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JAAPA JANUARY 2012;25(1) | CLOSTRIDIUM DIFFICILE • INTERNAL HERNIA • CRP IN RENAL CANCER • OLDER PHYSICIAN ASSISTANTS • LARGE-VESSEL ISCHEMIC STROKE
J O U R N A L O F T H E A M E R I CA N ACA D E M Y O F P H YS I C I A N A SS I STA N TS
COMMENTARY Celebrating 25 years of JAAPA
PHARMACOLOGY CONSULT Managing opioid allergy
TOPICS IN INFECTIOUS DISEASES Universal vaccination for inﬂuenza
RESEARCH REPORT Characteristics of clinically active older physician assistants
>>Earn 1 AAPA Category I CME credit with this issue CME Current management of Clostridium difﬁcile infection
CME Acute large-vessel ischemic stroke
Internal hernia, PAGE 37
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Reamer L. Bushardt, PharmD, PA-C, Editor in chief
CEO, Jennifer L. Dorn
Jim Anderson, PA-C, ATC, University of Washington Medicine— IT Services, Seattle, WA • Diane Bruessow, RPA-C, DFAAPA, 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 Dehn, MPA, PA-C, DFAAPA, College of Health and Human Services, Northern Arizona University, Flagstaff • Alexandra Godfrey, MS, PA-C, St. Joseph’s Mercy Hospital, Ypsilanti, MI • Wanda C. Gonsalves, MD, Medical University of South Carolina, Charleston • 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 M. Klingler, MS, PA-C, Salmon River Clinic, Stanley, ID • Brian T. Maurer, PA-C, Enfield Pediatric Associates, Enfield, CT • Steve Wilson, PA-C, Peninsula Regional Medical Center, Salisbury, MD
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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
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Brief Report: Richard Dehn, MPA, PA-C, DFAAPA • Critically Appraised Topic: Mark E. Archambault, DHSc, PA-C • Case of the Month: Erich Fogg, PA-C, MMSc • A Day in the Life: Zachary Hartsell, MPAS, PA-C • Dermatology Digest: Joe R. Monroe, PA-C, MPAS • Diagnostic Imaging Review: Julie Edmiston, PA-C, RT • Emergency Medicine Notes: Alexandra Godfrey, MS, PA-C • Genomics in PA Practice: Michael Rackover, PA-C, MS; Constance Goldgar, MS, PA-C • Humane Medicine: Brian T. Maurer, PA-C • PA Quandaries: F. J. Gianola, PA; Jim Anderson, PA-C, ATC • Pharmacology Consult: Larissa DeDea, PharmD, BCPS, PA-C • Quick Recertiﬁcation Series: Dawn Colomb-Lippa, MHS, PA-C; Amy M. Klingler, MS, PA-C • The Surgical Patient: Steve Wilson, PA-C • Topics in Infectious Disease: Roy A. Borchardt, PA-C, PhD • When the Patient Asks: Mary L. Hewett, MS, PA-C
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 25, Number 1, January 2012. 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 www.jaapa.com. Periodicals postage rate paid at New York, NY 10001 and additional mailing ofﬁces. © 2012 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.
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Table of Contents VO L. 2 5, N O. 1
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10 WEB ARTICLES FOR JANUARY 12 COMMENTARY 25 years of JAAPA: Honoring the past, awaiting the future Leslie A. Kole, PA-C
14 COMMENTARY A quarter-century of JAAPA: A long, remarkable journey Sarah Zarbock, PA-C
17 PHARMACOLOGY CONSULT Prescribing opioids safely in patients with an opiate allergy Larissa DeDea, PharmD, BCPS, PA-C
18 DERMATOLOGY DIGEST What is behind this postpartum puzzler? Joe R. Monroe, PA-C, MPAS
32 CME ARTICLE Clostridium difficile: A new look at an old but increasingly deadly infection Jacqueline S. Barnett, MSHS, PA-C
37 THE SURGICAL PATIENT An internal hernia causes abdominal pain and small bowel obstruction Lisa Vieira, DHS, PA-C; Sonia James, RN, MA, ACNP-BC, CCRN
CONTENTS CONTINUED ON PAGE 8
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:
23 CLINICAL WATCH HIV/AIDS: Improved outcomes, less disparity CHAC, the Clinical and Health Affairs Commission of the AAPA
Medical knowledge Interpersonal and communication skills Patient care Professionalism
27 TOPICS IN INFECTIOUS DISEASES Battling influenza: Universal vaccination is the primary weapon Roy A. Borchardt, PA-C, PhD; Kenneth V. I. Rolston, MD 6
JAAPA • JANUARY 2012 • 25(1) • www.jaapa.com
Addressed in the articles on pages 17, 18, 23, 27, 32, 37, 45, 54, 60, 63, 65, 73 17, 68 17, 18, 23, 27, 32, 37, 45, 54, 60, 63, 65, 68, 73 12, 14, 17, 18, 23, 27, 32, 37, 45, 48, 54, 60, 63, 65, 68, 73
Practice-based learning and improvement
17, 18, 23, 27, 32, 37, 45, 54, 63, 65, 73
32, 48, 54
Contents 45 CASE REPORT C-reactive protein: A clinically useful biomarker in renal cell carcinoma Timothy V. Johnson, MD; Jennifer DeLong, PA; Viraj A. Master, MD, PhD
48 RESEARCH REPORT The characteristics of clinically active older physician assistants Roderick S. Hooker, PhD, MBA, PA; Christal Ramos, MPH; R. Paola Daly, MHS; Raymond Fang, MS
54 CME ARTICLE
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 JAAPA.com for more details of our 25th anniversary celebration!
State-of-the-art interventions in acute large-vessel ischemic stroke Robert F. Brach, PA-C
59 CME POSTTEST 60 QUICK RECERTIFICATION SERIES Hypoparathyroidism; Meniere disease Barbara Poetzsch, PhD, RPA-C
63 DIAGNOSTIC IMAGING REVIEW A different kind of headache in a patient with migraines Jason Ausmus, PA-C; Rahul Sharma, MD, MBA, FACEP
65 GENOMICS IN PA PRACTICE Chromosomal microarray testing W. Andrew Faucett, MS, CGC; Melissa Savage, MS, CGC
68 EMERGENCY MEDICINE NOTES Expiration date Alexandra Godfrey, MS, PA-C
69 CLASSIFIED ADVERTISING 73 CASE OF THE MONTH Cynthia Bunde, MPAS, PA-C; Bernadette Howlett, PhD; Nicholas Ogami; Rebecca Hall 8
JAAPA • JANUARY 2012 • 25(1) • www.jaapa.com
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 email@example.com. List your areas of expertise in the message, and attach a CV. COVER ILLUSTRATION: Christy Krames
THIS MONTH’S ARTICLES
www.jaapa.com/online-only Online-only articles Online Review Article Chikungunya virus: An emerging condition in the industrialized world Alicia Weitzel, BS; Paul P. Rega, MD, FACEP; Christopher E. Bork, PhD, EMT-B, FASAHP When the Patient Asks Does my child need ﬂuoride supplements? Yekaterina Manyoky; Brian N. Fink, PhD Interpreting ECGs James F. Ginter, MPAS, PA-C; Patrick J. Loftis, PA-C, MPAS, RN POEMs • Survivors of out-of-hospital cardiac arrest have lower memory scores • Smoking cessation counseling for pregnant women lacks effectiveness • BE progresses to cancer at only 0.12% per year • Oral care with chlorhexidine reduces the risk of VAP in intubated patients • Adjuvant increases efﬁcacy of inﬂuenza vaccine in infants and children • Daily probiotic reduces upper RTI duration in elderly
Online columns Ask a Librarian! Our experts answer your questions about how to ﬁnd information and resources in medical libraries. 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 Clinical informatics certiﬁcation may be on the way for PAs The American Medical Informatics Association (AMIA) recently announced its intent to develop a certiﬁcation in clinical informatics for non-MDs.
Health Disparities Blog AAPA Health Disparities Work Group
Social media reconsidered Amy M. Klingler, MS, PA-C After several conversations with my colleagues on the editorial board, I have started to reconsider my aversion to Twitter. Shift work disorder: More than just poor sleep? Zachary Hartsell, MPAS, PA-C Preliminary data are beginning to suggest that shift work may have more negative effects on health than just disrupting sleep.
Screening for abuse: Intimate partner violence does not follow any rules The discussion of intimate partner violence (IPV) is not always front and center in the United States.
The January Challenge Describe the most important medical advance of the past 25 years. Go to the JAAPA 25th Anniversary Monthly Challenge on www.jaapa.com to send us your answer, and you could win a $100 gift card.
JAAPA • JANUARY 2012 • 25(1) • www.jaapa.com
COMMENTARY Leslie A. Kole, PA-C, was founding editor of JAAPA and worked on staff for 17 years. She works part time at Mobile Med, Janssen Family Medicine, and Pain Management Specialists in Montgomery County, Maryland. She is a member of AAPA’s Professional Practice Commission.
25 years of JAAPA: Honoring the past, awaiting the future
his issue heralds in the 25th anniversary of JAAPA. I am honored to have been there at the very beginning, and I appreciate the opportunity to share a few memories of getting the Journal off the ground. When I think back to the early years of JAAPA, I picture myself surrounded—no, practically buried—by paper. I had the messiest office at AAPA; people could hardly see if I was in there for the stacks of manuscripts, clipped articles, magazines, and folders waiting to be filed. The accumulation of medical journals functioned as my office furniture. Why did my vision for JAAPA require so much paper? Back in those days, an author was required to submit three hard copies of a manuscript. Once the manuscript arrived at AAPA’s headquarters, it inevitably spawned more paper, depending on how many peer reviewers were assigned to critique the article. The peer reviewers were sent more paper, in the way of manuscript evaluation forms that they were expected to complete and return in an expedited manner. Depending on my assessment and the opinions of the peer reviewers, the author would be sent correspondence, usually several pages worth, outlining revisions that were required if the article was to ever see the light of day. Vast forests were saved the day Tanya Gregory took over as editor in 2001; she catapulted the Journal into modern times by transitioning all JAAPA transactions to the electronic realm. Paging through old issues, I remember how much work was initially involved in creating this journal. Establishing an editorial board, writing a statement of editorial purpose, developing article submission requirements and criteria for acceptance or rejection, soliciting potential authors, setting deadlines, and communicating with the publisher (then C.V. Mosby) were among those tasks. We devoted much care to setting up JAAPA’s peer review process and teaching clinicians how to assess and suggest improvements for articles. As a consequence, the journal’s quality continued to improve, leading to a huge milestone in 1999 when it was accepted into the National Library of Medicine’s revered Medline database. The PA profession was only 20 years old when JAAPA was launched. There was so much going on. Leaders were making inroads with organized medicine and with regulators to reduce barriers to our effective utilization. Our clinical roles expanded, and specialization spread. To mirror the maturation of the profession, JAAPA planned 12
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and published special issues focusing on preventive medicine, medical care to the underserved, surgical specialties, multicultural medicine, and public health. To voice PAs’ opinions on key socioeconomic and health care policies, we published guest editorials on controversies and trends in health care and conducted roundtables on topics such as obesity, the HIV epidemic, and managed care. As the saying goes, as much as things change, they seem to stay the same. Can you believe that in the summer of JAAPA’s first year, the following sentence appeared in Marshall Sinback’s President’s Message: “The radical changes that have transformed health care delivery systems and the financing of health care will continue into the next decade, requiring PAs to remain involved in legislative, regulatory, and policy making activities that affect the profession.”1 Does that sound familiar? That was in 1988! After a quarter of a century, are we really only now at the brink of change? Much of the credit for JAAPA’s success goes to the Journal ’s editorial boards and the staff of our publishers, who worked creatively and tirelessly to meet the challenges of putting together a journal that would appeal to such a diverse profession. Some of the thorniest issues, like how to satisfy PAs in subspecialties or how much content should be allocated to research, came up time and time again at our editorial board meetings and are probably still being debated today. And thanks of course to the PA authors, who chiseled precious time out of hectic clinic schedules to contribute to their journal. Twenty-five years later, my den at home is as cluttered as my office once was at AAPA. I have bound JAAPA volumes dating back to 1988 strewn all over the floor. This trip down memory lane has made me realize that journals in general have become unbound, unleashed, liberated by technologic advances that give readers much greater and much faster access to needed information. Yet, even as I learn to use point-of-care modalities to help me with clinical decision-making in my practice, I still bring my print medical journals with me everywhere. I turn first to JAAPA, impressed with each issue and the progress the journal has made in the 25 years since it launched, the broad spectrum that it now encompasses, and the tremendous future it has yet to cover. JAAPA REFERENCE 1. Sinback MF. President’s message. JAAPA. 1988;1(4):253.
COMMENTARY Sarah Zarbock, PA-C, was the editor in chief of JAAPA from 2003 to mid-2011.
A quarter-century of JAAPA: A long, remarkable journey
t’s amazing to realize that as 2012 begins, we are celebrating JAAPA’s 25th anniversary. During my 8 years as the Journal’s editor in chief, I used one guiding principle more than any other: when writing for PAs in JAAPA, it is crucial to distinguish between what the reader needs to know and what the writer wants to say. Sometimes this distinction is a small one—that is, the specific information the author wants to provide is what PAs need to know to stay current and improve their clinical practice. Sometimes, however, there may be a great deal to say, but only a small portion of it is relevant to the reader. I found this “needto-know” approach, whether in my own writing or when evaluating manuscripts, to be a very helpful way to evaluate the Journal’s content. To honor JAAPA’s 25-year accomplishment, I have several things that I think you need to know and a few more that I want to say. JAAPA’s readership surveys have consistently shown, first and foremost, that PA readers want information they can use. In order to meet that expectation, the editorial board continually evaluates, with considerable input from the peer reviewers, what information is needed by a “typical” JAAPA reader. Initially, the typical reader was a PA in primary care or family practice, but over time that reader became less typical, reflecting changes in the demographics of PAs. For several years now, AAPA census data have shown that more PAs are practicing in specialties and that the percentage who practice in primary care has decreased.1 So how can JAAPA continue to meet the informational needs of the readers who make up its changing demographic? Four national PA organizations produced “Competencies for the Physician Assistant Profession,” a document adopted as policy by the House of Delegates in 2005; it describes competencies that all physician assistants, regardless of specialty or practice setting, are expected to acquire and maintain throughout their careers.2 Since that time, JAAPA has categorized its articles according to these core competencies. But as more PAs work in specialty practices, they most likely will be using that specialty’s professional journals to keep up to date. The JAAPA editorial board will continue to be challenged by these changes when selecting content and determining how to move the Journal forward. The Internet is now where much of the world obtains most of its information, and the Web and mobile delivery channels represent a never before seen opportunity to both 14
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disseminate and obtain clinical information. Especially over the past 10 years, JAAPA has participated in this rapid expansion of information through its own Web site and its growing use of social media. The JAAPA Web site is more than just an archive of what appears in the print journal, and the growth opportunities for the Journal represented by the Web are both exciting and challenging. It seems inevitable that one day, medical publishers will no longer use paper and the US Postal Service to distribute their journals. In the meantime, JAAPA’s editorial board will continue to focus energy on how to best use its Web site to meet the informational needs of our profession. Editors in chief usually leave their personal stamp on the journals they oversee. I am a strong believer in the value of the humanities and their application to medical practice and journalism. PAs are far more than just clinicians. They need to nurture their abilities of observation, empathy, and self-reflection—skills that are essential for humane medical care. I think it’s also valuable for PAs to have a place to share their experiences—a journal of their own. I am especially pleased to have helped develop the Humane Medicine, Day in the Life, and Emergency Medicine Notes departments in JAAPA. JAAPA is at a crossroads as we celebrate its 25th anniversary in 2012. My predecessor, Leslie Kole, who founded the Journal back in 1988, handed me a remarkable publication that she created and developed over 17 years. One of JAAPA’s primary distinctions is that it’s the only peer-reviewed journal specifically and only for PAs. Our profession needs and should have its own journal; our readership surveys tell us that, too. The future choices made by the editorial board about JAAPA’s direction will be based on the shifting demographics of the profession and its changing informational needs, but the focus will always be on keeping the content relevant whether it is delivered in an article or through social media; in print, online, or on a mobile device. JAAPA has come a long and remarkable way in the past quarter-century. I can’t help but wonder what it will look like when celebrating its 50th year! JAAPA REFERENCES 1. American Academy of Physician Assistants. Physician assistant census report. Results from the 2010 AAPA census. http://www.aapa.org/uploadedFiles/content/Common/Files/2010_Census_ Report_Final.pdf. Accessed December 8, 2011. 2. Competencies for the physician assistant profession. http://www.nccpa.net/pdfs/Deﬁnition% 20of%20PA%20Competencies%203.5%20for%20Publication.pdf. Accessed December 8, 2011.
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.
Prescribing opioids safely in patients with an opiate allergy
rue immunologic opioid allergy is rare. Most patients are actually reporting a known adverse effect of the drug, or a pseudoallergy. Pseudoallergic drug reactions mimic true immunologic reactions, but they are not immune-mediated. Such reactions have been coined nonimmune hypersensitivity reactions (or anaphylactoid reactions). The most common adverse effects of opiates are drowsiness and GI upset (nausea, vomiting, constipation) and should be noted on the patient record as such. Proper documentation allows clinicians to choose a better alternative without the concern for cross-allergy with other opioids. Nonimmune hypersensitivity reactions to opioids are very common and occur much more frequently than immunologic (IgE-mediated) reactions. Unfortunately, distinguishing between the two clinically may be difficult. Pseudoallergic reactions result when direct stimulation of mast cells leads to release of mediators, such as histamine. Itching is a common symptom; flushing, hives, sweating, and mild hypotension may also occur. The most common offenders in pseudoallergic reactions are the low-potency opiates (meperidine [Demerol, generics], codeine, and morphine). For prevention and treatment of nonimmune hypersensitivity reactions, first, determine if the patient truly requires an opiate. Try scheduled acetaminophen or an NSAID if no contraindications exist. If a narcotic is required, give the lowest possible dose because histamine release is a dose-dependent effect. Another option is to prescribe a highpotency opioid, which is less likely to cause histamine release. The following agents are listed in order of increasing potency: meperidine, codeine, morphine, hydrocodone, oxycodone (Oxecta,
OxyContin, Roxicodone, generics), hydromorphone (Dilaudid, Exalgo, generics), fentanyl (Duragesic, generics).1 Finally, concurrent administration of an antihistamine (such as diphenhydramine [Benadryl, generics]) may be effective. To determine what opioids may be safely prescribed in a patient with a documented allergy, a detailed description of the reaction is crucial. A true allergic reaction may include severe hypotension or cardiovascular collapse; angioedema or swelling of the lips, tongue, face, or mouth; bronchospasm or respiratory distress; or cutaneous reactions other than hives, flushing, or itching (such as rash or erythema multiforme). In a patient reporting any of these symptoms, care should be taken to avoid the offending agent, and the patient should be asked what opioids he or she has taken safely in the past. Knowledge of opioid metabolism is also helpful in differentiating a true allergy from a pseudoallergy and avoiding agents that may result in cross-reactivity. For example, codeine is metabolized to morphine and hydrocodone is metabolized to hydromorphone. Therefore, codeine should be avoided in patients with a morphine allergy. Alternatively, patients
who report an allergy to hydromorphone but can tolerate hydrocodone are unlikely to have a true IgE-mediated allergy. If a patient with a history of opiate anaphylaxis requires a narcotic analgesic and has never been challenged with an alternative opioid, the safest option is to consult an immunologist or choose a drug from a different structural class (Table 1). The patient must be monitored closely for anaphylaxis. Because true opiate allergy is so rare, there is not enough information to accurately assess the risk of cross-allergy between the different structural classes. Patients can be allergic to more than one structural group and may exhibit cross-reactivity between classes. If you cannot clearly determine whether a patient has experienced an immune-mediated allergic reaction versus a nonimmune hypersensitivity reaction, take into consideration the severity of the reaction, extent of systemic involvement, previous exposure, and timing of the symptoms in relation to drug administration. JAAPA REFERENCE 1. Analgesic options for patients with allergic-type opioid reactions. Pharmacist’s Letter/Prescriber’s Letter. 2006; 22(220201).
TABLE 1. Opioid agents by structural class Structural class
• Methadone (Dolophine, Methadose, generics)
• Propoxyphene (withdrawn from US market)
• • • • •
• • • • •
• Fentanyl • Meperidine
Buprenorphine Butorphanol (Stadol, generics) Codeine Hydrocodone Hydromorphone
Levorphanol Morphine Nalbuphine Oxycodone Oxymorphone (Opana, generics)
• Remifentanil (Ultiva) • Sufentanil (Sufenta, generic)
www.jaapa.com • JANUARY 2012 • 25(1) • JAAPA
Dermatology Digest J OE R. M ONROE, PA-C , M PAS
FIGURE 1 Vesicles and bullae
What is behind this postpartum puzzler? Joe Monroe practices at the Dawkins Dermatology Clinic, Oklahoma City, Oklahoma, and is the department editor for Dermatology Digest. The author has indicated no relationships to disclose relating to the content of this article.
›WHICH OF THE FOLLOWING
Following the delivery of a healthy infant, the 28-year-old mother began to experience intense itching on her neck. Within 48 hours, the itching was even more intense and a rash had begun to appear on the trunk, arms, and legs. Over the next week, the patient was seen in five different medical venues, including emergency rooms and urgent care clinics, and by an infectious disease specialist. During that time, she was given five different diagnoses: shingles, staphylococcal infection, contact dermatitis, herpes simplex, and pruritic urticarial papules and plaques of pregnancy (PUPPP). These diagnoses led to prescriptions for numerous medications, including oral and systemic corticosteroids, antiviral medications (acyclovir, valacyclovir), oral and systemic antibiotics (ciprofloxacin [Cipro] and ceftriaxone [Rocephin]), as well as oral and systemic antihistamines (diphenhydramine). Nevertheless, both the symptoms and the extent of involvement worsened, and she was referred to dermatology. On examination, the patient was afebrile and did not appear ill. The rash was extensive, especially on the neck, arms, and legs, where large collections of vesicles and bullae were circumscribed by annular, erythematous borders (Figure 1). The bullae were uniformly tense and remained intact despite digital pressure, which also failed to extend the margins of the blisters. Results of laboratory studies ordered 4 days previously, including a CBC and comprehensive metabolic panel, were within normal limits. Using a 4-mm punch, specimens of perilesional skin were obtained for routine hematoxylin and eosin processing and direct immunofluorescent studies. The pathology report showed IgG deposited along the basement membrane as well as subepidermal vesicles, all consistent with a diagnosis of pemphigoid gestationis (PG), a rare blistering disease associated with pregnancy.
