April 2018 Clinical Advisor by The Clinical Advisor

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■■Type 2 diabetes guideline ■■Adolescent depression ■■Varicose veins and DVT STAT CONSULT

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Editor Colby Stong editor@clinicaladvisor.com Associate editor Madeline Morr Assistant editor Rita Aghjayan Contributing editors Mark P. Brady, PA-C; Philip R. Cohen, MD; Deborah L. Cross, MPH, CRNP, ANP; Sharon Dudley-Brown, PhD, FNP; Abimbola Farinde, PharmD; Laura A. Foster, CRNP, FNP; Abby A. Jacobson, PA; Maria Kidner, DNP, FNP; Joan W. Kiely, MSN, CRNP; Debra August King, PhD, PA; Ann W. Latner, JD; Mary Newberry, CNM, MSN; Claire Babcock O’Connell, MPH, PA; Kathy Pereira, DNP, FNP; Sherril Sego, DNP, FNP; Ann Walsh, PA-C, SCT(ASCP); Kim Zuber, PA-C Production editor Kim Daigneau Group art director, Haymarket Medical Jennifer Dvoretz Production manager Krassi Varbanov Circulation manager Paul Silver National accounts manager Alison McCauley, 973.224.6414 alison.mccauley @ haymarketmedical.com Publisher Kathleen Hiltz, 201.774.1078 kathleen.hiltz@haymarketmedia.com Editorial director Kathleen Walsh Tulley General manager, medical communications Jim Burke, RPh CEO, Haymarket Media, Inc. Lee Maniscalco All correspondence to: The Clinical Advisor 275 7th Avenue, 10th Floor, New York, NY 10001 For advertising sales, call 646.638.6085. For reprints, contact Wright’s Reprints at 877.652.5295. Persons appearing in photographs in “Newsline,” “The Legal Advisor,” and “Clinical Challenge” are not the actual individuals mentioned in the articles. They appear for illustrative purposes only. The Clinical Advisor ® (USPS 017-546, ISSN 1524-7317),Volume 21, Number 4, is published 12 times a year, monthly, by Haymarket Media, Inc., 275 7th Avenue, 10th Floor, New York, NY 10001. For Advertising Sales & Editorial, call (646) 638-6000 (M–F, 9am–5pm, ET). The Clinical Advisor is available on a paid subscription basis at the following annual rates: $75 USA, $85 Canada, $110 for all other foreign, in U.S. dollars, Single copy price: USA $20, Foreign $30. To order or update a paid subscription visit our website at www. ClinicalAdvisor.com or call (800) 436-9269. Periodicals postage rate paid at NewYork, NY, and additional mailing offices. Postmaster: Send changes of address to The Clinical Advisor, c/o Direct Medical Data, 10255 W. Higgins Rd., Suite 280, Rosemont, IL 60018. All rights reserved. Reproduction in whole or in part without permission is prohibited.

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EXPERTS If a patient has you stumped, write us and we’ll forward your query to one of our consultants and publish the response in Advisor Forum.You can also use this space to contribute a clinical pearl of your own or comment on another letter.

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.

CLINICAL PEARLS

It cannot be beat.—TERRI JORDAN, ARNP, Daytona Beach, Fla. (202-2)

NEUTROPHILS AND LYMPHOCYTES In interpreting a complete blood count with differential, anytime the neutrophils and lymphocytes are numerically close, it is a viral cause; when the neutrophils and lymphocytes are numerically distant, it is a bacterial cause. This is very helpful in determining treatment.—DONNA CARTER, FNP-C, Scottsburg, Ind. (202-1) GENERIC “CAINE” IS EFFECTIVE FOR WOUND CARE For pain relief, most pharmacies offer a “caine” at 2-510%, and basically nothing higher, for between $5 and $30 per tube. I work in wound care and use Walmart’s

INTRA-ARTICULAR INJECTIONS FOR SEVERE OSTEOARTHRITIS Patients with severe osteoarthritis in the knees seem to do better with intra-articular injections if you have them sit up and dangle their legs off the examination table and distract the knee slightly when administering the injection.—ROSEMARY LEDBETTER, PhD, PA, Troy, Ill. (202-3)

YOUR COMMENTS SLIPPED CAPITAL FEMORAL EPIPHYSIS IN OBESE ADOLESCENTS I just read the CME/CE article by Marilou Shreve, DNP, APRN, entitled, “Assessing and treating pediatric obesity” [ June 2015]. I was concerned regarding the oversight of a critical issue in obese adolescents: the increased risk of slipped capital femoral epiphysis (SCFE). This was not addressed in the article. The case study (p. 55) gave incomplete advice regarding the evaluation of an obese adolescent male with knee pain. The most common etiology of the insidious onset of knee pain in children is the hip, due to referred pain from the

Equate brand—vagicaine 20% benzocaine. When using this before debriding a wound, give it three minutes to sedate the nerves, then perform the procedure. I get good results, as patients say. It relieves pain and burning for $1.88.

Advisor F

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

orum

These are lette and successe rs from practitioners s, observat around the below. We ions, and country who OUR CONSULTANTS pearls with invite you want to shar to participa their colle e their clinic agues. Resp te. al problems onding cons ultants are identified CON SULTAT IONS

TREATM ENT FOR INFECT URINAR ION SGLT2 REC MALE CHI S IN THE UNC Y TRACT IRCUMCI LD FOR DIA EPTOR BLOCKE If a male SED child conti Deborah L. Cross, MPH, CRNP, Laura A.BET Foster,ES CRNP, FNP, Abby A. Jacobson, PA-C, RS Abimbola Farinde, PhD, PharmD, With the nues toassociate ANP-BC, is practices family medicine is a physician assistant is a professor redevprogram adven t ofPrimary circu SGLT2 recep at Delaware Valley urinaryattract director, Gerontology NP elop Program, mcisi Columbia Southern moda litywith Palmetto on be perfo for type tor infecPhysicians Dermatology University of Pennsylvania School blockersGroup University 2 diabe rmed? regarding inCare as a treatm in Wilmington, Del. in Orange Beach, Ala. useCharleston, S.C. tes, is there ent urology is of Nursing, Philadelphia. any evide NATHAN in patients with to protect the is well advise nce or data type 1 diabe GARDNE d tes mellitus?— R, PA-C, continues to to recommend a circum upper tracts, the kidne CPAAPA, ys. develo cision It p recurr•ent 44 THE ADVISOR AUGUST 2015 •on www.ClinicalAdvisor.com Castleton, severaCLINICAL l consideration urinary tract the male child who As it currently stands N.Y. , SGLT2 s that infections. for glycemic impede the receptor blocke There are control in ability to cleansenter into this decisio rs are FDA adults with n. Poor hygien should the e and quell -approved child have e may appro diet and exercise, but with type 2 diabetes phimosis, simpl infection potential. appropriate the in ved conjun FDA for use in patien Moreover, AdvisorForum_CA0815.indd urine 44 9/29/15ction 2:38 PM e cathet culture can ts with type has stated that they ketoacidosi steroid cream be a challenge. erization to obtain s, or those are not may tempo an FAR with severe 1 diabetes, patients with Having a short tion of the rarily solve renal functi diabetic steroid the trial of informINDE, PhD, Pharm these issues tenden , though after for infection D (See bottom on.—ABIMBOL ation about once again.—C cy redevelops, placin cessaA Dr. Farinde.) of this page Milwaukee g (203-2) for more , Wis. (203- OLEEN ROSEN, the child at risk 1) DNP, FNP -C, CLI Philip R. Cohen, MD,

is clinicaltions associate professor , shou ld of dermatology, University a of Texas Medical Center, The focus of Houston.

NICAL

Send us your letter Advisor Forum, The s with questions New York, and comm Clinical Advisor ents to: , 114 clinicaladvisoNY 10001. You may contacWest 26th Street , please indicatr.com. If you are writing in t us by e-mail at 4th Floor, each item. e so by including response editor@ to a the Letters are policy is edited for number in parent published letter, to heses at length and contribution print the author ’s name with clarity. The Clinicathe end of s will be accepted. l Advisor the letter. No anonym ’s ous

Write us today.

OUR CO

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PEARLS

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VAGINA L RESULT DISCHARGE AND ING FRO If a female M TAMPON ODOR patient has USE a ask if she uses tamp history of vaginal disch ons. If she the pelvic arge with says “yes,” exam when cond odor, that you woul , do not enter ucting the rotating of d to take a pap smea vagina in the same the specu way r. Instead, the cervix. lum Most retain from side to side start shallow until reach ed tampons ing are lodge d in the fold

Philip R.

Cohen, MD, is clinical associa te profess of dermat or ology, of Texas MedicaUniversity l Center, Houston.

SEND TO The Clinical Advisor 275 7th Avenue, 10th floor New York, NY 10001

62 THE CLINI

Deborah L. Cross, MPH, ANP-B

CRNP, C, is associa te program director, Geronto logy NP Program University of Pennsyl vania School , of Nursing , Philadelphia.

CAL ADVI

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Abimbo la Farinde

, PhD,

is a profess PharmD, or at Columb ia Souther n Univers in Orange ity Beach, Ala.

• www.Clinic

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Laura A.

Foster,

practices familyCRNP, FNP, with Palmett medicine o Primary Care Physicia ns in Charles ton, S.C.

Abby A.

Jacobso

is a physicia n, PA-C, n at Delawa assistant re Dermatology Valley in Wilmington,Group Del.

.indd 62

9/29/15

2:44 PM

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www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • APRIL 2018 1

CONTENTS APRIL 2018

NEWS AND COMMENT

FEATURES

7 An approach to acute 1 infectious diarrhea Conducting a thorough history is an important first step in managing patients with acute infectious diarrhea.

Newsline ■■The American College of Physicians

(ACP) has developed guidance recommendation statements for the pharmacologic treatment of type 2 diabetes, as published in the Annals of Internal Medicine. The ACP now advises that patients with type 2 diabetes should be treated to achieve an A1C between 7% and 8%, rather than 6.5% to 7%. ■■The American Academy of Pediatrics (AAP) has updated clinical practice guidelines to assist primary care clinicians in the management of adolescent depression, as published in Pediatrics. ■■Cesarean delivery is associated with a reduced rate of urinary incontinence and pelvic organ prolapse compared with vaginal delivery, but it is adversely associated with fertility, future pregnancy, and long-term childhood outcome, according to a study published in PLoS Medicine. ■■Ovarian cancer risk is elevated in women with sisters or paternal grandmothers who have been affected, according to a study that was published in PLoS Genetics. ■■Varicose veins are associated with a significantly increased risk of incident deep venous thrombosis risk, though pulmonary embolism and peripheral artery disease are unclear, according to a study published in JAMA.

MAKING CONTACT

CME/CE Focus on safety:

CME/CE Feature posttest

Varicose veins and deep venous thrombosis 9

Managing postoperative pain The scope of the opioid epidemic has prompted clinicians to reexamine prescribing patterns and adopt a multimodal approach.

DEPARTMENTS 5

Stat Consult: Sudden cardiac death 52

Web Roundup A summary of our most recent opinion, news, and multimedia content from ClinicalAdvisor.com Dermatology Clinic n Painful plaques on the elbows n Blistering skin on a boy’s hands

and feet Continues on page 4

Legal Advisor: Voiding a noncompete clause 56

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CONTENTS 52

Stat Consult Sudden cardiac death

Legal Advisor A clinician attempts to void a noncompete clause that prevented her from practicing within 50 miles of her former employer and soliciting any of her former patients for 18 months after leaving her job.

DEPARTMENTS cont’d

ADVISOR FORUM 43

Your Comments ■ LARC implant dimensions

My Most Memorable Patient ■ Celebrating life at the end of life

Case Files ■ Postobstruction diuresis

“I’m not sure what I am, but I believe I’m a product of Norway.”

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NEWSLIN

■ Type 2 diab etes guidelin ■ Adolescent e depression ■ Varicose veins and DV T STAT CO NSULT

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

iac death

A clinician atte a noncompet mpts to void e clause

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DIARRHEA Campylobact er jejuni infe ction can lead to food poisoning and diarrhea .

EXCLUSIVE TO THE WEB AT

ClinicalAdvisor.com Web Exclusives

Multimedia

ClinicalAdvisor.com/News

ClinicalAdvisor.com/Multimedia High fiber diet is beneficial for gut bacteria development in patients with type 2 diabetes According to researchers at Rutgers University, a diet high in fiber promotes gut bacteria that helps blood glucose control. Watch the video here:

Cerebral palsy, epilepsy risk associated with lower Apgar score Epilepsy and cerebral palsy risks are inversely related to 5- and 10-minute Apgar scores in singlet newborns born at term. Low-fat vs low-carbohydrate diets for weight loss Overweight adults who followed a low-fat diet did not experience a significant difference in weight loss compared with those on a low-carbohydrate diet for 12 months. Noninvasive coronary testing may prevent need for future invasive tests Low-risk acute coronary syndrome patients may require fewer referrals for invasive coronary angiography if they had initial noninvasive testing such as stress echocardiography or cardiovascular magnetic resonance.

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

ClinicalAdvisor.com/HighFiberDietVideo

The Waiting Room Official Blog of The Clinical Advisor ClinicalAdvisor.com/WaitingRoom Sharon M. O’Brien, MPAS, PA-C Progressive supranuclear palsy Patients with the disorder may have difficulty with sleep/wake regulation that can lead to profound sleep deprivation. Jim Anderson, MPAS, PA-C, DFAAPA Navigating the waters of independently practicing PAs Over the years, there have been several attempts to put more space between PAs and MDs, including multiple efforts to have the professional association, AAPA, endorse a different title.

ClinicalAdvisor.com/cartoons

Case Study in Urgent Care ClinicalAdvisor.com/CaseStudy

Brady Pregerson, MD A gradually progressive rash after a URI A 33-year-old man presents to the emergency department for 6 small spots on his chest, arms, and legs that gradually grew in diameter after using a topical cream and cephalexin. Read the full case at: ClinicalAdvisor.com/CaseRashURI

MAKING CONTACT

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Newsline A P R I L 2 018

Cesarean delivery affects future pregnancy page 9

Ovarian cancer may be paternally inherited page 9

Varicose veins lead to higher risk of DVT page 9

THE AMERICAN College of Physicians (ACP) has developed guidance recommendation statements for the pharmacologic treatment of type 2 diabetes, as published in the Annals of Internal Medicine. The ACP’s Clinical Guidelines Committee analyzed national guidelines that addressed hemoglobin A1c (HbA1c) targets for treating type 2 diabetes in nonpregnant outpatient adults. Based on its review, the ACP recommends that patients with type 2 diabetes should be treated to achieve an A1C between 7% and 8%, rather than 6.5% to 7%. “The evidence shows that for most people with type 2 diabetes, achieving an A1C between 7%

and 8% will best balance longterm benefits with harms such as low blood sugar, medication burden, and costs,” stated Jack Ende, MD, president of the ACP. Key recommendations are: 1. Clinicians should personalize goals for glycemic control in patients with type 2 diabetes on the basis of a discussion of benefits and harms of pharmacotherapy, patients’ preferences, patients’ general health and life expectancy, treatment burden, and costs of care. 2. Clinicians should aim to achieve an HbA1c level between 7% and 8% in most patients with type 2 diabetes. 3. Clinicians should consider deintensifying pharmacologic

New type 2 diabetes guideline recommends moderate HbA1C target The ACP recommends that patients with type 2 diabetes should be treated to achieve an HbA1C level between 7% and 8%, rather than 6.5% to 7%.

therapy in patients with type 2 diabetes who achieve HbA1c levels less than 6.5%. 4. Clinicians should treat patients with type 2 diabetes to minimize symptoms related to hyperglycemia and avoid targeting an HbA1c level in patients with a life expectancy less than 10 years due to advanced age (80 years or older), residence in a nursing home, or chronic conditions (such as dementia, cancer, endstage kidney disease, severe COPD, congestive heart failure) because the harms outweigh the benefits.

New guidelines issued for adolescent depression in primary care THE AMERICAN ACADEMY of Pediatrics (AAP) has updated clinical practice guidelines to assist primary care clinicians in the management of adolescent depression, as published in Pediatrics. One of the guidelines’ major updates is the endorsement of universal adolescent depression screening for those aged 12 and older using a formal depression self-report tool. The Guidelines for Adolescent Depression in Primary Care (GLAD-PC) had not been updated since 2008. “It has been over 10 years since the initial publication and AAP endorsement of GLAD-PC, yet many primary care pediatricians still are not practicing evidence-based management of adolescent

depression,” stated Rachel A. Zuckerbrot, MD, FAAP, and Amy H. Cheung, MD, the lead authors of the guidelines and members of the GLAD-PC project team. “Some even say it is not in their scope of practice despite the AAP endorsement.” Part I of the guidelines addresses practice preparation, identification, assessment, and initial management of adolescent depression in primary care settings, whereas Part II addresses treatment and ongoing management of adolescent depression. The guidelines were updated for youth aged 10 to 21 years and correspond to initial phases of adolescent depression management in primary care, including the identification of at-risk youth, assessment and diagnosis, and initial management.

