

• Waist circumference, lipid profile, BP, fasting glucose • No pediatric criteria; diagnosis is based on adult criteria.

See treatment for dyslipidemia, hypertension, and T2DM


Amenorrhea, irregular menses (<9 cycles/y), hirsutism, severe acne, acanthosis nigricans

Hormone testing consisting of total and free testosterone, insulin, LH, FSH, DHEAS, SHBG

• Refer to endocrinologist or gynecologist to initiate and monitor treatment to protect fertility • Weight reduction


Acanthosis nigricans, polyuria, polydipsia, unexpected weight loss

• Screening begins at puberty or age 10 y and is repeated every 2 y when BMI is ≥95th percentile or BMI is ≥85th percentile in a child with two additional risk factors, such as family history or signs of insulin resistance • Diagnosis is made with fasting glucose, random glucose, or oral glucose tolerance test • A1C determination should also be ordered every 3 mo, with the goal being <6.5% or 7% • Children with T2DM should have yearly renal function testing and retinal examinations

• Patients with a fasting glucose level ≥126 mg/dL or a random glucose level ≥200 mg/dL should be referred to a pediatric endocrinologist • Fasting glucose levels of 126-200 mg/ dL and A1C <8.5% treated with lifestyle changes and metformin • Metformin is prescribed to nonketotic children at low doses and increased as tolerated every 2 wk to a maximum of 2,000 mg/d • Fasting glucose levels >200 mg/dL and A1C >8.5% (or ketosis) should be treated with insulin until glucose control is gained • Insulin should be added in patients who cannot achieve control after 3-6 mo of metformin therapy.

Abdominal ultrasound may show gallstones and cholecystitis

Treat as in adults



• Intermittent colicky RUQ pain, jaundice • Rapid weight loss increases risk of gallstones

Hepatic steatosis or NAFLD

•Usually asymptomatic •Some patients may have hepatomegaly, RUQ pain, stigmata of liver disease.

• LFTs every 2 y starting at age 10 y for children with BMI ≥95th percentile and those with a BMI in the 85th-94th percentile with risk factors • Elevated hepatic aminotransferases at 4-5 times normal; elevated GGT levels and alkaline phosphatase at 3 times normal; bilirubin, albumin, and PT may rise later • Ultrasound may show fatty changes • Liver biopsy is gold standard for diagnosis

• Most cases are benign • Weight reduction improves LFT results • Refer to pediatric hepatologist when ALT or AST levels are 2 times normal on two different occasions


Hip or knee pain, pain when walking, decreased range of motion in hip

Bilateral frog-leg radiographic view of the hips

Refer to orthopedic surgeon

Blount disease

Often painless, bowing of tibia (tibia vara), abnormal gait

AP radiograph of affected knee while standing

Refer to orthopedic surgeon

Severe recurrent headaches with photophobia, double vision if cranial nerve VI is impaired, blurred optic disks

• MRI of brain with contrast • CSF studies

Requires urgent referral to neurology if pseudotumor cerebri is suspected

NEUROLOGIC SYSTEM Pseudotumor cerebri

MENTAL HEALTH Eating disorder

Dental erosion, callus Complete metabolic panel on knuckles, binge/ purge behaviors

• Refer to psychiatrist • Possible inpatient treatment


Decreased selfesteem and selfconfidence, withdrawal from social activities, school avoidance, sleep disturbance

Psychiatric examination

Refer to psychiatrist


Wheezing, exertional dyspnea, exercise intolerance

• Pulmonary function testing • Decrease in functional residual capacity, FEV1, and FVC • FEV1/FVC should be normal

• Treat patient as usual • Provide guidance regarding physical activity and outdoor play


Daytime sleepiness, snoring, hyperactivity, aggression, elevated BP, nocturnal enuresis, tonsillar hypertrophy

• Overnight sleep study to measure AHI • AHI of 5/h establishes diagnosis of OSA • AHI of 30/h represents severe disease

• Weight reduction • Adenotonsillectomy for patients with tonsillar or adenoid hypertrophy • Refer to pulmonologist for further recommendations.


Key: AHI, apnea-hypoapnea index; A1C, glycosylated hemoglobin; AP, anteroposterior; BMI, body mass index; DHEAS, dehydroepiandrosterone sulfate; FEV1, forced expiratory volume in 1 second; FSH, follicle-stimulating hormone, FVC, forced vital capacity; GGT, gamma-glutamyl transpeptidase; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; LFT, liver function test; LH, luteinizing hormone; NAFLD, nonalcoholic fatty liver disease; OSA, obstructive sleep apnea; PT, prothrombin time; RUQ, right upper quadrant; SCFE, slipped capital femoral epiphysis; SHBG, sex hormone-binding globulin; T2DM, type 2 diabetes mellitus.


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. According to the CDC, the best way to monitor weight in children is to a. Measure waist circumference b. Perform skinfold tests c. Calculate body mass index d. Use scale measures

7. One of the most common cardiac comorbidities of childhood obesity is a. Cardiomyopathy b. Hypertension c. Mitral valve prolapse d. Coronary disease

2. The rate of obesity is highest in children who are a. 8 to 10 years old b. 10 to 11 years old c. 12 to 14 years old d. 15 to 17 years old

8. The mainstay of treatment for childhood dyslipidemia is a. Diet and exercise b. Fish oil supplements c. Statins d. Fibrates

3. In 2008, the prevalence of childhood obesity was found to be highest among a. Non-Hispanic blacks b. Non-Hispanic whites c. Hispanics d. American Indian/Alaskan natives 4. Childhood obesity can be attributed to a. Growth hormone deficiency b. Addison disease c. Hyperthyroidism d. Adrenal insufficiency 5. A funduscopic finding associated with pseudotumor cerebri is a. Cotton patch exudates b. Flame-shaped hemorrhages c. Blurring of the optic disk margins d. Kayser–Fleischer rings 6. Starting at age 10 years, children deemed to be at increased risk of metabolic syndrome should begin testing for a. Liver function b. Oral glucose tolerance c. Triglyceride level d. Urinary albumin level

64 JAAPA • DECEMBER 2011 • 24(12) •

9. Which medication can be started when the fasting blood glucose is between 126 and 200 mg/dL? a. Sitagliptin b. Chlorpropamide c. Glipizide d. Metformin 10. Childhood obesity can predispose a child to a. Scoliosis b. Hip dysplasia c. Slipped capital femoral epiphysis d. Metatarsus varus 11. The primary goal of dietary intervention for treatment of childhood obesity is to a. Increase servings of fruits and vegetables b. Reduce total caloric intake c. Decrease intake of fat d. Avoid overly processed foods 12. The suggested first-line drug for obesity unresponsive to lifestyle modifications is a. Sibutramine b. Exenatide c. Fenfluramine d. Orlistat

What’s New in … MI C H ELE TA FFA RO-NES KEY, PA-C


Screening, staging, targeted therapies


ung cancer is the most common cancer worldwide and the most common cause of cancer-related deaths in US adults. An estimated 221,130 new cases of lung cancer are expected to occur in the United States in 2011, with an estimated 156,940 deaths.1 Tobacco smoking is the primary risk factor for the development of lung cancer and is thought to account for 90% of all lung cancer diagnoses.2 When compared with never-smokers, persons who have quit smoking still have a 20-fold increased risk of developing a primary lung cancer. In the United States, however, 9% of women and 19% of men who develop lung cancer are considered never-smokers or have smoked fewer than 100 cigarettes in their lifetime.3

›HISTOLOGICAL SUBTYPES There are three forms of non-small cell lung cancer (NSCLC). Adenocarcinoma is more common in light or never-smokers and former smokers.4 This subtype is further delineated to include bronchoalveolar carcinomas and adenosquamous carcinoma. Squamous cell carcinoma is typically seen more often in smokers. Large cell carcinomas constitute 5% of lung cancer diagnoses.4 Small cell lung cancer is a distinctly different subtype; it is typically more aggressive than NSCLC and carries a poorer prognosis.

›SCREENING: LOW-DOSE CT OR CHEST RADIOGRAPH? Historically, diagnosis of lung cancer has been based on the patient’s symptoms or is arrived at incidentally. Chest radiograph and sputum cytology have been widely studied as screening tools for lung cancer, but they have not been shown to reduce mortality. In August 2011, the results of the National Lung Screening Trial were published in The New England Journal of Medicine.5 Over a 2-year period, this study enrolled more than 50,000 patients considered to be at high risk for lung cancer. The study included people 55 to 74 years of age Michele Taffaro-Neskey works in the Department of Thoracic/Head and Neck Medical Oncology, M.D. Anderson Cancer Center, Houston, Texas. The author has indicated no relationships to disclose relating to the content of this article.

with at least a 30-pack-year smoking history and former smokers who had quit within the past 15 years. Participants were randomized to receive three annual screenings using either low-dose CT or single-view posteroanterior chest radiography. The results showed a 20% reduction in mortality from lung cancer for those who underwent low-dose CT compared with those who had chest radiography.5 A 6.7% reduction in all-cause mortality with CT screening was attributed to the discovery of other pathologies, such as granulomatous disease, emphysema, and cardiovascular abnormalities.5 This is a landmark study and will likely change the way most health care providers screen for lung cancer. However, frequency of screening after 3 years and cost remain significant issues. No clinical practice guidelines exist for lung cancer screening, but guidelines are being developed by The American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN).

›UPDATED STAGING As of January 2010, the 7th edition of the TNM Classification of Malignant Tumours became the standard for classifying lung cancer.6 Changes include new subdivisions of stage T1 to stage T2 tumors, based on size cutoffs, and the division of metastases into M1a and M1b, based on location. The most important of these changes is the classification of pleural effusions and separate tumor nodules. Because patients with a pleural effusion have an average survival similar to that of patients with distant metastases, the presence of a malignant pleural effusion is now classified as M1a, or stage IV disease.7 Conversely, separate tumor nodules in the same lobe are now classified as T4, rather than M1, although these lesions can have a lesser overall stage.

