November 2011 Clinical Advisor by The Clinical Advisor

THE CLINICAL ADVISOR • NOVEMBER 2011

A F O RU M F O R P H YS I C I A N A S S I S TA N T S

NEWSLINE

■ Screening for PAD ■ Shorter hep C regimens ■ Heart-friendly NSAIDs ADVISOR FORUM

■ Treating high triglycerides ■ Sesame oil to lower BP ■ Can fish oil cause GERD? LEGAL ADVISOR

How risky is giving medical advice over the phone?

✶ FREE CME COURSES!

■ Dermatology Clinic

BLEEDING “THORN BLISTER” PAGE 93

VOLUME 14, NUMBER 11

■ Dermatologic Look-Alikes

PAPULES ON THE NIPPLE GLANDS PAGE 109 Expanded job listings! www.ClinicalAdvisor.com/Jobs

| N OV E M B E R 2 011 | www.ClinicalAdvisor.com

CME: ADULTS WITH DIABETIC

KETOACIDOSIS Without insulin (blue), fat is used for fuel instead of glucose.

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Persons appearing in photographs in “Newsline,” “The Legal Advisor,” and “Clinical Challenge” are not the actual individuals mentioned in the articles.They appear for illustrative purposes only. The Clinical Advisor® (USPS 017-546, ISSN 1524-7317), Volume 14, Number 11, is published 12 times a year, monthly, for $75.00 per year in the United States; $85.00 in Canada; $110.00 for all other foreign, in U.S. dollars, by Haymarket Media, Inc., 114 West 26th Street, 4th Floor, New York, NY 10001. Single copy: $20 U.S.; $30 foreign. www.ClinicalAdvisor.com. To order or update your paid subscription, call 800.436.9269. Periodicals postage rate paid at New York, NY, and additional mailing offices. POSTMASTER: Send all address changes to:The Clinical Advisor, c/o DMDData Inc., 2340 River Road, Des Plaines, IL 60018. Call 800.430.5450 to change your address or make other subscription inquiries. Requests for subscriptions from outside the United States must be accompanied by payment. All rights reserved. Reproduction in whole or in part without permission is prohibited. Copyright © 2011.

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“My ringtone is the sound of a can opener.”

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER 2011 3

Editor Joe Kopcha, editor@clinicaladvisor.com Managing editor Marina Galanakis Senior editor Delicia Yard Web editor Nicole Blazek Contributing editors Bruce D. Askey, MSN, CRNP; Philip R. Cohen, MD; Peter F. Cohn, MD; JoAnn Deasy, PA-C, MPH; Melody French, PhD, PA, FNP; Virginia H. Joslin, PA-C, MPH; Norma M. Keller, MD; Debra August King, PhD, PA; Ann W. Latner, JD; Cheryl F. MacDonald, MSN, MPH, CRNP; Malka G. Messner, RPA-C, MPAS; Daniel R. Mishell Jr, MD; Claire B. O’Connell, MPH, PA-C; Patrick G. O’Connor, MD, MPH; Michael E. Ryan, DO; Sherril Sego, FNP, DNP; Lisa Stern, APRN; Karen T. Vujevich, RN-C, MSN, CRNP; Julee B. Waldrop, MS, PNP; Reuben W. Zimmerman, PA-C; Michael E. Zychowicz, RN, MS, NP-C Group art director, Haymarket Medical Jennifer Dvoretz Assistant art director Natasha Marcano-Dillon Production director Leslie Carsman Circulation manager Paul Silver Assistant circulation manager Monica Bond Audience development director John Crewe National accounts manager Alison McCauley, 646.638.6098 alison.mccauley@haymarketmedical.com Group publisher Thomas P. Hennessy, 646.638.6085 tom.hennessy@haymarketmedia.com Editorial director Tanya Gregory Vice president, medical magazines and digital products Jim Burke CEO, Haymarket Media Inc. Lee Maniscalco

CONTENTS NOVEMBER 2011

NEWS AND COMMENT 16

Newsline ■ Glucose, cholesterol, and cognitive decline ■ Guideline lowers PAD screening age to 65 ■ Vitamin E may hurt prostate, and saw palmetto doesn’t help ■ Adenoidectomy does not stop URTIs in kids ■ Prehypertension hikes risk of stroke ■ Hepatitis C regimens can be shorter ■ Psoriasis and CV death ■ Opioids may lead to pneumonia in the elderly ■ Naproxen the most heart-friendly NSAID? ■ Biweekly visits help control diabetes

DEPARTMENTS

CME/CE Dermatology Clinic

CME/CE Management of diabetic ketoacidosis in adults When developing a plan of care for this acute complication of diabetes mellitus, search for the inciting stressor.

MAKING CONTACT

■ After getting stuck by a thorn, a man developed a rapidly growing red blister.

Testing for CVD in the asymptomatic 42

Evaluating heart risk in asymptomatic patients An evidence-based guideline can help clinicians lower the burden of coronary deaths in this population.

Stat Consult Find out the most recent information on testing, diagnosis, and treatment of prediabetes.

■ A single nodule with a peau d’orange surface was found on a baby’s chest.

FEATURES 33

78 Cholesterol may raise Alzheimer risk 16

Drug Update ■ Once-daily therapy for postherpetic neuralgia ■ Injectable gel for fecal incontinence

119 Commentary

Antibiotic stewardship to preserve benefits Originally considered “magic bullets,” antibiotics must be used appropriately to protect their effectiveness.

Clinical Challenge Days after falling from a window, a firefighter presented with ecchymosis and fi xed flexion in the hand.

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

Continues on page 8

Fasciotomy on a wrist injured in a fall 97

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While there are many diabetes complications,

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

ONLY LYRICA IS RECOMMENDED AS LEVEL A by AAN evidence-based guideline for the treatment of painful diabetic neuropathy (PDN)1 “If clinically appropriate, pregabalin should be offered for the treatment of PDN (Level A).”1 The medical organizations that developed this guideline (the AAN, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation) recognize that specific care decisions are the prerogative of the patient and physician caring for the patient, based on all of the circumstances involved. For full guideline, visit www.aan.com/guidelines. Level A=Established as effective, based on at least 2 Class I studies. Class I level evidence includes a randomized, controlled clinical trial of the intervention of interest with masked or objective outcome assessment, in a representative population, and other specified criteria. AAN=American Academy of Neurology. LYRICA is indicated for the management of neuropathic pain associated with Diabetic Peripheral Neuropathy, management of Postherpetic Neuralgia, as adjunctive therapy for adult patients with Partial Onset Seizures, and management of Fibromyalgia. PBP01859D/407532-01

02-08531_D_R1_LYR_DPN_Asize_JA.indd 1

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

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

September 2011

10/20/11 5:44 PM

CONTENTS DEPARTMENTS, cont’d

■ Xanthelasmata associated with increased risk of cardiovascular disease and mortality independent of lipid levels

104 Legal Advisor Medical advice given over the phone causes harm to an infant with flulike symptoms and leads to a lawsuit.

ADVISOR FORUM

109 CME/CE Dermatologic Look-Alikes Two cases of painless breast papules— one on a woman’s areola, the other on a man’s nipple glands. 113 CME/CE Posttest

cataract surgery

Diagnosis by phone ends in tragedy 104

■ And more

114 Alternative Meds Update Quercetin, a powerful antioxidant found in a variety of plants, acts like an antihistamine and may help protect against cancer and heart disease. 117 Evidence-Based Medicine ■ Pulse oximetry screening may detect congenital heart defects in newborn infants ■ Early antiretroviral therapy may reduce transmission in HIV-discordant heterosexual couples

Consultations ■ Treating elevated triglycerides ■ What caused this nail dystrophy? ■ Safe use of periocular steroid ■ Stopping warfarin before

Clinical Pearls ■ “Alarming” teen contraceptive-pill

compliance ■ The devil is in the “D-TAILS” ■ Easing children’s anxiety over cast removal ■ And more 69

Yellow eyelid plaques may indicate CVD 117

Your Comments ■ Prostate screening: every one or two years? ■ Withhold judgment when discussing firearms in the home

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U.S. health care performs poorly on national scorecard Access to U.S. health care is declining despite the fact that costs are higher than ever. Heart failure admissions decline in U.S. U.S. heart failure (HF) hospitalizations decreased by 29.5% during the past decade, data from a fee-for-service Medicare claims analysis conducted from 1998 to 2008 indicate. Task force recommends Pap testing every three years The U.S. Preventive Services Task Force says screening too frequently for cervical cancer may cause unnecessary anxiety, increases in invasive diagnostic procedures and over treatment with procedures that pose potentially more harm than benefit.

Derm Dx Interact with your peers by viewing the images and offering your diagnosis and comments. ClinicalAdvisor.com/DermDx Pruritic rashes that run in the family A 54-year-old woman presented with a 26-year history of intermittent, malodorous, pruritic skin lesions. Several of her relatives have experienced similar rashes.

MAKING CONTACT

Viral vs. Bacterial Pharyngitis It is important that clinicians differentiate between bacterial and viral forms of pharyngitis, as limiting antibiotic use, particularly macrolides, can reduce emerging resistance among bacterial pathogens, including sore throat-causing streptococcus pneumoniae. Type 2 Diabetes Complications Type 2 diabetes accounts for 90% to 95% of all cases of diabetes in the United States. In 2007, the direct medical cost for these patients was $116 billion and the indirect cost for disability, work loss and premature mortality was $58 billion.

The Waiting Room Official Blog of The Clinical Advisor ClinicalAdvisor.com/Blog Julee Waldrop, DNP, PNP, FNP Nurses that earn doctorate degrees deserve the title “doctor” Physician groups’ insinuations that nurses with doctorate degrees, who want to use the title “doctor” are confusing patients and misrepresenting themselves, are obtrusive and offensive. Robyn Carlisle, MSN, CNM, WHNP Exercising during pregnancy: How much is too much? News reports featuring the pregnant Chicago marathoner have caused many to question the safety of exercising during pregnancy. Midwife and runner, Robyn Carlisle, MSN, CNM, WHNP, explains the benefits and offers guidelines. Leigh Montejo, MSN, FNP-BC Encouraging adolescent health with group visits Group health care visits could improve adolescent health by encouraging commitment to a prevention-based lifestyle and help shift U.S. health care away from a system based on treating diseases, to one that aims at stopping them before they begin.

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Expand your practice In addition to the award-winning news and features found every month in our print edition, ClinicalAdvisor.com is an invaluable resource that now offers: • Free on-line CME/CE • Job advice and salary information • Medical slideshows • Derm Dx

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CME CE

PROGRAM OUTLINE NOVEMBER 2011

0.5 CREDITS

Page 33 FEATURE Management of diabetic ketoacidosis in adults John J. Beneck, MSPA, PA-C ■ LEARNING OBJECTIVES: • Describe what happens when glucagon is released in the liver. • Identify the most common stressor in patients with hyperglycemic crisis. • Understand the role of fluid resuscitation in managing diabetic ketoacidosis. • Explain the basic dosing strategies involved in basal/bolus insulin therapy.

0.5 CREDITS

Page 93 DERMATOLOGY CLINIC Case #1: Chest nodule with a swollen, pitted surface Susan Weinhofer, RN

Case #2: Bleeding blister forms after thorn accident Esther Stern, NP-C ■ LEARNING OBJECTIVES: • To increase awareness of dermatologic conditions, their diagnosis, and up-to-date treatment.

Page 109 DERMATOLOGIC LOOK-ALIKES Yellow papules near the nipple Noah S. Scheinfeld, MD, JD ■ LEARNING OBJECTIVE: • To improve the clinician’s ability to distinguish and properly treat dermatologic conditions with similar presentations.

Page 113 POSTTEST

This program has been reviewed and is approved for a maximum of 1 hour of AAPA Category I CME credit by the Physician Assistant Review Panel. Approval is valid for one year from the issue date of November 2011. Participants may submit the self-assessment at any time during that period. This program was planned in accordance with AAPA’s CME Standards for Enduring Material Programs and for Commercial Support of Enduring Material Programs. The Nurse Practitioner Associates for Continuing Education (NPACE) is an approved provider of continuing education by the Massachusetts Association of Registered Nurses, Inc. (MARN), an accredited approver by the American Nurses Credentialing Center’s Commission on Accreditation (ANCC). NPACE designates this educational activity for a maximum of 1 contact hour of credit. Participants should only claim credit commensurate with the extent of their participation in the activity.

12 THE CLINICAL ADVISOR • NOVEMBER 2011 • www.ClinicalAdvisor.com

Newsline

Taking opioids heightens risk of pneumonia page 23

Saw palmetto useless in men with BPH page 19

N O V E M B E R 2 0 11

PCP visits every two weeks controls diabetes page 24

Glucose, cholesterol, and cognitive decline

MRI of a patient with dementia shows atrophy of the brain.

A separate finding connected abnormal lipid metabolism with AD. Brain specimens were taken from autopsies performed between 1998 and 2003. The subjects had undergone clinical examinations, including lipid measurements, in 1988. At that time, none of the patients had any signs of AD, but 34% had been diagnosed with dementia by the time of death. Cholesterol levels had been significantly higher in patients with AD-related neuritic plaques than in those with no such plaques. A total of 86% of persons with high cholesterol had brain plaques, compared with 62% of others. The results suggest that dyslipidemia increases the risk of plaque-type pathology (Neurology. 2011;77:1068-1075). No link was found between high cholesterol and neurofibrillary tangles, which develop in the brain with AD.

Antidepressant use in the United States Almost 11% of Americans aged 12 years and older take antidepressant medication

20 15 Percent

TYPE 2 DIABETES may significantly raise a person’s odds of developing dementia; intensive lowering of blood glucose doesn’t help prevent cognitive decline in such patients; and people with high cholesterol may be at heightened risk for Alzheimer disease (AD). These were the findings from three separate studies exploring risk factors for dementia. In one initiative, 1,017 dementiafree, community-dwelling people aged 60 years and older who underwent a 75-g oral glucose tolerance test were followed for up to 15 years (Neurology. 2011;77:1126-1134). A total of 150 participants had diabetes, and 232 developed dementia. The subjects with diabetes were twice as likely to develop dementia as those with normal levels of blood glucose. The risks of developing allcause dementia, AD, and vascular dementia increased significantly when blood glucose was still high

two hours after a meal. However, no such association was observed for fasting plasma glucose levels. Despite the link between abnormal glucose levels and dementia, intensive glucose-lowering therapy is unlikely to counteract the effects of hyperglycemia on the brain. In the ACCORD MIND study, reported online by The Lancet Neurology, Lenore J. Launer, PhD, and co-investigators enrolled 2,977 patients who had been assigned to the ACCORD trial’s intensive glucose-lowering therapy (designed to keep hemoglobin [Hb] A1c below 6.0%) or standard treatment (HbA1c target of 7.0% to 7.9%). Although members of the intensive-treatment group had a significantly larger total brain volume at 40 months, cognitive outcomes did not differ from the standard-therapy participants.

14.5%

40-59

60 years and older

10.8% 10 6.1% 5 0

Source: CDC/NCHS, National Health and Nutrition Examination Surveys, 2005-2008

15.9%

3.7% 12 years and older

16 THE CLINICAL ADVISOR • NOVEMBER 2011 • www.ClinicalAdvisor.com

12-17

18-39

Newsline BECAUSE PERSONS aged 65 years and older have a one-in-five chance of having either symptomatic or asymptomatic peripheral artery disease (PAD), an updated management guideline recommends that people in that age group be considered for anklebrachial index (ABI) diagnostic testing, rather than waiting until they reach the age of 70 as an earlier version of the guideline had suggested. “Age alone appears to defi ne a patient population at such a high risk of PAD that we can justify using a cost-effective and risk-free test like the ABI,” explained guideline writinggroup chairperson Thom Rooke, MD, in a statement announcing the release of the document, which was published online ahead of print by Circulation (available at circ.ahajournals. org/content/early/2011/09/29/ CIR.0b013e31822e80c3.long; accessed October 15, 2011).

The guideline, issued by the American College of Cardiology Foundation and the American Heart Association, updates 2005 recommendations. The earlier document suggested using the resting ABI to establish the lower-extremity PAD diagnosis in patients with suspected of having the condition, defi ned as individuals with exertional leg symptoms, with nonhealing wounds, who were aged 70 years and older or who were aged 50 years and older with a history of smoking or diabetes. The 2011 update modifies the definition of patients with suspected lower-extremity PAD to include individuals with one or more of the following: exertional leg symptoms, nonhealing wounds, aged 65 years and older, or aged 50 years and older with a history of smoking or diabetes. ABI is the only cardiovascular disease diagnostic test that can be applied in an age-def ined

Guideline lowers PAD screening age to 65

Illustration of the superficial femoral artery of a leg with PAD.

clinical population with such a high detection rate, low to no risk, and low cost. However, the ABI recommendation is intended for office-based and vascular laboratory diagnostic use and is not intended as a population screening tool.

Vitamin E may hurt prostate, and saw palmetto doesn’t help Two separate studies bring information regarding the relationship between a specific supplement and the prostate. In one trial involving 35,533 men from 427 study sites, dietary supplementation with vitamin E significantly increased the risk of prostate cancer among healthy men ( JAMA. 2011;306:1549-1546; available at jama.ama-assn.org/content /306/14/1549.long, accessed October 15, 2011). Overall, 17% more cases of prostate cancer developed among men who took 400 IU of vitamin E per day over seven years than among men who took a placebo. In the other study, saw palmetto was found to be no more effective than placebo in reducing urinary symptoms in men

suffering from benign prostatic hyperplasia (BPH), despite the fact that saw palmetto fruit extracts have become widely used for this purpose. Investigators randomized 369 men aged 45 years and older, with a peak urine flow rate of at least 4 mL/second, to one, two, and then three 320-mg daily doses of saw palmetto extract or placebo, with the dose increases occurring at 24 and 48 weeks. Between baseline and 72 weeks, mean American Urological Association Symptom Index scores fell from 14.42 to 12.22 points with saw palmetto extract, compared with a drop from 14.69 to 11.70 points with placebo ( JAMA. 2011;306:1344-1351).

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER 2011 19

Newsline CHILDREN WHO underwent adenoidectomy to manage recurrent upper-respiratory-tract infections (URTIs) continued to have a comparable infection rate to youngsters who went the watchful-waiting route. Acute URTI is the most common diagnosis in children in primary care. Although adenoidectomy is usually done to reduce URTI incidence, evidence of the effectiveness of this approach is scarce, contends a team led by Professor Anne Schilder in a study reported on BMJ.com (available at www. bmj.com/content/343/bmj.d5154. long; accessed October 15, 2011). To learn more about the effectiveness of adenoidectomy for URTI, the investigators conducted a trial of 111 children in the Netherlands, aged 1 to 6 years,

Rhinoscopy shows adenoid vegetations in a child.

who had recurrent URTI and had been selected for adenoidectomy. The children were randomized to a strategy of immediate adenoidectomy (surgery within six weeks) or initial watchful waiting (40% of the watchful-waiting group members underwent surgery over the course of follow-up).

During median follow-up of 24 months, 7.91 episodes of URTI per person-year occurred in the adenoidectomy group, compared with 7.84 in the watchfulwaiting group. Children who had undergone adenoidectomy had significantly more days with fever than did the other youths. URTI prevalence decreased over time in both groups. In a separate project, probiotics were found to be better than placebo in reducing the number of persons experiencing acute URTI episodes. However, Bi Rong Dong, MD, and associates cautioned that their review of randomized controlled trials for The Cochrane Library had some limitations, and that the studies they evaluated had no data on older people.

Prehypertension hikes risk of stroke BP ONLY slightly above the normal range may increase a person’s risk of stroke by nearly 80% compared with normotensive individuals. An analysis of studies involving 518,520 participants from North America and Asia indicated that those with prehypertension had a 55% greater chance of suffering a future stroke than did those with normal BP. This result held regardless of sex, race/ethnicity, systolic or diastolic prehypertension, or type of stroke. The relative risk of future stroke rose to 79% among people at the

high end of the prehypertension spectrum (130-139 mm Hg systolic or 85-89 mm Hg diastolic). For those with lower-range prehypertension (120-129 systolic or 80-84 diastolic), stroke risk was 22% higher than for normotensive subjects; this increase was deemed nonsignificant by the investigators (Neurology. 2011;77:1330-1337). The researchers cautioned that prehypertension-driven stroke risk is especially relevant in nonelderly persons, and recommended that young and middle-aged persons check their blood pressure regularly and make specific lifestyle

To protect against stroke, have an apple or a pear a day.

22 THE CLINICAL ADVISOR • NOVEMBER 2011 • www.ClinicalAdvisor.com

modifications to lower higherthan-normal measurements. One simple lifestyle step that may protect against stroke is to have an apple or a pear a day. As Linda M. Oude Griep, MSc, and colleagues described in Stroke, they analyzed data from 20,069 men and women, aged 20 to 65 years, who were free of cardiovascular disease at baseline. During 10 years of follow-up, each 25-g/day increase in intake of white-fleshed fruits and vegetables (mainly apples and pears, but also bananas, cauliflower, chicory, and cucumbers) was associated with a 9% lower risk of stroke.

TOP PHOTO: © ISM / PHOTOTAKE ; BOTTOM PHOTO: © ISTOCK PHOTO.COM / DOMINIQUE LANDAU

Adenoidectomy does not stop URTIs

Psoriasis and CV death RECENT research demonstrates that people who have had a heart attack are more likely to die from cardiovascular disease, suffer recurrent MI or stroke, or die from all causes if they have psoriasis than if they don’t. A total of 462 persons with psoriasis (mean age: 69.5 years) and 48,935 controls (mean age: 70.6 years) with first-time MI were followed for an average of 19.5 months and 22 months, respectively. During that time: • Incidence rates for all-cause mortality per 1,000 patient-years were 138.3 for patients with psoriasis and 119.4 for those without, representing a 16% greater risk of death for the psoriasis group. • Incidence rates per 1,000 patient-years for deaths for a composite of cardiovascular death, recurrent MI, or stroke were 24% higher for the psoriasis group (185.6 vs. 149.7).

More aggressive secondary prevention of CVD is needed.

“This fi rst study of the impact of psoriasis on prognosis after first-time MI indicated a significantly poor prognosis in patients with psoriasis,” aff irmed the investigators, who called for further studies of this association ( J Intern Med. 2011;270:237-244). “Furthermore, the poor prognosis faced by psoriasis patients who have had a heart attack suggests the need for a more aggressive approach to secondary prevention of cardiovascular disease in this group of patients.”

Opioids may lead to pneumonia in the elderly Taking opioids appears to heighten an older person’s risk of developing pneumonia, indicates a recent study. Sascha Dublin, MD, PhD, and colleagues conducted a case-control study involving 3,061 adults aged 65 to 94 years. A total of 144 (13.9%) of the 1,039 people with pneumonia and 161 (8%) of the 2,022 matched controls were users of prescription opioids. As the investigators noted in an onlinefirst report for Journal of the American Geriatrics Society, persons taking long-acting opioids such as sustained-release morphine

were more than three times more likely to contract pneumonia than were those not taking these painkillers. In addition, people were more than three times as likely as nonusers to get pneumonia during their first 14 days of opioid use. Pneumonia was nearly 1.9 times more likely to occur in those using immunosuppressive opioids compared with those not taking opioids. Benzodiazepines, like opioids, are sedatives and can slow respiratory rate and increase the risk of aspiration, but these agents were not found to increase the user’s pneumonia risk.

Hepatitis C regimens can be shorter PATIENTS WITH chronic hepatitis C virus (HCV) infection undergoing treatment for the first time may be able to cut the duration of therapy in half. Persons with HCV genotype 1 often need 48 weeks of treatment with peginterferon–ribavirin. A research team led by Fred Poordad, MD, compared this treatment with a 24-week regimen of peginterferon–ribavirin, with the antiviral agent telaprevir coadministered for the first 12 weeks. Telaprevir received FDA approval for use against HCV in May 2011. Vertex Pharmaceuticals, maker of the telaprevir tablet Incivek, funded the study, which was published online by The New England Journal of Medicine. The 540 participants had received no previous treatment for their HCV infection. They took 750 mg of telaprevir three times a day, for 12 weeks, in addition to receiving peginterferon–ribavirin therapy. A total of 352 participants (65%) had an extended rapid virologic response—undetectable levels of HCV RNA at weeks 4 and 12. The overall rate of sustained virologic response was 72%. The researchers randomly assigned 322 of the rapid-response patients to receive either 24 weeks or 48 weeks of therapy. At the end of the study, 149 (92%) in the 24-week group and 140 (88%) in the 48-week group had a sustained virologic response.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER 2011 23

Newsline Naproxen the most heart-friendly NSAID? A REVIEW of widely used nonsteroidal anti-inflammatory drugs (NSAIDs) suggests naproxen and low-dose ibuprofen are least likely to raise cardiovascular risk, whereas diclofenac in doses available without a prescription heightens risk. Researchers reviewed 30 casecontrol studies involving 184,946 cardiovascular events and 21 cohort studies that described outcomes in more than 2.7 million exposed individuals. Of the extensively studied drugs, the highest overall risks were seen with rofecoxib, with a relative risk (RR) of 1.45, and diclofenac, with an RR of 1.40. Ibuprofen (1.18) and naproxen (1.09) had the lowest risks, with both appearing to be free of risk at lower doses. Ibuprofen risk was seen only with higher

doses, and naproxen was riskneutral at all doses. (The majority of ibuprofen studies defi ned high doses as >1,200 mg/day; above that point, the drug doubled the risk of cardiovascular events.) “The data here suggest that naproxen is superior to ibuprofen in terms of cardiovascular safety,” wrote the investigators (PLoS Med. 2011;8: e1001098; available at www.ncbi.nlm.nih.gov/pmc/ articles/PMC3181230/, accessed October 15, 2011). “This is the fi rst evidence to show a significant difference between these two drugs.” Diclofenac was associated with a statistically significant 22% increase in risk at low doses. In pair-wise analyses, celecoxib was indistinguishable from naproxen, but overall, celecoxib was

Naproxen reduces the level of prostaglandins.

associated with statistically significant risk increases. While calling naproxen the safest NSAID choice for patients at high risk of cardiovascular events, the authors acknowledged that its advantage over ibuprofen and celecoxib is small and must be balanced with GI risks.

