July 2016 Clinical Advisor by The Clinical Advisor

THE CLINICAL ADVISOR • JULY 2016

A P E E R - R E V I E W E D F O RU M F O R N U R S E P R AC T I T I O N E R S

NEWSLINE

■ Screening for syphilis ■ Pancreatic cancer guideline ■ Febrile seizure risk CONFERENCE COVERAGE

■ AAPA Roundup ■ AANP Roundup

J U LY 2 016

| www.ClinicalAdvisor.com

DETECTING AND PREVENTING

SKIN CANCER

A nodular melanoma on a superficial spreading melanoma.

LEGAL ADVISOR

A clinician/patient mistake ALT MEDS UPDATE

D-mannose

n Dermatologic Look-Alikes

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Editor Colby Stong, editor@ClinicalAdvisor.com Senior editor Sandhya George Associate digital content editor Hannah Dellabella Assistant editor Lauren Biscaldi Contributing editors Mark P. Brady, PA-C; Philip R. Cohen, MD; Deborah L. Cross, MPH, CRNP, ANP; Sharon Dudley-Brown, PhD, FNP; Abimbola Farinde, PharmD; Laura A. Foster, CRNP, FNP; Abby A. Jacobson, PA; Maria Kidner, DNP, FNP; Joan W. Kiely, MSN, CRNP; Debra August King, PhD, PA; Ann W. Latner, JD; Mary Newberry, CNM, MSN; Claire Babcock O’Connell, MPH, PA; Kathy Pereira, DNP, FNP; Sherril Sego, DNP, FNP; Ann Walsh, PA-C, SCT(ASCP); Kim Zuber, PA-C Production editor Kim Daigneau

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“He’s an indoor cat.” www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JULY 2016 3

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CONTENTS J U LY 2 0 1 6

NEWS AND COMMENT

DEPARTMENTS

14 Newsline ■■New guidelines support the use of metabolic surgery as an option for type 2 diabetes and obesity. ■■USPSTF recommends widespread screening for syphilis. ■■Concomitant vaccinations may increase febrile seizure risk. ■■A guideline for pancreatic cancer ■■FDA issues warning for loperamide and risk of cardiac events. ■■How effective are antidepressants in children? ■■Behavioral interventions can provide significant sleep benefits in infants. ■■Extending adjuvant aromatase inhibitor therapy for breast cancer

12 Web Roundup A summary of our most recent opinion, news, and multimedia content from ClinicalAdvisor.com

Metabolic surgery for diabetes, obesity 14

57 Dermatologic Look-Alikes Hyperpigmented patches 63 Legal Advisor A clinician and patient mistake

FEATURES 20 Detecting skin cancer in primary care More cases of skin cancer are diagnosed each year than of breast, prostate, lung, and colon cancers combined, and early detection is critical.

Widespread syphilis screening urged 15

30 CME Anaphylaxis management: achieving optimal care Swift intervention and follow-up are key to treating this life-threatening allergic reaction, but the treatment guidelines are not well understood. 39 CME Feature posttest

MAKING CONTACT

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51 Dermatology Clinic n Plaques, erosions around orifices and acral regions n A subcutaneous nodule near the eyebrow

66 AAPA Conference Roundup ■■PA malpractice case rates slightly increasing ■■Bupivacaine liposome injectable improves total knee arthroplasty outcomes ■■AAPA House of Delegates opposes proposed NCCPA recertification requirements ■■And more Continues on page 10

A clinician and patient mistake 63

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CONTENTS DEPARTMENTS cont’d AANP Conference Roundup ■ AANP supports bill for full practice authority for NPs in veteran health care ■ Long-acting reversible contraception effective in nulliparous adolescents ■ Misconceptions common regarding probiotics ■ And more

Alternative Meds Update D-mannose

“You could have had a fi lm career, but you were needed here to fetch the paper.”

ADVISOR FORUM 44

Your Comments ■ Improving health literacy ■ Suboxone: the methadone of the decade

Clinical Pearls ■ In place of vaginal steroid cream ■ Assessing for rebound tenderness

“We’re going to run some tests: blood work, a CT scan, and the S.A.T.’s.”

HOW TO CONTACT US AL

F O RU M

CONFEREN CE COVERA GE

■ AAPA Rou ndup ■ AANP Rou ndup LEGAL ADV

ISOR

A clinician/p

FOR NU R S E P R AC TIT

IONERS

J U LY 2 016

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dvisor.com

DETECT ING AND PREVEN TING

SKIN C AN

CER

A nodular melanom a on a supe rficial spreading melanom a.

atient mistake

ALT MED S UPDATE

D-mannose

• Send it by e-mail to editor@ClinicalAdvisor.com

■ Dermatolo gic

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19, NUMB ER 7

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VIEWED

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A PEERRE

NEWSLIN

■ Screenin g for syphilis ■ Pancreati c canc ■ Febrile seizu er guideline re risk

VOLUM E

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EXCLUSIVE TO THE WEB AT

ClinicalAdvisor.com Web Exclusives

The Waiting Room

ClinicalAdvisor.com/News

Official Blog of The Clinical Advisor ClinicalAdvisor.com/WaitingRoom

Routine primary care screening improves detection of melanomas Primary care screening can help patients avoid the need for more aggressive therapy and potentially save lives.

Jim Anderson, MPAS, PA-C, DFAAPA Door open or door closed? Drawing inspiration from patients in recovery Patients facing addiction are not from another planet—they are our parents, our siblings, our neighbors, and our friends.

Levonorgestrel, low-dose estrogen associated with lower risk for adverse vascular events among oral contraceptives Compared with other estrogen doses and progestogen types, low-dose estrogen with levonorgestrel had a decreased risk of adverse events

Sharon M. O’Brien, MPAS, PA-C Hyperarousal and use of prescription sleep aids Hyperarousal is linked to an increased likelihood of a patient using prescription sleep aids.

Aspirin significantly reduces the risk for secondary stroke Aspirin significantly reduces the risk of a recurrent stroke 6 weeks after a transient ischemic attack or minor stroke.

Jillian Knowles, MMS, PA-C Overcrowding in the emergency department Emergency department clinicians are faced with a number of challenges as EDs become more crowded.

Cartoon Archive

Multimedia

The Clinical Advisor’s monthly cartoons are also available online.

ClinicalAdvisor.com/Multimedia

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“Wait! Come back!”

MAKING CONTACT

Jim Anderson discusses practices in prescribing opioids and treating addiction Jim Anderson, MPAS, PA-C, DFAAPA, talks about the restrictions placed on PAs for prescribing suboxone to treat opioid addiction at the 2016 annual meeting of the American Academy of PAs (AAPA). Watch it here: ClinicalAdvisor.com/AndersonAAPA16 Kathy Kemle discusses the importance of caring for a patient’s emotional needs Kathy Kemle, MS, PA-C, shares a story about fulfilling a patient’s final wish to see her son graduate high school during the 2016 annual meeting of the American Academy of PAs (AAPA). Watch it here: ClinicalAdvisor.com/KemleAAPA16

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Advisor 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 ClinicalAdvisor.com/AdvisorDx. Learn more about diagnosing and treating these conditions, and see how you compare with your fellow colleagues.

Ortho Dx

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Unresolved ankle pain after sports injury A 10-year-old boy presents with a 4-month history of right ankle pain. The pain started after he twisted his ankle during a baseball game. He was diagnosed with an ankle sprain, was placed in a walking boot for 4 weeks, and underwent 3 weeks of physical therapy, but he continues to have pain. You suspect tarsal coalition. WHICH IMAGING IS BEST IN THIS CASE?

• Magnetic resonance imaging • Bone scan • Computed tomography • Arthrogram ● See the full case at ClinicalAdvisor.com/OrthoDx_July16

Derm Dx A large ulceration and tortuous varicosities A 90-year-old woman presents with an ulceration that has been on her left leg for >1 year. The ulcer had been ascribed to venous insufficiency and was treated conservatively elsewhere. When lightly debrided, the ulceration displays an erythematous granular base. CAN YOU DIAGNOSE THE CONDITION?

• Venous ulceration • Arterial ulceration • Basal cell carcinoma • Squamous cell carcinoma ● See the full case at ClinicalAdvisor.com/DermDx_July16

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Clinical practice guideline for pancreatic cancer page 16

New guidelines support use of metabolic surgery as treatment for type 2 diabetes, obesity METABOLIC surgery should be considered a valid treatment option for patients with type 2 diabetes and obesity, according to a joint statement published in Diabetes Care. The statement was released by the 2nd Diabetes Surgery Summit (DSS-II), which is comprised of a multidisciplinary group of 48 international clinicians and scholars, including representatives of leading diabetes organizations. The DSS-II defines metabolic surgery as “the use of [gastrointestinal] surgery with the intent to treat [type 2 diabetes] and obesity.” The DSS-II developed 32 conclusions regarding the use of metabolic surgery for type 2 diabetes. The recommendations are organized into multiple categories: generalities, metabolic surgery versus traditional bariatric surgery, defining goals and success of metabolic surgery, patient selection, preoperative workup, choice of procedure, and postoperative follow-up. Recommendations include the following: • There is sufficient clinical and mechanistic evidence to include GI surgery as an antidiabetes intervention for patients with type 2 diabetes and obesity. • Algorithms for treating type 2 diabetes should include scenarios in which metabolic surgery

can be considered a treatment option in addition to lifestyle, nutritional, and/or pharmacologic interventions. • Metabolic surgery should not follow the guidelines of traditional bariatric surgery, which is intended for weight loss. New guidelines consistent with international diabetes standards of care must be developed for metabolic surgery. • Metabolic surgery should be performed in high-volume centers by multidisciplinary teams with expertise in the management of diabetes and GI surgery. • Whereas the goal of bariatric surgery is weight loss, the goal of metabolic surgery for patients with type 2 diabetes and obesity is reducing the complications of diabetes, as well as improving hyperglycemia and other metabolic abnormalities.

Metabolic surgery is a valid treatment option for type 2 diabetes and obesity, according to a statement from DSS-II.

Effective sleep interventions for infants page 18

• Contraindications for metabolic surgery include: diagnosis of type 1 diabetes (unless surgery is indicated for other reasons such as obesity); current drug or alcohol abuse; uncontrolled psychiatric illness; lack of comprehension of the risks/benefits, expected outcomes, or alternatives; and lack of commitment to nutritional supplementation and long-term follow-up. • Metabolic surger y should be considered as an option for treating type 2 diabetes in patients with class I obesity (BMI 30.0 to 34.9 kg/m 2) with inadequately controlled hyperglycemia despite optimal medical intervention by either oral or injectable medications, including insulin. • Preoperative patient evaluation should include an assessment of endocrine, metabolic, physical, nutritional, and psychologic health. • Of the 4 accepted operations for metabolic surgery, Roux-en-Y gastric bypass appears to have the most favorable risk-benefit profile for most patients with type 2 diabetes. • Longer-term studies are needed for vertical sleeve gastrectomy, though current evidence suggests it results in significant weight loss and major improvement of type 2 diabetes. • Follow-up should include surgical and nutritional evaluations at least every 6 months for the first 2 years post-surgery. Follow-ups should occur at least annually thereafter.

Newsline

Syphilis screening is urged by the USPSTF page 15

14 THE CLINICAL ADVISOR • JULY 2016 • www.ClinicalAdvisor.com

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USPSTF recommends widespread screening for syphilis

SYPHILIS SCREENING is recommended in all asymptomatic, nonpregnant adults and adolescents, including patients coinfected with other sexually transmitted infections (STIs), according to a statement from the U.S. Preventive Services Task Force (USPSTF) published in JAMA. The USPSTF found “convincing evidence” that syphilis screening in asymptomatic, nonpregnant

Cases of primary and secondary syphilis have increased between 2000 and 2014.

persons “provides substantial benefit,” according to the statement, an update to the task force’s 2004 recommendations on syphilis screening. “Effective treatment with antibiotics can prevent progression to late-stage disease, with small associated harms, providing an overall substantial health benefit.” The recommendation to screen all at-risk persons received an A recommendation from the USPSTF. Since 2000, the incidence of cases of primary and secondary syphilis has been increasing; 19,999 cases were reported in 2014. Untreated syphilis progresses to late-stage syphilis in 15% of cases. Symptoms of latestage syphilis include the development of inflammatory lesions throughout the body, leading to cardiovascular or organ dysfunction. Neurosyphilis may occur at

any stage of the disease, and may result in blindness, paresis, tabes dorsalis, and dementia. Based on 2014 surveillance data, men who have sex with men (MSM) and both men and women living with HIV have the highest risk of contracting a syphilis infection. Overall, men accounted for 90.8% of all cases of primary and secondary syphilis. Data showed that 61.1% of all cases of primary and secondary syphilis occurred among MSM; one-half of all MSM diagnosed with syphilis were also coinfected with HIV. In particular, men between the ages of 20 and 29 years had the highest prevalence rate—nearly 3 times higher than the average population of US males. The most common screening test for syphilis is a combination of nontreponemal and treponemal antibody tests.

ADMINISTERING a trivalent inactivated inf luenza vaccine (IIV3) on the same day as a pneumococcal conjugate vaccine (PCV) or a diphtheria-tetanus-acellularpertussis (DTaP)-containing vaccine is associated with a higher risk for febrile seizure in children aged 6 to 23 months, according to a study in Pediatrics. The excess risk of administering IIV3, PCV, and DTaP-containing vaccines concomitantly was 30 febrile seizures per 100,000 children vaccinated, compared with administering the vaccines on separate days.

The study included data from the Vaccine Safety Datalink on children aged 6 to 23 months who had a febrile seizure during prespecified time intervals after receiving 1 or more vaccines of any type. The study period included 5 inf luenza seasons (2006 to 2007 through 2010 to 2011). The day of vaccination was defined as day 0. After 1,915,108 vaccination events, the researchers identified 596 potential febrile seizure cases that occurred during the prespecified time intervals of day 0 to day 1 or day 14 to day

Timing of IIV3, PCV, and DTaP vaccines may be linked to seizure risk.

20 postvaccination, with the latter functioning as the control group. Of these, 333 febrile seizure events were able to be confirmed by medical charts and were included in the analysis. Only PCV 7-valent had an independent risk for febrile seizure (incidence rate ratio [IRR], 1.98). When administered by itself, IIV3 had no independent risk for febrile seizure (IRR 0.46). However, the risk increased when IIV3 was administered with either PCV (IRR 3.50) or a DTaP-containing vaccine (IRR, 3.50).

Concomitant vaccinations may increase febrile seizure risk

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Newsline ASCO releases clinical guideline for pancreatic cancer THE AMERICAN Society of Clinical Oncology (ASCO) has released a clinical practice guideline for the treatment of patients with localized pancreatic cancer, published in the Journal of Clinical Oncology. A panel of medical oncology, radiation oncology, surgical oncology, palliative care, and advocacy experts reviewed literature from January 2002 to June 2015. In total, 9 randomized controlled trials met the systemic review criteria and were used to develop the guideline. The guideline includes the following recommendations when dealing with patients with

Treatment of localized pancreatic cancer is addressed.

potentially curable pancreatic cancer: • Patients should undergo a multiphase CT scan of the abdomen and pelvis using a pancreatic protocol or an MRI to assess the anatomic relationships of the primary tumor and the presence of intra-abdominal metastases. A serum level of CA 19-9 and baseline standard laboratory studies should be obtained. • The baseline performance status, symptom burden, and comorbidity profile should be assessed in each patient. • The standard of care should be multidisciplinary collaboration

to determine treatment, care plans, and disease management. • A patient who undergoes preoperative therapy should have a complete restaging evaluation before final surgical planning. • Patients with resected pancreatic cancer who did not undergo preoperative therapy should be offered 6 months of adjuvant chemotherapy with either gemcitabine or f luorouracil plus folinic acid. Adjuvant treatment should begin within 8 weeks of surgical resection. • For patients who received preoperative therapy, a total of 6 months of adjuvant therapy is recommended.

TAKING HIGHER than recommended doses of the antidiarrheal loperamide can cause serious adverse cardiac events that can lead to death, according to a safety announcement from the FDA. Most reported serious adverse events occurred in individuals who were intentionally misusing or abusing loperamide to self-treat symptoms of opioid withdrawal or to achieve a feeling of euphoria. The FDA recommends that clinicians consider loperamide as a possible cause of unexplained cardiac events, including QT intervention prolongation, Torsades de Pointes or other ventricular arrhythmias, syncope, and cardiac arrest. If loperamide-induced cardiotoxicity is suspected, clinicians are advised to discontinue loperamide and begin therapy to manage and

prevent cardiac arrhythmias and other adverse events. If loperamide-associated Torsades de Pointes persists after pharmacotherapy, electrical pacing or cardioversion should be considered. The risk of cardiac adverse events may increase when high doses of loperamide are taken with certain other drugs that inhibit loperamide metabolism

Misuse of the antidiarrheal is linked to serious cardiac events, per the FDA.

or transport. Medications that interact with loperamide include cimetidine, clarithromycin, erythromycin, gemfibrozil, itraconazole, ketoconazole, quinidine, quinine, ranitidine, and ritonavir. Clinicians are advised to use caution when prescribing loperamide to patients with a predisposition to QT interval prolongation, Torsades de Pointes, or other serious arrhythmias. They should also use caution if a patient takes other medications that interact with loperamide, as they may increase loperamide concentrations by blocking pathways of loperamide elimination. The FDA recommends counseling patients about the cardiac risks of loperamide and instructing them not to take more than the recommended dose.

FDA issues warning for loperamide and risk of cardiac events

16 THE CLINICAL ADVISOR • JULY 2016 • www.ClinicalAdvisor.com

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Accreditation Boston University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Boston University School of Medicine designates this activity for a maximum of 2 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Continuing Nursing Education Provider Unit, Boston University School of Medicine is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation. CNE Contact Hours: 2, all of which is pharmacology credit worthy. Disclosure This educational activity is supported by an independent educational grant from the ER/LA Opioid Analgesic REMS Program Companies. Please see http://ce.er-la-opioidrems.com/IwgCEUI/ rems/pdf/List_of_RPC_Companies. pdf for a listing of the member companies. This activity is intended to be fully compliant with the ER/ LA Opioid Analgesic REMS education requirements issued by the US Food & Drug Administration.