IS NOT PART OF THE DIFFERENTIAL DIAGNOSIS? • Herpes simplex • PUPPP • Bullous pemphigoid • Cicatricial pemphigoid
JAAPA • JANUARY 2012 • 25(1) • www.jaapa.com
›DISCUSSION The disorder that was totally ruled out was herpes simplex, which would have exhibited an entirely different histologic picture, as would herpes zoster. The other three diagnoses belonged in a reasonable differential. Pemphigoid gestationis is the newer name for what for many years was called herpes gestationis, despite having no connection with herpes. The old term managed to create confusion, conveying the false impression that herpes-related conditions were somehow common in pregnancy. PG is a rare autoimmune process of unknown cause. Cross-reactivity between placental tissue and epidermal cells is suspected of playing a key role, as both have demonstrable anti-HLA antibodies. Fortunately, PG occurs in only 1 of every 50,000 to 60,000 pregnancies, almost always in the third trimester, and it has no effect on fetal health. PUPPP is much more common, occurring in 1 in every 160 to 240 pregnancies and typically manifesting with pruritic, urticarial (hivelike) papules and plaques confined to the stretch marks on the abdomen. A late third-trimester phenomenon, PUPPP is more common in first pregnancies than in subsequent ones. The patient was started on prednisone, 0.5 mg/kg/day. She became asymptomatic within 36 hours, and the dosage was tapered over the next month. In many acute blistering diseases, a firm diagnosis can only be obtained histologically. The medical specialty most likely to know how and where to biopsy, what studies are indicated, and how to interpret the results and then treat the specific disease is dermatology. JAAPA.
Clinical Watch C H AC , T H E C LI N I CA L A ND HEA LT H A FFA I RS CO M M I SS I ON OF T HE A A PA
Improved outcomes, less disparity
lights three main themes in the prevention section and puts forth focused 5-year objectives (Table 1): (1) Increase education on prevention in communities where HIV prevalence is highly concentrated (2) Expand prevention of transmission through utilization of evidence-based practice tools (3) Educate the general public on the existing threat of HIV/AIDS. The NHAS report indicates that communities and groups with high HIV prevalence and incidence (Table 2) should engage in intensified education and prevention actions. Groups at high risk, such as men who have sex with men and injection drug users, should receive resources, tools, and amenities on education and prevention.3 Finally, program accountability must be in place to understand the methods and utilization of resources.3 The report emphasizes that prevention must be conducted using evidencebased approaches, suggesting that single-focus education practices, such as abstinence-only programs or condom usage campaigns, are not effective.4 According to the Joint United Nations Programme on HIV/AIDS (UNAIDS), duplicative, overlapping, and combined
›WHO SHOULD READ THIS? All clinically practicing PAs.
›WHY IS THIS IMPORTANT? The first cases of HIV infection were diagnosed more than 30 years ago in the United States. Since then, more than half a million Americans have died of AIDS. Currently, more than 1 million people live with HIV infection, and approximately 50,000 are newly infected each year.1 A report from the Kaiser Foundation noted that in 1995, more than 40% of Americans felt that HIV/AIDS was a national priority.2 By 2009, however, that percentage had dropped to less than 6%.2 Despite significant advances in the prevention and treatment of HIV/AIDS, the White House Office of National AIDS Policy released the National HIV/AIDS Strategy (NHAS) for the United States 3 to renew focus and dedicate attention to HIV/AIDS management. The report addresses the prevention of new HIV cases in the United States, improving outcomes of people living with HIV/ AIDS in the United States, and eliminating health disparities related to HIV/AIDS.3 Physician assistants need to be aware of the impact these strategies will have on reducing transmission rates and decreasing the prevalence of HIV/AIDS in our communities, particularly as 30 million new patients enter the health care system under the Patient Protection and Affordable Care Act.
Prevention The NHAS report high-
TAKE-HOME POINTS ■ Rigorous education on prevention
remains the most effective way of reducing the incidence and prevalence of HIV/AIDS. ■ While major inroads have been achieved in the management of HIV/ AIDS, the disease should remain a health care priority. ■ Preventive interventions need to be evidence-based and monitored for effectiveness. ■ All health care providers, especially primary care providers, should maintain up-to-date knowledge about HIV/AIDS.
prevention education is more effective in preventing new infections than are isolated singular messages.5 Evidence suggests that HIV-positive people tend to take steps to avoid disease transmission.6 Thus, the NHAS report recommends improved funding for the utilization of innovative combined awareness and prevention strategies that target highrisk geographic and community groups. Finally, in order for prevention education to be effective, broader audiences must be reached, and the NHAS report indicates that all groups and communities should be inundated with social marketing campaigns and promotion of age-appropriate education on HIV and sexually transmitted infections (STIs). Sustained outreach programs and seminars should be included in order to maximize educational effectiveness. Improving outcomes Three main goals were identified in the NHAS report in order to appropriately address the second principle of improving patient outcomes: (1) Establish a seamless system to facilitate continuous and coordinated quality care (2) Increase the number and diversity of available providers (3) Provide support for people living with HIV who have comorbid conditions. One potential solution may be implementing programs that immediately link patients with new diagnoses to quality care through a network of communications and availability of funding and resources. Early initiation of antiretroviral therapy has been demonstrated to improve outcomes.7 In addition, promoting collaborative opportunities
This article was written by Folusho E. Ogunﬁditimi, MPH, PA-C. Contributors included the other members and staff of CHAC 2011-2012: Alison C. Essary, MHPE, PA-C (chair); Gilbert A. Boissonneault, PhD, PA-C; Anthony E. Brenneman, MPAS, PA-C; Marie-Michèle Léger, MPH, PA-C; and Thomas Moreau, PA-C, MS.
www.jaapa.com • JANUARY 2012 • 25(1) • JAAPA
Clinical Watch TABLE 1. Five-year HIV prevention goals of NHAS3 Benchmark
TABLE 2. Annual incidence of new HIV infections in high-risk groups11
Decrease by 25%
5 persons infected each year per 100 people living with HIV
Decrease by 30%
Number of people living with HIV who know of their infection
Number of people with newly diagnosed HIV who have regular health care within 3 mo
New HIV infection (annual) HIV transmission rate
Key: NHAS, National HIV/AIDS Strategy.
among health care providers and health care services, with the use of electronic medical records and information technology media, will aid in establishing a seamless coordination of care. Identifying, training, and increasing clinically competent health care providers is another recommendation of the national strategy to improve outcomes in HIV/AIDS patients. This can be done by incentivizing primary care providers and reproductive, sexual, and mental health care experts to provide HIV/AIDS services. Finally, the report indicates that overall outcomes will be influenced by the provision of housing, food, transportation, and other supportive services to persons with HIV/AIDS by federal and state agencies. These services will aid in the adherence to and maintenance of treatment regimens and management of comorbidities. Reducing health disparities
Reducing disparities in HIV-related groups and communities remains a priority for health care policy makers. Groups with higher transmission rates of HIV have been marginalized and isolated.8 The NHAS report has made reducing health disparities in HIV/AIDS communities a primary concern and considers this effort paramount to decreasing new cases and deaths. Some of the main strategies in the report include reducing HIV-related mortality in highrisk communities, adopting community level practices in high-risk groups, and reducing stigma and discrimination
New infections (%) 44
Injection drug users
Key: MSM, men having sex with men.
against HIV patients. To accomplish these goals, the report suggests that highrisk groups require access to assays for viral load and CD4 cell counts. These tests should be readily available to all persons regardless of race, gender, sexual preference, or socioeconomic status. The report also suggests the piloting of holistic medicine therapies that have been shown to aid in prevention as well as treatment of comorbidities. To combat stigmas, the NHAS report calls for engagement of faithbased and community organizations to condemn stereotypes and discriminatory practices. The report also suggests that communities should promote public leadership among people living with HIV, which may influence legislation that eliminates stigmas and discrimination. Finally, the report calls on federal agencies to strengthen and enforce existing civil rights laws that prohibit discrimination based on sexual preferences, gender, and race.
›WHAT ELSE IS IMPORTANT TO KNOW? HIV vaccines The NHAS report notes that while significant effort has been dedicated to the development of vaccines for HIV over the past 30 years, results have been tepid to date. Munier and colleagues suggest that renewed research targeting envelopebased immunogens, coupled with a prime poxvirus vector and protein boosters, might show some promise.9
24 JAAPA • JANUARY 2012 • 25(1) • www.jaapa.com
Preexposure prophylaxis (PrEP)
The use of antiretrovirals by HIVnegative persons who are in a committed relationship with an HIV-positive person has shown promise as a method of HIV prevention. Decreases in transmission rates between 39% and 73% are seen, depending on specific antiretroviral usage.10 JAAPA REFERENCES 1. Centers for Disease Control and Prevention. Diagnoses of HIV Infection and AIDS in the United States and Dependent Areas, 2009. HIV Surveillance Report, Vol 21. http://www.cdc. gov/hiv/surveillance/resources/reports/2009report/index. htm. Updated February 16, 2011. Accessed December 7, 2011. 2. Kaiser Family Foundation. 2009 Survey of Americans on HIV/AIDS: Summary of Findings on the Domestic Epidemic. http://www.kff.org/kaiserpolls/upload/7889.pdf. Published April 2009. Accessed December 7, 2011. 3. The White House Ofﬁce of National AIDS Policy. National HIV/ AIDS Strategy for the United States. http://www.whitehouse. gov/sites/default/ﬁles/uploads/NHAS.pdf. Released July 2010. Accessed December 7, 2011. 4. Auerbach JD, Coates TJ. HIV prevention research: accomplishment and challenges for the third decade of AIDS. Am J Public Health. 2000;90(7):1029-1032. 5. UNAIDS. Press statement. UNAIDS promotes combination HIV prevention towards universal access goals. http:// www.unaids.org/en/Resources/PressCentre/ Pressreleaseandstatementarchive/2009/March/ 20090318ComprehensivePrevention/. Published March 2009. Accessed December 7, 2011. 6. Marks G, Crepaz N, Janssen RS. Estimating sexual transmission of HIV from persons aware and unaware that they are infected with the virus in the USA. AIDS. 2006;20(10):1447-1450. 7. Kitahata MM, Gange SJ, Abraham AG, et al. Effect of early versus deferred antiretroviral therapy for HIV on survival. N Engl J Med. 2009;360(18):1815-1826. 8. El-Sadr WM, Mayer KH, Hodder SL. AIDS in America— forgotten but not gone. N Engl J Med. 2010;362(11)967-970. 9. Munier CM, Andersen CR, Kelleher AD. HIV vaccines: progress to date. Drugs. 2011;71(4):387-414. 10. Hurt CB, Eron JJ Jr, Cohen MS. Pre-exposure prophylaxis and antiretroviral resistance: HIV prevention at a cost? Clin Infect Dis. 2011;Oct 5. [Epub ahead of print] 11. Centers for Disease Control and Prevention. HIV in the United States. http://www.cdc.gov/hiv/resources/factsheets/us.htm. Updated November 7, 2011. Accessed December 7, 2011.
Distributed by: Ortho Dermatologics Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc., Los Angeles, CA 90045 © OMP 2011 11DD0126 07/11 RETIN-A MICRO ® is a registered trademark of Ortho-McNeil Pharmaceutical, Inc. MICROSPONGE ® is a registered trademark of AMCOL International Corporation.
8/3/11 10:22 AM
Job #: MIC-0402 Brief Summary PI - UPDATE
New Zealand white rabbits were treated with Retin-A Micro (tretinoin gel) microsphere, 0.1%, at doses of 0.2, 0.5, and 1.0 mg/kg/day, administered topically for 24 hours a day while wearing Elizabethan collars to prevent ingestion of the drug. There appeared to be increased incidences of certain alterations, including domed head and hydrocephaly, typical of retinoid-induced fetal malformations in this species, at 0.5 and 1.0 mg/kg/day. Similar malformations were not observed at 0.2 mg/kg/day, 3 times the maximum human systemic dose of tretinoin after topical administration of Retin-A Micro (tretinoin gel) microsphere, 0.1%, normalized for total body surface area. In a repeat study of the highest topical dose (1.0 mg/kg/day) in pregnant rabbits, these effects were not seen, but a few alterations that may be associated with tretinoin exposure were seen. Other pregnant rabbits exposed topically for six hours to 0.5 or 0.1 mg/ kg/day tretinoin while restrained in stocks to prevent ingestion, did not show any teratogenic effects at doses up to 17 times (1.0 mg/kg/day) the maximum human systemic dose after topical administration of Retin-A Micro (tretinoin gel) microsphere, 0.1%, adjusted for total body surface area, but fetal resorptions were increased at 0.5 mg/kg. In addition, topical tretinoin in non Retin-A Micro (tretinoin gel) microsphere formulations was not teratogenic in rats and rabbits when given in doses of 42 and 27 times the maximum human systemic dose after topical administration of Retin-A Micro (tretinoin gel) microsphere, 0.1%, normalized for total body surface area, respectively, (assuming a 50 kg adult applied a daily dose of 1.0 g of 0.1% gel topically). At these topical doses, however, delayed ossification of several bones occurred in rabbits. In rats, a dose-dependent increase of supernumerary ribs was observed. Oral tretinoin has been shown to be teratogenic in rats, mice, rabbits, hamsters, and subhuman primates. Tretinoin was teratogenic in Wistar rats when given orally or topically in doses greater than 1 mg/kg/day (8 times the maximum human systemic dose normalized for total body surface area). However, variations in teratogenic doses among various strains of rats have been reported. In the cynomolgus monkey, which metabolically is more similar to humans than other species in its handling of tretinoin, fetal malformations were reported for doses of 10 mg/kg/day or greater, but none were observed at 5 mg/kg/day (83 times the maximum human systemic dose normalized for total body surface area), although increased skeletal variations were observed at all doses. Dose-related increases in embryolethality and abortion also were reported. Similar results have also been reported in pigtail macaques. Topical tretinoin in animal teratogenicity tests has generated equivocal results. There is evidence for teratogenicity (shortened or kinked tail) of topical tretinoin in Wistar rats at doses greater than 1 mg/kg/day (8 times the maximum human systemic dose normalized for total body surface area). Anomalies (humerus: short 13%, bent 6%, os parietal incompletely ossified 14%) have also been reported when 10 mg/kg/day was topically applied. Supernumerary ribs have been a consistent finding in rats when dams were treated topically or orally with retinoids. There are no adequate and well-controlled studies in pregnant women. Retin-A Micro should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. With widespread use of any drug, a small number of birth defect reports associated temporally with the administration of the drug would be expected by chance alone. Thirty human cases of temporally associated congenital malformations have been reported during two decades of clinical use of Retin-A. Although no definite pattern of teratogenicity and no causal association has been established from these cases, five of the reports describe the rare birth defect category holoprosencephaly (defects associated with incomplete midline development of the forebrain). The significance of these spontaneous reports in terms of risk to the fetus is not known. Non-Teratogenic Effects: Topical tretinoin has been shown to be fetotoxic in rabbits when administered 0.5 mg/kg/day (8 times the maximum human systemic dose applied topically and normalized for total body surface area), resulting in fetal resorptions and variations in ossification. Oral tretinoin has been shown to be fetotoxic, resulting in skeletal variations and increased intrauterine death in rats when administered 2.5 mg/kg/day (21 times the maximum human systemic dose applied topically and normalized for total body surface area). There are, however no adequate and well-controlled studies in pregnant women. Animal Toxicity Studies: In male mice treated topically with Retin-A Micro (tretinoin gel) microsphere 0.1%, at 0.5, 2.0, or 5.0 mg/kg/day tretinoin (2, 8, or 21 times the maximum human systemic dose after topical administration of Retin-A Micro (tretinoin gel) microsphere, 0.1%, normalized for total body surface area) for 90 days, a reduction in testicular weight, but with no pathological changes were observed at the two highest doses. Similarly, in female mice there was a reduction in ovarian weights, but without any underlying pathological changes, at 5.0 mg/kg/day (21 times the maximum human dose). In this study there was a dose-related increase in the plasma concentration of tretinoin 4 hours after the first dose. A separate toxicokinetic study in mice indicates that systemic exposure is greater after topical application to unrestrained animals than to restrained animals, suggesting that the systemic toxicity observed is probably related to ingestion. Male and female dogs treated with Retin-A Micro (tretinoin gel) microsphere, 0.1%, at 0.2, 0.5, or 1.0 mg/kg/day tretinoin (5, 12, or 25 times the maximum human systemic dose after topical administration of Retin-A Micro (tretinoin gel) microsphere, 0.1%, normalized for total body surface area, respectively) for 90 days showed no evidence of reduced testicular or ovarian weights or pathological changes. Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Retin-A Micro (tretinoin gel) microsphere, 0.1% or 0.04%, is administered to a nursing woman. Pediatric Use: Safety and effectiveness in children below the age of 12 have not been established. Geriatric Use: Safety and effectiveness in a geriatric population have not been established. Clinical studies of Retin-A Micro did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. ADVERSE REACTIONS: The skin of certain sensitive individuals may become excessively red, edematous, blistered, or crusted. If these effects occur, the medication should either be discontinued until the integrity of the skin is restored, or the medication should be adjusted to a level the patient can tolerate. However, efficacy has not been established for lower dosing frequencies. True contact allergy to topical tretinoin is rarely encountered. Temporary hyper- or hypopigmentation has been reported with repeated application of tretinoin. Some individuals have been reported to have heightened susceptibility to sunlight while under treatment with tretinoin. OVERDOSAGE: Retin-A Micro (tretinoin gel) microsphere, 0.1% and 0.04%, is intended for topical use only. If medication is applied excessively, no more rapid or better results will be obtained and marked redness, peeling, or discomfort may occur. Oral ingestion of large amounts of the drug may lead to the same side effects as those associated with excessive oral intake of Vitamin A. Rx only.