SEEING A primary-care provider (PCP) every two weeks is the best way for patients with diabetes to achieve target levels of hemoglobin (Hb) A1c, BP, and LDL. This optimum schedule emerged from the results of a retrospective cohort study of 26,496 primarycare patients with diabetes and elevated measurements in the above-named areas (Arch Intern Med. 2011;171:1542-1550). In a comparison of patients who had encounters with their providers every one to two weeks vs. every three to six months: (1)

median time to meeting a target HbA1c level of <7.0% was 4.4 months vs. 24.9 months for persons not using insulin, and 10.1 months vs. 52.8 months for insulin users; (2) median time to achieving a BP measurement of <130/85 mm Hg was 1.3 vs. 13.9 months; and (3) median time to LDL levels of <100 mg/dL was 5.1 vs. 32.8 months. This information comes at a time when 42% of 627 U.S. PCPs believe their patients are receiving too much medical care, according to another report in—ironically—the same issue

24 THE CLINICAL ADVISOR • NOVEMBER 2011 • www.ClinicalAdvisor.com

of Archives of Internal Medicine (pp. 1582-1585). Only 6% of the respondents felt their patients were receiving too little care. The most important factors leading them to practice more aggressively were malpractice concerns, clinical performance measures, and having inadequate time to spend with patients. Financial incentives also came into play, with 62% of the clinicians expressing their belief that diagnostic testing would be reduced if it did not generate revenue for medical subspecialists. ■

TOP PHOTO: © CMSP; BOTTOM PHTO: © ISTOCKPHOTO.COM / RICH LEGG

Biweekly visits help control diabetes

DrugUpdate New drug information from the publishers of MPR

Once-daily therapy for postherpetic neuralgia Product: Gralise Company: Depomed Active ingredient:

Gabapentin 300 mg, 600 mg; tabs. Indication: Postherpetic neuralgia (PHN) Pharmacology: The mechanism by which gabapentin exerts its analgesic action is unknown but in animal models of analgesia, gabapentin prevents allodynia (pain-related behavior in response to normally innocuous stimulus) and hyperalgesia (exaggerated response to painful stimuli). Gabapentin is structurally related to the neurotransmitter gammaaminobutyric acid (GABA) but has no effect on GABA binding, uptake, or degradation. In vitro studies have shown that gabapentin binds with high affinity to the α2δ subunit of voltageactivated calcium channels; however, the relationship of this binding to the effects of gabapentin remains to be elucidated. It is hypothesized that gabapentin antagonizes thrombospondin binding to

α2δ-1 as a receptor involved in excitatory synapse formation and suggested that gabapentin may function therapeutically by blocking new synapse formation. Clinical trials: The efficacy of Gralise in the management of PHN was demonstrated in a doubleblind, placebo-controlled, multicenter study. This study enrolled patients with PHN persisting for at least six months following healing of herpes zoster rash and a minimum baseline pain-intensity score of at least 4 on an 11-point numerical pain rating scale

Gralise is formulated to manage pain following herpes zoster infection.

ranging from 0 (no pain) to 10 (worst possible pain). This 11-week study compared Gralise 1,800 mg once daily with placebo. A total of 221 and 231 patients were treated with Gralise or placebo, respectively. The study treatment including titration for all patients comprised a 10-week treatment period followed by one week of dose tapering. Double-blind treatment began with titration starting at 300 mg/day and titrated up to a total daily dose of 1,800 mg over two weeks, followed by eight weeks fixed-dosing at 1,800 mg once daily, and then one week of dose tapering. During the stable-dosing period, patients took three active or placebo tablets each night with the evening meal. During baseline and treatment, patients recorded their pain in a daily diary using an 11-point numeric pain rating scale. The mean baseline pain score was 6.6 and 6.5 for Gralise and placebotreated patients, respectively. At study endpoint, treatment with Gralise statistically significantly improved the mean pain score from baseline. Adults: Swallow whole; do not crush, split or chew tabs.

Tissue-bulking agent Active ingredient: Dextranomer microspheres 50 mg/mL, sodium hyaluronate 15 mg/mL; gel for submucosal injection. Indication: Treatment of fecal incontinence in patients who have failed conservative therapy (e.g., diet, fiber therapy, antimotility drugs). Pharmacology: Solesta is a biocompatible tissue-bulking agent, consisting of dextranomer microspheres and stabilized sodium hyaluronate. While the exact mechanism of action has not been identified, it is hypothesized that Solesta may narrow the anal canal and allow for better sphincter control. Clinical trials: Clinical data supporting the safety and effectiveness of Solesta are available from three clinical studies. The main body of clinical evidence came from a multicenter, prospective, randomized, placebo-controlled

Continued pg. 32

Injectable gel for fecal incontinence Product: Solesta Company: Oceana

Therapeutics Pharmacologic class:

For more products, visit www.eMPR.com

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER 2011 31

DrugUpdate Gralise from pg. 31

Children: <18 years: not

Take once daily with the evening meal. ≥18 years: initially 300 mg on Day 1, 600 mg on Day 2, 900 mg on Days 3–6, 1,200 mg on Days 7–10, 1,500 mg on Days 11–14, titrate up to 1,800 mg on Day 15. Renal impairment: creatinine clearance (CrCl) 30–60 mL/min: 600–1,800 mg. CrCl <30 mL/min or on hemodialysis: not recommended.

recommended. Warnings/Precautions: Not interchangeable with other gabapentin products. Epilepsy. Increased risk of suicidal thoughts/ behavior. Monitor for worsening of depression, suicidal thoughts/behavior, and unusual changes in mood/behavior. Renal impairment. Avoid abrupt cessation; if discontinuing,

withdraw gradually over the course of one week or longer. Elderly. Pregnancy (Cat. C). Nursing mothers: not recommended. Interactions: May affect or be affected by hydrocodone. Potentiated by morphine. Separate dosing of aluminum- or magnesium-containing antacids by at least two hours. May cause false-positive results with urine protein tests.

Solesta from pg. 31

Adults: See literature. Bowel preparation of rectum using enema required prior to injection. Prophylactic antibiotics are recommended. Inject slowly in deep submucosal layer in the proximal part of the high-pressure zone of the anal canal about 5 mm above the dentate line. Four 1-mL injections are to be given in the following order: posterior, left lateral, anterior, right lateral. Keep needle in place for 15 to 30 seconds to minimize leakage. A new needle should be used for each syringe and injection site. Post-treatment: Avoid hot baths and physical activity during first 24 hours, antidiarrheal drugs, sexual intercourse, strenuous physical activity for one week, anal manipulation for one month. Retreatment: If needed, may repeat with maximum 4 mL no sooner than four weeks

after first injection. Point of injection should be made in between initial injections, shifted one-eighth of a turn. Children: <18 years: not recommended. Contraindications: Active inflammatory bowel disease. Immunodeficiency disorders or ongoing immunosuppressive therapy. Previous radiation treatment to the pelvic area. Significant mucosal or full-thickness rectal prolapse. Active anorectal conditions (e.g., abscess, fissures, sepsis, bleeding, proctitis, other infections). Anorectal atresia, tumors, stenosis or malformation. Rectocele. Rectal varices. Presence of existing implant in anorectal region. Warnings/Precautions: Used by clinicians experienced in anorectal procedures who have successfully completed training and a certification program in Solesta

study of the product’s effectiveness and safety. The study included 206 patients (136 Solesta, 70 placebo) and consisted of a six-month, double-blinded phase followed by an open-label phase in which patients originally randomized to placebo treatment were offered Solesta. The primary efficacy objective of the study required: (1) demonstrating a statistically significant Solesta effect after six months of treatment; (2) meeting a predefined threshold for clinical significance; and (3) showing durability of the Solesta benefit up to 12 months after treatment. All three of these endpoints were met. Additionally, patients have been followed for more than two years, and the corresponding data showed no decline in effectiveness.

For more products, visit www.eMPR.com

32 THE CLINICAL ADVISOR • NOVEMBER 2011 • www.ClinicalAdvisor.com

Adverse reactions:

Dizziness, somnolence, headache, lethargy, peripheral edema, diarrhea, dry mouth, pain in extremity. How supplied: Tabs 300 mg—30; 600 mg—90; 30-Day starter pack—78 (9 ⫻ 300 mg + 69 ⫻ 600 mg) For more information, call 866.458.6389 or visit www.Depomedinc.com.

injection procedure. Do not inject intravascularly; may cause vascular occlusion. Avoid injecting in midline of anterior wall of rectum in men with enlarged prostate. Complete external sphincter disruption. Significant chronic anorectal pain. Previous anorectal procedures. Bleeding diathesis. Pregnancy. Nursing mothers. Interactions: Concomitant anticoagulants, antiplatelets: increased risk of bleeding at injection site. Adverse reactions: Anal hemorrhage, anorectal discomfort, chills, diarrhea, injection site hemorrhage, pain. How supplied: Syringe (1 mL)—4 (with needles) For more information, call 732.318.3800 or visit www.Solestainfo.com. ■

CME CE FEATURE

■ LEARNING OBJECTIVES : • Describe what happens when glucagon is released in the liver. • Identify the most common stressor in patients with hyperglycemic crisis. • Understand the role of fluid resuscitation in managing diabetic ketoacidosis. • Explain the basic dosing strategies involved in basal/bolus insulin therapy. ■ COMPLETE THE POSTTEST: Page 113 ■ ADDITIONAL CME/CE: Pages 93, 109

JOHN J. BENECK, MSPA, PA-C

Management of diabetic ketoacidosis in adults When developing a plan of care for individuals in diabetic ketoacidosis—an acute complication of diabetes mellitus—search for the inciting stressor.

Insulin (blue dots) controls blood sugar by promoting glucose uptake in the liver and muscles.

iabetic Ketoacidosis (DKA) is a serious acute complication of diabetes mellitus, manifested by a life-threatening hyperglycemic crisis. DKA is defined by the presence of the triad of hyperglycemia, anion gap metabolic acidosis, and ketonemia.1 While the condition is a medical emergency, it can be effectively treated. Nevertheless, the burden of hospitalization is high, and the total cost of care is estimated to be in the billions. The keys to successful treatment are timely diagnosis, appropriate initial intervention, recognition of concomitant illness, appropriate electrolyte management, and attentive transition to oral feeding and subcutaneous insulin upon normalization of pH. The most recent CDC reporting data show 123,000 discharges for DKA in 2007. Of those, 89% were older than age 15 years, with males outnumbering females by a few percentage points.2 These hospitalizations came at a steep price, with direct and indirect costs of $2.4 billion. This amount accounted for one quarter of the total direct costs

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER 2011 33

CME CE

DIABETIC KETOACIDOSIS

The release of glucagon is inhibited by the presence of insulin and glucose and stimulated by the presence of catecholamines and glucocorticoids. of caring for these patients. For patients requiring more than one DKA admission, it represented a full half of their total direct costs.3 Normal glucose management

To fully understand the various facets of effective DKA treatment, it is necessary to be familiar with the roles of select hormones in managing glucose loads. A nondiabetic adult holds only about 5 g of glucose in circulation at any given time. This is roughly the same amount of glucose contained in a bite-sized candy bar and about one-eighth of the amount found in a 12-oz can of cola. To prevent a doubling or tripling of the serum glucose concentration with the ingestion of common sugar loads, hormonal regulation of glucose concentration must be brisk and effective. On the other hand, to prevent hypoglycemia during periods of fasting, counter-regulation must be equally robust. The liver is the primary glucose-regulating organ. It responds to insulin and glucagon, which are the main hormones responsible for glucose homeostasis. Both are produced and released by the pancreas. Their actions generally oppose each other in a regulatory/counterregulatory balance. Insulin. When the glucose load is absorbed into the blood, insulin is released from the beta cells of the pancreatic islets. The insulin serves a number of functions important to glucose regulation and utilization (Table 1). Overall, it stimulates glucose uptake and utilization as fuel. Insulin also allows for storage of excess glucose for later use. In this way, the presence of insulin provides a mechanism for removing excess glucose from circulation and preventing hyperglycemia, and is thus considered a regulatory hormone. Glucagon. Glucagon is active primarily in the liver (Table 2), and its effect is essentially the opposite of that of insulin. Glucagon is released from the alpha cells of the pancreatic islets. Its release is inhibited by the presence of insulin and glucose and stimulated by the presence of catecholamines and glucocorticoids. For this reason, glucagon levels tend to increase during times of low blood-glucose concentrations and stress. It acts in a number of ways to increase serum glucose concentration and inhibit its storage. In this way, the presence of glucagon prevents hypoglycemia, and is thus considered a counter-regulatory hormone. Table 3 lists the other major counter-regulatory hormones and their primary actions.

Predisposing abnormalities

To develop DKA, the patient must experience a relative insulin deficiency4 (very little circulating insulin) in the setting of increased counter-regulatory hormone concentrations. This relative lack of insulin sets the stage for a series of events that result in elevation of blood glucose, breakdown of adipose tissue triglycerides, uncontrolled production of ketoacids, and eventual overwhelming of the kidneys’ capacity to compensate through increased excretion of glucose and ketoacids. This cascading series of events may occur as a result of marked hypoinsulinemia, such as TABLE1. Insulin action in various tissues In the pancreas • Directly inhibits glucagon release In the liver • Stimulates glycogen synthesis and inhibits glycogenolysis • Stimulates glycolysis and inhibits gluconeogenesis In the muscle • Stimulates glucose uptake and glycogen synthesis In the adipose tissue • Stimulates glucose uptake • Inhibits triglyceride breakdown

TABLE 2. Glucagon action in the liver Stimulates gluconeogenesis and glucose release Inhibits glycolysis Inhibits fatty acid synthesis Stimulates amino acid uptake Stimulates ketoacid production

TABLE 3. Other counter-reglulatory hormones Catecholamines (released by the adrenal glands) • Inhibit insulin release (alpha adrenergic ) • Stimulate glucagon release • Stimulate liver gluconeogenesis Cortisol (released by the adrenal glands) • Inhibits insulin release • Stimulates liver gluconeogenesis • Inhibits glucose uptake in muscle and adipose tissue Growth hormone (released by the pituitary gland) • Inhibits insulin action • Stimulates lipolysis

34 THE CLINICAL ADVISOR • NOVEMBER 2011 • www.ClinicalAdvisor.com

The most frequent stressor is infection. Other possible precipitating stresses include MI, stroke, pancreatitis, trauma, and alcohol or drug abuse. occurs in either new-onset type 1 diabetes or in a known type 1 diabetic patient who omits his or her insulin doses. Otherwise, DKA is typically set in motion by a stressor. Inadequate insulin results in decreased glucose uptake in the liver, adipose tissue, and skeletal muscle, as well as increased glucose release from the liver. As a result, serum glucose levels rise while the tissues simultaneously are starved for fuel. Compounding this situation is a decrease in renal perfusion, which accompanies intravascular volume depletion, leading to decreased capacity for renal glucose clearance. Stress increases the levels of counter-regulatory hormones, leading to decreased circulating insulin and increased insulin resistance.

electrolytes, including potassium, sodium, phosphate, and magnesium. Dehydration is inevitable, and when it occurs to an extent great enough to decrease GFR, the kidneys’ ability to compensate is lost. The acidosis worsens, as does the hyperglycemia. The patient is left with severe metabolic derangement, electrolyte abnormalities, and, in some cases, acute renal failure. Respiratory compensation. The presence of metabolic acidosis causes respiratory compensation in the form of increased minute ventilation to “blow off ” CO2 and raise pH. In addition, acetone enters the alveoli and is exhaled, resulting in the characteristic “fruity breath.” Patient presentation

Hyperglycemia to DKA

The ability to exist in this state of “accelerated starvation” is determined by the individual’s ability to self-hydrate and maintain adequate glomerular fi ltration rate (GFR) with renal clearance of glucose and ketoacids. This delicate balance is overwhelmed in the presence of significant stress. The most frequent stressor is infection, which is found in 40% to 50% of patients with hyperglycemic crisis. Other possible precipitating stressors include MI, stroke, pancreatitis, trauma, and alcohol or drug abuse.4 Stress increases the counter-regulatory hormone concentrations, compounding the dysregulation. Breakdown of adipose tissue stores. Lack of insulin in the adipose tissue in the presence of catecholamines leads to enhanced lypolysis and free fatty acid delivery to the liver where, in the presence of glucagon, fatty acids are used in the production of ketoacids, an alternative fuel. With high glucagon levels and high fatty acid availability, ketoacids are rapidly produced. Gluconeogenesis and glycogenolysis are promoted while glucose uptake and utilization are further impaired. Serum glucose levels rise further. Lipolysis continues. Ketoacids are generated out of control. Alkaline buffers—primarily bicarbonate—are consumed. Ketoacid anion levels rise, and an anion gap metabolic acidosis results. Renal compensation. The kidneys decrease glucose reabsorption, and excess glucose is released in the urine. Ketoacids and their associated anions are excreted in the urine as well. This leads to osmotic diuresis and the polydipsia/ polyuria phenomenon. Through osmotic diuresis, the kidneys continue to excrete glucose, hydrogen ions, and ketoacid anions. The fluid loss results in the depletion of various

Signs and symptoms of DKA are dependent on the individual circumstances that drive the patient to seek care. The person may present with symptoms suggestive of infection, stroke, acute coronary syndrome, or other stressors. Such early symptoms of DKA as weight loss and polyuria with polydipsia may go unrecognized by the patient.1 The various symptoms of electrolyte disturbance may precipitate a visit to the primary-care office or the emergency department (ED). As dehydration occurs, decreased skin turgor, tachycardia, hypotension, and weakness develop.3 Eventually, the acidosis itself becomes symptomatic and may hide the symptoms of the stressor. Signs and symptoms include tachypnea (Kussmaul respirations), nausea and vomiting, abdominal pain, and fruity breath. Late features include focal neurologic signs and, finally, lethargy and coma.1 Late in its course, DKA can be readily detected using commonly obtained objective tools. However, it remains imperative that the provider caring for these patients recognize the following: • In patients presenting early, appropriate treatment of the presenting stressor and recognition of the risk of fulminant DKA can minimize the impact on the patient. • In patients presenting later in the course when DKA is more apparent, it is essential to recognize that the patient suffers not only from DKA, but also from severe dehydration, marked electrolyte disturbances, and the stressor, which, if undetected, could be devastating to the patient. In fact, in older patients with serious concomitant illness, the mortality associated with DKA is most frequently caused by the stressor.3 Continues on page 36

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CME CE

DIABETIC KETOACIDOSIS

Routine labs include a complete blood count, serum electrolytes, serum glucose level, blood urea nitrogen, creatinine, and anion gap. Initial evaluation

In consideration of the wide variety of potential stressors and the inability to predict where on the continuum of DKA a patient will present, the initial evaluation must begin with an assessment of mental status and airway, breathing, and circulation. Subsequent to this and the provision of emergent interventions as dictated by that assessment, address the patient’s volume status. In addition, the search for the precipitating event should begin early in the process.5 Routine labs include a complete blood count, serum electrolytes, serum glucose level, blood urea nitrogen (BUN), creatinine, and anion gap. In an individual with DKA, these labs will reveal: • An elevated anion gap due to the presence of excess ketoacid anions • Low bicarbonate (HCO3-) due to the decreased level of unbound alkaline buffer • Elevated serum glucose If DKA was not previously suspected, these three findings provide a clue that it may be present. Additional testing targeted toward assessing for the presence and severity of DKA should include:1 • Urinalysis with glucose and ketones • Serum ketones • Arterial blood gases • Serum osmolality • ECG Testing related to the stressor

Additional testing aimed at identifying the stressor may be done in a situation-dependent fashion. Perform a chest x-ray to assess for pulmonary abnormalities. Draw urine, sputum, or blood cultures if infection is suspected. Other situational-dependent studies include imaging of the brain, abdomen, or other area as symptoms dictate.5 Finally, fluid or excretion testing should be performed as warranted (e.g., stool, emesis, effusions).

number of cations and anions in the serum are essentially equal. However, a typical basic metabolic panel does not measure all of the circulating ions (Table 4). The term gap refers to the difference between the primary cations and anions that are measured in a typical basic metabolic panel. Sodium is the primary cation. Chloride and bicarbonate are the primary anions. The anion gap is the numeric result of subtracting the sums of the chloride and bicarbonate concentrations from that of the sodium: Na+ - (Cl- + HCO3-) This gap becomes important in assessing etiology. In a case of metabolic acidosis attributable to ingestion or endogenous overproduction of an acid, the acid ionizes to form a hydrogen cation and an anion (depending on the type of acid). In a case of aspirin overdose, this could be salicylic acid anions; sepsis produces lactic acid anions; and in DKA, ketoacid anions are produced. Multiple sources of measured and unmeasured anions may be present spontaneously. In the end, the total number of anions cannot significantly exceed the number of cations, so the more unmeasured anions that circulate, the less measured anions will be found. The anion gap essentially refers to an estimate of unmeasured anions in the serum. In DKA, ketoacids are produced that ionize into hydrogen cations and ketoacid anions. These anions are not measured in a basic metabolic panel, so when their levels rise, so does the anion gap. DKA should be part of the differential diagnosis in any patient who presents with constitutional symptoms or positive ketones and a blood glucose concentration >250mg/ dL. It should also be considered in any patient with diabetes who presents with any serious illness or stressor.6 The American Diabetes Association (ADA) defines DKA as a combination of hyperglycemia with a blood glucose ≥250 mg/dL, a metabolic acidosis with bicarbonate ≤18 mEq/L, an anion gap >10, and arterial pH ≤7.30 in the setting of moderate ketonemia or ketonuria.3 TABLE 4. Overview of a typical basic metabolic panel Sodium (Na+) Potassium (K+)

Differential diagnosis

A myriad of conditions can cause metabolic acidosis. For diagnostic purposes, this broad diagnosis is divided into two types: anion gap and non-anion gap metabolic acidosis. The term gap simply refers to the difference between the number of positive ions (cations) and negative ions (anions). The total

Chloride (Cl-) Bicarbonate (HCO3-) Blood urea nitrogen Creatinine Glucose

36 THE CLINICAL ADVISOR • NOVEMBER 2011 • www.ClinicalAdvisor.com

Patients with diabetic ketoacidosis will require admission to intensive care. This allows access to cardiac monitoring and close observation. Hyperosmolar hyperglycemic state (HHS) is another form of hyperglycemic crisis. This condition is more typically found in individuals with severely uncontrolled type 2 diabetes. These patients are insulin-resistant and are felt to possess enough circulating insulin to inhibit lipolysis and excess ketogenesis but not enough to stimulate glucose uptake and utilization. They tend to have a more severe degree of volume depletion and impaired renal function, which decreases the ability to excrete excess glucose. Such individuals present with severe hyperglycemia and its associated hyperosmolality, but they do not have as large an elevation in anion gap or acidosis as seen in DKA. Management of DKA

Disposition. Generally, patients with DKA will require admission to the hospital in an intensive-care setting. This allows access to cardiac monitoring and close observation while providing aggressive fluid resuscitation and electrolyte replacement. It also allows for the titration of insulin by infusion with frequent blood-glucose monitoring. The patient’s diet should be designated as nothing by mouth (NPO). Further carbohydrate and/or fat ingestion have the potential for undermining efforts to eliminate ketoacids and control blood glucose levels, and there is an increased risk of vomiting and aspiration in DKA. Fluid management. Fluid resuscitation is the first step in DKA therapy.3 The total fluid deficit is estimated to be 3.0 to 6.0 L in DKA.5 Fluid is replaced as a crystalloid bolus to improve GFR followed by an infusion to maintain it. • As a rule, a bolus of 15-20 mL/kg (1.0-1.5 L) of normal saline3 is given in the first hour. This may prove overly aggressive for patients with cardiac compromise and should be adjusted accordingly. • The rate and fluid type of initial infusion following the bolus is based on the patient’s hemodynamics, hydration, electrolyte levels, and urinary output. For hemodynamically stable patients with adequate urine output, start with 0.45% NaCl or 0.9% NaCl at 250-500 mL/hr. For patients with normal or high corrected serum sodium, use 0.45% NaCl. For patients with low corrected serum sodium, 0.9% NaCl is advised.3 • Hemodynamically stable patients who require 40 mEq/L of potassium supplementation (see Potassium in the next column) should be given 0.45% NaCl, as the added potassium increases the osmolality of the solution.5

• Patients with cardiac compromise or poor urine output may become fluid-overloaded or could potentially experience too rapid a drop in serum osmolality and should have a slower infusion. Regular insulin. Insulin may be given either in an IV bolus followed by infusion or by infusion alone. The ADA recommends a bolus of 0.1 units/kg followed by a continuous infusion of 0.1 units/kg/hr. If no bolus is given, the recommended initial IV infusion rate is 0.14 units/kg/hr.3 Aim to decrease the serum glucose by at least 50-70 mg/dL in the first hour, followed by a steady decline until the level is ≤200 mg/dL.5 Once the glucose level has dropped below 200 mg, the goal is to maintain it between 150-200 mg/dL until the acidosis resolves. Potassium. Potassium is the primary intracellular cation. About 98% of potassium is stored within the cells of the body. Only 2% is present in the extracellular fluid (ECF). During the evolution of DKA, potassium is lost in a number of ways. Osmotic diuresis causes potassium loss through renal excretion. Both increased serum osmolality and the lack of circulating insulin cause potassium to move out of the cells and into the ECF, compounding this loss. In addition, diuresis-induced hypovolemia increases aldosterone levels that promote sodium retention at the expense of potassium.5 Patients experiencing vomiting or diarrhea may also experience GI losses. In total, it is estimated that patients with DKA suffer a 3-5 mEq/kg potassium deficit.7 Despite these losses, the increased delivery of potassium to the ECF from the intracellular space usually causes the serum concentration of potassium to be normal and, in some cases, high. This regular concentration of the ECF potassium creates the illusion of normalcy, despite the fact that total body potassium stores are almost always low. This concept becomes important in understanding the risk of potentially devastating hypokalemia in treating DKA. Insulin administration causes a rapid shift of potassium out of the ECF and into the cells. In addition, fluid resuscitation can be expected to cause a dilutional decrease in serum potassium concentration. For this reason, the ADA recommendations encompass a three-tiered approach to potassium regulation during fluid and insulin therapy for DKA: • Patients with a serum potassium concentration >5.2 mEq/L should receive insulin and IV fluid without potassium, but the level should be checked every two hours.3 Continues on page 38