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Newsline Antidepressants Behavioral interventions can provide ineffective in significant sleep benefits in infants children? The infants were randomGRADUATED EXTINCTION and bedtime fading may provide significant sleep benefits for infants and have no long-term effect on parent-child attachment or child emotions or behavior, according to research published in Pediatrics. Michael Gradisar, PhD, Associ ate Professor at the School of Psychology at Flinders University in Adelaide, Australia, and colleagues conducted a randomized controlled trial of 43 infants between the ages of 6 and 16 months to evaluate the effects of behavioral interventions on the sleep/wakefulness of the infants, as well as the potential for later emotional or behavioral problems and parent-child attachment.

Graduated extinction, bedtime fading may be effective for infants.

ized to receive either graduated extinction (n=14), bedtime fading (n=15) or sleep education control (n=14). Data were collected via parent-reported sleep diaries and infant actigraphy; infant stress was measured via salivary cortisol sampling in the morning and the afternoon, and maternal stress was self-reported. At 12 months, mothers completed an assessment of their child’s emotional and behavioral problems. The researchers found significant interactions for sleep latency, number of awakenings, and wake after sleep onset; large decreases in sleep latency were found in the graduated extinction and bedtime fading groups.

Extending therapy may be beneficial for breast cancer FOR POSTMENOPAUSAL women with hormone receptor–positive early breast cancer, extending adjuvant aromatase inhibitor treatment from 5 years to 10 years can increase rates of disease-free survival and decrease incidence of contralateral breast cancer, according to a study published in the New England Journal of Medicine. However, rates of overall survival were not higher with aromatase inhibitor compared with placebo The study included 1,918 postmenopausal women with primary breast cancer who had received 4.5 to 6 years of adjuvant therapy with an aromatase inhibitor. Participants were randomly assigned to receive 2.5 mg of letrozole or placebo orally once a day for an additional 5 years.

During the mean follow-up of 6.3 years, there were 165 events involving disease recurrence or the occurrence of contralateral breast cancer (67 in the letrozole group versus 98 in the placebo group) and 200 deaths (100 in each group). The 5-year disease-free survival rate was 95% in the letrozole group and 91% in the placebo group. The 5-year overall survival rate was 93% in the letrozole group and 94% in the placebo group. The annual incidence rate of contralateral breast cancer was 0.21% in the letrozole group compared with 0.49% in the placebo group. Participants in the letrozole group had a higher frequency of bone-related toxic events, compared with those who received a placebo. n

ANTIDEPRESSANTS may be ineffective for the treatment of major depressive disorder in children and adolescents, according to a study published in The Lancet. Of the 14 antidepressants included in the study, only fluoxetine was more effective than placebo for lessening the symptoms of depression. Venlafaxine was associated with an increased risk of suicidal thoughts and attempts compared with placebo and 5 other antidepressants. “The balance of risks and benefits of antidepressants for the treatment of major depression does not seem to offer a clear advantage in children and teenagers, with probably only the exception of fluoxetine. We recommend that children and adolescents taking antidepressants should be monitored closely, regardless of the antidepressant chosen, particularly at the beginning of treatment,” stated the researchers. The meta-analysis of 34 trials included 5,260 participants. Fluoxetine was the only antidepressant that was significantly more effective than placebo. Fluoxetine was more tolerable compared with duloxetine (odds ratio [OR], 0.31) and imipramine (OR, 0.23). Patients who were given imipramine, venlafaxine, and duloxetine were more likely to discontinue treatment due to adverse events compared with those given placebo (OR, 5.49, 3.19, and 2.80, respectively).

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FEATURE: ABBY A. JACOBSON, MS, PA-C

Detecting skin cancer in primary care More cases of skin cancer are diagnosed each year than of breast, prostate, lung, and colon cancers combined, and early detection is critical.

xamining a patient’s skin and identifying potential skin cancers are the responsibility of every clinician in every medical specialty. Certainly specialists in primary care and dermatology take the lead in skin cancer detection, but practitioners in many other medical specialties also have the opportunity to examine the skin. All clinicians—from the orthopedic provider, who may examine the arm and shoulder for a rotator cuff tear, to the ear, nose, and throat provider, who may tug on the patient’s ear and feel roughness at the top of the pinna (Figure 1)—have the opportunity to identify a potential skin cancer or precancerous lesion. There are more new cases of skin cancer each year than of breast, prostate, lung, and colon cancers combined.1 This means that as clinicians, we need to be more aware of how skin cancer detection can become a part of almost every medical visit. Early detection is one of the most important prognostic factors in the long-term survival of a patient with skin cancer. The early discovery of a skin cancer can be the difference between life and death, or between office-based surgery and surgery, radiation, and chemotherapy. As long as you have the opportunity to view a patient’s skin, you have the opportunity to identify a skin cancer and potentially save that patient’s life.

Close-up of a nodular melanoma on a superficial spreading melanoma.

Melanoma

The deadliest and most dangerous form of skin cancer is melanoma. Melanoma rates in the United States doubled from 1982 to 2011.2 One person dies of melanoma every 57 minutes.3

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Risk factors for skin cancer • Skin that burns easily • Blond or red hair • History of excessive sun exposure, including tanning bed use, and sunburns • Diseases or treatments that suppress the immune system • Personal history of skin cancer or family history of melanoma in a first-degree relative • Presence of more than 50 moles, atypical moles, or large moles

An important clue to the diagnosis of a potential melanoma that neither the ABCDE criteria nor the Glasgow checklist captures is a sign called the “ugly duckling syndrome.” When one lesion clearly does not look like the other lesions on a patient’s skin, there should be concern for malignancy, and a biopsy may be warranted. Areas that should receive special consideration include the hands and feet, nails, and genitals. Ethnic groups with more pigment in their skin naturally tend to develop melanomas at a lower rate. When melanomas do develop, they often occur on the palms of the hands and soles of the feet, or in the nails. Because the diagnosis is frequently delayed, melanoma in a person of color carries a much worse prognosis. If you see a pigmented lesion in a nail or nail bed, on the palm of a hand, or on the sole of a foot of a patient of any ethnic background, it is suggested that the input of a dermatology provider be obtained. Dermoscopy can help a clinician view pigmented lesions and more readily differentiate cancers from benign growths. Benign growths to be considered in the differential diagnosis of a melanoma include benign nevi, lentigines, seborrheic © IMAGE COURTESY OF TANIA COHEN, PA-C, MPAS.

Evaluating a lesion and deciding whether a biopsy is required can be among the most daunting tasks for providers not familiar with the identification of skin cancer. Either of two systems can be used for this evaluation: 1. ABCDE mnemonic. This is widely endorsed in the medical community and presented to patients. A stands for asymmetry; if you draw a line down the center of a lesion, is each side a mirror image of the other? B stands for border; does the lesion have a clear, circular border, or is it oddly shaped, like a paisley motif? C stands for color; is the lesion of the same color throughout? D stands for diameter; is the diameter of the lesion greater than 6 mm? E stands for evolution; a new lesion or one that is changing should raise the clinician’s index of suspicion. Evolution may actually be the most important predictor within this tool. Ask your patient how long the lesion has been present and if it is changing in any way. In a retrospective study, the sensitivity of the ABCDE system for identifying a lesion as a melanoma was 97% when one of the five criteria was used and 43% when all five were used jointly.4 By contrast, the specificity was 36% when a single criterion was used and 100% when all five criteria were used.4 Sensitivity is the percentage of suspicious lesions that are correctly identified as melanomas (true diagnosis). Specificity is the percentage of suspicious lesions that are correctly identified as not being melanomas. 2. Glasgow 7-point checklist. This is another set of criteria for referral or biopsy. The presence of any major feature (see sidebar below) is an indication for biopsy. Additionally, the presence of any of the minor criteria reinforces the need for biopsy. As stated above, the emphasis on change as a crucial diagnostic factor should be noted. One small study found a sensitivity of 100% and a specificity of 37% when the Glasgow checklist was used in the diagnosis of 65 melanomas and 100 benign pigmented lesions.5 However, this system is less widely used and therefore less well studied than the ABCDE system at present.

Glasgow 7-point checklist Major criteria: • New lesion, change in size of prior lesion • Change in shape • Change in color Minor criteria: • Diameter ≥7 mm • Inflammation • Crusting or bleeding • Sensory change FIGURE 1. Basal cell carcinoma on the ear. www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JULY 2016 21

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DETECTING SKIN CANCER IN PRIMARY CARE

keratosis, and vascular lesions such as venous lakes and purpura. A dermatoscope is a handheld microscope that also illuminates lesions with direct and polarized light. Dermatoscopes can cost between $250 and $3,000. Multiple conferences and textbooks are available that can help a clinician learn how to use a dermatoscope properly in the decision-making process. As a dermatology provider, I personally find this tool absolutely invaluable. If a clinician is unsure about a lesion or has looked at a lesion repeatedly while debating what to do, the patient should be referred to a dermatology practice (Figure 2). Skin biopsy is a relatively low-risk procedure, and in the case of melanoma, the benefit of early diagnosis far outweighs the risk of skin biopsy. Melanomas are aggressive and deadly. To highlight this fact, it is important to note that when a patient has a melanoma with a thickness of 0.75 mm or more, sentinel lymph node biopsy (SLNB) is recommended. SLNB is also advised for patients who have melanomas with a thickness of less than 0.75 mm if there is a high risk for metastasis.6 Risk factors for metastasis include ulceration of the primary tumor, a mitotic rate of 1/mm2 or higher, and lymphovascular invasion.6 Any patient with a melanoma and a clinically palpable lymph node must undergo fine-needle biopsy of the lymph node. Patients who have stage I melanoma with no metastasis have a 5-year survival rate between 92% and 97%.7 In contrast, patients who have stage IV melanoma have a 5-year survival rate between 15% and 20%.7

FIGURE 2. Subtle melanoma on the chin.

FIGURE 3. A classic lesion of basal cell carcinoma.

Basal cell carcinoma (BCC) is the most common skin cancer. These skin cancers grow slowly and can destroy local tissue. In rare instances, BCC can even invade local bone structure. If untreated, BCC can bleed and can become sore and ulcerated, negatively impacting daily life. The typical BCC is a pearly papule with a glossy appearance (Figure 3). Small telangiectases may be visible within the lesion and are easier to visualize with a dermatoscope. A common chief complaint of patients with BCC is “a pimple that will not heal” (Figure 4). A pimple (especially when treated with an over-the-counter topical agent such as benzoyl peroxide or a prescribed topical antibiotic) should not last longer than 3 weeks. The appearance of BCCs can be subtle. It is recommended that you ask patients the following questions: “Do you have anything new on your skin? Do you have any new lumps or bumps? Do you have anything that bleeds?” Patients often know their own bodies very well, and with a subtle BCC, you may need the patient’s help to flag the area (Figure 5).

FIGURE 4. Patients may refer to some subtle basal cell carcinomas, such as these, as pimples that will not heal.

IMAGES COURTESY OF TANIA COHEN, PA-C, MPAS.

Basal cell carcinoma

FIGURE 5. Subtle basal cell carcinomas, such as this, may require help from the patient to flag the area.

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FIGURE 6. Basal cell carcinomas near the eyes and lips that are surgically removed can result in functional issues.

FIGURE 7. Squamous cell carcinoma can present as a shallow ulcer with built-up edges covered by a plaque or scab.

Squamous cell carcinoma

Squamous cell carcinoma (SCC) is more aggressive than BCC, with a much higher rate of metastasis. SCC can present clinically in many different ways. It can appear as a shallow ulcer with built-up edges covered by a plaque or scab (Figure 7), as a cutaneous horn (Figure 8), or as a scaly, erythematous plaque that is unresponsive to topical steroids. Because the incidence of SCC is highest in fair-skinned individuals with sun exposure, the areas where SCC occurs most often in white patients are the head and neck, dorsal surfaces of the hands and forearms, and the legs.8,9 SCC on the ears or preauricular surfaces or at mucocutaneous interfaces (ie, the lips, genitalia, and perianal area) can be more aggressive, with rates of metastasis of up to 30% in some studies.10-12 SCC that occurs in a genital or perianal area is most likely associated with exposure to human papillomavirus.13 Patients with a history of organ transplant and subsequent immunosuppressive medication are at increased risk for the development of multiple SCCs. A shave or punch biopsy can be performed to diagnose SCC. Treatment depends on the level of risk, location of the

IMAGES COURTESY OF TANIA COHEN, PA-C, MPAS.

BCC is typically diagnosed by shave biopsy, and most BCCs are treated surgically. It is within the standard of care to treat BCCs with electrodessication and curettage, excision, Mohs surgery, or in some instances, topical prescription chemotherapy. The definitive surgical treatment of BCCs can leave significant scars that may interfere with the functioning of adjacent structures. BCCs frequently develop on the face, where scarring can have a substantially negative impact. The surgical removal of lesions near the eyes and lips can create functional problems; for example, downward pulling on an eyelid can result in chronic ectropion (Figure 6). Long-term ectropion can lead to dry eye, corneal problems, and blindness. The best way to minimize the potential for the negative side effects of BCC treatment is to detect BCCs early. The treatment of choice may be Mohs surgery if a BCC develops in a cosmetically sensitive area or an area where repair could cause anatomic malfunction, is aggressive, occurs in a patient with immune suppression, is in an area where the recurrence rate is known to be high, or is recurrent. Mohs surgery involves the stepwise surgical removal of a lesion together with the performance of in-office histology during the procedure before closure. After each section of skin is removed, it is fixed and analyzed to detect remaining tumor and check for clear margins. This process allows the clinician to be sure that the margins are clear but no more tissue is taken than necessary. The repair is then done on site, typically on the same or next day.

FIGURE 8. Squamous cell carcinoma can clinically present as a cutaneous horn, seen here.

lesion, cosmesis, and patient comorbidities. Surgery—either excision, Mohs surgery, or electrodessication and curettage—is the gold standard treatment for most SCCs. For high-risk cases of SCC, surgical excision or Mohs surgery is preferred. In one study, in which 260 patients with high-risk SCCs underwent Mohs surgery, the recurrence rate after almost 4 years was only 1%.14 Radiation therapy can be used when the concern for metastasis or recurrence is high or complete surgical treatment is not possible. Once metastasis has developed, a multidisciplinary team can determine the potential benefits of chemotherapy and radiation, and if any surgical resection is possible.

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DETECTING SKIN CANCER IN PRIMARY CARE

Actinic keratosis

IMAGE COURTESY OF TANIA COHEN, PA-C, MPAS.

Actinic keratosis (AK) results from sun damage and is believed to be a precancerous lesion that can develop into SCC.15 Although there is debate among healthcare providers regarding the percentage of AK lesions that progress to SCC, the treatment is relatively low risk. AK typically presents as an erythematous, scaly macule (Figure 9), a papule, or a plaque. AK lesions feel rough or scaly when palpated by the clinician. They can be solitary or multiple. Typically, there are signs of sun damage to the surrounding skin. AK can sometimes be pigmented. Lesions can present on the lip, in which case it is known as actinic cheilitis. Many times, the patient will complain of constant dryness or fissuring of the lips that is not relieved with moisturizers and low-dose topical steroids. In some cases, AK can be subtle and hard to distinguish from a simple patch of dry skin. However, dry skin will resolve after treatment with a topical steroid of appropriate strength and aggressive moisturization. AK will not resolve with topical steroids, although a slight decrease in scaliness or erythema can be noted. The diagnosis of AK is typically clinical. However, if there is any doubt regarding whether a lesion is AK, a biopsy should be performed to distinguish the lesion from SCC or a benign condition such as inflamed seborrheic keratosis or an eczematous process. There are many ways to treat AK. The most commonly used treatment, especially for a solitary lesion, is liquid nitrogen cryotherapy (cryosurgery). Cryosurgery can be painful and leave scars. Patients in whom extensive scarring may occur, who cannot tolerate the discomfort of liquid nitrogen, or who have multiple AK lesions or an area of AK with extensive surrounding sun damage are good candidates for topical field therapy. Treatment modalities for field therapy include prescription

FIGURE 9. Actinic keratosis often presents as an erythematous, scaly macule.

POLL POSITION

Which of the following is part of your routine evaluation of patients regarding skin cancer?

■ Screen for actinic exposure and risk factors ■ Recommend patients at high risk to undergo full-skin screening examinations with a dermatology provider. ■ Recommend daily use of a sunscreen with a sun protection factor ■ All of the above

4.27% 4.27% 0.67%

n=445

90.79%

For more polls, visit ClinicalAdvisor.com/Polls.

topical 5-fluorouracil (5-FU), topical imiquimod, topical ingenol mebutate, topical diclofenac, and photodynamic therapy (PDT). All of these therapies will cause irritation, inflammation, soreness, scabs, and temporary sensitivity to sunlight. Prevention

When it comes to skin cancers, the saying, “an ounce of prevention is worth a pound of cure,” holds true. Even better than detecting a skin cancer is preventing one. Screen all patients for actinic exposure and risk factors. Counsel patients on the proper use of sunscreen and sun-protective clothing and, when possible, on avoiding the sun during the hours of peak exposure. Regular daily use of a sunscreen with a sun protection factor (SPF) of 15 or higher reduces the risk for developing skin cancer by 40% to 50%.16 In addition, ensure that patients who are at high risk for skin cancer undergo full-skin screening examinations with a dermatology provider on a regular basis. Patients who have had a skin cancer are likely to develop additional skin cancers. Patients with a history of SCC have a 50% chance of developing another skin cancer within the first 5 years.17 In 40% of patients with a BCC, a second BCC will develop within 5 years.17 Because of the relative ease of treating some skin cancers, patients (and providers) can forget that patients with a history of any skin cancer require regular full-skin examinations. The dermatology provider will help determine the frequency of recommended skin examinations based on the patient’s history and risk factors. ■ Abby A. Jacobson, MS, PA-C, is an assistant professor at Thomas Jefferson University in Philadelphia, and a dermatology physician assistant at Family Dermatology of Reading, PA.

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References 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA: Cancer J Clin. 2016;66(1):7-30. 2. Guy GP, Thomas CC, Thompson T, Watson M, Massetti GM, Richardson LC. Vital signs: melanoma incidence and mortality trends and projections—United States, 1982–2030. MMWR Morb Mortal Wkly Rep. 2015;64(21):591-596. 3. American Cancer Society. Cancer facts & figures 2015. http://www.cancer. org/acs/groups/content/@editorial/documents/document/acspc-044552.pdf. 4. Thomas L, Tranchand P, Berard F, et al. Semiological value of ABCDE criteria in the diagnosis of cutaneous pigmented tumors. Dermatology. 1998;197(1):11-17. 5. MacKie RM. Clinical recognition of early invasive malignant melanoma. BMJ. 1990;301(6759):1005-1006. 6. Morton DL,Thompson JF, Cochran AJ, et al. Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med. 2014;370(7):599-609.

