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CLINICAL WATCH NCQA quality improvement guidelines 21



RESEARCH REPORT Trauma patient satisfaction with PAs 42

HUMAN DISSECTION Leadership case study: Cynthia Booth Lord, MHS, PA-C


QUICK RECERTIFICATION SERIES Acute and chronic adrenal insufficiency


>>Earn 1 AAPA Category I CME credit with this issue CME Acute appendicitis


CME Infectious mononucleosis


CME Posttest


Appendicitis PAGE 32

psychoactive substances. Tolerance is a state of adaptation in which exposure to a drug induces changes that result in diminution of one or more of the drug effects over time. Tolerance may occur to both desired and undesired effects of drugs and may develop at different rates for different effects. Addiction is a primary, chronic, neurobiological disease with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is a treatable disease, using a multidisciplinary approach, but relapse is common. Studies of abuse potential in former drug abusers found that the effects of single doses of 40 mg of oral zolpidem tartrate were similar, but not identical, to diazepam 20 mg, while 10 mg of oral zolpidem tartrate was difficult to distinguish from placebo. Because persons with a history of addiction to or abuse of drugs or alcohol are at increased risk for misuse, abuse and addiction of zolpidem, they should be monitored carefully when receiving Intermezzo. 9.3 Dependence: Physical dependence is a state of adaptation that is manifested by a specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist. Sedative-hypnotics have produced withdrawal signs and symptoms following abrupt discontinuation. These reported symptoms range from mild dysphoria and insomnia to a withdrawal syndrome that may include abdominal and muscle cramps, vomiting, sweating, tremors, and convulsions. The following adverse events which are considered to meet the DSM-III-R criteria for uncomplicated sedative-hypnotic withdrawal were reported during U.S. clinical trials with other oral zolpidem formulations following placebo substitution occurring within 48 hours following the last zolpidem treatment: fatigue, nausea, flushing, lightheadedness, uncontrolled crying, emesis, stomach cramps, panic attack, nervousness, and abdominal discomfort. These reported adverse events occurred at an incidence of 1% or less. However, available data cannot provide a reliable estimate of the incidence, if any, of dependence during treatment at recommended doses. Post-marketing reports of abuse, dependence, and withdrawal resulting from use of oral zolpidem tartrate have been received. 10 OVERDOSAGE: 10.1 Signs and Symptoms: In post-marketing experience of overdose with oral zolpidem tartrate alone, or in combination with CNS-depressant agents, impairment of consciousness ranging from somnolence to

coma, cardiovascular and/or respiratory compromise, and fatal outcomes have been reported. 10.2 Recommended Treatment: General symptomatic and supportive measures should be used along with immediate gastric lavage where appropriate. Intravenous fluids should be administered as needed. Zolpidem’s sedative-hypnotic effect was shown to be reduced by flumazenil and therefore flumazenil may be useful; however, flumazenil administration may contribute to the appearance of neurological symptoms (convulsions). As in all cases of drug overdose, respiration, pulse, blood pressure, and other appropriate signs should be monitored and general supportive measures employed. Hypotension and CNS depression should be treated by appropriate medical intervention. Sedating drugs should be withheld following zolpidem overdosage, even if excitation occurs. The value of dialysis in the treatment of overdosage has not been determined, although hemodialysis studies in patients with renal failure receiving therapeutic doses have demonstrated that zolpidem is not dialyzable. As with management of all overdosage, the possibility of multiple drug ingestion should be considered. The healthcare provider may wish to consider contacting a poison control center for up-to-date information on the management of hypnotic drug overdosage. 14.2 Special Safety Studies: Driving Study: A randomized, double-blind, placebo-controlled, active-control, single-center, four-period, crossover study in 40 healthy subjects was conducted to evaluate the effects of middle-of-the-night administration of Intermezzo on next-morning driving performance. The four randomized treatments included Intermezzo 3.5 mg four hours before driving, Intermezzo 3.5 mg three hours before driving, placebo, and a positive control (an unapproved sedative-hypnotic) given nine hours before driving. The primary outcome measure was the change in the standard deviation of lateral position (SDLP), a measure of driving impairment. The results were analyzed using a symmetry analysis, which determined the proportion of subjects whose change from their own SDLP in the placebo condition was statistically significantly above a threshold thought to reflect clinically meaningful driving impairment. When driving began 3 hours after taking Intermezzo, testing had to be terminated for one subject (a 23-year old woman) due to somnolence. Overall, the symmetry analysis showed a statistically significant impairing effect at 3 hours. When driving began 4 hours after taking Intermezzo, statistically significant impairment was not found, but numerically Intermezzo was worse than placebo. Zolpidem

blood levels were not measured in the driving study, and the study was not designed to correlate specific blood level with degree of impairment. However, the estimated blood level of zolpidem in patients whose SDLP worsened according to the symmetry analysis is considered to present a risk for driving impairment. In some women, the 3.5 mg dose of Intermezzo results in zolpidem blood levels that remain at or sometimes considerably above this level 4 or more hours after dosing. Therefore, the recommended dose for women is 1.75 mg. A small negative effect on SDLP may remain in some patients 4 hours after the 1.75 mg dose in women, and after the 3.5 mg dose in men, such that a potential negative effect on driving cannot be completely excluded. Rebound effects: In studies performed with other zolpidem formulations (5 mg to 10 mg oral zolpidem tartrate) given at bedtime, there was no objective (polysomnographic) evidence of rebound insomnia at recommended doses seen in studies evaluating sleep on the nights following discontinuation. There was subjective evidence of impaired sleep in the elderly on the first post-treatment night at doses above the recommended elderly dose of 5 mg oral zolpidem tartrate. Memory impairment in controlled studies: Controlled studies in adults utilizing objective measures of memory yielded no consistent evidence of next-day memory impairment following the administration at bedtime of 5 mg to 10 mg oral zolpidem tartrate. However, in one study involving zolpidem tartrate doses of 10 mg and 20 mg, there was a significant decrease in next-morning recall of information presented to subjects during peak drug effect (90 minutes post-dose), i.e., these subjects experienced anterograde amnesia. There was also subjective evidence from adverse event data for anterograde amnesia occurring in association with the administration of oral zolpidem tartrate, predominantly at doses above 10 mg. Healthcare professionals can telephone Purdue Pharma’s Medical Services Department (1-888-726-7535) for information on this product. Distributed by: Purdue Pharma L.P., Stamford, CT 06901-3431 ©2012, Purdue Pharma L.P. Revised 02/2012 302880-0C-A

THIS MONTH’S ARTICLES Online-only articles Case of the Month Lisa Jansen; Margaret King-Schumacher, PA-C, MJ Interpreting ECGs James F. Ginter, MPAS, PA-C; Patrick J. Loftis, PA-C, MPAS, RN

How flowers make us better PAs Jim Anderson, PA-C, ATC I’m finally starting to get this “humanities in medicine” thing. Maybe you got it a long time ago, but it’s just coming into focus for me.

The May Challenge What’s the most important member benefit of belonging to AAPA and why? Go to JAAPA 25th Anniversary Monthly Challenge on to send us your answer, and you could win a $100 gift card. • MAY 2012 • 25(5) • JAAPA


PUBLISHING STAFF Editor Tanya Gregory, PhD Production editor/Web producer Rick Maffei Web editor Traci Dantoni Manuscript editor Lauren Rich Editorial coordinator Candy Iemma Art director Andrew Bass Group art director, Haymarket Medical Jennifer Dvoretz Group circulation manager Paul Silver VP, audience development and operations John Crewe Group production manager Kathleen Millea

Vice president and publisher Dominic Barone Publishing director Mark Bugni Vice president, medical magazines Jim Burke, RPh CEO, Haymarket Media Inc Lee Maniscalco Sales office Haymarket Media Inc, 114 West 26th Street, 4th Floor, New York, NY 10001; Phone: (646) 638-6000; Fax: (646) 638-6117 Editorial office Haymarket Media Inc, 25 Philips Parkway, Suite 105, Montvale, NJ 07645; Phone: (201) 799-4821; Fax: (201) 391-0880 Classified sales office Russell Johns Associates, LLC Phone: (877) 394-1388; Fax: (727) 445-9380; Reprints Wright’s Reprints (877) 652-5295 Permissions



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

Chief executive officer, Jennifer L. Dorn

Jim Anderson, PA-C, ATC, University of Washington Medicine— IT Services, Seattle, WA • Diane Bruessow, RPA-C, DFAAPA, New York, NY • L. Gail Curtis, MPAS, PA-C, DFAAPA, AAPA Board of Directors • Richard Dehn, MPA, PA-C, DFAAPA, College of Health and Human Services, Northern Arizona University, Flagstaff • Alexandra Godfrey, MS, PA-C, St. Joseph’s Mercy Hospital, Ypsilanti, MI • Wanda C. Gonsalves, MD, Medical University of South Carolina, Charleston • 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

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

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


American Academy of Physician Assistants 2318 Mill Road, Suite 1300 Alexandria, VA 22314

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 5, May 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 800436-9269 or visit 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.

(703) 836-2272;




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

M AY 2 0 1 2

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5 WEB ARTICLES FOR MAY 12 EDITORIAL What could PAs become if they answer the call to leadership? Reamer L. Bushardt, PharmD, PA-C

32 CME ARTICLE Acute appendicitis: Can antibiotics ever take the place of surgery? Ben V. Christensen, MHS, PA-C; Dawn Colomb-Lippa, MHS, PA-C

37 CASE REPORT 16 PHARMACOLOGY CONSULT Clostridium difficile infection: Managing the risks Larissa DeDea, PharmD, BCPS, PA-C

20 DERMATOLOGY DIGEST What caused this painful skin erosion? Joe R. Monroe, PA-C, MPAS

21 CLINICAL WATCH Quality improvement: Tobacco use, diabetes, and vaccines CHAC, the Clinical and Health Affairs Commission of the AAPA

Floppy iris syndrome: A drug-related complication of cataract surgery Elizabeth “Fizzy” Ramsey, MS, PA-C; Barton L. Ramsey III, MD; Jennifer Childers, MS, PA-C CONTENTS CONTINUED ON PAGE 11

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:

27 TOPICS IN INFECTIOUS DISEASES Surgical site infection: Knowledge of the likely pathogens is key Roy A. Borchardt, PA-C, PhD; Kenneth V. I. Rolston, MD


Addressed in the articles on pages

Medical knowledge

16, 20, 27, 32, 37, 52, 67, 69, 71, 73, 79

Interpersonal and communication skills

12, 30, 42, 64, 69, 75

Patient care

30 JAAPA 25TH ANNIVERSARY POETRY COMPETITION December, Krista Wark Rogaski, MS, PA-C Blue Healer, Marti Trunnell, RN, PA-C Two Asleep, Christopher Wright, BA 8

JAAPA • MAY 2012 • 25(5) •


16, 20, 21, 27, 32, 37, 42, 52, 67, 69, 71, 73, 75, 79 12, 16, 20, 21, 27, 30, 32, 37, 42, 52, 64, 67, 69, 71, 73, 75, 79

Practice-based learning and improvement

16, 20, 21, 27, 32, 37, 42, 52, 67, 69, 71, 73, 79

Systems-based practice

12, 21, 30, 42, 64, 75

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. • Unprotected 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. • Retin-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

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.

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.

Contents 42 RESEARCH REPORT Trauma patient satisfaction with physician assistants: Testing a structural equation model Gina M. Berg, PhD; Robin E. Crowe, MA; Sue Nyberg, MHS, PA-C; Charles Burdsal, PhD

52 SURGICAL REVIEW Surgical considerations in invasive breast cancer: A clinician’s update Brian K. Yorkgitis, PA-C, DO; Amy J. Goldberg, MD, FACS

58 CME ARTICLE Pathogenesis, diagnostic testing, and management of mononucleosis Stacey Singer-Leshinsky, MS Ed, RPA-C

63 CME POSTTEST 64 HUMAN DISSECTION Leadership case study: Cynthia Booth Lord, MHS, PA-C Reamer L. Bushardt, PharmD, PA-C

67 QUICK RECERTIFICATION SERIES Acute and chronic adrenal insufficiency Jami S. Smith, MPA, PA-C

Yale PA student Harrison Reed won the JAAPA 25th Anniversary Challenge for April. His description of the skills essential for success as a PA:

A PA’s most essential skills are not learned in the classroom. They are founded on the PA’s individual principles and honed by life experience. While PAs need critical thinking and a wealth of knowledge to diagnose and treat disease, their greatest strength lies in their compassion as human beings. PAs must first listen to and understand their patients. They must naturally express this empathetic connection. They should understand how to treat the patient’s disease and the patient’s humanity. All providers must practice sound medicine. Exceptional PAs practice compassion. Visit to see the Anniversary Challenge for May and submit your answer. You could win a $100 gift card.

69 WHEN THE PATIENT ASKS Is caffeine safe during pregnancy? Shefali Patel, PA-C; Denise Rizzolo, PA-C, PhD

71 DIAGNOSTIC IMAGING REVIEW Right leg pain after a fall in a patient with a prosthesis Major Amelia M. Duran-Stanton, OPA-C, PhD, DScPAS-CO; Major Joseph Alderete, MD

73 GENOMICS IN PA PRACTICE Parkinson disease Nguyen H. Park, MS, PA-C

75 EMERGENCY MEDICINE NOTES Nepenthe Alexandra Godfrey, MS, PA-C


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.

79 CASE OF THE MONTH Lauren Neighbors; John L. Abt, DO, FACEP; Joyce Wagner, MCMS, PA-C

COVER ILLUSTRATION: Mike Austin • MAY 2012 • 25(5) • JAAPA


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

What could PAs become if they answer the call to leadership?


hat do a course offered at West Point, an essay published in 1970, and the southern African philosophy of ubuntu have in common? The answer might just change the way you think about how we propel the PA profession into the forefront of a turbulent, rapidly evolving health care environment. I was a pharmacist practicing in a hospital-owned cancer center when I decided to become a PA. I was hungry to learn a set of diagnostic skills that I was lacking, and the mission of the PA profession to help physicians help their patients appealed to me immensely. After a start in rural family medicine and now nearly a decade in PA education at two academic medical centers, I am overwhelmed by the magnitude of our country’s health problems and the disarray of our broken delivery system. Even so, and I feel guilty saying it, both could contribute to an even brighter future for PAs. We can become the access that so many patients lack, and our values could reshape the character of American health care. Because of my growing interest in leadership, I began to investigate our profession’s most influential people. These are unsung heroes and eclectic innovators—PAs who are transforming the cultures and environments in which we train, practice, and live. I am trying, in a new department in JAAPA introduced in this issue, to deconstruct the character of these leaders and extract pearls of wisdom and practical life lessons to share. I believe their stories will help us realize our aptitudes for leadership, demystify the path to making lasting change, and invigorate us to lead our profession forward. The stories could be a course of study for each of us, so I am calling this new department Human Dissection. I will dissect different types of leaders, so we can all take a peek inside to study the relationships and structures of their character. You can read the first “dissection,” of Cynthia Booth Lord, on page 64. The criteria for candidates to profile are influenced by the attributes, talents, and factors that motivate great leaders. The criteria celebrate our past but also speak to necessary skills for future PA leaders—the kinds of people who can transform the way our nation cares for patients. This gets us back to what a course offered at West Point, an essay published in 1970, and the southern African philosophy of ubuntu have in common. Colonel Eric Kail directs a course at West Point on military leadership, and he contributed to a series of blogs for the Washington Post on leadership character.1 Col. Kail asks us to consider the two most influential people in our lives and why they left such an impression on us. He also draws us to reflect on the last crisis we faced in our professional lives, 12

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specifically when a decision by a key leader resulted in major losses or disaster. He believes the answer to both of these questions involves character. I am adopting his framework for investigating how great leaders engage courage, integrity, selflessness, empathy, collaboration, and reflection. In 1970, Robert Greenleaf published an essay called “The Servant as Leader,” which founded the modern philosophy of servant leadership.2 According to Greenleaf, “The servantleader is servant first. … Then conscious choice brings one to aspire to lead.” Many PAs are servant leaders, and the philosophy speaks to the character of our profession. I have noticed over the years that in order to be successful, servant leaders must adapt when transplanted into professional organizations, large hospitals or systems, or politics. An interesting adaptation involves drawing on a transformational leadership approach. In 1999, Yukl explained the essential steps: develop challenging and attractive visions collaboratively; connect vision to a strategy for its achievement; develop the vision and translate it to actions; express confidence, decisiveness, and optimism about the vision and its implementation; and realize the vision through small, planned steps and successes on the path to full implementation.3 Ubuntu is a humanistic concept found in southern Africa. In a way, ubuntu means “humanity,” but it is hard to define with an English word. Archbishop Desmond Tutu described ubuntu as learning to be a person through other people. I bet this resonates with you, as it did with me. Consider how your role in caring for patients has helped shape your personal identity. Ubuntu does not mean you cannot take steps to improve yourself. It means that by belonging to and caring for our community, we become ourselves. It is collaboration rather than isolation. For leaders, it means we must lead with interconnectedness. Our profession is filled with people of virtuous character. Imagine what we could become if we answered the call for great leadership. Consider the future of the profession if those entering our ranks were developed as servant leaders, taught how to transform the communities around them, and embraced ubuntu. JAAPA REFERENCES 1. Leadership character: A six-part series by West Point’s Col. Eric Kail. Washington Post Web site. Accessed April 12, 2012. 2. What is servant leadership? Accessed April 12, 2012. 3. Yukl G. An evaluation of conceptual weaknesses in transformational and charismatic leadership theories. Leadership Quarterly. 1999;10:285-305.

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

Clostridium difficile infection: Managing the risks ›DO PPIs INCREASE THE RISK OF C DIFFICILE INFECTION? Proton pump inhibitors (PPIs) are one of the most commonly prescribed medications in both the inpatient and outpatient setting. Although most patients experience no adverse effects with these drugs, data are emerging that PPIs are not as benign as initially thought. Chronic use has been linked to an increased risk of fractures, pneumonia, B12 deficiency, and hypomagnesemia.1 Additionally, the FDA recently issued a statement warning patients and providers about an increased risk of Clostridium difficile-associated diarrhea (CDAD) with the use of PPIs. C difficile infection is most commonly associated with antibiotic use. Fluoroquinolones, clindamycin, and broad-spectrum penicillins and cephalosporins are the agents most frequently implicated. Antibiotics disrupt the normal colonic flora, allowing for overgrowth of C difficile. In contrast, the mechanism of C difficile infection with PPIs is related to gastric acid suppression and elevation of gastric pH. Gastric acid is well known to play an essential role in the immune system; however, why suppression of gastric acid increases the risk of CDAD remains unclear. The FDA is warning patients who take PPIs to seek immediate medical care if diarrhea develops that does not improve. PAs should evaluate for CDAD in these patients, particularly if abdominal pain, leukocytosis, or fever is present. As with most medications, the lowest possible effective dose of PPIs should be prescribed. Some studies found a direct relationship between increasing gastric acid suppression and C difficile infection. Patients who take PPIs more than once daily appear to be 16

at highest risk, and H2 receptor antagonists (H2RAs) have the lowest risk.1 Prescribe an H2RA before a PPI in patients with symptoms of gastroesophageal reflux. In hospitalized patients, PPIs are commonly prescribed unnecessarily for stress ulcer prophylaxis in patients who are not at high risk. Stress ulcer prophylaxis is indicated in critically ill patients who are coagulopathic, on mechanical ventilation, have a recent history (within the past year) of GI ulceration or bleeding, and in those who have suffered a major trauma or burn injury. Prophylaxis may also be considered for patients in the ICU who have occult GI bleeding, are on highdose glucocorticoid therapy, or have prolonged length of ICU stay (greater than 1 week). Keep in mind that steroid therapy alone has not been conclusively shown to cause stress ulcers in the absence of other risk factors.2 In summary, be judicious about prescribing PPIs and understand that this class of medication is not without risk. Know that most hospitalized medical patients do not require stress ulcer prophylaxis. Finally, in accordance with FDA recommendations, evaluate for CDAD in patients who take PPIs and develop persistent diarrhea.

›CAN PROBIOTICS REDUCE C DIFFICILE INFECTIONS? Probiotics are live, nonpathogenic organisms that are often prescribed to colonize the GI tract. The theory is that restoring gut flora with probiotics will reduce bacterial overgrowth of pathogenic organisms such as C difficile. Unfortunately, there is not much good evidence supporting probiotic therapy for this use. Probiotics should not be used for an initial episode of C difficile infection,

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but some patients with recurrent C difficile infection benefit from probiotics. Adjunctive therapy with probiotics should be reserved for patients without significant comorbid conditions who have recurrent C difficile infection that is not severe. Saccharomyces boulardii 500 mg twice daily for 28 days in combination with oral vancomycin (500 mg 4 times daily for 10 days) was found to reduce recurrent infection.3 Alternatively, Lactobacillus GG (Culturelle) 1 to 2 capsules once daily for 10 days may also be effective.3 Probiotics should also not be prescribed to most patients for the prevention of CDAD. However, elderly patients without significant comorbidities may benefit if probiotics are initiated within 2 days of antibiotic therapy.3 Lactobacillus species in combination with other probiotics (Bifidobacterium bifidum and Streptococcus thermophilus) are the best studied for CDAD prophylaxis. Treat for 3 weeks, or until 1 week after stopping antibiotics. Finally, some evidence supports using probiotics to prevent and treat antibiotic-associated diarrhea not caused by C difficile infection. Multiple strains of probiotics are effective. However, for the treatment and prevention of CDAD, use proven regimens in carefully selected patients. Avoid probiotics in immunocompromised patients because of the small risk of bacteremia or fungemia. JAAPA REFERENCES 1. PL detail-document, proton pump inhibitors (PPIs) and C. difficile. Pharmacist’s Letter/Prescriber’s Letter. March 2012;28(3). 2. Weinhouse GL. Stress ulcer prophylaxis in the intensive care unit. Topic 1611; version 13.0. Updated April 8, 2011. Accessed April 19, 2012. 3. Davidson LE, Hibberd PL. Clostridium difficile and probiotics. Topic 2705; version 4.0. Updated March 24, 2011. Accessed April 19, 2012.

While there are many diabetes complications,

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

ONLY LYRICA IS RECOMMENDED AS LEVEL A by AAN evidence-based guideline for the treatment of painful diabetic neuropathy (PDN)1 “If clinically appropriate, pregabalin should be offered for the treatment of PDN (Level A).”1 The medical organizations that developed this guideline (the AAN, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation) recognize that specific care decisions are the prerogative of the patient and physician caring for the patient, based on all of the circumstances involved. For full guideline, visit Level A=Established as effective, based on at least 2 Class I studies. Class I level evidence includes a randomized, controlled clinical trial of the intervention of interest with masked or objective outcome assessment, in a representative population, and other specified criteria. AAN=American Academy of Neurology. LYRICA is indicated for the management of neuropathic pain associated with Diabetic Peripheral Neuropathy, management of Postherpetic Neuralgia, as adjunctive therapy for adult patients with Partial Onset Seizures, and management of Fibromyalgia. PBP01859A/291945-01

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© 2011 Pfizer Inc.

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

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

September 2011

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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



















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 1 0 1 3 2 0 Thinking abnormal† Tremor 1 1 1 2 1 0 Abnormal gait 1 0 1 3 1 0 Amnesia 3 1 0 2 1 0 Nervousness 0 1 1 1 1 0 Respiratory system Dyspnea 3 0 2 2 2 1 Special senses 3 1 3 6 4 2 Blurry vision‡ Abnormal vision 1 0 1 1 1 0 *PGB: pregabalin † Thinking abnormal primarily consists of events related to difficulty with concentration/attention but also includes events related to cognition and language problems and slowed thinking. ‡ Investigator term; summary level term is amblyopia. Other Adverse Reactions Observed During the Clinical Studies of LYRICA Following is a list of treatment-emergent adverse reactions reported by patients treated with LYRICA during all clinical trials. The listing does not include those events already listed in the previous tables or elsewhere in labeling, those events for which a drug cause was remote, those events which were so general as to be uninformative, and those events reported only once which did not have a substantial probability of being acutely life-threatening. Events are categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse reactions are those occurring on one or more occasions in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients. Events of major clinical importance are described in the Warnings and Precautions section. Body as a Whole – Frequent: Abdominal pain, Allergic reaction, Fever; Infrequent: Abscess, Cellulitis, Chills, Malaise, Neck rigidity, Overdose, Pelvic pain, Photosensitivity reaction; Rare: Anaphylactoid reaction, Ascites, Granuloma, Hangover effect, Intentional Injury, Retroperitoneal Fibrosis, Shock. Cardiovascular System – Infrequent: Deep thrombophlebitis, Heart failure, Hypotension, Postural hypotension, Retinal vascular disorder, Syncope; Rare: ST Depressed, Ventricular Fibrillation. Digestive System – Frequent: Gastroenteritis, Increased appetite; Infrequent: Cholecystitis, Cholelithiasis, Colitis, Dysphagia, Esophagitis, Gastritis, Gastrointestinal hemorrhage, Melena, Mouth ulceration, Pancreatitis, Rectal hemorrhage, Tongue edema; Rare: Aphthous stomatitis, Esophageal Ulcer, Periodontal abscess. Hemic and Lymphatic System – Frequent: Ecchymosis; Infrequent: Anemia, Eosinophilia, Hypochromic anemia, Leukocytosis, Leukopenia, Lymphadenopathy, Thrombocytopenia; Rare: Myelofibrosis, Polycythemia, Prothrombin decreased, Purpura, Thrombocythemia. Metabolic and Nutritional Disorders – Rare: Glucose Tolerance Decreased, Urate Crystalluria. Musculoskeletal System – Frequent: Arthralgia, Leg cramps, Myalgia, Myasthenia; Infrequent: Arthrosis; Rare: Chondrodystrophy, Generalized Spasm. Nervous System – Frequent: Anxiety, Depersonalization, Hypertonia, Hypesthesia, Libido decreased, Nystagmus, Paresthesia, Stupor, Twitching; Infrequent: Abnormal dreams, Agitation, Apathy, Aphasia, Circumoral paresthesia, Dysarthria, Hallucinations, Hostility, Hyperalgesia, Hyperesthesia, Hyperkinesia, Hypokinesia, Hypotonia, Libido increased, Myoclonus, Neuralgia; Rare: Addiction, Cerebellar syndrome, Cogwheel rigidity, Coma, Delirium, Delusions, Dysautonomia, Dyskinesia, Dystonia, Encephalopathy, Extrapyramidal syndrome, Guillain-Barré syndrome, Hypalgesia, Intracranial hypertension, Manic reaction, Paranoid reaction, Peripheral neuritis, Personality disorder, Psychotic depression, Schizophrenic reaction, Sleep disorder, Torticollis, Trismus. Respiratory System – Rare: Apnea, Atelectasis, Bronchiolitis, Hiccup, Laryngismus, Lung edema, Lung fibrosis, Yawn. Skin and Appendages – Frequent: Pruritus; Infrequent: Alopecia, Dry skin, Eczema, Hirsutism, Skin ulcer, Urticaria, Vesiculobullous rash; Rare: Angioedema, Exfoliative dermatitis, Lichenoid dermatitis, Melanosis, Nail Disorder, Petechial rash, Purpuric rash, Pustular rash, Skin atrophy, Skin necrosis, Skin nodule, Stevens-Johnson syndrome, Subcutaneous nodule. Special senses – Frequent: Conjunctivitis, Diplopia, Otitis media, Tinnitus; Infrequent: Abnormality of accommodation, Blepharitis, Dry eyes, Eye hemorrhage, Hyperacusis, Photophobia, Retinal edema, Taste loss, Taste perversion; Rare: Anisocoria, Blindness, Corneal ulcer, Exophthalmos, Extraocular palsy, Iritis, Keratitis, Keratoconjunctivitis, Miosis, Mydriasis, Night blindness, Ophthalmoplegia, Optic atrophy, Papilledema, Parosmia, Ptosis, Uveitis. Urogenital System – Frequent: Anorgasmia, Impotence, Urinary frequency, Urinary incontinence; Infrequent: Abnormal ejaculation, Albuminuria, Amenorrhea, Dysmenorrhea, Dysuria, Hematuria, Kidney calculus, Leukorrhea, Menorrhagia, Metrorrhagia, Nephritis, Oliguria, Urinary retention, Urine abnormality; Rare: Acute kidney failure, Balanitis, Bladder Neoplasm, Cervicitis, Dyspareunia, Epididymitis, Female lactation, Glomerulitis, Ovarian disorder, Pyelonephritis. Comparison of Gender and Race The overall adverse event profile of pregabalin was similar between women and men. There are insufficient data to support a statement regarding the distribution of adverse experience reports by race. Post-marketing Experience The following adverse reactions have been identified during postapproval use of LYRICA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Nervous System Disorders – Headache. Gastrointestinal Disorders – Nausea, Diarrhea. Reproductive System and Breast Disorders – Gynecomastia, Breast Enlargement. DRUG INTERACTIONS Since LYRICA is predominantly excreted unchanged in the urine, undergoes negligible metabolism in humans (<2% of a dose recovered in urine as metabolites), and does not bind to plasma proteins, its pharmacokinetics are unlikely to be affected by other agents through metabolic interactions or protein binding displacement. In vitro and in vivo studies showed that LYRICA is unlikely to be involved in significant pharmacokinetic drug interactions. Specifically, there are no pharmacokinetic interactions between pregabalin and the following antiepileptic drugs: carbamazepine, valproic acid, lamotrigine, phenytoin, phenobarbital, and topiramate. Important pharmacokinetic interactions would also not be expected to occur between LYRICA and commonly used antiepileptic drugs. Pharmacodynamics Multiple oral doses of LYRICA were co-administered with oxycodone, lorazepam, or ethanol. Although no pharmacokinetic interactions were seen, additive effects on cognitive and gross motor functioning were seen when LYRICA was co-administered with these drugs. No clinically important effects on respiration were seen. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C. Increased incidences of fetal structural abnormalities and other manifestations of developmental toxicity, including lethality, growth retardation, and nervous and reproductive system functional impairment, were observed in the offspring of rats and rabbits given pregabalin during pregnancy, at doses that produced plasma pregabalin exposures (AUC) ≥5 times human exposure at the maximum recommended dose (MRD) of 600 mg/day. When pregnant rats were given pregabalin (500, 1250, or 2500 mg/kg) orally throughout the period of organogenesis, incidences of specific skull alterations attributed to abnormally advanced ossification (premature fusion of the jugal and nasal sutures) were increased at ≥1250 mg/kg, and incidences of skeletal variations and retarded ossification were increased at all doses. Fetal body weights were decreased at the highest dose. The low dose in this study was associated with a plasma exposure (AUC) approximately 17 times human exposure at the MRD of 600 mg/day. A no-effect dose for