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CME CE

DIABETIC KETOACIDOSIS

To allow for precise titration of insulin therapy, perform glucose fingerstick checks every hour until the patient is stable. • Patients with a serum potassium concentration between 3.3 and 5.2 mEq/L should have 20-30 mEq of potassium added to each liter of IV fluid with a goal to maintain a level of 4.0-5.0 mEq/L.3 The addition of potassium to the infusion should be delayed until urine output has been established. • Patients with a serum potassium concentration <3.3 mEq/L should receive 20.0-30.0 mEq/hr of potassium until the concentration exceeds 3.3 mEq/L. These patients should not receive IV insulin until the serum potassium concentration is >3.3.3 Other electrolytes. Sodium: Sodium concentration may vary. Both sodium and water are lost during osmotic diuresis; however, water tends to be lost in a proportionally greater amount. As the patient becomes dehydrated, this increases the serum sodium concentration.1 On the other hand, increased serum osmolality draws water out of the cells, which dilutes the sodium and lowers the concentration.5 The sodium and water are replaced with fluid resuscitation (see Fluid management on previous page). Phosphate: Phosphate is the most abundant intracellular anion. Like potassium, it is present in small concentrations in the ECF, and its concentration decreases with insulin therapy. However, phosphate concentration is most important inside the cell, where it is involved in energy management and cell membrane maintenance. In DKA, phosphate replacement has not been shown to improve outcomes.3 Because IV phosphate replacement may induce hypocalcemia and hypomagnesemia,5 therapy should be limited to patients with serum concentrations <1.0 mg/dL or such complications associated with severe muscle weakness or cell membrane instability as cardiac compromise, respiratory depression, and hemolytic anemia. When given, 20.0-30.0 mEq/L is added to IV fluids, usually in the form of potassium phosphate, to replace some of the potassium chloride being administered.3 Magnesium: Stored primarily in and on the bone and not hormonally regulated, magnesium may also be depleted due to renal excretion during osmotic diuresis. Levels should be checked and losses replaced. Bicarbonate: It is tempting, in a case of metabolic acidosis with low bicarbonate, to try to increase both the pH and the bicarbonate level by administering sodium bicarbonate, but no evidence exists to suggest that this improves outcomes. Furthermore, sodium bicarbonate administration may cause physiologic deterioration,3 including hypokalemia attributable

to intracellular potassium shift, worsened cerebral acidosis (theoretically caused by decreased respiratory compensation), decreased tissue oxygen uptake, and cerebral edema. The ADA does recommend bicarbonate replacement therapy for patients with a pH <6.9, as this level results in a multitude of deleterious vascular defects. Bicarbonate should be given as 100 mmol (2 amps) in 400 mL H2O with 20.0 mEq potassium chloride over two hours. Repeat this therapy until the pH is >7.0.3 Osmolality. While it varies, osmolality in DKA may be high. Rapid correction of hyperosmolality risks cerebral edema, although in DKA this is primarily a complication seen in children and rarely in patients older than age 20 years.3 Nevertheless, IV fluid and glucose correction goals are geared toward minimizing any risk to the patient. These goals include cautious fluid resuscitation, avoidance of overcorrection of hyperglycemia, and the addition of dextrose to the IV fluid when serum glucose concentration decreases to <200 mg/dL.5 In any case, the osmolality should be corrected at a rate not to exceed 3 mOsm/kg/hr.7 Monitoring. Appropriate therapy for DKA brings about remarkable results leading to resolution. But these interventions may cause a variety of dramatic and potentially harmful effects as well. It is important to monitor patients closely to assure steady progress and avoid adverse events. • To allow for precise titration of insulin therapy, perform glucose fingerstick checks every hour until stable.3 • To minimize the risk of excessive hemodilution, monitor and document urine output. • Monitor electrolytes, BUN, and creatinine every two to four hours.3 • While pH is typically assessed on presentation as part of an arterial blood gas, subsequent checks may be performed every two to four hours3 on venous blood already drawn as part of electrolyte monitoring. The approximate value of the arterial pH can be obtained by adding 0.03 to the value of the venous pH. • If found to be high upon presentation, calculate serum osmolality every two to four hours. • Three types of ketones are produced in the liver in DKA. The first, acetoacetate, is later converted to acetone (which is acid/base neutral) and beta-hydroxybutyrate. The nitroprusside test is used to detect ketones in the serum or urine. However, this method detects only acetoacetate and acetone. It does not detect beta-hydroxybutyrate, the most abundant

38 THE CLINICAL ADVISOR • NOVEMBER 2011 • www.ClinicalAdvisor.com

The addition of insulin stops acid production by inhibiting fatty acid liberation from the adipose tissue and ketogenesis by the liver. ketoacid produced. This leads to two potential misinterpretations: (1) in the initial evaluation of DKA, low or moderate ketone levels do not rule out the possibility of significant ketoacidosis caused by undetected beta-hydroxybutyrate;1 and (2) during insulin therapy, some beta-hydroxybutyrate is converted back to acetoacetate. This may cause the levels of acetoacetate to rise during appropriate therapy. If the nitroprusside test is used as a monitor, it may be misinterpreted as showing a worsening of ketosis.5 In a perfect world

In a patient with functioning kidneys, the administration of appropriate fluids stimulates osmotic diuresis and improvement in serum glucose levels, pH, and ketoacid anion levels. In fact, the kidneys can excrete up to 30% of the ketoacid load.1 The addition of insulin stops acid production by inhibiting fatty acid liberation from the adipose tissue and ketogenesis by the liver. It also induces glucose uptake, causing serum glucose concentration to fall. Phosphate levels can be expected to fall to below normal values, but IV replacement is not usually indicated. The expectation is that glucose levels will be controlled as a consequence of DKA therapy, but the primary goal is cessation of ketoacid overproduction and elimination of these acids from the blood. The insulin infusion should be continued until the ketoacidois is resolved. This can be expected to occur in 12 to 24 hours. Resolution

Resolution of DKA is determined by the ADA to include the following conditions:3 • Blood glucose <200 mg/dL • Two of the following — HCO3- ≥15 mEq/L — Venous pH >7.3 — Calculated anion gap ≤12 mEq/L The decreased gap in combination with the normalization of the bicarbonate level indicates the clearing of the ketoacids.

given in basal/bolus fashion calculated first as total daily dose (TDD), which is based on insulin therapy the patient received at home prior to losing control. Alternatively, TDD may be estimated at 0.5 to 0.8 units/kg/day in an individual who has not previously been treated with insulin.3 Total daily insulin requirements may be significantly elevated for a few days following the resolution of DKA due to persistently elevated counter-regulatory hormone concentrations. These elevations predispose the patient to going back into acidosis if insulin levels are inadequate or stress levels increase further. Basal/bolus insulin therapy is generally broken down into long- and short-acting insulin as 50% basal and 50% bolus spread over three meals. Half of the TDD is given once daily as long-acting basal insulin (usually glargine [Lantus] or detemir [Levemir]). The other half is given as such short-acting insulin analogues as aspart (NovoLog), divided into thirds given at mealtime. For example, consider an individual weighing 90 kg with new onset type 1 diabetes who presents with DKA and is now controlled. Based on a TDD of 0.6 units/kg/day, a subcutaneous insulin strategy for this patient would include 54 units of insulin daily given as: 27 units basal (long-acting) insulin once daily; and 27 units short-acting insulin divided into thirds at mealtimes (nine units at each meal). Not all patients tolerate their first meal. Some will vomit, and others may eat only a small portion. During the transitional period as DKA patients are started on PO nutrition, the subcutaneous insulin should be given immediately after the first meal. This prevents hypoglycemia from insulin overdose in the event the patient is unable to eat the full meal. The insulin and the dextrose infusion should continue one to two hours after beginning subcutaneous insulin. Continues on page 40

AT A GLANCE ●

To develop diabetic ketoacidosis (DKA) the patient must experience a relative insulin deficiency in the setting of increased counter-regulatory hormone concentrations.

●

Appropriate treatment of the presenting stressor can minimize the impact of DKA on the patient.

●

The first step in DKA therapy is fluid resuscitation.

●

During therapy, closely monitor patients to assure steady progress and avoid adverse events.

Feeding/transition to subcutaneous insulin

The first mealtime after the acidosis has resolved and the patient feels that he or she can tolerate food is the time to begin feeding the patient. Subcutaneous insulin should be started simultaneously. Dosing of subcutaneous insulin is

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CME CE

DIABETIC KETOACIDOSIS

Patient education is key. Noncompliance and/or inability to control diabetes dramatically increase the likelihood that of a recurrence. This assures control in an uncertain phase and prevents ketoacid production prior to the basal insulin reaching steady state.3 Potential complications

Hyper- or hypoglycemia may occur in patients presenting with severe metabolic derangement. Frequent glucose monitoring with careful titration of IV insulin dosing can help prevent this complication. Hypokalemia can occur from intracellular shift of potassium with the administration of insulin. To minimize this risk, delay insulin administration when the serum potassium concentration is <3.3 mEq/L, and add potassium to the IV fluid when the concentration is <5.2 mEq/L. Cerebral edema is a complication primarily seen in children and young adults with DKA. It is rarely seen in adults aged 20 years and older.5 While it has been speculated that cerebral edema results from too rapid correction of hyperosmolality, the literature has not supported this conjecture. Nevertheless, it is recommended that serum osmolality be corrected at a rate no greater than 3 mOsm/kg/hr in patients presenting in a hyperosmolar state.7 On the other hand, IV administration of sodium bicarbonate to correct the metabolic acidosis has been associated with development of cerebral edema. Understanding that DKA occurs in the setting of relative insulin deficiency in concert with an inciting stressor should lead to the detection and treatment of the underlying stressor. This has become a major cause of mortality associated with DKA.3

A final thought

This article is intended as an overview of the evolution and treatment of DKA in the adult population. The recommendations contained herein are derived primarily from the ADA consensus statement published in July 2009, may not be applicable to all situations, and are not to be considered a substitute for clinical judgment. More comprehensive analysis of this topic is included in the full ADA statement.3 ■ Mr. Beneck is lead physician extender, hospitalist service, Mercy Hospital, Portland, Maine. The author has no relationships to disclose relating to the content of this article. References 1. Kitabchi AE, Rose BD. Clinical features and diagnosis of diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults. In: UpToDate, Basow DS, ed. UpToDate, Waltham, Mass., 2011. 2. Centers for Disease Control and Prevention. National Hospital Discharge Survey (NHDS) Reports and Tabulations, 2007. Available at www.cdc.gov/nchs/data/nhds/nhds071stlisteddiagnoses.pdf. 3. Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic crises in adult patients with diabetes. Diabetes Care. 2009;32:1335-1343. Available at care.diabetesjournals.org/content/32/7/1335.full. 4. Kitabchi AE. Epidemiology and pathogenesis of diabetic ketoacidosis and hyperosmolar hyperglycemic state. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, Mass., 2011. 5. Kitabchi AE, Rose BD. Treatment of diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults. In: UpToDate, Basow DS, ed. UpToDate, Waltham, Mass., 2011.

Discharge considerations

6. Umpierrez GE, Murphy MB, Kitabchi AE. Diabetic ketoacidosis and

Patient education is key. Noncompliance and/or inability to control diabetes dramatically increase the likelihood that of a recurrence. This doubles the cost of care for the patient3 and once again exposes him or her to the risks associated with DKA. The patient should have a follow-up appointment with the primary-care provider within seven to 10 days of discharge to assure adequate glucose control and to modify insulin dosing as needed.6 Diabetes education should be provided before leaving the hospital. Emphasize the significance of not omitting doses of insulin—especially the importance of continuing and appropriately adjusting basal insulin when patients get sick and may or may not be eating regular meals. Some patients will require referral to a specialized diabetes center for intensive education.

hyperglycemic hyperosmolar syndrome. Diabetes Spectrum. 2002;15:28-36. Available at spectrum.diabetesjournals.org/content/15/1/28.full. 7. Laine C, Turner BJ, Williams S, Wilson JF. In the clinic: Diabetic Ketoacidosis. Annals of Internal Medicine; supplement. 1 January, 2010: ITCH1-14. All electronic documents accessed October 15, 2011.

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40 THE CLINICAL ADVISOR • NOVEMBER 2011 • www.ClinicalAdvisor.com

FEATURE: CARL SHERMAN

Evaluating heart risk in asymptomatic patients An evidence-based guideline is available to help primary-care clinicians lower the burden of coronary deaths in this adult population.

In coronary atherosclerosis (shown here), plaque narrows the diameter of the arteries.

42 THE CLINICAL ADVISOR • NOVEMBER 2011 • www.ClinicalAdvisor.com

ests designed to assess risk of cardiovascular disease have multiplied in recent years. But most asymptomatic patients need few—if any—tests beyond standard lipid profiles and BP measurement, according to a guideline from the American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA).1 “This is a strong endorsement of standard risk assessment based on traditional risk factors,” said Philip Greenland, MD, professor of preventive medicine and medicine at Northwestern University’s Feinberg School of Medicine and chair of the committee that wrote the guideline. “In our estimation, there isn’t a single [additional] test that should be used on all healthy people.” The most important measure of cardiovascular risk in patients without symptoms, the authors emphasized, is a global coronary and cardiovascular estimate such as the Framingham Risk Score, which uses age, weight, BP, lipid parameters, and smoking status to assign patients to low-, intermediate-, and high-risk categories (generally <10%, 10-20%, >20%, respectively), based on the likelihood of a cardiovascular event within the next 10 years. The ACCF/AHA guideline endorses further testing “only in patients where the primary-care practitioner might feel uncertain after this risk assessment—typically those at ‘intermediate’ risk,” explained Dr. Greenland. Those at low risk generally need nothing beyond lifestyle modification, and it is unlikely that further

HEART RISK

The guideline authors gave the hemoglobin A1c test a weak recommendation for asymptomatic individuals without diabetes. testing will change treatment of those already judged to be at high risk. Although family history should be ascertained, it only modestly adds to the predictive power of global assessments, generally for patients at intermediate risk, the guideline authors wrote. Some tests may be useful when patients are unconvinced of the need for treatment based on such risk indicators as elevated cholesterol, Dr. Greenland affirmed. “If something like an imaging test is abnormal, it’s another piece of information that we can use to motivate the patient.” The guideline does not recommend any test unequivocally. At best, an assessment is described as “reasonable” or “useful” for specific groups; it “may be considered” for certain patients when evidence of utility is weaker. Lab tests beyond cholesterol

Tests are available to measure lipid parameters—lipoprotein, apolipoprotein, particle size, and density—beyond the standard profi le. None of these tests are recommended for asymptomatic patients. C-reactive protein (CRP), an index of infl ammatory activity believed to be a key process in atherosclerosis, has been the subject of considerable interest in recent years. The ACCF/AHA guideline recommends the test, but in a qualified way. Dr. Greenland noted that only one randomized controlled trial has provided data substantiating the utility of CRP in guiding treatment. The authors suggested that among men aged 50 years or older and women aged 60 years or older; with LDL levels <130 mg/dL; who are not on lipid-lowering drugs or hormones; and who are without diabetes, chronic kidney disease, or severe inflammatory conditions, CRP testing “can be useful” in selection for statin therapy. AT A GLANCE ●

A global coronary and cardiovascular estimate is the most important measure of risk in patients without symptoms.

●

Only one randomized trial has provided data substantiating the utility of C-reactive protein in guiding treatment.

●

The use of resting ECG in asymptomatic patients with hypertension or diabetes was endorsed.

●

The measurement of coronary artery calcium helps stratify cardiovascular risk beyond standard assessments.

CRP received a weaker endorsement (“may be reasonable”) for younger individuals judged to be at intermediate risk. For high-risk individuals and younger people at low risk, CRP testing is not recommended. The American Diabetes Association has endorsed hemoglobin (Hb) A1c as a screen for diabetes. Based on several studies associating HbA1c elevations with increased risk of CVD, the guideline authors gave the test a weak recommendation for asymptomatic individuals without diabetes. A similar endorsement was given to the use of lipoproteinassociated phospholipase A2 for intermediate-risk adults. The ACCF/AHA guideline calls urinalysis for microalbuminuria in patients with hypertension or diabetes a “reasonable” test, and gives it a weaker endorsement for those at intermediate risk without these conditions. The authors did not recommend measurement of natriuretic peptides in asymptomatic patients. Cardiac and vascular tests

The ACCF/AHA guideline endorses the use of resting ECG to assess risk in asymptomatic patients, noting that abnormal findings may indicate, among other problems, left ventricular hypertrophy (LVH), isolated ischemic abnormalities, atrial fibrillation, and even silent MI. Citing a sampling of the numerous studies that provide supporting data, the authors based the strength of their recommendation on the presence of hypertension or diabetes: resting ECG is deemed “reasonable” for individuals with one of these conditions, and “may be considered” in their absence. Although a number of studies suggest that transthoracic echocardiography provides information on LVH, which increases cardiovascular risk, evidence that the test can usefully guide therapy or motivate patients is weak. Consequently, the guideline authors gave the test a qualified endorsement for patients with hypertension—it “may be considered” for risk assessment—but did not recommend it for other asymptomatic individuals. The authors did not advocate stress echocardiography in asymptomatic patients at low or intermediate risk, although it was noted that this test may be indicated for more advanced evaluation of individuals with abnormal findings on such other tests as resting ECG. Other tests that the guideline calls “reasonable” for intermediate-risk patients include ankle-brachial index and

44 THE CLINICAL ADVISOR • NOVEMBER 2011 • www.ClinicalAdvisor.com

carotid intima-media thickness measurement. Exercise ECG (typically, treadmill testing) “may be considered” for such patients, particularly sedentary individuals who contemplate starting an exercise program. Coronary artery calcium

CT measurement of coronary artery calcium (CAC) is becoming more widespread. The guideline authors noted that the test helps stratify cardiovascular risk beyond standard assessments: Pooled data from a number of studies indicate a 2.8% annual rate of cardiac death or MI among intermediaterisk patients with an elevated CAC score—these patients should, in effect, be reassigned to the high-risk category. CAC testing appears to have a positive effect on patient behavior. An observational study found a doubling of selfreported lipid medication among patients with CAC scores in the top 75th percentile, and a randomized controlled trial suggested that interactions with the health-care provider “can be useful to reinforce lifestyle and treatment recommendations that could ensue from calcium testing,” the guideline states. The ACCF/AHA guideline recommends CAC measurement for patients at intermediate risk, and added that it “may be reasonable” for those at low to intermediate risk (6%-10%) but not for those whose risk is <6%. Noting that coronary atherosclerosis is widespread in diabetes, and that elevated CAC predicts the likelihood of cardiac events beyond conventional risk factors in this group, the authors recommended CAC measurement for patients who have diabetes but no symptoms of cardiovascular disease. ■

“I’ve hacked into our bank account.”

Mr. Sherman is a freelance medical writer in New York City. References 1. Greenland P, Alpert JS, Beller GA, et al. American Heart Association. 2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2010;122:2748-2764. Available at circ.ahajournals .org/content/122/25/2748.full. All electronic documents accessed October 15, 2011.

WHAT DO YOU THINK? Add your comments to this article —or any article — by going to www.ClinicalAdvisor.com.You will also see what your colleagues are saying.

“I’m in a band.” www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER 2011 45

FEATURE: ANN MARIE HART, PHD, FNP-BC

Antibiotic stewardship to preserve benefits Considered “magic bullets” when they first arrived on the scene, antibiotics must be used appropriately to protect their effectiveness.

Camplybacter jejuni (shown here) is highly resistant to broadspectrum antibiotics.

46 THE CLINICAL ADVISOR • NOVEMBER 2011 • www.ClinicalAdvisor.com

s. O, aged 35 years, presents to the urgent care clinic on a Sunday evening with urinary frequency, urgency, and burning that began suddenly that morning. She denies fever, chills, nausea, vomiting, genital lesions, vaginal discharge, or pain in her abdomen or back. During your interview with her, the patient reports that she is in a monogamous relationship with her husband of 10 years and they have two children, aged 6 and 4 years, both of whom were delivered vaginally with no complications. Her medical history is unremarkable; specifically, she has no history of diabetes, cancer, autoimmune disease, kidney disease, sexually transmitted diseases, or recent infections (urinary tract or other). She reports that she has not taken antibiotics in more than three years and has had only two urinary tract infections (UTIs) during her lifetime: the first occurred when she became sexually active in her 20s and the second when she went on a fiveday horseback trip eight years ago. Both UTIs responded to a short course of sulfamethoxazole/ trimethoprim (SMX/TMP; Bactrim, Septra). Ms. O indicates that she and her family had completed a three-day biking tour the day before she presented. She notes that she rode a bicycle for six or more hours on each of the three days, and wonders whether that may have contributed to her current symptoms. Her last menstrual period began two weeks ago and was normal. Her husband had had a vasectomy after the birth of their second child. The only medication Ms. O takes is vitamin

ANTIBIOTIC STEWARDSHIP

D3 2,000 IU daily; she has no known medication allergies. Ms. O denies any history of tobacco or illicit drug use. During a typical weekend, she consumes two to four glasses of wine. The patient describes her diet as “healthy” and consisting of fruits, vegetables, whole grains, dairy products, and lean protein sources. Her exercise regimen includes cycling or running on most days of the week. She works as a school nurse so that she can have the summers off to be with her children. During her initial evaluation, vital signs are temperature 98.4°F, pulse 68 beats per minute, BP 112/70 mm Hg. Ms. O weighs 120 lb and is 5 ft 5 in tall. She is in no acute distress. Physical examination reveals moderate suprapubic tenderness with no costovertebral angle or abdominal tenderness. Perineal exam is deferred. Dipstick analysis of a clean-catch urine specimen is positive for some leukocytes and a moderate amount of nitrites and negative for glucose, ketones, protein, and blood. You diagnose an acute uncomplicated UTI. Because of its benign presentation, you elect not to culture the patient’s urine. Ordinarily, you would prescribe SMX/TMP, but it’s after 7 pm and the local pharmacies are closed, so you provide Ms. O with enough samples for a three-day course of ciprofloxacin (Cipro) 250 mg b.i.d. and advise her that she can purchase pyridium, a urinary analgesic, in the OTC pharmacy aisle at a local supermarket. You also counsel her to increase her fluid intake and to contact the urgent-care clinic or her primary-care provider if her symptoms worsen or have not improved in 24 hours. The next evening, Ms. O calls to say that her symptoms are no better but they are no worse. You advise her to come in for a repeat urinalysis. Results show a large number of

POLL POSITION

Despite national estimates that 50% of primary-care providers overprescribe antibiotics for nonspecific URIs, readers favored a more conservative approach.

Discussion

Cases like this are not uncommon. The microorganisms associated with infections that were relatively easy to treat a decade ago (e.g., acute cystitis, Clostridium difficile colitis) are becoming increasingly resistant to both conventional and late-generation antibiotic therapies. Antimicrobial-resistant infections are associated with a host of problems. In addition to increasing morbidity and mortality, antimicrobial-resistant infections lead to higher health-related costs and challenge our ability to contain the spread of infection. Furthermore, with the high rate of global travel, antimicrobial resistance (AMR) has no boundaries and jeopardizes national and international health and economic security.1 Nurse practitioners and physician assistants routinely diagnose and treat infections, so it is critical that they understand AMR and how it impacts their practice. The purposes of this article are to (1) briefly review AMR, (2) discuss current trends in prescribing antibiotics and AMR, (3) review principles of appropriate antibiotic prescribing, and (4) discuss the concept of “antibiotic stewardship” and how NPs and PAs can become involved in the antibiotic stewardship campaign.

n=291

A. Prescribe a broad-spectrum antibiotic

History of AMR

B. Suggest OTC or prescription decongestants, antihistamines, and nasal spray 21.55%

60.27%

C. Consider narrow-spectrum antibiotics if symptoms haven’t improved after 10-14 days 8.75% D. Both A & B 5.72% E. Both B & C 2.02%

leukocytes and microhematuria, so you send the specimen for culture and sensitivity (C&S). You then advise Ms. O to “double up” on her ciprofloxacin, so that she is taking 500 mg b.i.d., and you prescribe enough for three more days to cover her until the C&S results are known. Approximately 48 hours later, the culture results reveal multiple colonies of Escherichia coli that are resistant to ciprofloxacin and levofloxacin (Levaquin) but sensitive to all other antibiotics on the panel, including ampicillin, amoxicillin/clavulanate (Augmentin), ceftriaxone (Rocephin), cefuroxime (Ceftin), nitrofurantoin (Furadantin, Macrodantin, Macrobid), and SMP/ TMX. You call Ms. O and advise her to stop the ciprofloxacin and start a three-day course of double-strength SMX/TMP twice daily. The next day, an elated Ms. O calls to thank you and reports that her symptoms have completely resolved.

F. Other

1.68%

For more polls, visit www.ClinicalAdvisor/polls

AMR is by no means a new phenomenon. Shortly after discovering penicillin in 1928, Alexander Fleming also observed AMR 2 and warned about its dangers in his 1945 Nobel prize acceptance speech,3 just as penicillin was being introduced into health care. Since then, AMR has grown exponentially, and for the past decade, it has been recognized as a major global health threat by both the CDC,5 and the World Health Organization.1,6 Continues on page 50

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ANTIBIOTIC STEWARDSHIP

Simply put, AMR is the failure of microorganisms (i.e., bacteria, fungi, viruses, some parasites) to be eliminated or curtailed by antibiotics to which they were previously sensitive (i.e., responsive). AMR is a naturally occurring phenomenon. Over time, microorganisms that are exposed to a particular antimicrobial agent will develop resistance mechanisms to that agent. These mechanisms are then transferable to other microorganisms, even some that have never been directly exposed to antibiotics. Clinicians can accelerate the development of AMR by putting more antibiotics into the environment; conversely, we can slow the rate of AMR by curtailing antibiotic use. However, whenever antibiotics are used (even appropriately for legitimate infections) AMR will develop. Microorganisms will find a way to survive.7 AMR is always in a state of transition.5 As antibiotic exposure varies, rates of AMR increase and decrease. Mechanisms by which microorganisms develop antibiotic resistance are often associated with a “fitness cost” that makes it more difficult for the microorganisms to survive and reproduce. As antibiotic pressure diminishes, many microorganisms will gradually lose their antibiotic-resistant mechanisms; however, this loss of resistance occurs much more slowly than development of resistance.7 For example, widespread use of second-generation macrolides (e.g., azithromycin [Zithromax], clarithromycin [Biaxin]) have resulted in an increase in macrolide-resistant strains of Streptococcus pneumoniae.8-10 However, at least one study has demonstrated that several years after macrolides were discontinued in a particular community, S. pneumoniae resistance to macrolides diminished precipitously.11 Although all microorganisms are subject to AMR, there are several highly resistant microorganisms of which clinicians need to be aware, including the gram-negative species E. coli, Neisseria gonorrhoeae, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Campylobacter jejuni, all of which are becoming increasingly resistant to broad-spectrum, late-generation antibiotics. Highly resistant gram-positive bacteria include Enterococcus faecalis, Enterococcus faecium, S. pneumoniae, Staphylococcus aureus, Staphylococcus epidermidis, and C. difficile.12 In addition, Acinetobacter baumannii is a highly resistant gram-positive organism that we are seeing more frequently as infected soldiers return from Iraq.5,12 A number of social, agricultural, and ecological factors have been linked to the rise in AMR rates observed over the past two decades;13 however, poor hand hygiene and inappropriate antibiotic use for acute respiratory infections (ARIs) that are primarily viral in etiology (e.g., acute nonstreptococcal pharyngitis, acute sinusitis, and acute bronchitis) have also contributed to the increase in AMR.14 Fortunately, the rates of inappropriate

TABLE 1. Principles of appropriate antibiotic prescribing 1. Obtain an accurate diagnosis. 2. Know the likely etiology. 3. Assess each patient for specific related health history that could alter the etiology of that individual's infection. 4. Obtain and use local antibiotic resistance data. 5. Use current, evidence-based prescribing information. 6. Have a backup plan. 7. Educate your patients. 8. Understand that antibiotic prescribing does not necessarily lead to patient satisfaction. 9. Use meticulous hand hygiene. 10. Hold your peers to these same principles.

antibiotic prescribing for viral ARIs have declined somewhat over the past decade.15-19 However, in children younger than age 14 years, clinicians continue to prescribe antibiotics more than 50% of the time for ARIs that are primarily viral in etiology.20 In addition, recent studies indicate an increase in the use of broad-spectrum antibiotics for ARIs.15,21 Antibiotic prescribing habits of NPs and PAs

A few studies have examined antibiotic prescribing habits for ARIs of NPs and PAs and have generally found no differences between physician and NP/PA prescribing rates. Although one study reported that NPs and PAs prescribed antibiotics for ARIs significantly more than physicians did (52.5 vs. 39.0%, P =.05),22 the study was limited by a disproportionately low number of NP and PA visits compared with physician visits (194,000 physician visits vs. 5,000 NP or PA visits).23 Other studies that have compared antibiotic prescribing for ARIs among physicians, NPs, and PAs have no found differences in prescribing rates.24,25 In addition, a study comparing antibiotic prescribing patterns for viral ARIs between physicians and NPs found no significant differences between the two groups.26 Even if there are no differences in how antibiotics are prescribed, the data overwhelmingly indicate that clinicians continue to make inappropriate decisions about antibiotics (both in quantity and type). Prescribing antibiotics appropriately

Appropriate prescribing of antibiotics is a realistic goal that practicing NPs and PAs can strive for to help control rising AMR rates. In turn, appropriate antibiotic prescribing can reduce morbidity, mortality, and health-related costs. Here

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ANTIBIOTIC STEWARDSHIP

TABLE 2. Evidence-based hand-hygiene practices Hand hygiene recommendations Wash hands with soap and water whenever they are visibly soiled with body fluids. Wash hands after using the toilet. If exposure to potential spore-forming pathogens is strongly suspected or proven, including outbreaks of Clostridium difficile, hand washing with soap and water is the preferred means.