›MOLECULAR TESTING AND TARGETED THERAPIES Personalized medicine is the future of cancer care, and development of targeted agents is at the forefront. Cytotoxic chemotherapy is nonspecific and damages both normal and tumor cells. Newer agents target specific biomarkers within tumor cells to inhibit growth and progression, leading to greater effectiveness and less toxicity. Perhaps the best example of biomarker-directed therapy can be extrapolated from the use of trastuzumab (Herceptin) in breast cancer. Approximately 20% of breast cancers overexpress the HER2/neu cell membrane receptor that cells need to grow and divide. Trastuzumab was developed as a monoclonal antibody that interferes with the HER2/neu receptor. The approval of trastuzumab in 1998 changed the face of HER2/neu-positive breast cancers and had a substantial impact on the treatment and survival of these patients. Continued on page 70 • DECEMBER 2011 • 24(12) • JAAPA


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 LYRICA is indicated for the management of neuropathic pain associated with Diabetic Peripheral Neuropathy, management of treatment of PDN (Level A).”1 Postherpetic Neuralgia, as adjunctive therapy for adult patients The medical organizations that developed this guideline with Partial Onset Seizures, and management of Fibromyalgia. (the AAN, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Selected safety information: Physical Medicine and Rehabilitation) recognize that specific LYRICA is contraindicated in patients with known hypersensitivity care decisions are the prerogative of the patient and physician to pregabalin or any of its other components. There have been caring for the patient, based on all of the circumstances involved. postmarketing reports of hypersensitivity in patients shortly after initiation of treatment with LYRICA. Adverse reactions For full guideline, visit included skin redness, blisters, hives, rash, dyspnea, and Level A=Established as effective, based on at least 2 wheezing. Discontinue LYRICA immediately in patients with these symptoms. Class I studies. There have been postmarketing reports of angioedema in Class I level evidence includes a randomized, controlled patients during initial and chronic treatment with LYRICA. Specific clinical trial of the intervention of interest with masked or symptoms included swelling of the face, mouth (tongue, lips, objective outcome assessment, in a representative population, and gums), and neck (throat and larynx). There were reports of and other specified criteria. life-threatening angioedema with respiratory compromise requiring emergency treatment. Discontinue LYRICA immediately in patients with these symptoms. AAN=American Academy of Neurology. PBP01859C/407531-01

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 placebo-treated 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 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 © 2011 Pfizer Inc.

All rights reserved.

have sufficient experience with LYRICA to determine its effect on cognitive and motor function. Higher frequency of weight gain and edema was observed in patients taking both LYRICA and thiazolidinedione antidiabetic drugs. Exercise caution when coadministering these drugs. Patients who are taking other drugs associated with angioedema such as angiotensin-converting enzyme inhibitors (ACE inhibitors) may be at increased risk of developing angioedema. Exercise caution when using LYRICA in patients who have had a previous episode of angioedema. For Full Prescribing Information and Medication Guide, please visit Please see the Brief Summary of Prescribing Information on adjacent pages. Reference: 1. Bril V, England JD, Franklin GM, et al. Evidence-based guideline: treatment of painful diabetic neuropathy. Report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology. 2011;76:1758-1765. September 2011

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 LYRICA is indicated for the management of neuropathic pain associated with Diabetic Peripheral Neuropathy, management of treatment of PDN (Level A).”1 Postherpetic Neuralgia, as adjunctive therapy for adult patients The medical organizations that developed this guideline with Partial Onset Seizures, and management of Fibromyalgia. (the AAN, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Selected safety information: Physical Medicine and Rehabilitation) recognize that specific LYRICA is contraindicated in patients with known hypersensitivity care decisions are the prerogative of the patient and physician to pregabalin or any of its other components. There have been caring for the patient, based on all of the circumstances involved. postmarketing reports of hypersensitivity in patients shortly after initiation of treatment with LYRICA. Adverse reactions For full guideline, visit included skin redness, blisters, hives, rash, dyspnea, and Level A=Established as effective, based on at least 2 wheezing. Discontinue LYRICA immediately in patients with these symptoms. Class I studies. There have been postmarketing reports of angioedema in Class I level evidence includes a randomized, controlled patients during initial and chronic treatment with LYRICA. Specific clinical trial of the intervention of interest with masked or symptoms included swelling of the face, mouth (tongue, lips, objective outcome assessment, in a representative population, and gums), and neck (throat and larynx). There were reports of and other specified criteria. life-threatening angioedema with respiratory compromise requiring emergency treatment. Discontinue LYRICA immediately in patients with these symptoms. AAN=American Academy of Neurology. PBP01859C/407531-01

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 placebo-treated 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 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 © 2011 Pfizer Inc.

All rights reserved.

have sufficient experience with LYRICA to determine its effect on cognitive and motor function. Higher frequency of weight gain and edema was observed in patients taking both LYRICA and thiazolidinedione antidiabetic drugs. Exercise caution when coadministering these drugs. Patients who are taking other drugs associated with angioedema such as angiotensin-converting enzyme inhibitors (ACE inhibitors) may be at increased risk of developing angioedema. Exercise caution when using LYRICA in patients who have had a previous episode of angioedema. For Full Prescribing Information and Medication Guide, please visit Please see the Brief Summary of Prescribing Information on adjacent pages. Reference: 1. Bril V, England JD, Franklin GM, et al. Evidence-based guideline: treatment of painful diabetic neuropathy. Report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology. 2011;76:1758-1765. September 2011

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)* ≥60 150 300 450 600 30–60


15–30 <15

Dose Regimen BID or TID















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 placebo-controlled 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 placebo-treated 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 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 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 co-administering 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 31% of LYRICAtreated patients compared to 9% of placebo-treated patients; somnolence was experienced by 22% of LYRICA-treated patients compared to 7% 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 LYRICAtreated 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 long-term 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 LYRICAassociated 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, 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 LYRICAtreated, 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 (3%). 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”.

461070Euro_B_pg1 K


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 1 0 1 3 2 0 Thinking abnormal† 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 3 1 3 6 4 2 Blurry vision‡ 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, 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. 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 http://www. 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], suggestive of physical dependence. 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 pregabalintreated 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 repeated-dose 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-0294-21.0 June 2011


© 2011 Pfizer Inc.

All rights reserved.

461070Euro_B_pg2 K


What’s New in … Several biomarkers have been discovered as prognostic and predictive markers for NSCLC, the best-known of which include epidermal growth factor receptor (EGFR), the KRAS oncogene, and the EML4-ALK (echinoderm microtubule-associated proteinlike 4 and anaplastic lymphoma kinase) fusion oncogene. The EGFR gene controls downstream intracellular pathways that regulate cell proliferation, motility, and apoptosis. Mutations can lead to constant activation of these pathways, resulting in cancer and disease progression. In NSCLC, mutations in the tyrosine kinase domain of EGFR, most commonly in exons 19 and 21, predict treatment benefit with tyrosine kinase inhibitors (TKIs), such as erlotinib (Tarceva) and gefitinib (Iressa).8 Randomized controlled trials with both TKIs were found to improve survival in patients with advanced disease after failure of first- or second-line therapy compared with placebo.9,10 Clinical parameters that determined responsiveness to treatment included adenocarcinoma histology, female gender, Asian ethnicity, and being a nonsmoker. EGFR mutations are estimated to occur in about 10% of white patients and up to 50% of Asian patients with NSCLC.11 The effectiveness of EFGR TKIs versus standard chemotherapy has been evaluated. Patients likely to respond to the TKIs had a 60% response rate and statistically significantly improvement in progression-free survival.12 Those without a mutation derived more benefit from standard chemotherapy. Current first-line therapy for patients with NSCLC harboring an activating EGFR mutation is TKI monotherapy rather than chemotherapy. KRAS is another biomarker involved in malignant transformation. Mutations in the KRAS oncogene occur in both NSCLC and colorectal cancer. A KRAS mutation is prognostic of poor survival and predictive of diminished benefit to EGFR TKIs as well as to some types of chemotherapy.13 Testing for KRAS mutation in clinical practice is reserved for prognostic purposes, as no targeted therapy is available. In September 2011, the FDA granted accelerated early approval to crizotinib (Xalkori) for patients with advanced NSCLC that harbors rearrangements of the ALK gene. This is a major breakthrough in the treatment of lung cancer and adds another subset of patients that can be treated based on the molecular profile of the tumor. Approximately 5% of patients will have the EML4-ALK rearrangement and clinical parameters similar to those with EGFR mutations, which include light or never-smokers with adenocarcinoma. EML4-ALK translocations and EGFR mutations are also mutually exclusive. Crizotinib, which is a smallmolecule inhibitor of ALK, was shown to have an almost 90% disease control rate in patients with an ALK rearrangement who had already received therapy for NSCLC.14

›NEW THERAPIES, NEW ISSUES In the United States, erlotinib and crizotinib are the only FDA-approved targeted therapies for NSCLC. Both agents 70 JAAPA • DECEMBER 2011 • 24(12) •

are available in oral formulations, so adherence and cost can be a challenge. For patients without insurance coverage who would have to pay out-of-pocket costs, 1-month supplies of erlotinib and crizotinib can cost up to $5,000 and $10,000, respectively. Compared with chemotherapy, the TKIs are better tolerated, but they are not without side effects. The major toxicities seen with EGFR TKIs are acneiform rash and diarrhea. These can typically be controlled with topical and OTC medications. There is also an established algorithm for the treatment of EGFR TKI dermatologic toxicity. Crizotinib can induce GI side effects, such as nausea and diarrhea, as well as visual disturbances. A baseline ophthalmologic examination should be considered for all patients starting this medication.

›TRANSLATING RESEARCH TO PRACTICE New screening guidelines for lung cancer are on the horizon. Presently, low-dose CT screening has shown a reduction in lung cancer mortality, but cost and access are prohibitive. Using clinical and histologic characteristics to stratify patients at the time of diagnosis is imperative for determining the best course of action. Approaches to lung cancer treatment are rapidly changing and evolving with the development of targeted therapy. Molecular analysis, including testing for EGFR, KRAS, and EML4-ALK mutations, can guide treatment decisions for certain subgroups of patients. Analysis of several other biomarkers is possible, but the three discussed here are the only markers proven to have predictive or prognostic value. JAAPA REFERENCES 1. National Cancer Institute. Lung cancer. Accessed November 9, 2011. 2. National Cancer Institute. Lung and bronchus cancer (invasive). csr/1975_2004/results_merged/sect_15_lung_bronchus.pdf. Accessed November 9, 2011. 3. Wakelee HA, Chang ET, Gomez SL, et al. Lung cancer incidence in never smokers. J Clin Oncol. 2007;25(5):472-478. 4. Alberg AJ, Ford JG, Samet JM, et al. Epidemiology of lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest. 2007;132(3 suppl):29S-55S. 5. National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365(5):395-409. 6. Sobin LH, Gospodarowicz MK, Wittekind C, eds. TNM Classification of Malignant Tumours, 7th Edition. Malden, MA; Wiley-Blackwell: 2009. 7. Goldstraw P, Crowley J, Chansky K, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thorac Oncol. 2007;2(8):706-714. 8. Sequist LV, Bell DW, Lynch TJ, Haber DA. Molecular predictors of response to epidermal growth factor receptor antagonists in non-small-cell lung cancer. J Clin Oncol. Feb 10 2007;25(5):587-595. 9. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005;353(2):123-132. 10. Kris MG, Natale RB, Herbst RS, et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA. 2003;290(16):2149-2158. 11. National Comprehensive Care Network. NCCN clinical practice guidelines in oncology (NCCN Guidelines): non-small cell lung cancer. nscl.pdf. Updated October 4, 2011. Accessed November 19, 2011. 12. Rosell R, Gervais R, Vergnenegre A, et al. Erlotinib versus chemotherapy (CT) in advanced non-small cell lung cancer (NSCLC) patients (p) with epidermal growth factor receptor (EGFR) mutations: interim results of the European Erlotinib Versus Chemotherapy (EURTAC) phase III randomized trial. Paper presented at; 2011 American Society of Clinical Oncology Annual Meeting; June 3-7, 2011: Chicago, IL. Abstract 7503. 13. Slebos RJ, Kibbelaar RE, Dalesio O, et al. K-RAS oncogene activation as a prognostic marker in adenocarcinoma of the lung. N Engl J Med. 1990;323(9):561-565. 14. Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010;363(18):1693-1703.