Magenta rules indicate BLEED – TRIM – LIVE — DO NOT PRINT
MIC-0402 Brief PI update_m3.indd 1
% Bleed Size: N/A Trim Size: 8.125"w x 11"h Live Size: N/A Prints: 5/5: 4C — •C •M •Y •K + SAQ/same First round mechanical built by: pnj
FOR TOPICAL USE ONLY. NOT FOR OPHTHALMIC, ORAL, OR INTRAVAGINAL USE. Brief Summary Retin-A Micro® (tretinoin gel) microsphere, 0.1% and 0.04% is a formulation containing 0.1% or 0.04%, by weight, tretinoin for topical treatment of acne vulgaris. This formulation uses patented methyl methacrylate/glycol dimethacrylate crosspolymer porous microspheres (MICROSPONGE® System) to enable inclusion of the active ingredient, tretinoin, in an aqueous gel. IMPORTANT NOTE: This information is a BRIEF SUMMARY of the complete prescribing information provided with the product and therefore should not be used as the basis for prescribing the product. This summary has been prepared by deleting information from the complete prescribing information such as certain text, tables, and references. The physician should be thoroughly familiar with the complete prescribing information before prescribing the product. INDICATIONS AND USAGE: Retin-A Micro (tretinoin gel) microsphere, 0.1% and 0.04%, is indicated for topical application in the treatment of acne vulgaris. The safety and efficacy of the use of this product in the treatment of other disorders have not been established. CONTRAINDICATIONS: This drug is contraindicated in individuals with a history of sensitivity reactions to any of its components. It should be discontinued if hypersensitivity to any of its ingredients is noted. PRECAUTIONS: General: • The skin of certain individuals may become excessively dry, red, swollen, or blistered. If the degree of irritation warrants, patients should be directed to temporarily reduce the amount or frequency of application of the medication, discontinue use temporarily, or discontinue use all together. Efficacy at reduced frequencies of application has not been established. If a reaction suggesting sensitivity occurs, use of the medication should be discontinued. Excessive skin dryness may also be experienced; if so, use of an appropriate emollient during the day may be helpful. • U nprotected exposure to sunlight, including sunlamps, should be minimized during the use of Retin-A Micro (tretinoin gel) microsphere, 0.1% and 0.04%, and patients with sunburn should be advised not to use the product until fully recovered because of heightened susceptibility to sunlight as a result of the use of tretinoin. Patients who may be required to have considerable sun exposure due to occupation and those with inherent sensitivity to the sun should exercise particular caution. Use of sunscreen products (SPF 15) and protective clothing over treated areas are recommended when exposure cannot be avoided. • Weather extremes, such as wind or cold, also may be irritating to patients under treatment with tretinoin. • R etin-A Micro (tretinoin gel) microsphere, 0.1% and 0.04%, should be kept away from the eyes, the mouth, paranasal creases of the nose, and mucous membranes. • Tretinoin has been reported to cause severe irritation on eczematous skin and should be used with utmost caution in patients with this condition. Information for Patients: A Patient Information Leaflet has been prepared and is included with each package of Retin-A Micro (tretinoin gel) microsphere, 0.1% and 0.04%. Drug Interactions: Concomitant topical medication, medicated or abrasive soaps and cleansers, products that have a strong drying effect, products with high concentrations of alcohol, astringents, or spices should be used with caution because of possible interaction with tretinoin. Avoid contact with the peel of limes. Particular caution should be exercised with the concomitant use of topical over-the-counter acne preparations containing benzoyl peroxide, sulfur, resorcinol, or salicylic acid with Retin-A Micro (tretinoin gel) microsphere, 0.1% and 0.04%. It also is advisable to allow the effects of such preparations to subside before use of Retin-A Micro (tretinoin gel) microsphere, 0.1% and 0.04%, is begun. Carcinogenesis, Mutagenesis, Impairment of Fertility: In a 91-week dermal study in which CD-1 mice were administered 0.017% and 0.035% formulations of tretinoin, cutaneous squamous cell carcinomas and papillomas in the treatment area were observed in some female mice. These concentrations are near the tretinoin concentration of these clinical formulations (0.04% and 0.1%). A dose-related incidence of liver tumors in male mice was observed at those same doses. The maximum systemic doses associated with the administered 0.017% and 0.035% formulations are 0.5 and 1.0 mg/kg/day, respectively. These doses are two and four times the maximum human systemic dose applied topically, when normalized for total body surface area. The biological significance of these findings is not clear because they occurred at doses that exceeded the dermal maximally tolerated dose (MTD) of tretinoin and because they were within the background natural occurrence rate for these tumors in this strain of mice. There was no evidence of carcinogenic potential when 0.025 mg/kg/day of tretinoin was administered topically to mice (0.1 times the maximum human systemic dose, normalized for total body surface area). For purposes of comparisons of the animal exposure to systemic human exposure, the maximum human systemic dose applied topically is defined as 1 gram of Retin-A Micro (tretinoin gel) microsphere, 0.1% applied daily to a 50 kg person (0.02 mg tretinoin/kg body weight). Dermal carcinogenicity testing has not been performed with Retin-A Micro (tretinoin gel) microsphere, 0.04% or 0.1%. Studies in hairless albino mice suggest that concurrent exposure to tretinoin may enhance the tumorigenic potential of carcinogenic doses of UVB and UVA light from a solar simulator. This effect has been confirmed in a later study in pigmented mice, and dark pigmentation did not overcome the enhancement of photocarcinogenesis by 0.05% tretinoin. Although the significance of these studies to humans is not clear, patients should minimize exposure to sunlight or artificial ultraviolet irradiation sources. The mutagenic potential of tretinoin was evaluated in the Ames assay and in the in vivo mouse micronucleus assay, both of which were negative. The components of the microspheres have shown potential for genetic toxicity and teratogenesis. EGDMA, a component of the excipient acrylates copolymer, was positive for induction of structural chromosomal aberrations in the in vitro chromosomal aberration assay in mammalian cells in the absence of metabolic activation, and negative for genetic toxicity in the Ames assay, the HGPRT forward mutation assay, and the mouse micronucleus assay. In dermal Segment I fertility studies of another tretinoin formulation in rats, slight (not statistically significant) decreases in sperm count and motility were seen at 0.5 mg/kg/day (4 times the maximum human systemic dose applied topically, and normalized for total body surface area), and slight (not statistically significant) increases in the number and percent of nonviable embryos in females treated with 0.25 mg/kg/day (2 times the maximum human systemic dose applied topically and normalized for total body surface area) and above were observed. In oral Segment I and Segment III studies in rats with tretinoin, decreased survival of neonates and growth retardation were observed at doses in excess of 2 mg/kg/day (17 times the human topical dose normalized for total body surface area). Dermal fertility and perinatal development studies with Retin-A Micro (tretinoin gel) microsphere, 0.1% or 0.04%, have not been performed in any species. Pregnancy: Teratogenic Effects: Pregnancy Category C. In a study of pregnant rats treated with topical application of Retin-A Micro (tretinoin gel) microsphere, 0.1%, at doses of 0.5 to 1 mg/kg/day on gestation days 6-15 (4 to 8 times the maximum human systemic dose of tretinoin normalized for total body surface area after topical administration of Retin-A Micro (tretinoin gel) microsphere, 0.1%) some alterations were seen in vertebrae and ribs of offspring. In another study, pregnant
LASERS PRINTED AT
Topics in Infectious Diseases ROY A . BO RC H A R DT, PA-C , PhD; KENNET H V. I . ROLSTON, M D
Universal vaccination is the primary weapon
easonal influenza is a common respiratory viral infection with the capacity to affect the entire population, including healthy young adults. Influenza is associated with significant morbidity and mortality. Between 1976 and 2006, estimates of flu-associated deaths in the United States ranged from 3,000 to 49,000 people.1 Influenza accounts for more than 200,000 hospitalizations each year, and related economic costs exceed $87 billion.2
›PATTERNS OF ILLNESS In the United States, seasonal influenza can occur as early as October and continue through the following May; most cases, however, occur between November and April, and cases typically peak in January or February. Most people with influenza experience fever, cough, rhinorrhea, sore throat, headache, malaise, and myalgia. For the majority, the disease is self-limiting and resolves within 3 to 7 days. Children younger than 5 years, pregnant women, and adults older than 65 years are at higher risk for complications. Other high-risk groups include immunocompromised persons, such as those with cancer or HIV/AIDS; residents of nursing homes and other longterm care facilities; Native Americans; the morbidly obese (body mass index greater than 40 kg/m2); persons younger than 19 years receiving longterm aspirin therapy; and those with inherited metabolic disorders, liver disorders, neurologic disorders, and certain chronic diseases (such as asthma, chronic obstructive pulmonary disease,
cystic fibrosis, diabetes, end-stage renal disease, heart failure, congenital heart disease, and sickle cell anemia).1 Complications from influenza infection include development of otitis media, sinusitis, primary viral or secondary bacterial pneumonia, exacerbation of comorbid conditions, and coinfection with other pathogens.3 A study of the 2009 H1N1 influenza pandemic in critically ill children with neurologic conditions, immunosuppression, myocarditis, or female gender demonstrated a greater mortality risk following admission to the ICU. Among previously healthy children, methicillin-resistant Staphylococcus aureus coinfection of the lungs was the only risk factor for death.4
›TREATMENT AND PREVENTION Two types of influenza (A and B) account for the majority of circulating strains.5 Two classes of antiviral drugs,
TAKE-HOME POINTS ■ Early treatment can reduce the
severity and duration of inﬂuenza in high-risk populations. Neuraminidase inhibitors are the drugs of choice for treatment and chemoprophylaxis. Universal vaccination is recommended for people older than 6 months, with few exceptions. Vaccination should continue throughout the inﬂuenza season for high-risk persons. Cancer patients on chemotherapy or with hematologic malignancies are less likely to mount a complete protective response to vaccination.
neuraminidase inhibitors and adamantanes, are approved for the treatment of influenza. Neuraminidase inhibitors have activity against both influenza A and B. Influenza A strains have developed high resistance to the adamantanes, and these drugs have no activity against influenza B; therefore, they are not recommended for treatment. Early administration of antiviral agents can prevent infection (chemoprophylaxis) and/or reduce the severity and duration of illness. Treatment should be initiated within 48 hours of symptom onset, particularly in cases of suspected or documented severe influenza, complications, or progressive illness requiring hospitalization. The two currently available neuraminidase inhibitors, oseltamivir (Tamiflu) and zanamivir (Relenza), are the preferred drugs for treatment and chemoprophylaxis. High risk patients with suspected exposure should receive chemoprophylaxis. Resistance to neuraminidase inhibitors currently is low but has been increasing over the past 5 years.6 Vaccination is the most effective way to prevent infection. The CDC’s Advisory Committee on Immunization Practices (ACIP) has recommended “universal” vaccination for people 6 months and older. Vaccination is highly recommended for people at greater risk of developing influenza-related complications: pregnant women, children younger than 5 years, adults older than 50 years, people with chronic medical conditions, and residents of nursing homes and long-term care facilities. Close associates of high-risk persons also should be vaccinated. The influenza vaccine should be given The authors work in the Department of Infectious Diseases, Infection Control and Employee Health, University of Texas M.D. Anderson Cancer Center, Houston. Roy Borchardt is a physician assistant and the department editor, and Ken Rolston is a professor of medicine. The authors have indicated no relationships to disclose relating to the content of this article.
www.jaapa.com • JANUARY 2012 • 25(1) • JAAPA
Topics in Infectious Diseases yearly, before the onset of documented cases, and vaccination should continue throughout the influenza season. Some people may benefit from vaccination late in or even after the influenza season. These include those traveling to the Southern hemisphere, where influenza may still be active, and children younger than 9 years who are being vaccinated for the first time but who have still not received their second vaccine dose.7 The 2011-2012 vaccine contains the identical viral antigens present in last year’s vaccine. Nevertheless, people who received last year’s vaccine are expected to benefit from receiving the 2011-2012 vaccine because they subsequently will develop higher neutralizing antibody titers. Two vaccine forms are available, an inactivated trivalent influenza vaccine (TIV) and a live-attenuated nasal-spray flu vaccine (LAIV). The TIV is available as a regular influenza injection, high-dose influenza injection, and intradermal influenza injection. Protective antibodies develop 2 weeks after vaccination.7 Recent meta-analysis of studies of the TIV suggest the effectiveness of vaccination approaches 59% for people 18 to 65 years old, whereas the LAIV provided 83% effectiveness for children ages 6 months to 7 years.8 For children 6 months to 8 years old, two doses of vaccine should be given 4 weeks apart for optimal immunization. If a child received one or more doses of the 2010-2011 vaccine, only one dose of the 2011-2012 vaccine is required. If the child’s vaccine history is uncertain, two doses of the 2011-2012 vaccine should be administered 4 weeks apart. The regular TIV preferably should be given IM in the deltoid muscle in adults and older children or in the anterior lateral thigh muscle for infants and young children. An intradermal vaccine was licensed in May 2011 and is approved for people 18 to 64 years old.7 People older than 65 years should receive the high dose TIV. An LAIV is available for healthy, nonpregnant
people between 2 and 49 years old. LAIV should not be given to children with asthma or a history of wheezing with prior doses of live attenuated vaccine. People with underlying immunosuppressive medical conditions (such as cancer patients receiving chemotherapy), their household members and close contacts, and the health care workers expected to care for these patients should not receive LAIV.7 PAs should note that the vaccine is not approved for children younger than 6 months; instead, their household contacts and caregivers should be vaccinated. People experiencing a moderate to severe illness with fever should wait to receive the influenza vaccine until their symptoms diminish.7
›INFLUENZA IN CANCER PATIENTS Influenza infection in cancer patients not only imposes higher risk of complications but also can delay cancer treatments and result in suboptimal outcomes. Mortality from influenza in the pediatric cancer population approaches 9%, but whether cancer patients achieve adequate protection from vaccination is not well-defined. Less than 29% of pediatric cancer patients receiving chemotherapy achieve protective antibody titers following vaccination; however, for those who have completed chemotherapy, protective titers are observed in 85%.9 For pediatric cancer patients with solid tumors, 39% achieved full protection titers to all three strains of influenza following vaccination, and 19% had full protection to at least one or two strains.10 Although response to vaccination is suboptimal, all studies demonstrate some level of protection, so routine vaccination of the pediatric cancer population is recommended.9 For adults with cancer, protective responses depend on the underlying malignancy and whether the patient is immunosuppressed or receiving chemotherapy. Adults with solid tumors and those not receiving chemotherapy develop protective titers similar to titers
28 JAAPA • JANUARY 2012 • 25(1) • www.jaapa.com
in healthy adults.11 For adult patients with hematologic malignancies, such as acute myelogenous leukemia, the response is poorer, especially if T-cell depletion or other immunodeficiencies are present.9 For example, only 19% of patients with multiple myeloma develop protective titers. The poor response may reflect the impact of the chemotherapy on the immune response and not the underlying malignancy, because patients with lymphoproliferative disorders who are not receiving chemotherapy develop protective titers similar to those in controls.12 Few studies have been done on vaccination of patients who have received hematopoietic stem cell transplantation (HSCT). Influenza vaccination has no demonstrated benefit for patients less than 6 months after HSCT, but many experts still recommend it.9 JAAPA REFERENCES 1. Key facts about inﬂuenza (ﬂu) & ﬂu vaccine. National Institute of Allergy and Infectious Diseases Web site. http://www. niaid.nih.gov/topics/Flu/understandingFlu/Pages/keyFacts. aspx. Updated October 8, 2009. Accessed December 13, 2011. 2. Molinari NA, Ortega-Sanchez IR, Messonnier ML, et al. The annual impact of seasonal inﬂuenza in the US: Measuring disease burden and cost. Vaccine. 2007;25(27):5086-5096. 3. Writing Committee of the WHO Consultation on Clinical Aspects of Pandemic (H1N1) 2009 Inﬂuenza. Clinical aspects of pandemic 2009 inﬂuenza A (H1N1) virus infection. N Engl J Med. 2010;362(18):1708-1719. 4. Randolph AG, Vaughn F, Sullivan R, et al. Critically ill children during the 2009-2010 inﬂuenza pandemic in the United States. Pediatrics. November 7, 2011. doi:10.1542/peds.2011-0774. 5. Review of the 2011 winter inﬂuenza season, southern hemisphere. Wkly Epidemiol Rec. 2011;86(44):488-496. 6. Antiviral agents for the treatment and chemoprophylaxis of inﬂuenza—recommendations of the Advisory Committee on Immunization Practices (ACIP). 2011. MMWR Recomm Rpt. 2011;60(1):1-24. 7. Prevention and control of inﬂuenza with vaccines— recommendations of the Advisory Committee on Immunization Practices (ACIP), 2011. MMWR Morb Mortal Wkly Rpt. 2011;60(33):1128-1132. 8. Osterholm MT, Kelley NS, Sommer A, Belongia EA. Efﬁcacy and effectiveness of inﬂuenza vaccines: a systemic review and meta-analysis. Lancet Infect Dis. October 26, 2011. doi:10.1016/S1473-3099(11):70295-X. 9. Pollyea DA, Brown JM, Horning SJ. Utility of inﬂuenza vaccination for oncology patients. J Clin Oncol. 2010;28(14):2481-2490. 10. Chisholm J, Howe K, Taj M, Zambon M. Inﬂuenza immunisation in children with solid tumors. Eur J Cancer. 2005;41(15): 2280-2287. 11. Brydak LB, Guzy J, Starzyk J, et al. Humoral immune response after vaccination against inﬂuenza in patients with breast cancer. Support Care Cancer. 2001;9(1):65-68. 12. Robertson JD, Nagesh K, Jowitt SN, et al. Immunogenicity of vaccination against inﬂuenza, Streptococcus pneumoniae and Haemophilus inﬂuenza type B in patients with multiple myeloma. Br J Cancer. 2000;82(7):1261-1265.
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LYRICA® (pregabalin) CAPSULES BRIEF SUMMARY: For full prescribing information, see package insert. INDICATION AND USAGE LYRICA is indicated for: • Management of neuropathic pain associated with diabetic peripheral neuropathy DOSAGE AND ADMINISTRATION LYRICA is given orally with or without food. When discontinuing LYRICA, taper gradually over a minimum of 1 week. Neuropathic pain associated with diabetic peripheral neuropathy: • Administer in 3 divided doses per day • Begin dosing at 150 mg/day • May be increased to a maximum of 300 mg/day within 1 week • Dose should be adjusted for patients with reduced renal function Patients with Renal Impairment In view of dose-dependent adverse reactions and since LYRICA is eliminated primarily by renal excretion, adjust the dose in patients with reduced renal function. Base the dose adjustment in patients with renal impairment on creatinine clearance (CLcr), as indicated in Table 1. To use this dosing table, an estimate of the patient’s CLcr in mL/min is needed. CLcr in mL/min may be estimated from serum creatinine (mg/dL) determination using the Cockcroft and Gault equation: [140 - age (years)] x weight (kg) CLCr =
(x 0.85 for female patients) 72 x serum creatinine (mg/dL) Next, refer to the Dosage and Administration section to determine the recommended total daily dose based on indication, for a patient with normal renal function (CLcr ≥60 mL/min). Then refer to Table 1 to determine the corresponding renal adjusted dose. (For example: A patient initiating LYRICA therapy for postherpetic neuralgia with normal renal function (CLcr ≥60 mL/min), receives a total daily dose of 150 mg/day pregabalin. Therefore, a renal impaired patient with a CLcr of 50 mL/min would receive a total daily dose of 75 mg/day pregabalin administered in two or three divided doses.) For patients undergoing hemodialysis, adjust the pregabalin daily dose based on renal function. In addition to the daily dose adjustment, administer a supplemental dose immediately following every 4-hour hemodialysis treatment (see Table 1).
Table 1. Pregabalin Dosage Adjustment Based on Renal Function Creatinine Clearance Total Pregabalin Daily Dose (CLcr) (mL/min) (mg/day)* ≥60 150 300 450 600
Dose Regimen BID or TID
BID or TID
QD or BID
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”.
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Table 3 Treatment-emergent adverse reaction incidence in controlled trials in Neuropathic Pain Associated with Diabetic Peripheral Neuropathy (Events in at least 1% of all LYRICA-treated patients and at least numerically more in all LYRICA than in the placebo group) 75 mg/d 150 mg/d 300 mg/d 600 mg/d All PGB* Placebo Body System [N=77] [N=212] [N=321] [N=369] [N=979] [N=459] - Preferred term % % % % % % Body as a whole Asthenia 4 2 4 7 5 2 Accidental injury 5 2 2 6 4 3 Back pain 0 2 1 2 2 0 Chest pain 4 1 1 2 2 1 Face edema 0 1 1 2 1 0 Digestive system Dry mouth 3 2 5 7 5 1 Constipation 0 2 4 6 4 2 Flatulence 3 0 2 3 2 1 Metabolic and nutritional disorders Peripheral edema 4 6 9 12 9 2 Weight gain 0 4 4 6 4 0 Edema 0 2 4 2 2 0 Hypoglycemia 1 3 2 1 2 1 Nervous system Dizziness 8 9 23 29 21 5 Somnolence 4 6 13 16 12 3 Neuropathy 9 2 2 5 4 3 Ataxia 6 1 2 4 3 1 Vertigo 1 2 2 4 3 1 Confusion 0 1 2 3 2 1 Euphoria 0 0 3 2 2 0 Incoordination 1 0 2 2 2 0 Thinking abnormal† 1 0 1 3 2 0 Tremor 1 1 1 2 1 0 Abnormal gait 1 0 1 3 1 0 Amnesia 3 1 0 2 1 0 Nervousness 0 1 1 1 1 0 Respiratory system Dyspnea 3 0 2 2 2 1 Special senses Blurry vision‡ 3 1 3 6 4 2 Abnormal vision 1 0 1 1 1 0 *PGB: pregabalin † Thinking abnormal primarily consists of events related to difficulty with concentration/attention but also includes events related to cognition and language problems and slowed thinking. ‡ Investigator term; summary level term is amblyopia. Other Adverse Reactions Observed During the Clinical Studies of LYRICA Following is a list of treatment-emergent adverse reactions reported by patients treated with LYRICA during all clinical trials. The listing does not include those events already listed in the previous tables or elsewhere in labeling, those events for which a drug cause was remote, those events which were so general as to be uninformative, and those events reported only once which did not have a substantial probability of being acutely life-threatening. Events are categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse reactions are those occurring on one or more occasions in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients. Events of major clinical importance are described in the Warnings and Precautions section. Body as a Whole – Frequent: Abdominal pain, Allergic reaction, Fever; Infrequent: Abscess, Cellulitis, Chills, Malaise, Neck rigidity, Overdose, Pelvic pain, Photosensitivity reaction; Rare: Anaphylactoid reaction, Ascites, Granuloma, Hangover effect, Intentional Injury, Retroperitoneal Fibrosis, Shock. Cardiovascular System – Infrequent: Deep thrombophlebitis, Heart failure, Hypotension, Postural hypotension, Retinal vascular disorder, Syncope; Rare: ST Depressed, Ventricular Fibrillation. Digestive System – Frequent: Gastroenteritis, Increased appetite; Infrequent: Cholecystitis, Cholelithiasis, Colitis, Dysphagia, Esophagitis, Gastritis, Gastrointestinal hemorrhage, Melena, Mouth ulceration, Pancreatitis, Rectal hemorrhage, Tongue edema; Rare: Aphthous stomatitis, Esophageal Ulcer, Periodontal abscess. Hemic and Lymphatic System – Frequent: Ecchymosis; Infrequent: Anemia, Eosinophilia, Hypochromic anemia, Leukocytosis, Leukopenia, Lymphadenopathy, Thrombocytopenia; Rare: Myelofibrosis, Polycythemia, Prothrombin decreased, Purpura, Thrombocythemia. Metabolic and Nutritional Disorders – Rare: Glucose Tolerance Decreased, Urate Crystalluria. Musculoskeletal System – Frequent: Arthralgia, Leg cramps, Myalgia, Myasthenia; Infrequent: Arthrosis; Rare: Chondrodystrophy, Generalized Spasm. Nervous System – Frequent: Anxiety, Depersonalization, Hypertonia, Hypesthesia, Libido decreased, Nystagmus, Paresthesia, 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. aedpregnancyregistry.org/. 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.
EARN CATEGORY I CME CREDIT by reading this article and the article beginning on page 54 and successfully completing the posttest on page 59. 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 January 2012.
LEARNING OBJECTIVES ● ● ● ●
Recognize primary and secondary risk factors for Clostridium difﬁcile infection (CDI) Describe changes in the pattern of CDI within the United States Demonstrate knowledge of the risks and beneﬁts of current and emerging treatments for CDI Relate key steps that should be taken to prevent CDI
Clostridium difficile: A new look at an old but increasingly deadly infection Despite all that is known about risk factors and prevention, hypervirulent strains of this organism are causing disease in populations that once were considered low risk.