An alcohol-based hand rub is the preferred means for routine antisepsis in all other clinical situations, if hands are not visibly soiled. If alcohol-based hand rub is not available, wash hands with soap and water. Soap and alcohol-based hand rub should not be used concomitantly. When to perform hand hygiene: • Before and after touching patients • Before handling an invasive device for patient care, regardless of whether or not gloves are used • After contact with body fluids or excretions, mucous membranes, nonintact skin, or wound dressings • If moving from a contaminated body site to another body site during care of the same patient • After contact with inanimate surfaces and objects (including medical equipment) in the immediate vicinity of the patient • After removing sterile or nonsterile gloves • Before handling medication or preparing food

Source: World Health Organization. WHO Guidelines on Hand Hygiene in Health Care: First Global Patient Safety Challenge—Clean Care Is Safer Care. 2009. Available at whqlibdoc.who. int/publications/2009/9789241597906_eng.pdf, accessed October 15, 2011.

are 10 principles that I share with my students and strive to employ in my own clinical practice. (These principles are also summarized in Table 1): 1. Obtain an accurate diagnosis. Appropriate antibiotic prescribing begins with an accurate diagnosis. Inaccurate diagnoses lead to unnecessary antibiotic prescribing or to use of the wrong antibiotic. Take an honest look at your diagnostic skills. When was the last time you reviewed the differential diagnoses for sore throat, cough, or purulent nasal discharge? Where are you getting your diagnostic information? Are you using outdated sources? To guide your diagnosis, use current, research-based evidence, such as UpToDate, or a recent (i.e., published within the past five years) clinical guideline from a reputable professional organization, such as the CDC,

PEER PERSPECTIVES

the American Academy of Pediatrics, or the American College of Physicians, the Infectious Diseases Society of America (IDSA). Diagnostic decision-making should use a process that considers the wide spectrum of applicable differential diagnoses for the chief concern and carefully considers and rules out life-threatening conditions. Know the likely etiology. Once you’ve established an accurate diagnosis of infection, you need to consider the likely etiology or etiologies responsible for the infection and treat accordingly. At times, this can be determined through C&S. When C&S is not possible or practical, you’ll need to rely on empirical data. The Sanford Guide to Antimicrobial Therapy12 is an excellent resource that provides typical and atypical etiologies for most infectious diseases. The guide is updated annually and is available in a variety of print and electronic forms. Assess for related health history that could alter the etiology of the patient’s infection. Always consider and assess for other health and social history factors that could alter the etiology of the infection, such as drug and alcohol use, recent antibiotic use, recent hospitalizations, occupational history, and national or international travel to areas where certain diseases are endemic. For example, patients who work in inpatient, residential, or endoscopy laboratories may be more likely to have a resistant infection. Obtain and use local antibiotic resistance data. Make a point of regularly obtaining and reviewing antibiotic sensitivity data from your local laboratory or inpatient facility. Similarly, consider contacting your state health department to determine whether your state participates in a microbiological surveillance program from which you can access data. These data can be especially valuable if you need to select an antibiotic empirically. For example, if more than 20% of the E. coli strains in your community are resistant to SMX/TMP, then SMX/TMP should not be your fi rst-line choice for simple UTI.12 Use current, evidence-based prescribing information. In the same way that being up to date on diagnostic data is important, it is critical to base antibiotic

“There is no evidence to support the use of antibiotics to prevent strep-associated glomerulonephritis (see ClinicalAdvisor.com/PharyngitisSlideshow). Even if the strep is treated, antibiotics will not prevent glomerulonephritis because it is the result of an immune-complex reaction." — Michael Villanueva, PA-C, Moreno Valley, Calif. (via ClinicalAdvisor.com)

52 THE CLINICAL ADVISOR • NOVEMBER 2011 • www.ClinicalAdvisor.com

prescribing on the most current, evidence-based information. These resources will guide your initial choice and dose of antibiotics, as well as duration of treatment. They also can provide guidance regarding the decision for place of treatment (i.e., inpatient or outpatient) or the need for referral to an infectious-disease expert. Some good examples include The Sanford Guide, Prescriber’s Letter, the CDC’s Morbidity and Mortality Weekly Report (MMWR), and clinical guidelines from the IDSA. Information regarding the diagnosis and treatment of infectious diseases can change rapidly, so consider subscribing to an automatic, electronic daily update service, such as Journal Watch (www.jwatch.org) or Physician’s First Watch (firstwatch.jwatch.org). 6. Have a backup plan. As you develop an initial treatment plan for your patient’s infection, think about your next course of action should the infection worsen or not respond to initial treatment or if the patient develops an allergy or intolerance to the antibiotic. Consider whether your plan will include rethinking the initial diagnosis, obtaining a C&S, changing antibiotics, or consulting with an infectious-disease specialist. No matter how experienced or astute a clinician you are, initial treatment plans will fail from time to time, and backup planning will likely save you precious time in the long run. 7. Educate your patients. Well-informed patients are more likely to adhere to the recommended treatment regimen and to seek assistance if anything goes awry (i.e., symptoms are worsening, signs of allergy develop). Carefully explain your diagnostic reasoning and treatment recommendations, as well as what to watch for and what to do in the event that problems arise. Patients often do not remember details from office visits, so your best course of action is to put all TABLE 3. Antimicrobial resistance websites Centers for Disease Control and Prevention (CDC). Get Smart: Know When Antibiotics Work. Available at www.cdc.gov/getsmart. Infectious Diseases Society of America (IDSA). Antimicrobial Resistance at the State Level. Available at www.idsociety.org/AR_by_State/. Tufts University—Alliance for the Prudent Use of Antibiotics. Available at www.tufts.edu/med/apua/. World Health Organization (WHO). Antimicrobial Resistance. Available at www.who.int/mediacentre/factsheets/fs194/en/ All electronic documents accessed October 15, 2011.

CLINICAL SLIDESHOW For additional information on the evaluation of bacterial vs. viral pharyngitis, view the slideshow at ClinicalAdvisor.com/PharyngitisSlideshow.

important information in writing. A number of electronic programs (including some electronic medical record systems) have patient information templates for various conditions. Be sure to read these templates (and revise them as needed) before distributing them to patients. 8. Understand that antibiotic prescribing does not necessarily lead to patient satisfaction. Clinicians frequently prescribe antibiotics for viral ARIs because they believe that doing so will lead to patient satisfaction. The psychology between antibiotic prescribing and patient satisfaction is complex and beyond the scope of this article. However, a growing body of literature indicates that patients and parents (even those who specifically ask for antibiotics) are satisfied when they feel that the clinician has listened to them and they have received honest, nonpatronizing information, regardless of whether they receive a prescription for an antibiotic.27-29 9. Practice meticulous hand hygiene. Although hand hygiene is not an antibiotic prescribing principle, all the previously noted prescribing measures amount to little if clinicians are not routinely engaging in effective hand hygiene. Poor hand hygiene by health care workers (HCWs) is a major source of disease transmission and has greatly contributed to the rise in AMR.14 A recent analysis of multiple studies of HCWs’ adherence to hand hygiene procedures indicated that on average, HCWs adhere to recommended hand hygiene procedures only 38.7% of the time.30 With the advent of alcohol-based hand sanitizers, hand hygiene is quicker, more accessible, and less irritating than ever before. See Table 2 for a brief summary of current, evidence-based hand hygiene recommendations. 10. Hold your peers to these same principles. Antibiotics have significant societal and global implications,32 and every prescribing clinician needs to be aware of how his or her antibiotic prescribing habits

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER 2011 53

ANTIBIOTIC STEWARDSHIP

AT A GLANCE ●

The microorganisms associated with infections that were relatively easy to treat a decade ago (e.g., acute cystitis, Clostridium difficile colitis) are becoming increasingly resistant to both conventional and late-generation antibiotic therapies.

●

Whenever antibiotics are used (even appropriately for legitimate infections), AMR will develop.

●

Committing to the 10 antibiotic prescribing principles is an excellent way to demonstrate antimicrobial stewardship.

●

Antimicrobial stewardship encompasses a range of formal and informal approaches designed to conserve antibiotics.

contribute to AMR. Table 3 provides a list of electronic AMR resources that may help doubting colleagues. Antimicrobial stewardship

After first appearing in the medical literature in 1996,32 the term antimicrobial stewardship has become an increasingly popular idea to help contain AMR and sustain antibiotic effectiveness. Merriam-Webster defi nes stewardship as “the conducting, supervising, or managing of something; especially the careful and responsible management of something entrusted to one’s care.” Similar to environmental campaigns, which emphasize the earth’s limited natural resources and challenge us to live in a more environmentally friendly manner, antimicrobial stewardship campaigns challenge clinicians to be better stewards of our antimicrobial resources. Antimicrobial stewardship encompasses a range of formal and informal approaches designed to conserve antibiotics, including educational programs, clinical guidelines, committees, and surveillance policies. 33,34 Inpatient, outpatient, and combined inpatient/outpatient antimicrobial stewardship campaigns do exist. The CDC’s Get Smart campaign is considered one of the best examples of a combined inpatient/outpatient campaign 35 and provides a wealth of evidence-based information and resources for patients and clinicians alike. In addition, antimicrobial stewardship campaigns have a small but growing body of research to support their effectiveness.34,36,37 For clinicians who choose not to join or start an antimicrobial

MAKING CONTACT

stewardship group, committing to the 10 antibiotic prescribing principles is an excellent way to demonstrate antimicrobial stewardship. Conclusion

Like water, soil, and fossil fuels, antibiotics ought to be considered precious resources that require responsible management. If we are not vigilant about appropriate antibiotic prescribing now, a “postantibiotic era” will be inevitable. NPs and PAs have a long history of providing safe, highquality care. As experts in health care, NPs and PAs should assume a leading role in the antimicrobial stewardship campaign. At a minimum, NPs and PAs should consider adopting the aforementioned 10 appropriate antibiotic prescribing principles. ■ Dr. Hart is associate professor and coordinator of the Doctor of Nursing Practice program at the Fay W. Whitney School of Nursing, University of Wyoming, in Laramie. References 1. World Health Organization. Combat Drug Resistance: No action today, no cure tomorrow. Available at www.who.int/world-health-day/2011/ world-health-day2011-brochure.pdf. 2. Fleming A. On the antibacterial action of cultures of penicillium, with special reference to their use in the isolation of B. influenzae. Br J Exp Pathol. 1929;10:226-236. 3. Fleming A. Penicillin. Nobel Lecture, December 11, 1945. Available at www.nobelprize.org/nobel_prizes/medicine/laureates/1945/fleminglecture.html. 4. Interagency Task Force on Antimicrobial Resistance. A Public Health Action Plan to Combat Antimicrobial Resistance. Part 1: Domestic Issues. Available at www.cdc.gov/ drugresistance/actionplan/aractionplan-archived.pdf. 2001. 5. Interagency Task Force on Antimicrobial Resistance. A Public Health Action Plan to Combat Antimicrobial Resistance. Available at www.cdc. gov/drugresistance/pdf/public-health-action-plan-combat-antimicrobialresistance.pdf. 2011. 6. World Health Organization. WHO Global Strategy for Containment of Antimicrobial Resistance. 2001. Available at www.who.int/drugresistance/ WHO_Global_Strategy_English.pdf. 7. Andersson DI, Hughes D. Antibiotic resistance and its cost: is it possible to reverse resistance? Nat Rev Microbiol. 2010;8:260-271.

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54 THE CLINICAL ADVISOR • NOVEMBER 2011 • www.ClinicalAdvisor.com

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Go mobile with us mobile.ClinicalAdvisor.com

8. Skalet AH, Cevallos V, Ayele B, et al. Antibiotic selection pressure

23. Hart AM. Response to differences in antibiotic prescribing. Am J Med.

and macrolide resistance in nasopharyngeal Streptococcus pneumoniae: a

2006;119:e21-22. Available at download.journals.elsevierhealth.com/pdfs/

cluster-randomized clinical trial. PLos Med. 2010;14:e1000377.

journals/0002-9343/PIIS0002934305007151.pdf.

9. Bergman M, Huikko S, Huovinen P, et al. Macrolide and azithromycin use

24. Gonzales R, Barrett PH Jr, Crane LA, Steiner JF. Factors associated

are linked to increased macrolide resistance in Streptococcus pneumoniae.

with antibiotic use for acute bronchitis. J Gen Intern Med. 1998;13:541-548.

Antimicrob Agents Chemother. 2006;50:3646-3650. Available at aac.asm.

Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC1496997/.

org/cgi/reprint/50/11/3646.

25. Gonzales R, Steiner JF, Lum A, Barrett PH Jr. Decreasing antibiotic

10. Pihlajamäki M, Kotilainen P, Kaurila T, et al. Macrolide-resistant

use in ambulatory practice: impact of a multidimensional intervention

Streptococcus pneumoniae and use of antimicrobial agents. Clin Infect Dis.

on the treatment of uncomplicated acute bronchitis in adults. JAMA.

2001;15:483-488. Available at cid.oxfordjournals.org/content/33/4/483.long.

1999;281:1512-1519. Available at jama.ama-assn.org/content/281/16/1512.

11. Haug S, Lakew T, Habtemariam G, et al. The decline of pneumococcal

long.

resistance after cessation of mass antibiotic distributions for trachoma.

26. Ladd E. The use of antibiotics for viral upper respiratory tract

Clin Infect Dis. 2010;51:571-574. Available at cid.oxfordjournals.org/con-

infections: an analysis of nurse practitioner and physician prescrib-

tent/51/5/571.long.

ing practices in ambulatory care, 1997-2001. J Am Acad Nurse Pract.

12. Gilbert DN, Moellering RC Jr, Eliopoulos GM, et al. The Sanford Guide

2005;17:416-424.

to Antimicrobial Therapy 2011. 41st ed. Sperryville, VA: Antimicrobial

27. White D, Moir A, Zweifler J, Hughes S. Parental satisfaction without

Therapy, Inc.; 2011.

antibiotics. Nurse Pract. 2010;35:40-42.

13. Wynne AL. Drugs used in treating infectious diseases. In: Woo TM,

28. van Duijn HJ, Kuyvenhoven MM, Schellevis FG, Verheij TJ. Illness

Wynne AL, eds. Pharmacotherapeutics for Nurse Practitioner Prescribers. 3rd

behaviour and antibiotic prescription in patients with respiratory tract

ed. Philadelphia, PA: F.A. Davis; 2011:625-744.

symptoms. Br J Gen Pract. 2007;57:561-568. Available at www.ncbi.nlm.nih.

14. Allegranzi B, Pittet D. Role of hand hygiene in healthcare-associated

gov/pmc/articles/PMC2099639/?tool=pubmed.

infection prevention. J Hosp Infect. 2009;73:305-315.

29. Welschen I, Kuyvenhoven M, Hoes A, Verheij TJ. Antibiotics for acute

15. Grijalva CG, Nuorti JP, Griffi n MR. Antibiotic prescription rates

respiratory tract symptoms: patients’ expectations, GPs’ management and

for acute respiratory tract infections in US ambulatory settings. JAMA.

patient satisfaction. Fam Pract. 2004;21:234-237.

2009;302:758-766. Available at jama.ama-assn.org/content/302/7/758.

30. World Health Organization. WHO Guidelines on Hand Hygiene in

long.

Health Care: First Global Patient Safety Challenge—Clean Care is Safer Care.

16. Gonzales R, Corbett KK, Wong S, et al. “Get smart Colorado”: impact

2009. Available at whqlibdoc.who.int/publications/2009/9789241597906

of a mass media campaign to improve community antibiotic use. Med Care.

_eng.pdf.

2008;46:597-605.

31. Sarkar P, Gould IM. Antimicrobial agents are societal drugs: how should

17. Vanderweil SG, Pelletier AJ, Hamedani AG, et al. Declining antibiotic

this influence prescribing? Drugs. 2006;66:893-901.

prescriptions for upper respiratory infections, 1993-2004. Acad Emerg

32. McGowan JE Jr, Gerding DN. Does antibiotic restriction prevent resis-

Med. 2007;14:366-369. Available at onlinelibrary.wiley.com/doi/10.1197/j.

tance? New Horiz. 1996;4:370-376.

aem.2006.10.096/pdf.

33. Bosso JA, Drew RH. Application of antimicrobial stewardship to

18. Miller GE, Hudson J. Children and antibiotics: analysis of reduced use,

optimise management of community acquired pneumonia. Int J Clin Pract.

1996-2001. Med Care. 2006;44(5 suppl):I36-I44.

2011;65:775-783. Available at onlinelibrary.wiley.com/doi/10.1111/j.1742-

19. Roumie CL, Halasa NB, Grijalva CG. et al. Trends in antibiotic pre-

1241.2011.02704.x/pdf.

scribing for adults in the United States—1995-2002. J Gen Intern Med.

34. Tamma PD, Cosgrove SE. Antimicrobial stewardship. Infect Dis Clin

2005;20:697-802.

North Am. 2011;25:245-260.

20. Centers for Disease Control and Prevention. Office-related antibi-

35. Centers for Disease Control and Prevention. Get smart: Know when

otic prescribing for persons aged ≤14 years — United States, 1993-1994

antibiotics work. Available at www.cdc.gov/getsmart/.

to 2007-2008. MMWR Morb Mortal Wkly Rep. 2011;60(34):1153-1156.

36. Braxton CC, Gerstenberger PA, Cox GG. Improving antibiotic stew-

Available at www.cdc.gov/mmwr/preview/mmwrhtml/mm6034a1.htm.

ardship: order set implementation to improve prophylactic antimicro-

21. Shapiro DJ, Gonzales R, Cabana MD, Hersh AL. National trends in visit

bial prescribing in the outpatient surgical setting. J Ambul Care Manage.

rates and antibiotic prescribing for children with acute sinusitis. Pedatrics.

2010;33:131-140.

2011;127:28-34.

37. Toth NR, Chambers RM, Davis SL. Implementation of a care bundle for

22. Roumie CL, Halasa NB, Edwards KM, et al. Differences in antibiotic

antimicrobial stewardship. Am J Health Syst Pharm. 2010;67:746-749.

prescribing among physicians, residents, and nonphysician clinicians. Am J Med. 2005;118:641-648.

All electronic documents accessed October 15, 2011.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER 2011 55

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

Inside the Forum NOVEMBER 2011

Consultations Testing for cold intolerance . . . . . . . .58 Next step for endometrial hyperplasia . .58 Can too much fish oil lead to GERD? . . . . . . . . . . . . . . . . . . .58 Mysterious stomach pain when coughing . . . . . . . . . . . . . . . .65 Nonalcoholic fatty liver disease . . . . . .66

Clinical Pearls “Alarming” teen contraceptive-pill compliance . . . . . . . . . . . . . . . . . . .66 The devil is in the “D-TAILS” . . . . . .66 Easing children’s anxiety over cast removal. . . . . . . . . . . . . . . . . . .66 Improvised medication spacer . . . . . . .69 Wiping out UTIs in women. . . . . . . .69

Your Comments Prostate screening: every one or two years? . . . . . . . . . . . . . . . . . . . .69 Withhold judgment when discussing firearms in the home . . . . . . . . . . . .75

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

CONSULTATIONS TREATING ELEVATED TRIGLYCERIDES If triglycerides are a more significant indicator of cardiovascular disease (CVD) risk in women than in men, is it appropriate to treat even if LDL is normal? If so, what is the best medication to use?—JOAN A. PETERS-GILMARTIN, PA-C, Mashpee, Mass. I take elevated triglycerides seriously regardless of gender, especially when the patient exhibits such global markers of metabolic syndrome as hypertension, low HDL, impaired glucose tolerance/ diabetes mellitus, and/or central obesity. The 2004 update to the National Cholesterol Education Program cholesterol guidelines (available at www.nhlbi.nih.gov/guidelines/cholesterol/index. htm, accessed October 15, 2011) states that metabolic syndrome automatically puts the patient at very high risk of coronary artery disease. That said, the primary goal remains to lower LDL levels, in this case, to <70 mg/dL whenever possible with the use of statins. Once the effect of statins is seen, combination therapy utilizing fenofi brate or prescription fi sh oil can be effective at lowering triglycerides. The only time triglycerides should be the primary focus is when the level is >500 mg/dL, putting the patient in danger of pancreatitis. Please don’t forget what a difference lifestyle changes can make, especially reducing consumption of simple carbohydrates and increasing exercise.—Rebecca H. Bryan, APRN, CNP (157-1)

OUR CONSULTANTS

Bruce D. Askey, MSN, CRNP, is

Rebecca H. Bryan, APRN, CNP, is a

Eileen Campbell, MSN, CRNP,

Philip R. Cohen, MD, is clinical

a clinician in the Department of Hepatology/ Gastroenterology at the Guthrie Clinic in Sayre, Pa.

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

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

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

Deborah L. Cross, MPH, CRNP, ANPBC, is associate

program director, gerontology NP program, University of Pennsylvania School of Nursing, Philadelphia

56 THE CLINICAL ADVISOR • NOVEMBER 2011 • www.ClinicalAdvisor.com

JoAnn Deasy, PA-C, MPH,

Virginia H. Joslin, PA-C, MPH, is

a primary-care clinician, teaches in the PA program at Pace UniversityLenox Hill Hospital, New York City.

assistant professor and PA Program division director at Emory University School of Medicine in Atlanta.

Maria Kidner, DNP, FNP-C, is

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

WHAT CAUSED THIS NAIL DYSTROPHY? A 58-year-old woman has a 1-mm wide, slightly raised linear area along the length of her fourth left fingernail. Her other nails are normal. She is generally healthy with a history of mild intermittent asthma treated with azelastine (Astelin) nasal spray and a fluticasone and salmeterol (Advair) inhaler. Could her nail changes be related to her medical condition?— CHRISTINE SPOHN, SNP-C, RN, Eaton, Colo. It is unlikely that her nail changes are secondary to her medical condition. Nail changes that result from systemic conditions usually affect all the nails and not just a single nail plate. The area responsible for nail-plate growth is the nail matrix, which is located beneath the proximal nail fold and extends beneath the nail plate as the lunula. A raised linear defect extending along the entire length of the nail would suggest a lesion that affected the associated nail matrix. To determine the etiology of the nail dystrophy, consider roentgenograms of the affected digit, nail-plate avulsion and biopsy of the nail matrix, or both.—Philip R. Cohen, MD (157-2)

risk of thinning the eyelids is real, as is the possibility of increased intraocular pressure. I limit the use of these agents to one to two weeks, while nonsteroids can be used without limitation.—Jeffrey M. Weinberg, MD (157-3)

STOPPING WARFARIN BEFORE CATARACT SURGERY I get many requests for preoperative physical exams from the patients in my rural health-care clinic. Does an individual undergoing cataract surgery with standby or local anesthesia need a full workup if he or she has been stable on current medications, regardless of medical history? Should warfarin (Coumadin) be stopped before cataract surgery? If so, how many days prior to the procedure is recommended?— COLETTE THOMPSON, FNP, Lexington, Ga.

SAFE USE OF PERIOCULAR STEROID What kind of steroid cream is safe for dermatitis of the eyelid and periorbital area, and how long can it be used? Are there any adjunct measures that can be taken? How real is the danger of thinning the skin of the eyelid and/or increasing intraocular pressure?—MANSURUR R. KHAN, MD, Pasadena, Calif.

Cataract surgery that is anticipated to the anterior chamber only is considered a low-risk procedure that does not require stopping warfarin, dabigatran (Pradaxa), or aspirin. However, a procedure that is anticipated to include the posterior chamber carries a high risk for bleeding within a closed space, and all anticoagulants need to be stopped 10 days prior. If clopidogrel (Plavix), prasugrel (Effient), or ticagrelor (Brilinta) are on your patient’s medication list, please clarify the last stent placement before stopping for non-life-threatening surgeries. Drug-eluting coronary artery stents must be protected for one year before stopping for elective surgeries.—Maria Kidner, DNP, FNP-C (157-4)

Given the side effects of topical corticosteroids, especially around the eyes, I routinely recommend the use of a nonsteroid preparation, such as topical pimecrolimus (Elidel) or tacrolimus (Protopic). If a steroid is used, I choose a low-potency formulation, such as hydrocortisone cream 1% or 2.5%, or an ophthalmic preparation. The

SESAME OIL TO LOWER BP I have read that researchers in India found that men who replaced the corn and vegetable oils in their diets with sesame seed oil lowered their BP by more than 30 points in just 60

Debra August King, PhD, PA,

Samuel J. Mann, MD is associate

Daniel R. Mishell Jr, MD, is chairman

Sherril Sego, FNP-C, DNP, is a

Daniel G.Tobin, MD, is assistant

Julee B.Waldrop, DNP, is associate

Jeffrey Weinberg, MD, is director of

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

professor of clinical medicine, Weill Medical College of Cornell University, New York City

of the Department of Obstetrics and Gynecology, University of Southern California, Los Angeles.

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

professor of medicine, Yale University School of Medicine, New Haven, Conn.

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

clinical research, Department of Dermatology, St. Luke’s-Roosevelt Hospital Center, New York City.

Claire Babcock O’Connell, MPH, PA-C, is an

associate professor, University of Medicine and Dentistry of New Jersey, PA program, Piscataway.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER 2011 57

Advisor Forum There have been many studies concerning BP and dietary fatty acids, involving manipulation of either diet or supplements. Of course, results vary, but a reasonable consensus can be conveyed. Fish oil, in particular eicosapentaenoic acid, seems to lower systolic BP by about 5 mm Hg. Interestingly, this fall in BP is seen only in people consuming fi sh less often than three times a week. In those consuming fi sh more than three times a week, the fi sh-oil supplement had no effect on BP. This is analogous to the effect of potassium supplements: Potassium supplements lower BP in people with potassium-defi cient diets. The more holistic approach is to improve the diet rather than take supplements. Studies also seem consistent in finding that corn oil does not lower BP. Finally, the effect of linoleic acid is controversial, with lowering of BP seen in some studies but not in others. I would doubt that sesame oil is uniquely potent among vegetable oils and would strongly doubt that it lowers BP by 30 mm Hg. I have not seen a study specifically addressing sesame oil, but even if it were effective, a decrease of 5 mm Hg would be as much as could be expected.—Samuel J. Mann, MD (157-5)

TESTING FOR COLD INTOLERANCE An elderly man complains of feeling cold all the time, even though the weather is warm. There is no evidence of anemia on a complete blood count; thyroid studies are normal. What additional studies should be ordered?—FELIX N. CHIEN, DO, Newport Beach, Calif. Cold intolerance is difficult to define and may refer to either local or systemic symptoms that can be acute or chronic. Hypothyroidism is the most well-known etiology, but there are many causes and the history and physical exam are crucial to direct further testing. For example, acute localized symptoms (such as in the hand) can imply vascular injury, and this should be ruled out. A history of recent trauma, clotting disorders, and focal neurologic symptoms and signs may provide important clues. Prior neuromuscular damage may lead to focal but chronic symptoms such as with postpolio syndrome. Similarly, post-traumatic cold intolerance can last for years after injury. Acute systemic cold intolerance, especially if accompanied by orthostasis, nausea, fatigue, or fever, could be the result of adrenal insufficiency or sepsis, and both should be considered. Chronic systemic symptoms can result from low body weight (as with anorexia nervosa or chronic illness) or advanced peripheral vascular disease. Depression, fibromyalgia, and sleep deprivation have also been associated with cold intolerance.—Daniel G. Tobin, MD (157-6)

days. Does this work? If so, how much oil must be ingested each day?—GERARD K. NASH, DO, Amarillo, Tex.