After the error, then what? The emotional impact of errors on clinicians


uch has been written about the impact of errors on patients. Most of the literature examines how they occur, the variety of ways in which they are viewed, what can be done to prevent them, and how they are disclosed. In this month’s column, we examine the impact of errors on those who make them.

›HYPOTHETICAL CASE David, an experienced PA serving in a hospitalist role, is asked to manage the discharge medications for Sylvia, an oncology patient. Sylvia has a variety of postsurgical complications and is taking more than 100 mg/day of methadone and up to 100 mg/day of oxycodone. Her ongoing pain has been difficult to control, with complications including both nausea and ileus. Sylvia and her family are insistent about moving away from oral opioids completely and want to switch her to a fentanyl patch alone, an approach that they say has worked in the past. David has performed opioid conversions many times, moving patients from patient-controlled analgesia to oral medications, and he feels confident about making such conversions. He has little experience with methadone and fentanyl patches, however, although he recently had a role in two such conversions. David is not able to contact the attending who is overseeing Sylvia’s case, and staff residents seem unenthused about helping him. Thirdyear resident Janica says, “You know more about this stuff than I do, David. I can’t help you.” David attempts to Jim Anderson is a clinical informatics educator for University of Washington Medicine—IT Services and a member of the clinical faculty of the MEDEX Northwest PA program at the University of Washington School of Medicine in Seattle. He is a member of the JAAPA editorial board.

contact a team pharmacist who has been helpful before in working through tricky opioid conversions, but he is not able to reach anyone from pharmacy. David has an opioid conversion table that he frequently uses to good effect, and he has previously accessed several Web sites for help with opioid conversions. He begins by systematically going through Sylvia’s current opioid regimen. Using the tools he has, he comes up with a plan to gradually move her from her oral medications and convert her to fentanyl patches completely over a period of 7 days, Per past instructions from his colleagues on the hospital pain team, he calculates Sylvia’s total opioid dose, translates it to a morphine equivalency, and figures out a comparable fentanyl patch dose. Aware that this is a potentially dangerous conversion, he checks his calculations several times. Finally, he is confident that he has arrived at the proper dose of fentanyl patch. He asks Phillip and Renita, two residents in the surgical service, to review his calculations; both say “looks good to me.” David considers delaying Sylvia’s discharge until he can have his attending and pharmacy colleagues go over the case, but he is confident that his medication discharge plan is safe. Sylvia is in good spirits and pleased to be going home as she is discharged with her conversion plan. Five days later, Sylvia develops severe respiratory depression, which worsens over a 2-day period. She is brought to the hospital on day 8, and despite efforts to reverse the opioid overdose, she dies later that day from respiratory depression related to opioid overmedication. Later that day, David is shocked when his attending tells him about Sylvia’s death. His supervising physician is very upset. A

review board finds that David made a significant error in estimating the morphine equivalent of methadone. This resulted in Sylvia’s receiving a fentanyl patch dose almost 20 times the opioid dose she was receiving in the hospital.

›WHEN THE PROVIDER BECOMES THE “SECOND VICTIM” Significant and harmful medical errors occur regularly, but experience shows that physicians and other providers have difficulty finding support after committing the error or in offering support to fellow providers who have erred.1 This has resulted in significant emotional challenges for providers, who become “second victims.”2 Waterman describes the struggles facing clinicians who have made significant medical errors. These include increased anxiety about future errors, decreased confidence in medical decision making, compromised sleep, job dissatisfaction, and harm to their reputation. Additionally, physicians consistently report a lack of resources in such settings, with only 10% noting that health care organizations provided adequate support in coping with stress related to their having committed a medical error.3 White and Gallagher note that participating in a medical error can have both short- and long-term consequences:4 Following involvement in an error, health care workers at all levels of training commonly experience a complex range of feelings, including guilt, self-doubt, embarrassment, disappointment, self-blame, a sense of inadequacy, and fear [8,9].... These emotions may persist for months or years and contribute to the already substantial stress of medical training by triggering burnout and depression [11]. Continued on page 72 • DECEMBER 2011 • 24(12) • JAAPA


PA QUANDARIES “Achieving self-forgiveness can be both essential and elusive for the clinician who has committed a medical error.” ›PREDICTABLE POSTEVENT TRAJECTORY In their discussion of the second victim phenomenon, Scott and Hirschinger describe the stages caregivers go through as predictable “postevent trajectories:”2 1. The first stage is described as a “chaos and accident” response, in which the clinician learns of the event and works to figure out what happened and why it transpired. 2. The authors describe the second stage as “intrusive reflections.” Here, the clinician committing the error may reevaluate the scenario in an attempt to understand what happened and how it might have been prevented. This might include disturbed and haunted reenactments and rumination about what transpired, as well as guilt and shame. 3. The third stage involves “restoring personal integrity,” as the clinician strives for acceptance and support from the work and social setting; this may include management of “grapevine” gossip, with mounting fear of the professional, personal, and financial damage that may accompany the error. 4. Stage 4 brings realization of how serious the event was, with continued anxiety about it and its consequences. Here, symptoms of the physical and psychosocial stress being felt by the clinician may manifest symptomatically. 5. In the fifth stage, the clinician may reach out for personal and professional support. Concerns about litigation typically emerge during this phase, with increasingly intense introspection eliciting painful self-questioning, such as “Why did I do this?” “Is there something wrong with me?” “Who can help me as I go through this?” 6. Finally, in stage six, the clinician’s actions and thoughts lead to either

dropping out (“Can I handle this work?”), surviving and coping (“How could I have prevented this?” “Why do I feel so bad?”), or thriving (“How can I improve safety?” “What can I learn from this?”) Other characteristics of the thriving phase may include seeing the event as motivation to advocate for patient safety and framing the error event within the broader perspective of previously successful life behaviors and medical practice.

›AND THEN WHAT? Recovery from the error event typically leads the clinician to do some significant soul searching about whether to drop out, survive, or thrive. Dropping out includes either leaving the medical profession or making a change in locale: “Overall, I didn’t feel it was a good environment to stay in, in terms of healing, is why I chose to leave. But in the new unit, it was very helpful. I moved over to another service. I think a fresh start was good for me. It was devastating during that period. It affected me greatly and made me question my abilities. Was I ready to be an attending?”2 Surviving is described as being able to continue at a satisfactory level of performance but citing ongoing inability to move on from the event: “I figured out how to cope and how to say yes, I made a mistake. And that mistake caused a bad patient outcome but I haven’t figured out how to forgive myself for that yet or to forget it. It’s impossible to let go.”2 Thriving, the third of the predictable recovery paths, is characterized by the clinician’s continuing to remember and be impacted by the event in the larger context of making something positive come from the error experience: “I couldn’t really avoid getting back in the ambulance so what I did

72 JAAPA • DECEMBER 2011 • 24(12) •

do was actually get back in the ambulance before the end of my shift and did a test ride to try to figure out why I was having so much trouble with the BP readout. I definitely needed to figure out a way for some good to come out of this horrible experience. I was questioning myself over and over again about what happened to me but then I thought, you know what, I’ve just had this experience in my life where I had to encounter this tragedy but it made me a better person. It really did, and it gave me more insight.”2

›CAN THE CLINICIAN FIND SELF-FORGIVENESS? Self-forgiveness can be both essential and elusive for the clinician involved in an error event. The clinician may feel that being forgiven by the patient must precede self-forgiveness, but Berlinger offers a perspective that separates the two. She notes that the possibility of self-forgiveness may be preceded by the clinician’s achieving a full understanding of his or her own role in the event and by responding to the needs created by the harm.4 Berlinger and others also propose that institutions provide enhanced response and support, with Scott and Hirschinger suggesting the need for an institutional awareness campaign that encourages open dialogue about second victims. This awareness may assist clinicians in growing personally and professionally in the face of such adversity, while enhancing the future safety of patients.5 JAAPA F.J. Gianola, PA, and Jim Anderson, PA-C, ATC, department editors REFERENCES 1. Newman MC. The emotional impact of mistakes on family physicians. Arch Fam Med. 1996;5(2):71-75. 2. Scott SD, Hirschinger LE, Cox KR, et al. The natural history of recovery for the healthcare provider “second victim” after adverse patient events. Qual Saf Health Care. 2009;18(5): 325-330. 3. Waterman AD, Garbutt J, Hazel E, et al. The emotional impact of medical errors on practicing physicians in the United States and Canada. Jt Comm J Qual Patient Saf. 2007;33(8):467-476. 4. Berlinger N. Resolving harmful medical mistakes—is there a role for forgiveness? Virtual Mentor—AMA J Ethics. 2011; 13(9):647-654. 5. White A, Gallagher TH. After the apology—coping and recovery after errors. Virtual Mentor—AMA J Ethics. 2011;13(9):593-600.

Diagnostic Imaging Review JA MI E P. FA I RGR I EV E ; U RV I R. S HA H, M D; JOS EPH M . CA NDELA RI O, FNP-BC

FIGURE 1. Gas in the left inguinal canal was suspicious for hernia.

