June 2013 Clinical Advisor by The Clinical Advisor

The Clinical ADVISOR • june 2013

A FORUM FOR NURSE PRACTITIONERS

NEWSLINE

■■Check for scarring on ECG ■■CT scans do double-duty ■■Depression overdiagnosed

advisor forum

■■Diagnosing fatigue ■■Cancer in frequent fliers ■■Swimmer’s ear solution

| j une 2 01 3 | www.ClinicalAdvisor.com

CE: eValuation of

peptic ulcers Stress or bacteria can thin protective stomach mucus and lead to gastric ulcers (shown).

legal advisor

A difference of opinion leads to a costly diagnostic error

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n Dermatology Clinic

dusky abdominal bullae page 87

Volume 16, Number 6

n Dermatologic Look-Alikes

erythematous trunk plaque page 99 Expanded job listings! www.ClinicalAdvisor.com/Jobs

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Download the new app for the iPhone, iPad,and Android— created specifically for nurse practitioners and physician assistants from the publishers of the highest rated journal for these health-care professionals. With the Clinical Advisor app you can: • Take Derm Dx quizzes to learn about difficultto-identify dermatology conditions, and then see how you performed against your peers. • Use medical calculators to do things like assess liver function, convert HbA1C to mean plasma glucose, evaluate BP, determine BMI and more. • Read the latest news about breakthrough treatments, disease outbreaks, drug approvals and recalls, and clinical research.

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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 5, 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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6 the clinical advisor • june 2013 • www.ClinicalAdvisor.com

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LEVEL

contents june 2013

News and comment

Departments

26 Newsline ■■Aspirin raised heart risk in diabetes ■■Check ECG for ventricular scarring ■■Exercise-induced bronchoconstriction guide ■■Depression is diagnosed too often ■■CT screens for osteoporosis ■■Antibiotics prescribed for unproven UTIs ■■Screen all adults for alcohol misuse ■■Other risks of non-melanoma skin cancer

79 Derm Dx Read the clinical descriptions, view the images, and make your diagnosis at ClinicalAdvisor.com. 80 Legal Advisor How should a clinician deal with a difference of opinion with the attending physician on duty? Risks of non-melanoma skin cancer 39

110 Commentary

87 CME/CE Dermatology Clinic n A pregnant woman develops a tender erythematous patch on the abdomen after receiving subcutaneous heparin.

features 42 CME/CE Clinical evaluation of peptic ulcer disease Most often caused by use of nonsteroidal anti-inflammatory drugs or bacterial infection, peptic ulcer disease usually presents as epigastric pain.

83 Clinical Challenge A woman with diabetes complains of worsening malaise and fatigue, and bilateral extremity cramps.

n Extremely painful vesicles develop on

the back, chest, and breast of a woman aged 69 years. A review of peptic ulcer disease 42

52 Assessment of peritonsillar abscess This infection manifests as a collection of pus and is often a complication of tonsillitis that may require referral to a specialist or hospitalization.

91 Alternative Meds Update One of the most abundant minerals found in nature, salt is used to treat respiratory conditions as well as atopic dermatitis and psoriasis. Continues on page 18

61 Raising awareness of primary aldosteronism Persistently elevated aldosterone levels is an underdiagnosed cause of hypertension that can result in significant vascular end-organ disease.

making contact

CA0613_TOC.indd 8

When to trust your instincts 80

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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

5/10/13 6:48 PM

>>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

K02CAN13075

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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, 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

5/10/13 7:25 PM

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

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Stroke costs expected to double by 2030 Higher stroke prevalence in an aging population brings the total projected stroke costs to $240.67 billion by 2030. Protection better with whole-cell pertussis vaccine Teens who received DTaP were six times more likely to get pertussis during the 2010-2011 California outbreak than those given DTwP.

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Itchy blisters with a sore throat A woman, aged 32 years, presents with itchy blisters over her entire body that have been present for four days.

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Robyn Carlisle, MSN, CNM, WHNP “Common sense” homebirth guidelines are a step in the right direction Although there have been advances in the care of pregnant women, birth should still be viewed as a natural event, not a medical event.

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contents june 2013

News and comment

Departments

110 Commentary

87 CME/CE Dermatology Clinic n A pregnant woman develops a tender erythematous patch on the abdomen after receiving subcutaneous heparin.

83 Clinical Challenge A woman with diabetes complains of worsening malaise and fatigue, and bilateral extremity cramps.

n Extremely painful vesicles develop on

the back, chest, and breast of a woman aged 69 years. A review of peptic ulcer disease 42

52 Assessment of peritonsillar abscess This infection manifests as a collection of pus and is often a complication of tonsillitis that may require referral to a specialist or hospitalization.

91 Alternative Meds Update One of the most abundant minerals found in nature, salt is used to treat respiratory conditions as well as atopic dermatitis and psoriasis. Continues on page 18

61 Raising awareness of primary aldosteronism Persistently elevated aldosterone levels is an underdiagnosed cause of hypertension that can result in significant vascular end-organ disease.

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When to trust your instincts 80

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Newsline

Ventricular scarring seen on ECG page 32

j u n e 2 0 13

CT scans can also screen for osteoporosis page 35

Intervening to reduce alcohol misuse page 39

Aspirin raised heart risk in diabetes

Aspirin treatment was associated with modestly increased risks for nonfatal and fatal coronary heart disease (CHD) in persons with type 2 diabetes and no previous cardiovascular disease (CVD) in an observational study (BMJ Open. 2013;3:e002688, available at www .ncbi.nlm.nih.gov/pmc/articles /pmid/23604419/, accessed May 15, 2013). The study focused on men and women with type 2 diabetes who were served in primary-care practices or in hospital outpatient clinics. The participants, aged 30 to 80 years, were free of CVD, including atrial fibrillation and congestive heart failure, at baseline. They were followed for a mean 3.9 years. The cohort was divided into two study groups based on aspirin exposure at baseline: One group consisted of 4,608 patients with aspirin treatment and the other

Significantly increased risk of heart disease was found in aspirin users.

group consisted of 14,038 patients with no aspirin treatment. No evidence was found of beneficial effects from aspirin on cardiovascular outcomes or death in persons with type 2 diabetes and no previous CVD. Rather, aspirin users had a significantly increased risk of nonfatal CHD and fatal CHD compared with the nonaspirin group. When men and women were analyzed separately, the heightened risk of cardiovascular outcomes was seen among the women but not among the men. Aspirin use was associated with a significantly increased risk of ventricular ulcer, particularly in women. However, the risk for cerebral or ventricular bleeding did not differ between the aspirin users and the nonusers. “The results support the trend towards more restrictive use of aspirin in patients with type 2

diabetes and no previous CVD,” wrote Nils Ekström and colleagues. “More research is needed to explore the differences in aspirin’s effects in women and men.” In another BMJ journal, the results of a meta-analysis revealed that in persons with type 2 diabetes, a coronary artery calcium score of 10 or higher predicts allcause mortality or cardiovascular events, or both, and cardiovascular events alone, with high sensitivity but low specificity (BMJ. 2013;346f1654; available at www .bmj.com/content/346/bmj .f1654, accessed May 15, 2013). “Clinically, the finding of a coronary artery calcium score of less than 10 may facilitate risk stratif ication by enabling the identification of people at low risk within this high-risk population,” concluded Caroline K. Kramer and coauthors.

Children aged 0–17 years with an allergic condition Food allergy prevalence was similar in all ages, but skin allergy prevalence decreased with age, and respiratory allergy prevalence increased with age. SOURCE: CDC/NCHS, Health Data Interactive, National Health Interview Survey

0-4 years

5-9 years

10-17 years

20.8%

17.4% 14.2% 13.1%

15 10 5 0

10.9%

10.8%

5.0% 5.1% 5.0%

Food allergy

Skin allergy

Respiratory allergy

26 the clinical advisor • june 2013 • www.ClinicalAdvisor.com

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5/24/13 3:09 PM

Newsline Primary-care clinicians should be aware that the ECG finding of left anterior fascicular block (LAFB) may predict heart failure, sudden cardiac death, or atrial fibrillation. In LAFB, a blockage of the one of the branches that delivers electrical signals to a part of the left ventricle, scarring occurs in that part of the heart. Although LAFB has been considered a benign ECG finding, its longterm consequences have not been comprehensively studied, according to new information conveyed in a recent research letter ( JAMA (2013;309[15]:1587-1588). The study results described in the letter indicate that LAFB may be an immediately accessible marker of left heart fibrosis, which raises the risks for heart

failure, sudden cardiac death, and atrial fibrillation. This conclusion is based on an analysis of data from 1,664 persons older than age 65 years who had been followed for 16 years. None of the participants had any evidence of cardiovascular disease or diabetes. However, compared with the men and women who had normal ECGs, persons whose ECGs exhibited LAFB were at 143% greater risk for heart failure, 89% greater risk for atrial fibrillation, and 57% greater risk for sudden cardiac death, after adjustments were made for potential confounding variables. “This study may suggest that LAFB, even in the absence of known high blood pressure or diabetes, should be thought of as a cardiovascular risk factor,” noted

Check ECG for ventricular scarring

Left heart fibrosis raises the risk for heart failure.

study senior author and electrophysiologist Gregory Marcus, MD, of the University of California– San Francisco (UCSF) School of Medicine, in a UCSF statement. “Those patients with LAFB perhaps should be considered the same as someone with established cardiovascular risk factors.”

All persons with exerciseinduced bronchoconstriction (EIB) should perform warmup exercises before engaging in planned exercise, advises the American Thoracic Society (ATS) in its new clinical practice guideline on the diagnosis and management of this condition. This is just one of evidence-based recommendations promoted by the ATS to help combat EIB, the acute airway narrowing that occurs as a result of exercise. EIB can be triggered by cold air, dry air, ambient ozone, and airborne particulate matter. “These

Triggers include dry air, ambient ozone, and airborne particulates.

and other environmental factors may contribute to the increased prevalence of EIB seen among competitive ice skaters, skiers, swimmers and distance runners,” noted the ATS when announcing the availability of the guideline (Am J Respir Crit Care Med. 2013;187[9]:1016-1027). Although the exact prevalence of EIB among persons with asthma is unknown, it is estimated to be as high as 20% in persons without asthma, and even higher for athletes: up to 70% for Olympic and elite-level athletes. “While EIB is common, there are

effective treatments and preventive measures, both pharmacological and nonpharmacological,” assured Jonathan Parsons, MD, chair of the committee that drafted the statement. However, clinicians should be aware that many of the treatments, including beta-agonists, are banned or restricted in competitive athletics. “The recommendations in these guidelines synthesize the latest clinical evidence that will help guide the management of EIB in patients with or without asthma and in athletes at all levels of competition,” Parsons said.

Exercise-induced bronchoconstriction guide

32 the clinical advisor • june 2013 • www.ClinicalAdvisor.com

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5/24/13 3:09 PM

Newsline Depression CT screens for osteoporosis is diagnosed too often

Abdominal CT images that include the lumbar spine can identify osteoporosis.

identify patients with osteoporosis or normal BMD without additional radiation exposure or cost. Once the diagnosis of osteoporosis is made, the clinician may need to remind patients to pick up their newly prescribed bisphosphonates, agents commonly used in the treatment of osteoporosis and similar bone diseases. Kristi Reynolds, PhD, MPH, and colleagues announced in Osteoporosis International that among 8,454 eligible women aged 55 years and older with a new prescription for oral bisphosphonate medication, nearly one third (2,497, or 29.5%) failed to pick up the filled prescription within 60 days of the order date. Reynolds’ team learned that failing to pick up the initial prescription, or primary nonadherence, was more likely to occur in older women, in women who used the emergency department, and in women whose prescribing providers had been practicing for less than 10 years.

Antibiotics prescribed for unproven UTIs Nearly half of women aged 70 years and older who received a diagnosis of urinary tract infection (UTI) in an emergencydepartment setting did not have confirmatory findings on urine culture, yet were administered or prescribed antibiotics nonetheless. As described in Journal of the American Geriatrics Society, a retrospective chart review by Leonard Mermel, DO, and colleagues revealed that only 87 of 153 women

(57%) who received a diagnosis of UTI in an emergency department in Providence, R.I., had a positive urine culture. Of the remaining 66 with negative cultures, 63 (95%) were given antibiotics or received a prescription for such drugs. The method of urine procurement affected the ability of a urinalysis to predict the culture result: False-positives were more common with the clean-catch method than with catheterization (48% vs. 31%).

Depression overdiagnosis and overtreatment is common in community settings, recent research demonstrates. In a sample of 5,639 persons, only 38.4% of participants with 12-month clinician-identified depression met the major depressive episode (MDE) criteria set forth in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Only 14.3% of adults aged 65 years or older met the criteria. Persons with more education and persons with worse overall health were more likely to meet the criteria. The majority of participants were prescribed psychiatric medications, whether they met the 12-month MDE criteria or not. But those who did not meet the criteria used fewer services and reported less distress and impairment in role functioning. “There is a need for improved targeting of diag nosis and treatments of depression and other ment a l d isorder s in [community] settings,” concluded study author Ramin J. Mojtabai, PhD, in his report for Psychotherapy and Psychosomatics (2013;82[3]:161-169). This high rate of false-positive depression diagnoses was attributed in part to clinicians’ uncertainty about the diagnostic criteria and to the relatively low prevalence of depression in community settings.

A bdom i na l C T s c a n s obtained for clinical indications other than osteoporosis can also be used to assess bone mineral density (BMD), a study indicates. Citing osteoporosis underdiagnosed in their report (Ann Intern Med. 2013;158[8]:588-595), investigators studied 1,867 adults undergoing CT and dual-energy x-ray absorptiometry (DEXA). As noted in a statement from Annals of Internal Medicine, DEXA of the hips and lumbar spine is widely recognized as the reference standard for the diagnosis of osteoporosis). The tests were performed within six months of one another for each patient over the course of 10 years. Nearly half the patients with an osteoporotic vertebral compression fracture identified by the CT scan had been classified as having normal BMD by the DEXA scan. The results showed that even if obtained for other reasons, abdominal CT images that include the lumbar spine can be used to

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41917_AT-090_27253_Reg_ASz_Ad 2

090-34105

6/2/11 5:33 PM

Job Number: 15993 Revision No: 0 Date: 12/03/12

Newsline The United States Preventive Services Task Force (USPSTF) has determined that clinicians should screen all adults aged 18 years and older, including pregnant women, for alcohol misuse. The USPSTF recommends three tools for such screening in the primary-care setting: the Alcohol Use and Disorders Identif ication Test (AUDIT), t he abbrev i at ed AU DI TConsumption (AUDIT-C), and single-question screening, such as asking a patient, “How many times in the past year have you had four [for women and all persons older than 65 years] or five [for men] drinks in a day?” Because counseling interventions in the primary-care setting can positively affect unhealthy drinking behaviors in adults, the

USPSTF recommends brief (up to 15 minutes, depending on the approach taken) behavioral counseling interventions to reduce alcohol misuse in persons engaged in risky or hazardous drinking. Brief multicontact behavioral counseling, in which each contact lasts for six to 15 minutes, seems to have the best evidence of effectiveness, according to the task force. In addition to faceto-face sessions, interventions may be delivered by means of written self-help materials, computer- or Web-based programs, and telephone counseling. They may include cognitive behavioral strategies such as action plans, drinking diaries, stress management, or problem-solving. The USPSTF is restricting its alcohol-misuse screening and

Screen all adults for alcohol misuse

Interventions lasting six to 15 minutes are recommended.

intervention recommendations to adult patients. However, in another new recommendation, the task force urges HIV screening for all individuals aged 15 to 65 years, including pregnant women, and even patients younger and older if they are at increased risk for the infection.

A prospective study has uncovered a modestly increased risk of subsequent malignancies among persons with a history of non-melanoma skin cancer (NMSC). A s Jia l i Ha n, Ph D, a nd col leagues noted in PLOS Medicine (available at www. ncbi.nlm.nih.gov/pmc/articles /pmid/23630459/; accessed May 15, 2013), NMSC is the most common cancer in the United States. Consisting mainly of basal cell carcinoma and squamous cell carcinoma, NMSC has a low mortality rate, but previous

A history of NMSC was associated with risk of lung cancer in women.

studies suggest that patients may have a higher risk for developing other cancers. The researchers explored this association in self-identif ied white men and women participating in the Health Professionals Follow-up Study (HPFS) and the Nurses’ Health Study (NHS). After following 46,237 HPFS men from June 1986 to June 2008 and 107,339 women from June 1984 to June 2008, Han’s team documented 29,447 incident cancer cases other than NMSC. A personal history of NMSC was significantly associated with

a 15% higher risk of other primary cancers in men and a 26% higher risk of other primary cancers in women, or 11% and 20%, respectively, when melanoma was excluded from the analysis. NMSC history was significantly associated with an increased risk of melanoma in both men and women, and with a heightened risk of breast and lung cancers in women. The authors pointed out that although further research is warranted, their observational findings should be interpreted cautiously. n

Other risks of non-melanoma skin cancer

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5/28/13 11:10 AM

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Infectious Disease, Endocrine System, Hematologic System, Dermatologic System

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Reproductive System, Gastrointestinal System/ Nutrition, Genitourinary System

ACCREDITATION INFORMATION This program has been reviewed and is approved for a maximum of 27.25 hours of AAPA Category 1 CME credit by the Physician Assistant Review Panel. Approval is valid from the issue date of October 17, 2012 through January 15, 2014. Participants may submit the self-assessment at any time during that period. This program was planned in accordance with the AAPA’s CME Standards for Enduring Material Programs and for Commercial Support of Enduring Material Programs. This program has been planned without commercial support. Developed by

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0.5 credits

Page 42 Feature Clinical evaluation of peptic ulcer disease Kasey Crosby and Kathy Dexter, MLS, MHA, MPA, PA-C Kasey Crosby and Kathy Dexter, MLS, MHA, MPA, PA-C, have no relationships to disclose relating to the content of this article.

■■ Learning objectives: • Explain the factors associated with the development of peptic ulcer disease. • Describe in which patients a “test and treat” approach can be used. • Name the medication that should not be given for up to two weeks prior to performing a rapid urease test. • Identify the medication used in first-line triple therapy in non-penicillin-allergic patients with Helicobacter pylori-related ulcers. 0.5 credits

Page 87 Dermatology Clinic Dusky bullae on the lower abdomen Sonal Parikh and Erin Reese, MD Sonal Parikh and Erin Reese, MD, have no relationships to disclose relating to the content of this article.

Painful vesicles covering the back and chest Esther Stern, NP-C Esther Stern, NP-C, has 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 99 Dermatologic Look-Alikes Erythematous plaques on the trunk 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 103 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 June 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: • Explain the factors associated with the development of peptic ulcer disease. • Describe in which patients a “test and treat” approach can be used. • Name the medication that should not be given for up to two weeks prior to performing a rapid urease test. • Identify the medication used in first-line triple therapy in non-penicillin-allergic patients with Helicobacter pylori-related ulcers. n complete the posttest: Page 103 n additional CME/CE: Pages 87, 99 Turn to page 41 for additional information on this month’s CME/CE courses.

Kasey Crosby and Kathy Dexter, MLS, MHA, MPA, PA-C

Clinical evaluation of peptic ulcer disease Most often caused by use of nonsteroidal anti-inflammatory drugs or bacterial infection, peptic ulcer disease usually presents as epigastric pain.