Excessive ovarian hormones lead to endometrial hyperplasia (shown).

NEXT STEP FOR ENDOMETRIAL HYPERPLASIA How would you proceed with a 64-year-old woman who has complex endometrial hyperplasia and secretory changes? The patient is not receiving hormone replacement therapy, and her follicle-stimulating hormone and luteinizing hormone levels are appropriately elevated. Does she require dilatation and curettage?—ROY A. HART, DO, Moline, Ill. If the diagnosis of endometrial hyperplasia in a postmenopausal woman is made after endometrial biopsy, it is advisable to perform curettage to observe the histologic findings from a greater area of the endometrial cavity than is accessible with a biopsy instrument. Endometrial cancer may be present in only one area of the endometrial cavity. If the biopsy or curettage reveals complex endometrial hyperplasia with atypia, it is best to perform a hysterectomy, since many of these lesions will progress to carcinoma.—Daniel R. Mishell Jr, MD (157-7)

CAN TOO MUCH FISH OIL LEAD TO GERD? Is there any indication that taking too much fish oil— particularly green-lipped mussel oil—can cause stomach problems in a person with a history of gastroesophageal reflux disease?—BOB STUKENBERG, LHNA, Irvine, Calif. I found this unbiased discussion of green-lipped mussel oil in comparison with other sources of omega-3 fatty acids (www.wellnessresources.com/health/articles/dha_krill_oil_green_lipped_ mussel_which_is_best/, accessed October 15, 2011). As potent anti-inflammatory agents, omega-3 fatty acids are vital to health and well-being. They balance out the typical American diet, which

58 THE CLINICAL ADVISOR • NOVEMBER 2011 • www.ClinicalAdvisor.com

is full of inflammatory omega-6 fatty acids. There is not sufficient evidence to argue green-lipped mussel oil’s superiority over other less expensive sources. All fish oils are known to have significant GI side effects of dyspepsia and fishy burps. Some brands are more tolerable than others, and it can help to keep the capsules in the freezer or to consume them after a meal. Excellent studies have been done on prescription fish oil (Lovaza), which provides consistent dosing and is the only version officially recommended by the American Heart Association to reduce the risk of second heart attack. – Rebecca H. Bryan, APRN, CNP (157-8)

Mysterious stomach pain when coughing A man aged 58 years has a history significant for hypertension, obesity, Barrett’s esophagus, and reflux. He reports intermittent, dull, right-upper-quadrant (RUQ) pain below the ribs when he lies on his right side. The pain worsens with coughing or inspiration. Typically, the pain occurs intermittently over a two-week period and then subsides for several weeks before recurring. He is status post cholecystectomy and right hemicolectomy (due to an ileocecal tubovillous adenomatous polyp). The RUQ

pain began immediately following the hemicolectomy. Abdominal and pelvic CT reveals diffuse steatosis of the liver and a small subcapsular area of complete fatty replacement of liver parencyma in the anterior segment of the right hepatic lobe. Although the radiologist believes this occurred after a segmental infarct, possibly related to the patient’s gallbladder surgery, it was not visualized on CT after the procedure. Amylase and lipase are normal, and alanine aminotransferase is slightly elevated (eight points above normal). The patient was referred to a surgeon and a gastroenterologist. The specialists did not mention the segmental infarct and offered no explanation for the man’s pain. Could this infarct be the cause? If not, what else should I be looking for?—DAWN GIORGIO, PA, Queensbury, N.Y. Since the RUQ pain is described as chronic rather than acute (as it might be if related to an infarct in the liver), it is probably attributable to fatty liver disease. Having said that, however, the idea that this patient may have had an infarct in his liver needs to be evaluated as well. Did he have prior ultrasound or CT to determine how long ago this infarct occurred? What risk factors does he have for an infarct (e.g., a recent cardiovascular assault or

www.ClinicalAdvisor.com • the clinical advisor • November 2011 65

Advisor Forum

NONALCOHOLIC FATTY LIVER DISEASE An ultrasound on a 51-year-old man with mild alanine aminotransferase (ALT) elevation (77 units/L) showed gross, grade 3 fatty infiltration of the liver. He does not drink alcohol or use IV drugs, nor does he complain of abdominal pain. A hepatitis panel was negative, and random glucose was normal. Of what significance is the ultrasound finding? Does it require followup?—LEIGH BEARS, NP, New London, Conn. Nonalcoholic fatty liver disease (NAFLD) is rapidly emerging as one of the most common “incidental findings” identified with radiographic testing. One in four adults is found to have the condition when undergoing abdominal ultrasound. Although common, NAFLD is anything but benign. Liver biopsy reveals advanced fibrosis in up to 50% of those with NAFLD, and up to 16% have cirrhosis. The mild elevation of ALT described here suggests mild liver inflammation. NAFLD commonly occurs in the presence of such conditions as diabetes mellitus, obesity, hyperlipidemia, hypertriglyceridemia, and hypothyroidism as well as with rapid weight loss, such as that seen with starvation diets, and with a number of pharmacologic agents. Since treatment of underlying conditions is necessary, these entities should be considered when managing patients with NAFLD. Liver biopsy is the gold standard for diagnosing NAFLD. Ultrasound analysis is not very specific because other liver diseases, such as iron overload (hemochromatosis), can resemble fatty liver. Fortunately, a biopsy is generally not necessary unless the condition resists treatment. Since the patient described has already been tested for diabetes, he should now be evaluated for thyroid disease and hyperlipidemia/hypertriglyceridemia. A thorough medication history should also be obtained. In addition, if he is overweight, a referral to a dietitian for gradual weight loss is in order. Liver enzymes should be rechecked after three to six months and, if still elevated, liver biopsy should be considered. A biopsy showing fibrosis often provides muchneeded incentive for lifestyle modification. For more information, refer to Sleisenger M, Fordtran J, eds. Gastrointestinal and Liver Disease: Pathophysiology/Diagnosis/Management. 7th ed. Philadelphia, Pa: WB Saunders; 2002:1393-1401.—Bruce D. Askey, MSN, CRNP (157-10)

CLINICAL PEARLS “ALARMING” TEEN CONTRACEPTIVE-PILL COMPLIANCE Teens often tell me they forget to take their birth-control pills (BCPs), sometimes as often as three or more times per cycle. However, I notice that they never seem to forget their cell phones. Prior to leaving the exam room, I instruct patients taking BCPs to set the alarm feature on their phones for the time they plan to take their pill. This intervention can be used for other medications and treatment plans as well.—VANILLA BROOKS, MN, FNP, Wilmington, Calif. (157-11)

THE DEVIL IS IN THE “D-TAILS” When teaching students how to obtain a patient history, I tell them to focus on getting certain crucial “D-TAILS”: Duration of symptoms, Type of pain, Associated factors, Influencing factors, Location, and Severity. – KENYA BEARD, EdD, GNP-BC, NP-C, ACNP-BC, New York City (157-12)

EASING CHILDREN’S ANXIETY OVER CAST REMOVAL Throughout my 11 years in orthopedics, I have put casts on a considerable number of young children with wrist or forearm fractures. Many of them are terrified of the

ischemic event)? Does he have antiphospholipid syndrome? Other differential diagnoses of the RUQ pain need to be considered, such as sphincter of Oddi dysfunction and adhesions from the patient’s prior right hemicolectomy.—Sharon Dudley-Brown, PhD, FNPBC, co-director, gastroenterology & hepatology, Nurse Practitioner Fellowship Program, Johns Hopkins University Schools of Medicine & Nursing, Baltimore (157-9)

“I’m too busy recommending things to experience them myself.”

66 THE CLINICAL ADVISOR • NOVEMBER 2011 • www.ClinicalAdvisor.com

Advisor Forum

YOUR COMMENTS

The removal of a cast with a saw can be scary for some children.

cast saw, which makes removal quite challenging. In an effort to make the experience less scary, I tell them that it is going to sound like mommy’s vacuum cleaner. Next, I tell them that it is going to tickle like crazy, so try not to laugh. Sure enough, most giggle right through the whole thing.—SANDRA RADCLIFF, PA-C, St. Thomas, Virgin Islands (157-13)

IMPROVISED MEDICATION SPACER After eight medical-mission trips to the developing world, I have learned how to make do with the resources that are available. When an asthmatic patient does not have the resources to purchase an inhalation spacer, a 16- or 20-oz plastic bottle will do. Cut out a hole just big enough to insert the end of the inhaler into the bottom of the bottle. Instruct the patient to place the uncapped bottle opening in his or her mouth and the inhaler in the hole at the bottom. Instill one puff of medication into the bottle, and have patient take in several deep breaths until the mist of medication is no longer visible. Repeat if two puffs of medication are indicated.—ARDEN MOULIN, WHCNP, Grapevine, Tex. (157-14)

WIPING OUT UTIS IN WOMEN I see a fair number of women in my practice with recurrent urinary tract infections (UTIs). I recommend switching from using toilet paper to unscented baby wipes. This change has substantially reduced the frequency of recurrent UTIs in my practice.—PAULA A. CRINKLAW, FNP-BC (157-15)

PROSTATE SCREENING: EVERY ONE OR TWO YEARS? I might be dead today if my clinician had followed the prostate screening guidelines you outlined (“When to screen for prostate cancer,” October 2011). My prostate specific antigen (PSA) levels had been below 2.0 ng/mL for 10 years before spiking to 3.6 ng/mL in one year. Under the two-year guideline, I would have been an extra year into a rapidly accelerating PSA with very negative consequences. I urge every man older than age 50 years to have his PSA measured annually. Evidence-based statistics are interesting, but for the people who fall outside two standard deviations, the results can be tragic. When dealing with cancer, practice on the side of reducing mortality and morbidity, not reducing costs to the insurance company.—HENRY INTILI, FNP, Atlanta Prior to issuing updated early-detection recommendations in 2010, the American Cancer Society’s prostate cancer advisory committee looked very closely at the evidence related to screening intervals. This thorough review determined that although the majority of men undergoing PSA screening in the United States are tested on an annual basis, there is no randomized-controled trial data or other strong evidence to support this practice. As a matter of fact, the two largest trials to demonstrate a mortality benefit associated with screening for prostate cancer had screening intervals of two years (Lancet Oncol. 2010;11:725-732) and four years (N Engl J Med. 2009;360:1320-1328, available at www.nejm.org/doi/full/10.1056/NEJMoa0810084, accessed October 15, 2011). A number of modeling studies have compared annual screening with screening every two years. These studies have consistently estimated that a two-year screening interval cuts the number of unnecessary prostate biopsies in half, with only a small decrease in life-years saved ( J Urol. 1999;162:741-748, and JAMA. 2000;284:13991405, available at jama.ama-assn.org/content/284/11/1399. long, accessed October 15, 2011). Other researchers have looked at the potential delay in prostate cancer detection associated with biannual screening vs. screening every year. These studies have estimated a delay of five to six months on average. Given the very slow rate of growth of most prostate cancers, such a delay is not likely to significantly impact long-term survival for the vast majority of diagnosed men. Based on the strength of the medical evidence, the American Cancer Society continues to recommend that men with an initial PSA level of <2.5 ng/mL can safely extend their screening

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER 2011 69

Advisor Forum interval to every two years.—Durado D. Brooks, MD, MPH, Director, Prostate and Colorectal Cancers, American Cancer Society (157-16)

Editor’s note: These comments were written in response to a post in The Waiting Room, our collection of expert blogs. To read more, visit the website at www.ClinicalAdvisor.com/blog.

Guns and ammunition and their availability within a home is a valid issue for review with any patient, but the pediatric review must be conducted in the presence of an adult living within the domicile as a parent or legal guardian. The first question must be, “May we discuss the presence of arms and ammunition within the home?” Launching into such a discussion without permission to do so incites suspicion and even hostility. Too many of us gun owners are already wary of well meaning but blundering efforts by agencies and organizations trying to help. The clinician reviewer should have extensive knowledge of firearms and proper storage methods and be ready to offer methods of remediation where there appears to be need (without being judgmental). Use the same consideration in gun issues that would be used in discussing any other potentially hazardous concern within the home. The examiner may be hostile to gun ownership, but that hostility has no place in dealing with patients.— EDWIN NOVAK, PA-C, Park Rapids, Minn. (157-18) ■

“Look, I took my own kidney out.”

WITHHOLD JUDGMENT WHEN DISCUSSING FIREARMS IN THE HOME Dr. Waldrop raises an important subject (“Florida gun law interferes with patient relationships,” posted September 14, 2011). There is a dramatic difference between counseling parents about gun safety and documenting whether guns are kept in the home. The latter does not change a thing about the safety of the environment. Because of the constant assault on the right of gun ownership by antigun advocates, gun owners are sensitive to any intrusion and do not want to listen to lectures about the evils of ownership, which such counseling frequently implies. Clinicians have to garner the cooperation of parents to accomplish our goals, and routine counseling about child safety (including such environmental factors as poisons, knives, and guns) without adding political bias should be the norm. The ultimate goal is assuring safety without intrusion into the private matters of the parents. This can best be achieved by garnering the cooperation of all parties involved instead of resentment.— BRUCE MILLER, PA, St. Cloud, Minn. (157-17)

“Let’s walk him and pitch to the bishop.”

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER 2011 75

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“In the kitchen, I’m more of an aggregator than a content creator.” 76 THE CLINICAL ADVISOR • NOVEMBER 2011 • www.ClinicalAdvisor.com

Stat Consult

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

Prediabetes BY ALAN DRABKIN, MD, AND ROBERT K. SMITHERMAN, MD

Dr. Drabkin is a clinical editor for DynaMed (www.ebscohost.com /dynamed), a database of comprehensive updated summaries covering more than 3,200 clinical topics, and Assistant Clinical Professor of population medicine at Harvard Medical School. Dr. Smitherman is a doctor of internal medicine at Medical Clinic of North Texas and a peer reviewer for DynaMed.

Description • Metabolic findings between normal glucose homeostasis and diabetes Also called

• • • • • •

Impaired glucose tolerance (IGT) Impaired fasting glucose (IFG) Impaired fasting glycemia Abnormal glucose tolerance Glucose intolerance Latent diabetes

ICD-9 codes

• 790.21 impaired fasting glucose • 790.22 impaired glucose tolerance test (oral) • 790.29 other abnormal glucose Definitions • Prediabetes defined as any of — IGT ■ Defi ned as 2-hour 75 g oral glucose tolerance test levels 140-199 mg/dL (7.8-11 mmol/L) ■ Normal levels on this test <140 mg/dL (7.8 mmol/L) — IFG ■ Defi ned as fasting plasma glucose levels 100-125 mg/dL (5.6-6.9 mmol/L) ■ Normal fasting glucose <100 mg/dL (5.6 mmol/L) — Hemoglobin (Hb) A1c 5.7% -6.4% (may be less sensitive than IGT or IFG)

Epidemiology

• Prevalence increasing — 9.7% prevalence among U.S. adults aged 40-74 years (1988-1994) — 26% prevalence among U.S. adults aged >20 years (1999-2002) A high-fiber, low-fat diet is associated with sustained weight loss and reduced incidence of diabetes.

Causes

• Insulin resistance — Obesity (most common cause) — Type B insulin resistance Continues on page 80

78 THE CLINICAL ADVISOR • NOVEMBER 2011 • www.ClinicalAdvisor.com

Stat Consult • Insufficient insulin secretion (beta-cell dysfunction) — Possible accelerated age-related loss of beta-cell function

Physical examination

• Funduscopic exam • Foot exam (tinea, ulceration) • Distal sensation and proprioception

Likely risk factors

• Risk factors for diabetes — Metabolic conditions ■ Obesity/metabolic syndrome ■ Polycystic ovary syndrome (PCOS) ■ Gestational diabetes — Modifiable lifestyle factors ■ Dietary factors ■ Lack of exercise ■ Smoking — Demographic factors ■ Race/ethnicity » Blacks and Hispanics (in the United States) » Aborigines (in Australia) ■ Lower socioeconomic status

Making the diagnosis

• Diagnosis based on any of — Two-hour 75 g oral glucose tolerance test levels 140-199 mg/dL — Fasting plasma glucose levels 100-125 mg/dL — HbA1c levels 5.7% -6.4% • Capillary glucose may be approximately 10% higher than venous glucose. Rule out

• Drug-induced hyperglycemia • Systemic metabolic disorder — Cushing syndrome — Hyperthyroidism • Liver disease

Prognosis

• IGT and IFG associated with increased risk of — Progression to diabetes mellitus (DM) — Mortality — Cardiovascular disease History

• Usually asymptomatic (found on screening exam) • Medication use — Drug-induced hyperglycemia may occur with ■ Thiazide-type diuretics (high doses) ■ Beta blockers ■ Protease inhibitors ■ Atypical antipsychotics ■ Corticosteroids ■ Niacin ■ Pentamidine ■ Phenytoin ■ Sympathomimetic drugs • Medical history (ask about) — Hypertension, hyperlipidemia, obesity — Recurrent yeast infections — Renal disease, eye disease, neuropathy, heart disease — History of gestational diabetes, PCOS, delivery of infant with macrosomia • Family history of diabetes, coronary artery disease, kidney disease, or eye or retinal disease • Diet, exercise, substance use

Testing to consider

• • • • • •

Fasting plasma glucose HbA1c Oral glucose tolerance test Metabolic panel Liver function tests Thyroid-stimulating hormone

Lifestyle changes

• Dietary changes might reduce incidence of type 2 diabetes for patients with IGT. • Selected foods associated with reduced risk for diabetes — Whole grains ■ Brown rice may decrease and white rice may increase diabetes risk — Nuts and peanut butter — Dairy (especially low-fat) — Green vegetables, fruits and berries, margarine and oil, and poultry — Caffeinated coffee — Associations of reduced risk for diabetes with fruit and vegetable intake less consistent • High-fiber, low-fat diet associated with sustained weight reduction and reduced incidence of diabetes • Lifestyle changes can reduce incidence of diabetes more effectively than can metformin or placebo.

80 THE CLINICAL ADVISOR • NOVEMBER 2011 • www.ClinicalAdvisor.com

Continues on page 88

Stat Consult

Medications

• Lifestyle and pharmacologic interventions reduce rate of progression to type 2 DM in patients with IGT. • Antidiabetic agents that each appear to reduce rate of progression to type 2 DM — Biguanides (metformin) ■ Metformin reduces incidence of new-onset diabetes in patients with prediabetes. — Alpha-glucosidase inhibitors (acarbose, voglibose) ■ Acarbose » Evidence for delay of progression to diabetes mixed » High rate of side effects ■ Voglibose reduces development of type 2 DM in high-risk patients. — Thiazolidinediones (rosiglitazone, pioglitazone) ■ Rosiglitazone reduces incidence of diabetes in patients with IGT and no cardiovascular disease, but increases risk of heart failure (use restricted in the United States). ■ Pioglitazone may delay onset of type 2 DM (use restricted in Europe). — Combination therapies ■ Low-dose combination metformin and rosiglitazone reduces progression to type 2 DM. • Other agents — Orlistat ■ May reduce incidence of type 2 DM ■ May prevent or improve IGT in obese adults — ACE inhibitors and angiotensin receptor blockers ■ May reduce risk for new-onset type 2 DM ■ In patients with IGT, valsartan may reduce diabetes but no differences in cardiovascular outcomes.

Screening and prevention

• Screening for prediabetes followed by lifestyle intervention in overweight and obese patients is cost-effective. • Recommendations for screening — From the American Diabetes Association ■ Adults older than age 45 years ■ Adults of any age if overweight or obese (BMI ≥ 25) with any high-risk features for diabetes ■ Overweight children older than age 10 years (or after puberty onset if earlier) with two or more of the following: » Family history » Signs or conditions associated insulin resistance (acanthosis nigricans, hypertension, dyslipidemia or PCOS) » Maternal history of diabetes/gestational diabetes » Ethnic group at increased risk ■ Repeat screening every three years if normal, or every year if at increased risk for future diabetes — From the United States Preventive Services Task Force ■ Adults with BP >135/80 mm Hg — From the Canadian Task Force on Preventive Health Care ■ Adults with hypertension or hyperlipidemia. ■

• Structured education program with pedometer may be effective for improving glucose tolerance. • Lifestyle changes (with considerable support) can reduce risk for type 2 DM in patients with IGT. — Results sustained over seven years — 10-year mortality and cardiovascular morbidity not significantly different

Herbs and supplements

• Agents that may improve fasting plasma glucose — Chinese herbal medicines — Opuntia ficus-indica • Agents without documented effect — Chromium supplementation — Ginkgo biloba extract (EGb 761) 88 THE CLINICAL ADVISOR • NOVEMBER 2011 • www.ClinicalAdvisor.com

“L.L. Bean.”

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CME Dermatology Clinic CE

■ LEARNING OBJECTIVES: To increase awareness of dermatologic conditions, their diagnosis, and up-to-date treatment. ■ COMPLETE THE POSTTEST: Page 113

■ ADDITIONAL CME/CE: Pages 33, 109

CASE #1

Chest nodule with a swollen, pitted surface SUSAN WEINHOFER, RN

A solitary, oval, and nontender nodule appeared spontaneously on the chest of a boy aged 9 months. The 1.5-cm ⫻ 1.0-cm nodule was located on the lateral aspect of the left chest wall and had a yellowish-brown center and a peau d’orange surface appearance, and developed an erythematous surrounding base when palpated. The child’s history included eczema, bilateral ear infections, and wheezing with upper respiratory infections. All of the child’s immunizations were up to date. His medications included fluoride supplementation, and he had no known allergies. The child was afebrile and asymptomatic. What is your diagnosis? Turn to page 94.

CASE #2

Bleeding blister forms after thorn accident ESTHER STERN, NP-C

A white man aged 59 years presented with a “thorn blister” on his fi nger that appeared two months prior. The man worked in the produce section of a large supermarket, and he believed that he was stuck by a thorn while handling fruit, causing a red blister that initially grew rapidly but then remained stable in size. The patient reported no associated pain, itching, or numbness, although he complained that the blister frequently bled and that significant pressure and bandaging was required to stop the bleeding. There was no personal or family history of skin cancer. What is your diagnosis? Turn to page 95. www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER 2011 93

CME CE

CASE #1

Dermatology Clinic

Mastocytosis

Mastocytosis is a disorder that is characterized by mast cell proliferation with accumulation within various organs, most often the skin.1 Most children present with transient cutaneous cases. Systemic involvement is possible in children; however, it is rare.2 The major classification subgroups for childhood mastocytosis include cutaneous mastocytosis (CM), indolent systemic mastocytosis, systemic mastocytosis (SM) with an associated clonal hematologic nonmast cell linage disease, aggressive systemic mastocytosis, mast cell leukemia, mast cell sarcoma, and extracutaneous mastocytoma.1 CM in children can be classified further into four common forms: urticaria pigmentosa, mastocytoma of the skin, diffuse cutaneous mastocytosis, and telangiectasia macularis eruptiva perstans.1 Types of mastocytosis include solitary mastocytoma, paucicellular mastocytosis, and urticarial pigmentosa. Of these, urticarial pigmentosa is the most common and presents as oval or round red-brown macules, papules, or plaques numbering from a few to thousands.1 Mastocytosis affects infants and children twice as frequently as it does adults.3 Most of the patients diagnosed with mastocytosis are children, with 75% of the cases occurring in infancy or early childhood, and peaking again in patients aged 30 to 49years.1 Mastocytosis affects males and females equally, and most reported cases are in individuals of Caucasian decent.1 A diagnosis for this patient was made from the history, physical examination, and a positive Darier’s sign. When diagnosing a child with suspected mastocytosis, a thorough history and comprehensive physical examination of the skin should be completed. Documentation should include duration of the disease (noting any increases or decreases in lesions), exacerbating factors (e.g., heat, exertion, food, and medications), family history, and lesion characteristics (e.g., pruritus, erythema) 2 The Darier’s sign, induced by gently stroking, rubbing, or scratching a small area of the affected skin, should be performed on any suspicious areas.1-4 A positive sign is the development of erythema over or around the lesion and indicates the presence of mast cells within the lesion. This change is attributable to the mast cell degranulation induced by the physical stimulation.1 To prevent progression

to generalized flushing and hives, uncontrolled rubbing or scratching of mastocytomas should be avoided in those with a history of a systemic reaction.1 The Dariers’s sign is highly specific for mastocytosis. In combination with clinical findings, it may be more accurate than a skin biopsy.3 A 3-mm punch biopsy is useful when the diagnosis is unclear. Specimens should be placed in formalin and undergo histopathologic staining with Giemsa.2,4 Further testing may include a complete blood count with differential, liver function tests, plasma or urinary histamine levels, and serum tryptase. Bone marrow biopsies are not usually performed in children but may be done if the fi ndings suggest SM; if there are abnormalities on the blood count; or if hepatomegaly, splenomegaly, or lymphadenopathy are noted.2,4,5 Differential diagnoses include carcinoid, lentigo, herpes simplex, linear immunoglobulin A dermatosis, lymphocytoma cutis, cutaneous pseudolymphoma, epidermis

Documentation should include duration of the disease, exacerbating factors, family history, and lesion characteristics. bullosa, macular amyloidosis, nodular localized cutaneous amyloidosis, melanocytic naevi, xanthomas, or juvenile xanthogranulomas. Most children experience complete regression of symptoms by puberty with no systemic involvement. The prognosis depends on the age of onset. Individuals who exhibit signs before age 2 years often have an excellent prognosis, with resolution by puberty. Those with onset after age 10 years tend to have a poorer prognosis; the mastocytosis tends to be more persistent, is often associated with systemic findings, and carries a higher risk of malignant transformation.1 There is no cure for mastocytosis, and treatment is aimed at symptomatic relief and avoidance of triggers. Histamine 1 (H1) and histamine 2 (H2) blockers are useful in decreasing pruritus and flushing. Oral disodium cromoglycate is another option to alleviate pruritus, whealing, and flushing. Additionally, epinephrine auto-injectors (EpiPens) are often prescribed for potential anaphylaxis due to excessive mast cell mediator release.6 Advise patients to avoid medications that may precipitate mediator release. Triggers include but are not limited to medications (e.g., morphine, codeine, aspirin, nonsteroidal anti-inflammatory drugs, polymyxin B, vancomycin

94 THE CLINICAL ADVISOR • NOVEMBER 2011 • www.ClinicalAdvisor.com

[Vancocin], quinine), neuromuscular blocking agents (i.e., succinylcholine [Anectine], tubocurarine, scopolamine [Transderm Scop], pancuronium [Pavulon]), and all types of radiographic contrast media.1,2,5 Measures should be taken to avoid dietary and physical triggers. Foods that induce mast cell mediator release (e.g., hot/spicy foods, alcohol, cheese, shellfish, hot drinks, and food containing metabisulfites) should be avoided.1,2,5 Other triggers include such physical stimuli as emotional stress, temperature extremes, physical exertion, and excessive rubbing of the skin.1 Education should be aimed at the avoidance of physical triggers and other substances that can initiate a reaction. Individuals with mastocytosis should be informed of the importance of notifying all health-care personnel of the diagnosis so that appropriate measures can be taken to avoid triggers and ensure safety. The child in this case was treated symptomatically with H1 antihistamines, given an EpiPen kit, and followed yearly. The parents were educated regarding the diagnosis and triggers and given instructions about how and when to use the EpiPen. The child’s mastocytoma resolved over weeks, and he had no further lesions or systemic involvement. ■ Ms. Weinhofer is enrolled in the Family Nurse Practitioner program at Carlow University in Pittsburgh. After completing the program in December, she will work in a pediatric primary-care office in Greensburg, Pa. The author has no relationships to disclose regarding the content of this article.