rat embryo-fetal developmental toxicity was not established. When pregnant rabbits were given LYRICA (250, 500, or 1250 mg/kg) orally throughout the period of organogenesis, decreased fetal body weight and increased incidences of skeletal malformations, visceral variations, and retarded ossification were observed at the highest dose. The no-effect dose for developmental toxicity in rabbits (500 mg/kg) was associated with a plasma exposure approximately 16 times human exposure at the MRD. In a study in which female rats were dosed with LYRICA (50, 100, 250, 1250, or 2500 mg/kg) throughout gestation and lactation, offspring growth was reduced at ≥100 mg/kg and offspring survival was decreased at ≥250 mg/kg. The effect on offspring survival was pronounced at doses ≥1250 mg/kg, with 100% mortality in high-dose litters. When offspring were tested as adults, neurobehavioral abnormalities (decreased auditory startle responding) were observed at ≥250 mg/kg and reproductive impairment (decreased fertility and litter size) was seen at 1250 mg/kg. The no-effect dose for pre- and postnatal developmental toxicity in rats (50 mg/kg) produced a plasma exposure approximately 2 times human exposure at the MRD. There are no adequate and well-controlled studies in pregnant women. Use LYRICA during pregnancy only if the potential benefit justifies the potential risk to the fetus. To provide information regarding the effects of in utero exposure to LYRICA, physicians are advised to recommend that pregnant patients taking LYRICA enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www. Labor and Delivery The effects of LYRICA on labor and delivery in pregnant women are unknown. In the prenatal-postnatal study in rats, pregabalin prolonged gestation and induced dystocia at exposures ≥50 times the mean human exposure (AUC (0–24) of 123 µg•hr/mL) at the maximum recommended clinical dose of 600 mg/day. Nursing Mothers It is not known if pregabalin is excreted in human milk; it is, however, present in the milk of rats. Because many drugs are excreted in human milk, and because of the potential for tumorigenicity shown for pregabalin in animal studies, decide whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and efficacy of pregabalin in pediatric patients have not been established. In studies in which pregabalin (50 to 500 mg/kg) was orally administered to young rats from early in the postnatal period (Postnatal Day 7) through sexual maturity, neurobehavioral abnormalities (deficits in learning and memory, altered locomotor activity, decreased auditory startle responding and habituation) and reproductive impairment (delayed sexual maturation and decreased fertility in males and females) were observed at doses ≥50 mg/kg. The neurobehavioral changes of acoustic startle persisted at ≥250 mg/kg and locomotor activity and water maze performance at ≥500 mg/kg in animals tested after cessation of dosing and, thus, were considered to represent long-term effects. The low effect dose for developmental neurotoxicity and reproductive impairment in juvenile rats (50 mg/kg) was associated with a plasma pregabalin exposure (AUC) approximately equal to human exposure at the maximum recommended dose of 600 mg/day. A no-effect dose was not established. Geriatric Use In controlled clinical studies of LYRICA in neuropathic pain associated with diabetic peripheral neuropathy, 246 patients were 65 to 74 years of age, and 73 patients were 75 years of age or older. In controlled clinical studies of LYRICA in neuropathic pain associated with postherpetic neuralgia, 282 patients were 65 to 74 years of age, and 379 patients were 75 years of age or older. No overall differences in safety and efficacy were observed between these patients and younger patients. In controlled clinical studies of LYRICA in fibromyalgia, 106 patients were 65 years of age or older. Although the adverse reaction profile was similar between the two age groups, the following neurological adverse reactions were more frequent in patients 65 years of age or older: dizziness, vision blurred, balance disorder, tremor, confusional state, coordination abnormal, and lethargy. LYRICA is known to be substantially excreted by the kidney, and the risk of toxic reactions to LYRICA may be greater in patients with impaired renal function. Because LYRICA is eliminated primarily by renal excretion, adjust the dose for elderly patients with renal impairment. DRUG ABUSE AND DEPENDENCE Controlled Substance LYRICA is a Schedule V controlled substance. LYRICA is not known to be active at receptor sites associated with drugs of abuse. As with any CNS active drug, carefully evaluate patients for history of drug abuse and observe them for signs of LYRICA misuse or abuse (e.g., development of tolerance, dose escalation, drug-seeking behavior). Abuse In a study of recreational users (N=15) of sedative/hypnotic drugs, including alcohol, LYRICA (450 mg, single dose) received subjective ratings of “good drug effect,” “high” and “liking” to a degree that was similar to diazepam (30 mg, single dose). In controlled clinical studies in over 5500 patients, 4% of LYRICA-treated patients and 1% of placebo-treated patients overall reported euphoria as an adverse reaction, though in some patient populations studied, this reporting rate was higher and ranged from 1 to 12%. Dependence In clinical studies, following abrupt or rapid discontinuation of LYRICA, some patients reported symptoms including insomnia, nausea, headache or diarrhea [see Warnings and Precautions, Abrupt or Rapid Discontinuation], suggestive of physical dependence. OVERDOSAGE Signs, Symptoms and Laboratory Findings of Acute Overdosage in Humans There is limited experience with overdose of LYRICA. The highest reported accidental overdose of LYRICA during the clinical development program was 8000 mg, and there were no notable clinical consequences. Treatment or Management of Overdose There is no specific antidote for overdose with LYRICA. If indicated, elimination of unabsorbed drug may be attempted by emesis or gastric lavage; observe usual precautions to maintain the airway. General supportive care of the patient is indicated including monitoring of vital signs and observation of the clinical status of the patient. Contact a Certified Poison Control Center for up-to-date information on the management of overdose with LYRICA. Although hemodialysis has not been performed in the few known cases of overdose, it may be indicated by the patient’s clinical state or in patients with significant renal impairment. Standard hemodialysis procedures result in significant clearance of pregabalin (approximately 50% in 4 hours). NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis A dose-dependent increase in the incidence of malignant vascular tumors (hemangiosarcomas) was observed in two strains of mice (B6C3F1 and CD-1) given pregabalin (200, 1000, or 5000 mg/kg) in the diet for two years. Plasma pregabalin exposure (AUC) in mice receiving the lowest dose that increased hemangiosarcomas was approximately equal to the human exposure at the maximum recommended dose (MRD) of 600 mg/day. A no-effect dose for induction of hemangiosarcomas in mice was not established. No evidence of carcinogenicity was seen in two studies in Wistar rats following dietary administration of pregabalin for two years at doses (50, 150, or 450 mg/kg in males and 100, 300, or 900 mg/kg in females) that were associated with plasma exposures in males and females up to approximately 14 and 24 times, respectively, human exposure at the MRD. Mutagenesis Pregabalin was not mutagenic in bacteria or in mammalian cells in vitro, was not clastogenic in mammalian systems in vitro and in vivo, and did not induce unscheduled DNA synthesis in mouse or rat hepatocytes. Impairment of Fertility In fertility studies in which male rats were orally administered pregabalin (50 to 2500 mg/kg) prior to and during mating with untreated females, a number of adverse reproductive and developmental effects were observed. These included decreased sperm counts and sperm motility, increased sperm abnormalities, reduced fertility, increased preimplantation embryo loss, decreased litter size, decreased fetal body weights, and an increased incidence of fetal abnormalities. Effects on sperm and fertility parameters were reversible in studies of this duration (3–4 months). The no-effect dose for male reproductive toxicity in these studies (100 mg/kg) was associated with a plasma pregabalin exposure (AUC) approximately 3 times human exposure at the maximum recommended dose (MRD) of 600 mg/day. In addition, adverse reactions on reproductive organ (testes, epididymides) histopathology were observed in male rats exposed to pregabalin (500 to 1250 mg/kg) in general toxicology studies of four weeks or greater duration. The no-effect dose for male reproductive organ histopathology in rats (250 mg/kg) was associated with a plasma exposure approximately 8 times human exposure at the MRD. In a fertility study in which female rats were given pregabalin (500, 1250, or 2500 mg/kg) orally prior to and during mating and early gestation, disrupted estrous cyclicity and an increased number of days to mating were seen at all doses, and embryolethality occurred at the highest dose. The low dose in this study produced a plasma exposure approximately 9 times that in humans receiving the MRD. A no-effect dose for female reproductive toxicity in rats was not established. Human Data In a double-blind, placebo-controlled clinical trial to assess the effect of pregabalin on sperm motility, 30 healthy male subjects were exposed to pregabalin at a dose of 600 mg/day. After 3 months of treatment (one complete sperm cycle), the difference between placebo- and pregabalintreated subjects in mean percent sperm with normal motility was <4% and neither group had a mean change from baseline of more than 2%. Effects on other male reproductive parameters in humans have not been adequately studied. Animal Toxicology and/or Pharmacology Dermatopathy Skin lesions ranging from erythema to necrosis were seen in repeated-dose toxicology studies in both rats and monkeys. The etiology of these skin lesions is unknown. At the maximum recommended human dose (MRD) of 600 mg/day, there is a 2-fold safety margin for the dermatological lesions. The more severe dermatopathies involving necrosis were associated with pregabalin exposures (as expressed by plasma AUCs) of approximately 3 to 8 times those achieved in humans given the MRD. No increase in incidence of skin lesions was observed in clinical studies. Ocular Lesions Ocular lesions (characterized by retinal atrophy [including loss of photoreceptor cells] and/or corneal inflammation/mineralization) were observed in two lifetime carcinogenicity studies in Wistar rats. These findings were observed at plasma pregabalin exposures (AUC) ≥2 times those achieved in humans given the maximum recommended dose of 600 mg/day. A no-effect dose for ocular lesions was not established. Similar lesions were not observed in lifetime carcinogenicity studies in two strains of mice or in monkeys treated for 1 year. LAB-0294-21.0 June 2011


© 2011 Pfizer Inc.

All rights reserved.

Dermatology Digest J OE R. M ONROE, PA-C , M PAS

FIGURE 1 Stellate scarring on the ankle

What caused this painful skin erosion? 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.

›CASE A 66-year-old woman was referred to dermatology for evaluation of striking changes to the skin of both ankles over the past year. On one side, the skin had begun to erode in a focal area, causing pain in the process. Pronounced purplishbrown livedoid hyperpigmentation covered the skin posterior to both malleoli. The lesions were totally nonblanchable by digital pressure, and both had extensive central stellate scarring overlying atrophic skin (Figure 1). On the right ankle, a 2.5-⫻1.5-cm superficial erosion was seen centrally. No erythema was present in or around the lesions. The patient was previously treated with oral ciprofloxacin (Cipro) 500 mg twice a day for 10 days without any effect. She had no history of connective tissue disease, joint pain, unexplained fever, or diabetes and denied any chronic swelling in her legs, feet, or ankles. She had never smoked. Previous laboratory findings were normal.

›THE MOST LIKELY DIAGNOSIS IS • Necrobiosis lipoidica diabeticorum • Venous insufficiency • Livedoid vasculopathy • Atrophie blanche ›DISCUSSION The correct answer is livedoid vasulopathy (LV), an unusual condition caused by localized thrombosis of unknown origin. Formerly called livedo reticularis, livedoid vasculopathy is often mistakenly called vasculitis. However, it is actually not an inflammatory condition because it lacks the nuclear dust and extravasated RBCs seen with true leukocytoclastic vasculitis. Rather, LV is a hyalinizing vascular disease characterized by segmental hyalinization, endothelial proliferation, and focal thrombosis of the dermal vessels. Until 1998, LV was thought to be a secondary phenomenon, perhaps resulting from primary conditions such as connective

20 JAAPA • MAY 2012 • 25(5) •

tissue disease. It is now known to be a primary diagnostic entity. The average age of presentation for LV is 45 years, with 71% of cases occurring in women. Livedoid vasulopathy can affect multiple areas. Bilateral lower extremity disease is present in 81% of cases; ulcers manifest in 70% of cases; and atrophie blanche is involved in 71% of cases. Biopsy will show intraluminal thrombosis in affected patients. The peculiar type of stellate scarring seen in this case, atrophie blanche (AB), is seen far more often in venous insufficiency, signs of which were missing in the patient. AB can be seen as an end point of a number of other conditions, including chronic superficial phlebitis and peripheral arterial insufficiency. Differential diagnosis Necrobiosis diabeticorum lipoidica, usually associated with diabetes, is sometimes mistaken for LV. However, it is more common on unilateral anterior tibial areas and does not involve purpura. Venous insufficiency (VI) is an extremely common problem that can cause hyperpigmentation of the lower legs and, in a minority of cases, localized erosions and ulcers that may result in stellate scarring. However, VI begins with and is ultimately caused by chronic edema of the legs. Atrophie blanche is a scar type, not a diagnosis. The differential for LV also includes lichen sclerosus et atrophicus and systemic sclerosis, both of which were effectively ruled out clinically. In this case, the health care team felt that the diagnosis was clear enough to forgo a biopsy, which has the potential to create a larger, deeper, nonhealing wound in this thinskinned and poorly vascularized area. Treatment Typically, pentoxifylline (Trental, generics) 400 mg 3 times a day, low-molecular-weight heparin, hyperbaric oxygen, and nifedipine (Adalat, Afeditab, Procardia, generics) are used to treat LV. This patient was given pentoxifylline and referred to the local wound care clinic to be treated with compression, elevation, and daily whirlpool use. JAAPA



Tobacco use, diabetes, and vaccines ›WHO SHOULD READ THIS? All PAs.

›WHY IS THIS IMPORTANT? Last fall, the National Committee for Quality Assurance (NCQA) released its annual State of Health Care Quality report, which provides a snapshot of health care quality in the United States. In the report, benchmarks for various indicators of preventive and chronic care are evaluated, using an evidence-based approach.1 The most recent iteration continues to stress improvement in multiple domains of chronic and preventive health care. Highlighted in this article are three clinical conditions that impact patient care across the life span: type 2 diabetes mellitus (T2DM), tobacco cessation counseling, and immunizations. US health care providers adhere to evidence-based guidelines in 55% of patient encounters, and patients currently receive approximately 50% of the recommended preventive services.2,3 Barriers include insufficient time, inadequate reimbursement, and limited access to portable medical records.2 High-quality chronic patient care is further hindered by the fragmented health care system.2 The application of health information technology (HIT), including electronic health records (EHRs) and clinical decision support (CDS), shows promise in improving health care quality and patient outcomes. Examples of how HIT can be incorporated into clinical practice to

potentially improve preventive and chronic patient care include decision support based on evidence-based guidelines; incorporation of electronic reminders for patients and health care providers; and access to comprehensive, portable medical records.2

›WHAT DOES THE NCQA REPORT SAY? Type 2 diabetes mellitus Identified as the seventh leading cause of death in the United States and the leading cause of kidney failure, T2DM has been diagnosed in nearly 26 million Americans.4,5 An additional 79 million adults have prediabetes, which is recognized as a risk factor in the development of both diabetes and cardiovascular disease.4,6 Glycosylated hemoglobin (A1C) is the recommended biomarker for assessing glycemic control over the previous 3 months.6 Patients with A1C levels between 6.0% and 6.5% have a 10-fold higher risk of diabetes than those with a lower A1C and should receive patientcentered counseling on weight control, diet, and physical activity.6 According to the NCQA, A1C screening practices among health care providers have improved in the past 10 years, yet between 10% and 20% of patient cases remain overlooked annually.1 In 2010, of those patients with diabetes who did receive screening, up to 46% demonstrated poor glycemic control, with an A1C greater than 9%.1 In addition to pharmacologic TAKE-HOME POINTS ■ Approximately 50% of patients

receive the recommended preventive services. ■ PAs are encouraged to practice using evidence-based guidelines. ■ Health information technology has potential to facilitate evidence-based practice.

intervention, medical nutrition therapy (MNT) and education on diabetes self-management are key evidencebased components of prevention and management plans. Medical nutrition therapy demonstrates reductions in both A1C and LDL cholesterol, particularly when clinical nutritionists are incorporated into the health care team. Education on diabetes selfmanagement empowers patients in a collaborative decision-making process that leads to reductions in A1C, weight, and health care costs.6 In managing patients with diabetes, HIT has the potential to provide support across multiple domains, including portable health information (eg, exchange of information with other providers, hospitals, and laboratories), application of evidence-based guidelines, and prompting patients to complete routine screening tests.2 Tobacco Approximately 440,000 deaths occur annually secondary to tobacco use or secondhand smoke, and 45 million US adults currently smoke.7,8 Nicotine has chemical dependency prevalence rates higher than those of any other substance.7 Finally, tobacco use continues to be the leading cause of preventable death in the United States.8 Fewer than 5% of patients are successful in attempts to quit smoking, even with the help of health care providers.7,9 According to the NCQA, the intervention rates of health care providers have improved over the past 10 years. Nonetheless, between 65% and 74% of patients who smoke receive counseling, which indicates the need for further improvement.1 Continued on page 22 This article was written by Anthony E. Brenneman, MPAS, PA-C, and Alison C. Essary, MHPE, PA-C (chair, CHAC). Contributors included the other members and staff of CHAC 2011-2012; Gilbert Boissonneault, PhD, PA-C; Thomas Moreau, PA-C, MS; Folusho Ogunfiditimi, PA-C; and Marie-Michèle Léger, MPH, PA-C. • MAY 2012 • 25(5) • JAAPA


Clinical Watch “To date, approximately 50% of office-based practices use any type of EHR, with only 10% using a comprehensive system.” HIT may be incorporated within the framework of counseling patients on lifestyle changes, including tobacco use. Patient decision aids and electronic reminders offer the necessary tools to support patients. Patient decision aids are educational materials used to communicate evidence-based information and ease the medical decision-making process. Decision aids have demonstrated promising data in improving patient outcomes, including tobacco cessation.10 Health care providers can also implement electronic reminders in advance of the patient visit, increasing the likelihood that they will ask about tobacco use at each office visit. Immunizations The most costeffective mechanism to reduce morbidity and mortality is immunization.11,12 Overall immunization rates have slowly increased over the past 10 years, although many have stalled or decreased in the past 5 years, likely a result of misconceptions about efficacy or side effects.1 In the pediatric patient population, nearly 40% of parents delay or refuse at least one recommended immunization.11 Adults also need to be encouraged to maintain current immunizations, particularly the influenza vaccine and, when appropriate, the pneumococcal vaccine. According to the NCQA report, only 52% of adults older than 65 years receive the recommended influenza vaccine.1 Compliance with adult immunization recommendations may be enhanced through the use of HIT-generated reminders for both health care providers and patients.

›WHAT’S NEW? The NCQA report illustrates the need for quality improvement among health care providers and the patients they serve, and HIT has been touted as one potential solution to improving patient care in the United States.1 Health information technology is broadly defined as including EHRs, personal health records, and health information exchange portals. Electronic health records may also include CDS systems, metrics, and documentation that support these meaningful-use endeavors. The potential exists within these systems to facilitate real-time patient care, including application of current guidelines, use of decision aids, and recommended treatment options.2 To date, approximately 50% of office-based practices use any type of EHR, with only 10% using a comprehensive system. Similarly, approximately 12% of hospitals report using a comprehensive EHR.3

›WHAT ELSE IS IMPORTANT TO KNOW? Our health system poorly incorporates supportive, evidence-based tools that have demonstrable effect in improving patient care.13 In addition, the health care system merits improvement in managing chronically ill patients who transition over multiple systems SEE THE ONLINE VERSION OF THIS ARTICLE TO LINK TO Sidebar: Implementing individual electronic health records

of care.13 The literature supports an ongoing research agenda for HIT, particularly in areas where data are mixed, such as patient outcomes and patient safety.14 JAAPA Acknowledgment The authors would like to thank Richard Rohrs, PA-C, and Kevin M. Schuer, MPH, PA-C, for their review of the manuscript.

REFERENCES 1. National Committee for Quality Assurance (NCQA). Continuous Improvement and the Expansion of Quality Measurement. The State of Health Care Quality 2011. http:// tabid=836. Published 2011. Accessed April 3, 2012. 2. Shih SC, McCullough CM, Wang JJ, et al. Health information systems in small practices. Am J Prev Med. 2011;41(6):603-609. 3. Institute of Medicine. Health IT and Patient Safety: Building Safer Systems for Better Care. Washington, DC; The National Academies Press: 2012. 4. Number of Americans with diabetes rises to nearly 26 million [news release]. Atlanta, GA: Centers for Disease Control and Prevention; January 26, 2011. releases/2011/p0126_diabetes.html. Accessed April 3, 2012. 5. Kidney Disease of Diabetes, National Kidney and Urologic Diseases Information Clearinghouse, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDKD). aspx. Accessed April 3, 2012. 6. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2012;35(suppl 1):S64-S71. 7. US Department of Health and Human Services, Office of the Surgeon General. How tobacco smoke causes disease: the biology and behavioral basis for smoking-attributable disease: a report of the surgeon general. http://www. html. Accessed April 3, 2012. 8. Vital signs: current cigarette smoking among adults aged ≥18 years—United States, 2005-2010. Centers for Disease Control and Prevention Web site. preview/mmwrhtml/mm6035a5.htm?s_cid=%20mm6035a5. htm_w Accessed April 3, 2012. 9. Fiore MC, Jaén CR, Bailey WC. A clinical practice guideline for treating tobacco use and dependence: 2008 update: A U.S. Public Health Service Report. Am J Prev Med. 2008;35(2):158-176. 10. Agency for Healthcare Research and Quality. Innovation profile: culturally appropriate, interactive decision aid yields high quit rates among underserved, low-literacy Latino and Hispanic smokers. http://www.innovations.ahrq. gov/content.aspx?id=3254. Published September 28, 2011. Updated September 28, 2011. Accessed April 3, 2012. 11. Centers for Disease Control and Prevention. An ounce of prevention: what are the returns? Second edition. ftp://ftp. Revised October 1999. Accessed April 3, 2012. 12. Rappuoli R, Miller HI, Falkow S. Medicine. The intangible value of vaccination. Science. 2002;297(5583):937-939. 13. Berwick DM. What “patient-centered” should mean: confessions of an extremist. Health Aff (Millwood). 2009;28(4):w555-w565. 14. Romano MJ, Stafford RS. Electronic health records and clinical decision support systems: impact on national ambulatory care quality. Arch Intern Med. 2011;171(10):897-903.

