July 2013 Clinical Advisor by The Clinical Advisor

The Clinical ADVISOR • july 2013 Volume 16, Number 7

A F O R U M F O R p h y s i c i a n a s s i s taNTS

NEWSLINE

■■NSAID risks predictable ■■Prevent unsafe injections ■■Pain meds tied to ED

advisor forum

■■Options for tinnitus ■■Nocturnal leg cramps ■■Discussing spiritual health

| j u ly 2 01 3 | www.ClinicalAdvisor.com

the race to save a

severed hand After an accident with a miter saw, a surgical team rushes to reattach the victim’s limb.

legal advisor

A medication error leads to permanent brain damage

✶ free cME courses!

n Dermatology Clinic

painful, enlarging foot lesions page 71

n Dermatologic Look-Alikes

tender and sessile neck papule page 77 Expanded job listings! www.ClinicalAdvisor.com/Jobs

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Editor Joe Kopcha, editor@clinicaladvisor.com Managing editor Marina Galanakis Senior editor Delicia Yard Web editor Nicole Blazek Contributing editors Bruce D. Askey, MSN, CRNP; Rebecca H. Bryan, APRN, CNP; Eileen F. Campbell, MSN, CRNP; Philip R. Cohen, MD; Deborah L. Cross, MPH, CRNP, ANP-BC; Sharon Dudley-Brown, PhD, FNP-BC; Maria Kidner, DNP, FNP-C; Joan W. Kiely, MSN, CRNP; Debra August King, PhD, PA; Ann W. Latner, JD; Claire B. O’Connell, MPH, PA-C; Kathy Pereira, MSN, FNP-BC; Sherril Sego, FNP, DNP; Julee B. Waldrop, MS, PNP; Kim Zuber, PA-C Art director Andrew Bass Group art director, Haymarket Medical Jennifer Dvoretz Production director Kathleen Millea Circulation manager Paul Silver Audience development director John Crewe National accounts manager Alison McCauley, 646.638.6098 alison.mccauley @ haymarketmedical.com Group publisher Thomas P. Hennessy, 646.638.6085 tom.hennessy @ haymarketmedia.com Editorial director Jeff Forster Vice president, medical magazines and digital products Jim Burke CEO, Haymarket Media, Inc. Lee Maniscalco All correspondence to: The Clinical Advisor 114 West 26th Street, 4th Floor, New York, NY 10001 For advertising sales, call 646.638.6085. For reprints, contact Wright’s Reprints at 877.652.5295. Persons appearing in photographs in “Newsline,” “The Legal Advisor,” and “Clinical Challenge” are not the actual individuals mentioned in the articles.They appear for illustrative purposes only. The Clinical Advisor® (USPS 017-546, ISSN 1524-7317), Volume 16, Number 7, is published 12 times a year, monthly, for $75.00 per year in the United States; $85.00 in Canada; $110.00 for all other foreign, in U.S. dollars, by Haymarket Media, Inc., 114 West 26th Street, 4th Floor, New York, NY 10001. Single copy: $20 U.S.; $30 foreign. www.ClinicalAdvisor.com. To order or update your paid subscription, call 800.436.9269. Periodicals postage rate paid at New York, NY, and additional mailing offices. POSTMASTER: Send all address changes to: The Clinical Advisor, c/o DMDData Inc., 2340 River Road, Des Plaines, IL 60018. Call 800.430.5450 to change your address or make other subscription inquiries. Requests for subscriptions from outside the United States must be accompanied by payment. All rights reserved. Reproduction in whole or in part without permission is prohibited. Copyright © 2013.

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AMA defines obesity as a disease In the latest turn in an ongoing debate, the American Medical Association has labeled obesity as a disease.

Top 10 Issues in Men’s Health The gap in life expectancy between men and women has been shrinking, but several health factors still work against men. Fortunately, many of the top risks can be prevented or treated if diagnosed early. Learn more about men’s health with this slideshow.

Increased consumption of red meat tied to type 2 diabetes A recent study suggests an association between eating red meat and the onset of type 2 diabetes mellitus. HCV screening recommended for high-risk individuals and baby boomers People with a history of drug use through injection and those born between 1945 and 1965 are particularly vulnerable to hepatitis C infection.

Derm Dx Interact with your peers by viewing the images and offering your diagnosis and comments. CliniAd.com/15gJgE0

The Waiting Room Official Blog of The Clinical Advisor CliniAd.com/VwgfCl Sharon M. O’Brien, MPAS, PA-C Traumatic brain injuries may cause sleep disturbances in soldiers Many military personnel are exposed to multiple explosions that may induce brain injuries and sleep problems. Robyn Carlisle, MSN, CNM, WHNP Suspending personal bias from patient care Clinicians are entitled to their own beliefs, but should we be imposing our values on patients? Leigh Montejo, MSN, FNP-BC NPs play an important role in preventing errors More procedures are being implemented to help nurse practitioners and other health-care providers avoid errors. Jessica Swanson Access to quality food lacking in Hispanic neighborhoods “Food deserts” in low-income areas contribute to high obesity rates.

White spots on sun-damaged skin At his annual skin check, a man who worked outside for 40 years presents with numerous white spots on his arms.

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Robyn Carlisle, MSN, CNM, WHNP The facts about Plan B As the laws regulating emergency contraception change, make sure you know the facts and are educating your patients.

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Now Available

...it’s time.

For more information, including clinical data, visit BELVIQ.com.

BELVIQ® is a registered trademark of Arena Pharmaceuticals GmbH. LORC0127

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Printed in USA.

1/2013

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contents j u ly 2 0 1 3

News and comment

Departments

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

Newsline ■■Risks of NSAID use can be

predicted ■■Diabetes progresses more rapidly

in kids 61 Legal Advisor A strong dose of an opioid administered to a woman recovering from surgery causes permanent damage.

■■Arthritic patients should walk

more often ■■CDC guide to injection safety ■■Anticholinergic medications can impair cognition ■■Weight loss reduces psoriasis severity ■■Heartburn could warn of throat cancer ■■Pain meds may be tied to erectile dysfunction

Gastric reflux may signal throat cancer 22

71 CME/CE Dermatology Clinic n V-shaped notching of the fingernails accompanies an eruption of greasy hyperpigmented and hyperkeratotic papules on a woman’s chest and scalp.

85 Commentary

features 36 CME/CE Workplace stress and career burnout among clinicians A shrinking pool of primary-care providers coupled with the extension of coverage to millions of previously uninsured individuals raises the potential for increased clinician anxiety.

n A woman develops blue-black papules

How to minimize job-related stress 36

Continues on page 18

A dosage error leads to malpractice 61

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on the feet, buttocks, and extremities as well as vascular lesions of the GI tract. 75 Alternative Meds Update Because it stimulates the hormone adiponectin, which modulates glucose and lipid metabolism, raspberry ketone is being studied as a weight-loss aid.

42 Simple treatment for pediatric bedwetting When treating a young patient for monosymptomatic enuresis, the clinician must be sure to assess the physical, emotional, and developmental maturity of the child.

making contact

63 Clinical Challenge A woman is rushed to the emergency department after severing her hand in a woodworking accident at home.

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contents 77 CME/CE Dermatologic Look-Alikes Two patients present for treatment of vascular papules—one an infant with enlarging and thickening scalp lesions, the other a man with an erythematous and sessile growth on his neck. 81 CME/CE Posttest

54 Consultations ■■Options for chronic tinnitus ■■Standard of care for patients with elevated liver enzymes ■■Antifungal therapy in the elderly ■■Nocturnal leg cramping

Hyperkeratotic papules with nail changes 71

“Are you sure everyone will know we’re being ironic?”

55 Clinical Pearls ■■Pain-relief cocktail for stomatitis ■■Look for the “ugly” skin lesion ■■Prevent DVT in patients with folicacid deficiency 56 Your Comments ■■What does “a homosexual lifestyle” insinuate? ■■Addressing spiritual health

Vascular lesions on a newborn’s scalp 77

“Son, if you can’t say something nice, say something clever but devastating.”

advisor forum

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6/27/13 12:33 PM

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INVOKANA™ (canagliflozin) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. INVOKANA™ is not recommended in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS >>History of a serious hypersensitivity reaction to INVOKANA™. >>Severe renal impairment (eGFR <30 mL/min/1.73 m2), end stage renal disease, or patients on dialysis. WARNINGS and PRECAUTIONS >>Hypotension: INVOKANA™ causes intravascular volume contraction. Symptomatic hypotension can occur after

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initiating INVOKANA™, particularly in patients with impaired renal function (eGFR <60 mL/min/1.73 m2), elderly patients, and patients on either diuretics or medications that interfere with the renin-angiotensin-aldosterone system (eg, angiotensin-converting-enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs]), or patients with low systolic blood pressure. Before initiating INVOKANA™ in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. Please see additional Important Safety Information and Brief Summary of full Prescribing Information on the following pages.

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ENVISION NEW

W BLE NO ILA A AV

In adults with type 2 diabetes,

POSSIBILITIES Introducing INVOKANATM—the first and only treatment option approved in the United States that reduces the reabsorption of glucose in the kidneys via sodium glucose co-transporter-2 (SGLT2) inhibition1 A1C Reductions as Monotherapy INVOKANATM monotherapy provided statistically signiﬁcant A1C reductions vs placebo at 26 weeks1

Change in A1C (%) from baseline (adjusted mean)

A1C Change From Baseline With INVOKANA™ Monotherapy1 0.2

+0.14

0 DIFFERENCE FROM PLACEBO

DIFFERENCE FROM PLACEBO

–0.4

(95% CI: –1.09, –0.73); P<0.001

(95% CI: –1.34, –0.99); P<0.001

–0.6

–0.77

–0.2

– 0.91

– 1.16

–0.8

–1.03 –1.0 –1.2

Placebo (n=192; mean baseline A1C: 7.97%)

INVOKANATM 100 mg (n=195; mean baseline A1C: 8.06%)

INVOKANATM 300 mg (n=197; mean baseline A1C: 8.01%)

Effect on Weight* Statistically significant weight reductions vs placebo at 26 weeks (P<0.001)1 >> Difference from placebo†: 100 mg: –2.2%; 300 mg: –3.3% Impact on Systolic Blood Pressure (SBP)* Statistically significant SBP lowering vs placebo at 26 weeks (P<0.001)2 >> Difference from placebo†: 100 mg: –3.7 mm Hg; 300 mg: –5.4 mm Hg

A1C Reductions vs Sitagliptin INVOKANATM 300 mg demonstrated greater A1C reductions vs sitagliptin 100 mg, in combination with metformin + a sulfonylurea, at 52 weeks (P<0.05)1 >> Difference from sitagliptin†: –0.37% Incidence of Hypoglycemia Monotherapy over 26 weeks: 100 mg: 3.6%; 300 mg: 3.0%; placebo: 2.6%1 With metformin and a sulfonylurea over 52 weeks: INVOKANATM 300 mg: 43.2%; sitagliptin 100 mg: 40.7%1 >> Insulin and insulin secretagogues are known to cause hypoglycemia. INVOKANA™ can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue Convenient Once-Daily Dosing1 >> Recommended starting dose: INVOKANA™ 100 mg >> Dose can be increased to 300 mg in patients tolerating 100 mg, who have an eGFR of ≥60 mL/min/1.73 m2 and require additional glycemic control The most common (≥5%) adverse reactions were female genital mycotic infection, urinary tract infection, and increased urination. References: 1. Invokana [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc; 2013. 2. Stenlöf K, Cefalu WT, Kim KA, et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab. 2013;15(4):372-382.

Learn more at INVOKANAhcp.com/journal

INVOKANATM is not indicated for weight loss or as antihypertensive treatment. *Prespeciﬁed secondary endpoint. †Adjusted mean.

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IMPORTANT SAFETY INFORMATION (continued from first page)

WARNINGS and PRECAUTIONS (cont’d) >>Impairment in Renal Function: INVOKANA™ (canagliflozin) increases serum creatinine and decreases eGFR. Patients with hypovolemia may be more susceptible to these changes. Renal function abnormalities can occur after initiating INVOKANA™. More frequent renal function monitoring is recommended in patients with an eGFR below 60 mL/min/1.73 m2. >>Hyperkalemia: INVOKANA™ can lead to hyperkalemia. Patients with moderate renal impairment who are taking medications that interfere with potassium excretion, such as potassium-sparing diuretics, or medications that interfere with the renin-angiotensin-aldosterone system are more likely to develop hyperkalemia. Monitor serum potassium levels periodically after initiating INVOKANA™ in patients with impaired renal function and in patients predisposed to hyperkalemia due to medications or other medical conditions. >>Hypoglycemia With Concomitant Use With Insulin and Insulin Secretagogues: Insulin and insulin secretagogues are known to cause hypoglycemia. INVOKANA™ can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with INVOKANA™. >>Genital Mycotic Infections: INVOKANA™ increases the risk of genital mycotic infections. Patients with a history of genital mycotic infections and uncircumcised males were more likely to develop genital mycotic infections. Monitor and treat appropriately. >>Hypersensitivity Reactions: Hypersensitivity reactions (eg, generalized urticaria), some serious, were reported with INVOKANA™ treatment; these reactions generally occurred within hours to days after initiating INVOKANA™. If hypersensitivity reactions occur, discontinue use of INVOKANA™; treat per standard of care and monitor until signs and symptoms resolve. >>Increases in Low-Density Lipoprotein (LDL-C): Doserelated increases in LDL-C occur with INVOKANA™. Monitor LDL-C and treat per standard of care after initiating INVOKANA™. >>Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with INVOKANA™ or any other antidiabetic drug.

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DRUG INTERACTIONS >>UGT Enzyme Inducers: Rifampin: Co-administration of canagliflozin with rifampin, a nonselective inducer of several UGT enzymes, including UGT1A9, UGT2B4, decreased canagliflozin area under the curve (AUC) by 51%. This decrease in exposure to canagliflozin may decrease efficacy. If an inducer of these UGTs (eg, rifampin, phenytoin, phenobarbitol, ritonavir) must be co-administered with INVOKANA™ (canagliflozin), consider increasing the dose to 300 mg once daily if patients are currently tolerating INVOKANA™ 100 mg once daily, have an eGFR greater than 60mL/min/1.73 m2, and require additional glycemic control. Consider other antihyperglycemic therapy in patients with an eGFR of 45 to less than 60 mL/min/1.73 m2 receiving concurrent therapy with a UGT inducer and requiring additional glycemic control. >>Digoxin: There was an increase in the area AUC and mean peak drug concentration (Cmax) of digoxin (20% and 36%, respectively) when co-administered with INVOKANA™ 300 mg. Patients taking INVOKANA™ with concomitant digoxin should be monitored appropriately. USE IN SPECIFIC POPULATIONS >>Pregnancy Category C: There are no adequate and wellcontrolled studies of INVOKANA™ in pregnant women. Based on results from rat studies, canagliflozin may affect renal development and maturation. In a juvenile rat study, increased kidney weights and renal pelvic and tubular dilatation were evident at ≥0.5 times clinical exposure from a 300-mg dose. These outcomes occurred with drug exposure during periods of animal development that correspond to the late second and third trimester of human development. During pregnancy, consider appropriate alternative therapies, especially during the second and third trimesters. INVOKANA™ should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. >>Nursing Mothers: It is not known if INVOKANA™ is excreted in human milk. INVOKANA™ is secreted in the milk of lactating rats, reaching levels 1.4 times higher than that in maternal plasma. Data in juvenile rats directly exposed to INVOKANA™ showed risk to the developing kidney (renal pelvic and tubular dilatations) during maturation. Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing

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>>Pediatric Use: Safety and effectiveness of INVOKANA™ in pediatric patients under 18 years of age have not been established. >>Geriatric Use: Two thousand thirty-four (2034) patients 65 years and older, and 345 patients 75 years and older were exposed to INVOKANA™ in nine clinical studies of INVOKANA™. Patients 65 years and older had a higher incidence of adverse reactions related to reduced intravascular volume with INVOKANA™ (such as hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration), particularly with the 300-mg daily dose, compared to younger patients; more prominent increase in the incidence was seen in patients who were ≥75 years of age. Smaller reductions in HbA1C with INVOKANA™ relative to placebo were seen in older (65 years and older; -0.61% with INVOKANA™ 100 mg and -0.74% with INVOKANA™ 300 mg relative to placebo) compared to younger patients (-0.72% with INVOKANA™ 100 mg and -0.87% with INVOKANA™ 300 mg relative to placebo).

>>Hepatic Impairment: No dosage adjustment is necessary in patients with mild or moderate hepatic impairment. The use of INVOKANA™ has not been studied in patients with severe hepatic impairment and it is therefore not recommended. OVERDOSAGE >>There were no reports of overdose during the clinical development program of INVOKANA™ (canagliflozin). In the event of an overdose, contact the Poison Control Center. It is also reasonable to employ the usual supportive measures, eg, remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment as dictated by the patient’s clinical status. Canagliflozin was negligibly removed during a 4-hour hemodialysis session. Canagliflozin is not expected to be dialyzable by peritoneal dialysis. ADVERSE REACTIONS >>The most common (≥5%) adverse reactions were female genital mycotic infections, urinary tract infections, and increased urination. Adverse reactions in ≥2% of patients were male genital mycotic infections, vulvovaginal pruritis, thirst, nausea, and constipation.

K02CAN13149

human kidney. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from INVOKANA™, a decision should be made whether to discontinue nursing or to discontinue INVOKANA™, taking into account the importance of the drug to the mother.

Please see Brief Summary of full Prescribing Information on the following pages.

>>Renal Impairment: The efficacy and safety of INVOKANA™ were evaluated in a study that included patients with moderate renal impairment (eGFR 30 to <50 mL/min/ 1.73 m2). These patients had less overall glycemic efficacy and had a higher occurrence of adverse reactions related to reduced intravascular volume, renal-related adverse reactions, and decreases in eGFR compared to patients with mild renal impairment or normal renal function (eGFR ≥60 mL/min/1.73 m2); patients treated with INVOKANA™ 300 mg were more likely to experience increases in potassium. The efficacy and safety of INVOKANA™ have not been established in patients with severe renal impairment (eGFR <30 mL/min/1.73 m2), with end-stage renal disease (ESRD), or receiving dialysis. INVOKANA™ is not expected to be effective in these patient populations.