Atypical manifestations of a potentially fatal infection ›CASE A 40-year-old male was seen in the emergency department (ED) of another facility with complaints of increasingly severe pain, pressure, and swelling in the left groin and in the skin of the penis and scrotum. The patient believed his symptoms, which had begun 5 days earlier, resulted from a groin strain he sustained while installing wiring in a ceiling. An ultrasound done before the patient’s visit to the ED showed left testicular microlithiasis, a small varicocele, and a hydrocele. An abdominal radio-

graph done as part of that same evaluation showed no evidence of ileus or small bowel obstruction. According to the patient, the presumed diagnosis was left inguinal hernia (LIH), varicocele, and hydrocele. He was given morphine for pain in the ED, advised to follow up with his primary care physician (PCP), and sent home on hydrocodone, which relieved the pain temporarily. The pain was adequately controlled with hydrocodone and acetaminophen until day 8, when the patient presented to our ED. At that time, he

complained of generalized groin pain, which he rated as 10 on a 10-point scale, and lower abdominal pain, which he described as constant and gradually increasing. He reported decreased appetite and nausea with several episodes of emesis and said that he had not had a bowel movement for 4 days. There had been no trauma to the area. The patient admitted to being sexually active but denied recent unprotected sex. The medical history was significant for alcohol abuse. He had no history of surgery. Physical examination revealed tachycardia (heart rate, 118 beats per minute); other vital signs were unremarkable. Swelling and induration were noted along the pubic symphysis and left groin. Tense, cordlike swelling was visible along the left inguinal canal, and palpation detected a firm mass extending beyond the external inguinal ring into the scrotum. The mass was nonreducible, and the area along the left groin was exquisitely tender to palpation. The skin of the penis and scrotum was edematous, and the testes were mildly tender to palpation bilaterally. There was no evidence of trauma. Laboratory results were remarkable for a WBC count of 25,970 /µL, with a left shift and 19% bands. Results of urinalysis (UA) were unremarkable. Concerned about a possible incarcerated hernia, the clinician in the ED consulted a surgeon, who agreed with the diagnosis. He obtained consent for an exploratory laparotomy and LIH repair and ordered abdominal/ pelvic CT with contrast (Figure 1 and Figure 2). Because the genitalia were involved, the surgeon consulted a urologist, who also agreed with the diagnosis of an incarcerated LIH. What do the CT scans show?

Jamie Fairgrieve is a student in the PA program at Jefferson College of Health Sciences, Roanoke, Virginia. Urvi Shah is a volunteer and Joseph Candelario is a nurse practitioner in the emergency department at the Veterans Affairs Medical Center, Salem, Virginia. The authors have indicated no relationships to disclose relating to the content of this article.

74 JAAPA • DECEMBER 2011 • 24(12) •

›DISCUSSION An early slice on the CT scan showed gas in the left inguinal canal (Figure 1)

Diagnostic Imaging Review and supported the diagnosis of left inguinal hernia. However, subsequent slices (Figure 2) revealed subcutaneous emphysema in the perineum, indicative of a scrotal abscess. The patient underwent emergent incision and drainage (I&D) with application of a wound vacuum. He was treated with vancomycin, piperacillin/ tazobactam, and metronidazole until culture results revealed the presence of gram-positive bacilli resembling Corynebacterium and Propionibacterium species, Peptostreptococcus anaerobius, and Staphylococcus epidermidis (resistant to penicillin). On the recommendation of an infectious disease consultant, the antibiotic regimen was switched to clindamycin, ampicillin/sulbactam, vancomycin, and piperacillin/ tazobactam. The patient had two more surgical procedures during his hospital stay: On day 10, he underwent debridement of gas gangrene of the left scrotum and prepubic tissue. Then on day 15, he underwent another debridement and the wound vacuum was changed. He was discharged in stable condition on day 18. CT revealed gas formation in the perineum, a finding characteristic of Fournier gangrene but not of inguinal hernia. Numerous cases in the literature compare and contrast imaging modalities that can support the diagnosis of Fournier gangrene. However, the patient in this case presented with signs and symptoms suggestive of an inguinal hernia, and the diagnosis was considered to be a hernia by clinicians in two separate EDs, a surgeon, and a urologist. CT assisted in determining the accurate etiology of the patient’s condition. Fournier gangrene is a rapidly progressing necrotizing fasciitis specifically involving the perineal, genital, or perianal regions, although classically limited to the scrotum and penis. The condition is rare and mainly affects men between the ages of 50 and 60 years.

FIGURE 2. Gas in the perineum ruled out inguinal hernia and revealed a necrotizing fasciitis with gas production (Fournier gangrene).

Fournier gangrene is usually precipitated by hypoxia and local ischemia, so patients presenting with this condition often have comorbidities, such as diabetes, alcoholism, and cancer.1 Possible causative organisms include clostridia, streptococci, staphylococci, Escherichia coli, peptostreptococci, and Candida. Culture often reveals more than one bacterial species.1 The synergistic effects of the pathogens, which originate from the rectum, anus, adjacent skin, and lower urinary tract, cause thrombosis of small subcutaneous vessels. The thrombosis progresses rapidly to gangrenous involvement of the surrounding skin and fascia.2 The patient typically presents 2 to 7 days following onset of fever and malaise and complains of feeling tired. Clinical symptoms include pain, perineal pruritus, and swelling of the external genitalia associated with fever and chills.3 Left untreated, the rapidly progressing infection results in sepsis, and multiorgan failure follows shortly thereafter.1 Physical examination reveals local tenderness; edema; and bronzing of the scrotal skin, which progresses to erythema and occasionally vesicle formation.3

76 JAAPA • DECEMBER 2011 • 24(12) •

Crepitus may be appreciated in some cases (50%) and is a hallmark of Fournier gangrene.3 In this case, the patient presented with pain, swelling, and induration along the pubic symphysis, with a palpable firm mass extending beyond the external inguinal ring into the scrotum. This presentation appeared more characteristic of an incarcerated inguinal hernia than Fournier gangrene. Laboratory findings can include hyponatremia and leukocytosis with a left shift.1 Diagnosis of Fournier gangrene is highly dependent on clinical examination, although radiography may help when physical findings are ambiguous.4 Radiography usually reveals notable swelling of the scrotal tissues and areas of hyperlucency.4 Ultrasound will demonstrate vesicles filled with gas in the soft tissues.1 An incarcerated inguinoscrotal hernia can be recognized by gas in the scrotum, but visualization of gas in the obstructed bowel lumen, away from the scrotal borders, is characteristic of Fournier gangrene.5 CT is thought to be helpful in confirming the diagnosis and is typically used to evaluate the extent of disease and detect a potential underlying cause.4 In this case, however, CT was the key component in distinguishing among the etiologies and was the differentiating factor between an inguinal hernia and Fournier gangrene. Classic CT findings in this condition include asymmetric fascial thickening, fat stranding, abscess formation, and subcutaneous emphysema.1 CT also allows for visualization of most of the perineal structures that become involved in the disease.3 Treatment of Fournier gangrene focuses on halting progression of the underlying sepsis. Surgical debridement of the affected area, I&D of the necrotic lesion, and broad-spectrum antibiotics against both aerobic and anaerobic bacteria are vital in proper management.1 Multiple surgical

JAAPA needs manuscripts! debridements are usually necessary to remove all the necrotic tissue and prevent the spread of bacteria.1 The mortality rate of Fournier gangrene varies from 21% to greater than 70% if the infection is not treated within the first few days.3,4

›CONCLUSION Based on the patient’s history and physical examination findings, as well as laboratory and reported ultrasound results, four different providers arrived at the diagnosis of incarcerated inguinal hernia. The CT with contrast ordered by the general surgery consultant allowed the clinicians to distinguish between gas in the inguinal canal (representing an inguinal hernia) and gas in the perineum (revealing necrotizing fasciitis). Because this patient did not present with symptoms specific to Fournier gangrene, CT proved to be a significant diagnostic tool, allowing for expedient diagnosis and treatment of this surgical emergency. Consideration of further imaging studies, such as CT, is crucial when clinical presentations are atypical and questions of dissemination or other organ involvement arise. In this case, CT was helpful in differentiating between an incarcerated inguinal hernia and Fournier gangrene. The scanning modality proved to be both highly sensitive and specific in detecting abnormally located gas and provided reliable visualization of the site and extent of the infection.3 JAAPA Julie Edmiston, PA-C, RT, department editor REFERENCES 1. Ðaba R, Grzybowski A, Prokop J, et al. Fournier’s gangrene: historical survey, current status, and case description. Med Sci Monit. 2009;15(2):CS34-39. 2. Vick R, Carson CC 3rd. Fournier’s disease. Urol Clin North Am. 1999;26(4):841-849. 3. Rajan DK, Scharer KA. Radiology of Fournier’s gangrene. AJR Am J Roentgenol. 1998;170(1):163-168. 4. Grayson DE, Abbott RM, Levy AD, Sherman PM. Emphysematous infections of the abdomen and pelvis: a pictorial review. Radiographics. 2002;22(3):543-561. 5. Dogra VS, Smeltzer JS, Poblette J. Sonographic diagnosis of Fournier’s gangrene. J Clin Ultrasound. 1994;22(9):571-572.

Interested in being published in the premier journal for physician assistants? We’re looking for PA authors to write for these departments: Case of the Month, a forum for case reports that reveal interesting, unusual, or instructive presentations of common problems. A Day in the Life, a diary-style narrative that reflects the great variety of work that PAs do and the challenges and rewards of being a PA. The Surgical Patient, which covers innovations in surgical care, procedure outlines, interesting surgical case histories, and more. Diagnostic Imaging Review, a brief case description, followed by a discussion of how the imaging studies obtained revealed the diagnosis. When the Patient Asks, JAAPA’s patient education department, which includes a separate review for the PA and a handout for the patient. See our author guidelines, available at, for more details.

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

An unlikely afternoon hero: When being there is good enough In his forties it came to him he’d never be a professor, write important papers, or teach a dozen worried residents. But a Lutheran minister’s son ruptured his spleen, and a sharp old doc down south of Carroll called him in. Homer took out his spleen and saved his life. Oh, he knew any surgeon worth his salt could have done it, too. But he was the one who was there... The splenectomy that night was Homer’s turning point. From then on he was satisfied to be the surgeon who was there. —George S. Bascom, “Being There.”


he sits quietly on her mother’s lap. A child’s blanket is draped over the crook of her left arm, the corner clutched tightly in her left hand close to her mouth. The right arm lies pronated across her thigh. The mother strokes her hair, whispering into her ear. Together they form a portrait which might have been painted by Mary Cassatt. “What’s wrong?” I ask, holding the little girl’s chart in my hand. “She won’t move her right arm,” the mother tells me. “As near as we can tell, it looks like it’s her wrist, but we’re not sure.” “When did she start to favor it?” The mother looks at the father, who sits on the small step stool at the far end of the exam room. “Sometime late yesterday afternoon,” he says. “I had her out to the park.” “Did she trip or fall down?” I ask. He shakes his head. “She was hanging on the monkey bars, but she didn’t fall.” He demonstrates by holding both hands clenched above his head—a gesture of helplessness. “Did you pick her up and swing her around holding her by the hands?” Once again he shakes his head. “How did she sleep last night?” “Terrible. She was up most of the night whimpering. We couldn’t console her.” “Sounds like nobody got any sleep,” I say. “Well, let’s have a look.” Gently, I lift the child’s hand from her lap. “Let’s count your fingers,” I say, checking each MCP joint in turn. I palpate the wrist and then move to the shoulder, running my fingers along the length of the clavicle. She doesn’t wince once. Next I drop my fingers to her elbow. When I attempt to supinate the forearm, she wrenches her face; tears well up in her eyes. Now I have my diagnosis. “I’m sorry,” I murmur, as I apply gentle pressure to the radial head and hyperpronate the arm. Beneath the pads of my fingers I feel a reassuring click.