Tell us what you think! Go to to comment on this article. 22 JAAPA • MAY 2012 • 25(5) •

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


Knowledge of the likely pathogens is key


urgical site infection (SSI) is a common postoperative complication1 estimated to occur in 5% of the nearly 30 million surgeries performed each year.2 SSI accounts for 14% to 17% of all hospital-acquired infections and roughly 38% of hospitalacquired infections in surgical patients.2 The results of SSI include prolonged hospitalization, delayed healing, increased health care costs, and serious adverse events. In a survey of general and vascular surgery patients, SSIs on average increased the length of hospital stay by 4.3 days and attributed costs by more than $10,497.3 In the United States, adverse events associated with SSIs are estimated to result in 8,200 deaths annually,4 at a cost of about $10 billion.5

›TYPES OF SSI The three types of surgical site infection are superficial incisional SSI, deep incisional SSI, and organ/space SSI. Superficial incisional SSI involves the subcutaneous space between the skin and muscular fascia. Typically, these infections exhibit at least one of the following: (1) local signs and symptoms of pain or tenderness, swelling, and erythema; (2) purulent drainage from the surgical incision; and/or (3) positive results on culture obtained from fluid or tissue from the incisional wound. Superficial incisional SSI usually manifests within 30 days after the surgical procedure. Deep incisional SSI involves the deep soft tissue layers of fascia and muscle, manifests with the same clinical findings as superficial incisional SSI, and also occurs within

30 days of the operation; however, some deep incisional SSIs may appear up to 1 year later if a prosthetic device was placed at the time of surgery. Organ/space SSI can involve any organ or space other than the surgical skin incision; the time to manifestation is the same as that of deep-tissue SSI. Organ/ space SSIs are treated separately as an infection of each specific organ or space involved. Any deep incisional SSI that does not resolve after appropriate treatment should be worked up as a possible organ/space SSI.1

›SIGNS AND SYMPTOMS Surgical site infection is often associated with fever, but this typically does not occur during the first 48 hours postoperatively. Those few infections that do manifest with clinical evidence of soft tissue infection and fever within 48 hours are usually due to Streptococcus pyogenes or Clostridium species. These infections will produce wound drainage and involve organisms identifiable on Gram stain. Rarely, early postoperative fever with systemic signs is due to toxic shock syndrome secondary to staphylococcal wound infection. Most SSIs will

TAKE-HOME POINTS ■ Surgical site infection (SSI) is a

common complication of surgical procedures. ■ Most SSIs are monomicrobial infections due to Staphylococcus aureus. ■ Polymicrobial infections with grampositive and gram-negative microorganisms, with or without yeast, are not uncommon.

be asymptomatic for at least 5 days and often without clinical manifestations for up to 2 weeks. The primary treatment for SSI is surgical incision and drainage of infected fluid and/or removal of infected tissue or material. Whether to treat an SSI with antimicrobial agents depends on the severity and location of the infection and the local susceptibility/resistance patterns of pathogens isolated at the hospital or facility.1

›MONOMICROBIAL INFECTIONS Single organisms often cause SSI, with gram-positive species being the most frequently identified causative agents. Among gram-positive organisms, Staphylococcus aureus is the predominant pathogen, especially if the surgical procedure was a clean operation that did not enter the abdomen or genital tract. Other gram-positive organisms, such as coagulase-negative Staphylococcus, Enterococcus, and Streptococcus species, are involved less frequently.6 Among S aureus isolates, increasing antimicrobial resistance has resulted in more SSIs due to methicillin-resistant S aureus (MRSA) than to methicillin-sensitive S aureus (MSSA), with concerns that MRSA is associated with poorer outcomes.2 Gram-negative species, predominantly the enteric gram-negative rods, including Pseudomonas aeruginosa and the Enterobacteriaceae family, such as Escherichia coli, Klebsiella and Enterobacter species, and Proteus mirabilis, can occur as the monomicrobial pathogen, particularly in surgeries involving the perineum or axilla.6 In addition to enteric gram-negative 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. • MAY 2012 • 25(5) • JAAPA


Topics in Infectious Diseases “Antimicrobial prophylaxis to prevent SSIs is tailored to the surgical procedure and the overall risk factor assessment of the patient.” rods, anaerobic bacteria, such as Peptostreptococcus, Propionibacterium, Prevotella, Veillonella, Bacteroides, and Clostridium species, can cause SSI in head, neck, or chest surgeries.7 Finally, yeast, such as Candida albicans, occasionally causes monomicrobial SSI.2

›POLYMICROBIAL INFECTIONS Often overlooked is the possibility that surgical site infection is polymicrobial in nature. SSIs of the head, neck, and chest are frequently polymicrobial because of the abundance of mixed aerobic and anaerobic flora in the oropharyngeal regions and surgical site exposure to oropharyngeal flora.7 Anaerobic bacteria can be difficult to culture, especially if the infected fluid or tissue is not processed in a timely and appropriate manner; hence, anaerobes should be suspected as contributors to SSIs in tissues where they reside as normal flora, such as the oropharyngeal cavity, axilla, perineum, and GI tract.8 A good example is illustrated by results seen with percutaneous endoscopic gastrostomy (PEG) tube placement in cancer patients.9 PEG tube placement is frequently used for longterm enteral access in patients who are unable to swallow.10 Polymicrobial infection was noted to occur in 47% of all PEG SSIs examined in 78 cancer patients. Seventy-eight distinct microorganisms were isolated from 27 different patients. Culture results showed that five different microorganisms were isolated from one patient, four microorganisms from three patients, and two or three microorganisms from 23 patients. Gram-positive organisms were present in 34% of polymicrobial SSIs, with MSSA being the most common isolate. In addition to bacterial pathogens, yeast

of the Candida species can be a component of the polymicrobial SSI.9

›ANTIMICROBIAL PROPHYLAXIS Antimicrobial prophylaxis (AP) to prevent SSIs is tailored to the surgical procedure and the overall risk factor assessment of the patient. Risk factors include patient age; nutritional, smoking, glucose control, and immunosuppression status; presence of coexisting remote-site infections; colonization with known pathogenic microorganisms; and length of preoperative stay. Ideally, an AP agent should be bactericidal, nontoxic, and inexpensive, and it should have activity against common microorganisms known to cause infection after a given procedure. The choice of perioperative AP agents is typically directed against gram-positive microorganisms that comprise the normal skin flora, such as staphylococci and streptococci. Addition of a gram-negative antimicrobial agent is warranted if surgery involves perforation of a hollow viscus organ. Antimicrobial prophylaxis should be discontinued within 24 hours after surgery termination. The one exception may be cardiothoracic surgery, in which some patients benefit from AP extended to 48 hours.11 Recent changes in perioperative AP reflect the increasing need to cover resistant organisms, such as MRSA, and other microbial flora with the potential for causing polymicrobial SSI. In the past, a first-generation cephalosporin, such as cefazolin (Ancef, Kefzol, generics), was given preoperatively 1 hour prior to skin incision. Depending upon prevalence within the community or medical

28 JAAPA • MAY 2012 • 25(5) •

facility, attention should now focus on targeted prophylaxis against MRSA and gram-negative pathogens, when indicated. In general, broad-spectrum antimicrobial agents, such as carbapenems, should be avoided.11 The potential for polymicrobial SSI justifies considering the use of broader AP. SSI is the most common complication of breast cancer surgery, and 31% of these infections are polymicrobial.12 As was seen with surgical site infections of the PEG tube in cancer patients, MSSA is the most common gram-positive organism found in polymicrobial SSIs in breast cancer patients. A multi-institutional study of 97 hospitals with culture-confirmed SSIs demonstrated that about 33% of all SSIs were polymicrobial.2 When a polymicrobial SSI is anticipated, initial broad-spectrum AP congruent with antimicrobial stewardship surveillance data can be used until culture results justify de-escalation to a narrower spectrum agent.12 JAAPA REFERENCES 1. Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Infect Dis. 2005;41(10):1373-1406. 2. Weigelt JA, Lipsky BA, Tabak YP, et al. Surgical site infections: causative pathogens and associated outcomes. Am J Infect Control. 2010;38(2):112-120. 3. Boltz MM, Hollenbeak CS, Julian KG, et al. Hospital costs associated with surgical site infections in general and vascular surgery patients. Surgery. 2011;150(5):934-942. 4. Klevens MR, Edwards JR, Richards CL Jr, et al. Estimating health care-associated infections and deaths in U.S. hospitals, 2002. Public Health Rep. 2007;122(2):160-166. 5. Scott RD II. The Direct Medical Costs of Healthcare-Associated Infections in U.S. Hospitals and the Benefits of Prevention. Published March 2009. Accessed April 11, 2012. 6. Anderson DJ. Surgical site infections. Infect Dis Clin North Am. 2011;25(1):135-153. 7. Brook I. Microbiology and management of post-surgical wounds infection in children. Pediatr Rehabil. 2002;5(3):171-176. 8. Brook I. Antimicrobial treatment of anaerobic infections. Expert Opin Pharmacother. 2011;12(11):1691-1707. 9. Rolston KV, Mihu C, Tarrand JJ. Current microbiology of percutaneous endoscopic gastrostomy tube (PEG tube) insertion site infections in patients with cancer. Support Care Cancer. 2011;19(8):1267-1271. 10. Gauderer MW. Percutaneous endoscopic gastrostomy and the evolution of contemporary long-term enteral access. Clin Nutr. 2002;21(2):103-110. 11. Enzler MJ, Berbari E, Osmon DR. Antimicrobial prophylaxis in adults. Mayo Clin Proc. 2011;86(7):686-701. 12. Rolston KV, Mihu C, Tarrand JJ. Current microbiology of surgical site infections associated with breast cancer surgery. Wounds. 2010;22(5):132-135.

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Two Asleep By Christopher Wright

Blue Healer By Marti Trunnell My task laid out before me It daunts And haunts Yet beckons. I pound this sum of spirit In to data bytes I reckon. Squeeze their stories in to these boxes Pound round pegs in to square holes. This prime directive, at odds with my own: “Objectify this soul.” Data cannot begin to convey Despair within these eyes Data can but byte this hand Where is the compromise? Cool touch of hand to burning brow Cool hope for heated doubt This fire of spirit burning here “Step back. I’ll put it out.” I’ll go and fetch my pitcher Pour a soothing draft; It can then be said, As they depart, “For a moment there, I laughed.”

POETS: Krista Wark Rogaski, MS, PA-C, Department of General and Trauma Surgery, Jersey City Medical Center, Jersey City, New Jersey. Marti Trunnell, RN, PA-C, Intermountain Health Care, South Sandy Clinic, Sandy, Utah. Christopher Wright, BA, secondyear student, Rosalind Franklin University of Medicine and Science PA program, North Chicago, Illinois. JUDGES: Alexandra Godfrey, MS, PA-C, and Brian T. Maurer, PA-C, JAAPA editorial board; Sarah Zarbock, PA-C, JAAPA editor in chief, 2003-2011.

Daylight lit him poorly by the window; a grey cloak hefted over him and his hands, fingering yellowed pages of some treasured story, looked tired and cracked consigned now to less industrial tasks. He fell asleep soon enough, His book butterflied near the foot of her hospital bed He’d found once, behind their home after a storm, the top of a spruce tree “A few hundred feet and we’d be visiting the gates,” he would tell her. She would nod, of course, and flit a idle roll across her eyes. He would kiss her cheek, and their fingers would ravel and knot together like pink wooden roots In under a month he had fashioned the spruce top into a great, clunky table. “Ninety two years”. He’d accounted for each whorl in blue ink on the skin of his calf, and she had helped him tally the age. The table was at home, boorish but beguiling and Underneath, their names scrawled black in charred letters “Purple hydrangeas for her bedside table” he thought, after driving home for a pillow, -that red and yellow quilt she had made and his book of course “A few more days” “She’s on the mend” “Go home now. Get rest. She’ll thank you for it.” He stayed. His home was here. The proper trimmings could be felt like scent on an overcoat or a quilt, or a book Conversations too those without words, spoken by gestures of heaving breath and the hours that accumulate between two sleeping bodies Their Illness was shared and burden parceled out scattered like crumbled bark, like kitchen sweepings, like fallen limbs and the tops of trees


EARN CATEGORY I CME CREDIT by reading this article and the article beginning on page 58 and successfully completing the posttest on page 63. 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 May 2012.


List key aspects of the history, physical examination, and workup that can accurately diagnose acute appendicitis Recognize the most common and major complications of acute appendicitis Describe medical management for selected patients with acute appendicitis

Acute appendicitis: Can antibiotics ever take the place of surgery? Antibiotic therapy eliminates postoperative complications and lowers costs, but the methodology of some studies may be weak and the rate of recurrence is high.

Ben V. Christensen, MHS, PA-C; Dawn Colomb-Lippa, MHS, PA-C

32 JAAPA • MAY 2012 • 25(5) •

© Mike Austin


cute appendicitis was first described in the United States more than 100 years ago by Reginald Fitz, who recognized that early diagnosis and prompt surgical treatment were essential to prevent potentially detrimental complications.1 Today, appendectomy is still considered the gold standard for treatment of acute appendicitis.2 This condition affects more than 300,000 Americans annually and is one of the most common reasons for emergent surgery in the United States.3 As early as the 1950s, however, medical management with antibiotic therapy was shown to be a successful alternative treatment for acute appendicitis in certain patients. In 1959, Coldrey reported on 471 patients with acute appendicitis who had been effectively treated with penicillin, streptomycin, chloramphenicol, or Terramycin.4 More recently, a randomized clinical trial demonstrated a success rate of 90.8% in the treatment of specific patients with acute appendicitis using combination IV and oral antibiotics.5 The study, which was conducted in Sweden, also reported decreased costs.5 Why, then, do most clinicians see surgery as the best management approach for appendicitis? Is medical management ever an acceptable therapy for appendicitis? When do the benefits of medical management outweigh the risks? Furthermore, are outcomes better and complications fewer with medical management than with appendectomy? This article reviews the diagnosis and treatment of acute appendicitis and evaluates whether conservative medical management is a realistic, safe, and viable alternative when surgery may not be an option.

FIGURE 1. Acute appendicitis


Males are affected more often than females by appendicitis, with an estimated male-to-female ratio of 1.4:1. Approximately 1 in every 1,000 hospital discharges is associated with a diagnosis of appendicitis. Appendicitis has burdened patients in a wide age range. In the United States in 2007, 45% (149,000) of those with this diagnosis were between 15 and 44 years old.3 Patients younger than age 15 years accounted for approximately 24% (71,000) of patients with appendicitis, and those older than 65 years accounted for approximately 9% (27,000).3 Occlusion of the appendiceal lumen is believed to be the main etiologic mechanism of acute appendicitis (Figure 1). A variety of different agents may be involved, including feces (fecolith); parasites; enlarged lymph tissue; inflammatory lesions; and, rarely, neoplasms. However, obstruction of the appendiceal lumen does not account for all cases of appendicitis. Another hypothesis suggests that acute appendiceal inflammation may be due to infection with Yersinia organisms, since a high volume of antibodies against these bacteria have been associated with confirmed cases of appendicitis.6 Once the lumen of the appendix is obstructed, the intestinal mucus that continues to be produced has nowhere to drain. Eventually, the blood supply to the appendix is cut off and intestinal bacteria are allowed to proliferate, leading to inflammation and swelling. Without treatment, the inflamed appendix may become necrotic (gangrenous) and prone to perforation. This inevitably causes spillage of intestinal contents into the peritoneum, and life-threatening peritonitis may ensue.6 CLINICAL PRESENTATION

While the diagnosis of acute appendicitis is mainly clinical, no one sign or symptom is synonymous with this disease. Instead, multiple signs and symptoms are involved.7 The classic presentation of acute appendicitis includes onset of symptoms within 24 to 48 hours of appendiceal inflammation. New-onset periumbilical pain may or may not eventually migrate to the right lower quadrant. The patient may complain of a decrease in appetite, nausea, vomiting, and less commonly, diarrhea and constipation. However, these classic signs are not found in all cases, with women experiencing variation in signs and symptoms more often than men.8

Physical examination may reveal pain located in the right lower quadrant or, more specifically, at a point one-third of the way between the anterior superior iliac spine and the umbilicus (McBurney point). Patients may also have a positive Rovsing sign, which is right lower-quadrant pain on palpation of the left lower quadrant. In some cases, patients will have pain when the underlying obturator or psoas muscles are stretched.6,7 According to Laméris and colleagues, migration of pain from the epigastric area to the right lower quadrant along with right lower-quadrant tenderness and a rigid abdomen are among the most definitive diagnostic signs and symptoms.8 DIFFERENTIAL DIAGNOSIS

The differential diagnosis of acute appendicitis includes essentially any condition that can cause an acute abdomen. Some of the primary causes of acute abdomen that might be confused with acute appendicitis include

“In certain ‘less severe’ cases of suspected appendicitis, antibiotic treatment may be considered a realistic alternative to surgery.” small-bowel obstruction, acute cholecystitis, pancreatitis, pyelonephritis, gastroenteritis, ovarian torsion, and pelvic inflammatory disease.7 The differential for acute appendicitis may seem daunting, but a through history and physical examination will aid clinicians in finding the appropriate diagnosis. WORKUP

Just as the presentation of acute appendicitis is multifactorial, no solitary test is the test of choice for acute appendicitis, nor is one sign or symptom diagnostic of the disease. Using the previously discussed clinical signs, along with laboratory and radiologic information, the clinician can home in on a diagnosis. The workup should include a CBC; a recent retrospective study discovered that 80% of patients with confirmed appendicitis had an increased WBC count.8 Based on the values obtained from the CBC, such as the WBC count, along with other determinations, such as the C-reactive protein

KEY POINTS ■ Acute appendicitis is the most common reason for surgery in the United States. ■ Because acute appendicitis can be difficult to detect, practitioners should combine the history, physical findings, and results of tests to

help with the diagnosis. ■ Although conservative management with antibiotics has been proven to be successful since the 1950s, the recurrence rate demon-

strated in more recent studies is fairly high. ■ Surgical appendectomy is still the gold standard of treatment for acute appendicitis. • MAY 2012 • 25(5) • JAAPA


CME Appendicitis (CRP) level, which may be elevated , a diagnosis of acute appendicitis can be considered either likely or highly unlikely. However, medicine is rarely so black and white. When the signs, symptoms, and laboratory data indicate uncertainty, a quantitative scoring system can be used. One such system is the Alvarado score, which combines components of the patient history, physical examination, and laboratory data, assigning points for each component: • Anorexia, 1 point • Elevated temperature (37.3°C or higher), 1 point • Leukocytosis (WBC count >10,000/µL), 2 points • Migration of pain to the right iliac fossa (right lower quadrant), 1 point • Nausea and/or vomiting, 1 point • Rebound tenderness, 1 point • Shift of differential to the left (more than 75% neutrophils), 1 point • Tenderness to palpation in the right iliac fossa (right lower quadrant), 2 points.9 The higher the score, the more likely the patient is to have acute appendicitis (Table 1).9 Other diagnostic testing may include abdominal CT. Currently, the routine use of abdominal CT for suspected acute appendicitis is controversial because such imaging may increase exposure to radiation and, when contrast is used, can lead to possible renal damage or anaphylactic reaction.10 That being said, CT may be done more often than not in order to prevent the possibility of legal action. One could also perform an ultrasound (US) examination to look for general loss of peristalsis; however, the sensitivity of US is lower than that of CT and depends on the experience of the operator.7 Even with the patient history, physical examination, and laboratory and radiologic data, the most experienced clinician may miss a diagnosis of acute appendicitis. Therefore, the recommendation is to use multiple modalities that have been found to be safe and necessary to diagnose the pathology.8 SURGICAL TREATMENT

The gold standard of treatment for acute appendicitis is appendectomy in order to prevent detrimental outcomes resulting from possible perforation.1,2 Patients should receive nothing by mouth for at least 6 to 12 hours prior to surgery, and they should be given IV hydration and analgesia. As with many surgical procedures, antibiotics are given before operation to reduce the chance of postoperative wound infection.11 Appendectomy is achieved by one of two methods. The first method is the so-called open appendectomy, which is performed through an opening at the McBurney point. The second method is the laparoscopic approach; it utilizes smaller incisions through which a camera, graspers, and cautery may be inserted. Of the two methods, laparoscopy has become standard of care in most operative cases.7 Complications Perforation of the appendix as a result of untreated appendiceal inflammation is the most prominent complication of appendicitis.6 Subsequent spillage may result in peritonitis, which may, in turn, be fatal. Therefore, 34 JAAPA • MAY 2012 • 25(5) •

TABLE 1. Likelihood of appendicitis based on the Alvarado score9 Diagnosis of appendicitis








Very probable


the threshold to treat suspected appendicitis is low. This low threshold has resulted in an overall mortality rate for acute appendicitis in the United States of approximately 0.1%.9 Among the possible intraoperative complications is allergic reaction to drugs, including malignant hyperthermia. As with other surgeries, postoperative complications may include wound infection, atelectasis, deep venous thrombosis (DVT), and postoperative fever.12 One study found major complications, which included reoperation, abscess formation, and small-bowel obstruction, to be three times higher in patients undergoing appendectomy than in those receiving medical management with antibiotics.5 Prognosis Once symptoms begin, prompt diagnosis and treatment will influence patient outcome. Any delay allows increased inflammation and therefore raises the risk of perforation. One study illustrated that perforation rates come close to 10% at 24 hours after onset of symptoms.13 However, differences in morbidity rates do not appear to be clinically relevant when comparing treatment initiated within 6 hours to treatment initiated within 24 hours.14 One must also keep in mind that recurrence rates for patients treated conservatively with antibiotics range from 15% to 35%.5,15 Even with the threat of perforation, the prognosis of a patient with acute appendicitis is believed to be excellent if treatment is initiated early. ANTIBIOTIC THERAPY: A REALISTIC ALTERNATIVE?

Whether nonsurgical antibiotic treatment for acute appendicitis is a realistic alternative is the subject of much debate among some medical clinicians. Advocates of conservative treatment with antibiotics argue that it could help reduce cost and eliminate surgical complications.5 Opponents point out that the risk of recurrence after antibiotic treatment may be too high, reaching 35% in one study.15 Although antibiotic therapy for the treatment of acute appendicitis is not a new idea, it has been met with skepticism in the medical and surgical communities.7 Earlier studies were of meager design and retrospective in nature, but in the mid-1990s, study design improved.2 Eriksson and colleagues conducted the first randomized study evaluating antibiotic therapy versus appendectomy for the treatment of acute appendicitis.15 This study was then followed by two other notable randomized trials analyzing treatment with antibiotics compared with appendectomy.2,5,16 In all three studies, patients with suspected appendicitis, based on CRP level, WBC count, US, and/or CT, were randomized to treatment with either appendectomy or

TABLE 2. Intravenous and oral antibiotic regimens for appendicitis2 Study

IV antibiotic regimen

Oral antibiotic regimen

Eriksson et al (1995)15

Cefotaxime 2 g every 12 h plus imidazole 800 mg daily, both given for 2 d

Ofloxacin 200 mg 2 times daily plus tinidazole 500 mg 2 times daily for 8 d

Hansson et al (2009)5

Cefotaxime 1 g 2 times daily plus metronidazole 1.5 g once for at least 24 h

Ciprofloxacin 500 mg 2 times daily plus metronidazole 400 mg 3 times daily for 10 d

Styrud et al (2006)16

Cefotaxime 2 g every 12 h plus imidazole 800 mg daily, both given for 2 d

Ofloxacin 200 mg 2 times daily plus tinidazole 500 mg 2 times daily for 10 d

antibiotic therapy consisting of IV cefotaxime and a nitroimidazole, followed by 8 to 10 days of a fluoroquinolone and a nitroimidazole (Table 2).2 A meta-analysis of these studies illustrated that 68% of patients with a presumed diagnosis of acute appendicitis were successfully treated with antibiotic therapy alone, consistent with the theory that up to 70% of patients with appendicitis may be successfully treated in this way.14 All three studies combined for a recurrence rate of 15%.2 Antibiotic therapy was shown to have a 1.8% better treatment efficacy compared with surgery, which had a treatment success rate of 90.2%. Moreover, when compared with surgery, antibiotic management decreases the risk of major complications by one-third and reduces treatment costs by one-half.5 Another randomized study found that conservative treatment led to decreased pain when compared with surgical treatment.17 Note that for patients presenting with an appendiceal mass (abscess), antibiotic therapy is currently viewed as the primary treatment, followed by appendectomy to prevent recurrence of the mass or acute appendicitis.18 Recurrence rates in patients who had an appendiceal mass treated with antibiotics are similar to those of patients without a mass who received antibiotic therapy.2 Results with antibiotic treatment are promising. However, each of the retrospective studies had weaknesses. The Eriksson study had only 40 participants and an overall recurrence rate reaching 35%.15 In addition, the follow-up period was only 1 month.15 Another study, conducted by Styrud and colleagues, excluded women participants, in accordance with a decision made by an ethics committee.16 Women may have been excluded because the diagnosis of acute appendicitis in women is sometimes more difficult than diagnosis in men.8 In the most recent randomized study, by Hansson and colleagues, long-term follow-up was not by clinical examination but instead via a questionnaire or a telephone interview.5 Additionally, the two most recent randomized trials (those led by Styrud and Hansson) had a high “crossover rate”; that is, certain patients who were

initially assigned to antibiotic therapy were converted to the surgery group if either the surgeon or patient requested the change. Finally, although all three studies used clinical signs for the selection of subjects, diagnostic testing was not universal. One study relied heavily on CRP level when selecting patients, while another deemed CRP levels to be of little importance.2 CONCLUSION

Acute appendicitis is one of the most common reasons for emergent surgery worldwide, including in the United States. Diagnosis can be challenging and relies mainly on clinical signs and symptoms. Patients suspected of having appendicitis are treated swiftly, in hopes of avoiding perforation that may lead to peritonitis. For more than a century, treatment of appendicitis has been surgical, with little consideration given to alternative treatment. After review of the literature, appendectomy is still the gold standard for treatment of acute appendicitis. Even when the diagnosis of acute appendicitis is uncertain but likely, appendectomy may still be performed. Complications from appendectomy are rare, but they do occur and may include death. Recently, conservative management of acute appendicitis with antibiotic therapy has been considered a more realistic alternative treatment approach, with randomized trials illustrating success for more than two-thirds of patients. Advocates of antibiotic treatment for acute appendicitis point out advantages compared with surgery. First, conservative management eliminates postoperative complications. Second, costs of antibiotic therapy are lower than those of surgery. There is less chance of morbidity and mortality with antibiotics than with surgery. Finally, antibiotic therapy for acute appendicitis would fill the treatment void in patients for whom surgery may not be an option. They include patients who have multiple comorbidities or who are immunodeficient. Evidence-based studies in these populations may prove to be difficult to perform, so data to support this argument are likely to be scant. Skeptics have their reasons for opposing antibiotic therapy. Alternative therapy has a significant recurrence rate. Also, although recent studies are promising, the high crossover rate among participants in two studies has the potential to skew the data and invalidate the study’s randomization. Another negative aspect of antibiotic treatment could be the potential for increased antibiotic resistance, as is seen in other areas of medicine. Because the diagnosis of appendicitis is not always certain, incorrect usage of antibiotics in a patient without appendicitis could ultimately produce resistance. The results of the studies presented should not be ignored, however. In certain “less severe” cases of suspected appendicitis (for example, in patients with a low WBC count and minimal inflammation noted on imaging), antibiotic treatment would be a realistic alternative to surgery. One suggestion for future studies is to develop a more • MAY 2012 • 25(5) • JAAPA


CME Appendicitis standardized objective process when selecting patients with suspected acute appendicitis for randomization, perhaps using an assessment tool such as the Alvarado score. Also, analytical studies should be conducted pertaining to the costs of antibiotic therapy versus appendectomy. Clearly, more research is needed before antibiotic therapy becomes a widely accepted treatment modality for acute appendicitis, but for patients in whom the diagnosis is not clear, antibiotic therapy may someday be the treatment of choice. JAAPA Editor’s note: As this article was going to press, a new meta-analysis was published comparing antibiotic treatment versus appendectomy for the primary treatment of acute appendicitis. The meta-analysis found that antibiotics were safe and effective for this use and should be considered as a primary treatment. See Varadhan KK et al. BMJ. 2012;344:e2156. Ben Christensen practices orthopedics at The Steadman Clinic in Vail, Colorado. Dawn Colomb-Lippa is a professor of physician assistant studies at Quinnipiac University in Hamden, Connecticut, and practices clinically in orthopedics. The authors have indicated no relationships to disclose relating to the content of this article. REFERENCES 1. Fitz R. On perforating inflammation of the vermiform appendix with special reference to its early diagnosis and treatment. N Engl J Med. 1935;213(6):245-248. 2. Varadhan KK, Humes DJ, Neal KR, Lobo DN. Antibiotic therapy versus appendectomy for acute appendicitis: a meta-analysis. World J Surg. 2010;34(2):199-209.