Janssen Pharmaceuticals, Inc. Canagliflozin is licensed from Mitsubishi Tanabe Pharma Corporation. © Janssen Pharmaceuticals, Inc. 2013

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April 2013

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INVOKANA™

(canagliflozin) tablets, for oral use Brief Summary of Prescribing Information. IndIcatIons and Usage INVOKANA™ (canagliflozin) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus [see Clinical Studies (14) in full Prescribing Information]. Limitation of Use: INVOKANA is not recommended in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. contraIndIcatIons • History of a serious hypersensitivity reaction to INVOKANA [see Warnings and Precautions]. • Severe renal impairment (eGFR less than 30 mL/min/1.73 m2), end stage renal disease or patients on dialysis [see Warnings and Precautions and Use in Specific Populations]. WarnIngs and PrecaUtIons Hypotension: INVOKANA causes intravascular volume contraction. Symptomatic hypotension can occur after initiating INVOKANA [see Adverse Reactions] particularly in patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2), elderly patients, patients on either diuretics or medications that interfere with the renin-angiotensinaldosterone system (e.g., angiotensin-converting-enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs]), or patients with low systolic blood pressure. Before initiating INVOKANA in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. Impairment in renal Function: INVOKANA increases serum creatinine and decreases eGFR. Patients with hypovolemia may be more susceptible to these changes. Renal function abnormalities can occur after initiating INVOKANA [see Adverse Reactions]. More frequent renal function monitoring is recommended in patients with an eGFR below 60 mL/min/1.73 m2. Hyperkalemia: INVOKANA can lead to hyperkalemia. Patients with moderate renal impairment who are taking medications that interfere with potassium excretion, such as potassium-sparing diuretics, or medications that interfere with the renin-angiotensin-aldosterone system are more likely to develop hyperkalemia [see Adverse Reactions]. Monitor serum potassium levels periodically after initiating INVOKANA in patients with impaired renal function and in patients predisposed to hyperkalemia due to medications or other medical conditions. Hypoglycemia with concomitant Use with Insulin and Insulin secretagogues: Insulin and insulin secretagogues are known to cause hypoglycemia. INVOKANA can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue [see Adverse Reactions]. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with INVOKANA. genital Mycotic Infections: INVOKANA increases the risk of genital mycotic infections. Patients with a history of genital mycotic infections and uncircumcised males were more likely to develop genital mycotic infections [see Adverse Reactions]. Monitor and treat appropriately. Hypersensitivity reactions: Hypersensitivity reactions (e.g., generalized urticaria), some serious, were reported with INVOKANA treatment; these reactions generally occurred within hours to days after initiating INVOKANA. If hypersensitivity reactions occur, discontinue use of INVOKANA; treat per standard of care and monitor until signs and symptoms resolve [see Contraindications and Adverse Reactions]. Increases in Low-density Lipoprotein (LdL-c): Dose-related increases in LDL-C occur with INVOKANA [see Adverse Reactions]. Monitor LDL-C and treat per standard of care after initiating INVOKANA. Macrovascular outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with INVOKANA or any other antidiabetic drug. adverse reactIons The following important adverse reactions are described below and elsewhere in the labeling: • Hypotension [see Warnings and Precautions] • Impairment in Renal Function [see Warnings and Precautions] • Hyperkalemia [see Warnings and Precautions] • Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions] • Genital Mycotic Infections [see Warnings and Precautions] • Hypersensitivity Reactions [see Warnings and Precautions] • Increases in Low-Density Lipoprotein (LDL-C) [see Warnings and Precautions] clinical studies 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 the rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Pool of Placebo-Controlled Trials: The data in Table 1 is derived from four 26-week placebo-controlled trials. In one trial INVOKANA was used as monotherapy and in three trials INVOKANA was used as add-on therapy [see Clinical Studies (14) in full Prescribing Information]. These data reflect exposure of 1667 patients to INVOKANA and a mean duration of exposure to

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INVOKANA™ (canagliflozin) tablets INVOKANA of 24 weeks. Patients received INVOKANA 100 mg (N=833), INVOKANA 300 mg (N=834) or placebo (N=646) once daily. The mean age of the population was 56 years and 2% were older than 75 years of age. Fifty percent (50%) of the population was male and 72% were Caucasian, 12% were Asian, and 5% were Black or African American. At baseline the population had diabetes for an average of 7.3 years, had a mean HbA1C of 8.0% and 20% had established microvascular complications of diabetes. Baseline renal function was normal or mildly impaired (mean eGFR 88 mL/min/1.73 m2). Table 1 shows common adverse reactions associated with the use of INVOKANA. These adverse reactions were not present at baseline, occurred more commonly on INVOKANA than on placebo, and occurred in at least 2% of patients treated with either INVOKANA 100 mg or INVOKANA 300 mg. table 1: adverse reactions From Pool of Four 26−Week Placebo-controlled studies reported in ≥ 2% of InvoKana-treated Patients* InvoKana InvoKana Placebo 100 mg 300 mg Adverse Reaction n=646 n=833 n=834 3.2% 10.4% 11.4% Female genital mycotic infections† ‡ Urinary tract infections 4.0% 5.9% 4.3% Increased urination§ 0.8% 5.3% 4.6% 0.6% 4.2% 3.7% Male genital mycotic infections¶ Vulvovaginal pruritus 0.0% 1.6% 3.0% Thirst# 0.2% 2.8% 2.3% Constipation 0.9% 1.8% 2.3% Nausea 1.5% 2.2% 2.3% * The four placebo-controlled trials included one monotherapy trial and three add-on combination trials with metformin, metformin and sulfonylurea, or metformin and pioglitazone. † Female genital mycotic infections include the following adverse reactions: Vulvovaginal candidiasis, Vulvovaginal mycotic infection, Vulvovaginitis, Vaginal infection, Vulvitis, and Genital infection fungal. Percentages calculated with the number of female subjects in each group as denominator: placebo (N=312), INVOKANA 100 mg (N=425), and INVOKANA 300 mg (N=430). ‡ Urinary tract infections includes the following adverse reactions: Urinary tract infection, Cystitis, Kidney infection, and Urosepsis. § Increased urination includes the following adverse reactions: Polyuria, Pollakiuria, Urine output increased, Micturition urgency, and Nocturia. ¶ Male genital mycotic infections include the following adverse reactions: Balanitis or Balanoposthitis, Balanitis candida, and Genital infection fungal. Percentages calculated with the number of male subjects in each group as denominator: placebo (N=334), INVOKANA 100 mg (N=408), and INVOKANA 300 mg (N=404). # Thirst includes the following adverse reactions: Thirst, Dry mouth, and Polydipsia. Abdominal pain was also more commonly reported in patients taking INVOKANA 100 mg (1.8%), 300 mg (1.7%) than in patients taking placebo (0.8%). Pool of Placebo- and Active-Controlled Trials: The occurrence of adverse reactions was also evaluated in a larger pool of patients participating in placebo- and active-controlled trials. The data combined eight clinical trials [see Clinical Studies (14) in full Prescribing Information] and reflect exposure of 6177 patients to INVOKANA. The mean duration of exposure to INVOKANA was 38 weeks with 1832 individuals exposed to INVOKANA for greater than 50 weeks. Patients received INVOKANA 100 mg (N=3092), INVOKANA 300 mg (N=3085) or comparator (N=3262) once daily. The mean age of the population was 60 years and 5% were older than 75 years of age. Fifty-eight percent (58%) of the population was male and 73% were Caucasian, 16% were Asian, and 4% were Black or African American. At baseline, the population had diabetes for an average of 11 years, had a mean HbA1C of 8.0% and 33% had established microvascular complications of diabetes. Baseline renal function was normal or mildly impaired (mean eGFR 81 mL/min/1.73 m2). The types and frequency of common adverse reactions observed in the pool of eight clinical trials were consistent with those listed in Table 1. In this pool, INVOKANA was also associated with the adverse reactions of fatigue (1.7% with comparator, 2.2% with INVOKANA 100 mg, and 2.0% with INVOKANA 300 mg) and loss of strength or energy (i.e., asthenia) (0.6% with comparator, 0.7% with INVOKANA 100 mg and 1.1% with INVOKANA 300 mg). In the pool of eight clinical trials, the incidence rate of pancreatitis (acute or chronic) was 0.9, 2.7, and 0.9 per 1000 patient-years of exposure to comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. In the pool of eight clinical trials with a longer mean duration of exposure to INVOKANA (68 weeks), the incidence rate of bone fracture was 14.2, 18.7, and 17.6 per 1000 patient years of exposure to comparator, INVOKANA

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INVOKANA™ (canagliflozin) tablets

100 mg, and INVOKANA 300 mg, respectively. Upper extremity fractures occurred more commonly on INVOKANA than comparator. In the pool of eight clinical trials, hypersensitivity-related adverse reactions (including erythema, rash, pruritus, urticaria, and angioedema) occurred in 3.0%, 3.8%, and 4.2% of patients receiving comparator, INVOKANA 100 mg and INVOKANA 300 mg, respectively. Five patients experienced serious adverse reactions of hypersensitivity with INVOKANA, which included 4 patients with urticaria and 1 patient with a diffuse rash and urticaria occurring within hours of exposure to INVOKANA. Among these patients, 2 patients discontinued INVOKANA. One patient with urticaria had recurrence when INVOKANA was re-initiated. Photosensitivity-related adverse reactions (including photosensitivity reaction, polymorphic light eruption, and sunburn) occurred in 0.1%, 0.2%, and 0.2% of patients receiving comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Other adverse reactions occurring more frequently on INVOKANA than on comparator were: Volume Depletion-Related Adverse Reactions: INVOKANA results in an osmotic diuresis, which may lead to reductions in intravascular volume. In clinical studies, treatment with INVOKANA was associated with a dosedependent increase in the incidence of volume depletion-related adverse reactions (e.g., hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration). An increased incidence was observed in patients on the 300 mg dose. The three factors associated with the largest increase in volume depletion-related adverse reactions were the use of loop diuretics, moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m2) and age 75 years and older (Table 2) [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Use in Specific Populations]. table 2: Proportion of Patients With at Least one volume depletion-related adverse reactions (Pooled results from 8 clinical trials) comparator InvoKana InvoKana group* 100 mg 300 mg Baseline characteristic % % % Overall population 1.5% 2.3% 3.4% 75 years of age and older† 2.6% 4.9% 8.7% eGFR less than 2† 2.5% 4.7% 8.1% 60 mL/min/1.73 m Use of loop diuretic† 4.7% 3.2% 8.8% * Includes placebo and active-comparator groups † Patients could have more than 1of the listed risk factors Impairment in Renal Function: INVOKANA is associated with a dosedependent increase in serum creatinine and a concomitant fall in estimated GFR (Table 3). Patients with moderate renal impairment at baseline had larger mean changes. table 3: changes in serum creatinine and egFr associated with InvoKana in the Pool of Four Placebo-controlled trials and Moderate renal Impairment trial

In a trial carried out in patients with moderate renal impairment with a baseline eGFR of 30 to less than 50 mL/min/1.73 m2 (mean baseline eGFR 39 mL/min/1.73 m2) [see Clinical Studies (14.3) in full Prescribing Information], the proportion of patients who experienced at least one event of significant renal function decline, defined as an eGFR 30% lower than baseline, was 6.9% with placebo, 18% with INVOKANA 100 mg, and 22.5% with INVOKANA 300 mg. At the end of treatment, 4.6% with placebo, 3.4% with INVOKANA 100 mg, and 3.4% with INVOKANA 300 mg had a significant renal function decline. In a pooled population of patients with moderate renal impairment (N=1085) with baseline eGFR of 30 to less than 60 mL/min/1.73 m2 (mean baseline eGFR 48 mL/min/1.73 m2), the overall incidence of these events was lower than in the dedicated trial but a dose-dependent increase in incident episodes of significant renal function decline compared to placebo was still observed. Use of INVOKANA was associated with an increased incidence of renalrelated adverse reactions (e.g., increased blood creatinine, decreased glomerular filtration rate, renal impairment, and acute renal failure), particularly in patients with moderate renal impairment. In the pooled analysis of patients with moderate renal impairment, the incidence of renal-related adverse reactions was 3.7% with placebo, 8.9% with INVOKANA 100 mg, and 9.3% with INVOKANA 300 mg. Discontinuations due to renal-related adverse events occurred in 1.0% with placebo, 1.2% with INVOKANA 100 mg, and 1.6% with INVOKANA 300 mg [see Warnings and Precautions]. Genital Mycotic Infections: In the pool of four placebo-controlled clinical trials, female genital mycotic infections (e.g., vulvovaginal mycotic infection, vulvovaginal candidiasis, and vulvovaginitis) occurred in 3.2%, 10.4%, and 11.4% of females treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Patients with a history of genital mycotic infections were more likely to develop genital mycotic infections on INVOKANA. Female patients who developed genital mycotic infections on INVOKANA were more likely to experience recurrence and require treatment with oral or topical antifungal agents and anti-microbial agents [see Warnings and Precautions]. In the pool of four placebo-controlled clinical trials, male genital mycotic infections (e.g., candidal balanitis, balanoposthitis) occurred in 0.6%, 4.2%, and 3.7% of males treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Male genital mycotic infections occurred more commonly in uncircumcised males and in males with a prior history of balanitis or balanoposthitis. Male patients who developed genital mycotic infections on INVOKANA were more likely to experience recurrent infections (22% on INVOKANA versus none on placebo), and require treatment with oral or topical antifungal agents and anti-microbial agents than patients on comparators. In the pooled analysis of 8 controlled trials, phimosis was reported in 0.3% of uncircumcised male patients treated with INVOKANA and 0.2% required circumcision to treat the phimosis [see Warnings and Precautions]. Hypoglycemia: In all clinical trials, hypoglycemia was defined as any event regardless of symptoms, where biochemical hypoglycemia was documented (any glucose value below or equal to 70 mg/dL). Severe hypoglycemia was defined as an event consistent with hypoglycemia where the patient required the assistance of another person to recover, lost consciousness, or experienced a seizure (regardless of whether biochemical documentation of a low glucose value was obtained). In individual clinical trials [see Clinical Studies (14) in full Prescribing Information], episodes of hypoglycemia occurred at a higher rate when INVOKANA was co-administered with insulin or sulfonylureas (Table 4) [see Warnings and Precautions]. table 4: Incidence of Hypoglycemia* in controlled clinical studies

Placebo n=646 Creatinine (mg/dL)

0.84

0.82

eGFR (mL/min/1.73 m2)

87.0

88.3

88.8

Week 6 Change

Creatinine (mg/dL)

0.01

0.03

0.05

eGFR (mL/min/1.73 m2)

-1.6

-3.8

-5.0

End of Treatment Change*

Creatinine (mg/dL)

0.01

0.02

0.03

eGFR (mL/min/1.73 m2)

-1.6

-2.3

-3.4

Baseline Pool of Four PlaceboControlled Trials

InvoKana InvoKana 100 mg 300 mg n=833 n=834

InvoKana InvoKana Placebo 100 mg 300 mg n=90 n=90 n=89 Baseline Moderate Week 3 Renal Impairment Change Trial End of Treatment Change*

Creatinine (mg/dL)

1.61

1.62

1.63

eGFR (mL/min/1.73 m2)

40.1

39.7

38.5

Creatinine (mg/dL)

0.03

0.18

0.28

eGFR (mL/min/1.73 m2)

-0.7

-4.6

-6.2

Creatinine (mg/dL)

0.07

0.16

0.18

eGFR (mL/min/1.73 m2)

-1.5

-3.6

-4.0

* Week 26 in mITT LOCF population In the pool of four placebo-controlled trials where patients had normal or mildly impaired baseline renal function, the proportion of patients who experienced at least one event of significant renal function decline, defined as an eGFR below 80 mL/min/1.73 m2 and 30% lower than baseline, was 2.1% with placebo, 2.0% with INVOKANA 100 mg, and 4.1% with INVOKANA 300 mg. At the end of treatment, 0.5% with placebo, 0.7% with INVOKANA 100 mg, and 1.4% with INVOKANA 300 mg had a significant renal function decline.

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Monotherapy (26 weeks) Overall [N (%)] In combination with Metformin (26 weeks) Overall [N (%)] Severe [N (%)]† In combination with Metformin (52 weeks) Overall [N (%)] Severe [N (%)]† In combination with sulfonylurea (18 weeks) Overall [N (%)] In combination with Metformin + sulfonylurea (26 weeks) Overall [N (%)] Severe [N (%)]†

Placebo (n=192) 5 (2.6) Placebo + Metformin (n=183)

InvoKana 100 mg (n=195) 7 (3.6) InvoKana 100 mg + Metformin (n=368)

InvoKana 300 mg (n=197) 6 (3.0) InvoKana 300 mg + Metformin (n=367)

3 (1.6) 0 (0) glimepiride + Metformin (n=482) 165 (34.2) 15 (3.1) Placebo + sulfonylurea (n=69) 4 (5.8) Placebo + Metformin + sulfonylurea (n=156) 24 (15.4) 1 (0.6)

16 (4.3) 1 (0.3) InvoKana 100 mg + Metformin (n=483) 27 (5.6) 2 (0.4) InvoKana 100 mg + sulfonylurea (n=74) 3 (4.1) InvoKana 100 mg + Metformin + sulfonylurea (n=157) 43 (27.4) 1 (0.6)

17 (4.6) 1 (0.3) InvoKana 300 mg + Metformin (n=485) 24 (4.9) 3 (0.6) InvoKana 300 mg + sulfonylurea (n=72) 9 (12.5) InvoKana 300 mg + Metformin + sulfonylurea (n=156) 47 (30.1) 0

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INVOKANA™ (canagliflozin) tablets

table 4: Incidence of Hypoglycemia* in controlled clinical studies (continued)

UGT1A9, UGT2B4, decreased canagliflozin area under the curve (AUC) by 51%. This decrease in exposure to canagliflozin may decrease efficacy. If an inducer of these UGTs (e.g., rifampin, phenytoin, phenobarbital, ritonavir) must be co-administered with INVOKANA (canagliflozin), consider increasing the dose to 300 mg once daily if patients are currently tolerating INVOKANA 100 mg once daily, have an eGFR greater than 60 mL/min/1.73 m2, and require additional glycemic control. Consider other antihyperglycemic therapy in patients with an eGFR of 45 to less than 60 mL/min/1.73 m2 receiving concurrent therapy with a UGT inducer and require additional glycemic control [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) in full Prescribing Information]. digoxin: There was an increase in the area AUC and mean peak drug concentration (Cmax) of digoxin (20% and 36%, respectively) when co-administered with INVOKANA 300 mg [see Clinical Pharmacology (12.3) in full Prescribing Information]. Patients taking INVOKANA with concomitant digoxin should be monitored appropriately. Use In sPecIFIc PoPULatIons Pregnancy: Teratogenic Effects: Pregnancy Category C: There are no adequate and well-controlled studies of INVOKANA in pregnant women. Based on results from rat studies, canagliflozin may affect renal development and maturation. In a juvenile rat study, increased kidney weights and renal pelvic and tubular dilatation were evident at greater than or equal to 0.5 times clinical exposure from a 300 mg dose [see Nonclinical Toxicology (13.2) in full Prescribing Information]. These outcomes occurred with drug exposure during periods of animal development that correspond to the late second and third trimester of human development. During pregnancy, consider appropriate alternative therapies, especially during the second and third trimesters. INVOKANA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. nursing Mothers: It is not known if INVOKANA is excreted in human milk. INVOKANA is secreted in the milk of lactating rats reaching levels 1.4 times higher than that in maternal plasma. Data in juvenile rats directly exposed to INVOKANA showed risk to the developing kidney (renal pelvic and tubular dilatations) during maturation. Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from INVOKANA, a decision should be made whether to discontinue nursing or to discontinue INVOKANA, taking into account the importance of the drug to the mother [see Nonclinical Toxicology (13.2) in full Prescribing Information]. Pediatric Use: Safety and effectiveness of INVOKANA in pediatric patients under 18 years of age have not been established. geriatric Use: Two thousand thirty-four (2034) patients 65 years and older, and 345 patients 75 years and older were exposed to INVOKANA in nine clinical studies of INVOKANA [see Clinical Studies (14.3) in full Prescribing Information]. Patients 65 years and older had a higher incidence of adverse reactions related to reduced intravascular volume with INVOKANA (such as hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration), particularly with the 300 mg daily dose, compared to younger patients; more prominent increase in the incidence was seen in patients who were 75 years and older [see Dosage and Administration (2.1) in full Prescribing Information and Adverse Reactions]. Smaller reductions in HbA1C with INVOKANA relative to placebo were seen in older (65 years and older; -0.61% with INVOKANA 100 mg and -0.74% with INVOKANA 300 mg relative to placebo) compared to younger patients (-0.72% with INVOKANA 100 mg and -0.87% with INVOKANA 300 mg relative to placebo). renal Impairment: The efficacy and safety of INVOKANA were evaluated in a study that included patients with moderate renal impairment (eGFR 30 to less than 50 mL/min/1.73 m2) [see Clinical Studies (14.3) in full Prescribing Information]. These patients had less overall glycemic efficacy and had a higher occurrence of adverse reactions related to reduced intravascular volume, renal-related adverse reactions, and decreases in eGFR compared to patients with mild renal impairment or normal renal function (eGFR greater than or equal to 60 mL/min/1.73 m2); patients treated with INVOKANA 300 mg were more likely to experience increases in potassium [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Adverse Reactions]. The efficacy and safety of INVOKANA have not been established in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2), with ESRD, or receiving dialysis. INVOKANA is not expected to be effective in these patient populations [see Contraindications and Clinical Pharmacology (12.3) in full Prescribing Information]. Hepatic Impairment: No dosage adjustment is necessary in patients with mild or moderate hepatic impairment. The use of INVOKANA has not been studied in patients with severe hepatic impairment and is therefore not recommended [see Clinical Pharmacology (12.3) in full Prescribing Information].