“I laugh at all your jokes. How come you never laugh at mine?”

7. American Cancer Society. Survival rates for melanoma skin cancer, by stage. http://www.cancer.org/cancer/skincancer-melanoma/detailedguide/ melanoma-skin-cancer-survival-rates-by-stage. Last reviewed May 19, 2016. Last revised May 20, 2016. 8. English DR, Armstrong BK, Kricker A, Winter MG, Heenan PJ, Randell PL. Demographic characteristics, pigmentary and cutaneous risk factors for squamous cell carcinoma of the skin: a case-control study. Int J Cancer. 1998;76(5):628-634. 9. Lim JL, Asgari M. Clinical features and diagnosis of cutaneous squamous cell carcinoma (SCC). UpToDate. http://www.uptodate.com/contents/ clinical-features-and-diagnosis-of-cutaneous-squamous-cell-carcinoma-scc. Updated March 16, 2016. 10. Weinberg AS, Ogle CA, Shim EK. Metastatic cutaneous squamous cell carcinoma: an update. Dermatol Surg. 2007;33(8):885-899. 11. Rowe DE, Carroll RJ, Day CL Jr. Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for treatment modality selection. J Am Acad Dermatol. 1992;26(6):976-990. 12. Brantsch KD, Meisner C, Schonfisch B, et al. Analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: a prospec-

tive study. Lancet Oncol. 2008;9(8):713-720. 13. Eliezri YD, Silverstein SJ, Nuovo GJ. Occurrence of human papillomavirus type 16 DNA in cutaneous squamous and basal cell neoplasms. J Am Acad Dermatol. 1990;23(5 Pt 1):836-842. 14. Pugliano-Mauro M, Goldman G. Mohs surgery is effective for high-risk cutaneous squamous cell carcinoma. Dermatol Surg. 2010;36(10):1544-1553. 15. Padilla RS, Sebastian S, Jiang Z, Nindl I, Larson R. Gene expression patterns of normal human skin, actinic keratosis, and squamous cell carcinoma: a spectrum of disease progression. Arch Dermatol. 2010;146(3):288-293. 16. Johnson SM. Black is the new orange. Pract Dermatol. 2016;13(4):40-41. 17. Karagas MR, Stukel TA, Greenberg ER, Baron JA, Mott LA, Stern RS. Risk of subsequent basal cell carcinoma and squamous cell carcinoma of the skin among patients with prior skin cancer. Skin Cancer Prevention Study Group. JAMA. 1992;267(24):3305-3310. All electronic documents accessed May 27, 2016.

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CME FEATURED COURSE

n EDUCATIONAL OBJECTIVES At the conclusion of this activity, participants should be better able to: • Implement current guidelines for recognition, diagnosis, and optimal management of anaphylaxis • Adopt the use of injectable epinephrine as the only suitable first-line treatment for anaphylaxis or possible anaphylaxis • Provide post-treatment counseling and emergency action plans incorporating epinephrine autoinjectors for at-risk patients and their caregivers n COMPLETE THE POST-TEST: Page 39

Release Date: March 15, 2016 Expiration Date: July 31, 2017 Estimated Time to Complete: 30 minutes Accredited Provider: This educational activity is provided by Haymarket Medical Education. Commercial Supporter: This activity is supported by an educational grant from Mylan Pharmaceuticals. Program Description: Anaphylaxis, an acute, systemic, potentially life-threatening allergic reaction, is so commonly misdiagnosed or underreported that reliable statistics about it are elusive, but its prevalence is increasing. Swift intervention is required, followed by comprehensive follow-up, including development of an emergency action plan. Yet alarmingly wide gaps are documented between usual care and optimal, guidelines-concordant anaphylaxis care. These gaps are apparent among emergency department (ED) personnel as well as allergists, primary care physicians, and others. Anaphylaxis recognition and diagnosis are challenging, familiarity with management guidelines is suboptimal, and too few understand that first-line treatment, whether in a clinical setting or when administered by patients/caregivers, should always be epinephrine. Furthermore, patients frequently get inadequate follow-up, although they require testing to identify triggers, counseling about trigger avoidance, and prescriptions for epinephrine autoinjectors along with clear instructions about why, how, and when to use them. Intended Audience: Emergency room physicians, allergists, primary care physicians, nurse practitioners, physician assistants, and other clinicians who provide care to patients with a history of, or who are at risk for, anaphylaxis Conflict of Interest Disclosure Policy: In accordance with the ACCME Standards for Commercial Support, HME requires that individuals in a position to control the content of an educational activity disclose all relevant financial relationships with any commercial interest. HME resolves all conflicts of interest to ensure independence, objectivity, balance, and scientific rigor in all its educational programs.

Faculty Dislosure: Dr. Wood has no disclosures to report with any commercial interest relative to this CME activity. Accredited Provider Disclosure: Haymarket Medical Education staff involved in the planning and content review of this activity have no relevant financial relationships to disclose. Accreditation Statement: Haymarket Medical Education is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. Designation Statement: Haymarket Medical Education designates this enduring material for a maximum of 0.50 AMA PRA Category 1 CreditTM. Physicians should claim only those credits commensurate with the extent of their participation in the activity. Disclosure of Unlabeled Use: This educational activity may contain discussion of approved and/or investigational uses of agents that are not indicated by the FDA. Mylan Pharmaceuticals and HME do not recommend the use of any agent outside of the labeled indications. Disclaimer: The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of Mylan Pharmaceuticals and HME. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. If you have any questions relating to the accreditation of this activity, please contact cmequestions@haymarketmedical.com. Instructions: There are no fees for participating in and receiving CME credit for this activity. During the period March 15, 2016 through July 31, 2017, participants must: 1) read the learning objectives and faculty disclosures; 2) complete the pre-assessment test; 3) study the educational activity; 4) complete all polling questions; 5) complete the post-test and submit it online. A statement of credit will be issued only upon receipt of the above elements and a post-test score of 70% or higher. All components must be completed and submitted online at myCME.com/July16CAfeature.

Faculty Joseph P. Wood, MD, JD, FACEP, FAAEM Assistant Professor of Emergency Medicine Vice Chair, Department of Emergency Medicine Mayo Clinic Scottsdale, AZ

Provided by

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CME

FEATURED COURSE: JOSEPH P. WOOD, MD, JD, FACEP, FAAEM

Anaphylaxis management: achieving optimal care Swift intervention and follow-up are key to treating this life-threatening allergic reaction, but the treatment guidelines are not well understood.

atricia L, a 37-year-old receptionist, is brought to the emergency department (ED) in an ambulance. She reports experiencing severe cramps, diaphoresis, flushing, nausea, and abdominal pain that began about a half hour after she ate dinner. Her back is itchy and has diffuse hives. The airway is patent, lung sounds are present and clear bilaterally, there are normal heart sounds, and there is abdominal tenderness on palpation. Electrocardiogram shows normal sinus rhythm. The patient is afebrile. Upon further questioning, she indicates that her dinner included shellfish. Patricia’s vital signs are: • Pulse: 100 beats/minute • Respiratory rate: 25 breaths/minute • Blood pressure: 100/70 mm Hg What is the patient’s likely diagnosis?

First step: reaching an accurate diagnosis of anaphylaxis

Swift management of anaphylaxis is key.

Anaphylaxis, a potentially life-threatening allergic reaction, occurs within minutes to hours of contact with an allergen.1 Accurate diagnosis of this emergent condition is critical, but it is often missed because early signs and symptoms are easily confused with those of other conditions.2 Multiple chart reviews and surveys of EDs have found that patients are frequently given a diagnosis of acute allergic reaction rather than anaphylaxis.3 Multiple national and international organizations have issued definitions and guidelines for anaphylaxis recognition, diagnosis, and treatment in the

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past 10 years. Among them are the National Institute of Allergy and Infectious Diseases; Food Allergy Research and Education (FARE, formerly known as the Food Allergy and Anaphylaxis Network); the American Academy of Allergy, Asthma & Immunology (AAAAI) in collaboration with the American College of Allergy, Asthma & Immunology (ACAAI); and the World Allergy Organization (WAO).4-6 Table 1 displays the diagnostic criteria of the WAO. Epidemiology

A 2006 review of epidemiologic studies found anaphylaxis to be a relatively common problem, affecting up to 2% of the US population, with an estimated 50 to 2000 episodes per 100,000 persons, or a lifetime prevalence of 0.05% to 2.0%.7 The largest number of incident cases was found among children and adolescents, but anaphylaxis can occur at any age. TABLE 1. World Allergy Organization (WAO) clinical criteria for diagnosing anaphylaxis6

Fatalities are relatively rare, but when they do occur, they occur quickly and unpredictably, often before emergency medical service (EMS) personnel can arrive or before the patient can get to the ED. There are several different estimates of the incidence of anaphylactic fatalities. It is estimated to cause death in 0.65% to 2.0% of patients (ie, 1 to 3 deaths per 1 million population).8 In the United Kingdom, 1 case of fatal anaphylaxis per 3 million individuals annually (~20 deaths) has been reported.9 An analysis of 3 major national databases found the mortality rate in patients with anaphylaxis treated in US EDs or hospitals to be between 0.25% and 0.33% (63 to 99 deaths annually).10 Presentation

Anaphylaxis is characterized by an array of complex mechanisms, triggers, clinical presentations, degrees of severity, and rates of progression.2 For this reason, reaching an accurate diagnosis can be challenging (Table 2). A common misconception, TABLE 2. Approaching the differential diagnosis6

Anaphylaxis is highly likely when any 1 of the following 3 criteria is fulfilled:

Multiple conditions and syndromes need to be considered in the differential diagnosis of anaphylaxis, including:

1. A cute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or both (eg, generalized hives; pruritus or flushing; swollen lips, tongue, or uvula) and at least 1 of the following: • Respiratory compromise (eg, dyspnea, wheeze, bronchospasm, stridor, reduced peak expiratory flow, hypoxemia) • Reduced blood pressure or associated symptoms of end-organ dysfunction (eg, hypotonia, syncope, incontinence)

Acute asthma

2. Two or more of the following that occur rapidly after exposure to a likely allergen for that patient a (minutes to several hours): • Involvement of the skin/mucosal tissue (eg, generalized hives; itch-flush; swollen lips, tongue, or uvula) • Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak expiratory flow, hypoxemia) • Reduced blood pressure or associated symptoms (eg, hypotonia, syncope, incontinence) • Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)

Cardiovascular (eg, myocardial infarction, pulmonary embolus)

3. Reduced blood pressure after exposure to known allergen for that patient b (minutes or hours) • Infants and children: low systolic blood pressure (age-specific) or >30% decrease in systolic blood pressurec • Adults: systolic blood pressure <90 mm Hg or >30% decrease from that person’s baseline

Nonorganic disease (eg, vocal cord dysfunction, hyperventilation)

a Or other trigger; eg, immunologic but immunoglobulin (Ig)E-independent or nonimmunologic (direct) mast cell activation. b For example, after an insect sting; reduced blood pressure might be the only manifestation of anaphylaxis. c Low systolic blood pressure for children: <70 mm Hg from 1 month to 1 year; <70 mm Hg + 2X age from 1 to 10 years; <90 mm Hg from 11 to 17 years. Normal heart rate: 80-140 beats/min at age 1-2 years; 80-120 beats/min at age 3 years; and 70-115 beats/min after age 3 years. Infants are more likely to have respiratory compromise than hypotension or shock, which is more likely to be manifest initially by tachycardia than by hypotension.

Syncope Anxiety/panic attack Aspiration of foreign body

Neurologic event (eg, seizure, cerebrovascular event) Postprandial syndromes (eg, pollen-food allergy syndrome, monosodium glutamate, sulfites, food poisoning) Excess endogenous histamine (eg, mastocytosis/clonal mast cell disorders, basophilic leukemia) Flush syndromes (eg, perimenopause)

Shock (hypovolemic, distributive, septic) Nonallergic angioedema Angiotensin-converting enzyme (ACE) inhibitor–associated angioedema Hereditary angioedema types I, II, and III Systemic capillary leak syndrome Red man syndrome (vancomycin-related) Pheochromocytoma (paradoxical response)

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even among physicians, is that a diagnosis of anaphylaxis can be given only in the presence of shock, so its less obvious presentations frequently go unrecognized. Although multiple organ systems are typically affected, a diagnosis of anaphylaxis can be made even if only 1 organ system is involved (Table 3).6 The clinical history is the most important tool in determining whether a patient is having an anaphylactic episode and identifying what triggered it.11 When a patient presents with characteristic symptoms and signs, a detailed history should be taken, including onset of symptoms, agents encountered prior to the reaction (eg, foods, medication, insect bites/ stings, latex), and activities (eg, exercise, sexual activity).12 Although symptoms can occur within seconds after exposure to the trigger, the more typical symptom onset takes place within 5 to 30 minutes. Sometimes symptoms do not appear until several hours after contact with the trigger. More rapid symptom onset is associated with a more severe and life-threatening reaction.4 Symptoms usually resolve within hours of treatment; however, up to 20% of reactions are biphasic, with a recurrence of symptoms after a 1- to 8-hour asymptomatic period.13 Laboratory tests are not necessarily helpful in confirming or ruling out anaphylaxis, and treatment with epinephrine should not be delayed pending test results.6 Nevertheless, the clinical diagnosis can sometimes be supported by documentation of elevated concentrations of serum or plasma total tryptase or plasma histamine.5 Normal serum tryptase and plasma histamine levels do not preclude a clinical diagnosis of anaphylaxis.6

and angiotensin receptor blockers [ARBs]) contributes to vulnerability toward medication-induced anaphylaxis.17 An analysis of diagnosis, presentation, and management of vulnerable patient groups can be found in Table 4. ■ Based on these criteria, Patricia’s symptoms meet the definition of anaphylaxis: the onset of her illness was acute (following a meal whose contents are suggestive of a potential trigger); she has persistent, classic gastrointestinal symptoms; and she has itching and hives. Her heart rate and respiratory rate are both mildly elevated and her blood pressure is mildly low. What type of anaphylaxis does Patricia likely have? Pathophysiology

The pathophysiology of anaphylaxis is complex and multifactorial, involving IgE-mediated and non–IgE-mediated reactions as well as nonimmune and idiopathic processes TABLE 3. Signs and symptoms of anaphylaxis6 Organ system

Symptoms

Skin, subcutaneous and mucosa

• Flushing, itching, urticaria, angioedema, morbilliform rash, pilor erection • Periorbital itching, erythema, edema, conjunctival erythema, tearing • Itching of lips, tongue, palate, external auditory canals; swelling of lips, tongue, uvula • Itching of genitalia, palms, soles

Respiratory

• Nasal itching, congestion, rhinorrhea, sneezing • Throat itching/tightness, dysphonia, hoarseness, stridor, dry staccato cough • Lower airways: increased respiratory rate, dyspnea, chest tightness, deep cough, wheezing/ bronchospasm, decreased peak expiratory flow • Cyanosis • Respiratory arrest

Gastrointestinal

• Abdominal pain, nausea, vomiting (stringy mucus), diarrhea, dysphagia

Cardiovascular

• Chest pain • Tachycardia, bradycardia (less common), other arrhythmias, palpitations • Hypotension, feeling faint • Urinary/fecal incontinence, shock • Cardiac arrest

Central nervous system

• Aura of impending doom, uneasiness • Infants and children: sudden behavioral changes • Throbbing headache (pre-epinephrine) • Altered mental status, confusion • Dizziness • Tunnel vision

Other

• Metallic taste in the mouth • Cramps/bleeding due to uterine contractions

Diagnostic challenges

Anaphylaxis is often difficult to recognize in vulnerable populations, such as infants, children, and the elderly. Diagnostic challenges are traceable to verbal inadequacy as well as nonclassic presentations.14-17 A recent analysis of data from the European Anaphylaxis Registry examined trends in 1970 patients under the age of 18 years and found that different triggers predominated at different stages of childhood.18 Overall, food items were the most frequent trigger (66%), followed by insect venom (19%). Peanuts were triggers in all age groups, but milk and eggs were prevalent elicitors in the first 2 years, while hazelnuts and cashews predominated in preschool-aged children. There was a continuous shift from food-induced to insect venom–induced and drug-induced anaphylaxis up to age 10 years. In children under age 10, vomiting and cough were prevalent symptoms, while nausea, throat tightness, and dizziness were prevalent later in life. In the elderly, the high rate of polypharmacy (eg, betablockers, angiotensin-converting enzyme [ACE] inhibitors,

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(Table 5).6 IgE and non-IgE antibodies trigger a cascade of inflammatory and vasoactive substances via mast cells and basophil activation. In IgE-mediated anaphylaxis, antigenspecific antibodies bind to mast cells and basophils upon exposure to the antigen; subsequent reexposure to that antigen triggers mast cell and/or basophil degranulation. Preformed mediators (histamine), enzymes (tryptase), and cytokines (tumor necrosis factor [TNF]) are released, activating eosinophils, which in turn release more inflammatory mediators. T cells are implicated in non-IgE-mediated reactions, which are typically more delayed in onset than are IgE-mediated reactions (4-28 hours after exposure to the allergen).19-21 Both IgE- and non–IgE-mediated reactions culminate in the release of histamines, which play a central role in anaphylaxis. Local histamine release in the skin is responsible for

urticaria, while hemodynamic and cardiovascular changes are associated with systemic histamines. Histamine binds to H1 and H2 receptors on target cells, both of which mediate flushing, hypotension, and headache, while only H1 receptors mediate tachycardia, pruritus, rhinorrhea, and bronchospasm.19 Agents such as opioids, dextrans, protamine, and vancomycin are more likely to trigger nonimmunologicmediated reactions. Idiopathic anaphylaxis is considered a diagnosis of exclusion, given only after all other explanations have been exhausted.22 ■ Patricia’s symptoms appeared shortly after she consumed shellfish, a trigger known to be IgE-mediated. Now that the diagnosis of anaphylaxis has been established, what is your next step?