Gastric ulcers (shown) occur when excesssive acid perforates the stomach wall.

eptic ulcer disease (PUD) is a common dis order in the United States, with approximately 500,000 new cases diagnosed each year and 4 million cases of ulcer recurrence.1 Complications related to PUD cause nearly 15,000 deaths annually.2 Men are affected slightly more often than women, and although peptic ulcers can occur at any age, individuals aged 30 years to 55 years are more likely to have duodenal ulcers, whereas gastric ulcers occur most often between age 55 years and age 70 years.1 A peptic ulcer is defined as a disruption in the mucosa of the stomach or duodenum >5 mm in diameter and extending to the submucosa.1-3 Peptic ulcers occur when there is an imbalance between the protective factors of the mucosa and such aggressive factors as acid and pepsin.1-3 The majority of ulcers are located in the duodenum, and approximately 90% occur within 3 cm of the pylorus.1,2 Etiology

Approximately 90% of PUD cases are caused by Helicobacter pylori infection or nonsteroidal

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anti-inflammatory drug (NSAID) use.1,4,5 H. pylori, a gramnegative bacteria, is able to withstand the acidic conditions in the stomach by using urease to produce ammonia.2,3 This bacteria causes several changes in its host that lead to ulcer development, including activation of the inflammatory response, increase in gastric-acid secretion, and impairment in the mucosal defense system.5 H. pylori infection is relatively common, with more than 50% of people worldwide being infected; ulcer development occurs in 5% to 10% of these cases.3 H. pylori is present in 75% to 90% of individuals with duodenal ulcers.1 Although H. pylori is only able to colonize gastric epithelial cells, excess secretion of gastric acid causes gastric metaplasia in the duodenal bulb, which enables duodenal colonization.3 The prevalence of H. pylori tends to be higher in developing countries; the United States has a prevalence of approximately 30%.2 Predisposing factors for H. pylori infection include poor socioeconomic status, less education, crowded or unclean living conditions, unsanitary food or water, and exposure to gastric contents of an individual infected with H. pylori.2 NSAIDs, including aspirin, are associated with an increased risk of gastric and duodenal mucosal injury (e.g., erosions, ulcers, and ulcer complications). Studies have shown that 15% to 30% of patients using NSAIDs have ulcers, and clinically significant ulcers and ulcer complications are present in 3% to 4.5% of NSAID users.5 Furthermore, NSAID users have been found to have a fourfold increased risk of ulcer complications, and patients who take low-dose aspirin have a twofold to threefold increased risk of ulcer bleeding.3 It has been shown that NSAID users who are also infected with H. pylori are at increased risk for PUD.3,4 NSAIDs decrease inflammation through the inhibition of prostaglandins.4 Nonselective NSAIDs accomplish this by inhibiting COX-1 and COX-2 enzymes.1 Mucosal damage results mainly from COX-1 inhibition, which is involved in mucosal defense, and inhibition of thromboxane A2, which causes bleeding.5 This knowledge led to the development of COX-2-selective NSAIDs, which are associated with a decreased risk of ulcers and ulcer complications.3,5 However, COX-2-selective NSAIDs are associated with an increased risk of cardiovascular complications.1 Although H. pylori and NSAID use are the most common causes of PUD, clinicians must be aware of other potential causes, including acid hypersecretory states, cytomegalovirus, Crohn’s disease, lymphoma, medications, and such chronic medical illnesses as cirrhosis and chronic kidney disease.1 The cause of some ulcers remains unknown. Additional contributory factors associated with PUD include stress,

cigarette smoking, alcohol use, lower socioeconomic status, and genetics.2,5,6 Clinical presentation

Epigastric pain is the characteristic symptom associated with PUD.1,3 A review of 30 studies found that abdominal pain and epigastric pain were the most common symptoms associated with PUD, with each occurring in 81% of study participants.7 Patients may describe the pain as gnawing, dull, aching, or “hunger-like.”1 Pain relief following the intake of food or antacids and the return of pain during the fasting state and/or pain during the night that awakens the individual is reported in some cases, especially in those with duodenal ulcers.3,5 Such symptoms as fullness, bloating, early satiety, and nausea may also be seen in patients with PUD.3 Although less common, weight loss and vomiting may be associated with gastric ulcers as well.1,5 The majority of individuals with PUD go through periods of waxing and waning pain, during which time they will be symptomatic for as long as several weeks followed by painfree periods ranging from months to years.1 Chronic ulcers, particularly those caused by NSAID use, may be present without any symptoms.3 Such complications as upper GI bleeding or perforation may be the first indication of PUD in these indivuduals.3 Interestingly, age may impact clinical presentation. Several studies have found that younger patients more often reported abdominal pain, whereas bleeding was more common in older individuals.7 In addition to the signs and symptoms noted above, several other components of the patient history may lead to the diagnosis of PUD. For example, the patient may report a history of cigarette smoking: Ulcers and ulcer complications have been found to occur more frequently in smokers, and smoking has been found to have a negative effect on ulcer healing rates and responsiveness to therapy.2 A positive family history of PUD may be present. First-degree relatives of patients with duodenal ulcers have an increased likelihood of ulcer development exists in.2 Other contributory factors associated with PUD include alcohol use, psychological stress, decreased prostaglandin levels associated with aging, and use of such medications as bisphosphonates, potassium chloride, and immunosuppressants.5 Such diseases as systemic mastocytosis, chronic pulmonary disease, chronic renal failure, cirrhosis, nephrolithiasis, and alpha–1 antitrypsin deficiency are strongly associated with PUD as well and may be part of the patient’s medical history.2 In the absence of ulcer-related complications, the physical exam of an individual with PUD may be completely normal.1

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CME CE

peptic ulcer disease

The most common exam finding in patients with PUD is epigastric tenderness to palpation.2 Some patients will have a positive fecal occult blood test or fecal immunochemical test.1 Bleeding, perforation, penetration, and obstruction are the four major complications associated with PUD, and it is important to be familiar with the clinical presentation of each.1,8 The most common complication is GI hemorrhage.3,8 Potentially life-threatening bleeding occurs in up to 15% of PUD patients, and ulcer bleeding is associated with a 7% overall mortality rate.1,8 Bleeding is more common in NSAID-related ulcers, and elderly patients and those with other comorbidities are most at risk.1,8 Patients may present with melena, hematemesis, or hematochezia, all of which should be treated as an emergency situation.1,8 A complete blood count (CBC) may reveal anemia due to blood loss.5 Perforation of the GI wall can cause contents to spill into the abdominal cavity, possibly leading to acute peritonitis.8 Patients may present with severe abdominal pain of sudden onset. Physical exam may reveal a rigid abdomen and rebound tenderness, and lab results are typically positive for leukocytosis.1 Another complication of PUD is ulcer penetration into such nearby structures as the pancreas, liver, and biliary tree. The patient history may include a change in the typical pattern and intensity of symptoms. The clinician should consider ulcer penetration if severe, constant pain is reported in conjunction with radiating pain to the back.1 Gastric-outlet obstruction can occur when swelling and scarring from peptic ulcers causes narrowing of the duodenum.1,8 The patient may report early satiety, vomiting, and weight loss, and a succussion splash may be audible in the epigastrium on physical examination.1 Diagnostic testing

Alarm features of dyspepsia include age greater than 55 years with new-onset disease, family history of upper-GI cancer, weight loss, GI bleeding, dysphagia, odynophagia, iron-deficiency anemia, persistent vomiting, palpable mass or lymphadenopathy, and jaundice (Table 1).9 If the patient is aged 55 years or younger and does not exhibit any alarm features, the American Gastroenterological Association (AGA) recommends a “test and treat” approach (Figure 1),10 which involves using such noninvasive tests as the urea breath test, stool antigen test, and serologic testing to detect possible H. pylori infection.5 If one of these tests is positive, the patient is treated for H. pylori infection without having to undergo endoscopy, which proves to be both cost-effective and less invasive for the patient.5 A

study found the AGA’s recommended approach to be just as effective and safe as prompt endoscopy in the management of dyspeptic patients in the primary-care setting, with only 33% of patients requiring endoscopy following the test-andtreat method.11 The decision as to which noninvasive test is most appropriate depends on the prevalence of H. pylori in the area, the clinical setting, and the individual patient.5 Since serology testing for anti-H. pylori antibody cannot make the distinction between an active and past infection, the urea breath test or stool antigen test are recommended as initial diagnostic studies.5,10 While commonly used, the test-and-treat method is not always necessary. If the prevalence of H. pylori infection in a particular area is <5% and the patient is aged 55 years or younger with no alarm features, it is recommended that empiric proton pump inhibitor (PPI) therapy be started first, as testing for H. pylori is unlikely to be beneficial.10 However, the decision as to whether to test for H. pylori first or treat empirically with PPI therapy depends on the prevalence of H. pylori in the area as well as patient and provider preferences.12 Patients older than age 55 years or those of any age with alarm features should undergo upper GI endoscopy first.9 Endoscopy enables direct visualization of the mucosa and is the most sensitive and specific test.2 Endoscopy also allows a tissue sample to be obtained for biopsy to rule out malignancy in cases of gastric ulcers or to detect H. pylori infection using the rapid urease test.1,2,5 In addition, endoscopy can determine whether blood loss is attributable to a bleeding ulcer.2 A benign-appearing ulcer on endoscopy requires no further endoscopic testing as long as the biopsy results are negative for malignancy, dysplasia, and atypical cells. If biopsy results are positive, however, a second endoscopy should be performed Table 1. Alarm features requiring endoscopy Age >55 years with new-onset dyspepsia Family history of upper-GI cancer Weight loss GI bleeding Dysphagia Odynophagia Iron-deficiency anemia Persistent vomiting Palpable mass or lymphadenopathy Jaundice Adapted from Talley NJ, Vakil NB, Moayyedi P. American Gastroenterological Association technical review on the evaluation of dyspepsia. Gastroenterology. 2005;129:1756-1780.

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Figure 1. Diagnosis and treatment algorithm for peptic ulcer disease

Dyspepsia

Age >55 years or alarm features present YES

H. pylori prevalence <5%

Endoscopy with biopsy and rapid urease test

Treat based on endoscopic findings

yes

Empiric PPI therapy for four to eight weeks

Noninvasive H. pylori testing positive

fails

H. pylori eradication triple therapy

Endoscopy with biopsy and rapid urease test

fails

positive

negative

H. pylori eradication quadruple therapy

Treat based on endoscopic findings

Consider other disorders with similiar presentations

Retest for H. pylori four to eight weeks after therapy to confirm eradication

negative PPI therapy for four to eight weeks or H2 receptor antagonist therapy for six to eight weeks. Discontinue NSAID therapy, if possible. fails

If symptoms persist after eradication, treat with PPI therapy for four weeks. Ulcers >1 cm or ulcer complications also require additional PPI therapy

Endoscopy with biopsy and rapid urease test

fails positive

negative

Treat based on endoscopic findings

Consider other disorders with similar presentations

Endoscopy positive

negative

Treat based on endoscopic findings

Consider other disorders with similar presentations

Adapted from: Harmon RC, Peura DA. Evaluation and management of dyspepsia. Therap Adv Gastroenterol. 2010;3:87-98; and Talley NJ. American Gastroenterological Association medical position statement: evaluation of dyspepsia. Gastroenterology. 2005;129:1753-1755.

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CME CE

peptic ulcer disease

Proton pump inhibitors impede urease activity and can affect the results of the rapid urease test, the stool antigen test, and the urea breath test. 12 weeks after initiation of treatment to ensure proper healing. If the ulcer is not healing as it should, malignancy should be considered.1 Patients who are suspected of having such ulcer-related complications as perforation, penetration, or obstruction should undergo an abdominal CT scan. Although laboratory testing is typically normal in uncomplicated PUD, a CBC is useful in detecting anemia or leukocytosis, which may indicate the presence of ulcer complications.1 When testing for H. pylori, it is important to keep in mind that PPIs impede urease activity and can affect the results of the rapid urease test, the stool antigen test, and the urea breath test.1,5 PPIs should be withheld at least two weeks prior to performing these tests.12 Because bleeding reduces the sensitivity of invasive tests, an endoscopic rapid urease test and histologic testing should be performed in conjunction with the urea breath test in patients with actively bleeding ulcers.5 Differential diagnosis

Dyspepsia is the most common symptom in PUD, occurring in 80% to 90% of patients.1,3,12 However, dyspepsia can occur in other diseases as well, causing these conditions to present similarly to PUD. Gastroesophageal reflux disease (GERD). Epigastric pain or discomfort may occur in individuals with GERD.12 Although 20% of dyspeptic patients have GERD, other symptoms are much more common in the presentation of this disorder, including heartburn and regurgitation.1,12 GERD is associated with two patterns of reflux: upright and supine. Upright reflux occurs during the daytime, is commonly characterized by postprandial heartburn, and may be accompanied by regurgitation. Supine reflux typically occurs at night when the individual is lying down.12 In most cases, GERD is clinically diagnosed using the patient history. Although it can present similarly to PUD with such symptoms as dyspepsia, GERD is the most likely diagnosis if the predominant symptom is heartburn.1,12 Functional dyspepsia. Functional (or nonulcer) dyspepsia is defined as dyspepsia lasting for at least three months without any organic, systemic, or metabolic cause.10,12,13 Up to 60% of patients with dyspepsia have functional dyspepsia, making this condition more common than dyspepsia attributable to organic causes.10,13 Since functional dyspepsia is a diagnosis of exclusion, a definitive diagnosis should not be made until an endoscopy is performed and at least six

months have passed since the initial onset of symptoms.13 Although the exact pathophysiologic mechanisms involved in functional dyspepsia remain unclear, possible contributory factors include genetics, psychosocial distress, and alterations in GI motor and sensory function.10,13 Some patients with dyspepsia may be infected with H. pylori in the absence of peptic ulcers or other endoscopic findings and are therefore considered to have functional dyspepsia.10 It is recommended that these patients undergo anti-H. pylori therapy.10,13 Gastric cancer. Gastric cancer is found in only 1% of individuals with dyspepsia and is uncommon in patients with uncomplicated dyspepsia who are younger than age 55 years.1,12 Most patients with gastric cancer will present with such symptoms as anorexia, early satiety, and weight loss.14 Anorexia may be present in patients with gastric ulcers, but individuals with uncomplicated PUD typically do not experience significant weight loss.1 An upper GI endoscopy can be performed to rule out malignancy and should be ordered if any alarm features are present.1,2,12 Food and medications. Eating too fast or overeating can cause indigestion that can manifest as dyspepsia.1 High-fat foods, alcohol, and coffee also can cause indigestion.2 A number of medications may also lead to dyspepsia, including NSAIDs, calcium antagonists, bisphosphonates, steroids, theophyllines, and nitrates.1,12,13 Food or medication intolerances can usually be diagnosed with a thorough patient history. Treatment

The goals of PUD treatment and the treatment regimen depend on the etiologic agent involved in the disease process. Ulcers that are not caused by H. pylori infection can be treated with four to eight weeks of PPI therapy (Table 2).5,9 Uncomplicated duodenal ulcers can be treated with a PPI for four weeks, while uncomplicated gastric ulcers require eight weeks of therapy.1,5 The six PPIs currently on the market are omeprazole (Prilosec), rabeprazole (AcipHex), esomeprazole (Nexium), lansoprazole (Prevacid), dexlansoprazole (Dexilant), and pantoprazole (Protonix), and each is equally effective in treating PUD.1 As stated previously, individuals in areas where H. pylori prevalence is <5% may be started on empiric PPI therapy without undergoing H. pylori testing.10 If the patient remains symptomatic after four to eight weeks of

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Uncomplicated duodenal ulcers can be treated with an H2–receptor antagonist for six weeks, and uncomplicated gastric ulcers require eight weeks. PPI therapy, an endoscopy and biopsy should be ordered.12 The patient should be treated based on the endoscopic findings, including H. pylori eradication therapy if positive for infection.12 If the patient is H. pylori–negative, has a negative endoscopy, and continues to be symptomatic despite PPI therapy, consider other disorders that may present similarly to PUD.10,12 H2–receptor antagonists inhibit nocturnal acid secretion and can also be used in the treatment of PUD but require more time to provide pain relief and ulcer healing than do PPIs. Four H2–receptor antagonists are currently on the market: cimetidine (Tagamet), ranitidine (Tritec, Zantac), famotidine (Fluxid, Pepcid), and nizatidine (Axid). Uncomplicated duodenal ulcers can be treated with an H2–receptor antagonist for six weeks, and uncomplicated gastric ulcers require eight weeks of treatment. In cases of complicated ulcers, PPIs are preferred over H2–receptor antagonists.1 NSAID use should be discontinued in patients with NSAID-related ulcers whenever possible.1,13 If NSAID therapy cannot be discontinued, the addition of a oncedaily PPI is recommended.1,12 This concomitant treatment results in healing of duodenal ulcers after four weeks and of gastric ulcers after six to eight weeks.5 Another option is to replace a nonselective NSAID with a COX-2 inhibitor, a selective NSAID that is associated with a decreased incidence of ulcers.1,12,13 The mucosal protective agent misoprostol (Cytotec) can also be administered simultaneously with NSAID treatment to reduce the risk of ulcer complications.1,13 In the case of a refractory ulcer, in which the patient has a confirmed ulcer on endoscopy and remains symptomatic after treatment with a PPI or H2–receptor antagonist, H. pylori infection or surreptitious NSAID or aspirin use must be ruled out. Since the sensitivity of H. pylori tests are less than 100%, it is possible that the infection was originally missed due to a false-negative result.3 Such other ulcer-causing conditions as Zollinger-Ellison syndrome should be ruled out as well.3,5 If the patient is confirmed to be negative for H. pylori infection and other conditions, an additional six to eight weeks of b.i.d. PPI therapy may be needed.5 In cases of H. pylori-related PUD, the goal of treatment is to eradicate the bacteria. The standard first-line treatment is triple therapy consisting of a PPI b.i.d., clarithromycin (Biaxin) 500 mg b.i.d., and amoxicillin 1 g b.i.d. for seven to 14 days (Table 3).1,5,10 Amoxicillin is preferred over metronidazole (Flagyl)

because more bacterial strains are resistant to metronidazole.1,5 In cases of penicillin allergy, however, metronidazole 500 mg b.i.d. can be substituted.1,5 H. pylori infection is successfully eliminated in 70% to 95% of patients using the triple therapy regimen.5 Although seven, 10-, and 14-day regimens are all effective, 10-day and 14-day regimens have been found to be 7% to 9% more effective in the eradication of H. pylori Table 2.Treatment for ulcers not related to H. pylori infection Uncomplicated ulcers: • PPI therapy –– Duodenal ulcers: four weeks –– Gastric ulcers: eight weeks OR • H2-receptor antagonist therapy –– Duodenal ulcers: six weeks –– Gastric ulcers: eight weeks

Complicated ulcers: • PPI therapy

Discontinue NSAID therapy, if possible • If patient must continue NSAID therapy: –– PPI once daily with NSAID therapy OR –– Substitute COX-2 inhibitor for nonselective NSAID OR –– Misoprostol (Cytotec) with NSAID therapy Refractory ulcers confirmed on endoscopy: • If negative for H. pylori, NSAID use, or other conditions, consider an additional six to eight weeks b.i.d. PPI therapy. Adapted from: McQuaid KR. Gastrointestinal disorders. In: SJ McPhee, MA Papadakis, MW Rabow, eds. Current Medical Diagnosis & Treatment. New York, N.Y.: The McGraw-Hill Companies, Inc.; 2011:540-541, 586-595.

Table 3.Treatment of H. pylori–related ulcers First-line triple therapy: • PPI b.i.d., clarithromycin (Biaxin) 500 mg b.i.d., and amoxicillin 1 g b.i.d. for seven to 14 days • Penicillin allergy: substitute metronidazole (Flagyl) 500 mg b.i.d.

Second-line quadruple therapy: • PPI b.i.d.; bismuth subsalicylate 120 mg four times daily; tetracycline 500 mg four times daily; and metronidazole 250 mg four times daily or 500 mg three times daily for at least seven days

Confirm successful eradication with H. pylori testing four to eight weeks after therapy and at least two weeks after PPI therapy. After H. pylori is eradicated, additional PPI therapy may be needed: • Ulcers >1 cm or ulcer complications: PPI once daily for two to four weeks (duodenal ulcers) or four to six weeks (gastric ulcers) • If patient continues to be symptomatic: four-week course of PPI therapy Adapted from: McQuaid KR. Gastrointestinal disorders. In: SJ McPhee, MA Papadakis, MW Rabow, eds. Current Medical Diagnosis & Treatment. New York, N.Y.: The McGraw-Hill Companies, Inc.; 2011:540-541, 586-595.