CASE #2

Pyogenic granuloma

Clinical examination of the lesion revealed a 7-mm friable erythematous nodule with a thin collarete of scale at the periphery, located on the lateral aspect of the left index finger. The patient was advised to have a shave biopsy done, allowing for removal of the lesion and confirmation of the clinical diagnosis pyogenic granuloma (PG). Also known as a lobular capillary hemangioma, PG is a very common benign proliferation of blood vessels within the skin or mucous. The condition was first described in 1897 by two French surgeons. Despite its name, a PG is neither pyogenic/infectious nor granulomatous. The lesion typically grows quickly and is thus often suspected to be a cutaneous malignant tumor. It evolves into a semi-fi rm, red, exophytic papule or nodule. The overlying skin may be intact, ulcerated, or broken, at times forming a unique collarete surrounding the lesion. Although asymptomatic, patients may complain of profuse bleeding that occurs spontaneously or from minor indirect trauma to the lesion. PG occurs most often on the fingers, hands, upper trunk, and face. In addition, it is seen rather frequently in the oral cavity. PG is the most common benign tumor of the gingiva.1 Other common sites in the oral cavity include the

References 1. Medscape Reference. Mastocytosis. Available at emedicine.medscape. com/article/1057932-overview. 2. Heide R, Beishuizen A, De Groot H, et al. Mastocytosis in children: a protocol for management. Pediatr Dermatol. 2008;25:493-500. 3. Hannaford R, Rogers M. Presentation of cutaneous mastocytosis in 173

Several smaller satellite lesions may emerge after the appearance—or even disappearance—of the primary lesion.

children. Australas J Dermatol. 2001;42:15-21. 4. UpToDate. Evaluation and diagnosis of mastocytosis (cutaneous and systemic). Available at www.uptodate.com/contents/evaluation-anddiagnosis-of-mastocytosis-cutaneous-and-systemic. 5. UpToDate. Treatment and prognosis of cutaneous mastocytosis. Available at www.uptodate.com/contents/treatment-and-prognosis-ofcutaneous-Mastocytosis. 6. Brockow K, Jofer C, Behrendt H, Ring J. Anaphylaxis in patients with mastocytosis: a study on history, clinical features and risk factors in 120 patients. Allergy. 2008;63:226-232. All electronic documents accessed October 15, 2011.

lips, tongue, and buccal mucosa. Rarely, PG may proliferate internally in the GI tract, larynx, or cornea. At times, several smaller satellite lesions may emerge after the appearance—or even disappearance—of the primary lesion.2 Incidence is greatest in school-aged children and young adult women, although the condition may occur at any age. There is a slightly increased prevalence in the female sex. Although PG has no defi nite known cause, mechanical trauma is often reported to occur prior to onset, and this may explain the frequent incidence of lesions in areas prone

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER 2011 95

CME CE

Dermatology Clinic

to trauma, particularly the hands and mouth. Similarly, PGs have been reported to occur on the penile shaft following circumcision.3 An embedded foreign body is commonly discovered to be the cause of a recurring PG. Hormonal changes, such as those that occur with pregnancy or oral contraceptive use, are also associated with the development of PG. Granuloma gravidarum and pregnancy tumor are unique descriptions used for lesions occurring during preg-

Although spontaneous resolution has been known to occur, surgical removal is the recommended treatment. nancy that are typically seen on the oral mucosa or gingiva and generally occur in the second or third trimesters.4 Systemic retinoids, used in the treatment of several chronic dermatologic conditions, and indinavir (Crixivan), used in antiretroviral therapy, have also been implicated in its pathogenesis. Rare cases of numerous exuberant PGs have been described in patients being treated with isotretinoin (Accutane) for acne vulgaris.5 There is controversy as to whether infection with the Bartonella species plays an etiologic role.6 Because the presentation of a PG can mimic that of other benign conditions (e.g., cherry angioma, glomus tumor, bacillary angiomatosis) or more serious malignant conditions (e.g., amelanotic malignant melanoma, Kaposi’s sarcoma, Spitz nevus, basal cell carcinoma), microscopic confirmation of the diagnosis is imperative. Histopathologic findings of lobules of capillaries and venules separated by edematous septa with a mixed inflammatory cell infi ltrate are characteristic of a PG. Although spontaneous resolution has been known to occur, surgical removal is the recommended treatment. Shave biopsy is generally the preferred option, allowing for acceptable cosmetic outcome and histopathologic analysis of the specimen. After removal, electrodessication of the base of the lesion is recommended to control bleeding, and studies have suggested that it may prevent recurrences. Recurring PGs (a common phenomenon) that are refractory to standard treatments are best removed with a full-thickness skin excision. Second-line treatments include pulsed dye laser therapy, silver nitrate cautery, cryotherapy, and sclerotherapy with monoethanolamine oleate. Topical medications that have been tried with varying success include imiquimod (Aldara)

and tretinoin. Systemic steroids may be indicated for recurrent giant PG or for lesions with significant satellitosis. If a medication has been implicated as the trigger, cessation of the medication may induce spontaneous regression. Granuloma gravidarum may resolve after parturition. Patients should be advised that PG is a benign tumor, and histopathology will confirm the diagnosis. After treatment, the surgical sites should be monitored closely for uncontrolled bleeding or signs of infection. If evidence of recurrence appears, patients should return promptly for treatment. If a medication has been implicated as a cause, patients should be educated to be cautious with future usage. The patient in this case was treated with shave removal of the lesion, and histopathology confi rmed the diagnosis of PG. Three months later, he returned with recurrence— albeit smaller in size—of the primary lesion. Various treatment options were discussed, and the patient opted for repeat shave removal with thorough needle hyfrecation of the base. The lesion was treated successfully with a minimal scar now evident at the site. ■ Ms. Stern is a family nurse practitioner at Advanced Dermatology & Skin Surgery, P.C., in Lakewood, N.J. The author has no relationships to disclose regarding the content of this article. References 1. Jafarzadeh H, Sanatkhani M, Mohtasham N. Oral pyogenic granuloma: a review. J Oral Sci. 2006;48:167-175. 2. Zaynoun ST, Juljulian HH, Kurban AK. Pyogenic granuloma with multiple satellites. Arch Dermatol. 1974;109:689-691. 3. Paller AS, Mancini AJ. Hurwitz Clinical Pediatric Dermatology. 4th ed. Philadelphia, Pa.: Elsevier Saunders; 2011:281-282. 4. James WD, Berger TG, Elston DM. Errors in metabolism. In: Andrews’ Diseases of the Skin: Clinical Dermatology. 10th ed. Philadelphia, Pa.: Saunders-Elsevier; 2006:808. 5. James WD, Berger TG, Elston DM. Errors in metabolism. In: Andrews’ Diseases of the Skin: Clinical Dermatology. 10th ed. Philadelphia, Pa.: Saunders-Elsevier; 2006:592. 6. Lee J, Lynde C. Pyogenic granuloma: pyogenic again? Association between pyogenic granuloma and Bartonella. J Cutan Med Surg. 2001; 5:467-470.

MORE DERMATOLOGY ON THE WEB Test your diagnostic skills. Our FREE archive of Dermatology Clinic and Dermatologic Look-Alikes is now available online at www.ClinicalAdvisor.com/Derm.

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Clinical Challenge Acute onset of pain and a noncompressible area in the anterior forearm LINDSEY BARKSON, MSN, FNP-BC

After a high-impact fall, a middle-aged firefighter presents with ecchymosis and fixed flexion in the right arm and hand.

A 42-year-old, right-handed man presented to the emergency department (ED) with increasing pain and weakness in his dominant forearm. Six days earlier, Mr. J, a firefighter, had fallen through a window, landing on his outstretched right arm while on the job. Mr. J reported hearing a pop when he fell, but did not think it was anything serious; he reported no sustained lacerations. Mr. J continued to work after the accident, but pain in his right arm increased over the next few days. He came to the ED when he began to find it hard to make a fist with his right hand.

CASE #1

1. PHYSICAL EXAMINATION

FIGURE 1. Ecchymosis and moderate edema on ulnar side of the elbow

Initial survey showed significant ecchymosis and moderate edema on the volar and ulnar sides of the right wrist and the ulnar side of the elbow (Figure 1). Mr. J. reported pain with palpation over right distal radius and distal ulna on the volar side. This area was hard to the touch and not compressible. Begining mid-forearm and extending proximally, the volar and dorsal sides of the forearm were soft and compressible. Mr. J reported pain with active and passive supination, extension, and flexion of his right wrist. Fingers on his right hand were fixed in flexion and Mr. J was unable to actively extend them. When passively extended, he reported increased but tolerable pain. When we tested nerve function in the right hand, Mr. J could not make the “OK” sign, cross his fingers, or abduct fingers. He reported normal feeling to light touch in the right upper extremity. Radial and ulnar pulses were intact: capillary refill time was normal. Mr. J had full active and passive range of motion in the right elbow, without pain. X-rays of the forearm, wrist, and hand were unremarkable.

2. HISTORY

FIGURE 2. An immediate fasciotomy was performed with incision extending from the medial aspect of the proximal forearm distally over the transverse carpal ligament.

Mr. J has a history of primary antiphospholipid antibody syndrome, a condition characterized by vascular thromboses.1 He is currently taking

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER 2011 97

Clinical Challenge aspirin and fondaparinux sodium (Arixtra) daily for anticoagulation. Mr. J’s history reveals that he has been treated for several deep vein thromboses and a pulmonary embolism. In addition, since becoming a firefighter, Mr. J has had bleeding in the thigh, which was treated nonoperatively. He is under the supervision of a hematologist, and reports that his syndrome is well managed with current protocol.

3. DIFFERENTIAL DIAGNOSIS Differential diagnoses for Mr. J included fracture, muscle contusion, torn ligament, and compartment syndrome. Fracture was ruled out with negative films. Muscle contusion did not explain the severe pain and inability to actively range fingers. It was thought a muscle or ligament tear could cause hemorrhaging leading to noncompressible compartment syndrome. However, this did not explain the hard forearm compartment. Compartment syndrome was suspected immediately due to a hard, noncompressible anterior compartment of the forearm. However, Mr. J did not present as one would expect a person with compartment syndrome to present. He was able to tolerate the pain associated with passive extension of his right fingers. He was also able to actively flex and extend his wrist with only moderate pain. In addition, he had intact sensation and intact radial and ulnar pulses. To confirm the suspected diagnosis of compartment syndrome, a Stryker quick-pressure monitor (a side-port needle) was inserted and revealed an anterior compartment pressure of 87 mm Hg. It was suspected that Mr. J had torn his flexor carpi radialis and that his anticoagulant therapy led to a bleed in the forearm, causing compartment syndrome.

4. TREATMENT AND OUTCOME In the ED, Mr. J consented to an emergency fasciotomy and carpal tunnel release. In surgery, a long incision was made from the medial aspect of the proximal forearm, extending distally over the transverse carpal ligament into the proximal palm (Figure 2). Once the overlying fascia was incised, there was an immediate softening and decompression of the compartment proximally. Distally, the muscle showed evidence of extreme edema and it immediately herniated through the initial fasciotomy. All compartments were decompressed, and all muscle in the proximal and distal forearm appeared to be viable and healthy. No evidence of a muscle or ligament tear was found in the forearm. Sutures were placed to close the carpal tunnel, and one loose suture was placed proximally to cover the median

nerve. A sterile bandage and a splint were placed, and Mr. J was admitted to hospital. On postoperative day one, Mr. J had no pain and had regained the ability to actively flex his fingers on the right side. He was also able to cross his fingers, make an “OK” sign, and abduct fingers, showing that his ulnar, median, and radial nerves were intact. He was not able to actively extend fingers, but had no pain with passive extension. Once the edema recedes, presumably in a five-day period, Mr. J will go back to the operating room for delayed primary closure of fasciotomy wounds. Our anticipation is that he will make a full recovery, since the compartment syndrome was found and decompressed before muscle necrosis occurred.

5. DISCUSSION Compartment syndrome is caused by an increase in intracompartmental pressure within a confined space, causing oxygen deprivation and resulting in cell damage.2 Early identification of compartment syndrome is critical to avoid amputation or even death.3 Compartment syndrome is most commonly seen in the forearm or lower leg after a traumatic, high-impact injury.2 Compartments are made up of a group of tissues and their associated nerves and vessels, covered and contained by a fascia.4 The fascia is not elastic and therefore does not allow for an increase in the compartment volume or pressure.3 Compartment syndrome occurs when the pressure in one of these compartments increases greatly as a result of swelling and/or hemorrhage.3 This usually occurs after a traumatic injury, but can also be associated with surgery, compressive bandages, casts, fractures, burns, snake or spider bites, crush injuries or electrical injuries.2,4,5 An increase in compartment pressure leads to vessel collapse, causing decreased blood flow to the cells in the area. If not addressed quickly, ischemia can occur, leading to more edema and cell death.6 Eventually, if not treated, necrosis will occur resulting in rhabdomyolysis. In severe cases, this can lead to renal failure, multi-organ failure, and death.6 Diagnosing compartment syndrome is based on a careful history, a through physical exam, and a high index of suspicion due to the mechanism of injury.5 The most common

WHAT’S YOUR STORY? Do you have your own clinical challenge? Your colleagues would love to read about it. Go to www.ClinicalAdvisor.com and check out our writers’ guidelines.

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Visit myCME.com for complimentary CME/CE activities symptom of acute compartment syndrome (ACS) is severe pain that is out of proportion to the clinical picture.4 Patients with compartment syndrome also generally have pain with passive extension of the muscle compartment, altered sensation, muscle weakness, and tense, tender compartments.5 Several techniques can measure the intracompartmental pressure. The two most widely used are invasive devices: the slit-catheter and the side-port needle.2 Prompt treatment is necessary to avoid contractures, amputation, multi-organ failure, and possible death.5 Nonsurgical treatments include immediate removal of casts, compressive dressings, tourniquets, or splints.6 The affected extremity should be elevated to heart level, but no higher, to ensure maximum perfusion while decreasing swelling.2 Immediate fasciotomy is the standard treatment for ACS.2 The goal is to decompress the affected compartments before muscle necrosis.2 In the forearm, fasciotomies are performed on both the dorsal and volar aspects with extension into the carpal tunnel.2 Compartment syndrome can be devastating if not treated quickly and correctly. It is usually the result of high-impact trauma. The most important factors in diagnosing compartment syndrome in a patient are a thorough physical exam and detailed history, coupled with a high degree of suspicion. Decompression with fasciotomy is the definitive way to ensure a satisfactory outcome. ■ Ms. Barkson is a family nurse practitioner specializing in hand and orthopedic trauma at Riverside Methodist Hospital in Columbus, Ohio.

CLINICIAN GUIDE Identifying and Co-Managing the HIV-Infected Adult www.myCME.com

CLINICAL CASES

HIV Testing for a Female High School Student AND Opt-Out Testing in Pregnancy www.myCME.com OVERALL LEARNING OBJECTIVES*

2. Konstantakos EK, Dalstrom DJ, Nelles ME, et al. Diagnosis and manage-

Upon completion of this program, participants should be better able to: t Describe the rationale for implementing “opt-out” HIV testing, as recommended by the CDC t Implement initial treatment decisions for a patient newly diagnosed with HIV t Discuss the importance of opt-out HIV testing for pregnant women, to prevent mother-to-child transmission

ment of extremity compartment syndrome: An orthopaedic perspective.

*For a complete listing of learning objectives, please see each individual activity

References 1. Favaloro, EJ, Wong RW. Laboratory testing for the antiphospholipid syndrome: making sense of antiphospholipid antibody assays. Clin Chem Lab Med. 2011;49:447-461.

Am Surg. 2007;73:1199-1209. 3. Wright E. Neurovascular impairment and compartment syndrome.

FACULTY

Paediatr Nurs. 2009;21:26-29.

Albert Einstein College of Medicine

4. Bucholz RW, Court-Brown CM, Heckman JD, Tornetta III P. Rockwood

Jason Leider, MD, PhD (Chair) Susan F. LeLacheur, DrPH, PA-C

and Green’s Fractures in Adults: Vol. 1, 7th ed. Philadelphia, Pa.: Lippincott

The George Washington University School of Medicine

Williams & Wilkins; 2010:689-703.

Julie Stewart, DNP, MSN, MPH, FNP-BC

5. Malik AA, Khan WS, Chaudhry A, et al. Acute compartment syn-

Sacred Heart University

drome—a life and limb threatening surgical emergency. J Perioper Pract. 2009;19:137-142.

Sponsored by

6. Burkhart KJ, Mueller LP, Prommersberger KJ, Rommens PM. Acute compartment syndrome of the upper extremity. Eur J Trau Emer Surg. 2007;33:584-588. Supported by educational grants from

Derm Dx

EXCLUSIVE TO THE WEB

INTERACT WITH YOUR PEERS by viewing the images and offering your diagnosis and comments. To post your answer, obtain more clues, or view similar cases, visit ClinicalAdvisor.com/DermDx. Learn more about diagnosing and treating these conditions, and see how you compare with your fellow colleagues.

Reticulated erythema on the lumbar back A 36-year-old woman presented for evaluation of a blanchable, mottled rash on her lower back and bilateral flanks after a surgery. WHAT IS YOUR DIAGNOSIS?

• • • •

Allergic reaction to device Erythema ab igne Trauma secondary to surgical procedure Panniculitis

● See the full case at ClinicalAdvisor.com/DermDx1011A

Papules on a healthy young athlete’s groin An otherwise healthy 24-year-old man presented complaining of asymptomatic lesions on his groin for the past two months. He is an avid bicyclist and attributed the lesions to irritation from the friction of his bicycle seat and clothing. WHAT IS YOUR DIAGNOSIS?

• • • • •

Folliculitis Condyloma acuminata Lichen planus Molluscum contagiosum Phthiriasis pubis

● See the full case at ClinicalAdvisor.com/DermDx1011B

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

Fine, dry scales on the trunk and extremities

100 THE CLINICAL ADVISOR • NOVEMBER 2011 • www.ClinicalAdvisor.com

Intermittent, malodorous, pruritic skin lesions

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 with the latest information about conditions seen in everyday practice. Running no more than 2,500 words, 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, for which we pay extra. Charts, tables, and algorithms are also encouraged. References are optional; if you opt not to use any, please provide a recommended reading list of books, articles, and Web sites. In addition, include your curriculum vitae, which should list all current titles and affi liations. 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. We pay extra for any photographs or images that we use. The length should be about 1,500 words. Please include your title, affi liations, and curriculum vitae. 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 brief description of the patient and/or his 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, how the correct diagnosis was achieved, 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. COMMENTARY is our guest editorial page. It gives you the opportunity to sound off on an issue of importance to your colleagues nationwide. Support your views with as many facts, statistics, studies, and personal anecdotes as possible. A typical Commentary runs about 700 words in length. To discuss your editorial ideas, contact us by phone at 646.638.6077; by e-mail to editor@clinicaladvisor.com; or by mail to: The Clinical Advisor, 114 West 26th Street, 4th Floor, New York, NY 10001.

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LEGAL ADVISOR CASE

The simplest rules almost always apply

BY ANN W. LATNER, JD

Ms. B realized instinctively—moments into her interview—that this was the job she wanted. At age 27, the young NP listened carefully as Dr. Y, her prospective employer and a 56-yearold pediatrician, described the often difficult working conditions in his small clinic. She was not deterred by the fact that Dr. Y’s practice was set in the heart of a depressed, urban area, where many patients were so poor they were unable to follow the simplest of recommendations. Nor was she put off by the overcrowded waiting room or the long work hours he described. For her, this was the chance of a lifetime—the opportunity to give something back. Ms. B had grown up in a neighborhood much like this one. She felt a different texture here, but the telltale markings were the same: constant hardship, abject difficulty, and loss. Ms. B remembered her mother’s constant focus to obliterate the obstacles that prevented her from going to school, from enjoying a life filled with professional meaning—and she knew this was where she wanted to be. But one crisp September morning two years into her career at the clinic, a phone call changed

A young clinician working in a depressed area gives advice over the phone— advice that causes harm.

The phone call came from a distressed mother asking for help: Her baby is vomiting, feverish, and crying nonstop.

104 THE CLINICAL ADVISOR • NOVEMBER 2011 • www.ClinicalAdvisor.com

everything. Ms. B had just come on duty when the mother of a 21-month-old child called the practice looking for advice. Mrs. R’s baby was throwing up, feverish, and wouldn’t stop crying. Mrs. R also reported that her son was unwilling even to try to stand or walk. “Should I bring him in?” she asked. “No,” Ms. B said to the mother. “It sounds like influenza. You don’t need to come in now. He should get better in a few days.” It had not taken long for Ms. B’s idealism to wane. Under pressure, she had gradually found herself adopting a more hardened attitude towards patients who used the practice as an emergency clinic or tried to get free medical help over the telephone. Early in her tenure at the clinic, Dr. Y informed Ms. B that she needed to cut back on the amount of time she spent with each patient. Continues on page 108

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.

LEGAL ADVISOR “I appreciate your efforts,” Dr. Y began, “but we have too many patients and too little time to see them all.” After that, Ms. B began speeding up her examinations as she tried to comply with Dr. Y’s suggestion that she spend 15 minutes or less per patient when possible. Three days after that initial phone call, Mrs. R showed up in the office with her baby boy, who was still quite sick. Ms. B was with a patient, but briefed Dr. Y on the phone conversation and the flulike symptoms that Mrs. R had described. Dr. Y was harried; his earlier appointments had taken longer than expected, and he was running behind.

Knowing which symptoms can be left untreated and which warrant attention can be challenging—even face-to-face. He rushed mother and child into an exam room and made a cursory examination of the baby, who screamed loudly when his abdomen was palpated. A few minutes later, Mrs. R and her son left the clinic. Ms. B was too busy to ask Dr. Y what he had diagnosed, and by the next day, she’d forgotten about it—until the local hospital called. “That was the hospital,” a shaken Ms. B told Dr. Y. “Baby R died today. They say it was acute appendicitis.” Extremely upset by losing her first patient—a baby at that—it took Ms. B several months to recover. And just when routine normalcy was settling in again, Dr. Y was served with papers. Mrs. R was suing him for negligence in the death of her child. In addition, as Ms. B’s employer, the suit claimed he was indirectly responsible for medical advice delivered over the phone. The coroner’s report was introduced at trial; the cause of death was acute appendicitis, which had been gangrenous for two to six days. The heartbroken mother testified about how she had relied on the NP’s phone diagnosis of influenza, and held off on bringing her child to the doctor for three days because of that diagnosis. Mrs. R also testified that when she did bring the baby in, Dr. Y spent only a few minutes examining the child and he ignored the fact that the baby screamed loudest when his stomach area was touched. “They told me my boy had the flu,” the mother sobbed, “and that I should take him home to rest. But the next day he was dead.” When Ms. B was called to testify, she described her initial conversation with Mrs. R in detail.

“Do you generally make diagnoses without even seeing the patient?” asked the plaintiff ’s attorney. “Well… sometimes,” Ms. B murmured. “Do you think you can adequately diagnose a patient on the phone,” opposing counsel pressed, “especially a baby who can’t describe his own symptoms?” After Ms. B spent an uncomfortable hour on the stand, it was Dr. Y’s turn. The plaintiff’s attorney grilled him about the little time he spent with the boy. Although Dr. Y’s attorney did what he could to diffuse the situation, the facts—the cursory exam, the incorrect phone diagnosis—were damning. The jury returned almost immediately with a guilty verdict and awarded $1.25 million in damages. Legal background

Ms. B was not personally sued in this case, even though the plaintiff’s attorney alleged that she was negligent in her phone diagnosis. Instead, the decision was made to sue Dr. Y, both for his own negligence in treating the patient and as Ms. B’s employer. As a general rule, physicians have larger malpractice insurance limits than nurses, so suing the physician is a tactical decision on the part of the plaintiff’s attorney. Protecting yourself

Making a diagnosis on the phone can be dangerous, yet clinicians get calls all the time asking for help with seemingly routine problems. Knowing which symptoms can be left untreated and which warrant attention can be challenging—even in a face-to-face examination. While the fever and vomiting certainly could have been signs of a viral illness, the child’s unwillingness to stand (or walk) might have been a clue that he was suffering from something else. It is important, even when discussing symptoms over the phone, to ask as many questions as necessary: “How long has the child had fever? Is his abdomen swollen or tender? Does he cry more when you touch one side of his stomach?” Aside from probing further, Ms. B should have insisted that the child be brought in for examination if he didn’t improve the next day. Appendicitis is a fairly common pediatric ailment, and it can complicate soon after occurrence. Urgent medical care is often required, as the appendix can burst within one or two days after symptom onset. Lastly, Dr. Y’s negligence in not giving a thorough examination in inexcusable. Taking the time needed to properly evaluate each patient is fundamental, despite the economic pressures of practicing medicine today. ■ Ms. Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.

108 THE CLINICAL ADVISOR • NOVEMBER 2011 • www.ClinicalAdvisor.com

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24 2 4

HRS H RS

DEXILANT 30 mg provides effective maintenance of EE healing • 66% of patients remained healed over 6 months with DEXILANT 30 mg (n=125) vs 14% with placebo (n=119; p<0.00001). Study primary endpoint.1,2 Results of a 6-month, multicenter, double-blind, placebo-controlled, randomized study of patients who had successfully completed an EE study and showed endoscopically confirmed healed EE. Based on crude rate estimates, patients who did not have endoscopically documented relapse and prematurely discontinued were considered to have relapsed.