I lay the child’s arm down in her lap. “There. All better?” The child stares at me with jeweled tears beaded on her cheeks, dewdrops on pink rose petals. A hush falls over the room. No one moves. “Let me see if I can find her something to reach for,” I say, darting out of the room. Momentarily, I return with a lollipop. I offer it to the little girl, holding it up to her eye level. “Would you like a lollipop? Yes? Go ahead, you can have it.” She hesitates, then reaches up for the pop with her right hand. “That’s the first time I’ve seen her move that arm all day,” the mother says. The father stares at his daughter from his perch in the corner. Dumbfounded at first, in a husky voice he utters one word: “Amazing.” “She probably partially dislocated one of the bones in her forearm when she was hanging from the monkey bars,” I explain. “We call it a subluxation. I popped it back into place. She’ll be fine now.” The mother has removed the plastic wrapper from the candy, and the child is busily sucking the pop. Her right arm is fully functional. Drool falls from her lower lip onto her sundress. The mother runs her fingers through her daughter’s hair. The father jumps up from his seat and thrusts his outstretched hand toward me. “Thanks, Doc,” he says, pumping my arm. Something akin to joy has replaced the former look of concern on his face. “Just avoid any sudden tugs on that arm, and she’ll do fine,” I tell them. I step out of the room, leaving them to gather up their things, and find a nook to jot a note in the chart. Moments later, I pass the couple in the hallway. The little girl is running ahead, squealing with delight. The mother smiles at me as they walk by. The father stops, turns and shakes my hand once again. “Amazing,” he says. And so in the middle of a humdrum summer afternoon at the office, in between sobbing febrile toddlers and heartbroken adolescents, those patients whose suffering I can do little to alleviate, momentarily I become a hero to one family. Subluxation of the radial head; nursemaid’s elbow—a common pediatric problem with a straightforward solution. I am no magician; any clinician worth his salt could have reduced it as well. This afternoon, I just happened to be the one who was there. Over three decades of practice, being there has been enough. JAAPA • DECEMBER 2011 • 24(12) • JAAPA


Case of the Month

Carol von Michaelis, PA-C

capillary refill time was less than 2 seconds; and sensation was intact distally. Strength was equal in both legs, and hamstring tightness was noted with a popliteal angle of 45°. A radiograph of the right knee was obtained (Figure 1).


Anterior cruciate ligament injury Meniscus injury Osteochondritis dissecans Osteochondroma

›DISCUSSION FIGURE 1. Initial right knee radiograph

›CASE A 12-year-old male presented with right knee pain that began after he fell during football practice about 18 months before. Shortly after the injury, the patient noted mild swelling and feelings of minor instability. The pain, which became localized over his anterior knee, seemed to wax and wane. The patient rated the pain at its most severe as 7 on a 10-point scale. One month after the injury, a pediatrician diagnosed knee strain. The patient played football for the entire season, but because the injury was not getting better over time, he was referred to pediatric orthopedics for further evaluation. Medical history was significant only for seasonal allergies, and except for occasional ibuprofen for sportsrelated pain, the patient was taking no medication. His gait was normal and symmetric. No swelling, effusion, or ecchymosis was noted in the right knee. Range of motion in the hips, knees, and ankles was full and painless bilaterally. The anterior region of the right knee was mildly tender, but there was no pain to palpation over the joint line. The knee was stable to varus and valgus stress at 0° and 30°. Lachman test was negative with a solid end point. Results of a McMurray test, patellar grind test, and dial test were also negative. Pedal pulses were 2+ bilaterally;

The diagnosis was osteochondritis dissecans (OCD) of the right medial condyle. MRI showed that the cartilage was intact and the lesion was stable. The patient was placed in a cylinder cast for 6 weeks. He was instructed to refrain from highimpact activity but was allowed to bear weight on the affected leg. At the 6-week follow-up visit, repeat radiographs showed a healing lesion. The patient was allowed a gradual return to sports but was told that if he felt any pain, he was to stop the activity and return to the clinic. The patient will be seen every 6 months until the knee lesion is completely healed. Osteochondritis dissecans was discussed in the literature as early as 1870 when Paget described a process of necrosis that resulted in a loose body in the knee.1 Juvenile osteochondritis dissecans (JOCD) occurs most commonly in the active patient between the ages of 10 and 20 years and affects males twice as often as it does females.2 The incidence of OCD in the knee is 3 to 6 of every 10,000 patients.2 The cause is unknown but believed to be associated with repetitive trauma.3 Other possible causes are related to genetics, inflammation, and ischemia.3 In JOCD, subchondral bone becomes soft and necrotic, leaving the cartilage to bear the weight of the joint. The most common location for an OCD lesion is the femoral condyle, but the talar dome and capitellum are also routinely affected. An untreated lesion can separate

from the surrounding tissue, causing a loose body in the joint. Early treatment is imperative for a good prognosis. OCD lesions are typically found first on a plain radiograph, after which an MRI is obtained. A fat-saturated proton-density weighted MRI is the best way to evaluate the stability of the lesion and condition of cartilage. Treatment of OCD is controversial, and evidence-based research is still in its early stages. Current treatment approaches depend on the stability of the lesion and the maturity of the skeleton.3 Conservative treatment for 3 to 6 months is the first-line approach for stable lesions, while operative treatment is indicated for loose lesions.3 Conservative approaches range from restricting activity to casting, and operative treatment ranges from arthroscopic drilling that will stimulate a healing response to fixation of the lesion. Patients who have an immature skeleton and a stable lesion with no cartilage damage have the best prognosis. Any patient suspected of having JOCD should be referred to a pediatric orthopedic specialist. Most patients exhibit healing within 6 weeks of casting, but full lesion healing often takes more than 6 months to a year. The chance of recurrence is low in patients who adhere to therapy. JAAPA Carol von Michaelis worked with John Polousky, MD, who is affiliated with the Research in Osteochondritis Dissecans of the Knee (ROCK) study group and the Rocky Mountain Youth Sports Medicine Institute in Centennial, Colorado. The author has indicated no relationships to disclose relating to the content of this article. Erich Fogg, PA-C, MMSc, department editor REFERENCES 1. O’Connor MA, Palaniappan M, Khan N, Bruce CE. Osteochondritis dissecans of the knee in children: a comparison of MRI and microscopic findings. J Bone Joint Surg Br. 2002;84(2):258-262. 2. Johnson MP. Physical therapist management of an adult with osteochondritis dissecans of the knee. http://ptjournal.apta. org/content/85/7/665.full.pdf. Accessed November 17, 2011. 3. Polousky JD. Juvenile osteochondritis dissecans. Sports Med Arthrosc. 2011;19(1):56-63. • DECEMBER 2011 • 24(12) • JAAPA


case report

Rhinocerebral mucormycosis: A rare fungal infection linked to diabetes Although usually prevented by the immune system, this disease is common in patients who are immunocompromised. As in this case, early detection and treatment are key.

Sarah Asman, MPA, PA-C; Mehrdad M. Behnia, MD, FACP, FCCP CASE

A 37-year-old male presented to his primary care physician with acute onset periorbital edema, tinnitus, and nasal congestion. He attributed his symptoms to ongoing chronic sinusitis. On physical examination, the patient was afebrile and had ptosis of the right eyelid with periorbital edema and erythema. Edema and hypertrophy of the nasal turbinates and posterior pharynx were also present. His history included hypertension and chronic anxiety. The patient denied smoking but admitted to drinking alcohol socially. His physician made the primary diagnosis of periorbital cellulitis and admitted him to the hospital for treatment, where he was started on clindamycin, vancomycin, and piperacillin-tazobactam. Two days after admission, the patient exhibited altered mental status. On neurologic examination, he had facial asymmetry due to complete ptosis and significant edema of the right eyelid. Extraocular movements were intact but limited during upward gaze in the right eye. CT of the brain showed cavernous sinus thrombosis with similar changes to the orbit, a semiacute right frontal lobe infarct, and diffuse sinusitis (Figure 1). Heparin was started in conjunction with ceftriaxone for the cavernous sinus thrombosis, and the patient’s previous antibiotic regimen was discontinued. Based on an elevated hemoglobin A1C level of 7.8% and random blood glucose level of 260 mg/dL, a presumptive diagnosis of type 2 diabetes mellitus was made. On hospital day 3, the patient’s neurologic condition began to deteriorate acutely. He exhibited some posturing with blindness of the right eye; the right pupil became dilated and nonreactive. CT of the head showed hemorrhage in the area where the right frontal lobe infarct had been (Figure 2). Left pupillary response was intact. Heparin was stopped, and the patient was intubated because of concern that the airway was compromised. The following day, repeat CT of the head showed a large frontal bleed with surrounding edema and mass effect as well as subarachnoid hemorrhage (Figure 3).


B FIGURE 1. CT showing cavernous sinus thrombosis (a) and orbit thrombosis (b), with the red arrow indicating the pathologic area • december 2011 • 24(12) • JAAPA E1

case report | Rhinocerebral mucormycosis The patient underwent a frontal lobectomy with removal of the blood clot. A complete right ethmoidectomy, right maxillary sinus antrostomy, frontal sinusotomy, and sphenoidectomy were also performed. Intraoperatively, significant devitalized mucous membranes were seen within the nasal cavity that were suspicious for an acute fungal process. The area was debrided, and pathology was consistent with mucormycosis. The patient was started on IV amphotericin B and anidulafungin. Multiple debridements of the right nasal cavity were subsequently performed. Bilateral myringotomy with insertion of a tympanostomy was also performed, and he was started on hyperbaric oxygen therapy (HBO). His condition started to improve dramatically, and he was subsequently discharged to an outpatient rehabilitation program on posaconazole after 21 days of treatment with amphotericin B, anidulafungin, and ceftriaxone.