8 THE CLINICAL ADVISOR • APRIL 2018 • www.ClinicalAdvisor.com

Cesarean delivery may affect fertility Ovarian cancer had an increased risk of asthma up may have CESAREAN delivery is associ- Cesarean to the age of 12 years (OR, 1.21; ated with a reduced rate of urinary delivery is n = 887,960; 13 studies) and obesity paternal link incontinence and pelvic organ adversely prolapse compared with vaginal delivery, but it is adversely associated with fertility, future pregnancy, and long-term childhood outcome, according to a study published in PLoS Medicine. Eighty studies (29,928,274 participants) from high-income countries were analyzed. Compared with vaginal delivery, cesarean delivery was associated with a decreased risk of urinary incontinence (odds ratio [OR], 0.56; n = 58,900; 8 studies) and pelvic organ prolapse (OR, 0.29; n = 39,208; 2 studies). Children delivered by cesarean delivery

associated with fertility, future pregnancy, and long-term childhood outcome.

up to the age of 5 years (OR, 1.59; n = 64,113; 6 studies). Pregnancy after cesarean delivery was associated with an increased risk of miscarriage (OR, 1.17; n = 151,412; 4 studies) and stillbirth (OR, 1.27; n = 703,562; 8 studies), but not perinatal mortality (OR, 1.11; n = 91,429; 2 studies). Pregnancy following cesarean delivery was associated with an increased risk of placenta previa (OR, 1.74; n = 7,101,692; 10 studies), placenta accreta (OR, 2.95, 1.32 to 6.60; n = 705,108; 3 studies), and placental abruption (OR, 1.38, 1.27 to 1.49; n = 5,667,160; 6 studies).

Varicose veins increase risk for DVT VARICOSE VEINS are associated with a significantly increased risk of incident deep venous thrombosis (DVT) risk, though pulmonary embolism (PE) and peripheral artery disease (PAD) are unclear, according to a study published in JAMA. The investigation included a total of 425,968 participants— aged 20 or older—who presented with varicose veins (n = 212,984) or control group participants (n = 212,984) without varicose veins and were matched with a given propensity score. Individuals who were diagnosed with DVT, PE, or PAD before the commencement were ineligible for the study. The participants with varicose veins predominantly consisted of

The risk for deep venous thrombosis is significantly increased in patients who have varicose veins, according to researchers.

women (69.3%), and the group average age was 54.5 years. Control cohort participants (70.3% women) had an average age of 54.3 years. Follow-up examination was required for all participants in both groups. In the case group, median follow-up durations were 7.5 (DVT), 7.8 (PE), and 7.3 years (PAD), while the control group had follow-up years of 7.6 (DVT), 7.7 (PE), and 7.4 (PAD). The case group had a greater incidence rate for all 3 primary outcomes with absolute risk differences (ARD) of 5.32 for DVT, 0.20 for PE, and 4.51 for PAD. Hazard ratios for the case group compared to patients without varicose veins were 5.30 for DVT, 1.73 for PE, and 1.72 for PAD.

OVARIAN CANCER risk is elevated in women with sisters or paternal grandmothers who have been affected, according to a study that was published in PLoS Genetics. Researchers hypothesized that ovarian cancer may be X-linked and the associated genes may be passed from the paternal grandmother though the father’s inherited genetic material. The investigators conducted a series of tests using DNA from 186 women with ovarian cancer who were registered in the Familial Ovarian Cancer Registry at Roswell Park Cancer Institute via germline X-chromosome sequencing. They reported an earlier ageof-onset in paternal grandmothers compared with maternal grandmothers (hazard ratio [HR], 1.59), though both were mutually exclusive from BRCA1 and BRCA2. To confirm X-linked association, the researchers measured the correlation between prostate cancer in men and ovarian cancer in their mothers and daughters (odds ratio [OR], 2.34). Mothers who did not have ovarian cancer but had affected daughters had significantly more female than male offspring (OR, 1.96). “We have presented evidence that there may exist an X-linked model of transmission of an ovarian cancer susceptibility gene,” the authors wrote. n

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • APRIL 2018 9

FEATURE: SHARMISTHA SAHA, MD, PAUL HOBBS, MD, MAURA HOLCOMB, MD

An approach to acute infectious diarrhea Conducting a thorough history is an important first step in determining the proper management of patients with acute infectious diarrhea.

Campylobacter jejuni infection can frequently result in diarrhea.

iarrhea has an effect across the world. It is responsible for about 2 million deaths annually worldwide.1 In developing countries, it is one of the leading causes of morbidity and mortality among children.1,2 In industrialized nations such as the United States, diarrheal illness may not prove as deadly, but it profoundly affects health care and the economy. It has been estimated that between 179 and 375 million episodes (ranging from 0.6 to 1.4 episodes per person per year) of acute diarrhea occur in the United States annually.2-5 Diarrhea is also responsible for 4% of hospitalizations in children6,7 and 5000 deaths due to foodborne illness yearly.5,7 Although the incidence of disease is highest in children,7 up to 89% of deaths from acute diarrheal illness occur in elderly persons 65 years of age and older.8 Diarrheal illness comes at a great cost. It is estimated that in the United States, diarrhea costs close to $6 billion every year in the form of medical bills and lost productivity.9 Many definitions of diarrhea exist, but the one used by Herbert. L DuPont is commonly accepted: “Diarrhea is generally defined as the passage of three or more unformed stools per day, often in addition to other enteric symptoms, or the passage of more than 250 g of unformed stool per day.”8 Diarrhea can be subcategorized temporally as acute (<14 days), persistent (between 14 and 29 days), or chronic (>29 days).2,9 Despite the far-reaching effects of diarrhea on health in the United States and abroad, it appears that clinicians rarely follow distinct patterns in diagnosing and treating acute diarrheal illness.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • APRIL 2018 17

AN APPROACH TO ACUTE INFECTIOUS DIARRHEA

The information available about diarrhea, including the various causes, diagnostic tests, and complexities of treatment, is growing, making the management of acute diarrheal illness potentially challenging for clinicians. A knowledgeable and well-rounded approach to acute diarrheal illness should improve patient outcomes, help minimize antibiotic resistance and unnecessary treatments, and reduce the national burden of disease. History and physical examination

When a patient with diarrhea is encountered, following stabilization if necessary, it is important that the clinician conduct a thorough history to determine the proper workup and diagnosis. According to the Infectious Diseases Society of America (IDSA) practice guidelines for the management of acute diarrhea, the history of the present illness should include information about the stool characteristics, such as the presence of blood, quantity of stool and frequency of passage, how the illness began, its duration, and signs and symptoms of dehydration.9 The patient should also be assessed for associated symptoms, such as fever, abdominal cramping, nausea, and vomiting. Questions should be asked to gain information about the extent of dehydration, such as the degree of thirst and the ability of elderly patients to perform activities of daily living.10 In patients with severe dehydration, fever, or bloody diarrhea, infants, the elderly, and the immunocompromised, the social history is important as well; this information should

Case study George H. is a 30-year-old white man with no significant past medical history. He reports 2 days of diarrhea (five bowel movements per day, consisting of watery, brown stools) associated with abdominal cramps, nausea, body aches, and fatigue. He returned from a 1-week-long trip to Mexico yesterday. Throughout the trip, he frequently ate fresh fruits and street food. His brother, who accompanied him on the trip, is experiencing similar symptoms. Vital signs are as follows: temperature of 98.8°F, heart rate of 95 beats/min, respiratory rate of 15/min, and blood pressure of 130/78 mm Hg. On examination, he appears minimally lethargic, his mucous membranes are dry, and his skin turgor is decreased. Abdominal examination shows a distended abdomen with normal bowel sounds and diffuse abdominal tenderness without guarding or rebound. Rectal examination shows brown stool without blood or mucus. The remainder of the physical examination is unremarkable. How should George H. be managed?

include any sick contacts, travel history, and activities such as camping, hiking, and swimming in natural ponds or swimming pools. Questions should be asked about diet (specifically the ingestion of undercooked meat, seafood, or raw milk), exposure to animals, time spent in a day care facility or hospital, and recent sexual history. The history should also include questions about medications, especially antibiotic use, other medical conditions, and the past medical history.9 Questions about any family history of gastrointestinal conditions should be asked if a hereditary condition such as inflammatory bowel disease or carcinoma is suspected. This detailed information will provide clues about the cause of the illness and direct the clinician toward an appropriate workup and management plan. The physical examination is critical in assessing the severity of hypovolemia and in ruling out life-threatening conditions. Signs of hypovolemia for which the patient should be evaluated include the pulse and the sitting and standing blood pressures. Other signs include the jugular venous pressure, skin turgor, capillary refill, mucosal dryness, and sunken eye sockets.11 An abdominal examination should be performed on every patient presenting with diarrhea, regardless of its severity. Palpation is critical to determine the presence of peritoneal signs, which can indicate serious conditions or surgical emergencies that sometimes present with diarrhea, including appendicitis, pancreatitis, diverticulitis, ischemic colitis, and adnexitis. A rectal examination is also recommended for every patient to examine the character of the stool.11 This is important especially in elderly patients to compensate for poor historians or patients with poor vision preventing them from detecting the presence of blood in the stool, as an example. Differential diagnosis

The two broad etiological categories of diarrhea are infectious and noninfectious. Infectious diarrhea can be divided into bacterial, viral, and protozoal categories. We will first investigate diarrhea caused by bacteria. Most cases of diarrhea can have many causes but are selflimited, resolve quickly, and rarely undergo a clinical investigation. Even when a case is studied, a specific etiological agent is often not identified. Although most cases have a limited effect on morbidity and mortality, more severe cases require prompt attention. It is then important for the clinician to have a proper differential to avoid unnecessary testing and, when indicated, to initiate proper treatment to minimize the effect of disease. Data from the Centers for Disease Control and Prevention from 2012 provide some perspective regarding the most common infectious agents specifically causing foodborne illnesses. In descending order of incidence and reported as the number

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of cases per 100,000 people in the United States, they were as follows: Salmonella (16.42), Campylobacter (14.30), Shigella (4.50), Cryptosporidium (2.60), Shiga toxin Escherichia coli non-O157 (1.16), Shiga toxin E. coli O157 (1.12), Vibrio (0.41), Yersinia (0.33), Listeria (0.25), and Cyclospora (0.03).2,12 In children younger than 5 years of age, the most common agents were Cryptosporidium and all bacteria except Listeria and Vibrio.12 Listeria and Vibrio were most common in adults 65 years of age or older.12 These common bacterial agents of diarrhea can be transmitted in a multitude of ways and present in a variety of patterns, depending on the particular pathogen. Bacterial diarrhea Salmonella. Patients present acutely with nausea, vomiting, and bloody or nonbloody diarrhea.11 Most Salmonella species, except S. typhi and S. paratyphi (causes of typhoid fever), are acquired through poultry and livestock.3,13 Proof of spread of nontyphoidal salmonellosis from person to person spread has remained elusive, despite the small infective dose.13 All serotypes of Salmonella are pathogenic to humans and appear to have the greatest effect on infants and the elderly.11 Campylobacter. Infectious diarrhea due to Campylobacter species is similar to nontyphoidal salmonellosis.13 Campylobacter is an important cause of dysentery but can also cause nonbloody diarrhea.11 Campylobacter infection is associated with undercooked poultry11 but can also be acquired from sources such as meat, dairy, and contaminated water.13 A solid person-to-person link has yet to be established.13 Rarely, Campylobacter is a cause of Guillain-Barré syndrome.11 A clue in the history, such as diet, environmental exposure, or ascending weakness/paralysis, may be useful in diagnosing infection caused by Campylobacter species. Shigella. Shigellosis often presents with bloody diarrhea. Because Shigella is found in the stool of infected patients and is highly contagious with a small infective dose, shigellosis is commonly associated with outbreaks, especially in young children.3,13 Therefore, day care centers and families are particularly vulnerable. Secondary cases are frequently related to contact with sick individuals.13 Shigella dysenteriae is a particularly virulent strain that produces Shiga toxin (causing hemolytic uremic syndrome [HUS]), and infection with this organism has close to 10% fatality rates in certain regions of the world.11 Clues to the diagnosis are dysentery in a young child, a history of outbreaks at a visited day care center or institution, and exposure to an individual with dysentery. Escherichia coli O157:H7. Enterohemorrhagic E. coli (EHEC), also a producer of Shiga toxin, is an important cause of dysentery in the United States.11 It can cause not only severe hemorrhagic colitis but also HUS, which develops

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in about 6% to 8% of cases and is reported in up to 13% of children.3,13 Transmission is typically through contaminated meat, although secondary cases can occur following personto-person contact.13 About 20% of people exposed to EHEC can be expected to develop symptoms. Escherichia coli non-O157:H7. Other strains of E. coli, such as enteroaggregative E. coli (EAEC) and enterotoxigenic E. coli (ETEC), although not routinely isolated, are increasingly recognized as causes of acute infectious diarrhea.8 ETEC and EAEC are commonly associated with “traveler’s” diarrhea, identified in 30% and 26% of cases, respectively.14 These agents are most commonly spread through fecally contaminated food and water.14,15 Most cases consist of watery diarrhea, are self-limited, and resolve without treatment within 3 days.13 Enteropathogenic E. coli (EPEC) and enteroinvasive E. coli (EIEC) are other strains known to cause acute diarrheal illness.11 Vibrio. Vibrio species are a common cause of diarrhea in developing countries through the contamination of water supplies.11 Specifically, V. cholerae causes large volume loss (“rice water” stools), necessitating aggressive rehydration strategies.11 Because of the highly infectious nature of this organism, its ability to cause outbreaks, and its potential lethality, any case of V. cholerae infection should be reported to the proper health authorities.11 Another species, V. vulnificus, is associated with the consumption of raw or undercooked seafood. Listeria. L. monocytogenes is a less common although still clinically important, cause of foodborne illness, especially in the setting of outbreaks.16 Listeria can be found in many different sources, including soil, water, food (eg, dairy, delicatessen meat products), and the feces of humans and animals.17 Listeriosis ranges from acute diarrheal illness in healthy persons to invasive disease in the immunocompromised.17

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AN APPROACH TO ACUTE INFECTIOUS DIARRHEA

Viral diarrhea frequently presents as watery, noninvasive diarrhea of acute onset, often associated with low-grade fever and headache. Patients commonly present with mild gastrointestinal symptoms such as nausea and watery diarrhea, fever, and even muscle and joint aches.17 Pregnant women are especially vulnerable; they are approximately 13 times more likely than the general population to have listeriosis.16 Clues to the diagnosis include gastrointestinal complaints following reports of a food outbreaks/food contamination and a flulike illness preceded by diarrhea in a pregnant woman.16 Yersinia. Yersinia species, most commonly Y. enterocolitica, can cause acute diarrheal illness. In addition to diarrhea, Yersinia can cause ileitis and mesenteric lymphadenitis,18 mimicking the symptoms of persistent appendicitis.2 The organisms are transmitted fecal-orally in contaminated food and water.18 Despite the availability of modern methods, identifying the sources of outbreaks of yersiniosis has proved difficult.18 A possible clue to the diagnosis is persistent right lower quadrant pain in a patient with diarrhea and a normal appendix. Clostridium difficile. Lastly, an important form of diarrhea is antibiotic-associated diarrhea. Causing about 10% to 20% of cases, Clostridium difficile is responsible for most cases of antibiotic-associated colitis.19 The presentation can range from a mild diarrheal illness to pseudomembranous colitis, systemic illness, and sepsis.20 The most common association is recent antibiotic use with the new onset of significant diarrhea and/or abdominal pain.20 The most commonly implicated antibiotics are clindamycin, broad-spectrum penicillins, and cephalosporins, although any agent may be the cause.19 C. difficile colitis is also contagious, evidenced by its ability to spread environmentally and from person to person.13 Feared complications of C. difficile colitis range from dehydration to toxic megacolon and perforation, and the possible need for colectomy. The most commonly implicated risk factors include advanced age, recent exposure to antibiotics, and hospitalization.19 Relapses are common, with rates approaching 20% to 25% of cases following antibiotic treatment.19 Viral diarrhea Viral diarrhea frequently presents as watery, noninvasive diarrhea of acute onset, often associated with nonspecific systemic symptoms such as low-grade fever, headache, myalgia, and incidence during the winter months. In immunocompetent adults, symptoms are usually self-limited, lasting less than 48 hours, but they may persist for longer than 1 week. Prolonged and severe illness occurs more often in young children, the elderly, and hospitalized or immunodeficient patients.