Jacqueline S. Barnett, MSHS, PA-C
© David M. Martin, M.D. / Photo Researchers, Inc.
lostridium difficile, a spore-forming, grampositive, anaerobic bacillus, has reemerged to become the leading cause of nosocomial infectious diarrhea and a worldwide public health threat.1 Over the past decade, the changing epidemiology of C difficile infection (CDI) has been demonstrated by epidemic outbreaks of drug-resistant, toxin-producing, hypervirulent strains causing severe disease, disease recurrence, and death.2 CDI has placed a huge financial burden on the US health care system, with cost estimates of $3.2 billion annually.3 Antibiotic use continues to be the leading risk factor for CDI. However, other factors implicated in this changing infection include host immunity, comorbid diseases, the use of gastric acid-altering medications, and the use of specific antibiotics, such as fluoroquinolones and clindamycin (Cleocin, generics).1,4 Increased incidences of CDI are being reported in the community and in persons without traditional risk factors.4,5 Efficient and effective diagnosis remains a challenge; treatment options are limited; and currently, a vaccine does not exist. Preventing and controlling this disease through antibiotic stewardship, good hand hygiene, and environmental disinfection is imperative. This article provides current evidence about CDI that will enable physician assistants to serve as leaders in the prevention and intervention efforts required to curb the resurgence of this old infection. CHANGING EPIDEMIOLOGY AND RISK FACTORS
In the United States, an estimated 500,000 cases of CDI occur annually.6 Over the 7-year period of 1996 to 2003, the discharge diagnosis rate of CDI increased almost 100% 32 JAAPA • JANUARY 2012 • 25(1) • www.jaapa.com
FIGURE 1. Pseudomembranous colitis seen on colonoscopy
from 31 per 100,000 to 61 per 100,000.7 Similar increases in incidence rates were seen in Europe and Canada, with epidemic proportions impacting the infirm and the elderly.1,8 As the rates of CDI increased, the severity and complications of the disease also increased, with more cases of prolonged hospitalization, disease recurrence, colectomy, toxic megacolon, and death.2,4 The risk of developing CDI is directly related to the number of antibiotics to which a person is exposed, as well as the length of exposure and the spectrum of antibiotic coverage.4 Any antibiotic that disturbs colonic flora, including a single dose for surgical prophylaxis, is a risk factor for CDI.9 Several medications have been linked to CDI, including penicillins, cephalosporins, and lincosamides. In 1978, clindamycin phosphate, a lincosamide, was the first antibiotic associated with C difficile and pseudomembranous colitis (PMC)(Figure 1).10 More recently, widespread use of fluoroquinolones has been associated with a 3-fold increased risk of CDI.11 Fluoroquinolones are known to significantly decrease colonic flora, and this may be a factor in their high association with CDI. The use of gastric acid-altering medications, such as proton pump inhibitors (PPIs), has also increased in recent years; and although the evidence is not clear-cut, some patients taking PPIs have experienced increased rates of CDI.12 The decrease in gastric acid resulting from these medications is thought to facilitate colonization and transit of C difficile through the stomach to the bile-laden small bowel, promoting growth of the organism. Advanced age, antibiotic use, current or previous hospitalization, and comorbid disease remain traditional risk factors for CDI (Table 1). Host immunity and low production of antibody against C difficile toxins are associated with developing active disease versus asymptomatic colonization. Transplant recipients and others on immunosuppressant therapy or chemotherapeutic agents face an increased risk of CDI.4 Inflammatory bowel disease (IBD) has recently been identified as a risk factor for CDI, as rates of CDI infection are higher in patients with IBD and these patients may have a worse outcome.1,4 C difficile-associated diarrhea (CDAD) and IBD may manifest very similarly. Clinicians should be judicious in their management of patients with IBD, so that they do not overlook a complicating CDI. GI surgery and procedures that manipulate the GI tract disrupt colonic function and are risk factors for CDI.9
TABLE 1. Risk factors for CDI
Host factors • Age ≥65 y • Comorbidities, IBD • Compromised immune status • Peripartum females
Factors that disrupt colonic ﬂora and bowel functioning
Factors that increase exposure to C difﬁcile
• Antibiotic use • Immunosuppression and chemotherapeutic agents • Gastric acid-altering medications and PPIs (conﬂicting evidence) • GI surgery and manipulation • Obstruction, ileus
• Antiperistaltic medications • Contact with spores on hands and objects • Contaminated food, water, soil, pets • Hospitalization • Stays in ICU or long-term care facilities
Key: IBD, inﬂammatory bowel disease; PPI, proton pump inhibitor.
Community-acquired C difficile infection (CA-CDI) rates are on the rise in the pediatric and young adult population and in pregnant women.4,5 Community sources of CDI include exposure to recently hospitalized patients, soil, pets, water, animals used for food, meats, and vegetables.2,6 PATHOPHYSIOLOGY Pathogenesis As a spore-forming anaerobic bacterium, C
difficile is difficult to isolate and grow in culture and deserving of the name “difficile.” Colonization with C difficile occurs primarily in the colon and is rare in other parts of the body. The preference of C difficile for the colon is most likely related to the anaerobic colonic environment. Antibiotic treatment resulting in a lack of competing flora creates an environment that allows the anaerobic bacilli to grow and thrive.2 The virulence of C difficile is related to the two toxins that it produces: endotoxin A (TxA) and cytotoxin B (TxB). Both toxins cause intestinal permeability and cytoskeletal reactions. The release of toxins in the colon triggers a cascade of increased fluid secretion, inflammation, and tissue necrosis that can form a pseudomembrane of immune cells. Epidemic strains Between 1989 and 1992, an epidemic of CDI associated with clindamycin use was reported in the United States.13 A follow-up study between 2000 and 2003
KEY POINTS ■ Incidence and prevalence rates of Clostridium difﬁcile infection (CDI) are increasing, along with reports of community-acquired CDI.
Hypervirulent C difﬁcile strains are causing worldwide epidemics. ■ Diagnosis is conﬁrmed by culture or the presence of C difﬁcile toxins or toxin strains in the stool. ■ The ﬁrst step in treatment is to discontinue the offending antibiotic, unless there are convincing contraindications to doing so. ■ Metronidazole is not as effective as vancomycin for severe disease or recurrent infection. FDA-approved medications to treat severe
or recurrent CDI are lacking. ■ To control CDI, antibiotic stewardship and environmental infection controls are a must.
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CME C difficile infection TABLE 2. Recommendations for the treatment of CDI Supportive clinical data
Initial episode, mild or moderate
Leukocytosis with a WBC count of ≤15,000 cells/μL and a serum creatinine level < 1.5 times the premorbid level
Metronidazole, 500 mg 3 times daily by mouth for 10-14 d
Initial episode, severea
Leukocytosis with a WBC count of ≥15,000 cells/μL or a serum creatinine level ≥1.5 times the premorbid level
Vancomycin, 125 mg 4 times daily by mouth for 10-14 d
Initial episode, severe, complicated
Hypotension or shock, ileus, megacolon
Vancomycin, 500 mg 4 times daily by mouth or by nasogastric tube, plus metronidazole, 500 mg every 8 h IV. If complete ileus, consider adding rectal instillation of vancomycin.
Strength of recommendation
Same as for initial episode
Vancomycin in a tapered and/or pulsed regimen
The criteria proposed for deﬁning severe or complicated CDI are based on expert opinion. These may need to be reviewed in the future upon publication of prospectively validated severity scores for patients with CDI.
Reprinted with permission. Cohen SH, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difﬁcile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol. 2010;31(5):431-455. Published by: The University of Chicago Press on behalf of The Society for Healthcare Epidemiology of America. 2010. All rights reserved.
identified a virulent strain of C difficile that was highly resistant to fluoroquinolones.14 This strain, named BI/NAP1/027, was also found in Canada and Europe and produced 16 to 23 times more toxin, was highly infectious, and more virulent than earlier identified strains.2,6 Most recently noted in the literature as NAP1/BI/027, this epidemic strain has been linked to increased incidence, complications, morbidity, and mortality of CDI.9 Transmission C difficile exists in vegetative and spore forms. The vegetative form is more common, sensitive to
“The gold standard for diagnosing CDI is the cell culture cytotoxic assay, a specialized test that has a high specificity and sensitivity.” oxygen, and easily eradicated even with brief air exposure.15 In the spore form, C difficile is primarily transmitted person to person through the fecal-oral route and through fomite instrumentation.9 C difficile spores can survive harsh environments because they are resistant to high heat, alcoholbased hand sanitizers, ultraviolet light, and many chemicals 34 JAAPA • JANUARY 2012 • 25(1) • www.jaapa.com
used for cleaning.2,6 Therefore, even with cleaning, spores contaminate and survive on the surfaces of health care facilities and on the hands of health care workers. CLINICAL MANIFESTATIONS AND DIAGNOSIS Signs and symptoms The disease manifestations of CDI
range from asymptomatic colonization to mild diarrhea, fulminant colitis, and death. Typically, CDI begins with watery diarrhea that may be associated with nausea, fever, and lower-abdominal cramping or pain. Mucus may be present in the stool, but frank blood or hematochezia are rare. Findings on the physical examination are usually unremarkable, except in cases of severe colitis, when the patient may present with abdominal pain and distention. Laboratory evaluation may reveal leukocytosis and hypoalbuminemia. In severe disease, CT may demonstrate colonic wall thickening, and inflammation and pseudomembranes may be visible on endoscopy as raised yellowish plaques. Sigmoidoscopy and colonoscopy are not recommended as diagnostic screening tests because only 50% of patients with CDI form visible colonic pseudomembranes.2 CDI can progress rapidly; and if it does, it is associated with severe disease and poorer outcomes, as seen in fulminant and pseudomembranous colitis.1 These patients may exhibit highvolume, foul-smelling diarrhea (15-30 episodes a day), which may be bloody; marked leukocytosis; fever; hypoalbuminemia;
hypotension; and rising creatinine levels.1,15 Patients with fulminant colitis and PMC may progress from initial diagnosis to colectomy in 5 days. In advanced disease, such as with PMC, 20% of patients may not present with watery diarrhea; instead they present with an ileus and marked abdominal distention and pain.1 This presentation is not characteristic of classic CDI and could lead to an incorrect diagnosis. Testing Accurate and timely diagnosis of CDI remains a challenge and should be based on the patient’s history and findings on physical examination, associated risk factors, clinical presentation, laboratory results, and identification of C difficile or its toxin or toxigenic strain in unformed stool. The gold standard for diagnosing CDI is the cell culture cytotoxic assay. This test has high specificity and sensitivity but requires specialized laboratory techniques; it is both labor- and time-intensive.15 Most laboratories in the United States use enzyme immunoassays (EIAs) for diagnosing CDI by detecting C difficile toxins in stool samples. EIAs have a rapid turnaround time and are easy to perform, although they have a higher false-negative rate over the more sensitive cell culture cytotoxic assay.9 Laboratories typically diagnose CDI using a two-step approach. Initially, stool is screened with an EIA that detects glutamate dehydrogenase, a C difficile antigen, and positive results are confirmed with an EIA toxin test. Real-time polymerase chain reaction (PCR) tests that detect C difficile toxins (sensitivity, 90-95%; specificity, 95-96%) are rapid, easy to perform, and becoming more commonly used.4,9 One such PCR test was approved by the FDA in 2011. It detects the presence of C difficile in the stool and determines whether the bacterium is the epidemic BI/NAP1/027 strain.16 Stool testing on asymptomatic patients and repeat stool tests of cure are not recommended.9 CURRENT AND EVOLVING THERAPIES Treatment For 25 years, oral vancomycin (Vancocin),
metronidazole (Flagyl, generics), or combinations of both medications have served as the primary treatment of CDI.4 Clinical guidelines to date have shown these medications to be equally effective.9,17 However, a recent study by Zar and colleagues showed decreased efficacy of metronidazole in patients with severe CDI: The cure rate was 76% for metronidazole and 97% for vancomycin.18 The Society for Healthcare Epidemiology of America and the Infectious Diseases Society of America (SHEA-IDSA) provide current guidelines for treating CDI (Table 2).9 The first step in treatment is to discontinue the offending antibiotics if at all possible. Empiric therapy should be administered if severe or complicated CDI is suspected. Intravenous vancomycin does not reach adequate concentration in the colonic lumen and is not recommended for the treatment of CDI. Many clinicians continue CDI therapy for at least 1 week after the offending antibiotic is discontinued. If clinicians choose to prolong CDI therapy, the guidelines recommend using vancomycin instead of metronidazole. SHEA-IDSA guidelines do not make recommendations for treating CDI
“Because the alcohol-based hand sanitizers are not effective at killing C difficile spores, soap and water should be used for hand washing.” when contraindications to stopping the offending antibiotic exist. In cases of fulminant colitis or toxic megacolon, colectomy may be a lifesaving intervention. The changing epidemiology of CDI has seen an approximately 20% recurrence rate of infection in those patients treated with vancomycin and metronidazole.19 The first recurrence of CDI should be treated with the same medication as the initial infection. However, metronidazole should not be utilized in subsequent recurrences because of its associated neurotoxicity; instead tapered or alternative dosing of vancomycin should be instituted.9 Patients with CDI should not be treated with medications that decrease colonic peristalsis, such as antidiarrheals, as these agents may place patients at greater risk for complications.2 In May 2011, fidaxomicin (Dificid) was approved by the FDA for the treatment of CDI.20 Fidaxomicin was found to be as effective as vancomycin. Patients receiving fidaxomicin had fewer recurrences of the nonvirulent strain of CDI.21 Evolving therapies Rifaximin (Xifaxan) and teicoplanin are two other agents utilized in treating CDI. Both medications have reported efficacy rates comparable to that of vancomycin, and rifaximin has been efficacious in treating initial and recurrent CDI. However, questions arise regarding resistance to rifaximin, and teicoplanin is not approved for use in the United States.4 Stool infusion therapy, also known as fecal bacteriotherapy, is being utilized as a way to replenish gut flora and treat CDI. Donor stool flora is infused either through a nasogastric tube or rectally. Studies utilizing fecal therapy are showing great promise, with 90% patient success rates.22 Early treatment success has also been observed in patients who received monoclonal antibodies against C difficile along with either metronidazole or vancomycin.23 Additional TABLE 3. CDI prevention and control techniques9,15,26 Environmental cleaning programs should utilize hypochlorite solutions and target high-use contaminated areas. Isolate infected patients. Practice antibiotic stewardship. Replace electronic rectal thermometers with disposable single-use rectal thermometers. Use soap and water to wash hands. Wash hands between patient visits, and wear protective gowns and gloves.
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CME C difficile infection “Clostridium difficile infection is primarily a preventable disease. Therefore, even one death from this infection is unacceptable.” emerging and investigational therapies include toxinbinding agents, other probiotic agents, and IV immunoglobulin (IVIG).22 PREVENTION AND CONTROL
The single most modifiable risk factor associated with development of CDI is antibiotic therapy. The best prevention and intervention techniques must be targeted to decrease the use of antibiotics in the general population. Two recent studies showed 50% and 70% decreases in CDI incidence rates when prescribers complied with institutional prescribing policies.24,25 Providers and institutions should implement a systemsbased practice approach that considers the indications of each medication, employs medication intervention only if necessary, and utilizes medications with the narrowest spectrum and for the shortest duration (antibiotic/medication stewardship). Antibiotic therapy should be based on local disease epidemiology, but limiting the routine use of cephalosporins and clindamycin may be beneficial. Whenever possible, utilize antibiotics that have the lowest risk associated with CDI. PAs practice the tenets of beneficence and nonmalfeasance and would not intentionally place patients at risk for CDI and the consequences of this infection. Therefore, utilizing a systems-based approach to practice will help to ensure that PAs are mindful in their efforts to prevent CDI. Along with antibiotic stewardship, vigilant hand hygiene and infection control measures must be instituted in health care settings to decrease the spread of infection (Table 3). Because alcohol-based hand sanitizers are not effective at killing C difficile spores, soap and water should be used for hand washing.9 Hypochlorite (bleach)-based disinfectants and solutions have been shown to decrease rates of CDI contamination on high-use surfaces subject to contamination, such as control switches, bed rails, commodes, faucets, and doors.15,26 Use of disposable rectal thermometers will reduce CDI related to fomite instrumentation.9 CONCLUSION
CDI has reemerged as a serious public health threat, with more virulent strains causing severe disease and infecting those in the community who are at low risk for the disease. Preventing and controlling this disease is a huge challenge. Diagnosing CDI remains problematic, as no single test is sensitive enough, specific enough, or fast enough; and treatment options remain limited. CDI is primarily a preventable disease. Therefore, even one death from this infection is unacceptable. Antibiotic 36 JAAPA • JANUARY 2012 • 25(1) • www.jaapa.com
stewardship and strict environmental infection control polices provide the best public health prevention and control strategies. PAs are well positioned to serve as leaders and educators within their practice settings to combat the reemerging public health threat of C difficile. JAAPA Jacqueline Barnett is an assistant professor of health care sciences in the PA program at The George Washington University School of Medicine and Health Sciences in Washington, DC. The author has indicated no relationships to disclose relating to the content of this article. REFERENCES 1. DuPont HL, Garey K, Caeiro JP, Jiang ZD. New advances in Clostridium difﬁcile infection: changing epidemiology, diagnosis, treatment and control. Curr Opin Infect Dis. 2008;21(5):500-507. 2. Heinlen L, Ballard JD. Clostridium difﬁcile infection. Am J Med Sci. 2010;340(3):247-252. 3. O’Brien JA, Lahue BJ, Caro JJ, Davidson DM. The emerging infectious challenge of Clostridium difﬁcile-associated disease in Massachusetts hospitals: clinical and economic consequences. Infect Control Hosp Epidemiol. 2007;28(11):1219-1227. 4. Ananthakrishnan AN. Clostridium difﬁcile infection: epidemiology, risk factors and management. Nat Rev Gastroenterol Hepatol. 2011;8(1):17-26. 5. Centers for Disease Control and Prevention (CDC). Severe Clostridium difﬁcile-associated disease in populations previously at low risk—four states, 2005. MMWR Morb Mortal Wkly Rep. 2005;54(47):1201-1205. 6. Rupnik M, Wilcox MH, Gerding DN. Clostridium difﬁcile infection: new developments in epidemiology and pathogenesis. Nat Rev Microbiol. 2009;7(7):526-536. 7. McDonald LC, Owings M, Jernigan DB. Clostridium difﬁcile infection in patients discharged from US short-stay hospitals, 1996-2003. Emerg Infect Dis. 2006;12(3):409-415. 8. Janka J, O’Grady NP. Clostridium difﬁcile infection: current perspectives. Curr Opin Crit Care. 2009;15(2):149-153. 9. Cohen SH, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difﬁcile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol. 2010;31(5):431-455. 10. Bartlett JG. Historical perspectives on studies of Clostridium difﬁcile and C difﬁcile infection. Clin Infect Dis. 2008;46(suppl 1):S4-S11. 11. Pépin J, Saheb N, Coulombe MA, et al. Emergence of ﬂuoroquinolones as the predominant risk factor for Clostridium difﬁcile-associated diarrhea: a cohort study during an epidemic in Quebec. Clin Infect Dis. 2005;41(9):1254-1260. 12. Surawicz C. The acid test: is proton pump inhibitor therapy an independent risk factor for Clostridium difﬁcile-associated disease? Gastroenterology. 2007;133(1):355-357. 13. Johnson S, Samore MH, Farrow KA, et al. Epidemics of diarrhea caused by a clindamycinresistant strain of Clostridium difﬁcile in four hospitals. N Engl J Med. 1999;341(22):1645-1651. 14. McDonald LC, Killgore GE, Thompson A, et al. An epidemic, toxin gene-variant strain of Clostridium difﬁcile. N Engl J Med. 2005;353(23):2433-2441. 15. McFee RB, Abdelsayed GG. Clostridium difﬁcile. Dis Mon. 2009;55(7):439-470. 16. Food and Drug Administration. FDA news release. FDA clears test for bacteria that can cause serious intestinal disease. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ ucm250498.htm. Published April 8, 2011. Accessed December 2, 2011. 17. Voelker R. Increased Clostridium difﬁcile virulence demands new treatment approach. JAMA. 2010;303(20):2017-2019. 18. Zar FA, Bakkanagari SR, Moorthi KMLST, Davis MB. A comparison of vancomycin and metronidazole for the treatment of Clostridium difﬁcile-associated diarrhea, stratiﬁed by disease severity. Clin Infect Dis. 2007;45(3):302-307. 19. Johnson S. Recurrent Clostridium difﬁcile infection: a review of risk factors, treatments, and outcomes. J Infect. 2009;58(6):403-410. 20. Food and Drug Administration. FDA news release. FDA approves treatment for Clostridium difﬁcile infection. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm257024. htm. Published May 27, 2011. Accessed December 2, 2011. 21. Louie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for Clostridium difﬁcile infection. N Engl J Med. 2011;364(5):422-431. 22. Salkind AR. Clostridium difﬁcile: an update for the primary care clinician. South Med J. 2010; 103(9):896-902. 23. Lowy I, Molrine DC, Leav BA, et al. Treatment with monoclonal antibodies against Clostridium difﬁcile toxins. N Engl J Med. 2010;362(3):197-205. 24. O’Connor KA, Kingston M, O’Donovan M, et al. Antibiotic prescribing policy and Clostridium difﬁcile diarrhoea. QJM. 2004;97(7):423-429. 25. Wilcox MH, Freeman J, Fawley W, et al. Long-term surveillance of cefotaxime and piperacillintazobactam prescribing and incidence of Clostridium difﬁcile diarrhoea. J Antimicrob Chemother. 2004;54(1):168-172. 26. Hacek DM, Ogle AM, Fisher A, et al. Signiﬁcant impact of terminal room cleaning with bleach on reducing nosocomial Clostridium difﬁcile. Am J Infect Control. 2010;38(5):350-353.
The Surgical Patient An internal hernia causes abdominal pain and small bowel obstruction
47-year-old female presented to the emergency department (ED) with a 2-day history of cramping abdominal pain in the left upper and lower quadrants. The pain had been intermittent until 3 AM that morning, when it became constant and increased in severity, which she rated as 10 on the 10-point pain scale. The patient also complained of nausea but reported no eructation, diarrhea, constipation, bleeding from the rectum, fevers, or chills. Her weight had been stable. There had been no change in her bladder or bowel habits. Her last bowel movement, which she reported as normal, had occurred 2 days prior to presentation. She denied any previous episodes of abdominal pain and had not experienced any recent trauma. She was not taking any OTC medications, including laxatives. Review of systems The patient had no significant medical history. Surgical history included laparoscopy for egg harvesting at age 40 years. She did not smoke, consume alcohol, or use recreational drugs, and she was not allergic to any medications. Her family history was noncontributory. She denied chest pain and dyspnea. Assessment Because of the severity of her pain, the patient was assisted onto the stretcher for evaluation. On initial examination, she was alert and oriented to person, place, and time. Her appearance was consistent with her stated age. She was visibly in pain, tearful, and uncomfortable but in no acute distress. Vital signs were as follows: BP, 150/78 mm Hg; pulse, 53 beats per minute; respirations, 18 breaths per minute; temperature, 98°F. Oxygen saturation was 99% on room air. A focused physical examination revealed a soft, nondistended abdomen. Lowpitched bowel sounds were heard in all four quadrants. Palpation detected tenderness in the left upper and lower quadrants and mild guarding. The patient had no organomegaly, rebound tenderness, or peritoneal signs. Rectal examination found no palpable masses; stool in the vault was minimal and guaiac-negative.