In combination with Metformin + sulfonylurea (52 weeks) Overall [N (%)] Severe [N (%)]† In combination with Metformin + Pioglitazone (26 weeks) Overall [N (%)] In combination with Insulin (18 weeks) Overall [N (%)] Severe [N (%)]†

sitagliptin + Metformin + sulfonylurea (n=378) 154 (40.7) 13 (3.4) Placebo + Metformin + Pioglitazone (n=115) 3 (2.6)

InvoKana 100 mg + Metformin + Pioglitazone (n=113) 3 (2.7)

InvoKana 300 mg + Metformin + sulfonylurea (n=377) 163 (43.2) 15 (4.0) InvoKana 300 mg + Metformin + Pioglitazone (n=114) 6 (5.3)

Placebo (n=565) 208 (36.8) 14 (2.5)

InvoKana 100 mg (n=566) 279 (49.3) 10 (1.8)

InvoKana 300 mg (n=587) 285 (48.6) 16 (2.7)

* Number of patients experiencing at least one event of hypoglycemia based on either biochemically documented episodes or severe hypoglycemic events in the intent-to-treat population † Severe episodes of hypoglycemia were defined as those where the patient required the assistance of another person to recover, lost consciousness, or experienced a seizure (regardless of whether biochemical documentation of a low glucose value was obtained) Laboratory Tests: Increases in Serum Potassium: Dose-related, transient mean increases in serum potassium were observed early after initiation of INVOKANA (i.e., within 3 weeks) in a trial of patients with moderate renal impairment [see Clinical Studies (14.3) in full Prescribing Information]. In this trial, increases in serum potassium of greater than 5.4 mEq/L and 15% above baseline occurred in 16.1%, 12.4%, and 27.0% of patients treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. More severe elevations (i.e., equal or greater than 6.5 mEq/L) occurred in 1.1%, 2.2%, and 2.2% of patients treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. In patients with moderate renal impairment, increases in potassium were more commonly seen in those with elevated potassium at baseline and in those using medications that reduce potassium excretion, such as potassium-sparing diuretics, angiotensinconverting-enzyme inhibitors, and angiotensin-receptor blockers [see Warnings and Precautions]. Increases in Serum Magnesium: Dose-related increases in serum magnesium were observed early after initiation of INVOKANA (within 6 weeks) and remained elevated throughout treatment. In the pool of four placebo-controlled trials, the mean change in serum magnesium levels was 8.1% and 9.3% with INVOKANA 100 mg and INVOKANA 300 mg, respectively, compared to -0.6% with placebo. In a trial of patients with moderate renal impairment [see Clinical Studies (14.3) in full Prescribing Information], serum magnesium levels increased by 0.2%, 9.2%, and 14.8% with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Increases in Serum Phosphate: Dose-related increases in serum phosphate levels were observed with INVOKANA. In the pool of four placebo controlled trials, the mean change in serum phosphate levels were 3.6% and 5.1% with INVOKANA 100 mg and INVOKANA 300 mg, respectively, compared to 1.5% with placebo. In a trial of patients with moderate renal impairment [see Clinical Studies (14.3) in full Prescribing Information], the mean serum phosphate levels increased by 1.2%, 5.0%, and 9.3% with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Increases in Low-Density Lipoprotein Cholesterol (LDL-C) and non-HighDensity Lipoprotein Cholesterol (non-HDL-C): In the pool of four placebocontrolled trials, dose-related increases in LDL-C with INVOKANA were observed. Mean changes (percent changes) from baseline in LDL-C relative to placebo were 4.4 mg/dL (4.5%) and 8.2 mg/dL (8.0%) with INVOKANA 100 mg and INVOKANA 300 mg, respectively. The mean baseline LDL-C levels were 104 to 110 mg/dL across treatment groups [see Warnings and Precautions]. Dose-related increases in non-HDL-C with INVOKANA were observed. Mean changes (percent changes) from baseline in non-HDL-C relative to placebo were 2.1 mg/dL (1.5%) and 5.1 mg/dL (3.6%) with INVOKANA 100 mg and 300 mg, respectively. The mean baseline non-HDL-C levels were 140 to 147 mg/dL across treatment groups. Increases in Hemoglobin: In the pool of four placebo-controlled trials, mean changes (percent changes) from baseline in hemoglobin were -0.18 g/dL (-1.1%) with placebo, 0.47 g/dL (3.5%) with INVOKANA 100 mg, and 0.51 g/dL (3.8%) with INVOKANA 300 mg. The mean baseline hemoglobin value was approximately 14.1 g/dL across treatment groups. At the end of treatment, 0.8%, 4.0%, and 2.7% of patients treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively, had hemoglobin above the upper limit of normal. drUg InteractIons Ugt enzyme Inducers: Rifampin: Co-administration of canagliflozin with rifampin, a nonselective inducer of several UGT enzymes, including

137193_L01.indd 8

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INVOKANA™ (canagliflozin) tablets

“Trust me. He wasn’t so great and powerful until he went on Oprah.”

overdosage There were no reports of overdose during the clinical development program of INVOKANA (canagliflozin). In the event of an overdose, contact the Poison Control Center. It is also reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment as dictated by the patient’s clinical status. Canagliflozin was negligibly removed during a 4-hour hemodialysis session. Canagliflozin is not expected to be dialyzable by peritoneal dialysis. PatIent coUnseLIng InForMatIon See FDA-approved patient labeling (Medication Guide). Instructions: Instruct patients to read the Medication Guide before starting INVOKANA (canagliflozin) therapy and to reread it each time the prescription is renewed. Inform patients of the potential risks and benefits of INVOKANA and of alternative modes of therapy. Also inform patients about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and HbA1C testing, recognition and management of hypoglycemia and hyperglycemia, and assessment for diabetes complications. Advise patients to seek medical advice promptly during periods of stress such as fever, trauma, infection, or surgery, as medication requirements may change. Instruct patients to take INVOKANA only as prescribed. If a dose is missed, advise patients to take it as soon as it is remembered unless it is almost time for the next dose, in which case patients should skip the missed dose and take the medicine at the next regularly scheduled time. Advise patients not to take two doses of INVOKANA at the same time. Inform patients that the most common adverse reactions associated with INVOKANA are genital mycotic infection, urinary tract infection, and increased urination. Inform female patients of child bearing age that the use of INVOKANA during pregnancy has not been studied in humans, and that INVOKANA should only be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Instruct patients to report pregnancies to their physicians as soon as possible. Inform nursing mothers to discontinue INVOKANA or nursing, taking into account the importance of drug to the mother. Laboratory Tests: Due to its mechanism of action, patients taking INVOKANA will test positive for glucose in their urine. Hypotension: Inform patients that symptomatic hypotension may occur with INVOKANA and advise them to contact their doctor if they experience such symptoms [see Warnings and Precautions]. Inform patients that dehydration may increase the risk for hypotension, and to have adequate fluid intake. Genital Mycotic Infections in Females (e.g., Vulvovaginitis): Inform female patients that vaginal yeast infection may occur and provide them with information on the signs and symptoms of vaginal yeast infection. Advise them of treatment options and when to seek medical advice [see Warnings and Precautions]. Genital Mycotic Infections in Males (e.g., Balanitis or Balanoposthitis): Inform male patients that yeast infection of penis (e.g., balanitis or balanoposthitis) may occur, especially in uncircumcised males and patients with prior history. Provide them with information on the signs and symptoms of balanitis and balanoposthitis (rash or redness of the glans or foreskin of the penis). Advise them of treatment options and when to seek medical advice [see Warnings and Precautions]. Hypersensitivity Reactions: Inform patients that serious hypersensitivity reactions such as urticaria and rash have been reported with INVOKANA. Advise patients to report immediately any signs or symptoms suggesting allergic reaction or angioedema, and to take no more drug until they have consulted prescribing physicians. Urinary Tract Infections: Inform patients of the potential for urinary tract infections. Provide them with information on the symptoms of urinary tract infections. Advise them to seek medical advice if such symptoms occur. Active ingredient made in Belgium Finished product manufactured by: Janssen Ortho, LLC Gurabo, PR 00778 Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560 Licensed from Mitsubishi Tanabe Pharma Corporation © 2013 Janssen Pharmaceuticals, Inc. 10282400 K02CAN13080B

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Risks of NSAID use can be predicted

Use of NSAIDs doubled a person’s risk of heart failure.

All NSAIDs approximately doubled heart-failure risk and increased the risk of ulcers and other serious upper GI complications by two to four times. An accompanying statement from The Lancet noted that the elevated MI risk from NSAIDs seemed to be proportional to a patient’s underlying risk for such an event, with the highest risk therefore seen in persons with a history of heart disease or with hypertension, high cholesterol, or other cardiac risk factors. “While NSAIDs increase vascular and [GI] risks to a varying extent, our analyses indicate that the effects of different regimens in particular patients can be predicted, which may help [clinicians] choosing between alternative regimens to weigh up which type of NSAID is safest,” concluded lead author Colin Baigent.

Consumption of added sugars among U.S. adults Between 2005 and 2010, caloric intake from added sugars decreased linearly with age for men and women. Source: CDC/NCHS, National Health and Nutrition Examination Survey, 2005–2010

Total

Kilocalories

Nonsteroidal anti-inflammatory drugs (NSAIDs) increase vascular and GI risks, but the size of those risks can be predicted and can therefore guide clinicians in how best to prescribe these agents. The Coxib and Traditional NSAID Trialists’ Collaboration conducted meta-analyses of more than 600 randomized trials involving more than 353,000 participants to better characterize the vascular and GI effects of NSAIDS, including selective COX-2 inhibitors (coxibs) and traditional NSAIDs, particularly in persons at heightened risk of vascular disease. The main outcomes measured were major vascular events (nonfatal MI, nonfatal stroke, and vascular death), major coronary events (nonfatal MI and coronary death), stroke mortality, heart failure, and upper GI complications (perforation, obstruction, and bleed).

As reported in The Lancet, major vascular events rose by about one third from a coxib or from diclo fenac (Cataflam, Voltaren, Zipsor), mainly due to an increase in major coronary events. Higher-dose regimens of such older NSAIDs as diclofenac and ibuprofen are associated with similar risks of heart disease: For every 1,000 persons allocated to one year of high-dose diclofenac or ibuprofen therapy, three people would experience an avoidable heart attack, one of which would be fatal. Ibuprofen significantly increased major coronary events, but not major vascular events. Naproxen did not significantly increase major vascular events. Vascular death was increased significantly by coxibs and by diclofenac, and was increased nonsignificantly by ibuprofen, but was not increased by naproxen.

400 350 300 250 200 150 100 50 0

20-39 years

40-59 years

60 years and older

397 335

338 224

Men

239

275

236 182

Women

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Newsline Children with type 2 diabetes are more likely to develop cardiovascular and other complications more quickly and at a higher rater than are newly diagnosed adults, according to the most recent findings of the ongoing Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. The research focused on 699 children and adolescents, aged 10 to 17 years at baseline (July 2004– February 2009), with recent-onset type 2 diabetes. The participants were randomized to receive metformin, metformin plus rosiglitazone (Avandia), or metformin plus intensive lifestyle interventions. They also were given statins if they had an LDL level of at least 130 mg/dL or a triglyceride level of at least 300 mg/dL.

As noted in a statement from the American Diabetes Association, these patients were developing early and rapidly progressing signs of heart disease, kidney disease, poor glycemic control, and diabetes-related eye disease. This was even true of the youths undergoing the two-drug therapy, previously shown to be the most effective treatment for maintaining glycemic control. For example, LDL, apolipoprotein B, triglycerides, and non-HDL cholesterol all increased over 12 months before stabilizing for the next 24 months. Over the three years, youths with an LDL level >130 mg/dL or who were using LDL-lowering therapy doubled, from 4.5% to 10.7%. Triglycerides were lower in the metformin-plus-lifestyle group than in the metformin-only

Diabetes progresses more rapidly in kids

Study results point to a need for early and aggressive treatment.

group. Metformin-plus-lifestyle also weakened the negative effect of hyperglycemia on triglycerides and HDL in female participants. High-sensitivity C-reactive protein increased over time, but was lowest in persons receiving metformin plus rosiglitazone (Diabetes Care. 2013;36[6]:1758–1764).

Most adults with arthritis do little or no walking each week, despite research indicating that this activity can lower pain and improve function. I n ve s t i g a t o r s f r o m t h e CDC analyzed data from the 2011 Behavioral Risk Factor Surveillance System to estimate the distribution of average weekly minutes of walking among adults with arthritis by state, and to map the prevalence of low amounts of walking (<90 minutes per week). According to the research team, the 90-minute threshold was based on the minimum amount

Research shows that walking can lower pain and improve function.

of weekly walking that had been shown to reduce pain by 27% and improve function by 39% in a randomized controlled trial (MMWR. 2013;62[17]:331334; available at www.cdc.gov/ mmwr/preview/mmwrhtml/ mm6217a3.htm, accessed June 15, 2013). The analysis demonstrated that a median of 66% of adults with arthritis in all 50 states and the District of Columbia walked for fewer than 90 minutes per week, ranging from a low of just 58% in California to a high of 76.2% in Tennessee.

The median prevalence of walking was: • 53% for zero minutes per week • 13.1% for one minute to 89 minutes per week • 5.3% for 90 to 119 minutes per week • 5.6% for 120 to 149 minutes per week • 23.2% for 150 minutes or more per week. The authors of the report note that effective and safe interventions are available in the community and can help people with arthritis start and maintain a walking program.

Arthritic patients should walk more often

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Newsline CDC guide Meds can impair cognition to injection safety

Continuous exposure doubled the risk of cognitive impairment.

Campbell, a scientist at Indiana University Center for Aging Research, in a statement issued by the university. After adjustments were made for certain variables, the odds ratio for having a diagnosis of mild cognitive impairment was 2.73 among older adults who were exposed to at least three possible anticholinergics for at least 90 days, compared with older adults with no anticholinergic exposure. The odds ratio for having dementia was 0.43, Campbell’s team reported in the study, which will be published in an upcoming issue of Alzheimer’s & Dementia. Continuously taking such strong anticholinergics as sleeping pills or antihistamines for only 60 days caused memory problems and other indicators of mild cognitive impairment. Taking multiple drugs with weaker anticholinergic effects, such as many common OTC digestive aids, had a negative impact on cognition in 90 days.

Weight loss reduces psoriasis severity A low-calorie diet helped improve psoriasis symptoms in a randomized clinical trial of overweight persons with the skin disease. A total of 60 outpatients were randomized to an intervention group or a control group. The intervention featured a lowenergy diet of 800 to 1,000 kilocalories (kcal) per day for eight weeks, followed by eight weeks of reintroduction of normal food intake, reaching 1,200 kcal/day. Control group members ate healthy foods.

After 16 weeks, mean body weight loss was 15.4 kg (33.9 lb) greater in the intervention group. The mean differences in Psoriasis Area and Severity Index (PASI) and in Dermatology Life Quality Index (DLQI) were -2.0 and -2.0, respectively, also in favor of the intervention group. In a report for JAMA Dermatology, Peter Jensen, MD, PhD, called the PASI improvement “clinically important” and the DLQI change “a significant reduction.”

©science source / Peter Skinner

The U.S. experience with outbreaks attributed to unsafe injection practices has grown substantially over recent years, with at least 49 outbreaks occurring since 2001 as a result of extrinsic contamination of injectable medical products at the point of administration, noted a recent report from the CDC (MMWR. 2013;62[21]:423-425; available at www.cdc.gov/mmwr/preview/ mmwrhtml/mm6221a3.htm, accessed June 15, 2013). “To eliminate the problem of unsafe injections, injection safety interventions need to be implemented in all settings where injections are delivered,” advised the authors. “Many outpatient facilities, including oncology clinics, pain management clinics, and physician offices, typically do not fall with the purview of federal and state regulatory oversight of health-care facilities, thus making it difficult to monitor injection safety and other infection control practices.” The CDC continues to urge that health-care providers never administer medications from the same syringe to more than one patient, never enter a vial with a used syringe or needle, and never administer medications from single-dose vials to multiple patients. Aseptic technique should be maintained at all times, and used injection equipment should be disposed of properly.

Drugs with strong anticholinergic effects cause cognitive impairment in older adults who take them continuously for as few as 60 days, a retrospective cohort study has revealed. Taking multiple drugs with weak anticholinergic effects for 90 days can have a similar impact. To investigate the association between impairment in cognitive function and previous anticholinergic exposure, Noll Campbell, PharmD, and colleagues examined data from 3,690 older men and women (mean age 72 years; 70% female; 60% black) who were patients in primary-care clinics in Indianapolis. All participants had undergone cognitive assessment and had a one-year medicationdispensing record. “A high anticholinergic burden—either from one or multiple drugs—plus two or three months of continuous exposure to that high burden approximately doubled the risk of developing cognitive impairment,” affirmed

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Newsline Gastric reflux is an independent risk factor for squamous cancers of the pharynx and larynx, according to data from a newly released study. Gastric reflux can reach into the upper airway and damage the epithelial lining, a condition believed to be a risk factor for the development of laryngopharyngeal squamous cell carcinoma (LPSCC) (Cancer Epidemiol Biomarkers Prev. 2013;22[6]:10611068). However, the literature is conflicting. To better clarify this relationship, the researchers assessed the association of self-reported heartburn history and medication use among 631 persons with LPSCCs (468 with throat cancer and 163 with vocal-cord cancers) and 1,234 control subjects.

It was discovered that persons reporting a history of frequent heartburn who were neither heavy smokers nor heavy drinkers had a 78% increased risk of developing LPSCCs, after adjustments were made for patient age, gender, race, smoking, alcohol consumption, HPV 16 status, education, and BMI. Antacids may help protect persons with gastric reflux from LPSCCs: Compared with persons who never took heartburn medications, antacid users were 41% less likely to develop cancers of the throat and vocal cord. No such protective effect was seen with prescription medications or with home remedies. I n o t he r c a nc e r ne w s , evidence-based guidelines from the American College of Chest

Heartburn could warn of throat cancer

In heartburn, stomach acid (green) erupts up the esophagus.

Physicians recommend that clinicians offer low-dose CT scanning for lung cancer screening to people at significant risk for the disease due to age and smoking history (Chest. 2013;143[5 Suppl]:e78S-e92S).

Long-term opioid therapy was associated with greater use of medications for erectile dysfunction (ED) or testosterone replacement in an analysis of medical and pharmacy records of 11,327 men with a diagnosis of back pain (Spine. 2013;38[11]:909-915). “Men who take opioid pain medications for an extended period of time have the highest risk of ED,” explained lead study author Richard A. Deyo, MD, MPH, in a statement from Kaiser Permanente. “This does not mean that these medications cause ED, but the association is

High-dose patients were more likely to get ED prescriptions.

something patients and clinicians should be aware of when deciding if opioids should be used to treat back pain.” More than 19% of men who took high-dose opioids (>120 mg of morphine-equivalents) for at least four months also received ED prescriptions, compared with

less than 7% of opioid nonusers. The high-dose patients were more than 50% more likely than nonusers to get testosteronereplacement or ED prescriptions. Men with chronic pain may experience ED related to depression, smoking, age, or opioidrelated hypogonadism, wrote Deyo and colleagues. The 909 men in their analysis who received drugs for ED or testosterone replacement were significantly older than those who did not and had greater comorbidity, depression, use of sedative-hypnotics, and smoking. n

Pain meds may be tied to erectile dysfunction

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CME CE

program outline july 2013

0.5 credits

Page 36 Feature Workplace stress and career burnout among clinicians Mary Smith, DNP, FNP-BC, and Scott Hambleton, MD Mary Smith, DNP, FNP-BC, and Scott Hambleton, MD, have no relationships to disclose relating to the content of this article.

■■ Learning objectives: • Name the hospital-acquired infections associated with job-related burnout among registered nurses. • List the components of the burnout triad. • Identify healthy ways to prevent workplace stress and career burnout. • Discuss the ways in which maintenance of professional boundaries prevents career burnout. 0.5 credits

Page 71 Dermatology Clinic Hyperkeratotic papules with nail changes Audrey Chan, MD, and Grace Sun, MD Audrey Chan, MD, and Grace Sun, MD, have no relationships to disclose relating to the content of this article.

Multiple cutaneous and GI vascular lesions Kaitlyn Stortz and Erin Reese, MD Kaitylyn Stortz and Erin Reese, MD, have no relationships to disclose relating to the content of this article.

■■ Learning objectives: • To identify and diagnose dermatologic conditions and review up-to-date treatment.

Page 77 Dermatologic Look-Alikes Vascular papules Kerri Robbins, MD Kerri Robbins, MD, has no relationships to disclose relating to the content of this article.

■■ Learning objective: • To distinguish and properly treat dermatologic conditions with similar presentations.

Page 81 posttest

This program has been reviewed and is approved for a maximum of 1 hour of AAPA Category I CME credit by the Physician Assistant Review Panel. Approval is valid for one year from the issue date of July 2013. Participants may submit the self-assessment at any time during that period. This program was planned in accordance with AAPA’s CME Standards for Enduring Material Programs and for Commercial Support of Enduring Material Programs. Nurse Practitioner Associates for Continuing Education (NPACE) is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation. NPACE designates this educational activity for a maximum of 1 contact hour of credit. Participants should only claim credit commensurate with the extent of their participation in the activity.

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CME CE feature

n Learning objectives: • Name the hospital-acquired infections associated with job-related burnout among RNs. • List the components of the burnout triad. • Identify healthy ways to prevent workplace stress and career burnout. • Discuss the ways in which maintenance of professional boundaries prevents career burnout. n complete the posttest: Page 81 n additional CME/CE: Pages 71, 77 Turn to page 35 for additional information on this month’s CME/CE courses.

Mary Smith, DNP, FNP-BC, and Scott Hambleton, MD

Workplace stress and career burnout among clinicians A shrinking pool of providers coupled with the extension of coverage to millions of previously uninsured individuals may increase practitioner anxiety.