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CME CE

peptic ulcer disease

and are therefore preferred.5,10 In cases of treatment failure, commonly due to poor patient compliance or bacterial resistance, second-line quadruple therapy consisting of a PPI b.i.d., bismuth subsalicylate 120 mg four times daily, tetracycline (Sumycin) 500 mg four times daily, and metronidazole 250 mg four times daily or 500 mg three times daily for at least seven days can be used.5 Following successful treatment and eradication of H. pylori, ulcers are usually adequately healed and recurrence rates decreased, particularly in the absence of NSAID or aspirin use.5 All patients should undergo H. pylori testing four to eight weeks after therapy to confirm successful eradication.1,5 While confirmation can be done using the urea breath test, stool antigen test, or endoscopy with biopsy, the urea breath test is the preferred method.1,5 Make sure the patient has not taken PPIs within two weeks of H. pylori testing.12 Some cases may require additional PPI therapy after completion of eradication therapy. Patients with ulcers >1 cm or those with ulcer complications should remain on a once-daily PPI for two to four weeks for duodenal ulcers or four to six weeks for gastric ulcers.1,5 If symptoms continue after the infection is eradicated, a four-week course of PPI therapy should be prescribed.9,10 An endoscopy should be ordered if symptoms persist after H. pylori eradication therapy and PPI therapy, and endoscopic findings should determine subsequent treatment.12 Summary

PUD is a common disorder most often caused by H. pylori infection and NSAID use. Contributory factors associated with PUD include stress, cigarette smoking, alcohol use, lower socioeconomic status, and genetics. The clinical presentation of PUD most commonly includes epigastric pain with such symptoms as fullness, bloating, early satiety, and nausea also occurring in some patients. Other patients may be asymptomatic, especially those with chronic ulcers. Although the physical exam is usually normal in an individual with PUD, epigastric tenderness may be present. Other diseases can present similarly to PUD, and a thorough history, a physical exam, and appropriate diagnostic testing can aid in ruling these out. Diagnostic testing is determined by the patient’s age and the presence or absence of alarm features. Treatment is dependent on the cause of PUD. Non-H. pylorirelated cases should be treated with either PPI or H2–receptor antagonist therapy. H. pylori–related PUD requires triple therapy that includes antibiotics and a PPI. Additional PPI therapy may be needed in some cases. Such complications as GI bleeding, perforation of the GI wall, organ penetration,

and gastric outlet obstruction have been found to occur in some cases of PUD. n Ms. Crosby is a student in her clinical year in the physician assistant program at Georgia Regents University in Augusta, where Ms. Dexter is an assistant professor and clinical director. References 1. McQuaid KR. Gastrointestinal disorders. In: SJ McPhee, MA Papadakis, MW Rabow, eds. Current Medical Diagnosis & Treatment. New York, N.Y.: The McGraw-Hill Companies, Inc.; 2011:540-541, 586-595. 2. Del Valle J. Peptic ulcer disease and related disorders. In: Longo DL, Fauci AS, Kasper DL, et al, eds. Harrison’s Principles of Internal Medicine. 18th ed. New York, N.Y.: The McGraw-Hill Companies, Inc.; 2012:2438. 3. Malfertheiner P, Chan FK, McColl KE. Peptic ulcer disease. Lancet 2009;374:1449-1461. 4. Gustafson J, Welling D. “No acid, no ulcer”—100 years later: a review of the history of peptic ulcer disease. J Am Coll Surg. 2010;210:110-116. 5. Yuan Y, Padol IT, Hunt RH. Peptic ulcer disease today. Nat Clin Pract Gastroenterol Hepatol. 2006;3:80-89. 6. Rosenstock SJ, Jørgensen T, Bonnevie O, Andersen LP. Does Helicobacter pylori infection explain all socio-economic differences in peptic ulcer incidence? Genetic and psychosocial markers for incident peptic ulcer disease in a large cohort of Danish adults. Scand J Gastroenterol. 2004;39:823-829. 7. Barkun A, Leontiadis G. Systematic review of the symptom burden, quality of life impairment and costs associated with peptic ulcer disease. Am J Med. 2010;123:358-366. 8. Milosavljevic T, Kostic´-Milosavljevi´c M, Jovanovi´c I, Krstic´ M. Complications of peptic ulcer disease. Dig Dis. 2011;29:491-493. 9. Talley NJ, Vakil NB, Moayyedi P. American Gastroenterological Association technical review on the evaluation of dyspepsia. Gastroenterology. 2005;129:1756-1780. 10. Talley NJ. American Gastroenterological Association medical position statement: evaluation of dyspepsia. Gastroenterology. 2005;129:1753-1755. 11. Arents NL, Thijs JC, van Zwet AA, et al. Approach to treatment of dyspepsia in primary care: a randomized trial comparing “test-and-treat” with prompt endoscopy. Arch Intern Med. 2003;163:1606-1612. Available at archinte.jamanetwork.com/article.aspx?articleid=215816. 12. Harmon RC, Peura DA. Evaluation and management of dyspepsia. Therap Adv Gastroenterol. 2010;3:87-98. Available at www.ncbi.nlm.nih.gov/ pmc/articles/pmid/21180593/. 13. Summers A, Khan Z. Managing dyspepsia in primary care. Practitioner. 2009;253:23-27. 14. Cornett PA, Dea TO. Cancer. In: SJ McPhee, MA Papadakis, MW Rabow, eds. Current Medical Diagnosis & Treatment. New York, N.Y.: The McGrawHill Companies, Inc.; 2011:1549-1552. All electronic documents accessed May 15, 2013.

48 the clinical advisor • june 2013 • www.ClinicalAdvisor.com

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feature: David Areaux, MPAS, PA-C

Assessment of peritonsillar abscess This infection manifests as a collection of pus and is often a complication of tonsillitis that may require referral to a specialist or hospitalization.

The peritonsillar abscess can be seen as a white area to the right of the uvula.

peritonsillar abscess (PTA) is a puru lent infection with abscess formation between the palatine tonsil and its cap sule.1 These growths are often a complication of recent or current tonsillitis. Approximately 30% of all PTAs occur in persons aged 20 to 40 years,2 occurring most often from April to May and again from November to December, which coincides with the highest incidence of streptococcal pharyngitis and exudative tonsil litis.1 PTAs affect males and females equally. Evidence shows that chronic tonsillitis or mul tiple trials of oral antibiotics for acute tonsillitis may predispose an individual to the develop ment of a PTA.3 Although young children are seldom affected (unless they are immunocom promised), the infection can cause significant airway obstruction in these patients. Group A hemolytic Streptococcus is the most common cause of PTA; other possible causes are Staphylococcus aureus; Haemophilus influenzae; and various anaerobes, including Peptostreptococcus and Fusobacterium. Polymicrobial infections are also common (Table 1).1,3,4 Abscess formation begins two to eight days after the onset of symptoms.4 Infection spreads from the tonsil—usually unilateral—into sur rounding soft tissue, resulting in a collection of pus. Additional evaluation of surrounding deep neck spaces is important because the abscess in the peritonsillar space may continue to spread and involve the parapharyngeal and retro pharyngeal spaces. Continues on page 54

52 the clinical advisor • june 2013 • www.ClinicalAdvisor.com

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peritonsillar abscess

Table 1. Organisms commonly associated with peritonsillar abscess Aerobic bacteria

Anaerobic bacteria

Group A Streptococcus

Fusobacterium

Staphylococcus aureus

Peptostreptococcus

Haemophilus influenzae

Pigmented Prevotella

Streptococcus pyogenes

Bacteroides

poll position

Epiglottitis Infectious mononucleosis Lymphoma Peritonsillar cellulitis Retromolar retropharyngeal abscess All of the above

Adapted from Brook I. Microbiology and management of peritonsillar, retropharyngeal, and parapharyngeal abscesses. J Oral Maxillofac Surg. 2004;62:1545-1550, and Kieff DA, Bhattacharyya N, Siegel NS, Salman SD. Selection of antibiotics after incision and drainage of peritonsillar abscesses. Otolaryngol Head Neck Surg. 1999;120:57-61.

To prevent complications and further propagation of the infectious process, providers must be aware of the typical clinical presentation and diagnostic strategies to quickly assess and appropriately treat patients with PTA.2 Although unlikely with isolated PTA, significant edematous peritonsillar tissues may obstruct the airway, creating a lifethreatening medical emergency. Sore throat associated with stridor and increased respiratory effort can signal imminent respiratory distress and requires immediate evaluation and management in a hospital emergency department.4 Making the diagnosis

PTAs may present with a variety of symptoms, but the onset is usually marked by a sore throat. Symptoms typically develop three to five days before a patient seeks medical evaluation, and time from onset of symptoms to abscess formation is approximately two to eight days. Patients with a PTA appear ill and may be afebrile at first, but as the abscess progresses, a fever may develop. Presenting symptoms associated with a developing PTA may include severe sore throat, fever as high as 103°F (39°C), headache, malaise, odynophagia or drooling, neck pain, dysphagia, and otalgia. More severe symptoms may indicate illness other than simple viral or streptococcal pharyngitis and require immediate medical care (Table 2).5 A PTA is usually diagnosed based on patient history and a physical examination (Table 3).6 Physical exam findings

Which of the following should not be considered in the differential diagnosis of PTA? n=761 9.5%

2.9%

16.1% 69.3%

1.1% 1.1%

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

indicative of a diagnosis of PTA include trismus (inability to open the mouth because of muscle spasms), inferior and medial displacement of the tonsil, displaced soft palate/ uvula, change in voice (i.e., “hot potato” voice), rancid breath, tonsillar erythema, exudate on the tonsil, cervical lymphadenitis in the anterior chain, and asymmetric tonsillar hypertrophy. Differential diagnoses of PTA include epiglottitis (inflammation of the epiglottis), infectious mononucleosis, lymphoma, peritonsillar cellulitis, and retromolar or retropharyngeal abscess.1 When the diagnosis of PTA is in question, additional lab tests, needle aspiration (looking for pus), CT scan, or x-ray may be required to rule out such other upper airway illnesses as epiglottitis, retropharyngeal abscess, and peritonsillar cellulitis. Epiglottitis is primarily a disease of young children caused by H. influenzae. The key clinical difference between epiglottitis and PTA is severe pain in the absence of erythema.5 A retropharyngeal abscess is a pocket of pus that forms beneath the soft tissue in the back of the throat rather than the tonsil. Retropharyngeal abscess is rare in adulthood because the lymph nodes that give rise to this infection are generally atrophied by that point in time.5 Peritonsillar cellulitis is an infection of the soft tissue itself.

For more news, opinion, and clinical features concerning tonsillitis, visit our Infectious Diseases Information Center at

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TABLE 2. Red flags in a patient with sore throat

Treatment

Drainage, antibiotics, and supportive therapy to maintain hydration and control pain are the foundation of treatment for PTA.1 The primary drainage procedures are needle aspiration, incision and drainage, and immediate tonsillectomy. Drainage using any of these methods combined with antibiotic therapy will result in resolution of the PTA in more than 90% of cases.7 The gold standard for diagnosis of a PTA remains the collection of pus from the abscess through needle aspiration. The area should be anesthetized prior to aspiration with benzalkonium 0.5% spray followed by a gargle of lidocaine 2% (Xylocaine) with epinephrine. An 18-gauge spinal needle attached to a 10-mL syringe can be used to obtain material from the suspected abscess.3 Once collected, the fluid should be sent to the laboratory for Gram stain and culture to determine the appropriate treatment regimen. Only properly trained health-care providers should perform a needle aspiration of a PTA. Potential complications include hemorrhage and aspiration of pus and blood. If the abscess is located in the distal part of the tonsil, puncture of the carotid artery can occur.3 Although not routinely performed for the treatment of PTA, immediate tonsillectomy should be considered for patients who have strong indications for the procedure, including those who have symptoms of sleep apnea, a history of recurrent tonsillitis (four or more infections per year despite adequate medical therapy), or a recurrent or nonresolving PTA.7 Antibiotic therapy should include antimicrobials effective against group A Streptococcus and oral anaerobes.8 Some studies have reported that more than 50% of culture results demonstrated the presence of beta-lactamase-producing anaerobes, leading many clinicians to use broader-spectrum antibiotics as first-line therapy.9-11 Recommended antimicrobial regimens are listed in Table 4.1 It is important to remember that a PTA is very painful, and many patients have difficulty swallowing

Persistence of symptoms longer than one week without improvement Respiratory difficulty, particularly stridor Difficulty in handling secretions Difficulty swallowing Severe pain in absence of erythema A palpable mass Blood, even a small amount, in the pharynx or ear Adapted from Andreoli TE, Benjamin IJ, Griggs RC, Wing EJ, eds. Cecil Essentials of Medicine. 8th edition. Philadelphia, Pa.: Saunders Elsevier; 2010:949.

clinical slideshow For additional information on the differences between bacterial vs. viral pharyngitis, view the clinical slideshow at CliniAd.com/13Ln9IM.

and are unable to tolerate pills. These individuals will require liquid (outpatient) or IV (inpatient) formulations of medicine. In addition to antimicrobial therapy, steroids have been used to reduce edema and inflammation associated with PTA. The use of steroids in the treatment of PTA has not been widely studied, but a recent investigation reported that 32 patients who received a single high dose of IV steroids (methylprednisolone [A-methaPred, Depo-Medrol, SoluMedrol] 2 mg/kg to 3 mg/kg up to 250 mg) plus antibiotics responded much more quickly to treatment than did the 28 patients who received antibiotics plus placebo.1 If steroids are needed for a longer period or required on an outpatient basis, liquid prednisone can be prescribed. Continues on page 60

TABLE 3. Clinical differentiation of common conditions presenting as sore throat Feature

Viral pharyngitis

Bacterial tonsillitis

Peritonsillar abscess

Epiglottitis

Tonsillar enlargement

Usual

Rare

None

Tonsillar exudates

Occasional (mononucleosis)

Usual

Often

None

Tonsillar asymmetry

None

Usual

None

Trismus

None

Usual

None

Cervical adenopathy

Occasional

Usual (tender)

None

Tender larynx

Rare

None

Usual

Adapted from Goldman L, Ausiello, D, eds. Cecil Medicine. 23rd ed. Philadelphia, Pa.: Saunders Elsevier; 2008:2889.

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peritonsillar abscess

Table 4. Antimicrobial regimens for PTA IV therapy • Ampicillin/sulbactam (Unasyn) 3 g every six hours • Penicillin G 10 million units every six hours plus metronidazole (Flagyl) 500 mg every six hours; if allergic to penicillin, clindamycin (Cleocin) 900 mg every eight hours Oral therapy • Amoxicillin/clavulanic acid (Amoclav, Augmentin, Clavamox) 875 mg b.i.d. • Penicillin VK 500 mg four times daily plus metronidazole 500 mg four times daily • Clindamycin 600 mg b.i.d. or 300 mg four times daily Adapted from Fairbanks DN, ed. Pocket Guide to Antimicrobial Therapy in Otolaryngology—Head and Neck Surgery. 12th ed. Alexandria, Va.: American Academy of Otolaryngology—Head and Neck Surgery Foundation, Inc.; 2005:40.

5. Andreoli TE, Benjamin IJ, Griggs RC, Wing EJ, eds. Cecil Essentials of Medicine. 8th edition. Philadelphia, Pa.: Saunders-Elsevier; 2010:949. 6. Goldman L, Ausiello, D, eds. Cecil Medicine. 23rd ed. Philadelphia, Pa.: Elsevier; 2008:2889. 7. Herzon FS, Martin AD. Medical and surgical treatment of peritonsillar, retropharyngeal, and parapharyngeal abscesses. Curr Infect Dis Rep. 2006;8:196-202. 8. Brook I. The role of beta-lactamase producing bacteria and bacterial interference in streptococcal tonsillitis. Int J Antimicrob Agents. 2001;17:439-442. 9. Brook I. Microbiology and management of peritonsillar, retropharyngeal, and parapharyngeal abscesses. J Oral Maxillofac Surg. 2004;62:1545-1550. 10. Kieff DA, Bhattacharyya N, Siegel NS, Salman SD. Selection of anti biotics after incision and drainage of peritonsillar abscesses. Otolaryngol Head Neck Surg. 1999;120:57-61. 11. Ozbek C, Aygenc E, Unsal E, Ozdem C. Peritonsillar abscess: a comparison of outpatient i.m. clindamycin and inpatient i.v. ampicillin/sulbactam following needle aspiration. Ear Nose Throat J. 2005;84:366-368. All electronic documents accessed May 15, 2013.

Finally, and most important to the patient, is pain control. Adequate pain control plays an important role in compliance with treatment and in keeping the patient out of the hospital. There are multiple liquid forms of pain medication, ranging from OTC analgesics to prescription narcotics. Which one used is based upon a number of factors and is ultimately the provider’s preference. Topical anesthetic can also be beneficial and is available in liquid, gel, and spray forms. This medication provides temporary but very effective pain control. A clinician inexperienced in treating PTA should consult an otolaryngologist at the time of diagnosis to determine the appropriate surgical treatment.3 Most patients with a PTA can be treated in an outpatient setting, but a small percentage may require hospitalization.1 Hospital stays usually do not exceed two days and are required for pain control and hydration. It is important to make patients aware that the overall risk of developing a second PTA is approximately 10% to 15% and may require a tonsillectomy.1 n Mr. Areaux is an assistant professor in the Physician Assistant Department at Western Michigan University in Kalamazoo. References 1. Galioto NJ. Peritonsillar abscess. Am Fam Physician. 2008;77:199-202. Available at www.aafp.org/afp/2008/0115/p199.html. 2. Johnson RF, Stewart MG, Wright CC. An evidence-based review of the treatment of peritonsillar abscess. Otolaryngol Head Neck Surg. 2003;128:332-343. 3. Steyer TE. Peritonsillar abscess: diagnosis and treatment. Am Fam Physician. 2002;65:93-96. Available at www.aafp.org/afp/2002/0101/p93.html. 4. Clinical Key. Peritonsillar abscess. Available at www.clinicalkey.com/ topics/otolaryngology/peritonsillar-abscess.html.

“It’s the only treatment option he has under his current health plan.”

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feature: Joni Thanavaro, DNP, ANP-BC, ACNP-BC, GNP-BC, DCC

Raising awareness of primary aldosteronism Persistently elevated aldosterone levels is an underdiagnosed cause of hypertension that can result in significant vascular end-organ disease.