Laboratory studies CBC results included WBC count, 11.5 × 103/µL; hematocrit, 42%; and platelets, 221 × 103/ µL. Electrolyte results were normal. Other laboratory results included alkaline phosphatase, 52 U/L; ALT, 30 U/L; AST, 20 U/L; beta-human chorionic gonadotropin, less than 2.4 mIU/mL; lipase, 168 U/L; and total bilirubin, 1.2 mg/dL. A troponin assay was negative. Blood gas determinations were pH 7.33; PCO2, 38 mm Hg; PO2, 29 mm Hg; oxygen 21%; bicarbonate, 20 mEq/L. Base deficit was 5.4 mEq/L. Continued on page 43
© Christy Krames
Lisa Vieira, DHS, PA-C; Sonia James, RN, MA, ACNP-BC, CCRN
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The Surgical Patient Imaging studies CT of the abdomen and pelvis with IV contrast revealed multiple loops of dilated small bowel within the left upper quadrant. Thickened bowel walls with adjacent inflammatory changes and free fluid were consistent with a high-grade small-bowel obstruction (SBO), and there were signs suggestive of developing ischemia (Figure 1). Surgical procedure Following review of the abdominal/ pelvic CT scan and surgical consultation, a nasogastric tube and Foley catheter were placed and the patient was admitted to the surgery service. The patient’s status was NPO, and IV fluids were initiated to maintain intravascular volume, balance electrolytes, and ensure adequate urinary output. After the risks and benefits of emergent exploratory laparotomy were explained, informed consent was obtained. The patient was taken to the OR under general anesthesia. The surgical approach was through the abdominal cavity via a midline incision. When the bowel was inspected intraoperatively, several loops of necrotic small bowel were noted in the left upper quadrant; there was no evidence of perforation. The patient was partially eviscerated until a congenital adhesive band was found. The band was causing an internal hernia through which several loops of bowel were passing. The band was lysed, and approximately 2 feet of strangulated necrotic small bowel were resected with a primary anastomosis. The small bowel was measured from the ligament of Treitz to the ileocecal valve; approximately 315 cm of small bowel remained intact. The bowel was returned to its normal anatomic position in the abdominal cavity. The patient tolerated the procedure well and without complications. She was extubated in the OR and transferred to the postanesthesia care unit in stable condition.
“Diagnostic imaging combined with a high index of suspicion will help to avoid misdiagnosis of small-bowel obstruction.” Later she was moved to a postoperative unit for further monitoring and observation. Pain was managed with IV patient-controlled morphine titrated to comfort level as needed. The postoperative course was uneventful. By the fourth postoperative day, the patient was eating and had normal bowel function. She was discharged home on postoperative day 5. DISCUSSION
Internal hernias occur within the confines of the peritoneal cavity. They are typically described as a prolapse of intesti-
FIGURE 1. CT showed loops of dilated small bowel, thickened walls, and inﬂammatory changes.
nal loops formed by the protrusion of viscus through a normal or abnormal opening in the peritoneum or mesentery. Internal hernias are either acquired or congenital and can manifest with persistent or intermittent signs of obstruction. Acquired internal hernias can be the result of previous surgery, trauma, or a postinflammatory defect. Types of internal hernias and their relative incidences are as follows: paraduodenal, 53%; foramen of Winslow, 8%; transmesenteric, 8%; transomental, 1% to 4%; pericecal, 13%; intersigmoid, 6%; supravesical and pelvic, 6%.1 Congenital internal hernias are of the paraduodenal, pericecal, or transmesenteric subtypes. Paraduodenal hernias are left-sided in 75% of patients and believed to occur because of congenital herniation of the small bowel into the Landzert fossa, which is located left of the fourth portion of the duodenum. Transmesenteric hernias are usually related to prior abdominal surgery and are more likely to result in volvulus and ischemia than other types of internal hernia.2 Many studies have indicated a shift in the prevalence of common causes of internal hernia. This shift reflects an increase in mesenteric defects resulting from abdominal surgeries, such as roux-en-Y anastomosis following orthotopic liver transplant or gastric bypass for morbid obesity. There does not appear to be any predilection for internal hernia based on age or sex. The overall incidence of internal hernia is less than 1%. Without fundamental knowledge or a heightened awareness of internal hernia, many cases can be missed, misdiagnosed, or overlooked, resulting in significant morbidity and mortality. Small-bowel obstruction accounts for approximately 5.8% of cases of internal hernia. Obstruction is the most commonly encountered surgical disorder of the small bowel. Other causes of SBO are presented in Table 1. Once SBO occurs, treatment is crucial. Left www.jaapa.com • JANUARY 2012 • 25(1) • JAAPA
The Surgical Patient TABLE 1. Common causes of small bowel obstruction5 Abdominal surgery Adhesions Congenital abnormalities Foreign body Hernia Inﬂammatory bowel disease Intussusception Neoplasm Volvulus
untreated, the mortality rate due to bowel strangulation exceeds 50%. Clinical manifestations The manifestations of internal hernia vary. Hernias that resolve spontaneously or are easily reducible may not produce any symptoms. However, most patients complain of discomfort ranging from constant, vague epigastric pain to intermittent, colicky periumbilical pain. Patients may also present with abdominal distention, nausea, vomiting (especially after a large meal), constipation, and recurrent intestinal obstruction. Acute high-grade obstruction may manifest with tachycardia, hypotension, and dehydration. Patients in the early stages of high-grade obstruction may have a distended abdomen and hyperactive bowel sounds, while those in the late stage may present with paralytic ileus. Signs of peritonitis often suggest bowel strangulation, making those internal hernias clinically apparent at the time of examination.3 Symptom severity relates to the duration and reducibility of the hernia and to the presence or absence of incarceration and strangulation. Diagnosis The diagnosis of internal hernia is best made either by CT or high clinical index of suspicion and usually requires emergent exploration or diagnostic laparoscopy with further surgical intervention. Because of the propensity of these hernias to spontaneously reduce, patients are best imaged when they are symptomatic. CT is the preferred modality because it is generally available and is capable of imaging the characteristics necessary to diagnose internal hernia. CT enables the clinician to assess the transition point of obstruction as well as determine whether underlying pathology is present. Characteristic CT findings in internal hernia include a cluster of dilated bowel loops. Wall thickening, pneumatosis, or ascites are highly suspicious for bowel ischemia and usually lead to emergent surgical exploration.1 The radiologist usually makes the diagnosis of internal hernia based on the configuration of bowel loops, changes in the appearance of mesenteric vessels, and enhancement pattern of the bowel wall. 44 JAAPA • JANUARY 2012 • 25(1) • www.jaapa.com
Other imaging modalities should not be excluded. A simple plain radiograph may reveal multiple air-fluid levels, an indication of possible SBO. A small-bowel series may demonstrate bunched-up small bowel to the right or left of the colon. Bowel proximal to the hernia is dilated. The small bowel is not usually visible in the pelvis.3 Ultrasonography could lead to the diagnosis of internal hernia, especially with the help of an experienced radiologist. Clinical examination that reveals signs of SBO can also prompt surgical exploration. Such exploration may lead to a diagnosis of internal hernia. Treatment In general, all hernias should be repaired unless local or systemic conditions in the patient preclude a safe outcome. The possible exception to this generalization is a hernia with a wide neck and shallow sac that is expected to slowly enlarge.4 The principal treatment option in patients suspected of having an internal hernia, especially when there is concern for ischemia or bowel strangulation, is emergent surgical intervention in the hopes of improving the overall survival rate. The potential for lethal complications, such as bowel infarction or perforation, usually prompts emergent surgical intervention. Early diagnosis and prompt surgical intervention provide the only chance of a successful outcome. In cases involving SBO without suspicion for internal hernia, proper management depends on the nature of the obstruction. Partial obstruction can be managed conservatively with nasogastric decompression and IV fluid for several days. CONCLUSION
Diagnostic imaging combined with a high clinical index of suspicion will avoid misdiagnosis of small-bowel obstruction arising from an internal hernia. Correct diagnosis can prevent life-threatening complications and limit morbidity and mortality. JAAPA Lisa Vieira is a physician assistant and Sonia James is a nurse practitioner in the Department of Surgery at NYU Langone Medical Center, New York, NY. The authors have indicated no relationships to disclose relating to the content of this article. Steve Wilson, PA-C, department editor REFERENCES 1. Kohli A, Choudhury HS, Rajput D. Internal hernia: a case report. Ind J Radiol Imag. 2006;16(4): 563-566. 2. Blachar A, Federle MP. Internal hernia: an increasingly common cause of small bowel obstruction. Semin Ultrasound CT MR. 2002;23(2):174-183. 3. Yagnik V, Patel P, Patel A. Congenital internal hernia: a rare cause of small-bowel obstruction. http:// www.ispub.com/journal/the_internet_journal_of_surgery/volume_20_number_1_1/article/congenitalinternal-hernia-a-rare-cause-of-small-bowel-obstruction.html/. Accessed December 2, 2011. 4. Wantz GE. Abdominal wall hernias. In: Schwartz SI, Shires TG, Spencer FC, et al. Principles of Surgery. Vol 2. 7th ed. New York, NY: McGraw-Hill; 1999:1585-1612. 5. Burton E, McKeating J, Stahlfeld, K. Laparoscopic management of a small bowel obstruction of unknown cause. JSLS. 2008;12(3):299-302.
C-reactive protein: A clinically useful biomarker in renal cell carcinoma Biochemical markers of inﬂammation, speciﬁcally CRP, serve as adjuncts to TNM staging to help identify patients at increased risk for recurrence of kidney cancer.
Two patients were referred to our urology clinic for staging and management of renal masses. Patient 1 was a 68-year-old white female with a body mass index (BMI) of 21.3 kg/m2. MRI revealed a renal mass measuring 7.0 × 7.9 × 8.0 cm invading the right renal vein and extending to the inferior vena cava (IVC). Clinical staging suggested locally invasive disease in the absence of nodal or distant metastases. On resection, the mass measured 8.2 cm, and the diagnosis was grade 4 clear cell kidney cancer T3N0M0. Histologically, the mass demonstrated negative surgical margins, absence of invasion into the IVC wall, and absence of nodal metastasis. In addition to traditional TNM staging, we assessed inflammatory status by measuring the serum C-reactive protein (CRP). The initial CRP level (which we used as our “preoperative” value) was 215.46 mg/L (Table 1). Patient 2 was a 46-year-old white male with a BMI of 19.0 kg/m2. MRI revealed a renal mass measuring 11.0 × 11.1 × 11.0 cm and extending through the renal vein to the IVC. Clinical staging suggested locally invasive disease in the absence of nodal or distant metastases. On resection, the mass measured 7.9 cm, and the diagnosis was grade 3 clear cell kidney cancer T3N0M0. Histologically, the mass demonstrated negative surgical margins, absence of invasion into the IVC wall, and absence of nodal metastasis. Patient 2’s initial CRP level was 163.7 mg/L (Table 1). Both patients presented with similar disease states: locally invasive kidney cancer without known nodal or distant metastases. Therefore, both patients underwent potentially curative radical nephrectomy. In both cases, the diseased kidney and associated adrenal glands were removed. Additionally, draining lymph nodes were removed and analyzed pathologically for nodal metastasis. Pathologic analyses revealed a lack of nodal spread in both patients. The two patients were followed postoperatively. At each visit, serum CRP levels were measured and CT scans performed to identify metastases. Patient 1’s CRP levels declined precipitously, falling to less than 10 mg/L at 1
month postoperatively (Table 1). Patient 1 survived the first year after diagnosis without recurrence of disease. Patient 2’s CRP levels remained higher than 100 mg/L postoperatively (Table 1). He developed lung metastases 4 months after surgery and died 7 months after surgery. DISCUSSION
Each year, more than 50,000 cases of kidney cancer are diagnosed in the United States and more than 200,000
FIGURE 1. Renal carcinoma as seen on intravenous pyelography
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© BSIP / Photo Researchers, Inc.
Timothy V. Johnson, MD; Jennifer DeLong, PA; Viraj A. Master, MD, PhD
CASE REPORT | C-reactive protein TABLE 1. Preoperative and postoperative CRP levels for patients 1 and 2 CRP (mg/L) Preoperative
1 mo postoperative
3 mo postoperative
6 mo postoperative
12 mo postoperative
cases are diagnosed worldwide.1 Approximately 30% of all patients with kidney cancer present with known metastases.2 For patients who present with localized disease, nephrectomy remains the only definitive treatment. Despite surgical nephrectomy, 30% of patients who present with localized disease will develop postoperative metastases.2 At present, predicting which patients will go on to develop metastases is difficult. After initial staging, postoperative recurrence represents the single greatest prognostic factor.3 Patients who develop metastases have a median survival of 9 months, and fewer than 10% have an overall 5-year survival. In contrast, patients who do not develop metastases have a greater than 90% overall 5-year survival, depending on stage at diagnosis.2,4 Despite this poor prognosis, aggressive excision of metastases following early detection can dramatically improve survival by 25% to 60% in select patients.2 Therefore, clinicians have sought clinical markers to predict which patients will develop metastases. The ability to predict disease progression would allow clinicians to provide increased surveillance and early intervention, as well as appropriate counseling. The presented cases demonstrate the flaws in current prognostic tools and the need for selective increased surveillance. Patients 1 and 2 presented with identical malignancies based on traditional TNM staging. However, patient 1 survived her first year without recurrence, while patient 2 experienced recurrence and succumbed to his disease within 7 months of diagnosis. How can clinicians better predict which patients will develop metastases after surgery? Which patients need aggressive screening for recurrence? How long will patients live? These questions are answered in part by improved screening using inflammatory cytokines, such as CRP. CRP as an inﬂammation marker CRP is an acute phase reactant produced primarily in the liver in response to elevations in the levels of inflammatory cytokines, such as interleukin-6 (IL-6).5 CRP levels can increase 1,000-fold in a variety of patho-
logic states, including heart disease, atherosclerosis, type 2 diabetes mellitus, infections, autoimmune disease, and malignancies.5 Numerous studies have suggested an association between CRP and malignancies, such as upper urinary tract urothelial carcinoma, lymphomas, sarcomas, cerebral tumors, and kidney cancer.5 Some studies even suggest prognostic potential for C-reactive protein, ie, increased CRP values reflect an increased level of inflammation and therefore increased tumor burden. In kidney cancer, tumor progression typically involves local production of proinflammatory molecules, such as IL-6.5 Higher plasma IL-6 levels induce increased hepatic and intratumoral production of CRP. Consequently, increased IL-6 and CRP levels have both been associated with higher tumor stage and grade, greater tumor burden, and increased metastatic progression. Clinical utility of CRP The full utility of CRP measurements in kidney cancer remains to be determined. However, clinicians currently use CRP measurements in kidney cancer in three ways. Preoperative CRP levels can to help prepare patients for likely outcomes and guide treatment planning. Postoperatively, CRP levels can be monitored to assess response to treatment and reevaulate prognosis. Finally, clinicians can use postoperative CRP levels to guide aggressiveness of screening for future metastases and selection to clinical trials. Preoperative CRP levels can vary from 0 mg/L to greater than 300 mg/L.6 Traditionally, values above 10 mg/L were considered elevated and associated with increased risk of recurrence and mortality. However, recent data suggest that every unit increase in preoperative CRP level increases the likelihood of kidney cancer recurrence and mortality within the first year of diagnosis.6 Consequently, these preoperative laboratory values and empirical graphs depicting the relationship between CRP levels and the risk of recurrence and mortality are clinically useful as visual aids for patients and to help explain possible outcomes. While a preoperative CRP level is useful to prepare patients for likely outcomes, a postoperative CRP level (measured
TEACHING POINTS ■ A large percentage of patients with kidney cancer will present with or develop metastases. Metastatic spread is the greatest predictor
of mortality. ■ Emerging aggressive treatment can improve survival in some patients who develop metastases, but this treatment relies on early detection. ■ While traditional TNM staging remains integral in prognosis of kidney cancer, it has signiﬁcant limitations. ■ Preoperative and postoperative biochemical markers of inﬂammation, speciﬁcally CRP, serve as adjuncts to TNM staging to help iden-
tify patients at increased risk for recurrence. These tools should help guide intensity of counseling, follow-up surveillance of recurrence, and enrollment in clinical trials.
46 JAAPA • JANUARY 2012 • 25(1) • www.jaapa.com
1 month postoperatively) remains the better predictor of recurrence and survival.7 In fact, once postoperative CRP is measured, preoperative CRP is rendered insignificant.7 Each unit increase in postoperative CRP increases the patient’s risk of recurrence and mortality within the first year of diagnosis.7 For example, patients 1 and 2 had preoperative CRP values of similar magnitude. The CRP values of both patients suggested potential poor outcomes and warranted aggressive treatment. Postoperatively, patient 1’s CRP level fell dramatically, while patient 2’s CRP remained elevated. These changes suggest that patient 1 responded favorably to nephrectomy and warranted nothing more than standard screening for recurrence. However, patient 2’s CRP values suggested continued subclinical disease, warranting increased surveillance for potential metastases or even consideration of chemotherapy for subclinical disease, as is done for such diseases as testis cancer. CONCLUSION
A significant number of patients with renal cell carcinoma will develop metastases, even after potentially curative surgery for localized disease. Therefore, selective surveillance is needed for patients with increased postoperative risk of recurrence and mortality. C-reactive protein, a biomarker
Cincinnati SportsMedicine Research & Education Foundation Presents the 27th Annual
Frank R Noyes, MD Matthew L Busam, MD Marc T Galloway, MD Samer S Hasan, MD, PhD Thomas N Lindenfeld, MD Stephen J O’Brien, MD Anthony A Romeo, MD Edward M Wojtys, MD Timothy P Heckmann, PT Julie Jasontek, PT Michael A McCormack, PT George J Davies, PT Russell M Paine, PT Kevin E Wilk, DPT And More...
of inflammation, correlates with tumor burden and spread of disease. In renal cell carcinoma, preoperative and postoperative CRP determinations are clinically useful for counseling patients and guiding therapy and aggressiveness of postoperative surveillance. JAAPA When this article was written, the authors were members of a research team in the Department of Urology, Emory University College of Medicine, Atlanta, Georgia. Timothy Johnson was a student at the College of Medicine. Jennifer DeLong was a PA and Viraj Master was an assistant professor in the Department of Urology. The authors have indicated no relationships to disclose relating to the content of this article. REFERENCES 1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2009. CA Cancer J Clin. 2009;59(4):225-249. 2. Klatte T, Lam JS, Shuch B, et al. Surveillance for renal cell carcinoma: why and how? When and how often? Urol Oncol. 2008;26(5):550-554. 3. Ljungberg B. Prognostic markers in renal cell carcinoma. Curr Opin Urol. 2007;17(5):303-308. 4. Escudier B. Sunitinib for the management of advanced renal cell carcinoma. Expert Rev Anticancer Ther. 2010;10(3):305-317. 5. Jabs WJ, Busse M, Krüger S, et al. Expression of C-reactive protein by renal cell carcinomas and unaffected surrounding renal tissue. Kidney Int. 2005;68(5):2103-2110. 6. Johnson TV, Abbasi A, Owen-Smith A, et al. Absolute preoperative C-reactive protein predicts metastasis and mortality in the ﬁrst year following potentially curative nephrectomy for clear cell renal cell carcinoma. J Urol. 2010;183:480-485. 7. Johnson T, Abbasi A, Owen-Smith A, et al. Postoperative better than preoperative C-Reactive Protein at predicting outcome following potentially curative nephrectomy for renal cell carcinoma. Urology. 2010;76(3):766.e1-e5.
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The characteristics of clinically active older physician assistants Roderick S. Hooker, PhD, MBA, PA; Christal Ramos, MPH; R. Paola Daly, MHS; Raymond Fang, MS
ABSTRACT Objective: To prepare for future health workforce requirements, planners need an understanding of the clinical activity of physician assistants (PAs) and their career trajectory. We compared the characteristics of clinically active older PAs to younger PAs. Method: PAs were identiﬁed from all respondents aged 60 years or older at the time they participated in the annual census of the AAPA from 2005 through 2009. The most recent year of census participation was selected for analysis. This cadre of older PAs was compared with PAs younger than 60 years. Variables included age, gender, year of PA graduation, duration of being a PA, and clinical activity by self-identiﬁed work location and specialty.
fter 4 decades of professional development, the physician assistant (PA) profession has emerged as an established and capable workforce in American medicine. This development has boosted the profession onto the world stage at a time when health organizations are looking for new ideas in labor.1 With the PA movement gaining momentum in various sectors of medicine, reexamination of the original group is needed to understand what can be expected of this career option. In the United States, PAs make up a multigenerational workforce. Although age differences in preferences, attitudes, and work habits have been studied in physicians and nurses, little is known about such differences in PAs. Some of the differences in age and gender are related to recruitment and retention policies, with supply-and-demand cycles in nursing largely responsible for age gaps.2 Other research has used age to identify management and teamwork issues among different age strata of nurses, as well as for workforce planning implications.3-5 Older nurses have been a topic of study in order to identify strategies to retain an older generation as a solution to nursing shortages.6,7 Physicians have enjoyed a career that is largely recession-proof, and most have the option of staying or leaving when desired. Whereas the relatively mature sectors of the medical profession involving nurses and physicians has allowed longer observation of the career span, the PA 48 JAAPA • JANUARY 2012 • 25(1) • www.jaapa.com
Result: A total of 48,692 PAs participated in at least one census from 2005 through 2009. Approximately 5% (2,340) met the age criteria and were clinically active. Clinically active older PAs reported working a mean of 39 hours per week and were employed in a rural setting more often than their younger counterparts. Nearly one-half of older respondents reported their specialty to be primary care. Conclusion: Although the career span of a PA is only vaguely understood, a small but signiﬁcant portion of clinicians appear to remain in the workforce into their seventh decade. They distinguish themselves by working proportionally more in primary care and nonurban areas than younger PAs. Older PAs may represent an American trend by remaining employed longer than historically observed. Gaps in the understanding of role behavior of PAs could be improved with longitudinal databases.
profession is only now reaching the point that an older generation is available for observation. Knowing the clinical activity of PAs and their career trajectory has been a topic of interest to workforce planners and modelers.8-10 What PAs do in a clinical setting is important, but how long they do it (ie, the duration of the career) is of equal importance for replacement planning. While production of PAs is established by the graduation rate and their clinical role is known through a yearly survey, attrition and retention are the parts of the career arc that are least understood. One way of understanding the stability of a labor force is by taking stock of workers employed at different times of their career. The older PA may help to fill in some gaps about duration of employment. We set out to examine the distribution of PAs whose age is in the 90th percentile (60 years or older) and called them older PAs. Our interest centers on knowing what older PAs do from a clinical perspective. We suggest that if accurate models of workforce predictions are required for workforce planners, then knowing the labor pool input and career span are needed variables. Our research question is straightforward: “What are the characteristics of clinically active older PAs”? METHODS
The AAPA annual census for all PA respondents spanning a 5-year period, 2005 through 2009, was probed.11 All PAs
In 2012, JAAPA celebrates its 25th anniversary, and we invite you to help us celebrate ... all year long Look for anniversary-related articles and events in print, on the JAAPA Web site, and at the annual conference in Toronto in May.