Burnout is caused by emotional exhaustion, depersonalization, and a reduced sense of accomplishment.

ccording to the U.S. Health Resources and Services Administration (HRSA), a number of places in the United States are considered Health Professional Shortage Areas (HPSAs). HSPSas are defined as geographic regions that have shortages of primary medical care, dental care, and mentalhealth providers. Additionally, the HRSA classifies medially underserved areas/populations (MUA/Ps) as locations that have an insufficient number of primary-care providers, high rates of infant mortality and poverty, and/or a high number of elderly individuals. According to recent data, there are 5,805 primarycare HPSAs in the United States, encompassing 55.3 million residents.1 A total of 15,431 practitioners would be needed in these areas to meet the current demand for primary-care providers, which translates to a population-to-practitioner ratio of 2,000:1.1 Factor this information into the realization that the Affordable Care Act enacted in 2010 promises to extend health coverage to millions of presently uninsured individuals, and the potential

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Burnout among registered nurses has a negative impact on patient outcomes, decreases quality of care, and contributes to rising health costs. to create a breeding ground for stress and burnout among U.S. health-care providers becomes very strong. A number of recent studies have established that stress and burnout are on the rise among health-care providers. Research has also shown a strong correlation between the presence of burnout among health-care providers, increased medical errors, poor patient outcomes, and increased healthcare costs. It is critical for providers to be cognizant of the early signs and symptoms of stress and burnout, the most effective ways to prevent and manage these conditions, and the potential negative consequences of unaddressed stress and burnout. Review of the literature The Mayo Clinic and the American Medical Association (AMA) surveyed 7,288 physicians in June 2011 using the Maslach Burnout Inventory (MBI), a 22-item questionnaire designed to measure perceived burnout in human-services professions. The MBI, which was created by Christina Maslach, PhD, a professor of psychology at the University of California, Berkeley, rates burnout as low, moderate, or high. The Mayo Clinic/AMA survey results revealed that 45.8% of physicians experience at least one symptom related to burnout in the work setting, and 37.9% of physicians had a high level of emotional exhaustion. This same study also found that almost 60% of physicians who practice emergency medicine, internal medicine, and family medicine had high levels of burnout.2 The figures from this study indicated that burnout rates among physicians had nearly doubled when compared with previous studies, which revealed rates ranging from 26.5% to 30%.3-5 A pilot study of 384 orthopedic residents and 264 orthopedic faculty members at two academic training programs was conducted to determine the quality of life and presence of burnout risk factors among the participants. The residents and faculty completed an anonymous survey that was developed based on the MBI, the General Health Questionnaire-12, and the Revised Dyadic Adjustment Scale. The results showed 56% of the orthopedic residents and 28% of the faculty members had high levels of burnout. In addition, 16% of residents and 28% of the faculty reported symptoms pertaining to psychological distress.6 A second part of the pilot study looked at how the spouses of residents and attending physicians are affected by training and academic practice. The respondents included 259 spouses

of orthopedic residents and 169 spouses of orthopedic faculty. The findings revealed the presence of psychological distress in 18% of resident spouses and in 10% of faculty spouses. A correlation was noted between decreased satisfaction of the spouses and excessive irritability among their mates.7 Nurses, like physicians, are also at high risk for developing stress and burnout, especially nurses who work in environments in which patients are critically or terminally ill and staffing is insufficient. Because nurses are very often the front-line providers of health care and frequently witness the suffering of their patients, they are more likely to experience emotional distress and physical exhaustion, which are precursors to burnout. A descriptive, cross-sectional survey investigated the prevalence of burnout among oncology nurses. A total of 153 nurses completed the survey, with the participant breakdown being 132 registered nurses, 10 medical assistants, six patient-care technicians, and five radiology technicians. Nearly half (44%) of the inpatient staff was found to be at high risk for experiencing burnout, compared with 33% of the outpatient staff.8 Another study investigated job-related burnout among registered nurses and explored whether this problem influences the development of hospital-acquired infections among inpatients. A significant association was found between burnout among registered nurses and the development of surgical-site infections as well as catheter-associated urinarytract infections. This study also found hospitals that were able to lower the burnout rate of registered nurses by 30% had 6,239 fewer infections, which translated into an annual cost savings of $68 million.9 It has become clear that burnout among registered nurses has a negative impact on patient outcomes, decreases quality of care, and contributes significantly to rising health costs. Stress and burnout

The terms stress and burnout have very distinct and separate meanings. Stress was defined in 1926 by endocrinologist Hans Selye as “non-specific [biological] response of the body to any demand placed upon it.”10 Nevertheless, stress remains difficult to understand. Is it attributable to specific causes, effects, or a combination of the two? Is it the body’s reaction to stimuli that disturbs the body’s equilibrium, or do the stimuli cause the disturbance? Continues on page 38

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clinician burnout

Cognitive symptoms of excessive stress include irritability, anger, anxiety, hyper-vigilance, impaired concentration, and decreased libido. The term burnout was coined in the 1970s and referred to a reaction to interpersonal job-related stressors.11,12 Prolonged stressors can lead to burnout. Eustress vs. distress. Stress can present in two forms: eustress and distress. Eustress is a healthy form of stress and is related to such desirable life events as participating in a challenge, winning a race, receiving a promotion, watching a scary movie, riding a roller coaster, and engaging physical strength training. Eustress leads to feelings of excitement, motivation, contentment, and fulfillment. Distress, on the other hand, is an unhealthy form of stress that may include physical and emotional strain or tension or persistent stress that is not resolved through coping and adaptation. Distress may also be a precursor of anxiety, depression, substance abuse, addiction, compassion fatigue, and burnout. The human body is designed to give warning signals of stress overload that may include physical and cognitive symptoms. Physical signs and symptoms include insomnia or disturbed sleep, digestive problems, headaches, low energy, chronic tiredness, psychosomatic illnesses, muscle tension, teeth grinding, hypertension, and tachycardia. The cognitive symptoms of excessive stress may consist of irritability, anger, anxiety, hypervigilance, impaired concentration, and decreased libido. Chronic stress leads to overengagement; over-reactive emotions; hyperactivity; and a sense of urgency, panic, phobias, and anxiety-type disorders. The symptoms of stress overload are often seen by the sufferer as obstacles to performance and success that he or she merely wants to eliminate. The symptoms seldom slow down the Table 1.The burnout triad Emotional exhaustion • Fatigue on arising in the morning • Feeling emotionally drained from work • Perceiving working with others all day as a strain • Perceiving working with others as no longer enjoyable Depersonalization • Dehumanized perception of others • More callous actions toward others • Negative or cynical attitudes toward patients • Treatment of patients as impersonal objects • Indifference to what happens to patients Decreased sense of personal accomplishment • Feeling of ineffectively dealing with patients’ problems • Feeling unable to positively influence the lives of others • Not feeling exhilarated after working closely with patients

victim, until the final blow is struck and the ulcer, stroke, or heart attack occurs.13 Lack of balance in one’s life can lead to stress overload, depletion of emotional reserves, insufficient coping skills, and ultimately burnout. Burnout. No standardized system-wide approach or treatment for burnout exists, a condition not included in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.14 Herbert J. Freudenberger, a German-born American psychologist most widely known for his contributions to understanding and treating stress, burnout, and substance abuse, was the first to use the term burnout in 1974. Freudenberger defined burnout as a state of mental and physical exhaustion brought on by an individual’s professional life.15 The most widely accepted definition of burnout comes from Maslach, who defines it as emotional exhaustion, depersonalization and reduced sense of personal accomplishment that can occur among individuals who do “people work” of some kind (Table 1).16 Among health-care providers, emotional exhaustion is characterized by physical and emotional depletion and fatigue. Signs of emotional exhaustion may include feeling fatigued on arising in the morning, feeling emotionally drained from work, and feeling that working with patients all day is a strain and no longer enjoyable. Depersonalization consists of negative or cynical attitudes and feelings about patients and a dehumanized perception of others. Examples of depersonalization include viewing patients as impersonal objects, acting more callus toward others, and not caring what happens to patients. A reduced sense of personal accomplishment may include the feeling of ineffectively dealing with the problems of patients, the inability to positively influence the lives of others, and the lack of feeling exhilarated after working closely with patients. Burnout is associated with higher ratings of emotional exhaustion and depersonalization and lower ratings of personal accomplishment. Clinician burnout that is ignored and goes unaddressed will ultimately have negative effects on every aspect of one’s family and social life and can lead to such conditions as depression, anxiety, and substance abuse. The initial signs and symptoms of burnout may be difficult to recognize because the process typically occurs over a lenghty period of time. It is important to be aware of the presence of the signs and symptoms of burnout as soon as possible, because early recognition and intervention can restore balance and prevent the development

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Clinicians who fail to find effective and healthy ways to manage personal and professional stress are more likely to develop unhealthy habits. of other psychiatric conditions. Early recognition can also help avoid the professional consequences of burnout, including potential patient harm. Managing stress

Stress management is the key to maintaining a healthy balance in life and preventing career burnout. Clinicians who fail to find effective and healthy ways to manage personal and professional stress are more likely to develop unhealthy habits. Although unhealthy ways of coping with stress may seem effective temporarily, such behavior can eventually lead to more damage. Health-care providers must acknowledge the presence of stress in their lives, reflect on the ways that stress is currently being managed, and develop healthy coping strategies to successfully manage stressors. Unhealthy habits. It is important to be aware of unhealthy habits that may slowly develop over time, such as overeating; under-eating; binge drinking; using drugs to relax; smoking; sleeping too much; withdrawing from friends, family, or participation in activities that were enjoyable in the past; checking out mentally; and lashing out at others in an abusive fashion. Such unhealthy habits will ultimately have a negative effect on family, friends, coworkers, and patients and will only compound the person’s current level of stress. If current habits are not improving the individual’s overall emotional or physical health, it is time to consider developing more healthy habits. Healthy habits. The most effective way to manage stress and prevent the occurrence of detrimental coping mechanisms and, ultimately, professional burnout is to develop healthy habits. Healthy activities allow the body and mind to decompress, relax, and recharge. Such beneficial activities may include getting regular exercise, eating nutritious food, getting sufficient sleep, listening to music, spending time outside in nature, interacting with a pet, watching a funny movie, or soaking in a hot bath. Such social interaction as calling or visiting with a close friend or family member is also a healthy, stress-relieving activity. Some individuals find relaxation by writing in a journal, working in a garden, or reading a book.

should also learn how to say no to additional requests, stay away from individuals who create a stressful environment, or simply be more assertive. Giving priority to activities a person deems most important can be a very effective way to manage stress levels. However, not all stress is unavoidable, and change lies at the heart of effective management of unavoidable stress. Devising healthy ways to manage unavoidable stress is one of the keys to preventing burnout. Strategies on coping with unavoidable stress may include changing the way one communicates, changing how one chooses to react to a situation, and changing one’s expectations and attitude. The person should consider expressing feelings instead of keeping them inside, being open to compromise, being more assertive, and improving time management. He or she should have realistic expectations, admit that perfection does not exist, and focus on the positive aspects of a situation. Realizing that the behavior of others cannot be controlled enables one to focus on factors that can be controlled. Talking with a trusted friend or therapist and learning to forgive others are additional ways of managing unavoidable stressors. Continues on page 40

Table 2. Strategies to prevent burnout Avoid such unhealthy habits as: • Overeating/undereating • Binge drinking • Drug use • Smoking • Sleeping too much • Withdrawing from friends, family, or activities that were once enjoyable • Checking out mentally • Taking your stress out on others in an abusive fashion Develop such healthy habits as: • Regular exercise • Healthy nutrition • Interacting with a pet • Watching a funny movie • Long, warm baths • Reading • Writing in a journal • Gardening

Avoidable vs. unavoidable stressors

Maintain professional boundaries

Learning to better manage stress requires the person to change either the current situation or the way he or she reacts to the situation. Avoiding stressful events or individuals is one way to keep stress levels in check. The person

• Ensures adequate self-care of the health-care provider • Serves as a healthy barrier for the health-care provider • Decreases disruptive or intimidating behavior by the health-care provider • Ensures that patient harm does not occur

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clinician burnout

Disruptive behavior in a health-care setting is associated with increased medical errors, poor patient satisfaction, staff turnover, and burnout. Preventing and treating burnout

The ability to prevent burnout ultimately depends on the effective management of stress, which requires rigorously setting and keeping boundaries at the workplace. A strategy to prevent burnout should include avoiding unhealthy habits, developing healthy habits, and maintaining professional boundaries (Table 2). Differentiating between avoidable and unavoidable stressors is another important aspect of burnout prevention. Attention to underlying illness is imperative, and prompt treatment of such health problems or psychiatric conditions as substance-use disorders or major depressive disorder is a primary component of an effective burnoutprevention strategy. As noted previously, implementing these strategies will require changes to be made in one’s daily lifestyle and behaviors as well as rigorous maintenance of personal and professional boundaries. Maintaining professional boundaries

The topic of personal and professional boundaries is extremely important and deserving of much thought and attention. Although a detailed discussion of the subject is beyond the scope of this article, several aspects of maintenance of professional boundaries may have significant impact on prevention and treatment of burnout among health-care providers. From the provider’s standpoint, maintenance of professional boundaries primarily prevents burnout through the mandate for self-care. Health-care providers are expected to commit to ongoing professional development and excellence in patient care. However, the expectation of providing care for others is difficult or impossible to achieve when it is separated from the imperative to care for oneself. Maintaining personal boundaries to ensure adequate self-care is a fiduciary duty owed to the patient, because the presence of burnout does not excuse any patient harm that may result. Self-care demands incorporation of healthy behaviors, including adequate exercise and healthy eating, as well as avoidance of unhealthy behaviors and excessive use of addictive substances. Increased stress is associated with increased substance use as providers search for relief. Substance abuse can lead to addiction, which exponentially increases stress and the potential for career burnout. Strict adherence to professional boundaries minimizes stress associated with difficult patient interactions. These

boundaries ensure that patient harm does not occur by preventing psychological, financial, and sexual exploitation of the patient. However, maintenance of professional boundaries also serves as a protective barrier for the provider by establishing ground rules for the professional services that promote self-care. For example, not allowing after-hours refills of controlled substances could minimize unnecessary stress by eliminating a potential negative patient interaction before it happens. Finally, maintaining professional boundaries reduces disruptive or intimidating behaviors on the part health-care providers. Disruptive behavior in a health-care setting is associated with increased medical errors, poor patient satisfaction, staff turnover, and burnout. On January 1, 2009, The Joint Commission (www.jointcommission.org) enacted new standards for accredited hospitals and programs centering on a code of conduct that defines acceptable, disruptive, and inappropriate behaviors exhibited by health-care workers, as well as a process for managing disruptive and inappropriate behaviors.17 In short, The Joint Commission mandated enforcement of professional boundaries to strengthen the protective barrier against disruptive behavior by employees. The anticipated result is a less stressful environment that ultimately reduces burnout and the potential for patient harm. Conclusion

Stress and burnout are on the rise among health-care providers. Research has shown a correlation between burnout among providers, negative patient outcomes, and increased health costs. With the current shortage of practitioners and increasing pressure to do more work with less help, clinician burnout could be a major national problem for the foreseeable future. Health-care providers must be aware of effective ways to manage stress, recognize the signs of potential burnout, and adopt effective prevention strategies. Professionalism demands adequate self-care, and clinicians owe it to themselves as well as to their loved ones, colleagues, and patients to fulfill this duty. n Dr. Smith is Assistant Professor of Nursing, Mississippi University for Women, Columbus, Miss.; and Adjunct Faculty, Capstone College of Nursing, University of Alabama, Tuscaloosa, Ala. Dr. Hambleton is Medical Director, Mississippi Professionals Health Program, Ridgeland, Miss.

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References 1. Health Resources and Services Administration. Shortage Designation: Health Professional Shortage Areas & Medically Underserved Areas/ Populations. Available at www.hrsa.gov/shortage/. 2. Shanafelt TD, Boone S, Tan L, et al. Burnout and satisfaction with worklife balance among U.S. physicians relative to the general U.S. population. Arch Intern Med. 2012;172:1377-1385. Available at archinte.jamanetwork. com/article.aspx?articleid=1351351. 3. Shanafelt TD, Sloan JA, Habermann TM. The well-being of physicians. Am J Med. 2003;114:513-519. 4. McMurray JE, Linzer M, Konrad TR, et al. The work lives of women physicians. J Gen Intern Med. 2000;15:372-380. Available at www.ncbi.nlm.nih. gov/pmc/articles/PMC1495474/. 5. Williams ES, Konrad TR, Linzer M, et al. Physician, practice, and patient characteristics related to primary care physician physical and mental health: results from the Physician Worklife Study. Health Serv Res. 2002;37:

“Now you’re probably all asking yourselves, ‘Why must I learn to read and write?’”

119-141. 6. Sargent MC, Sotile W, Sotile MO, et al. Quality of life during orthopaedic training and academic practice. Part 1: orthopaedic surgery residents and faculty. J Bone Joint Surg Am. 2009;91:2395-2405. 7. Sargent MC, Sotile W, Sotile MO, et al. Quality of life during orthopaedic training and academic practice: Part 2: spouses and significant others. J Bone Joint Surg Am. 2012;94:e145(1-6). 8. Potter P, Deshields T, Divanbeigi J, et al. Compassion fatigue and burnout: prevalence among oncology nurses. Clin J Oncol Nurs. 2010;14:E56-E62. 9. Cimiotti JP, Aiken LH, Sloane DM, Wu ES. Nurse staffing, burnout, and health care–associated infection. Am J Infect Control. 2012;40:486-490. Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC3509207/. 10. Selye H. The Stress of Life. New York, N.Y.: McGraw-Hill;1978:29. 11. Maslach C, Schaufeli WB, Leiter MP. Job burnout. Annu Rev Psychol.

“Look where you’re going!”

2001;52:397-422. practice. Career Development International. 2009;14:204-220. Available at www.wilmarschaufeli.nl/publications/Schaufeli/311.pdf. 13. Enrichment Journal. Depressed, stressed, and burned out: What’s going on in my life? Available at enrichmentjournal.ag.org/200603/200603_020_ burnout.cfm. 14. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington, D.C.: American Psychiatric Association; 2000. 15. Freudenberger HJ. Staff burnout. Journal of Social Issues. 1974;30:159-165. 16. Maslach C. Burnout: The cost of caring. Los Altos, Calif.: Malor Books; 2003:3. 17. The Joint Commission. Sentinel Event Alert, Issue 40: Behaviors that undermine a culture of safety. Available at www.jointcommission.org/ assets/1/18/SEA_40.PDF. All electronic documents accessed June 15, 2013.

“Here’s the deal. I’ll stop playing my bagpipes when you stop playing your banjo.”

12. Schaufeli WB, Leiter MP, Maslach C. Burnout: 35 years of research and

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feature: Coleen Weber Rosen, DNP, APNP, FNP-C, and Teri Kaul, PhD, MSN, APRN-BC

Simple treatment for pediatric bedwetting When treating a young patient for monosymptomatic enuresis, be sure to assess the physical, emotional, and developmental maturity of the child.

nuresis, or bedwetting, is described as episodes of urinary incontinence during sleep in children age 5 years and older. Monosymptomatic enuresis is incontinence in children who have no other lower urinary tract symptoms and no history of bladder dysfunction. Children with monosymptomatic enuresis have never achieved an acceptable period of nighttime dryness and are described as having primary enuresis. Another population of children with monosymptomatic enuresis includes those who have developed nocturnal incontinence after a dry period of at least six months. These children are described as having secondary enuresis.

ÂŠ thinkstock

The physiology of bladder control

Bedwetting is more common in boys and often resolves spontaneously.