TABLE 4. Anaphylaxis in vulnerable populations6,14,15,17 Infants

Children

Elderly

Pregnant women

Primary trigger

• Food allergens (especially milk)

• Food allergens (especially peanuts)

• Medication allergy • Subclinical CV disease

• Oxytocin (during labor/ delivery) • Antimicrobial for group B hemolytic streptococcal infection prophylaxis • L atex • Muscle relaxants

Presenting symptoms

• Dysphagia • Drooling • Persistent vomiting • Irritability • Pruritus • Hypotension • Hives • Wheezing • Dyspnea • C V symptoms less common

• B ehavioral changes (eg, irritability, cessation of play, clinging to parent) • W heezing • Dyspnea • C V symptoms less common

• C an present as ACS (angina, MI, arrhythmias) before or in the absence of epinephrine injection

• U terine cramping • Lower back pain • Preterm labor

Treatment

• IM epinephrine dose 0.01 mg/kg of a 1:1000 (1 mg/mL) solution • Autoinjector dose: 0.15 mg for children who weigh 10-25 kg; 0.3 for those who weigh >25 kg • Monitor for potential hypertension based on lower normal values than in children/adults • Monitor for cough/respiratory distress (could be symptoms of pulmonary edema) • Place child in comfortable (not necessarily recumbent) position with legs elevated in the event of respiratory distress and/or vomiting

• IM epinephrine dose 0.01 mg/kg of a 1:1000 (1 mg/mL) solution • Autoinjector dose: 0.15 mg for children who weigh 10-25 kg; 0.3 for those who weigh >25 kg • Place child in comfortable (not necessarily recumbent) position with legs elevated in the event of respiratory distress and/ or vomiting

• No absolute contraindication to treatment with epinephrine in patients with CVD and limited cardiac reserve or concurrent medications (eg, beta-adrenergic blockers) • Weigh risks/benefits carefully

• Epinephrine IM injection • Supplemental oxygen • Management of hypotension • Place patient semirecumbent on left side, with lower extremities elevated • Monitor maternal oxygenation, BP, cardiac rate/function • Monitor fetal heart rate

ACS, acute coronary syndrome; BP, blood pressure; CV, cardiovascular; CVD, cardiovascular disease; IM, intramuscular; MI, myocardial infarction.

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Epinephrine: The only evidence-based first-line treatment

It is critical for a patient diagnosed with anaphylaxis to receive appropriate first-line treatment with intramuscular (IM) epinephrine.5,6 Undertreatment or treatment with other agents increases the risk for worsening reactions, dangerous biphasic reactions (eg, those occurring up to 72 hours post exposure), and fatal complications.2 Multiple studies have found that even when anaphylaxis is correctly diagnosed, corticosteroids or antihistamines rather than epinephrine are often given as first-line interventions.3 One reason is that misunderstandings abound regarding the safety, dosing, and administration of epinephrine. Many clinicians believe that it is a dangerous drug that should be reserved only as a last resort for cases of shock or when other agents have failed.2,23,24 While side effects (pallor, tremor, anxiety, palpitations, dizziness, and headache) are common upon administration of epinephrine, they are usually transient and indicate that the patient has indeed received a therapeutic dose. Serious adverse effects (eg, ventricular arrhythmias, hypertensive crisis, and pulmonary edema) may occur in the setting of epinephrine overdose—most commonly after intravenous (IV) bolus injection, excessively rapid IV infusion, or an erroneous IV injection of a 1 mg/mL (1:1000) epinephrine solution instead of an appropriately diluted 0.1 mg/mL (1:10,000) epinephrine solution.25 Epinephrine is not contraindicated in patients with known or suspected cardiovascular disease or in middle-aged or elderly patients without coronary artery disease but who are at increased risk of acute coronary syndrome due to age.6 In contrast to the strong evidence base for epinephrine, there is no clinical evidence supporting the efficacy of antihistamines or glucocorticoids as first-line treatment for anaphylaxis (with or without the presence of shock): IM epinephrine is the only recommended first-line treatment.3,26,27 Failure to promptly treat patients with suspected anaphylaxis with epinephrine is associated with an increased risk of fatality, hypoxia/ischemia, encephalopathy, and biphasic reaction. It is critical to recognize that IM epinephrine should be administered when a patient presents with symptoms of anaphylaxis, even if uncertainty about the diagnosis remains.28 Epinephrine mechanism of action

Epinephrine is an agonist to the beta1-, beta 2-, and alphaadrenergic receptors. It increases vasoconstriction, blood pressure, heart rate, and bronchodilation.11 Its alpha-agonist

effects trigger vasoconstriction, thus decreasing the mucosal edema, preventing and relieving upper airway obstruction, and increasing blood pressure—thereby preventing and relieving shock.25 Its beta1 effects increase the rate and force of cardiac contractions, while its beta2 effects increase bronchodilation and decrease the release of histamine, tryptase, and other inflammatory mediators from mast cells and basophils.25 Second-line agents

Antihistamines (H1- and H2-agonists) and glucocorticoids are considered second-line agents. The evidence for their use in anaphylaxis is extrapolated from their use in treatment of other conditions. Antihistamines have a slower onset of action than epinephrine; beta2-agonists can be helpful with lower respiratory tract symptoms but cannot be substituted for epinephrine because they have minimal alpha-agonist vasoconstrictor effects and do not prevent upper airway obstructions. H2-antihistamines can potentially contribute to decreased flushing and headache, but rapid IV administration can increase hypotension. Glucocorticoids are commonly used to relieve protracted symptoms and prevent biphasic anaphylaxis, although there is scant evidence to support this practice, which is extrapolated from their utility in acute asthma.6 TABLE 5. Anaphylaxis mechanisms and selected triggers6 Mechanism

Triggers (examples)

Immunologic (IgE-dependent)

• Foods (peanuts, tree nuts, shellfish, fish, milk, eggs, soybeans, peaches, sesame) • Venoms (stinging insects) • Medications (β-lactam antibiotics, NSAIDs, biologic agentsa) • Natural latex • Aeroallergens • R adiocontrast media a

Immunologic (not IgE-dependent)

• Radioconstrast media a • NSAIDsa • Dextrans (eg, high-molecular-weight iron) • B iologic agentsa (eg, some monoclonal antibodies)

Nonimmunologic (direct mast cell activation)

• Physical factors (eg, exercise, cold, heat, sunlight) • Ethanol • Medications (eg, opioids)

Idiopathic

• Previously unrecognized allergies (?) • Mastocytosis/clonal mast cell disorder?

IgE, immunoglobulin E; NSAIDs, nonsteroidal anti-inflammatory drugs. a T riggers anaphylaxis via more than 1 mechanism.

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Delivery systems and dosing considerations

While epinephrine is available in IM, subcutaneous (SC), and IV formulations, the IM injection into the midanterolateral aspect of the thigh is recommended by most guidelines as the route of choice.25 When injected into skeletal muscle, epinephrine has a vasodilator effect that facilitates rapid absorption into the central circulation. The pros and cons of each delivery system are found in Table 6. To promptly achieve peak plasma and tissue epinephrine concentrations, patients should receive an IM injection of 0.01 mg/kg of a 1:1000 (1 mg/mL) solution, up to a maximum of 0.5 mg in adults and 0.3 mg in children. The dose can be repeated every 5 to 15 minutes as needed, depending on the severity of the episode and the response to the initial injection. Most patients, however, respond to prompt administration of 1 to 2 doses.6 ■ Patricia is treated with a therapeutic dose of IM epinephrine, after which she experiences resolution of her nausea, stomach cramps, and hives. Her pulse, respiration, and blood pressure normalize Now that Patricia has stabilized, what is your next step? Discharging patients following an anaphylactic episode

When a patient’s symptoms have resolved, the duration of monitoring in a healthcare setting should be individualized

based on the severity of the episode.6 Patients who have experienced moderate respiratory or cardiovascular compromise should be monitored for at least 4 hours, and possibly for as long as 8 to 10 hours. Patients with severe or protracted anaphylaxis require longer or more intense monitoring. Biphasic reactions can occur anywhere from 1 to 72 hours after initial symptom onset.29 In cases involving children, approximately 5% to 20% experience a biphasic reaction, with 3% having a significant reaction requiring oxygen, vasopressors, intubation, repeat epinephrine administration, or unscheduled bronchodilator treatment. Since biphasic reactions typically occur within the first 4 to 6 hours after initial symptom onset, it is “reasonable” to discharge patients after that time period. Parents of children with an anaphylactic reaction must be counseled to monitor for this potential occurrence for up to 72 hours. Because patients remain at risk for subsequent anaphylactic reactions after their initial presentation, optimal treatment requires education, counseling, and plans for long-term management. Epinephrine autoinjectors are considered the cornerstone of emergency preparedness.25 It is critical to emphasize that, in the rare event that anaphylaxis is immediately life-threatening, time is of the essence. While emergency services should be called at once, treatment must be administered immediately, without waiting for EMS to arrive. The time from exposure to the allergen to full cardio-

TABLE 6. Pros and cons of epinephrine routes of administration in anaphylaxis25 Delivery system

Pros

Cons

Intramuscular (IM)

• Vasodilation effect in skeletal muscle • Skeletal muscle is highly vascular, leading to rapid absorption • Drug injected into vastus lateralis reaches central circulation rapidly • B enefit-to-risk ratio is optimal • Most commonly recommended route worldwide

• Currently available autoinjector needle lengths and gauges are not optimal for IM injection in overweight or obese patients • Not effective in poor/absent muscle effusion due to shock or cardiorespiratory arrest

Subcutaneous (SC)

• Readily accessible sites of injection

• Even in a 1:100,000 dilution, epinephrine leads to vasoconstriction/blanching of SC tissue • Epinephrine slows its own absorption from SC tissue • SC tissue is more poorly vascularized than skeletal muscle • Low tissue epinephrine levels potentially lead to increased vasodilation and increased mediator release • R apid epinephrine absorption is more critical in anaphylaxis than in asthma

Intravenous (IV)

• Optimal for patients with severe anaphylaxis who have not responded to IM administration and/or are experiencing profound hypotension/shock with imminent cardiorespiratory arrest

• Establishing peripheral intravenous route for administration may be difficult in these patients • Narrower benefit-to risk ratio • G reater risk of iatrogenic error • Optimally given through infusion pump and central line, requires training, experience, and constant monitoring

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pulmonary arrest varies. A British study found that approximately half of the 20 fatalities recorded annually in the United Kingdom were iatrogenic, and a quarter of them were due to food or insect venom, respectively. The median time to cardiac arrest was 30 minutes for food, 15 minutes for venom, and 5 minutes for iatrogenic reactions.30 National and international allergy association guidelines recommend that all patients seen in the primary care or emergency setting for anaphylaxis receive the following at discharge: • Prescription for at least 2 epinephrine autoinjectors: Since patients may experience a biphasic reaction, ensuring that they have an autoinjector is essential immediately after leaving the healthcare facility. And since there may be a recurrence even after the 72-hour period, they must have a second autoinjector on hand. Children at risk for anaphylaxis also need to have 2 doses of epinephrine accessible because the first dose may not be administered effectively, symptoms may persist even if the first dose was effective, or the child may experience a biphasic episode.14 • Education regarding why, when, and how to use epinephrine autoinjectors: Patients and caregivers must be trained to use autoinjectors correctly. Between 1994 and 2007, more than 15,000 epinephrine injections from autoinjectors were performed incorrectly, causing injury and lost doses.31 • A personalized emergency action plan: Patients and caregivers need an action plan preparing them for selfmanagement in the event of an emergency, emphasizing prompt use of epinephrine followed by prompt medical assistance; common signs and symptoms of anaphylaxis; and when and how epinephrine should be administered. Also, patients should have some type of medical identification on their person at all times.5,6 • Referral for medical follow-up to identify triggers of anaphylaxis: A follow-up consultation with a specialist in allergy/immunology should be arranged to confirm the patient’s specific trigger or triggers. Education should be provided regarding trigger avoidance, and written information about anaphylaxis prevention should be disseminated in the community. Immunomodulation (eg, SC venom immunotherapy) should be utilized if relevant.5,6 Since severe allergies, especially food allergies, cause significant anxiety and reduced quality of life, it is critical that clinicians provide information about and manage the anxiety of both caregivers and patients who are at risk for anaphylaxis. Implementation and use of management protocols in EDs that specify these instructions have been

shown to statistically improve the number of patients with anaphylaxis who receive follow-up care.32 Any interaction for the education and counseling of patients with anaphylaxis for the long-term management of this condition also needs to recognize and address specific features unique to each individual that may prove a barrier to the effective management of anaphylaxis or impede strategies to reduce its recurrence.6,23 This should include a discussion of economic aid for allergy medicines, including epinephrine autoinjectors, and the number of autoinjectors needed (eg, for home, office/school, purse/pocket), as well as the education of a wider caregiver population (eg, school staff/officials, babysitters, coworkers). Furthermore, the treatment of adolescents requires careful consideration of when to transition responsibility from caregivers to the patient and counseling about the risks associated with common behaviors that could transmit life-threatening allergens (eg, kissing). All healthcare facilities should have a posted, written anaphylaxis emergency protocol and healthcare providers should rehearse the plan regularly. Autoinjectors with epinephrine should always be kept on hand. The sidebar, A Cautionary Tale, describes litigation brought against a nurse and a home infusion company for failing to have an epinephrine autoinjector available for a child who experienced anaphylaxis while receiving a transfusion of methylprednisolone. ■ Since Patricia’s anaphylactic episode was relatively mild, without significant respiratory or cardiovascular compromise, she can be discharged at the discretion of the clinician. The length of monitoring is highly individualized and will depend on degree of recovery. Patricia’s clinician decides to discharge her after a 6-hour period of observation. Upon discharge, Patricia receives a prescription for 2 epinephrine autoinjectors. The clinician reviews an emergency plan with her and encourages her to consult an allergist or immunologist. Patricia follows up with an allergist, and skin testing reveals that she is indeed allergic to shellfish. She informs her family and purchases medical identification jewelry. With a careful avoidance of triggers, she does not have a recurrence of anaphylaxis. Conclusion

Anaphylaxis is a potentially life-threatening allergic reaction that has a significant economic and quality-of-life impact on patients and their caregivers. Death from anaphylaxis is preventable and requires that the multidisciplinary team encountering emergent reactions be competent in their ability to quickly diagnose this condition and implement recommended

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A cautionary tale—Medicolegal implications of emergency anaphylaxis care A few years ago, a nurse employed by a company that specialized in home infusions administered intravenous (IV) methylprednisolone to a 12-year-old girl with uveitis. The patient had received these infusions on 3 prior occasions without incident. However, within seconds after treatment initiation, the patient complained that she was unable to breathe. The nurse discontinued the infusion and requested that the patient’s mother immediately call 911. The patient had a seizure. Attempts to engage in mouth-to-mouth resuscitation were unsuccessful. The patient’s condition rapidly deteriorated, and she went into full respiratory and then cardiac arrest, suffering significant oxygen loss that resulted in severe and permanent hypoxic brain damage. The family filed a malpractice suit, which the defendant nurse attempted to have dismissed on the grounds that epinephrine was not included in the box of supplies delivered by the company to the patient’s home and that the patient’s physician did not prescribe it. In an effort to have the case dismissed, her attorney therefore argued that she had no way of obtaining the medication without a prescription. The trial court denied the nurse’s motion for dismissal, concluding that she and the infusion company should have taken reasonable steps to ensure that epinephrine was available prior to starting the infusion. As the plaintiff’s attorney pointed out, anaphylaxis is a known complication of IV methylprednisolone, and the product monograph advises those administering the drug to “keep epinephrine immediately available.” The nurse appealed, but the appellate court affirmed the initial decision, stating that:

treatment guidelines. In addition, patients and their caregivers require long-term, patient-centered care in the form of epinephrine autoinjector training, emergency anaphylaxis action plans, and counseling on allergen avoidance. ■

“…the notion that a nurse should be aware of the importance of having epinephrine available when administering medication in the home setting is not a difficult one to embrace. After all, the fact that epinephrine is the antidote to anaphylaxis is widely known among laypeople…. Moreover, the administration of epinephrine is far from a radical procedure. Rather, the medicine is easily transportable in the form of auto-injector devices….” The appellate court also noted that although the treating physician had not ordered epinephrine, the role of registered nurses has evolved: “…the role of the registered nurse has changed, in the last few decades, from that of a passive, servile employee to that of an assertive, decisive health care provider. Today, the professional nurse monitors complex physiological data, operates sophisticated lifesaving equipment, and coordinates the delivery of a myriad of patient services. As a result, the reasonably prudent nurse no longer waits for and blindly follows physicians’ orders.” (65 NY2d 71) Although this case involved a nurse and a home infusion company, it is a cautionary tale for all healthcare providers, regardless of the setting of care. In short, while a particular practice may be common (in this case, the physician prescribing IV methylprednisolone without an accompanying order for epinephrine) that does not mean that it should be regarded as the standard of care. Source: Supreme Court, Appellate Division, First Department, New York. Applewhite v Accuhealth, Inc. FindLaw website. http://caselaw.findlaw.com/ny-supreme-court-appellatedivision/1549897.html. Decided December 28, 2010. Accessed February 23, 2016.

5. Simons FE, Ardusso LR, Dimov V, et al. World Allergy Organization anaphylaxis guidelines: 2013 update of the evidence base. Int Arch Allergy Immunol. 2013;162(3):193-204. 6. Simons F, Ardusso LR, Bilò MB, et al. World Allergy Organization anaphylaxis guidelines: summary. J Allergy Clin Immunol. 2011;127(3):587-593.

References

7. Lieberman P, Camargo CA Jr, Bohlke K, et al. Epidemiology of anaphy-

1. Gupta RS. Anaphylaxis in the young adult population. Am J Med.

laxis: findings of the American College of Allergy, Asthma and Immunology

2014;127(1):S17-S24.

Epidemiology of Anaphylaxis Working Group. Ann Allergy Asthma Immunol.

2. Fineman SM, Bowman SH, Campbell RL, et al. Addressing barriers to emergency

2006;97(5):596-602.

anaphylaxis care: from emergency medical services to emergency department

8. Moneret-Vautrin DA, Morisset M, Flabbee J, et al. Epidemiology of life-

to outpatient follow-up. Ann Allergy Asthma Immunol. 2015;115(4):301-305.

threatening and lethal anaphylaxis: a review. Allergy. 2005;60(4):443.

3. Sclar DA, Lieberman PL. Anaphylaxis: underdiagnosed, underreported,

9. Pumphrey R. Anaphylaxis: can we tell who is at risk of a fatal reaction?

and undertreated. Am J Med. 2014;127(1):S1-S5.

Curr Opin Allergy Clin Immunol. 2004;4(4):285.