Aldosterone is released from the adrenal zona glomerulosa and zona fasciculata (both shown).

rimary aldosteronism (PAL) is a clinical disorder that results from excessive production and release of aldosterone by the adrenal gland.1-3 First described by Jerome W. Conn, MD, in 1955, the disorder is also known as “Conn syndrome.”1 High levels of aldosterone increase reabsorption of sodium and loss of potassium in the distal tubule of the kidney. This leads to mild hypernatremia, hypertension, severe hypokalemia, and alkalosis.1-3 Failure to eliminate hyperaldosteronism can result in significant vascular end-organ damage even if the patient has optimal BP.4 Excessive aldosterone production affects the mineralocorticoid receptors in the brain, myocardium, blood vessels, kidney, and colon. The vascular end-organ disease associated with PAL exceeds the damage observed with the corresponding degree of hypertension and includes ischemic cardiac disease, atrial fibrillation, cerebrovascular events, and renal dysfunction.5-9 PAL also has been shown to increase left ventricular mass.10 Proper diagnosis and treatment can lead to symptom improvement and resolution of hypertension. Prevalence

Historically, PAL was considered to be relatively rare.2,5,11 However, recent studies indicate that it is responsible for 6% to 13% of all cases of hypertension.5,11,12 PAL is also the most common reason for secondary hypertension and is even more common in resistant hypertension. The reported incidence of PAL is 20% to 30% in patients with resistant hypertension (i.e., those www.ClinicalAdvisor.com • the clinical advisor • june 2013 61

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primary aldosteronism

who continue to have BP above goal (140/90 mm Hg) in spite of consistently taking three or more antihypertensive medications).11,13 Etiology

Most cases of excessive aldosterone secretion in persons with newly diagnosed hypertension are associated with idiopathic hyperaldosteronism (IHA).14,15 IHA results from bilateral hyperplasia and enlargement of the adrenal glands.6,16 Because IHA is often responsive to angiotensin II, some cases may be secondary to a disruption in the reninangiotensin system rather than to true PAL.16 Patients with IHA are generally older than 40 years and have moderate hypertension, hypokalemia, and serum aldosterone (SA) elevations.5,6,13,17 Another common cause of PAL is aldosterone-producing adenoma (APA).14,15,18 Compared with IHA patients, those with APA are usually younger and tend to have more severe hypertension, lower serum potassium levels, and higher SA levels.5,13,17 Adenomas that are detected during imaging for nonadrenal-related causes are called “incidentalomas”3; fewer than 2% of these adenomas are secreting tumors.19 Rare types of familial hyperaldosteronism also exist; diagnosis requires genetic confirmation.3,16,20,21 Clinical presentation

Severe or resistant hypertension is usually the only sign associated with PAL.2,22 Although hypokalemia is considered a hallmark of hyperaldosteronism, most patients with PAL have normal potassium levels; hypokalemia is believed to be a late manifestation.2,23,24 Symptoms attributable to hypokalemia include muscle weakness, cramping, palpitations, headache, polyuria, and transient paralysis.1,25 Making the diagnosis

A diagnostic workup for PAL is warranted in any patient thought to be at increased risk.2,5,23 The Endocrine Society has provided clinical practice guidelines for both the diagnosis and treatment of PAL.2 Figure 1 represents a summary of those guidelines.26 Diagnosis requires three steps, including case detection, case confirmation, and subtype classification.2,3,24 Step 1: Case detection. Obtain initial screening blood tests to determine SA, plasma renin activity (PRA), and the SA-to-PRA ratio (ARR).2,3 Because these values are affected by diurnal variation and the individual’s posture, the ARR should be measured mid-morning, two to four hours after the patient has gotten out of bed and has been

ambulating.3 An SA level >16 ng/dL is high, while a PRA <0.5 ng/mL/hr is low; a very high ARR (>50) is diagnostic for PAL.2,3,23 Because ARR is now used as a screening test in hypertensive persons with hypokalemia and in those with severe or resistant hypertension and normokalemia, the diagnosis of PAL has increased 10-fold.3 If the ARR is abnormal, referral to an endocrine specialist is recommended for steps 2 and 3 evaluation. Step 2: Case confirmation. The diagnosis of PAL needs to be confirmed by demonstrating autonomous aldosterone production independent of its normal regulator, angiotensin II.3 Four tests used for confirmation are the fludrocortisone suppression test (FST), the saline loading test (SLT), the oral sodium loading test (OSLT), and the captopril challenge test (CCT). Although most experts recommend the SLT or OSLT, the FST with a high-salt diet is regarded as more accurate and reliable for a definitive diagnosis of PAL.3,28 Step 3: Subtype classification. Differentiating IHA from APA is necessary to ensure appropriate patient management.14,15 Radiographic imaging and an adrenal vein sample of aldosterone are used to determine PAL subtypes and evidence of unilateral or bilateral hypersecretion.3 Radiographic imaging CT and MRI are frequently used to detect an adrenal mass in patients with positive results on screening and confirmation tests.2,5 Radiographic imaging is increasingly being used to diagnose APA because it is convenient, less invasive, less expensive, and readily available.2,5 CT has a sensitivity of 40% to 100%, and MRI has a sensitivity of 70% to 100%.6,29,30 Radiographic imaging cannot differentiate a secreting from a nonsecreting tumor, but it may help differentiate between a benign and a malignant nodule based on fat content.6 A nodule with a high fat content is more likely to be benign, whereas a large tumor (>2.5 cm) is more likely to be malignant.6 Adrenal vein sample Although this procedure has a relatively low success rate, it is still considered the gold standard for determining the cause of PAL. The low success rate is related to the technical difficulty of placing catheters in the correct locations.3,5,6,30 Blood samples are obtained from both adrenal veins and from the inferior vena cava for measurement of aldosterone and cortisone. An aldosterone-to-cortisone ratio (ACR) from the adrenal vein that is more than four times higher than the ACR from the peripheral vein indicates increased aldosterone secretion.31 Treatment

The goal of treatment is to normalize circulating aldosterone levels in order to prevent the mortality associated

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Figure 1. Evaluation for primary aldosteronism (PAL) Characteristics indicating high risk for PAL

• Hypertension with hypokalemia • JNC7 stage 2 (BP 160-179/100-109 mm Hg) or stage 3 hypertension (BP >180/110 mm Hg)27 • Resistant hypertension (BP >140/90 mm Hg with three or more antihypertensive medications) • Hypertension at early age (<20 years old) • Hypertension with cerebrovascular accident at young age (<40 years old) • Hypertension with adrenal incidentaloma • Hypertension with PAL in first-degree relatives

Step 1: Case detection

Positive

Step 2: Case confirmation

Positive Suspected familial hyperaldosteronism: Needs genetic evaluation

Step 3: Subtype classification

Positive

Unilateral aldosteroneproducing adenoma

SA >16 ng/dL* PRA <0.5 ng/mL/hr* ARR >50—diagnostic*; >25—probable

FST SA >6 ng/dL + PRA <1 ng/mL/hr* SLT SA >6 ng/dL* OSLT Urinary aldosterone >24 µg/24 hr* CCT SA >16 ng/dL, PRA <0.5 ng/m/hr + ARR >50*

CT MRI AVS ACR from adrenal vein >4 ACR from peripheral vein Surgery not desired

Negative

Exclude PAL

Bilateral idiopathic hyperaldosteronism

Medical treatment

Laparoscopic adrenalectomy

* indicates diagnostic values Key: ACR = aldosterone-to-cortisone ration; ARR = aldosterone-renin ratio; AVS = adrenal vein sample; CCT = captopril challenge test; FST = fludrocortisone suppression test; JNC7 = The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; OSLT = Oral saline loading test; PAL = primary aldosteronism; PRA = plasma renin activity; SA = serum aldosterone; SLT = saline loading test. Adapted from Funder JW, Carey RM, Fardella C, et al. Case detection, diagnosis, and treatment of patients with primary aldosteronism: an Endocrine Society Clinical Practice guideline. J Clin Endocrinol Metab. 2008;93:3266-3281.

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primary aldosteronism

Table 1. Pharmacotherapy for hyperaldosteronism2,3,5 Agent

Mechanism of action

Spironolactone

Nonselective aldosterone receptor antagonist

Eplerenone

Selective aldosterone receptor antagonist; 60% of spironolactone activity

Amiloride

Potassium-sparing diuretic

be cognizant of these guidelines and determine when referral is appropriate for diagnostic procedures and treatment. n Dr. Thanavaro is associate professor of nursing and coordinator of the Adult/Gerontolocial Nurse Practitioner Program, St. Louis University School of Nursing. References

with hypertension, hypokalemia, and end-organ damage.5 Patients with IHA frequently respond to monotherapy with a mineralocorticoid receptor antagonist, although some may require amiloride (Midamor) in addition to antihypertensive medications to achieve optimal BP control.3,5 Most APAs are benign adenomas; adrenocortical cancer is rare. Because of the potential risk of malignancy, a large tumor should either be surgically removed or monitored by radiographic imaging on a yearly basis. Pharmacotherapy Medications used in the treatment of hyperaldosteronism are summarized in Table 1. They include spironolactone (Aldactone), eplerenone (Inspra), and amiloride. Surgical treatment Approximately one-third of all PAL patients have clear lateralization of aldosterone production and will benefit from unilateral adrenalectomy.3 Chronic suppression of the renin-angiotensin axis may cause transient postoperative hypoaldosteronism, and a liberal sodium diet should be allowed to prevent hypokalemia after surgery. IV infusion of 0.9% sodium chloride may be necessary to avoid postoperative fluid volume depletion.3,5

1. Conn JW. Presidential address. Part I, Painting background. Part II, Primary aldosteronism, a new clinical syndrome. J Lab Clin Med. 1955;45:3-17. 2. Funder JW, Carey RM, Fardella C, et al. Case detection, diagnosis, and treatment of patients with primary aldosteronism: an Endocrine Society Clinical Practice guideline. J Clin Endocrinol Metab. 2008;93:3266-3281. Available at jcem.endojournals.org/content/93/9/3266.long. 3. Stowasser M, Gordon RD, Rutherford JC, et al. Diagnosis and management of primary aldosteronism. J Renin Angiotensin Aldosterone Syst. 2001;2:156-169. Available at jra.sagepub.com/content/2/3/156.long. 4. Stowasser M, Sharman J, Leano R, et al. Evidence for abnormal left ventricular structure and function in normotensive individuals with familial hyperaldosteronism type I. J Clin Endocrinol Metab. 2005;90:5070-5076. Available at jcem.endojournals.org/content/90/9/5070.long. 5. Young WF Jr. Minireview: primary aldosteronism—changing concepts in diagnosis and treatment. Endocrinology. 2003;144:2208-2213. Available at endo.endojournals.org/content/144/6/2208.long. 6. Patel SM, Lingam RK, Beaconsfield TI, et al. Role of radiology in the management of primary aldosteronism. Radiographics. 2007; 27:1145-1157. Available at radiographics.rsna.org/content/27/4/1145.long. 7. Born-Frontsberg E, Reincke M, Rump LC, et al. Cardiovascular and cerebrovascular comorbidities of hypokalemic and normokalemic primary aldosteronism: results of the German Conn’s Registry. J Clin Endocrinol

Prognosis

Metab. 2009;94:1125-1130. Available at jcem.endojournals.org

Unilateral adrenalectomy results in improvement or resolution of hypertension and hypokalemia with normal serum aldosterone and PRA levels in 30% to 60% of APA patients.3,18,32-34 Hypertension usually resolves within one to six months. Persistent hypertension is more likely in older patients, those who required two or more antihypertensive medications preoperatively, and those with a longer duration of hypertension and underlying renal dysfunction.33-35 Adrenalectomy for APA is more cost-effective than longterm medical therapy.36

/content/94/4/1125.long. 8. Giacchetti G, Ronconi V, Turchi F, et al. Aldosterone as a key mediator of the cardiometabolic syndrome in primary aldosteronism: an observational study. J Hypertens. 2007;25:177-186. 9. Milliez P, Girerd X, Plouin PF, et al. Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol. 2005;45:1243-1248. 10. Muiesan ML, Salvetti M, Paini A, et al. Inappropriate left ventricular mass in patients with primary aldosteronism. Hypertension. 2008;52:529-534. Available at hyper.ahajournals.org/content/52/3/529.long. 11. Calhoun DA, Jones D, Textor S, et al. Resistant hypertension: diagnosis,

Take-home message

PAL is more common than previously recognized, and screening blood tests have increased our ability to diagnose the disorder in patients with severe or resistant hypertension. Adherence to diagnostic and treatment guidelines facilitates effective patient management. Primary-care clinicians should

evaluation, and treatment: a Scientific Statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Circulation. 2008; 117:e510-e526. Available at circ. ahajournals.org/content/117/25/e510.long. 12. Schwartz GL, Turner ST. Screening for primary aldosteronism in essential hypertension: diagnostic accuracy of the ratio of plasma aldosterone

64 the clinical advisor • june 2013 • www.ClinicalAdvisor.com

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primary aldosteronism

concentration to plasma renin activity. Clin Chem. 2005:51:386-394.

29. Espiner EA, Ross DG, Yandle TG, et al. Predicting surgically remedial pri-

Available at www.clinchem.org/content/51/2/386.long.

mary aldosteronism: role of adrenal scanning, posture testing, and adrenal

13. Calhoun DA. Is there an unrecognized epidemic of primary aldosteron-

vein sampling. J Clin Endocrinol Metab. 2003;88:3637-3644. Available at jcem.

ism? (Pro). Hypertension. 2007;50:447-453. Available at hyper.ahajournals.

endojournals.org/content/88/8/3637.long.

org/content/50/3/447.long.

30. Magill SB, Raff H, Shaker JL, et al. Comparison of adrenal vein sampling

14. Gallay BJ, Ahmad S, Xu L, et al. Screening for primary aldosteronism

and computed tomography in the differentiation of primary aldosteronism.

without discontinuing hypertensive medications: plasma aldosterone-renin

J Clin Endocrinol Metab. 2001;86:1066-1071. Available at jcem.endojournals.

ratio. Am J Kidney Dis. 2001;37:699-705.

org/content/86/3/1066.long.

15. Rossi GP, Bernini G, Caliumi C, et al. A prospective study of the preva-

31. Young WF, Stanson AW, Thompson GB, et al. Role for adrenal venous

lence of primary aldosteronism in 1,125 hypertensive patients. J Am Coll

sampling in primary aldosteronism. Surgery. 2004;136:1227-1235.

Cardiol. 2006;48:2293-2300.

32. Plouin PF, Amar L, Chatellier G. Trends in the prevalence of primary

16. Padfield PL. Primary aldosteronism, a common entity? The myth per-

aldosteronism, aldosterone-producing adenomas, and surgically correctable

sists. J Hum Hypertens. 2002;16:159-162.

aldosterone-dependent hypertension. Nephrol Dial Transplant. 2004;19:774-

17. Kaplan NM. The current epidemic of primary aldosteronism: causes and

777. Available at ndt.oxfordjournals.org/content/19/4/774.long.

consequences. J Hypertens. 2004;22:863-869.

33. Catena C, Colussi G, Nadalini E, et al. Cardiovascular outcomes in

18. Karagiannis A, Tziomalos K, Kakafika AI, et al. Medical treatment as an

patients with primary aldosteronism after treatment. Arch Intern Med.

alternative to adrenalectomy in patients with aldosterone-producing adeno-

2008;168:80-85. Available at archinte.ama-assn.org/cgi/reprint/168/1/80.

mas. Endocr Relat Cancer. 2008;15:693-700. Available at erc.endocrinology-

34. Fukudome Y, Fujii K, Arima H, et al. Discriminating factors for recurrent

journals.org/content/15/3/693.long.

hypertension in patients with primary aldosteronism after adrenalectomy.

19. Barzon L, Sonino N, Fallo F, et al. Prevalence and natural history of adre-

Hypertens Res. 2002;25:11-18.

nal incidentalomas. Eur J Endocrinol. 2003;149:273-285.

35. Lumachi F, Ermani M, Basso SM, et al. Long-term results of adrenalec-

20. Mulatero P. A new form of hereditary primary aldosteronism: familial

tomy in patients with aldosterone-producing adenomas: multivariate analy-

hyperaldosteronism type III. J Clin Endocrinol Metab. 2008;93:2972-2974.

sis of factors affecting unresolved hypertension and review of the literature.

Available at jcem.endojournals.org/content/93/8/2972.long.

Am Surg. 2005;71:864-869.

21. So A, Duffy DL, Gordon RD, et al. Familial hyperaldosteronism type II is

36. Sywak M, Pasieka JL. Long-term follow-up and cost benefit of

linked to the chromosome 7p22 region but also shows predicted heteroge-

adrenalectomy in patients with primary hyperaldosteronism. Br J Surg.

neity. J Hypertens. 2005;23:1477-1484.

2002;89:1587-1593.

22. Calhoun DA. Aldosteronism and hypertension. Clin J Am Soc Nephrol. 2006;1:1039-1045. Availaable at cjasn.asnjournals.org/content/1/5/1039.long.

All electronic documents accessed May 15, 2013.

23. Fardella CE, Mosso L, Gómez-Sánchez C, et al. Primary hyperaldosteronism in essential hypertensives: prevalence, biochemical profile, and © The New Yorker Collection 2013 from cartoonbank.com. All Rights Reserved.

molecular biology. J Clin Endocrinol Metab. 2000;85:1863-1867. Available at jcem.endojournals.org/content/85/5/1863.long. 24. Mulatero P, Stowasser M, Loh KC, et al. Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents. J Clin Endocrinol Metab. 2004;89:1045-1050. Available at jcem. endojournals.org/content/89/3/1045.long. 25. Young WF. Primary aldosteronism: renaissance of a syndrome. Clin Endocrinol (Oxf). 2007;66:607-618. 26. Thanavaro JL. Diagnosis and management of primary aldosteronism. Nurse Pract. 2011;36:12-22. 27. National Heart Lung and Blood Institute. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Available at www.nhlbi.nih.gov /guidelines/hypertension/jnc7full.pdf. 28. Mulatero P, Milan A, Fallo F, et al. Comparison of confirmatory tests for the diagnosis of primary aldosteronism. J Clin Endocrinol Metab. 2006;91: 2618-2623. Available at jcem.endojournals.org/content/91/7/2618.long.

“I consider myself bipartisan-curious.”

66 the clinical advisor • june 2013 • www.ClinicalAdvisor.com

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XARELTO® (rivaroxaban) tablets

Active Ingredient Made in Germany Finished Product Manufactured by: Janssen Ortho, LLC Gurabo, PR 00778 Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560 Licensed from: Bayer HealthCare AG 51368 Leverkusen, Germany Revised: March 2013 © Janssen Pharmaceuticals, Inc. 2011 10185206 K02X13125BBM

“You got better-looking as you got older—up to a point.”

“O.K., big cheer here, but nothing that might be construed as pressure. Quiet now, but a supportive quiet. Watch your body language.”

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adverse reactions in nursing infants from rivaroxaban, a decision should be made whether to discontinue nursing or discontinue XARELTO, taking into account the importance of the drug to the mother. Pediatric Use: Safety and effectiveness in pediatric patients have not been established. Geriatric Use: Of the total number of patients in the RECORD 1-3 clinical studies evaluating XARELTO, about 54% were 65 years and over, while about 15% were >75 years. In ROCKET AF, approximately 77% were 65 years and over and about 38% were >75 years. In the EINSTEIN DVT, PE and Extension clinical studies approximately 37% were 65 years and over and about 16% were >75 years. In clinical trials the efficacy of XARELTO in the elderly (65 years or older) was similar to that seen in patients younger than 65 years. Both thrombotic and bleeding event rates were higher in these older patients, but the risk-benefit profile was favorable in all age groups [see Clinical Pharmacology (12.3) and Clinical Studies (14) in full Prescribing Information]. Females of Reproductive Potential: Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician. Renal Impairment: In a pharmacokinetic study, compared to healthy subjects with normal creatinine clearance, rivaroxaban exposure increased by approximately 44 to 64% in subjects with renal impairment. Increases in pharmacodynamic effects were also observed [see Clinical Pharmacology (12.3) in full Prescribing Information]. Nonvalvular Atrial Fibrillation: In the ROCKET AF trial, patients with CrCl 30 to 50 mL/min were administered XARELTO 15 mg once daily resulting in serum concentrations of rivaroxaban and clinical outcomes similar to those in patients with better renal function administered XARELTO 20 mg once daily. Patients with CrCl 15 to 30 mL/min were not studied, but administration of XARELTO 15 mg once daily is also expected to result in serum concentrations of rivaroxaban similar to those in patients with normal renal function [see Dosage and Administration (2.3) in full Prescribing Information]. Treatment of DVT and/or PE, and Reduction in the Risk of Recurrence of DVT and of PE: In the EINSTEIN trials, patients with CrCl values <30 mL/min at screening were excluded from the studies. Avoid the use of XARELTO in patients with CrCl <30 mL/min. Prophylaxis of DVT Following Hip or Knee Replacement Surgery: The combined analysis of the RECORD 1-3 clinical efficacy studies did not show an increase in bleeding risk for patients with CrCl 30 to 50 mL/min and reported a possible increase in total venous thromboemboli in this population. Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 30 to 50 mL/min. Avoid the use of XARELTO in patients with CrCl <30 mL/min. Hepatic Impairment: In a pharmacokinetic study, compared to healthy subjects with normal liver function, AUC increases of 127% were observed in subjects with moderate hepatic impairment (Child-Pugh B). The safety or PK of XARELTO in patients with severe hepatic impairment (Child-Pugh C) has not been evaluated [see Clinical Pharmacology (12.3) in full Prescribing Information]. Avoid the use of XARELTO in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy. OVERDOSAGE: Overdose of XARELTO may lead to hemorrhage. Discontinue XARELTO and initiate appropriate therapy if bleeding complications associated with overdosage occur. A specific antidote for rivaroxaban is not available. Rivaroxaban systemic exposure is not further increased at single doses >50 mg due to limited absorption. The use of activated charcoal to reduce absorption in case of XARELTO overdose may be considered. Due to the high plasma protein binding, rivaroxaban is not expected to be dialyzable [see Warnings and Precautions and Clinical Pharmacology (12.3) in full Prescribing Information].