RESEARCH REPORT | Older PAs who reported being clinically active and were 60 years of age or older were isolated, and the most recent year of census participation was used for analysis. The responses of this cadre of older PAs were compared with the most recent responses of the cohort of younger PAs (younger than 60 years). Variables examined for differences between older and younger PAs included age, gender, year of PA graduation, duration of being a PA, and clinical activity by self-identified work location and specialty. Descriptive and inferential statistics were applied. Chi-square and Student t tests were performed to characterize results found for PAs by age-group. RESULTS
A total of 48,692 PAs participated in at least one census from 2005 through 2009. Of the aggregated survey of PAs, nearly two-thirds (64%) were female, mean age was 41 years, and mean duration of experience in clinical practice as a PA was 10 years. Table 1 details the distribution of all observed variables for all PAs. From this population, 2,340 respondents met the criteria of clinically active older PAs (5%). In this cadre of interest, 79% were between the ages of 60 and 65 years, 16% were aged 65 to 70 years, and 4% were aged 70 years or older. One-third (31%) of the older cohort was female (Figure 1). The duration of being a PA for the older cohort ranged from 1 to 40 years, with a mean of 26 years (median, 31 years). Clinically active older PAs reported working a mean of 39 hours per week for their primary clinical employer, compared to a mean of 41 hours per week reported by younger PAs who participated in the census (Figure 2). Each progressively older age band reported working fewer hours. However, older PAs reported spending more hours on call per month than younger ones (Figure 2). Compared with younger PAs, older PAs were more likely to report their primary workplace to be a rural health center, community health center, or setting other than a hospital or physician office (Figure 3). These PAs were also more likely than younger PAs to report working in a rural or nonmetropolitan area based on postal codes. Older PAs are significantly more likely to report their specialty to be in primary care (defined as family medicine, general internal medicine, and general pediatrics), compared with younger clinically active PAs (Table 2). Within the older PA cohort, the oldest PAs were more likely to report their specialty as primary care, with two-thirds (64%) of PAs aged 70 years or older in this practice sector. DISCUSSION
The structure of the American workforce is changing and becoming older.12 This shift has been accompanied by a new dynamic in labor, ie, older workers remaining employed beyond traditional retirement age.13 Workers in their 60s conceivably have been part of the labor force for 4 decades (inclusive of taking time off to raise a family). The findings from the AAPA census suggest that PAs are no 50 JAAPA • JANUARY 2012 • 25(1) • www.jaapa.com
exception: More than 2,000 PAs are working well into their 60s, and some are working into their 70s. Older PAs were more likely than their younger colleagues to be practicing in shortage areas, such as primary care or rural locations. Understanding the nature of these choices can help inform policy makers as they try to motivate medical providers to practice in these areas.14-16 However, whether differences in work setting are related to generational preference or to age remains unclear. In other words, have older PAs remained in primary care because that is where most early PAs practiced? Or, is primary care a better fit for those in an older cohort for some other reason? Approximately one-third of older PAs are women (compared with the women who have made up the majority of PAs for the past 2 decades). Historically, baby boomergeneration (1946-1964) males made up the bulk of PAs at the profession’s inception. Another characteristic of the early PA movement was that many of those who entered this educational track did so after one or two other careers, such as nursing or physical therapy, and consequently were TABLE 1. Characteristics of all PAs from 2005-2009 aggregate census survey Characteristics of all PAs Percent female
Mean age (y)
Mean years in clinical practice
Mean hours worked per week
Mean hours on call per month
Primary work setting (%) Hospital
Rural health center
Community health center
TABLE 2. Primary specialty by PA age-group Primary specialty
Younger PAs (%)
Older PAs (%)
Primary care (family medicine, general internal medicine, and general pediatrics)
Internal medicine subspecialtiesa
Pediatric subspecialties a
RESEARCH REPORT | Older PAs FIGURE 1. Male and female clinically active older PAs
FIGURE 2. Clinical activity reported by PA age-group
(#''' DXc\ /''
/' -' 41
Number of PAs
older. In contrast, new PA entrants tend to have less health background or alternative career experience than the older generation and thus tend to graduate at an earlier age then the older cohort. The average age of PA graduates in 2010 was 29 years. Using date of graduation to assess the duration of a career, a plurality of respondents had been a PA for more than 30 years. Changes in the gender distribution and background of those entering the profession in more recent years may have important implications for future practice patterns as the newer generation of PAs continues their careers. Looking for insight as to why older workers remain employed reveals that physician retirement patterns are associated with medical specialty; those in high-stress roles, such as surgical specialties, retire earlier.17,18 Even when a US doctor reports being in retirement, he or she may be clinically active on a part-time basis.19 However, a 2006 survey of physicians aged 50 years and older reported that at least one-third said they would retire immediately if income were not a factor.20 Such findings suggest that projecting future practice and retirement patterns among older doctors may prove challenging, as the economy and reimbursement structure change. On the other hand, research on career satisfaction suggests that both males and females are generally satisfied with being a PA, which may contribute to retention.21 If PAs are following patterns similar to those of physicians, specialty PAs may have retired earlier than those in primary care, explaining the preference for primary care among the older PAs observed here.22 Since the beginning of the century, more PAs have selected nonprimary care specialties,23 ie, those same areas of medicine from which physicians have tended to retire earlier.24,25 According to the AAPA censuses, nearly one-half of respondents in 2000 practiced in primary care, but by 2005, that number had 52 JAAPA • JANUARY 2012 • 25(1) • www.jaapa.com
fallen to around 40%, and in 2010, approximately one-third of census participants were practicing in primary care. It is unclear what the implications are (or will be) for workforce projections as younger cohorts of PAs age. LIMITATIONS
The limitation that pervades most survey work is the low response rate (although the AAPA census is considered fairly representative of the profession at large). Although the response rate of the AAPA census has drifted downward since the beginning of this century, we were able to bolster this sample by aggregating 5 years of surveys and using the most recent response for our analysis. This cumulative strategy increases the sample size for analysis, but it also groups PA responses from 2005 through 2009, which may have had different influences one year over the next. The extent to which PAs have changed in this 5-year period may affect the generalizability of findings from this multiyear sample to the true population of older PAs at one point in time. Another limitation is the large cadre of new graduates (6,776 in 2010) that is skewing the PA population pyramid. The smaller baby boomer generation that participated in the early development of the profession is retiring, and those remaining clinically active are disproportionally represented.26 Because a majority of first- and second-generation PAs are not in the workforce, we wonder when they left and why. One solution to help mitigate this problematic area of medical workforce analysis would be to faithfully track a cohort. Population modeling with age-specific rates of attrition would be one of many values produced by a longitudinal study of PAs. CONCLUSION
As the career span of a PA is gradually revealed, a small but significant portion of clinicians appear to remain in the
FIGURE 3. Primary work settings by PA age-group a
35 29.7 20.6
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workforce beyond their seventh decade. They distinguish themselves by working proportionally more in primary care and nonurban areas than the population of younger PAs. In general, older PAs may represent an American trend by remaining employed longer than their parents. Gaps in the understanding of role behavior of PAs could be improved with a dedicated longitudinal database. The number of PAs self-reported to be working beyond age 60 years may speak both to the type of people who select this career as well as to the rewarding and flexible nature of the occupation. In the midst of projected primary care provider shortages, both the production of new health care providers and the longevity of older clinically active providers will be important factors in addressing the population’s growing health care needs. JAAPA Roderick Hooker is a senior director at The Lewin Group in Falls Church, Virginia. Christal Ramos is a senior research associate in the School of Public Health and Health Services, The George Washington University, Washington, DC. Paola Daly is a survey research analyst and Raymond Fang is vice president of research for the American Academy of Physician Assistants, Alexandria, Virginia. The authors have indicated no relationships to disclose relating to the content of this article.
REFERENCES 1. Hooker RS, Kuilman L. Physician assistant education: ﬁve countries. J Physician Assist Educ. 2011;22(1):53-58. 2. Hart SM. Generational diversity: impact on recruitment and retention of nurses. J Nurs Admin. 2006;36(1):10-12. 3. Sherman RO. Leading a multigenerational nursing workforce: issues, challenges and strategies. Online J Issues Nurs. 2006;11(2):3. 4. McNeese-Smith DK, Crook M. Nursing values and a changing workforce: values, age, and job stages. J Nurs Adm. 2003;33(5):260-270. 5. Buerhaus PI, Staiger DO, Auerbach DI. Implications of an aging registered nurse workforce. JAMA. 2000;283(22):2948-2954. 6. Moye JP. The Search for Factors to Retain Older North Carolina Registered Nurses in the Workforce [dissertation]. Greenville, NC: Eastern Carolina University; 2006. 7. Krail KA. Retaining the retiring nurse: keeping the nursing shortage at bay. Nurse Leader. 2005;3(2):33-36. 8. Sargen M, Hooker RS, Cooper RA. Gaps in the supply of physicians, advance practice nurses, and physician assistants. J Am Coll Surg. 2011;212(6):991-999. 9. Hooker RS, Cawley JF, Everett CM. Predictive modeling physician assistant supply: 2010-2025. Public Health Rep. 2011;126(5):708-716. 10. Hooker RS. Physician assistants, economics, and workforce modeling. JAAPA. 2010;23(7):10. 11. American Academy of Physician Assistants. National Physician Assistant Census Report 2009. http://www.aapa.org/uploadedFiles/content/Common/Files/National_Final_with_Graphics.pdf. Accessed December 22, 2011. 12. Mosisa A, Hipple S. Trends in labor force participation in the United States. Mon Labor Rev. 2006;129(10):35-57. 13. Purcell PJ. Older workers: employment and retirement trends. Mon Labor Rev. 2000;123(10): 19-30. 14. Bodenheimer T, Pham HH. Primary care: current problems and proposed solutions. Health Aff (Millwood). 2010;29(5):799-805. 15. Workforce Issues in Health Care Reform: Assessing the Present and Preparing for the Future: Hearings before the Senate Committee on Finance; 111th Cong (2009) (testimony of Fitzhugh Mullan, MD). 16. Colwill JM, Cultice JM, Kruse RL. Will generalist physician supply meet demands of an increasing and aging population? Health Aff (Millwood). 2008;27(3):w232-w241. 17. Dill MJ, Salsberg ES (Center for Workforce Studies). The Complexities of Physician Supply and Demand: Projections Through 2025. Washington, DC: Association of American Medical Colleges; 2008. 18. Bound J, Schoenbaum M, Waidmann T. Race and education differences in disability status and labor force attachment. J Hum Resour. 1995;30(5):S227-S267. 19. Jewett EA, Brotherton SE, Ruch-Ross H. A national survey of ‘inactive’ physicians in the United States of America: enticements to reentry. Hum Resour Health. 2011;9:7. 20. Kirch DG, Salsberg E; Association of American Medical Colleges. The physician workforce challenge: response of the academic community. Ann Surg. 2007;246(4):535-540. 21. LaBarbera DM. Gender differences in the vocational satisfaction of physician assistants. JAAPA. 2010;23(10):33-39. 22. Nicholson S. Physician specialty choice under uncertainty. J Labor Econ. 2002;20(4):816-847. 23. Cooper RA. New directions for nurse practitioners and physician assistants in the era of physician shortages. Acad Med. 2007;82(9):827-828. 24. Hooker RS, Cawley JF, Leinweber W. Career ﬂexibility of physician assistants and the potential for more primary care. Health Aff (Millwood). 2010;29(5):880-886. 25. Morgan PA, Hooker RS. Choice of specialties among physician assistants in the United States. Health Aff (Millwood). 2010;29(5):887-892. 26. Hooker RS, Cawley JF, Asprey DP. Physician Assistants: Policy and Practice. 3rd ed. Philadelphia, PA: FA Davis; 2010.
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EARN CATEGORY I CME CREDIT by reading this article and the article beginning on page 32 and successfully completing the posttest on page 59. 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 January 2012.
LEARNING OBJECTIVES ● ● ●
Describe the etiologic factors associated with large-vessel ischemic stroke Differentiate the risks and beneﬁts of IV rtPA, intra-arterial rtPA, and mechanical clot retrieval for large-vessel ischemic stroke Discuss the importance of the time window in selecting the most appropriate treatment
State-of-the-art interventions in acute large-vessel ischemic stroke The treatments for large-vessel ischemic stroke include IV rtPA, IA rtPA, and mechanical clot retrieval. All must be used soon after symptom onset for the best outcome.
Robert F. Brach, PA-C
54 JAAPA • JANUARY 2012 • 25(1) • www.jaapa.com
No ﬂow of blood to this area
Middle cerebral artery
Internal carotid artery
Large-vessel ischemic stroke
© Fairman Studios LLC
troke is the third leading cause of death and the first leading cause of disability in the United States. Approximately 795,000 new cases of stroke occur each year.1 Stroke is broadly divided into ischemic and hemorrhagic types. Ischemic stroke accounts for 87% of all strokes.1 Nearly half of these are caused by the sudden blockage of a large cerebral vessel.2 Acute ischemic stroke caused by a large-vessel occlusion carries a worse prognosis than small-vessel ischemic stroke, in terms of both death rate and long-term recovery.2 Onset of stroke is often sudden and dramatic. Patients may present with focal signs, such as arm weakness, facial droop, or slurred speech. The American Heart Association (AHA) has launched a public education campaign emphasizing the importance of quick recognition and treatment of stroke. This is because with the treatments available today, time matters. If a blocked cerebral artery is reopened soon enough, stroke and symptom progression may be halted or even reversed. Despite campaigns for both public and professional awareness, less than 2.4% of patients suffering a large-vessel ischemic stroke receive intervention treatments that are available to reopen the blocked vessel.3 This article reviews the major treatments for large-vessel ischemic stroke, including IV recombinant tissue plasminogen activator (rtPA), intra-arterial (IA) rtPA, and mechanical clot retrieval. All these treatments must be used during the first “golden hours” following symptom onset, when cerebral artery recanalization may have great effect in reducing morbidity and mortality.
At 4:30 PM, a 37-year-old woman was sitting on the couch at a friend’s house when she suddenly developed garbled speech and left-sided weakness. The patient was brought to a nearby hospital, where her medical history was carefully reviewed. There had been no recent surgery, trauma, or anticoagulation. Vital signs remained stable. Laboratory studies were ordered. Noncontrast CT revealed no intracranial hemorrhage. A teleconference with a major university hospital was called. The patient was assigned a National Institutes of Health Stroke Scale (NIHSS) score of 17. At 5:30 PM, the patient was given 70 mg of IV rtPA (0.9 mg/kg). She was then transported via helicopter to the university hospital. At arrival, her NIHSS remained stable at 17. CT arteriography revealed an abrupt cutoff of the right middle cerebral artery, as well as hypodensity in the temporal and parietal lobes suspicious for an evolving right middle cerebral artery (MCA) stroke. The patient was brought to the neurointervention suite for further evaluation and treatment. Cerebral angiography confirmed the CT arteriography finding of proximal right MCA blockage (Figure 1). At 8:30 PM, 4 mg of rtPA was injected directly into the clot via an intra-arterial microcatheter. At 9:00 PM, a MERCI Retriever device was deployed, and the right MCA was opened after just one pass (Figure 2). The next day, an echocardiogram revealed a previously undiscovered patent foramen ovale (PFO). Although no deep venous thrombosis was found, it was possible that a clot had traveled from the venous system through the PFO and into the brain to occlude the artery. Timely diagnosis, response, and intervention resulted in a good outcome for this patient. Three days after presenting to the hospital with aphasia and hemiparesis, she was discharged home with only minor residual symptoms. She was placed on anticoagulation therapy and referred to cardiology for repair of the PFO. BACKGROUND
Often called a brain attack, a stroke occurs when blood flow to part of the brain is blocked and metabolic demand is not met. Ischemic cerebral tissue does not function normally, accounting for focal symptoms, such as facial droop, aphasia, or limb weakness. If the ischemia continues long enough, brain
infarction occurs. In the case of large-vessel ischemic stroke, an initial core area of infarct is often surrounded by a watershed area of ischemic tissue called the penumbra. If circulation is restored during the first hours of a stroke, some or all of the penumbra may be salvaged. As time goes on, however, the penumbra converts to infarcted tissue. As stroke volume increases, risk increases that opening a blocked vessel may result in catastrophic intracerebral hemorrhage rather than reperfusion,4,5 because necrotic, infarcted vessels cannot contain blood. This phenomenon, known
“Large-vessel strokes account for about 46% of all ischemic strokes per year; one large-vessel stroke occurs almost every 90 seconds.” as hemorrhagic conversion, imparts severe time limitations on the treatment of large-vessel ischemic stroke. In the same respect, if a stroke’s volume initially exceeds more than one-third of the vessel’s territory, intervention is usually not attempted because the risk of hemorrhage outweighs the chance of reperfusion. Large-vessel strokes account for about 46% of all ischemic strokes (320,000) per year, with one large-vessel stroke occurring almost every 90 seconds.1,2 Large vessels (those greater than 2 mm) in the brain are any of the major cerebral arteries, including the internal carotid, middle cerebral, anterior cerebral, vertebral, or basilar arteries. These vessels may become suddenly blocked by one of two mechanisms: an embolus traveling from or through the heart, or thrombus formation. In thrombotic stroke, the stigmata of atherosclerosis are often present, including older age, high cholesterol levels, and hypertension. The rupture of atherosclerotic plaque in one of the large cerebral arteries leads to sudden clot or thrombus formation, much like what happens in an acute MI. In embolic stroke, large emboli are often cardiogenic and associated with atrial fibrillation, mechanical valves, or endocarditis. However, up to one-half of persons referred to stroke centers are younger than 65 years and often do
KEY POINTS ■ Effective interventions are available for acute large-vessel ischemic stroke, but only 2.4% of stroke patients receive them. All must
be delivered within 3 to 8 hours of symptom onset, with the shortest time to recanalization and thus reperfusion being the strongest determinant of a good outcome. ■ The primary advantage of IV rtPA is the relative ease and rapidity of administration. However, IV administration of rtPA has the disadvantage of introducing a large dose systemically, which increases the risk of unwanted bleeding. ■ Intra-arterial (IA) rtPA delivers a much smaller dose (2-4 mg) directly to the site of occlusion, reducing the systemic effects of IV administration, and it can be used within 6 hours of symptom onset. However, IA rtPA takes more time and more specialized resources to administer than IV rtPA. ■ Two mechanical clot extraction devices are also available for treating this type of stroke.
www.jaapa.com • JANUARY 2012 • 25(1) • JAAPA
CME Ischemic stroke not have preexisting heart disease or an “atherosclerotic” profile. In younger stroke victims, a role for PFO has been suggested. Under the right circumstances, an embolus may pass from the venous to the arterial system via an atrial septal defect and eventually block a cerebral artery.6 Blockage of a large cerebral vessel corresponds with a higher NIHSS score. The NIHSS score is a measure of stroke severity rated from 0 to 42 based on findings from a physical examination. A higher number reflects greater impairment. A score of 1 to 7 reflects a mild impairment; 8 to 15, moderate impairment; and greater than 15, severe impairment. Fischer and colleagues found that an NIHSS score greater than or equal to 12 had a 91% predictive positive value of a central large-vessel stroke.7 No matter the cause, large-vessel ischemic stroke is a true medical emergency. Actions taken during the first few hours significantly impact the extent of future disability.
FIGURE 1. Preintervention cerebral angiogram, anteroposterior view, shows occlusion of the right middle cerebral artery (MCA) (arrow).
FIGURE 2. Postintervention cerebral angiogram shows restored perfusion to the right MCA (arrow).