3. Hall MJ, DeFrances CJ, Williams SN, et al. National Hospital Discharge Survey: 2007 Summary. Hyattsville, MD: National Center for Health Statistics; 2010. 4. Coldrey E. Five years of conservative treatment of acute appendicitis. J Int Coll Surg. 1959;32(3): 255-261. 5. Hansson J, Körner U, Khorram-Manesh A, et al. Randomized clinical trial of antibiotic therapy versus appendectomy as primary treatment of acute appendicitis in unselected patients. Br J Surg. 2009;96(5):473-481. 6. Silen W. Acute appendicitis and peritonitis. In: Kasper D, Braunwald E, Fauci A, et al, eds. Harrison’s Principles of Internal Medicine. 16th ed. New York, NY: McGraw-Hill; 2005:1805-1807. 7. Humes DJ, Simpson J. Acute appendicitis. BMJ. 2006;333(7567):530-534. 8. Laméris W, van Randen A, Go PM, et al. Single and combined diagnostic value of clinical features and laboratory tests in acute appendicitis. Acad Emerg Med. 2009;16(9):835-842. 9. Alvarado A. A practical score for the early diagnosis of acute appendicitis. Ann of Emerg Med. 1986;15(5):557-564. 10. Lee CC, Golub R, Singer AJ, et al. Routine versus selective abdominal computed tomography scan in the evaluation of right lower quadrant pain: a randomized controlled study. Acad Emerg Med. 2007;14(2):117-122. 11. Bowater RJ, Stirling SA, Lilford RJ. Is antibiotic prophylaxis in surgery a generally effective intervention? Testing a generic hypothesis over a set of meta-analysis. Ann Surg. 2009; 249(4):551-556. 12. Tingstedt B, Isaksson J, Andersson R. Long-term follow-up and cost analysis following surgery for small bowel obstruction caused by intra-abdominal adhesions. Br J Surg. 2007;94(6):743-748. 13. Papaziogas B, Tsiaousis P, Koutelidakis A, et al. Effect of time on risk of perforation in acute appendicitis. Acta Chir Belg. 2009;109(1);75-80. 14. Mason RJ. Surgery for appendicitis: is it necessary? Surg Infect (Larchmt). 2008;9(4):481-488. 15. Eriksson S, Granström L. Randomized controlled trial of appendectomy versus antibiotic therapy for acute appendicitis. Br J Surg. 1995;82(2):166-169. 16. Styrud J, Eriksson S, Nilsson I, et al. Appendectomy versus antibiotic treatment in acute appendicitis. A prospective multicenter randomized controlled trial. World J Surg. 2006;30(6):1033-1037. 17. Malik AA, Bari SU. Conservative management of acute appendicitis. J Gastrointest Surg. 2009; 13(5):966-970. 18. Lai HW, Loong CC, Chiu JH, et al. Interval appendectomy after conservative treatment of an appendiceal mass. World J Surg. 2006;30(3):351-357.

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Floppy iris syndrome: A drug-related complication of cataract surgery Older patients who are about to undergo cataract removal should be asked to provide a complete medication history, one that includes drugs no longer being taken.

FIGURE 1. Impaired pupil dilation and billowing iris

FIGURE 2. Iris prolapse to the temporal corneal incision

CASE • MAY 2012 • 25(5) • JAAPA

Figures 1-3 courtesy of David F. Chang, MD

A 61-year-old male presented to the ophthalmologist for routine vision screening with a chief complaint of nighttime glare and decreased visual acuity. The patient’s history was positive for asthma, osteoarthritis, kidney stones, and gastric ulcers; he denied other systemic illnesses. A medication summary was obtained from the patient and his primary care provider to determine if any medications the patient was taking could be contributing to the ocular pathology. The only medication reported was a combination drug composed of diclofenac and misoprostol (Arthrotec) for osteoarthritis. Vision of 20/400 on a glare test and detectable opacification of the lens of the left eye indicated a cataract requiring surgical removal. The impact of visual impairment on the patient’s life was another important factor in determining the need for surgery. The patient was scheduled for cataract extraction and measured for a replacement intraocular lens (IOL). The surgery took place at an ambulatory surgical center,

where he was prepped with preoperative anesthetic drops and monitored by an anesthesiologist. The procedure began with pupil dilation in order to allow full visualization of the cataract and room for manipulation of the lens. With the aid of viscoelastic material to stabilize the iris, the capsulorrhexis was successful. However, on initiation of the phacoemulsification stage of the procedure, an unexpected physiologic event was encountered. Rather than remaining dilated, the pupil constricted, became floppy, and billowed in and out of the plane of view. The change in chamber dynamics, obstruction of view, and behavior of the iris resulted in rupture of the posterior capsule. Placement of an IOL in the presence of capsular compromise is challenging and at times not feasible. This serious complication required further care from a retina specialist to remove cataract fragments from the posterior segment and implant the IOL. Ophthalmologists refer to this phenomenon as intraoperative floppy iris syndrome (IFIS). This is a common complication in a specified population of patients but not anticipated in a patient with a straightforward medical history. On further questioning, the patient recalled that he had taken tamsulosin (Flomax) for the treatment of benign

Elizabeth “Fizzy” Ramsey, MS, PA-C; Barton L. Ramsey III, MD; Jennifer Childers, MS, PA-C


CASE REPORT | Floppy iris syndrome prostatic hyperplasia (BPH). At the time the initial medication history was provided, he felt that the information about tamsulosin was unimportant because he had not taken the medication for an extended period and had discontinued it more than 1 year prior. DISCUSSION Cataract removal procedure A complete ophthalmologic

workup allows the clinician to estimate the patient’s visual outcome and determine the risk involved with surgery. Type and degree of lens opacification is quantified by a slitlamp examination. Vision is assessed through the use of a glare test, which involves imposition of bright light on the pupil during a visual acuity evaluation. Vision of 20/50 or worse is an indication for surgical intervention. The procedure involves removing the opacified lens and replacing it with an artificial IOL. Two clear, beveled, self-sealing incisions are made in the cornea; the larger incision is positioned temporally and another limbal incision is placed 30° to 40° from the initial incision, at the discretion of the surgeon, to be used as a side port. A cir-

“Prevention of IFIS requires a collaborative effort among the involved ophthalmologists and prescribing providers.” cular opening, called a capsulorrhexis, is made in the anterior lens capsule, allowing ultrasonic fragmentation of the lens nucleus. Using an instrument that operates by means of a small ultrasonically vibrating needle tip, phacoemulsification is the preferred method for fragmenting the nucleus of the lens prior to extraction through the same probe and incision site. Manual manipulation of the lens is performed with a second instrument through the side port. Following complete removal of the lens, a compactly folded IOL is placed through the larger incision and unfolded within the capsular bag. Placement of the IOL in the posterior chamber may not be possible if the capsular bag is torn, as happened in this case.

Tamsulosin and its relationship to IFIS Intraoperative floppy iris syndrome was first reported in 2005 following retrospective and prospective studies carried out by David F. Chang, MD, and John R. Campbell, MD.1,2 The researchers observed a consistent triad of features that distinguish IFIS and involve a flaccid iris stroma that ripples and billows in response to ordinary intraocular fluid currents (Figure 1), a tendency for the floppy iris stroma to prolapse toward the incisions despite proper incision construction (Figure 2), and progressive intraoperative pupil constriction despite standard preoperative pharmacologic measures designed to prevent this event.1 This unique intraoperative behavior of the iris has been linked to the use of selective alpha1-adrenergic antagonists commonly prescribed for treating the symptoms of BPH.1 Uroselective agents, in addition to other alpha-blockers, relax smooth muscle in the bladder neck and prostate. The most common alpha1-receptor subtype found in both the iris dilator muscle and prostatic smooth muscle is the alpha1a-receptor. Tamsulosin, a commonly used agent in the treatment of BPH, is selective for alpha1areceptors. Risk of IFIS and receptor subtype affinity were observed in several studies, which concluded that risks were significantly higher for tamsulosin compared with the risks for other uroselective agents, such as alfuzosin (Uroxatral, generics), doxazosin (Cardura, generics), and terazosin (Hytrin, generics).3-5 The relaxing action on the iris accounts for the dysfunctional pupil constriction during cataract surgery. Incidence and prevalence of IFIS Because it has fewer systemic effects than similar agents, tamsulosin remains one of the most popular agents for treatment of BPH. This popularity increases the potential risk of IFIS in the aging population.6,7 Several studies have observed a greater association of IFIS with tamsulosin than with other alphablockers due to the selective alpha1a-receptor blockade.3-5 Another prospective study showed that 90% of 167 patients taking tamsulosin exhibited some degree of IFIS.2 Although severity varies, IFIS fundamentally predisposes patients to multiple intraoperative and postoperative complications, including vitreous prolapse from capsule rupture, retinal detachment, pupil deformity, damage to the iris, and photophobia.1,2,6 The severity of iris damage can be observed in Figure 3. A recent Canadian study of almost

KEY POINTS ■ Intraoperative floppy iris syndrome (IFIS) involves a flaccid iris stroma, a tendency for the floppy iris stroma to prolapse toward the

two incisions despite proper incision construction, and progressive intraoperative pupil constriction. ■ Risk of IFIS is significantly higher with use of tamsulosin compared with other nonselective alpha blockers, such as alfuzosin, doxazosin,

and terazosin. ■ The American Academy of Ophthalmology and the American Society of Cataract and Refractive Surgery recommend involving an

ophthalmologist before initiating treatment with alpha1-antagonists in patients with known cataracts. ■ Prescribing providers should make note of the patient’s latest ophthalmologic examination, consider visual acuity or the presence of

cataracts, and recommend seeing an ophthalmologist before initiating treatment with tamsulosin.

38 JAAPA • MAY 2012 • 25(5) •

CASE REPORT | Floppy iris syndrome prostatic hyperplasia (BPH). At the time the initial medication history was provided, he felt that the information about tamsulosin was unimportant because he had not taken the medication for an extended period and had discontinued it more than 1 year prior. DISCUSSION Cataract removal procedure A complete ophthalmologic

workup allows the clinician to estimate the patient’s visual outcome and determine the risk involved with surgery. Type and degree of lens opacification is quantified by a slitlamp examination. Vision is assessed through the use of a glare test, which involves imposition of bright light on the pupil during a visual acuity evaluation. Vision of 20/50 or worse is an indication for surgical intervention. The procedure involves removing the opacified lens and replacing it with an artificial IOL. Two clear, beveled, self-sealing incisions are made in the cornea; the larger incision is positioned temporally and another limbal incision is placed 30° to 40° from the initial incision, at the discretion of the surgeon, to be used as a side port. A cir-

“Prevention of IFIS requires a collaborative effort among the involved ophthalmologists and prescribing providers.” cular opening, called a capsulorrhexis, is made in the anterior lens capsule, allowing ultrasonic fragmentation of the lens nucleus. Using an instrument that operates by means of a small ultrasonically vibrating needle tip, phacoemulsification is the preferred method for fragmenting the nucleus of the lens prior to extraction through the same probe and incision site. Manual manipulation of the lens is performed with a second instrument through the side port. Following complete removal of the lens, a compactly folded IOL is placed through the larger incision and unfolded within the capsular bag. Placement of the IOL in the posterior chamber may not be possible if the capsular bag is torn, as happened in this case.

Tamsulosin and its relationship to IFIS Intraoperative floppy iris syndrome was first reported in 2005 following retrospective and prospective studies carried out by David F. Chang, MD, and John R. Campbell, MD.1,2 The researchers observed a consistent triad of features that distinguish IFIS and involve a flaccid iris stroma that ripples and billows in response to ordinary intraocular fluid currents (Figure 1), a tendency for the floppy iris stroma to prolapse toward the incisions despite proper incision construction (Figure 2), and progressive intraoperative pupil constriction despite standard preoperative pharmacologic measures designed to prevent this event.1 This unique intraoperative behavior of the iris has been linked to the use of selective alpha1-adrenergic antagonists commonly prescribed for treating the symptoms of BPH.1 Uroselective agents, in addition to other alpha-blockers, relax smooth muscle in the bladder neck and prostate. The most common alpha1-receptor subtype found in both the iris dilator muscle and prostatic smooth muscle is the alpha1a-receptor. Tamsulosin, a commonly used agent in the treatment of BPH, is selective for alpha1areceptors. Risk of IFIS and receptor subtype affinity were observed in several studies, which concluded that risks were significantly higher for tamsulosin compared with the risks for other uroselective agents, such as alfuzosin (Uroxatral, generics), doxazosin (Cardura, generics), and terazosin (Hytrin, generics).3-5 The relaxing action on the iris accounts for the dysfunctional pupil constriction during cataract surgery. Incidence and prevalence of IFIS Because it has fewer systemic effects than similar agents, tamsulosin remains one of the most popular agents for treatment of BPH. This popularity increases the potential risk of IFIS in the aging population.6,7 Several studies have observed a greater association of IFIS with tamsulosin than with other alphablockers due to the selective alpha1a-receptor blockade.3-5 Another prospective study showed that 90% of 167 patients taking tamsulosin exhibited some degree of IFIS.2 Although severity varies, IFIS fundamentally predisposes patients to multiple intraoperative and postoperative complications, including vitreous prolapse from capsule rupture, retinal detachment, pupil deformity, damage to the iris, and photophobia.1,2,6 The severity of iris damage can be observed in Figure 3. A recent Canadian study of almost

KEY POINTS ■ Intraoperative floppy iris syndrome (IFIS) involves a flaccid iris stroma, a tendency for the floppy iris stroma to prolapse toward the

two incisions despite proper incision construction, and progressive intraoperative pupil constriction. ■ Risk of IFIS is significantly higher with use of tamsulosin compared with other nonselective alpha blockers, such as alfuzosin, doxazosin,

and terazosin. ■ The American Academy of Ophthalmology and the American Society of Cataract and Refractive Surgery recommend involving an

ophthalmologist before initiating treatment with alpha1-antagonists in patients with known cataracts. ■ Prescribing providers should make note of the patient’s latest ophthalmologic examination, consider visual acuity or the presence of

cataracts, and recommend seeing an ophthalmologist before initiating treatment with tamsulosin.

38 JAAPA • MAY 2012 • 25(5) •

Floppy iris syndrome | CASE REPORT collaborative effort among ophthalmologists and prescribing providers. Ophthalmologists must inquire about previous or current use of alpha1-antagonists and request medication histories from primary care providers. The American Academy of Ophthalmology and the American Society of Cataract and Refractive Surgery recommend involving an ophthalmologist before initiating treatment with alpha1antagonists in patients with known cataracts.9,10 Primary care providers can be instrumental in instructing patients to share their full medication history with their ophthalmologists, as well as with other surgical specialists. Moreover, prescribing providers should make note of the patient’s latest ophthalmologic examination, consider visual acuity or the presence of cataracts, and recommend seeing an ophthalmologist prior to initiating treatment with tamsulosin. JAAPA FIGURE 3. Iris damage leads to pupil deformity following cataract surgery in a patient taking tamsulosin; note the loss of iris tissue in one quadrant from intraoperative prolapse out of the temporal corneal incision.

100,000 men showed that those who had taken tamsulosin before undergoing cataract surgery had 2.3 times the risk of postoperative complications.6 To further complicate the situation, IFIS can occur more than 1 year after discontinuation of tamsulosin.1,2,4,6,8 Accordingly, halting the medication prior to surgery does not seem to decrease complication rates. CONCLUSION

Primary care providers must be aware of the varied prescribing considerations for a wide range of medications and, within that framework, realize the medicolegal complications associated with such pharmacologic therapies. Much success has been observed in the use of tamsulosin for BPH. In contrast, this medication may produce significant iris problems and complications during cataract extraction. Cataract removal is the most frequent outpatient operation performed in the United States, and BPH is a prevalent condition among aging men.8 Prevention of IFIS requires a

Fizzy Ramsey practices internal medicine in Danville, Kentucky. Barton Ramsey practices general ophthalmology, also in Danville, Kentucky. Jennifer Childers is an assistant professor in the PA program at Marietta College, Marietta, Ohio. The authors have indicated no relationships to disclose relating to the content of this article. REFERENCES 1. Chang DF, Campbell JR. Intraoperative floppy iris syndrome associated with tamsulosin. J Cataract Refract Surg. 2005;31(4):664-673. 2. Chang DF, Osher RH, Wang L, Koch DD. Prospective multicenter evaluation of cataract surgery in patients taking tamsulosin (Flomax). Ophthalmology. 2007;114(5):957-964. 3. Blouin MC, Blouin J, Perreault S, et al. Intraoperative floppy iris syndrome associated with alpha1adrenoreceptors; comparison of tamsulosin and alfuzosin. J Cataract Refract Surg. 2007;33(7): 1227-1234. 4. Cantrell MA, Bream-Rouwenhorst HR, Steffensmeier A, et al. Intraoperative floppy iris syndrome associated with alpha1-adrenergic receptor antagonists. Ann Pharmacother. 2008;42(4):558-563. 5. Palea S, Chang DF, Rekik M, et al. Comparative effect of alfuzosin and tamsulosin on the contractile response of isolated rabbit prostatic and iris dilator smooth muscles: possible model for intraoperative floppy-iris syndrome. J Cataract Refract Surg. 2008;34(3):489-496. 6. Bell CM, Hatch WW, Fischer HD, et al. Association between tamsulosin and serious ophthalmic adverse events in older men following cataract surgery. JAMA. 2009;301(19):1991-1996. 7. Chang DF. Floppy iris syndrome: why BPH treatment can complicate cataract surgery [editorial]. Am Fam Physician. 2009;79(12):1051, 1055-1056. 8. Chang DF, Braga-Mele R, Mamalis N, et al. Clinical experience with intraoperative floppy-iris syndrome: results of the 2008 ASCRS member survey. J Cataract Refract Surg. 2008;34(7):1201-1209. 9. Cullen KA, Hall MJ, Golosinskiy A. Ambulatory Surgery in the United States, 2006. National Health Statistics Reports; no. 11. Revised. Hyattsville, MD: National Center for Health Statistics; 2009. 10. Chang DF, Braga-Mele R, Mamalis N, et al. ASCRS white paper: clinical review of intraoperative floppy-iris syndrome. J Cataract Refract Surg. 2008;34:2153-2162.

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Trauma patient satisfaction with physician assistants: Testing a structural equation model Gina M. Berg, PhD; Robin E. Crowe, MA; Sue Nyberg, MHS, PA-C; Charles Burdsal, PhD

ABSTRACT Objective: Physician assistants (PAs) are increasingly utilized in the health care workforce and should be aware of how their interpersonal and technical skills are perceived by patients. The purpose of this study was to test associations among Perceived Interpersonal Care, Perceived Technical Care, and Global Satisfaction.

Methods: This cross-sectional telephone survey of recently discharged trauma patients tested a structural equation model which hypothesized that interpersonal satisfaction ratings predicted technical care and global satisfaction ratings. Results: A total of 251 completed surveys were analyzed. Results indicated a relationship among interpersonal care, technical care, and global satisfaction. Satisfaction with interpersonal care predicted satisfaction with technical care.


As are utilized in the US health care workforce in primary care and are increasingly practicing in specialty disciplines.1,2 Evaluation of PA integration into patient care indicates a notable level of quality and has been met with great acceptance.3 The literature has demonstrated an equivalence in care between PAs and other health care providers,4-6 improvements in outcomes,6,7 and savings in supervising physician time and other costs.8,9 Moreover, high patient satisfaction with PA care has been demonstrated in a variety of settings,10,11 including trauma departments.12 Components of satisfaction with PAs include shorter wait times and/or length of stay (LOS)13 and friendliness.14 Since PAs are increasingly accepted in health care settings and are involved in direct patient contact,3 they must understand the impact of their caregiving on patients’ perceptions of overall care. In fact, interpersonal care has been shown to be a determinant of patient satisfaction.15-20 Patients are generally considered capable of judging the quality of the interpersonal aspects of delivery of care. Their perceptions of care are formed through interactions that are characterized by warmth, sensitivity, and comfort.21 Furthermore, although patients often rate technical care to be the most important aspect of care,24 it is not always the strongest predictor.25,26 Willson and McNamara found that experimental manipulation of courtesy in vignettes of patient encounters 42 JAAPA • MAY 2012 • 25(5) •

Conclusion: In this study of how satisfied recently discharged trauma patients are with care by physician assistants, perceptions of technical care were associated with perceptions of interpersonal care, or how the patient was treated as a person. Since physician assistants have direct patient contact, this association demonstrates the strength of the PA-patient relationship as an asset to the health care organization.

Gina Berg is director of trauma services research, Wesley Medical Center, Wichita, Kansas, and research assistant professor, Department of Preventive Medicine and Public Health, Kansas University School of Medicine–Wichita. Robin Crowe is a research associate, Department of Preventive Medicine and Public Health, Kansas University School of Medicine–Wichita. Sue Nyberg is chair, associate professor, and program director, Department of Physician Assistant, Wichita State University, Wichita, Kansas. Charles Burdsal is a professor in the Community-Clinical Program, Department of Psychology, Wichita State University. The authors have indicated no relationships to disclose relating to the content of this article.

resulted in variations in perceived satisfaction.27 Moreover, Chang and colleagues demonstrated that objective ratings of patient care and patient perceptions of care were not correlated.28 However, these studies primarily involved physicians and nurses. Thus, as PAs continue to assume a greater role in the health care workforce and are involved in patient encounters, they need to be aware of the impact their interpersonal skills have on patients’ perception of the overall quality of care provided. The purpose of this study was to propose and test a model of patient satisfaction that demonstrated a hypothesized path relationship between the latent variables: Perceived Interpersonal Care (PIC), Perceived Technical Care (PTC), and Global Satisfaction. Specifically, the purpose was to demonstrate that patient perceptions of technical care can be predicted by judgments of interpersonal care using structural equation modeling (SEM).29 Unique to a trauma population is that care is typically centered on (and judged through) one hospitalized care event without a prior provider-patient relationship and follow-up care is conducted by other providers outside the trauma environment. METHODS Participants This was a prospective, cross-sectional study

using telephone surveys of recently discharged level I (emergent) and level II (urgent) trauma patients admitted to

their care. Perceived Interpersonal Care, Perceived Technical Care, and Global Satisfaction are defined in Table 1. Procedures Institutional Review Board approval was obtained. Patients or their representative gave informed consent at the time of discharge. Patients were surveyed if they were 18 years or older; family members were surveyed if the patient was 17 years or younger or unable to respond. Up to five calls were made to each participant, and surveys were completed within 4 weeks of hospital discharge. Statistical analysis Descriptive and comparative data analyses were conducted using PASW, Version 1830; structural equation modeling was done using Analysis of Moment Structure (AMOS).30 Structural equation modeling is a statistical technique that tests hypothesized relationships among observed and latent (constructs) variables.29 Relationships between variables are demonstrated in path diagrams. The relationships among PIC, PTC, and Global Satisfaction were examined. The maximum likelihood estimation method was used for all models. Fit indices and change in chi-square statistics were compared for model improvement. Change in chi-square was evaluated at P < .05. A sample size of 200 is adequate; fewer than 10 cases per estimated parameter is acceptable if the estimated size of the effect is large.30 The comparative fit index (CFI) is reported here as recommended for small sample sizes; a value of 0.9 or more was representative of a well-fitting model.31

TABLE 1. Interpersonal and technical care definitions28 Interpersonal care


Showing regard for another’s feelings and/or circumstances


Being polite or showing good manners


Inclined to help or support


Considerate and helpful


Easily liked and pleasing


Agreeable and enjoyable


Being responsive to the feelings of others


Feeling sympathy or being compassionate

Technical care


Having skill, knowledge, and qualifications


The ability to do something well


Knowledge gained from previous experiences


Working in the best possible manner with the least waste of time and effort


Error-free and consistent with a standard


Being properly qualified


Being qualified by instruction or training


Completed without carelessness and with attention to detail

Note: Survey questions included giving the respondent the definition of these terms28 (observed variables represented by rectangles in Figure 1) and asked the respondent to rate the PA on each term defined. Example: “Friendly is defined as being inclined to help or support. On a scale of 1, not friendly at all, to 6 very friendly, how friendly would you rate the physician assistant?” Global satisfaction was measured (1 = very dissatisfied to 6 = very satisfied).

a level I trauma center which utilizes a trauma team model that includes PAs. Patients were excluded if they were unable to provide a phone number, were non-English speaking, presented with severe mental illness, were incarcerated, or were deceased at the time of contact. Material Questions were Likert-type (scale: 1 = negative to 6 = positive) and inquired about such areas as demographics, satisfaction ratings, and personal ability to judge the quality of their health care (1 = very unqualified to 6 = very qualified). Respondents were given definitions for interpersonal and technical care27 and asked to rate the PA who provided

RESULTS Demographics Of 1,724 level I and level II trauma patients

discharged during the study time period, 435 (25.2%) gave consent for participation. Of those who consented, 278 participated, for a response rate of 63.9%. Of those who were surveyed, 27 were excluded because they could not recall a PA involved in their care; thus the total included in the analysis was 251 (57.7%). The sample proportionally represented the trauma population (Table: Demographics of total level I and II trauma patients and respondents, in the online version of this article). Respondents were predominantly white (90.6%) and male (64.1%); average age was 42.4 years. The majority reported an education level of “some college or less” (72%); an annual household income of $40,000 or less (50.4%); and being employed in a field other than the medical profession (87.6%). In addition, the majority of respondents (73.3%) rated themselves as highly qualified to judge the quality of their health care. Continued on page 49

TABLE 2. Model fit indices ␹2















Model specified



















Difference in models

Note: Chi square/df = ratio (ideal is less than 3.0); CFI, Comparative fit index (acceptable is equal to or greater than 0.9); TLI, Tucker-Lewis fit index (also Non-normed fit index; acceptable is equal to or greater than 0.9); RMSEA, root mean square error of approximation (good fit = 0.05 or below). • MAY 2012 • 25(5) • JAAPA


Trauma patient satisfaction | RESEARCH REPORT FIGURE 1. Structural model of PA interpersonal and technical care on global satisfaction









Overall satisfaction



Perceived physician assistant interpersonal care

Global satisfaction


R 2 =.494

PA-PTC Perceived PA technical care R 2 =.785

Trauma satisfaction Recom trauma Return trauma Resolve health








Note: Standardized coefficient reported; ␹2/df ratio = 1,103.331/643.212 = 1.715; TLI = .896; CFI = .917; RMSEA = .107. Path diagram: Ovals represent constructs, coefficient equals correlation between constructs; rectangles represent observed variables, coefficient equals loading on corresponding construct; circles represent residual error. Arrows represent relationships; arrows between constructs represent hypothesized paths