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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 june 2013

Consultations Diagnosing fatigue. . . . . . . . . . . . . . . 76 Frequency of asthma assessment. . . . . 76 Occupational cancer risks of flying . . . . . . . . . . . . . . . . . . . . . 77 Quantifying proteinuria. . . . . . . . . . . 77

Clinical Pearls Make a wish and blow out the flashlight. . . . . . . . . . . . . . . . . . 78 The solution to swimmer’s ear. . . . . . 78

Your Comments Proper technique for an intramuscular injection. . . . . . . . . . . 78

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.

Consultations Diagnosing fatigue Aside from the obvious first-visit history and screening to rule out anemia, hypothyroidism, depression, and Lyme disease, what is the most appropriate method for working up a diagnosis of fatigue?—AMY LEE HEIMINK, ANP, Marlboro, N.Y. Over the years, I have come to rely heavily on sleep pattern. Does the patient sleep enough, and of what quality is that sleep? The Epworth Sleepiness Scale is very useful in that determination. Following that assessment, workups to explore lupus, fibromyalgia, and diabetes should be conducted.—Sherril Sego, FNP-C, DNP (176-1)

Frequency of asthma assessment How often should the progress of asthma patients be assessed? At what point is it safe to consider stopping a steroid metereddose inhaler?—KATHLEEN M. ST. GERMAIN, PA-C, Springfield, Va. Asthma is a chronic condition, and optimal treatment requires a quality relationship between practitioner and patient. The four steps of asthma severity are mild intermittent, mild persistent, moderate persistent, and severe persistent. The patient must be educated about the severity of his or her condition and the pharmacologic and nonpharmacologic

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.

76 the clinical advisor • june 2013 • www.ClinicalAdvisor.com

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treatment options. Studies have shown that patients who understand the disease and treatment plan suffer fewer exacerbations and complications. Long-term control medications are recommended. Treatment options include oral corticosteroids, inhaled corticosteroids, cromolyn sodium (Intal) or nedocromil, long-acting ß2-agonists, leukotriene modifiers, and theophylline. Specific choice depends on the severity of the individual’s symptoms, his or her understanding of use and delivery methods, compliance, and a willingness to become active in disease management. All patients should keep a log of their symptoms and need for rescue medication as well as use of long-term control medications. The key is to “treat up” the asthma scale, and consider stepping down once stabilized. For example, if someone diagnosed with mild intermittent asthma develops increasing symptoms that meet the criteria for moderate persistent asthma, treatment must be adjusted to include rescue medication (short-acting bronchodilator) and daily medication (inhaled corticosteroid and either a long-acting inhaled ß2-agonist, theophylline, or long-acting oral ß2-agonist). Once the symptoms have been stabilized, the patient and the practitioner can decide to step down to treatment guidelines for mild persistent asthma, specifically rescue medication plus daily anti-inflammatory (inhaled corticosteroid, cromolyn or nedocromil, a leukotriene modifier). Eventual cessation of the inhaled corticosteroid would depend on patient response and stability. If a patient is symptom-free and not relying on rescue medication, you can attempt to wean from daily inhaled corticosteroids. The most important aspects of this plan are the constant monitoring of symptoms, communication between the patient and the practitioner, and willingness to return to daily antiinflammatory medication if the patient’s symptoms worsen.—Claire Babcock O’Connell, MPH, PA-C (176-2)

occupational cancer risks of flying I am concerned about the dangers of occupational exposure to cosmic radiation. Has any research been conducted to

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.

determine whether the incidence of various types of skin cancer is greater in people who fly for a living (e.g., pilots, flight attendants, frequent flyers, and military personnel) compared with the general public?—MARCIA C. RAY, ARNP, Milton, Fla. Epidemiologic studies of mortality and cancer incidence in pilots and flight crew have been performed (Occup Environ Med. 2003;60:805806; available at oem.bmj.com/content/60/11/805.long, accessed May 15, 2013). Pilots are at increased risk of malignant melanoma, nonmelanoma skin cancer, and possibly acute myelogenous leukemia. Flight-crew members are at increased risk for malignant melanoma and breast cancer. Cancer risk factors can be occupational exposures (longer flights at higher altitudes resulting in greater cosmic ionizing radiation dose rates, irregular working hours, and disturbance of circadian rhythm) and nonoccupational (lifestyle and reproductive history).—Philip R. Cohen, MD (176-3)

Quantifying proteinuria What is the best method to use when quantifying proteinuria in children and adults: 24-hour urine collections for total protein, random urine protein:creatinine ratio, or microalbumin:creatinine ratio?—JANET GOSHORN, ARNP-BC, Clermont, Fla. Developmental issues and severity of illness (hospitalized or outpatient) may influence your choice of test. It is possible to obtain a 24-hour urine specimen from children who are toilettrained. The same is not true of infants and young toddlers who are still in diapers (unless catheterized for 24 hours). Therefore, a spot urine protein:creatinine ratio is the measurement of choice. Microalbumin:creatinine ratio is recommended as part of routine surveillance in patients with conditions that increase the risk of kidney

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 failure (e.g., diabetes). The purpose of this measurement is to detect kidney failure as early as possible. The urine protein:creatinine ratio is a very accurate measurement for monitoring persistent proteinuria, especially if the specimen is a first-morning void. Some studies have shown the urine protein:creatinine ratio to be a better predictor of progression to renal failure than the 24-hour urine specimen.—Julee B. Waldrop, DNP (176-4)

Clinical pearls Make a wish and blow out the flashlight During physical examination of the respiratory system, it is often difficult to get young patients to take deep breaths. As a solution, hold your penlight up and pretend to gently blow it out like a candle. When you need to listen to a full breath, ask the child if he or she is able to blow out the light. Continue until all areas are auscultated.—BETH HOGAN QUIGLEY, MSN, RN, CRNP, Philadelphia, Pa. (176-5)

Your comments

“Can I borrow those kittens for an hour? I want to freak out the people who had me spayed.”

Proper technique for an intramuscular injection The Legal Advisor case that appeared in the April 2013 issue (“Swine flu crisis stirs debate”) serves as a useful reminder to always check the patient record before starting a procedure. However, the accompanying photo is a perfect example of what not to do when administering an intramuscular injection to a child. The photo shows the needle at an angle that is too low for the appropriate deltoid placement, with no support of the skin and no way to stabilize the arm. The child should be secured at the untreated arm by the parent or another staff member. The clinician giving the injection should use both hands: one to stabilize the arm, stretching the skin with fingers spread in a “V,” and the other hand injecting the vaccine. The angle of the needle should be 90° to the arm at the deltoid muscle.—ALIDA HERRERA, NP-C, Sylva, N.C. (176-7) n

The solution to swimmer’s ear Mix one part white vinegar with three parts distilled water in a one-pint jar. A drop or two of this solution in the ear canal nightly will help prevent otitis externa, or swimmer’s ear, by stabilizing the ear’s pH.—LISA MAHLER, ARNP, Wheeler, Tex. (176-6)

“Your husband’s doing well, but we’re going to need to keep him overnight because he’s funny and I’m lonely.”

78 the clinical advisor • june 2013 • www.ClinicalAdvisor.com

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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 fellow colleagues.

Itchy blisters with a sore throat A woman, aged 32 years, presents with itchy blisters over her entire body that have been present for four days. She complains she has a slight sore throat and painful lesions in her mouth. The patient reports that she has been feeling unwell for the past seven days. What is your diagnosis?

• Stevens-Johnson syndrome • Varicella • Erythema multiforme • Gianotti-Crosti syndrome

● See the full case at CliniAd.com/10VWVyT

Painful patches and plaques A woman, aged 38 years, develops skin lesions on her buttocks, thighs, and arms five days after starting a medication. Her medical history is significant for atrial fibrillation, diabetes, depression, obesity, and migraines. The patient’s current medications are listed below. Which medication is responsible?

• Naproxen • Paroxetine (Paxil, Pexeva) • Metformin (Fortamet, Glucophage, Glumetza, Riomet) • Warfarin (Coumadin, Jantoven) ● See the full case at CliniAd.com/18PY8hL

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.

Cysts on the torso and arms

Papules on the nose and cheek

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LEGAL ADVISOR CASE

A costly diagnostic mistake

By Ann W. Latner, JD

It was, as usual, a busy day in the emergency department (ED) of the medical center where Ms. P worked as a urology physician assistant. Ms. P assisted the on-call urologist and treated patients when the physician was not in. Most of Ms. P’s patients were older, so she remembered the cases that strayed from this pattern. One of these cases was Mr. E, a teenager who had presented to the ED approximately six weeks earlier complaining of blood in his urine.The urologist, Dr. B, was in that day and handled the case, but Ms. P was surprised when she saw the teenager back in the ED only a month and a half later. Before speaking with the patient, who was waiting in the examination room with his mother, Ms. P reviewed the clinical notes from his previous visit. Laboratory results revealed both hematuria and proteinuria. Dr. B had noted the diagnosis as a urinary tract infection (UTI) and prescribed antibiotics, which apparently had failed to work. The patient was now complaining of continued hematuria as well as a fever, sore throat, and right flank pain. Ms. P questioned both the patient

How should a clinician handle a difference of opinion with the attending physician on duty?

The patient returned to the emergency department, complaining that he was spitting up blood and that he had pain in his side below his ribs.

and his mother to determine whether he’d taken his antibiotic properly. Mr. E had followed the protocol correctly. After examining the teenager, Ms. P decided to call Dr. B to discuss the exam, evaluation, and treatment plan.The urologist could be irritable when he felt his personal time was being infringed on, but Ms. P thought a call was necessary. She believed that the patient should have improved greatly after taking the antibiotic, and not taken a turn for the worse. Part of her quietly questioned whether the original diagnosis of a UTI was correct. Ms. P called Dr. B, who was at a family function. The physician was brusque and clearly wanted to be off the phone. Ms. P described Mr. E’s new symptoms, and explained that the antibiotic had not helped. The urologist told her to prescribe a different antibiotic. Continues on page 82

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.

80 the clinical advisor • june 2013 • www.ClinicalAdvisor.com

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1-800-813-HOPE (4673) www.cancercare.org

5/13/08 10:05:24 AM

LEGAL ADVISOR “What about the new symptoms?” Ms. P asked. “Those are consistent with a UTI,” replied Dr. B. “Don’t worry about it.” “But is there any other possible diagnosis we should consider?” pressed Ms. P. “It’s a UTI,” said the physician. “If it doesn’t resolve, he’ll be back and we can question it then.” Ms. P hung up the phone feeling unsettled. Her instincts told her that this wasn’t a straightforward UTI. But the ED was getting busy, and Ms. P knew she couldn’t devote much more time to this case. She noted the doctor’s instructions in the chart, prescribed another antibiotic, and told the patient to come back if he didn’t feel better. Two years later, Mr. E returned to the ED, complaining that he was spitting up blood and had pain in his side below his ribs. Tests showed that his kidneys were not functioning. A renal

Don’t ignore your instincts. If something feels wrong, take the time to follow up and pursue other angles. biopsy revealed that the patient had late-stage immunoglobulin A nephropathy, a severe kidney disease that would require hemodialysis three times a week. A specialist concluded that the kidney disease had progressed too long without treatment, resulting in irreversible kidney damage. Mr. E and his mother found an attorney who encouraged them to sue the urologist and Ms. P for failing to diagnose nephritis during the two ED visits.The attorney hired a pediatric nephrologist to go over the records and act as an expert in the case.The state in which this case took place required an expert’s certification to initiate a medical malpractice suit. In his certification for the lawsuit, the nephrologist alleged that Dr. B and Ms. P had departed from the standards of practice among members of the same health professions with similar training and experience by failing to include nephritis as a differential diagnosis for the patient when he presented to the ED. Ms. P explained to her defense attorney that she had had reservations about the diagnosis at the time, but had not noted anything on the chart and had deferred to Dr. B.The attorney explained that without notes proving that she had challenged the diagnosis, they had no choice but to proceed on the basis that the presentation appeared to be a UTI. “We do have one possibilty,” said the attorney. “The expert they used to get the case certified was a nephrologist, not a urologist. Since he is not in the same field, I am going to argue that the certification is invalid.”

The attorney made a motion to dismiss, arguing that the nephrologist was not a qualified expert.The lower court agreed and dismissed the case. However, the plaintiffs appealed, and the case went to court. Legal background

The appeals court had to determine whether the lower court erred in determining that a board-certified nephrologist was not qualified as an expert to testify that a urologist and a PA violated the standard of care in treating the patient. Previous case law in the state had held that it wasn’t necessary for a certifying or testifying expert witness in a medical malpractice case to be the same kind of health-care provider as the defendant, but the expert must be in a related field. In deciding whether nephrology and urology were related, the court considered two things. First, the court looked at the definition of both fields of practice and concluded that they share a common focus on the kidneys. Next, the court looked at the circumstances of the case to determine whether nephrology and urology overlap in the context of the treatment or procedure at issue. Since the treatment in this case involved a differential diagnosis, the court questioned the expert about whether in his practice of nephrology he had participated in on-call services for EDs that required him to make differential diagnoses. The expert testified that he had, and that he often had to refer patients to other specialists, particularly urologists. The expert also testified that he had treated patients in the ED with both hematuria and proteinuria.The court ruled that the certification of the case was valid. Both Ms. P and Dr. B ended up settling out of court. The plaintiff received a sum close to the limits of their respective liability coverage. Protecting yourself

Do not ignore your instincts. If something feels wrong, take the time to follow up and pursue other angles. Ms. P could have asked another physician to take a look at the patient if she was uncomfortable with Dr. B’s diagnosis. She also could have questioned whether there could be another cause for the hematuria. Coming up with a differential diagnosis can be challenging, but it is important to look past your particular specialty when considering possible diagnoses. Had either Dr. B or Ms. P been willing to consider other alternatives to a UTI, the young man’s irreversible kidney damage might have been prevented. n Ms. Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.

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Clinical Challenge An obese woman presents with polyuria and blurred vision By Michele D. Tinge, MPAS, PA-C

A patient recently diagnosed with diabetes complains of worsening malaise and fatigue as well as bilateral extremity cramps.

After diagnosis, the patient was referred for diabetes education.

Mrs. T, aged 40 years, presented to the clinic with complaints of polyuria, polydipsia, and blurred vision, progressively worsening over a period of weeks. An obese woman with a family history of diabetes, Mrs. T underwent laboratory studies confirming fasting hyperglycemia (353 mg/dL), glucosuria, and elevated hemoglobin (Hb)A1c (10.2%). She was newly diagnosed with type 2 diabetes and started on metformin (Fortamet, Glucophage, Glumetza, Riomet) 500 mg daily and sent for a dietary consultation and diabetic education. Mrs. T was given a glucometer and told to check her blood glucose at least once a day, and to report to the office in eight days with her readings; withfurther adjustments would be made thereafter. Unfortunately, Mrs. T failed to report with her blood glucose levels, nor did she appear for a scheduled two-month follow-up visit. Three months after initial presentation, she came into the office with several more complaints. She reported progressive malaise and fatigue, bilateral upper and lower extremity cramps, nausea, abdominal pain, and headache. She denied fever and chills, but a review of systems was positive for an unintentional 50-lb weight loss over the past five months. She reported no cough, chest pain, or palpitations, but admitted to shortness of breath at rest. She had significant nausea but no vomiting and complained of early satiety and slight constipation. No dark or bloody stools were reported. Mrs. T’s abdominal pain was described as generalized achiness and cramp-like, worsening with food. She had urinary frequency, but no dysuria. She had a dull nonlocalized headache and felt offbalance and was having difficulty concentrating. Moreover, her blurry vision and polydipsia had not improved. Mrs. T stated that she took the metformin as directed and was checking her blood glucose on occasion. Her numbers, including fasting numbers, ranged from 300 mg/dL to 400 mg/dL.

CASE

Continues on page 84

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Clinical Challenge 1. Examination A physical examination revealed an ill-appearing obese woman. Mrs. T was afebrile with the following vitals: BP 152/84, pulse 72 beats per minute and regular, respiratory rate 20 breaths per minute, weight 250 lb, height 68 in (BMI 41.5). Notably, the woman’s weight was down from 308 lb, measured four months ago. Her head and neck exam was unremarkable. The ears, nose, and throat were also normal with moist mucous membranes. Mrs. T’s lungs were clear to auscultation and percussion, and no cough was apparent. A cardiovascular exam showed regular heart sounds with an intact S1 and S2 and no audible murmurs. Her abdomen was protuberant but revealed normoactive bowel sounds. She was tympanic and soft to percussion and palpation, respectively. Diffuse, nonlocalized tenderness was noted with no rebound or guarding and no fluid wave. No obvious organomegaly or mass was noted on presentation. Mrs. T’s skin had good turgor and was dry to the touch with no rash. A 1-cm abscess actively draining pus-like fluid was noted beneath her right breast. The abscess was mildly tender with surrounding erythema extending approximately 1 cm in every direction. There was no lower-extremity edema, and pulses were 2+ and symmetric. Neurologic exam revealed a lethargic woman who was oriented to person, place, and time. Despite a flat affect, Mrs. T’s judgment appeared intact. However, she had mild difficulty expressing her thoughts and completing sentences. Her gait was sluggish and mildly off-balance. Deep tendon reflexes throughout were 2+ and symmetric, and her strength of upper and lower extremities was normal and symmetric. Motor power and sensory perception were intact.

2. Laboratory Data A study of Mrs. T’s lab results requires a retrospective view of those from three months earlier, which included a basic metabolic profile (BMP), urinalysis, lipid panel, HbA1c, and urine microalbumin/creatinine ratio. Her fasting blood glucose was 353 mg/dL; blood urea nitrogen and creatinine were 7.0 mg/dL and 0.76 mg/dL, respectively. Sodium, potassium, and calcium levels were all normal. Mrs. T’s carbon dioxide reading was 19 mmol/L (reference range 20-32). Her urine showed a specific gravity of >1.030 and had 3+ glucosuria and 1+ ketonuria. A trace of protein was also found. Her fasting lipid panel expressed a total cholesterol level of 199 mg/dL, triglycerides modestly high at 154 mg/dL, HDL 37 mg/dL, and LDL above goal at

131 mg/dL. The microalbumin/creatinine ratio was normal. Her HbA1c, however, was very high at 10.2%. When Mrs. T presented to the clinic three months later, a finger-stick glucose was 386 mg/dL, which led to a BMP and complete blood count. WBC was 16.3 × 103/µL with a left shift: neutrophils 13.2 (reference range 1.63-6.96). Hemoglobin and hematocrit were 16.1 g/dL and 50.9%, respectively, and platelets were normal at 327 × 103/µL. Most remarkable was a nonfasting glucose of 403 mg/dL and bicarbonate of 6.5 mmol/L (reference range 24.4-33.0). Mrs. T’s potassium was 5.7 mmol/L, sodium 131 mmol/L, chloride 102 mmol/L (reference range 98-107), and calcium 9.0 mg/dL.