56 JAAPA • JANUARY 2012 • 25(1) • www.jaapa.com
In 1995, the National Institute of Neurological Disorders and Stroke (NINDS) determined that patients who were given IV rtPA within 3 hours of symptom onset were 30% more likely to have little or no disability at 3 months than patients given placebo.8 In 1996, the FDA approved recombinant tissue plasminogen activator for IV treatment of acute ischemic stroke.9 A serine protein found on the endothelial cells that line blood vessels, tissue plasminogen activator enzymatically converts plasminogen to plasmin. Plasmin is an enzyme that breaks down many blood proteins, notably fibrin, in a process called fibrinolysis, thereby dissolving clots. Marketed as alteplase, rtPA is a genetically engineered glycoprotein that is produced by recombinant DNA technology. Its indications include clot lysis in the setting of thromboembolism and acute ischemic stroke. The primary advantage of IV rtPA is the relative ease and rapidity of administration. Once the patient has had an appropriate basic workup; CT to rule out intracranial hemorrhage; and an evaluation by a stroke neurologist, either in person or via teleconsult, 0.9 mg/kg of alteplase is given via combined IV bolus and 60-minute infusion. However, IV administration of rtPA has the disadvantage of introducing a large dose systemically, which increases the risk of unwanted bleeding. Thus, strict exclusion criteria must be observed when considering candidates for rtPA administration (see Table 1). In 2000, Clarke and colleagues concluded that patients derived no benefit and even had an increased risk of intracerebral hemorrhage when IV rtPA was administered 3 hours after symptom onset.10 However, in 2008, these findings were revised by the European Cooperative Acute Stroke Study (ECASS) III. ECASS III showed that significant benefit may be achieved by extending the administration window of IV rtPA from 3 hours to 4.5 hours in an even more highly restricted patient group.4,9 Based on these and other findings, the AHA and the American Stroke Association issued an advisory in 2009 expanding the time window for the use of IV rtPA from 3 hours to 4.5 hours in a select subgroup of patients: Excluded are patients older than 80 years, those with an NIHSS score greater than 25, patients taking oral anticoagulants, and those with a history of both stroke and diabetes.11 IV rtPA can be an effective first-line treatment for largevessel occlusive stroke. Recanalization rates for IV rtPA alone have been reported as 6% to 31% for the middle cerebral artery and 13% to 30% for the internal carotid artery.12,13 Despite this proven efficacy, use of IV rtPA has been very limited. Although an estimated 28.7% of victims of ischemic stroke (both large-vessel and small-vessel) could benefit from IV rtPA, only 1% to 3% receive it.3 Reasons for low usage include delays in presenting to the hospital, lack of designated stroke centers, and lack of 24-hour CT availability, with delay in presentation being a major culprit.3 The effectiveness of IV rtPA administration appears to be highly time-dependent. An NINDS study compared outcomes at 3 months in patients treated with IV rtPA 0 to 90 minutes
and 91 to 180 minutes after symptom onset. The researchers concluded that the 0- to 90-minute group was more likely to have a favorable outcome (odds ratio [OR], 2.11) compared with the 91- to 180-minute group (OR, 1.69).14 Until the advent of interventions using an intra-arterial catheter for large-vessel stroke, the outlook for patients was bleak. Often the result was death or disability. While IV rtPA remains a mainstay of treatment, its widespread use remains hampered by its multiple contraindications, the 3-hour time window for administration, and the relative resistance of a large clot burden to fibrinolysis. INTRA-ARTERIAL RTPA
In 1998, the Prolyse in Acute Cerebral Thromboembolism (PROACT) II study explored the use of the plasminogen activator prourokinase delivered directly into middle cerebral artery clots within 6 hours of symptom onset. The study concluded that despite a slightly greater risk of intracerebral hemorrhage, plasminogen activator delivered in this manner resulted in significantly higher rates of recanalization than did placebo and better overall outcome at 90 days.15 PROACT II opened the door to the use of IA rtPA, which has several advantages. It delivers a much smaller dose (2-4 mg) directly to the site of occlusion, reducing the systemic effects of IV administration. Also, IA rtPA can be used within 6 hours of symptom onset. Thus, a patient who suffers a stroke during open-heart surgery or who arrives at the hospital too late for IV rtPA may be considered for IA rtPA. Intra-arterial rtPA can be used either by itself or in addition to IV rtPA. Disadvantages of IA rtPA include the requirement for cerebral angiography in a dedicated neuroangiography suite, which lengthens time to actual drug delivery. Also, IA rtPA can only be given at a stroke center by a highly skilled neurointerventional physician to direct its delivery. Thus, it takes more time and more specialized resources to administer. Nonetheless, results have been promising.4,16 MECHANICAL THROMBECTOMY: MERCI RETRIEVER SYSTEM
In 2004, the FDA approved use of the first mechanical intra-arterial thrombectomy device, the MERCI Retriever (Concentric Medical, Mountain View, CA) for use in largevessel occlusive stroke. The MERCI Retriever is passed through a catheter that has been placed just proximal to the clot. After being passed through the clot, the MERCI device forms a helical or corkscrew shape to help grab the clot. Under manual aspiration and withdrawal of the device back into the catheter, the clot may be removed and the vessel opened. The 10 types of available MERCI Retriever devices correspond to differences in vessel size and clot characteristics. A MERCI Retriever may be deployed up to 8 hours after symptom onset. Moreover, it can be used in patients who are either ineligible for or have not responded to IV rtPA therapy. The retriever may also be used in conjunction with IA rtPA. Theoretically, use of a mechanical thrombectomy
TABLE 1. Criteria for IV rtPA therapy for ischemic stroke11,20 Characteristics of patients with ischemic stroke who could be treated with rtPA in the 0- to 3-hour window • • • • • • • • • • • • • • • • • • • • •
Ischemic stroke causing measurable neurologic deﬁcit Neurologic signs should not be clearing spontaneously Neurologic signs should not be minor and isolated Caution should be exercised in treating a patient with major deﬁcits No subarachnoid hemorrhage Symptom onset <3 h before beginning treatment No head trauma or prior stroke in previous 3 mo No MI in previous 3 mo No GI or urinary tract hemorrhage in previous 21 d No major surgery in previous 14 d No arterial puncture at a noncompressible site in the previous 7 d No history of previous intracranial hemorrhage BP <185 mm Hg systolic and <110 mm Hg diastolic No evidence of active bleeding or acute trauma (fracture) Not taking an oral anticoagulant or, if taking, INR ≤1.7 If heparin was administered in past 48 hours, aPTT must be normal Platelet count ≥100,000/μL Blood glucose ≥50 mg/dL (2.7 mmol/L) If seizure, no postictal residual neurologic impairments CT does not show a large (ie, greater than one-third cerebral hemisphere) stroke Patient or family members understand the potential risks and beneﬁts from treatment
Characteristics of patients with ischemic stroke who should NOT receive IV rtPA during the 3- to 4.5-hour time window • • • •
Age >80 y Taking oral anticoagulants NIHSS score >25 History of both diabetes and previous stroke
Key: aPTT, activated partial thromboplastin time; INR, international normalized ratio; NIHSS, National Institutes of Health Stroke Scale; rtPA, recombinant tissue plasminogen activator.
FIGURE 3. Penumbra aspiration devices showing separator (colored) and aspiration catheter. (Courtesy of Penumbra, Inc, Mountain View, CA)
www.jaapa.com • JANUARY 2012 • 25(1) • JAAPA
CME Ischemic stroke device has several distinct advantages: a longer time window for treatment, greater efficacy in opening largevessel occlusions, and potentially less risk of causing hemorrhage.17 In the Multi MERCI trial, later-generation MERCI retriever devices achieved 57.3% recanalization in treatable vessels and 69.5% recanalization when used in conjunction
“Reopening a suddenly blocked artery offers the greatest hope of saving threatened brain tissue from progressing to infarction.” with IA rtPA. In this series of patients, whose NIHSS score averaged 19, favorable clinical outcome occurred in 36% of patients with overall mortality of 34%.18 MECHANICAL THROMBECTOMY: THE PENUMBRA DEVICE
The Penumbra system (Penumbra, Inc, Alameda, CA) recently gained approval for sale in the United States and is the second device now available for mechanical clot extraction (Figure 3). It uses an aspiration/debulking process to remove the clot. A separator is repeatedly passed into the clot to break it up, while continuous aspiration is maintained at -20 mm Hg through the guide catheter by the Penumbra machine. In the Penumbra Pivotal Stroke Trial, 125 patients with large-vessel ischemic stroke were treated with the device. Overall, 81.6% vessel revascularization was achieved. At 90 days, all-cause mortality was 32.8%, similar to the MERCI trial results, while 25% of patients achieved a favorable outcome.19 CONCLUSION
The woman in the case study presented earlier in this article benefited from all that modern medicine has to offer: She received IV rtPA within 2 hours of symptom onset, IA rtPA within 4.5 hours, and complete recanalization via the MERCI device at 5.5 hours. Administration of both IV and IA rtPA likely helped to soften the thrombus, which allowed the MERCI device to work more effectively. While the patient had some residual deficit, appropriate therapy and aftercare enabled her to return to a meaningful, independent life. Reopening the lumen of a suddenly blocked cerebral artery offers the greatest hope for saving threatened brain
SEE THE ONLINE VERSION OF THIS ARTICLE TO LINK TO NIH Stroke Scale ninds.nih.gov/doctors/NIH_Stroke_Scale.pdf
58 JAAPA • JANUARY 2012 • 25(1) • www.jaapa.com
tissue from progressing to infarction, as well as for limiting infarct size. Today’s armamentarium includes IV rtPA, IA rtPA delivered directly to the clot, and two mechanical clot extraction devices. All these treatments must be delivered within 3 to 8 hours of symptom onset, with the shortest time to recanalization and thus reperfusion being the strongest determinant of a good outcome. Large-vessel occlusive stroke remains a devastating event that resists cure even under the most ideal treatment circumstances. As new therapies and technologies emerge and as hospital systems, the public, and clinicians work together to make timely treatment more widely available, outcomes like the one presented in our case study will become increasingly common. JAAPA Robert Brach practices in the Department of Neurosurgery, Brigham and Women’s Hospital, Boston, Massachusetts, and is an associate in surgery at Harvard Medical School, also in Boston. The author has indicated no relationships to disclose relating to the content of this article. REFERENCES 1. Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics—2011 update: a report from the American Heart Association. Circulation. 2011;123(4):e18-e209. 2. Smith WS, Lev MH, English JD, et al. Signiﬁcance of large vessel intracranial occlusion causing acute ischemic stroke and TIA. Stroke. 2009;40(12):3834-3840. 3. Kleindorfer D, Xu Y, Moomaw CJ, et al. US geographic distribution of rt-PA utilization by hospital for acute ischemic stroke. Stroke. 2009;40(11):3580-3584. 4. Molina CA. Reperfusion therapies for acute ischemic stroke: current pharmacological and mechanical approaches. Stroke. 2011;42(1 suppl):S16-S19. 5. van der Worp HB, van Gijn J. Clinical practice: acute ischemic stroke. N Engl J Med. 2007;357(6): 572-579. 6. Kizer JR, Devereux RB. Clinical practice: patent foramen ovale in young adults with unexplained stroke. N Engl J Med. 2005;353(22):2361-2372. 7. Fischer U, Arnold M, Nedeltchev K, et al. NIHSS score and arteriographic ﬁndings in acute ischemic stroke. Stroke. 2005;36(10):2121-2125. 8. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med. 1995;333(24):1581-1587. 9. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359(13):1317-1329. 10. Clark WM, Albers GW, Madden KP, Hamilton S. The rtPA (alteplase) 0- to 6-hour acute stroke trial, part A (A0276g): results of a double-blind, placebo-controlled, multicenter study. Thromblytic therapy in acute ischemic stroke study investigators. Stroke. 2000;31(4):811-816. 11. del Zoppo GJ, Saver JL, Jauch EC, Adams HP Jr. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator: a science advisory from the American Heart Association/American Stroke Association. Stroke. 2009;40(8):2945-2948. 12. Saqqur M, Uchino K, Demchuk AM, et al. Site of arterial occlusion identiﬁed by transcranial Doppler predicts the response to intravenous thrombolysis for stroke. Stroke. 2007;38(3):948-954. 13. Alexandrov AV, Molina CA, Grotta JC, et al. Ultrasound-enhanced systemic thrombolysis for acute ischemic stroke. N Engl J Med. 2004;351(21):2170-2178. 14. Marler JR, Tilley BC, Lu M, et al. Early stroke treatment associated with better outcome: the NINDS rt-PA stroke study. Neurology. 2000;55(11):1649-1655. 15. del Zoppo GJ, Higashida RT, Furlan AJ, et al. PROACT: a phase II randomized trial of recombinant pro-urokinase by direct arterial delivery in acute middle cerebral artery stroke. PROACT Investigators. Prolyse in Acute Cerebral Thromboembolism. Stroke. 1998;29(1):4-11. 16. Furlan A, Higashida R, Wechsler L, et al. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. JAMA. 1999;282(21):2003-2011. 17. Baker WL, Colby JA, Tongbram V, et al. Neurothrombectomy devices for the treatment of acute ischemic stroke: state of the evidence. Ann Intern Med. 2011;154(4):243-252. 18. Smith WS, Sung G, Saver J, et al. Mechanical thrombectomy for acute ischemic stroke: ﬁnal results of the Multi MERCI trial. Stroke. 2008;39(4):1205-1212. 19. Penumbra Pivotal Stroke Trial Investigators. The Penumbra Pivotal Stroke Trial: safety and effectiveness of a new generation of mechanical devices for clot removal in intracranial large vessel occlusive disease. Stroke. 2009;40(8):2761-2768. 20. Adams HP Jr, del Zoppo G, Alberts MJ, et al. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: the American Academy of Neurology afﬁrms the value of this guideline as an educational tool for neurologists. Stroke. 2007;38(5):1655-1711.
E X P I R AT I O N DAT E : J A N U A RY 2 0 1 3
All posttests must be completed and submitted online. AAPA members should complete and submit posttests on the AAPA Web site by going to www.aapa.org and searching for keyword JAAPA post-tests. All others may complete and submit posttests online at no charge at www.myCME.com. To obtain 1 hour of AAPA Category I CME credit, PAs must receive a score of 70% or better on each test taken.
CLOSTRIDIUM DIFFICILE, PAGE 32 1. A 3-fold increased risk of Clostridium difﬁcile infection (CDI) has been associated with the widespread use of a. Cephalosporins b. Macrolides c. Fluoroquinolones d. Sulfonamides 2. Rates of CDI are higher and outcomes are worse in patients with a. Peptic ulcer disease b. Inﬂammatory bowel disease c. Celiac disease d. Ulcerative colitis 3. A typical initial manifestation of CDI is a. Marked abdominal distension b. Vomiting c. Dyspepsia d. Watery diarrhea
ISCHEMIC STROKE, PAGE 54 7. A frequent cause of embolic stroke is a. Atrial ﬁbrillation b. Atrial septal defect c. Patent foramen ovale d. Myocardial infarction 8. A National Institutes of Health Stroke Scale (NIHSS) score of 8 to 15 reﬂects a. Mild impairment b. Moderate impairment c. Major impairment d. Severe impairment 9. The combined IV bolus dose and 60-minute infusion of alteplase is a. 0.3 mg/kg b. 0.6 mg/kg c. 0.9 mg/kg d. 1.2 mg/kg
4. Fulminant and pseudomembranous colitis is associated with rising levels of a. Creatinine b. Potassium c. Calcium d. Albumin
10. Patients excluded from the expanded use of alteplase (from 3 hours to 4.5 hours) are those a. Older than 65 years b. With an NIHSS score greater than 10 c. With metabolic syndrome d. Taking oral anticoagulants
5. The gold standard for diagnosing CDI is a. A PCR test b. A cell culture cytotoxic assay c. Stool culture and sensitivity testing d. Small bowel biopsy
11. An advantage of intra-arterial (IA) rtPA is that it a. Can be given at any trauma center b. Can be used within 6 hours of symptom onset c. Is not associated with an increased risk of intracerebral hemorrhage d. Takes less time to administer
6. Because of its associated neurotoxicity, repeated recurrences of CDI should not be treated with a. Vancomycin b. Amoxicillin c. Metronidazole d. Clarithromycin
12. Which of the following is an advantage of a mechanical thrombectomy device? a. Greater efﬁcacy in opening large-vessel occlusions b. Potentially less risk of causing hemorrhage c. Longer time window for treatment d. All of the above
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Quick Recertiﬁcation Series BA R BA RA POETZSC H, PhD, RPA-C
›GENERAL FEATURES • Primary hypoparathyroidism is a relatively uncommon condition that is characterized by inadequate parathyroid hormone (PTH) activity, resulting in hypocalcemia. • Decreased secretion of PTH occurs following destruction or removal of the parathyroid glands, particularly in the treatment of hyperparathyroidism. • Incidental destruction may occur during thyroid, laryngeal, or head or neck surgery or may result from extensive irradiation to the face, neck, or mediastinum. • Hypoparathyroidism can also have an autoimmune etiology and is a common feature of polyglandular autoimmune syndrome type I, a familial disorder. • Other rare causes include genetic defects or mutations and storage or infiltrative disease of the parathyroid glands. ›CLINICAL ASSESSMENT • Manifestations of hypoparathyroidism are primarily related to hypocalcemia (total serum calcium, 7.0-7.5 mg/dL). • Acute disease causes neuromuscular irritability—circumoral tingling, extremity paresthesias, tetany, carpopedal spasm, laryngospasm, muscle cramps, and seizures. • Some patients have only vague symptoms (fatigue, emotional instability, anxiety, or depression) with or without neuromuscular symptoms. • Hyperactive deep tendon reflexes, This Quick Recertiﬁcation Series is not meant to replace in-depth studying for the recertiﬁcation exam and should be used only as an adjunct. Furthermore, the information contained here may not be sufﬁcient to provide diagnosis and treatment in the clinical setting.
Chvostek sign, and Trousseau sign may all be present. • Chronic hypocalcemia may lead to mental status changes; cataracts; dry, coarse skin; brittle nails; and brittle, sparse hair and eyebrows.
›DIAGNOSIS • Low serum and urinary calcium levels. Since the calcium ion is highly bound to protein, a total calcium level cannot be interpreted without knowing the total protein or albumin level as well. • Low parathyroid hormone and magnesium levels • Low serum phosphate but normal alkaline phosphatase levels • Measurement of 25-hydroxyvitamin D level is important to exclude vitamin D deficiency as a cause of hypocalcemia. • CT of the skull may show dense bones and calcifications of the basal ganglia, especially with chronic hypocalcemia. • Severe hypocalcemia may also cause prolonged QT intervals and abnormal T waves on ECG. ›TREATMENT • Emergency treatment for acute hypocalcemia includes airway management, IV calcium gluconate, vitamin D supplementation, and magnesium supplementation if levels are low. • Intravenous calcium gluconate: Calcium infusion drips should be started at 0.5 mg/kg/hour and increased to 2 mg/kg/hour as needed, with an arterial line placed for frequent measurement of ionized calcium. • Maintenance therapy includes oral calcium (500 mg to 2 g 2-4 times daily) and vitamin D supplements (1,25-dihydroxyvitamin D or calcitriol). • Monitor total serum calcium every 3 months, and maintain level at 8 to 8.6 mg/dL.
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>>QUESTIONS & ANSWERS<< 1. A 42-year-old woman develops a tingling sensation in her hands on postoperative day 2 following a total thyroidectomy for papillary thyroid cancer. She appears anxious and complains of muscle cramps. Which of the following is the most appropriate initial step to manage this condition? a. 75 μg of levothyroxine b. 10 mL of 10% magnesium sulfate IV c. Continuous infusion of calcium gluconate d. Stat IM dose of synthetic parathyroid hormone Answer: c Explanation: Intravenous calcium gluconate is the appropriate treatment for severe, symptomatic hypocalcemia, although high-dose oral calcium supplementation (up to 1-2 g every 4 hours) may be sufﬁcient for patients with mild symptoms. This patient is experiencing postthyroidectomy hypocalcemia, likely due to transient ischemia of the parathyroid gland. Unless the parathyroid glands were inadvertently excised during the procedure, the condition is likely to be self-limited and will resolve in a few days. If the hypocalcemia persists, calcium and vitamin D supplementation will be necessary. There is no role for thyroid hormone replacement in the treatment of hypocalcemia, and synthetic parathyroid hormone is a treatment for osteoporosis. Magnesium sulfate may be beneﬁcial if magnesium levels are low but would not be the initial step.
SUGGESTED READING • Goltzman D. Clinical manifestations of hypocalcemia. UpToDate Web site. http://www.uptodate.com/contents/ clinical-manifestations-of-hypocalcemia?source=search_ result&selectedTitle=5%7E93. Updated October 15, 2008. Accessed December 6, 2011. • Goltzman D. Etiology of hypocalcemia in adults. UpToDate Web site. http://www.uptodate.com/contents/etiology-ofhypocalcemia-in-adults?source=searchresult& selectedTitle=1%7E16. Updated March 18, 2011. Accessed December 6, 2011.
Continued on page 62
Quick Recertiﬁcation Series • Goltzman D. Treatment of hypocalcemia. UpToDate Web site. http://www.uptodate.com/contents/treatment-ofhypocalcemia?source=search_result&selectedTitle= 2%7E93. Updated July 27, 2010. Accessed December 6, 2011. • Wallace DJ. Hypoparathyroidism in emergency medicine. Medscape Web site. http://emedicine.medscape.com/ article/767744-overview. Updated April 15, 2009. Accessed December 6, 2011.
MENIERE DISEASE ›GENERAL FEATURES • Meniere disease, also known as endolymphatic hydrops, is an idiopathic disorder of the inner ear that typically manifests in the fifth decade of life. • The cause of Meniere disease is unclear. Anatomic, infectious, immunologic, and allergic factors have been implicated. • The primary symptoms include the triad of episodic vertigo, tinnitus, and sensorineural hearing loss. • Histologically, there is distention of the endolymphatic system, leading to degeneration of vestibular and cochlear hair cells. • Incidence ranges from 10 to 150 cases per 100,000 persons each year. • Meniere disease affects men and women with equal frequency.
›CLINICAL ASSESSMENT • Meniere disease is characterized by episodic attacks of vertigo that may last for hours. • Other symptoms include unilateral, Barbara Poetzsch is an associate professor and preclinical coordinator at The Center for Physician Assistant Studies, Albany Medical College, Albany, New York. The author has indicated no relationships to disclose relating to the content of this article.
fluctuating sensorineural hearing loss (usually low frequency); constant or intermittent tinnitus; and aural fullness.
›DIAGNOSIS • The diagnosis should be made based on the clinical presentation. • Imaging should be used if the initial presentation or course is unusual and nonmedical management is planned. MRI with gadolinium contrast can be used to exclude retrocochlear pathology, such as a vestibular neuroma or demyelinating disorder that can mimic Meniere disease.
›TREATMENT • Therapy is directed at control of the vertigo. • Primary management of Meniere disease includes a low-salt diet and diuretics, specifically dyazide. • Other options for therapy: – Dietary restriction of caffeine, nicotine, alcohol, monosodium glutamate (MSG), and foods containing theophylline – Vestibular suppressants, including meclizine (Antivert, generics) and diazepam (Diazepam Intensol, Diastat, Valium, generics) – Antiemetic medications, including prochlorperazine suppository (Compro, generic), can help manage acute episodes. – A short course of oral corticosteroids may help acute severe exacerbations. – Antihistamines may help reduce symptoms related to environmental or food allergies. – Intratympanic gentamicin therapy
>>QUESTIONS & ANSWERS<< 1. Which of the following is not a symptom of Meniere disease? a. b. c. d.
Aural fullness Tinnitus Purulent aural discharge Sensorineural hearing loss
Answer: c Explanation: Aural fullness, tinnitus, and sensorineural hearing loss are all symptoms of Meniere disease.
2. Which of the following best describes the vertigo of Meniere disease? a. Single, constant, severe attack b. Mild, occasional episodes that last for seconds c. Episodic attacks that last for minutes to hours d. Mild attacks that last for weeks Answer: c Explanation: Meniere disease is characterized by episodic attacks of vertigo that last for minutes to hours, sensorineural hearing loss, tinnitus, and aural fullness.
– Surgical treatments include endolymphatic sac surgery and vestibular nerve sections when medical management is unsuccessful. – Patients may benefit from hearing aids and vestibular rehabilitation to help with balance and equilibrium. JAAPA Dawn Colomb-Lippa, MHS, PA-C; Amy M. Klingler, MS, PA-C, department editors
Interested in writing for the Quick Recertiﬁcation Series? E-mail us at email@example.com
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Diagnostic Imaging Review JASON AUSMUS, PA-C; RAHUL SHARMA, MD, MBA, FACEP
differential; hemoglobin, 14.4 g/dL; hematocrit, 40.4%; platelets, 192×103/ µL. Results of a basic metabolic panel, liver panel, and coagulation studies were normal; a urine pregnancy test was negative. The patient was given IV fluids and analgesics. Because this headache was different from previous headaches, a CT scan of the head without contrast was ordered (Figure 1). What does the
FIGURE 1 Noncontrast CT shows increased density (white arrow) in the expected location of the left transverse venous sinus.