In the developed world, viral agents should be highest on the list of differential diagnoses for acute diarrhea. Of these, Norwalk virus (Norovirus) is the most common cause of acute diarrhea in adults. Norwalk virus infection usually presents abruptly, with symptoms of nausea, vomiting, and diarrhea, after a 12- to 48-hour incubation period, although patients may present with only vomiting or diarrhea. Most cases are self-limited and last 1 to 3 days, but more prolonged illness occurs in about 10% of cases.21 Norwalk virus infection is exceptionally virulent, (only 18 virus particles are required to cause infection) and is transmitted via virus particles shed in stool and vomit. Contaminated food and drinking water commonly cause outbreaks in restaurants, cruise ships, healthcare facilities, schools, and day care facilities.21 Norwalk-like viruses in the family Caliciviridae are other strains causing infection that presents similarly to Norwalk virus infection and are responsible for more than 90% of diarrheal cases in the United States.13 Rotavirus is the most common cause of serious diarrhea in children up to 23 months of age; patients present with severe nausea and vomiting that often leads to hospitalization.11 Children usually acquire rotavirus infection from day care facilities where hygiene is not ideal.13 Immunity to rotavirus is typically acquired by the age of 2 years, so infection is less common in older children and adults22; however, 15% to 33% of adults in families with children infected with rotavirus may acquire a mild infection.13 Other viral pathogens responsible for acute diarrhea include adenovirus, astrovirus, calicivirus, enterovirus, and coronavirus.10 In the case of virally acquired diarrheas, diagnosing the specific species is often not of great clinical concern because the treatment and management are usually the same: rehydration, electrolyte repletion, and symptomatic management. Parasitic diarrhea Parasites are the final category of infectious agents causing acute diarrheal illness. In the developed world, parasites are the least common etiologic agents, causing fewer than 10% of infections, most of which are due to Cryptosporidium and Giardia lamblia.22 Both of these organisms are transmitted fecal-orally. Cryptosporidium causes a self-limited, watery diarrhea that presents within hours after oocyst ingestion in immunocompetent persons but has a severe, prolonged course in the elderly and immunocompromised; it is a major cause of wasting in patients who have AIDS.23 In industrialized countries, Cryptosporidium is acquired mainly through contaminated swimming pools

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In the developed world, parasites are the least common etiologic agents and are mostly due to Cryptosporidium and Giardia lamblia. and drinking water because the durable cysts are chlorineresistant. In the United States, most Cryptosporidium infections are reported in children during the summer months, correlating with the opening of community swimming pools.24 The infection can also spread quickly from person to person in places where hygiene is poor, and outbreaks occur in day care facilities and hospitals less commonly.25 Travelers to developing countries often acquire cryptosporidiosis from contaminated drinking water or animal contact.22 Giardia causes a delayed infection 7 to 14 days after ingestion of the cysts25 in which large-volume steatorrhea is often associated with weight loss. The infection is self-limited but often lasts more than 7 days; in some patients it persists to become a chronic infection, lasting more than 14 days.25 Giardia infection is acquired via contaminated water and food and during person-to-person contact in places with poor hygiene. Less commonly, Giardia infection can be sexually transmitted during anal intercourse. Other parasites, including Entamoeba, Cyclospora, and Microspora, are uncommonly found among the immunocompetent population in developed countries, but organisms may persist in returning travelers and cause opportunistic infections in patients with AIDS in industrialized countries.22 Further workup

After a thorough history and physical examination have been conducted, there are still times when it is necessary to pursue further testing. Using clinical judgment is crucial to provide a cost-effective yet revealing diagnostic workup.2 Studies have shown that diagnostic yields from stool cultures are as low as 1.5% to 5.6%.2 Extrapolation of data leads to estimated costs for each positive culture result ranging from $952 to $1200.2,9,26 Although a negative stool culture result can still hold valuable information, the poor sensitivity of stool cultures and their broad misuse inflate costs.9 That information notwithstanding, diagnostic testing can be useful in a number of situations. Avoiding testing can increase the use of inappropriate empirical antibiotic therapies, with a subsequent increase in resistant bacterial strains and side effects.9 Also, the use of antibiotics in some cases of diarrhea prolongs and worsens the illness.9 Lastly, a properly selected antibiotic regimen reduces the strain of disease and in some cases is life-saving.9 Because most cases are self-limited and last less than a day,4 and given the potentially high costs and low yields of diagnostic tests in most cases of diarrhea,2,9 fecal testing should be reserved for patients with features indicating severe illness, such as the

following: persistent diarrhea, diarrhea accompanied by fever, recent antibiotic use, and the presence of blood and/or pus, tenesmus, and dehydration.2,9 In the presence of these factors, it is appropriate to test for causes of inflammatory diarrhea, such as Salmonella, Shigella, Campylobacter, and Shiga toxin–producing E. coli (STEC, especially in patients with dysentery).2 Other important situations to consider are elderly patients (especially those in nursing homes), those who are immunocompromised, food handlers, day care center employees, and suspected outbreaks.8 If inflammatory diarrhea is being considered, fecal microscopic neutrophils or lactoferrin can supplement a diagnosis.2,9 The sensitivity and specificity of fecal leukocytes in diagnosing inflammatory diarrhea are relatively high, 73% and 84%, respectively.2,26 For lactoferrin, the sensitivity and specificity are 92% and 79%, respectively.2,26 The acute onset of dysentery and/or the presence of HUS should trigger specific testing for Shiga toxin and culture for E. coli O157:H7.2 Entamoeba histolytica testing should be considered when bloody stools are found in recent travelers and immigrants from regions of endemicity, “such as tropical Africa, Asia, or Latin America.”2,3 A history suggestive of recent seafood consumption may prompt a culture for Vibrio species.2 A presentation mimicking persistent appendicitis with diarrhea can suggest Yersinia enterocolitica or Yersinia pseudotuberculosis.2 A common cause of nosocomial diarrhea is C. difficile. Stool cultures and tests for toxins should be promptly considered in hospitalized patients with an acute onset of diarrhea, especially in those who are of advanced age or have recently taken antibiotics.2,19 Any antibiotic may be the cause, but the most common agents are clindamycin, the broad-spectrum penicillins, and the cephalosporins.19 Toxin screens have proved to be the gold standard for diagnosing C. difficile colitis.19 Imaging studies such as abdominal radiography and computed tomography along with endoscopic procedures can be helpful, but they are not as sensitive or specific, and they are more expensive than toxin assays.19 Some important caveats about fecal testing should be mentioned.19 Researchers found that to prevent unnecessary testing, fecal tests other than those for C. difficile should not be performed on patients hospitalized for more than 3 days unless they are older than 65 years of age, immunocompromised, or neutropenic, are infected with HIV, or have other pre-existing comorbidities.2,19 Other, less likely causes of diarrhea may be considered given the appropriate clinical history. A history of persistent

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AN APPROACH TO ACUTE INFECTIOUS DIARRHEA

FIGURE 1. Algorithm for the management of infectious diarrhea. • Obtain history and physical examination. • Evaluate severity of illness. • Provide symptomatic treatment. • Obtain specimen for analysis if severe, bloody, inflammatory, or persistent diarrhea, or if outbreak suspected.

A. Community-acquired or traveler’s diarrhea (especially if persistent diarrhea, significant fever, or blood in stool) Culture or test for: • Salmonella • Shigella • Campylobacter • Escherichia coli O157:H7 and Shiga toxin (especially if bloody stools, HUS) • Clostridium difficile toxins A, B (if recent antibiotic use or chemotherapy)

B. Nosocomial diarrhea (onset after >3 days in hospital)

C. Persistent diarrhea for >7 days (especially in cases of immunocompromise)

Culture or test for: • C. difficile toxins A, B • Panel A in cases of suspected outbreak or systemic enteric infection, patients with bloody stools, and infants

Consider protozoa: • Giardia • Cryptosporidium • Cyclospora • Isospora belli If HIV+, add: • Microspora • Mycobacterium avium complex • Cytomegalovirus

HIV = human immunodeficiency virus; HUS = hemolytic uremic syndrome. Modified from Guerrant et al9 and from Thielman and Guerrant.2

diarrhea following exposure to untreated water, such as occurs during camping or hiking, should trigger a workup for protozoa such as Giardia and Cryptosporidium.2 The sensitivity of enzyme immunoassays is very high, about 95%, and they are more effective than simple microscopic fecal analysis.2 Furthermore, in those patients who have advanced AIDS and CD4 cell counts below 50/mm3 with persistent diarrhea, “stool studies for Cryptosporidium, Microsporidia, Cyclospora, and Isospora” are appropriate.2 Other causes of diarrhea in patients with advanced HIV infection can be explored by collecting blood cultures or taking biopsy specimens to evaluate for Mycobacterium avium complex and cytomegalovirus.2 Persistent diarrhea with fecal indicators of inflammation in the face of a negative workup for infectious causes should prompt an evaluation for inflammatory bowel disease.2,27 In most cases of acute diarrhea, a single stool sample should be sufficient for licensed laboratories.11 The sample should be studied as soon as possible (within 4 hours) for microscopic analysis and within 12 hours for stool cultures or other standard tests.8 Multiple stool samples may be needed for some cases of C. difficile colitis, inflammatory bowel disease, and diarrhea caused by parasites.2,28 The role of endoscopy in the investigation of diarrhea is essentially limited to cases in which the previous workup has remained inconclusive, symptoms have persisted, or treatment has failed.2,29,30 Specifically, endoscopy is indicated in

cases of suspected C. difficile colitis and dysentery in which the results stool studies, including toxin assays and cultures, have proved negative.8 Flexible sigmoidoscopy has a role and may be used initially to investigate acute diarrhea in several situations: patients with suspected C. difficile colitis, pregnant patients, those with significant comorbidities, and those with symptoms that are largely left-sided.30 Endoscopic findings can help differentiate infectious diarrhea from inflammatory bowel disease.8 Routine esophagogastroduodenoscopy (EGD) is not indicated.30 Instead, EGD should be reserved for patients with negative results of laboratory studies and lower gastrointestinal tract endoscopy because inflammatory bowel disease is a rare cause of diarrheal symptoms.30 The working differential at that time should include celiac disease and Crohn disease, intestinal Giardia infection, and pancreatic insufficiency, among others.30 The choice of any further diagnostic studies, including serum studies, imaging, urinalysis, and anoscopy or endoscopy, should be determined by the severity of illness along with the clinical and epidemiological features.9 Treatment

The first step for managing any patient with diarrhea is to determine the severity of dehydration according to the estimated volume loss and the symptoms and signs noted on physical examination. The following discussion applies

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only to adults with acute diarrhea; children and the elderly are managed differently. Oral rehydration is recommended to alleviate mild dehydration, which often causes minimal to no signs or symptoms. Although not always clinically apparent, volume deficiency is still present to a small degree because of fluid loss through diarrhea. Rehydration should be accomplished with oral rehydration salts mixed with water to ensure that electrolytes are also replenished; Pedialyte is an acceptable alternative to oral rehydration salts. The patient should sip these gradually, consuming 1.5 to 2 times the estimated volume of stool lost per day.10 Sports drinks such as Gatorade and Powerade are designed to replace electrolytes lost in sweat during workout and are not adequate to replace fluid lost during acute diarrhea. Moderate to severe dehydration, hypovolemic shock, or mild dehydration with the inability to tolerate oral rehydration should be managed with intravenous lactated Ringer solution. Lactated Ringer solution is preferred to normal saline because it can quickly correct the potassium deficit that develops during diarrhea. At least half of the estimated volume deficit should be replaced in the first 4 hours after presentation and the rest in 24 hours, with oral rehydration added whenever possible to make up for ongoing losses. For patients with ongoing bouts of heavy diarrhea, fluids should be continued to match the amount of loss, in addition to oral potassium supplements.10 The further treatment of acute infectious diarrhea should depend on the suspected etiology, with viral illness requiring symptomatic management and bacterial illness requiring antibiotics in certain instances. Typically, diarrhea with a viral cause is self-limited, and therapy is focused on rehydration and symptomatic relief. The most commonly used agents to relieve symptoms include loperamide and bismuth subsalicylate.11 Loperamide is an antimotility agent that antagonizes the opioid receptors of smooth muscle in the gastrointestinal tract to decrease peristalsis and increase gut transit time; it also has an antisecretory function. Bismuth subsalicylate functions as both an antimicrobial and an antisecretory agent. Studies have shown that loperamide is more effective and relieves symptoms faster than does bismuth subsalicylate.31 According to the IDSA practice guidelines, bacterial gastroenteritis may be treated empirically or specifically with antibiotics, depending on the etiology. If the patient has been traveling internationally and the symptoms consist of watery, nonbloody stool in an afebrile patient, the illness may be classified as traveler’s diarrhea. Traveler’s diarrhea is most often caused by ETEC or EAEC32 but may also be caused by a number of noninvasive bacterial or viral pathogens. In mild cases, defined as the passage of one to three loose stools per

day that does not limit activity, symptomatic therapy with loperamide or bismuth subsalicylate is sufficient, without the need for antibiotics; ondansetron and promethazine are other agents that may be administered for travelers who will be traveling for long periods of time with little access to care.32 For more severe cases, empirical antibiotic therapy is indicated and can limit the duration of illness to as little as 1.5 days if taken at the first sign of illness.8 Fluoroquinolones for adults and trimethoprim-sulfamethoxazole for children cover most of the bacteria causing traveler’s diarrhea, with the exception of bacteria in certain areas of Asia.9,33 For adult visitors to South and Southeast Asia, macrolides should be administered instead. In these areas, Campylobacter jejuni is another common cause of diarrhea and is often fluoroquinolone-resistant.32 Symptomatic Continues on page 28

Case Study Review Questions 1. What do the history and physical examination findings of George H., provided at the beginning of the article, suggest is the most likely cause of his symptoms? a. enterotoxigenic Escherichia coli (ETEC) b. Campylobacter jejuni c. Norwalk virus d. Giardia species e. Crohn disease 2. What laboratory studies and procedures should be performed for George H.? a. fecal testing for Clostridium difficile toxin b. colonoscopy c. stool culture for Salmonella, Shigella, and Campylobacter d. fecal ova and parasites e. none of the above 3. What method of rehydration should be recommended for George H.? a. oral rehydration b. intravenous administration of lactated Ringer solution c. intravenous administration of normal saline d. a and b e. a and c 4. What medication(s) should be prescribed to George H.? a. loperamide b. ciprofloxacin c. metronidazole d. erythromycin e. a and b Answers: 1. a, 2. e, 3. a, 4. e

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AN APPROACH TO ACUTE INFECTIOUS DIARRHEA

TABLE 1. Antibiotic dosages indicated for acute diarrhea caused by specific pathogens Pathogens

Antibiotics and recommended dosages

BACTERIA Shigella species

TMP-SMZ, 160 and 800 mg, respectively, twice daily for 3 days or ciprofloxacin, 500 mg twice daily for 3 days

Campylobacter species

Erythromycin, 500 mg twice daily for 5 days

Escherichia coli species except EHEC/STEC

TMP-SMZ, 160 and 800 mg, respectively, twice daily for 3 days or ciprofloxacin, 500 mg twice daily for 3 days

Aeromonas/Plesiomonas

TMP-SMZ, 160 and 800 mg, respectively, twice daily for 3 days or ciprofloxacin, 500 mg twice daily for 3 days

Vibrio cholerae O1 and O139

Doxycycline, 300-mg single dose or tetracycline, 500 mg 4 times daily for 3 days or TMPSMZ, 160 and 800 mg, respectively, twice daily for 3 days or single dose of fluoroquinolone

Clostridium difficile

Discontinue offending antibiotics if possible; metronidazole, 250 mg 4 times daily to 500 mg 3 times daily for 10 days

PARASITES Giardia

Metronidazole, 250-750 mg 3 times daily for 7-10 days

Cryptosporidium species

If severe, paramomycin, 500 mg 3 times daily for 7 days

Isospora and Cyclospora species

TMP-SMZ, 160 and 800 mg, respectively, twice daily for 7 days (may be extended to 10 days for Isospora)

EHEC = enterohemorrhagic E. coli; STEC = Shiga toxin–producing E. coli; TMP-SMZ, trimethoprim-sulfamethoxazole. From Infectious Diseases Society of America.9

therapy may be used concurrently with antibiotics in more severe cases to limit the severity and duration of illness.8 For patients traveling internationally with limited access to medical care, it is often impractical to visit a doctor after an uncomplicated diarrhea develops; in these instances, selftherapy with symptomatic agents and empirical antibiotics brought in traveler kits has been shown to be effective.32,34 Of course, travelers should be educated about the presentation of traveler’s diarrhea and the importance of rehydration and electrolyte repletion in such scenarios.32 Emphasis should be placed on using the provided drugs only if the stool is not bloody and the patient is afebrile. Patients should also be instructed to take sanitary precautions, such as frequently washing their hands and avoiding street food while traveling, to lower the likelihood of acquiring a diarrheal illness.32

In invasive cases of bacterial diarrhea, specific antibiotic therapy based on culture results is safer to use than empirical therapy because it reduces the risk for the development of multidrug resistance of the offending organism or gut colonization by other multidrug-resistant strains; for example, the use of vancomycin to treat C. difficile colitis increases the risk for colonization with vancomycin-resistant enterococci. For these reasons, the antimicrobial spectrum should be narrowed whenever possible and the duration of antibiotic therapy minimized.11 Specific antibiotics are also indicated for parasitic acute diarrhea. The following table, adapted from the practice guidelines of the IDSA, provides examples of antibiotics and dosages indicated for acute diarrhea caused by specific pathogens. It should be noted that the dosages listed apply only to immunocompetent adults and should not be the recommended therapy for children and immunocompromised adults. Additional options for antibiotic therapy and the indications for children, the immunocompromised, and patients with comorbidities and severe illness can be found in the IDSA practice guidelines. Exceptions to antibiotic therapy Antibiotics are not always indicated for invasive bacterial diarrhea, most notably in cases of nontyphoidal Salmonella gastroenteritis. Nontyphoidal Salmonella gastroenteritis in immunocompetent patients usually causes self-limited diarrhea, and antibiotics do not significantly shorten the course. In addition, antibiotics prolong fecal shedding of this pathogen, increasing the risk for transmission. Antibiotic treatment should be undertaken only in newborns up to 6 months old, individuals older than 50 years of age, and persons with a prosthesis, valvular heart disease, severe atherosclerosis, cancer, or uremia. Infection with EHEC strain O157, also known as STEC, is another exception to antibiotic therapy; data indicate that antibiotic therapy may be associated with an increased risk for HUS,9,33 and a consensus has not been reached regarding any benefit of antibiotic therapy. Yersinia infections are also usually self-limited, and only patients with severe infection or bacteremia require antibiotics.9 Agents to relieve symptoms must be used with caution in cases of invasive diarrhea, and loperamide must be avoided completely when fever or bloody diarrhea is present because of the risk for fulminant colitis in patients with severe bacterial gastroenteritis. In suspected cases of EHEC or STEC, antimotility agents must be avoided because of the increased risk for HUS.9 n Sharmistha Saha, MD, is a pediatric resident at the Baylor College of Medicine, Paul Hobbs, MD, is a physician at Barnes Jewish Hospital, Washington University in St. Louis,and Maura Holcomb, MD, is a dermatologist at the Memorial Hermann Sugar Land Hospital in Texas.