3. Discussion Diabetic ketoacidosis (DKA) and its counterpart hyperosmolar hyperglycemic state (HHS) are both severe complications of diabetes mellitus. The conditions differ in the amount of ketosis and severity of hyperglycemia but can also have some overlapping features. In general, DKA is seen more frequently in type 1 insulindependent diabetes and is a common presentation in the new onset of that condition. Typically, patients who develop DKA have higher arterial pH and lower bicarbonate levels than those who have HHS. Individuals with HHS frequently have type 2 diabetes with uncontrolled hyperglycemia, in which serum glucose measurements may reach >1,000 mg/dL. Urine and serum ketones are seen infrequently in HHS, since those patients may still have a small amount of endogenous insulin production. Urine and serum ketones are both associated with significant water deficit. DKA and HHS may be precipitated by such events as infection or inadequate insulin therapy. Compromised fluid intake is often a contributing factor, particularly in the elderly.1 HHS often develops more insidiously than does DKA, possibly over weeks rather than days. In both conditions, hyperglycemia is accompanied by polyuria, polydipsia, and weight loss. As severity increases, such neurologic symptoms as lethargy and obtundation, which can lead to coma in severe cases, can be seen. Neurologic deficits are more commonly seen in HHS due to the greater degree of hyperosmolality. Hyperventilation and abdominal pain are more commonly seen in DKA and correlate in severity with the degree of acidosis.2 Fluid depletion tends to be greater in HHS than DKA, yet fluid replacement is paramount in the treatment of both. Providers must take care not to replete fluids too rapidly so as to avoid cerebral edema associated with rapid reduction in the plasma

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The best part? IT’S FREE! So don’t wait. Download the Clinical Advisor app today to start experiencing the benefits of this essential resource at the point-of-care.

Clinical Challenge osmolality. Typically, isotonic saline is used.3 Once fluid replacement is initiated, continuous insulin infusion is the treatment of choice, with careful monitoring of potassium levels.4 In fact, potassium chloride is typically added to the replacement fluid once the serum levels fall, reflecting potassium entering the cells once again with infusion of insulin.5

4. Summary Mrs. T was admitted to the hospital intensive care unit with a diagnosis of diabetic ketoacidosis, possibly precipitated by cellulitis. She was fluid-resuscitated with normal saline and then given an insulin drip. The infection on her right breast resolved with a short course of antibiotics, and her obtundation and malaise were completely abated on discharge. Mrs. T received diabetes education, was started on longacting insulin, and on discharge was using rapid-acting insulin while counting carbohydrates. She now checks her blood glucose approximately four times a day. Mrs. T continues to be followed by an endocrinologist and hopes to begin using an insulin pump in the near future. This patient’s initial presentation as an obese woman aged 40 years with impaired fasting glucose yielded a natural tendency to diagnose her with type 2 non-insulin-dependent diabetes. However, Mrs. T’s progressive weight loss and hyperglycemia despite metformin therapy, coupled with lab data supporting an acidotic state, illustrates why the astute clinician must keep an open differential diagnosis to include type 1 diabetes. n

“By ‘lighten up’ do you mean ‘dumb down’?”

Ms. Tinge is a physician assistant at Alton Internal Medicine in Alton, Ill.

References 1. Wachtel TJ, Silliman RA, Lamberton P. Prognostic factors in the diabetic hyperosmolar state. J Am Geriatr Soc. 1987; 35:737-741. 2. Kitabchi AE, Umpierrez GE, Murphy MB, et al. Management of hyperglycemic crises in patients with diabetes. Diabetes Care. 2001; 24:131-153. Available at care.diabetesjournals.org/content/24/1/131.long. 3. Waldhäusl W, Kleinberger G, Korn A, et al. Severe hyperglycemia: effects of rehydration on endocrine derangements and blood glucose concentration. Diabetes. 1979; 28:577-584. 4. Barrett EJ, DeFronzo RA. Diabetic ketoacidosis: diagnosis and treatment. Hosp Pract (Off Ed). 1984;19:89-95. 5. Umpierrez GE, Cuervo R, Karabell A, et al. Treatment of diabetic keto acidosis with subcutaneous insulin aspart. Diabetes Care. 2004; 27:18731878. Available at care.diabetesjournals.org/content/27/8/1873.long. All electronic documents accessed May 15, 2013.

“I like my late-night humor unfunny.”

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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 103

n additional CME/CE: Pages 42, 99

Turn to page 41 for additional information on this month’s CME/CE courses.

CASE #1

Dusky bullae on the lower abdomen Sonal Parikh and Erin Reese, MD

A pregnant black woman, aged 37 years, who had a history of pre-eclampsia and pulmonary embolism and was on subcutaneous heparin, presented to labor and delivery with a tender, 4-cm, dusky, and erythematous patch on the lower abdomen. On admission, it was noted that other similar-appearing lesions continued to occur, all at sites where subcutaneous heparin had been administered. A number of these lesions later progressed to form central flaccid bullae.

What is your diagnosis? Turn to page 88

CASE #2

Painful vesicles covering the back and chest Esther Stern, NP-C

A woman, aged 69 years, presented with a very painful rash on her chest and back. The pain began two days earlier and appeared to worsen rapidly. The woman reported that she had been feeling ill, run down, and fatigued. Her only medications were prescription drugs to control her hypertension and her elevated cholesterol. Physical examination revealed numerous small vesicles and a few erosions on an inflamed erythematous base, extending from the right mid-back anteriorly to the right anterior chest and right breast.

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CME CE

CASE #1

Dermatology Clinic

Heparin-induced skin necrosis

Given the patient’s history and skin findings, a diagnosis of heparin-induced skin necrosis was rendered. The diagnosis was confirmed when discontinuation of heparin led to lack of new lesions and cessation of progression of prior lesions. Heparin-induced skin necrosis was first reported in 1973 by physician Richard O’Toole after observing what he described as a localized allergic reaction to subcutaneous heparin in four different patients whose skin lesions became progressively necrotic over time.1 This complication is uncommon but likely underreported and preferentially affects middle-aged women with a history of thromboembolic disorders.2,3 Necrotic skin changes classically appear five to 10 days following initiation of heparin therapy, administered either intravenously or subcutaneously.4,5 Individuals with prior exposure to heparin tend to develop lesions as early as three days after administration.3 While both unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) have been reported to cause this reaction, UFH is more frequently implicated.4 As this case illustrates, heparin-induced skin necrosis typically begins as a tender, small, erythematous macule that evolves into a larger, dusky, and variably necrotic patch that often features a central bulla.6 Necrosis typically develops at the site of heparin administration and preferentially occurs at sites rich in subcutaneous adipose tissue (e.g., abdomen, thighs, buttocks, and breasts).6 Although rare, there have also been reports of skin involvement at sites distant from the injection.7 There are many hypotheses regarding the pathogenesis of heparin-induced skin necrosis, whose histopathology is characterized by microvascular thrombi of dermal vessels, epidermal necrosis, and a variable inflammatory infiltrate.2,4 Some patients may develop circulating antibodies against the heparin-platelet factor 4 (PF4) complex, leading to a hypercoagulable state. In patients with heparin-induced thrombocytopenia (HIT), this antibody-antigen complex leads to platelet activation, removal of platelets from the circulation, and ultimately, thrombocytopenia. Thombotic complications may ensue.2,8 Although circulating heparin-PF4 antibodies are often detected in individuals with heparin-induced skin necrosis, these patients rarely demonstrate profound thrombocytopenia or significant activation of the coagulation cascade, which is seen in classic HIT.2,7 It remains important to evaluate patients for these

associations, however. Another theory is that deposition of immune complexes within dermal vessels leads to vasculitis, a type III (Arthus type) hypersensitivity reaction.2,9 However, biopsies of affected skin generally do not demonstrate findings of vasculitis. Others postulate that the skin findings are the result of cutaneous trauma caused by repeated, improperly performed injections, or that heparin may be poorly absorbed due to decreased vasculature in adipose tissue.2,9 Other clinical entities that can present similarly to heparininduced skin necrosis include calciphylaxis, pyoderma gangrenosum, disseminated intravascular coagulation (DIC), leukocytoclastic vasculitis, and other bullous disorders.5 Calciphylaxis causes painful, stellate ulcerations with necrotic eschar and is usually seen in the setting of end-stage renal disease in patients with abnormal calcium and phosphate metabolism. Biopsy reveals calcium deposits within vessels. Pyoderma gangrenosum is characterized by cribriform ulcerations with an undermined border. These ulcerations

Necrosis typically develops at the site of heparin administration and occurs at sites rich in subcutaneous adipose tissue. can occur in sites of trauma to the skin, known as the pathergy phenomenon. Pyoderma gangrenosum is usually seen in the setting of rheumatologic disease, inflammatory bowel disease, or hematologic malignancy. Pyoderma gangrenosum is a diagnosis of exclusion and responds to immunosuppressive therapy. DIC is seen in the setting of septic shock and can cause widespread microvascular occlusion known as purpura fulminans, wherein there are large areas of cutaneous hemorrhage and necrosis. Unlike heparin-induced skin necrosis, lab tests in patients with DIC will demonstrate significant activation of coagulation cascade with thrombocytopenia. Leukocytoclastic vasculitis is described clinically as palpable purpura and is a hypersensitivity reaction to any number of causes (e.g., medication, infection, malignancy, connective tissue disease). Histopathology is characteristic. Such other bullous diseases as pemphigus, pemphigoid, bullous erythema multiforme, and bullous fixed-drug eruption can be easily distinguished from heparin-induced skin necrosis by their biopsy findings and clinical history. Heparin-induced skin necrosis must be distinguished from delayed-type hypersensitivity (DTH) to heparin. DTH presents as an eczematous eruption with erythematous scaling

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plaques at injection sites with symptoms of pruritus; this presentation contrasts with heparin-induced skin necrosis, which has a dusky, necrotic, sometimes bullous appearance with pain being the primary symptom. Histology of DTH shows spongiosis with dermal lymphocytes, which again differs from the thrombosis seen in heparin-induced skin necrosis.6 Warfarin (Coumadin, Jantoven) can also induce skin necrosis that similarly favors sites of increased fatty tissue, primarily in women. The onset of skin findings is usually within one to 10 days after starting warfarin, and lesions are symmetric and progress from netlike dusky patches into painful ulcerations. This complication occurs in those with underlying coagulation disorders, usually protein C or S deficiency.6 Heparin-induced skin necrosis is a clinical diagnosis; however, histology can assist in confirming the diagnosis and in distinguishing this from the other entities discussed. Histology of the lesion characteristically demonstrates inflammation with epidermal necrosis as well as microvascular thrombi in the dermal vessels, usually in the absence of vasculitis.2 Management involves early recognition of the condition and the discontinuation of all heparin products. Continued use of such products can lead to exacerbation of the skin lesions and possible systemic thrombotic complications.3 If heparinPF4 antibodies are present (as is the case in most instances of heparin-induced skin necrosis), it is important to exclude a diagnosis of HIT by checking the patient’s platelet count. If thrombocytopenia is present, the alternative anticoagulant must not be a heparin product. In other words, switching from LMWH to UFH will still be problematic. It is also reasonable to check for other markers of abnormal coagulation, although these parameters are generally normal.2 Alternative options for patients still requiring anticoagulation include such nonheparin preparations as danaparoid (Orgaran), fondaparinux (Arixtra), and hirudins.6 Warfarin therapy can be initiated, but be mindful of the delay in its anticoagulatory effect.2 Once the offending heparin agent is discontinued, the clinical course of the necrosis is typically uneventful. Some patients may require surgical debridement of the lesion and, rarely, reconstructive surgery with a skin graft. If the skin necrosis is a manifestation of HIT, systemic complications, including venous and arterial thrombosis, may occur and can lead to fatal outcomes.9 However, those thrombotic complications tend to occur with thrombocytopenia, which is not typically seen in individuals with heparin-induced skin necrosis.9 The patient in this case had a positive heparin-PF4 antibody but a normal platelet count. The woman’s coagulation workup was notable for protein-S deficiency. Her heparin was discontinued in favor of fondaparinux, with a plan to transition

to warfarin. Her skin was managed with simple wound care, and she healed uneventfully. Ms. Parikh is a third-year medical student at Virginia Commonwealth University, in Richmond, where Dr. Reese is an assistant professor of dermatology. References 1. O’Toole RD. Letter: Heparin: adverse reaction. Ann Intern Med. 1973;79:759. 2. Handschin AE, Trentz O, Kock HJ, Wanner GA. Low molecular weight heparin-induced skin necrosis—a systematic review. Langenbecks Arch Surg. 2005;390:249-254. 3. Drew PJ, Smith MJ, Milling MA. Heparin-induced skin necrosis and low molecular weight heparins. Ann R Coll Surg Engl. 1999;81:266-269. Available at www.ncbi.nlm.nih.gov/pmc/articles/pmid/10615196/. 4. Jörg I, Fenyvesi T, Harenberg J. Anticoagulant-related skin reactions. Expert Opin Drug Saf. 2002;1:287-294. 5. Khan Z, Watson DK. Heparin-induced skin necrosis. BJOG. 2000;107:1315-1316. 6. Trautmann A, Seitz CS. The complex clinical picture of side effects to anticoagulation. Med Clin North Am. 2010;94:821-834. 7. Bilen O, Teruya J. Complications of anticoagulation. Dis Mon. 2012;58: 440-447. 8. Girolami B, Girolami A. Heparin-induced thrombocytopenia: a review. Semin Thromb Hemost. 2006;32:803-809. 9. Wütschert R, Piletta P, Bounameaux H. Adverse skin reactions to low molecular weight heparins: frequency, management and prevention. Drug Saf. 1999;20:515-525. All electronic documents accessed May 15, 2013.

CASE #2

Shingles

After a chickenpox infection or shingles vaccination, the varicella zoster virus (VZV) remains dormant in the sensory nerves, establishing lifelong latent infection. A reactivation of this virus causes a painful rash in the dermatome innervated by the corresponding sensory ganglion. In the United States, almost 100% of adults are seropositive for anti-VZV antibodies after age 30 years,1 and thus are at risk for shingles, also known as herpes zoster.

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CME CE

Dermatology Clinic

Shingles may occur at any age but are most common in the senior population. Adults younger than age of 45 years have a risk of one in 1,000 of developing shingles; seniors have a risk at least four times that rate.2 This increased risk is likely a result of declining immunity with advancing age. Women have a slightly higher incidence of shingles than do men, and blacks have a lower risk of developing zoster than do whites. After advanced age, the next largest risk factor is immunosuppression, whether as a result of malignancy, infection, or medications. Pregnant women and premature infants should be considered at high risk for infection and more severe disease. Shingles presents as a unilateral rash that affects only one or two dermatomes. The thoracic, cranial, and lumbar dermatomes are the most frequently affected. Many individuals with shingles describe feeling pain in the affected area prior to the appearance of the rash. Other prodromal symptoms include tenderness, paresthesia, and local temperature disturbances. These symptoms usually are attributed to other conditions. The rash of herpes zoster rapidly appears within a day or two of the onset of pain. The rash may initially present with papules on a base of erythema; however, these papules quickly develop into weeping vesicles that may appear pustular at times. Some lesions may appear necrotic or hemorrhagic. After three to five days, crust formation occurs. In the mildest cases of shingles, only several lesions may be visible, and patients may not even be aware of the presence of the rash. In the more severe form, the rash may occur on the entire dermatome and even extend to the neighboring dermatomes. Other physical exam findings may include local lymphadenopathy and sensory or motor nerve changes. The shingles rash usually resolves spontaneously, with the duration being determined by age and immune status. Younger patients may heal in two to three weeks, and elderly patients or those with more severe disease may require six or more weeks to recover. Scarring is dependent on lesion severity. Bacterial superinfection, although uncommon, should be considered in persisting skin lesions. Zoster affecting the face requires very careful attention. In cases of eye or nose involvement, immediate treatment is prudent to prevent complications. Hutchinson’s sign refers to the presence of a vesicle or other zoster lesion on the tip of the nose, which almost always indicates ocular involvement and the need for immediate ophthalmology referral. The major morbidity associated with shingles is postherpetic neuralgia (PHN), which is defined as chronic pain persisting weeks, months, or even years after the lesions have healed. Since PHN is often associated with depression, all

patients with persisting symptoms should be given careful consideration and appropriate treatment. Diagnosis of herpes zoster is usually made clinically, and prompt assessment is essential. A Tzanck smear or direct fluorescent antibody staining can aid in the diagnosis. The differential diagnoses to consider include acute contact dermatitis with vesiculation (e.g., a phytoallergic response), bullous impetigo, insect bites, necrotizing fasciitis, and erysipelas. If the diagnosis is made less than 72 hours after the onset of symptoms, antiviral systemic therapy should be started to accelerate wound healing, decrease acute pain, and possibly minime the risk of PHN. Acyclovir (Zovirax) 800 mg orally four times a day for seven to 10 days is often the first line of treatment. Supportive treatment may include bed rest, application of a moist dressing to the involved dermatome, and nonsteroidal anti-inflammatory drugs. Consider narcotic analgesics to achieve early control of pain, if appropriate. The use of oral prednisone has not been shown to reduce the risk of PHN. Ophthalmic zoster has the highest incidence of PHN, and IV antiviral agents may be indicated in those situations. Significant immunosuppression and disseminated infection are other indications for IV treatment and hospitalization. The CDC reported an annual incidence of 96 deaths caused by herpes zoster, almost all of which occurred in elderly people and those with compromised immune systems.3 The treatment for PHN includes the use of pregabalin (Lyrica), gabapentin (Horizant, Neurontin), and tricyclic antidepressants. Topical capsaicin or topical anesthetics may be appropriate for more minor and localized symptoms. The patient in this case was treated with oral famciclovir (Famvir) and educated regarding the disease process as well as risk of transmission to nonimmune children and adults. Five days later, she reported feeling significantly better, and her rash was noted to have a dramatic decrease in erythema and had progressed to crusting. n Ms. Stern is a family nurse practitioner at Advanced Dermatology & Skin Surgery, P.C., in Lakewood, N.J. References 1. Fitzpatrick TB, Johnson RA, Wolff K, Suurmond R, eds. Color Atlas and Synopsis of Clinical Dermatology, 6th ed. New York, N.Y.: McGraw-Hill; 2009:837. 2. James WD, Berger TG, Elston DM. Andrews’ Diseases of the Skin: Clinical Dermatology. 11th ed. Philadelphia, Pa.: Saunders-Elsevier; 2011:379. 3. Mahamud A, Marin M, Nickell SP, et al. Herpes zoster-related deaths in the United States: validity of death certificates and mortality rates, 19792007. Clin Infect Dis. 2012;55:960-966.

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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.

Salt

Sodium chloride (NaCl), more commonly known as salt, is found in abundance in nature and is without a doubt the most frequently used condiment around the globe. Its use as a seasoning, as a preservative, and for medicinal purposes has been documented in almost every civilization. Salt is an essential part of daily life, and this is reflected in several language derivations. In fact, the word “salary,” which comes from the Latin “salarium,” denotes money that was paid to Roman soldiers so they could buy salt rations.1 Likewise, the Austrian city of Salzburg literally translates as the “salt fortress” and derives its name from the barges carrying salt on the Salzach river.1 Background Regular consumption of salt is necessary for proper functioning of the nervous system, as well as for the regulation of water balance in cells.2 Salt is found in a variety of forms. Sea salt is so abundant that there has been no scientific discussion of reserves.3 Other salt deposits are scattered around the world in areas thought to have once been ancient oceans that evaporated, leaving large salt deposits. The total world production of salt is estimated to be 290 million tons, with the United States being the largest producer at more than 44 million tons.3 In folk medicine, warm saltwater gargles for sore throats and salt poultices for soft-tissue infections are two of many commonly used salt therapies.4

Science The majority of clinical trials researching the efficacy of salt therapy target respiratory conditions. Therapeutic methods

range from spending time in a natural salt caveto breathing aerosolized hypertonic salt water. In the respiratory tract, salt’s mechanism of action is multifaceted. Because salt particles are smaller than most particulate matter in the air, they can be inhaled deeper into the airways. Once in the respiratory tract, salt triggers a cascade of therapeutic events. Salt acts as a mucolytic, allowing natural ciliary action to improve: it decreases bronchial edema; it is an antimicrobial; and, due to these properties as well as an anti-inflammatory action, salt suppresses bronchial hyperreactivity.5 Aerosolized hypertonic saline has been studied as a treatment for cystic fibrosis. Researchers randomized 24 cystic fibrosis patients to receive either nebulized hypertonic saline (5 ml of 7% NaCl) four times a day with or without pretreatment with amiloride (Midamor), a mild diuretic. Treatments were continued for two weeks with pulmonary function and mucus clearance measured at baseline and periodically during therapy. At the end of the trial, the study group that used only nebulized saline showed a twofold improvement in both

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alternative meds update depending on the concentration and purity, cost $30 to $100 for a one-month supply.