Children learn bladder control at various ages during the potty-training years. Most children begin to stay dry during the night roughly at age 3 years. Continence and micturition involves a balance between the urethral sphincter closing and the detrusor muscle contracting. The proximal urethra and bladder are both located within the pelvis. Normally, urethral pressure exceeds the bladder pressure, which results in urine remaining in the bladder. As it increases or decreases, intra-abdominal pressure is transmitted to the urethra and bladder equally. This transmission leaves the pressure differentials unchanged, which results in continence maintenance. Normal voiding and urine elimination is the result of changes in both of these pressure factors signaling the need to void. As

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the urethral pressure falls, the bladder pressure rises, thus contracting the detrusor muscle and opening the sphincters of the urethra for micturition. Briefly, the development of continence is as follows: • Infancy: voiding occurs frequently, reflexively, and without voluntary control. • Age 6 months to age 12 months: bladder capacity increases and voiding frequency decreases. • Age 1 year to age 2 years: conscious sensation and ability to feel fullness develops; child is able to postpone voiding briefly by contracting the sphincter • Age 2 years to age 3 years: volitional voiding develops; child is able to initiate voiding, relax the pelvic floor, and inhibit voiding through the cerebral cortex • Age 4 years: bladder volume increases; child is able to remain dry for two to three hours and void five to eight times per day. Assessing monosymptomatic enuresis

The clinician must consider all the potential causes for a child’s nocturnal enuresis. Occasionally, the fullness sensation association and coordination between the bladder and the brain is not yet fully developed in some children. This lack of coordination tends to result in incontinence. Bedwetting is not the child’s fault. No child consciously and purposely enjoys wetting his or her bed. Nocturnal enuresis is common in families in which at least one parent experienced bedwetting as a child: There is a strong correlation for inheritance. The pattern and trend of bedwetting typically follows an outgrowth of the nocturnal enuresis at roughly the same age as the afflicted parent. This correlation is important to note, since it can be very reassuring to the child that the parent eventually outgrew bedwetting and therefore he or she will, too. Because primary monosymptomatic enuresis has a high rate of spontaneous resolution, it will be self-limiting. Bedwetting appears to occur more frequently in boys. A study involving more than 6,000 children found that roughly seven out of 100 boys and three out of 100 girls wet their beds at night a minimum of once a month.1 One potential explanation as to why boys are more frequent bedwetters

poll position

What is your go-to treatment of choice for bedwetting? n=291

Dry bed training: 31% Enuresis alarm: 25% Drug therapy: 14% Combination of drug therapy and enuresis alarm: 30%

30%

14%

31%

25%

For more polls, visit CliniAd.com/10TDwDb.

is the belief that girls tend to mature faster and develop the brain-bladder control association more quickly. However, this theory is based on observation rather than data. Nocturnal enuresis may also be related to the child’s bladder capacity. Some children hold a smaller volume of urine than what is considered normal for their age. To quickly estimate bladder capacity in milliliters, take the child’s age in years, add two, and multiply by 30. For example, a child aged 3 years has a bladder capacity of approximately 150 mL (i.e., [3 + 2] × 30=150). A diminished level of vasopressin may be factorial in the child with primary monosymptomatic enuresis. Vasopressin is a hormone that reduces overnight urine production and concentrates the urine. The body’s inability to decrease the volume of urine and concentrate it can be another challenge in achieving nocturnal continence. Finally, deep sleep further prevents the child from experiencing the fullness sensation of the bladder and from awakening to go to the bathroom in a timely manner. Physical, emotional, and developmental maturity

A child who shows no interest or concern with regard to his or her bedwetting is most likely not ready to take ownership of the behavior. The topic is best discussed with the parents

For more news, opinion, and clinical features concerning children’s health, visit our Pediatrics Information Center at

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after the initial assessment of the child. Likewise, a child who continues to have multiple daytime voiding accidents should work toward building dryness during the daytime before conquering the night. According to guidelines from the United Kingdom’s National Institute for Health and Clinical Excellence, the prevalence of childhood primary enuresis diminishes with age. Prevalence at age 5 years is 16%, falls to 5% by age 10 years, and is 1% to 2% by age 15 years.2 It must be emphasized that enuresis is not a disease but rather a constellation of symptoms to be managed and changed through behavior modification.3 To treat pediatric enuresis, the health-care provider needs to assess both the patient’s and the family’s readiness to take on the problem. Does the child care that he or she wets the bed? Def ined expectations must be discussed and established from the onset. Some parents may simply wish for reassurance that the enuresis is not caused by a physical abnormality. Such parents are not interested in commencing a long-term therapy. If short-term dryness is a priority, the provider should emphasize that bedwetting is not the child’s fault and should instruct the parents not to punish the child for bedwetting. Parents who are having difficulty coping with bedwetting or are exhibiting anger or blame toward the child may require additional support and referral. The clinician should stress to the parents and patient that a prudent treatment program for enuresis involves several methods of therapy, used in sequence or in combination. The course of care may be prolonged; it may fail in the short term and is often associated with relapses. The parents must be willing to participate and provide support. Guidance and direction will also be necessary in the school environment. Therapy should be goal-oriented, and follow-up must be consistent. Plan of care

The typical plan of care starts at the initial appointment by assigning the child “homework.” This is done to set the tone for expectation and commitment toward the process. Homework usually is pared down to three manageable tasks that the child should fully incorporate into his or her routine before the next clinic visit. First, the usual recommendation is to have the child boost daily fluid intake substantially by carrying a water bottle throughout the day. The child is instructed to drink the liquid between 8:00 a.m. and 4:00 p.m. each day. This hydration promotes the cycling of the bladder, so the clinician should place the child on a timed voiding

clinical slideshow Breastfeeding may protect against bedwetting. For more information on the benefits of breastfeeding, view the clinical slideshow at CliniAd.com/14tblcH.

schedule with intervals of no longer than two hours between micturition. This process provides a solid connection and memory associating a full bladder with the act of voiding. For a child in school during the day, advise parents to send a tactful note to the teacher that explains the presence of the water bottle and the need for the child to have access to a restroom. The last piece of homework assigned is to encourage healthy daily bowel elimination. If the child describes hard and painful bowel movements, a prescription for a mild laxative is usually given with instructions on titration to establish one to two soft stooling patterns each day. The child should return to the clinic six to eight weeks later, at which point the clinician should note patterns and trends toward nocturnal dryness or the diminishment in volume of nighttime urine. Symptom improvement is typically noted, which in turn stimulates the child to continue the process. If the symptoms worsen or if the child is resistant to the implementation of the clinician’s recommendations, the provider should suggest motivational rewards that are personal and interactive rather than material. For example, parents can allow the child to pick what movie the entire family watches together, or give the child “alone time” with the parent to read a book. Rewards should be given to reflect the child’s earnest effort at implementation of the urologic homework. Waxing and waning of dry and continent nights are normal in the treatment of bedwetting, even in children who follow all recommendations. It is important for the clinician to provide support at this time to improve the child’s selfesteem.4 The provider may consider the use of desmopressin (DDAVP), a medication used to control the symptoms of a certain type of diabetes insipidus, or “water diabetes,” in which the body produces an abnormally large amount of urine. The oral dosing for this medication is to commence at 0.2 mg at bedtime and titrate up over several days to a total of 0.6 mg (i.e., three pills nightly). The child should stay at one pill for a few nights to determine whether the drug has any impact on promoting dryness or decreasing overnight

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A.B., a healthy and thriving boy aged 8 years, had never achieved complete nighttime dryness since being pottytrained at age 3 years. The boy mentioned that he occasionally recalled experiencing a dry night or two, but it had not been sequential or predictable. A.B. was a Boy Scout and was preparing for an overnight trip to the organization’s annual jamboree taking place three months later. The child was highly motivated to stop his bedwetting before his trip. To date, the only treatment modality tried was stopping beverages after suppertime. The boy’s parents reported that he was a scant drinker of beverages during the daytime, with the majority of his fluid intake occurring right after he arrived home from school at 4:00 p.m. A.B. was also an infrequent daytime voider and reported going to the restroom only once a day during school hours. He tended to have constipation, producing one to two painful bowel movements per week. The boy’s father had been a bedwetter until age 7 years. A.B. systematically and regimentally followed all of the clinician’s recommendations of robust daily hydration, a timed voiding schedule, and regular post-meal daily bowel eliminations. He was followed up sequentially at threemonth intervals and noted to have progressive and sustained nocturnal continence. He was given effective tools to continue this pattern of successfully resolved nocturnal enuresis. At his most recent visit, A.B. reported with great confidence and satisfaction that he had been able to attend the Boy Scout jamboree without incident.

and direction. This long-term guidance and support helps the family and the patient to maintain the stamina required to stay the course of care to ensure the best outcome. n Dr. Rosen is a family nurse practitioner specializing in pediatric urology at the Children’s Hospital of Wisconsin in Milwaukee. Dr. Kaul is the director of the Graduate Nursing Program and an associate professor at Concordia University, Mequon, Wisc. References 1. Su MS, Li AM, So HK, et al. Nocturnal enuresis in children: prevalence, correlates, and relationship with obstructive sleep apnea. J Pediatr. 2011;159:238-242. 2. National Institute for Health and Clinical Excellence. Nocturnal enuresis—the management of bedwetting in children and young people (CG 111). Available at www.nice.org.uk/guidance/CG111. 3. DeFoor WR Jr, Tobias N. Simple behavioral modification may be effective first-line treatment in resolution of nocturnal enuresis. J Pediatr. 2009;155:760. 4. Longstaffe S, Moffatt ME, Whalen JC. Behavioral and self-concept changes after six months of enuresis treatment: a randomized, controlled trial. Pediatrics. 2000;105(4 Pt 2):935-940. Available at pediatrics.aappublications.org/content/105/Supplement_3/935.long. 5. Neveus T, Eggert P, Evans J, et al. Evaluation of and treatment for monosymptomatic enuresis: a standardization document from the International Children’s Continence Society. J Urol. 2010;183:441-447. All electronic documents accessed June 15, 2013.

urine output. If the patient is held effectively on one or two pills, this is the preferred dose. Another treatment option for resistant nocturnal enuresis is a bedwetting alarm.5 These devices can be useful but require long-term commitment. Typically, the alarm takes three to four months to prove effective, and the child must be highly motivated to use it night after night. Clinicians and parents can consider using the bedwetting alarm in tandem with desmopressin. Sustained nighttime dryness over the course of several months suggests that the symptoms of nocturnal enuresis have been quelled. If the child is on desmopressin, it is recommended that the family titrate down the dose one month prior to the clinic visit to learn how the child will behave off the medication. At all times throughout the process of treating nocturnal enuresis, the clinician must provide the necessary reassurance

A case study of nocturnal enuresis

“First, you’re gonna dig a hole.”

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Advisor Forum These are letters from practitioners around the country who want to share their clinical problems and successes, observations, and pearls with their colleagues. Responding consultants are identified below. We invite you to participate.

Inside the Forum j u ly 2 0 1 3

Consultations Options for chronic tinnitus. . . . . . . . 54 Standard of care for patients with elevated liver enzymes. . . . . . . . . . . 54 Antifungal therapy in the elderly. . . . . 55 Nocturnal leg cramping. . . . . . . . . . . 55

Clinical Pearls Pain-relief cocktail for stomatitis. . . . . 55 Look for the “ugly” skin lesion. . . . . . 56 Prevent DVT in patients with folic-acid deficiency. . . . . . . . . . . . . 56

Your Comments What does “a homosexual lifestyle” insinuate? . . . . . . . . . . . . . . . . . . . . 56

Send us your letters with questions and comments to: Advisor Forum, The Clinical Advisor, 114 West 26th Street, 4th Floor, New York, NY 10001. You may also fax (646) 638-6117, or contact us by e-mail at letters@ clinicaladvisor.com. If you are writing in response to a published letter, please indicate so by including the number in parentheses at the end of each item. Letters are edited for length and clarity. The Clinical Advisor’s policy is to print the author’s name with the letter. No anonymous contributions will be accepted.

Addressing spiritual health with your patients. . . . . . . . . . . . . . 56

Consultations options for Chronic tinnitus What treatments are available for patients suffering from chronic tinnitus?—AMY LEE HAIMINK, MSN, ANP, Marlboro, N.Y. Assuming other treatable pathology has been ruled out, I have had excellent results with tapered prednisone. Three days at each level, using 40-mg, 30-mg, 20-mg, and 10-mg doses, is very effective.—Sherril Sego, FNP-C, DNP (177-1)

Standard of care for patients with elevated liver enzymes What is the standard of care for a patient with elevated liver function tests? There is no evidence of hepatitis A, B, or C, and an abdominal ultrasound shows only fatty liver. Is a gastroenterology consult required? Or is it sufficient to watch and wait? Many of these patients also have hyperlipidemia and/or type 2 diabetes.—MARY JOSEPHS, PA-C, Gilbert, Ariz. Fatty liver is the most common cause of elevated liver enzymes in the United States. Fatty liver is most often the result of alcohol use but is also caused by diabetes, obesity, chronic hepatitis (namely hepatitis C), and medications. Less common causes of fatty liver

Our Consultants

Rebecca H. Bryan, APRN, CNP,

Eileen Campbell, MSN, CRNP,

Philip R. Cohen, MD,

is a lecturer in the Family Health NP Program, University of Pennsylvania School of Nursing, Philadelphia.

is associate program director, Family Health NP Program, University of Pennsylvania School of Nursing, Philadelphia.

is clinical associate professor of dermatology, University of Texas Medical Center, Houston.

Deborah L. Cross, MPH, CRNP, ANP-BC, is associate program

director, Gerontology NP Program, University of Pennsylvania School of Nursing, Philadelphia.

Maria Kidner, DNP, FNP-C,

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

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are hemochromatosis, Wilson disease, a1-antitrypsin deficiency, autoimmune disorders, and liver cancer. Most cases of elevated liver enzymes are discovered on screening of asymptomatic patients. It is important to compare recent determinations with old records to see if this is a new finding. Carefully evaluate all risk factors, including alcohol, medications, lifestyle factors, and family history. Patients should be screened for hepatitis, autoimmune disorders, and iron-study abnormalities. The liver can be assessed via ultrasound or CT to look for tumors; biopsy is reserved for definitive diagnosis of such potentially treatable conditions as Wilson disease and hemochromatosis. Patients should be instructed to lose weight, avoid alcohol and other toxins, and have their liver enzymes monitored for any change.—Claire Babcock O’Connell, MPH, PA-C (177-2)

Antifungal therapy in the elderly Is an oral antifungal agent appropriate in a man aged 76 years who has a two-year history of onychomycosis? Treatment with ciclopirox 8% nail lacquer and gel in combination with 40% urea [Carmol 40] gel has been unsuccessful. The patient reports no pain and has had no cellulitis or other complications related to his onychomycosis. He takes warfarin [Coumadin, Jantoven] for a history of deep vein thrombosis but is otherwise healthy.—ANN KUEHL, PA-C, Mokena, Ill. Because nonfungal nail changes in the elderly can mimic onychomycosis, it may be prudent to obtain fungal-culture confirmation of clinically suspicious tinea unguium prior to starting systemic antimycotic therapy. Such systemic antifungals as terbinafine (Lamisil) and itraconazole (Onmel, Sporanox) can be used in older individuals, provided baseline laboratory studies are normal and appropriate periodic follow-up studies are performed. However, caution is advised when using systemic antifungals in a patient who is concurrently receiving warfarin. Itraconazole can increase the plasma

Debra August King, PhD, PA,

is senior physician assistant at New York-Presbyterian Hospital, New York City.

Mary Newberry, CNM, MSN

provides well-woman gynecologic care as a midwife with Prima Medical Group, Greenbrae, Calif.

concentration of warfarin, thereby enhancing its anticoagulant effect. There have been spontaneous reports of an increase or a decrease in the prothrombin time (PT) of patients taking oral terbinafine and warfarin concomitantly. However, a causal relationship between terbinafine tablets and these changes has not been established. In patients receiving warfarin anticoagulation, initial and periodic evaluation of bleeding parameters (PT and international normalized ratio) should be considered while they are concurrently being treated with either itraconazole or terbinafine.—Philip R. Cohen, MD (177-3)

Nocturnal leg cramping I frequently hear adult patients complain of episodes of nocturnal leg cramping. What diagnostic tests are indicated and what treatment modalities are recommended?—SUSAN CALLOWAY, FNP-C, St. Joseph, Mo. Any leg pain should first be investigated for neurologic and vascular causes. If an electromyogram and vascular studies are normal, quinine sulfate may be used (one to two 325-mg capsules at bedtime). The mechanism of action is poorly understood but is thought to involve regulation of the sodium content in the muscle fibers. Side effects are rare blood dyscrasias and occasional GI upset. For neuropathic leg pain, gabapentin (Horizant, Neurontin) and amitriptyline at bedtime also work well.—Sherril Sego, FNP-C, DNP (177-4)

Clinical pearls Pain-relief cocktail for stomatitis To alleviate pain associated with stomatitis, have the patient swish and spit with a mixture of equal parts diphenhydramine (Benadryl Liquid Elixir) and Maalox four times a day (before

Claire O’Connell, MPH, PA-C,

teaches in the PA Program at the New Jersey Medical School and Rutgers University, Piscataway, N.J.

Sherril Sego, FNP-C, DNP,

is a primary-care nurse practitioner at the Department of Veterans Affairs Medical Center in Kansas City, Mo.

Julee B.Waldrop, DNP,

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

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Advisor Forum meals and at bedtime). The diphenhydram ine takes away the pain, and the Maalox coats the inside of the mouth.— JANICE NAPIER, FNP, San Augustine, Tex. (177-5)

Look for the “ugly” skin lesion When examining skin, pay particular attention to any “ugly duckling” lesion that does not match the others; this is the one to watch, remove, or treat. I have found this tip especially helpful in individuals with an abundance of moles, freckles, or other skin lesions.—MICHELLE OWENS, FNP, New Ulm, Minn. (177-6) Prevent DVT in patients with folic-acid deficiency Check the homocysteine level of any individual with folicacid deficiency. If elevated, these patients may be at risk for deep vein thrombosis. Early detection allows for the use of such preventive measures as compression stockings and aspirin therapy to decrease platelet aggregation.—GLADYS ELLIS, FNP-BC, ARNP, Fort Pierce, Fla. (177-7)

Your comments What does a “homosexual lifestyle” insinuate? The May 2013 Dermatology Clinic (“Purple plaques on a homosexual man”) included a patient description that read, “Social history revealed a homosexual lifestyle with no illicit drug use.” What is a “homosexual lifestyle” and exactly how does it differ from a “heterosexual lifestyle”? Most of the gay and lesbian people that I know are either celibate or in longterm monogamous relationships. Are they living a lifestyle that would predispose them to HIV? How is this prejudicial term an appropriate part of a clinical description? I take offense at the presumption that “homosexual” and “sexually promiscuous” are synonyms. This is an insult to all people with a same-gender sexual orientation. If what is meant by the medical description is that this man had multiple sexual partners of the same sex, then say that—just as you would describe a heterosexual person with multiple sexual partners.— GRETCHEN BRAUER-RIEKE, MSN, Milwaukie, Ore. The phrase “homosexual lifestyle” was in no way meant to be politicized, imply a lifestyle of sexual promiscuity, or infer prejudice. As mentioned in the article, a particular subtype of Kaposi

sarcoma (KS) is more common in men who are homosexual and HIV-positive. The patient’s sexual orientation was merely used as a clinical clue to prompt the reader in making the diagnosis of KS, given the clinical picture and very short descriptive vignette. The authors apologize for any offense; certainly none was intended.— Julia R. Nunley, MD (177-8) Editor’s note: These comments were written in response to a post in The Waiting Room, our collection of expert blogs. To read more, visit the website at CliniAd.com/VwgfCl.

addressing spiritual health with your patients I treat a number of victims of child abuse. There is no way to fully help families navigate to a place of healing from such a trauma of betrayal without considering where they get their spiritual strength (“Suspending personal bias from patient care,” available at CliniAd.com/18Wn2hl, accessed June 15, 2013). Forgiveness of themselves and others and finding meaning in suffering is a crucial journey undertaken by each individual. Every day, I help people lean into the places that have given them solace in the past. Cognizant of the many roads that lead to this goal, we keep a resource list of providers in the community who can help them complete this walk back to wholeness and peace.—ANNE TROY, RN, FNP, New Orleans (177-9) I frequently discuss spiritual health in my primary-care practice. I find such discussions most applicable when treating patients dealing with mental-health issues or stress. I work with a military population, and my patients and their families face tremendous life stressors and personal sacrifice. When I see a patient about increased stress, anxiety, or depression, I usually talk about getting back to the basics. After addressing the benefits of nutrition, exercise, and adequate sleep, I ask if the patient has a faith. If so, I usually recommend getting back in touch with like-minded folks, attend a service, pray, meditate, or make an appointment with a military chaplain. It is important to emphasize that there is a very strong mind-body link, and an imbalance in this link can manifest in a physical way. When I discuss spirituality, the patient is almost always visibly relieved to have this part of their life acknowledged and validated. I have never had a negative response to this type of discussion.—MARGO HOPPIS, PA-C, Shoreline, Wash. (177-10) n

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Derm Dx

exclusive to the web

Interact with your peers by viewing the images and offering your diagnosis and comments. To post your answer, obtain more clues, or view similar cases, visit CliniAd.com/10KIbCF. Learn more about diagnosing and treating these conditions, and see how you compare with your colleagues.

White spots on sun-damaged skin A man, aged 65 years, presents for an annual skin check. He complains of many white spots on his arms. The patient has a history of several basal cell skin cancers. He worked outdoors on an oil rig for 40 years. What is your diagnosis?

• Poikiloderma of Civatte • Stellate pseudoscars • Cutis rhomboidalis nuchae • Favre-Racouchot syndrome

● See the full case at CliniAd.com/15gJgE0

Hyperkeratotic peeling palms and soles after chemotherapy A man develops painful bullous and desquamative hyperkeratotic plaques on the palms and soles. The lesions started three weeks after the patient began chemotherapy for metastatic melanoma. What is your diagnosis?

• Hand-foot syndrome • Palmar-plantar erythrodysesthesia • Hand-foot skin reaction • Chemotherapy-induced acral erythema ● See the full case at CliniAd.com/16o6IT1

Have you missed any recent Derm Dx cases? Go to CliniAd.com/10KIbCF for a complete archive of past quizzes as well as additional images of last month’s other cases.

Droopy eyebrow after surgery

Brown patches on the face

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LEGAL ADVISOR CASE

Questioning the doctor’s orders

A strong dose of an opioid administered to a woman recovering from surgery causes permanent damage.