Satisfaction comparison by demographics When comparing overall satisfaction with PAs, there were no differences based on demographics (age, sex, level of education, race) between participants who reported being dissatisfied and participants who reported being satisfied or in overall satisfaction with a prior stay or satisfaction with prior trauma care. The only significant difference found for interpersonal care was that medical professionals were proportionately less satisfied than nonmedical professionals (P = .05). Satisfaction with technical care did not differ based on participant demographics. However, patients dissatisfied with a prior stay were significantly less satisfied with their recent stay (P = .01). Structural equation model Included in the model were 251 cases,20 observed variables, and 83 estimated parameters. Figure 1 displays the strength of the relationships between latent factors and each directly observed variable as well as the relationships between the latent variables. The independence model that tested if the variables are uncorrelated was rejected (␹2 [170] = 1103.33; P < .001). Fit indices (Table 2) indicated that the sample had a moderate fit to the model; (␹2 [167] = 643.21; P < .001; CFI = .917). A chi-square difference test indicated a significant improvement in fit between the measurement model and the hypothesized model (␹2 [3] = 329.14; P < .001). Figure 1 summarizes the factor loadings

that emerged from the structural model. Table 3 summarizes the means, unstandardized regression coefficients and their P value, and squared multiple correlations. Effects Perceived Interpersonal Care had a strong direct effect on Perceived Technical Care (.886) and accounted for 78.5% of the variance. PIC (–.152) did not have a significant direct effect on Global Satisfaction. PTC (.834) had a significant direct effect on Global Satisfaction. PIC also had a significant indirect effect (.739) on Global Satisfaction through PTC (Figure 1). DISCUSSION

The purpose of this study was to propose and test a model of patient satisfaction with PA care that demonstrated a hypothesized path relationship among the latent variables: PIC, PTC, and Global Satisfaction. The study population proportionally represented the trauma population for this institution. Respondents to this survey considered themselves very qualified to judge the quality of their health care. A relationship exists among PIC, PTC, and Global Satisfaction. Specifically, high interpersonal ratings predicted high technical ratings. Patients’ perceptions of how the PA treated them as a person influenced their beliefs about the PA’s ability to provide quality care. This is congruent with previous studies that have also demonstrated an • MAY 2012 • 25(5) • JAAPA


RESEARCH REPORT | Trauma patient satisfaction TABLE 3. Mean ratings and unstandardized regression estimates (n = 251) Factor

Mean (SD)

Unstandardized coefficient

P value

Squared multiple correlation R2

Global satisfaction

Overall satisfaction

5.04 (1.23)




Satisfaction with trauma care

5.53 (.89)




Resolution of health problem

5.31 (.99)




Recommend trauma center

5.34 (1.13)




Return to trauma if needed

5.23 (1.39)





5.59 (.82)





5.67 (.68)





5.60 (.74)





5.60 (.75)












5.57 (.81)

Overall interpersonal satisfaction

5.59 (.83)


5.56 (.80)


5.53 (.87)





5.51 (.87)





5.56 (.86)





5.63 (.72)





5.66 (.77)





5.48 (.96)






5.61 (.76)





5.62 (.70)





5.51 (.96)




Overall technical satisfaction

5.55 (.90)

Note: Mean standard deviation (SD) score for PAs on observed variables (rectangles in Figure 1). Global Satisfaction Scale (1 = very dissatisfied, 6 = very satisfied). Survey questions included giving the respondent the definition of these terms28 (observed variables represented by rectangles in Figure 1) and asked the respondent to rate the PA on each term defined. Example: “Friendly is defined as being inclined to help or support. On a scale of 1, not friendly at all, to 6 very friendly, how friendly would you rate the physician assistant?” Coefficient represents loading on corresponding construct; P value reported for unstandardized coefficient; squared multiple correlation is the estimated variance.

association between interpersonal care and patient satisfaction.15,19,27 If patients rated the PA as friendly, sympathetic, etc, they also rated the PA as accurate and competent. Similarly, if patients rated the PA as unfriendly, unsympathetic, etc, they also rated the PA as inaccurate, incompetent, and inexperienced. Donabedian was among the first to incorporate patient opinion as a measure of quality health care and identify structure and process.23 Process refers to what care is given (technical) and how it is delivered (interpersonal).23 Access to care,32 explanations of care,33 and clarity and level of understanding of discharge instructions17 are process elements that contribute to patient satisfaction. Evidence indicates that interpersonal satisfaction is explained by prompt response to patient needs, communication, and efficiency of care,20 with the most 50 JAAPA • MAY 2012 • 25(5) •

important determinant being whether or not the patient felt cared for as a person.18 Furthermore, perceptions of care are formed through interaction,21 which can be further associated with the development of trust.35 Since PAs are in the position of having substantial contact with the patient (acquiring history and physical examination information and explaining course of care and discharge instructions), they have the opportunity to develop positive interpersonal perceptions and patient trust. Moreover, this validates and emphasizes the asset of the PA to the health care team. Given that patient judgments of technical and overall care are highly correlated with judgments of interpersonal care, the clinical implication for PAs is that they must have the ability to relate to the patient on an interpersonal level in order to facilitate a better patient-provider relationship. Interpersonal care,

as measured here, is courtesy, kindness, consideration, and sensitivity and can be easily demonstrated in communication behaviors such as the following: (1) introducing yourself, (2) saying the patient’s name during each encounter, (3) listening without interrupting, (4) explaining the process, and (5) being observant of patient or family member concerns. As important members of the health care team, PAs will want to understand the concept of patient satisfaction and how it is linked to perceptions of quality medical care. Moreover, satisfaction with care is important in the overall provider-patient relationship because studies have demonstrated a positive relationship between satisfaction with care and treatment adherence. In turn, treatment adherence has been shown to be associated with patient trust in physicians36 and satisfaction,37 but evidence demonstrating this with PA-patient relationships is scant. LIMITATIONS

Study limitations included biases based on exclusion criteria, as well as volunteer bias and social desirability, or desire to respond in a favorable light. This research was purposefully conducted in a trauma population, which often requires immediate diagnosis and treatment that precludes relationship building before rendering care. However, the acute crisis itself may have led to greater psychological need for the patient than routine health care does. Furthermore, this study was conducted in the Midwest, and the patient population may not represent trauma populations in more urban areas. CONCLUSION

This study adds to the evidence that patient perceptions of quality care are strongly influenced by their perception of their interpersonal care, or how they were treated as a person. Furthermore, this study introduces this relationship relevant to PAs, whereas the satisfaction literature is prevalent in physician and nursing disciplines. Structural equation modeling revealed a predictive association of patients’ perceptions of interpersonal care to technical care and their effects on global satisfaction. Moreover, the patients were very confident in their ability to judge the quality of their care. Since PAs have direct patient contact, this association demonstrates the strength of the PA-patient relationship as an asset to the health care organization. Although patients often rate technical care as the most important aspect of the patient encounter, a positive perception of interpersonal care is often the strongest predictor of overall patient satisfaction. Thus, PAs should be aware of the impact of their interpersonal skills on the perception the patient has of the overall quality of care provided. Furthermore, PA education should emphasize the importance of the patient-provider relationship. JAAPA Acknowledgments The authors wish to acknowledge the contributions of the staff of Wesley Medical Center Trauma Services for blindly allowing themselves to be evaluated and collecting consents; Francie Ekengren, MD; Charles Fox, PhD; Barbara Chaparro, PhD; Paul Ackerman, PhD, and Darwin Dorr, PhD, for editorial inputs; Daniel Clark, RN, Trauma Registrar; and Bryant Wong for data collection.

REFERENCES 1. Larson EH, Hart LG. Growth and change in the physician assistant workforce in the United States, 1967-2000. J Allied Health. 2007;36(3):121-130. 2. Morgan PA, Hooker RS. Choice of specialties among physician assistants in the United States. Health Aff (Millwood). 2010;29(5):887-892. 3. Nyberg SM, Keuter KR, Berg GM, et al. Acceptance of physician assistants and nurse practitioners in trauma centers. JAAPA. 2010;23(1):35-37, 41. 4. Dhuper S, Choksi S. Replacing an academic internal medicine residency program with a physician assistant-hospitalist model: a comparative analysis study. Am J Med Qual. 2009;24(2):132-139. 5. Bevis L, Berg-Copas GM, Thomas BW, et al. Outcomes of tube thoracostomies performed by advanced practice providers vs trauma surgeons. Am J Crit Care. 2008;17(4):357-363. 6. Miller W, Riehl E, Napier M, et al. Use of physician assistants as surgery/trauma house staff at an American College of Surgeons-verified level II trauma center. J Trauma. 1998;44(2):372-376. 7. Mains C, Scarborough K, Bar-Or R, et al. Staff commitment to trauma care improves mortality and length of stay at a level I trauma center. J Trauma. 2009;66(5):1315-1320. 8. Roblin DW, Howard DH, Becker ER, et al. Use of midlevel practitioners to achieve labor cost savings in the primary care practice of an MCO. Health Serv Res. 2004;39(3):607-626. 9. Morgan PA, Shah ND, Kaufman JS, Albanese MA. Impact of physician assistant care on office visit resource use in the United States. Health Serv Res. 2008;43(5 pt 2):1906-1922. 10. Mathur M, Rampersad A, Howard K, Goldman GM. Physician assistants as physician extenders in the pediatric intensive care unit setting—a 5-year experience. Pediatr Crit Care Med. 2005; 6(1):14-19. 11. Wilson IB, Landon BE, Hirschhorn LR, et al. Quality of HIV care provided by nurse practitioners, physician assistants, and physicians. Ann Intern Med. 2005;143(10):729-736. 12. Nyberg SM, Waswick W, Wynn T, Keuter K. Midlevel providers in a level I trauma service: experience at Wesley Medical Center. J Trauma. 2007;63(1):128-134. 13. Ducharme J, Alder RJ, Pelletier C, et al. The impact on patient flow after the integration of nurse practitioners and physician assistants in 6 Ontario emergency departments. CJEM. 2009;11(5):455-461. 14. Baldwin KA, Sisk RJ, Watts P, et al. Acceptance of nurse practitioners and physician assistants in meeting the perceived needs of rural communities. Public Health Nurs. 1998;15(6):389-397. 15. González-Valentín A, Padín-López S, de Ramón-Garrido E. Patient satisfaction with nursing care in a regional university hospital in southern Spain. J Nurse Care Qual. 2005;20(1):63-72. 16. Boudreaux ED, Mandry CV, Wood K. Patient satisfaction data as a quality indicator: a tale of two emergency departments. Acad Emerg Med. 2003;10(3):261-268. 17. Boudreaux ED, D’Autremont S, Wood K, Jones GN. Predictors of emergency department patient satisfaction: stability over 17 months. Acad Emerg Med. 2004;11(1):51-58. 18. Yarnold PR, Michelson EA, Thompson DA, Adams SL. Predicting patient satisfaction: a study of two emergency departments. J Behav Med. 1998;21(6):545-563. 19. Schwartz CE, Brotman S, LaRocca N, Lee H. Patient perception of quality of care provided by specialists and generalists. Mult Scler. 1998;4(5):426-432. 20. Marr J, Greengarten M. Patient satisfaction: a customer service approach. Healthc Manage Forum. 1995;8(3):52-56. 21. Wysong PR, Driver E. Patients’ perceptions of nurses’ skill. Crit Care Nurse. 2009;29(4):24-37. 22. Rubin HR. Can patients evaluate the quality of hospital care? Med Care Rev. 1990;47(3):267-326. 23. Miller GE. The assessment of clinical skills/competence/performance. Acad Med. 1990;65(9 suppl):S63-S67. 24. Donabedian A. The quality of care. How can it be assessed? 1988. Arch Pathol Lab Med. 1997; 121(11):1145-1150. 25. Merkouris A, Papathanassoglou ED, Lemonidou C. Evaluation of patient satisfaction with nursing care: quantitative or qualitative approach? Int J Nurs Stud. 2004;41(4):355-367. 26. Boudreaux ED, Ary RD, Mandry CV, McCabe B. Determinants of patient satisfaction in a large, municipal ED: the role of demographic variables, visit characteristics, and patient perceptions. Am J Emerg Med. 2000;18(4):394-400. 27. Raper JL. A cognitive approach to patient satisfaction with emergency department nursing care. J Nurs Care Qual. 1996;10(4):48-58. 28. Willson P, McNamara JR. How perceptions of a simulated physician-patient interaction influence intended satisfaction and compliance. Soc Sci Med. 1982;16(19):1699-1704. 29. Chang JT, Hays RD, Shekelle PG, et al. Patients’ global ratings of their health care are not associated with the technical quality of their care. Ann Intern Med. 2006;144(9):665-672. 30. Tabachnick BG, Fidell LS. Using Multivariate Statistics. 4th ed. Needham Heights, MA: Allyn & Bacon; 2001. 31. PASW [computer program]. Version 18.0. Somers, NY: IBM Corporation; 2009. 32. Byrne B. Structural Equation Modeling with AMOS: Basic Concepts, Applications, and Programming. Mahwah, NJ: Lawrence Erlbaum Associates; 2001. 33. Ammentorp J, Mainz J, Sabroe S. Parents’ priorities and satisfaction with acute pediatric care. Arch Pediatr Adolesc Med. 2005;159(2):127-131. 34. Chang K. Dimensions and indicators of patients’ perceived nursing care quality in the hospital setting. J Nurs Care Qual. 1997;11(6);26-37. 35. Chu-Weininger MY, Balkrishnan R. Consumer satisfaction with primary care provider choice and associated trust. BMC Health Serv Res. 2006;6:139. 36. Hillen MA, de Haes HC, Smets EM. Cancer patients’ trust in their physician—a review. Psychooncology. 2011;20(3):227-241. 37. Bennett JK, Fuertes JN, Keitel M, Phillips R. The role of patient attachment and working alliance on patient adherence, satisfaction, and health-related quality of life in lupus treatment. Patient Educ Couns. 2011;85(1):53-59. • MAY 2012 • 25(5) • JAAPA



Surgical considerations in invasive breast cancer: A clinician’s update Breast cancer requires a multidisciplinary approach in which all clinicians should have a fundamental knowledge of the armamentarium of other team members.


reast cancer is the second leading cause of cancer death among females. More than 225,000 new cases are diagnosed each year; roughly 2,000 of those patients are male. Approximately 40,000 patients die annually from the disease.1 Surgical resection remains the primary treatment modality. All clinicians should understand the surgical treatment options currently utilized in the diagnosis and treatment of this condition so they may better assist affected patients.2


When a breast lesion is detected by clinical examination or radiologic study, the primary care provider can obtain a diagnostic (rather than screening) mammogram or ultrasound (US) to assist in further diagnosis. Once there is suspicion for breast cancer, a tissue diagnosis is needed to confirm or refute the findings.3 One method used in evaluating a palpable breast mass is fine-needle aspiration (FNA), in which a small-gauge needle

A. Traditional mastectomy

FIGURE 1. Types of mastectomy incisions

52 JAAPA • MAY 2012 • 25(5) •

is inserted into the mass and the contents aspirated. FNA can be done in the office by an experienced primary care provider or breast specialist. The specimen undergoes limited evaluation by cytology alone. This technique lacks the ability to differentiate invasive from noninvasive cancer.4 Minimally invasive breast biopsy (MIBB) utilizes percutaneous needle techniques to obtain a biopsy sample. Core needle biopsy (CNB) uses a large-bore hollow needle to sample the lesion, allowing the specimen’s tissue architecture to be examined for invasive cancer. The sample can also be analyzed for receptor status. At the time of biopsy, a radiographic marker should be placed, allowing the clinician to locate the lesion in the event that further procedures are needed or to identify a previously biopsied lesion radiographically.5 Image guidance, using US, MRI, or stereotaxis with mammography, will aid in obtaining a specimen. These adjuncts are useful in nonpalpable lesions to guide the biopsy.4 If the results are questionable or the specimen is inadequate, these biopsy techniques can be repeated or the patient can be referred for open (excisional) biopsy.6 Continued on page 54

B. Periareolar skin-sparing mastectomy

C. Nipple-sparing mastectomy

© Fairman Studios, LLC

Brian K. Yorkgitis, PA-C, DO; Amy J. Goldberg, MD, FACS

SURGICAL REVIEW | Breast cancer Excisional biopsy can be guided by palpation, needle localization, US, or a radiologic marker inserted at during a previous MIBB. Clinicians should make every possible attempt to avoid excisional biopsy for histologic diagnosis.6 Using image-guided percutaneous biopsy as the initial technique to obtain tissue for diagnosis eliminates the need for an open diagnostic procedure, particularly in the setting of benign disease. Percutaneous diagnostic methods have been shown to decrease cost and potential breast disfigurement compared with open diagnostic procedures.6

the nipple-areolar complex (NAC) is removed in any type of mastectomy. Recently, the nipple-sparing mastectomy (NSM) has become a treatment option. It allows the patient to retain this important esthetic structure. The premise of NSM is derived from the fact the NAC is a rare site of cancerous foci in breast cancer.8 Figure 1 provides an illustration of selected mastectomy incisions. Complications of mastectomy include local recurrence, seroma, surgical site infection (SSI), flap necrosis, nerve injury, bleeding or hematoma, chronic pain, restricted range of motion, and lymphedema.2,9



The surgical specimen is an integral component of proper staging, which requires knowledge of tumor features, such as size. Lymph node involvement is an important prognostic factor, in addition to assisting in the guidance of therapies.3 Surgery in metastatic (stage IV) disease is not curative but may increase survival and quality of life.3 The most common sites of metastasis are the bone, lung, pleura, soft tissue, and liver, in order of decreasing prevalence. Surgical procedures may be necessary in the areas of metastasis to improve quality of life and disease control.7

The landmark National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-06 revolutionized surgical treatment of breast cancer. This study provided the clinical evidence showing that breast conservation therapy with radiation therapy has equivalent survival to modified radical mastectomy in early-stage cancer.10 Commonly referred to as a lumpectomy, quadrantectomy, or segmental mastectomy, BCT involves removing the tumor bed and achieving disease-free margins while maintaining uninvolved breast tissue.3 Several techniques may be employed to help accurately locate the tumor. They include palpation alone, US, radiologic clip placed at the time of MIBB, and localization with a radiologic needle placed in the area to be excised. If final pathology results show residual tumor at the specimen margin(s), a patient should undergo further resection to achieve tumorfree margins. Proper orientation of the original specimen allows identification of involved margins that can guide reexcision limited to those areas. If orientation of the original specimen cannot be confirmed, a rim of tissue around the entire previously excised area must be removed.11 Not all patients are candidates for BCT. Absolute contraindications include inflammatory breast cancer, pregnancy (because of the contraindication of radiation therapy), two or more primary tumors in different quadrants of the breast or diffuse malignant-appearing microcalcifications, inability to achieve disease-free margins after reasonable surgical attempts, and previous radiation to the breast that requires retreatment with an excessively high total radiation dose.11 Relative contraindications include advanced breast cancer, tumors comprising greater than 20% to 25% of the total breast volume, and history of collagen vascular disease. Other reasons patients choose not to have BCT include the peace of mind that comes with removal of all breast tissue that could harbor disease or inability/unwillingness to receive radiation therapy.3,11,12 Young patients who are at risk of recurrence and certain aggressive biologic subtypes should be educated on the future implications of BCT, including recurrence and new cancer foci.12

“The sentinel lymph node biopsy has been developed as a less invasive procedure for examining the patient’s nodal status.” MASTECTOMY

The historic Halsted radical mastectomy, which involves removal of the entire breast, axillary lymph nodes, and chest muscles, has been abandoned for less aggressive procedures. Popularized in the late 1970s, the modified radical mastectomy (MRM) procedure is typically utilized in patients who are not candidates for breast conservation therapy (BCT) or in those who elect removal of the entire breast.2 MRM removes the breast tissue along with level I and II lymph nodes (located in the area of the latissimus dorsi to pectoralis minor muscles and behind the pectoralis minor muscle, respectively), sparing level III lymph nodes (located medial to the pectoralis minor muscle). The anatomic borders of an MRM are as follows: • Lateral—anterior margin of the latissimus dorsi muscle • Medial—sternal border • Superior—subclavius muscle • Inferior—2 to 3 cm below the inframammary fold.7 Simple mastectomy involves the removal of all breast tissue, sparing the lymph nodes.6 Two additional variations of mastectomy exist. The skinsparing mastectomy (SSM) involves retention of a skin envelope where the breast tissue was, allowing for improved cosmetic results and reconstruction options. Traditionally, 54 JAAPA • MAY 2012 • 25(5) •

LYMPH NODE PROCEDURES Axillary lymph node dissection (ALND) has been the stan-

dard in diagnosis and treatment of nodal metastasis. ALND typically removes level I and II nodes. Complete ALND involves removal of level I to level III nodes. Significant

FIGURE 2. The transverse rectus abdominis muscle (TRAM) flap for breast reconstruction

morbidities are associated with ALND, which include nerve damage, seroma, lymphedema, SSI, limited arm motion, and pain. Patients whose lymph nodes appear suspicious on clinical or radiologic examination should undergo ALND.6 Ultrasound of the axillae has been used to assist in the diagnosis of lymphatic invasion. US may identify abnormal nodes that are not clinically palpable, since 30% to 45% of patients with clinically negative axillae harbor metastatic disease. Suspicious lymph nodes discovered by this modality or clinical examination can be evaluated by FNA. This allows the clinician to identify nodal disease and proceed to axillary dissection without an intermediate open diagnostic procedure.13 In the NSABP B-04 trial, Fisher and colleagues changed the clinician’s view when they showed that nodal disease was valuable only for staging and prevention of axillary recurrence.14 ALND with negative metastatic nodes provided no increased survival benefit. An important consideration is that these trials examined only patients with early-stage disease.12 The sentinel lymph node biopsy (SLNB), an alternative to ALND, has been developed as a less invasive procedure to examine nodal status. SLNB is used in patients with clinically nonpalpable nodes. Caution should be exercised in patients with larger tumors and those previously treated with neoadjuvant therapy. SLNB for inflammatory breast disease exposes a patient to a significantly high risk of falsenegative results, on the order of 20%, which is unacceptable to most clinicians. Most studies have evaluated SLNB in the setting of early-stage cancer. This procedure reliably diagnoses axillary metastasis in 98% of patients. Overall survival at 5 years between node-negative ALND and SNLB shows no statistical significance in recent studies.12 Patients undergoing SLNB should be educated regarding the risk of false-negative results. Most published falsenegative rates range between 0.3% and 0.5%.15 SLNB involves sampling the first node(s) that the lymph supply of a tumor will drain.2 The procedure involves injecting

the periareolar area with either a technetium-labeled sulfur colloid and/or blue dye. The axilla is then examined for signs of the radioactive marker or dye uptake by lymph nodes. When using the radioactive tracer, a gamma counter is used to locate the highest intensity of the tracer. This is usually the location of the sentinel node, and dissection is undertaken until it is localized. Once found, a 10-second in vivo count is performed. Once the node is excised, a 10-second ex vivo count is done. Further probing and dissection should be performed to locate any additional sentinel nodes. Any node that has absorbed the tracer to a measurement of 10% of the highest ex vivo count or that has taken up dye is termed a sentinel node and should be removed.7 Sentinel nodes are commonly examined intraoperatively by pathology for evidence of nodal involvement and adequacy of specimen. If the specimen is negative intraoperatively, no further axillary node removal is necessary at that time.16 Controversy arises when permanent pathology differs from a negative intraoperative result. One panel of experts believes that ALND should be performed in patients with macrometastases (deposits greater than 2 mm) on permanent histologic examination. In the setting of micrometastases, ALND can be optional, with consideration of axillary irradiation in BCT patients. When metastases are smaller than 0.2 mm, the recommendation is not to do ALND. Patients with positive SLNB who do not proceed to ALND should be educated on their potential for increased risk of axillary node recurrence.5 When the intraoperative SLNB result is positive, the surgeon historically can proceed to ALND in appropriate candidates during the same anesthetic sitting. In a recent study, Giuliano and colleagues found that SLNB was not inferior in overall survival to ALND in limited lymph node metastatic disease when patients underwent BCT and systemic therapy. In this series, tumors were T1 (less than 2 cm) and T2 (2- to 5-cm) lesions.16 This topic continues to be controversial and should be individualized to patient • MAY 2012 • 25(5) • JAAPA


SURGICAL REVIEW | Breast cancer

Latissimus dorsi skin flap

Latissimus dorsi m.