FIGURE 2. Left, CT demonstrating right frontal lobe hemorrhage (red arrow) FIGURE 3. Right, CT showing frontal hemorrhage (red arrow) and surrounding edema and mass effect (yellow arrow)


Rhinocerebral mucormycosis is a rare fungal infection that historically is seen in the immunocompromised. Previously referred to as zygomycosis, changes in high-level taxonomy in reference to molecular phylogenetic analyses led to the class Zygomycota being renamed as Glomeromycota.1 Although this fungus is ubiquitous in the environment, the disease is usually prevented by the immune system and is therefore rare. As with other types of fungi, the most desirable environment for rhinocerebral mucormycosis to grow is in wet, damp places such as soil, composting vegetation, and bread. Well-recognized risk factors for the disease include diabetes mellitus, leukemia, aplastic anemia, myelodysplastic syndrome, blood dyscracias, immunosuppressive therapy in organ transplantation, renal disease, sepsis, and severe burns.2 The disease is primarily found in those who are immunocompromised, but it may also manifest in immunocompetent persons.3 In fact, in one study, nearly 20% of mucormycosis cases occurred in patients with “no underlying medical condition,” although the latter group had a history of penetrating trauma, surgery, or burns.3 Disease progression Rhinocerebral mucormycosis generally progresses in three stages.2 The first stage occurs after the fungal spores have been inhaled and infect the paranasal sinuses, resulting in formation of necrotic lesions in the nasal mucosa, turbinates, or hard palate.2 The second

stage is characterized by direct extension of the disease into the maxillary sinus or invasion of the surrounding vasculature. During the last stage, the fungus spreads into the cribriform plate or the orbital apex.2 Rhinocerebral mucormycosis usually manifests as an acute sinus infection but can lead to serious complications such as cavernous sinus thrombosis and vascular invasion if not treated early.4,5 Table 1 lists the distinguishing features of both bacterial sinusitis and rhinocerebral mucormycosis. Delayed treatment may also cause the disease to spread rapidly to adjacent structures such as the brain and orbits or to occlude the carotid artery, causing an internal carotid artery pseudoaneurysm.2,4,5 If the fungus invades the blood vessels extensively, infarction and necrosis of the involved tissue will eventually result.2 Treatment As of now, treatment options for rhinocerebral mucormycosis are still being optimized. Current therapy for the invasive disease includes treating the underlying predisposing factors, antifungal therapy, and surgical debridement of the affected tissues. Early recognition of the disease and treating the underlying cause of mucormycosis, such as diabetes, are key to improving outcomes. The antifungal treatment of choice for mucormycosis is amphotericin B, although very high doses are required because of the relative resistance of the fungus to the drug.

TEACHING POINTS ■■ Rhinocerebral mucormycosis is a rare fungal infection that historically is seen in the immunocompromised. ■■ Well-recognized risk factors for the disease include diabetes mellitus, leukemia, aplastic anemia, myelodysplastic syndrome, blood

dyscracias, immunosuppressive therapy in organ transplantation, renal disease, sepsis, and severe burns. ■■ The infection progresses in three stages and usually manifests as an acute sinus infection. If not treated early, it can lead to serious

complications such as cavernous sinus thrombosis and vascular invasion. ■■ Current therapy for the invasive disease includes treating the underlying predisposing factors, antifungal therapy, and surgical

debridement of the affected tissues. ■■ Early recognition of the disease and treating the underlying cause of mucormycosis are key to improving outcomes. • december 2011 • 24(12) • JAAPA E2

case report | Rhinocerebral mucormycosis TABLE 1. Features of bacterial sinusitis and rhinocerebral mucormycosis10 Sinusitis

Rhinocerebral mucormycosis


• Unilateral facial pain over maxillary dentition or maxillary sinuses, between eyes (ethmoid sinuses), over forehead (frontal sinuses) or head vertex (sphenoid sinuses) • Acute onset (1-4 weeks), purulent green or yellow nasal discharge or expectoration • Associated symptoms including cough, malaise, nasal congestion, fever, and headache

• Severe facial pain • Clear- to strawcolored nasal drainage • Visual symptoms may be noted at presentation in absence of significant nasal findings


• Tenderness to palpation of the affected sinuses • Red, swollen nasal turbinates

• Pathognomic finding: black eschar on the middle turbinate • Nasal mucosa can also appear normal or slightly pale


• Two-thirds of untreated patients with acute bacterial rhinosinusitis will improve symptomatically within 2 weeks • Consider antibiotics when symptoms last longer than 10-14 d or when symptoms are severe • First-line therapy is amoxicillin, trimethoprimsulfamethoxazole, or doxycycline

• Prompt wide surgical debridement and amphotericin B by IV infusion or lipid-based amphotericin B in patients with renal insufficiency • Some evidence to suggest iron chelator therapy as adjunct treatment

Amphotericin B works by binding to ergosterol, increasing the permeability of the fungal cell mebranes.6 Amphotericin B can be nephrotoxic, and renal indices should be monitored during therapy. Several studies have indicated that lipid formulations of amphotericin B, such as liposomal amphotericin B, may result in improved response rate and survival, reduction of fungal burden, and lesser nephrotoxicity.1 Surgical debridement is fundamental in combination with antifungal therapy because patients treated with antifungal therapy alone have very low cure rates.5 HBO has been reported by some to improve treatment outcomes in patients with rhinocerebral mucormycosis. Although no definitive evidence exists that this treatment can lower mortality, it has been used to ameliorate tissue

hypoxia and lactic acidosis associated with mucormycosis.2 In one case study, three presumptive benefits of HBO were as follows: a) increased oxygenation to the vessels and tissues distal to the affected sites with resulting improvement in acidosis; b) inhibited growth of the fungus caused by the decrease in acidosis; and c) fungicidal properties of oxygen when provided in high quantities.7 Outcome In our patient, treatment was initiated with amphotericin B, anidulafungin (Eraxis), and ceftriaxone. Anidulafungin is an echinocandin antifungal that inhibits fungal cell wall synthesis by inhibiting beta 1,3 glucan.8 We thought that the combination of antifungals would be most beneficial to this patient based on the extent of the disease while the ceftriaxone would provide simultaneous broad spectrum coverage for other opportunistic bacteria. In addition, the additive effects of the two antifungals from different classes could potentiate a greater response to both drugs while attenuating the need for higher doses of amphotericin B required for extensive disease involvement. Posaconazole is a triazole oral antifungal with a good safety profile that blocks the synthesis of ergosterol. It can be used as salvage therapy or in conjunction with amphotericin B or echinocandin in the treatment of mucormycosis, although randomized trials are not available to prove its complete efficacy.9 Deferasirox, an oral iron chelator used for treatment of iron overload, has in vitro fungicidal activity against Mucorales. A phase II study, “DefrasiroxAmbisome Therapy for Mucormycosis,” has been completed, but results are yet to be published (NCT00419770). CONCLUSIONS

This report summarizes the case of a patient with mucormycosis of the sinuses requiring extensive sinus debridement and cavernous sinus thrombosis. The hospital course was complicated by a large, frontal intracranial bleed with mass effect requiring craniotomy. He was treated with 21 days of IV amphotericin B, anidulafungin, and ceftriaxone in conjunction with HBO and outpatient posaconazole. Although mucormycosis is rare, clinicians must hold a high index of suspicion when dealing with patients who present with symptoms like those in our patient. Although complaints such as nasal congestion and periorbital edema are common in the primary care setting, the health care provider must take into account the patient’s underlying comorbidities when formulating a differential diagnosis. In this case report, undiagnosed diabetes mellitus was the precursor to the development of mucormycosis. Recognition and correction of the factors that predispose patients to rhinocerebral mucormycosis are critical in order to avoid serious complications of this rare infection. JaApa At the time this article was written, Sarah Asman was a PA student at Georgia Health Sciences University, Augusta, Georgia. She currently practices at Southern Surgical Group, West Columbia, South Carolina. Mehrdad Behnia is clinical associate professor of medicine at Georgia Health Sciences University. The authors have indicated no relationships to disclose relating to the content of this article. • december 2011 • 24(12) • JAAPA E3

case report | Rhinocerebral mucormycosis REFERENCES 1. Sun HY, Singh N. Mucormycosis: its contemporary face and management strategies. Lancet Infect Dis. 2011;11(4):301-311. 2. Alvernia JE, Patel RN, Cai DZ, et al. A successful combined endovascular and surgical treatment of a cranial base mucormycosis with an associated internal carotid artery pseudoaneurysm. Neurosurgery. 2009;65(4):733-740; discussion 740. 3. Cano P, Horseman MA, Surani S. Rhinocerebral mucormycosis complicated by bacterial brain abscess. Am J Med Sci. 2010;340(6):507-510. 4. Ibrahim AS, Spellberg B, Edwards J Jr. Iron acquisition: a novel perspective on mucormycosis pathogenesis and treatment. Curr Opin Infect Dis. 2008;21(6):620-625. 5. Ibrahim M, Chitnis S, Fallon K, Roberts T. Rhinocerebral mucormycosis in a 12-year-old girl. Arch Neurol. 2009;66(2):272-273.

6. Moen MD, Lyseng-Williamson KA, Scott LJ. Liposomal amphotericin B: a review of its use as empirical therapy in febrile neutropenia and in the treatment of invasive fungal infections. Drugs. 2009;69(3):361-392. 7. Price JC, Stevens DL. Hyperbaric oxygen in the treatment of rhinocerebral mucormycosis. Laryngoscope. 1980;90(5 pt 1):737-747. 8 Chen SC, Slavin MA, Sorrell TC. Echinocandin antifungal drugs in fungal infections: a comparison. Drugs. 2011;71(1):11-41. 9. Spellberg B, Walsh TJ, Kontoyiannis DP, et al. Recent advances in the management of mucormycosis: from bench to bedside. Clin Infect Dis. 2009;48(12):1743-1751. 10 McPhee S, Papadakis M, Rabow M, eds. Lange Current Medical Diagnosis and Treatment. 48th ed. New York, NY: McGraw Hill; 2009. • december 2011 • 24(12) • JAAPA E4

Critically Appraised Topic RAC H E L E. S M I T H , BS N; WI LSO N CRONE, MD, PhD

Is rifaximin an effective treatment option for irritable bowel syndrome?


32-year-old female presents to the GI clinic complaining of ongoing symptoms of irritable bowel syndrome (IBS). Her primary complaints are bloating, gas, abdominal pain/discomfort, frequent loose stools, and bowel urgency. The diagnosis of diarrhea-predominant IBS was made 2 years ago and based on Rome II criteria. Physical examination, history, stool cultures, and colonoscopy yielded no significant findings. She has tried diet modification, stress reduction, antispasmodics, antidepressants, antidiarrheals, and probiotics. Except for some resolution of stool consistency with the antidiarrheal agents, her symptoms have been unrelieved.


In a 32-year-old female with diarrheapredominant IBS, would rifaximin (Xifaxan) provide adequate global relief of symptoms?