4. Lieberman P, Nicklas R, Oppenheimer J, et al. The diagnosis and man-

10. Ma L, Danoff TM, Borish L. Case fatality and population mortality

agement of anaphylaxis practice parameter: 2010 update. J Allergy Clin

associated with anaphylaxis in the United States. J Allergy Clin Immunol.

Immunol. 2010;126(3):477-480.

2014;133(4):1075-1083.

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11. Arnold JJ, Williams PM. Anaphylaxis: recognition and management. Am Fam Physician. 2011;84(10):1111-1118.

CME

12. Kim H, Fischer D. Anaphylaxis. Allergy Asthma Clin Immunol. 2011;7 (suppl 1):S6. 13. Stark BJ, Sullivan TJ. Biphasic and protracted anaphylaxis. J Allergy Clin Immunol. 1986;78(1 pt 1):76-83.

POST-TEST Expiration date: July 31, 2017

14. Dinakar C. Anaphylaxis in children: current understanding and key issues in diagnosis and treatment. Curr Allergy Asthma Rep. 2012;12(6):641-649.

FEATURED COURSE

15. Dosanjh A. Infant anaphylaxis: the importance of early recognition.

CREDITS: 0.50 AMA PRA Category 1 Credit TM

J Asthma Allergy. 2013;6:103-107. 16. Topal E, Bakirtas A, Yilmaz O, et al. Anaphylaxis in infancy compared

For more credit information, please turn to p. 30.

with older children. Allergy Asthma Proc. 2013;34(3):233-238. 17. Khan BQ, Lieberman P. Anaphylaxis in the elderly. Aging Health. 2008;4(4):377-387. 18. Grabenhenrich LB, Dölle S, Moneret-Vautrin A, et al. Anaphylaxis in children and adolescents: The European Anaphylaxis Registry [published online January 21, 2016]. J Allergy Clin Immunol. doi:10.1016/j.jaci.2015.11.015. 19. Simons FE. Anaphylaxis pathogenesis and treatment. Allergy. 2011;66 (suppl 95):31-34. 20. Peavy RD, Metcalfe DD. Understanding the mechanisms of anaphylaxis. Curr Opin Allergy Clin Immunol. 2008;8(4):310-315. 21. Johnson RF, Peebles RS Jr. Anaphylactic shock: pathophysiology, recognition, and treatment. Semin Respir Crit Care Med. 2004;25(6):695-703. 22. Lenchner K, Grammer LC. A current review of idiopathic anaphylaxis. Curr Opin Allergy Clin Immunol. 2003;3(4):305-311. 23. Bennett JR, Fromer L, Hayden ML. Anaphylaxis challenges on the front line: perspectives from community medicine. Am J Med. 2014;127(1):S25-S33. 24. Wood JP, Traub SJ, Lipinski C. Safety of epinephrine for anaphylaxis in the emergency setting. World J Emerg Med. 2013;4(4):245-251. 25. Simons KJ, Simons ER. Epinephrine and its use in anaphylaxis: current issues. Curr Opin Allergy Clin Immunol. 2010;10(4):354-361. 26. O’Leary FM, Hokin B, Enright K, Campbell DE. Treatment of a simu lated child with anaphylaxis: an in situ two-arm study. J Paediatr Child Health. 2013;49(7):541-547. 27. Dhami S, Panesar SS, Roberts G, et al. Management of anaphylaxis: a systematic review. Allergy. 2014;69(2):168-175. 28. Lieberman PL. Recognition and first-line treatment of anaphylaxis. Am J Med. 2014;127(1):S6-S11. 29. Cheng A. Emergency treatment of anaphylaxis in infants and children. Paediatr Child Health. 2011;16(1):35-40. 30. Pumphrey RS. Lessons for management of anaphylaxis from a study of fatal reactions. Clin Exp Allergy. 2000;30(8):1144-1150.

1. What is the most important tool in determining whether a patient is having an anaphylactic reaction? a. Clinical history b. Physical examination c. Laboratory testing of plasma histamine d. Laboratory testing of serum or plasma total tryptase 2. In the treatment of anaphylaxis, antihistamines and glucocorticoids are: a. First-line agents b. Second-line agents c. Always contraindicated d. Safer than epinephrine 3. Under what circumstance might a patient develop serious adverse effects to epinephrine? a. Preexisting cardiovascular disease b. Age >65 c. Polypharmacy d. Overdose as a result of bolus injection 4. For how long after an anaphylactic reaction has resolved should patients be monitored for a potential biphasic reaction? a. 6 to 12 hours b. 24 hours c. 48 hours d. 72 hours 5. Upon discharge from the emergency department, a patient with anaphylaxis should receive a prescription for: a. Oral glucocorticoids b. A beta2-agonist inhaler c. 1 epinephrine autoinjector d. 2 epinephrine autoinjectors

31. Simons FE, Edwards ES, Read EJ Jr, et al. Voluntarily reported unintentional injections from epinephrine auto-injectors. J Allergy Clin Immunol. 2010;125:419-423. 32. Nowak RM, Macias CG. Anaphylaxis on the other front line: perspec-

TO TAKE THE POST-TEST please go to: myCME.com/July16CAfeature

tives from the emergency department. Am J Med. 2014;127(1):S34-S44.

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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.

YOUR COMMENTS IMPROVING HEALTH LITERACY Thank you for publishing the article, “Steps for improving health literacy” [May 2016, p. 110]. Health literacy is an unrecognized contributor to many adverse health outcomes. A health-literate healthcare organization can do much to help patients understand health information and use the information to make decisions about their health. However, there are two points recommended in the article that should be updated. It is no longer recommended that patients with low health literacy be identified. Instead, Universal Health Literacy Precautions are recommended (Agency for Healthcare Research and Quality. AHRQ health literacy universal precautions toolkit. Available at: http://www.ahrq.gov/ professionals/quality-patient-safety/quality-resources/tools/ literacy-toolkit/index.html [Accessed June 14, 2016]). While some providers are concerned that using plain language 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 contact us by e-mail at editor@ 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.

with health-literate patients will offend, studies show that patients with adequate health literacy prefer to receive health information in an easier to understand format (Meppelink CS, Smit EG, Buurman BM, van Weert JC. Should we be afraid of simple messages? The effects of text difficulty and illustrations in people with low or high health literacy. Health Commun. 2015;30[12]:1181-1189). Further, research indicates that patients with limited literacy will avoid contact with the healthcare system if they fear that their literacy issues will be discovered (Easton P, Entwistle VA, Williams B. How the stigma of low literacy can impair patient-professional spoken interactions and affect health: insights from a qualitative investigation. BMC Health Serv Res. 2013;13:319.) When Universal Precautions are used, all patients receive health information in a way that they are able to understand, and no one is subject to stigmatization due to low health literacy. It is important to ensure that written materials for patients are easy to understand, but this involves much more than writing to a particular grade level. Writing style and formatting are equally important when developing patient education materials (Centers for Medicare & Medicaid Services. Toolkit for making written material clear and effective. Available at: https://www.cms.gov/Outreachand-Education/Outreach/WrittenMaterialsToolkit/index. html?redirect=/writtenmaterialstoolkit/ [Accessed June 14, 2016]. The Centers for Medicare & Medicaid Services offers

OUR CONSULTANTS

Philip R. Cohen, MD,

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.

Abimbola Farinde, PhD, PharmD,

is a professor at Columbia Southern University in Orange Beach, Ala.

Laura A. Foster, CRNP, FNP,

Abby A. Jacobson, MS, PA-C,

practices family medicine with Palmetto Primary Care Physicians in Charleston, S.C.

is an assistant professor at Thomas Jefferson University and a dermatology PA at Family Dermatology of Reading, Pa.

44 THE CLINICAL ADVISOR • JULY 2016 • www.ClinicalAdvisor.com

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a toolkit to help healthcare organizations develop documents that are reader friendly. When evaluating the readability of a document, Flesch-Kincaid is no longer recommended, since it underestimates reading level (Centers for Medicare & Medicaid Services). If a readability formula is used, the Simple Measure of Gobbledygook (SMOG) or Fry methods are preferred (Centers for Medicare & Medicaid Services). Again, thank you for addressing health literacy as an important healthcare topic. I hope that you will consider future articles to update and expand on the information presented.—RUTH De REGO, DNP, ANP-BC, Albuquerque, N. Mex. (213-1)

because insurance does not cover their visits. I do not know what the answer is, but this certainly is not it. Obviously, I have strong feelings about this issue due to the handling of the medications and the patients involved. Patients with chronic pain cannot get the medications they need in this country now. Addicts are dying more on the streets today than ever before, and people are also not getting the correct treatment they need.—SALENA STEADE, FNP-BC, Mobile, Ala. (213-2)

SUBOXONE: THE METHADONE OF THE DECADE I work with many patients in family practice and mental health, but I also have many patients, as well as family and friends, who are in recovery from addiction. Suboxone is not the answer [Advisor Forum, May 2016, p. 60]. Suboxone has become a crutch for many. What was supposed to be short-term relief to help opiate addicts withdraw from opiates has become a growing epidemic in and of itself. Many tell me that they have been on this drug for 3, 4, and even 8 years. They also tell me that this medication is harder to quit than the opiates it was supposed to help them stop using in the first place. Suboxone has become the methadone of this decade. I saw a 44-year-old patient yesterday who has been on methadone for 12 years because he had back surgery. We are always looking for a quick fix, and it just does not work. Suboxone can be injected, despite what we are told by pharmaceutical companies. There is no easy answer, but this is not it. It is trading one drug for another. It seems physicians at times have become legal drug dealers (this is opinion, not fact), charging $200 each visit to these patients

IN PLACE OF VAGINAL STEROID CREAM For a patient with atrophic vaginitis or lichen sclerosus et atrophicus, itching is a main concern. To decrease use of a vaginal steroid cream, you can have the patient put either shortening or olive oil, first thing in the morning after voiding, on their toilet paper and wipe with it. It does cut down on the itching, with a noticeable difference right away. In the first few days, use this technique about 2 to 3 times a day, and then after that just once a day or more often if the patient has a flare-up.—VIRGINIA JONES, FNP, AP/MHNP, Lecanto, Fla. (213-3)

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.

CLINICAL PEARLS

ASSESSING FOR REBOUND TENDERNESS When I have a pediatric patient with acute abdominal pain and need to assess rebound tenderness, I do not apply pressure to the painful area. Instead, I finish my exam, then have the patient jump off the exam table or get down and jump in place and see if it causes splinting due to the pain elicited. That way, I am not the “bad guy” causing pain to my patient, but I still get the information that I need.—DEB WOLF, PA-C, Syracuse, N.Y. (213-4) n

Claire O’Connell, MPH, PA-C,

Katherine Pereira, DNP, FNP,

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

is assistant professor, Duke University School of Nursing, Durham, N.C.

Sherril Sego, FNP-C, DNP,

is an independent consultant in Kansas City, Mo.

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Dermatology Clinic CASE #1

Plaques, erosions around orifices and acral regions MELINDA LIU, BA, AND MAURA HOLCOMB, MD

A 7-month-old male who had been born prematurely presents with a 2-month history of diarrhea, failure to thrive, alopecia, and rash involving the perioral, perianal, and acral areas. He had been treated unsuccessfully for presumed atopic dermatitis with topical corticosteroids. He was exclusively breastfed until 2 months ago, when he was transitioned to formula. Examination reveals an irritable, thin infant with sharply demarcated red, inflamed, scaly plaques and erosions around his mouth, anus, eyes, hands, and feet. What is your diagnosis? Turn to page 52.

CASE #2

A subcutaneous nodule near the eyebrow ESTHER STERN, NP

A 64-year-old woman presents with a 6-month history of a slowly enlarging bump near her left eyebrow. The patient says it appeared suddenly and became a nuisance as it enlarged. She denies any pain, tenderness, or oozing, and any other similar lesions elsewhere. Physical examination reveals a 6-mm nontender subcutaneous mobile nodule on the left lateral eyebrow. There is no overlying ulceration or central punctum, and no discharge is noted. What is your diagnosis? Turn to page 53. www.clinicaladvisor.com • THE CLINICAL ADVISOR • JULY 2016 51

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Dermatology Clinic CASE #1

Acrodermatitis enteropathica

Acrodermatitis enteropathica (AE) is a rare, autosomal recessive disease characterized by pink, scaly plaques and erosions around the orifices and acral regions and caused by poor zinc absorption.1-3 It is linked to mutations in the SLC39A4 gene (solute carrier family 39 [zinc transporter], member 4) on chromosome 8q24.3.2,4 Zinc forms the critical component of the catalytic site of hundreds of enzymes and is essential for healthy immune function, wound healing, central nervous system development, normal taste and smell, and gastrointestinal and reproductive function; it can be found in nuts, oats, soy flour, cheese, leafy vegetables, and shellfish.2-4 Clinical findings of AE are highly variable, reflect the severity of AE, and are equivalent to those observed in dietary zinc deficiency. 2,3 However, in AE, symptoms manifest approximately 4 to 6 weeks after weaning from breast milk, or in weeks 4 to 10 of life in formula-fed infants, as existing zinc stores are depleted.1,3 This phenomenon is thought to occur as a result of low molecular weight-binding agents in human milk, which increase the bioavailability of zinc and delay the onset of symptoms.3 In contrast, cow milk contains more zinc-binding phytates, which prevent zinc absorption in the duodenum and jejunum. Early signs include perioral, perianal, and acral dermatitis.4 Classically, these lesions are well demarcated, pink to red, erythematous, scaly, and variably eroded plaques.2 Pustules, blisters, and bullae may develop.2 In more advanced disease, alopecia, nail dystrophy, diarrhea, delayed wound healing, angular stomatitis, conjunctivitis, blepharitis, increased susceptibility to infection, and failure to thrive are observed.1,2 Infants manifesting signs of AE are irritable, withdrawn, and sensitive to light.1 If the zinc deficiency is not addressed, patients develop hypogonadism, delayed puberty, pica, impaired taste and smell, night blindness, and neuropsychiatric symptoms, including mood changes, tremors, and jitteriness.1 AE is diagnosed through clinical history and examination. Laboratory testing, response to zinc supplementation, and cutaneous histopathology can help confirm the diagnosis. Historically, AE was defined by a triad of symptoms including periacral and periorificial dermatitis, alopecia,

and diarrhea; however, the complete triad only manifests in 25% of cases.5 The most common clinical symptoms are cutaneous lesions.5 Low serum alkaline phosphatase (ALP) and zinc levels are also diagnostic and improve with zinc therapy.1 Plasma zinc deficiency is defined by levels lower than 70 mcg/dL in morning fasting samples and lower than 65 mcg/dL in nonfasting samples.3 Blood samples should be obtained before breakfast and before taking multivitamins or supplements containing zinc.3 Up to 60% to 80% of serum zinc is bound to albumin; therefore, the zinc value must be corrected for abnormal albumin levels.3 ALP is a zinc-dependent metalloenzyme, and low serum ALP levels support a diagnosis of zinc deficiency, although levels may be normal in mild cases.1,3 If plasma zinc and serum ALP levels are normal and clinical suspicion remains high, a trial of zinc supplementation can be conducted to assess clinical response.3,5 Although transient neonatal zinc deficiency, also known as acquired zinc deficiency of lactogenic origin, responds rapidly to zinc supplementation as well, interruption of zinc therapy should not induce a relapse in symptoms in these patients unlike in patients with AE.5 Key points for acrodermatitis enteropathica Clinical presentation

• Characterized by erythematous, dry, scaly patches and plaques, which may evolve into crusted vesiculobullous, erosive, and psoriasiform lesions • Lesions are classically perioral, perianal, and acral • Loss of hair, nail dystrophy, mucosal findings, and delayed wound healing • Infants are irritable and withdrawn and have growth impairment

Differential diagnosis

AELE of cystic fibrosis, AELE unrelated to zinc deficiency, biotin deficiency, kwashiorkor, atopic dermatitis, cutaneous candidiasis, epidermolysis bullosa

Diagnosis

• Diagnosed clinically and can be confirmed through laboratory testing demonstrating low plasma zinc and serum ALP levels, response to zinc supplementation, and cutaneous histopathology • Consider genetic testing for family members because this is a chronic condition requiring life-long zinc supplementation

Management

• Oral zinc (1–3 mg/kg/d) will cure all clinical manifestations within 1–2 weeks and needs to be continued through adulthood; plasma/serum zinc levels should be monitored every 3–6 months • Copper levels should be evaluated

AELE, acrodermatitis enteropathica-like eruption; ALP, alkaline phosphatase

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Biopsy of AE lesions reveals findings consistent with nutritional deficiency.2 The first finding to appear is typically nonspecific cytoplasmic pallor.3 In advanced disease, a collection of findings referred to as necrolysis, including ballooning and reticular degeneration and necrosis of keratinocytes in stratum spinosum and granulosum, are observed.2,3 Chronic lesions typically exhibit psoriasiform hyperplasia with little to no cytoplasmic pallor.3

The patient responded rapidly to oral supplemental zinc sulfate at 1 mg/kg/d. Clinical response was observed within 5 days, and the patient continues to be maintained on supplemental therapy. Melinda Liu, BA, is a medical student and Maura Holcomb, MD, is a dermatology resident at Baylor College of Medicine in Houston. References

Patients with AE are treated with oral zinc dosed at 2 to 3 mg/kg/d, which resolves all clinical manifestations within 1 to 2 weeks.