Summary Data show that the various forms of salt therapy are safe and effictive. However, many conditions require more than one type of therapy or medication. Consider salt therapy for patients with psoriasis in particular, as this treatment has shown significant efficacy in reducing sympto matic lesions. n Sea-salt baths are effective in treating psoriatic lesions (shown).

Excessive salt consumption has been deemed potentially dangerous, but no warnings were found for topical applications.

Safety

References 1. Salt Institute. References on salt in history. Available at www. saltinstitute.org/Articles-references/References-on-salt-use/ References-on-salt-use/References-on-salt-in-history. 2. Huang AL, Chen X, Hoon MA, et al.The cells and logic for mammalian sour taste detection. Nature. 2006;442:934-938. 3. U.S. Geological Survey. Mineral Commodity Summaries 2012. Available at minerals.usgs.gov/minerals/pubs/mcs/2012/ mcs2012.pdf. 4. Gunn JC. Gunn’s New Family Physician. 100th ed. Cincinnati, Ohio: Moore, Wilstach & Moore;1869:302. 5. Chervinskaya AV, Zilber NA. Halotherapy for treatment of respiratory diseases. J Aerosol Med. 1995;8:221-232. 6. Chervinskaya A. Halotherapy in controlled salt chamber microclimate for recovering medicine. Alergologia Info. 2011;6:24-32. 7. Donaldson SH, Bennett WD, Zeman KL, Knowles MR,Tarran R, Boucher RC. Mucus clearance and lung function in cystic fibrosis with hypertonic saline. N Engl JMed. 2006 ;354:241-250. 8. Oprita B, Pandrea C, Dinu B, Aignatoaie B. Saltmed—The therapy with sodium chloride dry aerosols. Thera Pharmacol Clin Tox. 2010;14:201-204. 9. Klein A, Schiffner R, Schiffner-Rohe J, et al. A randomized clinical trial in psoriasis: synchronous balneophototherapy with bathing in Dead Sea salt solution plus narrowband UVB vs.

Although excessive salt consumption has been deemed potentially dangerous—especially for cardiovascular, renal, or endocrine conditions—no warnings were found for topical applications.10,11

Cost, how supplied

narrowband UVB alone (TOMESA-study group). J Eur Acad Dermatol Venereol. 2011;25:570-578. 10. Portugal-Cohen M, Oran M, Merrik E, et al. A Dead Sea water-enriched body cream improves skin severity scores in children with atopic dermatitis. J Cosmetics Dermatol Sci Appl. 2011;1:71-78. 11. Health.gov. Dietary guidelines for Americans. Available at

Ionic salt generators, used in inhalation therapy, cost anywhere from $50 to several hundred dollars.Topical salt products are widely available and,

www.health.gov/DietaryGuidelines. All electronic documents accessed May 15, 2013.

immediate and sustained mucus clearance, and nearly a 7% improvement in pulmonary function (as measured by forced expiratory volume in one second [FEV1]). The hypothesis for the dramatic difference in the two groups was that by allowing the natural water-retaining action of the salt to function uninhibited by diuresis, the mucolytic action was much more effective.6 A study of the effect of dry salt aerosol on lung function focused on 393 patients with severe obstructive pulmonary disease. Participants were assigned to traditional therapy (aimed at bronchodilatation) alone or to traditional therapy coupled with aerosol salt therapy.After one hour, the patients receiving dual therapy showed an increase of 6.5% in oxygen saturation levels and a 26% reduction in respiratory rate compared with only 3% and 19%, respectively, in the standard-therapy group.7 Dermatology is another emerging area for salt therapy.About 2% to 3% of the world’s population is afflicted with psoriasis. In a phase 3 trial, researchers randomized 367 psoriaris patients to either traditional ultraviolet light therapy (UVT) alone or UVT and bathing in a Dead Sea hypertonic salt solution.After 35 treatments, the combination group showed a 46% greater symptom improvement than the UVT-only group.8 Salt also may relieve atopic dermatitis in children with severe disease. Researchers compared topical therapies of traditional emollient cream with therapies utilizing cream enriched with Dead Sea salts. Eighty-six children were randomized, and at the end of 12 weeks, participants receiving the Dead Sea salt-enriched cream showed significant improvement in all symptom areas.9

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Stat Consult

A quick review of common conditions, using the best global evidence

Description

• Effect of sudden reduction or cessation of alcohol intake after heavy or prolonged a lcohol use

Alcohol withdrawal

ICD-9 codes

by Alan Drabkin, MD

Dr. Drabkin is a clinical editor for DynaMed (www.ebscohost.com/ dynamed), a database of comprehensive updated summaries c overing more than 3,200 clinical topics, and Assistant Clinical Professor of Population Medicine at Harvard Medical School.

• 291 alcoholic psychoses ——291.0 alcohol withdrawal delirium ——291.1 alcohol amnestic syndrome ——291.2 other alcoholic dementia ——291.3 alcohol withdrawal hallucinosis ——291.8 other specified alcoholic psychosis ■■ 291.81 alcohol withdrawal ■■ 291.82 alcohol induced sleep disorders ■■ 291.89 other alcoholic psychosis ——291.9 unspecified alcoholic psychosis Who is most affected

• Those consuming more than four to five drinks per day, especially for longer than one month Causes

• Sudden reduction or cessation of alcohol intake after prolonged consumption Pathogenesis

• Increased autonomic central nervous system (CNS) activity Complications

• 5%-15% mortality with delirium tremens (DTs) • Chronic auditory hallucinations • Acute myopathy • Wernicke-Korsakoff syndrome • Alcoholic ketoacidosis Associated conditions Delirium tremens, commonly known as “the shakes,” is indicative of alcohol withdrawal.

• Acute medical complications of alcoholism • Other illicit drug use and withdrawal • Depression and other psychiatric disorders Chief concern

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Stat Consult a gitation, anorexia, nausea, vomiting, tension, anxiety, sweating, restlessness ——Hallucinations (usually visual), disorientation, low-grade fever ——Seizures Progression of withdrawal symptoms after stopping alcohol

• Minor withdrawal symptoms—stage 1 (six to 12 hours) • Alcoholic hallucinosis—stage 2 (12-24 hours) • Withdrawal seizures—stage 3 (24-48 hours) • DTs—stage 4 (3-7 days; can occur up to 14 days) Social history

• Ask about other substance use or concurrent medical/ psychiatric conditions

• Alcohol withdrawal delirium ——Altered consciousness ——Altered cognition or development of perceptual disturbance not likely due to dementia ——Rapid development with fluctuation in severity ——Symptoms developed during or shortly after withdrawal. Rule out

• Thyrotoxicosis • Anticholinergic drug poisoning • Amphetamine abuse • Cocaine abuse • CNS infection or hemorrhage • Withdrawal from ——Benzodiazepines ——Opiate • Other causes of seizures

General physical

• Hyperventilation • Tachycardia • Hypertension • Hyperthermia • Tremor, irritability, agitation, sweating • Concurrent medical conditions • Signs of chronic alcoholism Signs of Wernicke-Korsakoff syndrome

• Abnormal ocular motility • Drooping eyelid • Confusion • Ataxia Making the diagnosis

• Alcohol withdrawal syndrome ——Stopping/decreasing heavy and prolonged alcohol use in patients ——Two or more of the following within hours or days of stopping or decreasing alcohol use ■■ Autonomic hyperactivity (sweating, tachycardia) ■■ Increased hand tremor ■■ Difficulty sleeping ■■ Nausea or vomiting ■■ Hallucinations ■■ Psychomotor agitation ■■ Anxiety ■■ Seizures (tonic-clonic) ——Significant distress or impairment ——Symptoms not caused by medical disorder

Testing to consider

• Blood alcohol • Urine drug screen • Folate, thiamine • Serum electrolytes • Complete blood count • Liver tests (AST/ALT/GGT/AlkPhos/serum bilirubin and albumin) • PT/PTT/INR • Tests for bacterial infections • Neuroimaging Specific blood tests

• Findings in alcohol induced liver disease ——Elevated AST <300 units/mL ——AST/ALT ratio >2 ——GGT/AlkPhos ratio >2.5 ——Serum bilirubin >5 mg/dL ——INR elevated • Biochemical markers not reliable • Magnesium and phosphorus deficiencies common Diet

• Nutritional supplementation if necessary Treatment setting

• Outpatient treatment possible for most patients • Consider inpatient care if ——History of ■■ Severe withdrawal symptoms

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Stat Consult Withdrawal seizures or DTs Multiple prior detoxifications ——Psychiatric or medical illness ——Recent very high alcohol consumption ——Pregnancy ——Absent reliable support network ■■ ■■

Medications

• General considerations ——Correct hydration status ——Give 100 mg thiamine to patient intramuscularly/ intravenously/orally before glucose load (to avoid Wernicke encephalopathy). ——Give multivitamins daily. ——Drug treatment if Clinical Institute Withdrawal Assessment for Alcohol scale (CIWA-Ar) score >8 • Benzodiazepines ——May reduce alcohol withdrawal symptoms, seizures and recurrent seizures ——Lorazepam (Ativan) or oxazepam (Serax) not dependent on liver metabolism ——Lorazepam appears as effective as diazepam (Valium, Valrelease) and chlordiazepoxide for reducing alcohol withdrawal symptoms. ——Inpatient dosing options for prevention of DTs ■■ Fixed-schedule »»Lorazepam 2 mg orally every six hours for four doses, then 1 mg orally every six hours for eight doses »»Chlordiazepoxide 50 mg orally every six hours for four doses, then 25 mg orally every six hours for eight doses »»Diazepam 10 mg orally every six hours for four doses, then 5 mg orally every six hours for eight doses »»Additional medication if CIWA-Ar >8-10 ■■ Symptom-triggered regimens when CIWA-Ar≥ 8-10 »»Chlordiazepoxide 50-100 mg orally every hour »»Diazepam 10-20 mg orally every hour »»Lorazepam 2-4 mg orally every hour »»Assess with CIWA-Ar one hour after every dose ■■ Outpatient dosing options if CIWA-Ar scores >8 »»Lorazepam 2-4 mg orally every six hours for four doses, then 1-2 mg orally every six hours for eight doses »»Chlordiazepoxide 50-100 mg orally every six hours for four doses, then 25-50 mg orally every six hours for eight doses »»Diazepam 10-20 mg orally every six hours for

four doses, then 5-10 mg orally every six hours for eight doses • Anticonvulsants ——Insufficient evidence for reducing alcohol withdrawal seizures ——Carbamazepine and gabapentin (Horizant, Neurontin) appear at least as effective as lorazepam for reducing alcohol withdrawal symptoms. ——Pregabalin (Lyrica), lorazepam, and tiapride appear similarly effective for preventing withdrawal symptoms. ——Potential dosing regimens ■■ Carbamazepine 200 mg four times daily on day 1, tapering to zero over five days ■■ Phenobarbital (Donnatal) 60-120 mg four times daily on day 1, tapering to zero over five days ——Phenytoin (Dilantin, Phenytek) not recommended for treatment of alcohol withdrawal • Gamma-hydroxybutyrate (GHB) (sodium oxybate) ——GHB 50 mg/kg/day might reduce alcohol withdrawal symptoms and help maintain abstinence. • Other medications ——Evidence comparing different drug classes for reducing seizures is limited; significant evidence only supportive for benzodiazepines. ——Beta blockers and clonidine not recommended as monotherapy. ——If used alone, neuroleptics may increase mortality and duration of delirium. ——Baclofen and diazepam appear similarly effective. Prognosis

• Tremors and hallucinations subside in hours to days • 5%-15% mortality for untreated DTs • Admission blood alcohol level >0.15 g/dL associated with more severe withdrawal • CIWA-Ar ——Score ranges from 0-67 ——Clinical action based on score ■■ <10—no treatment ■■ 10-20—follow-up assessment soon ■■ >20—start treatment or increase dosage • Older patients are at increased risk for cognitive and functional impairment during withdrawal. Screening

• Alcohol Use Disorders Identification Test (AUDIT) screen identifies hospital patients who develop clinically significant alcohol withdrawal symptoms. n

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CME CE

Dermatologic Look-Alikes n Learning objective: To distinguish and properly treat dermatologic conditions with similar presentations. n complete the posttest: Page 103

n additional CME/CE: Pages 42, 87

Turn to page 41 for additional information on this month’s CME/CE courses.

Erythematous plaques on the trunk Kerri Robbins, MD

CASE #1

CASE #2

A woman, aged 41 years, complained of a rash on her right posterior axilla. The lesion was associated with a mild burning sensation, but no pruritus or pain was reported. The woman had been hiking while on vacation in Connecticut two weeks earlier. A few days after the hike, her husband removed a tick attached to her right axilla. The eruption developed the following week. She had no systemic complaints. Physical examination revealed an erythematous annular plaque that had a bull’s-eye appearance.

A man, aged 36 years, presented with a rash on his left flank and abdomen. The rash began three months earlier as an erythematous plaque that seemed to be enlarging. Most recently, the man noticed new enlarging lesions on the left abdomen. There was no associated pain or pruritus. No prior treatment had been initiated. Review of systems was otherwise negative. On physical examination, erythematous, slightly edematous, indurated plaques with a peripheral lilac border in some areas were appreciated on the left flank and abdomen.

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CME CE

CASE #1

Dermatologic Look-Alikes

Lyme disease

In the 1970s, a physician named Steere was asked to investigate an outbreak described as a pediatric type of arthritis preceded by erythema migrans. The outbreak happened around Lyme, Conn., and thus Lyme disease was recognized. In the 1980s, Burgdorferi isolated a new spirochete from erythema migrans that became known as Borrelia burgdorferi. Soon thereafter, it was found that B. burgdorferi was transmitted by such various species of Ixodes ticks as I. scapularis, I. pacificus, and I. ricinus. Lyme disease has a global distribution, and infection occurs most often between May and November, with a peak incidence in June and July. In the United States, cases are most often seen in the Northeast, Midwest, and certain areas of the West Coast. The 10 most affected states are Connecticut, Delaware, Maryland, Massachusetts, Minnesota, New Jersey, New York, Pennsylvania, Rhode Island, and Wisconsin.1 At least 20,000 cases of Lyme disease occur each year in the United States; however, due to underreporting and misdiagnosis, the actual number may be as high as 60,000 to 100,000.

The early localized disease occurs three to 32 days after the tick bite and is characterized by erythema migrans. The natural hosts for Ixodes ticks are white-footed mice and white-tailed deer. I. scapularis is the principal vector for cases seen in the northeastern and central United States and in Canada. I. pacificus, as the name implies, is seen more commonly on the Pacific coast. Not all individuals who have been bitten by an Ixodes tick or who have positive serologic tests for B. burgdorferi develop Lyme disease. The risk of contracting acute Lyme borreliosis in areas endemic for the disease has been estimated to be only 1% of those who are bitten by the tick,2 perhaps owing to the fact that the tick must be attached for at least 24 hours. After an Ixodes tick bite, the Borrelia organisms enter the body, and spirochetal lipoproteins trigger an innate immune

response. Type 1 helper T-cells respond to the invader by activating the adaptive immune system, causing T-cells and B-cells to facilitate the synthesis of autoantibodies to different antigens presented by B. burgdorferi. The pathogen counterstrikes by resisting macrophage elimination and disseminating throughout the body. The organism attaches itself to areas the human immune system will not strike, such as brain and epithelial cells. It also uses intracellular junctions to penetrate into the cytoplasm and induce production of tumor necrosis factor-α. The early localized disease occurs three to 32 days (median seven days) after the tick bite and is characterized by erythema migrans, an annular erythematous plaque that spreads centrifugally. The center of the plaque may be a lighter color or have a bull’s-eye appearance, and the overall diameter is usually >5 cm. The lesion favors the trunk, popliteal fossa, axilla, and groin. Some patients may complain of a burning sensation, but rarely is it pruritic or painful. If left untreated, the lesion usually lasts less than six weeks. In approximately 25% of patients, multiple lesions may be present due to multiple tick bites or disseminated disease. Disseminated lesions are often less pronounced and smaller in size and usually appear days to weeks after the initial erythema migrans.3 Influenza-like symptoms may be seen. Approximately 60% of the patients with erythema migrans who are not treated will develop arthritis, 10% will develop a neurologic complication, and 5% will develop a cardiac manifestation.4 Acrodermatitis chronica atrophicans is another indicator of late-stage Lyme borreliosis and is mainly seen in Europe. Histologic examination is often nonspecific. Most cases demonstrate a superficial and deep perivascular and interstitial infiltrate of lymphocytes, plasma cells, and eosinophils. With the help of a Warthin-Starry stain, spirochetes may be seen in the upper dermis. Erythema migrans may be misdiagnosed as an arthropod assault, erysipelas, cellulitis, urticaria, allergic contact dermatitis, morphea, sarcoidosis, borderline or tuberculoid leprosy, nonpigmented fixed drug eruption, erythema multiforme, erythema annulare centrifugum, tumid lupus erythematosus, granuloma annulare, tinea corporis, syphilis, pityriasis rosea, psoriasis, or erythema gyratum repens. To properly distinguish between Lyme disease and other entities, attempt to isolate B. burgdorferi from tissue or fluids. Culture and polymerase chain reaction analysis are specific but not sensitive and not available in most areas. The more commonly employed detection method is confirmation of anti-Borrelia antibodies via enzyme-linked immunosorbent

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assay followed by Western blotting. It should be noted that the Western blot method has a high false-negative rate because the peak immunoglobulin M response occurs three to six weeks after the infection, and most patients present prior to this time. Such preventive measures as personal avoidance strategies and inspecting for ticks after returning from outdoor activities are worthwhile in tick-infested areas. The treatment of choice for adults and children aged 8 years or older is doxycycline 100 mg by mouth b.i.d. for 14 to 21 days. Amoxicillin 500 mg (or cefuroxime [Ceftin] 500 mg) by mouth b.i.d. for 14 to 21 days is an alternative treatment for pregnant women and children younger than age 8 years. Although treatment is not recommended for all tick bites, a single 200-mg dose of doxycycline taken within 72 hours of an I. scapularis tick bite is effective at preventing the development of Lyme borreliosis.5 Lyme disease is rarely fatal, and prognosis is excellent with proper treatment. However, it is very important to follow patients to make sure treatment is successful and that no further sequelae of the disease develop. The patient in this case was treated with doxycycline 100 mg by mouth b.i.d. for 21 days. No signs of disease sequelae were noted on her follow-up visit.