IBS is a functional GI disorder characterized by abdominal pain and discomfort associated with constipation, diarrhea, or both, as well as abdominal bloating and gas. The exact etiology is unknown, but it is thought to be multifactorial. There may be some linkage to small-intestinal bacterial overgrowth (SIBO). Based on lactulose breath tests, the estimated prevalence of SIBO in those with IBS has varied from 10% to 84%.1 Bacterial overgrowth may contribute to symptoms in a subset of IBS patients, possibly those with postinfectious IBS. Current treatment for IBS is focused on lifestyle changes and various pharmacotherapy individualized to the patient’s most bothersome symptoms. Various treatments

are available, although most are not uniformly effective.2 Rifaximin is a minimally absorbed, broad-spectrum antibiotic that has good safety and side effect profiles and has been associated with a low risk for bacterial resistance. It is currently approved by the FDA for use in traveler’s diarrhea and hepatic encephalopathy.


RESULTS A search of the PubMed and Cochrane databases using the keywords rifaximin AND irritable bowel syndrome, with limits of humans, English language, and studies within the past 10 years, retrieved 38 articles. A majority of the articles addressed SIBO and traveler’s diarrhea. No meta-analyses on rifaximin’s use in IBS were found. There were reviews regarding the medication and traveler’s diarrhea or SIBO but no systematic reviews about IBS and rifaximin. A follow-up, focused PubMed search of rifaximin AND IBS treatment with clinical trial limit and no language limits retrieved a total of eight articles. Another search, using the Clinical Queries tool of PubMed in the therapy domain with both narrow and broad scopes, did not identify additional articles. After reviewing the handful of articles that were applicable to the clinical question, two studies were selected. The first study, a recent, large, multicenter, randomized controlled trial (RCT), had a higher level of evidence and more direct focus on the clinical question. It investigated the effects of rifaximin on global IBS symptoms and on abdominal bloating3 and was an elaboration of a smaller RCT by the same group.4 The second study, which had a lower level of evidence, was

a recently published retrospective cohort study that examined retreatment with rifaximin and subsequent duration of symptom relief.5 Notably, all three studies had the same lead author.


In the first study identified, Pimentel

and colleagues conducted parallel, phase 3, double-blind RCTs (TARGET1 and TARGET2) within two separate multicenter groups (N = 1,260).3 Subjects were older than 18 years (average age, 46 years), mostly female (75%), and mostly white (90%). All patients had IBS based on Rome II criteria and had undergone a colonoscopic examination in the 2 years prior to enrollment. The patients were randomly assigned to receive either rifaximin 550 mg or placebo three times daily for 2 weeks, after which they were followed for an additional 10 weeks. At the conclusion of the 14-day treatment period, patients were assessed in the clinic and through telephone interviews. The patients evaluated their average daily amount of abdominal pain/discomfort/bloating versus stool consistency on separate Likert scales and responded to a general question about overall relief of symptoms since starting the study. Relief of symptoms was defined as a decrease of at least 30% from baseline in weekly mean ratings of IBS-related abdominal pain and discomfort and a weekly mean stool consistency score of less than 4 Rachel Smith is a student at the Center for Physician Assistant Studies, Albany Medical College, Albany, New York. Wilson Crone is an assistant professor and basic science instructor, also at the Center for Physician Assistant Studies. The authors have indicated no relationships to disclose relating to the content of this article. • december 2011 • 24(12) • JAAPA


Critically Appraised Topic for at least 2 of the 4 weeks during a given month. Results were analyzed in a modified intention-to-treat fashion. All patients who took at least one dose of the drug or placebo were included in their respective categories, with only two (of 1,260) patients not included in the analysis after refusing any dose. During weeks 3 to 6, 254 (41%) of 624 patients on rifaximin improved globally, whereas of 634 on placebo, 201 (32%) showed improvement. This absolute rate difference of 9% allows calculation of the number needed to treat (NNT), which was equal to 12, with a 95% confidence interval (CI) of 7-27.6 The odds ratio for the relief of global IBS symptoms on rifaximin versus placebo during the entire 3-month study was 1.44 (95% CI, 1.17-1.77; P <.001). No differences in side effect rates were reported between the treatment and placebo groups. A higher-than-usual placebo response rate is often seen in controlled trials of pharmacologic treatment for IBS.1 A systematic review conducted to examine the placebo response rate seen in 45 placebo-controlled RCTs for IBS treatments highlighted that the average placebo response rate was 40.2% (95% CI, 35.9%-44.4%), with a range of 16% to 71%.7 In this context, the studies by Pimentel and colleagues had relatively low and acceptable placebo rates. A second concern was possible development of antibiotic resistance, either as a side effect or as a loss of efficacy. Rifaximin is structurally similar to rifampin, which is occasionally used to treat staphylococcal foreign body infections.8 When concerns of resistance and cross-resistance were raised in response to the publication of their study, the researchers pointed out that gut flora resistance was not seen in their study population or in others treated with rifaximin. Also worth noting is that the 2011 RCT study by Pimentel and colleagues was funded by a grant from Salix Pharmaceuticals, which manufactures rifaximin. The authors noted that the

data collection and interpretation were done independently. The second study identified was a retrospective cohort study conducted by Pimentel and other researchers. This study consisted of a large-scale chart review of patients with an IBS diagnosis who were treated with rifaximin during January 2007 to January 2011 at a single tertiary-care medical center.5 Subjects (average age, 47 years; 61% female) had a diagnosis of either diarrhea-predominant or mixed IBS. Exclusion criteria included constipation-predominant IBS, other chronic GI disorders, a history of GI surgery, current narcotic use, and concurrent use of another antibiotic. Patients who had been treated with rifaximin and returned after symptom relapse for rifaximin retreatment were further evaluated to assess the effects of retreatment. The retreatment date was designated as the relapse date. A total of 522 charts were reviewed, with 187 meeting the study inclusion criteria; 169 patients were treated with rifaximin and 71 received retreatment. Of the 169 patients initially treated with rifaximin, 148 were seen for follow-up and 111 (75%) had noticed improvement in their symptoms. Of the 71 patients receiving retreatment, 48 received a second treatment; 22, a third retreatment; 9, a fourth retreatment, and 4, a fifth retreatment. Those who were retreated exhibited no decline in response to rifaximin, with at least 75% reporting improvement in their symptoms after each retreatment. The median duration of benefit at each of the retreatment periods was a minimum of 4 months (range, 0.5-45 months). The retrospective nature of this study did not allow researchers to incorporate additional details elicited from subjects. In addition, designation of the patient office revisit as the relapse date obscured differences among patients suffering breakthrough symptoms compared with those who were experiencing a gradual buildup of symptoms. Finally, those patients who did not revisit the office

for follow-up were not included at all in the analysis of that round of treatment, either as a success or a failure, leaving a question as to whether or not those individuals perceived a benefit. Regardless, while this retrospective study does not focus on the clinical question of success following first-time treatment, it does demonstrate the long-term effectiveness of treatment and retreatment with rifaximin in a clinical setting dedicated to patients with IBS.


Given the nature of current symptombased IBS treatment, it is significant to find a promising medication that may treat an underlying cause of IBS. In both studies, only some patients experienced relief with rifaximin. Further studies are needed to identify the possible subgroups of IBS patients who are responsive to the medication, as well as to ensure confirmation of the therapy’s effectiveness by more than one research group. Nevertheless, rifaximin may be a valid treatment option in those with IBS who have had no relief from traditional medications and lifestyle modifications. jaapa Mark E. Archambault, DHSc, PA-C, department editor

REFERENCES 1. Frissora CL, Cash BD. Review article: the role of antibiotics vs. conventional pharmacotherapy in treating symptoms of irritable bowel syndrome. Aliment Pharmacol Ther. 2007;25(11):1271-1281. 2. Khan S, Chang L. Diagnosis and management of IBS. Nat Rev Gastroenterol Hepatol. 2010;7(10):565-581. 3. Pimentel M, Lembo A, Chey WD, et al. Rifaximin therapy for patients with irritable bowel syndrome without constipation. N Engl J Med. 2011;364(1):22-32. 4. Pimentel M, Park S, Mirocha J, et al. The effect of a non­ absorbed oral antibiotic (rifaximin) on the symptoms of the irritable bowel syndrome: a randomized trial. Ann Intern Med. 2006;145(8):557-563. 5. Pimentel M, Morales W, Chua K, et al. Effects of rifaximin treatment and retreatment in nonconstipated IBS subjects. Dig Dis Sci. 2011;56(7):2067-2072. 6. GraphPad Software. Quick Calcs. quickcalcs/NNT1.cfm. Accessed November 8, 2011. 7. Patel SM, Stason WB, Legedza A, et al. The placebo effect in irritable bowel syndrome trials: a meta-analysis. Neurogastroenterol Motil. 2005;17(3):332-340. 8. Valentin T, Leitner E, Rohn A, et al. Rifaximin intake leads to emergence of rifampin-resistant staphylococci. J Infect. 2011;62(1):34-38. • december 2011 • 24(12) • JAAPA


Patient-oriented evidence that matters

Surgery effective for spinal stenosis unresponsive to conservative treatment

Clinical question Is surgery effective

in patients with symptomatic lumbar spinal stenosis? Bottom line In patients with symptomatic lumbar spinal stenosis that does not improve with 3 to 6 months of conservative treatment, those who are then treated surgically appear to do better than those treated with continued conservative measures. Since these authors only found a small number of studies, publication bias is a concern. (LOE = 1a–) Synopsis These authors searched multiple databases for randomized trials comparing surgery with conservative treatment in patients with symptomatic lumbar spinal stenosis. They do not describe searching for unpublished sources of data. Two authors independently evaluated the quality of the studies with disagreements settled by consensus with the third author. Ultimately, they included 11 publications of 5 small studies (918 patients). They report that, overall, the quality of the included studies was good, although none of the studies were blinded and most used self-reported outcomes. In each of the studies, patients did not undergo surgery until after they had failed 3 to 6 months of conservative treatment. Four of the studies compared decompressive surgery; one evaluated an interspinous implant. This latter study was the only industry-sponsored study. The comparison treatments were quite varied and included orthotic devices, physical therapy, nonsteroidal antiinflammatory drugs, analgesics, transcutaneous electrical nerve stimulation, ultrasound, and epidural steroids. Follow-up ranged between 2 and 10 years. The original intent was to pool the data. However, these authors exercised restraint and decided to abandon this strategy when they saw significant heterogeneity in interventions, com

parisons, study quality, patient selection, and outcomes. The authors note that the patients receiving conservative treatment improved, but in all of the studies the degree of improvement was greater in patients treated surgically. They also noted that the benefit of surgery was noticeable by 3 to 6 months and remained constant for up to 2 to 4 years. After 2 to 4 years, the treatment differences tended to be smaller. Since they only found 5 small studies, the potential for publication bias in favor of positive studies is a real concern.


systematic review of randomized controlled trials. Spine.

ratio for hysterectomy rose with the number of CDs, reaching an absolute risk of approximately 9% with 5 or more CDs (odds ratio = 15; 95% confidence interval [CI], 7-34). The absolute risk of placenta previa with any number of CDs was 1.2% (0.8-1.5 CI) and increased from 1.0% with one prior CD to 2.8% with 3 or more. The incidence of placenta accreta increased with the number of CDs up to an approximately 7% absolute risk with 5 or more CDs. There was no observed increase in the risk of perioperative infection. The abstract cited increased risks of transfusion and composite maternal morbidity, but details were not provided in this publication.