1. Gupta M, Mahajan VK, Mehta KS, Chauhan PS. Zinc therapy in dermatology: a review. Dermatol Res Pract. 2014;2014:709152. 2. Iyengar S, Chambers C, Sharon VR. Bullous acrodermatitis enteropathica: case report of a unique clinical presentation and review of the literature. Dermatol Online J. 2015;21(4). doj_26272. 3. Corbo MD, Lam J. Zinc deficiency and its management in the pediatric population: a literature review and proposed etiologic classification. J Am

The simultaneous appearance of skin and gastrointestinal symptoms in the setting of the classic timing of symptom onset after weaning from breastfeeding should alert clinicians to consider zinc deficiency.4 The differential for AE includes acrodermatitis enteropathica-like eruption (AELE) of cystic fibrosis, AELE unrelated to zinc deficiency, biotin deficiency, kwashiorkor, and atopic dermatitis.3 Unlike AE, these conditions are not associated with decreased plasma zinc, and serum ALP levels are usually normal.3,4 In addition, patients with AELE associated with cystic fibrosis exhibit respiratory symptoms and will have positive sweat chloride test results; patients with AELE unrelated to zinc deficiency develop symptoms due to the low protein diet used for maintenance of underlying metabolic disorders; and patients with biotin deficiency have brittle hair, myalgias, and sensorineural hearing loss. Patients with kwashiorkor are edematous, have severely decreased muscle mass, and changes in hair color. Patients with atopic dermatitis have family members with other atopic conditions, have a pruritic rash, and do not have gastrointestinal or hair involvement. Patients with AE are treated with oral zinc dosed at 2 to 3 mg/kg/d, which resolves all clinical manifestations within 1 to 2 weeks.1,2 However, supplementation must be continued through adulthood.1,4 Plasma zinc levels should be monitored every 3 to 6 months to ensure adequate supplementation.2 Copper levels should also be monitored because zinc administration can interfere with copper absorption.2 Clinicians should consider genetic testing in family members, as diagnosis has prognostic and treatment impact on other children in the family.4 Early diagnosis and treatment is critical because untreated AE can be fatal.4

Acad Dermatol. 2013;69(4):616.e1-624.e1. 4. Jung AG, Mathony UA, Behre B, et al. Acrodermatitis enteropathica: an uncommon differential diagnosis in childhood—first description of a new sequence variant. J Dtsch Dermatol Ges. 2011;9(12):999-1002. 5. Küry S, Kharfi M, Schmitt S, Bézieau S. Clinical utility gene card for: acrodermatitis enteropathica [published online December 14, 2011]. Eur J Hum Genet. 2012;20(3). doi:10.1038/ejhg.2011.227.

CASE #2

Pilar cyst

Pilar cyst, also known as trichilemmal or isthmus-catagen cyst, is relatively common and mostly benign. Approximately 90% of these lesions are found on the scalp,1 an area with an obviously high concentration of hair follicles; infrequently, they develop elsewhere, including on the face, trunk, and extremities. Frequency in the general population is approximately 5% to 10%, and lesions mostly occur in the middle-aged years. Occurrence is somewhat more frequent in women but equal across racial populations. Although pilar cysts often arise sporadically, there is a known genetic component of the autosomal dominant inheritance type and therefore, this condition is often found in many family members. The cysts can occur as a single lesion or multiple lesions can be present simultaneously. Pilar cysts arise from the outer hair follicle sheath and fill with keratin and its breakdown products. The cyst wall is a

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Dermatology Clinic was educated regarding its benign nature and the treatment options. Because the lesion was cosmetically very bothersome to the patient, she requested surgical excision, which was successfully performed without complications. Three months later, the patient returned for a routine follow-up visit and was satisfied with the cosmetic outcome. There were no signs of recurrence of the lesion. n Esther Stern, NP, is a family nurse practitioner at Advanced Dermatology & Skin Surgery, P.C., in Lakewood, N.J. References 1. Epidermal nevi, neoplasms, and cysts. In: James WD, Berger TG, Elston DM, eds. Andrews’ Diseases of the Skin: Clinical Dermatology. 12th ed. Philadelphia, PA: Elsevier; 2015. 2. Hendricks DL, Liang MD, Borochovitz D, Miller T. A case of multiple pilar tumors and pilar cysts involving the scalp and back. Plast Reconstr Surg. 1991;87(4):763-767. 3. McGavran MH, Binnington B. Keratinous cysts of the skin. Identification and differentiation of pilar cysts from epidermal cysts. Arch Dermatol. 1966;94(4):499-508. 4. Stone MS. Cysts. In: Bolognia JL, Jorizzo JL, Schaffer JV, eds. Dermatology. 3rd ed. St. Louis, MO: Elsevier Saunders; 2012;1820-1821. 5. Mehrabi D, Leonhardt JM, Brodell RT. Removal of keratinous and pilar cysts with the punch incision technique: analysis of surgical outcomes. Dermatol Surg. 2002;28(8):673-677.

“Sorry, Vince, but we need a leader with both feet on the ground.”

grayish white color and is often very thick and resistant to rupture. These cysts tend to grow slowly until they become stable in size, at which time they persist indefinitely. A proliferating trichilemmal cyst is a benign yet aggressive variant of the common pilar cyst.2 It occurs when a cyst grows aggressively at its original site, leading to very large exophytic nodules that can ulcerate. Rare cases of malignant transformation with these lesions have been reported.1 Diagnosis is typically clinically straightforward when the lesion appears on the scalp, particularly if numerous lesions are present. Pilar cysts can be differentiated from epidermal inclusion cysts by considering the location of the lesion and noting the absence of a central punctum and the presence of a thick, durable cyst wall.3 Other common conditions to consider in the differential diagnoses and to rule out include pilomatricoma, squamous cell carcinoma, nodulocystic basal cell carcinoma, Merkel cell carcinoma, and lipoma. If the diagnosis in uncertain, a skin biopsy with hematoxylin and eosin stain can aid in the diagnosis. Stratified squamous epithelium is observed on the outer layer of the cyst wall and lacks the granular layer that is typically seen in an epidermal inclusion cyst. Densely packed eosinophilic-staining keratin debris fills the cyst and occasionally, focal calcification is observed. Observation of a pilar cyst with cyst wall rupture reveals a foreign body giant cell reaction.4 It should be noted that lesions located on the midline of the scalp or back should be radiographed prior to any invasive diagnostic procedure in order to rule out intracranial or intraspinal extension. Patients often seek consultation for removal because the lesions are functionally or cosmetically bothersome. Some are large enough to interfere with helmet or hat use. Others may become intermittently inflamed and tender and occasionally prone to superinfection. Treatment options are primarily surgical in nature and best considered when lesions are not inflamed or ruptured. Incision and drainage typically only provides temporary relief. If the cyst wall is not removed, the lesion will likely recur. For this reason, surgical excision with removal of the intact cyst is the most common treatment. This is usually performed in an outpatient setting with the use of local anesthesia. A skilled surgeon can minimize trauma and scarring by using a smaller punch biopsy to empty the cyst contents first and then remove the remaining cyst wall.5 As the patient in our case presented with a cystic nodule in a location that does not typically present with benign cystic lesions, a skin biopsy was necessary to confirm the correct diagnosis and rule out malignancy. A 3-mm punch biopsy confirmed the diagnosis of pilar cyst. The patient

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Dermatologic Look-Alikes Hyperpigmented patches SERGEY REKHTMAN, AND JULIA R. NUNLEY, MD

CASE #1

CASE #2

A 22-year-old man presents with an 8-week history of an asymptomatic rash on his face, torso, and groin. He is otherwise healthy, and a review of symptoms finds he is negative for fever, malaise, joint pains, and headaches. He is a student at the local college and reports having had unprotected sex with several partners over the past year. Physical examination reveals several hyperpigmented annular plaques on his face and scalp. Scaly papules are noted over his torso and proximal extremities; two verrucous, flesh-colored plaques are present on the shaft of his penis. Generalized, nontender adenopathy is palpable; no ulcers or mucosal lesions are present.

A 44-year-old woman with a history of intermittent migraines presents with dark spots appearing on her leg over the past year. Initially, there was only one, but over time two others appeared. Her medications include naproxen for her headaches and an oral contraceptive. When the spots first appeared, they were reddish-purple in color and mildly itchy; they subsequently turned black. Review of symptoms is negative for anything obviously contributory. Physical examination reveals three well-demarcated, hyperpigmented patches on her right lower leg. No other lesions are noted, and there is no lymphadenopathy.

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Dermatologic Look-Alikes CASE #1

Annular secondary syphilis

Annular lesions, also known as annular syphilids, are one of many potential cutaneous manifestations of secondary syphilis. Syphilis is caused by the spirochete Treponema pallidum, which is transmitted primarily via sexual contact. Because syphilis has such an extensive variety of clinical manifestations, it has been called “the great imitator.” Left untreated, the disease naturally progresses through different stages. The primary lesion of syphilis (thus, primary syphilis) is called a chancre and designates the site of inoculation. A chancre is a painless, firm, eroded papule with a raised and indurated margin; although more commonly seen in the genitalia, other inoculation sites have been well-described. Even without therapy, the chancre involutes spontaneously within 3 to 6 weeks. In untreated individuals, secondary syphilis develops 6 to 12 weeks later and is characterized by systemic manifestations and a large variety of cutaneous findings. Signs and symptoms of secondary syphilis also spontaneously involute but may recur months later in those who still have untreated disease. The timing of the third phase, tertiary syphilis, is highly variable. It may manifest as early as 1 year after the primary infection or decades later. Tertiary syphilis can lead to devastating systemic involvement of the viscera, bones, and cardiovascular and central nervous systems, and it is beyond the scope of this discussion. Throughout history, the incidence of syphilis has fluctuated markedly. The discovery of penicillin in 1928 allowed some to hope that all bacterial infections, including syphilis, would be eradicated worldwide. Syphilis infection rates did decrease substantially for several decades; however, the human immunodeficiency virus (HIV) epidemic has been associated with resurgence. With the advent of highly active antiretroviral therapy for HIV infection, the incidence of syphilis again declined until the year 2000, at which point it again began to rise. In 2005, there were 2.9 reported cases of syphilis per 100,000 persons, and this figure increased to 5.3 cases per 100,000 persons in 2013.1 The mucocutaneous findings of secondary syphilis are highly variable. Most common is a papulosquamous cutaneous eruption consisting of small, scaly macules and papules that may be reddish-brown or skin-colored; lesions may enlarge, coalesce, and develop various morphologic patterns as they

mature. Widespread distribution is customary, and lesions are commonly found on the palms of the hands and soles of the feet. The characteristic reddish-brown, scaly macules on the palms and soles have been dubbed copper penny lesions because their color is similar to that of copper pennies. When present, these lesions are highly suggestive of secondary syphilis. In the groin, secondary syphilis may mimic human papilloma virus-induced condyloma; those lesions due to syphilis are called condyloma lata. Patients may also develop a patchy alopecia and nonspecific mucosal lesions. Pustular lesions are very rare, as are vesicles and bulla; vesicular lesions are seen predominately in newborns and HIV-affected patients.2 An estimated 6% of patients with secondary syphilis develop annular syphilids.3 These lesions develop as annular plaques with slightly raised borders; some lesions may become verrucous. Although any site can be affected, they are common on the head and neck.4 A number of constitutional and systemic signs are common, but not uniformly present, in secondary syphilis, and these include low-grade fever, lymphadenopathy, malaise, headache, myalgias, dysphagia, and mild hepatosplenomegaly.2 A good rule of thumb is to consider syphilis in any patient with a constitutional illness and a generalized eruption. Diagnosing syphilis serologically is a multistep process. Screening is initiated with more sensitive, but less specific, nontreponemal tests including the rapid plasma reagin and venereal disease research laboratory tests. Specimens with a positive test result should then be tested with the more specific fluorescent treponemal antibody absorption test. Unfortunately, HIV infection and other causes of immunosuppression may lead to false-negative serologic results. Conversely, conditions such as systemic lupus erythematosus, pregnancy, or a concurrent acute febrile illness may lead to a false-positive serologic result.2 If available and performed properly, dark field microscopy allows direct visualization of the spirochetes in aspirated fluid. Unfortunately, this is more of historic interest, because dark field microscopy is no longer readily available to most practitioners. Results from a skin biopsy may be suggestive, or even diagnostic, of syphilis if the spirochetes can be identified with special staining. Unfortunately, histologic findings are more often nonspecific. Epidermal changes of acanthosis, parakeratosis, and neutrophilic infiltration have been described. Perivascular dermal infiltrates containing lymphocytes and plasma cells can also be seen; the presence of dermal plasma cells in a nonmucosal site may be suggestive of syphilis.4 The differential diagnosis of annular syphilids includes disorders with similarly annular lesions such as tinea corporis, Continues on page 61

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Dermatologic Look-Alikes granuloma annulare, discoid lupus, tumid lupus, lichen planus, fixed drug eruption (FDE), and erythema multiforme. Lesional duration and symptoms, epidermal changes, and bedside testing can help to exclude several of these conditions. Lesions of secondary syphilis are typically scaly and short-lived; most lesions self-involute within a few months, although there are reports of more chronic lesions. Scale is not predominant in granuloma annulare or tumid lupus. Although scaly, lichen planus and tinea corporis are typically pruritic. A potassium hydroxide test at bedside can diagnose tinea corporis. Discoid lupus has scarring, not seen in syphilis. Erythema multiforme and FDEs have fairly specific clinical courses that can help confirm the diagnosis clinically. However, if suspected, a biopsy result is helpful, as histology of these conditions is highly specific. Treatment for syphilis is determined by the stage of the disease. Immune-competent individuals with primary or secondary syphilis can be treated with a one-time intramuscular injection of 2.4 million units of penicillin G benzathine. Penicillin-allergic patients may be treated with a 14-day course of 500 mg of tetracycline four times daily or 100 mg of doxycycline twice daily.2 Longer courses of treatment are required for tertiary syphilis. Pregnant patients with a penicillin allergy require desensitization and treatment with penicillin. In our case, the amalgamation of clinical findings strongly suggested the diagnosis of secondary syphilis, which was confirmed by serologic testing. Our patient was sent to the Virginia Department of Health and treated with 2.4 million units of intramuscular penicillin G benzathine. The Health Department also communicated with at-risk contacts.

CASE #2

Fixed drug eruption

Cutaneous reactions are the most common type of adverse drug event. Among hospitalized patients receiving medications, it is estimated that 2.2% develop a cutaneous drug reaction.5 The morphology, timing, and prognosis of these cutaneous reactions are highly variable and are, in large part, dependent upon the type of immunologic reaction produced. The most common drug eruption is due to a type IV hypersensitivity reaction and

presents as the classic morbilliform eruption with generalized pruritic erythematous macules and papules. Lesscommon reactions include urticaria and angioedema, due to a type I hypersensitivity reaction; these may be mild or life threatening. Other potentially life-threatening reactions include the poorly understood Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis, which represents a disease spectrum that is determined by the percentage of detached body surface area.6 Other cutaneous reactions are typically less serious and include erythema multiforme, drug hypersensitivity reactions, and fixed drug eruption (FDEs).

Among hospitalized patients receiving medications, it is estimated that 2.2% develop a cutaneous drug reaction. In the 1980s, 94% of reported cutaneous reactions were morbilliform rashes and 5% were urticarial.5 Historically, FDEs were rarely described, which may have been due to either a lower incidence or lower level of awareness of the condition. Since then, the reported incidence has dramatically increased; FDE is now estimated to be either the second or third highest category of drug-related cutaneous reaction, representing 9% to 22% of total reactions.7 A variety of drugs have been implicated, but more commonly reported culprits include nonsteroidal anti-inflammatory drugs (NSAIDs) and antibiotics, particularly sulfamethoxazole/ trimethoprim and tetracycline.8 A FDE has multiple unique clinical characteristics that can make it a readily diagnosable condition. The original outbreak typically follows the use of the culprit medication, occurring approximately 1 to 2 weeks later. The primary lesion is a mildly symptomatic, erythematous to violaceous, circular plaque that is usually 1 to 3 cm in diameter. Residual hyperpigmentation persists after inflammation of the lesion resolves. With re-exposure to the same medication, the same location will again become inflamed; the inclusion of the word fixed in the term describes this predilection for recurrence in the exact fixed anatomic site.6 Subsequent exposures often lead to recurrence within 24 to 48 hours, and to the development of additional lesions. FDE can affect any part of the body, but frequently affects the lips, genitalia, and extremities. Over time, with multiple exposures, numerous sites can develop; rarely does the outbreak become generalized. The majority of patients do not have

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Dermatologic Look-Alikes associated symptoms, but localized pruritus occurs in 24% of FDE cases and pain occurs in 3.8%.8 The pathogenesis of FDE is hypothetically due to a localized increased concentration of intraepidermal CD8+ T-effector memory (TEM) cells that were primed during the initial outbreak. These cells are quiescent between exposures, but upon reintroduction of the culprit drug, the TEM cells are activated, release large amounts of interferon γ and cytotoxic granules, and cause keratinocyte destruction and the resultant repeat inflammatory reaction.9 Although the classic clinical course makes this diagnosis relatively straightforward, one must be familiar with FDE and distinguish it from other dermatologic conditions to make the correct diagnosis. Recurrent outbreaks of herpes simplex virus infection often result in a postinflammatory hyperpigmented patch, but these outbreaks are typically more symptomatic, associated with blister development, and have a scalloped border. Annular lesions of erythema multiforme and SJS often have a morphologic pattern similar to that of FDE; however, patients with erythema multiforme and SJS typically have innumerable lesions, not just a few, and typically appear ill. Finally, any inflammatory dermatosis may lead to a postinflammatory hyperpigmentation that may be confused with FDE, including lichen planus, contact dermatitis, and annular syphilids.

offending agent. Patient education of generic/trade names of the offending drug and the possibility of cross reactivity, especially among NSAIDs, should be stressed. Lesional symptoms such as itching and swelling can be treated with oral antihistamines and topical corticosteroids. In general, no treatment is required because the natural history of this eruption is generally benign and self-limiting. Reassurance should be given that with time, the symptoms and hyperpigmentation will resolve. If necessary, one could try a bleaching agent such as hydroquinone, although the effects may be slow and minimal. In our case, the patient was diagnosed with FDE due to naproxen use. She was advised to avoid this class of NSAIDs. Fortunately, she could tolerate ibuprofen, and there was no recurrence of the eruption. Over time, the residual hyperpigmentation faded and she was lost to dermatologic follow-up. n Sergey Rekhtman is a medical student and Julia R. Nunley, MD, is a professor of dermatology and program director of dermatology at the Medical College of Virginia Hospitals of Virginia Commonwealth University in Richmond. References 1. Patton ME, Su JR, Nelson R, Weinstock H; Centers for Disease Control and Prevention (CDC). Primary and secondary syphilis—United States, 2005-2013. MMWR Morb Mortal Wkly Rep. 2014;63(18):402-406. 2. Scaling papules, plaques, and patches. In: Marks JG, Miller JJ, eds.

The diagnosis of FDE is largely clinical; biopsy results will support the diagnosis but will not identify the etiologic agent.

Lookingbill & Marks’ Principles of Dermatology. 5th ed. New York, NY: Elsevier Saunders; 2013:123-125. 3. Chapel TA. The signs and symptoms of secondary syphilis. Sex Transm Dis. 1980;7(4):161-164. 4. Pournaras CC, Masouye I, Piletta P, et al. Extensive annular verrucous late secondary syphilis. Br J Dermatol. 2005;152(6):1343-1345. 5. Bigby M, Jick S, Jick H, Arndt K. Drug-induced cutaneous reactions.