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8. DuPont HL. Acute infectious diarrhea in immunocompetent adults.

2003-2005. MMWR Surveill Summ. 2007;56:1-10.

N Engl J Med. 2014;370:1532-1540. doi: 10.1056/NEJMra1301069

25. Huang DB, White AC. An updated review on Cryptosporidium and Giardia.

9. Guerrant RL, Van Gilder T, Steiner TS, et al; Infectious Diseases Society

Gastroenterol Clin North Am. 2006;35:291-314, viii. doi: 10.1016/j.gtc.2006.03.006

of America. Practice guidelines for the management of infectious diarrhea.

26. Choi SW, Park CH, Silva TMJ, Zaenker EI, Guerrant RL. To culture

Clin Infect Dis. 2001;32:331-351. doi: 10.1086/318514

or not to culture: fecal lactoferrin screening for inflammatory bacterial

10. Manatsathit S, Dupont HL, Farthing M, et al; Working Party of the

diarrhea. J Clin Microbiol. 1996;34:928-932.

Program Committ of the Bangkok World Congress of Gastroenterology

27. Fine KD, Ogunji F, George J, Niehaus MD, Guerrant RL. Utility of

2002. Guideline for the management of acute diarrhea in adults.

a rapid fecal latex agglutination test detecting the neutrophil protein,

J Gastroenterol Hepatol. 2002;17 Suppl:S54-S71.

lactoferrin, for diagnosing inflammatory causes of chronic diarrhea. Am J

11. Organisation WG. Acute diarrhea: epidemiologic features. World

Gastroenterol. 1998;93:1300-1305. doi: 10.1111/j.1572-0241.1998.413_l.x

Health. 2008;(March):1-29.

28. Deshpande A, Pasupuleti V, Patel P, et al. Repeat stool testing for Clostridium

12. Centers for Disease Control and Prevention. Incidence and trends

difficile using enzyme immunoassay in patients with inflammatory bowel disease

of infection with pathogens transmitted commonly through food—

increases diagnostic yield. Curr Med Res Opin. 2012;28:1553-1560.

foodborne diseases active surveillance network, 10 U.S. sites, 1996-2012.

29. ASGE Standards Practice Committee. Shen B, Khan K, Ikenberry SO,

MMWR Morb Mortal Wkly Rep. 2013;62:283-287.

et al. The role of endoscopy in the management of patients with diarrhea.

13. Musher DM, Musher BL. Contagious acute gastrointestinal infections.

Gastrointest Endosc. 2010;71:887-892. doi: 10.1016/j.gie.2009.11.025

N Engl J Med. 2005;352:1267-1268; author reply 1267-1268. doi: 10.1056/

30. Lasson A, Kilander A, Stotzer PO. Diagnostic yield of colonoscopy

NEJM200503243521221

based on symptoms. Scand J Gastroenterol. 2008;43:356-362.

14. Adachi JA, Jiang ZD, Mathewson JJ, et al. Enteroaggregative Escherichia

31. DuPont HL, Flores Sanchez J, Ericsson CD, et al. Comparative efficacy

coli as a major etiologic agent in traveler’s diarrhea in 3 regions of the

of loperamide hydrochloride and bismuth subsalicylate in the management

world. Clin Infect Dis. 2001;32:1706-1709. doi: 10.1086/320756

of acute diarrhea. Am J Med. 1990;88:15S–19S.

15. Huang DB, Okhuysen PC, Jiang ZD, DuPont HL. Enteroaggregative Escherichia

32. Steffen R, Hill DR, DuPont HL. Traveler’s diarrhea: a clinical review.

coli: an emerging enteric pathogen. Am J Gastroenterol. 2004;99:383-389.

JAMA. 2015;313:71-80. doi: 10.1001/jama.2014.17006

16. Management of pregnant women with presumptive exposure to

33. Scheiring J, Andreoli SP, Zimmerhackl LB. Treatment and outcome of

Listeria monocytogenes. Committee Opinion No. 614. American College of

Shiga-toxin-associated hemolytic uremic syndrome (HUS). Pediatr Nephrol.

Obstetricians and Gynecologists. Obstet Gynecol. 2014;124:1241-1244.

2008;23:1749-1760. doi: 10.1007/s00467-008-0935-6

17. Barbuddhe SB, Chakraborty T. Listeria as an enteroinvasive gastrointes-

34. DuPont HL, Ericsson CD, Farthing MJ, et al. Expert review of the evidence

tinal pathogen. Curr Top Microbiol Immunol. 2009;337:173-195.

base for self-therapy of travelers’ diarrhea. J Travel Med. 2009;16:161-171.

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • APRIL 2018 29

Beyond Rx : OTC Corner A S U P P L E M E N T TO T H E C L I N I C A L A DV I S O R

National Survey Finds Losing Weight Is Harder Than Ever, in Part Because of Americans’ Busy, Modern Lifestyle

AUTHORS Daniel de Carvalho

Global Director of Corporate Communications, Zaluvida Brooke Schoonenberg, MS, RDN, LDN

Woman’s Center for Wellness at Woman’s Hospital Baton Rouge, LA

About the National Survey ‘The Truth about Weight Loss’

The survey was conducted online within the United States by The Harris Poll on behalf of Zaluvida between October 13 and November 6, 2017. The consumer arm of the survey included a total of 1,005 U.S. adults ages 18+, of whom, 713 are currently trying (n=429) or have ever tried (n=284) to lose weight. The professional arm of the survey included 961 U.S. adults ages 18+ who are primary care physicians (n=458) or pharmacists (n=503). For complete research method, including weighting variables and subgroup sample sizes, please contact press@i-remove.com.

new national survey, “The Truth aboutWeight Loss,” indicates that today’s modern lifestyle exacerbates the challenge of losing weight, making weight loss more difficult than ever for U.S. adults. It found that 77% of primary care physicians (PCPs) believe losing weight is harder today than it was for previous generations because of the busy, modern lifestyle of Americans; 69% say it’s harder for Americans to lose weight now compared to just 10 years ago. Findings also suggest that U.S. adults who are trying to lose weight may be relying on approaches that are outdated and incompatible with how they live— 89% of PCPs believe Americans need to take a new approach to weight loss that fits with today’s busy, modern lifestyle. Further complicating the situation, results indicate that although the majority of PCPs and U.S. adults agree that advice and support from a healthcare professional (HCP) are necessary in order to successfully lose weight (93% and 66%, respectively), people may not get professional counsel regarding weight loss as much as either group would like. Among the 69% of U.S. adults who have ever tried or are currently trying to lose weight, most say they did not consult an HCP (68%),

30 SUPPORTED BY ZALUVIDA, MAKERS OF I-REMOVE®

primarily because they don’t view weight loss as a medical issue (45%). Those who are overweight are somewhat less likely to seek support from an HCP than those who are severely or morbidly obese. However, the vast majority of PCPs feel it’s important to intervene and discuss weight loss/ management with overweight patients before they become obese (96%). The survey was conducted online between October 13 and November 6, 2017 by The Harris Poll on behalf of Zaluvida, makers of I-REMOVE®. It included nearly 1,000 HCPs (458 PCPs and 503 pharmacists) and more than 1,000 U.S. adults (18 years and older). This article explores key findings among PCPs and U.S. adults, and examines potential implications that physicians’ assistants (PAs) and nurse practitioners (NPs) may want to consider when working with the healthcare team to counsel patients about weight loss. In keeping with Zaluvida’s mission to tackle some of the most critical challenges in health care, including obesity, the survey was designed to provide important new information about weight loss in the context of today’s busy, modern lifestyle, and to help facilitate HCP/patient dialogue on this topic.

Are your overweight patients losing their weight-loss battle?

Recommend I-REMOVE®—a clinically tested way to deliver up to 3X more weight loss than diet alone without undesirable side effects*1,2 In combination with a healthy lifestyle, I-REMOVE® can help: • Powered by Litramine , it has a dual mechanism of fat binding for decreased fat absorption and increasing satiety, which together result in a reduced calorie load*1-3

Mean weight loss in overweight patients1 WEEK 0

WEEK 8

WEEK 12

-1

MEAN WEIGHT LOSS, LBS

• Over an 11-year period (2006-2017), only 0.003% of patients have reported any product-related health complaints*4

WEEK 4

• Efficacy has been validated by 5 clinical trials in addition to in vitro and animal studies. Results are published in discerning journals such as Obesity and Journal of Obesity

-2 -3 -4 -5 -6 -7 -8 P value <0.001 -9

Litramine® group n=41

Placebo group n=40

References: 1. Grube B, Chong PW, Lau KZ, Orzechowski HD. A natural fiber complex reduces body weight in the overweight and obese: a double-blind, randomized, placebo-controlled study. Obesity (Silver Spring). 2013;21:58-64. 2. Grube B, Chong PW, Alt F, Uebelhack R. Weight maintenance with Litramine (IQP-G-002AS): A 24-week double-blind, randomized, placebo-controlled study. J Obes. 2015;2015:1-6. 3. Uebelhack R, Busch R, Alt F, Beah ZM, Chong PW. Effects of cactus fiber on the excretion of dietary fat in healthy subjects: a double blind, randomized, placebo-controlled, crossover clinical investigation. Curr Ther Res Clin Exp. 2014;76:39-44. 4. Data on file. InQpharm.

* These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.

Visit iremoveprofessional.com to learn more and sign up for future sample offers and updates alli is a registered trademark of GlaxoSmithKline Consumer Healthcare. ©2017 InQpharm. North America, LLC. All Rights Reserved. October 2017 1248685

Available in Walgreens pharmacies and other retailers located next to alli® ®

Beyond Rx : OTC Corner (96%). They believe the three biggest contributors to Americans being overweight/obese are:American diets being too heavily reliant on unhealthy food choices that are more convenient (89%), lack of exercise (88%), and today’s screen-focused lifestyle (73%).

Today’s Lifestyle May Be Taking a Toll on Weight & Health

In questions to both PCPs and U.S. adults, the survey explored the impact today’s lifestyle has on our daily lives and some of the health-related consequences. For example, the vast majority of PCPs and U.S. adults say screen time (i.e., everyday use of mobile, tablet, and computer screens) keeps Americans from moving around today as much as we did in years past (95% and 88%, respectively), and that on-demand services (such as meal delivery, ride sharing, streaming TV, online shopping, etc.) are having the same effect in decreasing Americans’ overall activity level (82% and 80%, respectively). PCPs are also worried about a trend toward eating habits driven by lack of time, with the vast majority being concerned that Americans not taking the time to plan healthy meals will negatively impact their weight (98%) and their family’s weight (97%). It may not be surprising then that an overwhelming majority of PCPs say that, in general, Americans are eating more and moving less these days

The Dilemma for HCPs

Perhaps at least in part as a result of these lifestyle factors, approximately four in 10 U.S. adults are currently trying to lose weight (41%). However, most indicate that they are caught in a cycle of frustration and failure, with about six in 10 of them saying they’re frustrated by repeated efforts to do so (59%).Typically, these respondents have attempted to lose weight five times in the past five years; the majority say the last time they tried to lose weight, they gave up (66%), with the greatest proportion doing so within just 30 days from when they began trying (43%). Only 29% of U.S. adults who are currently trying to lose weight are confident that they’ll be able to achieve their current weight-loss goals. PCPs are aware of the uphill battle Americans face to lose weight

Biggest Contributors to Americans Being Overweight/Obese The typical American diet is too heavily reliant on unhealthy food choices that are more convenient

89%

Lack of exercise

88% 73%

Today's screen-focused lifestyle

66%

People are less active due to our busy, modern lifestyle

61%

Stress Lack of understanding of what constitutes healthy food choices

59% 49%

Lack of sleep

47%

Lack of affordable healthy food options People today don't have enough time to plan and prepare healthy meals

PCPs

41% 17%

Smoking Normal aging changes

15%

BASE: ALL QUALIFIED PCPs (n=458)

Side effects of medications

14%

Q810. In your experience, which of the following are the biggest contributors to Americans being overweight/obese? Please select all that apply.

Other

32 SUPPORTED BY ZALUVIDA, MAKERS OF I-REMOVE®

today— on average, they say only 12% of their patients are able to lose weight and keep it off. They also say dieting can have unwanted consequences, and can even lead to additional weight gain. For example, 77% of PCPs say that after going through a period of extremely reduced calorie intake, a person’s body will prepare for the next “starvation” period and the person may gain weight in response. But, while nearly all PCPs believe that it is important to intervene and discuss weight loss/management with overweight patients before they become obese (96%), only approximately one-third feel they have time to counsel their overweight patients about weight loss (32%). There is also a disconnect in how U.S. adults view their HCPs role in providing counsel about weight loss. While the majority believe that advice and support from an HCP are necessary in order to successfully lose weight (66%), most don’t apply this belief to their own situations and behaviors. Among the 69% of U.S. adults who have ever tried to lose weight, only approximately onethird say that they actually discussed or developed a specific weight-loss plan with an HCP (32%). The Time Is Now

Despite the fact that being overweight and/or obese may increase a person’s risk for many health problems—including heart disease, diabetes, certain cancers, and others—of those who have not discussed a weight-loss plan with an HCP, the main barrier by far is not thinking of weight as a medical issue (45%), followed distantly by not thinking their HCP can help (13%). Those who are severely or morbidly obese are somewhat more likely to rely on professional help for a plan (53%), or

advice (45%), but still those numbers are relatively low considering the potential health implications of severe and morbid obesity, and patients who are overweight but not yet obese may be falling through the cracks just when intervention could potentially help avoid increased risk. As part of the healthcare team, there is an opportunity for NPs and PAs to impact positive change by initiating a constructive dialogue about weight loss when time allows. While there is no “magic bullet” approach in today’s world, 89% of PCPs say having a plan/ method is an important factor for successful weight loss. And, most think the plan needs to be sustainable (79%), not time-consuming (56%), and not demanding sudden/major shifts to a patient’s daily routine (54%). Yet the subject of weight loss can be frustrating for HCPs, too. More than eight in 10 PCPs wish they had more weight-loss options to offer patients who are overweight (i.e., not yet obese) (85%), and the majority say that having a weight-loss product/aid that fits into one’s lifestyle without unpleasant side effects would make it easier for their patients to lose weight (63%). Conclusion

These survey results shine a new light on the issue of being overweight and its impact on Americans, highlighting how today’s lifestyle can play a role in sabotaging overall fitness and health. NPs and PAs in particular have an opportunity to evaluate how they can best work with their colleagues to improve dialogue around healthy lifestyle habits and effective weight-loss strategies that work with patients’ modern lifestyles. Results underscore that by providing counsel and support, HCPs may be able to increase their patients’ chances for reaching and maintaining weight-loss

WHY THE WEIGHT-LOSS DIALOGUE GETS STALLED 96% – it’s important to intervene and discuss weight loss/management with overweight patients before they become obese PCPs (n=458)

• Only 32% feel they have enough time to counsel their overweight patients on weight loss 68% – never discussed/developed a plan with an HCP

U.S. ADULTS WHO EVER TRIED/ ARE CURRENTLY TRYING TO LOSE WEIGHT (n=713)

• #1 Reason for not discussing weight loss with an HCP – 45% don’t think of it as a medical issue » 50% of overweight adults, 34% of obese adults, and 19% of severely/morbidly obese adults feel this way

goals. Findings also demonstrate an opportunity for HCPs to intervene and discuss weight management strategies with overweight patients before they become obese, particularly since patients who are overweight but not yet obese may be less likely to view weight loss as a medical issue, and therefore also less likely to broach the subject with an HCP—even if they are actively trying to lose weight and struggling to do so. Importantly, these findings also point to the role dieticians can play as part of an integrated and comprehensive approach to primary care. While not all practices have registered dieticians on staff, given the challenges associated with losing weight today combined with the potential health implications of letting weight go unchecked, their contributions may be more important than ever. Patients may benefit from expert advice that can steer them away from outdated and/or unhealthy approaches to weight loss—such as crash diets which can eventually lead to weight gain—and instead toward a healthy plan that can be integrated into their lifestyle. Along with making healthy and sustainable changes to diet and exercise,

results further suggest that having an effective weight-loss product/aid that works without unpleasant side effects may be an important tool for helping patients lose weight. While one HCP may not have time to tackle the issue of weight management during a single visit, a sustained team approach may be more effective in not only framing weight loss as a medical issue, but encouraging patients to initiate more open conversations with their HCPs. For more resources about weight loss dialogue with patients, go to www.i-removeprofessional.com/ resources/. For more survey findings, please visit www.weightlossfindings.com. About Zaluvida & I-REMOVE ®

Zaluvida, the makers of I-REMOVE, is a global, integrated life science group that is pioneering therapies and technologies to tackle some of the most critical challenges in health care, including obesity, antimicrobial resistance, and greenhouse gas emissions. I-REMOVE, the number one-selling weightloss formula in Europe, is now available in the U.S. as a dietary supplement.