By Ann W. Latner, JD

Ms. K had recently graduated nursing school. She had hoped to find a job in a pediatrician’s office but ended up with a higher paying though less interesting position in a rehabilitation center. Her plan was to remain at this job until she paid off her student loans, and then move on to something more in line with her original goal. Little did Ms. K know that her first year in practice would be marred by a mistake that would haunt her for the next several years. Mrs. O, aged 55 years, had been sent from the hospital to the rehab center for a one-week stay following foot surgery. Ms. K was on duty when Mrs. O arrived. After Mrs. O was settled in her room, Ms. K made sure that the order for the patient’s pain medication had been sent to the institution’s pharmacy. This is where the trouble began. Unbeknownst to Ms. K, the patient’s physician had mistakenly written a prescription for morphine. The physician intended to write the prescription for 50 mg of intramuscular meperidine (Demerol) but incorrectly wrote the order for morphine instead. While the dose

The pharmacist expressed concern about the written orders, indicating that the dosage was unusually high for morphine.

was appropriate for Demerol, it was excessive for morphine. The pharmacist called Ms. K to express concern about the prescription, indicating that the dosage was unusually high for morphine. He added that the pharmacy did not even have that amount of morphine on hand. The rehab center’s policy was that in an event such as this, the nurse should contact the physician to double-check the medication order, but Ms. K was inexperienced and instead of contacting the doctor, she contacted the rehab center’s administrative office. An administrator gave Ms. K permission to give Mrs. O the morphine. Ms. K, several other nurses, and the pharmacist all had to scour the facility to come up with the dose prescribed. The entire supply of morphine from the pharmacy as well as from emergency kits on the patient-care floors was combined into Cases presented are based on actual occurrences. Names of participants and details have been changed. Cases are informational only; no specific legal advice is intended. Persons pictured are not the actual individuals mentioned in the article.

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LEGAL ADVISOR a single 30-mg dose that was given to the patient. The process of collecting the morphine and getting approval had taken a long time, and Ms. K’s shift was over. She left without charting the dose or monitoring the patient’s respiratory status. That night, the nurses on duty noticed signs of respiratory depression in the patient but did not report it to the attending physician. At about 6 a.m. the next day, Mrs. O was found unresponsive with pinpoint pupils and barely breathing. She was taken by ambulance to the hospital, and numerous doses of naloxone were given on the way. At the hospital, it was discovered that Mrs. O had suffered a mild heart attack and was in renal failure due to the lack of oxygen from narcotic-related respiratory depression. She ultimately

Ms. K testified that the pharmacist told her that the dose of morphine was high, and that she had contacted administration for approval before giving the patient the medication. When questioned by the plaintiff’s attorney, Ms. K was forced to report that she knew the dose was high and could cause respiratory distress. She was embarrassed to admit that she had rushed home before charting the information, thinking that she could just do it the next day. After two days of deliberations, the jury awarded $3.2 million to Mrs. O and her husband. The jurors found the rehab center liable for neglect and the center and the physician liable for negligence. Legal background

Although it was the physician who made the original mistake, the rehab center was held most responsible. suffered brain damage and spent six months in the hospital relearning how to walk, talk, eat, and groom herself. She will need 24-hour supervision to assist with daily activities for the rest of her life. When Ms. K heard about what had happened to the patient, she was stricken with guilt and remorse. Every employee in the rehab center was discussing the situation, and Ms. K felt that people were talking about her behind her back, despite the fact that many of those same nurses had taken part in helping put together the dose of morphine. After Mrs. O was released from the hospital, her husband sought the counsel of a plaintiff’s attorney to assess whether they might have grounds for a lawsuit. After hearing the story and reviewing the medical records, the attorney informed them that they definitely had a case against both the physician and the rehab center. When the rehab center was notified about the impending lawsuit, the administrator called Ms. K into her office and advised her that although she wasn’t personally being sued, she and several of the other nurses, as well as the administrator herself, would certainly be called to testify. Ms. K was advised to speak to the rehab center’s defense attorney. With great trepidation, Ms. K met with the attorney, who explained the legal process to her. He told her that she would probably have to testify at both a deposition and at trial, if the case went that far, and that it was important that her story be the same each time.

As part of the verdict, the jurors also had to apportion liability among the parties involved. In cases in which there are multiple defendants, it is common for the judge or jury to apportion the guilt according to who was most at fault. Although it was the physician who made the original mistake, the rehab center was held most responsible because the order could have (and should have) been questioned before the medication was administered to the patient. The jurors found the rehab center to be 90% liable and the physician to be 10% liable. Protecting yourself

Any clinician who has a question as to whether a medication or dose is appropriate should ask the prescribing physician. Ms. K’s first mistake was that she did not follow the rehab center’s policy and call the physician; instead, she sought approval from an administrator. Ms. K’s second mistake was that she did not chart the dose or check the patient for respiratory depression—even though she was aware that the dose was unusually high and that morphine can cause respiratory depression. Not charting this information also meant that the staff on the next shift was not fully informed about the situation. Sadly, this case demonstrated failures on many levels. The pharmacist’s warning was ignored. Several nurses were involved in pooling together a dose of medication that clearly should have set off alarm bells for many of the clinicians. Yet despite all this, no one bothered to consult the prescribing physician. Perhaps as a new clinician, Ms. K was embarrassed to question the medication order of a supervising physician. However, picking up the phone would have protected the physician, the rehab center, Ms. K, and most important, the patient. Never be afraid to ask a question. It could make a world of difference. n

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Clinical Challenge Accidental hand amputation requires extensive surgery Pamela Horn, MS, CNP, ONP-C, and Lawrence Lubbers, MD

A woman is rushed to the emergency department after severing her hand in a woodworking accident at home. 1

Mrs. P, aged 63 years, is an energetic and right-handdominant grandmother who enjoys woodworking and frequently uses table saws and other mechanical tools. Two years ago, she was cutting wood with a miter saw in her basement when she looked down on the ground after “feeling something” and saw her hand and part of her arm lying on the floor. Instantly, she crawled upstairs, looked outside, saw someone, and called out for help. A stranger walking by came to her assistance. While applying direct pressure to Mrs. P’s residual limb, the good samaritan called 911. The paramedics arrived quickly, wrapped the limb in nonadherent sterile gauze dressing, and continued to apply pressure to control the bleeding. An IV solution of sterile saline was initiated as well. Mrs. P arrived in the trauma bay less than one hour after sustaining her injury. The medics did not bring the amputated limb to the emergency department (ED). A next-door neighbor placed the limb in a plastic bag before following the medics to the ED and giving the amputated limb to the trauma staff (Figures 1 and 2). The limb was then irrigated with sterile saline, wrapped in saline-soaked sterile gauze, placed in a plastic bag, and put in a tub of ice.

CASE

1. History

Figures 1 and 2. X-rays show the amputated appendage after arrival in the trauma bay (Figure 1) and the patient’s truncated forearm (Figure 2).

Mrs. P’s medical history was positive for hypertension, but she had stopped taking her medication because of the high cost. She had an otherwise unremarkable medical and surgical history. She denied drinking alcohol or taking illicit drugs, and her toxicology screen was negative. Mrs. P’s history was positive for tobacco use (one pack day for more than 30 years). The patient also reported that she drank several cups of coffee per day and ate chocolate almost daily. On examination, Mrs. P was alert and oriented but slightly lethargic due to pain medication

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Clinical Challenge administered in the ED. Her vital signs were stable but slightly hypertensive. Her lungs were clear, and her heart rate, heart rhythm, and ECG were normal. Serum lab tests and urinalysis were normal. The amputated hand was appropriately preserved, and at the one-hour mark, the fingertips were just slightly dusky. Both distal and proximal edges of the amputated arm were ragged with exposed bone.

2. Treatment Treatment in the trauma bay consisted primarily of ruling out any other injuries, inserting a Foley catheter, updating Mrs. P’s tetanus immunization, and administering IV antibiotics and aspirin. A hand surgeon outlined two possible treatment options and described the risks and benefits of both. The first option was a revision amputation that would be completed mid-forearm. Mrs. P would eventually need a prosthesis, which might be unaffordable given her limited budget. The second option was a replantation. This would require Mrs. P to consent to a long surgical procedure, make a firm commitment to change her dietary habits, immediately quit smoking, and agree to long-term intensive therapy sessions. Mrs. P was adamant in her decision: She wanted to try to save her arm, no matter the outcome, and she would do whatever was asked of her in return.

3. Surgical course The patient was taken to the operating room (OR) to begin what became an eight-hour procedure. Surgery was prolonged in part due to two episodes of arterial thrombosis that were likely attributable to Mrs. P’s smoking. General anesthesia was initiated along with a brachial block. Standard prepping and draping procedures commenced. The radius and ulna were initially stabilized with plateand-screw fixation after trimming, shortening, and realignment (Figures 3 and 4). Surgery continued with tendon repair using both Teno Fix (an intratendinous soft-tissue anchoring device) and cruciate-X suture methods. The 3-cm shortening of the bones helped with the repair. The Teno Fix tendonrepair device results in lower rupture rates and similar functional outcomes when compared with conventional repair.1 Teno Fix was utilized in four locations. The basilic vein was then repaired end-to-end using a microscope and microsurgical instruments. Once this repair

Figures 3 and 4. Postoperative x-rays show radius and ulna stabilization with plate-and-screw fixation.

was completed, the ulnar nerve and artery were repaired. The remaining tendons, including the sublimus, brachioradialis, and extensor tendons, were repaired next. Reduction and pinning of the proximal interphalangeal joints of the fingers was carried out to prevent early contracture caused by the loss of intrinsic muscle function. Controlled motion (passive and subsequently active) is necessary to prevent: (1) rupture of repaired structures, (2) tendon adhesions, and (3) joint contractures. Loose closure was carried out, noting no constriction at the transection site. A dressing and splint were applied to the wound. The patient was transported to the post-anesthesia care unit, and her hand was elevated at heart level. She was started on an IV heparin drip to maintain vascular patency after the declotting of the arterial thrombosis. Warming lights were used to keep the extremity warm as well. Mrs. P’s hospital stay was uneventful. She was discharged on postoperative day 4. At that time, occupational therapy was already in progress, and range-of-motion exercises had been initiated. At home, she maintained her strict caffeine-free diet (including abstaining from chocolate). She stopped smoking

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Clinical Challenge 5

a patient and/or family. Mrs. P was very fortunate because the hospital to which she was transported has an affiliation with a hand-and-microsurgery physician group.

5. Management of amputated limbs

Figures 5 and 6. Five-month follow-up shows arm extension after repair (Figure 5) and a subsequent x-ray (Figure 6).

and took aspirin as instructed (81 mg per day for two months). With each clinic visit, motion improvement has been shown (Figures 5 and 6). Mrs. P was extremely compliant with her occupational therapy. Her neural/sensory recovery progressed, and gabapentin (Neurontin) was initiated for burning pain, which subsequently abated.

4. Replantation outcomes Survival of an amputated upper extremity is a difficult outcome to achieve and is dependent on microvascular patency of the arteries and veins.2 Ultimate function is determined by the outcome of the tendon, nerve, bone, and joint repairs. Replantation surgeons are thoroughly trained and skilled in the repair of all five tissues in the upper extremity (i.e., bone/joint, muscle/tendon, nerve, vessel, and skin).2 The surgeon not only needs microsurgery knowledge, but should also be able to predict recovery outcome, thereby relaying realistic expectations when discussing options with

Preserving an amputated part can be accomplished in one of two ways.2 In one approach, the amputated part should first be wrapped in sterile gauze soaked with lactated ringers or saline solution and then placed in a plastic bag or specimen container. The bag or container should then be kept on ice. The amputated part should never be placed directly on ice or frozen, and dry ice or slush should never be used. The second technique is the immersion method: The amputated part is placed in a plastic bag filled with sterile lactated ringers or saline solution, and the bag is put in a container on ice. Goldner, et al. believe that the part is less likely to be frozen using this method and that there is less chance of strangulation due to wrapping.2 The instructions are easier to explain, and maceration secondary to immersion is not an issue. Either method is effective in preserving parts for up to 24 hours. If not cooled, however, tissues may only survive for approximately six hours without circulation, especially if muscles are involved.2 The surgical sequence is almost always carried out in the same fashion (Table 1): Damaged skin and soft tissue should be excised first, followed by bone shortening. This sequence allows for better fixation and ensures that vascular structures have enough length for anastomoses after the vessels are trimmed.3 A number of methods have been suggested for bone stabilization.4,5 In this case, plate-and-screw fixation was the best choice for more rigid fixation.2 Following bone fixation, the extensor and flexor tendons are repaired. In addition to the Teno Fix soft-tissue anchor technique, there Table 1: Operative sequence for digital and hand replantation. 1. Locate and tag the vessels and nerves. 2. Debride the damaged skin and tissue. 3. Shorten and fix the bone. 4. Repair the extensor tendons. 5. Repair the flexor tendons. 6. Anastomose the arteries. 7. Repair the nerves. 8. Anastomose the veins. 9. Obtain skin coverage.

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Clinical Challenge 7

Many surgeons prefer to repair the veins before repairing the arteries to have a cleaner field and to reduce blood loss.9 However, if the tourniquet is used judiciously, the artery can be repaired first and a clear field maintained. Once the limb is revascularized and hemostasis is obtained, the skin should be loosely closed, and there should be no tension on the skin. Fasciotomies are performed if there is any indication of compression or constriction, especially for the intrinsic muscles of the hand. The wounds are generally covered with sterile gauze impregnated with petrolatum, and should not be placed circumferentially due to the cast-like effect once blood saturates and clots within the dressing. If swelling occurs, constriction could cause vascular shutdown. The dressing should be bulky, nonconstrictive, and usually supported by a splint.2

6. Postoperative care

Figures 7 and 8. Clinic visit seven months postoperatively shows hand flexion (Figure 7) and follow up x-ray (Figure 8).

are several popular methods of suturing repair, such as the the Tajima technique,6 Kessler and modified Kessler,7 and the cruciate-X pattern.7 Microsurgical vessel and nerve repair occur next. It is important to note that there are many factors that lead to a successful repair besides the quality of the repair itself. The patient’s arm needs to be rewarmed; metabolically, there should be no acidosis, which could lead to vasospasm; and arterial blood flow should be spurting from the proximal end prior to the repair.2 Several types of treatments are available to facilitate revascularization. The injured artery needs to be sharply incised until normal intima is visualized using high-power magnification. If the length is not conducive due to tension—which can cause flattening of the vessel—additional bone trimming or vein and/or nerve grafting may be needed. Although not mandatory, it is best to attempt anastomoses of two veins for every artery.8 Primary nerve repair is almost always accomplished using end-to-end repair technique. Otherwise, nerve reconstruction may be necessary.

Postoperative care typically consists of elevation and warming. At times, anticoagulants are used, but this is a controversial topic. Anticoagulants were used in this case because the patient was a longtime smoker and declotting was necessary. Watchful waiting consists of lowering the hand if arterial inflow is diminished and elevating the hand more if venous outflow is slow.2 A digital thermometer is used frequently for temperature measurements, as this is a reliable indicator of perfusion.10 The patient’s room should be kept comfortably warm. To decrease the potential for vasoconstriction, patients are not permitted to smoke or to drink caffeine. Bed rest is usually indicated the first two to three days, and then activity is slowly increased. Generally, replantation patients are on antibiotics for one week.2 Patients should be instructed to wrap the extremity in a blanket if they go outside in cooler temperatures.

7. Discussion The overall process from injury to discharge in Mrs. P’s case was very efficient. The medics did a good job treating the patient; however, they could have taken the time to locate the amputated part and follow appropriate procedures. The trauma team moved through the intake and admission process smoothly, and the OR staff acted immediately to arrange for this infrequent, yet life-altering, surgical procedure. It should be noted that OR readiness starts at the time the call is received. In this case, the OR staff members

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Clinical Challenge were alerted to Mrs. P’s status by the paramedics, and they mobilized while she was being transported. The physician was able to succinctly and quickly describe to the patient what was needed and the part she would have to play. The patient’s outcome was excellent, largely due to the facts that an experienced surgeon was available, the OR was immediately available, the OR team was experienced and highly competent, and the patient complied with all postoperative instructions. The surgeon who treated Mrs. P is confident that her functional outcome will be everything originally anticipated (Figures 7 and 8). n Ms. Horn is the former director of the Hand and Orthopedic Trauma Mid-Level Providers Unit at Riverside Methodist Hospital in Columbus, Ohio. Dr. Lubbers is a specialist in hand and microvascular surgery in private practice in Columbus and the inventor of the Teno Fix soft tissue anchor.

“Whoa! Way too much information.”

References 1. Su BW, Solomons M, Barrow A, et al. A device for zone-II flexor tendon repair. J Bone Joint Surg Am. 2006;88A:37-49. 2. Goldner RD, Urbaniak JR. Replantation. In: Wolfe SW, Hotchkiss RN, Pederson WC, Kozin SH. Green’s Operative Hand Surgery, 6th ed. Philadelphia, Pa.: Churchill Livingstone; 2011:1585-1602. 3. Arakaki A, Tsai TM. Thumb replantation: survival factors and re-exploration in 122 cases. J Hand Surg Br. 1993;18:152-156. 4. Brown ML, Wood MB. Techniques of bone fixation in replantation surgery. Microsurgery. 1990;11:255-260. 5. Sud V, Freeland AE. Skeletal fixation in digital replantation. Microsurgery. 2002;22:165-171. Clin Orthop Relat Res. 1984;184:41-49. 7. Rao R, Bhosale A, Ramesh M, et al. The four strand cruciate suture design—a new technique for TA repair. J Orthopaedics. 2008;5e14. Available at www.jortho.org/2008/5/3/e14. 8. Lee BL, Chung, HY, Kim WK, et al. The effects of the number and ratio of repaired arteries and veins on the survival rate in digital replantation. Ann Plast Surg. 2000;44:288-294. 9. Chuang DC, Lai JB, Cheng SL, et al. Traction avulsion amputation of the major upper limb: a proposed new classification, guidelines for acute management, and strategies for secondary reconstruction. Plas Reconstr Surg. 2001;108:1624-1638. 10. Reagan DS, Grundberg AB, George MJ. Clinical evaluation and temperature monitoring in predicting viability in replantations. J Reconstr Microsurg. 1994;10:1-6. All electronic documents accessed June 15, 2013.

“If this turns out to be the right form, let me know.”

6. Tajima T. History, current status, and aspects of hand surgery in Japan.

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CME CE

Dermatology Clinic n Learning objectives: To identify and diagnose dermatologic conditions and review up-to-date treatment. n complete the posttest: Page 81

n additional CME/CE: Pages 36, 77

Turn to page 35 for additional information on this month’s CME/CE courses.

CASE #1

Hyperkeratotic papules with nail changes Audrey Chan, MD, and Grace Sun, MD

A black woman, aged 52 years, presented for follow-up of an eruption on the central chest, back, and scalp. Other than a history of depression, she was healthy. Family history was negative for first-degree relatives with similar skin findings. Current medications included isotretinoin, fluocinolone acetonide oil, and fluoxetine. Physical exam was notable for greasy hyperpigmented and hyperkeratotic papules in a seborrheic distribution and for V-shaped notching of the fingernails with red and white longitudinal lines. Biopsy revealed acantholytic dyskeratosis, corps ronds, and corps grains. What is your diagnosis? Turn to page 72

CASE #2

Multiple cutaneous and GI vascular lesions Kaitlyn Stortz and Erin Reese, M.D.