The diagnosis of FDE is largely clinical; biopsy results will support the diagnosis of FDE but will not identify the etiologic agent. A biopsy may be necessary to exclude other diagnoses. Although a patient’s medication history may be enlightening, it could be difficult to discern the specific culprit in the setting of polypharmacy. An oral rechallenge is usually diagnostic but not always possible or wise. Recently, patch testing has been useful in determining the culprit in certain cases with minimal risk to the patient. Lesional patch testing identified the offending drug in 40% of the patients tested. Unfortunately, this patch testing is only available in certain centers, but this same study demonstrated NSAIDs to be the most likely group of drugs to cause FDE.10 Once the diagnosis of FDE is established and the culprit drug suspected, the key to management is avoidance of the

A report from the Boston Collaborative Drug Surveillance Program on 15,438 consecutive inpatients, 1975 to 1982. JAMA. 1986;256(24): 3358-3363. 6. Specialized erythema. In: Marks JG, Miller JJ, eds. Lookingbill & Marks’ Principles of Dermatology. 5th ed. New York, NY: Elsevier Saunders; 2013:208-211. 7. Lee AY. Fixed drug eruptions. Incidence, recognition, and avoidance. Am J Clin Dermatol. 2000;1(5):277-285. 8. Mahboob A, Haroon TS. Drugs causing fixed eruptions: a study of 450 cases. Int J Dermatol. 1998;37(11):833-838. 9. Mizukawa Y, Yamazaki Y, Shiohara T. In vivo dynamics of intraepidermal CD8+ T cells and CD4+ T cells during the evolution of fixed drug eruption. Br J Dermatol. 2008;158(6):1230-1238. 10. Andrade P, Brinca A, Gonçalo M. Patch testing in fixed drug eruptions—a 20-year review. Contact Dermatitis. 2011;65(4):195-201.

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LEGAL ADVISOR CASE

A clinician and patient mistake

BY ANN W. LATNER, JD

Ms. P, aged 29 years, was a newly graduated nurse practitioner when she took her first job in a rural primary health clinic on federal land. The clinic was located in the same building as the area’s only hospital, emergency department, and long-term nursing facility. Ms. P began working there in early spring, and shortly thereafter, it was anticipated by health authorities that the following winter would bring a potentially serious H1N1 flu epidemic. To address this potential threat, a task force was formed. One of the task force’s primary concerns was to protect the fragile patient population in the nursing facility. By late spring, the task force had come up with a protocol for how to deal with area residents who were experiencing flu symptoms. Signs that read, “STOP: If you have any flu symptoms, DO NOT ENTER the building! Go home and call XXX-XXXX,” were posted on the clinic door and around the building. Calling the number would connect the caller to a recorded message that advised those with symptoms of H1N1 flu virus on what to do.

It is well-accepted that healthcare practitioners have a duty to their patients, but do patients have a duty as well? Clinicians must ask leading questions that will help elicit appropriate responses and help them better understand their patients’ complaints.

The recorded message stated: “… if the sick person has a temperature of 100 degrees and other flu symptoms, you should call our clinic. DO NOT GO there … Please call first. They will then advise you what the next step should be....” The message also provided advice as to where to obtain further information (CDC website) and concluded “… if you or your loved one have any of the serious symptoms described, or just cannot figure out what the best thing is to do … then, and only then … call the clinic’s hotline at XXX-XXXX.” Ms. P was one of the clinicians assigned to handle the hotline calls, and she was instructed to ask patients about their symptoms, and specifically, if they were experiencing chest pain and breathing problems, shortness of breath, dehydration, fever for more than 5 days, dizziness or fainting spells, and difficulty eating. In particular, the task force Cases presented are based on actual occurrences. Names of participants and details have been changed. Cases are informational only; no specific legal advice is intended. Persons pictured are not the actual individuals mentioned in the article.

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LEGAL ADVISOR was most concerned about chest pain and shortness of breath, which could be red flags indicating pneumonia, rather than flu. One Friday, Mrs. O, aged 52 years, who ran a childcare center in the town, began feeling tired and worn out, but she assumed it was due to a hard week. The next day, she was feverish, dizzy, and vomiting. She took Tylenol for the fever but could not keep down any liquids. She assumed she had caught something from one of the children with whom she worked — a common hazard of her job. On Sunday, Mrs. O felt ill and achy and could not get out of bed. The Tylenol did not seem to be helping, and her temperature was 104° F. Still, neither she, nor her husband or adult daughter, called the clinic or the hospital. Monday came, and Mrs. O still felt unwell and was experiencing chest pain.

The court decided that Ms. P and Mrs. O were equally at fault for the delay in treatment of Mrs. O’s pneumonia. On Tuesday, still feeling terrible, and short of breath, Mrs. O asked her daughter to call the clinic. Ms. P answered the call. The daughter spoke to Ms. P and relayed her mother’s symptoms, but she did not mention chest pain or shortness of breath, nor did Ms. P specifically ask. From Ms. P’s perspective, the symptoms that the daughter related—fever, nausea, achiness, exhaustion, etc. — were consistent with the flu, and they had been seeing a lot of cases in the clinic. She asked the daughter if there were any other symptoms but did not ask specifically about chest pain or breathing issues, and when the daughter replied “No,” Ms. P told the patient to stay at home and not come to the clinic. “She should start feeling better in another day or two,” Ms. P said. However, this was not the case. On Wednesday, Mrs. O worsened. Her husband brought her into the clinic late Wednesday afternoon, and she was immediately sent to the emergency department and diagnosed with pneumonia. She received IV fluids, antibiotics, and oxygen, and had chest x-rays taken. The chest x-rays revealed that her condition had become so critical that it was beyond what the small hospital could treat, and she had to be airlifted to a larger hospital. Mrs. O eventually recovered but had large medical bills and lost income, so she consulted an attorney who advised her to sue. At trial, both Ms. P and Mrs. O testified. Ms. P was asked directly if she had inquired about serious symptoms, such as difficulty breathing or chest pain, which could indicate

pneumonia. She admitted that she had not specifically asked. Ms. P was asked by the plaintiff’s attorney whether she would have given different advice to the patient had she known of those symptoms, and she had to confess that she would have advised Mrs. O to go to the hospital immediately. The court decided that Ms. P and Mrs. O were equally at fault for the delay in treatment of Mrs. O’s pneumonia. Therefore, Mrs. O only received 50% of the lost wages, medical expenses, and other costs she was claiming, rather than the full award. Legal background

The court held that the standard of care required Ms. P to get a detailed medical history from Mrs. O. In particular, the court held that Ms. P had an affirmative duty to inquire into Mrs. O’s specific complaints rather than just use an oblique question, such as, “Are there any other symptoms?” Ms. P failed the patient by not following the clinic’s protocol and specifically asking about symptoms that could indicate pneumonia or other serious emergency illness. However, the court also held that Mrs. O “had a duty to timely and accurately report her symptoms to a healthcare provider and a duty to timely seek medical aid for illness.” The court wrote that the “plaintiff breached that duty by failing to timely seek medical advice as her symptoms of illness other than flu developed.” Thus, the court was only willing to award Mrs. O half of the medical expenses that resulted from her having to be transferred and treated at a larger hospital. Protecting yourself

Mrs. O should have sought medical help earlier. However, Ms. P was aware of the clinic’s protocol, and more importantly, the reason behind it. She knew that it was essential to identify patients who might have pneumonia or need immediate medical attention. And, she knew that directly asking about some of the symptoms of pneumonia, such as chest pain or breathing difficulties, would be most helpful in identifying the problem. Yet, she neglected to follow the clinic’s protocol, and she failed to get a detailed medical history from the patient. An ill patient may not think to mention every symptom or may not be aware of which symptoms are most worth mentioning. As the clinician, it is your responsibility to ask the leading questions that will help you get your answers and understand your patient’s complaints. Communication, which includes asking these questions, is a crucial key for a healthcare practitioner. n Ms. Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.

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Conference Roundup 2016 Annual Meeting of the AAPA American Academy of PAs San Antonio

PA MALPRACTICE CASE RATES SLIGHTLY INCREASING The rate of malpractice cases among physician assistants (PAs) has been slightly increasing, while median payments and reasons for payments remain unchanged, according to researchers. The study included data from 2005 to 2014, during which there were 3,621 adverse actions and 1,415 malpractice cases among PAs. For physicians, there were 63,634 adverse actions and 108,038 malpractice cases. For nurse practitioners (NPs), there were 1,440 adverse actions and 1,442 malpractice cases. For physicians, the risk of adverse actions and malpractice was 9.9 to 16.6 per 1,000 providers (11%). For PAs, this risk was 1.40 to 2.35 per 1,000 providers (3.3%), and for NPs, it was 1.09 to 1.43 per 1,000 providers (1.3%). During the course of the study, rates of malpractice declined among physicians, remained steady among NPs, and increased slightly among PAs. While median malpractice payments have remained steady for both PAs and NPs, payments have decreased slightly among physicians. The reasons for malpractice payments have remained largely unchanged among PAs, NPs, and physicians. Overall, PAs and NPs are faced with malpractice suits much less frequently compared with their physician counterparts.

Between 2005 and 2014, there were 3,621 adverse actions and 1,415 malpractice cases among PAs, according to study results.

AAPA HOUSE OF DELEGATES OPPOSES PROPOSED NCCPA RECERTIFICATION REQUIREMENTS The American Academy of PAs House of Delegates (HOD) has expressed its opposition to the National Commission on Certification

of PAs (NCCPA) proposed changes to the PA recertification process. On the final day of the HOD 2016 meeting, which took place at the annual meeting of the American Academy of PAs (AAPA), the delegates voted to pass the AAPA Board-submitted resolution (B-01) “Elimination of High Stakes Recertification Testing for PAs.” Two additional resolutions were passed—one endorsing the Federation of State Medical Boards’ maintenance of licensure principles, and the other urging the NCCPA to maintain its current recertification examination process. The HOD decision follows several months of discussion between AAPA and NCCPA regarding recertification concerns. The proposed changes were announced in November 2015. Public comment on this issue had been scheduled to close on June 15; in February, the NCCPA agreed to postpone this date to allow the HOD to debate the issue and take a position. “We believe that the balanced information and resources we have proactively and consistently provided about the proposal have resulted in an educated and collegial conversation on this important matter among PAs across the country, and that the HOD appropriately reflected the views of its constituents during deliberations,” said AAPA president Jeffrey Katz, PA-C, DFAAPA. The AAPA opposition to the NCCPA proposal surrounds concerns that the new model — including a proctored, closed-book exam in one of 10 to 12 specialty areas, in addition to periodic take-home exams throughout the 10-year recertification cycle — would limit the PA’s clinical flexibility as well as detract from patients’ access to care as PAs remove themselves from their practice to study for and take the exams.

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BUPIVACAINE LIPOSOME INJECTABLE IMPROVES TOTAL KNEE ARTHROPLASTY OUTCOMES For patients undergoing total knee arthroplasty (TKA), addition of bupivacaine liposome injectable improves clinical outcomes compared with traditional local anesthetics, researchers reported. Patients who received the bupivacaine liposome injectable suspension were able to ambulate farther and were discharged slightly sooner compared with patients who received the usual anesthetics. The study included 104 patients who had been diagnosed with knee osteoarthritis and were scheduled for TKA with one of 2 surgeons (surgeon A or surgeon B) from February 2015 to September 2015. Patients were grouped by age into 4 groups: <60 years, 61 to 70 years, 71 to 80 years, and >80 years. The researchers recorded pain control, ambulation on POD 0, total ambulation distance, length of stay, and discharge to home versus discharge to extended care facility.

“It is the view of the Board that these proposed requirements, particularly when coupled with the CME requirements already in place for PAs, are unnecessary and potentially harmful to patients and PAs,” said AAPA Board member William T. Reynolds, Jr., MPAS, PA-C, DFAAPA. The resolution passed by the HOD included the following 6 statements of AAPA policy: 1. AAPA supports assessing general medical knowledge for initial certification and licensing of PAs. 2. AAPA supports the use of evidence-based alternatives to testing for maintenance of certification. 3. AAPA opposes any requirement that PAs take a closedbook, proctored exam in a specialty area for maintenance of certification. 4. AAPA opposes any requirement that PAs take multiple examinations during a 10-year recertification cycle. 5. AAPA supports uncoupling maintenance of certification requirements from maintenance of license and prescribing privileges in state laws 6. AAPA urges NCCPA and the NCCPA Foundation to undertake rigorous and replicable research to determine the relationship, if any, between taking the NCCPA recertification test and patient outcomes, safety, and satisfaction. The AAPA has pledged continued close monitoring of NCCPA’s actions on this issue and advocacy against the adoption of the proposed recertification changes; AAPA is committed to protecting patient access to medical care and the flexibility of the PA profession.

The addition of bupivacaine liposome injectable improves clinical outcomes in patients undergoing total knee arthroplasty.

Preoperatively, all patients were administered one dose of oral celecoxib at 200 mg, oral oxycodone sustained release at 10 mg, and oral gabapentin at 300 mg. Intraoperatively, all patients underwent spinal anesthesia with an adductor canal nerve block at case end. Patients of surgeon A (n=58) were also administered 20 mL of bupivacaine liposome injectable (266 mg/mL) with 50 mL of bupivacaine 0.25%, for a total volume of 70 mL. Patients of surgeon B (n=46) were administered 30 mL of ropivacaine 0.5%, 20 mL of lidocaine 0.5%, and 1 mL of ketorolac (30 mg), for a total of 51 mL of local anesthetic. Postoperatively, all patients received scheduled analgesia with oral celecoxib at 200 mg daily for 10 days, ketorolac at 15 to 30 mg intravenously every 6 hours (3 doses), acetaminophen at 1000 mg intravenously every 8 hours (2 doses), and oral gabapentin at 300 mg daily at night until discharge. Other pain medication was dispensed as needed, including oral oxycodone immediate release at 5 mg every 3 hours for moderate pain, oral oxycodone immediate release at 10 mg every 3 hours for severe pain, and oral oxycodone immediate release at 5 mg twice daily before physical therapy (not given within 40 minutes of prior narcotic administration). Pain was well-controlled in 83% of surgeon A’s patients and in 89% of surgeon B’s patients. Patients in group A were able to ambulate farther on POD 0 (mean, 17.1 feet) compared with patients in group B (mean, 10.5 feet). Over one session, patients in group A ambulated greater distances (mean, 317 feet) compared with patients in group B (mean, 273 feet). Patients in group A had an average length of stay that was 0.3 days less than patients in group B. In group A, 74% of patients were discharged to home during the study period, compared with 57% in group B.

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COMPARING THE RETURN ON INVESTMENT OF ADVANCED PRACTICE MEDICAL DEGREES IN PAs VS NPs Advanced medical degrees offer a higher return on investment for physician assistants (PAs) compared with nurse practitioners (NPs), according to researchers. Christopher K Craig, MMS, PA-C and colleagues, of the Wake Forest School of Medicine Department of General Surgery in Winston-Salem, North Carolina, completed an analysis comparing the return on investment in PA versus NP careers incorporating national salary data, federal income taxes, and student loans. Data were collected from the 2012 Bureau of Labor Statistics Occupational Employment Statistics database. The researchers calculated a net present value (NPV) at a 5% discount rate, incorporating salary as a positive cash flow and subtracting both federal income taxes and student loan repayments as negative cash flow. NPVs were compared to analyze projected return on investment at the time of retirement. Final cost of educational loans upon repayment for both PAs and NPs was averaged at $129,484. The median salary for PAs was $90,930 per year, while median salary for NPs was $89,960 per year. NPV for PAs was nearly $17,000 higher for PAs—$781,323 compared with $764,348 for NPs. “These data show that physician assistants have a higher return on investment when compared to their nurse practitioner colleagues,” said Dr Craig. “[M]ost PA programs allow candidates to matriculate immediately after obtaining a bachelor’s degree, while NP schools often require at least 1 year, if not 2, of nursing experience prior to entering their program “NPs and PAs are expected to fill the void of physicians and provide care for the growing and aging population.… The burden of student loan and tuition increases has many young adults carefully assessing differences in reimbursement among advanced practice providers,” Dr Craig concluded. DELAYED IMMUNIZATIONS AND BREASTFEEDING OVER AGE 1 MAY INCREASE RISK FOR CARIES Delayed immunization status, a low appointment attendance rate, and breastfeeding at 12 and/or 15 months of age are risk factors for caries in young children, researchers reported. Patrick Killeen, MS, PA-C, chief physician assistant at Western Connecticut Health Systems in Danbury, and colleagues sought to identify health screening measures from the well-child encounter that may also be associated with the risk for caries. They obtained dental health information

Conference Roundup

Delayed immunizations and breastfeeding at 12 and/or 15 months of age may increase the risk for caries in young children.

from a major tertiary pediatric center and conducted a crosssectional univariate analysis with more than 40 variables related to routine nutrition, safety, development, and other screenings contained within the 12- and 15-month wellchild templates to determine their association with “lifetime caries experience” or “caries risk status.” A total of 1,736 patients had a 12- and/or 15-month preventive medical visit(s) and at least one dental appointment (mean age, 40 months). In addition to observing wellaccepted risk factors for caries such as Hispanic ethnicity and high poverty rate, the researchers found that delayed immunization status, a history of missed appointments, and still breastfeeding at 12 and/or 15 months of age were also associated with an increased risk. “The new risk factors for caries identified in this analysis are standard parts of well-child care that medical pediatric providers are adept at asking and require little or no additional data input above baseline well-child screening measures,” stated Mr. Killeen. “Next steps toward improving provider adherence to oral health screening at well-child visits are to incorporate these variables into a new medically specific caries-risk assessment tool within the electronic health record. Earlier oral health screenings, prompting more referrals of young children to a dental home, will help provide access to preventive dental services to those children most at risk for dental problems.” n