Posterier View

Anterior View

Anterior View

FIGURE 3. The latissimus dorsi muscle can be transferred on a pedicle containing the original blood supply.

preference following education on the risks and the surgeon’s comfort. The rate of complications of ALND versus SLNB is significant. One report showed the rate of complications to be 75% in the ALND group versus 25% in SNLB group. Additionally, lymphedema from ALND is 13% compared to 2% in the SLNB group.17 RECONSTRUCTION

Although oncologic resection is the primary goal of surgery for breast cancer, clinicians must also address options of reconstruction. The type of reconstruction must be individualized, taking into account overall health, body habitus, oncologic procedure being performed, and patient preference.3 The treatment should be multidisciplinary and include a plastic surgeon, when warranted, early in the oncologic surgical planning.18 In 1998, the Federal Breast Reconstruction Law was passed. This law prevents insurance carriers from considering breast reconstruction, including contralateral symmetry procedures, as elective after oncologic surgery.3 There are several approaches to the timing of reconstruction. Immediate procedures are accomplished during the oncologic resection. This allows the patient to awaken from anesthesia without experiencing the total loss of a breast and may have significant emotional benefits. Delayed reconstruction occurs after the initial oncologic procedure. This may be suitable for patients wishing to explore their options or when a reconstructive surgeon is unavailable. Immediate delayed-type procedures offer a third option. Implant insertion after tissue expansion is done in an immediate-delayed fashion. This method is used in women who are not candidates for autologous tissue reconstruction or who do not want additional surgery on a donor site.18 Tissue expanders can be inserted at the time of mastectomy. These expanders are placed in the subpectoral region and then filled in an incremental fashion until the desired volume is reached. Typically, they are overexpanded by 25% to allow improved cosmetic profile of the final implant. Once the desired size is achieved, a permanent implant is placed 56 JAAPA • MAY 2012 • 25(5) •

during a subsequent operative time.3,18 Complications include capsular contracture and implant deflation. Because of the natural ptosis of the breast and shape of the implant, about 60% of implant reconstructions need contralateral mammoplasty to achieve symmetry.19 Materials used in implant reconstruction include silicone or saline.3 Silicone was removed from the US market in 1992. In 2006, however, the FDA reapproved silicone implants after literature review found no significant increased risk to patients.18 Silicone offers a softer, more natural texture. Nevertheless, some women are fearful of previous warnings about the silicone material and choose saline. Another option is to use an acellular dermal matrix that is sewn onto the pectoralis major. It relies on vascular ingrowth and incorporation into the area. The advantages of implant reconstruction include not having surgery on additional areas of the body for harvest of autologous tissue. Implant reconstruction can be immediate (simplest option) or delayed. This technique requires that skin flaps from the mastectomy be adequate to cover the implant, but often they are not. This can result in increased risk of skin necrosis and poor cosmesis.18 Capsular contracture is the most common long-term complication, which may require additional surgery for correction. Contracture is increased in breasts that have been irradiated.3 Autologous tissue reconstruction takes tissue from one part of the body and relocates it to the oncologic surgical site. These procedures can be done in an immediate or delayed fashion. There are many options for these reconstructions. The transverse rectus abdominis muscle (TRAM) flap takes skin, subcutaneous fat, and the rectus abdominis muscle to reconstruct the breast (Figure 2). The flap can be performed on a vascular pedicle, keeping the original blood supply, or as a free tissue transfer, in which the blood supply is severed and reconstructed microsurgically to blood supply closer to the new location. This may not be an option for patients who are very thin or obese, smokers, recipients of a coronary artery bypass graft using the internal mammary

artery, those who have had previous abdominal surgery, or those with significant comorbid conditions. Specific risks to this procedure include abdominal wall hernias and flap failure, usually due to loss of its blood supply. The TRAM flap is noted to have a natural shape, with an aging process similar to that of the contralateral breast.3,18 Another option is the deep inferior epigastric perforator (DIEP) flap, in which the rectus muscles are left in situ, preserving the integrity of the abdominal wall. This procedure requires significant microsurgery and carries an increased risk of partial or total flap loss. The gluteus muscle can be used by creating either a superior or inferior gluteal artery perforator flap. The disadvantage of the gluteal techniques is possible injury to the sciatic nerve and the location of the donor tissue, which can result in discomfort when sitting and noticeable donor site deformity.18 The latissimus dorsi muscle can also be used (Figure 3). Because of its proximity to the breast, the muscle can be transferred on a pedicle containing the original blood supply. Maintaining its native blood supply improves graft survival. The latissimus dorsi can also be used in salvage procedures in previously irradiated areas. The myocutaneous flap often lacks volume to recreate adequate breast size, and implant supplementation may be necessary. Careful planning of axillary procedures is needed prior to surgery because the tissue is brought to the chest through the axilla.3 Nipple and areola reconstruction is typically done in a staged fashion. The goal is to match the contralateral side since small differences in color and appearance can be obvious. A tattoo with mineral pigment can be used. Additionally, a full-thickness graft obtained from the contralateral areola, excess abdominal tissue, medial thigh, or the mastectomy scar can be used.18 POSTSURGICAL SCREENING

Surveillance for recurrent and new disease is important after the management of invasive breast cancer. Patients who have had invasive breast cancer have an increased risk of newly diagnosed contralateral disease—about twice that of patients without a previous diagnosis of breast cancer. Clinical examination and history should be performed every 4 to 6 months during the first year after diagnosis. Thereafter, they can be performed annually when the patient is not undergoing treatment. The patient should be educated on signs and symptoms of recurrence and seek clinical evaluation for any changes. Current recommendations regarding radiologic studies are the same as screening recommendations for those without a cancer history. This includes yearly mammography for early detection of recurrence and new cancer. The radiologist interpreting these studies should be made aware of the patient’s history, since surgery and radiation therapy may alter imaging. Unless the patient is thought to be at high risk for recurrence, testing for tumor markers; blood tests; and additional radiographic images, including high-resolution ultrasonography or MRI, in asymptomatic

patients are not recommended. Compared with mammography, these methods have a lower specificity and a high rate of false-positive results. This may cause unnecessary anxiety and subject the patient to painful procedures that have not demonstrated increased survival rates. Further evaluation is indicated for patients with signs and/or symptoms of recurrence, new cancer, or metastatic disease.20 CONCLUSION

Invasive breast cancer diagnosis and treatment options must be individualized to each patient. Surgeons play an integral role in treatment but are part of a multidisciplinary team that includes primary care clinicians, radiologists, and medical and radiation oncologists, when appropriate. All clinicians involved in the care of a breast cancer patient should have a fundamental knowledge of the treatment and diagnostic armamentarium of other team members in order to deliver optimal care. JAAPA Brian Yorkgitis practices in clinical surgery, Temple University Hospital, Philadelphia, PA. Amy Goldberg is a professor of surgery at Temple University Hospital. The authors have indicated no relationships to disclose relating to the content of this article. REFERENCES 1. American Cancer Society. Cancer Facts & Figures 2012. American Cancer Society. http://www. pdf. Published 2012. Accessed April 19, 2012. 2. Hammer C, Fanning A, Crowe J. Overview of breast cancer staging and surgical treatment options. Cleve Clin J Med. 2008;75(suppl 1):S10-S16. 3. Hulvat MC, Hansen NM, Jeruss JS. Multidisciplinary care for patients with breast cancer. Surg Clin North Am. 2009;89(1):133-176. 4. Vlastos, G, Verkooijen HM. Minimally invasive approaches for diagnosis and treatment of earlystage breast cancer. Oncologist. 2007;12(1):1-10. 5. Silverstein MJ, Recht A, Lagios MD, et al. Image-detected breast cancer: state-of-the-art diagnosis and treatment. J Am Coll Surg. 2009;209(4):504-520. 6. Meisner AL, Fekrazad MH, Royce ME. Breast disease: benign and malignant. Med Clin North Am. 2008;92(5):1115-1141. 7. Hunt KK, Newman LA, Copeland EM III, Bland KI. The breast. In: Brunicardi FC, Andersen DK, Billar TR, et al, eds. Schwartz’s Principles of Surgery. 9th ed. New York, NY: McGraw-Hill; 2010:423-473. 8. Gupta A, Borgen PI. Total skin sparing (nipple sparing) mastectomy: what is the evidence? Surg Oncol Clin N Am. 2010;19(3):555-566. 9. Davies K, Allan L, Roblin P, et al. Factors affecting post-operative complications following skin sparing mastectomy with immediate breast reconstruction. Breast. 2011;20(1):21-25. 10. Fisher B, Bauer M, Margolese R, et al. Five-year results of a randomized clinical trial comparing total mastectomy and segmental mastectomy with or without radiation in the treatment of breast cancer. N Engl J Med. 1985;312(11):665-673. 11. Marrow M, Harris JR. Practice guideline for the breast conservation therapy in the management of invasive breast carcinoma. J Am Coll Surg. 2007;205(2):362-376. 12. Khan SA, Eladoumikdachi F. Optimal surgical treatment of breast cancer: implications for local control and survival. J Surg Oncol. 2010;101(8):677-686. 13. Devaraj S, Iqbal M, Donnelly J, Corder AP. Axillary ultrasound in invasive breast cancer: experience of our surgeons. Breast J. 2011;17(2):191-195. 14. Fisher B, Redmond C, Fisher ER, et al. Ten-year results of a randomized clinical trial comparing radical mastectomy and total mastectomy with or without radiation. N Engl J Med. 1985;312(11): 674-681. 15. Fortunato L, Mascaro A, Amini M, et al. Sentinel lymph node biopsy in breast cancer. Surg Oncol Clin N Am. 2008;17(3):673-699. 16. Giuliano AE, Hunt KK, Ballman KV, et al. Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. JAMA. 2011:305(6):569-575. 17. Lucci A, McCall LM, Beitsch PD, et al. Surgical complications associated with sentinel lymph node dissection (SLND) plus axillary lymph node dissection compared with SLND alone in the American College of Surgeons Oncology Group Trial Z0011. J Clin Oncol. 2007;25(24):3657-3663. 18. Hu E, Alderman AK. Breast reconstruction. Surg Clin North Am. 2007;87(2):453-467. 19. Petit J, Rietjens M, Garusi C. Breast reconstruction techniques in cancer patients: which ones, when to apply, which immediate and long term risks? Crit Rev Oncol Hematol. 2001;38(3):231-239. 20. Hayes DF. Follow-up of patients with early breast cancer. N Engl J Med. 2007;356(24):2505-2513. • MAY 2012 • 25(5) • JAAPA



EARN CATEGORY I CME CREDIT by reading this article and the article beginning on page 32 and successfully completing the posttest on page 63. 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 May 2012.


Describe the pathogenesis of infectious mononucleosis (IM) Correlate clinical and laboratory findings in patients with IM Recognize patients presenting with IM, and provide counseling on potential complications Discuss emerging management strategies for patients with IM

Pathogenesis, diagnostic testing, and management of mononucleosis Because Epstein-Barr virus is highly contagious and linked to various complications and malignancies, familiarity with transmission risks and the differential diagnosis is essential.

Stacey Singer-Leshinsky, MS Ed, RPA-C


nfectious mononucleosis (IM), formerly known as glandular fever, is a common clinical syndrome associated with Epstein-Barr virus (EBV) (Figure 1). Historically, the term glandular fever described a specific illness that was characterized by fever, sore throat, swollen lymph nodes, and fatigue. Later, the features of glandular fever were identified pathologically as a mononuclear leukocytosis. When this discovery was made, the name of the disease was changed to mononucleosis based on its attack site: the mononuclear lymphocytes. Today, research has shown the direct effect on lymphocytes.1 By identifying acute IM early, PAs can lower the risk of transmission and infection of susceptible hosts. Left untreated, IM can have serious complications. This article reviews the identification, diagnosis, and management of IM.

Epstein-Barr virus is a herpesvirus that primarily infects the epithelial cells of the oropharynx and tonsils.2 Infection in the tonsillar crypt epithelial cells results in viral replication and shedding. Transmission of EBV requires intimate contact with the saliva of an infected person, as happens with kissing or sharing a drinking glass.3 Viral shedding is highest in the first year postinfection and can continue throughout life in smaller amounts, thereby extending the length of transmissibility. EBV infects B lymphocytes, resulting in the proliferation and secretion of a number of different types of antibodies, including EBV-specific antibodies; heterophile antibodies; and autoantibodies, such as rheumatoid factor and antinuclear antibodies. The secretion of these various antibodies is referred to as polyclonal activity.3 After the 58 JAAPA • MAY 2012 • 25(5) •

© 3D4Medical / Photo Researchers, Inc.


FIGURE 1. Microscopic view of infectious mononucleosis

virus has invaded the host, it is kept in check by the action of natural killer cells and cytotoxic T cells.4 This cellular immune response limits the extent of primary IM and controls chronic infection. The symptoms of acute IM are a direct result of cytokines that are released from activated T cells.5 Because the symptoms of EBV infection are T-cell mediated, the initial viral load will determine the level of T-cell response and, thus, the severity of illness. Increased viral load will lead to increased T-cell response and increased symptoms. EBV can remain latent in infected B lymphocytes, which serve as lifelong viral reservoirs, expressing only a restricted number of EBV genes that are hidden from host immune surveillance cells.6 If the virus is reactivated, shedding can occur in the saliva and genital secretions of asymptomatic persons.7 EPIDEMIOLOGY AND RISK FACTORS

Most EBV transmission occurs through direct contact with saliva, but transmission also occurs during the birth process and through exposure to blood products.3 The virus has been identified in both male and female genital tracts, leading to a possible risk of infection after sexual contact with an infected partner.3 The overall incidence of IM in the United States is 500 cases per 10,000 persons per year.6 Symptomatic IM tends to occur in adolescents and young adults, although it can affect patients of any age. IM is found equally in all groups; there are no predispositions based on gender, race, ethnicity, or sexual orientation. Older adults are usually not susceptible because 95% have had prior exposure to EBV and possess lifetime latent infection.6 Infection control techniques have lowered the risk of infection. No specific seasonal pattern has been identified. CLINICAL PRESENTATION

Primary IM has an incubation period of 30 to 50 days postexposure and is a self-limiting disease. Most cases are found in young adults between 14 and 24 years of age.9 Older adults often present with clinical manifestations of hepatitis. Young children present with nonspecific mild symptoms that can conceal the diagnosis.6 The clinical diagnosis is suggested by classic symptoms of fatigue, malaise, fever, adenopathy, and pharyngitis. Prodromal symptoms include malaise, headache, and lowgrade fever. Symptoms of EBV can range from a mild flulike illness to a prolonged, debilitating disease.6

Typical physical examination findings include posterior cervical, axillary, and/or inguinal lymphadenopathy. Ten percent of patients present with a generalized maculopapular, urticarial, or petechial rash. These clinical findings should alert the clinician to suspect EBV infection.2,8 An enlarged spleen is found in 15% to 65% percent of IM patients.6 If abdominal discomfort and/or decreased hematocrit is noted, splenic rupture, though rare, can occur in 0.5% to 1% of cases.6 EBV can affect virtually any organ system and can be associated with such complications as hepatitis, pneumonia, myocarditis, mesenteric adenitis, myositis, genital ulcers, and renal failure. The symptoms of IM typically last 2 to 4 weeks, although fatigue and myalgias can persist for months. The diagnosis of IM is usually eliminated by the absence of fatigue and lymphadenopathy.2 Given that the initial presentation of the acute retroviral syndrome of HIV is clinically indistinguishable from IM (sore throat; lymphadenopathy, often including splenomegaly; fever; and malaise), a sexual/drug history should be obtained if the patient is at risk for HIV infection. DIFFERENTIAL DIAGNOSIS

When patients present with fever, rash, weakness, myalgia, and headache, acute retroviral syndrome is always a consideration. Prompt diagnosis is crucial because early treatment can reduce the risk of complications and transmission.10 Approximately 90% of cases of mononucleosislike syndrome are due to EBV. Another 5% to 10% of patients are actually exhibiting a mononucleosislike syndrome caused by other infectious agents, such as cytomegalovirus (CMV). Infection with CMV is more common in older populations.10 Complaints of pharyngitis raise the possibility of streptococcal or CMV infection. Bacterial infections, such as acute streptococcal pharyngitis, do not manifest with the atypical lymphocytes commonly seen in EBV. The pharyngitis, lymphadenopathy, and splenomegaly associated with CMV are usually mild. A patient exhibiting signs of splenomegaly and lymphadenopathy should have additional testing to rule out lymphoma. Protozoal etiologies of mononucleosis syndrome manifest with mild symptoms in the immunocompetent patient. A mononucleosislike syndrome with atypical lymphocytosis can be induced by such drugs as phenytoin (Dilantin, Phenytek, generics), carbamazepine, isoniazid, or minocycline.8 The differential diagnosis6,8 of mononucleosislike syndrome is presented in Table 1. Continued on page 60

KEY POINTS ■ EBV infects B lymphocytes, resulting in the proliferation and secretion of a number of different types of antibodies, including EBV■ ■ ■ ■

specific antibodies; heterophile antibodies; and autoantibodies (eg, rheumatoid factor and antinuclear antibodies). Older adults are usually not susceptible because 95% of them have had prior exposure to EBV and have lifetime latent infection. Hematologic findings provide clues in the analysis of IM, while serologic tests confirm infection. The mainstay treatment for primary IM is supportive care. Encourage adequate fluid and nutritional intake. Eventually, EBV might be utilized as a tumor marker in malignancy, assisting in staging, prognosis, and response to therapy. • MAY 2012 • 25(5) • JAAPA


CME Mononucleosis TABLE 1. Differential diagnosis of mononucleosislike syndrome6,8 Pathogen

Distinguishing features and laboratory findings


Corynebacterium diphtheriae

Formation of pseudomembrane in the pharynx, associated with myocarditis

Group A streptococci

Abrupt-onset sore throat, anterior cervical lymphadenopathy, tonsillar and pharyngeal erythema, scarlatiniform rash, absence of hepatosplenomegaly, little to no fatigue, positive results on rapid antigen detection test and throat culture

Mycoplasma pneumoniae

Dry cough, pneumonia

Neisseria gonorrhoeae

Tonsillitis, history of orosexual exposure; consider CDC guidelines in treatment


Toxoplasma gondii

History of ingestion of undercooked meats; small, nontender anterior lymphadenopathy; heterophile antibody-negative, positive for anti-toxoplasma IgM and IgG antibodies on ELISA



Pharyngitis, conjunctivitis, cough, fever


Viral respiratory syndrome symptoms

Influenza virus

Sudden-onset high fever, cough, and other viral symptoms

Parainfluenza virus

Upper respiratory infection, croup


Viral respiratory syndrome symptoms



Negative for heterophile antibody, mild pharyngitis, anicteric hepatitis, prolonged fever, cervical lymphadenopathy, positive for anti-CMV IgM, spin-amplified urine culture for CMV with pp65 antigen detection, elevated CMV-PCR

Coxsackievirus A

Vesicles on pharynx and soft palate, hand-foot-and-mouth disease


Infectious mononucleosis, tender posterior cervical lymphadenopathy, tonsillar enlargement, splenomegaly, positive for heterophile antibody and EBV anti-VCA IgM, IgG


Negative for heterophile antibody, positive ELISA with Western blot, painful mucocutaneous lesions, lymphadenopathy, maculopapular rash, diarrhea, nausea, vomiting, weight loss, sexual history


Roseola infantum, anterior cervical lymphadenopathy, negative for heterophile antibody, elevated anti-HHV-6 IgM and IgG levels, positive for HHV-6 PCR

Key: CMV, cytomegalovirus; EBV, Epstein-Barr virus; ELISA, enzyme-linked immunosorbent assay; HHV-6, human herpesvirus 6; Ig, immunoglobulin; PCR, polymerase chain reaction; VCA, viral capsid antigen.


Any patient presenting with the classic symptoms of IM should have a CBC and undergo screening for EBV (rapid test for heterophile antibodies), group A streptococcal pharyngitis (rapid antigen testing, throat culture), and quantitative polymerase chain reaction (PCR) test for possible HIV exposure.6 Hematologic findings provide clues in the analysis of IM, while serologic tests confirm infection. Characteristic laboratory findings of IM include an absolute lymphocytosis of greater than 50% with 10% atypical lymphocytes (activated cytotoxic T cells).3 The heterophile antibody, or monospot, test is a rapid latex agglutination serologic screening test for IgM antibodies to Paul-Bunnell antigens found on the surface of EBV-infected B cells. Heterophile antibodies are produced during the acute phase of IM. Test results are positive in up to 40% of patients during the first week of illness and in 90% of patients in later 60 JAAPA • MAY 2012 • 25(5) •

weeks.3 Because the heterophile antibody is present in many patients during the acute phase of illness, it is considered a good screening test for patients showing symptoms of the disease. Patients who have symptoms of IM but are negative for the heterophile antibody should have further serum testing for EBV-specific antibodies via indirect immunofluorescence assay (IFA). The two tests together, the heterophile antibody and EBV-specific antibody tests, have a sensitivity of 95% to 99%.3 The IFA has a high specificity and is therefore considered the gold standard for diagnosis. False-positive heterophile antibody test results can occur in patients with lymphoma, viral hepatitis, malaria, and autoimmune disease.3 Some examples of EBV-specific antibodies include antibodies to early antigen (EA) and to viral capsid antigen (VCA). These antibodies are detected by IFA on EBV-infected cells. Antibody to EA is noted in the serum during the initial stage of viral replication and is usually not detectable 3 to 6 months

TABLE 2. Interpretation of laboratory findings in suspected IM Interpretation

Atypical lymphocytes

Heterophile antibodies





Acutely infected





Past infection



Not infected and/or susceptible to disease

Key: +, positive; − negative; EA, early antigen; EBNA, Epstein-Barr nuclear antigen; Ig, immunoglobulin; VCA, viral capsid antigen.

after acute infection. IgM antibody against the viral capsid antigens (VCA-IgM) is the most useful marker for identification of acute IM because it appears at the onset of symptoms and usually disappears by 3 months.3 The presence of EA and VCA-IgM confirms primary infection with EBV. Absence of VCA-IgM is strong evidence against primary EBV infection.2 VCA-IgG antibodies are detectable at the onset of IM and remain positive for life. Their presence indicates development of immunity and is not useful in distinguishing primary from past infection.3 IgG antibodies to Epstein-Barr nuclear antigen (EBNA) become evident 6 to 8 weeks after onset of symptoms and remain positive for life.2 Since this marker appears later in the disease process, it offers strong evidence against primary EBV infection. PAs must be able to differentiate between active contagious infection, pathologic infection, and chronic latent infection. Table 2 is a summary of laboratory results and the stages of IM in which they occur. While negative heterophile antibody results might help to rule out IM, the clinician should always remain vigilant for the presence of mononucleosislike illnesses, such as acute retroviral syndrome, toxoplasmosis, or CMV or human herpesvirus-6 as the etiology of infection.8 If the patient is pregnant, follow up with nucleic acid testing for CMV and HIV because these infections have been linked to pregnancy and fetal complications. When suspicion for EBV is high despite failure to detect antibody, testing for EBV DNA on B cells is warranted.7 Also keep in mind that testing too early in the course of illness can result in decreased sensitivity because the immune response is too low. MANAGEMENT

The mainstay treatment for primary IM is supportive care. Encourage adequate fluid and nutritional intake. Analgesics and antipyretics, such as acetaminophen or NSAIDs, relieve symptoms of fever, throat discomfort, and myalgia. Corticosteroids, once thought to be safe, should be reserved for patients with severe complications. Routine use can lead to serious side effects, including immunosuppression and bacterial superinfection.11 Immunosuppression during a viral illness has been linked to malignancy. Prednisone 40 to 60 mg/day over 2 to 3 days with tapering over 2 weeks can prevent airway obstruction if there is severe tonsillar hypertrophy; autoimmune hemolytic anemia; severe thrombocytopenia; or progressive neurologic disease, such as multiple sclerosis (MS).2,6 Patients should refrain from participation in any sport for a minimum of 3 weeks after the onset of illness and from participation in strenuous contact sports for 4 weeks after the onset of illness to avoid the risk

of splenic rupture.6 Restrictions should be placed on intimate contact because viral shedding is greatest during acute IM. The clinician can prevent transmission by observing universal precautions, including proper hand washing. Infected patients should avoid donating blood products, which carries a small risk of transmission. The likelihood of a cutaneous reaction to penicillin and other antibiotics is increased in patients with acute IM. A maculopapular rash can occur in up to 95% of patients treated with antimicrobials.6,13 The pathophysiology remains unclear, although EBV might alter the immune status of the host, enhancing a hypersensitivity reaction to certain drugs and their metabolites.13 Most studies have found that this immune response reverses on resolution of symptoms, but one study found persistence of a delayed immune reaction to penicillin in a small number of some patients.14 All patients presenting with rash and a history of recent acute IM should undergo allergy testing. COMPLICATIONS

Most cases of mononucleosis resolve without sequelae in 3 to 4 weeks. Potentially life-threatening complications include splenic rupture, upper airway obstruction secondary to lymphoid hyperplasia, and mucosal edema.6,12 Ineffective immune T-cell response to EBV infection can result in excessive B-cell proliferation and in B-lymphocyte malignancies and lymphomas. The presence of EBV DNA in the malignant cells of neoplasms suggests that EBV might contribute to the pathogenesis of such malignancies as Hodgkin disease, Burkitt lymphoma, nasopharyngeal carcinoma, and gastric tumors.5,7,15 EBV is capable of infecting B lymphocytes, squamous epithelial cells, glandular epithelial cells, smooth muscle cells, T cells, natural killer cells, and follicular dendritic cells. If an infected cell transforms into a malignant cell, every daughter cell will be similar.7 Eventually, EBV might be utilized as a tumor marker in malignancy, assisting in staging, prognosis, and response to therapy.7 There is a rare increased risk of hematologic, neurologic, and autoimmune disease. Elevated antibody levels against EBV have been found in those affected with systemic lupus erythematosus (SLE), MS, and rheumatoid arthritis (RA), among others.16 Male patients with X-linked lymphoproliferative syndrome appear normal until a primary IM infection turns fatal as a result of lack of T cell response. Because these patients are unable to limit infection of B lymphocytes, death occurs due to bone marrow failure, irreversible hepatitis, and malignant • MAY 2012 • 25(5) • JAAPA


CME Mononucleosis TABLE 3. Complications of mononucleosis16 Hematologic Aplastic anemia Disseminated intravascular coagulation Hemolytic anemia Hemolytic uremic syndrome Thrombocytopenia Thrombotic thrombocytopenic purpura Neurologic Aseptic meningitis Chronic fatigue syndrome Facial nerve palsy Guillain-Barré syndrome Meningoencephalitis Multiple sclerosis Optic neuritis Peripheral neuritis Transverse myelitis Autoimmmune Multiple sclerosis Systemic lupus erythematosus Rheumatoid arthritis

lymphoma.6 Hypogammaglobulinemia, B lymphocyte lymphoma, or both develop in those who do survive.6,12 Hemophagocytic lymphohistiocytosis manifests as prolonged fever, lymphadenopathy, hepatosplenomegaly, rash, hepatic dysfunction, and cytopenia.6,12 The most common complications of mononucleosis syndrome are presented in Table 3. ONGOING RESEARCH

Antiviral agents, specifically valacyclovir (Valtrex, generics), show some promise in the management of IM. A small randomized, controlled clinical trial, conducted by the FDA, enrolled 20 Minnesota college students with laboratory-confirmed primary EBV. The oral washings of subjects who took valacyclovir showed a transient decrease in Epstein-Barr viral load (leading to a decrease in severity of symptoms and sequelae).17 A lower viral load also translates to a reduction in viral shedding and subsequent decreased transmission. Discontinuation of valacyclovir was associated with a rebound in oral viral load. Because this study was small, results need to be confirmed with a larger placebo-controlled trial. Nucleoside analogues, such as famciclovir (Famvir, generics) or valganciclovir (Valcyte), might be attractive candidates for prospective trials. Research is ongoing to establish a suitable vaccine to prevent EBV infection. A phase 2 trial randomized 181 healthy, EBV-seronegative young adults to receive either a placebo or recombinant EBV subunit glycoprotein 350 (gp350) vaccine 62 JAAPA • MAY 2012 • 25(5) •

in a 3-dose regimen. The vaccine targets gp350, a viral protein located on the EBV capsid that allows the virus to enter B cells, by attaching to CD21 antigens located on the surface of B cells.18 Results showed that the vaccine was effective in preventing the development of IM but did not offer increased protection against asymptomatic EBV infection. The study did not address the risk of developing complications and malignancies associated with IM.18 The vaccine is safe and welltolerated. A superior vaccine would incorporate T-cell target antigens. This would help T cells to recognize and destroy infected B cells, which remain infected for life, leading to a chronic carrier state.4 The development of a vaccine is clinically feasible to prevent IM and urgently needed since many serious malignancies are associated with EBV infection. CONCLUSION

Because EBV is highly contagious and is linked to numerous complications, malignancies, and death, clinicians must be familiar with risks for transmission and other possible etiologies. Serologic testing is vital to diagnosis. PAs who remain alert to the possibility of infection with EBV can help to prevent unnecessary complications and improve the prognosis of those infected with this disease. JAAPA Stacey Singer-Leshinsky is an assistant professor at the St. John’s University PA program, Queens, New York. The author has indicated no relationships to disclose relating to the content of this article. REFERENCES 1. Harmening DM. Clinical Hematology and Fundamentals of Hemostasis. 5th ed. Philadelphia, PA: FA Davis; 2009. 2. Ebell MH. Epstein-Barr virus infectious mononucleosis. Am Fam Physician. 2004;70(7):1279-1287. 3. Stevens CD. Clinical Immunology and Serology: A Laboratory Perspective. 3rd ed, Philadelphia, PA: FA Davis; 2010. 4. Long HM, Taylor GS, Rickinson AB. Immune defence against EBV and EBV-associated disease. Curr Opin Immunol. 2011;23(2):258-264. 5. Crawford DH, Macsween KF, Higgins CD, et al. A cohort study among university students: identification of risk factors for Epstein-Barr virus seroconversion and infectious mononucleosis. Clin Infect Dis. 2006;43(3):276-282. 6. Luzuriaga K, Sullivan JL. Infectious mononucleosis. N Engl J Med. 2010;362(21):1993-2000. 7. Gulley ML, Tang W. Laboratory assays for Epstein-Barr virus-related disease. J Mol Diagn. 2008; 10(4):279-292. 8. Hurt C, Tammaro D. Diagnostic evaluation of mononucleosis-like illness. Am J Med. 2007;120(10): 911.e1-911.e8. 9. McKenzie SB, Williams JL. Clinical Laboratory Hematology. 2nd ed. Upper Saddle River, NJ: Pearson; 2010. 10. Wang X, Yang K, Wei C, et al. Coinfection with EBV/CMV and other respiratory agents in children with suspected infectious mononucleosis. Virol J. 2010;7:247. 11. Thompson SK, Doerr TD, Hengerer AS. Infectious mononucleosis and corticosteroids: management practices and outcomes. Arch Otolaryngol Head Neck Surg. 2005;131(10):900-904. 12. Lerner AM, Beqaj SH, Gill K, et al. An update on the management of glandular fever (infectious mononucleosis) and its sequelae caused by Epstein-Barr virus (HHV-4): new and emerging treatment strategies. Virus Adaptation and Treatment. 2010;2:135-145. 13. Gruchalla RS, Pirmohamed M. Antibiotic allergy. N Engl J Med. 2006;354(6):601-609. 14. Jappe U. Amoxicillin-induced exanthema in patients with infectious mononucleosis: allergy or transient immunostimulation? Allergy. 2007;62(12):1473-1475. 15. Hadinoto V, Shapiro M, Greenough TC, et al. On the dynamics of acute EBV infection and the pathogenesis of infectious mononucleosis. Blood. 2008;111(3):1420-1427. 16. Niller HH, Wolf H, Minarovits J. Regulation and dysregulation of Epstein-Barr virus latency: implications for the development of autoimmune diseases. Autoimmunity. 2008;41(4):298-328. 17. Balfour HH, Hokanson KM, Schacherer RM, et al. A virologic pilot study of valacyclovir in infectious mononucleosis. J Clin Virol. 2007;39(1):16-21. 18. Sokal EM, Hoppenbrouwers K, Vandermeulen C, et al. Recombinant gp350 vaccine for infectious mononucleosis: a phase 2, randomized, double-blind, placebo-controlled trial to evaluate the safety, immunogenicity, and efficacy of an Epstein-Barr virus vaccine in healthy young adults. J Infect Dis. 2007;196(12):1749-1753.