SUPPORTED BY ZALUVIDA, MAKERS OF I-REMOVE® 33

CME CE FEATURED COURSE

n EDUCATIONAL OBJECTIVES At the conclusion of this activity, participants should be better able to: • Describe the scope and burden of the current opioid epidemic • Discuss the rationale for the use of multimodal pain management strategies in the postoperative setting • Identify individual risk factors, opioid medications, and medication interactions that place individuals at increased risk for opioid-related adverse drug events or substance use disorders • Apply the American Pain Society recommendations regarding multimodal, patient-specific, and procedure-specific treatments for patients experiencing postoperative pain in an effort to enhance recovery after surgery

n COMPLETE THE POSTTEST: Page 42

Estimated Time to Complete: 30 minutes

Designation Statement: Haymarket Medical Education designates this enduring material for a maximum of 0.50 AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Accredited Provider: This activity is provided by Haymarket Medical Education (CME/AMA), Global Education Group (ANCC), and the American Society of Health-System Pharmacists (CPE).

Accreditation Statement: Global Education Group is accredited with distinction as a provider of continuing nursing education by the American Nurses Credentialing Center’s (AANC’s) Commission on Accreditation.

Commercial Supporter: This activity is supported by an educational grant from Pacira Pharmaceuticals, Inc.

Designation Statement: This educational activity for 0.50 contact hours is provided by Global Education Group. Nurses should claim only the credit commensurate with the extent of their participation in the activity. This activity is jointly provided by Global Education Group and Haymarket Medical Education for ANCC credit.

Release Date: February 16, 2018 Expiration Date: February 15, 2019

Program Description: Opioid medications provide highly effective analgesia to patients with postsurgical pain, but not without multiple well-documented risks. In response, clinical focus has increasingly moved to identifying and implementing perioperative strategies to manage pain with less reliance on opioids. A multimodal approach using medications that affect the central and peripheral nervous systems as well as nonpharmacologic interventions can be successful, but depend on collaborative care from all members of a surgical patient’s healthcare team. Intended Audience: Physicians, pharmacists, nurse practitioners, nurses, and others involved in the management of patients experiencing or at risk for postoperative pain

Accredited Provider Disclosure: Haymarket Medical Education staff involved in the planning and content review of this activity have no relevant financial relationships to disclose. American Society of Health-System Pharmacists staff involved in the planning and content review of this activity have no relevant financial relationships to disclose. Liddy Knight, Ashley Marostica, RN, and Andrea Funk of Global Education Group have no relevant financial relationships to disclose.

Conflict of Interest Disclosure Policy: In accordance with the ACCME Standards for Commercial Support, Haymarket Medical Education (HME), American Society of Health-System Pharmacists (ASHP), and Global Education Group require that individuals in a position to control the content of an educational activity disclose all relevant financial relationships with any commercial interest. HME resolves all conflicts of interest to ensure independence, objectivity, balance, and scientific rigor in all its educational activities.

Disclosure of Unlabeled Use: This CME/CE/CPE activity may or may not discuss investigational, unapproved, or off-label use of drugs. Participants are advised to consult prescribing information for any products discussed. The information provided in this CME/CE/CPE activity is for continuing medical education purposes only and is not meant to substitute for the independent medical judgment of a physician relative to diagnostic and treatment options for a specific patient’s medical condition.

Faculty

Disclaimer: The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of Haymarket Medical Education, American Society of Health-System Pharmacists, Global Education Group, or Pacira Pharmaceuticals, Inc. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

Darin J. Correll, MD Department of Anesthesiology, Perioperative and Pain Medicine Brigham and Women’s Hospital Assistant Professor of Anesthesia Harvard Medical School Boston, MA Dr. Correll has no relevant financial relationships to disclose. Julie Golembiewski, PharmD Clinical Assistant Professor, Pharmacy Practice University of Illinois at Chicago College of Pharmacy Chicago, IL Dr. Golembiewski receives consulting fees from Pacira Pharmaceuticals, Inc. Lois J. Pizzi, MSN, ACNS-BC, RN-BC Clinical Nurse Specialist—Pain Management UPMC Shadyside Hospital Pittsburgh, PA Ms. Pizzi is on the speakers bureau for Mallinckrodt Pharmaceuticals. Accreditation Statement: Haymarket Medical Education is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

Instructions: There are no fees for participating in and receiving CME credit for this activity. During the period February 16, 2018, through February 15, 2019, participants must: 1) read the learning objectives and faculty disclosures; 2) complete the pre-assessment test; 3) study the educational activity; 4) respond to all polling questions in the online version of the activity; and 5) complete the posttest and evaluation form and submit it online. A statement of credit will be issued only upon receipt of the above elements and a posttest score of 70% or higher. All components must be completed and submitted online at ClinicalAdvisor.com/Apr18feature. If you have any questions relating to your certificate or other issues with the activity, please contact myCME.Support@haymarketmedical.com. Provided by

CME CE FEATURED COURSE: DARIN J. CORRELL, MD; JULIE GOLEMBIEWSKI, PHARMD; LOIS J. PIZZI, MSN, ACNS-BC, RN-BC

Focus on safety: Managing postoperative pain The scope of the opioid epidemic has prompted clinicians to reexamine prescribing patterns and adopt a multimodal approach to pain management.

Opioids provide effective analgesia in the postoperative setting, but they are associated with a risk of adverse events.

pioids provide highly effective analgesia to patients with moderate or severe postoperative pain, but their use is associated with numerous adverse events (AEs) and the potential for addiction, dependence, and abuse.1,2 At present, 60% of drug overdose deaths involve an opioid, and 91 people die every day from an opioid overdose.3 Notably, 40% of the deaths caused by an opioid overdose involve prescription opioids.1,4

Opioid prescribing patterns

The opioid prescribing pattern in the United States (US) has changed in recent years, with the total number of prescriptions dispensed peaking in 2012 and declining between 2012 and 2016.5 Despite the decline, however, the national opioid prescribing rate in 2016 remains high: In 2016, 66.5 opioid prescriptions were issued per 100 persons. Although that figure marks the lowest rate in more than a decade, it still represents more than 214 million total opioid prescriptions.5 The rate of opioid prescribing varies widely by US region. For example, some US counties have opioid prescribing rates 7 times higher than the national rate, and approximately 25% of US counties dispense enough opioid prescriptions to supply every county resident with one.5 In 2016, Alabama had the highest prescribing rate, and the District of Columbia had the lowest (121.0 vs 32.5 opioid prescriptions dispensed per 100 persons, respectively).6 Figure 1 shows opioid prescribing rates by state stratified into 4 categories. www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • APRIL 2018 35

CME CE

FEATURED COURSE

FIGURE 1. Opioid prescribing rates by state6

<64.1

64.1–82.9

83.0–107.1

>107.1

Retail opioid prescriptions dispensed per 100 persons. Centers for Disease Control and Prevention. US prescribing rate maps. https://www.cdc.gov/drugoverdose/maps/rxrate-maps.html.

Opioids have long been regarded as the standard of care for the management of acute postoperative pain.7 In fact, in a recent US survey of 200 surgeons, 94% of them reported that they frequently prescribe opioids to manage postoperative pain, and 91% reported that they frequently feel pressure to prescribe more opioids than are actually needed by their patients.8 The same survey, which also included responses from 500 patients who had undergone orthopedic or soft tissue surgery, found that 1 in 10 patients became addicted to or dependent on opioids after postsurgical exposure.8 Each year, an estimated 70 million people in the US who undergo surgery receive an opioid; thus, based on these survey findings, as many as 7 million people could potentially become addicted to or dependent on opioids annually.8 Management of postoperative pain

Evidence suggests that progress in managing postoperative pain has been slow and generally remains suboptimal. In a 1995 survey of 300 US hospitals, only 42% reported having an acute pain management program, with an additional 13% reporting plans to establish such a program.9 In the same survey, which included 500 adults who had undergone surgery, 77% reported pain after surgery; of these, 80% reported experiencing moderate to extreme pain.9 A survey of 250 surgical patients conducted in 2003 showed similar results: About 80% of patients experienced acute pain after surgery, with 86% of patients reporting moderate, severe, or extreme pain.10 In a 2014 survey of 300 surgical

patients, about 86% reported postoperative pain; of these, 75% described the pain in the immediate postoperative period as moderate or extreme, and 74% stated that they still had moderate or extreme levels of pain after discharge.11 A wide array of options is available for the management of postoperative pain, and strategies continue to evolve.12 Opioids are commonly used in the postoperative setting because they are effective, relatively inexpensive, and easily administered orally and parenterally; furthermore, some opioid formulations have a longer duration of action than other agents.13 In recent years, however, the scope and burden of the US opioid epidemic has prompted healthcare providers to reexamine opioid prescribing patterns and to consider the use of other analgesics. Surgery has been called “an unintentional gateway to the opioid epidemic,” but the problem can be addressed through collaborative efforts to maintain an open dialogue about opioid-sparing strategies among key stakeholders, including healthcare executives, hospital administrators, pharmacists, surgeons, and patients.2 To that end, reducing patient exposure to prescription opioids by implementing multimodal analgesia (ie, the use of various analgesic agents and techniques that target different mechanisms of action) has recently emerged as an effective pain management strategy in patients undergoing various surgical procedures.12 The rationale for the use of multimodal analgesia includes the potential for additive or synergistic effects and improved pain relief compared with single-agent strategies.12 POLLING QUESTION

Is the American Pain Society guideline for the use of multimodal management of postoperative pain followed in your workplace? a. b. c. d.

Yes, fully Yes, but only somewhat No Not applicable

American Pain Society guideline for the management of postoperative pain

In 2016, the American Pain Society (APS)—with input from the American Society of Anesthesiologists and the American Society of Regional Anesthesia and Pain Medicine—published its first-ever clinical practice guideline on the management of postoperative pain.12 The guideline, aimed at all clinicians who manage postoperative pain, was developed by a 23-member multidisciplinary panel

36 THE CLINICAL ADVISOR • APRIL 2018 • www.ClinicalAdvisor.com

TABLE 1. APS pharmacological recommendations Local, intra-articular, or topical techniques

Neuraxial or regional anesthetic techniques

• Opioids • NSAIDs and/or acetaminophen • Gabapentin or pregabalin • IV ketaminea

Generally not used for thoracotomy

Epidural with local anesthesia (with or without opioid), intrathecal opioid, paravertebral block

Total hip or total knee replacement

• Opioids • NSAIDs and/or acetaminophen • Gabapentin or pregabalin • IV ketaminea

Intra-articular local anesthetic and/or an opioid

Epidural with local anesthetic (with or without opioid), intrathecal opioid, site-specific regional anesthetic technique with local anesthetic

Open laparotomy

• Opioids • NSAIDs and/or acetaminophen • Gabapentin or pregabalin • IV ketaminea • IV lidocaine

Local anesthetic at incision

Epidural with local anesthetic (with or without opioid), transversus abdominis plane block

Surgery type

Systemic pharmacologic therapy

Thoracotomy

IV lidocaine infusion

Adapted from Chou R, et al. J Pain. 2016;17(2):131-157. IV, intravenous; NSAIDs, nonsteroidal anti-inflammatory drugs. a Consider for opioid-tolerant or otherwise complex patients (panel consensus).

that systematically reviewed the evidence and provided pain management recommendations in the postoperative setting.12 Each recommendation received a grade for strength of recommendation (strong or weak) and for the quality of evidence (high, moderate, or poor).12 In brief, the panel recommended offering multimodal analgesia for postoperative pain in children and adults (strong recommendation; high-quality evidence), further suggesting that “around-the-clock nonopioid analgesics and nonpharmacologic therapies” be routinely incorporated into multimodal analgesia regimens.12 The panel cautioned that patients must be appropriately monitored to identify and manage AEs that differ by analgesic agent and technique.12 (Go to ClinicalAdvisor.com/Apr18feature for a table summarizing the APS recommendations for management of postoperative pain.) The composition of multimodal regimens is dependent on the type of surgery, individual clinical factors, and patient preference.12 The APS guidelines encourage “the use of local anesthetic-based regional anesthesia techniques for surgical procedures of the extremities, abdomen, and thorax,” due to the demonstrated efficacy of these techniques when used in conjunction with systemic analgesics.12 Although many multimodal strategies are available for use, few have been rigorously investigated in specific surgeries.12 The APS recommends cognitive modalities and transcutaneous electrical nerve stimulation as nonpharmacologic strategies and an epidural with a local anesthetic (with or without an opioid) or an intrathecal opioid as neuraxial

anesthetic techniques for 4 commonly performed surgeries: thoracotomy, total hip replacement, total knee replacement, and open laparotomy. For all of these surgeries, the other APS pharmacologic recommendations are presented in Table 1.12 Multimodal pain management strategies: Faculty commentary

The 3 faculty members providing expert commentary for this activity concurred that the use of a multimodal pain management strategy should be strongly considered in the postoperative setting, and all of them have experience with its implementation in their respective facilities. To promote a multimodal strategy, it is important to consider nonpharmacologic treatments at the very beginning of the order set, Darin Correll, MD, noted. “If it is necessary to move from nonpharmacologic to pharmacologic options, the starting point is a nonopioid agent, usually acetaminophen, unless contraindicated. All patients should also receive an NSAID [nonsteroidal anti-inflammatory Acetaminophen, the most commonly used oral analgesic worldwide, is effective and inexpensive for the management of mild pain and is associated with a low AE profile if used as recommended.14,15 Unlike NSAIDs, acetaminophen does not irritate the gastric mucosa, affect platelet function, or lead to renal insufficiency.15 Acetaminophen is associated with a substantial opioid-sparing effect.15

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • APRIL 2018 37

CME CE

FEATURED COURSE

drug], unless there is a reason not to use one. After these options, one looks at opioid choices,” he said. POLLING QUESTION

In your workplace, are surgical patients advised to continue taking nonprescription analgesics after discharge? a. b. c. d.