For more coverage of AAPA 2016, please log on to ClinicalAdvisor.com/AAPA2016

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Writers’ Guidelines The Clinical Advisor welcomes submissions from its readers. Writing for us is an opportunity to share your knowledge and experience with your colleagues — and to collect a fee in the bargain! We pay an honorarium for every submission we accept. We’ll be glad to work with you to develop your ideas into compelling articles. As for length, that depends on which kind of article you submit. CLINICAL FEATURES update our readers on the latest information about conditions seen in everyday practice. Running approximately 2,500 to 5,000 words, including the references, features can be written either as regular narratives or as a series of questions and answers. Topics should be selected with the busy primary-care clinician in mind; specialists should review specialty topics from the primary-care point of view. If at all possible, articles should be accompanied by clinical photos. Charts, tables, and algorithms are also encouraged. Please include your title and affiliation. CLINICAL CHALLENGE is our popular department comprising histories of difficult cases. Each case is presented as a step-by-step, chronological account, revealing the author’s thought processes along the way. It is divided into sections in this order: the patient presentation; the patient history; the twists and turns eventually leading to a diagnosis; the treatment and outcome; and a discussion of the lessons learned or of the condition in general. The length should be about 1,500 words, and accompanying images are encouraged. Please include your title and affiliation. DERMATOLOGY CLINIC is a department that presents photos of actual cases and asks readers to identify the condition. Each case opens with one or two color photos and a 75-to-100-word description of the patient presentation, without giving away the diagnosis. This is followed by a 750-to-1,000-word summary that includes a fuller description of the ailment, an explanation of how the correct diagnosis was reached, a general review of the condition along with a differential diagnosis, and a description of the patient’s treatment and outcome. Topics must be approved by the editor prior to submission. Please include your title and affiliation. COMMENTARY is our guest editorial page. It gives you the opportunity to sound off on an issue of importance to your colleagues nationwide. A typical Commentary runs about 600 words in length. Please include your title and affiliation. To discuss your editorial ideas, contact us by phone at 646.638.6078; by e-mail to editor@ClinicalAdvisor.com; or by mail to The Clinical Advisor, 114 West 26th Street, 4th Floor, New York, NY 10001. www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • JULY 2016 75

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Conference Roundup AANP 2016 National Conference American Association of Nurse Practitioners San Antonio

AANP SUPPORTS BILL FOR FULL PRACTICE AUTHORITY FOR NPs IN VETERAN HEALTH CARE The American Association of Nurse Practitioners (AANP) voiced their support of a Veterans Administration (VA) bill that would standardize full practice authority for nurse practitioners (NPs) throughout the VA healthcare system. AANP partnered with San Antonio veteran groups for a press conference at the AANP 2016 National Conference. “Today, veterans needlessly wait far too long to receive the health care they deserve,” said Cindy Cooke, DNP, FNP-C, FAANP, President of the AANP. “The US Department of Veterans Affairs has put forward a solid plan to adopt a 21st century approach to healthcare delivery that will address that need.” The proposed bill aims to standardize the level of care that NPs are able to provide at VA facilities throughout the country, providing veterans with access to the highest level of NP-provided care, as well as reduced wait times and increased healthcare flexibility. Currently, NPs are able to practice at the highest level in 21 states, plus the District of Columbia. According to Dr Cooke, more than 7000 veterans regularly wait up to 30 days to receive care; more than 4800 must wait between 31 and 60 days. “The model put forward [by the VA] is backed by decades of research … as well as recommendations by leading scientific policy organizations, including the Institute of Medicine and the National Council of the State Boards of Nursing,” Dr Cooke said. “I know the political hurdles that the association is going to face,” said Roberto E. De La Garza, Army Judge Advocate General (JAG)

The proposed bill aims to standardize the level of care that NPs are able to provide at VA facilities throughout the country.

Corps, Retired, and former member of the Texas House of Representatives. “I believe firmly that we should have a healthcare system that is available to all veterans.” Alicia Rossiter, DNP, ARNP, PNP-BC, FNP, FAANP, Lieutenant Colonel Retired, United States Air Force and Program Director of the University of South Florida V-CARE, also voiced her support. “The VA has an access problem; 80% of veterans are not being seen in the VA,” she said. “They’re being seen in the civilian sector due to these access problems. We need to bring these veterans back to the VA to be cared for by healthcare providers—NPs, CRNAs, physicians, PAs—where they can get culturally competent care by individuals who know about serviceconnected diseases, risk factors, comorbidities secondary to military service.” “We need to bring them back in so that they can receive this care by providers who are aware of their unique healthcare needs,” added Dr Rossiter. Enrique Martin, a US Air Force veteran of Desert Storm, summarized his view on the bill, saying, “No veteran should have to wait for health care. Period.” Other advocates of the bill include Elizabeth Barker, US Navy Captain, Retired, RN-CS, FNP, PhD, ACHE, and Jimmie O. Keenan, Major General, Retired, 24th Corps Chief of the Army Nurse Corps. “It’s frustrating on a professional level to not be able to access your patients,” said Dr Barker. “This proposal that the VA has put in is superb. We are prepared for high-quality care. We have over 50 years of research that demonstrates that the care of NPs has outcomes that are equal or better to our physician colleagues.”

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“It is not a ‘we versus them,’” added Major General Keenan. “It is a ‘we all’ supporting our veterans to make sure they get the care they deserve.” “It’s time to make this care directly and more readily accessible to our nation’s veterans,” said Dr Cooke, “and to open access to care for our veterans in our nation’s veterans healthcare system.” The bill was opened to public comment on May 25, 2016. After a 60-day period, the VA will make its decision on whether to pass the bill, taking these public comments into account.

LONG-ACTING REVERSIBLE CONTRACEPTION EFFECTIVE IN NULLIPAROUS ADOLESCENTS Long-acting reversible contraception (LARC) methods are highly effective birth control options for nulliparous adolescents, according to researchers. Amy Bigham, DNP, RN, FNP-BC, COI, Associate Professor at the Ida V. Moffett School of Nursing at Samford University in Birmingham, Alabama, presented clinical practice guidelines focused on new labeling practices and new products surrounding LARC. More than 40% of adolescents in the United States aged between 15 and 19 years are sexually active; the majority of those teens report using contraception methods that include condoms, oral contraception, and withdrawal. High failure rates surrounding these methods regularly result in adolescent pregnancies, 80% of which are unplanned. “This statistic indicates a need for reliable and effective contraceptive methods for adolescents,” wrote Dr Bigham. “The American College of Obstetricians and Gynecologists (ACOG) recommends the use of LARC in adolescents due to the top-tier efficacy and safety.” Upon their introduction, the FDA recommended LARC for use only in women who had experienced childbirth. Other barriers to wide use of LARC include lack of familiarity with these methods, misconceptions regarding cost or efficacy, lack of access to providers who will perform the insertion procedures, and safety concerns regarding LARC use in adolescents. “When considering birth control options for the nulliparous adolescent, LARC should be considered a viable option,” concluded Dr Bigham. MISCONCEPTIONS COMMON REGARDING PROBIOTICS Recognizing common misconceptions about probiotics can help nurse practitioners (NPs) determine the most appropriate probiotics for their patients, according to researchers. The study authors addressed 2 common misconceptions about probiotics. The first misconception was “All probiotics

are the same.” They noted that different strains of probiotics have different health effects. The benefits can vary by genus, species/sub-species, and strain. The researchers used clinical evidence to provide recommended strains of probiotic for various clinical conditions (see Table 1). The second misconception they addressed was “More probiotic is better.” Currently, the researchers noted, there is no conclusive evidence to show that probiotics with higher concentrations of bacteria or more species/strains improve their efficacy and health benefits. Different types of bacteria are effective at different amounts, they said, and the recommended amount and number of strains should be based on clinical studies that demonstrate a health benefit. “Making clinical recommendations for probiotics is complicated by growing numbers of products and a paucity of validated data,” said the researchers. “However, [NPs] who keep these common misconceptions in mind will be better able to evaluate and recommend specific probiotics to their patients.” TABLE 1. Recommended strains of probiotic for various clinical conditions Clinical conditions Recommended strain(s) with clinical evidence Antibioticassociated diarrhea

Saccharomyces boulardi, Lactobacillus rhamnosus GG, Lactobacillus casei DN114 001, combined; or Lactobacillus acidophilus CL1285 plus Lactobacillus casei

Atopic dermatitis

Lactobacillus rhamnosus GG

Clostridium difficile-associated disease

Lactobacillus rhamnosus GG, Saccharomyces boulardi

Gut transit time

Bifidobacterium lactis DN-173 010

Inflammatory bowel disease (IBD): pouchitis

Lactobacillus acidophilus SD5212, Lactobacillus paracasei SD5218, Lactobacillus bulgaricus SD5210, Lactobacillus plantarum SD5209, Bifidobacterium infantis SD5220, Bifidobacterium longum SD5219, Bifidobacterium breve SD5206, Streptococcus thermophilus SD5207, combined

IBD: ulcerative colitis

Escherichia coli Nissle 1917; or Lactobacillus acidophilus SD5212, Lactobacillus paracasei SD5218, Lactobacillus bulgaricus SD5210, Lactobacillus plantarum SD5209, Bifidobacterium infantis SD5220, Bifidobacterium longum SD5219, Bifidobacterium breve SD5206, Streptococcus thermophilus SD5207, combined

Irritable bowel syndrome

Bifidobacterium longum 35624

Immune support

Lactobacillus rhamnosus GG, Bifidobacterium lactis HN019, Bifidobacterium lactis BB-12, Lactobacillus casei DN114001, Lactobacillus acidophilus LAFT1

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MANY PATIENTS LACK KNOWLEDGE ABOUT NSAIDs AND THEIR RISKS Patients lack understanding about non-steroidal anti-inflammatory drugs (NSAIDs) and their associated risks, researchers reported. To ensure that patients are using NSAIDs safely and effectively, clinicians should educate patients who indicate use of these medications. The researchers surveyed 1,056 demographically representative adults from the general US population; 515 of whom reported experiencing pain at least twice a week or pain due to surgery. A total of 810 (77%) of respondents reported experiencing pain, including at least one of the following: chronic pain, recurrent pain, general pain, or pain as a result of surgery, injury, or aging. Among those who had experienced pain, 497 reported using over-the-counter (OTC) medications and 277 reported using a prescription pain medication. When asked if they knew what NSAIDs were, 495 (47%) of survey participants said they did not, including 282 participants who reported taking pain medication in the last 12 months. Many respondents who indicated that they had some knowledge of NSAIDs were unable to identify common NSAIDs and NSAID-containing products: 78% failed to identify Excedrin, 55% failed to identify Advil, 54% failed to identify Aleve, 54% failed to identify naproxen, and 42% failed to identify ibuprofen. Although 58% (351 out of 608) of prescription NSAID or OTC pain medicine users knew that there are risks associated with NSAIDs, only 27% (166 out of 608) knew that the FDA recommends using the lowest effective NSAID dose for the shortest duration possible. About half (52%) of medication users were unaware of low-dose pain medication options, and 33% of users believed that they needed a high-dose treatment for their pain. After learning about FDA recommendations, 58% (351 out of 608) reported that they would discuss their pain medication with their clinicians. “Patients experiencing pain should have conversations with their healthcare providers in order to learn more about the safe use of pain medications,” concluded the researchers. GAPS EXIST IN CLINICIAN KNOWLEDGE OF GOUT MANAGEMENT Effective gout management is critical to improving overall patient care coordination, according to researchers. Michael Zychowicz, DNP, ANP, ONP, FAAN, FAANP, Associate Professor and Director of the MSN program at

Conference Roundup

Close-up of the inflamed right knee of a man, aged 66 years, with a diagnosis of gout.

Duke University School of Nursing, and colleagues, conducted a survey of 88 NPs and PAs to identify knowledge gaps and barriers surrounding the diagnosis, treatment, and management of gout; 25 NPs and PAs participated in an in-depth, qualitative telephone interview. The researchers also conducted qualitative telephone interviews with 12 gout patients to identify barriers related to symptom recognition, diagnosis, treatment, and follow-up care. Among all NPs and PAs surveyed, diagnostic and treatment confidence was around 50%; researchers identified misconceptions surrounding the underlying nature of gout and found that clinician use of the full range of diagnostic tools was limited. Issues were also identified surrounding the prescribing of allopurinol and a limited use of febuxostat as a urate-lowering therapy (ULT) in eligible patients. Additionally, clinicians were unsure of appropriate monitoring and care coordination strategies and did not optimally utilize prophylactic therapy. “Opportunities exist to educate clinicians on effective gout management and improve overall patient care coordination, specifically in regards to the monitoring of serum uric acid (SUA) levels, appropriate allopurinol dose adjustments, simultaneous initiation of prophylaxis and ULT, and selection of ULT in the presence of renal disease,” concluded Dr Zychowicz. n

For more coverage of AANP 2016, please log on to ClinicalAdvisor.com/AANP2016

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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 an independent consultant in Kansas City, Mo.

D-mannose

D-mannose is being increasingly used as an effective alternative to antibiotics for various conditions. A simple sugar, d-mannose is found naturally in high amounts in many fruits such as apples, oranges, and peaches, as well as blueberries and cranberries. Vegetables, including green beans, cabbage, and broccoli, are also a common source. In addition, d-mannose occurs naturally in some cells in the human body and is thought to be a prebiotic, because consumption of d-mannose stimulates and fosters the growth of good bacteria in the digestive tract. Cranberries are a natural source of D-mannose.

Background Chemically, d-mannose is considered a simple sugar. Structurally, it is similar to glucose, but it is absorbed more slowly in the gastrointestinal tract. This accounts for its lower glycemic index. Compared with actual glucose, which is readily absorbed and has a glycemic index of 100, mannose must first be converted into fructose and then into glucose, significantly blunting the insulin response and reducing its impact on blood sugar levels. After mannose is absorbed by the gut, it is not stored in the liver like glucose but is filtered out of the body directly by the kidneys.

Science Mannose is of interest to health researchers for its possible use in a variety of conditions. One of these is its potential application as an early marker of impaired glucose tolerance. In a study of 273 subjects with and without diabetes

that investigated the relationship between fasting plasma mannose levels and fasting plasma glucose levels,1 mannose absorption showed a relatively fl at postingestion curve, compared with glucose, with less variability throughout the day. The fluctuations were, however, very closely correlated, suggesting the possibility that mannose might be used to detect alterations in glucose metabolism earlier than is currently possible. Perhaps the most promising use for d-mannose is as an anti-infective agent. Most research to date has been done in the area of urinary tract infection (UTI), specifically in women. This common complaint accounts for nearly 8 million visits to a healthcare office and 1.5 million trips to an emergency department each year, at a cost of more than $3.5 billion in the United States.2 In addition, there are a growing number of reports that document microbial resistance to traditional antibiotics, increasing both the cost and morbidity of this complaint.3 Continues on page 84

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ALTERNATIVE MEDS UPDATE A study of nearly 200 female college students presenting with symptoms of UTI found that more than 40% of infections were resistant to first- and second-line antibiotics.3 The most common offender in UTI is Escherichia coli.4 Interestingly, there is a littleknown triad involving d-mannose, E coli, and UTI. For generations, women have been told to drink cranberry juice when symptoms of a UTI begin. The high d-mannose content in cranberry juice is the most likely reason for its efficacy for symptoms of UTI. E coli are known to adhere to uroepithelial cells,4 and d-mannose has been shown to block E coli receptors effectively and literally flush bacteria away.5 D-mannose has also been found to slow recurrence of UTI. A group of researchers studied 60 women with recurrent UTI (defined as ≥3 occurrences within the previous 12 months).6 Participants were randomly assigned to either trimethoprim/sulfamethoxazole or daily d-mannose for 24 weeks. In the antibiotic group, the mean time to recurrence of UTI was approximately 53 days. For the group treated with d-mannose, time to recurrence of UTI was 200 days.6

Safety, interactions

A daily dose of 2 g has been recommended to prevent recurrence of UTI.8 The average cost to treat acute symptoms of UTI for the recommended 2 to 3 days is approximately $20.

Summary

The most common offender in UTI is Escherichia coli.

D-mannose may be an effective first step in treating patients with antimicrobial resistance.

Healthcare providers must always assess patients with UTI symptoms appropriately for more serious conditions, but for those with UTI that would otherwise be treated with antibiotics, d-mannose may be one of many first steps in the war against antimicrobial resistance. n References 1. Sone H, Shimano H, Ebinuma H, et al. Physiological changes in circulating mannose levels in normal, glucose-intolerant, and diabetic subjects. Metabolism. 2003;52(8):1019-1027. 2. Amalaradjou MAR, Venkitanarayanan K. Natural approaches for controlling urinary tract infections. In: Tenke P (ed). Urinary Tract Infections. InTech. http://www. intechopen.com/books/urinary-tract-infections/naturalapproaches-for-controlling-urinary-tract-infections. October 3, 2011. 3. Olson RP, Harrell LJ, Kaye KS. Antibiotic resistance in urinary isolates of Escherichia coli from college women with

D-mannose is considered very safe because it occurs naturally in many foods. Doses higher than what is consumed through normal dietary intake, however, may result in abdominal bloating or diarrhea.7 D-mannose supplements should not be used during pregnancy or when breastfeeding, and individuals with diabetes mellitus should not take d-mannose. No actual drug interactions are known.

How supplied, dose, cost

urinary tract infections. Antimicrobial Agents Chemother. 2009;53(3):1285-1286. 4. Abbo LM, Hooton TM. Antimicrobial stewardship and urinary tract infections. Antibiotics (Basel). 2014;3(2):174-192. 5. Bouckaert J, Berglund J, Schembri M, et al. Receptor binding studies disclose a novel class of high-affinity inhibitors of the Escherichia coli FimH adhesion. Molec Microbiol. 2005;55(2):441-455. 6. Porru D, Parmigiani A, Tinelli C, et al. Oral d-mannose in recurrent urinary tract infections in women: a pilot study. J Clin Urol. 2014;7(3):208-213. 7. Kiefer D. Vitamins & supplements. D-mannose. WebMD. http://www.webmd.com/vitamins-and-supplements/dmannose-uses-and-risks. June 14, 2015. 8. Kranjčec B, Papeš D, Altarac S. D-mannose powder for prophylaxis of recurrent urinary tract infections in women: a randomized clinical trial. World J Urol. 2014;32(1):79-84. All electronic documents accessed May 27, 2016.

A dose of 2 g every 2 to 3 hours is usually recommended for the management of uncomplicated UTI. Foods high in d-mannose, such as black currants, red currants, gooseberries, cranberries, tomatoes, apples, peaches, oranges, blueberries, and certain vegetables, may also help with symptoms but will likely not contain a sufficient amount of d-mannose to treat a UTI adequately. 84 THE CLINICAL ADVISOR • JULY 2016 • www.ClinicalAdvisor.com

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