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

ACUTE APPENDICITIS, PAGE 32 1. Occlusion of the appendiceal lumen is rarely caused by a. Neoplasm b. Parasites c. Enlarged lymph tissue d. Fecoliths 2. A classic sign of acute appendicitis is a. Decrease in appetite b. Nausea and vomiting c. Constipation and diarrhea d. All of the above 3. The Rovsing sign is a. Migration of pain from the epigastric area to the right lower quadrant b. Pain when the underlying obturator or psoas muscles are stretched c. Right lower-quadrant pain on palpation of the left lower quadrant d. Pain felt on the release of pressure over the right lower quadrant 4. The Alvarado quantitative scoring system assigns 2 points to a. Elevated temperature (37.3°C or higher) b. Leukocytosis (WBC count >10,000/␮L) c. Shift of differential to the left (more than 75% neutrophils) d. Nausea and/or vomiting 5. The most prominent complication of appendicitis is a. Perforation of the appendix b. Allergic reaction to drugs c. Small bowel obstruction d. Abscess formation 6. In three studies, patients with suspected appendicitis initially received a. Gentamicin b. Azithromycin c. Cefotaxime d. Ciprofloxacin

INFECTIOUS MONONUCLEOSIS, PAGE 58 7. Symptomatic infectious mononucleosis (IM) occurs more commonly in a. Males b. Adolescents c. Whites d. Homosexuals 8. A classic symptom of IM is a. Pharyngitis b. Petechial rash c. Photophobia d. Severe myalgias 9. What type of adenopathy is typical in patients with IM? a. Posterior cervical b. Axillary c. Inguinal d. All of the above 10. A mononucleosislike syndrome with atypical lymphocytosis may occur with use of a. Amitriptyline b. Diphenhydramine c. Phenytoin d. Acyclovir 11. Which marker offers strong evidence against primary infection with Epstein-Barr (EB) virus? a. IgG antibodies to EB nuclear antigen (EBNA) b. IgM antibody against the viral capsid antigens (VCA-IgM) c. Early antigen (EA) d. Heterophile antibody 12. Patients with acute IM have an increased likelihood of a cutaneous reaction to a. Allopurinol b. Penicillin c. Hydralazine d. Carbamazepine • MAY 2012 • 25(5) • JAAPA


Human Dissection R E A ME R L. BU S HA RDT, PharmD, PA-C


Cynthia Booth Lord, MHS, PA-C

© John Hassett

C Cindy Lord with Quinnipiac PA students

I recently had the chance to talk with Cindy about her career, her personal life, and her path to leadership. I provided her with a list of questions in advance of our conversation. At the start, though, Cindy told me she that although she had read the questions I gave her and understood the big picture, she wanted to talk spontaneously and just see where the conversation went. This turned out to be a great idea. Here is the anatomy of leadership as it has been for her.

ynthia Booth Lord completed her physician assistant training at Yale University and later earned a master’s degree at Quinnipiac University. She has been associated with the Quinnipiac PA program since it began in 1994 and for the past 14 years has served as its director. Her experiences with leadership in the physician assistant profession began at Yale, where she was the liaison between the American Academy of Physician Assistants’ student society and the organization now known as PAEA (the Physician Assistant Education Association). Cindy has served in multiple positions within the Connecticut Academy of Physician Assistants, including as president. Nationally, she has served on various AAPA committees and as president of AAPA. her reflections on family are encouragement and community. Cindy said that many of the clichés about Greek families—she comes from a Greek family—hold true to her personal experience. Her personal identity centers on family and community. If Cindy had lived in the 19th century, I am confident she would have been a transcendentalist. Like Emerson and Thoreau, she believes in the innate goodness of people and is naturally a bit skeptical of an overly organized society.

■ Lesson 1: Make your own rules.

Cindy’s parents placed enormous value on civil engagement and community service. Her mother was the kind of parent who was “always there.” To me, she sounded like the kind of parent highly dedicated teachers love—and the type who often annoys the teachers who are just trying to get by. Cindy has thought long and hard about the types of leadership roles society made available to her mother compared to the opportunities she herself has had because times have changed and because she blazed her own trail. The two major themes that emerge from

■ Lesson 2: Our childhood dramatically impacts our adulthood.

During our conversation, Cindy’s key leadership attributes became clear. She is ambitious and driven to create lasting change. She is confident, but her confidence is balanced by reflection. She appears to be genetically predisposed to create a ruckus once in a while, but this in turn is balanced with a fundamental desire to please. Young leaders sometimes fail when they push an agenda too aggressively or challenge a convention without the depth or breadth of experiences to justify change. Leaders

64 JAAPA • MAY 2012 • 25(5) •

of all ages and levels of experience can fail if they care too much about pleasing others. Cindy continues to wrestle with this conundrum in her own life, and I am reassured that such an experienced leader and seasoned educator still struggles with when to be “good cop” and when to be “bad cop.” Her strength seems to flow from a set of interrelated missions. She is proud to be a PA in family medicine and is energized by her connections with patients and families. And she loves to teach. She founded the student PA society at Quinnipiac University, and she is driven to shape rich opportunities to develop leadership potential and a sense of community service within her students. She expects the privileged to give back to the less fortunate. She is definitely a servant leader. She has always been drawn to service, and the natural consequence has been an aspiration to lead. Continued on page 66

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

Human Dissection Cindy remembers that when she first chose to lead, she was in middle school. This is surprisingly consistent with a social phenomenon that many children’s destinies are set between 5th and 6th grade. Some public school systems informally acknowledge a child’s perceived aptitude for college versus a technical career at this point, and the course is set. ■ Lesson 3: Volunteerism is a path to leadership, available to everyone.

Cindy’s enthusiasm overflowed when we talked about ways to help the next generation of PAs embrace service and leadership roles that can advance the profession. She immediately built a vision of this future with me. She threw out strategies and encouraged me that they would work. She was confident, decisive, and optimistic. She was ready to start the ball rolling. She channeled quintessential transformational leadership skills. I had tapped into her passion, and her enthusiasm was infectious. Consider your past involvement with a professional committee or team meeting at work, or maybe with a local society or professional organization. Think about that one person who always complains, who always criticizes other people’s ideas, and who seems to thrive when nothing gets done. That person is the polar opposite of Cindy. She might even be willing to send a van full of Quinnipiac PA students in ski masks to handle that troublesome person for you, in return for a few hundred hours of your time devoted to community service. ■ Lesson 4: A positive attitude brings strength, energy, and initiative.

Cindy’s leadership development has been experiential: Serve first, and learn as you go along. She described this as the “absolute best, most challenging way to learn how to be a leader.” When she talked about how she made all the big decisions in her life related to professional leadership, I was struck by two

things. One—she has a strong support system of mentors and experienced providers she regularly turns to for advice. And two—she makes these decisions collaboratively with her husband and family. She admitted a few essential truths about professional ambition and family life. No one can be everywhere, all the time. No one can be everything for everybody. She works very hard to balance her roles as a PA, educator, wife, and mother. For Cindy, “it is important for me to be at big games and special events for my children, but it is also important that they view me as a successful professional.” Some days are completely exhausting, she admitted. All leaders are at risk of losing control of their personal margin, and she believes it requires regular maintenance. ■ Lesson 5: Don’t let your personal ambition compete with your overall goals.

For the moment, Cindy has stepped back from major leadership roles. She views her experiences with her state organization and AAPA as a long course in leadership development. It was an ultimate service-learning experience, and now she is exploring how she can put her skills to use in her own community. Two elements of this perspective are really appealing. She positions herself as a perpetual learner, and she graciously makes room for new talent to emerge. This led us into a discussion of a complicated issue affecting many professional organizations: leadership succession and longevity. Continuity is important for associations and organizations, especially when networking and relationship-building are critical to the mission. Every PA organization benefits from the tireless dedication of a few unnaturally service-oriented volunteers. Cindy pointed out, however, that these people are mutants of a sort and believes young PAs should not to try to emulate them. Service roles do not have to take over your life to be impactful. Cindy made a conscious choice to step out of the spotlight after her service as AAPA’s

66 JAAPA • MAY 2012 • 25(5) •

president elect, president, and then past president. She sees it as necessary to support leadership succession and also as a way to ensure that AAPA benefits from the enthusiasm and creativity that changes in leadership can bring. In her role at Quinnipiac University, she regularly applies a principle called the “reach back,” which means constantly being on the prowl for junior faculty members or students with that leadership spark, then leveraging her position to help them connect with leadership opportunities. She likes to see the people around her be successful more than she enjoys personal success. For her, the most intimidating part of making that first leap into leadership was finding the courage to pursue it. She uses encouragement to help her faculty, students, and colleagues make the leap. Then she revels in an afterglow when people she has touched get bitten by the service bug. ■ Lesson 6: Celebrate the success of others.

In this issue’s Editorial, I announced a plan to explore leadership as epitomized by individual PAs in the hopes that their stories will help each of us realize our aptitude for leadership, demystify the path to making lasting change, and invigorate PAs to lead the profession forward. This case study of Cindy Lord reveals the consummate servant leader. She uses her passion for our profession and a genuine respect for community to inspire those around her. I discovered Cindy already embraces the African philosophy of ubuntu I described in my Editorial. She leads with a true sense of interconnectedness. I also learned that volunteerism, such as in a regional professional society, is an excellent place to gain leadership skills. Cindy believes the formula for kick-starting a leadership career is a simple one requiring a passion for serving others, a willingness to listen even when you disagree, availability of willing mentors, and a few seconds of courage—just enough time to volunteer for that first role. JAAPA

Quick Recertification Series JA M I S. S M I T H, M PA , PA-C

ACUTE ADRENAL INSUFFICIENCY ›GENERAL FEATURES • Acute adrenal insufficiency is an emergency condition caused by an insufficient amount of cortisol. • This crisis may occur during treatment of chronic adrenal insufficiency or it may be the primary manifestation. • Causes – The condition may be triggered by stressful situations, such as trauma, surgery, infection, dehydration, hyperthyroidism, or prolonged fasting in a patient with undiagnosed or untreated adrenal insufficiency. – Sudden withdrawal of adrenocortical hormone in a patient with chronic insufficiency or temporary insufficiency from exogenous corticosteroids may be a trigger. – Bilateral adrenalectomy or removal of a functioning adrenal tumor; sudden destruction of the pituitary gland; or administration of etomidate during intubation are all potential causes. – Injury to both adrenals from hemorrhage, trauma, anticoagulation therapy, thrombosis, or infection may also result in acute adrenal insufficiency. ›CLINICAL ASSESSMENT • Symptoms may include – Weakness and fatigability – Abdominal pain with nausea, vomiting, and diarrhea – Anorexia or unintentional weight loss 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.

– Fever – Confusion and headache • Physical examination may demonstrate – Hypotension, tachycardia, and tachypnea – Skin hyperpigmentation – Sparse axillary hair • Laboratory findings may include – Hypoglycemia – Hypokalemia – Hyponatremia

>>QUESTIONS & ANSWERS<< 1. Which of the following is not a cause of acute adrenal insufficiency? a. Stressful situation in a patient with chronic adrenal insufficiency b. Adrenal infarction c. Administration of vecuronium d. Bilateral adrenalectomy

›DIAGNOSIS • Diagnosis is made by simplified cosyntropin test, in which an IM injection of synthetic adrenocorticotropic hormone (ACTH) is given and serum cortisol levels are measured between 30 and 60 minutes later. • Low serum cortisol level and decreased serum cortisol response are diagnostic. ›TREATMENT • If acute adrenal insufficiency is suspected, a serum cortisol level should be obtained immediately followed by administration of 100 to 300 mg IV hydrocortisone with aggressive normal saline resuscitation, without waiting for the results. • After the initial dose, IV infusions of 50 to 100 mg should be administered every 6 hours for the first day. The same dose should be given the second day every 8 hours and then adjusted based on symptoms. – Hypoglycemia and other electrolyte abnormalities should be corrected with special attention to correcting hyperkalemia. – Rehydration with 5% dextrose and normal saline must be given. – The precipitating cause should be treated. Broad-spectrum antibiotics should be considered, as bacterial infection frequently precipitates the crisis.

Answer: c Explanation: A stressful situation in a patient with chronic adrenal insufficiency, adrenal infarction, or bilateral adrenalectomy may cause acute adrenal insufficiency. Administration of etomidate, not vecuronium, may cause acute adrenal insufficiency. 2. Which of the following diagnoses should be considered in a patient who presents with abdominal pain, nausea, vomiting with refractory hypotension, and a normal CT of the abdomen? a. b. c. d.

Ruptured spleen Dehydration Acute adrenal insufficiency Large liver laceration

Answer: c Explanation: In a patient who presents with the classic symptoms of acute adrenal insufficiency and refractory hypotension, acute adrenal insufficiency should be suspected. 3. Which of the following laboratory findings is diagnostic for acute adrenal insufficiency? a. b. c. d.

Hypoglycemia Hypokalemia Hyponatremia Low serum cortisol and decreased serum cortical response

Answer: d Explanation: Although a patient with acute adrenal insufficiency can present with hypoglycemia, hypokalemia and hyponatremia, the findings of low serum cortisol and decreased serum cortical response must be present for diagnosis.

Continued on page 68 • MAY 2012 • 25(5) • JAAPA


Quick Recertification Series CHRONIC ADRENOCORTICAL INSUFFICIENCY ›GENERAL FEATURES • Chronic adrenocortical insufficiency (Addison disease) is an uncommon disorder caused by destruction or dysfunction of the adrenal cortices. • Primary disease is characterized by a chronic deficiency of cortisol that causes elevated serum ACTH levels and subsequent skin hyperpigmentation. Secondary adrenocortical insufficiency may result from pituitary failure. • Causes – Autoimmune destruction of the adrenal glands is the most common cause. – Tuberculosis is the leading cause in areas of the world where tuberculosis is prevalent. – Bilateral adrenal hemorrhage or congenital syndromes may also trigger disease. ›CLINICAL ASSESSMENT • History is significant for the following conditions: – Weakness and fatigability – Nausea, vomiting, and anorexia – Fever and weight loss – Myalgia and arthralgia – Anxiety and mental irritability • Physical examination – Diffuse tanning of skin in both nonexposed and exposed areas with prominence in the knuckles, elbows, knees, posterior neck, and palmar creases – Sparse axillary and pubic hair – Orthostatic hypotension – Small heart, hyperplasia of lymphoid tissues, and vitiligo Jami Smith is assistant professor and academic coordinator of the PA program at Arcadia University, Glenside, Pennsylvania. She practices emergency medicine in the Philadelphia area. The author has indicated no relationships to disclose relating to the content of this article.

• Laboratory findings – Hyperkalemia (in primary disease), hyponatremia, hypoglycemia (more common in secondary and tertiary disease), or hypercalcemia – Neutropenia and anemia – Antiadrenal antibodies and antithyroid antibodies

›DIAGNOSIS • Low 8:00 AM plasma cortisol level accompanied by elevated ACTH levels is diagnostic; a low ACTH level indicates secondary disease. • Diagnosis is made by a simplified cosyntropin test if cortisol levels rise 20 mcg within 30 to 60 minutes of synthetic ACTH administration. • Low serum dehydroepiandrosterone (DHEA) levels are characteristic. • When Addison disease is not clearly autoimmune, a chest radiograph can rule out tuberculosis or other causes. ›TREATMENT • Patients should be well-educated about their condition and the potential for infections to cause an acute adrenal crisis. Medications should be titrated to the lowest dose that relieves symptoms. Glucocorticoid dosing should be increased during mild to severe illness to prevent acute adrenal crisis. • Hydrocortisone is the corticosteroid replacement of choice in doses ranging from 15 to 30 mg orally daily in 2 or 3 divided doses. Dexamethasone and prednisone are treatment alternatives. • For patients requiring mineral corticoid replacement, fludrocortisone acetate has a sodium-retaining effect. Doses range from 0.05 to 0.3 mg orally daily or every other day. • DHEA may improve the patient’s sense of well-being, increase muscle mass, and reverse bone loss at the femoral neck, particularly in female patients.

68 JAAPA • MAY 2012 • 25(5) •

>>QUESTIONS & ANSWERS<< 1. Which of the following is not a sign or symptom of chronic adrenocortical insufficiency? a. b. c. d.

Nausea and vomiting Sparse axillary hair Hypertension Hyperpigmentation of skin creases

Answer: c Explanation: Nausea, vomiting, sparse axillary hair, and hyperpigmentation of the skin creases may all manifest with chronic adrenocortical insufficiency. 2. Which of the following is the corticosteroid replacement of choice in a patient with chronic adrenocortical insufficiency? a. b. c. d.

Prednisolone Prednisone Hydrocortisone Methylprednisolone

Answer: c Explanation: Hydrocortisone is the corticosteroid replacement of choice in doses ranging from 15 to 30 mg orally daily in 2 or 3 divided doses. 3. Which test result is diagnostic for primary chronic adrenal insufficiency? a. Low 8:00 AM plasma cortisol level accompanied by elevated ACTH levels b. Elevated morning plasma cortisol levels accompanied by elevated ACTH levels c. Elevated 8:00 AM plasma cortisol level accompanied by low ACTH levels d. Low 8:00 AM plasma cortisol level accompanied by low ACTH levels Answer: a Explanation: Low 8:00 AM plasma cortisol level accompanied by elevated ACTH levels is diagnostic; a low ACTH level indicates secondary disease. Dawn Colomb-Lippa, MHS, PA-C; Amy Mercantini Klingler, MS, PA-C, department editors

When the Patient Asks S H E FA LI PAT E L, PA-C ; DENI S E RI ZZO LO, PA-C , PhD

Q: Is caffeine safe during pregnancy?


affeine, a mild neurostimulant, is the most popular pharmacologically active substance consumed worldwide.1 Although not addictive, withdrawal of caffeine may cause symptoms such as fatigue, drowsiness, weakness, and headaches. Caffeine is found in coffee, tea, soft drinks, energy drinks, chocolate, and cocoa products. Medications for colds, headaches, and allergies as well as diet pills, diuretics, and stimulants may also contain caffeine. At childbearing age and during pregnancy, caffeine consumption can negatively affect both the mother and the fetus.

›PHARMACOKINETICS AND METABOLISM Caffeine can cause increased heart rate or BP, palpitations, insomnia, irritability, jitteriness, nervousness, muscle tremors, heartburn, and dehydration.2 Caffeine is highly soluble and easily crosses cell membranes, including the placenta; after ingestion, it can be noted in tissue within 30 to 45 minutes. Levels peak within 2 hours, and the amniotic fluid and fetal blood contain large quantities.2,3 Metabolism of caffeine depends upon certain genetic and environmental factors as well as how quickly the maternal cytochrome P450 1A2 processes the caffeine.

›USE DURING PREGNANCY Fetal effects Caffeine can cause insomnia or a longer duration of arousal, inconsistent and rapid heart rate, a lower basal heart rate, increased breathing activity, and inconsistent blood flow.4 Studies show decreased birth weight (less than 5 lb 8 oz) and restricted fetal growth (length) with consumption greater than 300 mg/day.3,5,6 Pregnancy loss Some studies show an increased risk of miscarriage when consumption is greater than

300 mg/day,7 while others show an increased risk when greater than 600 mg/day.3 Stefanidou and colleagues demonstrated that caffeine consumption greater than 100 mg/day during childbearing age and early gestation heightened the risk of miscarriage; risk increased three-fold with each additional 100 mg/day.8 Anderson and colleagues found caffeine consumption of less than 200 to 300 mg/day is unlikely to increase the risk of spontaneous abortion or adversely affect fetal growth.1 However, the effects of consuming greater than 300 mg/day remain unclear. A minor correlation has been found between caffeine consumption and stillbirth or fetal death.

or soft drink per day.10 The American Pregnancy Association advises avoiding caffeine altogether.11 The exact safe level of caffeine intake during pregnancy remains debatable, but most experts recommend reducing intake to less than 100 to 200 mg/day.1 JAAPA


REFERENCES 1. Anderson K, Nisenblat V, Norman R. Lifestyle factors in people seeking infertility treatment - A review. Aust N Z J Obstet Gynaecol. 2010;50(1):8-20. 2. Eating and nutrition: Caffeine in pregnancy. March of Dimes. caffeine.html. Published May 2010. Accessed April 11, 2012. 3. Norman RJ, Nisenblat V. The effects of caffeine on fertility and on pregnancy outcomes. UpToDate. Updated January 11, 2012. Accessed April 11, 2012. 4. Mulder EJ, Tegaldo L, Bruschettini P, Visser GH. Foetal response to maternal coffee intake: role of habitual versus non-habitual caffeine consumption. J Psychopharmacol. 2010;24(11):1641-1648. 5. CARE study group. Maternal caffeine intake during pregnancy and risk of fetal growth restriction: a large prospective observational study. BMJ. 2008;337:a2332. doi: 10.1136/bmj.a2332. 6. Bakker R, Steegers EA, Obradov A, et al. Maternal caffeine intake from coffee and tea, fetal growth, and the risks of adverse birth outcomes: the Generation R Study. Am J Clin Nutr. 2010;91(6):1691-1698. 7. Peck JD, Leviton A, Cowan LD. A review of the epidemiologic evidence concerning the reproductive health effects of caffeine consumption: a 2000-2009 update. Food Chem Toxicol. 2010;48(10):2549-2576. 8. Stefanidou EM, Caramellino L, Patriarca A, Menato G. Maternal caffeine consumption and sine causa recurrent miscarriage. Eur J Obstet Gynecol Reprod Biol. 2011;158(2):220-224. 9. Hey E. Coffee and pregnancy. BMJ. 2007;334(7590):377. 10. Doheny K. Moderate Caffeine Intake Safe During Pregnancy, Experts Say. US News Health. http://health. articles/2010/07/21/moderate-caffeine-intake-safe-duringpregnancy-experts-say. Published July 21, 2010. Accessed April 11, 2012. 11. What’s the Real Scoop on Caffeine During Pregnancy. American Pregnancy Association. http://www.americanpregnancy. org/pregnancyhealth/caffeine.html. Updated March 2011. Accessed April 11, 2012.

BREASTFEEDING Caffeine can be detected in breast milk 15 minutes after consumption, with levels peaking about 1 hour later. According to the American Academy of Pediatrics, caffeine can be consumed in low doses (less than 200 to 300 mg/day) during breastfeeding.3 However, ingested caffeine can cause a longer duration of arousal, increased heart rate, lower basal heart rate, and increased breathing activity in the infant. Sleep disturbance as well as infants being wide-eyed, overly active, and irritable have been reported with consumption greater than 500 mg/day.3,4 If complete avoidance is not possible, intake should be limited to less than 200 mg/day.

›HOW MUCH IS SAFE? Since 1980, the FDA has advised women to avoid or limit caffeine intake during pregnancy.9 The March of Dimes recommends no more than 200 mg/day.2 New American College of Obstetricians and Gynecologists guidelines state women can drink one cup of coffee

Shefali Patel works in the emergency department at Trinitas Regional Medical Center in Elizabeth, New Jersey. Denise Rizzolo is a clinical assistant professor at the Pace University PA program, New York, New York, and an associate professor at the Seton Hall University PA program, South Orange, New Jersey. The authors have indicated no relationships to disclose relating to the content of this article. Mary L. Hewett, MS, PA-C, department editor • MAY 2012 • 25(5) • JAAPA


Patient Information Q: Is caffeine safe during pregnancy?


›HOW CAN CAFFEINE AFFECT ME DURING PREGNANCY? During pregnancy, caffeine can cross through the placenta and affect the fetus’s developing cells. Studies show that consuming greater than 200 mg/ day of caffeine can cause a decrease in birth weight (less than 5 lb 8 oz) and fetal growth (length). It is recommended to reduce caffeine consumption to this amount or less. Congenital malformations and negative effects on fetal and placenta blood flow are possible, and the fetus may experience a longer duration of arousal and increased heart rate or breathing activity. With an abundant caffeine intake (greater than 300 mg/day), the risk of miscarriage, stillbirth, and fetal death or demise increases. Some studies show increased risk of miscarriage when consumption is greater than 300 mg/day

caffeine is consumed. Infants younger than 6 months cannot break down and excrete caffeine easily and therefore are more sensitive to intake. However, studies have found that fetuses of habitual caffeine consumers were not as affected, possibly because tolerance developed. If complete avoidance is not possible, the breastfeeding mother should limit intake to less than 200 mg/day.


while others show an increased risk at greater than 600 mg/day. Other studies suggest caffeine consumption, even 100 mg/day, during childbearing age and early gestation predispose the patient to a higher risk of miscarriage that increases by about three times with every additional 100 mg/day consumed. The exact safe amount of caffeine consumption during pregnancy is unknown; it is predicted to be less than 100 to 200 mg/day.