A 25-year-old woman complained of painful and enlarging lesions on her feet that had been present for most of her life. The woman also had been born with a large vascular malformation on the left elbow that was treated with excision. At age 2 years, she had developed profound anemia, and workup showed multiple vascular lesions of the GI tract. She required iron supplementation and transfusions but ultimately underwent GI resection. Skin examination showed noncompressible, blue-black, vascular, and slightly verrucal papules on the feet, buttocks, and extremities. Family history was unremarkable. What is your diagnosis? Turn to page 73 www.ClinicalAdvisor.com • the clinical advisor • july 2013 71

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CME CE

CASE #1

Dermatology Clinic

Darier disease

Darier disease, also known as keratosis follicularis, is an autosomal dominant disorder that typically affects the skin, nails, and mucous membranes. Men and women are affected equally. While Darier disease is inherited in an autosomal dominant fashion, it is common for patients to deny a family history of the condition, likely due to variable expressivity of the gene mutation. Nearly 70% of patients with Darier disease present between age 6 years and age 20 years; however, the peak age of onset is during puberty.1 This genodermatosis is caused by a gene mutation in ATP2A2, which encodes for the protein product SERCA2, an endoplasmic reticulum calcium ATPase. Mutations of this gene result in the inadequate filling of endoplasmic reticulum calcium stores, causing a cascade of pathologic responses resulting in acantholysis and apoptosis. Recently, a novel missense mutation in the ATP2A2 gene that presents with late-onset Darier disease (the patient presented with symptoms that started at age 75 years) has been reported.2

Nearly all individuals with Darier disease also present with papules on the palms and soles with keratin-filled depressions. Darier disease has a chronic course characterized by hyperkeratotic papules located in a seborrheic distribution, primarily on the chest, back, scalp, face, and lateral neck. Individual papules can coalesce into verrucous plaques. Rarely, papules may be intermixed with hypomelanotic macules or vesicles and bullae. These lesions are often malodorous, and pruritus is a common complaint. Other cutaneous findings include flat, skin-colored or brownish papules on the dorsal hands and feet, a symptom seen in approximately 50% of patients. Nearly all patients present with papules on the palms and soles with keratin-filled depressions. Perhaps the most pathognomonic finding is longitudinal red and/or white lines with V-shaped notching at the distal nail plate. An infrequent manifestation of Darier disease is the presence of whitish papules in the oral mucosa, most commonly the palate. Rarely, Darier

disease has been associated with extracutaneous involvement, namely the esophagus and eyes.3 UV irradiation, sweating, heat, and occlusion may exacerbate skin lesions associated with Darier disease, and lithium carbonate has been reported to worsen skin manifestations. Complications from Darier disease include secondary infections by yeast, dermatophytes, and bacteria. Painful swelling may be seen with salivary-gland obstruction if Darier disease involves the salivary ducts. An association between Darier disease and such neuropsychiatric disorders as epilepsy, mental retardation, and schizoaffective disorders is being studied. Other rare complications include corneal ulcerations and staphylococcal endophthalmitis. There are a few case reports of cutaneous squamous cell carcinoma arising in patients with Darier disease. There are currently three known subtypes of Darier disease. The acral hemorrhagic type presents with blue-black irregularly shaped macules on the palms, soles, and dorsal hands. Segmental type 1 presents with unilateral cutaneous lesions along Blaschkoâ&#x20AC;&#x2122;s lines and results from genetic mosaicism caused by postzygotic somatic mutations. Segmental type 2 is characterized by generalized Darier disease with a linear streak of increased severity. This type occurs in patients with a heterozygous germline mutation in addition to a somatic loss of heterozygosity of the wild-type allele in a segmental area. A biopsy will demonstrate acantholysis with apoptotic keratinocytes, referred to as corps ronds and corps grains. Acantholysis is defined by keratinocytes that have lost intercellular adhesion. Corps ronds are enlarged apoptotic keratinocytes in the upper layer of the epidermis. Corps grains are small apoptotic keratinocytes in the stratum corneum. Although genetic testing is available, the diagnosis of Darier disease is often made on clinical grounds and confirmed by skin biopsy. The differential diagnosis of Darier disease includes severe seborrheic dermatitis, Grover disease, and acrokeratosis verruciformis of Hopf. Seborrheic dermatitis can be distinguished from Darier disease by the absence of nail changes, keratotic papules on the palms, and mucosal changes.4 A skin biopsy would definitively distinguish between these two entities. Grover disease most commonly affects middle-aged men. Although Grover disease tends to affect the chest and back as does Darier disease, this condition spares the scalp, palms, and soles. Another distinguishing feature of Grover disease is that the red-brown papules are discrete and do not coalesce into plaques as in Darier disease. It is difficult to distinguish Grover disease from Darier disease by skin biopsy, as acantholysis and apoptotic keratinocytes are seen in both. Finally, acrokeratosis verruciformis of Hopf presents with flat-wartlike papules on the dorsal extremities, as seen in Darier disease. Some

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patients initially diagnosed with acrokeratosis verruciformis of Hopf later developed characteristic skin lesions and were subsequently diagnosed with Darier disease. Persons with Darier disease are advised to wear lightweight clothes to minimize friction and sweating. Topical therapies may be initiated for mild disease. Topical corticosteroids may be effective in many patients. Corticosteroid potency is typically selected based on anatomic location. For example, a low-potency steroid (e.g., hydrocortisone 2.5% ointment or triamcinolone 0.1% cream) may be used sparingly on the face or intertriginous areas. A higher-potency steroid (e.g., triamcinolone 0.1% ointment or clobetasol 0.05% ointment) will typically be required on the trunk or extremities. To avoid such side effects as tachyphylaxis, cutaneous atrophy, or steroid acne, the patient should be placed on an intermittent schedule or alternating schedule with a steroid-sparing agent (e.g., tacrolimus 0.1% ointment [Protopic] or pimecrolimus 1% cream [Elidel]). Antimicrobial cleansers may also be used, as patients are susceptible to secondary bacterial infections. Intralesional triamcinolone may be used alone or as adjunctive treatment for localized and/or refractory lesions. Patients with generalized disease often require such systemic agents as retinoids. However, the efficacy of such retinoids as acitretin (Soriatane) or isotretinoin is not well established. Surgical therapies for refractory disease can be successful and include wide excision and grafting and superficial ablative techniques (CO2 laser, erbium:YAG laser). In this case, acitretin 25 mg daily with topical corticosteroids was initiated. The patient showed no improvement following months of therapy, so acitretin was discontinued and isotretinoin initiated. Some improvement has been noted. Dr. Chan is a second-year resident and Dr. Sun is a third-year resident, both in the Department of Dermatology at Baylor College of Medicine in Houston. References 1. Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology. 2nd ed. St. Louis, Mo.: Elsevier-Mosby; 2008:791-796. 2. Ueo D, Hamada T, Hashimoto T, et al. Late-onset Darier’s disease due to a novel missense mutation in the ATP2A2 gene: a different missense mutation affecting the same codon has been previously reported in acrokeratosis verruciformis. J Dermatol. 2013;40:280-281. 3. Thiagarajan MK, Narasimhan M, Sankarasubramanian A. Darier disease with oral and esophageal involvement: a case report. Indian J Dent Res. 2011;22:843-846. 4. Schwartz JL, Clinton TS. Darier’s disease misdiagnosed as severe seborrheic dermatitis. Mil Med. 2011;176:1457-1459.

CASE #2

Blue rubber bleb nevus syndrome

This patient had been diagnosed in her childhood with blue rubber bleb nevus syndrome (BRBNS), a rare congenital condition in which patients develop both cutaneous and visceral venous malformations, with the GI tract being the most common extracutaneous site of involvement.1 BRBNS was first described by Gascoyen in 1860 in a patient with vascular hamartomas of the skin and GI tract. The clinical findings were further delineated in 1958 by Bean, who used the term blue rubber bleb nevus syndrome to describe the appearance and texture of the cutaneous vascular lesions, which he likened to rubber nipples. The condition is also called Bean syndrome.2 As illustrated by the patient in this case, most reported cases of BRBNS are of sporadic inheritance, but reports of autosomal dominant transmission exist.3 The gene defect has yet to be identified,3 but some studies have localized a possible mutation to chromosome 9p.2 There is no gender or race predilection.4 Given the rarity of the condition, the initial diagnosis may be delayed or incorrect. Patients usually present with vascular skin lesions within the first few years of life (often at birth), but the diagnosis of BRBNS is not generally rendered until childhood, when the complications of GI hemorrhage become apparent.1 The pathogenesis of BRBNS is poorly understood, but some have proposed that disordered angiogenesis or enlargement of dormant vessels may be causative.4 Cutaneous examination in patients with BRBNS can reveal three types of vascular lesions, which are generally present at birth and become larger (1 mm to 10 cm) and more numerous (up to hundreds) over time.2 Type I lesions are sizable and disfiguring venous malformations that can progressively enlarge and compress surrounding tissues. Surgical intervention is often required to preserve vital structures.2,3 The patient in this case had a type I lesion of the left elbow. Type II lesions are the classic blebs as described by Bean. These lesions are blue in color because of the underlying blood-filled sac, and they protrude from the skin like rubber nipples. On palpation, type II lesions are rubbery and compressible and may be associated with pain and hyperhidrosis. Type III lesions (as seen on the feet

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CME CE

Dermatology Clinic

of the patient in this case) are nonblanchable, blue-black papules.2 Biopsy reveals dilated and blood-filled capillary spaces lined by endothelial cells residing in the dermis or the subcutis.2 These findings most closely resemble venous malformations. Based on histology, cutaneous lesions in BRBNS have been incorrectly labeled as hemangiomas, but the microscopic features of hemangiomas often show increased mast cells in the dermis with vascular channels demonstrating a prominent basement membrane, findings not seen in the classic venous malformations of BRBNS.2 The dermatoscopic features of these vascular lesions have also been described.5 These lesions can occur anywhere on the skin surface, but they are most commonly located on the upper extremities, trunk, and perineum.3 There have been no reports of malignant transformation of these lesions, but they tend not to involute.2,3 Unlike the GI lesions described below, it is unusual for patients to experience spontaneous bleeding of the skin lesions.1 Although cutaneous lesions are clinically apparent early in life and rarely require medical intervention (with the exception of the type I lesions), GI vascular malformations are not usually apparent until later in childhood, when hemorrhagic complications ensue.1 The lesions of the GI tract are more friable than those of the skin, resulting most often in chronic occult bleeding that presents with melena and anemia.3 Rarely, more brisk hemorrhage can occur. Lesions are most often found in the small bowel but can be present anywhere along the GI tract from the mouth to the anus.4 In addition to GI involvement, extracutaneous lesions have been reported in the central nervous system, genitourinary tract, spleen, liver, eye, adrenal glands, and thyroid.1,2 Skeletal problems can occur as a result of pressure from an adjacent vascular malformation, either in the joint space or along the bone.2 Patients in whom the diagnosis of BRBNS is suspected based on typical cutaneous findings should undergo a complete history and physical examination, complete blood count, and stool guaiac test. Positive guaiac test and anemia necessitate a full investigation of the GI tract to identify bleeding sites.2 Endoscopy, CT scan, MRI, angiography, or barium studies can be used.1,2 In the absence of significant GI bleeding, conservative management with iron supplementation and transfusions may be sufficient. Use of interferon and corticosteroids has been reported, but these measures have not been as efficacious in treating bleeding complications from BRBNS as they have been in treating

infantile hemangiomas.2,4 Surgical management is reserved for cases in which the lesions are localized to a limited segment of the bowel that is amenable to resection.4 Otherwise, endoscopic management by means of sclerotherapy, band ligation, laser coagulation, or polypectomy is preferred due to the high rate of recurrence of the vascular lesions.4 Cutaneous lesions are only treated if they are symptomatic or cosmetically troubling; laser therapy, curettage, excision, and sclerotherapy have been reported as helpful.2 Differential diagnosis includes other genodermatoses with vascular lesions of both the skin and the viscera. OslerWeber-Rendu (hereditary hemorrhagic telangiectasia) syndrome presents with punctate vascular lesions of the skin, lungs, and GI tract. Maffucci syndrome is distinguished by prominent bony abnormalities and malignant transformation of the skeletal lesions. Klippel-TrenaunayWeber is characterized by unilateral soft tissue and bony hypertrophy with overlying venous malformation and rare hematochezia from gut or rectal involvement.2 Prognosis for individuals diagnosed with BRBNS is generally good, and only patients with extensive internal involvement may have shortening of their lifespan.3 Patient monitoring depends on the individual presentation, according to organ-system involvement and severity of manifestations.4 The patient in this case had several symptomatic skin lesions that were successfully excised. She has no current complaints of GI bleeding but is seen regularly by hematology for monitoring of iron-deficiency anemia, which is well-controlled with oral supplementation. n Ms. Stortz is a third-year medical student at Virginia Commonwealth University in Richmond, where Dr. Reese is an assistant professor of dermatology. References 1. Deng ZH, Xu CD, Chen SN. Diagnosis and treatment of blue rubber bleb nevus syndrome in children. World J Pediatr. 2008;4:70-73. 2. Nahm WK, Moise S, Eichenfield LF, et al. Venous malformations in blue rubber bleb nevus syndrome: variable onset of presentation. J Am Acad Dermatol. 2004;50(5 Suppl):S101-S106. 3. Thrash B, Patel M, Shah KR, et al. Cutaneous manifestations of gastro intestinal disease: part II. J Am Acad Dermatol. 2013;68: 211.e1-211.e33. 4. Ertem D, Acar Y, Kotiloglu E, et al. Blue rubber bleb nevus syndrome. Pediatrics. 2001;107:418-420. 5. Mejia-Rodriguez S, Valencia-Herrera A, Escobar-Sanchez A, MenaCedillos C. Dermoscopic features in bean (blue rubber bleb nevus) syndrome. Pediatr Dermatol. 2008;25:270-272.

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alternative meds update

What you should know about the herbs and supplements patients use

By Sherril Sego, FNP-C, DNP. Ms. Sego is a staff clinician at the VA Hospital in Kansas City, Mo., where she practices adult medicine and women’s health. She also teaches at the nursing schools of the University of Missouri and the University of Kansas.

Raspberry ketones

According to the Centers for Disease Control, more than one-third of all adults in the United States are obese. This statistic translates into more than $150 billion per year spent in medical costs associated with obesity.1 Researchers continue to look for safe and effective weight-loss products, one of the latest of which is raspberry ketone. On a recent episode of his television show, Dr. Oz referred to raspberry ketone as “the number one miracle in a bottle,” while pointing out the ways that this product contributes to weight loss.2

Background Raspberry ketone is the chemical compound found in red raspberries (Rubus idaeus) that produces the fruity aroma.3 This chemical has long been prized for flavoring in foods and beverages but has only recently been looked at for its potential health benefits. Unfortunately, the yield of raspberry ketone from the actual berry is low, making the product scarce and expensive.3 Consequently, researchers have rigorously worked to develop synthetic versions of the product.

Science Long before the Dr. Oz show, researchers were monitoring the literature for the safety and efficacy of raspberry ketone. Its very modest strength of evidence rating of “C” indicates that there was insufficient evidence to either support or discourage human use for medical reasons.The exact metabolic action of raspberry ketone is theorized as being twofold. One action is

the stimulation of the hormone adiponectin.Adiponectin is a potent enhancer of fatty acid oxidation glucose regulation, as well as an inhibitor of lipid accumulation.The second mechanism of action is thought to be the stimulation of naturally occurring norephinephrine-mediated lipolysis.4 Seeking to verify these mechanisms, researchers studied the effects of standardized raspberry ketone on cultured mammalian adipocytes. A treatment strength of 10 micrograms was used and the effect on lipolysis, fatty acid oxidation and adiponectin activity was measured at 24 and 48 hours.The concentration of extracellular glycerol was the marker for lipolysis, and at 24 hours showed a dramatic 300% increase over the untreated control mixture. Adiponectin activity was measured by Western blot analysis and, at 48 hours, showed an increase of nearly 100%.5 Another laboratory study explored the effect of raspberry ketone on adipose tissue mass in rats and mice.4 The group of rodents tested was pre-fed with a high fat diet for six to 10 weeks. The same groups were then fed the same high-fat diets with standardized raspberry ketone mixture added.At the

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alternative meds update end of treatment, each rodent was anesthetized and the liver removed and weighed. Gross body weight owas also recorded, and both weights were compared with previous identically fed rodent groups. Compared with the control group that had been fed a normal diet and to the test group of high-fat diet with no intervention, gross body weights increased by more than 20%.Rodents fed the high-fat diet with raspberry ketone added nearly equaled the results of the normal-diet group, with an increase of only 7%. Liver weights followed the same trend, with the treatment group equaling the normal-diet group.4 A second investigation using rat models studied raspberry ketone for its potential effect in preventing and treating non-alcoholic steatohepatitis. Control and treatment groups of rats fed either standard or high-fat diets were examined for the presence or degree of fatty infiltrate in liver cells. All treatment groups were significantly improved. It was believed that these outcomes were attributable to two specific actions of raspberry ketone in protecting hepatocytes and promoting the active inhibition of fatty infiltration.6 The only randomized, placebo-controlled, double-blind human study combined raspberry ketone with five other supplements known to enhance weight loss. A total of 45 obese adults completed an eight-week trial of exercise and controlled diet, and, in the test group, supplementation with the raspberry ketone combination.All measurements of body weight in the test group were significantly lower at the end of the study than those of the control group.7 It is unknown how much of this effect was attributable to the raspberry ketone alone.

cautious with initial use. In vitro raspberry ketones inhibit the action of warfarin (Coumadin, Jantoven), so patients on this anticoagulant should discuss its use with a provider prior to use.

How supplied, dose, and cost Most formulations of raspberry ketone are in capsule form.The recommended dose varies widely, but most sources suggest 600 mg with a full glass of water before breakfast and supper. Monthly costs for this dose range are from $30 to $50. Raspbery ketones are the latest in an arsenal of weight-loss products.

In a second study using rat models, raspberry ketone was studied specifically for its potential effect in both preventing and treating non-alcoholic steatohepatitis.

Safety, drug interactions

Summary The search for a “magic” cure for obesity continues.While the safety data for raspberry ketones is encouraging and the laboratory research promising, the results of the single human trial are probably the most realistic. Supplements may very well enhance weight loss, but for true success, they should be combined with a healthy and calorie-conscious diet plus daily exercise. References 1. Centers for Disease Control. Adult obesity.. Available at www.cdc.gov/vitalsigns/AdultObesity. 2.The Dr. Oz Show. Raspberry ketone. Available at www. doctoroz.com/videos/miracle-fat-burner-bottle. 3. Beekwilder J, van der Meer IM, Sibbesen O, et al. Microbial production of natural raspberry ketone. Biotechnol J. 2007;2: 1270-1279. 4. Park KS. Park KS. Raspberry ketone increases both lipolysis and fatty acid oxidation in 3T3-L1 adipocytes. Planta Med. 2010;76:1654-1658. 5. Wang L, Meng X, Zhang F. Raspberry ketone protects rats fed high-fat diets against nonalcoholic steatohepatitis. J Med Food. 2012;15:495-503. 6. Morimoto C, Satoh Y, Hara M, et al. Anti-obese action of raspberry ketone. Life Sci. 2005;77:194-204. 7. Lopez HL, Ziegenfuss TN, Hofheins JE, et al. Eight weeks of supplementation with a multi-ingredient weight loss product enhances body composition, reduces hip and waist girth, and increases energy levels in overweight men and women. J Int Soc Sports Nutr. 2013;10:22-27. Available at www.jissn.com/ content/10/1/22. All electronic documents accessed on June 15, 2013.

As with any plant product, allergic reactions are always possible. Because of the known smoothmuscle contractility action of red raspberry, pregnant women should not use this product. Safety for use in children and lactating women has not been proven. Raspberry ketone has a chemically similar structure to synephrine, a known stimulant. Individuals with heart disease or hypertension should be 76 the clinical advisor • july 2013 • www.ClinicalAdvisor.com

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Dermatologic Look-Alikes

CME CE

n Learning objective: To distinguish and properly treat dermatologic conditions with similar presentations. n complete the posttest: Page 81

n additional CME/CE: Pages 36, 71

Turn to page 35 for additional information on this month’s CME/CE courses.

Vascular papules Kerri Robbins, MD

CASE #1

CASE #2

A white infant, aged 2 months, was seen in the dermatology clinic for two seemingly asymptomatic scalp lesions. When the infant’s mother first noticed the lesions at approximately age 2 weeks, she thought they were scratch marks. However, over the past six weeks, the lesions had thickened and were continuing to enlarge. The infant was born one month premature but was otherwise healthy. On physical examination, two erythematous vascular papules were noted on the scalp. The remainder of the exam was within normal limits.

A white man, aged 28 years, presented with a tender lesion that had been present for one month on the upper area of his right neck. The man recalled having a mosquito bite in that area that had never healed and that grew rapidly to its present state. More recently, he felt as though the growth had stabilized. He had stopped shaving that area because minor trauma resulted in significant bleeding. Medical history and review of systems was otherwise negative. On physical examination, a 9-mm, erythematous, and sessile papule was noted on the right upper neck.