Conclusions of comparative efficacy cannot be drawn from this information. Indications DEXILANT is indicated for healing all grades of erosive esophagitis (EE) for up to 8 weeks, maintaining healing of EE and relief of heartburn for up to 6 months, and treating heartburn associated with symptomatic non-erosive gastroesophageal reflux disease (GERD) for 4 weeks.

Average patient costs for DEXILANT are less than all other branded Rx PPIs†‡§ †Based on average out-of-pocket costs for commercially insured patients.

Cost comparisons do not imply comparable safety, efficacy, or FDA-approved indications.

Important Safety Information DEXILANT is contraindicated in patients with known hypersensitivity to any component of the formulation. Hypersensitivity and anaphylaxis have been reported with DEXILANT use. Symptomatic response with DEXILANT does not preclude the presence of gastric malignancy. Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Hypomagnesemia has been reported rarely with prolonged treatment with PPls. Most commonly reported adverse reactions were diarrhea (4.8%), abdominal pain (4.0%), nausea (2.9%), upper respiratory tract infection (1.9%), vomiting (1.6%), and flatulence (1.6%). Do not co-administer atazanavir with DEXILANT because atazanavir systemic concentrations may be substantially decreased. DEXILANT may interfere with absorption of drugs for which gastric pH is important for bioavailability (e.g., ampicillin esters, digoxin, iron salts, ketoconazole). Patients taking concomitant warfarin may require monitoring for increases in international normalized ratio (INR) and prothrombin time. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Concomitant tacrolimus use may increase tacrolimus whole blood concentrations. Please see adjacent brief summary of prescribing information for DEXILANT. ‡ Wolters Kluwer Pharma Solutions, Dynamic Claims, ≤30 days supply, commercial plans only, September 2010–March 2011. §Average commercial patient cost for a 30-day prescription represents patient out-of-pocket expenses after use of programs such as electronic vouchers and Instant Savings cards.

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Median percentage of 24-hour heartburn-free periods of the maintenance of healed EE study—overall treatment1,2

CONTRAINDICATIONS DEXILANT is contraindicated in patients with known hypersensitivity to any component of the formulation. Hypersensitivity and anaphylaxis have been reported with DEXILANT use [see Adverse Reactions]. WARNINGS AND PRECAUTIONS Gastric Malignancy Symptomatic response with DEXILANT does not preclude the presence of gastric malignancy. Bone Fracture Several published observational studies suggest that proton pump inhibitor (PPI) therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines [see Adverse Reactions]. Hypomagnesemia Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI. For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically [see Adverse Reactions]. ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of DEXILANT was evaluated in 4548 patients in controlled and uncontrolled clinical studies, including 863 patients treated for at least 6 months and 203 patients treated for one year. Patients ranged in age from 18 to 90 years (median age 48 years), with 54% female, 85% Caucasian, 8% Black, 4% Asian, and 3% other races. Six randomized controlled clinical trials were conducted for the treatment of EE, maintenance of healed EE, and symptomatic GERD, which included 896 patients on placebo, 455 patients on DEXILANT 30 mg, 2218 patients on DEXILANT 60 mg, and 1363 patients on lansoprazole 30 mg once daily. Most Commonly Reported Adverse Reactions The most common adverse reactions (≥2%) that occurred at a higher incidence for DEXILANT than placebo in the controlled studies are presented in Table 2. Table 2: Incidence of Adverse Reactions in Controlled Studies Placebo DEXILANT DEXILANT DEXILANT Lansoprazole 30 mg 60 mg Total 30 mg (N=896) (N=455) (N=2218) (N=2621) (N=1363) Adverse Reaction % % % % % Diarrhea 2.9 5.1 4.7 4.8 3.2 Abdominal Pain 3.5 3.5 4.0 4.0 2.6 Nausea 2.6 3.3 2.8 2.9 1.8 Upper Respiratory 0.8 2.9 1.7 1.9 0.8 Tract Infection Vomiting 0.8 2.2 1.4 1.6 1.1 Flatulence 0.6 2.6 1.4 1.6 1.2 Adverse Reactions Resulting in Discontinuation In controlled clinical studies, the most common adverse reaction leading to discontinuation from DEXILANT therapy was diarrhea (0.7%). Other Adverse Reactions Other adverse reactions that were reported in controlled studies at an incidence of less than 2% are listed below by body system: Blood and Lymphatic System Disorders: anemia, lymphadenopathy; Cardiac Disorders: angina, arrhythmia, bradycardia, chest pain, edema, myocardial infarction, palpitation, tachycardia; Ear and Labyrinth Disorders: ear pain, tinnitus, vertigo; Endocrine Disorders: goiter; Eye Disorders: eye irritation, eye swelling; Gastrointestinal Disorders: abdominal discomfort, abdominal tenderness, abnormal feces, anal discomfort, Barrett’s esophagus, bezoar, bowel sounds abnormal, breath odor, colitis microscopic, colonic polyp, constipation, dry mouth, duodenitis, dyspepsia, dysphagia, enteritis, eructation, esophagitis, gastric polyp, gastritis,

gastroenteritis, gastrointestinal disorders, gastrointestinal hypermotility disorders, GERD, GI ulcers and perforation, hematemesis, hematochezia, hemorrhoids, impaired gastric emptying, irritable bowel syndrome, mucus stools, oral mucosal blistering, painful defecation, proctitis, paresthesia oral, rectal hemorrhage, retching; General Disorders and Administration Site Conditions: adverse drug reaction, asthenia, chest pain, chills, feeling abnormal, inflammation, mucosal inflammation, nodule, pain, pyrexia; Hepatobiliary Disorders: biliary colic, cholelithiasis, hepatomegaly; Immune System Disorders: hypersensitivity; Infections and Infestations: candida infections, influenza, nasopharyngitis, oral herpes, pharyngitis, sinusitis, viral infection, vulvo-vaginal infection; Injury, Poisoning and Procedural Complications: falls, fractures, joint sprains, overdose, procedural pain, sunburn; Laboratory Investigations: ALP increased, ALT increased, AST increased, bilirubin decreased/increased, blood creatinine increased, blood gastrin increased, blood glucose increased, blood potassium increased, liver function test abnormal, platelet count decreased, total protein increased, weight increase; Metabolism and Nutrition Disorders: appetite changes, hypercalcemia, hypokalemia; Musculoskeletal and Connective Tissue Disorders: arthralgia, arthritis, muscle cramps, musculoskeletal pain, myalgia; Nervous System Disorders: altered taste, convulsion, dizziness, headaches, migraine, memory impairment, paresthesia, psychomotor hyperactivity, tremor, trigeminal neuralgia; Psychiatric Disorders: abnormal dreams, anxiety, depression, insomnia, libido changes; Renal and Urinary Disorders: dysuria, micturition urgency; Reproductive System and Breast Disorders: dysmenorrhea, dyspareunia, menorrhagia, menstrual disorder; Respiratory, Thoracic and Mediastinal Disorders: aspiration, asthma, bronchitis, cough, dyspnoea, hiccups, hyperventilation, respiratory tract congestion, sore throat; Skin and Subcutaneous Tissue Disorders: acne, dermatitis, erythema, pruritis, rash, skin lesion, urticaria; Vascular Disorders: deep vein thrombosis, hot flush, hypertension Additional adverse reactions that were reported in a long-term uncontrolled study and were considered related to DEXILANT by the treating physician included: anaphylaxis, auditory hallucination, B-cell lymphoma, bursitis, central obesity, cholecystitis acute, dehydration, diabetes mellitus, dysphonia, epistaxis, folliculitis, gout, herpes zoster, hyperlipidemia, hypothyroidism, increased neutrophils, MCHC decrease, neutropenia, rectal tenesmus, restless legs syndrome, somnolence, tonsillitis. Other adverse reactions not observed with DEXILANT, but occurring with the racemate lansoprazole can be found in the lansoprazole prescribing information, ADVERSE REACTIONS section. Postmarketing Experience The following adverse reactions have been identified during post-approval of DEXILANT. As these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders: autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura Ear and Labyrinth Disorders: deafness Eye Disorders: blurred vision Gastrointestinal Disorders: oral edema, pancreatitis General Disorders and Administration Site Conditions: facial edema Hepatobiliary Disorders: drug-induced hepatitis Immune System Disorders: anaphylactic shock (requiring emergency intervention), exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis (some fatal) Metabolism and Nutrition Disorders: hypomagnesemia, hyponatremia Musculoskeletal System Disorders: bone fracture Nervous System Disorders: cerebrovascular accident, transient ischemic attack Renal and Urinary Disorders: acute renal failure Respiratory, Thoracic and Mediastinal Disorders: pharyngeal edema, throat tightness Skin and Subcutaneous Tissue Disorders: generalized rash, leucocytoclastic vasculitis DRUG INTERACTIONS Drugs with pH-Dependent Absorption Pharmacokinetics DEXILANT causes inhibition of gastric acid secretion. DEXILANT is likely to substantially decrease the systemic concentrations of the HIV protease inhibitor atazanavir, which is dependent upon the presence of gastric acid for absorption, and may result in a loss of therapeutic effect of atazanavir and the development of HIV resistance. Therefore, DEXILANT should not be co-administered with atazanavir. DEXILANT may interfere with the absorption of other drugs where gastric pH is an important determinant of oral bioavailability (e.g., ampicillin esters, digoxin, iron salts, ketoconazole). Warfarin Co-administration of DEXILANT 90 mg and warfarin 25 mg did not affect the pharmacokinetics of warfarin or INR [see Clinical Pharmacology]. However, there have been reports of increased INR and prothrombin time in patients receiving PPIs and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with DEXILANT and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time. Tacrolimus Concomitant administration of dexlansoprazole and tacrolimus may increase whole blood levels of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.

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BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION DEXILANT (dexlansoprazole) delayed-release capsules for oral use INDICATIONS AND USAGE DEXILANT is indicated for: • the healing of all grades of erosive esophagitis (EE) for up to 8 weeks • maintaining healing of EE and relief of heartburn for up to 6 months • the treatment of heartburn associated with symptomatic non-erosive gastroesophageal reflux disease (GERD) for 4 weeks.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic potential of dexlansoprazole was assessed using lansoprazole studies. In two 24-month carcinogenicity studies, Sprague-Dawley rats were treated orally with lansoprazole at doses of 5 to 150 mg per kg per day, about 1 to 40 times the exposure on a body surface (mg/m2) basis of a 50 kg person of average height [1.46 m2 body surface area (BSA)] given the recommended human dose of lansoprazole 30 mg per day. Lansoprazole produced dose-related gastric ECL cell hyperplasia and ECL cell carcinoids in both male and female rats [see Clinical Pharmacology]. In rats, lansoprazole also increased the incidence of intestinal metaplasia of the gastric epithelium in both sexes. In male rats, lansoprazole produced a dose-related increase of testicular interstitial cell adenomas. The incidence of these adenomas in rats receiving doses of 15 to 150 mg per kg per day (4 to 40 times the recommended human lansoprazole dose based on BSA) exceeded the low background incidence (range = 1.4 to 10%) for this strain of rat. In a 24-month carcinogenicity study, CD-1 mice were treated orally with lansoprazole doses of 15 to 600 mg per kg per day, 2 to 80 times the recommended human lansoprazole dose based on BSA. Lansoprazole produced a dose-related increased incidence of gastric ECL cell hyperplasia. It also produced an increased incidence of liver tumors (hepatocellular adenoma plus carcinoma). The tumor incidences in male mice treated with 300 and 600 mg lansoprazole per kg per day (40 to 80 times the recommended human lansoprazole dose based on BSA) and female mice treated with 150 to 600 mg lansoprazole per kg per day (20 to 80 times the recommended human lansoprazole dose based on BSA) exceeded the ranges of background incidences in historical controls for this strain of mice. Lansoprazole treatment produced adenoma of rete testis in male mice receiving 75 to 600 mg per kg per day (10 to 80 times the recommended human lansoprazole dose based on BSA). A 26-week p53 (+/-) transgenic mouse carcinogenicity study of lansoprazole was not positive. Lansoprazole was positive in the Ames test and the in vitro human lymphocyte chromosomal aberration assay. Lansoprazole was not genotoxic in the ex vivo rat hepatocyte unscheduled DNA synthesis (UDS) test, the in vivo mouse micronucleus test or the rat bone marrow cell chromosomal aberration test. Dexlansoprazole was positive in the Ames test and in the in vitro chromosome aberration test using Chinese hamster lung cells. Dexlansoprazole was negative in the in vivo mouse micronucleus test. The potential effects of dexlansoprazole on fertility and reproductive performance were assessed using lansoprazole studies. Lansoprazole at oral doses up to 150 mg per kg per day (40 times the recommended human lansoprazole dose based on BSA) was found to have no effect on fertility and reproductive performance of male and female rats. PATIENT COUNSELING INFORMATION To ensure the safe and effective use of DEXILANT, this information and instructions provided in the FDA-approved Patient Information Leaflet should be discussed with the patient. Inform the patient to watch for signs of an allergic reaction as these could be serious and may require that DEXILANT be discontinued. Advise the patient to immediately report and seek care for any cardiovascular or neurological symptoms including palpitations, dizziness, seizures, and tetany as these may be signs of hypomagnesemia [see Warnings and Precautions]. Advise the patient to tell their health care provider if they take atazanavir, tacrolimus, warfarin and drugs that are affected by gastric pH changes [see Drug Interactions]. Advise the patient to follow the dosing instructions in the Patient Information Leaflet and inform the patient that: • DEXILANT is available as a delayed release capsule. • DEXILANT may be taken without regard to food. • DEXILANT should be swallowed whole. • Alternatively, DEXILANT capsules can be administered as follows: – Open capsule; – Sprinkle intact granules on one tablespoon of applesauce; – Swallow immediately. Granules should not be chewed. – Do not store for later use. Distributed by Takeda Pharmaceuticals America, Inc. Deerfield, IL 60015 DEXILANT is a trademark of Takeda Pharmaceuticals North America, Inc. and used under license by Takeda Pharmaceuticals America, Inc. Trademark registered with the U.S. Patent and Trademark office. All other trademark names are the property of their respective owners. ©2009, 2011 Takeda Pharmaceuticals America, Inc. DEX006 R14_BS Revised: June 2011 L-LPD-0611-2

References: 1. DEXILANT (dexlansoprazole) package insert, Takeda Pharmaceuticals America, Inc. 2. Metz DC, Howden CW, Perez MC, et al. Aliment Pharmacol Ther. 2009;29:742-754. DEXILANT and DEXILANT (with design) are trademarks of Takeda Pharmaceuticals North America, Inc., registered in the U.S. Patent and Trademark Office and used under license by Takeda Pharmaceuticals America, Inc. Dual Delayed Release is a trademark of Takeda Pharmaceuticals North America, Inc. and used under license by Takeda Pharmaceuticals America, Inc.

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USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects Pregnancy Category B. There are no adequate and well-controlled studies with dexlansoprazole in pregnant women. There were no adverse fetal effects in animal reproduction studies of dexlansoprazole in rabbits. Because animal reproduction studies are not always predictive of human response, DEXILANT should be used during pregnancy only if clearly needed. A reproduction study conducted in rabbits at oral dexlansoprazole doses up to approximately 9 times the maximum recommended human dexlansoprazole dose (60 mg per day) revealed no evidence of impaired fertility or harm to the fetus due to dexlansoprazole. In addition, reproduction studies performed in pregnant rats with oral lansoprazole at doses up to 40 times the recommended human lansoprazole dose and in pregnant rabbits at oral lansoprazole doses up to 16 times the recommended human lansoprazole dose revealed no evidence of impaired fertility or harm to the fetus due to lansoprazole [see Nonclinical Toxicology]. Nursing Mothers It is not known whether dexlansoprazole is excreted in human milk. However, lansoprazole and its metabolites are present in rat milk following the administration of lansoprazole. As many drugs are excreted in human milk, and because of the potential for tumorigenicity shown for lansoprazole in rat carcinogenicity studies [see Nonclinical Toxicology], a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness of DEXILANT in pediatric patients (less than 18 years of age) have not been established. Geriatric Use In clinical studies of DEXILANT, 11% of patients were aged 65 years and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified significant differences in responses between geriatric and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Renal Impairment No dosage adjustment of DEXILANT is necessary in patients with renal impairment. The pharmacokinetics of dexlansoprazole in patients with renal impairment are not expected to be altered since dexlansoprazole is extensively metabolized in the liver to inactive metabolites, and no parent drug is recovered in the urine following an oral dose of dexlansoprazole. Hepatic Impairment No dosage adjustment for DEXILANT is necessary for patients with mild hepatic impairment (Child-Pugh Class A). DEXILANT 30 mg should be considered for patients with moderate hepatic impairment (Child-Pugh Class B). No studies have been conducted in patients with severe hepatic impairment (Child-Pugh Class C). OVERDOSAGE There have been no reports of significant overdose of DEXILANT. Multiple doses of DEXILANT 120 mg and a single dose of DEXILANT 300 mg did not result in death or other severe adverse events. However, serious adverse events of hypertension have been reported in association with twice daily doses of DEXILANT 60 mg. Non-serious adverse reactions observed with twice daily doses of DEXILANT 60 mg include hot flashes, contusion, oropharyngeal pain, and weight loss. Dexlansoprazole is not expected to be removed from the circulation by hemodialysis. If an overdose occurs, treatment should be symptomatic and supportive. CLINICAL PHARMACOLOGY Pharmacodynamics Serum Gastrin Effects The effect of DEXILANT on serum gastrin concentrations was evaluated in approximately 3460 patients in clinical trials up to 8 weeks and in 1023 patients for up to 6 to 12 months. The mean fasting gastrin concentrations increased from baseline during treatment with DEXILANT 30 mg and 60 mg doses. In patients treated for more than 6 months, mean serum gastrin levels increased during approximately the first 3 months of treatment and were stable for the remainder of treatment. Mean serum gastrin levels returned to pre-treatment levels within one month of discontinuation of treatment. Enterochromaffin-Like Cell (ECL) Effects There were no reports of ECL cell hyperplasia in gastric biopsy specimens obtained from 653 patients treated with DEXILANT 30 mg, 60 mg or 90 mg for up to 12 months. During lifetime exposure of rats dosed daily with up to 150 mg per kg per day of lansoprazole, marked hypergastrinemia was observed followed by ECL cell proliferation and formation of carcinoid tumors, especially in female rats [see Nonclinical Toxicology]. Effect on Cardiac Repolarization A study was conducted to assess the potential of DEXILANT to prolong the QT/QTc interval in healthy adult subjects. DEXILANT doses of 90 mg or 300 mg did not delay cardiac repolarization compared to placebo. The positive control (moxifloxacin) produced statistically significantly greater mean maximum and time-averaged QT/QTc intervals compared to placebo.

CME CE

Dermatologic Look-Alikes ■ LEARNING OBJECTIVE: To improve the clinician’s ability to distinguish and properly treat dermatologic conditions with similar presentations. ■ COMPLETE THE POSTTEST: Page 113

■ ADDITIONAL CME/CE: Pages 33, 93

Yellow papules near the nipple NOAH S. SCHEINFELD, MD, JD

CASE #1

CASE #2

A woman presented with a several-month history of yellow, enlarging papules on the areola of the breast. The papules did not itch, burn, or hurt at the time of presentation. There was no history of any new product use or lesions present on other areas. No sexually transmitted diseases (STDs) were reported. The woman was not taking any medications. No follicular-centric quality to the papules was detected. Skin biopsy showed intracytoplasmic inclusion bodies on hematoxylin and eosin staining.

A man aged 30 years presented with a complaint of acne. It was observed that the glands of his nipples were notable for protuberant papules that had a red, yellow, and whitish hue. The papules did not itch, burn, or hurt. The man reported no history of discharge from the nipples. Palpation of the papules was unremarkable. When rubbed, the papule became a little more firm. The patient was not noted to have similar lesions or rosacea on the face. A decision was made to take a biopsy of the lesions.

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CASE #1

Dermatologic Look-Alikes

Molluscum contagiosum

Mol luscum contagiosum (MC) is one of the most common dermatologic conditions encountered by pediatricians and, along with genital warts, among the most prevelant of the STDs. Of all viral infections, MC is perhaps the most protean in its dermatologic incarnations.1 MC is best understood as a follicular process. The condition was named in 1817 for its domed, delled shape (similar to that of a mollusk) and propensity to proliferate. The dell is the center of a follicle, and the rim around the dell is a proliferation of the virally infected cells, which are referred to as molluscum bodies. The histological appearance of these minute ovoid eosinophilic structures is distinctive. Clinically, molluscum bodies can resemble a bacterial or herpetic folliculitis, inflamed cyst, or some type of aberrant sebacous hyperplasia (as seen in this case).2 Two nonviral diseases also carry the appellation molluscum. Skin tags that manifest in pregnancy are referred to as molluscum fibrosum gravidarum, and keratoacantomas—a rapidly proliferating type of squamous cell carcinoma with a benign course—are referred to as keratic or keratotic molluscum, molluscum pseudocarcinomatosus, molluscum sebaceum, and keratinous molluscum. Mollusca are caused by the molluscum contagiosum virus (MCV), a large, double-stranded DNA poxvirus in the same family as cowpox and smallpox. MCV has no animal reservoir; however there have been a few reports of MC occurring in chickens, sparrows, pigeons, chimpanzees, kangaroos, a dog, and a horse.3 The four subtypes of MC behave in an identical manner clinically. Subtype I (found in 75% to 90% of individuals with MC) and II are common, and subtype III and IV are rare.3 MC is spread through direct contact or by fomites, including any erose scraping tools used on the skin, razors (in particular those used to shave genital areas), bath towels,

MORE DERMATOLOGY ON THE WEB Test your diagnostic skills. Our FREE archive of Dermatology Clinic and Dermatologic Look-Alikes is now available online at www.ClinicalAdvisor.com/Derm.

skin-smoothing utensils, tattoo instruments, and beauty parlor paraphernalia. Communal swimming pools can also be a source of MC. In adults, the most common source of spread is skinto-skin contact, likely during a sexual encounter. While many individuals carry MCV—almost 100% of children are exposed to MCV at some point—only 5% to 10% develop lesions of MC.3 The average incubation time of MCV is between two and seven weeks but can be as long as 26 weeks. Researchers have used nonstandardized serum antibodies, complement fi xation, fluorescent antibody, tissue-culture

The lesions usually appear in the groin beneath the line of the umbilicus and on the genitals and buttocks. neutralization, and agar-gel diffusion techniques to assess MC. Specific MC protein antibodies have been noted in approximately 80% of patients with MC clinically and in about 15% of controls.4 MC manifests as smooth, umbilicated, usually concentric papules that typically measure 1 to 20 mm in diameter. They can be white, flesh-colored, translucent, yellow, pink, or red (especially when irritated). Firm to the touch, MC lacks the gelatinlike consistency of cutaneous cryptococcosis. The central dell or umbilication sits atop a white, waxy, and curdlike core that can be popped out with comedone extractor. This core can be viewed immediately under a microscope in what is known as a crush preparation on a slide with Papanicolaou, Wright, or Giemsa stain. MC can manifest as single lesions, in groups, in plaques, in folliculitis-like patterns, and in pseudo Koebner-type (linear) arrays. MC can affect any part of the body except for the palms and soles. Distribution in children and adults differ. In children, MC tends to occur on any body area or in areas affected by atopic dermatitis. In immunosuppressed individuals (particularly those with HIV), the face and neck are commonly affected. In the 1980s and 1990s, the prevalence of MCV in patients with HIV was perhaps 20%. With very low CD4 cell counts (i.e., >100 cells/mm3), the prevalence of MC approaches 30% to 40%. In the age of antiretroviral therapy, MC has somehow receded as a dermatosis of HIV. As a common STD, the distribution of MC is distinct. In immunocompetent adults, the lesions usually appear in the groin beneath the line of the umbilicus and on the genitals

110 THE CLINICAL ADVISOR • NOVEMBER 2011 • www.ClinicalAdvisor.com

and buttocks. If MC is found outside of the underwear/groin area of an adult, consider an HIV test. Such a distribution is likely attributable to some form of intimate contact with another person. The diagnosis of MC in most cases is clinically obvious. A central dell or umbilication will be present either directly or secondary to freezing the lesions. As in this case, pseudocystic MC, yellow sebaceous hyperplasia type MC, cystic MC, giant MC, pedunculated MC, and MC associated with other cutaneous pathology (especially cysts) can lead to diagnostic uncertainty. Other follicular diseases can coexist with MC, in particular an epidermal inclusion cyst likely secondary to MCV spreading into another disease state that affects the follicle. Commonly, MC occurs secondary to shaving. Advise all patients with MC not to use a razor on the affected area. If absolutely necessary, trim the hair with scissors. Most cases of MC in immunocompetent adults or children last months and spread contiguously. In children, virtually all cases abate by puberty. Individual papules of MC tend to last for one to two months. MC can recur after its initial clearance in approximately one third of patients, but many develop immunity. It is not clear whether MC’s recrudescence iterates a new infection, an ongoing disease exacerbation, some depression of immunity (as seen in herpes simpex and varicella viruses), or rebound from a quiescent viral state. MC is a common infection and accounts for approximately 1% of all diagnosed skin diseases.3 A review of the data from the National Disease and Therapeutic Index Survey from 1966 to 1983 shows that the incidence of MC is increasing,5 perhaps attributable to changes in genital shaving practices among men and women. MC has no systemic manifestations but can evoke an eczematous reaction in 10% of patients, most commonly in children.3 It is unclear whether this reflects an immune phenomenon or a worsening of atophy. It has been noted that eyelid MC can be severe and can include scarring of the peripheral cornea. In immunocompetent, nonatopic individuals, MC is typically a self-limited disease that does not require treatment.3 When deemed appropriate, multiple local therapeutic options are available for MC.3,6 However, no single intervention has been shown to be convincingly effective in treating MC.3 Lesions can be frozen or popped open with a comedone extractor. Lack of therapeutic success can occur, particularly against the backdrop of immunosuppression. As lesions spread, multiple treatment sessions can be required. Scarring from lesions and treatment is not common. In this patient, treatment with liquid nitrogen resulted in resolution of the papules.