Yes, routinely Sometimes Never Not applicable

Dr. Correll added that postoperative patients are usually still taking an opioid, along with other analgesia, at hospital discharge. “Unfortunately, many physicians do not think about advising their patients to continue taking acetaminophen or an NSAID after discharge, but rather assume that patients will do this on their own,” he said. “It’s important to expressly tell patients to continue taking nonopioid options for some period of time after they are home. Patients need to know that they should not stop taking these agents just because a doctor is not prescribing it to them. They should also be told to continue some of the nonpharmacologic strategies, such as the use of ice or heat. They can implement all of these pain management approaches on their own.” “Multimodal pain management makes so much sense,” said Lois J. Pizzi, MSN, ACNS-BC, RN-BC. “When you are on a multimodal plan, you start with acetaminophen and/ or an NSAID, and when you must move to an opioid, you keep the nonopioid first step intact to facilitate reduction in the opioid needed for pain relief. Using a combination of medications with different mechanisms of action can lead to fewer side effects and can reduce the opioid doses needed Traditional (nonselective) NSAIDs are associated with gastrointestinal (GI), hematologic, cardiovascular, and renal AEs.14-16 • Traditional NSAIDs include aspirin, diclofenac, ibuprofen, naproxen, indomethacin, ketoprofen, and piroxicam. The cyclooxygenase (COX)-2 selective NSAID celecoxib seems to be associated with less risk of GI toxicity than the nonselective NSAIDs.15 In the perioperative setting, COX-2 inhibitors are not associated with an increased bleeding risk, as they do not affect platelet function. Although meloxicam is not labeled as a COX-2 inhibitor, it has a very high ratio of COX-2/COX-1 inhibition and has not been found to increase bleeding risk.17

to achieve pain relief. These medications complement each other and help to facilitate well-rounded pain management.” Julie Golembiewski, PharmD, noted that pharmacists generally tend to think about drugs, but should also be aware of the many nondrug-related strategies that can help to alleviate pain. “Nurses use many simple pain management strategies in postoperative patients that are very important,” she said. “For example, teaching a patient who has undergone an abdominal surgery to hold a pillow over the incision while coughing can make all the difference in the world.” Combining analgesics may allow the use of lower total doses of some drugs15 and reduce the need for opioids.18,19 Data from several studies have shown that the administration of NSAIDs or other analgesics in combination with an opioid is associated with a reduction in opioid consumption. For example, data from 52 randomized, placebo-controlled trials in 4893 adult surgical patients showed that median average 24-hour morphine consumption was reduced by 15% to 55% with all regimens that included nonopioid agents (acetaminophen, NSAIDs, or selective COX-2 inhibitors) administered in conjunction with morphine delivered via a patient-controlled anesthesia (PCA) device.17 Furthermore, an analysis of 60 randomized controlled trials in adults who had undergone major surgery showed that the addition of acetaminophen (paracetamol), NSAIDS, or COX-2 inhibitors to PCA morphine reduced 24-hour morphine consumption by 6.3 mg to 10.9 mg.19 Adopting a multimodal approach has led to a reduction in the use of PCA pumps and naloxone in their respective facilities, according to Dr. Golembiewski and Ms. Pizzi. Dr. Golembiewski explained that multimodal strategies are most commonly used in patients undergoing total hip and total knee replacement surgery at her facility. “In these patients, we use a multimodal approach much earlier— usually starting preoperatively—and no longer rely on a PCA opioid regimen postoperatively.” Discharge medication

Providing opioids to surgical patients at discharge could potentially lead to long-term opioid use, opioid dependence, or diversion to individuals other than the intended surgical patient.14 A retrospective cohort study investigating patterns of analgesic use after low-risk surgery in 391,139 older, opioid-naïve patients found that the prescription of analgesics immediately following ambulatory surgery was common and led to long-term use.20 In the study, opioids were newly prescribed to 7.1% of patients within 7 days of hospital discharge and prescribed to 7.7% of patients 1 year after surgery.20 During this time, oxycodone use increased from 5.4% within 7 days of surgery to 15.9%

38 THE CLINICAL ADVISOR • APRIL 2018 • www.ClinicalAdvisor.com

Faculty suggestions for identifying and addressing prescription opioid abuse, misuse, and diversion in postoperative patients Dr. Correll: “The question is whether we can change the risk, as opposed to the people who are at higher risk. Do patients at higher risk need some sort of tighter follow-up? In that regard, I think we are just not paying attention at all. Obviously, you can’t tell a patient, ‘We just ripped you open and shoved something in or took something out of you, but because you’re at risk, you don’t get any opioid at all, and here’s some acetaminophen and a stick to bite on.’ The patient will probably need an opioid for a period of time, and some patients need follow-up more promptly than 4 to 6 weeks after surgery, because they might already be in trouble by that time.” Ms. Pizzi: “If we send patients home with uncontrolled pain, and there is some substance abuse in their family or their living situation, we could potentially open them up to trouble. We have to pay attention to the patients’ environments when they leave the hospital.” Dr. Correll: “It is important to understand the patient’s home situation and what we can do in and around it. Although I don’t know with certainty that I have the answer, it seems better to follow up with patients who are at risk as opposed to saying, ‘Well, then you get nothing.’” Ms. Pizzi: “Patients who are in the process of recovery, or have been through recovery, can be faced with surgery or a medical emergency that warrants the need for them to have opioid pain medications. These patients deserve pain relief and we should be able to offer the medication and the support that they need. We must be cognizant of their situation so that when they do get discharged, they are not facing an even greater risk because they’ve been in the hospital and needed pain medication.” Ms. Pizzi: “Pennsylvania and other states require the use of a PDMP to look at a patient’s history of filling prescriptions for controlled substances. It is a way to look at what prescriptions have been filled by the patient and who is prescribing

at 1 year after surgery.20 The primary analysis showed that patients who received an opioid prescription within 7 days of surgery were 44% more likely to become long-term opioid users within 1 year compared with those who received no such prescription.20 A secondary analysis showed that patients who began taking NSAIDs within 7 days of surgery were nearly 4 times more likely to become long-term NSAID users compared with patients who did not take NSAIDs.20

the medications. Looking at this record would also allow the practitioner to see which opioid pain medications have been prescribed and to be prepared to adjust the postoperative pain management plan because they have deemed that the patient is opioid-tolerant. Tolerance can be due to either a chronic pain condition or a substance abuse issue.” Dr. Golembiewski: “We do have physicians that look at the PDMP, but it’s not necessarily the surgeons. It’s our pain physicians, sickle-cell physicians, and other physicians caring for patients with chronic pain. At present, we have not implemented a standard process for assessing each patient who requires an opioid for analgesia for potential abuse by using a validated screening tool. Furthermore, I don’t know that all our surgeons would be on board with regular use of such a tool because of the challenge of adding one more step when seeing a patient in a very busy surgical clinic and when most patients are referred to our surgeons by physicians outside our system. That makes it very difficult to coordinate the postoperative plan of care among healthcare providers.” Dr. Correll: “We have an education committee at my institution that includes people from the pain side and the addiction side. I try to impress upon people that both sides need to stop living in their own little silos and realize the value of crosstalk.” Ms. Pizzi: “If I think that opioids could potentially be a problem for a patient, I take the path of least resistance and discuss the matter with the nurse practitioner or the physician assistant. The doctor typically is too busy, whereas the nurse practitioner or the physician assistant has a little more time to be able to talk to the patient with me. You have to get the person who is most available and can take some action with you. You need to look at red flags from the patient or family member and make an assessment. If a patient is trying to break into his or her PCA pump with a dinner knife—and I’ve seen it—there is a problem.”

Other reports shed light in a somewhat different direction. A review of claims data found that new persistent opioid use after either major or minor surgery was associated with behavioral and pain disorders.21 Recently published findings of a retrospective cohort study indicate that among opioid-naïve patients, the duration of postsurgical opioid use, rather than opioid dosage, was the most important predictor of misuse. The authors note that a single opioid

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • APRIL 2018 39

CME CE

FEATURED COURSE

prescription refill was associated with a 40% greater risk of potential misuse.22 When asked whether clinicians are either severely limiting opioid use or not prescribing them at all to patients at hospital discharge, Ms. Pizzi described a “Meds to Go” initiative developed by the emergency department (ED) at her facility. “If a patient who has recently undergone surgery presents to the ED with a problem pertaining to his or her discharge pain medication, we will not send them out into the cold; however, at the same time, we cannot be responsible for prescribing the patient’s postoperative pain medication,” she said. “What usually happens is that the pharmacy will issue 2 doses of oxycodone, maybe some acetaminophen with it, and instruct the patient to call his or her surgeon the next day. Of course, this puts the onus back on the treating physician, who is the one who needs to take the responsibility for managing that patient’s postdischarge pain.” Opioid-related adverse events

Opioids provide effective analgesia in the postoperative setting, but their use may be limited by the risk of opioidrelated AEs, such as nausea, vomiting, constipation, urinary retention, postoperative ileus, pruritus, and central nervous system effects.7,23 Additionally, postoperative opioid-induced respiratory depression (OIRD) has been shown to be a significant cause of brain damage and death in the perioperative period.24 Claims analysis data have shown that 88% of OIRD events occurred within 24 hours of surgery, and that improved monitoring and response could have prevented 97% of such events.24 Factors contributing to OIRD included multiple prescribers, concomitant administration of nonopioid sedating medication, and inadequate assessment or response by the nursing staff.24 According to the Joint Commission, the potential for the occurrence of OIRD should always be considered because25: • The risk may be greater in patients receiving higher doses of opioids • The incidence may be higher than reported, including in clinical trials • Some patients are at higher risk, including those ——With sleep apnea ——Who are morbidly obese, very young, elderly, and very ill ——Who concomitantly receive other drugs that are central nervous system and respiratory depressants

A retrospective analysis of more than 21 million inpatient discharges reported in a US administrative database showed that the use of opioids and sedatives are independent and additive risk factors for in-hospital cardiopulmonary resuscitation.26 Specifically, patients who received opioids alone and sedatives alone had a 1.81-fold and 1.82-fold increased risk of in-hospital cardiopulmonary resuscitation, respectively, and those who received both opioids and sedatives had a 3.4-fold increased risk of in-hospital cardiopulmonary resuscitation compared with those who received neither opioids nor sedatives.26 As we move toward limiting opioids, gabapentinoids (ie, gabapentin and pregabalin) are more and more frequently being prescribed perioperatively for their opioid-sparing and adjuvant analgesic effects. Their inherent risk of increased sedation has become well known, but a recent retrospective study in patients undergoing laparoscopic surgery showed an increased rate of respiratory depression when gabapentinoids were used in multimodal analgesic regimens, especially in elderly patients.27 Vigilance should also be maintained in other patients with an elevated baseline risk for respiratory depression, including those who are morbidly obese or have obstructive sleep apnea.28 Data suggest that nearly 14% of patients who receive an opioid experience opioid-related AEs.23,29 Several patientrelated factors, including male sex, age ≥65 years, obesity, presurgery opioid use, and a higher score on the Charlson Comorbidity Index, have also been associated with an increased risk of opioid-related AEs.23 Patients who develop an opioid-related AE, compared with those who do not, have been shown to have a longer hospital stay, a higher cost of care, an increased risk of 30-day readmission, and higher in-patient mortality.23 Risk assessment for opioid abuse and misuse

Numerous guidelines have been established to promote safe prescribing of opioids, all of which include similar recommendations for risk assessment and monitoring.30 Prescription drug monitoring programs (PDMPs), electronic databases that track controlled substance prescriptions at the state level, were established “to improve opioid prescribing, inform clinical practice, and protect patients at risk.”31 Although PDMPs have shown to be effective, the abuse, misuse, and diversion of prescription opioids nonetheless remains a serious public health problem because of the potential for addiction, physical dependence, overdose, suicide, accidents, or death.32 Clinician education can help to facilitate well-informed, individualized decision-making about whether to initiate, modify, or discontinue opioid treatment.30

40 THE CLINICAL ADVISOR • APRIL 2018 • www.ClinicalAdvisor.com

en/New-Research-Opioid-Addiction-and-Dependence-After-Surgery-is-

Benefits of PDMPs include31:

Significantly-Higher-than-Previously-Known.html. Accessed December 14, 2017.

• Allow healthcare providers to see a patient’s prescribing history, which may help to inform prescribing decisions

9. Warfield CA, Kahn CH. Acute pain management programs in U.S.

• Provide real-time data if the prescription is entered into the system when the controlled substance is dispensed • Can be used by state health departments to better understand the opioid epidemic and evaluate interventions • May be integrated into electronic health record systems, allowing physicians to delegate access to physician assistants and nurse practitioners

hospitals and experiences and attitudes among U.S. adults. Anesthesiology. 1995;83:1090-1094. 10. Apfelbaum JL, Chen C, Mehta SS, Gan TJ. Postoperative pain experience: results from a national survey suggest postoperative pain continues to be undermanaged. Anesth Analg. 2003;97:534-540. 11. Gan TJ, Habib AS, Miller TE, et al. Incidence, patient satisfaction, and perceptions of postsurgical pain: results from a US national survey. Curr Med Res Opin. 2014;30:149-160. 12. Chou R, Gordon DB, de Leon-Casasola OA, et al. Management of postoperative pain: a clinical practice guideline from the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine,

The faculty offered their suggestions for identifying and addressing prescription opioid abuse, misuse, and diversion in postoperative patients in the sidebar on page 39. n

and the American Society of Anesthesiologists’ Committee on Regional

This is part 1 of a three-part series on postoperative pain management. To access parts 2 and 3, go to myCME.com/postopseries.

operative pain. US Pharm. 2015;40(3):HS17-HS20.

Anesthesia, Executive Committee, and Administrative Council. J Pain. 2016;17(2):131-157. 13. Ferlas B, Born M. Liposomal bupivacaine: a new option for post 14. Schug SA, Chandrasena C. Postoperative pain management following ambulatory anesthesia: challenges and solutions. Ambulatory Anesth. 2015;2:11-20. 15. Kamming D, Chung F, Williams D, et al. Pain management in ambula-

References

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2. Gan TJ. Opinion: hospital formularies can play key role in reducing opioid

gov/Drugs/DrugSafety/ucm451800.htm. Updated November 16, 2017.

epidemic. Managed Healthcare Executive website. http://managedhealth-

Accessed January 30, 2018.

careexecutive.modernmedicine.com/managed-healthcare-executive/news/

17. Younan M, Atkinson TJ, Fudin J. A practical approach to discontinuing

opinion-hospital-formularies-can-play-key-role-reducing-opioid-epidemic.

NSAID therapy prior to a procedure. Pract Pain Manag. 2013;13(10).

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https://www.practicalpainmanagement.com/issue/1310. Updated

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December 9, 2013. Accessed February 2, 2018.

understanding the epidemic. https://www.cdc.gov/drugoverdose/epidemic/

18. Elia N, Lysakowski C, Tramer MR. Does multimodal analgesia with

index.html. Updated August 30, 2017. Accessed December 13, 2017.

acetaminophen, nonsteroidal anti-inflammatory drugs, or selective cyclo-

4. Centers for Disease Control and Prevention. Opioid overview: data

oxygenase-2 inhibitors and patient controlled analgesia morphine offer

overview. https://www.cdc.gov/drugoverdose/data/index.html. Updated

advantages over morphine alone? Anesthesiology. 2005;103:1296-1304.

July 18, 2017. Accessed December 14, 2017.

19. McDaid C, Maund E, Rice S, et al. Paracetamol and selective and non-

5. Centers for Disease Control and Prevention. Opioid overdose: U.S.

selective non-steroidal anti-inflammatory drugs (NSAIDs) for the reduc-

prescribing rate maps. https://www.cdc.gov/drugoverdose/maps/rxrate-

tion of morphine-related side effects after major surgery: a systematic

maps.html. Updated July 31, 2017. Accessed January 30, 2018.

review. Health Technol Assess. 2010;14:1-50.

6. Centers for Disease and Control and Prevention. Opioid overdose: U.S.

20. Alam A, Gomes T, Zheng H, et al. Long-term analgesic use after low-risk

state prescribing rates, 2016. https://www.cdc.gov/drugoverdose/maps/

surgery: a retrospective cohort study. Arch Intern Med. 2012;172:425-430.

rxstate2016.html. Updated July 31, 2017. Accessed December 14, 2017.

21. Brummett CM, Waljee JF, Coesling J, et al. New persistent opioid

7. Gan TJ. Poorly controlled postoperative pain: prevalence, consequences,

use after minor and major surgical procedures in US adults. JAMA Surg.

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2017;152(6):e170504.

8. New research: opioid addiction and dependence after surgery is significantly

22. Brat GA, Agniel D, Beam A, et al. Postsurgical prescriptions for opioid

higher than previously known [news release]. Parsippany, NJ: Globe Newswire;

naïve patients and association with overdose and misuse: retrospective

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cohort study. BMJ. 2018;360:j5790. https://doi.org/10.1136/bmj.j5790.

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23. Kessler ER, Shah M, Gruschkus SK, Raju A. Cost and quality

analgesic therapy with gabapentin and its association with postoperative

implications of opioid-based postsurgical pain control using administrative

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claims data from a large health system: opioid-related adverse events

28. Correll DJ. Multimodal analgesia and the vigilance of Heimdall.

and their impact on clinical and economic outcomes. Pharmacotherapy.

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2013;33(4):383-391.

29. Gan TJ, Lubarsky DA, Flood EM, et al. Patient preference for acute

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30. Alford DP. Opioid prescribing for chronic pain—achieving the

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31. Centers for Disease Control and Prevention. Opioid overdose: what

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states need to know about PDMPs. https://www.cdc.gov/ drugoverdose/

26. Overdyk FJ, Dowling O, Marino J, et al. Association of opioids and sedatives

pdmp/states.html. Updated October 3, 2017. Accessed January 2, 2018.

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prescription opioid analgesics in the management of chronic noncancer

27. Cavalcante AN, Sprung J, Schroeder DR, Weingarten TN. Multimodal

pain. Pain Manag. 2016;6(5):497-508.