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CME CE

CASE #1

Dermatologic Look-Alikes

Infantile hemangioma

Infantile hemangioma, a benign endothelial-cell neoplasm, is the most common soft-tissue tumor occurring in the neonatal period. Despite early efforts to distinguish between the various vascular tumors, the term hemangioma was frequently used as a generic term to encompass all vascular anomalies. In 1982, Mulliken and Glowacki were the first to recommend that vascular birthmarks be classified according to their biological and clinical behavior.1 Today, vascular birthmarks are divided into two broad categories: vascular tumors and vascular malformations. Vascular tumors, which include infantile hemangiomas, usually appear in the neonatal period, and their clinical course is marked by an early proliferative phase lasting several months followed by slow spontaneous resolution over several years. Vascular malformations are thought to represent errors in vascular morphogenesis. These malformations also usually appear during the neonatal period but, unlike infantile hemangiomas, do not proliferate rapidly or resolve spontaneously. Infantile hemangiomas are thought to arise sporadically and appear more commonly in females, with a 2.5:1 female-to-male ratio.2 Other risk factors include white race, low birth weight, premature infants, multiple gestations, advanced maternal age, and chorionic villus sampling. Infantile hemangiomas are thought to represent localized areas of abnormal angiogenesis; however, the exact pathogenesis is largely unknown. Some hypothesize that a somatic mutation occurs in a normal microvasculature endothelial cell or that hemangiomas arise from immature endothelial progenitor cells. Another theory asserts that such extrinsic factors as fibroblasts, mesenchymal cells, adipocytes, mast cells, and monocytes cause endothelial cells to undergo aberrant proliferation. Still others believe that hemangioma cells are of placental origin, because infantile hemangiomas share an immunohistochemical phenotype with placental endothelium. One such marker is erythrocyte-type glucose transporter protein-1 (GLUT1), which is expressed by infantile hemangiomas during all stages of their development but is not expressed by other vascular tumors or malformations. Most likely, several mechanisms under the control of multiple genes, in addition

to local effects, play a role in the initiation, proliferation, and involution of hemangiomas. Hemangiomas can occur anywhere on the skin, including mucosal surfaces. They are described as being superficial (50% to 60% of cases), deep (15% of cases), or mixed (25% to 35% of cases).3 In superficial hemangiomas, the abnormality lies within the superficial dermis. Superficial hemangiomas are bright-red in color during the proliferative phase and have been referred to as as strawberry hemangiomas. Deep hemangiomas lie within the deep dermis and/or subcutis. Clinically, deep hemangiomas are blue-purple masses with minimal or no overlying skin changes. Mixed hemangiomas have both superficial and deep components and can further be classified as being either focal or segmental. Segmental lesions are often described as “plaquelike” or “diffuse” and appear to arise from a broad area or developmental unit. The natural history of a hemangioma follows three phases: proliferation, involution, and involuted. Most hemangiomas begin as telangiectasias surrounded by a border of pallor, faint erythematous macules, or blue bruiselike patches. Superficial hemangiomas classically proliferate for several months and clinically become warmer, firmer, and raised. Deep lesions may proliferate for up to one year. Involution usually begins around the first year of life and continues for several years. The first signs of involution within a superficial hemangioma are often a color change from deep red to gray-purple and a flattening of the surface. Although most hemangiomas are small and require no intervention, some may become problematic. Ulceration is the most common complication, occurring in approximately 10% of all infantile hemangiomas.4 The lip, neck, and anogenital regions that are affected with large, mixed, and segmental hemangiomas are most at risk for ulceration. Large hemangiomas may distort normal tissues, interfere with the function of certain structures (e.g., periocular, nasal tip, lip, ear, anogenital), or lead to significant cosmetic impairment. Segmental lesions have a higher incidence of such associated systemic anomalies as PHACES syndrome (Posterior fossa malformations, Hemangiomas, Arterial lesions, Cardiac abnormalities, Eye abnormalities, Sternal abnormalities), laryngeal involvement, spinal dysraphism, and GI and genitourinary anomalies. Multiple hemangiomas may signify a risk for visceral hemangiomatosis. Histology depends on the developmental stage of the hemangioma. Proliferating tumors are characterized by collections of endothelial cells, pericytes, and vascular lumens. Once involution is complete, the lesion is predominately composed of fibrofatty tissue and a few vessels where the

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tumor lobules used to reside. As discussed earlier, GLUT-1 is expressed during all stages of infantile hemangioma development but is absent in other vascular tumors and malformations. Early superficial hemangiomas may be misdiagnosed as capillary malformations, telangiectasias, or trauma. Deep hemangiomas may mimic venous, lymphatic, or combined venous-lymphatic malformations. Other soft-tissue tumors should also be considered in the differential diagnosis. Pyogenic granulomas may mimic hemangiomas, but these lesions usually arise after the first few months of life. Small hemangiomas are often managed without active intervention. Timolol maleate (Blocadren) 0.5% gel-forming solution, a topical nonselective beta-blocker, has recently been reported as an effective treatment for superficial hemangiomas.5 Complicated hemangiomas usually require systemic treatment with propranolol (Inderal, InnoPran, Pronol), corticosteroids, interferon α (Intron A, Roferon-A), or vinca alkaloids. Studies have shown that 30% of untreated hemangiomas will involute by age 3 years, 50% by age 5 years, 70% by age 7 years, and 90% by age 9 years.2 Following involution, some hemangiomas may appear normal, while others may leave behind atrophic, fibrofatty, or telangiectatic residua. Once involuted, laser therapy or surgical excision may be undertaken for cosmetic improvement if desired. Because the lesions in this case were asymptomatic and posed no cosmetic concern (any residua would be hidden by the infant’s hair) the parents decided not to treat.

CASE #2

Pyogenic granuloma

In 1897, Poncet and Dor believed that Botryomyces infection was the cause of pyogenic granuloma. Although they were the first to describe the disease, it was not until 1904 that Hartzell named it granuloma pyogenicum.6 Hartzell and others were under the impression that the lesions were a granulation tissue-type response to an infectious agent. The exact pathogenesis is still unknown; however, there is no evidence to suggest a pyogenic agent as the cause, nor is the

histologic appearance granulomatous. Immunohistochemical studies have demonstrated a clear endothelial-cell predominance with positive staining of endothelial cells for such vascular markers as CD31 and pericytes for smooth-muscle actin. Pyogenic granulomas occur equally in males and females. The condition afflicts people of all ages but is more commonly seen in children and young adults. Racial predilection and familial predisposition are not contributing factors. The exact etiology of pyogenic granuloma is unknown. Some believe that pyogenic granulomas are a benign neoplasm, while others believe that they may represent reactive neovascularization. In about one-third of cases, a history of pre-existing injury or irritation can be elicited, which supports the theory of reactive neovascularization. It has been suggested that abnormal blood flow may be the culprit because pyogenic granulomas occasionally erupt within pre-existing port-wine stains. Certain medications, including systemic retinoids, indinavir (Crixivan), and anti-epidermal growth factor receptor antibodies, may predispose patients to the development of pyogenic granulomas or pyogenic granuloma-like lesions. Patients will report a history of a bright-red sessile or pedunculated papule that has been growing rapidly over the course of several weeks to months. Once its final size is reached (rarely >2 cm), the growth of the lesion will stabilize, and the liesion will persist indefinitely until destroyed. One study found the most common site of involvement to be the gingiva, followed by the fingers, lips, face, and tongue.7 The lesions are very friable and will frequently ulcerate and bleed, even with minor trauma. Interestingly, pregnant women are more at risk of developing gingival lesions (epulis of pregnancy). Histologically, a well-circumscribed and exophytic mass of angiomatous tissue is appreciated protruding above the normal skin. A collarette of acanthotic epidermis usually constricts the lesion at its base, and ulcerations are commonly seen on the surface. Dilated and congested capillaries are often grouped into discrete lobules by dense fibrous bands; hence, the alias lobular capillary hemangioma. The capillaries are lined by flattened and slightly plump endothelial cells that are surrounded by an edematous fibromyxoid interstitial stroma. Occasional mast cells, lymphocytes, and plasma cells may also be seen. Mitotic activity and cytologic atypia are variable. Pyogenic granulomas are often diagnosed clinically. However, amelanotic melanoma should be considered in the differential diagnosis. In the setting of an immunosuppressed patient, Kaposi sarcoma or bacillary angiomatosis should also be considered. If suspected clinically, Kaposi sarcoma can be confirmed histologically by the expression of the latency-associated nuclear antigen or polymerase chain reaction detection

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of human herpesvirus-8.8 Bartonella henselae and Bartonella quintana, the etiologic agents of bacillary angiomatosis, are best observed with either a Warthin-Starry silver stain or a Grocott methenamine silver stain. Although infantile hemangiomas are also included in the differential diagnosis, these tend to arise within the first couple weeks of life, while pyogenic granulomas most commonly develop in childhood and young adulthood. Histologically, thick intervening bands of dense fibrous tissue are appreciated in pyogenic granulomas but are not seen in infantile hemangiomas. Immunohistochemical

References 1. Mulliken JB, Glowacki J. Hemangiomas and vascular malformations in infants and children: a classification based on endothelial characteristics. Plast Reconstr Surg. 1982;69:412-422. 2. Moroz B. Long-term follow-up of hemangiomas in children. In: Williams HB (ed.). Symposium on Vascular Malformations and Melanocytic Lesions. St. Louis, Mo.: C.V. Mosby; 1983:162-171. 3. Esterly NB. Cutaneous hemangiomas, vascular stains and malformations, and associated syndromes. Curr Probl Pediatr. 1996 Jan;26(1):3-39. 4. Chamlin SL, Haggstrom AN, Drolet BA, et al. Multicenter prospective study of ulcerated hemangiomas. J Pediatr. 2007;151:684-689.

Full-thickness excision with suture repair may result in less postoperative bleeding and a lower recurrence rate.

5. Chakkittakandiyil A, Phillips R, Frieden IJ, et al. Timolol maleate 0.5% or 0.1% gel-forming solution for infantile hemangiomas: a retrospective, multicenter, cohort study. Pediatr Dermatol. 2012;29:28-31. 6. Hartzell MB. Granuloma pyogenicum (botryomycosis of French authors). J Cutan Dis. 1904;22:520-523. 7. Kerr DA. Granuloma pyogenicum. Oral Surg Oral Med Oral Pathol. 1951;4:158. 8. Hammock L, Reisenauer A, Wang W, et al. Latency-associated nuclear

analysis is also helpful when differentiating between the two disorders because placenta-associated vascular proteins such as GLUT-1, Lewis Y antigen, FcγRII, and merosin are present in infantile hemangiomas and absent from pyogenic granulomas. If left untreated, most pyogenic granulomas will remain indefinitely. However, those that occur during pregnancy may resolve following parturition. Eliminate any provoking factors that exist (e.g., a medication). For most lesions, shave excision followed by electrosurgery is curative. Electrodesiccation and curettage, alone or in combination, is another treatment option and may be performed following the shave excision. Full-thickness excision of the lesion with suture repair may result in less postoperative bleeding and a lower recurrence rate (2.94%).9 Other treatment options include topical imiquimod (Aldara, Zyclara) cream, alitretinoin (Panretin) gel, injectable sclerosing agents, topical phenol, and silver nitrate cauterization. Good results have also been achieved with such laser systems as carbon dioxide, argon, pulsed-dye, and neodymium-doped yttrium aluminum garnet (Nd:YAG) lasers.10,11 Occasionally, multiple satellite lesions develop within the general vicinity of the treated primary lesion. These satellite lesions have been successfully treated with intralesional and systemic corticosteroids.12,13 Regardless of the treatment modality, patients should be advised that pyogenic granulomas can recur. The patient in this case was offered a shave excision followed by curettage and electrodesiccation to the base. The lesion has not recurred. n

antigen expression and human herpesvirus-8 polymerase chain reaction

Dr. Robbins is a resident in the Department of Dermatology at Baylor College of Medicine in Houston.

“It turns out crows find a bunch of dead crows more frightening than a man made out of hay.”

in the evaluation of Kaposi sarcoma and other vascular tumors in HIVpositive patients. Mod Pathol. 2005;18:463-468. 9. Lee J, Sinno H, Tahiri Y, Gilardino MS. Treatment options for cutaneous pyogenic granulomas: a review. J Plast Reconstr Aesthet Surg. 2011;64:1216-1220. 10. Tay YK, Weston WL, Morelli JG. Treatment of pyogenic granuloma in children with the flashlamp-pumped pulsed dye laser. Pediatrics. 1997;99:368-370. 11. Hammes S, Kaiser K, Pohl L, et al. Pyogenic granuloma: treatment with the 1,064-nm long-pulsed neodymium-doped yttrium aluminum garnet laser in 20 patients. Dermatol Surg. 2012;38:918-923. 12. Parisi E, Glick PH, Glick M. Recurrent intraoral pyogenic granuloma with satellitosis treated with corticosteroids. Oral Dis. 2006;12:70-72. 13. Tursen U, Demirkan F, Ikizoglu G. Giant recurrent pyogenic granuDermatol. 2004;29:40-41.

loma on the face with satellitosis responsive to systemic steroids. Clin Exp

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posttest Expiration date: July 2014

Nurse Practitioner Associates for Continuing Education (NPACE) is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation. The Nurse Practitioner Associates for Continuing Education designates this educational activity for a maximum of 1.0 contact hours of credit. Participants should only claim credit commensurate with the extent of their participation in the activity. Posttests must be completed and submitted online. NPs may register at no charge at www.mycme.com.You must receive a score of 70% or better on each test taken to obtain credit.

credits: 0.5

Feature

Dermatology Clinic

Dermatologic Look-Alikes

page 36

page 71

page 77

Workplace stress and career burnout among clinicians

Case #1: Darier disease

Case #1: Infantile hemangioma

1. A significant association has been shown between job-related burnout and hospital-acquired infection due to a. Ventilator use b. Urinary-tract catheterization c. Peripheral arterial line d. Central venous catheter

1. What is a rare manifestation of Darier disease? a. Papules intermixed with hypomelanotic macules b. Hyperkeratotic chest papules c. Brownish macules on the hands d. Papules that coalesce into verrucous plaques

1. What is a risk factor for infantile hemangioma? a. Gestational diabetes b. Young maternal age c. Low birth weight d. Black race

2. What condition is included in the description of clinician burnout? a. Dehumanized perception of others b. Feeling emotionally drained from work c. Inability to positively influence the lives of others d. All of the above

2. Red-brown papules that do not coalesce into plaques distinguish Darier disease from a. Seborrheic dermatitis b. Grover disease c. Psoriasis vulgaris d. Systemic lupus erythematosus

3. What is a healthy way to prevent burnout? a. Writing in a journal b. Spending more time alone c. Sleeping longer than usual d. Zoning out during stressful moments 4. The maintenance of professional boundaries prevents burnout by a. Minimizing stress associated with difficult patient interactions b. Ensuring adequate self-care of the health-care provider c. Decreasing disruptive or intimidating behaviors by the health-care provider d. All of the above To take the Posttest please go to CliniAd.com/1aQYE03

CASE #2: Blue rubber bleb nevus syndrome (BRBNS) 3. What is the most common extracutaneous site of involvement with BRBNS? a. Central nervous system b. Adrenal glands c. GI tract d. Thyroid gland 4. The lesions of type 1 BRBNS a. Progressively enlarge and compress surrounding tissues b. Protrude from the skin c. Appear as blue-black papules d. Are associated with hyperhidrosis

2. What is a treatment for superficial hemangiomas? a. Systemic corticosteroids b. Timolol maleate (Blocadren) gel-forming solution c. Laser therapy d. Surgical excision CASE #2: Pyogenic granuloma 3. What medication predisposes patients to the development of pyogenic hemangiomas? a. Indinavir (Crixivan) b. Lamivudine (Epivir) c. Famciclovir (Famvir) d. Zidovudine (Retrovir) 4. What is a treatment for pyogenic hemangioma? a. Full-thickness excision b. Silver nitrate cauterization c. Topical imiquimod (Aldara, Zyclara) d. All of the above

To take the Posttest please go to CliniAd.com/12n3SbG

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CME

posttest Expiration date: July 2014

This program has been reviewed and is approved for a maximum of 1 hour of AAPA Category I CME credit by the Physician Assistant Review Panel. Approval is valid for one year from the issue date of July 2013. Participants may submit the self-assessment at any time during that period. This program was planned in accordance with AAPA’s CME Standards for Enduring Material Programs and for Commercial Support of Enduring Material Programs. Posttests must be completed and submitted online. PAs may register at no charge at www.mycme.com. To obtain 1.0 hour of AAPA Category I CME credit, you must receive a score of 70% or better on each test taken. credits: 0.5

credits: 0.5

Feature

Dermatology Clinic

Dermatologic Look-Alikes

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page 71

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Workplace stress and career burnout among clinicians

Case #1: Darier disease

Case #1: Infantile hemangioma

1. What is a risk factor for infantile hemangioma? a. Gestational diabetes b. Young maternal age c. Low birth weight d. Black race

2. Red-brown papules that do not coalesce into plaques distinguish Darier disease from a. Seborrheic dermatitis b. Grover disease c. Psoriasis vulgaris d. Systemic lupus erythematosus

To take the Posttest please go to CliniAd.com/12n3SbG

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Classifieds CLASSIFIEDS

For For advertising advertising information, information, contact: contact: Russell Johns Associates, LLC Tom at 646-638-6085 1001 Hennessy S Myrtle Ave, #7, Clearwater, FL 33756 or email: Tom.Hennessy@ClinicalAdvisor.com Phone: 877.394.1388 or 727.443.7667 • Fax: 727.445.9380 • E-mail: ca@russelljohns.com

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North Country Emergency Medical Consultant’s PC is recruiting a Physician Assistant or Nurse Practitioner to join our current group of 9 physicians, 5 physician assistants and 2 nurse practitioners. NC-EMC, P.C. contracts with Samaritan Medical Center to staff the ED which has an annual volume of 53,000. The PAs work closely with the MDs and staff the ED in both the Urgent Care and Rapid Clinical Evaluation area. SMC recently opened a new ED 11/10 which has in-ED radiology, CT scan, ED Ultrasound and point of care testing. The compensation package includes $120,000.00 salary, plus benefits for approximately 144 hours/month. A RVU-based productivity bonus is awarded quarterly. Upstate New York is an outdoor enthusiast’s paradise with 4-season recreation in the world famous Thousand Islands, Lake Ontario region and the Adirondack Mountains. Montreal, Toronto, Finger Lakes region and NYC are a short drive away. Syracuse International Airport is within a one hour drive. If this opportunity interests you AND you have a minimum of 3 years Emergency Medicine/Urgent Care experience, please send your CV and cover letter to: Dr. Maja Lundborg-Gray President, North Country Emergency Medical Consultants, P.C. Emergency Department 830 Washington Street Watertown, New York 13601 Fax: 315-785-4314 Email: MLGRAY@shsny.com (preferred route)

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For advertising information, contact: Tom Hennessy at 646-638-6085 or email: Tom.Hennessy@ClinicalAdvisor.com

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Tom Hennessy (646) 638-6085 Tom.Hennessy@ ClinicalAdvisor.com

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COMMENTARY Jordan Hopchik, MSN, FNP-BC, is a gastroenterology nurse practitioner at the Philadelphia VA Medical Center and a Doctor of Nursing student at La Salle University in Philadelphia.

Colonoscopy tips from the front lines As primary-care providers, we are challenged every day to make recommendations to our patients for age- and gender-related preventive screening tests. Some type of colorectal cancer (CRC) screening test should be performed around age 50 for men and women at average risk for the disease. Still considered the gold standard for CRC screening, colonoscopy enables direct visualization of the lining of the colon and rectum while allowing the endoscopist to biopsy or remove polyps or suspicious lesions at the same time.

For an excellent bowel prep, the patient should stop consuming dietary fiber at least three days prior to the colonoscopy.

If a patient decides to have a colonoscopy or if the test is highly recommended because the patient has a first-degree relative with CRC, we can empower him or her with a few written instructions to help ensure that the colonoscopy is safe for the patient and has an optimal procedural outcome. As the first gastroenterology nurse practitioner in Pennsylvania credentialed to perform colonoscopy and having undergone two colonoscopies myself, I have learned what really matters when shopping around for a good gastroenterologist. Some endoscopy centers are more like a ssembly-line factories. Polyps and lesions could be missed because the endoscopist does not spend enough time looking for abnormalities, or because of operator fatigue, or because surveillance is recommended sooner than expected by gastroenterology guidelines. Endoscopists are supposed to meet or exceed colonoscopy performance indicators when doing the procedure. Those indicators include reaching the cecum, describing the bowel-preparation quality, and making appropriate surveillance recommendations (Gastroenterology. 2012;143:844-857; available at download.journals.elsevierhealth.com/pdfs/ journals/0016-5085/PIIS0016508512008128. pdf, accessed June 15, 2013). In addition, precancerous polyps should be detected at least 25% of the time in men and at least 15% of the time in women, as noted by Douglas K. Rex, MD,

in 2007 in Journal Watch Gastroenterology (available at gastroenterology.jwatch.org/cgi/content/ full/2007/112/1; accessed June 15, 2013). Here are a few tips we can share with patients who are contemplating having or already planning to have a screening colonoscopy. • For an excellent bowel preparation, the patient should stop consuming dietary fiber at least three days prior to the colonoscopy. • The patient should drink strictly clear liquids and have no solid food for 24 to 48 hours before the colonoscopy based on his or her defecation frequency, prescribed medications, and exercise patterns. • The patient should follow a split-dose bowelcleanser preparation regimen in which the first dose is taken 8 to 10 hours before the second to improve the patient’s tolerance of the preparation formula and to enhance endoscopic visualization. • When meeting with the gastroenterologist, the patient should ask what the physician’s precancerous (adenomatous) polyp detection rate is and what the physician’s typical scope-withdrawal time is. Scope-withdrawal time should exceed six minutes; otherwise, polyps and lesion could be missed. • The patient should ask the gastroenterologist which group’s guidelines the physician uses when recommending a surveillance interval schedule, such as the American Society for Gastrointestinal Endoscopy. n

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