A different kind of headache in a patient with migraines ›CASE A 28-year-old female with a history of migraines and hepatitis B infection presented to the emergency department (ED) for evaluation of a left-sided headache that began approximately 12 hours earlier. She described the headache as a squeezing sensation that had begun gradually on the left side of her neck, jaw, and left ear, with radiation to the anterior aspect of her head and nausea. The headache was intermittently relieved with OTC analgesics and rest. Within the past several months, her primary care physician had diagnosed migraines but had not ordered any imaging studies. According to the patient, this headache was different from previous headaches because it was localized to the left neck and ear and had an intensity
of 4 on a 10-point scale. She denied any sick contacts, recent travel, trauma, fever, chills, photophobia, visual changes, sinus congestion, numbness, or tingling. The patient reported using oral contraceptives (OCs) for the past 2 months and ibuprofen for her headaches. The remainder of her medical history was unremarkable. Physical examination The patient appeared well and was in no distress. Her vital signs were temperature, 36.2°C (97.2°F); heart rate, 95 beats per minute; BP 133/85 mm Hg; respirations, 16 breaths per minute; oxygen saturation was 98% on room air. Findings on the physical examination, including a detailed neurologic assessment, were unremarkable. Her laboratory test results were as follows: WBC count, 8.9×103/µL, with a normal
Jason Ausmus is the chief PA in the Department of Emergency Medicine at New York PresbyterianWeill Cornell Medical Center, New York, New York. Rahul Sharma is an assistant professor at Weill Cornell Medical College, assistant director for operations, and medical director for the PAs in the Department of Emergency Medicine. The authors have indicated no relationships to disclose relating to the content of this article.
The CT scan revealed a hyperdensity within the left transverse sinus. Given this nonspecific CT finding, cerebral venous sinus thrombosis (CVST) was suspected and magnetic resonance venography (MRV) of the brain with and without contrast was ordered (Figure 2). The contrast-enhanced MRV showed the presence of thrombus and absence of blood flow to the left transverse and sagittal sinuses, confirming the diagnosis of CVST. CT with contrast and MRI with MRV are the modalities of choice for the diagnosis of CVST. CT with contrast will show a filling defect in the affected venous sinuses, a finding known as the empty delta sign. While MRV is required for the diagnosis of venous sinus thrombosis, an MRI of the brain is done concurrently to identify other potential abnormalities in the brain, such as ischemia, edema, or hemorrhage. Cerebral venous sinus thrombosis is a rare cause of headache. Left untreated, it can cause significant morbidity and mortality. Contributing factors include ethnic background, hypercoagulable states, trauma, cancer, and medication history. CVST is more common in women than men at a ratio of 3 to 1.1 It is seen in younger patients as an uncommon form of cerebrovascular accident occurring in fewer than 1% of all cases.1 The most common risk factor is use of oral contraceptives (OCs). Women who take
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Diagnostic Imaging Review OCs have a 10-fold increased risk of developing cerebral venous sinus thrombosis.2 Headache is the most common presenting symptom. Many patients have a normal CT scan on initial presentation.2 The quality of the headache is not particularly helpful in distinguishing CVST from other causes of headache, as there are many conditions that can manifest with either headache or facial pain. Cerebral venous sinus thrombosis headaches can be described as either diffuse or localized, with a gradual onset of symptoms that can last for months, much like a migraine. A small number of thrombus headaches do manifest acutely, which can be concerning for subarachnoid hemorrhage or idiopathic intracranial hypertension if accompanied by focal neurologic deficits. Patients with CVST can also present with sinus pressure, ear pain, visual disturbance, seizure, or altered mental status.2,3 Laboratory studies should include a CBC, basic metabolic panel, and tests for prothrombin time (PT)/ partial thromboplastin time (PTT)/ international normalized ratio (INR), ESR, and C-reactive protein (CRP). A D-dimer test may be limited in value because the level declines from the time of onset.1 Hypercoagulation studies may reveal an underlying condition that can contribute to making the diagnosis. Treatment Patients with CVST should receive anticoagulation therapy with either unfractionated heparin or fractionated low molecular weight heparin (LMWH), followed by warfarin therapy. Other therapies can include direct thrombolytics or thrombectomy, depending on the severity of clinical presentation. All patients should be admitted to the stroke unit for observation of potential increasing neurologic deficits, seizure, or thrombotic or hemorrhagic events that can occur during initial treatment. Our patient was started on LMWH, had a neurologic consultation, and
ent early will recover, but long-term complications can include continual headache, depression, and fatigue.3 Isolating the underlying factor is helpful in determining the length of coagulation therapy after discharge. For most conditions, the typical length of treatment is 3 to 6 months, but lifelong anticoagulation therapy is required with inherited conditions.3 Repeat imaging and neurologic follow-up are needed to check for new thrombus formation and assess response to treatment. FIGURE 2. Contrast-enhanced magnetic resonance venography (MRV) shows normal ﬂow with no ﬁlling defect to the right transverse and superior sagittal sinuses (two larger white arrows). On the left, there is no visualization of the left transverse and sagittal sinuses (small white arrow) because the thrombus has blocked blood ﬂow.
was admitted to the neurologic service. The patient had an ESR of 24 mm/ hour and a D-dimer of 646 mg/L, but the findings for the remainder of her coagulation workup were negative. The patient was also started on warfarin. Her symptoms eventually resolved, and she was discharged home with a recommendation to continue warfarin therapy for 6 months. Her OC was stopped because it was a likely contributing factor to thrombus formation. Prognosis The prognosis for cerebral venous sinus thrombosis is variable, with poor outcomes related to severe neurologic deficits and death from either secondary complications or the thrombus itself. Other conditions associated with poor outcome include infection of the CNS, hemorrhage, decreased mental status, or coma at presentation.1 Female patients have a far better prognosis than males, perhaps because of medical screening for prothrombotic conditions, early presentation with headache as the initial symptom, and age at diagnosis even in the setting of multiple risk factors.1,3 Most patients who pres-
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›CONCLUSION Cerebral venous sinus thrombosis is a rare cause of headache that can be easily overlooked. Initial misdiagnosis of patients with CVST has been reported in approximately 73% of cases.3 While a small percentage of patients will demonstrate sudden neurologic compromise, the neurologic examination of many patients is unremarkable. Therefore, those patients with continual headaches unresponsive to pharmacologic therapy may benefit from imaging. While initial studies can include a CT, MRV is required to confirm the diagnosis of CVST. Treatment options can be based on initial presentation, but anticoagulation remains the cornerstone. Outcome of this condition can be affected by initial presentation and risk factors. Clinicians should always have a high degree of suspicion for CVST in patients with nonspecific neurologic complaints. JAAPA Julie Edmiston, PA-C, RT, department editor REFERENCES 1. Saposnik G, Barinagarrementeria F, Brown RD Jr, et al. Diagnosis and management of cerebral venous thrombosis: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011;42(4):1158-1192. 2. Fischer C, Goldstein J, Edlow J. Cerebral venous sinus thrombosis in the emergency department: retrospective analysis of 17 cases and review of the literature. J Emerg Med. 2010;38(2):140-147. 3. Bentley JN, Figueroa RE, Vender JR. From presentation to follow-up: diagnosis and treatment of cerebral venous thrombosis. Neurosurg Focus. 2009;27(5):E4.
GENOMICS IN PA PRACTICE W. ANDREW FAUCETT, MS, CGC; MELISSA SAVAGE, MS, CG C
Chromosomal microarray testing Chromosomal microarray testing
›CLINICAL BOTTOM LINE • Chromosomal microarray testing (CMA) uses molecular probes to detect gains or losses of segments of DNA (copy number variations [CNVs]) or copy neutral changes, such as loss of heterozygosity or uniparental disomy, depending on the type of microarray. • CMA testing offers a significant improvement over routine chromosomal studies in detecting clinically significant chromosomal deletions and duplications that are not visible by routine chromosome studies (Gbanded karyotype).1,2 • Recent guidelines and publications have recommended that CMA should replace G-banded karyotyping for the evaluation of children with autism spectrum disorders, developmental delay/intellectual impairment, and/or multiple congenital anomalies. Deletions and duplications found in these children have been published in recent papers.1,3,4 • Primary care management pearls – Genetic counseling should be provided prior to ordering CMA testing to ensure that patients and families understand the types of information that may be reported. – If a child has clinical symptoms of a known genetic syndrome, such as Down syndrome, testing for that specific condition should be considered first.1 W. Andrew Faucett is director of policy and education for the Genomic Medicine Institute at Geisinger Health System in Danville, Pennsylvania. Melissa Savage is a research coordinator at Columbia University in New York, New York. The authors have indicated no relationships to disclose related to the content of this article.
– Providing clinical information to the laboratory along with the sample will increase the ability of the laboratory to interpret unique CNVs.2 – Clinicians and patients should be aware that they may receive results indicating a “variant of unknown significance” (VOUS). This means that there is not enough information at this time to report the CNV as pathogenic or benign. As additional information is obtained, a VOUS may be reclassified.2,5 – In general, clinically significant findings include known microdeletion or microduplication syndromes, deletions of genes that are known to be associated with disease due to loss of one copy (haploinsufficiency), and large deletions or duplications involving multiple genes.5
›WHAT IS CMA TESTING? • A CMA test uses molecular markers spaced along the chromosomes
to detect deletions, duplications, or unbalanced rearrangements of DNA; or loss of heterozygosity or uniparental disomy (in the case of a single nucleotide polymorphism [SNP]-based array). The markers are most dense in areas of known clinical significance, so that even very small deletions and duplications in these regions can be detected. Most CMA tests also include backbone coverage (the regions outside the areas of known clinical significance) to detect deletions or duplications of 100 to 500 kilobases in the rest of the genome. Comparatively, traditional G-banded karyotypes can detect deletions or duplications of 5 to 10 megabases in size.5 CMA testing cannot detect point mutations or very small deletions or duplications in genes. CMA will find a pathogenic deletion or duplication in 15% to 20% of children tested for autism spectrum disorder, developmental delay/intellectual impairment, and/
© Alfred Pasieka / Photo Researchers, Inc.
An example of a DNA microarray
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GENOMICS IN PA PRACTICE “Different laboratories offer different types and levels of coverage for CMA tests. Talk with the lab to ensure that the proper test is ordered.”
• Currently, CMA is not considered a first-line test for epilepsy or neuropsychiatric disorders. • Identification of small CNVs is common; most have no known clinical significance at this time.
or congenital anomalies. G-banded karyotype will detect an abnormality in 3% to 5% of the same population.1,2 • To determine pathogenicity of a CNV, laboratories will consider the size of the deletion or duplication, the particular genes in the area, whether the deletion or duplication is inherited from one of the parents, reports of similar deletions or duplications in published literature and databases, and the symptoms displayed by the patient.3,5
CMA TESTING • CMA testing requires a blood sample—usually both an EDTA (purple top) and a sodium heparin (green top) tube. • Samples should be shipped at room temperature and not be refrigerated or frozen. • Parental samples may be requested to help determine the clinical significance of some findings. JAAPA
›LIMITATIONS/CAUTIONS • Different laboratories offer different types and levels of coverage for CMA tests. Discussion with the laboratory about each patient is important to ensure that the appropriate test is ordered.5,6 • CMA cannot detect low-level mosaicism, inversions, balanced chromosome translocations, or point mutations in genes. In couples with a history of multiple miscarriages and a child with autism, developmental delay, and/or multiple congenital anomalies, a G-banded karyotype may be needed. • Some laboratories use SNP-based arrays, which may identify incest or consanguinity.
REFERENCES 1. Miller DT, Adam MP, Aradhya S, et al. Consensus statement: chromosomal microarray is a ﬁrst-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010;86(5):749-764. 2. Coulter ME, Miller DT, Harris DJ, et al. Chromosomal microarray testing inﬂuences medical management. Am J Hum Genet. 2011;13(9):770-776. 3. Kaminsky EB, Kaul V, Paschall J, et al. An evidence-based approach to establish the functional and clinical signiﬁcance of copy number variants in intellectual and developmental disabilities. Genet Med. 2011;13(9):777-784. 4. Manning M, Hudgins L; Professional Practice and Guidelines Committee. Array-based technology and recommendations for utilization in medical genetics practice for detection of chromosomal abnormalities. Genet Med. 2010;12(11):742-745. 5. Kearney HM, Thorland EC, Brown KK, et al. American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants. Genet Med. 2011;13(7):680-685. 6. Kearney HM, South ST, Wolff DJ, et al. American College of Medical Genetics recommendations for the design and performance expectations for clinical genomic copy number microarrays intended for use in the postnatal setting for detection of constitutional abnormalities. Genet Med. 2011;13(7):676-679.
Web resources for providers American College of Medical Genetics and Genomics www.acmg.net Array Genomic Hybridization www.ncbi.nlm.nih.gov/sites/ GeneTests/lab/clinical_lab_service_ id/234754?db=genetests The International Standards for Cytogenomic Arrays Consortium www.iscaconsortium.org
Web resources for patients Chromosome Disorder Outreach www.chromodisorder.org NIH Ofﬁce of Rare Diseases Research Genetic and Rare Diseases Information Center (GARD) http://rarediseases.info.nih.gov/ GARD/Default.aspx?PageID=4 Unique www.rarechromo.org
Michael A. Rackover, PA-C, MS; Constance Goldgar, MS, PA-C, department editors
Visit V is www.jaapa.com to read more Genomics in PA Practice online. G en Choose C hoo Departments on the main navigation bar, and a click on Genomics in PA Practice.
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EMERGENCY MEDICINE NOTES Alexandra Godfrey, MS, PA-C, practices emergency medicine at a hospital in the Midwest. She is a member of the JAAPA editorial board.
“My patient died 45 minutes after he left the ER. His death was beautiful and awful.”
y patient died 45 minutes after he left the ER. His death was beautiful and awful. I remember snapshot moments that will last to eternity: the sylphlike granddaughter wrapping her delicate arms tightly around my patient’s quivering body, the weary sister resting her gnarly hand over her brother’s trembling fingers, the soldier son standing to attention, listening to his father’s wishes. I thought, he’s fragile and wasting away, but their bond remains radiant and strong. No beauty in my patient’s final hour. A devoted grandfather of seven, a skilled classical composer with cobalt blue eyes and the fine fingers of a pianist, he died with a belly full of air and funky yellow contrast dye. He spent his last hour listening to the dissonant lament of the CT scanner as it took cross sectional pictures of his abdomen and pelvis. Images of death’s approach ordered as a final request. My patient’s last wish: he had wanted to know his diagnosis, his prognosis; how much time he had? Not long: 5 hours, 300 minutes, 36,000 beats; a fast tempo. An easy post mortem calculation. Did he die with the click of the metronome in his head? My patient was 84 years old. He had presented with abdominal pain. One of the nurses brought him to my attention early on his final evening. 7 PM. “Alexandra, would you see the man in room 43? He is in pain and looks sick.” I respond immediately to the nurse’s request. She rarely asks for much. I walk into room 43. I see an elderly man lying curled up, a sheet entwining his upper body, just covering his midriff. The man’s contracted and atrophied legs are exposed. A sore festers on his left heel, and a long, ragged scar bisects his right knee. Age comes at a price. The man writhes with pain. His movements stop only when he pauses to vomit. He tries to speak, but his tongue sticks like a burr to the roof of his mouth. The telemetry alarm beeps constantly. His heart rate is too fast. I introduce myself, then straighten the man’s pillow and tuck it under his head. I rinse a washcloth in cold water and 68 JAAPA • JANUARY 2012 • 25(1) • www.jaapa.com
wipe the man’s dry, cracked lips. He puts out his tongue, trying to catch the water trickling from the cloth. I ask the man to tell me more about his pain. He says it started at 3 AM, waking him from sleep. He describes it as diffuse and colicky. He had oatmeal for breakfast but started vomiting shortly after. He has not kept anything down since. Around noon, he had an episode of bloody diarrhea: bright red blood, enough to color the toilet water, not enough to worry him. This happened twice more during the afternoon. He called his neighbor at 5 PM when he could stand the pain no longer. She dropped him here, and his family is coming. When I examine his abdomen, he is minimally tender all quadrants with hyperactive bowel sounds; no guarding, rigidity, or rebound. I order fluids, pain meds, abdominal labs, cardiac enzymes, and plain films of the abdomen. The patient’s ECG done in triage shows atrial fibrillation, but his current strip is NSR. No history of anticoagulants. An hour later, the man’s test results show his lactate level is elevated at 3.9. He has a WBC count of 13.2 and a normal H&H. The radiologist calls me. The man appears to have free air under his right diaphragm consistent with a perforation, but the x-ray is not definitive given some abnormal lung findings. He suggests CT to clarify. I call the surgery resident, who promptly reviews the films, also questions a perforated bowel, and states he will come to see my patient. I return to my patient. His family is at his bedside, watching over him with gentle concern. I discuss the test findings with them. My patient listens to me, then to the resident. He recommends prompt admission to the SICU and a CT scan. He warns an emergency operation may be needed. The patient interrupts: he does not want surgery, he cannot stand the thought of it, an operation will surely kill him. He moves his hands rapidly and precisely as he speaks: crescendo, diminuendo, release. Silence descends. The clock ticks. Is this the end? The resident places a hand softly on my patient’s arm, letting him know that we will respect his wishes. I talk with my patient and his family. They understand that without an operation he may die. My patient is DNR. He declines surgery, but he wants to know his life expectancy. He wants a CT. I explain the process to him: the drinking of contrast; the risk of vomiting; the futility, perhaps. My patient and his family, however, want a clear diagnosis and prognosis. They insist. I order the scan, but my heart aches. The patient’s family remains with him until he leaves the ER. The floor nurse discovers his still body 20 minutes after he returns from CT; 5 hours after we met. I read the CT report post mortem. I hope in his last moments, my patient forgot the mechanical whirr of the CT scanner and instead remembered the music of the spheres, the sound of his son’s heels clicking to attention, the tender embrace of his granddaughter, and the rough but loving touch of his sister’s worn skin. Expiration date: is this beyond medicine’s reach? JAAPA
Case of the Month ›CASE A 35-year-old female reported a 10-year history of intermittent bilateral mastalgia. The patient stated that a cold environment caused “severe” pain in both breasts, but the pain resolved in a warmer environment. Her symptoms, which occurred in the winter and in air-conditioned rooms in the summer, were significant enough to limit her activities in cold environments. She denied pain in the fingers or toes on exposure to cold temperatures. There was no nipple discharge and no history of breast disease or breast surgery. The patient was gravida 2, para 0, aborta 2, with no history of breastfeeding. At the time of this visit, she was sexually active but not using any contraception and was seeking information on contraceptive options as well. She was taking no prescription, OTC, or herbal medications. A current smoker (1 pack per day), she had a 17-pack-year history. Her medical history included mild hyperlipidemia and a cholecystectomy 9 years ago. Family history was negative for Raynaud phenomenon and breast cancer. Examination The breast examination of this obese white female was normal, with no tenderness to palpation. There was no supraclavicular or axillary lymphadenopathy, masses, or nipple discharge. The remainder of the examination was unremarkable, except for a thyroid nodule, which was later determined to be benign. No tests were performed.
›WHAT IS YOUR DIAGNOSIS? • • • •
Candida infection Fibrocystic breasts Raynaud phenomenon Malignancy
›DISCUSSION The patient’s history and symptoms suggested a diagnosis of primary Raynaud phenomenon (RP) of the breasts. A literature search that included the Internet and PubMed found case reports of RP
Cynthia Bunde, MPAS, PA-C; Bernadette Howlett, PhD; Nicholas Ogami; Rebecca Hall
in the nipples, but only in breastfeeding women.1,2 A provisional diagnosis of primary RP was made. Raynaud phenomenon is a vasospastic ischemic condition, most commonly affecting the digits.3 Classically, the area affected by RP undergoes a sequential color change from white (blanching due to ischemia caused by vasospasm) to blue (cyanosis) to red (rewarming and return of blood flow). This patient did not report any color change, and it was not observed on examination. Maneuvers to induce an attack by cooling the patient are not recommended.4 Raynaud phenomenon is classified as primary or secondary. Primary RP is characterized by ongoing episodic digital ischemia in the absence of signs or symptoms of underlying connective tissue disease. Primary RP usually affects women between the ages of 15 and 30 years.4 Secondary RP typically appears at a later age. It is most commonly associated with connective tissue, vascular, endocrine, neoplastic, or hematologic disorders.3 In both primary and secondary forms, symptoms are often exacerbated by nicotine, as well as some prescription medications (including beta-blockers and some migraine medications).3 Emotional stressors have been implicated as triggers of RP due to stimulation of the sympathetic nervous system.4 The prevalence of RP varies among different populations and can range from 3% to 20% in women and 3% to 14 % in men.4 Patients in whom primary RP has been diagnosed do not typically experience serious injury. The disease is more of a nuisance than a threat to health. Secondary RP has been used as a marker to indicate an underlying connective tissue disorder. Treatment Since the overall mechanism of Raynaud phenomenon has yet to be fully understood, there is no well-defined treatment.3 Conservative approaches include wearing warmer clothing over the affected areas as well
as relaxation and stress management techniques. Calcium channel blockers, alpha-blockers, and vasodilators can be utilized. Nifedipine, a calcium channel blocker, is the most commonly described treatment.2-4 Smoking cessation should be recommended because of the association between nicotine and RP. Outcome Our patient was given a prescription for 30 mg of extendedrelease nifedipine to be taken once daily. Contraceptive options and smoking cessation were also addressed. Two months later, the patient reported that her symptoms had subsided and she was able to return to normal activities of daily living free from mastalgia. At a wellness visit 1 year later, she said that the prescribed dose of nifedipine had resolved the breast pain, and she was then using nifedipine as needed. Comment Although primary RP is fairly easy to diagnose when patients report symptoms in the digits, this case reminds us that the disease can manifest in uncommon locations. Strict attention to the history and prescribing an appropriate treatment have allowed this patient to live a normal life free of pain. JAAPA The authors are afﬁliated with the Department of Physician Assistant Studies at Idaho State University, Pocatello. Cynthia Bunde is afﬁliate faculty and practices at the Pocatello Women’s Health Clinic; Bernadette Howlett is an associate professor and research coordinator; Nicholas Ogami is a student; Rebecca Hall is a research assistant. The authors have indicated no relationships to disclose relating to the content of this article. Erich Fogg, PA-C, MMSc, department editor REFERENCES 1. Lawlor-Smith L, Lawlor-Smith C. Vasospasm of the nipple—a manifestation of Raynaud’s phenomenon: case reports. BMJ. 1997;314(7081):644-645. 2. Holmen OL, Backe B. An underdiagnosed cause of nipple pain presented on a camera phone. BMJ. 2009;339:631-632. 3. Adee AC. Managing Raynaud’s phenomenon: a practical approach. Am Fam Physician. 1993;47(4):823-829. 4. Wigley FM. Clinical manifestations and diagnosis of the Raynaud phenomenon. UpToDate Web site. http://www. uptodate.com/contents/clinical-manifestations-anddiagnosis-of-the-raynaud-phenomenon?source=search_ result&selectedTitle=1~136. Updated January 25, 2011. Accessed December 2, 2011.
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