›CAN I STILL BREASTFEED IF I DRINK CAFFEINE? Caffeine can be detected in breast milk 15 minutes after consumption and may cause a longer duration of fetal arousal and increased fetal heart rate or breathing activity. According to the American Academy of Pediatrics, caffeine can be consumed in low doses (less than 200-300 mg/day) during breastfeeding. Reports of babies experiencing sleep disturbances and being wide-eyed, overly active, and irritable have surfaced when more than 500 mg/day of

One cup of coffee contains about 100 mg of caffeine. However, the cup size, brewing method, and brand impact the true amount of caffeine. For example, one 8 oz cup of Starbucks coffee contains more caffeine (about 250 mg) than two to three cups of coffee elsewhere. Soft drinks also contain caffeine (12 oz of Coca-Cola contains 46 mg and 8.3 oz of Red Bull energy drink contains 80 mg). There are many ways to reduce your intake of caffeine. Drink plenty of water to stay hydrated and reduce cravings. Replace caffeinated beverages with decaffeinated options, and exercise regularly to fight withdrawal symptoms and stay energized. Switching from brewed to instant coffee and steeping tea for a shorter period of time can decrease the caffeine content in these beverages.

›THE BOTTOM LINE Excessive caffeine intake harms the pregnancy and the fetus in many different ways. Since 1980, the FDA has advised women to avoid or limit their caffeine intake during pregnancy. Although study results about the exact safe level of caffeine consumption are conflicting, many studies recommend reducing intake to less that 100 to 200 mg per day or eliminating it completely. JAAPA

70 JAAPA • MAY 2012 • 25(5) •

© / Hannes Eichinger

affeine is a mild neurostimulant that causes temporary improvements in mental and physical function. It is the most popular substance that affects the function of the body that is consumed worldwide. Caffeine is found in many products such as coffee, tea, soft drinks, energy drinks, chocolate, and cocoa products. Some medications for colds, headaches, and allergies as well as diet pills, diuretics, and stimulants also contain caffeine. Caffeine can cause an increased heart rate, palpitations, high blood pressure, insomnia, irritability, jitteriness, nervousness, muscle tremors, heartburn, and dehydration. While caffeine is not addictive, it can cause fatigue, drowsiness, weakness, and headaches if you abruptly stop taking it. Consuming caffeine at childbearing age and during pregnancy can affect not only the mother but the fetus as well.

Diagnostic Imaging Review M AJ O R A ME LI A M. D U RA N -STA N TO N, O PA-C , PhD, DSc PAS-CO ; M A JOR JOS EPH A LDERETE, MD

moon face and buffalo hump. Her right lower extremity was internally rotated and shortened compared to the left. Tenderness was present on the midanterior aspect of the right thigh. She was neurovascularly intact distally, and her skin appeared to be healthy. The orthopedic team was consulted and plain radiographs of the right femur were ordered (Figure 1). What does the

FIGURE 1 Anteroposterior radiograph of the right hip

radiograph reveal?


Right leg pain after a fall in a patient with a prosthesis ›CASE A 28-year-old female with juvenile rheumatoid arthritis (JRA) presented to the emergency department in March 2010 with pain in her right leg and inability to bear weight. She stated that when she stepped down from sitting on a stool at home, she accidentally twisted her right leg and felt immediate pain with instability. JRA had been diagnosed when the patient was 2 years old, and she had been taking oral corticosteroids ever

since. She underwent bilateral total hip arthroplasty (THA) in 2007 and bilateral total knee arthroplasty in 2008. In February 2009, she required left THA revision after she sustained a Vancouver type C periprosthetic fracture (PPF) from a low-impact injury. A revision of a left periprosthetic fracture open reduction internal fixation (ORIF) caused by nonunion was completed in November 2009. On examination, the patient was obese with short stature and noticeable

Amelia Duran-Stanton is an orthopedic PA and the Phase 2 Clinical Coordinator, Interservice Physician Assistant Program, Womack Army Medical Center, Fort Bragg, North Carolina. Joseph Alderete is an orthopedic surgeon and an adjunct professor, San Antonio Uniformed Services Health Education Consortium (SAUSHEC) Orthopedic Surgery Residency Program, Brooke Army Medical Center, Fort Sam Houston, Texas. He specializes in orthopedic oncology. The authors have indicated no relationships to disclose relating to the content of this article.

Radiograph of the right femur showed a Vancouver type C short spiral oblique periprosthetic fracture. Plain radiographs of her left femur showed that the nonunion appeared to be healing (not pictured). Periprosthetic fractures have a high complication rate, poor functional outcomes, and a high death rate.1-4 Risk factors that predisposed this particular patient to PPFs include osteoporosis, female sex, juvenile rheumatoid arthritis, and previous hip surgery.5 Prevention of PPFs is the key to management.6,7 Females with RA usually experience cortical thinning and a decrease in cancellous bone density.1 Periprosthetic fractures are a serious complication of total hip and knee replacements caused by minor mechanisms of injury.7 When treating a patient with both rheumatoid arthritis and a PPF, the orthopedic surgeon is faced with the challenge of placing the internal fixation on soft bone and operating in a compromised mechanical environment caused by previous total arthroplasties.1 The Vancouver classification system, the most widely used and reliable system of its sort, is used to describe PPFs based on the location of the fracture site and can assist the surgeon in planning which constructs to use.2,7 According to the Vancouver system, Type A fractures are located at the trochanter, type B fractures surround the stem of the femoral component, and type C fractures are located below the tip of the femoral • MAY 2012 • 25(5) • JAAPA


Diagnostic Imaging Review prosthesis.2,6 The system also allows the classification to be broken down further based on the stability of the prosthesis and remaining bone stock.7 Treatment Vancouver type A fractures are often managed conservatively while Vancouver type B fractures usually require open reduction internal fixation using a combination of cable plates, cerclage wires, and grafts. Treatment of Vancouver type C PPFs includes retrograde nailing, locking plates, or cable plating.2,3 Approximately half of all Vancouver type C fractures require revision, and prior surgical interventions typically interrupt the blood supply and damage the tissue, contributing to a slow healing process.3,4 In this patient, the left femur PPF nonunion was treated with a lateral distal femur plate with multiple unicortical locking buttress screws (two proximally and three distally), bone autograft from the proximal tibial metaphysis in the nonunion site, and a femoral cortical strut graft with two cables on

the anterior-posterior aspect of the femur. Three additional cables were applied to augment fixation of the proximal fragment. Four months later, the right PPF was treated with an interfragmentary lag screw to establish apposition and compression of the fracture. A locking plate and cable were placed proximally, and a large fragment standard cortical compression screw and four unicortical locking screws were also placed and proximally augmented by two cables. During both operations, radiographs were obtained to ensure that the total knee arthroplasties were not placed in nonanatomic alignments by fixing the femora. At her 6-month follow-up visit, the patient was doing well, and her hip-to-ankle radiograph showed no construct failure and interval healing at the fracture sites. JAAPA

official policy or position of Womack Army Medical Center, Brooke Army Medical Center, the U.S. Army Medical Department, the U.S. Army Office of the Surgeon General, the Department of the Army, the Department of Defense, or the U.S. Government. REFERENCES

Julie Edmiston, PA-C, RT, department editor Disclaimer: The view(s) expressed herein are those of the author(s) and do not reflect the

1. Bogoch ER, Moran EL. Bone abnormalities in the surgical treatment of patients with rheumatoid arthritis. Clin Orthop Relat Res. 1999;(366):8-21. 2. Young SW, Pandit S, Munro JT, Pitto RP. Periprosthetic femoral fractures after total hip arthroplasty. ANZ J Surg. 2007;77(6):424-428. 3. Young SW, Walker CG, Pitto RP. Functional outcome of femoral peri prosthetic fracture and revision hip arthroplasty: a matched-pair study from the New Zealand Registry. Acta Orthop. 2008;79(4):483-488. 4. Zuurmond RG, van Wijhe W, van Raay JJ, Bulstra SK. High incidence of complications and poor clinical outcome in the operative treatment of periprosthetic femoral fractures: An analysis of 71 cases. Injury. 2010;41(6):629-633. 5. Haddad FS, Masri BA, Garbuz DS, Duncan CP. The prevention of periprosthetic fractures in total hip and knee arthroplasty. Orthop Clin North Am. 1999;30(2):191-207. 6. Tsiridis E, Haddad FS, Gie GA. The management of periprosthetic femoral fractures around hip replacements. Injury. 2003;34(2):95-105. 7. Mitchell PA, Masri BA, Duncan CP. Periprosthetic fractures: classification and management. Techniques in Orthopaedics. 2001;16(3):291-309.


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Your very own malpractice team With your career and your financial future at stake, Marsh U.S. Consumer, a service of Seabury & Smith, Inc., recommends a personal malpractice plan for every physician assistant—even if your employer offers a liability plan as well. That’s why Marsh set up the proliability plan for physician assistants. proliability delivers best-in class benefits … backed by a defense team specializing in medical malpractice claims. Whether you’re standing before a judge or defending yourself before a licensing board, you want the best defense a physician assistant can get.

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Parkinson disease ›CONDITION Parkinson disease

›CLINICAL BOTTOM LINE • Parkinson disease (PD) is a chronic, progressive, neurodegenerative disorder that affects movement, coordination of movement, and speech. PD is characterized by a distinct set of clinical findings including resting tremor, rigidity, and bradykinesia.1 Other symptoms may include depression, difficulty speaking or swallowing, balance problems, and sleep disruptions, among others. Progressive loss of brain function and early death are possible if the disease advances. PD was originally associated with a loss of dopaminergic neurons in the substantia nigra with Lewy bodies found postmortem in intact nigral cells.2 • Family history is important, as PD may be inherited in an autosomal dominant or autosomal recessive pattern. Genetics are thought to cause approximately 10% of cases, primarily occurring in patients with younger-onset disease. The effects of multiple genes in combination with environmental issues such as exposure to pesticides or herbicides are thought to cause most PD cases.3,4 • Genetic testing can help to identify the genes and mutations linked to PD. This knowledge helps to distinguish the varying inheritance patterns for PD, assists families in decision making, and increases what is known about the disease. Nguyen Park is a faculty member in the PA program at the University of New Mexico in Albuquerque, New Mexico, and is the primary Special Environmental Health Registry clinician at the VA Medical Center. The author has indicated no relationships to disclose relating to the content of this article.

• Primary care management pearls – Take a three-generation family history, making special note of any family members with a history of movement disorder as well as the age of onset. – Document occupational or lifetime exposure to pesticides or herbicides (eg, Agent Orange), as they have been linked to a lifetime increased risk of developing PD.3-5 – Assess the fall risk of the household before the disease progresses to prevent future accidents. – Refer the patient and family for caretaker training and counseling, especially because 1 in 5 affected persons develops depression.6 – Encourage the patient to participate in occupational, physical, and speech therapy to help slow the progression of disease and compensate for the loss of coordination and motor function.

›WHAT IS PARKINSON DISEASE? • Prevalence and epidemiology PD is the second most common neurodegenerative disorder. It occurs most frequently in patients older than 50 years, with a 1% to 2% lifetime risk.7 PD occurs more frequently in males than in females with an incidence rate of 19 per 100,000 versus 9.9 per 100,000, respectively.8 The disease appears to be less common among African Americans than whites.8 Those who were exposed to certain types of pesticides developed PD 2.5 times more frequently than those not exposed.3 The cumulative lifetime risk among firstdegree relatives of affected persons with non-Mendelian forms of PD is 3% to 7%.6

• Characteristics The majority of PD cases appear to be sporadic, but genetic factors contribute particularly when the disease manifests at younger than 50 years.6 Patients with PD experience four primary symptoms: tremor, bradykinesia, rigidity, and postural instability as disease progresses. Other pathognomonic features include micrographia and masked facies.9 Symptom severity varies. Some patients suffer from severe tremor while others experience only a mild tremor in association with the constellation of other symptoms. • PD can be characterized by the age of onset. Juvenile-onset PD is defined as onset at younger than 20 years; early-onset PD is diagnosed with onset at younger than 50 years; and late-onset PD is an onset at older than 50 years. Postmortem analysis demonstrates loss of dopaminergic neurons in the substantia nigra as well as the presence of Lewy bodies (intracytoplasmic inclusions) in intact nigral cells.

›DIFFERENTIAL DIAGNOSIS6 • Alzheimer disease • Corticobasal degeneration, essential tremor • Drug-induced parkinsonism • Lewy body dementia • Parkinsonism-predominant multiple system atrophy (formerly called striatonigral degeneration) • Postencephalitic conditions • Progressive supranuclear palsy

›DIAGNOSIS • The diagnosis of PD is based on both clinical findings and the pathologic postmortem finding of lesions in the substantia nigra, which indicates a loss of dopaminergic • MAY 2012 • 25(5) • JAAPA


GENOMICS IN PA PRACTICE “Molecular genetic testing should be offered to relatives if a disease-causing mutation for PD has been identified in the family.” neurons and Lewy bodies. Therefore, some degree of uncertainty is expected. A decrease in symptoms with levodopa supports a diagnosis of Parkinson disease.

›MANAGEMENT • No cure currently exists for PD, but pharmacologic therapy is effective at controlling symptoms. Dopamine replacement with dopamine agonists is the primary choice of therapy.1 CatecholO-methyltransferase (COMT) inhibitors, monoamine oxidase B (MAO-B), or anticholinergics may be useful. Other drugs, such as bromocriptine (Parlodel, Cycloset, generics), pramipexole (Mirapex, Mirapex ER, generics), and ropinirole (Requip, Requip XL, generics), may also be effective. More invasive treatments can be utilized when medication no longer controls symptoms.10 All patients with pathognomonic symptoms

Online resources For clinicians • Overview of the genetics of PD: NBK1223 • Overview of the diagnosis and management of PD: www.ncbi. For patients • National Parkinson Foundation Web site: • Patient information from the US National Library of Medicine: pubmedhealth/PMH0001762 • MedlinePlus Parkinson disease interactive tutorial: www.nlm. parkinsonsdisease/htm/index.htm

should be referred to a neurologist, preferably one who specializes in movement disorders.

›GENETICS OF PD • Heritability pattern/familial risk – Autosomal dominant Probands have at least one parent with the condition, although de novo mutations represent an unknown proportion of cases. Family history may be incomplete if death of the parents occurred before the onset of symptoms. Siblings and offspring of probands with an affected parent carry a 50% risk of inheriting the mutation.6 – Autosomal recessive Each sibling of an affected person has a 25% chance of developing PD, a 50% chance of being an asymptomatic carrier, and a 25% chance of being an unaffected noncarrier. Siblings determined to be unaffected have a 2 in 3 risk of being a carrier.6 • Genes identified The following genes have been implicated in some forms of PD: – Autosomal dominant PD Four known genes cause mutations: SNCA (PARK1), UCHL1 (PARK5), LRRK2 (PARK8), and one mapped gene (PARK3).6 – Autosomal recessive PD Mutations occur in 3 known genes: PARK2 (PARK2), PARK7 (PARK7), and PINK1 (PARK6).6 – Susceptibility to PD Mutations occur in NR4A2, SNCAIP, and mitochondrial DNA deletions.6 • Genetic testing – Testing Molecular genetic testing is not available for all genes identified. Tests are available only for LRRK2, PARK2, PARK7, PINK1, and SNCA.6 The provider should evaluate each case of PD

74 JAAPA • MAY 2012 • 25(5) •

individually because testing is limited, PD cases are highly heterogeneous, and the risk to first-degree relatives varies widely. – Referral Patients with PD and their first-degree relatives should be referred for a thorough neurologic evaluation. Molecular genetic testing should be offered to relatives if a disease-causing mutation has been identified in the family. • Benefits and limitations of testing – Genetic testing must always be tied to clinical findings because genotype/phenotype correlation is not fully understood. Genetic testing may assist in family planning for those with identified mutations in PARK2 and LRRK2 genes; however, incomplete penetrance of gene expression means that persons carrying known linked genetic mutations may never develop PD. JAAPA Michael A. Rackover, PA-C, MS; Constance Goldgar, MS, PA-C, department editors REFERENCES 1. Sloan EP, Handel DA, Gaines SA. Chapter 167. Chronic Neurologic Disorders. In: Tintinalli JE, Stapczynski JS, Cline DM, et al, eds. Tintinalli’s Emergency Medicine: A Comprehensive Study Guide. 7th ed. New York, NY: McGraw-Hill; 2011. URL: Accessed April 2, 2012. 2. Braak H, Braak E. Pathoanatomy of Parkinson’s disease. J Neurol. 2000;247 Suppl 2:II3-II10. 3. Costello S, Cockburn M, Bronstein J, et al. Parkinson’s disease and residential exposure to maneb and paraquat from agricultural applications in the central valley of California. Am J Epidemiol. 2009;169(8):919-926. 4. Tanner CM, Kamel F, Ross GW, et al. Rotenone, paraquat, and Parkinson’s disease. Environ Health Perspect. 2011; 119(6):866-872. 5. National Research Council. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press; 2009:515-527. 6. Pankratz ND, Wojcieszek J, Foroud T. Parkinson Disease Overview. In: Pagon RA, Bird TD, Dolan CR, et al, eds. GeneReviews. Seattle, WA: University of Washington, Seattle; 1993-2012. URL: NBK1223/. Updated July 9, 2009. Accessed April 2, 2012. 7. Elbaz A, Bower JH, Maraganore DM, et al. Risk tables for parkinsonism and Parkinson’s disease. J Clin Epidemiol. 2002;55(1):25-31. 8. Van Den Eeden SK, Tanner CM, Bernstein AL, et al. Incidence of Parkinson’s disease: variation by age, gender, and race/ ethnicity. Am J Epidemiol. 2003;157(11):1015-1022. 9. Hughes AJ, Daniel SE, Ben-Shlomo Y, Lees AJ. The accuracy of diagnosis of parkinsonian syndromes in a specialist movement disorder service. Brain. 2002;125(Pt 4):861-870. 10. Molecular ‘Tweezers’ Break Up Toxic Aggregations Of Proteins, Halt Parkinson’s Disease In Animal Model. Medical News Today. php. Published March 6, 2012. Accessed April 2, 2012.

EMERGENCY MEDICINE NOTES Alexandra Godfrey, MS, PA-C, practices emergency medicine at St. Joseph’s Mercy Hospital, Ypsilanti, Michigan. She is a member of the JAAPA editorial board.

“The mother needs kindness, hope, compassion—not a dismal discourse on pain.”

Nepenthe Better to light one candle than to curse the darkness. —Chinese proverb


he fat man sleeps. The chatter of the nurses, the monitor alarms, and the shrieking protests of the overloaded gurney wheels fail to wake him. EMS gives their report as they roll him in: 38-year-old male with altered mental status, RR 14, P 57, SaO2 85%, BP 90/60. Alert and oriented to name only. Family is en route. Per caregiver, patient fell this morning, hitting his head and exacerbating his chronic back pain. He takes oxycodone daily. The patient has been difficult to wake since noon. The sleeping man is vast. It takes six of us to lift him. We move him in a single wave motion from gurney to mattress, trying to place him squarely on the bed. Still, he looks uncomfortable. His body flows like an ocean across the bed; belly floating over hips and chest, legs and arms cascading over frame, head tipped awkwardly to the right. He breathes slowly. I watch the rise and fall of his chest as numbers flash on the monitor. The flow of his breathing is like an ebbing tide. I call his name, rub on his sternum, force his eyes open. I want him to wake up to answer my questions: is he bleeding, infected, well-medicated? I call to him again, shaking him more roughly now, demanding his attention. His eyes pop wide open, revealing pools of rust brown and pinpoint pupils that speak of downregulation, CO2 intoxication, and coma. He stares at me with his empty, miotic eyes. Rush, euphoria, tranquility; the man is drifting away. I bring him back with Narcan. He responds quickly. I smile at him, tell him we need to talk. He smiles politely back at me. In his eyes a nightmare dances; they shift and falter as I question him further. I ask him to tell me about his day. The man says he woke up with back pain. He stumbled out of bed, tripped and hit the

floor, knocking his head. He cannot recall whether he lost consciousness. I ask him, “How did you get up? What next?” He remembers pulling himself up from the floor and reaching for his oxycodone. He had a prescription for 90 pills. I look him in the eyes now; softly I ask, “How many did you take?” He shakes his head; then murmurs, “I don’t know.” Was he trying to go all the way? I ask him: “Did you want to end your life?” He lets out a sad laugh and turns his face away from me. I touch him on his arm, repeating my question. I need him with me now. This time he answers: “No, I wanted to stop the pain. No matter what I do, I hurt. I have lost my job, my wife, and my kids. I have tried to kick the drugs. I cannot do this anymore. Look at me: I am a loser. I tried to talk with my doctor but he didn’t listen. No one listens. I am alone. Who wants me?” The man is caught in a deep blue funk. Tears flow down his face. I remind him I am listening to him. He is wanted here. He needs to be in the hospital. He responds by asking me for morphine. He pleads for more. I am firm in my denial. I tell him more pain medications would kill him. I keep him on a monitor, watch his breathing closely, and order a head CT. The man goes to CT 20 minutes later. His mom arrives while he is gone. His mom’s face holds the deep, questioning angst of a traumatized parent. “Where did I go wrong?” she asks. “I have tried to help him lose weight, tried to help him kick the drugs. He won’t listen to me. I pray to God he will hear me. He puts up all his defenses. Someday I’ll find him dead.” She pauses for a moment, and then adds in a whisper, “You gave him these drugs. You, people like you. So tell me: how I save him?” I do not feel like a savior. I suppress the desire to say I did not prescribe his drugs, force his hand to bottle, instruct him to take too much. Convoluted explanations focused on personal responsibility, self-control, pain management, withdrawal, tolerance, and addiction fill my mind. I am high on rhetoric. Is this my rush, euphoria, tranquility? Am I seeking absolution? I look again at the mother. She needs kindness, hope, compassion—not a dismal discourse on pain. I tell her I am here to help. For now, we are focusing on her son’s airway and breathing. Later we will address his chronic pain, opiate dependence, and substance abuse. I assure her she is not alone. Relief floods in: “Thank you,” she says. When her son comes back from CT, his oxygen levels continue to drop in spite of repeated doses of Narcan. I start a Narcan drip and admit him to the ICU. His mom cries as he leaves. He pleads with her to stop; the water keeps on falling. I see him try to straighten himself on the bed. The weight of his body defeats him. He is uncomfortable but his breathing is strong and steady. I worry about his future. Will he overcome the pain? Will he trip and stumble, then crash his mother’s dreams and return in mine? I don’t have the answers. Perhaps there’s pain in every salvation. JAAPA • MAY 2012 • 25(5) • JAAPA


Case of the Month FIGURE 1 Nonblanching petechiae on the neck

›CASE A 59-year-old female presented to the emergency department (ED) with constant oral bleeding that began that morning while the patient was brushing her teeth. Nothing stopped the bleeding, prompting her visit to the ED. For three days prior, the patient had noticed her gums intermittently oozing blood while she brushed her teeth and a foul odor on her breath, which others had mentioned to her. Blood was present in her urine and stool. No weight loss, nausea or vomiting, fatigue, or change in appetite or diet had occurred. She denied any recent trauma, travel, accident, or illness and was not taking any prescription or OTC medications or supplements. The patient had no significant history and had not sought medical care in 12 years or dental care in 5 years. She stated that she had stopped smoking more than 10 years ago and denied current alcohol or illicit drug use or sexually transmitted infections. She had no known allergies. Physical examination The patient’s vital signs were as follows: temperature, 98.4ºF; heart rate, 110 beats per minute; respiratory rate, 22 breaths

Lauren Neighbors; John L. Abt, DO, FACEP; Joyce Wagner, MCMS, PA-C

per minute; BP, 131/77 mm Hg; and oxygen saturation, 98% on room air. Examination of the skin revealed nonblanching petechiae on all extremities but not on the face, palms, or soles of the feet (Figure 1). There was ecchymosis and swelling of the right cheek, bright red blood on the oral mucosa, and a blood-filled blister on the right buccal mucosa. The neck exhibited full range of motion with no ecchymosis or swelling, lymphadenopathy, or bruits. Cardiac examination revealed S1 and S2 heart sounds with tachycardia and regular rhythm; no murmurs, gallops, or rubs were detected. Breath sounds were clear to auscultation bilaterally; no wheezing, rhonchi, or rales were heard. Inspection of the abdomen and trunk revealed diffuse nonblanching petechiae. The abdomen itself was soft, nontender, and nondistended. Bowel sounds were heard in all four quadrants. Laboratory studies Prothrombin time, international normalized ratio, activated partial thromboplastin time, comprehensive metabolic panel, CBC with differential, type and screen, urinalysis, and antinuclear antibody tests were ordered. Platelet count was 8×103/µL with decreased platelet morphology. WBC count was 1.7×109/L, and RBCs identified in urine were too numerous to count.


Thrombocytopenia Disseminated intravascular coagulation Idiopathic thrombocytopenic purpura Thrombotic thrombocytopenic purpura

›DISCUSSION The patient had idiopathic thrombocytopenic purpura (ITP), also known as immune thrombocytopenia or autoimmune thrombocytopenic purpura. This clotting disorder can lead to easy or excessive

bruising and bleeding. It is primarily a disease of increased peripheral platelet destruction in the absence of toxic exposure and is associated with a low platelet count. In patients afflicted with the disease, antibodies produced by the immune system attach to the platelets, thereby marking the platelets for destruction. The spleen then removes the platelets from circulation. Hemorrhage is the most serious complication of ITP, with intracranial hemorrhage being the most significant. Acute ITP often follows an acute infection and resolves spontaneously. Chronic ITP persists longer than 6 months and has no specific cause. Treatment The patient was transferred from the ED to the intensive care unit, and a hematology consult was ordered. She was started on normal saline 100 cc/hour. She was also started on immune globulin 35 g IV and methylprednisolone 60 mg IV every 8 hours for 3 days to decrease the activity of the immune system and thereby raise the platelet count. At discharge, the patient was instructed to follow up immediately with a primary care physician, whom she should alert at the first sign of any idiopathic bleeding. She was also instructed to avoid plateletimpairing medications such as aspirin and ibuprofen and to monitor herself for signs of infection. Lastly, she was advised to choose low-impact physical activities to avoid the risk of injury and bleeding. JAAPA Lauren Neighbors is a student and Joyce Wagner is clinical coordinator and a graduate professor in the PA program at Keiser University, Ft. Lauderdale, Florida. John Abt is an associate professor of emergency medicine at Jackson Health System, Miami, Florida. The authors have indicated no relationships to disclose relating to the content of this article. Erich Fogg, PA-C, MMSc, department editor

Tell us what you think! Go to to comment on this article. • MAY 2012 • 25(5) • JAAPA



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76 JAAPA • MAY 2012 • 25(5) •

Professional Opportunities and Development for Physician Assistants




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16th Annual Certification and Recertification Review for Physician Assistants August 14-17, 2012 Oregon Health & Science University Physician Assistant Program ✦ Portland, Oregon Last year’s attendees said: Newly graduated PAs will be prepared ✦ Exceptionally well organized - absolutely for the PANCE; experienced PAs will outstanding! benefit from the general review format in preparation for the PANRE. Curriculum ✦ Well-focused lectures covered blueprint content well. I plan to attend again to is based on the NCCPA Exam Blueprint. recertify.

Registration includes a comprehensive ✦ Excellent course! Well worth the trip. I will definitely recommend to colleagues. syllabus and flash drive of the material presented; continental breakfasts, lunches This program has been reviewed and is approved for a maximum of 28 hours of AAPA Category I CME credit by and refreshments will be provided. the Physician Assistant Review Panel. Physician assistants Online registration is now available.

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78 JAAPA • MAY 2012 • 25(5) •


JAAPA May 2012  

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

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