CASE #2

Sebaceous hyperplasia

Areolar glands (also called g lands of Montgomer y) are sebaceous glands in the nipple that secrete a lipoid fluid. The glands’ function is not fully known, but it has been suggested that the glands and their secretions contain a lubricating and protective substance that alters the skin’s pH and discourages bacterial growth. This secretion helps keep the skin healthy and the areola elastic. Areolar glands also secrete a small amount of milk. Found on the surface of the skin, Montgomery tubercles can be barely noticeable, can be noticeable as protuberant projections on the areola, or can have increased turgor after exposure or stimulation. Montgomery tubercles and glands become more prominent during pregnancy and lactation. The number of Montgomery glands ranges from four to 28. A study of samples from 12 modified radical mastectomy specimens looked at 1,536 serial sections of areolar tubercles.7 In 34 of 35 tubercles, a mammary lactiferous duct was associated with a sebaceous apparatus. This lactiferous duct ascended from deeper mammary parenchyma and entered the sebaceous gland. Histopathologic changes identified included features of fibrocystic disease, atypical intraductal hyperplasia, and carcinoma in situ. Because the areolar tubercle has two components—a sebaceous gland and a mammary duct arising from deeper breast parenchyma—diseases of the breast may also involve the areola independent of papilla-nipple involvement. Areolar glands can be flesh-toned, yellow, pink, red, or white in color. They do not contain any distinct material; rather their color is an optical function of the thickness of the skin and the chromophores in the skin (water, hemoglobin, melanin, and secretory material). Some women squeeze the glands to extract the seemingly whitish-yellow contents, which can lead to scarring. The areolar glands’ role in mother-infant interactions may pertain to protective, mechanical, and communicative functions. The secretion of areolar glands from lactating women elicits selective, unconditional responses in neonates. Areolar secretions from lactating women are especially crucial for optimal mother/neonate interaction in human newborns. Volatile compounds carried in these substrates appear to play a key role in establishing behavioral and physiologic

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processes pertaining to milk transfer and production, and hence, survival. It is thought that the human breast areolae may function as scent organs, with morphologic data supporting the possible involvement of aereolar glands and tubercles in maternal-neonatal coadaptation and the early engagement of attachment and bonding. A morphologic study of neonates between birth and day 3 compiled the number, secretory status, and spatial distribution of areolar glands. Researchers collected data on the infants’ weight variation, the mothers’ perception of the infant’s behavior at breast, and duration between delivery and onset of lactation. Areolar glands were seen in virtually all women, and great individual variations existed. The areolar distribution was nonrandom, and approximately 20% of the women had areolar glands giving off a secretion. The

with complex nosology. Apocrine variants of both in situ and invasive cancer exist. Common iterations of apocrine metaplastic lesions include those with fibrocystic change and apocrine adenoma, apocrine change within sclerosing adenosis, atypical apocrine lesions, and apocrine malignancies. Isolated areolar apocrine chromhidrosis—a rare phenomenon that usually occurs in the axilla—has been reported.12 A diagnosis of sebaceous hyperplasia was explained to the patient in this case. No treatment was necessary. ■ Dr. Scheinfeld is assistant clinical professor of dermatology at Columbia University in New York City, where he has a private practice. The author has no relationships to disclose relating to the content of this article. References 1. Scheinfeld N. Treatment of molluscum contagiosum: a brief review and

A manifestation of rosacea, sebaceous hyperplasia commonly occurs on the face and occasionally on the neck.

discussion of a case successfully treated with adapelene. Dermatol Online J. 2007;13:15. Available at dermatology.cdlib.org/133/case_reports /molluscum/scheinfeld.html. 2. Scheinfeld NS. Molluscum contagiosum. Skinmed. 2008;7:89-92. 3. Hanson D, Diven DG. Molluscum contagiosum. Dermatol Online J. 2003;9:2. Available at dermatology.cdlib.org/92/reviews/molluscum/diven.

quantity of areolar glands related positively with neonatal weight gain between birth and day 3 and the mother’s perception of the infant’s latching speed and sucking activity. The quantity of areolar glands also related positively with the onset of lactation in first-time mothers. The authors concluded that maternal endowment with areolar glands may contribute to an infant’s breastfeeding performance and early growth, and the mother’s lactation onset.8 Sebaceous hyperplasia is one reason for the yellow appearance of areolar glands and tubercles. A manifestation of rosacea that increases in frequency with age, sebaceous hyperplasia commonly occurs on the face and occasionally on the neck. Fordyce’s spot-like lesions have been seen on both areolae of women.9 The histology of the lesions showed sebaceous hyperplasia. Areolar sebaceous hyperplasia in men—an uncommon entity first noted in 1985—manifests clinically as yellowish thickening of the areolae and histopathologically by large numbers of mature hyperplastic sebaceous lobules connected to the surface of the skin through short, hairless, infundibular canals.10 A variety of morphologies of male areolar sebaceous hyperplasia occur, including unilateral areolar sebaceous hyperplasia and unilateral sebaceous hyperplasia as a plaque.11 In the female breast after age 25 years, apocrine metaplasia (aberrant growth of aprocrine glands) remains a most common clinical finding. The apocrine cell has a variety of atmans

html. 4. Medscape Reference. Molluscum contagiosum. Available at emedicine. medscape.com/article/910570-overview. 5. Becker TM, Blount JH, Douglas J, Judson FN. Trends in molluscum contagiosum in the United States, 1966-1983. Sex Transm Dis. 1986;13:88-92. 6. van der Wouden JC, van der Sande R, van Suijlekom-Smit LW, et al. Interventions for cutaneous molluscum contagiosum. Cochrane Database Syst Rev. 2009;4:CD004767. 7. Smith DM Jr, Peters TG, Donegan WL. Montgomery’s areolar tubercle. A light microscopic study. Arch Pathol Lab Med. 1982;106:60-63. 8. Doucet S, Soussignan R, Sagot P, Schaal B. The secretion of areolar (Montgomery’s) glands from lactating women elicits selective, unconditional responses in neonates. PLoS One. 2009;4:e7579. Available at www .ncbi.nlm.nih.gov/pmc/articles/PMC2761488/. 9. Tsuji T, Yamauchi R. Areolar sebaceous hyperplasia with a Fordyce’s spot-like lesion. J Dermatol. 1994;21:524-526. 10. Catalano PM, Ioannides G. Areolar sebaceous hyperplasia. J Am Acad Dermatol. 1985;13:867-868. 11. Fariña MC, Soriano ML, Escalonilla P, et al. Unilateral areolar sebaceous hyperplasia in a male. Am J Dermatopathol. 1996;18:417-419. 12. Griffi th JR. Isolated areolar apocrine chromhidrosis. Pediatrics. 2005;115:e239-e241. Available at pediatrics.aappublications.org /content/115/2/e239.full. All electronic documents accessed October 15, 2011.

112 THE CLINICAL ADVISOR • NOVEMBER 2011 • www.ClinicalAdvisor.com

POSTTEST Expiration date: November 2012

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

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Dermatology Clinic

Dermatologic Look-Alikes

page 33

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Management of diabetic ketoacidosis in adults

Case #1: Mastocytosis

Case #1: Molluscum contagiosum

1. What is a positive Darier’s sign? a. Rubbing a lesion causes development of erythema. b. Pinpoint bleeding occurs after scale is removed. c. Pushing a blister causes separation of the dermis. d. Minor trauma leads to new lesions.

5. How does molluscum contagiosum (MC) manifest? a. Flat-topped, shiny, and violaceous papule b. Flat lesion with rough surface resembling cauliflower heads c. Solid, firm, and thick plaque with little or no scaling d. Smooth, umbilicated, and concentric papules 1 to 20 mm in diameter

2. Which medication is associated with mastocytosis? a. Atorvastatin (Lipitor) b. Sertraline (Zoloft) c. Acetaminophen d. Vancomycin (Vancocin)

6. Where is MC commonly seen in immunosuppressed individuals, particularly those with HIV? a. Groin area b. Intertriginous areas c. Face and neck d. Soles of feet

1. Glucagon action in the liver inhibits a. Glucose storage b. Ketoacid production c. Glucose release d. Amino acid uptake 2. What is the most frequent stressor in patients with hyperglycemic crisis? a. Trauma b. Drug abuse c. Infection d. Myocardial infarction 3. For hemodynamically stable patients with adequate urine output, which of the following is used in fluid resuscitation? a. Dextran (Dexferrum, Imferon, INFeD) b. Ringer’s lactate c. D5W (5% dextrose) d. 0.9% NaCl 4. When starting basal/bolus insulin therapy in diabetic ketoacidosis, which insulin should be divided into thirds given at mealtime? a. Insulin glargine (Lantus) b. Insulin aspart (NovoLog) c. Insulin detemir (Levemir) d. Insulin injection regular (Humulin R U-100) TO TAKE THE POSTTEST please go to ClinicalAdvisor.com/CMEFeatureNov2011

Case #2: Pyogenic granuloma 3. Where does pyogenic granuloma (PG) most frequently occur? a. Back b. Hands c. Scalp d. Lower extremities

Case #2: Sebaceous hyperplasia

4. What is the preferred option for treating PG? a. Shave biopsy b. Cryotherapy c. Systemic steroids d. Watchful waiting

8. The quantity of areolar glands relates positively with a. Neonatal weight gain between birth and day 3 b. Milk production in nulliparous women c. Risk of developing mastitis d. Length of time breastfeeding

7. Based on research, what percentage of women have areolar glands that give off secretions? a. 5% c. 35% b. 20% d. 50%

TO TAKE THE POSTTEST please go to ClinicalAdvisor.com/DermNov2011

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER 2011 113

CME

POSTTEST Expiration date: November 2012

This program has been reviewed and is approved for a maximum of 1 hour of AAPA Category I CME credit by the Physician Assistant Review Panel. Approval is valid for one year from the issue date of November 2011. Participants may submit the self-assessment at any time during that period. This program was planned in accordance with AAPA’s CME Standards for Enduring Material Programs and for Commercial Support of Enduring Material Programs. Posttests must be completed and submitted online. PAs may register at no charge at myCME.com. To obtain 1.0 hour of AAPA Category I CME credit, you must receive a score of 70% or better on each test taken. CREDITS: 0.5

CREDITS: 0.5

Feature

Dermatology Clinic

Dermatologic Look-Alikes

page 33

page 93

page 109

Management of diabetic ketoacidosis in adults

Case #1: Mastocytosis

Case #1: Molluscum contagiosum

1. What is a positive Darier’s sign? a. Rubbing a lesion causes. development of erythema b. Pinpoint bleeding occurs after scale is removed. c. Pushing a blister causes separation of the dermis. d. Minor trauma leads to new lesions.

2. Which medication is associated with mastocytosis? a. Atorvastatin (Lipitor) b. Sertraline (Zoloft) c. Acetaminophen d. Vancomycin (Vancocin)

6. Where is MC commonly seen in immunosuppressed individuals, particularly those with HIV? a. Groin area b. Intertriginous areas c. Face and neck d. Soles of feet

Case #2: Pyogenic granuloma 3. Where does pyogenic granuloma (PG) most frequently occur? a. Back b. Hands c. Scalp d. Lower extremities

Case #2: Sebaceous hyperplasia

4. What is the preferred option for treating PG? a. Shave biopsy b. Cryotherapy c. Systemic steroids d. Watchful waiting

7. Based on research, what percentage of women have areolar glands that give off secretions? a. 5% c. 35% b. 20% d. 50%

TO TAKE THE POSTTEST please go to ClinicalAdvisor.com/DermNov2011

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • NOVEMBER 2011 113

ALTERNATIVE MEDS UPDATE What you should know about the herbs and supplements patients use By Sherril Sego, FNP-C, DNP. Ms. Sego is a staff clinician at the VA Hospital in Kansas City, Mo., where she practices adult medicine and women’s health. She also teaches at the nursing schools of the University of Missouri and the University of Kansas.

Quercetin

Like many other substances in natural medicine, quercetin is a type of plant-based chemical, or phytochemical. In fact, quercetin is a common chemical pigment found in the rinds and barks of a wide variety of plants. Quercetin is a flavonol, or potent antioxidant, that is found in red wine, onions, green tea, apples, berries, and cruciferous vegetables.1 Its value in treating and preventing many illnesses has been recognized for decades and has made it a very popular component in the herbal and supplement marketplace.

Background Quercetin, derived from the Latin term quercetum, meaning “oak forest,” was named in 1857.2 Since then, the substance has been isolated and studied as an adjunctive therapy for many conditions that are known to be either caused or exacerbated by oxidative damage.

Science As an antioxidant, quercetin is thought to stabilize cell membrane permeability and reduce the transport of oxidative agents such as prostaglandins and other cytokines.3 Quercetin also has vascular effects, such as the inhibition of platelet aggregation, and it promotes endothelial function by allowing rapid transport of nitric oxide and subsequent vasodilation.3 Other benefits that come from membrane stabilization include antihistaminic effects due to mast cell stabilization.3 Studies evaluating the potential value of quercetin on cancer cells

due to immunomodulatory up-regulation and inhibition of cellular proliferation are also under way.4 As an antihistamine, quercetin has been studied for its action in subjects with atopic asthma or reactive airway disease. In one study, researchers developed various extracts of quercetin and applied them to cultured cell lines of human airway smooth muscle that had been stimulated by antigenic compounds.5 Since human muscle that is asthmatic for long periods of time eventually undergoes cellular hypertrophic proliferation, the quercetin extract was used to determine its inhibitory effect on that process. The extract was found to totally abolish the proliferation of smooth muscle cells in the test culture.5 Quercetin also has an effect on allergic rhinitis. Researchers have determined the histamine-blocking effect of quercetin compared to an active control using cromolyn (Nasalcrom).6 Data showed a mast-cell stabilization blocking histamine release that was 46% lower in untreated cells, compared with 58% stabilization in cells treated with cromolyn.6

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ALTERNATIVE MEDS UPDATE In cardiovascular diseases, quercetin has multiple potential benefits. Scientists have noted that populations whose diets were particularly high in flavonol-rich foods have a lower incidence of atherosclerosis and cardiac diseases.7 A group of British scientists studied the use of a quercetin extract in six healthy human subjects.8 The participants’ blood was sampled at designated time frames after ingestion of the extract. The samples were monitored to determine the level of platelet-aggregating activity. Platelet aggregation was virtually eliminated at all testing times and serum concentrations of quercetin.8 In a larger randomized, placebo-controlled trial, 42 patients with prehypertension or stage 1 hypertension were given either placebo or a quercetin supplement for 28 days.9 Subjects with prehypertension showed no change after treatment in either arm of the trial, but those with stage 1 hypertension showed a nearly 10-mm Hg drop in systolic pressure and a 5-mm Hg drop in diastolic readings.9

Safety, interactions Quercetin has not been studied in pregnant or lactating women, or in infants and children. Consequently, patients in those groups should avoid use of quercetin unless approved by their healthcare provider. The most common side effect of quercetin is headache and tingling of the arms and legs. Isolated cases of kidney damage have been reported after prolonged, high-dose usage.10 Concomitant use with fluoroquinolones may reduce the effectiveness of the antibiotic.10

to prevent illness or improve management of chronic disease. Quercetin is recommended as adjunctive alternative medication in most patient populations. ■ References 1. ACS cancer treatment information page. American Cancer Society website. Available at www.cancer.org /Treatment. 2. Boots A, Haenen G, Bast A. Health effects of quercetin: from antioxidant to nutraceutical. Eur J Pharmacol. 2008;585:325-337. 3. Formica JV, Regelson W. Review of the biology of

Quercetin has been shown to be effective against allergic rhinitis.

Quercetin and related bioflavonoids. Food Chem Toxicol. 1995;33:1061-1080. 4. Bobe G, Weinstein SJ, Albanes D, et al. Flavonoid

Quercetin is a yellow crystalline pigment present in plants, which is used as a food supplement to boost immunity and reduce allergic responses.

intake and risk of pancreatic cancer in male smokers. Cancer Epidemiol Biomarkers Prev. 2008;17:553-562. Available at cebp.aacrjournals.org/content/17/3/553.full. 5. Chaabi M, Freund-Michel V, Frossard N, et al. Antiproliferative effect of Euphorbia stenoclada in human airway smooth muscle cells in culture. Journal Ethnopharmacol. 2007;109:134-139. 6. Otsuka H, Inaba M, Fujikura T, Kunitomo M. Histochemical and functional characteristics of metachromatic cells in the nasal epithelium in allergic rhinitis: studies of nasal scrapings and their dispersed cells. J Allergy Clin Immunol. 1995;96:528-536. Available at www.jacionline.org/article/S0091-6749%2895%2970297-0 /fulltext. 7. Bischoff SC. Quercetin: potentials in the prevention and therapy of disease. Curr Opin Clin Nutr Metab Care. 2008;11:733-740. 8. Hubbard GP, Wolfram S, Lovegrove JA, Gibbins JM. Ingestion of quercetin inhibits platelet aggregation and essential components of the collagen-stimulated plate-

Dosage and cost

let activation pathway in humans. J Thromb Haemost. /doi/10.1111/j.1538-7836.2004.01067.x/full. 9. Edwards R, Lyon T, Litwin SE, et al. Quercetin reduces blood pressure in hypertensive subjects. J Nutr. 2007;137:2405-2411. Available at jn.nutrition.org /content/137/11/2405.full. 10. UMMC complementary medicine page. University of

Summary

Maryland Medical Center website. Available at www.umm .edu/altmed/articles/quercetin-000322.htm.

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All electronic documents accessed on October 15, 2011.

2004;2:2138-2145. Available at onlinelibrary.wiley.com

Recommended daily oral intake of quercetin as a supplement varies, but the average dose is 500 mg twice daily. At this dosage, a month’s supply costs about $20. Quercetin can be found in powder-fi lled capsules, liquids, or teas.10

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

PULSE OXIMETRY SCREENING MAY DETECT CONGENITAL HEART DEFECTS IN NEWBORN INFANTS Level 2: Mid-level evidence Diagnosis of congenital heart disease in newborns is sometimes delayed until after hospital discharge, increasing the risk of illness and death. A 2009 scientific statement from the American Academy of Pediatrics (AAP) and American Heart Association (AHA) stated that pulse oximetry screening after 24 hours of life but before hospital discharge may detect critical congenital heart disease, but that the utility of pulse oximetry in clinical practice is not yet established (Circulation. 2009;120:447-458). Several large cohort studies have shown pulse oximetry to be a highly specific screening tool for newborns ( J Pediatr. 2008;152:761765, BMJ. 2009;338:a3037 and Pediatrics. 2003;111:451-455). Two new articles have added information to guide clinicians: one provides further evidence for the efficacy of pulse oximetry screening and the other describes an algorithm for a standardized approach to routine screening. In a new cohort study, 20,055 newborn infants had pulse oximetry measurement in right upper and lower limbs (Lancet. 2011;378: 785-794). Results were classified as abnormal if the oxygen saturation was <95% in either limb or if the difference in oxygen saturation between limbs was >2% when both limbs were >95%. Infants with abnormal tests had a clinical exam, followed either by echocardiography or repeat pulse oximetry in one to two hours. All infants with normal pulse oximetry measurement were followed for 12 months for missed congenital heart defects.

In a recently published algorithm, oxygen saturation levels in newborns were classified as abnormal if saturation was <90% in either foot.

Major congenital heart defects (defi ned as causing death or requiring invasive intervention within 12 months of age) were detected in 53 infants by echocardiography or clinical follow-up. Of these infants, 24 were found to have critical congenital heart disease. For major congenital defects, pulse oximetry was highly specific (99%) and had very high negative predictive value (99.86%). Sensitivity (49%) and positive predictive value (13.33%) were relatively low. The positive likelihood ratio was 49.9 and the negative likelihood ratio was 0.51. These results suggest that infants with normal pulse oximetry are highly unlikely to have congenital defects and that infants with abnormal results would benefit from further testing. The diagnostic performance was similar for infants with critical congenital disease. In an analysis of 169 infants who had abnormal pulse oximetry screens and normal echocardiograms, noncardiac illnesses requiring urgent medical interventions were found in 23.7%. Routine use of pulse oximetry to screen for congenital heart disease has not yet been recommended by AAP/AHA, and has not been advised by the Department of Health and Human Services (HHS), due to lack of an implementation plan. As part of the effort to develop that plan, a study group organized by the AAP, the AHA, the American College of Cardiology Foundation, and the HHS has recently published an algorithm for screening for critical congenital heart disease in well-baby and The quality of the evidence supporting each item is rated from Level 1 (highest) to Level 3 (lowest). Absolute risk reductions are presented as the number needed to treat (NNT) for one patient to benefit. Absolute risk increases are presented as the number needed to harm (NNH).

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Evidence-Based Medicine intermediate-care nurseries using pulse oximetry. Under this algorithm (which differs slightly from the protocol described above), pulse oximetry is performed 24 to 48 hours after birth on the right hand and either the right or left foot. The screen is abnormal if oxygen saturation is <90% in either location. The screen is normal if oxygen saturation is ≥95% in the hand or foot and there is ≤3% difference between hand and foot. Hourly rescreens are recommended in infants with saturations between 90% and 95% or if the difference is >3% (Pediatrics. 2011;128:740-752). The algorithm has not been tested in a randomized trial, so it is uncertain what the relative benefits vs. harms would be for such an approach. Xanthelasma palpebrarum, a yellowish deposit of cholesterol underneath the eyelid, is identified as an independent CV risk factor.

XANTHELASMATA IS ASSOCIATED WITH INCREASED RISK OF CARDIOVASCULAR DISEASE AND MORTALITY INDEPENDENT OF LIPID LEVELS Level 1: Likely reliable evidence Xanthelasmata (yellowish eyelid plaques) and arcus corneae (peripheral corneal opacities) are lipid deposits that have been associated with hyperlipidemia (Circulation. 1986;73:I108-I118). A recent study investigated these phenomena in connection with cardiovascular disease in a cohort of 12,745 persons aged 20-93 years (median age about 53 years) without ischemic vascular disease at baseline (BMJ. 2011;343:d5497). Patients were followed for a mean of 22 years with 100% follow-up. Xanthelasmata may be a marker for patients at higher risk of cardiovascular disease. The baseline prevalence was 4.4% for xanthelasmata and 24.8% for arcus corneae. During follow-up, 14.7% had a MI, 29% developed ischemic heart disease, and 66.7% died. Risks associated with xanthelasmata and arcus corneae were evaluated in analyses adjusted for age, sex, total cholesterol, triglycerides, body mass index, hypertension, diabetes, and other cardiovascular risk factors. Presence of xanthelasmata was associated with a significantly increased risk of MI (21.8% vs. 14.4%, p <0.05, adjusted hazard ratio [HR] 1.48), ischemic heart disease (38.5% vs. 28.6%, p <0.05, adjusted HR 1.39), and mortality (79.2% vs. 66.2%, p <0.05, adjusted HR 1.14). These associations remained significant in subgroup analyses stratified by 10-year age increments including patients as young as 40-49 years old. There was no significant association between xanthelasmata and either ischemic stroke or ischemic cerebrovascular disease. Arcus corneae were not significantly associated with any vascular outcomes or mortality. ■

118 THE CLINICAL ADVISOR • NOVEMBER 2011 • www.ClinicalAdvisor.com

EARLY ANTIRETROVIRAL THERAPY MAY REDUCE TRANSMISSION IN HIVDISCORDANT HETEROSEXUAL COUPLES Level 2: Mid-level evidence Observational studies have previously shown that antiretroviral therapy (ART) may reduce the transmission of HIV in serodiscordant couples (Cochrane Database Syst Rev. 2011;5:CD009153). A new unblinded randomized trial suggests that early initiation of ART for the infected partner may reduce transmission more effectively than delaying ART until the CD4 count has fallen (N Engl J Med. 2011;365:493-505, available at www.nejm.org/doi/full/10.1056/NEJMoa1105243, accessed October 15, 2011). A total of 1,763 stable heterosexual couples from nine countries (54% African participants) in which one partner was HIV-1-positive were randomized to early ART vs. delayed ART. Half of the infected partners were men, and the CD4 counts in the infected partners at the start of the trial ranged from 350-550 cells/mcL. The early group started therapy immediately. The delayed group began treatment following two consecutive tests showing CD4 count ≤250 cells/mcL or after the development of AIDS-related illness. All participants had counseling on risk reduction and condom use. Uninfected partners were tested for HIV every three months. In median 1.7 years of follow-up, there were 39 total cases of HIV transmission, 28 of which were virologically linked to the infected partner. Of the linked transmissions, there was 1 case in the early ART group vs. 27 cases in the delayed ART group, with incidence rates of 0.1 vs. 1.7 per 100 personyears (hazard ratio 0.04, p <0.001). The infected partners were also followed for clinical events including death, World Health Organization stage 4 events, severe bacterial infections, and pulmonary TB. Early ART was associated with a reduced incidence of clinical events (incidence rate 2.4 vs. 4 per 100 person-years, hazard ratio 0.59, p=0.01).

COMMENTARY Elizabeth Houser, RN, BSN, is an emergency-department nurse at Indiana (Pa.) Regional Medical Center and an FNP student (MSN) at Carlow University, Pittsburgh.

High on bath salts: what to know A 21-year-old man slashed his throat and ended his life with a gunshot to his head. An 11-year-old boy was found dead after hanging himself in his bedroom. A girl attacked her sleeping mother with a machete. These are just a few of the alarming stories associated with new synthetic drugs called “bath salts.” Far from your typical bath-enhancing products, these bath salts are intended to be snorted, smoked, or injected. According to the American Association of Poison Control Centers (www. aapcc.org) and the U.S. Department of Justice (www.justice.gov), “bath salts” were being sold on the Internet and at gas stations, smoke shops, and convenience stores under such street names as

Hallucinations and psychotic behavior can be long-lasting, enduring even after the substance is eliminated from the body.

“Blizzard,” “Cloud Nine,” and “Ocean Snow.” They are typically found as white, light tan, or brown powders, and are believed to contain psychoactive chemicals known as mephedrone and/or methylenedioxypyrovalerone (MDPV). MDPV is structurally related to cathinone, an active alkaloid found in the khat plant (a stimulant plant that produces leaves that are chewed much like coca leaves), methamphetamine, and methylenedioxymethamphetamine (MDMA, or “ecstasy”) (www.deadiversion.usdoj.gov/ drugs_concern/mdpv.pdf ). MDPV functions as a dopamine-norepinephrine reuptake inhibitor, producing stimulatory effects on the central nervous system and cardiovascular system (www.hdap.org/mdpv.html). Sympathomimetic reactions are similar to those caused by methamphetamine, ecstasy, and cocaine (Prescriber’s Letter. March 2011;27:270-312). Side effects include tachycardia, hypertension, euphoria, hallucinations, psychosis, paranoid delusions, agitation, and diminished requirement for food and sleep. The psychosis can cause extreme violent, combative, and self-injurious behavior. The most profound side effects from large overdoses include seizure, rhabdomyolysis, and renal failure (www.epmonthly.com/subspecialties/toxicology/ bath-salt-abuse-hits-epidemic-proportions/). The subjective effects of bath salts last approximately three to four hours, but the physical side effects, such as tachycardia and hypertension, can

last six to eight hours (www.deadiversion.usdoj. gov/drugs_concern/mdpv.pdf ). Some reports indicate it can take 36 to 48 hours to come down from a bath-salt “high,” and that hallucinations and psychotic behavior can be long-lasting, enduring even after the substance is eliminated from the body. Bath salts are thought to be highly addictive, even in small doses (www.deadiversion .usdoj.gov/drugs_concern/mdpv.pdf). MDPV is undetectable with routine urine and blood drug tests. Tests that detect both MDPV and mephedrone can be costly, and the detection window is limited to approximately 48 to 72 hours (www.hdap.org/mdpv.html). Treatment of bath-salt users is symptomatic and supportive, generally involving fluid administration; benzodiazepines for chemical sedation; and physical restraints for severe combativeness, agitation, or physical hallucinations. Psychiatric monitoring is also recommended until hallucinations and suicidal or homicidal ideation pass. Reports to poison-control centers increased from 303 in 2010—when bath salts first surfaced—to 4,720 by August 31, 2011 (www. aapcc.org). On September 7, 2011, the U.S. Drug Enforcement Administration used its emergency scheduling authority to make these substances illegal for at least one year (http://www.justice. gov/dea/pubs/pressrel/pr090711.html). ■ All electronic documents accessed October 15, 2011.

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