CME CE

POSTTEST Expiration date: February 15, 2019

Credit Designation: A statement of credit will be issued only upon receipt of a completed pre-assessment test, polling questions, activity evaluation form, and posttest with a score of 70% or higher. All components must be completed and submitted online at ClinicalAdvisor.com/Apr18feature. CREDITS: 0.50 | Focus on safety: Managing postoperative pain

1. Which statement is correct regarding current opioid use in the United States? a. Opioid prescribing rates are generally equivalent across US states. b. The adverse event profile associated with opioids has dramatically reduced opioid use in the surgical setting. c. Prescription opioids are responsible for nearly all drug overdose deaths in the US. d. Opioid prescribing has declined in recent years. 2. Which statement is correct regarding multimodal management of postoperative pain? a. The American Pain Society (APS) 2016 guidelines update several earlier such guidelines on the management of postoperative pain. b. The APS guidelines focus solely on prescription pharmacologic interventions for postoperative pain. c. The APS guidelines recommend incorporating a combination of nonopioid analgesics and nonpharmacologic therapies into multimodal analgesia regimens.

d. The majority of multimodal strategies have been rigorously assessed in randomized controlled trials among patients undergoing all commonly performed surgical procedures. 3. Which of the following factors has been shown in studies to contribute to postdischarge opioid dependence or misuse in previously opioid-naïve surgical patients? a. Duration of postsurgical opioid use b. Postsurgical opioid dosing levels c. Major but not minor surgical procedure d. Orthopedic but not abdominal surgical procedure 4. Which statement is correct about prescription drug monitoring programs (PDMPs)? a. PDMP use is mandated in all US states. b. PDMPs can inform a postoperative pain management plan by informing prescribers if a patient may be opioid-tolerant. c. PDMPs are routinely used in the postoperative setting to assess individual patients’ history of opioid use. d. PDMPs cannot be integrated into electronic health records.

TO TAKE THE POSTTEST please go to: ClinicalAdvisor.com/Apr18feature

42 THE CLINICAL ADVISOR • APRIL 2018 • www.ClinicalAdvisor.com

YOUR COMMENTS LARC IMPLANT DIMENSIONS The recent article on LARC [“Long-acting reversible contraceptives,” Feb. 2018, p. 23] stated that the Nexplanon implant is 4 cm x 2 cm. In fact, it is 4 cm x 2 mm.—SUSANNA LEVIN, WHNP, New Rochelle, N.Y. (234-1)

MY MOST MEMORABLE PATIENT CELEBRATING LIFE AT THE END OF LIFE My most memorable patient? There are too many from which to choose in any category (that happens when we get “long in the tooth”), but a favorite story that I have told my graduate students, friends, and family is about Grandma R, as she liked to be referred to. I had only been an NP for 2 years at the time. Grandma’s granddaughter was a professional colleague and friend who Send us your letters with questions and comments to: Advisor Forum, The Clinical Advisor, 275 7th Avenue, 10th Floor, New York, NY 10001.You may contact us by e-mail at editor@clinicaladvisor.com. If you are writing in response to a published letter, please indicate so by including the number in parentheses at the end of each item. Letters are edited for length and clarity. The Clinical Advisor’s policy is to print the author’s name with the letter. No anonymous contributions will be accepted.

had been one of my preceptors 15 years prior when we had worked together as staff nurses in critical care. She was a demanding professional and taught me to be an aggressive patient advocate, no matter the costs. I knew that this would be difficult but was honored that a nurse whom I had held in such high esteem would request that I care for her loved one. Grandma was 97 years old with aortic stenosis so severe that one could hear the murmur when you walked in the room; she also had decompensated heart failure and recurrent bouts of acute on chronic renal failure. We walked the tightrope daily trying to keep her comfortable. The consulting cardiologist had nothing left to offer, and so we would find ourselves pulse dosing diuretics and searching for ways to keep her out of frank renal failure, which sometimes required a small IV fluid bolus. Grandma had a bright disposition and was deeply religious; she called me to her room one day to say that she had been praying and decided that it was time to go meet her Lord and that she wanted to stop her medicines, except for the ones that would keep her comfortable. I consulted with her son who had power of attorney. He was one of 12 and needed to ask his siblings. Subsequently, all agreed but they did not want hospice services. They wanted me to manage her end-of-life care. We did switch gears a bit and added morphine to reduce preload and the forthcoming anxiety and restlessness was expected with cessation of the diuretics. Grandma was insistent that she wanted to be as alert as possible to the end.

OUR CONSULTANTS

Philip R. Cohen, MD,

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

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

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

Abimbola Farinde, PhD, PharmD,

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

Laura A. Foster, CRNP, FNP,

Abby A. Jacobson, MS, PA-C,

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

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

www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • APRIL 2018 43

Advisor Forum Things went well for a couple days when she summoned me to gather her family at the bedside, as she wanted to say her final goodbyes. Her son arranged that, and there was a lovely gathering from the late afternoon into the evening. Grandma wanted to nap and asked that nobody leave, including me. The evening wore on, and, hard to believe, all 12 children were in the room with intermittent visits from some of the grandchildren (and me, of course). They never left her side. When Grandma awoke, she exclaimed, “What a wonderful rest! Now I feel like I can go on!” She asked her children to line up according to age, then began to speak. She called each child by name and remarked about how proud she was to have been blessed with a child of God that she had been entrusted to raise. She told of an accomplishment of theirs that made her feel like her life had been worthwhile. She told of a lesson that she had hoped they learned about life. She told them all that she would have never, ever traded one moment if she could live again. With a wink in her eye, and not a dry eye in the room, Grandma said “Well, I have to go now. Remember that we will all be together again someday. That is God’s promise.” Grandma waved goodbye and said, “I love you” and closed her eyes. We stood in amazement, nobody uttering a word. Grandma stopped breathing within moments. The funeral was truly a celebration of life reaffirmed! The family was abuzz with the experience and there was no grief, only happiness and stories about the best mom that ever lived! In my years of practice since that time, I have attended “good deaths” and “bad deaths” but none so profound as Grandma’s death. My prayer for all is that we can somehow find our way in this life to have courage, forgiveness, and blessings like Grandma R and her family. I think of her often.—JEFFREY DOUGLASS, SR, FNP, NP-C, Westland, Mich. (234-2)

Debra August King, PhD, PA,

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

Mary Newberry, CNM, MSN,

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

CASE FILES POSTOBSTRUCTION DIURESIS Contributed by Sherril Sego, FNP-C, DNP Mr J was an 89-year-old man with a long history of problems voiding due to increasing benign prostatic hyperplasia. He was on tamsulosin and finasteride for years when he began to experience worsening dementia. As his dementia progressed, it became necessary to move him to a long-term care facility. Aides noted that his stream was more of a slow dribble. When asked, his wife assured them that it had been that way for years. One morning, Mr J was found unconscious on the floor. He was transported to the nearest emergency department where he was found to have a K+ of 6.5 mEq/L and a creatinine of 12.1 mg/dL. A Foley catheter was inserted and 2 liters of urine returned in less than 3 hours. He was treated emergently with IV insulin in a D5 ½ NS drip and transported to a tertiary care facility. During the next few hours his lab values normalized. He continued to produce large amounts of urine amounting to nearly 8 liters in the first 24 hours. However, as his immediate status improved, it became apparent that he was producing urine far in excess of normal. Soon the staff was replacing K+ and NS to keep up with the loss. Postobstruction diuresis (POD) can occur when retained urine is allowed to drain without periodic clamping of the catheter to allow volume and pressure sensors to adjust. POD is a rare but potentially lethal complication associated with the relief of urinary obstructions. Urine production exceeding 200 mL per hour for 2 consecutive hours or producing greater than 3 L of urine in 24 hours is diagnostic of POD. Mr J was eventually discharged back to the LTC in stable condition with a permanent Foley catheter in place. (234-3) n

Claire O’Connell, MPH, PA-C,

an associate professor at the Rutgers University Physician Assistant Program, Piscataway, N.J.

44 THE CLINICAL ADVISOR • APRIL 2018 • www.ClinicalAdvisor.com

Katherine Pereira, DNP, FNP,

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

Sherril Sego, FNP-C, DNP,

is an independent consultant in Kansas City, Mo.

Dermatology Clinic CASE #1

Painful plaques on the elbows MARGARET BARTON AND JESSICA BOULAVSKY, MD

A 71-year-old Caucasian man with myelodysplastic syndrome and on chemotherapy with azacitidine presented to the hospital with 2 days of high fever and 4 days of worsening skin lesions. The lesions appeared on the elbows as “blood blisters,” which grew larger and more painful. He denied any other new medications. He was placed on broad spectrum antibiotics by infectious disease physicians out of concern for ecthyma gangrenosum, and dermatology was consulted. On examination, violaceous, edematous plaques with a central pseudovesicle were seen on the bilateral elbows. Punch biopsies were performed for tissue culture and histology. What is your diagnosis? Turn to page 49

CASE #2

Blistering skin on a boy’s hands and feet JOAN FERNANDEZ, JESSICA BOULAVSKY, MD

A 15-month-old boy presents with a history of skin blistering since birth, primarily on his hands, feet, and the perioral face. Blisters and erosions also involve the trunk, some in an annular configuration. There is no family history of neonatal blistering or skin fragility. Over time, the patient has had a decreased number of new vesicles and bullae associated with trauma and friction but has developed thicker skin on the soles of the feet and dystrophic nails. What is your diagnosis? Turn to page 50 www.ClinicalAdvisor.com • THE CLINICAL ADVISOR • APRIL 2018 45

Dermatology Clinic CASE #1

Sweet syndrome

Sweet syndrome (SS) is a dermatologic disorder with clinical and histologic features that can be associated with several systemic disorders and medications.1 It was first reported in 1964 by Robert Sweet, who described ‘an acute febrile dermatosis’ he witnessed in 8 middle-aged women.2 The patients he described had skin eruptions that resembled erythema multiforme, fever, and polymorphonuclear leukocytosis. In general, SS presents with characteristic skin findings of painful erythematous plaques, nodules, or papules, as well as prodromal symptoms such as malaise, fever, and arthalgias.3 SS can be classified into three groups: idiopathic or classical, drug-induced, and malignancy-associated, each of which may have unique aspects of presentation. Classical SS generally affects women aged 30 to 50 years and may be associated with infection, pregnancy, or autoimmune diseases such as inflammatory bowel disease.1 Many drugs have been implicated in causing SS, with granulocyte colony-stimulating factor considered one of the most common.3 Other implicated medications include antibiotics, antiepileptic drugs, anti-HIV drugs, antihypertensives, antineoplastics, antipsychotics, antithyroid hormone synthesis drugs, contraceptives, diuretics, nonsteroidal antiinflammatory agents, and retinoids.1 As seen in our patient with myelodysplastic syndrome (MDS), the onset of SS can herald, follow, or appear simultaneously with the diagnosis of a patient’s neoplasm.1 About one-fifth of patients with SS have an associated malignancy, most commonly hematologic disease.4 SS is often associated with MDS, multiple myeloma, acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), and solid tumors. A recent study showed that malignancy-associated SS is associated with the histiocytoid or subcutaneous subtype, lack of arthralgia, and cytopenias, including leukopenia, thrombocytopenia, and anemia.5 Men and women with malignancy-associated SS have lower hemoglobin levels, compared with other variations of SS. In addition, malignancy-associated SS affects older patients than other classifications of SS.3 Monitoring for flares of SS is important, as these may represent recurrence of the underlying disease and can be the first sign.4

The differential diagnosis for SS is vast, as SS may resemble several conditions clinically and histologically. The differential for SS includes drug eruptions; infectious and inflammatory disorders such as bacterial sepsis, cellulitis, erysipelas, and panniculitis; neoplastic conditions such as leukemia cutis; reactive erythemas such as erythema multiforme and erythema nodosum; and vasculitis such as leukocytoclastic vasculitis and periarteritis nodosa.1 On histology, SS is characterized by neutrophillic infiltration located in the upper dermis. However, a variant with neutrophils and histiocytes in the dermis exists, known as histiocytoid SS, and is more commonly associated with MDS and malignancy than the classical neutrophilic variant.5,6 Kulasekararaj et al described 15 patients with SS who had ‘immune dysregulation’ secondary to MDS. On biopsy, the prominent findings included mild spongiosis of the epidermis, intense neutrophilic infiltrate in the reticular

About one-fifth of patients with Sweet syndrome have an associated malignancy, most commonly hematologic disease. dermis, leukocytoclasis, lymphocytes and histiocytes in the infiltrate, and dilatation of blood vessels with endothelial swelling. The diagnosis of chronic relapsing SS can be delayed because the pathology is not always representative of classical neutrophil-rich SS and instead contains lymphocytic and histiocytoid infiltrates.7 Although it is regarded to be beneficial to treat underlying malignancy and stop any offending drug agent, in certain cases of SS, the treatment for SS and its corresponding efficacy is remarkably similar regardless of classification.1,3,6 Most patients have a complete response to therapy. Systemic steroids are the most commonly administered agent and considered first-line.6 Second-line therapies include dapsone, colchicine, and systemic agents such as cyclosporine, azathioprine, etanercept, thalidomide, and anakinra. 3 However, relapse of SS is common upon corticosteroid reduction in those patients with MDS.8 Relapsing-remitting SS is a harbinger of myelodysplastic syndrome, and chronic relapsing-remitting of SS can be recalcitrant to treatment. Kulasekararaj et al demonstrated that most patients in their study with MDS and SS had to be maintained on a higher doses of steroids and that the response to immunosuppressive therapy is variable.7 Corticosteroids were effective in

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Dermatology Clinic all patients; yet lower doses of prednisolone (lower than 15 mg) usually resulted in relapse of SS. Cases of azacitidine-associated SS have been reported in the literature.9 However, some patients with MDS may achieve clinical remission of refractory SS while being on azacytidine, making the drug’s role in SS unclear.10,11 The patient was treated with systemic steroids and colchicine; however, the patient relapsed several times, particularly following blood transfusions. He later passed away from complications of his underlying condition. Margaret Barton is a 4th year medical student at Virginia Commonwealth University in Richmond, and Jessica Boulavsky, MD, is a dermatology resident at the Baylor College of Medicine in Houston. References 1. Cohen PR. Sweet’s syndrome—a comprehensive review of an acute febrile neutrophilic dermatosis. Orphanet J Rare Dis. 2007;2:34. 2. Sweet RD. An acute febrile neutrophilic dermatosis. Br J Dermatol. 1964;76:349-356. 3. Rochet MN, Chavan RN, Wada DA, Gibson LE. Sweet syndrome: clinical presentation, associations, and response to treatment in 77 patients. J Am Acad Dermatol. 2013;69:557-564. 4. Raza S, Kirkland R, Patel A, et al. Insight into Sweet’s syndrome and associated-malignancy: a review of the current literature. Int J Oncol. 2013;42:1516-1522. 5. Nelson CA, Noe MH, McMahon CM, et al. Sweet syndrome in patients with and without malignancy: A retrospective analysis of 83 patients from a tertiary academic referral center. J Am Acad Dermatol. 2018;78:303-309. 6. Ghoufi L, Ortonne N, Ingen-Housz-Oro S, et al. Histoid Sweet syndrome is more frequently associated with myelodysplastic syndromes than the classical neutrophilic variant: a comparative series of 62 patients. Medicine (Baltimore). 2016;95:e3033. 7. Kulasekararaj AG, Kordasti S, Basu T et al. Chronic relapsing remitting Sweet syndrome—a harbinger of myelodysplastic syndrome. Br J Haematol. 2015;170:649-656. 8. Wang Y, Zhuang JL, Zhao WL, et al. Clinical analysis of Sweet syndrome with myelodysplastic syndrome. Zhongua Yi Xue Za Zhi. 2016;96:1755-1757. 9. Bonazza S, Dalton B, Hardin J, Metelitsa A. Histiocytoid variant of Sweet syndrome associated with azacitidine recurrence upon rechallenge. Can J Hosp Pharm. 2015;68: 339-341. 10. Lin C, Yeh S, Tin T. Azacitidine is effective for the treatment of myelodysplastic syndrome and accompanied Sweet syndrome. Ann Hematol. 2015;94:1925-1926. 11. Martinelli S, Rigolin G, Leo G, et al. Complete remission of Sweet’s syndrome after azacytidine treatment for concomitant myelodysplastic syndrome. Int J Hematol. 2014; 99:663-667.