Marshall NE, Fu R, Guise JM. Impact of multiple cesarean deliver-

Kovacs FM, Urrútia G, Alarcón JD. Surgery versus conservative treatment for symptomatic lumbar spinal stenosis: a

Risk of serious maternal morbidity with multiple cesarean deliveries

Clinical question Are multiple cesar-

ean deliveries associated with an increased risk of serious maternal morbidity? Bottom line Serious maternal morbidity—including hysterectomy, placenta accreta, and placenta previa—increases with the number of cesarean deliveries (CDs). These risks should be considered in the decision to attempt trial of labor after a CD. (LOE = 2a) Synopsis This systematic review and meta-analysis of observational studies was undertaken to determine the risk of serious maternal morbidity related to increasing numbers of CDs. The authors included 21 studies published from 1980 to 2009 from developed countries with 2,282,922 deliveries. They excluded studies of women without prior CD; studies of fewer than 10 participants; studies of breech delivery; and those with exclusive focus on preterm delivery, low birth weight, or multiple births. Study quality was methodically rated by 2 investigators, and studies rated as poor quality were also excluded. Hysterectomy (7 studies) increased with the number of CDs. The odds

ies on maternal morbidity: a systematic review. Am J Obstet

Gynecol. 2011;205(3):262.e1-262.e8.

High-dose saw palmetto no better than placebo for BPH symptoms Clinical question Is high-dose saw

palmetto effective in reducing lower urinary tract symptoms associated with benign prostatic hyperplasia? Bottom line Saw palmetto extract— given in doses up to 3 times the standard recommended daily dose—was no more effective than placebo in improving lower urinary tract symptoms in men with benign prostatic hyperplasia (BPH). (LOE = 1b) Synopsis These investigators identified 369 healthy men, 45 years or older, meeting criteria for clinically significant lower urinary tract symptoms using a standard BPH symptom scoring tool. Exclusion criteria included recent treatment with an alpha-blocker or 5-alpha-reductase inhibitor, and coagulopathy or use of anticoagulants. Patients randomly received (concealed allocation assignment) standardized saw palmetto fruit extract beginning at 320 mg per day with dose escalation to double and triple dose at 24 and 48 weeks, respectively, or identical placebo. Study participants unaware • december 2011 • 24(12) • JAAPA


Patient-oriented evidence that matters

of treatment group assignment selfassessed outcomes. Complete follow-up occurred for 97% of patients at 72 weeks. Using modified intention-to-treat analysis including participants who took at least 1 dose of study medication and with at least 1 follow-up visit, the proportion of patients achieving a predetermined clinically relevant improvement was similar in the saw palmetto and placebo groups (42.6% vs 44.2%, respectively). An analysis of dose response also showed no difference between the saw palmetto and placebo groups. A perprotocol analysis, including only participants compliant with all doses and all visits, similarly found no differences between the saw palmetto and placebo groups. There were also no differences between the treatment groups in any of the secondary outcomes including nocturia; global assessment of quality of life, including sexual function; sleep quality; or prostatitis symptoms. Adverse events were minimal and similar in both groups. The study was 90% powered to detect a clinically relevant difference. Barry MJ, Meleth S, Lee JY, et al; Complementary and Alternative Medicine for Urological Symptoms (CAMUS) Study Group. Effect of increasing doses of saw palmetto extract on lower urinary tract symptoms: a randomized trial. JAMA. 2011;306(12):1344-1351.

Benefits and harms of atypical antipsychotics for off-label use

Clinical question How effective and

safe are atypical antipsychotics when used for off-label conditions? Bottom line The risks and benefits of various atypical antipsychotics are mixed for off-label conditions. See the synopsis for individual conditions and associated effective drugs. Risks in the elderly are significant, including death, stroke, and extrapyramidal symptoms. (LOE = 1a–) Synopsis Atypical antipsychotics are commonly used in clinical practice for off-label conditions including

agitation in dementia, anxiety, eating disorders, insomnia, substance abuse, and obsessive-compulsive disorder (OCD). These investigators thoroughly searched multiple databases including PubMed, EMBASE, PsycInfo, and the Cochrane Registry. Other sources included FDA and Health Canada regulatory documents and references of relevant publications. English-languageonly randomized trials were used to assess efficacy outcomes and both clinical trials and large observational trials were used to assess adverse events. Four investigators independently critiqued studies for inclusion criteria and methodologic quality using standard rating scales. Disagreements were resolved by consensus. The overall strength of evidence was classified as high, moderate, or low. Formal assessments were also performed to detect publication bias and heterogeneity. Studies meeting inclusion criteria included 162 clinical trials for efficacy outcomes and 231 observational trials for adverse events. In the treatment of elderly patients with dementia and symptoms including psychosis, mood alterations, and aggression, small but statistically significant effect sizes were observed for aripiprazole (Abilify), olanzapine (Zyprexa), and risperidone (Risperdal). Only quetiapine (Seroquel) was significantly associated with an improvement in generalized anxiety. Similarly, only risperidone was effective for OCD. However, the level of evidence for the use of risperidone for OCD was classified as moderate on the basis of potential publication bias. There was no conclusive evidence of effectiveness for any of the atypical antipsychotics for insomnia, eating disorders, or substance abuse. The evidence was noted as mixed regarding personality disorders and PTSD. Adverse events in the elderly included an increased risk of death (number needed to treat to harm [NNTH] = 87), stroke (NNTH = 53 for risperidone), extrapyramidal symptoms (NNTH = 10 for olanzapine and


20 for risperidone), and urinary tract symptoms (NNTH = 16-36). Adverse events in the nonelderly included weight gain, fatigue, akathisia, and extrapyramidal symptoms. Maher AR, Maglione M, Bagley S, et al. Efficacy and comparative effectiveness of atypical antipsychotic medications for off-label uses in adults: a systematic review and meta-analysis. JAMA. 2011;306(12):1359-1369.

Adenoidectomy does not decrease URIs in children

Clinical question Does adenoidectomy

decrease infections in children with recurrent respiratory tract infections? Bottom line Adenoidectomy with or without myringotomy had no clinical benefit as compared with watchful waiting in children aged 1 year to 6 years with recurrent upper respiratory tract infection (URI). Rates of infection declined over 2 years in both groups. (LOE = 1b) Synopsis To identify patients, these investigators sought referrals from ear, nose, and throat surgeons in 13 hospitals for patients aged 1 to 6 years whom they selected for adenoidectomy with or without myringotomy to treat recurrent URI. The 111 children were randomized, using concealed allocation, to receive no treatment or adenoidectomy with or without myringotomy. No masking occurred. URI was defined as fever with at least 2 symptoms of nasal stuffiness or mouth breathing, nasal discharge, sore throat, or cough. Over the next 2 years, there were 7.91 episodes of URI per person per year in the adenoidectomy group and 7.84 episodes in the comparison group. Days of URI and middle ear complaints with fever were similar between the groups, as was health-related quality of life. Children who had surgery had significantly more days of fever than did children in the comparison group. van den Aardweg MT, Boonacker CW, Rovers MM, et al. Effectiveness of adenoidectomy in children with recurrent upper respiratory tract infections: open randomised controlled trial.

BMJ. 2011;343:d5154 • december 2011 • 24(12) • JAAPA


Patient-oriented evidence that matters

Dabigatran cost-effective for AF prophylaxis in select patients

Clinical question Is dabigatran cost-

effective as compared with warfarin for patients with atrial fibrillation? Bottom line Dabigatran is only costeffective for patients who have a poorly controlled international normalized ratio (INR) or who are at high risk of bleeding and/or stroke. It is worth pulling the article to review Figure 3, which can be used to guide point-ofcare decision making. (LOE = 2b) Synopsis Dabigatran, an oral direct thrombin inhibitor, is an expensive but more convenient alternative to warfarin because it does not require monitoring. It is argued that although the direct drug cost of dabigatran is much higher than that of warfarin, the cost is offset by not needing visits for monitoring. This cost-effectiveness analysis, funded by the American Heart Association, attempts to determine whether this is true. The authors compared 6 strategies: no treatment, aspirin once daily, aspirin plus clopidogrel, warfarin, dabigatran 110 mg twice daily, and dabigatran 150 mg twice daily.

The base case was the typical 70-year-old patient with atrial fibrillation, a moderate risk of stroke, and no contraindication to anticoagulation. The authors also varied the risk of stroke (based on the CHADS2 score) and risk of major bleeding (based on the HEMORR2HAGES score) to see the impact of changing risk on the optimal strategy. The authors used reasonable estimates of benefits, harms, and costs in their model, and they performed sensitivity analyses to study the effect of varying the base estimates. For example, the risk of stroke was varied from 0.8/100 to 13.7/100 person-years; major bleeding from 1.9/100 to 10.4/100 person-years; patient age from 60 years to 80 years; and time in the therapeutic INR range from less than 57% to more than 72%. In the Markov model, patients moved from one health state to another or stayed in the same health state each month. This was repeated for up to 20 years, with the costs and outcomes determined for each of the 6 strategies. For the base case, warfarin cost an additional $12,000 per qualityadjusted life year (QALY) compared with aspirin. (A therapy is generally


considered cost-effective if it costs less than $50,000/QALY). Dabigatran 150 mg cost $86,000/QALY using the base case assumption, while dabigatran 110 mg cost $150,000/QALY. Dual therapy with aspirin and clopidogrel resulted in fewer QALYs for higher cost, so it wasn’t even in the running. For the base case, dabigatran was cost-effective for patients at high risk of stroke (CHADS2 score = 3 or higher) and those at moderate risk of stroke but at high risk of bleeding. The sensitivity analysis also showed that for patients who had less than 57% time in the therapeutic range, dabigatran was the preferred option if the CHADS2 score was 2 or higher, but if patients spent more than 72% of time in range, dabigatran was never the preferred option. For patients with a CHADS2 score of 0 or 1, treatment with aspirin or no treatment was often the preferred strategy. Shah SV, Gage BF. Cost-effectiveness of dabigatran for stroke prophylaxis in atrial fibrillation. Circulation. 2011;123(22): 2562-2570.

Levels of evidence in Bottom line are explained at Copyright © 1995-2011 John Wiley & Sons, Inc. All rights reserved. • december 2011 • 24(12) • JAAPA


JAAPA December 2011 Issue  

JAAPA December 2011 full issue PDF

Read more
Read more
Similar to
Popular now
Just for you