CASE #2

Morphea

This patient was diagnosed with morphea, also known as localized scleroderma. Scleroderma is an inflammatory condition of the dermis and subcutaneous fat that is ultimately characterized by diffuse, hard, smooth, and immobile scarlike plaques. There are both cutaneous and systemic types of scleroderma. Cutaneous types are usually asymmetric with a patchy or linear distribution and do not involve internal organs. These types include localized morphea, morphealichen sclerosus et atrophicus overlap, generalized morphea, atrophoderma of Pasini and Pierini, pansclerotic morphea, morphea profunda, nodular or keloid morphea, and linear scleroderma. Systemic types of scleroderma begin as symmetric digital sclerosis that extends proximally toward the trunk. They are usually associated with Raynaud’s phenomenon, and

there is involvement of internal organs. Systemic scleroderma includes CREST syndrome and progressive systemic sclerosis. The term scleroderma is derived from the Greek words skleros, meaning hard, and derma, meaning skin. The history of morphea dates back to 400 b.c., when Hippocrates first described a condition with thickening of the skin. A survey conducted in Olmstead County, Minn., is believed to be one of the most extensive population-based studies of morphea.6 This study showed an incidence of 27 per million people and a prevalence that increases with age. The disease favors women over men by a ratio of 2.6 to 1, with the exception of linear morphea, which does not demonstrate gender preference. The exact pathogenesis of morphea remains unknown. However, sclerosis of the skin is thought to involve three major components: (1) vascular damage; (2) activated T-cells (which produce interleukin 4 and transforming growth factor-β); and (3) altered connective tissue production by fibroblasts. An increased prevalence of certain autoantibodies has also been demonstrated, including single-strand DNA (more often in linear morphea), antifibrillin 1, antiphospholipid, antihistone, antitopoisomerase IIα, and antinuclear antibody (more common in juvenile linear morphea or adult generalized morphea). Unfortunately, the trigger for sclerosis remains unknown. It is hypothesized that local triggers in the skin may cause morphea, whereas generalized trauma may lead to systemic sclerosis. One intensively investigated trigger was B. burgdorferi, the pathogen responsible for Lyme disease and erythema migrans. Researchers focused on B. burgdorferi as a triggering agent because the progression of the erythematous plaque in morphea and erythema migrans is similar, and some cases of morphea had improved following administration of penicillin. Originally, studies isolated B. burgdorferi from the urine and/or skin of some patients with morphea, and messenger RNA specific for Borrelia was appreciated in several.7,8 However, larger subsequent studies have shown no such correlation.9 This article focuses on the clinical features of plaque-type morphea, the most common variant. Lesions begin as erythematous edematous plaques that become sclerotic and expand centrifugally to a diameter of approximately 2 cm to 15 cm. Active lesions have a lilac border, whereas inactive lesions become hyperpigmented. Hair follicles and sweat glands are frequently lost. Patients may complain of pruritus; however, this is more likely a result of the overlying xerosis rather than being a true manifestation of morphea. Lesions, usually located on the trunk, can be multiple and asymmetric and may enlarge significantly or remain stable in size. Continues on page 102

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CME CE

Dermatologic Look-Alikes

On low-power microscopic examination, thickening of the dermis will give the specimen a squared-off appearance. In the acute phase, a perivascular lymphocytic infiltrate with plasma cells is appreciated most prominently at the junction of the dermis and subcutaneous fat. In later stages, the collagen is thickened, and inflammation may be minimal. The thickened collagen bundles eventually replace the subcutaneous tissue, causing the eccrine glands to appear trapped within the mid-portion of the thickened dermis. At this stage, pilosebaceous units are usually absent. The differential diagnosis of morpheaform skin lesions includes graft-versus-host disease, lipodermatosclerosis, sclerosis at injection sites, radiation-induced morphea, chemical/ toxin exposures, porphyria, Winchester syndrome, eosinophilia-myalgia syndrome, eosinophilic fasciitis, congenital fascial dystrophy, progeria, scleredema, scleromyxedema, and keloids/hypertrophic scars. Although inflammatory morphea and erythema migrans may appear to be similar at first, the lesions of erythema migrans are not indurated and often have a lighter-colored center. Most important, morphea should be differentiated from systemic sclerosis. This can be accomplished by appreciating digital sclerosis, Raynaud’s phenomenon, and internal organ involvement in the latter. Ultrapotent topical steroids may reduce the inflammation of superficial morphea, and injection of triamcinolone into the active margins of morphea may halt progression. Other topical therapies that have been successful in the treatment of limited superficial inflammatory lesions include calcipotriene (Dovonex, Sorilux) and tacrolimus (Prograf ).10 It should be noted that these are off-label uses of the medications. Phototherapy with bath psoralen plus UVA or UVA1 therapy seems promising and has been shown to improve widespread deep morphea in approximately two-thirds of patients.10,11 Narrowband UVB may be appropriate for widespread superficial dermal plaques.10 For rapidly progressing disease, some have advocated weekly methotrexate (Rheumatrex, Trexall) combined with pulsed, high-dose corticosteroids.10,12 Other systemic therapies with limited evidence include treatment with penicillin and vitamin A derivatives. Physical therapy may be needed to prevent impaired mobility, and reconstructive surgery can help to alleviate persistent contractures. Plaque-type morphea is a relatively harmless disease that usually progresses over the course of three to five years and then regresses slowly over a period of years. Some patients may develop disfigurement, contractures, or growth retardation depending on the affected area. Prompt treatment can help to avoid these complications.

In this case, a punch biopsy revealed inflammatory morphea. Therapeutic options were discussed, and the patient declined phototherapy or systemic treatment. Occluded tacrolimus 0.1% ointment b.i.d. was administered, and the lesions showed minimal improvement at a three-month follow-up exam. n Dr. Robbins is a resident in the Department of Dermatology at Baylor College of Medicine in Houston. References 1. Bacon RM, Kugeler KJ, Mead PS; Centers for Disease Control and Prevention (CDC). Surveillance for Lyme disease—United States, 19922006. MMWR Surveill Summ. 2008;57:1-9. Available at www.cdc.gov/ mmwr/preview/mmwrhtml/ss5710a1.htm. 2. Tijsse-Klasen E, Jacobs JJ, Swart A, et al. Small risk of developing symptomatic tick-borne diseases following a tick bite in the Netherlands. Parasit Vectors. 2011;4:17. Available at www.ncbi.nlm.nih.gov/pmc/articles/ pmid/21310036/. 3. de Mik EL, van Pelt W, Docters-van Leeuwen BD, et al. The geographical distribution of tick bites and erythema migrans in general practice in the Netherlands. Int J Epidemiol. 1997;26:451-457. Available at ije.oxfordjournals.org/content/26/2/451.long. 4. Wormser GP. Clinical practice. Early Lyme disease. N Engl J Med. 2006;354:2794-2801. 5. Nadelman RB, Nowakowski J, Fish D, et al. Prophylaxis with single-dose doxycycline for the prevention of Lyme disease after an Ixodes scapularis tick bite. N Engl J Med. 2001;345:79-84. Available at www.nejm.org/doi/ full/10.1056/NEJM200107123450201. 6. Peterson LS, Nelson AM, Su WP, et al. The epidemiology of morphea (localized scleroderma) in Olmsted County 1960-1993. J Rheumatol. 1997;24:73-80. 7. Aberer E, Neumann R, Lubec G. Acrodermatitis chronica atrophicans in association with lichen sclerosus et atrophicans: tubulo-interstitial nephritis and urinary excretion of spirochete-like organisms. Acta Derm Venereol. 1987;67:62-65. 8. Aberer E, Klade H, Stanek G, Gebhart W. Borrelia burgdorferi and different types of morphea. Dermatologica. 1991;182:145-154. 9. Weide B, Schittek B, Klyscz T, et al. Morphoea is neither associated with features of Borrelia burgdorferi infection, nor is this agent detectable in lesional skin by polymerase chain reaction. Br J Dermatol. 2000;143:780-785. 10. Zwischenberger BA, Jacobe HT. A systematic review of morphea treatments and therapeutic algorithm. J Am Acad Dermatol. 2011;65:925-941. 11. Ghoreschi K, Röcken M. Phototherapy of sclerosing skin diseases. Dermatology. 2002;205:219-220. 12. Uziel Y, Feldman BM, Krafchik BR, et al. Methotrexate and corticosteroid therapy for pediatric localized scleroderma. J Pediatr. 2000;136:91-95. All electronic documents accessed May 15, 2013.

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posttest Expiration date: June 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 42

page 87

page 99

Clinical evaluation: peptic ulcer disease

Case #1: Heparin-induced skin necrosis 1. Heparin-induced skin necrosis preferentially occurs in/on a. Antecubital fossae b. Subcutaneous adipose tissue c. Extensor surfaces d. Flexural creases

Case #1: Lyme Disease

1. Which factor is associated with the development of peptic ulcer disease? a. Cigarette smoking b. Use of bisphosphonates c. Psychological stress d. All of the above 2. A “test and treat” approach is used in patients who are younger than age 55 years and have a. Weight loss b. Iron-deficiency anemia c. Epigastric tenderness d. Persistent vomiting 3. Which medication should not be given for up to two weeks prior to performing a rapid urease test? a. Proton pump inhibitors b. H2 blockers c. Antacids d. Prostaglandin analogs 4. What medication is used in first-line triple therapy in non-penicillinallergic patients with Helicobacter pylori-related ulcers? a. Bismuth subsalicylate b. Clarithromycin (Biaxin) c. Tetracycline (Sumycin) d. Metronidazole (Flagyl)

To take the Posttest please go to ClinicalAdvisor.com/CMEFeaturexxxx

2. Which clinical entity that presents similarly to heparin-induced skin necrosis is usually seen in the setting of end-stage renal disease? a. Calciphylaxis b. Pyoderma gangrenosum c. Leukocytoclastic vasculitis d. Bullous pemphigoid Case #2: Shingles 3. Hutchinson sign indicates the presence of a vesicle or other zoster lesion at which location? a. Tip of the nose b. Scalp c. Lumbar region d. Chest 4. What class of antidepressants is used in the treatment of postherpetic neuralgia? a. Atypical antidepressants (Bupropion) b. Monoamine oxidase inhibitors c. Selective serotonin reuptake inhibitors (Fluoxetine) d. Tricyclic agents (Amitriptyline)

1. What is the dermatologic manifestation of Lyme disease? a. Small, grouped vesicles with an erythematous base b. Annular erythematous plaque that spreads centrifugally c. Pink to red papules with silvery scales d. Solid, firm, thick plaques with scaling 2. What is the treatment of choice for Lyme disease in adults and in children older than age 8 years? a. Doxycycline b. Amoxicillin c. Erythromycin d. Ciprofloxacin (Cipro, Proquin) Case #2: Morphea 3. What is a clinical feature of plaquetype morphea? a. Lilac border on active lesions b. Lesions usually located on the trunk c. Loss of hair follicles and sweat glands d. All of the above 4. What is the treatment for superficial inflammatory lesions? a. Phototherapy with UVA b. Weekly methotrexate (Rheumatrex, Trexall) c. Ultrapotent topical steroids d. Vitamin A derivatives

To take the Posttest please go to ClinicalAdvisor.com/Dermxxxx

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CME

posttest Expiration date: June 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 June 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

page 42

page 87

page 99

Clinical evaluation: peptic ulcer disease

Case #1: Heparin-induced skin necrosis 1. Heparin-induced skin necrosis preferentially occurs in/on a. Antecubital fossae b. Subcutaneous adipose tissue c. Extensor surfaces d. Flexural creases

Case #1: Lyme Disease

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Evidence-Based Medicine This department uses the best available scientific findings to offer practice guidance on a wide range of conditions seen in primary care.The author, Alan Ehrlich, MD, is a senior deputy editor for DynaMed, Ipswich, Mass., and assistant professor of Family Medicine at University of Massachusetts Medical School in Worcester. DynaMed (www.ebscohost.com/dynamed/) is a database that provides evidence-based information on more than 3,200 clinical topics and is updated daily through systematic surveillance covering more than 500 journals.The most important evidence identified is summarized here.

intramuscular Midazolam May Be More Effective than IV Lorazepam for Prehospital Seizure Cessation Level 2: Mid-level evidence Intravenous benzodiazepine, most commonly lorazepam (Ativan), is the preferred first-line treatment for prolonged epileptic seizures in the emergency department, but IV medication can be difficult for first responders to administer.An alternative is for paramedics to give intramuscular midazolam (Versed) , a treatment commonly used due to its speed and relative simplicity of administration. A randomized trial compared these two options for use by paramedics prior to hospital arrival in 893 children and adults with seizures lasting longer than five minutes and persisting after the arrival of the paramedics (N Engl J Med. 2012;366:591600; available at www.nejm.org/doi/full/10.1056/ NEJMoa1107494, accessed May 15, 2013). Doses were midazolam 10 mg or lorazepam 4 mg for adults and children weighing >40 kg (88 lbs), and midazolam 5 mg or lorazepam 2 mg for smaller children. Blinding was maintained by IV placebo for the midazolam group and by intramuscular placebo for the lorazepam group. Patients were excluded for major trauma, hypoglycemia, cardiac arrest, heart rate <40 beats per minute, pregnancy, known allergy to intervention, or estimated weight <13 kg (28.6 lbs). The randomized intervention was given to 99% of the midazolam group, but to only 63% of the lorazepam group. Of those not receiving lorazepam, convulsions stopped prior to treatment in 64%, and paramedics failed to start the IV in 28%.All randomized patients were included in an intention-to-treat analysis. Seizures were terminated without need for rescue medication in 73.4% for intramuscular midazolam vs. 63.4% for IV lorazepam (p <0.001,

NNT 10). Intramuscular midazolam was associated with lower rates of hospitalization (57.6% vs. 65.6%, p<0.05, NNT 13) and intensive care admission (28.6% vs. 36.2%, p <0.05, NNT 14).There were no significant differences in endotracheal intubation within 30 minutes or seizure recurrence within 12 hours of emergency department arrival. Similar results were obtained in per-protocol analyses.

In December 2011, the FDA recommended that providers not alter their current practice for treating depression during pregnancy.

SSRI Exposure During Later Pregnancy May Increase Risk of Persistent Pulmonary Hypertension of the Newborn Level 2: Mid-level evidence Persistent pulmonary hypertension of the newborn (PPHN) is a life-threatening condition in which the infant fails to transition from high pulmonary vascular resistance and low pulmonary blood flow characteristic of fetal circulation to low pulmonary vascular resistance and high pulmonary blood flow of postnatal circulation. It occurs in 0.1%-0.2% of live births, with death in 10%-20% of cases (N Engl J Med. 2006;354:579-587; available at www .nejm.org/doi/full/10.1056/NEJMoa052744, accessed May 15, 2013). To date, evidence for a link between maternal use of selective serotonin reuptake inhibitors (SSRIs) for depression and risk of PPHN has been inconsistent. In December 2011, the FDA recommended that providers not alter their current practice for treating depression during pregnancy. However, a large retrospective cohort study, published one month after the FDA The quality of the evidence supporting each item is rated from Level 1 (highest) to Level 3 (lowest). Absolute risk reductions are presented as the number needed to treat (NNT) for one patient to benefit. Absolute risk increases are presented as the number needed to harm (NNH).

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Paramedics can administer intramuscular midazolam for seizures.

Gastroesophageal reflux (shown) is common in pediatric asthma.

statement, strongly suggests that SSRI exposure does increase PPHN risk (BMJ. 2012;344:d8012; available at www.bmj .com/content/344/bmj.d8012, accessed May 15, 2013). A total of 1,618,255 infants born after 33 weeks gestational age in five Nordic countries were evaluated for maternal use of any SSRIs. Mothers were stratified by date of SSRI exposure (at >20 weeks gestational age, prior to pregnancy or before eight weeks gestational age, or no exposure). PPHN developed in 0.29% of infants with later pregnancy exposure, 0.19% of infants with early pregnancy exposure, and 0.12% of infants with no exposure. Later exposure to any SSRI was associated with a significant increase in PPHN risk compared with no exposure (adjusted hazard ratio 2.1, 95% CI 1.5-3, NNH 416-1,666). Early exposure was associated with a trend toward increased risk. Results of subgroup analyses for individual SSRIs were similar to the overall analysis. While there now appears to be a significantly increased risk, the condition is rare and the absolute risk remains low.These risks must be weighed against the benefits of treating the depression and compared with alternative options for the mother.

(PPIs) are sometimes prescribed for children to improve asthma control, even in the absence of GER symptoms. A new randomized trial investigated the effects of a PPI on asthma outcomes in 306 children with asthma poorly controlled by inhaled corticosteroids ( JAMA. 2012;307:373-381; available at jama.jamanetwork.com/article.aspx?articleid=1104902, accessed May 15, 2013). Children (mean age 11 years) were randomized to lansoprazole (Prevacid) vs. placebo for 24 weeks. All children were free of GER symptoms. Exclusion criteria included any reflux symptoms requiring treatment, any previous use of PPIs or other anti-reflux medications, or history of anti-reflux surgery. The lansoprazole dose was 15 mg/day for children weighing <30 kg (66 lbs) and 30 mg/day for children weighing >30 kg. The primary outcome was change in score on the Asthma Control Questionnaire (ACQ), which assesses wheezing, shortness of breath, nocturnal symptoms, activity level, bronchodilator use, and pulmonary function. A change of 0.5 points is considered clinically important (reduction indicates improvement). At 24 weeks, there were no significant differences in ACQ scores (mean reduction 0.1 points for lansoprazole vs. 0.2 points for placebo). Lansoprazole was associated with higher rates of upper respiratory infection (63% vs. 49%, p=0.02, NNH 7), sore throat (52% vs. 39%, p=0.02, NNH 7), and bronchitis (7% vs.2% p=0.04, NNH 20). There were no significant differences in asthma-related quality-of-life outcomes or in rate of episodes of poor asthma control. A group of 115 children had esophageal pH measurements prior to randomization, and 43% were found to have asymptomatic gastroesophageal reflux. There were no significant differences in any asthma outcomes when comparing lansoprazole vs. placebo even in this subgroup. n

Lansoprazole Increases Adverse Events Without Improving Asthma Control in Children Without Symptomatic Gastroesophageal Reflux Level 2: Mid-level evidence Gastroesophageal reflux (GER) is common in children with asthma, and the National Heart, Lung, and Blood Institute recommends treatment for GER symptoms, especially in children with frequent episodes of nocturnal asthma (Allergy Clin Immunol. 2007;120:S94-S138). Proton pump inhibitors

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COMMENTARY Scott Stegall, PhD, PA-C, is an Army-trained PA and COO of the Physician Assistant Political Alliance (www.PhysicianAssistantPoliticalAlliance.org). He practices in rural health.

The politics of the greater good Legislators count on physicians, physician assistants (PAs), and nurse practitioners (NPs) to provide them with accurate information and quality suggestions for improving health care. The problem is, each group has its own agenda and interests that may or may not actually be good for health care. I have been involved in health-care politics in Texas for about 15 years. It seems like a complicated mess, but I think I can summarize the greater issues with each group and how they impact our policymaking process. These are broad generalizations because explaining in detail in these 600 or so words is impossible.

I have seen wonderful providers turn into merciless idealogues when they enter the capitol building.

PAs’ legislative desires are hampered by the belief they have to go to physicians for “permission” to try to change health-care policy. They are also encumbered with being lumped in with NPs as being “the same thing.” NPs want independent practice. Everyone knows it but the words are rarely spoken out loud because the idea is so volatile. This issue alone colors everything they attempt to do at the political and regulatory levels. Physicians want to be in charge of everything “medicine.” The Texas Medical Association even refers to itself and its members as “medicine.” Physician organizations will often do things under the guise of “patient safety” that are, in fact, only to protect the control of medicine and the associated financial rewards. By now many people are offended by my suppositions. Keep in mind these are generalizations and are mostly in regard to the regulatory and political aspects of health care. I have friends and colleagues in each profession and believe the overwhelming majority are caring professionals who only want the best for their patients. However, I have also seen wonderful providers become merciless idealogues when they enter the capitol building. So what is my point? The process of providing health care has been corrupted by personal interests. As health-care dollars get smaller and regulation gets bigger, this has only worsened.

I recently had the privilege of participating in a think-tank type of group. The group’s only mission is to improve health-care quality, access, and costs. This group disallows any personal agendas. Everyone is on equal footing, free to introduce any idea that might meet the stated goals. Over a period of 18 months or more broad concepts are developed, then refined, then fine-tuned, and an action plan is made. Each participant then goes back to his or her home base to promote these ideas. I found two things most interesting about this group. The first was the concept that every idea was worth discussing and possibly adopting if it was good for health care. The second was the makeup of the group: There were CEOs of hospital systems, vice-presidents of insurance companies, PAs, NPs, physicians, legislative aides, representatives of hospice and home-health organizations, and more. After spending years clawing and fighting to get the simplest things done legislatively, I saw, in its purest sense, what health-care policymaking could be like absent self-interest. It renewed my faith in what I had come to believe was a terminally flawed system. So my question is this: Is it possible for all of us to rise above our own interests and the interests of our respective groups, and try to fix the health-care system by working together? I dare to dream. n

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