CASE #2

Epidermolysis bullosa simplex-Dowling Meara

Epidermolysis bullosa (EB) was f irst described in the 1880s. However, it was not until 1962 that a classification scheme among this group of inherited blistering diseases was developed.1 EB encompasses a group of hereditary disorders characterized by blistering of the skin upon exposure to mechanical stress. EB is traditionally divided into 3 major groups based on the level of dermoepidermal separation. These groups include EB simplex (EBS), junctional EB, and dystrophic EB. Among these 3 groups, EBS is the most frequent form of EB, with an approximate prevalence ranging from 1:20,000 to 1:50,000. EBS-Dowling Meara (EBS-DM) is almost exclusively inherited as an autosomal dominant disorder2 that is 100% penetrant,3 and it encompasses approximately 25% of all EBS cases,4 but can also arise from spontaneous mutation. This disease is the result of mutations in either the KRT5 gene, encoding keratin 5, or the KRT14 gene, encoding keratin 14.5 Patients who have EBS-DM often present at birth with widespread, severe blistering. The hallmark feature of its presentation is intact vesicles in grouped or annular configuration. Because of this appearance, EBS-DM was initially named EB-herpetiformis, despite there being no association between this disease and herpetic infection.1 The blisters may appear spontaneously or erupt with minimal trauma due to increased skin fragility. The greatest morbidity and risk of mortality in patients with EBS-DM is in infancy, when these groups of blisters are most severe, leading to recurrent skin infections (Staphylococcus aureus and Pseudomonas aeruginosa) and septicemia (S. aureus, P. aeruginosa, Enterococcus cloacae).5 Mucosal involvement of EBS-DM can lead to interference with feeding and tracheolaryngeal compromise, which can result in infant demise.3 As these patients age, the blistering tends to improve, and the keratoderma of the palms and soles may progress.6 Other symptoms include dystrophic

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and discolored nails, as well as post-inflammatory hyperpigmentation or hypopigmentation at the blister site.1 Skin biopsies of vesicles and bullae will demonstrate a subepidermal blister with paucity of infi ltrating inflammatory cells. In addition to standard hematoxylin and eosin staining, additional samples for transmission electron microscopy (TEM) or immunomapping are recommended. TEM findings show blistering above the skin basement membrane at the level of the basal keratinocytes. Immunofluorescence can be used to detect antibodies to keratin 5 and keratin 14 to detect and classify EBS-DM.7 When considering the diagnosis of EBS-DM, the various disease categories under the larger umbrella of epidermolysis bullosa should be considered, especially as EBS-DM often is confused with junctional or severe recessive dystrophic EB, which can only be defi nitively differentiated with immunomapping or TEM. Additionally, if there is no family history of blistering, congenital herpes simplex infection should be strongly considered and evaluated.1 A diagnosis of EBS-DM should be suspected in a neonate presenting with fragility of the skin manifested by blisters in annular groups or clusters, nail dystrophy, or a weak cry as a result of laryngeal involvement.3 The blisters that occur in patients with EBS-DM are more often hemorrhagic than those seen in other forms of EBS. Mucosal involvement is frequently present in severely affected neonates, which manifests as multiple oropharyngeal blisters. These blisters have the potential to seriously interfere with feeding, and the patient may require a feeding tube to ensure adequate nutrition. Once these blisters have healed, transient milia and minor scarring may be present,2 but a large majority of blisters heal without scarring.6 There is currently no curative treatment for patients with EBS-DM. The therapeutic approaches used for these patients are valuable for symptom management and infection prevention. The major underlying tenants of treatment are avoiding blistering events and ensuring proper wound care. Well-fitting clothes and shoes are essential, and patients often benefit from PT/OT. Additionally, because EBSDM is inherited in an autosomal dominant fashion, genetic counseling should be considered or offered for those with the disease who are planning to conceive. Our patient was biopsied as a neonate for both H&E and induced blister for immunomapping by a specialty laboratory. Genetic testing was performed to confirm mutation in KRT5 for diagnosis of EBS-DM. He is followed regularly by dermatology, gastroenterology, pediatric dentistry, or other services. Careful wound care is performed by his

mother to reduce trauma-induced blistering and improve discomfort. Urea cream is used to soften nails and the plantar keratoderma. He follows with physical therapy and occupational therapy as well. The family was also given information about the Dystrophic Epidermolysis Bullosa Research Association of America for additional resources. ■ Joan Fernandez is a medical student, and Jessica Boulavsky, MD, is a dermatology resident at the Baylor College of Medicine in Houston. References 1. Fine JD. Inherited epidermolysis bullosa. Orphanet J Rare Dis. 2010;5:12. 2. Yordanova I, Vassileva S, Demerjieva Z, et al. Epidermolysis bullosa simplex Dowling-Meara: a case report. J IMAB. 2008;14:59-62. 3. Pfendner EG, Bruckner AL. Epidermolysis bullosa simplex. In: Pagon RA, Adam MP, Ardinger HH, et al, eds. GeneReviews. Seattle: University of Washington; 1998:1993-2016. Available at: https://www.ncbi.nlm.nih.gov/ books/NBK1369/ 4. Bergman R, Harel A, Sprecher E. Dyskeratosis as a histologic feature in epidermolysis bullosa simplex-Dowling Meara. J Amer Acad Dermatol. 2007;57:463-466. 5. Titeux M, Mazereeuw-Hautier J, Hadj-Rabia S, et al. Three severe cases of EBS Dowling-Meara caused by missense and frameshift mutations in the keratin 14 gene. J Investigat Dermatol. 2006;126:773-776. 6. Chamcheu JC, Siddiqui IA, Syed DN, et al. Keratin gene mutations in disorders of human skin and its appendages. Arch Biochem Biophys. 2011;508:123-137. 7. Chan LS. Blistering skin diseases. Boca Raton, FL: CRC Press; 2009:87-90.

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Stat Consult

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

Description

Sudden cardiac death ALAN DRABKIN, MD

Dr Drabkin is a senior clinical writer 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.

• death within 1 hour of onset of any symptom Incidence/prevalence

• general population — 0.36–1.28 per 1,000 person-years • athletes — young athletes (< 35 years old) ranges 0.7– 3 per 100,000 athletes — in older athletes (≥ 35 years old) reported to be higher than in young athletes and increases with increasing age Cardiac conditions with increased risk of sudden cardiac death (SCD)

• • • • •

coronary artery disease (CAD) nonischemic cardiomyopathy valvular heart disease congenital heart disease arrhythmogenic right ventricular dysplasia • anomalous coronary artery origin • primary electrophysiologic conditions — congenital long QT syndrome — short-QT syndrome — Wolff-Parkinson-White syndrome — idiopathic ventricular fibrillation — Brugada syndrome — catecholaminergic polymorphic ventricular tachycardia (CPVT)

Possible risk factors

Colored 3D CT scan of the aortic valve of a 66-year-old man with heart valve disease.

• higher baseline C-reactive protein levels • ma huang, an herbal ephedra source • possible genetic risk factors — common variant at chromosome 9p21 — homozygosity for Gln27Glu single nucleotide polymorphism in beta-2 adrenergic receptor (ADRB2) — RyR2-encoded cardiac ryanodine receptor mutation — mutation of cardiac troponin T • long-term cocaine use Continues on page 54

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Stat Consult Causes

• ventricular fibrillation most common cause of SCD • SCD may also be caused by other cardiac tachycardias, bradycardias, or pulseless electrical activity • commotio cordis is a phenomenon of sudden death caused by blunt nonpenetrating impact to left chest ——70 identified or suspected cases ——128 cases in US Commotio Cordis Registry • 69% of women with SCD have no history of cardiac disease, but most have ≥ 1 risk factor for cardiac disease Pathogenesis

• possible pathophysiology of SCD ——predisposition to SCD due to stable cardiac abnormalities ——abnormal myocardial substrate triggered by ≥1 precipitating factor ——combination of susceptible myocardium and precipitating factor results in ■■ ventricular fibrillation ■■ pulseless ventricular tachycardia ■■ pulseless electrical activity ■■ asystole ——sudden cardiac arrest occurs, followed by death if resuscitation not initiated and successful • acute coronary lesions, including plaque disruption and thrombi, reported to be found in 20%-80% of autopsies of persons with SCD Making the diagnosis

• natural death due to cardiac causes occurring within 1 hour of symptom onset and ——excluding trauma as mechanism for death ——timing and mode of death unexpected

correlation not identified using conventional diagnostic techniques and if arrhythmia relation suspected ——transthoracic echocardiography (TTE) for assessment of left ventricular (LV) function and detection of structural heart disease ■■ tests to consider for all patients at risk for SCD, if TTE uninformative of left ventricular function »»cardiac magnetic resonance imaging (cMRI) »»cardiac computed tomography (CT) • consider coronary angiography to identify or rule out significant obstructive coronary artery disease (CAD) in ——patients with life-threatening ventricular arrhythmias ——SCD survivors with moderate-to-high risk of CAD according to age and symptoms • general findings associated with increased risk in some patient populations ——decreased left ventricular ejection fraction (LVEF) ——ECG findings ■■ prolonged QRS interval ■■ prolonged QT interval ■■ presence of QT dispersion ■■ abnormal signal-averaged ECG ■■ low-frequency short-term heart rate variability (HRV) ——abnormal long-term ambulatory ECG (Holter monitoring) ■■ nonsustained ventricular tachycardia ■■ long-term HRV ■■ heart rate turbulence ——abnormal exercise test/functional status ■■ exercise capacity ■■ New York Heart Association (NYHA) functional class ■■ heart rate recovery ■■ recovery ventricular ectopy ■■ T-wave alternans ——baroreceptor sensitivity (BARS)

Testing considerations for all patients at risk of SCD

Prevention and treatment

• tests indicated in all patients at risk for SCD ——electrocardiography (ECG) ■■ resting ECG ■■ ambulatory ECG for detection and diagnosis of arrhythmias ■■ signal-averaged ECG to improve diagnosis of arrhythmogenic right ventricular dysplasia (ARVD) ■■ cardiac event recorders to determine if transient arrhythmias are cause of sporadic symptoms ■■ implantable loop recorders to establish cause of sporadic symptoms (such as syncope) if rhythm-symptom

• primordial prevention ——preventing development of risk factors for cardiovascular disease ——may include lifestyle interventions to optimize ■■ blood pressure ■■ weight ■■ glucose ■■ cholesterol ■■ smoking cessation ■■ diet ■■ physical activity

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• primary prevention—prevention in patients who are at risk for but have not yet experienced episodes of sustained ventricular tachycardia, ventricular fibrillation, or resuscitated cardiac arrest ——implantable cardioverter defibrillator recommended for primary prevention of SCD in selected patients with nonischemic dilated cardiomyopathy or ischemic heart disease if all of ■■ ≥40 days postmyocardial infarction ■■ left ventricular ejection fraction (LVEF) »»≤35% if New York Heart Association (NYHA) Class II or III symptoms on chronic guidelinedirected medical therapy »»≤30% if NYHA Class I symptoms on chronic guideline-directed medical therapy ■■ reasonable expectation of meaningful survival for >1 year ——beta blockers recommended, unless contraindicated, for patients with ■■ coronary artery disease and heart failure or prior myocardial infarction with »»left ventricular ejection fraction ≤40% »»normal left ventricular function ■■ asymptomatic heart failure with reduced ejection fraction with or without history of myocardial infarction or acute coronary syndrome ■■ symptomatic heart failure with reduced ejection fraction to reduce mortality ——angiotensin-converting enzyme (ACE) inhibitors recommended, unless contraindicated, for patients with atherosclerotic cardiovascular disease and any of ■■ left ventricular ejection fraction ≤40% ■■ hypertension ■■ diabetes ■■ chronic kidney disease ——angiotensin II receptor blockers (ARBs) recommended for patients intolerant of ACE inhibitors ——aldosterone blockade recommended for ■■ postmyocardial infarction patients with all of »»heart failure and/or diabetes »»already receiving therapeutic doses of ACE inhibitor plus beta blocker »»left ventricular ejection fraction ≤40% »»no significant renal dysfunction »»no hyperkalemia ■■ patients with NYHA Class III and IV heart failure and left ventricular ejection fraction ≤35% ■■ patients with NYHA Class II heart failure and

history of prior cardiovascular hospitalization or increased plasma natriuretic peptide levels and left ventricular ejection fraction ≤35% ——statins indicated for virtually all patients with known cardiovascular disease ——antiarrhythmic medications, such as amiodarone, generally not recommended ——antihypertensive medications: do not reduce sudden cardiac death but may reduce fatal myocardial infarction • secondary prevention—prevention in patients who have survived prior sustained ventricular tachycardia or cardiac arrest ——implantable cardioverter defibrillator (ICD) therapy indicated in patients with ■■ history of cardiac arrest due to ventricular fibrillation or hemodynamically unstable ventricular tachycardia, after evaluation to exclude reversible causes »»structural heart disease and spontaneous sustained ventricular tachycardia »»syncope of undetermined origin and clinically relevant sustained ventricular tachycardia or ventricular fibrillation induced at electrophysiologic study ■■ addition of amiodarone to implantable cardiac defibrillator may increase mortality in patients with previous cardiac arrest or syncope due to ventricular tachycardia/ventricular fibrillation n

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LEGAL ADVISOR CASE

Voiding a noncompete clause

BY ANN W. LATNER, JD

Ms D was a 35-year old nurse practitioner (NP) with several years of solid experience when she was offered a job in a pharmacy. The pharmacy had a medical clinic specializing in weight management, hormone therapy, and aesthetic services, including injectable fillers and laser therapy, and Ms D was offered a position in the clinic. The interviews went well, and she was feeling positive about the potential job. When she accepted the offer and met with human resources to complete the required paperwork, she was informed that she was required to sign an employment contract. The contract was long, with tiny print. Ms D had never been asked to sign an employment contract before. When she questioned the human resources person about it, she was told, “you can’t take the job without signing the contract.” Ms D really wanted the job and was afraid to make too much of a fuss about the employment contract, so she skimmed it quickly, signed it, and began her orientation. One of the provisions of the employment contract was a noncompete clause, which stated that Ms D would be prevented from practicing

A clinician attempts to void a restrictive noncompete clause that she had signed before beginning her current job as an NP. The clause prevented her from practicing within 50 miles of the pharmacy and soliciting any of its patients for 18 months after leaving her job.

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within 50 miles of the pharmacy and soliciting any pharmacy patients for 18 months after leaving or being terminated from the job. Ms D had no experience with employment contracts or noncompete clauses and did not really understand the clause at the time she signed the contract. Over the next 3 years, Ms D saw patients on a daily basis. Her practice within the pharmacy grew as her reputation spread, and new patients began coming in to see her. She developed close relationships with many of her patients, especially the female patients whom she was helping with hormone replacement therapy. While she enjoyed the work itself, she was not as happy with her employer, whom she believed cut corners and kept staff salaries too low. By the time Ms D had been there for 3 years, she believed that she had helped develop a thriving business in the clinic. She had introduced new 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.

offerings and had been innovative in coming up with ways for the clinic to expand. But she thought that her employer was unappreciative and was just looking for a way to replace her with a less expensive employee. She turned out to be right. When she asked for a raise, the company fired her and replaced her with a more junior NP whom they could pay less. Ms D was unhappy with the termination but decided to use the opportunity to start her own business. She rented space, took care of all the logistics, and launched her own practice. She did not solicit her former patients from the pharmacy’s clinic, and her new business was more than 20 miles away from where she used to work. Nonetheless, it was not long before she received a notice that her former employer was taking her to court, based on a breach of the noncompete clause in the employment contract. The pharmacy was seeking an injunction against her to prevent her from practicing. Ms D hired an attorney who claimed to specialize in employment contracts. When they went to court, however, the judge ultimately granted the pharmacy’s request for a temporary injunction prohibiting Ms D from soliciting, contacting, or providing services to her past patients. The pharmacy immediately sent out a letter to its patients informing them that due to the judge’s order, Ms D could not legally treat them. Ms D received tearful calls from former patients, begging her to see them, yet she could not. Six months went by before Ms D was able to find another attorney to take on the case. The attorney appealed the court’s original ruling, arguing that the noncompete clause was overly restrictive and that it prevented patients from seeing the healthcare practitioner of their choice. This time the judge agreed with her, holding that the clause was unreasonably restrictive, and noting that Ms D had not been soliciting her former patients. After that 6-month delay, Ms D was able to launch her business without any legal ramifications. Legal background

It is not unusual for employment contracts to have a noncompete clause. A noncompete clause is a restrictive clause designed to protect employers from having employees take business away when they leave. It can restrict by miles (ie, a 50-mile radius from where the person worked), or by geographic location (ie, it can prevent a former employee from working in the same county or even city). Noncompete clauses also specify how long the restriction will be in force (ie, 18 months). The less restrictive a noncompete clause is, the more likely it will stand up in court. Courts will sometimes strike down clauses that are overly

restrictive, using a “reasonableness” requirement. Extremely long noncompete clauses (lasting for years) or with very large geographic areas (which may require the clinician to have to relocate) may be viewed as unreasonably restrictive, as in this case. A noncompete clause is most likely to be enforced if it is limited in time and the geographic scope is specific or narrow (ie, a 10-mile radius from the place of former employment). Protecting yourself

Let’s be clear. A noncompete clause is not for your benefit. It is for the benefit of your employer. So, it is best to avoid one in the first place, if possible. If you are offered a job that requires you to sign an employment contract, read the contract completely. Do not skim, do not skip small print, and do not make assumptions about ‘boilerplate material.’ You will have to live by the terms of this contract, so make sure you understand it.

A noncompete clause is most likely to be enforced if it is limited in time and the geographic scope is specific or narrow. Better yet, have an attorney read it and give you an opinion on the noncompete clause. While you may not be able to get a potential employer to leave it out completely, you may be able to negotiate the terms of the clause. For example, if your employer is proposing a 50-mile radius clause, you might suggest a 10-mile clause instead. If they are suggesting a three-year term for the clause, you might suggest a one-year term, instead. When a court is confronted with a violation of a noncompete clause, it must weigh the interests of the employer with public policy concerns (such as whether the clause interferes with the nurse–patient relationship), as well as reasonableness of the clause itself. Making sure that the clause is very narrow in scope about what it restricts is the best way to protect yourself. Consider asking for a ‘honeymoon period’ of 3 to 6 months of employment before the clause kicks in. This will protect you if the job does not work out early on and you want to move on without restrictions. But always keep in mind that if you sign a contract, you are legally required to abide by the terms, so be sure that you completely understand what you are signing. n Ms Latner, a former criminal defense attorney, is a freelance medical writer in Port Washington, N.Y.

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